TW201120038A - Azaindole derivatives - Google Patents

Abstract

The present invention provides compounds of formula (I): compositions comprising such compounds; the use of such compounds in therapy (such as asthma or COPD); and methods of treating patients wich such compounds; wherein R1 to R20 and A1 are as defined herein.

Description

201120038 VI. Description of the Invention: [Technical Field] The present invention relates to azaindole derivatives and methods for preparing the same, intermediates for preparing the derivatives, and compositions containing the derivatives And the use of such derivatives. [Prior Art] The azaindole derivatives of the present invention are inhibitors of tissue kallikrein and have various therapeutic applications, particularly for the treatment of inflammatory diseases such as asthma and chronic obstructive pulmonary disease (C〇pd). The compounds of the invention are selective inhibitors of human tissue kallikrein (KLK1). In particular, its ability to inhibit KLK1 is greater than its ability to inhibit other ephedrine proteases. Human tissue kallikrein KLKI (EC.3.4.21.35, also known as hKl, glandular kallikrein and urinary kallikrein) is a tryptase serine protease belonging to the kallikrein gene family. There are 14 other members (including prostate-specific antigens) in the kallikrein gene family (g M. Y〇usef et al., and 2, 1, 22, 18 sentences. Other closely related pancreas Proteatin serine proteases include plasma kallikrein, thrombin, trypsin, and plasmin. Active KLK1 is a membrane-bound enzyme and is widely expressed in the pancreas, salivary glands, colon, kidney, lymph nodes, prostate, small intestine, The strongest performance was observed in the stomach, thyroid, and vagina. KLK1 was moderately expressed in the lungs and in saliva, and its activity was also measured in the sputum of patients after chronic lung injury. KLK1 can be restricted by Sexual protein f hydrolyzed by kininogen release 151650.doc 201120038 Low molecular weight kininogen release of kallikin, while bradykinin is released from high molecular weight kininogen (K. D, Bhoola et al. 'P/iarwaco/ogica / i^v.,1992,4 4, 1). Kinins such as pancreatic kinin (Lys-bradykinin) and bradykinin are potent inflammatory mediators. The action of kinins is through activation of two major bradykinin receptor subtypes B1. And B2, both of which are members of the seven trans-membrane G protein-coupled receptor family. The B 1 receptor is involved in a chronic response and is based on Low content 'but its up-regulation after tissue damage and/or inflammation, and B2 receptor is involved in acute reaction and constitutive. KLK1 also activates matrix metalloproteinase (MMP), collagenase and gelatinase, and cleaves Insulin-like growth factor binding protein-3 (JA Clements et al., CW?. Heart V. C7h. Ζαέ. • SW·, 2004, 41, 265-312). It has also been reported that KLK1 directly activates slow-acting receptors. (C. Hecquet, '2〇〇〇, 39, 508-515). Kinin has been shown to be an important mediator of allergic inflammation (such as asthma and hay fever) (SC Chrstiansen et al., /. C7h. /« Ναί., 1987, 79, 188-197) and the enzyme responsible for releasing kinins in the trachea of asthmatic individuals is KLK 1 (S·C·Chrstiansen, j. ν. and 1992 145, 900-905). It has also been shown that inflammatory cells release KLK1 (IT Lauredo's 'Am. J. Physiol. Lung Cell Mol. Physiol' 2QQ4, 286 734). Inhibition of KLK1 can be a novel approach to the treatment of asthma.

In addition, 'KLK 1 is involved in a variety of other disease conditions, including acute inflammatory disease (T. Griesbacher, Pharmacology, 2000, 60 1 13 ; T

Griesbacher et al., «/. P/zarwaco/., 2003, 139, 299), 151650.doc 201120038 Inflammatory bowel disease (A· Stadnicki, DzgaMve (10) d Dbease, 2005, 37, 648; A. Stadnicki et al. Digestive Diseases and *SWe«ce, 2003, 48, 615), Arthritis (RW Colman,

Immunopharmacology, 1999, 43, 103 > R. J. Williams, Brit. «/. 1997, 36, 420). High levels of circulating KLK1 induce chronic hypotension, and the non-selective KLK1 inhibitor aprotinin has been shown to inhibit this condition (J. S Sharma et al, Pharmacology, 1995, 50, 3 63 ; Q. Song et al.

Immunopharmacology, 1996, 32, 105) ° Antagonists of kinins, such as bradykinin receptor antagonists, have previously been studied as potential therapeutic agents for the treatment of a variety of inflammatory conditions (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 airway diseases (WM Abraham et al., £2^.«/· P/zarw·, 2006, 533, 215) Evidence suggests that KLK1 plays a role in cancer (KD Bhoola et al. 'Cwrr. / «vew. Drwgs, 2007, 8, 462). KLK1 plays a role in enhancing tumor invasiveness via activation of matrix metalloproteinases, collagenase and gelatinase (KD Bhoola et al, 5z_o/. C/zem., 2001, 382, 77; H. Tschesche et al., £χρ · A/d βίο Plant, 1969, 247Α, 545). In addition, KLK1 is indirectly involved in promoting proliferation through the release of mitogenic kinin (RA Roberts et al./Ce". \Aw.Pl989, 94, 527) ° KLK1 is also involved in growth factor regulation and is involved in Various growth factors are processed in the precursors of 151650.doc -6 · 201120038 (eg EGF, NGF). Endogenous KLK1 inhibitors include serine protease inhibitors (serpin), kallistatin, anti-protein C, cm-antichymotrypsin, and Oh-antichymotrypsin. Aprotinin is also a potent non-selective KLK1 inhibitor. Low molecular weight KLK1 inhibitors have previously been reported (M. Szelke et al, WO 199204371; M. Szelke et al, WO 199507291; C Olivier et al, P. " ☆ *?, 2000, 705; Μ. M Staveski et al, WO 2003101941; M. Tokumasu et al, WO 2005095327; J. Burton et al, US 5464820). KLK1 inhibitors have been reported to exhibit activity in the following animal moldings: allergic inflammation (M. Szelke et al, 5^2. J. Med. and I, 1994, 27, 1943; DM Evans et al, 1996, 32 , 117), citric acid-induced cough (RL Featherstone et al., Lw «g, 1996, 174, 269) and acute pancreatitis (T. Griesbacher et al., P.mrwaco/., 2002, 137 , 692). KLK1 inhibitors have also been shown to be active in cancer models (KLK1 inhibitors inhibit tumor cell migration in a dose-dependent manner in matrigel invasion assays) (W_C. Wolf et al., dw. J. ΡαΑο/, 2001, 159, 1797). Human KLK1 antibodies that inhibit KLK1 with naim efficacy have been shown to be active in the allergic sheep asthma model. This antibody inhibits late bronchoconstriction and completely blocks tracheal overreaction (DJ Sexton et al, WO 2006017538; DJ Sexton et al, ^〇c/^w· «/owrwa/, 2009, 422, 383) 〇 in vitro binding to KLK1 And the hyaluronic acid that inactivates KLK1 has been shown to block bronchoconstriction induced by porcine pancreatic elastase in sheep (M. Scuri et al. 151650.doc 201120038 person, ··. and eipz'r. Cr"· Care Mei/., 2001, 164, 1855) The kallikrein-binding protein (KBP) is a serine protease inhibitor (serpin) that specifically binds to tissue kallikrein and inhibits kallikrein activity. KBP has been shown to inhibit retinal neovascularization and reduce vascular leakage by down-regulating vascular endothelial growth factor (VEGF) (G. Gao # A > Diabetologia, 2003, 46, 689) and to inhibit VEGF production by reducing VEGF production. Gastric cancer growth (L. Lu et al., Mo/. Caweer. 772er., 2007, 6, 3297). VEGF is also associated with blood-retinal barrier destruction, and blood-retinal barrier destruction is a hallmark of diabetic retinopathy (D. A. Antonettie et al., 1998, 47, 1953). VEGF is also implicated in the remodeling of tracheal vascular structures in chronic inflammation (D. M. McDonald, Am. J. Respir. Crit. Care Med., 2Qd\, 164, S39). The selectivity of other members of the tryptase-like serine protease family, especially for plasma kallikrein, is an important issue. Tissue kallikrein inhibitors exhibiting weak plasma kallikrein activity have previously been reported (M. Szelke et al., «/· Med. and 1994, 27, 1935 and DM Evans # A > Immunopharmacology, 1996, 32 , 11 7), but still require other compounds that selectively inhibit tissue kallikrein. Synthetic plasma kallikrein inhibitors have been revealed in several groups. Such inhibitors include ketamine ketamine derivatives (WO 92/04371 and D. M. Evans et al., /ww Mwop/zarwaco/ogy, 1996, 32, 115-116),

Serotonin and spermidine derivatives (WO 95/07291, WO

\/94/29335), benzoquinone derivatives (jsturzbecher et al., 5 (four) Yi Mei price 〇 /. Λα., 1994, 27, 1929-1934), guanic acid derivatives (US 151650.doc 201120038 5,187 , 157) and amine methyl 5 hexamethylene derivatives (ν·Teno et al., CTzew. P/mrm. square μ//., 1993, 41, 1079-1090). Non-peptide bacterial kallikrein inhibitors have also been reported (W. B. Young et al., (10) Cangzhou, 2006, 16, 2034 and WO 2008/016883). The compounds of the present invention and their pharmaceutically acceptable salts have the advantage that they are selective KLK1 inhibitors (and thus their side effects are likely to decrease). In addition, it may be more effective than prior art compounds, may have a longer duration of action, may have greater bioavailability or may have other more desirable properties. SUMMARY OF THE INVENTION In one aspect, the invention provides a compound of formula (I): ΟΠΠΠΜ

2 3 R R

Η Ο (I) R4 wherein: is independently selected from H, hydroxy, (CiCi oxy, (C2-c, 接# (Cl'c 6 earth, (C2-C6) alkynyl, (C3-C10) ring Smoldering, alkyl, aryl, miscellaneous, tert-butyl, aryl (C丨-C: 4) alkyl- and heteroaryl (Ci R is selected from hydrazine, (Cl_Ci〇) alkyl and (c2_alkenyl; 15I650.doc 201120038 r4 and R5 are independently selected from fluorene and (CVCd alkyl; Α1 is selected from CR6 and S(0)R7; r6 is selected from R7 and the following formulas II, III and IV Group:

R10

R11

(m) U vj U1) / is selected from (cvc6) alkyl, (c2-c6), (c3_Ci) cycloalkyl, aryl and aryl (Cl_C4) alkyl; R8 and R9 are independent Selected from η, (Cl_Cl-like, (Vc6) dilute, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl (fluorene) alkyl- and heteroaryl (Cl_C4) alkyl R; ° and R11 are independently selected from H, (CVCi〇)alkyl, Α·. alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl-, Aryl (c2-c4) dilute, heteroaryl (CVC4) alkyl...s〇2(c|_C6)alkyl, -so2aryl and _s〇2 aryl(Ci_c4)alkyl; , Rl. and /11 may form a 4-member to 7-membered N-containing ring together with the nitrogen atom to which they are attached, and the ring contains optionally a hetero atom selected from N, 〇 and 5, and optionally Substituted by a substituent independently selected from the group consisting of alkyl, (Cl C6) alkoxy, dentate, CN and a radical, the N-containing ring may also be fused to an aryl group as appropriate; or R and R may be taken together The atoms connected together form a saturated or partially unsaturated 4 to 7-membered N-ring, and the N-containing ring contains another 151650.doc 201120038 selected from N, 〇 and S Substituting, and optionally substituted on carbon with hydrazine or two substituents independently selected from (c--C6)alkyl, (c丨·Ce)alkoxy, halo, CN and hydroxy; or R9 Exist and R8 and rig can be shaped together with the atoms to which they are attached

a 5-member, a 6-member, a 9-member or a 1-membered monocyclic or bicyclic ring containing 1^ aromatic ring, the N-containing aromatic ring optionally containing another hetero atom selected from N, hydrazine, and 5, and optionally on carbon Substituting 1, 2 or 3 substituents independently selected from (Ci_c6)alkyl, (Ci_CO alkoxy, halo, CN, aryl, c〇〇Rl5 and hydroxy; or R8 and R10 may be formed together Formula V or a group of formula 1 1 :

Rl\^(CH2)h

(CH2)g (v) (VI) R12 and R13 are independently selected from η, (4) 丨. Alkyl, (CVC6)alkenyl, (C3_ClG)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(Cl-C4)alkyl-, aryl (c2-c4)alkenyl- , heteroaryl (Ci_C4)alkyl-, _s〇2(c丨_C6)alkyl, -S02 aryl and _s〇2 aryl (Ci_c4)alkyl;

RaARb is independently selected from H, (Ci-C10) alkyl, (c2-c6) alkenyl, (CVClQ) ring-based, heterocycloalkyl, aryl, heteroaryl, aryl (Cl_C4) -, aryl (CVC4) dilute-, heteroaryl (Ci_C4), _, _s〇2 (Ci·C6) alkyl, _s〇2 aryl and _s〇2 aryl (c丨_c4) An alkyl group; or V together with the atom to which it is attached forms a saturated or partial 151650.doc • 11 - 201120038 Unsaturated 4 to 7 members contain an N ring, which contains another ring selected from the group consisting of Ν Ο and S a hetero atom, and optionally on carbon, or two substituents independently selected from (cvcd alkyl, (Cl_C6) alkoxy, functional, cn, and hydroxy; the N-containing ring may also be fused as appropriate To an aryl group; or Ra and Rb together with the atom to which they are attached may form a 5 member, 6 member, 9 member or 10 membered monocyclic or bicyclic ring containing an aromatic ring, optionally containing another N selected from the group consisting of N , 〇 and S heteroatoms, and optionally, on the carbon, 1, 2 or 3 independently selected from (CVC6) alkyl, (Ci_c6) alkoxy, halo, CN, aryl, COOR丨5 and Substituted by a substituent of a hydroxyl group; R14 is selected from the group consisting of ruthenium, (C]-C6), and (Cl_C6) , R, CN, CF3, COOR15, halo and NR15R16; R 5 and R 16 are independently selected from H and (c丨 alkyl; R17, R18, R19 and R20 are independently selected from H, hydroxy, Halogen, CN, (C^-C,.) alkyl and (CpC6) alkoxy; f and g are independently selected from 〇, 1, 2 and 3 such that f+g=1, 2 or 3 h is selected from 1 and 2; wherein: the alkyl group may be independently selected from (C3-C1Q)cycloalkyl, (Ci-Ce)alkoxy, OH, CN, CF3, COOR15, or 1 or 2, Substituting a gas and a substituent of NR15R16; the alkenyl group may optionally be selected from 1 or 2 substituents independently selected from the group consisting of (C3_C1G)cycloalkyl, (qQ)alkoxy, hydrazine H, CN, CF3, COORM, gas and NR15R16 Substituted; alkynyl may optionally be selected from (C3_C1Q), sulphur, 15I650.doc •12-201120038 CF3, COOR丨1 'fluorine and site selected from (C3-C1G)cycloalkane I and 1 or 2 Substituted (Ci-C^) alkoxy, hydrazine H, CN, nrHr12 substituents; alkoxy groups may be substituted by 1 or 2 mono-, OH, CN, CF3, COOR15; cycloalkyl a non-aromatic monocyclic or bicyclic hydrocarbon ring fused to an aryl group, wherein the cycloalkyl ring is The genus contains at most 2 double bonds; and wherein 'unless otherwise stated, ^% alkyl may be independently selected from (Ci_c6) alkyl, alkoxy, 〇H, 1 or 2, CN, CF3, COORi5, fluorine and f, 16:: generation: substituted; heterocycloalkyl is a C-bond or N-bonded 3 to 1 member non-aromatic monocyclic or

a bicyclic ring wherein the heterocyclic ring of the heterocyclic ring may contain 2 or 3 Z atoms selected from the group consisting of a hetero atom; and the heterocyclic ring may optionally contain a double bond, and The case is substituted on the carbon by 1 or 2 independently selected from (Cl%) alkyl, (to alkoxy, OH, CN, CF3, _ group, C00Rl5, Nr15r16 and aryl: substituent; aryl is contained a single aromatic ring or a fused aromatic ring system of 6 or 10 carbon atoms; wherein, unless otherwise stated, the aryl group is present at each occurrence: optionally up to 5 independently selected from (Cl-C6) alkyl, Ci_C6) alkoxy, OH ' functional group, CN, C00Ri5, ci^nr15r16 substituted by a diradical; heteroaryl group if possible contains 1, 2 or 3 independently selected from N, Nr1 151650.doc 201120038

9 or 10 members of monocyclic or bicyclic aromatic or the heteroaryl may be optionally substituted by c6) pit, (c^Cd alkoxy, CF3 and NR15r16 substituents; q is 0, 1 or 2; Its tautomers, stereoisomers, pharmaceutically acceptable salts and solvates. In another aspect, the invention provides a prodrug of a compound of formula (1) as defined herein or a pharmaceutically acceptable In another aspect, the invention provides an N-oxide of a compound of formula (1) as defined herein, or a prodrug or pharmaceutically acceptable salt thereof. It will be appreciated that certain compounds of the invention may be solvent In the form of a compound (eg, a hydrate) as well as an unsolvated form. It is understood that the invention encompasses all such solvate forms. In a subset of the compounds of formula (I): R1 is selected from (CVCJ alkyl, ( c3_Cl())cycloalkyl, heterocycloalkyl, aryl and heteroaryl; 'R2 is selected from H, hydroxy, (C|_C6)alkyl, (Ci_c6)alkoxy, (q·Cl〇) a cycloalkyl group and an aryl group; R3, R4 and R5 are independently selected from the group consisting of ruthenium and (Cl_C6) alkyl; A1 is selected from CR6 and s(0)R7; R6 is selected from R7 and Formula Η, ΠΙ and the group IV: 151650.doc -14- 201120038

(II) (III) R7 is selected from (CVCO alkyl, aryl and aryl (CVc4) alkyl group; R8 is selected from H, (Ci-G) alkyl, (C3-C... ring and Aryl (Ci_ c4) alkyl; R9 is selected from fluorene and (CVC6) alkyl; R10 is selected from fluorene, (Cl-C6) alkyl, (C3_Cl〇) cycloalkyl and aryl (Ci_C4) alkane R11 is selected from the group consisting of ruthenium and (Ci-Cs) alkyl; or R10 and R11 together with the nitrogen atom to which they are attached form a 5- to 6-membered N-containing ring, which may be 1 or 2 depending on the case. Ci_C6) substituted with an alkyl substituent; or R8 together with the atom to which it is attached forms a saturated or partially unsaturated 5-member to 6-membered N-containing ring which, depending on the case, is i or 2 on carbon ((^ -(:6)alkyl substituent substitution; or R9 absent and R8 and Ri〇 together with the atom to which they are attached form a 5 member, 6 member, 9 member or 1 member single or double ring containing 1 ^ aromatic ring The N-containing aromatic ring is optionally substituted on the carbon with hydrazine or two (Cl_c6) alkyl substituents; R12 is selected from the group consisting of fluorene and (CVC6) alkyl; R13 is selected from the group consisting of hydrazine, (C)-C0) alkyl , aryl and aryl (Cl_C4)alkyl _; RlRb is independently selected from the group consisting of hydrazine, (C丨-C6) alkyl, (C3-C6) cycloalkyl, Cycloalkyl, aryl, heteroaryl; 151650.doc -15- 201120038 or Ra and Rb together with the atoms to which they are attached form a saturated or partially unsaturated 5 to 6 member containing > N ring is substituted on the carbon by 1 or 2 (C^C:6) alkyl substituents; or ... and !^ can be combined with the atoms to which they are attached to form 5 members, 6 members, 9 members or 1 member. a monocyclic or bicyclic ring containing an N-aryl ring, optionally substituted with 1 or 2 (Ci-C6) substituents on the sarcophagus; R17, R18, Ri9 and R2G are independently selected from an alkyl group; Wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are as defined above; and tautomers, stereoisomers, pharmaceutically acceptable salts and solvents thereof In another subset of the compounds of formula (I): R1 is selected from (C3-C1())cycloalkyl and aryl; R2 is selected from fluorenyl and (C3-C1Q)cycloalkyl; R3, R4 and R5 are Η; Α1 is CR6; R6 is selected from the group consisting of R7 and the following formulae II and III:

(II) (III) R7 is an aryl (CVC4) alkyl group; R8 is selected from fluorene and (Ci-Ce) alkyl; 151650.doc -16- 201120038 R9 is hydrazine; R1Q is selected from hydrazine and (C) "C6"alkyl; R11 is selected from fluorene and (CVCd alkyl; or R1Q and R11 together with the nitrogen atom to which they are attached form a 5- to 6-membered N-containing ring, which may be 1 or 2 depending on the case. (q-C6) substituted with an alkyl substituent; or R8 and R1Q may form a saturated or partially unsaturated 5-member to 6-membered N-containing ring together with the atom to which they are attached, and the N-containing ring may optionally be on the carbon via j or 2 (CrCd alkyl substituent substituted; or R9 is absent and R8 and R1G together with the atom to which they are attached form a 5-member, cleavage, 9-member or 10-membered monocyclic or bicyclic n-containing aromatic ring containing N-aryl Cyclic substitution of 1 or 2 (C^-C:6) alkyl substituents on carbon; R12 is hydrazine; R13 is aryl (CVCO alkyl-; R17, R18, R19 and R20 are hydrazine; And alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are as defined above; and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof In another subset of the compounds of formula (I): R1 is selected from (C3-C1())cycloalkyl and aryl; R2 is selected from fluorene and (C3-C1G)cycloalkyl; R3, R4 and R5 are Η; Α1 is S(0)R7; R7 Is (CVC6)alkyl; 151650.doc •17- 201120038 R17, R18, R19 and R20 are Η; wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are as above And the tautomers, stereoisomers, pharmaceutically acceptable salts and solvates thereof. The present invention also encompasses the following aspects and combinations thereof: In one aspect, the present invention provides the following formula (1) a compound wherein R1 is selected from the group consisting of (C)-Ci〇)alkyl, (C3-C10) ring, aryl, heteroaryl and aryl (CVC4)alkyl-. In another aspect, The invention provides a compound of the following formula (1), wherein: is selected from the group consisting of (c--c6)alkyl, (c5-c1())cycloalkyl, aryl and heteroaryl. In another aspect, the invention provides the following A compound of the formula (1), wherein the rule 1 is selected from the group consisting of (C5-C1())cycloalkyl, aryl and heteroaryl. In another aspect, the invention provides a compound of the following formula (1), wherein r1 is as appropriate Substituted phenyl "as appropriate The base is selected from the substituents defined above for "aryl". In one aspect, the invention provides a compound of formula (1) wherein the rule 2 is selected from the group consisting of hydrazine, (Ci-CJ alkyl, OH, (Cl_c6) Alkoxy, (C3_CiQ)cycloalkyl and aryl. In another aspect, the invention provides a compound of formula (1) wherein R2 is selected from the group consisting of hydrazine, (C3-C10)cycloalkyl, and aryl. In another aspect, the invention provides a compound of formula (1) wherein R2 is selected from the group consisting of hydrazine, (CVC6) alkyl, OH, (CVC6) alkoxy, and (C3-C1Q)cycloalkyl. In another aspect, the invention provides a compound of formula (1) wherein R 2 is selected from the group consisting of hydrazine, OH, and ((: 4 &lt; 6) cycloalkyl. In another aspect, The invention provides a compound of formula (1) wherein R2 is hydrazine. In one aspect, the invention provides a compound of formula (I) wherein R3 is selected from the group consisting of hydrazine and (CrCJ alkyl. In another aspect the invention provides A compound of the formula (1), wherein R3 is hydrazine. In one aspect, the invention provides a compound of the formula (I) wherein R3 is Η and the carbon atom to which R3 is attached is palm-like and has a phantom configuration. In one aspect, the invention provides a compound of formula (1) wherein R 3 is deuterium and the carbon atom to which R 3 is attached is palmar and has a < and > configuration. In one aspect, the invention provides the following formula (I) A compound, wherein R4 is selected from the group consisting of hydrazine or (Ci-C6)alkyl. In another aspect, the invention provides a compound of formula (1) wherein R4 is hydrazine. In one aspect, the invention provides a compound of formula (1) Wherein R5 is selected from hydrazine or (CrCd alkyl). In another aspect, the invention provides the following formula (I) In one aspect, the invention provides a compound of formula (1) wherein Α is CR6. In another aspect, the invention provides a compound of formula (I) wherein Α1 is S ( 0) R7. I51650.doc 201120038 In one aspect, the invention provides a compound of formula (I) wherein R6 is selected from the group consisting of the following formulae (II), (III) and (IV):

In another aspect, the invention provides a compound of formula (I) wherein R6 is selected from the group consisting of the following formulae (II) and (III):

R8-R10, R11 (II) In another aspect, the invention provides a compound of formula (I) wherein R6 is a group of formula (II):

R10, R R8 11 (II). Wherein R6 is in another aspect, the invention provides a compound of formula (I) below: a group of formula (III): R1, 2

In another aspect, the invention provides a compound of formula (1) wherein R6 is a group of formula (IV): ' /\

