WO2016083816A1 - N-((heteroarylmethyl)-heteroaryl-carboxamide derivatives as plasma kallikrein inhibitors - Google Patents

N-((heteroarylmethyl)-heteroaryl-carboxamide derivatives as plasma kallikrein inhibitors Download PDF

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Publication number
WO2016083816A1
WO2016083816A1 PCT/GB2015/053610 GB2015053610W WO2016083816A1 WO 2016083816 A1 WO2016083816 A1 WO 2016083816A1 GB 2015053610 W GB2015053610 W GB 2015053610W WO 2016083816 A1 WO2016083816 A1 WO 2016083816A1
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Prior art keywords
methyl
carboxamide
amino
phenyl
pyrazole
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PCT/GB2015/053610
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French (fr)
Inventor
Alun John SMITH
Andrew Richard NOVAK
David Michael Evans
Hannah Joy EDWARDS
Michael John Stocks
Rebecca Louise DAVIE
Sally Louise MARSH
Simon Teanby Hodgson
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Kalvista Pharmaceuticals Limited
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Priority to SG11201809276QA priority Critical patent/SG11201809276QA/en
Publication of WO2016083816A1 publication Critical patent/WO2016083816A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to enzyme inhibitors that are inhibitors of plasma kallikrein and to pharmaceutical compositions containing and the uses of, such inhibitors.
  • 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 a/. "Kaliikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine, p483-493; J. W. Bryant et ⁇ ,, "Human plasma kallikrein-kinin system: physiological and biochemical parameters” Cardiovascular and haematologicai agents in medicinal chemistry, 7, p234-250, 2009; K. D. Bhoola et ai,
  • Plasma prekaliikrein is encoded by a single gene and synthesized in the liver. It is secreted by hepatocytes as an inactive plasma prekaliikrein 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 CI esterase inhibitor.
  • Patients who present with a genetic deficiency in CI esterase inhibitor suffer from hereditary angioedema (HAE) which results in intermittent swelling of face, hands, throat, gasfro-intesfinal tract and genitals.
  • HAE hereditary angioedema
  • 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.
  • a plasma kaiiikrein inhibitor should have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.
  • Plasma kaiiikrein inhibitors have been described previously, for example by Garrett et ai. ("Peptide aldehyde." J. Peptide Res. 52, p62-71 (1998)), T. Griesbacher et a!.
  • the molecules described in the known art suffer from limitations such as poor selectivity over related enzymes such as KLKl, thrombin and other serine proteases, and poor oral availability.
  • the large protein plasma kallikrein inhibitors present risks of anaphylactic reactions, as has been reported for Ecailantide.
  • the vast majority of molecules in the known art feature a highly polar and ionisable guanidine or amidine functionality. It is well known that such functionalities may be limiting to gut permeability and therefore to oral availability. For example, it has been reported by Tamie J.
  • ASP-634 An Oral Drug Candidate for Diabetic MacularEdema
  • ARVO 2012 May 6* - May 9* 2012, Fort Lauderdale, Florida, Presentation 2240 that ASP-440, a benzamidine
  • absorption may be improved by creating a prodrug such as ASP-634.
  • prodrugs can suffer from several drawbacks, for example, poor chemical stability and potential toxicity from the inert carrier or from unexpected metabolites.
  • indole amides are claimed as compounds that might overcome problems associated with drugs possessing poor or inadequate ADM E-tox and
  • BioCryst Pharmaceuticals Inc. have reported the discovery of the orally available plasma kallikrein inhibitor BCX4161 ("BCX4161, An Oral Kallikrein inhibitor: Safety and Pharmacokinetic Results Of a Phase 1 Study in Healthy Volunteers", Journal of Allergy and Clinical immunology.
  • Preferred compounds will possess a good pharmacokinetic profile and in particular will be suitable as drugs for oral delivery.
  • the present invention relates to a series of heterocyclic derivatives that are inhibitors of plasma kallikrein. These compounds demonstrate good selectivity for plasma kallikrein and are potentially useful in the treatment of impaired visual acuity, diabetic retinopathy, 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, cardiopulmonary bypass surgery and bleeding from post operative surgery.
  • the invention further relates to pharmaceutical compositions of the inhibitors, to the use of the compositions as therapeutic agents, and to methods of treatment using these compositions.
  • the present invention provides compounds closely related to or failing within the scope of, but not specifically disclosed in, our co-pending application PCT/ GB2014/051592.
  • the present invention provides compound selected from the group consisting of:
  • l-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H- pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide, and pharmaceutically acceptable salts and solvates thereof.
  • l-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carb ⁇ acid (3-chloro-1H- pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide, and pharmaceutically acceptable salts and solvates thereof.
  • the present invention provides a prodrug of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the present invention provides an N-oxide of a compound of the invention, or a prodrug or pharmaceutically acceptable salt thereof.
  • the compounds of the present invention are potent and selective inhibitors of plasma kailikrein. They are therefore useful in the treatment of disease conditions for which overactivity of plasma kailikrein is a causative factor.
  • 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 kailikrein 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.
  • 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, cardiopulmonary bypass surgery and bleeding from post operative surgery.
  • the disease or condition in which plasma kallikrein activity is implicated is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.
  • 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.
  • PDGF platelet-derived growth factor
  • VEGF endothelial growth factor
  • integrin alpha5betal steroids
  • therapeutic agents include those disclosed in EP2281885A and by S. Patei in Retina, 2009 Jun;29(6 Suppl):S45-8.
  • 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.
  • 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, Aielio L, Beck R, et al.
  • “Pharmaceutically acceptable salt” means a physiologically or toxicologicaily tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts.
  • 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.
  • 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.
  • Hemisaits of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.
  • 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 solvafed forms.
  • '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.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when the solvent is water.
  • compounds of the invention exist in one or more geometrical, optical, enantiomeric, diasfereomeric and tautomeric forms, including but not limited to cis- and irons-forms, f- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms.
  • a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof.
  • such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques).
  • such isomers can be prepared by the application or adaptation of known methods (e.g. asymmetric synthesis).
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • the compounds of formula (I) 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 nonfunctional (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.
  • 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).
  • the present invention provides a pharmaceuticai composition
  • a pharmaceuticai composition comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • 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- vitreai 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
  • parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternai, 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.
  • 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-iactone, poiyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations may be administered via surgical incision into the subcutaneous tissue, muscular tissue or directly into specific organs.
  • degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, polycapro-iactone, poiyhydroxybutyrate), polyorthoesters and polyanhydrides.
  • parenteral formulations under sterile conditions for example, by iyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) 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 cyciodextrins.
  • 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 microparticulafes, 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.
  • Formulations suitable for oral administration may also be designed to deliver the compounds of the invention in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic efficacy of the said compounds.
  • Means to deliver compounds in a rate- sustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.
  • rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion.
  • rate-sustaining polymers include hydroxypropyl methylceliulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.
  • 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 hydroxypropylmethylcei!ulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifylng 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, 2.001, 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, Mew York, 1980).
  • the total daily dose of the compounds of the invention is typically in the range 0.01 mg and 1000 mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg depending, of course, on the mode of administration.
  • 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 wiii readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • '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.
  • Automated FC refers to a Biotage purification system with UV directed sample collection using either SNAP ultra or ZIP Sphere cartridges.
  • AH 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 M DL information Systems or the Chemaxon software provided as a component of MarvinSketch or as a component of the IDBS E-WorkBook.
  • Method 8 The carboxylic acid component (1 eq), the amine component (1 eq) and HATU (1.1 eq) were suspended in anhydrous DCM (and DMF if required) and Et 3 N (6 eq) added. The reaction mixture was stirred at rt. The solvent was removed under vacuum. The residue was purified by automated FC.
  • Methylterephthalonitrile (1.42g, 9.99mmol) and Bredereck's reagent (3.48g, 19.98mmol) were dissolved in DMF (15mL). The reaction mixture was heated at 75 * C under nitrogen for 72hrs after which time the solvent was removed in vacuo. Trituration with Pet. Ether gave a bright yellow solid identified as 2-((E)- 2-dimethylamino-vinyl)-terephthalonitrile ester (1.88g, 0.95mmol, 95% yield).
  • l-Amino-isoquinoline-6-carbonitriie 200mg, l.lSmmo! was dissolved in methanol (20mL). This solution was cooled to D C. Nickel (II) chloride hexahydrate (28mg, 0.12mmoi) and di- tertbutyl dicarbonate (516g, 2,36mmoi) were added followed by sodium borohydride (313g, 8.22mmol) portionwise. The reaction mixture was stirred at 0 "C to room temp for 3 days. The MeOH was removed by evaporation.
  • 6-bromo-7-fluoro-2H-isoquinolin-1-one (0.560 g, 2.129 mmol) was converted to 6-bromo-1-chloro-7-fluoro-isoquinoline (460 mg, 82 % yleld).
  • 6-Bromo-1-chloro-7-fluoroisoquinoline (460 mg, 1.78 mmol) was converted using the typical amination procedure to 6-bromo-7-fluoroisoquinolin-1-amine (23.8 mg, 5.5% yleld).
  • 6-Bromo-7-fluoroisoquinolin-1-amine (23.8 mg, 0.099 mmol) was converted using the typical cyanation procedure to 1-amino-7-fluoroisoquinoline-6-carbonitrile (13.3 mg, 64.8 % yleld).
  • 6-Aminomethyl-5-fluoro-isoquinolin-1-ylamine was prepared in 6 steps from 4-bromo-N-(2,2-dimethyl- propionyloxy)-3-fluoro-benzamide using procedures described above.
  • 3-Aminomethyl-[l,7]naphthyridin-8-ylamine dihydrochloride was prepared in 8 steps from 5-bromo-3- methylpicolinic acid using procedures described above.
  • 6-Aminomethyl-5-methoxy-isoquinolin-1-ylamine dihydrochloride was prepared in 8 steps from 4- bromo-3-methoxy-2-methyl-benzoic acid using procedures described above.
  • This diazonium solution was diluted with toluene (60 mL) and added to a cooled 0 °C solution of copper cyanide (3.482 g, 38.91 mmoi) and sodium cyanide (4.76 g, 97.2 mmol) in water (30 mL) with vigorous stirring. The reaction was held at 0 °C and allowed to warm to rt after 1 hour. The reaction mixture was diluted with toluene (100 mL). The organic layer was extracted and washed with brine (200 mL), dried over magnesium sulfate, filtered and solvent removed in vacuo to afford 4-bromo-2-methoxy-6- methylbenzonitrile (7.02 g, 77 % yleld).
  • 6-Aminomethyl-8-methoxy-isoquinolin-1-ylamine dihydrochloride was prepared in 6 steps from 4- bromo-2-methoxy-6-methylbenzamide using procedures described above.
  • 6-Chloro-3-methyl-isoquinoline 750 mg, 4.22 mmol was dissolved in 1,2-dichloroethane (70 mL). To this solution was added N-bromosuccinimide (901 mg, 5.07 mmol) and azobisisobutyronitrile (69 mg, 0.42 mmol). The reaction was heated at reflux for 5 hrs. The reaction was diluted with DCM, brine was added and the layers were separated. The organic layer was dried over MgSO 4 , filtered and
  • 3-Azidomethyl-6-chloro-isoquinoline 300 mg, 1.37 mmoi was dissolved in ethanol (50 mL) and acetic acid (1 mL). Zinc powder (180 mg, 2.74 mmoi) was added portionwise. The reaction mixture was stirred at rt for 18 hrs. The mixture was through Celite and the residue washed with ethanol (50 mL).
  • CDl (3.24 g, 20.0 mmol) was added portionwise to a stirred suspension of 3-methoxypropanoic acid (1.81 mi, 19.2 mmol) in anhydrous MeCN (80 mL). The mixture was allowed to stir at rt for 1.5 hrs. A powdered mixture of magnesium chloride (1.57 g, 16.5 mmol) and methyl potassium maionate (4.5 g, 28.8 mmol) was added portionwise (note CO2 gas evolved). The mixture was allowed to stir at rt. Volatiies were removed in vacuo and hydrochloric acid (2M, 105 mL) was added. The solution was stirred at rt for 1 hr and extracted with DCM (3 x 100 mL).
  • Acetic anhydride 13.50 mi, 143 mmol was added to a suspension of ethyl 3-oxo-2,3-dihydro-1H- pyrazole-4-carboxylate (22.30 g, 143 mmol) in acetic acid (185 mL). The mixture was stirred at rt overnight. Solvents were removed in vacuo. The remaining solid was triturated from water (200 mL) and filtered, washing with water.
  • the aqueous layer was purified by SCX (10 g), washing with MeOH, eluting with 1% NHs/MeOH to afford 3-(methoxymethyi)-1-((6-(pyrroiidin-1-yi)pyridin-3-yl)methyl)-1H- pyrazole-4-carboxylic acid (336 mg, 0.882 mmol, 77% yield).
  • the crude material was purified by flash chromatography loading in dichloromethane, eluting with a gradient of 0 to 100% EtOAc/iso-Hexanes holding at 70% to elute methyl l-(4-((1H-pyrazol-1- yt)methyt)benzyl)-5-(methoxymethyl)-1H-pyrazoie-4-carboxylate (232 mg, 21.0 % yield) then 85% to elute methyl l-(4-((1H-pyrazol-1-yf)methyf)benzyl)-3-(methoxymethyi)-1H-pyrazole-4-carboxylate (494 mg, 52.0 % yield).
  • Ethyl-2-chloropyrimidine-5-carboxylate (300 g, 1.6 mol) was stirred in 1,4-dioxane (3000 mL) in an ice/water bath. Pyrrolidine (375 mL, 4.5 mol) was added and the mixture stirred for 3 hrs at rt. The reaction mixture was concentrated and separated between ethyl acetate (4000 mL) and water (4000 mL). The organics were washed with water (2000 mL) and saturated brine (3000 mL), dried over sodium sulfate, filtered and concentrated.
  • Acetic acid 2-pyrrolidin-1-yi-pyrimidin-5-ylmethyl ester (112.3 g, 0.51 mol) and methyl-3- (methoxymethyl)-1H-pyrazole-4-carboxylate (CAS no. 318496-66-1, synthesised according to the method described in WO 2012/009009) (86.3 g, 0.51 mol) were combined in acetonitriie (1500 mL). Trimethylsilyl trifluoromethanesulfonate (110.3 mL, 0.61 mol) was added. The mixture was heated to 65-70 °C for 3 hrs and then allowed to cool.
  • the reaction mixture was concentrated and separated between EtOAc (1500 mL) and saturated aqueous sodium hydrogen carbonate (1000 mL). The organics were washed with saturated aqueous sodium hydrogen carbonate (750 mL), washed with saturated brine (1000 mL), dried over sodium sulfate, filtered and concentrated to give a brown solid. The solid was dissolved in hot methanol. The solution was cooled to approximately 10 °C and stirred for 1 hour. The solid produced was filtered.
  • the remaining mixture was diluted with water (250 mL) and stirred and cooled in an ice/water bath. Glacial acetic acid (18 mL, 0.31 mol) was added and the mixture stirred for 1 hour. The solid produced was collected by filtration. The filtrates were cooled in an ice/water bath and glacial acetic acid (23 mL, 0.40 mol) was added. After 1 hour the solid produced was collected on top of the previous filter cake. The combined solids were washed with cold ethanol and dried in vacuo. The solid was dissolved in hot ethanol and cooled to rt. The solid produced was filtered and washed with cold ethanol (2 ⁇ 150 mL). The solid was dissolved in hot ethanol and cooled to rt.
  • ⁇ ,1'-Carbonytdiimidazole (26. Ig, 0.161 mole) was added to a suspension of 3-(methoxymethyl)-1-((2- (pyrrolidin-1-yl)pyrimidin-5-yi)methyi)-1H-pyrazole-4-carboxyiic acid (51. lg, 0.161 mole) in N- methylpyrrolidinone (200 mL) and stirred for 3 hrs to give the acylimidazol eintermediate.
  • acylimidazolide intermediate formed above was added in one portion and stirred for 18hrs.
  • the reaction mixture was poured into water (5000 mL) and stirred for 1.5 hrs.
  • the solid was collected by filtration, washed with water (2 x 250 mL), cold acetonitrile (250 mL) and tert-butyl methyl ether (250 mL) and dried in vacuo to give a white solid identified as 3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5- ylmethyl)-1H-pyrazole-4-carboxylic acid (l-amino-isoquinolin-6-ylmethyl)-amide (70.8 g, 93% yield).
  • MH + 473.0
  • the ability of the compounds to inhibit piasma kallikrein may be determined using the following biological assays:
  • Plasma kallikrein inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et a/., Int. J, Tiss. Reac. 1986, 8, 185; Shod et a/., Biochem. Pharmacol., 1992, 43, 1209;
  • KLKl inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et ai., int. J. Tiss. Reac. 1986, 8, 185; Shori et a/., Biochem. Pharmacol., 1992, 43, 1209; Sturzebecher et of., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025).
  • Human KLKl (Ca!lbiochem) 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 ICso value for the test compound was determined, Data acquired from this assay are shown in Table 12
  • Selected compounds were further screened for inhibitory activity against other trypsin-like serine proteases using the appropriate enzyme and chromogenic substrate (Chromogenix AB).
