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    • 专利摘要:
    The present invention relates to compounds of formula (I) useful for the treatment or prevention of inflammatory and immune cell-mediated diseases.
    公开号:KR20020015074A
    申请号:KR1020027000782
    申请日:2000-07-12
    公开日:2002-02-27
    发明作者:우장-핑；켈리테렌스알프레드；레미유르네엠.；골드버그다니엘알.；에마이조나단에밀리안；소켁로날드제이.
    申请人:데이비드 이. 프랭크하우저；베링거 인겔하임 파마슈티칼즈, 인코포레이티드；
    IPC主号:
    专利说明:

    Imidazioimidazoles and triazoles as anti-inflammatory agents
    [2] Research over the last decade has helped to identify the molecular actions involved in the body's cell-cell interactions, in particular those associated with the movement and activity of cells in the immune system. Springer, T. Nature, 1990, 346, 425-434. Cell adhesion molecules ("CAMs"), including cell surface proteins, in particular LFA-1, MAC-1 and gp150.95 (referred to by WHO nomenclature as CD18 / CD11a, CD18 / CD11b and CD18 / CD11c, respectively) and " Leukointegrins ”corresponded to the subject of pharmaceutical research and development aimed at interfering with the process of leukocyte release to the site of injury and the migration of leukocytes to separate targets. For example, the activity of structurally expressed integrins on leukocytes appears before leukocyte sunrise, a mandatory component of the inflammatory response, followed by tight ligand / receptor interactions between integrins (e.g., LFA-1), ICAM-1, One or several separate intracellular adhesion molecules (ICAMs), represented by ICAM-2, ICAM-3 or ICAM-4, are expressed on the vascular endothelial cell surface and other leukocytes. The interaction of CAMs with leucointegrin is an essential step in the general work of the immune system. All immune processes, such as antigen presentation, T-cell mediated cytotoxicity and leukocyte sunrise, require intracellular adhesion mediated by ICAM that interacts with leucointegrin. Kishimoto, T.K .; Rothlein; R.R. Adv. Pharmacol. 1994, 25, 117-138 and Diamond, M .; Springer, T. Current Biology, 1994, 4, 506-532.
    [3] Groups of individuals have been identified for the lack of adequate expression of leucointegrin, a symptom defined as "leukocyte adhesion deficiency". Anderson, D.C .; et al., Fed. Proc. 1985, 44, 2671-2677 and Anderson, D. C .; et al., J. Infect. Dis. 1985, 152, 668-689. These individuals are unable to operate normal inflammatory and / or immune response (s) due to the inactivation of these cells to attach to the cell substrate. These data indicate that the immune response is attenuated if the general form of lymphocytes is impossible due to the lack of functional adhesion molecules of the CD18 group. Indeed, LAD patients deficient in CD18 are unable to activate the immune response, and it is believed that antagonism of CD18, CD11 / ICAM interactions inhibits the immune response.
    [4] Antagonism of the interaction between CAM and leucointegrin can be realized by an agent acting on the two components. Specifically, blocking of CAM such as ICAM-1 or leucointegrin such as LFA-1 by antibodies acting on one or both of these molecules effectively inhibits the inflammatory response. In vitro models of inflammatory and immune responses inhibited by antibodies to CAM or leucointegrins involve antigen or mitogen-induced lymphocyte proliferation, homology accumulation of lymphocytes, T-cell mediated cytolysis and antigen-specific induction Included resistance. Association of in vitro studies is supported by in vivo studies using antibodies directed against ICAM-1 or LFA-1. For example, antibodies acting against LFA-1 prevent thyroid graft rejection in mice and can prolong cardiac allograft survival. Gorski, A .; Immunology Today, 1994, 15, 251-255. In an important sense, antibodies acting against ICAM-1 show in vivo efficacy as anti-inflammatory agents in human diseases such as renal allograft rejection and rheumatoid arthritis. Rothlein, R.R .; Scharschmidt, L., in: Adhesion Molecules; Wegner, C. D., Ed .; 1994, 1-38, Cosimi, C. B .; et al., J. Immunol. 1990, 144, 4604-4612 and Kavanaugh, A .; et al., Arthritis Rheum. 1994, 37, 992-1004], antibodies against LFA-1 have immunosuppressive effects in the prevention of bone marrow transplantation and early rejection of renal allografts [Fischer, A .; et al., Lancet, 1989, 2, 1058-1060 and Le Mauff, B .; et al., Transplantation, 1991, 52, 291-295].
    [5] It has also been demonstrated that the recombinant soluble type of ICAM-1 acts as an inhibitor of ICAM-1 interacting with LFA-1. Soluble ICAM-1 acts as a direct antagonist of CD18, CD11 / ICAM-1 interactions on cells and in vitro such as human mixed lymphocyte response, cytotoxic T cell response and T cell proliferation from diabetic patients responding to islet cells. Show an inhibitory activity in immune response mogels in Becker, JC; et al., J. Immunol. 1993, 151, 7224 and Roep, B. O .; et al., Lancet, 1994, 343, 1590.
    [6] Thus, the prior art demonstrates that large protein molecules that antagonize the binding of CAM to leucointegrin have therapeutic potential to mitigate the inflammatory and immune responses associated with the development of many autoimmune or inflammatory diseases. However, proteins have significant deficiencies as therapeutic agents, including their inability to be rigidly induced and the potential immunoreactivity that limits the usefulness of these molecules for long-term administration. In addition, protein-based therapies are generally expensive.
    [7] Several small molecules have been described in the literature to affect the interaction of CAM and leucointegrin. Natural products isolated from Tricilia rubra have been shown to be inhibitory in cell binding assays in vitro. Musza, L.L .; et al., Tetrahedron, 1994, 50, 11369-11378. A series of molecules [Boschelli, D. H .; et al., J. Med. Chem. 1994, 37, 717 and Boschelli, D. H .; et al., J. Med. Chem. 1995, 38, 4597-4614] have been found to be orally active in the reverse passive Arthus response, and the induced model of inflammation is characterized by neutrophil accumulation (Chang, Y.H .; et al., Eur. J. Pharmacol. 1992, 69, 155-164]. In addition, another series of molecules has been found to be orally active in the delayed-type hypersensitivity reactions of rats. Sanfilippo, P.J .; et al., J. Med. Chem. 1995, 38, 1057-1059. All these molecules exhibit nonspecific activity in both intracellular action to inhibit the transcription of ICAM-1 along with other proteins or to inhibit the activity of leucointegrin by unknown mechanisms. No molecule directly antagonizes the interaction of CAM with leucointegrin. Due to the lack of specific mechanisms of likelihood, selectivity and action, the small molecules described are not satisfactory for therapeutic use.
    [8] Small molecules with similar capabilities as large protein molecules to directly or selectively antagonize the binding of CAM to leucointegrin have become preferred as therapeutics. WO 9839303 describes small molecule inhibitors of the interaction of LFA-1 and ICAM-1. WO 9911258 describes fungal metabolite mevinolin and derivatives that bind to LFA-1 and block the interaction of LFA-1 with ICAM-1. WO 9949856 describes a class of peptido like inhibitors of ICAM that bind to LFA-1 and Mac-1.
    [9] Summary of the Invention
    [10] A first aspect of the invention includes a method for the treatment or prevention of inflammatory and immune cell-mediated diseases by administration of certain novel small molecules. These compounds inhibit the interaction of cell adhesion molecules, thereby specifically antagonizing the binding of human intracellular adhesion molecules (including ICAM-1, ICAM-2 and ICAM-3) to leucointegrin (specifically, CD18 / CD11a). By working. A second aspect of the present invention includes novel small molecules having the therapeutic activity described above. A third aspect of the present invention includes a method for preparing these novel compounds. The final aspect of the invention includes a pharmaceutical composition comprising the aforementioned compounds suitable for the prevention and treatment of inflammation and immune cell-mediated symptoms.
    [1] The present invention generally relates to a novel series of small molecules, their synthesis and their use in the treatment of inflammatory diseases.
    [11] In the first and broader embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention are included.
    [12]
    [13] In Formula I above,
    [14] A 1 is = N- or = C (H)-,
    [15] A 2 is = N-, = C (H)-or = C (R ')-[where R' is halogen, -CN, -Oalkyl, -CO 2 alkyl or -SO 2 alkyl, wherein an alkyl moiety Is 1 to 3 carbon atoms);
    [16] D is = N-, = C (R 1 )-, = C (H)-, = C (SO 2 R 1 )-, = C (S (O) R 1 )-, = C (C (O) R 1 )-, = C (C (O) H)-, = C (SR 1a )-, = C (OR 1a )-or = C (NHR 1a )-{where R 1 is (A) carbon number 1 Branched or straight chain alkyl of 6 to 6, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, wherein at least one hydrogen atom of an alkyl, alkenyl, cycloalkyl or cycloalkenyl group is independently Unsubstituted or (i) halogen, (ii) oxo, (iii) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, iso Oxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolyl, benzo [b] furanyl, benzo [b ] Thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinoli One or more hydrogen atoms of the aryl or heteroaryl group wherein the aryl or heteroaryl selected from the group consisting of nil, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, putridinyl and quinazolinyl Unsubstituted, (a) alkyl of 1 to 3 carbon atoms, (b) -COOH, (c) -SO 2 OH, (d) -PO (OH) 2 , (e) a group of the formula -COOR 8 , wherein R 8 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) a group of the formula -NR 9 R 10 , wherein R 9 and R 10 are each independently a hydrogen atom or a carbon atom Alkyl of 1 to 6, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or R 9 and R 10 together with a nitrogen atom between them constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring (G) a group of formula -CONR 11 R 12 , wherein R 11 and R 12 each independently represents a hydrogen atom, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or R 11 and R 12 together with a nitrogen atom therebetween form a saturated hydrocarbon bridge having 3 to 5 carbon atoms, Forms a click ring, one carbon atom of the hydrocarbon bridge may be unsubstituted or substituted with -O-, -S-, S (O)-, SO 2- , -NH- or -NMe-), ( h) a group of formula -OR 13 , wherein R 13 is a hydrogen atom or an alkyl or acyl group of 1 to 7 carbon atoms, (i) a group of formula -SR 14 , wherein R 14 is a hydrogen atom or 1 to Alkyl or acyl group of 7), (j) -CN, (k) Amidino groups wherein R 15 , R 16 and R 17 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 15 , R 16 and R 17 are nitrogen atom (s) between them Together to form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring), (l) halogen, (m) a group of the formula -NHCONHalkyl, wherein the alkyl moiety has 1 to 3 carbon atoms, Or (n) a group of formula -NHCOOalkyl, wherein the alkyl moiety has 1 to 3 carbon atoms, (iv) a group of formula -COOR 18 , wherein R 18 is a straight chain having 1 to 7 carbon atoms, or Branched alkyl or cycloalkyl having 3 to 6 carbon atoms, (v) -CN, (vi) a group of the formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently a hydrogen atom, 1 to 6 carbon atoms Alkyl or cycloalkyl having 3 to 6 carbon atoms, or R 19 and R 20 together with the nitrogen atom therebetween It forms a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge is unsubstituted, or -O-, -S-, S (O)-, SO 2- , -NH -Or-is substituted with -NMe-, (vii) a group of the formula -OR 21 wherein R 21 is a hydrogen atom or a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms, and at least one of an alkyl or acyl group The hydrogen atom is unsubstituted or substituted with a group independently selected from the group consisting of -OH-, -Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, -NH 2- , -NHMe and -NMe 2 (viii) a group of the formula -SR 22 , wherein R 22 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, and at least one hydrogen atom of the alkyl or acyl group is unsubstituted, or -OH, -O With alkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, -NH 2 , -NHMe and -NMe 2 And (ix) a group of formula -NR 23 R 24 wherein R 23 and R 24 are each independently (a) a hydrogen atom, (b) a straight chain having 1 to 7 carbon atoms Or branched alkyl or acyl, or cycloalkyl having 3 to 7 carbon atoms, wherein at least one hydrogen atom of the alkyl or acyl group is unsubstituted, or -OH, -Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, A group independently selected from the group consisting of -NH 2 , -NHMe and -NMe 2 ), (c) a group of formula-(CH 2 ) m COOH, wherein m is 0, 1 or 2, ( d) a group of the formula-(CH 2 ) n COOR 25 wherein n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms or (e) the formula-(CH 2 ) n Is a group of CONHR 25 , wherein n is 0, 1 or 2, and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms}, (x) Quaternary groups of wherein R 26 , R 27 and R 28 are each independently a branched or straight chain alkyl group having 1 to 7 carbon atoms and Q − is a pharmaceutically acceptable counter ion, (xi) imidazoli Nil, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, A 3-7 membered saturated or partially saturated heterocyclic group selected from N, O, C and S, including but not limited to benzodioxolyl, tetrahydrothiophenyl and sulfolanil, wherein the heterocyclic group It is unsubstituted or substituted, is substituted by mono- or multi-substituted) and (xii) a cycloalkyl group of 3 to 7 carbon atoms with oxo; is -R 100,
    [17] (B) branched or straight chain carboxylic acid groups having 3 to 6 carbon atoms,
    [18] (C) branched or straight chain phosphonic acid groups having 2 to 6 carbon atoms,
    [19] (D) branched or straight-chain sulfonic acid groups having 2 to 6 carbon atoms,
    [20] (E) chemical formula Amidino groups wherein r is 2, 3, 4, 5 or 6, R 29 , R 30 and R 31 are each independently a hydrogen atom or an alkyl having 1 to 3 carbons, and R 29 , R 30 and R Two of 31 together with the nitrogen atom (s) therebetween may further constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring),
    [21] (F) chemical formula Guanidino group of wherein s is 2, 3, 4, 5 or 6, R 32 , R 33 , R 34 and R 35 are each independently a hydrogen atom or alkyl of 1 to 3 carbon atoms, R 32 , Two of R 33 , R 34 and R 35 may further form a saturated hydrocarbon bridge of 3 to 5 carbon atoms with the nitrogen atom (s) therebetween to form a heterocyclic ring),
    [22] (G) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl , Triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimida Aryl or heteroaryl selected from the group consisting of zolyl, quinolinyl, isoquinolinyl, furinyl, quinolinyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Wherein one or more hydrogen atoms of aryl and heteroaryl are unsubstituted, or (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO 2 OH, (iv) -PO (OH) 2 , (v) a group of the formula -COOR 36 (wherein, R 36 is cycloalkyl having 1-5 carbon atoms straight or branched chain alkyl, or C 3 -C 5, Kill a), (vi) of formula -NR 37 R 38 group (wherein, R 37 and R 38 each independently represent a hydrogen atom, a C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or C 1 to 7 of the Or R 37 and R 38 together with the nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, (vii) a group of the formula -CONR 39 R 40 , wherein R 39 and R 40 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or R 39 and R 40 together with a nitrogen atom therebetween represent a saturated hydrocarbon bridge having 3 to 5 carbon atoms. To form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -S-, S (O)-, SO 2- , -NH- or -NMe- , (viii) a group of the formula -OR 41 (wherein, R 41 is a hydrogen atom, or carbon 1 to 7 is an alkyl or acyl group of a), (ix) a group of the formula -SR 42 (wherein, R 42 is an alkyl or acyl group of a hydrogen atom, or a carbon number of 1 to 7), (x) -CN, or ( xi) chemical formula Amidino groups wherein R 43 , R 44 and R 45 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, or two of R 43 , R 44 and R 45 are nitrogen atom (s) between them; And a saturated hydrocarbon bridge of 3 to 5 carbon atoms may be further configured to form a heterocyclic ring).
    [23] (H) a group of formula -NR 46 R 47 , wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted or polysubstituted phenyl, or R 100 wherein R 100 is defined above ),
    [24] (I) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl Saturated or unsaturated heterocyclic groups consisting of 3 to 7 ring atoms selected from N, O, C and S, including but not limited to, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanil Or a bicyclic heterocyclic group consisting of 8 to 11 atoms selected from N, O, C and S, wherein the heterocyclic group is unsubstituted or comprises: (i) oxo, (ii) -OR 101 where R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the alkyl group are unsubstituted, or -OH, -OR 110 , wherein R 110 is an alkyl residue having 1 to 6 carbon atoms Is substituted with -NH 2 , -NHMe or -NMe 2 ), (c ) Acyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the acyl group are unsubstituted, -OH, -OR 111 (where R 111 is an alkyl moiety having 1 to 6 carbon atoms), -NH 2 , -NHMe or -NMe 2 ), (d) -CONR 102 R 103 wherein R 102 and R 103 are each independently a hydrogen atom or alkyl of 1 to 7 carbon atoms, or R 102 and R 103 is a nitrogen atom between them Together to form a saturated hydrocarbon bridge having 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge is unsubstituted, -O-, -S-, S (O)-, SO 2- , -NH- or -NMe-, or (e) -COOR 104 (wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 where R 105 and R 106 are each independently (a) hydrogen atom, (b) cycloalkyl of 1 to 7 carbon atoms or straight-chain or branched alkyl having from 3 to 7 carbon atoms in the alkyl, (c) benzoyl, (d) benzyl Is (e) between the phenyl (wherein the phenyl ring is optionally substituted, -OR 112 (wherein R 112 is alkyl having a carbon number of 1 to 6), one is substituted or multi-substituted with a) or, R 105 and R 106 are those A saturated hydrocarbon bridge of 3 to 5 carbon atoms is formed together with the nitrogen atom to form a heterocyclic ring, and one carbon atom of the hydrocarbon bridge is unsubstituted or -O-, -S-, S (O)-, SO 2 -, -NH- or -NMe- is substituted; (iv) -COOR 107 (wherein R 107 is a hydrogen atom or straight or branched chain alkyl of 1 to 7 carbon atoms), (v) straight chain of 1 to 7 carbon atoms Or branched alkyl, alkenyl or alkynyl or alkynyl or cycloalkyl of 3 to 7 carbon atoms, wherein at least one hydrogen atom of the alkyl, alkenyl, alkynyl or cycloalkyl group is unsubstituted, or (a) oxo , (b) -OH, (c) -OR 113 wherein R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOC H 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 , wherein R 114 has 1 to 3 carbon atoms Alkyl, or a residue independently selected from the group consisting of 3 to 7 carbon atoms), (vi) an acyl having 1 to 7 carbon atoms, which may be linear, branched or cyclic, wherein at least one of the acyl groups The hydrogen atom is unsubstituted, or (a) -OH, (b) -OR 115 where R 115 is alkyl having 1 to 6 carbon atoms, (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 wherein R 116 is alkyl having 1 to 3 carbon atoms, (i) -CN, (j) halogen atom, (k) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl , Tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfone Heterocycles selected from the group consisting of ranyl and (l) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imida Zolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indah Zolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolinyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Substituted with residues independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of: (vii) -SO 2 R 108 wherein R 108 is (a) phenyl, naphthyl, indolyl, thiophenyl, Pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazole Reel, isoxazolyl, imidazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, Benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl , Aryl or heteroaryl selected from the group consisting of putridinyl and quinazolinyl, wherein the aryl or heteroaryl moiety is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 117 (where R 117 is hydrogen or alkyl having 1 to 6 carbon atoms), (b) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Thiomorpholinyl, thiazolidinyl, azefinyl, tetrahydro Heterocyclic groups selected from the group consisting of ranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl, and sulfolanil, wherein the heterocyclic group is unsubstituted, halogen atom, straight chain of 1 to 6 carbon atoms, or Branched alkyl and —OR 118 where R 118 is hydrogen or alkyl of 1 to 6 carbon atoms, or (c) straight or branched alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted, Halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 119 , wherein R 119 is substituted with one or more residues selected from the group consisting of hydrogen or alkyl of 1 to 6 carbon atoms), (viii) -COR 109 wherein R 109 is (a) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imida Sleepy, Sothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, Consisting of benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Aryl or heteroaryl selected from the group wherein the aryl or heteroaryl moiety is unsubstituted or substituted with a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 120 (wherein R 120 is hydrogen or alkyl of 1 to 6 carbon atoms And (b) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomor Polyyl, thiazolidinyl, azefinyl, Heterocyclic groups selected from the group consisting of trihydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein the heterocyclyl is unsubstituted, one or more halogen, 1 to 6 carbon atoms Is substituted with straight or branched chain alkyl or -OR 121 , wherein R 121 is hydrogen or alkyl having 1 to 6 carbon atoms, or (c) straight or branched chain alkyl having 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted. Or substituted with one or more residues selected from the group consisting of halogen atoms, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 122 , wherein R 122 is hydrogen or alkyl of 1 to 6 carbon atoms. ix) -CHO, (x) halogen atom and (xi) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxa Reel, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] Thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl And a moiety mono- or polysubstituted with a residue selected from the group consisting of aryl or heteroaryl selected from the group consisting of quinazolinyl},
    [25] (J) a halogen atom and
    [26] (K) -CN, R 1a is R 100 }
    [27] X is oxygen or sulfur atom,
    [28] R 3 is (A) a hydrogen atom or
    [29] (B) straight or branched chain alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 5 carbon atoms, wherein the alkyl or cycloalkyl group is unsubstituted or (i) a group of formula -OR 48 , wherein R 48 is hydrogen An atom or an alkyl or acyl group having 1 to 7 carbon atoms, or (ii) a group of the formula -NR 49 R 50 , wherein R 49 and R 50 are each independently a hydrogen atom, alkyl having 1 to 2 carbon atoms or 1 to C atoms Is acyl of 2), and
    [30] R 4 is of the formula — (CR 51 R 52 ) x (CR 53 R 54 ) y R 55 {where x is 0 or 1,
    [31] y is 0 or 1,
    [32] R 51 , R 52 and R 53 are each independently (A) a hydrogen atom, (B) a group of the formula -OR 56 , wherein R 56 is a hydrogen atom or alkyl or acyl having 1 to 7 carbon atoms, or (C ) Linear or branched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    [33] R 54 is (A) a group of formula R 57 , wherein R 57 is independently selected from the same class as R 1 or (B) a group of formula —OR 58 , wherein R 58 is from the same class as R 1 Is independently selected)
    [34] R 55 is phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxdiazolyl , Triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimida Aryl or heteroaryl selected from the group consisting of zolyl, quinolinyl, isoquinolinyl, furinyl, quinolinyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Wherein one or more hydrogen atoms of the aryl or heteroaryl group are unsubstituted or (A) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, Pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, Riazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl , Aryl or heteroaryl selected from the group consisting of quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Wherein one or more hydrogen atoms of aryl or heteroaryl are unsubstituted, or (i) straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted, halogen or Mono- or polysubstituted with oxo, (ii) a group of formula -COOR 60 , wherein R 60 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (iii) a formula -NR 61 group of R 62 (where , R 61 and R 62 each independently is an acyl of a hydrogen atom, a C 1 -C 6 alkyl with the alkyl or fluoroalkyl, C 3 -C 6 cycloalkyl or C 1 -C 7, R 61 and R 62 is a nitrogen therebetween Together with the atoms form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, (iv) a group of the formula -CONR 63 R 64 , wherein R 63 and R 64 are each independently a hydrogen atom, carbon number Alkyl of 1 to 6 or fluoroalkyl or cycloalkyl of 3 to 6 carbon atoms, or R 63 and R 64 together with a nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring ), (v) a group of formula -OR 65 , wherein R 65 is a hydrogen atom or an alkyl, fluoroalkyl, or acyl group having 1 to 7 carbon atoms, (vi) a group of formula -SR 66 , wherein R 66 Is a hydrogen atom or R 59 , independently substituted with an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, (vii) -CN, (viii) nitro or (ix) halogen) ,
    [35] (B) unsubstituted, monosubstituted or polysubstituted with a fluorine atom, further unsubstituted or monosubstituted with R 59 ,
    [36] (C) straight or branched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted or mono- or polysubstituted by halogen or oxo,
    [37] (D) a group of the formula -COOR 67 wherein R 67 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    [38] (E) a group of formula -NR 68 R 69 , wherein R 68 and R 69 each independently represent a hydrogen atom, alkyl having 1 to 6 carbon atoms or fluoroalkyl, cycloalkyl having 3 to 6 carbon atoms or 1 to 7 carbon atoms; Or R 68 and R 69 together with the nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one of R 68 and R 69 may further be a group R 59 have),
    [39] (F) a group of the formula -CONR 70 R 71 wherein R 70 and R 71 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms or fluoroalkyl or cycloalkyl having 3 to 6 carbon atoms, or R 70 and R 71 together with the nitrogen atoms between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one of R 70 and R 71 may further be a group R 59 ),
    [40] (G) a group of formula -COR 72 wherein R 72 is a hydrogen atom, straight or branched chain alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R 59 ,
    [41] (H) a group of the formula -OR 73 , wherein R 73 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group or R 59 with 1 to 7 carbon atoms,
    [42] (I) a group of the formula -SR 74 , wherein R 74 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group or R 59 having 1 to 7 carbon atoms,
    [43] (J) -CN,
    [44] (K) nitro or
    [45] (L) is independently substituted with halogen]
    [46] R 5 is Cl or trifluoromethyl,
    [47] Z is = N- or = C (R 6 )-, where R 6 is hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl,
    [48] R 7 is hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, -CN, nitro or trifluoromethyl and when Z is = N- or = C (H)-, R 7 is chlorine, trifluoro Methyl, -CN or nitro.
    [49] The term "pharmaceutically acceptable counter ions" as defined herein is generally considered to be all pharmaceutically acceptable counter ions to those skilled in the pharmaceutical arts. For a discussion of pharmaceutically acceptable counter ions, see Stephen M. Bergle, Lyle D. Bighley and Donald C. Monkhouse, "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 66 (1977), 1-19. You can quote. By way of non-limiting example, chlorine, bromine, acetate and sulfate ions are pharmaceutically acceptable counter ions.
    [50] Preferred compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein A 1 is = N- or = C (H)-,
    [51] A 2 is = N-, = C (H)-or = C (R ')-[where R' is halogen, -CN, -Oalkyl, -CO 2 alkyl or -SO 2 alkyl, wherein the alkyl moiety Is 1 to 3 carbon atoms);
    [52] D = N-, = C (R 1 )-, = C (H)-, = C (SO 2 R 1 )-, = C (S (O) R 1 )-, = C (C (O) R 1 )-, = C (C (O) H)-, = C (SR 1a )-, = C (OR 1a )-or = C (NHR 1a )-{where R 1 is (A) carbon number 1 Straight or branched chain alkyl of 6 to 6, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, wherein at least one hydrogen atom of the alkyl, alkenyl, cycloalkyl or cycloalkenyl group is unsubstituted Or (i) halogen, (ii) oxo, (iii) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl , Imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolinyl, benzo [b] furanyl, benzo [b] thio Phenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolylyl, isoquinolinyl, furinyl, quinolizinyl, synol Aryl or heteroaryl selected from the group consisting of nil, phthalininyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl, wherein at least one hydrogen atom of the aryl or heteroaryl group is unsubstituted, or (a ) Alkyl of 1 to 3 carbon atoms, (b) -COOH, (c) -SO 2 OH, (d) -PO (OH) 2 , (e) a group of the formula -COOR 8 , wherein R 8 is 1 to Linear or branched alkyl of 5 or cycloalkyl of 3 to 5 carbon atoms, (f) a group of formula -NR 9 R 10 , wherein R 9 and R 10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, Cycloalkyl having 3 to 6 carbon atoms or acyl having 1 to 7 carbon atoms, or R 9 and R 10 together with the nitrogen atom therebetween form a saturated hydrocarbon bridge having 3 to 5 carbon atoms to form a heterocyclic ring), ( g) a group of the formula -CONR 11 R 12 (wherein, R 11 and R 12 are each independently It wishes chair, or cycloalkyl alkyl or a carbon number of 1 to 6 carbon atoms of 3 to 6, R 11 and R 12 form a heterocyclic ring together with the nitrogen atom between them configure a saturated hydrocarbon bridge of 3 to 5 carbon atoms, and , One carbon atom of a hydrocarbon bridge is unsubstituted or substituted with -O-, -S-, S (O)-, -SO 2- , -NH- or -NMe-), (h) formula -OR 13 Wherein R 13 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, (i) a group of the formula -SR 14 , wherein R 14 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms (J) -CN, (k) Amidino groups wherein R 15 , R 16 and R 17 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 15 , R 16 and R 17 are nitrogen atom (s) between them Together to form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to further form a heterocyclic ring), (l) halogen, (m) a group of the formula -NHCONHalkyl, wherein the alkyl moiety has 1 to 3 carbon atoms Or (n) independently substituted with a group of the formula -NHCOOalkyl, wherein the alkyl moiety has 1 to 3 carbon atoms, (iv) a group of the formula -COOR 18 , wherein R 18 is a straight chain having 1 to 7 carbon atoms Or branched alkyl or cycloalkyl having 3 to 6 carbon atoms, (v) -CN, (vi) a group of the formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently a hydrogen atom, 1 to 6 carbon atoms Is alkyl or cycloalkyl having 3 to 6 carbon atoms, or R 19 and R 20 are Together with the small atoms, a saturated hydrocarbon bridge of 3 to 5 carbon atoms is formed to form a heterocyclic ring, wherein one carbon atom of the hydrocarbon bridge is unsubstituted or -O-, -S-, S (O)-, SO 2 , -NH- or -NMe-, (vii) a group of formula -OR 21 wherein R 21 is a hydrogen atom or a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms, and is an alkyl or acyl group At least one hydrogen atom of is unsubstituted or substituted with a group independently selected from the group consisting of -OH, -Oalkyl, wherein alkyl has 1 to 6 carbon atoms, -NH 2 , -NHMe and -NMe 2 (viii) a group of the formula -SR 22 , wherein R 22 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, and at least one hydrogen atom of the alkyl or acyl group is unsubstituted, or -OH, -O Alkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, -NH 2 , -NHMe and -Substituted with a group independently selected from the group consisting of -NMe 2 , (ix) a group of the formula -NR 23 R 24 , wherein R 23 and R 24 are each independently (a) a hydrogen atom, (b) carbon number 1 Straight or branched chain alkyl or acyl or cycloalkyl having 3 to 7 carbon atoms, and at least one hydrogen atom of the alkyl or acyl group is unsubstituted or -OH, -Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms. ), A group of -NH 2 , -NHMe and -NMe 2 , substituted with a group independently selected from the group consisting of (c) the formula-(CH 2 ) m COOH, wherein m is 0, 1 or 2 (d) a group of formula-(CH 2 ) n COOR 25 , wherein n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms, or (e) a formula-(CH 2 ) n CONHR 25 group (wherein, n is 0, 1 or 2, R 25 is a linear or branched alkyl) group having 1 to 6), (x) Chemistry Expression Quaternary groups of wherein R 26 , R 27 and R 28 are each independently a straight or branched chain alkyl group having 1 to 7 carbon atoms and Q − is a pharmaceutically acceptable counter ion, (xi) imidazoli Nil, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, Saturated or partially unsaturated heterocyclic groups consisting of 3 to 7 ring atoms selected from N, O, C and S, including but not limited to benzodioxolyl, tetrahydrothiophenyl and sulfonyl cyclic group is unsubstituted or substituted, it is substituted by mono- or multi-substituted in the cycloalkyl is) and (xii) an alkyl having from 3 to 7 carbon atoms with oxo; is -R 100a,
    [53] (B) straight or branched carboxylic acid group having 3 to 6 carbon atoms,
    [54] (C) a straight or branched chain phosphonic acid group having 2 to 6 carbon atoms,
    [55] (D) straight or branched chain sulfonic acid group of 2 to 6 carbon atoms,
    [56] (E) chemical formula Amidino groups wherein r is 2, 3, 4, 5 or 6, R 29 , R 30 and R 31 are each independently a hydrogen atom or an alkyl having 1 to 3 carbon atoms, and R 29 , R 30 and R Two of 31 together with the nitrogen atom (s) therebetween may further constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring),
    [57] (F) chemical formula Guanidino group of wherein s is 2, 3, 4, 5 or 6, R 32 , R 33 , R 34 and R 35 are each independently a hydrogen atom or alkyl of 1 to 3 carbon atoms, R 32 , Two of R 33 , R 34 and R 35 together with the nitrogen atom (s) therebetween may further form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring) ,
    [58] (G) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl , Triazolyl, tridiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimida Aryl or heteroaryl selected from the group consisting of zolyl, quinolinyl, isoquinolinyl, furinyl, quinolinyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Wherein the aryl or heteroaryl group is unsubstituted or comprises (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO 2 OH, (iv) -PO (OH) 2 , (v) groups of formula -COOR 36 (wherein, R 36 is a cycloalkyl group having 1 to 5 carbon atoms or straight or branched chain alkyl of 3 to 5 carbon atoms), (vi) A group of learning -NR 37 R 38 (wherein, R 37 and R 38 are each independently a hydrogen atom or an acyl, an alkyl group having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or 1 to 7 carbon atoms of a, R 37, and R 38 together with the nitrogen atoms between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, (vii) a group of the formula -CONR 39 R 40 , wherein R 39 and R 40 are each Independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or R 39 and R 40 together with a nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring; One carbon atom of the hydrocarbon bridge is unsubstituted or substituted with -O-, -S-, S (O)-, SO 2- , -NH- or -NMe-), (viii) formula -OR a group of 41 (wherein, R 41 is a hydrogen atom or 1 to 7 carbon atoms A keel or an acyl group), (ix) a group of the formula -SR 42 (wherein, R 42 is an alkyl or acyl group, a hydrogen atom or a C 1 -C 7), (x) -CN, or (xi) the formula Amidino groups wherein R 43 , R 44 and R 45 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 43 , R 44 and R 45 are nitrogen atom (s) between them; And a saturated hydrocarbon bridge of 3 to 5 carbon atoms may be further configured to form a heterocyclic ring).
