JP2002513384A - IL-8 receptor antagonist - Google Patents

Abstract

  (57) [Summary] The present invention relates to novel compounds of formula (I), pharmaceutical compositions and their use in the treatment of disease states mediated by chemokines, interleukin-8 (IL-8).

Description

DETAILED DESCRIPTION OF THE INVENTION                       IL-8 receptor antagonist Field of the invention   The present invention relates to a novel alkenediamino-substituted compound, a pharmaceutical composition, and a method for producing the same. And IL-8, GROα, GROβ, GROγ, ENA-78, and N It relates to their use in the treatment of diseases mediated by AP-2. Background of the Invention   Neutrophil attracting / activating protein-1 (NAP-1), monocyte-derived neutrophil chemotactic factor ( MDNCF), neutrophil activator (NAF), and T cell lymphocyte chemotaxis As a child, many different names were given to interleukin-8 (IL-8). Have been. Interleukin-8 binds to neutrophils, basophils and some T cells Chemical attractant. Interleukin-8 is mainly composed of TNF, IL-1 macrophages, fibroblasts, endothelium and endothelium exposed to α, IL-1β or LPS And nucleated cells, including epithelial cells, and LPS or chemotactic factors ( Produced by neutrophils themselves when exposed to, for example, FMLP). M. Baggiol ini et al. Clin. Invest. 84, 1945 (1989); Schroder et al. Immuno l. 139, 3474 (1987) and J.M. Immunol. 144, 2223 (1990); Strieter, et al, Sc ience 243 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al. , J. et al. Immunol. 148, 3216 (1992).   GROα, GROβ, GROγ and NAP-2 are also members of the chemokine α family Belong. Like IL-8, these chemokines are called by different names. For example, GROα, β, and γ are called MGSAα, β, and γ, respectively ( Norma growth stimulating activity). Richmond et al. Cell Physiology 129, 375 (1986 ) And Chang et al, J. et al. Immunol. 148, 451 (1992). CXC motif All of the α-family chemokines with an ELR motif before are IL-8B Receiving Binds to the body.   IL-8, GROα, GROβ, GROγ, ENA-78 and NAP-2 Stimulates many functions in vitro. They all convert to neutrophils Although shown to be chemotactic, IL-8 and GROα are not And basophil chemotaxis activity is shown. In addition, IL-8 is normal and Histamine release from basophils from a topical individual can be induced, In addition, GROα and IL-8 release lysosomal enzymes and release from neutrophils. A respiratory burst can be induced. IL-8 does not involve de novo protein synthesis Also shown to increase Mac-1 (CD11b / CD18) surface expression on neutrophils Have been. This may contribute to increased neutrophil adhesion to vascular endothelial cells . Many known diseases are characterized by massive neutrophil infiltration. IL-8 , GROα, GROβ, GROy and NAP-2 are neutrophil accumulation and activation These chemokines include xerobiosis and rheumatoid arthritis as they promote It is involved in a wide range of acute and chronic inflammatory diseases. Baggiolini et al, FEBS Lett. 307, 97 (1992); Miller et al, Crit. Rev. Immunol. 12, 17 (1992); 0ppen heim et al, Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J. Am. Clin. Inve st. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992); Do nnely et al., Lancet 341, 643 (1993). Furthermore, ELR chemokines (CXC Chemokines containing the amino acid ELR motif just before the chief are also angiostasis Are involved in Strieter et al, Science 258, 1798 (1992).   In vitro, IL-8, GROα, GROβ, GROγ and NAP -2 binds to 7-transmembrane, a receptor of the G-protein binding family. And activation, in particular by binding to the IL-8 receptor. Also apparently binds to B-receptors, causing neutrophil morphological changes, chemotaxis, condyles Induces granule release and respiratory burst. Thomas et al., J. Biol. Chem . 266, 14839 (1991); and Holmes et al., Science 253, 1278 (1991). This receiving For the development of non-peptide small molecule antagonists for members of the receptor family Has precedent. For an overview, see Progress in Drug Research, Vo 1.40, pp. 33-98 , Birkhauser Ver1ag, R in Basel 1993. Refer to the description of Freidinger. Therefore, IL The -8 receptor represents a promising target for the development of new anti-inflammatory agents.   Two high affinity human IL-8 receptors (77% homology) have been characterized. They bind to IL-8 with high affinity only to IL-8Rα, as well as I-8Rα. High affinity not only for L-8 but also for GROα, GROβ, GROγ and NAP-2 Is IL-8Rβ that binds with Holmes et al., Supra; Murphy et al., S. cience 253, 1280 (1991); Lee et al. Biol. Chem. 267, 16283 (1992); LaR osa et al., J. Biol. Chem. 267, 25402 (1992); and Gayle et al., J. Am. Biol . Chem. 268, 7283 (1993).   Therapies in this field, against compounds capable of binding to IL-8α or β receptors There is a need to continue. Therefore, increased IL-8 production (neutrophils and some Symptoms associated with T-cell chemotaxis to sites of inflammation) include IL-8 receptor Compounds that are inhibitors of body binding would benefit.Summary of the Invention   The present invention is mediated by chemokines that bind to IL-8α or β receptors Provided is a method of treating a disease, comprising an effective amount of a compound of formula (I) or a medicament thereof. Administering an acceptable salt. In particular, the chemokine is IL-8 .   The invention also relates to a mammal in need of inhibiting the binding of IL-8 to its receptor. A method for inhibiting the binding of IL-8 to its receptor in a method comprising the steps of: Administering the compound of I) to said mammal.   Useful in the present invention are structural formulas (I): [Wherein Z is cyano, nitro, CF_Three, C (O) NR_FifteenR₁₆, S (O)_TwoNR_FifteenR₁₆ , Or S (O)_TwoR₁₇Is;   R₁₈Is hydrogen, halogen, cyano, optionally substituted C_1-4Alkyl, halo Substitution C_1-4Alkyl, C (O) NR_FifteenR₁₆, An optionally substituted aryl, Optionally substituted aryl C_1-4Alkyl, heteroaryl which may be substituted Optionally substituted heteroaryl C_1-4Alkyl, even if substituted Good heterocyclic or optionally substituted heterocyclic C_{1- Four} Alkyl;   R is a functional group having an ionizable hydrogen and has a pKa of 10 or less. Is;   R₁Is hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl; C_1-10 Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Alkoxy; Azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl; Aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Alkylo Xy; heteroaryl; heteroarylalkyl; heterocyclic; hetero Cyclic C_1-4Alkyl; heteroaryl C_1-4Alkyloxy; aryl C_2-10 Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10 Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; ( CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁ C_2-10Alkenyl C (O) OR₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈ )_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR₁₉; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveIs independently selected from; Or two R₁The groups together form O- (CH_Two)_sO- or 5-6 member satiety May form a sum or unsaturated ring; where aryl, heteroaryl and The heterocyclic moiety may be substituted;   q is 0 or an integer having a value from 1 to 10;   t is 0 or an integer having a value of 1 or 2;   s is an integer having a value of 1 to 3;   R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Alkyl, substituted Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, substituted Optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4 Alkyl, heterocyclic, or heterocyclic C_1-4Alkyl Or R_FourAnd R_FiveIs oxygen, nitrogen together with the nitrogen to which they bind Or 5 to 7 which may contain an additional hetero atom selected from sulfur. Form a member ring;   m is an integer having a value of 1 to 3;   n is an integer having a value of 1 to 3;   Y is hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl; C_1-10A Lequil; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Alkoxy; a Jid; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl; Reel; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Alkyloxy Heteroaryl; heteroarylalkyl; heteroaryl C_1-4Alkyl Oxy; heterocyclic; heterocyclic C_1-4Alkyl; aryl C_{Two -Ten} Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10 Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; ( CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁ C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) O R₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (C R₈R₈)_qNHS (O)_TwoR_d; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveIndependently selected from Or two Y groups are taken together to form O- (CH_Two)_sO- or 5 It may form a 6-membered saturated or unsaturated ring; Reel and heterocyclic moieties may be substituted;   R₆And R₇Is independently hydrogen or C_1-4Is an alkyl group; or₆ And R₇Is oxygen, nitrogen or sulfur together with the nitrogen to which they bind Forming a 5- to 7-membered ring optionally containing additional heteroatoms selected from:   R₈Is hydrogen or C_1-4Independently selected from alkyl;   R_TenIs C_1-10Alkyl C (O)_TwoR₈Is;   R₁₁Is hydrogen, C_1-4Alkyl, optionally substituted aryl, substituted Aryl C_1-4Alkyl, optionally substituted heteroaryl, substituted An optionally substituted heteroaryl C_1-4Alkyl, optionally substituted hetero Cyclic or optionally substituted heterocyclic C_1-4Alkyl Is;   R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or substituted An optionally substituted arylalkyl;   R₁₃And R₁₄Is independently hydrogen or C_1-4Alkyl;   v is 0 or an integer having a value of 1 to 4;   R_FifteenAnd R₁₆Is independently hydrogen, optionally substituted C_1-4Alkyl, substituted Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, place Optionally substituted heteroaryl, optionally substituted heteroaryl C_{1- Four} Alkyl, optionally substituted heterocyclic, optionally substituted Heterocyclic C_1-4Alkyl or R_FifteenAnd R₁₆Are those Is selected from oxygen, nitrogen or sulfur together with the nitrogen to which it binds May form a 5- to 7-membered ring which may contain heteroatoms;   R₁₇Is C_1-4Alkyl, OR₁₁, Optionally substituted aryl, substituted Optional aryl C_1-4Alkyl, optionally substituted heteroaryl, Optionally substituted heteroaryl C_1-4Alkyl, optionally substituted hete Cyclocyclic or optionally substituted heterocyclic C_1-4Archi Is;   R₁₉Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, hete Lower aryl C_1-4Alkyl, heterocyclic, or heterocyclic C_{1 -Four} Alkyl, wherein all of these groups may be substituted;   R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Alkene , Heteroaryl, heteroaryl-C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocyclic, heterocyclic C_1-4Alkyl Where alkyl, aryl, arylalkyl, heteroaryl, heteroaryl Alkyl, heterocyclic, and heterocyclic alkyl rings are substituted May be   R₂₀Is W₁An optionally substituted heteroaryl, an optionally substituted C_{Five -8} Cycloalkyl, optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl or optionally substituted C_2-10Alkynyl; Asterisk here^*Represents the point of attachment of the ring;   E'-containing ring asterisk^*Represents the point of attachment of the ring. It is an acceptable salt.Detailed description of the invention   The compound of formula (I) may be an IL-8 or other receptor that binds to IL-8 α and β receptors. Veterinary treatment of non-human mammals requiring inhibition of chemokines Can be useful. Chemokines treated therapeutically or prophylactically in animals More mediated diseases include those described in the Methods of Treatment section herein. You.   