NZ788182A - Pyrazole derivatives as plasma kallikrein inhibitors - Google Patents

Abstract

The present invention provides a selection of compounds of formula (I): (I) compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds; wherein R5,R6,R7, A, B,W, X, Y and Z are as defined herein. atients with such compounds; wherein R5,R6,R7, A, B,W, X, Y and Z are as defined herein.

Description

WO 07983 PYRAZOLE DERIVATIVES AS PLASMA KALLIKREIN INHIBITORS This invention relates to enzyme inhibitors that are inhibitors of plasma kallikrein and to pharmaceutical compositions ning and the uses of, such inhibitors.

Background to the Invention The heterocyclic derivatives of the present invention are inhibitors of plasma kallikrein and have a number of therapeutic applications, particularly in the treatment of retinal vascular permeability associated with diabetic retinopathy and diabetic r edema.

Plasma kallikrein is a trypsin-like serine protease that can liberate kinins from kininogens (see K. D.

Bhoola et al., "Kallikrein-Kinin Cascade", Encyclopedia of Respiratory ne, 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; K. D. Bhoola et al., Pharmacological Rev., 1992, 44, 1; and D. J. Campbell, "Towards understanding the kallikrein-kinin system: insights from the ement of kinin es", Brazilian Journal of Medical and Biological Research 2000, 33, 665-677). It is an essential member of the intrinsic blood ation cascade although its role in this cascade does not involve the release of bradykinin or enzymatic ge.

Plasma prekallikrein is encoded by a single gene and synthesized in the liver. It is secreted by hepatocytes as an inactive plasma prekallikrein that circulates in plasma as a heterodimer complex bound to high lar weight kininogen which is activated to give the active plasma kallikrein. Kinins are potent ors of inflammation that act through G n-coupled ors and antagonists of kinins (such as bradykinin antagonists) have previously been investigated as potential therapeutic agents for the treatment of 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 major inhibitor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients who present with a genetic deficiency in C1 esterase tor suffer from hereditary angioedema (HAE) which results in intermittent swelling of face, hands, throat, gastro-intestinal tract and genitals. Blisters formed during acute episodes contain high levels of plasma kallikrein which cleaves high molecular weight kininogen liberating bradykinin leading to increased vascular permeability. Treatment with a large protein plasma kallikrein inhibitor has been shown to effectively treat HAE by preventing the release of bradykinin which causes increased vascular permeability (A. Lehmann "Ecallantide (DX-88), a plasma rein inhibitor for the treatment of hereditary angioedema and the tion of blood loss in on-pump thoracic surgery" Expert Opin. Biol. Ther. 8, p1187-99).

WO 07983 The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic r edema. It has been recently published that plasma kallikrein contributes to retinal vascular dysfunctions in diabetic rats (A. Clermont et al. "Plasma rein mediates l vascular ction and induces l ning in diabetic rats" Diabetes, 2011, 60, p1590-98). Furthermore, administration of the plasma kallikrein inhibitor ASP-440 rated both retinal vascular bility and retinal blood flow abnormalities in diabetic rats. Therefore a plasma kallikrein inhibitor should have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

Plasma kallikrein also plays a role in blood coagulation. The intrinsic coagulation cascade may be activated by factor XII (FXII). Once FXII is activated (to FXIIa), FXIIa triggers fibrin formation through the tion of factor XI (FXI) thus resulting in blood coagulation. Plasma kallikrein is a key component in the intrinsic coagulation e because it activates FXII to FXIIa, thus resulting in the activation of the intrinsic coagulation pathway. Furthermore, FXIIa also activates further plasma prekallikrein resulting in plasma kallikrein. This results in positive feedback amplification of the plasma kallikrein system and the intrinsic coagulation pathway (Tanaka et al. (Thrombosis Research 2004, 113, 333-339); Bird et al.

(Thrombosis and Haemostasis, 2012, 107, 1141-50).

Contact of FXII in the blood with negatively charged surfaces (such as the surfaces of external pipes or the membrane of the oxygenator that the blood passes during cardiopulmonary bypass surgery) induces a conformational change in zymogen FXII resulting in a small amount of active FXII (FXIIa). The formation of FXIIa triggers the formation of plasma kallikrein resulting in blood coagulation, as described above. tion of FXII to FXIIa can also occur in the body by contact with negatively charged surfaces on various sources (e.g. bacteria during , RNA from degrading , thus resulting in disseminated intravascular coagulation (Tanaka et al. (Thrombosis Research 2004, 113, 333-339)).

Therefore, inhibition of plasma rein would inhibit the blood coagulation cascade described above, and so would be useful in the treatment of disseminated intravascular coagulation and blood coagulation during cardiopulmonary bypass surgery where blood coagulation is not desired. For example, Katsuura et al. (Thrombosis Research, 1996, 82, 8) showed that administration of a plasma rein inhibitor, PKSI-527, for LPS-induced disseminated intravascular coagulation significantly suppressed the decrease in platelet count and fibrinogen level as well as the se in FDP level which usually occur in disseminated intravascular coagulation. Bird et al. (Thrombosis and Haemostasis, 2012, 107, 1141-50) showed that clotting time increased, and thrombosis was significantly d in plasma kallikrein-deficient mice. Revenko et al. (Blood, 2011, 118, 5302-5311) showed that the reduction of plasma likrein levels in mice using antisense ucleotide treatment resulted in rombotic effects. Tanaka et al. (Thrombosis Research 2004, 113, 333-339) showed that contacting blood with DX-88 (a plasma kallikrein inhibitor) resulted in an increase in activated clotting time (ACT). Lehmann et al. (Expert Opin. Biol. Ther. 2008, 1187-99) showed that Ecallantide (a plasma kallikrein inhibitor) was found to delay contact activated induced coagulation. Lehmann et al. de that ntide ”had in vitro anticoagulant effects as it ted the intrinsic y of coagulation by inhibiting plasma kallikrein”.

Plasma rein also plays a role in the inhibition of platelet activation, and therefore the cessation of bleeding. et activation is one of the earliest steps in hemostasis, which leads to platelet plug formation and the rapid cessation of bleeding following damage to blood vessels. At the site of vascular injury, the interaction between the exposed collagen and ets is critical for the retention and activation of platelets, and the subsequent cessation of bleeding.

Once activated, plasma kallikrein binds to collagen and thereby interferes with collagen-mediated activation of platelets mediated by GPVI receptors (Liu et al. (Nat Med, 2011, 17, 206—210)). As discussed above, plasma kallikrein inhibitors reduce plasma prekallikrein activation by inhibiting plasma kallikrein-mediated activation of factor XII and thereby reducing the positive feedback amplification of the kallikrein system by the contact activation system.

Therefore, inhibition of plasma kallikrein reduces the binding of plasma kallikrein to collagen, thus reducing the interference of plasma kallikrein in the cessation of bleeding. Therefore plasma kallikrein tors would be useful in the treatment of treating cerebral haemorrhage and bleeding from post operative surgery. For example, Liu et al. (Nat Med, 2011, 17, 206—210) demonstrated that systemic administration of a small molecule PK inhibitor, ASP-440, reduced hematoma expansion in rats. Cerebral hematoma may occur following intracerebral haemorrhage and is caused by ng from blood vessels into the surrounding brain tissue as a result of vascular injury. Bleeding in the cerebral haemorrhage model reported by Liu et al. was induced by surgical ention involving an on in the brain parenchyma that damaged blood vessels. These data demonstrate that plasma kallikrein inhibition d bleeding and hematoma volume from post operative surgery. Bjérkqvist et al. (Thrombosis and Haemostasis, 2013, 110, 399- 407) demonstrated that aprotinin (a protein that inhibits serine proteases including plasma kallikrein) may be used to decrease erative bleeding.

Other complications of diabetes such as cerebral haemorrhage, pathy, cardiomyopathy and neuropathy, all of which have associations with plasma kallikrein may also be considered as targets for a plasma kallikrein inhibitor.

Synthetic and small molecule plasma kallikrein inhibitors have been described previously, for e by 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 ), Evans ("Selective dipeptide inhibitors of kallikrein" W003/076458), Szelke et al. ("Kininogenase inhibitors" WO92/04371), D. M. 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” W02005/123680), J.

StUrzbecher 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. lopment 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 tors and their preparation and use" W008/049595), Zhang et al. ("Discovery of highly potent small molecule kallikrein inhibitors" Medicinal try 2, 53 (2006)), Sinha et al. bitors of plasma kallikrein" W008/016883), Shigenaga et al. (”Plasma Kallikrein tors” W02011/118672), and Kolte et al. (”Biochemical characterization of a novel high-affinity and ic kallikrein inhibitor”, British Journal of Pharmacology (2011), 162(7), 1639-1649). Also, Steinmetzer et al. (”Serine protease inhibitors” W02012/004678) describes cyclized peptide analogs which are inhibitors of human plasmin and plasma kallikrein.

To date, no small molecule synthetic plasma rein inhibitor has been approved for medical use. The molecules described in the known art suffer from limitations such as poor selectivity over related enzymes such as KLK1, thrombin and other serine proteases, and poor oral availability. The large protein plasma kallikrein tors present risks of lactic reactions, as has been reported for Ecallantide.

Thus there remains a need for nds that selectively inhibit plasma kallikrein, that do not induce anaphylaxis and that are orally available. Furthermore, the vast majority of molecules in the known art feature a highly polar and ionisable guanidine or amidine functionality. It is well known that such functionalities may be limiting to gut permeability and therefore to oral bility. For example, it has been reported by Tamie J. Chi/cote and o Sinha (”ASP-634: An Oral Drug Candidate for Diabetic MacularEdema”, ARVO 2012 May 6th — May 9th, 2012, Fort Lauderdale, a, Presentation 2240) that ASP-440, a benzamidine, suffers from poor oral availability. It is further reported that absorption may be improved by creating a prodrug such as ASP-634. However, it is well known that prodrugs can suffer from several drawbacks, for example, poor chemical ity and potential toxicity from the inert carrier or from unexpected metabolites. In another report, indole amides are claimed as compounds that might overcome problems associated with drugs possessing poor or inadequate ADME-tox and physicochemical properties although no inhibition against plasma kallikrein is presented or claimed (Griffioen et al, ”Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases”, WOZOlO, 142801).

BioCryst ceuticals Inc. have reported the discovery of the orally available plasma kallikrein inhibitor BCX4161(”BCX4161, An Oral Kallikrein Inhibitor: Safety and cokinetic Results Of a Phase 1 Study In Healthy eers”, l of Allergy and al Immunology, Volume 133, Issue 2, Supplement, February 2014, page A339 and ”A Simple, Sensitive and Selective Fluorogenic Assay to r Plasma Kallikrein Inhibitory Activity of BCX4161 in Activated Plasma”, Journal of Allergy and Clinical Immunology, Volume 133, Issue 2, Supplement ry 2014, page AB40). However, human doses are relatively large, currently being tested in proof of t studies at doses of 400 mg three times daily.

There are only few reports of plasma kallikrein inhibitors that do not feature guanidine or amidine functionalities. One example is Brandl et al. (”N-((6-amino-pyridinyl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein” W02012/017020), which bes compounds that feature an amino- pyridine functionality. Oral efficacy in a rat model is demonstrated at relatively high doses of 30 mg/kg and 100 mg/kg but the pharmacokinetic profile is not reported. Thus it is not yet known whether such compounds will provide sufficient oral availability or efficacy for progression to the clinic. Other examples are Brandl et al. (”Aminopyridine tives as plasma kallikrein inhibitors” W02013/111107) and Flohr et al. (”5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors” W02013/111108). However, neither of these nts report any in vivo data and therefore it is not yet known r such compounds will provide sufficient oral availability or efficacy for progression to the clinic. Another example is Allan et al. ”Benzylamine tives” W02014/108679.

Therefore there remains a need to develop new plasma kallikrein inhibitors that will have utility to treat a wide range of disorders, in particular to reduce retinal vascular permeability ated with diabetic retinopathy and diabetic macular edema. Preferred compounds will possess a good cokinetic profile and in particular will be suitable as drugs for oral delivery.

WO 07983 Summary of the ion The present invention relates to a series of heterocyclic derivatives that are inhibitors of plasma kallikrein. These compounds demonstrate good selectivity for plasma kallikrein and are potentially useful in the treatment of impaired visual acuity, diabetic retinopathy, r edema, hereditary angioedema, es, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, athy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress me, disseminated intravascular coagulation, blood ation during cardiopulmonary bypass surgery and bleeding from post operative surgery. The invention further relates to pharmaceutical compositions of the inhibitors, to the use of the compositions as therapeutic agents, and to methods of treatment using these compositions.

The present invention provides compounds closely related to, or falling within the scope of, but not specifically disclosed in, our co-pending application PCT/GBZOlS/053615 6/083820).

In a first aspect, the present invention provides compounds selected from the group consisting of: N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(4-methylpyrazol- 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(4-fluoromethoxypyridazinyl)methyl](methoxymethyl)({4-[(2-oxopyridin- 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide; hoxymethyl)-N-[(5-methoxypyridazinyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(6-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazolecarboxamide; 3-amino-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methy|)(trifluoromethyl)pyrazolecarboxamide; 3-(dimethylamino)-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-cyanofluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(4-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(4-methoxy-3,5-dimethylpyridin-Z-yl)methyl](methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanomethoxypyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[3-(dif|uoromethy|)methoxypyridinyl]methy|}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|oromethoxypyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|orocyanopyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoro-S-methylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanomethy|pyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanomethoxypyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[6-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-[(3,5-difluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-ch|oromethy|pyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 1-({4-[(5-f|uoro-Z-oxopyridin-l—y|)methyl]pheny|}methy|)-N-[(3-fluoro methoxypyridin-Z-yl)methyI](methoxymethy|)pyrazoIecarboxamide; N-[(5-methoxymethylpyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; chloro-S-methoxy-l—methylpyrazoly|)methyI](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-methoxy-1,4-dimethylpyrazoly|)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-ch|oromethy|pyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2,6-difluoro-3,5-dimethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; methoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(6-cyanof|uoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyI](dimethy|amino)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(2-cyanomethoxyphenyl)methyl]({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](dimethylamino)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-{[5-methoxy-Z-(trifluoromethy|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-{[2-(dif|uoromethy|)methoxyphenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[5-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methy|]pheny|}methy|)pyrazoIecarboxamide; N-[(2,6-difluoromethoxyphenyl)methyl](dimethylamino)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- oxopyridin-l—y|)methy|]pyridin-Z-y|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l—y|)methy|]pyridiny|}methy|)pyrazoIecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({5-[(2-oxopyridin hy|]pyridin-Z-yl}methy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({6-[(2-oxopyridin y|)methy|]pyridinyl}methy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({4-[(2- oxopiperidin-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrro|idin-l— y|)pyrimidin-S-yl]methyl}pyrazo|ecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl]{[2-(pyrrolidin-l—y|)pyrimidin-S- yl]methyl}(trif|uoromethyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(4-methy|pyrazol-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(4- methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; WO 07983 N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(4- methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]pheny|}methy|)(trif|uoromethy|)pyrazoIecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazoIyl)pheny|]methy|}({4-[(2-oxopyridin y|)methy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide; 3-amino-N-{[2-fluoromethoxy(1,2,3,4-tetrazoly|)phenyl]methy|}({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-{[2-fluoro(1,2,3,4-tetrazo|—1-y|)phenyl] methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(dimethylamino)-N-{[2-fluoromethoxy(1,2,3,4-tetrazoly|)pheny|]methyI}({4- [(2-oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(dimethylamino)-N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(dimethylamino)-N-{[2-fluoro(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-{[5-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- oxopyridin-l—y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-{[2-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(methoxymethyl)({4-[(2-oxopyridiny|)methy|]pheny|}methy|)-N-{[2-(1,2,3,4- tetrazol-l—y|)phenyl]methyl}pyrazolecarboxamide; 3-(methoxymethyl)-N-{[2-methy|—6-(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanof|uorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) {[6-(pyrro|idiny|)pyridiny|]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)pheny|] methyl}(methoxymethy|){[6- (pyrrolidin-l—yl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- lidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[6- (pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- lidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidin yl)pyridinyl]methyl}(trifluoromethyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidinyl)pyridin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidinyl)pyridin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[5-methoxy(1,2,3,4-tetrazol- 1-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates f.

In a further aspect of the present invention, also provided is a compound selected from the group consisting of: N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(4-methylpyrazol- ethyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(4-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-chlorocyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-chlorofluoropyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3,5-difluoropyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; fluoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-fluoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-chloromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(4-chloromethylpyrazolyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof.

In another aspect of the present invention, also provided is a nd ed from the group consisting of: N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(4-methylpyrazol- 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-amino-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; N-[(3-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-cyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; (difluoromethyl)methoxypyridinyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(4-methoxymethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(4-methoxymethylpyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[6-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; 1-({4-[(5-f|uoro-Z-oxopyridin-l—y|)methyl]pheny|}methy|)-N-[(3-fluoro methoxypyridin-Z-yl)methyI](methoxymethy|)pyrazoIecarboxamide; 3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(2- idin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-methoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]pheny|}methyl)pyrazoIecarboxamide; N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; o-N-[(6-cyanof|uoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methy|]pheny|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyI](dimethy|amino)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(2-cyanomethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-{[5-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- oxopyridin-l—y|)methy|]pyridin-Z-y|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l—y|)methy|]pyridiny|}methy|)pyrazoIecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({5-[(2-oxopyridin y|)methy|]pyridin-Z-yl}methy|)pyrazoIecarboxamide; wo 2017/207983 N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({6-[(2-oxopyridin yl)methyl]pyridinyl}methyl)pyrazolecarboxamide; N-[(2-cyanomethoxyphenyl)methyl]({4-[(5-fluorooxopyridin yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrrolidin yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl]{[2-(pyrrolidin-l-yl)pyrimidin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; N-[(2-cyanofluorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[6-(pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; and pharmaceutically acceptable salts and es thereof.

In a further aspect of the present ion, also provided is a compound selected from the group consisting of: N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- oxopyridin-l-yl)methyl]pyridinyl}methyl)pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l-yl)methyl]pyridinyl}methyl)pyrazolecarboxamide; cyanomethoxyphenyl)methyl](methoxymethyl)({5-[(2-oxopyridin hyl]pyridinyl}methyl)pyrazolecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({6-[(2-oxopyridin yl)methyl]pyridinyl}methyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof.

In a further aspect of the present invention, also provided is a compound selected from the group consisting of: f|uoromethoxypyridin-Z-yl)methyl](methoxymethyl)({4-[(4-methylpyrazol- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 3-(methoxymethyl)-N-[(6-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin yl)methyl]pheny|}methy|)pyrazoIecarboxamide; 3-amino-N-[(3-fluoromethoxypyridin-Z-yl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoromethoxypyridin-Z-yl)methyl]({4-[(2-oxopyridin y|)methyl]pheny|}methy|)(trif|uoromethy|)pyrazoIecarboxamide; 3-(dimethylamino)-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-cyano-Z-methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(methoxymethyl)-N-[(4-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxy-3,5-dimethylpyridin-Z-yl)methyl](methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|orocyanopyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3,5-difluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-ch|oromethy|pyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 1-({4-[(5-f|uoro-Z-oxopyridin-l—y|)methyl]pheny|}methy|)-N-[(3-fluoro methoxypyridin-Z-yl)methyI](methoxymethy|)pyrazoIecarboxamide; N-[(5-methoxymethylpyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methy|)pyrazoIecarboxamide; N-[(4-ch|oromethy|pyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(2- idin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-methoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- idin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(6-cyanof|uoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; cyanof|uoromethoxyphenyl)methyI](dimethy|amino)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-{[5-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyI](methoxymethy|)({5-[(2- oxopyridin-l—y|)methy|]pyridin-Z-y|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l—y|)methy|]pyridiny|}methy|)pyrazoIecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrro|idin-l— y|)pyrimidin-S-yl]methyl}pyrazo|ecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) ({4-[(4-methylpyrazol-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(4- methylpyrazol-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; 3-amino-N-{[5-chloro(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-chloro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-chloro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[2-(1,2,3,4- tetrazol-l-yl)phenyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[6-(pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; (3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and es thereof.

In a further aspect of the present invention, also ed is a compound selected from the group ting of: 3-amino-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; 3-(dimethylamino)-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(4-methoxy-3,5-dimethylpyridin-Z-yl)methyl](methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|orocyanopyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-ch|oromethy|pyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 1-({4-[(5-f|uoro-Z-oxopyridin-l—y|)methyl]pheny|}methy|)-N-[(3-fluoro ypyridin-Z-yl)methyI](methoxymethy|)pyrazoIecarboxamide; 3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-methoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(6-cyanof|uoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyI](dimethy|amino)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methy|)pyrazoIecarboxamide; N-{[5-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- oxopyridin-l—y|)methy|]pyridin-Z-y|}methy|)pyrazoIecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l-yl)methyl]pyridinyl}methyl)pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl]({4-[(5-fluorooxopyridin hyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrrolidin yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) ({4-[(4-methylpyrazol-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(4- methylpyrazol-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; 3-amino-N-{[5-chloro(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-chloro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-chloro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; hoxymethyl)({4-[(2-oxopyridinyl)methyl]phenyl}methyl)-N-{[2-(1,2,3,4- tetrazol-l-yl)phenyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[6-(pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof.

In a further aspect of the present ion, also provided is a compound selected from the group consisting of: 3-amino-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-f|uoromethoxypyridin-Z-yl)methyl]({4-[(2-oxopyridin hy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide; N-[(4-methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 1-({4-[(5-f|uoro-Z-oxopyridin-l—y|)methyl]pheny|}methy|)-N-[(3-fluoro methoxypyridin-Z-yl)methyI](methoxymethy|)pyrazoIecarboxamide; 3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(6-cyanof|uoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyI](dimethy|amino)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l—y|)methy|]pyridiny|}methy|)pyrazoIecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(4-methy|pyrazol-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|)({4-[(4- methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazoIyl)pheny|]methy|}({4-[(2-oxopyridin y|)methy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide; 3-amino-N-{[5-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) {[6-(pyrro|idiny|)pyridiny|]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; (3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof.

In a further aspect of the present invention, also provided is a compound selected from the group consisting of: N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrrolidin yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl]{[2-(pyrrolidin-l-yl)pyrimidin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[6-(pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[6- (pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) yrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- lidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[6- (pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- lidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidin yl)pyridinyl]methyl}(trifluoromethyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidinyl)pyridin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidinyl)pyridin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; (3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[5-methoxy(1,2,3,4-tetrazol- 1-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof.

In a yet further aspect of the present invention, also provided is a compound selected from the group consisting of: N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrrolidin yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) yrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy ,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidin yl)pyridinyl]methyl}(trifluoromethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide and pharmaceutically able salts and solvates thereof.

In a red aspect of the present invention, also provided is a compound that is N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrrolidinyl)pyrimidin yl]methyl}pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the t invention, also provided is a compound that is N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[6-(pyrrolidin yl)pyridinyl]methyl}pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the present invention, also provided is a compound that is N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2-(pyrrolidin yl)pyrimidinyl]methyl}pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the present invention, also provided is a compound that is N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2-(pyrrolidin yl)pyrimidinyl]methyl}pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the t invention, also ed is a compound that is 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4-tetrazol yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the t invention, also provided is a compound that is 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4-tetrazol yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the invention, also provided is a nd that is N-{[5-methoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl){[2-(pyrrolidinyl)pyrimidinyl]methyl}pyrazole carboxamide; or a pharmaceutically acceptable salt or solvate thereof.

