TWI675832B - New enzyme inhibitors - Google Patents

Abstract

The invention provides a selection of compounds of formula (I):

Compositions comprising the compounds; use of the compounds in therapy, such as in the treatment or prevention of diseases or conditions involving plasma kallikrein activity; and methods of treating patients with the compounds.

Description

Novel enzyme inhibitors

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

The heterocyclic derivative of the present invention is an inhibitor of plasma kallikrein and has many therapeutic applications, specifically, it is used to treat retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

Plasma kallikrein is a trypsin-like serine protease that can release kinin from kininogen (see KDBhoola et al., "Kallikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine , pp. 483-493; JWBryant et al., "Human plasma kallikrein-kinin system: physiological and biochemical parameters" Cardiovascular and haematological agents in medicinal chemistry , 7, pp. 234-250, 2009; KDBhoola et al., Pharmacological Rev. , 1992, 44 , 1; and DJ Campbell, "Towards understanding the kallikrein-kinin system: insights from the measurement of kinin peptides ", Brazilian Journal of Medical and Biological Research 2000, 33 , 665-677). It is an essential member of the endogenous coagulation cascade, although its role in this cascade does not involve bradykinin release or enzyme division. Plasma prekinin is encoded by a single gene and is synthesized in the liver. It is secreted by liver cells as inactive plasma prokinin, which is circulated in the plasma as a heterodimer complex bound to high molecular weight kininogen, which is activated to produce active plasma kinin Peptide release hormone. Kinin is an effective mediator of inflammation that works via G protein-coupled receptors, and antagonists of kallikrein (such as bradykinin antagonists) have been previously studied as potential therapeutic agents for the treatment of a variety of conditions (F. Marceau And D. Regoli, Nature Rev., Drug Discovery, 2004, 3 , 845-852).

It is believed that plasma kallikrein plays a role in a variety of inflammatory conditions. The main inhibitor of plasma kallikrein is serine protease inhibitor C1 esterase inhibitor. Patients presenting with a C1 esterase inhibitor genetic deficiency suffer from hereditary angioedema (HAE), which causes intermittent swelling of the face, hands, throat, gastrointestinal tract, and genitals. The blister formed during the acute attack contained a higher level of plasma kallikrein, which cleaves high molecular weight kininogen and releases bradykinin, resulting in increased vascular permeability. Treatment with large protein plasma kallikrein inhibitors has been shown to effectively treat HAE by preventing the release of bradykinin that increases vascular permeability (A. Lehmann "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery " Expert Opin. Biol. Ther. 8, pp. 1187-99).

The plasma kallikrein-kinin system is abnormally high in patients with advanced diabetic macular edema. Plasma kallikrein has recently been reported to promote retinal vascular dysfunction in diabetic rats (A. Clermont et al. "Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats" Diabetes , 2011, 60, 1590-98 page). In addition, administration of the plasma kallikrein inhibitor ASP-440 improves both retinal vascular permeability and abnormal retinal blood flow in diabetic rats. Therefore, plasma kallikrein inhibitors 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 hemorrhage) that are all associated with plasma kallikrein Blood, kidney disease, cardiomyopathy, and neuropathy) can also be considered as targets of plasma kallikrein inhibitors.

Synthetic and small molecule plasma kallikrein inhibitors have been previously described, for example by Garrett et al. ("Peptide aldehyde ..." J. Peptide Res. 52, pp. 62-71 (1998)), T. Griesbacher et al. ("Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats" British Journal of Pharmacology 137, pp. 692-700 (2002)), Evans ("Selective dipeptide inhibitors of kallikrein" WO03 / 076458), Szelke et al. (`` Kininogenase inhibitors '' WO92 / 04371), DMEvans et al. ( Immunolpharmacology , 32, pp. 115-116 (1996)), Szelke et al. (`` Kininogen inhibitors '' WO95 / 07921), Antonsson Et al. (`` New peptides derivatives '' WO94 / 29335), J. Corte et al. (`` Six membered heterocycles useful as serine protease inhibitors '' WO2005 / 123680), J. St. Urzbecher et al. ( Brazilian J. Med. Biol. Res. 27, pages 1929-34 (1994)), Kettner et al. (US 5,187,157), N. Teno et al. ( Chem. Pharm. Bull. 41, pages 1079-1090 (1993)), WBYoung et al. ("Small molecule inhibitors of plasma kallikrein " Bioorg. Med. Chem. Letts . 16, pages 2034-2036 (2006)), Okada et al. (" Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship " Chem .Pharm.Bull. 48, 1964-72 (2000)), Steinmetzer et al. ("Trypsin-like serine protease inhibitors and their preparation and use" WO08 / 049595), Zhang et al. ("Discovery of highly potent small molecule kallikrein inhibitors " Medicinal Chemistry 2, pages 545-553 (2006), Sinha et al. (" Inhibitors of plasma kallikrein "WO08 / 016883), Shigenaga et al. (" Plasma Kallikrein Inhibitors "WO2011 / 118672), and Kolte et al. ( "Biochemical characterization of a novel high-affinity and specific kallikrein inhibitor", described in British Journal of Pharmacology (2011), 162 (7), 1639-1649). In addition, Steinmetzer et al. ("Serine protease inhibitors" WO2012 / 004678) describe cyclic peptide analogs that are inhibitors of human plasmin and plasma kallikrein.

To date, no small molecule synthetic kallikrein inhibitors have been approved for medical use. The molecules described in the known technology are limited, such as poor selectivity to related enzymes such as KLK1, thrombin, and other serine proteases, and poor oral availability. As reported for Ecallantide, large protein plasma kallikrein inhibitors are at risk for allergic reactions. Therefore, there remains a need for compounds that selectively inhibit plasma kallikrein without inducing a systemic allergic response and are orally available. In addition, most molecules in the known technology are characterized by highly polar and ionizable guanidine or hydrazone functionality. It is well known that such functionalities are intestinal permeability and therefore may be restrictive to oral usability. For example, Tamie J. Chilcote and Sukanto Sinha ("ASP-634: An Oral Drug Candidate for Diabetic MacularEdema", ARVO May 6, 2012-May 9, 2012, Fort Lauderdale, Florida, show 2240 ) Reports that ASP-440 (a benzamidine) has poor oral usability. Further reports may improve absorption by producing prodrugs such as ASP-634. However, well-known prodrugs may have several disadvantages, such as poor chemical stability and potential toxicity from inert carriers or from unexpected metabolites. In another report, indolinamide was claimed to be a compound that may solve problems associated with drugs with poor or insufficient absorption, deposition, metabolism, secretion and toxicity (ADME-tox), and physicochemical properties, although they do not present or Inhibition of plasma kallikrein is advocated (Griffioen et al., "Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases", WO2010, 142801).

BioCryst Pharmaceuticals Inc. has reported discovery of orally available plasma kallikrein BCX4161 ("BCX4161, An Oral Kallikrein Inhibitor: Safety and Pharmacokinetic Results Of a Phase 1 Study In Healthy Volunteers", Journal of Allergy and Clinical Immunology, Vol. 133, 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, AB40 page). However, human doses are relatively large, and are currently tested at a dose of 400 mg three times daily in a proof-of-concept study.

Plasma kallikrein inhibitors that are not characterized by guanidine or hydrazone functional groups are rarely reported. An example is Brandl et al. ("N-((6-amino-pyridin-3-yl) methyl) -heteroaryl-carboxamides as inhibitors of plasma kallikrein" WO2012 / 017020), whose description is characterized by an amine-pyridine functional group Of compounds. Oral efficacy in a rat model was demonstrated at relatively high doses of 30 mg / kg and 100 mg / kg, but no pharmacokinetic profile was reported. Therefore, it is unknown whether these compounds will provide adequate oral availability or efficacy for clinical progress. Other examples are Brandl et al. ("Aminopyridine derivatives as plasma kallikrein inhibitors" WO2013 / 111107) and Flohr et al. ("5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors" WO2013 / 111108). However, none of these literatures report any in vivo data, and it is therefore unknown whether the compounds will provide adequate oral availability or efficacy for clinical progress. Another example is Allen et al. "Benzylamine derivatives" WO2014 / 108679.

Therefore, there is still a need to develop new plasma kallikrein inhibitors that have the effect of treating a variety of conditions, particularly reducing the retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. The preferred compounds will have a good pharmacokinetic profile and will be particularly suitable as drugs for oral delivery.

The present invention relates to a series of heterocyclic derivatives as plasma kallikrein inhibitors. These compounds demonstrate good selectivity to plasma kallikrein and are potentially suitable for the treatment of visually impaired vision, diabetic retinopathy, macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, kidney disease, myocardium Disease, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery, and postoperative bleeding. The invention further relates to pharmaceutical compositions of these inhibitors, their use as therapeutic agents, and methods of using these compositions for treatment.

The present invention provides compounds which are closely related to or fall within the scope of our application PCT / GB2014 / 051592, but are not specifically disclosed therein.

In the first aspect, The present invention provides a 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-((1-aminoisoquinolin-6-yl) methyl) -3- (methoxymethyl) -1-((5-((4-methyl-1H-pyrazole-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-isoquinoline-6-ylmethyl) ) -Amidamine; 3-methoxymethyl-1- (4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) ) -Amidine; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine -3-yl] methyl} pyrazole-4-carboxamide; N-[(1-amino-5-fluoroisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine- 3-yl] methyl} pyrazole-4-carboxamide; N-[(1-amino-5-methoxyisoquinolin-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-yl Methyl) -amidine; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine -5-yl] methyl} pyrazole-4-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine- 5-yl] methyl} pyrazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-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) pyrimidine -5-yl] methyl} pyrazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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) pyrimidine- 5-yl] methyl} pyrazole-4-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) Pyrimidin-5-yl] methyl} pyrazole-4-carboxamide; 1- [2- (3, 3-difluoro-pyrrolidin-1-yl) -pyrimidin-5-ylmethyl] -3-methoxymethyl-1H-pyrazole-4-carboxylic acid (1-amino-isoquinoline-6- Methyl) -amidine; 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-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -3- (methoxymethyl) pyrazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-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-difluoropyrrolidin-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-methoxyisoquinolin-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-isoquine Phenyl-6-ylmethyl) -amidamine; 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-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl Yl) phenyl] methyl} pyrazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl Yl) 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-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl Yl) phenyl] methyl} pyrazole-4-carboxamide; 3-ethoxymethyl-1- (4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl ) -Amidine; N-[(1-aminoisoquinolin-6-yl) methyl] -1-{[2- (pyrazol-1-ylmethyl) pyrimidin-5-yl] methyl} -3- (tri Fluoromethyl) pyrazole-4-carboxamide; N-[(1-aminoisoquinolin-6-yl) methyl] -1-({3-fluoro-4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl Yl) -3- (methoxymethyl) pyrazole-4-carboxamide; N-[(1-aminoisoquinolin-6-yl) methyl] -1-({2-fluoro-4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl Yl) -3- (methoxymethyl) pyrazole-4-carboxamide; 3-cyclopropyl-1- (2-fluoro-4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-yl Methyl) -amidine; 3-cyclopropyl-1- [4- (4-fluoro-pyrazol-1-ylmethyl) -benzyl] -1H-pyrazole-4-carboxylic acid (1-amino-isoquinoline-6 -Methyl) -amidamine; 1- [4- (4-fluoro-pyrazol-1-ylmethyl) -benzyl] -3-methoxymethyl-1H-pyrazole-4-carboxylic acid (1-amino-isoquinoline -6-ylmethyl) -amidamine; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl Yl) -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-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -3- (methoxymethyl) pyrazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-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-methoxyisoquinolin-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 Yl) -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-methylpyrazole-1 -Yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole-1 -Yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole- 1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-amino-7-methylisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole- 1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; 1- (6-pyrrolidin-1-yl-pyridin-3-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo [2, 3-b] pyridin-5-ylmethyl) -amidamine; 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 -Formamidine; 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; 1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo [2, 3-b] pyridin-5-ylmethyl) -amidamine; 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-formamidine 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- Formamidine N-({5-chloro-7H-pyrrolo [2, 3-b] pyridin-3-yl} methyl) -1-({6- [isopropyl (methyl) amino] pyridin-3-yl} methyl) -3- (trifluoromethyl) pyridine Azole-4-methylamidine; 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-pyrrole And [2, 3-b] pyridin-5-ylmethyl) -amidamine; 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) -amidamine; 3-amino-N-({3-chloro-1H-pyrrolo [2, 3-b] pyridin-5-yl} methyl) -1-({4-[(4-methylpyrazol-1-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-side oxypyridin-1-yl) methyl] phenyl } Methyl) pyrazole-4-carboxamide; 3-amino-N-[(3-chloro-1H-indazol-5-yl) methyl] -1-({4-[(2-side oxypyridin-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-side oxypyridin-1-yl) methyl] phenyl} methyl) pyrazole 4-formamidine N-({3-fluoro-1H-pyrrolo [2, 3-b] pyridin-5-yl} methyl) -3- (methoxymethyl) -1-({4-[(2- pendant oxypyridin-1-yl) methyl] phenyl} methyl Yl) 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-({1-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- pendant oxypyridin-1-yl) methyl] phenyl} methyl Yl) pyrazole-4-carboxamide; 3-amino-N-[(6-chloroisoquinolin-3-yl) methyl] -1-({4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl Yl) 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 Yl} pyrazole-4-carboxamide; N-[(1-amino-7-methylisoquinolin-6-yl) methyl] -2-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl Yl} imidazole-4-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -2-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl Yl} 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-methoxyisoquinolin-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-methoxyisoquinolin-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 Yl} imidazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[4- (pyrazol-1-ylmethyl) phenyl ] Methyl} imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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 Yl} imidazole-4-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-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] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -2-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl Phenyl] 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-methoxyisoquinolin-6-yl) methyl] -2-methyl-1-({4-[(4-methylpyrazol-1-yl) Methyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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-methylpyrazol-1-yl) Methyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-amino-7-fluoroisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-methylpyrazol-1-yl) methyl Phenyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-methylpyrazol-1-yl ) Methyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-amino-8-methoxyisoquinolin-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-1-yl) methyl Phenyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-amino-5-methoxyisoquinolin-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 Yl) -2-methylimidazole-4-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl Yl) -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-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} Methyl) -2-methylimidazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-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-methoxyisoquinolin-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-1-yl) methyl Phenyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-fluoropyrazol-1-yl) methyl Phenyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-fluoropyrazol-1-yl) methyl ] Phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-fluoropyrazol-1-yl) Methyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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-methoxyisoquinolin-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-ylmethyl) -1H-imidazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)- Amidine 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) pyridin-3-yl] methyl Yl} imidazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -2-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl ] Methyl} imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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) pyridin-3-yl] methyl Yl} imidazole-4-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-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-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] Methyl} imidazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[6- (pyrrolidin-1-yl) pyridine-3- Yl] methyl} imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[6- (pyrrolidin-1-yl) pyridine-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-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[6- (pyrrolidin-1-yl) pyridine-3- Yl] methyl} imidazole-4-carboxamide; N-[(6-chloroisoquinolin-3-yl) methyl] -2-methyl-1-({4-[(2-oxopyridin-1-yl) methyl] phenyl} methyl Yl) 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 -Formamidine; 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 -Formamidine; N-[(1-aminoisoquinolin-6-yl) methyl] -2-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] methyl} imidazole- 4-formamidine 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 Yl} imidazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -2-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl ] Methyl} imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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 Yl} imidazole-4-carboxamide; N-[(1-amino-8-methoxyisoquinolin-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-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[2- (pyrrolidin-1-yl) pyrimidine-5- Yl] methyl} imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[2- (pyrrolidin-1-yl) pyrimidine-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-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[2- (pyrrolidin-1-yl) pyrimidine-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- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -2-methylimidazole-4-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -2-methylimidazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-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-methoxyisoquinolin-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-methoxyisoquinolin-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-methoxyisoquinolin-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-methoxyisoquinolin-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} pyridine Azole-4-methylamidine; 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 -Formamidine; 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 -Formamidine; 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 -Formamidine; 3-amino-N-[(7-chloroquinolin-2-yl) methyl] -1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] methyl} pyrazole-4- Formamidine N-[(1-Amino-7-methoxyisoquinolin-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) pyridine- 3-yl] methyl} pyrazole-4-carboxamide; N-[(1-amino-8-methoxyisoquinolin-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-1-yl) pyridine -3-yl] methyl} pyrazole-4-carboxamide; N-[(1-aminoisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl] phenyl} (Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-aminoisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazol-1-yl) methyl Phenyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl }-1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl }-1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl ) Phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl) Phenyl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl ) Phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl Phenyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl Phenyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl ] Phenyl} methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) Methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) Methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl ] Phenyl} methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) Methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole-1 -Yl) methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl ) Phenyl) methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl ) Phenyl) methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl) Phenyl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl ) Phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole- 1-yl) methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole- 1-yl) methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole-1 -Yl) methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl Group) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl Group) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine -3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine -3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine- 3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) Pyridin-3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) Pyridin-3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine- 3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) Pyridin-3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine -5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine -5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine- 5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) Pyrimidin-5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) Pyrimidin-5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine- 5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) Pyrimidin-5-yl] methyl} -1, 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- (methoxymethyl) -1, 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) -1, 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- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5- (methoxymethyl) -1, 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) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl ] Methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl ] Methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl ] Methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl ] Methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl ] Methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl ] Methyl} -1, 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-1, 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-1, 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-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5-methyl-1, 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-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5-methyl-1, 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 its pharmaceutically acceptable salts and solvates.

