WO2019106359A1

WO2019106359A1 - Enzyme inhibitors

Info

Publication number: WO2019106359A1
Application number: PCT/GB2018/053440
Authority: WO
Inventors: Rebecca Louise DAVIE; Hannah Joy EDWARDS; David Michael Evans; Simon Teanby Hodgson; Stephen John PETHEN; Richard Simon Todd
Original assignee: Kalvista Pharmaceuticals Limited
Priority date: 2017-11-29
Filing date: 2018-11-28
Publication date: 2019-06-06
Also published as: TW201925188A

Abstract

This invention relates to enzyme inhibitors that are inhibitors of plasma kallikrein and to pharmaceutical compositions containing and the uses of, such inhibitors.Specifically, the invention relates to compounds of formula (I): Formula (I) and tautomers,stereoisomers, pharmaceutically acceptable salts and solvates thereof; wherein R1 to R15, and Q are as defined herein.

Description

ENZYME INHIBITORS

This invention relates to enzyme inhibitors that are inhibitors of plasma kallikrein and to pharmaceutical compositions containing 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 macular 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 Medicine, p483-493; J. W. Bryant et al., "Human plasma kallikrein-kinin system: physiological and biochemical parameters" Cardiovascular and haematological agents in medicinal chemistry, 7, p234-250, 2009; K. D. Bhoola et al., Pharmacological Rev., 1992, 44, 1; and D. J. Campbell, "Towards understanding the kallikrein-kinin system: insights from the measurement of kinin peptides", Brazilian Journal of Medical and Biological Research 2000, 33, 665-677). It is an essential member of the intrinsic blood coagulation cascade although its role in this cascade does not involve the release of bradykinin or enzymatic cleavage. 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 molecular weight kininogen which is activated to give the active plasma kallikrein. Kinins are potent mediators of inflammation that act through G protein- coupled receptors 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 Cl esterase inhibitor. Patients who present with a genetic deficiency in Cl esterase inhibitor 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 kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery" Expert Opin. Biol. The r. 8, P1187-99). The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular edema. It has been recently published that plasma kallikrein contributes to retinal vascular dysfunctions in diabetic rats (A. Clermont et al. "Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats" Diabetes, 2011, 60, pl590-98). Furthermore, administration of the plasma kallikrein inhibitor ASP-440 ameliorated both retinal vascular permeability 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 activation of factor XI (FXI) thus resulting in blood coagulation. Plasma kallikrein is a key component in the intrinsic coagulation cascade 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.

Activation of FXII to FXIIa can also occur in the body by contact with negatively charged surfaces on various sources (e.g. bacteria during sepsis, RNA from degrading cells), thus resulting in disseminated intravascular coagulation (Tanaka et al. (Thrombosis Research 2004, 113, 333-339)).

Therefore, inhibition of plasma kallikrein 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, 361-368) showed that administration of a plasma kallikrein inhibitor, PKSI-527, for LPS-induced disseminated intravascular coagulation significantly suppressed the decrease in platelet count and fibrinogen level as well as the increase 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 reduced in plasma kallikrein-deficient mice. Revenko et al. (Blood, 2011, 118, 5302-5311) showed that the reduction of plasma prekallikrein levels in mice using antisense oligonucleotide treatment resulted in antithrombotic 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. conclude that Ecallantide "had in vitro anticoagulant effects as it inhibited the intrinsic pathway of coagulation by inhibiting plasma kallikrein".

Plasma kallikrein also plays a role in the inhibition of platelet activation, and therefore the cessation of bleeding. Platelet 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 platelets 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 inhibitors 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 bleeding 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 intervention involving an incision in the brain parenchyma that damaged blood vessels. These data demonstrate that plasma kallikrein inhibition reduced bleeding and hematoma volume from post-operative surgery. Bjorkqvist 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 postoperative bleeding.

Other complications of diabetes such as cerebral haemorrhage, nephropathy, 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 example 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 (2002)), Evans ("Selective dipeptide inhibitors of kallikrein" WO03/076458), Szelke et al. ("Kininogenase inhibitors" WO92/04371), D. M. Evans et al. (Immunolpharmacology, 32, pll5-116 (1996)), Szelke et al. ("Kininogen inhibitors"

WO95/07921), Antonsson et al. ("New peptides derivatives" W094/29335), J. Corte et al. ("Six membered heterocycles useful as serine protease inhibitors" W02005/123680), J. StOrzbecher et al. ( Brazilian J. Med. Biol. Res 27, pl929-34 (1994)), Kettner et al. (US 5,187,157), N. Teno et al. (Chem. Pharm. Bull. 41, pl079- 1090 (1993)), W. B. Young et al. ("Small molecule inhibitors of plasma kallikrein" Bioorg. Med. Chem. Letts. 16, p2034-2036 (2006)), Okada et al. ("Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship" Chem. Pharm. Bull. 48, pl964-72 (2000)), Steinmetzer et al. ("Trypsin-like serine protease inhibitors and their preparation and use" WO08/049595), Zhang et al. ("Discovery of highly potent small molecule kallikrein inhibitors" Medicinal Chemistry 2, p545- 553 (2006)), Sinha et al. ("Inhibitors of plasma kallikrein" W008/016883), Shigenaga et al. ("Plasma Kallikrein Inhibitors" WO2011/118672), and Kolte et al. ("Biochemical characterization of a novel high- affinity and specific kallikrein inhibitor", British Journal of Pharmacology (2011), 162(7), 1639-1649). Also, Steinmetzer et al. ("Serine protease inhibitors" W02012/004678) describes cyclized peptide analogs which are inhibitors of human plasmin and plasma kallikrein.

To date, the only selective plasma kallikrein inhibitor approved for medical use is Ecallantide. Ecallantide is formulated as a solution for injection. It is a large protein plasma kallikrein inhibitor that presents a risk of anaphylactic reactions. Other plasma kallikrein inhibitors known in the art are generally small molecules, some of which include highly polar and ionisable functional groups, such as guanidines or amidines.

Recently, plasma kallikrein inhibitors that do not feature guanidine or amidine functionalities have been reported. For example Brandi et al. ("N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein" W02012/017020), Evans et al. ("Benzylamine derivatives as inhibitors of plasma kallikrein" W02013/005045), Allan et al. ("Benzylamine derivatives" WO2014/108679), Davie et al. ("Heterocyclic derivates" WO2014/188211), and Davie et al. ("N-((het)arylmethyl)-heteroaryl-carboxamides compounds as plasma kallikrein inhibitors" W02016/083820).

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 associated with diabetic retinopathy and diabetic macular edema. Preferred compounds will possess a good pharmacokinetic profile and in particular will be suitable as drugs for oral delivery. Summary of the Invention

The present invention relates to a series of heterocyclic derivatives that are inhibitors of plasma kallikrein. These compounds have been found to demonstrate surprisingly good pharmacokinetic properties, in particular, in vitro permeability. In addition, they demonstrate good selectivity for plasma kallikrein and so are potentially useful in the treatment of a number of diseases in which plasma kallikrein is implicated, in particular, in the treatment of impaired visual acuity, diabetic retinopathy, 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 coagulation during cardiopulmonary bypass surgery, bleeding from post-operative surgery and retinal vein occlusion.

In particular, in a first aspect, the present invention provides compounds of formula (I),

R1 and R2 are independently selected from the group consisting of H, alkyl, halo,

cycloalkyl, -OCF₃, alkoxy, -OFI, -NR6R7, -NR6COR7 and -COOR6, wherein at least one of R1 and R2 is not H;

R3 and R4 are independently selected from the group consisting of H, alkyl, alkoxy and halo;

Q is pyridyl substituted with at least one of R12, R13, R14 and R15, wherein R12, R13, R14 and R15 are selected from the group consisting of alkyl, alkoxy, -OFI, halo, -CN, heteroaryl,

aryl, -COOR6, -NHCOR6, -CONR6R7, -OCF₃ and -CF₃;

R5 is selected from the group consisting of FI, alkyl, cycloalkyl, alkoxy, halo, OFI, aryl, heteroaryl,

N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl,

N-linked piperazinyl, -NR6R7, -CN, -COOR6, -CONR6R7, -NR6COR7 and -CF₃; R6 and R7 are independently selected from H or alkyl or where R6 and R7 are joined to the same atom, R6 and R7 can together with the N atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocyclic ring, optionally containing an additional heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di- substituted with substituents selected from the group consisting of oxo, alkyl, alkoxy, -OH, halo and -CF3; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C1-C10) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms (C3-C10), which may optionally be substituted with 1 or 2 substituents independently selected from the group consisting

of -(

and -NR8R9; cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 7 carbon atoms, which may optionally be substituted with a substituent selected from alkyl, alkoxy and -NR6R7; alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms or a branched O-linked

hydrocarbon of between 3 and 6 carbon atoms (C₃-C₆); alkoxy may optionally be substituted with 1 or 2 substituents independently selected from the group consisting

of

aryl is phenyl, biphenyl or naphthyl, which may optionally be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkoxy, -

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, S and O; wherein heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkoxy, -

R8 and R9 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert- butyl, or where both R8 and R9 are attached to the same atom, R8 and R9 can together with the nitrogen atom to which they are attached form piperidine, morpholine, piperazine or pyrrolidine; RIO and Rll are independently selected from H, -CHF2, -CF3, -CN, -OCF3, alkoxy, -OFI, -NR8R9, methyl, ethyl and propyl, or together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring; and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof; and wherein the compound of formula (I) is not

It has surprisingly been found that the compounds of formula (I) exhibit particularly good pharmacokinetic properties, for example, good metabolic clearance as evidenced by the data included herein. Without wishing to be bound be theory, the inventors believe that it is the combination of the substituted pyridone group at the left hand side of the molecule with the substituted pyridyl group at the right hand side of the molecule which results in these improved effects.

As noted above, R1 and R2 are independently selected from the group consisting of H, alkyl, halo, -CFIF2, - CF3, -CN, cycloalkyl, -OCF3, alkoxy, -OFI, -NR6R7, -NR6COR7 and -COOR6 wherein at least one of R1 and R2 is not FI. Preferably R1 and R2 are independently selected from the group consisting of alkyl,

halo, -CF3, -CFIF2 and -CN. Alternatively, R1 and R2 are independently selected from the group consisting of -CFIF2, -CN, cycloalkyl, -OCF3, -NR6R7, -NR6COR7 and -COOR6; wherein cycloalkyl and R6 and R7 are as defined above.

Alternatively or in combination with the definitions of R1 and R2 above, it is preferred that at least one of R1 and/or R2 is not unsubstituted alkyl or cycloalkyl.

As is clear from Formula (I), the substituents R1 and R2 may be at any position around the pyridone ring. In one preferred embodiment, the pyridone ring of the compound of formula (I) is substituted with H at the 6' position and R1 and R2 are in any of the 3', 4' and/or 5' positions on the pyridone ring. Thus, in such embodiments, the compound of formula (I) has the formula (IA) below:

wherein Rl, R2, R3, R4, R5, RIO, Rll and Q are as defined for formula (I). In a further preferred embodiment, the pyridone ring of the compound of formula (I) is substituted at the 3' and/or 5' positions. Thus, in such embodiments, the compound of formula (I) has formula (IB) below:

wherein Rl, R2, R3, R4, R5, RIO, Rll and Q are as defined for formula (I).

