This invention relates to aminothiazole derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.

Background to the Invention The aminothiazole 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). The compounds of the invention are selective inhibitors of human tissue kallikrein (KLK1). In particular, they show an ability to inhibit KLK1 which is greater than their ability to inhibit other trypsin-like serine proteases.

Human tissue kallikrein , LK1 (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 KLK1 is a membrane-bound enzyme and is widely expressed. Strongest expression is observed in the pancreas, salivary gland, colon, kidney, lymph node, prostate, small intestine, stomach, thyroid gland and vagina. There is moderate expression of KLK1 in the lung, as well as expression in the saliva and its increased activity has also been detected in the sputum of patients following chronic lung injury. KLK1 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 ( . 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. Bl receptors are involved in chronic responses and have low expression at basal levels but are upregulated following tissue injury and/or inflammation whilst B2 receptors are involved in acute responses and are constitutively expressed. 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). There are also reports that KLK1 can directly activate the bradykinin receptors (C. Hecquet et al., Mol. Pharmacol, 2000, 39, 508-515).

Kinins have been shown to be important mediators in allergic inflammation such as asthma and hayfever (S. C. Chrstiansen et al., J. Clin. Invest., 1987, 79, 188-197) and that the enzyme chiefly responsible for the liberation of kinins in the airways of asthmatic subjects is 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 KLK1 may be a novel approach for the treatment of asthma. In addition 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).

High levels of circulating KLK1 induce chronic hypotension, Aprotinin a non-selective KLK1 inhibitor has been shown to suppress this (J. N. Sharma et al, Pharmacology, 1995, 50, 363; Q. Song et al., Immunopharmacology, 1996, 32, 105).

Antagonists of kinins (such as bradykinin receptor antagonists) 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). In particular bradykinin B2 receptor antagonists have been investigated as potential treatments for airways disease (W. M. Abraham et al., Eur. J. Pharm., 2006, 533, 215). There is also evidence that 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, 247 A, 545). Additionally KLKl is indirectly involved in promoting proliferation through the liberation of mitogenic kinins (R. A. Roberts et al., J. Cell. Sci., 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, oii- antitrypsin, and a i-antichymo trypsin. 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. Staveski et al., WO 2003101941; M. Tokumasu et al., WO 2005095327; J. Burton et al., US 5464820). 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., Immunopharmacology, 1996, 32, 1 17), 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). Hyaluronic acid which binds and inactivates KLKl in vitro has been shown to block porcine pancreatic elastase induced bronchoconstriction in sheep (M. Scuri et al., Am. J. Respir. Crit. Care Med., 2001, 164, 1855). Kallikrein-binding protein (KBP) is a serine protease inhibitor (serpin) which specifically binds to tissue kallikrein and inhibits kallikrein activity. KBP has been shown to inhibit retinal neovascularization and decrease vascular leakage by downregulation of vascular endothelial growth factor (VEGF) (G. Gao et al., Diabetologia, 2003, 46, 689) and to inhibit growth of gastric carcinoma by reducing VEGF production (L. Lu et al., Mol. Cancer. Ther., 2007, 6, 3297). 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).

Selectivity with respect to the other members of the trypsin-like serine protease family, particularly plasma kallikrein, is an important issue. Inhibitors of tissue kallikrein displaying poor plasma kallikrein activity have previously been reported (M. Szelke et al., Brazilian J. Med. Biol. Res. 1994, 27, 1935 and D. M. Evans et al., Immunopharmacology, 1996, 32, 117), but there remains a need for further compounds that selectively inhibit tissue kallikrein. Several groups have disclosed synthetic inhibitors of plasma kallikrein. These include arginineketomethylene derivatives (WO 92/04371 and D. M. Evans et al., Immunopharmacology, 1996, 32, 115-116), noragmatine and agmatine derivatives (WO 95/07291, WO 94/29335), benzamidine derivatives (J.Sturzbecher et al., Brazilian J. Med. Biol. Res., 1994, 27, 1929-1934), boronic acid derivatives (US 5,187, 157) and aminomethylcyclohexanoyl derivatives (N. Teno et al., Chem. Pharm. Bull., 1993, 41, 1079-1090). Non-peptide plasma kallikrein inhibitors have also been reported (W. B. Young et al., Bio. Med. Chem Lett., 2006, 16, 2034 and WO 2008/016883).

The compounds of the present invention, and their pharmaceutically acceptable salts, 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, they may have greater bioavailability or they may have other more desirable properties than the compounds of the prior art.

Summary of the Invention

In one aspect, the present invention provides compounds of formula (I):

wherein:

R ¹ and R ² are independently selected from H, hydroxyl, (Ci-Ci ₀ )alkyl, (Ci-C ₆ )alkoxy, (C ₂ -C ₆ )alkenyl, (C ₂ -C ₆ )alkynyl, (C3-Ci ₀ )cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl- and heteroaryl(Ci-C ₄ )alkyl-;

R ³ is selected from H, (Ci-Cio)alkyl and (C ₂ -C ₆ )alkenyl;

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 selecte

(II) (III) (IV) R ⁷ is selected from (Ci-C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₃ -Ci ₀ )cycloalkyl, aryl and aryl(C _r 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(Ci-C4)alkyl- and heteroaryl(Ci- C ₄ )alkyl-; R ¹⁰ and R ^{1 1} are independently selected from H, (C ₂ -C ₆ )alkenyl, (C ₃ - Cio)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;

or 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)-C6)alkyl, (C|-C ₆ )alkoxy, halo, CN and hydroxyl, said N-containing ring may also optionally be fused to an aryl group;

or R ⁸ and R ¹⁰ 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 _r C ₆ )alkoxy, halo, CN and hydroxyl;

or 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 (d-C ₆ )alkyl, (Ci-C ₆ )alkoxy, halo, CN, aryl, COOR ¹⁵ and hydroxyl;

or R ⁸ and R ¹⁰ ma together form a group according to formula V or formula VI:

(V) (VI)

R ¹² and R ¹³ are selected independently from H, (Ci-Ci ₀ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₃ Cio)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C C ₄ )alkyl-, aryl(C ₂ -C ₄ )alkenyl- heteroaryl(Ci-C ₄ )alkyl-, -S0 ₂ (C _r C ₆ )alkyl, -S0 ₂ aryl and -S0 ₂ aryl(Ci-C ₄ )alkyl;

R ^a and R ^b are selected independently from H, (Ci-Cio)alkyl, (C ₂ -C ₆ )alkenyl, (C ₃ Cio)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C|-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(C,-C ₄ )alkyl; or 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 I or 2 substituents independently selected from (C|- C ₆ )alkyl, (C _r C ₆ )alkoxy, halo, CN and hydroxyl; said N-containing ring may also optionally be fused to an aryl group;

or 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 (C _r

C ₆ )alkyl, (C,-C ₆ )alkoxy, halo, CN, aryl, COOR ¹⁵ and hydroxyl;

R ¹⁴ is selected from H, (d-C ₆ )alkyl, (C,-C ₆ )alkoxy, OH, CN, CF ₃ , COOR ¹⁵ , halo and NR ^,5 R ¹⁶ ;

R ¹⁵ and R ¹⁶ are independently selected from H and (CrC^alkyl;

R ¹⁷ is selected from H, hydroxyl, halo, CN, (C,-Ci ₀ )alkyl and (Ci-C ₆ )alkoxy;

f and g are independently selected from 0, 1, 2 and 3, such that f + g = 1, 2 or 3;

h is selected from 1 and 2;

wherein:

alkyl may optionally be substituted with 1 or 2 substituents independently selected from (C ₃ -Ci ₀ )cycloalkyl, (C _r 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, (C _r C ₆ )alkoxy, OH, CN, CF ₃ , COOR ¹⁵ , fluoro and NR ^,5 R ¹⁶ ; alkynyl may optionally be substituted with 1 or 2 substituents independently selected from (C ₃ -C, ₀ )cycloalkyl, (C _r 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 (C ₃ -C, ₀ )cycloalkyl, OH, CN, CF ₃ , COOR ¹⁵ , fluoro and NR ¹⁵ R ¹⁶ ; cycloalkyl is a non-aromatic mono- or bi-cyclic hydrocarbon ring, optionally fused to an aryl group, wherein said cycloalkyl ring optionally contains, where possible, up to 2 double bonds; and wherein, unless otherwise stated, said cycloalkyl may optionally be substituted with 1 or 2 substituents independently selected from (Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, OH, CN, CF ₃ , COOR ¹⁵ , fluoro and

NR ^I5 R ¹⁶ ; heterocycloalkyl is a C-linked or N-linked 3 to 10 membered non-aromatic, mono- or bi-cyclic ring, wherein said heterocycloalkyl ring contains, where possible, 1, 2 or 3 heteroatoms independently selected from N, NR ¹⁵ , S(0) _q and

O; and said heterocycloalkyl ring optionally contains, where possible, 1 or 2 double bonds, and is optionally substituted on carbon with 1 or 2 substituents independently selected from (C(-C ₆ )alkyl, (Ci-C ₆ )alkoxy, OH, CN, CF ₃ , halo, COOR ¹⁵ , NR ^,5 R ¹⁶ and aryl; aryl is a single or fused aromatic ring system containing 6 or 10 carbon atoms; wherein, unless otherwise stated, each occurrence of aryl may be optionally substituted with up to 5 substituents independently selected from (Ci-C ₆ )alkyl, (Ci-C ₆ )alkoxy, OH, halo, CN, COOR ¹⁵ , CF ₃ and NR ¹⁵ R ^!6 ; 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, NR ¹⁵ , S and O; wherein, unless otherwise stated, said heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from (C,-C ₆ )alkyl, (C _r C ₆ )alkoxy, OH, halo, CN, COOR ¹⁵ , CF ₃ and NR ¹⁵ R ¹⁶ ; q is 0, 1 or 2;

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

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

In one subset of the compounds of formula (I): R ^l is selected from (Ci-C ₆ )alkyl, (C3-C| ₀ )cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

R is selected from H, hydroxyl, (Ci-C ₆ )alkyl, (d-C6)alkoxy, (C ₃ -C ₁₀ )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 is selecte

(II) (III) (IV)

R ⁷ is selected from (Ci-C ₆ )alkyl, aryl and aryl(Ci-C ₄ )alkyl-;

R ⁸ is selected from H, (C,-C ₆ )alkyl, (C ₃ -Ci ₀ )cycloalkyl and aryl(Ci-C ₄ )alkyl;

R ⁹ is selected from H and (Ci-C6)alkyl;

R ¹⁰ is selected from H, (C _r C ₆ )alkyl, (C ₃ -Cio)cycloalkyl and aryl(d-C ₄ )alkyl;

R ¹¹ is selected from H and (Ci-C6)alkyl;

or R ¹⁰ and R ^{1 1} 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-

C6)alkyl substituents;

or 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-C ₆ )alkyl substituents; or 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 (C|-C ₆ )alkyl substituents;

R ¹² is selected from H and (C _r C ₆ )alkyl;

R ¹³ is selected from H, (C _r C ₆ )alkyl, aryl and aryl(Ci-C ₄ )alkyl-;

R ^a and R ^b are independently selected from H, (Ci-C ₆ )alkyl, (C3-C ₆ )cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

or 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 (Q-Cejalkyl substituents;

or 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 ₆ )alkyl substituents;

R ¹⁷ is selected from H and (C,-C ₆ )alkyl; wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are as defined above;

and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof. In another subset of the compounds of formula (I):

R ¹ is selected from (C ₃ -Cio)cycloalkyl and aryl;

R is selected from H and (C3-C ₁₀ )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;

(Π) (III) R ⁷ is aryl(C _r C ₄ )alkyl-; R is selected from H and (d-C ₆ )alkyl;

R ⁹ is H;

R ¹⁰ is selected from H and (Ci-C ₆ )alkyl;

R" is selected from H and (Ci-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 (Ci-

C ₆ )alkyl substituents;

or 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;

or 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 H;

R ¹³ is aryl(Ci-C ₄ )alkyl-;

R ¹⁷ is H; wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are as defined above;

and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof. The present invention also comprises the following aspects and combinations thereof:

In one aspect, 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-C ₄ )alkyl-.

In another aspect, the present invention provides a compound of formula (I) wherein R ¹ is selected from (Ci-C ₆ )alkyl, (C ₅ -Cio)cycloalkyl, aryl and heteroaryl.

In a further aspect, the present invention provides a compound of formula (I) wherein R ¹ is selected from (C ₅ -C|o)cycloalkyl, aryl and heteroaryl.

In a yet further aspect, the present invention provides a compound of formula (I) wherein

R ¹ is optionally substituted phenyl. Optional substituents are selected from those defined above for 'aryl'. In one aspect, the present invention provides a compound of formula (I) wherein R ² is selected from H, (C,-C ₆ )alkyl, OH, (C,-C ₆ )alkoxy, (C ₃ -Ci ₀ )cycloalkyl and aryl.

In another aspect, the present invention provides a compound of formula (I) wherein R ² is selected from H, (C3-Ci ₀ )cycloalkyl, and aryl.

In yet another aspect, 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 -Ci ₀ )cycloalkyl.

In yet still another aspect, the present invention provides a compound of formula (I) wherein R is selected from H, OH and (C4-C ₆ )cycloalkyl.

In a further aspect, 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 is selected from H and (Ci-C ₆ )alkyl.

In another aspect, the present invention provides a compound of formula (I) wherein R ³ is H.

In one aspect, 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.

In another aspect, 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.

In one aspect, the present invention provides a compound of formula (I) wherein R ⁴ is selected from H or (Ci-C ₆ )alkyl.

In another aspect, the present invention provides a compound of formula (I) wherein R ⁴ is H.

In one aspect, the present invention provides a compound of formula (I) wherein R ⁵ is selected from H or (Ci-C ₆ )alkyl.

In another aspect, the present invention provides a compound of formula (I) wherein R ⁵ is H.

In one aspect, the present invention provides a compound of formula (I) wherein A ¹ is CR ⁶ . In another aspect, the present invention provides a compound of formula (I) wherein A ¹ is S(0)R ⁷ .

In one aspect, the present invention provides a compound of formula (I) wherein R ⁶ is selected from

In another aspect, the present invention provides a compound of formula (I) wherein R ⁶ is selected from the groups of formulae (II) and (III) below

(II) (III).

In yet another aspect, the present invention provides a compound of formula (I) wherein R ⁶ is the group of formula (II) below

(Π).

In a further aspect, the present invention provides a compound of formula (I) wherein R ⁶ is the group of formula (III) below

(III). In yet a further aspect the present invention provides a compound of formula (I) wherein R ⁶ is the group of formula (IV) belo

In yet still a further aspect, the present invention provides a compound of formula (I) wherein R ⁶ is R ⁷ .

In one aspect, the present invention provides a compound of formula (I) wherein R is selected from (Ci-C ₆ )alkyl, (C ₃ -Cio)cycloalkyl, aryl and aryl(Ci-C ₄ )alkyl-.

In another aspect, the present invention provides a compound of formula (I) wherein R ⁷ is selected from (C|-C ₆ )alkyl, aryl and aryl(Ci-C ₄ )alkyl-.

In yet another aspect, 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(C ₍ -C ₄ )alkyl-.

In a further aspect, the present invention provides a compound of formula (I) wherein R ⁷ is selected from n-propyl or methyl substituted benzyl.

In one aspect, the present invention provides a compound of formula (I) wherein R ⁸ is selected from H, (C]-C ₆ )alkyl, (C ₃ -Ci ₀ )cycloalkyl and aryl(Ci-C4)alkyl.

In another aspect, the present invention provides a compound of formula (I) wherein R ⁸ is selected from H, (Ci-C ₆ )alkyl.

In a further aspect, the present invention provides a compound of formula (I) wherein R ⁸ is (d-C ₆ )alkyl.

In one aspect, the present invention provides a compound of formula (I) wherein R ⁹ is selected from H, (C,-C ₆ )alkyl.

In another aspect, the present invention provides a compound of formula (I) wherein R ⁹ is H.

In one aspect, 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. In one aspect, 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.

In one aspect, 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 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.

In another aspect, 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 and R are attached is chiral and has an (R) configuration. In one aspect, the present invention provides a compound of formula (I) wherein R ¹⁰ is selected from H, (Ci-Cio)alkyl, (C3-C ₁₀ )cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(Ci-C ₄ )alkyl-, aryl(C ₂ -C ₄ )alkenyl- and heteroaryl(Ci-C ₄ )alkyl-.

In another aspect, the present invention provides a compound of formula (I) wherein R ¹⁰ is selected from H, (Ci-C ₆ )alkyl, (C3-Cio)cycloalkyl and

In a furtheraspect, the present invention provides a compound of formula (I) wherein R ¹⁰ is selected from H, and (C ₄ -C ₆ )cycloalkyl.

In a yet another aspect, the present invention provides a compound of formula (I) wherein R ¹⁰ is selected from H and (C C ₆ )alkyl.

In yet a further aspect, the present invention provides a compound of formula (I) wherein R ¹⁰ is (C ₁ -C ₆ )alkyl.

In one aspect, the present invention provides a compound of formula (I) wherein R ¹¹ is selected from H and (C _t -Cio)alkyl.

In another aspect, the present invention provides a compound of formula (I) wherein R ^{1 1} is selected from H and (Ci-C ₆ )alkyl.

In a further aspect, the present invention provides a compound of formula (I) wherein R ¹¹ is (Ci-C ₆ )alkyl. In one aspect, 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 5-6 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-C ₆ )alkyl, (Ci-C ₆ )alkoxy, halo, CN and hydroxyl, said N-containing ring may also optionally be fused to an aryl group.

In another aspect, 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-C ₆ )alkyl substituents.

In one aspect, 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 )alkyl, (Ci-C ₆ )alkoxy, halo, CN and hydroxyl.

o

In another aspect, the present invention provides a compound of formula (I) wherein R 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 (d-C6)alkyl substituents.

In one aspect, 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 )alkyl, (Ci-Q)alkoxy, halo, CN, aryl, COOR ¹⁵ and hydroxyl.

In another aspect, 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 (Q- C ₆ )alkyl, (Ci-C ₆ )alkoxy, halo, CN, aryl, COOR ¹⁵ and hydroxyl. In a further aspect, 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 (Ci-C ₆ )alkyl substituents.

In one aspect, the present invention provides a compound of formula (I) wherein R is selected from H and (Ci-C6)alkyl.

In another aspect, the present invention provides a compound of formula (I) wherein R is H.

In one aspect, 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(Cr C ₄ )alkyl-.

In another aspect, the present invention provides a compound of formula (I) wherein R ¹³ is selected from H, (Ci-C ₆ )alkyl, aryl and aryl(Ci-C ₄ )alkyl-.