    [59] (H) a group of the formula -NR 46 R 47 wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted or polysubstituted phenyl, or R 100a , wherein R 100a is defined above ),
    [60] (I) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl Saturated or unsaturated heterocyclic groups consisting of 3 to 7 ring atoms selected from N, O, C and S, including but not limited to, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanil Or a bicyclic heterocyclic group consisting of 8 to 11 atoms selected from N, O, C and S, wherein the heterocyclic group is unsubstituted, or (i) oxo, (ii) -OR 101 , wherein R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein the hydrogen atom of the alkyl group is unsubstituted, or -OH, -OR 110 , wherein R 110 is an alkyl residue having 1 to 6 carbon atoms ), it is replaced by -NH 2, -NHMe or -NMe 2), (c) tan 1 to an acyl (wherein the hydrogen atoms of the acyl group of 7 is optionally substituted, -OH, -OR 111 (wherein R 111 is an alkyl moiety having 1 to 6), -NH 2, -NHMe or -NMe 2 ), (d) -CONR 102 R 103 , wherein R 102 and R 103 are each independently a hydrogen atom or an alkyl having 1 to 7 carbon atoms, or R 102 and R 103 together with a nitrogen atom therebetween; It forms a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge is unsubstituted, or -O-, -S-, S (O)-, SO 2- , -NH -Or -NMe-) or (e) -COOR 104 (wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 where R 105 and R 106 are Each independently (a) a hydrogen atom, (b) straight or branched chain alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, (c) benzoyl, (d) benzyl or (e) phenyl Wherein the phenyl ring is unsubstituted or mono- or polysubstituted with -OR 112 (where R 112 is alkyl having 1 to 6 carbon atoms), or R 105 and R 106 are carbon atoms together with the nitrogen atom between them It forms a saturated hydrocarbon bridge of 3 to 5 to form a heterocyclic ring, wherein one carbon atom of the hydrocarbon bridge is unsubstituted or -O-, -S-, S (O)-, -SO 2- , -NH -Or-is substituted with -NMe-, (iv) -COOR 107 (wherein R 107 is a hydrogen atom or straight or branched chain alkyl of 1 to 7 carbon atoms), (v) straight or branched alkyl of 1 to 7 carbon atoms , Alkenyl or alkynyl having 2 to 7 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, wherein at least one hydrogen atom of alkyl, alkenyl, alkynyl or cycloalkyl is unsubstituted, or (a) oxo, (b ) -OH, (c) -OR 113 wherein R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 , wherein R 114 is alkyl having 1 to 3 carbon atoms or cycloalkyl having 3 to 7 carbon atoms (Vi) acyl having 1 to 7 carbon atoms, which may be linear, branched or cyclic, wherein at least one hydrogen atom of the acyl group is unsubstituted, or (a) -OH, (b) -OR 115 , wherein R 115 is alkyl having 1 to 6 carbon atoms, (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 wherein R 116 is alkyl having 1 to 3 carbon atoms, (i) -CN, (j) halogen atom, (k) imidazolinyl, imida Zolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, Tetrahydrothiophenyl and sulfolanil Heterocycles selected from the relevant classes and (l) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, Isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, Consisting of benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Substituted with residues independently selected from the group consisting of aryl or heteroaryl selected from the class), (vii) -SO 2 R 108 , wherein R 108 is (a) phenyl, naphthyl, indolyl, thiophenyl, pyridyl , Pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxa Reel, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] Thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl And aryl or heteroaryl selected from the group consisting of quinazolinyl, wherein the aryl or heteroaryl moiety is unsubstituted, halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 117 where R 117 is hydrogen or Is substituted with one or more residues selected from the group consisting of alkyl having 1 to 6 carbon atoms), (b) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholinyl, thiomorpholinyl, thiazole Heterocyclic groups selected from the group consisting of diyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanil, wherein the heterocyclic group is unsubstituted or halogen An atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 118 where R 118 is hydrogen or alkyl of 1 to 6 carbon atoms, or is substituted with one or more residues selected from the group consisting of Straight or branched alkyl of 7 wherein the alkyl moiety is unsubstituted or consists of a halogen atom, straight or branched alkyl of 1 to 6 carbon atoms and -OR 119 where R 119 is hydrogen or alkyl of 1 to 6 carbon atoms is substituted with one or more moieties selected from the class) is a), (viii) -COR 109 (wherein, R 109 is (a) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, blood Midinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, Indolizinyl, isoindolinyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, Aryl or heteroaryl selected from the group consisting of cinnalinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl, wherein the aryl or heteroaryl moiety is unsubstituted, halogen atom, carbon number 1 Straight chain or branched chain alkyl of 6 to 6 and -OR 120 (wherein R 120 is substituted with one or more residues selected from the group consisting of hydrogen or alkyl of 1 to 6 carbon atoms), (b) imidazolinyl, imida Zolidinyl, pyrrolinyl, pyrrolidi , Consisting of piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanilyl Heterocyclic groups selected from the class wherein heterocyclyl is unsubstituted or substituted with one or more halogens, straight or branched chain alkyl of 1 to 6 carbon atoms, or -OR 121 , wherein R 121 is hydrogen or alkyl of 1 to 6 carbon atoms (C) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted or halogen, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 122 where R 122 is hydrogen or (Ix) -CHO, (x) a halogen atom and (xi) phenyl, naphthyl, indolyl, thiophenyl, p) Dill, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, Triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinone Mono- or polysubstituted by a moiety independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of nolinyl, synnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl ],
    [61] (J) a halogen atom and
    [62] (K) -CN, R 1a is R 100a },
    [63] X is oxygen or sulfur atom,
    [64] R 3 is (A) a hydrogen atom or
    [65] (B) straight or branched chain alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, wherein the alkyl and cycloalkyl groups are unsubstituted, or (i) a group of formula R 48 , wherein R 48 is a hydrogen atom or Alkyl or acyl group of 1 to 7 carbon atoms or (ii) a group of formula -NR 49 R 50 , wherein R 49 and R 50 are each independently a hydrogen atom, alkyl of 1 to 2 carbon atoms or of 1 to 2 carbon atoms You know,
    [66] R 4 is a group of the formula —CH 2 R 55 wherein R 55 is phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, iso Oxazolyl, imidazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolyl, benzo [b] furanyl, benzo [b ] Thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnaolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, puteri Aryl or heteroaryl selected from the group consisting of diyl and quinazolinyl, wherein at least one hydrogen atom of the aryl or heteroaryl group is unsubstituted or (A) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyri Midinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxoxazolyl, already Zolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indah Zolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolinyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Aryl or heteroaryl selected from the class consisting of: at least one hydrogen atom of aryl or heteroaryl is unsubstituted, or (i) straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein Or cycloalkyl is unsubstituted or mono- or polysubstituted by halogen or oxo, (ii) a group of the formula -COOR 60 , wherein R 60 is straight or branched alkyl of 1 to 5 carbon atoms or of 3 to 5 carbon atoms Cycloal A), (iii) a group of the formula -NR 61 R 62 (wherein, R 61 and R 62 each independently represent a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms alkyl, cycloalkyl or C 1 of 3 to 6 carbon atoms Or R 61 and R 62 together with the nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring), (iv) a group of the formula -CONR 63 R 64 Wherein R 63 and R 64 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms or fluoroalkyl or cycloalkyl having 3 to 6 carbon atoms, or R 63 and R 64 together with a nitrogen atom therebetween To form a saturated hydrocarbon bridge of from 5 to 5 to form a heterocyclic ring, (v) a group of the formula -OR 65 , wherein R 65 is a hydrogen atom or an alkyl, fluoroalkyl or acyl group having 1 to 7 carbon atoms ), (vi) chemical formula- R which is a group of SR 66 , wherein R 66 is a hydrogen atom or an alkyl, fluoroalkyl or acyl group having 1 to 7 carbon atoms, (vii) -CN, (viii) nitro or (ix) substituted by halogen) 59a ,
    [67] (B) unsubstituted, monosubstituted or polysubstituted with a fluorine atom, unsubstituted or further monosubstituted with R 59a ,
    [68] (C) straight or branched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted or mono- or polysubstituted by halogen or oxo,
    [69] (D) a group of the formula -COOR 67 wherein R 67 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    [70] (E) a group of formula -NR 68 R 69 , wherein R 68 and R 69 each independently represent a hydrogen atom, alkyl having 1 to 6 carbon atoms or fluoroalkyl, cycloalkyl having 3 to 6 carbon atoms or 1 to 7 carbon atoms; Or ac 68 or R 69 together with the nitrogen atoms between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one of R 68 and R 69 may further be R 59a ),
    [71] (F) a group of the formula -CONR 70 R 71 wherein R 70 and R 71 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms or fluoroalkyl or cycloalkyl having 3 to 6 carbon atoms, or R 70 and R 71 together with the nitrogen atoms between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one of R 70 and R 71 may further be R 59a ),
    [72] (G) a group of the formula -COR 72 wherein R 72 is a hydrogen atom, straight or branched chain alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R 59a ,
    [73] (H) a group of the formula -OR 73 wherein R 73 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group or R 59a having 1 to 7 carbon atoms,
    [74] (I) a group of formula -SR 74 , wherein R 74 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group or R 59a having 1 to 7 carbon atoms,
    [75] (J) -CN,
    [76] (K) nitro or
    [77] (L) is independently substituted with halogen]
    [78] R 5 is Cl or trifluoromethyl,
    [79] Z is = N- or = C (R 6 )-, wherein R 6 is hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl,
    [80] R 7 is hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, -CN, nitro or trifluoromethyl and when Z is = N- or = C (H)-, R 7 is chlorine, trifluoro Methyl, -CN or nitro.
    [81] Preferred compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein A 1 is = N- or = C (H)-,
    [82] A 2 is = N- or = C (H)-,
    [83] D is = N-, = C (R 1 )-, = C (H)-, = C (SO 2 R 1 )-, = C (C (O) H)-or = C (C (O) R 1 )-{wherein R 1 is (A) straight or branched chain alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, wherein alkyl, alkenyl, cyclo At least one hydrogen atom of the alkyl or cycloalkenyl group is unsubstituted, (i) oxo, (ii) phenyl, wherein one hydrogen atom of the phenyl group is unsubstituted, or (a) alkyl having 1 to 3 carbon atoms, (b) -COOH, (c) -SO 2 OH, (d) -PO (OH) 2 , (e) a group of the formula -COOR 8 , wherein R 8 is straight or branched chain alkyl or carbon number of 1 to 5 carbon atoms Cycloalkyl of 3 to 5), (f) a group of formula -NR 9 R 10 , wherein R 9 and R 10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or Acyl having 1 to 7 carbon atoms, or R 9 and R 10 are these Together with the nitrogen atom in between form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, (g) a group of the formula -CONR 11 R 12 , wherein R 11 and R 12 are each independently Or a hydrogen atom, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or R 11 and R 12 together with a nitrogen atom therebetween form a saturated hydrocarbon bridge having 3 to 5 carbon atoms to form a heterocyclic ring. Wherein one carbon atom of the saturated hydrocarbon bridge is unsubstituted or substituted with -O-, -NH- or -NMe-, (h) a group of the formula -OR 13 , wherein R 13 is a hydrogen atom or 1 carbon atom To alkyl or acyl of (7) to (7), (i) a group of formula -SR 14 , wherein R 14 is a hydrogen atom or an alkyl or acyl of 1 to 7 carbon atoms, (j) -CN or (k) Amidino groups wherein R 15 , R 16 and R 17 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 15 , R 16 and R 17 are nitrogen atom (s) between them And a saturated hydrocarbon bridge of 3 to 5 carbon atoms may be further configured to form a heterocyclic ring), (l) a group of the formula -NHCONHalkyl, wherein the alkyl moiety has 1 to 3 carbon atoms, or ( m) a group of the formula -NHCOOalkyl, wherein the alkyl moiety is substituted with a group of 1 to 3 carbon atoms, (iii) a group of the formula -COOR 18 , wherein R 18 is a straight or branched chain of 1 to 7 carbon atoms Alkyl or cycloalkyl of 3 to 6 carbon atoms, (iv) a group of the formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or of 3 to 6 carbon atoms Cycloalkyl, or R 19 and R 20 together with the nitrogen atom between them Form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-), (v) A group of -OR 21 wherein R 21 is a hydrogen atom or a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms, and at least one hydrogen atom of the alkyl or acyl group is unsubstituted, or -OH-, -Oalkyl ( Wherein the alkyl moiety is substituted with a group independently selected from the group consisting of 1 to 6 carbon atoms, -NH 2 , -NHMe and -NMe 2 ), (vi) a group of formula -NR 23 R 24 , wherein R 23 and R 24 each independently represent (a) a hydrogen atom, (b) a straight or branched chain alkyl or acyl having 1 to 7 carbon atoms or an acyl or a cycloalkyl having 3 to 7 carbon atoms, wherein at least one hydrogen atom of the alkyl or acyl group is substituted Or -OH, -Oalkyl Standing, the alkyl moiety is 1 to 6 carbon atoms), is replaced by a group independently selected from the class consisting of -NH 2, -NHMe and -NMe 2), (c) the formula - group of (CH 2) m COOH (wherein , m is 0, 1 or 2, (d) a group of the formula-(CH 2 ) n COOR 25 wherein n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms ) Or (e) a group of the formula-(CH 2 ) n CONHR 25 , wherein n is 0, 1 or 2 and R 25 is a straight or branched chain alkyl of 1 to 6 carbon atoms, (vii) Chemical formula Quaternary groups of wherein R 26 , R 27 and R 28 are each independently a straight or branched chain alkyl group having 1 to 7 carbon atoms and Q − is a pharmaceutically acceptable counter ion; or (viii) 3 to C carbon atoms Independently substituted with a cycloalkyl group of 7] -R 100b ,
    [84] (B) straight or branched carboxylic acid group having 3 to 6 carbon atoms,
    [85] (C) a straight or branched chain phosphonic acid group having 2 to 6 carbon atoms,
    [86] (D) straight or branched chain sulfonic acid group of 2 to 6 carbon atoms,
    [87] (E) chemical formula Amidino groups wherein r is 2, 3, 4, 5 or 6, R 29 , R 30 and R 31 are each independently a hydrogen atom or an alkyl having 1 to 3 carbon atoms, and R 29 , R 30 and R Two of 31 together with the nitrogen atom (s) therebetween may further constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring),
    [88] (F) chemical formula Guanidino group of wherein s is 2, 3, 4, 5 or 6, R 32 , R 33 , R 34 and R 35 are each independently a hydrogen atom or alkyl of 1 to 3 carbon atoms, R 32 , Two of R 33 , R 34 and R 35 may further form a saturated hydrocarbon bridge of 3 to 5 carbon atoms with the nitrogen atom (s) therebetween to form a heterocyclic ring),
    [89] (G) phenyl [where at least one hydrogen atom of the phenyl group is unsubstituted or (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO 2 OH, (iv) -PO (OH ) 2 , (v) a group of formula -COOR 36 , wherein R 36 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a group of formula -NR 37 R 38 ( Wherein R 37 and R 38 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or acyl having 1 to 7 carbon atoms, or R 37 and R 38 together with the nitrogen atom therebetween; A group of saturated hydrocarbon bridges having 3 to 5 carbon atoms to form a heterocyclic ring, (vii) a group of the formula -CONR 39 R 40 , wherein R 39 and R 40 are each independently a hydrogen atom, 1 carbon atom to 6, or an alkyl or cycloalkyl having 3 to 6, R 39 and R 40 is a nitrogen atom between them Form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-), (viii) A group of formula -OR 41 , wherein R 41 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, (ix) a group of formula -SR 42 , wherein R 42 is a hydrogen atom or of 1 to 7 carbon atoms Alkyl or acyl group), (x) -CN or (xi) Amidino groups wherein R 43 , R 44 and R 45 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 43 , R 44 and R 45 are nitrogen atom (s) between them; Together with a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring);
    [90] (H) a group of formula -NR 46 R 47 wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted or polysubstituted phenyl, or R 100b , wherein R 100b is defined above ),
    [91] (I) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl , A saturated or unsaturated heterocyclic group selected from the group consisting of tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanil, wherein the heterocyclic group is unsubstituted, or (i) oxo, (ii) -OR 101 {where R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the alkyl are unsubstituted, or -OH, -OR 110 , wherein R 110 represents Is substituted with 1 to 6 alkyl residues), -NH 2 , -NHMe or -NMe 2 ), (c) acyl having 1 to 7 carbon atoms (wherein all hydrogen atoms of acyl are unsubstituted or -OH,- OR 111 , wherein R 111 is alkyl of 1 to 6 carbon atoms, is substituted with -NH 2 , -NHMe or -NMe 2 ), (D) -CONR 102 R 103 ( wherein, R 102 and R 103 are each independently a hydrogen atom or an alkyl group having 1 to 7, R 102 and R 103 is 3 to 5 carbon atoms together with the nitrogen atom between them To form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-} or (e) -COOR 104 , R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 wherein R 105 and R 106 are each independently (a) a hydrogen atom, (b) a straight chain having 1 to 7 carbon atoms Or branched alkyl or cycloalkyl having 3 to 7 carbon atoms, (c) benzoyl, (d) benzyl or (e) phenyl, wherein the phenyl ring is unsubstituted or -OR 112 wherein R 112 is alkyl having 1 to 6 carbon atoms a) one is a substituted or multi-substituted with a) or, R 105 and R 106 has a carbon number of 3 together with the nitrogen atom between them To form a heterocyclic ring, wherein one carbon atom of the hydrocarbon bridge is unsubstituted or substituted with -O-, -NH- or -NMe-), (iv) COOR 107 wherein R 107 is a hydrogen atom or straight or branched chain alkyl of 1 to 7 carbon atoms, (v) straight or branched chain alkyl of 1 to 7 carbon atoms, alkenyl or alkynyl of 2 to 7 carbon atoms, or 3 carbon atoms At least one hydrogen atom of a cycloalkyl group of about 7 to which alkyl, alkenyl, alkynyl or cycloalkyl group is unsubstituted or (a) oxo, (b) -OH, (c) -OR 113 where R 113 is alkyl having 1 to 6 carbon atoms), (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i)- CO 2 R 114 , wherein R 114 is substituted with a residue independently selected from the group consisting of alkyl having 1 to 3 carbon atoms or cycloalkyl having 3 to 7 carbon atoms ), (vi) acyl having 1 to 7 carbon atoms, which may be linear, branched or cyclic, wherein at least one hydrogen atom of the acyl group is unsubstituted or (a) -OH, (b) -OR 115 (wherein R 115 is alkyl having 1 to 6 carbon atoms), (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 (wherein R 116 is alkyl having 1 to 3 carbon atoms), (i) -CN, (j) halogen atom, (k) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, pipe From the class consisting of lidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azefinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanil Heteroaryl selected and (l) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl , Oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, Aryl selected from the class consisting of benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cynolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, putridinyl and quinazolinyl Or a residue independently selected from the group consisting of heteroaryl), (vii) -SO 2 R 108 wherein R 108 is (a) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl , Furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indoli Genyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzti A group consisting of azolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Aryl or heteroaryl selected from: wherein the aryl or heteroaryl moiety is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 117 , wherein R 117 is hydrogen or alkyl of 1 to 6 carbon atoms (B) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholi Heterocyclic groups selected from the group consisting of nil, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanil, wherein Hete The cyclic group is optionally substituted, a halogen atom, a straight or branched chain alkyl, and -OR 118 group of 1 to 6 carbon atoms substituted with one or more moieties selected from the class consisting of (wherein, R 118 is hydrogen or alkyl having 1 to 6 carbon atoms) Or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted or is a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 119 where R 119 is hydrogen or carbon atoms Is substituted with one or more residues selected from the group consisting of 1-6 alkyl), (viii) -COR 109 wherein R 109 is (a) phenyl, naphthyl, indolyl, thiophenyl, pyridyl , Pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, tria Genil, Indoridge Isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnaolinyl , Aryl or heteroaryl selected from the group consisting of phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl, and quinazolinyl, wherein the aryl or heteroaryl moiety is unsubstituted, halogen atom, of 1 to 6 carbon atoms Straight or branched chain alkyl and -OR 120 , wherein R 120 is hydrogen or substituted with one or more residues selected from the group consisting of alkyl having 1 to 6 carbon atoms, (b) imidazolinyl, imidazolidinyl, Pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepineyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothio Phenyl and sulfolanil Heterocyclic groups selected from the class of the foregoing, wherein the heterocyclic groups are unsubstituted or include one or more halogen, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 121 , wherein R 121 is hydrogen or 1 to 6 carbon atoms Or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted or is a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 122 , wherein R 112 is hydrogen or alkyl having 1 to 6 carbon atoms); and (ix) -CHO, (x) halogen atom and (xi) phenyl, naphthyl, indolyl , Thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyrida Genil, pyrazinyl, t Arginyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinine Mono- or polysubstituted by a moiety independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of nolinyl, synnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl ],
    [92] (J) a halogen atom and
    [93] (K) -CN is selected from the group consisting of
    [94] X is an oxygen atom,
    [95] R 3 is straight or branched alkyl having 1 to 3 carbon atoms,
    [96] R 4 is of the formula —CH 2 R 55 wherein R 55 is aryl or heteroaryl selected from the group consisting of phenyl, pyridyl and pyrimidinyl, wherein at least one hydrogen atom of the aryl or heteroaryl group is unsubstituted, (A) aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl and thiazolyl, wherein aryl or heteroaryl is unsubstituted or (i) carbon number Straight or branched chain alkyl of 1 to 6 or cycloalkyl of 3 to 6 carbon atoms, wherein the alkyl or cycloalkyl group is unsubstituted or mono- or polysubstituted by halogen or oxo, (ii) -CN, (iii) R 59b , nitro or (iv) substituted by halogen),
    [97] (B) methyl, unsubstituted, trisubstituted with fluorine atoms, unsubstituted or monosubstituted with R 59b ,
    [98] (C) straight or branched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted or monosubstituted with halogen or oxo,
    [99] (D) a group of the formula -COOR 67 wherein R 67 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    [100] (E) a group of formula -COR 72 wherein R 72 is a halogen atom, straight or branched chain alkyl of 1 to 5 carbon atoms, cycloalkyl or R 59b of 3 to 5 carbon atoms,
    [101] (F) a group of formula -OR 73 wherein R 73 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group or R 59b having 1 to 7 carbon atoms,
    [102] (G) -CN,
    [103] (H) nitro or
    [104] (I) is independently substituted with halogen]
    [105] R 5 is Cl,
    [106] Z is = C (H)-,
    [107] R 7 is Cl.
    [108] Preferred compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein A 1 is = N-,
    [109] A 2 is = C (H)-,
    [110] D is = C (R 1 )-, = C (H)-, = C (SO 2 R 1 )-, = C (C (O) H)-or = C (C (O) R 1 )-{ Wherein R 1 is (A) straight or branched chain alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, wherein alkyl, alkenyl, cycloalkyl or cycloal At least one hydrogen atom of the kenyl group is unsubstituted, (i) oxo, (ii) phenyl, wherein one hydrogen atom of the phenyl group is unsubstituted, (a) alkyl of 1 to 3 carbon atoms, (b)- COOH, (c) -SO 2 OH, (d) -PO (OH) 2 , (e) a group of the formula -COOR 8 , wherein R 8 is straight or branched alkyl of 1 to 5 carbon atoms or of 3 to 5 carbon atoms Cycloalkyl), (f) a group of the formula -NR 9 R 10 , wherein R 9 and R 10 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or 1 to 7 carbon atoms of or acyl, R 9 and R 10 are those used In the form a heterocyclic ring by constructing a saturated hydrocarbon bridge of 3 to 5 carbon atoms together with the nitrogen atom), (g) a group of the formula -CONR 11 R 12 (wherein, R 11 and R 12 are each independently a hydrogen atom , Alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or R 11 and R 12 together with a nitrogen atom therebetween form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, hydrocarbon One carbon atom of the bridge is unsubstituted or substituted with -O-, -NH- or -NMe-, (h) a group of the formula -OR 13 , wherein R 13 is a hydrogen atom or an alkyl having 1 to 7 carbon atoms Or an acyl group), (i) a group of the formula -SR 14 , wherein R 14 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, (j) -CN, (k) Amidino groups wherein R 15 , R 16 and R 17 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 15 , R 16 and R 17 are nitrogen atom (s) between them And a saturated hydrocarbon bridge of 3 to 5 carbon atoms may be further configured to form a heterocyclic ring), (l) a group of the formula -NHCONHalkyl, wherein the alkyl moiety has 1 to 3 carbon atoms, or (m A group of formula -NHCOOalkyl, wherein the alkyl moiety has from 1 to 3 carbon atoms, and (iii) a group of formula -COOR 18 , wherein R 18 is straight or branched chain alkyl of 1 to 7 carbon atoms or Cycloalkyl of 3 to 6), (iv) a group of formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms , R 19 and R 20 are carbon atoms together with the nitrogen atom between them. To form a saturated hydrocarbon bridge of 3 to 5 to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-), (v) A group of OR 21 , wherein R 21 is a hydrogen atom or a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms, and at least one hydrogen atom of the alkyl or acyl group is unsubstituted, or -OH, -Oalkyl, wherein An alkyl moiety is substituted with a group independently selected from the group consisting of 1 to 6 carbon atoms, -NH 2 , -NHMe and -NMe 2 ), (vi) a group of formula -NR 23 R 24 , wherein R 23 and R 24 is independently (a) hydrogen atom, (b) cycloalkyl, (wherein one or more hydrogen atoms of the alkyl or acyl group of 1 to 7 carbon atoms with linear or branched alkyl or acyl, or 3 to 7 carbon atoms in the unsubstituted , -OH, -Oalkyl, where Moiety is a C 1 -C 6), -NH 2, is replaced by a group independently selected from the class consisting of -NHMe and -NMe 2), (c) the formula - (CH 2) m COOH group (where, m is the 0, 1 or 2), (d) a group of the formula-(CH 2 ) n COOR 25 , wherein n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms, or ( e) a group of formula-(CH 2 ) n CONHR 25 where n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms, and (vii) Quaternary groups of wherein R 26 , R 27 and R 28 are each independently a linear or branched alkyl group having 1 to 7 carbon atoms and Q − is a pharmaceutically acceptable counter ion; or (viii) 3 to C carbon atoms Independently substituted with a cycloalkyl group of 7] -R 100c ,
    [111] (B) straight or branched carboxylic acid group having 3 to 6 carbon atoms,
    [112] (C) a straight or branched chain phosphonic acid group having 2 to 6 carbon atoms,
    [113] (D) straight or branched chain sulfonic acid group of 2 to 6 carbon atoms,
    [114] (E) chemical formula Amidino groups wherein r is 2, 3, 4, 5 or 6, R 29 , R 30 and R 31 are each independently a hydrogen atom or an alkyl having 1 to 3 carbon atoms, and R 29 , R 30 and R Two of 31 together with the nitrogen atom (s) therebetween may further constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring),
    [115] (F) chemical formula Guanidino group of wherein s is 2, 3, 4, 5 or 6, R 32 , R 33 , R 34 and R 35 are each independently a hydrogen atom or alkyl of 1 to 3 carbon atoms, R 32 , Two of R 33 , R 34 and R 35 may further form a saturated hydrocarbon bridge of 3 to 5 carbon atoms with the nitrogen atom (s) therebetween to form a heterocyclic ring),
    [116] (G) phenyl [where at least one hydrogen atom of the phenyl group is unsubstituted or (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO 2 OH, (iv) -PO (OH ) 2 , (v) a group of formula -COOR 36 , wherein R 36 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a group of formula -NR 37 R 38 ( Wherein R 37 and R 38 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or acyl having 1 to 7 carbon atoms, or R 37 and R 38 together with the nitrogen atom therebetween; A saturated hydrocarbon bridge of 3 to 5 carbon atoms is formed to form a heterocyclic ring), (vii) a group of the formula -CONR 39 R 40 , wherein R 39 and R 40 are each independently a hydrogen atom, 1 to 6 carbon atoms the alkyl or cycloalkyl having 3 to 6, R 39 and R 40 are burnt together with the nitrogen atom between them A saturated hydrocarbon bridge of number 3 to 5 forms a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-), (viii) A group of —OR 41 , wherein R 41 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, (ix) a group of formula —SR 42 , wherein R 42 is a hydrogen atom or an alkyl having 1 to 7 carbon atoms Or an acyl group), (x) -CN or (xi) Amidino groups wherein R 43 , R 44 and R 45 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 43 , R 44 and R 45 are nitrogen atom (s) between them; And a saturated hydrocarbon bridge of 3 to 5 carbon atoms may be further configured to form a heterocyclic ring).
