NZ714027B2 - Heterocyclic derivates - Google Patents

Heterocyclic derivates Download PDF

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NZ714027B2
NZ714027B2 NZ714027A NZ71402714A NZ714027B2 NZ 714027 B2 NZ714027 B2 NZ 714027B2 NZ 714027 A NZ714027 A NZ 714027A NZ 71402714 A NZ71402714 A NZ 71402714A NZ 714027 B2 NZ714027 B2 NZ 714027B2
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amide
amino
isoquinolinylmethyl
benzyl
methyl
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NZ714027A
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NZ714027A (en
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Rebecca Louise Davie
Hannah Joy Edwards
David Michael Evans
Simon Teanby Hodgson
Iain Miller
Andrew Richard Novak
Alun John Smith
Michael John Stocks
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Kalvista Pharmaceuticals Limited
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Priority claimed from PCT/GB2014/051592 external-priority patent/WO2014188211A1/en
Publication of NZ714027A publication Critical patent/NZ714027A/en
Publication of NZ714027B2 publication Critical patent/NZ714027B2/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

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

Description

HETEROCYCLIC DERIVATES This invention relates to cyclic derivatives that are inhibitors of plasma kallikrein and to pharmaceutical compositions containing and the uses of, such derivatives.
Background to the Invention The heterocyclic tives of the present invention are inhibitors of plasma kallikrein and have a number of therapeutic applications, particularly in the ent of l vascular bility associated with diabetic retinopathy and diabetic macular edema.
Plasma kallikrein is a trypsin-like serine protease that can liberate kinins from gens (see K. D.
Bhoola et al., "Kallikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine, p483-493; J. W. Bryant et al., "Human plasma kallikrein-kinin system: physiological and biochemical parameters" Cardiovascular and haematological agents in medicinal chemistry, 7, p234-250, 2009; K. D. Bhoola et al., Pharmacological Rev., 1992, 44, 1; and D. J. Campbell, "Towards understanding the kallikrein-kinin : ts from the measurement of kinin peptides", Brazilian Journal of Medical and Biological Research 2000, 33, 665-677). It is an essential member of the intrinsic blood coagulation cascade although its role in this cascade does not involve the release of bradykinin or enzymatic cleavage.
Plasma prekallikrein is encoded by a single gene and synthesized in the liver. It is secreted by hepatocytes as an inactive plasma prekallikrein that circulates in plasma as a heterodimer x bound to high molecular weight kininogen which is activated to give the active plasma kallikrein. Kinins are potent mediators of inflammation that act h G protein-coupled receptors and antagonists of kinins (such as bradykinin antagonists) have previously been investigated as potential therapeutic agents for the treatment of a number of disorders (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, 3, 845-852).
Plasma rein is thought to play a role in a number of inflammatory disorders. The major inhibitor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients who present with a c deficiency in C1 esterase inhibitor suffer from hereditary angioedema (HAE) which results in intermittent swelling of face, hands, throat, gastro-intestinal tract and genitals. Blisters formed during acute episodes contain high levels of plasma kallikrein which cleaves high lar weight kininogen liberating bradykinin leading to sed vascular permeability. Treatment with a large protein plasma kallikrein inhibitor has been shown to effectively treat HAE by preventing the e of bradykinin which causes increased vascular permeability (A. Lehmann "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic y" Expert Opin. Biol. Ther. 8, p1187-99).
The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular edema. It has been recently published that plasma kallikrein contributes to retinal vascular dysfunctions in diabetic rats (A. Clermont et al. "Plasma kallikrein mediates l vascular ction and induces retinal thickening in diabetic rats" Diabetes, 2011, 60, p1590-98). Furthermore, administration of the plasma kallikrein inhibitor ASP-440 ameliorated both retinal vascular bility and retinal blood flow abnormalities in diabetic rats. Therefore a plasma kallikrein inhibitor should have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.
Other complications of diabetes such as cerebral haemorrhage, nephropathy, cardiomyopathy and neuropathy, all of which have associations with plasma kallikrein may also be considered as targets for a plasma kallikrein inhibitor.
Synthetic and small molecule plasma kallikrein inhibitors have been described previously, for example by Garrett et al. ("Peptide aldehyde…." J. e Res. 52, p62-71 (1998)), T. Griesbacher et al.
("Involvement of tissue kallikrein but not plasma rein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats" British Journal of Pharmacology 137, p692-700 (2002)), Evans ("Selective dipeptide inhibitors of kallikrein" WO03/076458), Szelke et al. ("Kininogenase inhibitors" WO92/04371), D. M. Evans et al. (Immunolpharmacology, 32, p115-116 (1996)), Szelke et al.
("Kininogen inhibitors" WO95/07921), Antonsson et al. ("New es tives" WO94/29335), J.
Corte et al. (”Six membered heterocycles useful as serine protease inhibitors” WO2005/123680), J.
Stürzbecher et al. lian J. Med. Biol. Res 27, p1929-34 (1994)), r et al. (US 5,187,157), N. Teno et al. (Chem. Pharm. Bull. 41, p1079-1090 (1993)), W. B. Young et al. ("Small molecule inhibitors of plasma kallikrein" Bioorg. Med. Chem. Letts. 16, p2034-2036 ), Okada et al. ("Development of potent and selective plasmin and plasma kallikrein tors and studies on the structure-activity relationship" Chem. Pharm. Bull. 48, p1964-72 ), Steinmetzer et al. ("Trypsin-like serine se inhibitors and their preparation and use" 49595), Zhang et al. ("Discovery of highly potent small molecule kallikrein inhibitors" Medicinal Chemistry 2, p545-553 (2006)), Sinha et al. ("Inhibitors of plasma kallikrein" WO08/016883), Shigenaga et al. (“Plasma Kallikrein Inhibitors” WO2011/118672), and Kolte et al. (“Biochemical characterization of a novel high-affinity and specific rein inhibitor”, British Journal of Pharmacology (2011), 162(7), 1639-1649). Also, etzer et al. ne protease inhibitors” WO2012/004678) describes cyclized peptide analogs which are inhibitors of human plasmin and plasma kallikrein.
To date, no small molecule synthetic plasma kallikrein inhibitor has been approved for medical use. The molecules bed in the known art suffer from limitations such as poor selectivity over related enzymes such as KLK1, thrombin and other serine proteases, and poor oral bility. The large protein plasma kallikrein tors present risks of anaphylactic ons, as has been reported for Ecallantide.
Thus there remains a need for compounds that selectively inhibit plasma rein, that do not induce anaphylaxis and that are orally available. Furthermore, the vast majority of molecules in the known art feature a highly polar and ble guanidine or e functionality. It is well known that such functionalities may be limiting to gut permeability and therefore to oral availability. For example, it has been reported by Tamie J. Chilcote and Sukanto Sinha (“ASP-634: An Oral Drug Candidate for Diabetic MacularEdema”, ARVO 2012 May 6th – May 9th, 2012, Fort Lauderdale, a, Presentation 2240) that ASP-440, a benzamidine, suffers from poor oral availability. It is further ed that absorption may be improved by creating a prodrug such as ASP-634. However, it is well known that prodrugs can suffer from several drawbacks, for example, poor chemical stability and potential toxicity from the inert r or from unexpected metabolites. In another report, indole amides are claimed as compounds that might overcome problems associated with drugs possessing poor or uate ADME-tox and physicochemical properties although no inhibition against plasma kallikrein is presented or claimed (Griffioen et al, “Indole amide derivatives and related compounds for use in the treatment of neurodegenerative es”, WO2010, 142801). st Pharmaceuticals Inc. have reported the discovery of the orally available plasma kallikrein inhibitor BCX4161 (“BCX4161, An Oral Kallikrein Inhibitor: Safety and Pharmacokinetic Results Of a Phase 1 Study In Healthy Volunteers”, Journal of Allergy and Clinical Immunology, Volume 133, Issue 2, Supplement, ry 2014, page AB39 and “A Simple, Sensitive and Selective Fluorogenic Assay to Monitor Plasma Kallikrein Inhibitory Activity of BCX4161 in Activated Plasma”, Journal of Allergy and Clinical Immunology, Volume 133, Issue 2, Supplement February 2014, page AB40). However, human doses are relatively large, currently being tested in proof of concept studies at doses of 400 mg three times daily.
There are only few reports of plasma rein inhibitors that do not feature guanidine or amidine functionalities. One example is Brandl et al. (“N-((6-amino-pyridinyl)methyl)-heteroaryl-carboxamides as tors of plasma kallikrein” /017020), which describes compounds that feature an amino- ne functionality. Oral efficacy in a rat model is demonstrated at relatively high doses of 30 mg/kg and 100 mg/kg but the pharmacokinetic profile is not reported. Thus it is not yet known whether such compounds will provide sufficient oral availability or efficacy for progression to the clinic. Other examples are Brandl et al. (“Aminopyridine derivatives as plasma kallikrein inhibitors” WO2013/111107) PCT/GB 2014/051 592 — 26—06—2015 and Flohr et al. (”S-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors" W02013/111108). However, neither of these documents report any in vivo data and ore it is not yet known whether such compounds will provide sufficient oral bility or efficacy for progression to the .
Therefore there remains a need to develop new plasma kallikrein inhibitors that will have utility to treat a wide range of disorders, in particular to reduce l vascular bility associated with diabetic retinopathy and diabetic macular edema. Preferred nds will possess a good pharmacokinetic profile and in particular will be le as drugs for oral delivery.
Summary of the Invention The t invention relates to a series of cyclic derivatives that are inhibitors of plasma kallikrein. These compounds demonstrate good selectivity for plasma kallikrein and are potentially useful in the treatment of impaired visual acuity, diabetic retinopathy, macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and bleeding from post operative surgery. The invention further relates to pharmaceutical compositions of the inhibitors, to the use of the compositions as therapeutic , and to methods of treatment using these compositions.
In a first aspect, the present invention provides compounds of formula I 0 rZI Formula (I) wherein B is a fused 6,5- or 6,6-heteroaromatic bicyclic ring, containing N and, optionally, one or two additional heteroatoms ndently selected from N, O and S, which is optionally mono-, di or tri-substituted with a substituent selected from alkyl, , OH, halo, CN, COOR8, CONR8R9, CF; and NR8R9; wherein when 8 is a fused 6,5-heteroaromatic bicyclic ring, it is linked to —CONH-(CH2)- via its 6-membered ring component; AMENDED SHEET PCT/GB 51 592 — 2015 W, X, Y and Z are independently selected from C, N, O and S, such that the ring containing W, X, Y and Z is a five membered aromatic heterocycle; wherein, R5, R6 and R7 are independently absent or independently selected from H, alkyl, halo, OH, aryl, heteroaryl, -NR8R9, CN, COOR8, CON R8R9, -NR8COR9, CF3, and R16; wherein at least one of R5, R6 and R7 is t and is independently selected from alkyl, halo, OH, aryl, heteroaryl, -N R8R9, CN, COOR8, CONR8R9, —NR8COR9, CF3 and R16; A is ed from aryl and heteroaryl; R8 and R9 are independently selected from H and alkyl; R16 is a carbon-containing 3-, 4-, 5- or 6-membered monocyclic ring system which may be aromatic, saturated or unsaturated non-aromatic and which may optionally contain 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the ring system R16 is in turn optionally substituted with tuents selected from alkyl and 0x0; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (Ci-Cm) or a branched saturated hydrocarbon of n 3 and 10 carbon atoms (Cg-Clo); alkyl may ally be substituted with 1 or 2 substituents independently selected from (C1-C6)a|koxy, OH, CN, CF3, COOR10, CONR10R11, fluoro and NR10R11; alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C1-C6) or a branched O-linked hydrocarbon of between 3 and 6 carbon atoms (C3-C6); alkoxy may optionally be substituted with 1 or 2 tuents independently selected from OH, CN, CF3, COOR10, CONR10R11, fluoro and NR10R11; aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, morpholinyl, dinyl, aryl, -(CH2)0_3-O-heteroaryl, arylb, -O-arylb, -(CH2)1_3-arylb, -(CH2)1_3-heteroaryl, - COOR10, ~CONR10R11, 1.3-NR14R15, CF3 and -NR10R11; arylb is phenyl, biphenyl or naphthyl, which may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, morpholinyl, piperidinyl, -COOR10, - CONR10R11, CF3 and NR10R11; AMENDED SHEET PCT/GB 2014/051 592 - 182015 heteroaryl is a 5, 6, 9 or 10 membered mono— or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members independently selected from N, NR8, S and O; heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, OCFg, halo, CN, aryl, morpholinyl, piperidinyl, -(CH2)1.3-aryl, heteroaryl”, -COOR10, -CONR10R11, CF; and -NR10R11; heteroarylb is a 5, 6, 9 or 10 membered mono— or bi—cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members independently selected from N, NR8, S and 0; wherein heteroarylb may be optionally substituted with 1, 2 or 3 substituents ndently selected from alkyl, alkoxy, OH, halo, CN, morpholinyl, piperidinyl, aryl, ~(CH2)1.3-aryl, -COOR10, -CONR10R11, CF; and NR10R11; R10 and R11 are independently selected from H and alkyl or R10 and R11 er with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocylic ring which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, F and CF; R14 and R15 are independently selected from alkyl, arylb and heteroaryl”; or R14 and R15 together with the en atom to which they are attached form a carbon-containing 4-, 5—, 6- or 7-mem bered heterocylic ring which may be saturated or unsaturated with 1 or 2 double bonds, and ally may be oxo su bstituted; and tautomers, isomers, stereoisomers ding omers, diastereoisomersand racemic and scalemic mixtures f), pharmaceutically acceptable salts and solvates thereof, wherein the compound of formula (I) is not: N H \ \I—CH7_N4_C \ /m c1 \P _3 Me “'2 ‘h In another aspect the present ion provides a prodrug of a compound of formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.
AMENDED SHEET PCT/GB 2014/051 592 - 18—03—2015 in yet another aspect the present invention provides an N-oxide of a compound of formula (I) as herein defined, or a prodrug or pharmaceutically able salt thereof.
It will be understood that certain nds of the present invention may exist in solvated, for example hydrated, as well as ated forms. It is to be understood that the present invention encompasses all such solvated forms.
In a second aspect, the invention comprises a subset of the compounds of formula I, AMENDED SHEET A R6 X Z R5 R7 H O B Formula (I) A, W, X, Y and Z are as defined in the first aspect above; B is a fused 6,5- or 6,6-heteroaromatic bicyclic ring, containing N and, ally, one or two additional heteroatoms independently selected from N, O and S, which is ally mono-, di or tri-substituted with a substituent selected from alkyl, alkoxy, OH, halo, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein when B is a fused 6,5-heteroaromatic ic ring, it is linked to -CONH–CH2- via its 6-membered ring component; R5, R6 and R7 are independently absent or independently selected from H, alkyl, halo, OH, aryl, heteroaryl and CF3; with the proviso that at least one of R5, R6 and R7 must be present and when so present be independently selected from alkyl, halo, aryl, heteroaryl and CF3; heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members independently selected from N, NR8, S and O; heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, aryl, morpholinyl, piperidinyl, -(CH2)1aryl, heteroarylb, -COOR10, -CONR10R11, CF3 and -NR10R11; alkyl, alkoxy, aryl, heteroarylb, R8, R9, R10 and R11 are as defined in the first aspect above; and tautomers, s, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
In another aspect, the invention comprises a compound ing to the first aspect above, n B is a fused 6,6-heteroaromatic bicyclic ring, ning N and, optionally, one or two additional atoms independently selected from N, O and S, which is optionally mono-, di or tri-substituted with a substituent selected from alkyl, alkoxy, OH, halo, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein alkyl, , R8 and R9 are as defined in the first aspect above.
In another aspect, the invention comprises a compound according to the second aspect above, wherein B is a fused 6,6-heteroaromatic bicyclic ring, containing N and, optionally, one or two additional heteroatoms independently selected from N, O and S, which is optionally mono-, di or tri-substituted with a substituent selected from alkyl, alkoxy, OH, halo, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein alkyl, alkoxy, R8 and R9 are as defined in in the first aspect above.
In another aspect, the invention comprises a compound ing to the first aspect above, wherein B is selected from ally mono-, di or tri-substituted isoquinolinyl wherein said optional substituent(s) are selected from alkyl, alkoxy, OH, F, Cl, CN, COOR8, CONR8R9, CF3 and NR8R9; and wherein alkyl, alkoxy, R8 and R9 are as defined in the first aspect above.
In another aspect, the invention comprises a compound according to the second aspect above, wherein B is ed from optionally mono-, di or tri-substituted isoquinolinyl wherein said optional substituent(s) are selected from alkyl, , OH, F, Cl, CN, COOR8, CONR8R9, CF3 and NR8R9; and wherein alkyl, alkoxy, R8 and R9 are as defined in the first aspect above.
In another aspect, the invention comprises a subset of the compounds of formula (I), as defined by formula (II), A R6 X Z R5 W R1 R2 R7 H N NH Formula (II) wherein R1, R2 and R3 are independently selected from H, alkyl, COOR8, CONR8R9, OH, alkoxy, NR8R9, F and Cl; and wherein A,W, X, Y, Z, R5, R6, R7, alkyl, alkoxy, R8 and R9 are as defined in the first or second aspect above; and tautomers, isomers, stereoisomers (including enantiomers, reoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
In another aspect, the invention comprises a subset of the compounds of a (I), as d by formula (II), A R6 X Z R5 W R1 R2 R7 H N NH R3 Formula (II) wherein W, X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is a five-membered heterocycle selected from pyrrole, pyrazole, imidazole, 1, 2, 3-triazole and 1, 2, 4-triazole; R5, R6 and R7 are independently absent or independently selected from H, alkyl, halo, OH, aryl, heteroaryl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9 and CF3; wherein at least one of R5, R6 and R7 is present and is independently selected from alkyl, halo, OH, aryl, heteroaryl, -NR8R9 CN, COOR8, CONR8R9, R9, R16 and CF3; R1, R2 and R3 are independently selected from H, alkyl, COOR8, 9, OH, alkoxy, NR8R9, F and Cl; and wherein A, R8, R9, alkyl, alkoxy, aryl and aryl are as defined in the first aspect above; and tautomers, isomers, stereoisomers (including omers, diastereoisomers and c and ic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
In another aspect, the invention ses a subset of the compounds of formula (I), as defined by formula (II), A R6 X Z R5 W R1 R2 R7 H N NH Formula (II) wherein W, X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is a five-membered heterocycle selected from pyrrole, pyrazole, imidazole, 1, 2, 3-triazole and 1, 2, 4-triazole; R5, R6 and R7 are independently absent or independently selected from H, alkyl, halo, aryl, heteroaryl and CF3; wherein at least one of R5, R6 and R7 is present and is independently selected from alkyl, halo, aryl, heteroaryl, and CF3; R1, R2 and R3 are independently selected from H, alkyl, COOR8, CONR8R9, OH, alkoxy, NR8R9, F and Cl; and wherein A, R8, R9, alkyl, alkoxy, aryl and heteroaryl are as defined in the first aspect above; and ers, isomers, isomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), ceutically acceptable salts and solvates thereof.
In another , the invention comprises a subset of the compounds of formula (I), as defined by formula (IIa), A R6 X R5 W R1 R2 R7 H N NH Formula (IIa) wherein R1, R2 and R3 are independently selected from H, alkyl, COOR8, CONR8R9, OH, alkoxy, NR8R9, F and Cl; and wherein A, W, X, Y, R5, R6, R7, alkyl, alkoxy, R8 and R9 are as defined in the first or second aspect above; and tautomers, isomers, stereoisomers ding enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and es thereof.
In another aspect, the ion comprises a subset of the compounds of formula (I), as defined by formula (IIa), A R6 X R5 W R1 R2 R7 H N NH Formula (IIa) wherein R1, R2 and R3 are independently selected from H, alkyl, COOR8, CONR8R9, OH, alkoxy, NR8R9, F and Cl; W, X and Y are independently selected from C, N, O and S, such that the ring containing W, X and Y is a five-membered membered aromatic heterocycle; and wherein A, R5, R6, R7, alkyl, alkoxy, R8 and R9 are as defined in the first or second aspect above; and tautomers, isomers, stereoisomers ding enantiomers, diastereoisomers and racemic and scalemic es thereof), pharmaceutically acceptable salts and solvates thereof.
In r aspect, the invention comprises a compound ing to the first aspect above, wherein B is a fused 6,5- heteroaromatic bicyclic ring, containing N and, optionally, one or two additional heteroatoms independently selected from N, O and S, which is optionally mono-, di or tri-substituted with a substituent selected from alkyl, alkoxy, OH, halo, CN, COOR8, CONR8R9, CF3 and NR8R9; n alkyl, , R8 and R9 are as defined in the first aspect above.
In another aspect, the invention comprises a compound according to the second aspect above, wherein B is a fused 6,5- heteroaromatic bicyclic ring, containing N and, optionally, one or two additional heteroatoms independently ed from N, O and S, which is optionally mono-, di or tri-substituted with a substituent selected from alkyl, alkoxy, OH, halo, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein B is linked to -CONH–CH2- via its 6-membered ring component; and wherein alkyl, , R8 and R9 are as defined in the first aspect above.
In another aspect, the ion comprises a compound according to the first or second aspect above, n B is a fused 6,5- heteroaromatic bicyclic ring, containing N and, optionally, one or two additional atoms independently selected from N, O and S, which is optionally mono-, di or trisubstituted with a substituent selected from alkyl, F, Cl and -CN; and wherein alkyl is as defined in the first aspect above.
In another aspect, the invention ses a compound according to the first aspect above, wherein B is selected from optionally substituted indole, optionally substituted indazole and ally substituted 1H-pyrrolo[2,3-b]pyridine; wherein said optional substituents are selected from alkyl, alkoxy, OH, F, Cl, CN, COOR8, CONR8R9, CF3 and NR8R9; and wherein alkyl, alkoxy, R8 and R9 are as defined in the first aspect above.
In another aspect, the invention comprises a compound according to the second aspect above, wherein B is selected from optionally substituted indole, ally substituted indazole and optionally substituted 1H-pyrrolo[2,3-b]pyridine; wherein said optional tuents are selected from alkyl, alkoxy, OH, F, Cl, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein said indole, indazole or 1H-pyrrolo[2,3- b]pyridine ring is linked to -CONH–CH2- via its 6-membered ring component; and wherein alkyl, alkoxy, R8 and R9 are as defined in the first aspect above.
In another aspect, the invention comprises a compound according to the first or second aspect above, wherein B is selected from optionally substituted indole, optionally tuted indazole and optionally substituted 1H-pyrrolo[2,3-b]pyridine; wherein said optional substituents are ed from alkyl, F, Cl and -CN; and wherein alkyl is as defined in the first aspect above.
In another aspect, the invention comprises a compound according to the first aspect above, wherein B is selected from optionally mono-, di or tri-substituted 1H-pyrrolo[2,3-b]pyridine, wherein said optional tuent(s) are selected from alkyl, alkoxy, OH, F, Cl, CN, COOR8, CONR8R9, CF3 and NR8R9; and n alkyl, alkoxy, R8 and R9 are as defined in the first aspect above.
In another aspect, the invention comprises a compound according to the second aspect above, wherein B is selected from optionally mono-, di or tri-substituted 1H-pyrrolo[2,3-b]pyridine, wherein said optional substituent(s) are selected from alkyl, alkoxy, OH, F, Cl, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein said rolo[2,3-b]pyridine ring is linked to -CONH–CH2- via its 6-membered ring component; and wherein alkyl, alkoxy, R8 and R9 are as defined in the first aspect above.
In r aspect, the invention comprises a nd according to the first or second aspect above, wherein B is selected from optionally mono-, di or tri-substituted 1H-pyrrolo[2,3-b]pyridine; wherein said optional substituents are selected from alkyl, F, Cl and -CN; and wherein alkyl is as defined in the first aspect above.
In another aspect, the invention comprises a subset of the compounds of formula (I), as defined by formula (III), A R6 X Z R5 W R1 R7 H O NH Formula (III) n R1 and R3 are independently selected from H, alkyl, COOR8, CONR8R9, OH, alkoxy, NR8R9, F and Cl; and wherein A, W, X, Y, Z, R5, R6, R7, alkyl, alkoxy, R8 and R9 are as defined in the first aspect above; and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and c and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
In another aspect, the invention comprises a subset of the compounds of formula (I), as defined by formula (III), A R6 X Z R5 W R1 R7 H O NH Formula (III) wherein W, X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is a five-membered heterocycle selected from pyrrole, pyrazole, imidazole, 1, 2, 3-triazole and 1, 2, 4-triazole; R5, R6 and R7 are independently absent or independently ed from H, alkyl, halo, aryl, heteroaryl and CF3; wherein at least one of R5, R6 and R7 is present and is independently selected from alkyl, halo, aryl, heteroaryl, and CF3; R1 and R3 are independently selected from H, alkyl, COOR8, CONR8R9, OH, alkoxy, NR8R9, F and Cl; and wherein A, R8, R9, alkyl, alkoxy, aryl and heteroaryl are as defined in the first aspect above; and tautomers, isomers, stereoisomers (including enantiomers, reoisomers and racemic and scalemic es thereof), pharmaceutically acceptable salts and solvates thereof.
In another aspect, the invention comprises a subset of the nds of formula (I), as defined by formula (III), A R6 X Z R5 W R1 R7 H O NH R3 a (III) wherein W, X, Y and Z are independently selected from C and N, such that the ring ning W, X, Y and Z is a five-membered heterocycle ed from pyrrole, pyrazole, imidazole, 1, 2, 3-triazole and 1, 2, 4-triazole; PCT/GB 2014/051 592 — 26—06—2015 R5, R6 and R7 are independently absent or ndently selected from H, alkyl, halo, aryl, heteroaryl and CF3; wherein at least one of R5, R6 and R7 is t and is independently selected from alkyl, halo, aryl, heteroaryl, and CF3; R1 and R3 are independently selected from H and alkyl; and n A, alkyl, aryl, heteroaryl are as defined in the first aspect above; and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and c and ic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
Also described herein are compounds defined by a (IV), A B6 ki’o‘fli‘Y R4 0 \ Formula (lV) wherein R4 is independently ed from H, alkyl, COOR8, CONR8R9, OH, alkoxy, NR8R9, F and Cl; and wherein A, W, X, Y, Z, R5, R6, R7, alkyl, alkoxy, R8 and R9 are as defined in the first aspect above; and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
Also described herein is a subset of the compounds defined by formula (IV), A 56 Y R4 0 \ N,NH Formula (lV) wherein W, X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is a five—membered heterocycle selected from pyrrole, pyrazole, imidazole, 1, 2, 3-triazole and 1, 2, 4—triazole; AMENDED SHEET PCT/GB 2014/051 S92 — 26—06—2015 R5, R6 and R7 are independently absent or independently selected from H, alkyl, halo, aryl, heteroaryl, , -CN, cyclopropyl and CF; and at least one of R5, R6 and R7 is not absent and is independently ed from alkyl, halo, aryl, heteroaryl, -NR8R9, -CN, cyclopropyl and CF;; R4 is selected from H, alkyl, COOR8, CONR8R9, OH, alkoxy, NR8R9, F and Cl; and wherein A, R8, R9, alkyl, alkoxy are as defined in the first aspect above; and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
Also described herein is a subset of the compounds defined by a (IV), A llR6 x’Y\ R4 [W0 2’R5\ 0 \ N’NH Formula (IV) wherein W, X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is a five-membered heterocycle selected from pyrrole, pyrazole, imidazole, 1, 2, zole and 1, 2, 4—triazole; R5, R6 and R7 are independently absent or independently selected from H, alkyl, halo, aryl, heteroaryl and CF; and at least one of R5, R6 and R7 is not absent and is independently selected from alkyl, halo, aryl, aryl, and CF;; R4 is selected from H, alkyl, COOR8, CONR8R9, OH, alkoxy, NR8R9, F and CI; and wherein A, R8, R9, alkyl, alkoxy are as defined in the first aspect above; and tautomers, isomers, isomers (including enantiomers, diastereoisomers and c and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates f.
The present invention also comprises the following limitations, which may be applied to any of the s of the invention described above: B is a fused 6,5 or 6,6—heteroaromatic bicyclic ring, containing N and, optionally, one or two additional heteroatoms independently selected from N, O and S, which is optionally mono-, di or tri-substituted with a substituent selected from alkyl, alkoxy, OH, halo, CN, COOR8, CONR8R9, CF; and AMENDED SHEET NR8R9; wherein R8 and R9 are independently selected from H and alkyl; wherein when B is a fused 6,5-heteroaromatic bicyclic ring, it is linked to n- via its 6-membered ring component.
• B is a fused 6,5 or 6,6-heteroaromatic bicyclic ring, containing one, two or three N atoms, and no other heteroatoms, which is optionally mono- substituted with a substituent selected from alkyl, , OH, halo, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein R8 and R9 are independently selected from H and alkyl.
• B is a fused 6,6-heteroaromatic bicyclic ring containing one N atom, and no other heteroatoms, which is optionally mono- tuted with a substituent ed from alkyl, alkoxy, OH, halo, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein R8 and R9 are independently selected from H and alkyl.
• B is a fused 6,6-heteroaromatic bicyclic ring, containing one N atom and, optionally, one or two additional heteroatoms independently selected from N and O, which is ally mono- substituted with a substituent selected from alkyl, alkoxy, OH, halo, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein R8 and R9 are independently selected from H and alkyl.
• B is a fused teroaromatic bicyclic ring, containing one N atom, and no other heteroatoms, which is optionally mono- substituted with a substituent selected from alkyl, alkoxy, OH, and NR8R9; wherein R8 and R9 are independently selected from H and alkyl.
• B is a fused 6,6-heteroaromatic bicyclic ring, ning one N atom, and no other heteroatoms, which is optionally mono- substituted with NR8R9; wherein R8 and R9 are independently selected from H and alkyl.
• B is a fused 6,5- heteroaromatic bicyclic ring, containing N and, optionally, one or two additional heteroatoms independently selected from N, O and S, which is optionally mono-, di or trisubstituted with a substituent selected from alkyl, F, Cl and –CN.
• B is a fused 6,5- heteroaromatic bicyclic ring, ning N and, optionally, one or two additional heteroatoms independently selected from N, O and S, which is ally mono-, di or tri- substituted with a substituent selected from alkyl, F, Cl and –CN; wherein B is linked to -CONH–CH2- via its 6-membered ring component.
• B is selected from optionally substituted indole, ally substituted le and optionally substituted 1H-pyrrolo[2,3-b]pyridine; wherein said optional substituents are selected from alkyl, F, Cl and –CN.
• B is selected from optionally substituted indole, optionally substituted indazole and optionally substituted 1H-pyrrolo[2,3-b]pyridine; wherein said optional substituents are selected from alkyl, F, Cl and –CN; and wherein said indole, indazole or 1H-pyrrolo[2,3-b]pyridine ring is linked to -CONH– CH2- via its 6-membered ring component.
• B is optionally mono-, di or tri-substituted isoquinolinyl, wherein said optional substituent(s) are selected from alkyl, alkoxy, OH, F, Cl, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein R8 and R9 are independently ed from H and alkyl.
• B is ally mono-substituted isoquinolinyl; wherein said optional substituent is selected from alkyl, alkoxy, OH, and NR8R9; n R8 and R9 are independently selected from H and alkyl.
• B is optionally substituted 1H-pyrrolo[2,3-b]pyridine wherein said optional substituent(s) are selected from alkyl, alkoxy, OH, F, Cl, CN, COOR8, CONR8R9, CF3 and NR8R9 and wherein R8 and R9 are independently selected from H and alkyl.
• B is selected from optionally mono-, di or tri-substituted rolo[2,3-b]pyridine; wherein said optional substituents are selected from alkyl, F, Cl and –CN; and wherein said 1H-pyrrolo[2,3- dine ring is linked to -CONH–CH2- via its 6-membered ring component.
• Preferably, B is ally mono-substituted isoquinolinyl, wherein said optional substituent is NR8R9; wherein R8 and R9 are independently selected from H and alkyl.
• Preferably, B is optionally di- or tri-substituted isoquinolinyl, wherein one of said optional substituent is NR8R9 and the other said optional substituents are alkyl; wherein R8 and R9 are independently selected from H and alkyl.
• More ably, B is optionally di- or tri-substituted isoquinolinyl, wherein one of said optional substituent is NR8R9 and the other said optional substituents are alkyl; n R8 and R9 are H.
• More ably, B is optionally mono-substituted isoquinolinyl, wherein said optional tuent is NR8R9; and wherein R8 and R9 are H.
• More preferably, B is optionally di- or tri-substituted isoquinolinyl, wherein one of said optional substituent is NR8R9 and the other one or two said optional substituents are alkyl; wherein R8 and R9 are H.
• R1, R2, R3 and R4 are independently selected from H, alkyl, COOR8, CONR8R9, OH, alkoxy, NR8R9, F and Cl.
• Preferably, R1, R2, R3 and R4 are independently selected from H, alkyl, Cl and F.
• Preferably, R1, R2, R3 and R4 are independently selected from H, alkyl and Cl.
• More preferably, R1, R2 and R3 are independently selected from H and alkyl.
• More preferably, R1, R2 and R3 are independently selected from H and methyl.
• More preferably R4 is ed from H and Cl.
• W, X, Y and Z are independently ed from C, N, O and S, such that the ring containing W, X, Y and Z is a five-membered aromatic heterocycle.
PCT/GB 2014/051 592 — 18—03—2015 W, X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is a five-mem bered aromatic heterocycle.
W, X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is selected from pyrrole, pyrazole, imidazole, 1, 2, 3-triazole and 1, 2, 4-triazole.
Preferably, X is N.
WisC,XandYareNandZisCor N.
X and Y are N and W and Z are C.
X, Yand Z are N and W is C.
X and Z are N and W and Y are C.
W is N and X, Y and Zare C.
X is N and W, Y and Z are C.
R5, R6 and R7 are ndently absent or independently ed from H, alkyl, halo, OH, aryl, heteroaryl, , CN, COOR8, CONR8R9, -NR8COR9, CF3, and —R16, wherein at least one of R5, R6 and R7 is present and is independently selected from alkyl, halo, OH, aryl, heteroaryl, -NR8R9, CN, COOR8, CON R8R9, -NR8COR9, R16 and CF3.
R5, R6 and R7 are independently absent, or are independently selected from H, alkyl, halo, OH, aryl, heteroaryl and CF3, wherein at least one of R5, R6 and R7 is present and is independently selected from alkyl, halo, OH, aryl, heteroaryl and CF3.
R5 is absent or is selected from H, alkyl, —NR8R9, -CN, R16, CF; and aryl.
R5 is absent or is selected from H, alkyl, —NR8R9, -CN, ropyl, CF; and aryl.
R5 is absent or is ed from H, methyl, -NH2, -CN, cyclopropyl, CF; and aryl.
R5 is absent or is selected from H, methyl, -NH2, cyclopropyl, CF3 and aryl.
R5 is absent or is selected from H, alkyl, CF3 and aryl.
R5 is absent or is selected from H, methyl, CF; and phenyl.
R6 and R7 are independently absent, or are independently selected from H, alkyl, aryl and CF3.
R6 and R7 are independently absent, or are independently selected from H, methyl, ethyl, yl, phenyl and CF3. ably, R5 is H and R6 and R7 are methyl.