In yet another aspect, the present invention provides a compound of formula (I) wherein R ¹³ is aryl(C,-C ₄ )alkyl-.

In a further aspect, the present invention provides a compound of formula (I) wherein R is benzyl.

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 (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 ¹³ is attached is chiral and has an (S) configuration.

In one aspect, 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 (R) configuration, and wherein one of R and R is H and the other of R and R is not H, and the carbon atom to which R ¹² and R ¹³ are attached is chiral and has an (S) configuration. In another aspect, 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 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 are attached is chiral and has an (R) configuration.

In one aspect, the present invention provides a compound of formula (I) wherein R ^a and R ^b are independently selected from H, (C _r Ci ₀ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₃ -C ₁ o)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(Ci-C4)alkyl-, aryl(C ₂ -C ₄ )alkenyl-, heteroaryl(Ci- C ₄ )alkyl-, -S0 ₂ (C C ₆ )alkyl, -S0 ₂ aryl and -S0 ₂ aryl(C _r C ₄ )alkyl.

In another aspect, 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 ₆ )cycloalkyl, heterocycloalkyl, aryl, heteroaryl.

In a further aspect, 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-C ₆ )alkoxy, halo, CN and hydroxyl; said N-containing ring may also optionally be fused to an aryl group.

In yet a further aspect, 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

In yet still a further aspect, 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 (C]-C ₆ )alkyl, (Ci-C6)alkoxy, halo, CN, aryl, COOR ¹⁵ and hydroxyl.

In yet still another further aspect, 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-C6)alkyl substituents. In one aspect, the present invention provides a compound of formula (I) wherein R is H.

In one aspect, 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 is selected from H, halo, and (Ci-C ₆ )alkyl.

In another aspect, the present invention provides a compound of formula (I) wherein R ¹⁷ is selected from H and (Ci-C ₆ )alkyl.

In yet another aspect, the present invention provides a compound of formula (I) wherein R ¹⁷ is H.

In one aspect, the present invention provides a compound of formula (I) selected from: (R)-2-Amino-3-methyl-pentanoic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-naphthalen- 1 -yl-ethyl} -amide;

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4-f luoro-phenyl)-ethyl]-2- (isopropyl-methyl-amino)-propionamide;

3-Methyl- 1 H-pyrrole-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -dichloro-phenyl)-ethyl]- 2-hydroxy-3 -phenyl-propionamide ;

(S)-N-(2-Amino-thiazol-5-ylmethyl)-3-naphthalen-l-yl-2-(prop ane-l-sulfonylamino)- propionamide;

(S)-l-Methyl-pyrrolidine-2-carboxylic acid {(R)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2,2-dicyclohexyl-ethyl } -amide;

(R)-Pyrrolidine-2-carboxylic acid [(S)-l -[(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- (3,4-difluoro-phenyl)-ethyl]-amide; (R)-2-Amino-3-methyl-pentanoic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-carbamoyl]- 2-(3 ,4-difluoro-phenyl)-ethyl] -amide;

(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-l -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-( 3,4-difluoro-phenyl)-ethyl]- 2-dipropylamino-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -difluoro-phenyl)-ethyl]- 2-(isopropyl-methyl-amino)-propionamide;

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3 ,4-difluoro-phenyl)-ethyl]- 2-diethylamino-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -difluoro-phenyl)-ethyl]- 2-dimethylamino-propionamide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -difluoro-phenyl)-ethyl]-

2-dimethylamino-propionamide;

(S)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;

(R)- 1 -Ethyl-pyrrolidine-2-carboxy lie acid [(S)- 1 -[(2-amino-thiazol-5 -ylmethyl)- carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;

(R)- 1 -Isopropyl-pyrrolidine-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyi)- carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;

(R)-l -Isopropyl-piperidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;

(R)- 1 -Methyl-piperidine-2-carboxylic acid [(S)- 1 - [(2-amino-thiazol-5 -ylmethyl)- carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;

(S)-l -Methyl -piperidine-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;

(R)-N-[(S)-l -[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4-difluoro-ph enyl)-ethyl]-

2-dimethylamino-3-phenyl-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3 ₅ 4-difluoro-phenyl)-ethyl]- 2-dimethylamino-3-phenyl-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -difluoro-phenyl)-ethyl]- 2-piperidin- 1 -yl-propionamide; (R)-N-[(S)- 1 - [(2- Amino-thiazol -5-ylmethyl)-carbamoyl] -2-(3 ,4-difluoro-phenyl)-ethyl] - 2-piperidin- 1-yl-propionamide;

(S)-N-(2-Amino-thiazol-5-ylmethyl)-3-(3,4-difluoro-phenyl)-2 -(2-diisopropylamino- acetylamino)-propionamide;

(S)-N-(2-Amino-thiazol-5-ylmethyl)-3-(3,4-difluoro-phenyl )-2-[2-(2,6-dimethyl- piperidin-l-yl)-acetylamino]-propionamide;

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4-f luoro-phenyl)-ethyl]-2- dimethylamino-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyI]-2-(4-f luoro-phenyl)-ethyl]-2- diethylamino-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4-f luoro-phenyl)-ethyl]-2- piperidin- 1 -yl-propionamide;

(R)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl )-ethyl]-2- piperidin- 1 -yl-propionamide;

(S)-N-(2-Amino-thiazol-5-ylmethyl)-2-[2-(2,6-dimethyl-piperi din-l-yl)-acetylamino]-3- (4-fluoro-phenyl)-propionamide;

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyi)- carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;

(S)-N-[(S)-l -[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl )-ethyl]-2- (isopropyl-methyl-amino)-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3-f luoro-phenyl)-ethyl]-2- dimethylamino-propionamide;

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylrnethyl)-carbamoyl]-2-(3-fluoro-pheny l)-ethyl]-2- diethylamino-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3-f luoro-phenyl)-ethyl]-2^ piperidin-1 -yl-propionamide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3-f luoro-phenyl)-ethyl^ piperidin- 1 -yl-propionamide;

(R)- 1 -Methyl-pyrrolidine-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(2-fluoro-phenyl)-ethyl]-amide; (S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(2-f luoro-phenyl)-ethyl]-2- (isopropyl-methyl-amino)-propionamide;

(R)-l-Methyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-naphthalen- 1 -yl-ethyl} -amide;

(S)-N- { (S)- 1 - [(2-Amino-thiazol-5-ylmethyl)-carbamoyl] -2-naphthalen- 1 -yl-ethyl} -2- (isopropyl-methyl-amino)-propionamide;

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-naph thalen-l-yl-ethyl}-2- diethylamino-propionamide;

(S)-N- { (S)- 1 -[(2-Amino-thiazol-5 -ylmethyl)-carbamoy l]-2-naphthalen- 1 -yl-ethyl } -2- piperidin-l -yl-propionamide;

(R)-N- {(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-naphthalen- 1 -yl-ethyl } -2- piperidin- 1 -yl-propionamide;

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-naph thalen-l-yl-ethyl}-2- dimethylamino-3-phenyl-propionamide;

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4-c hloro-phenyl)-ethyl]-2- (isopropyl-methyl-amino)-propionamid;

(R)- 1 -Methyl-pyrrolidine-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl] -2-(3 -chloro-phenyl)-ethyl] -amide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3-c hloro-phenyl)-ethyl]-2- (isopropyl-methyl-amino)-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazoI-5-ylmethyl)-carbamoyl]-2-(3-c hloro-phenyl)-ethyl]-2- dimethylamino-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-( 3-chloro-phenyl)-ethyl]-2- diethylamino-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3-c hloro-phenyl)-ethyl]-2- piperidin- 1 -yl-propionamide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3-c hloro-phenyl)-ethyl]-2- piperidin-l-yl-propionamide;

(R)- 1 -Methyl-pyrrolidine-2-carboxylic acid [(S)- 1 - [(2-amino-thiazol-5 -ylmethyl)- carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide; (S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -dichloro-phenyl)-ethyl]- 2-(isopropyl-methyl-amino)-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -dichloro-phenyl)-ethyl]- 2-dimethy 1 amino-propionamide ;

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4-dichloro-ph enyl)-ethyl]- 2-diethylamino-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -dichloro-phenyl)-ethyl]- 2-piperidin- 1 -yl-propionamide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -dichloro-phenyl)-ethyl]- 2-piperidin- 1 -yl-propionamide;

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-p-to lyl-ethyl}-2-(isopropyl- methyl-amino)-propionamide;

(R)- 1 -Methyl-pyrrolidine-2-carboxylic acid {(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-p-tolyl-ethy] } -amide;

(R)-l-Methyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl] -2-m-tolyl-ethyl } -amide;

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-m-to lyl-ethyl}-2-(isopropyl- methyl-amino)-propionamide;

(R)- 1 -Methyl-pyrrolidine-2-carboxylic acid {(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-o-tolyl-ethyl}-amide;

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-o-to lyl-ethyl}-2-(isopropyl- methyl-amino)-propionamide;

(R)-Pyrrolidine-2-carboxylic acid {(S)-l -[(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- cyclohexyl -ethyl } -amide ;

(R)-l-Methyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-cyclohexyl-ethyl} -amide;

(S)- 1 -Methyl-pyrroIidine-2-carboxylic acid {(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-cyclohexyl-ethyl}-amide;

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-cycl ohexyl-ethyl}-2- (isopropyl-methyl-amino)-propionamide;

(S)-N- { (S)- 1 -[(2- Amino-thiazol-5 -ylmethyl)-carbamoyl] -2-cyclohexyl-ethyl } -2- dimethylamino-propionamide; (S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-cycl ohexyl-ethyl}-2- diethylamino-propionamide;

(R)-l-Ethyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-cyclohexyl-ethyl} -amide;

(R)-l-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-cyclohexyl-ethyl}-amide;

(R)-l -Methyl-piperidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-cyclohexyl-ethyl}-amide;

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-cycl ohexyl-ethyl}-2- piperidin-l-yl-propionamide;

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-cycl ohexyl-ethyl}-2- piperidin- 1 -yl-propionamide;

3 -Methyl- 1 H-pyrrole-2-carboxylic acid {(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-naphthalen- 1 -yl -ethyl } -amide;

lH-Indole-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- naphthalen- 1 -yl-ethyl } -amide;

(S)-N-(2-Amino-thiazol-5-ylmethyl)-3-naphthalen-l-yl-2-(2-m- tolyl-acetylamino)- propionamide;

3,5-Dimethyl-lH-pyrrole-2-carboxylic acid [(S)-l -[(2-amino-thiazol-5-ylmethyl)- carbamoyl] -2-(3 ,4-difluoro-phenyl)-ethyl] -amide;

3-Methyl- 1 H-pyrrole-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;

lH-Indole-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4- difluoro-phenyl)-ethyl] -amide;

3 -Methyl- lH-pyrrole-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;

3-Methyl- 1 H-pyrrole-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;

3-Methyl- 1 H-pyrrole-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(2-fluoro-phenyl)-ethyl]-amide;

3-Methyl- 1 H-pyrrole-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide; 3-Methyl-lH-pyrrole-2-carboxylic acid [(S)-l- -amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;

3 -Methyl- 1 H-pyrroIe-2-carboxylic acid {(S)-l- -amino-thiazol-5-ylmethyl)- carbamoyl]-2-p-tolyl-ethyl } -amide;

3 -Methyl- 1 H-pyrrole-2-carboxylic {(S)-l- -amino-thiazol-5-ylmethyl)- carbamoyl]-2-m-tolyl-ethyl}-amide;

3 -Methyl- 1 H-pyrrole-2-carboxylic acid {(S)-l- -amino-thiazol-5-ylmethyl)- carbamoyl] -2-o-tolyl-ethyl } -amide;

3 -Methyl- 1 H-pyrrole-2-carboxylic acid {(S)-l- (2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-cyclohexyl-ethyl} -amide;

(R)-N- {(S)- 1 -[(2- Amino-thiazol-5-ylmethyl)-carbamoyl]-2-naphthalen- 1 -yl-ethyl } -2- hydroxy-3-phenyl-propionamide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -difluoro-phenyl)-ethyl]- 2-hydroxy-3-phenyl-propionamide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-( 4-fluoro-phenyl)-ethyl]-2- hydroxy-3-phenyl-propionamide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3-f luoro-phenyl)-ethyl]-2- hydroxy-3 -phenyl -propionamide ;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(2-f luoro-phenyl)-ethyl]-2- hydroxy-3-phenyl-propionamide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4-c hloro-phenyl)-ethyl]-2- hydroxy-3-phenyl-propionamide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3-c hloro-phenyl)-ethyl]-2- hydroxy-3 -phenyl-propionamide;

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-p -tolyl-ethyl}-2-hydroxy-3- pheny 1-propionamide ;

(R)-N- { (S)- 1 - [(2-Amino-thiazol-5 -ylmethyl)-carbamoyl]-2-m-tolyl -ethyl } -2-hydroxy-3 - phenyl-propionamide;

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-o-to lyl-ethyl}-2-hydroxy-3- phenyl-propionamide;

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-cycl ohexyl-ethyl}-2- hydroxy-3 -phenyl-propionamide; (R)-N- { (S)- 1 - [(2-Amino-thiazol-5 -ylmethyl)-carbamoyl] -2-naphthalen- 1 -yl-ethyl } -2- hydroxy-butyramide;

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-naph thalen-l-yl-ethyl}-2- hydroxy-3 -methyl-butyramide;

(S)-N-{(S)-1 -[(2- Amino-thiazol-5-ylmethyl)-carbamoyl]-2-naphthalen-l -yl-ethyl} -2- hydroxy-3-methyl-butyramide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -difluoro-phenyl)-ethyl]- 2-hydroxy-3-methyl-butyramide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -difluoro-phenyl)-ethyl]- 2-hydroxy-3-methyl-butyramide;

and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof.

In another aspect, the invention provides a compound of formula (I) selected from: (S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4-f luoro-phenyl)-ethyl]-2- (isopropyl-methyl-amino)-propionamide;

(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -difluoro-phenyl)-ethyl]- 2-(isopropyl-methyl-amino)-propionamide;

(R)- 1 -Ethyl-pyrrolidine-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoy 1] -2-(3 ,4-difluoro-pheny l)-ethyl ] -amide ;

(R)-l -Isopropyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl] -2-(3 ,4-difluoro-phenyl)-ethyl] -amide;

(R)- 1 -Methyl-piperidine-2-carboxylic acid [(S)- 1 - [(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;

(R)- 1 -Methyl-pyrrolidine-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-naph thalen-l-yl-ethyl}-2- (isopropyl-methyl-amino)-propionamide;

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl] -2-(4-chloro-phenyl)-ethyl] -amide; (S)-N-[(S)-1 (2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4-chloro-phenyl)- ethyl]-2- (isopropyl-methyl-amino)-propionamide;

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl] -2-(3 -chloro-phenyl)-ethy 1] -amide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-( 3-chloro-phenyl)-ethyl]-2- (isopropyl-methyl-amino)-propionamide;

(R)- 1 -Methyl-pyrrolidine-2-carboxylic acid [(S)- 1 -[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -dichloro-phenyl)-ethyl]- 2-(isopropyl-methyl-amino)-propionamide;

(S)-N- [(S)- 1 - [(2- Amino-thiazol-5 -ylmethyl)-carbamoyl]-2-(3 ,4-dichloro-phenyl)-ethyl] - 2-diethylamino-propionamide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -dichloro-phenyl)-ethyl]- 2-piperidin- 1 -yl-propionamide;

(S)-N-{(S)-1 -[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-p-tolyl-ethyl}-2 -(isopropyl- methyl-amino)-propionamide;

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-m-to lyl-ethyl}-2-(isopropyl- methyl-amino)-propionamide;

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-cycl ohexyl-ethyl}-2- (isopropyl-methyl-amino)-propionamide;

(R)-l-Methyl-piperidine-2-carboxylic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl] -2-cyclohexyl-ethyl } -amide;

and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof. The skilled person will appreciate that each of the compounds identified above, or identified in the Examples provided herein below, taken alone or with any combination of the other identified compounds represents an independent aspect of the invention.

Therapeutic Applications

As previously mentioned, 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. In particular, 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). 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.

Other 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. asthma, angina), RDS (respiratory distress syndrome); hypotension (e.g. shock due to haemorrhage, septicaemia or anaphylaxis, carcinoid syndrome, dumping syndrome); oedema (e.g. burns, brain trauma, angioneurotic oedema whether or not as a result or treatment with inhibitors of angiotensin converting enzyme); pain and irritation (e.g. burns, wounds, cuts, rashes, stings, insect bites), migraine; male contraceptive agents by virtue of inhibition of prostate kallikrein; prevention of excessive blood loss during surgical procedures.

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. cough).

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). 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.

Asthma

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 KLK1 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).

Allergic Rhinitis

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.

Chronic obstructive pulmonary disease (COPD Chronic obstructive pulmonary disease (COPD) is a disease involving inflammation of the airways. 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 L 1 inhibitor can be used to ameliorate at least one symptom of COPD. A KLK1 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

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 KL 1 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. Current treatment strategies for acute exacerbations of asthma rely heavily on bronchodilators and inhaled or systemic corticosteroids. 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

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).

Chronic pancreatitis - this condition often starts with bouts of acute pancreatitis, and eventually becomes a permanent condition. The pancreas becomes constantly inflamed. The KLKl inhibitor can be used to ameliorate or prevent at least one symptom of pancreatitis. Rheumatoid Arthritis CRA

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 KLKl 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 KLKl 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.

Angiogenesis-Associated and Neoplastic Disorders

In one embodiment, a KLK1 inhibitor may be administered to a subject to modulate angiogenesis or other processes associated with neoplasia and tumour growth.

For example 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).

In particular, 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 rumour.

Examples of 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 lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemagioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma and retinoblastoma.

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. 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. Examples of such other agents include:

(i) other antiangiogenic agents (e.g. linomide, angiostatin, razoxane);

(ii) 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).

(iii) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as antimetabolites (e.g. fluoropyrimidines like 5-fIuorouracil, 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. vinca alkaloids lsuch 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). Accordingly, 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 KLK1 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.

In one aspect, 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), and SIRS (systemic inflammatory response syndrome); smooth muscle spasm (e.g. asthma, angina), RDS (respiratory distress syndrome) , rhino-conjunctivitis, rhinorrhoea, urticaria, a neoplastic disorder, chronic bronchitis, chronic respiratory obstruction, pulmonary fibrosis and pulmonary emphysema. In another aspect, 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),

In yet another aspect, 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). In a further aspect, the disease or condition in which KLKl activity is implicated is a respiratory disorder selected from asthma (allergic and non-allergic) and cough.