In another aspect, a 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-((1-aminoisoquinoline-6- (Methyl) 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 Yl] -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -amidamine; 3-methoxymethyl-1- (4-pyrazol-1-yl Methyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -amidamine; 3-methoxymethyl-1- (2-pyrrole Pyridin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -amidamine; N-[(1-amine Methyl-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-methoxyiso Phenyl-6-yl) methyl] -3- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] methyl} pyrazole-4-carboxamidine Amine; 1- [2- (3,3-difluoro-pyrrolidin-1-yl) -pyrimidin-5-ylmethyl] -3-methoxymethyl-1H-pyrazole-4-carboxylic acid (1 -Amino-isoquinolin-6-ylmethyl) -amidamine; 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-pyridine- 3-ylmethyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -amidamine; N-[(1-amino-5-methylisoquine Phenyl-6-yl) methyl] -3- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl} pyrazole-4-carboxamide ; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[4- (pyrazol-1-yl (Methyl) phenyl] methyl} pyrazole-4-carboxamide; 3-ethoxymethyl-1- (4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole- 4-formic acid (1-amino-isoquinolin-6-ylmethyl) -fluorenamine; 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 -Formic acid (1-amino-isoquinoline-6-ylmethyl) -Amidamine; 3-cyclopropyl-1- [4- (4-fluoro-pyrazol-1-ylmethyl) -benzyl] -1H-pyrazole-4-carboxylic acid (1-amino-iso Quinolin-6-ylmethyl) -amidamine; 1- [4- (4-fluoro-pyrazol-1-ylmethyl) -benzyl] -3-methoxymethyl-1H-pyrazole 4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -fluorenamine; 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-methoxyisoquinolin-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-fluoropyrazole 1-yl) methyl] phenyl} methyl) -3- (trifluoromethyl) pyrazole-4-carboxamide; N-[(1-amino-7-fluoroisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole-1 -Yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-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-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-amino-8-methyl Oxyisoquinolin-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-methylisoquinoline- 6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl) pyrazole-4 -Formamidine; 1- (6-pyrrolidin-1-yl-pyridin-3-ylmethyl) -3- Fluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine; 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-formamidine; 1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrole Benzo [2,3-b] pyridin-5-ylmethyl) -fluorenamine; 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-carboxamide; 3-methoxymethyl-1- [4- (4-methyl-pyrazol-1-ylmethyl) -benzyl Yl] -1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine; 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) -fluorenamine; N-({3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl} methyl) -3- (formaldehyde Oxymethyl) -1-[(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) Pyrazol-4-carboxamide; 2-methyl-1- (6-pyrrolidin-1-yl-pyridin-3-ylmethyl) -1H-imidazole-4-carboxylic acid (1-amino-isoquine Phenyl-6-ylmethyl) -fluorenamine; 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-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] methyl} imidazole-4-carboxamide; N-[(1-aminoisoquinoline- 6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl) -1,2,4-triazole 3-formamidine; N-[(1-aminoisoquinolin-6-yl) methyl] -5- ( Methoxymethyl) -1-({4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl) -1,2,4-triazole-3-carboxamide ; N-[(1-Aminoisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-methylpyrazol-1-yl) methyl] benzene Methyl} methyl) imidazole-4-carboxamide; and pharmaceutically acceptable salts and solvates thereof.

In another aspect, a 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-((1-aminoisoquinoline-6- (Methyl) methyl) -3- (methoxymethyl) -1-((5-((4-methyl-1H-pyrazol-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) ) -Amine; 3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquine -6-ylmethyl) -fluorenamine; 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-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine-5- Methyl] 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-methoxyisoquinoline-6- (Methyl) methyl] -3- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl} pyrazole-4-carboxamide; 3-ethyl Oxymethyl-1- (4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -fluorene Amine; N-[(1-amine Isoquinolin-6-yl) methyl] -1-({3-fluoro-4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl) -3- (methoxy Methylmethyl) pyrazole-4-carboxamide; N-[(1-aminoisoquinolin-6-yl) methyl] -1-({2-fluoro-4-[(4-methylpyridine Azol-1-yl) methyl] phenyl} methyl) -3- (methoxymethyl) pyrazole-4-carboxamide; 3-cyclopropyl-1- (2-fluoro-4-pyridine) Azole-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -amidamine; 3-cyclopropyl-1- [ 4- (4-fluoro-pyrazol-1-ylmethyl) -benzyl] -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -fluorenamine; 1- [4- (4-fluoro-pyrazol-1-ylmethyl) -benzyl] -3-methoxymethyl-1H-pyrazole-4-carboxylic acid (1-amino-isoquinoline -6-ylmethyl) -amidamine; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -3- (methoxymethyl) pyrazole-4-methylamidine; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -1- ( {4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl) -3- (methoxymethyl) pyrazole-4-carboxamide; N-[(1-amine Isoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl) -3- (trifluoromethyl) pyridine Azole-4-methylamidine; N-[(1-amino-7-methoxyisoquinolin-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-carboxamidine Amine; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyridine Azol-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; 1- (6 -Pyrrolidin-1-yl-pyridin-3-ylmethyl) -3-trifluoromethyl-1H-pyrazole- 4-formic acid (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine; 3-methoxymethyl-1- [4- (4-methyl- Pyrazol-1-ylmethyl) -benzyl] -1H-pyrazol-4-carboxylic acid (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine ; 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) -fluorenamine; 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 another aspect, a compound selected from the group consisting of 3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole is provided. 4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -amidamine; 1- [2- (3,3-difluoro-pyrrolidin-1-yl) -pyrimidin-5-ylmethyl] -3-methoxymethyl-1H-pyrazole-4-carboxylic acid (1-amine -Isoquinolin-6-ylmethyl) -amidamine; 1- (6-pyrrolidin-1-yl-pyridin-3-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4 -Formic acid (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine; and pharmaceutically acceptable salts and solvates thereof.

In another aspect, N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[4 -(Pyrazol-1-ylmethyl) phenyl] methyl} pyrazole-4-carboxamide, and pharmaceutically acceptable salts and solvates thereof.

In another aspect, there is provided: 3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid (1-amine -Isoquinoline-6-ylmethyl) -amidamine, and pharmaceutically acceptable salts and solvates thereof.

In another aspect, there is provided: 1- (6-pyrrolidin-1-yl-pyridin-3-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro- 1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine, and its pharmaceutically acceptable salts and solvates.

In another aspect, there is provided: N-[(1-aminoisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-methylpyrazole- 1-yl) methyl] phenyl} methyl) imidazole-4-carboxamide, and pharmaceutically acceptable salts and solvates thereof.

In another aspect, 1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro- 1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine, and its pharmaceutically acceptable salts and solvates.

In another aspect, the invention provides a prodrug of a compound of the invention, or a medicament thereof Acceptable salt.

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

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

Therapeutic applications

As mentioned previously, the compounds of the invention are potent and selective inhibitors of plasma kallikrein. Therefore, it is suitable for treating disease conditions in which excessive activity of plasma kallikrein is a causative factor.

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

The invention also provides the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition involving plasma kallikrein activity.

The invention also provides a compound of the invention for use in the treatment or prevention of a disease or condition involving plasma kallikrein activity.

The invention also provides a method for treating a disease or condition involving plasma kallikrein activity, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.

In one aspect, the disease or condition involving plasma kallikrein activity is selected from the group consisting of impaired vision, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, kidney disease, Cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and postoperative bleeding.

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

Combination therapy

The compounds of the invention can be administered in combination with other therapeutic agents. Suitable combination therapies include a compound of the invention in combination with one or more agents selected from the group consisting of: inhibition of platelet-derived growth Agents for growth factor (PDGF), endothelial growth factor (VEGF), integrin α5β1, steroids, other agents that inhibit plasma kallikrein, and other inflammation inhibitors. Specific examples of therapeutic agents that can be combined with the compounds of the present invention include their therapeutic agents disclosed in EP2281885A and disclosed by S. Patel in Retina, June 2009; 29 (Suppl. 6): S45-8.

When a combination therapy is adopted, the compound of the present invention and the combination medicaments may exist in the same or different pharmaceutical compositions, and may be administered separately, sequentially, or simultaneously.

In another aspect, the compounds of the invention can be administered in combination with laser treatment of the retina. A combination of laser therapy and intravitreal VEGF inhibitors is known for the treatment of diabetic macular edema (Elman M, Aiello L, Beck R, et al. "Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema ". Ophthalmology. April 27, 2010).

definition

"Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt, and includes, where appropriate, a pharmaceutically acceptable base addition salt and a pharmaceutically acceptable acid addition salt . For example, (i) in the case where the compound of the present invention contains one or more acidic groups (such as a carboxyl group), the pharmaceutically acceptable base addition salts include sodium salt, potassium salt, calcium Salts, magnesium and ammonium salts, or salts with organic amines such as diethylamine, N -methyl-glucosamine, diethanolamine or amino acids (e.g. lysine) and the like ; (Ii) in the case where the compound of the present invention contains a basic group such as an amine group, pharmaceutically acceptable acid addition salts that can be formed include hydrochloride, hydrobromide, sulfate, Phosphate, acetate, citrate, lactate, tartrate, mesylate, succinate, oxalate, phosphate, ethanesulfonate, tosylate, benzenesulfonate, naphthalene Sulfonate, maleate, adipic acid, fumarate, hippurate, camphor, hydroxynaphthoate, p-acetamidobenzoate, dihydroxybenzene Formate, hydroxynaphthoate, succinate, ascorbate, oleate, bisulfate, and the like.

Hemi-salts of acids and bases can also be formed, such as hemi-sulphate and hemi-calcium 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).

A "prodrug" refers to a compound that can be converted into a compound of the invention in vivo by metabolic means (for example, by reducing oxidation by hydrolysis, reduction). Suitable groups for the formation of prodrugs are described in "The Practice of Medicinal Chemistry", 2nd ed., Pages 561-585 (2003) and F, J. Leinweber, Drug Metab . Res ., 1987, 18 , 379 in.

The compounds of the invention can exist in both unsolvated and solvated forms. The term "solvate" as used herein describes a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (eg, ethanol). When the solvent is water, the term "hydrate" is used.

The compounds of the present invention exist in one or more geometric, optical, enantiomeric, diastereomeric and tautomeric forms, including (but not limited to) cis and trans, E and Z, R Type, S type and meso type, ketone type and enol type. Unless otherwise stated, references to a particular compound include all such isomeric forms, including racemic and other mixtures thereof. Where appropriate, these isomers can be separated from their mixtures by applying or improving known methods such as chromatography and recrystallization techniques. Where appropriate, these isomers can be prepared by applying or modifying a known method such as asymmetric synthesis.

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

General method

The biomedical properties of compounds of formula (I) (such as solubility and solution stability (over the entire pH), permeability, etc.) should be evaluated to select the most appropriate dosage form and route of administration for treating the proposed indications. It can 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 in any combination thereof). general To be specific, it will be administered in the form of a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe functionalities (i.e., drug release rate control) and / or non-functionality (i.e., processing aids or diluents) that can impart to formulations other than the compounds of the present invention Any ingredients. The choice of excipient will largely 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.