  • the activity against the following human enzymes was tested (substrate in brackets):- thrombin (5 -2238), plasmin (S- 2390) and trypsin (S-2222).
  • the enzyme was incubated at 25 °C with the chromogenic substrate.
  • Residual enzyme activity was determined by measuring the change in optical absorbance at 405nm.

Abstract

The present invention provides a selection of compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (for example in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated); and methods of treating patients with such compounds.

Description

N-((HETEROARYLMETHYL)-HETEROARYL-CARBOXAMIDE DERIVATIVES AS PLASMA KALLIKREIN 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 a/., "Kaliikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine, p483-493; J. W. Bryant et αί,, "Human plasma kallikrein-kinin system: physiological and biochemical parameters" Cardiovascular and haematologicai agents in medicinal chemistry, 7, p234-250, 2009; K. D. Bhoola et ai,
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 prekaliikrein is encoded by a single gene and synthesized in the liver. It is secreted by hepatocytes as an inactive plasma prekaliikrein 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 CI esterase inhibitor. Patients who present with a genetic deficiency in CI esterase inhibitor suffer from hereditary angioedema (HAE) which results in intermittent swelling of face, hands, throat, gasfro-intesfinal 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. Tn' er. 8, pll87-99). The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular edema. It has been recently published that plasma kaiiikrein contributes to retinal vascular dysfunctions in diabetic rats (A. Clermont et al. "Plasma kaiiikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats" Diabetes, 2011, 60, pl590-98). Furthermore, administration of the plasma kaiiikrein inhibitor ASP-440 ameliorated both retina! vascular permeability and retinal blood flow abnormalities in diabetic rats. Therefore a plasma kaiiikrein inhibitor should have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.
Other complications of diabetes such as cerebral haemorrhage, nephropathy, cardiomyopathy and neuropathy, all of which have associations with plasma kaiiikrein may also be considered as targets for a plasma kaiiikrein inhibitor. Synthetic and small molecule plasma kaiiikrein inhibitors have been described previously, for example by Garrett et ai. ("Peptide aldehyde...." J. Peptide Res. 52, p62-71 (1998)), T. Griesbacher et a!.
("Involvement of tissue kaiiikrein but not plasma kaiiikrein 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 kaiiikrein" WO03/076458), Szelke et al, ("Kininogenase inhibitors" WG92/04371), D. M. Evans et a!, {!mrnunoipharmacoiogy, 32, pll5-116 (1996)), Szelke ef ai. ("Kininogen inhibitors" WO95/07921), Antonsson et ai. ("New peptides derivatives" W094/29335), J. Corte et al. ("Six membered heterocycles useful as serine protease inhibitors" WO2005/123680), J. Sturzbecher et ai. [Brazilian J. Med. Bioi. Res 27, pl929-34 (1994)), Kettner ef ai. (US 5,187,157), N. Teno ef ai. [Chem. Pharm. Bull. 41, pl079-1090 (1993)), W. B. Young ef ai. ("Small molecule inhibitors of plasma kaiiikrein" Bioorg. Med. Chem. Letts. 16, p2034-2036 (2006)), Okada ef al. ("Development of potent and selective plasmin and plasma kaiiikrein inhibitors and studies on the structure-activity relationship" Chem. Pharm. Bull. 48, pl964-72 (2000)), Steinmetzer ef al. ("Trypsin-like serine protease inhibitors and their preparation and use" WO08/049595), Zhang ef al. ("Discovery of highly potent small molecule kaiiikrein inhibitors" Medicinal Chemistry 2, p545-553 (2006)), Sinha ef al. ("Inhibitors of plasma kaiiikrein" WO08/016883), Shigenaga et al. ("Plasma Kaiiikrein Inhibitors" WO2011/118672), and Kolfe ef al. ("Biochemical characterization of a novel high-affinity and specific kaiiikrein inhibitor", British journal of Pharmacology (2011), 162(7), 1639-1649). Also, Steinmetzer ef al. ("Serine protease inhibitors" WO2012/004678) describes cyclized peptide analogs which are inhibitors of human plasmin and plasma kaiiikrein. To date, no small molecule synthetic plasma kallikrein inhibitor has been approved for medical use. The molecules described in the known art suffer from limitations such as poor selectivity over related enzymes such as KLKl, thrombin and other serine proteases, and poor oral availability. The large protein plasma kallikrein inhibitors present risks of anaphylactic reactions, as has been reported for Ecailantide. Thus there remains a need for compounds that selectively inhibit plasma kallikrein, that do not induce anaphylaxis and that are orally available. Furthermore, the vast majority of molecules in the known art feature a highly polar and ionisable guanidine or amidine functionality. It is well known that such functionalities may be limiting to gut permeability and therefore to oral availability. For example, it has been reported by Tamie J. Chilcote and Sukanto Sinha ("ASP-634: An Oral Drug Candidate for Diabetic MacularEdema", ARVO 2012 May 6* - May 9* 2012, Fort Lauderdale, Florida, Presentation 2240) that ASP-440, a benzamidine, suffers from poor oral availability. It is further reported that absorption may be improved by creating a prodrug such as ASP-634. However, it is well known that prodrugs can suffer from several drawbacks, for example, poor chemical stability and potential toxicity from the inert carrier or from unexpected metabolites. In another report, indole amides are claimed as compounds that might overcome problems associated with drugs possessing poor or inadequate ADM E-tox and
physicochemicai properties although no inhibition against plasma kallikrein is presented or claimed (Griffioen et ai, "Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases", WO2010, 142801). BioCryst Pharmaceuticals Inc. have reported the discovery of the orally available plasma kallikrein inhibitor BCX4161 ("BCX4161, An Oral Kallikrein inhibitor: Safety and Pharmacokinetic Results Of a Phase 1 Study in Healthy Volunteers", Journal of Allergy and Clinical immunology. Volume 133, Issue 2, Supplement, February 2014, page AB39 and "A Simple, Sensitive and Selective Fluorogenic Assay to Monitor Plasma Kallikrein Inhibitory Activity of BCX4161 in Activated Plasma", Journal of Allergy and Clinical immunology, Volume 133, Issue 2, Supplement February 2014, page AB40). However, human doses are relatively large, currently being tested in proof of concept studies at doses of 400 mg three times daily.
There are only few reports of plasma kallikrein inhibitors that do not feature guanidine or amidine functionalities. One example is Brandl et al. ("N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein" WO2012/017020), which describes compounds that feature an amino- pyridine functionality. Oral efficacy in a rat model is demonstrated at relatively high doses of 30 mg/kg and 100 mg/kg but the pharmacokinetic profile is not reported. Thus it is not yet known whether such compounds will provide sufficient oral availability or efficacy for progression to the clinic. Other examples are Brandl et al. ("Aminopyridine derivatives as plasma kallikrein inhibitors" WO2013/111107) and Flohr et al. ("5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors" WO2013/111108). However, neither of these documents report any in vivo data and therefore it is not yet known whether such compounds will provide sufficient oral availability or efficacy for progression to the clinic. Another example is Allen et al. "Benzylamine derivatives" WO2014/108679.
Therefore there remains a need to develop new plasma kallikrein inhibitors that will have utility to treat a wide range of disorders, in particular to reduce retinal vascular permeability 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 demonstrate good selectivity for plasma kallikrein and are potentially useful 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, cardiopulmonary bypass surgery and bleeding from post operative surgery. The invention further relates to pharmaceutical compositions of the inhibitors, to the use of the compositions as therapeutic agents, and to methods of treatment using these compositions.
The present invention provides compounds closely related to or failing within the scope of, but not specifically disclosed in, our co-pending application PCT/ GB2014/051592. In a first aspect, the present invention provides compound selected from the group consisting of:
N-{(1-Aminoisoquinolin-6-yl)methyl)-3-{methoxymethyl)-1-{(6-(pyrrolidin-1- yl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxamide dihydrochloride;
N-({l-Aminoisoquinolin-6-yl)methyl)-3-{methoxymethyl)-1-((5-({4-methyl-1H-pyrazol- l-yl)methyl)pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide;
3-Cyano-1-[6-(3,3-difluoro-pyrrolidin-1-yl)-5-methoxy-pyridin-3-ylmethyl]-1H- pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
3-Methoxymethyl-1-(4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide; N-[(l-amino-5-methylisoquinolin-6-y!)methy!]-3-(methoxymethyl)-l-{[6-(pyrroiidin-l- yl)pyridin-3-yl3methyl}pyr3zole-4-carboxamide;
N-((l-amino-5-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-l-{[6-(pyrroiidin-l- yl)pyridin-3-yl]methyl}pyrazoie-4-carboxamide;
N-[(l-amino-5-methoxyisoquinolin-6-yl)methyl]-3-(methoxymethyl)-l-{(6-{pyrrolidin- l-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
3-methoxymethyl-l-(2-pyrrolidin-l-yt^yrimidin-5-ylmethyl)-lH-pyrazole-4-carboxylic acid (l-amino-isoquino!in-6-ylmethy!)-amide;
N-[(l-amino-5-methylisoquinolin-6-yl)methylJ-3-(methoxymethyl)-l-{[2-(pyrrolidin-l- yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-[(l-amino-5-fluoroisoquinolin-6-yl)methyl]-3-(methoxyrnethy!)-l-fl2-(pyrro!idiri-l- yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-[(l-amino-5-methoxyisoquinoiin-6-yl)methyl]-3-(methoxymethyl)-l-{[2-(pyrrolidin- l-yl)pyrimidin-5-yljmethyl}pyrazole-4-carboxamide;
N-{(l-amino-7-methylisoquinolin-6-yl)methylJ-3-(methoxymethyl)-l-{[2-(pyrroiidin-l- yl)pyrimidin-5-yl]methyl}pyrazoie-4-carboxamide;
N-[(l-amino-7-methoxyisoquinolin-6-yl)methyl]-3-(methoxymethyl)-l-{(2-(pyrrolidin- l-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-[(l-amino-7-fluoroisoquinoiin-6-yl)methyl]-3-{methoxymethyl)-l-{l2-(pyrroiidin-l- yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-[(l-amino-8-methoxyisoquinofin-6-yl)methyl]-3-(methoxymethyl)-l-{[2-(pyrrolidin- l-yl)pyrimidin-5-yljmethyl}pyrazole-4-carboxamide; l-[2-(33-difluoro^yrroiidin-l-yl)-pyrimidin-5-ylmethyl]-3-methoxymethyl-lH- pyrazoie-4-carboxylic acid (l-amino-isoquinolin-6-ylmethyl)-amide;
N-[(l-amino-5-methylisoquinolin-6-yl)methyl]-l-{[2-(3,3-difluoropyrrolidin-l- yl)pyrimidin-5-yl]rnethyl}-3-(rnethoxyrnethyl)pyrazole-4-carboxarnide;
N-[(l-amino-5-fluoroisoquinolin-6-yl)methyl]-l-{[2-(3,3-difluoropyrrolidin-l- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazoie-4-carboxamide;
N-[(l-amino-5-rnethoxyisoquinoiin-6-yl)rnethyl)-l-{[2-(3<3-difiuoropyrroiidin-l- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazoie-4-carboxamide;
N-[(l-amino-7-methoxyisoquinotin-6-yl)methyl]-l-{[2-(3,3-diftuoropyrrotidin-l- yl)pyrimtdin-5-yl]methyl}-3-(methoxyrnethyl)pyrazote-4-carboxamide;
N-[(l-amino-7-methylisoquinoiin-6-yl)methyl]-l-{l2-(3/3-difiuoropyrroiidin-l- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(1-arn!no-7-fluoro!Soquinoljn-6-yl}methyl]-1-{[2-{3,3-difluoropyrroljdin-1- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;
3-(2-methoxy-ethyl)-1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl}phenyl]methyl}pyrazo!e-4-carboxamide;
3-ethoxymethyl-1-(4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-{[2-(pyrazol-1-ylmethyl)pyrimidin-5-yl]methyl}- 3-(trifluoromethyl)pyrazole-4-carboxamide
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({3-fluoro-4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({2-fluoro-4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
3-cyclopropyl-1-(2-fluoro-4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
3-cyclopropyl-1-[4-(4-fluoro-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
l-[4-(4-fluoro-pyrazol-1-ylmethyl)-benzyl]-3-methoxymethyl-1H-pyrazole-4- carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide; N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazo!-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl] phenyl }methyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; l-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-{[2-(pyrrolidin-1-yl)pyridin-4- yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide; 3-amino-N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-{[2-(pyrrolidin-1- yl)pyridin-4-yl]methyl}pyrazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-3-cyano-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
3-amino-N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide; l-(2-Pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxyli^ acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-3-(methoxymethyl)-1-{[2- (pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-{[6-(3/3-difluoropyrrolidin-1- yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;
3-amino-N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-{[6-(3,3- difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-{[6-(3,3-difluoropyrrolidin-1- yl)pyridin-3-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-[(6-ethoxy-5-fluoropyridin-3- yl)methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-({6- [isopropyl(methyl)amino]pyridin-3-yl}methyl)-3-(trifluoromethyl)pyrazole-4- carboxarnide;
3-amino-1-{[6-(benzyloxy)pyridin-3-yl]methyl}-N-({3-chloro-1H-pyrrolo[2,3-b]pyridin- 5-yl}methyl)-1H-pyrazole-4-carboxamide
3-amino-N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-{[6- (phenoxymethyl)pyridin-3-yl]methyl}-1H-pyrazole-4-carboxamide
3-amino-N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-[(6-phenoxypyridin-3- yl)methyl]-1H-pyrazole-4-carboxamide
3-methoxymethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4- carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
3-cyano-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3- chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
3-amino-N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-(methoxymethyl)-1-[(2- methylquinolin-6-yl)methyl]pyrazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-[(7-chloroquinolin-3-yl)methyl]- 3-(methoxymethyl)pyrazole-4-carboxamide;
3-amino-N-[(3-chloro-1H-indol-5-yl)methyl]-1-({4-[(2-oxopyridin-1- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
3-amino-N-[(3-ch!oro-1H-indazo!-5-yl)methyl]-1-({4-[(2-oxopyridin-1- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-({3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-cyclopropyl-1-({4-[(2-oxopyridin- l-yl)methyl]phenyl}methyl)pyrazo!e-4-carboxamide;
N-({3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-(methoxymethyl)-1-({4-[(2- oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-({4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-({4-[(2-oxopyridin-1- yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-({l-methylpyrazolo[3,4-b]pyridin-5-yl}methyl)-1-({4-[(2-oxopyridin-1- yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-({3-chloro-1H-pyrrolo[2,3-c]pyridin-5-yl}methyl)-3-(methoxymethyl)-1-({4-[(2- oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
3-amino-N-[(6-chloroisoquinolin-3-yl)methyl]-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(6-chloroisoquinolin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(6-chloroisoquinolin-3-yl)methyl]-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3- (trifluoromethyl)pyrazole-4-carboxamide;
N-[(6-chloroisoquino!in-3-yl)methyl]-3-{methoxymethyl)-1-{i6-(pyrro!idin-1-yl)pyridin- 3-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl)methyl]-2-methyl-1-{[4-{pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyljphenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyljphenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide; N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyljphenyl}methyl)irnidazole-4-carboxarnide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)rnetbylj-2-cyclopropyl-1-{{4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-arnino-7-methylisoquino!in-6-yl)methylj-1-({4-[{4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]pbenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-fluoropyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-fluoropyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide; N-[(l-arnino-5-fluoroisoquinolin-6-yl)methyl]-2-cyciopropyl-l-({4-[(4-fluoropyrazol-l- yl)methylJphenyl}methyl)imidazoie-4-carboxamide;
N-((l-arnino-5-methoxyisoquinolin-6-yf)methyl]-2-cyclopropyl-l-({4-{(4-fluoropyrazol- l-yl)methyl]phenyl}methyl)imidazote-4-carboxamide;
N-[(l-amino-7-methoxyisoquinolin-6-yl)methyl]-2-cyclopropyl-l-({4-[(4-fluoropyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(l-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cycfopropyf-l-({4-((4-fluoropyrazol-l- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(l-amino-8-methoxyisoquinolin-6-yl)methyl]-2-cyclopropyl-l-({4-[(4-fluoropyrazol-
1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
2- methyl-l-(6-pyrrolidin-l-yl-pyridin-3-ylmethyl)-lH-irnidazole-4-carboxylic acid (1- amino-isoquinolin-6-y!methyl)-amide;
N-[(l-amino-7-methylisoquinolin-6-yl)methyl]-2-methyl-l-{[6-(pyrroiidin-l-yl)pyridin-
3- yl]methyl}imidazote-4-carboxamide;
N-{(l-amino-5-methylisoquinolin-6-yl)methyl]-2-methyl-l-{[6-(pyrroiidin-l-yl)pyridin- 3-yl]methyl}imidazole-4-carboxamide;
N-[(l-amino-5-fluoroisoquinolin-6-yl)methyl]-2-methyl-l-{l6-(pyrrolidin-l-yl)pyridin- 3-yl]methyl}imidazofe-4-carboxamide;
N-[(l-amino-5-methoxyisoquinolin-6-yl)methyl3-2-methyl-l-{[6-(pyrrolidin-l- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(l-amino-7-methoxyisoquinolin-6-yl)methyl]-2-methyl-l-{[6-(pyrrolidin-l- yt)pyridin-3-yl3methyl}imidazole-4-carboxamide;
N-{(l-amino-7-fluoroisoquinolin-6-yl)methyl]-2-methyl-l-{(6-(pyrrolidin-l-yl)pyridin- 3-yl]methyl}imidazoie-4-carboxamide;
N-[(l-amino-8-methoxyisoquinolin-6-yl)methyl]-2-methyl-l-{[6-{pyrrolidin-l- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(l-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-l-{l6-(pyrrolidin-l- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(l-amino-5-methylisoquinolin-6-yl)methyl]-2-cyc!opropyl-l-{{6-(pyrrolidin-l- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-((l-arnino-5-fluoroisoquinolin-6-yl)methyl3-2-cyclopropyl-l-{[6-(pyrrolidin-l- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(l-amino-5-methoxyisoquinolin-6-yl)methyl]-2-cyciopropyl-l-{[6-(pyrrolidin-l- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide; N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[6-(pyrrolidiri-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(6-chloroisoquinolin-3-yl)methyl]-2-methyl-1-({4-[(2-oxopyridin-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-2-methyl-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-2-methyl-1-({4-[(2-oxopyridiri-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-aminoisoquino!in-6-yl)methyl]-2-methyl-l-{ [2-(pyrro!idin-1-yl)pyrirnidin-5- yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide; N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidiri-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrsmidin-5-yljmethyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3,3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3,3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3,3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3,3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3,3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[6-(3,3- difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}imidazole-4-carboxamide; N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3,3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
3-amino-N-[(3-chloro-1H-indazol-5-yl)methyl]-1-{[6-(pyrrolidin-1-yl)pyridin-3- yl]methyl}pyrazole-4-carboxamide;
N-({3-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl}methyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3- yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-({5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3- yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-({3-chloro-1H-pyrrolo[2,3-c]pyridin-5-yl}methyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3- yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;
3-amino-N-[(7-chloroquinolin-2-yl)methyl]-1-{[6-(pyrrolidin-1-yl)pyridin-3- yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin^ l-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin- l-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide; N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide^
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide; N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyljphenyl}methyl}-5-methyl-l,2,4-triazoie-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide;
N-[{l-arnino-8-methoxylsoquino!irs-6-yl)methylj-1-({4-[(4-fiuoropyrazoi-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazo!e-3-carboxarnide; N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazo!e-3-carboxarnide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-(pyrrolidin- l-yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-(pyrrolidin l-yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-(pyrrolidin- l-yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-ynmethyl}-l,2,4-triazoie-3-carboxarnide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[2-(pyrrolidin- l-yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxyisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[2-{pyrrolidjn- l-yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[2-(pyrrolidin- l-yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide; N-[(1-amino-y-methylisoquinolin-S-yl]methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-(rnethoxymethyl)-l,2,4-triazole-3<arboxarnide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-{[6-(pyrrolidin-1-yl)pyridin 3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-methyl-1-{[6-(pyrrolidin-1-yl)pyridin 3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-methyl-1-{[6-(pyrrolidin-1-yl)pyridi 3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[{1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-{[6-(pyrrol!din-1-yl)pyridin- 3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide; N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2-,4-triazo!e-5-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-methyl-l,2,4-triazole-5-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3i3-difluoropyrrolidin-1- yl)pyrimidin-5-yl] methyl }-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrirnid!n-5-yl]methyl}-5-methyl- l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-methylpyrazol-1- yl)methyljphenyl}methyl)imidazole-4-carboxamide;
and pharmaceutically acceptable salts and solvates thereof.
