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WO2011051672A1 - Dérivés azaindole - Google Patents

Dérivés azaindole Download PDF

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Publication number
WO2011051672A1
WO2011051672A1 PCT/GB2010/001997 GB2010001997W WO2011051672A1 WO 2011051672 A1 WO2011051672 A1 WO 2011051672A1 GB 2010001997 W GB2010001997 W GB 2010001997W WO 2011051672 A1 WO2011051672 A1 WO 2011051672A1
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Prior art keywords
pyridin
pyrrolo
ethyl
ylmethyl
carbamoyl
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PCT/GB2010/001997
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English (en)
Inventor
David Michael Evans
Christine Elizabeth Allan
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Vantia Ltd
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Vantia Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • This invention relates to azaindole derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
  • the azaindole derivatives of the present invention are inhibitors of tissue kallikrein and have a number of therapeutic applications, particularly in the treatment of inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the compounds of the invention are selective inhibitors of human tissue kallikrein (KLKl). In particular, they show an ability to inhibit KLKl which is greater than their ability to inhibit other trypsin-like serine proteases.
  • KLKl Human tissue kallikrein , KLKl (EC.3.4.21.35, also known as hKl , glandular kallikrein and urinary kallikrein) is a trypsin-like serine protease belonging to the kallikrein gene family of which there are 14 other members (including prostate specific antigen) (G. M. Yousef et al., Endocrine Rev., 2001, 22, 184). Other closely related trypsin-like serine proteases include plasma kallikrein, thrombin, trypsin and plasmin. Active KLKl is a membrane-bound enzyme and is widely expressed.
  • KLKl can liberate the kinins from kininogens by limited proteolysis, kallidin is released from low molecular weight kininogen whilst bradykinin is released from high molecular weight kininogen (K. D. Bhoola et al., Pharmacological Rev., 1992, 44, 1).
  • Kinins such as kallidin (Lys-bradykinin) and bradykinin are potent mediators of inflammation.
  • the actions of kinins are mediated by activation of two main bradykinin receptor subtypes, B 1 and B2, both of which are members of the seven trans-membrane G protein-coupled receptor families.
  • KLK1 also activates the matrix metalloproteases (MMPs), pro-collagenase and pro-gelatinases and cleaves insulin-like growth factor binding protein-3 (J. A. Clements et al., Crit. Rev. Clin. Lab. Sci., 2004, 41, 265-312).
  • MMPs matrix metalloproteases
  • KLK1 can directly activate the bradykinin receptors (C. Hecquet et al., Mol. Pharmacol, 2000, 39, 508-515).
  • KLK1 S. C. Chrstiansen et al., Am. Rev. Respir. Dis., 1992, 145, 900-905. It has also been demonstrated that inflammatory cells release KLK1 (I. T. Lauredo et al., Am. J. Physiol. Lung Cell Mol. Physiol., 2004, 286, 734). Inhibition of KL 1 may be a novel approach for the treatment of asthma.
  • KLK1 has been implicated in a number of other disease states including acute pancreatitis (T. Griesbacher, Pharmacology, 2000, 60, 1 13; T. Griesbacher et al., Br. J. Pharmacol., 2003, 139, 299), inflammatory bowel disease (A. Stadnicki, Digestive and Liver Disease, 2005, 37, 648; A. Stadnicki et al., Digestive Diseases and Science, 2003, 48, 615), arthritis (R. W. Colman, Immunopharmacology, 1999, 43, 103; R. J. Williams, Brit. J. Rheumatology, 1997, 36, 420).
  • Antagonists of kinins have previously been investigated as potential therapeutic agents for the treatment of a number of inflammatory disorders (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, 3, 845-852).
  • bradykinin B2 receptor antagonists have been investigated as potential treatments for airways disease (W. M. Abraham et al., Eur. J. Pharm., 2006, 533, 215).
  • KLKl plays a role in cancer (K. D. Bhoola et al., Curr. Opin. Invest. Drugs, 2007, 8, 462).
  • KLKl plays a role in increasing tumor invasiveness via activation of matrix metalloproteases, pro-collagenases and pro-gelatinases (K. D. Bhoola et al., Biol. Chem., 2001 , 382, 77; H. Tschesche et al., Adv. Exp. Med. Biol, 1969, 247A, 545).
  • KLKl is indirectly involved in promoting proliferation through the liberation of mitogenic kinins (R. A. Roberts et al., J Cell. Sc/ ' ., 1989, 94, 527).
  • KLKl is also involved in growth factor regulation and is implicated in processing of precursors of various growth factors e.g. EGF, NGF.
  • Endogenous inhibitors of KLKl include the serpins, kallistatin, antiprotein C, oci- antitrypsin, and ai-antichymotrypsin.
  • Aprotinin is also a potent non-selective KLKl inhibitor.
  • Low molecular weight inhibitors of KLKl have previously been reported (M. Szelke et al, WO 199204371 ; M. Szelke et al., WO 199507291 ; C. Olivier et al., Peptides, 2000, 705; M. M.
  • KLKl inhibitors have been reported to display activity in animal models of allergic inflammation (M. Szelke et al., Braz. J. Med. Biol. Res., 1994, 27, 1943; D. M. Evans et al., Immunopharm cology, 1996, 32, 117), citric acid induced cough (R. L. Featherstone et al., Lung, 1996, 174, 269) and acute pancreatitis (T. Griesbacher et al., Br. J. Pharmacol, 2002, 137, 692).
  • KLKl inhibitors have also been shown to be active in models of cancer (tumor cell migration in a matrigel invasion assay is inhibited in a dose-dependant manner by a KLKl inhibitor) (W. C. Wolf et al., Am. J. Pathol, 2001, 159, 1797).
  • a human KLKl antibody that inhibits KLKl with nanomolar potency has been shown to be active in an allergic sheep model of asthma. The antibody inhibited the late phase bronchoconstriction and completely blocked airway hyperresponsiveness (D. J. Sexton et al., WO 2006017538, D. J. Sexton et al., Biochem. Journal, 2009, 422, 383).
  • KBP Kallikrein-binding protein
  • VEGF has also been linked with blood-retinal barrier breakdown which is a hallmark of diabetic retinopathy (D. A. Antonettie et al., Diabetes, 1998, 47, 1953). VEGF has also been implicated in remodeling of airway vasculature in chronic inflammation (D. M. McDonald, Am. J. Respir. Crit. Care Med., 2001 , 164, S39).
