Heterocyclic compounds useful as inhibitors of tyrosine kinases

[0001] (Technical field) Benefits from US Provisional Patent Application No. 60 / 157,922 (included herein for reference) filed on October 6, 1999 are alleged here. The present invention is based on formula (I) :. [0002] [Chemical 18]<img file="JP5036112B2_D0001.tif" />[0003] (During the ceremony, Ar₁, R_a, R₄, R₅, X and Y relate to substitutional compounds (as defined below), which are beneficial as inhibitors of certain protein tyrosine kinases and thus diseases resulting from inappropriate cell proliferation (these are autoimmune diseases). , Including chronic inflammatory diseases, allergic diseases, transplant rejection and cancer). The present invention also relates to a method for preparing these compounds and a pharmaceutical composition containing these compounds. [0004] (Background technology) Tyrosine kinases play essential roles in cell signaling and regulation of cell proliferation by phosphorylating tyrosine residues in peptides and proteins. Improper activation of tyrosine kinases is known to be associated with a variety of conditions, including immune and oncological disorders. T cells have been well demonstrated to play an important role in regulating the immune response (F. Powrie and RL Coffman, Immunol. Today, 1993, 14, 270). T cell activation is often the initiation event for many inflammatory and autoimmune diseases. In addition to their role in immune surveillance, T cells can become autoreactive by recognizing self-antigens, thereby resulting in autoimmune diseases such as rheumatoid arthritis and inflammatory bladder disease. [0005] The T cell receptor (TCR) is an antigen-specific component of T cells that is activated when the receptor is engaged with a foreign or self-antigenic peptide. When TCR is activated, a series of enzyme-mediated signaling cascades is initiated, which results in the production of pre-inflammatory cytokines such as interleukin-2 (IL-2). The release of IL-2 is clinically important. This is because this lymphokine is required for T lymphocyte proliferation, differentiation, and effector function. Clinical studies have shown that interference with IL-2 activity effectively suppresses the in vivo immune response (TA Waldmann, Immunol. Today, 1993, 14, 270). Therefore, agents that suppress T lymphocyte activation and subsequent IL-2 production, or block IL-2 activity, are therapeutic to selectively suppress the immune response of patients in need of such immunosuppression. Above useful. [0006] The eight members of the src family of tyrosine kinases are src, lck, fyn, lyn, hck, fgr, blk and yes (JB Bolen, JS Brugge, Ann. Rev. Immunol., 1997, 15, 371). These are divided into two groups based on their pattern of tissue expression. src, fyn and yes have a broad distribution, while expression of lck, lyn, hck, fgr, and blk is largely restricted to hematopoietic cells. The therapeutic effect of suppressing the kinases of the src family is confirmed by linking the functional defects found in gene disruption studies in mice. src (-/-) mice had severe abnormalities in osteogenesis. Therefore, suppression of src may be beneficial in treating osteoporosis. lck (-/-) mice show a complete lack of CD4 + cells and are unable to take an antigen-dependent immune response. A particularly important kinase is p56lck, which is expressed only in T cells. Within the TCR signaling cascade, the tyrosine kinase p56lck is an element required to initiate an activation response from the TCR intracellular domain to other signaling proteins. For example, T cells lacking the p56lck protein are unable to signal in the T cell receptor (DB Straus and A. Weiss, Cell, 1992, 70, 585). Reverse transfection of p56lck into these cell lines restores TCR responsiveness. Inactivation of the p56lck gene has also been shown to result in a lack of proper thymocyte development in mice (TJ Molina et al., Nature, 1992, 357, 161). [0007] The conclusion drawn from these studies is that p56lck plays an important role in T cell maturation and antigen-induced T cell activation. Therefore, drugs that block p56lck effectively block T cell function and act as immunosuppressants for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, lupus, graft rejection and allergic diseases. It will have potential utility (JH Hanke et al., Inflamm. Res., 1995, 44, 357). Inhibitors of other members of the src family of non-receptor tyrosine kinases are also beneficial in treating a variety of conditions. src is present in osteoclasts and is important for osteogenesis. For example, inactivation of p60src reduces bone resorption by osteoclasts (P. Soriano et al., Cell 1991, 64, 693, BF Boyce et al., J. Clin. Invest 1992, 90, 1622), therefore, inhibitors of kinase activity in p60src treat osteoporosis, Paget's disease and inflammation of bones and joints. Can be beneficial to. [0008] src kinase has been known to be activated in tumors, including breast and colon cancers, melanomas and sarcomas. For example, some primary tumors and tumor cell lines from patients with breast cancer, colon cancer, melanoma and sarcoma have been shown to have elevated src kinase activity, with active src mutations showing some advanced colon cancer. Seen at. Inhibitors of src kinase have significant antiproliferative activity against cancer cell lines (MM Moasser et al., Cancer Res., 1999, 59, 6145) and suppress the transformation of cells into a carcinogenic phenotype (R. Karni et al., Oncogene, 1999, 18, 4654) suggested that src kinase inhibitors could be beneficial anti-cancer agents. In addition, src family kinases are involved in signal transduction in several cell types. For example, fyn, like lck, is involved in T cell activation. hck and fgr are involved in Fc gamma receptor-mediated oxidation bursts of neutrophils. src and lyn are thought to be important for Fc epsilon-induced degranulation of mast cells and thus may play a role in asthma and other allergic diseases. Kinase lyn is involved in the cellular response to DNA damage induced by ultraviolet light (T. Hiwasa, FEBS Lett. 1999, 444, 173) or ionizing radiation (S. Kumar, J. Biol Chem, 1998, 273, 25654). It is known. Inhibitors of lyn kinase can thus be beneficial as enhancers in radiation therapy. [0009] Platelet-derived growth factor is a potent mitogen for smooth muscle cells. Its receptor (PDGFR) is a member of the receptor tyrosine kinase family (L. Claesson-Welsh, J. Biol Chem, 1994, 269, 32023). PDGF is associated with atherosclerosis and restenosis (KE Bornfeld, Trends Cardiovasc. Med., 1996, 6, 143). In addition, receptor tyrosine kinases, including PDGFR kinase, include ovarian cancer (MB Dabrow et al., Gynecologic Oncology, 1998, 71, 29) and prostate cancer (SM Sintich et al., Endocrinology, 1999, 140, 3411) and glial blastoma ( It has been shown as a contributor to cancer, including BJ Silver, BioFactors, 1992, 3, 217) (A. Levitzki and A. Gazit, Science, 1995, 267, 1782). Inhibitors of PDGFR kinase are thus beneficial in the treatment of fibrosis, restenosis and PDGF-dependent tumors. [0010] A paper has appeared in the literature of drugs that suppress the kinase activity of p56lck kinase and thus suppress T cell activation. These are the natural product Lavendustin A and its analogues (MS Smyth, J. Med. Chem., 1993, 36, 3010), the natural product Damnacanthal (CR Faltynek et al., Biochemistry, 1995, 34, 12404), and fungi. Contains 1-methoxyagloclabin (R. Padmanabha et al., Bioorganic and Med. Chem. Letters, 1998, 8, 569) isolated from the extract. Other reported inhibitors are WIN 61651 (J. Enzyme Inhibition, 1995, 9, 111), pyrazolopyrimidine PP1 and PP2 (Hanke et al., J. et al.). Includes Biol Chem, 1996, 271, 695) and indanone and indandione derivatives (JL Bullington et al., Bioorganic and Med. Chem. Letters, 1998, 8, 2489). AP Spader et al. (WO 98/54157, 1998) describe quinoline and quinoxaline compounds that suppress p56lck and PDGFR kinase. A condensed polycyclic 2-aminopyrimidine derivative that suppresses p56lck has been reported by JM Davis et al. (WO 98/28281, 1998). J. Das et al. Claimed a series of benzothiazole amides as inhibitors of lck and other src family kinases (WO 99/24035, 1999). Inhibitors of PDGFR kinase and src family kinase were outlined by HDH Showalter, AJ Kraker, Pharmacol. Ther., 1997, 76, 55. Several patents on lck inhibitors have been published by PM Traxler, Exp. It is outlined in Opin. Ther. Patents, 1997, 7, 571, and PM Traxler, Exp. Opin. Ther. Patents, 1998, 8, 1599. [0011] U.S. Pat. No. 4,176,184 discloses imidazoisoquinoline-dione, which is described as beneficial as a cardiac stimulant, antithrombotic, antithrombotic and antiarrhythmic agent. German Patent No. 3410168A1 discloses imidazole isoquinoline-dione derivatives, these compounds are described as beneficial as cardiotonics, and the substituents on the condensed imidazole ring are C.₁-C₄A pyridine ring bridged to an imidazole carbon by an alkyl group, vinyl group or chemical bond. EP322746A1 discloses heterocyclic lactam derivatives described as beneficial as cardiac stimulants, antihypertensives and vasodilators. The compounds of the invention correspond to a class of novel structures, which differs from previously reported tyrosine kinase inhibitors. [0012] (Disclosure of Invention) The studies support that inhibition of the kinase is beneficial in the treatment of various conditions. Therefore, it is an object of the present invention to provide a novel compound that suppresses PDGFR kinase and src family kinases including lck, src, fyn, lyn, hck, fgr, blk and yes. A further object of the present invention is to use the novel compounds of the present invention for diseases and symptoms mediated by src family tyrosine kinase and PDGFR kinase, such as autoimmune diseases, transplant rejection, psoriasis, osteoporosis, Paget. To provide a method for treating diseases, cancers (including src-dependent tumors and PDGF-dependent tumors), atherosclerosis, restenosis and allergic diseases. Yet another object of the present invention is to provide a method for preparing the above-mentioned novel compound and a pharmaceutical composition containing these. [0013] (Best mode for carrying out the invention) The src family tyrosine kinase and PDGFR kinase described above show some homology in their amino acid structure. Due to the structural differences between individual src family kinases and PDGFR kinases, it is believed that the different compounds of the invention may have different inhibitory potency on individual tyrosine kinases. Thus, some of the compounds of the invention can also be expected to be most effective in treating diseases mediated by tyrosine kinases, which they most strongly suppress. The special compounds disclosed herein have been shown to be active inhibitors of p56lck kinase, p60src kinase and PDGFR kinase. See the section entitled "Assessment of Biological Properties" disclosed herein. In its broadest conceptual aspect, the present invention presents the equation I: [0014] [Chemical 19]<img file="JP5036112B2_D0002.tif" />[0015] Provided are a novel compound of the above, and a pharmaceutically acceptable acid derivative or salt derivative thereof. During the ceremony Ar₁Is an aromatic or non-aromatic carbocyclic ring, heteroaryl or heterocycle, wherein the carbocyclic ring, heteroaryl or heterocycle is optionally one or more Rs.₁, R₂And R₃May be replaced by X is NH, NC_1-3Alkyl, N-cyclopropyl, S or O, Y is NR₁₅, S or O, R_aIs H, C_1-10Alkyl, C_2-10Alkenyl or C_2-10Alkynes, each of which may be branched, cyclic, or R_aAre aryl or heteroaryl, each R_aIndependently need more than one C_1-6Alkyl, C_1-6Alkoxy, halogen, OH, oxo, NR₁₀R₁₁, Aryl or heteroaryl, and each aryl or heteroaryl may be halogen, OH, C as required._1-3Alkyl, C_1-3Alkoxy, hydroxy C_1-3Alkyl and (CH₂)_mNR₁₀R₁₁May be substituted with one or more groups selected from, and R_aIs combined in 4th or 5th place, [0016] R₁And R₂Are the same or different, H, halogen, CN, NO₂, C_1-10Branched or unbranched saturated or unsaturated alkyl, C_1-10Branched or unbranched alkoxy, C_1-10Branched or unbranched acyl, C_1-10Branched or unbranched acyloxy, C_1-10Branched or unbranched alkylthio, aminosulfonyl, di-(C_1-3) Alkylaminosulfonyl, NR₁₀R₁₁, Aryl, Aryl, Aryloxy, Arylsulfonyl, Heteroaryl and Heteroaryloxy.