In a further aspect, provided is a compound selected from the group consisting of:
N-((1-aminoisoquinolin-6-yl)methyl)-3-(m
yl)methyl)-1H-pyrazole-4-carboxamide dihydrochloride;
N-((1-aminoisoquinolin-6-yl)methyl)-3-(methoxymethyl)-1-((5-((4-methyl-1H-pyrazol-1- yl)methyl)pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide; 3-cyano-1-[6-(3,3-difluoro-pyrrolidin-1-yl)-5-methoxy-pyridin-3-ylmethyl]-1H-pyrazole-4- carboxylic acid (1-arnino-isoquinolin-6-ylmethyl)-amide;
3-methoxymethyl-1-(4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide;
3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl}-arnide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }pyrazole-4-carboxamide; l-[2-(3,3-difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethyl]-3-methoxymethyl-1H-pyrazole-4- carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;
3-(2-methoxy-ethyl)-1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}pyrazole-4-carboxamide;
3-ethoxymethyl-1-(4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1-amino- isoquinolin-6-ylmethyl)-amide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({3-fluoro-4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({2-fluoro-4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
3-cyclopropyl-1-(2-fluoro-4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide;
3-cyclopropyl-1-[4-(4-fluoro-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide; l-[4-(4-fluoro-pyrazol-1-ylmethyl)-benzyl]-3-methoxymethyl-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide; N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1-yl)methyl]phenyl}methyl)- 3-(trifluoromethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazoi-1-yl)methyljphenyl}methyl)pyrazo!e-4-carboxarnide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; l-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
3- amino-N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-{[2-(pyrrolidin-1-yl)pyridin
4- yl]methyl}pyrazole-4-carboxamide; l-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-{[6-(3,3-difluoropyrrolidin-1- yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-{{5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-({6- [isopropyl(methyl)amino]pyridin-3-yl}methyl)-3-(trifluoromethyl)pyrazole-4- carboxarnide;
3-methoxymethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide; 3-cyano-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxyl!C acid (3- chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
N"{{3-chloro- lH-pyrrolo[2;3-b]pyridin-5"yl}methyl)-3-(methoxymethyl)-4-[{2" methylquinolin-6-yl)methyl]pyrazole-4-carboxamide;
N-[(6-chloroisoquinolin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(6-chloroisoquinolin-3-yl)methyl]-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3- (trifluoromethyl)pyrazole-4-carboxamide;
2-methyl-1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-1H-imidazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide;
N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-2-m
yl]methyl}imidazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)irnidazole-4-carboxarnide; and pharmaceutically acceptable salts and solvates thereof.
In a further aspect, provided is a compound selected from the group consisting of:
N-((1-aminoisoquinolin-6-yl)methyl)-3-(m
yl)methyl)-1H-pyrazole-4-carboxamide dihydrochloride;
N-((1-aminoisoquinolin-6-yl)methyl)-3-(methoxymethyl)-1-({5-((4-methyl-1H-pyrazoi-1- yl)methyl)pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide;
3-methoxymethyl-1-(4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide;
3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide; N-[(1-amino-5-methylisoquinolin-6-yl)m
yl)pyrimidin-5-yl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}pyrazole-4-carboxamide;
3-ethoxymethyl-1-(4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1-amino- isoquinolin-6-ylmethyl)-amide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({3-fluoro-4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({2-fluoro-4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
3-cyclopropyl-1-(2-fluoro-4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide;
3-cyclopropyl-1-[4-(4-fluoro-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide; l-[4-(4-fluoro-pyrazol-1-ylmethyl)-benzyl]-3-methoxymethyl-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1-yl)methyl]phenyl}methyl)-
3-(trifluoromethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazoi-1-yl)methyljphenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4- methylpyrazoi-1-yl)methyljphenyl}methyl)pyrazo!e-4-carboxarnide; l-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
3-methoxymethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
3-cyano-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3- chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
N-[(1-aminoisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-methylpyrazol-1- yl)rriethyl]phenyl}methyl)irnidazo!e-4-carboxamide; and pharmaceutically acceptable salts and solvates thereof.
In a further aspect, provided is a compound selected from the group consisting of:
3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide; l-[2-{3,3-difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethylj-3-methoxymethyl-1H-pyrazole-4- carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide; l-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
and pharmaceutically acceptable salts and solvates thereof.
In a further aspect, provided is:
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-{pyrazoi-1- ylmethyl)phenyl]methyl}pyrazole-4-carboxamide, and pharmaceutically acceptable salts and solvates thereof.
In a further aspect, provided is:
3-methoxymethyl- l-{2- pyrrolidin-4-yl-pyrimidin-5-ylmethyl)- lH-pyrazole-4-carboxylic acid (1-amino- isoquinolin-6-ylmethyl)-amide, and pharmaceutically acceptable salts and solvates thereof.
In a further aspect, provided is: l-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H- pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide, and pharmaceutically acceptable salts and solvates thereof.
In a further aspect, provided is:
N-[(1-aminoisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide, and pharmaceutically acceptable salts and solvates thereof.
In a further aspect, provided is: l-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carb^ acid (3-chloro-1H- pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide, and pharmaceutically acceptable salts and solvates thereof.
In another aspect the present invention provides a prodrug of a compound of the invention, or a pharmaceutically acceptable salt thereof.
In yet another aspect the present invention provides an N-oxide of a compound of the invention, 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.
Therapeutic Applications
As previously mentioned, the compounds of the present invention are potent and selective inhibitors of plasma kailikrein. They are therefore useful in the treatment of disease conditions for which overactivity of plasma kailikrein 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 kailikrein 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, cardiopulmonary bypass surgery and bleeding from post operative surgery.
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.
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. Patei 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, Aielio 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
"Pharmaceutically acceptable salt" means a physiologically or toxicologicaily 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.
Hemisaits of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.
For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
"Prodrug" refers to a compound 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 solvafed 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, diasfereomeric and tautomeric forms, including but not limited to cis- and irons-forms, f- 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).
In the context of the present invention, references herein to "treatment" include references to curative, palliative and prophylactic treatment.
General Methods
The compounds of formula (I) 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 nonfunctional (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 pharmaceuticai 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- vitreai 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, intrasternai, 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-iactone, poiyhydroxybutyrate), 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 iyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of formula (I) 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 cyciodextrins. 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 microparticulafes, 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.
Formulations suitable for oral administration may also be designed to deliver the compounds of the invention in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic efficacy of the said compounds. Means to deliver compounds in a rate- sustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.
Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion. Examples of rate-sustaining polymers include hydroxypropyl methylceliulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.
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 hydroxypropylmethylcei!ulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifylng 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, 2.001, 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, Mew York, 1980). For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.01 mg and 1000 mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg depending, of course, on the mode of administration.
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 wiii readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
Examples
In these examples the following abbreviations and definitions are used:
Figure imgf000033_0001
All reactions were carried out under an atmosphere of nitrogen unless specified otherwise. 1H NM R spectra were recorded on a Bruker (400MHz) spectrometer with reference to deuterium solvent and at rt. Molecular ions were obtained using LCMS which was carried out using a Chromolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient 10% to 90% 0.1% HCQ2H/MeCN into 0.1% HCQ2H/H2Q 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. Automated FC refers to a Biotage purification system with UV directed sample collection using either SNAP ultra or ZIP Sphere cartridges.
AH 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 M DL information Systems or the Chemaxon software provided as a component of MarvinSketch or as a component of the IDBS E-WorkBook.
General Methods:
Alkylation
Performed with K2CO3 unless otherwise stated in either DMF, MeCN or acetone at between rt and 80 °C. Saponification
Performed using either LiOH.H2O in THF/water or NaQH in methanol or ethanoi at reflux. Amide formation
Method A: To the carboxylic acid component (1 eq) in DCM (and DMF if required) at 0 °C was added HOBt (1.2 eq) and EDC (1.4 eq). The reaction mixture was stirred for 10 min then Et3N (5 eq) and the amine component (1 eq) were added and the reaction stirred at rt. The reaction was diluted with CHCl3 (50 mL) and washed with brine (20 mL). The organic layer was dried (MgS04), filtered and concentrated in vacuo and then purified by automated FC.
Method 8: The carboxylic acid component (1 eq), the amine component (1 eq) and HATU (1.1 eq) were suspended in anhydrous DCM (and DMF if required) and Et3N (6 eq) added. The reaction mixture was stirred at rt. The solvent was removed under vacuum. The residue was purified by automated FC.
Method C: To the carboxylic acid component (1 eq) in DCM (and DMF if required) was added HBTU (1.2 eq), Et3N (5 eq) and the amine component (1 eq) and the reaction stirred at rt. The reaction was diluted with CHCU (50 mL) and washed with brine (20 mL). The organic layer was dried (MgSCU), filtered and concentrated and then purified by automated FC.
Intermediates ("B" ring):
Al. 2-({E)-2-Dimethylamino-vinYl)-terephthalonitri!e ester
Methylterephthalonitrile (1.42g, 9.99mmol) and Bredereck's reagent (3.48g, 19.98mmol) were dissolved in DMF (15mL). The reaction mixture was heated at 75 *C under nitrogen for 72hrs after which time the solvent was removed in vacuo. Trituration with Pet. Ether gave a bright yellow solid identified as 2-((E)- 2-dimethylamino-vinyl)-terephthalonitrile ester (1.88g, 0.95mmol, 95% yield).
3H NMR (CD3OD) δ: 3.20 (6H, s), 5.34 (1H, d, J = 13.4Hz), 7.21 (1H, dd, J = 8.0Hz, 1.4Hz), 7.9 (1H, d, 13.4Hz), 7.61 (1H, d, J = 8.0Hz), 7.94 (1H, d, J =1.2Hz)
A2. l-Amino-2-{2,4-dimethoxy-ben2y!)-l,2-dihydro-isoquinoline-6-carbonitrile
2-((£)-2-Dimethylamino-vinyl)-terephthalonitrile ester (1.85g, 9.38mmol) was dissolved in 1,3-dimethyl- 3,4,5,6-tetrahydro-2(lH)-pyrimidinone (5mL) and 2,4-dimethoxybenzylamine (2.35g, 14.07mmoi) was added. The reaction mixture was heated at 75 *C under nitrogen. After 3hrs the reaction mixture was cooled and diethyl ether/ Pet. Ether (15:85) was added. The yellow solid was filtered off, dried in vacuo, and identified as l-amino-2-(2,4-dimethoxy-benzyl)-l,2-dihydro-isoquinoline-6-carbonitrile (2.65g, 8.38mmol, 89% yield)
[MH]' = 320
lH NMR (CDjOD) δ: 3.85 (3H, s), 3.92 (3H, s), 5.02 (2H, s), 6.39 (1H, d, J = 7.4Hz), 6.57 (1H, dd, J = 8.4Hz, 2.4Hz), 6.66 (1H, d, J = 2.4Hz), 7.18 (1H, d, J = 8.4Hz), 7.24(1H, d, J = 7.4Hz), 7.72 (1H, dd, J = 8.5Hz, 1.4Hz), 7.93 (1H,S), 8.45 (1H, d, J = 8.5 Hz)
A3. l-Amino-isoquinoline-6-carbonitrile l-Amino-2 {2,4 dimethoxy-benzy!) l,2-dihydro-!SoquinoNne-6-carbon!tri!e {1.6g, S.Ommot) was dissolved in anisoie {17mL) and trifluoroacetic acid (20mL). The reaction mixture was heated at 105°C under nitrogen for 12hrs after which time the reaction mixture was cooied, diethyl ether/Pet. Ether (3:7) was added, the resultant soiid was filtered off, dried in vacuo and identified as l-amino-isoquino!ine-6- carbonitriie (770mg, 4.54mmo!.. 91% ).
[MH]* = 170.
:H NMR (CDsOD) δ: 7.23 - 7.25 (1H, d, J = 6.9Hz), 7.65 (1H, d, J = 6.8Hz), 8.11 (1H, dd, J = 8.7Hz, 1.6Hz), 8.33 (1H, s), 8.45 (1H, d, J = 8.7Hz). A4. (l-Ammo-isoquinoiin-6-ylmethyl)-carbamic acid tert-butyf ester
l-Amino-isoquinoline-6-carbonitriie (200mg, l.lSmmo!) was dissolved in methanol (20mL). This solution was cooled to D C. Nickel (II) chloride hexahydrate (28mg, 0.12mmoi) and di- tertbutyl dicarbonate (516g, 2,36mmoi) were added followed by sodium borohydride (313g, 8.22mmol) portionwise. The reaction mixture was stirred at 0 "C to room temp for 3 days. The MeOH was removed by evaporation. The residue was dissolved in CHCb (70mL), washed with sat NaHC03 (30 mL), water (30 mL), brine (30 mL), dried (Na2SO.) and evaporated in vacuo to give a ye!low oil identified as (l-amino-isoquinoiin-6- ylmethyl)-carbamic acid tert-Butyl ester (llOmg, 0.4mmol, 34?^ yield).
[MH]* = 274. AS. 6-Aminomethyl-isoquinolin-l-ylamine hydrochloride
(l-Amino-isoquino!in-6-ylmethy!)-carbamic acid tert-Butyl ester (llOmg, 0.40mmol) was dissolved in 4M HCS in dioxane (40ml). After 18 hrs at rt the solvent was removed in vacuo to give a pale brown soiid identified as 6-aminomethyl-isoquinolin-l-y!amine hydrochloride (67mg, 0.39mmol, 96% yield).
[MH]* = 174.