  • the compounds of the present invention have the advantage that they are selective inhibitors of KLKl (and so are likely to have reduced side effects). In addition, they may be more potent, they may be longer acting, T B2010/001997
  • the present invention provides compounds of formula (I):
  • R 1 and R 2 are independently selected from H, hydroxyl, (Ci-Cio)alkyl, (Ci-C 6 )alkoxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -Cio)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl- and heteroaryl(Ci-C 4 )alkyl-;
  • R 3 is selected from H, (Ci-Ci 0 )alkyl and (C 2 -C6)alkenyl;
  • R 4 and R 5 are independently selected from H and (Ci-C6)alkyl
  • a 1 is selected from CR 6 and S(0)R 7 ;
  • R 6 is selected from R 7 and the groups of formulae II, III and IV below;
  • R 7 is selected from (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 3 -Ci 0 )cycloalkyl, aryl and aryl(Ci- C 4 )alkyl-;
  • R 8 and R 9 are independently selected from H, (Ci-Cio)alkyl, (C 2 -C 6 )alkenyl, (C 3 - Cio)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C]-C 4 )alkyl- and heteroaryl(Ci- C 4 )alkyl-;
  • R 10 and R 11 are independently selected from H, (Ci-C 10 )alkyl, (C 2 -C 6 )alkenyl, (C 3 - Cio)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(Ci-C 4 )alkyl-, aryl(C2-C 4 )alkenyl-, heteroaryl(C 1 -C 4 )alkyl-, -S0 2 (C,-C 6 )alkyl, -S0 2 aryl and -S0 2 aryl(C,-C4)alkyl;
  • R 10 and R 1 1 together with the nitrogen atom to which they are attached may form a 4-7 membered N-containing ring, optionally containing one further heteroatom selected from N, O and S, and optionally substituted with 1 or 2 substituents independently selected from (C)-C 6 )alkyl, (Ci-C 6 )alkoxy, halo, CN and hydroxyl, said N-containing ring may also optionally be fused to an aryl group;
  • R and R together with the atoms to which they are attached may form a saturated or partially unsaturated 4-7 membered N-containing ring, optionally containing one further heteroatom selected from N, O and S, and optionally substituted on carbon with 1 or 2 substituents independently selected from (Ci- C 6 )alkyl, (C]-C 6 )alkoxy, halo, CN and hydroxyl;
  • R 9 is absent and R 8 and R 10 together with the atoms to which they are attached may form a 5, 6, 9 or 10 membered mono- or bi-cylic N-containing aromatic ring, optionally containing one further heteroatom selected from N, O and S, and optionally substituted on carbon with 1, 2 or 3 substituents independently selected from (Ci-C 6 )alkyl, (CrC 6 )alkoxy, halo, CN, aryl, COOR 15 and hydroxyl;
  • R 8 and R 10 may together form a group according to formula V or formula VI:
  • R 12 and R 13 are selected independently from H, (Ci-Cio)alkyl, (C 2 -C 6 )alkenyl, (C 3 - C 10 )cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl-, aryl(C 2 -C 4 )alkenyl-, heteroaryl(C]-C 4 )alkyl-, -S0 2 (C r C 6 )alkyl, -S0 2 aryl and -S0 2 aryl(C r C 4 )alkyl;
  • R a and R b are selected independently from H, (C,-Ci 0 )alkyl, (C 2 -C 6 )alkenyl, (C 3 - Cjo)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(Ci-C 4 )alkyl-, ary
  • R a and R b together with the atoms to which they are attached may form a saturated or partially unsaturated 4-7 membered N-containing ring, optionally containing one further heteroatom selected from N, O and S, and optionally substituted on carbon with 1 or 2 substituents independently selected from (Ci- C 6 )alkyl, (Ci-C 6 )alkoxy, halo, CN and hydroxyl; said N-containing ring may also optionally be fused to an aryl group;
  • R a and R b together with the atoms to which they are attached may form a 5, 6,
  • R 14 is selected from H, (Ci-C 6 )alkyl, (C r C 6 )alkoxy, OH, CN, CF 3 , COOR 15 , halo and NR 15 R 16 ;
  • R 15 and R 16 are independently selected from H and (Ci-C )alkyl
  • R 17 , R 18 , R 19 and R 20 are independently selected from H, hydroxyl, halo, CN, (C r Cio)alkyl and (Ci-C 6 )alkoxy;
  • h is selected from 1 and 2;
  • alkyl may optionally be substituted with 1 or 2 substituents independently selected from (C 3 -C 10 )cycloalkyl, (Ci-C 6 )alkoxy, OH, CN, CF 3 , COOR 15 , fluoro and NR 15 R 16 ;
  • alkenyl may optionally be substituted with 1 or 2 substituents independently selected from (C 3 -Ci 0 )cycloalkyl, (Ci-C 6 )alkoxy, OH, CN, CF 3 , COOR 15 , fluoro and NR I 5 R 16 ;
  • alkynyl may optionally be substituted with 1 or 2 substituents independently selected from (C 3 -C, 0 )cycloalkyl, (Ci-C 6 )alkoxy, OH, CN, CF 3 , COOR 11 , fluoro and NR n R 12 ;
  • alkoxy may optionally be substituted with 1 or 2 substituents independently selected from (
  • q 0, 1 or 2; and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof.
  • the present invention provides a prodrug of a compound of formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.
  • the present invention provides an N-oxide of a compound of formula (I) as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.
  • R 1 is selected from (Ci-Cejalkyl, (C 3 -Cio)cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
  • R 2 is selected from H, hydroxyl, (Ci-C6)alkyl, (Ci-C 6 )alkoxy, (C 3 -Cio)cycloalkyl and aryl;
  • R 3 , R 4 and R 5 are independently selected from H and (Ci-C 6 )alkyl
  • a 1 is selected from CR 6 and S(0)R 7 ;
  • R 6 is selected from R 7 and the groups of formulae II, III, and IV below;
  • R 7 is selected from (Ci-C6)alkyl, aryl and aryl(Ci ⁇ C4)alkyl-;
  • R 8 is selected from H, (Ci-C 6 )alkyl, (C 3 -Cio)cycloalkyl and aryl(C r C 4 )alkyl;
  • R 9 is selected from H and (Cj-C6)alkyl
  • R 10 is selected from H, (Ci-C 6 )alkyl, (C 3 -C, 0 )cycloalkyl and aryl(C C 4 )alkyl;
  • R" is selected from H and (C 1 -C 6 )alkyl; or R 10 and R 11 together with the nitrogen atom to which they are attached may form a 5-6 membered N-containing ring, optionally substituted with 1 or 2 (Q- C6)alkyl substituents;
  • R 8 and R 10 together with the atoms to which they are attached may form a saturated or partially unsaturated 5-6 membered N-containing ring, optionally substituted on carbon with 1 or 2 (Ci-C6)alkyl substituents;
  • R 9 is absent and R 8 and R 10 together with the atoms to which they are attached may form a 5, 6, 9 or 10 membered mono- or bi-cylic N-containing aromatic ring, optionally substituted on carbon with 1 or 2 (Ci-C 6 )alkyl substituents;
  • R 12 is selected from H and (C i -C 6 )alkyl;
  • R 13 is selected from H, (Ci-C 6 )alkyl, aryl and aryl(Ci-C 4 )alkyl-;
  • R a and R b are independently selected from H, (Ci-C 6 )alkyl, (C 3 -C6)cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • R and R b together with the atoms to which they are attached may form a saturated or partially unsaturated 5-6 membered N-containing ring, optionally substituted on carbon with 1 or 2 (Ci-C 6 )alkyl substituents;
  • R a and R b together with the atoms to which they are attached may form a 5, 6, 9 or 10 membered mono- or bi-cylic N-containing aromatic ring, optionally substituted on carbon with 1 or 2 (d-C6)alkyl substituents;
  • R 17 , R 18 , R 19 and R 20 are independently selected from H and (C r C6)alkyl; wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are as defined above; and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof.
  • R 1 is selected from (C3-Cio)cycloalkyl and aryl;
  • R 2 is selected from H and (C 3 -Cio)cycloalkyl
  • R 3 , R 4 and R 5 are H
  • A' is CR 6 ;
  • R 6 is selected from R 7 and the groups of formulae II and III below;
  • R 7 is aryl(C,-C 4 )alkyl-
  • R 8 is selected from H and (C C 6 )alkyl
  • R 9 is H
  • R 10 is selected from H and (C,-C 6 )alkyl
  • R 1 1 is selected from H and (Ci-C6)alkyl
  • R 10 and R 11 together with the nitrogen atom to which they are attached may form a 5-6 membered N-containing ring, optionally substituted with 1 or 2 (Ci-
  • R and R together with the atoms to which they are attached may form a saturated or partially unsaturated 5-6 membered N-containing ring, optionally substituted on carbon with 1 or 2 (Ci-C 6 )alkyl substituents;
  • R 9 is absent and R 8 and R 10 together with the atoms to which they are attached may form a 5, 6, 9 or 10 membered mono- or bi-cylic N-containing aromatic ring, optionally substituted on carbon with 1 or 2 (Ci-C6)alkyl substituents; R 12 is H;
  • R 13 is aryl(Ci-C 4 )alkyl-
  • R 17 , R , 8 , R 19 and R' u are H; wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are as defined above; and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof.
  • R 1 is selected from (Cj-Cio)cycloalkyl and aryl;
  • R 2 is selected from H and (C3-Ci 0 )cycloalkyl;
  • R 3 , R 4 and R 5 are H
  • a 1 is S(0)R 7 ;
  • R 7 is (C]-C 6 )alkyl
  • R ,7 , R ,& , R !9 and R 20 are H;
  • alky alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are as defined above;
  • the present invention also comprises the following aspects and combinations thereof:
  • the present invention provides a compound of formula (I) wherein R 1 is selected from (Ci-Cio)alkyl, (C3-Cio)cycloalkyl, aryl, heteroaryl and aryl(Ci-C4)alkyk
  • R 1 is selected from (Ci-C 6 )alkyl, (C5-Cio)cycloalkyl, aryl and heteroaryl.
  • the present invention provides a compound of formula (I) wherein R 1 is selected from (C 5 -Cio)cycloalkyl, aryl and heteroaryl.
  • the present invention provides a compound of formula (I) wherein R l is optionally substituted phenyl.
  • Optional substituents are selected from those defined above for 'aryl'.
  • the present invention provides a compound of formula (I) wherein R is selected from H, (Ci-C 6 )alkyl, OH, (Ci-C6)alkoxy, (C3-Cio)cycloalkyl and aryl.
  • the present invention provides a compound of formula (I) wherein R 2 is selected from H, (C3-Cio)cycloalkyl, and aryl.