In some embodiments of the invention, the compounds have either formula (I), formula (IA) or formula (IB), preferably formula (IB), wherein Rl is FI and R2 is selected from the group consisting of alkyl, halo, -CFIF2, - CF3, -CN, cycloalkyl, -OCF3, alkoxy, -OFI, -NR6R7, -NR6COR7 and -COOR6, preferably alkyl, alkoxy, -CN, halo, -CF3, -CFIF2 and -CN, preferably wherein alkyl is C1-3 alkyl, or R2 is selected from the group consisting of -CFIF2, -CN, cycloalkyl, -OCF3, -NR6R7, -NR6COR7 and -COOR6; wherein cycloalkyl and R6 and R7 are as defined above. In other embodiments of the invention, the compounds have either formula (I), formula (IA) or formula (IB), preferably formula (IB), wherein R1 is H and R2 is selected from the group consisting of alkyl, halo, - CHF₂, -CF3, -CN, -OCF3, alkoxy, -OH, -NR6R7, -NR6COR7 and -COOR6, wherein alkyl, if present, is substituted with 1 or 2 substituents independently selected from the group consisting

of - and -NR8R9, preferably with 1 or 2

substituents, more preferably 1 substituent, independently selected from the group consisting of -(Ci-

In other embodiments of the invention, the compounds have either formula (I), formula (IA) or formula (IB), preferably formula (IB), wherein R1 is H and R2 is selected from the group consisting

In alternative embodiments of the invention, the compounds have either formula (I), formula (IA) of formula (IB) above, preferably Formula (IB) wherein R2 is FI and R1 is selected from the group consisting of preferably alkyl,

halo, -CF3, -CH F₂ and -CN, preferably wherein alkyl is C_1-3 alkyl, or R1 is selected from the group consisting of -CH F₂, -CN, cycloalkyl, -OCF3, -NR6R7, -NR6COR7 and -COOR6; wherein cycloalkyl and R6 and R7 are as defined above.

In other embodiments of the invention, the compounds have either formula (I), formula (IA) or formula (IB), preferably formula (IB), wherein R2 is FI and R1 is selected from the group consisting of alkyl, halo, - CH F₂, -CF₃, -CN, -OCF₃, alkoxy, -OFI, -NR6R7, -NR6COR7 and -COOR6, wherein alkyl, if present, is substituted with 1 or 2 substituents independently selected from the group consisting

of -

and -NR8R9, preferably with 1 or 2 substituents, more preferably 1 substituent, independently selected from the group consisting of -(Ci-

In other embodiments of the invention, the compounds have either formula (I), formula (IA) or formula (IB), preferably formula (IB), wherein R2 is H and R1 is selected from the group consisting

of -

In alternative embodiments of the invention, the compounds have either formula (I), formula (IA) or formula (IB) above i.e. both where R1 and R2 are at any position on the pyridone ring or where they are positioned according to formula (IA) or formula (IB) above, and both R1 and R2 are not H such that the pyridone ring is di-substituted. The substituents R3 and R4 are selected from the group consisting of H, alkyl, alkoxy and halo. In some embodiments, one of R3 and R4 is not H. In one such embodiments, R3 is H and R4 is selected from the group consisting of H, alkyl, alkoxy and halo, preferably alkoxy, in particular methoxy, and halo, in particular -F or -Cl. Alternatively, R4 is H and R3 is selected from the group consisting of H, alkyl, alkoxy and halo, preferably alkoxy, in particular methoxy, and halo, in particular -F or -Cl. Alternatively, R3 and R4 may both be H.

R5 is selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, halo, OH, aryl, heteroaryl,

N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl,

N-linked piperazinyl, -NR6R7, -CN, -COOR6, -CONR6R7, -NR6COR7 and -CF₃, wherein R6 and R7 are as defined in formula (I). In some embodiments, R5 is selected from the group consisting of H, -CH₂OCH₃, cycloalkyl, -NR6R7, -NR6COR7, -CN and -CF₃; wherein cycloalkyl and R6 and R7 are as defined in claim 1. Preferably R5 is alkyl substituted with -(Ci-Ce)alkoxy, particularly preferably -CH₂OCH₃.

R6 and R7 are as defined above in relation to Formula (I). In some embodiments, R6 and R7 are independently selected from the group consisting of H or alkyl, optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl or when R6 and R7 are joined to the same atom, R6 and R7 can together with the N atom to which they are attached form a piperidine ring, a morpholine ring, a piperazine ring or a pyrrolidine ring.

R8 and R9 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert- butyl, or where both R8 and R9 are attached to the same atom, R8 and R9 can together with the nitrogen atom to which they are attached form piperidine, morpholine, piperazine or pyrrolidine.

RIO and Rll are independently selected from -NR8R9, methyl, ethyl

and propyl, or together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring. Preferably one of RIO and Rll is H and the other is methyl. In an alternative preferred embodiment, both RIO and Rll are methyl. In a yet further preferred

embodiment, together with the carbon atom to which they are attached, RIO and Rll form a cyclopropyl ring. Most preferably, RIO and Rll are both H.

Q is pyridyl substituted with at least one of R12, R13, R14 and R15, wherein R12, R13, R14 and R15 are selected from the group consisting of alkyl, alkoxy, -OH, halo, -CN, heteroaryl, -COOR6, -NHCOR6, -CONR6R7, -OCF₃ and -CF₃. Preferably R12, R13, R14 and R15 are selected from the group consisting of -F, alkyl, more preferably methyl, and alkoxy, more preferably methoxy.

Preferably, Q is 2-pyridyl, specifically Q is:

Where Q has this structure, preferably R12, which is in an ortho position relative to the point of attachment to the remainder of the compound, is -F or methyl.

Where Q has the structure shown above, preferably R13, which is positioned para to the N atom of the pyridine ring, is methoxy.

Where Q has the structure shown above, preferably R12 is -F or methyl, R13 is methoxy and R14 and R15 are both H.

More preferably, where Q has the structure shown above, preferably R12 is -F, R13 is methoxy and R14 and R15 are both H.

In one embodiment of the present invention, the compounds of the present invention are compounds of formula (IA), more preferably formula (IB), wherein R1 and R2 are selected from the group consisting of alkyl, halo, -CN, -CF₃ and -CFIF2, R3 and R4 are both H, R5 is alkyl substituted with -(Ci-C₆)alkoxy, particularly preferably -CFl₂0CFI₃, and Q is as defined above in relation to formula (I), preferably, wherein Q is:

wherein R12 is -F or methyl, most preferably -F, R13 is methoxy and R14 and R15 are both H. The present invention also encompasses, but is not limited to, the compounds listed below:

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(3-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(5-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;

l-({4-[(3-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(4-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;

l-({4-[(4-chloro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-chloro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-5-(trifluoromethyl)pyridin-l- yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-3-(trifluoromethyl)pyridin-l- yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

l-({4-[(3-cyano-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(2-methyl-6-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;

l-({4-[(3,5-dichloro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-chloro-4-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-chloro-3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-chloro-3-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-ethyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-cyano-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3-cyclopropyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-

3-(methoxymethyl)pyrazole-4-carboxamide; l-({4-[(4-cyano-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-tert-butyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-cyclopropyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-

3-(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[3-(methoxymethyl)-2-oxopyridin-l- yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(3-fluoro-5-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3,5-dimethyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-

3-(methoxymethyl)pyrazole-4-carboxamide;

l-[(4-{[3-(difluoromethyl)-2-oxopyridin-l-yl]methyl}phenyl)methyl]-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-[(4-{[5-(difluoromethyl)-2-oxopyridin-l-yl]methyl}phenyl)methyl]-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3-chloro-5-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-[(4-{[3-(aminomethyl)-2-oxopyridin-l-yl]methyl}phenyl)methyl]-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(3-methoxy-2-oxopyridin-l-yl)methyl]phenyl}methyl)-3-

(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-chloro-3-methoxy-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3,4-dimethyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-

3-(methoxymethyl)pyrazole-4-carboxamide;

l-[(4-{[5-(aminomethyl)-2-oxopyridin-l-yl]methyl}phenyl)methyl]-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(5-isopropyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-3-

(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-ethyl-3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3-chloro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide; l-({2-fluoro-4-[(3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3,5-dimethyl-2-oxopyridin-l-yl)methyl]-2-fluorophenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({2-fluoro-4-[(5-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-fluoro-3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(5-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-3-

(trifluoromethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-3-

(trifluoromethyl)pyrazole-4-carboxamide;

3-cyclopropyl-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(3-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;

l-({2-fluoro-4-[(5-fluoro-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2- yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3,5-difluoro-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]- 3- (methoxymethyl)pyrazole-4-carboxamide;

l-[(4-{[5-fluoro-2-oxo-3- (trifluoromethyl)pyridin-l- yl]methyl}phenyl)methyl]-N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide;

l-[(4-{[5-chloro-2-oxo-3- (trifluoromethyl)pyridin-l- yl]methyl}phenyl)methyl]-N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide;

l-({2-fluoro-4-[(5-fluoro-3-methyl-2-oxopyridin- l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide;

l-({3-fluoro-4-[(5-fluoro-3-methyl-2-oxopyridin- l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide;

l-({3-fluoro-4-[(5-fluoro-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2- yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-fluoro-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]-3- (trifluoromethyl)pyrazole-4-carboxamide;

l-({4-[(5-fluoro-3-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2- yl)methyl]-3- (trifluoromethyl)pyrazole-4-carboxamide;

3-cyclopropyl-l-({4-[(5-fluoro-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2- yl)methyl]pyrazole-4- carboxamide; 3-cyclopropyl-l-({4-[(5-fluoro-3-methyl-2- oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3- fluoro-4- methoxypyridin-2-yl)methyl]pyrazole-4- carboxamide;

l-({4-[l-(5-fluoro-2-oxopyridin-l-yl)ethyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[2-(5-fluoro-2-oxopyridin-l-yl)propan-2-yl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(4-methoxy-3-methylpyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

l-({3-fluoro-4-[(3-methyl-2-oxopyridin- l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2- yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

The present invention also encompasses, but is not limited to, the compounds listed below:

(methoxymethyl)pyrazole-4-carboxamide;

(methoxymethyl)pyrazole-4-carboxamide; l-({4-[(5-chloro-4-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

(methoxymethyl)pyrazole-4-carboxamide;

3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(4-cyano-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

3-(methoxymethyl)pyrazole-4-carboxamide;

(methoxymethyl)pyrazole-4-carboxamide; l-({4-[(5-chloro-3-methoxy-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

3-(methoxymethyl)pyrazole-4-carboxamide;

(methoxymethyl)pyrazole-4-carboxamide;

l-({2-fluoro-4-[(3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

(trifluoromethyl)pyrazole-4-carboxamide;

(methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

The present invention also encompasses but is not limited to, the compounds listed below:

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(5-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; l-({4-[(3-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide;

3-(methoxymethyl)pyrazole-4-carboxamide;

(methoxymethyl)pyrazole-4-carboxamide;

l-({2-fluoro-4-[(3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide; l-({4-[(3,5-dimethyl-2-oxopyridin-l-yl)methyl]-2-fluorophenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

(trifluoromethyl)pyrazole-4-carboxamide;

(methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(3-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide

(methoxymethyl)pyrazole-4-carboxamide;

(methoxymethyl)pyrazole-4-carboxamide; l-[(4-{[3-(difluoromethyl)-2-oxopyridin-l-yl]methyl}phenyl)methyl]-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(2-methyl-6-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamidel-({4-[(4-cyano-2-oxopyridin-l-yl)methyl]phenyl}methyl)-

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

(methoxymethyl)pyrazole-4-carboxamide;

l-[(4-{[3-(difluoromethyl)-2-oxopyridin-l-yl]methyl}phenyl)methyl]-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(3-methoxy-2-oxopyridin-l-yl)methyl]phenyl}methyl)-3-

(methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

(methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof. The present invention also encompasses but is not limited to, the compounds listed below:

(methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

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

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

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

The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and an amount of one or more pharmaceutically acceptable solvents, for example, ethanol. The term 'hydrate' is employed when the solvent is water.