81. 3-Chloro-lH-pyrrolo{2,3-b]pyridine-S-carbonitnie
5-Cyano-7-azaindole (1.0 g, 6.99 mmol) was dissolved in dry DMF (5 mL). To this solution was added N- chiorosuccinimide (1.12 g, 8.38 mmol) at 40 °C. The reaction mixture was stirred at 55 °C for 5 hrs and cooled to rt and left stirring for 2 days. The mixture was diluted with water (40 mL) and stirred for a further 18 hrs. The solid was filtered off and dried to give 3-chloro-lH-pyrrolo[2,3-bjpyridine-5- carbonitrile (1.1 g, 89% yield).
[MH]* = 178.2
82. (3-Chioro-lH-pyrroio[2,3-b]pyridin-5-ylmethyl)-carbamic acid tert-Butyl ester 3-Cbloro-lH-pyrrolo[2,3-b]pyridine -5-carbonitriSe (1.0 g, 5.63 mmoi) was dissolved in methanol (150 mL). This solution was coo!ed to 0 °C. Nickel (IS) chloride hexahydrate (134 mg, 0.56 mmoi) and di- tertbutyl dicarbonate (2.46 g, 11.3 mmoi) were added followed by sodium borohydride (1.49 g, 39.4 mmoi) portionwise. The reaction mixture was allowed to warm to rt and stirred for 18 hrs. The MeOH was removed in vacuo. The residue was dissolved in CHCSj (70 mL), washed with sat. aq. NaHC03 (30 rnL), water (30 mL).. brine (30 mL), dried (Na2S04) and evaporated in vacuo. The residue was purified by Hash chromatography (silica), eluent 3% MeOH, 97% CHCi3 to give (3-chioro lH-pyrroio[2,3 b]pyridin -5- ylmethyl) carbamic acid tert-butyl ester (870 mg, 55% yield).
f>1H]÷ = 282.2
83. C-{3-Chloro-lH-pyrrolo[2,3-b]pyndin-5-yf)-methylamine
(3-Chloro- lH pyrrolo[2,3-b]pyridin-5 ylmethyl) carb3rnic acid tert-butyl ester (870 mg, 3.09 mmoi) was dissolved in 4M HCi in dioxan (150 mL). After one hour at rt the solvent was removed in vacuo to give C- (3-chioro-lH-pyrroio[2,3-bjpyrtdin-5-yl)-methylamtne (650 mg, 97?^ yield).
CI. 4-Bromo-5-fluoro-2-methyl benzamide
To dry THF (25 mL, 305 mmoi) at rt was added 4-bromo-5-fiuoro-2-methylbenzoic acid (5.43 g, 23.30 mmo!) foilowed by CD! (4.91 g, 30.3 mmoi) which was added portionwise at rt. The solution was left to stir at rt for 3 hrs. Ammonium hydroxide (10 ml, 90 mmoi) was then added. The resulting reaction mixture was left to stir at rt overnight. The solvent was then concentrated under reduced pressure at 40 "C to 15 mi. and the resulting solution was slowly quenched into water (100 mi.). An off white solid precipitated and was filtered under reduced pressure, washed with water (50 ml) and isohexanes. The product was dried in a vacuum oven to afford 4-hromo-5-fSuoro-2-methylbenzamide (4.92 g, 86 % yield) used directly in the next step without purification.
[ΜΗ]· = 232.0/234.2
C2. (£)-4-Bromo-N-((dimethylamino)rnethylene}-5-f!uoro-2-methylbenzarnide
In dry THF (30 mL, 366 mmoi) was dissolved 4-bromo-5-fiuoro-2-methylbenzamide (4.92 g, 21.20 mmoi), to which l,l-dimethoxy-N,N-dimethylmethanamine (3.19 mL, 23.32 mmoi) were added. The reaction was heated at 60 "C over two nights. The reaction mixture was evaporated under reduced pressure to give (f )-4-bromo-N-((dimethylamino)methylene)-5-fluoro-2-methylben2amide (6.0 g, 97% yield) identified as the desired product.
[MH]+ = 287/289 C3. 6-Bromo-7-fiuoro-2H-isoquinoiin-l-one (E)-4-Bromo-N-((dimethylamino)methylene)-5-fluoro-2-methylbenzamide (6.0 g, 20.90 mmol) was dissolved in dry THF (30 mL, 366 mmol) to which potassium tert-butoxide (2.66 g. 22.99 mmol) was added at rt. The solution was warmed to 60 °C for 3 days. The reaction mixture was cooled and then quenched into 1M citric acid (200 mL), a solid precipitated and was filtered under reduced pressure, washed with water and dried in a vacuum oven at 40 QC for 3 hrs. Flash column chromatography on silica eluting with ethyl acetate -isohexane, in gradient steps up to 60% ethyl acetate gave 6-bromo-7- fluoro-2H-isoquinolin-1-one (560 mg. 10.2% yleld).
[MH]+ = 242/244 C4. 6-Bromo-1-chIoro-7-fLuoro-isoquinoIine
The following typical chiorirsation procedure was used
To dry toluene (typically 13 mL per gram of starting material) was added the appropriate pyridinone starting material (1 eq) and diisopropylaime (3 eq) followed by neat phosphoryl trichloride (3 eq). The suspension was heated to 130 °C overnight. The reaction mixture was allowed to cool to rt and then quenched into water and then further diluted with water. The mixture was extracted with EtOAc, the combined organics were washed with sodium carbonate solution, followed by brine, dried over magnesium sulphate, filtered and evaporated in vacuo at 45 °C to dryness. The crude material was purified by trituration or flash column chromatography. Following the typical chlorination procedure, 6-bromo-7-fluoro-2H-isoquinolin-1-one (0.560 g, 2.129 mmol) was converted to 6-bromo-1-chloro-7-fluoro-isoquinoline (460 mg, 82 % yleld).
[MH]+ = 259.8/261.8/263,8
C5, 6-brorrio-7-fluoroisoquinolin-l-amir!e
The following typical animation procedure was used
A mixture of the appropriate chloroisoquinoline (1 eq), ammonium acetate (15 eq) and phenol (15 eq) were heated to 140 °C overnight. After cooling, the reaction mixture was partitioned between 2N NaOH and DCM. The organic layer was collected and the aqueous extracted with further DCM. The organics were phase separated using a phase separating cartridge and concentrated in vacuo. The crude material was purified using flash column chromatography eluting with 1% ammonia in methanol/DCM.
6-Bromo-1-chloro-7-fluoroisoquinoline (460 mg, 1.78 mmol) was converted using the typical amination procedure to 6-bromo-7-fluoroisoquinolin-1-amine (23.8 mg, 5.5% yleld).
[MH]+ = 240.8/242.8 C6, l-amIrso-7-fluoroisoq!J!nol!ne-6-carbonitri!e
The following typical cyarsation procedure was used
To a stirred solution of dicyanozinc (1 eq) and the appropriate arylbromide (1 eq) in DM F was added Pd(Ph3P)4 (0.1 eq). The reaction was heated to 100 °C overnight. The reaction was quenched into ice- water (30 mL), the resulting solid filtered, washed with water and dried under reduced pressure. The crude material was purified by SXC cartridge eluting with neat methanol (150 mL) followed by 1% ammonia/methanol (250 mL).
6-Bromo-7-fluoroisoquinolin-1-amine (23.8 mg, 0.099 mmol) was converted using the typical cyanation procedure to 1-amino-7-fluoroisoquinoline-6-carbonitrile (13.3 mg, 64.8 % yleld).
[MH]+ = 188
C7. tert-butyl ((1-arriino-7-fluoroisoqL!inonn-6-yl)rriethyl)carbamate
The following typical nitriie reduction procedure was used
To dry methanol was added the appropriate aryl nitriie (1 eq) followed by nickel chloride hexahydrate (0.1 eq) and di-tert-butyl dicarbonate (2 eq). The mixture was cooled in an ice-salt bath to -5 °C and sodium borohydride (7 eq) was added portionwise maintaining the reaction temperature at approximately 0 °C. The reaction was left stirring at 0 °C and slowly allowed to warm to rt overnight. The solvent was removed in vacuo at 40 °C. The residue was taken up with chloroform (30 mL) and washed with sodium hydrogen carbonate (15 mL). The crude material was purified by flash column
chromatography eluting with (1% ammonia-methanol)-DCM.
Following the typical nitriie reduction procedure 1-amino-7-fluoroisoquinoline-6-carbonitrile (13 mg, 0.063 mmol) was converted to tert-butyl ((1-amino-7-fluoroisoquinolin-6-yl)methyl)carbamate (12. mg, 64.6% yleld).
[MH]+ = 292
C8, 6-{Arniriorrsethyl}-7-fluoroisoquirioliri-l-"arrsir!8 dihydrochloride
To a flask containing tert-butyl ((1-amino-7-fluoroisoquinolin-6-yl)methyl)carbamate (12 mg, 0.040 mmol) was added dry hydrochloric acid (6M in 2-propanol) (47.1 μΙ, 0.283 mmol). The reaction was stirred at rt overnight. Solvent was removed under reduced pressure to give a dark yellow oil which was tritutrated with ether to give 6-(aminomethyl)-7-fluoroisoquinolin-1-amine dihydrochloride
(10.7 mg, 98% yleld).
[MH]+ = 192 Dl. tert-Butyl pivaloyloxycarbamate
ieri-Butyl hydroxycarbamate (15.0 g, 113 mmol) was dissolved in acetonitriie (300 mL). Pivalic anhydride (25.4 mL, 124 mmol) was added as a steady stream and the resulting mixture heated to reflux overnight. After 18 hrs, the reaction mixture was allowed to cool to rt, then concentrated under vacuum. The residue was partitioned between EtOAc (350 mL) and NaHC(¾ (200 mL). The layers were separated and the organic fraction washed with NaHCOs (3 x 100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford iert-butyl pivaloyloxycarbamate (26.38 g. 97 mmol, 86 % yleld).
D2. O-Pivaloylhydroxylamine trifluoromethanesuifonate
ieri'-Butyl pivaloyloxycarbamate (26.38 g, 97 mmol) was dissolved in dry diethyl ether (237 mL). The reaction mixture was cooled to 0 °C and then triflic acid (8.80 mL, 99 mmol) was added (vigorous evolution of gas noted). The mixture was stirred at 0 °C for 5 min and then allowed to warm to rt. After 1 hour iso-hexanes (250 mL) was added and the mixture stirred for 10 min. The resulting solid was filtered, washed with hexanes (3 x 50 mL) and then dried in the vacuum oven overnight to afford O- pivaloylhydroxylamine trifluoromethanesuifonate (24.83 g, 91% yleld).
D3, 4-Bromo-3-methoxybenzoyl chloride
4-Bromo-3-methoxybenzoic acid (0.50 g, 2.164 mmol) was suspended in dry DCM (5.01 mL). Oxalyl chloride (0,227 mL, 2,60 mmol) was added drop-wise over 5 min. Dry DMF (1 drop) was added and gas evolved. The resulting mixture was stirred at ambient temperature. Dissolution slowly occurred over 45 min. After a total of 1.5 hrs, solvents were removed under vacuum to afford 4-bromo-3-methoxybenzoyl chloride (539 mg).
D4. 4-Bromo-3-methoxy-M-{pivaloyloxy}benzamide
To a dry flask under an atmosphere of nitrogen was added O-pivaloylhydroxylamine
trifluoromethanesuifonate (547 mg, 1.944 mmol) dissolved in EtOAc (5.5 mL). Water (5.5 mL) and then sodium carbonate (458 mg, 4.32 mmol) were added. The resulting mixture was cooled to 0 °C and then a solution of 4-bromo-3-methoxybenzoyl chloride (539 mg, 2.16 mmol) in EtOAc (5.5 mL) was added in one portion. The reaction was stirred at 0 °C. After 1.5 hrs the reaction mixture was diluted with EtOAc (10 mL) and quenched with wafer (5 mL) and NaHCOs (15 mL). The layers were separated and the aqueous was extracted with EtOAc (2 x 20 mL). The combined organic fractions were washed with brine (20 mL), dried (MgS04), filtered and concentrated under reduced pressure. Multiple triturations from iso-hexanes afforded 4-bromo-3-mef hoxy-N-(pivaloyloxy)benzamide (378 mg, 47.7 % yleld).
[MH]+ = 330.1/332.1 x D5. 6-Bromo-7-methoxy isoquinolin-l(2H)-one
Vinyl acetate (62.8 μΐ, 0.681 mmol) was added to a N2 degassed solution of [CpRhChh (5.62 mg, 9.09 μηιοΙ), caesium acetate (52.3 mg, 0.273 mmol) and 4-bromo-3-methoxy-N -(pivaloylQxy)benzamide (150 mg, 0.454 mmol) in anhydrous MeOH (1.5 mL) in a sealed vial under a IM2 atmosphere. The reaction was allowed to stir at 50 °C for 1 hour, forming a precipitate. The reaction was cooled to rt and stirred over a weekend. The reaction mixture was filtered, washing with a small quantity of MeOH to afford 6-bromo- 7-methoxylsoquinolin-l(2H)-one (73 mg, 63% yleld) identified as desired product.
[MH]+ = 254.0/256.0
D6. (1-Amino-7-methoxy-isoquinolin-6-vlmethyl)-carbamic acid tert-Butyl ester
6-Bromo-7-methoxylsoquinolin-l(2H)-one was converted to (1-Amino-7-methoxy-isoquinolin-6- ylmethylj-carbamic acid tert-butyl ester using typical chlorination, amination, cyanafion and nitrile reduction procedures. [MH]+ = 304.1
D7, 6-Aminomethyl-7-methoxy-isoquinolin -l-ylamine dihycroehloride
A suspension of tert-butyl ((1-amino-7-methoxylsoquinolin-6-yl)methyl)carbamate (120 mg, 0.396 mmol) hydrochloric acid, 6M in 2-propanoi (462 μL, 2.77 mmol) was heated at 40 °C for 1 hour. The mixture was allowed to stir for a further 45 min at rt then treated with diethyl ether (2.5 mL) and the solid filtered and dried under vacuum to afford 6-(aminomethyl)-7-methoxylsoquinolin-1-amine dihydroehloride (102.5 mg, 89 % yleld).
[MH]+ = 204.0
El. 4-Bromo-5-fluoro-N-hydroxy-benzamide
4-Bromo-3-fluorobenzoic acid (5.0 g, 22.83 mmol) was dissolved in dry DM F (10 mL) at ambient temperature and GDI (5.55 g, 34.2 mmol) was added portionwise, vigorous effervescence was observed. On completion of the addition the reaction solidified. Further dry DMF (6 mL) was added and the resultant slurry was left to stir at rt for 3 hrs. Neat hydroxylamine hydrochloride (3.17 g, 45.7 mmol) was added, forming a solution (some effervescence/heat noted). The mixture was allowed to stir over a weekend. The reaction mixture was quenched into water (200 mL) resulting in an off white precipitate, which was filtered and washed with water, then dried under vacuum overnight to afford 4-bromo-3- fluoro-N-hydroxy-benzamide (3,14 g, 58.2% yleld).
[MH]+ = 234,1/236.1
E2. 4-Bromo-ISS--(2,2-dImethyl-propionyloxy)-3-fluoro-benzamide
To anhydrous MeCN (25 mL) was suspended 4-bromo-3-fluoro-N-hydroxybenzamide (3.14 g, 13.42 mmol). Piva!ic anhydride (2.75 mL, 13.42 mmoi) was added and the resulting mixture was heated at reflux for 3 hrs. The reaction mixture was cooled to rt and poured into saturated aq. NaHCO3, (100 mL) then extracted with EtOAc (3 x 75 mL). The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The crude materia! was purified by automated flash chromatography loading in DCM and eluting with a gradient of 0 to 30% EtOAc/iso-Hexanes to afford 4-bromo-N-(2,2-dimethyl- propionyloxy)-3-fluoro-benzamide (2.56 g, 58.2% yleld) as a white powder.
[MH]+ = 318.0/320.0
E3. S-Aminomethyl-5-fluoro-isoquinolin-1-ylamine
6-Aminomethyl-5-fluoro-isoquinolin-1-ylamine was prepared in 6 steps from 4-bromo-N-(2,2-dimethyl- propionyloxy)-3-fluoro-benzamide using procedures described above.
[MH]+ = 192
F. 3-Aminomethyl-[l,7]naphthyridin-8-ylamine dihydrochloride
3-Aminomethyl-[l,7]naphthyridin-8-ylamine dihydrochloride was prepared in 8 steps from 5-bromo-3- methylpicolinic acid using procedures described above.
[MH]+ = 175
G1. 4-Bromo-3-methoxy-2-methyl-benzoic acid methyl ester
A solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate (1.0 g, 4.08 mmoi) in dry MeCN (7 mL) was treated with potassium carbonate (0.677 g, 4.90 mmol), then iodomethane (0.762 mL, 12.24 mmoi) and the mixture heated at 50 °C for 5 hrs. Solvents were removed in vacuo and the residue partitioned between EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with further EtOAc (2 x 20 mL) and the combined organics washed with brine (20 mL), dried (MgSO4), filtered and concentrated to give 4-bromo-3-methoxy-2-methyl-benzoic acid methyl ester (974 mg, 91 % yleld).