  • the present invention provides a compound of formula (I) wherein
  • R 2 is selected from H, (Ci-C 6 )alkyl, OH, (C,-C 6 )alkoxy and (C 3 -C, 0 )cycloalkyl.
  • the present invention provides a compound of formula (I) wherein R 2 is selected from H, OH and (C4-C6)cycloalkyl.
  • the present invention provides a compound of formula (I) wherein R 2 is H. In one aspect, the present invention provides a compound of formula (I) wherein R 3 is selected from H and (Ci-C6)alkyl.
  • the present invention provides a compound of formula (I) wherein R 3 is H.
  • the present invention provides a compound of formula (I) wherein R 3 is H and the carbon atom to which R 3 is attached is chiral and has an (S) configuration.
  • the present invention provides a compound of formula (I) wherein R 3 is H and the carbon atom to which R is attached is chiral and has an (R) configuration.
  • the present invention provides a compound of formula (I) wherein R 4 is selected from H or (Ci-C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 4 is H.
  • the present invention provides a compound of formula (I) wherein R 5 is selected from H or (Ci-C6)alkyl.
  • the present invention provides a compound of formula (I) wherein R 5 is H.
  • the present invention provides a compound of formula (I) wherein A 1 is CR 6 .
  • the present invention provides a compound of formula (I) wherein A 1 is S(0)R 7 .
  • the present invention provides a compound of formula (I) wherein R 6 is selected from the groups of formulae (II), (III) and (IV) below
  • the present invention provides a compound of formula (I) wherein R 6 is selected from the groups of formulae (II) and (III) below
  • the present invention provides a compound of formula (I) wherein R 6 is the group of formula (II) belo
  • the present invention provides a compound of formula (I) wherein R 6 is the group of formula (IV) belo (IV).
  • the present invention provides a compound of formula (I) wherein R 6 is R 7 . 7
  • the present invention provides a compound of formula (I) wherein R is selected from (Ci-C 6 )alkyl, (C 3 -Ci 0 )cycloalkyl, aryl and aryl(C]-C4)alkyl-.
  • the present invention provides a compound of formula (I) wherein R is selected from (Ci-C 6 )alkyl, aryl and aryl(Ci-C4)alkyl-.
  • the present invention provides a compound of formula (I) wherein R 7 is selected from (Ci-C 6 )alkyl and (Ci-C 6 )alkyl substituted aryl(Ci-C 4 )alkyl-.
  • the present invention provides a compound of formula (I) wherein R 7 is selected from n-propyl or methyl substituted benzyl.
  • R 7 is selected from n-propyl or methyl substituted benzyl.
  • the present invention provides a compound of formula (I) wherein R is selected from H, (Ci-C 6 )alkyl, (C 3 -Ci 0 )cycloalkyl and aryl(Ci-C 4 )alkyl.
  • the present invention provides a compound of formula (I) wherein R is selected from H, (Ci-C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R is (C r C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 8 is aryl(Ci-C 4 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 9 is selected from H, (C, -C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 9 is H.
  • the present invention provides a compound of formula (I) wherein one of R 8 and R 9 is H and the other of R 8 and R 9 is not H, and the carbon atom to which R 8 and R 9 is attached is chiral and has an (R) configuration.
  • the present invention provides a compound of formula (I) wherein one of R 8 and R 9 is H and the other of R 8 and R 9 is not H, and the carbon atom to which R 8 and R 9 is attached is chiral and has an (S) configuration.
  • the present invention provides a compound of formula (I) wherein R is H and the carbon atom to which R 3 is attached is chiral and has an (R) configuration, and wherein one of R 8 and R 9 is H and the other of R 8 and R 9 is not H, and the carbon atom to which R 8 and R 9 are attached is chiral and has an (S) configuration.
  • the present invention provides a compound of formula (I) wherein R 3 is H and the carbon atom to which R 3 is attached is chiral and has an (S) configuration, and wherein one of R 8 and R 9 is H and the other of R 8 and R 9 is not H, and the carbon atom to which R 8 and R 9 are attached is chiral and has an (R) configuration.
  • the present invention provides a compound of formula (I) wherein R 10 is selected from H, (Ci-Cio)alkyl, (C 3 -C 10 )cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(Ci-C 4 )alkyl-, aryl(C 2 -C 4 )alkenyl- and heteroaryl(C r C 4 )alkyl-.
  • the present invention provides a compound of formula (I) wherein R 10 is selected from H, (Ci-C 6 )alkyl, (C 3 -Cio)cycloalkyl and aryl(Ci-C 4 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 10 is selected from H, (C[-C 6 )alkyl and (C 4 -C )cycloalkyl.
  • the present invention provides a compound of formula (I) wherein R 10 is selected from H and (Ci-C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 10 is (C,-C 6 )alkyl. In one aspect, the present invention provides a compound of formula (I) wherein R 1 1 is selected from H and (Ci-C 10 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 1 1 is selected from H and (Ci-C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 11 is (Ci-C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 10 and R 11 together with the nitrogen atom to which they are attached may form a 5-6 membered N-containing ring, optionally containing one further heteroatom selected from N, O and S, and optionally substituted with 1 or 2 substituents independently selected from (Ci-C6)alkyl, (C]-C 6 )alkoxy, halo, CN and hydroxyl, said N-containing ring may also optionally be fused to an aryl group.
  • the present invention provides a compound of formula (I) wherein R 10 and R 1 1 together with the nitrogen atom to which they are attached may form a 5 to 6 membered N-containing ring, optionally substituted with 1 or 2 (Ci-C6)alkyl substituents.
  • the present invention provides a compound of formula (I) wherein R 8 and R 10 together with the atoms to which they are attached may form a saturated or partially unsaturated 5-6 membered N-containing ring, optionally containing one further heteroatom selected from N, O and S, and optionally substituted on carbon with 1 or 2 substituents independently selected from (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, halo, CN and hydroxyl.
  • the present invention provides a compound of formula (I) wherein R 8 and R 10 together with the atoms to which they are attached may form a saturated 5-6 membered N-containing ring, optionally substituted on carbon with 1 or 2 (Ci-C 6 )alkyl substituents.
  • the present invention provides a compound of formula (I) wherein R 9 is absent and R 8 and R 10 together with the atoms to which they are attached may form a 5, 6, 9 or 10 membered mono- or bi-cylic N-containing aromatic ring, optionally containing one further heteroatom selected from N, O and S, and optionally substituted on carbon with 1, 2 or 3 substituents independently selected from (Ci-C 6 )alkoxy, halo, CN, aryl, COOR 15 and hydroxyl.
  • the present invention provides a compound of formula (I) wherein R 9 is absent and R 8 and R 10 together with the atoms to which they are attached may form a 5, 6, 9 or 10 membered mono- or bi-cylic N-containing aromatic ring, optionally substituted on carbon with 1, 2 or 3 substituents independently selected from (Ci- C 6 )alkyl, (C,-C 6 )alkoxy, halo, CN, aryl, COOR 15 and hydroxyl.
  • the present invention provides a compound of formula (I) wherein R 9 is absent and R 8 and R 10 together with the atoms to which they are attached may form a 5, 6, 9 or 10 membered mono- or bi-cylic N-containing aromatic ring, optionally substituted on carbon with 1 or 2 (Cj-C6)alkyl substituents.
  • the present invention provides a compound of formula (I) wherein R 12 is selected from H and (d-C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 12 is H.
  • the present invention provides a compound of formula (I) wherein R 13 is selected from H, (Ci-C 6 )alkyl, aryl, heteroaryl, aryl(Ci-C 4 )alkyl- and heteroaryl(Ci- C 4 )alkyl-.
  • the present invention provides a compound of formula (I) wherein R 13 is selected from H, (C]-C 6 )alkyl, aryl and aryl(Ci-C 4 )alkyl-.
  • the present invention provides a compound of formula (I) wherein R 13 is aryl(Ci-C 4 )alkyl-.
  • the present invention provides a compound of formula (I) wherein R 13 is benzyl.
  • the present invention provides a compound of formula (I) wherein one of R 12 and R 13 is H and the other of R 12 and R 13 is not H, and the carbon atom to which R 12 and R 13 is attached is chiral and has an (R) configuration. In one aspect, the present invention provides a compound of formula (I) wherein one of R 12 and R 13 is H and the other of R 12 and R 13 is not H, and the carbon atom to which R 12 and R is attached is chiral and has an (S) configuration.