₁And R₂May be partially or completely halogenated if required, or oxo, OH, NR if required₁₀R₁₁, C_1-6Branched or unbranched alkyl, C_3-7Cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono-or di (C)_1-3) It may be substituted with 1 to 3 groups independently selected from the alkylaminocarbonyl. R₃Is H, halogen, OH, (CH₂)_nNR₁₀R₁₁, CONR₁₀R₁₁, (CH₂)_nCO₂R₁₂, C_1-3Alkyl (OH, C if necessary_1-3Alkoxy (may be halogenated if desired) or C_1-3May be substituted with alkylthio) R₄And R₅A or B together with the atoms to which they are bonded [0017] [Chemical 20]<img file="JP5036112B2_D0003.tif" />[0018] Completed the condensed ring system of R₆Is C_1-3Alkyl or H, R₇Is branched or non-branched C_1-6Alkyl or H, R₈Is H, branched or unbranched, saturated or unsaturated C_1-6Alkyl (Phenyl, OH or C as needed_1-3May be substituted with alkoxy), or R₈Is (CH₂)_mNR₁₀R₁₁, (CH₂)_mNR₁₀COR₁₂, (CH₂)_nCO₂R₁₂, (CH₂)_nCONR₁₀R₁₁Or R₈Are phenyl or heteroaryl, each needing C_1-3Alkyl, C_1-3Alkoxy, OH, -SO₃May be replaced with H or halogen, R₉Is H, CN or CONR₁₀R₁₁Or R₉Is branched or non-branched C_1-10Alkyl, C_3-10Cycloalkyl, C_5-7Cycloalkenyl, C_2-6Alkenyl, C_2-6Alkyne, each with one or more Cs as needed_3-10Cycloalkyl, C_3-10Cycloalkylidene, C_5-7Cycloalkenyl, halogen, OH, oxo, CN, C_1-3Alkoxy, C_1-3Acyloxy, NR₁₀R₁₁, NR₁₀CONR₁₀R₁₁, NR₁₀C (= NR₁₀) NR₁₀R₁₁, NR₁₀COR₁₂, NR₁₀S (O)_pR₁₂, SR₁₂, CONR₁₀R₁₁, CO₂R₁₂, C (R)₁₀) = NNR₁₀R₁₁, C (R)₁₀) = NNR₁₀CONR₁₀R₁₁, Aryloxy, arylthio, aryl or heteroaryl, each aryloxy, arylthio, aryl or heteroaryl is optionally C_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_nNR₁₀R₁₁Or O (CH₂)_2-4NR₁₀R₁₁May be replaced with, or R₉Is an aryl, heteroaryl, or heterocycle, and each aryl, heteroaryl, or heterocycle is required by C._1-3Alkyl (phenyl or NR if required₁₀C (= NR₁₀) NR₁₀R₁₁May be replaced with), C_1-3Alkoxy, halogen, CN, oxo, (CH₂)_nNR₁₀R₁₁, (CH₂)_nCO₂R₁₂, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁May be substituted with 1 to 3 groups selected from, or [0019] R₈And R₉Together are saturated or unsaturated 5- or 6-membered aromatic or non-aromatic carbocyclic rings (1 or 2 Cs as required)_1-3Alkyl, OH, oxo or (CH₂)_nNR₁₀R₁₁It may be substituted with, or if necessary, spiro-condensed into a 1,3 dioxolane group or a 1,3 dithiolane group, and each 1,3 dioxolane group or 1,3 dithiolane group may be optionally C._1-6Alkyl, C_1-6Alkoxy, OH or (CH₂)_nNR₁₀R₁₁May be replaced by) R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-6Alkyl, C_3-8Cycloalkyl, aryl, aryl C_1-3Selected from alkyl and heteroaryl, said alkyl, cycloalkyl, aryl, aryl C_1-3Alkyl or heteroaryl is OH, C as needed_1-3Alkoxy, CN, NO₂, C_1-3Acyloxy, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄, May be substituted with aryl or heteroaryl, or [0020] R₁₀And R₁₁Together form a 3--7-membered alkylene chain that completes a ring around the N atom to which they are bonded, said alkylene chain being O, S (O) if necessary._pAnd NR₁₃May be interrupted by, and the ring may be interrupted by C if necessary._1-3Alkyl, C_1-3Alkoxy, OH,-(CH₂)_nNR₁₃R₁₄, CONR₁₃R₁₄Or NR₁₃COR₁₄May be replaced by R₁₂Is H, C_1-6Alkyl or C_3-8Cycloalkyl, each alkyl or cycloalkyl is phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with, or R₁₂Is a phenyl or heterocycle (C if necessary_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_mNR₁₀R₁₁, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁It may be substituted with 1 to 3 groups selected from), R₁₃And R₁₄H and C independently_1-6Alkyl (C if necessary_1-3(May be substituted with alkoxy, OH or phenyl), or R₁₃And R₁₄Together form a chain that completes the ring, the chain being (CH₂)_4-5Or (CH₂)₂O (CH₂)₂And R₁₅Is H or C_1-3Alkyl m is 1-4, n is 0-3, and p is 0-2. [0021] [0021] In one embodiment of the invention Ar₁But a) Cycloalkyl groups selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, b) Cycloalkenyl groups selected from cyclopentenyl, cyclohexenyl, cycloheptenyl, c) Phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl, d) Pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, frill, isooxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indole, benzimidazolyl, benzofuranyl, benzoxazolyl Heteroaryl selected from zolyl, benzopyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl, or cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexano Pyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinolin, cyclohexanoquinolin, cyclopentanoisoquinoline, cyclohexanoisoquinolin, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzoimidazole, cyclo Condensed heteroaryl selected from pentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene, or e) Heterocycles selected from pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolydinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl. [0022] Ar above₁More than one R each need₁, R₂And R₃May be replaced by R_aIs H, C_1-6Alkyl, C_2-5Alkenyl, C_2-5Alkynyl, phenyl or heteroaryl (chosen from pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, frills, thiazolyl and thienyl), each R_aIf you need more than one phenyl, halogen, C_1-3Alkyl, C_1-3Alkoxy, OH, oxo, or NR₁₀R₁₁May be replaced with R_aIs in 4th place, R₁And R₂Is as defined earlier, R₃Is H, halogen, methyl, methoxy, hydroxymethyl or OH, R₈Is H, branched or unbranched, saturated or unsaturated C_1-3Alkyl (may be substituted with OH if desired), or R₈Is (CH₂)_2-3NR₁₀R₁₁, (CH₂)_nCO₂R₁₂Or (CH₂)_nCONR₁₀R₁₁And R₉Is CN or CONR₁₀R₁₁Or R₉Is branched or non-branched C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkyne (one or more Cs each required_5-7Cycloalkyl, C_5-7Cycloalkylidene, C_5-7Cycloalkenyl, OH, CN, C_1-3Acyloxy, NR₁₀R₁₁, NR₁₀CONR₁₀R₁₁, NR₁₀C (= NR₁₀) NR₁₀R₁₁, NR₁₀COR₁₂, NR₁₀S (O)_pR₁₂, CONR₁₀R₁₁, CO₂R₁₂, C (R)₁₀) = NNR₁₀R₁₁, C (R)₁₀) = NNR₁₀CONR₁₀R₁₁, Aryl or heteroaryl), and each aryl or heteroaryl is optionally C_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_nNR₁₀R₁₁Or O (CH₂)_2-4NR₁₀R₁₁May be replaced with, or R₉Are aryl, heteroaryl or heterocycles, each requiring C_1-3Alkyl (phenyl or NR if required₁₀C (= NR₁₀) NR₁₀R₁₁May be replaced with), C_1-3Alkoxy, halogen, CN, oxo, (CH₂)_nNR₁₀R₁₁, (CH₂)_nCO₂R₁₂, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁May be substituted with 1 to 3 groups selected from, or [0023] R₈And R₉Together with saturated or unsaturated 5- or 6-membered aromatic or non-aromatic carbocyclic rings (C_1-3It may be substituted with alkyl or OH, or optionally spirocondensed to a 1,3 dioxolane group or a 1,3 dithiolane group, with each 1,3 dioxolane group or 1,3 dithiolane group as required. C_1-3Alkyl, C_1-3Alkoxy, OH or (CH₂)_nNR₁₀R₁₁May be replaced by) R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-6Alkyl, C_3-8Selected from cycloalkyl, benzyl and phenyl, said alkyl, cycloalkyl, benzyl or phenyl is optionally OH, C_1-3Alkoxy, C_1-3Acyloxy, CN, NO₂, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄Or may be replaced with phenyl, or R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (each required C_1-3Alkyl, C_1-3Alkoxy, OH,-(CH₂)_nNR₁₃R₁₄, CONR₁₃R₁₄Or NR₁₃COR₁₄May be replaced by) R₁₂Is H, C_1-6Alkyl or C_5-7Cycloalkyl, phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with, or R₁₂Is a phenyl or heterocycle, each requiring C_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_mNR₁₀R₁₁, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁May be substituted with 1 to 3 groups selected from R₁₃And R₁₄H and C independently_1-6Alkyl (C if necessary_1-3(May be substituted with alkoxy, OH or phenyl), or R₁₃And R₁₄Together form a chain that completes the ring, and the chain is (CH).