    [117] (H) a group of the formula -NR 46 R 47 wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted phenyl, or R 100c , wherein R 100c is as defined above ],
    [118] (I) saturated or unsaturated heterocyclic groups selected from the group consisting of pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein the heterocyclic group is unsubstituted or , (i) oxo, (ii) -OR 101 , wherein R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the alkyl group are unsubstituted, or -OH, —OR 110 where R 110 is an alkyl moiety having 1 to 6 carbon atoms, substituted with —NH 2 , —NHMe or —NHe 2 , (c) acyl having 1 to 7 carbon atoms, wherein all of the acyl groups The hydrogen atom is unsubstituted, -OH, -OR 111 , wherein R 111 is an alkyl moiety of 1 to 6 carbon atoms, -NH 2 , -NHMe or -NMe 2 is substituted, (d) -CONR 102 R 103 (wherein, R 102 and R 103 are each independently a hydrogen atom or an alkyl group having 1 to 7, R 102 and R 103 is the nitrogen atom between them Together form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-) or (e) -COOR 104 (wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 where R 105 and R 106 are each independently (a) a hydrogen atom, (b) carbon number Straight or branched chain alkyl of 1 to 7 or cycloalkyl of 3 to 7 carbon atoms, (c) benzoyl, (d) benzyl or (e) phenyl, wherein the phenyl ring is unsubstituted or -OR 112 where R 112 is carbon Mono- or polysubstituted), or R 105 and R 106 together with the nitrogen atom therebetween form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, and One carbon atom of the bridge is unsubstituted, -O-, -NH- or Is substituted with -NMe-), (iv) -COOR 107 ( wherein, R 107 is a straight or branched alkyl, a hydrogen atom, containing from 1 to 7 carbon atoms), (v) C 1 -C 7 linear or branched chain alkyl, C2- Alkenyl or alkynyl or cycloalkyl of 3 to 7 carbon atoms, wherein the alkyl, alkenyl, alkynyl or cycloalkyl group is unsubstituted, or (a) oxo, (b) -OH, (c)- OR 113 where R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 wherein R 114 is substituted with a moiety independently selected from the group consisting of alkyl having 1 to 3 carbon atoms or cycloalkyl having 3 to 7 carbon atoms, (vi) straight chain, acyl of 1 to 7 carbon atoms which may be branched or cyclic (where one or more hydrogen atoms of the acyl group is unsubstituted or substituted with, (a) -OH, (b ) -OR 115 ( wherein R 115 is C 1 -C 6 Is alkyl), (c) -NH 2, (d) -NHMe, (e) -NMe 2, (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 ( wherein, R 116 has a carbon number Heteroalkyl selected from the group consisting of 1 to 3 alkyl), (i) -CN, (j) halogen atom, (k) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl And (l) a residue independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl), (vii) -SO 2 R 108 wherein R 108 is (a) aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl and pyrazolyl, wherein aryl Or the heteroaryl moiety is unsubstituted, halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 117 (wherein R 117 is Hydrogen or at least one moiety selected from the group consisting of alkyl having 1 to 6 carbon atoms), (b) from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl Selected heterocyclic groups, wherein the heterocyclic groups are unsubstituted or substituted with halogen atoms, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 118 (wherein R 118 is hydrogen or alkyl of 1 to 6 carbon atoms) Or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted, halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 119; (Wherein R 119 is hydrogen or substituted with one or more residues selected from the group consisting of alkyl having 1 to 6 carbon atoms), (viii) -COR 109 where R 109 is (a) aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl and pyrazolyl, wherein the aryl or heteroaryl moiety is substituted Or substituted with one or more residues selected from the group consisting of halogen atoms, alkyl having 1 to 6 carbon atoms and -OR 120 , wherein R 120 is hydrogen or alkyl having 1 to 6 carbon atoms, (b) pyrroli Heterocyclic groups selected from the group consisting of diyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein heterocyclyl is unsubstituted or one or more halogens, straight or branched chain of 1 to 6 carbon atoms alkyl, and -OR 121 is substituted by (wherein R 121 is hydrogen or alkyl having 1 to 6 carbon atoms)), or (c) c 1 -C 7 straight or branched alkyl (wherein the alkyl moiety is Unsubstituted or ring, a halogen atom, a straight or branched chain alkyl, and -OR 122 group of 1 to 6 carbon atoms is substituted with one or more moieties selected from the class consisting of (wherein, R 122 is hydrogen or alkyl having 1 to 6 carbon atoms))) , (ix) -CHO, (x) halogen atom and (xi) phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl and imidazolylo Mono- or polysubstituted by a moiety independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of:
    [119] (J) a halogen atom and
    [120] (K) -CN); and
    [121] X is an oxygen atom,
    [122] R 3 is straight or branched alkyl having 1 to 3 carbon atoms,
    [123] R 4 is a group of the formula —CH 2 R 55 wherein R 55 is unsubstituted or aryl or heteroaryl selected from the group consisting of (A) phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl; Wherein one of the hydrogen atoms of aryl or heteroaryl is unsubstituted, or (i) straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein the alkyl or cycloalkyl group is unsubstituted or halogen Or mono- or polysubstituted with oxo), (ii) -CN, (iii) nitro or (iv) halogen],
    [124] (B) methyl,
    [125] (C) straight or branched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted or mono- or polysubstituted by halogen or oxo,
    [126] (D) a group of the formula -COOR 67 wherein R 67 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    [127] (E) a group of formula -COR 72 wherein R 72 is a hydrogen atom, straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    [128] (F) a group of the formula -OR 73 , wherein R 73 is a hydrogen atom, alkyl or a fluoroalkyl or acyl group having 1 to 7 carbon atoms,
    [129] (G) -CN,
    [130] (H) nitro or
    [131] (I) phenyl substituted by halogen}
    [132] R 5 is Cl,
    [133] Z is = C (H)-,
    [134] R 7 is Cl.
    [135] Further preferred compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein A 1 is = N-,
    [136] A 2 is = C (H)-,
    [137] D is = C (H)-, = C (SO 2 R 1 )-or = C (C (O) R 1 )-{where R 1 is (A) straight or branched chain alkyl of 1 to 6 carbon atoms, carbon number Alkenyl of 2 to 6 or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, wherein at least one hydrogen atom of an alkyl, alkenyl, cycloalkyl or cycloalkenyl group is unsubstituted, or (i) oxo, (ii ) A group of formula -COOR 18 , wherein R 18 is straight or branched chain alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (iii) a group of formula -CONR 19 R 20 , wherein R is 19 and R 20 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or R 19 and R 20 together with a nitrogen atom between them constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms To form a heterocyclic ring, where one carbon atom of the hydrocarbon bridge is substituted Or not, -O-, is replaced by -NH- or -NMe-), (iv) a group of the formula -OR 21 (wherein, R 21 is a linear or branched alkyl or acyl of 1 to 7 carbon atoms or a hydrogen atom, One or more hydrogen atoms of the alkyl or acyl group are unsubstituted or independently selected from the group consisting of —OH, —Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, —NH 2 —NHMe and —NMe 2 ; (V) a group of formula -NR 23 R 24 , wherein R 23 and R 24 are each independently (a) a hydrogen atom, (b) a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms or Cycloalkyl having 3 to 7 carbon atoms, wherein at least one hydrogen atom of the alkyl or acyl group is unsubstituted, or -OH, -Oalkyl, wherein alkyl has 1 to 6 carbon atoms, -NH 2 , -NHMe and- Substituted with a group independently selected from the group consisting of NMe 2 ), (c) a formula-(CH 2 ) m COOH, wherein m is 0, 1 or 2, (d) a group of the formula-(CH 2 ) n COOR 25 , where n is 0, 1 or 2 and R 25 has 1 to 6 carbon atoms Or (e) a group of the formula-(CH 2 ) n CONHR 25 , wherein n is 0, 1 or 2, and R 25 is straight or branched alkyl of 1 to 6 carbon atoms , (vi) chemical formula A quaternary group of a quaternary group of (wherein R 26 , R 27 and R 28 are each independently a linear or branched alkyl group having 1 to 7 carbon atoms and Q − is a pharmaceutically acceptable counter ion) or (vii ) is replaced by a group independently selected from cycloalkyl of 3 to 7 carbon atoms; an -R 100d,
    [138] (B) straight or branched carboxylic acid group having 3 to 6 carbon atoms,
    [139] (C) a straight or branched chain phosphonic acid group having 2 to 6 carbon atoms,
    [140] (D) straight or branched chain sulfonic acid group of 2 to 6 carbon atoms,
    [141] (E) chemical formula Amidino groups wherein r is 2, 3, 4, 5 or 6, R 29 , R 30 and R 31 are each independently a hydrogen atom or an alkyl having 1 to 3 carbon atoms, and R 29 , R 30 and R Two of 31 together with the nitrogen atom (s) therebetween may further constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring),
    [142] (F) chemical formula Guanidino group of wherein s is 2, 3, 4, 5 or 6, R 32 , R 33 , R 34 and R 35 are each independently a hydrogen atom or alkyl of 1 to 3 carbon atoms, R Two of 32 , R 33 , R 34 and R 35 may further form a saturated hydrocarbon bridge of 3 to 5 carbon atoms with the nitrogen atom (s) therebetween to form a heterocyclic ring),
    [143] (G) a group of formula -NR 46 R 47 , wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted phenyl, or R 100d , wherein R 100d is as defined above to be),
    [144] (H) saturated or unsaturated heterocyclic groups selected from the group consisting of pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein the heterocyclic group is unsubstituted or , (i) oxo, (ii) -OR 101 , wherein R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the alkyl group are unsubstituted, or -OH, —OR 110 where R 110 is an alkyl moiety of 1 to 6 carbon atoms, substituted with —NH 2 , —NHMe or —NMe 2 , (c) acyl having 1 to 7 carbon atoms, wherein all of the acyl groups The hydrogen atom is unsubstituted, -OH, -OR 111 , wherein R 111 is an alkyl moiety of 1 to 6 carbon atoms, -NH 2 , -NHMe or -NMe 2 is substituted, (d) -CONR 102 R 103 (wherein, R 102 and R 103 are each independently a hydrogen atom or an alkyl group having 1 to 7, R 102 and R 103 is the nitrogen atom between them Together form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe) or (e)- COOR 104 (wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 where R 105 and R 106 are each independently (a) a hydrogen atom, (b) 1 carbon Straight or branched chain alkyl of 7 to 7 or cycloalkyl of 3 to 7 carbon atoms, (c) benzoyl, (d) benzyl or (e) phenyl, wherein the phenyl ring is unsubstituted or -OR 112 wherein R 112 is 1 Monoalkyl or polysubstituted), or R 105 and R 106 together with the nitrogen atom therebetween form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, and a hydrocarbon bridge One carbon atom of unsubstituted, -O-, -NH- Is substituted with -NMe-), (iv) -COOR 107 ( wherein, R 107 is a hydrogen atom or a straight or branched chain alkyl of 1 to 7 carbon atoms), (v) C 1 -C 7 linear or branched chain alkyl, C2- Alkenyl or alkynyl or cycloalkyl having 3 to 7 carbon atoms, wherein at least one hydrogen atom of alkyl, alkenyl, alkynyl or cycloalkyl is unsubstituted, or (a) oxo, (b) -OH, (c) -OR 113 where R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h ) -CO 2 H and (i) -CO 2 R 114 , wherein R 114 is substituted with a residue independently selected from the group consisting of alkyl having 1 to 3 carbon atoms or cycloalkyl having 3 to 7 carbon atoms, ( vi) acyl having 1 to 7 carbon atoms, which may be straight chain, branched or cyclic, wherein at least one hydrogen atom of the acyl group is unsubstituted, or (a) -OH, (b) -OR 115 , wherein R 115 is alkyl having 1 to 6 carbon atoms), (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 wherein R 116 is alkyl having 1 to 3 carbon atoms, (i) -CN, (j) halogen atom, (k) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholi A heterocycle selected from the group consisting of aryl, (l) a residue independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl ), (Vii) -SO 2 R 108 wherein R 108 is selected from the group consisting of (a) phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl and pyrazolyl Aryl or heteroaryl, wherein the aryl or heteroaryl moiety is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms -OR 117 is substituted with one or more moieties selected from the class consisting of (wherein, R 117 is hydrogen or alkyl having 1 to 6)), (b) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl And a heterocyclic group selected from the group consisting of thiomorpholinyl, wherein the heterocyclic group is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 118 (wherein R 118 is hydrogen or Substituted with one or more residues selected from the group consisting of alkyl having 1 to 6 carbon atoms) or (c) straight or branched chain alkyl having 1 to 7 carbon atoms wherein the alkyl residues are unsubstituted or halogen atoms, 1 to 6 carbon atoms a straight or branched alkyl, and -OR 119 is substituted with one or more moieties selected from the class consisting of (wherein, R 119 is hydrogen or alkyl having 1 to 6 carbon atoms)), a ), (Viii) -COR 109 (wherein, R 109 is (a) phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, and aryl or heteroaryl selected from the class consisting of pyrazolyl From aryl, wherein the aryl or heteroaryl moiety is unsubstituted or consists of a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 120 , wherein R 120 is hydrogen or alkyl of 1 to 6 carbon atoms Substituted with one or more residues selected), (b) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein heterocyclyl is unsubstituted or, one or more halogen, straight or branched c 1 -C 6 alkyl, or -OR 121 is replaced by (wherein, R 121 is hydrogen or alkyl having 1 to 6 carbon atoms)), or (c) straight c 1 -C 7 Or branched chain alkyl (wherein the alkyl moiety is unsubstituted or substituted with a halogen atom, a straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 122 (wherein R 122 is selected from the class consisting of hydrogen or alkyl having 1 to 6 carbon atoms) (Ix) -CHO, (x) halogen atom and (xi) phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl Mono- or polysubstituted by a moiety independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of isoxazolyl and imidazolyl],
    [145] (I) selected from the class consisting of halogen atoms,
    [146] X is an oxygen atom,
    [147] R 3 is straight or branched alkyl having 1 to 3 carbon atoms,
    [148] R 4 is a group of the formula —CH 2 R 55 wherein R 55 is unsubstituted or in the 4 position aryl or heteroaryl selected from the group consisting of (A) phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl; Wherein the aryl or heteroaryl group is unsubstituted, or (i) straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein the alkyl or cycloalkyl group is unsubstituted or substituted with halogen or oxo is substituted or multi-substituted), (ii) -CN, the R 59d (iii) nitro, or (iv) is replaced by a halogen),
    [149] (B) methyl,
    [150] (C) straight or branched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted or monosubstituted with halogen or oxo,
    [151] (D) a group of the formula -COOR 67 wherein R 67 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    [152] (E) a group of formula -COR 72 wherein R 72 is a hydrogen atom, straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    [153] (F) a group of the formula -OR 73 , wherein R 73 is a hydrogen atom, alkyl or a fluoroalkyl or acyl group having 1 to 7 carbon atoms,
    [154] (G) -CN,
    [155] (H) nitro or
    [156] (I) phenyl substituted with halogen],
    [157] R 5 is Cl,
    [158] Z is = C (H)-,
    [159] R 7 is Cl.
    [160] Particularly preferred compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein A 1 is = N-,
    [161] A 2 is = C (H)-,
    [162] D is = C (SO 2 R 1 )-or = C (C (O) R 1 )-{wherein R 1 is (A) straight or branched chain alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or Cycloalkyl or cycloalkenyl having 3 to 6 carbon atoms, wherein at least one hydrogen atom of the alkyl, alkenyl, cycloalkyl or cycloalkenyl group is unsubstituted, or (i) oxo, (ii) a group of the formula -COOR 18 (Wherein R 18 is straight or branched chain alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms), (iii) a group of formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently hydrogen An atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or R 19 and R 20 together with the nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, One carbon atom of the hydrocarbon bridge is unsubstituted, -O-, -NH- or -NMe-, (iv) a group of formula -OR 21 wherein R 21 is a hydrogen atom or a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms, one of an alkyl or acyl group The above hydrogen atoms are unsubstituted or substituted with a group independently selected from the group consisting of -OH, -Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, -NH 2 , -NHMe and -NMe 2 ; or (v) a group of the formula -NR 23 R 24 , wherein R 23 and R 24 are each independently selected from (a) a hydrogen atom, (b) a straight or branched chain alkyl or acyl or C3 to C7 carbon group having from 1 to 7 carbon atoms A group independently selected from the group consisting of alkyl, wherein the alkyl or acyl group is unsubstituted, or -OH, -Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, -NH 2 , -NHMe and -NMe 2 (C) a chemical formula-(CH 2 ) m COOH, wherein m is 0, 1 or 2), (d) formula-(CH 2 ) n COOR 25 , wherein n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms, or (e) (CH 2) n CONHR group of 25 is replaced with independently a (, where, n is 0, 1 or 2, R 25 is a C 1 -C 6 straight or branched alkyl))] is -R 100e,
    [163] (B) a group of the formula -NR 46 R 47 wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted phenyl, or R 100e , wherein R 100e is as defined above ],
    [164] (C) a saturated or unsaturated heterocyclic group selected from the group consisting of pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein the heterocyclic group is unsubstituted or , (i) oxo, (ii) -OR 101 , wherein R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the alkyl group are unsubstituted, or -OH, —OR 110 where R 110 is an alkyl moiety of 1 to 6 carbon atoms, substituted with —NH 2 , —NHMe or —NMe 2 , (c) acyl having 1 to 7 carbon atoms, wherein all of the acyl groups The hydrogen atom is unsubstituted, -OH, -OR 111 , wherein R 111 is an alkyl moiety of 1 to 6 carbon atoms, -NH 2 , -NHMe or -NMe 2 is substituted, (d) -CONR 102 R 103 (wherein, R 102 and R 103 are each independently a hydrogen atom or an alkyl group having 1 to 7, R 102 and R 103 is the nitrogen atom between them Together form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-) or (e) -COOR 104 (wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 where R 105 and R 106 are each independently (a) a hydrogen atom or (b) carbon number Straight or branched chain alkyl of 1 to 7 or cycloalkyl of 3 to 7 carbon atoms, or R 105 and R 106 together with a nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, One carbon atom of the hydrocarbon bridge is unsubstituted or substituted with -O-, -NH- or -NMe-, (iv) -COOR 107 where R 107 is a hydrogen atom or a straight or branched chain having 1 to 7 carbon atoms Alkyl), (v) straight or branched chain having 1 to 7 carbon atoms Alkyl, alkenyl or alkynyl or alkynyl or cycloalkyl of 3 to 7 carbon atoms, wherein at least one hydrogen atom of the alkyl, alkenyl, alkynyl or cycloalkyl group is unsubstituted, or (a) oxo, ( b) -OH, (c) -OR 113 wherein R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g)- NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 wherein R 114 is alkyl having 1 to 3 carbon atoms or cycloalkyl having 3 to 7 carbon atoms. Substituted), (vi) acyl having 1 to 7 carbon atoms, which may be straight, branched or cyclic, wherein at least one hydrogen atom of the acyl group is unsubstituted or (a) -OH, (b) -OR 115 ( Wherein R 115 is alkyl having 1 to 6 carbon atoms), (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 wherein R 116 is alkyl having 1 to 3 carbons C), (i) -CN, (j) halogen atoms, (k) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, and (l) phenyl , Substituted with a residue independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl, (vii) -SO 2 R 108 , R 108 is (a) phenyl, wherein the phenyl moiety is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 117 , wherein R 117 is hydrogen or alkyl of 1 to 6 carbon atoms Substituted with one or more residues selected from the group consisting of: (b) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl, wherein heterocyclic Click Group is Chi Or not, a halogen atom, a linear or branched C 1 -C 6 alkyl, and -OR 118 is substituted with one or more moieties selected from the class consisting of (wherein, R 118 is hydrogen or alkyl having 1 to 6 carbon atoms)), or (c ) Straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted or halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 119 where R 119 is hydrogen or alkyl of 1 to 6 carbon atoms ), (Viii) -COR 109 , wherein R 109 is (a) phenyl, wherein the phenyl moiety is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 120 , wherein R 120 is hydrogen or alkyl having 1 to 6 carbon atoms); and (b) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl Class Heteroatom selected from the cyclic group (wherein heterocyclic cyclic group is optionally substituted with one or more halogen, straight or branched chain alkyl, or -OR 121 group of 1 to 6 carbon atoms (wherein R 121 is hydrogen or alkyl of 1 to 6 carbon atoms ) Or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted, or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 122 , wherein R 122 is Is substituted with one or more residues selected from the group consisting of hydrogen or alkyl having 1 to 6 carbon atoms) and (ix) mono- or polysubstituted residues independently selected from the group consisting of -CHO. Is chosen},
    [165] X is an oxygen atom,
    [166] R 3 is straight or branched alkyl having 1 to 3 carbon atoms,
    [167] R 4 is a group of the formula —CH 2 R 55 wherein R 55 is unsubstituted or in the 4 position aryl or heteroaryl selected from the group consisting of (A) phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl; wherein one of the hydrogen atoms of the aryl or heteroaryl is an unsubstituted or substituted, (i) methyl, (ii) -CN, (iii ) nitro, or (iv) is replaced by a halogen) R 59e,
    [168] (B) methyl,
    [169] (C) -CN,
    [170] (D) nitro or
    [171] (E) phenyl substituted with halogen],
    [172] R 5 is Cl,
    [173] Z is = C (H)-,
    [174] R 7 is Cl.
    [175] More particularly preferred compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein A 1 is = N-,
    [176] A 2 is = C (H)-,
    [177] D is = C (SO 2 R 1 )-or = C (C (O) R 1 )-{where R 1 is (A) straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms [ Wherein one to three hydrogen atoms of the alkyl or cycloalkyl group are unsubstituted or (i) oxo, (ii) a group of the formula -COOR 18 , wherein R 18 is straight or branched chain alkyl or carbon number of 1 to 7 carbon atoms Cycloalkyl of 3 to 6), (iii) a group of formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms , R 19 and R 20 together with the nitrogen atom therebetween form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, and one carbon atom of the hydrocarbon bridge is unsubstituted or -O-, -NH - or is substituted by -NMe-), (iv) a group of the formula -OR 21 (wherein, R 21 is hydrogen Here, or 1 to 7 carbon atoms is a straight or branched chain alkyl or acyl group of a) or (v) a group of the formula -NR 23 R 24 (wherein, R 23 and R 24 are each independently (a) hydrogen (b) C 1 Straight or branched chain alkyl or acyl or cycloalkyl having 3 to 7 carbon atoms, (c) a group of formula-(CH 2 ) m COOH, wherein m is 0, 1 or 2, (d) formula-( CH 2 ) a group of n COOR 25 , where n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms or (e) a group of the formula-(CH 2 ) n CONHR 25 ( here, n is 0,1 or 2, R 25 is optionally substituted independently with a carbon number of 1 to 6 is a straight or branched chain alkyl))] is -R 100e,
    [178] (B) a saturated heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein the heterocyclic group is unsubstituted or (i) oxo, (ii) -OR 101 wherein R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein one hydrogen atom of the alkyl group is unsubstituted, or -OH, -OR 110 , , R 110 is an alkyl moiety having 1 to 6 carbon atoms), -NH 2 , -NHMe or -NMe 2 is substituted, (c) acyl having 1 to 7 carbon atoms, wherein one hydrogen atom of the acyl group Or -OH, -OR 111 where R 111 is an alkyl moiety of 1 to 6 carbon atoms, is substituted with -NH 2 , -NHMe or -NMe 2 , (d) -CONR 102 R 103 , R 102 and R 103 are each independently a hydrogen atom or an alkyl group having 1 to 7, R 102 and R 103 is a 3 carbon atoms together with the nitrogen atom between them within By constructing a saturated hydrocarbon bridge of 5 to form a heterocyclic ring, it is optionally substituted with one C atom of the hydrocarbon The bridge is replaced by -O-, -NH- or -NMe-) or (e) -COOR 104 ( Wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 wherein R 105 and R 106 are each independently (a) a hydrogen atom or (b) having 1 to 7 carbon atoms Straight or branched alkyl or cycloalkyl having 3 to 7 carbon atoms, wherein the alkyl or cycloalkyl group is unsubstituted, or -OH, -OR 123 , wherein R 123 is an alkyl moiety of 1 to 6 carbon atoms, -NH 2 , Mono-substituted with -NHMe, -NMe 2 , pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, or R 105 and R 106 together with a nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms; To form a heterocyclic ring, one of the hydrocarbon bridges Small atoms are unsubstituted or substituted with -O-, -NH-, or -NMe-), (iv) -COOR 107 where R 107 is a hydrogen atom or straight or branched chain alkyl of 1 to 7 carbon atoms (v) straight or branched chain alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein one to three hydrogen atoms of the alkyl or cycloalkyl group are unsubstituted, or (a) oxo, (b)- OH, (c) -OR 113 where R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 wherein R 114 is substituted with a residue independently selected from the group consisting of alkyl having 1 to 3 carbons or cycloalkyl having 3 to 7 carbons) (vi) acyl having 1 to 7 carbon atoms, which may be straight, branched or cyclic, wherein one or two hydrogen atoms of the acyl group are unsubstituted, or (a) -OH, (b) -OR 115 where , R 115 is Alkyl having 1 to 6 carbon atoms), (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 , R 116 is alkyl having 1 to 3 carbon atoms), (i) -CN, (j) halogen atom, (k) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl A heterocycle selected from the class and (l) a residue selected from the group consisting of aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl), (vii ) -SO 2 R 108 where R 108 is (a) phenyl (wherein the phenyl moiety is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 117 (wherein R 117 is hydrogen or Alkyl having 1 to 6 carbon atoms), (b) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl Cyclic Tero group (wherein the heterocyclic group is optionally substituted, consisting of a halogen atom, a straight-chain or branched alkyl having 1 to 6 carbon atoms, and -OR 118 (wherein R 118 is hydrogen or alkyl having 1 to 6 carbon atoms) Or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted, halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 119 ( Wherein R 119 is substituted with one residue selected from the group consisting of hydrogen or alkyl having 1 to 6 carbon atoms), (viii) -COR 109 where R 109 is (a) phenyl (where phenyl residue is unsubstituted or substituted with a halogen atom, a C 1 -C 6 straight or branched chain alkyl, and -OR 120 of one of the moieties selected from the class consisting of (wherein, R 120 is hydrogen or alkyl having 1 to 6 carbon atoms) Substituted), (b) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein the heterocycle is unsubstituted, one halogen, Straight or branched chain alkyl of 1 to 6 carbon atoms or -OR 121 , wherein R 121 is hydrogen or alkyl of 1 to 6 carbon atoms, or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein alkyl The moiety is unsubstituted or substituted with one moiety selected from the group consisting of a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 122 where R 122 is hydrogen or alkyl of 1 to 6 carbon atoms. And (ix) mono- or di-substituted with residues independently selected from the group consisting of -CHO.
    [179] X is an oxygen atom,
    [180] R 3 is straight or branched alkyl having 1 to 3 carbon atoms,
    [181] R 4 is a group of the formula —CH 2 R 55 wherein R 55 is unsubstituted or in the 4 position aryl or heteroaryl selected from the group consisting of (A) phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl; wherein one of the hydrogen atoms of the aryl or heteroaryl group is unsubstituted or substituted, is substituted with (i) methyl, (ii) -CN, (iii) nitro, or (iv) halogen) of R 59e,
    [182] (B) methyl,
    [183] (C) -CN,
    [184] (D) nitro or
    [185] (E) phenyl substituted with halogen],
    [186] R 5 is Cl,
    [187] Z is = C (H)-,
    [188] R 7 is Cl.
    [189] Second preferred compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A 1 is = N-,
    [190] A 2 is = C (H)-,
    [191] D is = C (SO 2 R 1 )-{where R 1 is (A) methyl and
    [192] (B) a saturated heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholine, wherein the heterocyclic group is unsubstituted, or (i) oxo, (ii) -OR 101 Wherein R 101 represents (a) hydrogen, (b) alkyl of 1 to 7 carbon atoms, wherein one hydrogen atom of the alkyl group is unsubstituted, or -OH, -OR 110 , wherein R 110 represents 1 to Is an alkyl moiety of 6), -NH 2 , -NHMe or -NMe 2 , or (c) acyl having 1 to 7 carbon atoms, wherein one hydrogen atom of the acyl group is unsubstituted, or -OH,- OR 111 , wherein R 111 is an alkyl moiety of 2 to 6 carbon atoms, substituted with -NH 2 , -NHMe or -NMe 2 ), (iii) -CONR 105 R 106 , wherein R 105 and R 106 are each independently (a) hydrogen atom or (b) a cycloalkyl containing from 1 to 7 carbon atoms or straight or branched chain alkyl of 3 to 7 carbon atoms (wherein the alkyl addition Cycloalkyl is optionally substituted, -OH, -OR 123 (wherein, R 123 is a C 1 to 6 alkyl), -NH 2, -NHMe, -NMe 2, pyrrolidinyl, piperidinyl, piperazinyl Or mono-substituted with morpholinyl, or R 105 and R 106 together with the nitrogen atom therebetween form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted Or (substituted with -O-, -NH- or -NMe-)), (iv) -COOR 107 wherein R 107 is a hydrogen atom or straight or branched chain alkyl of 1 to 7 carbon atoms, (v) Straight or branched chain alkyl of 1 to 7 carbon atoms, wherein one or two hydrogen atoms of the alkyl group are unsubstituted or (a) oxo, (b) -OH, (c) -OR 113 , wherein R 113 is carbon Alkyl of 1 to 6), (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 (wherein, R 114 is burnt Substituted with a residue independently selected from the group consisting of alkyl of 1 to 3 or cycloalkyl of 3 to 7 carbon atoms), (vi) acyl of 1 to 7 carbon atoms, which may be linear, branched or cyclic One or two hydrogen atoms of the acyl group are unsubstituted, or (a) -OH, (b) -OR 115 , wherein R 115 is alkyl having 1 to 6 carbon atoms, (c) -NH 2 , (d ) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 wherein R 116 is alkyl having 1 to 3 carbon atoms, (i) -CN (j) a halogen atom, (k) a heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl and (l) phenyl, thiophenyl, pyridyl, pyri It is substituted with pyrimidinyl, furyl, pyrrolyl and oxazolyl moieties selected from the class consisting of aryl or heteroaryl selected from the class consisting of a), (vii) -SO 2 R 108 ( W Standing, R 108 is (a) pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl wherein the cyclic group between heteroatom selected from the class consisting of (wherein the heterocyclic group is unsubstituted or substituted, straight-chain having 1 to 6 carbon atoms Or branched chain alkyl and -OR 118 , wherein R 118 is substituted with one residue selected from the group consisting of hydrogen or alkyl having 1 to 6 carbon atoms, (viii) -COR 109 wherein R 109 is (a) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the heterocyclyl is unsubstituted or one halogen, straight or branched chain of 1 to 6 carbon atoms alkyl, or -OR 121 with a substituted (herein, R 121 is hydrogen or alkyl having 1 to 6 carbon atoms))), and (ix) is from the class consisting of mono- or disubstituted with a -CHO moiety selected independently; It is selected from the class of binary luer} and,
    [193] X is an oxygen atom,
    [194] R 3 is methyl,
    [195] R 4 is R 59e formula -CH 2 R 55 group (wherein, R 55 is unsubstituted or substituted with a 4-position (A) phenyl, a pyridyl and pyrimidinyl aryl or heteroaryl selected from the class consisting of aryl,
    [196] (B) -CN,
    [197] (C) nitro or
    [198] (D) is substituted with halogen),
    [199] R 5 is Cl,
    [200] Z is = C (H)-,
    [201] R 7 is Cl.
    [202] It is preferred that the compound of formula (I) has one or more chiral centers. Preferred compounds of formula (I) are compounds with complete stereochemistry of formula (II).
    [203]
    [204] Also preferred are the following specific compounds or pharmaceutically acceptable salts thereof.