The compounds of the invention intended for medical use can be administered in solid or liquid form, such as lozenges, capsules or solutions. Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods of making them will be apparent to those skilled in the art. Such compositions and methods of making them can be found, for example, in Remington's Pharmaceutical Sciences, 19th edition (Mack Publishing Company, 1995).

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

In order to treat conditions such as retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema, the compounds of the present invention may be administered in a form suitable for injection into a patient's eye area, and particularly suitable for intravitreal injection. It is envisaged that formulations suitable for such uses will be in the form of a sterile solution of the compound of the invention in a suitable aqueous vehicle. The composition can be administered to a patient under the supervision of the attending physician.

The compounds of the invention can also be administered directly into the bloodstream, subcutaneous tissue, muscle or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques.

Parenteral formulations are usually aqueous or oily solutions. In the case where the solution is aqueous, sugars (including (but not limited to) glucose, mannitol, sorbitol, etc.), salts, carbohydrates, and buffering agents (preferably to a pH of 3 to 9) Excipients but For some applications, it may be more suitable to be formulated as a sterile non-aqueous solution or in a dry 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, polylactide Caprolactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations can be administered by surgical incision into subcutaneous tissue, muscle tissue or directly into specific organs.

The preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be easily accomplished using standard medical techniques familiar to those skilled in the art.

The solubility of a compound of formula (I) for the preparation of parenteral solutions can be increased by using appropriate formulation techniques, such as the incorporation of co-solvents and / or solubility enhancers such as surfactants, micellar structures, and cyclopastes fine).

In one embodiment, the compounds of the invention can be administered orally. Oral administration may involve swallowing to allow the compound to enter the gastrointestinal tract; and / or buccal, translingual, or sublingual administration whereby the compound enters the bloodstream directly from the mouth.

Formulations suitable for oral administration include solid plugs, solid particles, semi-solids, and liquids (including heterogeneous or dispersed systems) such as lozenges; softeners containing multiple or nano particles, liquids, emulsions, or powders Or hard capsules; lozenges (including liquid-filled types); chewables; gels; fast-dispersing dosage forms; films; oval suppositories; sprays; and buccal / mucosal adhesive patches.

Formulations suitable for oral administration can also be designed to deliver the compounds of the invention in an immediate release manner or in a rate-maintaining manner, where the release profile can be delayed, pulsed, controlled, sustained, or delayed in a certain manner, and continued or modified to Optimize the therapeutic efficacy of these compounds. Means of delivering compounds in a rate-sustaining manner are known in the art and include slow-release polymers that can be formulated with such compounds to control their release.

Examples of rate-maintaining polymers include those that can be used to The combination of etch releases the degradable and non-degradable polymers of these compounds. Examples of rate-maintaining polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sansin Glue, polymethacrylate, polyethylene oxide and polyethylene glycol.

Liquid (including multiphase and dispersion systems) formulations include emulsions, solutions, syrups, and elixirs. These formulations can be presented as fillers in soft or hard capsules (e.g. made from gelatin or hydroxypropyl methylcellulose), and usually comprise a carrier (e.g. water, ethanol, polyethylene glycol, propylene glycol, Methyl cellulose or a suitable oil) and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by rehydrating solids such as from sachets.

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

Formulations of lozenges are discussed in H. Lieberman and L. Lachman's Pharmaceutical Dosage Forms: Tablets, Volume 1 (Marcel Dekker, New York, 1980).

For administration to human patients, the total daily dose of a compound of the invention is usually in the range of 0.01 mg to 1000 mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg, of course, depending on the mode of administration.

The total dose can be administered in single or divided doses, and may exceed the typical range given herein based on the judgment of the physician. These dosages are based on ordinary human individuals weighing about 60 kg to 70 kg. Physicians will be able to easily determine dosages for individuals (such as infants and the elderly) who weigh outside this range.

Examples

In these examples, the following abbreviations and definitions are used:

Unless otherwise specified, all reactions were performed under a nitrogen atmosphere.

The ¹ H NMR spectrum was recorded on a Bruker (400 MHz) spectrometer with deuterium solvent as reference and at room temperature.

LCMS was used to obtain molecular ions. LCMS used a Chromolith Speedrod RP-18e column, 50 × 4.6mm, 0.1% HCO ₂ H / MeCN in 0.1% HCO ₂ H / H ₂ with a 10% to 90% linear gradient over 13 minutes. Solution in O, flow rate 1.5mL / min, or using Agilent, X-Select, acidic, 5% -95% MeCN / water over 4 minutes. Data were collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electrospray ionization and a Thermofinnigan Surveyor LC system.

In the case where the product is purified by flash chromatography, "silicon dioxide" means 0.035 to 0.070 mm (220 to 440 mesh) of silica gel (such as Merck Silicone 60) used for chromatography, and up to 10 applied Nitrogen pressure at psi accelerates column dissolution. Waters 2525 binary gradient pumping system was used for reverse phase preparative HPLC purification using a Waters 2996 photodiode array detector at a flow rate of typically 20 mL / min. Automation FC refers to the use of Biotage purification system for UV-directed sample collection with SNAP ultra or ZIP Sphere cartridges.

All solvents and commercial reagents were used as is.

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

General method: Alkylation

Unless stated otherwise, it is carried out with K ₂ CO ₃ in DMF, MeCN or acetone between room temperature and 80 ° C.

Saponification

This was performed using LiOH.H ₂ O in THF / water or NaOH-containing methanol or ethanol under reflux.

Formamide

Method A: HOBt (1.2 equivalents) and EDC (1.4 equivalents) were added to DCM (and if necessary, DMF) containing carboxylic acid component (1 equivalent) at 0 ° C. The reaction mixture was stirred for 10 minutes, followed by addition of Et ₃ N (5 eq) and the amine component (1 eq.) And the reaction was stirred at room temperature. The reaction was diluted with CHCl ₃ (50mL) and washed with brine (20mL) and washed. The organic layer was dried (MgSO _4), filtered and concentrated in vacuo, followed by purification by automated FC.

Method B: The carboxylic acid component (1 equivalent), the amine component (1 equivalent), and HATU (1.1 equivalent) were suspended in anhydrous DCM (and if necessary, DMF) and Et ₃ N (6 equivalent) was added. The reaction mixture was stirred at room temperature. The solvent was removed in vacuo. The residue was purified by automated FC.

Method C: Add HBTU (1.2 equivalents), Et ₃ N (5 equivalents), and amine component (1 equivalent) to DCM (and if necessary, DMF) containing the acid component (1 equivalent) and at room temperature The reaction was stirred. The reaction was diluted with CHCl ₃ (50mL) and washed with brine (20mL) and washed. The organic layer was dried (MgSO _4), filtered, and concentrated, followed by purification by automated FC.

Intermediate ("B" ring): A1. 2-((E) -2-Dimethylamino-vinyl) -terephthalonitrile

Methyl terephthalonitrile (1.42 g, 9.99 mmol) and Bredereck's reagent (3.48 g, 19.98 mmol) were dissolved in DMF (15 mL). The reaction mixture was heated at 75 ° C. under nitrogen for 72 hours, after which time the solvent was removed in vacuo. Wet trituration with petroleum ether gave a bright yellow solid, identified as 2-((E) -2-dimethylamino-vinyl) -terephthalonitrile (1.88 g, 0.95 mmol, yield 95%).

¹ H NMR (CD ₃ OD) 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. 1-Amino-2- (2,4-dimethoxy-benzyl) -1,2-dihydro-isoquinoline-6-carbonitrile

Dissolve 2-(( E ) -2-dimethylamino-vinyl) -terephthalonitrile (1.85 g, 9.38 mmol) in 1,3-dimethyl-3,4,5,6- To tetrahydro-2 (1H) -pyrimidone (5 mL) and 2,4-dimethoxybenzylamine (2.35 g, 14.07 mmol) was added. The reaction mixture was heated at 75 ° C under nitrogen. After 3 hours, the reaction mixture was cooled and diethyl ether / petroleum ether (15:85) was added. The yellow solid was filtered off, dried in vacuo and identified as 1-amino-2- (2,4-dimethoxy-benzyl) -1,2-dihydro-isoquinoline-6-carbonitrile (2.65 g, 8.38 mmol, 89% yield).

[MH] ⁺ = 320

¹ H NMR (CD ₃ OD) 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 = 8.5Hz)

A3. 1-amino-isoquinoline-6-carbonitrile

1-Amino-2- (2,4-dimethoxy-benzyl) -1,2-dihydro-isoquinoline-6-carbonitrile (1.6 g, 5.0 mmol) was dissolved in anisole ( 17 mL) and trifluoroacetic acid (20 mL). The reaction mixture was heated at 105 ° C. under nitrogen for 12 hours, after which the reaction mixture was cooled, diethyl ether / petroleum ether (3: 7) was added, the resulting solid was filtered off, dried in vacuo, and identified as 1- Amino-isoquinoline-6-carbonitrile (770 mg, 4.54 mmol, 91%).

[MH] ⁺ = 170.

¹ H NMR (CD ₃ OD) 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. (1-Amino-isoquinolin-6-ylmethyl) -aminocarboxylic acid third butyl ester

1-Amino-isoquinoline-6-carbonitrile (200 mg, 1.18 mmol) was dissolved in methanol (20 mL). This solution was cooled to 0 ° C. Nickel (II) chloride hexahydrate (28 mg, 0.12 mmol) and di-tert-butyl dicarbonate (516 g, 2.36 mmol) were added, followed by sodium borohydride (313 g, 8.22 mmol) in portions. The reaction mixture was stirred at 0 ° C to room temperature for 3 days. The MeOH was removed by evaporation. The residue was dissolved in CHCl ₃ (70 mL), washed with saturated NaHCO ₃ (30 mL), water (30 mL), brine (30 mL), dried (Na ₂ SO ₄ ), and evaporated in vacuo to give a yellow oil. It was identified as (1-amino-isoquinolin-6-ylmethyl) -aminocarboxylic acid third butyl ester (110 mg, 0.4 mmol, yield 34%).

[MH] ⁺ = 274.

A5. 6-Aminomethyl-isoquinolin-1-ylamine hydrochloride

(1-Amino-isoquinolin-6-ylmethyl) -aminocarboxylic acid third butyl ester (110 mg, 0.40 mmol) was dissolved in a 4M solution of HCl in dioxane (40 mL). After 18 hours at room temperature, the solvent was removed in vacuo to give a light brown solid identified as 6-aminomethyl-isoquinolin-1-ylamine hydrochloride (67 mg, 0.39 mmol, yield 96% ).

[MH] ⁺ = 174.

B1. 3-Chloro-1H-pyrrolo [2,3-b] pyridine-5-carbonitrile

5-cyano-7-azaindole (1.0 g, 6.99 mmol) was dissolved in anhydrous DMF (5 mL). To this solution was added N-chlorosuccinimide (1.12 g, 8.38 mmol) at 40 ° C. The reaction mixture was stirred at 55 ° C for 5 hours and cooled to room temperature and kept stirring for 2 days. The mixture was diluted with water (40 mL) and stirred for another 18 hours. The solid was filtered off and dried to give 3-chloro-1H-pyridine Pyrro [2,3-b] pyridine-5-carbonitrile (1.1 g, 89% yield).

[MH] ⁺ = 178.2

B2. (3-Chloro-1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -aminocarboxylic acid tert-butyl ester

3-Chloro-1H-pyrrolo [2,3-b] pyridine-5-carbonitrile (1.0 g, 5.63 mmol) was dissolved in methanol (150 mL). This solution was cooled to 0 ° C. Nickel (II) chloride hexahydrate (134 mg, 0.56 mmol) and di-tert-butyl dicarbonate (2.46 g, 11.3 mmol) were added, followed by sodium borohydride (1.49 g, 39.4 mmol) in portions. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The MeOH was removed in vacuo. The residue was dissolved in CHCl ₃ (70 mL), washed with a saturated aqueous solution of NaHCO ₃ (30 mL), water (30 mL), brine (30 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 97% CHCl _{3 to} give (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -Tert-butyl carbamate (870 mg, 55% yield).

[MH] ⁺ = 282.2

B3. C- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -methylamine

(3-Chloro-1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -carbamic acid third butyl ester (870 mg, 3.09 mmol) was dissolved in 4M HCl in dioxane (150 mL) in. After one hour at room temperature, the solvent was removed in vacuo to give C- (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-yl) -methylamine (650 mg, 97% yield ).

C1. 4-bromo-5-fluoro-2-methylbenzamide

To anhydrous THF (25 mL, 305 mmol) at room temperature was added 4-bromo-5-fluoro-2-methylbenzoic acid (5.43 g, 23.30 mmol), followed by CDI (4.91 g, 30.3 mmol). Add in portions at warm temperatures. The solution was allowed to stir at room temperature for 3 hours. Then ammonium hydroxide (10 mL, 90 mmol) was added. The resulting reaction mixture was allowed to stir at room temperature overnight. The solvent was then concentrated to 15 mL at 40 ° C under reduced pressure and the resulting solution was slowly quenched into water (100 mL). An off-white solid precipitated and was filtered under reduced pressure, washed with water (50 mL) and isohexane. The product was dried in a vacuum oven to obtain 4-bromo-5-fluoro-2-methylbenzamide (4.92 g, 86% yield), which was used in the next step without purification.

[MH] ⁺ = 232.0 / 234.2

C2. ( E ) -4-bromo-N-((dimethylamino) methylene) -5-fluoro-2-methylbenzamide

4-Bromo-5-fluoro-2-methylbenzamide (4.92 g, 21.20 mmol) was dissolved in anhydrous THF (30 mL, 366 mmol), and 1,1-dimethoxy-N, N- was added thereto. Dimethyl methylamine (3.19 mL, 23.32 mmol). The reaction was heated at 60 ° C for two nights. The reaction mixture was evaporated under reduced pressure to obtain ( E ) -4-bromo-N-((dimethylamino) methylene) -5-fluoro-2-methylbenzamide (6.0 g, 97% yield Rate), which was identified as the desired product.