AMENDED SHEET • R14 and R15 are independently selected from alkyl, arylb and heteroarylb; or R14 and R15 together with the nitrogen atom to which they are attached form a carbon containing 4-, 5-, 6- or 7- membered heterocylic ring which may be saturated or unsaturated with 1 or 2 double bonds, and optionally may be oxo substituted.
• R14 and R15 are independently selected from alkyl and arylb; or R14 and R15 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or ered carbon ning heterocylic ring which may be saturated or unsaturated with 1 or 2 double bonds, and optionally may be oxo tuted.
• R14 and R15 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7- membered carbon containing cylic ring which may be saturated or unsaturated with 1 or 2 double bonds, and optionally may be oxo substituted.
• R16 is a carbon-containing 3-, 4-, 5- or 6-membered monocyclic ring system which may be aromatic, saturated or unsaturated non-aromatic and which may optionally contain 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the ring system R16 is in turn optionally substituted with tuents selected from alkyl and oxo.
• R16 is a carbon-containing 3-, 4-, 5- or 6-membered monocyclic ring system which may be aromatic, ted or unsaturated non-aromatic and which may optionally contain 1 or 2 heteroatoms selected from N, O and S, wherein the ring system R16 is in turn optionally substituted with substituents selected from methyl, ethyl and oxo.
• R16 is selected from oxazole, thiophene, cyclopropyl, cyclobutyl, pyrrolidinyl and morpholinyl, each optionally tuted with substituents selected from methyl and oxo.
• X and Y are N, W and Z are C, and R5 and R7 are H.
• X, Y and Z are N, W is C, and R7 is H.
• W is N, X, Y and Z are C, R7 is ethyl, R6 is methyl and R5 is H.
• X is N, W, Y and Z are C, R5 is H and R6 and R7 are methyl.
• X and Y are N, W and Z are C, and R5 is selected from alkyl, halo, OH, aryl, heteroaryl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9, R16 and CF3, and R7 is H.
• X and Y are N, W and Z are C, and R5 is selected from alkyl, -NR8R9, -CN, cyclopropyl, CF3 and aryl, and R7 is H.
• X and Y are N, W and Z are C, and R5 is ed from methyl, -NH2, -CN, cyclopropyl, CF3 and R7 is H.
• X and Y are N, W and Z are C, and R5 is R16 and R16 is as previously defined in the first aspect above.
• X and Y are N, W and Z are C, and R5 selected from alkyl, halo, OH, aryl, aryl and CF3, and R7 is • A is selected from aryl and heteroaryl, each optionally substituted as specified in the first aspect above.
• A is heteroaryl optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, aryl, morpholinyl, piperidinyl, 0, -CONR10R11, CF3 and -NR10R11; wherein R10 and R11 are selected from H and alkyl or R10 and R11 together with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocylic ring which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, F and CF3.
• A is heteroaryl optionally tuted with a substituent selected from alkyl, alkoxy, OH, halo, CN, aryl, morpholinyl and dinyl.
• Preferably, A is heteroaryl substituted by phenyl.
• Preferably, A is aryl substituted by 1; wherein R10 and R11 are selected from H and alkyl or R10 and R11 together with the nitrogen atom to which they are attached form a carboncontaining 4-, 5-, 6- or 7-membered heterocylic ring which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, F and CF3.
• Preferably, A is thiazolyl substituted by .
• Preferably, A is phenyl substituted by heteroaryl, -(CH2)1heteroaryl and -(CH2)1NR14R15.
• Preferably, A is selected from: ,. , , , , , , and .
• Preferably, A is selected from: , , and .
• Preferably, A is selected from: , and , and R10 and R11 are as defined in the first aspect above.
The present invention also encompasses, but is not limited to, the compounds listed in the s below.
In an aspect, the invention comprises a compound selected from: 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide; 2,5-Dimethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 2,5-Dimethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 1-Ethylmethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; lmethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 1-[4-(Pyridinyloxy)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)- amide; 3-Methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino- isoquinolinylmethyl)-amide; 3-Cyclopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 3-Isopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid noisoquinolinylmethyl )-amide; 3-Cyclobutyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 3-Hydroxymethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 3-Cyano[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino- isoquinolinylmethyl)-amide; yl[4-(4-methyl-pyrazolylmethyl)-benzyl]-thiazolecarboxylic acid (1-aminoisoquinolinylmethyl 3-(3,5-Dimethyl-isoxazolyl)[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]morpholinyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; -Amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide; 1-(6-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; opropyl(5-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid no-isoquinolinylmethyl)-amide; 1-[4-(4-Methylpyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]phenyl-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 3-Amino[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 3-Methoxymethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 3-Difluoromethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]thiophenyl-1H-pyrazolecarboxylic acid (1- isoquinolinylmethyl)-amide; 5-Amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid (1-amino-isoquinolin yl)-amide; 1-(2-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-(6-Ethoxy-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino- isoquinolinylmethyl)-amide; 1-[2-(3,3-Difluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-(3,3-Difluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-((R)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-((S)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole ylic acid no-isoquinolinylmethyl)-amide; 1-[6-((S)Fluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazolecarboxylic acid no-isoquinolinylmethyl)-amide; 1-[6-((R)Fluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-((S)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-((R)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(2-Pyrrolidinyl-pyrimidinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-(5-Pyrrolidinyl-pyrazinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-[2-((S)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-(3-Hydroxymethyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-((R)Hydroxymethyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(6-Propoxy-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 1-(5-Fluoropyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(6-Ethoxyfluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-(4-Pyrazolylmethyl-benzyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino- nolinylmethyl)-amide; 1-[4-(4-Cyano-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-[4-(4-Carbamoyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(6-Pyrazolylmethyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-(2-Pyrazolylmethyl-thiazolylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- isoquinolinylmethyl)-amide; 1-[2-(4-Methyl-pyrazolylmethyl)-thiazolylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Cyclopropyl{6-[(2-methoxy-ethyl)-methyl-amino]-pyridinylmethyl}-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Cyclopropyl[6-(3,3-difluoro-pyrrolidinyl)-pyridinylmethyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Cyclopropyl(4-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Cyclopropyl(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 3-Cyclopropyl(4-[1,2,3]triazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 3-Cyclopropyl(6-phenoxy-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl hloroethoxy-pyridinylmethyl)cyclopropyl-1H-pyrazolecarboxylic acid (1-amino- isoquinolinylmethyl)-amide; 3-Cyclopropyl(6-diethylaminofluoro-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-(5-Chloropyrrolidinyl-pyridinylmethyl)cyclopropyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 3-Amino(6-ethoxy-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide; 3-Amino(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl and pharmaceutically acceptable salts and solvates thereof.
In an , the invention comprises a compound selected from: 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide; 4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (6-methyl-1H- pyrrolo[2,3-b]pyridinylmethyl)-amide; 2,5-Dimethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 2,5-Dimethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 1-Ethylmethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-Ethylmethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 1-[4-(Pyridinyloxy)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)- amide; 1-[4-(4-Methylpyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid no-isoquinolin ylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide; 2,5-Dimethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 2,5-Dimethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (1H-pyrrolo[2,3- b]pyridinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1H-pyrrolo[2,3- b]pyridinylmethyl)-amide; and pharmaceutically acceptable salts and es thereof.
In an aspect, the invention comprises a compound selected from: 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide; 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1-amino-isoquinolin- 7-ylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide; 2,5-Dimethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1- aminoisoquinolinylmethyl)-amide; 1-Ethylmethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-Ethylmethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1- aminoisoquinolinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolin- thyl)-amide; 1-(2-Phenyl-thiazolylmethyl)-1H-imidazolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide; 1-(2-Phenyl-thiazolylmethyl)-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)- amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (1- aminoisoquinolinylmethyl)-amide; and pharmaceutically acceptable salts and solvates thereof.
In an aspect, the invention ses a compound selected from: 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid hyl-1H- pyrrolo[2,3-b]pyridinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (1H-pyrrolo[2,3- b]pyridinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1H-pyrrolo[2,3- b]pyridinylmethyl)-amide; 2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (1H- pyrrolo[2,3-b]pyridinylmethyl)-amide; 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (4,6- dimethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1H-pyrrolo[2,3- b]pyridinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (4,6-dimethyl-1H- pyrrolo[2,3-b]pyridinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (4,6- dimethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-amide; PCT/GB 2014/051 592 — 26-06—2015 1-[4—(4-Methyl-pyrazo|—1—ylmethyl)-benzyl]trifluoromethyl-1H-pyrazole—4-carboxylic acid (1H- pyrrolo[2,3-b]pyridinylmethyl)-amide; 1-[4-(4—Methyl-pyrazol-1—y|methyl)-benzyl1trifluoromethyl-lH—pyrazolecarboxylic acid (1H- indolylmethyl)-amide; 3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazole—4-carboxylic acid (1H-indazol- 4-ylmethyl)-amide; 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazo|ecarboxy|ic acid (1H- indazoly|methyl)—amide; and pharmaceutically acceptable salts and solvates thereof.
Therapeutic Applications As previously ned, the compounds of the present invention are potent and selective inhibitors of plasma kallikrein. They are therefore useful in the treatment of e ions for which over- activity of plasma kallikrein is a causative factor.
Accordingly, the present invention provides a compound of formula (I) for use in medicine.
The present invention also provides for the use of a compound of a (I) in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated.
The present invention also provides a nd of formula (I) for use in the treatment or prevention of a e or condition in which plasma kallikrein activity is implicated.
The present invention also provides a method of treatment of a disease or condition in which plasma kallikrein activity is implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound of a (I).
In one aspect, the e or condition in which plasma kallikrein ty is implicated is selected from impaired visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel AMENDED SHEET e, arthritis, inflammation, septic shock, hypotension, cancer, adult atory distress me, disseminated intravascular coagulation, cardiopulmonary bypass surgery and bleeding from post operative surgery.
In a preferred aspect, the disease or condition in which plasma kallikrein activity is implicated is l vascular permeability associated with diabetic retinopathy and diabetic macular edema.
Combination Therapy The compounds of the present invention may be administered in combination with other therapeutic agents. Suitable combination therapies include a compound of formula (I) combined with one or more agents selected from agents that inhibit platelet-derived growth factor (PDGF), endothelial growth factor (VEGF), integrin alpha5beta1, ds, other agents that inhibit plasma kallikrein and other inhibitors of inflammation. Specific examples of eutic agents that may be combined with the compounds of the present invention include those disclosed in 885A and by S. Patel in Retina, 2009 Jun;29(6 Suppl):S45-8.
When combination therapy is employed, the compounds of the present invention and said combination agents may exist in the same or different pharmaceutical compositions, and may be administered separately, sequentially or simultaneously.
In another aspect, the compounds of the present invention may be stered in combination with laser treatment of the . The ation of laser therapy with intravitreal injection of an inhibitor of VEGF for the treatment of diabetic macular edema is known (Elman M, Aiello L, Beck R, et al.
“Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema” .Ophthalmology. 27 April 2010).
Definitions The term "alkyl" includes saturated hydrocarbon residues including: - linear groups up to 10 carbon atoms (C1-C10), or of up to 6 carbon atoms (C1-C6), or of up to 4 carbon atoms (C1-C4). Examples of such alkyl groups e, but are not limited, to C 1 - methyl, C2 - ethyl, C3 - propyl and C4- n-butyl. - branched groups of between 3 and 10 carbon atoms (C3-C10), or of up to 7 carbon atoms ), or of up to 4 carbon atoms (C3-C4). Examples of such alkyl groups include, but are not limited to, C 3 - iso-propyl, C4 - sec-butyl, C4 - iso-butyl, C4 - tert-butyl and C5 - neo-pentyl. each optionally substituted as stated above.
Cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 7 carbon atoms; n cycloalkyl may be optionally substituted with a substituent selected from alkyl, alkoxy and NR10R11; wherein R10 and R11 are independently selected from H and alkyl or R10 and R11 er with the nitrogen to which they are attached form a 4-, 5-, 6- or 7-membered heterocylic ring which may be saturated or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, F and CF3. Cycloalkyl groups may contain from 3 to 7 carbon atoms, or from 3 to 6 carbon atoms, or from 3 to 5 carbon atoms, or from 3 to 4 carbon atoms.
Examples of suitable monocyclic cycloalkyl groups include cyclopropyl, utyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term "alkoxy" includes ed hydrocarbon residues including: - linear groups of n 1 and 6 carbon atoms (C1-C6), or of n 1 and 4 carbon atoms ).
Examples of such alkoxy groups e, but are not limited to, C1 - methoxy, C2 - ethoxy, C3 - npropoxy and C4 - n-butoxy. - branched groups of between 3 and 6 carbon atoms (C3-C6) or of between 3 and 4 carbon atoms (C3- C4). Examples of such alkoxy groups include, but are not limited to, C 3 - iso-propoxy, and C4 - secbutoxy and tert-butoxy. each optionally substituted as stated above.
Unless otherwise stated, halo is selected from Cl, F, Br and I.
Aryl is as defined above. Typically, aryl will be optionally substituted with 1, 2 or 3 substituents.
Optional substituents are selected from those stated above. Examples of suitable aryl groups include phenyl and naphthyl (each optionally substituted as stated above). ably aryl is selected from phenyl, tuted phenyl (substituted as stated above) and naphthyl.
Heteroaryl is as defined above. es of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, lyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, zinyl, pyrimidinyl, nyl, indolyl, benzimidazolyl, benzotriazolyl, quinolinyl and isoquinolinyl (optionally substituted as stated above). Preferably heteroaryl is selected from pyridyl, benzothiazole, indole, N-methylindole, thiazole, substituted thiazole, thiophenyl, furyl, pyrazine, pyrazole and substituted pyrazole; wherein substituents are as stated above.
The term "N-linked", such as in "N-linked heterocycloalkyl", means that the heterocycloalkyl group is joined to the remainder of the molecule via a ring nitrogen atom.
The term "O-linked", such as in ked hydrocarbon e", means that the hydrocarbon residue is joined to the remainder of the molecule via an oxygen atom.
In groups such as –COOR* and -(CH2)1aryl, "-" denotes the point of attachment of the substituent group to the remainder of the molecule.
"Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and includes, when appropriate, ceutically acceptable base on salts and pharmaceutically acceptable acid addition salts. For example (i) where a nd of the invention ns one or more acidic groups, for example carboxy groups, pharmaceutically acceptable base addition salts that can be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, N-methyl-glucamine, diethanolamine or amino acids (e.g. lysine) and the like; (ii) where a compound of the invention contains a basic group, such as an amino group, pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, es, tartrates, mesylates, succinates, oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates, camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates and the like. lts of acids and bases can also be formed, for example, hemisulfate and lcium salts.
For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
“Prodrug” refers to a nd which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for forming prodrugs are described in ‘The Practice of Medicinal try, 2nd Ed. 585 (2003) and in F. J. Leinweber, Drug Metab. Res., 1987, 18, 379.
The compounds of the ion can exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when the solvent is water.
Where compounds of the invention exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and trans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, ing racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers can be prepared by the application or tion of known s (e.g. asymmetric synthesis).
In the context of the present invention, references herein to "treatment" include nces to curative, palliative and prophylactic treatment.
General s The compounds of formula (I) should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication. They may be administered alone or in combination with one or more other compounds of the ion or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable ents.
The term ’excipient’ is used herein to describe any ingredient other than the compound(s) of the invention which may impart either a functional (i.e., drug e rate lling) and/or a nonfunctional (i.e., processing aid or diluent) characteristic to the formulations. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and ity, and the nature of the dosage form.
Compounds of the invention ed for pharmaceutical use may be administered as a solid or liquid, such as a tablet, capsule or solution. Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those d in the art. Such compositions and methods for their preparation may be found, for example, in Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
Accordingly, the present invention provides a pharmaceutical composition comprising a compound of a (I) and a pharmaceutically acceptable r, diluent or excipient.
For the treatment of conditions such as retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema, the compounds of the invention may be administered in a form suitable for injection into the ocular region of a patient, in particular, in a form suitable for intravitreal injection. It is envisaged that formulations suitable for such use will take the form of sterile solutions of a compound of the invention in a suitable aqueous vehicle. The compositions may be administered to the patient under the supervision of the attending physician.
The compounds of the invention may also be administered ly into the blood stream, into aneous tissue, into muscle, or into an internal organ. Suitable means for parenteral administration include enous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) ors, needle-free injectors and infusion techniques.
Parenteral formulations are typically aqueous or oily solutions. Where the solution is aqueous, excipients such as sugars (including but not restricted to glucose, l, sorbitol, etc.), salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably ated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
Parenteral formulations may include implants derived from degradable polymers such as ters (i.e., ctic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations may be administered via surgical incision into the subcutaneous tissue, ar tissue or directly into specific organs.
The ation of parenteral formulations under sterile ions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of nds of formula (I) used in the preparation of eral solutions may be increased by the use of riate formulation techniques, such as the incorporation of co-solvents and/or solubility-enhancing agents such as surfactants, micelle structures and cyclodextrins.
In one embodiment, the compounds of the ion may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and liquid (including multiple phases or dispersed s) such as tablets; soft or hard capsules containing multi- or articulates, s, emulsions or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
Formulations le for oral administration may also be designed to deliver the compounds of the invention in an ate e manner or in a rate-sustaining manner, wherein the release profile can be delayed, , controlled, sustained, or delayed and sustained or modified in such a manner which optimises the eutic efficacy of the said compounds. Means to deliver compounds in a rate - ning manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.
Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer n. es of rate-sustaining polymers include hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, xanthum gum, polymethacrylates, polyethylene oxide and polyethylene glycol.
Liquid (including multiple phases and dispersed systems) formulations include emulsions, solutions, syrups and elixirs. Such formulations may be presented as s in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, ene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those bed in Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986.
The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. man and L. Lachman (Marcel Dekker, New York, 1980).
For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.01 mg and 1000 mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg depending, of course, on the mode of administration.
The total dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the y. tic s The compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using riate materials, and are further exemplified by the specific examples provided herein below. Moreover, by utilising the ures described herein, one of ordinary skill in the art can y prepare additional nds that fall within the scope of the present invention d herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
The compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those bed previously herein above.
It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to avoid their unwanted participation in a reaction leading to the formation of the compounds. Conventional protecting groups, for example those bed by T. W. Greene and P. G. M. Wuts in ctive groups in organic chemistry” John Wiley and Sons, 4th Edition, 2006, may be used. For example, a common amino protecting group suitable for use herein is tert-butoxy carbonyl (Boc), which is readily removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as dichloromethane. Alternatively the amino protecting group may be a benzyloxycarbonyl (Z) group which can be removed by hydrogenation with a ium catalyst under a hydrogen atmosphere or 9- fluorenylmethyloxycarbonyl (Fmoc) group which can be removed by solutions of ary organic amines such as diethylamine or piperidine in an organic ts. Carboxyl groups are typically protected as esters such as methyl, ethyl, benzyl or tert-butyl which can all be removed by hydrolysis in the presence of bases such as lithium or sodium hydroxide. Benzyl protecting groups can also be removed by hydrogenation with a ium st under a hydrogen here whilst tert-butyl groups can also be removed by trifluoroacetic acid. Alternatively a trichloroethyl ester protecting group is removed with zinc in acetic acid. A common hydroxy protecting group le for use herein is a methyl ether, deprotection conditions comprise refluxing in 48% aqueous HBr for 1-24 hours, or by stirring with borane tribromide in romethane for 1-24 hours. atively where a hydroxy group is protected as a benzyl ether, deprotection conditions se hydrogenation with a palladium st under a hydrogen atmosphere.
The compounds according to general formula I can be prepared using conventional synthetic methods for example, but not limited to, the route outlined in Scheme 1. The amine 2 is coupled to an acid 1 to give the compound 3 This ng is typically carried out using standard coupling condition such as hydroxybenzotriazole and carbodiimide such as water soluble carbodiimide in the presence of an organic base. Other standard coupling methods e the reaction of acids with amines in the presence of 2-(1H-benzotriazoleyl)-1,1,3,3-tetramethylaminium hexafluorophosphate or benzotriazoleyl-oxy-tris-pyrrolidino-phosphoium hexaffluorophosphate or bromo-trispyrolidinophosphoium hexafluorophosphate in the presence of organic bases such as triethylamine, diisopropylethylamine or ylmorpholine. Alternatively the amide formation can take place via an acid chloride in the presence of an organic base. Such acid chlorides can be formed by methods well known in the literature, for example reaction of the acid with oxalyl chloride or thionyl chloride.
A Y z R2 NH R5 O R1 L X OH R1 z R2 W + N R6 Y N R7 O H N X W NH 2 R7 R3 2 R3 N 1 2 3 Scheme 1 Alternatively compounds according to l formula I can be prepared using the route exemplified in Scheme 2. The acid 1 can be coupled to an amine 4 using suitable coupling methods as previously described to give compound 5 in which the second amino group is amino-protected with a standard protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9- fluorenylmethyloxycarbonyl (Fmoc). In a typical second step the protecting group is removed to give compound 3 using standard methods as previously described.
R5 R5 O R1 A Y z R2 NHPG 1 z L X R2 OH R1 R6 N W + N Y H H N X W NHPG R7 O 1 2 R7 R3 1 4 R5 O R1 z R2 R6 Y N X W NH R7 R3 2 Scheme 2 Alternatively nds according to general a I can be prepared using the route outlined in Scheme 3. The acid 6 can be coupled to an amine 4 using suitable coupling methods as previously described to give compound 7 in which the second amino group is amino-protected with a standard protecting group such as tert-butyloxycarbonyl (Boc), oxycarbonyl (Z) or 9- fluorenylmethyloxycarbonyl (Fmoc). In a typical second step the nitrogen of the heterocyclic ring is alkylated with compound 8 to give compound 9. The alkylation can be carried out in the presence of a base such as potassium carbonate, cesium carbonate, sodium carbonate or sodium hydride in which case the leaving group is a halide or sulphonate. Alternatively the alkylation may be carried out using an alcohol under Mitsunobu conditions in the presence of nylphosphine. In a third step the protecting group is d to give compound 10 using standard methods as previously described.
R5 R5 O R1 Y z R2 NHPG HN z R2 OH R1 + N R6 W N N N W NHPG + A LG R7 O H N 1 2 H R7 R3 1 6 4 7 8 R5 O R1 R5 O R1 z R2 z R2 R6 Y N R6 N N H H X W NH W NHPG R7 R3 2 N R7 R3 1 A N A N 10 9 Scheme 3 Alternatively compounds according to general a I can be prepared using the route ed in Scheme 4. The pyrrole 15 can be formed in two steps the first of which involves reaction of the sodium salt of an alkyl ketoacetate 11 with a chloroketone 12 in the presence of a base such as potassium carbonate to give compound 13 which in a l second step is reacted with the amine 14 in the presence of an acid such as but not limited to sulphonic acid derivatives e.g. p-toluenesulphonic acid to yield compound 15 which in a typical third step is subsequently hydrolysed to the corresponding acid 16 using standard methods as described previously. In a typical fourth step the acid 16 can be coupled to an amine 2 using suitable coupling methods as usly described to give nd 17. The second amino group may be amino-protected with a standard protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenylmethyloxycarbonyl (Fmoc), if such tion is used the final step will involve removal of the protecting group using standard methods as previously described.
O OPG O 2 O OPG + Cl 2 + A NH R7 O R6 R7 O 2 11 12 13 14 R2 NH 2 R6 R6 N A A + N H N OH N OPG 2 2 R3 O R7 O 2 16 15 O R1 R6 N N NH R7 R3 2 A N Scheme 4 Alternatively nds according to general formula I can be ed using the route outlined in Scheme 5. The triazole 19 can be formed by reaction of an alkyl propiolate with the azide 18 under azide alkyne Huisgen cycloaddition conditions employing a catalyst such as copper salts with abscorbic acid derivatives. In a typical second step the ester is hydrolysed to the corresponding acid 20 using standard methods as described previously. In a typical third step the acid 20 can be coupled to an amine 2 using suitable coupling methods as previously described to give compound 21. The second amino group may be protected with a standard protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenylmethyloxycarbonyl (Fmoc), if such tion is used the final step will involve removal of the protecting group using standard methods as previously described.
A N N OPG N 2 + OPG A N 2 O 3 18 19 O R1 N R2 R2 NH N 2 N H R1 A N N N NH N R3 2 + N OH A H N N 2 21 2 20 Scheme 5 atively compounds according to general formula I can be prepared using the route outlined in Scheme 6. The imidazole 23 can be formed by reaction of the acrylate derivative 22 with the amine 14 in the presence of organic bases such as ropylethylamine or triethylamine. In a typical second step the ester is hydrolysed to the corresponding acid 24 using standard methods as described previously. In a typical third step the acid 24 can be d to an amine 2 using le coupling methods as previously described to give compound 25. The second amino group may be amino-protected with a standard protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9- fluorenylmethyloxycarbonyl (Fmoc), if such protection is used the final step will involve removal of the protecting group using standard methods as previously described.
CN A N N OPG N 2 + OPG A NH 2 O 2 22 14 23 O R1 N R2 R2 NH N 2 H R1 A N N NH N R3 2 + N OH A H N N 2 2 24 Scheme 6 Alternatively compounds according to general a I can be prepared using the route outlined in Scheme 7. In a typical first step the nitrogen of the heterocyclic ring is derivatised by reaction of compound 7 with the sulphonyl de 26 in the presence of organic bases such as diisopropylethylamine or triethylamine to give compound 27. In a typical final step the ting group is removed to give nd 28 using standard methods as previously described.
R5 O R1 R5 O R1 O z R2 z R2 R6 N N N H R6 N H S N W NHPG N W NHPG O R3 A Cl R7 H R7 R3 1 + S O A N R5 O R1 z R2 R6 Y N X W NH O R7 R3 2 Scheme 7 Examples The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used: DCM Dichloromethane DMF N,N-Dimethylformamide EtOAc Ethyl Acetate 2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouronium HATU hexafluorophosphate(V) hrs Hours HOBt Hydroxybenzotriazole LCMS Liquid tography mass spectrometry Me Methyl MeCN Acetonitrile MeOH Methanol Min Minutes MS Mass um Nuclear magnetic resonance spectrum – NMR spectra were recorded at a frequency of 400MHz unless otherwise indicated Pet. Ether Petroleum ether fraction boiling at 60-80°C Ph Phenyl rt room temperature THF Tetrahydrofuran TFA Trifluoroacetic acid All reactions were carried out under an atmosphere of nitrogen unless specified otherwise. 1H NMR spectra were ed on a Bruker (400MHz) spectrometer with reference to deuterium solvent and at rt.
Molecular ions were obtained using LCMS which was d out using a Chromolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient 10% to 90% 0.1% HCO2H/MeCN into 0.1% HCO2H/H2O over 13 min, flow rate 1.5 mL/min, or using Agilent, X-Select, acidic, 5-95% MeCN/water over 4 min. Data was collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electospray ionisation in conjunction with a Thermofinnigan Surveyor LC system.
Chemical names were generated using the Autonom re provided as part of the ISIS draw package from MDL ation Systems.
Where products were purified by flash chromatography, ‘silica’ refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Merck silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column n. Reverse phase preparative HPLC cations were d out using a Waters 2525 binary gradient pumping system at flow rates of typically 20 mL/min using a Waters 2996 photodiode array detector.
All solvents and commercial reagents were used as received.
EXAMPLE 1 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide A. 2-Acetyloxo-pentanoic acid ethyl ester Ethylacetoacetate sodium salt (17.10g, 112mmol) was suspended in acetone (500mL). Potassium carbonate (15.54g, 112mmol) and potassium iodide (3.73g, 22.48mmol) were added and the resulting solution was refluxed. Chloroacetone (11.41g, 124mmol) was added dropwise over a period of 5 min.
Once the on was te the mixture was heated under reflux for a further 2 hrs. The reaction mixture was allowed to cool to rt and the solid material was filtered off and washed with acetone. The resultant filtrate was evaporated and purified by flash chromatography (silica), eluent 75% Pet. Ether, % EtOAc, fractions combined and evaporated in vacuo to give a yellow oil fied as 2-acetyloxo- pentanoic acid ethyl ester (10.1g, 54.2mmol, 48% yield).
B. 1-[2-phenyl)-thiazolylmethyl]-2,5-dimethyl-1H-pyrrolecarboxylic acid ethyl ester 2-Acetyloxo-pentanoic acid ethyl ester (1.8g, 9.66mmol) was dissolved in toluene , 2-phenylthiazoylmethylamine (2.02g, mol) and p-toluenesulphonic acid (183mg, 0.97mmol) were added. The on mixture was heated at reflux for 4 hrs after which time it was diluted with ethyl acetate and washed with NaHCO3 L), water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 85% Pet. Ether, % EtOAc, ons combined and evaporated in vacuo to give a colourless oil identified as 1-[2- phenyl)-thiazolylmethyl]-2,5-dimethyl-1H-pyrrolecarboxylic acid ethyl ester (1.26g, 3.69mmol, 38% yield).
[M+H]+ = 341.
C. 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid 1-[2-Phenyl)-thiazolylmethyl]-2,5-dimethyl-1H-pyrrolecarboxylic acid ethyl ester (1.07g, 3.14mmol) was dissolved in ethanol (50mL). Sodium hydroxide (629mg, 15.72mmol) in water (5mL) was added. The reaction e was heated at 90°C for 3 days after which time the solvent was removed in vacuo. The residue was diluted with water and ied to pH1 with 1M HCl and extracted with ethyl acetate (3x 50mL). The combined extracts were washed with water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo to give an off white solid identified as 2,5-dimethyl(2-phenyl-thiazolylmethyl)- 1H-pyrrolecarboxylic acid (980mg, 3.14mmol, 100% yield).
[M+H]+ = 313.
D. 2-((E)Dimethylamino-vinyl)-terephthalonitrile ester Methylterephthalonitrile (1.42g, 9.99mmol) and Bredereck's reagent (3.48g, 19.98mmol) were dissolved in DMF (15mL). The on mixture was heated at 75°C under nitrogen for 72hrs after which time the solvent was removed in vacuo. ation with Pet. Ether gave a bright yellow solid fied as 2-((E)- 2-dimethylamino-vinyl)-terephthalonitrile ester (1.88g, 0.95mmol, 95% yield). 1H NMR (CD 3OD) 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) E. 1-Amino(2,4-dimethoxy-benzyl)-1,2-dihydro-isoquinolinecarbonitrile 2-((E)Dimethylamino-vinyl)-terephthalonitrile ester (1.85g, 9.38mmol) was dissolved in 1,3-dimethyl- 3,4,5,6-tetrahydro-2(1H)-pyrimidinone (5mL) and 2,4-dimethoxybenzylamine (2.35g, mol) was added. The reaction mixture was heated at 75°C under nitrogen. After 3hrs the reaction mixture was cooled and diethyl ether/ Pet. Ether (15:85) was added. The yellow solid was filtered off, dried in vacuo, and identified as 1-amino(2,4-dimethoxy-benzyl)-1,2-dihydro-isoquinolinecarbonitrile (2.65g, 8.38mmol, 89% yield) [M+H]+ = 320 1H NMR (CD 3OD) 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), H, d, J = 7.4Hz), 7.72 (1H, dd, J = 8.5Hz, , 7.93 (1H,s), 8.45 (1H, d, J = 8.5 Hz) F. 1-Amino-isoquinolinecarbonitrile 1-Amino(2,4-dimethoxy-benzyl)-1,2-dihydro-isoquinolinecarbonitrile (1.6g, 5.0mmol) was dissolved in e (17mL) and trifluoroacetic acid (20mL). The reaction mixture was heated at 105°C under nitrogen for 12hrs after which time the reaction mixture was cooled, l ether/Pet. Ether (3:7) was added, the resultant solid was filtered off, dried in vacuo and fied as 1-amino-isoquinoline carbonitrile (770mg, 4.54mmol, 91% ).
[M+H]+ = 170. 1H NMR (CD 3OD) 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).
G. (1-Amino-isoquinolinylmethyl)-carbamic acid tert-butyl ester 1-Amino-isoquinolinecarbonitrile (200mg, 1.18mmol) was dissolved in methanol . This solution was cooled to 0°C. Nickel (II) chloride hexahydrate (28mg, 0.12mmol) and di-tertbutyl dicarbonate (516g, 2.36mmol) were added followed by sodium borohydride (313g, 8.22mmol) portionwise. The reaction mixture was d at 0°C to room temp for 3 days. The MeOH was removed by evaporation. The residue was dissolved in CHCl3 (70mL), washed with sat NaHCO3 (1x30mL), water (1x30mL), brine (1x30mL), dried (Na2SO4) and ated in vacuo to give a yellow oil identified as (1-amino-isoquinolin- 6-ylmethyl)-carbamic acid tert-butyl ester (110mg, 0.4mmol, 34% yield).
[M+H]+ = 274.
H. 6-Aminomethyl-isoquinolinylamine hydrochloride (1-Amino-isoquinolinylmethyl)-carbamic acid utyl ester (110mg, 0.40mmol) was dissolved in 4M HCl in dioxane . After 18 hrs at rt the solvent was removed in vacuo to give a pale brown solid identified as 6-aminomethyl-isoquinolinylamine hydrochloride (67mg, 0.39mmol, 96% yield).
[M+H]+ = 174.
I. 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (87mg, 0.28mmol) was dissolved in CH2Cl2(15mL). This solution was cooled to 0°C. 6-Aminomethyl-isoquinolinylamine hydrochloride (48mg, 0.28mmol) was added followed by HOBt (45mg, 0.31mmol) and triethylamine (147mg, 1.4mmol). Water soluble carbodiimide (75mg, ol) was then added. After 18 hrs at 0°C to rt, reaction mixture was diluted with chloroform (200mL) and washed with NaHCO3 (1x50mL), water L), brine (1x50mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent dichloromethane:MeOH:NH3 (100:10:1), ons combined and evaporated in vacuo to give a white solid identified as 2,5-dimethyl(2-phenyl-thiazolylmethyl)-1H- ecarboxylic acid (1-amino-isoquinolinylmethyl)-amide (68mg, 0.14mmol, 52% yield).
[M+H]+ = 468. 1H NMR: (d6-DMSO), δ: 2.28 (3H, s), 2.56 (3H, s), 4.52 (2H, d, J= 5.9Hz), 5.18 (2H, s), 6.33 (1H, s), 7.05 (1H, d, J= 6.4Hz), 7.31 (1H, s), 7.48 - 7.52 (3H, m), 7.55 (1H, d, J= 9.9Hz), 7.65 (1H, s), 7.68 (1H, d, J= 6.5Hz), 7.81 - 8.00 (2H, s, br.), 7.89 - 7.91 (2H, m), 8.25 (1H, t, J= 5.9Hz), 8.32 (1H, d, J= 8.6Hz).
EXAMPLE 2 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide A. methyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (93mg, 0.30mmol) was dissolved in CH2Cl2 (15mL). This on was cooled to 0°C. 7-Aminomethyl-isoquinolinylamine hydrochloride (C. A. A. Van Boeckel et al.,WO 98/47876) (56mg, 0.33mmol) was added followed by HOBt (48mg, 0.32mmol) and triethylamine , 2.1mmol). Water soluble carbodiimide (80mg, 0.42mmol) was then added. After 18 hrs at 0°C to rt reaction mixture was diluted with chloroform (200mL) and washed with NaHCO3 (1x50mL), water (1x50mL), brine (1x50mL), dried (Na2SO4) and ated in vacuo. The residue was purified by flash chromatography a), eluent dichloromethane:MeOH:NH3 (100:10:1), fractions combined and evaporated in vacuo to give a white solid identified as 2,5-dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1-amino- isoquinolinylmethyl)-amide (30mg, 0.06mmol, 21% yield).