N

I

Rb (IV). In another aspect, the invention provides a compound of formula (1) wherein R6 is R7. In one aspect, the invention provides a compound of formula (1) wherein R7 is selected from the group consisting of (G-C6)alkyl, (C3_Ci〇)cycloalkyl, aryl and aryl (Ci cj alkyl-oxime in another In one aspect, the invention provides a compound of formula (1) wherein R7 is selected from the group consisting of (q-Cd alkyl, aryl and arylalkyl). In another aspect, the invention provides a compound of formula (1) wherein R7 Is selected from the group consisting of (Ci-C: 6) alkyl and aryl substituted by (Ci_c0) alkyl (Ci 〇 alkyl. In another aspect, the present invention provides a compound of the following formula (1), wherein R7 is selected from N-propyl or methyl substituted benzyl. In one aspect, the invention provides a compound of formula (1) wherein R8 is selected from the group consisting of H, (CVC6)alkyl, (c3_Ciq)cycloalkyl, and aryl ( (VC4) Alkyl. In another aspect, the invention provides a compound of formula (1) wherein r8 is selected from the group consisting of hydrazine, ((: 丨-(:6) alkyl). In another aspect, the invention provides A compound of the formula (1) wherein hydrazine is (CVC6)alkyl. In another aspect, the invention provides a compound of the formula (1) wherein r8 is 151650.doc -21 - 201120038 aryl (CVC4) In one aspect, the invention provides a compound of formula (1) wherein R9 is selected from H, (CVC6)alkyl. In another aspect, the invention provides a compound of formula (1) wherein R9 is hydrazine. In one aspect, the invention provides a compound of formula (1) wherein "one of the ruthenium 9 is ruthenium and the other of R8 and R9 is not η, and the carbon atom to which R8 and R9 are attached has a palmarity And having a configuration. In one aspect, the invention provides a compound of the following formula (1), wherein one of R8 and R9 is deuterium and the other of R8 and R9 is not H, and ... and the ruler 9 are attached thereto. The carbon atom has a palmarity and has a [phantom configuration. In one aspect, the invention provides a compound of the following formula (1), wherein R3 is Η and the carbon atom to which R3 is attached has a palmarity and a (foot) configuration, And wherein one of R8 and R is 11 and the other of the ultra 8 and the ulnar 9 is not H, and the carbon atoms to which R8 and R9 are attached are palmar and have a configuration. In another aspect The present invention provides a compound of the following formula (1), wherein R3 is fluorene and the carbon atom to which R3 is attached is palm-like and has a "phantom type, and one of r8 and R And the other of R8 and R9 is not deuterium, and the deuterium atom to which R8&amp;r9 is attached has a palmarity and a configuration. In one aspect, the invention provides a compound of the following formula (1), wherein R1〇 Is selected from the group consisting of hydrazine, (Ci_C10) alkyl, (C3_Cl()) cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl (Cl_C4) alkyl, aryl (c^C4) alkenyl And a heteroaryl (C1-C4)alkyl group. In another aspect, the invention provides a compound of the following formula (I), wherein Ri 151650.doc -22- 201120038 is selected from the group consisting of Η, ((VCd) , (C3-C1()) cycloalkyl and aryl (Ci_c4). In another aspect, the invention provides a compound of formula (I) wherein R10 is selected from the group consisting of hydrazine, (CVC6) alkyl, and (C4-C6) cycloalkyl. In another aspect, the invention provides a compound of formula (I) wherein R10 is selected from the group consisting of hydrazine and (CVC6) alkyl. In another aspect, the invention provides a compound of formula (1) wherein r10 is (CVC6)alkyl. In one aspect, the invention provides a compound of formula (1) wherein R1 is selected from the group consisting of hydrazine and (CrCw) alkyl. In another aspect, the invention provides a compound of formula (1), wherein r11 is selected from the group consisting of hydrazine and (CVCd alkyl. In another aspect, the invention provides a compound of formula (1) wherein R11 is (CVC6)alkyl In one aspect, the invention provides a compound of formula (1) wherein r10 and R11, together with the nitrogen atom to which they are attached, form a 5 to 6 membered ring containing optionally another N selected from the group consisting of N a hetero atom of 0 and S, and optionally substituted by 1 or 2 substituents independently selected from the group consisting of (Ci-C6)alkyl, (CVC6)alkoxy, yl, CN and hydroxy, In another aspect, the present invention provides a compound of the formula (1) wherein r1〇 and R together with the nitrogen atom to which they are attached form a 5-member to 6-membered N-containing ring, including N Cyclic conditions are substituted by 1 or 2 ((VC6) hydryl substituents. In the present invention, the invention provides a compound of the following formula (1), wherein R8 and 151650.doc -23- 201120038 may form a saturation together with the atoms to which they are attached or Partially unsaturated 5 members 3' This contains a hetero atom selected from N, 〇 and s depending on the situation. Alternatively, or two substituents independently selected from the group consisting of (c, -c6) alkoxy, yl, CN, and a thiol group. The invention provides a compound of formula (I) wherein R8, together with the atom to which it is attached, forms a saturated 5- to 6-membered N-containing ring which is optionally substituted on the carbon via (4) (Ci_c6) leukoyl substituents In one aspect, the invention provides a compound of formula (1) wherein Μ is absent and R and R 彳 together with the atom to which they are attached form a 6 member, 9 member or 10 membered monocyclic or bicyclic ring. The N-containing aromatic ring optionally contains another hetero atom selected from N, fluorene and 8, and optionally, on the carbon, 2 or 3 independently selected from (C丨_C6)alkyl, (c丨_ C6) Substituent substitution of alkoxy, halo, CN, aryl, COOR15 and hydroxy. In another aspect, the invention provides a compound of formula (1) wherein R9 is absent and R8 and rig are attached thereto The atoms together form a 5-member, a 6-member, a 9-member or a 1-membered monocyclic or bicyclic ring containing an aromatic ring, which is optionally selected from 1 to 2 or 3 independently on the carbon (q-C6). )alkyl, c丨-C6) alkoxy, halo, CN, aryl, COOR15 and a substituent of a hydroxy group. In another aspect, the invention provides a compound of formula (1) wherein R9 is absent and R8 and R1G are together The atoms to which they are joined together form a 5-membered, 6-membered, 9-membered or 1-membered monocyclic or bicyclic N-containing aromatic ring. The N-containing aromatic ring is optionally substituted on the carbon by 1 or 2 (CrCd alkyl substituents). In one aspect, the invention provides a compound of formula (I) wherein R12 is selected from the group consisting of hydrazine and (CrCO alkyl. 15I650.doc -24 - 201120038 In another aspect, the invention provides the following formula (I) A compound wherein R12 is Η in one aspect, the invention provides a compound of formula (1) wherein R1 3 is selected from the group consisting of hydrazine, (CVC6) alkyl, aryl, heteroaryl, aryl (Cl_C4^-) Heterocyclic (C丨-C4) alkyl group. In another aspect, the invention provides a compound of formula (1) wherein rH is selected from the group consisting of hydrazine, (CVC6) alkyl, aryl and aryl (Ci_C4)alkyl. In another aspect, the invention provides a compound of formula (1), wherein R13 is aryl (CVC4)alkyl-. In another aspect, the invention provides a compound of formula (1) wherein R13 is benzyl. In one aspect, the invention provides a compound of formula (I) wherein R12 and R13 are Η and the other of the ruler and the ruler 3 is not H, and the ruler and the ruler are 3 The attached carbon atom has a (8) configuration for palmar I. In the present invention, the present invention provides a compound of the following formula (I), wherein R 2 and the other of them are H_a_Rl^Rl3, and the other is not Η, and r1^r1: the carbon atom to which it is attached It is palmar and has a configuration. The present invention provides a compound of the following formula (I), wherein R3 in the agricultural form is p and the carbon atom to be bonded has a „ sex and has a (8) configuration/ and wherein the ^ and ^ are in the group ^^12 and Rl3 The other one is not inhibited, and the rabbit atoms to which R" and R are attached are palmar and have the (8) configuration. In the present invention, the present invention provides a compound of the following formula (1) in which the dry (10) configuration of carbon 3 to which R is attached, and wherein the other is Η and the other of 11] 2 and 11] 3 a compound of the formula (1), wherein Ra is 11 and 1^2 15l650.doc -25- 201120038 and R13 are bonded to a palm atom and have a (any) configuration β in one aspect, wherein the present invention provides a compound of the following formula (1), wherein Ra And Rb are independently selected from the group consisting of hydrazine, (C"C丨〇)alkyl, (C2-C6)alkenyl, (C3_Cl〇)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkane Aryl(c2-c4)alkenyl, heteroaryl(Ci_c4)alkyl..._s〇2(Ci C6)alkyl, -S02 aryl and -S〇2 aryl (c-c4) alkyl In another aspect, the invention provides a compound of formula (1), wherein R and R are independently selected from the group consisting of hydrazine, (C-C6)alkyl, (C3_C6)cycloalkyl, heterocycloalkyl, aryl A heteroaryl group. In another aspect, the invention provides a compound of formula (I) wherein, together with the atom to which they are attached, a saturated or partially unsaturated 4 member to 7 member containing N ring, N ring-like case contains another miscellaneous source selected from N, 〇 and 8. And optionally substituted on the carbon via hydrazine or two substituents independently selected from the group consisting of alkyl, (Cl_C6) methoxy, dentate '(3) and hydroxy; the N-containing ring may also be fused to the aryl group as appropriate. In another aspect, the present invention provides a compound of the following formula (1), wherein ^ is bonded to the attached atom to form a saturated or partially unsaturated 5-membered product, and 1 or 2 are on the carbon depending on the case ( CVC6) Alkyl Substituent Substitution. b 3 Sample Trinkle' The present invention provides a compound of formula (I) wherein Ra and indole together with the atom to which they are attached form a 5 member, 6 member, 9 member or early or bicyclic ring. N-aryl ring, the N-containing ring optionally contains another - selected from N, a hetero atom 'and optionally, on the carbon, i, 2 or 3 independently selected from the group consisting of (1 6) alkyl (Cl_C6), The functional group, CN, aryl, COOR15 151650.doc -26· 201120038 and substituent substitution of a hydroxyl group. In another aspect, the present invention provides a compound of the following formula (1), wherein the ruler 3 and Rb may together with the atom to which they are attached Forming a 5-, 6-, 9- or 1-membered monocyclic or bicyclic N-containing aromatic ring together, the N-containing aromatic ring may be argon or carbon (Ci-C6) on the carbon as the case may be. In one aspect, the invention provides a compound of formula (1) wherein is hydrazine. In one aspect, the invention provides a compound of formula (1) wherein R15 is hydrazine. In one aspect, the invention A compound of the formula (1) wherein R16 is hydrazine is provided. In one aspect, the invention provides a compound of the formula (1) wherein R17, R18, R19 and R20 are independently selected from H, halo and (Ci_C6)alkyl. In another aspect, the invention provides a compound of formula (1) wherein R17, R18, R19&R2 are independently selected from η or (Ci_c6)alkyl. In another aspect, the invention provides a compound of formula (I) wherein R17, R18, R丨9 and R2. Is H. In one aspect, the invention provides a compound of formula (1) selected from the group consisting of: (R)·3-methyl·2·methylamino-pentanoic acid {(S)-2-(3,4-difluoro-benzene) -1[(1Η-pyrrolo[2,3-b]pyridin-5-ylindenyl)-aminecarboxylidene]-ethyl}-decylamine; (R)-l-fluorenyl-pyrrole Acridine_2_ decanoic acid {(s)_2_(3,4-difluoro-phenyl)pyrrolo[2,3-b]pyridine-5-ylindolyl)-aminocarboxylidene (S) -N-{(S)-2-(3,4-dioxin-stupyl)pyrolo[2,3-b]»pyridin-5-ylmethyl)-aminocarboxamide ]-Ethyl}-2-(isopropyl-methyl-amino)-propanamide; 151650.doc -27- 201120038 3 -Methyl-1H-0 ratio p each-2-decanoic acid {(S )-2-(4-fluoro-phenyl)-1-[(1Η-° 比略和[2,3-15]0 ratio bit-5-ylindenyl)-amine-branthyl]-ethyl} - stearamine; (11)-:^-{(3)-2-(3,4-dichloro-phenyl)-1-[(ex-.bibromo[2,3-13]. -5-ylmethyl)-amine-methyl]-ethyl}-2-yl-3-phenyl-propanamine; (S)-3-naphthalen-1-yl-2-(2-propane- 1-Continuously charged amino)-Ν-(1Η-°Biloze[2,3-b].Bite--5-ylmethyl)-propanol; (S)-3-methyl-2 Amidino-pentanoic acid {(R)-2,2-dicyclohexyl-1-[(1Η-πϋπ-[2,3-b]pyridine-5- (S)-l-fluorenyl-pyrrolidine-2-carboxylic acid {(R)-2,2-dicyclohexyl-1-[(1H) -pyrrolo[2,3-b].pyridin-5-ylindenyl)-aminecarboxylidene]-ethyl}-decylamine; (R)-2-amino-3-indenyl-valeric acid {(S)-2-naphthalene-buyl-1-[(1H-.pyrolo[2,3-b]pyridin-5-ylindolyl)-aminecarboxylidene]-ethyl}-decylamine (S)-2-(isopropyl-indolyl-amino)-N-{(S)-2-naphthalen-1-yl-1-[(1H-»比咯和[2,3-b Pyridine-5-ylindenyl)-amine-mercapto]-ethyl}-propanamine; (R)-l-methyl-pyrrolidine-2-furic acid {(S)-2-naphthalene-1 -yl-1-[(1H-pyrrolo[2,3-1)]pyridin-5-ylindenyl)-amineindolyl]-ethyl}-decylamine; (R)-2-diamine曱-3-mercapto-pentanoic acid {(S)-2-(3,4-difluoro-phenyl)-1_[(1H-pyrrolo[2,3-b].pyridin-5-yl-yl) (A)-N-{(S)-2-(3,4-difluoro-phenyl)-1-[(ΐΗ-&quot;比比和[ 2,3-b]'^pyridin-5-ylindenyl)-amine methyl-based]-ethyl}-2-(ethyl-fluorenyl-amino)-propanol; (8)-^ 1-{(8)-2-(3,4-difluoro-phenyl)-1-[(111-咐) &lt;Bromo[2,3&quot;^]»bipyridin-5-ylmethyl)-amine fluorenyl]-ethyl}-2-dimethylamino-propionamide; (S)-l-A Benzyl-pyrrolidine-2-carboxylic acid {(S)-2-(3,4-difluoro-phenyl)-1-[(1Η- 151650.doc •28· 201120038 11 洛洛和[2,3-b Pyridine _5_ylindenyl)-amine-methyl hydrazino]-ethyl decylamine; (R)-l-ethyl- fluorenidine_2_ decanoic acid {(s)_2_(3,4-difluoro- Phenyl 11 is more than [2,3-b]. Bisyl-5-ylmethyl)-aminoindenyl]-ethyldoxime; (R)-1_isopropyl-pyrrolidine -2-decanoic acid {(S)-2-(3,4-difluoro-phenyl)-1_[(1H-pyrrolo[2,3_b]pyridine·5-ylmethyl)-aminecarboxyl] -ethyl}-decylamine; (R)-l-isopropyl-piperidine_2_carboxylic acid KS)_2_(3,4-difluoro-phenyl)-^[(ΙΗ-° ratio 0 and [2 , 3-b]pyridine·5-ylmethyl)-aminoindenyl]-ethyl}·decylamine; (R)-l-methyl-piperidine_2-decanoic acid {(s)_2-( 3,4-difluoro-phenyl)_1_[(1Η-.pyrolo[2,3-b]pyridine-5-ylmethylamine decylethyldoxime; (S) -3-( 3,4-Difluoro-phenyl)_2-(2-diisopropylamino-acetamido)-N-(1H-0pyrolo[2,3-b]pyridine-5-ylindenyl) -propanolamine; (S)-3-(3,4-difluoro-styl)_2-[2-(2,6-didecyl- (pyridine-1-yl)-acetamido]-N-(1H-indolo[2,3-b]pyridin-5-ylindenyl)-propanamine; (R)-l-methyl- Pyrrolidine-2-carboxylic acid {(S)-2-(4-fluoro-phenyl)-1-[(1Η-.pyrolo[2,3-b]pyridin-5-ylindenyl)-amine oxime (醯)-N-{(S)-2-(4-fluoro-phenyl)-1-[(1Η-α比咯和[2,3-b] .Bistidine-5-ylmethyl)-amine-methyl]ethyl}_2-(isopropyl-methyl-amino)-propanamine, (S)-2-didecylamino-N- {(S)-2-(4-Fluoro-phenyl)-bu [(1H-.bibromo[2,3-b]0 is more than 5-methyl-)-aminomethyl]-B _ propylamine, (S)-2-(ethyl-methyl-amino)-N-{(S)-2-(4-fluoro-phenyl)·1-[(1Η-吼) And [2,3-b]pyridin-5-ylindenyl)-amine-indenyl]-ethyl}-propanin; (R)-l-fluorenyl ratio 11 each. S)-2-(3-Fluoro-phenyl)-: 1-[(1Η-.pyrolo[2,3-b]°pyridin-5-ylmethyl)-amine thiol]_B _ 醯 醯 ;; 151650.doc • 29- 201120038 (8)-^[-{(8)-2-(3-fluoro-phenyl)-1-[(111-〇比咯和[2,3 -1)](吼)-5-ylmercapto)-amine-mercapto]-ethyl}-2-(isopropyl-indolyl-amino)-propanamide; (S)-2-diindole Amino-N-{(S)-2-(3-fluoro- Phenyl)-1-[(1Η-indolo[2,3·b]pyridin-5-ylmethyl)-amineindolyl]-ethyl}-propionamide; (S)-2-( Ethyl-methyl-amino)-N-{(S)-2-(3-fluoro-phenyl)-1-[(1Η-η比咯和[2,3-b]e ratio bite-5 -(indenyl)-aminoglycolyl]-ethyl}-propanol; (R)-l-fluorenyl-pyrrolidine-2-furic acid {(S)-2-(2-fluoro-phenyl )-1-[(1Η-pyrrolo[2,3-b]»pyridin-5-ylindenyl)-amineindolyl]-ethyl}-decylamine; (S) -N-{(S )-2-(2-fluoro-phenyl)-1-[(1Η-pyrho[2,3-b]. (Bi)-l-fluorenyl-pyrrolidinium-(l)-indolyl-pyrrolidinium-pyridyl-pyridylamine-pyridylamine 2-formic acid {(S)-2-(4-a-phenyl)-[[1Η-pyrrolo[2,3-b]pyridin-5-ylmethyl)-aminecarboxylidene]-ethyl }- guanamine; (S) -N-{(S)-2-(4-gas-phenyl)-bu [(1Η-»比比和[2,3-b]° pyridine-5-yl Mercapto)-aminoindenyl]-ethyl}-2-(isopropyl-methyl-amino)-propanamine; (R)-l-methyl-pyrrolidine-2-carboxylic acid {(S -2-(3-Gas-phenyl)-1-[(1Η-pyrrolo[2,3-b]pyridin-5-ylindenyl)-amineindolyl]-ethyl}-decylamine; (S) -N-{(S)-2-(3-chloro-phenyl)-1-[(1Η-&quot;比比和[2,3-b]&quot; pyridine-5-yl fluorenyl )-Aminoindenyl]-ethyl}_2-(isopropyl-methyl-amino)-propanin; (S)-N-{(S)-2-(3- gas-phenyl)· 1-[(1Η-β&oxo[2,3-b]°pyridin-5-ylindenyl)-aminoindolyl]-ethyldiamino-propylamine; (S)- N-{(S)-2-(3- gas-phenyl)-1-[(1Η-.pyrolo[2,3-b]nb-pyridin-5-ylmethyl)-amine fluorenyl] -ethyl}_2_(ethyl-indolyl-amino)-propanin; (R)-l-methyl-depico bite, 2-decanoic acid {(S)-2-(3,4- Dichloro- -1[(1Η-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amineindolyl l·ethyl}-decylamine; 15I650.doc •30- 201120038 (S) -N-{(S)-2-(3,4·dichloro-phenyl)-1-[(1Η-&quot;bido[2,3-b]acridin-5-ylmethyl)- Aminomethyl]-ethyl}-2-(isopropyl-methyl-amino)-propanol; (S)-N-{(S)-2-(3,4-dichloro-benzene ))-1-[(1Η-η比比和[2,3_b]e-pyridin-5-ylmethyl)-aminecarbamyl]-ethyl}-2-dimethylamino-propanamide: (S)-N-{(S)-2-(3,4-dichloro-phenyl)-1-[(1Η-.pyrolo[2,3-b].pyridin-5-ylindole ()-Aminomethyl]]-ethyl}-2-(ethyl-fluorenyl-amino)·propanamine; (R)-l-nonylpyrrolidine-2-carboxylic acid {(S)- 1-[(1H-pyrrolo[2,3-b]pyridin-5-ylindenyl)-amine fluorenyl]-2-p-tolyl-ethyl}-decylamine; (S) -2-( Isopropyl-methyl-amino)-N-{(S)-l-[(lH-.pyrolo[2,3-b].pyridin-5-ylindenyl)-aminecarbenyl ]-2-p-tolyl-ethyl}-propionamine; (R) -l-decyl-pyrrolidine-2-carboxylic acid {(S)-1-[(1H-pyrrolo[2,3-b] Pyridine-5-ylmethyl)-amine-mercapto]-2-m-tolyl-ethyl}-decylamine; (S)-2-(isopropyl-indenyl-amino)-N-{ (S)-l -[(lH-. (r)-l-decyl-pyrrolidine; (R)-l-decyl-pyrrolidine -2-carboxylic acid {(S)-1-[(1H-pyrrolo[2,3-b]pyridin-5-ylindenyl)-amine fluorenyl]-2-o-tolyl-ethyl} (S) -2-(isopropyl-indolyl-amino)-N-{(S)-l-[(lH-° than s-[2,3-b]. than pyridine-5- (indenyl)-aminoindenyl]-2-o-tolyl-ethyl}-propanin; (R) -l-methylpyrrolidine-2-carboxylic acid {(S)-2-cyclohexyl- 1-K1H-&quot;Birdo[2,3-b]pyridin-5-ylmercapto)-amine-mercapto]-ethyl}-decylamine; (S) -l - fluorenyl-° ratio Each bite-2-decanoic acid {(S)-2-cyclohexyl-l-IXH indolobutolo[2,3-b]pyridin-5-ylindolyl)-aminecarboxylidene]-ethyl}_ Indoleamine; (S)-N-{(S)-2-cyclohexyl-1-[(1Η-°pyrolo[2,3-b]tIpyridin-5-ylmethyl)-amine formazan ]]-ethyl}-2·(isopropyl-methyl-amino)-propanamide; 151650.doc -31 - 201120038 (S)-N-{(S)-2-cyclohexyl-1- [(1H-.Pyrolo[2,3-b]«bipyridin-5-ylmethyl)-aminoindenyl]-ethyl}·2_diamido-propionamide; (S) -N-{(S)-2-cyclohexyl-1-[(1Η-.pyrolo[2,3-b]° pyridine-5-ylmethylamine oxime (2-ethyl}-2-(ethyl-fluorenyl-amino)-propanamine; (R)-l-ethyl-pyrrolidine-2-furic acid {(S)-2-cyclohexyl- 1-[(1H-pyrrolo[2,34]pyridin-5-ylindenyl)-amineindolyl]-ethyl}-decylamine; (R)-l-isopropyl-pyrrolidine-2- {(S)-2-cyclohexyl-1-[(1H-pyrrolo[2,3-b]pyridin-5-ylindenyl)-amineindolyl]-ethyl}-decylamine; R) -l-decyl-piperidine-2·decanoic acid {(S)-2-cyclohexyl-1-[(1H-pyrrolo[2,3_b].pyridin-5-ylmethyl)- Aminomethyl]-ethyl}-decylamine; 3-mercapto-1H-pyrrole-2-carboxylic acid {(S)_2-naphthalen-1-yl-1-[(1H-pyrrolo[2,3_b] Pyridine-5-ylindenyl)-amine-mercapto]-ethyldoximine; 1H-indole-2-carboxylic acid {(S)-2-naphthalen-1-yl-1-[(1H-pyrrole) And [2,3-b]pyrodo_5-ylmercapto)-aminecarboxylidene]-ethyl}-decylamine; 3,5-dimercapto-1H-pyrrole-2-furoic acid {(S )-2-(3,4-difluoro-phenyl)-1-[(ih-pyrrolo[2,3-b]pyridin-5-ylindolyl)-amineindolyl]-ethyl}- Indoleamine; 3-methyl-1H-pyrrole-2-furic acid {(S)-2-(3,4-difluoro-phenyl)-1-[(1Η-pyrrolo[2,3-b] »Bistidine-5-ylmercapto)-amine-mercapto]-ethyl}-decylamine; 1H-indole-2-furic acid {(S)-2-(3,4-difluoro-phenyl) )-卜[( 1H-pyrrolo[2,3-bppyridin-5-ylmercapto)-aminecarboxylidene]-ethyl}-decylamine; (S)-3-(3,4-difluoro-phenyl) -Ν-(1Η-. Bisolo[2,3-b]pyridin-5-ylindenyl)-2-(2-o-phenylphenyl-acetamido)-propanamine; 3-methyl-1H-pyrrole-2- {(S)-2-(3-Fluoro-phenyl)-1-[(1Η-pyrrolo[2,3-b]pyridin-5-ylindenyl)-aminecarboxyl]-ethyl }-decylamine; 151650.doc 32· 201120038 3_methyl_ih-0 ratio p each_2_formic acid {(S)-2-(2-form-local)-1_[(1 Η-0 ratio Slightly 弁[2,3-b]pyridin-5-ylmethyl)-aminecarboxamido l-ethyldoxime; 3_methyl_iH-n than 〇2--2-decanoic acid {(S) -2-(4-chloro-bensyl)-1-[(1Η-° ratio η each [2,3-b] acridine-5-ylindenyl)-amine-mercapto]-ethyl bromide Amine; 3-methyl-1H-pyrrole-2-carboxylic acid {(S)-2-(3·chlorophenyl)-1-[(1Η-α比哈和[2,3-bP than pyridine-5 -ylmethyl)-amine-mercapto]-ethyldoximine; 3-methyl-1Η-° ratio σ-_2-decanoic acid {(S)-2-(3,4-dichloro-benzene Base)-1-[(out-» ratio °[2,3-b]° ratio bit-5-ylmethyl)-aminemethanyl]ethyldoxime, 3_mercapto·1H_ Pyrrole-2-decanoic acid {(S)-1-[(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amineyl]-2-p-phenylene··B {}}}, 7-mercapto-1H-pyrrolecarboxylic acid {(S)_1_[(1H-pyrrolo[2,3_b]pyridin-5-ylmethyl _Aminyl]-2-m-tolyl-ethyl}-bristamine, 3-mercapto-1H-pyrrole_2_decanoic acid {(S)-1-[(1H-pyrrolo[2,3 -b]pyridine-5-ylindenyl)-aminoindenyl]-2-o-tolyl-ethyl}·chiral amine; 3-mercapto-1H-pyrrole-2·carboxylic acid KS)-2_cyclohexyl Ratio of U,3-b]° to bite-5-ylmethyl)-amine oxime]-ethyl styrene; (R)-2-yl-N-{(S)-2- Naphthalen-1-yl-1-[(1Η-Π比洛和[2,3-b]nt. _5_ hydrazinyl)-amine methyl]-ethyl}_3-phenyl-propanamide '(R)-N-{(S)-2-(3,4-Difluoro-phenyl)-1-[(1Η-pyrrolo[2,3-b]pyridine-5-ylindenyl)-amine (R)-N-{(S)-2-(4-fluoro-phenyl)-1-[(1Η- ··Birdo[2,3-b]acridin-5-ylmercapto)-amine-mercapto]Ethyl}-2-hydroxy-3-phenyl-propanamine; (R)-N -{(S)-2-(3·gas-phenyl)·ι_[(1Η-pyrolo[2,3-b]»biidine_5_ylindolyl)-amineindolyl]-ethyl 2-hydroxy-3-phenyl-propanamide; 151650.doc •33· 201120038 (R)-N-{(S)-2-(2-fluoro-styl)-1-[(1Η-σ Ratio of [2,3-b]°tb°--5-ylindenyl)-aminomethylindenyl]-ethyl}-2-hydroxy-3-phenyl-propanamide; (R) -N-{(S)-2-(4-Gas-phenyl)-1-[(1Η-pyrrolo[2,3b]pyridin-5-ylindolyl)-aminecarboxylidene]-ethyl} -2-hydroxy-3-phenyl-propionamide; (R)-N-{(S)-2-(3-chloro-phenyl)-1-[(1Η-η比咯和[2,3 -b]. (bi)-2-hydroxy-3-phenyl-N-{((pyridin-5-ylmethyl)-amine-methylcarbonyl]-ethyl}-2-hydroxy-3-phenyl-propanamine S)-1-[(1H-indolo[2,3-b]«·bipyridin-5-ylindenyl)-aminoindolyl]-2-p-tolyl-ethyl}-propanamide ; (尺)-2-hydroxy-3-phenyl-:^-{(5)-1-[(111-&quot;比比和[2,3-1)]&quot;比啶-5_基曱())-aminomethyl hydrazino]-2-m- phenyl-ethyl}-propanamine; (11)-2-hydroxy-3-phenyl-&gt; 1-{(8)-1-[( -(比比和[2,3-13].pyridin-5-ylmethyl)-aminemethanyl]-2-o-phenylphenyl-ethylpropiamine; (R) -N-{( S)-2-cyclohexyl-1-[(1H-.pyrolo[2,3-b]indolepyridin-5-ylmethyl)·amine hydrazino]-ethyl}-2-yl group -3 -Phenyl-propylamine, (S)-3-(3,4-difluoro-phenyl)-2-(propan-1-sulfonylamino)-N-(1H-pyrrolo[2 , 3-b]pyridin-5-ylindenyl)-propanamine; (S)-3-(4-fluoro-phenyl)-2-(propan-1-sulfonylamino)-indole-(1Η - «Birazolo[23_b]pyridin-5-ylindenyl)-propanamine; (S)-3-(3-fluoro-phenyl)-2-(propan-1-sulfonylamino)- Ν-(1Η-«Birdo[2,3_b]pyridin-5-ylindenyl)-propanamine; (S)-3-(2-fluoro-phenyl)-2-(propane-1- Sulfur Amino)-N-(1H-°pyrolo[2,3-b]pyridin-5-ylmethyl)-propanin; (S)-3-(4-Gas-phenyl)-2- (propane-1-sulfonylamino)-N-(1H-° ratio 咯[2,3-5]° ratio bit-5-ylmethyl)-propanolamine, 151650.doc -34· 201120038 ( S)-3-(3-Chloro-phenyl)-2-(propan-1-sulfonylamino)-N-(1H-.pyrolo[2,3-b]pyridin-5-ylmethyl )-propanolamine; (S)-3-(3,4-disorgano-phenyl)-2_(prosthetic-1-azeganyl)-Ν-(1Η-π ratio η和[2 , 3-b]0 than biting _5-ylmethyl)-propanol, (S)-2-(prodox-1), N-(1H-0 ratio slightly [2, 3-b]Dtt ate-5-ylindenyl)_3_p-tolyl-propionamine; (S)-2-(propan-1-sulfonylamino)-N-(1H-. 2,3-b]pyridin-5-ylindenyl)-3-m-tolyl-propionamide; (S)-3-cyclohexyl-2-(propan-1-sulfonylamino)-N-( 1H-lalocodo[2,3-b]pyridin-5-ylmethyl)-propanin; (S)-2-diamino-N-{(S)-2-pre-1-yl -1-[(1H-. The ratio is slightly [2,3-b]. (B)-N-{(S)-2-(3,4-difluoro- Phenyl:)_1-[(1Η-»比比和[2,3-b].pyridin-5-ylmethyl)-amineindolyl]-ethyl}-2-dimethylamino-3 -Phenyl-propanamine; (R)-2-hydroxy-N-{(S)-2-naphthalen-1-yl-1-[(1Η-〇 咯 并 [2,3-bp pyridine-- 5-(methyl)aminocarbazide]-ethyl}-butanamine; (R)-2-hydroxy-3-methyl-N-{(S)-2-naphthalen-1-yl-1 -[(1Η-°pyrolo[2,3-b]pyridin-5-ylindenyl)-aminecarboxylidene]-ethyl}-butanamine; (S)-2-hydroxy-3-indole -N-{(S)-2-naphthalen-1-yl-1-K1H-. Bis-[2,3_b]pyridin-5-ylindenyl)-aminecarboxylidene]-ethyl}-butanamine; (R) -N-{(S)-2-(3,4-di Fluoro-phenyl)-1-[(1Η-°pyrho[2,3-bppyridyl-5-ylindenyl)-amineindolyl]-ethyl}-2-hydroxy-3-methyl -butyramine; (S) -N-{(S)-2-(3,4-difluoro-phenyl)-bu [(1Η-β* pyrrolo[2,3-b]acridine-5_ Methyl)-amine-mercapto]-ethyl}-2-hydroxy-3-indolyl-butanamine; 151650.doc -35- 201120038 and its tautomers, stereoisomers, medicinal Acceptable salts and solvates. In another aspect, the invention provides a compound of formula (1) selected from the group consisting of: (R)-3-methyl-2-indenyl-decanoic acid {(S)-2-(3,4-dibenzene) ()) ([1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-aminecarboxylidene] ethyl bromide; (R)-1-indenyl-. Each bite 2-carboxylate {(S)-2-(3,4-dioxa-n-pylpyrrolo[2,3-b]pyridin-5-ylmethyl)-aminecarbamyl]-B (b)-N-{(S)-2-(3,4-difluoro-phenyl) small [(1Η-»比比和[2,3-b]&quot;5-(indenyl)-aminoindenyl]-ethyl}-2-(isopropyl-methyl-amino)-propanamine; (S)-2-(isopropyl-indenyl-amine Base)_n_{(S)-2-naphthalen-1-yl-1-[(1H-pyrrolo[2,3-b]0-biti-5-ylmethyl)-amine-methyl]-ethyl }-propanamide, (11)-1-ethyl-pyrrolidine-2-decanoic acid {(3)-2-(3,4-difluoro-phenyl)-bu[(1^-pyrrolo[ 2,3-b]pyridin-5-ylindenyl)-aminoindenyl]-ethyl}-decylamine; (R)-isopropyl-pyridin-2-indole {(S)- 2-(3,4-Difluoro-phenyl)-1-[(lH-ηpyrolo[2,3-b]pyridin-5-ylmethyl)-aminecarboxylidene]-ethyl}-醢amine; (R)-l-methyl·piperidin-2-furic acid {(S)-2-(3,4-difluoro-phenyl)-1-[(1Η-pyrrolo[2,3 -b]pyridine-5-ylindenyl)-aminoindenyl]-ethylguanamine; (S)-3-(3,4-difluoro-phenyl)_2_(2-diisopropylamino-B醯Amino)_N_(1H_pyrrolo[2,3-b]pyridine-5-ylmethyl)-propanamine; (S)-3-(3,4-difluoro-phenyl)·2_[2 ·(2,6_二曱_ piperidine-diyl)-acetamido]-indole-(1Η-pyrrolo[2,3_b]pyridine-5-ylmethylpropionamide; (S)-N-{(S):2- (4-fluoro-phenyl).pyrolo[2,3b]0-pyridyl-5-ylmethyl)-amine-methylmethyl]-ethyl b-2-(isopropyl-methyl-amino)-prop Indoleamine; 151650.doc •36- 201120038 (R)-l-mercapto-indolyl-2-indole {(S)-2-(4-a-phenyl)-indole-[(1Η·pyrrole) And [2,3-b]pyridin-5-ylindenyl)-aminoindenyl]-ethyldoximine; (8)-;^-{(8)-2-(4-chloro-phenyl )-1-[(11'1-.pyrolo[2,3-1)]»pyridin-5-ylmercapto)-aminecarinyl]-ethyl}-2-(isopropyl- Methyl-amino)-propanamine; (3)-:^-{(8)-2-(3-chloro-phenyl)-1-[(111-.bibromo[2,3-1 )]1-pyridin-5-ylmethyl)-amine-methylmethyl]-ethyl}-2-(isopropyl-methyl-amino)-propanamine; (R) -l-methyl -pyrrolidine-2-decanoic acid {(S)-2-(3,4-dichloro-phenyl)·1-[(1Η-°pyrho[2,3-b]pyridine-5-yl- (-)-N-{(S)-2-(3,4-dichloro-phenyl)-1-[(1Η-吼) [2,3-b]°pyridin-5-ylmethyl)-amineindolyl]-ethyl}-2-(isopropyl-methyl-amino)-propanamine; (S)- 2- (different Yl - methyl - amino) -N - {(S) -l - [(lH-nfc〇 and each [2,3-b]. (β)-2-(isopropyl-methyl-amino)_N- {(S)-1-[(1H-D is more than B and [2,3-b].pyridin-5-ylmethyl)-aminoindenyl]-2-inter-p-phenyl-ethyl} -propanolamine; (S)-N-{(S)_2_cyclohexyl-1-[(1H-pyrrolo[2,3-b]acridin-5-ylmethyl)-aminocarbamyl] -ethyl}-2-(isopropyl-methyl-amino)-propanamine; (R)-l-decyl-piperidine-2-furic acid {(S)-2-cyclohexyl-1 -[(1H-pyrrolo[2,3-b].pyridin-5-ylmethyl)-aminoindolyl]-ethyldoxime; and tautomers, stereoisomers, pharmaceuticals thereof Learnably acceptable salts and solvates. Those skilled in the art will recognize that each of the compounds identified in the examples identified above or hereinafter provided, in any combination, alone or in combination with other identified compounds, represent an independent aspect of the invention. Therapeutic Applications 151650.doc -37- 201120038 As mentioned previously, the compounds of the invention have a variety of therapeutic applications due to their ability to inhibit klki, particularly for the treatment of inflammatory diseases such as asthma and COPD. In particular, the compounds of the invention are useful in the treatment of respiratory conditions involving airway inflammation, such as asthma (allergic and non-allergic), including exacerbations caused by asthma and chronic obstructive pulmonary disease (COPD). These compounds are also used to treat other forms of allergic inflammation, including allergic rhinitis (hay fever), nasal conjunctivitis, rhinorrhea, urticaria, excessive production of pulmonary mucus, formation of ascites, chronic bronchitis, chronic airway obstruction, and lungs. Fibrosis and lung swelling. Other inflammatory conditions which may be treated by the compounds of the invention include multiple syndromes, arthritis, rheumatoid arthritis, osteopathic arthritis, osteoarthritis, rhinitis, sinusitis, inflammatory horse disease ( Such as Crohn's disease and ulcerative colitis, diabetes-mediated diabetes, acute otitis and interstitial cystitis, thermal injury, crush, conjunctivitis, periodontal disease, chronic prostate Inflammation, chronic recurrent phlegm, inflammatory skin conditions (such as psoriasis, eczema), cirrhosis, spinal trauma and round (systemic inflammatory response syndrome); smooth muscle cancer climbing (eg (4) asthma, angina), RDS (respiratory distress syndrome); hypotension (such as shock caused by hemorrhage, sepsis or systemic allergic reaction, cancer-like group, gastric dumping), edema (such as burns, _ injury, hematoma (whether or not Caused by angiotensin-converting enzyme inhibitor treatment)); pain and irritation (such as burns, wounds, incisions, rashes, stab wounds, insect bites), migraine's Kallikrein produced 151650.doc -38- 201120038 contraceptive agent 'to prevent excessive blood loss during surgical procedures. The compounds of the invention may also be used to treat conditions (e.g., cough) that may be responsive to the release of inflammatory mediators. The compounds of the invention are also useful in the treatment of conditions involving modulation of growth factors, such as vascular endothelial growth factor (vEGF), which may involve increased vascular permeability (e.g., diabetic retinopathy and septic shock). The compounds of the invention are useful in the treatment of neoplastic conditions (eg, adenocarcinoma, tumor angiogenesis), and in particular, can be used to reduce angiogenesis associated with = (eg, cancer and tumor growth), and to modulate angiogenesis and neoplasia and Other processes associated with tumor growth, and in particular, can be used to block tumor angiogenesis and/or cancer cell invasion and metastasis. Asthma Asthma is a chronic lung condition that can be classified as allergic (endogenous) or non-allergic (exogenous). Patients with asthma suffer from difficulty breathing due to stenosis or obstruction of the trachea, making it difficult to inhale and exhale air. This stenosis can be caused by tracheal inflammation and bronchoconstriction. Symptoms of asthma include, for example, wheezing, shortness of breath, bronchoconstriction, tracheal overreaction, decreased lung capacity, fibrosis, tracheal inflammation, and mucus production. Another symptom of asthma is the deterioration caused by the onset of initial asthma, which has a significant incidence of morbidity in the disease. KLK1 inhibitors can be used to ameliorate or prevent at least one symptom of asthma: KLK1 inhibitors can also be combined with other agents for the treatment of asthma (eg inhaled steroids, oral steroids, long-acting beta-agonists, leukotriene modifiers, cromolyn) Cromolyn sodium and ned〇cr〇mil, theophymne and anti-IgE antibodies (see below) were administered together. 151650.doc -39- 201120038 Allergic rhinitis Allergic rhinitis or "wild grass early", "related to allergic reactions to pollen from grass, trees and weeds. When an individual inhaled pollen is inhaled by an individual who is allergic to rhinitis, it triggers antibody production and histamine liberation. Symptoms of allergic rhinitis include (but are not limited to) cough; headache; eyelids, eye, mouth, throat or nasal itching; sneezing 嗓 'nasal congestion' wheezing; throat disease · Η ... ^, session, and tears. The symptoms associated with hay fever are significantly different between different people, and J • Allergic rhinitis can be associated with other conditions such as asthma. Chronic obstructive pulmonary disease (C〇PD> Chronic obstructive pulmonary disease ((7) Kiss is a disease involving tracheal inflammation. Emphysema and chronic bronchitis belong to (10) D. It is a serious lung disease and carries H, it * appears in In elderly patients. (3) causes excessive inflation of the structure called alveoli or air sac in the lung. The rupture of the alveolar wall causes a decrease in lung smoking capacity. Patients suffering from itfc« disease may first experience shortness of breath and cough. KLK1 inhibitors can be used to improve at least A c〇pD symptom inhibitor can also be combined with another agent for treating c〇pD (eg, inhaled steroids, oral steroids, long-acting beta-agonists, leukotriene modifiers, sodium cromoglycate, and nedocromil, Theophylline and anti-IgE antibodies (see below) are administered together. Cough and cough can be caused by viral infections caused by inflammation of the upper respiratory tract (throat and trachea). The viral infections include the common cold, influenza, laryngitis and bronchitis. These viral infections can also cause coughing in the lower respiratory tract (bronchial). Cough includes asthma, bronchitis, influenza, and whooping cough (Wh〇0Ping cough/pe Rtussis) a variety of diseases and symptoms of the disease, and 151650.doc 201120038 can also be used as a side effect of the use of certain drugs such as ACE inhibitors. Inhaled individuals often have a cough, which often causes thin fluid exhalation A loud cough. The illusion inhibitor can be used to ameliorate or prevent at least one coughing symptom. Deterioration caused by asthma and chronic obstructive pulmonary disease (C〇pD). Individuals with asthma and COPD begin to have certain lungs and trachea in their lungs There is a risk of deterioration in the overreaction of the substances that trigger these morbidity. During the deterioration, the endotracheal lining is suddenly swollen and inflamed. The muscles of these trachea will become tense and the production of mucus will increase. This combination makes the opening narrower. And may almost completely close it, making the dyspnea 'deteriorating rickets significantly and causing a disproportionate amount of asthma management costs, often worsening for at least a month after the deterioration. The current treatment strategies for acute asthma exacerbations are largely Depends on bronchodilators and inhaled or systemic corticosteroids. Lamps can be used to improve or prevent at least one type of deterioration. Inhibitors may also be combined like .KLK1 further treatment of asthma and COPD primer &lt; Deteriorating agents (eg inhaled steroids, oral steroids, long-acting beta agonists, leukotriene modifiers - sodium cromolyn and nedocromil, theophylline and anti-IgE antibodies) (see below) versus. Pancreatitis Sputum inflammation is a pancreatic inflammation. There are two types: Acute pancreatitis - inflammation develops rapidly within a few hours and usually heals without leaving permanent damage, but it can be fatal if complications occur (5% of cases). Chronic pancreatitis. This condition usually begins with multiple episodes of acute pancreatitis and eventually becomes a permanent condition. The pancreas continues to be inflamed. 151650.doc 41 201120038 KLK1 inhibitors can be used to ameliorate or prevent at least one pancreatic inflammation. Rheumatoid Arthritis (RA) This condition is characterized by inflammation of the inner lining of joints and/or other internal organs. It is usually chronic but can include bursts. Symptoms include joint inflammation, swelling, difficulty moving, pain, and fever. KLK1 inhibitors can be used to ameliorate or prevent at least one symptom of rheumatoid arthritis. KLK1 inhibitors can be administered with another agent for the treatment of rheumatoid arthritis (such as NSAIDs and aspirin, analgesics and corticosteroids). This additional agent helps to relieve joint pain, stiffness and swelling. Osteoarthritis Osteoarthritis is a degenerative joint disease. It is characterized in that the articular cartilage is broken, causing the bones to rub against each other, causing pain and loss of exercise capacity. KLK1 inhibitors can be used to ameliorate or prevent at least one symptom of osteoarthritis. The KLK1 inhibitor can be administered in combination with another agent for treating rheumatoid arthritis, such as a corticosteroid or NS AID. Hyaline Tube Formation Correlation and Neoplastic Disorders In one embodiment, KLK1 inhibitors can be administered to an individual to modulate angiogenesis or other processes associated with neoplasia and tumor growth. For example, KLK1 inhibitors can be used to reduce angiogenesis (eg, uncontrolled or undesirable angiogenesis), such as angiogenesis associated with the following conditions: vascular malformations and cardiovascular disorders (eg, atherosclerosis, restenosis, and arteriovenous Malformations), chronic inflammatory diseases (eg diabetes, inflammatory bowel disease, psoriasis and rheumatoid arthritis), skin conditions (eg arterial ulcers, systemic vasculitis and scleroderma) or ocular conditions (eg by newborns) Vascular 151650.doc •42· 201120038 Blindness caused by sexual diseases, neovascular glaucoma, corneal neovascularization, trachoma, diabetic retinopathy and myopia degeneration). In particular, KLK1 inhibitors can be used to reduce angiogenesis associated with neoplasia, such as cancer and tumor growth, such as benign, malignant or metastatic tumor growth. Examples of cancerous conditions include, but are not limited to, solid tumors, soft tissue tumors, and metastatic lesions. Examples include sarcomas, adenocarcinomas, and carcinomas of various organ systems, such as invading the lungs, breasts, lymph, gastrointestinal (eg, colon) and genitourinary tract (eg, renal urothelial cells), pharyngeal, prostate, sarcoma of the ovary, adenocarcinoma, and Cancer, and adenocarcinoma including malignant diseases such as most colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung cancer, pharyngeal cancer, small intestine cancer, esophageal cancer, and other cancers. Exemplary solid tumors that can be treated include: fibrosarcoma, mucinous sarcoma, liposarcoma chondrosarcoma, osteogenic sarcoma, chordoma, lymphoproliferative sarcoma (lymphanangioendotheliosarcoma), synovial tumor, mesothelioma, Ewing's tumor (Ewing's) Tumour), leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary carcinoma, papillary adenocarcinoma , cystadenocarcinoma, myeloid carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, non-small cells Lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, cholangiocarcinoma, craniopharyngioma, ependymoma, pineal adenoma, hemangioblastoma, acoustic neuroma, oligodendrocyte Tumor, meningiomas, melanoma, neuroblasts 151650.doc -43- 201120038 Tumor and retinoblastoma. KLK1 inhibitors are also useful in the treatment of cancers, such as epithelial or endocrine tissue malignancies, including respiratory cancers, gastrointestinal cancers, genitourinary cancers, and melanoma. Exemplary cancers include adenocarcinomas and carcinomas of the cervix, lung, prostate, breast, head and neck, colon and ovarian tissue. KLK1 inhibitors can also be used to treat sarcomas, such as mesenchymal malignancies. The KLK1 inhibitor can be administered in combination with another agent for treating a neoplastic and/or metastatic disorder. Examples of such other agents include: (1) other anti-angiogenic agents (e.g., lin〇mide, angiostatin, razoxane); (ii) cytostatic agents , such as anti-estrogen agents (such as tamoxifan, toremifene, raloxifene), progesterone (such as megestr〇i acetate), ^ Aromatization inhibitors (such as anastrox (ie), anti-progestin, anti-androgen (eg, flutamide, nilutamide) ), bicalutamide, anti-invasive agents (eg, metalloproteinase inhibitors (such as marimastat) and urokinase plasminogen activator receptor function inhibitors); (iii) Anti-proliferative/anti-neoplastic drugs and combinations thereof used in medical oncology such as antimetabolites (eg, fluoropyrimidines such as 5-fluorouracil, purine and adenosine analogs, cytosine arabinoside) )); embedded anti-tumor antibiotics (example Such as anthracycline 151650.doc -44 - 201120038 (anthracycline), such as cranberry (doxorubicin), daunorubicin (daunomycin), epirubicin (epirubicin); rhythm derivatives (such as cisplatin ), carboplatin ('carboplatin); alkylating agents (such as chlorambucil, cyclophosphamide); anti-mitotic agents (such as vinca alkaloid, such as Changchun) New base (vincristine); and taxoids such as TAXOL® (paclitaxel), TAXOTERE® (docetaxel); topoisomerase inhibitors (eg epipodophyllotoxin (eg epipodophyllotoxin) Epipodophyllotoxin) 'such as etoposide and teniposide); and proteasome inhibitors such as VELCADE® (bortezomib). Accordingly, the present invention provides a compound of formula (1) for use in therapy. The invention also provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of a disease or condition involving KLK1 activity. Diseases or conditions involving KLK1 activity include inflammation, respiratory disorders, conditions involving the regulation of growth factors, and neoplastic disorders. Specific examples of such diseases and conditions include those listed above. The invention also provides a compound of formula (I) for use in the treatment or prevention of a disease or condition involving KLK1 activity. Diseases or conditions involving KLK1 activity include inflammatory diseases, respiratory conditions, conditions involving the regulation of growth factors, and neoplastic diseases. Specific examples of such diseases and conditions include those listed above. The invention also provides a method of treating a disease or condition involving KLK1 activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I). Diseases or conditions involving KLK1 activity include inflammation, respiratory diseases 151650.doc • 45· 201120038, diseases involving the 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 involving KLK1 activity is selected from the group consisting of an inflammatory or respiratory condition or condition selected from the group consisting of asthma (allergic and non-allergic), chronic obstructive pulmonary disease (COPD), allergic Rhinitis (hay fever), cough, deterioration caused by asthma and chronic obstructive pulmonary disease (c〇PD), multiple sclerosis, arthritis, rheumatoid arthritis, osteoarthritis, 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 prostatitis, Chronic recurrent mumps, inflammatory skin conditions (eg psoriasis, eczema) and SIRS (systemic inflammatory response syndrome); smooth muscle spasms (eg asthma, angina), RDS (respiratory distress syndrome), rhinoconjunctivitis, rhinorrhea, sputum Measles, neoplastics, chronic bronchitis, chronic airway obstruction, pulmonary fibrosis, and emphysema. In another aspect, the disease or condition involving KLK1 activity is selected from the group consisting of sputum % (allergic and non-allergic) 'chronic obstructive pulmonary disease (c〇pD), allergic rhinitis (wild fever), cough, by A worsening respiratory condition caused by asthma and chronic obstructive pulmonary disease (COPD). In another aspect, the disease or condition associated with KLK1 activity is selected from the group consisting of asthma (allergic and non-allergic) and exacerbations caused by asthma and chronic obstructive pulmonary disease (c〇pD). In another aspect, the disease or condition involving KLK1 activity is a respiratory condition selected from the group consisting of asthma (allergic and non-allergic) and cough. 151650.doc •46· 201120038 In another aspect, the disease or condition involving KLK1 activity is aggravation caused by asthma and chronic obstructive pulmonary disease (COPD). Combination Therapy This treatment can have important benefits for respiratory diseases. However, the efficacy of some of these agents is often unsatisfactory, especially for the treatment of c〇pD and the deterioration associated with tracheal disease. In addition, the complexity of the respiratory diseases such as sputum and COPD 'may be any kind of mediator alone may not be satisfactory for treating the disease alone, and the combination of therapeutic agents may be beneficial "monthly. In particular, Although the use of steroids can produce treatments, it is desirable to be able to use steroids at low doses to minimize the incidence and severity of undesirable side effects that may be associated with conventional melody, and with other agents such as KLK1 inhibitors. The combination of agents can result in a significant reduction in steroid dosage and thus minimize potential side effects. Thus, the compound can be used in combination with the compounds of the invention for the prevention and treatment of inflammatory lung diseases. The present invention also relates to prevention. And treatment of the following: pharmaceutical composition of the following respiratory diseases: asthma (allergic and non-allergic X including deterioration from asthma), allergic rhinitis and chronic obstructive pulmonary disease (COPD) ' § hai and other pharmaceutical compositions contain A therapeutically effective amount of a compound of the invention and/or a plurality of other therapeutic agents. The compositions are also useful for treating allergic inflammation of the formula' Allergic rhinitis (hay fever, nasal conjunctiva = rhinorrhea, expectoration 'excessive production of lungs (IV), formation of ascites, slow bronchitis s X 'chronic airway obstruction, pulmonary fibrosis and emphysema. Therefore, the present invention includes The compound of the present invention and/or a combination of a plurality of anti-inflammatory agents, bronchodilators, antihistamines, decongestants or antitussives 151650.doc • 47· 201120038 agents, wherein the compounds of the present invention and the combination agents are present in The same or different pharmaceutical compositions are administered 'alone, continuously or simultaneously. The combination may comprise two or three different pharmaceutical compositions. Suitable therapeutic agents for use in combination with the compounds of the invention include: (i) steroid glucocorticoids Examples of steroid glucocorticoid agonists which may be used in this embodiment include budesonide, fluticasone (for example in the form of propionate), mometasone (for example, Beta-valerate form), beclomethasone (for example in the form of 17-propionic acid vinegar or 17.1-21-dipropionic acid vinegar), cscienal (cjcies〇nide), gastropin (loteprednol) (for example in the form of etabonate), etipednol (in the form of, for example, dicloacetate), triamcinolone (for example in the form of a condensed acetonide), Flunisolide, zoticaasone, flomoxonide, roofleponide, butixocort (eg in the form of propionate), strong Prednisolone, prednisone, tipredane, steroid vinegar, for example 6α, 9α_二气-17α-[2-°夫基基基基)oxy]- 11 β -transcarbyl _ 16 α -mercapto-3 - oxo-androst-1,4 _diene-17β-thioformic acid S-fluoromethyl ester, 6α,9α·difluoro-11β-hydroxyl_ 16 α-Methyl-3-oxooxy-17α-propoxycarbonyl-androstidine-1,4-diene·ΐ7β_ thioformic acid S-(2-trioxy-tetrahydro-furan-3S-yl Ester and 6α,9α-difluoro-11β-hydroxy-16α-mercapto-17α-[(4-indolyl-1,3-thiazol-5-carbonyl)oxy]·3-sideoxy-androgen -1,4-diene-17β-thiodecanoic acid S-fluoromethyl 151650.doc -48- 201120038 ester, DE 4129535 and the like Alcohol esters, steroids of WO 2002/00679, WO 2005/041980, or steroids GSK 870086, GSK 685698 and GSK 799943; (ii) non-steroidal glucocorticoid receptor agonists; (iii) β2 adrenergic receptor agonist Agents such as albuterol (salbutamol), salmeterol, metaproterenol, terbutaline, fenoterol, and isoforms Procaterol, carmoterol, indacaterol, formoterol, arformoterol, Bpicucolol GSK- 159797 'GSK-597901' GSK-159802, GSK-64244, GSK-678007, TA-2005 and the following patents: EP1440966, JP05025045, W093/18007 'WO99/64035 ' US2002/0055651 ' US2005/0133417, US2005/5159448 , WO00/075114, WOOl/42193 'WOOl/83462, WO02/66422, W002/70490, WO02/76933, WO03/24439, W003/42160, WO03/42164, WO03/72539, W003/91204, WO03/99764, WO04 /16578, W004/016601, WO04/225 47, WO04/32921, WO04/33412, WO04/37768, WO04/37773, W004/37807 'WO0439762 'WO04/39766 'WO04/45618 , W004/46083 , WO04/71388 , W004/80964 , EP1460064 &gt; W004/087142 , 151650.doc -49-201120038 WO04/89892, EP01477167, US2004/0242622, US2004/0229904 'W004/108675, W004/108676, W005/033121, W005/040103, WO05/044787, W004/071388, WO05/058299, WO05/058867, W005/065650, W005/066140, W005/070908, W005/092840, W005/092841, W005/092860 'WO05/092887, W005/092861, W005/090288 'W005/092087, W005/080324, W005/ 080313, US20050182091, US20050171147, W005/092870 'W005/077361, DE10258695, W005/111002, W005/111005, W005/110990, US2005/0272769, W005/110359, W005/121065, US2006/0019991, W006/016245, W006/ 014704 , W006/031556 , WO06/032627 &gt; US2006/0 1 06075 ' US2006/0 1 062 1 3 ' W006/051373, W006/056471 ; (iv) White tristimulus regulators, such as montelukast Zarazutka St) or pranlukast; protease inhibitors, such as inhibitors of matrix metalloproteinases (eg MMP12) and TACE inhibitors, such as marimastat, DPC-333, GW_ 3333; (v) human hobby Human leukocyte elastase inhibitors, such as sivelestat and the compounds described in the following patents: WO04/043942, W005/021509, W005/021512, W005/026123, W005/026124, W004/024700, 151650. Doc -50- 201120038 W004/024701 ' W004/020410 , W004/020412 , W005/080372 , WO05/082863 , WO05/082864 , W003/053930 ; (vi) Phosphodiesterase-4 (PDE4) inhibitors, eg Luo Roflumilast, arofylline, cimomilast, Ibudilast, Lirimilast, Mesopram, ONO-6126 or 1vi-485; (vii) acid diacetate-7 inhibitor; (viii) kinase inhibitor, especially P38 mitogen-activated protein kinase (MAP Kinase) inhibitor; (ix) muscarinic receptor antagonist; X) Chemokine receptor function modulators, such as CCR1, CCR2, CCR3, C Antagonists of XCR2, CXCR3, CX3CR1 and CCR8, such as SB-332235, SB-656933, SB-265610, SB-225002, MC Pl (9-76), RS-504393, MLN-1202, INCB-3284; Xi) CRTH2 receptor agonist. DEFINITIONS The term "alkyl" includes saturated hydrocarbon residues including: - having up to 10 atoms (CVCw), or having up to 6 atoms (C"C6) or having up to 4 atoms (Ci-CJ's linear group) Examples of such alkyl groups include, but are not limited to, C" mercapto, C2 ethyl, C3 propyl, and C4 n-butyl. 151650.doc -51 · 201120038 - having 3 to 10 atoms (C3_C10), Or a branching group having up to 7 atoms (C3_C·?)' or having up to 4 atoms (CyC: 4). Examples of such alkyl groups include, but are not limited to, C3 isopropyl, C4 second Butyl, (i-butyl, C4 tert-butyl and c5 neopentyl. Each is optionally substituted as described above. The term "alkenyl" includes monounsaturated hydrocarbon residues which include: - 2 a linear group of up to 6 atoms (CrC6). Examples of such alkenyl groups include, but are not limited to, C2 ethylene, C3 1-propyl, C3 allyl, c4 2 -butyl. Branch groups to 8 atoms (C3_CS). Examples of such groups include, but are not limited to, c4 2 -methyl-2-propenyl and c6 2,3-diindenyl-2-butenyl. Depending on the situation Substituted as described above. The term "alkynyl" includes monounsaturated hydrocarbon residues having a carbon-carbon bond comprising: - a linear group having from 2 to 6 atoms (CyC6). Examples include, but are not limited to, C2 ethynyl, a丨-propynyl, C4 2 -butynyl. _ has 3 to 8 atoms (C3-C〇 branched chain groups. Examples of such alkynyl groups include (but not limited to) C4 3-methyl-1-propynyl. The term "alkoxy" includes a hydrazone-bonded hydrocarbon residue comprising: - having from 1 to 6 atoms (Ci_C6), or having one a linear group of up to 4 atoms. Examples of such alkoxy groups include, but are not limited to, C] methoxy, C2 ethoxy, C3 n-propoxy, and C4 n-butoxy. 6 atoms (C3_C6), or 151650.doc-52-201120038 branched chain groups having 3 to 4 atoms. Examples of such alkoxy groups include, but are not limited to, Cs isopropoxy and c4 second Butoxy and tert-butoxy. Each is optionally substituted as described above. Unless otherwise stated, the halo group is selected from the group consisting of CM, F, 81* and ί. The cycloalkyl group is as defined above. Cycloalkyl There are 4 to 1 carbon atoms or 5 to 10 slave atoms or 4 to 6 carbon atoms. Examples of suitable monocyclic ring burns include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. , cyclopentene, cyclopentane-1,3-diene, cyclohexene and cyclohexadiene (optionally substituted as described above). Examples of suitable bicyclic cycloalkyl groups include decalin and octahydro-1 //-茚 (substituted as described above). When fused with an aryl group, examples of a suitable 5% alkyl group include a guanidine group and 1,2,3,4-tetrahydronaphthyl group. The situation is replaced as described above). The hetero-based alkyl group is as defined above. Examples of suitable heterocyclic alkyl groups include epoxyethyl, aziridine, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, fluorenyl-methylpiperidinyl, Polinyl, Ν-methylmorpholinyl, thiomorpholinyl, thiomorpholinyl-丨-oxide, thiomorpholinyl-1,1-dioxide, piperazinyl, N-fluorenyl Piperazinyl, aziryl, oxazole, diazepht and 1,2,3,4-tetrahydropyridyl (substituted as described above). The aryl group is as defined above. Typically, the aryl group is optionally substituted with hydrazine, 2 or 3 substituents. Substituents which are optionally present are selected from the above. Examples of suitable aryl groups include phenyl and naphthyl (each of which is optionally substituted as described above). Heteroaryl is as defined above. Examples of suitable heteroaryl groups include thiophene I51650.doc-53-201120038, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiol, iso-salt, three. Sodium, succinyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, fluorenyl, benzoimidazolyl, benzotriazolyl, quinolyl And isoquinolyl (substituted as described above). The term "c linkage" as in "c-bonded heterocycloalkyl" means that a heterocycloalkyl group is attached to the remainder of the molecule via a ring carbon atom. The term "ν linkage" as used in "heterocycloalkylheterocycloalkyl" means that the heterocycloalkyl group is attached to the remainder of the molecule via a ring nitrogen atom. The term "ruthenium linkage" as used in "hydrocarbon residues of hydrazine linkage" means that a hydrocarbon residue is attached to the remainder of the molecule via an oxygen atom. In the group such as an aryl (C1-C4)alkyl- and -SOJCi-CJ alkyl group, "-" represents the point of attachment of the group to the rest of the molecule. "Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and, where appropriate, a pharmaceutically acceptable base addition salt and a pharmaceutically acceptable acid addition. salt. For example, (1) if the compound of the present invention contains one or more acidic groups (for example, a carboxyl group), the pharmaceutically acceptable addition salts which can be formed include sodium salts, potassium salts, about salts, town salts and salt salts. Or a salt formed with an organic amine such as diethylamine, decyl-glucosamine, diethanolamine or an amino acid (for example, an amine acid) and the like; (ii) if the compound of the present invention contains A pharmaceutically acceptable acid addition salt which can be formed by an assay group such as an amine group includes a hydrochloride, a hydrobromide, a sulfate, a sulphate, an acetate, a citrate, Lactate, tartrate, formazate, succinate, oxalate, sulphate, ethyl sulphate, toluene acid 151650.doc -54- 201120038 salt, besylate, naphthalene disulfonic acid Salt, maleate, fumarate, hippurate, hydroxynaphthoate, p-acetamidobenzoate, dihydroxybenzoate, hydroxynaphthoate, butyl Diacid salts, ascorbates, oleates, hydrogen sulfates and the like. It is also possible to form half salts of acids and bases, such as hemisulfate and hemicalcium salts. For a review of suitable salts, see rHandb〇〇k 〇f Pharmaceutieal Salts: Properties, SeIection and Use", (Wiley-VCH, Weinheim, Germany, 2002). "Prodrug" means a compound which can be converted in vivo to a compound of the invention by metabolic means, for example by hydrolysis, reduction or oxidation. Suitable groups for the formation of prodrugs are described in "The Practice Qf Medieinai"