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

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

The present invention also provides for the use of a compound 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 activity 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 kallikrein activity 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 syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, bleeding from post-operative surgery and retinal vein occlusion.

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

In an alternative preferred aspect, the disease or condition in which plasma kallikrein activity is implicated 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 activity is implicated is retinal vein occlusion. Combination Therapy

The compounds of the present invention may be administered in combination with other therapeutic 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 (PDGF), endothelial growth factor (VEGF), integrin alpha5betal, 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 disclosed 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 separately, sequentially or simultaneously.

In another aspect, the compounds of the present invention may be administered in combination 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". Ophthalmology. 27 April 2010).

Definitions

The term "alkyl" includes saturated hydrocarbon residues including:

linear groups up to 10 carbon atoms (Ci-Cio), or of up to 6 carbon atoms (Ci-Ce), or of up to 4 carbon atoms (C1-C4). Examples of such alkyl groups include, but are not limited, to Ci - methyl, C2 - ethyl, C3 - propyl and C₄- n-butyl.

branched groups of between 3 and 10 carbon atoms (C3-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 limited to, C3 - iso-propyl, C₄ - sec-butyl, C₄ - iso-butyl, C₄ - tert-butyl and C₅ - neo-pentyl,

each optionally substituted as stated above. Preferably alkyl is a linear group containing 1 to 4 carbon atoms (C4), or branched group containing 3 to 5 carbon atoms (C3-5).

Cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 7 carbon atoms, or between 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 -NR6R7; wherein R6 and R7 are independently selected from FI or alkyl or where R6 and R7 are joined to the same atom, R6 and R7 can together with the N atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocyclic ring, optionally containing an additional heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted with substituents selected from the group consisting of oxo, alkyl, alkoxy, -OH, halo and -CF₃. Alternatively, cycloalkyl may be substituted with a substituent selected from alkyl, alkoxy and -NR8R9; wherein R8 and R9 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, or where both R8 and R9 are attached to the same atom, R8 and R9 can together with the nitrogen atom to which they are attached form piperidine, morpholine, piperazine or pyrrolidine. Cycloalkyl groups may contain from 3 to 7 carbon atoms, or from 3 to 6 carbon atoms, or from 3 to 5 carbon atoms, or from 3 to 4 carbon atoms. Examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferably cycloalkyl is cyclopropyl.

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

linear groups of between 1 and 6 carbon atoms (Ci-Ce), or of between 1 and 4 carbon atoms (C₁-C₄). Examples of such alkoxy groups include, but are not limited to, Ci - methoxy, C₂ - ethoxy, C₃ - n-propoxy and C₄ - n-butoxy.

branched groups of between 3 and 6 carbon atoms (C₃-C₆) 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. Preferably, alkoxy is a linear or branched group containing 1 to 4 carbon atoms (C_1-4).

Unless otherwise stated, halo is selected from Cl, F, Br and I.

Aryl is as defined above. Typically, aryl will be optionally substituted with 1, 2 or 3 substituents. Optional substituents are selected from those stated above. Examples of suitable aryl groups include phenyl and naphthyl (each optionally substituted as stated above). Preferably aryl is selected from phenyl, substituted phenyl (wherein said substituents are selected from those stated above) and naphthyl.

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. Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, 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 remainder of the molecule via an oxygen atom.

In groups such as -(CH2)i-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, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, /V-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, pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates, camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates and the like.

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

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

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

The compounds of the 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, ethanol. The term 'hydrate' is employed when the solvent 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-, S- 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 includes all isotopic variants.

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

General Methods

The compounds of the invention should be assessed for their biopharmaceutical properties, such as solubility and solution stability (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 invention which may impart either a functional (i.e., drug release rate controlling) and/or a non-functional (i.e., processing aid or diluent) characteristic 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 solubility 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 preparation may be found, for example, in Remington's

Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995). Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.

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 suitable 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, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration 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 (preferably 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 vehicle 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 surgical 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 readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of the invention 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 sublingual administration 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; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.

Liquid (including multiple phases and dispersed systems) formulations include emulsions, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) 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 compounds 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 Patents, 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 patients, 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. If administered by intra-vitreal injection a lower dose of between 0.0001 mg (0.1 pg) and 0.2 mg (200 pg) per eye is envisaged, or between 0.0005 mg (0.5 pg) 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 further exemplified by the specific examples provided herein below. Moreover, by utilising the procedures described herein, one of ordinary 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 present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare 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 necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds 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, 4^th Edition, 2006, may be used. For example, a common amino protecting group suitable for use herein is tert-butoxy carbonyl (Boc), which is readily removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as dichloromethane. Alternatively the amino protecting group may be a benzyloxycarbonyl (Z) group which can be removed by hydrogenation 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 diethylamine or piperidine in an organic solvent. Carboxyl groups are typically protected as esters such as methyl, ethyl, benzyl or tert-butyl which can all be removed by hydrolysis in the presence of bases such as lithium or sodium hydroxide.

Benzyl protecting groups can also be removed by hydrogenation 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 H Br 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 catalyst 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 general formula I can be prepared using conventional synthetic methods for example, but not limited to, the route outlined in Scheme 1.

The halide 1 is reacted with substituted pyrazole 2 (step A) typically using potassium carbonate to give ester 3, requiring separation of regioisomsers confirming their identity by NOESY NMR. The ester is hydrolysed (Step B) using standard literature conditions such as NaOH, KOH, or LiOH. The acid (or salt) 4 is coupled to amine 5 (Step C) to give compound 6. This coupling is typically carried out using standard coupling conditions such as hydroxybenzotriazole and carbodiimide such as water soluble carbodiimide in the presence of an organic base. Other standard coupling methods include the reaction of acids with amines in the presence of 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethylaminium hexafluorophosphate or benzotriazole-l-yl-oxy-tris-pyrrolidino-phosphoium hexafluorophosphate or bromo-trispyrolidino- phosphoium hexafluorophosphate in the presence of organic bases such as triethylamine,

diisopropylethylamine or N-methylmorpholine. Alternatively, the amide formation can take place via an acid chloride in the presence of an organic base. Such acid chlorides can be formed by methods well known in the literature, for example reaction of the acid with oxalyl chloride or thionyl chloride. The alcohol 6 is transformed to chloride 7 (Step D) via the mesylate following standard procedures using methanesulfonyl chloride and triethylamine. Alkylation of chloride 7 with pyridone 8 (Step E) was completed typically using a base such as potassium carbonate.

Alternatively, compounds according to general formula I can be prepared using the route exemplified in Scheme 2 following similar synthetic methods to those described for Scheme 1.

Examples

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

All reactions were carried out under an atmosphere of nitrogen unless specified otherwise.

¹H NMR spectra were recorded on a Bruker (500MHz or 400MHz) spectrometer with reference to deuterium solvent and at rt and reported in ppm.

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% HCChH/MeCN into 0.1% HCO2H/H2O over 13 min, flow rate 1.5 mL/min, or using Agilent, X-Select, acidic, 5-95% MeCN/water over 4 min. Data was collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electospray ionisation in conjunction with a Thermofinnigan Surveyor LC system.

Where products 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 p.s.i accelerated column elution. Reverse phase preparative HPLC purifications were carried out using a Waters 2525 binary gradient 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 ISIS Draw package from MDL Information Systems or the Chemaxon software provided as a component of MarvinSketch or as a component of the IDBS E-WorkBook.

Examples of the invention

Synthesis of Intermediates

General Method A Methyl l-{[4-(hydroxymethyl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxylate

To a stirred solution of methyl-3-(methoxymethyl)-lH-pyrazole-4-carboxylate (1 g, 5.9 mmol) in a mixture of MeCN (15 mL) and DMF (10 mL) was added K2CO3 (1.62 g, 11.8 mmol) and [4- (chloromethyl)phenyl]methanol (0.92 g, 5.9 mmol). The resulting mixture was stirred at 70 ^°C for 2 hrs. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The aqueous phase was extracted with EtOAc (50 mL) and the combined organics were washed with water (100 mL) and brine (50 mL), then dried (MgSO^, filtered and concentrated in vacuo to afford a yellow oil. The crude product was purified by automated column chromatography eluting with hexane/ EtOAc to afford the title compound as a colourless oil (846 mg, 2.9 mmol, 48% yield)

[M+H]⁺ = 290.8

General Method B

l-{[4-(hydroxymethyl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxylic acid

To a stirred solution of methyl l-[4-(hydroxymethyl)phenyl]methyl]-3-(methoxymethyl)pyrazole-4- carboxylate (846 mg, 2.9 mmol) in MeOH (10 mL) was added a solution of KOH (245 mg, 4.4 mmol) in water (1 mL). The resulting solution was heated to 60 ^°C for 3 hrs. The reaction was cooled to rt and concentrated in vacuo. The product was used subsequently as a potassium salt (2.9 mmol, assumed quantitative yield). [M+H]⁺ = 277.1

General Method C

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-{[4-(hydroxymethyl)phenyl]methyl}-3-

(methoxymethyl)pyrazole-4-carboxamide

To a stirred solution of l-[[4-(hydroxymethyl)phenyl]methyl]-3-(methoxymethyl)pyrazole-4-carboxylic acid (805 mg, 2.9 mmol), (3-fluoro-4-methoxy-2-pyridyl)methanamine dihydrochloride (667 mg, 2.9 mmol) and N,N-diisopropylethylamine (2.5 mL, 14.6 mmol) in NMP (5 mL) was added HATU (1.66 g, 4.4 mmol) and the resulting mixture stirred at rt for 2hrs. Upon completion the reaction was diluted with water (80 mL) and EtOAc (50 mL) was added. The biphasic mixture was separated and the organic phase was washed with additional water (2 x 20 mL) and reduced in volume to about 15 mL whereupon a solid began to precipitate from solution. The solid was collected by filtration and dried in a desiccator for 2hrs. During this time, the combined aqueous phase had been left stirring resulting in the eventual precipitation of a second crop of solid. The mixture was filtered and the solid washed with water and air-dried on the filter. The combined solids were further dried in a desiccator to afford the desired compound (320 mg, 0.7 mmol, 26% yield) as an off-white solid.

[M+H]⁺ =415.2

General Method D

l-{[4-(chloromethyl)phenyl]methyl}-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide

To a stirred solution of N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-{[4-hydroxymethyl)phenyl]methyl}-3- (methoxymethyl)pyrazole-4-carboxamide (320 mg, 0.8 mmol) in DCM (10 mL) was added triethylamine (151 pL, 1.1 mmol) followed by methanesulfonyl chloride (78.2 pL, 1 mmol). The resulting reaction was stirred at 40 °C for 3 days. The reaction mixture was partitioned between DCM (10 mL) and saturated NH4CI(aq) (10 mL). The organic layer was collected and the aqueous layer extracted with further DCM (10 mL). The combined organics were washed with water (10 mL) and brine (10 mL), then dried (MgSCU), filtered and concentrated in vacuo to afford the title compound (330 mg, 0.7 mmol, 90% yield) as a brown solid which was used without further purification.

[M+H]⁺ = 433.1

4-(bromomethyl)-2-fluorobenzoic acid

A suspension of 2-fluoro-4-methyl-benzoic acid (2.5 g, 16.2 mmol) and l-bromopyrrolidine-2,5-dione (4.3 g, 24.2 mmol) in 1,2-dichloroethane (50 mL) was heated to reflux until a homogeneous solution was achieved. To the reaction was added AIBN (40 mg, 0.2 mmol) and the resulting mixture stirred at reflux for 2hrs. The reaction was cooled to rt and concentrated in vacuo, to afford a pale yellow solid. The material was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous phase was washed with water (25 mL) and brine (25 mL). The organic layer was dried (MgSCU), filtered and concentrated in vacuo to afford a pale yellow solid. The crude solid was triturated in 10% EtOAc/isohexane (50 mL) with stirring for 30 min. The suspension was filtered and the solid washed with additional 10% EtOAc/isohexane (15 mL) then dried in vacuo at 40 °C, to afford the title compound (2 g, 7.7 mmol, 48% yield) as a white solid.