[M+H]+ = 468. 1H NMR: (d6-DMSO), δ: 2.26 (3H, s), 2.57 (3H, s), 4.49 (2H, d, J = , 5.17 (2H, s), 6.32 (1H, s), 6.85 (2H, s, br), 6.88 (1H, d, J = 5.9Hz), 7.28 (1H, s), 7.46 - 7.52 (3H, m), 7.58 (1H, dd, J = 8.1, 0.9Hz), 7.65 (1H, d, J = 8.4Hz), 7.73 (1H, d, J = 5.9Hz), 7.89 - 7.92 (2H, m), 8.10 (1H, s, br), 8.17 (1H, t, J = 5.9Hz).
EXAMPLE 3 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1H-pyrrolo[2,3-b]pyridin ylmethyl)-amide A. 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1H-pyrrolo[2,3- b]pyridinylmethyl)-amide 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid , 0.38mmol) was dissolved in CH2Cl2(20mL) and DMF(2mL). This solution was cooled to 0°C. 5-Aminomethylazaindole hydrochloride (57mg, 0.38mmol), HOBt (62mg, 0.41mmol) and triethylamine (192mg, 1.92mmol). and water soluble carbodiimide (104mg, 0.54mmol) were then added. After 18 hrs at 0°C to rt reaction mixture was d with chloroform (100mL) and washed with NaHCO3 (1x30mL), water (1x50mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 4% MeOH, 96% dichloromethane, fractions combined and evaporated in vacuo to give a white solid identified as 2,5-dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrole ylic acid (1H-pyrrolo[2,3-b]pyridinylmethyl)-amide (62mg, 0.14mmol, 37% .
[M+H]+ = 442 1H NMR: (d6-DMSO), δ: 2.24 (3H, s), 2.55 (3H, s), 4.43 (2H, d, J= 6.0Hz), 5.15 (2H, s), 6.27 (1H, s), 6.38- 6.39 (1H, m), 7.22 (1H, s), 7.41 (1H, t, J= 2.9Hz), 7.46-7.51 (3H, m), 7.83 (1H, d, J= 1.6Hz), 7.85-7.90 (2H, m), 8.09 (1H, t, J= 6.0Hz), 8.17 (1H, d, J= 1.9Hz), 11.51 (1H, s).
REFERENCE EXAMPLE 4 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid no-isoquinolin ylmethyl)-amide A. 1-(4-Hydroxymethyl-benzyl)-1H-pyridinone 4-(Chloromethyl)benzylalcohol (5.0g, 31.93mmol) was dissolved in acetone (150mL) 2-hydroxypyridine (3.64g, 38.3mmol) and potassium carbonate (13.24g, 95.78mmol) were added and the reaction mixture was stirred at 50°C for 3 hrs after which time the solvent was removed in vacuo and the residue taken up in chloroform (100mL), this solution was washed with water (1x30mL), brine (1x30mL), dried 4) and evaporated in vacuo. The residue was ed by flash chromatography (silica), eluent 3%MeOH, 97% CHCl3, fractions combined and evaporated in vacuo to give a white solid identified as 1- (4-hydroxymethyl-benzyl)-1H-pyridinone (5.30g, 24.62mmol, 77% yield). + = 238 B. 1-(4-Bromomethyl-benzyl)-1H-pyridinone 1-(4-Hydroxymethyl-benzyl)-1H-pyridinone (2.30g, 6.97mmol) was ved in dichloromethane (250mL). To this solution was added phosphorous tribromide (5.78g, mol) The reaction mixture was stirred at rt for 18 hrs and diluted with CHCl3 (250mL) the filtrate was washed with saturated NaHCO3 (1x30mL), water (1x30mL), brine (1x30mL), dried (Na2SO4) and ated in vacuo to give a white solid which was identified as 1-(4-bromomethyl-benzyl)-1H-pyridinone (2.90g, 10.43mmol, 98% yield).
[M+H]+ = 278 C. 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester 1-(4-Bromomethyl-benzyl)-1H-pyridinone (2.80g, 10.07mmol) was dissolved in DMF (50mL) ethyl 1H- pyrazolecarboxylate , 12.08mmol) and caesium carbonate (9.84g, 30.2mmol) were added and the reaction mixture was stirred at 50°C for 18 hrs after which time the reaction mixture was diluted with EtOAc (100mL), this solution was washed with water (1x30mL), brine L), dried (Na2SO4) and evaporated in vacuo. The residue was ed by flash chromatography (silica), eluent 3%MeOH, 97% CHCl3, fractions combined and evaporated in vacuo to give a white foamy solid identified as 1-[4-(2-oxo- 2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester , 9.49mmol, 94% yield).
[M+H]+ = 338 D. 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester , 9.49mmol) was dissolved in THF (50mL) and water (5mL) lithium hydroxide (1.13g, 47.43mmol) was added. The reaction mixture was stirred at 50°C for 48 hrs after which time the solvent was concentrated in vacuo and the residue taken up in CHCl3 (150mL), the s layer was ted and acidified with 1M HCl to pH2 and extracted with CHCl3 L), the ed extracts were washed with water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo, the residue was triturated with EtOAc and Pet. Ether to give a white solid identified as 1-[4-(2-oxo-2H-pyridin ylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (3.20g, 6.14mmol, 65% yield).
[M+H]+ = 310, 332 (M+Na) E. 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (80mg, 0.26mmol) was dissolved in CH2Cl2 (2.5mL). HATU (108mg, 0.28mmol) was added followed by 6- (aminomethyl)isoquinolinamine (49mg, 0.28mmol) and N,N-diisopropylethylamine (67mg, 0.52mmol). After 18 hrs at rt the reaction mixture was diluted with chloroform (400mL) washed with NH4Cl (1x30mL), water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo giving a yellow oil. The e was purified by flash chromatography (silica), eluent romethane:MeOH:NH3 (100:10:1). Fractions combined and evaporated in vacuo to give a white solid identified as 1-[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide (22mg, 0.046mmol, 18% yield).
[M+H]+ = 465 1H NMR: (d6-DMSO), δ: 4.55 (2H, d, J = 6.0Hz), 5.08 (2H, s), 5.33 (2H, s), 6.23 (1H, td, J = 1.4, 6.7Hz), 6.40 (1H, dd, J = 1.3, 9.5Hz), 6.94 (1H, d, J = 6.1Hz), 7.10-7.32 (5H, m), 7.38-7.47 (2H, m), 7.59 (1H, s, br), 7.71- 7.81 (2H, m), 7.92 (1H, s), 8.21 (1H, d, J = 8.6Hz), 8.28 (1H, s), 8.72 (1H, t, J = 5.9Hz).
NCE EXAMPLE 5 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide A. 1-(4-Azidomethyl-benzyl)-1H-pyridinone 1-(4-Hydroxymethyl-benzyl)-1H-pyridinone (570mg, 2.65mmol) and 1,8-diazabicyclo[5.4.0]undec ene (806mg, 5.30mmol) were dissolved in DMF . Diphenylphosphoryl azide (1.09g, 3.97mmol) was added and the reaction mixture was stirred at rt for 3 hrs after which time the reaction mixture was diluted with EtOAc (100mL), this on was washed with water (1x30mL), brine (1x30mL), dried (Na2SO4) and ated in vacuo. The residue was purified by flash chromatography (silica), eluent 3%MeOH, 97% CHCl3, fractions combined and evaporated in vacuo to give a white foamy solid identified as 1-(4-azidomethyl-benzyl)-1H-pyridinone (430mg, ol, 68% yield).
[M+Na]+ = 361 B. 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid ethyl ester 1-(4-Azidomethyl-benzyl)-1H-pyridinone (340mg, ol), ethyl propiolate (139mg, 1.41mmol), (+)-sodium L-ascorbate ( 280mg, ol) and copper (II) sulphate ydrate (71mg, 0.28mmol) were dissolved in tert-butanol (20mL) and water (5mL). The reaction mixture was stirred at rt for 18 hrs after which time the reaction mixture was diluted with chloroform (100mL), this solution was washed with water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The residue was triturated with ethyl acetate and Pet. Ether to give a white solid identified as 1-[4-(2-oxo-2H- pyridinylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid ethyl ester (430mg, 1.27mmol, 90% yield).
[M+H]+ = 486 C. 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid ethyl ester (110mg, 0.32mmol) was dissolved in THF (50mL) and water (5mL), lithium hydroxide (39mg, 1.62mmol) was added. The reaction mixture was stirred at 50°C for 18 hrs after which time the t was trated in vacuo and the residue taken up in EtOAc (50mL), the aqueous layer was ted, acidified with 1M HCl to pH2 and extracted CHCl3 (3x50mL) the combined ts were washed with water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 97% CHCl3, fractions combined and ated in vacuo to give a colourless oil identified as 2-oxo-2H-pyridinylmethyl)-benzyl]-1H-[1,2,3]triazole carboxylic acid (140mg, 0.45mmol, 49% yield).
D. 2-Oxo-2H-pyridinylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide 1-[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (100mg, 0.26mmol) was dissolved in CH2Cl2 (3.5mL). HATU (147mg, 0.39mmol) and 6-(aminomethyl)isoquinolinamine (61.4mg, 0.35mmol) were added followed by N,N-diisopropylethylamine (67mg, 0.52mmol). After 1 hour at rt the reaction mixture was diluted with chloroform (400mL) washed with NH4Cl (1x30mL), water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo giving a yellow oil. Trituration with methanol/diethyl ether (3:7, 10mL) gave a yellow solid identified as 1-[4-(2-oxo-2H-pyridin ylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide (107mg, 0.22mmol, 85% yield).
[M+H]+ = 466 1H NMR: (d6-DMSO), δ: 4.61 (2H, d, J = 6.2 Hz), 5.08 (2H, s), 5.63 (2H, s), 6.22 (1H, td, J = 1.4, 6.7 Hz), 6.34-6.48 (1H, m), 7.12 (1H, d, J = 6.7 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.34 (2H, d, J = 8.3 Hz), 7.41 (1H, ddd, J = 2.1, 6.6, 8.9 Hz), 7.63 (1H, dd, J = 1.5, 8.7 Hz), 7.67 (1H, d, J = 6.7 Hz), 7.72 (1H, s); 7.74-7.81 (1H, m), 8.42 (3H, d, J = 8.7 Hz), 8.67 (1H, s), 9.26 (1H, t, J = 6.2 Hz).
EXAMPLE 6 1-Ethylmethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide A. Ethyl 1-ethylmethyl-1H-pyrrolecarboxylate To a colourless solution of ethyl 4-methyl-1H-pyrrolecarboxylate (0.5 g, 3.26 mmol) in DMF (5 mL) at 0°C was added sodium hydride (0.137 g, 3.43 mmol) (effervescence). After stirring for 30 min, ethyl iodide (0.317 mL, 3.92 mmol) was added to the sion. The resultant white thick suspension was stirred at RT over the week-end. The reaction mixture was diluted with water (10 mL) and EtOAc (50 mL) was added. The layers were separated and the organic phase was washed with water (4 x 10 mL) and saturated brine (20 mL). The organic was dried over Na2SO4, ed and concentrated in vacuo to afford a pale yellow oil (0.6456 g) that was dried further to afford ethyl 1-ethylmethyl-1H-pyrrole carboxylate (0.5657 g, 3.06 mmol, 94 % yield).
[M+H]+ = 182 B. Ethyl chloromethyl)benzoyl)ethylmethyl-1H-pyrrolecarboxylate The zinc(II) chloride (3.35 g, 24.61 mmol) was weighed out to a 100 mL flask and dried under vacuum at 120 °C for 2 hrs to remove any water. The flask was placed under nitrogen and a solution of 4- (chloromethyl)benzoyl chloride (4.0 g, 21.16 mmol) in anhydrous dichloroethane (25 mL) was added.
The mixture was cooled in an ice-bath and a solution of ethyl 1-ethylmethyl-1H-pyrrolecarboxylate (2.23 g, 12.30 mmol) in anhydrous dichloroethane (8 mL) was added dropwise. After 10 min, the icebath was removed and the reaction d to stir at 40 °C for 1h 30 min. The mixture wa s allowed to heat for a further 30 min, then poured into ice-water (200 mL) and extracted with DCM (3 x 125 mL).
The ed organics were washed with water (100 mL), 1M HCl (100 mL) and brine (100 mL), then dried (Na2SO4), filtered and concentrated. The crude mixture was ed by chromatography (silica) eluting with a gradient of 0 to 15% EtOAc/Iso-Hexanes, holding at 0% and 10% EtOAc to afford the d product ethyl 5-(4-(chloromethyl)benzoyl)ethylmethyl-1H-pyrrolecarboxylate (2.12 g, 6.16 mmol, 50.1 % yield) as a pale yellow solid and the undesired isomer ethyl 3-(4- (chloromethyl)benzoyl)ethylmethyl-1H-pyrrolecarboxylate (1.00 g, 2.097 mmol, 17.04 % yield) as a gummy solid, contaminated with romethylbenzoic acid.
[M+H]+ =334/336 C. Ethyl 5-((4-(chloromethyl)phenyl)(hydroxy)methyl)ethylmethyl-1H-pyrrolecarboxylate A on of ethyl 5-(4-(chloromethyl)benzoyl)ethylmethyl-1H-pyrrolecarboxylate (2.26 g, 6.77 mmol) in anhydrous THF (20 mL) and anhydrous MeOH (3 mL) was treated with sodium borohydride (0.512 g, 13.54 mmol) portionwise (an ice-bath was added after 5 min to control exotherm) and the mixture stirred at ambient temperature for 1 hour. HPLC (XSelect, 4min) indicated >95% conversion to the desired compound. A further 100 mg of sodium borohydride were added and the mixture stirred for a further 30 min. The reaction mixture was poured into saturated aqueous NH4Cl solution (120 mL) and stirred for 5 min. The aqueous layer was ted with DCM (3 x 50 mL) and the combined organics washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to afford ethyl 5-((4- (chloromethyl)phenyl)(hydroxy)methyl)ethylmethyl-1H-pyrrolecarboxylate (2.30 g, 6.84mmol) as a clear oily foam.
[M-H2O+H]+ = 318/320 D. Ethyl 5-(4-(chloromethyl)benzyl)ethylmethyl-1H-pyrrolecarboxylate A solution of ethyl 5-((4-(chloromethyl)phenyl)(hydroxy)methyl)ethylmethyl-1H-pyrrole carboxylate (2.16 g, 6.43 mmol) in anhydrous DCM (22 mL) was cooled in an ice-bath and d with 2,2,2-trifluoroacetic acid (9.85 mL, 129 mmol) then triethylsilane (1.233 mL, 7.72 mmol). The mixture was allowed to stir at ambient ature for 45 min. The mixture was poured carefully into saturated aqueous NaHCO3 solution (250 mL, cooled in an th) and the biphasic mixture stirred for 15 min before extraction with DCM (3 x 75 mL). The combined organics were washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated. The crude mixture was ed by chromatography (silica) eluting with a gradient of 0 to 10% EtOAc/Iso-Hexanes to afford ethyl 5-(4- omethyl)benzyl)ethylmethyl-1H-pyrrolecarboxylate (1.46 g, 4.34 mmol, 64.4 % yield) as a clear gummy oil.
[M+H]+ = 2 E. Ethyl 1-ethylmethyl(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrrolecarboxylate Ethyl 5-(4-(chloromethyl)benzyl)ethylmethyl-1H-pyrrolecarboxylate (715 mg, 2.236 mmol) and pyridin-2(1H)-one (425 mg, 4.47 mmol) were dissolved in anhydrous MeCN (8 mL) and potassium carbonate (618 mg, 4.47 mmol) added. The mixture was stirred at 67 °C (DrySyn bath temperature) overnight. The mixture was partitioned between EtOAc (30 mL) and water (30 mL). The pH was adjusted to ~7 with 1M HCl and the organic layer collected. The aqueous was extracted with further EtOAc (2 x 30 mL) and the combined cs washed with brine (30 mL), dried (MgSO4), filtered and concentrated.
The crude t was ed by chromatography (silica) g with a gradient of 10 to 90% EtOAc/Iso-Hexanes, holding at ~65% to elute product. Product ning fractions were combined to afford ethyl 1-ethylmethyl(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrrolecarboxylate (715 mg, 1.851 mmol, 83 % yield) as a pale yellow gum after drying overnight under vacuum.
[M+H]+ = 379 F. 1-Ethylmethyl(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrrolecarboxylic acid A solution of ethyl 1-ethylmethyl(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrrole carboxylate (621 mg, 1.641 mmol) in THF (11 mL), MeOH (7 mL) and water (10 mL) was treated with lithium hydroxide (295 mg, 12.31 mmol) and the mixture heated at 65 °C with stirring overnight. The majority of the ts were removed under vacuum. The resultant cloudy mixture was partitioned between EtOAc (20 mL) and water (20 mL) containing 1M NaOH (1 mL). The organic layer was discarded and the aqueous layer acidified to ~pH 6 with 1M HCl forming a precipitate. This was allowed to stand for 20 min before filtration, washing with water (10 mL). The solid was dried under vacuum in the presence of CaCl2 for 3 hrs to afford 1-ethylmethyl(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H- pyrrolecarboxylic acid (543 mg, 1.534 mmol, 93 % yield).
[M+H]+ = 351 G. 1-Ethylmethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide A scintillation vial was charged with 1-ethylmethyl(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H- pyrrolecarboxylic acid (75 mg, 0.214 mmol), 6-(aminomethyl)isoquinolinamine (40.8 mg, mol), HATU (90mg, 0.235 mmol) and DCM (3.5 mL). N,N-diisopropylethylamine (74.6 µL, 0.428 mmol) was added and the mixture allowed to stir over a weekend.
The mixture was diluted with DCM (containing trace MeOH for solubility) (3 mL) and saturated s NH4Cl (4 mL) and , then left to stand until the layers separated. The mixture was passed through a phase separation cartridge (15 mL), the organic layer collected then concentrated under vacuum. The crude material was purified by chromatography (silica) eluting with a gradient of 0.5 to 6.5% MeOH (1%NH3)/DCM to afford 1-ethylmethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrrole carboxylic acid (1-amino-isoquinolinylmethyl)-amide (97 mg, 0.188 mmol, 88% yield) as an off-white foam. 1H NMR: (d6-DMSO), δ: 0.94 (3H, t, J = 7.0Hz), 2.00 (3H, s), 3.93 (2H, s), 4.15 (2H, q, J = 6.9Hz), 4.49 (2H, d, J = 6.0Hz), 5.04 (2H, s), 6.21 (1H, td, J = 6.7,1.4Hz), 6.39 (1H, d, J = 9.1Hz), 6.70-6.74 (3H, m), 6.84 (1H, d, J = 5.6Hz), 7.04 (2H, d, J = 8.2Hz), 7.20 (2H, d, J = 8.2Hz), 7.33-7.44 (2H, m), 7.51 (1H, s), 7.68-7.81 (2H, m), 8.12 (1H, d, J = 8.6Hz), 8.48 (1H, t, J = 6.1Hz).
[M+H]+ = 506 EXAMPLE 7 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (1H- pyrrolo[2,3-b]pyridinylmethyl)-amide A. 1-(4-Chloromethyl-benzyl)trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester Polymer-supported triphenylphospine (3.0mmol/g, 3 equiv, 1.0g) was swollen in THF/dichloromethane (1:1, 100mL). Under a nitrogen atmosphere ethyl 3-trifluoromethyl-1H-pyrazolecarboxylate (1.0g, 4.80mmol) and 4-(chloromethyl)benzylalcohol , 5.76mmol) were added followed by a solution of diisopropyl arboxylate (1.46g, 7.21mmol) in chloromethane (1:1, 10mL) over a period of 30min. The reaction mixture was d at rt for 18 hrs, the mixture was ed and the resin was washed with 3 cycles of dichloromethane/methanol (15mL). The combined filtrates were evaporated in vacuo. Two main products were identified which were separated by flash chromatography (silica), eluent 20% EtOAc, 80% Pet. Ether, fractions combined and evaporated in vacuo to give white solids identified as 1-(4-chloromethyl-benzyl)trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester (450mg, l, 27% yield) and 1-(4-chloromethyl-benzyl)trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester (1.12g, 3.23mmol, 67% yield) [M+H]+ = 347 B. 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester 1-(4-Chloromethyl-benzyl)trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester (980mg, 2.84mmol) was dissolved in acetone (50mL). 2-Hydroxypyridine (323mg, 3.39mmol) and potassium carbonate (1.17g, 8.48mmol) were added and the reaction mixture was stirred at 50°C for 3 hrs after which time the solvent was removed in vacuo and the residue taken up in EtOAc (100mL), this solution was washed with water (1x30mL) and brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The e was purified by flash chromatography (silica), eluent 3%MeOH, 97% CHCl3, fractions combined and evaporated in vacuo to give a less oil identified as 1-[4-(2-oxo-2H-pyridinylmethyl)-benzyl]- 3-trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester (1.10g, ol, 96% yield).
[M+H]+ = 406 C. 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester (1.10g, 2.71mmol) was dissolved in THF (50mL)and water (5 mL), and lithium hydroxide (325mg, 13.57mmol) was added. The reaction mixture was stirred at 50°C for 18 hrs after which time the solvent was concentrated in vacuo and the residue taken up in EtOAc , the aqueous layer was extracted and acidified with 1M HCl to pH2 and extracted CHCl3 (3x50mL). The combined ts were washed with water (1x30mL) and brine (1x30mL), dried (Na2SO4) and evaporated in vacuo to give a white solid identified as 1-[4-(2-oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (980mg, 2.60mmol, 96% yield).
[M+H]+ = 379 D. 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (1H- pyrrolo[2,3-b]pyridinylmethyl)-amide 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (80mg, 0.21mmol) was dissolved in CH2Cl2(50mL) and DMF (2.5mL). This solution was cooled to 0°C. 5- ethylazaindole hydrochloride (37mg, 0.25mmol) was added ed by HOBt (32mg, 0.23mmol) and triethylamine (64mg, 0.64mmol). Water soluble carbodiimide (49mg, 0.25mmol) was then added. After 18 hrs at 0°C to rt reaction mixture was diluted with chloroform (200mL), NaHCO3 L), water (1x30mL), brine (1x30mL), ), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 8%MeOH, 92% CHCl3, fractions combined and evaporated in vacuo. The residue was freeze dried from water/aceton itrile to give a white solid identified as 1-[4-(2-oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid rrolo[2,3-b]pyridinylmethyl)-amide (55mg, 0.11mmol, 51% yield).
[M+H]+ = 507 1H NMR: (d6-DMSO), δ: 4.45 (2H, d, J = 5.7Hz), 5.07 (2H, s), 5.39 (2H, s), 6.20 (1H, q, J = 7.6Hz), 6.38-6.41 (2H, m), 7.28 (4H, s), 7.41-7.46 (2H, m), 7.76 (1H, q, J = , 7.85 (1H, d, J = 1.7Hz), 8.17 (1H, d, J = 2.0Hz), 8.41 (1H, s), 8.75-8.77 (1H, m), 11.59 (1H, s).
EXAMPLE 8 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (4,6- dimethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-amide A. -Butyl-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile A e of 5-aminotert-butyl-1H-pyrrolecarbonitrile (2.6g, 15.93 mmol ) and pentane-2,4-dione (1.595g, 15.93mmol,) were dissolved in ethanol (80mL) and concentrated HCl (0.2mL) was added. The on mixture was heated at reflux for 18 hrs. The mixture was concentrated in vacuo and the crude purified by flash tography (silica) eluting in step gradients 95:5 to 9:1 Pet. Ether/ethyl acetate to give a yellow oil identified as 1-tert-butyl-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile (3.05g,13mmol, 84% yield).
[M+H]+ = 228.4 1H NMR: (CDCl 3), δ: 1.81 (9H, s), 2.58 (3H, s), 2.70 (3H, s), 6.84 (1H, s), 7.75 (1H, s) B. 5-Bromotert-butyl-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile A solution of 1-tert-butyl-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile (2.820g, 12.4 mmol) in dichloromethane (50mL) under an atmosphere of N2 was cooled to at least -5°C (Ice/NaCl, 3:1). 1,3- Dibromo-5,5-dimethylhydantoin (1.774g, 6.203mmol) was then added and the reaction was stirred at - 5°C or below. After stirring at -5°C further 1,3-dibromo-5,5-dimethylhydantoin (88mg, 0.31mmol) was added and stirring continued at -5°C for a further 3 hrs The reaction mixture was quenched with Na2SO3 (aq) before warming the reaction to rt. 1M NaOH was added and the layers separated. The s phase was ted with dichloromethane (2×10 mL), the ed organic extracts were washed with brine (2×10 mL) and concentrated in vacuo. The crude product was purified by flash column chromatography on silica eluting with Pet. Ether/ethyl acetate 95:5. Fractions containing product were concentrated and the residue recrystalised from ethyl acetate/Pet. Ether to give a white solid identified as 5-bromotert-butyl-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile (3.19g, 10.42mmol, 84% yield).
[M+H]+ = 305.7 1H NMR: (CDCl 3), δ: 1.81 (9H, s), 2.78 (3H, s), 2.82 (3H, s), 7.78 (1H, s) C. 5-Bromo-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile -Bromo(tert-butyl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile (2.1 g, 6.87 mmol) was added portionwise to a stirring suspension of aluminum trichloride (2.75 g, 20.6 mmol) in chlorobenzene (160 mL). After the addition, the mixture was heated to 100 °C overnight g a black gummy solution. After 24 hrs, the reaction was allowed to cool then poured into water (300mL) and dichloromethane (300 mL). The mixture was treated usly with conc. HCl (135 mL) and the mixture stirred for 10 min then filtered, washing with water and dichloromethane. The resultant solid was dried under vacuum in the presence of CaCl2 over a weekend to give a pale grey solid identified as 5-bromo- 4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile (1.56mg, ol, 90% yield).
D. o-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine A suspension of 5-bromo-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile (1.56 g, 6.16mmol) in conc. hydrochloric acid, 37% (235 mL) was heated at reflux overnight. Further conc. HCl (100mL) was added and the reaction was heated at reflux for a r 20 hrs. The mixture was cooled and poured into ice-water (1 L) and neutralised with 2N NaOH until pH 9, g a precipitate. This was filtered, washed with water then dried under vacuum in the presence of CaCl2 to give a grey solid identified as 5- bromo-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (1.3g, 5.72mmol, 92% yield).
[M+H]+ = 225.1 1H NMR: (CDCl 3), δ: 2.66 (3H, s), 2.82 (3H, s), 6.49 (1H, dd, J = 3.5, 2.1 Hz), 7.29 (1H, dd, J = 3.4, 2.7 Hz), 11.14 (1H, br.s) E. 4,6-Dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile -Bromo-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (1.3g, 5.72mmol) was dissolved in N,N- dimethylacetamide (20mL). The on was degassed with N2 before the addition of zinc powder (45mg, 0.693mmol), zinc acetate (127mg, 0.693mmol), 1,1'-bis(diphenylphosphino)ferrocene (128mg, 0.23mmol), Zn(CN)2 (339mg, 2.888mmol) and tris(dibenzylideneacetone)dipalladium(0) (106mg, mol). The reaction was heated at 120°C for 48hrs. After cooling to rt the reaction was diluted with ethyl acetate and washed with 2M NH4OH and brine. Organic layer was dried over MgSO4 and filtered. After concentration in vacuo crude product was purified by flash column chromatography on silica eluting with 9:1, 8:2, 7:3, 1:1. (Pet. Ether/Ethyl acetate). Fractions were collected and concentrated in vacuo. The yellow solid was triturated in l ether to give an off white solid fied as 4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile (660mg, 3.83mmol, 67% yield).
[M+H]+ = 172.1 1H NMR: (CDCl 3), δ: 2.76 (3H, s), 2.86 (3H, s), 6.59 (1H, dd, J = 3.5, 2.0 Hz), 7.36 (1H, dd, J = 3.5, 2.4 Hz), 10.86 (1H, br.s) F. (4,6-Dimethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-carbamic acid tert-butyl ester 4,6-Dimethyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile , 3.56mmol) was dissolved in methanol (75mL). This solution was cooled to 0°C. Nickel (II) chloride hexahydrate (85mg, 0.36mmol) and ditertbutyl dicarbonate (1.56g, 7.13mmol) were added followed by sodium borohydride (943mg, 24.94mmol) portionwise. The reaction e was stirred at 0°C to room temp for 18 hrs. The MeOH was removed by evaporation. The e was ved in CHCl3 (70mL), washed with sat NaHCO3(1x30mL), water (1x30mL) and brine (1x30mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. Purified by flash chromatography, (silica), eluant 40%Pet. Ether, 60% EtOAc to give white solid fied as identified as (4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-carbamic acid tert- butyl ester (710mg, 2.56mmol, 72% yield).
[M+H]+ = 276.1 1H NMR: (CDCl 3), 1.49 (9H, s), 2.61 (3H, s), 2.71 (3H, s), 4.46 (1H, br.s), 4.51 (2H, d, J = 4.4 Hz), 6.50 (1H, dd, J = 3.5, 2.0 Hz), 7.25 (1H, dd, J = 3.4, 2.5 Hz), 9.64 (1H, br.s); G. C-(4,6-Dimethyl-1H-pyrrolo[2,3-b]pyridinyl)-methylamine hydrochloride 4,6-Dimethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-carbamic acid tert-butyl ester (710mg, 2.56mmol) was dissolved in 4M HCl in dioxane (10mL). After 2 hrs at rt the solvent was removed in vacuo to give a yellow solid identified as C-(4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinyl)-methylamine hydrochloride (360mg, 2.00mmol, 80% yield).
[M+H]+ = 176.4 1H NMR: (d6-DMSO), 2.53 (3H, s), 2.60 (3H, s), 3.94 (2H, s), 4.76 (2H, br.s), 6.43 (1H, d, J = 2.3 Hz), 7.28 (1H, dd, J = 3.2, 1.9 Hz), 11.32 (1H, br.s) H. 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (4,6- dimethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-amide 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (80mg, 0.21mmol) was dissolved in CH2Cl2(50mL) and DMF(2.5mL). This on was cooled to 0°C. C-(4,6- Dimethyl-1H-pyrrolo[2,3-b]pyridinyl)-methylamine hydrochloride (44mg, 0.25mmol) was added followed by HOBt (32mg, 0.23mmol) and triethylamine (64mg, 0.64mmol). Water soluble carbodiimide (49mg, ol) was then added. After 18 hrs at 0°C to rt on mixture was diluted with chloroform (200mL) and washed with NaHCO3 (1x30mL), water (1x30mL) and brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The e was purified by flash chromatography (silica), eluent 8%MeOH, 92% CHCl3, fractions combined and evaporated in vacuo. The residue was freeze dried from water/acetontrile to give a white solid identified as 1-[4-(2-oxo-2H-pyridinylmethyl)-benzyl] trifluoromethyl-1H-pyrazolecarboxylic acid imethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-amide (55mg, 0.11mmol, 51% yield).
[M+H]+ = 535 1H NMR: (d6-DMSO), δ: 4.69 (2H, d, J = 5.8Hz), 5.07 (2H, s), 5.40 (2H, s), 6.21-6.24 (1H, m), 6.39 (1H, d, J = 9.0Hz), 7.00 (1H, d, J = , 7.26-7.30 (5H, m), 7.39-7.44 (2H, m), 7.77 (1H, q, J = 6.6Hz), 8.14 (1H, s), 8.43 (1H, s), 8.89 (1H, t, J = 5.8Hz), 13.11 (1H, s).
EXAMPLE 9 2,5-Dimethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-amino- nolinylmethyl)-amide A. [4-(4-Methyl-pyrazolylmethyl)-phenyl]-methanol 4-(Chloromethyl)benzylalcohol (5.47g, ol) was dissolved in acetone (50mL) 4-methylpyrazole (2.86g, 34.9mmol) and potassium carbonate (5.07g, 36.7mmol) were added and the reaction mixture was stirred at rt for 18 hrs and at 60°C for 30 hrs after which time the t was removed in vacuo and the residue taken up in EtOAc (100mL), this solution was washed with water (1x30mL), brine (1x30mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient of 10 to 80% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white solid identified as [4-(4-methyl-pyrazolylmethyl)-phenyl]-methanol (3.94g, 18.90mmol, 54% yield).
[M+H]+ = 203 B. 1-(4-Chloromethyl-benzyl)methyl-1H-pyrazole [4-(4-Methyl-pyrazolylmethyl)-phenyl]-methanol (2.03g, 10.04mmol) and triethylamine (1.13g, 11.54mmol) was dissolved in dichloromethane (40mL). To this solution was added methanesulphonyl chloride (1.26g, mol) dropwise. The reaction mixture was stirred at rt for 18 hrs and diluted with CHCl3 (250mL) the filtrate was washed with saturated NH4Cl (1x30mL), water L), brine (1x30mL), dried (Na2SO4) and ated in vacuo. The residue was purifie d by flash chromatography (silica), eluent gradient of 0 to 60% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white solid fied as 1-(4-chloromethyl-benzyl)methyl-1H-pyrazole (1.49g, 6.62mmol, 60% yield).
[M+H]+ = 221, 223 C: 2,5-Dimethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid methyl ester A solution of methyl methyl-1H-pyrrolecarboxylate (0.382 g, 2.492 mmol) in anhydrous DMF (8 mL) was cooled in an ice-bath, then treated sequentially portionwise with sodium hydride (0.071 g, 2.95 mmol), then chloromethyl)benzyl)methyl-1H-pyrazole (0.50 g, 2.266 mmol) and the mixture allowed to stir at ~ 5 °C for 1 hour. The ice-bath was removed and the mixture stirred for a further 45 min. Further sodium hydride (~0.5 eq) was added and the mixture allowed to stir overnight. The reaction was quenched with water (40 mL) and attempted to extract into DCM(3 x 40 mL), but presence of DMF caused emulsion. Combined DCM layers were washed with brine, dried (Na2SO4), filtered and concentrated. Brine (40 mL) was added to the initial aqueous layer and this extracted with EtOAc (3 x 40 mL). The combined EtOAc layers were washed with water (3 x 20 mL), brine (30 mL), dried (MgSO4), and concentrated with the DCM extract residue (4 mbar @ 55 ºC) to remove residual DMF. The compound was purified by chromatography (silica) eluting with a gradient of 0 to 70% EtOAc/Iso-Hexanes to afford 2,5-dimethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid methyl ester (602 mg, 1.748 mmol, 77 % yield) as a pale yellow oil which crystallized slowly on standing.