    [205]
    [206]
    [207]
    [208]
    [209]
    [210]
    [211] Further described are certain compounds useful as intermediates in the synthesis of the compounds of the present invention. Especially chemical formula {Where R 1 is (A) hydrogen, (B) halogen atom and (C) SO 2 - M + [where M + is (i) Li + , (ii) Na + , (iii) K + or ( iv) MgX + , wherein X is halogen, and R 2 is selected from (A) halogen atom, (B) (i) phenyl, (ii) pyridyl and (iii) pyrimidyl Selected from the group consisting of aryl and (C) CN selected.
    [212] Synthesis of Compounds of the Invention
    [213] The compounds of the present invention can be prepared by the general methods described below. Typically, the reaction process is monitored by thin layer chromatography (TLC) if necessary. If desired, the intermediates and products can be purified by chromatography on silica gel and / or recrystallization and characterized by one or more of the following techniques: NMR, mass spectra and melting point. Starting materials and reagents are all commercially available or can be prepared by one of ordinary skill in the art using the methods described in the chemical literature.
    [214] Intermediates used in the preparation of compounds of formula (I) can be prepared by the methods and schemes (I) described below.
    [215]
    [216] Suitable amino acid III is dissolved in a liquid base such as NaOH, KOH, Na 2 CO 3 , NaHCO 3 , K 2 CO 3 or KHCO 3 and warmed between about 20 to 90 ° C. Suitable isocyanate IV is added to the mixture and the resulting solution is basically stirred until the reaction is complete. While cooling, the mixture is acidified and the resulting ureidoacetic acid is separated into an organic solvent by filtration or extraction. The solvent is removed to produce the intermediate ureidoacetic acid. In the process described in Sauli, US in particular 4,099,008, intermediate ureidoacetic acid is an organic or liquid solvent in the presence of a catalytic amount of acid (e.g. sulfonic acid, methanesulfonic acid, benzenesulfonic acid or hydrochloric acid). Thermocycling in the middle yields the desired hydantoin V. The workup consists of the collection of hydantoin by filtration and purification (eg silica gel chromatography or recrystallization).
    [217] If thiocarbonyl VII is required, some reagents known in the literature convert carbonyl to thiocarbonyl. A typical sequence involves heating the material for 1 to 48 hours in a high boiling solvent such as tetralin with a reagent such as P 2 S 3 . The product is then separated under relatively standard conditions, such as dilution of the mixture with an organic solvent such as EtOAc, and the mixture is washed with water and saturated NaCl solution, dried and concentrated. Purification is carried out by silica gel chromatography or recrystallization to afford intermediate VI.
    [218] Intermediate VI is selectively hydrolyzed to the desired monothiocarbonyl compound according to the selection conditions. In general, thiocarbonyl at the 4-position of the ring is further affected by nuclear affinity conditions. It can be converted to 4-oxo species (VII) by acid hydrolysis after treatment with liquid ethanolamine. Purification is readily performed by silica gel chromatography or recrystallization.
    [219] Alternatively, the methyl or ethyl ester of compound III is substituted with aryl thioisocyanate (IV: instead of -NCO) for about 1 to 24 hours at about 50 to 100 ° C. in an inert atmosphere in a suitable solvent such as 1,4-dioxane. NCS) can give compound VII.
    [220] When using racemates III and esters of compound III, the product (V or VII) is a racemate on an asymmetric carbon. By starting with a single enantiomer of III or an ester of III, a single enantiomer of V or VII is obtained.
    [221] Compounds of formula (I) wherein A 1 is N, A 2 is CH and D is CH can be synthesized as described in Scheme II and below.
    [222]
    [223] Azide VIII is added to a PPh 3 solution in an inert atmosphere in a suitable solvent such as toluene and then stirred at ambient temperature for about 12 to 24 hours. Then, suitable thiohydantoin VII is added and the reaction is heated to about 130 to 140 ° C. for about 1 to 4 days in a sealed tube, preferably in an inert atmosphere, concentrated and purified by silica gel chromatography to give compound IX To obtain. An acid, such as trifluoroacetic acid, is added to a solution of compound IX in a solvent, such as dichloroethane, and heated to about 50 to 100 ° C. for about 12 to 24 hours under an inert atmosphere, followed by formula I (wherein A 1 is N, A 2 is CH and D is CH.
    [224] The homologue of Formula I, wherein A 1 is N and A 2 is CH, is a homologue of Formula D wherein D is carbon substituted with various groups such as halogen, CN, CHO, alkyl group, alkyl or aryl sulfide, sulfoxide or sulfone III and as described below.
    [225]
    [226] In Scheme III, M is a metal atom such as Li or Mg, Hal is Cl, Br or I, E is a functional group convertible by an electron affinity reagent and Cl, Br, I, CN, alkyl, CHO, SO 2 M, SO 2 R or CO 2 R, wherein R is alkyl or aryl, but is not limited thereto.
    [227] The desired N-halosuccinimide (about 1 molar equivalent) is dissolved in a solution of the formula I (wherein A 1 is N, A 2 is CH and D is CH) in a suitable solvent such as methylene chloride, Partially added at 10 ° C. to ambient temperature, preferably about 0 ° C. and stirred for about 2 to 15 hours. After workup and purification, a compound of formula I is obtained, wherein A 1 is N, A 2 is CH and D is C-Cl, C-Br or CI.
    [228] Halogen-substituted compound I, wherein A 1 is N, A 2 is CH, and D is C-Cl, C-Br or CI, is an organometallic reagent (e.g. alkyl or aryl lithium or Grignard reagent) Treatment with an organic metal intermediate I, wherein A 1 is N, A 2 is CH, and D is CM, where M is a metal atom such as Li or Mg. Such organometallic intermediates include N-chloro-, bromo- or iodo-succinimide, tosyl cyanide, alkyl or aryl sulfonyl chlorides, alkyl or aryl disulfides, alkyl- or arylthiosulfonates, alkyl or aryl chloro Reaction with an electron affinity such as formate, alkyl halide, N, N-dimethylformamide or sulfur dioxide yields a homologue of compound I, wherein A 1 is N and A 2 is CH, wherein D Is carbon substituted by various groups such as Cl, Br, I, CN, alkyl group, alkyl or aryl sulfone, alkyl or aryl sulfide, CHO, sulfinate salt). Sulphides may be further oxidized with reagents such as potassium peroxymonosulfate or m-chlorobenzoic acid to give sulfoxides or sulfones. The sulfonate salts can be further transformed as described below to yield sulfones and sulfonamides.
    [229] More specifically, compound I, wherein D is CN, wherein A 1 is N and A 2 is CH, corresponds to the corresponding halide [referably iodide (I: wherein A 1 is N and A 2 is CH and D is C0I)] using an alkyl magnesium reagent (e.g., cyclopentyl magnesium bromide) in a solvent such as THF, about -78 ° C to 0 ° C, preferably about -30 ° C to -40 ° C. Treatment for about 1 to 5 hours under an inert gas at to generate organomagnesium species I, wherein A 1 is N, A 2 is CH and D is C-Mg. Tosyl cyanide is then added and the reaction is allowed to slowly warm to ambient temperature for about 1 to 24 hours. Work up and purify to afford compound I, wherein A 1 is N, A 2 is CH and D is C-CN.
    [230] Compound I, wherein A 1 is N, A 2 is CH, D is C-SO 2 R, wherein R is alkyl or aryl, is organomagnesium species I, wherein A 1 is N, A 2 is CH and D is C-Mg) by treatment with alkyl or aryl sulfonyl chloride as described above. Alternatively, alkyl- or aryldisulfides or alkyl- or arylthiosulfonates (eg prepared by oxidizing the corresponding alkyl or aryl disulfides such as m-chloroperoxybenzoic acid in a suitable solvent such as methylene chloride) After addition, the reaction was heated at about reflux temperature of the solvent for about 1 to 3 hours, worked up and purified and then Compound I [where A 1 is N, A 2 is CH and D is C-SR ( Wherein R is alkyl or aryl). The product can be oxidized to the corresponding sulfoxide or sulfone using a suitable oxidizing agent such as potassium peroxymonosulfate or m-chloroperoxybenzoic acid.
    [231] Compound I, wherein D is C-CO 2 R, wherein D is an alkyl or aryl group, wherein A 1 is N and A 2 is CH, dissolves the organomagnesium species generated above in a solvent such as THF. Treating the reaction with a suitable alkyl or aryl chloroformate prior to warming the reaction to room temperature for about 30 minutes to 1 hour under an inert atmosphere at about -20 to -78 ° C, preferably at about -40 ° C It can be obtained by. It is then quenched, for example, with aqueous sodium bicarbonate, worked up and purified to yield Compound I (where A 1 is N, A 2 is CH and D is C—CO 2 R).
    [232] Compound I, wherein D is C-CHO, wherein A 1 is N and A 2 is CH, employs alkyl lithium, such as n-BuLi, in a solvent such as THF, about -50 to -120 ° C., preferably Is a solution of the corresponding halide [referably iodide (I: wherein A 1 is N, A 2 is CH and D is CI) at about −100 ° C. under an inert atmosphere for about 15 minutes to 1 hour. It can be obtained by treating. N, N-dimethylformamide is added and the reaction is slowly raised to about 0 ° C. and stirred for 1 hour. It is then quenched with, for example, aqueous ammonium chloride, worked up and filtered to give compound I, wherein A 1 is N, A 2 is CH and D is C-CHO.
    [233] One of the specific compounds of the present invention can be synthesized by treating the organomagnesium intermediate as generated above with sulfur dioxide to generate the intermediate magnesium sulfinate salt. Treatment of these intermediates with alkylating agents (eg alkyl halides) results in further compounds of Formula I wherein D is C-SO 2 R, wherein R is alkyl, wherein A 1 is N and A 2 is CH Can be obtained. The intermediate magnesium sulfinate salt can also be treated with N-chlorosuccinimide to yield sulfonyl chloride I (where A 1 is N, A 2 is CH and D is C-SO 2 Cl). have. Sulfonyl chloride is treated with an amine to give the desired sulfonamide I [where A 1 is N, A 2 is CH and D is C—SO 2 NRR ′ where R and R ′ are hydrogen, alkyl or aryl Groups, or together include part of a heterocyclic ring).
    [234] Homologue of compound I, wherein D is C-SO 2 NRR 'wherein R and R' together comprise part of a heterocyclic ring and R and / or R 'contains a secondary nitrogen such as piperazine Wherein A 1 is N and A 2 is CH) can be substituted with secondary nitrogen such as acyl, alkyl, aryl, carbamyl or sulfonyl as described below, and is shown in Scheme IV.
    [235]
    [236] In Scheme IV, R ″ is a functional group that can be converted by an electron affinity reagent and is an alkyl group, COR, CONRR ′, CO 2 R or SO 2 R, wherein R or R ′ is alkyl or aryl However, it is not limited thereto.
    [237] The heteroatoms of the compounds are treated with reagents such as alkanoyl or aroyl chlorides, alkanoyl or aroyl anhydrides, alkyl halides, alkyl or aryl sulfonyl chlorides or alkyl or aryl isocyanates, where Compound I (wherein A 1 is N And A 2 is CH), D is sulfonamide which may itself be further substituted with various groups such as alkyl or aryl amides, alkyl amines, alkyl or aryl sulfonamides and alkyl or aryl ureas Is carbon substituted with.
    [238] More specifically, compound I, wherein A 1 is N, A 2 is CH and D is the carbon itself is substituted with N-acylated piperazinesulfonamide is corresponding piperazinesulfonamide The solution of can be obtained by treating with a suitable carboxylic acid at about 20 ° C. for about 2 to 24 hours in a solvent such as N, N-dimethylformamide in the presence of a coupling agent such as polystyrene resin-bonded carbodiimide.
    [239] Then, post-treatment and purification to afford the acylated D piperacillin jinseol compound of carbon which is substituted with a phone amide I (wherein, A 1 is N, A 2 is CH).
    [240] Alternatively, these compounds may be prepared by reacting the corresponding piperazinesulfonamide solution in a solvent such as dichloromethane, in the presence of a base such as triethylamine, at about −20 to 20 ° C., preferably at 0 ° C., from about 15 to Obtained by treatment with a suitable alkanoyl or aroyl chloride for 2 hours. It is then quenched, for example with aqueous sodium bicarbonate, worked up and purified to give the desired acylated piperazinesulfonamide.
    [241] Compound I, wherein D is carbon substituted with piperazinesulfonamide, which is itself added during the urea bond, wherein A 1 is N and A 2 is CH, provides the corresponding piperazinesulfonamide solution with dichloromethane. In the same solvent, it can be obtained by treatment with a suitable isocyanate at about 0 to 40 ° C., preferably at about 20 ° C. for about 2 to 24 hours. Subsequent post-treatment and purification yields compound I wherein D is carbon substituted with urea functional piperazinesulfonamide, wherein A 1 is N and A 2 is CH.
    [242] Alternatively, compound I, wherein D is carbon itself substituted with piperazinesulfonamide, which is further N-sulfonylated, wherein A 1 is N and A 2 is CH is the corresponding piperazinesulfone The amide solution can be obtained by treating with a suitable sulfonyl chloride in a solvent such as dichloromethane in the presence of a base such as diethylamine for about 15-20 minutes at about -20 to 20 ° C, preferably about 0 ° C. Can be. Subsequently, for example, compound I (wherein, A 1 is N and A 2 is CH), for example, quenched with aqueous sodium bicarbonate, worked up and purified, and D is carbon substituted with sulfonylated piperazinesulfonamide. To obtain.
    [243] Functional group modifications known in the art can be used to modify the substituents of phase D described above to obtain further compounds of the invention.
    [244] A 2 is halogen, CN, CHO, an alkyl group, an alkyl or aryl sulfide, sulfoxide carbon substituted with various groups, such as the side or sulfone compound I (wherein, A 1 is N, D is CH) is the describing It can be prepared as described in Scheme V. In Scheme V, M is a metal atom such as Li or Mg, Hal is Cl, Br or I and E is an electron affinity reagent (Cl, Br, I, CN, alkyl, CHO, SO 2 M, SO 2 R Or CO 2 R, but not limited thereto), and R is alkyl or aryl.
    [245]
    [246] The desired N-halosuccinimide (about 2 molar equivalents to Compound I) is added to Compound I (wherein A 1 is N at about -10 ° C to ambient temperature, preferably about 0 ° C, in a suitable solvent such as methylene chloride) A 2 is CH and D is CH) and stirred for about 2-15 hours. Subsequent workup and purification yields compound I, wherein A 1 is N and A 2 and D are C-Cl, C-Br or CI.
    [247] Compound I, wherein A 1 is N and A 2 and D are C-Cl, C-Br or CI is about -78 to 0 ° C, preferably about -30 to-, in a suitable solvent such as THF Obtained by treatment with alkyl magnesium bromide, such as cyclopentyl magnesium bromide, at 40 ° C. under inert atmosphere for about 1-5 hours. Aqueous acid such as 1N hydrogen chloride or saturated NH 4 Cl solution is added. Subsequent workup and purification afford compound I, wherein A 1 is N, A 2 is C-Cl, C-Br or CI, and D is CH.
    [248] Halogen-substituted compound I, wherein A 1 is N, A 2 is C-Cl, C-Br or CI, and D is CH is treated with an organometallic reagent (e.g. alkyl or aryl lithium) or magnesium reagent This can be transformed into organometallic intermediate I (wherein A 1 is N, A 2 is CM, D is CH and M is a metal atom such as Li or Mg). Such organometallic reagents include N-chloro-, bromo- or iodo-succinimide, tosyl cyanide, alkyl halides, alkyl or aryl sulfonyl chlorides, alkyl or aryl disulfides, alkyl- or arylthiosulfonates, alkyl Or reacted with an electron affinity such as aryl chloroformate, N, N-dimethylformamide or sulfur dioxide so that A 2 is Cl, Br, I, CN, alkyl group, alkyl or aryl sulfone, alkyl or aryl sulfide, CHO or It is possible to obtain homologues of compound I, wherein A 1 is N and D is CH, which is carbon substituted with various groups such as sulfinate salts. Sulphides may be further oxidized to sulfoxides or sulfones using reagents such as potassium peroxymonosulfate or m-chlorobenzoic acid. In addition, sulfinate salts can be reacted with alkylating agents, such as alkyl bromide or iodide, to obtain sulfones. Alternatively, the sulfinate salt can be transformed with sulfonyl chloride using a chlorinating agent such as NCS. Sulfonyl chloride can be reacted with an amine to yield sulfonamide I, where A 1 is N, A 2 is C-SO 2 NR 1 R 2 , and D is CH.
    [249] More specifically, compounds I, wherein A 2 is C-CN, C-SO 2 R, CO 2 R, wherein R is alkyl or aryl, C = CHO, C-SO 2 Cl and C-SO 2 NRR ' Wherein A 1 is N and D is CH can be prepared from the corresponding halide or organomagnesium species as described in Scheme III above for D.
    [250] Transformation of functional groups well known in the art can be used to modify the substituents on A 2 described above to obtain further compounds of the invention.
    [251] Functional group transformation also applies to derivatization of R 4 . In particular, when R 4 is a brominated or iodinated benzyl group, these halogens can often be substituted by aryl groups by techniques known in the art, for example, a solution of a halogenated benzyl group may be combined with a mixture of toluene and ethanol. Aryl boronate for about 2 to 24 hours at about 75 to 110 ° C., preferably at about 85 ° C., using a metal catalyst such as Pd (PPh 3 ) 4 in the presence of a base such as aqueous sodium carbonate in the same solvent, Substitution is performed by treatment with an organometallic reagent such as boric acid or stanan. Subsequent workup and purification yields Compound I, wherein R 4 is CH 2 C 4 H 6 Ar and Ar is furyl, phenyl, pyridyl, pyrimidyl and thiophenyl, but is not limited thereto.
    [252] Compounds of formula I, wherein A 1 , A 2, and D are N, can be prepared as described in Scheme VI below.
    [253]
    [254] Intermediate VII is treated with an alkylating agent such as diethyl sulfate in an aqueous base and a suitable solvent such as THF. After workup and purification, the intermediate is treated with a suitable oxidizing agent such as potassium peroxymonosulfate to give sulfoxide X. The solution of compound X is then treated with NaN 3 at ambient temperature for about 12 to 24 hours. Work up and purify to afford carboxylic acid XI. The intermediate XI is then subjected to standard peptide coupling conditions, for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBT) and diiso. Propylethylamine is treated in a suitable solvent such as DMF at ambient temperature for about 5 to 24 hours. Subsequent workup and purification yields compound I, wherein A 1 , A 2 and D are N.
    [255] Compounds of formula (I) wherein A 1 is N, A 2 is N and D is CH can be prepared as described in Scheme VII below.
    [256]
    [257] Intermediate X (Scheme VI) is treated with formic acid hydrazide for about 5 to 24 hours at about 50-100 ° C., under an inert atmosphere in a suitable solvent such as DMSO, post-treated and purified to yield compound XII. Intermediate XII is treated with a catalytic amount of an acid such as p-toluenesulfonic acid in a suitable solvent such as toluene. Molecular sieves or traps can be used to collect the water formed in the reaction. The reaction is heated at reflux for about 3 to 12 hours. Purification affords the desired compound of formula I, wherein A 1 is N, A 2 is N and D is CH.
    [258] A homologue of compound I, wherein D is C substituted with various groups, where A 1 is N and A 2 is N, is a homologue of compound I (a feather is A 1 is N and A 2 is CH) It may be prepared as described.
    [259] The invention is further described by the following synthetic examples.
    [260] Synthetic Example
    [261] Example 1
    [262]
    [263] A solution of amino-ester XIII and 3,5-dichlorophenylisothiocyanate (1: 1 molar ratio) in 1,4-dioxane is heated at 90 ° C. for 10 hours under N 2 . The mixture is concentrated to afford the thiohydantoin derivative XIV. The product is characterized by 1 H NMR and mass spectroscopy.
    [264] Anise XV (9.0 mmol) is added to a solution of PPh 3 (9.0 mmol) in toluene (20 mL) under N 2 . After stirring overnight at room temperature, thiohydantoin XIV (4.5 mmol) is added. The mixture is sealed in a pressure tube under N 2 , heated at 130-140 ° C. for 3-4 days, concentrated and purified by silica gel chromatography to give the product XVI. The product is characterized by 1 H NMR and mass spectroscopy.
    [265] Trifluoroacetic acid (TFA, 5-6 equivalents) is added to a solution of XVI in dichloroethane. The mixture is heated at 90 ° C. overnight under N 2 . The residue is taken up in EtOAc, washed with saturated NaHCO 3 , dried over Na 2 SO 4 and concentrated. The residue is purified by silica gel chromatography to give the title compound 1 (melting point: 36 to 37.5 ° C.). The product is characterized by 1 H NMR and mass spectroscopy.
    [266] Example 2
    [267]
    [268] To a solution of compound 1 (1.82 g, 4.04 mmol) in CH 2 Cl 2 (20 mL) cooled to 0 ° C. was added a small amount of N-iodosuccinimide (1.43 g, 6.04 mmol). Pyridinium p-toluenesulfonate (100 mg, 0.40 mmol) is added and the mixture is stirred at 0 ° C. for 3 hours with N-iodosuccinimide (400 mg, 1.68 mmol) added until the reaction is complete. The mixture is diluted with CH 2 Cl 2 , washed with 10% Na 2 SO 3 solution, dried and concentrated. The residue is purified by silica gel chromatography to give a mixture of title compound 2 (1.86 g) and 2a (0.53 g). The product is characterized by 1 H NMR and mass spectroscopy.
    [269] In addition, diiodide 2a as the only product is prepared from compound 1 using at least 2 molar equivalents of N-iodine succinimide in the same manner as described above.
    [270] Example 3
    [271]
    [272] A solution of Compound 2 (33 mg, 0.0572 mmol) in THF is treated with a 2.0 M solution of cyclopentylmagnesium bromide (57 μl, 0.114 mmol) at −30 ° C. under nitrogen. The mixture is stirred at −30 ° C. for 2 hours before adding a solution of tosyl cyanide (70 mg, 0.367 mmol) in THF (0.5 mL). The mixture is stirred at −30 ° C. for 1 hour and then at room temperature overnight. The reaction is quenched at 0 ° C. with saturated NH 4 Cl solution. Extraction with EtOAc, followed by purification by silica gel chromatography yields compound 3 (9.5 mg, 35%) as a foam. The product is characterized by 1 H NMR and mass spectroscopy.
    [273] Example 4
    [274]
    [275] A solution of Compound 2 (32 mg, 0.055 mmol) in THF is treated with n-BuLi (44 μl, 1.5 M, 0.067 mmol) at −100 ° C. under nitrogen. The mixture is stirred at −100 ° C. for 15 minutes before adding DMF (50 μl). The mixture is stirred at −100 ° C. for 15 minutes and then at 0 ° C. for 1 hour before adding saturated NH 4 Cl solution (1 mL). Extraction with EtOAc then purification by silica gel chromatography yields compound 4 (3.0 mg, 11%) as an oil. The product is characterized by 1 H NMR and mass spectroscopy.
    [276] Example 5
    [277]
    [278] A solution of compound 2 (2.5 g, 4.33 mmol) in THF (25 mL) is treated with cyclopentylmagnesium bromide (2.6 mL, 2M, 5.2 mmol) at -40 ° C. under argon. The mixture is stirred at −40 ° C. for 40 minutes and then bubbled with SO 2 for at least 1 minute. The mixture is stirred for 15 minutes at -40 [deg.] C. and 1 hour at room temperature before concentrating twice in vacuo from anhydrous THF to give solid magnesium salt 5.
    [279] Example 6
    [280]
    [281] Magnesium salt 5 (1.00 g, 1.62 mmol) is dissolved in anhydrous DMF (5 mL) and treated with MeI (0.5 mL, 8 mmol) for 1.5 h at room temperature. Subsequently, the reaction is terminated by heating at 40 to 50 ° C. for 1 hour. The reaction is stopped by diluting the reaction mixture to moles. Extraction with EtOAc, followed by purification by silica gel chromatography yields compound 6 (3.66 g, 66%). Melting point 92-93 ° C. The product is characterized by 1 H NMR and mass spectroscopy.
    [282] Example 7
    [283]
    [284] In this example, racemate iodine 2b is used as starting material. Compound 2b is prepared by the same method as Compound 2 using racemate 1.
    [285] To a solution of anhydrous LiCl (10.0 mg, 0.236 mmol) and CuCN (10.5 mg, 0.117 mmol) in THF (0.2 mL) cooled at -20 ° C, CH 3 MgBr (1.4 M in THF, 0.21 mL, 0.294 mmol) was added to N. Add under 2 The solution is stirred at -20 ° C for 15 minutes. A solution of compound 2b (34 mg, 0.059 mmol) in THF (0.5 mL) was added. The reaction mixture is stirred at −20 ° C. for 2 hours before quenching with saturated NH 4 Cl at 0 ° C. and then overnight at room temperature. The mixture is extracted with EtOAc, dried over Na 2 S0 4 and concentrated. The residue is purified via preparative thin layer chromatography (prep-TLC) to give 2 mg of compound 7 (yield: 6%). The product is characterized by 1 H NMR and mass spectroscopy.
    [286] Example 8
    [287]
    [288] In this example, racemate diiodide 2c is used as starting material. Compound 2c is prepared by the same method as Compound 2a using racemate 1.
    [289] To a solution of compound 2c (766 mg, 1.09 mmol) in THF (10 mL) is added cyclopentylmagnesium bromide (2.0 M in ether, 1.36 mL, 2.72 mmol) at −30 ° C. under nitrogen. The solution is stirred at −30 ° C. for 1.5 hours before adding saturated aqueous NH 4 Cl solution. The mixture is warmed to room temperature and extracted with EtOAc. The organic layer is dried over Na 2 S0 4 and concentrated. The residue is purified by silica gel chromatography to give iodide 8. The product is characterized by 1 H NMR and mass spectroscopy.
    [290] Example 9 (9. BIRT0938XX)
    [291]
    [292] To a solution of iodide 8 (113 mg, 0.196 mmol) in THF (1 mL) is added cyclopentylmagnesium bromide (2.0 M in ether, 0.293 mL, 0.586 mmol) at −40 ° C. under nitrogen. The solution is stirred at −35 ° C. for 90 minutes before adding methyl chloroformate (0.1 mL, 1.47 mmol). The mixture is stirred at −35 ° C. for 30 minutes before adding saturated aqueous NH 4 Cl solution and then at room temperature for 1 hour. The mixture is extracted with EtOAc, the organic layer is dried over Na 2 SO 4 and concentrated. The residue is purified by silica gel chromatography to give product 9 (16 mg). The product is characterized by 1 H NMR and mass spectroscopy.
    [293] Example 10 (10. BIRT0937XX)
    [294]
    [295] A solution of iodide 8 (32 mg, 0.055 mmol) in THF (0.8 mL) is treated with cyclopentylmagnesium bromide (2.0 M in ether, 83 μl, 0.166 mmol) at −30 ° C. under nitrogen. The mixture is stirred at −30 ° C. for 1 hour before adding a solution of tosyl cyanide (53 mg, 0.28 mmol) in THF (0.2 mL). The mixture is stirred at −30 ° C. for 10 minutes and then at room temperature for 1 hour. The reaction is quenched with saturated NH 4 Cl at 0 ° C. Extraction with EtOAc followed by purification by silica gel chromatography yields 10 (10 mg) as a foam. The product is characterized by 1 H NMR and mass spectroscopy.
    [296] Example 11
    [297]
    [298] A solution of iodide 8 (88 mg, 0.152 mmol) in THF (1 mL) was treated with cyclopentylmagnesium bromide (2.0 M in ether, 230 μl, 0.46 mmol) at −30 ° C. under nitrogen. The mixture is stirred at −30 ° C. for 1 hour before adding methanesulfonyl chloride (60 μl, 0.775 mmol). The mixture is stirred at −30 ° C. for 1 hour and then at room temperature for 1 hour. The reaction is quenched at 0 ° C. with saturated NaHCO 3 solution. Extraction with EtOAc, then purification by silica gel chromatography yields compound 11 (18 mg, 35%). The product is characterized by 1 H NMR and mass spectroscopy.
    [299] Example 12
    [300]
    [301] A solution of compound 6 (0.1 g, 0.19 mmol) in 2 ml of toluene was treated with 5-trimethylstannylpyrimidine (0.07 g, 0.28 mmol) and Pd (PPh 3 ) 4 (22 mg, 0.02 mmol) and the mixture was overnight Heat to reflux. While cooling, the solvent is removed by rotary evaporator and the residue is purified by preparative TLC. Yields 50.4 mg of compound 12. Melting point 139 to 141 ° C. The product is characterized by 1 H NMR and mass spectroscopy.
    [302] Example 13
    [303]
    [304] A solution of 0.8 ml of compound 6 (90 mg, 0.17 mmol), 1 ml of EtOH and 2 M NaHCO 3 in 2 ml of toluene was added to pyridine-3-boronic acid (37 mg, 0.22 mmol) and Pd (PPh 3 ) 4 (20 mg, 0.02 mmol). To be processed. The mixture is heated to reflux for 1.5 hours. While cooling, the solvent is removed by rotary evaporator and the residue is purified by silica gel chromatography. Yields 50.4 mg of compound 13. Melting point 80-82 ° C. The product is characterized by 1 H NMR and mass spectroscopy.
    [305] Example 14
    [306]
    [307] A solution of Compound 2 (100 mg, 0.17 mmol) in 2.5 mL of THF is treated with cyclopentylmagnesium bromide (0.14 mL, 2M in ether, 0.28 mmol) at -40 ° C. under argon. The mixture is stirred at −40 ° C. for 40 minutes and then bubbled with SO 2 for 1 hour. The mixture is stirred for 15 minutes at −40 ° C., then for 1 hour at room temperature and finally at 45 ° C. before concentrating twice in vacuo from anhydrous THF to give a solid magnesium salt. The magnesium salt is treated with a mixture of triethylamine (0.035 mL, 0.36 mmol) and N-chlorosuccinimide (71 mg, 0.53 mmol). After 15 minutes, excess piperazine (119 mg, 1.38 mmol) is added and the reaction is stirred at room temperature for 3 hours. The mixture is then quenched by addition of saturated NH 4 Cl solution and extracted with EtOAc. While concentration, the crude product is purified by preparative TCL to give compound 14 (26 mg) as an oil. The product is characterized by 1 H NMR and mass spectroscopy.
    [308] Example 15
    [309]
    [310] 2.00 mL of 1N NaOH is added to a solution of 0.85 g of Compound XIV (1.91 mmol) and 0.30 mL of diethyl sulfate (0.35 g, 2.30 mmol) in 8.5 mL of THF with stirring in an ice bath. After 10 minutes of cooling, the reaction is warmed to room temperature and stirred for 3.5 hours. Liquid ammonium chloride is added and the reaction is extracted with EtOAc, dried over MgSO 4 and concentrated in vacuo to give an oil (0.98 g). Flash chromatography on silica gel yields 0.77 g (85%) of compound XVII as a clear oil. The product is characterized by 1 H NMR and mass spectroscopy.
    [311] 0.60 g of potassium peroxymonosulfate (1.13 mmol) in 2.5 ml of 4 x 10 -4 M EDTA was added to 7.56 ml of acetone and 0.76 g of compound XVII (1.61 mmol) in 2.5 ml of H 2 O and 0.68 g of NaHCO 3 (8.05 mmol). Is added to the stirred suspension. After stirring for 5 hours, the reaction is diluted with EtOAc and washed with saturated Na 2 SO 3 and brine. The combined liquid phases are extracted with EtOAc and the combined organic phases are dried over MgSO 4 and concentrated in vacuo to yield 0.82 g of compound XVIII as a clear oil. The product is characterized by 1 H NMR and mass spectroscopy.