In a yet further aspect, the disease or condition in which KLKl activity is implicated is exacerbations resulting from asthma and chronic obstructive pulmonary disease (COPD).

Combination Therapy

Current treatments for respiratory diseases can yield important benefits, however, the efficacy of some of these agents is often far from satisfactory, in particular in the treatment of COPD and exacerbations related to airways disease. Moreover, in view of the complexity of respiratory diseases such as asthma and COPD it is possible that any one mediator may not satisfactorily treat the disease alone and a combination of therapeutic agents may prove advantageous. In particular whilst the use of steroids may lead to therapeutic effects, it is desirable to be able to use steroids in low doses to minimise the occurrence and severity of undesirable side effects that may be associated with regular administration and combination with another agent such as a KLKl inhibitor may enable the dose of the steroid to be significantly reduced and therefore minimise potential side effects. Thus, other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung. Thus the present invention is also concerned with pharmaceutical 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. Such 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 buildup, chronic bronchitis, chronic respiratory obstruction, pulmonary fibrosis and pulmonary emphysema.

Accordingly, 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:

(i) Steroidal glucocorticoid agonists. Examples of a steroidal glucocorticoid agonist that may be used in this embodiment 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. as acetonide), flunisolide, zoticaasone, flumoxonide, roofleponide, butixocort, (e.g. as propionate ester), prednisolone, prednisone, tipredane, steroid esters e.g. 6a, 9a-difluoro-17a-[2-furanylcarbonyl)oxy]-l i p-hydroxy-16a-methyl- 3-oxo-androsta-l,4-diene-17 -carbothioic acid S-fluoromethyl ester, 6a, 9a- difluoro- 11 β-hydroxy- 16a-methyl-3-oxo- 17a-propionyloxy-androsta- 1 ,4- diene-17P-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl) ester and 6a, 9a-difluoro- 1 1 β-hydroxy- 16a-methyl- 17a -[(4-methyl- 1 ,3-thiazole-5- carbonyI)oxy]-3-oxo- androsta-l,4-diene-17 -carbothioic acid S- fluoromethyl ester, steroid esters according to DE 4129535, steroids according to WO 2002/00679, WO 2005/041980 or steroids GSK 870086, GSK 685698 and GSK 799943.

(ii) A non-steroidal glucocorticoid receptor agonist; (iii) A p2-adrenoreceptor agonist, for example albuterol (salbutamol), salmeterol, metaproterenol, terbutaline, fenoterol, procaterol, carmoterol, indacaterol, formoterol, arformoterol, picumeterol, GS -159797, GSK-597901, GSK- 159802, GSK-64244, GS -678007, TA-2005 and also compounds of EP 1440966, JP05025045, WO93/18007, WO99/64035, US2002/0055651 , US2005/0133417, US2005/5159448, WO00/075114, WO01/42193, WO01/83462, WO02/66422, WO02/70490, WO02/76933, WO03/24439, WO03/42160, WO03/42164, WO03/72539, WO03/91204, WO03/99764, WO04/16578, WO04/016601, WO04/22547, WO04/32921, WO04/33412, WO04/37768, WO04/37773, WO04/37807, WO0439762, WO04/39766, WO04/45618, WO04/46083, WO04/71388, O04/80964, EP1460064, WO04/087142, WO04/89892, EP01477167, US2004/0242622,

US2004/0229904, WO04/108675, WO04/108676, WO05/033121 , WO05/040103, WO05/044787, WO04/071388, WO05/058299,

WO05/058867, WO05/065650, WO05/066140, WO05/070908, WO05/092840, WO05/092841 WO05/092860, WO05/092887, WO05/092861, WO05/090288, WO05/092087, WO05/080324, WO05/080313, US20050182091, US20050171147, WO05/092870, WO05/077361 , DEI 0258695, WO05/1 1 1002, WO05/1 1 1005, WO05/110990, US2005/0272769, WO05/110359, WO05/121065, US2006/0019991, WO06/016245, WO06/014704, WO06/031556,

WO06/032627, US2006/0106075, US2006/0106213, WO06/051373, WO06/056471 ;

(iv) A leukotriene modulator, for example montelukast, zafirlukast or pranlukast; protease inhibitors, such as inhibitors of matrix metalloprotease for example MMP12 and TACE inhibitors such as marimastat, DPC-333, GW-3333;

(v) Human neutrophil elastase inhibitors, such as sivelestat and those described in WO04/043942, WO05/021509, WO05/021512, WO05/026123, WO05/026124, WO04/024700, WO04/024701 , WO04/020410, WO04/020412, WO05/080372, WO05/082863, WO05/082864, WO03/053930;

(vi) Phosphodiesterase-4 (PDE4) inhibitors, for example roflumilast, arofylline, cimomilast, Ibudilast, Lirimilast, Mesopram, ONO-6126 or lC-485; (vii) Phosphodiesterase-7 inhibitors;

(viii) Kinase inhibitors, particularly P38 MAPKinase inhibitors;

(ix) Muscarinic receptor antagonists;

(x) Modulators of chemokine receptor function, for example antagonists of CCR1 , CCR2, CCR3, CXCR2, CXCR3, CX3CR1 and CCR8, such as SB- 332235, SB-656933, SB- 265610, SB-225002, MC P- 1 (9-76), RS-504393, MLN-1202, INCB-3284; and

(xi) CRTH2 receptor agonists. Definitions

The term "alkyl" includes saturated hydrocarbon residues including:

- linear groups up to 10 atoms (Ci-Cio), or of up to 6 atoms (Ci-C ₆ ), or of up to 4 atoms (Ci-C ₄ ). Examples of such alkyl groups include, but are not limited, to d - methyl, C - ethyl, C ₃ - propyl and C ₄ - n-butyl.

- branched groups of between 3 and 10 atoms (C ₃ -Cio), or of up to 7 atoms (C ₃ -C ₇ ), or of up to 4 atoms (C ₃ -C ). Examples of such 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 C ₅ - neo-pentyl. each optionally substituted as stated above.

The term "alkenyl" includes monounsaturated hydrocarbon residues including:

- linear groups of between 2 and 6 atoms (C ₂ -C ). Examples of such alkenyl groups include, but are not limited to, C ₂ - vinyl, C ₃ - 1-propenyl, C ₃ - allyl, C ₄ - 2-butenyl

- branched groups of between 3 and 8 atoms (C ₃ -Cg). Examples of such alkenyl groups include, but are not limited to, C ₄ - 2-methyl-2-propenyl and C ₆ - 2,3-dimethyl-2- butenyl.

each optionally substituted as stated above.

The term "alkynyl" includes monounsaturated hydrocarbon residues having a carbon- carbon triple bond including:

- linear groups of between 2 and 6 atoms (C2-C ₆ ). Examples of such 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 -Cg). Examples of such alkynyl groups include, but are not limited to, C ₄ - 3 -methyl- 1-propynyl.

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

- linear groups of between 1 and 6 atoms (CpC ₆ ), or of between 1 and 4 atoms (Q- C ₄ ). Examples of such alkoxy groups include, but are not limited to, Ci - methoxy, C ₂ - ethoxy, C ₃ - n-propoxy and C ₄ - n-butoxy.

- branched groups of between 3 and 6 atoms (C ₃ -C ₆ ) or of between 3 and 4 atoms (C ₃ - C ₄ ). Examples of such alkoxy groups include, but are not limited to, C ₃ - iso- propoxy, and C ₄ - sec-butoxy and tert-butoxy.

each optionally substituted as stated above.

Unless otherwise stated, 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. Examples of 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). Examples of suitable bicyclic cycloalkyl groups include decahydronaphthalene, octahydro-lH-indene (optionally substituted as stated above). Examples of 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. Examples of suitable 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. Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, quinolinyl and isoquinolinyl (optionally substituted as stated above). The term "C-linked", such as in "C-Iinked heterocycloalkyl", means that the heterocycloalkyl group is joined to the remainder of the molecule via a ring carbon atom.

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 "O-linked hydrocarbon residue", means that the hydrocarbon residue is joined to the remainder of the molecule via an oxygen atom. In groups such as aryl(CrC ₄ )alkyI- and -S0 ₂ (Ci-C ₆ )alkyl, "-" denotes the point of attachment of the group to the remainder of the molecule.

"Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts. For example (i) where a compound of the invention contains one or more acidic groups, for example carboxy groups, pharmaceutically acceptable base addition salts that can be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, 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, 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.

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

"Prodrug" refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for forming 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. 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, diastereomenc and tautomeric forms, including but not limited to cis- and tram-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers can be prepared by the application or adaptation of known methods (e.g. asymmetric synthesis).

Typical configurations of the compounds of formula (I) include:

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

General Methods

The compounds of formula (I) should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication. 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.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention which may impart either a functional (i.e., drug release rate controlling) and/or a non-functional (i.e., processing aid or diluent) characteristic to the formulations. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of 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.

Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the said compounds by diffusion or a combination of diffusion and polymer erosion. Examples of rate-sustaining polymers include hydroxypropyl 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 formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980). The compounds of the invention may also be administered directly into the blood stream, into subcutaneous tissue, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous or oily solutions. Where the solution is aqueous, excipients such as sugars (including but restricted to glucose, manitol, sorbitol, etc.) salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

Parenteral formulations may include implants derived from degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, polycapro-lactone, polyhydroxybutyrate), polyorthoesters and polyanhydrides. These formulations may be administered via surgical incision into the subcutaneous tissue, muscular tissue or directly into specific organs.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of 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. For intranasal use, 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.

Prior to use in a dry powder or suspension formulation, the drug product 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.

Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of formula (I), may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus 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. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

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 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.

Synthetic methods

The compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the specific examples provided herein below. Moreover, by utilising the procedures described herein, one of ordinary skill in the art can readily prepare additional compounds that fall within the scope of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

The compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above.

It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to avoid their unwanted participation in a reaction leading to the formation of the compounds. Conventional protecting groups, for example those described by T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry" John Wiley and Sons, 4 ^th Edition, 2006, may be used. For example, a common amino protecting group suitable for use herein is tert-butoxy carbonyl (Boc), which is readily removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as dichloromethane. Alternatively the amino protecting group may be a benzyloxycarbonyl (Z) group which can be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere or 9-fluorenylmethyloxycarbonyl (Fmoc) group which can be removed by solutions of secondary organic amines such as diethylamine or piperidine in an organic 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.

In the following schemes: R'-R ¹³ , R ^a and R ^b are as previously defined for the compounds of formula (I);

PG|, PG ₂ or PG ₃ is a suitable protecting group;

R ³⁰ is H, (Ci-Cio)alkyl, halogen, hydroxyl or (C ₁ -C ₆ )alkoxy;

R ³¹ and R ³² are independently selected from H, (Ci-Cio)alkyl, (C ₂ -C ₆ )alkenyl, (C ₃ - C _]0 )cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C!-C4)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(C ₁ -C ₄ )alkyl.

The compounds according to general formula I can be prepared using conventional synthetic methods. In a typical first step, the aminomethylaminothiazole (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). The use of such groups is well known in the art. Where 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, diiso ropylethylamine or N-methylmorpholine.

The protecting group of (3) is removed using standard methods described previously to yield the amine 4).

3 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). Where R or R 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).

7

The amine (7) is further derivatised by reductive alkylation with a suitable aldehyde or ketone to yield the alkylated amine (8). Typically, 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.

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.

12

Alternatively 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, tnchloroethyl ester (16) by reaction with the required amine followed by the deprotection using standard methods. Typically, 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.

9

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). 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. The carboxyl protecting group of (17) is removed by standard methods described previously following the coupling reaction. The amide bond forming reactions may be carri

The amine (4) is coupled using the standard peptide coupling conditions described previously to a pyrrole derivative (19). Where R or R 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). Such 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.

20 22 The amine (4) is coupled using the standard peptide coupling conditions described previously to a lactic acid derivative (23). Where R ¹ or R ² has a reactive functional group such as an amine or a carbox lic acid, this group will also be protected.

23

Compound (24) can also be synthesised from compound (26). Such 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). Where R or R has a reactive functional group such as an amine or a carbox lic 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.

27

29

28 30

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 roup will also be protected.

32 31 Compound (32) can also be synthesised from compound (34). Such 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 pe tide coupling conditions described above.

31

33

The amine (4) can be derivatised by reaction with an amine (35) in the presence of a suitable agent such as 1 , 1 -carbonyldiimidazolejo give the urea derivative (36). 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.

NH

35

Compound (36) can also be synthesised from compound (38). Such 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.

37

36 38

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:

{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-naphtha len-l-yl-ethyl}-carbamic acid tert-butyl ester;

(S)-2-amino-N-(2-amino-thiazol-5-ylmethyl)-3-naphthalen- 1 -yl-propionamide; ((R)-l-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-nap hthalen-l-yl- ethylcarbamoyl}-2-methyl-butyl)-carbamic acid tert-butyl ester;

[(S)-l -[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4-difluoro-ph enyl)-ethyl]- carbamic acid tert-butyl ester;

(S)-2-Amino-N-(2-amino-thiazol-5-ylmethyl)-3 -(3 ,4-difluoro-phenyl)-propionamide; [(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4-fluoro- phenyl)-ethyl]-carbamic acid tert-butyl ester;

(S)-2-Amino-N-(2-amino-thiazol-5-ylrnethyl)-3-(4-fluoro-phen yl)-propionarnide;

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-( 4-fluoro-phenyl)-ethyl]-2- (isopropyl-methyl-amino)-propionamide;

[(S)-l-[(2-Amino-thiazol-5-ylrnethyl)-carbamoyl]-2-(3,4-dich loro-phenyl)-ethyl]- carbamic acid tert-butyl ester;

(S)-2-Amino-N-(2-amino-thiazol-5-ylrnethyl)-3-(3,4-dichloro- phenyl)-propionamide;

3 -Methyl- 1 H-pyrrole-2-carboxylic acid [(S)- 1 - [(2-amino-thiazol-5 -ylmethyl)- carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -dichloro-phenyl)-ethyl]-

2-hydroxy-3-phenyl-propionamide;

(S)-2-Amino-3-naphthalen-l-yl-propionic acid methyl ester;

(S)-3-Naphthalen-l-yl-2-(propane-l-sulfonylamino)-propionic acid methyl ester;

(S)-3-Naphthalen- 1 -yl-2-(propane- 1 -sulfonylamino)-propionic acid;

(S)-N-(2-Arnino-thiazol-5-ylmethyl)-3-naphthalen-l-yl-2-( ropane-l-sulfonylarnino)- propionamide;

(R)-2-tert-Butoxycarbonylamino-3,3-dicyclohexyl-propionic acid;

{(R)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2,2-dicyc lohexyl-ethyl}-carbamic acid tert-butyl ester;

(R)-2-Amino-N-(2-amino-thiazol-5-ylmethyl)-3,3-dicyclohexyl- propionamide;

(S)-l-Methyl-pyrrolidine-2-carboxylic acid {(R)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl] -2,2-dicyclohexyl-ethyl } -amide;

and pharmaceutically acceptable salts and solvates thereof.

In one aspect, the present invention provides a process for the preparation of a compound of formula (I),

with a compound of formula (VII):

under standard peptide coupling conditions; wherein R'-R ⁵ , R ¹⁷ and A ¹ are as previously defined for the compounds 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

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

DMF N,N-Dimethylformamide

EtOAc Ethyl Acetate

hrs Hours 2-( 1 H-Benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium

HBTU

hexafluorophosphate

HOBt Hydroxybenzotriazole

He Isoleucine

LCMS Liquid chromatography mass spectrometry

Me Methyl

MeCN Acetonitrile

MeOH Methanol

Min Minutes

MS Mass spectrum

Nal Napthylalanine

Nuclear magnetic resonance spectrum - NMR spectra were

NMR

recorded at a frequency of 400MHz unless otherwise indicated

Pet. Ether Petroleum ether fraction boiling at 60-80°C

Phe Phenylalanine

Pro Proline

THF Tetrahydrofuran

TFA Trifluoroacetic acid

All reactions were carried out under an atmosphere of nitrogen unless specified otherwise. 1H 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 11 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.

Chemical names were generated using the Autonom software provided as part of the ISIS draw package from MDL Information 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 elution. Reverse phase preparative HPLC purifications were carried out using a Waters 2525 binary gradient pumping system at flow rates of typically 20ml/min using a Waters 2996 photodiode array detector.

All solvents and commercial reagents were used as received. EXAMPLE 1

fR)-2-Amino-3-methyl-pentanoic acid !(S)-l-f(2-amino-thiazol-5-ylmethyl)- carbamovU-2-naphthalen-l-yl-ethv -amide

A. [5-(tert-Butoxycarbonylamino-methyl)-thiazol-2-yl|-carbamic acid tert-butyl ester

2-Aminothiazole-5-carbonitrile (5.0g, 39.95mmol) was dissolved in methanol (250ml). This solution was cooled to 0 C. Nickel (II) chloride hexahydrate (0.95g, 4.0mmol) and di-tertbutyl dicarbonate (17.44g, 80mmol) were added followed by sodium borohydride (10.6g, 280mmol) portionwise. The reaction mixture was stirred at O C to room temp for 18hrs. The MeOH was removed by evaporation. The residue was dissolved in EtOAc (200ml), washed with sat NaHC0 ₃ (lx50mls), water (lx50mls), brine (lx50mls), dried (Na ₂ S0 ₄ ) and filtered through PS paper and evaporated in vacuo to give a brown oil. The residue was purified by flash chromatography (silica), eluant 3% MeOH, 97% CHCI3 to give an orange oil identified as the title compound.

Yield = 4.30g, 13.05mmol, 33% B. 5-Aminomethyl-thiazol-2-ylamine dihydrochloride

[5-(tert-Butoxycarbonylamino-methyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (l .lg, 3.34mmol) was treated with 4M HCl/dioxan (lOOmls). After one hour at room temperature the solvent was removed to give a yellow solid identified as the title compound.

Yield = 630mg, 3.12mmol, 93%

[M+H]+ = 130.15

C. {(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-naphthaIen -l-yI-ethyl}- carbamic acid tert-butyl ester

5-Aminomethyl-thiazol-2-ylamine dihydrochloride (90mg, 0.45mmol) was dissolved in CH ₂ Cl ₂ (20mls) and DMF(2mls). This solution was cooled to 0 ^° C. Boc-lNal-OH

(154mg, 0.49mmol) was added followed by HOBt (120mg, 0.89mmol) and water soluble carbodiimide (102mg, 0.53mmol). After 15mins triethylamine (135mg,

1.34mmol) was added. After 18 hrs at 0 ^° C to room temperature the solvent was removed in vacuo and the residue taken up in EtOAc (70mls), this solution was 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 3%MeOH, 97% CHCI3, fractions combined and evaporated in vacuo to give a foamy white solid identified as the title compound.

