TREA

Aminopyridine Derivatives

Follow

Information

  • Patent Application
  • 20100076015
  • Publication Number
    20100076015
  • Date Filed
    April 28, 2009
    17 years ago
  • Date Published
    March 25, 2010
    16 years ago
Information
Abstract
The present invention provides compounds of formula (I):
Description

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


BACKGROUND OF THE INVENTION

The aminopyridine 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, KLK1 (EC.3.4.21.35, also known as hK1, 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 (K. D. Bhoola et al., Pharmacological Rev., 1992, 44, 1). Kinins such as kallidin (Lys-bradykinin) and bradykinin are potent mediators of inflammation. The actions of kinins are mediated by activation of two main bradykinin receptor subtypes, B1 and B2, both of which are members of the seven trans-membrane G protein-coupled receptor families. B1 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, 113; 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 KLK1 plays a role in cancer (K. D. Bhoola et al., Curr. Opin. Invest. Drugs, 2007, 8, 462). KLK1 plays a role in increasing tumor invasiveness via activation of matrix metalloproteases, pro-collagenases and pro-gelatinases (K. D. Bhoola et al., Biol. Chem., 2001, 382, 77; H. Tschesche et al., Adv. Exp. Med. Biol., 1969, 247A, 545). Additionally KLK1 is indirectly involved in promoting proliferation through the liberation of mitogenic kinins (R. A. Roberts et al., J. Cell. Sci., 1989, 94, 527).


KLK1 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 KLK1 include the serpins, kallistatin, antiprotein C, α1-antitrypsin, and α1-antichymotrypsin. Aprotinin is also a potent non-selective KLK1 inhibitor. Low molecular weight inhibitors of KLK1 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., U.S. Pat. No. 5,464,820). KLK1 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, 117), citric acid induced cough (R. L. Featherstone et al., Lung, 1996, 174, 269) and acute pancreatitis (T. Griesbacher et al., Br. J. Pharmacol., 2002, 137, 692). KLK1 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 KLK1 inhibitor) (W. C. Wolf et al., Am. J. Pathol, 2001, 159, 1797). A human KLK1 antibody that inhibits KLK1 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).


Hyaluronic acid which binds and inactivates KLK1 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 (U.S. Pat. No. 5,187,157) and aminomethylcyclohexanoyl derivatives (N. Teno et al., Chem. Pharm. Bull., 1993, 41, 1079-1090).


The compounds of the present invention, and their pharmaceutically acceptable salts, have the advantage that they are selective inhibitors of KLK1 (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:


R1 and R2 are independently selected from H, OH, (C1-C10)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, (C3-C10)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C1-C4)alkyl- and heteroaryl(C1-C4)alkyl-;


R3 is selected from H, (C1-C10)alkyl and (C2-C6)alkenyl;


R4 and R5 are selected from H, (C1-C10)alkyl, (C2-C6)alkenyl, (C3-C10)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C1-C4)alkyl- and heteroaryl(C1-C4)alkyl-;


R6 and R7 are selected from H, (C1-C10)alkyl, (C2-C6)alkenyl, (C3-C10)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C1-C4)alkyl-, aryl(C2-C4)alkenyl-, heteroaryl(C1-C4)alkyl-, —SO2(C1-C6)alkyl, —SO2aryl and —SO2aryl(C1-C4)alkyl;

    • or R6 and R7 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 (C1-C6)alkyl, (C1-C6)alkoxy, halo, CN and hydroxyl, said N-containing ring may also optionally be fused to an aryl group;
    • or R4 and R6 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 (C1-C6)alkyl, (C1-C6)alkoxy, halo, CN and hydroxyl;
    • or R5 is absent and R4 and R6 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 (C1-C6)alkyl, (C1-C6)alkoxy, halo, CN, aryl, COOR14 and hydroxyl;
    • or R4 and R6 may together form a group according to formula II or formula III:







R8, R9 and R10 are independently selected from H, (C1-C10)alkyl, halogen, hydroxyl and (C1-C6)alkoxy;


R11 is selected from H and (C1-C6)alkyl;


R12 is selected from H and (C1-C6)alkyl;


R13 is selected from H, (C1-C6)alkyl, (C1-C6)alkoxy, OH, CN, CF3, COOR14, halo and NR14R15;


R14 and R15 are independently selected from H and (C1-C6)alkyl;


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 (C3-C10)cycloalkyl, (C1-C6)alkoxy, OH, CN, CF3, COOR14, halo and NR14R15;
    • alkenyl may optionally be substituted with 1 or 2 substituents independently selected from (C3-C10)cycloalkyl, (C1-C6)alkoxy, OH, CN, CF3, COOR14, halo and NR14R15;
    • alkoxy may optionally be substituted with 1 or 2 substituents independently selected from (C3-C10)cycloalkyl, OH, CN, CF3, COOR14, halo and NR14R15;
    • cycloalkyl is a non-aromatic mono- or bi-cylic 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 (C1-C6)alkyl, (C1-C6)alkoxy, OH, CN, CF3, COOR14 , halo and NR14R15;
    • 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, NR14, S(O)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 (C1-C6)alkyl, (C1-C6)alkoxy, OH, CN, CF3, halo, COOR14, NR14R15 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 (C1-C6)alkyl, (C1-C6)alkoxy, OH, halo, CN, COOR14, CF3 and NR14R15;
    • heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing 1 or 2 N atoms and, optionally, an NR14 atom, or one NR14 atom and an S or an O atom, or one S atom, or one O atom; wherein, unless otherwise stated, said heteroaryl may be optionally substituted with 1, 2 or 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, OH, halo, CN, COOR14, CF3 and NR14R15;
    • 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):


R1 is selected from (C1-C6)alkyl, (C3-C10)cycloalkyl, heterocycloalkyl, aryl and heteroaryl;


R2 is selected from H, (C1-C6)alkyl, OH, (C1-C6)alkoxy, (C3-C10)cycloalkyl and aryl;


R3 is selected from H and (C1-C6)alkyl;


R4 is selected from H, (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C4)alkyl-, aryl and aryl(C1-C4)alkyl-;


R5 is selected from H and (C1-C6)alkyl;


R6 is selected from H and (C1-C6)alkyl;


R7 is selected from H, (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C4)alkyl-, aryl, heteroaryl, aryl(C1-C4)alkyl-, aryl(C2-C4)alkenyl-, heteroaryl(C1-C4)alkyl- and —SO2(C1-C6)alkyl;

    • or R6 and R7 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 fused to an aryl group;
    • or R4 and R6 together with the atoms to which they are attached may form a 5 or 6 membered N-containing ring, optionally containing one carbon-carbon double bond, and optionally containing one further heteroatom selected from O and S, wherein said N-containing ring is optionally substituted on carbon with 1 or 2 substituents independently selected from (C1-C6)alkyl, halo, CN and hydroxyl;
    • or R5 is absent and R4 and R6 together with the atoms to which they are attached may form a 5, 6 or 9 membered mono- or bi-cyclic N-containing aromatic ring, optionally containing one further heteroatom selected from N and O, and optionally substituted on carbon with 1, 2 or 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, CN, aryl, COOR14 and hydroxyl;
    • or R4 and R6 may together form a group according to formula II or formula III:







R8, R9 and R10 are indepently selected from H, (C1-C10)alkyl, halogen, hydroxyl and (C1-C6)alkoxy;


R11 is selected from H and (C1-C10)alkyl;


R12 is selected from H and (C1-C6)alkyl;


R13 is H;


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, alkenyl, 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 R1 is selected from (C1-C10)alkyl, (C3-C10)cycloalkyl, aryl, heteroaryl and aryl(C1-C4)alkyl-.


In another aspect, the present invention provides a compound of formula (I) wherein R1 is selected from (C1-C6)alkyl, (C5-C10)cycloalkyl, aryl and heteroaryl.


In a further aspect, the present invention provides a compound of formula (I) wherein R1 is selected from (C5-C10)cycloalkyl, aryl and heteroaryl.


In a yet further aspect, the present invention provides a compound of formula (I) wherein R1 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 R2 is selected from H, (C1-C6)alkyl, OH, (C1-C6)alkoxy, (C3-C10)cycloalkyl and aryl.


In another aspect, the present invention provides a compound of formula (I) wherein R2 is selected from H, (C1-C6)alkyl, OH, (C1-C6)alkoxy and (C3-C10)cycloalkyl.


In yet another aspect, the present invention provides a compound of formula (I) wherein R2 is selected from H, OH and (C4-C6)cycloalkyl.


In a further aspect, the present invention provides a compound of formula (I) wherein R2 is H.


In one aspect, the present invention provides a compound of formula (I) wherein R3 is selected from H and (C1-C6)alkyl.


In another aspect, the present invention provides a compound of formula (I) wherein R3 is H.


In one aspect, the present invention provides a compound of formula (I) wherein R3 is H and the carbon atom to which R3 is attached is chiral and has an (S) configuration.


In another aspect, the present invention provides a compound of formula (I) wherein R3 is H and the carbon atom to which R3 is attached is chiral and has an (R) configuration.


In one aspect, the present invention provides a compound of formula (I) wherein R4 is selected from H, (C1-C10)alkyl, (C3-C10)cyclo alkyl, (C3-C10)cycloalkyl(C1-C4)alkyl-, aryl, heteroaryl, heteroaryl(C1-C4)alkyl- and aryl(C1-C4)alkyl-.


In another aspect, the present invention provides a compound of formula (I) wherein R4 is selected from (C1-C10)alkyl, (C3-C10)cycloalkyl, aryl, heteroaryl, heteroaryl(C1-C4)alkyl- and aryl(C1-C4)alkyl-.


In a further aspect, the present invention provides a compound of formula (I) wherein R4 is selected from H, (C1-C10)alkyl, (C3-C10)cycloalkyl, aryl and aryl(C1-C4)alkyl-.


In a yet further aspect, the present invention provides a compound of formula (I) wherein R4 is selected from H and (C1-C6)alkyl, (C4-C6)cycloalkyl, optionally substituted phenyl and optionally substituted phenyl(C1-C4)alkyl-. Optional substituents are selected from those defined above for ‘aryl’.


In one aspect, the present invention provides a compound of formula (I) wherein R5 is selected from H and (C1-C6)alkyl.


In another aspect, the present invention provides a compound of formula (I) wherein R5 is H.


In one aspect, the present invention provides a compound of formula (I) wherein one of R4 and R5 is H and the other of R4 and R5 is not H, and the carbon atom to which R4 and R5 is attached is chiral and has an (R) configuration.


In another aspect, the present invention provides a compound of formula (I) wherein one of R4 and R5 is H and the other of R4 and R5 is not H, and the carbon atom to which R4 and R5 is attached is chiral and has an (S) configuration.


In one aspect, the present invention provides a compound of formula (I) wherein R3 is H and the carbon atom to which R3 is attached is chiral and has an (R) configuration, and wherein one of R4 and R5 is H and the other of R4 and R5 is not H, and the carbon atom to which R4 and R5 are attached is chiral and has an (S) configuration.


In another aspect, the present invention provides a compound of formula (I) wherein R3 is H and the carbon atom to which R3 is attached is chiral and has an (S) configuration, and wherein one of R4 and R5 is H and the other of R4 and R5 is not H, and the carbon atom to which R4 and R5 are attached is chiral and has an (R) configuration.


In one aspect, the present invention provides compounds of formula (I) wherein R6 is selected from H, (C1-C10)alkyl, (C3-C10)cyclo alkyl, (C3-C10)cycloalkyl(C1-C4)alkyl-, aryl, aryl(C1-C4)alkyl- and —SO2(C1-C6)alkyl.


In another aspect, the present invention provides compounds of formula (I) wherein R6 is selected from H and (C1-C6)alkyl.


In a further aspect, the present invention provides compounds of formula (I) wherein R6 is H.


In one aspect, the present invention provides compounds of formula (I) wherein R7 is selected from H, (C1-C10)alkyl, (C3-C10)cyclo alkyl, (C3-C10)cycloalkyl(C1-C4)alkyl-, aryl, heteroaryl, aryl(C1-C4)alkyl-, aryl(C2-C4)alkenyl-, heteroaryl(C1-C4)alkyl-, —SO2(C1-C6)alkyl and —SO2aryl.


In another aspect, the present invention provides compounds of formula (I) wherein R7 is selected from H, (C1-C6)alkyl, (C3-C10)cycloalkyl, aryl, heteroaryl, aryl(C1-C4)alkyl-, aryl(C2-C4)alkenyl-, heteroaryl(C1-C4)alkyl- and —SO2(C1-C6)alkyl.


In a further aspect, the present invention provides compounds of formula (I) wherein R7 is selected from H, (C1-C6)alkyl, aryl, aryl(C1-C4)alkyl-, aryl(C2-C4)alkenyl-, heteroaryl(C1-C4)alkyl- and —SO2(C1-C6)alkyl.


In a yet further aspect, the present invention provides compounds of formula (I) wherein R7 is selected from H, (C1-C6)alkyl, phenyl and phenyl(C1-C4)alkyl-.


In a still further aspect, the present invention provides compounds of formula (I) wherein R7 is selected from H and (C1-C6)alkyl.


In one aspect, the present invention provides compounds of formula (I) wherein R6 and R7 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 (C1-C6)alkyl, (C1-C6)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 compounds of formula (I) wherein R6 and R7 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 O, and optionally substituted with 1 or 2 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, CN and hydroxyl, said N-containing ring may also optionally be fused to an aryl group.


In a further aspect, the present invention provides compounds of formula (I) wherein R6 and R7 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 O, and optionally fused to a phenyl group.


In a yet further aspect, the present invention provides compounds of formula (I) wherein R6 and R7 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 O, and optionally substituted with 1 or 2 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, CN and hydroxyl.


In a yet further aspect still, the present invention provides compounds of formula (I) wherein R6 and R7 together with the nitrogen atom to which they are attached may form a group selected from pyrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, piperidinyl and morpholinyl, wherein each of said groups may optionally be substituted with 1, 2 or 3 substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo and hydroxyl.


In one aspect, the present invention provides compounds of formula (I) wherein R4 and R6 together with the atoms to which they are attached may form a saturated or 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 (C1-C6)alkyl, (C1-C6)alkoxy, halo, CN and hydroxyl;


In another aspect, the present invention provides compounds of formula (I) wherein R4 and R6 together with the atoms to which they are attached may form a 4-7 membered N-containing ring, optionally containing one carbon-carbon double bond, optionally containing one further heteroatom selected from N, O and S, and optionally substituted on carbon with 1 or 2 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, CN and hydroxyl. Typically in this aspect, R5 is H and the carbon to which R4 and R5 are attached is chiral and has an (R) configuration.


In yet another aspect, the present invention provides compounds of formula (I) wherein R4 and R6 together with the atoms to which they are attached may form a 5 or 6 membered N-containing ring, optionally containing one carbon-carbon double bond, and optionally containing one further heteroatom selected from O and S, wherein said N-containing ring is optionally substituted on carbon with 1 or 2 substituents independently selected from (C1-C6)alkyl, halo, CN and hydroxyl. Typically in this aspect, R5 is H and the carbon to which R4 and R5 are attached is chiral and has an (R) configuration.


In a further aspect, the present invention provides compounds of formula (I) wherein R5 is absent and R4 and R6 together with the atoms to which they are attached may form a 5, 6 or 9 membered N-containing mono- or bi-cyclic aromatic ring, optionally containing one further heteroatom selected from N and O, and optionally substituted on carbon with 1, 2 or 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, aryl, COOR14 and hydroxyl.


In a yet further aspect, the present invention provides compounds of formula (I) wherein R4 and R6 together with the atoms to which they are attached may form a group selected from pyrolidinyl, thiazolidinyl, tetrahydroisoquinolinyl, dihydro-1H-pyrrolyl, piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, indolyl and benzimidazolyl, wherein each of said groups may optionally be substituted with 1, 2 or 3 substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, aryl, COOR14 and hydroxyl.


In one aspect, the present invention provides compounds of formula (I) wherein R4 and R6 may together form a group according to formula II or formula III:







wherein R13 is H and f and g are independently selected from 0, 1, 2 and 3, such that f+g=1, 2 or 3; and h is selected from 1 and 2.


In one aspect, the present invention provides compounds of formula (I) wherein R8, R9 and R10 are independently selected from H, (C1-C10)alkyl and halogen.


In another aspect, the present invention provides compounds of formula (I) wherein R8, R9 and R10 are independently selected from H and (C1-C6)alkyl.


In a further aspect, the present invention provides compounds of formula (I) wherein R8, R9 and R10 are independently selected from H and methyl.


In a yet further aspect, the present invention provides compounds of formula (I) wherein one of R8, R9 and R10 is methyl and the other two are H.


In a yet further aspect still, the present invention provides compounds of formula (I) wherein R8, R9 and R10 are H.


In one aspect, the present invention provides compounds of formula (I) wherein R11 is H.


In one aspect, the present invention provides compounds of formula (I) wherein R12 is H.


In one aspect, the present invention provides a compound of formula (I) selected from:


(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Benzyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-2-(Methanesulfonyl-methyl-amino)-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-(2-diethylamino-acetylamino)-3-(3,4-difluoro-phenyl)-propionamide;


(S)-2-Amino-3-methyl-pentanoic acid {(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide;


(S)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide;


(R)-2-Amino-N—[(S)-1-[(6-amino-pyridin-3-ylmethyl)carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-3-(4-chloro-phenyl)-propionamide;


(R)-2-Amino-N—[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-3-methyl-butyramide;


(R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide;


(R)-2-Amino-4-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide;


(S)-2-(2-Amino-acetylamino)-N-(6-amino-pyridin-3-ylmethyl)-3-(decahydro-naphthalen-1-yl)-propionamide;


(R)-2-Amino-N—[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(decahydro-naphthalen-1-yl)-2-(2-methylamino-acetylamino)-propionamide;


(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide;


(R)-2-Amino-N—{(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-3-methyl-butyramide;


(R)-Pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-phenyl-ethyl}-amide;


(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide;


(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-o-tolyl-ethyl}-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-cyano-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-2-yl-ethyl}-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-pentafluorophenyl-ethyl}-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-tert-butyl-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-2-Amino-N—[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-phenyl-propionamide;


(R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(S)-Thiazolidine-4-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(S)-2-((R)-2-Amino-2-phenyl-acetylamino)-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-propionamide;


(S)-2-((S)-2-Amino-2-phenyl-acetylamino)-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-propionamide;


(R)-2-Amino-N—[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-(4-chloro-phenyl)-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-methylamino-3-phenyl-propionamide;


(R)-2-Amino-N—[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3,3-dimethyl-butyramide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-methylamino-propionamide;


(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-2,5-Dihydro-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-4,4-Difluoro-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-2-Amino-N—[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-4-phenyl-butyramide;


(R)-2-Amino-N—[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-cyclohexyl-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-2-(2-methylamino-acetylamino)-propionamide;


(R)-2-Amino-N—[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-3-(4-chloro-phenyl)-propionamide;


(R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-Piperidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-ylethyl}-amide;


(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide;


(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


(R)-Piperidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-methylamino-acetylamino)-propionamide;


(R)-2-Amino-N—[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-3-phenyl-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-methylamino-3-phenyl-propionamide;


(S)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(S)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-methylamino-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-methylamino-propionamide;


N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-methyl-2-methylamino-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-methylamino-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-methylamino-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-3-methyl-2-methylamino-butyramide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-pentafluorophenyl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-methoxy-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-phenyl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-tert-butyl-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-o-tolyl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-p-tolyl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-methoxy-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-fluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2,4-dichloro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-pyridin-4-yl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-quinolin-2-yl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide;


(S)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-o-tolyl-ethyl}-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-p-tolyl-ethyl}-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-methoxy-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-fluoro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2,4-dichloro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-pyridin-4-yl-ethyl}-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide;


(R)-1-Ethyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Propyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide


(R)-1-Isobutyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


{(R)-2-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethylcarbamoyl]-pyrrolidin-1-yl}-acetic acid methyl ester;


{(R)-2-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethylcarbamoyl]-pyrrolidin-1-yl}-acetic acid;


(R)-1-Ethyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-1-Ethyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide;


(R)-1-Ethyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


(R)-1-Propyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-1-Benzyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Benzyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-1-(4-Chloro-benzyl)-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-(3-Chloro-benzyl)-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(2R,4R)-4-Hydroxy-1-methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-2-Methyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-2-[2-(isopropyl-methyl-amino)-acetylamino]-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-[2-(benzyl-methyl-amino)-acetylamino]-3-(3,4-dichloro-phenyl)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-2-(2-dimethylamino-acetylamino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-2-[2-(isobutyl-methyl-amino)-acetylamino]-propionamide;


(R)-2-(Isopropyl-methyl-amino)-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-[2-(isopropyl-methyl-amino)-acetylamino]-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-diisopropylamino-acetylamino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-dipropylamino-acetylamino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-diisobutylamino-acetylamino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-phenethylamino-acetylamino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-[2-(methyl-phenethyl-amino)-acetylamino]-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-{2-[methyl-((E)-3-phenyl-allyl)-amino]-acetylamino}-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-{2-[(4-chloro-benzyl)-methyl-amino]-acetylamino}-3-(3,4-difluoro-phenyl)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-{2-[(3-chloro-benzyl)-methyl-amino]-acetylamino}-3-(3,4-difluoro-phenyl)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-{2-[(2-chloro-benzyl)-methyl-amino]-acetylamino}-3-(3,4-difluoro-phenyl)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-{2-[(4-methoxy-benzyl)-methyl-amino]-acetylamino}-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-[2-(butyl-methyl-amino)-acetylamino]-3-(3,4-difluoro-phenyl)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-[2-(isobutyl-methyl-amino)-acetylamino]-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-[2-(cyclohexylmethyl-methyl-amino)-acetylamino]-3-(3,4-difluoro-phenyl)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-piperidin-1-yl-acetylamino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-morpholin-4-yl-acetylamino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-3,4-dihydro-1H-isoquinolin-2-yl-acetylamino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-3,4-dihydro-2H-quinolin-1-yl-acetylamino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-[2-(methyl-phenyl-amino)-acetylamino]-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(isobutyl-methyl-amino)-propionamide;


(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-dimethylamino-3,3-dimethyl-butyramide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-dimethylamino-3,3-dimethyl-butyramide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-isopropylamino-3-phenyl-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-dimethylamino-3-phenyl-propionamide;


(R)-2-Amino-N—[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-3-methyl-butyramide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide;


(2R)-3-Methyl-2-methylamino-pentanoic acid [(R)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-Pyrrolidine-2-carboxylic acid [(R)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(R)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(S)-Thiazolidine-4-carboxylic acid [(R)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-4,4-Difluoro-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(S)—N—[(R)-1-[(6-Amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-methylamino-3-phenyl-propionamide;


(R)-2-Amino-N—[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-propionamide;


(R)-2-Amino-N—[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-(4-chloro-phenyl)-propionamide;


(R)-2-Amino-N—[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-pyridin-3-yl-propionamide;


(R)—N-(6-Amino-2-methyl-pyridin-3-ylmethyl)-2-((S)-2-amino-2-phenyl-acetylamino)-3-(3,4-dichloro-phenyl)-propionamide;


(S)-2-((R)-2-Amino-2-cyclohexyl-acetylamino)-N-(6-amino-2-methyl-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-propionamide;


(R)-2-Amino-N—[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3,3-dimethyl-butyramide;


(R)-2-Amino-N—[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-cyclohexyl-propionamide;


(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-1,2,3,4-Tetrahydro-quinoline-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid {(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-2,4-dimethyl-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide;


(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-5-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


(R)-1-Methanesulfonyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)-2-Methanesulfonylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-(methanesulfonyl-methyl-amino)-propionamide;


(R)-2-(Methanesulfonyl-methyl-amino)-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide;


(R)-2-Amino-3-methyl-pentanoic acid {(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide;


(S)-Pyrrolidine-2-carboxylic acid {(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide;


(S)-2-Amino-N—{(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-3-phenyl-propionamide;


(S)-2-Amino-N—{(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-3,3-dimethyl-butyramide;


(S)—N—{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-2-methylamino-propionamide;


(S)-3-Methyl-2-methylamino-pentanoic acid {(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide;


(R)-2-(2-Amino-acetylamino)-N-(6-amino-pyridin-3-ylmethyl)-3,3-dicyclohexyl-propionamide;


(R)—N-(6-Amino-pyridin-3-ylmethyl)-3,3-dicyclohexyl-2-(2-methylamino-acetylamino)-propionamide;


(R)—N-(6-Amino-pyridin-3-ylmethyl)-3,3-dicyclohexyl-2-(2-dimethylamino-acetylamino)-propionamide;


(S)-1-Methyl-pyrrolidine-2-carboxylic acid {(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide;


(S)-2-Amino-3-methyl-pentanoic acid {(1R,2R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-hydroxy-2-phenyl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-phenyl-ethyl}-methyl-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


1H-Pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide;


1H-Pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


1H-Pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


3,4,5-Trimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-phenyl-ethyl}-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(;6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-o-tolyl-ethyl}-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-pentafluorophenyl-ethyl}-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-biphenyl-4-yl-ethyl}-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-p-tolyl-ethyl}-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-methoxy-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-tert-butyl-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-quinolin-2-yl-ethyl}-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-trifluoromethyl-phenyl)-ethyl]-amide;


4-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


4-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2,5-dichloro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-fluoro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-trifluoromethyl-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide;


5-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-1H-pyrrole-2-carboxylic acid methyl ester;


5-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-1H-pyrrole-2-carboxylic acid;


5-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-4-methyl-1H-pyrrole-2-carboxylic acid;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


1H-Imidazole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


1H-Imidazole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;


1H-Imidazole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


1-Methyl-1H-imidazole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


5-p-Tolyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


5-p-Tolyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide;


5-p-Tolyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


5-p-Tolyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide;


5-p-Tolyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


5-p-Tolyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


1H-Benzoimidazole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


5-Methoxy-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


5-Fluoro-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


5-Hydroxy-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


5-Methoxy-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


5-Fluoro-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


1-Methyl-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;


5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid [(R)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide;


5-Methoxy-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide;


1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide; 5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


5-Fluoro-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


1H-Benzoimidazole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-pentafluorophenyl-ethyl}-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


5-Fluoro-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


1H-Benzoimidazole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-methoxy-phenyl)-ethyl]-amide;


1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide;


1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide;


5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide;


1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide;


(S)-3-Methyl-2-methylamino-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-methyl-2-methylamino-butyramide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-3-methyl-2-methylamino-butyramide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-methylamino-3-phenyl-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(cyclohexylmethyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-dimethylamino-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(ethyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(methyl-propyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(butyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-3-methyl-butyramide;


(S)-2-(Isopropyl-methyl-amino)-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-diisopropylamino-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-dimethylamino-3-phenyl-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(ethyl-methyl-amino)-3-phenyl-propionamide;


(S)-2-(Isopropyl-methyl-amino)-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-diethylamino-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-pyrrolidin-1-yl-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-pyrrolidin-1-yl-propionamide;


(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-dimethylamino-3-methyl-butyramide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-3-hydroxy-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(ethyl-methyl-amino)-3-hydroxy-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-diethylamino-3-hydroxy-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-diethylamino-3-hydroxy-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-3-diethylamino-succinamic acid methyl ester;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-[2-(2,6-dimethyl-piperidin-1-yl)-acetylamino]-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-pyrrolidin-1-acetylamino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-(ethyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-(methyl-propyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-(butyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-3-methyl-butyramide;


(S)-2-(Isopropyl-methyl-amino)-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-diisopropylamino-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2(isopropyl-methyl-amino)-3-phenyl-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-2-diethylamino-propionamide;


(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-[2-(2,6-dimethyl-piperidin-1-yl)-acetylamino]-3-(4-fluoro-phenyl)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(4-fluoro-phenyl)-2-(2-piperidin-1-yl-acetylamino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-(2-diethylamino-acetylamino)-3-(4-fluoro-phenyl)-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-(isopropyl-methyl-amino)-propionamide;


(S)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-(methyl-propyl-amino)-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-(ethyl-methyl-amino)-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-dipropylaminopropionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-dimethylamino-3-hydroxy-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-(ethyl-methyl-amino)-3-hydroxy-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-3-hydroxy-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-diethylamino-3-hydroxy-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-diethylamino-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-dimethylamino-propionamide;


(S)—N—(6-Amino-pyridin-3-ylmethyl)-3-cyclohexyl-2-[2-(2,6-dimethyl-piperidin-1-yl)-acetylamino]-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-cyclohexyl-2-(2-diisopropylamino-acetylamino)-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(decahydro-naphthalen-1-yl)-2-(2-diisopropylamino-acetylamino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-2-dimethylamino-3-phenyl-propionamide;


(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-dimethylamino-3-methyl-butyramide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-dimethylamino-3-phenyl-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-2-(2-piperidin-1-yl-acetylamino)-propionamide;


(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-dimethylamino-3-methyl-butyramide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-dimethylamino-3-phenyl-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-(ethyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-diethylamino-propionamide;


N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3-chloro-phenyl)-2-(2-piperidin-1-yl-acetylamino)-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-2-(ethyl-methyl-amino)-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-2-diethylamino-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-2-(ethyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-2-diethylamino-propionamide;


N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-(2-piperidin-1-yl-acetylamino)-3-(3-trifluoromethyl-phenyl)-propionamide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-trifluoromethyl-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-trifluoromethyl-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-(2-piperidin-1-yl-acetylamino)-3-(4-trifluoromethyl-phenyl)-propionamide;


(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-amide;


N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(4-chloro-phenyl)-2-[2-(2,6-dimethyl-piperidin-1-yl)-acetylamino]-propionamide;


(S)-2-[(S)-2-(Isopropyl-methyl-amino)-propionylamino]-4-methyl-pentanoic acid (6-amino-pyridin-3-ylmethyl)-amide;


(S)—N-(6-Amino-2-methyl-pyridin-3-ylmethyl)-2-(2-diethylamino-acetylamino)-3-(4-fluoro-phenyl)-propionamide;


(S)—N-(6-Amino-2-methyl-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-[2-(2,6-dimethyl-piperidin-1-yl)-acetylamino]-propionamide;


(S)—N-(6-Amino-2-methyl-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-piperidin-1-yl-acetylamino)-propionamide;


(R)—N—[(S)-1-[(6-Amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N—[(S)-1-[(6-Amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-piperidin-1-yl-propionamide;


(S)—N—{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-2-dimethylamino-propionamide;


(S)—N—{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-2-hydroxy-ethyl}-2-(isopropyl-methyl-amino)-propionamide;


(R)—N-(6-Amino-pyridin-3-ylmethyl)-3-cyclohexyl-2-[(S)-2-(isopropyl-methyl-amino)-propionylamino]-butyramide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-(isopropyl-methyl-amino)-N-methyl-propionamide;


S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-diethylamino-N-methyl-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-dipropylamino-propionamide;


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


In another aspect, the present invention provides a compound of formula (I) selected from:


(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-1-Ethyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Propyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Isobutyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Ethyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-diisopropylamino-acetylamino)-propionamide;


(R)-1-Methyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-dimethylamino-3,3-dimethyl-butyramide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


(S)-1-Methyl-pyrrolidine-2-carboxylic acid {(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;


3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;


3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-methyl-2-methylamino-butyramide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(ethyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-diethylamino-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-diethylamino-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;


(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-dimethylamino-3-methyl-butyramide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-2-(isopropyl-methyl-amino)-propionamide;


(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;


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 and ascites build-up.


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.


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 KLK1 inhibitor can be used to ameliorate at least one symptom of COPD.


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 KLK1 inhibitor can be used to ameliorate or prevent at least one symptom of cough.


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 KLK1 inhibitor can be used to ameliorate or prevent at least one symptom of pancreatitis.


Rheumatoid Arthritis (RA)


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 KLK1 inhibitor may be used to ameliorate or prevent at least one symptom of rheumatoid arthritis. A KLK1 inhibitor can be administered with another agent for treating rheumatoid arthritis, such as NSAIDs and aspirin, analgesics and corticosteroids which help reduce joint pain, stiffness and swelling.


Osteoarthritis


Osteoarthritis is a degenerative joint disease. It is characterised by the breakdown of cartilage in the joint, thus causing bones to rub against each other, causing pain and loss of movement. A KLK1 inhibitor can be used to ameliorate or prevent at least one symptom of osteoarthritis. A KLK1 inhibitor can be administered with another agent for treating rheumatoid arthritis, such as a corticosteroid or an NSAID.


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 tumour.


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-fluorouracil, purine and adenosine analogues, cytosine arabinoside); Intercalating antitumour antibiotics (e.g. anthracyclines like doxorubicin, daunomycin, epirubicin); platinum derivatives (e.g. cisplatin, carboplatin)alkylating agents (e.g. chlorambucil, cyclophosphamide); antmitotic agents (e.g. 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 KLK1 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 the treatment or prevention of a disease or condition in which KLK1 activity is implicated. Diseases or conditions in which KLK1 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 KLK1 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 KLK1 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 KLK1 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 or a neoplastic disorder.


In another aspect, the disease or condition in which KLK1 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 a further aspect, the disease or condition in which KLK1 activity is implicated is a respiratory disorder selected from asthma (allergic and non-allergic) and cough.


DEFINITIONS

The term “alkyl” includes saturated hydrocarbon residues including:

    • linear groups up to 10 atoms (C1-C10), or of up to 6 atoms (C1-C6), or of up to 4 atoms (C1-C4). Examples of such alkyl groups include, but are not limited, to C1-methyl, C2-ethyl, C3-propyl and C4-n-butyl.
    • branched groups of between 3 and 10 atoms (C3-C10), or of up to 7 atoms (C3-C7), or of up to 4 atoms (C3-C4). Examples of such alkyl groups include, but are not limited to, C3-iso-propyl, C4-sec-butyl, C4-iso-butyl, C4-tert-butyl and C5-neo-pentyl.


each optionally substituted as stated above.


The term “alkenyl” includes monounsaturated hydrocarbon residues including:

    • linear groups of between 2 and 6 atoms (C2-C6). Examples of such alkenyl groups include, but are not limited to, C2-vinyl, C3-1-propenyl, C3-allyl, C4-2-butenyl
    • branched groups of between 3 and 8 atoms (C3-C8). Examples of such alkenyl groups include, but are not limited to, C4-2-methyl-2-propenyl and C6-2,3-dimethyl-2-butenyl.


each optionally substituted as stated above.


The term “alkoxy” includes O-linked hydrocarbon residues including:

    • linear groups of between 1 and 6 atoms (C1-C6), or of between 1 and 4 atoms (C1-C4). Examples of such alkoxy groups include, but are not limited to, C1-methoxy, C2-ethoxy, C3-n-propoxy and C4-n-butoxy.
    • branched groups of between 3 and 6 atoms (C3-C6) or of between 3 and 4 atoms (C3-C4). Examples of such alkoxy groups include, but are not limited to, C3-iso-propoxy, and C4-sec-butoxy and tert-butoxy.


each optionally substituted as stated above.


Unless otherwise stated, halo is selected from Cl, 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-1,3-diene, cyclohexene and cyclohexa-1,4-diene (optionally substituted as stated above). Examples of suitable bicyclic cycloalkyl groups include decahydronaphthalene, octahydro-1H-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-linked 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(C1-C4)alkyl- and —SO2(C1-C6)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, 2nd Ed. pp 561-585 (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, diastereomeric and tautomeric forms, including but not limited to cis- and trans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, 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:







Other 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 l-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.


In the present case, compounds of the present invention may be conveniently combined with an additional therapeutic agent or agents.


For example, as mentioned above, 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.


If a combination of active agents is administered, then they may be administered simultaneously, separately or sequentially.


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 60 kg to 70 kg. 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, 4th Edition, 2006, may be used. For example, a common amino protecting group suitable for use herein is tert-butoxy carbonyl (Boc), which is readily removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as dichloromethane. Alternatively the amino protecting group may be a benzyloxycarbonyl (Z) group which can be removed by hydrogenation with a 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:


R1-R7 and R11 are as previously defined for the compounds of formula (I);


PG1, PG2 or PG3 is a suitable protecting group;


R20 is H, (C1-C10)alkyl, halogen, hydroxyl or (C1-C6)alkoxy;


R21 is H, (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C4)alkyl-, aryl, heteroaryl, aryl(C1-C4)alkyl-, aryl(C2-C4)alkenyl-, or heteroaryl(C1-C4)alkyl-;


R22 is H, (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C4)alkyl-, aryl, heteroaryl, aryl(C1-C4)alkyl-, aryl(C2-C4)alkenyl-, or heteroaryl(C1-C4)alkyl-; and


R23 is H, (C1-C6)alkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C4)alkyl-, aryl or aryl(C1-C4)alkyl-.


The compounds according to general formula I can be prepared using conventional synthetic methods. In a typical first step, 5-aminomethyl-pyridin-2-ylamine or substituted 5-aminomethyl-pyridin-2-ylamine (3) is prepared by reduction of the corresponding nitrile (2). This can be achieved either by direct reduction of the nitrile by hydrogenation in a suitable solvent such as methanol in the presence of a suitable catalyst such as palladium on charcoal in the presence of an acid such as hydrochloric acid or reduction with a suitable borohydride in the presence of a suitable transition metal such as cobalt or nickel chloride in a suitable solvent such as methanol at room temperature; or by trapping out of the tert-butoxycarbonyl (Boc) protected amine(4) (using, for example, the method as described in S. Caddick et al., Tetrahedron Lett., 2000, 41, 3513) which is then subsequently deprotected by standard means described previously to give the amine(3).







Alternatively amine (3) can be prepared from the corresponding acid (5) via a primary amide (6). Typically, acid (5) is treated with ammonia in the presence of a suitable coupling reagent in a suitable solvent such as dichloromethane and DMF at room temperature. The resulting amide (6) is then reduced with a reducing agent such as lithium aluminium hydride in a suitable solvent such as tetrahydrofuran at room temperature to yield amine (3).







In a typical second step, the amine (3) is coupled using standard peptide coupling conditions to an alpha amino acid (7) 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 R21 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-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate or benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoium hexaffluorophosphate or bromo-trispyrolidino-phosphoium hexafluorophosphate in the presence of organic bases such as triethylamine, diisopropylethylamine or N-methylmorpholine.


Error! Objects cannot be Created from Editing Field Codes

The protecting group of (8) is removed using standard methods described previously to yield the amine (9).







The amine (9) is coupled using the standard peptide coupling conditions described previously to an alpha amino acid (10) suitably amino-protected with a suitable protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenylmethyloxycarbonyl (Fmoc). Where R1 or R2 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 (11) is removed using the standard methods described previously to give the amine (12).







The amine (12) is further derivatised by reductive alkylation with a suitable aldehyde or ketone to yield the alkylated amine (13). Typically, amine (12) 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 15 can also be prepared by coupling the alkylated alpha amino acid (14) with the amine (9) using standard peptide coupling conditions described previously.







Alkylated alpha amino acids (17) can be prepared by the reductive alkylation of the parent alpha amino acid in which the carboxyl group is unprotected (16) or in which it is protected as an ester with a standard protecting group such as a methyl, tert-butyl or trichloroethyl ester (18), following alkylation this protecting group is removed using standard methods described previously. Typical conditions for carrying out the reductive alkylation are described above.







Alternatively the alpha amino acid (14) may be prepared from the corresponding bromoacetic acid derivative, suitably carboxyl-protected with a standard protecting group, such as a methyl, tert-butyl, trichloroethyl ester (19) by reaction with the required amine followed by the deprotection using standard methods. Typically, bromoacetic acid derivative (19) is allowed to react with the amine in the presence of a base such as diisopropylethylamine or potassium or sodium carbonate in a suitable solvent such as acetonitrile or tetrahydrofuran at room temperature.







Compound (11) can also be synthesised from the dipeptide (22) 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 (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.







The amine 12 can be further derivatised by reaction with a sulphonyl chloride in the presence of a base such as triethylamine or diisopropylamine to yield the sulphonamide (23).







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)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-carbamic acid tert-butyl ester;


(S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-naphthalen-1-yl-propionamide ditrifluoroacetate;


((R)-1-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethylcarbamoyl}-2-methyl-butyl)-carbamic acid tert-butyl ester;


[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-carbamic acid tert-butyl ester;


(S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-(decahydro-naphthalen-1-yl)-propionamide dihydrochloride;


{(R)-1-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethylcarbamoyl]-2-methyl-butyl}-carbamic acid tert-butyl ester;


{(S)-1-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-methyl-butyl}-carbamic acid tert-butyl ester;


(S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-propionamide dihydrochloride;


{(R)-1-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-methyl-butyl}-methyl-carbamic acid tert-butyl ester;


(R)-2-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester;


[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester;


(S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-propionamide dihydrochloride;


{(S)-1-[(6-Amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-carbamic acid tert-butyl ester;


(S)-2-Amino-N-(6-amino-2-methyl-pyridin-3-ylmethyl)-3-naphthalen-1-yl-propionamide dihydrochloride;


{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-carbamic acid tert-butyl ester;


(R)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3,3-dicyclohexyl-propionamide ditrifluoroacetate; and


((S)-1-{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethylcarbamoyl}-2-methyl-butyl)-carbamic acid tert-butyl ester.


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







comprising the reaction of a compound of formula (IV):







with a compound of formula (V):







under standard peptide coupling conditions; wherein R1-R12 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-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate or benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoium hex affluorophosphate or bromo-trispyrolidino-phophoium 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


HBTU
2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium



hexafluorophosphate


HOBt
Hydroxybenzotriazole


Ile
Isoleucine


LCMS
Liquid chromatography mass spectrometry


Me
Methyl


MeCN
Acetonitrile


MeOH
Methanol


Min
Minutes


MS
Mass spectrum


Nal
Napthylalanine


NMR
Nuclear magnetic resonance spectrum - NMR spectra were



recorded at a frequency of 270 or 400 MHz unless otherwise



indicated


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


Phe
Phenylalanine


Pro
Proline


PyBOP ®
Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoium



hexafluorophosphate


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 Jeol EX 270 (270 MHz) or Brucker Avance III (400 MHz) 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, 50×4.6 mm, with a linear gradient 10% to 90% 0.1% HCO2H/MeCN into 0.1% HCO2H/H2O 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 20 ml/min using a Waters 2996 photodiode array detector.