[MH] ⁺ = 287/289

C3. 6-bromo-7-fluoro-2H-isoquinolin-1-one

( E ) -4-Bromo-N-((dimethylamino) methylene) -5-fluoro-2-methylbenzamide (6.0 g, 20.90 mmol) was dissolved in anhydrous THF (30 mL, 366 mmol) To this, potassium tert-butoxide (2.66 g, 22.99 mmol) was added at room temperature. 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 out and filtered under reduced pressure, washed with water and dried in a vacuum oven at 40 ° C for 3 hours. Flash column chromatography on silica gel (isolated with ethyl acetate-isohexane, gradient step to 60% ethyl acetate) to give 6-bromo-7-fluoro-2H-isoquinolin-1-one (560mg, 10.2 %Yield).

[MH] ⁺ = 242/244

C4. 6-bromo-1-chloro-7-fluoro-isoquinoline Use the following typical chlorination procedure

To anhydrous toluene (usually 13 ml per gram of starting material) are added the appropriate pyridone starting material (1 eq.) And diisopropylamine (3 eq.), Followed by pure phosphonium trichloro (3 eq.). The suspension was heated to 130 ° C overnight. The reaction mixture was allowed to cool to room temperature, then quenched into water, and then diluted with additional water. The mixture was extracted with EtOAc, and the combined organics were washed with sodium carbonate solution, followed by brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo at 45 ° C. The crude material was purified by wet milling or flash column chromatography.

After a 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% yield).

[MH] ⁺ = 259.8 / 261.8 / 263.8

C5. 6-bromo-7-fluoroisoquinolin-1-amine Use the following typical amination procedure

An appropriate mixture of chloroisoquinoline (1 equivalent), ammonium acetate (15 equivalents), and phenol (15 equivalents) was 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 solution was extracted with other DCM. The organics were phase separated using a phase separation cartridge and concentrated in vacuo. The crude material was purified using flash column chromatography and eluted with 1% ammonia in methanol / DCM.

6-Bromo-1-chloro-7-fluoroisoquinoline (460 mg, 1.78 mmol) was converted to 6-bromo-7-fluoroisoquinoline-1-amine (23.8 mg, 5.5% yield) using a typical amination procedure .

[MH] ⁺ = 240.8 / 242.8

C6. 1-amino-7-fluoroisoquinoline-6-carbonitrile Use the following typical cyanation procedure

To a stirred solution of zinc dicyano (1 eq) and appropriate aryl bromide (1 eq) in DMF was added Pd (Ph ₃ P) ₄ (0.1 eq). The reaction was heated to 100 ° C overnight. The reaction was quenched into ice-water (30 mL), and the resulting solid was filtered, washed with water and dried under reduced pressure. The crude material was purified by a SXC filter cartridge, and then dissolved with pure methanol (150 mL), followed by 1% ammonia / methanol (250 mL).

6-Bromo-7-fluoroisoquinoline-1-amine (23.8mg, 0.099mmol) was converted to 1-amino-7-fluoroisoquinoline-6-carbonitrile (13.3mg, 64.8%) using a typical cyanation procedure Yield).

[MH] ⁺ = 188

C7. ((1-Amino-7-fluoroisoquinolin-6-yl) methyl) aminocarboxylic acid third butyl ester Use the following typical nitrile reduction procedure

Add an appropriate aryl nitrile (1 eq) to anhydrous methanol followed by nickel chloride hexahydrate (0.1 equivalent) and di-tert-butyl dicarbonate (2 equivalents). The mixture was cooled to -5 ° C in an ice-salt bath and sodium borohydride (7 equivalents) was added in portions to maintain the reaction temperature at approximately 0 ° C. The reaction was stirred at 0 ° C and slowly warmed to room temperature overnight. The solvent was removed in vacuo at 40 ° C. The residue was taken up with chloroform (30 mL) and washed with sodium bicarbonate (15 mL). The crude material was purified by flash column chromatography and dissolved with (1% ammonia-methanol) -DCM.

After a typical nitrile reduction procedure, 1-amino-7-fluoroisoquinoline-6-carbonitrile (13 mg, 0.063 mmol) was converted to ((1-amino-7-fluoroisoquinoline-6-yl) methyl Propyl) amino butyl formate (12 mg, 64.6% yield).

[MH] ⁺ = 292

C8. 6- (Aminemethyl) -7-fluoroisoquinoline-1-amine dihydrochloride

To a flask containing ((1-amino-7-fluoroisoquinolin-6-yl) methyl) amino formate (12 mg, 0.040 mmol) was added anhydrous hydrochloric acid (6M, 2-propanol Middle) (47.1 μl, 0.283 mmol). The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure to give a dark yellow oil, which was triturated with ether to give 6- (aminemethyl) -7-fluoroisoquinoline-1-amine dihydrochloride (10.7 mg, 98% yield).

[MH] ⁺ = 192

D1. Tert-Butylaminocarbamate

The third butyl hydroxyaminoformate (15.0 g, 113 mmol) was dissolved in acetonitrile (300 mL). Pivalic anhydride (25.4 mL, 124 mmol) was added as a steady stream and the resulting mixture was heated to reflux overnight. After 18 hours, the reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was partitioned between EtOAc (350mL) and NaHCO ₃ (200mL). The layers were separated and the organic fractions were washed with NaHCO ₃ (3 × 100 mL), dried (MgSO ₄ ), filtered and concentrated under reduced pressure to obtain tert-pentyloxycarbamic acid third butyl ester (26.38 g, 97 mmol, 86 %Yield).

D2. O-pentamidine hydroxylamine trifluoromethanesulfonate

Pentamyloxycarbamic acid third butyl ester (26.38 g, 97 mmol) dissolved in anhydrous ethyl acetate Ether (237 mL). The reaction mixture was cooled to 0 ° C, and then trifluoromethanesulfonic acid (8.80 mL, 99 mmol) was added (note that a vigorous evolution of gas was noted). The mixture was stirred at 0 ° C for 5 minutes, and then warmed to room temperature. After 1 hour, isohexane (250 mL) was added and the mixture was stirred for 10 minutes. The obtained solid was filtered, washed with hexane (3 × 50 mL), and then dried overnight in a vacuum oven to obtain o-pentavaloxamine trifluoromethanesulfonate (24.83 g, 91% yield).

D3. 4-bromo-3-methoxybenzyl chloride

4-Bromo-3-methoxybenzoic acid (0.50 g, 2.164 mmol) was suspended in anhydrous DCM (5.01 mL). Ethylene chloride (0.227 mL, 2.60 mmol) was added dropwise over 5 minutes. Anhydrous DMF (1 drop) was added and gas evolved. The resulting mixture was stirred at ambient temperature. Dissolution occurred slowly over 45 minutes. After a total of 1.5 hours, the solvent was removed under vacuum to obtain 4-bromo-3-methoxybenzidine chloride (539 mg).

D4. 4-bromo-3-methoxy-N- (pentamyloxy) benzamide

To a dry flask under a nitrogen atmosphere was added ortho-pentamidine hydroxylamine trifluoromethanesulfonate (547 mg, 1.944 mmol) dissolved in EtOAc (5.5 mL). Water (5.5 mL) was added, followed by sodium carbonate (458 mg, 4.32 mmol). The resulting mixture was cooled to 0 ° C, and then a solution of 4-bromo-3-methoxybenzyl 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 hours, the reaction mixture was diluted with EtOAc (10mL) and washed with water (5mL) and NaHCO ₃ (15mL) and quenched. The layers were separated and the aqueous solution was extracted with EtOAc (2 x 20 mL). The combined organic portions were washed with brine (20mL), dried (MgSO _4), filtered and concentrated under reduced pressure. Wet trituration from isohexane gave 4-bromo-3-methoxy-N- (t-pentamyloxy) benzamide (378 mg, 47.7% yield).

[MH] ⁺ = 330.1 / 332.1

D5. 6-bromo-7-methoxyisoquinoline-1 (2H) -one

Add vinyl acetate (62.8 μL, 0.681 mmol) to [CpRhCl ₂ ] ₂ (5.62 mg, 9.09 μmol), cesium acetate (52.3 mg, 0.273 mmol), and 4-bromo-3 in a sealed vial under N ₂ atmosphere - methoxy -N- (pivaloyl acyl group) benzoyl amine (150mg, 0.454mmol) in dry MeOH (1.5mL) in a solution of N ₂ degassed. The reaction was stirred at 50 ° C for 1 hour, and a precipitate formed. The reaction was cooled to room temperature and stirred over the weekend. The reaction mixture was filtered and washed with a small amount of MeOH to obtain 6-bromo-7-methoxyisoquinolin-1 (2H) -one (73 mg, 63% yield), which was identified as the desired product.

[MH] ⁺ = 254.0 / 256.0

D6. (1-amino-7-methoxy-isoquinolin-6-ylmethyl) -aminocarboxylic acid third butyl ester

6-Bromo-7-methoxyisoquinoline-1 (2H) -one is converted to (1-amino-7-methoxy-isoquinoline) using typical chlorination, amination, cyanation, and nitrile reduction procedures. -6-ylmethyl) -carbamic acid third butyl ester.

[MH] ⁺ = 304.1

D7. 6-Aminomethyl-7-methoxy-isoquinolin-1-ylamine dihydrochloride

((1-Amino-7-methoxyisoquinolin-6-yl) methyl) third butyl formate (120 mg, 0.396 mmol) hydrochloric acid, 6M in 2-propanol (462 μL, 2.77 mmol The suspension in) was heated at 40 ° C for 1 hour. The mixture was stirred for another 45 minutes at room temperature, then treated with ether (2.5 mL) and the solids were filtered and dried under vacuum to give 6- (aminemethyl) -7-methoxyisoquinoline-1-aminedi Hydrochloride (102.5 mg, 89% yield).

[MH] ⁺ = 204.0

E1. 4-Bromo-3-fluoro-N-hydroxy-benzamide

4-Bromo-3-fluorobenzoic acid (5.0 g, 22.83 mmol) was dissolved in anhydrous DMF (10 mL) at ambient temperature and CDI (5.55 g, 34.2 mmol) was added in portions, and vigorous foaming was observed. After the addition was complete, the reactants solidified. Additional anhydrous DMF (6 mL) was added and the resulting slurry was stirred at room temperature for 3 hours. Pure hydroxylamine hydrochloride (3.17 g, 45.7 mmol) was added to form a solution (notice some foaming / heating). The mixture was allowed to stir over the weekend. The reaction mixture was quenched into water (200 mL), resulting in an off-white precipitate, which was filtered and washed with water, followed by drying under vacuum overnight to obtain 4-bromo-3-fluoro-N-hydroxy-benzamide (3.14 g, 58.2% yield).

[MH] ⁺ = 234.1 / 236.1

E2. 4-Bromo-N- (2,2-dimethyl-propanyloxy) -3-fluoro-benzamide

4-Bromo-3-fluoro-N-hydroxybenzidine (3.14 g, 13.42 mmol) was suspended in anhydrous MeCN (25 mL). Pivalic anhydride (2.75 mL, 13.42 mmol) was added and the resulting mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and (100 mL) the extracted with EtOAc (3 × 75mL) was poured into saturated aqueous NaHCO _3. The combined organics were washed with brine, dried (MgSO _4), filtered and concentrated. The crude material was purified by automated flash chromatography load in DCM and isolated with a gradient of 0 to 30% EtOAc / isohexane to give 4-bromo-N- (2,2-dimethyl-propane) as a white powder. (Oxy) -3-fluoro-benzamide (2.56 g, 58.2% yield).

[MH] ⁺ = 318.0 / 320.0

E3. 6-Aminomethyl-5-fluoro-isoquinolin-1-ylamine

6-Aminomethyl-5-fluoro-isoquinolin-1-ylamine was prepared from 4-bromo-N- (2,2-dimethyl-propanyloxy) in 6 steps using the procedure described above ) -3-fluoro-benzamide.

[MH] ⁺ = 192

F. 3-Aminomethyl- [1,7]

Pyridin-8-ylamine dihydrochloride

啶-8-基胺二鹽酸鹽使用上文所述之程序以8個步驟製備自5-溴-3-甲基吡啶甲酸。 3-aminomethyl- [1,7]

Pyridin-8-ylamine dihydrochloride was prepared from 5-bromo-3-methylpicolinic acid in 8 steps using the procedure 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 mmol) in anhydrous MeCN (7 mL) was potassium carbonate (0.677 g, 4.90 mmol), followed by methyl iodide (0.762 mL). , 12.24 mmol) and the mixture was heated at 50 ° C for 5 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc (20 mL) and water (20 mL). The aqueous layer (2 × 20mL) and extracted with additional EtOAc and the combined organics were washed with brine (20mL), dried (MgSO _4), filtered and concentrated to give 4-bromo-3-methoxy-2-methyl - benzene Methyl formate (974 mg, 91% yield).

[MH] ⁺ = 259.0 // 261.0

G2. 4-Bromo-3-methoxy-2-methyl-benzoic 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 heated at 50 ° C for 1.5 hours. The solvent was removed in vacuo and the residue was 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 HCl, a white powder precipitated, which was filtered and dried overnight in vacuo to give 4-bromo-3-methoxy-2-methyl-benzoic acid (805 mg, 87% Yield).

[MH] ⁺ = 244.9 / 246.9

G3. 6-Aminomethyl-5-methoxy-isoquinolin-1-ylamine dihydrochloride

6-Aminomethyl-5-methoxy-isoquinolin-1-ylamine dihydrochloride was prepared from 4-bromo-3-methoxy-2- in 8 steps using the procedure described above. Methyl-benzoic acid.

[MH] ⁺ = 204.0

H1. 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 dropwise bromine (5.80 mL, 113 mmol) in acetic acid ( 20 mL). After half the bromine was added, the reaction mixture solidified due to precipitation. Add additional acetic acid (30 mL) and continue stirring. After the addition was complete, the reaction was allowed to stir for 4 hours. The reaction mixture was filtered to give a light brown filter cake, which was washed with additional acetic acid (30 mL), followed by isohexane (50 mL). The solid was washed in EtOAc (300 mL) followed by NaOH (2M, 200 mL). The organics were washed with brine (200 mL), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give 4-bromo-2-methoxy-6-methyl-phenylamine (20.14 g, 81% yield) .