Chemistry, 2nd edition, page 561_585 (2〇〇3) and? ^^(8) ZVwgMeiM. and u·, 1987, 18, 379. The compounds of the invention may exist in unsolvated as well as solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more (four) pharmaceutically acceptable solvent molecules (9), such as ethanol, in the stoichiometric amount of the compound of the invention. Use when water. Where the compounds of the invention exist in one or more geometric, optical, enantiomeric, diastereomeric, and tautomeric forms, including but not limited to, cis and trans, penta and type 2, and Type, (4) and meso-type, ketone and dilute alcohol. Unless otherwise stated, reference to a particular compound includes all such isomeric forms' including its racemic mixtures and other present compounds. Where appropriate, the isomers can be separated from their mixtures by the application or modification of known methods (e.g., layering and crystallization techniques). Where appropriate, such isomers may be prepared by the application or G modification of known methods (e.g., asymmetric synthesis) by 15l650.doc -55· 201120038. Typical configurations of compounds of formula (I) include.

"Treatment" includes reference to Harmony. In the context of the present invention, sexual, palliative and prophylactic treatments are mentioned herein. The general method should assess the biomedical properties of the compound of formula (I) - 1 king such as solubility and solution stability (between pH values), penetrability, etc. Suitable for treatment 151650.doc • 56 · 201120038 Suggested dosage forms and route of administration. The compound of the present invention may be in the form of a (tetra) crystalline or amorphous product. It can be obtained, for example, in the form of a solid, a powder or a film by methods such as immersion, crystallization, cold drying, dryness, therapeutic drying, and smelting; Conventional Drying, including Static/Dynamic Feeding, &quot;Wire, Microwave or Radio Frequency Drying, Bing 7 Crystallization and Amorphous Heart Methods can be used to assist in forming the above, either alone or in combination with one or more other compounds of the invention or trays One or a combination of other drugs (or in any combination thereof) is administered in the form of a formulation which is associated with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe the functional (ie, drug release rate control) and/or non-functional (ie, processing aid or diluent) characteristics of a formulation other than a compound of the present invention. Any ingredient. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the formulation. Pharmaceutical compositions suitable for the delivery of the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remingt Gn, s Phamaeeutieal Seien (10) 19th Edition (Mack Publishing Company, 1995). Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (1) and a pharmaceutically acceptable carrier, diluent or excipient. The compounds of the invention can be administered orally. Oral administration can involve sore throat to allow the compound to enter the gastrointestinal tract; and/or by frequency, translingually or sublingually, whereby the compound enters the bloodstream directly from the oral cavity. 151650.doc -57· 201120038 Formulations suitable for oral administration include solid plugs, solid particulates, semi-solids and liquids (including multiphase or dispersion systems), such as tablets; containing multiparticulate or nanoparticulates, Soft or hard capsules for liquids, lotions or powders; ingots (including liquid-filled); chewables; gels; fast dispersing formulations; films' ovate suppositories; sprays; and buccal/mucoad adhesion Patch. Formulations suitable for oral administration can also be designed to deliver a compound of formula (1) in an immediate release manner or in a rate-continuous manner, wherein the release profile can be delayed, pulsed, controlled, sustained or delayed and sustained or such that The method of optimizing the therapeutic efficacy of the compound is improved. The manner in which the compounds are delivered in a rate-sustaining manner is known in the art and includes slow release polymers that can be formulated with the compounds to control the release of such compounds. Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be used to release such compounds by diffusion or diffusion in combination with the polymer's surname. Examples of rate-sustaining polymers include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and three cents. Glue, polymethacrylate, polyethylene oxide and polyethylene glycol. Liquid (including multiphase and dispersion systems) formulations include emulsions, suspensions, solutions, syrups and elixirs. The formulations may be present as a filler in a soft or hard capsule (for example made of gelatin or hydroxypropyl decyl cellulose) and typically comprise a carrier such as water, ethanol, polyethylene glycol, propylene glycol, hydrazine. A cellulose or suitable oil; and one or more emulsifiers and/or suspending agents. Liquid formulations can also be prepared by reconstituting, for example, a solid in a sachet. The compounds of the present invention can also be used in rapidly dissolving, rapidly 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, Volume 1, H. Lieberman and L. Lachman (Marcel

Dekker, New York, 1980). The compounds of the invention may also be administered directly into the bloodstream, into the subcutaneous tissue, into the muscle or into the viscera. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Devices suitable for parenteral administration include needle (including microneedle) syringes, needle-free injectors, and infusion techniques. Parenteral formulations are typically aqueous or oily solutions. If the solution is an aqueous solution, then a sugar such as, but not limited to, glucose, mannitol, sorbitol, etc., a salt, a carbohydrate, and a buffer (preferably having a pH of 3 to 9) may be used. Shape agents, but for some applications, they may be more suitable for formulation into a sterile non-aqueous solution or formulation into a dry form for use in combination with a suitable vehicle such as sterile pyrogen-free water. Parenteral formulations may include implants derived from degradable polymers such as polyester (ie, polylactic acid, polylactide, polylactide-co-glycolide, poly Caprolactone, polyhydroxybutyrate), polyorthoesters and polymethylene anhydride. This sputum formulation can be administered to subcutaneous tissue, muscle tissue, or directly into a specific organ via a surgical incision. For example, the preparation of parenteral formulations under sterile conditions by lyophilization can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art. 151650.doc •59· 201120038 The solubility of the compound of formula (i) for the preparation of parenteral solutions can be increased by the use of suitable § weekly techniques such as the incorporation of cosolvents and/or dissolution enhancers, such as interfaces Active agent, cell structure and cyclodextrin. The compounds of the invention may also be administered intranasally or by inhalation, usually in the form of a dry powder (either alone, in a mixture (for example in the form of a dry blend with lactose) or, for example, with a phospholipid (such as phospholipid choline). Mixed mixed component particle form) is applied from a dry powder inhaler, in the form of an aerosol spray with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or fluoropropane The pressure vessel, pump, sprinkler, nebulizer (preferably a nebulizer using an electrohydrodynamic force to produce a fine mist) or a nebulizer is administered or administered as a nasal drop. For intranasal use, the powder may comprise a bioadhesive such as chitsan or cyclodextrin. A pressurized container, pump, sprinkler, nebulizer or nebulizer containing a solution or suspension of a compound of the invention, for example, comprising an aqueous solution of ethanol, ethanol or for dispersing, dissolving or prolonging release Suitable substitute agents, propellants as solvents, and optionally surfactants such as sorbitan trioleate, oleic acid or oligolactic acid, dry powder or suspension Prior to use in the formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be accomplished by any suitable comminuting method such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticle, high pressure homogenization or spray drying. Capsules (for example made of gelatin or hydroxypropyl decyl cellulose), foaming agents and 151650.doc 201120038 A cartridge for use in an inhaler or insufflator can be formulated to contain a compound of the invention, a suitable powder matrix ( A powder mixture such as lactose or starch) and a potency modulator such as L-leucine, mannitol or magnesium stearate. Lactose may be in the form of water or in the form of a monohydrate. The latter is preferred. Other suitable agents include polydextrose, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. Formulations for inhaled/intranasal administration may be formulated using, for example, pGLA, a release and/or modified release formulation. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release formulations. In the present invention, two or two separate pharmaceutical compositions (at least one of which contains a compound of formula (1)) may be required, for example, for the purpose of treating a particular disease or condition for administration of a combination of active ingredients. It is preferred to combine in a kit format suitable for co-administration of such compositions. Thus, the kit of the present invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of the formula (1) of the present invention; and a member member 4 for holding a composition of the S-like composition, such as a container, Separate bottles or separate-treated packaging. An example of such a kit is "usually used as a blister pack for encapsulating tablets, capsules and the like. The month set is particularly suitable for administration to different dosage forms (eg oral and at different dosing intervals) Investigate the individual M compounds, or adjust the individual compositions. In order to assist the compliance, the kits can be equipped with the so-called memory aids. In order to invest in human patients, too / The total daily dose of the compound of the month is usually 151650.doc •61· 201120038 in the range of 0.01 mg to 1000 mg, or 〇mg to 25〇mg, or ! mg to 50 mg, of course, depending on the mode of administration. The total daily dose may be administered in a single dose or in divided doses and may be decided by the physician to be outside the typical range set forth herein. These doses are based on an average human subject having a body weight of from about 6 kilograms to about 7 kilograms. It is easy to determine the dosage of the individual whose weight is outside this range, such as infants and the elderly. Synthetic method The compound of the present invention can be prepared by using a suitable substance according to the following procedures and examples. It is exemplified by the specific examples provided below. Further, by the procedures described herein, one of ordinary skill in the art can readily prepare other compounds within the scope of the invention as claimed herein. However, the compounds illustrated in the examples should not be considered The composition is considered to be the only class of the invention. The examples further illustrate the details of preparing the compounds of the invention. Those skilled in the art will readily appreciate that such compounds can be prepared using the conditions of the following preparation procedures and known variations of the process. The compound may be isolated as a pharmaceutically acceptable salt thereof, such as a salt as hereinbefore described. It may be desirable to protect the reactive functional groups (e.g., hydroxyl, amine, Sulfhydryl or carboxyl groups) to avoid unnecessarily participating in the reaction to form such compounds. Conventional protecting groups can be used, for example, by T. w. Greene and p. GM wuts in "Protective gr〇ups in organic chemistry" John The protecting group described in Wiley and Sons, 4th edition, 2〇〇6. For example, the common amines used in this article The protecting group is a third butoxycarbonyl group (B〇c) which is easily removed by treatment with an acid such as trifluoroacetic acid or chlorine 151650.doc-62·201120038 hydrogen in an organic solvent such as dioxindole. Alternatively, the amine protecting group may be a benzyloxy group (8) group which may be removed by hydrogenation of a w catalyst under a hydrogen atmosphere; or a 9-methoxycarbonyl (Fmoc) group, which may be utilized Containing a secondary organic amine (such as a two-amine or an organic solvent solution removed. The carboxyl group is usually protected as an ester, such as an oxime ester, a benzamidine, or a third butanine, all of which can be oxidized by, for example, chlorine ^ or gas oxidization in the presence of hydrolysis to remove. The benzyl protecting group can also be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere, while the third butyl group is also removed by trifluoroacetic acid. Alternatively, the trichloroacetate protecting group is removed in acetic acid. Commonly used in this paper is a mystery. The conditions for removing the protecting group include refluxing in a 48% aqueous solution of hydrazine to 24 hours, or by stirring in methylene chloride with borane tribromide. ! Up to 24 hours. Alternatively, if the hydroxy group is protected as anisole, the conditions for removal of the protecting group include = hydrogenation of the palladium catalyst under a hydrogen atmosphere. In the following schemes: R1-!^3, Ra&amp;Rb is as previously defined for the compound of formula (1); PG!, PG2 or PG3 is a suitable protecting group; R is Η, ((:, -(:10)alkyl) , dentate, hydroxy or (Ci_C6) alkoxy; R3 and R32 are independently selected from H, (Ci_Ci) alkyl, (C2_C6), (C3_cI())cycloalkyl, heterocycloalkyl, Aryl, heteroaryl, aryl (c"q)alkyl-, aryl(c2-c4)alkenyl, heteroaryl(Ci_C4)alkyl...C6)alkyl, _S〇2 aryl and Δ02 aryl (C,-^)alkyl. The compound of formula 1 can be prepared using conventional synthetic methods. In a typical first step, the amine methyl azaindole (1) is coupled to 151650 using standard peptide coupling conditions. Doc-63- 201120038 Amino acid (2) which is suitably protected by a standard protecting group such as a third butoxycarbonyl (Boc), benzyloxycarbonyl or 9-fluorenyl oxycarbonyl (Fmoc) 〇 The use of groups is well known in the art. If R1 or R2 has a reactive functional group such as an amine or a carboxylic acid, the group is also protected. Standard peptide coupling methods involve the acid and amine in hydroxybenzene. Triazole and carbonized Amine (such as water-soluble carbodiimide) or 2-(indole-benzotriazole small) hexafluorophosphate-1,1,3,3-tetramethylammonium or benzotriazole-hexafluorophosphate-丨--oxy-parameter _ (N-» 咯 咬 )) _ scale or hexafluorodeoxybromo bromide - ginseng (N_ D than pyridyl) _ scale in the presence of 'in the case of triethylamine, diisopropyl The reaction is carried out in the presence of an amine or an organic base of N-methylmorpholine.