₂)_4-5Or (CH₂)₂O (CH₂)₂And R₁₅The compound of the above formula (I) in which is H is provided. [0024] In another embodiment Ar₁Is phenyl or pyridyl, each with one or more Rs as needed₁, R₂And R₃May be replaced by (as defined below) X is NH or N-CH₃And Y is NH and R_aIs H, hydroxy C_1-2Alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridyl (which may be halogenated if desired), phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C_3-5Alkyne (C_1-3(Substituted with alkoxy or phenyl) R₁And R₂Are the same or different, H, halogen, C_1-3Alkyl (its C)_1-3Alkyl may be partially or completely halogenated if desired), NO₂, NR₁₃R₁₄Selected from R₃Is H, halogen, methoxy or methyl, R₄And R₅Together to complete the fused ring of formula B, R₈Is H, C_1-3Alkyl (may be substituted with OH if desired), or R₈Is (CH₂)_2-3NR₁₀R₁₁Or CO₂R₁₂And R₉Is CN or R₉Is methyl, C_2-3Alkenyl or C_2-3Alkyne (one or more Cs each required_5-7Cycloalkylidene, C_5-7Cycloalkenyl, OH, CN, NR₁₀R₁₁, NR₁₀CONR₁₀R₁₁, NR₁₀COR₁₂, NR₁₀S (O)_pR₁₂, CONR₁₀R₁₁, CO₂R₁₂, C (R)₁₀) = NNR₁₀R₁₁Or may be substituted with heteroaryl), or R₉Is aryl or heteroaryl (C if necessary_1-3Alkyl (may be substituted with phenyl if desired), C_1-3Alkoxy, halogen, amino or CONH₂It may be substituted with 1 to 3 groups selected from), or [0025] R₈And R₉Cyclopentene ring spiro-condensed into a 1,3 dioxolane group together (C if the 1,3 dioxolane group is required)_1-3Alkyl, C_1-3Alkoxy, OH or (CH₂)_nNR₁₀R₁₁May be replaced by) R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-3Alkyl, C_5-7Selected from cycloalkyl or phenyl, said alkyl, cycloalkyl or phenyl is optionally OH, C_1-3Alkoxy, C_1-3Acyloxy, NO₂, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄Or may be replaced with phenyl, or R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (each required C_1-3Alkyl, C_1-3Alkoxy, OH, (CH₂)_nNR₁₃R₁₄, CONR₁₃R₁₄Or NR₁₃COR₁₄May be replaced by) R₁₂Is H, C_1-3Alkyl or C_5-7Cycloalkyl, phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with, or R₁₂Is phenyl, or is a saturated 4- to 6-membered nitrogen-containing heterocycle, each requiring C_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_mNR₁₀R₁₁, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁May be substituted with 1 to 3 groups selected from R₁₃And R₁₄H and C independently_1-3Alkyl (C if necessary_1-3(May be substituted with alkoxy or OH), or R₁₃And R₁₄Together form a chain that completes the ring, and the chain is (CH).₂)_4-5Or (CH₂)₂O (CH₂)₂The compound of formula (I) described immediately before is provided. [0026] In yet another embodiment Ar₁Is phenyl R_aIs H or hydroxymethyl R₁And R₂Are the same or different, halogen, methyl (may be partially or fully halogenated if desired), NO₂And NH₂Selected from R₃Is H, chloro, fluoro, bromo or methoxy, R₁₀And R₁₁May be the same or different, each independently H, OH, methoxy, branched or unbranched C_1-3Alkyl or C_5-7Selected from cycloalkyl, said alkyl or cycloalkyl is required OH, NR₁₃R₁₄Or may be replaced with phenyl, or R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (each required C_1-2Alkyl, NR₁₃R₁₄, CONR₁₃R₁₄Or NR₁₃COR₁₄(May be replaced by) and R₁₂May be replaced with morpholino if necessary C_1-3Alkyl or R₁₂Is phenyl, or azetidinyl, pyrrolidinyl or piperidinyl (each required C)_1-3Alkyl, C_1-3Provided are compounds of formula (I) just described above (which may be substituted with one to three groups selected from alkoxy and halogen). In another sub-conceptual aspect, the present invention presents the equation I: [0027] [Chemical 21]<img file="JP5036112B2_D0004.tif" />[0028] Provided are a novel compound of the above, and a pharmaceutically acceptable acid derivative or salt derivative thereof. During the ceremony Ar₁Is an aromatic or non-aromatic carbocyclic ring, heteroaryl or heterocycle, and the carbocyclic ring, heteroaryl or heterocycle is optionally one or more Rs.₁, R₂And R₃May be replaced by X is NH, NC_1-3Alkyl, N-cyclopropyl, S or O, Y is NR₁₅, S or O, R_aIs H, C_1-10Alkyl, C_2-10Alkenyl or C_2-10It is an alkynyl, each of which may be branched, cyclic, or R._aAre aryl or heteroaryl, and each R_aIs independently required for more than one C_1-3Alkyl, C_1-6Alkoxy, halogen, OH, oxo, NR₁₀R₁₁, Aryl or heteroaryl, and each aryl or heteroaryl may be halogen, OH, C as required._1-3Alkyl, C_1-3Alkoxy, hydroxy C_1-3Alkyl and (CH₂)_mNR₁₀R₁₁May be substituted with one or more groups selected from, and R_aIs combined in the 4th or 5th place, [0029] R₁And R₂Are the same or different, H, halogen, CN, NO₂, C_1-10Branched or unbranched saturated or unsaturated alkyl, C_1-10Branched or unbranched alkoxy, C_1-10Branched or unbranched acyl, C_1-10Branched or unbranched acyloxy, C_1-10Branched or unbranched alkylthio, aminosulfonyl, di-(C_1-3) Alkylaminosulfonyl, NR₁₀R₁₁, Aryl, Aryl, Aryloxy, Arylsulfonyl, Heteroaryl and Heteroaryloxy.