  • the present invention provides a compound of formula (I) wherein R 3 is H and the carbon atom to which R 3 is attached is chiral and has an (R) configuration, and
  • the present invention provides a compound of formula (I) wherein R is H and the carbon atom to which R is attached is chiral and has an (S) configuration,
  • the present invention provides a compound of formula (I) wherein R a and R b are independently selected from H, (C]-Ci 0 )alkyl, (C2-C 6 )alkenyl, (C3-Cio)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C]-C )alkyl-, aryl(C 2 -C 4 )alkenyl-, heteroaryl(Ci- C 4 )alkyl-, -S0 2 (Ci-C 6 )alkyl, -S0 2 aryl and -S0 2 aryl(Ci-C 4 )alkyl.
  • R a and R b are independently selected from H, (C]-Ci 0 )alkyl, (C2-C 6 )alkenyl, (C3-Cio)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C]-
  • the present invention provides a compound of formula (I) wherein R a and R b are independently selected from H, (Ci-C 6 )alkyl, (C3-C )cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • the present invention provides a compound of formula (I) wherein R a and R b together with the atoms to which they are attached may form a saturated or partially unsaturated 4-7 membered N-containing ring, optionally containing one further heteroatom selected from N, O and S, and optionally substituted on carbon with 1 or 2 substituents independently selected from (Ci-C 6 )alkyl, (Ci-C6)alkoxy, halo, CN and hydroxyl; said N-containing ring may also optionally be fused to an aryl group.
  • the present invention provides a compound of formula (I) wherein R a and R b together with the atoms to which they are attached may form a saturated or partially unsaturated 5-6 membered N-containing ring, optionally substituted on carbon with 1 or 2 (Ci-C 6 )alkyl substituents
  • the present invention provides a compound of formula (I) wherein R a and R b together with the atoms to which they are attached may form a 5, 6, 9 or 10 membered mono- or bi-cylic N-containing aromatic ring, optionally containing one further heteroatom selected from N, O and S, and optionally substituted on carbon with 1, 2 or 3 substituents independently selected from (Ci-C6)alkyl, (CrC6)alkoxy, halo, CN, aryl, COOR 15 and hydroxyl.
  • the present invention provides a compound of formula (I) wherein R a and R b together with the atoms to which they are attached may form a 5, 6, 9 or 10 membered mono- or bi-cylic N-containing aromatic ring, optionally substituted on carbon with 1 or 2 (Ci-C )alkyl substituents.
  • the present invention provides a compound of formula (I) wherein R 14 is H.
  • the present invention provides a compound of formula (I) wherein R 15 is H. In one aspect, the present invention provides a compound of formula (I) wherein R 16 is H. In one aspect, the present invention provides a compound of formula (I) wherein R 17 , R 18 , R 19 and R 20 are independently selected from H, halo, and (C,-C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 17 , R 18 , R 19 and R 20 are independently selected from H or (Ci-C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R ,7 , R 18 , R 19 , and R 20 are H.
  • the present invention provides a compound of formula (I) selected from:
  • the compounds of the present invention have a number of therapeutic applications, particularly in the treatment of inflammatory diseases such as asthma and COPD, by virtue of their ability to inhibit KLK1.
  • the compounds of the present invention may be used for the treatment of respiratory disorders involving airways inflammation e.g. asthma (allergic and non- allergic) including exacerbations resulting from asthma and chronic obstructive pulmonary disease (COPD).
  • airways inflammation e.g. asthma (allergic and non- allergic) including exacerbations resulting from asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Such compounds may also be used to treat other forms of allergic inflammation including allergic rhinitis (hayfever), rhino-conjunctivitis, rhinorrhoea, urticaria, excess lung mucus production, ascites build-up, chronic bronchitis, chronic respiratory obstruction, pulmonary fibrosis and pulmonary emphysema.
  • inflammatory disorders that may be treated with the compounds of the present invention include, multiple sclerosis, arthritis, rheumatoid arthritis, osteopathic arthritis, osteoarthritis, rhinitis, sinusitis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), immune mediated diabetes, acute pancreatitis and interstitial cystitis, thermal injury, crush injury, conjunctivitis, periodontal disease, chronic prostate inflammation, chronic recurrent parotitis, inflammatory skin disorders (e.g. psoriasis, eczema), hepatic cirrhosis, spinal cord trauma and SIRS (systemic inflammatory response syndrome); smooth muscle spasm (e.g.
  • the compounds of the present invention may also be used to treat disorders that can be a response to the release of an inflammatory mediator (e.g.
  • the compounds of the present invention may also be used to treat disorders involving regulation of growth factors (e.g. vascular endothelial growth factor (VEGF)) which may involve increased vascular permeability (e.g. diabetic retinopathy and septic shock).
  • growth factors e.g. vascular endothelial growth factor (VEGF)
  • VEGF vascular endothelial growth factor
  • vascular permeability e.g. diabetic retinopathy and septic shock.
  • the compounds of the present invention may be used to treat a neoplastic disorder (e.g. metastatic pancreatic adenocarcinomas, tumour angiogenesis) in particular they may be used to reduce angiogenesis associated with neoplasms e.g. cancer and tumour growth and to modulate angiogenesis and other processes associated with neoplasia and tumour growth and in particular may be used to block tumour angiogenesis and/or cancer cell invasion and metastasis.
  • a neoplastic disorder e.g. metastatic pancreatic adenocarcinomas, tumour angiogenesis
  • Asthma is a chronic lung condition that may be classified as allergic (intrinsic) or non- allergic (extrinsic). Patients with asthma experience difficulty breathing as a result of narrowing or obstruction of the airway, making it more difficult to move air in and out. This narrowing can result from airway inflammation and bronchoconstriction. Symptoms of asthma include, for example, wheezing, shortness of breath, bronchoconstriction, airway hyperreactivity, decreased lung capacity, fibrosis, airway inflammation and mucus production. A further symptom of asthma is exacerbations resulting from the original asthma attack which account for a significant morbidity from the disease. A KLK1 inhibitor can be used to ameliorate or prevent at least one symptom of asthma.
  • a LK1 inhibitor can also be administered in conjunction with another agent for treating asthma e.g. inhaled steroids, an oral steroid, a long acting beta- agonist, a leukotriene modifier, cromolyn sodium and nedocromil, theophylline and an anti-IgE antibody (see below).
  • another agent for treating asthma e.g. inhaled steroids, an oral steroid, a long acting beta- agonist, a leukotriene modifier, cromolyn sodium and nedocromil, theophylline and an anti-IgE antibody (see below).
  • Allergic Rhinitis or "hay fever” involves an allergic reaction to pollen from grasses, trees, and weeds. When pollen is inhaled by an individual suffering from allergic rhinitis, antibody production and histamine release is triggered. Symptoms of allergic rhinitis include but are not limited to coughing, headache, itching of the eyes, mouth, throat, or nose, sneezing, nasal congestion, wheezing, sore throat, and watery eyes. The symptoms associated with hay fever vary significantly from person to person, and allergic rhinitis may be associated with other conditions such as asthma.
  • COPD Chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • Emphysema along with chronic bronchitis, is part of COPD. It is a serious lung disease and is progressive, usually occurring in elderly patients. COPD causes over- inflation of structures in the lungs known as alveoli or air sacs. The walls of the alveoli break down resulting in a decrease in the respiratory ability of the lungs. Patients with this disease may first experience shortness of breath and cough.
  • the KLKl inhibitor can be used to ameliorate at least one symptom of COPD.
  • a KLKl inhibitor can also be administered in conjunction with another agent for treating COPD e.g. inhaled steroids, an oral steroid, a long acting beta-agonist, a leukotriene modifier, cromolyn sodium and nedocromil, theophylline and an anti-IgE antibody (see below).
  • Cough can be caused by inflammation of the upper respiratory tract (throat and windpipe) due to a viral infection.
  • Viral infections include; the common cold, flu, laryngitis, and bronchitis. These viral infections can also spread to the lower respiratory tract (bronchi) to cause a cough.
  • a cough is a symptom of many illnesses and conditions including: asthma, bronchitis, influenza and whooping cough (pertussis) and may also result as a side effect from use of certain drugs such as ACE inhibitors. Individuals who smoke often have a smoker's cough, a loud, hacking cough which often results in the expiration of phlegm.
  • the KLKl inhibitor can be used to ameliorate or prevent at least one symptom of cough.
  • Exacerbations Resulting from Asthma and Chronic Obstructive Pulmonary Disease (COPD) Subjects suffering from asthma and COPD are at risk of an exacerbation when their lungs and airways begin to overreact to certain things that trigger these attacks. During an exacerbation the lining of the airways will suddenly become swollen and inflamed. The muscles of these airways will tighten up and the production of mucus will increase. This combination makes the openings much narrower and can almost close them altogether, making breathing hard. Exacerbations account for a significant morbidity and contribute a disproportionate amount to the cost of asthma management, symptoms frequently persist for at least a month following the exacerbation.