Suitably, in the compound of formula (I), R is 10 or less, preferably Has an pKa of about 3 to 9, more preferably about 3 to 7, A functional group that provides hydrogen. Such functional groups include hydroxy, carboxylic acid, thio- , SR_Two, OR_Two, NH-C (O) R_a, C (O) NR_{6 '}R_{7 '}, The formula NHS (O)_Two R_bA substituted sulfonamide represented by the formula: S (O)_TwoNHR_c, NHC (X_Two) NHR_b Or tetrazolyl, but is not limited to these.   Suitably, X_TwoIs oxygen or sulfur, preferably oxygen.   Preferably, the functional group is other than sulfonic acid, aryl, heteroaryl Or directly on the heterocyclic subcycle or SR_TwoIf Is OR_TwoAryl, heteroaryl, or heterocyclic And exists as a substituent on a partial ring. More preferably, R is OH, SH, or NHS (O)_TwoR_bIt is.   Suitably, R_TwoIs a substituted aryl, heteroaryl, or heterocyclic ring Wherein the ring provides an ionizable hydrogen having a pKa of 10 or less. Containing functional groups.   Suitably, R_{6 '}And R_{7 '}Is hydrogen, C_1-4Alkyl, aryl, aryl C_1-4 Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4A Lucyl, heteroaryl C_2-4Alkenyl, heterocyclic, heterocyclic Rick C_1-4Alkyl or heterocyclic C_2-4An alkenyl group, All of which are halogen; nitro; CF_ThreeHalo-substituted C_1-4Alkyl; meth C like Le_1-4Alkyl; C such as methoxy_1-4Alkoxy; NR₉C (O) R_aC (O) NR₆R₇S (O)_ThreeH; or C (O) OC_1-4A Alkyl may be independently substituted once to three times,_{6 '}And R_{7 '} One is hydrogen but both are not hydrogen.   Suitably, R₆And R₇Is independently hydrogen or C_1-4Whether it is an alkyl group Or R₆And R₇Together with the nitrogen to which they bind Forming a 5- to 7-membered ring optionally containing additional heteroatoms selected from Au I do. The heterocycle may be optionally substituted as defined herein.   Suitably, R_aIs aryl, aryl C_1-4Alkyl, heteroaryl, hetero Aryl C_1-4Alkyl, heterocyclic, or heterocyclic C_1-4 Alkyl groups, all of which are independently substituted by one to three groups The one to three groups may comprise further ionizable groups The one to three groups may be halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoxy, hydroxy, SH, C (O) NR₆R₇, NH -C (O) R_a, NHS (O)_TwoR_b, S (O)_TwoNR₆R₇, C (O) OR₈,Also Includes, but is not limited to, a tetrazolyl ring.   Suitably, R_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, a Reel C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, Hete Lower aryl C_2-4Alkenyl, heterocyclic, or heterocyclic C_1-4Alkyl or heterocyclic C_2-4Alkenyl groups, camphor All of which are halogen; nitro; CF_ThreeHalo-substituted C_1-4Alkyl; C like methyl_1-4Alkyl; C such as methoxy_1-4-Alkoxy; NR₉C (O) R_aC (O) NR₆R₇S (O)_ThreeH; or C (O) OC_1-4Alkyl May be independently substituted once to three times.   Suitably, R₉Is hydrogen or C_1-4Alkyl, and preferably hydrogen.   Preferably, R_bIs an optionally substituted phenyl, benzyl, or still It is. R_bWhen is heteroaryl, preferably it may be substituted A good thiazole, an optionally substituted thienyl, or an optionally substituted It is a quinolinyl ring. Preferably, R_bWhen the substituent is NR₉C (O) R_aIf it is, Preferably R_aIs an alkyl group such as methyl.   Suitably, R_cIs hydrogen, alkyl, aryl, aryl C_1-4Alkyl, Ally Le C_1-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroa Reel C_1-4Alkenyl, heterocyclic, heterocyclic C_1-4Archi Or heterocyclic C_1-4Alkenyl groups, all of which are halo Gen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoxy, N R₉C (O) R_a, C (O) NR₆R₇, S (O)_ThreeH or C (O) OC_1-4Al It may be independently substituted once to three times by killing. Preferably, R_cIs Phenyl which may be substituted.   In the compounds of formula (I), suitably₁Is hydrogen; halogen; nitro; Ano; CF_ThreeHalo-substituted C_1-10Alkyl; methyl, ethyl, isopropyl Or C such as n-propyl_1-10Alkyl; C_2-10Alkenyl; also methoxy Or C like ethoxy_1-10Alkoxy; halo such as trifluoromethoxy Substitution C_1-10Alkoxy; azide; (CR₈R₈)_qS (O)_tR_Four(If t is 0, 1 2); hydroxy; hydroxy C such as methanol or ethanol_{1- Four} Alkyl; aryl, such as phenyl or naphthyl; a, such as benzyl Reel C_1-4Alkyl; aryloxy such as phenoxy; benzyloxy Like aryl C_1-4Alkyloxy; heteroaryl; heteroarylalkyl Le; heteroaryl C_1-4Alkyloxy; aryl C_2-10Alkenyl; hetero Aryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈ )_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_Four R_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈ R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10Alkenyl C (O ) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC ( O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR₁₉ ; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveIndependently selected from; or two R₁The groups together form O- (CH_Two)_sO- or 5- or 6-membered saturated or unsaturated It may form a saturated ring. Aryl; heteroaryl, and heterocyclic All of the moieties may be substituted as defined below.   Suitably, s is an integer having a value of 1 to 3.   Suitably, q is 0 or an integer having a value from 1 to 10.   R₁Forms a dioxy bridge, preferably s is 1. R₁Garasara When a saturated or unsaturated ring is formed, it is preferably a naphthylene ring It is a six-membered ring that produces a stem. This naphthylene ring has another R₁Group (as defined above) ) May be independently substituted once to three times.   Suitably, R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Archi , Optionally substituted aryl, optionally substituted aryl C_1-4Al Killed, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4Alkyl, heterocyclic, or heterocyclic C_1-4Al Kill or R_FourAnd R_FiveTogether with the nitrogen to which they bind A 5- to 7-membered ring optionally containing a further heteroatom selected from / N / S Form.   Suitably, R₈Is hydrogen or C_1-4Independently selected from alkyl.   Suitably, R_TenIs CH_TwoC (O)_TwoH or CH_TwoC (O)_TwoCH_ThreeLike C_{1 -Ten} Alkyl C (O)_TwoR₈It is.   Suitably, R₁₁Is hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl, Heteroaryl, heteroaryl C_1-4Alkyl, heterocyclic, or Heterocyclic C_1-4Alkyl.   Suitably, R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or Is an optionally substituted arylalkyl.   R₁₉Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, hete Lower aryl C_1-4Alkyl, heterocyclic, or heterocyclic C_{1 -Four} Alkyl, and all of these groups may be substituted.   Preferably, R₁Is halogen, cyano, nitro, CF_Three, C (O) NR_FourR_Five, Lucenyl C (O) NR_FourR_Five, C (O) R_FourR_Ten, Alkenyl C (O) OR₁₂, F Teloaryl, heteroarylalkyl, heteroarylalkenyl, or S (O) NR_FourR_FiveAnd preferably R_FourAnd R_FiveAre both hydrogen or are Or one is phenyl. R₁Preferred ring substitution positions for It is the 4-position of a ring.   R is OH, SH or NSO_TwoR_bIs preferably R₁Is 3-position or It is substituted at the 4-position or di-substituted at the 3,4-position. Appropriately And the substituent is an electron withdrawing group. Preferably, R is OH, SH or NSO_TwoR_bso In some cases, R₁Is nitro, halogen, cyano, trifluoromethyl, or C ( O) NR_FourR_FiveGroup.   When R is a carboxylic acid, preferably R₁Is hydrogen, or preferably R₁Is substituted at the 4-position, more preferably trifluoromethyl or Has been replaced by b.   Suitably, R₁₃And R₁₄Is independently hydrogen, optionally substituted C_1-4Al Kill (which may be linear or branched as defined herein) Or R₁₃And R₁₄Is an optionally substituted aryl .   Suitably, v is 0 or an integer having a value from 1 to 4.   R₁₃Or R₁₄Is an optionally substituted alkyl group, the alkyl is Halogen; halo-substituted C such as trifluoromethyl_1-4Alkyl; hydroxy; Hydroxy C_1-4C such as alkyl, methoxy or ethoxy_1-4Alkoxy ; Halo-substituted C_1-10Alkoxy, S (O)_tR_FourAryl; NR_FourR_FiveNHC (O ) R_FourC (O) NR_FourR_FiveOr C (O) OR₈1 to 3 times independently It may be substituted.   Suitably, Y is hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Al Coxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4A Alkyl; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4A Alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Le C_1-4Alkyloxy; heterocyclic; heterocyclic C_1-4Archi Ru; aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclo Click C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_Five; C_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈ R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O ) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) OR₁₁; ( CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qN R_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR_d; (CR₈R₈)_qS (O)_TwoN R_FourR_FiveOr two Y groups are taken together to form O- (C H_Two)_sO- or a 5- or 6-membered saturated or unsaturated ring may be formed. the above The aryl, heteroaryl, and heterocyclic-containing moieties of It may be substituted as described in the specification.   When Y forms a dioxy bridge, preferably s is 1. Y is more When forming a saturated or unsaturated ring, preferably it is a naphthylene ring system. It is a 6-membered ring that produces a system. These rings are linked by another Y (as defined above) to 1 It may be substituted three to three times.   Suitably, R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_{2- Four} Alkenyl, heteroaryl, heteroaryl-C_1-4Alkyl, heteroaryl Le C_2-4Alkenyl, heterocyclic, heterocyclic C_1-4Alkyl, Or heterocyclic C_2-4An alkenyl group, wherein the above aryl, All heteroaryl and heterocyclic containing moieties are defined herein. It may be substituted as follows.   Preferably, Y is halogen, C_1-4Alkoxy, optionally substituted aryl Aryl, optionally substituted aryloxy or arylalkoxy, methylene Dioxy, NR_FourR_Five, Thio C_1-4Alkyl, thioaryl, halo-substituted alkoxy , An optionally substituted C_1-4Alkyl or hydroxyalkyl. Yo More preferably, Y is a mono- or di-substituted halogen, mono- or di-substituted. A Alkoxy, methylenedioxy, aryl, or alkyl; more preferred Is that these groups are mono- or di-substituted at the 2′-position or at the 2 ′-, 3′-position. I have.   Y may be substituted at any of the five positions on the ring, but is preferably , R is OH, SH, or NSO_TwoR_bAnd preferably Y is in the 2′-position Alternatively, the 3'-position is mono-substituted, preferably the 4'- is unsubstituted. Ring is di If substituted, R is OH, SH, or NSO_TwoR_bIf, preferably Substituents are present at the 2 'or 3' position of the monocyclic ring. R₁And both Y May be hydrogen, but at least one ring is substituted, preferably It is preferred that both rings are substituted.   