₁And R₂May be partially or completely halogenated if required, or oxo, OH, NR if required₁₀R₁₁, C_1-6Branched or unbranched alkyl, C_3-7Cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono-or di (C)_1-3) It may be substituted with 1 to 3 groups independently selected from the alkylaminocarbonyl. R₃Is H, halogen, OH, (CH₂)_nNR₁₀R₁₁, (CH₂)_nCO₂R₁₂, C_1-3Alkyl (OH, C if necessary_1-3Alkoxy (may be halogenated if desired) or C_1-3May be substituted with alkylthio) R₄And R₅A or B together with the atoms to which they are bonded [0030] [Chemical 22]<img file="JP5036112B2_D0005.tif" />[0031] Completed the condensed ring system of R₆Is C_1-3Alkyl or H, R₇Is branched or non-branched C_1-6Alkyl or H, R₈Is H, branched or unbranched, saturated or unsaturated C_1-6Alkyl (Phenyl, OH or C as needed_1-3May be substituted with alkoxy), or R₈Is (CH₂)_mNR₁₀R₁₁, (CH₂)_mNR₁₀COR₁₂, (CH₂)_nCO₂R₁₂, (CH₂)_nCONR₁₀R₁₁Or R₈Are phenyl or heteroaryl, each needing C_1-3Alkyl, C_1-3Alkoxy, OH, -SO₃May be replaced with H or halogen, R₉Is H or R₉Is branched or non-branched C_1-10Alkyl, C_3-10Cycloalkyl, C_2-6Alkenyl, C_2-6Alkynyl, each of which requires one or more halogens, OH, oxo, CN, C_1-3Alkoxy, NR₁₀R₁₁, NR₁₀COR₁₂, SR₁₂, CONR₁₀R₁₁, CO₂R₁₂, Aryloxy, arylthio, aryl or heteroaryl, each aryloxy, arylthio, aryl or heteroaryl is optionally C_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_nNR₁₀R₁₁Or O (CH₂)_2-4NR₁₀R₁₁May be replaced with, or R₉Is aryl or heteroaryl, and each aryl or heteroaryl is required C_1-3Alkyl (may be substituted with phenyl if desired), C_1-3Alkoxy, halogen, (CH₂)_nNR₁₀R₁₁, (CH₂)_nCO₂R₁₂, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁May be substituted with 1 to 3 groups selected from, or R₈And R₉Saturated or unsaturated 6-membered aromatic or non-aromatic carbocyclic rings together (1 or 2 OH, oxo or (CH as required)₂)_nNR₁₀R₁₁May be replaced by) [0032] R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-6Alkyl, C_3-8Cycloalkyl, aryl, aryl C_1-3Selected from alkyl and heteroaryl, said alkyl, cycloalkyl, aryl, aryl C_1-3Alkyl or heteroaryl is OH, C as needed_1-3Alkoxy, C_1-3Acyloxy, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄, May be substituted with aryl or heteroaryl, or R₁₀And R₁₁Together form a 3--7-membered alkylene chain that completes a ring around the N atom to which they are bonded, the alkylene chain being O, S (O) as needed._pAnd NR₁₃May be interrupted by, and the ring may be interrupted by C if necessary._1-3Alkyl, C_1-3Alkoxy, OH or-(CH₂)_nNR₁₃R₁₄May be replaced by R₁₂Is H, C_1-6Alkyl or C_3-8Cycloalkyl, each alkyl or cycloalkyl is phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with, or R₁₂Is phenyl (C if necessary_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_mNR₁₀R₁₁, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁It may be substituted with 1 to 3 groups selected from), R₁₃And R₁₄H and C independently_1-6Alkyl (C if necessary_1-3(May be substituted with alkoxy, OH or phenyl), or R₁₃And R₁₄Together form a chain that completes the ring, and the chain is (CH).₂)_4-5Or (CH₂)₂O (CH₂)₂And R₁₅Is H or C_1-3Alkyl m is 1-4, n is 0-3, and p is 0-2. [0033] In one embodiment of the invention Ar₁But a) Cycloalkyl groups selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, b) Cycloalkenyl groups selected from cyclopentenyl, cyclohexenyl, cycloheptenyl, c) Phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl, d) Pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, frill, isooxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indole, benzimidazolyl, benzofuranyl, benzoxazolyl Heteroaryl selected from zolyl, benzopyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl, or cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexano Pyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinolin, cyclohexanoquinolin, cyclopentanoisoquinoline, cyclohexanoisoquinolin, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzoimidazole, cyclo Condensed heteroaryl selected from pentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene, or e) Heterocycles selected from pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolydinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl. [0034] Ar above₁R each as required by one or more previously defined₁, R₂And R₃May be replaced by R_aIs H, C_1-6Alkyl, C_2-5Alkenyl, C_2-5Alkynyl, phenyl or heteroaryl (chosen from pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, frills, thiazolyl and thienyl), each R_aIf you need more than one phenyl, halogen, C_1-3Alkyl, C_1-3Alkoxy, OH, oxo, or NR₁₀R₁₁May be replaced with R_aIs in 4th place, R₃Is H, halogen, methyl, methoxy, hydroxymethyl or OH, R₈Is H, branched or unbranched, saturated or unsaturated C_1-3Alkyl (may be substituted with OH if desired), or R₈Is (CH₂)_2-3NR₁₀R₁₁, (CH₂)_nCO₂R₁₂Or (CH₂)_nCONR₁₀R₁₁And R₉Is branched or non-branched C_1-3Alkyl, C_2-4Alkenyl, C_2-4Alkyne (one or more OH, CN, NR each required₁₀R₁₁, CONR₁₀R₁₁, CO₂R₁₂, Aryl or heteroaryl), and each aryl or heteroaryl is optionally C_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_nNR₁₀R₁₁Or O (CH₂)_2-4NR₁₀R₁₁May be replaced with, or R₉Is aryl or heteroaryl (C if necessary_1-3Alkyl (may be substituted with phenyl if desired), C_1-3Alkoxy, halogen, (CH₂)_nNR₁₀R₁₁, (CH₂)_nCO₂R₁₂, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁It may be substituted with 1 to 3 groups selected from), or R₈And R₉Together form a saturated or unsaturated 6-membered aromatic or non-aromatic carbocyclic ring (which may optionally be replaced by OH ). [0035] R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-6Alkyl, C_3-8Selected from cycloalkyl, benzyl and phenyl, said alkyl, cycloalkyl, benzyl or phenyl is optionally OH, C_1-3Alkoxy, C_1-3Acyloxy, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄Or may be replaced with phenyl, or R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (each required C_1-3Alkyl, C_1-3Alkoxy, OH or-(CH₂)_nNR₁₃R₁₄May be replaced by) R₁₂Is H or C_1-6Alkyl (Phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with) R₁₃And R₁₄H and C independently_1-6Alkyl (C if necessary_1-3(May be substituted with alkoxy, OH or phenyl), or R₁₃And R₁₄Together form a chain that completes the ring, and the chain is (CH).₂)_4-5Or (CH₂)₂O (CH₂)₂And R₁₅The compound of formula (I) described immediately before is H is provided. [0036] In another embodiment of the invention Ar₁Is phenyl or pyridyl, X is NH or N-CH₃And Y is NH and R_aIs H, hydroxy C_1-2Alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridyl (which may be halogenated if desired), phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C_3-5Alkyne (C_1-3(Substituted with alkoxy or phenyl) R₁And R₂Are the same or different, halogen, C_1-3Alkyl (its C)_1-3Alkyl may be partially or completely halogenated if desired), NO₂, NR₁₃R₁₄Selected from R₃Is H, halogen, methoxy or methyl, R₄And R₅Together to complete the fused ring of formula B, R₈Is H, C_1-3Alkyl (may be substituted with OH if desired), or R₈Is (CH₂)_2-3NR₁₀R₁₁Or CO₂R₁₂And R₉Is methyl or C_2-3Alkenyl (one or more OH, CN, NR each required₁₀R₁₁, CONR₁₀R₁₁Or CO₂R₁₂May be replaced with), or R₉Is heteroaryl (C if necessary_1-3Alkyl (may be substituted with phenyl if desired), C_1-3It may be substituted with 1 to 3 groups selected from alkoxy, halogen or amino). [0037] R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-3Alkyl (OH, C if necessary_1-3Alkoxy, C_1-3Acyloxy, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄Or may be replaced with phenyl) R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (each required C_1-3Alkyl, C_1-3(May be substituted with alkoxy or OH), R₁₂Is H or C_1-3Alkyl (Phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with) R₁₃And R₁₄H and C independently_1-3Alkyl (C if necessary_1-3(May be substituted with alkoxy or OH), or R₁₃And R₁₄Together form a chain that completes the ring, and the chain is (CH).