  • a KLKl inhibitor can be used to ameliorate or prevent at least one symptom of the exacerbations.
  • a KLKl inhibitor can also be administered in conjunction with another agent for treating exacerbations resulting from asthma and COPD e.g. inhaled steroids, an oral steroid, a long acting beta-agonist, a leukotriene modifier, cromolyn sodium and nedocromil, theophylline and an anti-IgE antibody (see below).
  • Pancreatitis is an inflammation of the pancreas. There are two types:
  • Acute pancreatitis the inflammation comes on quickly over a few hours, and will usually go away leaving no permanent damage, although it can be fatal if complications occur (5% of cases).
  • the KLKl inhibitor can be used to ameliorate or prevent at least one symptom of pancreatitis.
  • This order is characterised by inflammation in the lining of the joints and/or other internal organs. It is typically chronic, but can include flare-ups. Symptoms include, inflammation of joints, swelling, difficulty moving, pain and fever.
  • a KLKl inhibitor may be used to ameliorate or prevent at least one symptom of rheumatoid arthritis.
  • a KL 1 inhibitor can be administered with another agent for treating rheumatoid arthritis, such as NSAIDs and aspirin, analgesics and corticosteroids which help reduce joint pain, stiffness and swelling. Osteoarthritis
  • Osteoarthritis is a degenerative joint disease. It is characterised by the breakdown of cartilage in the joint, thus causing bones to rub against each other, causing pain and loss of movement.
  • a KLK1 inhibitor can be used to ameliorate or prevent at least one symptom of osteoarthritis.
  • a KLK1 inhibitor can be administered with another agent for treating rheumatoid arthritis, such as a corticosteroid or an NSAID.
  • a KLK1 inhibitor may be administered to a subject to modulate angiogenesis or other processes associated with neoplasia and tumour growth.
  • a KLK1 inhibitor may be used to reduce angiogenesis (e.g. uncontrolled or unwanted angiogenesis) such as angiogenesis associated with vascular malformations and cardiovascular disorders (e.g. atherosclerosis, restenosis and arteriovenous malformations), chronic inflammatory diseases (e.g. diabetes mellitus, inflammatory bowel disease, psoriasis and rheumatoid arthritis), dermatological disorders (e.g. arterial ulcers, systemic vasculitis and scleroderma) or ocular disorders (e.g. blindness caused by neovascular disease, neovascular glaucoma, corneal neovascularization, trachoma, diabetic retinopathy and myopic degeneration).
  • angiogenesis e.g. uncontrolled or unwanted angiogenesis
  • angiogenesis associated with vascular malformations and cardiovascular disorders e.g. atherosclerosis, restenosis and arteriovenous malformations
  • chronic inflammatory diseases e.g. diabetes me
  • a KLK1 inhibitor can be used to reduce angiogenesis associated with neoplasia, e.g., cancer and tumour growth, e.g., growth of a benign, malignant, or metastatic tumour.
  • cancerous disorders include, but are not limited to, solid tumours, soft tissue tumours and metastatic lesions.
  • examples include sarcomas, adenocarcinomas and carcinomas of various organ systems such as those affecting lung, breast, lymphoid, gastrointestinal (e.g. colon) and genitourinary tract (e.g. renal urothelial cells), pharynx, prostate, ovary as well as adenocarcinomas which include malignancies such as most colon cancers, rectal cancer, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, pharynx, cancer of the small intestine, cancer of the esophagus and others.
  • Exemplary solid tumours that can be treated include: fibrosarcoma, myxosarcoma, liposarcoma, chrondrosarcoma. osteogenic sarcoma, chordoma, lymphanangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumour, leiomyosaarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, heptoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, cervical cancer, testicular tumour, lung carcinoma, small cell lung carcinoma, non-small cell
  • the KLK1 inhibitor can also be used to treat a carcinoma, e.g. a malignancy of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas and melanoma.
  • a carcinoma e.g. a malignancy of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas and melanoma.
  • Exemplary carcinoma include adenocarcinoma, carcinomas of tissue of the cervix, lung, prostate, breast, head and neck, colon and ovary.
  • the KLK1 inhibitor can also be used to treat sarcomas, e.g. malignant tumours of mesenchchymal derivation.
  • the KLK1 inhibitor can be administered in combination with another agent for treating neoplastic and/or metastatic disorders.
  • other agents include:
  • antiangiogenic agents e.g. linomide, angiostatin, razoxane
  • cytostatic agents such as antiestrogens(e.g. tamoxifan, toremifene, raloxifene), progestogens(e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole), antiprogestogens, antiandrogens(e.g. flutamide, nilutamide, bicalutamide), anti-invasion agents (e.g. metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function).
  • antiestrogens e.g. tamoxifan, toremifene, raloxifene
  • progestogens e.g. megestrol acetate
  • aromatase inhibitors e.g. anastrozole, letrozole
  • antiprogestogens e.g. flutamide, nilutamide,
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as antimetabolites (e.g. fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside); Intercalating antitumour antibiotics (e.g. anthracyclines like doxorubicin, daunomycin, epirubicin); platinum derivatives(e.g. cisplatin, carboplatin)alkylating agents (e.g. chlorambucil, cyclophosphamide); antmitotic agents(e.g.
  • antimetabolites e.g. fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside
  • Intercalating antitumour antibiotics e.g. anthracyclines like doxorubicin, daunomycin, epirubicin
  • vinca alkaloids l such as vincristine and taxoids like TAXOL® (paclitaxel), TAXOTERE® (docetaxel, topoisomerase inhibitors (e.g. epipodophyllotoxins such as etoposide and teniposide) and proteasome inhibitors such as VELCADE® (bortezomib).
  • TAXOL® paclitaxel
  • TAXOTERE® docetaxel
  • topoisomerase inhibitors e.g. epipodophyllotoxins such as etoposide and teniposide
  • proteasome inhibitors such as VELCADE® (bortezomib).
  • the present invention provides a compound of formula (I) for use in therapy.
  • the present invention also provides for the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prevention of a disease or condition in which KLKl activity is implicated.
  • Diseases or conditions in which KLKl activity is implicated include inflammation, respiratory disorders, disorders involving regulation of growth factors and neoplastic disorders. Specific examples of such diseases and conditions include those listed above.
  • the present invention also provides a compound of formula (I) for use in the treatment or prevention of a disease or condition in which KLKl activity is implicated.
  • Diseases or conditions in which KLKl activity is implicated include inflammation, respiratory disorders, disorders involving regulation of growth factors and neoplastic disorders. Specific examples of such diseases and conditions include those listed above.
  • the present invention also provides a method of treatment of a disease or condition in which KLKl activity is implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
  • Diseases or conditions in which KLKl activity is implicated include inflammation, respiratory disorders, disorders involving regulation of growth factors and neoplastic disorders. Specific examples of such diseases and conditions include those listed above.
  • the disease or condition in which KLKl activity is implicated is selected from an inflammatory or respiratory disorder or condition selected from asthma (allergic and non-allergic), chronic obstructive pulmonary disease (COPD), allergic rhinitis (hayfever), cough, exacerbations resulting from asthma and chronic obstructive pulmonary disease (COPD), multiple sclerosis, arthritis, rheumatoid arthritis, osteopathic arthritis, osteoarthritis, rhinitis, sinusitis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), immune mediated diabetes, acute pancreatitis and interstitial cystitis, conjunctivitis, periodontal disease, chronic prostate inflammation, chronic recurrent parotitis, inflammatory skin disorders (e.g.
  • psoriasis eczema
  • SIRS systemic inflammatory response syndrome
  • smooth muscle spasm e.g. asthma, angina
  • RDS respiratory distress syndrome
  • rhino-conjunctivitis e.g. asthma, angina
  • RDS respiratory distress syndrome
  • rhino-conjunctivitis e.g. rhinorrhoea
  • urticaria e.g. asthma, angina
  • a neoplastic disorder e.g. asthma, angina
  • chronic bronchitis chronic respiratory obstruction
  • pulmonary fibrosis chronic respiratory obstruction
  • pulmonary fibrosis pulmonary fibrosis
  • pulmonary emphysema emphysema
  • the disease or condition in which KLKl activity is implicated is a respiratory disorder selected from asthma (allergic and non-allergic), chronic obstructive pulmonary disease (COPD), allergic rhinitis (hayfever), cough, exacerbations resulting from asthma and chronic obstructive pulmonary disease (COPD),
  • the disease or condition in which KLKl activity is implicated is selected from asthma (allergic and non-allergic) and exacerbations resulting from asthma and chronic obstructive pulmonary disease (COPD).