[MH] ⁺ = 216/218

H2. 4-bromo-2-methoxy-6-methylbenzonitrile

4-Bromo-2-methoxy-6-methylaniline (7g, 32.4mmol) in a 3-neck round bottom flask at 0 ° C over 10 minutes in concentrated HCl (20mL) and water (80g crushed ice) To the stirred suspension was added sodium nitrite (2.347 g, 34.02 mmol) in portions. The internal temperature was maintained at 0 ° C for another 30 minutes. The reaction mixture was neutralized 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 mmol) and sodium cyanide (4.76 g, 97.2 mmol) in water (30 mL) with vigorous stirring. . The reaction was kept at 0 ° C and warmed to room temperature 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 the solvent was removed in vacuo to obtain 4-bromo-2-methoxy-6-methylbenzonitrile (7.02 g, 77% product rate).

H3. 4-bromo-2-methoxy-6-methylbenzamide

To a stirred solution of 4-bromo-2-methoxy-6-methylbenzonitrile (7.05 g, 31.2 mmol) in MeOH (50 mL) was added sodium hydroxide (1.247 g, 31.2 mmol) and heated to 90%. ℃ overnight. The reaction was filled 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 was extracted with DCM (150 mL). The organics were washed with brine (100 mL), then dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by silica gel flash column chromatography and dissolved with isohexane containing 0-100% EtOAc to obtain 4-bromo-2-methoxy-6-methylbenzamide (1.227 g, 15% product rate).

[MH] ⁺ = 244.0 / 246.0

H4. 6-Aminomethyl-8-methoxy-isoquinolin-1-ylamine dihydrochloride

6-Aminomethyl-8-methoxy-isoquinolin-1-ylamine dihydrochloride was prepared from 4-bromo-2-methoxy-6- in 6 steps using the procedure described above. Toluidine.

[MH] ⁺ = 204.2

J1. (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). Pyraldehyde 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 room temperature for 18 hours, after which time the solvent was removed in vacuo to obtain (4-chloro-benzyl)-(2,2-dimethoxy-1-methyl-ethyl) -Amine (1.80 g, 45% yield).

[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 over a period of 10 minutes at -10 ° C. To chlorosulfonic acid (100 mL). The reaction mixture was then stirred at 100 ° C. for 10 minutes, after which time the reaction mixture was cooled and poured into ice and neutralized (to pH 7) with 33% NaOH. Note that the temperature does not rise above 35 ° C. The reaction mixture was extracted with chloroform (3 × 100 mL). The combined organics were washed with water (100mL), washed with brine (100mL), dried (Na ₂ SO ₄₎ 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% yield).

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 were added N-bromosuccinimide (901 mg, 5.07 mmol) and azobisisobutyronitrile (69 mg, 0.42 mmol). The reaction was heated at reflux for 5 hours. The reaction was diluted with DCM, brine was added and the layers were separated. The organic layer was dried over MgSO _4, filtered and concentrated in vacuo. Flash column chromatography (dissociation with petroleum ether: ethyl acetate) gave 3-bromomethyl-6-chloro-isoquinoline (980 mg, 90% yield).

[MH] ⁺ = 255/257

J4. 3-Azidomethyl-6-chloro-isoquinoline

3-Bromomethyl-6-chloro-isoquinoline (980 mg, 3.820 mmol) was dissolved in DMF (20 mL). Add sodium azide (126 mg, 1.95 mmol). The reaction mixture was stirred at room temperature for 18 hours, after which time the reaction mixture was diluted with EtOAc (100 mL). The solution was washed with water (30 mL), brine (30 mL), dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. Flash chromatography (silica) (dissolved with 85% petroleum ether 60-80, 15% EtOAc) gave 3-azidomethyl-6-chloro-isoquinoline (570 mg, 68%).

[MH] ⁺ = 219

J5. C- (6-chloro-isoquinolin-3-yl) -methylamine

3-Azidemethyl-6-chloro-isoquinoline (300 mg, 1.37 mmol) was dissolved in ethanol (50 mL) and acetic acid (1 mL). Zinc powder (180 mg, 2.74 mmol) was added in portions. The reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered through diatomaceous earth and the residue was washed with ethanol (50 mL). The filtrate was evaporated in vacuo, dissolved in CHCl ₃ (150 mL), washed with saturated NaHCO ₃ (30 mL), water (30 mL), brine (30 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give C- (6-chloro-isoquinolin-3-yl) -methylamine (264 mg, 99% yield).

[MH] ⁺ = 193

Intermediate (other):

I. 1- (4-hydroxymethyl-benzyl) -1H-pyridin-2-one

4- (chloromethyl) benzyl alcohol (5.0 g, 31.93 mmol) was dissolved in acetone (150 mL). 2-hydroxypyridine (3.64 g, 38.3 mmol) and potassium carbonate (13.24 g, 95.78 mmol) were added and the reaction mixture was stirred at 50 ° C for 3 hours, after which time the solvent was removed in vacuo and the residue was dissolved in chloroform ( 100 mL). This solution was washed with water (30mL), washed (30mL), brine, dried (Na ₂ SO ₄₎ and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH / 97% CHCl _{3 to} give a white solid, which was identified as 1- (4-hydroxymethyl-benzyl) -1H-pyridine- 2-ketone (5.30 g, 24.62 mmol, 77% yield).

[M + Na] ⁺ = 238

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

1- (4-hydroxymethyl-benzyl) -1H-pyridin-2-one (8.45g, 39.3mmol), anhydrous DCM (80mL) and triethylamine (7.66ml, 55.0mmol) were cooled in an ice bath . Methanesulfonyl chloride (3.95 ml, 51.0 mmol) was added and stirred in an ice bath for 15 minutes. Remove the ice bath and continue stirring overnight at room temperature. The reaction mixture was partitioned between DCM (100 mL) and a saturated aqueous solution of NH ₄ Cl (100 mL). The aqueous layer was extracted with additional DCM (2 x 50 mL) and the combined organics were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give 1- (4-chloromethyl- Benzyl) -1H-pyridin-2-one (8.65 g, 36.6 mmol, 93% yield).

[MH] ⁺ = 234.1

II-2. 1- (4-Bromomethyl-benzyl) -1H-pyridin-2-one

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

[MH] ⁺ = 277.7

V. [4- (4-methyl-pyrazol-1-ylmethyl) -phenyl] -methanol

4- (chloromethyl) benzyl alcohol (5.47 g, 34.9 mmol) was dissolved in acetone (50 mL). 4-methylpyrazole (2.86 g, 34.9 mmol) and potassium carbonate (5.07 g, 36.7 mmol) were added and the reaction mixture was stirred at room temperature for 18 hours and at 60 ° C for 30 hours, after which time in vacuo The solvent was removed and the residue was dissolved in EtOAc (100 mL). This solution was washed with water (30mL), washed (30mL), brine, dried (MgSO ₄₎ and evaporated in vacuo. The residue was purified by flash chromatography (silicon dioxide) with a gradient of 10 to 80% EtOAc / isohexane as the eluent. The fractions were combined and evaporated in vacuo to give a white solid, which was identified as [4- (4-methyl -Pyrazol-1-ylmethyl) -phenyl] -methanol (3.94 g, 18.90 mmol, 54% yield).

[MH] ⁺ = 203

VI. 1- (4-chloromethyl-benzyl) -4-methyl-1H-pyrazole

[4- (4-methyl-pyrazol-1-ylmethyl) -phenyl] -methanol (2.03 g, 10.04 mmol) and triethylamine (1.13 g, 11.54 mmol) were dissolved in DCM (40 mL). To this solution was added dropwise methanesulfonyl chloride (1.26 g, 11.04 mmol). The reaction mixture was stirred at room temperature for 18 hours and diluted with CHCl ₃ (250mL). The mixture was washed with saturated NH ₄ Cl (30 mL), water (30 mL), brine (30 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silicon dioxide) with a gradient of 0 to 60% EtOAc / isohexane eluent, the fractions were combined and evaporated in vacuo to give a white solid, which was identified as 1- (4-chloroform) -Benzyl) -4-methyl-1H-pyrazole (1.49 g, 6.62 mmol, 60% yield).

[MH] ⁺ = 221,223

X. Methyl 5-methoxy-3-pentoxyvalerate

CDI (3.24 g, 20.0 mmol) was added portionwise to a stirred suspension of 3-methoxypropionic acid (1.81 ml, 19.2 mmol) in anhydrous MeCN (80 mL). The mixture was allowed to stir at room temperature for 1.5 hours. A powdery mixture of magnesium chloride (1.57 g, 16.5 mmol) and potassium methylmalonate (4.5 g, 28.8 mmol) was added in portions (note CO ₂ gas evolution). The mixture was allowed to stir at room temperature. The volatiles were removed in vacuo and hydrochloric acid (2M, 105 mL) was added. The solution was stirred at room temperature for 1 hour and extracted with DCM (3 x 100 mL). The organics were dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to obtain methyl 5-methoxy-3-pentoxyvalerate (2.69 g, 87% yield).

XI. 2-((dimethylamino) methylene) -5-methoxy-3- pendant valeric acid (Z) -methyl ester

Make 5-methoxy-3-pentoxyvaleric acid methyl ester (2.69g, 16.8mmol) and 1,1-dimethoxy-N, N-dimethylmethylamine (2.68ml, 20.2mmol) The mixture was stirred at room temperature overnight. The reaction mixture was reduced in vacuo and azeotroped with toluene (30 mL) to obtain crude 2-((dimethylamino) methylene) -5-methoxy-3- pendanopentanoic acid (Z) -methyl ester , Which was used without further purification.

XII. 3- (2-methoxyethyl) -1H-pyrazole-4-carboxylic acid methyl ester

To a stirred solution of 2-((dimethylamino) methylene) -5-methoxy-3-pentoxyvaleric acid (Z) -methyl ester (3.62 g, 16.82 mmol) in ethanol (50 mL) Add hydrazine hydrate (1.89 ml, 25.2 mmol) and heat to reflux for 4 hours. The reaction mixture was cooled to rt and diluted with EtOAc (200mL), (200mL aqueous solution), washed with NaHCO ₃ followed by brine (2 × 100mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 3- (2-methoxyethyl) -1H-pyrazole-4-carboxylic acid methyl ester (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 anhydrous DCM (20 mL) under a N ₂ atmosphere and PBr ₃ (276 μL, 2.94 mmol) was added. Anhydrous DMF (4 mL) was added and the reaction was stirred at room temperature for 2 hours. With dilute NaHCO ₃ (saturated diluted to 10%) (50mL) The reaction mixture was quenched. After stirring for 15 minutes, until foaming ceased, the layers were separated and the aqueous solution was adjusted to pH = 0 using 2M HCl. The precipitate was collected by vacuum filtration, washed with water and dried in an oven to obtain 4-bromomethyl-2-fluoro-benzoic acid (420 mg, 61% yield).

XVI. (4-bromomethyl-2-fluoro-phenyl) -methanol

4-Bromomethyl-2-fluoro-benzoic acid (420 mg, 1.80 mmol) was dissolved in anhydrous THF (20 mL) and cooled to -20 ° C. To this solution were added triethylamine (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 mmol) in water (2 mL) at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with EtOAc (200 mL) and the layers were separated. The organic layer was washed with 0.3M KHSO ₄ (50 mL), water (50 mL), brine (50 mL), dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo. The solid was purified by flash column chromatography on silica gel and dissolved with EtOAc / petroleum ether (85:15) to give (4-bromomethyl-2-fluoro-phenyl) -methanol.

XVII. (2-fluoro-4-pyrazol-1-ylmethyl-phenyl) -methanol

(4-Bromomethyl-2-fluoro-phenyl) -methanol (108 mg, 0.49 mmol) and pyrazole (37 mg, 0.54 mmol) were dissolved in MeCN (10 mL). K ₂ CO ₃ (136 mg, 0.99 mmol) was added and the reaction was heated to 50 ° C. The volatiles were removed in vacuo. EtOAc (60 mL) and water (20 mL) were added. The organic layer was dried, filtered and evaporated in vacuo. Purification by automated FC, gradient separation with a step of petroleum ether containing up to 50% EtOAc to obtain (2-fluoro-4-pyrazol-1-ylmethyl-phenyl) -methanol (94 mg, 94% yield) .

[MH] ⁺ = 206.7

XVIII. 1- (4-bromomethyl-3-fluoro-benzyl) -1H-pyrazole

(2-Fluoro-4-pyrazol-1-ylmethyl-phenyl) -methanol (94 mg, 0.46 mmol) was dissolved in anhydrous DCM (5 mL) under a N ₂ atmosphere. PBr ₃ (43 μL, 0.46 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture (diluted with saturated to 10%) (10mL) quenched layers were separated and washed with water (10 mL) and brine (10 mL) organics were washed with dilute NaHCO _3. The (Na ₂ SO ₄ ) organic layer was dried, filtered and concentrated in vacuo to obtain 1- (4-bromomethyl-3-fluoro-benzyl) -1H-pyrazole (80 mg, 65% yield).

[MH] ⁺ = 206.7

XX. 3-Phenoxy-2,3-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester

A solution of diethyl 2- (ethoxymethylene) malonate (40 g, 185 mmol) in absolute ethanol (400 mL) was treated with dropwise hydrazine hydrate (8.99 ml, 185 mmol). After approximately 20 minutes, 2N NaOH (25 mL) was slowly added (the reaction in an ice bath), followed by water (25 mL). The ice bath was removed and the mixture was stirred at room temperature for 1.5 hours. The ethanol was removed in vacuo and the aqueous layer was diluted with water (25 mL) and partitioned into EtOAc (100 mL). The aqueous layer was collected and cooled in an ice bath. The pH was adjusted to 5 with 1M HCl and a precipitate formed. The precipitate was filtered, washed with water and dried under vacuum in the presence of CaCl ₂ to obtain 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester (22.31 g, 76% yield ).

[MH] ⁺ = 157.1

XXI. 1-Ethyl-3-yloxy-2,3-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester

Acetic anhydride (13.50 ml, 143 mmol) was added to a suspension of 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester (22.30 g, 143 mmol) in acetic acid (185 mL) . The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The remaining solids were triturated from water (200 mL) and filtered and washed with water. The product was dried in a vacuum in the presence of CaCl ₂ to obtain 1-ethylfluorenyl-3- pendantoxy-2,3-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester (27.39 g, 94% yield rate).