In a preferred aspect of the invention, also provided is a compound that is N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidinyl)pyridinyl]methyl} (trifluoromethyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt or e thereof.

In a preferred aspect of the ion, also provided is a compound that is 1-{[2-(3,3-difluoropyrrolidin- 1-yl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl} (methoxymethyl)pyrazolecarboxamide; or a pharmaceutically able salt of solvate thereof. wo 2017/207983 In a preferred aspect of the invention, also provided is a compound that is N-[(3-fluoro methoxypyridinyl)methyl]({4-[(2-oxopyridinyl)methyl]phenyl}methyl) (trifluoromethyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate f.

In a preferred aspect of the invention, also provided is a nd that is cyanofluoro yphenyl)methyl](methoxymethyl)({5-[(2-oxopyridinyl)methyl]pyridin yl}methyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt or e thereof.

In a preferred aspect of the invention, also provided is a compound that is N-[(6-cyanofluoro methoxyphenyl)methyl](methoxymethyl)({6-[(2-oxopyridinyl)methyl]pyridin yl}methyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof.

In a yet further aspect of the present invention, also provided is a compound selected from the group consisting of: N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(4-methylpyrazol- 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(4-fluoromethoxypyridazinyl)methyl](methoxymethyl)({4-[(2-oxopyridin- ethyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(5-methoxypyridazinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(6-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-cyanofluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(4-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(4-methoxy-3,5-dimethylpyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-cyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[3-(dif|uoromethy|)methoxypyridinyl]methy|}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|oromethoxypyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|orocyanopyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoro-S-methylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; cyanomethy|pyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxymethylpyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanomethoxypyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[6-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-[(3,5-difluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-ch|oromethy|pyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 1-({4-[(5-f|uoro-Z-oxopyridin-l—y|)methyl]pheny|}methy|)-N-[(3-fluoro methoxypyridin-Z-yl)methyI](methoxymethy|)pyrazoIecarboxamide; N-[(5-methoxymethylpyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-chloro-S-methoxy-l—methylpyrazoly|)methyI](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-methoxy-1,4-dimethylpyrazoly|)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-ch|oromethy|pyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2,6-difluoro-3,5-dimethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) 2-oxopyridin-l—y|)methyl]pheny|}methyl)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(2- idin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-methoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methy|)pyrazoIecarboxamide; N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[5-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- oxopyridin-l—y|)methy|]pyridin-Z-y|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l—y|)methy|]pyridiny|}methy|)pyrazoIecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({5-[(2-oxopyridin y|)methy|]pyridin-Z-yl}methy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({6-[(2-oxopyridin y|)methy|]pyridinyl}methy|)pyrazoIecarboxamide; WO 07983 N-[(2-cyanomethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({4-[(2- oxopiperidin-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrro|idin-l— y|)pyrimidin-S-yl]methyl}pyrazo|ecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(4-methy|pyrazol-l—y|)methy|]pheny|}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(4- methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(4- pyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-{[5-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; ch|oro(1,2,3,4-tetrazoly|)pheny|]methyl}(methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(methoxymethyl)({4-[(2-oxopyridiny|)methy|]pheny|}methy|)-N-{[2-(1,2,3,4- tetrazol-l—y|)phenyl]methyl}pyrazolecarboxamide; 3-(methoxymethyl)-N-{[2-methy|—6-(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanof|uorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) {[6-(pyrro|idiny|)pyridiny|]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)pheny|]methyl}(methoxymethy|){[6- (pyrrolidin-l—yl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) {[2-(pyrrolidin-l—y|)pyrimidin-S-yl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)pheny|]methyl}(methoxymethy|){[2- (pyrrolidin-l—y|)pyrimidin-S-yl]methy|}pyrazo|ecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|){[6- (pyrrolidin-l—yl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|){[2- (pyrrolidin-l—y|)pyrimidin-S-yl]methy|}pyrazo|ecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[5-methoxy(1,2,3,4-tetrazol- 1-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates f.

In a yet further aspect of the present invention, also provided is a compound selected from the group consisting of: N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) ({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) ({4-[(4-methylpyrazol-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(4- methylpyrazol-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; 3-amino-N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-amino-N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; ethylamino)-N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}({4- opyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide; ethylamino)-N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[6-(pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[6- (pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) yrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}{[6-(pyrrolidin yl)pyridinyl]methyl}(trifluoromethyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}{[6-(pyrrolidinyl)pyridin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; (3,3-difluoropyrrolidinyl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidinyl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[5-methoxy(1,2,3,4-tetrazol- 1-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof.

In another aspect the present invention provides a prodrug of a compound of the invention, or a pharmaceutically able salt thereof.

In yet another aspect the present invention provides an N-oxide of a compound of the invention, or a g or pharmaceutically acceptable salt thereof.

It will be understood that certain compounds of the present invention may exist in solvated, for e hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms.

Therapeutic Applications As previously mentioned, the compounds of the present invention are potent and selective tors of plasma kallikrein. They are therefore useful in the treatment of disease conditions for which over- activity of plasma rein is a causative factor.

Accordingly, the present invention provides a nd of the invention for use in medicine.

The present invention also provides for the use of a nd of the invention in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated.

The present invention also provides a compound of the invention for use in the treatment or prevention of a disease or condition in which plasma kallikrein ty is implicated.

The present invention also provides a method of treatment of a disease or condition in which plasma kallikrein activity is implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound of the invention.

In one aspect, the disease or condition in which plasma rein activity is implicated is selected from impaired visual , diabetic pathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood ation during cardiopulmonary bypass surgery and bleeding from post operative surgery.

In a preferred aspect, the disease or condition in which plasma rein activity is implicated is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

In an ative preferred aspect, the disease or condition in which plasma kallikrein activity is ated is hereditary angioedema.

In an alternative preferred aspect, the disease or condition in which plasma kallikrein activity is implicated is diabetic macular edema.

In another aspect, the disease or condition in which plasma kallikrein ty is implicated is l vein occlusion. ation Therapy The compounds of the present invention may be administered in ation with other eutic agents. Suitable combination therapies include a compound of the invention combined with one or more agents selected from agents that inhibit platelet-derived growth factor , endothelial growth factor (VEGF), integrin alpha5beta1, steroids, other agents that inhibit plasma kallikrein and other inhibitors of inflammation. Specific examples of therapeutic agents that may be combined with the compounds of the present invention include those sed in EP2281885A and by S. Patel in Retina, 2009 Jun;29(6 Suppl):S45-8.

When combination therapy is employed, the compounds of the present invention and said combination agents may exist in the same or different pharmaceutical compositions, and may be administered tely, sequentially or simultaneously.

In another aspect, the compounds of the present invention may be administered in ation with laser treatment of the retina. The combination of laser therapy with intravitreal injection of an inhibitor of VEGF 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” almology. 27 April 2010).

Definitions The term "alkyl" includes saturated hydrocarbon residues including: - linear groups up to 10 carbon atoms (Cl-Clo), or of up to 6 carbon atoms (C1-C5), or of up to 4 carbon atoms (C1-C4). Examples of such alkyl groups include, but are not limited, to C1 - methyl, C2 - ethyl, C3 - propyl and C4- n-butyl. - ed groups of between 3 and 10 carbon atoms (Cg-C10), or of up to 7 carbon atoms (C3-C7), or of up to 4 carbon atoms (C3-C4). Examples of such alkyl groups include, but are not d to, C3 - iso- propyl, C4 - sec-butyl, C4 - iso-butyl, C4 - tert-butyl and C5 - neo-pentyl. each optionally substituted as stated above.

Cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 7 carbon atoms, or n 3 and 6 carbon atoms, or between 3 and 5 carbon atoms. Optionally, cycloalkyl may be substituted with a substituent selected from alkyl, alkoxy and 3; wherein R12 and R13 are independently selected from H and alkyl or R12 and R13 together with the nitrogen to which they are attached form a 4-, 5-, 6- or 7-membered heterocylic ring which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, F and CF3. Cycloalkyl groups may n 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 eptyl.

The term y" includes O-linked hydrocarbon residues including: - linear groups of between 1 and 6 carbon atoms (C1-C6), or of between 1 and 4 carbon atoms (C1-C4). es of such alkoxy groups include, but are not limited to, C1 - methoxy, C2 - ethoxy, C3 - n- propoxy and C4 - n-butoxy. - branched groups of between 3 and 6 carbon atoms ) or of between 3 and 4 carbon atoms (C3- C4). Examples of such alkoxy groups include, but are not limited to, C3 - iso-propoxy, and C4 - sec- butoxy and tert-butoxy. each optionally substituted as stated above.

Unless otherwise stated, halo is ed from Cl, F, Br and |.

Aryl is as defined above. Typically, aryl will be ally substituted with 1, 2 or 3 substituents.

Optional tuents are selected from those stated above. Examples of suitable aryl groups include phenyl and naphthyl (each optionally substituted as stated above). ably aryl is selected from phenyl, substituted phenyl (wherein said tuents are selected from those stated above) and yl.

Heteroaryl is as defined above. Typically, heteroaryl will be optionally substituted with 1, 2 or 3 substituents. Optional substituents are selected from those stated above. es of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, riazolyl, quinolinyl and isoquinolinyl (optionally substituted as stated above) The term "N-linked", such as in "N-linked pyrrolidinyl", means that the heterocycloalkyl group is joined to the remainder of the molecule via a ring nitrogen atom.

The term "O-linked", such as in "O-linked hydrocarbon residue", means that the hydrocarbon residue is joined to the der of the molecule via an oxygen atom.

In groups such as -(CH2)1.3-aryl, "-" denotes the point of attachment of the substituent group to the remainder of the molecule.

"Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts. For example (i) where a compound of the invention contains one or more acidic groups, for example carboxy groups, pharmaceutically acceptable base addition salts that can be formed include sodium, ium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, N-methyl-glucamine, diethanolamine or amino acids (e.g. lysine) and the like; (ii) where a compound of the invention contains a basic group, such as an amino group, ceutically acceptable acid addition salts that can be formed include hydrochlorides, romides, sulfates, ates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates, camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, s, bisulfates and the like.

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

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

”Prodrug” refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, ion or ion) to a compound of the invention. Suitable groups for g prodrugs are described in ’The Practice of Medicinal Chemistry, 2nd Ed. pp561-585 (2003) and in F. J. Leinweber, Drug Metab. Res., 1987, 18, 379.

The compounds of the invention can exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, l. The term 'hydrate' is employed when the t is water.

Where compounds of the invention exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and trans-forms, E— and Z—forms, R-, $— and meso-forms, keto-, and enol-forms, unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers can be prepared by the application or adaptation of known methods (e.g. asymmetric synthesis).

A reference to a particular compound also es all isotopic variants. wo 2017/207983 2017/051546 In the context of the present invention, references herein to "treatment" include references to curative, palliative and prophylactic ent.

General s The compounds of the invention should be assessed for their biopharmaceutical properties, such as solubility and solution ity (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation 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 ion which may impart either a functional (i.e., drug release rate controlling) and/or a non- functional (i.e., processing aid or diluent) teristic to the formulations. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on lity and stability, and the nature of the dosage form.

Compounds of the invention intended for pharmaceutical use may be administered as a solid or liquid, such as a tablet, capsule or solution. Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their ation may be found, for example, in Remington’s Pharmaceutical es, 19th Edition (Mack Publishing Company, 1995).

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the invention and a ceutically acceptable carrier, diluent or ent.

For the treatment of conditions such as retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema, the compounds of the invention may be administered in a form suitable for injection into the ocular region of a patient, in particular, in a form le for intra- vitreal injection. It is envisaged that formulations suitable for such use will take the form of sterile solutions of a compound of the invention in a suitable aqueous vehicle. The compositions may be administered to the patient under the supervision of the attending physician.

The compounds of the invention may also be administered directly into the blood stream, into subcutaneous tissue, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, uscular, intrasynovial and subcutaneous. Suitable devices for parenteral stration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous or oily solutions. Where the solution is aqueous, excipients such as sugars (including but not restricted to glucose, manitol, sorbitol, etc.), salts, carbohydrates and buffering agents rably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable e such as sterile, pyrogen-free water.

Parenteral formulations may include implants derived from degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations may be administered via al incision into the subcutaneous tissue, muscular tissue or directly into specific organs.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may y be lished using rd pharmaceutical techniques well known to those skilled in the The lity of compounds of the ion used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of co-solvents and/or solubility-enhancing agents such as surfactants, micelle structures and cyclodextrins.

In one embodiment, the compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or gual stration by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, emulsions or powders; es ding liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.

Formulations suitable for oral administration may also be designed to deliver the compounds of the invention in an immediate release manner or in a rate-sustaining , wherein the release profile WO 07983 can be delayed, , controlled, sustained, or delayed and sustained or modified in such a manner which ses the therapeutic efficacy of the said compounds. Means to deliver compounds in a rate- sustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.

Examples of rate-sustaining rs e degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion.

Examples of rate-sustaining rs include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, nyl alcohol, polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.

Liquid (including multiple phases and dispersed s) formulations include ons, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for example, from gelatin or ypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The nds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic s, 2001, 11 (6), 981-986.

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

For administration to human ts, the total daily dose of the compounds of the invention is typically in the range 0.1 mg and 10,000 mg, or between 1 mg and 5000 mg, or between 10 mg and 1000 mg depending, of course, on the mode of administration. |f administered by intra-vitreal injection a lower dose of between 0.0001 mg (0.1 ug) and 0.2 mg (200 pg) per eye is envisaged, or between 0.0005 mg (0.5 ug) and 0.05 mg (50 pg) per eye.

The total dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

Synthetic Methods The compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are r exemplified by the specific examples ed herein below. Moreover, by utilising the ures described herein, one of ry skill in the art can readily prepare additional compounds that fall within the scope of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the t invention. Those skilled in the art will readily tand that known variations of the conditions and processes of the following preparative procedures can be used to e these compounds.

The compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above.

It may be ary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of nds of the invention to avoid their unwanted participation in a reaction leading to the formation of the compounds. Conventional protecting groups, for example those described by T. W. Greene and P. G. M. Wuts in ”Protective groups in organic chemistry” John Wiley and Sons, 4th Edition, 2006, may be used. For example, a common amino ting group suitable for use herein is tert-butoxy carbonyl (Boc), which is readily removed by treatment with an acid such as oroacetic acid or hydrogen de in an organic t such as dichloromethane. Alternatively the amino protecting group may be a benzyloxycarbonyl (2) group which can be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere or 9- fluorenylmethyloxycarbonyl (Fmoc) group which can be removed by solutions of secondary organic amines such as lamine 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 ysis in the presence of bases such as lithium or sodium hydroxide. Benzyl protecting groups can also be removed by enation with a palladium catalyst under a hydrogen atmosphere whilst tert-butyl groups can also be removed by trifluoroacetic acid. Alternatively a trichloroethyl ester protecting group is removed with zinc in acetic acid. A common hydroxy protecting group suitable for use herein is a methyl ether, deprotection conditions comprise refluxing in 48% aqueous HBr for 1-24 hours, or by stirring with borane tribromide in dichloromethane for 1-24 hours. Alternatively where a hydroxy group is protected as a benzyl ether, deprotection conditions comprise hydrogenation with a palladium st under a hydrogen atmosphere.

Examples of synthetic methods that may be used to prepare 4-carboxyimidazoles are described in EP 1426364 A1 (”Imidazole-derivatives as factor Xa inhibitors”, p27-28).

The compounds according to l formula I below can be prepared using conventional synthetic methods for example but not limited to, the route outlined in Scheme 1. nds of formula (I) are d as follows: A II?6 )\(/<Y>\Z/ R5 o \—B Formula (I) wherein B is phenyl substituted with 1 to 4 substituents selected from alkylb, , OH, halo, CN, heteroaryl, COORS, NHCORS, CONR8R9, OCFg, and CFa; 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 to 3 substituents selected from alkylb, alkoxy, OH, oxo, halo, CN, aryl, COORS, NHCORS, CONR8R9, OCF3 and CF3; W is 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, lkyl, , halo, OH, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, ed piperazinyl, -NR8R9, CN, COORS, CONR8R9, -NR8COR9 and CF3; n at least one of R5 and R6 is present and is not H; R7 is H; A is ed from aryl and heteroaryl; wherein aryl is tuted with 1, 2 or 3 tuents independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, - (CH2)0.3-O-heteroaryl, arylb, -O-arylb, -(CH2)1.3-arylb, -(CH2)1.3-heteroaryl, -COOR10, -CONR10R11, -(CH2)0.3- NR10R11, OCF3 and CF3; and heteroaryl is substituted with 1, 2 or 3 substituents independently selected from alkyl, , OH, OCFg, halo, CN, aryl, -(CH2)1.3-aryl, -(CH2)0.3-NR10R11, heteroarylb, -COOR10, - CONR10R11 and CFa; R8 and R9 are independently selected from H and alkyl; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (Cl-Clo) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms 0); alkyl may ally be substituted with 1 or 2 substituents independently selected from (C1-C6)alkoxy, OH, CN, CF3, COOR10, CONR10R11, fluoro and NR10R11; alkylb is a linear saturated hydrocarbon having up to 6 carbon atoms or a branched ted hydrocarbon of between 3 and 6 carbon atoms (C3.5); alkylb may optionally be substituted with 1 or 2 substituents independently selected from )alkoxy, OH, CN, CF3, COOR10, CONR10R11 and fluoro; cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 6 carbon atoms; alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C1-C6) or a branched ed hydrocarbon of between 3 and 6 carbon atoms (C3-C5); alkoxy may optionally be substituted with 1 or 2 substituents independently selected from OH, CN, CF3, COOR10, CONR10R11, fluoro and NR10R11; aryl is phenyl, biphenyl or naphthyl; aryl may be ally substituted with 1, 2 or 3 substituents independently ed from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, - (CH2)0.3-O-heteroaryl, arylb, -O-arylb, -(CH2)1.3-arylb, -(CH2)1.3-heteroaryl, -COOR10, -CONR10R11, -(CH2)0.3- NR10R11, OCF3 and CFa; arylb is phenyl, yl or yl, which may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, -COOR10, -CONR10R11, CF3 and NR10R11; heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2, 3 or 4 ring members independently selected from N, NR8, S and O; heteroaryl may be optionally wo 2017/207983 substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, OCFg, halo, CN, aryl, -(CH2)1.3-aryl, -(CH2)0.3-NR10R11, heteroarylb, -COOR10, -CONR10R11 and CF3; heteroarylb is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, ning, where possible, 1, 2 or 3 ring members independently selected from N, NR8, S and 0; wherein heteroarylb may be optionally substituted with 1, 2 or 3 substituents independently ed from alkyl, alkoxy, OH, halo, CN, aryl, - (CH2)1.3-aryl, -COOR10, -CONR10R11, CF3 and NR10R11; R10 and R11 are independently selected from H, alkyl, arylb and heteroarylb or R10 and R11 er with the nitrogen atom to which they are ed form a carbon-containing 4-, 5-, 6- or 7-membered heterocylic 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 be optionally mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, halo and CF3; and tautomers, isomers, stereoisomers ding enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.

In Scheme 1, the amine 2 is coupled to an acid 1 to give the compound 3. This coupling is typically carried out using standard coupling conditions such as hydroxybenzotriazole and a carbodiimide, such as water soluble carbodiimide, in the ce of an organic base. Other standard coupling methods include the reaction of acids with amines in the presence of benzotriazoleyl)-1,1,3,3- tetramethylaminium uorophosphate, 2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3- tetramethylisouronium hexafluorophosphate(V), benzotriazoleyl-oxy-tris-pyrrolidino-phosphoium hexaffluorophosphate or bromo-trispyrolidino-phosphoium hexafluorophosphate in the presence of organic bases such as triethylamine, diisopropylethylamine or ylmorpholine. Alternatively the amide formation can take place via an acid chloride in the presence of an organic base. Such acid des can be formed by methods well known in the literature, for example reaction of the acid with oxalyl chloride or thionyl chloride. atively, the amide formation can take place via activation of the carboxylic acid using carbonyl diimidazole.

A \O>/Z< HZN /\X/ OH + \O>/Z<N lY—Z\ lY—Z\ H R6 R5 R6 R5 1 2 3 Schemel Alternatively compounds of the invention can be prepared using the route outlined in Scheme 2a. The acid 4 can be coupled to an amine 2 using suitable ng methods as usly described to give nd 5. In a typical second step the nitrogen of the heterocyclic ring is alkylated with compound 6 to give compound 7. 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 sulphonate. Alternatively the alkylation may be carried out using an alcohol under Mitsunobu conditions in the presence of triphenylphosphine.

F57 0 Fr? 0 HN/W>/Z<Q HN oH + 2 —» <Q N /Y Z\ [Y Z\ H R6 R5 R6 R5 4 2 5 R7 A/\LG1 v'v O /\N/ >J< A \Q N Y—Z H / \ R6 R5 Scheme2a In a variation of Scheme 2a compounds according to l formula I can be prepared using the route outlined in Scheme 2b. Scheme 2b differs from Scheme 2a in that the moiety Y is equal to N therefore a ting group strategy may be employed and the synthetic steps carried out in a different order. The pyrazole carboxylic acid, protected as an ester (PG) as described previously, compound 8, is alkylated wo 2017/207983 with compound 6. The alkylation can be d out in the presence of a base such as potassium carbonate, cesium carbonate, sodium carbonate or sodium hydride in which case the g group is a halide or su|phonate. Alternatively the alkylation may be carried out using an l under Mitsunobu conditions in the presence of triphenylphosphine. In this case there are two possible nitrogens for the alkylation to occur at therefore there is the possibility of two regioisomers 9 and 10 being .

Compounds 9 and 10 may be separated at this stage or at a subsequent stage in the synthesis using separation methods well known to those skilled in the art, for example by chromatography or by fractional crystallisation. The protecting group of compound 9 is removed by hydrolysis to give the corresponding acid 11 using standard methods as described previously. Compound 11 can be coupled to an amine 2 using suitable coupling methods as previously described to give compound 12. $7 0 HN/W>J< Fla R7 0 v'v O \ w , \_ OPG, /\N’ w N/ >J< N—Z\ —> A \—z ope1 + N—é OPG, R5 /\ —\ \ A A\/ L31 R5 R5 8 6 9 10 F57 0 A \>//< N—z OH _\ HZN 2 R F57 0 /\N/ $4 A \ N N=Z\ H Scheme2b Alternatively nds ing to the invention can be prepared using the route outlined in Scheme 3. The pyrrole 17 can be formed in two steps the first of which involves reaction of the sodium salt of an alkyl ketoacetate 13, lly protected with a protecting group (P6) as described previously, with a chloroketone 14 in the presence of a base such as potassium carbonate to give compound 15 which in a wo 2017/207983 typical second step is reacted with the amine 16 in the ce of an acid such as but not d to sulphonic acid derivatives e.g. p-toluenesulphonic acid to yield compound 17 which in a typical third step is subsequently hydrolysed to the corresponding acid 18 using standard methods as described previously. In a typical fourth step the acid 18 can be coupled to an amine 2 using suitable coupling methods as previously described to give compound 19. 0 OPG2 0 R6)J\/CI O OPG R7 0 R7 0 13 14 15 A/\NH2 R7 R7 0 0 /\N \ /\ A N \ OH <— A _ OPGZ R6 R6 18 17 HN 0 /\N \ Scheme 3 The amine, compound 2 can be prepared using conventional synthetic methods for example, but not limited to, the routes outlined in Scheme 4. The nitrile of nd 20 is reduced by standard reducing agents including but not limited to lithium aluminium e, sodium borohydride, sodium dride 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 catalytic enation is employed, it is possible to carry out in situ wo 2017/207983 tion of the resulting amino group, for e resulting in the carbamate 21, for example tert- butoxy carbamate. This may be helpful to enable for example purification by chromatography of the intermediate compound 21. The protecting group is uently d using standard conditions as described previously to give compound 2.