  • the disease or condition in which KLKl activity is implicated is a respiratory disorder selected from asthma (allergic and non-allergic) and cough.
  • the disease or condition in which KLKl activity is implicated is exacerbations resulting from asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • compositions for preventing and treating respiratory-tract disorders such as asthma (allergic and non-allergic) including exacerbations resulting from asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD) comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents.
  • asthma allergic and non-allergic
  • COPD chronic obstructive pulmonary disease
  • compositions may also be used to treat other forms of allergic inflammation including allergic rhinitis (hayfever), rhino-conjunctivitis, rhinorrhoea, urticaria, excess lung mucus production, ascites build- up, chronic bronchitis, chronic respiratory obstruction, pulmonary fibrosis and pulmonary emphysema.
  • allergic rhinitis hayfever
  • rhino-conjunctivitis rhinorrhoea
  • urticaria urticaria
  • excess lung mucus production ascites build- up
  • chronic bronchitis chronic respiratory obstruction
  • pulmonary fibrosis pulmonary fibrosis
  • pulmonary emphysema pulmonary emphysema
  • the invention includes a combination of a compound of the present invention, as hereinbefore described, with one or more anti-inflammatory, bronchodilator, antihistamine, decongestant or anti-tussive agents, said compounds of the present invention and said combination agents existing in the same or different pharmaceutical compositions, administered separately, sequentially or simultaneously.
  • Combinations may comprise two or three different pharmaceutical compositions.
  • Suitable therapeutic agents that could be used in combination with the compounds of the present invention include:
  • Steroidal glucocorticoid agonists examples include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17-propionate or 17,21-dipropionate esters), ciclesonide, loteprednol, (e.g. etabonate), etipednol (as e.g. dicloacetate), triamcinolone (e.g.
  • acetonide flunisolide, zoticaasone, flumoxonide, roofleponide, butixocort, (e.g. as propionate ester), prednisolone, prednisone, tipredane, steroid esters e.g.
  • a non-steroidal glucocorticoid receptor agonist A non-steroidal glucocorticoid receptor agonist
  • a 2-adrenoreceptor agonist for example albuterol (salbutamol), salmeterol, metaproterenol, terbutaline, fenoterol, procaterol, carmoterol, indacaterol, formoterol, arformoterol, picumeterol, GSK-159797, GSK-597901, GSK- 159802, GSK-64244, GSK-678007, TA-2005 and also compounds of EP1440966, JP05025045, WO93/18007, WO99/64035, US2002/0055651 , US2005/0133417, US2005/5159448, WO00/0751 14, WO01/42193, WOOl/83462, WO02/66422, WO02/70490, WO02/76933, WO03/24439, WO03/42160, WO03/42164, WO03/72539, WO03/91204, WO03/9976
  • WO05/026124 WO04/024700, WO04/024701, WO04/020410, WO04/020412, WO05/080372, WO05/082863, WO05/082864, WO03/053930;
  • Phosphodiesterase-4 (PDE4) inhibitors for example roflumilast, arofylline, cimomilast, Ibudilast, Lirimilast, Mesopram, ONO-6126 or lC-485;
  • Modulators of chemokine receptor function for example antagonists of CCR1, CCR2, CCR3, CXCR2, CXCR3, CX3CR1 and CCR8, such as SB-
  • alkyl includes saturated hydrocarbon residues including:
  • alkyl groups up to 10 atoms (Ci-Cio), or of up to 6 atoms (Ci-C 6 ), or of up to 4 atoms (d-C 4 ).
  • alkyl groups include, but are not limited, to Ci - methyl, C 2 - ethyl, C 3 - propyl and C 4 - n-butyl.
  • alkyl groups of between 3 and 10 atoms (C 3 -Ci 0 ), or of up to 7 atoms (C 3 -C 7 ), or of up to 4 atoms (C3-C4).
  • alkyl groups include, but are not limited to, C 3 - iso-propyl, C 4 - sec-butyl, C 4 - iso-butyl, C 4 - tert-butyl and C5 - neo-pentyl. each optionally substituted as stated above.
  • alkenyl includes monounsaturated hydrocarbon residues including:
  • alkenyl groups include, but are not limited to, C 2 - vinyl, C 3 - 1-propenyl, C 3 - allyl, C - 2-butenyl - branched groups of between 3 and 8 atoms (C 3 -C 8 ).
  • alkenyl groups include, but are not limited to, C 4 - 2-methyl-2-propenyl and C 6 - 2,3-dimethyl-2- butenyl.
  • alkynyl includes monounsaturated hydrocarbon residues having a carbon- carbon triple bond including:
  • alkynyl groups include, but are not limited to C 2 - ethynyl, C 3 - 1-propynyl, C 4 - 2-butynyl.
  • Branched groups of between 3 and 8 atoms (C 3 -C 8 ).
  • alkynyl groups include, but are not limited to, C 4 - 3 -methyl- 1-propynyl.
  • alkoxy includes O-linked hydrocarbon residues including:
  • alkoxy groups include, but are not limited to, C ⁇ - methoxy,
  • C 3 -C branched groups of between 3 and 6 atoms
  • C 3 - C 4 examples include, but are not limited to, C 3 - iso- propoxy, and C 4 - sec-butoxy and tert-butoxy.
  • halo is selected from CI, F, Br and I.
  • Cycloalkyl is as defined above.
  • Conveniently cycloalkyl groups may contain from 4 to 10 carbon atoms, or from 5 to 10 carbon atoms, or from 4 to 6 carbon atoms.
  • suitable monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentene, cyclopenta-l,3-diene, cyclohexene and cyclohexa-l,4-diene (optionally substituted as stated above).
  • bicyclic cycloalkyl groups include decahydronaphthalene, octahydro-lH-indene (optionally substituted as stated above).
  • suitable cycloalkyl groups, when fused with aryl, include indanyl and 1,2,3,4-tetrahydronaphthyl (optionally substituted as stated above).
  • Heterocycloalkyl is as defined above.
  • heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, N-methylpiperidinyl, morpholinyl, N-methyl morpholinyl, thiomorpholinyl, thiomorpholinyl- 1 -oxide, thiomorpholinyl- 1,1 -dioxide, piperazinyl, N-methylpiperazinyl, azepinyl oxazepinyl, diazepinyl, and 1 ,2,3,4- tetrahydropyridinyl (optionally substituted as stated above).
  • Aryl is as defined above. Typically, aryl will be optionally substituted with 1 , 2 or 3 substituents. Optional substituents are seleted from those stated above. Examples of suitable aryl groups include phenyl and naphthyl (each optionally substituted as stated above).
  • Heteroaryl is as defined above.
  • suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, quinolinyl and isoquinolinyl (optionally substituted as stated above).
  • C-linked such as in “C-linked heterocycloalkyl” means that the heterocycloalkyl group is joined to the remainder of the molecule via a ring carbon atom.
  • 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.
  • O-linked such as in "O-linked hydrocarbon residue" means that the hydrocarbon residue is joined to the remainder of the molecule via an oxygen atom.
  • “Pharmaceutically acceptable salt” means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts.
  • 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.
  • a compound of the invention contains a basic group, such as an amino group
  • pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, fumarates, hippurates, xinafoates, p- acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates and the like.
  • Hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.
  • Prodrug refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for forming pro-drugs are described in 'The Practice of Medicinal Chemistry, 2 nd Ed. pp561- 585 (2003) and in F. J. Leinweber, Drug Metab. Res., 1987, 18, 379. .
  • the compounds of the invention can exist in both unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when the solvent is water.
  • Typical configurations of the compounds of formula (I) include:
  • references herein to "treatment” include references to curative, palliative and prophylactic treatment.
  • the compounds of formula (I) should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, melt congealing and extrusion. Conventional drying processes including static/dynamic oven, infrared, microwave or radio frequency drying may be used to assist in the formation of the above crystalline and amorphous products.
  • excipients may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient' is used herein to describe any ingredient other than the compound(s) of the invention which may impart either a functional (i.e., drug release rate controlling) and/or a non-functional (i.e., processing aid or diluent) characteristic to the formulations.
  • the choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and liquid (including multiple phases or dispersed systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, emulsions or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
  • Formulations suitable for oral administration may also be designed to deliver the compounds of formula (I) in an immediate release manner or in a rate-sustaining manner, wherein the release profile can be delayed, pulsed, controlled, sustained, or delayed and sustained or modified in such a manner which optimises the therapeutic efficacy of the said compounds.
  • Means to deliver compounds in a rate-sustaining manner are known in the art and include slow release polymers that can be formulated with the said compounds to control their release.
  • rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion.
  • rate-sustaining polymers include hydroxypropyl 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, suspensions, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986.
  • the compounds of the invention may also be administered directly into the blood stream, into subcutaneous tissue, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, intrasynovial and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous or oily solutions. Where the solution is aqueous, excipients such as sugars (including but restricted to glucose, manitol, sorbitol, etc.) salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as sugars (including but restricted to glucose, manitol, sorbitol, etc.) salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • Parenteral formulations may include implants derived from degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations may be administered via surgical incision into the subcutaneous tissue, muscular tissue or directly into specific organs.
  • degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of co-solvents and/or solubility-enhancing agents such as surfactants, micelle structures and cyclodextrins.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1 ,1,2,3,3,3- heptafluoropropane, or as nasal drops.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or hydroxypropylmethylcellulose
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • kits suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • 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 daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • the compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the specific examples provided herein below. Moreover, by utilising the procedures described herein, one of ordinary skill in the art can readily prepare additional compounds that fall within the scope of the present invention claimed herein.
  • the compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention.
  • the examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • the compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above.
  • reactive functional groups e.g. hydroxy, amino, thio or carboxy
  • Conventional protecting groups for example those described by T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry” John Wiley and Sons, 4 th Edition, 2006, may be used.
  • 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.
  • the amino protecting group may be a benzyloxycarbonyl (Z) group which can be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere or 9-fluorenylmethyloxycarbonyl (Fmoc) group which can be removed by solutions of secondary organic amines such as diethylamine or piperidine in an organic solvents.
  • Carboxyl groups are typically protected as esters such as methyl, ethyl, benzyl or tert-butyl which can all be removed by hydrolysis in the presence of bases such as lithium or sodium hydroxide.
  • Benzyl protecting groups can also be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere whilst tert-butyl groups can also be removed by trifluoroacetic acid. Alternatively a trichloroethyl ester protecting group is removed with zinc in acetic acid.
  • a common hydroxy protecting group suitable for use herein is a methyl ether, deprotection conditions comprise refluxing in 48% aqueous HBr for 1-24 hours, or by stirring with borane tribromide in dichloromethane for 1-24 hours. Alternatively where a hydroxy group is protected as a benzyl ether, deprotection conditions comprise hydrogenation with a palladium catalyst under a hydrogen atmosphere.
  • R'-R 13 , R A and R B are as previously defined for the compounds of formula (I);
  • PGi, PG 2 or PG 3 is a suitable protecting group
  • R 30 is H, (CrCio)alkyl, halogen, hydroxyl or (C,-C 6 )alkoxy;
  • R 31 and R 32 are independently selected from H, (Ci-Cio)alkyl, (C 2 -C 6 )alkenyl, (C 3 - Ci 0 )cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(Ci-C 4 )alkyl-, aryl(C 2 -C 4 )alkenyl-, heteroaryl(Ci-C 4 )alkyl-, -S0 2 (Ci-C 6 )alkyl, -S0 2 aryl and -S0 2 aryl(Ci-C 4 )alkyl.
  • the compounds according to general formula I can be prepared using conventional synthetic methods.
  • the aminomethylazaindole (1) is coupled using standard peptide coupling conditions to an alpha amino acid (2) suitably amino-protected with a standard protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenylmethyloxycarbonyl (Fmoc).
  • a standard protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenylmethyloxycarbonyl (Fmoc).
  • R'or R 2 has a reactive functional group such as an amine or a carboxylic acid, this group will also be protected.
  • Standard peptide coupling methods include the reaction of acids with amines in the presence of hydroxybenzotriazole and carbodiimide such as water soluble carbodiimide, or 2-(lH- benzotriazole-l-yl)-l,l,3,3-tetramethylaminium hexafluorophosphate or benzotriazole-1- yl-oxy-tris-pyrrolidino-phosphoium hexaffluorophosphate or bromo-trispyrolidino- phosphoium hexafluorophosphate in the presence of organic bases such as triethylamine, diisopropylethylamine or N-methylmorpholine.
  • carbodiimide such as water soluble carbodiimide
  • the protecting group of (3) is removed using standard methods described previously to yield the amine (4).
  • the amine (4) is coupled using the standard peptide coupling conditions described previously to an alpha amino acid (5) suitably amino-protected with a suitable protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9- fluorenylmethyloxycarbonyl (Fmoc).
  • a suitable protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9- fluorenylmethyloxycarbonyl (Fmoc).
  • R 1 or R 2 has a reactive functional group such as an amine or a carboxylic acid, this group will also be protected.
  • the protecting group of the resulting protected dipeptide derivative (6) is removed using the standard methods described previously to give the amine (7).
  • the amine (7) is further derivatised by reductive alkylation with a suitable aldehyde or ketone to yield the alkylated amine (8).
  • amine (7) is allowed to react with the aldehyde or ketone in the presence of a suitable reducing agent such as sodium cyanoborohydride or sodium acetoxyborohydride in a suitable solvent such as methanol, at room temperature.
  • a suitable reducing agent such as sodium cyanoborohydride or sodium acetoxyborohydride in a suitable solvent such as methanol
  • Compound 10 can also be prepared by coupling the alkylated alpha amino acid (9) with the amine (4) using standard peptide coupling conditions described previously.
  • Alkylated alpha amino acids (12) can be prepared by the reductive alkylation of the parent alpha amino acid in which the carboxyl group is unprotected (11) or in which it is protected as an ester with a standard protecting group such as a methyl, tert-butyl or trichloroethyl ester (14), following alkylation this protecting group is removed using standard methods described previously. Typical conditions for carrying out the reductive alkylation are described above.
  • the alpha amino acid (9) may be prepared from the corresponding bromoacetic acid derivative, suitably carboxyl-protected with a standard protecting group, such as a methyl, tert-butyl, trichloroethyl ester (16) by reaction with the required amine followed by the deprotection using standard methods.
  • a standard protecting group such as a methyl, tert-butyl, trichloroethyl ester (16)
  • bromoacetic acid derivative (15) is allowed to react with the amine in the presence of a base such as diisopropylethylamine or potassium or sodium carbonate in a suitable solvent such as acetonitrile or tetrahydrofuran at room temperature.
  • Compound (11) can also be synthesised from the dipeptide (18) suitably amino-protected with a standard protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenylmethyloxycarbonyl (Fmoc).
  • a standard protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenylmethyloxycarbonyl (Fmoc).
  • Such a dipeptide can be prepared from two alpha amino acids one of which is amino-protected with a standard protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9- fluorenylmethyloxycarbonyl (Fmoc) whilst the other is carboxyl-protected with a standard protecting group such as an ester such as a methyl, tert-butyl, trichloroethyl ester.
  • a standard protecting group such as an ester such as a methyl, tert-butyl, trichloroethyl ester.
  • the carboxyl protecting group of (17) is removed by standard methods described previously following the coupling reaction.
  • the amide bond forming reactions may be carried out using the standard peptide coupling conditions described above.
  • the amine (4) is coupled using the standard peptide coupling conditions described previously to a pyrrole derivative (19). Where R 1 or R 2 has a reactive functional group such as an amine or a carboxylic acid, this group will also be protected.
  • Compound (20) can also be synthesised from compound (22).
  • a compound can be prepared from an alpha amino acid and a pyrrole derivative (19) with carboxylic acid functionality protected with a standard protecting group such as an ester such as a methyl, tert-butyl, trichloroethyl ester.
  • the carboxyl protecting group of (21) is removed by standard methods described previously following the coupling reaction.
  • the amide bond forming reactions may be carried out using the standard peptide coupling conditions described above.
  • amine (4) is coupled using the standard peptide coupling conditions described previously to a lactic acid derivative (23). Where R or R has a reactive functional group such as an amine or a carboxylic acid, this group will also be protected.
  • Compound (24) can also be synthesised from compound (26).
  • a compound can be prepared from an alpha amino acid and a lactic acid derivative (23) with carboxylic acid functionality protected with a standard protecting group such as an ester such as a methyl, tert-butyl, trichloroethyl ester.
  • the carboxyl protecting group of (25) is removed by standard methods described previously following the coupling reaction.
  • the amide bond forming reactions may be carried out using the standard peptide coupling conditions described above.
  • the amine (4) can be derivatised by reaction with a sulphonyl chloride (27) to give the sulphonamide derivative (28).
  • R 1 or R 2 has a reactive functional group such as an amine or a carboxylic acid, this group will also be protected.
  • Compound (28) can also be synthesised from compound (30).