    [312] 0.48 g of formic acid hydrazide (8.05 mmol) and 3.8 mL of anhydrous DMSO are added to the oil and the reaction is heated at 60 ° C. for 10 hours under argon. The white precipitate obtained by adding radish is extracted with EtOAc, washed with H 2 O, dried over MgSO 4 and concentrated in vacuo to give 0.72 g of solid product. Flash chromatography on silica gel gave 0.31 g of compound XIX (41%) as a white solid.
    [313] 0.15 g of compound XIX (0.319 mmol), 15 mg of p-toluenesulfonic acid, and 0.30 g of a 4 ′ molecular sieve are refluxed for 5.5 hours in 3 ml of toluene. The reaction is applied directly to a silica gel column and purified via flash chromatography to yield 0.12 g of compound 15 (82%) as a yellow foamed resin. The product is characterized by 1 H NMR and mass spectroscopy.
    [314] Example 16
    [315]
    [316] A solution of compound XVIII (Example 15) (130 mg, 0.266 mmol) in DMF (1 mL) was treated with NaN 3 (140 mg, 2.15 mmol) at room temperature for 20 hours. The mixture is diluted with H 2 O and extracted with EtOAc. The organic layer is dried over Na 2 S0 4 and concentrated. The residue is purified by silica gel chromatography to give compound XX (80 mg, 64%). The product is characterized by 1 H NMR and mass spectroscopy.
    [317] To a solution of compound XX (28 mg, 0.060 mmol) in DMF (0.5 mL) was added HOBT (16 mg, 0.118 mmol) and EDC (23 mg, 0.120 mmol). The mixture is stirred at room temperature for 2 hours before adding diisopropylethylamine (31 L, 0.18 mmol). The mixture is stirred at rt for 10 h, diluted with water and extracted with methylene chloride. The organic layer is dried, concentrated and purified by silica gel chromatography to give compound 16 (15 mg, 56%). The product is characterized by 1 H NMR and mass spectroscopy.
    [318] Example 17
    [319]
    [320] A mixture of 375 mg of compound 6 (0.709 mmol) and 70 mg of copper (I) cyanide (0.779 mmol) in 1.5 mL is stirred in anhydrous DMF and heated at 160 ° C. for 4 h under argon. After cooling, water and EtOAc are added, the reaction is filtered and the solid is washed with EtOAc to give 90 mg of a green solid. The filtrate is extracted with EtOAc, washed with water, dried and concentrated under reduced pressure to give 335 mg of resin. The solid was suspended in 2 mL of EtOAc, stirred with 16 L of SOCl 2 H 2 O overnight, EtOAc was added, the reaction was filtered, the filtrate was extracted with EtOAc, washed with H 2 O, dried and then depressurized Concentrate under. The combined crude products are purified by flash chromatography and dried at 60 ° C. in vacuo to yield 234 mg of compound 17 (69%) as a white resin. The product is characterized by 1 H NMR and mass spectroscopy.
    [321] Example 18
    [322]
    [323] A mixture of 2.50 g of Compound 1 (5.54 mmol) and 650 mg of copper (I) cyanide (7.20 mmol) in 8 ml of anhydrous DMF is stirred and heated at 160 ° C. for 5 hours under argon. After cooling, the mixture is poured into water, EtOAc is added, the reaction is filtered and the solid is washed with EtOAc to give 1.82 g of a gray solid. The filtrate is separated and the organic phase is washed with H 2 O and concentrated under reduced pressure to give 1.35 g of oil. The gray solid (1.4 g) was refluxed for 0.5 h in 0.27 mL SOCl 2 in 15 mL EtOAc. After cooling, H 2 O and EtOAc are added, the reaction is filtered and the solid is washed with EtOAc. The filtrate is extracted with EtOAc, the organic layer is dried and concentrated under reduced pressure. The crude products are combined and purified by flash chromatography to yield 890 mg of unreacted compound 1 (36%), 960 mg of compound XXI (46%) and mixed fraction 310.
    [324] N-iodosuccinimide (580 mg, 0.256 mmol) was added to a solution of 960 mg of compound XXI (2.44 mmol) and 61 mg of pyridinium p-toluenesulfonate (0.244 mmol) in 10 ml of methylene at 0 ° C. The reaction is warmed to room temperature and stirred overnight. The reaction mixture is concentrated under reduced pressure and the residue is diluted with EtOAc, washed with saturated aqueous Na 2 S 2 O 3 , dried and concentrated under reduced pressure. 310 mg of the mixed fractions are treated similarly as described above. After separation, the two residues are combined and purified by flash chromatography to yield 1.08 g of compound XXII (64%) as a resin. The product is characterized by 1 H NMR and mass spectroscopy.
    [325] Et 2 O was added in 2M cycle from pentyl bromide (1.24㎖, 2.48mmol) -50 ℃ a solution of a solution of anhydrous Et 2 O 20㎖ Compound XXII (2.06mmol) of 1.08g to give a white suspension. The reaction is stirred at −50 ° C. for 15 minutes and then bubbled with SO 2 for 2 minutes. The reaction mixture is further stirred at this temperature for 15 minutes and then at room temperature for 1 hour. The reaction is filtered and the solid is washed with Et 2 O and dried in vacuo at room temperature for 0.5 h to afford 1.44 g of compound 18 as a beige solid.
    [326] Example 19
    [327]
    [328] To a stirred solution of 177 mg of N-chlorosuccinimide (1.33 mmol) in dry THF (10 mL) was added 500 mg of compound 18 (0.709 mmol). The yellow solution obtained was stirred for 10 minutes. Piperazine (760 mg, 8.86 mmol) was added and the cloudy suspension obtained was stirred for 0.5 h. The reaction is filtered and the filtrate is washed successively with water and 2N NaOH, dried and concentrated under reduced pressure. The residue is purified by flash chromatography to give 225 mg of compound 19 (58%). The product is characterized by 1 H NMR and mass spectroscopy.
    [329] Examples 20-22
    [330]
    [331] Example 20
    [332] To a stirred solution of 71 mg N-chlorosuccinimide (0.532 mmol) in anhydrous THF (4 mL) was added 200 mg of compound 18 (0.283), and the yellow solution obtained was stirred for 10 minutes. Methyl isonipekotate (479 mL, 3.54 mmol) was added and the beige suspension obtained was stirred for 0.5 h. The reaction is filtered and the filtrate is washed successively with water and 2N NaOH, dried and then concentrated under reduced pressure. The residue was purified by preparative TLC to give 87 mg of compound 20 (51%). The product is characterized by 1 H NMR and mass spectroscopy.
    [333] Example 21
    [334] A stirred solution of 70 mg of compound 20 in 30% HBr in acetic acid is stirred at 50 ° C. for 3.5 hours. Water is added, the reaction is filtered and the solid is washed with H 2 O. The solid is dissolved in alcohol, precipitated with water, filtered and dried at 50 ° C. in vacuo to give 43 mg of beige powder. The liquid filtrate is extracted with EtOAc to give another 17 mg, giving a total of 60 mg of compound 21 (88%). The product is characterized by 1 H NMR and mass spectroscopy.
    [335] Example 22
    [336] A solution of 13 mg of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC) (0.069 mmol) and 34 mg of compound 21 (0.058 mmol) in 1 ml of CH 2 Cl 2 was 0.5 at 0 ° C. Stir for hours. Ammonia gas is bubbled for 1 minute, stirred at 0 ° C. for 15 minutes and then at room temperature for 7.5 hours. An additional 13 mg of EDC is added to the reaction, which is then saturated with NH 3 , sealed and stirred overnight. The reaction mixture is dried anhydrous under reduced pressure and the residue is purified by preparative TLC to give 13 mg of compound 22 (38%) as a resin. The product is characterized by 1 H NMR and mass spectroscopy.
    [337] Example 23
    [338]
    [339] A stirred solution of 27 mg of N-chlorosuccinimide (0.201 mmol) and 76 mg of compound 18 (0.107 mmol, approximately 80% purity) in 2 ml of dry THF is stirred at room temperature for 5 minutes. N-acetylpiperazine (86 mg, 0.67 mmol) is added and the resulting white suspension is stirred for 1 hour. The reaction mixture is diluted with EtOAc, filtered and the filtrate is washed successively with 2N HCl, 2N HaOH and H 2 O, dried and concentrated under reduced pressure. The residue was purified by preparative TLC to give 33.5 mg of compound 23 (53%). The product is characterized by 1 H NMR and mass spectroscopy.
    [340] Example 24
    [341] This example describes an alternative synthesis of intermediate XXI of Example 18.
    [342]
    [343] A solution of 15.1 ml of 1 M lithium bis (trimethylsilyl) amide (0.0151 mol) in THF is added to 5.00 g of compound XXIII (0.0126 mol) in 50 ml of anhydrous tetrahydrofuran at −10 ° C. and the orange solution is stirred for 0.5 h. A mixture of 2.96 g of bromo-5-toluonitrile (0.151 mol) in 15 mL of THF is added dropwise and the resulting suspension is stirred for 5 h between -10 and 0 ° C. Aqueous ammonium chloride is added and the aqueous layer is extracted with ether. The organic layer is dried and concentrated under reduced pressure. The residue is purified by flash chromatography and then recrystallized from CH 2 Cl 2 -pet ether to give 5.04 g of a white solid (78%). The product is characterized by 1 H NMR and mass spectroscopy.
    [344] A mixture of 5.00 g of Compound XXIV (9.67 mmol) and 5.78 ml of 40% benzyltrimethylammonium hydroxide (14.6 mmol) and 1.95 ml of 10N sodium hydroxide in 25 ml of 1,4-dioxane in H 2 O was mixed at room temperature for 15 hours. After stirring, it is heated at 40 ° C. for 1 hour. The mixture is cooled to room temperature, then 16.3 ml 6N HCl (96.7 mmol) is added and the mixture is stirred overnight. The solution of saturated aqueous Na 2 CO 3 and aqueous layer is extracted with EtOAc. The organic layer is dried, concentrated under reduced pressure and the residue is purified by flash chromatography to yield 2.78 g of compound XXV (82%) as an oil. The product is characterized by 1 H NMR and mass spectroscopy.
    [345] Thiophosgene (0.723 mL, 9.48 mmol) was added to a solution of 2.75 g of compound XXV (7.90 mmol) in 28 mL of CH 2 Cl 2 at 0 ° C. to give an orange solution. Triethylamine (4.40 mL, 31.6 mmol) is added and the dark solution is warmed to room temperature and stirred overnight. The reaction is diluted with EtOAc, washed with saturated aqueous NH 4 Cl, reextracted twice with EtOAc, dried and concentrated under reduced pressure. The residue is purified by flash chromatography to yield 1.35 g of recovered impurity XXV and 1.08 g of impurity XXVI. The recovered XXV is subjected to similar reaction conditions as above, separated and purified to further obtain 0.28 g of impurity XXVI. The two samples are combined and recrystallized by flash chromatography to yield 0.92 g of pure Compound XXVI. The product is characterized by 1 H NMR and mass spectroscopy.
    [346] Triphenylphosphine (1.18 g, 4.51 mmol) is added in part to a solution of 580 mg of compound XXVII (4.51 mmol) in 10 ml of xylene and stirred at room temperature for 2 hours. A 880 mg solution of Compound XXVI (2.25 mmol) in 2 ml of xylene is added and the reaction is heated to reflux for 3 days and then concentrated under reduced pressure. The residue is purified by flash chromatography to afford 420 mg of impurity XXVI and 290 mg of impurity XXVIII and are contaminated with triphenylphosphine oxide. A sample of compound XXVIII is treated in a pressure tube clarified with argon with 0.49 mL of trifluoroacetic acid (6.3 mmol) in 4 mL of 1,2-dichloroethane and heated at 110 ° C. overnight. The reaction is then treated with saturated aqueous Na 2 CO 3 , extracted with ether, dried and concentrated under reduced pressure. 420 mg of impurity XXVI is treated under conditions similar to those described above. After separation, both residues are combined and purified by flash chromatography to yield 120 mg of compound XXI (13%) as an oil. The product is characterized by 1 H NMR and mass spectroscopy.
    [347] Example 25
    [348]
    [349] To a stirred solution of magnesium salt 5 (2.61 g, 4.22 mmol) in THF (50 mL) was added N-chlorosuccinimide (0.79 g, 5.94 mmol). The resulting mixture is stirred at rt for 1 h, then poured into brine and extracted with EtOAc. The combined extracts are washed with brine, dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography to give 1.77 g of compound 25 (76%) as a foam, characterized by 1 H NMR and MS.
    [350] Example 26
    [351]
    [352] To a stirred solution of N-chlorosuccinimide (155 mg, 1.2 mmol) in THF (18 mL) was added compound 5 (600 mg, 0.97 mmol) at room temperature. The resulting yellow reaction mixture is stirred for 30 minutes, then a portion of piperazinone (214 mg, 2.1 mmol) is added followed by a few drops of DMSO. The reaction mixture is stirred overnight, then diluted with EtOAc, washed with brine, dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography to give 240 mg of compound 26 (40%) as a foam, characterized by 1 H NMR and MS.
    [353] Example 27
    [354]
    [355] To a stirred solution of compound 5 (308 mg, 0.50 mmol) in THF (12 mL) was added N-chlorosuccinimide (77.6 mg, 0.58 mmol) at −20 ° C. The resulting mixture is stirred for 10 minutes, warmed to 0 ° C. and then cooled to −30 ° C. L-proline methyl ester hydrochloride (50 mg, 0.81 mmol) is added, then triethylamine (0.12 mL) is added and the reaction mixture is stirred for 2 hours. The mixture is treated with saturated aqueous ammonium chloride and then extracted with diethyl ether. The organic layer is dried over MgSO 4 , filtered and the residue is purified by preparative TLC to give 127 mg of compound 27 (65%) as a foam which is characterized by 1 H NMR and MS.
    [356] Example 28
    [357]
    [358] To a stirred solution of N-chlorosuccinimide (325 mg, 2.4 mmol) in THF (10 mL) was added partially compound 5 (1.0 g, 1.6 mmol) at room temperature. The resulting yellow mixture is stirred for 5 minutes, then 4-acetylpiperazine (830 mg, 6.5 mmol) is added. The reaction mixture is stirred for 1 h, then washed with brine and the aqueous layer is extracted with EtOAc. The organic layer is washed successively with 1M HCl, saturated aqueous sodium bicarbonate and brine, then dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue was purified by silica gel chromatography to give 650 mg (melting point 153-155 ° C.) of compound 28 (63%) as a solid, characterized by 1 H NMR and MS. Alternatively, compound 28 may be prepared by a method using compound 14 (Example 14): Acetyl chloride (0.23 mL, 3.3 mmol) in a solution of compound 14 (200 mg, 0.33 mmol) in THF (20 mL). ) And triethylamine (0.23 mL, 1.65 mmol) were added at 0 ° C. The reaction mixture is warmed to room temperature for 1 hour and further stirred at this temperature for 1 hour. The mixture is poured into saturated aqueous sodium bicarbonate and the aqueous layer is extracted with EtOAc. The organic layer is dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue was purified by preparative TLC to give 193 mg of compound 28 (90%) as a solid, showing the same spectral properties as the title compound prepared by the foregoing method.
    [359] Example 29
    [360]
    [361] To a solution of compound 25 (900 mg, 1.6 mmol) in dichloromethane (10 mL) was added dropwise a solution of 1-Boc-piperazine (670 mg, 3.6 mmol) in dichloromethane at 0 ° C. The reaction mixture is warmed to room temperature and stirred for 2 hours. The mixture is diluted with EtOAc, washed successively with 0.1M HCl, water and brine, dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography to give 931 mg of compound 29 (82%) as a foam, characterized by 1 H NMR and MS.
    [362] Example 30
    [363]
    [364] This example describes an alternative synthesis of compound 14 (Example 14).
    [365] To a stirred solution of compound 29 (3.43 g, 4.9 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (5 mL, 65 mmol). The reaction mixture is allowed to warm to room temperature for 2 hours, then poured into 1M NaOH and extracted with dichloromethane. The organic layer is dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography to give 2.20 g of compound 14 (75%) as a foam, characterized by 1 H NMR and MS.
    [366] Example 31
    [367]
    [368] To a stirred solution of compound 14 (154 mg, 0.26 mmol) in dichloromethane (1.5 mL) is added methyl isocyanate (0.024 mL, 0.39 mmol). The reaction mixture is stirred for 0.5 h and then an additional amount of methyl isocyanate (0.024 mL, 0.39 mmol) is added. The reaction mixture is stirred for a further 0.5 h and then the solvent is removed under reduced pressure to yield compound 31 in portions and characterized by 1 H NMR and MS.
    [369] Example 32
    [370]
    [371] To a stirred solution of 3-hydroxypicolinic acid (138 mg, 0.99 mmol) in N, N-dimethylformamide (10 mL) was added PS-CDI resin (1.86 g, 1.65 mmol). After 1 h, compound 14 (200 mg, 0.33 mmol) is added and the reaction mixture is stirred overnight. The resin is filtered off, washed with dichloromethane and the combined organic layers are poured into water. The aqueous layer is extracted with dichloromethane and the organic layer is washed with brine, dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue is purified by preparative TLC to give 89 mg of compound 32 (37%) as a foam, characterized by 1 H NMR and MS.
    [372] Example 33
    [373]
    [374] To a stirred solution of morpholinoacetic acid (35 mg, 0.24 mmol) in N, N-dimethylformamide (8 mL) was added PS-CDI resin (425 mg, 0.48 mmol). After 1 h, compound 14 (50 mg, 0.08 mmol) is added and the reaction mixture is stirred overnight. The resin is filtered off, washed with dichloromethane and the combined organic layers are poured into water. The aqueous layer is extracted with dichloromethane and then the organic layer is washed with brine, dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue is purified by preparative TLC to give 59 mg of compound 33 (98%) as a foam, characterized by 1 H NMR and MS.
    [375] Example 34
    [376]
    [377] Compound 28 (29 mg, 0.045 mmol), 3,5-difluorophenylboronic acid (0.026 mL, 50% wt / wt in THF / H 2 O, 0.09 in a mixture of toluene (2 mL) and EtOH (1 mL) mmol) and P 2 Cl 2 (dppf) .CH 2 Cl 2 (1.8 mg, 0.0022 mmol) were added K 2 CO 3 (25 mg, 0.18 mmol) in water (0.5 mL). The reaction mixture is heated to reflux for 4 hours, then diluted with toluene, washed with brine, dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue is purified by preparative TLC to give 18.3 mg of compound 34 (60%) as a foam, characterized by 1 H NMR and MS.
    [378] Example 35
    [379]
    [380] Pd (PPh 3 ) 4 (120 mg, 0.11 mmol) was added to a stirred solution of compound 28 (300 mg, 0.47 mmol) and 5- (trimethylstannyl) pyrimidine (180 mg, 0.74 mmol) in toluene (10 mL), The reaction mixture is heated to reflux for 15 hours. Decolored charcoal is added to the mixture, stirred, filtered and the solvent is removed under reduced pressure. The residue was purified by preparative TLC to give 78 mg of compound 35 (26%) as a foam, characterized by 1 H NMR and MS.
    [381] Example 36
    [382]
    [383] Stirred solution of compound 31 (168 mg, 0.26 mmol) and pyridine-3-boronic acid propanediol ester (59 mg, 0.36 mmol) in a mixture of toluene (3 mL), ethanol (1.5 mL) and 2M aqueous sodium carbonate (1.25 mL) To Pd (PPh 3 ) 4 (59 mg, 0.05 mmol) is added. The reaction mixture is heated to reflux for 1 hour. The mixture is then filtered and the organic layer is diluted with EtOAc, washed with water, dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue is purified by preparative TLC to give 90 mg of compound 36 (32%) as a solid, characterized by 1 H NMR and MS.
    [384] Example 37
    [385]
    [386] To a stirred solution of compound 6 (195 mg, 0.37 mmol) and 3-thiophenboronic acid (94 mg, 0.74 mmol) in a mixture of toluene (4.4 mL), ethanol (2.2 mL) and 2M aqueous sodium carbonate (0.55 mL) was added. PPh 3 ) 4 (43 mg, 0.037 mmol) is added. The reaction mixture is heated to reflux for 3 hours and then diluted with EtOAc, washed successively with water and brine, dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue is purified by preparative TLC to give 123 mg of compound 37 (63%) as a foam, characterized by 1 H NMR and MS.
    [387] Example 38
    [388]
    [389] Stirred solution of compound 29 (860 mg, 1.23 mmol) and pyrimidine-5-boronic acid pinacol ester (506 mg, 2.46 mmol) in a mixture of toluene (7 mL), ethanol (3.5 mL) and 2M sodium carbonate (1.7 mL) Pd (PPh 3 ) 4 (142 mg, 0.12 mmol) was added to the reaction mixture, and the reaction mixture was heated to reflux for 1 hour. The mixture is diluted with EtOAc, washed successively with water and brine, then dried, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography to give 790 mg of Boc-protected compound 38 (92%) as a foam. To a stirred solution of Boc-protected compound 38 (704 mg, 1.0 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (3 mL) at room temperature. The reaction mixture is stirred for 2 hours, then poured into 1M sodium hydroxide and the aqueous layer is extracted with dichloromethane. The organic layer is washed with brine, dried over MgSO 4 , filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography to give 447 mg of compound 38 (64%) as a foam, characterized by 1 H NMR and MS.
    [390] The following additional compounds of the invention are prepared by methods analogous to those described above. Each compound below is characterized by NMR and MS.
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    [523] Description of Biological Features
    [524] The biological properties of each compound of formula I were investigated by the method of the experimental protocol described below.
    [525] LFA-1 Binding Inhibition Measurement Assay for ICAM-1
    [526] Purpose of the test:
    [527] This assay is designed to study the direct antagonism of the interaction of CAM, ICAM-1 with leucointegrin CD18 / CD11a (LFA-1) by test compounds.
    [528] Description of the assay protocol:
    [529] LFA-1 is immunopurified using TS2 / 4 antibody from 20 g pellets of human JY or SKW3 cells, see Dustin, MJ; et al., J. Immunol. 1992, 148, 2654-2660. LFA-1 is purified from SKW3 lysate by immunoaffinity chromatography on TS2 / 4 LFA-1 mAb Sepharose and eluted at pH 11.5 in the presence of 2 mM MgCl 2 and 1% octylglucoside. After collection and neutralization of fractions from the TS2 / 4 column, the samples are immersed and preliminarily removed using Protein G agarose.
    [530] Soluble forms of ICAM-1 are described in Marlin, S .; et al. Nature, 1990, 344, 70-72 and Arruda, A .; et al., Antimicrob. Agents Chemother. 1992, 36, 1186-1192, and are constructed, expressed, purified and characterized according to the methods described. In summary, isoleucine 454, located at the putative border between the foreign domain and domain 5 of the transmembrane domain, is transformed into a stop codon using standard oligonucleotide-directed mutations. This configuration yields molecules in which the first 453 amino acids of the membrane bound to ICAM-1 match. The expression vector, along with the transfected polyadenylation signal of the promoter, the splitting signal and the SV40 initial region, using the hamster dehydrofolate reductase gene, neomycin-resistant marker, and the coding region of sICAM-1 described above. It is constructed. Recombinant plasmids are transfected into CHO DUX cells using standard calcium phosphate methods. Cells pass through selective medium (G418) and colonies secreting sICAM-1 are amplified using methotrexate. sICAM-1 is purified from serum-free medium using conventional non-affinity chromatography techniques, including ion exchange and size exclusion chromatography.
    [531] LFA-1 bound to ICAM-1 was first incubated with sICAM-1 at 40 μg / ml in Dulbecco phosphate buffered saline with calcium and magnesium, further at 2 mM MgCl 2 and in 96-well plates at room temperature. Incubate in 0.1 mM of PMSF (dilution buffer). The plate is then blocked at 37 ° C. for 1 hour by the addition of 2% (w / v) bovine serum albumin in dilution buffer. The blocking solution is removed from the wells, the test compound is diluted, and about 25 ng of immunoaffinity purified LFA-1 is added. LFA-1 is incubated at 37 ° C. for 1 hour in the presence of test compound and ICAM-1. The wells are washed three times with dilution buffer. Bound LFA-1 is detected by addition of a polyclonal antibody against the peptide corresponding to the CD18 cytoplasmic tail in a dilution buffer and a 1: 100 dilution of 1% BSA and incubated at 37 ° C. for 45 minutes. The wells are washed three times with dilution buffer and bound polyclonal antibodies are detected by adding a 1: 4000 dilution of horseradish peroxidase conjugated to goat immunoglobulins detected against rabbit immunoglobulins. Incubate the reagents for 20 minutes at 37 ° C., wash the wells as described above, and add a substrate of horseradish peroxidase to each well to quantify the amount of LFA-1 binding to sICAM-1. Express the colorimetric signal ratio. Soluble ICAM-1 (60 μg / ml) is used as a positive control for inhibition of LFA-1 / ICAM-1 interaction. The lack of addition of LFA-1 to the binding assay is used as background control for all samples. Dose-response curves are obtained for all test compounds.
    [532] All compounds prepared in the above examples were tested in this assay and found to each have K d <10 μM.
    [533] Therapeutic Uses
    [534] The novel small molecules obtained by the present invention inhibit ICAM-1 / LFA-1 dependent homologous aggregation of human lymphocytes and human lymphocytes attached to ICAM-1. These compounds have therapeutic utility in the regulation of immune cell activity / proliferation, for example, competitive inhibition of intracellular ligand / receptor binding responses associated with CAMs and leucointegrins. More specifically, the compounds of the present invention are characterized by symptoms derived from the response of a nonspecific immune system in mammals (e.g. adult respiratory distress syndrome, shock, oxygen toxicity, secondary multiple organ damage syndrome due to pulmonary disease, secondary multiple organs due to trauma). Damage syndrome, cardiopulmonary bypass, myocardial infarction or tissue reperfusion injury due to the use of thrombolytic agents, acute glomerulonephritis, vasculitis, reactive arthritis, skin diseases with acute inflammatory components, stroke, heat damage, hemodialysis, leukocytosis, ulcers Symptoms arising from responses from colitis, necrotizing colitis and granulocyte transfusion-related syndromes and mammalian specific immune systems (e.g., psoriasis, organ / tissue transplant rejection, Raynaud syndrome) Reaction, autoimmune thyroiditis, dermatitis, multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes, uveitis, Crohn's disease It can be used in the treatment of certain inflammatory diseases, including lupus), inflammatory bowel disease, systemic lupus erythematosus, including the military and ulcerative colitis. The invention may also be used as an adjunct to minimize the toxicity of cytokine therapy in the treatment of asthma and cancer. In general, these compounds can be used for the treatment of diseases currently treatable via steroid therapy.
    [535] Accordingly, another aspect of the present invention is the provision of a method for the treatment or prevention of the above-described symptoms through the administration of a therapeutic or prophylactic amount of one or more compounds of formula (I).
    [536] According to the methods provided by the invention, the novel compounds of formula (I) may be administered alone or in combination with other immunosuppressive or anti-inflammatory agents for prophylactic or therapeutic purposes. When provided prophylactically, the immunosuppressive compound (s) are given prior to any inflammatory response or indication (eg, before, slightly after, or after transplantation of an organ or tissue, but not prior to all tissue rejection). ). Prophylactic administration of a compound of formula (I) prevents or reduces all subsequent inflammatory responses (eg, rejection of transplanted organs or tissues, etc.). Therapeutic administration of a compound of formula (I) reduces all substantial inflammation (eg, rejection of organ or tissue transplantation). Thus, the compounds of formula (I) according to the invention may be administered before the onset of inflammation (to suppress the expected inflammation) or after the onset of inflammation.
    [537] The novel compounds of formula (I) according to the invention can be administered in single or divided doses by oral, parenteral or topical route. Suitable oral dosages for the compounds of formula I range from about 0.1 mg to 10 mg per day. In parenteral administration, suitable dosage units may contain 0.1 to 250 mg of said compound, while suitable dosage units contain formulations containing 0.01 to 1% active ingredient. However, the dosage from patient to patient varies, and the dosage for all specific patients is determined by the clinician using criteria to determine the appropriate dosage for the patient's response to the drug as well as the dosage size and patient symptoms. It is understood that it depends on judgment.
    [538] When the compounds of the present invention are administered by the oral route, they may be administered in the form of pharmaceutical preparations containing them as medicaments and pharmaceutically suitable carrier materials. Such carrier material may be an inert organic or inorganic carrier material suitable for oral administration. Examples of such carrier materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene-glycols, mineral oil jelly and the like.
    [539] Pharmaceutical formulations may be prepared by conventional methods, and the final dosage form may be a solid dosage form (eg, tablets, dragees, capsules, etc.), or a liquid dosage form (eg, solvents, suspensions, emulsions, and the like). Pharmaceutical formulations can be applied to conventional pharmaceutical manipulations such as sterilization. In addition, pharmaceutical preparations may contain conventional adjuvants such as preservatives, stabilizers, emulsifiers, aroma-enhancers, wetting agents, buffers, salts for various osmotic pressures, and the like. For example, solid carrier materials including starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silica, dibasic calcium phosphate and high molecular weight polymers such as polyethylene glycol can be used.
    [540] For parenteral use, the compounds of formula (I) may be administered as liquid or non-liquid solutions, suspensions or emulsions in pharmaceutically acceptable oils or liquid mixtures, which form isotonic solutions with fungicides, antioxidants, preservatives, blood Buffers or other solvents, thickening agents, suspending agents or other pharmaceutically acceptable additives. Additives of this type are, for example, tartarate, citrate and acetate buffers for cotiness control, ethanol, propylene glycol, polyethylene glycol, complexing agents (e.g. EDTA), antioxidants (e.g. sodium bisulfite, Sodium metabisulfite and ascorbic acid), high molecular weight polymers such as liquid polyethylene glycols, and polyethylene derivatives of sorbitol anhydride. In addition, preservatives such as benzoic acid, methyl or propyl parabens, benzalkonium chloride and other quaternary ammonium compounds may be added if desired.
    [541] In addition, the compounds of the present invention may be administered as solutions for nasal application, and in addition to the compounds of the present invention may contain suitable buffers, tonicity modifiers, microbial preservatives, antioxidants and viscosity-increasing agents in liquid vehicles. . Examples of agents used to increase the viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbate or glycerin. The microbial preservative to be added may include benzalkonium chloride, thimerosal, chloro-butanol or phenylethyl alcohol.
    [542] In addition, the compounds provided by the present invention may be administered topically or as suppositories.
    [543] Formulation
    [544] Compounds of formula (I) can be formulated in a number of ways for therapeutic administration. Some exemplary formulations are described below.
    [545] Example A
    [546] Capsule or tablet
    [547] Example A-1Example A-2 ingredientamountingredientamount Compound of formula (I)250 mgCompound of formula (I)50 mg Starch160mgDicalcium phosphate160mg Microcrystalline cellulose90 mgMicrocrystalline cellulose90 mg Sodium starch glycolate10mgStearic acid5mg Magnesium stearate2mgSodium starch glycolate10mg Fumed Closable Silica1mgFumed Colloidal Silica1mg
    [548] Compounds of formula (I) are mixed in a powder mixture with premixed excipient materials as defined above with the exception of lubricants. The lubricant is then mixed and the resulting mixture compressed into tablets or filled with hard gelatin capsules.