[M+H]⁺ = 233.0/234.9

[4-(bromomethyl)-2-fluorophenyl]methanol

To a stirred solution of 4-(bromomethyl)-2-fluoro-benzoic acid (2 g, 7.7 mmol) in THF (30 mL) at rt was added borane tetrahydrofuran complex (20 mL, 20.0 mmol) dropwise over 5 min. The resulting solution was heated to reflux overnight. The reaction was cooled to 0 °C and slowly quenched by the portion-wise addition of MeOH (20 mL). The mixture was concentrated in vacuo and the residue re-concentrated to dryness from fresh MeOH (50 mL), to afford an orange oil which slowly solidified on standing. The residue was purified by column chromatography on silica (0-30% EtOAc in hexane) to afford the title compound (1.69 g, 7.1 mmol, 92% yield) as a white solid.

[MH-H₂0]⁺ 201.0/202.9

Methyl l-{[3-fluoro-4-(hydroxymethyl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxylate

Following general method A, methyl-3-(methoxymethyl)-lH-pyrazole-4-carboxylate (1 g, 5.9 mmol) was reacted with [4-(bromomethyl)-2-fluorophenyl]methanol (1.69 g, 7.1 mmol). Following the usual work up and purification the desired product was isolated (1.05 g, 3.3 mmol, 47% yield) as a colourless oil which solidified on standing. Regiochemistry was confirmed by NOESY NMR.

[M+H]⁺ = 309.1

¹H NMR (DMSO-d6, 500 MHz) d 3.24 (3H, s), 3.74 (3H, s), 4.51 (4H, d, J = 3.4 Hz), 5.25 (1H, t, J = 5.7 Hz), 5.34 (2H, s), 7.05 - 7.12 (2H, m), 7.44 (1H, t, J = 7.8 Hz), 8.45 (1H, s).

Lithio l-{[3-fluoro-4-(hydroxymethyl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxylate

Following a modification of general method B, methyl l-{[3-fluoro-4-(hydroxymethyl)phenyl]methyl}-3- (methoxymethyl)pyrazole-4-carboxylate (1.05 g, 3.4 mmol) was reacted with LiOH (0.12 g, 5.0 mmol) in a mixture of 1,4-dioxane (10 mL) and water (3 mL). After the usual work up, the solid was dried in vacuo at 40 °C for 2 hrs to afford the title compound as a white solid. The material was reacted without further purification, assuming quantitative yield.

[M+H]⁺ = 295.0 l-{[3-fluoro-4-(hydroxymethyl)phenyl]methyl}-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide

Following method C, lithium l-[[3-fluoro-4-(hydroxymethyl)phenyl]methyl]-3-(methoxymethyl)pyrazole-4- carboxylate (500 mg, 1.7 mmol), was reacted with (3-fluoro-4-methoxy-2-pyridyl)methanamine dihydrochloride (390 mg, 1.7 mmol). After the usual work up the crude material was purified by column chromatography on silica (1-10% MeOFI in DCM). The solid was triturated in a mixture of DCM (0.5 mL) and Et₂0 (4 mL). The solid was recovered by filtration and washed with Et₂0 to give the desired product (321 mg, 0.7 mmol, 44% yield) as a white solid.

[M+H]⁺ = 433.2 l-{[4-(chloromethyl)-3-fluorophenyl]methyl}-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide

To a solution of l-{[3-fluoro-4-(hydroxymethyl)phenyl]methyl}-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]- 3-(methoxymethyl)pyrazole-4-carboxamide (200 mg, 0.5 mmol) in DCM (4 mL) at 0 °C was added thionyl chloride (54 mί, 0.7 mmol) and the reaction stirred at rt for 1 hour. The reaction was concentrated in vacuo, to afford the title compound as a white foam (0.5 mmol, assumed quantitative yield).

[M+H]⁺ = 451.1/453.1

4-(bromomethyl)-3-fluorobenzoic acid

A suspension of 3-fluoro-4-methyl-benzoic acid (7 g, 45.4 mmol) and l-bromopyrrolidine-2,5-dione (8.08 g, 45.4 mmol) in CHCI3 (150 mL) was heated to reflux until a homogeneous solution was achieved. To the reaction was added AIBN (100 mg, 0.61 mmol) and the resulting mixture stirred at reflux overnight. The reaction was cooled to rt and concentrated in vacuo, to give an orange solid. The material was triturated with a mixture of DCM (50 mL) and isohexane (50 mL) and the by-product filtered off. The filtrate was concentrated in vacuo and purified by column chromatography eluting with isohexane in EtOAc (0-100%). The title compound (5.22 g, 13.4 mmol, 30% yield) was isolated as a white solid.

[M+HC0₂H]⁺ = 277.1/291.1

[4-(bromomethyl)-3-fluorophenyl]methanol

A solution of 4-(bromomethyl)-3-fluorobenzoic acid (5.2 g, 22.3 mmol) in anhydrous THF (70 mL), was treated with 1M borane tetrahydrofuran complex (4.79 g, 55.8 mmol) dropwise over 5 min. After the addition was complete and gas evolution had ceased the reaction mixture was heated under reflux for 24hrs. The reaction mixture was cooled to 0 °C and MeOH (15 mL) added dropwise under vigorous stirring. After the addition was complete the reaction mixture was concentrated to dryness, azeotroping with MeOH (150 mL). The crude product was purified by column chromatography on silica eluting with isohexane / TBME 0-30% to afford the desired compound (1.8 g, 8.22 mmol, 37% yield) as a grey solid.

¹H NMR (CDCIs, 400M HZ) d 4.44 (2H, s), 4.62 (2H, s), 7.00-7.07 (2H, m), 7.30 (1H, t, J = 7.8 Hz).

Methyl l-{[2-fluoro-4-(hydroxymethyl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxylate

Following general procedure A, a solution of methyl 3-(methoxymethyl)-lH-pyrazole-4-carboxylate (1.32 g, 7.7 mmol) in MeCN (15 mL) was reacted with [4-(bromomethyl)-3-fluoro- phenyljmethanol (1.7 g, 7.7 mmol) at 70 °C for 48 hrs. The cooled reaction mixture was filtered and the solid washed with acetonitrile (100 mL). The filtrate was concentrated to dryness in vacuo and the residue purified by column chromatography eluting with 100% TBME to afford the title compound (1.79 g, 5.2 mmol, 67% yield). Regiochemistry was confirmed by NOESY NMR.

[M+H]⁺ = 309.1

¹H NMR (CDCIs, 400MHz) d 3.44 (3H, s), 3.78 (3H, s), 4.66 (2H, s), 4.69 (2H, s), 5.31 (2H, s), 7.02 -7.15 (2H, m), 7.20 (1H, t, J=7.7 Hz), 7.83 (1H, s)

Lithio l-{[2-fluoro-4-(hydroxymethyl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxylate

Following a modification of general method B, a solution of methyl l-[[2-fluoro-4-

(hydroxymethyl)phenyl]methyl]-3-(methoxymethyl)pyrazole-4-carboxylate (1.8 g, 5.8 mmol) in a mixture of water (5 mL) and 1,4-dioxane (20 mL) was treated with LiOH (203 mg, 8.5 mmol) and the mixture heated at 70°C with stirring overnight. The solvent was removed under reduced pressure and the residue azeotroped with ethanol and toluene to afford the title compound (2 g, 5.7 mmol, 97% yield) as a brown solid, which was used without further purification. [M+H]⁺ = 295.1

l-{[2-fluoro-4-(hydroxymethyl)phenyl]methyl}-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide

Following method C, lithio l-{[2-fluoro-4-(hydroxymethyl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4- carboxylate (500 mg, 1.7 mmol) was reacted with (3-fluoro-4-methoxy-2-pyridyl)methanamine dihydrochloride (390 mg, 1.7 mmol). After the standard work up, the crude product was purified by column chromatography on silica eluting with 1-10% MeOH in DCM to afford the title compound (280 mg, 0.6 mmol, 39% yield) as a white solid.

[M+H]⁺ = 433.1 l-{[4-(chloromethyl)-2-fluorophenyl]methyl}-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide

To a stirred solution of l-{[2-fluoro-4-(hydroxymethyl)phenyl]methyl}-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide (250 mg, 0.6 mmol) in DCM (10 mL) at 0 °C was added thionylchloride (66.7 pL, 0.9 mmol). The reaction was stirred at rt overnight. The reaction mixture was concentrated in vacuo, to afford the title product (260 mg, 0.6 mmol, quantitative yield) as a pale yellow solid.

[M+H]⁺ = 451.1/453.1

General Method F

3-chloro-5-methylpyridin-2-ol

To a solution of 2,3-dichloro-5-methyl-pyridine (200 mg, 1.2 mmol) in tert-butanol (5 mL) was added potassium tert-butoxide (970 mg, 8.6 mmol) and the mixture heated at 100 °C for 8hrs. The cooled reaction mixture was concentrated to dryness and the residue treated with 2N HCI(aq) (10 mL). The resulting brown solid was collected by filtration and dried under vacuum at 50 °C. The title compound (80 mg, 0.3 mmol, 27% yield) was isolated as a brown solid.

¹H NMR (400 MHz, DMSO-d6) 2.02 (3H, d, J = 1.0 Hz), 7.19 (1H, dq, J = 2.2, 1.1 Hz), 7.64 (1H, d, J = 2.3 Hz) 11.92 (1H, s).

5-isopropylpyridin-2-ol

Following General Method F, 2-chloro-5-isopropyl-pyridine (190 mg, 1.2 mmol) was reacted at 120°C for 3hrs. After the usual work up, the product was purified by column chromatography on silica eluting with MeCN/MeOH 0-5% to afford the desired compound (140 mg, 0.8 mmol, 67% yield) as a colourless oil.

¹H NMR (d6-DMSO, 400M Hz) 1.12 (6H, d, J = 6.9 Hz), 2.71 (1H, sept, J = 6.9Hz), 6.44 (1H, d, J = 10.1 Hz), 7.24 (1H, s), 7.54 (1H, d, J = 9.6 Hz), OH not observed

General Method G

5-(difluoromethyl)-2-methoxypyridine

To a suspension of cesium carbonate (1.0 g, 3.1 mmol) in a mixture of MeOH (2 mL) and toluene (5 mL) was added 2-bromo-5-(difluoromethyl)pyridine (450 mg, 2.2 mmol) followed by palladium(ll) acetate (4.66 mg, 0.02 mmol) and di-tert-butyl-[l-(l,3,5-triphenylpyrazol-4-yl)pyrazol-3-yl]phosphane (21.5 mg, 0.04 mmol). The mixture was stirred at 80 °C in a focussed microwave reactor for 2 hrs. The reaction was cooled and the inorganics filtered off. The filtrate was concentrated and the residue taken up in TBME and again filtered to remove remaining traces of inorganics. Concentration of the TBM E filtrate afforded the title compound (300 mg, 1.2 mmol, 55% yield) as an oil. The product was used without further purification due to its volatility.

[M+H]⁺ = 160.5

¹H NMR (CDCI₃, 400M HZ) 3.97 (3H, s), 6.64 (1H, t, J = 56.0 Hz), 6.82 (1H, d, J = 8.6 Hz), 7.67 - 7.79 (1H, m), 8.28 (1H, t, J = 2.1 Hz)

2-methoxy-3,4-dimethylpyridine

Following general method G, starting from 2-chloro-3, 4-dimethyl-pyridine (250 mg, 1.8 mmol). The title compound (168 mg, 1.04 mmol, 59% yield) was isolated as a yellow oil.