[MH]+ = 259.0//261.0
G2. 4-Bromo-3-methoxy-2-methyl-benzo!c acid
A solution of methyl 4-bromo-3-methoxy-2-methylbenzoate (974 mg, 3.76 mmol) in THF (3 mL) and MeOH (0.5 mL) was treated with lithium hydroxide (180 mg, 7.52 mmol) and water (1 mL). The mixture was warmed at 50 °C for 1.5 hrs. Solvents were removed in vacuo and the residue partitioned between EtOAc (20 mL) and water (15 mL, containing 1 ml. 2N NaOH). The aqueous layer was collected and acidified to pH 5 with 1M HCI, precipitating a white powder which was filtered and dried overnight under vacuum to afford 4-bromo-3-methoxy-2-methyl-benzoic acid (805 mg, 87 % yleld).
[MH]+ = 244.9/246.9
G3, 6-Aminomethyl-5-methoxy-isoquinolin-1-ylamine dihydrochloride
6-Aminomethyl-5-methoxy-isoquinolin-1-ylamine dihydrochloride was prepared in 8 steps from 4- bromo-3-methoxy-2-methyl-benzoic acid using procedures described above.
[MH]+ = 204.0
HI, 4-Bromo-2-methoxy-6-methyl-phenylamine
To a stirred solution of 2-methoxy-6-methylaniline (15.44 g, 113 mmol) in MeOH (30 mL) and acetic acid (20 mL) at 0 °C was added a solution of bromine (5.80 mL, 113 mmol) in acetic acid (20 mL) dropwise. After half of the bromine was added the reaction mixture had solidfied due to precipitation. Additional acetic acid (30 mL) was added and stirring continued. After addition was complete the reaction allowed to stir for 4 hrs. The reaction mixture was filtered to give a light brown filter cake that was washed with additional acetic acid (30 mL) and then isohexanes (50 mL). The solid was in EtOAc (300 mL) and then washed with NaOH (2M, 200 mL). The organics were washed with brine (200 mL), dried over magnesium sulfate, filtered and solvent removed in vacuo to give 4-bromo-2-methoxy-6-methyl-phenylamine (20.14g, 81% yleld). [MH]+ = 216/218 H2. 4-Bromo-2-methoxy-6-methylbenzonitrile
To a stirred suspension of 4-bromo-2-methoxy-6-methylaniline (7 g, 32.4 mmoi) in cone. HCi (20 mL) and water (80 g of crushed ice) at 0 "C in a 3 necked round bottom flask was added sodium nitrite (2.347 g, 34.02 mmol) portionwise over 10 min. The internal temperature was maintained at 0 °C for a further 30 min. The reaction mixture was neutralised with solid sodium carbonate until a basic pH was measured. This diazonium solution was diluted with toluene (60 mL) and added to a cooled 0 °C solution of copper cyanide (3.482 g, 38.91 mmoi) and sodium cyanide (4.76 g, 97.2 mmol) in water (30 mL) with vigorous stirring. The reaction was held at 0 °C and allowed to warm to rt after 1 hour. The reaction mixture was diluted with toluene (100 mL). The organic layer was extracted and washed with brine (200 mL), dried over magnesium sulfate, filtered and solvent removed in vacuo to afford 4-bromo-2-methoxy-6- methylbenzonitrile (7.02 g, 77 % yleld).
H3, 4-Bromo-2-methoxy-6-methyIbenzamide To a stirred solution of 4-bromo-2-methoxy-6-methylbenzonitriie (7.05 g, 31.2 mmol) in MeOH (50 mL) was added sodium hydroxide (1.247 g, 31.2 mmoi) and heated to 90 °C overnight. The reaction was charged with additional solid sodium hydroxide (3.74 g, 94 mmol) and MeOH (50 mL) and then heated to 100 °C for 3 days. The reaction mixture was concentrated to remove MeOH and the product extracted with DCM (150 mL). The organics were washed with brine (100 mL) and then dried over magnesium sulfate, filtered and solvent removed in vacuo. The crude product was purified by flash column chromatography on silica eluting with 0-100% EtOAc in isohexanes to afford 4-bromo-2- methoxy-6-methylbenzamide (1.227 g, 15% yleld).
[MH]+ = 244.0/246.0
H4. 6-Aminomethyl-5-methoxy-isoquinolin-1-ylamine dihydrochloride
6-Aminomethyl-8-methoxy-isoquinolin-1-ylamine dihydrochloride was prepared in 6 steps from 4- bromo-2-methoxy-6-methylbenzamide using procedures described above.
[MH]+ = 204.2 Jl. (4-Chloro-benzyl) -{2,2-dimethoxy-1-methyl-ethyl)-amine
4-Chlorobenzylamine (2.0 g, 14.12 mmol) was dissolved in 1,2-dichloroethane (100 mL). Pyruvic aldehyde dimethyl acetal (1.835 g, 15.54 mmol) was added followed by sodium triacetoxyborohydride (4.49 g, 21.19 mmol). The reaction mixture was stirred at rt for 18 hrs after which time the solvent was removed in vacuo to afford (4-chloro-benzyl)-(2,2-dimethoxy-1-methyl-ethyl)-amine (1.80 g, 45% yleld).
[MH]+ = 244
J2. 6-Chloro-3-methyl-isoquinoline
(4-Chloro-benzyl)-(2,2-dimethoxy-1-methyl-ethyl)-amine (1.25 g, 16.55 mmol) was added dropwise to chlorosulphonic acid (100 mL) at -10 °C over a period of 10 min. The reaction mixture was then stirred at 100 °C for 10 min after which time the reaction mixture was cooled and poured into ice and neutralised (to pH7) with 33% isiaOH. Care was taken that temperature did not rise above 35 °C. The reaction mixture was extracted with chloroform (3 x 100 mL). The combined organics were washed with water (100 mL), brine (100 mL), dried (Na2SO4) and filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 97% chloroform to give 6-chloro-3-methyl- isoquinoline (750 mg, 82% yleld)
J3. 3-Bromomethyl-6-chloro-isoquinoline
6-Chloro-3-methyl-isoquinoline (750 mg, 4.22 mmol) was dissolved in 1,2-dichloroethane (70 mL). To this solution was added N-bromosuccinimide (901 mg, 5.07 mmol) and azobisisobutyronitrile (69 mg, 0.42 mmol). The reaction was heated at reflux for 5 hrs. The reaction was diluted with DCM, brine was added and the layers were separated. The organic layer was dried over MgSO4, filtered and
concentrated in vacuo. Flash column chromatography eluting with petroleum ethenethyl acetate afforded 3-bromomethyl-6-chloro-isoquinoline (980 mg, 90% yleld).
[MH]+ = 255/257
J4. 3-Azidomethyl-6-chloro-isoquinoline
3-Bromomethyl-6-chloro-isoquinoline (980 mg, 3.820 mmol) was dissolved in DM F (20 mL). Sodium azide (126 mg, 1.95 mmol) was added. The reaction mixture was stirred at rt for 18 hrs after which time the reaction mixture was diluted with EtOAc (100 mL). The solution was washed with water (30 mL), brine (30 mL), dried (NajSG^, filtered and evaporated in vacuo. Flash chromatography (silica), eluting with 85%Pet Ether 60-80, 15% EtOAc afforded 3-azidomethyl-6-chloro-isoquinoline (570 mg, 68%). [MH]+ = 219 J5. C-{6-Chloro-isoquinolin-3-yl)-methylamine
3-Azidomethyl-6-chloro-isoquinoline (300 mg, 1.37 mmoi) was dissolved in ethanol (50 mL) and acetic acid (1 mL). Zinc powder (180 mg, 2.74 mmoi) was added portionwise. The reaction mixture was stirred at rt for 18 hrs. The mixture was through Celite and the residue washed with ethanol (50 mL). The filtrates were evaporated in vacuo, dissolved in CHCl3 (150 mL), washed with sat NaHCOj (30 mL), water (30 mL), brine (30 mL), dried (Na2SO4) and evaporated in vacuo to give C-(6-chloro-isoquinolin-3-yl)- methylamine (264 mg, 99% yield)
[ΜΗ]+ = 193
Intermediates (other):
I. l-{4-Hydroxymethyl-benzyl)-1H-pyridin-2-one
4-(Chloromethyl)benzylalcohol (5.0 g, 31.93 mmoi) was dissolved in acetone (150 mL). 2-hydroxypyridine (3.64 g, 38.3 mmoi) and potassium carbonate (13.24 g, 95.78 mmoi) were added and the reaction mixture was stirred at 50 °C for 3 hrs after which time the solvent was removed in vacuo and the residue taken up in chloroform (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3%MeOH / 97% CHCU, to give a white solid identified as l-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one (5.30g, 24.62mmol, 77% yield).
[M+Nar = 238
II-l. l-(4-Chloromethyl-ben2yI)-1H-pyridin-2-one
l-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one (8.45 g, 39.3 mmoi), dry DCM (80 mL) and triethylamine (7.66 ml, 55.0 mmoi) were cooled in an ice bath. Methanesulfonyi chloride (3.95 ml, 51.0 mmoi) was added and stirred in ice bath for 15 min. The ice bath was removed and stirring continued at rt temperature overnight. The reaction mixture was partitioned between DCM (100 mL) and saturated aqueous NH4CI solution (100 mL). The aqueous layer was extracted with further DCM (2 x 50 mL) and the combined organics washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give l-(4- chloromethyl-benzyi)-1H-pyridin-2-one (8.65 g, 36.6 mmol, 93 % yield) as a pale yellow solid.
[MH]* = 234.1
11-2. l-(4-Bromomethyl-benzyl)-1H-pyridin-2-one l-(4-Hydroxymethyl-benzyf)-1H-pyridin-2-one (2.30 g, 6.97 mmot) was dissolved in DCM (250 mL). To this solution was added phosphorous tribromide (5.78 g, 21.37 mmol) The reaction mixture was stirred at rt for 18 hrs and diluted with CHCb (250 mL). The filtrate was washed with sat. NaHCOs (aq) (30 mL), water (30 mL), brine (30 mL), dried (Na2SO4) and evaporated in vacuo to give a white solid which was identified as l-(4-bromomethyl-benzyl)-1H-pyridin-2-one (2.90 g, 10.43 mmol, 98%).
[ΜΗ]+ = 277.7
V. [4-(4-Methyl-pyrazol-1-ylmethyl)-phenyl]-methanol
4-(Chloromethyl)benzylalcohol (5.47 g, 34.9 mmol) was dissolved in acetone (50 mL). 4-Methylpyrazole (2.86 g, 34.9 mmol) and potassium carbonate (5.07 g, 36.7 mmol) were added and the reaction mixture was stirred at rt for 18 hrs and at 60 °C for 30 hrs after which time the solvent was removed in vacuo and the residue taken up in EtOAc (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried (MgSCu) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient of 10 to 80% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white solid identified as (4-(4-methyl-pyrazol-1-ylmethyl)-phenyl]-methanol (3.94 g, 18.90 mmol, 54% yield). [ΜΗ]+ = 203
VI. l-(4~Chloromethyl-benzyl)-4-methyl- 1H-pyrazole
[4-(4-Methyi-pyrazol-1-ylmethyl)-phenylJ-methanol (2.03 g, 10.04 mmol) and triethylamine (1.13 g, 11.54 mmol) was dissolved in DCM (40 mL). To this solution was added methanesulphonyl chloride (1.26 g, 11.04 mmol) dropwise. The reaction mixture was stirred at rt for 18 hrs and diluted with CHCb (250 mL). The mixture was washed with saturated NH4CI (30 mL), water (30 mL), brine (30 mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient of 0 to 60% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white solid identified as l-(4-chloromethyl-benzyl)-4-methyl-1H-pyrazole (1.49 g, 6.62 mmol, 60% yield).
[ΜΗ]+ = 221, 223
X. Methyl 5-methoxy-3-oxopentanoate
CDl (3.24 g, 20.0 mmol) was added portionwise to a stirred suspension of 3-methoxypropanoic acid (1.81 mi, 19.2 mmol) in anhydrous MeCN (80 mL). The mixture was allowed to stir at rt for 1.5 hrs. A powdered mixture of magnesium chloride (1.57 g, 16.5 mmol) and methyl potassium maionate (4.5 g, 28.8 mmol) was added portionwise (note CO2 gas evolved). The mixture was allowed to stir at rt. Volatiies were removed in vacuo and hydrochloric acid (2M, 105 mL) was added. The solution was stirred at rt for 1 hr and extracted with DCM (3 x 100 mL). The organics were dried over magnesium sulfate, filtered and solvent removed in vacuo to afford methyl 5-methoxy-3-oxopentanoate (2.69 g, 87% yield). XI. (Z)-Methyl 2-((dimethylamino)methylene)-5-methoxy-3-oxopentanoate
A stirred mixture of methyi 5-methoxy-3-oxopentanoate (2.69 g, 16.8 mmot) and l,l-dimethoxy-N,N- dimethylmethanamine (2.68 ml, 20.2 mmoi) was left overnight at rt. Reaction mixture was reduced in vacuo and azetroped with toluene (30 mL) to afford crude (Z)-methyl 2-((dimethyiamino)methylene)-5- methoxy-3-oxopentanoate which was used without further purification.
XII. Methyl 3-(2-methoxyethyt)-1H-pyrazole-4-carboxylate
To a stirred solution of (Z)-methyl 2-((dimethylamino)methylene)-5-methoxy-3-oxopentanoate (3.62 g, 16.82 mmol) in ethanol (50 mL) was added hydrazine hydrate (1.89 ml, 25.2 mmol) and heated to reflux for 4 hrs. Reaction mixture cooled to rt and diluted with EtOAc (200 mL), washed with NaHCO3 (aq, 200 mL), then brine (2 x 100 mL), dried over magnesium sulfate, filtered and solvent removed in vacuo to give methyl 3-(2-methoxyethyl)-1H-pyrazole-4-carboxylate (2.42 g, 77% yield).
(MH]+ = 185.1
XV. 4-Bromomethyl-2-fluoro-benzoic acid
2-Fluoro-4-(hydroxymethyl)benzoic acid (500 mg, 2.94 mmol) was dissolved in dry DCM (20 mL), under an atmosphere of N2 and PBr3 (276 μΐ, 2.94 mmol) was added. Anhydrous DMF (4 mL) was added and the reaction stirred for 2 hrs at rt. The reaction mixture was quenched with dilute NaHCO? (sat diluted to 10%) (50 mL). After stirring for 15 mins, until bubbling ceased, the layers were separated and the aqueous adjusted to pH =0 using 2M HCI. The precipitate was collected by vaccum filtration, washed with water and dried in an oven to afford 4-bromomethyl-2-fiuoro-benzoic acid (420mg, 61% yield).
XVI. (4-Bromomethyl-2-fluoro-phenyl)-methanol
4-Bromomethyl-2-fluoro-benzoic acid (420 mg, 1.80 mmoi) was dissolved in anhydrous THF (20 mL) and cooled to -20°C. To this solution was added triethyiamine (0.75 mL, 5.41 mmol) and isobutyl chloroformate (0.283 mL, 2.16 mmol). The reaction mixture was stirred at -20°C for 1 hour and then poured into a solution of sodium borohydride (341 mg, 9.01 mmoi) in water (2 mL) at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 18 hrs. The reaction mixture was diluted with EtOAc (200 mL) and the layers separated. The organic layer was washed with 0.3M KHS04 (50 mL), water (50 mL), brine (50 mL), dried (Na2SO4), filtered and evaporated in vacuo. The solid was purified by flash column chromatography on silica, eluting with EtOAc/Pet Ether (85:15) to give (4-bromomethyl-2-fluoro-phenyl)- methanol. XVII. (2-FIuoro-4-pyrazol-1-ylmethyl-phenyl)-methanol (4-Bromomethyl-2-ftuoro-phenyf)-methanol (108 mg, 0.49 mmol) and pyrazoie (37 mg, 0.54 mmoi} were taken up in MeCN (10 mL). K2C03 (136 mg, 0.99 mmoi) was added and the reaction was heated to 50 °C. Volatiies were removed in vacuo. EtOAc (60 mL) and water (20 mL) were added. The organic layer was dried, filtered and evaporated in vacuo. Purified by automated FC eluting in step gradients up to 50% EtOAc in pet ether to afford (2-fluoro-4-pyrazol-1-ylmethyl-phenyl)-methanol (94 mg, 94% yieid). [ΜΗ]+ = 206.7
XVIII. l-{4-Bromomethyl-3-fluoro-benzyl)-1H-pyrazole
(2-Fluoro-4-pyrazol-1-ylmethyf-phenyl)-methanol (94 mg, 0.46 mmol) was dissolved in dry DCM (5 mL) under an atmosphere of N2. PBr3 (43 μL, 0.46 mmol) was added and the reaction stirred for 1 hour at rt. The reaction mixture was quenched with dilute NaHCOj (sat diluted to 10%) (10 mL) The layers were separated and the organic washed with water (10 mL) and brine (10 ml). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford l-(4-bromomethyl-3-fluoro-benzyl)-1H-pyrazole (80 mg, 65% yield).
[ΜΗ]+ = 206.7
XX. Ethyl 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate
A solution of diethyl 2-(ethoxymethylene)malonate (40 g, 185 mmol) in absolute ethanol (400 mL) was treated with hydrazine hydrate (8.99 mi, 185 mmol) dropwise. After approximately 20 min, 2N NaOH (25 mL) was added slowly (reaction in an ice-bath), then water (25 mL). The ice-bath was removed and the mixture stirred at rt for 1.5 hrs. The ethanol was removed in vacuo and the aqueous layer diluted with water (25 mL) and partitioned over EtOAc (100 mL). The aqueous layer was collected and cooled in an ice- bath. The pH was adjusted to 5 with 1M HCI, forming a precipitate. The precipitate was filtered, washing with water and dried in vacuo in the presence of CaCI2 to afford ethyl 3-oxo-2,3-dihydro-1H-pyrazole-4- carboxylate (22.31 g, 76% yield).