₂)_4-5Or (CH₂)₂O (CH₂)₂The compound of formula (I) described immediately before is provided. [0038] In yet another embodiment of the invention. Ar₁Is phenyl R_aIs H or hydroxymethyl R₁And R₂Are the same or different, halogen, methyl (may be partially or fully halogenated if desired), NO₂And NH₂Selected from R₃Is H, chloro, fluoro, bromo or methoxy, R₁₀And R₁₁May be the same or different, each independently H, OH, methoxy, branched or unbranched C_1-3Alkyl (OH, NR if necessary₁₃R₁₄Or may be replaced with phenyl) R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (C each as needed)_1-2(May be substituted by alkyl) and R₁₂May be replaced with morpholino if necessary C_1-3The compound of formula (I) described immediately before being alkyl is provided. In yet another embodiment of the invention, formula (Ia): [0039] [Chemical 23]<img file="JP5036112B2_D0006.tif" />[0040] Compounds, and pharmaceutically acceptable acid or salt derivatives thereof are provided. During the ceremony X is NH, NC_1-3Alkyl, N-cyclopropyl, S or O, R_aIs H, C_1-10Alkyl, C_2-10Alkenyl or C_2-10Alkynes, each of which may be branched, cyclic, or R_aAre aryl or heteroaryl, each R_aIndependently need more than one C_1-6Alkyl, C_1-6Alkoxy, halogen, OH, oxo, NR₁₀R₁₁, Aryl or heteroaryl, and each aryl or heteroaryl may be halogen, OH, C as required._1-3Alkyl, C_1-3Alkoxy, hydroxy C_1-3Alkyl and (CH₂)_mNR₁₀R₁₁May be substituted with one or more groups selected from, and R_aIs combined in 4th or 5th place, [0041] R₁And R₂Are the same or different, H, halogen, CN, NO₂, C_1-10Branched or unbranched saturated or unsaturated alkyl, C_1-10Branched or unbranched alkoxy, C_1-10Branched or unbranched acyl, C_1-10Branched or unbranched acyloxy, C_1-10Branched or unbranched alkylthio, aminosulfonyl, di-(C_1-3) Alkylaminosulfonyl, NR₁₀R₁₁, Aryl, Aryl, Aryloxy, Arylsulfonyl, Heteroaryl and Heteroaryloxy.₁And R₂May be partially or completely halogenated if required, or oxo, OH, NR if required₁₀R₁₁, C_1-6Branched or unbranched alkyl, C_3-7Cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono-or di (C)_1-3) It may be substituted with 1 to 3 groups independently selected from the alkylaminocarbonyl. R₃Is H, halogen, OH, (CH₂)_nNR₁₀R₁₁, CONR₁₀R₁₁, (CH₂)_nCO₂R₁₂, C_1-3Alkyl (OH, C if necessary_1-3Alkoxy (may be halogenated if desired) or C_1-3May be substituted with alkylthio) R₄And R₅A or B together with the atoms to which they are bonded [0042] [Chemical 24]<img file="JP5036112B2_D0007.tif" />[0043] Completed the condensed ring system of R₆Is C_1-3Alkyl or H, R₇Is branched or non-branched C_1-6Alkyl or H, R₈Is H, branched or unbranched, saturated or unsaturated C_1-6Alkyl (Phenyl, OH or C as needed_1-3May be substituted with alkoxy), or R₈Is (CH₂)_mNR₁₀R₁₁, (CH₂)_mNR₁₀COR₁₂, (CH₂)_nCO₂R₁₂, (CH₂)_nCONR₁₀R₁₁Or R₈Are phenyl or heteroaryl, each needing C_1-3Alkyl, C_1-3Alkoxy, OH, -SO₃May be replaced with H or halogen, R₉Is H, CN or CONR₁₀R₁₁Or R₉Is branched or non-branched C_1-10Alkyl, C_3-10Cycloalkyl, C_5-7Cycloalkenyl, C_2-6Alkenyl, C_2-6Alkyne, each with one or more Cs as needed_3-10Cycloalkyl, C_3-10Cycloalkylidene, C_5-7Cycloalkenyl, halogen, OH, oxo, CN, C_1-3Alkoxy, C_1-3Acyloxy, NR₁₀R₁₁, NR₁₀CONR₁₀R₁₁, NR₁₀C (= NR₁₀) NR₁₀R₁₁, NR₁₀COR₁₂, NR₁₀S (O)_pR₁₂, SR₁₂, CONR₁₀R₁₁, CO₂R₁₂, C (R)₁₀) = NNR₁₀R₁₁, C (R)₁₀) = NNR₁₀CONR₁₀R₁₁, Aryloxy, arylthio, aryl or heteroaryl, each aryloxy, arylthio, aryl or heteroaryl is optionally C_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_nNR₁₀R₁₁Or O (CH₂)_2-4NR₁₀R₁₁May be replaced with, or R₉Is an aryl, heteroaryl, or heterocycle, and each aryl, heteroaryl, or heterocycle is required by C._1-3Alkyl (phenyl or NR if required₁₀C (= NR₁₀) NR₁₀R₁₁May be replaced with), C_1-3Alkoxy, halogen, CN, oxo, (CH₂)_nNR₁₀R₁₁, (CH₂)_nCO₂R₁₂, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁May be substituted with 1 to 3 groups selected from, or [0044] R₈And R₉Together are saturated or unsaturated 5- or 6-membered aromatic or non-aromatic carbocyclic rings (1 or 2 Cs as required)_1-3Alkyl, OH, oxo or (CH₂)_nNR₁₀R₁₁It may be substituted with, or if necessary, spiro-condensed into a 1,3 dioxolane group or a 1,3 dithiolane group, and each 1,3 dioxolane group or 1,3 dithiolane group may be optionally C._1-6Alkyl, C_1-6Alkoxy, OH or (CH₂)_nNR₁₀R₁₁May be replaced by) R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-6Alkyl, C_3-8Cycloalkyl, aryl, aryl C_1-3Selected from alkyl and heteroaryl, said alkyl, cycloalkyl, aryl, aryl C_1-3Alkyl or heteroaryl is OH, C as needed_1-3Alkoxy, CN, NO₂, C_1-3Acyloxy, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄, May be substituted with aryl or heteroaryl, or [0045] R₁₀And R₁₁Together form a 3--7-membered alkylene chain that completes a ring around the N atom to which they are bonded, said alkylene chain being O, S (O) if necessary._pAnd NR₁₃May be interrupted by, and the ring may be interrupted by C if necessary._1-3Alkyl, C_1-3Alkoxy, OH,-(CH₂)_nNR₁₃R₁₄, CONR₁₃R₁₄Or NR₁₃COR₁₄May be replaced by R₁₂Is H, C_1-6Alkyl or C_3-8Cycloalkyl, each alkyl or cycloalkyl is phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with, or R₁₂Is a phenyl or heterocycle (C if necessary_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_mNR₁₀R₁₁, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁It may be substituted with 1 to 3 groups selected from), R₁₃And R₁₄H and C independently_1-6Alkyl (C if necessary_1-3(May be substituted with alkoxy, OH or phenyl), or R₁₃And R₁₄Together form a chain that completes the ring, the chain being (CH₂)_4-5Or (CH₂)₂O (CH₂)₂And m is 1-4, n is 0-3, and p is 0-2. [0046] In another embodiment of the invention X is NH or N-CH₃And R_aIs H, hydroxy C_1-2Alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridyl (which may be halogenated if desired), phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C_3-5Alkyne (C_1-3(Substituted with alkoxy or phenyl) and R_aIs combined in 4th place, R₁And R₂Are the same or