Yield = 68mg, 0.16mmol, 36%

[M+H] ⁺ = 470.27

D. (S)-2-Amino-N-(2-amino-thiazol-5-yImethyl)-3-naphthalen-l-yl -propionamide ditrifluoroacetate

{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-naphthalen -l-yl-ethyl}-carbamic acid tert-butyl ester (68mg, 0.16mmol) was dissolved in TFA (20mls). After one hour at room temperature the solvent was removed in vacuo to give a yellow oil identified as the title compound.

Yield = 88mg, 0.16mmol, 100%

[M+H]+ = 327.07 Ή NMR (CD ₃ OD) 3.52-3.61(2H,m), 3.98(lH,d,J=15.5Hz), 4.12-4.28(2H,m), 4.92(4H,s), 6.85(lH,s), 7.37-7.39(2H,m), 7.51 -7.57(3 H,m), 7.81 -7.9 l(2H,m), 8.07 (lH,d,J=8.1Hz). E. ((R)-l-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-nap hthalen-l-yl- ethylcarbamoyl}-2-methyl-butyl)-carbamic acid tert-butyl ester

(S)-2-Amino-N-(2-amino-thiazol-5-ylmethyl)-3 -naphthalen- 1 -yl-propionamide ditrifluoroacetate (70mg, 0.13mmol) was dissolved in CH ₂ C1 ₂ (20mls) and DMF (2mls).

o

This solution was cooled to 0 C. Boc-DIle-OH (32mg, 0.14mmol) was added followed by HOBt (34mg, 0.25mmol) and water soluble carbodiimide (29mg, 0.15mmol). After 15mins triethylamine (38mg, 0.38mmol) was added. After 18 hrs at 0 C to room temperature the solvent was removed in vacuo and the residue taken up in EtOAc (70mls), this solution was washed with NaHC0 ₃ (lx20mls), water (lx20mls), brine (lx20mls), dried (Na ₂ S0 ₄ ) and evaporated in vacuo giving a yellow oil. The residue was purified by flash chromatography (silica), eluent 3%MeOH, 97% CHC1 ₃ , fractions combined and evaporated in vacuo to give a colourless oil identified as the title compound.

Yield = 26mg, 0.048mmol, 38%

[M+H] ⁺ = 540.36

F. (R)-2-Amino-3-methyl-pentanoic acid {(S)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2-naphthalen-l-yl-ethyl}-amide difluoroacetate

((R)- 1 - {(S)- 1 -[(2 -Amino-thiazol-5-ylmethyl)-carbamoyl]-2 -naphthalen- 1 -yl- ethylcarbamoyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (26mg, 0.048mmol) was dissolved in TFA (20mls). After one hour at room temperature the solvent was removed in vacuo to give an orange oil. The residue was purified by Prep HPLC (Sunfire prep C18 OBD column. 19x250mm, 10μ). 10 to 90% 0.1% TFA/MeCN into 0.1%TFA/H ₂ O over 35 min at 20ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.

Yield = 6mg, 0.009mmol, 19%

[M+H] ⁺ = 440.24

1H NMR: (CD ₃ OD) 0.70-0.76 (6H,m) 1.15-1.30 (1H, m) 1.60-1.80 (1H, m) 3.29-3.32 (1H, m) 3.63-3.69 (2H, m) 4.25 (1H, d,J=33Hz) 4.86(lH,d,J=9.1Hz), 4.93-4.95 (8H, m) 6.95 (1H, s) 7.36-7.38 (2H, m) 7.50-7.56 (2H, m) 7.70-7.80 (1H, m) 7.87 (1H, d, J = 8.2 Hz) 8.17 (1H, d, J = 8.4 Hz)

EXAMPLE 2

(Rn-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-thiazol-5-ylmethyI)- carbamoyll^-O^-difluoro-phenvn-ethyll-amide

A. (R)-l- ethyl-pyrrolidine-2-carboxyIic acid ( -Me-DPro-OH)

H-DPro-OH (lO.Og, 86.9mmol) was dissolved in methanol (200mls), formaldehyde (37% by weight solution, 7mls) was added followed by 10% Pd/C (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 (i OOmls). 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 Yield = 10.72g, 83mmol, 96%

[M+H]+ = 130.17 B. [(S)-l-[(2-Amino-thiazol-5-yImethyl)-carbamoyl]-2-(3,4-diflu oro-phenyl)-ethyi]- carbamic acid tert-butyl ester

Boc-(3,4-difluoro)Phe-OH (270mg, 0.90mmol) was dissolved in CH ₂ C1 ₂ (IOOmls) and

DMF (lOmls), this solution was cooled to 0 C. 5-Aminomethyl-thiazol-2-ylamine dihydrochloride (199mg, 0.99mmol) was added followed by HOBt (145mg, 1.08mmol) and dissopropylethylamine (347mg, 2.69mmol). Water soluble carbodiimide (189mg, 0.99mmol) was then added. After 5 hours at 0 C to room temperature the solid had dissolved, the reaction mixture was diluted with CHC1 ₃ (150mls), this solution was washed with sat. NaHC0 ₃ (l 50mls), water (lx50mls), brine (l 50mls), dried (Na ₂ S0 ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3%MeOH, 97% CHC1 ₃ , fractions combined and evaporated in vacuo to give a white solid identified as the title compound.

Yield = 82mg, 0.20mmol, 73%

[M+H] ⁺ = 413.49

C. (S)-2-Amino-N-(2-amino-thiazol-5-yImethyl)-3-(3,4-difluoro-p henyl)- propionamide dihydrochloride

[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4-diflu oro-phenyl)-ethyl]- carbamic acid tert-butyl ester (80mg, 0.19mmol) was treated with 4M HCl/dioxin (50mls). After 1 hour at room temperature the solvent was removed in vacuo to give a white solid identified as the title compound.

Yield = 75mg, 0.19mmol, 100%

[M+H]+ = 313.37

D. (R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-[(2-amino-th.azol-5-ylmethyl)- carbamoyll-2-(3,4-difluoro-phenyl)-ethyl]-amide ditrifluoroacetate

(S)-2-Amino-N-(2-amino-thiazol-5-ylmethyl)-3-(3,4-difluoro-p henyl)-propionamide dihydrochloride (79mg, 0.21mmol) was dissolved in CH ₂ Cl ₂ (20mls) and DMF(2mls). This solution was cooled to 0 C. NMe-DPro-OH (29mg, 0.23mmol) was added followed by HOBt (33mg, 0.25mmol) and triethylamine (62mg, 0.62mmol). Water soluble carbodiimide(43mg, 0.22mmol) was then added. After 18 hrs at 0 ^° C to room temperature reaction mixture was diluted with chloroform (lOOmls) and washed with NaHC0 ₃ (lx20mls), water (lx20mls), brine (lx70mls), dried (Na ₂ S0 ₄ ) and evaporated in vacuo giving a yellow oil. The residue was purified by Prep HPLC (Sunfire prep CI 8 OBD column. 19x250mm, 10μ). 10 to 90% 0.1% TFA/MeCN into 0.1%TFA/H ₂ O over 35 min at 20ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.

Yield = 46mg, 0.19mmol, 34%

[M+H] ⁺ = 424.48

1H NMR: (CD ₃ OD) 1.77-1.79 (lH,m), 1.92-1.97 (lH,m), 2.17-2.28 (2H,m), 2.47-2.56 (lH,m), 2.95 (3H,s), 3.06 (lH,s), 3.14-3.28 (2H,m), 3.68-3.83 (lH,m), 4.10-4.15 (lH,m), 4.30-4.46 (2H,m), 4.63-4.75 (lH,m), 4.91 (3H, s ), 7.06-7.25 (3H,m), 8.82-8.90 (lH,m)

EXAMPLE 3

(S)-N-KSVl-K2-Amino-thiazol-5-ylmethylVcarbamoyll-2-(4-fl uoro-phenyl)-ethyll- 2-(isopropyl-methyl-amino)-propionamide

A. (S)-2-(IsopropyI-methyI-amino)-propionic acid

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

Yield = 2.48g, 17.1mmol, 88%

[M+H]+ = 146.36

B. [(S)-l-[(2-Amino-thiazol-5-ylmethyI)-carbamoyl]-2-(4-fluoro- phenyl)-ethyl]- carbamic acid tert-butyl ester

Boc-4-fluoro-Phe-OH (2.0g, 7.06mmol) was dissolved in CH ₂ C1 ₂ (lOOmls). To this solution was added HBTU (2.95g, 7.77mmol) and triethylamine (2.14g, 21.18mmol). After 20mins 2-amino-5-thiazolemethylamine hydrochloride (1.29g, 7.77mmol) was added. After a further 20 mins 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 S0 ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 7% CHC1 ₃ , fractions combined and evaporated in vacuo to give a white solid identified as the title compound. Yield = 1.575g, 3.99mmol, 57%

[M+H] ⁺ = 413.1 1

C. (S)-2-Amino-N-(2-amino-thiazol-5-ylmethyl)-3-(4-fluoro-pheny l)-propionamide dihydrochloride

[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4-fluoro- phenyl)-ethyl]-carbamic acid tert-butyl ester (1.575g, 3.99mmol) was treated with 4M HC1 in dioxan (lOOmls). After 1 hour at room temperature the solvent was removed in vacuo giving a white solid identified as the title compound.

Yield = 1.03g, 2.67mmol, 100%

[M+H]+ = 313.13 D. (S)-N-[(S)-l-[(2-Amino-thiazoI-5-yImethyl)-carbamoyI]-2-(4-f luoro-phenyl)- ethyl]-2-(isopropyl-methyl-amino)-propionaniide ditrifluooacetate

(S)-2-(Isopropyl-methyl-amino)-propionic acid (50mg, 0.34mmol) was dissolved in CH ₂ Cl ₂ (30mls) HBTU (144mg, 0.38mmol) and triethylamine (105mg, 1.03mmol) were added. After 20 mins at room temperature (S)-2-Amino-N-(2-amino-thiazol-5-ylmethyl)- 3-(4-fluoro-phenyl)-propionamide dihydrochloride (139mg, 0.38mmol) was added. After 20mins at room temperature the reaction mixture was diluted with CHC1 ₃ (50mls), this solution was washed with sat NaHC0 ₃ (lx30mls), water (lx30mls), brine (lx30mls), dried (Na ₂ S0 ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 7%MeOH, 93% CHC1 ₃ , fractions combined and evaporated in vacuo to give a white solid. The residue was further purified by Prep HPLC (Sunfire prep C 18 OBD column. 19x250mm, 10μ). 10 to 90% 0.1% TFA MeCN into 0.1%TFA/H2O over 35 min at 20ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.

Yield = 31mg, 0.047mmol, 14%

[M+H] ⁺ = 422.12

1H NMR: (CD ₃ OD) 1.12(3H,d,J= 5.44Hz), 1.26(6H,d,J= 6.53Hz), 1.32-1.39(lH,m), 1.55(3H,d,J= 6.52Hz), 2.52 (lH,s, br), 2.68(3H,s), 2.83 (lH,s, br), 2.91-2.99(lH,m), 3.18-3.23(1H, m), 3.95(1H, q, J= 6.85Hz), 4.31-4.44(2H,m), 7.05-7.13(3H,m), 7.31-7.35 (2H, m).

EXAMPLE 4

3-Methyl-lH-pyrrole-2-carboxylic acid f(S)-l-f(2-amino-thiazol-5-ylmethyl)- carbamoyll-2-(3,4-dichloro-phenyl)-ethyll-amide

A. [(S)-l-[(2-Amino-thiazoI-5-yImethyl)-carbamoyl]-2-(3,4-dichl oro-phenyI)-ethyl]- carbamic acid tert-butyl ester

Boc-3,4-dichloro-Phe-OH (l .Og, 2.99mmol) was dissolved in CH ₂ Ci ₂ (30mls). To this solution was added HBTU (1.13g, 2.99mmol) and triethylamine (1.26g, 8.98mmol). After 20mins 2-amino-5-thiazolemethylamine hydrochloride (545mg, 3.29mmol) was added. After 2 hrs at room temperature the reaction mixture was diluted with CHC1 ₃ (50mls), this solution was washed with sat. NaHC0 ₃ (lx30mls), water (lx30mls), brine (lx30mls), dried (Na ₂ S0 ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 6% MeOH, 94% CH ₂ C1 ₂ , fractions combined and evaporated in vacuo to give a white solid identified as the title compound.

Yield = 1.05g, 2.36mmol, 79%

[M+H] ⁺ = 445.06

B. (S)-2-Amino-N-(2-amino-thiazoI-5-yImethyl)-3-(3,4-dichloro-p henyl)- propionamide dihydrochloride

[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4-di chloro-phenyl)-ethyl]- carbamic acid tert-butyl ester (1.05g, 2.36mmol) was treated with 4M HCl in dioxan (20mls). After 1 hour at room temperature the solvent was removed in vacuo giving a pale brown solid identified as the title compound.

Yield = 980mg, 2.34mmol, 99%

[M+H]+ = 344.96

C. 3-Methyl-lH-pyrroIe-2-carboxyIic acid [(S)-l-[(2-amino-thiazoI-5-ylmethyl)- carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide

3-Methyl-lH-pyrrole-2-carboxylic acid (25mg, 0.20mmol) was dissolved in CH ₂ Cl ₂ (30mls) HBTU (76mg, 0.20mmol) and triethylamine (84mg, 603mmol) were added. After 1 hour at room temperature (S)-2-amino-N-(2-amino-thiazol-5-yImethyl)-3- (3,4-dichloro-phenyl)-propionamide dihydrochloride (92mg, 0.22mmol) was added. After 20mins at room temperature the reaction mixture was diluted with CHCI3 (50mls), this solution was washed with sat NaHC0 ₃ (lx30mls), water (lx30mls), brine (lx30mls), dried (Na ₂ S0 ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 8%MeOH, 92% CH ₂ C1 ₂ , fractions combined and evaporated in vacuo to give an off white solid identified as the title compound- Yield = 36mg, 0.08mmol, 40%

[M+H] ⁺ = 452.02 and 454.01

Ή NMR (d ⁶ -DMSO) 2.17(3H,s), 2.84-2.90(lH,m), 3.00-3.05(lH,m), 4.18-4.28(2H,m), 4.62-4.68(1 H,m), 5.91(lH,t,J= 2.3Hz), 6.76-6.78(4H,m), 7.23(lH,dd,J= 8.3,2.0Hz), 7.40(lH,d,J= 8.4Hz), 7.47-7.5 l(lH,m), 7.53(lH,d,J= 1.9Hz), 8.57(lH,t,J= 5.7Hz).

EXAMPLE 5

(R)-N-KS)-l-fr2-Amino-thiazol-5-ylmethvn-carbamoyl1-2-(3 _< 4-dichioro-phenvn- ethyll-2-hvdroxy-3-phenyl-propionamide

A. (R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4 -dichloro-phenyl)- ethyl]-2-hydroxy-3-phenyl-propionamide trifluoroacetate

(S)-2-Amino-N-(2-amino-thiazol-5-ylmethyl)-3-(3,4-dichlor o-phenyl)-propionamide dihydrochloride (lOlmg, 0.24mmol) was dissolved in CH2CI2 (lOmls). This solution was cooled to 0 C. D-3-Phenyllactic acid (40mg, 0.24mmol) was added followed by HOBt (39mg, 0.29mmol) and water soluble carbodiimide (65mg, 0.34mmol). After 15mins triethylamine (135mg, 0.96mmol) was added. After 18 hrs 0 ^° C to room temperature the reaction mixture was diluted with CHCI3 (50mls), this solution was washed with sat. 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 8%MeOH, 92% CH ₂ Cl ₂ .The residue was further purified by Prep HPLC (Sunfire prep CI 8 OBD column. 19x250mm, 10μ). 10 to 90% 0.1% TFA/MeCN into 0.1%TFA/H ₂ O over 35 min at 20ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.

Yield = lOmg, 0.02mmol, 7%

[M+H] ⁺ = 493.04 and 495.04

Ή NMR (CD ₃ OD) 2.83-2.90 (lH,m), 2.95-3.00 (lH,m), 3.05-3.11 (2H,m), 4.22-4.36 (3H,m), 4.56-4.62 (lH,m), 7.12 (lH,s), 7.17 (lH,dd,J= 8.2,2.0Hz), 7.20-7.31 (5H,m), 7.39 (lH,dJ= 2.0Hz), 7.44 (lH,d,J= 8.2Hz), 8.00 (lH,dJ= 8.0Hz), 8.56 (lH,t,J= 5.7Hz)

EXAMPLE 6

(S)-N-(2-Amino-thiazol-5-ylmethyl)-3-naphthalen-l-yl-2-(prop ane-l- sulfonylamino)-propionamide

A. (S)-2-Amino-3-naphthalen-l-yl-propioriic acid methyl ester hydrochloride

H-lNal-OH (5.0g, 23.2mmol) was dissolved in methanol(200mls). This solution was cooled to 0°C, thionyl chloride (5.9mls, 81mmol) was slowly added. After 3 hours 0°C to room temperature the solvent was removed in vacuo. The residue was recrystallised from MeOH/diethyl ether to give a white solid identified as the title compound.

Yield = 6.10g, 22.96mmol, 99%

[M+H] ⁺ = 230.10

B. (S)-3-Naphthalen-l-yI-2-(propane-l-suifonylamino)-propionic acid methyl ester

(S)-2-Amino-3-naphthalen-l -yl-propionic acid methyl ester hydrochloride (2.0g, 7.535mmol) was dissolved in dichloromethane (lOOmls). 1-propanesulphonyl chloride (1.29g, 9.03mmol) was added followed by triethylamine (1.68g, 16.6mmol). The reaction mixture was stirred at room temperature for 5 hours and diluted with CHCI ₃ (150mls), this solution was washed with 0.3M KHS0 ₄ (lx50mls), sat. NaHC0 ₃ (lx50mls), water (lx50mls), brine (lx50mls), dried (Na ₂ S0 ₄ ) and filtered through PS paper and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 2%MeOH, 98% CHC1 ₃ , fractions combined and evaporated in vacuo to give a white solid identified as the title compound.

Yield = 2.162g, 6.45mmol, 86%

[M+H] ⁺ = 336.13

C. (S)-3-Naphthalen-l-yl-2-(propane-l-sulfonylamino)-propionic acid (S)-3-Naphthalen-l-yl-2-(propane-l-sulfonylamino)-propionic acid methyl ester (2.16g, 6.64mmol) was dissolved in THF (lOOmls) and water (lOmls). Lithium hydroxide monohydrate (297mg, 7.1mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (150mls). This solution was washed with 1M hydrochloric acid (lx50mls), water (lx50mls), brine (lx50mls), dried (Na ₂ S04) and evaporated in vacuo to give a white solid identified as the title compound.