[MH]* = 157.1
XXI. Ethyl l-acetyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate
Acetic anhydride (13.50 mi, 143 mmol) was added to a suspension of ethyl 3-oxo-2,3-dihydro-1H- pyrazole-4-carboxylate (22.30 g, 143 mmol) in acetic acid (185 mL). The mixture was stirred at rt overnight. Solvents were removed in vacuo. The remaining solid was triturated from water (200 mL) and filtered, washing with water. The product was dried in vacuo in the presence of CaCI2 to afford ethyl 1-acetyl-3- oxo-2,3-dihydro-1H-pyrazole-4-carboxyiate (27.39 g, 94 % yieid).
[MH]* = 199.2 XXII. Ethyl 3-(2-methoxyethoxy)-1H-pyrazole-4-carboxylate
To a stirred solution of ethyl l-acetyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.0 g, 10.09 mmol) in DMF (10 mL) was added l-bromo-2-methoxyethane (0.948 ml, 10.09 mmoi) and K2C03 (1.395 g, 10.09 mmoi) and heated to 70 °C for 5 hrs. Reaction mixture cooled to rt and extracted with EtOAc (100 mL) and washed with water (100 mL). Organic phase was dried over magnesium sulfate, filtered and solvent removed in vacuo. Material taken up into MeOH (20 mL) and K2CO3 (1.395 g, 10.09 mmol) added and stirred at rt overnight. The mixture was diluted with water (30 mL) and product extracted with EtOAc (2 x 50 mL). The organics were washed with brine (20 mL), dried over magnesium sulfate, filtered and solvent removed in vacuo to afford ethyl 3-(2-methoxyethoxy)-1H-pyrazole-4-carboxylate (700 mg, 25.9 % yield). [ΜΗ]+ = 215.2
Examples:
Example 1.
N-((l-Aminotsoquinolin-6-yl)methyl)-3-(methoxymethyl)-1-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)- 1H-pyrazole-4-carboxamide dihydrochloride
Figure imgf000050_0001
Methyl l-((6-fluoropyridin-3-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate
To a stirred solution of methyl 3-(methoxymethyl)-1H-pyrazoie-4-carboxylate (758 mg, 4.45mmol); CAS no. 318496-66-1 (synthesised according to the method described in WO 2012/009009) and 5- (chloromethyl)-2-fluoropyridine (778 mg, 5.34 mmol) in DMF (8 mL) was added K2C03 (1231 mg, 8.91 mmol) and left at rt overnight. Reaction mixture diluted with EtOAc (150 mL) and washed with brine (2 x 100 mL), dried over magnesium sulfate, filtered and solvent removed. The crude product was purified by automated FC 0-60% (3:1 EtOAc: MeCN) in isohexanes) to afford:
isomer 1: methyl l-((6-fluoropyridin-3-yl)methyl)-5-(methoxymethyl)-1H-pyrazole-4-carboxylate (348 mg, 27.4%). MH+ = 280.1
Isomer 2: methyl l-((6-fluoropyridin-3-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylate (749 mg, 59.0%)
MH+ = 280.1 l-((6-Fluoropyridin-3-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxylic acid
General saponification method with lithium hydroxide afforded title compound (309 mg, 46.1%).
MH+ = 266.1 3-(Methoxymethyl)-1-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxylic acid
A solution of l-((6-fluoropyridin-3-yl)methyl)-3-(methoxymethyt)-1H-pyrazole-4-carboxylic acid (305 mg, 1.15 mmol) in anhydrous dioxanes (1 mL) was treated with pyrrolidine (236 μΙ, 2.87 mmot) and the mixture heated at 100 °C overnight. Solvents were removed under vacuum. The mixture was partitioned between EtOAc (10 mL) and water (10 mL, containing 2N NaOH to pH14). The aqueous layer was extracted with further EtOAc (3 x 15 mL) and the combined organics discarded. The aqueous layer was adjusted to pH 4/5 with 1M HCI. The aqueous layer was purified by SCX (10 g), washing with MeOH, eluting with 1% NHs/MeOH to afford 3-(methoxymethyi)-1-((6-(pyrroiidin-1-yi)pyridin-3-yl)methyl)-1H- pyrazole-4-carboxylic acid (336 mg, 0.882 mmol, 77% yield).
MH+ = 317.2
N-((l-Aminoisoquinolin-6-yl)methyi)-3-(methoxymethyl)-1 -((6-(pyrrolidin-1 -yl)pyridin-3-yl)methyl)- 1H-pyrazoIe-4-carboxamide dihydrochloride
Amide formed using amide formation method A. The product was treated with 4M HCI in dioxanes to afford the HCI salt of the title compound (90 mg, 0.164 mmol, 16.994 yield).
MH+ = 472.3
1H NMR (d6-DMSO): δ 1.90-2.08 (4H, m), 3.22 (3H, s), 3.49-3.56 (4H, m), 4.56 (2H, s), 4.60 (2H, d, J = 5.9Hz), 5.31 (2H, s), 7.05 (1H, d, J = 9.4Hz), 7.19 (1H, d, J = 7.0Hz), 7.64-7.73 (2H, m), 7.80 (1H, s), 7.88(1H, d, J = 8.7Hz), 8.07 (1H, s), 8.37 (1H, s), 8.58 (1H, d, J = 8.6Hz), 8.70 (1H, t, J = 5.9Hz), 9.14 (2H,br s), 13.34 (1H, br s), 13.73 (1H, br s). Example 2.
N-((l-Aminoisoquinolin-6-yl)methyi)-3-(methoxymethyl)-1-((S-((4-methyl-1H-pyrazol-1- yl)methyl)pyridin-2-yl)methyl)-1H-pyrazoie-4-carboxamide
Figure imgf000052_0001
5-(Chloromethyl)-2-rnethylpyridine
A solution of (6-methyipyridin-3-yl)methanol (5.04 g, 40.9 mmol) and triethylamine (7.99 mi, 57.3 mmol) in anhydrous DCM (85 mL) was cooled in an ice-bath before the addition of methanesutfonyl chloride (4.12 ml, 53.2 mmol) dropwise. On completion of the addition the ice-bath was removed and the mixture stirred at rt overnight. The reaction mixture was partitioned between DCM (100 mL) and sat. aq. NaHC03 (150 mL). The aqueous layer was extracted with further DCM (2 x 50 mL) and the combined organics dried (Na2SO4), filtered and concentrated in vacuo to afford 5-(chioromethyl)-2-methylpyridine (5.12 g, 87 % yield) which was used without further purification.
MH+ = 141.9
2-Methyl-5-((4-methyl-1H-pyrazol-1-yl)methyl)pyridine
To a stirred solution of 4-methyl-1H-pyrazole (3.60 ml, 43.4 mmol) and 5-(chloromethyl)-2- methylpyridine (5.12 g, 36.2 mmol) in MeCN (75 mL) under N2 was added potassium carbonate (7.50 g, 54.2 mmol) and the suspension stirred at 80 °C overnight. The volatiles were removed in vacuo. The residue was partitioned between EtOAc (150 mL) and water (150 mL). The aqueous was extracted with EtOAc (2 x 150 mL). The combined organic layers were dried (MgSCU), filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with a gradient of 50 to 100% EtOAc/iso-Hexanes to afford 2-methyl-5-((4-methyl-1H-pyrazol-1-yl)methyl)pyridine (2.58 g, 37.7 % yield). MH+ = 188.0
2-Methyl-5-((4-methyl-1H-pyrazoi-1-yl)methyl)pyridine-1-oxide
A solution of 2-methyl-5-((4-methyl-1H-pyrazot-1-yl)methyl)pyridine (0.50 g, 2.67 mmoi) in chloroform (15 mL) was treated portionwise with 3-chtorobenzoperoxoic acid (1.11 g, 3.20 mmoi). The mixture was allowed to stir at rt for 2 hrs. The reaction was cooled in an ice-bath and treated with 2N NaOH (5 mL) with vigorous stirring. The ice-bath was removed and the mixture allowed to stir for 20 minutes, forming a suspension and water (5 mL) added. The layers were allowed to separate and the organic collected. The aqueous was extracted with chloroform (2 x 20 mL) and the combined organics dried (Na2SO4), filtered and concentrated in vacuo to afford 2-methyl-5-((4-methyl-1H-pyrazol-1-yl)methyl)pyridinel- oxide (467 mg, 84% yield).
MH+ = 204
(5-((4-Methyl-1H-pyrazol-1-yl)methyl)pyridin-2-yl)methyl acetate
A solution of 2-methyl-5-((4-methyl-1H-pyrazol-1-yl)methyl)pyridine 1 -oxide (467 mg, 2.30 mmoi) in acetic anhydride (9770 μΙ, 103 mmoi) was heated to 95 °C (bath temperature) and the mixture allowed to stir for 2 hrs. Solvents were removed in vacuo and the residue purified by flash chromatography, loading in dichloromethane, eluting with a gradient of 50 to 100% EtOAc/lso-Hexanes to afford (5-((4- methyl-1H-pyrazol-1-yl)methyl)pyridin-2-yl)methyl acetate (410 mg, 61.8 % yield).
MH+ = 246.0
(5-((4-methyl-1H-pyrazol-1-yl)methyl)pyridin-2-yl)methanol
A solution of (5-((4-methyl-1H-pyrazol-1-yl)methyl)pyridin-2-yl)methyl acetate (410 mg, 1.42 mmoi) in MeOH (8 mL) was treated with a solution of potassium carbonate (471 mg, 3.41 mmoi) in water (2 mL) and the mixture stirred at rt for 2 hrs. The MeOH was removed in vacuo and the residue partitioned between EtOAc (20 mL) and water (8 mL). Sat. aq. NH4CI was added to ~pH 9 and the organic layer collected. The aqueous was extracted with further EtOAc (2 x 20 mL) and the combined organics dried (MgSO4), filtered and concentrated in vacuo to afford (5-((4-methyl-1H-pyrazol-1-yl)methyl)pyridin-2- yl)methanol (262 mg, 82 % yield).
MH4 = 203.9
2-(Chloromethyl)-S-((4-rnethyl-1H-pyrazol-1-yl)rnethyl)pyridine
Prepared using procedure for l-(-chloromethyl-benzyl)-4-methyl-1H-pyrazole N-((1-Ammoisoquinolin-6-yl)methyl)-3-(methoxymethyl)-1-((5-((4-methyl-1H-pyrazoi-1- yl)methyl)pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide
Prepared from 2-(chioromethyl)-5-((4-rnethyl-1H-pyrazol-1-yi)rnethyi)pyridine) methyl 3- (methoxymethyt)-1H-pyrazole-4-carboxyfate and 6-aminomethyl-isoquinolin-1-yiamine hydrochloride using general methods (core alkylation, saponification and amide formation method 8).
MH+ = 497.2
*H NMR (d6-DMSO): δ 1.98 (3H, s), 3.21 (3H, s), 4.56 (2H, s), 4.60 (2H, d, J = 5.9Hz), 5.29 (2H, s), 5.43 (2H, s), 7.17-7.28 (3H, m), 7.60 (1H, s), 7.62-7.75 (3H, m), 7.81 (1H, s), 8.37 (1H, s), 8.45 (1H, d, J = 2.3Hz), 8.56 (1H, d, J = 8.6Hz), 8.68 (1H, t, J = 5.9Hz), 9.11 (2H, brs), 13.28 (1H, s)
Example 3.
3-Cyano-1-[6-(3,3-difluoro-pyrrolidin-1-yl)-5-methoxy-pyridin-3-ylmethyl]-1 H-pyrazole-4-carboxylic acid {l-amino-isoquinolin-6-ylmethyl)-amide
Figure imgf000054_0001
{6-Chloro-S-methoxy-pyridin-3-yl)-methanol
To a stirred solution of 6-chloro-5-methoxy-nicotinic acid methyl ester (0.5 g, 2.48 mmol) in anhydrous THF (20 mL) cooled to 0 °C under nitrogen, was added UAIH4 (104 mg, 2.73 mmol). The reaction was allowed to warm to rt. The reaction was cooled to 0 °C and quenched with water. Potassium sodium tartrate (Rochelle's salt) was added and the mixture was filtered through Celite and washed with EtOAc (20 mL). The filtrate was separated and the aqueous extracted with EtOAc (20 mL). The combined organic layers were washed with brine (50 ml), dried over MgSO« and the solvent removed in vacuo. The residue was purified by automated FC (EtOAc/petrol) to afford (6-chloro-5-methoxy-pyridin-3-yl)- methanol (710 mg, 82% yield)
[ΜΗ]+ = 173.7
5-Bromomethyl-2-chloro-3-methoxy-pyridine (6-Chioro-5-methoxy-pyridin-3-yl)-methanol (710 mg, 4.09 mmoi) was dissolved in anhydrous DCM (15 mL), under an atmosphere of N2. P8r3 (384 mL, 4.09mmol) was added and the reaction stirred at rt. The reaction mixture was quenched with a dilute aqueous solution of NaHC03 (10%, 10 mL). The layers were separated and the organic layer washed with water (10 mL) and brine (10 ml). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by automated FC eluting with (EtO Ac/Petrol) to afford 5-bromomethyl-2-chioro-3-methoxy-pyridine (851 mg, 88% yield).
[ΜΗ]+ = 238.0 l-{6-Chloro-5-methoxy-pyridin-3-ylmethyl)-3-cyano-1H-pyrazole-4-carboxylic acid ethyl ester
3-Cyano-1H-pyrazole-4-carboxylic acid ethyl ester (139.7mg, 0.85mmol) was taken up in DMF and treated with potassium carbonate (233.8mg, 1.69mmol). 5-Bromomethyl-2-chloro-3-methoxy-pyridine (200 mg, 0.85 mmol) was added and reaction stirred at rt overnight. Diluted with DCM (30 mL) and washed with water (10 mL). The organic layer was washed with NaHC03 (1 x 10ml), brine (10 ml), dried (MgSO,), filtered and evaporated in vacuo. The residue was purified by automated FC (EtOAc/petrol) to afford l-(6-chloro-5-methoxy-pyridin-3-ylmethyl)-3-cyano-1H-pyrazole-4-carboxylic acid ethyl ester (157mg, 68% yield).
[ΜΗ]+ = 321.1
3-Cyano-1-[6-(3,3-difluoro-pyrrolidin-1-yl)-5- acid ethyl ester
To a suspension of l-(6-chloro-5-methoxy-pyridin-3-ylmethyl)-3-cyano-1H-pyrazole-4-carboxylic acid ethyl ester (41 mg, 0.13 mmoi) in 1,4-dioxane (1 mL) was added 3,3-dilfuoropyrroiidine hydrochloride salt (73.4 mg, 0.51 mmol) and Et3N (142.5 mL, 1.02 mmol). The reaction was heated at 125 "C. The reaction mixture was concentrated and purified by automated FC to afford 3-cyano-1-(6-(3,3-difluoro- pyrrolidin-1-yl)-5-methoxy-pyridin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid ethyl ester (40 mg, 80% yield).
[MH]' = 391.9
3-Cyano-1-[6-(3,3-difluoro-pyrrolidin-1-yl)-5-methoxy-pyridin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid
To 3-cyano-1-[6-(3,3-difiuoro-pyrrolidin-1-yl)-5-methoxy-pyridin-3-ylmethyl]-1H-pyrazoie-4-carboxylic acid ethyl ester (40 mg, 0.10 mmol) dissolved in THF (10 mL) was added lithium hydroxide monohydrate (12 mg, 0.13 mmol) in water (1 mL). The reaction mixture was stirred at 50 "C. NaOH (41 mg, 1.02 mmoi) was added and continued stirring at 50 *C for 6h. The reaction was concentrated to dryness in vacuo and acidified with 2M HCl to ~pH = 4-5. The aqueous layer was washed with 10% 2-propanol in chloroform (10 x 10 mL). The combined organics were dried and concentrated in vacuo to afford 3-cyano-1-[6-(3,3- difiuoro-pyrrolidin-1-yl)-5-methoxy-pyridin-3-yimethyl]-1H-pyrazoie-4-carboxylic acid.
[ΜΗ]+ = 364 3-Cyano-1-[6-(3,3-difluoro-pyrrolidin-1-yl)-5-methoxy-pyridin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid {l-amino-isoquinolin-6-ylmethyl)-amide
Prepared from 3-cyano-1-[6-(3,3-difluoro-pyrroiidin-1-yi)-5-methoxy-pyridin-3-ylmethyi]-1H-pyrazole-4- carboxylic acid and 6-aminomethyl-isoquinolin-1-ylamine hydrochloride using amide formation method A.