[M+H]+ = 338 D: 2,5-Dimethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid A solution of methyl 2,5-dimethyl(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrrole carboxylate (459 mg, 1.360 mmol) in tetrahydrofuran (8 mL), ol (5 mL) and water (7 mL) were treated with lithium ide (163 mg, 6.80 mmol) and the mixture heated at 65 ºC with stirring for 48 hrs until tion. The ty of the solvents were removed under . The ant cloudy mixture was partitioned between EtOAc (50 mL) and water (50 mL) containing 1M NaOH (2 mL). The organic layer was discarded and the aqueous layer acidified to ~pH3 with 1M HCl (turned cloudy). The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organics dried (MgSO4), filtered PCT/GB 2014/051 592 — 2015 and concentrated under vacuum to afford methyl(4—((4—methyl-1H-pyrazol—1-yl)methyl)benzy|)- 1H—pyrrolecarboxylic acid (448 mg, 1.358 mmol, 90 % yield) as a pale yellow solid.
[M+H]+ = 324 E: 2,5-Dimethyl[4—(4-methyl-pyrazolylmethyI)-benzyl]-1H-pyrroIecarboxylic acid no- nolinylmethyl)-amide A scintillation vial was charged with 2,5-dimethyl-1—(4-((4-methyl-1H-pyrazol-1|) methyl)benzy|)-1H- pyrrole-3—carboxylic acid (93 mg, 0.289 mmol), 6-(aminomethyl)isoquinolin-l—amine (80 mg, 0.462 mmol), HATU (121 mg, 0.318 mmol) and 25% DMF/DCM (3.5 mL). Next, N,N-diisopropylethylamine (101 pl, 0.577 mmol) was'added and the mixture allowed to stir overnight. The reaction mixture was diluted with MeOH (10 mL) to form a on. This was passed through a strong cation exchange chromatography column (3 g), washing with MeOH, eluting with 1% NH3/MeOH. The crude material was purified by chromatography (silica) eluting with a gradient of 0 to 8% MeOH/DCM(1% NH3) to afford 2,5- dimethyl-1—[4-(4-methyl-pyrazol-l—ylmethyl)-benzyI]-1H-pyrrolecarboxylic acid (1—amino-isoquinolin- 6-ylmethyl)-amide (66 mg, 0.134 mmol, 46.3 % yield) as a pale yellow powder.
[M+H]+ = 479 1H NM R: (d6-DMSO), 5: 1.99 (3H, d, J = 0.7Hz), 2.07 (3H, s), 2.37 (3H, s), 4.50 (2H, d,J = 6.0Hz), 5.07 (2H, s), 5.20 (2H, s), 6.37 (1H, d, J = 1.1Hz), 6.70 (2H, s), 6.83-6.92 (3H, m), 7.16 (2H, d,J = 8.2Hz), 7.22 (1H, s), 7.39 (1H, dd,J = 1.7, 8.6Hz), 7.52 (2H, s, br), 7.76 (1H, d,J = 5.8Hz), 8.13 (1H, cl, J = 8.6Hz), 8.21 (1H, t,J = 6.1Hz).
REFERENCE EXAMPLE 10 \ / ”ah—CI H.
AMENDED SHEET A. 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid ethyl ester 1-(4-Chloromethyl-benzyl)methyl-1H-pyrazole (986mg, 4.47mmol) was dissolved in DMF (28mL) ethyl 1H-imidazolecarboxylate (626mg, 4.47mmol) and potassium ate (1.42g, 10.28mmol) were added and the reaction mixture was stirred at rt for 3 days after which time the reaction mixture was diluted with EtOAc (100mL), this solution was washed with water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The residue was ed by flash chromatography a), eluent nt of 50 to 100% EtOAc in iso-Hexane, 2 products eluted the first at ~90% EtOAc/Iso-Hexane with the second eluting at 100% EtOAc. Fractions combined and evaporated in vacuo.
The first product eluted was isolated as a white solid identified as 3-[4-(4-methyl-pyrazolylmethyl)- benzyl]-3H-imidazolecarboxylic acid ethyl ester (675mg, 2.06mmol, 46% .
[M+H]+ = 325 The second product eluted was ed as a clear gum fied as 1-[4-(4-methyl-pyrazolylmethyl)- benzyl]-1H-imidazolecarboxylic acid ethyl ester (540mg, 1.652mmol, 37% .
[M+H]+ = 325 B. 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid ethyl ester (471mg, 1.45mmol) was dissolved in THF(7mL) ethanol (4.5mL) and water (6.3mL) lithium hydroxide (174mg, 7.26mmol) was added. The reaction mixture was stirred at 65°C for 2 hrs after which time the solvent was concentrated in vacuo and the residue taken up in CHCl3 (150mL), the aqueous layer was extracted and acidified with 1M HCl to pH2 and ted CHCl3 (3x50mL) the combined extracts were washed with water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The e was purified by flash chromatography (silica), eluent dichloromethane:MeOH:NH3 (100:10:1). Fractions combined and evaporated in vacuo to give a white solid identified as 1-[4-(4-methyl-pyrazolylmethyl)-benzyl]- 1H-imidazolecarboxylic acid (245mg, 0.82mmol, 51% yield).
[M+H]+ = 295 C. 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid (50mg, 0.169mmol) was dissolved in DMF/CH2Cl2(1:3, 3mL). HATU (71mg, 0.186mmol) was added followed by 6- (aminomethyl)isoquinolinamine (80mg, 0.464mmol) and N,N-diisopropylethylamine (44mg, 0.337mmol). After 18 hrs at rt reaction mixture was diluted with chloroform (400mL) washed with NH4Cl (1x30mL), water (1x30mL), brine (1x30mL), dried (Na2SO4) and evaporated in vacuo giving a yellow oil. The residue was purified by flash chromatography (silica), eluent romethane:MeOH:NH3 (100:10:1). fractions combined and evaporated in vacuo to give a white solid identified as 4-methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide (47mg, mol, 60% yield).
[M+H]+ = 452 1H NMR: (d6-DMSO), δ: 1.99 (3H, s), 4.52 (2H, d, J = 6.3Hz), 5.20 (1H, s), 5.22 (1H, s), 6.70 (2H, s), 6.83 (1H, d, J = 5.8Hz), 7.16-7.25 (3H, m), 7.26-7.32 (2H, m), 7.38 (1H, dd, J = 1.7, 8.6Hz), 7.46-7.56 (2H, m), .78 (2H, m), 7.85 (1H, d, J = 1.3Hz), 8.11 (1H, d, J = 8.6Hz), 8.58 (1H, t, J = 6.3Hz).
EXAMPLE 11 3-Methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide A. N'-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-hydrazinecarboxylic acid tert-butyl ester A solution of 1-(4-(chloromethyl)benzyl)methyl-1H-pyrazole (3.5 g, 15.86 mmol) and tert-butyl carbazate (8.38 g, 63.4 mmol) in absolute EtOH (21 mL) was treated with N,N-diisopropylethylamine (2.76 mL, 15.86 mmol) and the mixture stirred at 60 ºC for 24 hrs . LCMS indicated desired t and reaction of product with a second equivalent of starting chloride [445]+ in a 3 : 1 ratio. Solvents were removed under vacuum and the residue partitioned between EtOAc (150 mL) and saturated aqueous NH4Cl (turned cloudy, some water added). The organic layer was separated and washed with water (75 mL) and brine (75 mL), dried ), ed and concentrated. The residue was purified by chromatography (silica) eluting with a gradient of 0 to 50% EtOAc/Iso-Hexanes. Note chromaphore is weak; product streaked over many fractions. Every 5th fraction was examined by HPLC and the cleanest set of fractions combined to afford >7g of material. 1H NMR (DMSO-d6, 11191) showed ~85% purity aside from the presence of excess tert butyl carbazate. The product was purified by Kugelrohr distillation (3 runs until no more material evident in collection bulb) at 2.9 mBar / 110-115 ºC (indicated). 1H NMR (DMSO-d6) showed removal of the tert-butyl ate. The mixture was further purified by chromatography (silica) eluting with a gradient of 0 to 60% THF/DCM. The compound eluted more quickly than expected (in ~15% THF). Some clean product fractions were obtained at the tail of the peak to afford 1.77g of the desired compound at >95% purity by 1H NMR. Mixed ons were also ed and were consistent with the desired compound at 78% purity by 1H NMR.
[M+H]+ = 317 B. [4-(4-Methyl-pyrazolylmethyl)-benzyl]-hydrazine To a d solution of 4-tert-butyl 2-(4-((4-methyl-1H-pyrazol l)methyl)benzyl) hydrazinecarboxylate (369 mg, 1.166 mmol) in dioxane (5 mL) was added HCl 4M in dioxane (1 mL, 32.9 mmol) dropwise, a thick precipitate formed and stirring ued for 2 hrs. Reaction mixture was diluted with diethyl ether (20 mL). The thick precipitate did not break up on sonication. ts to filter the material were difficult. Drying for ~30 min on filter paper did not give dry solid. Material was slightly hygroscopic. The bulk was transferred into a flask and used directly in the next step without further purification [M+H]+ = 217 C. 3-Methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester To a stirred suspension of 5-acetyl-uracil (150mg, 0.971 mmol) and [4-(4-Methyl-pyrazolylmethyl)- benzyl]-hydrazine dihydrochloride (337 mg, 1.165 mmol) in EtOH (10 mL) was added conc HCl (0.5 mL) and the reaction heated at reflux (80 °C) for 24 hrs. A fine white suspension was observed. Analysis by LCMS showed the main peak [M+H]+ = 353 corresponding to the imine intermediate. After a further 3 hrs no further reaction had ed. The reaction e was charged with H2SO4 (conc.) (0.5 mL) and heated to 120°C for 50 min in a microwave. The reaction mixture was evaporated to dryness and the residue taken up into EtOAc (100 mL). The cs were washed with NaOH (2M, 50 mL), brine (50 mL), dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by chromatography (12 g column, 0-50% EtOAc in anes) to afford 3-methyl[4-(4-methyl-pyrazol ylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester (144 mg, 0.417 mmol, 42.9 % yield) as a colourless oil. Analysis by HPLC, (PFP column, 40% Methanol, acidic, 225 nm detection) showed clean 3- regioisomer.
[M+H]+ = 339 D. 3-Methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid To a stirred solution of 3-methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester (144 mg, 0.426 mmol) in THF (3 mL) and MeOH (2 mL) was added NaOH 2M (638 µl, 1.277 mmol) and left at RT overnight. Analysis showed clean conversion to the desired acid. Reaction mixture was acidified to pH5 using 1M HCl. The product was extracted into EtOAc (20 mL) and the organics washed with brine (2 x 20 mL), dried over magnesium sulfate, ed and solvent removed to give a white solid identified as 3-methyl(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazole carboxylic acid (83 mg, 0.254 mmol, 59.7 % yield).
[M+H]+ =311 E. 3-Methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide hydrochloride To a d solution of 3-methyl(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazole carboxylic acid (75 mg, 0.242 mmol) and 6-(aminomethyl)isoquinolinamine, 2HCl (59.5 mg, 0.242 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (169 µl, 0.967 mmol) and HATU (96 mg, 0.254 mmol). The reaction was stirred at rt for 2 hrs. is showed complete conversion to desired product. The reaction mixture was diluted with EtOAc (30 mL) and washed with NaOH (2M, 20 mL), brine (50 mL), dried over magnesium sulfate, ed and the t evaporated under reduced pressure. The crude solid was pre-absorbed onto silica before purification by chromatography (12 g column, 0-10% MeOH (1%NH3) in DCM, pausing at 5% to afford 3-Methyl[4-(4-methyl-pyrazol ylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide hloride (65.2 mg, 0.140 mmol, 58.0 % yield) as a white powder. The free base was taken up into MeOH (1 mL) and HCl 4M in dioxane (35.0 µl, 0.140 mmol, 1eq.) was added. A solid precipitated and the MeOH was removed under a flow of air. The dioxane was removed under . The residue was triturated from diethyl ether (5 mL) to afford 3-methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide hydrochloride (62 mg, 0.117 mmol, 48.6 % yield) as white solid.
[M+H]+ = 466 NMR (d6-DMSO) δ: 1.99 (3H, J= 0.7 Hz ), 2.31 (3H, s), 4.57 (2H, d, J = 5.9 Hz ), 5.23 (4H, d, J= 7.4 Hz ), 7.16–7.28 (6H, m), 7.54 (1H, t, J= 0.9 Hz ), 7.64–7.73 (2H, m), 7.79 (1H, d, J= 1.6 Hz ), 8.24 (1H, s), 8.54 (1H, d, J= 8.7 Hz ), 8.61 (1H, t, J= 6.0 Hz ), 9.05 (2H, br s), 13.14 (1H, s) EXAMPLE 12 3-Cyclopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide A. 1-(4-Bromomethyl-benzyl)methyl-1H-pyrazole [4-(4-Methyl-pyrazolylmethyl)-phenyl]-methanol (2.05g, 10.1mmol) was dissolved in dichloromethane (50mL). To this solution was added triphenylphosphine (3.05 g, 11.6 mmol). The resultant solution was cooled in an ice bath before carbon tetrabromide (3.69 g, 11.1 mmol) was added portionwise. The on mixture was stirred at rt for 18 hrs and diluted with CHCl3 (100mL). The filtrate was washed with saturated NaHCO3 (1x30mL), water (1x30mL) and brine (1x30m L), dried (Na2SO4) and evaporated in vacuo. The e was purified by flash tography (silica), eluent 95% Pet. Ether, 5% EtOAc, ons combined and evaporated in vacuo to give a white solid which was identified as 1-(4-bromomethyl-benzyl)methyl-1H-pyrazole (1.64g, 6.19mmol, 61% yield).
[M+H]+ = 265 B. 3-Cyclopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester Ethyl opropyl-1H-pyrazolecarboxylate (100mg, 0.56mmol) was dissolved in DMF (20mL). 1-(4- Bromomethyl-benzyl)methyl-1H-pyrazole (155mg, 0.58mmol) and potassium carbonate (153mg, 1.1mmol) were added and the reaction mixture was stirred at rt for 2 days after which time the reaction mixture was diluted with EtOAc (100mL), this solution was washed with water (1x30mL) and brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography a), eluent 98% dichloromethane, 2% methanol, fractions ed and evaporated in vacuo to give a white solid identified as 3-cyclopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazole carboxylic acid ethyl ester (190mg, 0.52mmol, 94% yield).
[M+H]+ = 365 C. 3-Cyclopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 3-Cyclopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester (190mg, 0.52mmol) was dissolved ethanol (10mL) and sodium ide (208mg, 5.2mmol) was added.
The reaction mixture was stirred at reflux for 18 hrs after which time the solvent was concentrated in vacuo and the residue taken up in CHCl3 (150mL), the aqueous layer was extracted and acidified with 1M HCl to pH2 and extracted CHCl3 (3x50mL). The combined extracts were washed with water (1x30mL) and brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography a), eluent dichloromethane:MeOH:NH3 (100:10:1) fractions combined and evaporated in vacuo to give a white solid identified as 3-cyclopropyl[4-(4-methyl-pyrazolylmethyl)- benzyl]-1H-pyrazolecarboxylic acid (150mg, 0.45mmol, 86% yield).
[M+H]+ = 337 D. 3-Cyclopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl 3-Cyclopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (65mg, 0.19mmol) was dissolved in CH2Cl2 (50mL) and DMF(2.5mL). This solution was cooled to 0°C. 6- Aminomethyl-isoquinolinylamine (34mg, 0.19mmol) was added followed by HOBt (31mg, 0.23mmol) and triethylamine (98mg, 0.97mmol). Water soluble carbodiimide (52mg, 0.27mmol) was then added.
After 18 hrs at 0°C to rt reaction mixture was diluted with chloroform (100mL) and IPA (10mLmL), washed with NaHCO3 L), water (1x30mL) and brine (1x30mL), dried (Na2SO4) and ated in vacuo giving a yellow oil. The residue was ed by flash chromatography (silica), eluent dichloromethane:MeOH:NH3 (100:10:1), fractions ed and evaporated in vacuo to give a white solid identified as 3-cyclopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide (46mg, 0.09mmol, 48% yield).
[M+H]+ = 496 1H NMR: (d6-DMSO), δ: 0.73-0.76 (2H, m), .84 (2H, m), 1.98 (3H, s), 2.55-2.67 (1H, m), 4.50 (2H, d, J= , 5.19 (2H, s), 5.21 (2H, s), 6.71 (2H, s), 6.85 (1H, d, J= 5.8Hz), 7.18 , 7.23 (1H, s), 7.36-7.39 (1H, m), 7.52 (2H, s), 7.76 (1H, d, J= 5.8Hz), 8.12 (2H, d, J= 8.4Hz), 8.46 (1H, t, J= 5.9Hz).
EXAMPLE 13 3-Isopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide A. Ethyl 3-isopropyl(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazolecarboxylate To a stirred solution of ethyl 3-isopropyl-1H-pyrazolecarboxylate (446 mg, 2.447 mmol) and 1-(4- (chloromethyl)benzyl)methyl-1H-pyrazole (540 mg, 2.447 mmol) in DMF (8 mL) was added K2CO3 (676 mg, 4.89 mmol) and d at rt ght. The reaction was diluted with brine (10 mL) and EtOAc (10 mL) and the layers separated. The aqueous was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure. The crude was purified by chromatography (24 g column, EtOAc in iso-Hexanes 0-50% yield) to afford ethyl 3-isopropyl(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazolecarboxylate (702 mg, 1.762 mmol, 72.0 % yield) as a thick pale yellow oil.
[M+H]+ = 367 B. 3-Isopropyl (4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazolecarboxylic acid To a stirred mixture of ethyl 3-isopropyl(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazole carboxylate (690 mg, 1.883 mmol) and lithium ide (135 mg, 5.65 mmol) in THF (8 mL) and water (4 mL) at rt was added lithium hydroxide (135 mg, 5.65 mmol). MeOH (1 mL) added to increase lity. The reaction was stirred and heated at 50 °C for 5 hrs. The reaction was allowed to cool to rt, ied to pH ~3 with 1M HCl and extracted with EtOAc (3 x 5mL). Organic dried (Mg2SO4), filtered and evaporated under reduced pressure to give) as a pale yellow solid. This sample crude was purified by chromatography (12 g column, (2:1 EtOAc-MeCN) in DCM 0-50% yield) to afford 3-isopropyl(4-((4- methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazolecarboxylic acid (256 mg, 0.749mmol, 40% yield).
No undesired 5-regioisomer was observed.
[M+H]+ = 339 C. 3-Isopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide hydrochloride To a stirred solution of 3-isopropyl(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazole carboxylic acid (129 mg, 0.381 mmol), 6-(aminomethyl)isoquinolinamine ochloride (100 mg, 0.406 mmol) and HATU (174 mg, 0.457 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (266 µL, 1.525 mmol). The resulting mixture was stirred at rt overnight. The reaction was diluted with EtOAc (15 mL) and washed with 2M NaOH (2 x 20 mL). Organic dried (Na2SO4), filtered and evaporated under reduced pressure. The crude was purified by tography (4 g column, MeOH in DCM 0-5% and 1% Et3N) to afford the desired compound as a free base. 1 H NMR in DMSO-d6 was consistent with the free amine structure. The product was dissolved in DCM (1 mL), 4M HCl in dioxane (124 µL, 0.496 mmol) added and the ing flocculent mixture stirred at rt for 15 min. The solvent was then evaporated under reduced pressure to give N-((1-aminoisoquinolinyl)methyl)isopropyl(4-((4- methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazolecarboxamide, HCl (170 mg, 0.319 mmol, 84 % yield) as a white solid.
[M+H]+ = 494 1H NMR: (d6-DMSO), δ: 1.17 (6H, d, J = 6.9 Hz ); 1.99 (3H, t, J = 0.7 Hz ); 3.57 (1H, hept, J = 6.2 Hz); 4.56 (2H, d, J = 5.8 Hz ); 5.25 (4H, d, J = 15.4 Hz ); 7.16 - 7.27 (6H, m); 7.55 (1H, q, J = 0.8 Hz ); 7.63 - 7.72 (2H, m); 7.79 (1H, d, J = 1.6 Hz ); 8.19 (1H, s); 8.54 (1H, d, J = 8.6 Hz ); 8.64 (1H, t, J = 5.9 Hz ); 9.08 (2H, s); 13.22 (1H, s).
EXAMPLE 14 3-Cyclobutyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl A. (E)-Ethyl 2-(cyclobutanecarbonyl)(dimethylamino)acrylate To a flask charged with ethyl 3-cyclobutyloxopropanoate (0.935 g, 5.49 mmol) was added 1,1- dimethoxy-N,N-dimethylmethanamine (0.876 mL, 6.59 mmol) and e (30 mL). Heated at 70 °C for 7 hrs. Reaction mixture was oped with toluene (2 x 30 mL) to remove any residual 1,1-dimethoxy-N,N-dimethylmethanamine. Quantitative yield assumed and material used directly in the next step.
[M+H]+ = 216 B. Ethyl 3-cyclobutyl-1H-pyrazolecarboxylate To a d solution of 1132-12 (E)-ethyl 2-(cyclobutanecarbonyl)(dimethylamino)acrylate (1.24 g, .50mmol) (crude) in EtOH (30 mL) was added hydrazine, H2O (0.803 mL, 8.26 mmol) and heated to reflux ght. Reaction mixture evaporated to remove excess hydrazine. Crude material was taken up into EtOAc (150 mL) and washed with NaHCO3 (aq, 100 mL), then brine (100 mL), dried over magnesium sulfate and t removed to afford ethyl 3-cyclobutyl-1H-pyrazolecarboxylate (709 mg, 3.54 mmol, 64.3 % yield) as a waxy solid on standing.
[M+H]+ = 195 C. 3-Cyclobutyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino- isoquinolinylmethyl)-amide hydrochloride Procedure as for Example 13 methods A-C [M+H]+ = 506 1H NMR: (d6-DMSO), δ: 1.70 - 1.83 (1H, m); 1.81 - 1.98 (1H, m); 1.99 (3H, d, J = 0.8 Hz ); 2.12 - 2.25 (4H, m); 4.55 (2H, d, J = 5.8 Hz ); 5.23 (2H, s); 5.29 (2H, s); 7.15 - 7.29 (6H, m); 7.55 (1H, t, J = 0.9 Hz ); 7.63 - 7.72 (2H, m); 7.78 (1H, d, J = 1.5 Hz ); 8.20 (1H, s); 8.49 - 8.61 (2H, m); 9.03 (2H, s); 13.11 (1H, s).
EXAMPLE 15 3-Hydroxymethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide A. 3-Hydroxymethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide hydrochloride Tribromoborane (118 µl, 0.118 mmol) was added to a stirred solution of 3-methoxymethyl[4-(4- methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid no-isoquinolinylmethyl)- amide (45 mg, 0.091 mmol) in DCM (0.3 mL). The resulting mixture was stirred at rt for 3 hrs. The t was evaporated under reduced pressure and the residue was absorbed on silica before purification by chromatography (4 g column, 0-10% MeOH in DCM, 1% Et3N) to afford the free base of the desired compound as a white solid. This solid was dissolved in DCM (1 mL) and MeOH (0.5 mL). 4M HCl in dioxane (29.5 µl, 0.118 mmol) was added and the resulting mixture was stirred at rt for 15 min.
The solvents were evaporated under reduced pressure to give oxymethyl[4-(4-methyl-pyrazol- 1-ylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide hydrochloride (39 mg, 0.075 mmol, 82 % yield) as a white solid.
[M+H]+ =482.3 1H NMR: (d6-DMSO), δ: 1.99 (3H, s), 4.56 (2H, s), 4.64 (2H, d, J = 5.8 Hz ), 5.22 (2H, s), 5.28 (2H, s), 7.16 - 7.31 (6H, m), 7.55 (1H, t, J = 0.9 Hz ), 7.63 - 7.74 (2H, m), 7.82 (1H, d, J = 1.6 Hz ), 8.34 (1H, s), 8.55 (1H, d, J = 8.7 Hz ), 8.90 - 9.05 (3H, m), 13.17 (1H, s).
EXAMPLE 16 3-Cyano[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide A. Ethyl 3-cyano[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylate Procedure as Example 13 method A [M+H]+ = 350 B. 3-Cyano[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid A stirred solution of ethyl 3-cyano(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazole carboxylate (100 mg, 0.286 mmol) in THF (0.3 mL) and MeOH (0.3 mL) was treated with a on of lithium hydroxide (10.28 mg, 0.429 mmol) in water (0.3 mL). The mixture was allowed to stir at t temperature for 18hrs. Solvents were removed under vacuum and the residue partitioned between EtOAc (1 mL) and water (1 mL). The c layer was removed and the aqueous layer adjusted to pH 4 with 1M HCl, forming a precipitate. This was briefly sonicated then filtered, g with copious water. On drying under vacuum, 3-cyano(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)- 1H-pyrazolecarboxylic acid (70 mg, 0.196 mmol, 68.5 % yield) was recovered as a white solid.
[M+H]+ = 322 C. 3-Cyano[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide hydrochloride A vial was charged with 3-cyano(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazole carboxylic acid (232 mg, 0.722 mmol), nomethyl)isoquinolinamine dihydrochloride (195 mg, 0.794 mmol), HATU (302 mg, 0.794 mmol), anhydrous DCM (4.5 mL) and ous DMF (1.5 mL). opropylethylamine (503 µl, 2.89 mmol) was added and the mixture allowed to stir at ambient temperature. A precipitate . Solvents were removed under , slurried in methanol and filtered to give 293 mg of solid. This was purified by strong cation exchange chromatography (8 g), loading in a large quantity of MeOH/DCM (3:1, ~150 mL), washing with MeOH, eluting with 1% NH3/MeOH to afford 243 mg of material. This was purified by chromatography (silica) eluting with a gradient of 0 to 10% MeOH (1% NH3/DCM) to afford 3-cyano[4-(4-methyl-pyrazolylmethyl)- benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide hydrochloride (193 mg, 56 % yield) as a white powder.
A sample of the product(60 mg) was dissolved in DCM (1 mL) and MeOH (0.5 mL) then treated with 4M HCl in dioxane (~100 μL), forming a precipitate. This was allowed to stand for 1 minute, then concentrated under vacuum to afford 63 mg of the mono-HCl salt [M+H]+ = 477 1H NMR: (d6-DMSO), δ: 1.98 (3H, s), 4.60 (2H, d, J = 5.8Hz), 5.24 (2H, s), 5.47 (2H, s), 7.17-7.28 (4H, m), 7.32 (2H, d, J = 8.1Hz), 7.55 (1H, s), 7.63-7.74 (2H, m), 7.82 (1H, s), 8.56 (1H, d, J = 8.6Hz), 8.61 (1H, s), 9.12 (2H, brs), 9.23 (1H, t, J = 5.9Hz), 13.29 (1H, s).
EXAMPLE 17 4-[(1-Amino-isoquinolinylmethyl)-carbamoyl][4-(4-methyl-pyrazolylmethyl)-benzyl]-1H- pyrazolecarboxylic acid A. 4-[(1-Amino-isoquinolinylmethyl)-carbamoyl][4-(4-methyl-pyrazolylmethyl)-benzyl]-1H- lecarboxylic acid hydrochloride A stirred suspension of 3-cyano[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid no-isoquinolinylmethyl)-amide (25 mg, 0.052 mmol) in MeOH (0.25 mL) was treated with a solution of lithium hydroxide (12.56 mg, 0.525 mmol) in water (0.25 mL). The mixture was allowed to stir at 60 °C (DrySyn bath temperature) overnight. The reaction was allowed to cool, then adjusted to pH 3 with 1M HCl. The precipitate was filtered, washing with water and dried under vacuum to afford a white powder. The mixture was taken up in DCM (0.5 mL) and MeOH (0.5 mL) and treated with 4M HCl in dioxane (29.5 µL, 0.118 mmol). The e was allowed to stand for 1 minute, then concentrated under vacuum to afford 4-[(1-amino-isoquinolinylmethyl)-carbamoyl][4-(4-methyl-pyrazol yl)-benzyl]-1H-pyrazolecarboxylic acid hydrochloride (20 mg, 0.036 mmol, 68.1 % yield) as a white powder.
[M+H]+ = 496 1H NMR: (d6-DMSO), δ: 1.98 (3H, s), 4.69 (2H, d, J = 5.8Hz), 5.23 (2H, s), 5.43 (2H, s), 7.18-7.26 (4H, m), 7.31 (2H, d, J = , 7.54 (1H, s), 7.63-7.77 (2H, m), 7.85 (1H, s), 8.57 (1H, d, J = 8.6Hz), 8.64 (1H, s), 9.13 (2H, brs), 10.04 (1H, t, J = 5.8Hz), 13.31 (1H, s), 14.85 (1H, brs).
EXAMPLE 18 4-Methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-thiazolecarboxylic acid (1-amino-isoquinolin- 6-ylmethyl)-amide A. 2-(4-Bromo-benzyl)methyl-thiazolecarboxylic acid ethyl ester A solution of 2-(4-bromophenyl)ethanethioamide (1.98 g, 8.60 mmol) and ethyl 2-chloro oxobutanoate (1.428 mL, 10.32 mmol) in pyridine (30 mL) and ethanol (30 mL) was stirred at 90°C for 18 hrs. Then the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), and 2N hydrochloric acid (100 mL) was added. The c layer was separated, washed with saturated brine (50 mL), dried 4), filtered and ated under reduced pressure. The crude was purified by chromatography (40 g column, EtOAc in Hex 0-50% yield) to afford 2-(4-bromo-benzyl)methyl-thiazolecarboxylic acid ethyl ester (1.33 g, 5.00 mmol, 52.1 % yield) as a white crystalline solid.
[M+H]+ = 340, 342 B. Potassium trifluoro(N-methylfomepizole)borate Potassium hexamethyldisilazide (2.992g, 15.00 mmol) was added dropwise to a stirred mixture of 4- -1H-pyrazole (1.067g, 13.00 mmol) and potassium bromomethyltrifluoroborate (2.008g, 10 mmol) in dioxane (10 mL). The resulting mixture stirred at 85 °C overnight then at rt over the weekend.
The reaction mixture was quenched with water (2 mL) and dried under reduced pressure (water bath at 50 °C). The crude solid was ved in a solution of hot HPLC grade acetone then filtered to remove KCl. The filtrate was concentrated under reduced pressure, dissolved in acetone (14 mL) and precipitated by addition of Et2O (30 mL) to afford the desired product (660 mg, 2.91 mmol, 29.1 % yield) as a white solid.
C. 4-Methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-thiazolecarboxylic acid ethyl ester A mixture of potassium oro(N-methylfomepizole)borate (386 mg, 1.911 mmol) and 2-(4-bromobenzyl )methyl-thiazolecarboxylic acid ethyl ester (591 mg, 1.737 mmol), in dioxane (4 mL) and water (1 mL) was stirred and heated at reflux for 1 hour. Sodium 2'-(dicyclohexylphosphino)-2,6- dimethoxy-[1,1'-biphenyl]sulfonate (89 mg, 0.174 mmol), [PdCl(allyl)]2 (31.8 mg, 0.087 mmol) and caesium carbonate (1698 mg, 5.21 mmol) in dioxane (8 mL) and water (2 mL) was degassed with argon for 15 min. Then, the e was heated and stirred at 100 °C overnight. The reaction mixture was diluted, absorbed on silica and purified by chromatography (12 g column, 0-50% EtOAc in isohexanes) to afford 4-methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-thiazolecarboxylic acid ethyl ester (278 mg, 0.547 mmol, 31.5 % yield) as a yellow thick oil.
[M+H]+ = 356 D. 4-Methyl[4-(4-methyl-pyrazolyl methyl)-benzyl]-thiazolecarboxylic acid To a stirred mixture of 4-methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-thiazolecarboxylic acid ethyl ester (278 mg, 0.782 mmol) in THF (1 mL) and water (0.5 mL) at rt was added sodium hydroxide (130 mg, 3.25 mmol). The ing solution was d at rt overnight and ated under reduced pressure. The residue was redissolved in 2M NaOH (5 mL) and ted with EtOAc (3 x 5 mL). Then, the aqueous was acidified to pH ~3 and extracted with EtOAc (3 x 5mL). Combined organics were dried (MgSO4), ed and evaporated under reduced pressure to give 4-methyl[4-(4-methyl-pyrazolyl methyl)-benzyl]-thiazolecarboxylic acid (232 mg, 0.602 mmol, 77 % yield) as a pale yellow solid.
[M+H]+ = 328 E. 4-Methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-thiazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide hydrochloride Procedure as for Example 13 method C [M+H]+ = 483 1H NMR: (d6-DMSO), δ: 2.00 (3H, s); 2.55 (3H, s); 4.28 (2H, s); 4.56 (2H, d, J = 5.8 Hz ); 5.23 (2H, s); 7.15 - 7.36 (6H, m); 7.56 (1H, t, J = 0.9 Hz ); 7.62 - 7.71 (2H, m); 7.78 (1H, d, J = 1.6 Hz ); 8.52 (1H, d, J = 8.7 Hz ); 8.80 (1H, t, J = 5.9 Hz ); 9.00 (2H, s); 13.04 (1H, s) E 19 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]oxo-2,3-dihydro-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide A. Ethyl 1-[4-(4-methyl-pyrazolylmethyl)-benzyl]oxo-2,3-dihydro-1H-pyrazolecarboxylate To a solution of sodium ethanolate (1418 mg, 20.83 mmol) and diethyl 2-(ethoxymethylene)malonate (842µl, 4.17 mmol) in EtOH (10mL) was added dropwise a solution of 1-(4-(hydrazinylmethyl)benzyl) methyl-1H-pyrazole, 2HCl (1446 mg, 5 mmol) in EtOH (20 mL) with cooling in an ice-water bath. The resulting mixture was stirred allowed to warm to rt overnight. The reaction mixture was trated under vacuum, then partitioned between DCM (50 mL) and water (50 mL, adjusted to pH 5 with 1N HCl). The aqueous layer was extracted with DCM (2 x 50 mL) and the combined organics washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to a yellow oil. This was ed by chromatography (silica) eluting with a gradient of 0 to 40% CM to afford 210 mg of ethyl 1-[4- (4-methyl-pyrazolylmethyl)-benzyl]oxo-2,3-dihydro-1H-pyrazolecarboxylate.
[M+H]+ = 341 B. 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]oxo-2,3-dihydro-1H-pyrazolecarboxylic acid A solution of ethyl 1-[4-(4-methyl-pyrazolylmethyl)-benzyl]oxo-2,3-dihydro-1H-pyrazole carboxylate (200 mg, 0.588 mmol) in a mixture of THF (2 mL) and MeOH (0.5 mL) was treated with lithium hydroxide (70.4 mg, 2.94 mmol) and water (0.75 mL). The mixture was allowed to stir at ambient temperature for 1 hour. Further water (0.5 mL) was added to clarify, and the mixture heated at 50 °C overnight. Organics were removed under vacuum and the aqueous transferred to a separating funnel with water (7 mL). The aqueous (at pH 10) was extracted with EtOAc (10 mL). The aqueous layer was collected and adjusted to pH 4 with 1M HCl, forming a precipitate. This was allowed to stand for 5 min, then ted to a fine powder before being collected by filtration, washing with a small quantity of water. On drying under vacuum in the ce of CaCl2, 1-[4-(4-methyl-pyrazolylmethyl)-benzyl]- 3-oxo-2,3-dihydro-1H-pyrazolecarboxylic acid (147 mg, 0.466 mmol, 79 % yield) was isolated as an off-white powder.