All solvents and commercial reagents were used as received.


Example 1
(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide






A. (6-Amino-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester

2-Amino-5-cyanopyridine (2.0 g, 16.8 mmol) was dissolved in methanol (100 ml). This solution was cooled to 0° C. Nickel (II) chloride hexahydrate (0.4 g, 1.67 mmol) and di-tertbutyl dicarbonate (7.33 g, 33.6 mmol) were added followed by sodium borohydride (4.49 g, 117 mmol) portionwise. The reaction mixture was stirred at 0° C. to room temp for 18 hrs. The MeOH was removed by evaporation. The residue was dissolved in EtOAc (100 ml), washed with sat NaHCO3 (1×50 mls), water (1×50 mls), brine (1×50 mls), dried (Na2SO4) and evaporated in vacuo to give a brown oil. Purified by flash chromatography, eluant 3% MeOH, 97% CHCl3 to give an orange oil identified as the title compound.


Yield=2.74 g, 12.25 mmol, 73%


[M+H]+=224.1


B. 5-Aminomethyl-pyridin-2-ylamine dihydrochloride

(6-Amino-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (2.74 g, 12.25 mmol) was dissolved in 4M HCl/dioxan (50 mls). After one hour at room temp the solvent was removed in vacuo to give a pale yellow solid identified as the title compound.


Yield=2.3 g, 12.1 mmol, 99%


[M+H]+=124.1


C. {(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-carbamic acid tert-butyl ester

Boc-1Nal-OH (1.0 g, 2.66 mmol) was dissolved in CH2Cl2 (30 mls). Triethylamine (0.805 g, 7.96 mmol) and HBTU (1.21 g, 3.18 mmol) was added followed by 5-aminomethyl-pyridin-2-ylamine dihydrochloride (0.52 g, 2.66 mmol). After 3 hours at room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 97% CHCl3, fractions combined and evaporated in vacuo to give a colourless oil identified as the title compound.


Yield=1.18 g, 2.15 mmol, 81%


[M+H]+=421.27


D. (S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-naphthalen-1-yl-propionamide ditrifluoroacetate

{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-carbamic acid tert-butyl ester (1.18 g, 2.81 mmol) was treated with trifluoroacetic acid (30 mls). After 1 hour at room temperature the solvent was removed in vacuo giving a pale brown solid identified as the title compound.


Yield=1.53 g, 2.8 mmol, 99%


[M+H]+=321.1


E. ((R)-1-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethylcarbamoyl}-2-methyl-butyl)-carbamic acid tert-butyl ester

(S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-naphthalen-1-yl-propionamide ditrifluoroacetate (120 mg, 0.22 mmol) was dissolved in CH2Cl2 (20 mls) and DMF (2 mls). This solution was cooled to 0° C. Boc-DIle-OH (65 mg, 0.28 mmol) was added followed by HOBt (65 mg, 0.48 mmol) and water soluble carbodiimide (62 mg, 0.31 mmol). After 15 mins triethylamine (49 mg, 0.49 mmol) was added. After 18 hrs 0° C. to room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 97% CHCl3, fractions combined and evaporated in vacuo to give a colourless oil identified as the title compound.


Yield=98 mg, 0.18 mmol, 81%


[M+H]+=534.3


F. (R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide ditrifluoroacetate

((R)-1-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethylcarbamoyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (89 mg, 0.16 mmol) was treated with trifluoroacetic acid (30 mls). After 1 hour at room temperature the solvent was removed in vacuo and the residue purified by Prep HPLC. (19×250 mm Sunfire C-18 Column) 10 to 90% 0.1% TFA/MeCN into 0.1%TFA/H2O over 35 min at 20 ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.


Yield 65 mg, 0.125 mmol, 78%


[M+H]+=434.2



1H NMR: (270 MHz) (CD3OD) 0.75 (6H, t, J=6.9 Hz), 1.1-1.2 (1H, m), 1.7-1.8 (1H, m), 3.31-3.37 (3H, m), 3.66-3.72 (3H, m), 4.14-4.26 (2H, m), 4.82-4.90 (5H, m), 6.87 (1H, d, J=8.4 Hz), 7.39 (2H, s), 7.49-7.61 (3H, m), 7.76-7.79 (1H, m), 7.86-7.89 (1H, m), 8.16-8.19 (1H, m), 8.65 (1H,s, br).


Example 2
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide






A. (S)-2-tert-Butoxycarbonylamino-3-(decahydro-naphthalen-1-yl)-propionic acid

Boc-1-napthylalanine (6.0 g, 19.053 mmol) was dissolved in methanol (150 mls). This solution was hydrogenated over 5% Rh on carbon (100 mg) at 70 psi and room temperature. After 2 days the catalyst was filtered off through celite and the residue washed with MeOH (100 mls). The combined filtrates were evaporated in vacuo to give a pale yellow oil identified as the title compound.


Yield=6.15 g, 19.05 mmol, 100%


B. [(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-carbamic acid tert-butyl ester

(S)-2-tert-Butoxycarbonylamino-3-(decahydro-naphthalen-1-yl)-propionic acid (800 mg, 2.43 mmol) was dissolved in CH2Cl2 (60 mls) and DMF (62 mls). This solution was cooled to 0° C. 5-Aminomethyl-pyridin-2-ylamine dihydrochloride (760 mg, 3.86 mmol) was added followed by HOBt (680 mg, 5.0 mmol) and water soluble carbodiimide (590 mg, 2.95 mmol). After 15 mins triethylamine (115 mg, 1.13 mmol) was added. After 18 hrs 0° C. to room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 97% CHCl3, fractions combined and evaporated in vacuo to give a yellow oil identified as the title compound.


Yield=310 mg, 0.72 mmol, 30%


C. (S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-(decahydro-naphthalen-1-yl)-propionamide dihydrochloride

[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-carbamic acid tert-butyl ester (310 mg, 0.72 mmol) was treated with 4M HCl in dioxan (30 mls). After 1 hour at room temperature the solvent was removed in vacuo giving a pale brown solid identified as the title compound.


Yield=290 mg, 0.72 mmol, 100%


D. {(R)-1-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethylcarbamoyl]-2-methyl-butyl}-carbamic acid tert-butyl ester

(S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-(decahydro-naphthalen-1-yl)-propionamide dihydrochloride (82 mg, 0.22 mmol) was dissolved in CH2Cl2 (20 mls) and DMF (2 mls). This solution was cooled to 0° C. Boc-DIle-OH (62 mg, 0.27 mmol) was added followed by HOBt (61 mg, 0.45 mmol) and water soluble carbodiimide (54 mg, 0.27 mmol). After 15 mins triethylamine (49 mg, 0.49 mmol) was added. After 18 hrs 0° C. to room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 97% CHCl3, fractions combined and evaporated in vacuo to give a yellow oil identified as the title compound.


Yield=55 mg, 0.10 mmol, 46%


E. (R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide ditrifluoroacetate

{(R)-1-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethylcarbamoyl]-2-methyl-butyl}-carbamic acid tert-butyl ester (45 mg, 0.083 mmol) was treated with trifluoroacetic acid (30 mls). After 1 hour at room temperature the solvent was removed in vacuo and the residue purified by Prep HPLC (19×250 mm Sunfire C-18 Column). 10 to 90% 0.1% TFA/MeCN into 0.1% TFA/H2O over 35 min at 20 ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.


Yield 27 mg, 0.04 mmol, 48%


[M+H]+=444.3



1H NMR: (270 MHz) (CD3OD) 0.96-1.05 (6H, m), 1.25-1.78 (28H, m), 3.76-3.86 (1H, m), 4.26-4.28 (3H, m), 6.97 (1H, d, J=9Hz), 7.74 (1H, s), 7.80-7.90 (1H, m)


Example 3
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide






A. 5-Aminomethyl-pyridin-2-ylamine dihydrochloride

6-Amino-3-pyridinecarbonitrile (12.5 g, 104 mmol) was dissolved (250 mls), 6M HCl (35 mls, 210 mmol) was added. 10% Pd/C (2.5 g) was added. The reaction mixture was shaken at 10 psi for 18 hours after which time the catalyst was filtered off through celite and the residue washed with methanol (200 mls) and water (20 mls). The combined filtrates were evaporated in vacuo to give a white solid. Recrystallised from MeOH/diethyl ether to give a white solid identified as the title compound


Yield=15.52 g, 79.2 mmol, 75%


[M+H]+=124.17


B. {(S)-1-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-methyl-butyl}-carbamic acid tert-butyl ester

Boc-3,4-dichloro-Phe-OH (1.71 g, 5.1 mmol) was dissolved in CH2Cl2 (30 mls) and DMF (3 mls). This solution was cooled to 0° C. 5-Aminomethyl-pyridin-2-ylamine dihydrochloride (1.0 g, 5.1 mmol) was added followed by HOBt (827 mg, 6.1 mmol) and water soluble carbodiimide (978 mg, 5.1 mmol). After 15 mins diisopropylethylamine (1.98 g, 15.3 mmol) was added. After 5 hrs 0° C. to room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 5% MeOH, 95% CHCl3, fractions combined and evaporated in vacuo to give a yellow oil identified as the title compound.


Yield=1.44 g, 3.28 mmol, 64%


[M+H]+=439.20


C. (S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-propionamide dihydrochloride

{(S)-1-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-methyl-butyl}-carbamic acid tert-butyl ester (1.44 g, 3.28 mmol) was treated with 4M HCl in dioxan (50 mls). After 1 hour at room temperature the solvent was removed in vacuo giving a pale brown solid identified as the title compound.


Yield=1.3 g, 3.15 mmol, 96%


[M+H]+=339.0, 340.9


D. {(R)-1-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-methyl-butyl}-methyl-carbamic acid tert-butyl ester

(S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-propionamide dihydrochloride (1.3 g, 3.3 mmol) was dissolved in CH2Cl2 (20 mls) and DMF (2 mls). This solution was cooled to 0° C. Boc-N-Me-DIle-OH (811 mg, 3.3 mmol) was added followed by HOBt (536 mg, 3.9 mmol) and water soluble carbodiimide (633 mg, 3.3 mmol). After 15 mins diisopropylethylamine (1.3 g, 9.9 mmol) was added. After 5 hrs 0° C. to room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 4% MeOH, 96% CHCl3, fractions combined and evaporated in vacuo to give a yellow oil identified as the title compound.


Yield=983 mg, 1.74 mmol, 53%


[M+H]+=566.25, 568.26


E. (R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide dihydrochloride

{(R)-1-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-2-methyl-butyl}-methyl-carbamic acid tert-butyl ester (983 mg, 1.74 mmol) was treated with 4M HCl in dioxan (30 mls). After 1 hour at room temperature the solvent was removed in vacuo, azetroped from toluene and the residue freeze dried from water to give a white solid identified as the title compound.


Yield 880 mg, 1.63 mmol, 94%


[M+H]+=466.01



1H NMR: (270 MHz) (CD3OD) 0.75-0.90 (7H, m), 1.20-1.40 (1H, m), 1.70-1.90 (1H, m), 2.62 (3H, s), 2.85-3.00 (1H, m), 3.15-3.25 (1H, m), 3.30-3.35 (2H, m), 3.65-3.75 (1H, m), 4.20-4.40 (2H, m), 4.60-4.70 (1H, m), 4.90-5.10 (2H, m), 6.90-7.10 (1H, m), 7.20-7.30 (1H, m), 7.40-7.50 (2H, m), 7.70-7.90 (2H, m), 8.75-8.85 (1H, m).


Example 4
(R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide






A. (R)-2-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

Boc-DPro-OH (238 mg, 1.11 mmol) was dissolved in CH2Cl2 (30 mls). Triethylamine (323 mg, 3.32 mmol) and HBTU (419 mg, 1.11 mmol) was added followed by (S)-2-amino-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-propionamide dihydrochloride (435 mg, 1.11 mmol). After 3 hours at room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 5% MeOH, 99% CHCl3, fractions combined and evaporated in vacuo to give a yellow oil identified as the title compound.


Yield=263 mg, 0.49 mmol, 44%


[M+H]+=536.2


B. (R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide dihydrochloride

(R)-2-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (263 mg, 0.49 mmol) was treated with 4M HCl in dioxan (30 mls). After 1 hour at room temperature the solvent was removed in vacuo, azetroped from toluene and the residue freeze dried from water to give a white solid identified as the title compound.


Yield 232 mg, 0.46 mmol, 93%


[M+H]+=436.0, 438.1



1H NMR: (270 MHz) (CD3OD) 1.60-2.10 (3H, m), 2.20-2.40 (1H, m), 2.80-3.50 (5H, m), 4.10-4.35 (3H, m), 4.55-4.85 (1H, m), 4.80-5.10 (3H, m), 6.90-7.00 (1H, m), 7.10-7.25 (1H, m), 7.30-7.50 (2H, m), 7.70-7.90 (2H, m), 8.70-8.90 (1H, m)


Example 5
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide






A. (R)-1-Methyl-pyrrolidine-2-carboxylic acid (N-Me-DPro-OH)

H-DPro-OH (10.0 g, 86.9 mmol) was dissolved in methanol (200 mls), formaldehyde (37% by weight solution, 7 mls) was added followed by 10% Pd/C (5 g). 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 (100 mls). The combined filtrates were evaporated in vacuo to give a white solid which was recystallised from MeOH/diethyl ether to give a white crystalline solid identified as the title compound


Yield=10.72 g, 83 mmol, 96%


[M+H]+=130.17


B. [(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester

Boc-3,4-difluoro-Phe-OH (5.0 g, 16.6 mmol) was dissolved in CH2Cl2(100 mls) and DMF (10 mls). This solution was cooled to 0° C. 5-Aminomethyl-pyridin-2-ylamine dihydrochloride (3.58 g, 18.2 mmol) was added followed by HOBt (2.69 g, 19.9 mmol) and water soluble carbodiimide (3.18 g, 16.6 mmol). After 15 mins diisopropylethylamine (6.44 g, 49.8 mmol) was added. After 5 hrs 0° C. to room temperature the reaction mixture was diluted with CHCl3 (150 mls), this solution was washed with sat. NaHCO3 (1×50 mls), water (1×50 mls), brine (1×50 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 5% MeOH, 95% CHCl3, fractions combined and evaporated in vacuo to give a yellow oil identified as the title compound.


Yield=5.79 g, 14.2 mmol, 88%


[M+H]+=407.16


C. (S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-propionamide dihydrochloride

[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester (5.79 g, 14.2 mmol) was treated with 4M HCl in dioxan (50 mls). After 1 hour at room temperature the solvent was removed in vacuo giving a pale brown solid identified as the title compound.


Yield=5.4 g, 14.2 mmol, 100%


[M+H]+=307.05


D. (R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide dihydrochloride

((S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-propionamide dihydrochloride (5.55 g, 14.6 mmol) was dissolved in CH2Cl2 (100 mls) and DMF (10 mls). This solution was cooled to 0° C. N-Me-DPro-OH (1.89 g, 14.63 mmol) was added followed by HOBt (2.37 g, 17.5 mmol) and water soluble carbodiimide (3.93 g, 20.5 mmol). After 15 mins diisopropylethylamine (5.67 g, 43.9 mmol) was added. After 5 hrs 0° C. to room temperature the reaction mixture was diluted with CHCl3 (150 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×50 mls), brine (1×50 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 7% MeOH, 93% CHCl3, fractions combined and evaporated in vacuo to give a white solid. This solid was dissolved in 4M HCl in dioxan (100 mls), after 30 mins the solvent was removed in vacuo and the residue freeze dried from water and MeCN to yield a white solid identified as the title compound.


Yield=2.9 g, 5.91 mmol, 40%


[M+H]+=418.06 1H NMR: (270 MHz) (CD3OD) 1.60-2.25 (3H, m), 2.40-2.60 (1H, m), 2.90 (3H, s), 3.10-3.20 (2H, m), 3.25-3.35 (2H, m), 3.60-3.75 (1H, m), 4.10-4.35 (3H, m), 4.60-4.80 (1H, m), 4.90-5.10 (2H, m), 6.90-7.30 (4H, m), 7.70-7.90 (2H, m), 8.75-8.90 (1H, m)


Example 6
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide






A. (R)-1-Isopropyl-pyrrolidine-2-carboxylic acid

H-DPro-OH (5.0 g, 43.3 mmol) was dissolved in methanol (200 mls), acetone (3.78 g, 58.1 mmol) was added followed by 10% Pd/C (2.5 g). 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 (100 mls). The combined filtrates were evaporated in vacuo to give a white solid which was recystallised from MeOH/diethyl ether to give a white crystalline solid identified as the title compound


Yield=5.747 g, 33.4 mmol, 77%


[M+H]+=158.14


B. (R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide ditrifluoroacetate

(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid (187 mg, 1.19 mmol) was dissolved in CH2Cl2(30 mls). Triethylamine (601 mg, 5.95 mmol) and HBTU (451 mg, 1.19 mmol) was added followed by ((S)-2-amino-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-propionamide dihydrochloride (451 mg, 1.19 mmol). After 3 hours at room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by Prep HPLC (19×250 mm Sunfire C-18 Column). 10 to 90% 0.1% TFA/MeCN into 0.1% TFA/H2O over 35 min at 20 ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.


Yield=63 mg, 0.094 mmol, 8%


[M+H]+=446.13



1H NMR: (270 MHz) (CD3OD) 1.15-1.21 (6H, m) 1.70 (1H, br, s) 1.95 (1H, br, s) 2.31 (1H, br, s) 2.80-3.07 (3H, m) 3.42-3.52 (2H, m) 4.12-4.18 (3H, m) 4.50-4.56 (1H, m) 4.87 (5H, br, s) 6.85-7.08 (4H, m) 7.64-7.70 (2H, m)


Example 7
(R)-1-Benzyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide






A. (R)-1-Benzyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide ditrifluoroacetate

(R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide dihydrochloride (50 mg, 0.075 mmol) was taken up in methanol/acetic acid (9:1, 10 mls). Benzaldehyde (7.9 mg, 0.075 mmol) was added and the solution stirred at room temp for 1 hour. Sodium cyanoborohydride (9.45 mg, 0.15 mmol) was added. After 18 hours at room temperature the solvent was removed in vacuo and the residue dissolved in CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by Prep HPLC (19×250 mm Sunfire C-18 Column). 10 to 90% 0.1% TFA/MeCN into 0.1% TFA/H2O over 35 min at 20 ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.


Yield=15 mg, 0.02 mmol, 26%


[M+H]+=526.06



1H NMR: (270 MHz) (CD3OD) 1.60-2.60 (4H, m), 2.80-2.90 (1H, m), 3.00-3.10 (1H, m), 3.20-3.40 (3H, m), 3.45-3.60 (1H, m), 4.05-4.40 (5H, m), 4.50-4.60 (1H, m), 4.75-4.95 (1H, m), 6.90-7.00 (1H, m), 7.05-7.10 (1H, m), 7.30-7.50 (7H, m), 7.65-7.80 (2H, m), 8.60-8.70 (1H, m)


Example 8
(R)-2-(Methanesulfonyl-methyl-amino)-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide






A. (R)-2-(Methanesulfonyl-methyl-amino)-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide trifluoroacetate

(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide ditrifluoroacetate (80 mg, 0.15 mmol) was dissolved in CH2Cl2 (30 mls). This solution was cooled to 0° C. triethylamine (30 mg, 0.30 mmol) was added followed by methanesulphonyl chloride (17 mg, 0.15 mmol). After 1 hr at 0° C. the reaction mixture was diluted with CHCl3 (150 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×50 mls), brine (1×50 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by Prep HPLC (19×250 mm Sunfire C-18 Column). 10 to 90% 0.1% TFA/MeCN into 0.1% TFA/H2O over 35 min at 20 ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.


Yield 10 mg, 0.015 mmol, 10%


[M+H]+=544.01



1H NMR: (270 MHz) (CD3OD) 0.54 (3H, d, J=6.70 Hz), 0.75-1.10 (5H, m), 1.45-1.60 (1H, m), 1.70-1.90 (1H, m), 2.86 (3H, s), 2.87 (3H, s), 3.10-3.30 (3H, m), 3.84 (1H, d, J=10.88 Hz), 4.10-4.40 (2H, m), 4.50-4.70 (1H, m), 6.95 (1H, d, J=9.15 Hz), 7.15-7.30 (1H, m), 7.35-7.50 (2H, m), 7.70-7.80 (2H, m), 8.35-8.50 (1H, m), 8.60-8.70 (1H, m)


Example 9
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl]-amide






A. 5-Aminomethyl-6-methyl-pyridin-2-ylamine

6-Amino-2-methylnicotinonitrile (2.0 g, 15.03 mmol) was dissolved in methanol (150 ml). This solution was cooled to 0° C. Cobalt chloride hexahydrate (8.0 g, 33.7 mmol) was added followed by sodium borohydride (6.4 g, 168 mmol) portionwise. The reaction mixture was stirred at 0° C. to room temp for 3 hrs and 3M HCl (100 ml) was added. The MeOH was removed by evaporation. The aqueous residue was washed with EtOAc (100 ml), basified with ammonium hydroxide and extracted with CHCl3 (3×150 ml). The combined organic extracts were washed with water (1×50 mls), brine (1×50 mls), dried (Na2SO4) and evaporated in vacuo to give a brown oil identified as the title compound.


Yield=820 mg, 5.99 mmol, 40%


B {(S)-1-[(6-Amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-carbamic acid tert-butyl ester

Boc-1Nal-OH (1.5 g, 4.76 mmol) was dissolved in CH2Cl2 (30 mls). Triethylamine (0.95 g, 9.5 mmol) and HBTU (1.98 g, 5.23 mmol) was added followed by 5-aminomethyl-pyridin-2-ylamine dihydrochloride (0.83 g, 4.76 mmol). After 3 hours at room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 97% CHCl3, fractions combined and evaporated in vacuo to give a colourless oil identified as the title compound.


Yield=1.5 g, 3.44 mmol, 72%


[M+H]+=435.29


C. (S)-2-Amino-N-(6-amino-2-methyl-pyridin-3-ylmethyl)-3-naphthalen-1-yl-propionamide dihydrochloride

{(S)-1-[(6-Amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-carbamic acid tert-butyl ester (1.5 g, 3.44 mmol) was treated with 4M HCl in dioxan (30 mls). After 1 hour at room temperature the solvent was removed in vacuo giving a pale brown solid identified as the title compound.


Yield=969 mg, 2.38 mmol, 69%


[M+H]+=334.1


D. (R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide ditrifluoroacetate

N-Me-DPro-OH (66 mg, 0.51 mmol) was dissolved in CH2Cl2 (30 mls). Triethylamine (110 mg, 1.1 mmol) and HBTU (211 mg, 0.56 mmol) was added followed by (S)-2-amino-N-(6-amino-2-methyl-pyridin-3-ylmethyl)-3-naphthalen-1-yl-propionamide dihydrochloride (200 mg, 0.51 mmol). After 3 hours at room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by Prep HPLC (19×250 mm Sunfire C-18 Column). 10 to 90% 0.1% TFA/MeCN into 0.1% TFA/H2O over 35 min at 20 ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.


Yield=118 mg, 0.27 mmol, 54%


[M+H]+=446.02



1H NMR: (400 MHz) (DMSO-d6) 1.8-2.0 (1H, m), 2.2-2.3 (3H, m), 2.5-2.6 (2H, m), 2.7-2.8 (3H, m), 3.0-3.3 (1H, m), 3.3-3.8 (6H, m), 3.7-4.3 (3H, m), 4.7-4.8 (1H, m), 6.7-6.9 (1H, d, J=8 Hz), 7.1-7.2 (1H, m), (7.3-7.4 (2H, m), 7.7-8.0 (3H, m), 8.2-8.3 (1H, m), 8.7 (1H, m), 9.1-9.3 (1H, m), 9.4-9.6 (1H, m)


Example 10
(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-(2-diethylamino-acetylamino)-3-(3,4-difluoro-phenyl)-propionamide






A. Diethylamino-acetic acid tert-butyl ester

Diethylamine (177 mg, 2.42 mmol) and potassium carbonate (401 mg, 2.90 mmol) were added to a solution of tert-butylbromoacetate (470 mg, 2.42 mmol) in acetonitrile (10 mls). After stirring at room temperature for 18 hours the solvent was removed in vacuo and the residue taken up in ethyl acetate (50 mls). This solution was washed with water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo giving a brown oil identified as the title compound.


Yield=240 mg, 1.28 mmol, 53%


[M+H]+=188.5


B. Diethylamino-acetic acid trifluoroacetate

Diethylamino-acetic acid tert-butyl ester (240 mg, 1.28 mmol) was dissolved in CH2Cl2 (4 mls). Trifluoroacetic acid (4 mls) was added. After 6 hours at room temperature the solvent was removed in vacuo giving a brown oil identified as the title compound.


Yield=310 mg, 1.26 mmol, 99%


[M+H]+=132.66


C. (S)—N-(6-Amino-pyridin-3-ylmethyl)-2-(2-diethylamino-acetylamino)-3-(3,4-difluoro-phenyl)-propionamide ditrifluoroacetate

((S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-propionamide dihydrochloride (155 mg, 0.41 mmol) was dissolved in CH2Cl2 (20 mls) and DMF (2 mls). This solution was cooled to 0° C. Diethylamino-acetic acid trifluoroacetate (100 mg, 0.41 mmol) was added followed by HOBt (66 mg, 0.49 mmol) and water soluble carbodiimide (86 mg, 0.45 mmol). After 15 mins triethylamine (200 mg, 2.04 mmol) was added. After 4 hrs 0° C. to room temperature the reaction mixture was diluted with CHCl3 (150 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 10% MeOH, 90% CH2Cl2, fractions combined and evaporated in vacuo to give a colourless oil. The residue was further purified by Prep HPLC. (19×250 mm Sunfire C-18 Column) 0 to 60% 0.1% TFA/MeCN into 0.1% TFA/H2O over 35 min at 20 ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.


Yield=60 mg, 0.09 mmol, 23%


[M+H]+=418.06



1H NMR: (400 MHz) (CD3OD) 1.26 (6H, t, J=6.9 Hz), 2.91-2.97 (1H, m), 3.10-3.21 (5H, m), 3.86-4.00 (2H, m), 4.22-4.34 (2H, m), 4.63-4.68 (1H, m), 6.97 (1H, d, J=9.2 Hz), 7.02-7.05 (1H, m), 7.12-7.23 (2H, m), 7.73 (1H, s), 7.77 (1H, dd, J=9.2, 2.0 Hz), 8.74 (1H, t, J=5.8 Hz).


Example 11
(S)-2-Amino-3-methyl-pentanoic acid [(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl]-amide






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

Boc-D-3,3-Diphenylalanine (4.86 g, 14.06 mmol) was dissolved in methanol (200 mls). This solution was hydrogenated over 5% Rh on carbon (500 mg) at 60 psi and room temperature. After 2 days at room temperature further 5% Rh on carbon (500 mg) was added and hydrogenation continued at 60 psi and room temperature for a further 3 days. After this time the catalyst was filtered off through celite and the residue washed with MeOH (100 mls). The combined filtrates were evaporated in vacuo to give a foamy white solid identified as the title compound,


Yield=4.95 g, 14 mmol, 100%


[M+H]+=354.28


B. {(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-carbamic acid tert-butyl ester

(R)-2-tert-Butoxycarbonylamino-3,3-dicyclohexyl-propionic acid (995 mg, 2.82 mmol) was dissolved in CH2Cl2 (30 mls). Triethylamine (712 mg, 7.04 mmol) and HBTU (1.07 g, 2.81 mmol) was added followed by 5-aminomethyl-pyridin-2-ylamine dihydrochloride (460 mg, 2.32 mmol). After 3 hours at room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 3% MeOH, 97% CHCl3, fractions combined and evaporated in vacuo to give a colourless oil identified as the title compound.


Yield=872 mg, 1.90 mmol, 81%


[M+H]+=495.39


C. (R)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3,3-dicyclohexyl-propionamide ditrifluoroacetate

{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-carbamic acid tert-butyl ester (872 mg, 1.90 mmol) was dissolved in TFA (30 mls). After one hour at room temperature the solvent was removed to give a pale orange identified as the title compound.


Yield=1.105 g, 1.88 mmol, 99%


[M+H]+=359.30


D. ((S)-1-[(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethylcarbamoyl]-2-methyl-butyl)-carbamic acid tert-butyl ester

(R)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3,3-dicyclohexyl-propionamide ditrifluoroacetate (90 mg, 0.158 mmol) was dissolved in CH2Cl2 (20 mls) and DMF (2 mls). This solution was cooled to 0° C. Boc-Ile-OH (42 mg, 0.187 mmol) was added followed by HOBt (47 mg, 0.31 mmol) and water soluble carbodiimide (35 mg, 0.18 mmol). After 15 mins triethylamine (31 mg, 0.31 mmol) was added. After 18 hrs 0° C. to room temperature the reaction mixture was diluted with CHCl3 (50 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×20 mls), brine (1×20 mls), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 4% MeOH, 96% CHCl3, fractions combined and evaporated in vacuo to give a colourless oil identified as the title compound.


Yield=73 mg, 0.13 mmol, 83%


[M+H]+=572.6


E. (S)-2-Amino-3-methyl-pentanoic acid {(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide ditrifluoroacetate

((S)-1-{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethylcarbamoyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (65 mg, 0.11 mmol) was treated with TFA (20 mls). After one hour at room temp the solvent was evaporated in vacuo to give a colourless oil identified as the title compound. Freeze dried from water to give white solid. The residue was further purified by Prep HPLC. (19×250 mm Sunfire C-18 Column) 10 to 90% 0.1% TFA/MeCN into 0.1% TFA/H2O over 35 min at 20 ml/min. Fractions combined and freeze dried to give a white solid identified as the title compound.


Yield 15 mg, 0.021 mmol, 19%


[M+H]+=472.4



1H NMR: (270 MHz) (CD3OD) 0.95-1.25 (18H, m), 1.52-1.70 (14H, m), 3.94 (1H, d, J=4.2 Hz), 4.19-4.27 (2H, m), 4.58 (1H, d, J=7.2 Hz), 4.90 (5H, s), 6.98 (1H, d, J=9.19 Hz), 7.79 (1H, d, J=1.5 Hz), 7.91 (1H, dd, J=2.9 Hz, 9.2Hz), 8.70-8.90 (1H, m)









TABLE 1







Compounds were synthesised as described for Examples 1 to 4






















Example

Stereochemistry

Mol



No
Y
of Y
R1
Wt
[M + H]+















12





S





443.33
444.4





13





R





511.27
512.5, 514.5





14





R





429.31
430.4





15





R





427.29
428.3





16





R





443.33
444.2





17











387.26
388.3





18





R





401.28
402.3





19











401.28
402.3





20





R





389.28
390.3





21





R





403.29
404.32





22





R





419.23
420.2





23





R





417.22
418.00





24





R





417.19
418.2, 420.2





25





R





451.22
452.2





26





R





383.23
384.2





27





R





397.25
398.3





28





R





397.25
398.3





29





R





401.22
402.3





30





R





451.22
452.2





31





R





408.23
409.3





32





R





419.21
420.4





33





R





401.22
402.1





34





R





433.25
434.2





35





R





451.15
452.4, 454.3





36





R





417.19
418.1, 420.2





37





R





399.23
400.1





38





R





437.20
438.1





39





R





419.21
420.26





40





R





422.24
423.2





41





R





439.20
440.24





42





R





465.24
466.2





43





R





433.23
434.28





44





R





415.24
416.00





45





R





431.21
432.1





46





R





431.21
432.2, 434.2





47





R





413.24
414.1





48





R





451.22
452.2





49





R





433.23
434.20





50





R





487.20
488.15





51





R





453.22
454.04





52





R





453.31
454.35





53





S





433.23
434.04





54





R





485.14
486.1, 488.2





55





R





435.12
435.9, 438.0





56





S





453.08
454.05





57





R





471.12
472.1, 474.0





58





S





471.12
472.1, 474.0





59





R





519.10
520.18, 522.18





60





R





499.15
500.20





61





R





451.15
452.19





62





R





423.12
423.9, 425.9





63





R





449.14
450.12, 452.12





64





R





497.14
498.1, 500.1





65





R





433.11
433.9, 460.0





66





R





471.10
472.1, 474.1





67





R





499.15
500.06





68





R





491.19
492.2, 494.2





69











409.11
409.96





70





R





519.16
519.95, 521.99





71





R





385.19
385.95





72





R





403.18
404.54





73





R





399.21
400.09





74





R





417.20
418.19





75





R





431.23
432.20





76





R





415.18
416.11





77





R





415.18
416.17





78





R





437.19
438.19





79











377.17
378.48





80





R





453.20
454.26





81





R





467.21
468.26





82





S





433.23
434.04





83





S





419.21
420.28





84





R





391.18
392.15





85





S





391.18
392.15





86





R





405.20
406.45





87





R





373.19
374.15





88





S





373.19
374.55





89





R





401.22
402.09
















TABLE 2







Compounds were synthesised as described for Examples 1 to 7 and 9 and 10






















Example

Stereochemistry

Mol



No
Y
of Y
R1
Wt
[M + H]+















90





R





449.14
450.01





91





R





449.20
450.10





92





R





431.23
432.24





93





R





415.18
416.1, 418.20





94





R





435.19
436.1





95





R





437.19
438.03





96





R





417.20
418.22





97





R





471.17
472.15





98





R





399.21
400.07





99





R





399.21
400.09





100





R





411.23
412.11





101





R





381.22
382.16





102





R





437.28
438.19





103





R





415.18
416.52





104





R





395.23
396.55





105





R





395.23
396.19





106





R





395.23
396.20





107





R





411.23
412.91





108





R





399.21
400.12





109





R





415.18
416.12, 418.10





110





R





449.14
450.14, 452.10





111





R





449.48
450.53





112





R





382.47
383.56





113





R





420.52
421.54





114





R





432.52
433.1





115





R





387.26
388.18





116





S





417.20
418.08





117





R





477.17
478.10





118





R





459.26
460.16





119





R





427.24
428.20





120





R





443.21
444.45





121





R





423.26
424.60





122





R





423.26
424.20





123





R





423.26
424.21





124





R





439.26
440.21





125





R





427.24
428.22





126





R





443.98
444.20





127





R





478.43
478.55





128





R





477.53
478.62





129





R





410.52
411.60





130





R





448.57
449.38





131





R





431.59
432.57





132





R





445.23
446.61





133





R





459.24
460.61





134





R





475.20
476.24





135





R





461.19
462.21





136





R





413.50
414.54





137





R





409.94
410.59





138





R





429.95
430.19





139





R





427.52
428.58





140





R





493.23
494.23





141





R





525.17
526.04, 528.02





142





R





528.01
528.57





143





R





528.01
528.56





144





R





431.21
432.29





145





R





413.22
414.13





146





R





459.53
460.57





147





R





441.25
442.21





148





R





433.46
434.45





149





R





479.21
480.60





150











451.15
452.21, 454.20





151





R





465.17
465.86





152











499.15
500.05





153











423.12
424.09





154











465.17
465.89





155





R





507.22
508.13





156











419.21
420.30





157











447.24
448.61





158











447.24
448.56





159











475.57
476.63





160











467.21
468.55





161











481.23
482.55





162











493.23
494.58





163











501.17
502.52





164











501.17
502.54





165











501.17
502.59





166











497.22
498.57





167











433.23
434.52





168











433.23
434.53





169











473.26
474.62





170











431.21
432.60





171











433.19
434.41





172











479.21
480.54





173











479.21
480.53





174











453.20
454.51





175





R





433.49
434.50





176





S





433.49
434.51





177





S





447.53
448.56





178





R





447.24
448.59





179





R





447.24
448.61





180





R





415.24
416.51





181





S





415.24
416.60





182





R





429.25
430.59





183





R





429.54
430.58





184





R





495.24
496.29





185





R





481.55
482.51
















TABLE 3







Compounds were synthesised as described for Examples 1 to 7 and 9 and 10



























Stereo








Example

chem.




Mol


No
Y
At Y
R1
R8
R9
R10
Wt
[M + H]+


















186





R





Me
H
H
443.33
444.3





187





R





Me
H
H
457.34
458.4





188





R





Me
H
H
479.19
480.20, 482.23





189





R





Me
H
H
449.14
450.7, 452.1





190





R





Me
H
H
463.15
464.11





191





R





Me
H
H
467.09
468.1





192





R





Me
H
H
485.12
486.13





193





R





Me
H
H
513.17
514.1





194





R





Me
H
H
517.14
518.1





195





R





Me
H
H
533.12
534.0, 536.6





196





R





Me
H
H
500.15
501.03





197





R





Me
H
H
485.14
486.18





198





R





Me
H
H
491.19
492.2





199





R





Me
H
H
465.17
466.2





200





R





Me
H
H
505.20
506.24





201





R





Me
H
H
463.15
464.16





202





R





Me
H
H
511.15
512.16





203





R





Me
H
H
461.28
462.23





204





R





Me
H
H
413.22
414.90





205





R





Me
H
H
431.21
432.16





206





R





Me
Me
H
445.52
446.56





207





R





Me
Me
H
461.56
462.54





208





R





Me
Me
H
471.36
472.30





209





R





H
H
Me
447.26
448.11
















TABLE 4







Compounds were synthesised as described for Examples 8






















Example

Stereochemistry

Mol



No
Q
of Y
R1
Wt
[M + H]+





210





R





513.10
513.98





211





R





529.13
530.30





212





R





501.10
502.04





213





R





531.20
532.07
















TABLE 5







Compounds were synthesised


as described for Examples 1 to 7 and 9 to 11





















Example

Stereochemistry
Mol



No
Y
of Y
Wt
[M + H]+














214





R
471.36
472.4





215





S
455.33
456.35





216





S
505.34
506.36





217





S
471.36
472.39





218





S
443.33
444.37





219





S
485.37
486.39





220






415.29
416.28





221






429.31
430.34





222






443.33
444.36





223





S
469.68
470.68
















TABLE 6







Compounds were synthesised as described for Examples 1 to 11























Example

Stereochemistry


Mol



No
Y
of Y
R2
R11
Wt
[M + H]+
















224





R
OH
H
399.49
400.3





225





R
H
Me
395.5
396.2









Example 226
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide






A. 3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide trifluoroacetate

((S)-2-Amino-N-(6-amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-propionamide dihydrochloride (800 g, 2.11 mmol) was dissolved in CH2Cl2(100 mls). This solution was cooled to 0° C. 3-Methylpyrrole-2-carboxylic acid (264 mg, 2.11 mmol) was added followed by HOBt (399 mg, 2.95 mmol) and water soluble carbodiimide (486 mg, 2.53 mmol). After 15 mins triethylamine (640 g, 0.63 mmol) was added. After 18 hrs 0° C. to room temperature the reaction mixture was diluted with CHCl3 (150 mls), this solution was washed with sat. NaHCO3 (1×20 mls), water (1×50 mls), brine (1×50 mls), dried (Na2SO4) and filtered through PS paper and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent 7% MeOH, 93% CHCl3, fractions combined and evaporated in vacuo to give an orange oil. The residue purified by Prep HPLC. (19×250 mm Sunfire C-18 Column) 10 to 90% 0.1% TFA/MeCN into 0.1% TFA/H2O over 35 min at 20 ml/min. Fractions combined and freeze dried to give a pale pink solid identified as the title compound.


Yield=368 mg, 0.70 mmol, 33%


[M+H]+=414.22



1H NMR: (CD3OD, 400 MHz) 2.30 (3H, s) 2.81-3.25 (2H, m) 4.17-4.35 (2H, m) 4.71 (1H, t, J=8.0 Hz) 5.25 (4H, br s) 6.00 (1H, s) 6.74-6.78 (1H, m) 7.08-7.14 (3H, m) 7.73-7.77 (2H, m) 8.73-8.79 (1H, m) 10.56 (1H, s).