In the compounds of formula (I), suitably Z is cyano, nitro, CF_Three, C (O ) NR_FifteenR₁₆, S (O)_TwoNR_FifteenR₁₆, Or S (O)_TwoR₁₇It is.   Suitably, R_FifteenAnd R₁₆Is independently hydrogen, optionally substituted C_1-4Al Killed, optionally substituted aryl, optionally substituted aryl C_1-4A Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Reel C_1-4Alkyl, optionally substituted heterocyclic, substituted Heterocyclic C_1-4Alkyl or R_FifteenAnd R_{1 6} Are selected from oxygen, nitrogen, or sulfur together with the nitrogen to which they bind. May form a 5- to 7-membered ring which may contain additional heteroatoms.   Suitably, R₁₇Is C_1-4Alkyl, OR₁₁An optionally substituted aryl, Optionally substituted aryl C_1-4Alkyl, heteroaryl which may be substituted Reel, optionally substituted heteroaryl C_1-4Alkyl, substituted Heterocyclic C or optionally substituted heterocyclic C_1-4 Alkyl; the optional substituents are as defined herein. It is.   In the compounds of formula (I), suitably₁₈Is hydrogen, halogen, cyano, substitution C that may be_1-4Alkyl, halo substituted C_1-4Alkyl, C (O) NR_FifteenR₁₆ , An optionally substituted aryl, an optionally substituted Reel C_1-4Alkyl, optionally substituted heteroaryl, substituted Good heteroaryl C_1-4Alkyl, optionally substituted heterocyclyl Or optionally substituted heterocyclic C_1-4Alkyl; The optional substituents are as defined herein.   The X ring is indicated by the point of attachment via its asterisk. X ring is R₁Base Or both the phenyl ring and the X ring are independently (R₁)_mMay be substituted by Suitably, when ring X is substituted, Preferably the nitrogen-containing X ring is C (O) NR_FourR_FiveNitrogen moieties due to amide functional groups such as And preferably R_FourOr R_FiveOne of which is phenyl Aryl which may be substituted. Preferably, a larger saturated nitrogen-containing ring May be substituted by an aryl ring.   In the compounds of formula (I), R₂₀Is W₁, An optionally substituted heteroaryl , An optionally substituted C_5-8Cycloalkyl, optionally substituted C_1-10 Alkyl, optionally substituted C_2-10Alkenyl or optionally substituted Replacement C_2-10Alkynyl.   Suitably, the E'-containing ring is May be selected.   The E'-containing ring represented by the point of attachment through the asterisk exists It can be. If not present, the ring is substituted by Y as shown. Phenyl group. The ring E is (Y)_nSubstituted by a group And may be saturated or unsaturated, and in the present specification, is substituted only in an unsaturated ring. It is shown as being replaced.   R₂₀Is an optionally substituted C_5-8In the case of a cycloalkyl ring, the ring is as described above. (Y)_nMay be substituted by   R₂₀Is an optionally substituted C_1-10Alkyl, optionally substituted C_2-10A Lucenyl, or optionally substituted C_2-20If alkynyl, these The group is halogen, nitro; cyano; halo-substituted C such as trifluoromethyl_1-10A Lequil; C_1-10Alkoxy; halo-substituted C_1-10Alkoxy; S (O)_tR_Four; Hydro Xy; hydroxy C_1-4Alkyl; aryloxy; aryl C_1-4Alkyloxy C; heteroaryloxy; heteroaryl C_1-4Alkyloxy; heterocyclyl Click; Heterocyclic C_1-4Alkyl; heterocyclic-oxy; Heterocyclic C_1-4Alkyloxy; NR_FourR_FiveC (O) NR_FourR_Five; C ( O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈C (O) R₁₁; C (O) OR₁₂; OC (O) R₁₁; NR_FourC (O) R₁₁Is independently substituted once to three times It may be. R₂₀Is an optionally substituted C_2-10Alkenyl, or substituted May be C_2-10When alkynyl, these groups are in addition to the other groups mentioned above. , Aryl, aryl C_1-4Alkyl, heteroaryl, and heteroaryl It may be substituted with alkyl.   In the compounds of formula (I), R₂₀Is a heteroaryl (HET) ring; Suitably, it is a heteroaryl ring or ring system. HET part is polycyclic If it is a system, the ring containing the heteroatom need not be directly attached to the urea moiety. Absent. All rings in this ring system may be substituted as defined herein. Good. Preferably, the HET moiety is pyridyl, 2-, 3-, or 4-pyridyl. It may be Jill. If the ring is a polycyclic system ring, preferably it is a benzene ring Zoimidazole, dibenzothiophene, or indole ring. Other interested Heterocyclic rings are thiophene, furan, pyrimidine, pyrrole, pyrazo , Quinoline, isoquinoline, quinazolinyl, pyridine, oxazole, thia Zol, thiadiazole, triazole, imidazole, or benzimidazo But not limited to them.   In the compound of formula (I), the HET ring is independently substituted once to three times by Y. (Ie (Y_(n))), Where n is an integer having a value of 1 to 3. Suitably, Y is hydrogen; halogen; nitro B; cyano; halo-substituted C_1-10Alkyl; C_1-10Alkyl; C_2-10Alkenyl; C_1-10 Alkoxy; halo-substituted C_1-10Alkoxy; azide; (CR₈R₈)_qS (O)_t R_Four; Hydroxy; hydroxy C_1-4Alkyl; aryl; aryl C_1-4Archi Aryl; aryloxy; aryl C_1-4Alkyloxy; heteroaryl; hetero Arylalkyl; heteroaryl C_1-4Alkyloxy; heterocyclic ; Heterocyclic C_1-4Alkyl; aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_q NR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five ; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈ )_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O ) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR_d; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveIndependently selected from; or two Y The groups together form O- (CH_Two)_sO- or 5- or 6-membered saturated or unsaturated A ring may be formed. These aryls, heteroaryls, and heterocycles The lick-containing moiety may be substituted as defined herein.   Suitably, R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_{2- Four} Alkenyl, heteroaryl, heteroaryl-C_1-4Alkyl, heteroaryl Le C_2-4Alkenyl, heterocyclic, heterocyclic C_1-4Alkyl, where alkyl, aryl, heteroaryl, and The telocyclic-containing moiety may be substituted as defined herein.   Preferably, R₂₀Is an optionally substituted phenyl, allyl, C_1-10Alkyl , Ethoxycarbonylethyl, dimethylacetal, 2-methoxyisopropyl Or 2-methoxyethyl.   As used herein, the term "optionally substituted" means, unless otherwise specified, fluorine, Halogen such as chlorine, bromine or iodine; hydroxy: hydroxy-substituted C_1-10 Alkyl; C such as methoxy or ethoxy_1-10Alkoxy; methylthio, me S (O) such as tylsulfinyl or methylsulfonyl_{m '}C_1-10Alkyl ( m ′ is 0, 1 or 2); NR_FourR_FiveAmino, mono and di- Substituted amino; NHC (O) R_FourC (O) NR_FourR_FiveC (O) OH; S (O)_TwoN R_FourR_Five; NHS (O)_TwoR_{twenty one}; Methyl, ethyl, propyl, isopropyl, and Is C such as t-butyl_1-10Alkyl; CF_ThreeHalo-substituted C_1-10Alkyl An optionally substituted aryl such as phenyl; benzyl or phenethyl Optionally substituted arylalkyl; optionally substituted heteroalkyl Cyclic; optionally substituted heterocyclic alkyl; substituted Optionally substituted heteroaryl; or optionally substituted heteroarylalkyl A group, such as aryl, heteroaryl, or heteroaryl. The cyclic moiety is halogen; hydroxy; hydroxy-substituted alkyl;_1-10 Alkoxy; S (O)_{m '}C_1-10Alkyl; NR_FourR_FiveAmino, such as in the group Mono and di-substituted amino; C_1-10Alkyl or CF_ThreeHalo-substituted C_{1 -Ten} It may be independently substituted once to three times with alkyl.   Suitably, R_{twenty one}Is C_1-4Alkyl, aryl, aryl C_1-4Alkyl, hetero Aryl, heteroaryl C_1-4Alkyl, heterocyclic, or hetero Cyclic C_1-4Alkyl.   Suitable pharmaceutically acceptable salts are well-known to those skilled in the art and include hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, tartaric acid , Citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicyl Acids, basic salts of inorganic and organic acids such as phenylacetic acid and mandelic acid Include. Further, for example, when the substituent comprises a carboxy group, it is pharmaceutically acceptable. The cation may be used to obtain a pharmaceutically acceptable salt of the compound of formula (I). suitable Various pharmaceutically acceptable cations are well known to those skilled in the art and include alkali metals, Includes potassium earth metal, ammonium and quaternary ammonium cations.   The following terms herein refer to: "Halo"-all halogens, i.e. chloro, fluoro, bromo and yo Mode. ・ "C_1-10“Alkyl” or “alkyl” —unless the chain length is limited, both are 1 Straight-chain and branched groups of from 10 to 10 carbon atoms, methyl, ethyl, n-propyl Ropyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t tert-butyl, n-pentyl and the like, but are not limited thereto. The term “cycloalkyl” as used herein is preferably a ring of 3 to 8 carbons Meaning cyclopropyl, cyclopentyl, cyclohexyl, etc. However, it is not limited to these.   The term "alkenyl" in this specification, in all cases, limits the chain length Unless otherwise indicated both straight and branched groups of 2 to 10 carbon atoms, Ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1 -Butenyl, 2-butenyl and the like, but are not limited thereto. "Aryl" -phenyl and naphthyl. . "Heteroaryl" (itself or "heteroaryloxy" or " -5- to 10-membered aromatic ring A system wherein one or more rings comprises N, O or S A compound containing one or more heteroatoms selected from the group Roll, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazoli Nil, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, Riazole, imidazole, or benzimidazole, but these Not limited to ・ "Heterocyclic" (itself or "heterocyclic alkyl") -Saturated or partially unsaturated 4- to 10-membered ring cis A group in which one or more rings consist of N, O, or S Containing one or more heteroatoms selected from , Piperidine, piperazine, morpholine, tetrahydropyran, or imida But not limited thereto. The term "arylalkyl" or "heteroarylalkyl" herein Refers to "heterocyclic alkyl" unless otherwise specified. C as defined above attached to an aryl or heterocyclic moiety_1-10Archi Means le. "Sulfinyl"-the oxide S (O) of the corresponding sulfide, the term "thio" Refers to sulfide and the term "sulfonyl" refers to fully oxidized S (O)_TwoBase U. The term “two Rs”₁The groups (two Y groups) together have 5 or 6 members May form a saturated or unsaturated ring of ". Or C₆Cycloalkenyl (ie cyclohexene) or C_FiveCycloal 5- or 6-membered partially saturated or unsaturated, such as kenyl moiety (cyclopentene) It refers to the formation of a phenyl moiety attached to the sum ring.   