[M+H]+ = 313 C. 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]oxo-2,3-dihydro-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide A scintillation vial was charged with 1-(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)oxo-2,3-dihydro- 1H-pyrazolecarboxylic acid (75 mg, 0.240 mmol), 6-(aminomethyl)isoquinolinamine dihydrochloride (65.0 mg, 0.264 mmol), HATU (100 mg, 0.264 mmol) and anhydrous DCM (2 mL) and anhydrous DMF (0.3 mL). N,N-Diisopropylethylamine (167 µl, 0.961 mmol) was added and the mixture allowed to stir at ambient ature for 2 hrs. Further HATU (30 mg), N,N-diisopropylethylamine (80 μL) and amine (20 mg) were added, along with DMF (1 mL). The mixture was heated at 40 °C for 2.5 hrs. The reaction was partitioned between EtOAc (25 mL) and 2N NaOH (15 mL). The aqueous layer was extracted with further EtOAc (2 x 25 mL) and the combined organics dried (MgSO4), filtered and concentrated. HPLC of the aqueous and isolated organics indicated that all product was in the aqueous layer. This was adjusted to pH 7 with conc. HCl ng some vely insoluble material) and extracted with EtOAc (containing trace MeOH, 2 x 30 mL) and DCM (containing trace MeOH, 30 mL).
The combined organics were dried (Na2SO4), ed and concentrated. The residue was triturated with DCM and then MeOH to afford ~15 mg of a yellow solid. Chromatography (silica) eluting with THF ed 1-[4-(4-methyl-pyrazolylmethyl)-benzyl]oxo-2,3-dihydro-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide (9 mg, 0.012 mmol, 4.81 % yield, 70% purity) as a white powder.
[M+H]+ = 468 NMR (d6-DMSO) δ: 1.98 (3H, s), 4.55 (2H, d, J= 6.0Hz), 5.09 (2H, s), 5.21 (2H, s), 6.82 (2H, br.s), 6.87 (1H, d, J= , 7.16-7.26 (5H, m), 7.38 (1H, dd, J= 8.6, , 7.52 (2H, m), 7.74 (1H, d, J= 5.8Hz), 7.93 (1H, t, J= 6.1Hz), 8.04 (1H, s), 8.14 (1H, d, J= 8.6Hz), 11.10 (1H, br.s).
EXAMPLE 20 3-(3,5-Dimethyl-isoxazolyl)[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide A: Ethyl 3-bromo-1H-pyrazolecarboxylate To a solution of tert-butyl nitrite (3.04 mL, 25.6 mmol) in anhydrous MeCN (80 mL) was added copper(II) bromide (5.71 g, 25.6 mmol). The mixture was stirred at ambient temperature for 1 hour under N2, then ethyl 3-amino-1H-pyrazolecarboxylate (3.39 g, 21.85 mmol) added in portions over 15 min. The mixture was d at ambient temperature for 30 min, then heated at 70 °C for 2 hrs. The reaction was allowed to cool and the acetonitrile removed under . The residue was ved in EtOAc (250 mL) and washed with brine (3 x 100 mL), dried (MgSO4), filtered and concentrated to a dark green solid (5.64 g, 18.02mmol, 82% yield, 70% purity). The product was used directly in the next step without purification.
[M+H]+ = 219/221 B: 3-Bromo[4-(4-methyl-pyrazolyl methyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester To a stirred suspension of ethyl o-1H-pyrazolecarboxylate (500 mg, 2.283 mmol) and 1-(4- (chloromethyl)benzyl)methyl-1H-pyrazole (504 mg, 2.283 mmol) in DMF (2.5 mL) was added potassium carbonate (631 mg, 4.57 mmol) and the mixture stirred at t temperature for 1.5 hrs.
Heating was increased to 50 °C for 24hrs then the reaction was diluted with EtOAc (50 mL) and water (30 mL) ning brine (30 mL). The aqueous layer was extracted with further EtOAc (2 x 40 mL) and the combined organics dried (MgSO4), filtered and concentrated. The crude al was purified by chromatography (silica) eluting with a gradient of 0 to 45% EtOAc/Iso-Hexanes holding at 40% to elute the two regioisomers.
-Bromo(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazolecarboxylic acid ethyl ester (54 mg, 0.100 mmol, 4.40 % yield) was isolated as a clear gum which crystallized on standing, 2D nOesy showed no interaction between the benzylic protons and the pyrazole core ring proton (at 8.03 ppm).
[M+H]+ = 403/405 The desired isomer 3-bromo(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazolecarboxylic acid ethyl ester (217 mg, 0.527 mmol, 23 % yield) was isolated as a clear gum which crystallized on standing. 2D nOesy showed an interaction between one of the pairs of benzylic protons and the pyrazole core ring proton (at 8.52 ppm) confirming the desired isomer.
[M+H]+ = 403/405 C: 3-(3,5-Dimethyl-isoxazolyl)[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester A mixture of o[4-(4-methyl-pyrazolyl methyl)-benzyl]-1H-pyrazolecarboxylic acid ethyl ester (85 mg, 0.211 mmol), 3,5-dimethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)isoxazole (58.8 mg, 0.263 mmol), potassium carbonate (65.5 mg, 0.474 mmol) and tetrakis(triphenylphosphine) palladium(0) (24.36 mg, 0.021 mmol) were combined in a microwave vial and dioxane (0.6 mL) and water (0.2 mL) were added. The mixture was degassed with N2 for 5 min, then heated at 100 °C for 5.5 hrs, then at t temperature overnight. The reaction e was partitioned between EtOAc (40 mL) and water (30 mL). The aqueous layer was extracted with r EtOAc (2 x 15 mL) and the combined organics washed with brine (20 mL), dried (MgSO4), filtered and concentrated. The crude residue was purified by chromatography a) g with a gradient of 0 to 60 % EtOAc/Iso-Hexanes to afford 3-(3,5-dimethylisoxazolyl)(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazole carboxylic acid ethyl ester (37 mg, 0.086 mmol, 41.0 % yield) as a white powder.
[M+H]+ = 420 D: 3-(3,5-Dimethyl-isoxazolyl)[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid A stirred solution of 3-(3,5-dimethyl-isoxazolyl)[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H- pyrazolecarboxylic acid ethyl ester (32.3 mg, 0.077 mmol) in THF (0.25 mL) and MeOH (0.25 mL) was treated with a solution of lithium hydroxide (4.61 mg, 0.193 mmol) in water (0.25 mL). A precipitate quickly formed. Further MeOH (0.5 mL) was added and the mixture was allowed to stir at t temperature for 3 hrs. LCMS indicated only ~15% hydrolysis. Further THF was added until solution formed (total volume ~2.5 mL). Further LiOH (5 mg) was added and the mixture heated at 50 °C for 3 hrs, then at ambient temperature overnight. Solvents were removed under vacuum and the residue partitioned between EtOAc (5 mL) and water (4 mL). The aqueous layer was adjusted to ~pH 4 with 1M HCl, forming a precipitate. This was filtered, washing with water, then dried under vacuum to afford 3- (3,5-dimethylisoxazolyl)(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazolecarboxylic acid (21 mg, 0.053 mmol, 69.0 % yield) as a white solid.
[M+H]+ = 392 E: 3-(3,5-Dimethyl-isoxazolyl)[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide hydrochloride A scintillation vial was charged with 3-(3,5-dimethylisoxazolyl)(4-((4-methyl-1H-pyrazol yl)methyl)benzyl)-1H-pyrazolecarboxylic acid (18.7 mg, 0.048 mmol), 6-(aminomethyl)isoquinolin amine dihydrochloride (18.81 mg, 0.076 mmol), HATU (19.98 mg, 0.053 mmol), anhydrous DCM (0.5 mL) and anhydrous DMF (0.15 mL). N,N-Disopropylethylamine (33.3 µl, 0.191 mmol) was added and the e allowed to stir at t temperature overnight. Solvents were d under vacuum. The residue was redissolved in MeOH (2 mL) and purified by strong cation exchange chromatography (1.5 g), washing with MeOH, eluting with 1% OH. The resultant material was purified by chromatography (silica) g with a gradient of 0 to 10% MeOH (0.3% CM to afford the free base as a white powder. The free base was dissolved in DCM (0.75 mL), then treated with 4M HCl in dioxane (26.3 µl, 0.105 mmol). This was allowed to stand for 10 min before being concentrated. On drying, 3-(3,5-dimethyl-isoxazolyl)[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide (19 mg, 0.030 mmol, 63.4 % yield) was isolated as a pale yellow powder.
[M+H]+ = 547 NMR (d6-DMSO): 1.98 (3H, s), 2.04 (3H, s), 2.21 (3H, s), 4.53 (2H, d, J= 5.9Hz), 5.23 (2H, s), 5.38 (2H, s), 7.15-7.26 (4H, m), 7.30 (2H, d, J= 8.2Hz), 7.54 (1H, s), 7.63-7.71 (2H, m), 7.76 (1H, s), 8.44 (1H, s), 8.53 (1H, d, J= 8.6Hz), 8.80 (1H, t, J= 6.0Hz), 9.09 (2H, brs), 13.26 (1H, brs).
EXAMPLE 21 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]morpholinyl-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide A: 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]morpholinyl-1H-pyrazolecarboxylic acid ethyl ester A microwave vial was charged with 3-bromo[4-(4-methyl-pyrazolyl methyl)-benzyl]-1H-pyrazole carboxylic acid ethyl ester (300 mg, 0.744 mmol), RuPhos Precatalyst, chloro(2-dicyclohexylphosphino- diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (34.7 mg, 0.045 mmol), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]yl)phosphine - RuPhos (20.83 mg, 0.045 mmol), morpholine (386 µl, 4.46 mmol), caesium carbonate (630 mg, 1.934 mmol) and anhydrous THF (5 mL).
The mixture was y ed with N2, and stirred at ambient temperature for 10 min, before heating to 85 °C (DrySyn bath temperature) overnight. LCMS indicated a ~1:1:1 mixture of starting material:debromination:product. Further RuPhos Precatalyst, chloro(2-dicyclohexylphosphino-2',6'- diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (34.7 mg, 0.045 mmol), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]yl)phosphine - RuPhos (20.83 mg, 0.045 mmol) and morpholine (150 μL) were added and the mixture stirred at 85 °C n bath temperature) overnight.
Solvents were removed under vacuum and the residue partitioned between EtOAc (10 mL) and water (10 mL). The aqueous was ted with EtOAc (10 mL) and the combined organics washed with brine (5 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica) eluting with a gradient of 0 to 80% EtOAc/Iso-Hexanes to afford 1-[4-(4-methyl-pyrazol ylmethyl)-benzyl]morpholinyl-1H-pyrazolecarboxylic acid ethyl ester (128 mg, 0.309 mmol, 41.6 % yield) as a clear gum.
[M+H]+ = 410 B: 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]morpholinyl-1H-pyrazolecarboxylic acid A stirred solution of ethyl 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]morpholinyl-1H-pyrazole carboxylic acid ethyl ester (125 mg, 0.305 mmol) in THF (1 mL) and MeOH (1 mL) was treated with a on of lithium hydroxide (18.28 mg, 0.763 mmol) in water (1 mL) and the mixture heated at 40 °C over a weekend. Any ing organic solvents were removed under vacuum and the residue PCT/GB 2014/051 S92 — 18—03—2015 partitioned n EtOAc (10 mL) and water (7 mL). The s layer was adjusted to ”pH 4 with 1M HCl. The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organics dried (MgSO4), filtered and trated to afford (4-methyl-1H-pyrazoIyl)methy|)benzyl)morpho|ino-1H- le-4—carboxylic acid (109 mg, 0.271 mmol, 89 % yield) as a gummy yellow solid.
[M+H]+ = 382 C: 1-[4-(4-Methyl-pyrazolylmethy|)-benzyl]morpholinyl-1H-pyrazolecarboxylic acid (1- isoquinolinylmethyl)-amide A scintillation vial was charged with 1-(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)morpho|ino-1H- pyrazolecarboxylic acid (106 mg, 0.278 mmol), 6-(aminomethyl)isoquinolin-l-amine dihydrochloride (82 mg, 0.333 mmol), HATU (116 mg, 0.306 mmol), anhydrous DCM (1 mL) and anhydrous DMF (0.3 mL).
N,N-Disopropylethy|amine (194 pl, 1.112 mmol) was added and the mixture allowed to stir at ambient temperature overnight. Solvents were removed under vacuum. The residue was redissolved in MeOH (2 mL) and purified by strong cation exchange chromatography (2.5 g), washing with MeOH, eluting with 1% NH3/MeOH. The resultant material was purified by chromatography (silica) eluting with a gradient of 0 to 10% MeOH (0.3% NH3)/DCM to afford the free base as a white foam. The free base was dissolved in DCM (0.75 mL) and MeOH (0.15 mL), then treated with 4M HCI in dioxane (153 pl, 0.611 mmol). This was allowed to stand for 10 min before being trated. On drying, 1-[4—(4-methyI-pyrazol ylmethyl)-benzyI]morpholinyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)- amide (125 mg, 0.212 mmol, 76 % yield) was isolated as a mono HCI salt, as a pale yellow powder.
[M+H]‘ = 537 NMR (d6-DMSO): 1.98 (3H, s), 3.03-3.10 (4H, m), 3.58-3.64 (4H, m), 4.58 (2H, d, J: 5.8Hz), 5.18 (2H, s), .23 (2H, s), 7.16-7.28 (6H, m), 7.55 (1H, s), 7.65—7.72 (2H, m), 7.79 (1H, s), 8.20 (1H, s), 8.48-8.60 (2H, m), 9.16 (2H, br.s), 13.39 (1H, br.s).
REFERENCE EXAMPLE 22 razol lmeth l-benz l-1H- razolecarbox lic acid 6-meth l-1H- blgyridin-S-ylmethyl)-amide AMENDED SHEET A. 6-Aminoiodomethylnicotinonitrile 6-Aminomethylnicotinonitrile (3.0 g, 22.53 mmol) and 1-iodopyrrolidine-2,5-dione (8.62 g, 38.3 mmol) were dissolved in dry DMF (35 mL). The brown solution was heated to 80 °C for 24 hrs after which time the reaction mixture was diluted with water (50 mL). Extracted with EtOAc (4 x 75 mL).
Combined organic layers were washed with water (5 x 30 mL), brine (50 mL) then dried (Na2SO4), filtered and concentrated in vacuo. The crude product was ed by chromatography on RediSep (80 g column, 0-30% EtOAc in iso-hexanes) to give a brown coloured solid identified as oiodo methylnicotinonitrile (3.0 g, 9.84 mmol, 43.7 % yield) [M+H]+ = 260 B. omethyl((trimethylsilyl)ethynyl)nicotinonitrile To a dried flask under N2 was added 6-aminoiodomethylnicotinonitrile (4 g, 13.13 mmol), triethylamine (2.74 mL, 19.69 mmol), dry THF (30 mL) and dry DCM (10 mL) to give an orange solution.
Degassed with N2 for 5 min before bis(triphenylphosphine)palladium(II) chloride (0.276 g, 0.394 mmol) and copper(I) iodide (0.125 g, 0.656 mmol) were added to give a black coloured suspension. Next, ethynyltrimethylsilane (2.040 mL, 14.44 mmol) was added drop-wise over 5 min ing in a red/brown coloured solution which was stirred at rt for 1 hour. The reaction mixture was partitioned with EtOAc (100 mL) and water (100 mL).The aqueous layer was extracted with EtOAc (2 x 50 mL) and the combined c layers were washed with water (2 x 50 mL) and brine (50 mL) then dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by chromatography on RediSep (80 g column, 0-25% EtOAc in iso-hexanes) to give a pale orange solid identified as 6-aminomethyl ((trimethylsilyl)ethynyl)nicotinonitrile (2.2 g, 9.40 mmol, 72 % yield) [M+H]+ = 230 C. N-Acetyl-N-(5-cyanomethyl((trimethylsilyl)ethynyl)pyridinyl)acetamide To a flask under N2 was added 6-aminomethyl((trimethylsilyl)ethynyl)nicotinonitrile (2.2 g, 9.59 mmol) and pyridine (15 mL, 9.59 mmol). The mixture was cooled in an ice bath before acetyl chloride (1.569 mL, 22.06 mmol) was added ise to give a light tan ed suspension. Stirred for 10 min, allowed to warm to rt then heated at 40 °C for 1 hour. Dry THF (10 mL) was added and the reaction was stirred for a further 2 hrs. Dry DCM (10 mL) added and stirred at rt for 3 days. Heated to 60 °C for 2 hrs.
Stirred at rt for a r 18 hrs. The volatiles were removed in vacuo and the residue was azeotroped with toluene (30 mL). LCMS showed mainly starting al and some evidence of mono and di acylation. Resuspended in DCM (20 mL) and treated with pyridine (1.940 mL, 23.98 mmol) then acetyl chloride (1.569 mL, 22.06 mmol). The resulting sion was stirred at rt for 18 hrs. LCMS showed conversion to mono and bis acylation with evidence of starting material present in m/z trace. The reaction was heated to 40 °C for 1 hour. LCMS showed conversion to bis-acylated material (~60% purity). Diluted with EtOAc (200 mL) and washed with 1N HCl (60 mL). Aqueous layer extracted with EtOAc (50 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 (30 mL), water (30 mL) and brine (30 mL) then dried (Na2SO4), filtered and concentrated in vacuo to a brown coloured residue (4.0 g). The crude product was purified by chromatography on RediSep (40 g column, 0-20% EtOAc in iso-hexanes). Material ed (4.0 g) as a brown oil. is by LCMS confirmed N- acetyl-N-(5-cyanomethyl((trimethylsilyl)ethynyl)pyridinyl)acetamide (60% purity by UV) along with 3 impurities (10-15% each). Material used in subsequent reaction without further purification/analysis.
D. 6-Methyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile To a flask under N2 was added N-acetyl-N-(5-cyanomethyl((trimethylsilyl)ethynyl)pyridin yl)acetamide (4.3 g, 6.86 mmol), dry THF (20.0 mL) followed by utylammonium fluoride (1.0 M in THF) (10.29 mL, 10.29 mmol). The dark brown reaction mixture was heated to 70 °C before being diluted with EtOAc (100 mL), washed with water (50 mL) and brine (50 mL) then dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by tography on RediSep (40 g column, 0- % EtOAc in iso-hexanes) and two major peaks eluted. To a flask under N2 was added N-(5-cyano ethynylmethylpyridinyl)acetamide (1.03 g, 3.21 mmol), dry THF (2.0 mL) to give a pale yellow solution. Next, tetrabutylammonium fluoride (1.0 M in THF) (15 mL, 15.00 mmol) was added and heated to 72 °C for 1 h to give a dark orange solution. HPLC showed complete consumption of starting material. Allowed to cool to rt. Diluted with EtOAc (150 mL) and washed with water (100 mL). Aqueous layer extracted with EtOAc (2 x 50 mL) before the combined organic layers were washed with water (2 x 50 mL), brine (50 mL) and dried 4), filtered and concentrated in vacuo to give an orange solid slurried in Et2O:MeOH (9:1, 15 mL), collected by filtration and washed with Et2O (15 mL). Dried by suction for 10 min then in vacuum oven for 1 h to give a tan solid fied as 6-methyl-1H-pyrrolo[2,3- dinecarbonitrile (0.69 g, 4.26 mmol, 74.7 % yield).
[M+H]+ = 158 E. utyl ((6-methyl-1H-pyrrolo[2,3-b]pyridinyl)methyl)carbamate To a flask under N2 was added: 6-methyl-1H-pyrrolo[2,3-b]pyridinecarbonitrile (0.64 g, 4.07 mmol), di-tert-butyl dicarbonate (1.777 g, 8.14 mmol), nickel(II) chloride (0.053 g, 0.407 mmol) and MeOH (50 mL) to give a pale tan coloured suspension. Cooled in an ice bath before sodium borohydride (1.078 g, 28.5 mmol) was added portion-wise over 1 hrs. Allowed to warm to rt in ice bath for 18 hrs. Volatiles were removed in vacuo and the brown residue was partitioned between DCM (100 mL) and saturated NaHCO3 (50 mL). Aqueous layer ted with DCM (2 x 30 mL) before the combined c layers were washed with brine (50 mL), dried (Na2SO4), filtered and trated in vacuo. Purified by column tography (RediSep 40 g, dry loaded, 0-100% EtOAc in iso-hexanes). Dried in vacuum oven (40 °C) overnight. Giving a white solid identified as tert-butyl ((6-methyl-1H-pyrrolo[2,3-b]pyridin yl)methyl)carbamate (0.74 g, 2.78 mmol, 68.2 % yield).
[M+H]+ = 262 F. 6-Methyl-1H-pyrrolo[2,3-b]pyridinyl)methanamine tert-Butyl ((6-methyl-1H-pyrrolo[2,3-b]pyridinyl)methyl)carbamate (0.74 g, 2.83 mmol) was suspended in DCM (7.0 mL). TFA (5 mL, 64.9 mmol) was added and the resulting clear yellow solution was stirred at rt for 1 hrs. al isolated by capture and release using strong cation exchange chromatography, g with MeOH (50 mL) and eluting with 1% NH3 in MeOH (100 mL).
Concentrated in vacuo and dried in vacuum oven (40 °C for 2 h) to give an off-white solid identified as 6- methyl-1H-pyrrolo[2,3-b]pyridinyl)methanamine (0.47 g, 2.62 mmol, 93 % yield).
[M+H]+ = 162 G. Ethyl 1-(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazolecarboxylate A solution of (4-((4-methyl-1H-pyrazolyl)methyl)phenyl)methanol (500 mg, 2.472 mmol), ethyl 1H- pyrazolecarboxylate (364 mg, 2.60 mmol) and triphenylphosphine (713 mg, 2.72 mmol) in anhydrous THF (8 mL) was treated dropwise with (E)-diisopropyl diazene-1,2-dicarboxylate (560 µL, 2.84 mmol).
After 4 hrs at rt the reaction e was concentrated onto silica and purified by flash chromatography (silica) eluting with a gradient of 10 to 100% Iso-Hexanes (product eluted at ~70% EtOAc).
Fractions were evaporated to give a white solid identified as ethyl 1-(4-((4-methyl-1H-pyrazol yl)methyl)benzyl)-1H-pyrazolecarboxylate (610 mg, 1.862 mmol, 75 % yield).
[M+H]+ = 325 H. 1-(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazolecarboxylic acid A solution of ethyl 1-(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazolecarboxylate (610 mg, 1.881 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was treated with lithium hydroxide (225 mg, 9.40 mmol) and the mixture heated at 50 °C with ng overnight. Solvents were removed under vacuum and the residue suspended between EtOAc (50 mL) and water (50 mL). The aqueous phase was adjusted to pH 1 with 1M HCl and the organic layer collected. The aqueous was extracted with EtOAc (2 x 50 mL) and the combined organics washed with brine (50 mL), dried (MgSO4), filtered and concentrated to give a white solid identified as 1-(4-((4-methyl-1H-pyrazolyl)methyl)benzyl)-1H- pyrazolecarboxylic acid (518 mg, 1.713 mmol, 91 % yield).
[M+H]+ = 297.
I. 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (6-methyl-1H-pyrrolo[2,3- b]pyridinylmethyl)-amide A llation vial was charged with (4-methyl-1H-pyrazolyl)methyl)benzyl)-1H-pyrazole carboxylic acid (0.092 g, 0.310 mmol) and suspended in dry DCM (3mL) to which was added (6-methyl- 1H-pyrrolo[2,3-b]pyridinyl)methanamine (0.050 g, 0.310 mmol), HATU (0.130 g, 0.341 mmol) and then N,N-disopropylethylamine (0.108 mL, 0.620 mmol), the suspension was left to stir at rt. The reaction mixture was evaporated and the resulting e quenched with saturated solution of ammonium chloride (5mL) and left to stir at rt overnight. The solid was filtered under reduced pressure and placed in the vacuum oven at 40°C for 2 days. The solid was triturated with ethyl acetate (5mL) doped with methanol (0.1mL), sonicated and then filtered under d pressure to give a pale brown solid which was placed in the vacuum oven at 40°C to give a white solid identified as 1-[4-(4-methyl- pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (6-methyl-1H-pyrrolo[2,3-b]pyridin ylmethyl)-amide (62mg, 0.14mmol, 37% yield).
[M+H]+ = 440 1H NMR: (d6-DMSO), δ: 1.98 (3H, t, J = 0.7Hz), 2.51 (3H, s), 4.45 (2H, d, J = 5.5Hz), 5.20 (2H, s), 5.30 (2H, s), 6.34 (1H, dd, J = 1.9, 3.4Hz), .19 (2H, m), 7.20-7.25 (3H, m), 7.32 (1H, dd, J = 2.4, 3.4Hz), 7.51 (1H, t, J = 0.9Hz), 7.74 (1H, s), 7.90 (1H, d, J = 0.7Hz), 8.25 (1H, d, J = 0.7Hz), 8.41 (1H, t, J = 5.5Hz), 11.37 (1H, s).
E 23 -Amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide A. 1-(4-Hydroxymethyl-benzyl)-1H-pyrazole 4-(Chloromethyl)benzyl alcohol (650mg, 4.15mmol) and pyrazole (311mg, 4.57mmol) were taken up in MeCN (30mL). K2CO3 (860.5mg, 6.23mmol) was added and the reaction was heated to 50°C for 48hrs.
Volatiles were removed in vacuo. Ethyl acetate (60mL) and water (20mL) added. c layer filtered and ated under vacuum. Purified by flash tography (silica) eluting with 40% EtOAc in Pet.
Ether to afford a colourless oil fied as 1-(4-hydroxymethyl-benzyl)-1H-pyrazole (480mg, 61% yield).
B. 1-(4-Bromomethyl-benzyl)-1H-pyrazole 1-(4-Hydroxymethyl-benzyl)-1H-pyrazole (480mg, 2.55mmol) and triphenylphosphine , 2.93mmol) were taken up in DCM (15mL). The resultant solution was cooled in an ice bath before carbon tetrabromide (930mg, 2.81mmol) was added portionwise. The mixture was stirred at RT for 18 hrs. The mixture was diluted with DCM, washed with water (2 x 50 mL) and brine (30 mL) and concentrated under vacuum. The crude material was purified via flash chromatography (silica) (20-40 % EtOAC/ Pet. Ether). The compound containing fractions were concentrated in vacuo to afford to an off white solid identified as 1-(4-bromomethyl-benzyl)-1H-pyrazole (410mg, 64% yield).
C. 3-Amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid ethyl ester and 5-Amino (4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid ethyl ester.
To 5-amino-1H-pyrazolecarboxylic acid ethyl ester (200mg, 1.29mmol) in acetonitrile (7mL) was added potassium carbonate (356mg, 2.58mmol) and 1-(4-bromomethyl-benzyl)-1H-pyrazole (324mg, ol) and the reaction stirred at rt for 18hrs. The reaction mixture was concentrated and the residue purified by column chromatography (silica) eluting with 6:6:7 itrile : Ethyl acetate : Pet.
Ether to afford 3-amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid ethyl ester , 31% yield) and 5-amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid ethyl ester (119mg, 28% yield).
D. 3-Amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid To 3-amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid ethyl ester (119mg, 0.37mmol) in ethanol (20mL) was added sodium hydroxide (102mg, 2.56mmol) and the reaction heated at reflux for 48hrs. The reaction mixture was cooled and concentrated in vacuo. The crude residue was dissolved in water (2 mL) and the pH adjusted to pH ~ 5 with 2M HCl (until on mixture turned ). EtOAc was added and solid went into organic layer but did not dissolve. Aqueous layer was removed and the organic layer filtered to afford an off white solid that was washed with diethyl ether to afford 3-amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid which was used in next step without further purification.
E. o(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide TFA salt To 3-amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid (49.1mg, 0.17mmol) in dichloromethane (15mL) and DMF (2mL) at 0°C was added HOBt g, 0.20mmol) and water soluble carbodiimide (44.3mg, 0.23mmol). After stirring for 15 min triethylamine (115µL, 0.83mmol) and 6 - aminomethyl-isoquinolinylamine (28.6mg, 0.17mmol) was added and the reaction allowed to warm to rt and stirred for 18 hrs. The reaction mixture was partitioned between EtOAc (30mL) and water (10mL). The organic layer was washed with brine . The organic layer was dried (MgSO4), filtered and concentrated. Purification by prep HPLC afforded o(4-pyrazolylmethyl-benzyl)-1H- pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide TFA salt as an off white solid.
[M+H]+ = 453 1H NMR: SO), δ: 2.98 (1H, br s), 4.02 (2H, br s), 4.55 (2H, d, J= 5.8Hz), 5.07 (2H, s), 5.31 (2H, s), 6.26 (1H, t, J= 2.0), 7.19-7.25 (5H, m), 7.44 (1H, d, 1.8Hz), 7.64 (1H, d, J= 7.0Hz), 7.68 (1H, dd, J= 8.7, 1.3 Hz), 7.79 (2H, dd, J= 9.0, 2.0Hz), 8.02 (1H, s), 8.49 (1H, d, J= 8.6Hz), 8.51 (1H, t, J= 5.7Hz), 8.93 (2H, br s), 12.84 (1H, br s).
EXAMPLE 24 1-(6-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide A. 5-Bromomethylfluoro-pyridine 2-Fuoromethylpyridine (5.0g, 45mmol) was dissolved in 1,2-dichloroethane (120mL). To this solution was added N-bromosuccinimide (9.61g, 54mmol) and isobutyronitrile (AIBN) , 4.5mmol).
The reaction was stirred at reflux. After 18 hrs the reaction mixture was diluted with chloroform (100mL) and washed with water (1x50mL) and brine L), dried (Na2SO4) and evaporated in vacuo.
The residue was purified by flash chromatography (silica), eluent 95% Pet. Ether, 5% EtOAc, fractions combined and evaporated in vacuo to give a yellow oil fied as 5-bromomethylfluoro-pyridine (6.89g, 36.25mmol, 81% yield).
[M+H]+ = 192 B. 1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester Ethyl 3-trifluoromethyl-1H-pyrazolecarboxylate (1.57g, 7.53mmol) was dissolved in DMF (20mL), 5- bromomethylfluoro-pyridine (1.3g, ol) and caesium carbonate (6.69g, 20.53mmol) were added and the reaction mixture was stirred at 50°C. After 18 hrs the reaction mixture was diluted with EtOAc (100mL), this solution was washed with water (1x30mL) and brine (1x30mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 85% Pet. Ether, % EtOAc, fractions combined and evaporated in vacuo to give a white solid fied as 1-(6-fluoropyridinylmethyl ifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester. (1.26g, 3.97mmol, 58% yield).
C. 1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid ethyl ester (1.26g, 3.97mmol) was ved in THF (50mL)and water (5mL) and lithium hydroxide (476mg, 19.86mmol) was added. The reaction mixture was stirred at 50°C. After 18 hrs the solvent was concentrated in vacuo and the e taken up in EtOAc (50mL), the aqueous layer was separated and acidified with 1M HCl to pH2 and extracted with CHCl3 (3x50mL). The combined extracts were washed with water (1x30mL) and brine (1x30mL), dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as 1-(6-fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (980mg, 3.39mmol, 85% .
[M+H]+ = 290 D. yrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 1-(6-Fluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (300mg, 1.04mmol) was dissolved in dioxane (25mL) and pyrrolidine (2mL) and the reaction mixture was stirred at 80°C. After 18 hrs the reaction mixture was diluted with EtOAc mL), this solution was washed with water (1x30mL) and brine (1x30mL), dried (Na2SO4) and ated in vacuo. The residue was purified by flash chromatography (silica), eluent 1% AcOH, 9%MeOH, 90% CHCl3, fractions combined and evaporated in vacuo to give a white foamy solid identified as 1-(6-pyrrolidinyl-pyridinylmethyl)trifluoromethyl- 1H-pyrazolecarboxylic acid. (267mg, 0.785mmol, 76% yield).
[M+H]+ = 341 E. 1-(6-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide 1-(6-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (180mg, 0.53mmol) was dissolved in CH2Cl2 (50mL) and DMF (2.5mL). This solution was cooled to 0°C. 6- Aminomethyl-isoquinolinylamine.HCl (122mg, 0.58mmol) was added followed by HOBt (77mg, 0.58mmol) and triethylamine (161mg, ol). Water soluble carbodiimide (122mg, 0.63mmol) was then added. After 18 hrs at 0°C to rt reaction e was diluted with chloroform (100mL) and isopropanol (10mL) and washed with NaHCO3 (1x30mL), water (1x30mL) and brine (1x30mL), dried (Na2SO4) and evaporated in vacuo giving a yellow oil. The residue was purified by flash chromatography (silica), eluent 15%MeOH, 85% CHCl3, fractions combined and evaporated in vacuo to give a white solid.
The residue was d with HCl in methanol (4mL), the solvent was evaporated in vacuo and the residue freeze dried from water/acetonitrile to give a white solid identified as 1-(6-pyrrolidinylpyridinylmethyl )trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)- amide (135mg, 0.254mmol, 48% yield).
[M+H]+ = 496 1H NMR: (d6-DMSO), δ: 2.01 (4H, t, J= 6.0Hz), 3.47 (4H, t, J= 6.3Hz), 4.59 (2H, d, J= 5.8Hz), 5.45 (2H, s), 7.10 (1H, d, , J= , 7.20 (1H, d, J= 7.1Hz), 7.70 (2H, dd, J= 1.2 and , 7.81 (1H, s), 7.94 (1H, d, J= 8.8Hz), 8.15 (1H, s), 8.58 (1H, d, J= 8.7Hz), 8.64 (1H, s), 9.17-9.20 (2H, m), 13.30 (1H, s).
EXAMPLE 25 3-Cyclopropyl(5-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide A: (6-Chloromethoxy-pyridinyl)-methanol To a stirred solution of romethoxy-nicotinic acid methyl ester (0.5g, 2.48mmol) in anhydrous THF (20mL) cooled to 0 oC under nitrogen, LiAlH 4 (104mg, 2.728mmol) was added. The reaction was d to warm to rt for 2 hrs. The reaction was cooled to 0 oC and ed with water (5mL). Potassium sodium te (Rochelle's salt) was added to help break up the suspension. The mixture was filtered through Celite, washing well with water (20mL) and ethyl acetate (100mL). The filtrate was collected and the layers separated. The aqueous extracted with ethyl acetate (3 x 20mL).
The combined organic layers were washed with brine (50mL), dried over MgSO4 and the t d in vacuo. The crude was purified by flash chromatography (silica) eluting in step gradients up to 40% Pet. Ether, 60% ethyl acetate. Pure ons were concentrated affording the title compound (6- chloromethoxy-pyridinyl)-methanol as a white solid (360mg, 2.074mmol, 84% yield).
[M+H]+ = 174 B. 5-Bromomethylchloromethoxy-pyridine Under an atmosphere of N2, (6-chloromethoxy-pyridinyl)-methanol (360 mg, 2.074 mmol) and triphenylphosphine (626 mg, 2.385 mmol) were dissolved in dry DCM (5 mL). The resultant solution was cooled in an ice bath before carbon tetrabromide (756 mg, 2.281 mmol) was added portionwise. The mixture was stirred at ambient temperature for 18 hrs. The mixture was diluted with dichloromethane (30 mL), washed with water (2 x 50 mL) and brine (30 mL), dried (MgSO4) and trated under vacuum. The crude material was purified by flash chromatography (silica) eluting in step gradients up to 85% Pet. Ether, 15% ethyl acetate. The compound containing fractions were concentrated in vacuo to afford a colourless oil identified as 5-bromomethylchloromethoxy-pyridine (220mg, 0.93 mmol, 45% yield).