different, H, halogen, C_1-3Alkyl (its C)_1-3Alkyl may be partially or completely halogenated if desired), NO₂, NR₁₃R₁₄Selected from R₃Is H, halogen, methoxy or methyl, R₄And R₅Together to complete the fused ring of formula B, R₈Is H, C_1-3Alkyl (may be substituted with OH if desired), or R₈Is (CH₂)_2-3NR₁₀R₁₁Or CO₂R₁₂And R₉Is CN or R₉Is methyl, C_2-3Alkenyl or C_2-3Alkyne (one or more Cs each required_5-7Cycloalkylidene, C_5-7Cycloalkenyl, OH, CN, NR₁₀R₁₁, NR₁₀CONR₁₀R₁₁, NR₁₀COR₁₂, NR₁₀S (O)_pR₁₂, CONR₁₀R₁₁, CO₂R₁₂, C (R)₁₀) = NNR₁₀R₁₁Or may be substituted with heteroaryl), or R₉Is aryl or heteroaryl (C if necessary_1-3Alkyl (may be substituted with phenyl if desired), C_1-3Alkoxy, halogen, amino or CONH₂It may be substituted with 1 to 3 groups selected from), or R₈And R₉Cyclopentene ring spiro-condensed into a 1,3 dioxolane group together (C if the 1,3 dioxolane group is required)_1-3Alkyl, C_1-3Alkoxy, OH or (CH₂)_nNR₁₀R₁₁May be replaced by) [0047] R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-3Alkyl, C_5-7Selected from cycloalkyl or phenyl, said alkyl, cycloalkyl or phenyl is optionally OH, C_1-3Alkoxy, C_1-3Acyloxy, NO₂, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄Or may be replaced with phenyl, or R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (each required C_1-3Alkyl, C_1-3Alkoxy, OH, (CH₂)_nNR₁₃R₁₄, CONR₁₃R₁₄Or NR₁₃COR₁₄May be replaced by) R₁₂Is H, C_1-3Alkyl or C_5-7Cycloalkyl, phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with, or R₁₂Is phenyl, or is a saturated 4- to 6-membered nitrogen-containing heterocycle, each requiring C_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_mNR₁₀R₁₁, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁May be substituted with 1 to 3 groups selected from R₁₃And R₁₄H and C independently_1-3Alkyl (C if necessary_1-3(May be substituted with alkoxy or OH), or R₁₃And R₁₄Together form a chain that completes the ring, and the chain is (CH).₂)_4-5Or (CH₂)₂O (CH₂)₂The compound of the above formula (Ia) is provided. [0048] In yet another embodiment of the invention. R_aIs H or hydroxymethyl R₁And R₂Are the same or different, halogen, methyl (may be partially or fully halogenated if desired), NO₂And NH₂Selected from R₃Is H, chloro, fluoro, bromo or methoxy, R₁₀And R₁₁May be the same or different, each independently H, OH, methoxy, branched or unbranched C_1-3Alkyl or C_5-7Selected from cycloalkyl, said alkyl or cycloalkyl is required OH, NR₁₃R₁₄Or may be replaced with phenyl, or R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (each required C_1-2Alkyl, NR₁₃R₁₄, CONR₁₃R₁₄Or NR₁₃COR₁₄(May be replaced by) and R₁₂May be replaced with morpholino if necessary C_1-3Alkyl or R₁₂Is phenyl, or azetidinyl, pyrrolidinyl or piperidinyl (each required C)_1-3Alkyl, C_1-3Provided are compounds of formula (Ia) just described above (which may be substituted with one to three groups selected from alkoxy and halogen). In yet another embodiment of the present invention, equation (Ia): [0049] [Chemical 25]<img file="JP5036112B2_D0008.tif" />[0050] Compounds, and pharmaceutically acceptable acid or salt derivatives thereof are provided. During the ceremony X is NH, NC_1-3Alkyl, N-cyclopropyl, S or O, R_aIs H, C_1-10Alkyl, C_2-10Alkenyl or C_2-10It is an alkynyl, each of which may be branched, cyclic, or R._aAre aryl or heteroaryl, and each R_aIs independently required for more than one C_1-6Alkoxy, halogen, OH, oxo, NR₁₀R₁₁, Aryl or heteroaryl, and each aryl or heteroaryl may be halogen, OH, C as required._1-3Alkyl, C_1-3Alkoxy, hydroxy C_1-3Alkyl and (CH₂)_mNR₁₀R₁₁May be substituted with one or more groups selected from, and R_aIs combined in the 4th or 5th place, R₁And R₂Are the same or different, H, halogen, CN, NO₂, C_1-10Branched or unbranched saturated or unsaturated alkyl, C_1-10Branched or unbranched alkoxy, C_1-10Branched or unbranched acyl, C_1-10Branched or unbranched acyloxy, C_1-10Branched or unbranched alkylthio, aminosulfonyl, di-(C_1-3) Alkylaminosulfonyl, NR₁₀R₁₁, Aryl, Aryl, Aryloxy, Arylsulfonyl, Heteroaryl and Heteroaryloxy.₁And R₂May be partially or completely halogenated if required, or oxo, OH, NR if required₁₀R₁₁, C_1-6Branched or unbranched alkyl, C_3-7Cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono-or di (C)_1-3) It may be substituted with 1 to 3 groups independently selected from the alkylaminocarbonyl. R₃Is H, halogen, OH, (CH₂)_nNR₁₀R₁₁, (CH₂)_nCO₂R₁₂, C_1-3Alkyl (OH, C if necessary_1-3Alkoxy (may be halogenated if desired) or C_1-3May be substituted with alkylthio) R₄And R₅A or B together with the atoms to which they are bonded [0051] [Chemical 26]<img file="JP5036112B2_D0009.tif" />[0052] Completed the condensed ring system of R₆Is C_1-3Alkyl or H, R₇Is branched or non-branched C_1-6Alkyl or H, R₈Is H, branched or unbranched, saturated or unsaturated C_1-6Alkyl (Phenyl, OH or C as needed_1-3May be substituted with alkoxy), or R₈Is (CH₂)_mNR₁₀R₁₁, (CH₂)_mNR₁₀COR₁₂, (CH₂)_nCO₂R₁₂, (CH₂)_nCONR₁₀R₁₁Or R₈Are phenyl or heteroaryl, each needing C_1-3Alkyl, C_1-3Alkoxy, OH, -SO₃May be replaced with H or halogen, R₉Is H or R₉Is branched or non-branched C_1-10Alkyl, C_3-10Cycloalkyl, C_2-6Alkenyl, C_2-6Alkynyl, each of which requires one or more halogens, OH, oxo, CN, C_1-3Alkoxy, NR₁₀R₁₁, NR₁₀COR₁₂, SR₁₂, CONR₁₀R₁₁, CO₂R₁₂, Aryloxy, arylthio, aryl or heteroaryl, each aryloxy, arylthio, aryl or heteroaryl is optionally C_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_nNR₁₀R₁₁Or O (CH₂)_2-4NR₁₀R₁₁May be replaced with, or R₉Is aryl or heteroaryl, and each aryl or heteroaryl is required C_1-3Alkyl (may be substituted with phenyl if desired), C_1-3Alkoxy, halogen, (CH₂)_nNR₁₀R₁₁, (CH₂)_nCO₂R₁₂, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁May be substituted with 1 to 3 groups selected from, or R₈And R₉Saturated or unsaturated 6-membered aromatic or non-aromatic carbocyclic rings together (1 or 2 OH, oxo or (CH as required)₂)_nNR₁₀R₁₁May be replaced by) [0053] R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-6Alkyl, C_3-8Cycloalkyl, aryl, aryl C_1-3Selected from alkyl and heteroaryl, said alkyl, cycloalkyl, aryl, aryl C_1-3Alkyl or heteroaryl is OH, C as needed_1-3Alkoxy, C_1-3Acyloxy, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄, May be substituted with aryl or heteroaryl, or R₁₀And R₁₁Together form a 3--7-membered alkylene chain that completes a ring around the N atom to which they are bonded, the alkylene chain being O, S (O) as needed._pAnd NR₁₃May be interrupted by, and the ring may be interrupted by C if necessary._1-3Alkyl, C_1-3Alkoxy, OH or-(CH₂)_nNR₁₃R₁₄May be replaced by R₁₂Is H, C_1-6Alkyl or C_3-8Cycloalkyl, each alkyl or cycloalkyl is phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with, or R₁₂Is phenyl (C if necessary_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_mNR₁₀R₁₁, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁It may be substituted with 1 to 3 groups selected from), R₁₃And R₁₄H and C independently_1-6Alkyl (C if necessary_1-3(May be substituted with alkoxy, OH or phenyl), or R₁₃And R₁₄Together form a chain that completes the ring, and the chain is (CH).