Yield = 1.85g, 5.76mmol, 89%

[M+H] ⁺ = 321.91

D. (S)-N-(2-Amino-thiazol-5-ylmethyl)-3-naphthalen-l-yI-2-(prop ane-l- sulfonylamino)-propionamide trifluoroacetate

(S)-3-Naphthalen-l-yl-2-(propane-l-sulfonylamino)-propionic acid (218mg, 0.68mmol) was dissolved in CH ₂ Cl ₂ (30mls), HBTU (283mg, 0.75mmol) and triethylamine (206mg, 2.03mmol) were added. After 20 mins at room temperature 2-amino-5- thiazolemethylamine hydrochloride (124mg, 0.75mmol) was added. After 20mins at room temperature the reaction mixture was diluted with CHC1 ₃ (50mls), this solution was washed with sat NaHC0 ₃ (lx30mls), water (lx30mls), brine (lx30mls), dried (Na ₂ S0 ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3%MeOH, 97% CHCI3, fractions combined and evaporated in vacuo to give a white solid. The residue was further purified by Prep HPLC (Sunfire prep CI 8 OBD column. 19x250mm, 10μ). 10 to 90% 0.1% TFA/MeCN into 0.1%TFA/H ₂ O over 35 min at 20ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.

Yield = 491mg, 0.09mmol, 13%

[M+H] ⁺ = 433.00

Ή NMR: (CD ₃ OD), 0.69 (3H,t,J=7.4Hz), 1.23-1.30 (lH,m), 1.32-1.44 (lH,m), 2.32- 2.41 (2H,m), 3.14-3.26 (lH,m), 3.64-3.69 (lH,m), 4.19-4.32 (3H,m), 4.90 (3H,s), 6.99 (lH,s), 7.38-7.43 (2H,m), 7.51-7.62 (2H,m), 7.81-7.83 (lH,m), 7.90-7.91 (lH,d, J=7.72Hz), 8.18 (lH,d,J=8.49Hz), 8.58-8.62(1 H,m)

EXAMPLE 7 (S)-l-Methyl-pyrroIidine-2-carboxylic acid ((RH-[(2-amino-thiazol-5-ylmethvO- carbamoyl]-2.2-dicvclohexyl-ethvI)-amide

A. (R)-2-tert-Butoxycarbonylamino-3,3-dicyclohexyl-propionic acid

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.

After this time the catalyst was filtered off through celite and the residue washed with eOH (lOOmls). The combined filtrates were evaporated in vacuo to give a foamy white solid identified as the title compound,

Yield = 4.95g, 14mmol, 100%

(M+H]+ = 354.28

B. {(R)-l-[(2-Amino-thiazol-5-ylmethyl)-carbamoyI]-2,2-dicycloh exyl-ethyl}- carbamic acid tert-butyl ester

(R)-2-tert-Butoxycarbonylamino-3,3-dicyclohexyl-propionic acid (l .Og, 2.83mmol) was dissolved in CH ₂ Cl ₂ (100mls). Triethylamine (859mg, 8.490mmol) and HBTU (1.18g, 3.114mmol) was added followed by 2-amino-5-thiazolemethylamine hydrochloride ( 15mg, 3.1 lmmol). After 20 mins at room temperature the reaction mixture was diluted with CHCI3 (150mls), this solution was washed with sat. NaHC03 (lx20mls), water (lx50mls), brine (lx50mls), dried (Na ₂ S0 ) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% methanol, 970% CHCI3, fractions combined and evaporated in vacuo to give a colourless oil identified as the title compound.

Yield = 700mg, 1.51mmol, 53%

[M+H] ⁺ = 465.08

C. (R)-2-Amino-N-(2-amino-thiazol-5-yImethyl)-3,3-dicyclohexyl- propionamide ditrifluoroacetate

{(R)- 1 -[(2-Amino-thiazol-5-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-e thyl} -carbamic acid tert-butyl ester (700mg, 1.51mmol) was treated with trifluoroacetic acid (50mls). After one hour at room temperature the solvent was removed to give a colourless oil identified as the title compound.

Yield = 890mg, 1.5mmol, 100%

[M+H]+ = 365.21

^! H NMR: (CD ₃ OD), 1.09-1.40 (10H,m), 1.52-1.91 (12H,m), 4.07 (lH,d,J=4.28Hz), 4.29-4.36 (lH,m), 4.54-4.61 (lH,m), 4.91 (6H,s), 7.21 (lH,s).

D. (S)-l-Methyl-pyrrolidine-2-carboxylic acid {(R)-l-[(2-amino-thiazol-5-ylmethyl)- carbamoyl]-2,2-dicycIohexyl-ethyl}-amide ditrifluoroacetate

N-Me-Pro-OH (60mg, 0.46mmol) was dissolved in CH ₂ C1 ₂ (30mls). Triethylamine (Hlrng, 1.392mmol) and HBTU (194mg, 0.51mmol) was added followed by (R)-2- amino-N-(2-amino-thiazol-5 -ylmethyl)-3 ,3 -dicyclohexyl-propionamide

ditrifluoroacetate (303mg, 0.51mmol). After 20mins at room temperature the reaction mixture was diluted with CHC1 ₃ (50mls), this solution was washed with sat. 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 7% methanol, 93% CHC1 ₃ , fractions combined and evaporated in vacuo. The residue was further purified by Prep HPLC (19x250 mm Sunfire C-18 Column) 10 to 90% 0.1% TFA/MeCN into 0.1%TFA/H ₂ O over 35 min at 20ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.

Yield = 32mg, 0.045mmol, 10%

[M+H] ⁺ = 476.27 Ή NMR: (CD ₃ OD) 1.04-1.38(12H, m), 1.50-1.82(1 lH,m), 2.05-2.15(2H, m), 2.25- 2.31(lH,m), 2.62-2.68(1 H,m), 2.98(3H,s), 3.25-3.32(l H, m), 3.76-3.81(lH, m), 4.20- 4.24(lH,m), 4.29-4.34(1 H,m), 4.44-4.49(1 H,m), 4.70(1H, d, J = 7.48 Hz), 4.91 (4H,s), 7.17(lH,s).

TABLE 1

Compounds were synthesised as described for Examples 1 to 7

TABLE 2

Compounds were synthesised as described for Examples 1 to 3

TABLE 3

Compounds were synthesised as described for Example 5

TABLE 4

1H NMR data for examples

Example Chemical Shifts

Solvent

No

1.70-1.78 (1 H,m), 1.88-1.93 (1H,m), 1.99- 2.09 (2H,m), 2.32-2.41 (1 H,m), 2.92-2.98 (2H,m), 3.20(1 H, dd, J=6.24, 13.88Hz),

CD ₃ OD

3.28-3.33 (2H,m), 4.27^.32 (2H,m), 4.72(1 H, dd, J=6.29, 9.25Hz), 4.91 (3H, s ), 5.55(1 H,s), 7.07-7.11 (1 H,m), 7.13(1 H,s), 7.17-7.26 (2H,m).

0.86-0.89(6H,m), 0.94-0.99(1 H,m), 1.24- 1.31 (1H,m), 1.76-1.81 (lH,m), 2.93(1H, dd, J=10.28, 14.08Hz ), 3.22(1 H, dd, J=5.48, 14.0Hz), 3.75 (1H,d, J=5.28Hz),

9 CD ₃ OD

4.38(2H, dd, J=15.49, 43.57Hz), 4.73(1 H, dd, J=5.57, 10.21Hz), 4.91 (5H, s ), 5.54(1H,s), 7.11(1H,s), 7.12-7.13 (1H,m), 7.21-7.27 (2H,m).

0.87 (3H,d, J = 6.92Hz), 0.90 (3H,d, J = 4.0Hz), 1.34-1.37 (1H,m), 1.816-1.85 (1H,m), 2.68(3H,s), 2.95(1H, dd, J=10.33, 14.05Hz ), 3.18(1H, dd, J=5.72, 14.09Hz),

10 CD3OD

3.68 (1H,d, J=4.96Hz), 4.32-4.45(2H, m), 4.71(1H, dd, J=5.68, 10.16Hz), 4.91 (6H, s ), 7.11(1H,s), 7.12-7.13 (1H,m), 7.21-7.27 (2H,m).

0.88-0.95 (6H,m), 1.17 (3H,d, J=7.00Hz), 1.36-1.52 (4H, m), 2.35-2.43 (4H,m), 2.93- 2.99(1H, m), 3.07-3.15 (1H,m), 4.28-4.32

11 CD ₃ OD

(1H,m), 4.39^.43 (1H,m), 4.601-4.64 (1H,m), 4.91 (5H, s ), 6.84 (1H,s), 6.99-7.03 (1H,m), 7.11-7.21(2H,m).

1.00- 1.07 (6H,m), 1.22-1.32 (4H,m), 2.20 (3H,s), 2.84-2.91 (3H,m), 3.05-3.10 (1H,m), 3.31(1H,s,br), 4.31 (2H, q, J=15.41Hz),

12 CD3OD

4.60 (1H, q, J=6.12Hz), 4.90 (2H,s), 6.79(1H,s), 6.99-7.11 (1H,m), 7.12-7.17 (2H,m).

1.01- 1.08 (6H,m), 1.17 (4H,q, J=5.65Hz), 2.45-2.51 (4H,m), 2.54-2.59(1 H, m), 2.93- 2.99(1 H, m), 3.07-3.16 (1H,m), 4.30-4.43

13 CD3OD

(2H,m), 4.61-4.66 (1H,m), 4.91 (4H, s ), 6.85 (1H,s), 7.00-7.03 (1H,m), 7.14- 7.21 (1H,m).

1.59(3H, d, J=7.0Hz ), 2.83 (6H,s, br), 2.96- 3.02(1H, m), 3.13-3.18(1H, m), 3.91 (1H,q,

14 CD3OD J=6.92Hz), 4.348(2H, dd, J=15.0, 50.1Hz),

4.69(1 H, dd, J=7.0, 8.56Hz), 4.91 (3H, s ), 5.54(1H,s), 7.09(1H,s), 7.10-7.11 (1H,m), 7.18-7.25 (2H,m).

1.44(3H, d, J=6.96Hz ), 2.90 (6H,s), 2.98- 3.03(1 H, m), 3.12-3.17(1 H, m), 3.88 (1 H,q, J=6.89Hz), 4.35(2H, dd, J=15.05, 48.14Hz),

15 CD ₃ OD

4.66(1H, dd, J=6.84, 8.76Hz), 4.91 (3H, s ), 7.09(1H,s), 7.07-7.10 (2H,m), 7.18-7.25 (2H,m).

2.05-2.09 (2H,m), 2.21-2.27 (1H,m), 2.56- 2.65 (1 H,m), 2.86 (3H,s), 2.99-3.16 (2H,m), 3.22-3.25 (1H,m), 3.71-3.76 (1H,m), 4.06-

16 CD ₃ OD 4.10 (1 H,m), 4.24-4.30 (1 H,m), 4.34-4.44

(1H,m), 4.65-4.73 (1H,m), 4.91 (4H, s ), 7.06 (1 H,s), 7.08-7.12 (1 H,m), 7.18-7.25 (2H,m)

1.18- 1.34 (3H,m), 1.75-1.82 (1H,m), 1.90- 2.08 (3H,m), 2.13-2.22 (1 H,m), 2.43-2.51 (2H,m), 2.94-3.03(1 H, m), 3.11-3.31(41-1,

17 CD ₃ OD m), 3.71-3.76 (1 H,m), 4.10^.18 (1H,m),

4.28-4.42 (2H,m), 4.69^.73(1 H, m), 4.92 (1H, s ), 7.07-7.13 (2H,m), 7.21-7.25 (2H,m), 8.82-8.89(1H,m).

1.19- 1.39 (6H,m), 1.79-1.90 (2H,m), 2.09- 2.18 (2H,m), 2.41-2.51 (1 H,m), 2.95-3.02 (1H,m), 3.14-3.20(1 H, m), 3.26-3.33(1 H,

18 CD ₃ OD

m), 3.57-3.69 (2H,m), 4.18-4.42 (3H,m), 4.68-4.74(11-1, m), 4.92 (2H, s ), 7.07-7.12 (2H,m), 7.18-7.26 (2H,m), 8.84-8.86(1 H,m). 1.33 (3H,d, J = 6.76Hz), 1.40 (3H,d, J = 6.68Hz), 1.57-1.63 (1H,nn), 1.75-2.05 (5H,m), 2.95-3.00 (4H,m), 3.11-3.16 (1 H,m), 3.41-3.47(1 H, m), 3.62 (1 H, q,

19 CD ₃ OD

6.68Hz), 3.92 (1H,dd, J= 2.68, 11.76Hz), 4.35 (2H,dd, J= 6.71 , 8.65Hz), 4.63 (1H,dd, J= 2.68, 11.76Hz), 4.91 (2H, s ), 7.07 (2H,S), 7.19-7.23 (2H,m).

1.58-1.63 (2H,m), 1.77-1.80 (1H,m), 1.95- 1.99 (4H,m), 2.84(3H,s), 2.97-3.00 (1 H,m),

20 CD ₃ OD 3.12-3.17 (2H,m), 3.52(1H, d, J=12.44Hz),

3.73(1 H, d, J=8.69Hz), 4.35 (2H,dd, J= 15.73, 46.78Hz), 4.66 (1 H,dd, J= 6.84, 8.68Hz), 4.91 (3H, s ), 7.06-7.09 (2H,m), 7.17-7.25 (2H,m).

1.60-1.64 (1 H,m), 1.65-1.81 (3H,m), 1.96-

2.05 (2H,m), 2.09-2.24 (1 H,m), 2.65(3H,s), 2.97-3.02 (1 H,m), 3.07-3.17 (2H,m), 3.40-

21 CD ₃ OD 3.53(1 H, m), 3.69-3.72 (1 H, m), 4.34

(2H,dd, J= 15.6, 44.73Hz), 4.70 (1 H,dd, J= 6.07, 8.64Hz), 4.91 (3H, s ), 7.11 (2H,s), 7.19-7.25 (2H,m).

2.54-2.60 (1 H,m), 2.75-2.80 (1 H,m), 3.05 (6H,s), 3.07-3.09 (1H,m), 3.39-3.42(1H,m),

4.06 (1 H, q, J=4.68Hz), 4.24-4.37 (3H, m),

22 CD ₃ OD

4.92(4H,s), 6.77-6.80 (1 H, m), 6.87-6.93 (1 H,m), 7.07-7.12 (2H, m), 7.19-7.22 (2H, m), 7.28-7.33 (3H, m).

2.86 (6H,s), 2.88-2.92 (1 H,m), 3.00- 3.03(1 H,m), 3.09-3.15(1H,m), 4.04- 4.08(2H, m), 4.13 (1H,d, J=15.61Hz), 4.25

23 CD ₃ OD

(1 H,d, J=15.69Hz), 4.58-4.62 (1 H, m), 4.92(4H,S), 7.02-7.05 (1 H, m), 7.11 (1H,s), 7.13-7.15 (2H, m), 7.30-7.36 (5H, m).

1.41 (3H,d, J= 6.89Hz ), 1.69-1.89 (6H,m), 2.79-2.85(4H,m), 2.99-3.04 (2H,m), 3.52-

24 CD ₃ OD 3.55 (1 H, m), 3.68-3.77 (1 H,m), 4.20 (2H,q,

J=15.48Hz), 4.58 (1H,t, J=2.92Hz), 4.76 (3H,s), 6.95 (2H,s), 7.06-7.10 (2H,m) 1.41 (3H,d, J= 6.93Hz ), 1.63-1.73 (1H, m), 1.90-2.05 (6H,m), 2.93-2.99(4H,m), 3.13- 3.26 (2H,m), 3.85 (1 H, q, J= 6.92Hz), 4.35

25 CD ₃ OD

(2H,q, J=15.40Hz), 4.63-4.67 (1H,m), 4.91 (3H,s), 6.93 (1 H,s), 7.06-7.09 (1H,m), 7.18- 7.25 (2H,m)

1.03 (12H,d, J= 6.49Hz ), 2.90-3.14(6H,m), 4.36 (2H,q, 15.0Hz), 4.64 (1 H,q, J=7.01 Hz),

26 CD ₃ OD

4.75 (4H,s), 6.85 (1 H, s), 6.98-7.01 (1 H,m), 7.11-7.20 (2H,m).

0.80 (3H,d, J= 6.24Hz ), 0.86 (3H,d, J= 5.55Hz ), 1.17-1.38 (4H,m), 1.47-1.31

27 CD ₃ OD

(2H,m), 1.47-1.60 (1 H,m), 2.37 (2H,s,br), 2.79-2.84(1 H,m), 2.93-2.99(3H, m), 4.19 (2H,q, 15.32Hz), 4.50 (1 H,t, J=7.44Hz), 4.75 (3H,s), 6.69 (1H, s), 6.85-6.88 (1 H,m), 7.00-7.04 (2H,m).

1.67-1.76 (1 H,m), 1.89-1.96 (1H,m), 2.09- 2.23 (2H,m), 2.43-2.53 (1 H,m), 2.94 (3H,s), 2.95-2.99 (1 H,m), 3.19-3.25 (3H,m), 3.67-

28 CD ₃ OD 3.72 (1 H,m), 4.10 (1 H,t, J=8.49Hz), 4.37

(2H,q, J= 15.61 Hz), 4.71-4.75 (1 H,m), 4.91 (2H, s ), 7.03-7.07 (2H,m), 7.11 (1 H,s), 7.28-7.31 (2H,m).