[ΜΗ]+ = 519.0
*H NMR (d6-DMSO): δ 2.42 (2H, dd, J = 14.4, 7.3 Hz), 3.73 (2H, t, J = 7.2 Hz), 3.75 (3H, s), 3.93 (2H, t, J = 13.7 Hz), 4.61 (2H, d, J = 5.8 Hz), 5.38 (2H, s), 7.21-7.24 (1H, m), 7.25 (1H, d, J = 1.8 Hz), 7.65 (1H, d, J = 7.0 Hz), 7.70 (1H, dd, J = 8.6, 1.7 Hz), 7.82-7.83 (2H, m), 8.46 (1H, s), 8.50 (1H, d, J = 8.7 Hz), 8.92 (2H, br.s), 9.11 (1H, t, J = 5.9 Hz), 12.82 (1H, br.s)
Example 4.
3-Methoxymethyl- 1-(4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1-amino- isoquinoiin-6-yimethyl)-amide
Figure imgf000056_0001
Methyl l-(4-((1H-pyrazol-1-yl)methyl)benzyl)-3-(methoxymethyl)-1H-pyrazoie-4-carboxyiate
To a stirred suspension of methyl 3-(methoxymethyl)-1H-pyrazoie-4-carboxylate (470 mg, 2.76 mmol) and l-(4-(chloromethyl)benzyl)-1H-pyrazole (571 mg, 2.76 mmol) in DMF (2.5 mL) was added potassium carbonate (763 mg, 5.52 mmol) and the mixture stirred at rt overnight. The reaction was diluted with EtOAc (30 mL) and water (25 mL) containing brine (25 mL). The aqueous layer was extracted with further EtOAc (2 x 30 mL) and the combined organics dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography loading in dichloromethane, eluting with a gradient of 0 to 100% EtOAc/iso-Hexanes holding at 70% to elute methyl l-(4-((1H-pyrazol-1- yt)methyt)benzyl)-5-(methoxymethyl)-1H-pyrazoie-4-carboxylate (232 mg, 21.0 % yield) then 85% to elute methyl l-(4-((1H-pyrazol-1-yf)methyf)benzyl)-3-(methoxymethyi)-1H-pyrazole-4-carboxylate (494 mg, 52.0 % yield).
[ΜΗ]+ = 341.1
3-Methoxymethyl- 1-(4-pyrazol-1-ylmethyl- benzyl)-1H-pyrazole-4-carboxylic acid (1-amino- isoquinolin-6-ylmethyl)-amide
Prepared from methyl l-(4-((1H-pyrazol-1-yl)methyl)benzyl)-3-(methoxymethyl)-1H-pyrazole-4- carboxylate and 6-aminomethyl-isoquinolin-1-ylamine hydrochloride using general methods
(saponification and amide formation method B).
[ΜΗ]+ = 482.3
XH NMR (d6-DMSO): δ 3.21 (3H, s), 4.56 (2H, s), 4.59 (2H, d, J = 5.8Hz), 5.26-5.34 (4H, m), 6.25 (1H, t, J = 2.1Hz), 7.17-7.22 (3H, m), 7.25 (2H, d, J = 8.2Hz), 7.44 (1H, d, J = 1.8Hz), 7.63-7.72 (2H, m), 7.79 (1H, s), 7.81 (1H, d, J = 2.3Hz), 8.31 (1H, s), 8.55 (1H, d, J = 8.6Hz), 8.66 (1H, t, J = 5.9Hz), 9.12 (2H, brs), 13.29 (1H, s)
Example 8
3-Methoxymethyl- 1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid (1-amino- isoquinoiin-6-yimethyl)-amide
Figure imgf000057_0001
Route A
5-Bromomethyl-2-chloro-pyridine
2-Chloro-5-methylpyrimidine (3.0 g, 23.3 mmol) was dissolved in 1,2-dichloroethane (120 mL). To this solution was added N-bromosuccinimide (4.98 g, 28.0 mmol) and azobisisobutyronitrile (1.15 g, 7.00 mmol). The reaction was stirred at 95 °C. After 18 hrs at 95 °C the reaction mixture was diluted with CHCl3 (150 mL), this solution was washed with sat. NaHCO3 (1x50 mL), water (1x50 mL), brine (1x50 mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 15% EtOAc, 85% Pet. Ether, fractions combined and evaporated in vacuo to give a yeliow oil identified as 5-bromomethyl-2-chloro-pyridine (1.64 g, 34%).
MH+ = 207.8 l-(2-Chloro-pyrimidin-5-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxyiic acid methyl ester
To a stirred solution of methyl 3-(methoxymethyi)-1H-pyrazole-4-carboxyiate (2.01g, 11.83mmoi); CAS no. 318496-66-1 (synthesised according to the method described in WO 2012/009009) and 5- bromomethyl-2-chloro-pyridine (2.70 g, 13.1 mmol) in DMF (8 mL) was added K2C03 (3.27 g, 23.7 mmol) and left at rt overnight. Reaction mixture diluted with EtOAc (150 mL) and washed with brine (2 x 100 mL), dried over magnesium sulfate, filtered and solvent removed. The crude product was purified by automated FC 0-60% (1:1 EtOAc: MeCN) in Pet. Ether to afford Isomers 1 and 2: isomer 1: l-(2-Chloro-pyrimidin-5-ylmethyl)-5-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester (420 mg, 12%); MH+ = 296.7
isomer 2: l-(2-Chloro-pyrimidin-5-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester (638 mg, 18%); MH+ = 296.7 3-Methoxyrnethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxYlic acid methyl ester
A solution of l-(2-chloro-pyrimidin-5-yimethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester (418 mg, 1.41 mmol) in anhydrous dioxane (1 mL) was treated with pyrrolidine (1.2 mL, 14.1 mmol) and the mixture heated at 100 °C overnight. Solvents were removed under vacuum. The residue was purified by automated FC 0-60% EtOAc in Pet. Ether to afford 3-methoxymethyl-1-(2-pyrrolidin-1-yl- pyrimidin-5-yimethyi)-1H-pyrazole-4-carboxylic acid methyl ester (290 mg, 0.88 mmol, 62% yield).
MH+ = 331.9
3-Methoxymethyl- 1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid
General saponification method with sodium hydroxide afforded title compound (250mg, 0.79mmoi, 90%).
MH+ = 317.9
3-Methoxymethyl- 1-(2-pyrrolidin-1-yl-pyrimidin-5-yimethyl)-1H-pyrazoie-4-carboxylic acid (l-amino- isoquinolin-6-ylmethyl)-amide Amide formed using amide formation method A. Purified by flash chromatography (silica), eiuent 15% methanol, 84% dichioromethane, 1% NH4OH, fractions combined and evaporated in vacuo to give a white solid identified as 3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-yimethyl)-1H-pyrazole-4- carboxylic acid (l-amino-isoquinolin-6-ylmethyl)-amide (163 mg, 0.35 mmoi, 44% yield).
MH+ = 473.0
1H NMR (DMSO): 1.88-1.94 (4H, m), 3.22 (3H, s), 3.44-3.45 (4H, m), 4.53 (2H, d, J = 5.8 Hz), 4.56 (2H, s), 5.15 (2H, s), 6.82 (2H, br.s), 6.87 (1H, d, J = 5.9 Hz), 7.39 (1H, d, J = 8.6 Hz), 7.54 (1H, s), 7.75 (1H, d, J = 5.9 Hz), 8.15 (1H, d, J = 8.3 Hz), 8.23 (1H, s), 8.38 (2H, s), 8.46 (1H, t, J = 5.8 Hz) Route B
Ethyl 2-(pyrrolidin-1-yf)pyrimidine-S-carboxylate
Ethyl-2-chloropyrimidine-5-carboxylate (300 g, 1.6 mol) was stirred in 1,4-dioxane (3000 mL) in an ice/water bath. Pyrrolidine (375 mL, 4.5 mol) was added and the mixture stirred for 3 hrs at rt. The reaction mixture was concentrated and separated between ethyl acetate (4000 mL) and water (4000 mL). The organics were washed with water (2000 mL) and saturated brine (3000 mL), dried over sodium sulfate, filtered and concentrated. The product was dried in the vacuum oven at approximately 45 °C to give a yellow solid identified as ethyl 2-(pyrrolidin-1-yl)pyrimidine-5-carboxylate (328 g, 92% yield). MH+ = 221.9 (2-(Pyrrolidin-1-Yl)pyrimidin-5-yl)methanol
To a stirred solution of ethyl 2-(pyrrolidin-1-yl)pyrimidine-5-carboxylate (100 g, 0.45 moles) in dry DCM (1000 mL) under N2 at 0 °C was added a solution of diisobutylaluminium hydride in hexanes (1.0M solution, 950 mL, 0.95 moles). Water (40 mL) was carefully added to the reaction mixture followed by a 15% aq. solution of sodium hydroxide (40 mL) and finally water (100 mL). Sodium sulfate (~200 g) was added and the mixture was stirred at rt for a further 18 hrs. The mixture was filtered through Celite and the filtrate was concentrated in vacuo to give a pale yellow solid identified as (2-(pyrroiidin-1- yi)pyrimidin-5-yl)methanol (81.0 g, 100% yield)
MH4 = 180.1 Acetic acid 2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl ester
To a stirred solution of (2-(pyrrolidin-1-yi)pyrimidin-5-yi)methanol (89.1 g, 0.50 moles) in dry DCM (900 mL) at 20 °C was added 4-(dimethylamino)pyridine (3.05 g, 0.025 moles) followed by acetic anhydride (50.8 g, 0.50 moles). The mixture was stirred at ambient temperature for a further 18 hrs. Water (700 mL) was added and the aqueous phase was extracted with DCM (500 mL) and the combined organics were dried (Na2SO4) and concentrated in vacuo to give a pale yetlow solid identified as acetic acid 2- pyrrolidin-1-yl-pyrimidin-5-ylmethyl ester (110 g, 100% yield).
MH+ = 221.8 3-Methoxymethyl- 1-(2-pYrrolidin-1-yi-pyrimidin-5-ylrnethyl)-1H-pyrazole-4-carboxylic acid methyl ester
Acetic acid 2-pyrrolidin-1-yi-pyrimidin-5-ylmethyl ester (112.3 g, 0.51 mol) and methyl-3- (methoxymethyl)-1H-pyrazole-4-carboxylate (CAS no. 318496-66-1, synthesised according to the method described in WO 2012/009009) (86.3 g, 0.51 mol) were combined in acetonitriie (1500 mL). Trimethylsilyl trifluoromethanesulfonate (110.3 mL, 0.61 mol) was added. The mixture was heated to 65-70 °C for 3 hrs and then allowed to cool. The reaction mixture was concentrated and separated between EtOAc (1500 mL) and saturated aqueous sodium hydrogen carbonate (1000 mL). The organics were washed with saturated aqueous sodium hydrogen carbonate (750 mL), washed with saturated brine (1000 mL), dried over sodium sulfate, filtered and concentrated to give a brown solid. The solid was dissolved in hot methanol. The solution was cooled to approximately 10 °C and stirred for 1 hour. The solid produced was filtered. The filtrate was concentrated to yield a beige solid identified as a mixture of 3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid methyl ester and 5-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid methyl ester (94 g).
MH+ = 332.0
3-(Methoxymethyl)-1-((2-(pyrrolidin-1-yl)pyrimidin-5-yl)methyl)-1H-pyra2ole-4-carboxylic acid
A mixture of 3-methoxymethyl-1-(2-pyrroiidin-1-yl-pyrimidin-5-yimethyl)-1H-pyrazoie-4-carboxylic acid methyl ester and 5-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid methyl ester (94 g) was stirred in methanol (188 mL) and water (200 mL). Potassium hydroxide (23.9 g, 0.43 mol) in water (82 mL) was added. The mixture was heated to 55-60 °C for 1 hour and allowed to cool. The majority of the methanol was removed under reduced pressure. The remaining mixture was diluted with water (250 mL) and stirred and cooled in an ice/water bath. Glacial acetic acid (18 mL, 0.31 mol) was added and the mixture stirred for 1 hour. The solid produced was collected by filtration. The filtrates were cooled in an ice/water bath and glacial acetic acid (23 mL, 0.40 mol) was added. After 1 hour the solid produced was collected on top of the previous filter cake. The combined solids were washed with cold ethanol and dried in vacuo. The solid was dissolved in hot ethanol and cooled to rt. The solid produced was filtered and washed with cold ethanol (2 χ 150 mL). The solid was dissolved in hot ethanol and cooled to rt. The solid product produced was filtered, washed with cold ethanol and tert-butyl methyl ether and dried in vacuo to afford a white, solid identified as 3- (rnethoxyrnethyl)-1-((2-(pyrrolidin-1-yi)pyrimidin-5-yl)methyl)-1H-pyrazole-4-carboxylic acid (49 g). MH+ = 317.7 3-Methoxymethyl- 1-(2-Pyrrolidin-1-yi-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid (1-amino- isoquinoiin-6-ylmethyl)-amide
Ι,1'-Carbonytdiimidazole (26. Ig, 0.161 mole) was added to a suspension of 3-(methoxymethyl)-1-((2- (pyrrolidin-1-yl)pyrimidin-5-yi)methyi)-1H-pyrazole-4-carboxyiic acid (51. lg, 0.161 mole) in N- methylpyrrolidinone (200 mL) and stirred for 3 hrs to give the acylimidazol eintermediate. 6- (Aminomethyi)isoquinoiin-1-amine dihydrochloride (47.5 g, 0.193 mole) was suspended in N- methylpyrrolidinone (240 mL) and heated to 55 °C - 60 °C. Triethylamine (102 mL, 0.73 mole) was added and the mixture was stirred for 1 hour, cooled and stirred for a further 1.5 hrs. The
acylimidazolide intermediate formed above was added in one portion and stirred for 18hrs. The reaction mixture was poured into water (5000 mL) and stirred for 1.5 hrs. The solid was collected by filtration, washed with water (2 x 250 mL), cold acetonitrile (250 mL) and tert-butyl methyl ether (250 mL) and dried in vacuo to give a white solid identified as 3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5- ylmethyl)-1H-pyrazole-4-carboxylic acid (l-amino-isoquinolin-6-ylmethyl)-amide (70.8 g, 93% yield). MH+ = 473.0 Example 64.
l-(2-Pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro- 1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide
Figure imgf000061_0001
l-(2-Chloro-pyrimidin-5-ylmethyl)-3-trifluorornethyl-1H-pyrazole-4-carboxylic acid ethyl ester
Ethyl 3-trifluoromethyl-1H-pyrazole-4-carboxylate (1.25 g, 6.01 mmoi) was dissolved in DMF (20 mL). 5- Bromomethyl-2-chloro-pyridine (1.50 g, 7.21 mmol) and cesium carbonate (2.94 g, 9.01 mmol) were added and the reaction mixture was stirred at rt for 3 hrs after which time the reaction mixture was diluted with EtOAc (100 mL), was washed with water (lx30mL), brine (lx30mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eiuent 60% Pet. Ether, 40% EtOAc to give a yefiow oil identified as l-(2-chioro-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H- pyrazole-4-carboxylic acid ethyl ester (710 mg, 35%).
MH* = 375.8 (MH+ + MeCN) l-(2-PyrroHdin-1-yl-pyrimidin-5-ytmethyl)-3- acid ethyl ester l-(2-Chloro-pyrimidin-5-ylmethyi)-3-trifiuoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (700 mg, 2.09 mmol) was dissolved in anhydrous dioxanes (25 mL) and pyrrolidine (10 mL) and the reaction mixture was stirred at 80 °C for 18 hrs after which time the reaction mixture was evaporated in vacuo. The residue was purified by flash chromatography (silica), eiuent 3%MeOH, 97% CHCU to give a yellow solid identified as l-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (760 mg, 99% yield).
MH* = 369.0 l-(2-Pyrrdidin-1-yl-pyrimidin-5-ylmethyl)-3-trif1uoromethyl- 1H-pyrazole-4-carboxylic acid
General saponification method with lithium hydroxide afforded l-(2-pyrrolidin-1-yl-pyrimidin-5- ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxyiic acid (596 mg, 85% yield).
MH* = 341.8 l-(2-Pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1H- pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide
l-(2-Pyrrolidin-1-yl-pyrimidin-5-ylmethyi)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (596 mg, 1.75 mmol) was dissolved in DCM (50 mL) and DMF (2.5 mL). This solution was cooled to 0 °C. 5-Aminomethyl azaindole (308 mg, 2.10 mmol) was added followed by HOBt (260 mg, 1.92 mmol) and triethylamine
(530 mg, 5.24 mmol). EDC (402 mg, 2.1 mmol) was added. After 18 hrs at 0 'C to rt reaction mixture was diluted with chloroform (200 mL), washed with NaHCOj (lx30mL), water (lx30mL), brine (lx30mL) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eiuent 6%MeOH, 94% CHCIs to give a white solid identified as l-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H- pyrazole-4-carboxylic acid (1H-pyrroio[2,3-b]pyridin-5-ylmethyi)-amide (620 mg, 75% yield).
MH* = 470.9 l-(2-Pyrrdidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chioro- 1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide l-(2-Pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1H- pyrrolo[2,3-b3pyridin-5-yimethyl)-amide (500 mg, 1.06 rnmol) was dissolved in acetonitrile (50 mL). To this solution was added N-chlorosuccinimide (149 mg, 1.12 rnmol). The reaction mixture was stirred at reflux for 7 hrs. The solvent was removed in vacuo and the residue taken up in EtOAc (100 mL), washed with sat. NaHC03 (lx20mL), water (lx20mL), brine (lx20mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eiuent 6%MeOH, 94% CHCU. The resulting material was dissolved in chloroform (100 mL) and this solution was washed with sat. NaHC03 (lx20mL), water (lx20mL), brine (lx20mL), dried (Na2SO4) and evaporated in vacuo to give a white solid identified as l-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trtfluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro- 1H-pyrrolo(2,3-b]pyridin-5-yimethyl)-amide (430 mg, 80% yield).