\\ HZN 2 R R 21 R Scheme 4 Examples The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used: aq Aqueous solution DCM Dichloromethane DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EtOAc Ethyl Acetate 2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) hrs Hours HOBt Hydroxybenzotriazole LCMS Liquid chromatography mass spectrometry Me Methyl MeCN Acetonitrile MeOH Methanol Min Minutes MS Mass spectrum Nuclear magnetic resonance spectrum — NMR spectra were recorded at a frequency of 400MHz unless otherwise indicated Pet. Ether Petroleum ether fraction boiling at 60-80°C Ph Phenyl SWFI Sterile water for ion rt room temperature THF Tetrahydrofuran TFA Trifluoroacetic acid All reactions were carried out under an atmosphere of nitrogen unless specified otherwise. 1H NMR spectra were recorded on a Bruker (400MHz) spectrometer with reference to deuterium solvent and at rt.

Molecular ions were obtained using LCMS which was carried out using a Chromolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient 10% to 90% 0.1% HCOzH/MeCN into 0.1% HCOzH/Hzo over 13 min, flow rate 1.5 mL/min, or using Agilent, X-Select, acidic, 5-95% ater over 4 min. Data was collected using a Thermofinnigan or MSQ mass spectrometer with spray ionisation in conjunction with a Thermofinnigan Surveyor LC system.

Where ts were purified by flash chromatography, ’silica’ refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Merck silica gel 60), and an applied pressure of nitrogen up to 10 psi accelerated column elution. Reverse phase preparative HPLC purifications were carried out using a Waters 2525 binary nt pumping system at flow rates of typically 20 mL/min using a Waters 2996 photodiode array detector.

All solvents and commercial reagents were used as received.

Chemical names were generated using automated software such as the Autonom software provided as part of the |S|S Draw package from MDL Information Systems or the on software ed as a component of MarvinSketch or as a component of the IDES E-WorkBook. wo 2017/207983 A. 1-(4-Hydroxymethyl-benzyl)-1H-pyridinone 4-(Chloromethyl)benzylalcohol (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 hrs after which time the solvent was removed in vacuo and the residue taken up in chloroform (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried (Na2504) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH / 97% CHCIg, to give a white solid identified as 1-(4-hydroxymethyl-benzyl)-1H-pyridinone (5.30g, 24.62mmol, 77% yield).

[M+Na]+ = 238 Bl. 1-(4-Chloromethyl-benzyl)-1H-pyridinone 1-(4-Hydroxymethyl-benzyl)-1H-pyridinone (8.45 g, 39.3 mmol), dry DCM (80 mL) and ylamine (7.66 ml, 55.0 mmol) were cooled in an ice bath. Methanesulfonyl chloride (3.95 ml, 51.0 mmol) was added and stirred in ice bath for 15 min. The ice bath was removed and stirring continued at rt temperature overnight. The on e was partitioned between DCM (100 mL) and saturated aqueous NH4C| solution (100 mL). The aqueous layer was extracted with further DCM (2 x 50 mL) and the ed organics washed with brine (50 mL), dried over , filtered and concentrated to give 1-(4- chloromethyl-benzyl)-1H-pyridinone (8.65 g, 36.6 mmol, 93 % yield) as a pale yellow solid.

[MH]+ = 234.1 BZ. 1-(4-Bromomethyl-benzyl)-1H-pyridinone 1-(4-Hydroxymethyl-benzyl)-1H-pyridinone (2.30 g, 6.97 mmol) was dissolved in DCM (250 mL). To this solution was added phosphorous tribromide (5.78 g, 21.37 mmol). The reaction mixture was stirred at rt for 18 hrs and diluted with CHC|3 (250 mL). The filtrate was washed with sat. NaHCOa (aq) (30 mL), water (30 mL), brine (30 mL), dried (Na2504) and evaporated in vacuo to give a white solid which was identified as romomethyl-benzyl)-1H-pyridinone (2.90 g, 10.43 mmol, 98%).

[M+H]+ = 277.7 C. Methyl 3-(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylate Potassium carbonate (519 mg, 3.76 mmol) was added to a solution of methyl hoxymethyl)-1H- pyrazolecarboxylate (320 mg, 1.88 mmol; CAS no. 3184961 (synthesised according to the method described in WO 09009)) 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 d with EtOAc (50 mL) and washed with brine (2 x 100 mL), dried over magnesium sulfate, filtered and reduced in vacuo. The crude product was purified by flash chromatography (40 g column, 0-100% EtOAc in isohexanes) to afford two wo 2017/207983 somers. The second isomer off the column was collected to afford methyl hoxymethyl)(4- ((2-oxopyridin-1(2H)-y|)methyl)benzyl)-1H-pyrazolecarboxylate (378 mg, 1.01 mmol, 53.7 % yield) as a colourless gum.

[MH]+= 368.2 D. 3-(Methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazolecarboxylic acid To methyl 3-(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methy|)benzyl)-1H-pyrazolecarboxylate (3.77 g, 10.26 mmol) in THF (5 mL) and MeOH (5 mL) was added 2M NaOH solution (15.39 ml, 30.8 mmol) and stirred at rt overnight. 1M HCl (50 mL) was added and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and reduced in vacuo to give 3- xymethyl)(4-((2-oxopyridin-1(2H)-y|)methyl)benzyl)-1H-pyrazolecarboxylic acid (1.22 g, 3.45 mmol, 33.6 % yield) as a white powder.

[MH]+= 354.2 G. Methyl-pyrazol-l-ylmethyl)-phenyl]-methanol 4-(Chloromethyl)benzylalcohol (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 rt for 18 hrs and at 60 °C for 30 hrs after which time the solvent was d in vacuo and the residue taken up in EtOAc (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient of 10 to 80% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white solid identified as [4-(4-methyl-pyrazolylmethyl)-phenyl]-methanol (3.94 g, 18.90 mmol, 54% yield).

[MH]+ = 203 H. 1-(4-Chloromethyl-benzyl)methyl-1H-pyrazole [4-(4-Methyl-pyrazolylmethyl)-pheny|]-methanol (2.03 g, 10.04 mmol) and triethylamine (1.13 g, 11.54 mmol) was dissolved in DCM (40 mL). To this solution was added methanesulphonyl chloride (1.26 g, 11.04 mmol) dropwise. The reaction mixture was stirred at rt for 18 hrs and d with CHC|3 (250 mL). The mixture was washed with saturated NH4C| (30 mL), water (30 mL), brine (30 mL), dried (Na2504) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient of 0 to 60% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white solid identified as hloromethyl-benzyl)methyl-1H-pyrazole (1.49 g, 6.62 mmol, 60% yield). wo 2017/207983 [MH]+= 221, 223 M. 3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester 1-(4-Bromomethyl-benzyl)-1H-pyridinone (850 mg, 3.06 mmol) was dissolved in DMF (10 mL). 5- Amino-1H-pyrazolecarboxylic 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 hrs after which time the reaction mixture was d with EtOAc (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried (Na2504) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient from 30% Pet Ether / 70% EtOAc to 100% EtOAc, to afford two regioisomers.

The second isomer off the column was collected to afford 3-amino[4-(2-oxo-2H-pyridiny|methyl)- benzyl]-1H-pyrazolecarboxylic acid ethyl ester (480 mg, 1.36mmol, 45% yield) as a white solid.

[MH]+= 353.1 N. 3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester (480 mg, 1.36 mmol) was dissolved in THF (50 mL) and water (5 mL). Lithium ide (16 3mg, 6.81 mmol) was added. The reaction mixture was stirred at 50 °C for 18 hrs after which time the volatiles were removed in vacuo and the aqueous residue washed with CHC|3 (150 mL). The aqueous layer was acidified with 1M HCI to pH7 and extracted with CHC|3 (3 x 50 mL). The ed extracts were washed with water (30 mL), brine (30 mL), dried (Na2504) and evaporated in vacuo to give a white solid identified as o[4-(2- oxo-2H-pyridin-l—ylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (370 mg, ol, 84% yield).

[M H]+ = 325.2 P. (2-Fluoromethoxy-benzyl)-carbamic acid tert-butyl ester 2-Fluoromethoxybenzonitrile (500 mg, 3.31 mmol) was dissolved in methanol (40 mL). This solution was cooled to 0 °C. Nickel (||) chloride hexahydrate (79 mg, 0.33 mmol) and di-tertbutyl dicarbonate (1.44g, 6.62mmol) were added followed by sodium borohydride (876 mg, 23.16 mmol) portionwise. The reaction mixture was stirred, allowed to warm to rt and stirred for 3 days. The MeOH was removed in vacuo. The residue was dissolved in CHC|3 (150 mL), washed with sat NaHCOa (aq) (50 mL), water (50mL), brine (50mL), dried (Na2504) and ated in vacuo. The residue was purified by tography (silica), eluent 20% EtOAc / 80% Pet. Ether, to give a white solid identified as (2-fluoromethoxy-benzyl)- carbamic acid tert-butyl ester (540 mg, 0.2 mmol, 64% yield). wo 2017/207983 [MH]+= 255.8 Q. 2-Fluoromethoxy-benzylamine hydrochloride (2-Fluoromethoxy-benzyl)-carbamic acid tert-butyl ester (600 mg, 2.35 mmol) was dissolved in 4M HCI in dioxan (40 mL). After 2 hrs at rt the solvent was removed in vacuo to give a pale yellow solid identified as 2-fluoromethoxy-benzylamine hydrochloride (414 mg, 2.17 mmol, 92% yield).

[MH]+= 155.9 T. 1-tert-Butyl l 3-aminopyrazole-1,4-dicarboxylate To 5-amino-1H-pyrazolecarboxylic 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 uL, 521 mg, 4.03 mmol) and the reaction stirred at rt overnight. Reaction mixture was diluted with DCM, water added, separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Flash tography afforded 1- tert-butyl 4-ethyl 3-aminopyrazole-1,4-dicarboxy|ate as a white solid (122 mg, 30% .

[MH]+= 256.2 U. Ethyl 3-acetamido-1H-pyrazolecarboxylate A mixture of 1-tert-butyl 4-ethyl 3-aminopyrazole-1,4-dicarboxy|ate and acetyl chloride was stirred at 0 °C then heated at reflux for 2 hrs. The excess acetyl chloride was removed in vacuo. Water was added and the resulting mixture stirred for 18 hrs at rt. The precipitate was collected by vaccum filtration and dried to afford ethyl 3-acetamido-1H-pyrazolecarboxylate as a white solid (46 mg). The aqueous te was ted with DCM (4 x 15 mL) and the combined organic layers were dried (MgSO4), filtered and trated in vacuo to afford a further crop of ethyl 3-acetamido-1H-pyrazolecarboxylate (48 mg) (overall yield 94 mg, 99 %).

[MH]+= 197.8 V. 5-Dimethylamino-1H-pyrazolecarboxylic acid ester WO 07983 -Amino-1H-pyrazolecarboxylic acid ester (1.0 g, 6.45 mmol) was dissolved in methanol (200 mL) and the solution purged with nitrogen. Formaldehyde (37% by weight, 4.5 mL, 21.18 mmol) was added followed by 10% Pd/C (1.0 g). The reaction e was shaked on a Parr hydrogenator at 10 psi for 18hrs. The reaction mixture was filtered through celite to remove the catalyst and the residue washed with methanol (200 mL) and water (20 mL). The combined filtrates were ated in vacuo. The crude residue was triturated with methanol/diethyl ether and the filtrate concentrated to afford a colourless oil identified as the title compound (1.1 g, 6.00 mmol, 93% yield).

[MH]+= 183.7 Reference Examples Reference examples A to 6 correspond to es 1, 2, 3, 41, 77, 83 and 126 of our co-pending application PCT/GBZOlS/053615 (W02016/083820).

Reference example H corresponds to example 88 of our co-pending application PCT/GBZOlS/053615 (W02016/083820).

Reference examples I and J are ues of es 7 and 27 of W02103/111108.

Reference example K is an analogue of example 79 of the present application.

Reference Example A N- 3 5-Dimethox benz | methox meth | 4- 2-oxo ridin-1 2H - | meth | benz | -1H- pyrazolecarboxamide Z/2\ < I o O/ O/(DI To a mixture of 3-(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methy|)benzyl)-1H-pyrazolecarboxylic acid (80 mg, 0.226 mmol), (3,5-dimethoxyphenyl)methanamine (45.4 mg, 0.272 mmol) and HATU (95 mg, 0.249 mmol) in anhydrous DCM (1.5 mL) and anhydrous DMF (0.3 mL) was added N,N- diisopropylethylamine (99 pl, 0.566 mmol) and the mixture d to stir at rt overnight. The reaction was concentrated in vacuo and the residue purified by flash chromatography loading in DCM, eluting with a gradient of 1 to 10% MeOH (containing 0.3% NH3)/DCM to afford a gum. This was dissolved in acetonitrile (0.5 mL) and water (3 mL) added, forming a precipitate. This was sonicated, then filtered and dried under vacuum to afford N-(3,5-dimethoxybenzyl)(methoxymethyl)(4-((2-oxopyridin-1(2H)- yl)methy|)benzyl)-1H-pyrazolecarboxamide (76 mg, 0.150 mmol, 66.1 % yield) as a sticky pale yellow solid.

NMR (d6-DMSO) 6: 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, , 6.37 (1H, t, J = , 6.40 (1H, dd, J = 9.2, 1.4Hz), 6.44 (2H, d, J = 2.3Hz), 7.20- 7.29 (4H, m), 7.41 (1H, ddd, J = 9.1, 6.6, 2.1Hz), 7.76 (1H, dd, J = 6.8, 2.1Hz), 8.24 (1H, s), 8.32 (1H, t, J = .9Hz).

[MH]+= 503.3 Reference Example B 3-Amino 4- 2-oxo-2H- ridin Imeth l-benz l-1H- razolecarbox lic acid 2-fluoro y-benzylamide 3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (75 mg, 0.23 mmol) was dissolved in DCM (20 mL) and DMF (1 ml). This solution was cooled to 0 °C. 2-Fluoromethoxy- benzylamine hydrochloride (53 mg, 0.28 mmol) was added followed by HOBt (34 mg, 0.25 mmol) and ylamine (70 mg, 0.69 mmol). Water soluble carbodiimide (53 mg, 0.28 mmol) was then added. The WO 07983 reaction mixture was stirred, allowed to warm to rt and stirred for 3 days. The e was diluted with chloroform (200 mL) and washed with NaHCOa (aq) (50m L), water (50m L) and brine (50m L), dried (Na2504) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 4% MeOH / 96% CHCIg, to give a white solid identified as 3-amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H- lecarboxylic acid 2-fluoromethoxy-benzylamide (92 mg, 0.20 mmol, 86% yield).

[MH]+ = 462.2 1H NMR: (d6-DMSO) 6: 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).

Reference Example C 1- 7-Chloro- uinolin Imeth thox meth l-1H- razolecarbox lic acid 2-fluoromethox - benzylamide /\N\N/fiNF 0 \CH3 \CH3 (7-Chloro-quinolinyl)-methanol 7-Chloroquinolinecarboxylic acid (500 mg, 2.4 mmol) was dissolved in anhydrous THF (20 mL) and cooled to -20 °C. To this solution was added triethylamine (1.0 mL, 7.23 mmol) and yl chloroformate (0.38 mL, 2.9 mmol). The reaction mixture was stirred at -20 °C for 20 min and then poured into a solution of sodium borohydride (731 mg, 19 mmol) in water (2 mL) at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 18 hours. The mixture was d with EtOAc (50 mL) and the layers separated.

The organic layer was washed with water (20 mL), brine (20 mL), dried 4), filtered and evaporated in vacuo to give a yellow solid. The solid was purified by chromatography on silica, eluting with EtOAc/Pet Ether to afford (7-chloro-quinolinyl)-methanol as an off white solid, 134 mg, 29% yield.

[MH]+= 194.1 3-Bromomethylchloro-quinoline (7-Chloro-quinolinyl)-methano| (134 mg, 0.692 mmol) was ved in DCM (5 mL). PBrg (65 uL, 0.692 mmol) was added and the reaction d for 3 hrs at rt. Upon completion, the reaction mixture was quenched with dilute NaHCOa (aq) (10m L). The layers were separated and the organic washed with water (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), ed and concentrated in vacuo to afford a yellow solid fied as 3-bromomethylchloro-quinoline (78mg, 44% yield).

[MH]+= 257.6 1-(7-Chloro-quinolinylmethyl)methoxymethyl-lH-pyrazolecarboxylic acid methyl ester Methyl 3-(methoxymethyl)-1H-pyrazolecarboxylate (51 mg, 0.304 mmol; CAS no. 3184961 (synthesised according to the method described in treated with potassium carbonate (84 mg, 0.608 mmol) and 3-bromomethylchloro-quinoline (78 mg, 0.304 mmol). The reaction was stirred overnight at rt. EtOAc (60 mL) and water (20 mL) were added and the layers separated. The c layer was washed with water (3 x 10 mL), brine (10 mL), dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by chromatography, eluting with EtOAc / Pet.Ether to afford two isomeric products. The faster running product was identified as the undesired regioisomer. The slower running product afforded a yellow oil and was identified as 1-(7-chloro-quinolin- 3-ylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid methyl ester (53 mg, 50% yield).

[MH]+= 345.8 hloro-quinolinylmethyl)methoxymethyl-lH-pyrazolecarboxylic acid To 1-(7-chloro-quinolinylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid methyl ester (53 mg, 0.153 mmol) in ethanol (10 mL) was added sodium hydroxide (61 mg, 1.53 mmol) and the reaction was heated at vigorous reflux for 4.5 hrs. 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% chlorofrom / 10% iso- propyl l (6 x 15 mL). The combined organic layers were dried (Na2504), filtered and concentrated in vacuo to give 1-(7-chloro-quinolinylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid as a pale wo 2017/207983 yellow solid (50 mg, 98% yield).

[MH]+= 332 1-(7-Chloro-quinolinylmethyl)methoxymethyl-lH-pyrazolecarboxylic acid 2-fluoromethoxy- amide 1-(7-Chloro-quinolinylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid (25 mg, 0.075 mmol) was taken up in DCM (5 mL) at 0 °C. To the solution was added ylamine (52 uL, 0.377 mmol), HOBt (12 mg, 0.09 mmol) and water soluble carbodiimide (20 mg, 0.106 mmol). After 15 min, 2-fluoro methoxy-benzylamine hydrochloride (14 mg, 0.075 mmol) was added and the reaction allowed to warm to rt and stirred for over the weekend. The on was diluted with CHC|3 (50 ml) and washed with sat. aq. NaHCOa (20 ml) followed by water (20 mL) and brine (20 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude t was purified by chromatography eluting with 6% Methanol / 94% DCM to give a white solid (16 mg, 45% yield) identified as 1-(7-chloro-quinolin ylmethyl)methoxymethyl-1H-pyrazolecarboxylic acid 2-fluoromethoxy-benzylamide.

[M H]+ = 469 1H NMR (DMSO): 3.20 (3H, s), 3.82 (3H, s), 4.41 (2H, d,J = 5.8Hz), 4.54 (2H, s), 5.57 (2H, s), .91 (1H, m), 7.03-7.09 (2H, m), 7.67 (1H, dd, J = 8.8, 2.1Hz), 8.07 (1H, d, J = 8.8Hz), 8.10 (1H, d, J = 1.9Hz), 8.30 (1H, d, J = 1.7Hz), 8.37 (1H, s), 8.39 (1H, t, J = 5.8Hz), 8.92 (1H, d, J = 2.2Hz) Reference Example D 3-Fluoromethoxy-pyridinecarbonitrile To a large microwave vial, cyanocopper (1.304 g, 14.56 mmol) was added to a solution of 2-bromo fluoromethoxypyridine (1 g, 4.85 mmol) in DMF (5 mL). The reaction vial was sealed and heated to 100 °C for 16 hrs. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The thick suspension was sonicated and required additional water (40 mL) and EtOAc (2 x 50 mL) with sonication to break-up the solid precipitated. The combined layers were filtered through a plug of celite and the organic layer isolated, washed with brine (50 mL), dried over magnesium sulfate, ed and the solvent removed under reduced pressure to give a pale green solid identified as the desired compound 3-fluoromethoxy- pyridinecarbonitrile (100 mg, 0.578 mmol, 12 % yield) (3-Fluoromethoxy-pyridinylmethyl)-carbamic acid tert-butyl ester 3-Fluoromethoxy-pyridinecarbonitrile (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 reaction temperature ”0 °C. The deep brown solution was left to stir at 0 °C and slowly allowed to warm to rt and then left to stir at rt for 3 hrs. The reaction mixture was evaporated to dryness at 40 °C to afford a black residue which was diluted with DCM (10 mL) and washed with sodium hydrogen carbonate (10 mL). An emulsion formed so the organics were separated via a phase ting cartridge and concentrated. The crude liquid was purified by chromatography eluting with EtOAc/ iso-Hexane to afford the title compound, (3-fluoromethoxy-pyridinylmethyl)-carbamic acid tert-butyl ester as a clear yellow oil (108 mg, 62 % yield) [MH]+= 257 luoromethoxy-pyridinyl)-methylamine hloride salt oromethoxy-pyridinylmethyl)-carbamic acid tert-butyl ester (108mg, 0.358mmol) was taken up in iso-propyl alcohol (1 mL) and then HCl (6N in iso-propyl alcohol) (1 mL, 0.578 mmol) was added at rt and left to stir at 40 °C for 2 hours. The reaction mixture was concentrated under reduced re and then triturated with ether, sonicated and then decanted to give a cream coloured solid (75 mg, 55% yield) identified as C-(3-fluoromethoxy-pyridinyl)-methylamine hydrochloride salt.

[MH]+= 157 3-Methoxymethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (3-fluoro- 4-methoxy-pyridinylmethyl)-amide hoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methy|)benzyl)-1H-pyrazolecarboxylic acid (75 mg, 0.212 mmol), C-(3-Fluoromethoxy-pyridinyl)-methylamine hydrochloride salt (49 mg, 0.212 mmol) and HATU (89 mg, 0.233 mmol) were ded in anhydrous DCM (3 mL) to which triethylamine (177 uL, 1.270 mmol) was added, sonicated and then left to stir at rt for 4 hours. The solvent was removed under reduced pressure and the resulting residue was ed with ammonium chloride solution (5 mL).