    [549] Example B
    [550] Parenteral solvents
    [551] ingredientamount Compound of formula (I)500 mg PEG 40040% of capacity Ethyl alcohol5% of capacity Brine55% of capacity
    [552] The excipient materials are mixed and then one of the compounds of formula (I) is added at the dose required for dissolution. Continue mixing until the solution is clear. The solution is then filtered into suitable vials or ampoules and sterilized by autoclaving.
    [553] Example C
    [554] Suspension
    [555] ingredientamount Compound of formula (I)100mg Citric acid1.92 g Benzalkonium chloride0.025% by weight EDTA0.1 wt% Polyvinyl alcohol10% by weight waterSufficient amount in 100 ml
    [556] The excipient material is mixed with water, then one of the compounds of formula (I) is added and mixing is continued until the suspension is homogeneous. The suspending agent is then transferred into a suitable vial or ampoule.
    [557] Example D
    [558] Topical formulations
    [559] ingredientamount Compound of formula (I)5 wt% Tefose 6313% by weight Labrafil M 1944 CS3 wt% Paramin oil8% by weight Methylparaben (MP)0.15% by weight Propylparaben (PP)0.05 wt% Deionized waterFill within 100
    [560] Tefose 63, Labrafil M 1944 CS, paraffin oil and water are mixed and heated at 75 ° C. until all components have melted. The mixture is then cooled to 50 ° C. with continuous stirring. Methylparaben and propylparaben are added with mixing and the mixture is cooled to ambient temperature. The compound of formula I is added to the mixture and mixed well.
    权利要求:
    Claims (21)
    [1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt thereof.
    Formula I

    In Formula I above,
    A 1 is = N- or = C (H)-,
    A 2 is = N-, = C (H)-or = C (R ')-[where R' is halogen, -CN, -Oalkyl, -CO 2 alkyl or -SO 2 alkyl, wherein an alkyl moiety Is 1 to 3 carbon atoms);
    D is = N-, = C (R 1 )-, = C (H)-, = C (SO 2 R 1 )-, = C (S (O) R 1 )-, = C (C (O) R 1 )-, = C (C (O) H)-, = C (SR 1a )-, = C (OR 1a )-or = C (NHR 1a )-{where R 1 is (A) carbon number 1 Branched or straight chain alkyl of 6 to 6, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, wherein at least one hydrogen atom of an alkyl, alkenyl, cycloalkyl or cycloalkenyl group is independently Unsubstituted or (i) halogen, (ii) oxo, (iii) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, iso Oxazolyl, imidazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolyl, benzo [b] furanyl, benzo [b ] Thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinoli One or more hydrogen atoms of the aryl or heteroaryl group wherein the aryl or heteroaryl is selected from the group consisting of Unsubstituted, (a) alkyl of 1 to 3 carbon atoms, (b) -COOH, (c) -SO 2 OH, (d) -PO (OH) 2 , (e) a group of the formula -COOR 8 , wherein R 8 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (f) a group of the formula -NR 9 R 10 , wherein R 9 and R 10 are each independently a hydrogen atom or a carbon atom Alkyl of 1 to 6, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or R 9 and R 10 together with a nitrogen atom between them constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring (G) a group of formula -CONR 11 R 12 , wherein R 11 and Each R 12 is independently a hydrogen atom, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or R 11 and R 12 together with a nitrogen atom between them form a saturated hydrocarbon bridge having 3 to 5 carbon atoms Forms a cyclic ring, one carbon atom of the hydrocarbon bridge may be unsubstituted or substituted with —O—, —S—, S (O) —, SO 2 —, —NH—, or —NMe—), (h) a group of formula -OR 13 , wherein R 13 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, (i) a group of formula -SR 14 , wherein R 14 is a hydrogen atom or 1 carbon atom To alkyl or acyl group of 7), (j) -CN, (k) Amidino groups wherein R 15 , R 16 and R 17 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 15 , R 16 and R 17 are nitrogen atom (s) between them Together to form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring), (l) halogen, (m) a group of the formula -NHCONHalkyl, wherein the alkyl moiety has 1 to 3 carbon atoms, Or (n) a group of formula -NHCOOalkyl, wherein the alkyl moiety is substituted with 1 to 3 carbon atoms, (iv) a group of formula -COOR 18 , wherein R 18 is a straight chain having 1 to 7 carbon atoms, or Branched chain alkyl, or a group of cycloalkyl having 3 to 6 carbon atoms, (v) -CN, (vi) a group of the formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently a hydrogen atom, 1 carbon atom to 6, or an alkyl or cycloalkyl having 3 to 6, R 19 and R 20 is a nitrogen atom between them Together to configure a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, it is optionally substituted with one C atom of the hydrocarbon The bridges, -O-, -S-, S (O ) -, SO 2 -, - NH- or -NMe-), (vii) a group of formula -OR 21 , wherein R 21 is a hydrogen atom or a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms, one of an alkyl or acyl group The above hydrogen atoms are unsubstituted or substituted with a group independently selected from the group consisting of -OH-, -Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, -NH 2- , -NHMe and -NMe 2 . ), (viii) a group of the formula -SR 22 , wherein R 22 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, and at least one hydrogen atom of the alkyl or acyl group is unsubstituted, or -OH, -Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, -NH 2 , -NH Me and —NMe 2 to a group independently selected from the group consisting of (ix) a group of formula —NR 23 R 24 wherein R 23 and R 24 are each independently (a) a hydrogen atom, (b) Straight or branched alkyl or acyl of 1 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms, wherein one or more hydrogen atoms of the alkyl or acyl group are unsubstituted, or -OH, -Oalkyl, wherein the alkyl moiety 1 to 6), -NH 2 , -NHMe, and -NMe 2 to a group independently selected from the group consisting of (c) a group of formula-(CH 2 ) m COOH, wherein m is 0, 1 Or 2), (d) a group of the formula-(CH 2 ) n COOR 25 , wherein n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms, or (e) — (CH 2 ) n is a group of CONHR 25 where n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms} , (x) Quaternary groups of wherein R 26 , R 27 and R 28 are each independently a branched or straight chain alkyl group having 1 to 7 carbon atoms and Q − is a pharmaceutically acceptable counter ion, (xi) imidazoli Nil, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, A 3-7 membered saturated or partially saturated heterocyclic group selected from N, O, C and S, including but not limited to benzodioxolyl, tetrahydrothiophenyl and sulfolanil, wherein the heterocyclic group It is unsubstituted or substituted, is substituted by mono- or multi-substituted) and (xii) a cycloalkyl group of 3 to 7 carbon atoms with oxo; is -R 100,
    (B) branched or straight chain carboxylic acid groups having 3 to 6 carbon atoms,
    (C) branched or straight chain phosphonic acid groups having 2 to 6 carbon atoms,
    (D) branched or straight-chain sulfonic acid groups having 2 to 6 carbon atoms,
    (E) chemical formula Amidino groups wherein r is 2, 3, 4,5 or 6, R 29 , R 30 and R 31 are each independently a hydrogen atom or an alkyl having 1 to 3 carbon atoms, and R 29 , R 30 and R Two of 31 together with the nitrogen atom (s) therebetween may further constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring),
    (F) chemical formula Guanidino group of wherein s is 2, 3, 4, 5 or 6, R 32 , R 33 , R 34 and R 35 are each independently a hydrogen atom or alkyl of 1 to 3 carbon atoms, R 32 , Two of R 33 , R 34 and R 35 may further form a saturated hydrocarbon bridge of 3 to 5 carbon atoms with the nitrogen atom (s) therebetween to form a heterocyclic ring),
    (G) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl , Triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimida Aryl or heteroaryl selected from the group consisting of zolyl, quinolinyl, isoquinolinyl, furinyl, quinolinyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Wherein one or more hydrogen atoms of aryl and heteroaryl are unsubstituted, or (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO 2 OH, (iv) -PO (OH) 2 (v) a group of the formula -COOR 36 , wherein R 36 is straight or branched chain alkyl of 1 to 5 carbon atoms, or cyclo of 3 to 5 carbon atoms Alkyl), (vi) a group of the formula -NR 37 R 38 , wherein R 37 and R 38 are each independently a hydrogen atom, alkyl having 1 to 6 carbons, cycloalkyl having 3 to 6 carbons or 1 to C 7 is acyl, or R 37 and R 38 together with the nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring), (vii) a group of formula -CONR 39 R 40 ( Wherein R 39 and R 40 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or R 39 and R 40 are saturated hydrocarbons having 3 to 5 carbon atoms with nitrogen atoms therebetween; Form a bridge to form a heterocyclic ring, wherein one carbon atom of the hydrocarbon bridge is unsubstituted or substituted with -O-, -S-, S (O)-, SO 2- , -NH- or -NMe- is), (viii) a group of the formula -OR 41 (wherein, R 41 is a hydrogen atom, Is a C 1 -C 7 alkyl or acyl group of a), (ix) a group of the formula -SR 42 (wherein, R 42 is a hydrogen atom, or an alkyl or acyl group having 1 to 7), (x) -CN, or (xi) Formula Amidino groups wherein R 43 , R 44 and R 45 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, or two of R 43 , R 44 and R 45 are nitrogen atom (s) between them; And a saturated hydrocarbon bridge of 3 to 5 carbon atoms may be further configured to form a heterocyclic ring).
    (H) a group of formula -NR 46 R 47 , wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted or polysubstituted phenyl, or R 100 wherein R 100 is defined above ),
    (I) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl Saturated or unsaturated heterocyclic groups consisting of 3 to 7 ring atoms selected from N, O, C and S, including but not limited to, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanil Or a bicyclic heterocyclic group consisting of 8 to 11 atoms selected from N, O, C and S, wherein the heterocyclic group is unsubstituted or comprises: (i) oxo, (ii) -OR 101 where R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the alkyl group are unsubstituted, or -OH, -OR 110 , wherein R 110 is an alkyl residue having 1 to 6 carbon atoms Is substituted with -NH 2 , -NHMe or -NMe 2 ), (c ) Acyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the acyl group are unsubstituted, -OH, -OR 111 (where R 111 is an alkyl moiety having 1 to 6 carbon atoms), -NH 2 , -NHMe or -NMe 2 ), (d) -CONR 102 R 103 wherein R 102 and R 103 are each independently a hydrogen atom or alkyl of 1 to 7 carbon atoms, or R 102 and R 103 is a nitrogen atom between them Together to form a saturated hydrocarbon bridge having 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge is unsubstituted, -O-, -S-, S (O)-, SO 2- , -NH- or -NMe-, or (e) -COOR 104 (wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 where R 105 and R 106 are each independently (a) hydrogen atom, (b) cycloalkyl of 1 to 7 carbon atoms or straight-chain or branched alkyl having from 3 to 7 carbon atoms in the alkyl, (c) benzoyl, (d) benzyl Is (e) between the phenyl (wherein the phenyl ring is optionally substituted, -OR 112 (wherein R 112 is alkyl having a carbon number of 1 to 6), one is substituted or multi-substituted with a) or, R 105 and R 106 are those A saturated hydrocarbon bridge of 3 to 5 carbon atoms is formed together with the nitrogen atom to form a heterocyclic ring, and one carbon atom of the hydrocarbon bridge is unsubstituted or -O-, -S-, S (O)-, SO 2 -, -NH- or -NMe- is substituted; (iv) -COOR 107 (wherein R 107 is a hydrogen atom or straight or branched chain alkyl of 1 to 7 carbon atoms), (v) straight chain of 1 to 7 carbon atoms Or branched alkyl, alkenyl or alkynyl or alkynyl or cycloalkyl of 3 to 7 carbon atoms, wherein at least one hydrogen atom of the alkyl, alkenyl, alkynyl or cycloalkyl group is unsubstituted, or (a) oxo , (b) -OH, (c) -OR 113 wherein R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOC H 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 , wherein R 114 has 1 to 3 carbon atoms Alkyl, or a residue independently selected from the group consisting of 3 to 7 carbon atoms), (vi) an acyl having 1 to 7 carbon atoms, which may be linear, branched or cyclic, wherein at least one of the acyl groups The hydrogen atom is unsubstituted, or (a) -OH, (b) -OR 115 where R 115 is alkyl having 1 to 6 carbon atoms, (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 wherein R 116 is alkyl having 1 to 3 carbon atoms, (i) -CN, (j) halogen atom, (k) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl , Tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfone Heterocycles selected from the group consisting of ranyl and (l) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imida Zolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indah Zolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolinyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Substituted with residues independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of: (vii) -SO 2 R 108 wherein R 108 is (a) phenyl, naphthyl, indolyl, thiophenyl, Pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazole Reel, isoxazolyl, imidazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, Benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl , Aryl or heteroaryl selected from the group consisting of putridinyl and quinazolinyl, wherein the aryl or heteroaryl moiety is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 117 (where R 117 is hydrogen or alkyl having 1 to 6 carbon atoms), (b) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Thiomorpholinyl, thiazolidinyl, azefinyl, tetrahydro Heterocyclic groups selected from the group consisting of ranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl, and sulfolanil, wherein the heterocyclic group is unsubstituted, halogen atom, straight chain of 1 to 6 carbon atoms, or Branched alkyl and —OR 118 where R 118 is hydrogen or alkyl of 1 to 6 carbon atoms, or (c) straight or branched alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted, Halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 119 , wherein R 119 is substituted with one or more residues selected from the group consisting of hydrogen or alkyl of 1 to 6 carbon atoms), (viii) -COR 109 wherein R 109 is (a) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imida Sleepy, Sothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, Consisting of benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Aryl or heteroaryl selected from the group wherein the aryl or heteroaryl moiety is unsubstituted or substituted with a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 120 (wherein R 120 is hydrogen or alkyl of 1 to 6 carbon atoms And (b) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomor Polyyl, thiazolidinyl, azefinyl, Heterocyclic groups selected from the group consisting of trihydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein the heterocyclyl is unsubstituted, one or more halogen, 1 to 6 carbon atoms Straight or branched chain alkyl or —OR 121 wherein R 121 is hydrogen or alkyl of 1 to 6 carbon atoms, or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted Or substituted with one or more residues selected from the group consisting of halogen atoms, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 122 , wherein R 122 is hydrogen or alkyl of 1 to 6 carbon atoms. ix) -CHO, (x) halogen atom and (xi) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxa Reel, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] Thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl And a moiety mono- or polysubstituted with a residue selected from the group consisting of aryl or heteroaryl selected from the group consisting of quinazolinyl},
    (J) a halogen atom and
    (K) -CN, R 1a is R 100 }
    X is oxygen or sulfur atom,
    R 3 is (A) a hydrogen atom or
    (B) straight or branched chain alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 5 carbon atoms, wherein the alkyl or cycloalkyl group is unsubstituted or (i) a group of formula -OR 48 , wherein R 48 is hydrogen An atom or an alkyl or acyl group having 1 to 7 carbon atoms, or (ii) a group of the formula -NR 49 R 50 , wherein R 49 and R 50 are each independently a hydrogen atom, alkyl having 1 to 2 carbon atoms or 1 to C atoms Is acyl of 2), and
    R 4 is of the formula — (CR 51 R 52 ) x (CR 53 R 54 ) y R 55 {where x is 0 or 1,
    y is 0 or 1,
    R 51 , R 52 and R 53 are each independently (A) a hydrogen atom, (B) a group of the formula -OR 56 , wherein R 56 is a hydrogen atom or alkyl or acyl having 1 to 7 carbon atoms, or (C ) Linear or branched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    R 54 is (A) a group of formula R 57 , wherein R 57 is independently selected from the same class as R 1 or (B) a group of formula —OR 58 , wherein R 58 is from the same class as R 1 Is independently selected)
    R 55 is phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxdiazolyl , Triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimida Aryl or heteroaryl selected from the group consisting of zolyl, quinolinyl, isoquinolinyl, furinyl, quinolinyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Wherein one or more hydrogen atoms of the aryl or heteroaryl group are unsubstituted or (A) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, Pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, Riazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl , Aryl or heteroaryl selected from the group consisting of quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Wherein one or more hydrogen atoms of aryl or heteroaryl are unsubstituted, or (i) straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted, halogen or Mono- or polysubstituted with oxo, (ii) a group of formula -COOR 60 , wherein R 60 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (iii) a formula -NR 61 group of R 62 (where , R 61 and R 62 each independently is an acyl of a hydrogen atom, a C 1 -C 6 alkyl with the alkyl or fluoroalkyl, C 3 -C 6 cycloalkyl or C 1 -C 7, R 61 and R 62 is a nitrogen therebetween Together with the atoms form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, (iv) a group of the formula -CONR 63 R 64 , wherein R 63 and R 64 are each independently a hydrogen atom, carbon number Alkyl of 1 to 6 or fluoroalkyl or cycloalkyl of 3 to 6 carbon atoms, or R 63 and R 64 together with a nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring ), (v) a group of formula -OR 65 , wherein R 65 is a hydrogen atom or an alkyl, fluoroalkyl, or acyl group having 1 to 7 carbon atoms, (vi) a group of formula -SR 66 , wherein R 66 Is a hydrogen atom or R 59 is an alkyl having 1 to, or with an alkyl, fluoroalkyl 7 acyl group), (vii) -CN, (viii) nitro, or (ix) is independently substituted with halogen),
    (B) unsubstituted, monosubstituted or polysubstituted with a fluorine atom, further unsubstituted or monosubstituted with R 59 ,
    (C) straight or branched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted or mono- or polysubstituted by halogen or oxo,
    (D) a group of the formula -COOR 67 wherein R 67 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    (E) a group of formula -NR 68 R 69 , wherein R 68 and R 69 each independently represent a hydrogen atom, alkyl having 1 to 6 carbon atoms or fluoroalkyl, cycloalkyl having 3 to 6 carbon atoms or 1 to 7 carbon atoms; Or R 68 and R 69 together with the nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one of R 68 and R 69 may further be a group R 59 have),
    (F) a group of the formula -CONR 70 R 71 wherein R 70 and R 71 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms or fluoroalkyl or cycloalkyl having 3 to 6 carbon atoms, or R 70 and R 71 together with the nitrogen atoms between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one of R 70 and R 71 may further be a group R 59 ),
    (G) a group of formula -COR 72 wherein R 72 is a hydrogen atom, straight or branched chain alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R 59 ,
    (H) a group of the formula -OR 73 , wherein R 73 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group or R 59 ,
    (I) a group of the formula -SR 74 , wherein R 74 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group or R 59 having 1 to 7 carbon atoms,
    (J) -CN,
    (K) nitro or
    (L) is independently substituted with halogen] R 5 is Cl or trifluoromethyl,
    Z is = N- or = C (R 6 )-, where R 6 is hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl,
    R 7 is hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, -CN, nitro or trifluoromethyl and when Z is = N- or = C (H)-, R 7 is chlorine, trifluoro Methyl, -CN or nitro.
    [2" claim-type="Currently amended] The compound of claim 1, wherein A 1 is = N- or = C (H)-,
    A 2 is = N-, = C (H)-or = C (R ')-[where R' is halogen, -CN, -Oalkyl, -CO 2 alkyl or -SO 2 alkyl, wherein the alkyl moiety Is 1 to 3 carbon atoms);
    D = N-, = C (R 1 )-, = C (H)-, = C (SO 2 R 1 )-, = C (S (O) R 1 )-, = C (C (O) R 1 )-, = C (C (O) H)-, = C (SR 1a )-, = C (OR 1a )-or = C (NHR 1a )-{where R 1 is (A) carbon number 1 Straight or branched chain alkyl of 6 to 6, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, wherein at least one hydrogen atom of the alkyl, alkenyl, cycloalkyl or cycloalkenyl group is unsubstituted Or (i) halogen, (ii) oxo, (iii) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl , Imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolinyl, benzo [b] furanyl, benzo [b] thio Phenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolylyl, isoquinolinyl, furinyl, quinolizinyl, synol Aryl or heteroaryl selected from the group consisting of nil, phthalininyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl, wherein at least one hydrogen atom of the aryl or heteroaryl group is unsubstituted, or (a ) Alkyl of 1 to 3 carbon atoms, (b) -COOH, (c) -SO 2 OH, (d) -PO (OH) 2 , (e) a group of the formula -COOR 8 , wherein R 8 is 1 to Linear or branched alkyl of 5 or cycloalkyl of 3 to 5 carbon atoms, (f) a group of the formula -NR 9 R 10 , wherein R 9 and R 10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, Cycloalkyl having 3 to 6 carbon atoms or acyl having 1 to 7 carbon atoms, or R 9 and R 10 together with the nitrogen atom therebetween form a saturated hydrocarbon bridge having 3 to 5 carbon atoms to form a heterocyclic ring), ( g) a group of the formula -CONR 11 R 12 , wherein R 11 and R 12 are each independently Hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or R 11 and R 12 together with a nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring; , One carbon atom of a hydrocarbon bridge is unsubstituted or substituted with -O-, -S-, S (O)-, -SO 2- , -NH- or -NMe-), (h) formula -OR 13 Wherein R 13 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, (i) a group of the formula -SR 14 , wherein R 14 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms (J) -CN, (k) Amidino groups wherein R 15 , R 16 and R 17 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 15 , R 16 and R 17 are nitrogen atom (s) between them Together to form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to further form a heterocyclic ring), (l) halogen, (m) a group of the formula -NHCONHalkyl, wherein the alkyl moiety has 1 to 3 carbon atoms Or (n) independently substituted with a group of the formula -NHCOOalkyl, wherein the alkyl moiety has from 1 to 3 carbon atoms, (iv) a group of the formula -COOR 18 , wherein R 18 is a straight chain having from 1 to 7 carbon atoms Or branched alkyl or cycloalkyl having 3 to 6 carbon atoms, (v) -CN, (vi) a group of the formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently a hydrogen atom, 1 to 6 carbon atoms Is alkyl or cycloalkyl having 3 to 6 carbon atoms, or R 19 and R 20 are Together with the small atoms, a saturated hydrocarbon bridge of 3 to 5 carbon atoms is formed to form a heterocyclic ring, wherein one carbon atom of the hydrocarbon bridge is unsubstituted or -O-, -S-, S (O)-, SO 2 , -NH- or -NMe-, (vii) a group of formula -OR 21 wherein R 21 is a hydrogen atom or a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms, and is an alkyl or acyl group At least one hydrogen atom of is unsubstituted or substituted with a group independently selected from the group consisting of -OH, -Oalkyl, wherein alkyl has 1 to 6 carbon atoms, -NH 2 , -NHMe and -NMe 2 (viii) a group of the formula -SR 22 , wherein R 22 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, and at least one hydrogen atom of the alkyl or acyl group is unsubstituted, or -OH, -O Alkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, -NH 2 , -NHMe and -Substituted with a group independently selected from the group consisting of -NMe 2 , (ix) a group of the formula -NR 23 R 24 , wherein R 23 and R 24 are each independently (a) a hydrogen atom, (b) 1 carbon Straight or branched chain alkyl or acyl or cycloalkyl having 3 to 7 carbon atoms, and at least one hydrogen atom of the alkyl or acyl group is unsubstituted or -OH, -Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms ), -NH 2 , -NHMe and -NMe 2 is substituted with a group independently selected from the group consisting of (c) a group of the formula-(CH 2 ) m COOH, wherein m is 0, 1 or 2 (d) a group of formula-(CH 2 ) n COOR 25 , wherein n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms, or (e) a formula-(CH 2 ) n CONHR 25 group (wherein, n is 0, 1 or 2, R 25 is a linear or branched alkyl) group having 1 to 6), (x) Chemistry Expression Quaternary groups of wherein R 26 , R 27 and R 28 are each independently a straight or branched chain alkyl group having 1 to 7 carbon atoms and Q − is a pharmaceutically acceptable counter ion, (xi) imidazoli Nil, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, Saturated or partially unsaturated heterocyclic groups consisting of 3 to 7 ring atoms selected from N, O, C and S, including but not limited to benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein cyclic group is unsubstituted or substituted, it is substituted by mono- or multi-substituted in the cycloalkyl is) and (xii) an alkyl having from 3 to 7 carbon atoms with oxo; is -R 100a,
    (B) straight or branched carboxylic acid group having 3 to 6 carbon atoms,
    (C) a straight or branched chain phosphonic acid group having 2 to 6 carbon atoms,
    (D) straight or branched chain sulfonic acid group of 2 to 6 carbon atoms,
    (E) chemical formula Amidino groups wherein r is 2, 3, 4, 5 or 6, R 29 , R 30 and R 31 are each independently a hydrogen atom or an alkyl having 1 to 3 carbon atoms, and R 29 , R 30 and R Two of 31 together with the nitrogen atom (s) therebetween may further constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring),
    (F) chemical formula Guanidino group of wherein s is 2, 3, 4, 5 or 6, R 32 , R 33 , R 34 and R 35 are each independently a hydrogen atom or alkyl of 1 to 3 carbon atoms, R 32 , Two of R 33 , R 34 and R 35 may further form a saturated hydrocarbon bridge of 3 to 5 carbon atoms with the nitrogen atom (s) therebetween to form a heterocyclic ring),
    (G) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxdiazolyl , Triazolyl, tridiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimida Aryl or heteroaryl selected from the group consisting of zolyl, quinolinyl, isoquinolinyl, furinyl, quinolinyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Wherein the aryl or heteroaryl group is unsubstituted or comprises (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO 2 OH, (iv) -PO (OH) 2 , (v) groups of formula -COOR 36 (wherein, R 36 is a cycloalkyl group having 1 to 5 carbon atoms or straight or branched chain alkyl of 3 to 5 carbon atoms), (vi) A group of learning -NR 37 R 38 (wherein, R 37 and R 38 are each independently a hydrogen atom or an acyl, an alkyl group having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or 1 to 7 carbon atoms of a, R 37, and R 38 together with the nitrogen atoms between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, (vii) a group of the formula -CONR 39 R 40 , wherein R 39 and R 40 are each Independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or R 39 and R 40 together with a nitrogen atom between them constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring. And one carbon atom of the hydrocarbon bridge is unsubstituted or substituted with -O-, -S-, S (O)-, SO 2- , -NH- or -NMe-), (viii) formula -OR a group of 41 (wherein, R 41 is a hydrogen atom or an Al containing from 1 to 7 carbon atoms Or an acyl group), (ix) a group of the formula -SR 42 (wherein, R 42 is an alkyl or acyl group, a hydrogen atom or a C 1 -C 7), (x) -CN, or (xi) the formula Amidino groups wherein R 43 , R 44 and R 45 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 43 , R 44 and R 45 are nitrogen atom (s) between them; And a saturated hydrocarbon bridge of 3 to 5 carbon atoms may be further configured to form a heterocyclic ring).
    (H) a group of the formula -NR 46 R 47 wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted or polysubstituted phenyl, or R 100a , wherein R 100a is defined above ),
    (I) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl Saturated or unsaturated heterocyclic groups consisting of 3 to 7 ring atoms selected from N, O, C and S, including but not limited to, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanil Or a bicyclic heterocyclic group consisting of 8 to 11 atoms selected from N, O, C and S, wherein the heterocyclic group is unsubstituted, or (i) oxo, (ii) -OR 101 , wherein R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein the hydrogen atom of the alkyl group is unsubstituted, or -OH, -OR 110 , wherein R 110 is an alkyl residue having 1 to 6 carbon atoms ), it is replaced by -NH 2, -NHMe or -NMe 2), (c) tan 1 to an acyl (wherein the hydrogen atoms of the acyl group of 7 is optionally substituted, -OH, -OR 111 (wherein R 111 is an alkyl moiety having 1 to 6), -NH 2, -NHMe or -NMe 2 ), (d) -CONR 102 R 103 , wherein R 102 and R 103 are each independently a hydrogen atom or an alkyl having 1 to 7 carbon atoms, or R 102 and R 103 together with a nitrogen atom therebetween; It forms a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge is unsubstituted, or -O-, -S-, S (O)-, SO 2- , -NH -Or -NMe-) or (e) -COOR 104 (wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 where R 105 and R 106 are Each independently (a) a hydrogen atom, (b) straight or branched chain alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, (c) benzoyl, (d) benzyl or (e) phenyl (Wherein the phenyl ring is optionally substituted, -OR 112 (wherein R 112 is a number of carbon atoms is 1 to 6 alkyl) monosubstituted or polysubstituted in), or, R 105 and R 106 are carbon atoms together with the nitrogen atom between them It forms a saturated hydrocarbon bridge of 3 to 5 to form a heterocyclic ring, wherein one carbon atom of the hydrocarbon bridge is unsubstituted or -O-, -S-, S (O)-, -SO 2- , -NH -Or-is substituted with -NMe-, (iv) -COOR 107 (wherein R 107 is a hydrogen atom or straight or branched chain alkyl of 1 to 7 carbon atoms), (v) straight or branched alkyl of 1 to 7 carbon atoms , Alkenyl or alkynyl having 2 to 7 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, wherein at least one hydrogen atom of alkyl, alkenyl, alkynyl or cycloalkyl is unsubstituted, or (a) oxo, (b ) -OH, (c) -OR 113 wherein R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 , wherein R 114 is alkyl having 1 to 3 carbon atoms or cycloalkyl having 3 to 7 carbon atoms (Vi) acyl having 1 to 7 carbon atoms, which may be linear, branched or cyclic, wherein at least one hydrogen atom of the acyl group is unsubstituted, or (a) -OH, (b) -OR 115 , wherein R 115 is alkyl having 1 to 6 carbon atoms, (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 wherein R 116 is alkyl having 1 to 3 carbon atoms, (i) -CN, (j) halogen atom, (k) imidazolinyl, imida Zolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, Tetrahydrothiophenyl and sulfolanil Heterocycles selected from the relevant classes and (l) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, Isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, Consisting of benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Substituted with residues independently selected from the group consisting of aryl or heteroaryl selected from the class), (vii) -SO 2 R 108 , wherein R 108 is (a) phenyl, naphthyl, indolyl, thiophenyl, pyridyl , Pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxa Zolyl, imidazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] Thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl And aryl or heteroaryl selected from the group consisting of quinazolinyl, wherein the aryl or heteroaryl moiety is unsubstituted, halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 117 where R 117 is hydrogen or Is substituted with one or more residues selected from the group consisting of alkyl having 1 to 6 carbon atoms), (b) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, Morpholinyl, thiomorpholinyl, thia Heterocyclic groups selected from the group consisting of lidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanil, wherein the heterocyclic group is unsubstituted, Halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 118 where R 118 is hydrogen or alkyl of 1 to 6 carbon atoms, or is substituted with one or more residues selected from the group consisting of (c) 1 carbon To straight or branched chain alkyl of 7 to 7 wherein the alkyl moiety is unsubstituted or is a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 119 where R 119 is hydrogen or alkyl of 1 to 6 carbon atoms (Viii) -COR 109 wherein R 109 is (a) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, p Limidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl , Indolinyl, isoindolinyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl Aryl or heteroaryl selected from the group consisting of cinnalinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl, wherein the aryl or heteroaryl moiety is unsubstituted, halogen atom, carbon number 1 to 6 straight or branched chain alkyl and -OR 120 , wherein R 120 is hydrogen or substituted with one or more residues selected from the group consisting of alkyl having 1 to 6 carbon atoms, (b) imidazolinyl, Dazolidinyl, pyrrolinyl, pyrrolidi , Consisting of piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanilyl Heterocyclic groups selected from the class wherein heterocyclyl is unsubstituted or substituted with one or more halogens, straight or branched chain alkyl of 1 to 6 carbon atoms, or -OR 121 , wherein R 121 is hydrogen or alkyl of 1 to 6 carbon atoms (C) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted or halogen, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 122 where R 122 is hydrogen or (Ix) -CHO, (x) a halogen atom and (xi) phenyl, naphthyl, indolyl, thiophenyl, p) Ridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, Triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinone Mono- or polysubstituted by a moiety independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of nolinyl, cinnalinenyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl ],
    (J) a halogen atom and
    (K) -CN, R 1a is R 100a },
    X is oxygen or sulfur atom,
    R 3 is (A) a hydrogen atom or
    (B) straight or branched chain alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, wherein the alkyl and cycloalkyl groups are unsubstituted, or (i) a group of formula R 48 , wherein R 48 is a hydrogen atom or Alkyl or acyl group of 1 to 7 carbon atoms or (ii) a group of formula -NR 49 R 50 , wherein R 49 and R 50 are each independently a hydrogen atom, alkyl of 1 to 2 carbon atoms or of 1 to 2 carbon atoms You know,
    R 4 is a group of the formula —CH 2 R 55 wherein R 55 is phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, iso Oxazolyl, imidazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolyl, benzo [b] furanyl, benzo [b ] Thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnaolinyl, phthalaninyl, quinoxalinyl, naphthyridinyl, puteri Aryl or heteroaryl selected from the group consisting of diyl and quinazolinyl, wherein at least one hydrogen atom of the aryl or heteroaryl group is unsubstituted or (A) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyri Midinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxoxazolyl, already Zolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indah Zolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolinyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Aryl or heteroaryl selected from the class consisting of: at least one hydrogen atom of aryl or heteroaryl is unsubstituted, or (i) straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein Or cycloalkyl is unsubstituted or mono- or polysubstituted by halogen or oxo, (ii) a group of the formula -COOR 60 , wherein R 60 is straight or branched alkyl of 1 to 5 carbon atoms or of 3 to 5 carbon atoms Cycloal A), (iii) a group of the formula -NR 61 R 62 (wherein, R 61 and R 62 each independently represent a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms alkyl, cycloalkyl or C 1 of 3 to 6 carbon atoms Or R 61 and R 62 together with the nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring), (iv) a group of the formula -CONR 63 R 64 Wherein R 63 and R 64 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms or fluoroalkyl or cycloalkyl having 3 to 6 carbon atoms, or R 63 and R 64 together with a nitrogen atom therebetween To form a saturated hydrocarbon bridge of from 5 to 5 to form a heterocyclic ring, (v) a group of the formula -OR 65 , wherein R 65 is a hydrogen atom or an alkyl, fluoroalkyl or acyl group having 1 to 7 carbon atoms ), (vi) chemical formula- R which is a group of SR 66 , wherein R 66 is a hydrogen atom or an alkyl, fluoroalkyl or acyl group having 1 to 7 carbon atoms, (vii) -CN, (viii) nitro or (ix) substituted by halogen) 59a ,
    (B) unsubstituted, monosubstituted or polysubstituted with a fluorine atom, unsubstituted or further monosubstituted with R 59a ,
    (C) straight or branched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted or mono- or polysubstituted by halogen or oxo,
    (D) a group of the formula -COOR 67 wherein R 67 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    (E) a group of formula -NR 68 R 69 , wherein R 68 and R 69 each independently represent a hydrogen atom, alkyl having 1 to 6 carbon atoms or fluoroalkyl, cycloalkyl having 3 to 6 carbon atoms or 1 to 7 carbon atoms; Or ac 68 or R 69 together with the nitrogen atoms between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one of R 68 and R 69 may further be R 59a ),
    (F) a group of the formula -CONR 70 R 71 wherein R 70 and R 71 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms or fluoroalkyl or cycloalkyl having 3 to 6 carbon atoms, or R 70 and R 71 together with the nitrogen atoms between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one of R 70 and R 71 may further be R 59a ),
    (G) a group of the formula -COR 72 wherein R 72 is a hydrogen atom, straight or branched chain alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R 59a ,
    (H) a group of the formula -OR 73 wherein R 73 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group or R 59a having 1 to 7 carbon atoms,
    (I) a group of formula -SR 74 , wherein R 74 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group or R 59a having 1 to 7 carbon atoms,
    (J) -CN,
    (K) nitro or
    (L) is independently substituted with halogen] R 5 is Cl or trifluoromethyl,
    Z is = N- or = C (R 6 )-, wherein R 6 is hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl,
    R 7 is hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, -CN, nitro or trifluoromethyl and when Z is = N- or = C (H)-, R 7 is chlorine, trifluoro A compound of formula (I) or a pharmaceutically acceptable salt thereof, which is methyl, -CN or nitro.