NMR (d6-DMSO) 2.06 (3H, s), 2.22 (3H, s), 3.83 (3H, s), 6.78 (1H, d, J = 5.1 Hz), 7.84 (1H, d, J = 5.1 Hz)

General Method H

5-(difluoromethyl)pyridin-2-ol

A solution of 5-(difluoromethyl)-2-methoxy-pyridine (500 mg, 3.1 mmol) and iodo(trimethyl)silane (0.9 mL, 6.3 mmol) in anhydrous MeCN (3 mL) was stirred at 70 °C for 2hrs. The cooled reaction mixture was poured into MeOH (30 mL) and the solution concentrated. The crude product was purified by a silica plug eluting with EtOAc (100%) to afford the product as a black solid. The product was dissolved in EtOAc (60 mL) and the solution treated with 10% aqueous sodium thiosulphate (1.5 mL) to remove the residual iodine. The mixture was dried (MgSO^, filtered and concentrated to dryness to yield the title compound (337 mg, 1.8 mmol, 57% yield) as a pale brown solid .

¹H NMR (400MHz, DMSO-d6) 6.44 (1H, d, J = 9.5 Hz), 6.81 (1H, t, J = 55.2 Hz), 7.58 (1H, dd, J = 9.6, 2.7 Hz),

7.73 (1H, q, J = 2.5 Hz), 11.87 (1H, s)

3,4-dimethylpyridin-2-ol

Following general method H, 2-methoxy-3, 4-dimethyl-pyridine (168 mg, 1.0 mmol) was reacted at 70 °C for 4hrs. The reaction was quenched with MeOH then the mixture was adsorbed onto silica and purified by flash chromatography on silica, eluting with 1-5% MeOH in DCM to afford the title compound (83 mg, 0.5 mmol, 55% yield) as an off-white solid.

[M+H]⁺ =124.1

¹H NMR (d6-DMSO) 1.90 (3H, s), 2.09 (3H, s), 5.99 (1H, d, J = 6.7 Hz), 7.08 (1H, d, J = 6.6 Hz), 11.26 (1H, s)

E. General procedure for alkylation of substitued pyridone

To a stirred solution of 7 (1 eq) in acetone or DMF (typically 10 mL) was added the required substituted pyridone 8 (1-2 eq) and K₂CO₃ (3 eq). The reaction mixture was stirred at rt to 80 °C for between 18-48hrs. After cooling to rt, the reaction mixture was concentrated in vacuo and the crude material was partitioned between DCM (10 mL) and water (10 mL). The organic phase was washed with water (5 mL) and brine (5 mL), then dried (MgSCU), filtered and concentrated in vacuo. The residue was purified by automated column chromatography eluting with 1-8% MeOH in DCM. Final compounds were either freeze dried from acetonitrile /water or the material was triturated with appropriate solvent mixtures.

The following compounds were synthesised according to general alkylation method E:

Example 35

l-({2-fluoro-4-[(3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide

Following method E, l-[[4-(chloromethyl)-2-fluoro-phenyl]methyl]-N-[(3-fluoro-4-methoxy-2- pyridyl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide (70 mg, 0.15 mmol) was reacted with 3-methyl- lH-pyridin-2-one (21 mg, 0.2 mmol) in acetone (2 mL) at 70 °C for 48hrs. After the standard purification and trituration in a mixture of DCM (0.5 mL) and Et₂0 (2 mL). The solid was recovered by filtration, washed with Et₂0 and dried under vacuum to afford the title compound (51 mg, 0.1 mmol, 62% yield) as a white solid.

¹H NMR (DMSO-d6, 500 MHz) 2.00 (3H, s), 3.25 (3H, s), 3.93 (3H, s), 4.50 (2H, s), 4.53 (2H, dd, J = 5.4, 2.2 Hz), 5.09 (2H, s), 5.34 (2H, s), 6.17 (1H, t, J = 6.7 Hz), 7.09 - 7.17 (2H, m), 7.19 (1H, t, J = 6.1 Hz), 7.26 (1H, t, J = 7.9 Hz), 7.31 (1H, d, J = 6.8 Hz), 7.66 (1H, dd, J = 6.9, 1.9 Hz), 8.21 - 8.30 (2H, m), 8.45 (1H, t, J = 5.4Hz) Example 36

l-({4-[(3,5-dimethyl-2-oxopyridin-l-yl)methyl]-2-fluorophenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide

Following method E, l-[[4-(chloromethyl)-2-fluoro-phenyl]methyl]-N-[(3-fluoro-4-methoxy-2- pyridyl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide (70 mg, 0.15 mmol) was reacted with 3,5- dimethyl-lH-pyridin-2-one (24 mg, 0.2 mmol) in acetone (2 mL) at 70 °C for 48hrs. After the standard work up and purification, the product was triturated in a mixture of DCM (0.5 mL) and Et₂0 (2 mL). The solid was recovered by filtration washing with Et₂0 and dried under vacuum to afford the title compound (42 mg,

0.07 mmol, 48% yield) as a white solid.

[M+H]⁺ = 538.2

¹H NMR (d6-DMSO, 500 MHz) 1.98 (6H, s), 3.26 (3H, s), 3.93 (3H, s), 4.50 (2H, s), 4.53 (2H, dd, J = 5.4, 2.2 Hz), 5.04 (2H, s), 5.34 (2H, s), 7.09 - 7.22 (4H, m), 7.26 (1H, t, J = 7.9 Hz), 7.44 (1H, s), 8.24 (2H, d, J = 6.0 Hz), 8.45 (1H, t, J = 5.4 Hz)

Example 32

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(5-isopropyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-

3-(methoxymethyl)pyrazole-4-carboxamide

Following method E, l-[[4-(chloromethyl)-2-fluoro-phenyl]methyl]-N-[(3-fluoro-4-methoxy-2- pyridyl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide (200 mg, 0.5 mmol) was reacted with 5- isopropyl-lH-pyridin-2-one (140 mg, 1.0 mmol) in DMF (2 ml) at 70 °C for 18hrs. After the usual work up, the crude product was purified by column chromatography on silica eluting with MeCN/MeOFI 0-5% to afford the desired compound (143 mg, 0.3 mmol, 57% yield) as a beige solid.

¹H NMR (d6-DMSO, 400M Hz) 1.11 (6H, d, J = 6.9 Hz), 2.58 - 2.74 (1H, m), 3.26 (3H, s), 3.93 (3H, s), 4.47 - 4.58 (4H, m), 5.04 (2H, s), 5.28 (2H, s), 6.39 (1H, d, J=9.3 Hz), 7.16 - 7.21 (1H, m), 7.21 - 7.29 (4H, m), 7.43 (1H, dd, J= 9.3, 2.7 Hz), 7.57 (1H, d, J = 2.6 Hz), 8.24 (1H, d, J = 5.6 Hz), 8.26 (1H, s), 8.43 (1H, t, J = 5.4Hz) Example 30

l-({4-[(3,4-dimethyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide

Following method E, l-[[4-(chloromethyl)-2-fluoro-phenyl]methyl]-N-[(3-fluoro-4-methoxy-2- pyridyl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide (100 mg, 0.2 mmol) was reacted with 3,4- dimethylpyridin-2-ol (45 mg, 0.3 mmol) in anhydrous DMF (1.5 mL) at rt for 48hrs. Following the standard work up and purification the isolated product was triturated in Et₂0 (1.5 mL). The solid was recovered by filtration and washed with Et₂0 and dried under vacuum to afford the title compound (40 mg, 0.07 mmol, 33% yield) as a white solid.

[M+H]⁺ = 520.2

¹H NMR (d6-DMSO, 400M Hz) 1.94 (3H, s), 2.09 (3H, s), 3.25 (3H, s), 3.92 (3H, s), 4.45 - 4.57 (4H, m), 5.04 (2H, s), 5.27 (2H, s), 6.07 (1H, d, J = 6.9 Hz), 7.13 - 7.30 (5H, m), 7.50 (1H, d, J = 7.0 Hz), 8.20 - 8.29 (2H, m), 8.42 (1H, t, J = 5.4 Hz)

Example 26

l-({4-[(3-chloro-5-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide

Following method E, l-[[4-(chloromethyl)-2-fluoro-phenyl]methyl]-N-[(3-fluoro-4-methoxy-2- pyridyl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide (225 mg, 0.5 mmol) was reacted with 3-chloro- 5-methylpyridin-2-ol (75 mg, 0.5 mmol) in acetone (5 mL) at 60 °C for 18hrs. Usual work up and column chromatography afforded the title compound (155 mg, 0.3 mmol, 52% yield) as an off-white solid. [M+H]⁺ = 540.2

¹H NMR (CDCIs, 400 MHz) 2.04 (3H, s), 3.45 (3H, s), 3.99 (3H, s), 4.66 (2H, s), 4.78 (2H, dd, J = 5.2, 2.1 Hz), 5.13 (2H, s), 5.22 (2H, s), 6.93 (1H, t, J = 6.1 Hz), 6.98 (1H, m), 7.20 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.39 (1H, d, J = 2.3 Hz), 7.96 (1H, s), 8.27 (1H, d, J = 5.7 Hz), 8.60 (1H, t, J = 5.1 Hz)

Example 25

l-[(4-{[5-(difluoromethyl)-2-oxopyridin-l-yl]methyl}phenyl)methyl]-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide

Following method E, l-[[4-(chloromethyl)phenyl]methyl]-N-[(3-fluoro-4-methoxy-2-pyridyl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide (100 mg, 0.2 mmol) was reacted with 5-(difluoromethyl)-lH- pyridin-2-one (40.2 mg, 0.3 mmol) at rt for 48hrs. The crude product was purified by reverse phase HPLC eluting with 20-60% MeCN/water and freeze dried to afford the title compound as a white solid (45 mg, 0.08mmol, 34% yield).

[M+H]⁺ = 542.2

¹H NMR (CDCIs, 400M Hz) 3.45 (3H, s), 3.99 (3H, s), 4.66 (2H, s), 4.79 (2H, dd, J = 5.0, 1.7 Hz), 5.13 (2H, s), 5.23 (2H, s), 6.41 (1H, s), 6.66 (1H, s), 6.93 (1H, t, J = 6.0 Hz), 7.22 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.43 (2H, dd, J = 7.3, 2.5 Hz), 7.97 (1H, s), 8.26 (1H, d, J = 5.8 Hz), 8.54 - 8.66 (1H, m)

Example 1

Following method E, l-[[4-(chloromethyl)phenyl]methyl]-N-[(3-fluoro-4-methoxy-2-pyridyl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide (300 mg, 0.7 mmol) was reacted with 3-methyl-lH-pyridin-2-one (91 mg, 0.8 mmol) in DMF (5 mL) at 50 °C for 18hrs. After the usual work up and purification, the product was triturated in 2-propanol (3 mL). The solid was recovered by filtration washing with 2-propanol and dried under vacuum to afford the title compound (135 mg, 0.264 mmol, 38% yield) as a white solid.

[M+H]⁺ = 506.2

¹H NMR (d6-DMSO, 500 MHz) 1.99 (3H, s), 3.26 (3H, s), 3.93 (3H, s), 4.51 (2H, s), 4.53 (2H, dd, J = 5.5, 2.2 Hz), 5.08 (2H, s), 5.28 (2H, s), 6.15 (1H, t, J = 6.7 Hz), 7.17 - 7.25 (3H, m), 7.25 - 7.32 (3H, m), 7.63 (1H, dd, J = 6.9, 2.0 Hz), 8.22 - 8.28 (2H, m), 8.43 (1H, t, J = 5.4 Hz)

Example 2

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(5-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide

Following method E, l-[[4-(chloromethyl)phenyl]methyl]-N-[(3-fluoro-4-methoxy-2-pyridyl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide (70 mg, 0.16 mmol) was reacted with 5-methyl-lH-pyridin-2-one (21 mg, 0.2 mmol) in acetone (3 mL) at 70 °C for 18hrs. The standard work up and purification afforded the title compound (37 mg, 0.07 mmol, 43% yield) as a white solid.