0.97-1.08 (6H,m), 1.14-1.19 (4H,m), 2.45- 2.51 (4H,m), 2.98-3.00 (1 H, m), 3.09-3.16

29 CD ₃ OD (1H,m), 4.29-4.42 (2H,m), 4.61-4.65

(1H,m), 4.91 (4H, s ), 6.84 (1 H,s), 7.00-7.04 (2H,m), 7.22-7.25 (2H,m)

0.97-1.08 (6H,m), 1.14-1.19 (4H,m), 2.45- 2.51 (4H,m), 2.98-3.00 (1 H, m), 3.09-3.16

30 CD ₃ OD (1H,m), 4.29-4.42 (2H,m), 4.61-4.65

(1H,m), 4.91 (4H, s ), 6.84 (1H,s), 7.00-7.04 (2H,m), 7.22-7.25 (2H,m)

1.56 (3H,d, J= 6.88Hz ), 1.60-1.68 (1 H,m), 1.73-1.93 (6H,m), 2.73-2.84(2H,m), 2.92- 3.01 (4H,m), 3.17-3.22 (1H,m), 3.47-3.56

31 CD ₃ OD

(1H, m), 3.80 (1 H,q, 6.68Hz), 4.65 (1H,q, J=15.49Hz), 4.77 (1 H,t, J=6.12Hz), 4.91 (2H,s), 7.03-7.12 (3H,m), 7.29-7.34 (2H,m) 1.41 (3H,d, J= 6.93Hz ), 1.56-1.58 (1 H,m), 1.86-2.05 (6H,m), 2.96-3.01 (4H,m), 3.15- 3.19 (1 H,m), 3.41-3.42 (1 H, m), 3.54-3.58

32 CD ₃ OD

(1H, m), 3.58 (1 H,q, 6.96Hz), 4.27-4.42 (2H,m), 4.65 (1 H,t, J=6.76Hz), 4.91 (2H,s), 7.03-7.11 (3H,m), 7.28-7.31 (2H,m) 0.93 (3H,d, J= 6.20Hz ), 1.00 (3H,d, J= 6.24Hz ), 1.24-1.47 (4H,m), 1.60-1.64 (2H,m), 1.70-1.75 (1 H,m), 2.49 (2H,s,br),

33 CD ₃ OD 2.95-3.00 (1 H,m), 3.09-3.14 (3H, m), 4.35

(2H,q, 15.08Hz), 4.63 (1 H,t, J=7.25Hz), 4.91 (3H,s), 6.84 (1 H, s), 6.99-7.05 (2H,m), 7.22-7.26 (2H,m) 1.57-1.74 (1 H,m), 1.88-1.95 (1 H.m), 2.15- 2.20 (1H,m), 2.43-2.50 (1 H,m), 2.94 (3H,s),

2.95- 3.00 (1 H,m), 3.17-3.26 (3H,m), 3.67-

34 CD ₃ OD 3.72 (1 H,m), 4.10 (1 H,t, J=8.44Hz), 4.36

(2H,q, J= 15.01 Hz), 4.75-4.79 (1 H,m), 4.91 (3H, s ), 6.99-7.02 (2H,m), 7.10 (1 H,s), 7.31-7.37 (2H,m).

1.13(3H,s, br), 1.26(6H,d,J= 6.56Hz), 1.32- 1.40(1H,m), 1.55(3H,d,J= 6.68Hz), 2.54 (1H,s, br), 2.68(3H,s), 2.87 (1 H,s, br), 2.94-

35 CD ₃ OD

3.00(1H,m), 3.19-3.25(1 H, m), 3.95(1 H, q, J= 6.88Hz), 4.32-4.45(2H,m), 7.02- 7.15(3H,m), 7.34-7.39 (2H, m).

1.58 (3H, d, J=6.97Hz ), 2.78 (6H,s), 2.99- 3.05 (1 H, m), 3.17-3.22 (1 H, m),3.86 (1 H,

36 CD ₃ OD q, J= 6.93Hz), 4.27^.31 (1H, m), 4.38-4.42

(1H, m), 4.70-4.76 (1H, m), 4.91 (4H, s ),

6.96- 7.14 (4H,m), 7.31-7.37 (1H,m) 0.99-1.07 (6H,m), 1.16 (3H,q, J =2.28Hz), 2.44-2.49(3H,m), 2.51-2.61 (1H,m), 2.96- 3.03 (1 H, m), 3.11-3.20 (1H,m), 4.34-4.38

37 CD ₃ OD

(2H,m), 4.66 (1 H,q, 1.88Hz), 4.91 (5H, s ), 6.84 (1H,s), 6.99-7.06 (2H,m), 7.28-7.34 (2H,m)

1.41 (3H,d, J= 6.92Hz ), 1.50-1.58 (1 H,m), 1.85-2.05 (6H,m), 2.99-3.05 (4H,m), 3.17- 3.22 (1 H,m), 3.41-3.42 (1 H, m), 3.54-3.58 (1H, m), 3.58 (1 H,q, 6.96Hz), 4.27-4.31

38 CD ₃ OD

(1H,m), 4.38-4.43 (1H,m), 4.68 (1H,t, J=6.60Hz), 4.92 (1 H,s), 7.02-7.05 (2H,m), 7.11 (2H, t, J= 4.45Hz), 7.32-7.35 (1 H,m), 8.84-8.87 (1 H,m).

1.56 (3H,d, J= 6.84Hz ), 1.61-1.72 (1 H,m), 1.74-1.93 (6H,m), 2.75-2.86(2H,m), 2.96- 3.02 (4H,m), 3.19-3.24 (1H,m), 3.56 (1H, s,

39 CD ₃ OD br), 3.82 (1H,q, 6.92Hz), 4.31-4.44 (2H,m),

4.79 (1 H,t, J=6.13Hz), 7.00-7.09 (2H,m), 7.11-7.15 (2H,m), 7.32-7.38 (1 H,m), 8.85- 8.88 (1 H,m). 1.69-1.78 (1H,m), 1.84-1.96 (1H,m), 2.12-

2.22 (1H,m), 2.51-2.53 (1H,m), 2.93 (3H,s), 3.01-3.07 (1H,m), 3.19-3.31 (2H,m), 3.66-

40 CD ₃ OD

3.71 (1H,m), 4.11 (1H,t, J=8.45Hz), 4.31- 4.43 (2H,m), 4.81-4.85 (1H,m), 4.91 (2H, s ), 7.08-7.15 (3H,m), 7.31-7.357 (2H,m). 1.16(3H,s, br), 1.26(6H,d,J= 6.44Hz), 1.29- 1.40(1H,m), 1.54(3H,d,J= 6.68Hz), 2.67(1 H,s, br), 2.72(3H,s), 2.93-

41 CD ₃ OD 2.95(1 H,m), 3.00-3.11(1 H, m), 3.94- 3.99(11-1, m), 4.29-4.44(2H,m), 4.71- 4.77(1 H,m), 7.05-7.17(3H,m), 7.29-7.36 (2H, m).

2.06-2.36 (4H, br m) 2.72-2.75 (1H, m) 2.90 (3H, s) 3.06 (3H, s) 3.60 (1H, s) 3.75-3.85 (2H, m) 4.09 (1H, t, J = 8.0 Hz) 4.42 (1H, t, J = 8.0 Hz) 4.52 (2H, s) 4.94 (1H, m) 7.33

42 CD ₃ OD

(1H, s) 7.37-7.46 (2H, m) 7.48-7.64 (2H, m) 7.74-7.84 (2H, m) 7.90 (1H, d, J = 8.0 Hz)

8.23 (1H, d, J = 8.0 Hz)

0.84 (3H, d, J = 4.0 Hz) 0.88 (3H, d, J = 4.0 Hz) 1.07 (3H, d, J = 4.0 Hz) 1.39 (1H, d, J =

4.0 Hz) 1.98 (3H, s) 2.53 -2.59 (1H, br m) 2.88 (1H, s) 3.44-3.49 (1H, m) 4.22 (2H, d,

43 CD ₃ OD j = 8.0 Hz) 4.75 (5H, s) 6.65 (1H, t,J = 4.0

Hz) 7.19-7.29 (2H, m) 7.37-7.47 (2H, m) 7.67 (1H, dd, J = 8.0, 4.0 Hz) 7.78 (1H ,d, J = 8.0 Hz) 8.11 (1H, d, J = 8.0 Hz)

1.01 (2H ,t ,J = 8.0 Hz) 1.16 (2H, t, J = 8.0 Hz) 1.52 (2H, d, J = 8.0 Hz) 1.77 (2H, d, J = 8.0 Hz) 2.38-2.43 (1H, m) 2.73-2.87 (1H, m) 3.10-3.15 (1H, m) 3.22-3.37 (3H, m) 3.44-3.53 (2H, m) 3.64-3.69 (1H, m) 3.85-

44 CD3OD

3.90 (1H, m) 4.30-4.35 (1H, m) 4.43-4.48 (1H, m) 4.55-4.59 (1H, m) 4.87-5.02 (1H, br m) 7.33 (1H, s) 7.38-7.44 (2H, m) 7.51-7.67 (2H, br m) 7.81 (1H, dd, J = 8.0, 4.0 Hz) 7.91-7.95 (1H, m) 8.27 (1H, d, J = 8.0 Hz) 8.83 (1 H, t, J = 8.0 Hz)

1.91-1.96 (6H, m) 2.71-2.77 (2H, m) 3.04- 3.14 (2H, m) 3.41-3.49 (1 H, m) 4.04 (2H, s) 4.57-4.61 (1H, m) 6.60 (1H, s) 6.94-7.00 (2H, m) 7.03-7.17 (3H, m) 7.19-7.25 (2H,

47 CD ₃ OD

m) 7.34-7.45 (2H, m) 7.57-7.64 (1 H, m) 7.74 (1H, d, J = 8.0 Hz) 8.07 (1H, d, J = 8.0 Hz)

1.62-1.71(3H,m), 2.07-2.11(1H,m),

2.13(3H,s), 2.24-2.33(1 H.m), 2.75- 2.79(1 H,m), 2.93-2.98(1 H,m), 3.02- 3.06(1 H,m), 3.11-3.16(1 H,m), 4.23-

48 CDC1 ₃

4.36(2H,m), 4.62-4.68(1 H,m), 5.47(2H,s), 6.67(1 H,s), 7.11(2H,d,J= 8.4Hz), 7.21(2H,d,J= 8.4Hz), 7.41(1H,t,J= 5.4Hz), 7.81(1 H,d,J= 8.6Hz).

0.84(6H,d,J= 6.5Hz), 0.98(3H,d,J= 7.0Hz), 1.83(3H,s), 2.59-2.68(1 H,m), 2.83- 2.90(1 H,m), 2.94-3.00(1 H,m), 3.10(1 H,q,J=

49 CDCI ₃ 7.0Hz), 4.11-4.22(2H,m), 4.49(1H,q,J=

7.7Hz), 5.12(2H,s), 6.53(1 H,s), 6.98- 7.02(3H,m), 7.09(2H,d,J= 8.3Hz), 7.80(1 H,d,J= 8.4Hz).

1.67-1.79(3H,m), 2.15(3H,s), 2.27- 2.34(1 H,m), 2.78-2.83(2H,m), 2.95- 3.01 (1H,m), 3.05-3.08(1 H,m), 3.14-

50 CDCI ₃

3.19(1 H,m), 4.24^.40(2H,m), 4.61- 4.67(1 H,m), 5.46(2H,s), 6.72(1H,s), 7.08- 7.38(4H,m), 7.86(1H,d,J= 8.2Hz).

1.28(6H,d,J= 6.6Hz), 1.37-1.44(1 H.m). 1.55(3H,d,J= 6.8Hz), 2.67(3H,s), 2.86-

51 CD ₃ OD 2.99(2H,m), 3.20-3.25(1 H,m), 3.96(1H,q,J=

6.8Hz), 4.32-4.46(2H,m), 7.13(1 H.s). 7.26- 7.36(4H,m), 8.89(1H,t,J= 5.0Hz).

1.06(3H,d,J= 7.0Hz), 2.10(6H,s), 2.93- 3.00(2H,m), 3.12-3.17(1 H,m), 4.25-

52 CDCI3

4.37(2H,m), 4.68(1H,q,J= 7.8Hz), 5.25(2H,s), 6.68(1H,s), 7.07-7.11(1H,m), 7.16-7.20(4H,m), 7.75(1 H,d,J= 8.4Hz). 0.95(6H,t,J= 7.1Hz), 1.08(3H,d,J= 7.0Hz), 2.30-2.48(4H,m), 2.94-2.99(1 H,m), 3.11- 3.16(1 H,m), 3.29(1 H,q,J= 6.9Hz), 4.22-

53 CDC1 ₃ 4.36(2H,m), 4.78(1 H,q,J= 7.8Hz),

5.53(2H,s), 6.60(1 H,s), 7.06-7.09(1 H,m), 7.15-7.19(3H,m), 7.49(1 H,t,J= 5.1 Hz), 7.98(1 H,d,J= 8.5Hz).

1.41-1.51(1H,m), 1.56(3H,d,J= 6.90Hz), 1.67-1.93(5H,m), 2.76-2.84(2H,m), 2.94- 3.00(2H,m), 3.18-3.24(1 H,m), 3.55-

54 CD ₃ OD

3.57(1 H,m), 3.84(1 H,q,J= 6.9Hz), 4.31- 4.44(2H,m), 4.78-4.82(1 H,m), 7.14(1 H,s), 7.25-7.38(4H,m), 8.89(1 H,t,J= 5.7Hz). 1.42(3H,d,J= 7.0Hz), 1.53-1.59(1 H,m), 1.87-1.99(5H,m), 2.97-3.03(3H,m), 3.17- 3.22(1 H,m), 3.42(1 H,br s), 3.58(1 H,br s),

55 CD ₃ OD

3.92(1 H,q,J= 6.9Hz), 4.29-4.42(2H,m), 4.66-4.70(1H,m), 7.12(1 H,s), 7.23- 7.36(4H,m).

1.61-1.77(4H,m), 2.19(3H,s), 2.28- 2.35(1H,m), 2.81-2.84(1 H,m), 2.96- 3.01(1 H,m), 3.05-3.08(1 H,m), 3.14-

56 CDCI3 3.19(1 H,m), 4.28-4.42(2H,m), 4.55- 4.61(1 H,m), 5.02(2H,s), 6.80(1H,s), 6.99- 7.01(1H,m), 7 06(1H,dd,J= 8.2,2.0Hz), 7.32-7.36(2H,m), 7.81(1 H,d,J= 8.5Hz). 0.99(6H,d,J= 6.5Hz), 1.16(3H,d,J= 7.0Hz), 2.01(3H,S), 2.72-2.81 (1H,m), 2.98- 3.04(1H,m), 3.10-3.15(1H,m), 3.27(1H,q,J= 7.0Hz), 4.35(2H,d,J= 5.5Hz), 4.54-

57 CDCI ₃

4.59(1 H,m), 5.00(2H,s), 6.80(1 H,s), 6.84(1H,t,J= 5.3Hz), 7.06(1 H,dd,J= 8.2,2.0Hz), 7.31(1H,d,J= 2.0Hz), 7.34- 7.39(1 H,m), 7.81(1 H,d,J= 7.5Hz).

1.59(3H,d,J= 7.0Hz), 2.82(6H,s), 3.00- 3.05(1 H,m), 3.14-3.19(1 H,m), 3.93(1 H,q,J=

58 CD ₃ OD 7.0Hz), 4.27^.42(2H,m), 4.68-4.72(1 H,m),

7.13(1H,s), 7.25(1 H,dd,J= 8.3,2.0Hz), 7.46- 7.48(2H,m), 8.87(1 H,t,J= 5.7Hz). 0.96(6H,t,J= 7.1 Hz), 1.10(3H,d,J= 7.0Hz), 2.31-2.47(4H,m), 2.92-2.98(1 H,m), 3.09- 3.14(1H,m), 3.29(1H,q,J= 7.0Hz),

59 CDC1 ₃ 4.30(2H,d,J= 5.5Hz), 4.74(1 H,q,J= 7.8Hz),

5.34(2H,s), 6.64(1 H,s), 7.04(1 H,dd,J= 8.2,2.0Hz), 7.27-7.36(3H,m), 7.97(1 H,d,J= 8.6Hz).

1.56(3H,d,J= 6.9Hz), 1.61-1.93(6H,m), 2.94-3.00(4H,m), 3.18-3.23(1 H,m),

3.56(1H,br s), 3.85(1 H,q,J= 6.9Hz), 4.31-

60 CD ₃ OD

4.44(2H,m), 4.77-4.81(1 H,m), 7.14(1 H,s), 7.27(1 H,dd,J= 8.3,2.0Hz), 7.48-7.50(2H,m), 8.88(1 H,t,J= 5.7Hz).

1.45(3H,d,J= 7.0Hz), 1.54-1.62(1 H,m),

1.86- 1.99(5H,m), 2.97-3.03(3H,m), 3.15- 3.20(1H,m), 3.42(1H,br s), 3.59(1 H,br s),

61 CD ₃ OD 3.93(1 H,q,J= 6.9Hz), 4.28-4.42(2H,m),

4.65-4.69(1 H,m), 7.13(1H,s), 7.24(1 H,dd,J= 8.3,2.0Hz), 7.46(1 H,d,J= 2.0Hz), 7.47- 7.49(1H,m).

1.07(3H,s), 1.22(3H,d,J= 6.4Hz), 1.54(3H,d,J= 6.8Hz), 2.35(3H,s), 2.64(3H,s), 2.86-2.92(1 H,m), 3.17-

62 CD ₃ OD

3.21(1H,m), 3.94(1H,q,J= 6.8Hz), 4.33- 4.44(2H,m), 4.84-4.88(1 H,m), 7.13- 7.21(5H,m), 8.86(1 H,S).

1.63-1.72(1 H,m), 1.82-1.93(1 H,m), 2.09- 2.19(1H,m), 2.33(3H,s), 2.40-2.49(1 H,m), 2.88-2.91(1 H,m), 2.93(3H,s), 3.17-

63 CD ₃ OD

3.23(2H,m), 3.66-3.71 (1 H,m), 4.12(1 H,t,J= 8.3Hz), 4.31-4.42(2H,m), 4.71-4.74(1 H,m), 7.11-7.17(5H,m), 8.87(1H,t,J= 5.7Hz). 1.60-1.69(1 H,m), 1.81-1.92(1 H,m), 2.09- 2.19(1H,m), 2.34(3H,s), 2.39-2.48(1 H,m),

2.87- 2.91(1 H,m), 2.93(3H,s), 3.16-

64 CD ₃ OD 3.25(2H,m), 3.65-3.71 (1H,m), 4.13(1 H,t,J=

8.3Hz), 4.32- .43(2H,m), 4.73-4.77(1 H,m), 7.06-7.10(4H,m), 7.19(1H,t,J= 7.5Hz), 8.89(1 H,t,J= 5.7Hz). 1.05(3H,s), 1.23(3H,d,J= 6.5Hz), 1.54(3H,d,J= 6.8Hz), 2.35(3H,s), 2.65(3H,s), 2.87-2.93(1 H,m), 3.18-

65 CD ₃ OD 3.23(1 H,m), 3.95(1H,q,J= 6.8Hz), 4.33- 4.453(2H,m), 4.87-4.91(1 H,m), 7.09- 7.15(4H,m), 7.21(1H,t,J= 7.5Hz), 8.86(1 H,t,J= 5.2Hz).