    [3" claim-type="Currently amended] The compound of claim 1, wherein A 1 is = N- or = C (H)-,
    A 2 is = N- or = C (H)-,
    D is = N-, = C (R 1 )-, = C (H)-, = C (SO 2 R 1 )-, = C (C (O) H)-or = C (C (O) R 1 )-{wherein R 1 is (A) straight or branched chain alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, wherein alkyl, alkenyl, cyclo At least one hydrogen atom of the alkyl or cycloalkenyl group is unsubstituted, (i) oxo, (ii) phenyl, wherein one hydrogen atom of the phenyl group is unsubstituted, or (a) alkyl having 1 to 3 carbon atoms, (b) -COOH, (c) -SO 2 OH, (d) -PO (OH) 2 , (e) a group of the formula -COOR 8 , wherein R 8 is straight or branched chain alkyl or carbon number of 1 to 5 carbon atoms Cycloalkyl of 3 to 5), (f) a group of formula -NR 9 R 10 , wherein R 9 and R 10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, or Acyl having 1 to 7 carbon atoms, or R 9 and R 10 are these Together with the nitrogen atom in between form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, (g) a group of the formula -CONR 11 R 12 , wherein R 11 and R 12 are each independently Or a hydrogen atom, alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, or R 11 and R 12 together with a nitrogen atom therebetween form a saturated hydrocarbon bridge having 3 to 5 carbon atoms to form a heterocyclic ring. Wherein one carbon atom of the saturated hydrocarbon bridge is unsubstituted or substituted with -O-, -NH- or -NMe-, (h) a group of the formula -OR 13 , wherein R 13 is a hydrogen atom or 1 carbon atom To alkyl or acyl of (7) to (7), (i) a group of formula -SR 14 , wherein R 14 is a hydrogen atom or an alkyl or acyl of 1 to 7 carbon atoms, (j) -CN or (k) Amidino groups wherein R 15 , R 16 and R 17 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 15 , R 16 and R 17 are nitrogen atom (s) between them And a saturated hydrocarbon bridge of 3 to 5 carbon atoms may be further configured to form a heterocyclic ring), (l) a group of the formula -NHCONHalkyl, wherein the alkyl moiety has 1 to 3 carbon atoms, or (m A group of formula -NHCOOalkyl, wherein the alkyl moiety has from 1 to 3 carbon atoms; and (iii) a group of formula -COOR 18 , wherein R 18 is straight or branched chain alkyl of 1 to 7 carbon atoms. Or cycloalkyl of 3 to 6 carbon atoms, (iv) a group of the formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cyclo of 3 to 6 carbon atoms Alkyl, or R 19 and R 20 together with the nitrogen atom between them Form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-), (v) A group of -OR 21 wherein R 21 is a hydrogen atom or a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms, and at least one hydrogen atom of the alkyl or acyl group is unsubstituted, or -OH-, -Oalkyl ( Wherein the alkyl moiety is substituted with a group independently selected from the group consisting of 1 to 6 carbon atoms, -NH 2 , -NHMe and -NMe 2 ), (vi) a group of formula -NR 23 R 24 , wherein R 23 and R 24 each independently represent (a) a hydrogen atom, (b) a straight or branched chain alkyl or acyl having 1 to 7 carbon atoms or an acyl or a cycloalkyl having 3 to 7 carbon atoms, wherein at least one hydrogen atom of the alkyl or acyl group is substituted Or -OH, -Oalkyl Standing, the alkyl moiety is 1 to 6 carbon atoms), is replaced by a group independently selected from the class consisting of -NH 2, -NHMe and -NMe 2), (c) the formula - group of (CH 2) m COOH (wherein , m is 0, 1 or 2, (d) a group of the formula-(CH 2 ) n COOR 25 wherein n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms ) Or (e) a group of the formula-(CH 2 ) n CONHR 25 , wherein n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms, (vii) Quaternary groups of wherein R 26 , R 27 and R 28 are each independently a straight or branched chain alkyl group having 1 to 7 carbon atoms and Q − is a pharmaceutically acceptable counter ion; or (viii) 3 to C carbon atoms Independently substituted with a cycloalkyl group of 7] -R 100b ,
    (B) straight or branched carboxylic acid group having 3 to 6 carbon atoms,
    (C) a straight or branched chain phosphonic acid group having 2 to 6 carbon atoms,
    (D) straight or branched chain sulfonic acid group of 2 to 6 carbon atoms,
    (E) chemical formula Amidino groups wherein r is 2, 3, 4, 5 or 6, R 29 , R 30 and R 31 are each independently a hydrogen atom or an alkyl having 1 to 3 carbons, and R 29 , R 30 and R Two of 31 together with the nitrogen atom (s) therebetween may further constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring),
    (F) chemical formula Guanidino group of wherein s is 2, 3, 4, 5 or 6, R 32 , R 33 , R 34 and R 35 are each independently a hydrogen atom or alkyl of 1 to 3 carbon atoms, R 32 , Two of R 33 , R 34 and R 35 may further form a saturated hydrocarbon bridge of 3 to 5 carbon atoms with the nitrogen atom (s) therebetween to form a heterocyclic ring),
    (G) phenyl [where at least one hydrogen atom of the phenyl group is unsubstituted or (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO 2 OH, (iv) -PO (OH ) 2 , (v) a group of formula -COOR 36 , wherein R 36 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a group of formula -NR 37 R 38 ( Wherein R 37 and R 38 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or acyl having 1 to 7 carbon atoms, or R 37 and R 38 together with the nitrogen atom therebetween; A saturated hydrocarbon bridge of 3 to 5 carbon atoms is formed to form a heterocyclic ring), (vii) a group of the formula -CONR 39 R 40 , wherein R 39 and R 40 are each independently a hydrogen atom, 1 to 6 carbon atoms the alkyl or cycloalkyl having 3 to 6, R 39 and R 40 are burnt together with the nitrogen atom between them A saturated hydrocarbon bridge of number 3 to 5 forms a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-), (viii) A group of —OR 41 , wherein R 41 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, (ix) a group of formula —SR 42 , wherein R 42 is a hydrogen atom or an alkyl having 1 to 7 carbon atoms Or an acyl group), (x) -CN or (xi) Amidino groups wherein R 43 , R 44 and R 45 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 43 , R 44 and R 45 are nitrogen atom (s) between them; Together with a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring);
    (H) a group of formula -NR 46 R 47 wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted or polysubstituted phenyl, or R 100b , wherein R 100b is defined above ),
    (I) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl , A saturated or unsaturated heterocyclic group selected from the group consisting of tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanil, wherein the heterocyclic group is unsubstituted, or (i) oxo, (ii) -OR 101 {where R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the alkyl are unsubstituted, or -OH, -OR 110 , wherein R 110 represents Is substituted with 1 to 6 alkyl residues), -NH 2 , -NHMe or -NMe 2 ), (c) acyl having 1 to 7 carbon atoms (wherein all hydrogen atoms of acyl are unsubstituted or -OH,- OR 111 , wherein R 111 is alkyl of 1 to 6 carbon atoms, is substituted with -NH 2 , -NHMe or -NMe 2 ), (D) -CONR 102 R 103 ( wherein, R 102 and R 103 are each independently a hydrogen atom or an alkyl group having 1 to 7, R 102 and R 103 is 3 to 5 carbon atoms together with the nitrogen atom between them To form a heterocyclic ring, wherein one carbon atom of the hydrocarbon bridge is unsubstituted or substituted with -O-, -NH- or -NMe-, or (e) -COOR 104 , , R 104 is alkyl having 1 to 7 carbon atoms}, (iii) a group of -CONR 105 R 106 , wherein R 105 and R 106 are each independently (a) a hydrogen atom, (b) 1 to 7 carbon atoms Straight or branched chain alkyl or cycloalkyl having 3 to 7 carbon atoms, (c) benzoyl, (d) benzyl or (e) phenyl, wherein the phenyl ring is unsubstituted or -OR 112 wherein R 112 is 1 to 6 carbon atoms Is mono- or polysubstituted), or R 105 and R 106 are burnt together with a nitrogen atom between them. A saturated hydrocarbon bridge of 3 to 5 minority forms a heterocyclic ring, one carbon atom of the hydrocarbon bridge is unsubstituted or substituted with -O-, -NH- or -NMe-), (iv ) -COOR 107 where R 107 is a hydrogen atom or straight or branched chain alkyl of 1 to 7 carbon atoms, (v) straight or branched chain alkyl of 1 to 7 carbon atoms, alkenyl or alkynyl of 2 to 7 carbon atoms, or Cycloalkyl having 3 to 7 carbon atoms, wherein at least one hydrogen atom of an alkyl, alkenyl, alkynyl or cycloalkyl group is unsubstituted, or (a) oxo, (b) -OH, (c) -OR 113 where , R 113 is alkyl having 1 to 6 carbon atoms), (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i ) to -CO 2 R 114 (wherein, R 114 are independently from the class consisting of a C 1 -C 3 alkyl or cycloalkyl of 3 to 7 carbon atoms of) the selected residues Is unsubstituted), (vi) straight-chain, at least one hydrogen atom of the C 1 -C 7 acylamino (wherein the acyl group of which may be branched or cyclic is unsubstituted or substituted with, (a) -OH, (b ) -OR 115 ( Wherein R 115 is alkyl having 1 to 6 carbon atoms), (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 where R 116 is alkyl having 1 to 3 carbon atoms, (i) -CN, (j) halogen atom, (k) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl , Consisting of piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanilyl Heteroaryl selected from the class and (l) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, Isoty Azolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolinyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benz Class consisting of thiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Substituted with a residue independently selected from the group consisting of aryl or heteroaryl), (vii) -SO 2 R 108 wherein R 108 is (a) phenyl, naphthyl, indolyl, thiophenyl, pyridyl, Pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl , Indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, Consisting of benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cinnolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl Aryl or heteroaryl selected from the group wherein the aryl or heteroaryl moiety is unsubstituted or substituted with a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 117 , wherein R 117 is hydrogen or alkyl of 1 to 6 carbon atoms And (b) imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomor Heterocyclic groups selected from the group consisting of polyyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanil, wherein , The heterocyclic group is optionally substituted, a halogen atom, a straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 118 one or more moieties selected from the class consisting of (wherein, R 118 is hydrogen or alkyl having 1 to 6 carbon atoms) Or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted or is a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 119 where R 119 is hydrogen Or at least one moiety selected from the group consisting of alkyl having 1 to 6 carbon atoms), (viii) -COR 109 wherein R 109 is (a) phenyl, naphthyl, indolyl, thiophenyl, Pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadizolyl, pyridazinyl, pyrazinyl , Triazinyl, phosphorus Dolginyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl, quinolininyl, cin Aryl or heteroaryl selected from the group consisting of nolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, pterridinyl and quinazolinyl, wherein the aryl or heteroaryl moiety is unsubstituted, halogen atom, carbon atoms from 1 to Straight or branched chain alkyl of 6 and —OR 120 where R 120 is hydrogen or substituted with one or more residues selected from the group consisting of alkyl of 1 to 6 carbon atoms, (b) imidazolinyl, imidazoli Dinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetra Hydrothiophenyl and sulfol The heterocyclic is selected from the class consisting Nilo group (wherein the heterocyclic group is optionally substituted with one or more halogen, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 121 (wherein R 121 is hydrogen or a 1 to 6 carbon atoms, Or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted or is a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 122 , wherein R 112 is hydrogen or alkyl having 1 to 6 carbon atoms); and (ix) -CHO, (x) halogen atom and (xi) phenyl, naphthyl, indolyl , Thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxdiazolyl, triazolyl, thiadiazolyl, pyrida Genil, Fira Nil, triazinyl, indolinyl, isoindoleyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, furinyl Mono- or multi-substituted by a moiety independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of quinolininyl, cinnaolinyl, phthalanyl, quinoxalinyl, naphthyridinyl, putridinyl and quinazolinyl Substituted;
    (J) a halogen atom and
    (K) -CN is selected from the group consisting of
    X is an oxygen atom,
    R 3 is straight or branched alkyl having 1 to 3 carbon atoms,
    R 4 is of the formula —CH 2 R 55 wherein R 55 is aryl or heteroaryl selected from the group consisting of phenyl, pyridyl and pyrimidinyl, wherein at least one hydrogen atom of the aryl or heteroaryl group is unsubstituted, (A) aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl and thiazolyl, wherein aryl or heteroaryl is unsubstituted or (i) carbon number Straight or branched chain alkyl of 1 to 6 or cycloalkyl of 3 to 6 carbon atoms, wherein the alkyl or cycloalkyl group is unsubstituted or mono- or polysubstituted by halogen or oxo, (ii) -CN, (iii) R 59b , nitro or (iv) substituted by halogen),
    (B) methyl, unsubstituted, trisubstituted with fluorine atoms, unsubstituted or monosubstituted with R 59b ,
    (C) straight or branched chain alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted or monosubstituted with halogen or oxo,
    (D) a group of the formula -COOR 67 wherein R 67 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    (E) a group of formula -COR 72 wherein R 72 is a halogen atom, straight or branched chain alkyl of 1 to 5 carbon atoms, cycloalkyl or R 59b of 3 to 5 carbon atoms,
    (F) a group of formula -OR 73 wherein R 73 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group or R 59b having 1 to 7 carbon atoms,
    (G) -CN,
    (H) nitro or
    (I) is independently substituted with halogen] R 5 is Cl,
    Z is = C (H)-,
    R 7 is Cl, or a pharmaceutically acceptable salt thereof.
    [4" claim-type="Currently amended] The compound of claim 1, wherein A 1 is = N-,
    A 2 is = C (H)-,
    D is = C (R 1 )-, = C (H)-, = C (SO 2 R 1 )-, = C (C (O) H)-or = C (C (O) R 1 )-{ Wherein R 1 is (A) straight or branched chain alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, wherein alkyl, alkenyl, cycloalkyl or cycloal At least one hydrogen atom of the kenyl group is unsubstituted, (i) oxo, (ii) phenyl, wherein one hydrogen atom of the phenyl group is unsubstituted, (a) alkyl of 1 to 3 carbon atoms, (b)- COOH, (c) -SO 2 OH, (d) -PO (OH) 2 , (e) a group of the formula -COOR 8 , wherein R 8 is straight or branched alkyl of 1 to 5 carbon atoms or of 3 to 5 carbon atoms Cycloalkyl), (f) a group of the formula -NR 9 R 10 , wherein R 9 and R 10 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or 1 to 7 carbon atoms of or acyl, R 9 and R 10 are those used In the form a heterocyclic ring by constructing a saturated hydrocarbon bridge of 3 to 5 carbon atoms together with the nitrogen atom), (g) a group of the formula -CONR 11 R 12 (wherein, R 11 and R 12 are each independently a hydrogen atom , Alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or R 11 and R 12 together with a nitrogen atom therebetween form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, hydrocarbon One carbon atom of the bridge is unsubstituted or substituted with -O-, -NH- or -NMe-, (h) a group of the formula -OR 13 , wherein R 13 is a hydrogen atom or an alkyl having 1 to 7 carbon atoms Or an acyl group), (i) a group of formula -SR 14 wherein R 14 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, (j) -CN, (k) Amidino groups wherein R 15 , R 16 and R 17 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 15 , R 16 and R 17 are nitrogen atom (s) between them And a saturated hydrocarbon bridge of 3 to 5 carbon atoms may be further configured to form a heterocyclic ring), (l) a group of the formula -NHCONHalkyl, wherein the alkyl moiety has 1 to 3 carbon atoms, or (m A group of formula -NHCOOalkyl, wherein the alkyl moiety has from 1 to 3 carbon atoms, and (iii) a group of formula -COOR 18 , wherein R 18 is straight or branched chain alkyl of 1 to 7 carbon atoms or Cycloalkyl of 3 to 6), (iv) a group of formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms , R 19 and R 20 are carbon atoms together with the nitrogen atom between them. To form a saturated hydrocarbon bridge of 3 to 5 to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-), (v) A group of OR 21 , wherein R 21 is a hydrogen atom or a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms, and at least one hydrogen atom of the alkyl or acyl group is unsubstituted, or -OH, -Oalkyl, wherein An alkyl moiety is substituted with a group independently selected from the group consisting of 1 to 6 carbon atoms, -NH 2 , -NHMe and -NMe 2 ), (vi) a group of formula -NR 23 R 24 , wherein R 23 and R 24 is independently (a) hydrogen atom, (b) cycloalkyl, (wherein one or more hydrogen atoms of the alkyl or acyl group of 1 to 7 carbon atoms with linear or branched alkyl or acyl, or 3 to 7 carbon atoms in the unsubstituted , -OH, -Oalkyl, where Moiety is a C 1 -C 6), -NH 2, is replaced by a group independently selected from the class consisting of -NHMe and -NMe 2), (c) the formula - (CH 2) m COOH group (where, m is the 0, 1 or 2), (d) a group of the formula-(CH 2 ) n COOR 25 , wherein n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms, or ( e) a group of formula-(CH 2 ) n CONHR 25 where n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms, and (vii) Quaternary groups of wherein R 26 , R 27 and R 28 are each independently a linear or branched alkyl group having 1 to 7 carbon atoms and Q − is a pharmaceutically acceptable counter ion; or (viii) 3 to C carbon atoms Independently substituted with a cycloalkyl group of 7] -R 100c ,
    (B) straight or branched carboxylic acid group having 3 to 6 carbon atoms,
    (C) a straight or branched chain phosphonic acid group having 2 to 6 carbon atoms,
    (D) straight or branched chain sulfonic acid group of 2 to 6 carbon atoms,
    (E) chemical formula Amidino groups wherein r is 2, 3, 4, 5 or 6, R 29 , R 30 and R 31 are each independently a hydrogen atom or an alkyl having 1 to 3 carbon atoms, and R 29 , R 30 and R Two of 31 together with the nitrogen atom (s) therebetween may further constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring),
    (F) chemical formula Guanidino group of wherein s is 2, 3, 4, 5 or 6, R 32 , R 33 , R 34 and R 35 are each independently a hydrogen atom or alkyl of 1 to 3 carbon atoms, R 32 , Two of R 33 , R 34 and R 35 together with the nitrogen atom (s) therebetween may further form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring) ,
    (G) phenyl [where at least one hydrogen atom of the phenyl group is unsubstituted or (i) alkyl of 1 to 3 carbon atoms, (ii) -COOH, (iii) -SO 2 OH, (iv) -PO (OH ) 2 , (v) a group of formula -COOR 36 , wherein R 36 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a group of formula -NR 37 R 38 ( Wherein R 37 and R 38 are each independently a hydrogen atom, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or acyl having 1 to 7 carbon atoms, or R 37 and R 38 together with the nitrogen atom therebetween; A saturated hydrocarbon bridge of 3 to 5 carbon atoms is formed to form a heterocyclic ring), (vii) a group of the formula -CONR 39 R 40 , wherein R 39 and R 40 are each independently a hydrogen atom, 1 to 6 carbon atoms the alkyl or cycloalkyl having 3 to 6, R 39 and R 40 are burnt together with the nitrogen atom between them A saturated hydrocarbon bridge of number 3 to 5 forms a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-), (viii) A group of —OR 41 , wherein R 41 is a hydrogen atom or an alkyl or acyl group having 1 to 7 carbon atoms, (ix) a group of formula —SR 42 , wherein R 42 is a hydrogen atom or an alkyl having 1 to 7 carbon atoms Or an acyl group), (x) -CN or (xi) Amidino groups wherein R 43 , R 44 and R 45 are each independently a hydrogen atom or alkyl having 1 to 3 carbon atoms, and two of R 43 , R 44 and R 45 are nitrogen atom (s) between them; And a saturated hydrocarbon bridge of 3 to 5 carbon atoms may be further configured to form a heterocyclic ring).
    (H) a group of the formula -NR 46 R 47 wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted phenyl, or R 100c , wherein R 100c is as defined above ],
    (I) saturated or unsaturated heterocyclic groups selected from the group consisting of pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein the heterocyclic group is unsubstituted or , (i) oxo, (ii) -OR 101 , wherein R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the alkyl group are unsubstituted, or -OH, —OR 110 where R 110 is an alkyl moiety having 1 to 6 carbon atoms, substituted with —NH 2 , —NHMe or —NHe 2 , (c) acyl having 1 to 7 carbon atoms, wherein all of the acyl groups The hydrogen atom is unsubstituted, -OH, -OR 111 , wherein R 111 is an alkyl moiety of 1 to 6 carbon atoms, -NH 2 , -NHMe or -NMe 2 is substituted, (d) -CONR 102 R 103 (wherein, R 102 and R 103 are each independently a hydrogen atom or an alkyl group having 1 to 7, R 102 and R 103 is the nitrogen atom between them Together form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-) or (e) -COOR 104 (wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 where R 105 and R 106 are each independently (a) a hydrogen atom, (b) carbon number Straight or branched chain alkyl of 1 to 7 or cycloalkyl of 3 to 7 carbon atoms, (c) benzoyl, (d) benzyl or (e) phenyl, wherein the phenyl ring is unsubstituted or -OR 112 where R 112 is carbon Mono- or polysubstituted), or R 105 and R 106 together with the nitrogen atom therebetween form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, and One carbon atom of the bridge is unsubstituted, -O-, -NH- or Is substituted with -NMe-), (iv) -COOR 107 ( wherein, R 107 is a straight or branched alkyl, a hydrogen atom, containing from 1 to 7 carbon atoms), (v) C 1 -C 7 linear or branched chain alkyl, C2- Alkenyl or alkynyl or cycloalkyl of 3 to 7 carbon atoms, wherein the alkyl, alkenyl, alkynyl or cycloalkyl group is unsubstituted, or (a) oxo, (b) -OH, (c)- OR 113 where R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 wherein R 114 is substituted with a moiety independently selected from the group consisting of alkyl having 1 to 3 carbon atoms or cycloalkyl having 3 to 7 carbon atoms, (vi) straight chain, acyl of 1 to 7 carbon atoms which may be branched or cyclic (where one or more hydrogen atoms of the acyl group is unsubstituted or substituted with, (a) -OH, (b ) -OR 115 ( wherein R 115 is C 1 -C 6 Is alkyl), (c) -NH 2, (d) -NHMe, (e) -NMe 2, (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 ( wherein, R 116 has a carbon number Heteroalkyl selected from the group consisting of 1 to 3 alkyl), (i) -CN, (j) halogen atom, (k) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl And (l) a residue independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl), (vii) -SO 2 R 108 wherein R 108 is (a) aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl and pyrazolyl, wherein aryl Or the heteroaryl moiety is unsubstituted, halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 117 (wherein R 117 is Hydrogen or at least one moiety selected from the group consisting of alkyl having 1 to 6 carbon atoms), (b) from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl Selected heterocyclic groups, wherein the heterocyclic groups are unsubstituted or substituted with halogen atoms, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 118 (wherein R 118 is hydrogen or alkyl of 1 to 6 carbon atoms) Or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted, halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 119; (Wherein R 119 is hydrogen or substituted with one or more residues selected from the group consisting of alkyl having 1 to 6 carbon atoms), (viii) -COR 109 where R 109 is (a) aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl and pyrazolyl, wherein the aryl or heteroaryl moiety is substituted Or substituted with one or more residues selected from the group consisting of halogen atoms, alkyl having 1 to 6 carbon atoms and -OR 120 , wherein R 120 is hydrogen or alkyl having 1 to 6 carbon atoms, (b) pyrroli Heterocyclic groups selected from the group consisting of diyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein heterocyclyl is unsubstituted or one or more halogens, straight or branched chain of 1 to 6 carbon atoms alkyl, and -OR 121 is substituted by (wherein R 121 is hydrogen or alkyl having 1 to 6 carbon atoms)), or (c) c 1 -C 7 straight or branched alkyl (wherein the alkyl moiety is Unsubstituted or ring, a halogen atom, a straight or branched chain alkyl, and -OR 122 group of 1 to 6 carbon atoms is substituted with one or more moieties selected from the class consisting of (wherein, R 122 is hydrogen or alkyl having 1 to 6 carbon atoms))) , (ix) -CHO, (x) halogen atom and (xi) phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl and imidazolylo Mono- or polysubstituted by a moiety independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of:
    (J) a halogen atom and
    (K) -CN); and
    X is an oxygen atom,
    R 3 is straight or branched alkyl having 1 to 3 carbon atoms,
    R 4 is a group of the formula —CH 2 R 55 wherein R 55 is unsubstituted or aryl or heteroaryl selected from the group consisting of (A) phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl; Wherein one of the hydrogen atoms of aryl or heteroaryl is unsubstituted, or (i) straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein the alkyl or cycloalkyl group is unsubstituted or halogen Or mono- or polysubstituted with oxo), (ii) -CN, (iii) nitro or (iv) halogen],
    (B) methyl,
    (C) straight or branched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted or mono- or polysubstituted by halogen or oxo,
    (D) a group of the formula -COOR 67 wherein R 67 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    (E) a group of formula -COR 72 wherein R 72 is a hydrogen atom, straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    (F) a group of the formula -OR 73 , wherein R 73 is a hydrogen atom, alkyl or a fluoroalkyl or acyl group having 1 to 7 carbon atoms,
    (G) -CN,
    (H) nitro or
    (I) phenyl substituted by halogen}
    R 5 is Cl,
    Z is = C (H)-,
    R 7 is Cl, or a pharmaceutically acceptable salt thereof.