An off white solid resulted which was sonicated, filtered under reduced pressure washed with water and then placed in the vac oven at 40 °C overnight. The crude material was purified by tography eluting with (1% ammonia-methanol) /DCM to afford the 3-methoxymethyl[4-(2-oxo-2H-pyridinylmethyl)- benzyl]-1H-pyrazolecarboxylic acid (3-fluoromethoxy-pyridinylmethyl)-amide as a white solid (67 mg, 64% yield) [MH]+ = 492 NMR (d6-DMSO) 6: 3.25 (3H, s), 3.92 (3H, s), 4.46-4.57 (4H, m), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J = 1.4, 6.7Hz), 6.39 (1H, ddd,J=0.7, 1.4, 9.2Hz),7.17-7.28(5H,m),7.41(1H,ddd,J=2.1, 6.6, 8.9Hz), 7.75 (1H, ddd,J = 0.7, 2.1, 6.8Hz), 8.21-8.29 (2H, m), 8.42 (1H, t, J = 5.4Hz) Reference Example E 6-Bromofluoromethoxy-benzoic acid To a suspension of 2-fluoromethoxybenzoic acid (10 g, 58.8 mmol) in acetic acid (50 mL) and water (50 mL) at rt was added bromine (6.06 mL, 118 mmol) dropwise. The reaction was then heated to 60 °C for 1 hr. The reaction was cooled to room temperature and the white itate was filtered. The solid was washed with water (200 mL) and iso-Hexane (50 mL) to give 6-bromofluoromethoxy-benzoic acid as white solid, 12.098 g, 82 % yield.

[MH]+= 249/251 (6-Bromofluoromethoxy-phenyl)-methanol To a stirred solution of 6-bromofluoromethoxy-benzoic acid (4.13 g, 16.58 mmol) in THF (20 mL) was added 4-methylmorpholine (1.914 mL, 17.41 mmol) and then isobutyl chloroformate (2.15 mL, 16.58 mmol). After 1 hour the reaction mixture was filtered to remove any salts generated, the solid was washed with additional THF (10 mL). The filtrate and washings were ed and cooled to 0 °C in an ice bath and then NaBH4(0.659 g, 17.41 mmol) in cold water (10 mL) was added in one portion (gas d), then allowed to warm to room ature and stirred for 2 hours. The reaction mixture was quenched by careful on of 1M HCl (30 mL) until acidic pH was obtained. The product was ted into diethyl ether (150 mL). The organic layer was then washed with 2M NaOH (2 x 100 mL) to removed starting carboxylic acid, then acidified by washing with 1M HCl (100 mL), followed by brine (100 mL), dried over magnesium sulfate, filtered and solvent d in vacuo. The crude product was purified by chromatography eluting with 0-50% EtOAc / iso-Hexane to afford (6-bromofluoromethoxy-phenyl)- methanol as a colourless oil, 1.37g, 50% yield.

[MH]+= 217/219 1-Bromochloromethylfluoromethoxy-benzene A solution of (6-bromofluoromethoxy-phenyl)-methanol (500 mg, 2.127 mmol) in anhydrous DCM (4 mL) was treated with triethylamine (415 uL, 2.98 mmol), followed by methanesulfonyl chloride (214 uL, 2.77 mmol). The mixture was allowed to stir at ambient temperature overnight. The reaction e was partitioned between DCM (50 mL) and sat. aq. NH4C| (40 mL). The organic layer was collected and the aqueous layer extracted with r DCM (40 mL). The combined cs were washed with water (40 mL), brine (40 mL), dried (Na2504), filtered and concentrated. The crude al was purified by chromatography eluting with a gradient of 0 to 30% EtOAc/iso-Hexane to afford 1-bromochloromethyl- 3-fluoromethoxy-benzene (468 mg, 86% yield) as a white solid. 2-(6-Bromofluoromethoxy-benzyl)-isoindole-1,3-dione To a on of 1-bromochloromethylfluoromethoxy-benzene (460 mg, 1.815 mmol) in anhydrous DMF (5 mL) was added potassium phthalimide (403 mg, 2.178 mmol) and the mixture heated at 90 °C overnight. The mixture was diluted with EtOAc (75 mL) and washed with water (3 x 35 mL), brine (35 mL), dried (Na2504), filtered and concentrated to a yellow solid. The crude material was purified by flash chromatography, eluting with a gradient of 0 to 50% EtOAc/ iso-Hexane. The d product 2-(6- bromofluoromethoxy-benzyl)-isoindole-1,3-dione was isolated as white s, 372 mg, 56% yield.

[MH]+ = 364.0/366.0 6-Bromofluoromethoxy-benzylamine A suspension of 2-(6-bromofluoromethoxy-benzyl)-isoindole-1,3-dione (0.368 g, 1.011 mmol) in methanol (7.5 mL) was treated with hydrazine hydrate (0.064 mL, 1.314 mmol) and the reaction e heated at reflux for 5 hrs. The crude mixture was loaded directly onto an SCX column (8 g), washed with MeOH and eluted with 1% NHg/MeOH to afford 6-bromofluoromethoxy-benzylamine (204 mg, 85 % yield) as a yellow oil [MH]+= 359 3-Methoxymethyl-l-[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 6-bromo- 2-fluoromethoxy-benzylamide A 25 mL flask was charged with 3-(methoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methy|)benzyl)-1H- pyrazolecarboxylic acid (130 mg, 0.368 mmol), (6-bromofluoromethoxy-benzylamine (86 mg, 0.368 mmol), HATU (154 mg, 0.405 mmol), ous DCM (3 mL) and anhydrous DMF (0.5 mL). N,N- Disopropylethylamine (160 uL, 0.920 mmol) was added and the mixture allowed to stir at ambient temperature overnight. The reaction was concentrated under vacuum and redissolved in MeOH (4 mL) then purified by SCX, washing with MeOH, eluting with 1% NHg/MeOH. The residue was further purified chromatography eluting with a gradient of 0 to 10% MeOH (containing 0.3% NH3) / DCM to afford 3- methoxymethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 6-bromo fluoromethoxy-benzylamide (191 mg, 89 % yield) as a white foam.

[MH]+= 571.2 3-Methoxymethyl-l-[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 6-cyano fluoromethoxy-benzylamide To a ed solution of dicyanozinc (24.13 mg, 0.205 mmol) and 3-methoxymethyl[4-(2-oxo-2H- pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 6-bromofluoromethoxy-benzylamide (90 mg, 0.158 mmol) in dimethylacetamide (1.2 mL) was added tetrakis(triphenylphosphine)palladium(0) (18.26 mg, 0.016 mmol) and the e heated to 110 °C overnight. The mixture was purified by chromatography eluting with a gradient of 0 to 10% (0.3% NH3/MGOH)/ DCM to give 3-methoxymethyl- 1-[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 6-cyanofluoromethoxy- benzylamide as a pale yellow foam, 21 mg, 25% yield.

[MH]+= 516.3 1H NMR SO) 6: 3.21 (3H, s), 3.92 (3H, s), 4.47-4.55 (4H, m), 5.06 (2H, s), 5.27 (2H, s), 6.21 (1H, td, J = 6.7, 1.4Hz), 6.39 (1H, d, J = 9.1Hz), 7.17-7.31 (5H, m), 7.40 (1H, ddd, J = 8.9, 6.6, 2.1Hz), 7.67 (1H, dd, J = 8.6, 1.5Hz), 7.75 (1H, dd, J = 6.8, 2.1Hz), 8.20 (1H, s), 8.40 (1H, t, J = 5.2Hz) Reference Example F 2-Chlorofluoromethoxy-benzaldehyde To an ice-salt cooled flask containing methanol (8 mL, 198 mmol) was slowly added sodium hydride (1.318 g, 33.0 mmol). Once the addition was complete the cooling bath was removed and then allowed to warm to rt. In a second vessel (250 mL flask), 2-chloro-3,6-difluorobenzaldehyde (5 g, 27.5 mmol) was dissolved in a mixture of ous methanol (60 mL, 1483 mmol) and THF (25 mL, 305 mmol) and warmed to 60 °C. Whilst at 60 °C the sodium methoxide solution was slowly added to the reaction mixture. Once the addition was complete the reaction mixture was left to heat at 60 °C overnight. The solvent was removed under reduced pressure to give a bright yellow solid which was quenched with water (100 mL), sonicated and then left to stir for 30 min. The resulting yellow solid was filtered, washed with water and then left to dry under reduced pressure before erring to a vacuum oven at 40 °C overnight. The crude was purified by tography g with EtOAc/ iso-Hexane to afford the desired compound 2-chloro methoxy-benzaldehyde as an off white solid, 3.19 g, 61% yield.

[MH]+ = 1 2-Chlorodifluoromethylfluoromethoxy-benzene 2-Chlorofluoromethoxy-benzaldehyde (2 g, 10.61 mmol) was dissolved in anhydrous DCM (30 mL, 466 mmol) under a nitrogen filled balloon and cooled in a salt-ice bath. To the solution diet? iris: is (4.20 mL, 31.8 mmol) was added dropwise to form a yellow solution. The reaction was stirred at 0 °C for 5 min and then the cooling bath was removed and the reaction allowed to warm to rt overnight.

The reaction mixture was slowly ed into saturated sodium hydrogen carbonate (100 mL), the c layer was separated, washed with brine (100 mL) and dried using a phase separating cartridge.

The solvent was removed under reduced pressure to give an orange oil, which was purified by chromatography eluting with EtOAc / iso-Hexane. 2-Chlorodifluoromethylfluoromethoxy- benzene (1.0g, 43% yield) was isolated as a pale yellow oil which solidified on standing. 2-Difluoromethylfluoromethoxy-benzonitrile 2-Chlorodifluoromethylfluoromethoxy-benzene (1g, 4.75 mmol) was dissolved in anhydrous dimethylacetamide (7 mL, 74.7 mmol) to which ozinc (0.558 g, 4.75 mmol) was added. Nitrogen was bubbled into the reaction mixture for 20 min then, tris(dibenzylideneacetone)dipalladium(0) (0.087 WO 07983 g, 0.095 mmol) and [1,1’bis(diphenylphosphino)ferrocene]dichloropalladium(||) complex with dichloromethane (0.139 g, 0.190 mmol) were added. The reaction e was heated at 150 °C overnight under an atmosphere of nitrogen. The reaction mixture was quenched into water (100 mL) and then extracted with EtOAc (3 x 200 mL). The combined organics were washed with brine (3 x 200 mL), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a dark brown oil. The crude product was purified by tography eluting with EtOAc / iso-Hexane to afford 2- difluoromethylf|uoromethoxy-benzonitrile (182 mg, 17 % yield) as a brown solid.

[MH]+ = 202.1 (2-Difluoromethylfluoromethoxy-benzyl)-carbamic acid tert-butyl ester 2-(Difluoromethyl)fluoromethoxy-benzonitrile (182 mg, 0.778 mmol) was dissolved in anhydrous methanol (5 mL, 124 mmol) to which Nickel Chloride hexahydrate (19 mg, 0.078 mmol) was added followed by di-tert-butyl dicarbonate (343 mg, 1.556 mmol). The resulting pale green solution was cooled in an ice-salt bath to -5 °C and then sodium borohydride (206 mg, 5.45 mmol) was added nwise, maintaining the reaction temperature ”0 °C. The deep brown solution was left to stir at 0 °C and slowly allowed to warm to rt overnight. The t was removed under reduced pressure and then partitioned between DCM (10 mL) and water (10 mL). The aqueous was re-extracted with DCM (2 x 10 mL). The combined organics were washed brine (10 mL), dried using a phase separating cartridge and trated in vacuo. The crude product was purified by tography eluting with EtOAc/ iso-Hexane to give (2- difluoromethylf|uoromethoxy-benzyl)-carbamic acid tert-butyl ester as a white waxy solid (158 mg, 63% yield).

[MNa]+ = 328 2-Difluoromethylfluoromethoxy—benzylamine hydrochloride (2-Difluoromethylfluoromethoxy-benzyl)-carbamic acid tert-butyl ester (158 mg, 0.492 mmol) was taken up in iso-propyl alcohol (1 mL) and then HCl (6N in iso-propyl alcohol) (1 mL, 0.778 mmol) was added and d at 40 °C for 1 hour. An off white precipitate formed and was collected via vacuum filtration and washed with iso-propyl alcohol (1 mL) to give the desired product 2-difluoromethylfluoro methoxy—benzylamine hloride as an off white solid (43 mg, 22% yield).

[MH]+ = 206 3-Methoxymethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 2- difluoromethylfluoromethoxy-benzylamide hoxymethyl)(4-((2-oxopyridin-1(2H)-yl)methy|)benzyl)-1H-pyrazolecarboxylic acid (58 mg, 0.162 mmol), 2-difluoromethylfluoromethoxy—benzylamine hloride salt (40.2 mg, 0.163 mmol) and HATU (68.3 mg, 0.180 mmol) were suspended in anhydrous DCM (3 mL) to which ylamine (91 (1L, 0.653 mmol) was added, sonicated and then left to stir at rt for 3 hrs. The solvent was removed under reduced pressure and the residue quenched with ammonium chloride solution (5 mL), resulting in a pale brown solid which was left to stir rt over the weekend. The solid was filtered under reduced pressure washed with water, dried under reduced pressure and then placed in the desiccator at 50 °C for 3 hours. The desired product, oxymethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]—1H-pyrazole carboxylic acid 2-difluoromethylfluoromethoxy-benzylamide (74 mg, 83 % yield) was isolated as a free flowing cream solid.

[MH]+ = 541.2 NMR (d6-DMSO) 6 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) Reference Example G 5-Bromomethylfluoro-pyridine 2-Fuoromethylpyridine (5.0 g, 45 mmol) was ved in 1,2-dichloroethane (120 mL). To this solution was added N-bromosuccinimide (9.61 g, 54 mmol) and azobisisobutyronitrile (739 mg, 4.5 mmol). The reaction was stirred at reflux (95 °C) for 5 hours then the reaction was cooled to rt. The reaction mixture was diluted with CHC|3 (50 mL) and was washed with sat. NaHCOa (1 x 20 mL), water (1 x 20 mL), ed by brine (1 x 20 mL), dried 4) and filtered through PS paper and evaporated in vacuo. The residue was purified by chromatography (silica), eluting with 10% EtOAc, 90% Pet. Ether, to give a colourless oil identified as 5-bromomethylfluoro-pyridine, 5.9g, 69% yield.

[MH]+ = 191.876 NMR (CDCI3): 4.46 (2H, s), 6.93 (1H, dd,J = 8.4, 3.0Hz), 7.84 (1H, td,J = 7.8, 2.6Hz), 8.23 (1H, d,J = 2.2Hz) 1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester Ethyl 3-trifluoromethyl-1H-pyrazolecarboxylate (1.57g, ol) was dissolved in DMF (20 mL), 5- Bromomethylfluoro-pyridine (1.3g, 6.84mmol) and cesium carbonate (6.69g, 20.53mmol) were added.

The reaction mixture was d at 50 °C for 18 hours after which time the on mixture was diluted with EtOAc (100 mL), this solution was washed with water (1 x 30 mL), brine (1 x 30 mL), dried (NazSO4) and filtered through PS paper and evaporated in vacuo. The residue was purified by chromatography (silica), eluting with 85% Pet. Ether, 15% EtOAc to give a white foamy solid (1.26 g, 58% yield) identified as 1-(6-fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester.

[MMeCN]+= 358.75 1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic 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) were added. The reaction mixture was stirred at 50 °C for 18 hrs after which time the solvent was concentrated in vacuo and the residue taken up in EtOAc (50 mL). The s layer was extracted and acidified with 1M HCI to pH2 and extracted with CHCI3 (3 x 50 mL). The ed extracts were washed with water (1 x mL) ed by brine (1 x 30 mL), dried (NazSO4) and filtered through PS paper and evaporated in vacuo. The residue was purified by chromatography (silica), eluting with 3%MeOH, 97% CHCIg, to give a colourless oil identified as 1-(6-fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid, 946 mg, 82% yield.

[MH]+= 289.82 1-(6-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (300 mg, 1.04 mmol) was ved in dioxane (25 mL) and pyrrolidine (2 mL) and the reaction mixture was stirred at 80 °C for 18 hrs. Upon completion 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 4) and filtered through PS paper and evaporated in vacuo. The residue was purified by chromatography eluting with 1% AcOH, 9% MeOH, 90% CHC|3 to give a white foamy solid (267 mg, 76% yield) identified as 1-(6-pyrrolidinyl-pyridinylmethyl)- 3-trifluoromethyl-1H-pyrazolecarboxylic acid.

[MH]+= 340.72 1-(6-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 2-fluoro methoxy-benzylamide 2-Fluoromethoxy-benzylamine hydrochloride (56 mg, 0.294 mmol) and yrrolidinyl-pyridin ylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (100 mg, 0.294 mmol) were combined and taken up in DCM (10 mL) at 0 °C. To the solution was added HOBt (48 mg, 0.353 mmol), ylamine (205 uL, 1.469 mmol) and water soluble carbodiimide (79 mg, 0.411 mmol). The reaction was allowed to warm to rt and stirred for 3 days. The reaction was diluted with CHC|3 (50 mL) and sat. aq. NaHCOa (20 mL) was added. The organic layer was ted, dried (MgSO4), filtered and concentrated. The crude product was ed by chromatography eluting with MeOH / DCM to afford the desired product 1-(6-pyrrolidinyl- pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 2-fluoromethoxy-benzylamide as a white solid, 95 mg, 68% yield.

[MH]+ = 478.0 1H NMR (DMSO) 6: 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) REFERENCE EXAMPLE H N-{[2-Fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide o N/ N fl \ CH3 [M+H]+= 529.3 1H NMR: (d6-DMSO) 3.18 (3H, s), 4.26 (2H, d, J = 5.0Hz), 4.42 (2H, s), 5.06 (2H, s), 5.24 (2H, s), 6.19-6.23 (1H, m), 6.38 (1H, d, J = 9.2Hz), 7.19 (2H, d, J = 8.1Hz), 7.24 (2H, d, J = 8.2Hz), 7.38-7.45 (2H, m), 7.56-7.65 (2H, m), 7.74 (1H, dd, J = 6.8, 1.8Hz), 8.11 (1H, s), 8.18 (1H, t, J = 5.2Hz), 9.84 (1H, s) |C50 (human PKal) = 1.1 nM |C50 (human KLK1)= >40,000 nM nce Example | An analogue of example 7 from 0 CI Reference Example J An analogue of example 27 from fl PI)\ N N\ H (\N 0 / \CHS nce Example K An analogue of example 79 of the present application. kwWM.

Exam les ofthe resent invention EXAMPLE 39 0X0 ridin lmeth l hen l meth l razolecarboxamide A. 6-tert-Butoxycarbonylaminofluoromethoxy-benzoic acid methyl ester Methyl 6-bromofluoromethoxybenzoate (2.0g, 7.6mmol) was dissolved in dioxan (50 mL). tert—Butyl carbamate (980 mg, 8.4 mmol), 4,5-(bis(diphenylphospheno)-9,9-dimethylxanthene (440 mg, 0.76 mmol), palladium (M) acetate (171 mg, 0.76 mmol) and cesium carbonate (4.95 g, 15.2 mmol) were added and the reaction mixture was d under an atmosphere of en at 100 °C for 18 hrs after which time the reaction mixture was diluted with EtOAc (100 mL), filtered through Celite and the residue washed with EtOAc (50 mL). The combined filtrates were evaporated in vacuo. The residue was purified by flash tography (silica), eluent 10% EtOAc, 90% Pet Ether to give a yellow oil which solidified on standing and was identified as 6-tert-butoxycarbonylaminofluoromethoxy-benzoic acid methyl ester (2.09 g, 6.97 mmol, 92%).

B. (3-Fluorohydroxymethylmethoxy-phenyl)-carbamic acid tert-butyl ester —Butoxycarbonylaminofluoromethoxy-benzoic acid methyl ester (480 mg, 1.6 mmol) was dissolved in THF (50 mL) and cooled to 0 °C under en. A 2M solution of m borohydride in THF (1.6 mL,3.21 mmol) was added dropwise. After 18 hrs at rt saturated aqueous ammonium chloride was added slowly and the reaction mixture ted with EtOAc (3 x 50mL). The combined organic extracts were washed with water (1x30 mL), brine (1x30 mL), dried (Na2504) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 60% EtOAc, 40% Pet Ether to give a white solid identified as (3-fluorohydroxymethylmethoxy-phenyl)-carbamic acid tert-butyl ester (426 mg, 1.57 mmol, 98%).

[MH]+= 277.7 C. (6-Aminofluoromethoxy-phenyl)-methanol (3-Fluorohydroxymethylmethoxy-phenyl)-carbamic acid tert-butyl ester (426 mg, 1.57 mmol) was dissolved in 4M HCI in dioxan (50 mL). After one hour at rt the solvent was removed in vacuo to give a white solid identified as (6-aminofluoromethoxy-phenyl)-methanol (320 mg, 1.54 mol, 98%).

D. (2-Fluoromethoxytetrazolyl-phenyl)-methanol (6-Aminofluoromethoxy-phenyl)-methanol (320 mg, 1.54 mmol) was dissolved in acetic acid (20 mL). Trimethyl ormate (491 mg, 4.62 mmol) and sodium azide (301 mg, 4.62 mmol) were added.

The reaction mixture was stirred at rt for 18 hrs after which time the reaction e was poured into water (50 mL) and extracted with EtOAc (2x 100 mL). This solution was washed with water (1x30 mL), brine (1x30 mL), dried (Na2504) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 60% EtOAc, 40% Pet Ether to give a yellow oil identified as (2-fluoro methoxytetrazolyl-pheny|)-methanol (160mg, 0.71mmol, 46%).

[M+H]+= 225.2 E. 1-(2-Bromomethylfluoromethoxy-phenyl)-1H-tetrazole (2-Fluoromethoxytetrazolyl-pheny|)-methanol (160 mg, 0.71 mmol) was dissolved in dichloromethane (50 mL). To this solution was added phosphorous tribromide (386 mg, 1.43 mmol). The reaction mixture was stirred at rt for 18 hrs and diluted with CHC|3 (100 mL), washed with sat. NaHCOa (1x30 mL), water (1x30 mL), brine (1x30 mL), dried (Na2504) and evaporated in vacuo to give a white solid identified as 1-(2-bromomethylfluoromethoxy-phenyl)-1H-tetrazole which was used without further purification (204 mg, 71 mmol, 100%).

[M+H+MeCN]+= 330.1 F. 1-(2-Azidomethylfluoromethoxy-phenyl)-1H-tetrazole 1-(2-Bromomethylfluoromethoxy-phenyl)-1H-tetrazole (205 mg, 0.71 mmol) was ved in DMF (20 mL). Sodium azide (93 mg, 1.43 mmol) was added. The reaction mixture was stirred at rt for 18 hrs after which time the on mixture was diluted with EtOAc (100mL). This solution was washed with water (1x30 mL), brine (1x30 mL), dried (Na2504) and evaporated in vacuo. The residue was ed by flash chromatography (silica), eluent 60% Pet Ether, 40% EtOAc to give a white solid identified as 1-(2- ethylfluoromethoxy-phenyl)-1H-tetrazole (128 mg, 0.51 mmol, 72%).