MH+ = 505.0
1H NMR (DMSO): 1.89-1.93 (4H,m), 3.44-3.47 (4H, m), 4.49 (2H, d, J= 5.8 Hz), 5.26 (2H, s), 7.66 (1H, d, J = 2.7 Hz), 7.82 (1H, d, J = 1.5 Hz), 8.27 (1H, d, J = 1.9 Hz), 8.36 (1H, s), 8.41 (2H, s), 8.77 (1H, t, J= 5.6 Hz), 11.93 (1H, s)
Figure imgf000063_0001
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Biological Methods
The ability of the compounds to inhibit piasma kallikrein may be determined using the following biological assays:
Determination of the IC50 for plasma kallikrein
Plasma kallikrein inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et a/., Int. J, Tiss. Reac. 1986, 8, 185; Shod et a/., Biochem. Pharmacol., 1992, 43, 1209;
Sturzebecher et a/., 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. Residua! 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 these assays are shown in Table 12
Selected compounds were further screened for inhibitory activity against the related enzyme KLKl. The ability of the compounds of formula (I) to inhibit KLKl may be determined using the following biological assay:
Determination of the IC50 for KLKl
KLKl inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et ai., int. J. Tiss. Reac. 1986, 8, 185; Shori et a/., Biochem. Pharmacol., 1992, 43, 1209; Sturzebecher et of., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human KLKl (Ca!lbiochem) 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 ICso value for the test compound was determined, Data acquired from this assay are shown in Table 12
Table 12
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Selected compounds were further screened for inhibitory activity against other trypsin-like serine proteases using the appropriate enzyme and chromogenic substrate (Chromogenix AB). The activity against the following human enzymes was tested (substrate in brackets):- thrombin (5 -2238), plasmin (S- 2390) and trypsin (S-2222). The enzyme was incubated at 25 °C with the chromogenic substrate.
Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 405nm.
Data acquired from these assays are shown in Table 13
Table 13: (Selectivity data)
Figure imgf000133_0001
Pharmacokinetics
Pharmacokinetic studies of the compounds in Table 14 were performed to assess the pharmacokinetics following a single oral dose in male Sprague-Dawiey 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 10% DMSO / 10% cremophor / 80% sterile water for injection. 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 14: (Oral exposure data)
Figure imgf000133_0002
Figure imgf000134_0001

Claims

1. A compound selected from:
N-((1-Aminoisoquinolin-6-yl)methyl)-3-(methoxymethyl)-1-((6-(pyrrolidin-1- yl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxamide dihydrochloride;
N-((1-Aminoisoquinolin-6-yl)methyl)-3-(methoxymethyl)-1-((5-((4-methyl-1H- pyrazol-1-yl)methyl)pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide;
3-Cyano-1-[6-(3,3-difluoro-pyrrolidin-1-yl)-5-methoxy-pyridin-3-ylmethyl]-1H- pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
3-Methoxymethyl-1-(4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide;
N-[{1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl}-1-{[6-{pyrrolidin- l-yl)pyridin-3-yl] methyl }pyrazoie-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[6- (pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4- carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin- l-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2- (pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin- l-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2- (pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2-
(pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide; l-[2-(3,3-difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethyl]-3-methoxymethyl-1H- pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-{[2-(3/3-difluoropyrrolidiri-1- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxarriide;
3-(2-methoxy-ethyl)-1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-1H-pyrazole-4- carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol- l-ylmethyl)phenyl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol- l-ylmethyl)phenyl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}pyrazo!e-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol- l-ylmethyl)phenyl] methyl }pyrazole-4-carboxamide;
3-ethoxymethyl-1-(4-pyrazol-1-ylmethyl-benzyl)-l H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide; N-[(1-aminoisoquinolin-6-yl)methyl]-1-{[2-(pyrazol-1-ylmethyl)pyrimidin-5- yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({3-fluoro-4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({2-fluoro-4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
3-cyclopropyl-1-(2-fluoro-4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
3-cyclopropyl-1-[4-(4-fluoro-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide; l-[4-(4-fluoro-pyrazol-1-ylmethyl)-benzyl]-3-methoxymethyl-1H-pyrazole-4- carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; l-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-{[2-(pyrrolidin-1-yl)pyridin-4- yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;
3-amino-N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-{[2-(pyrrolidin-1- yl)pyridin-4-yl]methyl}pyrazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-3-cyano-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
3-amino-N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }pyrazole-4-carboxamide; l-(2-Pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4- carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-3-(methoxymethyl)-1-{[2- (pyrrolidin-1-yl)pyrimidin-5-yl]methyl}pyrazole-4-carboxamide;
N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-{[6-(3,3-difluoropyrrolidin-1- yl)pyridin-3-yl] methyl }-3-(trifluoromethyl)pyrazole-4-carboxamide;
3-amino-N-({3-chloro-1H-pyrroio[2,3-b]pyridin-5-yl}methyl}-1-{[6-{3,3- difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-{[6-{3,3-difluoropyrroiidin-1- yl)pyridin-3-yl]methyl}-3-(methoxymethyl)pyrazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-[(6-ethoxy-5-fluoropyridin-3- yl)methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-({6-
[isopropyl(methyl)amino]pyridin-3-yl}methyl)-3-(trifluoromethyl)pyrazole-4- carboxamide; 3-amino-1-{[6-(benzyloxy)pyridin-3-yl]methyl}-N-({3-chloro-1H-pyrrolo[2,3- b]pyridin-5-yl}methyl)-1H-pyrazole-4-carboxamide
3-amino-N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-{[6- (phenoxymethyl)pyridin-3-yl]methyl}-1H-pyrazole-4-carboxamide
3-amino-N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-[(6-phenoxypyridin-3- yl)methyl]-1H-pyrazole-4-carboxamide
3-methoxymethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4- carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
3-cyano-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
3-amino-N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-(methoxymethyl)-1-[(2- methylquinolin-6-yl)methyl]pyrazo!e-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-[(7-chloroquinolin-3- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide;
3-amino-N-[(3-chloro-1H-indol-5-yl)methyl]-1-({4-[(2-oxopyridin-1- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
3-amino-N-[(3-chloro-1H-indazol-5-yl)methyl]-1-({4-[(2-oxopyridin-1- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-({3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-cyclopropyl-1-({4-[(2- oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-({3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-(methoxymethyl)-1-({4-[(2- oxopyridiri-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-({4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-1-({4-[(2-oxopyridin-1- yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-({l-methylpyrazolo[3,4-b]pyridin-5-yl}methyl)-1-({4-[(2-oxopyridin-1- yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-({3<hloro-1H-pyrrolo[2,3-c]pyridin-5-yl}methyl)-3-(methoxymethyl)-1-({4-[(2- oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
3-amino-N-[(6-chloroisoquinolin-3-yl)methyl]-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(6-chloroisoquinolin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(6-chloroisoquinolin-3-yl)methyl]-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3- (trifluoromethyl)pyrazole-4-carboxamide;
N-[(6-chloroisoquinolin-3-yl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl] methyl }imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}imidazole-4-carboxamide; N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[{1-amino-8-methoxyisoquinolin-6-yl)methyl]-2-methyl-1-({4-[{4-methylpyrazoi-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide; N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-2-methylimidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-fluoropyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-fluoropyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-fluoropyrazol- l-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4- fluoropyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4- fluoropyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-fluoropyrazol-
1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4- fluoropyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
2- methyl-1-(6-pyrrolidin-1-yl-pyridin-3-ylrriethyl)-1H-imidazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-methyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-methyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[{1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-{[6-(pyrrolidin-1-yl)pyrid!n-
3- yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide; N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-{[6-(pyrrolidin-1-yl)pyridi 3-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[{l-arnino-5-fluoroisoquinolin-6-yl)methyl]-2-cyc!opropyl-1-{[6-(pyrroiidiii-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}irnidazo!e-4-carboxarnide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(6-chloroisoquinolin-3-yl)methyl]-2-methyl-1-({4-[(2-oxopyridin-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-({3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-2-methyl-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-({5-chloro-7H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-2-methyl-1-({4-[(2-oxopyridin-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrroljdin-1-yl)pyrimidin-5- yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide; N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidiri-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[{1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cyc!opropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }imidazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3i3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[{1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-2-methylimidazole-4-carboxamide; N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3,3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3,3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3,3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3/3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3,3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[6-(3,3- difluoropyrrolidin-1-yl)pyridin-3-yl]methyl}imidazole-4-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-2-cyclopropyl-1-{[2-(3,3- difluoropyrrolidin-1-yl)pyrimidin-5-yl]methyl}imidazole-4-carboxamide;
3-amino-N-[(3-chloro-1H-indazol-5-yl)methyl]-1-{[6-(pyrrolidin-1-yl)pyridin-3- yl]methyl}pyrazole-4-carboxamide;
N-({3-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl}methyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3- yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-({5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3- yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;
N-({3-chloro-1H-pyrrolo[2,3-c]pyridin-5-yl}methyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3- yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide;
3-amino-N-[(7-chloroquinolin-2-yl)methyl]-1-{[6-(pyrrolidin-1-yl)pyridin-3- yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[6- (pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[6- (pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin- l-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide; N-[(1-aminoisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-rriethyl-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol- l-ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol- l-ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide; N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxarnide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamjde;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl}-5-{rnethoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide; N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[4-(pyrazol- l-ylmethyl)phenyl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4-
FTiethylpyrazol- l-yl)methyl]phenyl}FTiethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxarnide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl}-5-{rnethoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-(pyrrolidi^ l-yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-(pyrrolidin- l-yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-
(pyrrolidin-1-yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[{1-amino-7-methoxyisoquinolin-6-yl)methyl]-5-(rnethoxymethyl)-1-{[6- (pyrrolidin-1-yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[6- (pyrrolidin-1-yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-1-{[2-(pyrrolidin l-yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-(methoxymethyl)-l-{[2-(pyrrolidin- l-yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carbox3mide;
N-[(1-amino-5-fiuoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-l-{[2-(pyrrofidin-l- yl)pyrimidtn-5-yl]methyl}-l,2,4-triazoie-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-l-{[2- (pyrrolidin-l-yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-(methoxymethyl)-l-{[2- (pyrrolidin-l-yl)pyrimidin-5-yl]methyl}-l,2,4-triazo!e-3-carboxamide;
N-((1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-(methoxymethyl)-l-{[2-(pyrrolidin-l- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl)-5-(methoxymethyl)-l-{[2- (pyrro!idin-l-yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-((1-amino-7-methylisoquinolin-6-yl)methyl]-l-{[2-(3,3-difluoropyrrolidin-l- yl)pyrimidin-5-yl]methyl}-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-((1-amino-5-methylisoquinolin-6-yl)methyl]-l-{{2-(3,3-difiuoropyrrolidin-l- yl)pyrimidin-5-yl]methyl}-5-(methoxymethyl)-l,2,4-triazoie-3-carboxamide;
N-((1-amino-5-fluoroisoquinolin-6-yl)methyl]-l-{l2-(3,3-difluoropyrrolidin-l- yl)pyrimidin-S-yl]methyl}-5-(methoxyrnethytJ-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-l-{[2-(3,3-difiuoropyrrolidin-l- yl)pyrimidin-5-yl]methyl}-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methylj-l-{[2-(3,3-dtfluoropyrrolidin-l- yl)pyrimidin-5-yljmethyl}-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-((1-amino-7-fluoroisoquinolin-6-yl)methyl]-l-{(2-(3,3-difluoropyrrolidin-l- yl)pyrimidin-5-yl]methyl}-5-(methoxymethyl)-l,2,4-triazoie-3-carboxamide;
N4(l-arnino-8-methoxylsoquinolin-6-yl)methyl]-l-{[2-{3,3-difluoropyrrolidin-l- yl)pyrimidin-5-yl]methyl}-5-(methoxymethyl)-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-methyl-l-{[6-(pyrrolidin-l-yl)pyridin- 3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-methyl-l-{(6-(pyrrolidin-l- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yt)methyl]-5-methyl-l-{[6-(pyrrolidin-l- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-methyl-l-{[6-(pyrrolidin-l- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide; N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[6-(pyrrolidiri-1- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-{[6-(pyrrolidin-1-yl)pyridin- 3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[6-(pyrrolidin-1- yl)pyridin-3-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[{l-arnino-7-fluoroisoquinolin-6-yl)methyl]-5-methyl-1-{i2-{pyrrolidirs-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-5-methyl-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl]methyl}-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-methyl-l,2,4-triazole-3-carboxamide;
N-[{1-amino-5-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl] methyl }-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-7-fluoroisoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-methyl-l,2,4-triazole-3-carboxamide;
N-[(1-amino-8-methoxylsoquinolin-6-yl)methyl]-1-{[2-(3,3-difluoropyrrolidin-1- yl)pyrimidin-5-yl]methyl}-5-methyl-l,2,4-triazole-3-carboxamide; N-[(1-aminoisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)imidazole-4-carboxamide;
and pharmaceutically acceptable salts and solvates thereof. A compound according to claim 1, selected from:
N-((1-aminoisoquinolin-6-yl)methyl)-3-(m
yl)methyl)-1H-pyrazole-4-carboxamide dihydrochloride;
N-{(1-aminoisoquinolin-6-yl)methyl)-3-(methoxymethyl)-1-({5-((4-methyl-1H-pyrazoi-1- yl)methyl)pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide;
3-methoxymethyl-1-(4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide;
3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-{methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-{methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[2-(pyrrolidin-1- yl)pyrimidin-5-yl] methyl }pyrazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-{[4-(pyrazol-1- ylmethyl)phenyl]methyl}pyrazole-4-carboxamide;
3-ethoxymethyl-1-(4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1-amino- isoquinolin-6-ylmethyl)-amide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({3-fluoro-4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({2-fluoro-4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
3-cyclopropyl-1-(2-fluoro-4-pyrazol-1-ylmethyl-benzyl)-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide;
3-cyclopropyl-1-[4-(4-fluoro-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (1- amino-isoquinolin-6-ylmethyl)-amide; l-[4-(4-fluoro-pyrazol-1-ylmethyl)-benzyl]-3-methoxymethyl-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1- yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide;
N-[(1-aminoisoquinolin-6-yl)methyl]-1-({4-[(4-fluoropyrazol-1-yl)methyl]phenyl}methyl)- 3-(trifluoromethyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methoxylsoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-5-fluoroisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol- l-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-5-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide;
N-[(1-amino-7-methylisoquinolin-6-yl)methyl]-3-(methoxymethyl)-1-({4-[(4- methylpyrazoi-1-yl)methylj phenyl }methyl)pyrazo!e-4-carboxarnide; l-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
3-methoxymethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
3-cyano-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3- chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
N-[(1-aminoisoquinolin-6-yl)methyl]-2-cyclopropyl-1-({4-[(4-methylpyrazol-1- yl)methyl]phenyl}methyl)irnidazo!e-4-carboxamide; and pharmaceutically acceptable salts and solvates thereof.
3, A compound according to claim 1, selected from:
3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide; l-[2-(3,3-difluoro-pyrrolidin-1-yl)-pyrimidin-5-ylmethyl]-3-methoxymethyl-1H-pyrazole-4- carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide; l-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide;
and pharmaceutically acceptable salts and solvates thereof.
4, A compound according to claim 1, which is N-[{1-amino-7-methoxylsoquinolin-6-yl)methyl] -3- (methoxymethyl)-1-{[4-(pyrazol-l"ylmethyl)phenyl]methyl}pyrazole-4-carboxamide. and
pharmaceutically acceptable salts and solvates thereof.
5, A compound according to claim 1, which is 3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5- ylmethyl)-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)-amide, and pharmaceutically acceptable salts and solvates thereof,
6, A compound according to claim 1, which is l-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3- trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide, and pharmaceutically acceptable salts and solvates thereof.
7. A compound according to claim 1, which is N-[(l-aminoisoquinolin-6-yl)methyl]-2-cyclopropyl-1- ({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamidei and pharmaceutically acceptable salts and solvates thereof.
8. A compound according to claim 1, which is l-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3- trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amide, and pharmaceutically acceptable salts and solvates thereof.
9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier, diluent or excipient.
10. A compound according to any one of claims 1 to 8 for use in medicine.
11. The use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated,
12. 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 according to any one of claims 1 to 8.
13. A compound according to any one of claims 1 to 8 for use in a method of treatment of a disease or condition in which plasma kallikrein activity is implicated.
14. The use of claim 11, the method of claim 12 or a compound for use according to claim 13 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, cardiopulmonary bypass surgery and bleeding from post operative surgery.
15. The use of claim 11, the method of claim 12 or a compound for use according to claim 13, wherein the disease or condition in which plasma kaiiikrein activity is implicated is retina! vascular permeability associated with diabetic retinopathy and diabetic macular edema.
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