TABLE 7







Compounds were synthesised as described for Example 226
























Example





Mol



No
R16
R17
R18
R
R1
Wt
[M + H]+

















227
H
H
H
H





423.26
424.3





228
H
H
H
H





413.19
414.3





229
H
H
H
H





431.16
432.4





230
Me
Me
Me
H





473.20
474.10





231
Me
H
Me
H





441.22
442.27





232
Me
H
Me
H





459.19
460.2





233
Me
H
Me
H





459.12
460.1, 462.1





234
Me
H
Me
H





405.22
406.1





235
Me
H
Me
H





425.16
426.2, 428.2





236
Me
H
Me
H





409.19
410.1





237
Me
H
Me
H





391.20
392.22





238
Me
H
Me
H





397.25
398.26





239
Me
H
Me
H





425.16
425.92





240
Me
H
Me
H





459.19
460.21





241
Me
H
Me
H





430.21
431.1





242
Me
H
Me
H





409.19
410.12





243
Me
H
Me
H





427.18
428.1





244
Me
H
Me
H





405.22
406.24





245
Me
H
Me
H





445.17
446.21





246
Me
H
Me
H





447.15
448.1, 450.1





247
Me
H
Me
H





407.20
408.0





248
Me
H
Me
H





445.17
446.1





249
Me
H
Me
H





427.18
428.22





250
Me
H
Me
H





447.17
448.16





251
Me
H
Me
H





481.15
482.0





252
Me
H
Me
H





467.23
468.18





253
Me
H
Me
H





405.22
406.15





254
Me
H
Me
H





421.21
422.15





255
Me
H
Me
H





435.23
436.13





256
Me
H
Me
H





447.26
448.21





257
Me
H
Me
H





442.21
443.54





258
Me
H
Me
H





445.17
446.18





259
H
Me
H
H





411.15
412.13





260
H
Me
H
H





395.18
396.15





261
Me
H
H
H





395.18
396.14





262
Me
H
H
H





411.15
412.41





263
Me
H
H
H





445.11
446.38, 448.1





264
Me
H
H
H





445.11
446.09, 448.1





265
Me
H
H
H





395.18
396.44





266
Me
H
H
H





411.15
412.39, 414.3





267
Me
H
H
H





411.15
412.12





268
Me
H
H
H





391.20
392.45





269
Me
H
H
H





395.18
396.42





270
Me
H
H
H





413.17
414.42





271
Me
H
H
H





445.17
446.42





272
Me
H
H
H





445.17
446.18





273
Me
H
H
H





383.23
384.48





274
H
H
CO2Me
H





489.16
490.1





275
H
H
CO2H
H





475.15
476.20





276
Me
H
CO2H
H





489.16
490.17





277
Me
H
Me
Me





473.20
474.1





278
Me
H
Me
Me





455.23
456.22





279
Me
H
Me
Me





439.18
440.18





280
Me
H
Me
Me





473.14
474.2





281
Me
H
Me
Me





419.23
420.25





282
Me
H
Me
Me





473.20
474.20





283
Me
H
Me
Me





444.23
445.31





284
Me
H
Me
Me





441.20
442.20





285
Me
H
Me
Me





423.21
424.15





286
Me
H
H
Me





427.18
428.44
















TABLE 8







Compounds were synthesised as described for Example 226






















Example







No
Y
R
R1
Mol Wt
[M + H]+















287





H





382.16
383.04





288





H





382.16
383.03





289





H





414.18
415.02





290





H





396.17
397.24





291





H





410.19
411.52





292





H





503.23
504.18





293





H





509.19
510.17





294





H





489.20
490.18





295





H





487.18
488.12





296





H





521.14
522.12, 524.12





297





H





487.18
488.13





298





H





463.20
464.4





299





H





464.2
465.2





300





H





493.21
494.2





301





H





481.19
482.2





302





H





479.20
480.2





303





Me





477.22
478.23





304





Me





507.23
508.24





305





Me





495.21
496.3





306





H





477.22
478.3





307





H





481.17
482.5





308





H





511.18
512.3





309





Me





495.19
496.11





310





Me





525.20
526.19





311





H





431.18
432.2





312





H





461.19
462.2





313





H





447.15
448.2, 550.2





314





H





477.16
478.2, 480.2





315





Me





461.16
462.16





316





Me





491.17
492.23





317





H





427.20
428.20





318





H





457.21
458.20





319





Me





441.22
442.25





320





Me





495.12
496.18





321





Me





525.13
526.22





322





Me





495.19
496.2





323





H





449.17
450.2





324





H





467.16
468.10





325





H





449.17
449.88, 451





326





H





467.16
468.08





327





H





479.18
480.09





328





H





450.16
451.19





329





H





503.14
504.1





330





H





431.18
432.12





331





H





449.17
450.21





332





H





461.19
462.22





333





H





432.17
433.21





334





H





443.20
444.17





335





H





469.16
470.19





336





Me





466.21
467.1





337





Me





496.22
497.1





338





H





419.23
420.17
















TABLE 9







Compounds were synthesised as described for Examples 1 to 4






















Example

Stereochemistry

Mol



No
Y
of Y
R1
Wt
[M + H]+





339





S





403.29
404.57





340





R





415.24
416.20





341





R





417.19
417.99





342





R





465.19
465.91
















TABLE 10







Compounds were synthesised as described for Examples 1 to 7 and 9 and 10






















Example

Stereochem-

Mol



No
Y
istry of Y
R1
Wt
[M + H]+





343





S





487.28
488.61





344





S





405.20
406.49





345





S





419.21
420.53





346





S





433.23
434.48





347





S





447.24
448.57





348





S





461.26
462.61





349





S





475.28
476.58





350





S





461.26
462.54





351





S





481.23
482.48





352





S





495.24
495.56





353





S





475.28
476.58





354





S





445.23
446.23





355





S





433.23
434.39





356





S





431.21
432.11





357





R





431.21
432.15





358





R





447.24
448.22





359





R





433.23
434.03





360





S





449.22
450.46





361





S





435.21
436.17





362





S





449.22
450.47





363





R





449.22
450.45





364





S





491.23
492.25





365











459.24
460.51





366











417.20
418.29





367





S





401.22
402.40





368





S





415.24
416.57





369





S





429.25
430.57





370





S





443.27
444.59





371





S





457.29
458.62





372





S





443.27
444.55





373





S





491.27
492.62





374





S





427.24
428.51





375





R





427.24
428.50





376





S





415.24
416.51





377





R





429.25
430.51





378











441.25
442.52





379











413.22
414.47





380











401.22
402.32





381





S





403.29
404.57





382





S





387.26
388.53





383





S





403.29
404.56





384





S





389.28
390.27





385





S





431.33
432.57





386





S





391.26
392.25





387





S





405.27
406.26





388





S





419.29
420.27





389





S





419.29
420.26





390





S





403.29
404.55





391





S





375.26
376.50





392











429.31
430.57





393











417.31
418.53





394











471.36
472.67





395





S





457.34
458.64





396





R





441.31
442.60





397





R





505.34
506.66





398





R





479.19
480.14, 482.12





399





R





465.17
466.19





400





R





513.17
514.11, 516.10





401





S





465.17
466.35





402





R





477.17
478.44





403





S





477.17
478.73





404











463.15
464.41





405





R





445.22
446.48, 448.40





406





R





431.21
432.20





407





R





479.21
480.17





408





S





417.19
417.94





409





S





431.21
432.20





410





S





431.21
432.20





411





S





443.21
444.45





412











429.19
430.44





413





S





397.25
398.24





414





S





411.26
412.27





415





S





411.26
412.27





416





S





451.22
452.20





417





S





465.24
466.01





418





S





465.52
466.62





419





R,S





477.24
478.49





420











463.22
464.47





421





R





477.24
478.51





422





S





477.24
478.51





423











463.22
464.48





424





R





447.24
448.50





425





R,S





445.23
446.48, 448.40





426











457.22
458.49, 460.48





427





S





363.26
364.51
















TABLE 11







Compounds were synthesised as described for Examples 1 to 7 and 9 and 10



























Stereo-








Example

chem.




Mol



No
Y
At Y
R1
R8
R9
R10
Wt
[M + H]+





428











Me
H
H
415.24
416.20





429











Me
H
H
473.26
474.53





430











Me
H
H
445.23
446.49





431





R





Me
H
H
459.24
460.50





432





S





Me
H
H
429.50
460.50
















TABLE 12







Compounds were synthesised as described for Examples 1 to 7


and 9 to 11























Stereo-




Example

chemistry




No
Y
of Y
Mol Wt
[M + H]+





433





S
485.37
486.66





434





S
405.20
406.49
















TABLE 13







Compounds were synthesised as described for Examples 1 to 11

























Stereo-






Example

chemistry






No
Y
of Y
R2
R11
Mol Wt
[M + H]+





435





S
OH
H
419.29
420.57





436





S
Me
H
417.31
418.50





437





S
H
Me
417.31
418.49





438





S
H
Me
417.31
418.46





439





S
H
Me
431.33
432.57
















TABLE 14








1H NMR data for examples










Example

Frequency



No
Solvent
(MHz)
Chemical Shifts













12
CD3OD
270
0.95-1.05 (6H, m), 1.10-2.10 (28H, m),





3.78-3.82 (1H, m), 4.25-4.34 (3H, m), 6.92-6.98 (1H,





m), 7.61-7.84 (2H, m)


13
CD3OD
270
0.90-1.96 (22H, m), 2.70-2.98 (2H, m),





3.09-3.18 (4H, m), 4.05-4.20 (2H, m), 6.96 (1H, d,





J = 9.1 Hz), 7.22-7.30 (4H, m), 7.72 (1H, s),





7.80-7.90 (2H, m)


16
CD3OD
270
1.00 (6H, d), 1.13-2.1 (28H, m), 3.75-3.95 (1H,





m), 4.15-4.35 (2H, m), 6.97 (1H, d, J = 8.9 Hz),





7.72 (1H, s), 7.86 (1H, d, J = 8.7 Hz),





8.80-8.90 (1H, m)


19
CD3OD
270
1.19-1.78 (23H, m), 2.71 (3H, s), 3.83 (2H, s),





4.26-4.32 (3H, m), 6.97 (1H, d, J = 9.1 Hz),





7.74 (1H, s), 7.84-7.87 (1H, m), 8.85 (1H, s, br)


20
CD3OD
270
0.99-1.14 (8H, m), 1.21-1.32 (6H, m),





1.40-1.71 (6H, m), 3.19-3.21 (2H, m), 3.76 (1H, d,





J = 5.2 Hz), 4.27-4.39 (3H, m), 4.91 (5H, s),





6.97 (1H, d, J = 9.4 Hz), 7.74 (1H, s), 7.86 (1H, d,





J = 8.2 Hz), 8.70-8.90 (1H, m)


21
CD3OD
270
0.9-1.0 (7H, m), 1.4-1.8 (7H, m), 2.4-2.6 (5H,





m), 3.3-3.7 (10H, m), 4.0-4.4 (3H, m)





6.9-7.0 (1H, d, J = 7 hz), 7.8-7.9 (2H, m), 8.7-8.9 (2H, m)


22
CD3OD
270
0.65 (3H, d, J = 6.9 Hz), 0.86 (3H, d, J = 6.9 Hz),





1.28-1.29 (1H, m), 1.88-1.91 (1H, m),





3.30-3.56 (3H, m), 3.66-3.68 (3H, m), 4.08-4.19 (2H, m),





4.63-4.85 (3H, m), 6.85-6.89 (1H, m),





7.33-7.37 (2H, m), 7.46-7.59 (4H, m), 7.75-7.71 (1H, m),





7.84-7.87 (1H, m), 8.18 (1H, d, J = 7.6 Hz)


24
CD3OD
270
0.81-0.83 (6H, m), 1.10-1.30 (2H, m),





2.95-3.20 (1H, m), 3.27-3.30 (3H, m), 3.71 (1H, d,





J = 5.2 Hz), 4.21 (2H, s), 4.7-4.9 (1H, m),





4.91 (4H, s), 6.94 (1H, d, J = 9.1 Hz), 7.21-7.36 (4H,





m), 7.68 (1H, s), 7.76 (1H, d, J = 9.4 Hz),





8.5-8.7 (1H, s, br)


25
CD3OD
270
0.81-0.87 (6H, m), 1.27-1.30 (2H, m),





3.19-3.29 (1H, m), 3.30-3.31 (3H, m), 3.73 (1H, d,





J = 5.2 Hz), 4.21-4.22 (2H, m), 4.71-4.77 (1H, m),





4.91 (4H, s), 6.94 (1H, d, J = 9.1 Hz),





7.42-7.52 (3H, m), 7.66-7.69 (2H, s), 7.74-7.79 (1H, m),





8.5-8.7 (1H, s, br)


26
CD3OD
270
0.75-0.80 (6H, m), 1.10-1.30 (1H, m),





1.60-1.85 (1H, m), 2.83-2.92 (1H, m), 3.14-3.21 (1H, m),





3.68 (1H, d, J = 5.2 Hz), 4.22-4.26 (2H, m),





4.65-4.67 (1H, m), 4.90 (6H, s), 6.94 (1H, d,





J = 8.8 Hz), 7.21-7.27 (5H, m), 7.68-7.76 (2H, m),





8.60-8.80 (1H, m)


27
CD3OD
270
0.77 (6H, t, J = 7.28 Hz), 1.10-1.40 (1H, m),





1.60-1.80 (1H, m), 2.29 (3H, s), 2.75-2.95 (1H, m)





3.12-3.28 (1H, m), 3.29-3.31 (2H, m), 3.68 (1H,





d, J = 5.1 Hz), 4.22-4.26 (2H, m), 4.62-4.64 (1H,





m), 4.90 (5H, s), 6.92-7.15 (4H, m),





7.69-7.75 (2H, m), 8.65-8.90 (1H, m)


28
CD3OD
270
0.83 (6H, t, J = 6.6 Hz), 0.90-1.10 (1H, m),





1.60-1.80 (1H, m), 2.34 (3H, s), 2.85-3.00 (1H, m),





3.12-3.28 (1H, m), 3.29-3.31 (2H, m), 3.71 (1H,





d, J = 5.4 Hz), 4.16-4.23 (2H, m), 4.63-4.68 (1H,





m), 4.90 (5H, s), 6.92 (1H, d, J = 9.2 Hz),





7.06-7.14 (3H, m), 7.63-7.69 (2H, m), 8.65-8.90 (1H,





m)


29
CD3OD
270
0.77-0.82 (7H, m), 1.17-1.30 (1H, m),





1.6-1.8 (1H, m), 2.91-2.95 (1H, m), 3.29-3.30 (1H, m),





3.68 (1H, d, J = 5.2 Hz), 4.22-4.27 (2H, m),





4.62-4.66 (1H, m), 4.91 (4H, s), 6.94-7.09 (4H, m),





7.28-7.31 (2H, m), 7.71-7.79 (2H, m),





8.5-8.7 (1H, m)


30
CD3OD
270
0.72-0.77 (7H, m), 1.17-1.30 (1H, m),





1.6-1.8 (1H, m), 2.98-3.05 (1H, m), 3.25-3.30 (1H, m),





3.66 (1H, d, J = 5.2 Hz), 4.26 (2H, s),





4.71-4.77 (1H, m), 4.91 (4H, s), 6.95 (1H, d, J = 9.1 Hz),





7.51-7.59 (4H, m), 7.73 (1H, s), 7.75-7.80 (1H,





m), 8.5-8.7 (1H, s, br)


31
CD3OD
270
0.70-1.05 (7H, m), 1.10-1.30 (1H, m),





1.60-1.80 (1H, m), 2.90-3.10 (1H, m), 3.20-3.40 (2H, m),





3.69 (1H, d, J = 5.18 Hz), 4.20-4.40 (2H, m),





4.65-4.75 (1H, m), 4.90-5.10 (4H, m), 6.97 (1H, d,





J = 9.15 Hz), 7.40-7.90 (6H, m), 8.70-8.90 (1H,





m)


32
CD3OD
270
0.75-1.30 (8H, m), 1.65-1.80 (1H, m),





2.80-2.95 (1H, m), 3.10-3.20 (1H, m), 3.25-3.35 (2H, m),





3.60-3.80 (2H, m), 4.15-4.35 (2H, m),





4.65-4.80 (1H, m), 4.90-5.10 (3H, m), 6.90-7.20 (4H, m),





7.70-7.85 (2H, m)


33
CD3OD
270
0.70-1.00 (6H, m), 1.10-1.30 (1H, m),





1.60-1.80 (1H, m), 2.80-2.95 (1H, m), 3.10-3.20 (1H, m),





3.25-3.35 (2H, m), 3.65-3.75 (1H, m),





4.15-4.40 (2H, m), 4.50-4.70 (1H, m), 4.80-5.00 (4H, m),





6.90-7.10 (3H, m), 7.20-7.30 (2H, m),





7.65-7.80 (2H, m), 8.70-8.90 (1H, m)


34
CD3OD
270
0.48 (3H, t, J = 7.13 Hz) 0.65-0.80 (3H, m),





1.00-1.20 (1H, m), 1.55-1.70 (1H, m), 3.00-3.10 (1H,





m), 3.25-3.40 (2H, m), 3.60-3.80 (2H, m),





4.10-4.35 (2H, m), 4.80-4.95 (1H, m), 4.95-5.05 (4H,





m), 6.74 (1H, d, J = 9.15 Hz), 7.30-7.85 (9H, m),





8.70-8.80 (1H, m)


35
CD3OD
270
0.70-0.90 (7H, m), 1.15-1.30 (1H, m),





1.65-1.80 (1H, m), 2.80-2.95 (1H, m), 3.10-3.20 (1H,





m), 3.25-3.35 (2H, m), 3.60-3.80 (2H, m),





4.15-4.35 (2H, m), 4.70-4.80 (1H, m), 4.90-5.10 (3H,





m), 6.90-7.00 (1H, m), 7.15-7.25 (1H, m),





7.35-7.50 (2H, m), 7.70-7.80 (2H, m)


36
CD3OD
270
0.80-0.89 (6H, m), 1.18 (1H, br, s), 1.71 (1H, br,





s), 2.88-2.91 (1H, m), 3.14-3.21 (1H, m),





3.70 (1H, d, J = 4.7 Hz), 4.25 (1H, s), 4.63 (1H, t, J = 3.9 Hz),





4.91 (7H, s), 6.96 (1H, d, J = 8.9 Hz),





7.26 (4H, s), 7.72-7.78 (2H, m), 8.75 (1H, s)


37
CD3OD
270
0.81 (6H, s), 1.24 (1H, s), 1.73 (1H, s),





2.74-2.83 (1H, m), 3.06-3.11 (1H, m), 3.31 (1H, s),





3.71 (1H, s), 4.24 (1H, s), 4.57 (1H, br, s), 4.91 (7H,





s), 6.69 (2H, d, J = 6.9 Hz), 6.94 (1H, d, J = 8.6 Hz),





7.05 (2H, d, J = 6.9 Hz), 7.73 (2H, d, J = 9.7 Hz)


38
CD3OD
270
0.84-0.86 (6H, m), 1.24-1.29 (1H, m),





1.77-1.79 (1H, m), 2.91-2.99 (1H, m), 3.14-3.19 (1H, m),





3.30 (1H, s), 3.73 (1H, d, J = 4.9 Hz), 4.24 (2H,





s), 4.71 (1H, t, J = 3.5 Hz), 4.90 (5H, s),





6.95 (1H, d, J = 9.1 Hz), 7.09-7.19 (2H, m)





7.74-7.83 (2H, m), 8.75-8.78 (1H, m)


39
CD3OD
270
0.80-0.85 (6H, m), 1.25 (1H, s), 1.74 (1H, s),





2.92 (1H, s), 3.19-3.32 (2H, m), 3.71-3.73 (1H,





m), 4.27 (2H, s), 4.69 (1H, t, J = 5.2 Hz),





4.93 (6H, s), 6.89-6.99 (4H, m), 7.75-7.84 (2H, m)


40
CD3OD
270
0.60-0.80 (6H, m), 1.10-1.30 (1H, m),





1.60-1.75 (1H, m), 3.00-3.15 (1H, m), 3.20-3.40 (2H, m),





3.69 (1H, d, J = 5.42 Hz), 4.10-4.30 (2H, m),





4.65-4.80 (2H, m), 4.90-5.10 (6H, m), 6.80-6.90 (1H,





m), 6.95-7.20 (3H, m), 7.30-7.40 (1H, m),





7.50-7.60 (3H, m), 8.60-8.70 (1H, m)


41
CD3OD
270
0.77-0.91 (5H, m), 1.23 (1H, s), 1.71 (1H, s),





3.17-3.31 (2H, m), 3.41-3.46 (1H, m), 3.72 (1H,





s), 4.22 (2H, s), 4.82-4.91 (7H, m), 6.88 (1H, d, J = 7.9 Hz),





7.37 (3H, s), 7.65 (2H, s), 7.87 (2H,





s), 8.75 (1H, s)


42
CD3OD
270
0.65-0.85 (7H, m), 1.15-1.30 (1H, m),





1.65-1.80 (1H, m), 2.60 (3H, s), 2.90-3.10 (1H, m),





3.20-3.40 (3H, m), 3.61 (1H, d, J = 4.94 Hz),





4.20-4.40 (2H, m), 4.65-4.90 (1H, m), 4.90-5.10 (2H, m),





6.96 (1H, d, J = 9.15 Hz), 7.45-7.90 (6H, m),





8.75-8.90 (1H, m)


43
CD3OD
270
0.70-0.95 (7H, m), 1.20-1.40 (1H, m),





1.70-1.90 (1H, m), 2.50-2.70 (3H, m), 2.85-2.95 (1H, m),





3.05-3.20 (1H, m), 3.25-3.35 (2H, m),





3.60-3.70 (1H, m), 4.15-4.30 (2H, m), 4.55-4.70 (1H, m),





4.90-5.00 (2H, m), 6.90-7.30 (4H, m),





7.70-7.90 (2H, m), 8.70-8.80 (1H, m)


44
CD3OD
270
0.70-0.90 (7H, m), 1.20-1.35 (1H, m),





1.65-1.85 (1H, m), 2.60 (3H, s), 2.80-2.95 (1H, m),





3.05-3.20 (1H, m), 3.25-3.40 (2H, m), 3.63 (1H, d,





J = 4.94 Hz), 4.20-4.35 (2H, m), 4.55-4.70 (1H,





m), 4.90-5.10 (2H, m), 6.90-7.10 (3H, m),





7.20-7.35 (2H, m), 7.70-7.85 (2H, m),





8.70-8.85 (1H, m)


45
CD3OD
270
0.70-0.90 (7H, m), 1.20-1.40 (1H, m),





1.60-1.75 (1H, m), 2.60 (3H, s), 2.80-2.95 (1H, m),





3.10-3.20 (1H, m), 3.25-3.40 (2H, m), 3.63 (1H, d,





J = 4.70 Hz), 4.20-4.40 (2H, m), 4.60-4.70 (1H,





m), 4.90-5.10 (2H, m), 6.90-7.10 (1H, m),





7.15-7.40 (4H, m), 7.70-7.85 (2H, m), 8.70-8.90 (1H,





m)


46
CD3OD
270
0.82 (6H, s), 1.28 (1H, s), 1.77 (1H, s), 2.60 (3H,





s), 2.86-2.95 (1H, m), 3.11-3.18 (1H, m),





3.65 (1H, s), 4.25 (2H, s), 4.63 (1H, t, J = 6.2 Hz),





4.92 (5H, s), 6.97 (1H, d, J = 9.2 Hz), 7.27 (4H,





s), 7.76 (2H, d, J = 9.4 Hz), 8.78 (1H, s)


48
CD3OD
270
0.84-0.96 (6H, m), 1.34-1.38 (1H, m),





1.78-1.83 (1H, m), 2.61 (3H, s), 2.95-3.03 (3H, m),





3.68 (1H, d, J = 4.7 Hz), 4.24 (2H, s), 4.64-4.70 (1H,





m), 4.91 (5H, s), 6.95 (1H, d, J = 9.2 Hz),





7.11-7.21 (2H, m), 7.75-7.82 (2H, m)


50
CD3OD
270
0.8-0.9 (6H, m), 1.2-1.4 (1H, m), 1.6-1.9 (1H,





m), 2.4-2.6 (7H, m), 2.9-3.2 (2H, m),





3.7-3.8 (1H, m), 4.0-4.4 (1H, m), 4.6-4.8 (1H, m),





6.85 (1H, d, J = 7 Hz), 7.8-8.0 (3H, m), 8.8-8.9 (1H,





m), 9.15 (1H, d, J = 7 Hz)


51
CD3OD
270
0.78 (7H, s), 1.28 (1H, s), 1.76 (1H, s), 2.61 (3H,





s), 3.21-3.44 (3H, m), 3.67 (1H, s), 4.22 (2H, s),





4.82-4.94 (4H, m), 6.89 (1H, d, J = 9.4 Hz),





7.39 (3H, s), 7.67 (2H, s), 7.88 (2H, s), 8.81 (1H, s)


52
CD3OD
270
0.6-0.8 (6H, m), 1.0-1.1 (1H, m), 1.3 (9H, s),





1.7-1.8 (1H, m), 2.4-2.6 (6H, m), 2.7-2.9 (1H,





m), 3.0-3.2 (1H, m), 3.5-3.8 (1H, m),





4.1-4.2 (2H, m), 4.5-4.6 (1H, m), 6.95 (1H, d, J = 8 Hz),





7.1-7.3 (4H, m), 7.8-7.9 (2H, m), 8.3 (1H, m),





8.8-8.9 (2H, m)


53
CD3OD
400
0.85-1.00 (6H, m), 1.10-1.30 (1H, m),





1.50-1.70 (1H, m), 1.85-1.95 (1H, m), 2.47 (2H, s),





2.90-3.10 (2H, m), 3.25-3.35 (1H, m), 3.625 (1H. d,





J = 4 Hz), 4.10-4.30 (2H, m), 4.67 (1H, t, J = 8 Hz),





4.85-5.00 (2H, m), 6.90-7.00 (2H, m),





7.05-7.30 (2H, m), 7.70-7.80 (2H, m), 8.70-8.80 (1H, m)


54
CD3OD
270
2.70-3.10 (4H, m), 3.20-3.40 (2H, m),





4.00-4.35 (3H, m), 4.40-4.45 (1H, m), 4.80-5.10 (3H, m),





6.90-7.50 (9H, m), 7.60-7.80 (2H, m),





8.60-8.80 (1H, m)


55
CD3OD
270
1.60-2.10 (3H, m), 2.20-2.40 (1H, m),





2.80-3.50 (5H, m), 4.10-4.35 (3H, m), 4.55-4.85 (1H, m),





4.80-5.10 (3H, m), 6.90-7.00 (1H, m),





7.10-7.25 (1H, m), 7.30-7.50 (2H, m), 7.70-7.90 (2H, m),





8.70-8.90 (1H, m)


56
CD3OD
270
2.90-3.00 (2H, m), 3.05-3.20 (1H, m),





3.25-3.40 (3H, m), 4.10-4.35 (4H, m), 4.40-4.50 (1H, m),





4.60-4.70 (1H, m), 4.90-5.10 (3H, m),





6.90-7.00 (1H, m), 7.10-7.20 (1H, m), 7.30-7.50 (2H, m),





7.70-7.80 (2H, m)


57
CD3OD
270
2.65-2.80 (1H, m), 3.00-3.20 (1H, m),





3.25-3.40 (3H, m), 4.10-4.40 (2H, m), 4.60-4.70 (1H, m),





4.90-5.00 (2H, m), 6.80-6.90 (1H, m),





6.95-7.05 (1H, m), 7.10-7.20 (2H, m), 7.25-7.50 (5H, m),





7.70-7.80 (2H, m), 8.70-8.80 (1H, m)


58
CD3OD
270
2.90-3.10 (2H, m), 3.25-3.40 (3H, m),





3.90-4.25 (2H, m), 4.50-4.65 (1H, m), 4.90-5.20 (2H, m),





6.85-7.00 (1H, m), 7.05-7.15 (1H, m),





7.20-7.80 (9H, m), 8.50-8.60 (1H, m)


59
CD3OD
270
2.70-3.10 (4H, m) 3.20-3.40 (2H, m),





4.05-4.35 (3H, m), 4.50-4.60 (1H, m), 4.80-5.00 (3H, m),





6.90-7.50 (8H, m), 7.65-7.80 (2H, m),





8.70-8.80 (1H, m)


60
CD3OD
270
2.64 (3H, s), 2.70-2.90 (2H, m), 2.95-3.15 (2H,





m), 3.25-3.40 (2H, m), 3.95-4.40 (4H, m),





4.90-5.10 (2H, m), 6.90-7.30 (9H, m), 7.65-7.75 (2H,





m), 8.70-8.80 (1H, m)


61
CD3OD
270
0.89 (9H, s), 2.85-3.00 (1H, m), 3.10-3.20 (1H,





m), 3.25-3.35 (2H, m), 3.54 (1H, s),





4.10-4.25 (2H, m), 4.60-4.70 (1H, m), 4.90-5.10 (3H, m),





6.90-7.10 (1H, m), 7.15-7.25 (1H, m),





7.35-7.45 (2H, m), 7.70-7.80 (2H, m), 8.70-8.80 (1H, m)


62
CD3OD
270
1.35 (3H, d, J = 6.94 Hz), 2.62 (3H, s),





2.85-2.95 (1H, m), 3.05-3.15 (1H, m), 3.25-3.40 (2H, m),





3.70-3.90 (1H.m), 4.10-4.30 (2H, m),





4.50-4.70 (1H, m), 4.90-5.10 (2H, m), 6.90-7.00 (1H, m),





7.10-7.20 (1H, m), 7.25-7.50 (2H, m),





7.65-7.80 (2H, m), 8.70-8.80 (1H, m)


63
CD3OD
270
1.46-1.63 (2H, m) 1.83 (2H, d, J = 10.9 Hz)





2.00 (1H, d, J = 14.1 Hz) 2.83-2.97 (2H, m)





3.10-3.18 (1H, m) 3.30-3.37 (1H, m) 3.79 (1H, dd, J = 8.6,





3.0 Hz) 4.21 (2H, q, J = 7.7 Hz) 4.59-4.65 (1H,





m) 4.93 (6H, s) 6.94 (1H, d, J = 9.2 Hz)





7.16 (1H, dd, J = 8.2, 2.0 Hz) 7.37-7.42 (2H, m)





7.71-7.76 (2H, m)


64
CD3OD
270
2.75-3.00 (2H, m), 3.16-3.25 (2H, m),





3.25-3.40 (2H, m), 4.10-4.40 (5H, m), 4.65-4.80 (1H, m),





4.90-5.00 (2H, m), 6.90-7.00 (1H, m),





7.15-7.50 (7H, m), 7.70-7.80 (2H, m), 8.70-8.85 (1H, m)


65
CD3OD
270
2.95-3.15 (2H, m), 3.25-3.35 (1H, m),





4.00-4.35 (4H, m), 4.55-4.70 (1H, m), 4.80-5.00 (3H, m),





5.05-5.15 (1H, m), 5.70-5.85 (1H, m),





5.95-6.10 (1H, m), 6.90-7.05 (1H, m), 7.10-7.20 (1H, m),





7.30-7.50 (2H, m), 7.65-7.80 (2H, m),





8.70-8.85 (1H, m)


66
CD3OD
270
2.20-2.50 (1H, m), 2.75-3.00 (2H, m),





3.05-3.20 (1H, m), 3.25-3.40 (2H, m), 3.65-3.80 (2H, m),





4.10-4.35 (2H, m), 4.50-4.75 (2H, m),





4.80-5.10 (2H, m), 6.90-7.05 (1H, m), 7.10-7.20 (1H, m),





7.30-7.50 (2H, m), 7.65-7.80 (2H, m),





8.70-8.85 (1H, m)


67
CD3OD
270
0.80-2.00 (2H, m), 2.30-2.50 (2H, m),





2.80-2.95 (1H, m), 3.10-3.20 (1H, m), 3.25-3.35 (2H, m),





3.85-3.95 (1H, m), 4.15-4.40 (2H, m),





4.60-4.70 (1H, m), 4.90-5.10 (3H, m), 6.90-7.50 (9H, m),





7.70-7.85 (2H, m), 8.70-8.85 (1H, m)


68
CD3OD
270
0.70-0.95 (2H, m), 1.00-1.30 (4H, m),





1.40-1.80 (7H, m), 2.80-2.95 (1H, m), 3.10-3.40 (3H, m),





3.80-3.90 (1H, m), 4.15-4.35 (2H, m),





4.60-4.70 (1H, m), 4.80-5.10 (3H, m), 6.90-7.00 (1H, m),





7.15-7.25 (1H, m), 7.35-7.50 (2H, m),





7.70-7.85 (2H, m), 8.70-8.85 (1H, m)


70
CD3OD
270
2.75-3.20 (4H, m), 3.05-3.15 (2H, m),





4.05-4.25 (3H, m), 4.50-4.65 (1H, m), 4.85-5.00 (4H, m),





6.90-7.75 (11H, m)


72
CD3OD
270
1.70-1.77 (1H, m), 1.85-1.94 (1H, m),





1.98-2.04 (1H, m), 2.29-2.38 (1H, m), 2.89-2.95 (1H, m),





3.11-3.17 (1H, m), 3.31-3.37 (2H, m),





4.16-4.20 (1H, m), 4.26-4.30 (2H, m), 4.64 (1H, dd,





J = 6.56, 8.92), 4.86 (4H, s), 6.96 (1H, d,





J = 9.1 Hz), 7.02-7.04 (1H, m), 7.11-7.20 (3H, m),





7.76-7.79 (1H, m), 8.60-8.75 (1H, m)


73
CD3OD
270
1.44-1.61 (3H, m), 1.81-2.03 (3H, m),





3.13-3.18 (1H, m), 3.30-3.37 (1H, m), 3.77 (1H, dd, J = 8.6,





3.2 Hz), 4.21 (2H, s), 4.56-4.62 (1H, m),





4.92 (3H, br, s), 6.92-7.01 (3H, m),





7.20-7.25 (2H, m), 7.69-7.76 (2H, m), 8.6 1-8.68 (2H, m)


74
CD3OD
270
1.37-1.94 (7H, m), 2.80-2.83 (3H, m),





2.87-2.91 (1H, m), 3.30-3.32 (1H, m), 3.76-3.80 (1H, m),





4.22 (2H, m), 4.60-4.65 (1H, m), 4.99 (2H, s)





6.93-7.19 (4H, m), 7.71-7.79 (2H, m),





8.66-8.69 (1H, m)


75
CD3OD
270
1.08-1.10 (2H, d, J = 6.5 Hz), 1.54-1.58 (2H, m),





1.78-1.94 (3H, m), 2.94 (1H, s), 3.28-3.33 (3H,





m), 3.66-3.80 (3H, m), 4.12-4.22 (3H, m),





4.79-4.82 (1H, m), 6.84 (1H, d, J = 2.2 Hz),





7.34-7.36 (3H, m), 7.45-7.58 (4H, m), 7.59-7.61 (1H, m),





7.73-7.77 (1H, m), 8.16 (1H, d, J = 8.2 Hz)


76
CD3OD
270
1.36-1.61 (3H, m), 1.81-1.84 (2H, m),





1.97-2.02 (1H, m), 2.98-3.07 (2H, m), 3.30-3.38 (3H, m),





3.76-3.82 (1H, m), 4.21 (1H, s), 4.75-4.80 (1H,





m), 4.92 (5H, s), 6.94 (1H, d, J = 9.02 Hz),





7.19-7.38 (4H, m), 7.68 (1H, s) 7.75-7.79 (1H, m)


77
CD3OD
270
1.39-1.84 (6H, m), 1.93-1.98 (1H, m),





2.83-3.01 (1H, m), 3.14-3.19 (1H, m), 3.21-3.30 (1H, m),





3.76-3.81 (1H, m) 4.23 (1H, s) 4.62-4.65 (1H,





m) 4.93 (5H, br, s), 6.94 (1H, d, J = 8.9 Hz),





7.15-7.25 (4H, m), 7.69-7.77 (1H, m),





8.66-8.73 (1H, m)


78
CD3OD
270
1.36-1.95 (6H, m), 3.14-3.17 (1H, m),





3.19-3.22 (1H, m), 3.29-3.42 (2H, m), 3.76-3.80 (1H, m),





4.18 (2H, d, J = 8.2 Hz), 4.75-4.79 (1H, m),





4.95 (5H, br, s), 6.86 (1H, dd, J = 8.2, 1.0 Hz),





7.30-7.39 (3H, m), 7.61-7.66 (2H, m), 7.82-7.86 (2H,





m)


80
CD3OD
400
2.70-2.80 (1H, m), 2.85-3.00 (2H, m),





3.05-3.15 (1H, m), 3.25-3.40 (3H, m), 4.05-4.30 (3H, m),





4.40-4.60 (1H, m), 4.80-5.10 (3H, m),





6.90-7.20 (6H, m), 7.25-7.40 (3H, m), 7.65-7.80 (2H, m)


81
CD3OD
400
2.70-2.80 (1H, m), 2.85-2.95 (3H, m),





3.00-3.15 (1H, m), 3.33 (3H, s), 4.05-4.30 (4H, m),





4.40-4.60 (1H, m), 4.80-5.00 (2H, m), 6.85-7.20 (6H,





m), 7.25-7.45 (3H, m), 7.65-7.80 (2H, m),





8.65-8.80 (1H, m)


82
CD3OD
400
0.85-1.00 (6H, m), 1.10-1.30 (1H, m),





1.50-1.70 (1H, m), 1.85-1.95 (1H, m), 2.47 (2H, s),





2.90-3.10 (2H, m), 3.25-3.35 (1H, m), 3.625 (1H, d,





J = 4 Hz), 4.10-4.30 (2H, m), 4.67 (1H, t, J = 8 Hz),





4.85-5.00 (2H, m), 6.90-7.00 (2H, m),





7.05-7.30 (2H, m), 7.70-7.80 (2H, m), 8.70-8.80 (1H, m)


83
CD3OD
400
0.90-1.10 (6H, m), 1.15-1.25 (1H, m),





1.45-1.60 (1H, m), 1.85-2.00 (1H, m), 2.90-3.10 (2H, m),





3.30-3.40 (2H, m), 3.70-3.80 (1H, m),





4.05-4.25 (2H, m), 4.56 (1H, t, J = 8 Hz), 4.80-5.10 (3H, m),





6.90-7.25 (4H, m), 7.60-7.80 (2H, m),





8.70-8.80 (1H, m)


84
CD3OD
400
1.34 (3H, d, J = 7.0 Hz), 2.65 (3H, s),





2.86-3.01 (1H, m), 3.06-3.19 (1H, m), 3.65-3.76 (1H, m),





4.21-4.30 (2H, m), 4.61-4.72 (1H, m), 4.85 (4H,





s), 6.99 (1H, d, J = 9.3 Hz), 7.03-7.07 (1H, m),





7.13-7.20 (2H, m), 7.77 (1H, d, J = 1.5 Hz),





7.82-7.85 (1H, m), 8.72-8.76 (1H, m)


85
CD3OD
400
1.50 (3H, d, J = 6.96 Hz), 2.56 (3H, s),





2.96-3.01 (1H, m), 3.06-3.11 (1H, m), 3.84 (1H, q,





J = 6.9 Hz), 4.15-4.28 (2H, m), 4.60 (1H, t,





J = 2.0 Hz), 4.86 (4H, s), 6.95-6.98 (1H, m),





7.04-7.07 (1H, m), 7.11-7.20 (2H, m), 7.74-7.84 (2H,





m), 8.56-8.68 (1H, m)


86
CD3OD
400
1.45 (3H, s), 1.59 (3H, s), 2.55 (3H, s),





2.97-3.03 (1H, m), 3.12-3.18 (1H, m), 4.22-4.28 (2H, m),





4.62-4.68 (1H, m), 8.86 (3H, s), 6.99 (1H, d,





J = 9.2 Hz), 7.05-7.07 (1H, m), 7.13-7.20 (2H, m),





7.76 (1H, d, J = 7.95 Hz), 7.81 (1H, dd, J = 2.0,





9.2 Hz), 8.31 (1H, d, J = 7.6 Hz), 8.66-8.68 (1H,





m)


87
CD3OD
400
1.12-1.16 (4H, m), 2.63 (3H, s), 2.88-2.97 (1H,





m), 3.12-3.20 (1H, m), 3.87 (1H, q, J = 4.0 Hz),





4.22 (2H, s), 4.59-4.66 (1H, m), 5.01 (4H, br s),





6.95-7.01 (3H, m), 7.22-7.26 (2H, m),





7.69-7.77 (2H, m)


88
CD3OD
400
1.49 (3H, d, J = 7.0 Hz), 2.53 (3H, s),





2.92-3.00 (1H, m), 3.05-3.19 (1H, m), 3.31-3.33 (4H, m),





3.79-3.82 (1H, m), 4.11-4.17 (1H, m),





4.23-4.28 (1H, m), 4.59-4.70 (1H, m), 6.94-7.01 (3H, m),





7.23-7.28 (2H, m), 7.68-7.71 (2H, m),





8.62-8.72 (1H, m)


90
CD3OD
270
1.70-2.00 (2H, m), 2.05-2.20 (1H, m),





2.40-2.60 (1H, m), 2.88 (3H, s), 2.90-3.40 (4H, m),





3.60-3.70 (1H, m), 4.00-4.40 (3H, m), 4.60-4.70 (1H,





m), 4.80-5.00 (2H, m), 6.90-7.00 (1H, m),





7.10-7.20 (1H, m), 7.30-7.50 (2H, m), 7.70-7.80 (2H,





m), 8.70-8.80 (1H, m)


91
CD3OD
270
1.50-1.70 (1H, m), 1.75-1.90 (1H, m),





2.00-2.20 (1H, m), 2.30-2.50 (1H, m), 2.86 (3H, s),





2.90-3.40 (5H, m), 3.55-3.70 (1H, m), 4.00-4.10 (1H,





m), 4.20-4.30 (2H, m), 4.70-4.80 (1H, m),





4.90-5.10 (1H, m), 6.95 (1H, d, J = 9.15 Hz),





7.40-7.60 (4H, m), 7.70-7.80 (2H, m), 8.75-8.90 (1H, m)


92
CD3OD
270
1.70-1.90 (2H, m), 1.95-2.20 (1H, m),





2.40-2.60 (1H, m), 2.85 (3H, s), 3.00-3.20 (1H, m),





3.30-3.33 (1H, m), 3.60-3.70 (2H, m), 4.03-4.08 (2H,





m), 4.18-4.23 (1H, m), 4.82-4.93 (5H, m),





6.86 (1H, d, J = 8.9 Hz), 7.33-7.36 (2H, m),





7.48-7.57 (4H, m), 7.74-7.78 (1H, m), 7.84-7.87 (1H, m),





8.16 (1H, d, J = 7.9 Hz)


93
CD3OD
270
1.61-1.68 (1H, m), 1.82-1.85 (1H, m),





2.03-2.11 (1H, m), 2.43 (1H, br, s) 2.88-2.95 (3H, m),





3.13-3.18 (2H, m), 3.65 (1H, br, s), 4.08 (1H, t, J = 8.2 Hz),





4.21 (2H, s), 4.65 (1H, t, J = 8.9 Hz),





4.93 (5H, s), 6.96 (1H, d, J = 9.7 Hz),





7.19-7.27 (4H, m), 7.73 (2H, d, J = 8.7 Hz)


94
CD3OD
270
1.78-1.92 (1H, m), 2.13-2.16 (1H, m),





2.47-2.51 (1H, m), 2.88 (4H, s), 2.98-3.01 (2H, m),





3.14-3.19 (1H, m), 3.64-3.69 (1H, m), 4.23 (2H, s),





4.70 (1H, t, J = 7.4 Hz), 4.92 (5H, s), 6.96 (1H,





d, J = 9.2 Hz), 7.12-7.23 (2H, m), 7.74-7.82 (2H,





m)


95
CD3OD
270
1.68-1.83 (2H, m), 2.07 (1H, s), 2.39 (1H, s),





2.86 (3H, s), 3.15-3.39 (2H, m), 4.07-4.24 (3H,





m), 4.83-4.92 (7H, m), 6.85 (1H, d, J = 5.9 Hz),





7.34 (3H, s), 7.62 (2H, s), 7.85 (2H, s)


96
CD3OD
270
3.85 (1H, s), 4.03 (1H, s), 4.59 (1H, s), 5.01 (3H,





s), 5.29-5.43 (2H, m), 5.79 (1H, s),





6.81-7.03 (7H, m), 8.96-9.09 (4H, m), 9.87 (2H, s)