[M+H]⁺ = 505.8

¹H NMR (d6-DMSO, 400 MHz) 2.00 (3H, s), 3.26 (3H, s), 3.93 (3H, s), 4.48 - 4.58 (4H, m), 5.02 (2H, s), 5.28

(2H, s), 6.36 (1H, d, J = 9.2 Hz), 7.18 - 7.31 (6H, m), 7.54 (1H, d, J = 2.2 Hz), 8.20 - 8.30 (2H, m), 8.43 (1H, t, J = 5.4 Hz) Example 3

(methoxymethyl)pyrazole-4-carboxamide

Following method E, l-[[4-(chloromethyl)phenyl]methyl]-N-[(3-fluoro-4-methoxy-2-pyridyl)methyl]-3-

(methoxymethyl)pyrazole-4-carboxamide (70 mg, 0.16 mmol) was reacted with 3-fluoro-lH-pyridin-2-one (21.9 mg, 0.19 mmol) in acetone (3 mL) at 70 °C overnight. The standard work up and purification afforded the title compound (39 mg, 0.07 mmol, 46% yield) as a white solid.

[M+H]⁺ = 509.7

¹H NMR (d6-DMSO, 400 MHz) 3.26 (3H, s), 3.93 (3H, s), 4.49 - 4.57 (4H, m), 5.15 (2H, s), 5.29 (2H, s), 6.22 (1H, td, J = 7.2, 4.6 Hz), 7.17 - 7.23 (1H, m), 7.27 (4H, q, J = 8.1 Hz), 7.39 (1H, ddd, J = 9.7, 7.6, 1.8 Hz), 7.65 (1H, dt, J = 6.9, 1.4 Hz), 8.21 - 8.30 (2H, m), 8.43 (1H, t, J = 5.4 Hz) Example 34

(methoxymethyl)pyrazole-4-carboxamide

Following method E, l-[[4-(chloromethyl)phenyl]methyl]-N-[(3-fluoro-4-methoxy-2-pyridyl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide (100 mg, 0.231 mmol) was reacted with 3-chloro-lH-pyridin-2- one (40 mg, 0.30 mmol) in acetone (2 mL) at 60 °C overnight. The standard work up and purification afforded the title compound (55.8 mg, 0.10 mmol, 45% yield) as a white solid.

[M+H]⁺ = 526.0 NM R (500 MHz, DMSO-d6) 3.27 (3H, s), 3.93 (3H, s), 4.52 (2H, s), 4.54 (2H, dd, J = 5.4, 2.2 Hz), 5.15 (2H, s), 5.30 (2H, s), 6.28 (1H, t, J = 7.0 Hz), 7.20 (1H, dd, J = 6.7, 5.5 Hz), 7.25 (2H, d, J = 8.2 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.75 (1H, dd, J = 7.3, 1.9 Hz), 7.86 (1H, dd, J = 6.8, 1.9 Hz), 8.29 - 8.22 (2H, m), 8.44 (1H, t, J = 5.4 Hz)

Example 38

l-({4-[(5-fluoro-3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide

Following a modification of method E, intermediate l-[[4-(chloromethyl)phenyl]methyl]-N-[(3-fluoro-4- methoxy-2-pyridyl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide (130 mg, 0.3 mmol) was reacted 5- fluoro-3-methyl-pyridin-2-ol (40 mg, 0.3 mmol), in DMF (2 mL) at 60°C for 48hrs. The cooled reaction mixture was diluted with DCM (50 mL), filtered, and the filtrated concentrated to dryness. The DMF wet residue was dissolved in MeOH (50 mL) and the solution treated with SCX (strong cation exchange) resin. The solution was removed and the resin washed with MeOH and the product recovered from the resin by washing with 0.7N ammonia in MeOH (50 mL). The ammoniacal solution was concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 0-5% MeOH in acetonitrile to afford the title compound (52 mg, 0.1 mmol, 31% yield) as a white solid.

[M+H]⁺ = 524.2

¹H NMR (d6-DMSO, 500MHz) 2.02 (3H, s), 3.26 (3H, s), 3.92 (3H, s), 4.51 (2H, s), 4.53 (2H, s), 5.03 (2H, s),5.28 (2H, s), 7.19 (1H, dd, J = 6.6, 5.7 Hz), 7.24 (2H, d, J = 8.2 Hz), 7.30 (2H, d, J = 8.3 Hz), 7.51 - 7.46 (1H, m),7.91 - 7.85 (1H, m), 8.24 (1H, d, J = 5.5 Hz), 8.27 (1H, s), 8.43 (1H, t, J = 5.3 Hz)

Example 8

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-3-(trifluoromethyl)pyridin- l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide

Following method E, l-[[4-(chloromethyl)phenyl]methyl]-N-[(3-fluoro-4-methoxy-2-pyridyl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide (50 mg, 0.11 mmol) was reacted with 3-(trifluoromethyl)-lH- pyridin-2-one (22.6 mg, 0.14 mmol). After the standard work up and purification, the product was triturated overnight in a mixture of Et₂0 (2 mL) and MeOH (0.1 mL). The solid was recovered by filtration washing with Et₂0 and dried under vacuum to afford the title compound (43 mg, 0.07 mmol, 63% yield) as a white solid.

[M+H]⁺ = 560.2

¹H NMR (d6-DMSO, 400 MHz) 3.26 (3H, s), 3.92 (3H, s), 4.47 - 4.56 (4H, m), 5.15 (2H, s), 5.30 (2H, s), 6.40 (1H, t, J = 6.9 Hz), 7.19 (1H, t, J = 6.1 Hz), 7.25 (2H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.91 - 7.98 (1H, m),

8.16 (1H, d, J = 6.9 Hz), 8.24 (1H, d, J = 5.5 Hz), 8.27 (1H, s), 8.43 (1H, t, J = 5.4 Hz)

Other examples

Methyl l-{[4-(chloromethyl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4-carboxylate

To a stirred solution of methyl l-{[4-(hydroxymethyl)phenyl]methyl}-3-(methoxymethyl)pyrazole-4- carboxylate (2.64 g, 9.1 mmol) in DCM (30 mL) at 0 °C was added triethylamine (1.77 mL, 12.7 mmol) followed by methanesulfonyl chloride (0.92 mL, 11.8 mmol) and the reaction mixture stirred for 30 min at rt then heated to 40 °C for 18hrs. After cooling to rt, the reaction mixture was concentrated in vacuo and purified by column chromatography eluting with isohexane/TBME to afford the title product (2.3 g, 7.1 mmol, 78% yield) as a colourless glass.

[M+H]⁺ = 308.8 NMR (CDCIs, 400M HZ) 3.43 - 3.52 (3H, m), 3.71-3.86 (3H, m), 4.57 (2H, d, J = 1.8Hz), 4.73 (2H, d, J = 2.0 Hz), 5.29 (2H, s), 7.21-7.25 (2H, m), 7.35-7.41 (2H, m), 7.79 (1H, d, J = 1.9 Hz).

Following method E, l-[[4-(chloromethyl)phenyl]methyl]-N-[(3-fluoro-4-methoxy-2-pyridyl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide (318 mg, 1.0 mmol) was reacted with 2-hydroxypyridine-3- carbaldehyde (152 mg, 1.2 mmol) in a mixture of THF (10 mL) and DMF (3 mL), at 70 °C for 72hrs. Standard work up and purification afforded the title compound (356 mg, 0.8 mmol, 83% yield) as a beige solid.

[M+H]⁺ = 396.1

¹H NMR (CDCIs, 400 MHz) 3.47 (3H, s), 3.79 (3H, s), 4.71 (2H, s), 5.18 (2H, s), 5.28 (2H, s), 6.24 - 6.45 (1H, m), 7.25 (2H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8.1 Hz), 7.59 (1H, dd, J = 6.6, 2.2 Hz), 7.80 (1H, s), 8.03 (1H, dd, J = 7.1, 2.2 Hz), 10.35 (1H, d, J = 0.8 Hz)

To a solution of methyl l-({4-[(3-formyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-3- (methoxymethyl)pyrazole-4-carboxylate (350 mg, 0.9 mmol) in DCM (5 mL) was added

diethylaminosulfurtrifluoride (0.26 mL, 1.9 mmol) and the reaction mixture stirred at rt for 18hrs. The reaction mixture was concentrated in vacuo and the crude product was purified by column

chromatography on silica eluting with EtOAc to afford the title compound (270 mg, 0.62 mmol, 69% yield) as a white solid.

[M+H]⁺ = 418.2

¹H NMR (400 MHz, CDCI₃) 3.47 (3H, s), 3.79 (3H, s), 4.72 (2H, s), 5.14 (2H, s), 5.27 (2H, s), 6.26 (1H, t, J = 6.9 Hz), 6.83 (1H, t, J = 55.3Hz), 7.23 (2H, d, J = 8.2 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.39 (1H, m), 7.68 (1H, dd, J = 6.9, 1.7 Hz), 7.79 (s, 1H) Lithium l-[[4-[[3-(difluoromethyl)-2-oxo-l-pyridyl]methyl]phenyl]methyl]-3-(methoxymethyl)pyrazole-4- carboxylate

To a solution of methyl l-[[4-[[3-(difluoromethyl)-2-oxo-l-pyridyl]methyl]phenyl]methyl]-3- (methoxymethyl)pyrazole-4-carboxylate (135 mg, 0.3 mmol) in a mixture of 1,4-dioxane (5 mL) and water (2 mL) was added LiOH (10 mg, 0.4 mmol). The mixture was heated at 70 °C for 4 hrs. After cooling to RT, the solvent was removed under reduced pressure and the residue azeotroped with a mixture of ethanol and toluene to afford the title compound as lithium salt (132 mg, 0.3 mmol, quantitative yield) as an off white powder.

Example 24

To a suspension of lithium l-[[4-[[3-(difluoromethyl)-2-oxo-l-pyridyl]methyl]phenyl]methyl]-3- (methoxymethyl)pyrazole-4-carboxylate (132 mg, 0.3 mmol) in a mixture of MeCN (10 mL) and DCM (10 mL) was added N,N-diisopropylethylamine (0.17 mL, 1.0 mmol) followed by HATU (135 mg, 0.3 mmol) and (3-fluoro-4-methoxy-2-pyridyl)methanamine dihydrochloride (88.6 mg, 0.4 mmol) and the reaction mixture was stirred for 1 hour at rt. The reaction mixture was diluted with DCM (50 mL) was washed with IN NaOH(aq) (50 mL). The organic phase was separated, dried over MgSCU, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with EtOAc (100%) to afford the desired product (105 mg, 0.18 mmol, 57% yield) as a white solid.