Removal of the protecting group of (3) using standard methods previously described to yield an amine

Coupling of the amine (4) to the amine group using standard peptide coupling conditions as previously described is suitably protected by a suitable protecting group such as a third butoxycarbonyl, benzoquinoneoxycarbonyl (z) or 9-yloxycarbonyl (Fmoc) group. Alpha amino acid (5). If R1 or Ruler 2 has a reactive s-energy group such as an amine or a retinoic acid, then the group is also protected. 151650.doc •64- 201120038 The vine is removed by the standard method described above. The protecting group of the taitai derivative (6) gives the amine

5

The amine (7) is further derivatized by reductive alkylation with a suitable aldehyde or ketone (8). 4 Often, the amine (7) is reacted with an acid or a ketone at room temperature in a suitable solvent such as methanol in the presence of a suitable reducing agent such as sodium cyanosulfonate or ethyl ethoxylate.

Ry〇 R32 R1 u

Compound 1 can also be prepared by coupling an alkylated alpha amine group (9) with an amine (4) using standard peptide coupling conditions as previously described. 151650.doc -65- 201120038

9 The alkylated alpha amino acid (12) can be prepared by reductive alkylation of the parent (X-amino acid) wherein the carboxyl group is unprotected (11) or wherein the carboxyl group is passed, for example, an oxime ester, a third butyl ester Or the standard protecting group of trichloroethyl ester is protected to the ester (14), which is removed after alkylation using standard methods previously described. Typical conditions for reductive alkylation are described above.

14 Alternatively, the alpha amino acid (9) can be reacted with the desired amine by the corresponding bromoacetic acid derivative 06) which is suitably protected by a standard protecting group such as a methyl ester, a third butyl ester or a trichloroethyl ester. Use the standard method to remove the protecting group to make I51650.doc •66· 201120038. The bromoacetic acid derivative (15) is reacted with an amine in the presence of a base such as diisopropylethylamine or potassium carbonate or sodium carbonate in a suitable solvent such as acetonitrile oxime tetrahydrofuran at room temperature.

The compound (11) may also be a dipeptide which is suitably protected from an amine group by a standard protecting group such as a third butoxycarbonyl group (B〇c), a benzyloxycarbonyl group (Z) or a 9-g-based fluorenyloxycarbonyl group (Fmoc). 18) Synthesis "The dipeptide can be prepared from two alpha amino acids, one of which is via an amine such as a third butoxycarbonyl (Boc), a benzyloxycarbonyl (oxime) or a 9-fluorenylmethoxycarbonyl group (Fmoc). The standard protecting group is protected, while the other is protected by a standard protecting group such as an ester such as methyl ester, tert-butyl ester or trichloroethyl ester. After the coupling reaction, the thiol protecting group of (17) is removed by the standard method previously described. The guanamine bond formation reaction can be carried out using the standard peptide coupling conditions described above.

151650.doc -67- 201120038

The amine (4) is coupled to the pyrrole derivative (19) using standard peptide coupling conditions as previously described. If R or R2 has a reactive functional group such as an amine or a tickic acid, the group is also protected.

Compound (20) can also be synthesized from compound (22). The compound can be prepared from the amino acid and the pyrrole derivative (19) wherein the carboxylic acid functional group is protected by a standard protecting group such as vinegar (such as decyl ester, second butyl ester, tri-ethyl ester). After the coupling reaction, the carboxyl protecting group of (21) is removed by standard methods previously described. The indoleamine bond formation can be reversed using the standard peptide coupling conditions described above. 151650.doc -68- 201120038

twenty one

The amine (4) is coupled to the lactic acid derivative (23) using standard peptide coupling conditions as previously described. This group is also protected if Ri or R has an amine or a slow acid. Criminal base R1

twenty three

Compound (24) can also be synthesized from compound (26). The compound can be prepared from an alpha amino acid and a lactic acid derivative (23) wherein the carboxylic acid functional group is subjected to a standard such as an ester (such as 151650.doc • 69· 201120038 曱s曰 second butyl@曰, dioxoethyl ester). Protection base protection. Removal of the (25) sclerosin protecting group after the coupling reaction by the standard method described above can be carried out using the standard peptide coupling conditions described above for the argon bond formation.

twenty three

25

An amine (sentence can be derivatized by reaction with a sulfonium vapor (27) to give a sulfonamide derivative (28). If Ri or R2 has a reactive functional group such as an amine or a carboxylic acid, The group is protected. R1

+

151650.doc -70- 201120038

The Cl compound (28) can also be synthesized from the compound (3〇). The compound can be prepared from alpha amino acids and sulfonium vapor compounds (27) wherein the carboxylic acid functional groups are protected by standard protecting groups such as esters such as methyl esters, tert-butyl esters, trichloroethyl esters. After the coupling reaction, the carboxyl protecting group of (29) is removed by standard methods previously described. The indole bond formation reaction can be carried out using the standard peptide coupling conditions described above.

The amine (4) can be derivatized by reaction with an acid gasification or a carboxylic acid (31) to give a decylamine derivative (32). If a carboxylic acid is used, the indole bond formation reaction can be carried out using the standard peptide coupling conditions described above. If R1 or R2 has a reactive g-energy group such as an amine or 151650.doc-71 · 201120038, it also protects this group.

+

31 Compound (32) can also be synthesized from 1,1-carbonyldiimidazole compound (34). The compound can be prepared from an alpha amino acid and an acid vapor or a carboxylic acid (31) wherein the additional tick functional group is protected by a standard protecting group such as an ester such as decyl ester, tert-butyl ester or tri-ethyl ester. After the coupling reaction, the carboxy protecting group of (33) is removed by standard methods as previously described. The indole bond formation reaction can be carried out using the standard peptide coupling conditions described above.

33

32 34 151650.doc • 72· 201120038 : (4) Derivatization can be carried out by reacting with an amine (IV) in the presence of a suitable reagent such as (d) bis[seat] to give a urea derivative (IV). This group is also protected if r^r2 and has a reactive functional group such as an amine or (d).

Compound (36) can also be synthesized from compound (38). The compound can be prepared from an alpha amino acid and an amine (35) wherein the tick functional group is protected by a standard protecting group such as a tallow (such as methyl ester, butyl butyl ester, trichloroethyl ester). After the coupling reaction, the carboxy protecting group of (37) is removed by standard methods as previously described. The indole bond formation reaction can be carried out using the standard peptide coupling conditions described above.

Ra NH

36 38 The invention also covers intermediate compounds useful for the synthesis of compounds of formula (i). As a result of I51650.doc • 73· 201120038, one aspect of the present invention provides an intermediate compound selected from the group consisting of: {(s&gt;2_(3,4-difluoro-phenylpyrrolo[2,3- b].pyridin-5-ylmethyl)-amine-carbamoyl]-ethyl-aminoglycolic acid tert-butyl ester; (s)_2-amino-3-(3,4-difluoro-benzene Base)-Ν-(1Η-.pyrolo[2,3-b]indolebi-5·ylindolyl)-propanamine; ((R)_b{(S)-2-(3,4 -difluoro-phenyl)-1-[(indole-pyrrolo[2,3-b]pyridin-5-ylindenyl)-aminecarbamyl]-ethylamine fluorenyl}_2_indolyl- Butyl)-methyl-aminocarbamic acid tert-butyl ester; (r)_3-methylamidoamine-pentanoic acid {(S)-2-(3,4-di-phenyl)-1-[ (ih_pyrrolo[2,3_b]° ratio _5_yl fluorenyl)·amine hydrazinyl l·ethyl}-decylamine; {(S)-2-(4-fluoro-phenyl than hydrazine [2,3-b]0 is more than 5-methyl-amino)-amine-mercapto]-ethyl}-aminocarboxylic acid tert-butyl; (S)-2·amino-3_(4_ Said phenyl hN-GH-11 ratio σ and [2,3-b] ° ratio biting 5-ylmethyl)-propanamide, {(8)-2-(3,4-dichloro- Phenyl)-1-[(111-pyrrolo[2,3-1)]acridin-5-ylmethyl)-aminecarboxylidene]-ethyl}-carbamic acid tert-butyl ester; (S )-2-amino-3 (3,4-diqi-bens)-Ν-(1Η-β ratio σ[2,3_b]Dit^-5-ylmethyl)-propanamine; {(S)-2-naphthalene- 1-yl-1-[(1Η-°Λ D each and [2,3-b]. specific bite-5-ylmethyl)-amine-mercapto]-ethyl}-aminocarboxylic acid tert-butyl ester (S)-2-Amino-3-na-1-yl-N-(1H-0 is 〇 并 丙 酿 ;; {(尺)-2,2-dicyclohexyl-1-[(111 -17 than the mouth of each [2,3-13]0 than 唆-5-ylmethyl)-amine 151650.doc • 74- 201120038 formazan]-ethyl}-carbamic acid tert-butyl ester; R)-2-amino-3,3-dicyclohexyl-indole-(1Η-pyrrolo[2,3-b]°pyridin-5-ylmethyl)-propionamide; and ((S) -l-{(R)-2,2-dicyclohexyl-1-[(1H-pyrrolo[2,3-b].pyridin-5-yl•methyl)-aminemethanyl]-B Hydrazinyl}-2-mercapto-butyl)-methyl-aminocarbamic acid tert-butyl ester. In one aspect, the invention provides a process for the preparation of a compound of formula (I)

It comprises a compound of formula (VI):

Η

/IV with a compound of formula (VII): 0 II, A, 〇H(VII) are reacted under standard peptide coupling conditions; wherein Ri-R5 and A1 are as previously defined for the compound of formula (1). Standard peptide coupling conditions include the use of an acid with an amine in a hydroxybenzotriazole and a carbodiimide (such as a water soluble carbodiimide) or a hexafluorophosphate 2 · (1 Η - benzotriazole 1-yl)-1, 1'3,3-tetramethylammonium or benzotriazole hexafluorophosphate _ 丨 yl-oxy-epoxy 151650.doc -75- 201120038 (N-.pyrrolidyl)-scale or bromine hexafluorophosphate - In the presence of hydrazine (N-.pyrrolidinyl)-oxime, it is reacted in the presence of an organic base such as triethylamine, diisopropylethylamine or N-mercaptomorpholine. These reactions are usually carried out in a solvent such as dioxane and dimethylguanamine. EXAMPLES The present invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used: DMF N,N-dimercaptoamine EtOAc Ethylmannate hrs Hour HBTU Hexafluorophosphate 2-( 1Η-benzotriazol-1-yl)-1,1,3,3-tetramethylhydrazine HOBt hydroxybenzotriazole lie isoleucine LCMS liquid chromatography mass spectrometry Me thiol MeCN acetonitrile MeOH methanol Min min MS Mass Spectrometry Nal Naphthylamine NMR Unless otherwise indicated, the nuclear magnetic resonance spectrum-NMR spectrum recorded a petroleum ether fraction of 151650.doc-76 with a boiling point of 60 ° C -80 ° C at a frequency of 270 MHz or 400 MHz. 201120038

Phe phenylalanine Pro Proline THF Tetrahydrofuran TFA Trifluoroacetic acid Unless otherwise specified, all reactions were carried out under a nitrogen atmosphere. The H NMR spectrum was referenced to a solvent on a Brucker Avance 111 (400 MHz) spectrometer and recorded at room temperature. Molecular state ions were obtained using LCMS using a Chromolith Speedrod RP - 18e column (5〇χ4·6 mm) with a linearity of 10% to 90% 0.1% HC02H/MeCN 0.1% HC02H/H20 over 11 minutes. Gradient and flow rate of 1.5 ml/min. Data were collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electrospray ionization in conjunction with a Thermofinnigan Surveyor LC system. The chemical name was generated using the Autonom software from MDL Information Systems as part of the ISIS drawing suite. If the product is purified by flash chromatography, "cerium oxide" means 0.035 to 0.070 mm (220 to 440 mesh) chromatography tannin (eg, Merck silicone 60) and the applied nitrogen pressure is at most 10 psi. Accelerate the column column dissolution. Reverse phase preparative HPLC purification was performed using a Waters 2525 binary gradient pumping system at a flow rate of typically 20 ml/min using a Waters 2996 photodiode array detector. All solvents and commercially available reagents are used as received. Example 1 (R)-3-Methyl-2-indenyl-pentanoic acid {(S)-2-(3,4-difluoro-phenyl)-1-[(1Η-151650.doc-77- 201120038 Bisolo[2,3-b]acridine·5-ylmethyl)-amine-methyl-diethyl}-decylamine

HN\A. {(S)-2-(3,4-Difluoro-phenyl)-l-[(lH-pyrrolo[2,3-b]pyridin-5-ylindenyl)-amine oxime 3-Ethyl}-carbamic acid tert-butyl ester Boc-3,4-difluoro-Phe-OH (1.0 g ' 3.32 mmol) was dissolved in CH 2 C 12 (100 ml) and DMF (5 ml). To this solution was added HBTU (1.26 g, 3.32 mmol) and triethylamine (1.00 g, 9.95 mmol). After 15 minutes, add C-(lH-° piroxime [2,3-b]° to bite-5-yl)-methylamine (5 12 mg, 3.49 mmol). The reaction mixture was diluted with CHC13 (150 ml Evaporate in a vacuum. The residue was purified by flash chromatography (EtOAc) eluting eluting eluting Stem 1.24 g, 2.88 mm 〇l, 87%. [M+H]+=431.2 〇Β·(S)-2-Amino-3-(3,4-di chrysin-1 1fluoro-phenyl)-indole-(1Η-pyrrolo[2,3- b] pyridyl-5-ylmethyl)-propanamide dihydrochloride was treated with 4 M HCl in dioxane (50) to treat {(S)-2-(3,4-difluoro-benzene) 151650.doc -78- 201120038 base) small _♦ each side bite ·5_ylmethyl)-amine fluorenyl]-ethyl}-amino decanoic acid third vinegar (1.24 g' 2.88 mm 〇 1). After &quot;, at room temperature, the solvent was removed in vacuo to give the title compound: 'No yield = 1.15 g, 2.84 mmol, 990/. . [M+H]+=33 1.16 〇C. ((R)-l-{(S)-2-(3,4-difluoro-phenyl) small [(1H•咐&amp; and [2 3 b </RTI> </RTI> </RTI> </RTI> <RTIgt; </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> </RTI> </RTI> </RTI> <RTIgt; -3-(3,4-Difluoro-phenyl)-indole·(1Η_pyrrolo[2,3b].pyridin-5-ylindenyl)-propanamide dihydrochloride (49 mg, 〇12 Mm 〇 1) was dissolved in CH 2 C 12 (10 ml). This solution was cooled to 〇t. Add 8 卞1^· DIle-OH (30 mg, 0.12 mmol), followed by HOBt (23 mg, 〇 17 mmol) and water-soluble carbodiimide (28 mg, 〇15 mm〇1). After 15 minutes, triethylamine (123 mg, 1-22 mmol) was added. Here. After 18 hours at room temperature, the reaction mixture was diluted with CHC13 (50 ml), washed with saturated NaHCO3 (1×20 ml), water (1×20 ml), brine (1×2 〇ml), dried (NaaSO4) and vacuum Evaporation. By flash chromatography (cerium dioxide), lysing agent 2.5% MeOH, 97.5% 0^2 (: 12 purified residue, mp. =63 mg, 0.11 mmol, 92% [M+H]+=558.25 ° D·(R)-3-methyl-2-methylamino-pentanoic acid {(S)_2_(3,4·difluoro -Phenyl) 151650.doc -79- 201120038 [(1H-Terazine [2,3_b]pyridine-5_ylmethyl)-amine-methylpyridylethyl bromide dihydrochloride ((R)- L-{(S)-2-(3,4-Difluoro-phenyl)-1-[(1Η-pyrrolo[2,3-b]pyridin-5-ylmethyl)-aminecarboxamido Benzyl aryl}_2-methyl-butylmethyl-carbamic acid tert-butyl ester (55 mg, 0.099 mmol) dissolved in CH2C12 (2 ml) and TFA (0,5 ml) t. After a few hours, the reaction mixture was diluted with EtOAc EtOAc (EtOAc) (EtOAc (EtOAcjjjjjjj The residue was purified by chromatography (EtOAc) eluting This solid was treated with 4M EtOAc (2 mL). EtOAc (jjjjjjjjjj CD3〇D) °·70'°·79 (8H, m), 1.63-1.75 (1H, m), 2.5〇(3H,s), 2.82(1H,dd,J=1〇1,l4〇Hz) , 3〇7(iHdd, J=5.9,14.0 Hz), 3.57 ”T , .,md, J=4.8 Hz), 4.45 (1H, dd, J=5.8, 14.9 Hz), 4.50 (m T c. , , n TT, } dd, J=5.8, 14.9 Hz), 4.53-4.61 (1H,m), 6.71 (1H,d,J=3 6 Hz),6 92 7 1〇(3H,claw),7 59 ( 1H, d, J=3.5 Hz), 8.26 (1H, d, J=1 〇Hz), 8 38 〇H, s), 8.62 (1H,d,J=7.6 Hz), 8.79 (1H, t,J = 5 8 Hz). Example 2 (R)-l-methyl-port ratio 4 bite-2-carboxylic acid {(s) 2 (3 4 difluorophenyl) small talk _ «Bile and [2,3-b] acridine-5 -ylmethyl)amine methyl hydrazide] ethyl hydrazide, 8 〇 151650.doc 201120038

A·(RM-methyl 4 Luobite I formic acid (N Me Dpr〇 side H-DPr〇-〇H (10.0 a, Ιλ 6 86·9 mmol) was dissolved in methanol (200 ml), and formaldehyde was added (37 Weight 0 / a * n 里 / 〇洛液, 7 mi), then add 10 〇 / 〇

Pd/C (5 g). The reaction mixture was shaken at 15 psi for 18 hours. After this time, the 卟 Λ Γ / Γ ^ lysing agent was filtered off through the diatomaceous earth and the residue was washed with Me 〇 H (10 〇 ml). The mixture was combined in a vacuum and the filtrate was obtained to give a white solid.

It was recrystallized from MeOH / EtOAc (methanol). Yield = 10.72 g, 83 mmol, 96. /. . [M+H]+=130.17. Β·(R)-l-methyl·咕 slightly biting formic acid {(8,2 2 (3,4•difluoro-phenyl)p [(1H-pyrrolo[2,3-b]pyridinyl) Aminomethyl]ethyldoxime di-trifluoroacetate salt (S)-2-amino-3-(3,4-difluoro-phenyl)_N_(1H_D ratio 咯[2,3氺0-pyridin-5-ylindenyl)-propanol dihydrochloride (5 mg, 〇12 mmol) was dissolved in CHzCl2 (10 ml). This solution was cooled to 〇〇c 〇.MN_Me_Dpro-OH (16 mg '0.12 mmol), followed by H〇Bt (23 mg, 0.17 mmol) and water-soluble carbodiimide (28 mg, 〇·ΐ 5 mmol). 15 minutes 15I650.doc • 81 · 201120038, add three Ethylamine (125 mg ' 1.24 mmol). After a few hours at room temperature, dilute the reaction mixture with CHC13 (50 ml), wash the solution with saturated NaHC03 (1×20 ml), water (1×20 ml), brine (1×20 ml) , dried (NaJO4) and evaporated in vacuo. EtOAc EtOAc (EtOAc). Prepared by preparative HpLC (19x250 mm Sunfire C-18 column) at 20 ml/min for 35 minutes 1 0. The yield of the title compound was obtained as a white solid. [M+H]+=442.52 » 丨H NMR: (CD3OD) 1.56-1.68 (1H, m), 1.72-1.86 (1H, m), 1.98-2.10 (1H, m), 2.28-2.42 (1H , m), 2.76 (3H, s), 2.80 (1H, dd, J-9.1, 13.9 Hz), 2.98-3.10 (2H, m), 3.48-3.60 (1H, m), 3.93 (1H, t, J = 8.4 Hz), 4.36 (1H, dd, J=5.7, 14.7 Hz), 4.41 (1H, dd, J=5.7, 14.7 Hz), 4.59 (1H, dd, J=6.5, 9.0 Hz), 6.45 (1H , d, J=3.5 Hz), 6.84-6.90 (1H, m), 6.92-7.06 (2H, m)5 7.38 (1H, d, J=3.5 Hz), 7.92 (1H, d, J=1.6 Hz) , 8.08 (1H, d, J = 1.6 Hz), 8.64 (1H, t, J = 5.7 Hz). Example 3 (S)-N-{(S)-2-(3,4-difluoro-phenyl) small [(1H-nb-pyrido[2,3-b]nb-pyridin-5-ylmethyl)- Aminomethylmercapto]-ethylidene 2-(isopropyl-methyl-amino)-propanamide 151650.doc •82· 201120038

A. (S)-2-(isopropyl-methyl-amino)·propionic acid N-Me-Ala-〇H (2.〇g, 15.5 mmol) was dissolved in decyl alcohol (200 ml) Acetone (1.3 g, 23.2 mmol) was added followed by 10% Pd/C (1.5 g). The reaction mixture was shaken at 15 psi for 18 hours. After this time the catalyst was filtered through EtOAc (EtOAc) (EtOAc) The combined filtrate was evaporated in vacuo to give crystals crystals crystals Yield = 2.48 g ' 17.1 mmol, 88%. [M+H]+=146.36. Β·(S)-N-{(S)-2-(3,4-Difluoro-phenyl)-l-[(iH-indolo[2,3_b]0-pyridin-5-ylmethyl )-Aminomethionylethyl}-2-(isopropyl-methyl-amino)-propionamine di-trifluoroacetate salt (8)-2-amino-3-(3,4-di Fluoro-phenyl)-;^-(1仏. Bis-[2,3-13]'1 to 11--5-ylmethyl)-propanamide dihydrochloride (194 mg, 0.48 mmol) Dissolved in CHzCl2 (25 ml). Cool this solution to "C. Add (8)·2_(isopropyl-methyl-amino)-propionic acid (70 mg, 0.48 mm〇i), followed by HOBt (91 mg '0.67 mmol) and water-soluble carbodiimide (1) 〇mg, 0.58 Mm). After 15 minutes 'Addition of triethylamine (487 mg, (82 151650.doc -83 - 201120038 mmol). After 18 hours at room temperature, dilute the reaction mixture with CHCi3 (5 〇, with saturated NaHCO3 (1×20 ml), water (lx20 ml), brine (1 χ 2 〇 ml), this solution was washed, dried (NajO4) and evaporated in vacuo. Purified residue by flash chromatography (cerium dioxide), eluting solvent 1% MeOH, 9 〇% CH2C12 The combined fractions were combined and evaporated in vacuo to give a white solid. EtOAc EtOAc EtOAc EtOAc EtOAc % TFA/MeCN 〇 1 。 fa / 固体 固体 固体 固体 固体 固体 固体 固体 M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M M H]+=458.2 ° 丨H NMR: (CD3OD) 1.14-1.12 (1Η,m), 1.29 (3Η, d, J= 6.6

Hz), 1.28-1.32 (1H, m), 1.38-1.56 (2H, m), 155 (3H, d, J=6.6 Hz), 2.68 (3H, s), 2.94-3.04 (2H, m)5 3.1 3-3.24 (1H, m), 3.87 (1H, brs), 4.01 (1H, q, J=7.0 Hz), 4.51-4.64 (2H, m), 4.80 (1H, brs), 6.79 (1H, d, J=3.3 Hz), 7.02-7.35 (3H, m), 7.69 (1H, d, J=3.3 Hz), 8.35-8.39 (2H, rn), 8.90 (1H, t, J=9.1 Hz). Example 4 3-Methyl-1H-pyrrole-2-carboxylic acid {(S)-2-(4-fluoro-phenyl)-i_[(1H•啦咯和[2,3-b]《比啶-5 -ylmethyl)-amine-carbamoyl]-ethyl}-decylamine 151650.doc -84· 201120038

A. {(S)-2-(4-Fluoro-phenyl)_1-[(1H-pyrrolo[2,3-b]acridin-5-ylmethyl)-aminecarboxylidene]-ethyl }-T-butyl carbazate Boc-4-fluoro-Phe-OH (459 mg '1.62 mm〇i) was dissolved in ch2C12 (30 ml). To this solution was added HBTU (615 mg, 1.62 mmol) and triethylamine (490 mg '4_86 mmol). After 15 minutes, c_(iH-n piroxi[2,3-b]0 ate-5-yl)-guanamine (250 mg '1.7 mmol) was added. After 2 hours at room temperature, dilute the reaction mixture with CHCIJ 150 ml), wash the solution with saturated NaHCO3 (1×50 ml), water (1×50 ml), brine (1×50 mi), dry (Na2S〇4) and in vacuo evaporation. The residue was purified by EtOAc EtOAc (EtOAc) Yield = 275 mg, 0.67 mmol, 41%. • [M+H]+=413.21. Β·(S)-2-Amino-3_(4-fluoro-phenyl)_Ν_(1Η·η比比和[2 3 b]Acridine-5·ylmethyl)-propanamide dihydrochloride Treatment of {(5)_2_(4_gas_phenyl)_ 1-[(1Η-.1 Η-[2,3 clock ratio bite_5_ base) with 4 M HC1 bismuth solution (1 〇ml) ψ ) _ _ _ _ 275 275 275 275 275 275 275 275 275 275 275 275 275 275 275 275 275 275 275 275 275 275 275 I i at room temperature 151650.doc •85-201120038, the solvent was removed in vacuo to give a yellow solid identified as the title compound. Yield = 260 mg, 0. 67 mmol, 100%. [M+H]+=313.21 〇C. 3-methyllo-2-carboxylic acid {(S)-2-(4j_phenyl)pyrho[2,3-b]acridin-5-ylmethyl --Aminomethyldiethyl}-nonylamine di-trifluoroacetate salt 3-methyl "pyrrol-1-carboxylic acid (74 mg, 0.38 mmol) dissolved in CH2CI2 (10 ml)" 〇°C, H〇Bt (60 mg, 0.45 mmol) and water-soluble carbodiimide (28 mg, 〇15 mm〇i) were added. After 2 minutes, '(S)-2-amino-3-(4-a-phenyl)-indole-(1Η-» is more than η[2,3-b]n than pyridine-5-yl Mercapto)-propanamide dihydrochloride (123 mg, 〇32 mm〇1) and triethylamine (3 20 mg, 3.19 mmol). After ≤°C to room temperature, the reaction mixture was diluted with CHC13 (50 ml). The solution was washed with saturated NaHC〇3 (1×2 〇ml), water (1×20 ml), brine (1×20 ml) and dried ( NhSCU) and evaporate in vacuum. The residue was purified by flash chromatography (EtOAc) elut elut elut elut elut elut The residue was further purified by preparative HPLC (19 x 250 mm Sunfire 18 column)&apos; with 20%/min containing 1% to 9% by weight over 35 minutes T with TFA/MeCN 〇.1% TFA/H2 。. The fractions were combined and lyophilized to give a white solid that was identified as the title compound. Yield = 48 mg, 〇.〇 9 mmol, 2811⁄4. [M+H]+=420.16 〇]H NMR (d6-DMSO) 2.17 (3H, s), 2.44-2.46 (1H, m), 2.83- 151650.doc • 86 - 201120038 2.92 (1H,m), 2.98 -3.06 (1H,m), 4.27-4.38 (2H,m), 4.62 (1H,q, J=4.0 Hz), 5.86 (1H, d, J=4.0 Hz), 6.35-6.37 (1H, m), 6.71-6.76 (1H, m), 6.95-7.03 (2H, m), 7.15.7 27 (2H, m), 7.35 (1H, d, J=4.0 Hz), 7.40-7.42 (1H, m), 7.71 (1H d J=4.0 Hz), 8.07 (1H, d, J=4.0 Hz), 8.57 (1H, t5 J=4.〇Hz) 11.08 (1H, s ). Example 5 (only)-]&gt;^-{(8)-2-(3,4-dichloro-phenyl)-1-[(111-11 is more than [2,3_]] 11 bite _5_ylmethyl)-aminemethanyl]_ethyl}-2-hydroxy-3-phenyl·propanamide

A. {(S)-2-(3,4-Digas-phenyl)-1-[(1Η-&quot;比比和[2,3-b]&quot;比啶_5_ylmethyl) -Aminomethyl)-ethyl}-carbamic acid tert-butyl ester Boc-3,4-digas-Phe-OH (1.0 g, 3.32 mmol) was dissolved in CH2C12 (100 ml) and DMF ( 5 ml). To this solution was added HBTU (1.26 g, 3.32 mmol) and triethylamine (1_00 g, 9.95 mmol). After 15 minutes, lanthanum (111-0 vs. 17 and [2, 3-1)] ° 咬-5-yl)-guanamine (512 111 L, 3.49 mmol) was added. After 2 hours at room temperature, the reaction mixture was diluted with CH.sub.3 (150 mL), washed with sat. NaHCO3 (1×50 ml), water (1×50 ml), brine (1×50 ml), dried (Na2S04) and evaporated in vacuo . The residue was purified by flash chromatography (EtOAc) elut elut elut elut elut elut elut elut Yield = 1.24 g, 2.88 mmol, 87%. [M+H] = 43 1.2. B. (S)-2-Amino-3-(3,4-dioxa-phenylpyrrolo[2 3 b]pyridin-5-ylmethyl)-propanamide dihydrochloride 4 M HC1 Treatment of {(s)_2_(34_diox, phenyl)-1-[(1Η-pyrrolo[2,3-b]pyridin-5-ylindenyl)-amine in dioxane solution (530 ml) Methylmercapto]-ethyl}-aminobutyric acid tert-butyl ester (1.24 g, 2.88 mmol). The solvent was removed in vacuo <RTI ID=0.0># </RTI> </ RTI> </ RTI> <RTIgt; Yield = 1·15 g, 2.84 mmol, 99%. [M+H] + = 331.16 〇C· (R)-N-{(S)-2-(3,4-dioxa·phenylindolo[2,夂bJefct pyridine-5-ylmethyl) -Amino-branched ethyl bromide 2-hydroxyl-3-phenyl-propionamide trifluoroacetate salt (3)-2-amino-3-(3,4-di-phenyl)-^[- (111-. 咯 并 [2, 3-1)] ton of 5-aminomethyl)-propanamide dihydrochloride (250 mg, 0.66 mmol) dissolved in CH2C12 (30 ml)*. This solution was cooled to 0 °C. d_3-Phenyllactate (109 mg, 0.66 mmol) was added followed by HOBt (107 mg, 0.79 mmol) and water-soluble carbodiimide (177 mg, 0.92 mmol). After 15 minutes 'diethylamine (200 mg' 1.98 mmol) was added. Here. After 1 hour at room temperature, dilute the reaction mixture with CHC13 (50 ml) and wash the solution with saturated NaHC03 151650.doc -88 · 201120038 (1x20 ml), water (1x20 ml), brine (lx2 〇ml) Dry (Na2S04) and evaporate in vacuo. Prepared by preparative HpLc core preparation type (1) 嶋 tube column, W coffee, (d), at 20 ml / min for 35 minutes containing 10% to 90% 〇 · 1% TFA / MeC ^ 〇 i% tfa / h2 〇 purification residue Things. The fractions were combined and cooled; dried in the east to give a white solid. Yield = 145 mg '0.26 mmol, 39%. [Μ+Η]+=455·12. H NMR (CD3OD) 2.70-3.10 (4H, m), 3.25-3.35 (2H, 4.10-4.25 (3H, m), 4.45-4.55 (1H, m), 4.90-5.10 (2H, m) 6.90-7.30 ( 9H, m), 7.65-7.80 (2H, m), 8.35-8.50 (1H, m). Example 6 (8)-3-naphthalen-1-yl-2-(propan-1-ene) _]\-(111-&quot;Biluo[2,3-匕]pyridin-5-ylmethyl)-propanamide