97
CD3OD
270
1.8-2.0 (4H, m), 2.1-2.3 (1H, m), 2.5-2.8 (1H,





m), 2.9-3.0 (3H, s), 3.0-3.3 (4H, m)





3.6-3.8 (1H, m), 4.0-4.3 (4H, m), 4.8-5.0 (1H,





m) 7.0 (1H, d, J = 7 Hz), 7.8-7.9 (2H, m)


98
CD3OD
270
1.60-2.20 (3H, m), 2.35-2.50 (1H, m), 2.87 (3H,





s), 2.90-3.35 (5H, m), 3.60-3.70 (1H, m),





4.00-4.30 (3H, m), 4.60-4.70 (1H, m), 4.90-5.10 (1H,





m), 6.90-7.10 (3H, m), 7.15-7.30 (2H, m),





7.70-7.80 (2H, m), 8.60-8.80 (1H, m)


99
CD3OD
270
1.65-1.70 (1H, m), 1.86-1.88 (1H, m),





2.09-2.12 (1H, m), 2.39-2.43 (1H, m), 2.88 (3H, s),





3.14-3.19 (2H, m), 3.30 (1H, s), 3.61-3.64 (1H, m),





4.06 (1H, t J = 8.4 Hz), 4.22-4.23 (2H, m),





4.69 (1H, t, J = 6.4 Hz), 4.92 (4H, br, s),





6.94-7.06 (4H, m), 7.24-7.29 (1H, m), 7.70-7.77 (2H, m)


100
d6DMSO
270
1.7-1.8 (1H, m), 1.9-2.0 (1H, m), 2.2-2.4 (1H,





m), 2.3-2.4 (1H, m), 2.5 (1H, s), 2.6-2.8 (4H,





m), 2.9-3.2 (1H, m), 3.3-3.6 (6H, m),





3.9-4.4 (2H, m), 4.6-4.8 (1H, m), 6.8-6.9 (2H, m),





7.0-7.1 (1H, d, J = 7 Hz), 7.2-7.3 (2H, m) 7.6-7.7 (1H,





d, J = 7 Hz), 7.8 (1H, s), 8.0-8.2 (1H, m),





8.8-8.9 (1H, m), 9.0-9.1 (1H, m)


101
d6DMSO
270
2.5 (3H, s), 3.0-3.3 (3H, m), 3.6-3.9 (3H, m),





3.7-4.0 (7H, m), 6.9-7.0 (1H, d, J = 9 Hz),





7.2-7.4 (4H, m), 7.7-7.6 (1H, d, J = 9 Hz), 7.77-7.8 (1H,





s), 8.2 (1H, s), 8.6 (2H, s), 9.3 (1H, s)


102
d6DMSO
270
1.0-1.1 (9H, s), 1.3-1.4 (1H, m), 1.8-2.0 (1H, m),





2.1-2.2 (1H, m), 2.5-2.4 (6H, m), 2.6 (3H, s),





3.8-4.0 (1H, m), 4.1-4.2 (2H, m), 4.6-4.8 (1H,





m), 6.5-6.8 (2H, m), 7.1-7.2 (2H, m),





7.3-7.35 (2H, m), 7.4-7.45 (1H, m), 7.9 (1H, s), 8.7 (1H,





s), 8.9 (1H, s)


103
CD3OD
400
1.66-1.74 (1H, m), 1.84-1.92 (1H, m),





2.08-2.18 (1H, m), 2.43-2.50 (1H, m), 2.89-2.93 (5H, m),





3.13-3.19 (2H, m), 3.65-3.69 (1H, m), 4.09 (1H,





t, J = 8.0 Hz), 4.24-4.30 (2H, m), 4.70-4.72 (1H,





m), 4.90 (3H, br, s), 7.01 (1H, d, J = 8.0 Hz),





7.10-7.13 (1H, m), 7.22-7.37 (3H, m), 7.72 (1H,





s), 7.76-7.89 (1H, m)


104
CD3OD
400
1.71-1.92 (2H, m), 2.09-2.15 (1H, m), 2.30 (3H,





s), 2.35-2.51 (1H, m), 2.89 (3H, s),





2.92-2.98 (1H, m), 3.13-3.19 (2H, m), 3.63-3.66 (1H, m),





4.07 (1H, t, J = 8.0 Hz), 4.16-4.25 (2H, m),





4.71 (1H, t, J = 8.0 Hz), 4.91 (4H, br, s), 6.95 (1H, d,





J = 12.0 Hz), 7.04-7.13 (4H, m), 7.65 (1H, s),





7.68-7.75 (1H, m)


105
CD3OD
400
1.63-1.70 (1H, m), 1.83-1.88 (1H, m),





2.06-2.16 (1H, m), 2.27 (3H, m), 2.37-2.46 (1H, m),





2.87-2.91 (3H, m), 3.12-3.19 (2H, m), 3.31-3.32 (1H,





m), 3.62-3.68 (1H, m), 4.07 (1H, t, J = 8.0 Hz),





4.21-4.30 (2H, m), 4.67-4.70 (1H, m), 4.90 (4H,





br, s), 6.89-7.05 (3H, m), 7.10-7.20 (1H, m),





7.64-7.79 (2H, m), 8.71-8.76 (1H, m)


106
CD3OD
400
1.64-1.73 (1H, m), 1.82-1.89 (1H, m),





2.04-2.15 (1H, m), 2.29 (3H, s), 2.37-2.47 (1H, m),





2.85-2.91 (4H, m), 3.10-3.19 (2H, m), 3.63-3.69 (1H,





m), 4.08 (1H,, t J = 8.0 Hz), 4.18-4.27 (2H, m),





4.65-4.67 (1H, m), 4.90 (4H, br, s),





6.89-6.94 (1H, m), 7.06-7.30 (4H, m, 7.65-7.74 (2H, m)


107
CD3OD
400
1.67-1.76 (1H, m), 1.82-1.93 (1H, m),





2.07-2.17 (1H, m), 2.41-2.49 (1H, m), 2.86-2.89 (4H, m),





3.07-3.20 (2H, m), 3.64-3.68 (1H, m),





3.69-3.75 (3H, m), 4.09 (1H, t, J = 8.0 Hz), 4.18-4.29 (2H,





m), 4.61-4.65 (1H, m), 4.92 (4H, br, s),





6.81 (2H, d, J = 8.0 Hz), 6.94-6.96 (1H, m), 7.13 (2H,





d, J = 8.0 Hz), 7.71-7.77 (2H, m)


108
CD3OD
400
1.70-1.76 (1H, m), 1.83-1.90 (1H, m),





2.09-2.16 (1H, m), 2.40-2.48 (1H, m), 2.88 (3H, s),





2.98-3.03 (1H, m), 3.13-3.25 (2H, m), 3.63-3.68 (1H,





m), 4.08 (1H, t, J = 8.0 Hz), 4.24-4.29 (2H, m),





4.74-4.82 (1H, m), 4.92 (4H, br, s),





7.03-7.08 (1H, m), 7.10-7.19 (2H, m), 7.23-7.33 (2H, m),





7.70-7.71 (1H, m), 7.77-7.84 (1H, m)


109
CD3OD
400
1.69-1.78 (1H, m), 1.81-1.92 (1H, m),





2.04-2.17 (1H, m), 2.42-2.51 (1H, m), 2.89 (3H, s),





3.05-3.20 (2H, m), 3.32-3.37 (1H, m), 3.62-3.68 (1H,





m), 4.10 (1H, t, J = 8.0 Hz), 4.23-4.36 (2H, m),





4.82-4.85 (5H, m), 6.97 (1H, d, J = 12.0 Hz),





7.19-7.29 (3H, m), 7.32-7.40 (1H, m), 7.71 (1H,





s), 7.79 (1H, dd, J = 8.0, 4.0 Hz)


110
CD3OD
400
1.76-1.83 (1H, m), 1.87-1.94 (1H, m),





2.11-2.19 (1H, m), 2.46-2.55 (1H, m), 2.89 (3H, s),





3.04-3.08 (1H, m), 3.10-3.19 (1H, m), 3.27-3.33 (1H,





m), 3.64-3.70 (1H, m), 4.10 (1H, t, J = 8.0 Hz),





4.19-4.27 (2H, m), 4.81 (1H, t, J = 8.0 Hz),





4.91 (4H, br s), 6.98 (1H, d, J = 12.0 Hz),





7.18-7.28 (2H, m), 7.43 (1H, s), 7.71-7.73 (1H, m),





7.77-7.80 (1H, m)


111
CD3OD
400
1.74-1.81 (1H, m), 1.88-1.94 (1H, m),





2.11-2.18 (1H, m), 2.45-2.52 (1H, m), 2.89 (4H, s),





3.11-3.21 (2H, m), 3.33-3.42 (1H, m), 3.64-3.70 (1H,





m), 4.11-4.30 (5H, m), 4.77 (2H, t, J = 8.0 Hz),





6.97 (1H, d, J = 8.0 Hz), 7.40-7.48 (2H, m),





7.51-7.61 (1H, m), 7.66-7.71 (2H, m),





7.78-7.83 (1H, m)


112
CD3OD
400
1.11 (2H, t, J = 4.0 Hz), 1.74-1.87 (1H, m),





1.90-1.95 (2H, m), 2.46-2.49 (1H, m), 2.88-2.90 (5H,





m), 3.11-3.18 (3H, m), 3.22-3.30 (3H, m),





3.50-3.55 (1H, m), 3.65-3.69 (1H, m), 4.11-4.16 (1H,





m), 4.22-4.37 (2H, m), 6.99 (2H, d, J = 8.0 Hz),





7.77 (1H, s), 7.87 (1H, dd, J = 8.0, 4.0 Hz),





7.93-8.01 (2H, m), 8.75-8.77 (2H, br, s), 8.87 (1H, t, J = 4.0 Hz)


113
CD3OD
400
1.54-1.59 (1H, m) 1.64-1.74 (1H, m)





1.92-1.99 (1H, m) 2.25-2.30 (1H, M) 2.72-2.76 (4H, m)





3.01-3.07 (3H, m) 3.18-3.23 (2H, m)





3.49-3.55 (1H, m) 3.94-4.12 (5H, m) 4.62 (1H, t, J = 4.0 Hz)





6.67 (1H, d, J = 8.0 Hz) 6.81-6.94 (1H, m)





6.99-7.07 (2H, m) 7.23 (1H, d, J = 8.0 Hz)





7.36-7.53 (3H, m)


114
CD3OD
400
1.69-1.80 (2H, m), 2.04-2.11 (1H, m),





2.43-2.48 (1H, m), 2.88 (3H, s), 3.11-3.18 (1H, m),





3.31-3.33 (1H, m), 3.46-3.51 (1H, m), 3.57-3.60 (1H,





m), 4.13 (1H, t, J = 8.0 Hz), 4.22-4.31 (2H, m),





4.92 (4H, br s), 5.11 (1H, t, J = 8.0 Hz),





6.85 (1H, d, J = 8.0 Hz), 7.71-7.81 (4H, m), 7.94 (1H,





m), 8.07-8.19 (2H, m), 8.60-8.64 (1H, m)


115
CD3OD
270
0.9-1.0 (3H, m), 1.1-1.4 (5H, m), 1.5-1.8 (8H,





m), 2.0-2.3 (3H, m) 2.6-2.7 (1H, m) 2.9 (3H, s),





3.1-3.3 (1H, m), 3.7-3.8 (1H, m) 4.0-4.5 (4H,





m), 7.0-7.1 (1H, d, J = 7 Hz), 7.7-7.8 (2H, s)





7.9-8.0 (1H, m)


116
CD3OD
400
1.90-2.25 (3H, m), 2.50-2.65 (1H, m), 2.82 (3H,





m), 2.90-3.25 (3H, m), 3.30-3.40 (2H, m),





3.65-3.80 (1H, m), 4.00-4.30 (3H, m), 4.55-4.70 (1H,





m), 4.85-5.00 (1H, m), 6.90-7.25 (4H, m),





7.65-7.80 (2H, m), 8.65-8.80 (1H, m)


117
CD3OD
270
1.24-1.29 (7H, m), 1.76-1.83 (2H, m),





2.00-2.05 (1H, m), 2.40 (1H, br, s), 2.89-2.94 (1H, m),





3.08-3.15 (2H, m), 3.49-3.64 (2H, m),





4.20-4.27 (3H, m), 4.63 (1H, t, J = 8.6 Hz), 4.98 (3H, br,





s), 6.95 (1H, d, J = 9.9 Hz), 7.16 (1H, d, J = 6.6 Hz),





7.38-7.41 (2H, m), 7.72-7.75 (2H, m)


118
CD3OD
270
1.20-1.35 (6H, m), 1.60-1.80 (2H, m),





1.90-2.10 (1H, m), 2.20-2.40 (1H, m), 3.15-3.70 (8H, m),





4.00-4.30 (3H, m), 4.75-4.95 (1H, m), 6.86 (1H,





d, J = 9.40 Hz), 7.30-7.90 (8H, m), 8.15-8.20 (1H,





m), 8.55-8.70 (1H, m)


119
CD3OD
270
1.20-1.30 (6H, m), 1.75-1.85 (2H, m),





2.03-2.15 (2H, m), 2.25-2.50 (1H, m), 2.88-2.96 (2H, m),





3.07-3.14 (2H, m), 3.49-3.70 (2H, m),





4.17-4.22 (3H, m), 4.61-4.65 (1H, m), 4.90-5.10 (1H, m),





6.92-7.02 (3H, m), 7.20-7.25 (2H, m),





7.70-7.74 (2H, m), 8.65-8.80 (1H, m)


120
CD3OD
400
1.26-1.30 (6H, m), 1.72-1.84 (2H, m),





2.00-2.09 (1H, m), 2.33-2.41 (1H, m), 2.92-2.98 (1H, m),





3.14-3.27 (2H, m), 3.50-3.63 (2H, m),





4.23-4.36 (3H, m), 4.67 (1H, t, J = 8.0 Hz), 4.93 (4H, br,





s), 6.75 (1H, d, J = 8.0 Hz), 7.18-7.35 (4H, m),





7.71-7.78 (2H, m)


121
CD3OD
400
1.26-1.30 (6H, m), 1.74-1.83 (2H, m),





2.00-2.08 (1H, m), 2.36-2.40 (3H, m), 2.95-3.00 (1H, m),





3.15-3.26 (2H, m), 3.50-3.64 (2H, m),





4.14-4.25 (3H, m), 4.68 (1h, t, J = 8.0 Hz), 4.91 (5H, br, s),





6.72 (1H, d, J = 8.0 Hz), 7.04-7.16 (4H, m),





7.64-7.79 (2H, m)


122
CD3OD
400
1.14-1.19 (6H, m), 1.57-1.69 (2H, m),





1.89-1.94 (1H, m), 2.18 (3H, s), 2.76-2.82 (1H, m),





2.99-3.12 (2H, m), 4.11-4.13 (3H, m), 4.53-4.57 (1H,





m), 4.92 (6H, br, s) 6.84 (1H, d, J = 8.0 Hz),





6.90-6.95 (3H, m), 6.99-7.08 (1H, m),





7.57-7.62 (2H, m), 8.75 (1H, d, J = 8.0 Hz)


123
CD3OD
400
1.11-1.30 (6H, m), 1.71-1.79 (2H, m),





2.01-2.05 (1H, m), 2.28 (3H, s), 2.87-2.93 (1H, m),





3.08-3.13 (1H, m), 3.19-3.25 (1H, m), 3.31-3.32 (1H,





m), 3.50-3.65 (2H, m), 4.14-4.35 (3H, m),





4.63 (1H, t, J = 8.0 Hz), 4.96 (4H, br, s), 6.95 (1H, d,





J = 8.0 Hz), 7.05-7.11 (4H, m), 7.71-7.75 (2H,





m)


124
CD3OD
400
1.26-1.30 (6H, m), 1.73-1.84 (1H, m),





2.00-2.08 (1H, m), 2.34-2.39 (1H, m), 2.86-2.91 (1H, m),





3.05-3.10 (1H, m), 3.19-3.26 (1H, m),





3.50-3.63 (2H, m), 3.75 (3H, s), 4.20-4.26 (3H, m),





4.60 (1H, t, J = 8.0 Hz), 4.94 (4H, br, s),





6.80-6.82 (2H, m), 6.94 (1H, dd, J = 8.0, 4.0 Hz),





7.13 (2H, d, J = 8.0 Hz), 7.70-7.72 (2H, m)


125
CD3OD
400
1.25-1.30 (6H, m), 1.73-1.84 (2H, m),





2.01-2.09 (1H, m), 2.34-2.43 (1H, m), 3.00-3.06 (1H, m),





3.19-3.26 (2H, m), 3.50-3.62 (2H, m),





4.22-4.36 (3H, m), 4.71-4.76 (1H, m), 4.98 (4H, br, s),





7.01 (1H, d, J = 8.0 Hz), 7.04-7.09 (2H, m),





7.23-7.36 (2H, m), 7.70 (1H, s), 7.77 (1H, dd, J = 8.0,





4.0 Hz)


126
CD3OD
400
1.26-1.30 (6H, m), 1.76-1.84 (2H, m),





2.01-2.10 (1H, m), 2.37-2.42 (1H, m), 3.09-3.14 (1H, m),





3.20-3.33 (2H, m), 3.50-3.63 (2H, m),





4.21-4.32 (3H, m), 4.80 (1H, t, J = 8.0 Hz), 4.88 (4H, br, s)





6.96 (1H, d, J = 8.0 Hz), 7.16-7.28 (2H, m),





7.37-7.47 (1H, m), 7.70 (1H, s) 7.75-7.83 (1H,





m), 8.69 (1H, t, J = 8.0 Hz)


127
CD3OD
400
1.07-1.17 (6H, m), 1.66-1.73 (2H, m),





1.93-2.00 (1H, m), 2.30-2.35 (1H, m), 2.96-3.04 (1H, m),





3.14-3.21 (2H, m), 3.40-3.52 (2H, m),





4.04-4.24 (3H, m), 4.65 (1H, t, J = 8.0 Hz), 4.88 (4H, br,





s), 6.90 (1H, d, J = 12.0 Hz), 7.05-7.18 (2H, m),





7.31 (1H, s), 7.62-7.73 (2H, m)


128
CD3OD
400
1.25-1.30 (6H, m), 1.76-1.89 (2H, m),





2.04-2.11 (1H, m), 2.37-2.44 (1H, m), 3.14-3.26 (2H, m),





3.31-3.38 (1H, m), 3.50-3.65 (2H, m),





4.15-4.37 (3H, m), 4.75 (1H, t, J = 8.0 Hz), 4.99 (4H, br,





s), 6.96 (1H, d, J = 8.0 Hz), 7.40-7.46 (2H, m),





7.51-7.55 (1H, m), 7.67-7.71 (2H, m), 7.78 (1H,





dd, J = 8.0, 4.0 Hz)


129
CD3OD
400
1.26-1.30 (5H, m), 1.78-1.87 (1H, m),





2.04-2.09 (1H, m), 2.39-2.44 (1H, m), 3.24-3.33 (3H, m),





3.44-3.63 (3H, m), 4.24-4.35 (3H, m),





4.82-4.89 (7H, m), 6.99 (1H, d, J = 12.0 Hz), 7.77 (1H, s),





7.84-7.89 (2H, m)


130
CD3OD
400
1.22-1.26 (6H, m), 1.67-1.75 (2H, m),





1.92-2.01 (1H, m), 2.26-2.32 (1H, m), 3.11-3.17 (2H, m),





3.30-3.33 (1H, m), 3.44-3.58 (2H, m),





4.09-4.14 (2H, m), 4.17-4.24 (1H, m), 4.71 (1H, t, J = 8.0 Hz),





4.93 (5H, br s), 6.85 (1H, d, J = 12.0 Hz),





6.92-7.01 (1H, m), 7.07-7.13 (2H, m), 7.34 (1H,





d, J = 8.0 Hz), 7.47-7.61 (3H, m)


131
CD3OD
400
1.27 (3H, t, J = 7.3 Hz), 1.72-1.81 (1H, m),





1.85-1.96 (1H, m), 2.06-2.19 (1H, m), 2.42-2.49 (1H,





m), 2.89-2.96 (2H, m), 3.09-3.29 (4H, m),





3.65-3.73 (1H, m), 4.10 (1H, t, J = 8.4 Hz), 4.16 (1H, d,





J = 15.1 Hz), 4.31 (1H, d, J = 15.1 Hz), 4.65 (1H,





dd, J = 7.0, 8.7 Hz), 4.86 (2H, s), 6.96 (1H, d,





J = 9.1 Hz), 7.01-7.04 (1H, m), 7.10-7.24 (2H, m),





7.74-7.78 (2H, m), 8.65-8.75 (1H, m)


132
CD3OD
400
0.95 (3H, t, J = 7.3 Hz), 1.55-1.61 (3H, m),





1.62-1.68 (1H, m), 1.70-1.87 (1H, m), 2.00-2.12 (1H,





m), 2.34-2.44 (1H, m), 2.89-3.33 (6H, m),





3.58-3.71 (2H, m), 3.97 (1H, dd, J = 7.2, 9.0 Hz),





4.21 (2H, s), 4.64 (1H, dd, J = 6.4, 9.0 Hz), 4.86 (1H, s),





6.72 (1H, d, J = 8.7 Hz), 7.00-7.04 (1H, m),





7.12-7.19 (2H, m), 7.54 (1H, dd, J = 2.2, 8.9 Hz),





7.80 (1H, d, J = 1.7 Hz)


133
CD3OD
400
0.97 (3H, d, J = 6.6 Hz), 1.03 (3H, d, J = 6.6 Hz),





1.71-1.79 (1H, m), 1.90-2.04 (2H, m),





2.07-2.23 (1H, m), 2.39-2.48 (1H, m), 2.85-3.04 (4H, m),





3.11-3.21 (2H, m), 3.74-3.79 (1H, m), 4.13 (1H,





t, J = 8.5 Hz), 4.18-4.34 (2H, m), 4.65 (1H, dd,





J = 6.7, 8.85 Hz), 4.87 (2H, s), 6.97 (1H, d,





J = 9.4 Hz), 7.01-7.05 (1H, m), 7.11-7.20 (2H, m),





7.76 (1H, d, J = 10.1 Hz), 7.78-7.81 (1H, m),





8.73-8.76 (1H, m)


135
CD3OD
400
1.70-1.80 (1H, m), 1.81-2.00 (1H, m),





2.05-2.20 (1H, m), 2.30-2.50 (1H, m), 2.80-2.95 (1H, m),





3.10-3.40 (6H, m), 3.70-3.85 (1H, m),





3.95-4.00 (1H, m), 4.05-4.15 (1H, m), 4.20-4.50 (3H, m),





4.60-4.70 (1H, m), 6.90-7.10 (1H, m),





7.11-7.30 (1H, m), 7.65-7.75 (1H, m), 7.80-7.90 (1H, m),





8.65-8.80 (1H, m)


136
CD3OD
400
1.27 (3H, t, J = 7.2 Hz), 1.71-1.80 (1H, m),





1.83-1.94 (1H, m), 2.07-2.17 (1H, m), 2.37-2.44 (1H, m),





2.89-2.98 (2H, m), 3.07-3.32 (6H, m),





3.66-3.72 (1H, m), 4.09 (1H, t, J = 8.4 Hz),





4.15-4.36 (2H, m), 4.63-4.67 (1H, m), 6.95-7.09 (3H, m),





7.22-7.30 (2H, m), 7.72-7.86 (2H, m),





8.69-8.72 (1H, m)


137
CD3OD
400
1.25-1.28 (3H, m), 1.66-1.70 (1H, m),





1.82-1.87 (1H, m), 2.04-2.12 (1H, m), 2.29 (3H, s),





2.36-2.41 (1H, m), 2.86-2.92 (1H, m), 3.10-3.27 (5H,





m), 3.31-3.33 (1H, m), 3.65-3.71 (1H, m),





4.10 (1H, t, J = 8.0 Hz), 4.18-4.28 (2H, m),





4.65-4.69 (1H, m), 4.87 (2H, br, s), 6.88 (1H, d, J = 12.0 Hz),





6.96-7.06 (3H, m), 7.10-7.17 (1H, m),





7.61-7.73 (2H, m)


138
CD3OD
400
1.25-1.28 (3H, m), 1.69-1.74 (1H, m),





1.83-1.97 (1H, m), 2.08-2.14 (1H, m), 2.40-2.45 (1H, m),





2.91-2.96 (1H, m), 3.11-3.33 (5H, m),





3.616-3.72 (1H, m), 4.12 (1H, t, J = 8.0 Hz),





4.19-4.28 (2H, m), 4.69 (1H, t, J = 4.0 Hz), 4.89 (3H, br,





s), 6.97 (1H, d, J = 8.0 Hz), 7.17-7.19 (1H, m),





7.22-7.29 (3H, m), 7.72 (1H, s), 7.77 (1H, dd, J = 8.0,





4.0 Hz)


139
CD3OD
400
0.97 (3H, t, J = 7.4 Hz), 1.65-1.77 (4H, m),





1.85-1.92 (1H, m), 2.07-2.15 (1H, m), 2.37-2.44 (1H,





m), 2.90-2.96 (2H, m), 3.03-3.20 (4H, m),





3.68-3.73 (1H, m), 4.10 (1H, t, J = 8.2 Hz),





4.20-4.29 (2H, m), 4.65 (1H, dd, J = 6.98, 8.61 Hz),





4.86 (1H, s), 6.95-7.02 (3H, m), 7.22-7.25 (2H, m),





7.72-7.76 (2H, m), 8.69-8.72 (1H, m)


140
CD3OD
400
1.65-1.70 (1H, m), 1.85-2.00 (1H, m),





2.10-2.25 (1H, m), 2.35-2.50 (1H, m), 2.80-2.90 (1H, m),





3.00-3.10 (1H, m), 3.25-3.40 (4H, m),





3.45-3.60 (1H, m), 4.10-4.40 (5H, m), 4.50-4.60 (1H, m),





6.90-7.00 (1H, m), 7.05-7.20 (2H, m),





7.40-7.65 (5H, m), 7.70-7.80 (2H, m), 8.60-8.80 (1H, m)


141
CD3OD
270
1.69-2.03 (4H, m), 2.89-2.94 (1H, m),





3.12-3.32 (4H, m), 4.17-4.28 (5H, m), 4.30-4.35 (1H, m),





4.96 (3H, br, s), 6.95 (1H, d, J = 8.9 Hz),





7.15-7.19 (2H, m), 7.33-7.42 (6H, m),





7.73-7.76 (2H, m)


143
CD3OD
400
1.71-1.76 (1H, m), 1.89-1.98 (1H, m),





2.12-2.18 (1H, m), 2.43-2.50 (1H, m), 2.84-2.90 (1H, m),





3.02-3.07 (1H, m), 3.31-3.33 (1H, m),





3.52-3.57 (1H, m), 4.11-4.18 (2H, m), 4.27-4.38 (3H, m),





4.56 (1H, dd, J = 7.2, 8.3 Hz), 4.86 (3H, s),





6.96-6.99 (2H, m), 7.05-7.17 (2H, m), 7.39-7.48 (3H,





m), 7.53 (1H, s), 7.75-7.77 (2H, m),





8.63-8.66 (1H, m)


144
CD3OD
400
1.50-2.00 (6H, m), 2.78 (3H, s), 2.85-2.95 (1H,





m), 3.05-3.15 (2H, m), 3.25-3.35 (2H, m),





3.40-3.50 (1H, m), 3.55-3.70 (1H, m), 4.10-4.30 (2H,





m), 4.50-4.60 (1H, m), 4.80-5.00 (1H, m),





6.90-7.20 (4H, m), 7.65-7.80 (2H, m),





8.70-8.80 (1H, m)


145
CD3OD
400
1.52-1.63 (2H, m), 1.72-1.93 (4H, m), 2.78 (3H,





s), 2.86-2.97 (2H, m), 3.08-3.14 (2H, m),





3.46-3.54 (1H, m), 3.65-3.69 (1H, m), 4.16 (1H, d,





J = 15.1 Hz), 4.25 (1H, d, J = 15.1 Hz), 4.59 (1H,





dd, J = 7.3, 8.4 Hz), 4.86 (3H, s), 6.92-7.02 (3H,





m), 7.21-7.24 (2H, m), 7.69-7.71 (2H, m)


146
CD3OD
400
1.32 (6H, dd, J = 6.66, 25.1), 1.56-1.61 (1H, m),





1.68-1.97 (4H, m), 2.90-2.98 (2H, m),





3.00-3.14 (1H, m), 3.44 (1H, d, J = 13.05 Hz),





3.54-3.74 (2H, m), 3.94-3.97 (1H, m), 4.14-4.30 (2H, m),





4.55-4.61 (1H, m), 4.86 (2H, m), 6.98 (1H, d,





J = 9.2 Hz), 7.06-7.12 (1H, m), 7.13-7.21 (2H, m),





7.76-7.81 (2H, m), 8.69-8.72 (1H, m),





8.86-8.92 (1H, m)


147
CD3OD
270
1.25-1.40 (6H, m), 1.44-1.92 (5H, m),





2.80-2.97 (2H, m), 3.30-3.36 (2H, m), 3.74-3.90 (2H, m),





4.11-4.28 (2H, m), 4.55-4.60 (1H, m), 4.90 (5H,





br, s), 6.92-7.00 (2H, m), 7.19-7.24 (2H, m),





7.66-7.69 (2H, m), 8.67-8.69 (1H, m)


148
CD3OD
400
1.82-1.88 (1H, m), 2.62-2.79 (1H, m),





2.91 (3H, s), 2.94-3.00 (1H, m), 3.08-3.18 (1H, m),





3.28-3.32 (1H, m), 3.57 (1H, d, J = 11.6 Hz),





4.07-4.34 (3H, m), 4.49 (1H, s, br), 4.62-4.69 (1H, m),





4.92 (3H, s), 6.96 (1H, d, J = 9.1 Hz),





7.00-7.03 (1H, m), 7.11-7.24 (2H, m), 7.73-7.81 (2H, m),





8.69-8.11 (1H, m)


149
CD3OD
400
2.87-2.98 (1H, m), 3.00 (3H, s), 3.04-3.15 (2H,





m), 3.20-3.26 (1H, m), 4.16-4.18 (2H, m),





4.20-4.34 (1H, m), 4.43 (1H, d, J = 15.4 Hz), 4.57 (1H,





d, J = 15.5 Hz), 4.65 (1H, dd, J = 7.05, 8.61 Hz),





4.86 (4H, s), 6.97 (1H, d, J = 9.1 Hz),





7.04-7.07 (1H, m), 7.12-7.36 (4H, m), 7.74-7.79 (2H, m),





8.72-8.75 (2H, m)


150
CD3OD
270
1.28-1.30 (6H, m), 2.75 (3H, s), 2.89-2.97 (2H,





m), 3.07-3.30 (2H, m), 3.40-3.45 (1H, m),





3.83-3.95 (2H, m), 4.12-4.27 (2H, m), 4.65 (1H, t, J = 6.9 Hz),





4.95 (2H, br, s), 6.93-6.96 (1H, m),





7.17 (1H, dd, J = 8.2, 1.5 Hz), 7.40 (2H, d, J = 8.2 Hz),





7.71 (2H, br, s)


151
CD3OD
270
1.25-1.50 (9H, m), 2.59 (3H, s), 2.85-3.15 (2H,





m), 3.25-3.35 (2H, m), 3.75-3.95 (2H, m),





4.05-4.35 (2H, m), 4.55-4.70 (1H, m), 4.90-5.10 (2H,





m), 6.85-6.95 (1H, m), 7.10-7.20 (1H, m),





7.35-7.45 (2H, m), 7.60-7.75 (2H, m)


152
CD3OD
270
2.79 (3H, s), 2.85-3.30 (3H, m), 3.80-3.95 (2H,





m), 4.10-4.30 (4H, m), 4.60-4.70 (1H, m),





4.90-5.10 (1H, m), 6.90-7.00 (1H, m), 7.10-7.20 (1H,





m), 7.30-7.50 (8H, m), 7.60-7.80 (2H, m),





8.60-8.80 (1H, m)


153
CD3OD
270
2.86 (6H, s), 2.90-310 (2H, m), 3.25-3.40 (2H,





m), 3.85-4.30 (2H, m), 4.55-4.70 (1H, m),





4.80-5.00 (1H, m), 6.90-7.00 (1H, m), 7.10-7.20 (1H,





m), 7.30-7.50 (2H, m), 7.60-7.80 (2H, m),





8.65-8.80 (1H, m)


154
CD3OD
270
0.98 (6H, d, J = 6.43 Hz), 1.95-2.15 (1H, m),





2.70-3.15 (7H, m), 3.25-3.40 (1H, m), 3.80-4.05 (2H,





m), 4.10-4.35 (2H, m), 4.60-4.70 (1H, m),





4.90-5.20 (2H, m), 6.90-7.00 (1H, m), 7.10-7.20 (1H,





m), 7.35-7.50 (2H, m), 7.65-7.80 (2H, m),





8.70-8.80 (1H, m)


155
CD3OD
270
0.75-0.90 (7H, m), 1.25-1.40 (7H, m),





1.60-1.80 (1H, m), 2.60 (3H, s), 2.65-3.05 (5H, m),





3.60-3.95 (2H, m), 4.10-4.40 (2H, m), 4.60-4.70 (1H,





m), 6.90-7.10 (1H, m), 7.15-7.25 (1H, m),





7.40-7.50 (2H, m), 7.60-7.80 (2H, m), 8.70-8.90 (1H,





m)


156
CD3OD
270
1.20-1.40 (6H, m), 2.75 (3H, s), 2.85-3.15 (2H,





m), 3.25-3.35 (1H, m), 3.40-4.00 (1H, m),





4.10-4.30 (2H, m), 4.55-4.70 (1H, m), 4.80-5.10 (4H,





m), 6.90-7.40 (4H, m) 7.65-7.90 (2H, m),





8.70-8.80 (1H, m)


157
CD3OD
400
1.16 (3H, d, J = 6.1 Hz), 1.27 (6H, d, J = 6.5 Hz),





1.34 (3H, d, J = 6.1 Hz), 2.90-3.16 (2H, m),





3.65-3.73 (2H, m), 3.81-3.97 (2H, m), 4.17-4.28 (2H,





m), 4.59-4.69 (1H, m), 6.95-6.98 (1H, m),





7.0-7.05 (1H, m), 7.12-7.19 (2H, m), 7.73-7.79 (2H,





m), 8.73-8.76 (1H, m).


158
CD3OD
400
0.95 (6H, t, J = 7.3 Hz), 1.65 (4H, br s),





2.89-2.95 (1H, m), 3.03-3.16 (6H, m), 3.88-4.03 (2H, m),





4.22-4.24 (2H, m), 4.63-4.67 (1H, m), 6.97 (1H,





d, J = 9.2 Hz), 7.03-7.06 (1H, m), 7.12-7.19 (2H,





m), 7.73 (1H, d, J = 1.2 Hz), 7.78 (1H, dd, J = 9.2,





2.1 Hz), 8.74 (1H, t, J = 5.9 Hz).


159
CD3OD
400
1.00 (12H, dd, J = 6.6, 3.0 Hz), 2.00-2.04 (2H, m),





2.89-3.18 (6H, m), 3.96-4.12 (2H, m),





4.24-4.25 (2H, m), 4.66-4.71 (1H, m), 6.97 (1H, d, J = 9.1 Hz),





7.04-7.07 (1H, m), 7.12-7.19 (2H, m),





7.74 (1H, d, J = 1.3 Hz), 7.79 (1H, dd, J = 9.2,





2.1 Hz).


160
CD3OD
400
2.91-3.10 (4H, m), 3.21-3.33 (3H, m),





3.78-3.89 (2H, m), 4.12-4.28 (2H, m), 4.60 (1H, s, J = 7.6 Hz),





6.95 (1H, d, J = 9.1 Hz), 7.00-7.03 (1H,





m), 7.09-7.16 (2H, m), 7.25-7.37 (5H, m),





7.71-7.75 (2H, m), 8.69 (1H, t, J = 5.8 Hz).


161
CD3OD
400
2.92-3.13 (7H, m), 3.32-3.38 (2H, m),





3.98-4.09 (2H, m), 4.17-4.27 (2H, m), 4.61-4.65 (1H, m),





6.95 (1H, d, J = 9.1 Hz), 7.01-7.04 (1H, m),





7.08-7.17 (2H, m), 7.24-7.35 (5H, m), 7.72 (1H, s),





7.75 (1H, dd, J = 9.2, 2.0 Hz), 8.73 (1H, t, J = 5.8 Hz).


162
CD3OD
400
2.86-2.95 (4H, m), 3.01-3.14 (1H, m),





3.87-4.04 (4H, m), 4.14-4.24 (2H, m), 4.58-4.66 (1H, m),





6.24-6.31 (1H, m), 6.87-7.03 (3H, m),





7.07-7.50 (7H, m), 7.71-7.77 (2H, m), 8.69-8.84 (1H, m).


163
CD3OD
400
2.83 (3H, s), 2.89-2.95 (1H, m), 3.02-3.11 (1H,





m), 3.89-3.99 (2H, m), 4.15-4.30 (4H, m),





4.59-4.63 (1H, m), 6.95 (1H, d, J = 9.0 Hz),





7.00-7.04 (1H, m), 7.10-7.17 (2H, m), 7.46-7.51 (4H, m),





7.72 (1H, d, J = 1.3 Hz), 7.76 (1H, dd, J = 9.1,





2.1 Hz), 8.72 (1H, t, J = 5.9 Hz).


164
CD3OD
400
2.84 (3H, s), 2.90-2.95 (1H, m), 3.02-3.12 (1H,





m), 3.90-4.01 (2H, m), 4.16-4.34 (4H, m),





4.60-4.64 (1H, m), 6.95 (1H, d, J = 9.1 Hz),





7.00-7.04 (1H, m), 7.10-7.17 (2H, m), 7.42-7.57 (4H, m),





7.72 (1H, d, J = 1.1 Hz), 7.76 (1H, dd, J = 9.1,





2.0 Hz), 8.72 (1H, t, J = 5.8 Hz).


165
CD3OD
400
2.87 (3H, s), 2.90-2.95 (1H, m), 3.02-3.12 (1H,





m), 3.97-4.08 (2H, m), 4.19-4.27 (2H, m),





4.43-4.54 (2H, m), 4.60-4.64 (1H, m), 6.95 (1H, d, J = 9.2 Hz),





7.01-7.04 (1H, m), 7.10-7.17 (2H, m),





7.42-7.63 (4H, m), 7.72 (1H, s), 7.76 (1H, dd, J = 9.1,





2.1 Hz), 8.72 (1H, t, J = 5.8 Hz).


166
CD3OD
400
2.81 (3H, s), 2.89-2.94 (1H, m), 3.06-3.11 (1H,





m), 3.84 (3H, s), 3.87-3.94 (2H, m),





4.15-4.27 (4H, m), 4.59-4.63 (1H, m), 6.95 (1H, d, J = 9.0 Hz),





6.99-7.03 (3H, m), 7.10-7.17 (2H, m),





7.38 (2H, d, J = 8.7 Hz), 7.72 (1H, d, J = 1.3 Hz),





7.75 (1H, dd, J = 9.1, 2.1 Hz), 8.71 (1H, t, J = 5.8 Hz).


167
CD3OD
400
1.55-1.85 (6H, m), 2.91-3.12 (4H, m),





3.35-3.45 (2H, m), 3.83-3.94 (2H, m), 4.16-4.30 (2H, m),





4.60-4.65 (1H, s), 6.96 (1H, d, J = 9.4 Hz),





7.01-7.04 (1H, m), 7.10-7.19 (2H, m), 7.72 (1H, d, J = 1.2 Hz),





7.76 (1H, dd, J = 9.2, 2.1 Hz), 8.71 (1H, t,





J = 5.8 Hz).


168
CD3OD
400
2.87 (3H, s), 2.90-2.95 (1H, m), 3.02-3.12 (1H,





m), 3.97-4.08 (2H, m), 4.19-4.27 (2H, m),





4.43-4.54 (2H, m), 4.60-4.64 (1H, m), 6.95 (1H, d, J = 9.2 Hz),





7.01-7.04 (1H, m), 7.10-7.17 (2H, m),





7.42-7.63 (4H, m), 7.72 (1H, s), 7.76 (1H, dd, J = 9.1,





2.1 Hz), 8.72 (1H, t, J = 5.8 Hz).


169
CD3OD
400
0.94-1.02 (2H, m), 1.16-1.37 (3H, m),





1.68-1.77 (6H, m), 2.88 (3H, s), 2.92-2.95 (3H, m),





3.10-3.15 (1H, m), 3.87-4.00 (2H, m), 4.18-4.28 (2H,





m), 4.64 (1H, t, J = 7.6 Hz), 6.96 (1H, d, J = 9.1 Hz),





7.02-7.05 (1H, m), 7.12-7.19 (2H, m),





7.73 (1H, s), 7.78 (1H, dd, J = 9.1, 2.0 Hz),





8.73 (1H, t, J = 5.8 Hz).


170
CD3OD
400
1.55-1.85 (6H, m), 2.91-3.12 (4H, m),





3.35-3.45 (2H, m), 3.83-3.94 (2H, m), 4.16-4.30 (2H, m),





4.60-4.65 (1H, s), 6.96 (1H, d, J = 9.4 Hz),





7.01-7.04 (1H, m), 7.10-7.19 (2H, m), 7.72 (1H, d, J = 1.2 Hz),





7.76 (1H, dd, J = 9.2, 2.1 Hz), 8.71 (1H, t,





J = 5.8 Hz)


171
CD3OD
400
2.92-2.97 (1H, m), 3.07-3.14 (1H, m),





3.31-3.32 (4H, m), 3.92-4.04 (6H, m), 4.17-4.26 (2H, m),





4.59-4.65 (1H, m), 6.96 (1H, d, J = 9.2 Hz),





7.01-7.04 (1H, m), 7.10-7.17 (2H, m), 7.72 (1H, s),





7.76 (1H, dd, J = 9.1, 2.0 Hz), 8.73 (1H, t, J = 5.9 Hz).