[M+H]⁺ = 542.2

^XH NM R (400 MHz, CDCI₃) 3.46 (3H, s), 3.99 (3H, s,), 4.66 (2H, s), 4.79 (2H, dd, J = 5.1, 2.2 Hz), 5.16 (2H, s), 5.25 (2H, s), 6.28 (1H, t, J = 6.9 Hz), 7.02 - 6.69 (2H, m), 7.24 (2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.40 (1H, ddd, J = 6.8, 2.1, 1.1 Hz), 7.70 (1H, dd, J = 6.9, 1.7 Hz), 8.27 (1H, d, J = 5.7 Hz), 7.95 (1H, s), 8.59 (1H, t, J

= 5.2 Hz)

To 4-(chloromethyl)benzylalcohol (4.50 g, 28.7 mmol) in acetone (150 mL) was added 5-fluoro-2- hydroxypyridine (3.57 g, 31.6 mmol) and K₂CO₃ (11.9 g, 24.2 mmol) and the reaction mixture was stirred at 50 °C for 36 hrs. The reaction mixture was cooled and solvent was removed in vacuo. The residue was taken up in CHCI₃ (150 mL) and washed with water (30 mL), dried (Na₂S0₄), filtered and evaporated. The aqueous layer was extracted with 20% 2-propanol-chloroform (3 x 50 mL). All organic layers were combined. The residue was adsorbed onto silica and purified by automated flash chromatography eluting with MeOH- DCM, to give a white solid identified as the title compound (5.65g, 24.2 mmol, 84%).

[M+H]⁺ = 234.2 l-(4-Bromomethyl-benzyl)-5-fluoro-lH-pyridin-2-one

To 5-fluoro-l-(4-hydroxymethyl-benzyl)-lH-pyridin-2-one (1.65g, 7.1 mmol) in DCM (100 mL) was added phosphorous tribromide (665 mL, 7.1 mmol) and the reaction stirred at rt for 2 hrs. The reaction mixture was diluted with CHCI₃ (100 mL) and washed with saturated NaHC0₃(aq) (50 mL), water (10 mL) and brine (10 mL). The organic layer was dried (IN^SCU), filtered and evaporated to give a colourless gum identified as the title compound which was used without further purification (1.85 g, 6.3 mmol, 88%).

[M+Na]⁺ = 318.2 l-[4-(5-Fluoro-2-oxo-2H-pyridin-l-ylmethyl)-benzyl]-3-methoxymethyl-lH-pyrazole-4-carboxylic acid methyl ester

To 3-methoxymethyl-lH-pyrazole-4-carboxylic acid methyl ester (259 mg, 1.5 mmol) in DMF (2 mL) was added l-(4-bromomethyl-benzyl)-5-fluoro-lH-pyridin-2-one (450 mg, 1.5 mmol) and K₂CO₃ (420 mg, 3.04 mmol). The reaction mixture was stirred at rt for 18 hrs. The reaction mixture was concentrated and then partitioned between EtOAc (60 mL) and water (20 mL) and washed sequentially with water (3x 10 mL) and brine (10 mL). The organic layer was dried (IN^SCU), filtered and evaporated. The crude residue was purified by automated flash chromatography eluting with EtOAc/acetonitrile-methanol to give two regioisomers. The regioisomers were identified by NOESY NMR and the title compound isolated as an off- white solid (327 mg, 0.85 mmol, 55%).

To l-[4-(5-fluoro-2-oxo-2H-pyridin-l-ylmethyl)-benzyl]-3-methoxymethyl-lH-pyrazole-4-carboxylic acid methyl ester (327mg, 0.85 mmol) in ethanol (50 mL) was added NaOH (339 mg, 8.5 mmol) and heated at vigorous reflux for 24hrs. The reaction mixture was cooled and concentrated. The crude residue was diluted with water (5mL) and washed with DCM (7mL). The aqueous phase was taken and adjusted to pH ~2 with 2M HCI and then extracted with 90% CH3CI / 10% 2-propanol (6 x 15mL). The organic layer was dried (Na SC> ), filtered and concentrated to give a pale yellow solid that was used without further purification. [M+H]⁺ = 371.8

To (4-methoxy-3-methylpyridin-2-yl)methanol (1.0 g, 6.5 mmol) in DCM (40 mL) was added phosphorous tribromide (3.53 g, 13.1 mmol) and the reaction stirred at rt for 2 hrs. The reaction mixture was diluted with CHCI3 (50 mL) and washed with saturated NaHCOs(aq) (100 mL), water (10 mL) and brine (10 mL). The organic layer was dried (IN^SCU), filtered and evaporated to give an orange solid identified as the title compound (1.17g, 5.4 mmol, 83%) which was used without further purification.

[M+H]⁺ = 216.14 and 218.15

To 2-bromomethyl-4-methoxy-3-methyl-pyridine (1.17g, 5.4 mmol) in DMF (10 mL) was added sodium azide (0.70 g, 10.8 mmol) and the reaction stirred at rt for 18 hrs under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (60 mL) and washed with water (4 x 20 mL) and brine (10 mL). The organic layer was dried (IN^SCU), filtered and concentrated. The crude residue was purified by automated flash chromatography eluting with pet. ether / EtOAc to afford the title compound as a yellow gum (0.30 g, 1.7 mmol, 31%).

^XH NM R (CDCI3, 400 MHz): 2.04 (3H, s), 3.71 (3H, s), 4.29 (2H, s), 6.59 (1H, d, J = 5.7 Hz), 8.17 (1H, d, J = 5.7

Hz).

10% Pd/C (75 mg, 0.7 mmol) was added under a nitrogen atmosphere to a solution of 2-azidomethyl-4- methoxy-3-methyl-pyridine (300 mg, 1.7 mmol) in MeOH (30 mL). The flask was flushed with hydrogen gas and the resulting mixture was stirred at rt for 1 hour under hydrogen. The vessel was subsequently purged with nitrogen gas and the crude reaction mixture was filtered through a short plug of Celite, The reaction vessel and Celite were rinsed with MeOH. The combined filtrates were concentrated in vacuo to provide the product as a yellow gum (240 mg, 1.6 mmol, 94%).

[M+H]⁺ = 153.2 Example 55

(methoxymethyl)pyrazole-4-carboxamide

Following method C, l-[4-(5-fluoro-2-oxo-2H-pyridin-l-ylmethyl)-benzyl]-3-methoxymethyl-lH-pyrazole-4- carboxylic acid (50 mg, 0.14 mmol) was reacted with C-(4-methoxy-3-methyl-pyridin-2-yl)-methylamine (21 mg, 0.14 mmol). After the usual work up the crude material was purified by automated flash chromatography eluting with MeOH-EtOAc / acetonitrile. The isolated product was freeze-dried from acetonitrile and water to afford the title compound as an off-white solid (38 mg, 0.08 mmol, 15%).

[M+H]⁺ = 506.2

¹H NMR (DMSO-d6) 2.11 (3H, s), 3.28 (3H, s), 3.85 (3H, s), 4.48-4.50 (4H, m), 5.01 (2H, s), 5.28 (2H, s), 6.44 (1H, dd, J = 10.0, 5.5 Hz), 6.96 (1H, d, J = 5.7 Hz), 7.24 (2H, d, J = 8.2 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.54-7.59 (1H, m), 8.03-8.05 (1H, dd, J = 4.4, 3.6 Hz), 8.28 (2H, t, J = 2.8 Hz), 8.44 (1H, t, J = 4.8 Hz).

3

O

Table 1

O

h3 n H o w o o

C/I o

3

O

o\

n H

O

w

O

C/I u_> o

*

O o\

n H

O

w

O

C/I u_> o

Table 2: Compound names

Biological Methods

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

Determination of the IC₅o for plasma kallikrein

Plasma kallikrein inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209;

Stiirzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human plasma kallikrein (Protogen) was incubated at 25 °C with the fluorogenic substrate H-DPro-Phe-Arg-AFC and various concentrations of the test compound. Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410nm and the IC₅o value for the test compound was determined.

Data acquired from this assay are shown in Table 4.

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

Determination of the IC₅o for KLK1

KLK1 inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Stiirzebecher et al., Biol. Chem. Hoppe-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 IC₅o value for the test compound was determined.

Data acquired from this assay are shown in Table 4.

Selected compounds were further screened for inhibitory 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 FXIa

FXIa inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Stiirzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human FXIa (Enzyme Research Laboratories) was incubated at 25 °C with the fluorogenic substrate Z-Gly-Pro-Arg-AFC and 40 mM of the test compound (or alternatively at various concentrations of the test compound in order to determine IC₅o). Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410nm and the IC50 value for the test compound was determined.

Data acquired from this assay are shown in Table 4. Factor XI la 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 Journal of Medicinal Chemistry 110 (2016) 181). Human Factor XI la (Enzyme Research Laboratories) was incubated 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 IC50 value for the test compound was determined.

Data acquired from this assay are shown in Table 4.

Table 4

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 Biocoat™ HTS fibrillar collagen 24 well multiwell insert system (1.0 pm, PET membrane, Corning 354803) in which 200,000 cells were seeded into each insert and maintained over 3 days before being utilised in the permeability assay. For the assay, 50 pM 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 measuring the test article in both compartments by LCMS following the 1 hour incubation. The integrity of the Caco-2 monolayers was confirmed by two methods, (i) comparison of pre- and post-experiment transepithelial electrical resistance (TEER) and, (ii) assessment of Lucifer Yellow flux.

The intrinsic clearance shown in Table 5 (intrinsic clearance and in vitro permeability data) 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 pM 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 clearance (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 (2002). Drug Metab Dispos 30: 1446-1454).

Table 5 (intrinsic clearance and in vitro permeability data)

The metabolic stability presented in Table 6 (metabolic stability) was determined using standard published methods (Obach RS (1999) Drug Metab Dispos 27(11); 1350-135). Human liver microsomes (1 mg/mL; Corning) were incubated with 5 mM test compound at 37 °C on a shaking platform (150 rpm). Samples were taken at 0 and 60 min. The percentage test compound remaining at 60 minutes was determined by ratio of LCMS peak areas. Table 6 (metabolic stability)

Plasma Protein Binding and Predicted Clearance

The fraction unbound in plasma was determined using ThermoScientific™ Pierce™ Rapid Equilibrium Dialysis Technology (Single-Use plate with inserts, 8K MWCO). 5 mM test compound was spiked into human or rat plasma (300 pL) and dialysed against 146.5 mM phosphate buffer (500 pL) 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 compound concentrations were determined in plasma and buffer compartments by LCMS against a calibration curve. The fraction unbound in plasma was determined using standard methodology (Waters NJ et al (2008) J Pharm Sci 97(10); 4586-95). Results are presented as percent plasma protein bound (%PPB).

The predicted plasma clearance (Clp) is calculated using the well-stirred model (Rowland M, Benet LZ, and Graham GG. Clearance concepts in pharmacokinetics. J Pharmacokinet Biopharm. (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, hepatic 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). The results are presented in Table 7 below.

Table 7

Pharmacokinetics

Pharmacokinetic studies of the compounds in Table 8 were performed to assess the pharmacokinetics following 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 vehicle. 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 analysed for concentration of test compound by LCMS. Oral exposure data acquired from these studies are shown below:

Table 8: Oral exposure data

Claims

1. A compound of formula (I),

wherein

R1 and R2 are independently selected from the group consisting of H, alkyl, halo, -

aryl, -COOR6, -NHCOR6, -CONR6R7, -OCF₃ and -CF₃;

R5 is selected from the group consisting of FI, alkyl, cycloalkyl, alkoxy, halo, OFI, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl,

N-linked piperazinyl, -NR6R7, -CN, -COOR6, -CONR6R7, -NR6COR7 and -CF₃;

R6 and R7 are independently selected from FI or alkyl or where R6 and R7 are joined to the same atom, R6 and R7 can together with the N atom to which they are attached form a carbon- containing 4-, 5-, 6- or 7-membered heterocyclic ring, optionally containing an additional heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted with substituents selected from the group consisting of oxo, alkyl, alkoxy, -OFI, halo and -CF₃; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (Ci-Cio) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms (C3-C10), which may optionally be substituted with 1 or 2 substituents independently selected from the group consisting

of

cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 7 carbon atoms, which may optionally be substituted with a substituent selected from alkyl, alkoxy and -NR6R7; alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (Ci-Ce) or a branched CD- linked hydrocarbon of between 3 and 6 carbon atoms (C₃-C₆); alkoxy may optionally be substituted with 1 or 2 substituents independently selected from the group consisting

of - , fluoro and -NR8R9;

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, S and O; wherein heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, alkoxy, -OH, halo, -CN, -COOR8, -CONR8R9, -CF₃, -CHF₂, -OCF₃ and -(CH₂)_0-3NR8R9;

R8 and R9 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, or where both R8 and R9 are attached to the same atom, R8 and R9 can together with the nitrogen atom to which they are attached form piperidine, morpholine, piperazine or pyrrolidine;

R10 and Rll are independently selected from H, -CHF₂, -CF₃, -CN, -OCF₃, alkoxy, -OH, -NR8R9, methyl, ethyl and propyl, or together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring; and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof; and wherein the compound of formula (I) is not

2. A compound or pharmaceutically acceptable salt or solvate thereof according to claim 1, having formula (IA):

wherein Rl, R2, R3, R4, R5, RIO, Rll and Q are as defined in claim 1.