[M+H+MeCN]+= 291.2 G. 2-Fluoromethoxytetrazolyl-benzylamine 1-(2-Azidomethylfluoromethoxy-phenyl)-1H-tetrazole (128 mg, 0.51 mmol) was dissolved in MeOH (40 mL) This solution was hydrogenated over 10% Pd/C (50 mg) at heric pressure for 2 hrs after which time the catalyst was filtered off through Celite and the residue washed with MeOH (100 mL). The combined filtrates were evaporated in vacuo to give a yellow oil identified as 2-fluoromethoxy tetrazolyl-benzylamine (100 mg, 0.45 mmol, 87%).

H. N-{[2-F|uoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide oxymethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (65 mg, 0.18 mmol) was dissolved in DCM (30 mL). (2-(1H-benzotriazolyl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (84mg, 0.22mmol) and isopropylethyamine (48 mg, 0.37 mmol) were added at rt. After 20 min 2-fluoromethoxytetrazolyl-benzylamine (43 mg, 0.19 mmol) was added and the reaction mixture d at rt for 18 hrs. The reaction mixture was diluted with CHC|3 (50 mL) and washed with sat NaHCOa (aq) (1x30 mL), water (1x30 mL), brine (1x30 mL), dried 4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography (silica), eluent 5% MeOH, 95% CHC|3 to give a white solid identified as the title compound (111 mg, 0.2 mmol, 47%).

[MH]+ = 559.4 1H NMR: (d6-DMSO) 6: 3.18 (3H, s), 3.94 (3H, s), 4.22 (2H, d, J = 4.8Hz), 4.41 (2H, s), 5.06 (2H, s), 5.24 (2H, s), 6.20-6.23 (1H, m), 6.39 (1H, d, J = 9.0Hz), 7.19 (2H, d, J = 8.2Hz), 7.24 (2H, d, J = 8.2Hz), 7.33-7.43 (3H, m), 7.75 (1H, dd,J = 6.8, 1.9Hz), 8.11 (1H, s), 8.15 (1H, t, J = 5.2Hz), 9.73 (1H, s) EXAMPLE 86 1- 2- 3 3-Difluoro rrolidin | rimidin | meth | -N- 2-fluoromethox 1 2 3 4-tetrazol | hen Imeth l methox meth | razolecarboxamide WO 07983 A. 2-(3,3-Difluoro-pyrrolidinyl)-pyrimidinecarboxylic acid ethyl ester Ethylchloropyrimidinecarboxylate (1.5 g, 8.04 mmol) was dissolved in dioxan (50 mL). 3,3- Difluoropyrrolidine hydrochloride (1.73 g, 12.06 mmol) and ylamine (2.44 g, 24.1 mmol) were added and the reaction mixture was stirred at 80 °C for 18 hrs after which time 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 (Na2504) and evaporated in vacuo. The e was purified by flash chromatography (silica), eluent 1% MeOH, 99% CHC|3 to give a pale yellow solid identified as 2- 3 3-difluoro- rrolidin l - rimidine-S- carboxylic acid ethyl ester (1.4 g, 5.44 mmol, 68% yield).

[MH]+= 258.2 B. [2-(3,3-Difluoro-pyrrolidinyl)-pyrimidinyl]-methanol 2- 3 3-Difluoro- in l - rimidinecarbox lic acid eth l ester (1.4 g, 5.44 mmol) was dissolved in toluene (50 mL). This solution was cooled to -78 °C under nitrogen and DIBAL (1M solution in toluene) (16.33 mL,16.33 mmol) was added dropwise. After 90 mins at this temperature the reaction was allowed to warm to rt and stirred for 2 hrs. The reaction mixture was cooled to 0 °C and 2M HCI was added se followed by iced water (50 mL). The precipitate was filtered off through Celite and the filtrate basified to pH9 with sodium carbonate. The organic layer was separated and the aqueous layer extracted with EtOAc (3 x 100 mL). The ed organic extracts were washed with water (1 x 30 mL), bine (1 x 30 mL), dried (Na2504) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 4% MeOH, 96% CHC|3 to give a white solid identified as [2-(3,3-difluoro- pyrrolidinyl)-pyrimidinyl]-methanol (650 mg, 3.02 mmol, 55% yield).

[MH]+= 216.3 C. Acetic acid 2-(3,3-difluoro-pyrrolidinyl)-pyrimidinylmethyl ester [2-(3,3-Difluoro-pyrrolidin-l—yl)-pyrimidinyl]-methanol (650 mg, 3.02 mmol) was dissolved in DCM (50 mL). This on was cooled to 0 °C, acetic anhydride (463 mg, 4.53 mmol), 4-(dimethylamino)pyridine (185 mg, 1.51 mmol) and pyridine (1.2 g, 15.1 mmol) were added. The reaction mixture was allowed to reach rt and stirred at rt for 2 hrs after which time the reaction mixture was diluted with CHC|3 (50 mL), washed with water (1 x 30 mL), brine (1 x 30 mL), dried (Na2504) and evaporated in vacuo. The residue was puried by flash chromatography a) eluent 80% Pet. Ether, 20% EtOAc to give a white solid identified as acetic acid 2-(3,3-difluoro-pyrrolidin-l—yl)-pyrimidinylmethyl ester (737 mg, 2.87 mmol, 95% yield).

[MH]+= 258.2 D. 2-[2-(3,3-Difluoro-pyrrolidinyl)-pyrimidinylmethyl]methoxymethyl-1H-pyrazole ylic acid methyl ester Acetic acid 2-(3,3-difluoro-pyrrolidin-l—yl)-pyrimidinylmethyl ester (695 mg, 2.7 mmol) was dissolved in dry acetonitrile (50 mL). To this solution was added methyl 3-(methoxymethyl)-1H-pyrazole carboxylate (CAS no. 3184961 (synthesised according to the method described in WO 2012/009009)) (460 mg, 2.7 mmol) and trimethylsilyl te (1.076 mL, 5.95 mmol). The reaction mixture was d at 80 °C for 18 hrs after which time the solvent was removed in vacuo and the e taken up in EtOAc (50 mL), washed with water (1 x 30 mL), brine (1 x 30 mL), dried (Na2504) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient from 30% Pet Ether, 70% EtOAc to 100% EtOAc to afford two isomeric products. The faster running product was identified as the undesired regioisomer. The slower running product afforded a yellow oil and was identified as 2-[2-(3,3-difluoro-pyrrolidinyl)-pyrimidinylmethyl]methoxymethyl-1H-pyrazole carboxylic acid methyl ester (210 mg, 0.57 mmol, 21% yield).

[MH]+= 368.3 E. 1-[2-(3,3-Difluoro-pyrrolidinyl)-pyrimidinylmethyl]methoxymethyl-1H-pyrazolecarboxylic 2-[2-(3,3-Difluoro-pyrrolidiny|)-pyrimidinylmethyl]methoxymethyl-1H-pyrazolecarboxylic acid methyl ester (210 mg, 0.57 mmol) was dissolved in THF (50 mL) and water (5 mL). Lithium hydroxide (68 mg, 2.86 mmol) was added. The reaction mixture was stirred at room temperature for 18 hrs after which time the reaction mixture was concentrated in vacuo and the residue was acidified with 1M HCI to pH2 and extracted CHC|3 (3 x50 mL). The combined extracts were washed with water (1 x 30 mL), brine (1 x 30mL), dried (Na2504) and evaporated in vacuo to give a white solid identified as 1-[2- ifluoro-pyrrolidiny|)-pyrimidinylmethyl]methoxymethyl-1H-pyrazolecarboxylic acid (130 mg, 0.37 mmol, 64% yield).

[MH]+= 354.2 F. 1-{[2-(3,3-Difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4-tetrazol- 1-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide 1-[2-(3,3-Difluoro-pyrrolidiny|)-pyrimidinylmethyl]methoxymethyl-1H-pyrazolecarboxylic acid (130 mg, 0.37 mmol) was dissolved in DCM (30 mL). (2-(1H-Benzotriazolyl)-1,1,3,3- tetramethyluronium hexafluorophosphate) (167 mg, 0.44 mmol) and N,N-diisopropylethyamine (143 mg, 1.1 mmol) were added at rt. After 20 min 2-fluoromethoxytetrazolyl-benzylamine (90 mg, 0.40 mmol) was added and the reaction mixture stirred at rt for 18 hrs. The on mixture was diluted with CHC|3 (50 mL) and washed with sat NaHCOa (aq) (1 x 30 mL), water (1 x 30 mL), brine (1 x 30 mL), dried (Na2504) and evaporated in vacuo to give a yellow oil. The e was purified by flash chromatography (silica), eluent 4% MeOH, 96% CHC|3 to give a white solid identified as 1-{[2-(3,3- difluoropyrrolidiny|)pyrimidinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4-tetrazol yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide (112 mg, 0.2 mmol, 55% yield).

[MH]+= 559.3 1H NMR (d6-DMSO) 5: .57 (2H, m), 3.18 (3H, s), 3.69 (2H, t,J=7.4 Hz), 3.87 (2H, t,J= ), 3.94 (3H, s), 4.22 (2H, d,J = 4.7Hz), 4.41 (2H, s), 5.15 (2H, s), 7.37-7.41 (2H, m), 8.09 (1H, s), 8.14 (1H, t, J = 5.2 Hz), 8.41 (2H, s), 9.73 (1H, s) EXAMPLE 79 N- 2-Fluoromethox 1 2 3 4-tetrazol | hen | meth | methox meth l 2- rrolidin- 1- | rimidin | meth | razolecarboxamide A. N-{[2-F|uoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide 3-Methoxymethyl(2-pyrrolidinyl-pyrimidinylmethyl)-1H-pyrazolecarboxylic acid (CAS no. 1938129—73-7 (synthesised according to the method described in WO 2016083816)) (200 mg, 0.63 mmol) was dissolved in DCM (30 mL). (2-(1H-Benzotriazolyl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (287 mg, 0.76 mmol) and N,N-diisopropylethyamine (244 mg, 1.89 mmol) were added at rt. After 20 min 2-fluoromethoxytetrazolyl-benzylamine (143 mg, 0.64 mmol) was added and the reaction e stirred at rt for 18 hrs. The reaction mixture was diluted with CHC|3 (50 mL) and washed with sat NaHCOa (aq) (1 x3 0 mL), water (1 x 30 mL), brine (1 x 30 mL), dried (Na2504) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography (silica), eluent 4% MeOH, 96% CHCI3 to give a white solid identified as N-{[2-fluoromethoxy(1,2,3,4- tetrazolyl)phenyl]methyl}(methoxymethyl){[2-(pyrrolidinyl)pyrimidinyl]methyl}pyrazole carboxamide (230 mg, 0.44 mmol, 70% yield).