172
CD3OD
400
2.93-2.99 (1H, m), 3.10-3.21 (3H, m), 3.56 (2H,





t, J = 6.0 Hz), 4.05-4.28 (4H, m), 4.45 (2H, s),





4.64-4.69 (1H, m), 6.97 (1H, d, J = 9.1 Hz),





7.03-7.06 (1H, m), 7.13-7.20 (3H, m), 7.26-7.34 (3H,





m), 7.73 (1H, d, J = 1.2 Hz), 7.78 (1H, dd, J = 9.2,





2.0 Hz), 8.76 (1H, t, J = 5.9 Hz).


173
CD3OD
400
1.85-1.94 (2H, m), 2.67 (2H, t, J = 6.3 Hz),





2.82-2.99 (2H, m), 3.13-3.25 (2H, m), 3.66-3.76 (2H,





m), 4.09-4.13 (2H, m), 4.48-4.53 (1H, m),





6.09-6.12 (1H, m), 6.49-6.52 (1H, m), 6.77-6.97 (6H,





m), 7.60 (1H, d, J = 1.4 Hz), 7.66 (1H, dd, J = 9.2,





2.1 Hz), 8.52 (1H, t, J = 5.8 Hz).


174
CD3OD
400
2.89-2.96 (1H, m), 2.99 (3H, s), 3.04-3.09 (1H,





m), 3.91 (2H, d, J = 1.4 Hz), 4.20-4.21 (2H, m),





4.58-4.63 (1H, m), 6.65 (2H, d, J = 8.1 Hz),





6.75 (1H, t, J = 7.3 Hz), 6.88-6.93 (2H, m),





6.99-7.10 (2H, m), 7.12-7.18 (2H, m), 7.67 (1H, d, J = 1.2 Hz),





7.73 (1H, dd, J = 9.2, 2.1 Hz), 8.58 (1H, t,





J = 5.8 Hz).


175
CD3OD
400
1.31 (6H, d, J = 6.5 Hz), 1.39 (3H, d, J = 6.6 Hz),





2.69 (3H, s), 2.93-3.03 (1H, m), 3.07-3.13 (1H,





m), 3.52 (1H, s, br), 4.01 (1H, q, J = 6.6 Hz),





4.17-4.28 (2H, m), 4.57-4.61 (1H, m), 4.86 (3H, s),





6.97 (1H, d, J = 9.1 Hz), 7.02-7.05 (1H, m),





7.11-7.24 (2H, m), 7.74-7.79 (2H, m), 8.71-8.82 (1H,





m)


176
CD3OD
400
1.26 (6H, d, J = 6.64 Hz), 1.51 (3H, d, J = 6.85),





2.64 (3H, s), 2.90-2.98 (2H, m), 3.07-3.17 (1H,





m), 3.94 (1H, q, J = 6.8 Hz), 4.16-4.21 (1H, m),





4.27-4.31 (1H, m), 4.60-4.80 (1H, m), 4.86 (3H,





s), 6.97 (1H, d, J = 9.2 Hz), 7.05-7.07 (1H, m),





7.14-7.22 (2H, m), 7.74-7.84 (2H, m),





8.70-8.89 (1H, m)


178
CD3 OD
400
0.43-0.54 (1H, m), 0.58-0.65 (6H, m),





0.97-1.10 (1H, m), 1.78-1.83 (1H, m), 2.64 (6H, s),





2.66-2.72 (1H, m), 2.89-2.99 (2H, m), 3.45-3.53 (2H,





m), 3.96-4.08 (2H, m), 4.31-4.37 (1H, m),





6.76 (1H, d, J = 9.4 Hz), 6.86-6.88 (1H, m),





6.93-7.00 (2H, m), 7.55 (1H, d, J = 1.2 Hz), 7.60 (1H, dd,





J = 2.1, 9.2 Hz), 8.51-8.59 (2H, m)


179
CD3OD
400
1.07 (9H, s), 3.00 (6H, s), 3.08-3.17 (2H, m),





3.62 (1H, s), 4.21-4.29 (2H, m), 4.52-4.58 (1H,





m), 4.86 (2H, s), 6.97 (1H, d, J = 9.1 Hz),





7.06-7.09 (1H, m), 7.14-7.21 (2H, m), 7.76-7.79 (2H,





m), 8.74-8.77 (1H, m), 8.94-8.96 (1H, m)


180
CD3OD
400
1.32 (6H, d, J = 8.0 Hz), 2.62-2.68 (5H, m),





2.84-2.95 (2H, m), 3.11-3.16 (2H, m),





3.81-3.86 (2H, m), 4.23 (3H, d, J = 4.0 Hz), 4.59-4.66 (2H,





m), 6.95-7.04 (3H, m), 7.23-7.27 (2H, m),





7.69-7.77 (1H, m), 7.83 (1H, dd, J = 8.0, 4.0 Hz),





8.70 (1H, t, J = 8.0 Hz)


181
CD3OD
400
1.14-1.18 (2H, m), 1.23 (6H, d, J = 6.6 Hz),





1.28-1.39 (2H, m), 1.50 (3H, d, J = 6.9 Hz), 2.61 (3H,





s), 2.85-2.94 (1H, m), 3.11-3.25 (1H, m),





3.91 (1H, t, J = 6.7 Hz), 4.18 (1H, d, J = 15.1 Hz),





4.28 (1H, d, J = 15.1 Hz), 4.58-4.78 (1H, m), 4.86 (1H,





s), 6.92-6.96 (1H, m), 6.98-7.04 (2H, m),





7.25-7.28 (2H, m), 7.74-7.78 (2H, m)


182
CD3OD
400
0.67-0.76 (1H, m), 0.83-0.87 (6H, m),





1.18-1.24 (1H, m), 1.99-2.05 (1H, m), 2.87 (6H, s),





2.89-2.97 (1H, m), 3.12-3.17 (1H, m), 3.62 (1H, d,





J = 5.0 Hz), 4.28 (2H, d, J = 5.7 Hz), 4.58 (1H, t,





J = 4.2 Hz), 4.86 (3H, s), 6.96-7.06 (3H, m),





7.27-7.30 (2H, m), 7.75-7.80 (2H, m), 8.73-8.76 (1H,





m)


183
CD3OD
400
1.05 (9H, s), 2.90-2.98 (1H, m), 3.00 (6H, s),





3.08-3.17 (1H, m), 3.59 (1H, s), 4.23 (2H, d,





J = 5.8 Hz), 4.52-4.60 (1H, m), 4.86 (3H, s),





6.89-7.03 (3H, m), 7.26-7.29 (2H, m), 7.73-7.76 (2H,





m), 8.71-8.73 (1H, m)


184
CD3OD
400
1.25-1.50 (6H, m), 2.40-2.60 (1H, m),





2.65-2.80 (1H, m), 3.00-3.20 (2H, m), 3.25-3.40 (3H, m),





4.05-4.40 (4H, m), 4.85-5.05 (2H, m),





6.70-7.00 (3H, m), 7.05-7.20 (3H, m), 7.25-7.35 (3H, m),





7.65-7.80 (2H, m), 8.60-8.70 (1H, m)


185
CD3OD
400
2.49-2.55 (1H, m), 2.70-2.81 (1H, m), 2.99 (6H,





s), 3.02-3.08 (1H, m), 3.33-3.37 (1H, m),





3.99-4.03 (1H, m), 4.18-4.24 (3H, m), 4.87 (3H, s),





6.73-6.76 (1H, m), 6.82-6.90 (1H, m), 6.95 (1H,





dd, J = 1.8, 8.3 Hz), 7.03-7.10 (1H, m),





7.15-7.18 (2H, m), 7.21-7.27 (3H, m), 7.72-7.75 (2H, m),





8.55-8.68 (1H, m)


186
CD3OD
270
0.8-2.1 (31H, m), 2.49 (3H, s), 3.6-3.9 (1H, m),





4.20-4.50 (3H, m), 6.7-6.9 (1H, m),





7.70-7.85 (1H, m), 7.9-8.1 (1H, m)


187
CD3OD
270
0.7-1.91 (33H, m), 2.56 (3H, s), 3.70-3.90 (1H,





s), 4.20-4.55 (3H, m), 6.7-6.9 (1H, m),





7.7-7.9 (1H, m), 8.5-8.9 (1H, m)


188
d6DMSO
270
0.8-1.0 (6H, m), 1.1-1.3 (1H, m), 1.5-1.8 (1H,





m), 2.4-2.8 (9H, m), 2.8-2.9 (1H, m),





3.0-3.1 (1H, m)





3.2-3.7 (3H, m), 4.0-4.2 (1H, m), 4.7-4.8 (1H,





m), 6.85 (1H, d, J = 7 Hz), 7.2-7.3 (1H, m),





7.5-7.6 (2H, m), 7.7-7.8 (1H, m),





8.5-8.6 (1H, m), 8.75-8.8 (1H, m).


189
CD3OD
270
3.6-4.0 (1H, m), 4.1-4.4 (6H, m), 4.7-5.2 (5H,





m), 5.9-6.3 (5H, m), 6.4-6.6 (1H, m),





8.5-8.7 (1H, m), 8.9-9.1 (1H, m), 9.2-9.3 (2H,





m), 9.4-9.7 (1H, m), 10.6-10.5 (1H, m)


190
CD3OD
270
1.7-2.3 (4H, m), 2.4-2.7 (5H, m), 2.8-3.4 (7H,





m), 3.6-3.8 (1H, m), 4.0-4.4 (3H, m),





4.6-4.8 (1H, m)





6.7-6.9 (1H, m), 7.0-7.2 (1H, m), 7.3-7.4 (2H,





m), 7.6-7.9 (1H, m) 8.6-8.9 (1H, m)


191
d6DMSO
270
2.4-2.6 (3H, s), 2.6-2.8 (9H, m), 4.1 (3H, s),





4.4-4.6 (1H, s),





6.8-6.9 (1H, m), 7.2-7.4 (1H, m), 7.4-7.8 (5H,





m)


192
d6DMSO
270
2.43 (3H, s), 2.4 (3H, s), 2.5-2.9 (2H, m),





3.5-3.8 (3H, m), 4.0-4.4 (3H, m), 4.5-4.7 (2H, m),





6.8-6.9 (1H, m), 7.1-7.2 (1H, m), 7.4-7.6 (2H, m),





7.8-7.9 (1H, m), 8.8-8.9 (1H, m), 9.0-9.1 (1H,





m)


193
CD3OD
270
2.3 (3H, s), 2.6 (4H, s), 2.7-2.8 (3H, m),





2.9-3.15 (3H, m), 3.3-3.4 (3H, m), 4.0-4.4 (5H, br, m),





6.7 (1H, d, J = 7 Hz), 6.9-7.0 (1H, m),





7.1-7.2 (3H, m), 7.25-7.3 (4H, m), 7.4-7.5 (1H, m),





7.6-7.7 (1H, m)


194
CD3OD
270
2.4-2.6 (3H, s), 2.7-3.2 (4H, m), 3.2-3.2 (5H, m),





4.0-4.1 (3H, m), 4.2-4.4 (2H, m), 4.5-4.6 (1H,





m)





6.8-6.9 (1H, m), 7.0-7.3 (5H, m), 7.2-7.4 (2H,





m), 7.6-7.8 (1H, m)


195
CD3OD
270
2.3-2.4 (4H, m), 2.6-3.1 (4H, m), 3.3-3.4 (5H,





m), 4.0-4.1 (2H, m), 4.2-4.3 (1H, m),





4.1-4.5 (1H, m)





6.8-6.9 (1H, m), 7.0-7.3 (3H, m), 7.3-7.6 (4H,





m), 7.7-7.9 (1H, s)


196
CD3OD
270
2.4-2.5 (4H, m), 2.8-3.1 (3H, m), 3.15-3.2 (1H,





m), 3.2-3.3 (3H, m), 4.0-4.1 (1H, m),





4.2-4.4 (3H, m) 4.5-4.8 (1H, m), 6.85 (1H, d, J = 7 Hz),





7.1-7.2 (1H, m), 7.3-7.4 (2H, m), 7.45-7.5 (1H,





m), 7.6-7.8 (1H, m), 8.0-8.1 (1H, m)





8.6-8 (3H, m)


197
CD3OD
270
3.0-3.1 (4H, m), 4.1-4.4 (3H, m), 4.7-4.9 (2H,





m), 5.75 (2H, s), 6.25 (2H, d, J = 7 Hz),





6.45 (2H, d, J = 7H), 7.0-7.4 (9H, m),





9.8-9.9 (1H, m)


198
CD3OD
270
0.7-0.95 (2H, m), 1.0-1.25 (2H, m), 1.3-1.5 (3H,





m), 1.6-2.0 (3H, m), 2.4-2.6 (3H, m),





2.8-3.0 (1H, m), 3.1-3.4 (8H, m) 3.5-3.8 (1H, m),





4.1-4.4 (3H, m), 4.6-4.8 (1H, m), 6.7-6.9 (1H, m),





7.1-7.3 (1H, m), 74-7.6 (2H, m), 7.7-7.8 (1H, m)


199
CD3OD
270
2.4-2.5 (4H, m), 2.8-3.1 (3H, m), 3.15-3.2 (1H,





m), 3.2-3.3 (3H, m), 4.0-4.1 (1H, m),





4.2-4.4 (3H, m) 4.5-4.8 (1H, m), 6.85 (1H, d, J = 7 Hz),





7.1-7.2 (1H, m), 7.3-7.4 (2H, m),





7.45-7.5 (1H, m), 7.6-7.8 (1H, m), 8.0-8.1 (1H, m)





8.6-8.8 (3H, m)


200
d6DMSO
270
1.0-1.3 (6H, m), 1.4-1.7 (5H, m), 2.4 (3H, s),





2.6 (2H, s), 2.7-2.9 (1H, m), 3.0-3.1 (1H, m),





3.7-3.8 (1H, m), 4.0-4.3 (2H, m), 4.7-4.8 (1H, m)





6.8-6.9 (1H, m), 7.1-7.2 (1H, m), 7.4-7.6 (2H m),





7.7 (1H, d, J = 8 Hz), 7.9-8.1 (4H, m), 8.6-8.7 (1H, m)





8.9-8.0 (1H, m)


201
CD3OD
270
1.8-1.9 (2H, m), 2.0-2.1 (1H, m), 2.4-2.5 (3H, s),





2.8-3.1 (3H, m), 3.2-3.3 (8H, m), 3.7-3.8 (1H,





m), 4.9-5.1 (1H, m) 6.7-6.9 (1H, m), 7.1-7.2 (1H,





m), 7.3-7.4 (2H, m), 7.6-7.8 (1H, m)


202
CD3OD
270
2.4 (3H, s), 2.7-3.0 (3H, m), 3.1-3.2 (2H, m),





3.3 (3H, s), 4.0-4.4 (5H, m), 4.6-4.8 (1H, m),





6.85 (1H, d, J = 7 Hz), 7.1-7.4 (8H, m), 7.75 (1H,





d, J = 7 Hz)


203
CD3OD
270
0.8-0.9 (6H, m), 1.3-1.4 (1H, m), 1.8-1.7 (1H,





m), 2.25 (3H, s), 2.6 (3H, s), 3.3-3.5 (3H, m),





3.6-3.7 (2H, m), 4.0-4.3 (2H, m), 4.8-4.9 (2H,





m), 6.6 (1H, d, J = 7 Hz), 7.3-7.4 (5H, m),





7.5-7.6 (3H, m), 7.7-8.0 (2H, m), 8.2-8.3 (1H, m)


204
CD3OD
400
1.72-1.77 (1H, m), 1.87-1.96 (1H, m),





2.10-2.17 (1H, m), 2.45 (3H, s), 2.89 (3H, s),





2.91-2.95 (1H, m), 3.07-3.10 (1H, m), 3.12-3.21 (1H, m),





3.63-3.69 (1H, m), 4.05 (1H, t, J = 8.5 Hz),





4.13-4.18 (1H, m), 4.25-4.31 (1H, m), 4.64 (1H, t,





J = 8.4 Hz), 4.86 (3H, s), 6.78 (1H, d, J = 9.0 Hz),





6.96-7.00 (2H, m), 7.19-7.28 (2H, m), 7.68 (2H,





d, J = 9.1 Hz), 8.65-8.67 (1H, m)


205
CD3OD
400
1.75-1.82 (1H, m), 1.89-1.96 (1H, m),





2.14-2.18 (1H, m), 2.47 (3H, s), 2.89 (3H, s),





2.92-2.93 (1H, s), 3.06-3.11 (1H, m), 3.15-3.22 (1H, m),





3.64-3.70 (1H, m), 4.06 (1H, t, J = 8.6 Hz),





4.13-4.18 (1H, m), 4.27-4.32 (1H, m), 4.64 (1H, t,





J = 8.1 Hz), 4.86 (3H, s), 6.79 (1H, d, J = 9.1 Hz),





7.00-7.07 (1H, m), 7.09-7.19 (2H, m), 7.71 (2H,





d, J = 9.1 Hz), 8.67-8.69 (1H, m)


206
CD3OD
400
1.71-1.80 (1H, m), 1.86-1.98 (1H, m),





2.10-2.20 (1H, m), 2.34 (3H, s), 2.42-2.48 (1H, m),





2.51 (3H, s), 2.88 (3H, s), 2.91-2.95 (1H, m),





3.05-3.10 (1H, m), 3.14-3.21 (1H, m), 3.64-3.70 (1H,





m), 4.09 (1H, t, J = 8.4 Hz), 4.21-4.33 (2H, m),





4.60-4.65 (1H, m), 6.66 (1H, s), 7.00-7.03 (1H,





m), 7.09-7.17 (2H, m), 8.47 (1H, t, J = 4.9 Hz),





8.87 (1H, d, J = 7.6 Hz)


207
CD3OD
400
0.80 (3H, d, J = 6.8 Hz), 0.83-0.89 (4H, m),





1.27-1.36 (1H, m), 1.76-1.82 (1H, m), 2.36 (3H, s),





2.52 (3H, s), 2.60 (3H, s), 2.88-2.94 (1H, m),





3.08-3.13 (1H, m), 3.66 (1H, d, J = 4.9 Hz),





4.30 (2H, d, J = 4.8 Hz), 4.56-4.62 (1H, m), 6.67 (1H,





s), 7.05-7.08 (1H, m), 7.12-7.19 (2H, m),





8.49 (1H, t, J = 4.9 Hz), 8.79 (1H, d, J = 7.5 Hz)


209
CD3OD
270
0.70-0.94 (7H, m), 1.16-1.32 (1H, m),





1.65-1.74 (1H, m,) 2.20 (3H, s), 3.30-3.40 (1H, m),





3.62-3.72 (2H, m), 4.05-4.28 (2H, m), 4.78-4.84 (1H,





m), 7.31-7.38 (2H, m), 7.45-7.57 (4H, m),





7.74-7.78 (1H, m), 7.84-7.87 (1H, m), 8.16 (1H, d, J = 8.2 Hz),





8.62 (1H, m)


210
CD3OD
270
1.70-1.90 (3H, m), 2.05-2.30 (1H, m),





2.80-3.05 (4H, m), 3.10-3.80 (5H, m), 4.10-4.40 (2H, m),





4.45-4.60 (1H, m), 6.90-7.05 (1H, m),





7.10-7.25 (1H, m), 7.30-7.50 (2H, m), 7.65-7.85 (2H, m),





8.25-8.40 (2H, m)


211
CD3OD
270
0.50-0.70 (3H, m), 0.75-0.90 (3H, m),





0.95-1.15 (1H, m), 1.40-1.70 (2H, m), 1.95-2.10 (1H, m),





2.80-2.95 (4H, m), 3.15-3.40 (4H, m),





3.50-3.70 (1H, m), 4.10-4.40 (2H, m), 4.50-4.70 (1H, m),





6.90-7.05 (1H, m), 7.15-7.30 (1H, m),





7.35-7.50 (1H, m), 7.65-7.90 (2H, m), 8.30-8.40 (1H, m),





8.50-8.70 (1H, m)


212
CD3OD
270
1.25-1.40 (3H, m), 2.80-3.15 (8H, m),





3.25-3.35 (2H, m), 4.10-4.60 (4H, m), 6.90-7.00 (1H, m),





7.10-7.20 (1H, m), 7.30-7.50 (2H, m),





7.60-7.80 (2H, m), 8.15-8.30 (1H, m), 8.40-8.55 (1H, m)


213
CD3OD
270
0.58 (2H, d, J = 6.7 Hz), 0.89 (2H, t, J = 7.2 Hz),





1.04-1.09 (1H, m), 1.53-1.56 (1H, m),





1.77-1.83 (1H, m), 2.86 (3H, s), 3.16-3.41 (3H, m),





3.86-3.90 (1H, m), 4.11-4.21 (2H, m), 4.90 (7H, s),





6.87 (1H, d, J = 9.2 Hz), 7.32-7.41 (3H, m),





7.63 (2H, d, J = 9.9 Hz), 7.86 (2H, t, J = 5.5 Hz),





8.39 (1H, t, J = 5.7 Hz), 8.71 (1H, d, J = 7.2 Hz)


214
CD3OD
270
0.87-1.27 (18H, m), 1.30-1.80 (14H, m),





3.78-3.80 (1H, m), 4.17-4.23 (2H, m), 4.58 (1H, d,





J = 9.1 Hz), 4.91 (4H, s), 6.98 (1H, d, J = 8.9 Hz),





7.81 (1H, s), 7.91 (1H, d, J = 9.2 Hz), 8.70-8.90 (1H,





m)


215
CD3OD
270
0.95-1.23 (10H, m), 1.53-1.76 (16H, m),





2.02-2.07 (4H, m), 2.40-2.60 (1H, m), 3.32-3.41 (2H,





m), 4.22-4.26 (2H, m), 4.40-4.42 (1H, m),





4.61 (1H, d, J = 7.0 Hz), 6.97 (1H, d, J = 9.1 Hz),





7.76 (1H, d, J = 1.5 Hz), 7.90 (1H, dd, J = 2.9 Hz,





9.2 Hz), 8.70-8.90 (1H, m)


217
CD3OD
270
1.11-1.22 (17H, m), 1.56-1.70 (14H, m),





3.81 (1H, s), 4.24-4.29 (2H, m), 4.59 (1H, d,





J = 7.2 Hz), 4.86-4.89 (5H, m), 6.99 (1H, d,





J = 9.2 Hz), 7.82 (1H, d), 7.93 (1H, dd, J = 2.0 Hz,





9.2 Hz), 8.60-8.70 (1H, m)


218
CD3OD
270
0.98-1.28 (8H, m), 1.52 (3H, d, J = 6.9 Hz),





1.63-1.81 (14H, m), 2.65 (3H, s), 3.93-3.95 (1H, m),





4.17-4.20 (1H, m), 4.28-4.30 (1H, m), 4.60 (1H,





d, J = 7.6 Hz), 4.96 (5H, s), 6.98 (1H, d, J = 9.1 Hz),





7.78 (1H, d), 7.919 (1H, dd, J = 1.9 Hz, 9.1 Hz),





8.70-8.80 (1H, m)


219
CD3OD
270
0.97-1.28 (18H, m), 1.54-1.70 (14H, m),





2.59 (3H, s), 3.3 (1H, d, J = 4.7 Hz), 4.23-4.29 (2H, m),





4.58 (1H, d, J = 7.7 Hz), 4.90 (4H, s), 6.98 (1H, d,





J = 9.1 Hz), 7.82 (1H, d, J = 1.5 Hz), 7.91 (1H,





dd, J = 2.3 Hz, 9.2 Hz), 8.70-8.90 (1H, m)


220
CD3OD
270
0.95-1.23 (8H, m), 1.52-1.73 (14H, m),





3.29-3.32 (2H, m), 3.67-3.86 (2H, m), 4.21-4.26 (1H,





m), 4.63 (1H, d, J = 6.4 Hz), 4.49 (5H, s),





6.98 (1H, d, J = 9.4 Hz), 7.76 (1H, d), 7.89 (1H, dd,





J = 2 Hz, 9.2 Hz), 8.60-8.70 (1H, m)


221
CD3OD
270
1.10-1.28 (8H, m), 1.52-1.73 (14H, m),





2.72 (3H, s), 3.29-3.32 (2H, m), 3.86 (2H, dd, J = 8.9,





15.8 Hz), 4.20-4.27 (2H, m), 4.63 (1H,





d, J = 6.5 Hz), 4.94 (3H, s), 6.97 (1H, d, J = 9.2 Hz),





7.76 (1H, d), 7.89 (1H, dd, J = 2.2 Hz, 7.3 Hz),





8.60-8.70 (1H, m)


222
CD3OD
270
1.10-1.28 (8H, m), 1.52-1.73 (14H, m),





2.93 (6H, s), 3.29-3.32 (2H, m), 4.01 (2H, d),





4.20-4.27 (2H, m), 4.66 (1H, d), 4.94 (2H, s),





7.01 (1H, d, J = 9.2 Hz), 7.77 (1H, s), 7.88 (1H, d),





8.60-8.70 (1H, m)


223

400
1.09-1.30 (12H, m), 1.64-1.76 (14H, m),





2.00-2.10 (2H, m), 2.19-2.26 (1H, m), 2.57-2.63 (1H,





m), 2.93 (3H, s), 3.20-3.27 (1H, m),





3.71-3.77 (1H, m), 4.17-4.24 (2H, m), 4.29-4.39 (1H, m),





4.64 (1H, d, J = 7.2 Hz), 6.99 (1H, d, J = 9.1 Hz),





7.80 (1H, d, J = 1.5 Hz), 7.92 (1H, dd,





J = 2.1, 9.2 Hz), 8.74-8.77 (1H, m)


224
CD3OD
270
0.87-0.96 (6H, m), 1.30-1.60 (1H, m),





1.70-2.10 (1H, m), 3.22-3.26 (2H, m), 3.71-3.76 (2H, m),





3.86-4.06 (1H, m), 4.51-4.53 (1H, m), 4.86 (6H,





s), 6.71-6.80 (1H, m), 7.18-7.45 (7H, m),





8.35-8.55 (1H, m)


225
CD3OD
270
0.8-0.9 (1H, m), 1.5-1.8 (1H, m), 1.9-2.1 (1H,





m), 2.2-2.4 (1H, m), 2.9 (3H, s), 2.5 (3H, s),





3.0-3.1 (3H, m), 3.3 (2H, s), 3.4-3.5 (2H, m),





3.6-3.8 (1H, m), 4.2-4.4 (3H, m), 5.65 (1H, dd, J = 7 Hz),





7.0-7.1 (1H, d, J = 9 Hz), 7.15-7.3 (4H, m),





7.7-7.9 (1H, m), 8.7-8.8 (1H, m)


227
CD3OD
270
1.19-1.78 (22H, m), 4.24-4.27 (2H, m),





4.50-4.60 (1H, m), 6.19 (1H, s), 6.89-6.97 (3H, m),





7.73 (1H, s), 6.86 (1H, dd, J = 2 Hz, 9 Hz),





7.85-7.88 (1H, m), 11.0 (1H, s, br)


228
CD3OD
270
3.47-3.54 (1H, m), 3.64-3.72 (1H, m),





4.04-4.11 (2H, m), 4.79-4.85 (1H, m), 4.89-4.91 (3H, m),





6.16-6.19 (1H, m), 6.81-6.93 (3H, m),





7.30-7.37 (2H, m), 7.46-7.56 (4H, m), 7.72-7.76 (1H, m),





7.84-7.88 (1H, m), 8.20 (1H, d, J = 7.9 Hz),





8.40-8.60 (1H, m), 10.8-11.10 (1H, s, br)


229
CD3OD
270
3.05-3.40 (3H, m), 4.15-4.30 (1H, m),





4.60-4.80 (1H, m), 4.90-5.00 (3H, m), 6.10-6.30 (1H, m),





6.80-7.00 (3H, m), 7.40-7.80 (3H, m),





8.55-8.70 (1H, m)


231
CD3OD
270
2.18 (3H, s), 2.20 (3H, s), 3.54-3.60 (1H, m),





3.64-3.72 (1H, m), 4.03-4.13 (2H, m), 4.80-4.86 (1H, m),





4.89-4.91 (2H, m), 5.71 (1H, d, J = 2.5 Hz),





6.16-6.19 (1H, m), 6.83 (1H, d, J = 8.9 Hz),





7.33-7.367 (2H, m), 7.476-7.54 (4H, m),





7.75-7.78 (1H, m), 7.85-7.886 (1H, m),





8.21 (1H, d, J = 7.7 Hz), 8.40-8.60 (1H, m),





10.8-11.10 (1H, s, br)


232
CD3OD
270
2.17 (3H, s), 2.19 (3H, s), 3.10-3.40 (4H, m),





4.15-4.30 (1H, m), 4.60-4.80 (1H, m),





4.90-5.10 (1H, m0, 5.71 (1H, s), 6.93 (1H, d, J = 9.15 Hz),





7.40-7.80 (6H, m), 8.60-8.80 (1H, m),





10.30-10.50 (1H, m)


233
CD3OD
270
2.10-2.30 (6H, m), 3.00-3.20 (2H, m),





3.25-3.40 (2H, m), 4.05-4.30 (2H, m), 4.70-4.85 (1H, m),





4.90-5.10 (1H, m), 5.72 (1H, s),





6.90-7.00 (1H, m), 7.10-7.25 (1H, m), 7.30-7.50 (2H, m),





7.65-7.80 (2H, m), 8.60-8.70 (1H, m0,





10.40-10.55 (1H, m)


234
CD3OD
270
2.18 (3H, s), 2.19 (3H, s), 2.27 (3H, s),





2.90-3.10 (2H, m), 3.25-3.35 (2H, m), 3.50-3.70 (1H, m),





4.15-4.30 (2H, m), 4.60-4.75 (1H, m),





5.71 (1H, s), 6.85-7.30 (5H, m), 7.60-7.80 (2H, m),





8.50-8.70 (1H, m), 10.30-40.50 (1H, m)


235
CD3OD
270
2.20 (6H, s), 3.00-3.35 (4H, m),





4.10-4.30 (2H, m), 4.60-4.75 (1H, m), 4.90-5.10 (1H, m),





5.72 (1H, s), 6.94 (1H, d, J = 9.15 Hz),





7.10-7.30 (4H, m), 7.60-7.80 (2H, m), 8.60-8.75 (1H, m),





10.30-10.50 (1H, m)


236
CD3OD
270
2.19 (6H, m), 3.00-3.40 (3H, m),





4.10-4.40 (2H, m), 4.60-4.80 (1H, m), 4.90-5.10 (2H, m),





5.72 (1H, s), 6.85-7.40 (5H, m),





7.60-7.80 (2H, m), 8.55-8.70 (1H, m), 10.40-10.50 (1H, m)


237
CD3OD
270
2.19 (6H, s), 3.07-3.20 (2H, m),





3.25-3.40 (3H, m), 4.05-4.40 (2H, m), 4.60-4.80 (1H, m),





5.71 (1H, s), 6.91-6.94 (1H, m), 7.23 (4H, s),





7.65-7.71 (3H, m), 8.50-8.70 (1H, m),





10.40-10.60 (1H, m)


238
d6-
270
1.3-1.8 (7H, m), 2.1-2.3 (6H, m), 2.5-2.6 (4H,



DMSO

m), 3.1-3.4 (3H, m), 4.2-4.3 (1H, d, J = 7 Hz),





6.7 (1H, s), 6.9-7.0 (1H, m), 7.2-7.3 (1H, m),





7.7-8.1 (3H, m), 8.6-8.7 (1H, m), 10.9-11 (1H, s)


239
CD3OD
270
2.19 (3H, s), 2.20 (3H, s), 3.20-3.30 (2H, m),





4.20-4.21 (2H, m), 4.78 (1H, t, J = J = 7.7 Hz),





5.71 (1H, s), 6.93 (1H, d, J = 9.1 Hz), 7.18-7.38 (7H, m),





7.68 (1H, s), 7.73-7.77 (1H, m), 8.50-8.70 (1H, m),





10.35-10.55 (1H, m)


240
CD3OD
270
2.19 (6H, s), 3.25-3.36 (2H, m), 4.21-4.23 (2H, m),





4.75 (1H, t, J = J = 7.4 Hz), 4.89 (2H, s),





5.71 (1H, s), 6.93 (1H, d, J = 9.2 Hz), 7.40-7.51 (3H, m),





7.66-7.78 (4H, m), 8.50-8.70 (1H, m),





10.35-10.55 (1H, m)


241
CD3OD
270
2.14 (3H, s), 2.18 (3H, s), 3.20-3.40 (4H, m),





4.00-4.30 (2H, m), 4.65-4.90 (1H, m),





4.95-5.05 (2H, m), 5.70 (1H, s), 6.70-7.60 (8H, m),





8.35-8.50 (1H, m), 10.30-10.50 (1H, m)


242
CD3OD
270
2.10-2.30 (6H, m), 2.80-3.50 (5H, m),





4.20-4.40 (2H, m), 4.50-4.70 (1H, m), 5.71 (1H, s),





6.80-7.10 (3H, m), 7.10-7.30 (2H, m),





7.60-7.80 (2H, m), 8.50-8.70 (1H, m), 10.30-10.50 (1H, m)


243
CD3OD
270
2.00-2.10 (1H, m), 2.15-2.30 (6H, m),





2.95-3.20 (2H, m), 3.25-3.35 (2H, m), 4.10-4.30 (2H, m),





4.60-4.70 (1H, m), 5.71 (1H, s),





6.90-7.20 (4H, m), 7.70-7.80 (2H, m), 8.60-7.70 (1H, m),





10.40-40.50 (1H, m)


244
CD3OD
270
2.21 (6H, s), 2.35 (3H, s), 3.12-3.15 (2H, m),





4.14-4.20 (2H, m), 4.60-4.75 (1H, m), 4.89 (3H, s),





5.72 (1H, s), 6.90 (1H, d, J = 9.2 Hz), 7.11-7.13 (5H, m),





7.61-7.65 (2H, m), 8.50-8.70 (1H, m)


245
CD3OD
270
2.20 (3H, s), 2.22 (3H, s), 3.08-3.15 (2H, m),





4.22 (1H, s), 4.68-4.735 (1H, m), 4.89 (3H, s),





5.72 (1H, s), 6.95 (1H, d, J = 8.4 Hz), 7.11-7.20 (3H, m),





7.74-7.81 (2H, m), 8.60-8.80 (1H, m),





10.43 (1H, s, br)


246
CD3OD
270
2.19 (6H, s) 3.03-3.10 (2H, m) 4.09-4.26 (2H,





m) 4.67 (1H, t, J = 7.4 Hz) 4.92 (5H, s)





5.71 (1H, s) 6.92 (1H, d, J = 9.9 Hz) 7.16-7.24 (4H,





m) 7.67 (2H, d, J = 7.4 Hz)


247
CD3OD
270
2.19 (6H, s) 3.00 (2H, br s) 3.31 (1H, s)





4.11-4.27 (2H, m) 4.60 (1H, t, J = 7.2 Hz) 4.91 (5H,





s) 5.71 (1H, s) 6.07 (2H, d, J = 7.9 Hz) 6.92 (1H,





d, J = 9.4 Hz) 7.02 (2H, d, J = 7.6 Hz) 8.55 (1H,





s) 10.45 (1H, s)


248
CD3OD
270
2.19 (3H, s) 2.21 (3H, s) 3.08-3.13 (2H, m)





3.30 (1H, s) 4.22-4.24 (2H, m) 4.69 (1H, t, J = 7.2 Hz)





4.90 (2H, s) 5.72 (1H, s) 6.95 (1H, d, J = 9.2 Hz)





7.05-7.17 (2H, m) 7.73-7.81 (2H, m)





8.69 (1H, t, J = 5.6 Hz) 10.43 (1H, s)


249
CD3OD
270
2.20 (6H, s) 3.08-3.12 (2H, m) 3.30 (1H, s)





4.18-4.25 (2H, m) 4.69 (1H, t, J = 7.2 Hz) 4.90 (2H,





s) 5.72 (1H, s) 6.79-6.83 (4H, m) 7.72-7.78 (2H,





m) 8.67 (1H, s) 10.44 (1H, s)


250
CD3OD
270
2.19 (6H, s) 3.31-3.42 (2H, m) 4.03-4.18 (2H, m)





4.90 (3H, s) 5.71 (1H, s) 6.81 (1H, d, J = 8.4 Hz)





7.34 (2H, s) 7.57 (2H, s) 7.86 (2H, s) 8.57 (1H,





s) 10.46 (1H, s)


251
d6-
270
2.2 (6H, s), 2.5 (3H, s), 3.0-3.3 (1H, m),



DMSO

4.0-4.2 (1H, m), 4.7-4.8 (1H, m), 5.7 (1H, s),





6.9-7.0 (1H, d, j = 7 Hz), 7.3 (1H, d, j = 7 Hz), 7.7-7.8 (2H,





m), 8.0-8.1 (1H, m), 8.6-8.8 (1H, m),





10.9-11.0 (1H, m).