Η A. {(S)-2-naphthalen-1-yl-1-[(1H-咐*pyrrolo[2,3-b]»bipyridin-5-ylindolyl)-aminecarboxylidine]- Ethyl}-carbamic acid tert-butyl ester Boc-l-Nal-OH (643 mg '2.04 mmol) was dissolved in CH2C12 (3〇151650.doc •89·201120038 ml). To this solution were added HBTU (773 mg, 2·04 mmol) and triethylamine (516 mg, 5.10 mmol). After 15 minutes, C-(lH-pyrroloindole-5-yl)-methylamine (250 mg, 1.7 mmol) was added. The reaction mixture was diluted with CHC13 (150 ml . The residue was purified by EtOAc (EtOAc) elute Yield = 520 mg, 1.17 mmol, 690/〇. [M+H]+=445.20 〇B. (S)-2-Alkyl-3-cain-1-yllosino[2,3-b]°tb ate-5-ylmethyl)propanamide II The hydrochloride salt was treated with 4 M HC1 bis solution (5 〇mi) {(s)_2_naphthalen-1-yl-1-[(1H-pyrrolo[2,3-b]pyridine-5-曱 ) ) _ _ _ _ _ _ 520 520 520 520 520 520 (520 mg ' 1.17 mmol). After 1 hour at room temperature, the solvent was removed in vacuo to afford a pale brown solid identified as the title compound. Yield = 487 mg, 1.17 mmol, 1 〇〇〇 /. . [Μ+Η] + = 345·19. C. (S)-3-naphthalen-1-yl-2-(propane-1_sulfonylamino)_Ν_(1Η_β is more than [2,3_b]B than bite-5-ylmethyl)-propyl (S)-2-Amino-3-naphthalen-1-yl-N-(1H-pyrrolo[2,3-b]pyridin-5-ylindenyl) propylamine Dihydrochloride (1 mg, 〇24 mm〇i) was dissolved in CH2C12 (50 ml). This solution was cooled to 〇 °c. Add n-propylsulfonate 151650.doc •90· 201120038 Chlorine (38 mg '0.26 mmol)' followed by the addition of triethylamine (48 mg, 0.48 mmol). After 18 hours at 〇 ° C to room temperature, the reaction mixture was diluted with CHC13 (50 ml), washed with saturated NaHC 3 (1 χ 20 ml), water (1 χ 20 ml), brine (1×20 ml) and dried. (Na2S04) and evaporated in vacuo. The residue was purified by preparative HPLC (Sunfire preparative C18 OBD column, 19×250 mm, 10 μ), with 20% to 90% 0.1% TFA/MeCN 0.1% TFA/H20 at 20 mL/min. The combined fractions were combined and cooled to dryness to afford a white solid that was identified as the title compound. Yield = 14 mg, 0.025 mmol, 10%. [Μ+Η]+=451·16. ]H NMR (CD3〇D) 0.71 (3H, t, J=7.44 Hz), 1.31-1.47 (2H, br m), 2.41-2.47 (2H, m), 2.67-3.72 (1H, m), 4.24- 4.34 (1H, m), 4.43-4.56 (3H, m)s 4.96(2H, s), 6.73 (1H, d, J=3.56 Hz), 7.33-7.37 (1H, m), 7.42 (1H, d, J=6.37 Hz), 7.55-7.61(2H, m), 7.64 (1H, d, J=3.6 Hz), 7.78 (1H, d, J=8.08 Hz), 7.90 (1H, d5 J=7.96 Hz), 8.16 (1H, d, J = 1.7 Hz), 8.22 (2H, d, J = 9.08 Hz), 8.63-8.66 (1H, m) 〇 Example 7 (S)-3-Methyl-2-methylamino- Valeric acid {(R)_2,2_dicyclohexyl small [(1H_pyrrolo[2,3-b]pyridin-5-ylmethyl)-aminecarboxamidoethyl bromide

151650.doc •91· 201120038 A·(R)-2-Tertidinoxycarbonylamino-3,3-dicyclohexyl-propionic acid Boc-D-3,3-di-bromoalanine (4.86 g, 14.06 mmol) was dissolved in decyl alcohol (200 ml). This solution was hydrogenated at 5% Rh/carbon (500 mg) at 60 psi and room temperature. After 2 days at room temperature, 5% Rh/carbon (500 mg) was added and hydrogenation was continued for another 3 days at 60 ps and room temperature. After this time, the catalyst was filtered through celite and washed with MeOH (100 mL). The combined filtrate was evaporated in vacuo to give a white solid. Yield = 4.95 g, 14 mmol, 100%. [M+H]+=354.28 ° Β· {(R)-2,2-dicyclohexyl-1-[(1H-pyrrolo[2,3-b]pyridine-S-ylmethyl)-amine A (R)-2-tert-butoxycarbonylamino-3,3-dicyclohexyl-propionic acid (721 mg, 2.04 mmol) was dissolved in decyl]-ethyl}-aminoformamidine tert-butyl ester CH2C12 (30 ml). Add triethylamine (516 mg ' 5.10 mmol) and HBTU (773 mg, 2.04 mmol), then add C-(1H-D ratios each [2,3-b] π to 0--5-yl)- Guanamine (250 mg, 1. 7 mmol). After 3 hours at room temperature, the reaction mixture was diluted with CH.sub.3.sub.3 (50 mL). washed with saturated NaHCO3 (1×20 ml), water (1×20 ml), brine (1×20 ml) dried (NaJO4) and evaporated in vacuo . The residue was purified by flash chromatography (EtOAc) elut elut elut elut elut elut Yield = 817 mg, 1.69 mmol, 100%. [M+H]+=483.30 ° C. (R)-2-Amino-3,3-dicyclohexyl-N-(1H-pyrrolo[2,3-b]pyridine_5· 151650.doc • 92- 201120038 Benzyl)-propanol dihydrochloride treated with 4 M HC1/dioxane (50 mi) {(R)_2,2 dicyclohexyl[(1H-pyrrolo[2,3-b] Pyridine_5_ylmercapto)-amine f-mercapto]-ethylglycolic acid terpene vinegar (817 mg ' 1.69 mmol). At room temperature, H, after the removal of the granules, was applied to the light-colored material identified as the title compound. Yield = 738 mg '1.62 mmol, 96%. [M+H]+=383.28 ° D. ((S)-l-{(R)-2,2-dicyclohexylpyrrolo[2 3 b]pyridine-&amp;-methylamine-mercapto]- Ethylamine mercapto 2-methyl-butyl)-methylaminocarbamic acid tert-butyl ester (R)-2-amino-3,3-dicyclohexyl_N_(1H-pyrrolo[ 2,3_b]pyridine_5_ylmercapto)-propanamide dihydrochloride (160 mg '0.35 mmol) was dissolved in CH2C12 (20 ml) and DMF (2 ml). This solution was cooled to hydrazine. Hey. Add to

Boc-NMe-Ile-OH (95 mg, 0.39 mmol) followed by H.sub.2Bt (57 mg, 0.42 mmol) and triethylamine (107 mg, K06.sup.1). Water-soluble carbodiimide (74 mg, 0.39 mmol) was then added. At 0. After 1 hour at room temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed with NaHC EtOAc (1×20 ml), water (1×20 ml), brine (1×20 ml), dried (NaJO4) and Evaporate in a vacuum. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut Yield = 120 mg, 0.2 mmol, 56%. [M+H]+=610.33. Ε·(S)-3-methyl-2-methylamino-pentanoic acid {(r)_2,2-dicyclohexyl-1-[(1H-pyr 15650.doc-93· 201120038 咯[2, 3-b]pyridin-5-ylindenyl)-amine-mercaptopurine}-guanamine di-trifluoroacetate was treated with TFA (25 ml) ((S)-l-{(R)-2,2 -dicyclohexyl·1-[(1Η-.pyrolo[2,3-b]pyridin-5-ylmethyl)-aminemethylmercapto]-ethylaminemethantyl 2-methyl-butyl Base)-decyl-amino decanoic acid tert-butyl ester (120 mg, 0.2 mmol). After 1 hour at room temperature, the solvent was evaporated in vacuo. Prepared by HPLC (19x250 mm Sunfire C-18 column) at 10 ml/min for 10 minutes with 10% to 90°/. 0.1% TFA/MeCN 0.1% TFA/H2O purified residue. The fractions were combined and lyophilized to give a white solid that was identified as the title compound. Yield 81 mg, 0.11 mmol, 56%. [M+H]+=510.33 ° NMR: (CD3OD) 0-97-1.14 (14H, m), 1.19-1.39 (5H, m), 1.58-1.72 (13H, m), 1.98-2.04 (lH, m ), 2.54(3H, s), 3.36(1H, t, J=1.76 Hz), 3.84(1H, t, J=4.8Hz), 4.54-4.67(3H, m), 6.68(1H, d, J = 3.48 Hz), 7.59 (1H, d, J=3.52Hz), 7.93(2H, dd, J=12.69, 1.68 Hz) 8.44 (1H, d, J=8'77 Hz), 8.90-8.93 (1H, m ). Example 8 (S)-l-Methyl-pyrrolidine-2-furic acid {(R)-2,2-dicyclohexyl-pyrroloindole 2,3-b]indole-5-ylmethyl) -Aminomethyl hydrazide]-ethyl decylamine 151650.doc •94- 201120038

A. (S)-l-Methyl-pyrrolidine-2-carboxylic acid {(R)-2,2-dicyclohexyl_1-[(1H-pyrrolo[2,3-b]pyridin-5-yl) Methyl)-aminomethylindenyl]-ethyl}-nonylamine di-trifluoroacetate salt (R)-2-amino-3,3-dicyclohexyl-N-(1H-pyrrolo[2, 3-b]pyridin-5-ylmethyl)-propanamide dihydrochloride (100 mg, 0.22 mmol) was dissolved in CH2Cl2 (20 ml) and DMF (2 ml). This solution was cooled to 0 °C. Add N-Me-Pro-OH (31 mg » 0.24 mmol) followed by HOBt (36 mg, 0.26 mmol) and triethylamine (67 mg, 0.66 mmol). Water-soluble carbodiimide (46 mg, 0.24 mmol) was then added. After 18 hours at room temperature, the reaction mixture was diluted with CH.sub.3 (50 mL). EtOAc (EtOAc) evaporation. By preparative HPLC (19x250 mm Sunfire C-18 column), 10% to 90% 0.1% butyl at 20 ml/min over 35 minutes? Into /] ^ ^ 0 ^ 0.1% Ding? Eight/0 purification residue. The fractions were combined and lyophilized to give a white solid. Yield = 62 mg, 0.086 mmol, 39%. [M+H]+=494_33 ° ]H NMR: (CD3OD) 0.98-1.29 (12H, m), 1.50-1.78 (1 1H, m), 151650.doc •95- 201120038 2.09-2.10 (3H, m) , 2.26-2.28 (1H, m), 2.60-2.63 (1H, m), 2.92 (3H, s), 3.25-3.31 (1H, m), 3.76-3.78 (1H, m), 4.16-4.20 (1H, m), 4.48-4.53 (1H, m), 4.62-4.71 (2H, m), 6.67 (1H, d, J=3.48 Hz) 7.58 (1H, d, J=3.52Hz), 8.31-8.35 (3H, m), 8.87-8.90 (1H, m). Table 1 Compounds were synthesized as described for Examples 1 to 3.

Example No. YY Stereochemical R1 Molecular Weight [Μ+Η]+ 9 PC R 〇9 457.25 458.29 10 S 〇9 471.26 472.75 11 R 〇9 455.23 456.23 12 R 471.24 472.2 13 y S 443.21 444.2 151650.doc •96· 201120038 14 Ά s 429.20 430.2 15 C&gt;ys 441.20 442.2 16 jK R 455.21 456.2 17 R 469.23 470.2 18 R 483.24 484.2 19 R 455.21 456.2 20 471.24 472.58 21 ό? 483.24 484.2 22 R 423.21 424.17 151650.doc -97- 201120038 23 X1&quot; s 439.24 440.17 24 s 411.21 412.22 25 , tj^ys Φ 425.22 426.21 26 R 423.21 424.19 27 S 439.24 440.18 28 Ά s 411.21 412.22 29 s &quot;9 425.22 426.22 30 R 423.21 424.21 31 s 439.24 440.22 32 R Cl Φ 439.18 440.16 151650. Doc -98- 201120038 33 S CI φ 455.21 456.19 34 R c&quot;9 439.18 440.15 35 X&quot; S 455.21 456.18 36 Ά S force 427.18 428.17 37 S Cl^9 441.19 442.19 38 R Cl 473.14 474.1 39 S Cl 489.17 490.14 40 S Cl 461.14 462.15 41 S Cl $ 475.15 476.14 42 9ν R 419.23 420.22 151650.doc ·99· 201120038 43 s 435.26 436.24 44 R 419.23 420.23 45 S 435.26 436.28 46 R 419.23 420.25 47 R 435.26 436.26 48 R 9 411.26 412.2 49 S 9 411.26 412.3 50 S 9 427.29 428.3 51 Ά s 9 399.26 400.3 52 ys 9 413.28 414.3 53 R 9 425.28 426.2 151650.doc • 100- 201120038 54 R 9 439.29 440.2 55 R 9 425.28 426.2 Table 2 The compounds were synthesized as described for Examples 1 to 3.

Example number Υ R1 Molecular weight [Μ+Η]+ 56 〇9 451.20 452.17 57 Η / 〇9 487.20 488.19 58 451.18 452.15 59 437.17 438.1 60 Η ' 473.17 473.17 I51650.doc • 101 - 201120038 61 462.19 463.18 62 419.18 420.13 63 419.18 420.15 64 CI 435.15 436.12 65 c,&quot;9 435.15 436.13 66 Λ . 469. 469.11 470.05 67 Λ 415.20 416.18 68 415.20 416.18 69 415.20 416.2 70 9 407.23 408.2 151650.doc -102- 201120038 Table 3 Compounds were synthesized as described for Example 5.

Example number X R1 Molecular weight [M+H]+ 71 9 492.22 493.2 72 9 478.18 479.48 73 9 460.19 461.15 74 9 460.19 461.12 75 9 460.19 461.17 76 9 Cl 476.16 477.13 77 9 c,? 476.16 477.15 151650.doc •103· 201120038 78 9 Φ 456.22 457.18 79 9 456.22 457.18 80 9 456.22 457.19 81 9 9 448.25 449.1 Table 4 The compounds were synthesized as described for Example 6.

Example No. R7 R1 Molecular Weight [Μ+Η]+ 82 nPr 436.14 437.12 83 nPr 418.15 419.1 84 nPr &quot;9 418.15 419.08 151650.doc -104· 201120038 85 nPr 418.15 419.13 86 nPr Cl 434.12 435.08 87 nPr 434.12 435.12 88 nPr Cl 468.08 469.08 89 nPr Φ 414.17 415.15 90 nPr 414.17 415.15 91 nPr 9 406.20 407.2 Table 5 The compounds were synthesized as described for Examples 1 to 8.

I51650.doc -105 - 201120038 Example number Stereochemistry of Y Y R1 Molecular weight [M+H]+ 92 R 〇9 519.64 520.22 93, broad R 505.57 506.20 Table 6 Compounds were synthesized as described for Example 5.