[MH] ⁺ = 199.2

XXII. 3- (2-methoxyethoxy) -1H-pyrazole-4-carboxylic acid ethyl ester

To a stirred solution of 1-acetamido-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester (2.0 g, 10.09 mmol) in DMF (10 mL) was added 1- Bromo-2-methoxyethane (0.948 ml, 10.09 mmol) and K ₂ CO ₃ (1.395 g, 10.09 mmol) and heated to 70 ° C. for 5 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc (100 mL) and washed with water (100 mL). The organic phase was dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The material was taken up in MeOH (20 mL) and K ₂ CO ₃ (1.395 g, 10.09 mmol) was added and stirred overnight at room temperature. The mixture was diluted with water (30 mL) and the product was extracted with EtOAc (2 x 50 mL). The organics were washed with brine (20 mL), dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give 3- (2-methoxyethoxy) -1H-pyrazole-4-carboxylic acid ethyl ester (700 mg, 25.9 %Yield).

[MH] ⁺ = 215.2

Example: Example 1. N-((1-aminoisoquinolin-6-yl) methyl) -3- (methoxymethyl) -1-((6- (pyrrolidin-1-yl) pyridin-3-yl) (Methyl) -1H-pyrazole-4-carboxamide dihydrochloride

1-((6-fluoropyridin-3-yl) methyl) -3- (methoxymethyl) -1H-pyrazole-4-carboxylic acid methyl ester

3- (methoxymethyl) -1H-pyrazole-4-carboxylic acid methyl ester (758mg, 4.45mmol); CAS number 318496-66-1 (synthesized according to the method described in WO 2012/009009) and 5 -To a stirred solution of (chloromethyl) -2-fluoropyridine (778 mg, 5.34 mmol) in DMF (8 mL) was added K ₂ CO ₃ (1231 mg, 8.91 mmol) and kept at room temperature overnight. The reaction mixture was diluted with EtOAc (150 mL) and washed with brine (2 x 100 mL), dried over magnesium sulfate, filtered, and the solvent was removed. The crude product was purified by automated FC 0-60% (3: 1 EtOAc: MeCN) in isohexane) to obtain:

Isomer 1: 1-((6-fluoropyridin-3-yl) methyl) -5- (methoxymethyl) -1H-pyrazole-4-carboxylic acid methyl ester (348 mg, 27.4%).

MH ⁺ = 280.1

Isomer 2: 1-((6-fluoropyridin-3-yl) methyl) -3- (methoxymethyl) -1H-pyrazole-4-carboxylic acid methyl ester (749mg, 59.0%)

MH ⁺ = 280.1

1-((6-fluoropyridin-3-yl) methyl) -3- (methoxymethyl) -1H-pyrazole-4-carboxylic acid

The title compound (309 mg, 46.1%) was obtained by a general saponification method of lithium hydroxide.

MH ⁺ = 266.1

3- (methoxymethyl) -1-((6- (pyrrolidin-1-yl) pyridin-3-yl) methyl) -1H-pyrazole-4-carboxylic acid

1-((6-fluoropyridin-3-yl) methyl) -3- (methoxymethyl) -1H-pyrazole-4-carboxylic acid (305 mg, 1.15 mmol) in anhydrous dioxane (1 mL) The solution was treated with pyrrolidine (236 μl, 2.87 mmol) and the mixture was heated at 100 ° C. overnight. The solvent was removed under vacuum. The mixture was partitioned between EtOAc (10 mL) and water (10 mL, containing 2N NaOH, to pH 14). The aqueous layer was extracted with additional EtOAc (3 x 15 mL) and the combined organics were discarded. The aqueous layer was adjusted to pH 4/5 with 1M HCl. The aqueous layer was purified by SCX (10 g), washed with MeOH, and dissolved with 1% NH ₃ / MeOH to obtain 3- (methoxymethyl) -1-((6- (pyrrolidin-1-yl) pyridine- 3-yl) methyl) -1H-pyrazole-4-carboxylic acid (336 mg, 0.882 mmol, 77% yield).

MH ⁺ = 317.2

N-((1-aminoisoquinolin-6-yl) methyl) -3- (methoxymethyl) -1-((6- (pyrrolidin-1-yl) pyridin-3-yl) (Methyl) -1H-pyrazole-4-carboxamide dihydrochloride

The amidine formation method A is used to form amidine. The product was treated with 4M HCl in dioxane to obtain the HCl salt of the title compound (90 mg, 0.164 mmol, 16.9% yield).

MH ⁺ = 472.3

¹ H 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-((1-aminoisoquinolin-6-yl) methyl) -3- (methoxymethyl) -1-((5-((4-methyl-1H-pyrazole-1- Yl) methyl) pyridin-2-yl) methyl) -1H-pyrazole-4-carboxamide

5- (chloromethyl) -2-methylpyridine

A solution of (6-methylpyridin-3-yl) methanol (5.04 g, 40.9 mmol) and triethylamine (7.99 ml, 57.3 mmol) in anhydrous DCM (85 mL) was cooled in an ice bath, and then formazan was added dropwise. Sulfonium chloride (4.12 ml, 53.2 mmol). After the addition was complete, the ice bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM (100mL) and saturated aqueous NaHCO ₃ (150mL). The aqueous layer was extracted with additional DCM (2 × 50 mL) and the combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 5- (chloromethyl) -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

Stir 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 N ₂ To the solution was added potassium carbonate (7.50 g, 54.2 mmol) and the suspension was 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 solution was extracted with EtOAc (2 x 150 mL). The combined organic layers were dried (MgSO _4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with a gradient of 50 to 100% EtOAc / isohexane to give 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-pyrazol-1-yl) methyl) pyridine-1-oxide

A solution of 2-methyl-5-((4-methyl-1H-pyrazol-1-yl) methyl) pyridine (0.50 g, 2.67 mmol) in chloroform (15 mL) was treated with 3-chloroperoxybenzoic acid (1.11 g, 3.20 mmol). The mixture was allowed to stir at room temperature for 2 hours. 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 was stirred for 20 minutes, a suspension was formed and water (5 mL) was added. The layers were separated and the organics were collected. The aqueous solution was extracted with chloroform (2 × 20 mL) and the combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 2-methyl-5-((4-methyl-1H-pyrazole-1) -Yl) methyl) pyridine 1-oxide (467 mg, 84% yield).

MH ⁺ = 204

(5-((4-methyl-1H-pyrazol-1-yl) methyl) pyridin-2-yl) acetic acid methyl ester

A solution of 2-methyl-5-((4-methyl-1H-pyrazol-1-yl) methyl) pyridine 1-oxide (467 mg, 2.30 mmol) in acetic anhydride (9770 μl, 103 mmol) was heated to 95 ° C (bath temperature) and the mixture was stirred for 2 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography, loaded in dichloromethane and eluted with a gradient of 50 to 100% EtOAc / isohexane to give acetic acid (5-((4-methyl-1H- Pyrazol-1-yl) methyl) pyridin-2-yl) methyl ester (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 mmol) in MeOH (8 mL) was used with potassium carbonate (471 mg , 3.41 mmol) in water (2 mL) and the mixture was stirred at room temperature for 2 hours. The MeOH was removed in vacuo and the residue was partitioned between EtOAc (20 mL) and water (8 mL). A saturated aqueous NH ₄ Cl solution was added to about pH 9 and the organic layer was collected. The aqueous solution was extracted with additional EtOAc (2 × 20 mL) and the combined organics were dried (MgSO ₄ ), filtered and concentrated in vacuo to give (5- ((4-methyl-1H-pyrazol-1-yl) formaldehyde Yl) pyridin-2-yl) methanol (262 mg, 82% yield).

MH ⁺ = 203.9

2- (chloromethyl) -5-((4-methyl-1H-pyrazol-1-yl) methyl) pyridine

Prepared using the procedure for 1-(-chloromethyl-benzyl) -4-methyl-1H-pyrazole.

N-((1-aminoisoquinolin-6-yl) methyl) -3- (methoxymethyl) -1-((5-((4-methyl-1H-pyrazole-1- Yl) methyl) pyridin-2-yl) methyl) -1H-pyrazole-4-carboxamide

Prepared from 2- (chloromethyl) -5-((4-methyl-1H-pyrazol-1-yl) methyl) pyridine, 3- (methoxymethyl) -1H-pyrazole-4-carboxylic acid methyl ester and 6-aminomethyl-isoquinolin-1-ylamine hydrochloride.

MH ⁺ = 497.2

¹ 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] -1H-pyrazole-4-carboxylic acid ( 1-amino-isoquinolin-6-ylmethyl) -fluorenamine

(6-chloro-5-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 LiAlH ₄ (104 mg, 2.73 mmol ). The reaction was warmed to room temperature. 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 solution was extracted with EtOAc (20 mL). With brine (50ml) the organic layers were washed, dried over MgSO _4, and solvent was removed in vacuo. The residue was purified by automated FC (EtOAc / petroleum) to obtain (6-chloro-5-methoxy-pyridin-3-yl) -methanol (710 mg, 82% yield).

[MH] ⁺ = 173.7

5-bromomethyl-2-chloro-3-methoxy-pyridine

(6-Chloro-5-methoxy-pyridin-3-yl) -methanol (710 mg, 4.09 mmol) was dissolved in anhydrous DCM (15 mL) under a N ₂ atmosphere. PBr ₃ (384 mL, 4.09 mmol) was added and the reaction was stirred at room temperature. The reaction mixture was diluted with aqueous NaHCO ₃ (10%, 10mL) and quenched. The layers were separated and the organic layer was washed with water (10 mL) and brine (10 mL). The organic layer was dried (Na ₂ SO _4), filtered and concentrated in vacuo. The residue was purified by automated FC and isolated with (EtOAc / petroleum) to obtain 5-bromomethyl-2-chloro-3-methoxy-pyridine (851 mg, 88% yield).

[MH] ⁺ = 238.0

1- (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 (139.7 mg, 0.85 mmol) was dissolved in DMF and treated with potassium carbonate (233.8 mg, 1.69 mmol). 5-Bromomethyl-2-chloro-3-methoxy-pyridine (200 mg, 0.85 mmol) was added and the reaction was stirred at room temperature overnight. Dilute with DCM (30 mL) and wash with water (10 mL). The organic layer was washed with NaHCO ₃ (1 × 10ml), washed (10ml), brine, dried (MgSO _4), filtered and evaporated in vacuo. Purification of the residue by automated FC (EtOAc / petroleum) gave 1- (6-chloro-5-methoxy-pyridin-3-ylmethyl) -3-cyano-1H-pyrazole-4-carboxylic acid ethyl Esters (157 mg, 68% yield).

[MH] ⁺ = 321.1

3-cyano-1- [6- (3,3-difluoro-pyrrolidin-1-yl) -5-methoxy-pyridin-3-ylmethyl] -1H-pyrazole-4-carboxylic acid ethyl ester

1- (6-Chloro-5-methoxy-pyridin-3-ylmethyl) -3-cyano-1H-pyrazole-4-carboxylic acid ethyl ester (41 mg, 0.13 mmol) in 1,4-bis To the suspension in oxane (1 mL) was added 3,3-difluoropyrrolidine hydrochloride (73.4 mg, 0.51 mmol) and Et ₃ N (142.5 mL, 1.02 mmol). The reaction was heated at 125 ° C. The reaction mixture was concentrated and purified by automated FC to obtain 3-cyano-1- [6- (3,3-difluoro-pyrrolidin-1-yl) -5-methoxy-pyridin-3-ylmethyl Ethyl] -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-difluoro-pyrrolidin-1-yl) -5-methoxy-pyridin-3-ylmethyl]-dissolved in THF (10 mL) To 1H-pyrazole-4-carboxylic acid ethyl ester (40 mg, 0.10 mmol) was added water (1 mL) containing lithium monohydrate (12 mg, 0.13 mmol). The reaction mixture was stirred at 50 ° C. NaOH (41 mg, 1.02 mmol) was added and stirring was continued at 50 ° C for 6 hours. The reaction was concentrated to dryness in vacuo and acidified with 2M HCl to about 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 give 3-cyano-1- [6- (3,3-difluoro-pyrrolidin-1-yl) -5-methoxy-pyridin-3-ylmethyl Group] -1H-pyrazole-4-carboxylic acid.

[MH] ⁺ = 364

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) -fluorenamine

Prepared from 3-cyano-1- [6- (3,3-difluoro-pyrrolidin-1-yl) -5-methoxy-pyridin-3-ylmethyl] -1H using amidine formation method A -Pyrazole-4-carboxylic acid and 6-aminomethyl-isoquinolin-1-ylamine hydrochloride.

[MH] ⁺ = 519.0

¹ H NMR (d6-DMSO): δ 2.42 (2H, dd, J = 14.4,7.3Hz), 3.73 (2H, t, J = 7.2Hz), 3.75 (3H, s), 3.93 (2H, t, J = 13.7Hz), 4.61 (2H, d, J = 5.8 Hz), 5.38 (2H, s), 7.21-7.24 (1H, m), 7.25 (1H, d, J = 1.8Hz), 7.65 (1H, d , J = 7.0Hz), 7.70 (1H, dd, J = 8.6,1.7Hz), 7.82-7.83 (2H, m), 8.46 (1H, s), 8.50 (1H, d, J = 8.7Hz), 8.92 (2H, br.s), 9.11 (1H, t, J = 5.9Hz), 12.82 (1H, br.s)

Example 4. 3-methoxymethyl-1- (4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) ) -Amidine

1- (4-((1H-pyrazol-1-yl) methyl) benzyl) -3- (methoxymethyl) -1H-pyrazole-4-carboxylic acid methyl ester

To methyl 3- (methoxymethyl) -1H-pyrazole-4-carboxylic acid (470 mg, 2.76 mmol) and 1- (4- (chloromethyl) benzyl) -1H-pyrazole (571 mg, 2.76 mmol) To a stirred suspension in DMF (2.5 mL) was added potassium carbonate (763 mg, 5.52 mmol) and the mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc (30 mL) and water (25 mL) containing brine (25 mL). The aqueous layer was extracted with additional EtOAc (2 × 30mL) and the combined organics were dried (MgSO _4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography, loaded in dichloromethane, and separated with a gradient of 0 to 100% EtOAc / isohexane, kept at 70% to dissolve 1- (4-((1H-pyrazol-1-yl ) Methyl) benzyl) -5- (methoxymethyl) -1H-pyrazole-4-carboxylic acid methyl ester (232 mg, 21.0% yield), then maintained at 85% to dissolve 1- (4- ((1H-pyrazol-1-yl) methyl) benzyl) -3- (methoxymethyl) -1H-pyrazole-4-carboxylic acid methyl ester (494 mg, 52.0% yield).