252
d6-
270
2.1-2.3 (7, m), 2.5-2.6 (3H, m), 2.8-3.1 (2H, m),



DMSO

4.0-4.2 (2H, m), 4.5-4.6 (1H, m), 5.7 (1H, s),





6.9-7.0 (1H, m) 7.0-7.2 (4H, m), 7.3-7.4 (1H,





m), 7.6-7.8 (2H, m), 8.0-8.1 (1H, m),





8.6-8.7 (1H, m), 10.9-11 (1H, m)


253
d6-
270
1.2 (9H, s), 2.1-2.15 (4H, d, j = 7 Hz), 2.5 (6H, s),



DMSO

2.8-3.1 (2H, m), 4.1-4.2 (2H, m), 4.6 (1H, m),





5.6 (1H, s), 6.9-7.0 (1H, d, j = 9 Hz), 7.1-7.4 (4H,





m), 7.8-7.9 (1H, m), 8.0 (1H, s), 8.6 (1H, m)


254
d6-
270
2.1 (6H, s), 2.5 (3H, s), 2.8-3.1 (3H, m),



DMSO

4.1-4.2 (2H, m), 4.6-4.8 (1H, m), 5.7 (1H, s),





6.7-6.8 (2H, m),





6.9-7.0 (1H, d, j = 7 Hz), 7.1-7.2 (2H, m),





7.25-7.30 (1H, d, j = 7 Hz). 7.7-7.9 (2H, m),





8.0-8.1 (1H, m), 8.6-8.7 (1H, m), 10.9 (1H, s)


255
d6-
270
1.4-1.5 (3H, t, j = 7 Hz), 2.2 (6H, s), 2.9-3.1 (1H,



DMSO

m), 3.3 (5H, s), 3.9-4.1 (2H, q, j = 7 Hz),





4.1-4.3 (1H, m), 4.6-4.8 (1H, m), 5.8 (1H, s),





6.8-6.9 (2H, d, j = 9 Hz), 6.91-6.94 (1H, d, j = 9 Hz),





7.0-7.11 (2H, d, j = 9 Hz), 7.7-7.8 (2H, m)





8.5-8.6 (1H, m), 10.5 (1H, s)


256
CD3OD
270
1.2 (9H, s), 2.1-2.15 (4H, d, j = 7 Hz), 2.5 (6H, s),





2.8-3.1 (2H, m), 4.1-4.2 (2H, m), 4.6 (1H, m),





5.6 (1H, s), 6.9-7.0 (1H, d, j = 9 Hz), 7.1-7.4 (4H,





m), 7.8-7.9 (1H, m), 8.0 (1H, s), 8.6 (1H, m)


257
CD3OD
400
2.07 (3H, s) 2.09 (3H, s) 3.22-3.24 (1H, m)





3.52-3.64 (1H, m) 3.69-3.75 (1H, m)





4.13-4.37 (2H, m) 4.81 (3H, br s) 5.02-5.05 (1H, M)





5.61 (1H, m) 6.76 (1H, d, J = 8.0 Hz) 7.40 (1H, s)





7.52-7.75 (4H, m) 7.80-7.90 (1H, m)





7.92-8.02 (2H, m) 8.66 (1H, t, J = 8.0 Hz)


258
CD3OD
400
2.24 (3H, s) 3.20-3.25 (1H, m) 3.30-3.36 (1H,





m) 4.23-4.33 (2H, m) 4.81 (1H, t, J = 8.0 Hz)





4.92 (4H, br s) 6.05-6.06 (1H, m) 6.85 (1H, d, J = 4.0 Hz)





6.99 (1H, d, J = 8.0 Hz) 7.47 (2H, d, J = 8.0 Hz)





7.60 (2H, d, J = 8.0 Hz)





7.79-7.82 (2H, m) 10.86 (1H, s)


259
CD3OD
270
2.06 (3H, s) 3.04-3.13 (3H, m) 4.16-4.18 (2H,





m) 4.66 (1H, t, J = 7.7 Hz) 4.93 (2H, s)





6.66 (2H, d, J = 6.9 Hz) 6.89 (1H, d, J = 9.9 Hz)





7.14-7.24 (4H, m) 10.6 (1H, s)


260
CD3OD
270
2.06 (3H, s) 3.01-3.18 (3H, m) 4.17 (2H, s)





4.63 (1H, t, J = 7.8 Hz) 4.91 (3H, br s) 6.65 (2H, d, J = 7.4 Hz)





6.88-6.98 (3H, m) 7.20-7.25 (2H, m)





7.68 (2H, d, J = 6.4 Hz) 10.6 (1H s)


261
CD3OD
400
2.25 (3H, s) 3.16-3.30 (3H, m) 4.17-4.26 (2H,





m) 4.68 (1H, t, J = 8.0 Hz) 4.94-4.99 (4H, m)





6.00-6.01 (1H, m) 6.99-7.01 (3H, m)





7.21-7.25 (2H, m) 7.72-7.75 (2H, m) 10.72 (1H, s)


262
CD3OD
400
2.30 (3H, s) 3.26-3.46 (2H, m) 4.30 (2H, d, J = 4.0 Hz)





4.86 (1H, t, J = 8.0 Hz) 4.91 (4H, br s)





6.05 (1H, d, J = 4.0 Hz) 6.83 (1H, s) 6.95 (1H, d,





J = 8.0 Hz) 7.20-7.27 (2H, m) 7.32-7.46 (2H, m0





7.72-7.77 (2H, m) 10.75 (1H, s)


263
CD3OD
400
2.29 (3H, s) 3.12-3.37 (2H, m) 4.22 (2H, d, J = 4.0 Hz)





4.84 (1H, t, J = 8.0 Hz) 4.99-5.08 (5H,





m 0 6.05 (1H, d, J = 4.0 Hz) 6.78-6.85 (1H, m)





6.98-7.07 (1H, m) 7.22-7.24 (1H, m) 7.43 (1H, t,





J = 4.0 Hz) 7.75-7.80 (2H, m) 10.76 (1H, s)


264
CD3OD
400
2.32 (3H, s) 3.12-3.19 (2H, m) 4.19-4.35 (2H,





m) 4.76 (1H, t, J = 4.0 Hz) 4.93 (4H, br s)





6.06 (1H, s) 6.858 (1H, t, J = 4.0 Hz) 7.00 (1H, dd, J = 8.0,





4.0 Hz) 7.20-7.29 (1H, m) 7.41-7.48 (2H,





m) 7.74-7.78 (2H, m) 10.75 (1H, br s)


265
CD3OD
400
2.30 (3H, s) 3.12-3.31 (2H, m) 4.19-4.39 (2H,





m) 4.82 (1H, t, J = 4.0 Hz) 5.00 (4H, br s)





6.04 (1H, d, J = 4.0 Hz) 6.83 (1H, s) 6.98-7.04 (3H,





m) 7.08-7.10 (1H, m) 7.25-7.32 (1H, m)





7.72-7.85 (2H, m) 10.80 (1H, s)


266
CD3OD
400
2.27 (3H, s) 3.12-3.30 (2H, m) 4.20-4.37 (2H,





m) 4.77 (1H, t, J = 8.0 Hz) 5.01 (4H, s)





6.05 (1H, t, J = 4.0 Hz) 6.84 (1H, t, J = 4.0 Hz)





6.97 (1H, d, J = 8.0 Hz) 7.21-7.24 (1H, m)





7.27-7.33 (3H, m) 7.74-7.77 (2H, m) 10.79 (1H, s)


267
CD3OD
400
2.28 (3H, s) 3.07-3.20 (2H, m) 4.19-4.35 (2H,





m) 4.75 (1H, t, J = 8.0 Hz) 5.07 (4H, s)





6.06 (1H, d, J = 4.0 Hz) 6.85 (1H, d, J = 4.0 Hz)





7.00 (1H, d, J = 8.0 Hz) 7.22-7.38 (4H, m)





7.73-7.79 (2H, m) 10.77 (1H, s)


268
CD3OD
400
2.27 (3H, s) 2.30 (3H, s) 3.10-3.29 (2H, m)





4.19-4.27 (2H, m) 4.77 (1H, t, J = 8.0 Hz) 5.24 (4H, s)





6.04 (1H, s) 6.82 (1H, s) 6.92-6.95 (1H, m)





7.04-7.09 (3H, m) 7.15-7.27 (1H, m) 7.68-7.74 (2H,





m) 10.80 (1H, s)


269
CD3OD
400
2.23 (3H, s) 3.12-3.26 (2H, m) 4.22-4.46 (2H,





m) 4.78 (1H, t, J = 4.0 Hz) 4.93 (4H, s)





6.05 (1H, t, J = 4.0 Hz) 6.84 (1H, t, J = 4.0 Hz)





6.91-7.04 (3H, m) 7.11-7.17 (1H, m) 7.26-7.34 (1H,





m) 7.75-7.80 (2H, m) 10.86 (1H, s)


270
CD3OD
400
2.31 (3H, s) 3.05-3.15 (2H, m) 4.26-4.39 (2H,





m) 4.60 (1H, t, J = 8.0 Hz) 4.93 (4H, br s)





6.06 (1H, s) 6.82-6.89 (4H, m) 7.00 (1H, d, J = 8.0 Hz)





7.78 (1H, s) 7.83 (1H, dd, J = 8.0, 4.0 Hz)





10.76 (1H, s)


271
CD3OD
400
2.27 (3H, s) 3.15-3.25 (1H, m) 3.33-3.37 (1H,





m) 4.32 (2H, s) 4.81 (1H, t, J = 8.0 Hz)





4.95 (4H, br s) 6.04 (1H, s) 6.83 (1H, s) 7.08 (1H, d, J = 8.0 Hz)





7.48-7.61 (4H, m) 7.71-7.88 (2H, m)





10.86 (1H, s)


272
CD3OD
400
2.24 (3H, s) 3.20-3.25 (1H, m) 3.30-3.36 (1H,





m) 4.23-4.33 (2H, m) 4.81 (1H, t, J = 8.0 Hz)





4.92 (4H, br s) 6.05-6.06 (1H, m) 6.85 (1H, d, J = 4.0 Hz)





6.99 (1H, d, J = 8.0 Hz) 7.47 (2H, d, J = 8.0 Hz)





7.60 (2H, d, J = 8.0 Hz)





7.79-7.82 (2H, m) 10.86 (1H, s)


273
CD3OD
400
0.96-1.08 (2H, m), 1.20-1.30 (3H, m),





1.43-1.51 (1H, m), 1.71-1.89 (7H, m), 2.40 (3H, s),





4.29-4.39 (2H, m), 4.55-4.61 (1H, m), 4.95 (4H, s),





6.08 (1, d, J = 2.3 Hz), 6.86 (1H, t, J = 2.7 Hz), 7.03 (1H,





d, J = 9.5 Hz) 7.82 (1H, d, J = 1.04 Hz) 7.9 (1H, dd, J = 9.24,





2.12 Hz) 8.70-8.81 (1H, m)


274
CD3OD
270
3.26-3.30 (1H, m) 3.82 (3H, s) 4.17 (2H, s)





4.75-4.89 (7H, m) 6.53 (1H, d, J = 8.4 Hz) 6.79 (2H,





s) 7.31 (1H, dd, J = 6.5, 2.2 Hz) 7.41-7.48 (3H,





m) 7.60 (1H, s) 7.75 (1H, d, J = 1.7 Hz)


275
CD3OD
270
3.25-3.32 (2H, m) 4.11-4.23 (1H, m)





4.68-4.75 (1H, m) 4.90 (7H, br s) 6.83-6.84 (2H, m)





6.92 (1H, d, J = 9.2 Hz) 7.48-7.57 (3H, m)





7.71-7.74 (2H, m) 8.68 (1H, d, J = 5.3 Hz)


276
CD3OD
270
2.21 (3H, s) 3.18-3.30 (3H, m) 4.21 (2H, s)





4.74 (1H, t, J = 7.4 Hz) 4.93 (5H, br s) 6.63 (1H, s)





6.91 (1H, d, J = 9.1 Hz) 7.48-7.56 (3H, m)





7.69-7.71 (2H, m) 8.73 (1Hs)


277
CD3OD
270
1.8-1.9 (2H, m), 2.2-2.4 (6H, m), 3.2-3.3 (2H,





m), 4.1-4.4 (4H, m), 4.7-4.9 (1H, m),





5.7-5.8 (1H, m) 6.2-6.4 (2H, m), 6.7-6.8 (1H, m),





7.1-7.2 (1H, m) 7.3-7.4 (4H, m), 7.5-7.6 (2H, m)


278
CD3OD
270
2.1 (4H, s), 2.2 (1H, s), 2.5 (5H, s), 4.0-4.1 (1H,





m), 4.7-4.9 (1H, m), 5.6 (1H, s), 6.5-6.7 (1H,





m), 7.4-7.6 (8H, m), 7.9-8.1 (2H, m),





8.3-8.4 (1H, m), 8.6-8.7 (1H, m), 9.9-10 (1H, m),





11 (1H, s)


279
CD3OD
270
1.3-1.5 (6, m), 3.0 (5H, m), 4.1-4.4 (2H, m),





4.7-4.9 (2H, m), 5.8 (1H, s), 6.2 (1H, d, J = 7 Hz),





6.5 (1H, d, J = 7 Hz), 7.0-7.4 (7H, m), 9.8 (1H, m)


280
CD3OD
270
1.3-1.5 (6, m), 3.0 (5H, m), 4.1-4.4 (2H, m),





4.7-4.9 (2H, m), 5.8 (1H, s), 6.2 (1H, d, J = 7 Hz),





6.5 (1H, d, J = 7 Hz), 7.0-7.4 (7H, m), 9.8 (1H, m)


281
CD3OD
270
2.2 (6H, s), 2.3 (2H, s), 2.4 (3H, s), 3.0-3.1 (2H,





m), 3.3 (3H, s), 4.0-4.4 (2H, m), 4.7-4.8 (1H, m),





5.7 (1H, s), 6.7 (1H, d, J = 7 Hz), 7.0-7.3 (5H,





m), 7.6 (1H, d, J = 7 Hz), 8.5 (1H, m),





10.5-10.8 (1H, m)


282
CD3OD
270
2.17 (6H, d, J = 3.2 Hz) 2.37 (3H, s)





3.24-3.33 (2H, m) 4.14-4.18 (2H, m) 4.78 (1H, t, J = 7.7 Hz)





4.98 (1H, s) 5.69 (1H, s) 6.71 (1H, d, J = 9.2 Hz)





7.44-7.48 (4H, m) 7.65-7.68 (3H, m)





8.57 (1H, t, J = 5.4 Hz) 10.46 (1H, s)


286
CD3OD
400
2.36 (3H, s) 2.49 (3H, s) 3.10-3.23 (2H, m)





4.17-4.22 (1H, m) 4.29-4.38 (1H, m) 4.76 (1H, t, J = 8.0 Hz)





4.93 (3H, br s) 6.05 (1H, s)





6.79-6.84 (2H, m) 7.05-7.07 (1H, m) 7.11-7.20 (2H, m)





7.74 (1H, d, J = 8.0 Hz) 8.67 (1H, t, J = 4.0 Hz)





10.89 (1H, br s)


287
CD3OD
270
3.10-3.15 (1H, m) 3.29-3.32 (1H, m) 4.19 (1H,





q, J = 6.7 Hz) 4.72 (1H, t, J = 7.7 Hz) 4.91 (5H,





br s) 6.92-6.99 (3H, m) 7.21-7.26 (2H, m)





7.40-7.41 (2H, m) 7.68 (2H, br s) 7.71 (1H, d, J = 2.2 Hz)


288
CD3OD
270
3.11-3.19 (1H, m) 3.30 (1H, s) 4.20 (1H, q, J = 8.9 Hz)





4.76 (1H, t, J = 7.4 Hz) 4.95 (6H, br s)





6.91-6.98 (3H, m) 7.05 (1H, d, J = 7.7 Hz)





7.22-7.27 (1H, m) 7.47 (2H, s) 7.68-7.73 (2H, m)


289
CD3OD
270
3.30 (1H, br s) 3.57-3.68 (1H, m) 3.97-4.18 (1H,





m) 4.91 (7H, br s) 6.82 (1H, d, J = 9.2 Hz)





7.32-7.39 (4H, m) 7.45-7.56 (4H, m) 7.75 (1H, d, J = 6.9 Hz)





7.86 (1H, d, J = 7.4 Hz) 8.21 (1H, d, J = 8.2 Hz)


291
CD3OD
270
2.22 (3H, s) 2.88-3.06 (1H, m) 3.11-3.19 (1H,





m) 3.94 (3H, s) 4.22 (2H, s) 4.65 (1H, t, J = 8.0 Hz)





4.88 (4H, S) 6.55 (1h, S) 6.94-7.06 (3H, m)





7.24-7.27 (2H, m) 7.72-7.76 (2H, m)


292
CD3OD
270
2.32 (3H, s) 2.79 (2H, s) 4.03-4.09 (2H, m)





4.88-4.94 (6H, m) 6.47 (2H, s) 6.78-6.81 (3H, s)





6.91-7.08 (2H, m) 7.16-7.53 (6H, m) 7.72-7.75 (1H,





m) 7.83-7.85 (1H, m) 8.18 (1H, s)


293
CD3OD
270
2.33 (3H, s) 3.30-3.48 (3H, m) 4.03-4.14 (2H,





m) 4.83-4.91 (5H, m) 6.82 (1H, s)





7.17-7.20 (2H, m) 7.31-7.56 (8H, m) 7.83-7.88 (2H, m)





11.06 (1H, br s)


294
CD3OD
270
1.27-1.37 (5H, m) 2.32 (2H, s) 3.13-3.15 (1H,





m) 3.17-3.23 (3H, m) 4.20 (1H, s) 4.30 (1H, s)





6.91 (1H, d, J = 3.7 Hz) 6.94-7.07 (1H, m)





7.16-7.25 (8H, m) 7.53 (1H, d, J = 8.2 Hz)





7.71-7.73 (1H, m)


295
CD3OD
270
1.32-1.36 (2H, m) 2.30 (3H, s) 3.20-3.38 (2H,





m) 4.16 (1H, s) 4.82-4.85 (1H, m) 4.92 (4H, br





s) 6.45 (1H, d, J = 3.9 Hz) 6.85-6.90 (2H, m)





7.12-7.35 (6H, m) 7.50 (2H, d, J = 7.9 Hz)





7.62-7.71 (2H, m)


296
CD3OD
270
1.33-1.37 (1H, m) 2.33 (3H, s) 3.01-3.20 (2H,





m) 3.30 (1H, s) 4.11-4.26 (2H, m) 4.70 (1H, t, J = 7.7 Hz)





4.91 (3H, s) 6.46 (1H, d, J = 3.9 Hz)





6.90-6.94 (2H, m) 7.17-7.25 (3H, m)





7.35-7.40 (2H, m) 7.53 (2H, d, J = 7.9 Hz) 7.68-7.70 (2H,





m)


297
CD3OD
270
1.27-1.32 (1H, m) 2.32 (3H, s) 3.07-3.17 (3H,





m) 4.17 (2H, d, J = 4.5 Hz) 4.69-4.72 (1H, m)





4.91 (2H, s) 6.46 (1H, s) 6.88-6.91 (2H, m)





7.16-7.26 (5H, m) 7.50-7.53 (2H, m) 7.65-7.69 (2H,





m) 8.61 (1H, d, J = 4.9 Hz) 11.03 (1H, s)


298
CD3OD
270
3.29-3.31 (1H, m), 3.58-3.73 (1H, m),





4.05-4.13 (2H, m), 4.89-4.91 (4H, m),





6.83 (1H, d, J = 9.1 Hz), 7.06-7.09 (1H, m),





7.15 (1H, s), 7.19-7.25 (1H, m), 7.34-7.62 (9H, m),





7.73-7.76 (1H, m), 7.84-7.88 (1H, m),





8.22 (1H, d, J = 7.6 Hz), 8.40-8.60 (1H, m)


299
CD3OD
270
3.61-3.71 (2H, m), 4.06-4.143 (2H, m),





4.90-4.97 (4H, m), 6.84 (1H, d, J = 9.1 Hz),





7.33-7.40 (4H, m), 7.49-7.55 (4H, m), 7.64-7.68 (2H, m),





7.74-7.77 (1H, m), 7.84-7.88 (1H, m),





8.26 (1H, d, J = 8.46 Hz), 8.40-8.60 (1H, m)


300
CD3OD
270
3.57-3.60 (1H, m), 3.67-3.71 (1H, m), 3.72 (3H, s),





4.05-4.13 (2H, m), 4.86-4.92 (4H, m),





6.81-6.91 (2H, m), 7.07 (1H, s), 7.29-7.33 (3H, m),





7.37-7.54 (6H, m), 7.73-7.77 (1H, m), 7.85-7.88 (1H, m),





8.22 (1H, d, J = 8.2 Hz), 8.45-8.47 (1H, m)


301
CD3OD
270
3.57-3.60 (1H, m), 3.707-3.73 (1H, m),





4.06-4.13 (2H, m), 4.86-4.92 (4H, m),





6.82 (1H, d, J = 9.1 Hz), 6.98-7.05 (1H, m),





7.12 (1H, s), 7.26-7.33 (3H, m), 7.36-7.55 (6H, m),





7.74-7.77 (1H, m), 7.85-7.88 (1H, m),





8.22 (1H, d, J = 8.2 Hz), 8.45-8.47 (1H, m)


302
CD3OD
270
3.56-3.59 (1H, m), 3.69-3.72 (1H, m),





4.05-4.13 (2H, m), 4.86-4.90 (6H, m), 6.78-6.84 (2H, m),





6.95-6.99 (2H, m), 7.23-7.27 (1H, m),





7.31-7.40 (2H, m), 7.48-7.54 (4H, m), 7.74-7.77 (1H, m),





7.85-7.88 (1H, m), 8.21 (1H, d, J = 8.2 Hz),





8.45-8.47 (1H, m)


303
CD3OD
270
2.1 (1H, s), 2.4 (2H, s), 2.6 (2H, s), 3.0-3.3 (2H,





m), 4.1-4.2 (2H, m), 4.7-4.8 (1H, m), 6.6 (1H,





m), 7.0-7.1 (1H, m), 7.2-7.3 (6H, m),





7.6-7.8 (4H, m), 8.8-8.9 (2H, m), 11.6 (1H, s)


304
CD3OD
270
2.0 (3H, s), 3.4-3.7 (3H, m), 3.8 (3H, s),





4.1-4.3 (2H, m), 4.8-5.2 (3H, m), 5.5 (1H, s),





6.2-6.3 (1H, m), 6.8-6.9 (1H, m),





7.0-7.1 (3H, m), 7.2-7.4 (3H, m), 7.4-7.6 (3H,





m), 7.8-7.9 (2H, m), 8.3 (1H, m)


305
CD3OD
270
2.17 (3H, s), 3.55-3.58 (1H, m), 3.65-3.68 (1H, m),





3.96-3.98 (1H, m), 4.115-4.13 (1H, m),





4.89-4.95 (4H, m), 6.63 (1H, d, J = 9.1 Hz),





6.98-6.84 (2H, m), 6.98-7.05 (1H, m), 7.13 (1H, s),





7.26-7.52 (6H, m), 7.74-7.76 (1H, m), 7.84-7.88 (1H, m),





8.17-8.19 (1H, m), 8.45-8.47 (1H, m)


306
CD3OD
270
3.40-3.60 (1H, m), 3.70-3.80 (1H, m),





3.89 (3H, d, J = 2.8 Hz), 4.05-4.11 (2H, m),





4.13-4.16 (1H, m), 4.89-4.91 (2H, m),





6.85 (1H, d, J = 8.9 Hz), 7.03 (1H, s),





7.07-7.12 (1H, m), 7.26-7.64 (9H, m), 7.76-7.78 (1H, m),





7.85-7.88 (1H, m), 8.22 (1H, d, J = 7.6 Hz),





8.50-8.59 (1H, m)


307
CD3OD
270
3.05-3.10 (1H, m), 3.25-3.40 (2H, m),





4.10-4.25 (2H, m), 4.85-4.95 (1H, m), 4.95-5.10 (4H, m),





6.50 (1H, d, J = 8.15 Hz), 7.00-7.80 (11H, m)


308
CD3OD
270
3.05-3.20 (1H, m), 3.25-3.40 (2H, m),





3.80 (3H, s), 4.10-4.25 (2H, m), 4.75-4.85 (1H, m),





4.95-5.05 (4H, m), 6.45-6.55 (1H, m),





6.85-6.90 (1H, m), 7.00-7.10 (2H, m), 7.25-7.80 (7H, m)


309
CD3OD
270
1.7-1.8 (3H, m), 2.1-2.2 (3H, s), 4.1-4.2 (2H, m),





4.3 (1H, s), 4.8-5.0 (1H, m), 6.1-6.2 (1H, d,





J = 7 Hz), 6.5-6.6 (1H, m), 7.0 (1H, s),





7.1-7.7 (10H, m), 9.4-9.5 (1H, m)


310
CD3OD
270
1.2-1.3 (2H, m), 1.8-2.1 (3H, m), 2.2-2.3 (2H,





m), 3.2-3.3 (2H, m), 3.8 (3H, s), 4.1-4.2 (2H, m),





4.8-4.9 (1H, m), 6.1-6.2 (1H, m) 7.1-7.4 (10H,





m)


311
CD3OD
270
3.00-3.40 (3H, m), 4.10-4.30 (2H, m),





4.70-4.80 (1H, m), 4.90-5.10 (3H, m), 6.80-7.80 (12H, m),





8.60-8.80 (1H, m)


312
CD3OD
270
3.00-3.40 (4H, m), 3.80 (3H, s),





4.15-4.30 (2H, m), 4.75-4.90 (1H, m), 4.95-5.10 (2H, m),





6.80-7.40 (9H, m), 7.60-7.80 (2H, m),





8.40-8.70 (1H, m)


313
CD3OD
270
3.00-3.40 (4H, m), 4.10-4.30 (2H, m),





4.80-4.90 (1H, m), 4.95-5.10 (3H, m), 6.90-7.80 (12H, m),





8.60-8.80 (1H, m), 10.90-11.10 (1H, m)


314
CD3OD
270
3.05-3.40 (4H, m), 3.80 (3H, s),





4.10-4.30 (2H, m), 4.70-4.90 (1H, m), 4.95-5.10 (2H, m),





6.80-7.40 (9H, m), 7.60-7.80 (2H, m),





8.60-8.75 (1H, m)


315
d6-
270
2.1 (2H, s), 2.4 (2H, s), 2.6 (3H, s), 3.0-3.3 (2H,



DMSO

m), 4.2-4.3 (2H, m), 4.8 (1H, br s), 6.8 (1H, br





m), 7.0-7.1 (1H, m),





7.1 (6H, m), 7.6-7.8 (2H, m), 8.8-8.9 (1H, m),





11.4 (1H, m)


316
CD3OD
270
2.4 (3H, s), 2.6 (3H, s), 2.9-3.2 (2H, m),





4.1-4.2 (2H, m), 4.6-4.7 (1H, s), 6.8-6.9 (1H, m),





7.1-7.4 (8H, m), 8.2-8.3 (3H, m), 8.8 (2H, s), 11.4 (1H,





s)


317
CD3OD
270
2.69 (3H, s), 3.00-3.25 (2H, m),





3.28-3.35 (1H, m), 4.15-4.30 (2H, m), 4.65-4.80 (1H, m),





4.90-5.10 (3H, m), 6.85-7.70 (12H, m),





8.55-8.70 (1H, m)


318
CD3OD
270
2.27 (3H, s) 3.00-3.25 (2H, m), 3.28-3.35 (1H, m),





3.80 (3H, s) 4.10-4.30 (2H, m), 4.75-4.85 (1H, m),





4.90-5.10 (4H, m), 6.80-7.50 (9H, m),





7.60-7.70 (2H, m), 8.50-8.70 (1H, m)


319
CD3OD
270
2.2 (3H, s), 2.4 (3H, s), 3.0-3.2 (2H, m),





3.2-3.4 (3H, m), 4.0-4.3 (2H, m), 4.7-4.8 (1H, m),





6.7-6.8 (1H, m), 7.0-7.3 (8H, m), 7.4-7.5 (1H, m),





7.6-7.7 (2H, m), 8.4-8.6 (1H, m)


320
CD3OD
270
2.4 (3H, s), 3.0-3.2 (3H, m), 3.3 (3H, s),





4.0-4.2 (2H, m), 4.7-4.8 (1H, m), 6.7 (1H, d, J = 7 Hz),





7.0-7.2 (4H, m), 7.3-7.5 (3H, m), 7.6-7.8 (2H,





m), 8.6-8.7 (1H, m)


321
CD3OD
270
2.4 (3H, s), 3.0-3.2 (2H, m), 3.3-3.5 (3H, s),





3.7 (3H, s), 4.0-4.4 (2H, m), 4.8-4.9 (2H, m),





6.6-6.8 (1H, m), 6.9-7.0 (1H, m), 7.1 (2H, s),





7.2-7.6 (4H, m), 7.7-7.8 (1H, m), 8.7-8.6 (1H, m)


322
d6-
270
2.38 (3H, s) 3.39-3.44 (2H, m) 4.12 (2H, s)



DMSO

4.79 (1H, d, J = 4.9 Hz) 6.76 (1H, d, J = 8.7 Hz)





7.04-7.07 (1H, m) 7.18-7.26 (2H, m) 7.37-7.50 (4H,





m) 7.62-7.72 (3H, m) 7.93 (2H, br s) 8.59 (1H,





s) 8.83 (1H, d, J = 7.9 Hz) 11.54 (1H, br s)


324
CD3OD
270
3.10-3.15 (1H, m) 3.22-3.30 (2H, m) 4.21 (2H,





s) 4.78 (1H, t, J = 7.7 Hz) 4.92 (4H, s) 6.91 (1H,





d, J = 8.4 Hz) 7.05-7.24 (5H, m) 7.41 (1H, d, J = 8.4 Hz)





7.58 (1H, d, J = 7.9 Hz) 7.71-7.78 (2H,





m)


325
CD3OD
270
3.12-3.33 (2H, m) 4.24 (1H, s) 4.76 (1H, s)





4.93 (6H, s) 7.10-7.24 (7H, m) 7.43 (1H, s) 7.62 (1H,





s) 7.74-7.78 (2H, m)


326
CD3OD
270
3.09-3.30 (2H, m) 4.21 (2H, s) 4.71-4.76 (1H, s)





4.91 (5H, s) 6.91-7.10 (7H, m) 7.72 (2H, s)





8.68 (1H, s)


327
CD3OD
270
1.36 (1H, s) 3.03-3.30 (2H, m) 3.79 (3H, s)





4.19 (2H, s) 4.70-4.76 (1H, m) 4.91 (4H, s)





6.88-7.27 (8H, m) 7.69 (2H, s)


328
CD3OD
270
3.11-3.21 (2H, m) 4.23 (2H, s) 4.73-4.79 (1H, t)





4.98 (5H, s) 6.93-7.16 (4H, m) 7.74-7.99 (4H,





m) 8.26 (1H, s) 9.33 (1H, s)


329
d6-
270
3.0-3.2 (1H, m) 3.3-3.4 (2H, m), 4.0-4.2 (3H,



DMSO

m), 4.8-4.9 (1H, m),





7-7.8 (8H, m), 8.0-8.1 (1H, m), 8.7-9.0 (2H, m)


330
CD3OD
270
3.12-3.19 (2H, m) 4.18 (2H, s) 4.73 (1H, br s)





4.91 (5H, s) 6.95-7.26 (8H, m) 7.60-7.66 (3H,





m) 8.64 (1H, br s)


331
CD3OD
270
3.09-3.30 (3H, m) 4.20 (2H, s) 4.71 (1H, br s)





4.89 (4H, br s) 6.96-7.10 (5H, m) 7.27-7.40 (4H,





m) 7.69 (2H, s)


332
CD3OD
270
3.09-3.30 (3H, m) 3.79 (3H, s) 4.19 (2H, s)





4.71 (1H, brs) 4.91 (4H, s) 6.91-7.05 (7H, m)





7.27-7.28 (2H, m) 7.67 (2H, s)


333
CD3OD
270
4.09-4.18 (2H, m) 5.19 (2H, s) 5.70-5.75 (1H,





m) 5.98 (5H, s) 7.89-7.97 (3H, m)





8.23-8.25 (2H, m) 8.85-9.00 (4H, m) 9.22 (1H, s)





10.34 (1H, s)


334
d6-
270
2.5 (3H, s), 2.9-3.1 (2H, m), 3.7 (3H, s),



DMSO

4.1-4.2 (2H, m), 4.5-4.6 (1H, m), 6.77-6.8 (1H, d,





J = 8 Hz), 6.9-6.93 (1H, d, J = 9 Hz), 7.00-7.06 (1H,





m), 7.14-7.3 (4H, m), 7.38-7.41 (1H, d, J = 8 Hz),





7.6-7.65 (1H, d, J = 8 Hz), 7.7-7.71 (1H, m),





7.91-8.0 (1H, m), 8.7-8.8 (1H, m), 11.5 (1H, s)


335
d6-
270
3.39 (7H, s) 4.19 (1H, s) 4.85 (1H, s)



DMSO

6.91-7.02 (2H, m) 7.18-7.23 (4H, m) 7.40-7.53 (4H, m)





7.80-8.01 (2H, m) 8.77 (1H, s) 11.52 (1H, s)


336
CD3OD
270
1.3-1.6 (1H, m), 2.2-2.3 (3H, m), 2.8-2.9 (1H,





m), 3.2-3.4 (6H, m), 4.0-4.4 (2H, m),





4.7-4.9 (1H, m), 6.5-6.6 (1H, m), 7.0-7.3 (6H, m),





7.4-7.6 (4H, m), 7.7-7.9 (1H, m)


337
CD3OD
270
2.2 (3H, s), 3.3-3.4 (6H, m), 3.8 (3H, s),





3.9-4.2 (2H, m), 4.8-5.0 (1H, m), 6.5-6.6 (1H, d, J = Hz),





6.9-7.0 (3, m), 7.1-7.2 (4H, m), 7.3-7.5 (3H,





m), 7.6-7.8 (1H, m), 8.3-8.4 (1H, m)


338
CD3OD
270
1.1-1.0 (2H, m), 1.5-1.8 (10H, m), 2.5 (3H, s),





4.1-4.2 (2H, m), 4.5-4.6 (1H, m), 6.9-7.1 (2H,





m), 7.2-7.3 (2H, m), 7.4-7.5 (1H, m),





7.6-7.7 (1H, m), 7.8-7.9 (1H, m), 8.0-8.1 (1H, s),





8.5-8.7 (2H, m), 11.6 (1H, s)


339
CD3OD
400
0.99-1.14 (10H, m), 1.22-1.39 (6H, m),





1.65-1.84 (9H, m), 1.98-2.09 (2H, m), 2.71 (3H, s),





4.24-4.44 (2H, m), 4.53 (1H, dd, J = 6.64, 8.8 Hz),





7.06 (1H, d, J = 9.16 Hz) 7.85 (1H, s),





7.95 (1H, dd, J = 1.96, 9.12 Hz), 8.79-8.82 (1H, m)


340
CD3OD
400
0.58-0.89 (5H, m) 1.15-1.25 (3H, m)





1.88-1.99 (1H, m) 2.51-2.54 (3H, m) 2.76-2.88 (2H, m)





3.01-3.22 (3H, m) 3.47-3.55 (1H, m)





4.11-4.21 (1H, m) 4.52-4.64 (1H, m) 6.87 (1H, d, J = 8.0 Hz)





7.05-7.19 (1H, m) 7.31-7.48 (2H, m)





7.65-7.77 (2H, m) 8.66 (1H, d, J = 4.0 Hz)


341
CD3OD
400
0.70 (3H, d, J = 8.0 Hz) 0.76 (3H, d, J = 8.0 Hz)





1.88-1.96 (1H, m) 2.46-2.54 (3H, m)





2.80-2.92 (1H, m) 3.03-3.17 (2H, m) 3.20-3.22 (1H, m)





3.49 (1H, t, J = 4.0 Hz) 4.12-4.16 (2H, m)





4.53-4.57 (1H, m) 4.77 (3H, br s) 6.89 (1H, d, J = 8.0 Hz)





7.10-7.22 (4H, m) 7.60 (1H, d, J = 4.0 Hz)





7.68 (1H, dd, J = 8.0, 4.0 Hz)


342
CD3OD
400
2.53 (3H, s) 2.55-2.62 (1H, m) 2.71-2.77 (1H,





m) 2.93-3.01 (2H, m) 3.95 (1H, t, J = 4.0 Hz)





4.09 (2H, d, J = 4.0 Hz) 4.34 (1H, t, J = 4.0 Hz)





4.82 (5H, br s) 6.83 (1H, dd, J = 8.0, 4.0 Hz)





6.92-6.99 (3H, m) 7.04 (1H, s) 7.09-7.20 (5H,





m) 7.58-7.61 (2H, m)


343
CD3OD
400
0.76-0.93 (2H, m), 1.15-1.38 (3H, m),





1.54 (3H, d, J = 6.6 Hz), 1.71-1.86 (6H, m),





2.41 (1H, br s), 2.83 (3H, s), 2.90-2.94 (2H, m),





3.09-3.14 (1H, m), 3.88 (1H, br s),





4.18-4.30 (2H, m), 4.63-4.68 (1H, m), 6.97 (1H, d, J = 9.1 Hz),





7.05-7.08 (1H, m), 7.14-7.21 (2H, m),





7.73 (1H, s), 7.78 (1H, d, J = 9.2 Hz),





8.70-8.73 (1H, m).


344
CD3OD
400
1.58 (3H, d, J = 8.9 Hz), 2.83 (6H, s),





2.90-3.05 (1H, m), 3.10-3.21 (1H, m),





3.90 (1H, q, J = 7 Hz), 4.18-4.23 (1H, m),





4.28-4.39 (1H, m), 4.67 (1H, t, J = 7.6 Hz), 4.91 (3H, s),





7.00 (1H, d, J = 9.0 Hz), 7.08-7.10 (1H, m),





7.16-7.30 (2H, m), 7.77 (1H, d, J = 3.96 Hz),





7.80 (1H, t, J = 7.04 Hz), 8.72-8.74 (1H, m).


345
CD3OD
400
1.26 (3H, t, J = 7.2 Hz), 1.53 (3H, d, J = 7.0 Hz),





2.78 (3H, s), 2.93-3.13 (4H, m), 3.89-3.94 (1H, m),





4.16-4.29 (2H, m), 4.63-4.67 (1H, m),





6.96 (1H, d, J = 9.1 Hz), 7.03-7.06 (1H, m),





7.10-7.20 (2H, m), 7.73 (1H, s), 7.76 (1H, dd, J = 9.2,





2.1 Hz), 8.70 (1H, t, J = 5.9 Hz).


346
CD3OD
400
0.92-0.99 (3H, m), 1.54 (3H, d, J = 7.0 Hz),





1.66-1.72 (2H, m), 2.80 (3H, s), 2.93-3.13 (4H, m),





3.90-3.99 (1H, m), 4.16-4.29 (2H, m), 4.62-4.66 (1H, m),





6.96 (1H, d, J = 9.1 Hz), 7.03-7.06 (1H, m),





7.11-7.20 (2H, m), 7.73 (1H, s), 7.77 (1H, dd, J = 9.1,





2.0 Hz), 8.71 (1H, t, J = 5.8 Hz).


347
CD3OD
400
0.94-0.97 (3H, m), 1.54 (3H, d, J = 7.0 Hz),





1.60-1.68 (2H, m), 2.80 (3H, s), 2.82-3.13 (6H, m),





3.91-3.96 (1H, m), 4.16-4.29 (2H, m), 4.62-4.66 (1H, m),





6.96 (1H, d, J = 9.2 Hz), 7.03-7.06 (1H, m),





7.11-7.20 (2H, m), 7.73 (1H, s), 7.74-7.78 (1H, m),





8.71 (1H, t, J = 5.9 Hz).


348
CD3OD
400
0.99-1.20 (9H, m), 1.30 (3H, d, J = 6.6 Hz),





1.39 (1H, s), 2.41 (1H, s), 2.60-2.70 (3H, m),





2.79-2.84 (1H, m), 2.95-3.01 (1H, m), 3.15-3.20 (1H, m),





3.81 (1H, s), 4.22-4.33 (2H, m), 7.02 (1H, d, J = 9.1 Hz),





7.06-7.09 (1H, m), 7.21-7.28 (2H, m),





7.80-7.83 (2H, m), 8.79-8.82 (1H, m).


349
CD3OD
400
0.98-1.05 (6H, m), 1.11-1.24 (3H, m),





1.30 (3H, d, J = 6.6 Hz), 1.37-1.40 (1H, m),





1.63 (1H, s), 2.07-2.09 (1H, m), 2.56-2.69 (3H, m),





2.83-2.86 (1H, m), 2.96-3.01 (1H, m),





3.14-3.19 (1H, m), 3.81-3.82 (1H, m), 4.22-4.33 (2H, m),





7.02 (1H, d, J = 9.1 Hz), 7.11-7.14 (1H, m),





7.21-7.28 (2H, m), 7.80-7.85 (2H, m), 8.80 (1H, s).


350
CD3OD
400
1.04-1.17 (6H, m) 1.30-1.47 (6H, m) 1.53 (3H,





d, J = 8.0 Hz) 2.94-3.04 (2H, m) 3.07-3.17 (1H,





m) 3.34-3.47 (1H, m) 3.90-4.06 (2H, m)





4.20 (1H, dd, J = 8.0, 4.0 Hz) 4.31-4.41 (1H, m)





4.63-4.78 (1H, m) 4.91-5.01 (2H, br m)





7.00-7.08 (1H, m) 7.11-7.17 (1H, m) 7.19-7.32 (2H, m)





7.74-7.77 (2H, m) 8.78 (1H, t, J = 4.0 Hz)


351
CD3OD
400
2.88-2.92 (7H, m), 2.99-3.04 (1H, m),





3.11-3.17 (1H, m), 3.39-3.42 (1H, m), 4.03-4.11 (2H, m),





4.16-4.22 (1H, m), 4.59 (1H, t, J = 7.8 Hz),





6.99-7.04 (2H, m), 7.10-7.35 (7H, m), 7.69-7.70 (1H, m),





7.72 (1H, s), 8.29 (1H, t, J = 5.8 Hz).


352
CD3OD
400
1.33 (3H, t, J = 6.9 Hz), 2.84-3.21 (9H, m),





4.03-4.23 (3H, m), 4.59-4.63 (1H, m), 6.99-7.05 (2H, m),





7.11-7.35 (7H, m), 7.70-7.71 (1H, m), 7.73 (1H, s),





8.30 (1H, t, J = 5.8 Hz).


353
CD3OD
400
0.98-1.05 (6H, m), 1.11-1.24 (3H, m),





1.30 (3H, d, J = 6.6 Hz), 1.37-1.40 (1H, m),





1.63 (1H, s), 2.07-2.09 (1H, m), 2.56-2.69 (3H, m),





2.83-2.86 (1H, m), 2.96-3.01 (1H, m),





3.14-3.19 (1H, m), 3.81-3.82 (1H, m), 4.22-4.33 (2H, m),





7.02 (1H, d, J = 9.1 Hz), 7.11-7.14 (1H, m),





7.21-7.28 (2H, m), 7.80-7.85 (2H, m), 8.80 (1H, s).


354
CD3OD
400
1.31 (2H, d, J = 8.0 Hz) 1.41 (2H, d, J = 8.0 Hz)





1.52-1.84 (6H, br m) 2.76-2.87 (3H, m)





2.93-3.08 (2H, m) 3.12-3.25 (1H, m) 3.45 (1H, br s)





3.67-3.79 (1H, m) 4.10-4.23 (2H, m)





4.45-4.49 (1H, m) 4.55-4.61 (1H, m) 6.86 (1H, d, J = 8.0 Hz)





6.90-6.95 (1H, m) 7.01-7.12 (2H, m)





7.57-7.68 (2H, m 08.64 (1H, t, J = 4.0 Hz)


355
CD3OD
400
1.28-1.49 (6H, m) 1.56 (3H, d, J = 8.0 Hz)





2.93-3.03 (2H, m) 3.14-3.29 (3H, m) 3.36-3.37 (1H,





m) 4.04 (1H, q, J = 8.0 Hz) 4.23-4.33 (2H, m)





4.65 (1H, q, J = 8.0 Hz) 5.00 (3H, m) 7.02 (1H,





d, J = 8.0 Hz) 7.10-7.12 (1H, m) 7.18-7.25 (2H,





m) 7.78-7.84 (2H, m) 8.81 (1H, t, J = 4.0 Hz)


356
CD3OD
400
1.22 (2H, d, J = 8.0 Hz) 1.36 (2H, d, J = 8.0 Hz)





1.91-1.93 (5H, br m) 2.71 (1H, br s)





2.78-2.88 (1H, m) 2.97-3.13 (3H, m) 3.21-3.24 (1H, m)





3.46 (1H, br s) 3.76-3.88 (1H, m) 4.07-4.15 (2H,





m) 4.42-4.54 (1H, m) 4.83 (1H, s) 6.87 (1H, dd,





J = 8.0, 4.0 Hz) 6.93-6.95 (1H, m)





7.02-7.08 (2H, m) 7.61-7.69 (2H, m)


357
CD3OD
400
1.46 (2H, d, J = 8.0 Hz) 1.59 (2H, d, J = 8.0 Hz)





2.10 (5H, br s) 2.96-3.03 (1H, m) 3.11-3.16 (1H,





m) 3.32-3.37 (5H, m) 3.87-3.96 (1H, m)





4.18-4.24 (1H, m) 4.30 (1H, s) 4.33 (1H, s)





4.63-4.70 (1H, m) 7.01 (1H, d, J = 8.0 Hz) 7.09 (1H, br s)





7.15-7.25 (2H, m) 7.77-7.83 (2H, m)


359
CD3OD
400
0.90 (6H, dd, J = 2.22, 6.72 Hz) 2.09-2.42 (1H,





m) 2.93 (6H, s) 2.97-3.03 (1H, m)





3.11-3.20 (1H, m) 3.66 (1H, d, J = 6.0 Hz) 4.28-4.31 (2H,





m) 4.61-4.65 (1H, m) 4.92 (4H, br s) 7.02 (1H,





d, J = 9.08 Hz), 7.11-7.15 (1H, m), 7.21-7.26 (2H,





m) 7.81-7.86 (2H, m), 8.79-8.82 (1H, m)


360
CD3OD
400
1.21 (3H, s), 1.27 (3H, d, J = 6.6 Hz), 2.78 (3H, s),





2.93-3.08 (2H, m), 3.23-3.28 (1H, m),





4.03-4.11 (3H, m), 4.25-4.41 (2H, m), 4.82 (1H, s),





7.02 (1H, d, J = 9.1 Hz), 7.11-7.14 (1H, m),





7.20-7.27 (2H, m), 7.79 (1H, d, J = 1.3 Hz), 7.85 (1H, dd, J = 9.2,





2.0 Hz), 8.72 (1H, t, J = 5.8 Hz).


361
CD3OD
400
1.31 (3H, t, J = 7.3 Hz), 2.90 (3H, s),





2.96-3.01 (1H, m), 3.14-3.23 (3H, m), 4.00 (1H, t, J = 4.5 Hz),





4.05-4.12 (2H, m), 4.23-4.34 (2H, m),





4.73-4.77 (1H, m), 7.01 (1H, d, J = 9.1 Hz),





7.09-7.12 (1H, m), 7.19-7.25 (2H, m), 7.77 (1H, d, J = 1.2 Hz),





7.82 (1H, dd, J = 9.1, 2.1 Hz), 8.70 (1H, t, J = 5.8 Hz).