1.66-1.75(1 H,m), 1.82-1.93(1 H,m), 2.09- 2.19(1 H,m), 2.41(3H,s), 2.44-2.51(1 H,m), 2.93(3H,s), 2.94-3.00(1 H,m), 3.17- 3.24(1 H,m), 3.27-3.32(1 H,m), 3.65-

66 CD ₃ OD

3.71(1 H,m), 4.14(1H,t,J= 8.3Hz), 4.29- 4.41(2H,m), 4.77-4.81 (1H,m), 7.08(1H,s), 7.09-7.14(1 H,m), 7.16-7.17(3H,m),

8.84(1 H,t,J= 5.7Hz), 8.93(1 H,d,J= 8.0Hz). 1.14(3H,S), 1.22(3H,d,J= 6.5Hz), 1.54(3H,d,J= 6.8Hz), 2.45(3H,s), 2.63(3H,s), 2.97-3.02(1 H,m), 3.21-

67 CD ₃ OD

3.29(1 H,m), 3.96(1 H,q,J= 6.8Hz), 4.31- 4.43(2H,m), 7.09(1H,s), 7.11-7.22(4H,m), 8.86(1H,s).

0.94-1.10(2H,m), 1.19-1.42(4H,m), 1.60- 1.80(7H,m), 1.99-2.19(3H,m), 2.47-

68 CD ₃ OD 2.56(1 H.m), 3.38-3.49(2H,m), 4.34- 4.41(3H,m), 4.43-4.50(1 H,m), 7.17(1 H,s), 8.78(1 H,d,J= 7.6Hz), 8.91(1 H,t,J= 5.8Hz). 0.94-1.09(2H,m), 1.22-1.42(4H,m), 1.61- 1.79(7H,m), 2.02-2.14(2H,m), 2.21- 2.31(1H,m), 2.61 -2.69(1 H,m), 2.98(3H,s),

69 CD ₃ OD 3.25-3.32(1 H,m), 3.74-3.80(1 H,m),

4.18(1 H,t,J= 8.2Hz), 4.36-4.42(2H,m), 4.45- 4.49(1 H,m), 7.17(1 H,s), 8.93(1 H,t,J= 5.8Hz).

0.96-1.08(2H,m), 1.19-1 44(4H,m),

1.65(2H,t,J= 7.3Hz), 1.74-1.84(5H,m), 2.01- 2.30(3H,m), 2.60-2.69(1 H,m), 2.97(3H,s),

70 CD ₃ OD 3.23-3.30(1 H,m), 3.73-3.79(1 H,m), 4.15- 4.19(1 H,m), 4.33-4.41 (2H,m), 4.43- 4.48(1 H,m), 7.16(1H,s), 8.92(1 H,t,J= 5.8Hz). 0.96-1.09(2H,m), 1.21-1.42(10H,m), 1.61- 1.73(7H,m), 1.79(3H,d,J= 9.8Hz),

71 CD ₃ OD 2.79(3H,s), 3.58(1H,br s), 4.11(1 H,q,J=

6.8Hz), 4.34-4.45(2H,m), 4.54-4.59(1 H,t,J= 7.7Hz), 7.17(1 H,s), 8.89(1 H,t,J= 5.7Hz). 0.95-1.08(2H,m), 1.19-1.43(4H,m),

1.62(3H,d,J= 7.0Hz), 1.64-1.80(7H,m),

72 CD ₃ OD 2.94(6H,s), 3.99(1 H,q,J= 7.0Hz), 4.34- 4.49(3H,m), 7.17(1 H,S), 8.89(1H,t,J= 5.7Hz).

0.85-1.01 (2H,m), 1.04(6H,t,J= 7.1 Hz), 1.10- 1.28(7H,m), 1.51-1.79(7H,m), 2.37-

73 CDC1 ₃ 2.55(4H,m), 3.35(1H,q,J= 7.0Hz), 4.32- 4.47(3H,m), 5.09(2H,s), 6.82(1 H,s), 7.09(1 H,t,J= 5.4Hz), 7.74(1H,d,J= 8.3Hz). 0.94-1.08(2H,m), 1.22-1.30 (4H,m), 1.34(3H,t,J= 7.3Hz), 1.63-1.79(7H,m), 2.02- 2.14(2H,m), 2.21-2.30(1 H,m), 2.60-

74 CD ₃ OD 2.68(1 H,m), 3.22-3.35(3H,m), 3.76- 3.80(1 H,m), 4.21(1H,t,J= 8.0Hz), 4.34- 4.41(2H,m), 4.44-4.48(1 H,m), 7.17(1 H,s), 8.95(1 H,t,J= 5.7Hz).

1.00-1.14(2H,m), 1.25-1 36(4H,m),

1.40(3H,d,J= 6.6Hz), 1.43(3H,d,J= 6.6Hz), 1.72(2H,t,J= 7.4Hz), 1.78-1.85(5H,m), 2.02- 2.18(2H,m), 2.21-2.31(1 H,m), 2.61-

75 CD ₃ OD 2.69(1H,m), 3.36-3.41 ( H,m), 3.63- 3.70(1H,m), 3.75-3.79(1 H,m), 4.35- 4.39(1H,m), 4.44(2H,d,J= 5.2Hz), 4.50(1H,t,J= 7.7Hz), 7.24(1 H,s), 9.01(1H,t,J= 5.8Hz).

0.94-1.08(2H,m), 1.22-1.40(4H,m),

1.65(2H,t,J= 7.3Hz), 1.71-1.88(8H,m), 1.97- 2.00(2H,m), 2.17-2.20(1H,m), 2.86(3H,s),

76 CD ₃ OD

3.12-3.18(1H,m), 3.53-3.57(1 H,m), 3.78- 3.82(1 H,m), 4.35-4.45(3H,m), 7.18(1H,s), 8.85(1 H,d,J= 6.9Hz), 8.96(1 H,t,J= 5.8Hz). 0.96-1.08(2H,m), 1.21-1.43(4H,m), 1.60-

77 CD ₃ OD 1.98(16H,m), 3.02-3.09(2H,m), 3.46(1 H.br s), 3.67(1 H,br s), 3.95(1 H,q,J= 6.9Hz), 4.34-4.50(3H,m), 7.16(1H,s), 8.88(1H,t,J= 5.8Hz).

0.98-1.08(2H,m), 1.25-1.41 (4H,m), 1.60- 1.98(16H,m), 3.02-3.09(2H,m), 3.47(1 H,br

78 CD ₃ OD s), 3.66(1H,br s), 3.96(1H,q,J= 6.9Hz),

4.34-4.49(3H,m), 7.17(1H,s), 8.93(1H,t,J= 5.8Hz).

2.12 (3H, s) 3.43-3.56 (2H, m) 3.93 (1H, s) 3.98 (1H, s) 4.02 (1H, s) 4.12 (1H, s) 5.89 (1H, s) 6.69 (1H, d, J = 4.0 Hz) 6.82 (1H, s)

79 CD ₃ OD 7.21-7.31 (2H, m) 7.38-7.48 (2H, m) 7.66

(1H, dd, J = 8.0, 4.0 Hz) 7.76 (1H, dd, J = 8.0, 4.0 Hz) 8.11 (1H, d, J = 8.0 Hz) 10.58 (1H, br s)

3.41-3.57 (2H, m) 3.62-3.78 (2H, m) 4.07 (1H, d, J = 4.0 Hz) 4.17 (1H, d, J = 4.0 Hz)

4.80- 4.86 (4H, br m) 6.81 (1H, s) 6.97 (1H, td, J = 4.0 Hz) 7.03 (1H, s) 7.12 (1H, td, J = 4.0 Hz) 7.23 (1H, t, J = 8.0 Hz) 7.30-7.34

80 CD ₃ OD

(2H, m) 7.39 (1H, td, J = 4.0 Hz) 7.44 (1H, td, J = 4.0 Hz) 7.51 (1H, d, J = 8.0 Hz) 7.65 (1H, d, J = 8.0 Hz) 7.85 (1H, d, J = 4.0 Hz) 8.40-8.44 (1H, m)

2.18 (3H, s) 3.20-3.22 (1H, m) 3.25-3.42 (3H, m) 3.98-4.03 (1H, m) 4.10-4.15 (1H, m) 4.56-4.63 (1H, m) 4.75-4.85 (3H, m)

6.81- 6.87 (3H, m) 6.95 (1H, d, J = 8.0 Hz)

81 CD ₃ OD

7.01-7.10 (1H, m) 7.14-7.20 (2H, m) 7.39- 7.44 (2H, m) 7.64 (1H, d, J = 8.0 Hz) 7.75 (1H, d, J = 8.0 Hz) 8.03 (1H, d, J = 8.0 Hz) 8.36 (1H, t, J = 8.0 Hz)

2.11(3H,s), 2.13(3H,s), 2.82-2.88(1 H,m), 2.99-3.03(1H,m), 3.31 (1H,s), 4.16- 4.27(2H,m), 4.61-4.67(1 H,m), 5.63(1 H,d,J=

82 d-DMSO

1.96Hz), 6.73 (1H,s), 6.77 (2H,s), 7.03- 7.07(1H,m), 7.19-7.32(3H,m), 8.53(1H,t,J= 5.60Hz).

2.16(3H,s), 2.83-2.89(1H,m), 3.00-

83 d ⁶ -DMSO

3.05(1 H,m), 4.21-4.24(2H,m), 4.62- 4.66(1 H,m), 5.90(1 H,t,J= 2.28Hz), 6.74- 6.77(4H,m), 7.05-7.08(1 H,m), 7.25- 7.31(3H,m), 7.39(1 H,d,J= 8.44Hz), 8.55(1 H,t,J= 5.68Hz).

CD ₃ OD 3.13-3.17(1H,m), 3.25-3.30(1 H,m), 4.33- 4.37(2H,m), 4.78^.83(1 H,m), 4.96-5.01

84 (1H,m), 7.10-7.30(9H,m), 7.47-7.49(1 H,m),

7.67(1 H,d,J= 8.04Hz), 8.52(1 H,d,J= 7.84Hz), 8.77(1 H,t,J= 5.89Hz).

CD ₃ 0D 2.28(3H,s), 3.05-3.10(2H,m), 3.18- 3.23(2H,m), 4.30(1 H,d,J= 15.0Hz), 4.42(1 H,d,J= 15.09Hz), 4.77(1 H,t,J=

85 6.88Hz), 4.91 (3H,s), 6.05(1 H,d,J= 2.44Hz),

6.84(2H,t,J= 0.84Hz), 6.99-7.03(2H,m), 7.23-7.26(2H,m).

2.31(3H,s), 3.12-3.17(1H,m), 3.19- 3.26(1 H,m), 4.27-4.31 (1 H,m), 4.37- 4.41(1H,m), 4.76-4.81 (1 H,m), 4.91(4H,s),

86 CD ₃ OD 6.06(1 H,d,J= 3.21Hz), 6.84(2H,t,J=

2.32Hz), 6.99-7.03(2H,m), 7.08- 7.11(2H,m), 7.30-7.35(1 H,m), 8.75- 8.78(1 H,m).

2.29(3H,s), 3.13-3.18(1 H,m), 3.23- 3.28(1 H,m), 4.30-4.34(1 H,m), 4.39- 4.42(1 H,m), 4.83-4.86(1 H,m), 4.91 (4H,s),

87 CD ₃ OD

6.04(1 H,d,J= 2.45Hz), 6.83(2H,t,J= 2.68Hz), 7.06-7.12 (2H,m), 7.26- 7.32(2H,m).

2.15(3H,s), 2.83-2.88(1 H,m), 3.00- 3.05(1 H,m), 4.17-4.27(2H,m), 4.61-

88 d ⁶ -DMSO 4.67(1 H,m), 5.90(1 H,t,J= 2.3Hz), 6.75- 6.78(4H,m), 7.24-7.30(4H,m), 7.35(1 H,d,J= 8.4Hz), 8.57(1H,t,J= 5.7Hz), 11.10(1H,s). 2.16(3H,s), 2.84-2.90(1 H,m), 3.01- 3.06(1 H,m), 4.18-4.28(2H,m), 4.62- 4.67(1 H,m), 5.90(1 H,t,J= 2.2Hz), 6.75-

89 d ⁶ -DMSO

6.77(4H,m), 7.19-7.28(3H,m), 7.35(1 H,s), 7.38(1 H,d,J= 8.4Hz), 8.57(1 H,t,J= 5.7Hz), 11.10(1 H,s). 2.29(3H,s), 2.34(3H,s), 3.06-3.11(1 H,m), 3.15-3.20(1 H,m), 4.27-4.40(2H,m), 90 CD3OD 4.75(1 H,t,J= 7.2Hz), 6.05(1 H,t,J= 2.3Hz),

6.84(1 H,t,J= 2.7Hz), 7.09-7.16(5H,m), 8.73(1H,t,J= 5.7Hz), 10.72(1 H,s).

2.21 (3H,s), 2.23(3H,s), 3.04-3.14(2H,m), 4.20-4.30(2H,m), 4.86(1 H,q,J= 7.1Hz), 5.51(2H,br s), 6.00(1 H,s), 6.58(1H,d,J=

91 CDC1 ₃

7.2Hz), 6.66(1 H,s), 6.73-6.74(1 H,m), 6.96- 7.03(3H,m), 7.12(1 H,t,J= 7.4Hz), 7.24- 7.26(1 H,m), 9.90(1H,s).

CD3OD 2.14(3H,s), 2.24(3H,s), 2.92-2.97(1 H,m),

3.04-3.10(1 H,m), 4.09-4.26(2H,m),

92 4.64(1 H,t,J= 7.4Hz), 5.88(1H,d,J= 2.4Hz),

6.62(1 H,s), 6.67(1 H,d,J= 2.5Hz), 6.91- 7.07(4H,m).

d ⁶ -DMSO 0.80-0.93(2H,m), 1.07-1.33(4H,m), 1.45- 1.73(7H,m), 2.25(3H,s), 4.12-4.25(2H,m),

93 4.42-4.48(1 H,m), 5.93(1 H,t, J= 2.2Hz), 6.73- 6.79(4H,m), 7.31(1H,d,J= 8.2Hz), 8.45(1 H,t,J= 5.8Hz),11.16(1 H,s).

CD ₃ OD 2.62-2.68 (1 H, m) 2.73 (2H, s) 3.24-3.43

(2H, m) 4.02 (1 H, s) 4.07-4.13 (2H, m) 4.60 (1 H, t, J = 8.0 Hz) 6.57 (1H, s) 6.95-7.21

94 (7H, m) 7.39-7.47 (2H, m) 7.63 (1 H, d, J =

8.0 Hz) 7.74 (1H, d, J = 8.0 Hz) 8. 1 (1H, d, J = 8.0 Hz)

CD ₃ OD 2.82-2.88(1 H,m), 2.94-2.99(1 H,m), 3.05- 3.10(2H,m), 4.23-4.30(3H,m), 4.56- 95 4.60(1H,m), 4.91 (4H,s), 7.00-7.04 (1H,m),

7.10(1 H,s), 7.13-7.31(6H,m), 8.00(1H,d,J= 8.04Hz), 8.51(1 H,t,J= 5.64Hz).

CD ₃ OD 2.80-2.86(1 H,m), 2.91 -2.97(1 H,m), 3.04- 3.10(2H,m), 4.23-4.31(3H,m), 4.57 (1H,t, J=

96

7.09Hz), 4.9 (5H,s), 6.82 (1 H,s), 6.97-7.02 (2H, m), 7.18-7.30(7H, m).

CD ₃ OD 2.80-2.87(1 H,m), 2.94-3.13(3H,m), 4.23- 97 4.31(3H,m), 4.61 (1 H,t, J= 7.16Hz), 4.9

(5H,s), 6.81 (1 H,s), 6.98-7.03 (3H, m), 7.24-7.32(61-1, m).

CD ₃ OD 2.80-2.85(1 H,m), 3.04-3.09(2H,m), 3.15- 3.20 (1 H,m), 4.23-4.29(3H,m), 4.62-4.67

98 (1 H,m), 4.91 (5H,s), 7.09-7.13 (2H, m),

7.22-7.31 (6H, m), 8.00 (1 H, d, J=8.0Hz), 8.55 (1 H, t, J=5.8Hz).

CD ₃ OD 2.82-2.89(1 H,m), 2.95-3.00(1 H,m), 3.04- 3.11 (2H,m), 4.23-4.34(3H,m), 4.57-

99

4.63(1H,m), 7.10(1H,s), 7.20-7.30(9H,m), 7.98(1H,d,J= 8.0Hz), 8.54(1 H,t,J= 5.8Hz).

CD ₃ OD 2.82-2.87(1 H,m), 2.97-3.02(1 H,m), 3.04- 3.12(2H,m), 4.21-4.35(3H,m), 4.57-

100

4.63(1H,m), 7.09(1 H,s), 7.14-7.31 (9H,m), 7.98(1 H,d,J= 8.0Hz), 8.55(1 H,t,J= 5.8Hz).

CD ₃ OD 2.19(3H,s), 2.67-2.72(1 H,m), 2.79- 2.84(1H,m), 2.88-2.94(2H,m), 4.07-

101 4.19(3H,m), 4.40-4.46(1 H,m), 6.94- 6.99(5H,m), 7.06-7.18(5H,m), 7.76(1 H,d,J= 7.9Hz), 8.33(1 H,t,J= 5.8Hz).

CD ₃ OD 2.33(3H,s), 2.81 -2.86(1 H,m), 2.94- 2.99(1 H,m), 3.02-3.08(2H,m), 4.22-

102 4.34(3H,m), 4.56-4.61 (1 H,m), 7.02(1 H,d,J=

7.6Hz), 7.05-7.08(3H,m), 7.16-7.31 (6H,m), 7.92(1 H,d,J= 7.9Hz), 8.49(1 H,t,J= 5.8Hz).

CDCI ₃ (CDCI3) 2.28(3H,s), 2.73-2.78(1 H,m), 2.91- 2.96(1 H,m), 3.03-3.10(2H,m), 4.01-

103 4.06(1 H,m), 4.20-4.25(2H,m), 4.67(1 H,q,J=

7.8Hz), 5.48(2H,s), 6.44(1 H,s), 7.01- 7.26(9H,m), 7.52(1 H,d,J= 8.2Hz).

CD ₃ OD 0.90-1.04(2H,m), 1.17-1.32(4H,m), 1.54- 1.81 (7H,m), 2.88-2.93(1 H,m), 3.09-

104 3.13(1 H,m), 4.32-4.36(3H,m), 4.40- 4.46(1 H,m), 7.16(1 H,s), 7.22-7.36(5H,m), 7.92(1 H,d,J= 7.9Hz), 8.58(1 H,t,J= 5.8Hz).