The compounds of the present invention exist as stereoisomers, regioisomers, or diastereomers. It will be appreciated that this may be done. These compounds have one or more asymmetric carbons May contain atoms and may exist in racemic and optically active forms . All of these compounds are included within the scope of the present invention. Production method   By applying some of the synthetic procedures shown in the scheme below, the compound of formula (I) A compound may be obtained. The syntheses shown in these schemes can be used for a variety of different R, R₁ And the preparation of compounds of formula (I) having an aryl group. During the scheme To Using substituents, which may be present, protected as appropriate to accommodate the described reaction Perform the reaction. In such cases, deprotection is performed later and then generally disclosed A compound of the nature is obtained. Once the urea nucleus is created, standard methods for functional group interconversion Can be applied to produce additional compounds having these formulas. Wear.   Thioimidate (2The title compound can be synthesized from Scheme 1). R ′ used in the scheme is R ′ as defined for compounds of formula (I)₁₈It is. As well Wherein R ″ is as defined for the compound of formula (I) (R₁₃R₁₄)_v-R₂₀Linkage It is di. Z is the same as defined for the compound of formula (I).                                Scheme 1   Electron-withdrawing methylene compounds1With LDA, alkyl lithium or potassium t -Synthesis of thioimidate by condensation with a strong base such as butoxide be able to. Then, the resulting anion is converted to a commercially available thioisocyanate (thioisocyanate). If the anate is not commercially available, place it in the presence of a base such as sodium bicarbonate. (Which can be synthesized by reacting the desired amine with thiophosgene) Can be. The resulting thioanion is then halogenated, such as methyl iodide. Alkylating with alkyl2Get.   Alternatively, a commercially available acid in the presence of a coupling reagent such as EDC3The amine By reacting with2Can also be synthesized (Scheme 2).                                Scheme 2   The corresponding thioamide is then synthesized by reacting the amide with Lawesson's reagent. Can be achieved. Finally, lithium diisopropylamide (LDA) or Deprotonation using a base such as sodium hexamethyldisilazane, followed by , Alkylation using methyl iodide2Thioimidating by getting Can be synthesized.   The thioimidate is then reacted with an ortho-functionalized aniline to give the title compound.5To Obtainable. High affinity for sulfur such as mercury oxide or silver acetate Oxidation of sulfur with the addition of metal salts Thus, by producing a better leaving group, the reaction can be accelerated.                                Scheme 3   Alternatively, thiourea or urea can be converted to the anion ZCH^-R '(ZCH_TwoR 'to L By reacting with a base such as DA) to give the title compound (5, Scheme 4) can also be synthesized. US provisional application filed June 27, 1996 USSN 60/020655 (agent processing number P50467P); 1996 1996 USSNO8 / 701299 filed on March 21 (agent number P503324-2) And US provisional application USSN 60/020657, filed June 27, 1996 Agent Process Number P50470P) (the disclosures of which are described herein by reference). Thiourea or urea is synthesized as described in (1).                                Scheme 4   Alternatively, the title compound is synthesized using a protected 2-hydroxyaniline. (US provisional application USSN 60/020, filed June 27, 1996) 655 (see proxy process number P50467P)). Then, thio This compound is converted to thioisocyanate using phosgene, and then RNH_Two And react with. Then, methanesulfonyl chloride and triethylamine This compound can be converted to the corresponding carbodiimide using a base such as this.                                Scheme 5   Then, in the presence of a base such as triethylamine or sodium hydride, Rubodiimide8, Scheme 5 with ZCH_TwoReact with R '9Can be obtained. This compound is then converted to Pd (PPh) in a polar solvent such as THF._Three)_Four, Hydrogenation Deprotection by standard conditions such as sodium borohydride and morpholine gives the desired 1 , 1 diaminoethylene10Can be obtained.   In the examples, all temperatures are in degrees Celsius (° C). Unless otherwise noted, fast Performed mass spectrum analysis with VG Zab mass spectrometer using atomic bombardment Was.¹HNMR (hereinafter, referred to as “NMR”) spectrum at 250 MHz or Uses a Bruker AM250 or AM400 spectrometer at 400 MHz, respectively. And recorded. Multiplicity: s = singlet, d = doublet, t = triple G, quartet, m = multiplet, br indicates spread signal You. Sat. is a saturated solution, equiv. Is the ratio of the molar equivalent of the reagent to the main reactant. Indicates a match.   Flash chromatography using Merck silica gel 60 (230-400 mesh) A torography was performed. Synthesis example   The present invention will be described with reference to the following examples. It is not intended to limit the scope of the light. All temperatures are in Celsius and all Solvents are of the highest purity that can be used and perform all reactions unless otherwise specified. It is carried out under anhydrous conditions and under an argon atmosphere.                                 Example 1 1-nitro-2- [2-hydroxy-4-cyanophenylamino] -2- [2- Of Pyridylamino] ethylene a) Preparation of 2-nitro-6-cyanophenol   2-cyanophenol (4.72 g, 40 mmol) was added to methylene chloride (80 ml). ) And then sodium nitrate (3.76 g, 44 mmol) was added. Then, sulfuric acid (40 ml / 3 M) was added, and then a catalytic amount of sodium nitrite was added. C Was added. The mixture was stirred. After 24 hours, the reaction mixture was diluted with methylene chloride. And extracted with water. Organic layer_FourAnd then filtered. solvent Was evaporated, and the obtained solid was subjected to silica gel chromatography (4% MeOH / C H_TwoCl_Two) To give the desired product (2.8 g, 42%). b) Preparation of 3-allyloxy-4-nitrobenzonitrile   3-Hydroxy-4-nitrobenzonitrile (5 g, 30.5 mmol) in a solution of cesium carbonate (15 g, 45.7 mmol) and Allyl bromide (3.15 ml, 35.6 mmol) was added. Reaction mixture at room temperature Stirred for 18 hours, then partitioned between ethyl acetate and water. Organic together The phases were dried and concentrated to give the desired product (5.85g, 94%). EI-MS m / z 205 (M⁺). c) Preparation of 2-allyloxy-4-cyanoaniline   3-allyloxy-4-nitrobenzonitrile (30 ml) in ethanol (30 ml) 5.85 g (28.68 mmol) in a solution of tin (II) chloride (32 g, 143. 4 mmol) was added. The reaction mixture was stirred at reflux for 4 hours, then Cooled to room temperature. NaHCO_Three(Aqueous solution) to pH = 7. Incidentally The reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO_FourDry Dry, filter and concentrate in vacuo to give the desired product (4.5 g, 90%). EI-M S m / z 175 (M⁺). d) Preparation of 2-allyloxy-4-cyanophenylthioisocyanate   CHCl_Three(150 ml) 2-allyloxy-4-cyanoaniline (1.5 g, 8.62 mmol) in a solution of 5.1 g of sodium bicarbonate in 73 ml of water. Was added, followed by thiophosgene (0.79 ml, 10.45 mmol). . The reaction mixture was stirred at room temperature for 16 hours. Then partitioned between ethyl acetate and water. I let you. The combined organic phases were extracted with MgSO_FourAnd concentrated to the desired product (1.6 g). , 86%). EI-MS m / z 217 (M⁺). e) N- (2-allyloxy-4-cyanophenyl)]-N '-[2-pyridyl Preparation of Thiourea   To a solution of 2-aminopyridine (1 eq) in DMF (3.0 ml) was added 2-ally Addition of loxy-4-cyanophenylthioisocyanate (1 equivalent) it can. The reaction mixture can be stirred at room temperature for 16 hours. Wash the obtained liquid Subject to Rica gel chromatography (ethyl acetate / hexane) to obtain desired product . f) N- (2-allyloxy-4-cyanophenyl) -N '-(2-pyridyl) Preparation of carbodiimide   CH_TwoCl_TwoOf thiourea (700 mg, 1.8 mmol) in (15 ml) At 0 ° C., methanesulfonyl chloride (0.29 ml, 3.6 mmol) and And triethylamine (0.75 ml, 5.4 mmol) can be added. The reaction mixture can be stirred at room temperature for 30 minutes. The reaction mixture was washed with ethyl acetate and And water. The combined organic phases were extracted with MgSO_FourAnd let it dry It can be concentrated. The obtained liquid is subjected to silica gel chromatography (acetic acid Chill / hexane) to give the desired product. g) 1-Nitro-2- [2-allyloxy-4-cyanophenylamino] -2- Preparation of [2-pyridylamino] ethylene   A solution of nitromethane (2.26 mmol) in dry DMF (2.4 ml) was added Under a gon atmosphere, sodium hydride (1.24 m) in DMF (1.2 ml) was used. mol) suspension. After stirring at room temperature for 30 minutes, DMF (2. A solution of carbodiimide (1.13 mmol) in 2 ml) can be added. You. The reaction mixture can be stirred at 100 ° C. for 1 hour. Then, acetate acetate It can be distributed between chill and water. The combined organic phases were extracted with MgSO_FourDry It can be dried, filtered and concentrated. The resulting liquid is quenched with triethylamine Chromatographed on treated silica gel (ethyl acetate / hexane). To give the desired product. h) 1-nitro-2- [2-hydroxy-4-cyanophenylamino] -2- [ Preparation of [2-pyridylamino] ethylene   1-Nitro-2- [2-allyloxy-4-cyano in morpholine (1 ml) Phenylamino] -2- [2-pyridylamino] ethylene (0.16 mmol) In a solution of Pd (PPh_Three)_Four(0.0064 mmol) can be added . The reaction mixture can be stirred at room temperature for 1 hour. Then, ethyl acetate and It can be partitioned between ammonium chloride (aqueous solution). The combined organic phases MgSO_Four, Filtered and then concentrated. The resulting liquid Is subjected to silica gel chromatography (ethyl acetate / hexane) to give the desired product. Get.   The pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by known methods, e. Obtained by treating a compound of formula (I) with an appropriate amount of an acid or base in the presence of a medium. Is also good. Treatment method   Converting a compound of formula (I) or a pharmaceutically acceptable salt thereof into a human or other mammal Cells, such as, but not limited to, monocytes and / or macrophages Excessive or unregulated IL-8 cytokine, or IL-8α or β receptor Production of other chemokines that bind to the body (also called type I or type II receptors) Disease states in humans or other mammals that are worsened or caused by life Can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of   Thus, the present invention relates to chemokines that bind to IL-8α or β receptors. A method for the treatment of a disease mediated by said compound, said method comprising an effective amount of a compound of formula (I) or Comprises administering a pharmaceutically acceptable salt thereof. Specifically, chemokines are IL -8, GROα, GROβ, GROγ, ENA-78, or NAP-2 .   Compounds of formula (I) may be used for chemokine function, in particular IL-8, GROα, GRO dose sufficient to inhibit the function of β, GROγ, ENA-78, or NAP-2. To bring them down to normal physiological levels, or In some cases, subnormal levels are improved to improve the disease state. example For example, in the present invention, IL-8, GROα, GROβ, GROγ, ENA-7 An abnormal level of 8, or NAP-2, constitutes: (I) a level of free IL-8 equal to or greater than 1 picogram per ml; Bell; (ii) cells above normal levels IL-8, GROα, GROβ, GROγ , ENA-78, or NAP-2 levels; or (iii) IL-8, respectively , GROα, GROβ, GROγ, ENA-78, or NAP-2 are produced IL-8, GROα, GROβ, G above basal level in cells or tissues Presence of ROγ, ENA-78, or NAP-2.   