[M+H]+ = 238 1H NMR (400 MHz, CDCl3) δ: 3.97 (3H, s), 4.47 (2H, s), 7.25 (1H, d, J= 2.0Hz), 8.01 (1H, d, J= 2.0Hz) C. 1-(6-Chloromethoxy-pyridinylmethyl)cyclopropyl-1H-pyrazolecarboxylic acid ethyl ester 3-Cyclopropyl-1H-pyrazolecarboxylic acid ethyl ester (60mg, 0.333mmol) was taken up in DMF (2mL) and treated with potassium carbonate (91mg, 0.660mmol). 5-Bromomethylchloromethoxypyridine (78mg, 0.330mmol) was added and the reaction stirred at rt over the weekend. Ethyl acetate (60mL) and water (20mL) were added and the layers separated. The organic layer was washed with water (3 x 15mL), brine (10mL), filtered and evaporated. The crude product was purified by flash tography (silica) eluting in step gradients up to 60% Pet. Ether, 40% ethyl acetate. 1-(6-Chloro methoxy-pyridinylmethyl)cyclopropyl-1H-pyrazolecarboxylic acid ethyl ester was isolated as a colourless oil which solidified on ng to a white solid, (78mg, 0.232mmol, 70% yield).
[M+H]+ = 336 D. 3-Cyclopropyl(5-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid ethyl ester A suspension of 1-(6-chloromethoxy-pyridinylmethyl)cyclopropyl-1H-pyrazolecarboxylic acid ethyl ester (78 mg, 0.232 mmol) in pyrrolidine (763 µLS, 9.282 mmol) and 1,4-dioxane (300 μL) was heated at 90 °C overnight. The reaction was then cooled and taken up in ethyl acetate (20mL), NaHCO3 (10mL) was added and the organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography (silica) eluting in step gradients up to 60% Pet. Ether, 40% ethyl acetate. 3-Cyclopropyl(5-methoxypyrrolidinyl-pyridin ylmethyl)-1H-pyrazolecarboxylic acid ethyl ester was ed as a colourless oil (85mg, 0.229mmol, 98% yield).
[M+H]+ = 371 E. 3-Cyclopropyl(5-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid To opropyl(5-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid ethyl ester (85mg, mol) in ethanol (20mL) was added sodium hydroxide (92mg, mol). The reaction mixture was heated at reflux overnight. Then the reaction was cooled and concentrated under reduced pressure. The crude residue was dissolved in water (2 mL) and the pH adjusted to pH ~ 4.7 with 2M HCl. The aqueous layer was washed with chloroform (3 x 10mL). The combined cs were concentrated to afford the desired product 3-cyclopropyl(5-methoxypyrrolidinyl-pyridin ylmethyl)-1H-pyrazolecarboxylic acid as a white solid (60mg, 0.175mmol, 76% yiel d).
[M+H]+ = 343 F. 3-Cyclopropyl(5-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1- isoquinolinylmethyl)-amide hydrochloride To 3-cyclopropyl(5-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid (60mg, 0.175 mmol) in dichloromethane (5mL) at 0°C was added HOBt (28mg, 0.210mmol) and 1-ethyl- imethylaminopropyl)carbodiimide (47mg, 0.245mmol). After 10-15 min triethylamine (122 µl, 0.876mmol) and 6-(aminomethyl)isoquinolinamine (30mg, 0.175mmol) was added. DMF (3mL) was added to aid solubility and the reaction allowed to warm to rt and stirred for 3 days. The reaction mixture was diluted with chloroform (50mL) and saturated aqueous NaHCO3 (15mL) added. The layers were separated and the organic layer washed with water (5 x 20mL), followed by brine (15mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (silica) eluting in step gradients up to 3.5% methanol, 95.5% dichloromethane, 1% NH4OH. The product was treated with HCl/dioxane for 30 min, concentrated in vacuo and freeze dried in acetonitrile/water. 3-Cyclopropyl(5-methoxypyrrolidinyl-pyridin ylmethyl)-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide was isolated as the di hydrochloride salt as an off white solid (50mg, 0.088mmol, 99% yield).
[M+H]+ = 498 1H NMR (d6-DMSO): 0.75-0.79 (2H, m), 0.81-0.87 (2H, m), .95 (4H, m), 2.57-2.63 (1H, m), 3.77 (4H, br.s), 3.86 (3H, s), 4.58 (2H, d, J= 5.8Hz), 5.19 (2H, s), 7.21 (1H, d, J= 7.0Hz), 7.41 (1H, d, J= 1.3Hz), 7.54 (1H, d, J= , 7.67-7.69 (1H, m), 7.69-7.72 (1H, m), 7.80 (1H, s), 8.31 (1H, s), 8.59 (1H, d, J= , 8.79 (1H, t, J= 5.8Hz), 9.17 (2H, br.s), 13.39 (1H, s) EXAMPLE 26 1-(6-Ethoxy-pyridinylmethyl)phenyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide A: 5-Chloromethylfluoro-pyridine A 500mL flask was charged with 2-fluoromethylpyridine (23.42 g, 211 mmol), 1-chloropyrrolidine-2,5- dione (42.2 g, 316 mmol), benzoic peroxyanhydride (1.361 g, 4.22 mmol), acetic acid (1mL, 17.47 mmol) and acetonitrile (132 mL, 2527 mmol). The reaction mixture was heated to reflux giving a pale yellow solution which was left to reflux for 5 hrs. The reaction mixture was cooled and quenched with water (20 mL), followed by ethyl acetate (30 mL) and brine (30 mL). The two phases were separated and the aqueous racted with ethyl acetate (30 mL). The combined organics were washed with brine (30 mL), dried over magnesium sulphate, filtered and ated to give a viscous orange suspension. The product was triturated with DCM (100 mL) and the ing solid removed by filtration. The filtrate was evaporated under reduced pressure to give a clear orange oil. The crude product was divided into two 19g batches and purified on a 330g silica column, liquid loaded in DCM and gradient eluted with ethyl acetate-Iso-hexane (5:95). Product ning fractions were combined and evaporated in vacuo to give a clear almost colourless oil identified as 5-(chloromethyl)fluoropyridine (14.6 g, 99 mmol, 46.9 % yield).
[M+H]+ = 146 B. 1-(6-Fluoro-pyridinylmethyl)phenyl-1H-pyrazolecarboxylic acid ethyl ester To a stirred solution of 5-(chloromethyl)fluoropyridine (750 mg, 5.15 mmol) and ethyl yl-1H- lecarboxylate (1114 mg, 5.15 mmol) in DMF (15 mL) was added K2CO3 (1424 mg, 10.30 mmol) and stirred at RT over the weekend. The reaction mixture was d with EtOAc (150 mL) and washed with water (100 mL) and brine (2 x 100 mL), dried over magneisum sulfate, filtered and crude material ated ly onto silica. The crude product was purified by chromatography (40 g column, 0-60% (3:1 EtOAc:MeCN) in isohexanes). 1-(6-Fluoro-pyridinylmethyl)phenyl-1H-pyrazolecarboxylic acid ethyl ester (1.69 g, 4.16 mmol, 81 % yield) was isolated as a waxy solid on standing, as a mixture of regioisomers. The material was used directly in the next step [M+H]+ = 326 C: 1-(6-Ethoxy-pyridinylmethyl)phenyl-1H-pyrazolecarboxylic acid To a stirred microwave vial containing ethanol (3 mL) was added sodium ethoxide (586 mg, 8.61 mmol) and 1-(6-fluoro-pyridinylmethyl)phenyl-1H-pyrazolecarboxylic acid ethyl ester (700 mg, 2.152 mmol). The reaction vessel was sealed and heated to 90 °C overnight. The reaction mixture was allowed to cool to rt and diluted with EtOAc (100 mL), NH4Cl (sat, 10 mL) and water (100 mL). The organics were washed with brine (100mL) and solvent was removed. The crude material was taken up into THF (10 mL) and MeOH (3 mL) then 2M NaOH (2152 µl, 4.30 mmol) was added and left at RT for 2 hrs. The reaction mixture was acidified to ~ pH 5 with 1M HCl and the t extracted into EtOAc (2 x 30 mL). The organics were washed with brine (30 mL), dried over ium sulfate, filtered and solvent removed.
The crude product was ed by chromatography (40 g column, 0-70% (3:1 EtOAc:MeCN, 1% acetic acid) in isohexanes) to afford 1-((6-ethoxypyridinyl)methyl)phenyl-1H-pyrazolecarboxylic acid (65 mg, 0.191 mmol, 9 % yield) as a white solid.
[M+H]+ =324 D: 1-(6-Ethoxy-pyridinylmethyl)phenyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolin ylmethyl)-amide To a stirred solution of 1-((6-ethoxypyridinyl)methyl)phenyl-1H-pyrazolecarboxylic acid (65 mg, 0.201 mmol) and 6-(aminomethyl)isoquinolinamine.2HCl (49.5 mg, 0.201 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (140 µl, 0.804 mmol) and HATU (84 mg, 0.221 mmol) and left at RT for 2 hrs. The reaction mixture was diluted with EtOAc (30 mL) and washed with NaOH (2 M, 20 mL) and then brine (2 x 40 mL). The cs were preabsorbed directly onto silica and purified by chromatography (12 g column, 0-7% MeOH (1% NH3) in DCM) to afford the free base of the title compound (54.2 mg, 0.100 mmol, 49.7 % yield) as a white powder. The solid was azeotroped from toluene (3 x 5 mL) under high vacuum to remove any residual N,N-diisopropylethylamine before salt formation. The material was suspended in DCM (3 mL) and HCl 4M in dioxane (27.1 µl, 0.109 mmol, 1eq) was added. The solvent was d under vacuum. The residue was suspended in water (3 mL) and then freeze dried overnight to give 1-(6-ethoxy-pyridinylmethyl)phenyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide as a HCl salt, as a white solid (54.2 mg, 0.100 mmol, 49.7 % yield).
[M+H]+ = 479.3 EXAMPLE 27 1-(6-Ethoxy-pyridinylmethyl)(2-methoxy-acetylamino)-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide A. 3-Amino(6-fluoro-pyridinylmethyl)-1H-pyrazolecarboxylic acid ethyl ester 1132-35 To a d on of 3-amino-1H-pyrazolecarboxylic acid ethyl ester (1.785 g, 11.51 mmol) in ethanol (10 mL) was added sodium ethoxide (1.566 g, 23.01 mmol). After 5 min a solution of 5- (chloromethyl)fluoropyridine (1.675 g, 11.51 mmol) in EtOH (3 mL) was added and the reaction heated to 80 °C. After 90 min the reaction mixture was reduced in volume under vacuum and then diluted with EtOAc (200 mL) and water (100 mL). The organics were isolated and washed with brine (100 mL), dried over magnesium sulfate, filtered and solvent removed. The crude product was purified by chromatography (80 g column, slowly 0-40% (3:1 EtOAc:MeCN) in isohexanes). The undesired somer 5-amino(6-fluoro-pyridinylmethyl)-1H-pyrazolecarboxylic acid ethyl ester was isolated from the first set of fractions (768 mg, 2.76 mmol, 24 % yield) as an oil that solidified to a waxy solid on standing. The desired isomer 3-amino(6-fluoro-pyridinylmethyl)-1H-pyrazolecarboxylic acid ethyl ester (712 mg, 2.61 mmol, 22.7% yield) was isolated as a waxy solid from the second set of fractions.
[M+H]+ =265 B. 3-Amino(6-ethoxy-pyridinylmethyl)-1H-pyrazolecarboxylic acid To a microwave vial ning EtOH (5 mL) was added NaH (260 mg, 6.51 mmol) and d to stir for min. To this was added a suspension of ethyl 3-amino((6-fluoropyridinyl)methyl)-1H-pyrazole carboxylate (430 mg, 1.627 mmol) in EtOH (4 mL). The mixture was sealed and heated to 90 °C overnight. NaOH (2M, 2 mL) was added and heated to 50 °C for 1 hour. The reaction mixture was evaporated to dryness and the residue dissolved in water (10 mL) and the pH adjusted to pH5 then extracted with EtOAc (10 x 20 mL). The ed organics were then evaporated. The crude material was purified by chromatography (12 g column, 0-70% (3:1 EtOAc:MeCN, 1% acetic acid in isohexanes) to afford 3-amino((6-ethoxypyridinyl)methyl)-1H-pyrazolecarboxylic acid (195 mg, 0.736 mmol, 45.2 % yield) as a white powder after azeotroping with toluene (2 x 20 mL).
[M+H]+ = 263 PCT/GB 2014/051 592 — 26—06—2015 C. 1-((6-Ethoxypyridinyl)methyI)-3v(2-methoxyacetamido)—1H-pyrazolecarboxylic acid To a stirred solution of 3-amino-l-((6-ethoxypyridin-3—yl)methyl)-1H-pyrazolecarboxylic acid (142 mg, 0.541 mmol) in DCM (3 mL) was added N,N-diisopropylethylamine (142 uL, 0.812 mmol) and 2- methoxyacetyl chloride (54.5 (1L, 0.596 mmol) and stirred at rt for 1 hour. The reaction mixture was evaporated to remove DCM. The crude residue was sonicated in water (10 mL). hloric acid (2M, 1 mL) was added and the product extracted into EtOAc (30 mL). The organic layer was dried over magnesium sulfate and solvent evaporated under reduced pressure to afford 1-((6-ethoxypyridin yl)methyl)—3-(2—methoxyacetamido)-1H—pyrazole-4—carboxylic acid as a yellow solid (160 mg, 0.469 mmol, 87 % .
[M+H]+ = 335 D. 1-(6-Ethoxy-pyridinylmethyl)(2-methoxy-acetvlamino)-1H-pyrazole-d-carboxylic acid (1- isoquinolin-G-ylmethyl)-amide hydrochloride To a stirred solution of 1-((6-ethoxypyridin-3—yl)methyl)(2-methoxyacetamido)-1H-pyrazo|e carboxylic acid (81.0 mg, 0.242 mmol), 6-(aminomethyl)isoquinolin-l-amine dihydrochloride (65.6 mg, 0.267 mmol) and HATU (111 mg, 0.291 mmol) in DMF (2 mL) was added triethylamine (135 pL, 0.969 mmol). The resulting mixture was stirred at rt overnight. The reaction mixture was then diluted with EtOAc (15 mL) and washed with 2M NaOH (2 x 20 mL). The organic was dried (NaZSO4), filtered and evaporated under reduced pressure. The crude was purified by chromatography (4 g , MeOH in DCM 0-5% and 1% Et3N) to afford the desired t as a free base. The product was dissolved in DCM (1 mL), 4M HCI in dioxane (79 pl, 0.315 mmol) added and the resulting e d at rt for 15 min.
The solvent was then evaporated under reduced pressure to give 1-(6-ethoxy-pyridinylmethyl)(2- methoxy-acetylamino)-1H~pyrazolecarboxylic acid (l-amino-isoquinolin-6—ylmethyl)-amide hydrochloride (47.5 mg, 0.089 mmol, 36.5 % yield) as a white solid.
[M+H] = 490 NMR (d6-DMSO) 1.31 (3H, t, J: 7.0Hz), 3.36 (3H, s), 3.96 (2H, s), 4.30 (2H, q, J: 7.0Hz), 4.60 (2H, d, J: .9Hz), 5.27 (2H, s), 6.83 (1H, dd, J: 0.7, 8.5Hz), 7.17 (1H, d, J: 6.8H2), .72 (3H, m), 7.73-7.78 (1H, m), .27 (2H, m), 8.40-8.50 (3H, m), 8.83 (1H, t, 1: 6.0Hz), 10.51 (1H, s), 12.74 (1H, s).
The compounds in the following tables were synthesised as described for Examples 1-3 and 6-27 and Reference Examples 4 and 5. Compounds 31-33, 45-50, 52, 105-109, 115-118 and 127-129 are reference examples.
AMENDED SHEET Table 1 e Number A Free Base MW [M+H]+ 28 492.6 493 29 481.6 482 468.6 469 Table 2 e Number W Z Y Free Base MW [M+H]+ 31 CH CH N 451.5 452 32 CH N CH 451.5 452 33 CH N N 452.5 453 34 C-CH3 C-CH3 N 479.6 480 CH C-Ph N 527.6 528 36 CH C-CF3 N 519.5 520 37 CH C-NH2 N 466.5 467 38 CH N 495.6 496 39 CH N 501.5 502 40 CH N 533.6 268 [M+2H]/2 41 CH C-CON(CH3)2 N 522.6 523 42 CH N 533.7 534 43 CH C-Cl N 486.0 486 Table 3 A W Y Free Base MW [M+H]+ Number 44 C-CH3 C-CH3 491.6 492 45 CH N 429.5 430 46 CH N 511.6 513 47 CH N 450.5 451 48 CH N 468.5 469 49 CH N 450.6 451 50 CH N 482.5 483 51 C-CF3 N 495.5 496 52 CH N 480.4 481 53 C-NH2 N 452.5 453 Table 4 e Number A Free Base MW [M+H]+ 54 495.5 496 55 470.5 471 56 531.5 532 57 531.5 532 58 509.5 510 59 509.5 510 60 513.5 514 61 513.5 514 62 509.5 510 63 509.5 510 64 496.5 497 65 496.5 497 66 484.5 485 67 509.5 510 68 509.5 510 69 525.5 526 (±)- 70 525.5 526 71 484.5 485 72 498.5 499 73 513.5 514 74 504.9 505 75 488.4 489 76 505.5 506 77 530.5 531 78 548.5 549 79 506.5 507 80 470.5 471 81 512.5 513 82 526.5 527 83 506.5 507 84 535.5 536 85 535.5 536 Table 5 e Number A Free Base MW [M+H]+ 86 485.6 486 87 503.6 504 88 497.6 498 89 497.6 498 90 467.6 468 91 478.6 479 92 496.5 497 93 490.6 491 94 477 477 95 487.6 488 96 469.6 470 97 502.0 502 Table 6 Example A Z Free Base MW [M+H]+ Number 98 C-NH2 417.5 418 99 C-NH2 442.5 443 100 3)2 470.6 471 101 524.6 525 102 522.6 523 103 509.6 [M+2H]/2 104 512.6 513 Table 7 e Free Base A V U Z [M+H]+ Number MW 105 N CH CH 485.6 486 106 N CH CH 442.5 443 107 N CH CH 424.5 425 e Free Base A V U Z [M+H]+ Number MW 108 N CH CH 423.5 424 109 N CH CH 456.5 457 110 CH C-CH3 C-CF3 506.5 507 111 CH N C-CF3 493.5 494 112 CH CH C-CF3 492.5 493.1 e Free Base A V U Z [M+H]+ Number MW 113 CH N C-NH2 453.5 454 114 N CH C-CF3 469.5 470 Table 8 Example Number R1 R3 Z Free Base MW [M+H]+ 115 H H N 426.5 427 116 H CH3 N 440.5 441 117 H H CH 425.5 426 118 CH3 CH3 CH 453.5 454 119 CH3 CH3 C-CF3 521.5 522 120 H H 465.6 466 121 H H C-CF3 493.5 494 e Number R1 R3 Z Free Base MW [M+H]+ 122 CH3 CH3 493.6 494 Table 9 Example Number A U V Free Base MW [M+H]+ 123 CH CH 492.5 493 124 N CH 493.5 494 125 CH N 493.5 494 e Number A U V Free Base MW [M+H]+ 126 N CH 506.5 507 Table 10 Example Number A Free Base MW [M+H]+ 127 527.9 528 128 503.9 504 129 540.9 541 Table 11 Example Name Number 1-Ethylmethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic 28 acid (1-amino-isoquinolinylmethyl)-amide 1-Ethylmethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1-amino- 29 isoquinolinylmethyl)-amide 1-Ethylmethyl(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrrolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino- 31 isoquinolinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-imidazolecarboxylic acid (1-amino- 32 isoquinolinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (1- 33 isoquinolinylmethyl)-amide 3,5-Dimethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 34 (1-amino-isoquinolinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]phenyl-1H-pyrazolecarboxylic acid (1- isoquinolinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 36 acid (1-amino-isoquinolinylmethyl)-amide 3-Amino[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1- 37 isoquinolinylmethyl)-amide 3-Methoxymethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic 38 acid (1-amino-isoquinolinylmethyl)-amide 3-Difluoromethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic 39 acid (1-amino-isoquinolinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl](2,2,2-trifluoro-ethyl)-1H-pyrazole 40 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazole-3,4-dicarboxylic acid 4-[(1- 41 amino-isoquinolinylmethyl)-amide] 3-dimethylamide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]thiophenyl-1H-pyrazolecarboxylic 42 acid (1-amino-isoquinolinylmethyl)-amide Name Number 3-Chloro[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1- 43 amino-isoquinolinylmethyl)-amide 2,5-Dimethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1- 44 amino-isoquinolinylmethyl)-amide 1-[2-(2,3-Dihydro-benzo[1,4]dioxinyl)-ethyl]-1H-pyrazolecarboxylic acid (1-amino- 45 isoquinolinylmethyl)-amide 1-(4-{[(2,4-Dimethyl-thiazolyl)-methyl-amino]-methyl}-benzyl)-1H-pyrazole 46 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 1-(6-Phenoxy-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1-amino-isoquinolin 47 ylmethyl)-amide 1-[3-(3-Fluoro-pyridinyloxy)-benzyl]-1H-pyrazolecarboxylic acid (1-amino- 48 isoquinolinylmethyl)-amide 1-[4-(Pyridinyloxy)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolin 49 ylmethyl)-amide 1-[4-(6-Fluoro-pyridinyloxymethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino- 50 isoquinolinylmethyl)-amide 1-(2-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 51 (1-amino-isoquinolinylmethyl)-amide 52 1-(5-Trifluoromethoxy-1H-indolylmethyl)-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide -Amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid (1-amino- 53 isoquinolinylmethyl)-amide 1-(2-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 54 (1-amino-isoquinolinylmethyl)-amide thoxy-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- 55 amino-isoquinolinylmethyl)-amide 3,3-Difluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole 56 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 3,3-Difluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole 57 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 1-[6-((R)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole 58 carboxylic acid (1-amino-isoquinolinylmethyl)-amide Example Name Number 1-[6-((S)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole 59 carboxylic acid no-isoquinolinylmethyl)-amide 1-[6-((S)Fluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole 60 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 61 1-[6-((R)Fluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide (S)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole 62 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 1-[6-((R)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole 63 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 1-(2-Pyrrolidinyl-pyrimidinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic 64 acid (1-amino-isoquinolinylmethyl)-amide 1-(5-Pyrrolidinyl-pyrazinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 65 (1-amino-isoquinolinylmethyl)-amide 1-(2-Isopropoxy-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- 66 amino-isoquinolinylmethyl)-amide 1-[2-((R)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole 67 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 1-[2-((S)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole 68 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 1-[6-(3-Hydroxymethyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H- 69 pyrazolecarboxylic acid no-isoquinolinylmethyl)-amide 1-[6-((R)Hydroxymethyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H- 70 pyrazolecarboxylic acid no-isoquinolinylmethyl)-amide 1-(6-Propoxy-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- 71 amino-isoquinolinylmethyl)-amide 1-(6-sec-Butoxy-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- 72 amino-isoquinolinylmethyl)-amide 1-(5-Fluoropyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazole 73 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 1-(6-Chloroethoxy-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic 74 acid (1-amino-isoquinolinylmethyl)-amide Example Name Number 1-(6-Ethoxyfluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 75 no-isoquinolinylmethyl)-amide 1-(4-Pyrazolylmethyl-benzyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- 76 amino-isoquinolinylmethyl)-amide 1-[4-(4-Cyano-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 77 acid (1-amino-isoquinolinylmethyl)-amide 1-[4-(4-Carbamoyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazole 78 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 1-(6-Pyrazolylmethyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic 79 acid (1-amino-isoquinolinylmethyl)-amide 1-(2-Ethoxy-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- 80 amino-isoquinolinylmethyl)-amide 1-(2-Pyrazolylmethyl-thiazolylmethyl)trifluoromethyl-1H-pyrazolecarboxylic 81 acid (1-amino-isoquinolinylmethyl)-amide 1-[2-(4-Methyl-pyrazolylmethyl)-thiazolylmethyl]trifluoromethyl-1H-pyrazole 82 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 1-(4-[1,2,4]Triazolylmethyl-benzyl)trifluoromethyl-1H-pyrazolecarboxylic acid 83 (1-amino-isoquinolinylmethyl)-amide 1-[4-(5-Methyl-2H-pyrazolyloxymethyl)-benzyl]trifluoromethyl-1H-pyrazole 84 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 1-[4-(3-Methyloxo-4,5-dihydro-pyrazolylmethyl)-benzyl]trifluoromethyl-1H- 85 pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide 3-Cyclopropyl{6-[(2-methoxy-ethyl)-methyl-amino]-pyridinylmethyl}-1H-pyrazole- 86 oxylic acid no-isoquinolinylmethyl)-amide 3-Cyclopropyl[6-(3,3-difluoro-pyrrolidinyl)-pyridinylmethyl]-1H-pyrazole 87 ylic acid (1-amino-isoquinolinylmethyl)-amide 3-Cyclopropyl(2-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazole 88 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 3-Cyclopropyl(4-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazole 89 carboxylic acid (1-amino-isoquinolinylmethyl)-amide 3-Cyclopropyl(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1- 90 amino-isoquinolinylmethyl)-amide Example Name Number 3-Cyclopropyl(4-[1,2,3]triazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid (1- 91 amino-isoquinolinylmethyl)-amide 3-Cyclopropyl[6-(2,2,2-trifluoro-ethoxy)-pyridinylmethyl]-1H-pyrazolecarboxylic 92 acid (1-amino-isoquinolinylmethyl)-amide 3-Cyclopropyl(6-phenoxy-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1-amino- 93 isoquinolinylmethyl)-amide 1-(5-Chloroethoxy-pyridinylmethyl)cyclopropyl-1H-pyrazolecarboxylic acid (1- 94 amino-isoquinolinylmethyl)-amide opropyl(6-diethylaminofluoro-pyridinylmethyl)-1H-pyrazolecarboxylic 95 acid (1-amino-isoquinolinylmethyl)-amide 3-Cyclopropyl(6-diethylamino-pyr idinylmethyl)-1H-pyrazolecarboxylic acid (1- 96 amino-isoquinolin ylmethyl)-amide 1-(5-Chloropyrrolidinyl-pyridinylmethyl)cyclopropyl-1H-pyrazolecarboxylic 97 acid (1-amino-isoquinolinylmethyl)-amide 3-Amino(6-ethoxy-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1-amino- 98 isoquinolinylmethyl)-amide 3-Amino(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1-amino- 99 isoquinolinylmethyl)-amide 3-Dimethylamino(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid 100 (1-amino-isoquinolinylmethyl)-amide 3-(1-Methyloxo-pyrrolidinyl)(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazole- 101 4-carboxylic acid (1-amino-isoquinolinylmethyl)-amide -Dimethyl-isoxazolyl)(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazole 102 carboxylic acid (1-amino-isoquinolinylmethyl)-amide yrrolidinyl-pyridinylmethyl)thiophenyl-1H-pyrazolecarboxylic acid (1- 103 amino-isoquinolinylmethyl)-amide 3-Morpholinyl(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid 104 (1-amino-isoquinolinylmethyl)-amide [(2,4-Dimethyl-thiazolyl)-methyl-amino]-methyl}-benzyl)-1H-pyrazole 105 carboxylic acid (1H-pyrrolo[2,3-b]pyridinylmethyl)-amide 1-[3-(3-Fluoro-pyridinyloxy)-benzyl]-1H-pyrazolecarboxylic acid (1H-pyrrolo[2,3- 106 b]pyridinylmethyl)-amide Example Name Number 1-[4-(Pyridinyloxy)-benzyl]-1H-pyrazolecarboxylic acid (1H-pyrrolo[2,3-b]pyridin 107 ylmethyl)-amide 1-(3-Phenoxy-benzyl)-1H-pyrazolecarboxylic acid rrolo[2,3-b]pyridin 108 ylmethyl)-amide 1-[4-(6-Fluoro-pyridinyloxymethyl)-benzyl]-1H-pyrazolecarboxylic acid (1H- 109 pyrrolo[2,3-b]pyridinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 110 acid (2-methyl-1H-indolylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 111 acid (1H-indazolylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 112 acid (1H-indolylmethyl)-amide 3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1H- 113 indazolylmethyl)-amide 1-(6-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 114 (1H-pyrrolo[2,3-b]pyridinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (1H- 115 pyrrolo[2,3-b]pyridinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-[1,2,3]triazolecarboxylic acid (6- 116 methyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1H- 117 pyrrolo[2,3-b]pyridinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (4,6-dimethyl- 118 1H-pyrrolo[2,3-b]pyridinylmethyl)-amide 4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 119 acid (4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-amide 3-Cyclopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 120 (1H-pyrrolo[2,3-b]pyridinylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 121 acid (1H-pyrrolo[2,3-b]pyridinylmethyl)-amide opropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 122 (4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-amide Example Name Number 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 123 acid (1H-indolylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 124 acid (1H-indazolylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 125 acid rrolo[2,3-b]pyridinylmethyl)-amide 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 126 acid (1H-indazolylmethyl)-amide 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 127 acid (5-chloro-1H-indazolylmethyl)-amide 1-(6-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid 128 (5-chloro-1H-indazolylmethyl)-amide 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 129 acid (5-chloro-1H-indazolylmethyl)-amide Table 12 NMR data of examples (solvent d6 DMSO) Example Chemical Shift (ppm) Number 0.94 (3H, t, J = 7.0Hz), 1.98 (3H, s), 2.00 (3H, s), 3.93 (2H, s), 4.15 (2H, q, J = 6.9Hz), 4.49 (2H, d, J = , 5.17 (2H, s), 6.70 (2H, s, br), 6.73 (1H, s), 6.84 (1H, d, J = 5.7Hz), 7.03 (2H, d, J = 8.2Hz), 7.12 (2H, d, J = 8.2Hz), 7.22 (1H, s), 7.37 (1H, dd, J = 8.6, 1.6Hz), 7.45- 7.55 (2H, m), 7.75 (1H, d, J = 5.8Hz), 8.12 (1H, d, J = 8.6Hz), 8.48 (1H, t, J = 6.1Hz) 1.10 (3H, t, J = 6.9Hz), 2.08 (3H, s), 4.11 (2H, s), 4.41 (2H, q, J = 6.9Hz), 4.56 (2H, d, J = 6.0Hz), 6.74 (1H, s), 7.19 (1H, d, J = 6.9Hz), 29 7.26 (1H, s), 7.46-7.50 (3H, m), .70 (2H, m), 7.76 (1H, d, J = 1.7Hz); 7.86-7.94 (2H, m), 8.48 (1H, d, J = 8.7Hz), 8.57 (1H, t, J = 6.1Hz), 8.79 (2H, s), 12.93 (1H, s).
Example Chemical Shift (ppm) Number 0.97 (3H, t, J = 6.9Hz), 1.86-1.95 (4H, m), 2.02 (3H, s), 3.29-3.34 (4H, m), 3.79 (2H, s), 4.19 (2H, q, J = 6.9Hz), 4.49 (2H, d, J = 6.0Hz), 6.35 (1H, d, J = 8.6Hz), 6.67-6.78 (3H, m), 6.84 (1H, d, J = 6.0Hz), 7.14 (1H, dd, J = 8.6, 2.5Hz), 7.37 (1H, dd, J = 8.6, 1.7Hz), 7.51 (1H, s), 7.74 (1H, d, J = 5.8Hz), 7.82-7.87 (1H, m), 8.12 (1H, d, J = 8.6Hz), 8.47 (1H, t, J = 6.1Hz). 1.98 (3H, s), 4.53 (2H, d, J = 5.9Hz), 5.21 (2H, s), 5.32 (2H, s), 6.85 (2H, s, br), 6.87 (1H, s), 6.88-7.18 (2H, m), 7.22-7.25 (3H, m), 7.39 31 (1H, dd, J = 8.6, 1.5Hz), 7.51-7.54 (2H, m), 7.74 (1H, d, J = , 7.92 (1H, s), 8.15 (1H, d, J = 8.6Hz), 8.26 (1H, s), 8.70 (1H, t, J = .9Hz). 1.98 (3H, s), 4.56 (2H, d, J = 6.2Hz), 5.22 (2H, s), 5.62 (2H, s), 6.79 (2H, s), 6.86 (1H, d, J = , 7.19-7.23 (3H, m), 7.32 (2H, d, J = , 7.41 (1H, dd, J = 8.6,1.6Hz), 7.52-7.54 (2H, m), 7.74 (1H, d, J = 5.8Hz), 8.13 (1H, d, J = 8.6Hz), 8.65 (1H, s), 9.18 (1H, t, J = 6.2Hz). 1.98 (3H, s), 4.56 (2H, d, J = 5.9 Hz ), 5.23 (2H, s), 5.37 (2H, s), 7.15 (1H, d, J = 6.8 Hz ), 7.19 – 7.24 (3H, m), 7.28 – 7.37 (5H, m), 7.54 (1H, s), 7.65 (1H, d, J = 8.6 Hz ), 7.70 (3H, dd, J = 3.1 , 7.2 Hz ), 7.76 (1H, s), 8.33 (1H, s), 8.47 (1H, d, J = 8.6 Hz ), 8.62 (2H, s), 8.78 (1H, t, J = 6.0 Hz ), 13.07 (1H, br s). 1.99 (3H, s), 4.51 (2H, d, J = 5.8 Hz), 5.23 (2H, s), 5.42 (2H, s), 6.73 (2H, br.s), 6.85 (1H, d, J = 5.8 Hz), 7.20 (1H, s), 7.22 (2H, d, J = 7.2 36 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.37 (1H, dd, J = 8.6, 1.1 Hz), 7.54 (2H, br.s), 7.77 (1H, d, J = 5.8 Hz), 8.14 (1H, d, J = 8.6 Hz), 8.47 (1H, s), 8.88 (1H, t, J = 5.9 Hz) 1.99 (3H, s), 4.55 (2H, d, J= 5.8 Hz ), 5.07 (2H, s), 5.22 (2H, s), 5.41 (2H, s), 7.15-7.29 (6H, m), 7.54 (1H, t, J= 0.9 Hz ), 7.59-7.71 (2H, m), 7.75 (1H, s), 8.03 (1H, s), 8.46 (1H, d, J= 8.6 Hz ), 8.53 (1H, t, J= 6.0 Hz ), 8.64 (2H, s), 12.95 (1H, s).