[MH]+= 523.4 1H NMR(d6-DMSO)6: 1.89-1.92 , 3.18 (3H, s), 3.45 (4H, t,J=6.7Hz), 3.93 (3H, s), 4.21 (2H, d,J = 4.6Hz), 4.42 (2H, s), 5.10 (2H, s), 7.33-7.41 (2H, m), 8.07 (1H, s), 8.15 (1H, t, J = 4.9 Hz), 8.33 (2H, s), 9.73 (1H,S) WO 07983 Table 1 0 R18 \ N \ N H \ / I 0 R15 N CH3 Example number R14 R15 R18 Free Base MW [M+H]+ 1 F MeO absent 478.5 479.3 Table 2 \ N \ K N\ H I I N/ Q / L O Y Example Free Base R5 Q R15 L K J [M+H]+ number MW 2 CH20Me C-F MeO CH N N 492.5 3 CH20Me C-H MeO CH N N 474.5 4 CH20Me C-H MeO N CH N 474.5 475.3 NHz C-F MeO CH CH N 462.5 463.3 6 CF3 C-F MeO CH CH N 515.5 516.3 7 NMez C-F MeO CH CH N 490.5 491.4 8 CH20Me C-H MeO N CH C-CN 498.5 499.3 9 CH20Me C-F MeO N CH C-CN 516.5 WO 07983 Example Free Base R5 Q R15 L K [M+H]+ number MW CHzoMe N MeO CH CH 474.5 475.3 Table 3 N R17 \ N \ N\ H N / N \CH3 Example Free Base T R14 R15 R16 R17 [M+H]+ number MW 11 H Me OMe Me H 501.6 502.4 12 H CN OMe H H 498.5 13 H CN H H H 468.5 469.3 14 H CHFz OMe H H 523.5 H H OMe Cl H 508.0 525.3 16 H CN H Cl H 503.0 [M+Na]+ 17 H F H Cl H 495.9 496.3 18 H F Cl H H 495.9 19 H F H Me H 475.5 H H OMe Me H 487.6 488.3 21 H CN H Me H 482.5 22 H Me OMe H H 487.6 488.3 23 H CN H H OMe 498.5 24 H F OMe H CHFz 541.5 H F OMe CHFz H 541.5 26 H F H F H 479.5 480.3 27 H F H H Me 475.5 476.3 28 H F Me H H 475.5 476.3 29 H Cl Me H H 492.0 492.3 F F OMe H H 509.5 510.3 WO 07983 Table 4 O R14 N H \/ W15 N N\N O \ / O N CH3 Example number R14 R15 Free Base MW [M+H]+ 31 H OMe 476.5 477.4 32 CI OMe 511.0 33 Me OMe 490.6 34 CI H 480.9 481.2 Table 5 0 R18 N H R1 16 \ R15 Example R5 R14 R15 R16 R17 R18 Free Base MW [M+H]+ number NHz OMe H H 479.5 480.3 36 CH20Me OMe H OMe 538.5 37 CH20Me CN H H OMe H 497.5 498.3 38 CH20Me CN OMe H H H 497.5 498.3 wo 2017/207983 2017/051546 Example R5 R14 R15 R16 R17 R18 Free Base MW [M+H]+ number 39 CHzoMe F OMe H H 5 ‘ N I 558.6 559.4 40 CHzoMe H OMe H H 5 ‘ N I 540.6 541.4 41 CHzoMe H OMe H H Me 486.6 487.4 42 CHzoMe F OMe H H CONHz 533.6 534.4 43 NHz F OMe H H CN 486.5 487.3 44 NMez F OMe H H CN 514.6 515.4 45 NHz H OMe H H CN 468.5 46 NMez H OMe H H CN 496.6 47 NHz H OMe H H CFg 511.5 48 NHz H OMe H H CHFz 493.5 49 CHzoMe H F H H 5 ‘ N I 528.5 529.3 50 NMez F OMe H H F 507.5 Table 6 0 R14 \ N CH3 /\N H A \N/ / WO 07983 Example Free Base [M+H]+ A R5 R14 number MW 1 \ / 51 Q CHzoMe F 516.5 517.3 \ N \ \ / 52 CHzoMe F 516.5 517.3 \ N 53 CHzoMe F 533.5 534.3 \ N 1 \ / 54 CH20Me H 498.5 \ N \ \ / 55 CH20Me H 498.5 \ N e Free Base [M+H]+ A R5 R14 number MW 56 CHzoMe H 515.5 \ N 57 Q@ CHzoMe F 519.6 520.2 Table 7 0 R18 N H N \ F \ 0 Example [NH-l] v R5 R18 Free Base MW number 58 N CHzoMe CN 479.5 480.3 59 N CFg CN 503.5 Table la 0 R18 \ N \ N\ H / I N / /N\ 0 R15 N \CH3 Example number R14 R15 R18 U Free Base MW [M+H]+ 60 F MeO j N I C 545.6 546.4 \N/ N/ 61 H MeO j N I C 527.6 528.4 \N/ N/ 62 F H j ‘N I c 515.5 \N/ N/ wo 2017/207983 2017/051546 Table 53 0 R18 R1 16 \ R15 Example R5 R14 R15 R16 R17 R18 Free Base MW [M+H]+ number 63 CFg j ‘N I H H OMe H 564.5 64 CFg 3‘” I H H H F 552.5 553.3 65 NHz 5‘” I H H OMe F 529.5 66 NH2 5 ‘N I H H OMe H 511.5 67 NHz 5‘” I H H H F 499.5 68 NMez 5‘” I H H OMe F 557.6 wo 2017/207983 2017/051546 Example R5 R14 R15 R16 R17 R18 Free Base MW [M+H]+ number 69 NMez j ‘N\ I H H OMe H 539.6 70 NMez j ‘N\ I H H H F 527.6 71 NH2 5 ‘N\ I H H CI H 516.0 516.3 72 CHzoMe 5‘N\ I H H CI H 545.0 545.3 73 CHzoMe 5‘N\ I H H H CI 545.0 545.3 74 CHzoMe 3‘N\ I H H H H 510.6 511.3 75 CHzoMe 5‘N\ I H H H Me 524.6 76 CHzoMe CN H H H F 485.5 Table 73 N \ R1 Example Free Base v R5 R14 R15 R18 [M+H]+ number MW 77 CH CHzoMe F OMe j ‘ N I 521.5 522.4 78 CH CHzoMe H OMe j ‘ N I 503.6 79 N CHzoMe F OMe j ‘ N I 522.5 523.4 80 N CHzoMe H OMe j ‘ N I 504.5 505.4 81 CH CHzoMe F H j ‘ N I 491.5 82 N CHzoMe F H j ‘ N I 492.5 WO 07983 Example Free Base v R5 R14 R15 R18 [M+H]+ number MW 83 CH CF3 F OMe j N I 545.5 546.1 84 CH CFg H OMe I ‘N I 527.5 85 CH CFg F H 3 ‘ N I 515.5 Table 7b 0 R18 N H / R1 N \ 5 \ O V \CH3 Example Free Base v R5 R14 R18 [M+H]+ number MW 86 N CH20Me F j N\ I 558.5 559.3 87 CH CH20Me F j N\ I 557.5 558.1 88 N CH20Me H j N I 540.5 541.2 89 CH CHzoMe H I 539.5 \ N Table 8: Comgound names Example Number 1 N-[(3-f|uoromethoxypyridin-Z-yl)methyl](methoxymethy|)({4-[(4- methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide 2 N-[(4-f|uoro-S-methoxypyridazinyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 3 3-(methoxymethyl)-N-[(5-methoxypyridazinyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 4 3-(methoxymethyl)-N-[(6-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 3-amino-N-[(3-fluoromethoxypyridin-Z-yl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 6 N-[(3-f|uoromethoxypyridin-Z-yl)methyl]({4-[(2-oxopyridin hy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide 7 3-(dimethylamino)-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide 8 N-[(5-cyano-Z-methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide 9 N-[(5-cyanofluoro-Z-methoxypyridinyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 3-(methoxymethyl)-N-[(4-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methy|)pyrazoIecarboxamide 11 N-[(4-methoxy-3,5-dimethylpyridin-Z-yl)methyl](methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide Example Number 12 N-[(3-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin- 1-y|)methyl] }methy|)pyrazoIecarboxamide 13 N-[(3-cyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 14 N-{[3-(dif|uoromethy|)methoxypyridinyl]methy|}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide N-[(5-ch|oromethoxypyridin-Z-yl)methyl]—3-(methoxymethy|)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methy|)pyrazoIecarboxamide 16 N-[(5-ch|orocyanopyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 17 N-[(5-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 18 N-[(4-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 19 N-[(3-f|uoro-S-methylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide N-[(4-methoxymethy|pyridinyl)methyI](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 21 N-[(3-cyanomethy|pyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide 22 N-[(4-methoxymethy|pyridinyl)methyI](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 23 N-[(3-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin- 1-y|)methy|]pheny|}methyl)pyrazoIecarboxamide 24 N-{[6-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methy|}(methoxymethy|)- 1-({4-[(2-oxopyridiny|)methyl]phenyl}methyl)pyrazoIecarboxamide N-{[5-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methy|}(methoxymethy|)- [(2-oxopyridiny|)methyl]phenyl}methyl)pyrazoIecarboxamide 26 N-[(3,5-difluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methy|)pyrazoIecarboxamide Example Number 27 N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide 28 N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]pheny|}methy|)pyrazoIecarboxamide 29 N-[(3-ch|oromethy|pyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 1-({4-[(5-f|uoro-Z-oxopyridin-l—y|)methyl]pheny|}methy|)-N-[(3-fluoro methoxypyridin-Z-yl)methyI](methoxymethy|)pyrazoIecarboxamide 31 N-[(5-methoxymethylpyrazoly|)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 32 N-[(4-chloro-S-methoxy-l—methylpyrazoly|)methyI](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 33 N-[(5-methoxy-1,4-dimethylpyrazoly|)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 34 N-[(4-ch|oromethy|pyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin- 1-yl)methyl]pheny|}methy|)pyrazoIecarboxamide 3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 36 N-[(2,6-difluoro-3,5-dimethoxyphenyl)methyl](methoxymethyl)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 37 N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 38 N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 39 f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|)- 1-({4-[(2-oxopyridiny|)methyl]phenyl}methyl)pyrazoIecarboxamide 40 N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 41 N-[(5-methoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide Number 42 N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 43 3-amino-N-[(6-cyanof|uoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 44 N-[(6-cyanof|uoromethoxyphenyl)methyl]—3-(dimethylamino)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 45 3-amino-N-[(2-cyanomethoxyphenyl)methyl]({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide 46 N-[(2-cyanomethoxyphenyl)methyl](dimethylamino)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 47 3-amino-N-{[5-methoxy-Z-(trifluoromethy|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 48 3-amino-N-{[2-(dif|uoromethy|)methoxyphenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 49 N-{[5-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(2- idin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 50 N-[(2,6-difluoromethoxyphenyl)methyl](dimethylamino)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide 51 N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- oxopyridin-l—y|)methyl]pyridin-Z-y|}methy|)pyrazoIecarboxamide 52 N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l—y|)methy|]pyridiny|}methy|)pyrazoIecarboxamide 53 N-[(6-cyanofluoromethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methyl]phenyl}methy|)(methoxymethyl)pyrazoIecarboxamide 54 N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({5-[(2-oxopyridin y|)methyl]pyridin-Z-yl}methy|)pyrazoIecarboxamide 55 N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({6-[(2-oxopyridin y|)methyl]pyridinyl}methy|)pyrazoIecarboxamide 56 N-[(2-cyanomethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methyl]phenyl}methy|)(methoxymethyl)pyrazoIecarboxamide Example Number 57 N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2- oxopiperidin-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide 58 N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrro|idin- 1-y|)pyrimidin-S-yl]methy|}pyrazo|ecarboxamide 59 N-[(6-cyanofluoromethoxyphenyl)methyl]{[2-(pyrrolidin-l—y|)pyrimidin-S- yl]methyl}(trif|uoromethyl)pyrazoIecarboxamide f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|)- 60 1-({4-[(4-methy|pyrazol-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(4- 61 methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(4- 62 methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin 63 y|)methy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide N-{[2-f|uoro(1,2,3,4-tetrazoIyl)pheny|]methy|}({4-[(2-oxopyridin 64 y|)methy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide o-N-{[2-fluoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- 65 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 3-amino-N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin- 66 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide 3-amino-N-{[2-fluoro(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin 67 y|)methyl]phenyl}methyl)pyrazoIecarboxamide 3-(dimethylamino)-N-{[2-fluoromethoxy(1,2,3,4-tetrazoly|)pheny|]methyI} 68 ({4-[(2-oxopyridin-l—yl)methyl]phenyl}methyl)pyrazoIecarboxamide 3-(dimethylamino)-N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- 69 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 3-(dimethylamino)-N-{[2-fluoro(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- 70 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 3-amino-N-{[5-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin 71 y|)methyl]phenyl}methyl)pyrazoIecarboxamide Example Number N-{[5-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- 72 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide N-{[2-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- 73 idin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide 3-(methoxymethyl)({4-[(2-oxopyridiny|)methy|]pheny|}methy|)-N-{[2-(1,2,3,4- 74 tetrazol-l—y|)phenyl]methyl}pyrazo|ecarboxamide 3-(methoxymethyl)-N-{[2-methy|—6-(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- 75 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide N-[(2-cyanof|uorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin 76 hyl]phenyl}methyl)pyrazoIecarboxamide N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|)- 77 1-{[6-(pyrro|idiny|)pyridinyl]methyl}pyrazolecarboxamide N-{[5-methoxy(1,2,3,4-tetrazoly|)pheny|]methyl}(methoxymethy|){[6- 78 (pyrrolidin-l—y|)pyridinyl]methyl}pyrazolecarboxamide N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|)- 79 1-{[2-(pyrro|idiny|)pyrimidin-S-yl]methy|}pyrazoIecarboxamide N-{[5-methoxy(1,2,3,4-tetrazoly|)pheny|]methyl}(methoxymethy|){[2- 80 (pyrrolidin-l—y|)pyrimidin-S-yl]methy|}pyrazo|ecarboxamide N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|){[6- 81 lidin-l—y|)pyridinyl]methyl}pyrazolecarboxamide N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|){[2- 82 (pyrrolidin-l—y|)pyrimidin-S-yl]methy|}pyrazo|ecarboxamide N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}{[6-(pyrro|idin 83 y|)pyridinyl]methyl}(trif|uoromethy|)pyrazoIecarboxamide N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}{[6-(pyrrolidin-l—y|)pyridin- 84 3-yl]methy| }(trif|uoromethy| )pyrazoIecarboxam ide N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}{[6-(pyrro|idiny|)pyridin 85 yl]methyl}(trif|uoromethyl)pyrazoIecarboxamide 1-{[2-(3,3-difluoropyrrolidin-l—y|)pyrimidin-S-yl]methy|}-N-{[2-fluoromethoxy 86 (1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|)pyrazoIecarboxamide Example Number 1-{[6-(3,3-difluoropyrrolidin-l—yl)pyridinyl]methyl}-N-{[2-fluoromethoxy 87 (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide 1-{[2-(3,3-difluoropyrrolidin-l—yl)pyrimidin-S-yl]methyl}-N-{[5-methoxy(1,2,3,4- 88 tetrazol-l—yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide (3,3-difluoropyrrolidin-l—yl)pyridinyl]methyl}-N-{[5-methoxy(1,2,3,4- 89 tetrazol-l—yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide Table 9: NMR data of examples (solvent d6 DMSO) Example Chemical shift Number 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 Reference (2H, s), 6.22 (1H, td,J = 6.7, 1.4Hz), 6.37 (1H, t, J = 2.3Hz), 6.40 (1H, dd, J = 9.2, Example A 1.4Hz), 6.44 (2H, d,J = 2.3Hz), 7.20-7.29 (4H, m), 7.41 (1H, ddd, J = 9.1, 6.6, , 7.76 (1H, dd,J = 6.8, 2.1Hz), 8.24 (1H, s), 8.32 (1H, t,J = 5.9Hz). 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- Reference 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 Example B (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). 3.82 (3H, s), 4.41 (2H, d,J = 5.8Hz), 4.54 (2H, s), 5.57 (2H, s), 6.87-6.91 (1H, m), Reference 7.03-7.09 (2H, m), 7.67 (1H, dd, J = 8.8, 2.1Hz), 8.07 (1H, d, J = 8.8Hz), 8.10 (1H, Example C d, J = 1.9Hz), 8.30 (1H, d, J = 1.7Hz), 8.37 (1H, s), 8.39 (1H, t, J = 5.8Hz), 8.92 (1H, d, J = 2.2Hz) 3.25 (3H, s), 3.92 (3H, s), .57 (4H, m), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, nce 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 Example D (1H,ddd,J=2.1, 6.6, ,7.75(1H,ddd,J=0.7, 2.1, 6.8Hz),8.21-8.29(2H, m), 8.42 (1H, t,J = 5.4Hz) 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, Reference td, J = 6.7, 1.4Hz), 6.39 (1H, d, J = , 7.17-7.31 (5H, m), 7.40 (1H, ddd,J = Example E 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 Chemical shift Number 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), Reference 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 Example F (1H, ddd,J = 0.7, 2.1, 6.8Hz), 8.08 (1H, t, J = 4.9Hz), 8.22 (1H, s) 1.90-1.94 (4H, m), 3.31-3.37 (4H, m), 3.82 (3H, s), 4.39 (2H, d,J = 5.6Hz), Reference 5.26(2H, s), 6.44 (1H, d,J = 8.6Hz), .90 (1H, m), 7.03-7.10 (2H, m), 7.50 Example 6 (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) 1.98 (3H, s ), 3.31 (3H, s), 3.92 (3H, s), 4.51 (2H, s), 4.53 (2H, dd, J = 5.4, 2.0Hz), .21 (2H, s), 5.28 (2H, s), 7.16-7.23 (6H, m), 7.52 (1H, s), 8.23 (1H, s), 8.25 (1H, d, J = 3.1Hz), 8.42 (1H, t,J = 5.2Hz) 3.24 (3H, s), 3.90 (3H, s), 4.39 (2H, d, J = 5.8Hz), 4.54 (2H, s), 5.07 (2H, s), 5.30 (2H, s), 6.22 (1H, dt, J = 6.8, , 6.39 (1H, d, J = 8.8Hz), 6.76 (1H, d, J = 0.7Hz), 7.25 (2H, d, J = , 7.28 (2H, d, J = , 7.39-7.43 (1H, m), 7.76 (1H, dd,J = 6.7, 2.2Hz), 8.28 (1H, s), 8.51 (1H, t, J = 5.8Hz), 8.72 (1H, d, J = 0.9Hz) 3.91 (3H, s), 4.46 (2H, dd, J = 5.6, 2.0Hz), 5.03 (2H, s), 5.06 (2H, s), 5.34 (2H, s, br), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 8.8Hz), 7.15-7.18 (1H, m), 7.19 (2H, d,J = , 7.26 (2H, d, J = 8.2Hz), 7.38-7.43 (1H, m), 7.75 (1H, dd, J = 6.8, 2.0Hz), 8.01 (1H, s), 8.21 (1H, d, J = 5.5Hz), 8.23 (1H, s) 3.92 (3H, s), 4.49 (2H, dd, J = 5.6, 2.0Hz), 5.08 (2H, s), 5.40 (2H, s), 6.21-6.24 (1H, m), 6.40 (1H, d, J = 9.0Hz), 7.16-7.25 (1H, m), 7.29 (4H, s), 7.39-7.43 (1H, m), 7.76 (1H, dd, J = 6.8, 2.0Hz), 8.21 (1H, d, J = 5.5Hz), 8.44 (1H, s), 8.70 (1H, t, J = 5.4Hz) 2.69 (6H, s), 3.92 (3H, s), 4.53 (2H, dd,J = 5.9, 2.0Hz), 5.07 (2H, s), 5.15 (2H, s), 6.20-6.24 (1H, m), 6.40 (1H, d, J = 8.9Hz), 7.16-7.28 (4H, m), 7.39-7.43 (1H, m), 7.76 (1H, dd, J = 6.9, 1.9Hz), 8.04 (2H, s), 8.23 (1H, d, J = 5.5Hz), 8.32 (1H, t,J = .4Hz) 3.23 (3H, s), 3.92 (3H, s), 4.49 (2H, d, J = 5.6Hz), 4.55 (2H, s), 5.08 (2H, s), 5.31 (2H, s), 6.21-6.25 (1H, m), 6.40 (1H, d, J = 9.6Hz), 6.84 (1H, s), 7.22-7.32 (4H, m), .43 (1H, m), 7.76 (1H, dd, J = 6.8, 1.9Hz), 8.28 (1H, s), 8.58 (1H, t, J = 5.7Hz) 8.66 (1H, s) 3.26 (3H, s), 3.89 (3H, s), 4.50 (2H, d, J = , 4.54 (2H, s), 5.07 (2H, s), 5.30 (2H, s), 6.20-6.24 (1H, m), 6.40 (1H, d, J = 8.8Hz), 6.81 (1H, d,J = 5.7Hz), 7.23- 7.28 (4H, m), 7.39-7.43 (1H, m), 7.76 (1H, dd, J = 6.5, 1.9Hz), 8.27 (1H, s), 8.41- 8.47 (2H, m) Chemical shift Number 11 2.28 (3H, s), 2.34 (3H, s), 3.24 (3H, s), 3.95 (3H, s), 4.52 (2H, s), 4.59 (2H, d,J = .2Hz), 5.07 (2H, s), 5.30 (2H, s), 6.21-6.25 (1H, m), 6.39 (1H, d, J = 8.8Hz), 7.24- 7.29 (4H, m), 7.39-7.44 (1H, m), 7.77 (1H, dd, J = 6.7, 1.9Hz), 8.26 (1H, s), 8.24 (1H, s), 8.60 (1H, t, J = 5.0Hz) 13 3.31 (3H, s), 4.52 (2H, s), 4.70 (2H, d, J = 5.4Hz), 5.07 (2H, s), 5.29 (2H, s), 6.22 (1H, td, J = 6.6, 1.3Hz), 6.39 (1H, d, J = 8.9Hz), 7.22-7.29 (4H, m), 7.38-7.43 (1H, m), 7.51 (1H, dd, J = 7.9, 4.9Hz), 7.76 (1H, dd, J = 6.8, , 8.26 (1H, s), 8.30 (1H, dd, J = 7.9, 1.6Hz), 8.62 (1H, t, J = , 8.79 (1H, dd, J = 6Hz) 16 3.25 (3H, s), 4.52 (2H, s), 4.66 (2H, d, J = 5.4Hz), 5.07 (2H, s), 5.29 (2H, s), 6.22 (1H, td, J = 6.6, 1.3Hz), 6.40 (1H, d, J = 8.9Hz), 7.22-7.28 (4H, m), 7.39-7.43 (1H, m), 7.76 (1H, dd,J = 6.6, 1.9Hz), 8.25 (1H, s), 8.59 (1H, d, J = 2.4Hz), 8.64 (1H, t, J = 5.3Hz), 8.87 (1H, d,J = 2.4Hz) 17 3.25 (3H, s), 4.48-4.56 (4H, m), 5.07 (2H, s), 5.28 (2H, s), 6.20-6.24 (1H, m), 6.40 (1H, d, J = 9.0Hz), 7.21-7.28 (4H, m), 7.39-7.43 (1H, m), 7.75 (1H, dd,J = 6.6, 1.9Hz), 8.07 (1H, dd, J = 9.8, 1.9Hz), 8.25 (1H, s), 8.46-8.56 (2H, m) 2.20 (3H, s), 3.22 (3H, s), 4.05 (3H, s), 4.55 (2H, s), 4.63 (2H, d, J = 5.5Hz), 5.07 (2H, s), 5.32 (2H, s), 6.23 (1H, dt, J = 6.6, 1.3Hz), 6.39 (1H, d, J = 8.9Hz), 7.25-7.29 (4H, m), 7.41 (1H, ddd, J = 8.8, 6.6, 2.1Hz), 7.45 (1H, br s), 7.78 (1H, dd, J = 6.6, 1.9Hz), 8.27 (1H, s), 8.46 (1H, s), 8.65 (1H, t,J = 5.5Hz) 22 2.11 (3H, s), 3.27 (3H, s), 3.85 (3H, s), 4.49 (2H, d, J = 4.9Hz), 4.50 (2H, s), 5.06 (2H, s), 5.27 (2H, s), .23 (1H, m), 6.39 (1H, d, J = , 6.96 (1H, d, J = .7Hz), 7.22-7.27 (4H, m), 7.38-7.43 (1H, m), 7.75 (1H, dd, J = 6.6, 2.0Hz), 8.27- 8.29 (2H, m), 8.43 (1H, t,J = 4.8Hz) 26 3.25 (3H, s), 4.51 (2H, s), 4.55 (2H, d, J = , 5.07 (2H, s), 5.28 (2H, s), 6.20- 6.24 (1H, m), 6.38-6.41 (1H, m), 7.21-7.28 (4H, m), 7.38-7.43 (1H, m), 7.75 (1H, dd, J = 6.7, 2.0Hz), 7.90-7.96 (1H, m), 8.25 (1H, s), 8.44-8.47 (2H, m) 27 2.44 (3H, s), 3.24 (3H, s), 4.52-4.54 (4H, m), 5.07 (2H, s), 5.28 (2H, s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 8.8Hz), 7.19-7.27 (5H, m), 7.38-7.43 (1H, m), 7.55-7.60 (1H, m), 7.76 (1H, dd, J = 8.6, 1.9Hz), 8.25 (1H, s), 8.40 (1H, t,J = 5.3Hz) 28 2.28 (3H, d, J = 1.0Hz), 3.26 (3H, s), 4.51 (2H, s), 4.56 (2H, dd, J = 5.0,1.2Hz),5.07 (2H, s), 5.28 (2H, s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 9.0Hz), 7.22-7.30 (5H, m), 7.38-7.43 (1H, m), 7.76 (1H, dd, J = 6.7, 1.9Hz), 8.23 (1H, d, J = 4.8Hz), 8.27 (1H, s), 8.44 (1H, t, J = 5.2Hz) Example Chemical shift Number 29 2.38 (3H, s), 3.29 (3H, s), 4.49 (2H, d,J = 1.8Hz), 4.62 (2H, d, J = 5.1Hz), 5.07 (2H, s), 5.29 (2H, s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 9.2Hz), 7.24 (2H, d, J = 8.5Hz), 7.26 (2H, d, J = 8.5Hz), 7.35 (1H, d, J = 4.9Hz), 7.38-7.45 (1H, m), 7.76 (1H, dd,J = 6.8, 1.9Hz), 8.29 (1H, s), 8.36 (1H, d, J = 4.8Hz), 8.48 (1H, t,J = 5.1Hz) 3.25 (3H, s), 3.92 (3H, s), 4.50 (2H s), 4.53 (2H, dd, J = 5.3, 2.0Hz), 5.01 (2H, s), .28 (2H, s), 6.43 (1H, dd, J = 10.0, 5.4Hz), 7.19 (1H, t, J = , 7.23 (2H, d,J = 8.2Hz), 7.29 (2H, d, J = 8.2Hz), 7.54-7.59 (1H, m), 8.02 (1H, t, J = 3.9Hz), 8.24 (1H, d,J = 5.5Hz), 8.26 (1H, s), 8.42 (1H, t, J = 5.3Hz) 31 3.23 (3H, s), 3.48 (3H, s), 3.81 (3H, s), 4.20 (2H, d, J = 5.5Hz), 4.52 (2H, s), 5.07 (2H, s), 5.27 (2H, s), 5.55 (1H, s), 6.22 (1H, dt, J = 6.8, 1.4Hz), 6.39 (1H, d, J = 8.8Hz), 7.23 (2H, d, J = 8.3Hz), 7.27 (2H, d, J = , 7.41 (1H, ddd, J = 8.9, 6.7, 2.2Hz), 7.75 (1H, dd, J = 6.8, 2.1Hz), 8.19 (1H, t, J = 5.5Hz), 8.23 (1H, s) 34 3.22 (3H, s), 3.77 (3H, s), 4.33 (2H, d, J = 5.7Hz), 4.50 (2H, s), 5.06 (2H, s), 5.27 (2H, s), 6.19-6.24 (1H, m), 6.39 (1H, d, J = 9.0Hz), 7.21-7.27 (4H, m), 7.38-7.43 (1H, m), 7.76 (1H, dd, J = 6.7, 1.9Hz), 7.89 (1H, s), 8.18 (1H, t,J = 5.2Hz), 8.24 (1H, 5) 3.81 (3H, s), 4.38 (2H, d, J = 5.0Hz), 5.01 (2H, s), 5.06 (2H, s), 5.37 (2H, br.s), 6.22 (1H, td,J = 6.7,1.3Hz),6.39(1H,d,J= 8.9Hz), 7.00 (1H, td, J = 9.2, 1.7Hz), 7.11 (1H, td, J = 9.3, 5.5Hz), 7.17 (2H, d, J = 8.2Hz), 7.25 (2H, d, J = 8.2Hz), 7.38-7.43 (1H, m), 7.76 (1H, dd, J = 6.7, 2.0Hz), 7.97 (1H, s), 8.10 (1H, t,J = 5.2Hz) 37 3.22 (3H, s), 3.91 (3H, s), 4.34 (2H, d, J = 5.7Hz), 4.53 (2H, s), 5.07 (2H, s), 5.29 (2H, s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 9.2Hz), 7.18 (1H, d,J = 8.6Hz), 7.23 (2H, d,J = , 7.26 (2H, d, J = 8.4Hz), 7.38-7.43 (1H, m), 7.56 (1H, d,J = 1.9Hz), 7.74 (1H, s), 7.75 (1H, d, J = 6.6Hz), 8.26 (1H, s), 8.27 (1H, t,J = 5.8Hz) 38 3.21 (3H, s), 3.91 (3H, s), 4.50 (2H, d, J = , 4.53 (2H, s), 5.07 (2H, s), 5.29 (2H, s), 6.20-6.24 (1H, m), 6.40 (1H, d, J = 8.8Hz), 7.04 (1H, d,J = 7.6Hz), 7.13 (1H, d, J = 8.2Hz), 7.23-7.28 (4H, m), 7.39-7.43 (1H, m), 7.60 (1H, t, J = 8.1Hz), 7.76 (1H, dd, J = 6.8, 1.9Hz), 8.26 (1H, s), 8.50 (1H, t, J = 5.6Hz) 39 3.18 (3H, s), 3.94 (3H, s), 4.22 (2H, d, J = 4.8Hz), 4.41 (2H, s), 5.06 (2H, s), 5.24 (2H, s), .23 (1H, m), 6.39 (1H, d, J = 9.0Hz), 7.19 (2H, d, J = 8.2Hz), 7.24 (2H, d, J = , 7.33-7.43 (3H, m), 7.75 (1H, dd,J = 6.8, 1.9Hz), 8.11 (1H, s), 8.15 (1H, t, J = 5.2Hz), 9.73 (1H, s) Example Chemical shift Number 40 3.19 (3H, s), 3.82 (3H, s), 4.16 (2H, d, J = 5.7Hz), 4.49 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, t, J = 5.3Hz), 6.39 (1H, d, J = 8.8Hz), .11 (2H, m), 7.22 (2H, d, J = , 7.26 (2H, d, J = 8.2Hz), .43 (1H, m), 7.48 (1H, d, J = 8.6Hz), 7.76 (1H, dd, J = 6.8, 2.0Hz), 8.19 (1H, s), 8.27 (1H, t, J = 5.6Hz), 9.76 (1H, s) 41 2.20 (3H, s), 3.17 (3H, s), 3.68 (3H, s), 4.32 (2H, d, J = 5.5Hz), 4.52 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 9.6Hz), 6.73 (1H, q, J = 2.8Hz), 6.80 (1H, d, J = 2.6Hz), 7.09 (1H, d, J = 8.3Hz), 7.25 (4H, q, J = 8.3Hz), 7.38-7.43 (1H, m), 7.75 (1H, d, J = 1.8Hz), 8.18 (1H, t, J = 5.6Hz), 8.25 (1H, s) 42 3.21 (3H, s), 3.92 (3H, s), 4.51-4.52 (4H, m), 5.06 (2H, s), 5.27 (2H, s), 6.18-6.22 (1H, m), 6.39 (1H, d, J = 8.8Hz), 7.20-7.30 (7H, m), 7.35-7.45 (1H, m), 7.66 (1H, dd, J = 8.7, 1.3Hz), 7.75 (1H, dd, J = 6.7, 1.9Hz), 8.20 (1H, s), 8.39 (1H, t, J = 5.1Hz) 43 3.92 (3H, s), 4.50 (2H, d, J = 4.7Hz), 5.07 (2H, s), 5.11 (2H, s), 6.03 (2H, s), 6.21- 6.25 (1H, m), 6.41 (1H, d, J = 8.9Hz),7.20-7.31 (5H, m), 7.39-7.44 (1H, m), 7.66 (1H, dd,J = 8.6,1.2Hz),7.76(1H,dd,J= 6.6, 1.9Hz), 8.09 (1H, s), 8.46 (1H, t,J = .0Hz) 44 2.73 (6H, s), 3.92 (3H, s), 4.53 (2H, d, J = 5.1Hz), 5.06 (2H, s), 5.15 (2H, s), 6.21- 6.24 (1H, m), 6.40 (1H, d, J = 9.1Hz), 7.19-7.29 (5H, m), .43 (1H, m), 7.67 (1H, d, J = 8.6Hz), 7.76 (1H, dd, J = 6.7, 1.8Hz), 8.04 (1H, s), 8.39 (1H, t, J = 4.9Hz) 49 3.20 (3H, s), 4.20 (2H, d,J = 5.7Hz), 4.49 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, dt, J = 6.6, 1.4Hz), 6.39 (1H, d, J = 9.0Hz), 7.23 (2H, d, J = 8.4Hz), 7.27 (2H, d, J = 8.3Hz), 7.39 - 7.43 (3H, m), 7.65 - 7.68 (1H, m), 7.76 (1H, dd, J = 6.5,1.9Hz), 8.20 (1H, s), 8.35 (1H, t,J = 5.7Hz), 9.85 (1H, s) 51 3.21 (3H, s), 3.92 (3H, s), 4.50 (2H, s), 4.53 (2H, d, J = 4.8Hz), 5.09 (2H, s), 5.38 (2H, s), 6.24 (1H, td, J = 6.7, 1.3Hz), 6.39 (1H, d, J = 8.8Hz), 7.14 (1H, d, J = 8.1Hz), 7.29 (1H, t, J = 8.5Hz), 7.39-7.44 (1H, m), 7.66-7.70 (2H, m), 7.84 (1H, dd,J = 7.0, 1.9Hz), 8.25 (1H, s), 8.42 (1H, t,J = 5.1Hz), 8.50 (1H, d, J = 2.0Hz) 52 3.20 (3H, s), 3.92 (3H, s), 4.50 (2H, s), 4.51 (2H, d, J = 5.0Hz), 5.15 (2H, s), 5.33 (2H, s), 6.24 (1H, td, J = 6.7, , 6.37 (1H, d, J = 9.0Hz), 7.19 (1H, d, J = 8.0Hz), 7.28 (1H, t,J = 8.4Hz), 7.41-7.46 (1H, m), 7.63 (1H, dd, J = 8.1, 2.2Hz), 7.67 (1H, dd, J = 8.7, 1.1Hz), 7.75 (1H, dd, J = 6.7, 1.8Hz), 8.24 (1H, s), 8.40 (1H, t,J = .1Hz), 8.44 (1H, d, J = 1.7Hz) 53 3.21 (3H, s), 3.92 (3H, s), 4.49 (2H, s), 4.51 (2H, d,J = , 5.01 (2H, s), 5.27 (2H, s), 6.43 (1H, dd, J = 10.0, 5.4Hz), 7.20-7.22 (2H, m), .30 (3H, m), 7.53- 7.58 (1H, m), 7.67 (1H, dd, J = 8.7, 1.3Hz), 8.01 (1H, dd, J = 8.0, 3.2Hz), 8.20 (1H, s), 8.39 (1H, t,J = 5.2Hz) Example Chemical shift Number 57 1.69 (4H, t, J = 3.3 Hz), 2.26-2.29 (2H, m), .16 (2H, m), 3.22 (3H, s), 3.39 (3H, s), 4.46 (2H, s), 4.51 (2H, s), 4.52 (2H, d,J = 4.9 Hz), 5.29 (2H, s), 7.17-7.22 (4H, m), 7.28 (1H, t, J = 8.5 Hz), 7.67 (1H, d, J = 8.6 Hz), 8.22 (1H, s), 8.40 (1H, t, J = 5.1 Hz) 58 1.89-1.92 (4H, m), 3.21 (3H, s), 3.43-3.46 (4H, m), 3.92 (3H, s), 4.51 (2H, s), 4.52 (2H, s), 5.13 (2H, s), 7.28 (1H, app.t,J = 8.5Hz), 7.67 (1H, dd, J = 8.6, 1.3Hz), 8.16 (1H, s), 8.35 (2H, s), 8.37-8.39 (1H, m) 60 1.98 (3H, s), 3.18 (3H, s), 3.94 (3H, s), 4.22 (2H, d,J = 4.7Hz), 4.42 (2H, s), 5.20 (2H, s), 5.24 (2H, s), 7.17 (4H, q, J = , 7.22 (1H, s), 7.33-7.41 (2H, m), 7.51 (1H, s), 8.10 (1H, s), 8.15 (1H, t, J = 5.3Hz), 9.73 (1H, s) 61 1.98 (3H, s), 3.19 (3H, s), 3.82 (3H, s), 4.16 (2H, d, J = 5.7Hz), 4.48 (2H, s), 5.21 (2H, s), 5.28 (2H, s), 7.06-7.11 (2H, m), 7.18-7.23 (5H, m), 7.48 (1H, d,J = 8.6Hz), 7.52 (1H, s), 8.18 (1H, s), 8.27 (1H, t, J = 5.7Hz), 9.76 (1H, s) 64 4.25 (2H, d,J = 4.8Hz), 5.07 (2H, s), 5.37 (2H, s), 6.20-6.24 (1H, m), 6.39 (1H, d, J = 9.0Hz), 7.25 (2H, d, J = 8.6Hz), 7.27 (2H, d, J = 8.6Hz), 7.40-7.46 (2H, m), 7.54- 7.65 (2H, m), 7.76 (1H, dd, J = 6.7, 1.9Hz), 8.25 (1H, s), 8.51 (1H, t,J = 5.0Hz), 9.80 (1H, s) 71 4.17 (2H, d,J = 5.8Hz), 5.05 (2H, s), 5.07 (2H, s), 5.34 (2H, s), 6.20-6.24 (1H, m), 6.39 (1H, dd, J = 9.8, 9.1Hz), 7.19 (2H, d, J = 8.1Hz), 7.26 (2H, d, J = 8.2Hz), 7.39- 7.43 (1H, m), 7.58 (1H, s), 7.62 (2H, d,J = 1.4Hz), 7.76 (1H, dd, J = 6.4,1.9Hz), 7.93 (1H, s), 8.30 (1H, t,J = 5.8Hz), 9.88 (1H, s) 72 3.20 (3H, s), 4.22 (2H, d, J = 5.8Hz), 4.49 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.20- 6.24 (1H, m), 6.39 (1H, d,J = 8.9Hz), 7.23 (2H, d,J = , 7.26 (2H, d,J = 8.4Hz), 7.38-7.43 (1H, m), 7.63 (3H, s), 7.75 (1H, dd, J = 7.0, 1.9Hz), 8.19 (1H, s), 8.34 (1H, t,J = 5.8Hz), 9.87 (1H, s). 73 3.16(3H, s), 4.26 (2H, d,J = 5.0Hz), 4.42 (2H, s), 5.05 (2H, s), 5.24 (2H, s), 6.19- 6.23 (1H, m), 6.39 (1H, d,J = 8.9Hz), .26 (4H, m), 7.38-7.42 (1H, m), 7.56- 7.63 (2H, m), 7.75 (1H, dd, J = 6.8, 2.1Hz), 7.82 (1H, dd, J = 7.6, 1.8Hz), 8.13 (1H, s), 8.15 (1H, t, J = 5.1Hz), 9.79 (1H, s) 74 3.19 (3H, s), 4.23 (2H, d, J = 5.7Hz), 4.49 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.20- 6.24 (1H, m), 6.39 (1H, d,J = 9.1Hz), 7.22 (2H, d,J = 8.4Hz), 7.26 (2H, d,J = 8.3Hz), 7.38-7.43 (1H, m), 7.53-7.57 (2H, m), 7.62 (2H, d, J = 3.0Hz), 7.75 (1H, dd, J = 6.9, , 8.19 (1H, s), 8.31 (1H, t, J = 5.8Hz), 9.86 (1H, s) Example Chemical shift Number 77 1.91 (4H, t, J = 6.52Hz), 3.18 (3H, s), 3.35 (4H, t, J = 8.6Hz), 3.93 (3H, s), 4.21 (2H, d, J = , 4.42 (2H, s), 5.09 (2H, s), 6.40 (1H, d, J = 8.7Hz), 7.33-7.43 (3H, m), 8.03 (1H, s), 8.05 (1H, d, J = 2.2Hz), 8.16 (1H, t, J = 5.2Hz), 9.74 (1H, s) 79 1.89-1.92 (4H, m), 3.18 (3H, s), 3.45 (4H, t, J = 6.7Hz), 3.93 (3H, s), 4.21 (2H, d, J = 4.6Hz), 4.42 (2H, s), 5.10 (2H, s), 7.33-7.41 (2H, m), 8.07 (1H, s), 8.15 (1H, t,J = 4.9Hz), 8.33(2H, s), 9.73(1H, s) 80 1.89-1.93 (4H, m), 3.19 (3H, s), 3.44-3.47 (4H, m), 3.82 (3H, s), 4.16 (2H, d,J = .7Hz), 4.49 (2H, s), 5.14 (2H, s), 7.07 (1H, t, J = , 7.09 (1H, s, J = 2.6Hz), 7.48 (1H, dd, J = 11.4, 3.2Hz), 8.15 (1H, s), 8.27 (1H, t,J = 5.8Hz), 8.31-8.34 (1H, m), 8.36 (1H, s), 9.76 (1H, s) 83 1.90-1.94 (4H, m), 3.35 (4H, t,J = 6.6Hz), 3.94 (3H, s), 4.20 (2H, d, J = 4.4Hz), 5.22 (2H, s), 6.43 (1H, d,J = , 7.34-7.41 (2H, m), 7.47 (1H, dd, J = 8.6, 2.4Hz), 8.10 (1H, d,J = 2.2Hz), 8.18 (1H, s), 8.48 (1H, t,J = 5.0Hz), 9.70 (1H, s) 86 2.50-2.57 (2H, m), 3.18 (3H, s), 3.69 (2H, t, J = 7.4Hz), 3.87 (2H, t,J = ), 3.94 (3H, s), 4.22 (2H, d, J = 4.7Hz), 4.41 (2H, s), 5.15 (2H, s), 7.37-7.41 (2H, m), 8.09 (1H, s), 8.14 (1H, t, J = , 8.41 (2H, s), 9.73 (1H, s) 87 2.46-2.57 (2H, m), 3.18 (3H, s), 3.59 (2H, t, J = 7.3Hz), 3.80 (2H, t, J = 8.9Hz), 3.93 (3H, s), 4.22 (2H, d, J = 4.8 Hz), 4.42 (2H, s), 5.14 (2H, s), 3.59 (1H, d, J = 8.6Hz), 7.33-7.41 (2H, m), 7.50 (1H, dd, J = 7.7, 2.3Hz), 8.06 (1H, s), 3.59 (1H, d, J = 2.2Hz), 8.14 (1H, t,J = 5.3 Hz), 9.74 (1H, s) 88 2.51-2.57 (2H, m), 3.19 (3H, s), 3.70 (2H, t, J = 7.3Hz), 3.82 (3H, s), 3.88 (2H, t, J = 13.1Hz), 4.16 (2H, d, J = 5.7Hz), 4.48 (2H, s), 5.19 (2H, s), 7.06 (1H, d, J = 2.5Hz), 7.09 (1H, s), 7.49 (1H, d, J = 8.3Hz), 8.18 (1H, s), 8.27 (1H, t,J = 5.6Hz),8.45 (2H, s), 9.77 (1H, s) ical Methods The ability of the compounds of formula (I) to inhibit plasma kallikrein may be determined using the following biological assays: Determination of the leo for plasma kallikrein Plasma kallikrein inhibitory activity in vitro was determined using standard published methods (see e.g.