Excessive or unregulated IL-8 production is implicated in worsening and / or onset There are many disease states. Diseases mediated by chemokines include psoriasis, atopy Dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease Disease, Crohn's disease, ulcerative colitis, stroke, septic shock, endotoxin shock C, gram-negative sepsis, toxin shock syndrome, heart and kidney reperfusion injury , Glomerulonephritis, thrombosis, graft-versus-host reaction, Alzheimer's disease, atypical graft rejection Including response, malaria, restenosis, angiogenesis or unwanted hematopoietic stem cell release You.   These diseases are mainly due to massive neutrophil infiltration, T cell infiltration, or new blood vessels. IL-8, GROα, GROβ, GROγ characterized by increased growth of Or the production of NAP-2, and these production increases are associated with neutrophil sites of inflammation It is responsible for the chemotactic inward or directional growth of endothelial cells. Other inflammatory In contrast to Itokine (IL-1, TNF, and IL-6), IL-8, G ROα, GROβ, GROγ or NAP-2 are neutrophil chemotaxis, elastase Enzyme release, including enzyme release, and enhanced superoxide production and activation (But not limited to these). IL-8 type I or Α-chemokines that operate through type II receptors, in particular GROα, GROβ, GROγ or NAP-2 promotes the directional proliferation of endothelial cells. May promote new tumor angiogenesis. Therefore, IL-8 induced activation Inhibition of chemotaxis or activation will directly reduce neutrophil infiltration.   Recent evidence also suggests a role for chemokines in treating HIV infection. Littleman et al., Nature 381, pp661 (1996) and Koup et al., Nature 381, pp667 (1996).   The present invention also provides a compound of the formula (I) Treatment in systemic sclerosis and preventive measures in individuals with potential CNS injury provide.   CNS injuries as defined herein are, for example, surgical open or penetrating heads. Head trauma, or closed head trauma, for example due to injury to the head area. Ischemic stroke, especially in the head, is also included in this definition.   Ischemic stroke is caused by insufficient blood supply to a particular head area, usually Narrow area as a result of local atherosclerotic closure of an obturator, thrombus, or blood vessel Is defined as a neurological disorder. The role of inflammatory cytokines in this case is clear As such, the present invention provides a means for the potential treatment of these injuries . Relatively small procedures can be performed for these acute injuries.   TNF-α is a proinflammatory drug that includes the expression of endothelial leukocyte adhesion molecules. Itokine. Inhibits TNF as leukocytes infiltrate into ischemic brain injury Or compounds that reduce its levels are useful in treating ischemic brain injury . Liu et al., Stoke, Vol. 25., No .. 7, pp 1481-1488 (1994) (see its disclosure) As described herein by reference).   Models of closed head injury and treatment with 5-LO / CO mixtures are described by Shohami et al. l., J. of Vaisc & Clinical Physiology and Pharmacology, Vol. 3, No. 2, p p. 99-107 (1992), the disclosure of which is deemed to be incorporated herein by reference. I smell Have been discussed. Treatments that suppress edema formation are likely to function in treated animals. Was found to improve.   Compounds of formula (I) inhibit IL-8 binding to IL-8α or β receptors Such inhibition can be, for example, a reduction in neutrophil chemotaxis and activation. Therefore it becomes clear. Finding that compounds of formula (I) are inhibitors of IL-8 binding Is the compound of formula (I) in the in vitro receptor binding assay described herein. Based on effect. Compounds of formula (I) may in some cases have recombinant type I and It has been shown to inhibit both type II IL-8 receptors. Preferably , The compounds are inhibitors of only one receptor, more preferably type II Is an inhibitor of   As used herein, the term “disease or condition mediated by IL-8” refers to IL- 8. Production of GROα, GROβ, GROγ, ENA-78, or NAP-2 itself. Raw or by IL-8, GROα, GROβ, GROγ, ENA-78, Or another monokine caused by NAP-2 (IL-1, IL-6 or TN F-8, GROα, G ROβ, GROγ, ENA-78, or NAP-2 should play a role. All disease states. For example, IL-1 is the major component and in response to IL-8 Disease states in which IL-1 production or action is increased or where IL-1 is secreted include: Therefore, it is considered a disease state mediated by IL-8.   As used herein, the term "chemokine-mediated disease or condition" refers to IL Chemokines that bind to -8α or β receptors (IL-8, GROα, GROβ, (Including but not limited to GROγ, ENA-78, or NAP-2) Refers to any disease state in which it plays a role. This term refers to the production of IL-8 itself. Another monokine (IL-1, IL-6) that is caused by raw or IL-8 Or TNF) to release IL-8 It will include disease states that are playing a role. For example, IL-1 is the main component Increased IL-1 production or action in response to IL-8, or IL-1 Are secreted as IL-8 mediated disease states. Is done.   As used herein, the term “cytokine” refers to an effect on cell function, immunity, inflammation or production. A secreted polypeptide that is a molecule that modulates cell-cell interactions in the blood response . Cytokines are monocytokins regardless of which cells produce them. But not limited to, and lymphokines. For example, in general Nokine is produced by mononuclear cells such as macrophages and / or monocytes. It is said to be secreted. However, many other cells also produce monokine. Cells, such as natural killer cells, fibroblasts, basophils, Neutrophils, endothelial cells, astrocytes of the brain, bone marrow stromal cells, epidermal keratinocytes and B cells There is a damper ball. It is generally said that lymphokines are produced by lymphocytes. ing. Examples of cytokines include interleukin-1 (IL-1), interloin Ikin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor- α (TNF-α) and tumor necrosis factor-β (TNF-β) Not limited to   The term “chemokine” in the present specification, like the above “cytokine”, affects cell functions. Molecules that resonate and modulate cell-cell interactions in the immune, inflammatory or hematopoietic response. Secreted polypeptide. Chemokines are secreted mainly through cell membranes and are Constant leukocytes, neutrophils, monocytes, macrophages, T cells, B cells, endothelial cells and Causes smooth muscle cell chemotaxis and activation. An example of a chemokine is IL-8 , GROα, GROβ, GROγ, ENA-78, NAP-2, IP-10, M Including IP-1α, MIP-β, PF4, and MCPs 1, 2, and 3, Not limited to these.   In order to use a compound of formula (I) or a pharmaceutically acceptable salt thereof for therapy, Typically, they will be formulated into pharmaceutical compositions according to standard pharmaceutical practice. Hence the book The invention provides an effective and non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier or Also relates to a pharmaceutical composition comprising a diluent.   Compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions containing them The product may be conveniently placed in a route conventionally used for drug administration, e.g. It may be administered orally or by inhalation. Compounds of formula (I) according to conventional procedures The conventional formula is prepared by mixing the product with a standard pharmaceutical carrier. The compounds of I) may be administered. The compound of formula (I) is activated by a known second therapeutic activation It may be administered in combination with a compound. These procedures involve mixing the ingredients, granulating and And tableting or dissolving to obtain the desired preparation. Pharmaceutically acceptable The form and characteristics of the carrier or diluent used will depend on the amount of active ingredient being mixed, the route of administration. , And other well-known factors. Responsible The body is "acceptable" in that it is compatible with the other ingredients of the formulation and does not harm its recipients. Be done. "   The pharmaceutical carrier employed can be, for example, a solid or liquid. Typical of solid carriers Examples include lactose, white clay, sucrose, talc, gelatin, agar, pectin, Labia gum, magnesium stearate, stearic acid and the like. Reference of liquid carrier Examples are molasses, peanut oil, olive oil, water and the like. Similarly, carrier or dilute The excipient is glyceryl monostearate or glyceryl distearate or Time delay materials well known in the art, such as mixtures of these with waxes. May be included.   Various dosage forms can be used. Therefore, when using a solid carrier, the formulation is tableted. Powder or pellets in a hard gelatin capsule, or Or sweetened tablets. Wide range of solid carriers But will preferably be from about 25 mg to about 1 g. If liquid carrier is used, mix Sterile injection such as syrup, emulsion, soft gelatin capsule, ampoule It will be in the form of a possible liquid or non-aqueous suspension.   The compound of formula (I) may be administered locally, ie, non-systemically. to this Is to administer the compound of formula (I) externally to the epithelium or to the oral cavity (approximately the mucosa). Administration, and the drip of such compounds into the ears, eyes and nose. In some cases, the compound does not enter the bloodstream significantly. In contrast, systemic administration is oral, intravenous, and abdominal. Intracavitary and intramuscular administration.   Formulations suitable for topical administration are liquids or semi-liquids suitable for penetration from the skin to the site of inflammation Body preparations (eg, liniment, lotion, cream, ointment or pasta), And drops suitable for administration to the eye, ear or nose. The active ingredient is applied topically. For example, 0.001% to 10% by weight of the formulation, for example, 1% to 2% by weight. It may account for the amount%. However, the active ingredient comprises 10% by weight of the formulation, preferably Will account for less than 5% by weight, more preferably between 0.1% and 1% by weight. .   The lotions of the present invention include those suitable for application to the skin or eyes. Eye low Preparations include sterile aqueous solutions that may contain bactericides and are compatible with the manufacture of drops. It may be manufactured by the same method. Lotion or linime to apply to skin Agents promote the drying of the skin and cool the skin, such as alcohol or Acetone and / or humectants such as glycerol or castor oil or Oils and fats such as peanut oil may be included.   