[MH] ⁺ = 341.1

3-methoxymethyl-1- (4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) ) -Amidine

Prepared from 1- (4-((1H-pyrazol-1-yl) methyl) benzyl) -3- (methoxymethyl) -1H- Pyrazole-4-carboxylic acid methyl ester and 6-aminomethyl-isoquinolin-1-ylamine hydrochloride.

[MH] ⁺ = 482.3

¹ H 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-isoquinolin-6-yl Methyl) -amidine

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 were 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 hours at 95 ° C, the reaction mixture was diluted with CHCl ₃ (150 mL). This solution was washed with saturated NaHCO ₃ (1 × 50 mL), water (1 × 50 mL), brine (1 × 50 mL), and dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 15% EtOAc, 85% petroleum ether, the fractions were combined and evaporated in vacuo to give a yellow oil, which was identified as 5-bromomethyl-2-chloro -Pyridine (1.64 g, 34%).

MH ⁺ = 207.8

1- (2-Chloro-pyrimidin-5-ylmethyl) -3-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester

Methyl 3- (methoxymethyl) -1H-pyrazole-4-carboxylic acid (2.01 g, 11.83 mmol); CAS number 318496-66-1 (synthesized according to the method described in WO 2012/009009) and To a stirred solution of 5-bromomethyl-2-chloro-pyridine (2.70 g, 13.1 mmol) in DMF (8 mL) was added K ₂ CO ₃ (3.27 g, 23.7 mmol) and kept at room temperature overnight. The reaction mixture was diluted with EtOAc (150 mL) and washed with brine (2 x 100 mL), dried over magnesium sulfate, filtered, and the solvent was removed. The crude product was purified by automated FC (petroleum ether containing 0-60% (1: 1 EtOAc: MeCN)) to obtain isomers 1 and 2:

Isomer 1: 1- (2-chloro-pyrimidin-5-ylmethyl) -5-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester (420 mg, 12%); MH ⁺ = 296.7

Isomer 2: 1- (2-chloro-pyrimidin-5-ylmethyl) -3-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester (638 mg, 18%); MH ⁺ = 296.7

3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid methyl ester

1- (2-Chloro-pyrimidin-5-ylmethyl) -3-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester (418 mg, 1.41 mmol) in anhydrous dioxane (1 mL) The solution was treated with pyrrolidine (1.2 mL, 14.1 mmol) and the mixture was heated at 100 ° C overnight. The solvent was removed under vacuum. Purification of the residue by automated FC (petroleum ether with 0-60% EtOAc) gave 3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H -Methyl pyrazole-4-carboxylic acid (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

The general saponification method of sodium hydroxide was used to obtain the title compound (250 mg, 0.79 mmol, 90%).

MH ⁺ = 317.9

3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-yl Methyl) -amidine

The amidine formation method A is used to form amidine. Purification by flash chromatography (silicon dioxide), eluent 15% methanol, 84% dichloromethane, 1% NH ₄ OH, combined fractions and evaporation in vacuo to give a white solid, identified as 3-methoxy Methyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)- Amidine (163 mg, 0.35 mmol, 44% yield).

MH ⁺ = 473.0

¹ H NMR (DMSO): 1.88-1.94 (4H, m), 3.22 (3H, s), 3.44-3.45 (4H, m), 4.53 (2H, d, J = 5.8Hz), 4.56 (2H, s) , 5.15 (2H, s), 6.82 (2H, br.s), 6.87 (1H, d, J = 5.9Hz), 7.39 (1H, d, J = 8.6Hz), 7.54 (1H, s), 7.75 ( 1H, d, J = 5.9Hz), 8.15 (1H, d, J = 8.3Hz), 8.23 (1H, s), 8.38 (2H, s), 8.46 (1H, t, J = 5.8Hz)

Route B 2- (Pyrrolidin-1-yl) pyrimidin-5-carboxylic acid ethyl ester

Ethyl 2-chloropyrimidine-5-carboxylate (300 g, 1.6 mol) was stirred in an ice / water bath containing 1,4-dioxane (3000 mL). Pyrrolidine (375 mL, 4.5 mol) was added and the mixture was stirred at room temperature for 3 hours. 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 a vacuum oven at approximately 45 ° C to give a yellow solid, which was identified as 2- (pyrrolidin-1-yl) pyrimidine-5-carboxylic acid ethyl ester (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 mole) in N ₂ at 0 ° C was added diisobutyl hydrogenation at 0 ° C. A solution of aluminum in hexane (1.0 M solution, 950 mL, 0.95 mole). Water (40 mL) was carefully added to the reaction mixture, followed by 15% aqueous sodium hydroxide solution (40 mL) and finally water (100 mL). Sodium sulfate (about 200 g) was added and the mixture was stirred at room temperature for another 18 hours. The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give a pale yellow solid, which was identified as (2- (pyrrolidin-1-yl) pyrimidin-5-yl) methanol (81.0 g, 100% yield).

MH ⁺ = 180.1

2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl acetate

To a stirred solution of (2- (pyrrolidin-1-yl) pyrimidin-5-yl) methanol (89.1 g, 0.50 mole) at 20 ° C in anhydrous DCM (900 mL) was added 4- (dimethylamino) ) Pyridine (3.05 g, 0.025 mole), followed by acetic anhydride (50.8 g, 0.50 mole). The mixture was stirred at ambient temperature for another 18 hours. Water (700 mL) was added and the aqueous phase was extracted with DCM (500 mL) and the combined organics were dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a pale yellow solid, which was identified as 2-pyrrolidin-1-yl acetate- Pyrimidin-5-ylmethyl ester (110 g, 100% yield).

MH ⁺ = 221.8

3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid methyl ester

2-Pyrrolidin-1-yl-pyrimidin-5-ylmethyl acetate (112.3g, 0.51mol) and methyl 3- (methoxymethyl) -1H-pyrazole-4-carboxylic acid (CAS No. 318496) -66-1, synthesized according to the method described in WO 2012/009009) (86.3 g, 0.51 mol) was combined in acetonitrile (1500 mL). Trimethylsilyl trifluoromethanesulfonate (110.3 mL, 0.61 ml) was added. The mixture was heated to 65-70 ° C for 3 hours and then allowed to cool. The reaction mixture was concentrated and separated between EtOAc (1500 mL) and a saturated aqueous sodium bicarbonate solution (1000 mL). The organics were washed with a saturated aqueous solution of sodium bicarbonate (750 mL), and washed with saturated brine (1000 mL). Dry over sodium sulfate, filter, and concentrate 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 resulting solid was filtered. The filtrate was concentrated to give a beige solid, which was identified as 3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid methyl ester and A mixture of 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-pyrazole-4-carboxylic acid

Add 3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid methyl ester and 5-methoxymethyl-1 A mixture of (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). Water (82 mL) containing potassium hydroxide (23.9 g, 0.43 mol) was added. The mixture was heated to 55-60 ° C for 1 hour and allowed to cool. Most 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 was stirred for 1 hour. The resulting solid was collected by filtration. The filtrate was cooled in an ice / water bath and glacial acetic acid (23 mL, 0.40 mol) was added. After 1 hour, the resulting solid was collected on top of the aforementioned filter cake. The combined solids were washed with cold ethanol and dried in vacuo. The solid was dissolved in hot ethanol and cooled to room temperature. The resulting solid was filtered and washed with cold ethanol (2 x 150 mL). The solid was dissolved in hot ethanol and cooled to room temperature. The resulting solid product was filtered, washed with cold ethanol and tert-butyl methyl ether, and dried in vacuo to obtain a white solid, which was identified as 3- (methoxymethyl) -1-((2- (pyrrolidine- 1-yl) pyrimidin-5-yl) methyl) -1H-pyrazole-4-carboxylic acid (49 g).

MH ⁺ = 317.7

3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-yl Methyl) -amidine

1,1'-carbonyldiimidazole (26.1 g, 0.161 mole) added to 3- (methoxymethyl) -1-((2- (pyrrolidin-1-yl) pyrimidin-5-yl) methyl ) -1H-pyrazole-4-carboxylic acid (51.1 g, 0.161 mole) at In a suspension in N-methylpyrrolidone (200 mL) and stirred for 3 hours, a fluorenylimidazole intermediate was obtained. 6- (Aminemethyl) isoquinolin-1-amine dihydrochloride (47.5g, 0.193 mole) was suspended in N-methylpyrrolidone (240mL) and heated to 55 ° C-60 ° C. Triethylamine (102 mL, 0.73 moles) was added and the mixture was stirred for 1 hour, cooled and stirred for another 1.5 hours. The fluorenyl imidazolium intermediate formed above was added in one portion and stirred for 18 hours. The reaction mixture was poured into water (5000 mL) and stirred for 1.5 hours. 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, which was identified as 3-methoxymethyl- 1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -fluorenamine (70.8 g, 93% yield).

MH ⁺ = 473.0

Example 64. 1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo [2,3- b) pyridin-5-ylmethyl) -amidamine

1- (2-Chloro-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.25 g, 6.01 mmol) 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 room temperature for 3 hours. After this time, the reaction mixture was stirred with EtOAc ( 100 mL), diluted with water (1 × 30 mL), brine (1 × 30 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 60% petroleum ether, 40% EtOAc to give a yellow oil, which was identified as 1- (2-chloro-pyrimidin-5-ylmethyl) -3- Trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (710 mg, 35%).

MH ⁺ = 375.8 (MH ⁺ + MeCN)

1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

1- (2-Chloro-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (700 mg, 2.09 mmol) was dissolved in anhydrous dioxane (25 mL) and pyrrole Pyridine (10 mL) and the reaction mixture was stirred at 80 ° C. for 18 hours, after which time the reaction mixture was evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 97% CHCl _{3 to} give a yellow solid, which was identified as 1- (2-pyrrolidin-1-yl-pyrimidine-5-ylmethyl Ethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (760 mg, 99% yield).

MH ⁺ = 369.0

1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid

1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (596 mg, 85% Yield).

MH ⁺ = 341.8

1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1H-pyrrolo [2,3-b] pyridine- 5-ylmethyl) -amidamine

1- (2-Pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -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-Aminomethylazaindole (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 hours at 0 ℃ to room temperature, the reaction mixture was diluted with chloroform (200 mL), with NaHCO ₃ (1 × 30mL), water (1 × 30mL), brine (1 × 30mL) was washed and evaporated in vacuo. The residue was purified by flash chromatography (silicon dioxide) with eluent 6% MeOH, 94% CHCl _{3 to} give a white solid, which was identified as 1- (2-pyrrolidin-1-yl-pyrimidine-5-ylmethyl) ) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine (620 mg, 75% yield).

MH ⁺ = 470.9

1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo [2,3- b) pyridin-5-ylmethyl) -amidamine

1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (1H-pyrrolo [2,3-b] pyridine- 5-ylmethyl) -fluorenamine (500 mg, 1.06 mmol) was dissolved in acetonitrile (50 mL). To this solution was added N-chlorobutanediimine (149 mg, 1.12 mmol). The reaction mixture was stirred at reflux for 7 hours. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL), washed with saturated NaHCO ₃ (1 × 20 mL), water (1 × 20 mL), brine (1 × 20 mL), dried (Na ₂ SO ₄ ) and Evaporate in vacuo. By flash chromatography (silicon dioxide), eluent 6% MeOH, 94% CHCl ₃ Purification of the residue. The resulting material was dissolved in chloroform (100 mL) and this solution was washed with saturated NaHCO ₃ (1 × 20 mL), water (1 × 20 mL), brine (1 × 20 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo, A white solid was obtained, which was identified as 1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H- Pyrrolop [2,3-b] pyridin-5-ylmethyl) -fluorenamine (430 mg, 80% yield).

MH ⁺ = 505.0

¹ H NMR (DMSO): 1.89-1.93 (4H, m), 3.44-3.47 (4H, m), 4.49 (2H, d, J = 5.8Hz), 5.26 (2H, s), 7.66 (1H, d, J = 2.7Hz), 7.82 (1H, d, J = 1.5Hz), 8.27 (1H, d, J = 1.9Hz), 8.36 (1H, s), 8.41 (2H, s), 8.77 (1H, t, J = 5.6Hz), 11.93 (1H, s)

Biological method

The ability of a compound to inhibit plasma kallikrein can be determined using the following bioassays:

IC for Plasma Kallikrein ₅₀ value

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

The data obtained from these analyses are shown in Table 12.

The compounds selected were further screened for their inhibitory activity on the related enzyme KLK1. The ability of a compound of formula (I) to inhibit KLK1 can be determined using the following biological analysis:

Determination of KLK1 IC ₅₀ value

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

The data obtained from this analysis are shown in Table 12.

Determination of enzyme selectivity

The selected compounds were further screened for the inhibitory activity against other trypsin-like serine proteases using an appropriate enzyme and chromogenix AB. Tested against the following human enzymes (substances in parentheses):-thrombin (S-2238), plasmin (S-2390) and trypsin (S-2222). Enzymes and chromogenic substrates were incubated at 25 ° C. Residual enzyme activity (initial reaction rate) was measured by measuring the change in absorbance at 405 nm.

The data obtained from these analyses are shown in Table 13.