3. A compound or pharmaceutically acceptable salt or solvate thereof according to any preceding claim, having formula (IB),

wherein Rl, R2, R3, R4, R5, RIO, Rll and Q are as defined in claim 1.

4. A compound or pharmaceutically acceptable salt or solvate thereof according to any preceding claim, wherein Rl is FI and R2 is selected from the group consisting of alkyl, alkoxy, CN, halo,

5. A compound or pharmaceutically acceptable salt or solvate thereof according to claim 4, wherein R2 is alkyl.

6. A compound of pharmaceutically acceptable salt or solvate thereof according to claim 5, wherein R2 is Ci alkyl.

7. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 4 to 6, wherein alkyl is substituted with 1 or 2 substituents selected from the group consisting of

8. A compound or pharmaceutically acceptable salt or solvate thereof according to claim 7, wherein alkyl is substituted with 1 substituent selected from the group consisting

of

9. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3, wherein R1 is H and R2 is selected from the group consisting

of - and -COOR6.

10. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3, wherein R2 is H and R1 is selected from the group consisting of alkyl, halo, -CF₃, -CHF₂ and CN.

11. A compound or pharmaceutically acceptable salt or solvate thereof according to claim 10, wherein R1 is alkyl.

12. A compound of pharmaceutically acceptable salt or solvate thereof according to claim 11, wherein R1 is Ci-₃ alkyl.

13. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 10 to 12, wherein alkyl is substituted with 1 or 2 substituents selected from the group consisting and -NR8R9.

14. A compound or pharmaceutically acceptable salt or solvate thereof according to claim 13, wherein alkyl is substituted with 1 substituent selected from the group consisting

of -

15. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3, wherein R2 is H and R1 is selected from the group consisting

of -CHF2, -CN, -OCF₃, -NR6R7, -NR6CONR7 and -COOR6.

16. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3, wherein both R1 and R2 are not H.

17. A compound or pharmaceutically acceptable salt or solvate thereof according to any preceding claim, wherein at least one of R1 and R2 is not unsubstituted alkyl or cycloalkyl.

18. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3, wherein R1 and R2 are independently selected from the group consisting of -CH F₂, -CN, cycloalkyl, -OCF3, -NR6R7, -NR6COR7 and -COOR6, wherein cycloalkyl and R6 and R7 are as defined in claim 1.

19. A compound or pharmaceutically acceptable salt or solvate thereof according to any preceding claim, wherein R3 is FI and R4 is selected from the group consisting of FI, alkyl, alkoxy and halo.

20. A compound or pharmaceutically acceptable salt or solvate thereof according to claim 19, wherein R4 is alkoxy or halo.

21. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 18, wherein wherein R4 is FI and R3 is selected from the group consisting of FI, alkyl, alkoxy and halo.

22. A compound or pharmaceutically acceptable salt or solvate thereof according to claim 19, wherein R3 is alkoxy or halo.

23. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 18, wherein R3 and R4 are both FI.

24. A compound or pharmaceutically acceptable salt or solvate thereof according to any preceding claim, wherein R5 is selected from the group consisting of FI, -CFI₂OCFl3, cycloalkyl, -

NR6R7, -NR6COR7, -CN and -CF3; wherein cycloalkyl and R6 and R7 are as defined in claim 1.

25. A compound or pharmaceutically acceptable salt or solvate thereof according to any preceding claim, wherein R6 and R7 are independently selected from FI or alkyl or when joined to the same atom, R6 and R7 can together with the N atom to which they are attached form a piperidine ring, a morpholine ring, a piperazine ring or a pyrrolidine ring.

26. A compound or pharmaceutically acceptable salt or solvate thereof according to any preceding claim, wherein alkyl is C1-3 alkyl.

27. A compound or pharmaceutically acceptable salt or solvate thereof according to any preceding claim, wherein one of RIO and Rll is H and the other is methyl.

28. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 26, wherein RIO and Rll are both methyl.

29. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 26, wherein RIO and Rll together with the carbon atom to which they are joined, form a cyclopropyl group.

30. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 26, wherein RIO and Rll are both H.

31. A compound or pharmaceutically acceptable salt or solvate thereof according to any preceding claim, wherein R12, R13, R14 and R15 are independently selected from the group consisting of -F, alkyl and alkoxy.

32. A compound or pharmaceutically acceptable salt or solvate thereof according to any preceding claim, wherein Q is:

wherein R12, R13, R14 and R15 are as defined in claim 1.

33. A compound or pharmaceutically acceptable salt or solvate thereof according to claim 32 wherein R12 is -F or methyl.

34. A compound or pharmaceutically acceptable salt or solvate thereof according to claim 32 or 33, wherein R13 is methoxy.

35. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 32 to 34, wherein R14 and R15 are both H.

36. A compound or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3, wherein R1 and R2 are selected from the group consisting of alkyl, halo, -CN, -CF3 and -CFIF2, R3 and R4 are both H, R5 is alkyl substituted with -(Ci-C₆)alkoxy and Q is:

wherein R12 is -F or methyl, most preferably -F, R13 is methoxy and R14 and R15 are both H.

37. A compound according to claim 1, selected from the group consisting of:

l-({4-[(3-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(4-chloro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-chloro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-5-

(trifluoromethyl)pyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-3-

(trifluoromethyl)pyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide; l-({4-[(3-cyano-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3,5-dichloro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

1-({4-[(5-chloro-4-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

1-({4-[(5-chloro-3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-ethyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-cyano-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3-cyclopropyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(4-cyano-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-tert-butyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-cyclopropyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[3-(methoxymethyl)-2- oxopyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

l-({4-[(3,5-dimethyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

1-[(4-{[3-(difluoromethyl)-2-oxopyridin-l-yl]methyl}phenyl)methyl]-N-[(3-fluoro-4-methoxypyridin-

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

1-[(4-{[5-(difluoromethyl)-2-oxopyridin-l-yl]methyl}phenyl)methyl]-N-[(3-fluoro-4-methoxypyridin-

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide; 1-({4-[(3-chloro-5-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(3-methoxy-2-oxopyridin-l- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-chloro-3-methoxy-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3,4-dimethyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(5-isopropyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3-chloro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

1-({2-fluoro-4-[(3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3,5-dimethyl-2-oxopyridin-l-yl)methyl]-2-fluorophenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

1-({2-fluoro-4-[(5-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

1-({4-[(5-fluoro-3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(5-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-l-({4-[(3-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;

1-({2-fluoro-4-[(5-fluoro-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-

2-yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide; l-({4-[(3,5-difluoro-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2- yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide;

1-({3-fluoro-4-[(5-fluoro-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-

2-yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-fluoro-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2- yl)methyl]-3- (trifluoromethyl)pyrazole-4-carboxamide;

1-({4-[(5-fluoro-3-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-

2-yl)methyl]-3- (trifluoromethyl)pyrazole-4-carboxamide;

3-cyclopropyl-l-({4-[(5-fluoro-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]pyrazole-4- carboxamide;

3-cyclopropyl-l-({4-[(5-fluoro-3-methyl-2- oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3- fluoro-4- methoxypyridin-2-yl)methyl]pyrazole-4- carboxamide;

l-({4-[l-(5-fluoro-2-oxopyridin-l-yl)ethyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(4-methoxy-3-methylpyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

1-({3-fluoro-4-[(3-methyl-2-oxopyridin- l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-

2-yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

38. A compound according to claim 1, selected from the group consisting of:

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(5-methyl-2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; l-({4-[(3-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-5-

(trifluoromethyl)pyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-3-

(trifluoromethyl)pyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

l-({4-[(3-cyano-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-tert-butyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide; l-({4-[(5-cyclopropyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

1-({4-[(3-chloro-5-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3,5-dimethyl-2-oxopyridin-l-yl)methyl]-2-fluorophenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide; 1-({2-fluoro-4-[(5-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(4-methoxy-3-methylpyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;and pharmaceutically acceptable salts and solvates thereof.

39. A compound according to claim 1, selected from the group consisting of:

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(3-methyl-2-oxopyridin-l- yl)methyl] phenyl }methyl)pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-3-

(trifluoromethyl)pyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(5-chloro-3-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide; l-({4-[(5-ethyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

40. A compound according to claim 1, selected from the group consisting of:

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-3-

(trifluoromethyl)pyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3,4-dimethyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide; l-({4-[(5-ethyl-3-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-[(4-{[3-(aminomethyl)-2-oxopyridin-l-yl]methyl}phenyl)methyl]-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide; l-[(4-{[5-(aminomethyl)-2-oxopyridin-l-yl]methyl}phenyl)methyl]-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

41. A compound according to claim 1, selected from the group consisting of:

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(3-methyl-2-oxopyridin-l- yl)methyl] phenyl }methyl)pyrazole-4-carboxamide

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-5-

(trifluoromethyl)pyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-3-

(trifluoromethyl)pyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

l-({4-[(3-cyano-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(2-methyl-6-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

42. A compound according to claim 1, selected from the group consisting of:

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-5-

(trifluoromethyl)pyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

43. A compound according to claim 1, selected from the group consisting of:

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-3-

(trifluoromethyl)pyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide; 1-({4-[(5-chloro-4-methyl-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

44. A compound according to claim 1, selected from the group consisting of:

N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-[(4-{[2-oxo-3-

(trifluoromethyl)pyridin-l-yl]methyl}phenyl)methyl]pyrazole-4-carboxamide;

2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;

and pharmaceutically acceptable salts and solvates thereof.

45. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 44 and a pharmaceutically acceptable carrier, diluent or excipient.

46. A compound or pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 44 for use in medicine.

47. The use of a compound or pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 44 in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated.

48. 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 or pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 44.

49. A compound or pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1 to 44 for use in a method of treatment of a disease or condition in which plasma kallikrein activity is implicated.

50. The use of claim 47, the method of claim 48 or a compound or pharmaceutically acceptable salt or solvate thereof for use as claimed in claim 49 wherein, the disease or condition in which plasma kallikrein activity 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 syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, bleeding from post operative surgery and retinal vein occlusion.

51. The use of claim 47, the method of claim 48 or a compound or pharmaceutically acceptable salt or solvate thereof for use as claimed in claim 49, wherein the disease or condition in which plasma kallikrein activity is implicated is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

52. The use of claim 47, the method of claim 48 or a compound or pharmaceutically acceptable salt or solvate thereof for use as claimed in claim 49, wherein the disease or condition mediated by plasma kallikrein is hereditary angioedema.

53. The use of claim 47, the method of claim 48 or a compound or pharmaceutically acceptable salt or solvate thereof for use as claimed in claim 49, wherein the disease or condition in which plasma kallikrein activity is implicated is diabetic macular edema.