The cream, ointment or pasta of the present invention is a semi-solid preparation of the active ingredient for external application. Is better. Use finely divided or powdered active ingredients neat or aqueous or non-aqueous As a solution or suspension in an ionic liquid, use appropriate machinery to May be manufactured by mixing with a non-greasy base material. The substrate is Hard mixed with alcohol, such as propylene glycol or macro gel, Carbohydrates such as soft or liquid paraffin, glycerol, beeswax, metal soaps Element; serum; almond, corn, peanut, castor or olive oil Oils and fats of natural origin; cottonseed oil or derivatives thereof or stearic acid or olein Fatty acids such as acids may be included. Sorbitan ester or its polyoxy Anionic, cationic or nonionic surfactants such as ethylene derivatives A suitable surfactant such as the following may be included in the formulation. Inducing natural gum and cellulose Suspending agents such as conductors or silica containing silica and other ingredients such as lanolin May be included.   Drops of the present invention include sterile aqueous or oily solutions or suspensions, And / or fungicides and / or other suitable preservatives, and preferably Manufactured by dissolving the active ingredient in a suitable aqueous solution containing a surfactant Is also good. The resulting solution is then clarified by filtration, transferred to a suitable container, and By sealing and autoclaving or maintaining at 98-100 ° C for half an hour. May be sterilized. Alternatively, the solution can be sterilized by filtration and then sterile. May be transferred to the container. Bactericides and fungicides suitable for inclusion in drops Examples of the agent include phenylmercuric nitrate or acetate (0.002%), Zalkonium (0.01%) and chlorohexidine acetate (0.01%). . Suitable solvents for the preparation of oily solutions are glycerol, diluted alcohol and propylene. Glycol.   The compounds of formula (I) can be administered parenterally, ie, intravenously, intramuscularly, subcutaneously, intranasally, It may be administered rectally, vaginally or intraperitoneally. Parenteral administration in subcutaneous and intramuscular forms Is generally preferred. Dosage forms suitable for such administration may be prepared by conventional methods. No. The compounds of formula (I) are administered by inhalation, ie by intranasal and oral inhalation. May be administered. Dosage forms suitable for such administration, such as aerosol formulation or metering The inhaler may be manufactured by a conventional method.   For all uses disclosed herein for compounds of formula (I), 1 The daily oral dosage regimen is preferably from about 0.01 to about 80 mg / kg body weight. There will be. The daily parenteral administration rule is preferably no more than about 0.001 per kg body weight Would be about 80 mg. The daily local administration rule is preferably between 0.1 mg and 1 mg. 50 mg will be administered 1 to 4 times, preferably 2 or 3 times a day. One day The rule of inhalation administration is preferably between about 0.01 mg / kg and about 1 mg / kg of body weight. Would. In addition, the optimal dose of the compound of the formula (I) or a pharmaceutically acceptable salt thereof is determined. And the interval between doses will depend on the nature and extent of the condition to be treated, the form of administration, the route and site, It is determined according to the individual patient to be treated and the optimal value is determined by conventional methods. It will be understood by those skilled in the art that In addition, optimal treatment course, A compound of formula (I) or a pharmaceutically acceptable compound thereof administered daily for a certain number of days The skilled artisan will be able to ascertain the salt dosage and frequency of administration using routine therapeutic decision testing courses. It will also be appreciated by those skilled in the art.   The invention will be described with reference to the following biological examples, which are merely illustrative. And does not limit the scope of the invention in any way.Biological examples   The inhibitory effects of the compounds of the present invention on IL-8 and GRO-α chemokines were determined by the following Imbi. Determined by Toro assay: Receptor binding assay   Specific activity of 2000 Ci / mmol [¹²⁵I] IL-8 (human recombinant) is available from Amersha m Corp., Arlington Heights, IL. Gro-α is NEN-New England Obtained from Nuclear. All other chemical reagents are of analytical grade. Already (Holmes, et al., Science, 1991, 253, 1278), High levels of recombinant human IL-8 type α and β receptors are separately It was expressed in hamster ovary cells. Homogenize buffer 10 mM Tris-HCl, 1 mM MgSO_Four, 0.5 mM EDTA (ethylene-diamine Tetra-acetic acid), 1 mM MPMSF (α-toluenesulfonyl fluoride), 0.5 m g / L leupeptin, pH 7.5, except that According to the protocol (Haour, et al., J Biol Chem., 249 pp 2194-2205 (1974) ) Chinese hamster ovary membrane was homogenized. Bovine serum albumin Membrane protein concentration using Pierce Co. microassay kit to be used as reference material To determine. All assays are in 96-well microplate format Do. Each reaction mixture contains 1.2 mM MgSO_Four, 0.1 mM EDTA, 25 mM N 20 mM Bis-Tris property containing aCl and 0.03% CHAPS And 0.4 mM Tris-HCl buffer¹²⁵I IL-8 (0.25 nM) or¹²⁵I Gro-α and 0.5 μg / ml IL-8Rα or 1. Includes 0 μl / ml IL-8Rβ membrane. In addition, it should be dissolved in DMSO beforehand. Drug or test compound to a final concentration of 0.01 nM to 100 μM. To be added. After 1 hour at room temperature, pre-press using a Tomtec 96-well harvester. The contents of the plate are collected on a glass fiber filter mat and 1% polyethyleneimine / Block with 0.5% BSA, 25 mM NaCl, 10 mM Tris- HCl, 1 mM MgSO_Four, 0.5 mM EDTA, 0.03% CHAPS, pH 7. Wash 3 times with 4. The filter is then dried and the Betaplate liquid scintillator Count on the application counter. As used herein, recombinant IL-8Rα, or Or type I receptor is called a non-permissive receptor Recombinant IL-8Rβ or type II receptor is a permissive receptor (permissive receptor) r).Chemotaxis assay:   The in vitro inhibitory properties of these compounds were measured using Current Protocols in Immunology. , Vol I, Suppl 1, Unit 6.12.3. (All disclosures are incorporated herein by reference. Neutrophil chemotaxis assay described in . Current Protocols in Immunology, vol I, Suppl 1, Unit 7.23.1 (see reference) The disclosure of which is all that is set forth herein). Neutrophils are isolated from human blood. Chemoattractants IL-8, GRO-α, G RO-β, GRO-γ and NAP-2 were used at a concentration of 0.1 to 100 nM. Under the 48 multiwell chamber (Neuro Probe, Cabin John, MD) Put it in the bar. Two chambers with 5 micron polycarbonate filter To separate. When testing a compound of the present invention, cells are added directly to the upper chamber. Prior to mixing them with the cells (0.001 nM to 1000 nM). 5% CO_Twoof Incubate for about 45 to 90 minutes at 37 ° C in a humidified incubator Allow the reaction to proceed. At the end of the incubation period, remove the polycarbonate membrane. Wash the top side, then use the Diff Quick Staining Protocol (Baxter Product s, McGaw Park, IL, USA). Chemotaxis toward chemokine More migrated cells are visually counted using a microscope. Generally, one sample Count the four fields and average these numbers to get the average number of migrating cells. Each sample Are tested in triplicate and are repeated at least 4 times for each compound. Specific cells No compound was added to (positive control cells), and these cells were Sexual response. If a negative control (unstimulated) is desired, Into the lower chamber Absent. Differences between the positive and negative controls indicate the chemotactic activity of the cells.Elastase release assay:   The ability of the compounds of the present invention to interfere with elastase release from human neutrophils test. Current Protocols in Immunology, vol I, Suppl 1, Unit 7.23.1 Neutrophils are isolated from human blood as described. Ringer's solution (NaCl11 8, KCl 4.56, NaHCO_Three 25, KH_TwoPO_Four 1.03, glucose 11.1, 0.88 × 10 PMNs in HEPES 5 mM, pH 7.4)⁶9 cell suspensions Add 50 μl to each well of a 6-well plate. The test compound (0 (0.001 to 1000 nM) and 50 μl of cytochalasin B (20 μg) / Ml) and 50 μl of Ringer's buffer. These cells for 5 minutes Warm (37 ° C, 5% CO_Two, 95% RH), then IL-8, GRO-α, G RO-β, GRO-γ or NAP-2 at a final concentration of 0.01 to 1000 nM And add. The reaction was allowed to proceed for 45 minutes, then the 96-well plate was Centrifuge (800 × g for 5 minutes), then take 100 μl of supernatant. Supernatant 2 in a 96-well plate and dissolved in phosphate buffered saline Stase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Jolla, CA) is added to a final concentration of 6 μg / ml. Immediately, Fluorescent 96-well plate reader (Cytoflour 2350, Millipore, Bedfor d, MA), and Nakajima et al., J. Mol. Biol. Chem., 254, 4027 (1979) Data is collected at 3 minute intervals according to the method. Elastase release from PMNs Measure the decomposition rate of MeOSuc-Ala-Ala-Pro-Val-AMC It is calculated byTNF-α assay in traumatic brain injury   This assay is based on experimental temporal fluid dab traumatic injury (TBI) in rats. ) To examine the expression of tumor necrosis factor mRNA in specific brain regions after is there. Adult Sprague-Dawley rats (n = 42) were treated with sodium pentobarbital (60 mg / kg, intraperitoneal injection), moderate intensity temporal fluid trauma Sexual injury (2.4 atm) was given over the center of the left temporal parietal cortex (n = 18). Also "false" Treatment (anesthesia, surgical treatment without trauma, n = 18) was also performed. Injury At 1, 6 and 24 hours after, the animals are sacrificed by decapitation, the brain is removed and the left (injured) Girth) parietal cortex (LC), corresponding site (RC) in contralateral right cortex, injury Cortex adjacent to the received parietal cortex (LA), corresponding adjacent site of the right cortex (RA), left A hippocampus (LH) and a right hippocampus (RH) are prepared. Isolate total RNA and After performing blot hybridization, TNF-α positive control RNA (macro (Phage = 100%). One hour after injury, the L of the injured hemisphere H (104 ± 17% of positive control, p <0.05 compared to mock), LC (10 T in 5 ± 21%, p <0.05 and LA (69 ± 8%, p <0.01) A significant increase in NF-α mRNA is observed. LH (46 hours after injury) ± 8%, p <0.05, LC (30 ± 3%, p <0.01) and LA (32 ± 3%, p <0.01), increased TNF-α mRNA expression is also observed But resolves by 24 hours after the injury. In the opposite hemisphere, 1 After hours, RH (46 ± 2%, p <0.01), RC (4 ± 3%) and RA (2 2 ± 8%), TNF-α mRNA expression increased, and 6 hours after trauma RH (28 ± 11%), RC (7 ± 5%) and RA (26 ± 6%, p <0 .05), and no increase is observed 24 hours after trauma. Impersonation ( Surgical treatment without injury) or untreated animals at any time In any hemisphere, and in any of the six brain sites, TNF-α  No consistent changes in mRNA expression are observed. These results indicate that sagittal fluid Temporal TNF-α mRNA expression was not impaired following brain injury from beating It shows that it changes in specific brain sites including hemispheric sites. TNF-α is a nerve Induces growth factor (NGF) and releases other cytokines from activated astrocytes This post-traumatic change in gene expression of TNF-α Plays an important role in the acute and regenerative response to wounds.CNS injury model for IL-β mRNA   This assay is based on experimental temporal fluid dab traumatic injury (TBI) in rats. )) Interleukin-1β (IL-1β) mRNA in specific brain regions after The purpose of this study is to examine the characteristics of local expression. Adult Sprague-Dawley rat (n = 42) Was anesthetized with sodium pentobarbital (60 mg / kg, intraperitoneal injection). Temporal fluid pat traumatic injury (2.4 atm) of moderate intensity in left temporal parietal cortex Given on center (n = 18). In addition, "sham" treatment (anaesthesia, surgical treatment without trauma) Processing). Animals are killed by decapitation at 1, 6 and 24 hours after injury The brain is removed and placed in the left (injured) parietal cortex (LC) and contralateral right cortex. (RC), cortex adjacent to damaged parietal cortex (LA), right skin Prepare corresponding adjacent sites of quality (RA), left hippocampus (LH) and right hippocampus (RH) You. Total RNA was isolated, Northern blot hybridization was performed, The amount of woven IL-1β mRNA was measured using the same gel loaded IL-1β positive macrophages. It is shown as a percentage of the radioactivity of the diage RNA. 1 hour after brain injury, wound Damaged hemisphere LC (20.0 ± 0.7% of positive control, n = 6, compared to mock treatment) P <0.05), LH (24.5 ± 0.9%, p <0.05) and LA (21. 5 ± 3.1%, p <0.05) Significantly significant IL-1β mRNA expression Increases were observed, LC (4.0 ± 0.4%, n = 6, p <0.05) and LH ( (5.0 ± 1.3%, p <0.05) at 6 hours after injury It is. In mock-treated or untreated animals, at any of the individual brain sites No IL-1β mRNA expression is observed. These results indicate that after TBI, Local stimulation of transient expression of IL-1β mRNA at a fixed site Is shown. These local changes in cytokines, such as IL-1β, may Play a role.   All publications cited herein, not limited to patents and patent applications, are referenced by reference. Accordingly, each is considered to be described in its entirety.   The above description fully discloses the invention including preferred embodiments of the invention. Honcho Modifications and improvements to the specifically disclosed embodiments of the specification are set forth in the following claims. is there. Without further elaboration, it is to be understood that one skilled in the art, using the preceding description, may utilize the present invention to its fullest extent. I am convinced that it is available. Therefore, the embodiments herein are merely illustrative of the present invention. It should, therefore, be understood that they do not limit the scope of the invention in any way. Exclusive rights or special The embodiments of the claimed invention are defined as follows.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 29/00 A61P 29/00 43/00 111 43/00 111 C07D 223/16 C07D 223/16 Z 235 / 04 235/04

Claims (1)

[Claims]   1. Chemokines that bind to IL-8α or β receptors in mammals A method of treating a mediated disease state, comprising: [Wherein Z is cyano, nitro, CF_Three, C (O) NR_FifteenR₁₆, S (O)_TwoNR_FifteenR₁₆, Or S (O)_TwoR₁₇Is;   R₁₈Is hydrogen, halogen, cyano, optionally substituted C_1-4Alkyl, halo Substitution C_1-4Alkyl, C (O) NR_FifteenR₁₆, An optionally substituted aryl, Optionally substituted aryl C_1-4Alkyl, heteroaryl which may be substituted Optionally substituted heteroaryl C_1-4Alkyl, even if substituted Good heterocyclic or optionally substituted heterocyclic C_{1- Four} Alkyl;   R is a functional group having an ionizable hydrogen and has a pKa of 10 or less. Is;   R₁Is hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl; C_1-10 Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Alkoxy; Azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl; Aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Alkylo Xy; heteroaryl; heteroarylalkyl; heterocyclic; hetero Cyclic C_1-4Alkyl; heteroaryl C_1-4Alkyloxy; aryl C_2-10 Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10 Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; ( CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10Alkene Le C (O) OR₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁ ; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR₁₉; (C R₈R₈)_qS (O)_TwoNR_FourR_FiveIndependently selected from; or two R₁Base Together form O- (CH_Two)_sO- or 5- or 6-membered saturated or unsaturated ring Where aryl, heteroaryl and heterocyclic The moieties may be substituted;   q is o or an integer having a value from 1 to 10;   t is 0 or an integer having a value of 1 or 2;   s is an integer having a value of 1 to 3;   R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Alkyl, substituted Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, substituted Optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4 Alkyl, heterocyclic, or heterocyclic C_1-4Alkyl Or R_FourAnd R_FiveIs oxygen, nitrogen together with the nitrogen to which they bind Or 5 to 7 which may contain an additional hetero atom selected from sulfur. Form a member ring;   m is an integer having a value of 1 to 3;   n is an integer having a value of 1 to 3;   Y is hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl; C_1-10A Lequil; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Alkoxy; a Jid; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl; Reel; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Alkyloxy Heteroaryl; heteroarylalkyl; heteroaryl C_1-4Alkyl Oxy; heterocyclic; heterocyclic C_1-4Alkyl; aryl C_{Two -Ten} Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10 Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; ( CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_q C (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) OR₁₁ C (O) R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁ ; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR_d; (C R₈R₈)_qS (O)_TwoNR_FourR_FiveIndependently selected from; or two Y groups are Together, O- (CH_Two)_sO- or a 5- or 6-membered saturated or unsaturated ring Where aryl, heteroaryl and heterocyclic moieties may be formed The minutes may be substituted;   R₆And R₇Is independently hydrogen or C_1-4Is an alkyl group; or₆ And R₇Is oxygen, nitrogen or sulfur together with the nitrogen to which they bind Forming a 5- to 7-membered ring optionally containing additional heteroatoms selected from:   R₈Is hydrogen or C_1-4Independently selected from alkyl;   R_TenIs C_1-10Alkyl C (O)_TwoR₈Is;   R₁₁Is hydrogen, C_1-4Alkyl, optionally substituted aryl, substituted Aryl C_1-4Alkyl, optionally substituted heteroaryl, substituted An optionally substituted heteroaryl C_1-4Alkyl, optionally substituted hetero Cyclic or optionally substituted heterocyclic C_1-4Alkyl Is;   R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or substituted An optionally substituted arylalkyl;   R₁₃And R₁₄Is independently hydrogen or C_1-4Alkyl;   v is 0 or an integer having a value of 1 to 4;   R_FifteenAnd R₁₆Is independently hydrogen, optionally substituted C_1-4Alkyl, substituted Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, place Optionally substituted heteroaryl, optionally substituted heteroaryl C_{1- Four} Alkyl, optionally substituted heterocyclic, optionally substituted Heterocyclic C_1-4Alkyl or R_FifteenAnd R₁₆Are those Is selected from oxygen, nitrogen or sulfur together with the nitrogen to which it binds. And may form a 5- to 7-membered ring which may contain heteroatoms;   R₁₇Is C_1-4Alkyl, OR₁₁, Optionally substituted aryl, substituted Optional aryl C_1-4Alkyl, optionally substituted heteroaryl, Optionally substituted heteroaryl C_1-4Alkyl, optionally substituted hete Cyclocyclic or optionally substituted heterocyclic C_1-4Archi Is;   R₁₉Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, hete Lower aryl C_1-4Alkyl, heterocyclic, or heterocyclic C_{1 -Four} Alkyl, wherein all of these groups may be substituted;   R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Alkene , Heteroaryl, heteroaryl-C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocyclic, heterocyclic C_1-4Alkyl Where alkyl, aryl, arylalkyl, heteroaryl, heteroaryl Alkyl, heterocyclic, and heterocyclic alkyl rings are substituted May be   R₂₀Is W₁An optionally substituted heteroaryl, an optionally substituted C_{Five -8} Cycloalkyl, optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl or optionally substituted C_2-10Alkynyl; Asterisk here^*Represents the point of attachment of the ring;   E'-containing ringMay be selected from; asterisk here^*Indicates the point of attachment of the ring] Administering to a mammal an effective amount of the compound or a pharmaceutically acceptable salt thereof. A method that includes   2. 2. The method according to claim 1, wherein the ionizable hydrogen has a pKa of 3 to 10. .   3. R is hydroxy, carboxylic acid, thiol, SR_Two, OR_Two, NH-C (O) R_a, C (O) NR_{6 '}R_{7 '}, NHS (O)_TwoR_b, S (O)_TwoNHR_c, NHC (X_Two ) NHR_bOr tetrazolyl;   R_TwoIs a substituted aryl, heteroaryl, or heterocyclic ring; Functionality wherein the ring provides an ionizable hydrogen with a pKa of 10 or less Containing a group;   R_aIs aryl, aryl C_1-4Alkyl, heteroaryl, heteroaryl C_1-4 Alkyl, heterocyclic, or heterocyclic C_1-4Alkyl group And all of them may be substituted;   R_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, aryl C_{2- Four} Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4Alkenyl, heterocyclic, heterocyclic C_1-4Alkyl, f Terror cyclic C_2-4An alkenyl group or camphor, all of which Is halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoki Si, NR₉C (O) R_a, C (O) NR₆R₇, S (O)_ThreeH or C (O) OC_{1 -Four} Optionally substituted one to three times by alkyl;   R_{6 '}And R_{7 '}Is hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl, Aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, f Teloaryl C_2-4Alkenyl, heterocyclic, heterocyclic C_1-4 Alkyl or heterocyclic C_2-4Alkenyl groups, all of which Is halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoki Si, NR₉C (O) R_a, C (O) NR₆R₇, S (O)_ThreeH or C (O) OC_{1 -Four} R may be independently substituted once to three times by alkyl;_{6 '}and R_{7 '}One is hydrogen but not both;   R₉Is hydrogen or C_1-4Alkyl;   R_cIs alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkene , Heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4Al Kenyl, heterocyclic, heterocyclic C_1-4Alkyl or hete Cyclic C_2-4Alkenyl groups, all of which are halogen, nitro, Halo-substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoxy, NR₉C (O) R_a , C (O) NR₆R₇, S (O)_ThreeH or C (O) OC_1-4Independent by alkyl And may be substituted one to three times;   X_Two3. The method of claim 2, wherein is oxygen or sulfur.   