Example Chemical Shift (ppm) Number 1.99 (3H, t, J = 0.7 Hz ); 3.22 (3H, s); 4.59 (4H, d, J = 15.7 Hz ); 5.23 (2H, s); 5.31 (2H, s); 7.16 - 7.29 (6H, m); 7.55 (1H, t, J = 0.9 Hz ); 38 7.69 (2H, td, J = 3.0 & 8.7 Hz ); 7.81 (1H, d, J = 1.6 Hz ); 8.31 (1H, s); 8.56 (1H, d, J = 8.6 Hz ); 8.64 (1H, t, J = 5.9 Hz ); 9.12 (2H, s); 13.29 (1H, s). 1.99 (3H, s); 4.59 (2H, d, J = 5.8 Hz ); 5.24 (2H, s); 5.41 (2H, s); 7.15 - 7.34 (7H, m); 7.55 (1H, t, J = 0.9 Hz ); 7.69 (2H, td, J = 2.4 & 8.6 Hz ); 7.81 (1H, d, J = 1.7 Hz ); 8.46 (1H, t, J = 1.2 Hz ); 8.55 (1H, d, J = 8.6 Hz ); 9.03-9.21 (3H, m); 13.25 (1H, s). 1.99 (3H, s), 3.95 (2H, q, J= 11.3 Hz ), 4.58 (2H, d, J= 5.8 Hz), 5.23 (2H, s), 5.35 (2H, s), 7.13-7.32 (6H, m), 7.54 (1H, s), 7.63-7.72 (2H, m), 7.78 (1H, s), 8.35 (1H, s), 8.52 (1H, d, J= 8.7 Hz ), 8.86 (1H, s), 9.00 (2H, s), 13.05 (1H, br s). 1.98 (3H, s), 2.92 (3H, s), 2.96 (3H, s), 4.52 (2H, d, J= 5.8Hz), 5.22 (2H, s), 5.35 (2H, s), 6.74 (2H, s), 6.84 (1H, d, J= 5.7Hz), 7.19 (2H, d, 41 J= 8.2Hz), 7.20-7.30 (3H, m), 7.36 (1H, dd, J= 8.6, , 7.49-7.55 (2H, m), 7.76 (1H, d, J= 5.8Hz), 8.13 (1H, d, J= 8.6Hz), 8.35 (1H, s), 9.08 (1H, t, J = 5.9Hz). 1.97 (3H, s), 4.59 (2H, d, J= , 5.22 (2H, s), 5.35 (2H, s), 7.16 - 7.23 (3H, m), 7.24 (1H, s), 7.30 (2H, d, J= 8.1Hz), 7.47 (1H, dd, J= 42 5.0, 3.0Hz), .57 (2H, m), 7.63-7.74 (2H, m), 7.81 (1H, s), 8.13 (1H, dd, J= 3.0, 1.2Hz), 8.36 (1H, s), 8.56 (1H, d, J= 8.6Hz), 8.85 (1H, t, J= 5.9Hz), 9.12 (2H, brs), 13.31 (1H, brs) 1.98 (3H, s), 4.51 (2H, d, J= 5.9Hz), 5.22 (2H, s), 5.29 (2H, s), 6.80 (2H, s), 6.87 (1H, d, J= 6.0Hz), 7.19 (2H, d, J= 8.2Hz), 7.23 (1H, s), 43 7.27 (2H, d, J= 8.2Hz), 7.39 (1H, dd, J 8.6, 1.8Hz), 7.50-7.57 (2H, m), 7.76 (1H, d, J= 5.8Hz), 8.14 (1H, d, J= 8.6Hz), 8.36 (1H, s), 8.58 (1H, t, J= 6.0Hz) Example Chemical Shift (ppm) Number 2.07 (3H, s), 2.37 (3H, s), 4.50 (2H, d, J = 6.0Hz), 5.06 (2H, s), 5.07 (2H, s), 6.23 (1H, dt, J = 1.4, 6.7Hz), 6.36 (1H, s), 6.39 (1H, d, J = 44 9.2Hz), 6.69 (2H, s, br), 6.79-6.94 (3H, m), .30 (2H, m), 7.35- 7.46 (2H, m), 7.52 (1H, d, J = 1.6Hz), 7.73-7.77 (2H, m), 8.12 (1H, d, J = 8.6Hz), 8.21 (1H, t, J = 6.1Hz). 2.98 (2H, t, J = 7.2Hz), 4.18 (4H, s), 4.30 (2H, t, J = 7.2Hz), 4.52 (2H, t, J = 5.9Hz), 6.59 (1H, dd, J = 8.2, 2.1Hz), 6.67 (1H, d, J = 2.0Hz), 45 6.69- 6.77 (3H, m), 6.84 (1H, d, J = 5.8Hz), 7.36 (1H, dd, J = 8.6, 1.6Hz), 7.51 (1H, s), 7.76 (1H, d, J = 5.8Hz), 7.92 (1H, s), 8.08-8.16 (2H, m), 8.68 (1H, t, J = 6.0Hz). 2.10 (3H, s), 2.47 (3H, s), 2.55 (3H, s), 3.87 (2H, s), 4.53 (2H, d, J = .9 Hz), 5.33 (2H, s), 6.83 (2H, br. s), 6.88 (1H, d, J = 5.8Hz), 7.20 (2H, d, J = , 7.26 (2H, d, J = 8.2Hz), 7.39 (1H, dd, J = 1.3, , 7.54 (1H, br. s), 7.74 (1H, d, J = 5.8Hz), 7.93 (1H, d, J = 0.6Hz), 8.14 (1H, d, J = 8.6Hz), 8.27 (1H, d, 0.6Hz), 8.70 (1H, t, J = 6.0Hz) 4.55 (2H, d, J = , 5.33 (2H, s), 6.74 (2H, s), 6.81-6.92 (3H, m), 7.05-7.19 (3H, m), 7.33-7.42 (3H, m), 7.55 (1H, d, J = 1.7Hz), 7.76 47 (1H, d, J = 5.8Hz), 7.83 (1H, dd, J = 7.4, 8.2Hz), 7.95 (1H, d, J = 0.7Hz), 8.15 (1H, d, J = 8.6Hz), 8.24 (1H, d, J = 0.8Hz), 8.71 (1H, t, J = 6.0Hz). 4.54 (2H, d, J = 5.9Hz), 5.37 (2H, s), 6.73 (2H, s), 6.86 (1H, d, J = .8Hz), 7.14-7.23 (3H, m), 7.31-7.41 (3H, m), 7.53 (1H, d, J = 48 1.7Hz), 7.75 (1H, d, J = 5.8Hz), 7.86 (1H, ddd, J = 1.5, 8.0, ), 7.92 (1H, dd, J = 1.5, 4.9Hz), 7.96 (1H, d, J = 0.7Hz), 8.13 (1H, d, J = 8.6Hz), 8.34 (1H, d, J = 0.8Hz), 8.73 (1H, t, J = 6.0Hz). 4.61 (2H, d, J = 5.9Hz), 5.37 (2H, s), 7.03 (1H, dt, J = 0.9, 8.3Hz), 7.09-7.15 (3H, m), 7.22 (1H, d, J = 7.0Hz), .37 (2H, m), 7.63- 7.72 (2H, m), 7.80 (1H, d, J = 1.6Hz), 7.85 (1H, dd, J = 2.0, 7.2, 8.3Hz), 7.97 (1H, d, J = 0.7Hz), 8.12 (1H, ddd, J = 0.8, 2.0, 5.0Hz), 8.35 (1H, d, J = 0.8Hz), 8.51 (1H, d, J = 8.6Hz), 8.87 (1H, t, J = 6.0Hz), 8.95 (1H, s), 13.04 (1H, s).
Example Chemical Shift (ppm) Number 4.53 (2H, d, J = , 5.28 (2H, s), 5.36 (2H, s), 6.71-6.73 (3H, m), 6.80 (1H, dd, J = 1.5, 8.0Hz), 6.85 (1H, d, J = 5.8Hz), 7.29 (2H, d, J = 8.2Hz), 7.37 (1H, dd, J = 1.6, 8.6Hz), 7.44 (2H d, J = 8.2Hz), 7.52 (1H, br. s), 7.75 (1H, d, J = 5.8Hz), 7.89 (1H, td, J = 8.0, 8.6Hz), 7.93 (1H, d, J = 0.5Hz), 8.13 (1H, d, J = 8.6 Hz), 8.29 (1H, d, J = 0.5 Hz), 8.70 (1H, t, J = 6.0 Hz). 1.91-1.94 (4H, s), 3.31-3.33 (4H, m), 4.61 (2H, d, J= 5.88Hz), .51(2H, s), 6.13 (1H, d, J= 5.24Hz), 6.17 (1H, s), 7.15 (1H, d, J= 51 6.72Hz), 7.65 (1H, d, J= 8.49Hz), 7.70 (1H, d, J= 6.72Hz), 7.78 (1H, s), 7.99 (1H, d, J= 5.16Hz), 8.16 (1H, s), 8.47 (1H, d, J= 8.60Hz), 8.57 (2H, br, s), 9.22(1H, t, J= 5.76Hz). 4.53 (2H, d, J = 5.9Hz), 5.52 (2H, s), 6.50 (1H, d, J = 1.3Hz),6.70 (2H, s), 6.84 (1H, d, J = 5.7Hz), 7.05 (1H, dd, J = 8.8, 1.5Hz), 7.36 (1H, dd, J = 8.6, 1.7Hz), 7.43 (1H, d, J = 8.8Hz), 7.51 (2H, s), 7.75 (1H, d, J = .8Hz), 7.96 (1H, d, J = 0.6Hz), 8.12 (1H, d, J = 8.6Hz), 8.29 - 8.24 (1H, m), 8.72 (1H, t, J = 6.0Hz), 11.51 (1H, s) 3.40 (0.5H, br s), 4.57 (2H, d, J= 6.0Hz), 5.07 (2H, s), 5.29 (2H, s), 6.25 (1H, t, J= 2.0Hz), 6.32 (2H, br s), 6.52 (0.5H, br s), 7.13 (2H, d, J= 8.2Hz), 7.17 (2H, d, J= 8.0Hz), 7.24 (1H, d, J= 6.9Hz), 7.43 (1H, d, J= 1.6Hz), 7.64 (1H, d, J= , 7.69 (1H, dd, J= 8.6, 1.3Hz), 7.76 (1H, s), 7.79 (2H, s), 8.45 (1H, t, J= 5.7Hz), 8.50 (1H, d, J= 8.6Hz), 8.92 (2H, br s), 12.88 (1H, br s). 1.91-1.95 (4H, s), 3.33-3.37 (4H, m), 4.53 (2H, d, J= 5.8Hz), 5.38(2H, s), 6.36 (2H, d, J= , 6.76 (2H, s), 6.9(1H, d, J= 5.8Hz), 7.39 (1H, d, J= 8.6Hz), 7.55 (1H, s), H, d, J= 5.8Hz), 8.03(1H, t, J= 2.8Hz), 8.15 (1H, d, J = , 8.52 (1H, s), 8.93(1H, t, J= 5.4Hz). 1.31(3H,t,J= 7.0Hz), 4.30(2H,q,J= 7.0Hz), 4.60(2H,d,J= 5.8Hz), H,s), 6.83(1H,d,J= , 7.21(1H,d,J= 7.0Hz), 7.66 - 7.73(3H,m), 7.81(1H,s), 8.24(1H,d,J= 2.4Hz), 8.51(2H,d,J= 8.8Hz), 9.02(1H,t,J= 5.7Hz), 9.11(2H,br s), 13.33(1H,s) Example Chemical Shift (ppm) Number 2.53-2.68 (2H, m), 3.73 (2H, t, J = , 3.97 (2H, t, J = 12.9Hz), 4.60 (2H, d, J = , 5.53 (2H, s), 6.64 (1H, d, J = 5.7Hz), 6.87 56 (1H, brs), 7.19 (1H, d, J = 7.0Hz), .75 (2H, m), 7.82 (1H, s), 8.07 (1H, d, J = 5.6Hz), 8.58 (1H, d, J = 8.6Hz), 8.71 (1H, s), 9.15 (2H, brs), 9.25 (1H, t, J = 5.9Hz), 13.33 (1H, s). 2.53-2.66 (2H, m), 3.73 (2H, t, J = 7.4Hz), 3.96 (2H, t, J = 13.0Hz), 4.58 (2H, d, J = 5.9Hz), 5.41 (2H, s), 6.79-6.92 (1H, m), 7.20 (1H, d, J = 7.0Hz), 7.64-7.73 (2H, m), 7.78-7.88 (2H, m), 8.24 (1H, d, J = 2.1Hz), 8.53-8.62 (2H, m), 8.86-9.39 (3H, m), 13.27 (1H, s). 1.08 (3H, d, J = 6.6 Hz), 1.61 (1H, br.s), 2.12 (1H, br.s), 2.98 (3H, br.s), .65 (2H, m), 4.59 (2H, d, J = 5.8 Hz), 5.36 (2H, s), 7.21 58 (1H, d, J = 7.0 Hz), 7.66 (1H, d, J = 7.2 Hz), 7.69 (1H, d, J = 8.8 Hz), 7.80 (1H, s), 8.13 (1H, d, J = 1.8 Hz), 8.50 (1H, br.s), 8.52 (1H, d, J = 8.6 Hz), 8.93 (1H, br.s), 9.02 (1H, br.s), 12.87 (1H, br.s) 1.08 (3H, d, J = 6.4 Hz), 1.63 (1H, dd, J = 11.9, 8.8 Hz), 2.15 (1H, d, J = 5.8 Hz), 3.00-3.04 (3H, m), 3.43-3.50 (2H, m), 4.59 (2H, d, J = 5.8 Hz), 5.41 (2H, s), 7.21 (1H, d, J = 7.0 Hz), 7.67 (1H, d, J = 8.5 Hz), 7.69 (1H, dd, J = 8.8, 1.4 Hz), 7.81 (1H, s), 8.14 (1H, d, J = 1.7 Hz), 8.54 (2H, d, J = 8.7 Hz), 9.01 (1H, br.s), 9.08 (1H, br.s), 13.03 (1H, br.s) 2.11-2.44 (2H, m), 3.55-3.65 (1H, m), 3.73-3.94 (3H, m), 4.59 (2H, d, J = , 5.36-5.65 (3H, m), 7.06 (1H, brd, J= 9.1Hz), 7.19 (1H, 60 d, J = 6.9Hz), 7.64-7.74 (2H, m), 7.80 (1H, s), 7.94 (1H, brd, J = 9.1Hz), 8.21 (1H, d, J = 1.9Hz), 8.59 (1H, d, J = 8.6Hz), 8.64 (1H, s), 8.91-9.45 (3H, m), 13.39 (1H, s). 2.12-2.42 (2H, m), 3.55-3.65 (1H, m), 3.70-3.93 (3H, m), 4.59 (2H, d, J = 5.9Hz), 5.36-5.64 (3H, m), 7.06 (1H, brd, J= 9.1Hz), 7.19 (1H, 61 d, J = 7.0Hz), 7.64-7.74 (2H, m), 7.80 (1H, s), 7.92 (1H, brd, J = 9.1Hz), 8.21 (1H, d, J = 2.0Hz), 8.59 (1H, d, J = 8.6Hz), 8.64 (1H, s), 8.91-9.45 (3H, m), 13.41 (1H, s).
Example Chemical Shift (ppm) Number 1.16 (3H, d, J= 6.3Hz), 1.69-1.84 (1H, m), 1.95-2.22 (3H, m), 3.38- 3.47 (1H, m), 3.68-3.75 (1H, m), 4.33 (1H, br.s), 4.59 (2H, d, J= .9Hz), 5.44 (2H, s), 7.11 (1H, br.s), 7.19 (1H, d, J= 7.0Hz), 7.64- 7.73 (2H, m), 7.81 (1H, s), 7.92 (1H, br.d, J= 9.1Hz), .20 (1H, m), 8.60 (1H, d, J= 8.6Hz), 8.66 (1H, s), 8.91-9.45 (3H, m), 13.40 (1H, s), 13.85 (1H, brs). 1.16 (3H, d, J= , 1.70-1.84 (1H, m), 1.96-2.21 (3H, m), 3.37- 3.47 (1H, m), 3.68-3.75 (1H, m), 4.32 (1H, brs), 4.59 (2H, d, J= .8Hz), 5.44 (2H, s), 7.10 (1H, brs), 7.19 (1H, d, J= 7.0Hz), 7.64-7.73 (2H, m), 7.81 (1H, s), 7.92 (1H, br.d, J= , 8.13-8.20 (1H, m), 8.59 (1H, d, J= 8.7Hz), 8.66 (1H, s), 8.91-9.45 (3H, m), 13.38 (1H, s), 13.85 (1H, br.s). 1.90-1.93(4H,m), 3.45-3.49(4H,m), 4.59(2H,d,J= 5.8Hz), 5.30(2H,s), 64 7.22(1H,d,J= 7.0Hz), 7.65-7.70(2H,m), 7.80(1H,s), 8.39-8.45(3H,m), 8.50(1H,d,J= 8.6Hz), .99(3H,m),13.02(1H,s). 1.93-1.96 (4H, m), .44 (4H, m), 4.59 (2H, d, J= 5.8Hz), 5.39 (2H, s), 7.22 (1H, d, J= 7.0Hz), 7.65 (1H, d, J= 7.0Hz), 7.69 (1H, dd, 65 J= 8.6,1.3Hz), 7.80 (1H, s), 7.93 (1H, d, J= 1.3Hz), 8.19 (1H, d, J= 1.2Hz), 8.47 (1H, s), 8.51 (1H, d, J= 8.6Hz), 8.97-9.00 (3H, m), 12.90 (1H, s). 1.21-1.32 (6H, m), 4.61 (2H, d, J= 5.8Hz), 5.23 (1H, hept, J= 6.2Hz), .48 (2H, s), 6.51-6.56 (1H, m), 6.81 (1H, dd, J= 1.5, 5.3Hz), 7.21 66 (1H, d, J= 7.0Hz), 7.64-7.74 (2H, m), 7.82 (1H, d, J= , 8.14 (1H, dd, J= 0.7, 5.2Hz), 8.51-8.61 (2H, m), 8.88-9.12 (3H, m), 13.12 (1H, s). 1.09 (3H, d, J= 6.6Hz), 1.63 (1H, br.s), 2.14 (1H, br.s), 2.40 (3H, br.s), 3.02 (3H, br.s), 3.58 (1H, br.s), 3.66 (1H, br.s), 4.61 (2H, d, J= .8Hz), 5.53 (2H, br.s), 6.52 (1H, br.s), 7.21 (1H, d, J= 7.04Hz), 7.66 (1H, br.s), 7.69 (1H, dd, J= 9.7, 8.3Hz), 7.82 (1H, s), 7.97 (1H, d, J= .9Hz), 8.53 (1H, d, J= 8.7Hz), 8.62 (1H, s), 8.97 (1H, br.s), 9.12 (1H, br.s), 12.94 (1H, br.s) Example al Shift (ppm) Number 1.09 (3H, d, J= 6.6Hz), 1.64 (1H, br.s), 2.14 (1H, br.s), 3.01 (3H, br.s), 3.58 (1H, br.s), 3.67 (1H, br.s), 4.61 (2H, d, J= 5.9Hz), 5.54 (2H, br.s), 6.54 (1H, br.s), 7.21 (1H, d, J= 7.04Hz), 7.66 (1H, br.s), 7.70 (1H, dd, J= 9.0, 7.7Hz), 7.82 (1H, s), 7.97 (1H, d, J= 5.6Hz), 8.54 (1H, d, J= 8.4Hz), 8.63 (1H, s), 8.98 (1H, br.s), 9.13 (1H, br.s), 12.95 (1H, br.s) (isoquinoline NH2 obscured by solvent) 1.76-1.90 (1H, m), 2.02-2.14 (1H, m), .52 (1H, m), 3.29-3.54 (5H, m), 3.60-3.67 (2H, m), 4.59 (2H, d, J= 6.0Hz), 5.44 (2H, s), 7.05 69 (1H, br.s), 7.20 (1H, d, J= 6.9Hz), .73 (2H, m), 7.81 (1H, s), 7.91 (1H, d, J= 9.0Hz), 8.15 (1H, d, J= 1.8Hz), 8.59 (1H, d, J= 8.7Hz), 8.64 (1H, s), 8.96-9.41 (3H, m), 13.34 (1H, br.s), 13.70 (1H, br.s). 1.75-1.89 (1H, m), .14 (1H, m), 2.44-2.52 (1H, m), 3.29-3.54 (5H, m), 3.61-3.68 (2H, m), 4.59 (2H, d, J = 6.0Hz), 5.43 (2H, s), 7.04 (1H, brs), 7.20 (1H, d, J = 7.0Hz), 7.64-7.73 (2H, m), 7.81 (1H, s), 7.91 (1H, d, J = 9.1Hz), 8.15 (1H, d, J = 1.8Hz), 8.58 (1H, d, J = 8.6Hz), 8.64 (1H, s), 8.96-9.41 (3H, m), 13.33 (1H, brs), 13.70 (1H, brs). 0.95 (3H, t, J= 7.4Hz), 1.67-1.76 (2H, m), 4.21 (2H, t, J= 6.7Hz), 4.60 (2H, d, J= 5.9Hz), 5.42 (2H, s), 6.85 (1H, d, J= 8.6Hz ), 7.22 (1H, d, J= 7.0Hz), 7.64-7.76 (3H, m), 7.81 (1H, s), 8.24 (1H, d, J= 2.0Hz), 8.48- 8.56 (2H, m), 9.03 (3H, s), 13.03 (1H, s). 0.89 (3H, t, J= 7.4Hz ), 1.24 (3H, d, J= 6.2Hz ), 1.53–1.71 (2H, m), 4.60 (2H, d, J= 5.3Hz), 5.08 (1H, q, J= 6.2Hz), 5.41 (2H, s), 6.80 (1H, 72 d, J= 9.0Hz), 7.22 (1H, d, J= 7.0Hz), 7.64–7.73 (3H, m), 7.81 (1H, s), 8.22 (1H, d, J = 2.1Hz), 8.49–8.57 (2H, m), 8.84–9.18 (3H, m), 13.02 (1H, s). 1.87 (4H, q, J= , 3.53 (4H, q, J= 6.3Hz), 4.59 (2H, d, J= .8Hz), 5.32 (2H, s), 7.21 (1H, d, J= 7.0Hz), 7.46 (1H, dd, J= 1.7, .8Hz), 7.65-7.70 (2H, m), 7.81 (1H, s), 8.00 (1H, s), 8.43 (1H, s), 8.50 (1H, d, J= 8.7Hz), 8.98 (2H, t, J= 5.7Hz), 12.93 (1H, s).
Example Chemical Shift (ppm) Number 1.37 (3H, t, J= 6.9Hz), 4.16 (2H, q, J= 6.9Hz), 4.59 (2H, d, J= 5.8Hz), .52 (2H, s), 7.20 (1H, d, J= 6.9Hz), 7.65-7.70 (3H, m), 7.80 (1H, s), 8.00 (1H, d, J= 1.7Hz), 8.50 (2H, d, J= , 8.91 (1H, br.s), 8.98 (1H, t, J= 5.7Hz), 12.87 (1H, s). 1.34 (3H, t, J= , 4.00 (2H, q, J= 7.1Hz), 4.59 (2H, d, J= 5.8Hz), .44 (2H, s), 7.20 (1H, d, J= 7.0Hz), 7.65-7.75 (3H, m), 7.80 (1H, s), 8.07 (1H, d, J= 1.7Hz), 8.49 (2H, d, J= 10.7Hz), 8.91 (1H, br.s), 8.98 (1H, t, J= 5.8Hz), 12.92 (1H, s). 4.58 (2H, d, J= 5.8Hz), 5.33 (2H, s), 5.43 (2H,s), 6.26 (1H, t, J= 2.0Hz), 7.18-7.23 (3H, m), 7.31 (2H,d, J= 8.1Hz), 7.45 (1H, d, J= , 7.68-7.70 (2H, m), 7.80 (1H, s), 7.82 (1H, d, J= 2.1Hz), 8.53- 8.56 (2H,m), 9.04-9.07 (3H, m), 13.18 (1H, s) 4.58 (2H, d, J= 5.8Hz), 5.33 (2H, s), 5.43 (2H, s), 6.26 (1H, t, J= 2.0Hz), 7.18-7.23 (3H, m), 7.31 (2H, d, J= 8.1Hz), 7.45 (1H, d, J= 1.7Hz), 7.68-7.70 (2H, m), 7.80 (1H, s), 7.82 (1H, d, J= 2.1Hz), 8.53- 8.56 (2H, m), 9.04-9.07 (3H, m), 13.18 (1H, s). 4.58 (2H, d, J= 5.8Hz), 5.33 (2H, s), 5.43 (2H, s), 6.26 (1H, t, J= 2.0Hz), 7.18-7.23 (3H, m), 7.31 (2H, d, J= 8.1Hz), 7.45 (1H, d, J= 1.7Hz), 7.68-7.70 (2H, m), 7.80 (1H, s), 7.82 (1H, d, J= 2.1Hz), 8.53- 8.56 (2H, m), 9.04-9.07 (3H,m), 13.18 (1H, s). 1.30 (3H, t, J= 7.0Hz), 4.30 (2H, q, J= 7.0Hz), 4.61 (2H, d, J= 5.9Hz), .50 (2H, s), .65 (1H, m), 6.85 (1H, dd, J= 1.4, 5.3Hz), 7.22 80 (1H, d, J= 7.0Hz), 7.71 (2H, td, J= 3.4, 8.8Hz), 7.83 (1H, d, J= 1.6Hz), 8.16 (1H, dd, J= 0.7, 5.2Hz), 8.53-8.63 (2H, m), 8.80-9.20 (3H, m), 13.22 (1H, s). 0.72–0.80 (2H, m), 0.80–0.87 (2H, m), .63 (1H, m,), 3.02 (3H, s), 3.48 (2H, t, J= 5.8Hz), 3.57 (3H, s), 3.68 (2H, t, J= , 4.58 (2H, d, J= 5.9Hz), 5.07 (2H, s), 6.65 (1H, d, J= 6.7Hz), 7.23 (1H, 86 d, J= 6.9Hz), 7.46 (1H, d, J= 8.6Hz), 7.66 (1H, d, J= , 7.70 (1H, d, J= 8.7Hz), 7.80 (1H, s), 8.07 (1H, d, J= 2.2Hz), 8.12 (1H, s), 8.53 (1H, d, J = 8.6Hz), 8.59 (1H, t, J = 6.0Hz), 8.99 (2H, br s), 13.06 (1H, br s ).
Example Chemical Shift (ppm) Number 0.74–0.79 (2H, m), 0.79–0.87 (2H, m), 2.52–2.63 (3H, m), 3.60 (2H, t, J= 7.3Hz), 3.82 (2H, t, J= 13.3Hz), 4.57 (2H, d, J= 5.9Hz), 5.10 (2H, 87 s), 6.56 (1H, d, J= 8.5Hz), 7.18 (1H, d, J= , 7.53 (1H, dd, J= 2.4, , 7.59–7.70 (2H, m), 7.76 (1H, s), .16 (2H, m), 8.47 (1H, d, J= 8.6Hz), 8.53–8.89 (3H, m), 13.02 (1H, s). 0.73-0.77 (2H, m), 0.82-0.93 (2H, m), 1.91 (4H, t, J= 6.5Hz), 3.33 (4H, t, J= 6.4Hz), 3.75 (3H, s), 4.59 (2H, d, J= 5.8Hz), 5.10 (2H, s), 88 5.68 (1H, s), 5.82 (1H, s), 7.24 (1H, d, J= 6.8Hz), 7.65 (1H, br.s), 7.71 (1H, dd, J= 8.8, 1.4Hz), 7.81 (1H, s), 8.18 (1H, s), 8.52 (1H, d, J= 8.7Hz), 8.62 (1H, t, J= 5.5Hz), 8.96 (2H, br.s), 12.91 (1H, s) 0.71-0.75 (2H, m), 0.80-0.85 (2H, m), 2.02 (4H, s), 2.57-2.63 (1H, m), 3.53 (4H, br.s), 3.99 (3H, s), 4.59 (2H, d, J= 5.8Hz), 5.11 (2H, s), 6.34 (1H, s), 7.22 (1H, d, J= 7.0Hz), 7.66 (1H, d, J= 6.9Hz), 7.71 (1H, d, J= , 7.82 (2H, d, J= 14.9Hz), 8.16 (1H, s), 8.54 (1H, d, J= 8.6Hz), 8.63 (1H, br.s), 9.01 (2H, br.s), 12.81 (1H, br.s), 13.05 (1H, br.s) 0.70-0.80 (2H, m), 0.77-0.88 (2H, m), 1.95-2.05 (4H, m), 2.58 (1H, ddd, J= 3.2, 5.2, 8.3Hz), 3.52-3.94 (4H, m), 4.58 (2H, d, J= 5.8Hz), .22 (2H, s), 7.08 (1H, d, J= 9.4Hz), 7.17-7.24 (1H, m), .74 (2H, m), 7.77-7.90 (2H, m), 7.98-8.04 (1H, m), 8.28 (1H, s), 8.59 (1H, d, J= 8.6Hz), 8.73 (1H, t, J= 5.9Hz), 9.18 (2H, s), 13.40 (1H, s), 13.82 (1H, s). 0.72-0.84 (4H, m), 2.55-2.62 (1H, m), 4.57 (2H,d, J= 5.7Hz), 5.22 (2H, s), 5.60 (2H,s), 7.16-7.24 (3H,m), 7.28 (2H, d, J= 8.1Hz), 7.66- 7.71 (2H, m), 7.74 (1H,s), 7.80 (1H, s), 8.20 (2H, d, J= , 8.56 (1H, d, J= 8.6Hz), 8.64 (1H, t, J= 5.8Hz), 9.12 (2H, br.s), 13.32 (1H,s). 0.73-0.76 (2H, m), 0.77-0.82 (2H, m), 2.59 (1H, tt, J= 5.1, 8.3Hz), 4.59 (2H, d, J= 5.8Hz), 4.99 (2H, q, J= 9.1Hz), 5.24 (2H, s), 7.01 (1H, 92 dd, J= 0.7, , 7.23 (1H, d, J= 7.0Hz), 7.64-7.76 (3H, m), 7.81 (1H, d, J= 1.6Hz), 8.16-8.25 (2H, m), 8.55 (1H, d, J= 8.6Hz), 8.65 (1H, t, J= 5.9Hz), 9.09 (2H, s), 13.24 (1H, s).
Example Chemical Shift (ppm) Number 0.74-0.78 (2H, m), 0.80–0.86 (2H, m), 2.55-2.62 (1H, m ), 4.58 (2H, d, J= 5.9Hz), 5.23 (2H, s), 7.03 (1H, dd, J= 0.7, 8.5Hz), 7.09–7.14 (2H, m), 7.21 (2H, m), 7.38–7.45 (2H, m), 7.66 (1H, d, J= 7.2Hz), 7.70 (1H, dd, J= 1.7, 8.7Hz), 7.76 (1H, dd, J= 2.5, 8.5Hz), 7.80 (1H, d, J= 1.6Hz), 8.12 (1H, dd, J= 0.8, 2.5Hz), 8.20 (1H, s), 8.54 (1H, d, J= 8.6Hz), 8.62 (1H, t, J= 5.9Hz), 9.04 (2H, s, br), 13.13 (1H, s) 0.75-0.77 (2H, m), 0.82-0.85 (2H, m), 1.33 (3H, t, J= , 2.54- 2.60 (1H, m), 4.38 (2H, q, J= 7.0Hz), 4.58 (2H, d, J= 5.8Hz), 5.21 (2H, s), 7.23 (1H, d, J= 7.0Hz), 7.65 (1H, d, J= 6.9Hz), 7.69 (1H, q, J= 8.6Hz), 7.85 (1H, d, J= , 8.11 (1H, d, J= 2.0Hz), 8.16 (1H, s), 8.49 (1H, d, J= 8.7Hz), 8.58 (1H, t, J= ), 8.90 (2H, br. s), 12.89 (1H, s). 0.76-0.77 (2H, m), 0.81-0.85 (2H, m), 1..11 (6H, t, J= 6.97Hz), 2.55- 2.61 (1H, m), 3.46 (4H, t, J= 7.0Hz), 4.58 (2H, d, J= 5.85Hz), 5.11 (2H, s), 7.04 (1H, s), 7.17 (1H, s), 7.22(1H, t, J= ), 7.29 (1H, s), 7.65-7.71 (2H, m), 7.81 (1H, d, J= ), 7.93 (1H, d, J= 1.52Hz), 8.15 (1H, s), 8.52 (1H, d, J= 8.64Hz), 8.61 (1H, t, J= 5.92Hz), 9.02 (2H, br, s), 13.08 (1H, s). 0.74-0.79 (2H, m), 0.8-0.88 (2H, m), 1.11 (6H, t, J = 6.9Hz), 2.59 (1H, m ), 3.55 (4H, d, J = 15.4Hz), 4.58 (2H, d, J = 5.9Hz), 5.11 (2H, s, br), 6.5-7.1 (0.5, s, br), 7.22 (1H, d, J = 7.0 Hz ), 7.54 (0.5H, s, br), 7.66 (1H, d, J = 7.0Hz), 7.70 (1H, dd, J = 1.7, 8.6Hz), 7.80 (1H, d, J = 1.7Hz), 8.02 (1H, d, J = 2.3Hz), 8.17 (1H, s), 8.54 (1H, d, J = , 8.63 (1H, t, J = 6.0Hz), 9.04 (2H, s, br), 13.12 (1H, s, br) 0.75-0.77 (2H, m), 0.82-0.84 (2H, m), 1.85-1.88 (4H, m), 2.55-2.60 (1H, m), 3.61 (4H, t, J= 6.6Hz), 4.58 (2H, d, J= 5.8Hz), 5.12 (2H, s), 97 7.22 (1H, d, J= 7.0Hz), 7.59-7.71 (2H, m), 7.80 (1H, s), 8.04 (1H, d, J= 1.9Hz), 8.19 (1H, s), 8.55 (1H, d, J= 8.6Hz), 8.58 (1H, t, J= 5.7Hz), 9.10 (2H, br.s), 13.53 (1H, s).