Johansen et 0]., Int. J. Tiss. Reac. 1986, 8, 185; Shori et 0]., Biochem. col., 1992, 43, 1209; Stiirzebecher et 0]., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human plasma kallikrein (Protogen) was incubated at 25 °C with the fluorogenic substrate H-DPro-Phe-Arg-AFC and various concentrations of the test compound. Residual enzyme activity al rate of reaction) was determined by ing the change in optical absorbance at 410nm and the |C50 value for the test nd was determined.

Data acquired from this assay are shown in Table 10.

Determination of the Ki for plasma kallikrein Plasma kallikrein inhibitory ty in vitro was determined using standard published s (e.g.

Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; StUrzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human plasma kallikrein (Protogen) was incubated at 25 °C with 10 concentrations of the test compound and 8 concentrations of the fluorogenic substrate H-DPro-Phe-Arg-AFC spanning a range of at least 1/2><Km to 5><Km. Residual enzyme activity al rate of reaction) was determined by measuring the change in fluorescence at 410nm. The Ki value for the test compound was determined using the mixed-model inhibition equation (based on Equation 3.2 in: RA Copeland, Evaluation of Enzyme Inhibitors in Drug Discovery, Wiley 2005) in GraphPad Prism. The mixed model equation includes competitive, uncompetitive and noncompetitive inhibition as special cases and the parameter of Alpha to indicate mechanism of inhibition.

Data acquired from this assay are shown in Table 11.

Selected nds were further screened for inhibitory activity against the related enzyme KLK1. The ability of the compounds of formula (I) to t KLK1 may be ined using the following ical assay: Determination of the leo for KLK1 KLK1 inhibitory activity in vitro was determined using rd published methods (see e.g. Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; StUrzebecher et al., Biol. Chem. Seyler, 1992, 373, 1025). Human KLK1 (Callbiochem) was incubated at 25 °C with the fluorogenic substrate H-DVal-Leu-Arg-AFC and various concentrations of the test compound.

Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410nm and the |C50 value for the test compound was determined.

Data acquired from this assay are shown in Table 10. ed compounds were further screened for tory activity against the related enzyme FXIa. The ability of the compounds of formula (I) to inhibit FXIa may be determined using the following biological assay: Determination of the % inhibition for FXla FXIa tory activity in vitro was determined using standard published methods (see e.g. Johansen et 0]., Int. J. Tiss. Reac. 1986, 8, 185; Shori et 0]., Biochem. Pharmacol., 1992, 43, 1209; StUrzebecher et 0]., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human FXIa (Enzyme Research Laboratories) was incubated at 25 °C with the fluorogenic ate Z-Gly-Pro-Arg-AFC and 40 uM of the test compound (or alternatively at s concentrations of the test compound in order to determine ICso). Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410nm and the |C50 value for the test compound was determined.

Data acquired from this assay are shown in Table 10.

Factor X||a inhibitory activity in vitro was determined using standard published methods (see e.g. Shori et al., Biochem. Pharmacol., 1992,43, 1209; Baeriswyl et al., ACS Chem. Biol., 2015, 10 (8) 1861; Bouckaert et al., European l of Medicinal Chemistry 110 (2016) 181). Human Factor X||a (Enzyme Research Laboratories) was ted at 25°C with the fluorogenic substrate H-DPro-Phe-Arg-AFC and various concentrations of the test compound. Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410nm and the |C50 value for the test compound was ined.

Data acquired from this assay are shown in Table 10.

Table 10 leo % Inhibition Icso ICSO (human leo (human @ 40uM Example Number (human (human KLK1) FXla) nM (human PKal) nM FXlla) nM nM FXla) Reference Example A >10000 0 — Reference Example B 8.7 >10000 >40,000 8 >40,000 leo % Inhibition Icso ICSO (human leo (human @ 40uM Example Number (human (human KLK1) FXla) nM (human PKal) nM FXlla) nM nM FXla) Reference Example C Reference Example D “-- 0 Reference Example E n“- >40,000 Reference Example F “-- Reference Example 6 Reference Example H “-- >40,000 Example 7 from 2034 >40,000 >40,000 >40,000 Reference Example | ---->40,000 Example 14 from 110 >4000 >40,000 0 Example 27 from 731 >40000 0 0 Reference ExampleJ “-- >40,000 >40,000 “-->4,000 “-->40,000 >4,000 >40,000 >4,000 2450 >40000 >40,000 >40,000 lcso % tion leo “:50 (human leo (human @ 40uM Example Number (human (human KLK1) FXla) nM (human PKal) nM FXlla) nM nM FXla) 41 149 >4000 >40,000 >4,000 leo % Inhibition Icso ICSO (human leo (human @ 40uM Example Number (human (human KLK1) FXla) nM (human PKal) nM FXlla) nM nM FXla) 42 “-- 43 n“->4,000 44 >40000 49 >4000 51 >4,000 52 “-->4,000 53 >40,000 57 27.9 >40,000 >40,000 58 57.0 8500 >40,000 60 n- 4700 >40000 61 >40,000 >4000 64 n- 0 >4000 71 4600 >4000 72 0.7 >4000 10600 Inhibition @ >4000 127uM 73 23.1 >4000 >40,000 >4000 74 17.6 >40000 >40000 >40000 77 235 100 >40000 Reference example K 2.0 >40000 76 >40000 WO 07983 leo % Inhibition Icso ICSO (human leo (human @ 40pM Example Number (human (human KLK1) FXla) nM (human PKal) nM FXlla) nM nM FXla) 80 10.6 >4000 779 - >4000 88 8.3 >40000 4880 >40000 Table 11 Example Number Ki Alpha Reference Example H 0.52 nM 108 Example 14 from 139 nM 4 X 1017 39 0.26 nM 1.7 40 0.10 nM 2.2 60 0.30 nM 1.6 72 0.16 nM 6.0 77 0.17 nM 4.2 0.38 nM and 0.23 nM (two 7.08 and 2.16 (two individual determinations) individual determinations) Example Number Ki Alpha 80 14.8 83 2.24 86 2.78 88 2.9 nM 1 x 1022 Determination of enzyme ivity Human serine protease enzymes plasmin, thrombin and trypsin were d for enzymatic activity using an appropriate fluorogenic substrate. se activity was measured by monitoring the accumulation of liberated fluorescence from the substrate over 5 minutes. The linear rate of fluorescence increase per minute was expressed as percentage (%) activity. The Km for the cleavage of each substrate was determined by standard transformation of the Michaelis-Menten equation. The compound tor assays were performed at substrate Km concentration and activities were ated as the concentration of inhibitor giving 50% inhibition (IC50) of the uninhibited enzyme activity (100%).

Data acquired from these assays are shown in Table 12 below: Table 12 (Selectivity data) Example IC50 (nM) Number Plasmin Thrombin Trypsin 6 >40000 >40000 >40000 >40000 >40000 >40000 >40000 >40000 >40000 37 >40000 >40000 >40000 39 31200 19300 >40000 40 >40000 >40000 >40000 43 >40000 >40000 >40000 53 >40000 >40000 >40000 72 >40000 39200 >40000 74 >40000 >40000 >40000 79 12010 7310 >40000 Solubility data Solubility was determined in water and 0.1N HCI (aq). Test compounds were ted at 1 mg/mL for 24 hrs at 37 °C on a shaking rm (500 rpm). Samples were taken at 1, 4 and 24 hrs and centrifuged at 15,000 g for 10 min. Test compound concentration in the supernatant was determined by LCMS against a standard curve.

Example 0-1N HCI (aq) Water (mg/ml) Number (mg/mL) 22 0.06 0.29 0.02 39 0.007 72 0.046 79 0.093 36 0.05 0.001 In vitro ADME data In vitro permeability was determined using the Caco-2 model for oral absorption. The methodology was adapted from standard published methods (Wang Z, Hop C.E., Leung K.H. and Pang J. (2000)J Mass Spectrom 35(1); 71-76). The Caco-2 monolayers were established in a BiocoatTlvl HTS fibrillar collagen 24 well multiwell insert system (1.0 pm, PET membrane, g 354803) in which 0 cells were seeded into each insert and maintained over 3 days before being utilised in the permeability assay. For the assay, 50 uM test compound is added to the apical side of the inserts and incubated for 1 hour at 37 °C on a shaking platform (120 rpm). Apical to basolateral transport was determined by ing the test e in both tments by LCMS following the 1 hour incubation. The integrity of the Caco-2 monolayers was confirmed by two methods, (i) comparison of pre- and xperiment transepithelial electrical resistance (TEER) and, (ii) assessment of Lucifer Yellow flux.

The intrinsic clearance was determined using standard published methods (Obach RS (1999) Drug Metab Dispos 27(11); 1350-135). Rat or human liver microsomes (0.5 mg/mL; Corning) were incubated with 5 uM test compound at 37 °C on a shaking platform (150 rpm). Samples were taken at 0, 6, 12, 18, 24 and 60 min and test compound concentrations were determined by LCMS against a calibration curve. The intrinsic nce (Clint) was calculated using methodology described by Obach (Obach RS et al. (1997) J Pharmacol Exp Ther 283: 46—58.) or Lau (Lau YY et al . Drug Metab Dispos 30: 1446—1454).

Human liver rat liver microsome microsome (Clint Caco-Z (Papp Example Number (Clint uL/min/mg uL/min/mg x10'6 cm/s) protein) protein) Reference Example H NU1 L0 4s 12 Example 7 from Reference Example | \l \l H U'l UJ 15 Example 27 from WO 11108 \l H \l N \l Reference ExampleJ 110 187 12 -— 2 22 25 68 25 Human liver rat liver microsome microsome (Clint Caco-Z (Papp Example Number (Clint pL/min/mg pL/min/mg x10'6 cm/s) protein) 44 162 101 17 73 4 Human liver rat liver microsome microsome (Clint Caco-Z (Papp Example Number (Clint uL/min/mg uL/min/mg x10'6 cm/s) protein) protein) Reference Example K 87 4 Plasma Protein Binding (PPBl and Predicted Clearance The fraction unbound in plasma was determined using ThermoScientificTM PierceTM Rapid Equilibrium Dialysis Technology e-Use plate with inserts, 8K MWCO). 5 uM test compound was spiked into human or rat plasma (300 uL) and dialysed against 146.5 mM phosphate buffer (500 uL) for 5 hrs at 37°C, shaking at 1200 rpm. Reference samples from the non-dialysed plasma were taken before the incubation to enable an assessment of recovery. Test nd concentrations were determined in plasma and buffer compartments by LCMS against a calibration curve. The fraction unbound in plasma was determined using standard methodology s NJ et al (2008)J Pharm Sci 97(10); 4586-95).

Results are ted as percent plasma n bound (%PPB).

The ted plasma clearance (Clp) is calculated using the well-stirred model (Rowland M, Benet L2, and Graham 66. Clearance concepts in pharmacokinetics.J Pharmacokinet rm. (1973) 1:123— 136.), one of several models that can be used to extrapolate the in vitro data. The model assumes instantaneous and complete mixing of drug within the liver and is a function of intrinsic clearance, c blood flow and free fraction of drug in the blood. The predicted plasma clearance in mL/min/kg is presented as a percentage of hepatic blood flow (LBF).