OH Example No. XX Stereochemical R1 Molecular Weight [M+H]+ 94 R 〇9 430.50 431.22 95 Person R 444.53 445.17 96 Person S 〇9 444.53 445.12 97 Person R 430.26 431.15 151650.doc -106- 201120038 SFF 丄98 430.26 431.14 Table 7 Example 4 NMR data: Example number Solvent chemical shift 9 cd3od 0.70-0.79 (6H, m), 0.80-0.97 (1H, m), 1.16-1.41 (1H, m), 1.62-1.75 (1H, m) , 3.29-3.41 (2H, m), 3.62-3.72 (2H, m), 4.37-4.56 (2H, m), 4.82-4.88 (1H, m), 6.73 (1H, d, J=3.5 Hz), 7.24 -7.36 (2H, m), 7.41-7.54 (2H, m), 7.64 (1H, d, J=3.5 Hz), 7.70 (1H, d, J=8.0 Hz), 7.81 (1H,d,J=8.0 Hz), 8.12-8.24 (3H, m), 8.70-8.78 (1H, m). 10 cd3od 0.96-1.02 (3H, m), 1.15-1.20 (3H, m), 1.51 (3H, d, J=5.85Hz), 2.61 (3H, s, br), 3.46-3.52 (1H, m), 3.63-3.69 (1H, m), 4.44-4.58 (2H, m), 4.91 (4H, s)5 4.96-4.98 (1H, m), 6.67 (1H, d, J=3.48Hz), 7.33-7.42 ( 2H, m), 7.51-7.61(3H, m), 7.78 (1H, d, J=8.0 Hz), 7.89 (1H, d, J=8.09Hz), 8.07(1H, s), 8.20(1H, s ), 8.26 (lH, d, J = 8.45 Hz), 8.77 (1H, s, br). 11 CD30D 1.65-1.74 (1H, m), 1.81-1.88 (1H, m), 2.09-2.19 (1H, m), 2.40-2.49 (1H, m), 2.90 (3H, s), 3.14-3.21 (1H , m), 3.37-3.44 (1H, m), 3.62-3.74(2H, m), 4.08-4.12 (1H, m), 4.43-4.57 (1H, m), 4.93(3H, s), 6.75 (1H , d, J=3.48 Hz), 7.30-7.38 (2H, m), 7.50-7.57 (2H, m), 7.67 (1H, d, J-3.52 Hz), 7.75 (1H, d, J=8.0 Hz) , 7.86 (1H, d, J=8.08 Hz), 8.04-8.23 (4H, m), 8.74-8.77 (1H, m). 12 CD30D 0.69-0.80 (1H, m), 0.87-0.93 (6H, m), 1.21-1.31 (1H, m), 2.02-2.10 (1H, m), 2.88 (6H, s), 2.97 (1H, dd , J = 10.7, 13.8 Hz), 3_21 (1H, dd, J = 5.6, 14.1 Hz), 3.64 (1H, d, J = 5.0 Hz), 4.52-4.63 (2H, m), 4.65-4.69 (1H, m), 6.68 (1H, d, J=3.4Hz), 7.09-7.13 (1H, m)5 7.15-7.27 (2H, m), 7.59 (1H, d, J=3.4Hz), 8.22 (1H, d , J=1.6 Hz), 8.30 (1H, d, J=1.6 Ηζ), 8.86 (1Η, ζ·ί=5.8Ηζ). 13 CD30D 1.13 (3H, t, J=6.9Hz), 1.40 (3H, d, J=6.9Hz), 2.62-2.69 (1H, m), 2.65 (3H, s), 2.78-2.90 (1H, m) , 2.83 (1H, dd, J-8.4, 14.1 Hz), 2.99 (1H, dd, J=6.9, 13.6 Hz), 3.76 (1H, q, J=6.9Hz), 4.31-4.45 (2H, m), 4.57 (1H, t, J=7.7 Hz), 6.55 (1H, d, J=3.5Hz), 6.87-7.05 (3H, m), 7.46 (1H, d, J=3.5Hz), 8.06 (1H, d , J = 1.2 Hz), 8.12 (1H, d, J = 1.2 Hz), 8.64 (1H, t, J = 5_6 Hz). 151650.doc • 107· 201120038 14 CD3OD 1.41 (3H, d, J=7.1 Hz), 2.66 (6H, s), 2.84 (1H, dd, J=8.4, 13.9Hz), 2.98 (1H, dd, J= 6.6, 13.9 Hz), 3.71 (1H, q, J=7.1 Hz), 4.30-4.44 (2H, m), 4.54 (1H, t, J=7.7 Hz), 6.55 (1H, d, J=3.4Hz) , 6.85-7.04 (3H, m), 7.46 (1H, d, J=3.4Hz), 8.06 (1H, d, J=1.7 Hz), 8.11 (1H, d, J=1.7 Hz), 8.64 (lH, t, J = 5.8 Hz). 15 CD3OD 1.82-1.95 (2H, m), 2.00-2.09 (1H, m), 2.39-2.47 (1H, m), 2.69 (3H, s), 2.84 (1H, dd, J=8.4, 13.5Hz), 2.97 (1H, dd, J=7.7, 13.5Hz), 3.02-3.10 (1H, m), 3.53-3.59 (1H, m), 3.91 (1H, t5 J=8.4Hz), 4.29-4.42 (2H, m ), 4.52 (1H, t, 3=7.7 Hz), 6.54 (1H, d, J=3.6 Hz), 6.85-7.03 (3H, m), 7.46 (1H, d, J=3.6 Hz), 8.04 (1H , s), 8.10 (1H, s), 8.62 (1H, t, J = 5.8 Hz). 16 CD3OD 1.28 (3H, t, J=7.3 Hz), 1.75-1.83 (1H, m), 1.89-2.00 (1H, m), 2.13-2.22 (1H, m), 2.43-2.52 (1H, m)5 2.93-3.00 (2H, m), 3.15-3.31 (5H, m), 3.70-3.76 (1H, m), 4.12 (1H, t, J=8.1 Hz), 4.50-4.58 (2H, m), 4.73 ( 1H, t, J=8.1 Hz), 6.69 (1H, d, J=3.5Hz), 7.02-7.05 (1H, m), 7.09-7.20 (2H, m), 7.60 (1H, d, J=3.5Hz ), 8.19 (1H, d, J = 1.5 Hz), 8.27 (1H, d, J = 1.5 Hz), 8.82 (1H, t, J = 5.9 Hz). 17 CD3OD 1.28 (3H, d, J=6.6 Hz), 1.32 (3H, d, J=6.6 Hz), 1.79-1.93 (2H, m), 2.07-2.16 (1H, m), 2.39-2.47 (1H, m), 2.98 (1H, dds J=8.8, 13.8 Hz), 3.17 (1H, dd, J=8.8, 13.8 Hz), 3.25-3.32 (1H, m), 3.51-3.58 (1H, m), 3.63- 3.68 (1H, m), 4.23 (1H, dd, J=6.1, 9.4Hz), 4.54 (2H, d, J=4.4Hz), 4.71 (1H, t, J=8.0 Hz), 6.70 (1H, d , J=3.5Hz), 7.02-7.05 (1H, m), 7.10-7.20 (2H, m), 7.61 (1H, d, J=3.5Hz), 8.21 (1H, d, J=1.5Hz), 8.28 (1H, d, J = 1.5 Hz), 8.83 (1H, t, J = 5.8 Hz). 18 CD3OD 1.27 (3H, d, J=7.5Hz), 1.32 (3H, d, J=7.5Hz), 1.53-1.64 (1H, m), 1.72-2.02 (5H, m), 2.95-3.02 (2H, m), 3.11-3.16 (1H, m), 3.47 (1H, d, J=12.5Hz), 3.53-3.59 (1H, m), 3.91 (1H, dd, J=3.0, 12.0 Hz), 4.54 (2H , d, J=5.3 Hz), 4.65 (1H, t, J=7.8Hz), 6.71 (1H, d, J=3.5Hz), 7.02-7.05 (1H, m), 7.10-7.19 (2H, m) , 7.62 (1H, d, J = 3.5 Hz), 8.23 (1H, d, J = 1.5 Hz), 8.29 (1H, d, J = 1.5 Hz), 8.81 (1H, t, J = 5.8 Hz). 19 CD3OD 1.58-1.65 (2H, m), 1.72-1.83 (1H, m), 1.91-2.00 (3H, m), 2.80 (3H, s), 2.98 (1H, dd, J=8.8, 13.8Hz), 3.10-3.17 (2H, m), 3.52 (1H, d, J=12.5Hz), 3.70-3.75 (1H, m), 4.53-4.58 (2H, m), 4.67 (1H, t, J=7.3 Hz) , 6.74 (1H, d, J=3.5Hz), 7.01-7.05 (1H, m), 7.08-7.19 (2H, m)5 7.65 (1H, d, J=3.5Hz), 8.29 (1H, brs), 8.31 (1H, brs), 8.85 (1H, t, J=5.7 Hz). 151650.doc -108- 201120038 20 cd3od 1.00-1.30 (12H,m), 2.81 (1H, dd, J-8.8, 13.8 Hz), 3.02 (1H, dd, J=6.4, 13.8 Hz), 3.50-3.64 ( 3H, m), 3.68 (1H, d, J=16.9 Hz), 3.80 (1H, d, J=16.9 Hz), 4.35 (2H, d, J=5.7 Hz), 4.59 (1H, dd, J=6.4 , 8.8 Hz), 6.41 (1H, d, J=3.5 Hz), 6.85-7.00 (2H, m), 7.04 (1H, ddd, J=2.0, 7.7,11.5 Hz), 7.34 (1H, d, J= 3.5 Hz), 7.83 (1H, d, J=1.6 Hz), 8.05 (lH, s), 8.62 (lH, t, J=5_7Hz). 21 cd3od 0.92 (3H, d, J=6.6 Hz), 1.06 (3H, d, 3=6.6 Hz), 1.13-1.17 (1H, m), 1.28-1.55 (3H, m), 1.62-1.77 (3H, m), 2.81 (1H, dd, J=8.9, 13.8Hz), 3.00 (1H, dd, J=6.5, 14.1 Hz), 3.30-3.38 (1HS m), 3.57-3.73 (1H, m), 4.32- 4.43 (2H, m), 4.59 (1H, t, J=7.3 Hz), 6.53 (1H, d, J=3.5Hz), 6.85-6.89 (1H, m), 6.91-7.03 (2H, m), 7.45 (1H, d, J = 3.5 Hz), 8.04 (1H, d, J = 1.5 Hz), 8.12 (1H, d, J = 1.5 Hz), 8.68 (1H, t, J = 4.8 Hz). 22 CD30D 1.54-1.65 (lH,m), 1.70-1.84 (1H, m), 1.96-2.08 (1H, m), 2.26-2.38 (1H, m), 2.76 (3H, s), 2.80 (2H, dd , J=9.1, 13.8 Hz), 3.00-3.10 (2H, m), 3.54 (1H, ddd, J=3.8, 7.6, 11.4 Hz), 3.92 (1H, t, J=8.4 Hz), 4.32-4.43 ( 2H, m), 4.58 (1H, dd, J=6.6, 8.9 Hz), 6.45 (1H, d, J=3.5 Hz), 6.78-6.86 (2H, m), 7.06-7.13 (2H, m), 7.38 (1H, d, J = 3.5 Hz), 7.90 (1H, d, J = 1.5 Hz), 8_07 (1H, d, J = 1.3 Hz), 8.62 (1H, t, J = 5.7 Hz). 23 CD30D 0.98 (2H, brs), 1.08-1.15 (4H, m), 1.21-1.30 (2H, m), 1.37-1.46 (3H, m), 2.52-2.60 (3H, m), 2.73-2.87 (2H , m), 3.00-3.17 (2H, m), 3.85 (1H, dd, J=8.0, 4.0 Hz), 4.43-4.53 (2H, m), 4.58-4.67 (1H, br m), 6.63 (1H, d, J=4.0 Hz), 6.77-6.89 (2H, m), 7.05-7.16 (2H, m), 7.52 (1H, d, J=8.0 Hz), 8.21-8.26 (1H, m), 8.31-8.44 (1H, m). 24 CD30D 1.57 (3H, d, J=8.0 Hz), 2.80 (6H, br, s), 3.01-3.05 (1H, m), 3.14-3.19 (1H, m), 3.94 (1H, dd, J=8.0 , 4.0 Hz), 4.52-4.62 (2H, m), 4.78 (1H, t, J=8.0 Hz), 5.07 (3H, s), 6.84 (1H, d, J=4.0 Hz), 6.92-6.97 (2H , m), 7.25-7.29 (2H, m), 7.73 (1H, d, J=4.0 Hz), 8.35 (1H d, J=4.0 Hz), 8.43 (1H, d, J=4.0 Hz). 25 CD30D 1.19-1.40 (3H, m), 1.56 (3H, d, J=4.0 Hz), 2.79-2.88 (4H, m), 3.01-3.03 PH, m), 3.17-3.27 (1H, m), 3.96 (1H, q, J=8.0 Hz), 4.52-4.63 (2H, m), 4.75 (1H, t, J=8.0 Hz), 5.07 (3H, br, s), 6.83 (1H, d, J=4.0 Hz), 6.95-6.99 (2H, m), 7.26-7.38 (2H, m), 7.72 (1H, d, J=4.0 Hz), 8.34 (lH,s), 8.40 (lH,s)» 26 CD30D 1.70 -1.78 (1H, m), 1.87-1.98 (1H, m), 2.12-2.22 (1H, m), 2.44-2.53 (1H, m), 2.93 (3H, s), 2.98-3.03 (1H, m) , 3.18-3.28 (2H, m), 3.69-3.74 (1H, m), 4.15 (1H, t, J=8.0 Hz), 4.57-4.61 (2H, m), 4.74-4.80 (1H, m), 5.06 (3H, br, s), 6.87 (1H, d, J=4.0 Hz), 6.91-7.01 (2H, m), 7.08 (1H, d, J=4.0 Hz), 7.24-7.30 (1H, m), 7.75 (1H, d, J=4.0 Hz), 8.39 (1H, s), 8.52 (1H, d, J = 4.0 Hz). 151650.doc -109· 201120038 27 CD3OD 1.14-1.19 (3H, br, m), 1.27-1.39 (5H, m), 1.53-1.59 (4H, m), 2.67 (3H, br, s), 2.92-3.06 (2H, br, m), 3.22-3.26 (1H, m), 4.00 (1H, dd, J=8.0, 4.0 Hz), 4.55-4.64 (2H, m), 4.86 (1H, br, s), 6.80 (1H, d, J=4.0 Hz), 6.95-7.02 (1H, m), 7.03-7.07 (1H, m), 7.12 (1H, d, J=8.00 Hz), 7.27-7.32 (1H, m), 7.69 (1H,d,J=4.0 Hz), 8·34 (1H, s) 8.45 (1H, s). 28 CD3OD 1.56-1.68 (3H, m), 2.79 (6H, br, s), 2.93-2.97 (1H, m), 3.04-3.17 (1H, m), 3.90 (1H, q, J=8.0 Hz), 4.52-4.63 (2H, m), 4.76 (1H, t, J=8.0 Hz), 5.01 (3H, br, s), 6.85 (1H, d, J=4.0 Hz), 6.92 (1H, dd, J= 8.0,4.0 Hz), 7.03 (1H, dd, J-8.0, 4.0 Hz), 7.10 (1H, d, J=8.0 Hz) 7.23-7.28 (1H, m), 7.74 (1H, d, J=8.0 Hz) ), 8.35 (1H, d, J=4.0 Hz), 8.46 (1H, d, J=4.0 Hz). 29 CD3OD 1.27-1.38 (3H, m), 1.58 (3H, d, J=8.0 Hz), 2.79 (3H, br, s), 3.00-3.06 (2H, m), 3.18-3.29 (2H, m), 3.96 (1H, q, J=8.0 Hz), 4.53-4.64 (2H, m), 4.78 (1H, t, J=8.0 Hz), 4.99 (3H, br, s), 6.84 (1H, d, J= (4H, dd, J=8.0, 4.0 Hz) 1H, m), 7.74 (1H, d, J = 4.0 Hz), 8.35 (1H, d, J = 4.0 Hz), 8.45 (1H, d, J = 4.0 Hz). 30 CD3OD 1.74-1.82 (1H, m), 1.88-1.95 (1H, m), 2.09-2.21 (1H, m), 2.47-2.54 (1H, m), 2.91 (3H, s), 3.04-3.09 (1H , m), 3.17-3.29 (2H, m), 3.36-3.37 (1H, m), 3.67-3.72 (1H, m), 4.11 (1H, t, J=8.0 Hz), 4.57-4.61 (2H, m ), 4.83 (1H, t, J=8.0 Hz), 4.93 (2H, s), 6.78 (1HS d, J=4.0 Hz), 6.99-7.07 (2H, m), 7.24-7.28 (2H, m), 7.67 (1H, d, J = 4.0 Hz), 8.33 (2H, d, J = 8.0, 4.0 Hz). 31 CD3OD 1.03-1.17 (5H, m), 1.40-1.54 (4H, m), 2.68 (2H, s), 2.91-3.11 (3H, br, m), 4.01 (1H, q, J=4.0 Hz), 4.59-4.64 (2H, m), 4.98 (5H, br, s) 6.84 (1H, t, J=4.0 Hz), 7.06 (2H, br, s), 7.28 (2H, br, s), 7.74 (1H , d, J=4.0 Hz), 8.32-8.36 (1H, m), 8.43-8.47 (1H, m). 32 CD3OD 1.72-1.80 (1H, m), 1.88-2.00 (1H, m), 2.14-2.23 (1H, m), 2.45-2.55 (lH, m), 2.92 (3H, s), 2.95-2.98 (lH , m), 3.19-3.25 (2H, m), 3.70- 3.74 (1H, m), 4.15 (1H , t, J = 8.0 Hz), 4.55-4.64 (2H, m), 4.73-4.80 (1H , m ), 5.04 (3H, br, s), 6.85 (1H, d, J = 4.0 Hz), 7.20-7.27 (4H, m), 7.75 (1H, dd, J=8.0, 4.0 Hz), 8.37 (1H, s) 8·48 (1H, s). 33 CD3OD 1.12 (2H, br, s), 1.27 (3H, d, J=4.0 Hz), 1.50-1.54 (3H, m), 2.66 (3H, br, s), 2.90-3.03 (1H, m), 3.18-3.24 (1H, m), 3.95-4.00 (1H, m), 4.58-4.65 (2H, m), 4.87 (1H, br, s), 5.00 (5H, s), 6.83 (1H, d, J =4.0 Hz), 7.17-7.35 (4H, m), 7.72 (1H, t, J=4.0 Hz), 8.36 (1H, s), 8.44 (1H, s). 151650.doc •110· 201120038 34 CD3OD 1.71-1.78 (1H, m), 1.80-1.89 (1H, m), 2.13-2.23 (1H, m), 2.46-2.55 (1H, m), 2.93 (3H ,s ), 2.97-3.01 (1H, m), 3.22-3.27 (2H, m), 3.69- 3.74 (1H, m), 4.15 (1H, t, J=8.0 Hz), 4.61 (2H, t, J=4.0 Hz), 4.76-4.80 (1H, m), 5.13 (3H, br, s), 6.87 (lH,d, J=4.0 Hz), 7.19-7.27 (4H, m), 7.75 (1H, d, J= 4.0 Hz), 8.39 (1H, d, J=4.0 Hz), 8.52 (1H, d, J=4.0 Hz). 35 CD3OD 1.13 (2H, br, s), 1.21-1.30 (4H, m), 1.41-1.55 (3H, m), 2.67-2.76 (3H, m), 2.84-3.04 (2H, m), 3.14-3.26 (1H, m), 3.96 (1H, dd, J=8.0, 4.0 Hz), 4.49-4.61 (1H, br, m), 4.81 (1H, br, s), 4.96-5.01 (2H, m), 6.80 -6.84 (1H, m), 7.12-7.23 (4H, m), 7.28-7.34 (1H, m), 7.70-7.72 (1H, m), 8.35 (1H, s), 8.39-8.42 (1H, m) . 36 CD3OD 1.40 (3H, d, J=4.0 Hz), 2.80 (6H, br, s), 3.00-3.05 (1H, m), 3.16-3.23 (1H, m), 3.92 (1H, q, J=8.0 Hz), 4.53-4.63 (2H, m), 4.76 (1H, t, J=8.0 Hz), 5.08 (3H, br, s), 6.85 (1H, d, J=4.0 Hz), 7.16-7.32 (4H , m), 7.74 (1H, d, J = 4.0 Hz), 8.35 (1H, s), 8.46 (1H, s). 37 CD3OD U8-1.27(3H,m), 1.56(3H,d,J=8.0Hz), 2.79-2.85 (3H,m),3.18-3.23 (2H, m), 3.97 (1H, q, J=8.0 Hz), 4.54-4.64 (2H, m), 4.78 (1H, t, J=8.0 Hz), 5.09 (4H, br, s), 6.85 (1H, d, J=4.0 Hz), 7.18-7.32 (4H , m), 7.74 (1H, d, J = 4.0 Hz), 8.36 (1H, s), 8.48 (1H, s). 38 CD3OD 1.74-1.83 (1H, m), 1.91-2.01 (1H, m), 2.15-2.25 (1H, m), 2.48-2.55 (1H, m), 2.93 (3H, s), 2.95-3.00 (1H , m), 3.20-3.25 (2H, m), 3.69-3.75 (1H, m), 4.16 (1H, t, J=8.0 Hz), 4.58 (2H, d, J=4.0 Hz), 4.76 (1H, Dd, J=8.0, 4.0 Hz), 5.03 (3H, s), 6.85 (1H, d, J=4.0 Hz), 7.20 (1H, dd, J=8.0, 4.0 Hz), 7.37-7.42 (2H, m ), 7.74 (1H, d, J=4.0 Hz), 8.39 (1H, d, J=4.0 Hz), 8_51 (1H, d, J=4.0 Hz). 39 CD3OD 1.01 (2H, br, s), 1.13-1.19 (3H, m), 1.33-1.42 (4H, m), 2.54-2.58 (2H, m), 2.62-2.86 (2H, br, m), 3.05 -3.11 (1H, m), 3.23 (2H, q, J=4.0 Hz), 3.82 (1H, q, J=4.0 Hz), 4.35-4.50 (2H, br, m), 4.79 (2H, br, s ), 6.57-6.61 (1H, m), 6.96-7.12 (2H, m), 7.20-7.35 (2H, m), 7.49-7.51 (1H, m), 8.15 (1H, d, J=4_0 Hz), 8.18 (1H,d, J=4_0 Hz). 40 CD3OD 1.57 (3H, d, J=8.0 Hz), 2.59-2.65 (6H, m), 3.00-3.05 (1H, m), 3.14-3.27 (1H, m), 3.92 (1H, dd, J=8.0 , 4.0 Hz), 4.47-4.64 (2H, br, m), 4.72 (1H, t, J=8.0 Hz), 5.07 (3H, br, s), 6.81 (1H, d, &gt;8.0 Hz), 7.20 (1H, dd, J=8.0, 4.0 Hz), 7.36-7.40 (1H, m), 7.43 (1H, d, J=4.0 Hz), 7.71 (1H, d, J=4.0 Hz), 8.35 (1H, d, J=4.0 Hz), 8.41 (1H, d, J=4.0 Hz). 151650.doc -Ill - 201120038 41 CD3OD 1.34-1.41 (3H, m), 1.56 (3H, d, J=4.0 Hz), 2.63 (4H, s), 2.94-3.04 (2H, m), 3.16-3.21 ( 2H, m), 4.05 (1H, d, J=4.0 Hz), 4.53-4.64 (2H, m), 4.77 (1H, t, J=8.0 Hz), 5.08 (2H, s), 6.84 (1H, d , J=4.0 Hz), 7.22 (1H, dd, J=8.0, 4.0 Hz), 7.39 (1H, d, J=8.0 Hz), 7.45 (1H, d, J=4.0 Hz), 7.73 (1H, d , J=4.0 Hz), 8.37 (1H, d, J=4.0 Hz), 8.46 (1H, d, J-4.0 Hz) » 42 CD3OD 1.69-1.78 (1H, m), 1.87-1.94 (1H, m) , 2.08-2.19 (1H, m), 2.27 (3H, s), 2.42-2.52 (1H, m), 2.90-2.96 (4H, m), 3.16-3.24 (2H, m), 3.69-3.73 (1H, m), 4.13 (1H, t, J=8.0 Hz), 4.58-4.63 (2H, m), 4.73 (1H, dd, J=8.0, 4.0 Hz), 5.03 (3H, s), 6.84 (1H ,d , J=4.0 Hz), 7.04 (2H, d, J=8.0 Hz), 7.12 (2H, ds J=4.0 Hz), 7.74 (1H, d, J-4.0 Hz), 8.3.7 (1H, d, J = 4.0 Hz), 8.48 (1H, d, J = 4.0 Hz). 43 CD3OD 0.89 (2H, br, s), 0.99-1.09 (2H, m), 1.12-1.19 (2H, m), 1.26-1.36 (3H, m), 2.08-2.14 (4H, m), 2.41-2.52 (2H, m), 2.62-2.68 (2H, m), 2.74-2.80 (2H, m), 2.98-3.08 (1H, m), 3.16-3.18 (2H, m), 3.74 (1H, dd, J= 8.0, 4.0 Hz), 4.12-4.14 (2H, m), 6.56-6.64 (1H, m), 6.82-6.89 (2H, m), 6.93-7.09 (2H, m), 7.40-7.49 (1H, m) , 8.04-8.16 (2H, m). 44 CD3OD 1.42-1.50 (1H, m), 1.61-1.68 (1H, m), 1.84-1.96 (1H, m), 2.03 (3H, s), 2.12-2.26 (1H, m), 2.67-2.72 (4H , m), 2.93-0.98 (2H, m), 3.43-3.48 (1H, m), 3.89 (1H, t, J=8.0 Hz), 4.30-4.39 (2H, m), 4.50-4.55 (1H, m ), 4.79 (2H, s), 6.61 (1H, d, J=4.0 Hz), 6.71 (1H, d, J=4.0 Hz), 6.86-6.93 (4H, m), 7.49 (1H, d, J= 4.0 Hz), 8.11 (1H, d, J=4.0 Hz), 8.23 (lH, d, J = 4.0 Hz). 45 CD3OD 1.07(2H,br,s), 1.24(3H,d,J=4.0Hz), 1.52(3H,d,J=4._0Hz), 2.26-2.30 (3H, m), 2.40 (1H, br , s), 2.66 (2H, s), 2.76-2.80 (1H, m), 2.90-2.96 (1H, m), 3.16-3.23 (1H, m), 3.93-4.00 (1H, m), 4.56-4.65 (2H, m), 4.89 (1H, s), 5.00 (4H, br, s), 6.84 (1H, d, J=4.0 Hz), 7.04-7.08 (2H, m), 7.10-7.17 (2H, m ), 7.73 (1H, d, J=4.0 Hz), 8.33 (1H, s), 8.42 (1H, s). 46 CD3OD 1.74-1.83 (1H, m), 1.90-1.95 (1H, m), 2.15-2.21 (1H, m), 2.36 (3H, s), 2.48-2.55 (1H, m), 2.92 (3H, s ), 2.97-3.02 (1H, m), 3.17-3.29 (2H, m), 3.68-3.74 (1H, m), 4.16 (1H, t, J=8.0 Hz), 4.52-4.62 (2H, m), 4.76-4.81 (1H, m), 5.15 (3H, br, s), 6.86 (1H, d, J=4.0 Hz), 6.99-7.06 (1H, m), 7.08-7.20 (3H, m), 7.75 ( 1H, d, J=4.0 Hz), 8.32 (1H, d, J=4.0 Hz), 8.55 (1H, s). 151650.doc 112· 201120038 47 cd3od 1.15 (2H, br, s), 1.25 (3H, d, J=4.0 Hz), 1.54 (3H, d, J=4.0 Hz), 2.40 (3H, s), 2.67 ( 2H, s), 2.82-2.86 (1H, br, m), 3.02-3.05 (1H, m), 3.22-3.29 (1H, m), 3.97-4.02 (1H, m), 4.52-4.64 (2H, m ), 4.90 (1H, br, s), 5.05 (5H, s), 6.85 (1H, d, J=4.0 Hz), 7.00-7.16 (3H, m), 7.18-7.23 (1H, m), 7.74 ( 1H, d, J=4.0 Hz), 8.29-8.32 (1H, m), 8.40-8.45 (1H, m). 48 cd3od 0.93-1.07 (2H, m), 1.15-1.37 (4H, m), 1.63-1.79 (6H, m), 2.03-2.13 (3H, m), 2.22-2.32 (1H, m), 2.60-2.68 (1H, m), 2.94 (3H, s), 3.22-3.30 (1H, m), 3.73-3.79 (1H, m), 4.14 (1H, t, J=7.9Hz), 4.47-4.51 (1H, m ), 4.57-4.65 (2H, m), 6.72 (1H, d, J=3.3 Hz), 7.62 (1H, d, J=3.3 Hz), 8.35 (1H, s), 8.37 (1H, s), 8.91 (1H, t, J = 5.2 Hz). 49 CD30D 0.77-0.89 (2H, m), 1.01-1.11 (3H, m), 1.16-1.22 (1H, m), 1.47-1.65 (7H, m), 1.81-1.97 (2H, m), 1.99-2.08 (1H, m), 2.39-2.49 (1H, m), 2.80 (3H, s), 3.04-3.11 (1H, m), 3.55-3.61 (1H, m), 3.97 (1H, t, J=8.3 Hz ), 4.33 (1H, dd, J=6.9, 8.3 Hz), 4.41 PH, s), 6.49 (1H, d, J=3.5Hz), 7.40 (1H, d, J=3.5Hz), 8.06 (1H, d, J = 1.7 Hz), 8.13 (1H, d, J = 1.7 Hz), 8.67 (lH, t, J = 5.6 Hz). 50 CD30D 0.95-1.07 (2H, m), 1.15-1.42 (10H, m), 1.59 (3H, d, J=6.9Hz), 1.65-1.81 (7H, m), 2.78 (3H, s), 3.59 ( 1H, brs), 4.05-4.10 (1H, m), 4.52 (1H, t, J=6.9Hz), 4.59-4.61 (2H, m), 6.73 (1H, d, J=3.7 Hz), 7.63 (1H , d, J = 3.7 Hz), 8.34 (1H, s), 8.36 (1H, s), 8.88 (1H, t, J = 5.8Hz) » 51 CD30D 0.77-0.89 (2H, m), 0.97-1.10 ( 3H, m), 1.12-1.21 (1H, m), 1.43 (3H, d, J=7.0 Hz), 1.48-1.65 (7H, m), 2.77 (6H, s), 3.78 (1H, q, J= (7H, d, J=7.3 Hz) , d, J = 1.7 Hz), 8.15 (1H, d, J = 1.7 Hz), 8.68 (1H, t, J = 5.6 Hz). 52 CD30D 0.78-0.91 (2H, m), 1.00-1.11 (3H, m), 1.15-1.26 (1HS m), 1.23 (3H, t, J=6.9Hz), 1.44 (3H, d, J=6.9Hz ), 1.49-1.66 (7H, m), 2.75 (3H, s), 3.04-3.12 (2H, m), 3.86 (1H, q, J=7.0 Hz), 4.36 (1H, t, J=7.8Hz) , 4.44 (2H, s), 6.57 (1H, d, J=3.4Hz), 7.47 (1H, d, J=3.4Hz), 8.18 (1H, d, J=1.4Hz), 8_20 (1H,d, J = l_4 Hz), 8.71 (1H, t, J = 5.9 Hz). 53 CD30D 0.94-1.07 (2H, m), 1.18-1.39 (4H, m)51.28 (3H, t, J=7.7 Hz), 1.65-1.79 (7H, m), 2.02-2.12 (2H, m), 2.21 -2.28 (1H, m), 2.57-2.64 (1H, m), 3.18-3.31 (3H, m), 3.75-3.81 (1H, m), 4.13-4.18 (1H, m), 4.47-4.51 (1H, m), 4.55-4.65 (2H, m), 6.70 (1H, d, J=3.4Hz), 7.60 (1H, d, J=3.4Hz), 8.31-8.33 (2H,m),8.89 (1H,t , J = 5.8 Hz). 151650.doc -113 · 201120038 54 CD3OD 0.94-1.07 (2H, m), 1.19-1.37 (3H, m), 1.27 (3H, d, J=6.1 Hz), 1.32 (3H, d, J=6.1 Hz) , 1.65-1.71 (3H, m), 1.73-1.80 (4H, m), 1.99-2.12 (2H, m), 2.15-2.21 (1H, m), 2.53-2.61 (1H, m), 3.29-3.37 ( 3H, m), 3.52-3.59 (1H, m), 3.67-3.73 (1H, m), 4.23-4.27 (1H, m), 4.46-4.50 (1H, m), 4.53-4.64 (2H, m), 6.69 (1H, d, J-3.3 Hz), 7.59 (1H, d, J=3.3 Hz), 8.28 (1H, d, J=1.7 Hz), 8.32 (1H, d, J=1.7 Hz), 8.88 ( 1H, t, J = 5.8 Hz). 55 CD3OD 0.94-1.06 (2H,m), 1.18-1.30 (3H,m), 1.31-1.39 (1H, m), 1.62-1.88 (11H, m), 1.99 (2H, d, J= 12.9Hz), 2.15-2.20 (1H, m), 2.79 (3H, s), 3.13 (1H, dt, J=2.3, 12_9Hz), 3.53 (1H, d, J = 12.2Hz), 3·75 (1H, dd, J =2.3, 12.2Hz), 4.42-4.46 (1H, m), 4.56-4.66 (2H, m), 6.72 (1H, d, J=7.5Hz), 7.62 (1H, d, J=7.5Hz), 8.34 (1H, d, J = 1.7 Hz), 8.36 (1H, d, J = 1.7 Hz), 8.91 (1H, t, J = 5.6 Hz). 56 CD3OD 2.28 (3H, s), 3.54 (2H, q, J=7.08Hz), 3.65-3.70 (1H, m), 4.34-4.38 (1H, m), 4.49-4.54 (1H, m), 6.06 ( 1H, t, J=2.4 Hz), 6.75-6.78 (2H, m), 6.84 (1H, t, J=2.80Hz), 7.25-7.28 (1H, m), 7.36(lH,d, J=6.97 Hz ), 7.45-7.56 (4H, m), 7.67 (1H, d, J=3.57 Hz), 7.73 (1H, d, J=8.17 Hz), 7.87 (1H, t, J=7.96 Hz), 8.13-8.17 (2H, m), 8.26 (lH, d, J = 8.29 Hz), 8.56-8.57 (1H, m). 57 d6- DMSO 3.38-3.44 pH, m), 3.63 pH, s), 4-41 (2H, d, J = 5.84 Hz), 4.88-4.92 (1H, m), 6.41 (lH, q, J = 1.92) Hz), 7.01-7.13 (2H, m), 7.17-7.20(2H, m), 7.21-7.37(3H, m), 7.46-7.62(2H, m), 7.73-7.78(2H, m), 7.88( 1H, d, J = 7.65Hz), 8.14(lH,d, J=1.96 Hz), 8.32(1H, d, J= 8.48Hz), 8.67-8.72(2H,m), 11.48-11.61(1H, m ). 58 CD3OD 2.23 (3H, s), 2.24 (3H, s), 3.04 (1H, dd, J=7.1, 13.7 Hz), 3.15 (1H, dd, 3=1.1, 13.7 Hz), 4.40 (1H, d, J=14.6 Hz), 4.55 (1H, d, J=14.6 Hz), 4.77 (1H, t, J=7.1 Hz), 5.75 (1H, s), 6.48 (1H, d, J=3.5 Hz), 6.90 - 6.95 (1H, m), 7.00 (1H, td, J=8.3, 10.5 Hz), 7.12 (1H, ddd, J=2.1, 7.8,11.5 Hz), 7.42 (1H, d, J=3.5 Hz), 7.86 (1H, d, J=2.0 Hz), 8.14 (1H, d, J=1.9Hz). 59 CD3OD 1.22 (1H, t, J=6.9Hz), 2.32 (3H, s), 3.08-3.14 (1H, m), 3.17-3.23 (1H, m), 3.51-3.57 (1H, m), 4.50- 4.64 (2H, m), 4.78 (1H, t, J=7.7 Hz), 6.06 (1H, brs), 6.80 (1H, d, J=3.3 Hz), 6.84-6.85 (1H, m), 7.00-7.16 (3H, m), 7.69 (1H, d, J=3.3 Hz), 8.34 (1H, s), 8.39 (1H, s), 8.81 (1H, t, J=6.1 Hz), 10.73 (lH, brs) . 114- 151650.doc 201120038 60 CD3OD 1.13 (1H, t, J=7.0 Hz), 1.17-1.20 (1H, m), 2.96 (1H, dd, J=8.0, 13.6 Hz), 3.10 (1H, dd, J =8.0, 13.6 Hz), 3.29-3.34 (1H, m), 4.33-4.45 (2H, m), 4.67 (1H, t, J=7.5Hz), 6.56 (1H, d, J=3.4Hz), 6.90 -6.97 (3H, m), 7.02-7.13 (3H, m), 7.31 (1H, d, J=8.5Hz), 7.46 (1H, d, J=3.4Hz), 7.50 (1H,d, J=8.5 Hz), 8.12 (1H, d, J = 9.1 Hz), 8.61 (1H, t, J = 6.2 Hz). 61 CD3OD 2.17 (3H, s), 2.92 (1H, dd, J=8.5, 13.8 Hz), 3.10 (1H, dd, J=6.8, 13.8 Hz), 3.57 (2H, s), 4.45-4.56 (2H, m), 4.61 (1H, dd, J=7.0, 8.2 Hz), 6.68 (1H, d, J=3.5 Hz), 6.90-6.96 (1H, m), 7.00-7.18 (6H, m), 7.60 (1H , d, J = 3.5 Hz), 8.23 (2H, d, J = 10.8 Hz), 8.67 (1H, t, J = 5.6 Hz). 62 CD3OD 1.23 (2H, t, J=8.0 Hz), 2.16 (3H, s), 2.96-3.13 (3H, m), 4.32-4.50 (2H, m), 4.64-4.70 (1H, m), 5.91 ( 1H, d, J=4.0 Hz), 6.61-6.65 (1H, m), 6.70-6.72 (1H, m), 6.83-6.96 (2H, m), 6.97-7.04 (1H, m), 7.08-7.17 ( 1H, m), 7.56 (1H, d, J=4.0 Hz), 8.19 (1H, s), 8.25 (1H, s), 10.62 (lH, s). 63 CD3OD 2.09 (3H, s), 3.02-3.21 (2H, m), 4.36-4.46 (2H, m), 4.74 (1H, t, J= 4.0 Hz), 4.80 (4H, br, s), 5.88 ( 1H, d, J=4.0 Hz), 6.61-6.67 (2H, m), 6.80-6.94 (2H, m), 7.03-7.14 (2H, m), 7.54 (1H, d, J=4.0 Hz), 8.16 (1H, d, J = 4.0 Hz), 8.27 (1H, d, J = 4.0 Hz). 64 d6- DMSO 2.17 (2H, s), 2.50-2.55 (3H, s), 2.91-2.94 (1H, m), 3.03-3.09 (1H, m), 3.31 (1H, s), 4.40 (2H, t , J=8.0 Hz), 4.66-4.72 (1H, m), 5.91 (1H, d, J=4.0 Hz), 6.40 (1H, d, J=4.0 Hz), 6.77 (1H, d, J-4.0 Hz) ), 7.14-7.26 (2H, m), 7.40-7.45 (1H, m), 7.75 (1H, s), 8.12 (1H, s), 8.62 (1H, t, J=4.0 Hz), 1U2 (1H, s), 11.56 (1H, s). 65 d6- DMSO 2.18 (3H, d, J=4.0 Hz), 2.49 (3H, s), 2.89-2.94 (1H, m), 3.05-3.09 (2H, m), 4.39 (2H, s), 4.70 ( 1H, br s), 5.91 (1H, s), 6.43 (1H, s), 6.77 (1H, s), 7.13-7.22 (2H, m), 7.34 (1H , s), 7.47 (1H, s), 7.70 (1H, s), 8.15 (lH, s), 11.69 (lH, br, s). 66 CD3OD 2.21 (3H, s), 2.93-3.04 (2H, m), 4.34-4.38 (1H, m), 4.44-4.48 (1H, m), 4.64 (1H, t, J=8.0 Hz), 4.80 ( 3H, s), 5.89 (1H, d, J=4.0 Hz), 6.68-6.75 (2H, m), 6.91-6.99 (1H, m), 7.15 (1H, t, J=4.0 Hz), 7.22 (1H , d, J-4.0 Hz), 7.55 (1H, d, J=4.0 Hz), 8.19 (1H, d, J=4.0 Hz), 8.38 (1H, d, J=4.0 Hz), 10.59 (lH,brs ). 67 CD3OD 2.23-2.29 (4H, m), 3.09-3.19 (1H, m), 3.36-3.38 (6H, m), 4.58-4.63 (2H, m), 4.76 (1H, t, J=8.0 Hz), 6.05 (1H, d, J=4.0 Hz), 6.74 (1H, d, J=4.0 Hz), 6.85 (1H, d, J=4.0 Hz), 6.99-7.04 (2H, m), 7.10-7.17 (2H , m), 7.64 (1H, d, J=4.0 Hz), 8.24-8.29 (2H, m), 8.69 (1H, t, J-4.0 Hz). 151650.doc -115- 201120038 68 cd3od 2.09 (3H, s), 2.15 (3H, s), 2.88-3.05 (2H, m), 3.20-3.22 (2H, m), 4.33-4.38 (1H, m), 4.41-4.47 (1H, m), 4.63 (1H, t, J=8.0 Hz), 4.76 (1H, s), 5.89 (1H, t, J=4.0 Hz), 6.61 (1H, d, J=4.0 Hz) ), 6.68 (1H, d, J=4.0 Hz), 6.84-6.99 (4H, m), 7.57 (1H, d, J=4.0 Hz), 8.09 (2H, s), 10.57 (1H, br, s) . 69 cd3od 1.45-1.51 (1H, m), 2.39 (3H, s), 2.48 (3H, s), 3.22-3.36 (2H, m), 3.42-3.44 (2H, m), 4.49-4.54 (1H, m ), 4.61-4.67 (1H, m), 4.86 (1H, t, J=8.0 Hz), 6.13 (1H, d, J=4.0 Hz), 6.80-6.84 (1H, m), 6.90-6.96 (1H, m), 7.01-7.08 (1H, m), 7.14-7.21 (3H, m), 7.70 (1H, d, J=4.0 Hz), 8.26 (1H, s), 8.29 (1H, s), 10.92 (1H , br s). 70 CD30D 0.78-0.91 (2H, m), 1.02-1.29 (5H, m), 1.51-1.60 (5H, m), 1.66 PH, t, J = 11.7 Hz), 2.22 (3H, s), 2.67 (1H , brs), 4.42-4.49 (3H, m), 5.91 (1H, d, J=1.9Hz), 6.55 (1H, d5 J=3.3 Hz), 6.68 (1H, s), 7.43 (1H, d, J =3.3 Hz), 8_17 (1H, s), 8.20 (1H, s), 8.64 (1H, t, J = 5.6 Hz), 10.57 (1H, s). 72 CD30D 2.81 (1H, dd, J=7.8, 13.8 Hz), 2.92 (1H, dd, J=7.4, 13.6 Hz), 3.00-3.07 (2H, m), 4.24 (1H, dd, J=4.0, 7.8 Hz), 4.36-4.52 (2H, m), 4.58 (1H, t, J=7.4 Hz), 6.59 (1H, d, J=3.5 Hz), 6.88-6.95 (1H, m), 6.97-7.03 (1H , m), 7.04-7.11 (1H, m), 7.13-7.26 (5H, m), 7.50 (1H, d, J=3.5 Hz), 7.98 (1H, d, J=1.6 Hz), 8.17 (1H, s). 73 CD30D 2.80-2.86 (1H, m), 2.90-2.99 (1H, m), 3.01-3.10 (2H, m), 4.29-4.32 (1H, m), 4.46-4.50 (2HS m), 4.57-4.64 ( 1H, m), 5.06 (3H, s), 6.84 (1H, d, J=4.0 Hz), 6.88-6.98 (2H, m), 7.10-7.25 (8H, m), 7.73 (1H, d, J= 4.0 Hz), 8.30 (1H, s), 8.38-8.39 (1H, d, J = 4.0 Hz). 74 CD30D 2.65-2.75 (1H, m), 2.82-2.96 (3H, m), 4.13-4.16 (1H, m), 4.33-4.44 (2H, m), 4.51-4.62 (1H, m), 4.90 (4H ,br,s),6.66 (1H,d,J=4_0 Hz), 6.70-6.76 (2H, m), 6.86 (1H, d5 J=8.0 Hz), 6.92-7.08 (6H, m), 7.51 (1H , d, J = 4.0 Hz), 8.12 (1H, s) 5 8.28 (1H, s). 75 CD30D 2.57-2.72 (1H, br, m), 2.88-2.93 (2H, m), 3.00-3.09 (1H, m), 4.12 (lH, q, J=4.0Hz), 4.33-4.45 (2H, m ), 4.51 (lH, t, J = 8.0 Hz), 4.84 - 4.94 (4H, br, m), 6.70 (1H, d, J = 4.0 Hz), 6.81-6.86 (2H, m), 6.99-7.10 ( 7H, m), 7.58 (1H, d, J=4.0 Hz), 8.14 (1H, d, J=4.0 Hz), 8.27 (1H, d, J=4.0 Hz). 76 CD30D 2.08 (1H, s), 2.81-2.86 (1H, m), 2.91-3.00 (1H, m), 3.04-3.13 (2H, m), 4.30 (1H, q, J=4.0 Hz), 4.41- 4.65 (3H, br, m), 4.99 (3H, br, s), 6.82 (1H, d, J=4.0 Hz), 7.12-7.19 (5H, m), 7.23-7.29 (4H , m), 7.71 ( 1H, d, J=4_0 Hz), 8_35 (1H, s), 8.41 (1H, s). 15l650.doc -116- 201120038 77 CD3OD 2.80-2.86 (1H, m), 2.96-3.24 (2H, m), 4.13 (1H, q, J-4.0 Hz), 4.445-4.49 (1H, m), 4.54- 4.58 (1H, m), 4.64 (1H, t, J=8.0 Hz), 5.01 (5H, br, s), 6.83 (1H, d, J=4.0 Hz), 7.12-7.26 (9H, m), 7.71 (1H, d, J=4.0 Hz), 8.29 (1H, s), 8.36 (1H, s). 78 CD3OD 2.08 (3H, d, J-4.0 Hz), 2.80-2.89 (1H, m), 2.98-3.12 (3H, m), 4.28-4.36 (1H, m), 4.44-4.62 (3H, m), 5.02 (4H, br, s), 6.83 (1H, d, J=4.0 Hz), 6.97 (2H, d, J=8.0 Hz), 7.04 (2H, d, J=8.0 Hz), 7.15-7.25 (5H , m) 7.73 (1H, d, J=4.0 Hz), 8.29 (1H, d, J=4.0 Hz), 8.39 (1H, d, J=4.0 Hz). 79 CD3OD 2.07 (3H, s), 2.63-2.70 (1H, m), 2.80-2.99 (3H, m), 4.14 (1H, q, J=4.0 Hz), 4.26 (1H, d, J=8.0 Hz) , 4.41 (1H, d, J=8.0 Hz), 4.85 (5H, br, s), 6.63 (1H, d, J=4.0 Hz), 6.79-6.95 (4H, m), 6.98-7.15 (5H, m ), 7.82 (1H, d, J = 8.0 Hz), 8.08 (1H, d, J = 4.0 Hz), 8.10 (1H, d, &gt; 4.0 Hz). 80 CD3OD 2.35 (3H, s), 2.81-2.87 (1H, m), 2.92-3.08 (3H, m), 4.25-4.31 (1H, m), 4.32-4.39 (1H, m), 4.52-4.56 (1H , m), 4.80 (1H, t, J=8.0 Hz), 5.09 (4H, br s), 6.83 (1H, d, J=4.0 Hz), 6.92-6.96 (1H, m), 7.04-7.07 (3H , m), 7.12-7.19 (1H, m), 7.22-7.26 (4H, m), 7.73 (1H, d, J=4.0 Hz), 8_21 (1H, s), 8.38 (1H, d, J=4.0 Hz). 81 CD3OD 0.73-0.86 (2H, m), 1.02-1.13 (4H, m), 1.41-1.63 (7H, m), 2.71 (1H, dd, J=7.8, 13.8Hz), 2.92 (1H, dd, J =4.7, 13.8Hz), 4.16 (1H, dd, J=4.7, 7.5Hz), 4.27 (1H, dd, J=5.9, 9.4Hz), 4.38-4.47 (2H, m), 6.66 (1H, d, J=3.8Hz), 7.01-7.11 (5H, m), 7.52 (1H, d, J=3.8Hz), 8.20 (1H, d, J=1.3 Hz), 8.34 (1H, d, J=1.3 Hz) , 8.45 (1H, t, J=5.9Hz). 83 CD3OD 0.73 (3H, t, J=8.0 Hz), 1.35-1.52 (2H, brm), 2.52-2.59 (2H, m), 2.74-2.80 (1H, m), 2.92-2.97 (1H, m), 3.20-3.22 (1H, m), 3.96 (1H, q, J=4.0 Hz), 4.36-4.44 (2H, m), 4.76 (2H, br s), 6.62 (1H, d, J=4.0 Hz), 6.72-6.87 (2H, m), 7.09-7.15 (2H, m), 7.76 (1H, d, J=4.0 Hz), 8.19 (2H, dd, J=8.0, 4_0 Hz). 86 CD3OD 0.89 (3H, t, J=8.0 Hz), 1.49-1.67 (2H, m), 2.68-2.78 (2H, m), 2.90-2.95 (1H, m), 3.08-3.13 (1H, m), 3.37 (1H, s) 4.11-4.15 (1H, m), 4.55-4.60 (2H, m), 4.92 (2H, m), 6.79 (1H,d, J=4.0 Hz), 7.14-7.28 (4H,m ), 7_67 (1H, d, J = 4.0 Hz), 8.31 - 8.34 (2H, m). 87 CD3OD 0.87-0.91 (3H, m), 1.50-1.66 (2H, m), 2.67-2.79 (2H, m), 2.91-2.96 (1H, m), 3.09-3.14 (1H, m), 3.36-3.38 (1H, m), 4.13-4.17 (1H, m), 4.52-4.58 (2H, m), 4.92 (2H, s), 6.77 (1H, d, J=4.0 Hz), 7.19-7.29 (3H,m ), 7·33 (1H, s), 7.67 (1H, d, J = 4.0 Hz), 8.23-8.34 (2H, m). 151650.doc •117· 201120038 88 cd3od 0.73 (3H, t, J=8.0 Hz), 1.34-1.50 (2H, m), 2.55-2.68 (2H, m), 2.74-2.80 (1H, m), 2.91- 2.96 (1H, m), 3.99 (1H, t, J=8.0 Hz), 4.37-4.42 (2H, m), 4.79 (3H, s), 6.64 (1H, d, J=4.0 Hz), 7.05-7.10 (1H, m), 7.19-7.23 (1H, m), 7.28 (1H, d, J=4.0 Hz), 7.53 (1H, d, J= 4.0 Hz), 8.19 (1H,d, J=4.0 Hz) , 8.25 (1H, d, J = 4.0 Hz). 89 cd3od 0.85 (3H, t, J=8.0 Hz), 1.42-1.48 (1H, m), 1.54-1.62 (1H, m), 2.28 (3H, s), 2.61-2.69 (2H, m), 2.84- 2.89 (1H, m), 3.07-3.12 (1H, m), 4.12 (1H, t, J=8.0 Hz), 4.53-4.63 (2H, m), 4.98 (3H, s), 6.85 (1H, d, J=4.0 Hz), 7.06 (2H, d, J=8.0 Hz), 7.15-7.21 (2H, m), 7.72 (1H, d, J=4.0 Hz), 8.27 (1H, d, J=4.0 Hz) , 8.41 (1H, d, J = 4.0 Hz). 90 CD30D 0.85 (3H, t, J=8.0 Hz), 1.44-1.61 (2H, m), 2.30 (3H, s), 2.60-2.69 (2HS m), 2.85-2.91 (1H, m), 3.08-3.13 (1H, m), 4.13-4.17 (1H, m), 4·53-4_62 (2H, m), 4.96 (3H, s), 6.85 (1H, d, J=8.0 Hz), 7.02-7.09 (2H , m), 7.13-7.18 (2H, m), 7.70 (1H, d, J = 4.0 Hz), 8.31 (1H, d, J = 4.0 Hz), 8.37 (1H, d, J = 4.0 Hz). 91 CD30D 0.79-0.90 (5H, m), 1.04-1.15 (3H, m), 1.24-1.33 (lH, m), 1.43 (2H, t, J = 7.5 Hz), 1.54-1.69 (7H, m), 2.79 (2H, t, J=7.5Hz), 3.83 (1H, t, J=7.5Hz), 4.44-4.48 (2H, m), 6.65 (1H, d, J=3.4Hz), 7.52 (1H, d , J = 3.4 Hz), 8.24 (1H, d, J = 1.4 Hz), 8.37 (1H, d, J = 1.4 Hz), 8.71 (1H, t, J = 5.6 Hz). 92 CD30D 2.88-2.96 (2H, m) 3.22-3.44 (4H, br m) 3.56-3.62 (1H, m) 3.88-3.99 (1H, m) 4.05 (1H, dd, J=12.0, 4.0 Hz) 4.295- 4.30 (1H, m) 4.66-4.70 (1H, m) 4.71-4.80 (5H, m) 6.57 (1H, d, J=8.0 Hz) 7.02-7.30 (8H, m) 7.38-7.49 (3H, m) 7.59 (1H, d, J=8.0 Hz) 7.72 (1H, d, J=8.0 Hz) 7.83 (1H, d, J=4.0 Hz) 7.99 (1H, d, J=8.0 Hz) 8.11-8.16 (1H, m ). 93 CD30D 2.67-2.77 (6H, m) 2.83-2.88 (1H, m) 2.94-3.03 (1H, m) 3.08-3.14 (1H, m) 3.20-3.26 (1H, m) 3.85-3.94 (1H, m) 4.18-4.22 (1H, m) 4.32-4.37 (1H, m) 4.46 (1H, t, J=8.0 Hz) 4.79-4.84 (3H, br m) 6.67 (1H, d, J=4.0 Hz) 6.82-6.87 (1H, m) 6.89-6.98 (2H, m) 7.04-7.19 (4H, m) 7.56 (1H, d, J = 8.0 Hz) 8.14 (2H, s) 8.29 (1H, t, J = 4.0 Hz). 94 CD30D 0.77 (3H, t, J=8.0 Hz) 1.40-1.49 (1H, m) 1.58-1.668 (1H, m) 3.34-3.44 (2H, m) 3.85 (1H, q, J=4.0 Hz) 4.16 ( 1H, d, J=4.0 Hz) 4.33 (1H, d, J=4.0 Hz) 4.63-4.67 (1H, m) 4.73-4.88 (4H, m) 6.62 (1H, d, J=4.0 Hz) 7.07-7.11 (1H, m) 7.16 (1H, d, J=8.0 Hz) 7.26-7.40 (2H, m) 7.47-7.59 (2H,m) 7.67 (1H,d,J=8.0 Hz) 7.93 (2H, s) 8.07 (1H, d, J = 8.0 Hz). 151650.doc • 118- 201120038 95 CD3OD 0.79 (3H, d, J=8.0 Hz) 1.00 (3H, d, J=8.0 Hz) 2.02-2.10 (1H, m) 2.86 (1H, br s) 3.52-3.58 ( (2H, d, J=4.0 Hz) 7.20-7.27 (1H, m) 7.32-7.39 (1H, m) 7.43-7.52 (1H, m) 7.55-7.67 (2H, m) 7.73 (1H, d, J=8.0 Hz) 7.86 (1H, d, J = 8.0 Hz) 7.93-7.99 (1H, m) 8.12 (1H, d, J=4.0 Hz) 8.26 (1H, d, J=8.0 Hz) 8_49 (1H, t, J=8.0 Hz). 96 CD3OD 2.84-2.90 (2H, m) 3.07-3.19 (1H, m) 3.31-3.42 (1H, brm) 3.54-3.65 (2H, m) 4.22-4.29 (2H, m) 4.32-4.36 (1H, m) 4.58-4.62 (1H, m) 4.86-5.03 (7H, br m) 6.58 (1H, d, J=4.0 Hz) 7.10 (1H, d, J=8.0 Hz) 7.15-7.19 (1H, m) 7.41-7.51 (1H, m) 7.52-7.61 (1H, m) 7.63-7.70 (lH, m) 7.74 (1H, s) 7.85 (1H, d, J=8.0 Hz) 7.92-7.95 (1H, m) 7.98-8.01 ( 1H, m) 8.17 (lH, d, J = 8.0 Hz). 97 CD3OD 0.77 (3H , d, J=8.0 Hz) 0.95 (3H , d, J=8.0 Hz) 1.98-2.09 (1H, m) 2.93-3.04 (1H, m) 3.09-3.19 (1H, m) 3.88 ( 1H, d, J=4.0 Hz) 4.50-4.58 (2H, m) 4.63-4.68 (1H, m) 4.94-4.99 (4H, m) 6.82 (1H, t, J=4.0 Hz) 7.00-7.20 (3H, m) 7.70 (1H, d, J=8.0 Hz) 8.33 (1H, d, J=4.0 Hz) 8.40 (1H, d, J=4.0 Hz) &gt; 98 CD3OD 0.71 (3H , d, J=8.0 Hz) 0.94 (3H , d, J=8.0 Hz) 1.97-2.08 (1H, m) 2.96-3.05 (1H, m) 3.11-3.19 (1H, m) 3.90 (1H, d, J=4.0 Hz) 4.51-4.64 ( 2H, m) 4.67-4.72 (1H, m) 4.90-5.00 (4H, m) 6.82 (1H, t, J=4.0 Hz) 6.94-7.20 (3H, m) 7.71 (1H, d, J=4.0 Hz) 8.34 (1H, d, J=4.0 Hz) 8.41 (1H, d, J=4.0 Hz) &lt;Table 8 Instance Name Example No. Name 9 (R)-2·Amino-3-mercapto-valeric acid {(S)-2-naphthalen-1-yl-1-[(1H-pyrrolo[2, 3-b]pyridin-5-ylmethyl)-amine-methanol]-ethyl}-decylamine 10 (S)-2-(isopropyl-methyl-amino)-N-{(S) _2-naphthalen-1-yl-1-[(1Η-pyrrolo[2,3-b]pyridin-5-ylmethyl)-aminecarbamyl]•ethyl}-propanamide 11 (R)- 1 -Methylpyrrolidine-2-carboxylic acid {(S)-2-naphthalen-1-yl-1 -[(1H-pyrrolo[2,3-b]pyridin-5-ylindenyl)-amine oxime Brewing base••ethyl}-decylamine 12 (R)-2-dimethylamino-3-indolyl-pentanoic acid {(S)-2-(3,4-dilacyl-phenyl)-1- [(1Η-pyrrolo[2,3-7]. Bite-5-ylmethyl)-aminoindolyl]-ethyl}-nonylamine 13 (S)-N-{(S)_2-(3 ,4-difluoro-phenyl)-1-[(1Η-° 比比和[2,3-b]°pyridin-5-ylindenyl)-aminemethanyl]·ethyl} -2- (ethyl-methyl-amino)·propanol 151650.doc •119· 201120038 14 (S)-N-{(S)-2-(3,4-difluoro-phenyl)-H(1H_ °比比和[2,3-b]&quot;Bipyridin-5-ylmethyl)-amine fluorenyl]. Ethyl}-2-dimethylamino-propanamide 15 (S)-l- Indolylpyrrolidin-2-carboxylic acid {(S)-2-(3,4-difluoro-stupylpyrrolo[2,3-b]» than biti-5-ylmethyl)-aminecarboxyl 1-ethyl}- Amine amine 16 (R)-l-ethyl"pyrrolidine-2-carboxylic acid {(S)-2-(3,4-difluoro-phenyl)-i_[(ih-pyrrolo[2,3- bH唆-5-ylmercapto)-amine-mercapto-l-ethyldecylamine 17 (R)-l-isopropyl-»Byrrolidine-2-methyl Sman {(S)-2-(3 ,4-difluoro-phenyl)small [(1H_pyrrolo[2,3_b]e ratio biting_5_ylindenyl)-aminemethanyl 1-ethylbromide 18 (R)-l - Isopropyl-piperidine-2-carboxylic acid {(S)-2-(3,4-difluoro-phenyl)_ i _[(1 η ” 咯 [ [23_冲比 bit_5_ 曱基基)-Aminomethyl]-ethylbylamine 19 (R)-l-fluorenyl-〇 bottom bite-2·capric acid {(S)-2-(3,4-fluoro-phenyl)- 1-[(1Η·* 比略和定·5·ylmercapto)-amine-mercapto 1-ethyl}•decylamine 20 (S)_3-(3,4_di-phenyl)-2_ (2-diisopropylamino-ethinyl)·Ν-(1Η-° ratio slightly [2,3-b]° ratio bit-5-ylindenyl)-propanamide 21 (S)-3_ (3,4·difluoro-phenyl)-2-[2-(2,6-didecyl-Nylon-1 -yl)-acetamido]·ν_(ι Η-» 比略和[ 2,3-b]. Bisidine-5-ylmercapto)-propanamide 22 (R)-l-methyl ratio p each bite-2-carboxylic acid {(S)-2-(4-gas-phenyl)_ι·[(ιη · Bilu and [2,3_b]D ratio. D--5-ylmethyl)-amine decyl 1-ethyl}-decylamine 23 (S)-N-{(S)-2-(4 -fluoro-phenyl)-1-[(1Η-pyrrolo[2,3-b]pyridin-5-ylindenyl)-aminoindolyl]-ethyl}-2-(isopropyl-methyl -amino)-propanamide 24 (S)-2-:methylamino-N-{(S)-2-(4-fluoro-phenyl)-1-[(ΐΗ-° ratio) each [ 2,3-b].Bit-5-ylmethyl)-amine-mercapto]-ethyl}-propionamine 25 (S)-2-(ethyl-fluorenyl-amino)-N - {(S)-2-(4-Fluoro-phenyl)_ 1 _ [(1H-. ratio. each [2,3-7] 〇 _ _5_ mercapto)-amine thiol] -ethyl}-propanamine ' 26 (R)-l-decyl-pyrrolidine-2-carboxylic acid {(S)-2-(3-fluoro-phenyl)-1-[(ih-pyrrolo[ 2,3_b]pyridyl·5-ylmethyl)-aminoindenyl]-ethyl}-decylamine' soil 27 (S)-N-{(S)-:2-(3-fluoro-phenyl )-1-[(1Η-pyrrolo[2,3-b]pyridin-5-ylindenyl)-amine oxime]-ethyl}-2-(isopropyl-indenyl-amino)- Propylamine $ 28 (S) · 2-: guanamine-N-{(S)_2-(3·fluoro-phenyl)-1-[(ih" than argon [2,3 仲比 bit_ 5·ylmercapto)amine 29 (S)-2-(ethyl-fluorenyl- Base) *N-{(S)-:2-(;j-|^-phenylylpyrazine [2,3-7] 〇. 定_5·ylmethyl)-amine thiol]- Ethyl}-propanolamine '30 (RM-methylpirinol) -2-carboxylic acid {(S)-2_(2-fluoro-phenyl)-1_[ie _pyr. each [23 Zhongling 5 · 曱 ) ) - - - - - - - - - - - - - - - - 120 120 120 120 120 120 120 120 120 120 120 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 [(lH-&quot;Bis-[2,3-b]acridin-5-ylmethyl)-amine-methylmethyl]-ethyl}-2-(isopropyl-methyl-amino)- Propylamine 32 (RH-methyl-»byridine-2·carboxylic acid {(S)-2-(4-gas-stupyl)-1 ·[( 1 Η·°比咯和[2,3- b]pyridin-5-ylmethyl)-amine fluorenyl]•ethyl bromoamine 33 (S)-N_{(S)_2-(4-chloro-phenyl) small [(1H] ratio [2,3-b]acridin-5-ylindenyl)-amine f-yl]-ethyl}-2-(isopropyl-indolyl-amino)-propylamine 34 (R)-l -Methyl-pyrrolidine-2-carboxylic acid {(S)-2-(3-chlorophenyl) small [(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amine oxime Mercapto]-ethyl}-guanamine 35 (S)-N-{(S)-2-(3-gas-phenyl)-1-[(1Η-pyrrolo[2,;3-b]吼Pyridin-5-ylmethyl)-aminemethylmercapto]-ethyl}-2-(isopropyl-methyl-amino)-propanamide 36 (S)-N-{(S)-2- (3-gas- ))-1-[(1Η-pyrrolo[2,3-b]pyridin-5-ylmethyl)-aminemethylmercapto]•ethyl}-2-dimethylamino-propanamide 37 (S )-N-{(S)-2-(3-Gas-phenylpyrolo[2,3-b]&quot;bipyridin-5-ylindenyl)-aminemethylmercapto]-ethyl}- 2-(ethyl-methyl-amino)-propanol 38 (R)-l-decyl-pyrrolidine-2-carboxylic acid {(S)-2-(3,4-digas-stupyl) -ΐ-[(1Η-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amine methyl]-ethyl}-decylamine 39 (S)-N-{(S)- 2-(3,4-di-phenyl-phenyl) small [(1H]pyrolo[2,3-b]pyridine-5-ylindenyl)-aminecarboxylidene]-ethyl}-2·( Isopropyl-mercapto-amino)-propanamide 40 (S)-N_{(S)-2-(3,4-diqi·phenyl) small [(1Η-pyrrolo[2,3- b] Pyridin-5-ylmethyl)-amine-mercapto]-ethyl}-2-didecylamino-propanamide 41 (S)-N-{(S)-2-(3,4- Dioxo-phenyl)-indole (1Η-pyrrolo[2,3-b]pyridin-5-ylmethyl)-aminecarboxylidene]·ethyl}-2-(ethyl-methyl-amino group )- propylamine _·----a 42 .^---- 43 ___-^ 44 ----- 45 -- 46 --- 47 (R) bisindolyl-pyrrolidine-2-carboxylic acid {(S)-H(IH-pyrrolo[2,3-b]pyridin-5-ylindenyl)-aminecarbamyl 1-2-p-methylphenylethylamine ___ &quot;&quot ;--- -- ' 1 ------ - . - - - - (S&gt;2-(isopropyl-indolyl-amino)-N-{(S)-l-[(lH,pyrrolo[2,3-b]pyridine- 5-(indenyl)-aminomethylindenyl]-2-p-methylphenyl-ethyl}-propanamide (R)-l-indolebibitol-2-carboxylic acid {(S)-l-[ (lH-° ratio ° and [2, 3 seven]. °定-5-ylmethyl)-amine acetamido&gt; 2-meta-yl-ethyl}-decylamine (S&gt;2-(isopropyl-methyl-amino)-N-{ (S)-H(lH-»比比和[2,3-b]&quot;bipyridin-5-ylmercapto)-aminoindenyl]-2-m-f-yl-ethyl-propionamide (R )-l-methyl-pyrrolidine-2-carboxylic acid {(S)-1-[(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amineindolyl]-2- o-Athyl-ethyl oxime (S)-2-(isopropyl-methyl-amino)-N-{(S)-l-[(lH-«比比和[2,3_b] Pyridyl-5-ylindenyl)-amine-mercapto]-2-o-tolyl-ethyl}•propanamine I5l650.doc .121 - 201120038 48 - -- ~ (R)-l-methyl-pyrrole Acridine-2-decanoic acid {(S)-2·cyclohexyl-1-[(ih-pyrrolo[2,3_b]batch _5_ylmethyl)-aminemethanyl]-ethyl}-醯Amine 49 (S)-l-mercapto-purine pyridinium {(S)'2-cyclohexyl-1-[(1H-indolo[2,3-7;1pyridin-5-ylmethyl) _ Aminomethanyl]-ethyl}-nonylamine 50 (S)-N-{(S)-2-cyclohexyl-1-[(1Η-α-pyrolo[2,3-b]acridine- 5-ylmethyl)-amine-methylmethyl]-hexyl}-2-(isopropyl-methyl-amino)-propanamide 51 (S)-N-{(S)-2-cyclohexyl- 1-[(1Η-〇比比和[2,3-b]pyridin-5-ylindenyl)-amineindolyl]-ethyl}-2-dimethylamino-propyl Indole 52 (S)-N-{(S)-2-cyclohexyl-1-[(1H-.pyrho[2,3_b]&quot;bipyridin-5-ylmethyl)-amine fluorenyl ]-Ethyl}-2-(ethyl-fluorenyl-amino V propylamine _ 53 (R)-l-ethylpyrrolidine-2-carboxylic acid {(S)-2-cyclohexylpyrrole [2,3-7]pyridin-5-ylmethyl)-aminoindolyl]-ethyl}-nonylamine _ 54 (R)-l-isopropylpyrrolidine-2-carboxylic acid {(S)- 2-cyclohexyl-1-[(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amineindolyl 1-ethyl}-decylamine 55 (R)-1 -曱--l-pyridine-2-decanoic acid {(S)-2-cyclohexyl-1 -[(1H-&quot;pyrolo[2,3-b]pyridin-5-ylindenyl)-amine fluorenyl) ]-Ethyl}-nonylamine 56 3-methyl-1H-pyrrole-2-carboxylic acid {(S)-2-naphthalen-1-yl-1-[(1H-pyrrolo[2,3-b]吼Pyridin-5-ylmethyl)-aminoindenyl]-ethyldoximine 57 1H-indole-2-carboxylic acid {(3)-iso-l-l-yl-HOH-. Bis-[2,3 -b].pyridin-5-ylindenyl)-aminomethylindenyl]-ethyl}-decylamine 58 3,5-dimercapto-IH"pyrrol-2-carboxylic acid {(S)-2_( 3,4-Difluoro-phenylpyrrolo[2,3 sec. _ 5-ylmethyl)-amine carbaryl 1-ethyl hydrazide 59 3-mercapto-1H·pyrrole-2-indole Acid {(S)-2-(3,4-difluoro-phenyl)-1-[(1Η-pyrrolo[2,3-7]pyridin-5-ylindenyl)-amine Acyl l-ethyl} - amine stuffed 60 1H-.引及quot;朵-2-曱酸{(3)-2-(3,4_Difluoro-phenyl)-Η(1Η-&quot;比哈和[Hb]»比啶.5_基基基) _Aminomethyl]-ethyl)-nonylamine 61 (3)-3-(3,4-difluoro-phenyl ratio 0 and [2,3-b]° ratio bite-5-yl fluorenyl )-2-(2-o-tolyl-acetamido)-propanamide 62 3-methyl-1H-pyrrole-2-carboxylic acid {(s)-2-(3-fluoro-phenyl)_1_[ (1H_° ratio of [2,3-b]pyridin-5-ylmethyl)-amine decyl 1-ethyl}-decylamine... 63 3-mercapto-1Η-° ratio 0 each 2-carboxylic acid {(S)-2-(2-fluoro-phenyl) small [(out" is more than 0 and [2,3-b] ° bite 5-methyl)-amine A Styrene 1-ethyl decylamine 64 3-methyl-1H-0 pirox-2-carboxylic acid {(S)-2-(4-chloro-phenyl)-1·[(1Η_0-0 0和[2 , 3-b]°tb ate-5-ylindenyl)-amine sulfhydryl 1-ethyl}-decylamine... 151650.doc • 122· 201120038 65 3-methyl-1H-pyrrole-2-carboxylic acid { (S&gt;2-(3_Chloro-phenyl)pyrrolylmethyl)-amineindolyl]-ethyl}-brewed jj 66 3-methyl-1H-pyrrole-2-carboxylic acid {(幻-2- (3,4-di-phenyl-phenyl) small [ie-pyrrolo[2,3-b].pyridyl-5-ylindenyl)-aminemethanyl 1-ethyl}-skinny! _ 67 3-mercapto-1H-pyrrole·2_carboxylic acid {(S)_H(lH-°pyrho[Hb]pyridin-5-ylmercaptoaminecarbinyl]_2_p-tolyl-ethyl} - decylamine 68 3_methyl-1H-pyrrole_2_carboxylic acid {(S)-l-[(lH-°pyrho[Hb]pyridin-5-ylindenyl)-amine hydrazine]_2· M-phenyl-ethyl}-nonylamine _____ 69 3-methyl-1H-pyrrole-2_carboxylic acid {(S)-l-[(lH-«bibromo-Ob]pyro-5-yl胺 醯 ] ] ] ] ] 甲苯 甲苯 甲苯 甲苯 甲苯 甲苯 甲苯 甲苯 甲苯 甲基 甲基 甲基 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( And p,3-b]pyridylmethyl)-amine-mercapto]-ethyl}-nonylamine _ 71 (R)-2-yl-N-{(S)-2-naphthalen-1-yl -Η(1Η·pyrrolo[Hb]pyridine-:5-ylindenyl)-aminoindenyl]_ethyl}-3-phenyl-propionamide___土72 (11)-:^-{ (8)-2-(3,4-di-phenyl-phenyl)-bu [(1凡拉略和[2,3七]pyridine _5_ylindenyl)-amine oxime ethyl}-2 -hydroxy-3-phenyl-propionamide 73 (R)-N-{(S)-2-(4-fluoro-phenyl)-indole (1Η-pyrrolo)-2.hydroxy-3-phenyl Base-propionamine _ soil 74 (卟队卿 2-(3-fluoro-phenyl)-1-[(1Η-pyrrolo)-2-hydroxy-3-phenyl-propionamide 75 (R )-N-«S)-2-(2| 索pyrrolo[2,3 七]^^^^ yl}-2-hydroxy-3-phenyl-propanthene 76 (R)-N_{(S).2_(4_ gas-filament H-[(1H-pyridino)-2-hydroxy-3-phenyl-propanamine B 77 (R)-N_{( S)-2-(3| 笨基转和^基}-2-yl-3-phenyl-propanamine 乙 pivot. 咐咖] turn 5_基_糊-2-对78