    [5" claim-type="Currently amended] The compound of claim 1, wherein A 1 is = N-,
    A 2 is = C (H)-,
    D is = C (H)-, = C (SO 2 R 1 )-or = C (C (O) R 1 )-{where R 1 is (A) straight or branched chain alkyl of 1 to 6 carbon atoms, carbon number Alkenyl of 2 to 6 or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, wherein at least one hydrogen atom of an alkyl, alkenyl, cycloalkyl or cycloalkenyl group is unsubstituted, or (i) oxo, (ii ) A group of formula -COOR 18 , wherein R 18 is straight or branched chain alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (iii) a group of formula -CONR 19 R 20 , wherein R is 19 and R 20 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or R 19 and R 20 together with a nitrogen atom between them constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms To form a heterocyclic ring, where one carbon atom of the hydrocarbon bridge is substituted Or not, -O-, is replaced by -NH- or -NMe-), (iv) a group of the formula -OR 21 (wherein, R 21 is a linear or branched alkyl or acyl of 1 to 7 carbon atoms or a hydrogen atom, One or more hydrogen atoms of the alkyl or acyl group are unsubstituted or independently selected from the group consisting of —OH, —Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, —NH 2 —NHMe and —NMe 2 ; (V) a group of formula -NR 23 R 24 , wherein R 23 and R 24 are each independently (a) a hydrogen atom, (b) a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms or Cycloalkyl having 3 to 7 carbon atoms, wherein at least one hydrogen atom of the alkyl or acyl group is unsubstituted, or -OH, -Oalkyl, wherein alkyl has 1 to 6 carbon atoms, -NH 2 , -NHMe and- Substituted with a group independently selected from the group consisting of NMe 2 ), (c) a formula-(CH 2 ) a group of m COOH, where m is 0, 1 or 2, (d) a group of the formula-(CH 2 ) n COOR 25 , where n is 0, 1 or 2 and R 25 is 1 carbon To straight chain or branched alkyl of 6 to 6) or (e) a group of the formula-(CH 2 ) n CONHR 25 where n is 0, 1 or 2 and R 25 is straight or branched alkyl of 1 to 6 carbon atoms (Vi) chemical formula A quaternary group of a quaternary group of (wherein R 26 , R 27 and R 28 are each independently a linear or branched alkyl group having 1 to 7 carbon atoms and Q − is a pharmaceutically acceptable counter ion) or (vii ) is replaced by a group independently selected from cycloalkyl of 3 to 7 carbon atoms; an -R 100d,
    (B) straight or branched carboxylic acid group having 3 to 6 carbon atoms,
    (C) a straight or branched chain phosphonic acid group having 2 to 6 carbon atoms,
    (D) straight or branched chain sulfonic acid group of 2 to 6 carbon atoms,
    (E) chemical formula Amidino groups wherein r is 2, 3, 4, 5 or 6, R 29 , R 30 and R 31 are each independently a hydrogen atom or an alkyl having 1 to 3 carbon atoms, and R 29 , R 30 and R Two of 31 together with the nitrogen atom (s) therebetween may further constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring),
    (F) chemical formula Guanidino group of wherein s is 2, 3, 4, 5 or 6, R 32 , R 33 , R 34 and R 35 are each independently a hydrogen atom or alkyl of 1 to 3 carbon atoms, R Two of 32 , R 33 , R 34 and R 35 may further form a saturated hydrocarbon bridge of 3 to 5 carbon atoms with the nitrogen atom (s) therebetween to form a heterocyclic ring),
    (G) a group of formula -NR 46 R 47 , wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted phenyl, or R 100d , wherein R 100d is as defined above to be),
    (H) saturated or unsaturated heterocyclic groups selected from the group consisting of pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein the heterocyclic group is unsubstituted or , (i) oxo, (ii) -OR 101 , wherein R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the alkyl group are unsubstituted, or -OH, —OR 110 where R 110 is an alkyl moiety of 1 to 6 carbon atoms, substituted with —NH 2 , —NHMe or —NMe 2 , (c) acyl having 1 to 7 carbon atoms, wherein all of the acyl groups The hydrogen atom is unsubstituted, -OH, -OR 111 , wherein R 111 is an alkyl moiety of 1 to 6 carbon atoms, -NH 2 , -NHMe or -NMe 2 is substituted, (d) -CONR 102 R 103 (wherein, R 102 and R 103 are each independently a hydrogen atom or an alkyl group having 1 to 7, R 102 and R 103 is the nitrogen atom between them Together form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe) or (e)- COOR 104 (wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 where R 105 and R 106 are each independently (a) a hydrogen atom, (b) 1 carbon Straight or branched chain alkyl of 7 to 7 or cycloalkyl of 3 to 7 carbon atoms, (c) benzoyl, (d) benzyl or (e) phenyl, wherein the phenyl ring is unsubstituted or -OR 112 wherein R 112 is 1 Monoalkyl or polysubstituted), or R 105 and R 106 together with the nitrogen atom therebetween form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, and a hydrocarbon bridge One carbon atom of unsubstituted, -O-, -NH- Is substituted with -NMe-), (iv) -COOR 107 ( wherein, R 107 is a hydrogen atom or a straight or branched chain alkyl of 1 to 7 carbon atoms), (v) C 1 -C 7 linear or branched chain alkyl, C2- Alkenyl or alkynyl or cycloalkyl having 3 to 7 carbon atoms, wherein at least one hydrogen atom of alkyl, alkenyl, alkynyl or cycloalkyl is unsubstituted, or (a) oxo, (b) -OH, (c) -OR 113 where R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h ) -CO 2 H and (i) -CO 2 R 114 , wherein R 114 is substituted with a residue independently selected from the group consisting of alkyl having 1 to 3 carbon atoms or cycloalkyl having 3 to 7 carbon atoms, ( vi) acyl having 1 to 7 carbon atoms, which may be straight chain, branched or cyclic, wherein at least one hydrogen atom of the acyl group is unsubstituted, or (a) -OH, (b) -OR 115 , wherein R 115 is alkyl having 1 to 6 carbon atoms), (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 wherein R 116 is alkyl having 1 to 3 carbon atoms, (i) -CN, (j) halogen atom, (k) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholi A heterocycle selected from the group consisting of aryl, (l) a residue independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl ), (Vii) -SO 2 R 108 wherein R 108 is selected from the group consisting of (a) phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl and pyrazolyl Aryl or heteroaryl, wherein the aryl or heteroaryl moiety is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms -OR 117 is substituted with one or more moieties selected from the class consisting of (wherein, R 117 is hydrogen or alkyl having 1 to 6)), (b) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl And a heterocyclic group selected from the group consisting of thiomorpholinyl, wherein the heterocyclic group is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 118 (wherein R 118 is hydrogen or Substituted with one or more residues selected from the group consisting of alkyl having 1 to 6 carbon atoms) or (c) straight or branched chain alkyl having 1 to 7 carbon atoms wherein the alkyl residues are unsubstituted or halogen atoms, 1 to 6 carbon atoms a straight or branched alkyl, and -OR 119 is substituted with one or more moieties selected from the class consisting of (wherein, R 119 is hydrogen or alkyl having 1 to 6 carbon atoms)), a ), (Viii) -COR 109 (wherein, R 109 is (a) phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, and aryl or heteroaryl selected from the class consisting of pyrazolyl From aryl, wherein the aryl or heteroaryl moiety is unsubstituted or consists of a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 120 , wherein R 120 is hydrogen or alkyl of 1 to 6 carbon atoms Substituted with one or more residues selected), (b) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein heterocyclyl is unsubstituted or, one or more halogen, straight or branched c 1 -C 6 alkyl, or -OR 121 is replaced by (wherein, R 121 is hydrogen or alkyl having 1 to 6 carbon atoms)), or (c) straight c 1 -C 7 Or branched chain alkyl (wherein the alkyl moiety is unsubstituted or substituted with a halogen atom, a straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 122 (wherein R 122 is selected from the class consisting of hydrogen or alkyl having 1 to 6 carbon atoms) (Ix) -CHO, (x) halogen atom and (xi) phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl Mono- or polysubstituted by a moiety independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of isoxazolyl and imidazolyl],
    (I) selected from the class consisting of halogen atoms,
    X is an oxygen atom,
    R 3 is straight or branched alkyl having 1 to 3 carbon atoms,
    R 4 is a group of the formula —CH 2 R 55 wherein R 55 is unsubstituted or in the 4 position aryl or heteroaryl selected from the group consisting of (A) phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl; Wherein the aryl or heteroaryl group is unsubstituted, or (i) straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein the alkyl or cycloalkyl group is unsubstituted or substituted with halogen or oxo is substituted or multi-substituted), (ii) -CN, the R 59d (iii) nitro, or (iv) is replaced by a halogen),
    (B) methyl,
    (C) straight or branched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, wherein alkyl or cycloalkyl is unsubstituted or monosubstituted with halogen or oxo,
    (D) a group of the formula -COOR 67 wherein R 67 is straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    (E) a group of formula -COR 72 wherein R 72 is a hydrogen atom, straight or branched chain alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
    (F) a group of the formula -OR 73 , wherein R 73 is a hydrogen atom, alkyl or a fluoroalkyl or acyl group having 1 to 7 carbon atoms,
    (G) -CN,
    (H) nitro or
    (I) phenyl substituted with halogen],
    R 5 is Cl,
    Z is = C (H)-,
    R 7 is Cl, or a pharmaceutically acceptable salt thereof.
    [6" claim-type="Currently amended] The compound of claim 1, wherein A 1 is = N-,
    A 2 is = C (H)-,
    D is = C (SO 2 R 1 )-or = C (C (O) R 1 )-{wherein R 1 is (A) straight or branched chain alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or Cycloalkyl or cycloalkenyl having 3 to 6 carbon atoms, wherein at least one hydrogen atom of the alkyl, alkenyl, cycloalkyl or cycloalkenyl group is unsubstituted, or (i) oxo, (ii) a group of the formula -COOR 18 (Wherein R 18 is straight or branched chain alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms), (iii) a group of formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently hydrogen An atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or R 19 and R 20 together with the nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, One carbon atom of the hydrocarbon bridge is unsubstituted, -O-, -NH- or -NMe-, (iv) a group of formula -OR 21 wherein R 21 is a hydrogen atom or a straight or branched chain alkyl or acyl group having 1 to 7 carbon atoms, one of an alkyl or acyl group The above hydrogen atoms are unsubstituted or substituted with a group independently selected from the group consisting of -OH, -Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, -NH 2 , -NHMe and -NMe 2 ; or (v) a group of the formula -NR 23 R 24 , wherein R 23 and R 24 are each independently selected from (a) a hydrogen atom, (b) a straight or branched chain alkyl or acyl or C3 to C7 carbon group having from 1 to 7 carbon atoms A group independently selected from the group consisting of alkyl, wherein the alkyl or acyl group is unsubstituted, or -OH, -Oalkyl, wherein the alkyl moiety has 1 to 6 carbon atoms, -NH 2 , -NHMe and -NMe 2 (C) a group of formula-(CH 2 ) m COOH, where m is 0 , 1 or 2), (d) a group of the formula-(CH 2 ) n COOR 25 , wherein n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms, or (e ) general formula - (CH 2) n CONHR 25 group (wherein, n is 0, 1 or 2, R 25 is optionally substituted independently with a carbon number of 1 to 6 is a straight or branched alkyl))] is -R 100e ,
    (B) a group of formula -NR 46 R 47 wherein R 46 and R 47 are each independently a hydrogen atom, an unsubstituted or monosubstituted phenyl, or R 100e , wherein R 100e is as defined above )],
    (C) a saturated or unsaturated heterocyclic group selected from the group consisting of pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein the heterocyclic group is unsubstituted or , (i) oxo, (ii) -OR 101 , wherein R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein all hydrogen atoms of the alkyl group are unsubstituted, or -OH, —OR 110 where R 110 is an alkyl moiety of 1 to 6 carbon atoms, substituted with —NH 2 , —NHMe or —NMe 2 , (c) acyl having 1 to 7 carbon atoms, wherein all of the acyl groups The hydrogen atom is unsubstituted, -OH, -OR 111 , wherein R 111 is an alkyl moiety of 1 to 6 carbon atoms, -NH 2 , -NHMe or -NMe 2 is substituted, (d) -CONR 102 R 103 (wherein, R 102 and R 103 are each independently a hydrogen atom or an alkyl group having 1 to 7, R 102 and R 103 is the nitrogen atom between them Together form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted or substituted with -O-, -NH- or -NMe-) or (e) -COOR 104 (wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 where R 105 and R 106 are each independently (a) a hydrogen atom or (b) carbon number Straight or branched chain alkyl of 1 to 7 or cycloalkyl of 3 to 7 carbon atoms, or R 105 and R 106 together with a nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, One carbon atom of the hydrocarbon bridge is unsubstituted or substituted with -O-, -NH- or -NMe-, (iv) -COOR 107 where R 107 is a hydrogen atom or a straight or branched chain having 1 to 7 carbon atoms Alkyl), (v) straight or branched chain having 1 to 7 carbon atoms At least one hydrogen atom of alkyl, alkenyl or alkynyl or alkynyl, or cycloalkyl of 3 to 7 carbon atoms, wherein one or more hydrogen atoms of the alkyl, alkenyl, alkynyl or cycloalkyl group is unsubstituted, or (a) oxo, (b) -OH, (c) -OR 113 wherein R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) Residues independently selected from the class consisting of -NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 , wherein R 114 is alkyl having 1 to 3 carbon atoms or cycloalkyl having 3 to 7 carbon atoms (Vi) acyl having 1 to 7 carbon atoms, which may be straight, branched or cyclic, wherein at least one hydrogen atom of the acyl group is unsubstituted, or (a) -OH, (b) -OR 115 Wherein R 115 is alkyl having 1 to 6 carbon atoms, (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h)- CO 2 R 116 (wherein, R 116 is a C 1 -C 3 alkyl ), (i) -CN, (j) halogen atoms, (k) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl and (l) phenyl, Substituted with a residue independently selected from the group consisting of aryl or heteroaryl selected from the group consisting of thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl, (vii) -SO 2 R 108 R 108 is (a) phenyl, wherein the phenyl moiety is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 117 , wherein R 117 is hydrogen or alkyl of 1 to 6 carbon atoms Substituted with one or more residues selected from the group consisting of: (b) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein heterocyclic Group is chi Or not, a halogen atom, a linear or branched C 1 -C 6 alkyl, and -OR 118 is substituted with one or more moieties selected from the class consisting of (wherein, R 118 is hydrogen or alkyl having 1 to 6 carbon atoms)), or (c ) Straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted or halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 119 where R 119 is hydrogen or alkyl of 1 to 6 carbon atoms ), (Viii) -COR 109 , wherein R 109 is (a) phenyl, wherein the phenyl moiety is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 120 , wherein R 120 is hydrogen or alkyl having 1 to 6 carbon atoms); and (b) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl Made up of Heterocyclic group selected from wherein the heterocyclic group is unsubstituted or one or more halogen, straight or branched chain alkyl of 1 to 6 carbon atoms or -OR 121 , wherein R 121 is hydrogen or alkyl of 1 to 6 carbon atoms ) Or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted, or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 122 , wherein R 122 is Is substituted with one or more residues selected from the group consisting of hydrogen or alkyl having 1 to 6 carbon atoms) and (ix) mono- or polysubstituted residues independently selected from the group consisting of -CHO. Is chosen},
    X is an oxygen atom,
    R 3 is straight or branched alkyl having 1 to 3 carbon atoms,
    R 4 is a group of the formula —CH 2 R 55 wherein R 55 is unsubstituted or aryl or heteroaryl selected from the group consisting of (A) phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl; wherein one of the hydrogen atoms of the aryl or heteroaryl is an unsubstituted or substituted, (i) methyl, (ii) -CN, (iii ) nitro, or (iv) is replaced by a halogen) R 59e,
    (B) methyl,
    (C) -CN,
    (D) nitro or
    (E) phenyl substituted with halogen],
    R 5 is Cl,
    Z is = C (H)-,
    R 7 is Cl, or a pharmaceutically acceptable salt thereof.
    [7" claim-type="Currently amended] The compound of claim 1, wherein A 1 is = N-,
    A 2 is = C (H)-,
    D is = C (SO 2 R 1 )-or = C (C (O) R 1 )-{where R 1 is (A) straight or branched chain alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms [ Wherein one to three hydrogen atoms of the alkyl or cycloalkyl group are unsubstituted or (i) oxo, (ii) a group of the formula -COOR 18 , wherein R 18 is straight or branched chain alkyl or carbon number of 1 to 7 carbon atoms Cycloalkyl of 3 to 6), (iii) a group of formula -CONR 19 R 20 , wherein R 19 and R 20 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms , R 19 and R 20 together with the nitrogen atom therebetween form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, and one carbon atom of the hydrocarbon bridge is unsubstituted or -O-, -NH - or is substituted by -NMe-), (iv) a group of the formula -OR 21 (wherein, R 21 is hydrogen Here, or 1 to 7 carbon atoms is a straight or branched chain alkyl or acyl group of a) or (v) a group of the formula -NR 23 R 24 (wherein, R 23 and R 24 are each independently (a) hydrogen (b) C 1 Straight or branched chain alkyl or acyl or cycloalkyl having 3 to 7 carbon atoms, (c) a group of formula-(CH 2 ) m COOH, wherein m is 0, 1 or 2, (d) formula-( CH 2 ) a group of n COOR 25 , where n is 0, 1 or 2 and R 25 is straight or branched chain alkyl of 1 to 6 carbon atoms or (e) a group of the formula-(CH 2 ) n CONHR 25 ( here, n is 0,1 or 2, R 25 is optionally substituted independently with a carbon number of 1 to 6 is a straight or branched chain alkyl))] is -R 100e,
    (B) a saturated heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein the heterocyclic group is unsubstituted or (i) oxo, (ii) -OR 101 wherein R 101 represents (a) a hydrogen atom, (b) an alkyl having 1 to 7 carbon atoms, wherein one hydrogen atom of the alkyl group is unsubstituted, or -OH, -OR 110 , , R 110 is an alkyl moiety having 1 to 6 carbon atoms), -NH 2 , -NHMe or -NMe 2 is substituted, (c) acyl having 1 to 7 carbon atoms, wherein one hydrogen atom of the acyl group Or -OH, -OR 111 where R 111 is an alkyl moiety of 1 to 6 carbon atoms, is substituted with -NH 2 , -NHMe or -NMe 2 , (d) -CONR 102 R 103 , R 102 and R 103 are each independently a hydrogen atom or an alkyl group having 1 to 7, R 102 and R 103 is a 3 carbon atoms together with the nitrogen atom between them within By constructing a saturated hydrocarbon bridge of 5 to form a heterocyclic ring, it is optionally substituted with one C atom of the hydrocarbon The bridge is replaced by -O-, -NH- or -NMe-) or (e) -COOR 104 ( Wherein R 104 is alkyl having 1 to 7 carbon atoms), (iii) -CONR 105 R 106 wherein R 105 and R 106 are each independently (a) a hydrogen atom or (b) having 1 to 7 carbon atoms Straight or branched alkyl or cycloalkyl having 3 to 7 carbon atoms, wherein the alkyl or cycloalkyl group is unsubstituted, or -OH, -OR 123 , wherein R 123 is an alkyl moiety of 1 to 6 carbon atoms, -NH 2 , Mono-substituted with -NHMe, -NMe 2 , pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, or R 105 and R 106 together with a nitrogen atom between them form a saturated hydrocarbon bridge of 3 to 5 carbon atoms; To form a heterocyclic ring, one of the hydrocarbon bridges Small atoms are unsubstituted or substituted with -O-, -NH-, or -NMe-), (iv) -COOR 107 where R 107 is a hydrogen atom or straight or branched chain alkyl of 1 to 7 carbon atoms (v) straight or branched chain alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein one to three hydrogen atoms of the alkyl or cycloalkyl group are unsubstituted, or (a) oxo, (b)- OH, (c) -OR 113 where R 113 is alkyl having 1 to 6 carbon atoms, (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 wherein R 114 is substituted with a residue independently selected from the group consisting of alkyl having 1 to 3 carbons or cycloalkyl having 3 to 7 carbons) (vi) acyl having 1 to 7 carbon atoms, which may be straight, branched or cyclic, wherein one or two hydrogen atoms of the acyl group are unsubstituted, or (a) -OH, (b) -OR 115 where , R 115 is Alkyl having 1 to 6 carbon atoms), (c) -NH 2 , (d) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 , R 116 is alkyl having 1 to 3 carbon atoms), (i) -CN, (j) halogen atom, (k) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl A heterocycle selected from the class and (l) a residue selected from the group consisting of aryl or heteroaryl selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl), (vii ) -SO 2 R 108 where R 108 is (a) phenyl (wherein the phenyl moiety is unsubstituted or a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 117 (wherein R 117 is hydrogen or Alkyl having 1 to 6 carbon atoms), (b) pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl Cyclic Tero group (wherein the heterocyclic group is optionally substituted, consisting of a halogen atom, a straight-chain or branched alkyl having 1 to 6 carbon atoms, and -OR 118 (wherein R 118 is hydrogen or alkyl having 1 to 6 carbon atoms) Or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein the alkyl moiety is unsubstituted, halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms, and -OR 119 ( Wherein R 119 is substituted with one residue selected from the group consisting of hydrogen or alkyl having 1 to 6 carbon atoms), (viii) -COR 109 where R 109 is (a) phenyl (where phenyl residue is unsubstituted or substituted with a halogen atom, a C 1 -C 6 straight or branched chain alkyl, and -OR 120 of one of the moieties selected from the class consisting of (wherein, R 120 is hydrogen or alkyl having 1 to 6 carbon atoms) Substituted), (b) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein the heterocycle is unsubstituted, one halogen, Straight or branched chain alkyl of 1 to 6 carbon atoms or -OR 121 , wherein R 121 is hydrogen or alkyl of 1 to 6 carbon atoms, or (c) straight or branched chain alkyl of 1 to 7 carbon atoms, wherein alkyl The moiety is unsubstituted or substituted with one moiety selected from the group consisting of a halogen atom, straight or branched chain alkyl of 1 to 6 carbon atoms and -OR 122 where R 122 is hydrogen or alkyl of 1 to 6 carbon atoms. And (ix) mono- or di-substituted with residues independently selected from the group consisting of -CHO.
    X is an oxygen atom,
    R 3 is straight or branched alkyl having 1 to 3 carbon atoms,
    R 4 is a group of the formula —CH 2 R 55 wherein R 55 is unsubstituted or in the 4 position aryl or heteroaryl selected from the group consisting of (A) phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl; wherein one of the hydrogen atoms of the aryl or heteroaryl group is unsubstituted or substituted, is substituted with (i) methyl, (ii) -CN, (iii) nitro, or (iv) halogen) of R 59e,
    (B) methyl,
    (C) -CN,
    (D) nitro or
    (E) phenyl substituted with halogen],
    R 5 is Cl,
    Z is = C (H)-,
    R 7 is Cl, or a pharmaceutically acceptable salt thereof.
    [8" claim-type="Currently amended] The compound of claim 1, wherein A 1 is = N-,
    A 2 is = C (H)-,
    D is = C (SO 2 R 1 )-{where R 1 is (A) methyl and
    (B) a saturated heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholine, wherein the heterocyclic group is unsubstituted, or (i) oxo, (ii) -OR 101 Wherein R 101 represents (a) hydrogen, (b) alkyl of 1 to 7 carbon atoms, wherein one hydrogen atom of the alkyl group is unsubstituted, or -OH, -OR 110 , wherein R 110 represents 1 to Is an alkyl moiety of 6), -NH 2 , -NHMe or -NMe 2 , or (c) acyl having 1 to 7 carbon atoms, wherein one hydrogen atom of the acyl group is unsubstituted, or -OH,- OR 111 , wherein R 111 is an alkyl moiety of 2 to 6 carbon atoms, substituted with -NH 2 , -NHMe or -NMe 2 ), (iii) -CONR 105 R 106 , wherein R 105 and R 106 are each independently (a) hydrogen atom or (b) a cycloalkyl containing from 1 to 7 carbon atoms or straight or branched chain alkyl of 3 to 7 carbon atoms (wherein the alkyl addition Cycloalkyl is optionally substituted, -OH, -OR 123 (wherein, R 123 is a C 1 to 6 alkyl), -NH 2, -NHMe, -NMe 2, pyrrolidinyl, piperidinyl, piperazinyl Or mono-substituted with morpholinyl, or R 105 and R 106 together with the nitrogen atom therebetween form a saturated hydrocarbon bridge of 3 to 5 carbon atoms to form a heterocyclic ring, one carbon atom of the hydrocarbon bridge being unsubstituted Or (substituted with -O-, -NH- or -NMe-)), (iv) -COOR 107 wherein R 107 is a hydrogen atom or straight or branched chain alkyl of 1 to 7 carbon atoms, (v) Straight or branched chain alkyl of 1 to 7 carbon atoms, wherein one or two hydrogen atoms of the alkyl group are unsubstituted or (a) oxo, (b) -OH, (c) -OR 113 , wherein R 113 is carbon Alkyl of 1 to 6), (d) -OCOCH 3 , (e) -NH 2 , (f) -NHMe, (g) -NMe 2 , (h) -CO 2 H and (i) -CO 2 R 114 (wherein, R 114 is burnt Substituted with a residue independently selected from the group consisting of alkyl of 1 to 3 or cycloalkyl of 3 to 7 carbon atoms), (vi) acyl of 1 to 7 carbon atoms, which may be linear, branched or cyclic One or two hydrogen atoms of the acyl group are unsubstituted, or (a) -OH, (b) -OR 115 , wherein R 115 is alkyl having 1 to 6 carbon atoms, (c) -NH 2 , (d ) -NHMe, (e) -NMe 2 , (f) -NHCOMe, (g) oxo, (h) -CO 2 R 116 wherein R 116 is alkyl having 1 to 3 carbon atoms, (i) -CN (j) a halogen atom, (k) a heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl and (l) phenyl, thiophenyl, pyridyl, pyri It is substituted with pyrimidinyl, furyl, pyrrolyl and oxazolyl moieties selected from the class consisting of aryl or heteroaryl selected from the class consisting of a), (vii) -SO 2 R 108 ( W Standing, R 108 is (a) pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl wherein the cyclic group between heteroatom selected from the class consisting of (wherein the heterocyclic group is unsubstituted or substituted, straight-chain having 1 to 6 carbon atoms Or branched chain alkyl and -OR 118 , wherein R 118 is substituted with one residue selected from the group consisting of hydrogen or alkyl having 1 to 6 carbon atoms, (viii) -COR 109 wherein R 109 is (a) a heterocyclic group selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the heterocyclyl is unsubstituted or one halogen, straight or branched chain of 1 to 6 carbon atoms alkyl, or -OR 121 with a substituted (herein, R 121 is hydrogen or alkyl having 1 to 6 carbon atoms))), and (ix) is from the class consisting of mono- or disubstituted with a -CHO moiety selected independently; It is selected from the class of binary luer} and,
    X is an oxygen atom,
    R 3 is methyl,
    R 4 is R 59e formula -CH 2 R 55 group (wherein, R 55 is unsubstituted or substituted with a 4-position (A) phenyl, a pyridyl and pyrimidinyl aryl or heteroaryl selected from the class consisting of aryl,
    (B) -CN,
    (C) nitro or
    (D) is substituted with halogen),
    R 5 is Cl,
    Z is = C (H)-,
    R 7 is Cl, or a pharmaceutically acceptable salt thereof.
    [9" claim-type="Currently amended] The compound of formula I according to any one of claims 1 to 8, having a complete stereochemistry represented by formula II.
    Formula II

    [10" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, selected from the group consisting of:






    [11" claim-type="Currently amended] An inflammatory disease or immune cell-mediated method comprising administering a therapeutic or prophylactic amount of a compound according to any one of claims 1 to 10 to a host in need of treatment or prevention of an inflammatory disease or immune cell-mediated disease. How to treat or prevent a disease.
    [12" claim-type="Currently amended] The method according to claim 11, wherein the disease or condition is characterized by adult respiratory distress syndrome, shock, oxygen toxicity, secondary multi-organ damage syndrome by pulmonary disease, secondary multi-organ injury syndrome by trauma, cardiopulmonary bypass, myocardial infarction or thrombolytic agent. Tissue reperfusion injury, acute glomerulonephritis, vasculitis, reactive arthritis, dermatitis with acute inflammatory components, stroke, heat injury, hemodialysis, leukocytosis, ulcerative colitis, necrotizing colitis and granular cell transfusion related syndromes due to use Method selected from the group consisting of:
    [13" claim-type="Currently amended] The method of claim 11, wherein the disease or condition comprises psoriasis, organ / tissue transplant rejection, transplant-versus-host response and autoimmune disease, including Raynaud syndrome, autoimmune thyroiditis, dermatitis, multiple sclerosis, rheumatoid arthritis, insulin Inflammatory bowel disease including systemic diabetes mellitus, uveitis, Crohn syndrome and ulcerative colitis and systemic lupus erythematosus.
    [14" claim-type="Currently amended] The method of claim 11, wherein the disease or condition is asthma.
    [15" claim-type="Currently amended] The method of claim 11, wherein the condition is toxic associated with cytokine therapy.
    [16" claim-type="Currently amended] The method of claim 11, wherein the disease or condition is psoriasis.
    [17" claim-type="Currently amended] A pharmaceutical composition comprising a compound according to any one of claims 1 to 10.
    [18" claim-type="Currently amended] Chemical formula {Where R 1 is (A) hydrogen, (B) halogen atom and (C) SO 2 - M + [where M + is (i) Li + , (ii) Na + , (iii) K + or ( iv) MgX + , wherein X is halogen, and R 2 is selected from (A) halogen atom, (B) (i) phenyl, (ii) pyridyl and (iii) pyrimidyl Selected aryl and (C) CN.
    [19" claim-type="Currently amended] The chemical formula of claim 18 wherein Of compounds.
    [20" claim-type="Currently amended] The chemical formula of claim 18 wherein Of compounds.
    [21" claim-type="Currently amended] The chemical formula of claim 18 wherein Of compounds.
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    同族专利:
    公开号 | 公开日
    AT413402T|2008-11-15|
    SK286912B6|2009-07-06|
    SK2562002A3|2002-07-02|
    US6492408B1|2002-12-10|
    EE04965B1|2008-02-15|
    ES2316374T3|2009-04-16|
    TWI261591B|2006-09-11|
    EP1216247A1|2002-06-26|
    HU0203971A2|2003-03-28|
    CA2383017A1|2001-02-01|
    BG106312A|2002-09-30|
    UY26249A1|2001-01-31|
    US20040116426A1|2004-06-17|
    JP2003505460A|2003-02-12|
    NO20020275D0|2002-01-18|
    KR20070053363A|2007-05-23|
    IL147296A|2006-07-05|
    AU6209100A|2001-02-13|
    US7550494B2|2009-06-23|
    WO2001007440A1|2001-02-01|
    BG65865B1|2010-03-31|
    EE200200028A|2003-04-15|
    KR100767200B1|2007-10-17|
    IL147296D0|2002-08-14|
    NO20020275L|2002-02-04|
    PL352755A1|2003-09-08|
    DK1216247T3|2009-02-23|
    NO322707B1|2006-11-27|
    HU0203971A3|2005-01-28|
    AR029383A1|2003-06-25|
    YU3902A|2006-01-16|
    AU776496B2|2004-09-09|
    DE60040751D1|2008-12-18|
    RS50260B|2009-07-15|
    CZ2002191A3|2002-04-17|
    TR200200160T2|2002-10-21|
    EA004932B1|2004-10-28|
    MY155218A|2015-09-30|
    NZ517217A|2004-02-27|
    CO5180640A1|2002-07-30|
    HRP20020051A2|2003-10-31|
    US6689804B2|2004-02-10|
    EP1216247B1|2008-11-05|
    CN1372562A|2002-10-02|
    HK1048637A1|2005-02-25|
    US20030203955A1|2003-10-30|
    BR0012666A|2002-04-09|
    MXPA02000540A|2002-07-02|
    CN1166667C|2004-09-15|
    HK1048637B|2005-02-25|
    EA200200097A1|2002-08-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-07-21|Priority to US14490599P
    1999-07-21|Priority to US60/144,905
    1999-08-26|Priority to US15093999P
    1999-08-26|Priority to US60/150,939
    2000-07-12|Application filed by 데이비드 이. 프랭크하우저, 베링거 인겔하임 파마슈티칼즈, 인코포레이티드
    2002-02-27|Publication of KR20020015074A
    2007-10-17|Application granted
    2007-10-17|Publication of KR100767200B1
    优先权:
    申请号 | 申请日 | 专利标题
    US14490599P| true| 1999-07-21|1999-07-21|
    US60/144,905|1999-07-21|
    US15093999P| true| 1999-08-26|1999-08-26|
    US60/150,939|1999-08-26|
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