Pharmacokinetics

The pharmacokinetic studies of the compounds in Table 14 were performed to evaluate the pharmacokinetics after a single oral administration in male Sprague-Dawley rats. A single oral dose of 5 mL / kg was administered to two rats at a nominal 2 mg / mL (10 mg / kg) test compound in 10% DMSO / 10% cetyl alcohol polyoxyethylene ether / 80% sterile water for injection. After administration, blood samples were collected over a period of 24 hours. Sampling times were 5, 15, and 30 minutes, followed by 1, 2, 4, 6, 8, and 12 hours. After collection, blood samples were centrifuged, and the concentration of test compounds in the plasma fraction was analyzed by LCMS. The oral exposure data obtained from these studies show the following:

* Example 64 is formulated in 20% Labrasol (aqueous solution)

Claims (14)

A compound, It is 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-pyrazole-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-isoquinoline-6-ylmethyl) ) -Amidamine; 3-methoxymethyl-1- (4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) ) -Amidine; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine -3-yl] methyl} pyrazole-4-carboxamide; N-[(1-amino-5-fluoroisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine- 3-yl] methyl} pyrazole-4-carboxamide; N-[(1-amino-5-methoxyisoquinolin-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-yl Methyl) -amidine; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine -5-yl] methyl} pyrazole-4-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine- 5-yl] methyl} pyrazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-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) pyrimidine -5-yl] methyl} pyrazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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) pyrimidine- 5-yl] methyl} pyrazole-4-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) Pyrimidin-5-yl] methyl} pyrazole-4-carboxamide; 1- [2- (3, 3-difluoro-pyrrolidin-1-yl) -pyrimidin-5-ylmethyl] -3-methoxymethyl-1H-pyrazole-4-carboxylic acid (1-amino-isoquinoline-6- Methyl) -amidine; 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-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -3- (methoxymethyl) pyrazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-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-difluoropyrrolidin-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-methoxyisoquinolin-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-isoquine Phenyl-6-ylmethyl) -amidamine; 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-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl Yl) phenyl] methyl} pyrazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl Yl) 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-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl Yl) phenyl] methyl} pyrazole-4-carboxamide; 3-ethoxymethyl-1- (4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl ) -Amidine; N-[(1-aminoisoquinolin-6-yl) methyl] -1-{[2- (pyrazol-1-ylmethyl) pyrimidin-5-yl] methyl} -3- (tri Fluoromethyl) pyrazole-4-carboxamide; N-[(1-aminoisoquinolin-6-yl) methyl] -1-({3-fluoro-4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl Yl) -3- (methoxymethyl) pyrazole-4-carboxamide; N-[(1-aminoisoquinolin-6-yl) methyl] -1-({2-fluoro-4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl Yl) -3- (methoxymethyl) pyrazole-4-carboxamide; 3-cyclopropyl-1- (2-fluoro-4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-yl Methyl) -amidine; 3-cyclopropyl-1- [4- (4-fluoro-pyrazol-1-ylmethyl) -benzyl] -1H-pyrazole-4-carboxylic acid (1-amino-isoquinoline-6 -Methyl) -amidamine; 1- [4- (4-fluoro-pyrazol-1-ylmethyl) -benzyl] -3-methoxymethyl-1H-pyrazole-4-carboxylic acid (1-amino-isoquinoline -6-ylmethyl) -amidamine; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl Yl) -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-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -3- (methoxymethyl) pyrazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-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-methoxyisoquinolin-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 Yl) -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-methylpyrazole-1 -Yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole-1 -Yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole- 1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-amino-7-methylisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazole- 1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; 1- (6-pyrrolidin-1-yl-pyridin-3-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo [2, 3-b] pyridin-5-ylmethyl) -amidamine; 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 -Formamidine; 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; 1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo [2, 3-b] pyridin-5-ylmethyl) -amidamine; 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-formamidine 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- Formamidine N-({5-chloro-7H-pyrrolo [2, 3-b] pyridin-3-yl} methyl) -1-({6- [isopropyl (methyl) amino] pyridin-3-yl} methyl) -3- (trifluoromethyl) pyridine Azole-4-methylamidine; 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-pyrrole And [2, 3-b] pyridin-5-ylmethyl) -amidamine; 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) -amidamine; 3-amino-N-({3-chloro-1H-pyrrolo [2, 3-b] pyridin-5-yl} methyl) -1-({4-[(4-methylpyrazol-1-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-side oxypyridin-1-yl) methyl] phenyl } Methyl) pyrazole-4-carboxamide; 3-amino-N-[(3-chloro-1H-indazol-5-yl) methyl] -1-({4-[(2-side oxypyridin-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-side oxypyridin-1-yl) methyl] phenyl} methyl) pyrazole 4-formamidine N-({3-fluoro-1H-pyrrolo [2, 3-b] pyridin-5-yl} methyl) -3- (methoxymethyl) -1-({4-[(2- pendant oxypyridin-1-yl) methyl] phenyl} methyl Yl) 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-({1-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- pendant oxypyridin-1-yl) methyl] phenyl} methyl Yl) pyrazole-4-carboxamide; 3-amino-N-[(6-chloroisoquinolin-3-yl) methyl] -1-({4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl Yl) 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 Yl} pyrazole-4-carboxamide; N-[(1-amino-7-methylisoquinolin-6-yl) methyl] -2-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl Yl} imidazole-4-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -2-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl Yl} 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-methoxyisoquinolin-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-methoxyisoquinolin-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 Yl} imidazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[4- (pyrazol-1-ylmethyl) phenyl ] Methyl} imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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 Yl} imidazole-4-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-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] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -2-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl Phenyl] 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-methoxyisoquinolin-6-yl) methyl] -2-methyl-1-({4-[(4-methylpyrazol-1-yl) Methyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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-methylpyrazol-1-yl) Methyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-amino-7-fluoroisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-methylpyrazol-1-yl) methyl Phenyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-methylpyrazol-1-yl ) Methyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-amino-8-methoxyisoquinolin-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-1-yl) methyl Phenyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-amino-5-methoxyisoquinolin-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 Yl) -2-methylimidazole-4-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl Yl) -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-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} Methyl) -2-methylimidazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-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-methoxyisoquinolin-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-1-yl) methyl Phenyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-fluoropyrazol-1-yl) methyl Phenyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-fluoropyrazol-1-yl) methyl ] Phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-fluoropyrazol-1-yl) Methyl] phenyl} methyl) imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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-methoxyisoquinolin-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-ylmethyl) -1H-imidazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl)- Amidine 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) pyridin-3-yl] methyl Yl} imidazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -2-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl ] Methyl} imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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) pyridin-3-yl] methyl Yl} imidazole-4-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-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-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] Methyl} imidazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[6- (pyrrolidin-1-yl) pyridine-3- Yl] methyl} imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[6- (pyrrolidin-1-yl) pyridine-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-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[6- (pyrrolidin-1-yl) pyridine-3- Yl] methyl} imidazole-4-carboxamide; N-[(6-chloroisoquinolin-3-yl) methyl] -2-methyl-1-({4-[(2-oxopyridin-1-yl) methyl] phenyl} methyl Yl) 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 -Formamidine; 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 -Formamidine; N-[(1-aminoisoquinolin-6-yl) methyl] -2-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] methyl} imidazole- 4-formamidine 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 Yl} imidazole-4-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -2-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl ] Methyl} imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-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 Yl} imidazole-4-carboxamide; N-[(1-amino-8-methoxyisoquinolin-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-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[2- (pyrrolidin-1-yl) pyrimidine-5- Yl] methyl} imidazole-4-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[2- (pyrrolidin-1-yl) pyrimidine-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-methoxyisoquinolin-6-yl) methyl] -2-cyclopropyl-1-{[2- (pyrrolidin-1-yl) pyrimidine-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- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -2-methylimidazole-4-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -2-methylimidazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-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-methoxyisoquinolin-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-methoxyisoquinolin-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-methoxyisoquinolin-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-methoxyisoquinolin-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} pyridine Azole-4-methylamidine; 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 -Formamidine; 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 -Formamidine; 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 -Formamidine; 3-amino-N-[(7-chloroquinolin-2-yl) methyl] -1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] methyl} pyrazole-4- Formamidine N-[(1-Amino-7-methoxyisoquinolin-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) pyridine- 3-yl] methyl} pyrazole-4-carboxamide; N-[(1-amino-8-methoxyisoquinolin-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-1-yl) pyridine -3-yl] methyl} pyrazole-4-carboxamide; N-[(1-aminoisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl] phenyl} (Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-aminoisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazol-1-yl) methyl Phenyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl }-1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl }-1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[4- (pyrazol-1-ylmethyl) phenyl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl ) Phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl) Phenyl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl ) Phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl Phenyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl Phenyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl ] Phenyl} methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) Methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) Methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) methyl ] Phenyl} methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-({4-[(4-methylpyrazol-1-yl) Methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole-1 -Yl) methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl ) Phenyl) methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl ) Phenyl) methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl) Phenyl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[4- (pyrazol-1-ylmethyl ) Phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole- 1-yl) methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole- 1-yl) methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole-1 -Yl) methyl) phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-({4-[(4-methylpyrazole -1-yl) methyl] phenyl) methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl Group) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl Group) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} methyl ) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -1-({4-[(4-fluoropyrazol-1-yl) methyl] phenyl} (Methyl) -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine -3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine -3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine- 3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) Pyridin-3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) Pyridin-3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) pyridine- 3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[6- (pyrrolidin-1-yl) Pyridin-3-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine -5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine -5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine- 5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) Pyrimidin-5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) Pyrimidin-5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidine- 5-yl] methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -5- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) Pyrimidin-5-yl] methyl} -1, 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- (methoxymethyl) -1, 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) -1, 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- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5- (methoxymethyl) -1, 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) -1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5- (methoxymethyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl ] Methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl ] Methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[6- (pyrrolidin-1-yl) pyridin-3-yl ] Methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methylisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] Methyl) -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-5-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl ] Methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl ] Methyl} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-7-fluoroisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] methyl Base} -1, 2, 4-triazole-3-carboxamide; N-[(1-Amino-8-methoxyisoquinolin-6-yl) methyl] -5-methyl-1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl ] Methyl} -1, 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-1, 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-1, 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-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-5-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5-methyl-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5-methyl-1, 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-1, 2, 4-triazole-3-carboxamide; N-[(1-amino-8-methoxyisoquinolin-6-yl) methyl] -1-{[2- (3, 3-difluoropyrrolidin-1-yl) pyrimidin-5-yl] methyl} -5-methyl-1, 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 its pharmaceutically acceptable salts. The compound of claim 1, which is selected from the group consisting of: N-((1-aminoisoquinolin-6-yl) methyl) -3- (methoxymethyl) -1-((6- (pyrrolidine 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-formamidine; 3-methoxymethyl-1- (4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinoline -6-ylmethyl) -amidamine; 3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid (1 -Amino-isoquinolin-6-ylmethyl) -amidamine; 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-methylisoquine Phenyl-6-yl) methyl] -3- (methoxymethyl) -1-{[2- (pyrrolidin-1-yl) pyrimidin-5-yl] methyl} pyrazole-4-carboxamidine Amine; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[2- (pyrrolidine-1- ) Pyrimidin-5-yl] methyl} pyrazole-4-carboxamide; N-[(1-amino-5-methylisoquinolin-6-yl) methyl] -3- (methoxy Base ) -1-{[4- (pyrazol-1-ylmethyl) phenyl] methyl} pyrazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinoline -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 ) -Amidamine; 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-ring Propyl-1- (2-fluoro-4-pyrazol-1-ylmethyl-benzyl) -1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -Amidamine; 3-cyclopropyl-1- [4- (4-fluoro-pyrazol-1-ylmethyl) -benzyl] -1H-pyrazole-4-carboxylic acid (1-amino-iso Quinolin-6-ylmethyl) -amidamine; 1- [4- (4-fluoro-pyrazol-1-ylmethyl) -benzyl] -3-methoxymethyl-1H-pyrazole 4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -fluorenamine; 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-methoxyisoquinolin-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- (trifluoro (Methyl) pyrazole-4-carboxamide; N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1- ({4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; N-[(1-amino-5-fluoroisoquinoline -6-yl) methyl] -3- (methoxymethyl) -1-({4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl) pyrazole- 4-formamidine; 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) formamidine Group] -3- (methoxymethyl) -1-({4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl) pyrazole-4-carboxamide; 1- (6-pyrrolidin-1-yl-pyridin-3-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo [2,3- b] pyridin-5-ylmethyl) -fluorenamine; 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) -fluorenamine; 3-cyano-1- [4- (4-methyl-pyrazol-1-ylmethyl) -benzyl] -1H-pyrazole-4 -Formic acid (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine; N-[(1-aminoisoquinolin-6-yl) methyl]- 2-cyclopropyl-1-({4-[(4-methylpyrazol-1-yl) methyl] phenyl} methyl) imidazole-4-carboxamide; and its pharmaceutically acceptable salt. The compound of claim 1, which is 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) -amidamine; 1- [2- (3,3-difluoro-pyrrolidin-1-yl) -pyrimidin-5-ylmethyl] -3- Methoxymethyl-1H-pyrazole-4-carboxylic acid (1-amino-isoquinolin-6-ylmethyl) -amidamine; 1- (6-pyrrolidin-1-yl-pyridine-3- Methyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro-1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine; and Pharmaceutically acceptable salt. A compound as claimed in claim 1, which is N-[(1-amino-7-methoxyisoquinolin-6-yl) methyl] -3- (methoxymethyl) -1-{[4 -(Pyrazol-1-ylmethyl) phenyl] methyl} pyrazole-4-carboxamide, and pharmaceutically acceptable salts thereof. A compound as claimed in claim 1, which is 3-methoxymethyl-1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -1H-pyrazole-4-carboxylic acid (1-amine -Isoquinoline-6-ylmethyl) -amidamine, and pharmaceutically acceptable salts thereof. A compound as claimed in claim 1, which is 1- (6-pyrrolidin-1-yl-pyridin-3-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro- 1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine, and pharmaceutically acceptable salts thereof. A compound as claimed in claim 1, which is N-[(1-aminoisoquinolin-6-yl) methyl] -2-cyclopropyl-1-({4-[(4-methylpyrazole- 1-yl) methyl] phenyl} methyl) imidazole-4-carboxamide, and pharmaceutically acceptable salts thereof. A compound as claimed in claim 1, which is 1- (2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl) -3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-chloro- 1H-pyrrolo [2,3-b] pyridin-5-ylmethyl) -fluorenamine, and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier, diluent or excipient. A compound according to any one of claims 1 to 8 for use in medicine. A use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment or prevention of a disease or condition involving plasma kallikrein activity. A compound according to any one of claims 1 to 8 for use in a method of treating a disease or condition involving plasma kallikrein activity. The use according to claim 11, wherein the disease or condition involving plasma kallikrein activity is selected from the group consisting of visual impairment, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, and cerebral hemorrhage , Kidney disease, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and postoperative bleeding . The use according to claim 11, wherein the disease or condition involving plasma kallikrein activity is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.