362
CD3OD
400
1.26 (6H, t, J = 7.2 Hz), 2.95-3.01 (1H, m),





3.08-3.45 (5H, m), 4.03-4.09 (3H, m), 4.24-4.36 (2H, m),





4.75-4.79 (1H, m), 7.02 (1H, d, J = 9.2 Hz),





7.09-7.12 (1H, m), 7.19-7.26 (2H, m), 7.78 (1H, d, J = 1.2 Hz),





7.83 (1H, dd, J = 9.2, 2.1 Hz).


363
CD3OD
400
1.36 (6H, t, J = 7.3 Hz), 3.01-3.15 (2H, m),





3.31-3.38 (4H, m), 3.92-4.01 (2H, m), 4.10-4.12 (1H, m),





4.19-4.33 (2H, m), 4.61 (1H, t, J = 7.7 Hz),





7.00-7.02 (1H, m), 7.06-7.09 (1H, m), 7.15-7.25 (2H, m),





7.78-7.81 (2H, m), 8.77 (1H, t, J = 5.8 Hz).


364
CD3OD
400
1.26 (6H, t, J = 7.2 Hz), 1.37-1.43 (1H, m),





2.96-3.25 (7H, m), 3.76 (3H, s), 4.25-4.38 (3H, m),





4.75-4.79 (1H, m), 7.02 (1H, d, J = 9.5 Hz),





7.10-7.13 (1H, m), 7.20-7.28 (2H, m), 7.79 (1H, d, J = 1.7 Hz),





7.84 (1H, dd, J = 9.2, 2.2 Hz), 8.62 (1H, t, J = 5.8 Hz).


365
CD3OD
400
1.07 (3H, d, J = 8.0 Hz) 1.25 (3H, d, J = 4.0 Hz)





1.33-1.40 (1H, m) 1.50-1.72 (4H, m)





1.79-1.94 (4H, m) 2.92-3.01 (1H, m) 3.16-3.21 (1H, m)





3.53-3.65 (2H, m) 3.78-3.93 (2H, m)





4.16-4.27 (2H, m) 4.72 (1H, q, J = 4.0 Hz) 7.02 (1H, d, J = 12.0 Hz)





7.10 (1H, br s) 7.17-7.23 (2H, m)





7.75-7.84 (2H, m) 8.82-8.87 (1H, m)


366
CD3OD
400
2.09-2.12 (5H, m) 2.92-3.06 (2H, m)





3.12-3.20 (3H, m) 3.69-3.71 (3H, br m) 4.03-4.14 (2H, m)





4.26 (2H, s) 4.65 (1H, t, J = 8.0 Hz) 7.01 (2H, d,





J = 8.0 Hz) 7.06-7.09 (1H, m) 7.15-7.26 (2H, m)





7.77-7.86 (2H, m)


367
CD3OD
400
1.08-1.12 (3H, m), 1.39 (3H, d, J = 6.9 Hz),





2.61 (3H, s), 2.78-3.01 (4H, m), 3.74-3.79 (1H, m),





4.03-4.14 (2H, m), 4.52-4.58 (1H, m),





6.81-6.90 (3H, m), 7.10-7.15 (2H, m), 7.57 (1H, s),





7.61 (1H, dd, J = 9.2, 2.1 Hz), 8.56 (1H, t, J = 5.8 Hz).


368
CD3OD
400
0.78-0.84 (3H, m), 1.39 (3H, d, J = 7.0 Hz),





1.52-1.56 (2H, m), 2.63 (3H, s), 2.68-3.00 (4H, m),





3.74-3.79 (1H, m), 4.02-4.17 (2H, m), 4.49-4.53 (1H, m),





6.80-6.88 (3H, m), 7.10-7.14 (2H, m), 7.56 (1H, s),





7.58-7.61 (1H, m), 8.71 (1H, t, J = 5.6 Hz).


369
CD3OD
400
0.93-0.97 (3H, m), 1.32-1.40 (2H, m),





1.53 (3H, d, J = 6.9 Hz), 1.61-1.70 (2H, m),





2.78 (3H, s), 2.83-3.14 (4H, m), 3.90-3.98 (1H, m),





4.17-4.28 (2H, m), 4.63-4.67 (1H, m),





6.95-7.02 (3H, m), 7.19-7.28 (2H, m), 7.71 (1H, s),





7.74 (1H, dd, J = 9.2, 2.0 Hz), 8.69 (1H, t, J = 5.7 Hz).


370
CD3OD
400
0.99-1.13 (9H, m), 1.27 (3H, d, J = 6.4 Hz),





1.37 (1H, s), 2.40-2.53 (2H, m), 2.68 (3H, s),





2.94-3.00 (1H, m), 3.16-3.21 (1H, m), 3.78-3.79 (1H, m),





4.27-4.38 (2H, m), 7.01 (1H, d, J = 9.2 Hz),





7.07 (2H, t, J = 8.6 Hz), 7.32-7.36 (2H, m),





7.79-7.84 (2H, m), 8.81-8.89 (1H, m).


371
CD3OD
400
0.98 (3H, d, J = 6.4 Hz), 1.03 (3H, t, J = 7.2 Hz),





1.15 (3H, d, J = 6.2 Hz), 1.27 (3H, d, J = 6.4 Hz),





1.36-1.39 (1H, m), 1.58-1.63 (1H, m), 2.05-2.13 (1H, m),





2.46-2.49 (1H, m), 2.67 (3H, s), 2.71-2.75 (1H, m),





2.94-3.00 (1H, m), 3.15-3.20 (1H, m), 3.79 (1H, s),





4.27-4.36 (2H, m), 7.01 (1H, d, J = 9.2 Hz),





7.07 (2H, t, J = 8.4 Hz), 7.32-7.35 (2H, m),





7.79-7.84 (2H, m), 8.80 (1H, s).


372
CD3OD
400
1.16-1.33 (6H, m) 1.38 (6H, d, J = 8.0 Hz)





1.57 (3H, d, J = 8.0 Hz) 2.87-3.00 (2H, m)





3.13-3.18 (1H, m) 3.31-3.37 (1H, m) 3.96-4.05 (2H, m)





4.21 (1H, d, J = 12.0, 4.0 Hz) 4.34-4.48 (1H, m)





4.72-4.79 (1H, m) 4.96-5.06 (2H, br m)





7.00-7.07 (3H, m) 7.28-7.32 (2H, m) 7.71-7.74 (2H,





m) 8.76 (1H, t, J = 4.0 Hz)


373
CD3OD
400
1.19-1.26 (6H, m), 2.79-2.85 (5H, m),





3.00-3.08 (2H, m), 3.41-3.45 (1H, m), 4.03-4.08 (1H, m),





4.14-4.21 (2H, m), 4.70 (1H, s), 7.00-7.05 (3H, m),





7.23-7.34 (7H, m), 7.71-7.74 (2H, m),





8.16-8.19 (1H, m), 8.69 (1H, d, J = 8.6 Hz).


374
CD3OD
400
1.43 (3H, d, J = 8.0 Hz) 1.54-1.57 (1H, m)





1.85-1.99 (5H, m) 2.97-3.03 (3H, m) 3.12-3.17 (1H,





m) 3.36-3.41 (2H, M) 3.60 (1h, D, j = 8.0 Hz)





3.90 (1H, q, J = 8.0 Hz) 4.21-4.31 (2H, m)





4.60-4.64 (1H, m) 5.02-5.07 (2H, m) 6.92-7.08 (3H,





m) 7.28-7.31 (2H, m) 7.77-7.80 (2H, m)





8.77 (1H, t, J = 4.0 Hz)


375
CD3OD
400
1.40 (4H, d, J = 8.0 Hz) 1.51-1.57 (1H, m)





1.68 (3H, d, J = 12.0 Hz) 1.77-1.81 (1H, m)





2.57-2.71 (2H, m) 2.78-2.87 (2H, m) 3.00-3.05 (1H, m)





3.20-3.22 (1H, m) 3.40 (1H, d, J = 4.0 Hz)





3.61-3.69 (1H, m) 4.07-4.18 (2H, m) 4.58-4.62 (1H,





m) 4.81 (2H, br s) 6.84-6.93 (3H, m)





7.14-7.18 (2H, m) 7.61-7.66 (2H, m) 8.62 (1H, t, J = 4.0 Hz)


376
CD3OD
400
1.23-1.29 (6H, m) 1.55 (3H, d, J = 8.0 Hz)





2.78 (1H, br s) 2.87-3.04 (2H, m) 3.16-3.21 (2H, m)





3.32-3.34 (1H, m) 4.02 (1H, q, J = 8.0 Hz)





4.28 (2H, d, J = 4.0 Hz) 4.74 (1H, q, J = 8.0 Hz)





5.03 (4H, br s) 7.03-7.15 (3H, m) 7.25-7.37 (2H, m)





7.71-7.81 (2H, m)


377
CD3OD
400
0.70-0.78 (1H, m) 0.86-0.91 (6H, m)





1.24-1.32 (1H, m) 2.01-2.07 (1H, m) 2.92 (6H, m)





2.97-3.03 (1H, m) 3.21-3.27 (1H, m) 3.72 (1H, d, J = 8.0 Hz)





4.23-4.44 (2H, m) 4.64-4.72 (1H, m)





4.95 (3H, s) 6.96-7.04 (2H, m) 7.09 (1H, d, J = 8.0 Hz)





7.17 (1H, d, J = 8.0 Hz) 7.34-7.39 (1H,





m) 7.80 (1H, s) 7.86 (1H, dd, J = 8.0, 4.0 Hz)





8.84-8.92 (1H, m)


378
CD3OD
400
1.05 (2H, d, J = 8.0 Hz) 1.22-1.32 (4H, m)





1.45-1.50 (2H, m) 1.61-1.68 (1H, m) 1.78-1.95 (3H,





m) 2.95-3.01 (1H, m) 3.16-3.21 (1H, m)





3.50-3.55 (2H, m) 3.77-3.92 (2H, m) 4.26 (2H, s)





4.71 (1H, q, J = 8.0 Hz) 4.94 (4H, s) 6.99-7.05 (3H,





m) 7.28-7.36 (2H, m) 7.76-7.81 (2H, m)


379
CD3OD
400
1.56 (1H, s) 1.88 (6H, s) 2.88-3.00 (3H, m)





3.14-3.24 (1H, m) 3.34-3.37 (1H, m) 3.50 (1H, br s)





3.87-3.99 (2H, m) 4.26 (2H, s) 4.66-4.72 (2H,





m) 5.02 (2H, s) 6.96-7.02 (3H, m)





7.27-7.30 (2H, m) 7.75-7.80 (2H, m)


380
CD3OD
400
1.34-1.41 (6H, m) 2.95-3.01 (1H, m)





3.14-3.33 (5H, m) 3.37-3.40 (1H, m) 3.92-4.08 (2H, m)





4.21-4.39 (2H, m) 4.64-4.71 (1H, m)





4.86-4.92 (2H, m) 6.96-7.10 (3H, m) 7.27-7.31 (2H, m)





7.73-7.82 (2H, m) 8.73-8.76 (1H, m)


381
CD3OD
400
0.96-1.06 (2H, m) 1.24-1.44 (10H, m) 1.52 (3H,





d, J = 4.0 Hz) 1.79 (4H, d, J = 8.0 Hz) 2.79 (3H,





s) 3.36-3.37 (1H, m) 3.55-3.58 (1H, m)





3.89 (1H, br s) 4.12 (1H, d, J = 8.0 Hz)





4.28-4.35 (2H, m) 4.40-4.50 (1H, m) 7.04 (1H, d, J = 8.0 Hz)





7.81 (1H, s) 7.92 (1H, dd, J = 8.0, 4.0 Hz)





8.83 (1H, t, J = 8.0 Hz)


382
CD3OD
400
0.99-1.12 (2H, m), 1.14-1.42 (4H, m),





1.62-1.95 (7H, m), 2.07-2.28 (4H, m), 2.61-2.69 (1H, m),





2.93, 2.97 (3H, 2xs), 3.15-3.29 (3H, m),





3.75-3.89 (1H, m), 4.14-4.19 (1H, m), 4.31-4.37 (2H, m),





4.46 (1H, t, J = 7.7 Hz), 7.03 (1H, d, J = 9.24 Hz)





7.81 (1H, s), 7.92 (1H, dd, J = 9.24, 2.15 Hz)





8.78-8.81 (1H, m)


383
CD3OD
400
0.88-1.08 (6H, m), 1.22-1.50 (5H, m), 1.62 (3H, d,





J = 6.96 Hz), 1.64-1.69 (4H, m), 1.77-1.84 (8H, m),





2.94 (3H, s), 4.03 (1H, dd, J = 6.92, 13.81 Hz),





4.32-4.34 (2H, m), 4.47-4.53 (1H, m), 7.04 (1H, d, J = 9.09 Hz)





7.81 (1H, d, J = 1.05 Hz),





7.92 (1H, dd, J = 2.2, 9.28 Hz), 8.77-8.90 (1H, m)


384
CD3OD
400
0.96-1.08 (2H, m), 1.19-1.36 (4H, m), 1.40 (3H, t, J = 7.3 Hz),





1.61 (3H, d, J = 6.9 Hz), 1.65-1.83 (7H, m),





2.92 (3H, s), 3.22-3.28 (2H, m), 4.05 (1H, q, d, J = 6.9 Hz),





4.28-4.40 (2H, m), 4.46-4.50 (1H, m),





7.04 (1H, d, J = 9.6 Hz), 7.81 (1H, s), 7.93 (1H, dd, J = 9.2,





2.2 Hz), 8.79 (1H, t, J = 5.7 Hz).


385
CD3OD
400
0.99-1.00 (2H, m), 1.07 (6H, t, J = 7.24 Hz),





1.22-1.40 (6H, m), 1.61 (3H, d, J = 6.92 Hz),





1.66-1.87 (10H, m), 3.10-3.19 (2H, m, br),





3.21-3.28 (2H, m), 4.13 (1H, dd, J = 7.37, 13.84 Hz),





4.32 (2H, d, J = 5.72 Hz), 4.49 (1H, dd, J = 6.08, 9.2 Hz),





4.91 (2H, s), 7.04 (1H, d, J = 9.25 Hz) 7.81 (1H, s),





7.93 (1H, dd, J = 2.04, 9.16 Hz), 8.77-8.80 (1H, m)


386
CD3OD
400
0.84-0.95 (2H, m), 1.08-1.29 (4H, m),





1.52-1.70 (7H, m), 2.88 (6H, s), 3.91 (1H, t, J = 4.3 Hz),





3.96-4.04 (2H, m), 4.14-4.24 (2H, m),





4.35-4.39 (1H, m), 6.89 (1H, d, J = 9.1 Hz), 7.66 (1H, d, J = 1.4 Hz),





7.77 (1H, dd, J = 9.2, 2.1 Hz), 8.59 (1H, t, J = 5.8 Hz).


387
CD3OD
400
0.98-1.09 (2H, m), 1.19-1.33 (4H, m), 1.41 (3H, t, J = 7.3 Hz),





1.66-1.80 (7H, m), 3.00 (3H, s),





3.31-3.37 (2H, m), 4.10-4.17 (3H, m), 4.28-4.38 (2H, m),





4.49-4.53 (1H, m), 7.03 (1H, d, J = 9.4 Hz),





7.79 (1H, d, J = 1.2 Hz), 7.91 (1H, dd, J = 9.2, 2.2 Hz),





8.72 (1H, t, J = 5.8 Hz).


388
CD3OD
400
0.99-1.10 (2H, m), 1.21-1.33 (4H, m), 1.39 (3H, d, J = 6.3 Hz),





1.44 (3H, d, J = 6.6 Hz), 1.63-1.84 (7H, m),





2.89 (3H, s), 3.67 (1H, br s), 4.06-4.16 (3H, m),





4.32 (2H, s), 4.51-4.55 (1H, m), 7.03 (1H, d, J = 9.1 Hz),





7.80 (1H, d, J = 1.4 Hz), 7.91 (1H, dd, J = 9.2,





2.1 Hz), 8.71 (1H, t, J = 5.8 Hz).


389
CD3OD
400
0.95-1.10 (2H, m), 1.22-1.33 (4H, m), 1.40 (6H, t, J = 7.3 Hz),





1.63-1.84 (7H, m), 3.33-3.46 (4H, m),





4.07-4.19 (3H, m), 4.32 (2H, s), 4.50-4.54 (1H, m),





7.04 (1H, d, J = 9.0 Hz), 7.79 (1H, d, J = 1.4 Hz),





7.91 (1H, dd, J = 9.2, 2.1 Hz), 8.71 (1H, t, J = 5.8 Hz).


390
CD3OD
400
0.96-1.09 (3H, m), 1.13-1.29 (4H, m), 1.38 (6H, d,





J = 7.32 Hz), 1.60 (3H, d, J = 6.84 Hz),





1.65-1.83 (8H, m), 3.21-3.26 (2H, m),





4.08 (1H, dd, J = 6.92, 13.84 Hz), 4.32-4.38 (2H, m),





4.48-4.58 (1H, m), 4.91 (3H, s), 7.04 (1H, d, J = 9.05 Hz)





7.81 (1H, d, J = 1.05 Hz),





7.92 (1H, dd, J = 2.2, 9.28 Hz), 8.77-8.80 (1H, m)


391
CD3OD
400
0.96-1.08 (3H, m), 1.22-1.40 (5H, m), 1.61 (3H, d,





J = 6.96 Hz), 1.65-1.80 (7H, m), 2.95 (6H, s),





3.95-4.00 (1H, m), 4.32-4.38 (2H, m),





4.48-4.38 (1H, m), 4.46-4.54 (1H, m), 7.04 (1H, d, J = 9.09 Hz)





7.81 (1H, d, J = 1.36 Hz),





7.93 (1H, dd, J = 2.16, 9.28 Hz), 8.77-8.80 (1H, m)


392
CD3OD
400
0.94-1.09 (2H, m), 1.21-1.41 (10H, m),





1.49-1.99 (16H, m), 3.57-3.58 (2H, m, br), 3.91 (2H, s),





4.31-4.37 (2H, m), 4.49-4.51 (1H, m), 7.04 (1H, d,





J = 9.24 Hz) 7.81 (1H, d, J = 1.36 Hz),





7.92 (1H, dd, J = 2.07, 9.16 Hz), 8.82-8.83 (1H, m)


393
CD3OD
400
0.94-1.08 (2H, m), 1.18-1.43 (16H, m),





1.65-1.83 (7H, m), 3.76-3.83 (2H, m), 4.02 (2H, s),





4.26-4.39 (2H, m), 4.47-4.52 (1H, m), 7.04 (1H, d, J = 9.1 Hz),





7.81 (1H, d, J = 1.4 Hz), 7.92 (1H, dd, J = 9.1,





2.1 Hz), 8.77 (1H, d, J = 7.2 Hz), 8.85 (1H, t, J = 5.8 Hz).


394
CD3OD
400
1.13-1.85 (31H, m), 3.77-3.85 (2H, m),





3.97-4.03 (2H, m), 4.26-4.47 (3H, m), 7.03-7.05 (1H, m),





7.81 (1H, s), 7.92 (1H, dd, J = 9.2, 2.0 Hz),





8.71-8.91 (2H, m).


395
CD3OD
400
1.18-1.86 (28H, m), 2.79 (3H, s), 3.56 (1H, s),





4.08-4.13 (1H, m), 4.32 (2H, s), 4.42-4.46 (1H, m),





7.04 (1H, d, J = 9.1 Hz), 7.81 (1H, s), 7.93 (1H, dd, J = 9.2,





2.1 Hz), 8.84-8.91 (1H, m).


396
CD3OD
400
1.15-1.85 (19H, m), 2.04-2.12 (2H, m),





2.22-2.31 (1H, m), 2.63-2.72 (1H, m), 2.96-2.97 (3H, m),





3.25-3.32 (1H, m), 3.75-3.82 (1H, m),





4.19-4.45 (4H, m), 7.05 (1H, d, J = 9.1 Hz), 7.82 (1H, s),





7.91-7.95 (1H, m), 8.84-8.95 (1H, m).


397
CD3OD
400
0.98-1.81 (19H, m), 3.04 (6H, s), 3.10-3.16 (1H, m),





3.41-3.45 (1H, m), 3.91-3.97 (1H, m),





4.07-4.13 (1H, m), 4.18-4.26 (1H, m), 4.39-4.43 (1H, m),





7.04 (1H, d, J = 9.1 Hz), 7.28-7.41 (5H, m),





7.84 (1H, s), 7.91 (1H, dd, J = 9.3, 2.0 Hz),





8.56-8.61 (1H, m) 8.79-8.81 (1H, m).


398
CD3OD
400
0.53 (3H, d, J = 8.0 Hz) 0.62 (4H, t, J = 4.0 Hz)





1.33-1.43 (1H, m) 1.58-1.64 (1H, m) 2.11 (6H,





s) 2.57 (2H, d, J = 8.0 Hz) 2.89-2.97 (1H, m)





3.21 (1H, quintet, J = 4.0 Hz) 4.07 (2H, s)





4.53 (1H, dd, J = 16.0, 4.0 Hz) 4.75 (3H, s) 6.43 (1H,





d, J = 8.0 Hz) 7.00-7.08 (1H, m) 7.20-7.42 (3H,





m) 7.70 (1H, d, J = 8.0 Hz)


399
CD3OD
400
0.88-0.92 (6H, m) 2.31-2.42 (1H, m) 2.93 (6H,





s) 2.98-3.04 (1H, m) 3.11-3.20 (1H, m)





3.65 (1H, d, J = 4.0 Hz) 4.29 (2H, s) 4.63-4.69 (1H,





m) 4.96 (4H, br s) 7.02 (1H, dd, J = 8.0, 4.0 Hz)





7.27 (1H, dd, J = 8.0, 4.0 Hz) 7.35-7.49 (2H, m)





7.74-7.82 (2H, m)


400
CD3OD
400
2.23 (6H, s) 2.28-2.35 (1H, m) 2.48 (1H, dd, J = 8.0,





4.0 Hz) 2.68-2.89 (2H, m) 3.12-3.22 (2H,





m) 4.01-4.08 (2H, m) 4.18 (1H, t, J = 4.0 Hz)





4.75 (3H, s) 6.42 (1H, d, J = 8.0 Hz) 6.75 (1H,





dd, J = 8.0, 4.0 Hz) 7.00-7.09 (6H, m)





7.12-7.16 (2H, m) 7.66 (1H, d, J = 4.0 Hz)


401
CD3OD
400
0.94 (3H, d, J = 6.6 Hz) 0.99 (3H, d, J = 6.6 Hz)





1.17 (3H, d, J = 6.9 Hz) 2.16 (3H, s)





2.68-2.76 (1H, m) 2.78-2.90 (1H, m) 3.04-3.18 (1H, m)





3.36-3.43 (1H, m) 4.00-4.18 (2H, m)





4.56-4.61 (1H, m) 4.83 (4H, br s) 6.48 (1H, d, J = 8.0 Hz)





7.04 (1H, dd, J = 8.0, 4.0 Hz) 7.26 (1H, dd, J = 8.0,





4.0 Hz) 7.30-7.35 (2h, m) 7.73 (1H, d, J = 4.0 Hz)


402
CD3OD
400
1.33 (3H, d, J = 4.0 Hz) 1.37-1.44 (1H, m)





1.72-1.83 (6H, br m) 2.82-2.97 (3H, m)





3.00-3.07 (1H, m) 3.23-3.28 (1H, m) 3.47 (1H, br d, J = 4.0 Hz)





3.78-3.83 (1H, m) 4.07-4.19 (2H, m)





4.50-4.57 (1H, m) 4.81 (3H, br s) 6.87-6.94 (1H,





m) 7.12 (1H, dd, J = 8.0, 4.0 Hz) 7.32-7.38 (2H,





m) 7.61-7.67 (2H, m)


403
CD3OD
400
1.05 (1H, t, J = 8.0 Hz) 1.39 (4H, d, J = 4.0 Hz)





1.45-1.53 (1H, m) 1.69-1.77 (4H, m)





2.57-2.68 (2H, m) 2.76 (2H, s) 2.79-2.87 (2H, m)





2.97-3.07 (1H, m) 3.11-3.23 (2H, m) 3.67-3.78 (1H,





m) 4.04-4.18 (2H, m) 4.59-4.65 (1H, m)





6.86 (1H, d, J = 12.0 Hz) 7.07-7.77 (1H, m)





7.29-7.33 (2H, m) 7.62-7.66 (2H, m)


404
CD3OD
400
1.47-1.57 (1H, br m) 1.85-2.04 (5H, br m)





2.82-3.10 (3H, m) 3.16-3.22 (1H, m) 3.36-3.37 (1H,





m) 3.65 (1H, d, J = 4.0 Hz) 3.83-3.91 (2H, m)





4.20-4.32 (2H, m) 4.65-4.71 (1H, m) 4.99 (4H,





br s) 7.01 (1H, dd, J = 8.0, 4.0 Hz) 7.22 (1H, dd,





J = 8.0, 4.0 Hz) 7.44-7.48 (2H, m)





7.77-7.82 (2H, m)


405
CD3OD
400
0.55-0.66 (1H, m) 0.74-0.94 (6H, m)





1.07-1.18 (1H, m) 1.87-1.97 (1H, m) 2.77 (6H, s)





2.81-2.91 (1H, m) 3.13 (1H, dd, J = 8.0, 4.0 Hz)





3.22-3.23 (1H, m) 3.56 (1H, d, J = 4.0 Hz)





4.13-4.34 (2H, m) 4.50-4.60 (1H, m) 4.81 (3H, s)





6.94 (1H, d, J = 4.0 Hz) 7.11-7.24 (4H, m) 7.66 (1H,





s) 8.66-8.80 (1H, m)


406
CD3OD
400
0.87-0.90 (7H, m) 2.34-2.41 (1H, m) 2.93 (7H,





s) 3.00-3.03 (1H, m) 3.17-3.24 (1H, m)





3.69 (1H, d, J = 4.0 Hz) 4.22-4.31 (2H, m)





4.66-4.71 (1H, m) 4.98 (2H, br s) 7.02 (1H, d, J = 8.0 Hz)





7.21-7.39 (4H, m) 7.78 (1H, S) 7.83 (1H, dd, J = 8.0,





4.0 Hz)


407
CD3OD
400
2.55-2.58 (1H, m) 2.74-2.80 (1H, m) 3.03 (6H,





s) 3.08-3.14 (1H, m) 3.31-3.46 (1H, m)





4.07-4.11 (1H, m) 4.21-4.29 (2H, m) 4.33 (1H, t, J = 8.0 Hz)





4.93 (4H, br s) 6.91-7.00 (2H, m)





7.06 (1H, s) 7.15-7.25 (4H, m) 7.27-7.34 (3H, m)





7.70-7.73 (2H, m)


408
CD3OD
400
1.12 (3H, t, J = 7.0 Hz), 1.40 (3H, d, J = 6.9 Hz),





2.63 (3H, s), 2.80-3.05 (5H, m), 3.73-3.78 (1H, m),





4.00-4.20 (2H, m), 4.58-4.62 (1H, m),





6.84 (1H, d, J = 9.1 Hz), 7.08-7.18 (4H, m),





7.59 (1H, s), 7.62 (1H, dd, J = 9.2, 2.0 Hz),





8.60 (1H, t, J = 5.7 Hz).


409
CD3OD
400
0.97 (2H, d, J = 3.1 Hz), 1.11 (3H, d, J = 6.6 Hz),





1.20-1.22 (1H, m), 1.38 (3H, d, J = 6.6 Hz),





2.52 (3H, s), 2.73-2.84 (2H, m), 3.04-3.08 (1H, m),





3.78-3.83 (1H, m), 4.08-4.21 (2H, m),





6.86 (1H, d, J = 9.2 Hz), 7.09-7.19 (4H, m),





7.60 (1H, s), 7.62 (1H, d, J = 8.9 Hz), 8.64 (1H, t, J = 5.7 Hz).


410
CD3OD
400
1.11-1.18 (6H, m), 1.39 (3H, d, J = 7.0 Hz),





2.66-2.71 (1H, m), 2.80-3.05 (5H, m), 3.77-3.83 (1H, m),





4.04-4.20 (2H, m), 4.59-4.63 (1H, m),





6.85 (1H, d, J = 9.6 Hz), 7.08-7.19 (4H, m),





7.59 (1H, d, J = 1.0 Hz), 7.63 (1H, dd, J = 9.2, 2.1 Hz),





8.61 (1H, t, J = 5.7 Hz).


411
CD3OD
400
1.32-1.38 (1H, m) 1.43 (2H, d, J = 8.0 Hz)





1.55 (3H, d, J = 8.0 Hz) 1.79-1.84 (3H, m)





1.93-2.00 (2H, m) 2.78-2.87 (1H, m) 2.93-3.04 (2H, m)





3.12-3.27 (2H, m) 3.54-3.64 (1H, m)





3.85-3.94 (1H, m) 4.22-4.34 (2H, m) 4.65-4.69 (1H, m)





4.77-4.82 (1H, m) 7.01 (1H, dd, J = 8.0, 4.0 Hz)





7.21-7.39 (5H, m) 7.76 (1H, d, J = 4.0 Hz)





7.79-7.87 (1H, m)


412
CD3OD
400
1.40-1.67 (1H, br m) 1.88-1.91 (5H, m)





2.93-3.01 (3H, m) 3.19-3.26 (1H, m) 3.34-3.37 (1H,





m) 3.42-3.44 (1H, m) 3.52 (1H, d, J = 12.0 Hz)





3.86-3.99 (2H, m) 4.26 (2H, q, J = 8.0 Hz)





4.74 (1H, dd, J = 8.0, 4.0 Hz) 5.01 (3H, br s)





6.98 (1H, d, J = 8.0 Hz) 7.22-7.33 (4H, m) 7.67 (1H,





s) 7.78 (1H, dd, J = 8.0, 4.0 Hz)


413
CD3OD
400
1.25 (3H, s), 1.56 (3H, d, J = 7.0 Hz), 2.35 (3H, s),





2.76 (5H, s), 2.92-2.97 (1H, m), 3.14-3.19 (1H, m),





3.88-3.93 (1H, m), 4.21-4.35 (2H, m),





4.75-4.79 (1H, m), 6.99 (1H, d, J = 9.3 Hz),





7.08-7.13 (3H, m), 7.19-7.23 (1H, m), 7.72 (1H, s),





7.62 (1H, dd, J = 9.2, 1.9 Hz), 8.74 (1H, t, J = 5.7 Hz).


414
CD3OD
400
0.91 (2H, s), 1.07 (3H, d, J = 6.4 Hz),





1.20-1.22 (1H, m), 1.37 (3H, d, J = 6.5 Hz), 2.19 (3H, s),





2.50 (3H, s), 2.62 (1H, s), 2.72-2.78 (1H, m),





3.00-3.05 (1H, m), 3.75-3.80 (1H, m), 4.07-4.20 (2H, m),





6.84 (1H, d, J = 9.2 Hz), 6.92-6.98 (3H, m),





7.03-7.07 (1H, m), 7.58 (1H, s), 7.63 (1H, d, J = 8.7 Hz),





8.61 (1H, t, J = 5.7 Hz).


415
CD3OD
400
1.05-1.09 (6H, m), 1.38 (3H, d, J = 6.8 Hz),





2.18 (3H, s), 2.58-2.67 (1H, m), 2.74-3.02 (5H, m),





3.77 (1H, q, J = 6.9 Hz), 4.04-4.20 (2H, m),





4.61-4.65 (1H, m), 6.83 (1H, d, J = 9.2 Hz),





6.91-6.97 (3H, m), 7.01-7.06 (1H, m), 7.56 (1H, s),





7.59 (1H, dd, J = 9.1, 2.1 Hz), 8.58 (1H, t, J = 5.8 Hz).


416
CD3OD
400
1.08 (3H, br s), 1.40 (3H, d, J = 7.0 Hz), 2.63 (6H, br





s), 2.91-2.96 (1H, m), 3.11-3.16 (1H, m),





3.76 (1H, q, J = 6.6 Hz), 4.12 (2H, s),





4.62-4.66 (1H, m), 6.84 (1H, d, J = 9.1 Hz),





7.36-7.48 (4H, m), 7.59 (1H, d, J = 1.1 Hz), 7.64 (1H, dd, J = 9.2,





2.1 Hz), 8.64 (1H, t, J = 5.7 Hz).


417
CD3OD
400
1.08 (3H, br s), 1.25 (3H, d, J = 6.6 Hz),





1.35-1.42 (1H, m), 1.55 (3H, d, J = 6.8 Hz), 2.67 (3H, s),





2.88 (1H, s), 3.05-3.11 (1H, m), 3.30-3.35 (1H, m),





3.96 (1H, q, J = 6.8 Hz), 4.31 (2H, s), 7.02 (1H, d, J = 9.2 Hz),





7.53-7.67 (4H, m), 7.78 (1H, s),





7.84 (1H, d, J = 9.1 Hz), 8.83 (1H, t, J = 5.6 Hz).


418
CD3OD
400
1.22-1.30 (6H, m), 1.56 (3H, d, J = 6.9 Hz),





2.78-2.83 (1H, m), 3.06-3.33 (5H, m), 3.95 (1H, q, J = 6.9 Hz),





4.25-4.34 (2H, m), 4.81-4.85 (1H, m),





7.01 (1H, d, J = 9.5 Hz), 7.53-7.65 (4H, m),





7.77 (1H, d, J = 1.4 Hz), 7.81 (1H, dd, J = 9.2, 2.1 Hz),





8.81 (1H, t, J = 5.6 Hz),.


419
CD3OD
400
1.37-1.40 (2H, m) 1.55 (2H, d, J = 8.0 Hz)





1.62-1.94 (5H, m) 2.70-2.85 (1H, m) 2.91-2.99 (2H,





m) 3.03-3.20 (2H, m) 3.28-3.42 (2H, m)





3.50-3.59 (1H, m) 3.83-3.88 (1H, m) 3.92-3.99 (1H,





m) 4.20-4.33 (2H, m) 4.71-4.78 (1H, m)





4.84-4.89 (1H, m) 7.01 (1H, d, J = 8.0 Hz)





7.51-7.72 (4H, m) 7.77 (1H, s) 7.83 (1H, dd, J = 8.0, 4.0 Hz)


420
CD3OD
400
1.55 (1H, br s) 1.87 (5H, br s) 2.93-3.11 (3H, m)





3.28-3.37 (2H, m) 3.50 (1H, br s) 3.85-3.99 (2H,





m) 4.24-4.32 (2H, m) 4.75-4.81 (1H, m)





5.00 (5H, br, s) 7.00 (1H, d, J = 8.0 Hz)





7.50-7.62 (3H, m) 7.75-7.86 (2H, m)


421
CD3OD
400
1.41 (2H, d, J = 8.0 Hz) 1.56 (1H, br t, J = 4.0 Hz)





1.88 (5H, br s) 2.92-3.13 (3H, m)





3.25-3.30 (1H, m) 3.36-3.57 (3H, m) 3.83-3.97 (1H, m)





4.22-4.41 (2H, m) 4.71-4.78 (1H, m)





4.91-4.96 (4H, m) 6.99-7.04 (1H, m) 7.49 (2H, d, J = 8.0 Hz)





7.63 (2H, d, J = 8.0 Hz) 7.79-7.82 (2H, m)


422
CD3OD
400
1.32-1.42 (1H, m) 1.56 (3H, d, J = 8.0 Hz)





1.72-1.92 (5H, m) 2.86-2.97 (3H, m) 3.04-3.14 (1H,





m) 3.25-3.46 (2H, m) 3.56 (1H, br s)





3.79-3.84 (1H, m) 4.22-4.35 (2H, m) 4.82-4.96 (4H, m)





6.99-7.06 (1H, m) 7.48-7.55 (2H, m) 7.64 (2H,





d, J = 8.0 Hz) 7.79-7.84 (2H, m)


423
CD3OD
400
1.36-1.57 (1H, m) 1.87 (5H, br s) 2.93-3.09 (3H,





m) 3.20-3.37 (2H, m) 3.39 (1H, br s)





3.82-3.98 (2H, m) 4.27-4.31 (2H, m) 4.74-4.78 (1H, m)





4.94 (4H, br s) 7.00 (1H, d, J = 8.0 Hz)





7.50-7.57 (2H, m) 7.61-7.68 (2H, m) 7.78-7.83 (2H,





m)


424
CD3OD
400
0.71-0.81 (1H, m) 0.85-0.93 (6H, m)





1.21-1.44 (1H, m) 2.04-2.11 (1H, m) 2.98 (6H, s)





3.01-3.08 (1H, m) 3.19-3.27 (1H, m) 3.78 (1H, d, J = 4.0 Hz)





4.31-4.39 (2H, m) 4.65-4.69 (1H, m)





5.00 (3H, br s) 6.84-6.89 (1H, m) 6.99 (2H, d, J = 4.0 Hz)





7.05 (1H, d, J = 12.0 Hz) 73.82 (1H, s)





7.88 (1H, dd, J = 8.0, 4.0 Hz) 9.01 (1H, d, J = 4.0 Hz)


425
CD3OD
400
1.45 (2H, d, J = 8.0 Hz) 1.57 (2H, d, J = 8.0 Hz)





1.86 (3H, br s) 1.95 (1H, d, J = 8.0 Hz)





2.84-2.93 (1H, m) 3.00-3.06 (1H, m) 3.14-3.27 (1H,





m) 3.35-3.37 (1H, m) 3.60 (1H, br s)





3.87-3.96 (1H, m) 4.23-4.35 (2H, m) 4.61-4.71 (1H, m)





4.73-4.81 (1H, m) 4.97 (5H, s) 6.84-6.97 (3H,





m) 6.98-7.08 (1H, m) 7.78-7.81 (1H, m)





7.85-7.94 (1H, m)


426
CD3OD
400
1.05 (2H, d, J = 8.0 Hz) 1.24 (3H, d, J = 8.0 Hz)





1.32 (1H, d, J = 4.0 Hz) 1.49-1.72 (6H, br m)





2.95-3.01 (1H, m) 3.15-3.21 (1H, m) 3.26 (1H,





d, J = 6.4 Hz) 3.36-3.37 (2H, m) 3.75-3.87 (2H,





m) 4.14-4.28 (2H, m) 4.71-4.77 (1H, m)





4.98 (2H, s) 7.01 (1H, d, J = 8.0 Hz) 7.21-7.31 (4H,





m) 7.75-7.83 (2H, m) 8.79-8.89 (1H, m)


427
CD3OD
400
1.01 (6H, dd, J = 6.24, 14.0 Hz), 1.34 (3H, s, br),





1.43 (3H, s, br), 1.60 (3H, d, J = J = 6.83 Hz),





1.64-1.75 (4H, m), 2.79 (3H, s), 3.57 (1H, s, br),





4.10 = 4.12 (1H, m), 4.26-4.46 (3H, m), 4.91 (2H, s),





7.04 (1H, d, J = 8.17 Hz) 7.80 (1H, d, J = 1.4 Hz),





7.92 (1H, dd, J = 2.2, 9.28 Hz), 8.79-8.82 (1H, m)


428
CD3OD
400
1.19-1.21 (6H, br m) 2.50 (3H, s) 2.95-3.05 (1H,





m) 3.11-3.27 (5H, m) 3.33-3.36 (1H, m)





3.89-4.09 (2H, m) 4.19-4.30 (2H, m) 4.68 (1H, t, J = 4.0 Hz)





4.94 (2H, br s) 6.82 (1H, d, J = 8.0 Hz)





7.00-7.05 (2H, m) 7.25-7.33 (2H, m) 7.72 (1H,





d, J = 8.0 Hz) 8.70 (1H, t, J = 4.0 Hz)


429
CD3OD
400
0.99 (2H, d, J = 4.0 Hz) 1.24 (3H, d, J = 4.0 Hz)





1.33 (1H, d, J = 4.0 Hz) 1.47-1.59 (2H, m)





1.62-1.74 (2H, m) 1.78-1.93 (3H, m) 2.52 (3H, s)





2.92-3.01 (1H, m) 3.15-3.19 (1H, m) 3.53 (2H, t,





J = 4.0 Hz) 3.79-3.92 (2H, m) 4.02-4.22 (1H, m)





4.26-4.32 (2H, m) 4.71 (1H, t, J = 8.0 Hz)





6.83 (1H, d, J = 8.0 Hz) 7.03-7.09 (1H, m)





7.12-7.27 (2H, m) 7.76 (2H, d, J = 8.0 Hz) 8.76 (1H, t, J = 4.0 Hz)


430
CD3OD
400
1.58 (1H, br s) 1.88-1.91 (6H, br m) 2.51 (3H, s)





2.91-3.03 (3H, m) 3.10-3.13 (1H, m)





3.37-3.42 (1H, m) 3.51-3.53 (1H, br d, J = 8.0 Hz)





3.89-3.99 (2H, m) 4.17-4.31 (2H, m) 4.66 (1H, dd, J = 8.0,





4.0 Hz) 4.96 (2H, br s) 6.82 (1H, d, J = 8.0 Hz)





7.01-7.08 (2H, m) 7.14-7.24 (2H, m)





7.75 (1H, d, J = 12.0 Hz)


434
CD3OD
400
1.02-1.47 (12H, m), 1.58-1.77 (17H, m),





2.94 (6H, s), 4.06 (1H, q, J = 6.89 Hz),





4.22-4.27 (1H, m), 4.34-4.40 (1H, m),





4.65 (1H, d, J = 7.6 Hz), 7.04 (1H, d, J = 9.1 Hz),





7.85 (1H, d, J = 1.5 Hz), 7.97 (1H, dd, J = 2.1, 9.2 Hz),





8.77-8.80 (1H, m).