Example Predicted in vivo Predicted in vivo rat %PPB ) mm; "at, Number human Clp (%LBF) Clp (%LBF) Reference 84 87 Example H 14 26 s 6 e 86 90 97 2 3 Pharmacokinetics Pharmacokinetic studies of the compounds in Table 13 were performed to assess the pharmacokinetics ing a single oral dose in male Sprague-Dawley rats. Two rats were given a single po dose of 5 mL/kg of a nominal 2 mg/mL (10 mg/kg) composition of test compound in e. Following dosing, blood samples were collected over a period of 24 hours. Sample times were 5, 15 and 30 minutes then 1, 2, 4, 6, 8 and 12 hours. Following collection, blood samples were centrifuged and the plasma fraction ed for concentration of test compound by LCMS. Oral exposure data ed from these studies are shown below: Table 13: Oral exposure data Vehicle Dose po (mg/kg) Cmax (ng/mL) Tmax (min) Number % DMSO/10% Reference 9 5 351 60 Example B cremophor / 80% SWFI % DMSO/ 10% Reference 1o 5 1534 180 Example D cremophor / 80% SWFI % DMSO/10% Reference 5 397 30 Example E cremophor / 80% SWFI % DMSO/ 10% 6 2.2 1802 30 cremophor / 80% SWFI % DMSO/ 10% 22 9.1 1025 60 cremophor / 80% SWFI % DMSO/ 10% 4.3 756 38 cremophor / 80% SWFI % DMSO/ 10% 39 8.0 187 30 cremophor / 80% SWFI % DMSO/ 10% 77 7.0 845 90 cremophor / 80% SWFI Vehicle Dose po (mg/kg) Cmax (ng/mL) Tmax (min) Number % DMSO/ 10% 79 11.3 807 45 cremophor / 80% SWFI % DMSO/ 10% 36 5.0 981 30 cremophor / 80% SWFI

Claims (1)

CLAIMS A compound selected from the group ting of: N-[(3-f|uoromethoxypyridin-Z-yl)methyl](methoxymethyl)({4-[(4-methylpyrazol- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(4-f|uoro-S-methoxypyridazinyl)methyl](methoxymethyl)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 3-(methoxymethyl)-N-[(5-methoxypyridazinyl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 10 3-(methoxymethyl)-N-[(6-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; o-N-[(3-fluoromethoxypyridin-Z-yl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoromethoxypyridin-Z-yl)methyl]({4-[(2-oxopyridin 15 y|)methy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide; 3-(dimethylamino)-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(5-cyano-Z-methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 20 N-[(5-cyanofluoro-Z-methoxypyridinyl)methyl](methoxymethy|)({4-[(2- idin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(methoxymethyl)-N-[(4-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxy-3,5-dimethylpyridin-Z-yl)methyl](methoxymethy|)({4-[(2- 25 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanomethoxypyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 30 N-{[3-(dif|uoromethy|)methoxypyridinyl]methy|}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|oromethoxypyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|orocyanopyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin 35 y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoro-S-methylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanomethy|pyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin 10 y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanomethoxypyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 15 N-{[6-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; 5-difluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin 20 y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 25 N-[(3-ch|oromethy|pyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide; 1-({4-[(5-f|uoro-Z-oxopyridin-l—yl)methy|]phenyl}methy|)-N-[(3-fluoro ypyridin-Z-yl)methyI](methoxymethy|)pyrazoIecarboxamide; N-[(5-methoxymethylpyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin 30 y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-chloro-S-methoxy-l—methylpyrazoly|)methyI](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-methoxy-1,4-dimethylpyrazoly|)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-ch|oromethy|pyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2,6-difluoro-3,5-dimethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin 10 y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 15 N-[(5-methoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl] }methy|)pyrazoIecarboxamide; N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(6-cyanof|uoromethoxyphenyl)methyl]({4-[(2-oxopyridin 20 y|)methyl]phenyl}methyl)pyrazoIecarboxamide; cyanof|uoromethoxyphenyl)methyI](dimethy|amino)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(2-cyanomethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 25 cyanomethoxyphenyl)methyl](dimethylamino)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-{[5-methoxy-Z-(trifluoromethy|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-{[2-(dif|uoromethy|)methoxyphenyl]methyl}({4-[(2-oxopyridin 30 y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[5-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2,6-difluoromethoxyphenyl)methyl](dimethylamino)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; WO 07983 N-[(6-cyanof|uoromethoxyphenyl)methyI](methoxymethy|)({5-[(2- oxopyridin-l—y|)methy|]pyridin-Z-y|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l—y|)methy|]pyridiny|}methy|)pyrazoIecarboxamide; cyanofluoromethoxypheny|)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({5-[(2-oxopyridin y|)methy|]pyridin-Z-yl}methy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({6-[(2-oxopyridin 10 y|)methy|]pyridinyl}methy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({4-[(2- oxopiperidin-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; 15 N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrro|idin-l— y|)pyrimidin-S-yl]methyl}pyrazo|ecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl]{[2-(pyrrolidin-l—y|)pyrimidin-S- yl]methyl}(trif|uoromethyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) 20 ({4-[(4-methy|pyrazol-l—yl)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(4- methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(4- methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; 25 N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin y|)methy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazoIyl)pheny|]methy|}({4-[(2-oxopyridin y|)methy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide; 3-amino-N-{[2-fluoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- 30 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-{[2-fluoro(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; WO 07983 3-(dimethylamino)-N-{[2-fluoromethoxy(1,2,3,4-tetrazoly|)pheny|]methyI}({4- [(2-oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(dimethylamino)-N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- idin-l—y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 3-(dimethylamino)-N-{[2-fluoro(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-{[5-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[5-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- 10 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(methoxymethyl)({4-[(2-oxopyridiny|)methy|]pheny|}methy|)-N-{[2-(1,2,3,4- tetrazol-l—y|)phenyl]methyl}pyrazolecarboxamide; 15 3-(methoxymethyl)-N-{[2-methy|—6-(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanof|uorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) 20 {[6-(pyrro|idiny|)pyridiny|]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)pheny|]methyl}(methoxymethy|){[6- (pyrrolidin-l—yl)pyridinyl]methyl}pyrazolecarboxamide; f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) {[2-(pyrrolidin-l—y|)pyrimidin-S-yl]methyl}pyrazolecarboxamide; 25 N-{[5-methoxy(1,2,3,4-tetrazoly|)pheny|]methyl}(methoxymethy|){[2- (pyrrolidin-l—yl)pyrimidin-S-yl]methy|}pyrazo|ecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|){[6- (pyrrolidin-l—yl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|){[2- 30 (pyrrolidin-l—y|)pyrimidin-S-yl]methy|}pyrazo|ecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}{[6-(pyrro|idin y|)pyridinyl]methyl}(trif|uoromethy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}{[6-(pyrro|idiny|)pyridin yl]methyl}(trif|uoromethyl)pyrazoIecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidinyl)pyridin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l—yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- tetrazol-l—yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l—yl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4- tetrazol-l—yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[5-methoxy(1,2,3,4-tetrazol- 10 1-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically able salts and solvates thereof. 2. A compound according to claim 1, selected from the group consisting of: N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(4-methylpyrazol- 15 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(4-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-chlorocyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 20 N-[(5-chlorofluoropyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3,5-difluoropyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-fluoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin 25 yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-fluoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-chloromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 30 chloromethylpyrazolyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazolecarboxamide; and ceutically acceptable salts and solvates thereof. 3. A compound according to claim 1, selected from the group ting of: N-[(3-f|uoromethoxypyridinyl)methyl](methoxymethyl)({4-[(4-methylpyrazol- 1-yl)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(3-f|uoromethoxypyridinyl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; f|uoromethoxypyridinyl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide; N-[(3-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 10 N-[(3-cyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin hy|]phenyl}methyl)pyrazoIecarboxamide; N-{[3-(dif|uoromethy|)methoxypyridinyl]methy|}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxymethy|pyridinyl)methyl](methoxymethy|)({4-[(2-oxopyridin 15 y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxymethy|pyridinyl)methyl](methoxymethy|)({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 20 N-{[6-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methyl}(methoxymethy|) ({4-[(2-oxopyridiny|)methy|]phenyl}methy|)pyrazoIecarboxamide; 1-({4-[(5-f|uorooxopyridiny|)methy|]pheny|}methy|)-N-[(3-fluoro methoxypyridinyl)methyl](methoxymethy|)pyrazoIecarboxamide; 3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin 25 y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 30 N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)pheny|]methyl}(methoxymethy|) ({4-[(2-oxopyridiny|)methy|]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)pheny|]methyl}(methoxymethyl)({4-[(2- idin-l—y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(5-methoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin 35 y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(6-cyanof|uoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyI](dimethy|amino)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(2-cyanomethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-{[5-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(2- 10 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- idin-l—y|)methy|]pyridin-Z-y|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethy|)({6-[(2- oxopyridin-l—y|)methy|]pyridiny|}methy|)pyrazoIecarboxamide; 15 N-[(6-cyanofluoromethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({5-[(2-oxopyridin y|)methy|]pyridin-Z-yl}methy|)pyrazoIecarboxamide; cyanomethoxyphenyl)methyl](methoxymethyl)({6-[(2-oxopyridin 20 y|)methy|]pyridinyl}methy|)pyrazoIecarboxamide; N-[(2-cyanomethoxypheny|)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrro|idin-l— y|)pyrimidin-S-yl]methyl}pyrazo|ecarboxamide; 25 N-[(6-cyanof|uoromethoxyphenyl)methyl]{[2-(pyrrolidin-l—y|)pyrimidin-S- yl]methyl}(trif|uoromethyl)pyrazoIecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazoIyl)pheny|]methy|}({4-[(2-oxopyridin y|)methy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide; N-[(2-cyanof|uorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin 30 y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) {[6-(pyrro|idiny|)pyridiny|]methyl}pyrazo|ecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) {[2-(pyrrolidin-l—y|)pyrimidin-S-yl]methyl}pyrazo|ecarboxamide; 35 and pharmaceutically able salts and solvates thereof. 4. A compound ing to claim 1, selected from the group consisting of: N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- oxopyridin-l—yl)methyl]pyridinyl}methyl)pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l—yl)methyl]pyridinyl}methyl)pyrazolecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({5-[(2-oxopyridin 10 yl)methyl]pyridinyl}methyl)pyrazolecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({6-[(2-oxopyridin yl)methyl]pyridinyl}methyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof. 15 5. A compound according to claim 1, selected from the group consisting of: N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(4-methylpyrazol- 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(6-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 20 3-amino-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin hyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; 3-(dimethylamino)-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin 25 yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(4-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 30 N-[(4-methoxy-3,5-dimethylpyridinyl)methyl](methoxymethyl)({4-[(2- oxopyridin-l—yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-cyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-chlorocyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin 35 yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methy|]phenyl}methy|)pyrazoIecarboxamide; N-[(3,5-difluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin 10 y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-ch|oromethy|pyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 15 1-({4-[(5-f|uoro-Z-oxopyridin-l—y|)methyl]pheny|}methy|)-N-[(3-fluoro methoxypyridin-Z-yl)methyI](methoxymethy|)pyrazoIecarboxamide; N-[(5-methoxymethylpyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-ch|oromethy|pyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin 20 hyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 25 N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|)({4-[(2- 30 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-methoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-amino-N-[(6-cyanof|uoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyI](dimethy|amino)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-{[5-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- oxopyridin-l—y|)methy|]pyridin-Z-y|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- 10 oxopyridin-l—y|)methy|]pyridinyl}methy|)pyrazoIecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrro|idin-l— yl)pyrimidin-S-yl]methyl}pyrazo|ecarboxamide; 15 N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(4-methy|pyrazol-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(4- methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; f|uoro(1,2,3,4-tetrazoIyl)pheny|]methy|}({4-[(2-oxopyridin 20 y|)methy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide; 3-amino-N-{[5-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 25 N-{[2-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(methoxymethyl)({4-[(2-oxopyridiny|)methy|]pheny|}methy|)-N-{[2-(1,2,3,4- ol-l—y|)phenyl]methyl}pyrazolecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) 30 {[6-(pyrro|idiny|)pyridiny|]methyl}pyrazolecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) {[2-(pyrrolidin-l—y|)pyrimidin-S-yl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)pheny|]methyl}(methoxymethy|){[2- (pyrrolidin-l—y|)pyrimidin-S-yl]methy|}pyrazo|ecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof. 6. A nd according to claim 1, selected from the group consisting of: 3-amino-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin hyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; 10 3-(dimethylamino)-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-cyanomethoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(4-methoxy-3,5-dimethylpyridinyl)methyl](methoxymethyl)({4-[(2- 15 oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; chlorocyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-chlorofluoropyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 20 N-[(4-methoxymethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-fluoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-chloromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin 25 yl)methyl]phenyl}methyl)pyrazolecarboxamide; 1-({4-[(5-fluorooxopyridinyl)methyl]phenyl}methyl)-N-[(3-fluoro methoxypyridinyl)methyl](methoxymethyl)pyrazolecarboxamide; 3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 30 cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) ({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2- 35 oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; methoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methy|]pheny|}methy|)pyrazoIecarboxamide; 3-amino-N-[(6-cyanof|uoromethoxyphenyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyI](dimethy|amino)({4-[(2-oxopyridin- 1-yl)methyl]pheny|}methy|)pyrazoIecarboxamide; N-{[5-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(2- 10 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- oxopyridin-l—y|)methy|]pyridin-Z-y|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l—y|)methy|]pyridiny|}methy|)pyrazoIecarboxamide; 15 N-[(6-cyanofluoromethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrro|idin-l— y|)pyrimidin-S-yl]methyl}pyrazo|ecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) 20 ({4-[(4-methy|pyrazol-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(4- methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazoIyl)pheny|]methy|}({4-[(2-oxopyridin y|)methy|]phenyl}methy|)(trif|uoromethy|)pyrazoIecarboxamide; 25 3-amino-N-{[5-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- 30 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(methoxymethyl)({4-[(2-oxopyridiny|)methy|]pheny|}methy|)-N-{[2-(1,2,3,4- tetrazol-l—y|)phenyl]methyl}pyrazolecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) {[6-(pyrro|idiny|)pyridiny|]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof. 7. A compound ing to claim 1, selected from the group consisting of: 10 3-amino-N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; N-[(4-methoxymethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin 15 yl)methyl]phenyl}methyl)pyrazolecarboxamide; 1-({4-[(5-fluorooxopyridinyl)methyl]phenyl}methyl)-N-[(3-fluoro methoxypyridinyl)methyl](methoxymethyl)pyrazolecarboxamide; 3-amino-N-[(2,6-difluoromethoxyphenyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 20 fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) 2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(6-carbamoylfluoromethoxyphenyl)methyl](methoxymethyl)({4-[(2- 25 oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; o-N-[(6-cyanofluoromethoxyphenyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl](dimethylamino)({4-[(2-oxopyridin- 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 30 N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l-yl)methyl]pyridinyl}methyl)pyrazolecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyl]({4-[(5-fluorooxopyridin yl)methyl]phenyl}methyl)(methoxymethyl)pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) 35 ({4-[(4-methylpyrazol-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(4- methylpyrazol-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; 3-amino-N-{[5-chloro(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-chloro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) 10 {[6-(pyrrolidin-l-yl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidin-S-yl]methyl}pyrazolecarboxamide; (3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 15 and pharmaceutically acceptable salts and solvates thereof. A compound of claim 1 selected from the group consisting of: cyanofluoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrrolidin-l- yl)pyrimidin-S-yl]methyl}pyrazolecarboxamide; 20 cyanofluoromethoxyphenyl)methyl]{[2-(pyrrolidin-l-yl)pyrimidin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[6-(pyrrolidin-l-yl)pyridinyl]methyl}pyrazolecarboxamide; methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[6- 25 (pyrrolidin-l-yl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidin-S-yl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; 30 N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[6- (pyrrolidin-l-yl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidin 35 yl)pyridinyl]methyl}(trifluoromethyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidin-l-yl)pyridin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidin-l-yl)pyridin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4- 10 ol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidin-l-yl)pyridinyl]methyl}-N-{[5-methoxy(1,2,3,4-tetrazol- 1-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof. 15 A compound of claim 1 selected from the group consisting of: N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrrolidin-l- yl)pyrimidin-S-yl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) yrrolidin-l-yl)pyridinyl]methyl}pyrazolecarboxamide; 20 N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidin-S-yl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy 25 (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; 30 N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidin yl)pyridinyl]methyl}(trifluoromethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof. 10. A nd of claim 1, wherein the compound is N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrrolidin yl)pyrimidinyl]methyl}pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof. 11. A compound of claim 1, wherein the compound is N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[6-(pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof. 12. A nd of claim 1, wherein the compound is N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof. 13. A nd of claim 1, wherein the compound is N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; or a ceutically acceptable salt or solvate thereof. 14. A compound of claim 1, wherein the compound is 1-{[2-(3,3-difluoropyrrolidinyl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof. 15. A compound of claim 1, n the compound is 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- olyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof. 16. A compound of claim 1, wherein the compound is N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof. 17. A compound of claim 1, wherein the compound is N-{[2-fluoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}{[6-(pyrrolidin yl)pyridinyl]methyl}(trifluoromethyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof. 18. A compound of claim 1, wherein the compound is 1-{[2-(3,3-difluoropyrrolidinyl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4- tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt of solvate thereof. 19. A nd of claim 1, wherein the compound is N-[(3-fluoromethoxypyridinyl)methyl]({4-[(2-oxopyridin hyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof. 20. A compound of claim 1, wherein the compound is N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- idinyl)methyl]pyridinyl}methyl)pyrazolecarboxamide; or a pharmaceutically acceptable salt or solvate thereof. 21. A compound of claim 1, n the compound is N-[(6-cyanofluoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridinyl)methyl]pyridinyl}methyl)pyrazolecarboxamide; or a pharmaceutically able salt or solvate thereof. 22. A compound of claim 1 selected from the group consisting of: N-[(3-fluoromethoxypyridinyl)methyl](methoxymethyl)({4-[(4-methylpyrazol- 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(4-fluoromethoxypyridazinyl)methyl](methoxymethyl)({4-[(2-oxopyridin- 30 1-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(5-methoxypyridazinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(methoxymethyl)-N-[(6-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-[(5-cyano-Z-methoxypyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-cyanofluoro-Z-methoxypyridinyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(methoxymethyl)-N-[(4-methoxypyrimidinyl)methyl]({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxy-3,5-dimethylpyridin-Z-yl)methyl](methoxymethyI)({4-[(2- idin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanomethoxypyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin 10 y|)methy|]phenyl}methy|)pyrazoIecarboxamide; N-[(3-cyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[3-(dif|uoromethy|)methoxypyridinyl]methyl}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 15 N-[(5-ch|oromethoxypyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-chIorocyanopyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin 20 hyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-ch|orofluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoro-S-methylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 25 N-[(4-methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanomethy|pyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(4-methoxymethy|pyridin-Z-yl)methyI](methoxymethy|)({4-[(2-oxopyridin 30 y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-cyanomethoxypyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[6-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-(dif|uoromethy|)f|uoromethoxypyridin-Z-yl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-[(3,5-difluoropyridin-Z-yl)methyl](methoxymethyl)({4-[(2-oxopyridin hyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methy|]pheny|}methy|)pyrazoIecarboxamide; N-[(3-f|uoromethylpyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(3-ch|oromethy|pyridinyl)methyl](methoxymethyl)({4-[(2-oxopyridin 10 yl)methyl]pheny|}methyl)pyrazoIecarboxamide; [(5-f|uoro-Z-oxopyridin-l—y|)methyl]pheny|}methy|)-N-[(3-fluoro methoxypyridin-Z-yl)methyI](methoxymethy|)pyrazoIecarboxamide; N-[(5-methoxymethylpyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 15 N-[(4-chloro-S-methoxy-l—methylpyrazoly|)methyI](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-methoxy-1,4-dimethylpyrazoly|)methyI](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; ch|oromethy|pyrazoly|)methyl](methoxymethyl)({4-[(2-oxopyridin 20 y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2,6-difluoro-3,5-dimethoxypheny|)methyl](methoxymethyl)({4-[(2-oxopyridin- 1-y|)methy|]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 25 N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) ({4-[(2-oxopyridin-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(2- 30 oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(5-methoxymethylphenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-carbamoy|—2-fluoromethoxyphenyl)methyl](methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[5-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({5-[(2- oxopyridin-l—y|)methy|]pyridin-Z-y|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({6-[(2- oxopyridin-l—y|)methy|]pyridiny|}methy|)pyrazoIecarboxamide; N-[(6-cyanofluoromethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({5-[(2-oxopyridin 10 y|)methy|]pyridin-Z-yl}methy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyl](methoxymethyl)({6-[(2-oxopyridin y|)methy|]pyridinyl}methy|)pyrazoIecarboxamide; N-[(2-cyanomethoxyphenyl)methyI]({4-[(5-f|uoro-Z-oxopyridin-l— y|)methy|]phenyl}methy|)(methoxymethy|)pyrazoIecarboxamide; 15 cyanof|uoromethoxyphenyl)methyl](methoxymethyl)({4-[(2- oxopiperidin-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-[(6-cyanof|uoromethoxyphenyl)methyl](methoxymethyl){[2-(pyrro|idin-l— y|)pyrimidin-S-yl]methyl}pyrazo|ecarboxamide; N-{[2-f|uoromethoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethy|) 20 ({4-[(4-methy|pyrazol-l—y|)methyl]phenyl}methy|)pyrazoIecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyl)({4-[(4- methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; N-{[2-f|uoro(1,2,3,4-tetrazo|—1-y|)phenyl]methyl}(methoxymethy|)({4-[(4- methylpyrazol-l—y|)methyl]pheny|}methy|)pyrazoIecarboxamide; 25 N-{[5-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- idin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-ch|oro(1,2,3,4-tetrazoly|)phenyl]methyl}(methoxymethyI)({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; 3-(methoxymethyl)({4-[(2-oxopyridiny|)methy|]pheny|}methy|)-N-{[2-(1,2,3,4- 30 tetrazol-l—y|)phenyl]methyl}pyrazolecarboxamide; 3-(methoxymethyl)-N-{[2-methy|—6-(1,2,3,4-tetrazoly|)phenyl]methyI}({4-[(2- oxopyridin-l—y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-[(2-cyanof|uorophenyl)methyl](methoxymethyl)({4-[(2-oxopyridin y|)methyl]phenyl}methyl)pyrazoIecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[6-(pyrrolidin-l-yl)pyridinyl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[6- (pyrrolidin-l-yl)pyridinyl]methyl}pyrazolecarboxamide; fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidin-S-yl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[2-fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[6- 10 (pyrrolidin-l-yl)pyridinyl]methyl}pyrazolecarboxamide; fluoro(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy (1,2,3,4-tetrazolyl)phenyl] methyl}(methoxymethyl)pyrazolecarboxamide; 15 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidin-l-yl)pyridinyl]methyl}-N-{[5-methoxy(1,2,3,4-tetrazol- 20 1-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically acceptable salts and solvates thereof. 23. A compound of claim 1 selected from the group consisting of: N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) 25 ({4-[(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide; methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) ({4-[(4-methylpyrazol-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 30 N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)({4-[(4- methylpyrazol-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)(trifluoromethyl)pyrazolecarboxamide; 3-amino-N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2- 35 oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-amino-N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2-oxopyridin yl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(dimethylamino)-N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}({4- [(2-oxopyridinyl)methyl]phenyl}methyl)pyrazolecarboxamide; 3-(dimethylamino)-N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}({4-[(2- oxopyridin-l-yl)methyl]phenyl}methyl)pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[6-(pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[6- 10 (pyrrolidinyl)pyridinyl]methyl}pyrazolecarboxamide; N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl) {[2-(pyrrolidin-l-yl)pyrimidinyl]methyl}pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl){[2- (pyrrolidinyl)pyrimidinyl]methyl}pyrazolecarboxamide; 15 N-{[2-fluoromethoxy(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidin yl)pyridinyl]methyl}(trifluoromethyl)pyrazolecarboxamide; N-{[5-methoxy(1,2,3,4-tetrazolyl)phenyl]methyl}{[6-(pyrrolidinyl)pyridin yl]methyl}(trifluoromethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[2-fluoromethoxy 20 (1,2,3,4-tetrazolyl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[2-fluoromethoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 1-{[2-(3,3-difluoropyrrolidin-l-yl)pyrimidinyl]methyl}-N-{[5-methoxy(1,2,3,4- tetrazol-l-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; 25 1-{[6-(3,3-difluoropyrrolidinyl)pyridinyl]methyl}-N-{[5-methoxy(1,2,3,4-tetrazol-

1-yl)phenyl]methyl}(methoxymethyl)pyrazolecarboxamide; and pharmaceutically able salts and solvates f. 24. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt 30 or solvate thereof as claimed in any one of claims 1 to 23 and a pharmaceutically acceptable r, t or excipient. 25. A compound or pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 23 for use in medicine. 26. The use of a compound or pharmaceutically acceptable salt or solvate thereof as d in any one of claims 1 to 23 in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated. 27. A method of ent of a disease or condition in which plasma kallikrein activity is implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound or ceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 23. 10 28. A compound or pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 23 for use in a method of treatment of a disease or condition in which plasma kallikrein activity is implicated. 29. The use of claim 26, the method of claim 27 or a compound or pharmaceutically acceptable 15 salt or e thereof for use as claimed in claim 28 wherein, the e or ion in which plasma kallikrein ty is implicated is selected from impaired visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress 20 me, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery and ng from post operative surgery. 30. The use of claim 26, the method of claim 27 or a compound or pharmaceutically acceptable salt or e thereof for use as claimed in claim 28, wherein the disease or condition in 25 which plasma kallikrein activity is implicated is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. 31. The use of claim 26, the method of claim 27 or a compound or pharmaceutically able salt or solvate thereof for use as claimed in claim 28, wherein the disease or ion 30 mediated by plasma kallikrein is hereditary angioedema. 32. The use of claim 26, the method of claim 27 or a compound or pharmaceutically acceptable salt or solvate thereof for use as claimed in claim 28, n the disease or condition in which plasma kallikrein activity is implicated is diabetic macular edema. 33. The use of claim 26, the method of claim 27 or a compound or pharmaceutically acceptable salt or solvate thereof for use as d in claim 28, wherein the disease or condition in which plasma kallikrein activity is implicated is retinal vein occlusion.