15l650.doc -123 - 201120038 82 (S)-3-a4-difluoro-phenyl)-2-(propan-1-sulfonylamino)-indole-(1Η-° ratio 咯[2,3- b]&quot;Bipyridin-5-ylmethyl)-propanamide 83 (S)-3-(4-|l-styl)-2-(propan-1-sulfonylamino)pyrrolo[ 2,3-b]pyridin-5-ylindenyl)·propanamine 84 (S)-3-(3-fluoro-phenyl)-2-(propan-1-sulfonylamino)-indole- (1Η·»比比和[2,3-b]&quot;比比-5-ylmercapto)_propanamine 85 (S)-3-(2-f-phenyl)-2-(propane- 1-(M-amino)-N-(l H-pyrrolo[2,3-b].pyridin-5-ylindenyl)·propanamine 86 (S)-3-(4-chloro-stupid Base)-2-(propan-1 - guanidinium)-N-(1H-pyrrolo[2,3-b]pyridin-5-ylindenyl)-propanamine 87 (S)-3- (3-gas-phenyl)-2-(propylamine-1-ylindolyl)-N-(1H-pyrrolo[2,3-b]&quot;bipyridin-5-ylmethyl)-propyl Indoleamine 88 (S)-3-(3,4-dioxa-phenyl)-2-(propane-1 -sulfonylamino)-N-(l H-·»比比和[2,3七.Bistidine-5-ylmethyl)-propanamide 89 (S)-2-(propan-1-sulfonylamino)pyrrolo[2,3-b]pyridin-5-ylindenyl)- 3-p-Phenylphenyl-propanamide 90 (S)-2-(propan-1-propenylamino)-N-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl) -3-m-tolyl-propanamide 91 (S)-3-Cyclohexyl-2-(propan-1-sulfonylamino)pyrrolo[2,3-bl°pyridin-5-ylmethyl)-propanamide 92 (S)-2 -Diammonium-N-{(S)-2-naphthalen-1-yl-1-[(1H-pyrrolo[2,3-b]acridin-5-ylmethyl)-aminecarbamyl ]-Ethyl}-3-phenyl-propionamide 93 (S)-N-{(S)_2-(3,4-difluoro-phenyl)-1-[(1Η-pyrrolo[2, 3-b]pyridin-5-ylmethyl)-aminemethylmercapto]-ethyl}-2-dimethylamino-3-phenyl-propionamide 94 (R)-2-hydroxy-N-{ (S)-2-naphthalen-1-ylpyrrolo[2,3-b]pyridin-5-ylmethyl)-aminemethylmercapto]-ethyl}-butanamine 95 (R)-2-hydroxyl 3-methyl-N-{(S)-2-naphthalen-1-yl-1-[(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-aminecarboxamido 1 -ethyl}•butanamine 96 (S)-2-yl-3-methyl-N-{(s)-2-naphthalen-1-ylpyrho[2,3-b]0 to 0 ·5-ylindenyl)-amine 曱83⁄4-yl 1-ethylbutylidene 97 (R)-N-{(S)_2-(3,4-difluoro-phenylpyrrolo[2,3 VII]pyridin-5-ylmethyl)-amine fluorenyl]-;\暮}-2-ylamino-butylamine 98 (5) bucket {(8)-2-(3,4-di Fluoro-phenyl)-1-[(1}1-.咯 并 [2,3 比 啶-5-yl fluorenyl)-amino fluorenyl]- </ br> 2-carbyl-3-indolyl-butyl amide bio-system 151650.doc -124- 201120038 can be used The following biological assays determine the ability of a compound of formula (I) to inhibit KLK1: Determination of IC5 for KLK1 using standard methods disclosed (see, for example, Johansen et al, Int. J. Tiss. Reac. 1986, 8, 185; Shori et al, 61〇.1^111·

Pharmacol., 1992, 43, 1209; Sttirzebecher et al, Biol. Chem. Hoppe-Seyler, 1992, 373, 1025) assay for in vitro inhibition of KLK1 activity. Human KLK1 (Callbiochem) was incubated with the fluorescently-accepted H-DVal-Leu-Arg-AFC and test compounds at various concentrations at 37 °C. The residual enzyme activity (initial reaction rate) was determined by measuring the change in absorbance at 410 nm, and the IC5G value of the test compound was determined. Determination of Enzyme Selectivity These compounds were screened for further inhibition of the activity of the selected compounds against other tryptase serine proteases using suitable enzymes and chromogenic substrates (Chromogenix AB). The test was performed on the following human enzyme activities (supply in brackets): plasma kallikrein (S-23 02), thrombin (S-223 8), plasmin (S-2390), and trypsin (S) -2222). The enzyme was incubated with the chromogenic substrate at 37 °C. Residual enzyme activity (initial reaction rate) was measured by measuring the change in absorbance at 405 nm. The data obtained from this assay are shown in Tables 9 and 10 below: Table 9 (in vitro activity) Example number IC5G(nM) for KLK1 Example number IC5G(nM) for KLK1 1 0.83 50 0.23 2 0.88 51 7.3 151650 .doc -125- 201120038 3 0.46 52 2.2 4 3.6 53 2.3 5 3.5 54 4.1 6 11.9 55 0.8 7 4.4 56 6.9 8 11.7 57 &gt;1000 9 1.1 58 5.2 10 0.32 59 3.0 11 1.1 60 90.0 12 3.6 61 97.2 13 1.7 62 6.1 14 6.1 63 20.2 15 3.5 64 3.9 16 0.58 65 5.2 17 0.50 66 10.4 18 1.9 67 13.9 19 0.43 68 3.8 20 0.92 69 6.3 21 0.86 70 137.5 22 1.4 71 6.7 23 0.51 72 8.9 24 6.5 73 12.2 25 2.2 74 18.7 26 2.6 75 62.9 27 1.0 76 10.2 28 17.1 77 10.6 29 7.4 78 68.3 30 6.9 79 5.7 31 3.3 80 52.3 32 0.53 81 19.2 33 0.14 82 66.1 34 3.9 83 175.5 35 0.43 84 100.2 36 4.6 85 635.6 151650.doc •126· 201120038 37 2.1 86 79.3 38 0.71 87 95.3 39 0.29 88 28.1 40 3.0 89 302.3 41 1.1 90 78.7 42 2.9 91 180.2 43 0.8 92 25.16 44 1.7 93 35.92 45 0.6 94 14.85 46 2.5 95 12.00 47 1.4 96 24.80 48 2.2 97 14.71 49 9.0 98 55.61 Table ιο (selective data) Example number ICso(nM) plasma kallikrein thrombin plasmin plasmin 2 &gt;10000 &gt;10000 &gt;10000 &gt;10000 20 &gt;10000 &gt;10000 &gt;10000 &gt;10000 22 &gt;10000 &gt;10000 &gt;10000 &gt;10000 23 &gt;10000 &gt;10000 &gt;10000 &gt;10000 151650.doc 127-

Claims (1)