CD ₃ OD 0.93 (3H, t, J = 8.0 Hz) 1.56-1.67 (1 H, m)

1.73-1.83 (1 H, m) 3.52-3.67 (2H, m) 4.01 (1 H, q, J = 4.0 Hz) 4.12-4.15 (1 H, m) 4.25-

105

4.29 (1 H, m) 4.77-4.82 (1 H, m) 6.95 (1H ,s) 7.35-7.43 (2H, m) 7.51-7.64 (2H, m) 7.71- 7.83 (1 H, m) 7.91 (1 h, d, J = 8.0 Hz) 8.27 (1h, d,J = 8.0 Hz)

CD ₃ OD 0.66 (3H, d, J = 4.0 Hz) 0.84 (3H, d, J = 4.0

Hz) 1.84-1.95 (1H, m) 3.20-3.22 (1H, m) 3.35-3.46 (2H, m) 3.74 (1H, d, J = 4.0 Hz) 3.97-4.02 (1H, m) 4.08-4.13 (1H, m) 4.63-

106

4.68 (1H, m) 4.72-4.81 (4H, br m) 6.81 (1H, s) 7.20-7.28 (2H, m) 7.35-7.47 (2H, m) 7.64-7.70 (1H, m) 7.76 (1H, d, J = 8.0 Hz) 8.10 (1H, d, J = 8.0 Hz)

CD ₃ OD 0.66 (3H, d, J = 4.0 Hz) 0.92 (3H, d, J = 4.0

Hz) 1.94-2.09 (1H, m) 3.08 (1H, s) 3.49- 3.54 (1H, m) 3.59-3.64 (1H, m) 386-3.89 (1H, m) 4.14^.18 (1H, m) 4.28-4.32 (1H,

107 m) 4.79-4.86 (1H, m) 4.93-5.03 (4H, br m)

6.98 (1H, s) 7.36-7.46 (2H, m) 7.54-7.64 (2H, m) 7.75-7.82 (1H, m) 7.96 (1H, d, J = 8.0 Hz) 8.23 (1H, d, J = 8.0 Hz)

CD ₃ OD 0.81 (3H, d, J = 6.84 Hz), 0.99 (3H, d, J =

6.96 Hz), 2.01-2.09 (1H, m), 2.99-3.04 (1H, m), 3.10-3.15 (1H, m), 3.87 (1H, d, 108 J=3.64Hz), 4.31-4.38 (2H, m), 4.63-4.66

(1H, m), 4.91 (3H, s), 7.05-7.08 (1H, m), 7.16 (1H,s), 7.18-7.21 (2H, m), 8.03 (1H, d, J = 8.05 Hz), 8.74 (1H, t, J = 5.68 Hz).

CD ₃ OD 0.71 (3H, d, J = 6.88 Hz), 0.96 (3H, d, J =

6.93 Hz), 1.99-2.07 (1H, m), 2.99-3.05 (1H, m), 3.11-3.16 (1H, m), 3.86 (1H, d, J=3.68Hz), 4.27-4.28 (1H, m), 4.31-4.37 (1H, m), 4.63-4.69 (1H, m), 4.91 (3H, s), 7.07-7.10 (1H, m), 7.13 (1H,s), 7.16-7.23 (2H, m), 8.03 (1H, d, J = 8.13 Hz), 8.74 (1H, t, J = 5.80 Hz).

TABLE 5

Names of examples

Example Name

No (R)-Pyrrolidine-2-carboxylic acid [(S)-l-[(2-

8 amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4- difluoro-phenyl)-ethyl]-amide

(R)-2-Amino-3-methyl-pentanoic acid [(S)-l-[(2-

9 amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4- difluoro-phenyl)-ethyl]-amide

(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-

10 l-[(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- (3,4-difluoro-phenyl)-ethyl]-amide

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-yImethyl)-

11 carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2- dipropylamino-propionamide

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

12 carbamoyl] -2 -(3 ,4-difluoro-phenyl)-ethyl] -2- (isopropyl-methyl-amino)-propionamide

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

13 carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2- diethylamino-propionamide

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

14 carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2- dimethylamino-propionamide

(R)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

15 carbamoyl] -2-(3,4-difluoro-phenyl)-ethyl] -2- dimethylamino-propionamide

(S)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-

16 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4- difluoro-phenyl)-ethyl]-amide

(R)-l-Ethyl-pyrrolidine-2-carboxylic acid [(S)-l-

17 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4- difluoro-pheny l)-ethy 1] -amide

(R)-l-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-

18 1 -[(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- (3 ,4-difluoro-phenyl)-ethyl] -amide (R)-l-Isopropyl-piperidine-2-carboxylic acid [(S)-

19 1 -[(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- (3,4-difluoro-phenyl)-ethyl]-amide

(R)-l-Methyl-piperidine-2-carboxylic acid [(S)-l-

20 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4- difluoro-phenyl)-ethyl] -amide

(S)-l-Methyl-piperidine-2-carboxylic acid [(S)-l-

21 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4- difluoro-phenyl)-ethyl] -amide

(R)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

22 carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2- dimethylamino-3-phenyl-propionamide

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

23 carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2- dimethylamino-3-phenyl-propionamide

(S)-N-[(S)- 1 -[(2- Amino-thiazol-5-ylmethyl)-

24 carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2- piperidin- 1 -yl-propionamide

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

25 carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2- piperidin- 1 -yl-propionamide

(S)-N-(2-Amino-thiazol-5-ylmethyl)-3-(3,4-

26 difluoro-phenyl)-2-(2-diisopropylamino- acetylamino)-propionamide

(S)-N-(2-Amino-thiazol-5-ylmethyl)-3-(3,4-

27 difluoro-phenyl)-2-[2-(2,6-dimethyl-piperidin-l- yl)-acetylamino]-propionamide

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-

28 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4- fluoro-pheny l)-ethy 1] -amide

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

29 carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2- dimethylamino-propionamide (S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)- 30 carbamoyl]-2-(4-fluoro-phenyl)-ethyl] -2- diethylamino-propionamide

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

31 carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-piperidin- 1 -yl-propionamide

(R)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

32 carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-piperidin- 1 -yl-propionamide

(S)-N-(2-Amino-thiazol-5-yImethyl)-2-[2-(2,6-

33 dimethyl-piperidin-1 -yl)-acetylamino]-3-(4-fluoro- phenyl)-propionamide

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-

34 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3- fluoro-phenyl)-ethyl] -amide

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

35 carbamoyl] -2-(3 -fluoro-pheny l)-ethy 1] -2 - (isopropyl-methyl-amino)-propionamide

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

36 carbamo l] -2-(3 -fluoro-pheny l)-ethy 1] -2- dimethylamino-propionamide

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

37 carbamoyl] -2-(3 -fluoro-pheny l)-ethyl] -2 - diethylamino-propionamide

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

38 carbamoyl] -2-(3 -fluoro-phenyl)-ethyl] -2-piperidin- 1 -yl-propionamide

(R)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

39 carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-2-piperidin- 1 -yl-propionamide

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-

40 [(2-amino-thiazol-5-yImethyl)-carbamoyl]-2-(2- fluoro-phenyl)-ethyl] -amide (S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

41 carbamoyl]-2-(2-fluoro-phenyl)-ethyl]-2- (isopropyl-methyl-amino)-propionamide

(R)- 1 -Methyl-pyrrolidine-2-carboxylic acid { (S)- 1 -

42 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- naphthalen- 1 -yl-ethyl } -amide

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

43 carbamoyl] -2-naphthalen- 1 -yl-ethyl } -2-(isopropyl- methyl-amino)-propionamide

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

44 carbamoyl] -2-naphthalen- 1 -yl-ethyl } -2- diethylamino-propionamide

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

45 carbamoyl] -2-naphthalen- 1 -yl-ethyl } -2-piperidin- 1 -yl-propionamide

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

46 carbamoyl] -2-naphthalen- 1 -yl-ethyl } -2-piperidin- 1 -yl-propionamide

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

47 carbamoyl] -2-naphthalen- 1 -yl-ethyl } -2- dimethylamino-3-phenyl-propionamide

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-

48 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4- chloro-phenyl)-ethyl]-amide

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

49 carbamoyl]-2-(4-chloro-phenyl)-ethyl]-2- (isopropyl-methyl-amino)-propionamid

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-

50 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3- chloro-phenyl)-ethyl]-amide

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

51 carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2- (isopropyl-methyl-amino)-propionamide (S)-N-[(S)- 1 -[(2-Amino-thiazol-5-yImethyl)-

52 carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2- dimethylamino-propionamide

(S)-N-[(S)-l -[(2-Amino-thiazol-5-ylmethyl)-

53 carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2- diethylamino-propionamide

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

54 carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-piperidin- 1 -yl-propionamide

(R)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

55 carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-piperidin- 1 -yl-propionamide

(R)-l-Methyl-pyrrolidine-2-carboxylic acid [(S)-l-

56 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4- dichloro-phenyl)-ethyl]-amide

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

57 carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2- (isopropyl-methyl-amino)-propionamide

(S)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

58 carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2- dimethylamino-propionamide

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

59 carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2- diethylamino-propionamide

(S)-N-[(S)-l -[(2-Amino-thiazol-5-ylmethyl)-

60 carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2- piperidin- 1 -yl-propionamide

(R)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

61 carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2- piperidin- 1 -yl-propionamide

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

62 carbamoy l]-2-p-tolyl-ethyl } -2-(isopropyl-methyl- amino)-propionamide (R)-l-Methyl-pyrrolidine-2-carboxylic acid {(S)-l-

63 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-p- tolyl -ethyl } -amide

(R)-l -Methyl -pyrrolidine-2-carboxylic acid {(S)-l-

64 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-m- tolyl-ethyl} -amide

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

65 carbamoyl]-2-m-tolyl-ethyl}-2-(isopropyl-methyl- amino)-propionamide

(R)-l-Methyl-pyrroIidine-2-carboxyIic acid {(S)-l-

66 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-o- tolyl-ethyl } -amide

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

67 carbamoyl]-2-o-toIyl-ethyl } -2-(isopropyl-methyl- amino)-propionamide

(R)-Pyrrolidine-2-carboxylic acid {(S)-l-[(2-

68 amino-thiazol-5-ylmethyl)-carbamoyl]-2- cyclohexyl-ethyl } -amide

(R)-l -Methyl -pyrrolidine-2-carboxylic acid {(S)-l-

69 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- cyclohexyl-ethyl } -amide

(S)-l-Methyl-pyrrolidine-2-carboxylic acid {(S)-l-

70 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- cyclohexyl-ethyl } -amide

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

71 carbamoyl] -2-cyclohexyl-ethyl }-2-(isopropyl- methyl-amino)-propionamide

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

72 carbamoyl] -2-cyclohexyl-ethyl } -2-dimethylamino- propionamide

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

73 carbamoyl] -2-cyclohexyl-ethyl } -2-diethylamino- propionamide (R)-l-Ethyl-pyrrolidine-2-carboxylic acid {(S)-l-

74 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- cyclohexyl-ethyl } -amide

(R)-l-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-

75 1 -[(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- cyclohexyl-ethyl } -amide

(R)-l-Methyl-piperidine-2-carboxylic acid {(S)-l-

76 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2- cyclohexyl -ethyl } -amide

(S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

77 carbamoyl]-2-cyclohexyl-ethyl}-2-piperidin-l-yl- propionamide

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

78 carbamoyl]-2-cyclohexyl-ethyl} -2-piperidin- 1 -yl- propionamide

3-Methyl-lH-pyrrole-2-carboxylic acid {(S)-l-[(2-

79 amino-thiazol-5-ylmethyI)-carbamoyl]-2- naphthalen- 1 -yl-ethyl } -amide

lH-Indole-2-carboxylic acid {(S)-l-[(2-amino-

80 thiazol-5-ylmethyl)-carbamoyl]-2-naphthalen-l -yl- ethyl} -amide

(S)-N-(2-Amino-thiazol-5-ylmethyl)-3-naphthalen-

81

l-yl-2-(2-m-tolyl-acetylamino)-propionamide

3, 5 -Dimethyl- lH-pyrrole-2-carboxylic acid [(S)-l-

82 [(2-amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4- difluoro-phenyl)-ethyl] -amide

3-Methyl-lH-pyrrole-2-carboxylic acid [(S)-l-[(2-

83 amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3,4- difluoro-phenyl)-ethyl]-amide

lH-Indole-2-carboxylic acid [(S)-l-[(2-amino-

84 thiazol-5-ylmethyl)-carbamoyl]-2-(3,4-difluoro- phenyl)-ethyl] -amide

85 3-Methyl-lH-pyrrole-2-carboxylic acid [(S)-l-[(2- amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4-fluoro- phenyl)-ethyl] -amide

3-Methyl-lH-pyrrole-2-carboxylic acid [(S)-l-[(2-

86 amino-thiazol-5 -ylmethyl)-carbamoyl] -2-(3 -fluoro- pheny l)-ethy 1] -amide

3-Methyl-lH-pyrrole-2-carboxylic acid [(S)-l-[(2-

87 amino-thiazol-5-ylmethyl)-carbamoyl]-2-(2-fluoro- phenyl)-ethyl] -amide

3-Methyl-lH-pyrrole-2-carboxylic acid [(S)-l-[(2-

88 amino-thiazol-5-ylmethyl)-carbamoyl]-2-(4- chloro-phenyl)-ethyl]-amide

3 -Methyl- lH-pyrrole-2-carboxylic acid [(S)-l-[(2-

89 amino-thiazol-5-ylmethyl)-carbamoyl]-2-(3- chloro-pheny l)-ethyl] -amide

3-Methyl-lH-pyrrole-2-carboxylic acid {(S)-l-[(2-

90 amino-thiazol-5-ylmethyl)-carbamoyl]-2-p-tolyl- ethyl} -amide

3-Methyl-lH-pyrrole-2-carboxylic acid {(S)-l-[(2-

91 amino-thiazol-5-ylmethyl)-carbamoyl]-2-m-tolyl- ethyl} -amide

3 -Methyl- lH-pyrrole-2-carboxylic acid {(S)-l-[(2-

92 amino-thiazol-5-ylmethyl)-carbamoyl]-2-o-tolyl- ethyl} -amide

3-Methyl-lH-pyrrole-2-carboxylic acid {(S)-l-[(2-

93 amino-thiazol-5-ylmethyl)-carbamoyl]-2- cyclohexyl-ethyl } -amide

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

94 carbamoyl]-2-naphthalen- 1 -yl-ethyl } -2-hydroxy-3 - phenyl-propionamide

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

95 carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2- hydroxy-3-phenyl-propionamide

96 (R)-N-[(S)-1 -[(2-Amino-thiazol-5-ylmethyl)- carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-hydroxy- 3 -phenyl -propionamide

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

97 carbamoyI]-2-(3-fluoro-phenyl)-ethyl]-2-hydroxy- 3 -phenyl -propionamide

(R)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

98 carbamoyl]-2-(2-fluoro-phenyl)-ethyl]-2-hydroxy- 3 -phenyl -propionamide

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

99 carbamoyl] -2-(4-chloro-phenyl)-ethyl] -2 -hydroxy - 3 -phenyl -propionamide

(R)-N-[(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

100 carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-hydroxy- 3 -phenyl -propionamide

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

101 carbamoyl] -2-p-tolyl-ethyl } -2-hydroxy-3-phenyl- propionamide

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

102 carbamoyl]-2-m-tolyl-ethyl } -2-hydroxy-3-phenyl- propionamide

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

103 carbamoyl] -2-o-tolyl-ethyl } -2-hydroxy-3 -phenyl- propionamide

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

104 carbamoyl] -2-cyclohexyl-ethyl } -2-hydroxy-3 - phenyl-propionamide

(R)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

105 carbamoyl] -2-naphthalen- 1 -yl-ethyl } -2-hydroxy- butyramide

(R)-N- {(S)- 1 -[(2-Amino-thiazol-5-ylmethyl)-

106 carbamoyl]-2-naphthalen- 1 -yl-ethyl } -2-hydroxy-3 - methyl-butyramide

107 (S)-N-{(S)-l-[(2-Amino-thiazol-5-ylmethyl)- carbamoyl]-2-naphthalen- 1 -yl-ethyl } -2-hydroxy-3 - methyl-butyramide

(R)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

108 carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2- hydroxy-3-methyl-butyramide

(S)-N-[(S)-l-[(2-Amino-thiazol-5-ylmethyl)-

109 carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2- hydroxy-3 -methyl-butyramide

Biological Methods

The ability of the compounds of formula (I) to inhibit KLK1 may be determined using the following biological assays:

Determination of the ICso 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; Sttirzebecher et al, Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human KLK1 (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 ₅ o value for the test compound was determined.

Determination of enzyme selectivity

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.

Data acquired from these assays are shown in Tables 6 and 7 below:

TABLE 6

In vitro activity against KLK1

Example IC ₅₀ (nM)

No (KLK1)

1 10.2

2 3.5

3 2.01

4 10.54

5 13.18

6 1 17.1

7 283.0

8 6.66

9 15.36

10 4.22

1 1 1 11.66

12 1.70

13 7.30

14 27.03

15 265.7

16 18.28

17 3.69

18 4.56

19 15.21

20 0.87

21 92.32

22 128.98

23 85.05 24 56.32

25 289.93

26 7.26

27 5.71

28 4.86

29 42.79

30 9.27

31 18.80

32 96.58

33 10.29

34 14.28

35 5.73

36 139.02

37 30.70

38 289.93

39 7.33

40 37.72

41 15.51

42 224.61

43 0.90

44 365.82

45 27.69

46 7.33

47 37.23

48 1.28

49 0.35

50 2.95

51 1.64

52 40.36

53 7.79

54 17.60

55 57.19

56 1.15 57 0.25

58 7.58

59 1.64

60 3.04

61 19.43

62 1.82

63 9.05

64 7.52

65 2.57

66 30.45

67 9.50

68 20.02

69 23.86

70 87.69

71 1.77

72 71.59

73 5.71

74 21.52

75 37.67

76 4.43

77 21.65

78 110.44

79 17.03

80 83.11

81 412.08

82 19.21

83 33.19

84 131.02

85 50.29

86 5.73

87 368.73

88 25.39

89 17.58 90 81.43

91 28.52

92 102.33

93 >1000

94 39.19

95 49.81

96 76.76

97 114.42

98 1060.4

99 82.55

100 33.56

101 763.25

102 42.48

103 750.49

104 392.62

105 80.10

106 40.05

107 216.19

108 167.8

109 412.9

TABLE 7 (Selectivity data)

Additionally, examples 3 to 109 were tested and displayed IC50 values vs plasma kallikrein >1000nM.