4. R_TwoIs halogen, nitro, halo substituted C_1-10Alkyl, C_1-10Alkyl, C_1-10Alkoxy, hydroxy, SH, C (O) NR_{6 '}R_{7 '}, NH-C (O) R_a , NHS (O)_TwoR_b, S (O) NR_{6 '}R_{7 '}, C (O) OR₈Or tetrazoli The method according to claim 3, which may be substituted once to three times by a ring.   5. R is OH, NHS (O)_TwoR_bOr C (O) OH. Law.   6. R₁Is halogen, cyano, nitro, CF_Three, C (O) NR_FourR_Five, Alkenyl C (O) NR_FourR_Five, C (O) R_FourR_Ten, Alkenyl C (O) OR₁₂, Hetero ant Or heteroarylalkyl, heteroarylalkenyl, or S (O) NR_FourR_FiveThe method of claim 1, wherein   7. R₂₀Is W₁The method of claim 1, wherein   8. Y is halogen, C_1-4Alkoxy, optionally substituted aryl, substituted Arylalkoxy, methylenedioxy, NR_FourR_Five, Thio C_{1- Four} Alkyl, thioaryl, halo-substituted alkoxy, optionally substituted C_1-4A The method according to claim 1, which is alkyl or hydroxyalkyl.   9. R₂₀Is a heteroaryl, an optionally substituted alkyl, alkynyl or The method of claim 1, wherein is alkenyl.   10. R is OH, SH, or NHS (O)_TwoR_bAnd R₁Becomes an electron withdrawing group 2. The composition according to claim 1, further di-substituted at the 3-, 4- or 3,4-position. Method.   11. If the mammal has psoriasis, or atopic dermatitis, asthma, chronic obstructive pulmonary disease, Adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, sepsis Sexual shock, endotoxin shock, gram-negative sepsis, toxin shock Syndrome, stroke, heart and kidney reperfusion injury, glomerulonephritis, or thrombosis, Alz Chemo selected from Heimer's disease, graft-versus-host reaction, or allograft rejection 11. The method according to claim 1, wherein the disease is a disease mediated by Cain. The method described.   12. formula: [Wherein Z is cyano, nitro, CF_Three, C (O) NR_FifteenR₁₆, S (O)_TwoNR_FifteenR₁₆ , Or S (O)_TwoR₁₇Is;   R₁₈Is hydrogen, halogen, cyano, optionally substituted C_1-4Alkyl, halo Substitution C_1-4Alkyl, C (O) NR_FifteenR₁₆, An optionally substituted aryl, Optionally substituted aryl C_1-4Alkyl, heteroaryl which may be substituted Optionally substituted heteroaryl C_1-4Alkyl, even if substituted Yo Heterocyclic or optionally substituted heterocyclic C_1-4 Alkyl;   R is a functional group having an ionizable hydrogen and has a pKa of 10 or less. Is;   R₁Is hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl; C_1-10 Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Alkoxy; Azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl; Aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Alkylo Xy; heteroaryl; heteroarylalkyl; heterocyclic; hetero Cyclic C_1-4Alkyl; heteroaryl C_1-4Alkyloxy; aryl C_2-10 Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10 Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; ( CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁ C_2-10Alkenyl C (O) OR₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈ )_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR₁₉; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveIs independently selected from; Or two R₁The groups together form O- (CH_Two)_sO- or 5- or 6-membered saturated or unsaturated May form a saturated ring; wherein aryl, heteroaryl and heterocyclyl The lick portion may be substituted;   q is 0 or an integer having a value from 1 to 10;   t is 0 or an integer having a value of 1 or 2;   s is an integer having a value of 1 to 3;   R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Alkyl, substituted Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, substituted Optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4 Alkyl, heterocyclic, or heterocyclic C_1-4Alkyl Or R_FourAnd R_FiveIs oxygen, nitrogen together with the nitrogen to which they bind Or 5 to 7 which may contain an additional hetero atom selected from sulfur. Form a member ring;   m is an integer having a value of 1 to 3;   n is an integer having a value of 1 to 3;   Y is hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl; C_1-10A Lequil; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Alkoxy; a Jid; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl; Reel; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Alkyloxy Heteroaryl; heteroarylalkyl; heteroaryl C_1-4Alkyl Oxy; heterocyclic; heterocyclic C_1-4Alkyl; aryl C_{Two -Ten} Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10 Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; ( CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁ C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) O R₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (C R₈R₈)_qNHS (O)_TwoR_d; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveIndependently selected from Or two Y groups are taken together to form O- (CH_Two)_sO- or 5 It may form a 6-membered saturated or unsaturated ring; Reel and heterocyclic moieties may be substituted;   R₆And R₇Is independently hydrogen or C_1-4Is an alkyl group; or₆You And R₇From oxygen, nitrogen or sulfur together with the nitrogen to which they bind Forming a 5- to 7-membered ring optionally containing additional heteroatoms selected;   R₈Is hydrogen or C_1-4Independently selected from alkyl;   R_TenIs C_1-10Alkyl C (O)_TwoR₈Is;   R₁₁Is hydrogen, C_1-4Alkyl, optionally substituted aryl, substituted Aryl C_1-4Alkyl, optionally substituted heteroaryl, substituted An optionally substituted heteroaryl C_1-4Alkyl, optionally substituted hetero Cyclic or optionally substituted heterocyclic C_1-4Alkyl Is;   R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or substituted An optionally substituted arylalkyl;   R₁₃And R₁₄Is independently hydrogen or C_1-4Alkyl;   v is 0 or an integer having a value of 1 to 4;   R_FifteenAnd R₁₆Is independently hydrogen, optionally substituted C_1-4Alkyl, substituted Optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, place Optionally substituted heteroaryl, optionally substituted heteroaryl C_{1- Four} Alkyl, optionally substituted heterocyclic, optionally substituted Heterocyclic C_1-4Alkyl or R_FifteenAnd R₁₆Are those Is selected from oxygen, nitrogen or sulfur together with the nitrogen to which it binds May form a 5- to 7-membered ring which may contain heteroatoms;   R₁₇Is C_1-4Alkyl, OR₁₁, Optionally substituted aryl, substituted Optional aryl C_1-4Alkyl, optionally substituted heteroaryl, Optionally substituted heteroaryl C_1-4Alkyl, optionally substituted hete Cyclocyclic or optionally substituted heterocyclic C_1-4Archi Is;   R₁₉Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, hete Lower aryl C_1-4Alkyl, heterocyclic, or heterocyclic C_{1 -Four} Alkyl, wherein all of these groups may be substituted;   R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Alkene , Heteroaryl, heteroaryl-C_1-4Alkyl, heteroaryl C_2-4A Lucenyl, heterocyclic, heterocyclic C_1-4Alkyl Here, alkyl, aryl, arylalkyl, heteroaryl, heteroaryl Alkyl, heterocyclic, and heterocyclic alkyl rings are substituted May have been   R₂₀Is W₁An optionally substituted heteroaryl, an optionally substituted C_{Five -8} Cycloalkyl, optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl or optionally substituted C_2-10Alkynyl; Asterisk here^*Represents the point of attachment of the ring;   E'-containing ring asterisk^*Represents the point of attachment of the ring. Acceptable salt.   13. 13. The method according to claim 12, wherein the ionizable hydrogen has a pKa of 3 to 10. Method.   14． R is hydroxy, carboxylic acid, thiol, SR_Two, OR_Two, NH-C (O) R_a, C (O) NR_{6 '}R_{7 '}, NHS (O)_TwoR_b, S (O)_TwoNHR_c , NHC (X_Two) NHR_bOr tetrazolyl;   R_TwoIs a substituted aryl, heteroaryl, or heterocyclic ring; Functionality wherein the ring provides an ionizable hydrogen with a pKa of 10 or less Containing a group;   R_aIs aryl, aryl C_1-4Alkyl, heteroaryl, heteroaryl C_1-4 Alkyl, heterocyclic, or heterocyclic C_1-4Alkyl group And all of them may be substituted;   R_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, aryl C_{2- Four} Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4Alkenyl, heterocyclic, heterocyclic C_1-4Alkyl, f Terror cyclic C_2-4An alkenyl group or camphor, all of which Is halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Arco Kishi, NR₉C (O) R_a, C (O) NR₆R₇, S (O)_ThreeH or C (O) O C_1-4Optionally substituted one to three times by alkyl;   R_{6 '}And R_{7 '}Is hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl, Aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, f Teloaryl C_2-4Alkenyl, heterocyclic, heterocyclic C_1-4 Alkyl or heterocyclic C_2-4Alkenyl groups, all of which Is halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoki Si, NR₉C (O) R_a, C (O) NR₆R₇, S (O)_ThreeH or C (O) OC_1-4 R may be independently substituted once to three times by alkyl;_{6 '}And R_{7 '} One is hydrogen but not both;   R₉Is hydrogen or C_1-4Alkyl;   R_cIs alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkene , Heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4Al Kenyl, heterocyclic, heterocyclic C_1-4Alkyl or hete Cyclic C_2-4Alkenyl groups, all of which are halogen, nitro, Halo-substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoxy, NR₉C (O) R_a , C (O) NR₆R₇, S (O)_ThreeH or C (O) OC_1-4Independent by alkyl And may be substituted one to three times;   X_Two14. The method of claim 13, wherein is oxygen or sulfur.   15. R_TwoIs halogen, nitro, halo substituted C_1-10Alkyl, C_1-10Alkyl , C_1-10Alkoxy, hydroxy, SH, C (O) NR_{6 '}R_{7 '}, NH-C (O) R_a, NHS (O)_TwoR_b, S (O) NR_{6 '}R_{7 '}, C (O) OR₈Or tetrazo 15. The method according to claim 14, which may be substituted once to three times by a lyl ring.   16. R is OH, NHS (O)_TwoR_bOr C (O) OH. the method of.   17． R₁Is halogen, cyano, nitro, CF_Three, C (O) NR_FourR_Five, Alkene Le C (O) NR_FourR_Five, C (O) R_FourR_Ten, Alkenyl C (O) OR₁₂, Heteroa Reel, heteroarylalkyl, heteroarylalkenyl, or S (O) NR_FourR_Five13. The method of claim 12, wherein   18. R₂₀Is W₁13. The method of claim 12, wherein   19. Y is halogen, C_1-4Alkoxy, optionally substituted aryl, substituted Optionally substituted arylalkoxy, methylenedioxy, NR_FourR_Five, Thio C_1-4 Alkyl, thioaryl, halo-substituted alkoxy, optionally substituted C_1-4 The method according to claim 18, which is alkyl or hydroxyalkyl.   20. R₂₀Is heteroaryl, optionally substituted alkyl, alkynyl or 13. The method of claim 12, which is alkenyl.   21. R is OH, SH, or NHS (O)_TwoR_bAnd R₁Becomes an electron withdrawing group 13. The di-substituted at the 3-, 4- or 3,4-position. the method of.   22. 22. A compound according to any of claims 12 to 21 and pharmaceutically acceptable A pharmaceutical composition comprising a carrier or diluent.