Example Chemical Shift (ppm) Number 1.31 (3H, t, J = 7.0Hz), 4.29 (2H, q, J = 7.0Hz), 4.56 (2H, d, J = .8Hz), 5.05 (2H, s), 5.41 (2H, br.s), 6.80 (1H, d, J = 8.5Hz), 7.23 (1H, d, J = 7.0Hz), 7.60–7.71 (3H, m), 7.79 (1H, s), 8.02 (1H, s), 8.14 (1H, d, J = 2.0 Hz ), 8.50–8.57 (2H, m), 9.01 (2H, s), 13.06 (1H, s). 1.95-2.07 (4H, m), 3.52-3.58 (4H, m), 4.56 (2H, d, J= 5.8Hz), 5.13 (2H, s), 7.11 (1H, d, J= 9.4Hz), 7.20 (1H, d, J= 7.0Hz), 7.64-7.71 (2H, 99 m), 7.79 (1H, s), 7.89 (1H, dd, J= 9.4, , 8.02 (1H, d, J= 1.8Hz), 8.23 (1H, s), 8.59 (1H, d, J= 8.6Hz), 8.82 (1H, t, J= 6.0Hz), 9.19 (2H, brs), 13.41 (1H, s), 13.86 (1H, brs). 1.94 (4H, m), 2.71 (6H, s), 3.38 (4H, m ), 4.58 (2H, d, J= 5.9Hz), 5.04 (2H, s), 6.57 (1H, s, br), 7.21 (1H, d, J= 7.0Hz), 7.57 (1H, s, br), 7.63–7.71 (2H, m), 7.75–7.80 (1H, m), 8.00–8.08 (2H, m), 8.45 (1H, t, J= 6.0Hz), 8.51 (1H, d, J = 8.6Hz), 8.95 (2H, s, br), 13.05 (1H, s, br) 1.87-1.96 (4H, m), .66 (2H, m), 2.70 (3H, s), .43 (5H, m), 3.69 (1H, dd, J =9.5, 8.5Hz), 3.97-4.07 (1H, m), 4.49 (2H, d, J= .9Hz), 5.12 (2H, s), 6.43 (1H, d, J= 8.7Hz), 6.80 (2H, s), 6.86 (1H, d, J= 6.0Hz), 7.36 (1H, dd, J= 8.6, 1.7Hz), 7.47 (1H, dd, J= 8.7, 2.4Hz), 7.51 (1H, s), 7.75 (1H, d, J= 5.8Hz), 8.10 (1H, d, J= 2.5Hz), 8.13 (1H, d, J= 8.6Hz), 8.17 (1H, s), 8.59 (1H, t, J = 6.0Hz) 2.09 (3H, s), 2.46 (3H, s), 2.55 (3H, s), 3.86 (2H, s), 4.47 (2H, d, J = .8 Hz), 5.31 (2H, s), 6.40 (1H, dd, J = 1.9, 3.4 Hz), 7.18 (2H, d, J = 105 8.1 Hz), 7.25 (2H, d, J = 8.1 Hz), 7.43 (1H, dd, J = 2.7, 3.2 Hz), 7.85 (1H, d, J = 1.6 Hz), 7.88 (1H, d, J = 0.6 Hz), 8.17 (1H, d, J = 2.0 Hz), 8.24 (1H, d, J = 0.6 Hz), 8.59 (1H, t, J = 5.9 Hz), 11.6 Hz (1H, s) 4.48 (2H, d, J = 5.8Hz), 5.36 (2H, s), 6.41 (1H, dd, J = 1.9, 3.4Hz), 7.12-7.24 (3H, m), 7.26-7.37 (2H, m), 7.44 (1H, dd, J = 2.5, , 7.78-7.99 (4H, m), 8.18 (1H, d, J = 2.0Hz), 8.30 (1H, d, J = 0.7Hz), 8.62 (1H, t, J = 5.9Hz), 11.57 (1H, s).
Example Chemical Shift (ppm) Number 4.48 (2H, d, J = 5.8Hz), 5.35 (2H, s), 6.41 (1H, dd, J = 1.9, 3.4Hz), 7.02 (1H, dt, J = 0.9, 8.3Hz), 7.06-7.15 (3H, m), 7.27-7.36 (2H, m), 107 7.44 (1H, dd, J = 2.5, 3.4Hz), 7.81-7.88 (2H, m), 7.91 (1H, d, J = 0.7Hz), 8.12 (1H, ddd, J = 0.8, 2.0 , 4.9Hz), 8.18 (1H, d, J = , 8.30 (1H, d, J = 0.8Hz), 8.62 (1H, t, J = , 11.56 (1H, s). 4.48 (2H, d, J = 5.8Hz), 5.33 (2H, s), 6.41 (1H, dd, J =1.9, 3.4Hz); 6.90 (2H, ddq, J = 1.2, 2.5, 4.6Hz), 6.99 (3H, dq, J = 1.3, 7.9Hz), 108 7.08-7.19 (1H, m), 7.28-7.47 (4H, m), 7.81-7.92 (2H, m), 8.18 (1H, d, J = , 8.26 (1H, d, J = 0.7 Hz), 8.61 (1H, t, J = 5.9Hz), 11.57 (1H, s). 4.47 (2H, d, J = 5.9Hz), 5.23 (2H, s), 5.34 (2H, s), 6.40 (1H, dd, J =1.9, 3.4Hz), 6.78 (1H, dd, J = 2.2, 7.8 Hz), 6.79 (1H, dd, J = 1.5, 8.0 109 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.41-7.44 (3H, m), 7.84-7.85 (1H, m), 7.87-7.91 (2H, m), 8.17 (1H, d, J = 2.0 Hz), 8.25 (1H, s), 8.59 (1H, t, J = 5.9 Hz), 11.55 (1H, br. s) 1.98 (3H, s), 2.36 (3H, s), 4.40 (2H, d, J= , 5.22 (2H, s), 5.39 (2H, s), 6.06 (1H, d, J= 0.9Hz), 6.90 (1H, dd, J= 8.2, 1.5Hz), 7.18 (3H, m), 7.23 (1H, s), 7.29-7.26 (3H, m), 7.53 (1H, s), 8.41 (1H, d, J= 0.7Hz), 8.70 (1H, t, J= 5.8Hz), 11.85 (1H, br s). 1.98 (3H, s), 4.46 (2H, d, J= 5.9Hz), 5.22 (2H, s), 5.40 (2H, s), 7.19 (2H, d, J= 8.2Hz), 7.23 (1H, s), 7.30-7.27 (3H, m), 7.49 (1H, d, J= 8.6Hz), 7.54 (1H, s), 7.64 (1H, s), 8.03 (1H, s), 8.43 (1H, s), 8.81 (1H, t, J= 5.8Hz), 13.03 (1H, br s). 1.98 (3H, s), 4.42 (2H, d, J= 5.8Hz), 5.22 (2H, s), 5.39 (2H, s), 6.37- 6.38 (1H, m), 7.02 (1H, dd, J= 8.4, 1.6Hz), 7.19 (2H, d, J = 8.2Hz), 112 7.23 (1H, s), 7.27 (2H, d, J= 8.1Hz), 7.31-7.34 (2H, m), 7.44 (1H, s), 7.54 (1H, s), 8.42 (1H, d, J= 0.7Hz), 8.73 (1H, t, J= 5.8Hz), 11.05 (1H, br.s).
Example Chemical Shift (ppm) Number 4.67 (2H, d, J= 5.8Hz), 5.03 (2H, s), 5.06 (2H,s), 5.40 (2H, s), 6.20- 6.24 (1H,m), 6.39 (1H, d, J= 9.1Hz), 6.98 (1H, d, J= 6.9Hz), 7.19 (2H, 113 d, J= 8.1Hz), 7.25-7.29 (3H, m), 7.38-7.42 (2H, m), 7.75 (1H, dd, J= 6.7, 1.9Hz), 7.99 (1H, s), 8.15 (1H, s), 8.37 (1H, t, J= 5.8Hz), 13.06 (1H, s). 1.90-1.93 (4H, m), 3.33-3.36 (4H, m), 4.45 (2H, d, J= 5.7Hz), 5.24 (2H, s), 6.40-6.44 (2H, m), 7.44-7.47 (2H, m), 7.84 (1H, d, J = 1.6Hz), 8.12 (1H, d, J = 1.7Hz), 8.16 (1H, d, J = 1.9Hz), 8.33 (1H, s), 8.73-8.74 (1H, m), 11.57 (1H, s). 1.98 (3H, s), 4.50 (2H, d, J = 6.2Hz), 5.21 (2H, s), 5.60 (2H, s), 6.39 (1H, dd, J = 1.9, , .24 (3H, m), .32 (2H, m), 7.43 115 (1H, dd, J = 2.5, 3.4Hz), 7.51 (1H, t, J = 0.9Hz), 7.87 (1H, d, J = 2.1Hz), 8.19 (1H, d, J = 2.0Hz), 8.61 (1H, s), 9.08 (1H, t, J = 6.2Hz), 11.54 (1H, s). 1.98 (3H, t, J = 0.7Hz), 2.53 (3H, s), 4.50 (2H, d, J = 5.9Hz), 5.22 (2H, s), 5.61 (2H, s), 6.33 (1H, dd, J = 1.9, , 7.16-7.24 (3H, m), 7.28-7.34 (3H, m), 7.49-7.56 (1H, m), 7.75 (1H, s), 8.63 (1H, s), 8.94 (1H, t, J = 6.0Hz), 11.36 (1H, s). 1.98 (3H, t, J = 0.7Hz), 4.47 (2H, d, J = 5.8Hz), 5.20 (2H, s), 5.30 (2H, s), 6.40 (1H, dd, J = 1.9, 3.4Hz), 7.12-7.26 (5H, m), 7.43 (1H, dd, J = 117 2.5, 3.4Hz), 7.51 (1H, t, J = 0.9Hz), 7.82-7.92 (2H, m), 8.17 (1H, d, J = 2.0Hz), 8.23 (1H, d, J = 0.7Hz), 8.57 (1H, t, J = 5.9Hz), 11.55 (1H, 1.97 (3H, s), 2.49 (3H, s), 2.54 (3H, s), 4.51 (2H, d, J = 4.6Hz), 5.19 (2H, s), 5.27 (2H, s), 6.43 (1H, dd, J = 3.5, 1.9Hz), 7.12-7.24 (5H, m), 7.28 (1H, dd, J = 3.5, 2.4Hz), 7.50 (1H, s), 7.86 (1H, s), 7.97 (1H, t, J = 4.6Hz), 8.22 (1H, s), 11.32 (1H, s). 2.03 (3H, s), 2.57 (3H, s), 2.60 (3H, s), 4.56 (2H, d, J= 4.6Hz), 5.25 (2H, s), 5.41 (2H, s), .50 (1H, m), 7.22 (2H, d, J= 8.1Hz), 7.27- 7.30 (3H, m), 7.35 (1H, t, J= 5.9Hz), 7.57(1H, s), 8.29 (1H, t, J= 4.5Hz), 8.42 (1H, s), 11.39 (1H, s).
Example Chemical Shift (ppm) Number 0.71-0.77 (2H, m), 0.79-0.84 (2H, m), 1.98 (3H,s), 2.55-2.67 (1H, m), 4.45 (2H, d, J= 5.7Hz), 5.17 (2H, s), 5.20 (2H, s), 6.40 (1H, d, J= 120 3.3Hz), 7.16 (4H, s), 7.22 (1H, s), 7.44 (1H, d, J= 3.3Hz), 7.51 (1H, s), 7.85 (1H, s), 8.08 (1H, s), 8.17 (1H, d, J= 1.3Hz), 8.36 (1H, t, J= , 11.56 (1H, s) 1.98 (3H,s), 4.55 (2H, d, J= 5.7Hz), 5.21 (2H, s), 5.39 (2H, s), 6.40- 6.41 (1H, m), 7.19 (2H, d, J= 8.1Hz), 7.23 (1H, s), 7.26 (2H, d, J= 121 8.0Hz), 7.45 (1H, t, J= 2.9Hz), 7.52 (1H, s), 7.85 (1H, d, J= 1.6Hz), 8.17 (1H, d, J= 1.9Hz), 8.40 (1H, s), 8.75 (1H, t, J= 5.6Hz), 11.57 (1H, (1.98 (3H, s), 4.63 (2H, d, J= 5.8Hz), 5.21 (2H, s), 5.39 (2H, s), 6.51 (1H, m), 6.90 (1H, d, J= 7.0Hz), 7.03 (1H, dd, J= 8.0, 7.4Hz), 7.18 (2H, d, J= 8.2Hz), 7.23 (1H, s), 7.33-7.26 (4H, m), 7.53 (1H, s), 8.41 (1H, d, J= 0.6Hz), 8.74 (1H, t, J= 5.8Hz), 11.14 (1H, br s). 1.98 (3H, s), 4.69 (2H, d, J= 5.8Hz), 5.22 (2H, s), 5.40 (2H, s), 7.00 (1H, d, J= 7.0Hz), 7.18 (2H, d, J= 8.2Hz), 7.23 (1H, s), 7.30-7.26 (3H, m), 7.44 (1H, d, J= 8.3Hz), 7.54 (1H, s), 8.14 (1H, d, J= , 8.43 (1H, s), 8.89 (1H, t, J= 5.9Hz), 13.11 (1H, br s). 2.33 (3H, s), 4.66 (2H, d, J= 5.8Hz), 5.22 (2H, s), 5.41 (2H, s), 6.54- 6.55 (1H, m), 6.95 (1H, d, J= 4.8Hz), 7.20 (2H, d, J= 8.1Hz), 7.23 (1H, s), 7.29 (2H, d, J= 8.2Hz), 7.44 (1H, t, J= 3.0Hz), 7.53 (1H, s), 8.15 (1H,d, J= 4.8Hz), 8.45 (1H, s), 8.88 (1H, t, J= 5.9Hz), 11.64 (1H, s). 4.69 (2H, d, J= 5.8Hz), 5.07 (2H, s), 5.40 (2H, s), 6.21-6.24 (1H, m), 6.39 (1H, d, J= , 7.00 (1H, d, J= 6.9Hz), .30 (5H, m), 7.39-7.44 (2H, m), 7.77 (1H, q, J= 6.6Hz), 8.14 (1H, s), 8.43 (1H, s), 8.89 (1H, t, J= 5.8Hz), 13.11 (1H, s). 1.98 (3H, s), 4.69 (2H, d, J= 5.8Hz), 5.21 (2H,s), 5.38 (2H, s), 7.17- 127 7.26 (5H, m), 7.33 (1H, dd, J= 8.9, 2.0Hz), .53 (2H, m), 7.84 (1H, d, J= 1.8Hz), 8.36 (1H, s), 8.87 (1H, t, J= 5.8Hz), 13.05 (1H, s).
Example Chemical Shift (ppm) Number 1.89-1.93 (4H,s), 3.35-3.42 (4H, m), 4.68 (2H, d, J= 5.88Hz), .24(2H, s), 6.42 (1H, s, br), 7.34(1H, dd, J= 1.96, 8.92Hz), 7.48 (2H, d, J = 6.80Hz ), 7.51 (1H, d, J = 8.92Hz ), 7.83 (1H, d, J = 1.80Hz), 8.11 (1H, d, J = 2.2Hz), 8.28 (1H, d, J = 4.96Hz), 13.04 (1H, s). 4.69 (2H, d, J = 5.84Hz), 5.06 (2H, s), 5.38 (2H, s), 6.20-6.23 (1H, m), 6.39 (1H, d, J = 9.04Hz), 7.27 (4H, s), 7.32-7.34 (1H, 9- 7.43 (1H, m), 7.52 (1H, d, J = 8.88Hz), 7.74-7.82 (1H, m), 7.84 (1H, d, J = 1.64Hz), 8.36 (1H, s), 8.86 (1H, d, J = 5.44Hz), 13.04 (1H, s).
Biological Methods The ability of the compounds of formula (I) to inhibit plasma kallikrein may be determined using the ing ical assays: Determination of the IC50 for plasma kallikrein Plasma kallikrein inhibitory activity in vitro was determined using standard published methods (see e.g.
Johansen et 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 rein (Protogen) was incubated at 37oC with the fluorogenic substrate H-DPro-Phe-Arg-AFC and various concentrations of the test compound. Residual enzyme activity al rate of reaction) was determined by measuring the change in optical absorbance at 410nm and the IC50 value for the test compound was determined.
Data ed from these assays are shown in Table 13 below: Table 13 Example IC50 (human PKal) Number nM 1 54.7 2 2110 3 2690 6 9460 7 5.38 e IC50 (human PKal) Number nM 8 3.72 9 14.3 2.4 11 1.89 12 2.58 13 2.14 14 4.62 1.17 16 0.74 17 1190 18 32.0 19 994.0 0.89 21 6.46 22 132 23 0.33 24 9.66 7.31 26 205 27 128 28 63.7 29 620 1470 31 2.0 32 2.4 e IC50 (human PKal) Number nM 33 2.8 34 142 3.68 36 2.16 37 0.67 38 1.27 39 1.68 42 4.85 44 3.9 45 3060 46 803 47 2030 48 820 49 186 50 203 51 576 52 300 53 16.8 54 46.7 55 79.2 56 71.8 57 14.9 58 13.3 59 5.84 60 9.61 e IC50 (human PKal) Number nM 61 18.1 62 13.58 63 12.3 64 10.4 65 14.9 66 281 67 108 68 59.0 69 32.3 70 66.9 71 63.6 72 118 73 22.6 74 425 75 98.3 76 0.92 77 85.4 78 91.1 79 2.29 80 206 81 26.5 82 21.2 86 56.1 87 23.2 88 112 e IC50 (human PKal) Number nM 89 17.8 90 11.6 91 13.8 92 109 93 75.1 94 53.2 95 34.0 97 18.5 98 62.4 99 4.15 105 17000 106 12000 107 2300 108 22000 109 4200 110 562 111 217 112 60.6 113 13.3 114 304 115 177 116 507 117 78 118 14 119 86.6 Example IC50 (human PKal) Number nM 120 118 121 62.0 122 101 123 545 124 146 125 4010 126 22.9 127 537 128 24.9 129 2.14 Selected compounds were further screened for inhibitory activity t the related enzyme KLK1. The ability of the compounds of formula (I) to inhibit KLK1 may be determined using the following biological assay: Determination of the IC50 for KLK1 KLK1 inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Stürzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human KLK1 (Callbiochem) was incubated at 37oC with the fluorogenic substrate -Leu-Arg-AFC and various concentrations of the test compound. Residual enzyme activity (initial rate of reaction) was determined by ing the change in optical absorbance at 410nm and the IC50 value for the test compound was determined.
Data acquired from this assay are shown in Table 14 below: Table 14 (KLK1 Activity) Example IC50 (human KLK1) Number nM 1 >10000 e IC50 (human KLK1) Number nM 2 >10000 3 >10000 6 9460 7 >10000 8 >10000 9 >10000 >10000 11 8860 12 6060 13 5160 14 5970 6640 16 5730 17 >10000 18 >10000 19 >10000 >10000 21 >10000 22 >10000 23 >10000 24 >4000 2210 26 4730 27 3200 28 >10000 e IC50 (human KLK1) Number nM 29 >10000 5750 31 >10000 32 >10000 33 >10000 34 18170 >10000 36 >40000 37 3530 38 7840 39 8050 42 9050 44 7090 45 18570 46 27200 47 15750 48 4320 49 8090 50 >40000 51 11720 52 >40000 53 >10000 54 18250 55 3810 56 >10000 e IC50 (human KLK1) Number nM 57 >10000 58 3110 59 4000 60 9570 61 7660 62 >10000 63 5700 64 2790 65 960 66 >10000 67 8880 68 9760 69 4740 70 4910 71 >10000 72 >10000 73 1570 74 2770 75 1300 76 >1000 77 >10000 78 >10000 79 >10000 80 9280 81 8970 e IC50 (human KLK1) Number nM 82 4710 86 8790 87 6460 88 9630 89 960 90 4700 91 >10000 92 >10000 93 >10000 94 2000 95 9640 97 3010 98 3140 99 3460 105 >40000 106 >40000 107 38100 108 20630 109 >40000 110 >10000 111 7170 112 >10000 113 5950 114 1210 115 >10000 Example IC50 (human KLK1) Number nM 116 >10000 117 >10000 118 >40000 119 >4000 120 >10000 121 >10000 122 >10000 123 >10000 124 7230 125 >10000 126 >10000 127 >10000 128 >10000 129 >10000 Selected compounds were further screened for inhibitory activity against the related enzymes plasmin, thrombin, n, Factor Xa and Factor XIIa. The ability of the nds of formula (I) to these enzymes may be determined using the following biological assays: Determination of enzyme selectivity Human serine protease enzymes plasmin, thrombin, trypsin, Factor Xa and Factor XIIa were assayed for enzymatic activity using an appropriate fluorogenic substrate. Protease activity was measured by monitoring the accumulation of ted fluorescence from the substrate over 5 minutes. The linear rate of fluorescence se per minute was expressed as percentage (%) activity. The Km for the cleavage of each ate was determined by standard transformation of the Michaelis-Menten on. The compound inhibitor assays were performed at substrate Km concentration and activities were calculated as the concentration of inhibitor giving 50% inhibition (IC50) of the uninhibited enzyme activity (100%).
Data ed from these assays are shown in Table 15 below: Table 15 (Selectivity data) Example IC50 (nM) Number Factor XIIa Thrombin Trypsin Plasmin 1 >10000 >40000 >40000 >40000 2 >10000 6 >10000 11 >10000 12 >10000 13 >10000 14 >10000 18 >10000 22 >10000 24 >1000 28 >10000 >10000 33 >10000 34 >40000 >10000 36 >10000 37 >10000 38 >10000 39 >10000 44 >10000 45 >40000 46 >40000 47 >40000 48 >40000 49 >40000 50 >40000 51 >40000 52 >40000 54 >4000 55 >10000 56 >10000 57 >10000 59 >1000 60 >10000 61 >10000 62 >10000 63 >10000 67 >10000 68 >10000 105 >40000 106 >40000 107 >40000 108 >40000 109 >40000 110 >10000 111 >10000 112 >10000 115 >10000 116 >10000 117 >10000 118 >40000 119 >4000 120 >10000 123 >10000 124 >10000 126 >10000 cokinetics Pharmacokinetic s of the compounds in Table 16 were performed to assess the pharmacokinetics following a single oral dose in male Sprague-Dawley rats. Two rats were given a single po dose of 5 mL/kg of a nominal 2 mg/mL (10 mg/kg) composition of test compound in 5% cremophor:5% ethanol:90% phosphate buffered saline. Following dosing, blood samples were collected over a period of 24 hours. Sample times were 5, 15 and 30 minutes then 1, 2, 4, 6, 8, 12 and 24 hours. Following collection, blood samples were centrifuged and the plasma fraction analysed for concentration of test compound by LCMS. Oral exposure data ed from these studies are shown below: Table 16 (Oral exposure data) Example Number Dose po (mg/kg) Cmax (ng/mL) Tmax (min) 11 10 134 23 12 10 155 30 24 4 97 420 36 10 642 75 117 10 98 45 126 10 56 30

Claims (24)

1. A compound of formula (I), A R6 X Z R5 R7 H O B 5 Formula (I) wherein B is a fused 6,5- or 6,6-heteroaromatic bicyclic ring, containing N and, optionally, one or two additional heteroatoms independently selected from N, O and S, which is optionally mono-, di 10 or tri-substituted with a substituent selected from alkyl, alkoxy, OH, halo, CN, COOR8, 9, CF3 and NR8R9; n when B is a fused 6,5-heteroaromatic bicyclic ring, it is linked to (CH2)- via its 6-membered ring component; W, X, Y and Z are independently selected from C, N, O and S, such that the ring containing W, X, 15 Y and Z is a five membered aromatic heterocycle; R5, R6 and R7 are independently absent or independently selected from H, alkyl, halo, OH, aryl, heteroaryl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9, CF3, and R16; wherein at least one of R5, R6 and R7 is present and is independently selected from alkyl, halo, OH, aryl, heteroaryl, 20 -NR8R9, CN, COOR8, CONR8R9, -NR8COR9, CF3 and R16; A is selected from aryl and heteroaryl; R8 and R9 are independently selected from H and alkyl; R16 is a carbon-containing 3-, 4-, 5- or 6-membered monocyclic ring system which may be aromatic, saturated or rated non-aromatic and which may optionally contain 1, 2, 3 or 4 heteroatoms selected from N, O and S, n the ring system R16 is in turn optionally substituted with substituents selected from alkyl and oxo; alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (C1-C10) or a ed saturated hydrocarbon of between 3 and 10 carbon atoms (C3-C10); alkyl may optionally be substituted with 1 or 2 substituents independently selected from (C1-C6)alkoxy, OH, CN, CF3, 5 , CONR10R11, fluoro and NR10R11; alkoxy is a linear O-linked hydrocarbon of between 1 and 6 carbon atoms (C1-C6) or a ed O-linked hydrocarbon of between 3 and 6 carbon atoms (C3-C6); alkoxy may ally be substituted with 1 or 2 substituents independently selected from OH, CN, CF3, COOR10, 10 CONR10R11, fluoro and 1; aryl is phenyl, biphenyl or naphthyl; aryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, morpholinyl, piperidinyl, heteroaryl, -(CH2)0O-heteroaryl, arylb, -O-arylb, -(CH2)1 15 arylb, -(CH2)1heteroaryl, -COOR10, -CONR10R11, -(CH2)1NR14R15, CF3 and -NR10R11; arylb is phenyl, biphenyl or naphthyl, which may be optionally substituted with 1, 2 or 3 tuents independently selected from alkyl, alkoxy, OH, halo, CN, morpholinyl, piperidinyl, - COOR10, -CONR10R11, CF3 and NR10R11; heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members independently selected from N, NR8, S and O; heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, OCF3, halo, CN, aryl, morpholinyl, piperidinyl, -(CH2)1aryl, heteroarylb, -COOR10, - 25 CONR10R11, CF3 and -NR10R11; heteroarylb is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where le, 1, 2 or 3 ring members independently selected from N, NR8, S and O; wherein heteroarylb may be optionally substituted with 1, 2 or 3 tuents independently selected 30 from alkyl, , OH, halo, CN, morpholinyl, dinyl, aryl, -(CH2)1aryl, -COOR10, - CONR10R11, CF3 and NR10R11; R10 and R11 are independently selected from H and alkyl or R10 and R11 together with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocylic ring which may be ted or unsaturated with 1 or 2 double bonds and which may be optionally mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, F and CF3; 5 R14 and R15 are independently selected from alkyl, arylb and heteroarylb; or R14 and R15 together with the nitrogen atom to which they are attached form a carbon-containing 4-, 5-, 6- or 7-membered heterocylic ring which may be saturated or unsaturated with 1 or 2 double bonds, and optionally may be oxo substituted; 10 and tautomers, stereoisomers ding enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically able salts and solvates thereof; wherein the compound of formula (I) is not: 15
2. A compound according to claim 1, wherein B is a fused 6,6-heteroaromatic bicyclic ring, ning N and, ally, one or two additional heteroatoms independently selected from N, O and S, which is optionally mono-, di or tri-substituted with a substituent selected from alkyl, alkoxy, OH, halo, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein alkyl, alkoxy, R8 and R9 are as d in claim 1.
3. A compound according to claim 2, wherein B is selected from optionally substituted quinoline, optionally substituted isoquinoline, ally substituted quinoxaline, optionally substituted cinnoline, optionally substituted phthalazine, optionally substituted quinazoline, optionally substituted 1,2,4-benzotriazine, optionally substituted benzotriazine, optionally 25 tuted 1,7-naphthyridine, and optionally substituted 1,8-naphthyridine; wherein said optional substituents are selected from alkyl, alkoxy, OH, F, Cl, CN, COOR8, CONR8R9, CF3 and NR8R9; and wherein alkyl, alkoxy, R8 and R9 are as defined in claim 1.
4. A compound according to any one of claims 1 to 3, wherein B is selected from optionally mono-, di or tri-substituted isoquinolinyl wherein said optional tuent(s) are selected from alkyl, alkoxy, OH, F, Cl, CN, COOR8, CONR8R9, CF3 and NR8R9; and n alkyl, alkoxy, R8 and R9 are as defined in claim 1.
5. A compound according to claim 1, as defined by formula (II), A R6 X Z R5 W R1 R2 R7 H N NH Formula (II) wherein R1, R2 and R3 are independently selected from H, alkyl, COOR8, CONR8R9, OH, alkoxy, 10 NR8R9, F and Cl; and wherein A,W, X, Y, Z, R5, R6, R7, alkyl, alkoxy, R8 and R9 are as defined in claim 1.
6. A compound according to claim 5, n R1, R2 and R3 are independently selected from H and alkyl.
7. A nd according to claim 1, wherein B is a fused 6,5- heteroaromatic bicyclic ring, containing N and, ally, one or two additional heteroatoms independently selected from N, O and S, which is optionally mono-, di or tri-substituted with a substituent selected from alkyl, alkoxy, OH, halo, CN, COOR8, CONR8R9, CF3 and NR8R9; wherein alkyl, alkoxy, R8 20 and R9 are as defined in claim 1.
8. A compound according to claim 7, wherein B is selected from optionally tuted indole, optionally substituted indazole and ally tuted 1H-pyrrolo[2,3-b]pyridine; wherein said optional substituents are selected from alkyl, alkoxy, OH, F, Cl, CN, COOR8, 25 CONR8R9, CF3 and NR8R9; and wherein alkyl, alkoxy, R8 and R9 are as d in claim 1.
9. A compound according to claim 8, wherein B is selected from optionally mono-, di or tri-substituted 1H-pyrrolo[2,3-b]pyridine, wherein said optional substituent(s) are selected from alkyl, alkoxy, OH, F, Cl, CN, COOR8, CONR8R9, CF3 and NR8R9; and wherein alkyl, alkoxy, 30 R8 and R9 are as defined in claim 1.
10. A compound according to claim 1, as defined by a (III), A R6 X Z R5 W R1 R7 H O NH Formula (III) 5 wherein R1 and R3 are ndently selected from H, alkyl, COOR8, CONR8R9, OH, alkoxy, NR8R9, F and Cl; and wherein A, W, X, Y, Z, R5, R6, R7, alkyl, , R8 and R9 are as d in claim 1.
11. A compound according to claim 10, wherein R1 and R3 are ndently selected 10 from H and alkyl; and wherein alkyl is as defined in claim 1.
12. A compound according to any one of claims 1 to 11, wherein at least one of R5, R6 and R7 is present and is independently selected from alkyl, halo, OH, aryl, aryl and CF3; wherein alkyl, aryl and heteroaryl are as defined in claim 1.
13. A compound according to any one of claims 1 to 12 wherein W, X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is a fivemembered heterocycle selected from pyrrole, pyrazole, imidazole, 1, 2, 3-triazole and 1, 2, 4- triazole.
14. A compound according to any one of claims 1 to 13 wherein A is heteroaryl substituted by methyl, phenyl, morpholinyl, piperidinyl or -NR10R11 wherein phenyl is optionally substituted as defined in claim 1, and R10 and R11 are as defined in claim 1; or A is phenyl substituted by heteroaryl, -(CH2)1heteroaryl or -(CH2)1NR14R15, wherein heteroaryl, R14 25 and R15 are as defined in claim 1.
15. A nd according to claim 14 wherein A is selected from: , and , and R10 and R11 are as d in claim
16. A compound according to claim 14 wherein A is selected from: 5 ,. , , , , , , and . 10
17. A compound according to claim 1, selected from: 2,5-Dimethyl(2-phenyl-thiazolylmethyl)-1H-pyrrolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 2,5-Dimethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 2,5-Dimethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-Ethylmethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 5 1-Ethylmethyl[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrrolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 3-Cyclopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid 10 (1-amino-isoquinolinylmethyl)-amide; 3-Isopropyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; obutyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid no-isoquinolinylmethyl)-amide; 15 3-Hydroxymethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Cyano[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 4-Methyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-thiazolecarboxylic acid (1- 20 amino-isoquinolinylmethyl)-amide; 3-(3,5-Dimethyl-isoxazolyl)[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazole- 4-carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]morpholinyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 25 5-Amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid (1-aminoisoquinolinylmethyl )-amide; 1-(6-Pyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Cyclopropyl(5-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazole 30 carboxylic acid no-isoquinolinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]phenyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Amino[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1- isoquinolinylmethyl)-amide; 3-Methoxymethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 5 3-Difluoromethyl[4-(4-methyl-pyrazolylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]thiophenyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 5-Amino(4-pyrazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid (1-amino- 10 isoquinolinylmethyl)-amide; yrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(6-Ethoxy-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 15 1-[2-(3,3-Difluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid no-isoquinolinylmethyl)-amide; 1-[6-(3,3-Difluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-((R)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole 20 carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-((S)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-((S)Fluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 25 1-[6-((R)Fluoro-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-((S)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-((R)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole 30 carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(2-Pyrrolidinyl-pyrimidinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(5-Pyrrolidinyl-pyrazinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[2-((S)Methyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[6-(3-Hydroxymethyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H- pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 5 1-[6-((R)Hydroxymethyl-pyrrolidinyl)-pyridinylmethyl]trifluoromethyl-1H- pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(6-Propoxy-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; luoropyrrolidinyl-pyridinylmethyl)trifluoromethyl-1H-pyrazole 10 ylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(6-Ethoxyfluoro-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(4-Pyrazolylmethyl-benzyl)trifluoromethyl-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 15 1-[4-(4-Cyano-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-[4-(4-Carbamoyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(6-Pyrazolylmethyl-pyridinylmethyl)trifluoromethyl-1H-pyrazolecarboxylic 20 acid (1-amino-isoquinolinylmethyl)-amide; 1-(2-Pyrazolylmethyl-thiazolylmethyl)trifluoromethyl-1H-pyrazolecarboxylic acid no-isoquinolinylmethyl)-amide; 4-Methyl-pyrazolylmethyl)-thiazolylmethyl]trifluoromethyl-1H-pyrazole- 4-carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 25 3-Cyclopropyl{6-[(2-methoxy-ethyl)-methyl-amino]-pyridinylmethyl}-1H-pyrazole- 4-carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Cyclopropyl[6-(3,3-difluoro-pyrrolidinyl)-pyridinylmethyl]-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Cyclopropyl(4-methoxypyrrolidinyl-pyridinylmethyl)-1H-pyrazole 30 carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Cyclopropyl(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 3-Cyclopropyl(4-[1,2,3]triazolylmethyl-benzyl)-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 3-Cyclopropyl(6-phenoxy-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; 1-(5-Chloroethoxy-pyridinylmethyl)cyclopropyl-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 5 3-Cyclopropyl(6-diethylaminofluoro-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1-amino-isoquinolinylmethyl)-amide; 1-(5-Chloropyrrolidinyl-pyridinylmethyl)cyclopropyl-1H-pyrazole carboxylic acid (1-amino-isoquinolinylmethyl)-amide; 3-Amino(6-ethoxy-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1-amino- 10 isoquinolinylmethyl)-amide; 3-Amino(6-pyrrolidinyl-pyridinylmethyl)-1H-pyrazolecarboxylic acid (1- amino-isoquinolinylmethyl)-amide; and pharmaceutically acceptable salts and es thereof. 15
18. A compound according to claim 1, selected from: 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (1H-pyrrolo[2,3-b]pyridinylmethyl)-amide; 1-[4-(2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-amide; 20 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (4,6-dimethyl-1H-pyrrolo[2,3-b]pyridinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid rrolo[2,3-b]pyridinylmethyl)-amide; 1-[4-(4-Methyl-pyrazolylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic 25 acid (1H-indolylmethyl)-amide; 3-Amino[4-(2-oxo-2H-pyridinylmethyl)-benzyl]-1H-pyrazolecarboxylic acid (1H- indazolylmethyl)-amide; 2-Oxo-2H-pyridinylmethyl)-benzyl]trifluoromethyl-1H-pyrazolecarboxylic acid (1H-indazolylmethyl)-amide; 30 and ceutically acceptable salts and solvates thereof.
19. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 18 and a pharmaceutically acceptable carrier, diluent or excipient.
20. A compound as claimed in any one of claims 1 to 18 for use in ne.
21. The use of a compound as claimed in any one of claims 1 to 18 in the manufacture of a medicament for the treatment or prevention of a disease or condition in which plasma 5 kallikrein activity is implicated.
22. A compound as claimed in any one of claims 1 to 18 for use in a method of treatment of a disease or condition in which plasma kallikrein activity is implicated. 10
23. The use of claim 21, or a compound for use as claimed in claim 22 wherein, the e or condition in which plasma kallikrein ty is implicated is selected from impaired visual , diabetic retinopathy, ic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel e, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory 15 distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and bleeding from post operative surgery.
24. The use of claim 21, or a compound for use as claimed in claim 22, wherein the disease or condition in which plasma kallikrein activity is implicated is retinal vascular permeability 20 associated with diabetic retinopathy and diabetic macular edema.
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