435
CD3OD
400
1.07-1.51 (17H, m), 1.64 (3H, d, J = 6.89 Hz),





1.73-1.84 (3H, m), 2.08 (1H, d, J = 11.08 Hz), 2.79 (3H, s),





3.73-3.77 (2H, m), 4.22-4.27 (1H, m),





4.33-4.41 (2H, m), 4.60 (1H, d, J = 3 Hz), 7.04 (1H, d, J = 9.25 Hz),





7.82 (1H, d, J = 1.68 Hz), 7.95 (1H, dd, J = 6.0,





2.08 Hz), 8.71-8.79 (1H, m).


436
CD3OD
400
0.98-1.19 (3H, m), 1.24-1.44 (14H, m),





1.62 (3H, d, J = 6.8 Hz), 1.73-1.92 (3H, m),





2.10 (1H, d, J = 13.21 Hz), 2.78 (3H, s),





3.76 (2H, dd, J = 3.04 Hz, 8.24 Hz),





4.26-4.33 (1H, m), 4.37 (2H, d, J = 2.6 Hz), 4.60 (1H, d,





J = 3 Hz), 7.04 (1H, d, J = 9.05 Hz), 7.82 (1H, d, J = 1.12 Hz),





7.95 (1H, dd, J = 9.17, 2.08 Hz),





8.71-8.79 (1H, m).


437
CD3OD
400
0.97-1.51 (14H, m), 1.58 (3H, d, J = 6.65 Hz),





1.73-1.95 (8H, m), 2.79 (3H, s), 3.13 (3H, s),





4.26-4.37 (2H, m), 4.59-4.73 (1H, m), 5.17-5.21 (1H, m),





7.04 (1H, d, J = 7.36 Hz) 7.79 (1H, d, J = 1.1 Hz),





7.92 (1H, d, J = 7.84 Hz), 7.93 (1H, dd, J = 9.2, 2.08 Hz)





8.58-8.87 (1H, m)


438
CD3OD
400
0.97-1.33 (7H, m), 1.38 (6H, t, J = 7.2 Hz),





1.58 (3H, d, J = 6.81 Hz), 1.72-1.96 (8H, m),





3.12 (3H, s), 4.25-4.36 (2H, m),





4.51 (1H, dd, J = 7.0, 13.49 Hz), 4.91 (4H, s),





5.20-5.24 (1H, m), 7.04 (1H, d, J = 9.13 Hz)





7.791 (1H, d, J = 1.2 Hz), 7.92 (1H, dd, J = 2.12,





9.21 Hz), 8.58-8.78 (1H, m)


439
CD3OD
400
0.99-1.00 (2H, m), 1.07 (6H, t, J = 7.24 Hz),





1.22-1.40 (6H, m), 1.61 (3H, d, J = 6.92 Hz),





1.66-1.87 (10H, m), 3.10-3.19 (2H, m, br),





3.21-3.28 (2H, m), 4.13 (1H, dd, J = 7.37, 13.84 Hz),





4.32 (2H, d, J = 5.72 Hz), 4.49 (1H, dd, J = 6.08, 9.2 Hz),





4.91 (2H, s), 7.04 (1H, d, J = 9.25 Hz) 7.81 (1H, s),





7.93 (1H, dd, J = 2.04, 9.16 Hz), 8.77-8.80 (1H, m)
















TABLE 15







Names of the examples.








Example No.
Name











12
(S)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide


13
(R)-2-Amino-N-[(S)-1-[(6-amino-pyridin-3-ylmethyl)carbamoyl]-2-



(decahydro-naphthalen-1-yl)-ethyl]-3-(4-chloro-phenyl)-propionamide


14
(R)-2-Amino-N-[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-



(decahydro-naphthalen-1-yl)-ethyl]-3-methyl-butyramide


15
(R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide


16
(R)-2-Amino-4-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide


17
(S)-2-(2-Amino-acetylamino)-N-(6-amino-pyridin-3-ylmethyl)-3-



(decahydro-naphthalen-1-yl)-propionamide


18
(R)-2-Amino-N-[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-



(decahydro-naphthalen-1-yl)-ethyl]-propionamide


19
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(decahydro-naphthalen-1-yl)-2-



(2-methylamino-acetylamino)-propionamide


20
(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide


21
(R)-3-Methyl-2-methylamino-pentanoic acid {(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide


22
(R)-2-Amino-N-{(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-



naphthalen-1-yl-ethyl}-3-methyl-butyramide


23
(R)-Pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


24
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide


25
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-amide


26
(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-phenyl-ethyl}-amide


27
(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide


28
(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-o-tolyl-ethyl}-amide


29
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide


30
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide


31
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-cyano-phenyl)-ethyl]-amide


32
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



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


33
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


34
(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-naphthalen-2-yl-ethyl}-amide


35
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


36
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide


37
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-amide


38
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide


39
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



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


40
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide


41
(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide


42
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide


43
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-



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


44
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


45
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


46
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide


47
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-amide


48
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide


49
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-



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


50
(R)-3-Methyl-2-methylamino-pentanoic acid {(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-pentafluorophenyl-ethyl}-amide


51
(R)-3-Methyl-2-methylamino-pentanoic acid {(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide


52
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(4-tert-butyl-phenyl)-ethyl]-amide


53
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-



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


54
(R)-2-Amino-N-[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-



(3,4-dichloro-phenyl)-ethyl]-3-phenyl-propionamide


55
(R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


56
(S)-Thiazolidine-4-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


57
(S)-2-((R)-2-Amino-2-phenyl-acetylamino)-N-(6-amino-pyridin-3-



ylmethyl)-3-(3,4-dichloro-phenyl)-propionamide


58
(S)-2-((S)-2-Amino-2-phenyl-acetylamino)-N-(6-amino-pyridin-3-



ylmethyl)-3-(3,4-dichloro-phenyl)-propionamide


59
(R)-2-Amino-N-[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-



(3,4-dichloro-phenyl)-ethyl]-3-(4-chloro-phenyl)-propionamide


60
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



dichloro-phenyl)-ethyl]-2-methylamino-3-phenyl-propionamide


61
(R)-2-Amino-N-[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-



(3,4-dichloro-phenyl)-ethyl]-3,3-dimethyl-butyramide


62
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



dichloro-phenyl)-ethyl]-2-methylamino-propionamide


63
(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


64
(R)-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


65
(R)-2,5-Dihydro-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


66
(R)-4,4-Difluoro-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


67
(R)-2-Amino-N-[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-



(3,4-dichloro-phenyl)-ethyl]-4-phenyl-butyramide


68
(R)-2-Amino-N-[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-



(3,4-dichloro-phenyl)-ethyl]-3-cyclohexyl-propionamide


69
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-2-(2-



methylamino-acetylamino)-propionamide


70
(R)-2-Amino-N-[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-



trifluoromethyl-phenyl)-ethyl]-3-(4-chloro-phenyl)-propionamide


71
(R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


72
(R)-Pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide


73
(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


74
(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide


75
(R)-Piperidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-naphthalen-1-ylethyl}-



amide


76
(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide


77
(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


78
(R)-Piperidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide


79
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-



methylamino-acetylamino)-propionamide


80
(R)-2-Amino-N-[(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-



(3,4-difluoro-phenyl)-ethyl]-3-phenyl-propionamide


81
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)carbamoyl]-2-(3,4-difluoro-



phenyl)-ethyl]-2-methylamino-3-phenyl-propionamide


82
(S)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



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


83
(S)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-



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


84
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-methylamino-propionamide


85
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-methylamino-propionamide


86
N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-



phenyl)-ethyl]-2-methyl-2-methylamino-propionamide


87
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-methylamino-propionamide


88
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-methylamino-propionamide


89
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-3-methyl-2-methylamino-butyramide


90
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


91
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide


92
(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


93
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide


94
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide


95
(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide


96
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


97
(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-pentafluorophenyl-ethyl}-amide


98
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


99
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide


100
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-methoxy-phenyl)-ethyl]-amide


101
(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-phenyl-ethyl}-amide


102
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-tert-butyl-phenyl)-ethyl]-amide


103
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


104
(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-o-tolyl-ethyl}-amide


105
(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide


106
(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-p-tolyl-ethyl}-amide


107
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-methoxy-phenyl)-ethyl]-amide


108
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2-fluoro-phenyl)-ethyl]-amide


109
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide


110
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2,4-dichloro-phenyl)-ethyl]-amide


111
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-amide


112
(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-pyridin-4-yl-ethyl}-amide


113
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide


114
(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-quinolin-2-yl-ethyl}-amide


115
(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide


116
(S)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


117
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


118
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


119
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


120
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


121
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-o-tolyl-ethyl}-amide


122
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide


123
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-p-tolyl-ethyl}-amide


124
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(3-methoxy-phenyl)-ethyl]-amide


125
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(2-fluoro-phenyl)-ethyl]-amide


126
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide


127
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(2,4-dichloro-phenyl)-ethyl]-amide


128
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-amide


129
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-pyridin-4-yl-ethyl}-amide


130
(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide


131
(R)-1-Ethyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


132
(R)-1-Propyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


133
(R)-1-Isobutyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


134
{(R)-2-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethylcarbamoyl]-pyrrolidin-1-yl}-acetic acid methyl



ester


135
{(R)-2-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethylcarbamoyl]-pyrrolidin-1-yl}-acetic acid


136
(R)-1-Ethyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


137
(R)-1-Ethyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide


138
(R)-1-Ethyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


139
(R)-1-Propyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


140
(R)-1-Benzyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


141
(R)-1-Benzyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


142
(R)-1-(4-Chloro-benzyl)-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide


143
(R)-1-(3-Chloro-benzyl)-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide


144
(R)-1-Methyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


145
(R)-1-Methyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


146
(R)-1-Isopropyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



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


147
(R)-1-Isopropyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


148
(2R,4R)-4-Hydroxy-1-methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-



amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-



amide


149
(R)-2-Methyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid [(S)-1-



[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-



ethyl]-amide


150
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-2-[2-



(isopropyl-methyl-amino)-acetylamino]-propionamide


151
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



dichloro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide


152
(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-[2-(benzyl-methyl-amino)-



acetylamino]-3-(3,4-dichloro-phenyl)-propionamide


153
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-2-(2-



dimethylamino-acetylamino)-propionamide


154
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-2-[2-



(isobutyl-methyl-amino)-acetylamino]-propionamide


155
(R)-2-(Isopropyl-methyl-amino)-3-methyl-pentanoic acid [(S)-1-[(6-



amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-



amide


156
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-[2-



(isopropyl-methyl-amino)-acetylamino]-propionamide


157
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-



diisopropylamino-acetylamino)-propionamide


158
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-



dipropylamino-acetylamino)-propionamide


159
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-



diisobutylamino-acetylamino)-propionamide


160
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-



phenethylamino-acetylamino)-propionamide


161
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-[2-



(methyl-phenethyl-amino)-acetylamino]-propionamide


162
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-{2-



[methyl-((E)-3-phenyl-allyl)-amino]-acetylamino}-propionamide


163
(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-{2-[(4-chloro-benzyl)-methyl-



amino]-acetylamino}-3-(3,4-difluoro-phenyl)-propionamide


164
(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-{2-[(3-chloro-benzyl)-methyl-



amino]-acetylamino}-3-(3,4-difluoro-phenyl)-propionamide


165
(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-{2-[(2-chloro-benzyl)-methyl-



amino]-acetylamino}-3-(3,4-difluoro-phenyl)-propionamide


166
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-{2-[(4-



methoxy-benzyl)-methyl-amino]-acetylamino}-propionamide


167
(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-[2-(butyl-methyl-amino)-



acetylamino]-3-(3,4-difluoro-phenyl)-propionamide


168
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-[2-



(isobutyl-methyl-amino)-acetylamino]-propionamide


169
(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-[2-(cyclohexylmethyl-methyl-



amino)-acetylamino]-3-(3,4-difluoro-phenyl)-propionamide


170
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-



piperidin-1-yl-acetylamino)-propionamide


171
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-



morpholin-4-yl-acetylamino)-propionamide


172
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-3,4-



dihydro-1H-isoquinolin-2-yl-acetylamino)-propionamide


173
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-3,4-



dihydro-2H-quinolin-1-yl-acetylamino)-propionamide


174
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-[2-



(methyl-phenyl-amino)-acetylamino]-propionamide


175
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide


176
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide


177
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-(isobutyl-methyl-amino)-propionamide


178
(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide


179
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-dimethylamino-3,3-dimethyl-butyramide


180
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide


181
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide


182
(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


183
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-dimethylamino-3,3-dimethyl-butyramide


184
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-isopropylamino-3-phenyl-propionamide


185
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-dimethylamino-3-phenyl-propionamide


186
(R)-2-Amino-N-[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-



carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-3-methyl-butyramide


187
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-



amide


188
(2R)-3-Methyl-2-methylamino-pentanoic acid [(R)-1-[(6-amino-2-



methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-



amide


189
(R)-Pyrrolidine-2-carboxylic acid [(R)-1-[(6-amino-2-methyl-pyridin-3-



ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


190
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(R)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


191
(S)-Thiazolidine-4-carboxylic acid [(R)-1-[(6-amino-2-methyl-pyridin-



3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


192
(R)-4,4-Difluoro-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2-



methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-



amide


193
(S)—N-[(R)-1-[(6-Amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-



(3,4-dichloro-phenyl)-ethyl]-2-methylamino-3-phenyl-propionamide


194
(R)-2-Amino-N-[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-



carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-



propionamide


195
(R)-2-Amino-N-[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-



carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-(4-chloro-phenyl)-



propionamide


196
(R)-2-Amino-N-[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-



carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3-pyridin-3-yl-propionamide


197
(R)—N-(6-Amino-2-methyl-pyridin-3-ylmethyl)-2-((S)-2-amino-2-



phenyl-acetylamino)-3-(3,4-dichloro-phenyl)-propionamide


198
(S)-2-((R)-2-Amino-2-cyclohexyl-acetylamino)-N-(6-amino-2-methyl-



pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-propionamide


199
(R)-2-Amino-N-[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-



carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-3,3-dimethyl-butyramide


200
(R)-2-Amino-N-[(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-



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


201
(R)-Piperidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-



ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


202
(R)-1,2,3,4-Tetrahydro-quinoline-2-carboxylic acid [(S)-1-[(6-amino-2-



methyl-pyridin-3-ylmethyl)-carbamoyl]-



2-(3,4-dichloro-phenyl)-ethyl]-amide


203
(R)-3-Methyl-2-methylamino-pentanoic acid {(S)-1-[(6-amino-2-



methyl-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


204
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


205
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide


206
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2,4-



dimethyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-



ethyl]-amide


207
(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-2,4-



dimethyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-



ethyl]-amide


208
(R)-2-Amino-3-methyl-pentanoic acid [(S)-1-[(6-amino-2,4-dimethyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-



amide


209
(R)-2-Amino-3-methyl-pentanoic acid {(S)-1-[(6-amino-5-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


210
(R)-1-Methanesulfonyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


211
(R)-2-Methanesulfonylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


212
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



dichloro-phenyl)-ethyl]-2-(methanesulfonyl-methyl-amino)-



propionamide


213
(R)-2-(Methanesulfonyl-methyl-amino)-3-methyl-pentanoic acid {(S)-1-



[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-



ethyl}-amide


214
(R)-2-Amino-3-methyl-pentanoic acid {(R)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide


215
(S)-Pyrrolidine-2-carboxylic acid {(R)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2,2-dicyclohexyl-ethyl}-amide


216
(S)-2-Amino-N-{(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-



dicyclohexyl-ethyl}-3-phenyl-propionamide


217
(S)-2-Amino-N-{(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-



dicyclohexyl-ethyl}-3,3-dimethyl-butyramide


218
(S)—N-{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-



dicyclohexyl-ethyl}-2-methylamino-propionamide


219
(S)-3-Methyl-2-methylamino-pentanoic acid {(R)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide


220
(R)-2-(2-Amino-acetylamino)-N-(6-amino-pyridin-3-ylmethyl)-3,3-



dicyclohexyl-propionamide


221
(R)—N-(6-Amino-pyridin-3-ylmethyl)-3,3-dicyclohexyl-2-(2-



methylamino-acetylamino)-propionamide


222
(R)—N-(6-Amino-pyridin-3-ylmethyl)-3,3-dicyclohexyl-2-(2-



dimethylamino-acetylamino)-propionamide


223
(S)-1-Methyl-pyrrolidine-2-carboxylic acid {(R)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide


224
(S)-2-Amino-3-methyl-pentanoic acid {(1R,2R)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-hydroxy-2-phenyl-ethyl}-amide


225
(R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-phenyl-ethyl}-methyl-amide


227
1H-Pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide


228
1H-Pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


229
1H-Pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide


230
3,4,5-Trimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide


231
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


232
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide


233
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


234
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide


235
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


236
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide


237
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-phenyl-ethyl}-amide


238
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide


239
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide


240
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-amide


241
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide


242
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


243
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


244
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-o-tolyl-ethyl}-amide


245
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide


246
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide


247
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-amide


248
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide


249
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


250
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide


251
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-pentafluorophenyl-ethyl}-amide


252
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-biphenyl-4-yl-ethyl}-amide


253
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-p-tolyl-ethyl}-amide


254
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-methoxy-phenyl)-ethyl]-amide


255
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide


256
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-tert-butyl-phenyl)-ethyl]-amide


257
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-quinolin-2-yl-ethyl}-amide


258
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-trifluoromethyl-phenyl)-ethyl]-amide


259
4-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


260
4-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


261
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


262
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide


263
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2,5-dichloro-phenyl)-ethyl]-amide


264
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


265
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2-fluoro-phenyl)-ethyl]-amide


266
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


267
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-chloro-phenyl)-ethyl]-amide


268
3-Methyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide


269
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide


270
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


271
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide


272
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-trifluoromethyl-phenyl)-ethyl]-amide


273
3-Methyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide


274
5-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-



trifluoromethyl-phenyl)-ethylcarbamoyl]-1H-pyrrole-2-carboxylic acid



methyl ester


275
5-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-



trifluoromethyl-phenyl)-ethylcarbamoyl]-1H-pyrrole-2-carboxylic acid


276
5-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-



trifluoromethyl-phenyl)-ethylcarbamoyl]-4-methyl-1H-pyrrole-2-



carboxylic acid


277
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-



amide


278
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


279
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


280
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


281
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide


282
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-



amide


283
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide


284
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide


285
3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


286
3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide


287
1H-Imidazole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


288
1H-Imidazole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide


289
1H-Imidazole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


290
1-Methyl-1H-imidazole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


291
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


292
5-p-Tolyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


293
5-p-Tolyl-1H-pyrrole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide


294
5-p-Tolyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


295
5-p-Tolyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(2-chloro-phenyl)-ethyl]-amide


296
5-p-Tolyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


297
5-p-Tolyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


298
1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


299
1H-Benzoimidazole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


300
5-Methoxy-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


301
5-Fluoro-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


302
5-Hydroxy-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


303
1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-pyridin-3-



ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


304
5-Methoxy-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


305
5-Fluoro-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


306
1-Methyl-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide


307
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide


308
5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide


309
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide


310
5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-



amide


311
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide


312
5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide


313
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


314
5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


315
1H-Indole-2-carboxylic acid [(R)-1-[(6-amino-2-methyl-pyridin-3-



ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


316
5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


317
1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-m-tolyl-ethyl}-amide


318
5-Methoxy-1H-indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide


319
1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-2-methyl-pyridin-3-



ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-amide


320
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-



ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


321
5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


322
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-



ylmethyl)-carbamoyl]-2-(2-trifluoromethyl-phenyl)-ethyl]-amide


323
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-amide


324
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide


325
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide


326
5-Fluoro-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


327
5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


328
1H-Benzoimidazole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



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


329
1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-pentafluorophenyl-ethyl}-amide


330
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


331
5-Fluoro-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


332
5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


333
1H-Benzoimidazole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide


334
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-(4-methoxy-phenyl)-ethyl]-amide


335
1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-benzo[b]thiophen-3-yl-ethyl}-amide


336
1H-Indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-



ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide


337
5-Methoxy-1H-indole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-



pyridin-3-ylmethyl)-carbamoyl]-2-(1H-indol-3-yl)-ethyl]-amide


338
1H-Indole-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-



carbamoyl]-2-cyclohexyl-ethyl}-amide


339
(S)-3-Methyl-2-methylamino-pentanoic acid {(S)-1-[(6-amino-pyridin-



3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide


340
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



dichloro-phenyl)-ethyl]-3-methyl-2-methylamino-butyramide


341
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-



phenyl)-ethyl]-3-methyl-2-methylamino-butyramide


342
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-



phenyl)-ethyl]-2-methylamino-3-phenyl-propionamide


343
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-(cyclohexylmethyl-methyl-amino)-



propionamide


344
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-dimethylamino-propionamide


345
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-(ethyl-methyl-amino)-propionamide


346
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-(methyl-propyl-amino)-propionamide


347
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-(butyl-methyl-amino)-propionamide


348
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-3-methyl-



butyramide


349
(S)-2-(Isopropyl-methyl-amino)-3-methyl-pentanoic acid [(S)-1-[(6-



amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-



amide


350
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-diisopropylamino-propionamide


351
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-dimethylamino-3-phenyl-propionamide


352
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-(ethyl-methyl-amino)-3-phenyl-propionamide


353
(S)-2-(Isopropyl-methyl-amino)-3-methyl-pentanoic acid [(S)-1-[(6-



amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-



amide


354
N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-



phenyl)-ethyl]-2-piperidin-1-yl-propionamide


355
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-diethylamino-propionamide


356
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-pyrrolidin-1-yl-propionamide


357
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-pyrrolidin-1-yl-propionamide


358
(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide


359
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-dimethylamino-3-methyl-butyramide


360
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-3-hydroxy-2-(isopropyl-methyl-amino)-



propionamide


361
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-(ethyl-methyl-amino)-3-hydroxy-



propionamide


362
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-diethylamino-3-hydroxy-propionamide


363
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-2-diethylamino-3-hydroxy-propionamide


364
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



difluoro-phenyl)-ethyl]-3-diethylamino-succinamic acid methyl ester


365
(S)—N-(6-Amino-pyridin-3-ylmethyl)-



3-(3,4-difluoro-phenyl)-2-[2-(2,6-dimethyl-piperidin-1-yl)-



acetylamino]-propionamide


366
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-



pyrrolidin-1-yl-acetylamino)-propionamide


367
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-(ethyl-methyl-amino)-propionamide


368
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-(methyl-propyl-amino)-propionamide


369
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-(butyl-methyl-amino)-propionamide


370
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-(isopropyl-methyl-amino)-3-methyl-butyramide


371
(S)-2-(Isopropyl-methyl-amino)-3-methyl-pentanoic acid [(S)-1-[(6-



amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-



amide


372
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-diisopropylamino-propionamide


373
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-(isopropyl-methyl-amino)-3-phenyl-propionamide


374
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-piperidin-1-yl-propionamide


375
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-piperidin-1-yl-propionamide


376
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-



phenyl)-ethyl]-2-diethylamino-propionamide


377
(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide


378
(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-[2-(2,6-dimethyl-piperidin-1-yl)-



acetylamino]-3-(4-fluoro-phenyl)-propionamide


379
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(4-fluoro-phenyl)-2-(2-



piperidin-1-yl-acetylamino)-propionamide


380
(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-(2-diethylamino-acetylamino)-3-



(4-fluoro-phenyl)-propionamide


381
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-(isopropyl-methyl-amino)-propionamide


382
(S)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-amide


383
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-(methyl-propyl-amino)-propionamide


384
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-(ethyl-methyl-amino)-propionamide


385
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-dipropylaminopropionamide


386
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-dimethylamino-3-hydroxy-propionamide


387
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-(ethyl-methyl-amino)-3-hydroxy-propionamide


388
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-3-hydroxy-2-(isopropyl-methyl-amino)-propionamide


389
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-diethylamino-3-hydroxy-propionamide


390
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-diethylamino-propionamide


391
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-dimethylamino-propionamide


392
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-cyclohexyl-2-[2-(2,6-dimethyl-



piperidin-1-yl)-acetylamino]-propionamide


393
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-cyclohexyl-2-(2-



diisopropylamino-acetylamino)-propionamide


394
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(decahydro-naphthalen-1-yl)-2-



(2-diisopropylamino-acetylamino)-propionamide


395
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-



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


396
(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-



ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-amide


397
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-



naphthalen-1-yl)-ethyl]-2-dimethylamino-3-phenyl-propionamide


398
(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide


399
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



dichloro-phenyl)-ethyl]-2-dimethylamino-3-methyl-butyramide


400
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



dichloro-phenyl)-ethyl]-2-dimethylamino-3-phenyl-propionamide


401
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



dichloro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide


402
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



dichloro-phenyl)-ethyl]-2-piperidin-1-yl-propionamide


403
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-



dichloro-phenyl)-ethyl]-2-piperidin-1-yl-propionamide


404
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-dichloro-phenyl)-2-(2-



piperidin-1-yl-acetylamino)-propionamide


405
(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide


406
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-



phenyl)-ethyl]-2-dimethylamino-3-methyl-butyramide


407
(R)—N-[(S)-1-[6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-



phenyl)-ethyl]-2-dimethylamino-3-phenyl-propionamide


408
(S)—N-[(S)-1-[6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-



phenyl)-ethyl]-2-(ethyl-methyl-amino)-propionamide


409
(S)—N-[(S)-1-[6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-



phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide


410
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-



phenyl)-ethyl]-2-diethylamino-propionamide


411
N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-



phenyl)-ethyl]-2-piperidin-1-yl-propionamide


412
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3-chloro-phenyl)-2-(2-



piperidin-1-yl-acetylamino)-propionamide


413
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-



ethyl}-2-(ethyl-methyl-amino)-propionamide


414
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-



ethyl}-2-(isopropyl-methyl-amino)-propionamide


415
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-



ethyl}-2-diethylamino-propionamide


416
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-



trifluoromethyl-phenyl)-ethyl]-2-(ethyl-methyl-amino)-propionamide


417
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-



trifluoromethyl-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-



propionamide


418
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-



trifluoromethyl-phenyl)-ethyl]-2-diethylamino-propionamide


419
N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-



trifluoromethyl-phenyl)-ethyl]-2-piperidin-1-yl-propionamide


420
(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-(2-piperidin-1-yl-acetylamino)-



3-(3-trifluoromethyl-phenyl)-propionamide


421
(R)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-



trifluoromethyl-phenyl)-ethyl]-2-piperidin-1-yl-propionamide


422
(S)—N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-



trifluoromethyl-phenyl)-ethyl]-2-piperidin-1-yl-propionamide


423
(S)—N-(6-Amino-pyridin-3-ylmethyl)-2-(2-piperidin-1-yl-acetylamino)-



3-(4-trifluoromethyl-phenyl)-propionamide


424
(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-



pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-amide


425
N-[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-



phenyl)-ethyl]-2-piperidin-1-yl-propionamide


426
(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(4-chloro-phenyl)-2-[2-(2,6-



dimethyl-piperidin-1-yl)-acetylamino]-propionamide


427
(S)-2-[(S)-2-(Isopropyl-methyl-amino)-propionylamino]-4-methyl-



pentanoic acid (6-amino-pyridin-3-ylmethyl)-amide


428
(S)—N-(6-Amino-2-methyl-pyridin-3-ylmethyl)-2-(2-diethylamino-



acetylamino)-3-(4-fluoro-phenyl)-propionamide


429
(S)—N-(6-Amino-2-methyl-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-



2-[2-(2,6-dimethyl-piperidin-1-yl)-acetylamino]-propionamide


430
(S)—N-(6-Amino-2-methyl-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-



2-(2-piperidin-1-yl-acetylamino)-propionamide


431
(R)—N-[(S)-1-[(6-Amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-



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


432
(S)—N-[(S)-1-[(6-Amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-



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


433
(S)—N-{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-



dicyclohexyl-ethyl}-2-(isopropyl-methyl-amino)-propionamide


434
(S)—N-{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-



dicyclohexyl-ethyl}-2-dimethylamino-propionamide


435
(S)—N-{(R)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



2-hydroxy-ethyl}-2-(isopropyl-methyl-amino)-propionamide


436
(R)—N-(6-Amino-pyridin-3-ylmethyl)-3-cyclohexyl-2-[(S)-2-(isopropyl-



methyl-amino)-propionylamino]-butyramide


437
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-(isopropyl-methyl-amino)-N-methyl-propionamide


438
S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-diethylamino-N-methyl-propionamide


439
(S)—N-{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-



ethyl}-2-dipropylamino-propionamide









Biological Methods


The ability of the compounds of formula (I) to inhibit KLK1 may be determined using the following biological assays:


Determination of the IC50 for KLK1


KLK1 inhibitory activity in vitro was determined using standard published methods (see e.g. Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol., 1992, 43, 1209; Stürzebecher et al., Biol. Chem. Hoppe-Seyler, 1992, 373, 1025). Human KLK1 (Callbiochem) was incubated at 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 410 nm and the IC50 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 405 nm.


Data acquired from these assays are shown in Tables 16 and 17 below:









TABLE 16







(In vitro activity)










Example No
IC50 vs KLK1 (nM)














1
0.96



2
1.0



3
0.22



4
0.7



5
1.3



6
2.0



7
10.5



8
1.7



9
6.3



10
13.7



11
4.9



12
6.3



13
9.8



14
0.96



15
1.2



16
1.1



17
211



18
5.0



19
21.6



20
4.3



21
22.8



22
2.2



24
27.8



25
9.8



26
20.5



27
2.5



28
32.1



29
10.2



30
1.1



31
18.1



32
2.8



33
5.3



34
3.3



35
0.47



36
1.6



37
626



38
9.2



39
5.8



40
6.6



41
0.76



42
1.4



43
2.9



44
5.4



45
3.1



46
1.2



47
316



48
8.0



49
4.2



50
29.1



51
0.26



52
24.5



53
11.2



54
0.29



55
0.70



56
7.1



57
4.6



58
48.6



59
0.56



60
0.71



61
0.4



62
2.4



63
0.66



64
3.1



65
2.7



66
20.7



67
3.1



68
9.2



69
42.2



70
1.1



72
7.2



73
1.1



74
1.8



75
2.2



76
21.8



77
2.9



78
1.2



80
16.1



81
5.0



82
11.2



83
158



84
8.0



85
13.9



86
15.5



87
6.4



88
6.7



89
11.0



90
0.86



91
2.1



92
3.6



93
0.85



94
12.5



95
1.8



96
5.5



97
45.2



98
1.3



99
17.1



100
85.8



101
24.1



102
258



103
5.4



104
24.4



105
3.8



106
3.9



107
71.2



108
34.0



109
21.7



110
4.0



111
15.0



112
257



113
14.5



114
28.4



115
19.5



116
16.1



117
0.45



118
2.1



119
1.8



120
1.6



121
11.0



122
1.8



123
1.4



124
36.8



125
8.8



126
9.3



127
0.9



128
7.6



129
215



130
5.0



131
0.54



132
6.4



133
16.5



134
13.5



135
17.3



136
8.6



137
288



138
39.8



139
3.7



140
4.3



141
13.7



142
15.0



143
21.0



144
20.9



145
10.5



146
102



147
49.6



148
55.7



149
36.8



150
12.0



151
17.7



152
5.7



153
69.9



154
216



155
63.3



156
80.6



157
123.3



158
114.4



159
165.1



160
184.8



161
93.5



162
38.1



163
56.5



164
345



165
83.5



166
726



167
258



168
291



169
334



170
16.6



171
1.3



172
12.7



173
78.3



174
90.0



175
2.0



176
4.0



177
1.9



178
15.9



179
3.01



180
7.9



181
1.1



182
21.2



183
5.1



184
44.4



185
14.5



186
0.81



187
0.71



188
1.2



189
4.2



190
1.8



191
33.3



192
60.4



193
10.9



194
5.1



195
5.4



196
23.2



197
84.6



198
28.0



199
1.4



200
22.1



201
1.3



202
22.5



203
4.5



204
5.9



205
6.7



208
32.1



209
36.0



210
39.0



211
0.29



212
29.8



213
2.8



214
16.9



215
12.6



216
24.4



217
29.3



218
35.3



219
3.6



220
55.5



221
50.5



222
39.7



223
17.37



224
61.6



225
51.1



226
10.1



227
5.3



228
32.1



229
3.4



230
20.3



231
3.1



232
1.5



233
2.1



234
3.2



235
2.4



236
9.0



237
10.9



238
35.2



239
6.5



240
1.5



241
3.8



242
4.4



243
3.4



244
7.8



245
13.7



246
3.5



247
200



248
12.7



249
6.9



250
0.8



251
128



252
43.2



253
12.5



254
37.2



255
105



256
122



257
12.1



258
10.3



259
85.4



260
150



261
13.2



262
28.3



263
20.5



264
3.1



265
21.6



266
5.7



267
8.2



268
7.7



269
26.1



270
20.9



271
3.3



272
10.3



273
375



274
4.8



275
147



276
30.5



277
0.9



278
3.2



279
4.5



280
1.9



281
1.8



282
1.3



283
5.1



284
5.2



285
6.5



286
4.3



287
75.6



288
93.2



289
30.5



290
626



291
165



292
31.5



293
36.3



294
35.6



295
192



296
40.9



297
40.1



298
9.4



299
8.1



300
7.4



301
11.0



302
7.2



303
240



304
148



305
119



306
163



307
22.0



308
15.6



309
42.3



310
48.9



311
46.5



312
38.4



313
8.7



314
15.6



315
68.6



316
76.7



317
14.7



318
12.1



319
110



320
98.5



321
85.4



322
12.4



323
48.1



324
68.4



325
21.3



326
25.4



327
17.8



328
179



329
299



330
23.6



331
32.0



332
21.5



333
184



334
235



335
15.8



338
881



339
39.8



340
0.38



341
2.2



342
2.7



343
91.0



344
21.3



345
7.7



346
21.3



347
24.5



348
11.1



349
7.8



350
28.5



351
8.8



352
13.7



353
7.8



354
11.6



355
2.5



356
3.8



357
3.0



358
10.4



359
5.0



360
20.2



361
55.6



362
25.9



363
84.4



364
43.7



365
2.5



366
54.5



367
10.8



368
19.4



369
29.1



370
11.3



371
7.3



372
34.3



373
25.7



374
52.7



375
4.9



376
2.7



377
32.2



378
2.5



379
128



380
13.9



381
1.1



382
48.6



383
45.9



384
9.7



385
107



386
260



387
170



388
22.2



389
42.9



390
2.7



391
49.4



392
47.2



393
26.9



394
8.4



395
0.17



396
1.4



397
44.2



398
0.82



399
0.74



400
1.7



401
0.16



402
13.0



403
1.1



404
33.4



405
7.1



406
4.7



407
17.0



408
4.8



409
0.63



410
2.6



411
12.7



412
9.3



413
7.9



414
0.77



415
5.3



416
6.2



417
0.83



418
2.0



419
16.3



420
117



421
67.4



422
3.0



423
129



424
28.0



425
14.9



426
2.7



427
106



428
9.9



429
1.7



430
59.8



431
50.6



432
17.0



433
100



434
43.9



435
5.0



436
3.6



437
4.2



438
5.4



439
107

















TABLE 17







(Selectivity data)










IC50 (nM)












Example
Plasma





No
Kallikrein
Thrombin
Trypsin
Plasmin














1
>10000
>10000
>10000
>10000


2
>10000
>10000
>10000
>10000


3
>10000
>10000
>10000
>10000


4
>10000
>10000
>10000
>10000


5
>10000
>10000
>10000
>10000


11
>10000
>10000
>10000
>10000


13
>10000
>10000
>10000
>10000


20
>10000
>10000
>10000
>10000


25
>10000
>10000
>10000
>10000


26
>10000
>10000
>10000
>10000


27
>10000
>10000
>10000
>10000


29
>10000
>10000
>10000
>10000


30
>10000
>10000
>10000
>10000


54
>10000
>10000
>10000
>10000


55
>10000
>10000
>10000
>10000


59
>10000
>10000
>10000
>10000


60
>10000
>10000
>10000
>10000


61
>10000
>10000
>10000
>10000


62
>10000
>10000
>10000
>10000


90
>10000
>10000
>10000
>10000


91
>10000
>10000
>10000
>10000


92
>10000
>10000
>10000
>10000


213
>10000
>10000
>10000
>10000


131
>10000
>10000
>10000
>10000


145
>10000
>10000
>10000
>10000


157
>10000
>10000
>10000
>10000


176
>10000
>10000
>10000
>10000


226
>10000
>10000
>10000
>10000


227
>10000
>10000
>10000
>10000


228
>10000
>10000
>10000
>10000


229
>10000
>10000
>10000
>10000


231
>10000
>10000
>10000
>10000


232
>10000
>10000
>10000
>10000


233
>10000
>10000
>10000
>10000


234
>10000
>10000
>10000
>10000


235
>10000
>10000
>10000
>10000


242
>10000
>10000
>10000
>10000


243
>10000
>10000
>10000
>10000


277
>10000
>10000
>10000
>10000


355
>10000
>10000
>10000
>10000


365
>10000
>10000
>10000
>10000


381
>10000
>10000
>10000
>10000


390
>10000
>10000
>10000
>10000


398
>10000
>10000
>10000
>10000


400
>10000
>10000
>10000
>10000


437
>10000
>10000
>10000
>10000








Claims
  • 1. A compound of formula (I):
  • 2. A compound according to claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from (C1-C10)alkyl, (C3-C10)cycloalkyl, aryl, heteroaryl and aryl(C1-C4)alkyl- and R2 is selected from H, (C1-C6)alkyl, (C1-C6)alkoxy, OH, (C3-C10)cycloalkyl and aryl.
  • 3. A compound according to claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from (C1-C10)alkyl, (C3-C10)cycloalkyl, aryl, heteroaryl, heteroaryl(C1-C4)alkyl- and aryl(C1-C4)alkyl- and R5 is selected from H and (C1-C6)alkyl.
  • 4. A compound according to claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein: R4 and R6 together with the atoms to which they are attached may form a 4-7 membered N-containing ring, optionally containing one carbon-carbon double bond, optionally containing one further heteroatom selected from N, O and S, and optionally substituted on carbon with 1 or 2 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, CN and hydroxyl; orR5 is absent and R4 and R6 together with the atoms to which they are attached may form a 5, 6 or 9 membered mono- or bi-cyclic N-containing aromatic ring, optionally containing one further heteroatom selected from N and O, and optionally substituted on carbon with 1, 2 or 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, halo, aryl, COOR14 and hydroxyl; orR4 and R6 may together form a group according to formula II or formula III:
  • 5. A compound according to claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from H and (C1-C6)alkyl, and R7 is selected from H, (C1-C10)alkyl, (C3-C10)cycloalkyl, aryl, heteroaryl, aryl(C1-C4)alkyl-, aryl(C2-C4)alkenyl-, heteroaryl(C1-C4)alkyl-, —SO2(C1-C6)alkyl and —SO2aryl.
  • 6. A compound according to claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein R6 and R7 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 (C1-C6)alkyl, (C1-C6)alkoxy, halo, CN and hydroxyl, said N-containing ring may also optionally be fused to an aryl group.
  • 7. A compound according to claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein R8, R9 and R19 are independently selected from H, (C1-C10)alkyl and halogen, and R11 and R12 are H.
  • 8. A compound according to claim 1, selected from: (R)-1-Methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-naphthalen-1-yl-ethyl}-amide;(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-amide;(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;(R)-3-Methyl-2-methylamino-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,5-difluoro-phenyl)-ethyl]-amide;(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;(R)-1-Isopropyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;(R)-1-Ethyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;(R)-1-Propyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;(R)-1-Isobutyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;(R)-1-Ethyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;(S)—N-(6-Amino-pyridin-3-ylmethyl)-3-(3,4-difluoro-phenyl)-2-(2-diisopropylamino-acetylamino)-propionamide;(R)-1-Methyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;(R)-1-Methyl-piperidine-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-dimethylamino-3,3-dimethyl-butyramide;(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;(R)-1-Methyl-pyrrolidine-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;(S)-1-Methyl-pyrrolidine-2-carboxylic acid {(R)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2,2-dicyclohexyl-ethyl}-amide;3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-fluoro-phenyl)-ethyl]-amide;3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-amide;3-Methyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(4-fluoro-phenyl)-ethyl]-amide;3,5-Dimethyl-1H-pyrrole-2-carboxylic acid [(S)-1-[(6-amino-2-methyl-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-amide;(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl] -2-(3,4-dichloro-phenyl)-ethyl]-3-methyl-2-methylamino-butyramide;(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-(ethyl-methyl-amino)-propionamide;(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-difluoro-phenyl)-ethyl]-2-diethylamino-propionamide;(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-(isopropyl-methyl-amino)-propionamide;(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-2-diethylamino-propionamide;(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(decahydro-naphthalen-1-yl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;(R)-2-Dimethylamino-3-methyl-pentanoic acid [(S)-1-[(6-amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-amide;(R)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl]-2-dimethylamino-3-methyl-butyramide;(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3,4-dichloro-phenyl)-ethyl-2-(isopropyl-methyl-amino)-propionamide;(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-chloro-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;(S)—N—{(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-m-tolyl-ethyl}-2-(isopropyl-methyl-amino)-propionamide;(S)—N—[(S)-1-[(6-Amino-pyridin-3-ylmethyl)-carbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-2-(isopropyl-methyl-amino)-propionamide;and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof.
  • 9. A method of treatment of a disease or condition in which KLK1 activity is implicated comprising administration to a subject in need thereof a therapeutically effective amount of a compound according to claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof.
  • 10. The method of claim 9 wherein the disease or condition in which KLK1 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 or a neoplastic disorder.
  • 11. The method of claim 9 wherein the disease or condition in which KLK1 activity is implicated is 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),
  • 12. The method of claim 9 wherein the disease or condition in which KLK1 activity is implicated is selected from asthma (allergic and non-allergic) and cough.
  • 13. A pharmaceutical composition comprising a compound according to claim 1, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
Priority Claims (1)
Number Date Country Kind
GB 0807828.9 Apr 2008 GB national
CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. patent application No. 61/071,431, filed Apr. 29, 2008, and Great Britain application number GB 0807828.9, filed Apr. 29, 2008, both of which are incorporated herein by reference in their entirety for all purposes.

Provisional Applications (1)
Number Date Country
61071431 Apr 2008 US