  • Such a compound can be prepared from an alpha amino acid and a sulphonyl chloride (27) with carboxylic acid functionality protected with a standard protecting group such as an ester such as a methyl, tert-butyl, trichloroethyl ester.
  • the carboxyl protecting group of (29) is removed by standard methods described previously following the coupling reaction.
  • the amide bond forming reactions may be carried out using the standard peptide coupling conditions described above.
  • the amine (4) can be derivatised by reaction with acid chloride or carboxylic acid (31) to give the amide derivative (32). If a carboxylic acid is used the amide bond forming reactions may be carried out using the standard peptide coupling conditions described above. Where R 1 or R 2 has a reactive functional group such as an amine or a carboxylic acid, this group will also be protected.
  • Compound (32) can also be synthesised from compound (34).
  • a compound can be prepared from an alpha amino acid and a acid chloride or carboxylic acid (31) with additional carboxylic acid functionality protected with a standard protecting group such as an ester such as a methyl, tert-butyl, trichloroethyl ester.
  • the carboxyl protecting group of (33) is removed by standard methods described previously following the coupling reaction.
  • the amide bond forming reactions may be carried out using the standard peptide coupling conditions described above.
  • the amine (4) can be derivatised by reaction with an amine (35) in the presence of a suitable agent such as l,l -carbonyldiimidazole_to give the urea derivative (36).
  • a suitable agent such as l,l -carbonyldiimidazole_to give the urea derivative (36).
  • R or R has a reactive functional group such as an amine or a carboxylic acid, this group will also be protected.
  • Compound (36) can also be synthesised from compound (38).
  • a compound can be prepared from an alpha amino acid and an amine (35) with carboxylic acid functionality protected with a standard protecting group such as an ester such as a methyl, tert-butyl, trichloroethyl ester.
  • the carboxyl protecting group of (37) is removed by standard methods described previously following the coupling reaction.
  • the amide bond forming reactions may be carried out using the standard peptide coupling conditions described above.
  • the present invention also encompasses intermediate compounds that have utility in the synthesis of the compounds of formula (I). Accordingly, one aspect of the present invention provides an intermediate compound selected from the group including:
  • the present invention provides a process for the preparation of a compound of formula (I),
  • Standard peptide coupling conditions include the reaction of acids with amines in the presence of hydroxybenzotriazole and carbodiimide such as water soluble carbodiimide, or 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethylaminium hexafluorophosphate or benzotriazole-l-yl-oxy-tris-pyrrolidino-phosphoium hexaffluorophosphate or bromo- trispyrolidino-phosphoium hexafluorophosphate in the presence of organic bases such as triethylamine, diisopropylethylamine or N-methylmorpholine. These reactions are typically carried out in solvents such as dichloromethane and dimethylformamide. Examples
  • ⁇ NMR spectra were recorded on a Brucker Avance III (400MHz) spectrometer with reference to deuterium solvent and at room temperature.
  • Molecular ions were obtained using LCMS which was carried out using a Chromolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient 10% to 90% 0.1% HC0 2 H/MeCN into 0.1% HC0 2 H/H 2 0 over 1 1 min, flow rate 1.5 mL/min.
  • Data was collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electospray ionisation in conjunction with a Thermofinnigan Surveyor LC system.
  • N-Me-Ala-OH (2.0g, 15.5mmol) was dissolved in methanol (200mls), acetone (1.3g, 23.2mmol) was added followed by 10% Pd/C (1.5g). The reaction mixture was shaken at 15 psi for 18 hours. After this time the catalyst was filtered off through Celite and the residue washed with MeOH (lOOmls). The combined filtrates were evaporated in vacuo to give a white solid which was recrystallised from MeOH/diethyl ether to give a white crystalline solid identified as the title compound
  • Boc-4-fluoro-Phe-OH (459mg, 1.62mmol) was dissolved in CH 2 C1 2 (30mls). To this solution was added HBTU (615mg, 1.62mmol) and triethylamine (490mg, 4.86mmol). After 15mins C-(lH-pyrrolo[2,3-b]pyridin-5-yl)-methylamine (250mg, 1.7mmol) was added. After 2 hrs at room temperature the reaction mixture was diluted with CHC1 3 (150mls), this solution was washed with sat.
  • 3-Methylpyrrole-l -carboxylic acid (74mg, 0.38mmol) was dissolved in CH 2 C1 2 (lOmls). This solution was cooled to 0 C, HOBt (60mg, 0.45mmol) and water soluble carbodiimide(28mg, 0.15mmol) were added. After 20mins (S)-2-amino-3-(4-fluoro- phenyl)-N-(lH-pyrrolo[2,3-b]pyridin-5-ylmethyl)-propionamide dihydrochloride (123mg, 0.32mmol) and triethylamine (320mg, 3.19mmol) were added.
  • Boc-3,4-dichloro-Phe-OH (l .Og, 3.32mmol) was dissolved in CH 2 C1 2 (lOOmls) and DMF (5mls). To this solution was added HBTU (1.26g, 3.32mmol) and triethylamine (l .OOg, 9.95mmol). After 15mins C-(lH-Pyrrolo[2,3-b]pyridin-5-yl)-methylamine (512mg, 3.49mmol) was added. After 2 hrs at room temperature the reaction mixture was diluted with CHC1 3 (150mls), this solution was washed with sat.
  • Boc-l-Nal-OH (643mg, 2.04mmol) was dissolved in CH 2 C1 2 (30mls). To this solution was added HBTU (773mg, 2.04mmol) and triethylamine (516mg, 5.10mmol). After 15mins C-(lH-pyrrolo[2,3-b]pyridin-5-yl)-methylamine (250mg, 1.7mmol) was added. After 2 hrs at room temperature the reaction mixture was diluted with CHC1 3 (150mls), this solution was washed with sat. NaHC0 3 (lx50mls), water (lx50mls), brine (lx50mls), dried (Na 2 S04) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 1% MeOH, 99% CHC1 3 , fractions combined and evaporated in vacuo to give a white solid identified as the title compound.
  • Boc-D-3,3-Diphenylalanine (4.86g, 14.06mmol) was dissolved in methanol (200mls).
  • This solution was hydrogenated over 5% Rh on carbon (500mg) at 60psi and room temperature. After 2 days at room temperature further 5% Rh on carbon (500mg) was added and hydrogenation continued at 60psi and room temperature for a further 3 days.
  • reaction mixture was diluted with chloroform (50mls) and washed with NaHC0 3 (lx20mls), water (lx20mls), brine (lx20mls), dried (Na 2 S0 4 ) and evaporated in vacuo.
  • the residue was purified by flash chromatography (silica), eluent 50%EtOAc, 50% Pet. Ether, fractions combined and evaporated in vacuo to give a colourless oil identified as the title compound.
  • the ability of the compounds of formula (I) to inhibit KLKl may be determined using the following biological assays:
  • KLKl 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; Sturzebecher et al , Biol. Chem. Hoppe-Seyler, 1992, 373, 1025).
  • Human KLKl (Callbiochem) was incubated at 37°C with the fluorogenic substrate H- DVal-Leu-Arg-AFC and various concentrations of the test compound. Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410nm and the IC 50 value for the test compound was determined.
  • Selected compounds were further screened for inhibitory activity against other trypsin- like serine proteases using the appropriate enzyme and chromogenic substrate (Chromogenix AB).
  • the activity against the following human enzymes was tested (substrate in brackets):- plasma kallikrein (S-2302), thrombin (S-2238), plasmin (S- 2390) and trypsin (S-2222).
  • the enzyme was incubated at 37°C with the chromogenic substrate. Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 405nm.

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Abstract

La présente invention concerne des composés de formule (I) ; des compositions comprenant de tels composés ; l'utilisation de tels composés en thérapie (telle que pour l'asthme ou la broncho-pneumopathie chronique obstructive) ; et des procédés de traitement de patients par de tels composés. Dans cette formule, les R1 à R20 et A1 sont tels que définis ici.
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US9290485B2 (en) 2010-08-04 2016-03-22 Novartis Ag N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
WO2021032933A1 (fr) * 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzymes

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US9290485B2 (en) 2010-08-04 2016-03-22 Novartis Ag N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides
WO2021032933A1 (fr) * 2019-08-21 2021-02-25 Kalvista Pharmaceuticals Limited Inhibiteurs d'enzymes
US20220298138A1 (en) * 2019-08-21 2022-09-22 Kalvista Pharmaceuticals Limited Enzyme inhibitors
JP2022552048A (ja) * 2019-08-21 2022-12-15 カルビスタ・ファーマシューティカルズ・リミテッド 酵素阻害剤

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