201120038 VII. Patent application scope: 1. A compound of formula (I): R1 and R2 are independently selected from H, hydroxy, (CVCiG)alkyl, (Ci_C6) alkoxy, (C2-C6)alkenyl, (C2_C6)alkynyl, (c3_c-cycloalkyl, heteroalkyl, Aryl, heteroaryl, aryl (c^-cu)alkyl- and heteroaryl (ci'C4)alkyl; R3 is selected from fluorene, (eve,.)alkyl and (c2-c6) Alkenyl, R4 and R5 are independently selected from fluorene and (C丨-C6)alkyl; A1 is selected from CR6 and S(0)R7; R6 is selected from R7 and the following formulae ΠΙ, ΠΙ and IV group: (11) (HI) (IV); R7 is selected from the group consisting of (cvcj alkyl, (c2-c6) alkenyl, (c3-Cig) cycloalkyl, aryl and aryl (c]-c4) alkyl- 151650.doc 201120038 R8 and R9 are independently selected from η, (c--c1())alkyl, (C2-C6)alkenyl, (C3-C1Q)cycloalkyl, heterocycloalkyl, aryl , Heteroaryl, aryl (Ci_C4) Hyun " and /heteroaryl (Ci_c4) alkyl"; R10 and R11 are independently selected from H, (c丨π). Alkyl, (c2_C6) alkene , (C3-C10)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl (Ci-Cd alkyl-, aryl(C2_C4)alkenyl, heteroarylalkyl-, - S〇2(c丨-C6)alkyl, _s〇2 aryl and _s〇2 aryl (c) c4)alkyl; or R and R11 together with the nitrogen atom to which they are attached form 4 to 7 The member contains an N ring which optionally contains another hetero atom selected from the group consisting of 1^, 〇 and §, and optionally, oxime or independently selected from (Ci_C6)alkyl, (q-C6)alkoxy Substituted by a substituent of a radical, a halogen group, a CN and a hydroxyl group, the N-containing ring may also be fused to an aryl group as appropriate; «and !^ may be combined with the atom to which it is attached to form a saturated or partially unsaturated 4 to 7 Containing _, the N-containing ring optionally contains another hetero atom selected from N 〇 and s and optionally, on the carbon, 1 or 2 independently selected from (Cl-C6) alkyl, (Ci_C6) methoxy, a substituent substituted with a substituent of (3) and a hydroxyl group; or R9 is absent and may form a 5-membered, 6-membered, 9-membered or 10-membered monocyclic or bicyclic aromatic ring together with the atom to which it is attached, the N-containing ring The case contains another hetero atom selected from N, hydrazine and S, and optionally, on the carbon, 2 or 3 independently selected from (c, hydroxy, (C, -C6) oxy, south, CN Substituents of aryl, c, and hydroxy; or R8 and R1() may form a group of formula V or formula VI: J51650.doc •2- 201120038 R and R are independently selected from H, (Ci_Ci〇)alkyl, A.(5)alkenyl, (C3^°)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl (c, C4) An alkyl group, an aryl group (CrQ), a heteroaryl group, a heteroaryl group (Ci_(5), a aryl group, a 2 (1 C6) alkyl group, a _s〇2 aryl group, and a _s〇2 aryl group (c) _c^ ndyl group; RlRb, independently selected from H, (Ci-Ci.) alkyl, (C2-C6) alkenyl, (C3_Ci〇)% alkyl, heterozygous technology, its synthesis, heterozygous stagnation, heteroaryl Base, aryl (CV c4) alkyl-, aryl (C2_C4) alkenyl...heteroaryl (Ci_C4)alkyl, -SORCVC^alkyl, ·5〇2 aryl and _s〇2 aryl ( c] _c4) alkyl; or R and R together with the atom to which they are attached - form a saturated or partially unsaturated 4 to 7 member containing an N ring, the N ring optionally containing another N, 〇 and S a heteroatom, and optionally substituted on carbon with hydrazine or two substituents independently selected from ((VC6)alkyl, (CVC6)alkoxy, halo, CN and hydroxy; the N-containing ring is also visible The condition is fused to an aryl group; or Ra and Rb may together with the atom to which they are attached form a 5-, 6-, 9- or 10-membered monocyclic or bicyclic n-containing aromatic ring containing an N-aryl ring Optionally containing another heteroatom selected from the group consisting of N, hydrazine and S, and optionally, on the carbon, 1, 2 or 3 independently selected from (Cl_C6)alkyl, ((^C6) alkoxy, dentate , CN, aryl, C00R15 and a substituent of a hydroxyl group; 151650.doc 201120038 R14 is selected from the group consisting of hydrazine, (Ci-Ce) alkyl, (C-C6) alkoxy, OH, CN, CF3, COOR15, Halo and NR15R16; R15 and R16 are independently selected from H and (C丨-C6)alkyl; R17, R18, R19 and R2g are independently selected from η, hydroxy, halo, CN, (CrCio)alkyl And (CrQ) alkoxy; f and g are independently selected from 〇, 1, 2 and 3 such that f + g = 1, 2 or 3; h is selected from 1 and 2; wherein: Substituted by 1 or 2 substituents independently selected from (c3-C1G)cycloalkyl, (CrCe)alkoxy, hydrazine H, CN, CF3, COOR 5, fluoro and NR15R16; Or 2 substituents independently selected from the group consisting of alkyl, (Ci-C6) alkoxy, hydrazine H, CN, CF3, COOR15, fluorine, and NR15W6; the alkynyl group may be independently selected from 1 or 2 c3_Ciq)cycloalkyl, (C)-C6) alkoxy, 0H, CN, CF3, COOR11, gas and NRnR1 Substituted by a substituent of 2; the alkoxy group may be optionally substituted by 1 or 2 substituents independently selected from (C3_Ciq)cycloalkyl, OH, CN, CF3, COOR15, fluorine and 15 ft 16; a non-aromatic monocyclic or bicyclic hydrocarbon ring which is optionally bonded to an aryl group, wherein the cycloalkyl ring may optionally contain up to 2 double bonds, and wherein, unless otherwise stated, the cyclodyl group may be optionally ! Or 2 substituents independently selected from (Ci_C6) alkyl, a-potoxy, I51650.doc 201120038 OH 'CN, CF3, COORi5, ι and nr15r16; heterocycloalkyl is C-bonded or n-bonded a member of 3 to 1 member non-aromatic monocyclic or bicyclic, wherein the heterocycloalkyl ring may contain hydrazine, 2 or 3 heteroatoms independently selected from N, NR 15, 8(0) £ and 0 And the heterocycloalkyl ring may optionally contain deuterium or two double bonds, and optionally one or two independently selected from (Ci_C6) alkyl, alkoxy 'OH, CN, CF3 on carbon. Substituted with a substituent of _ group, COOR 丨5, nri5r16 and aryl; aryl is a mono-aryl or fused aromatic ring system containing 6 or 1 碳 carbon atoms; wherein, unless otherwise stated, aryl is present When present, it may be optionally substituted with up to 5 substituents independently selected from (Ci_C6)alkyl, (c-alkoxy, OH, *, CN, c〇〇rI5, (7) and im, "substituent; heteroaryl The base is a 5-, 6-, 9- or 1-membered monocyclic or bicyclic aromatic ring containing hydrazine, 2 or 3 ring members independently selected from n, NR, S and hydrazine; wherein, unless otherwise stated ,no The heteroaryl group is optionally substituted with 1, 2 or 3 independently selected from the group consisting of alkyl, alkoxy, OH, i, CN, C00r15, CF3 and nr15r1'^; q is 〇, 1 or 2 == isomers, stereoisomers, pharmaceutically acceptable salts and 2. Compounds as requested, or their tautomers, stereoisomers, 151650.doc 201120038 pharmaceutically acceptable a salt or a solvate wherein: R1 is selected from the group consisting of (CrCe)alkyl, (C3-C1G)cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R2 is selected from the group consisting of hydrazine, hydroxy, alkyl, (Cl_C6) alkoxy, (Cs-Cw)cycloalkyl and aryl; R3, R4 and R5 are independently selected from fluorene and (CVc6) alkyl; A1 is selected from CR6 and S(0)R7; Is selected from the group consisting of R and the following formula: and IV: (III) (IV); R7 is selected from (CVC6) alkyl, aryl and aryl (Ci_C4) alkyl C4) a base; R9 is selected from the group consisting of hydrazine and (C-C6) alkyl; C4) a base; Rn is selected from the group consisting of hydrazine and (CVC6) alkyl; Substituted Unsaturated 5 to 6 members contain an anthracene ring, ~Silver together form a saturated or a part of the ring containing the ring on the carbon by 151650.doc 201120038 1 or 2 ((^-(:6)) alkyl substituent Or R9 is absent and R8 and R1Q may form a 5-, 6-, 9- or 10-membered monocyclic or bicyclic n-containing aromatic ring together with the atom to which they are attached, the N-containing ring being optionally 1 on carbon or 2 (substituted by CrCJ alkyl substituent; R12 is selected from fluorene and (CVC6) alkyl; R is selected from fluorene, (C丨-C6) alkyl, aryl and aryl (c)_c4) alkyl _ R and R are independently selected from fluorene, (C丨-C6)alkyl, (c3_c6)cycloalkyl 'heterocycloalkyl, aryl, heteroaryl; or Ra and Rb may be bonded to the atom to which they are attached Forming a saturated or partially unsaturated 5- to 6-membered N-containing ring, the N-containing ring being optionally substituted on the carbon by 1 or 2 (Ci-CJ alkyl substituents; or the rulers 3 and 1^ may be attached thereto The atoms together form a 5-, 6-, 9- or 1-membered monocyclic or bicyclic aromatic ring, and the N-containing ring is optionally substituted on carbon or two (Cl-C6) alkyl substituents; R18, R19 and R2G are independently selected from h&amp; (Ci_Cj 3. A compound according to the formula or 2, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein a1 is S(0)R7. The compound of any one of the above, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein the uldent 7 is selected from the group consisting of (C-C6)alkyl, An aryl group and an aryl group (Ci_c4) alkyl group. 5. The compound of claim 1 or 2, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein a^ Cr6. 151650.doc 201120038 6 · If the request is $^卜人«物' or its tautomers, stereoisomers, pharmaceutically acceptable salts or solvates, where R6 is of the formula (II) ) Group: R10 R11 ^ (II) 〇::: the compound of item 6 'or its tautomer, stereoisomer, pharmaceutically acceptable salt or solvate, #R8 is selected from Η ' (Ci_ alkyl , (C3-Cl0)cycloalkyl and aryl (Cl-C4)alkyl. Gentry, 6 or 7 compound 'or its tautomer, stereoisomeric dry acceptable salt or solvent A compound wherein R9 is selected from the group consisting of η and (Ci-C6)alkyl. 9. A compound according to any one of items 6 to 8, or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable compound a salt or solvate thereof, which is selected from the group consisting of hydrazine, (Cj-Cg), cyclyl, («(3Cl0)^alkyl and aryl ((VC4)alkyl 0 10· as claimed in claims 6 to 9 Any one of the compounds into the god Miao sister μ mouth 'or its tautomers, stereoisomers, pharmaceutically acceptable ― ― ― + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Η and (C, _C6) phenotype β system 11. The compound of any one of claims 6 to 8, or ' # M ^ L I, the isomer, the stereoisomer, i is scientifically acceptable The salt or the wonderful one together with the nitrogen atom to which it is attached, where R and War 5 To 6 members containing a ring, i5J650.doc 201120038 The N ring is optionally substituted with 1 or 2 (Ci_c6) alkyl substituents. 12. The compound of claim 6, or its tautomers, stereoisomers a pharmaceutically acceptable salt or solvate wherein R8 and R10 together with the atom to which they are attached form a saturated or partially unsaturated 5-member to 6-membered N-containing ring. 1 or 2 (Cl_c6) alkyl substituents substituted; or 妒 absent and r8 and R1Q together with the atoms to which they are attached form a 5-, 0, 9 or 1 member monocyclic or bicyclic N-containing ring The N-containing ring is optionally substituted with 1 or 2 (Cl_C6) alkyl substituents on the carbon. 13. The compound of claim 5, or the tautomer, stereoisomer, or pharmaceutically acceptable a salt or solvate wherein R6 is a group of the following formula (III): OH (III). 14. The compound of claim 13, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein R!2 is selected from the group consisting of (C1-C6). 15_ The compound of claim 13 or 14, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of Η '(C,-C6) alkane Base, aryl and aryl (Ci_C4) alkyl. 16. The compound of any one of clauses 1 to 15, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein Rl 15J650.doc •9·201120038 17 18. 19. 20. The system is derived from (K6)alkyl, (C5_c1())cycloalkyl, aryl and heteroaryl. The compound of any one of claims 1 to 16, or a tautomer, isomer, pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of (C5_Cl0)cycloalkyl, aryl And heteroaryl. The compound of any one of items 1 to 17, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, wherein r2 is selected from the group consisting of H, (c3-c) ) cycloalkyl and aryl. The compound according to any one of items 1 to 18, or a tautomer thereof, a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof, wherein R3 to and R to the ruler 2) Independently selected from H or (CrCd alkyl. The compound of claim 1 &gt; y, which is selected from the group consisting of: (R)-3-carbyl [nu _ amidino-pentanoic acid {(s)_2- (3,4-difluoro-phenyl)-i- [(ΙΗ-览-oxoamine., -b]pyridin-5-ylindenyl)-amine fluorenyl]-ethyl}-fluorene (R -i-A &amp;Byrrolidine·2_decanoic acid {(S)-2_(3,4-difluoro-phenyl)-1-[(1H-% π each U,3-b]pyridine -5-ylmethyl)-amine-mercapto]-ethyl}-decylamine; (S) -N-{c〇\ _ -(3,4-difluoro-phenyl)-1_[(11{ -&lt;» ratio 0 and [2, 3-1)] 〇 咬 基 其 其 、 Α · · · · · · ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] Propylamine; 3-mercapto-m L 1 - 吼 _2 曱 { {(S)-2-(4-fluoro-phenyl)-i-[(lH-pyridyl)[2 3 Bl 'pyridin-5-ylmethyl)-amine-mercapto]-ethyl}-decylamine; \'^)-2-(3,4-di-phenyl)-1-[(111-.倍比和[2,3-13]. Ratio - 5 * A|&gt; A soil)-Aminomethylidene]-ethyl}-2-hydroxy-3-benzene -propanolamine; 151650.doc 201120038 (S)_3_naphthyl-2-(propane_)·sulfonylamino)-indole-(1Η-Βpyrrole and f2,3-b]pyridin-5-yl Methyl acrylamide, (S)-3-mercapto-2-f-amino-pentanoic acid {(R)-2,2-dicyclohexyl 0 to 11 each [2,3-b]pyridine- 5-(n-f-yl)-amine-mercapto]-ethyl}-decylamine, · (S)-l-methyl-pyrrolidine_2_carboxylic acid {(R)-2,2-dicyclohexylpyrrole [2,3-b]pyridin-5-ylmethyl)-amineindolyl]-ethyldoximine; (R)-2-amino-3-3-indolyl-valeric acid {(S)-2 -naphthalene-buji-b [UH-°pyrolo[2,3-b]pyridin-5-ylmethyl)-amineindolyl]-ethyldoxime; (S) -2-(iso Propyl-fluorenyl-amino)-N-{(S)-2-naphthalen-1-yl-1-[(1Η-°pyrolo[2,3-b]pyridylmethyl)-amine oxime (R)-l-fluorenyl-pyrrolidine-2-carboxylic acid {(s)-2_naphthalene_1-yl_1_[(1H_pyrrolo[2,3-b Pyridine _5-ylmethyl)-amine oxime-ethyl bromide; (R)-2-dimethylamino-3-methyl-pentanoic acid {(S)_2-(3'4-difluoro -phenyl)-1-[(1H-. Bis-[2,3-b]0-pyridin-5-ylmercaptoaminecarbamyl]-ethyldoximine; (S) -N-{(S)-2_(3,4-difluoro -Phenylpyrolo[2,3-b]°tb pyridine-5-ylindolyl)-aminoindenyl]-ethyl}-2_(ethyl·•indolyl-amino)-propanamide (S)-N-{(S)-2-(3,4-difluoro-phenylpyrolo[2,3-b]°pyridin-5-ylmethyl)-aminomethyl] -ethyl}-2_diammonium-propionamine; (S)-l-fluorenyl-pyrrolidine-2-carboxylic acid {(S)_2_(3,4-difluoro-phenyl)-1- [(1H-indolo[2,3_b]0-pyridin-5-ylindenyl)-aminodecylethyl}-decylamine; (R)-l-ethyl-pyrrolidine-2-carboxylic acid {(s)_2_(3,4-difluoro-phenyl 151650.doc -11 - 201120038 [(111-.pyrolo[2,3-1)]0-pyridin-5-ylmethyl)-amine (R)-l-isopropyl-pyrrolidine_2-carboxylic acid {(S)-2-(3,4-difluoro-phenyl)-bu[( 1Η-° 比比和[2,3-b]&quot;比淀-5-ylmethyl)-aminoindenyl]-ethyldoximine; (R)-l-isopropylbite·2_carboxylic acid {(S)-2-(3,4-Difluoro-phenyl)-1_[(1H-.pyrolo[2,3_b]acridine_5-ylmethyl)-aminecarboxyl]-B (b)-l-methyl-purine. _2_ Formic acid {(S)-2-(3,4-difluoro^-styl)_1-[(1H-pyrrolo[2,3_b]pyridine-5-ylmethyl)-amine thiol] -ethyl}-decylamine; (S)-3-(3,4-dioxa-phenyl)_2_(2-diisopropylaminoacetamido)_N_ (1H-pyrrolo[2,3-b Pyridine-5-ylmethyl)-propanamine; (S)-3-(3,4-difluoro-styl)_2_[2-(2,6-didecyl-0 bottom bite-1- Ethylamino]-N-(1H-. ratio η each [2,3_b] ° ratio. -5-ylindenyl)-propanamine; (R) -l-methyl-pyrrole Pyridinium 2 - decanoic acid {(S)-2-(4-fluoro-phenyl. More than 0 and [2,3-b]. than dimethylmethyl)-aminomethyl hydrazino]-ethyl} Indoleamine; (S)-N-{(S)-2-(4-fluoro-phenyl) small [(1H-pyrrolo[2,3-b].pyridin-5-ylindenyl)-amine Mercapto; μethyl}_2·(isopropyl-methyl-amino)-propanamine; (S)-2-diguanylamino group N_{(s) 2 (4·fluoro-phenyl Small [(1Η-吼[2,3-b]pyridin-5-ylindenyl)-amine-methylmethyl]-ethylpropiamine; (S)-2-(ethyl-fluorenyl-amine Base) n {(s) 2_(4_d base) 0 is more than [2,3-b].比 -5 _ _ _ ; ] ] ] ] ] ] 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯-(3-fluoro-phenyl)-1-[(1Η-pyrrolo[2,3-b].pyridin-5-ylindenyl)-amineindolyl]-ethyl}-decylamine; S) -N-{(S)-2-(3-fluoro-phenyl)-1-[(1Η-.pyrolo[2,3-b]°pyridin-5-ylmethyl)-amine Mercapto]-ethyl}-2-(isopropyl-methyl-amino)-propanamine; (S)-2-didecylamino-N-{(S)-2-(3- Fluoro-phenyl)-1-[(111-.pyrolo[2,3-b].pyridin-5-ylindenyl)-aminecarboxylidene]-ethyl}-propionamide; (S )-2-(ethyl-methyl-amino)-N-{(S)-2-(3-fluoro-phenyl)-1-[(1Η-.pyrolo[2,3-b] (Bi)-5-ylmethyl)-aminoindenyl]-ethyl}-propanin; (R)-l-methyl-. Bipiridine-2-carboxylic acid {(S)-2-(2-fluoro-phenyl)-1-[(1Η-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amine formazan (8)-;^{(3)-2-(2-fluoro-phenyl)-1-[(111-.pyrho[2,3-13]吼(pyridine-5-ylindenyl)-aminoindenyl]-ethyl}-2-(isopropyl-indolyl-amino)-propanylamine; (R)-l-methyl-tonolidine- 2-formic acid {(S)-2-(4-carbyl-phenyl)-1-[(1Η-pyrrolo[2,3-b]pyridin-5-ylmethyl)-aminemethylmercapto]-B (8)-:^-{(3)-2-(4-Ga-phenyl)-1-[(111-.pyrho[2,3-13]. 5-ylmethyl)-amine-mercapto]-ethyl}-2-(isopropyl-indolyl-amino)-propanin; (R) -l-fluorenyl. Bipiridine-2-carboxylic acid {(S)-2-(3-chloro-phenyl)-1-[(1Η-indolo[2,3-b]acridin-5-ylindenyl)-amine (S)-N-{(S)-2-(3-Gas-phenyl)-1-[(1Η-吼 并[2,3-b] Acridine-5- 151650.doc -13- 201120038 mercapto)-aminoindenyl]-ethyl}_2-(isopropyl-indenylamino)-propanamine; (8)-1^ -{(8)-2-(3-chloro-phenyl)-1-[(111-°pyrho[2,3-1)]»pyridin-5-ylmethyl)-amine ]-Ethyl}-2-dimethylamino-propanol; (8)-11'1-{(8)-2-(3-Gas-phenyl)-1-[(111-'1 ratio 11 each [2, 3-1)] '1 than bite-5-ylindenyl)-amine-mercapto]-ethyl}-2·(ethyl-fluorenyl-amino)-propanamide; (R) -l-methyl ratio 0 each pyridine_2_carboxylic acid {(S)_2_(3,4-digas phenyl)-1-[(1H-. ～0 且[2,3-b ]° ratio bit-5-ylmethyl)-amine-mercapto]-ethyldoxime; (8)-&gt;4-{(8)-2-(3,4-di-phenyl-phenyl) -1-[(111-» 比〇[2,3-13].pyridin-5-ylindenyl)-aminoindenyl]-ethyl}_2_(isopropyl-indenyl-amino group )-propanamide; (8)-1^-{(8)-2-(3,4-di-phenyl)-1-[(111-.pyrho[2,3-1)] ° than bite-5-yl fluorenyl)-amine-branched base]- (i)-N_{(S)-2-(3,4-dichloro-phenyl)-1-[(1Η-&quot;比比和[2 , (b)-l-methyl-- 0-pyrrolidine-2-decanoic acid {(S)_1-[(1H-0 is more than [2,3-b] pyridine _5_yl fluorenyl)-amine carbaryl]_2&quot;(Ethyl-ethyl}-bristamine; (8)-2-(isopropyl-methyl-amino)_1^-{(3)-1-[(111-.pyrho[2,3_b] Pyridyl-5-ylmethyl)-amine-methylmethyl]_2-p-tolyl-ethyl}-propanamine; (R)_1-methyl-0 to 11 bite·2_carboxylic acid {(Μ' Ί-ΓΟΗ-0 嘻 [ [2,3-b] 〇 β β _5_ ylmethyl)-amine hydrazino] m-phenyl-ethyl}-bristamine; 151650.doc -14. 201120038 (8)-2-(isopropyl-methyl-amino)_^-{(8)-1-[(111-'3 piroxi[2 3-b]. (B)-(M-IXIH-pyrrole) (R)-Methyl-pyrrolidine-2-carboxylic acid {(SM-IXIH-pyrrole) And [2,3-b]pyridin-5-ylindenyl)-aminomethylindenyl]_2-o-phenylene-ethyldoxime; (S)-2-(isopropyl-indenyl-amine Base)_N-{(S)-1-[(1H-0 is more than [2,3_b] ° ratio. -5-ylindenyl)-aminomethylindenyl]- 2-o-phenylene- Ethylpropionamide; (r)-1-methyl-0 to 0 each bite-2-decanoic acid {(S)-2-J hexyl hexa[2,3-b]pyridin-5-ylmethyl )-Aminoindenyl]•ethyl}-decylamine; (S)-l-Methyl-0 to 0 each a--2-indole {(S)-2-cyclohexyl-1-[(ΐΗ -α ratio slightly [2 3-b]B than dimethylmethyl)-amine methyl]-ethyl}-bristamine; (S)-N-{(S)-2-cyclohexyl ratio 0 And [2,3-b]0 is more than 5-amino-methyl)-amine-methyl]-ethyl}-2-(isopropyl-methyl-amino)-propanol; (S) -N-{(S)-2-cyclohexylpyrrolo[2,3-bppyridin-5-ylmethyl)-amine-sensitive group]-ethyl group 2-dimethylamino-propanamide (S)-N -{(S)-2-cyclohexyl-1-[(1Η-α ratio 0 and [2,3-b]D ratio bit-5-ylindenyl)-aminocarboxamidine ]-Ethyl}-2-(ethyl-indolyl-amino)-propanamine; (R)-1-B Base-0 to 11 each bite-2-decanoic acid {(S)-2-cyclohexyl-1-[(1Η-° than the mouth [2,3-b]D than bite-5-ylmethyl) -aminoglycolyl]-ethyldoxime; (R)-l-isopropyl ratio σ σ _2 曱 曱 曱 { ( ( { (S)-2-cyclohexyl-1-[(1Η-° ratio 0 each [2,3-b]0 ratio biting-5-ylmethyl)-amine aryl group]-ethyl hydrazine hydrazide '(R)-l-methyl-piperidine-2-carboxylic acid { (s)-2·cyclohexyl-1-[(1Η_〇 ratio 0 and [2,3-b]fl ratio 11--5-ylmethyl)-amine oxime]-ethyldoxime ; 151650.doc -15- 201120038 3-methyl-1H-pyrrole-2-carboxylic acid {(S)-2-naphthalen-1-yl-1-[(1H-pyrrolo[2,3-b]pyridine- 5-(indenyl)-aminocarboxylidene]-ethyl}-decylamine; 1H-indole-2-carboxylic acid {(S)-2-naphthalen-1-yl-1-[(1H-pyrrolo[ 2,3-b]pyridin-5-ylindenyl)-amine-mercapto]-ethyl}-decylamine; 3,5-dimercapto-1H-pyrrole-2-carboxylic acid {(S)-2- (3,4-difluoro-phenyl)-1-[(1H-.pyrho[2,3-b].pyridin-5-ylindenyl)-aminemethanyl]-ethyl}- Indoleamine; 3-methyl-1H-pyrrole-2-furic acid {(S)-2-(3,4-difluoro-phenylpyrrolo[2,3-b]pyridin-5-ylmethyl) -aminoindolyl]-ethyl}-decylamine; 1H-indole-2-carboxylic acid {(S)-2-(3,4-difluoro-phenyl)-1-[(1Η-pyridyl) And [2,3-b]pyridin-5-ylindenyl)-amine-mercapto]-ethyl}-decylamine; (S)-3-(3,4-difluoro-phenyl)-indole- (1Η-. Bisolo[2,3-b]»pyridin-5-ylindenyl)-2-(2-o-phenylidene-acetamido)-propanamine; 3-mercapto-1H-pyrrole- 2-formic acid {(S)-2_(3-fluorophenyl)-1-[(1Η·pyrrolo[2,3-b]pyridin-5-ylindolyl)-aminecarboxylidene]-ethyl} - guanamine; 3-methyl-1H-pyrrole-2-furic acid {(S)-2-(2-fluoro-phenyl)-1_[(1Η-pyrrolo[2,3-b]pyridine-5 -ylmethyl)-aminoindenyl]-ethyl}-decylamine; 3-methyl-1H-pyrrole-2-carboxylic acid {(S)-2-(4-a-phenyl)-1-[ (1Η-pyrrolo[2,3-b]acridin-5-ylindenyl)-amineindolyl]-ethyl}-decylamine; 3-mercapto-1H-0 ratio slightly-2-decanoic acid {(S)-2-(3-Gas-phenyl)-l-[(lH-0lt[rho][2,3-b]pyridin-5-ylindenyl)-aminecarboxylidene]-ethyl} - guanamine; 3-mercapto-1 Η-Π ratio 11 each -2-decanoic acid {(S)-2-(3,4-di-phenyl)-1-[(1Η·pyrrolo[2, 3-b]pyridin-5-ylmethyl)-aminoindenyl]-ethyl}-decylamine; 3-mercapto-1H-pyrrole-2-carboxylic acid {(S)-1-[(1H-pyrrole) And [2,3-b]pyridyl 151650.doc -16 - 201120038 pyridin-5-ylmethyl)-amine-mercapto]-2-p-tolyl-ethyl}-decylamine; 3-methyl-1H -pyrrole-2-carboxylic acid {(S)-1-[(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-amine A Yl] phenyl-2-m Yue - ethyl} - Amides; 3- Yue group -1H-. Bis-2-nonanoic acid {(S)-1-[(1H-.pyrolo[2,3-b]pyridin-5-ylindolyl)-aminecarboxylidene]-2-o-tolyl- Ethyl}-guanamine; 3-methyl-1H-pyrrole-2-carboxylic acid {(S)-2-cyclohexyl-1-[(1H-pyrrolo[2,3-b]acridin-5-yl) Methyl)-aminoindenyl]-ethyl}-decylamine; (R)-2-hydroxy-N-{(S)-2-naphthalen-1-yl-1-[(1Η-° ratio) [2,3-b]. Bite-5-ylmercapto)-carbamic acid]-ethyl}-3-phenyl-propanol, (R)-N-{(S)-2-( 3,4-Difluoro-phenyl)-1-[(1Η-.pyrolo[2,3-b]acridin-5-ylindolyl)-aminecarboxylidene]-ethyl}-2- Hydroxy-3-phenyl-propionamide; (R)-N-{(S)-2-(4-fluoro-phenyl)-1-[(1Η-.pyrolo[2,3-b] '^-pyridin-5-ylindenyl)-aminoindenyl]-ethyl}-2-hydroxy-3-phenyl-propanin; (R)-N-{(S)-2-(3 -fluoro-phenylpyrolo[2,3-b].pyridin-5-ylindenyl)-aminoindenyl]-ethyl-2-hydroxy-3-phenyl-propanamine; )-N-{(S)-2-(2-Fluoro-phenyl)-1-[(1Η-吼 吼[2,3-b].pyridin-5-ylindenyl)-amine oxime (1)-ethyl}-2-hydroxy-3-phenyl-propionamide; (11)-yi{(3)-2-(4-a-phenyl)-1-[(111-. And [2,31)] acridine-5-ylmethyl)-amine-mercapto]-ethyl 2-hydroxy-3-phenyl-propionamide; (R)-N-{(S)-2-(3-chloro-phenyl)-1-[(1Η-°比咯和[2,3- b] indopidine-5-ylmethyl)-amine-mercapto]-ethyl}-2-hydroxy-3-phenyl-propanin; (R)-2-hydroxy-3-phenyl-N -{(S)-1-[(1H-.pyrho[2,3-b].pyridin-5-ylmethyl)-aminecarbamido]-2-p-tolyl-ethyl}- Propylamine; (R)-2-hydroxy-3-phenyl-;^-{(8)-1-[(111-'1-pyrolo[2,3-13]acridine- 151650.doc - 17- 201120038 5-ylmethyl)-aminoindenyl]-2-m-tolyl-ethyl}-propionamide; (11)-2-hydroxy-3-phenyl-:^-{(8) -1-[(111-'&gt;pyrho[2,3-13]'&gt;pyridin-5-ylmethyl)-aminoindenyl]-2-o-phenylene-ethyl}- Propylamine; (R)-N-{(S)-2-cyclohexyl-1-[(1Η-η-pyrolo[2,3-b]acridin-5-ylindenyl)-amine formazan (S) -3-(3,4-di-denyl-phenyl)-2-(propanone-1-continued amine group) )-N-( 1H-. (r)-[2,3-b]pyridin-5-ylindenyl)-propanin; (S)-3_(4-fluoro-phenyl)-2-(propan-1-sulfonylamino)- N-(1H-.pyrolo[2,3-b]pyridin-5-ylindenyl)-propanamine; (S)-3-(3-fluoro-phenyl)-2-(propane-1 -sulfonylamino)-N-(1H-.pyrolo[2,3-b]pyridin-5-ylindenyl)-propanin; (S)-3-(2- gas-phenyl) -2-(propanol-1 - tra-amino)-Ν-(1Η-°piro[2,3-b]pyridin-5-ylindenyl)-propanamine; (S)-3- (4-Chloro-phenyl)-2-(propane-1 -sulfonylamino)-N-( 1H-.pyrolo[2,3-b]pyridin-5-ylindenyl)-propanamide (S)-3-(3-Gas-phenyl)-2-(propan-1-sulfonylamino)-N-(1H-.pyrolo[2,3-b]pyridin-5-yl Mercapto)-propanamine; (S)-3-(3,4-di-phenyl)-2-(propan-1-sulfonylamino)-N-(1H-pyrrolo[2,3 -b]pyridin-5-ylindenyl)-propanamine; (S)-2-(propane-1-sulfonylamino)-indole-(1Η-°pyrho[2,3-b]吼(S)-2-(propan-1-sulfonylamino)-N-(1H-&quot;b]pyridine_5_ylmercapto)-3-indolyl-propanamine; (S)-3-cyclohexyl-2-(propane-1-sulfonylamino) )-N-C1H-&quot;比比和[2,3_ 151650.doc -18· 201120038 b]° ratio σ--5-ylmethyl)-propanol, (S)-2-dimethylamino -N-{(S)-2-naphthalen-1-yl"-[UH-0 pyrrolo[2,3_b]pyridin-5-ylmethyl)-amine fluorenyl]-ethyl b 3_ Phenyl-propionamide '(S)-N-{(S)-2-(3,4-difluoro-phenyl) small [(1H-吼°[2,3-b]° ratio bite -5-ylindenyl)-aminomethylindenyl]-ethyldi-2-dimethylaminophenylpropylamine; (R)-2-hydroxy-N-{(S)-2-naphthalene-1- Pyrrolozepine P,3_b].pyridin-5-ylindenyl)-aminecarboxylidene]-ethyl}-butanamine; (R)-2-hydroxy-3-methyl-N-{(S )-2-naphthalen-1-yl-1-[(1H-0 to 17-[2,3-b]pyridin-5-ylmethyl)-aminecarboxylidene]-ethyl}-butanamine (S)-2-Hydroxy-3-methyl-N-{(S)-2-naphthalen-1-yl-1-[(1Η-°pyrho[2,3-b]pyridine-5- (methyl)-aminomethylamino]-ethyl}-butanamine; (R) -N-{(S)-2-(3,4-difluoro-phenylpyrrolo[2,3- Bpbi-pyridin-5-ylmercapto)-aminoindenyl]-ethyl}-2-hydroxy-3-indolyl-butanamine; (S) -N-{(S)-2-(3, 4-Difluoro-phenyl)-1-[(1Η-η-pyrolo[2,3-b]acridin-5-ylmethyl)-aminecarboxylidene]-ethyl}-2-hydroxy- 3-methyl-butyl Amine; and tautomers, stereoisomers, pharmaceutically acceptable salts and solvates. The compound of any one of claims 1 to 20, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, for use in therapy. A compound of any one of claims 1 to 20, or a tautomeric, ”" construct, a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture or prevention of KLKI activity for treatment or prevention. Disease 151650.doc -19·201120038 or a drug for a condition 23. A method of treating a disease or condition involving KLK1 activity, comprising administering to a subject in need thereof a therapeutically effective amount as claimed in claim 1 20 ^ A compound or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof. 24. The use of claim 22 or the method of claim 23, The disease or condition of KLK1 activity is selected from an inflammatory or respiratory condition or condition selected from the group consisting of asthma (allergic and non-allergic), chronic obstructive pulmonary disease (COPD), allergic rhinitis (hay fever), cough Deterioration caused by asthma and chronic obstructive pulmonary disease (COPD), multiple sclerosis, arthritis, rheumatoid arthritis, osteoarthritis, osteoarthritis, rhinitis, sinusitis, inflammatory bowel disease (such as Crohn's disease (Cr〇hn, sd Isease) and ulcerative colitis), immune-mediated diabetes, acute pancreatitis and interstitial cystitis, conjunctivitis, periodontal disease, chronic prostatitis, chronic recurrent mumps, inflammatory skin disorders (eg psoriasis, Eczema) and SIRS (systemic inflammatory response syndrome); smooth muscle spasms (eg asthma, angina), RDS (respiratory distress syndrome), rhinoconjunctivitis, rhinorrhea, urticaria, neoplastics, chronic bronchitis, chronic airway obstruction, Pulmonary fibrosis and emphysema 25. The use of claim 22 or the method of claim 23, wherein the disease or condition involving KLK1 activity is selected from the group consisting of asthma (allergic and non-allergic), chronic obstructive Pulmonary disease (COPD), allergic rhinitis (hay fever), cough, deterioration caused by asthma and chronic obstructive pulmonary disease (COPD) 26. The use of claim 22 or the method of claim 23, which involves 151650. Doc •20· 201120038 KLK1 active disease or condition is selected from asthma (allergic and non-allergic) and caused by asthma and chronic obstructive pulmonary disease (c〇PD) 27. A pharmaceutical composition comprising a compound according to any one of claims 2 to 2, or a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof, And pharmaceutically acceptable carriers, diluents or 'excipients. 151650.doc -21 - 201120038 IV. Designated representative drawings: (1) The representative representative of the case is: (none) (2) A brief description of the component symbol: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 151650.doc