₂)_4-5Or (CH₂)₂O (CH₂)₂And m is 1-4, n is 0-3, and p is 0-2. [0054] In another embodiment of the invention X is NH or N-CH₃And R_aIs H, hydroxy C_1-2Alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridyl (which may be halogenated if desired), phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C_3-5Alkyne (C_1-3(Substituted with alkoxy or phenyl) and R_aIs combined in 4th place, R₁And R₂Are the same or different, halogen, C_1-3Alkyl (its C)_1-3Alkyl may be partially or completely halogenated if desired), NO₂, NR₁₃R₁₄Selected from R₃Is H, halogen, methoxy or methyl, R₄And R₅Together to complete the fused ring of formula B, R₈Is H, C_1-3Alkyl (may be substituted with OH if desired), or R₈Is (CH₂)_2-3NR₁₀R₁₁Or CO₂R₁₂And R₉Is methyl or C_2-4Alkenyl (one or more OH, CN, NR each required₁₀R₁₁, CONR₁₀R₁₁Or CO₂R₁₂May be replaced with), or R₉Is heteroaryl (C if necessary_1-3Alkyl (may be substituted with phenyl if desired), C_1-3Alkoxy, halogen or (CH₂)_nNR₁₀R₁₁It may be substituted with 1 to 3 groups selected from), [0055] R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-3Alkyl (OH, C if necessary_1-3Alkoxy, C_1-3Acyloxy, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄Or may be replaced with phenyl) R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (each required C_1-3Alkyl, C_1-3(May be substituted with alkoxy or OH), R₁₂Is H or C_1-3Alkyl (Phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with) R₁₃And R₁₄H and C independently_1-3Alkyl (C if necessary_1-3(May be substituted with alkoxy or OH), or R₁₃And R₁₄Together form a chain that completes the ring, and the chain is (CH).₂)_4-5Or (CH₂)₂O (CH₂)₂The compound of formula (Ia) described immediately before is provided. [0056] In yet another embodiment of the invention. R_aIs H or hydroxymethyl R₁And R₂Are the same or different, halogen, methyl (may be partially or fully halogenated if desired), NO₂And NH₂Selected from R₃Is H, chloro, fluoro, bromo or methoxy, R₁₀And R₁₁May be the same or different, each independently H, OH, methoxy, branched or unbranched C_1-3Alkyl (OH, NR if necessary₁₃R₁₄Or may be replaced with phenyl) R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (C each as needed)_1-2(May be substituted by alkyl) and R₁₂May be replaced with morpholino if necessary C_1-3The compound of formula (Ia) described immediately before being alkyl is provided. In another aspect of the invention, an intermediate compound of formula (III) useful for the synthetic schemes and examples shown below is provided. In yet another aspect of the invention, special intermediate compounds of formula (III) with physiological activity (typical examples shown in Table 1 below) are provided. In those broadest conceptual aspects, the above intermediate compounds are represented by formula (III). [0057] [Chemical 27]<img file="JP5036112B2_D0010.tif" />[0058] [0058] During the ceremony Ar₁Is an aromatic or non-aromatic carbocyclic ring, heteroaryl or heterocycle, wherein the carbocyclic ring, heteroaryl or heterocycle is optionally one or more Rs.₁, R₂And R₃May be replaced by X is NH, NC_1-3Alkyl, N-cyclopropyl, S or O, Y is NR₁₅, S or O, R_aIs H, C_1-10Alkyl, C_2-10Alkenyl or C_2-10Alkynes, each of which may be branched, cyclic, or R_aAre aryl or heteroaryl, and each Ra is independently required to have one or more Cs._1-3Alkyl, C_1-6Alkoxy, halogen, OH, oxo, NR₁₀R₁₁, Aryl or heteroaryl, and each aryl or heteroaryl may be halogen, OH, C as required._1-3Alkyl, C_1-3Alkoxy, hydroxy C_1-3Alkyl and (CH₂)_mNR₁₀R₁₁May be substituted with one or more groups selected from, and R_aIs combined in 4th or 5th place, [0059] R₁And R₂Are the same or different, H, halogen, CN, NO₂, C_1-10Branched or unbranched saturated or unsaturated alkyl, C_1-10Branched or unbranched alkoxy, C_1-10Branched or unbranched acyl, C_1-10Branched or unbranched acyloxy, C_1-10Branched or unbranched alkylthio, aminosulfonyl, di-(C_1-3) Alkylaminosulfonyl, NR₁₀R₁₁, Aryl, Aryl, Aryloxy, Arylsulfonyl, Heteroaryl and Heteroaryloxy.₁And R₂May be partially or completely halogenated if required, or oxo, OH, NR if required₁₀R₁₁, C_1-6Branched or unbranched alkyl, C_3-7Cycloalkyl, phenyl, naphthyl, heteroaryl, aminocarbonyl and mono-or di (C)_1-3) It may be substituted with 1 to 3 groups independently selected from the alkylaminocarbonyl. R₃Is H, halogen, OH, (CH₂)_nNR₁₀R₁₁, (CH₂)_nCO₂R₁₂, C_1-3Alkyl (OH, C if necessary_1-3Alkoxy (may be halogenated if desired) or C_1-3May be substituted with alkylthio) R₄And R₅Together with the atoms to which they are bonded [0060] [Chemical 28]<img file="JP5036112B2_D0011.tif" />[0061] Completed the condensed ring system of R₆Is C_1-3Alkyl or H, R₇Is branched or non-branched C_1-6Alkyl or H, R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-6Alkyl, C_3-8Cycloalkyl, aryl, aryl C_1-3Selected from alkyl and heteroaryl, said alkyl, cycloalkyl, aryl, aryl C_1-3Alkyl or heteroaryl is OH, C as needed_1-3Alkoxy, C_1-3Acyloxy, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄, May be substituted with aryl or heteroaryl, or R₁₀And R₁₁Together form a 3--7-membered alkylene chain that completes a ring around the N atom to which they are bonded, said alkylene chain being O, S (O) if necessary._pAnd NR₁₃May be interrupted by, and the ring may be interrupted by C if necessary._1-3Alkyl, C_1-3Alkoxy, OH or-(CH₂)_nNR₁₃R₁₄May be replaced by R₁₂Is H, C_1-6Alkyl or C_3-8Cycloalkyl, each alkyl or cycloalkyl is phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with, or R₁₂Is phenyl (C if necessary_1-3Alkyl, C_1-3Alkoxy, halogen, (CH₂)_mNR₁₀R₁₁, (CH₂)_nCONR₁₀R₁₁And O (CH₂)_2-4NR₁₀R₁₁It may be substituted with 1 to 3 groups selected from), R₁₃And R₁₄H and C independently_1-6Selected from alkyl (optionally substituted with alkoxy, OH or phenyl) or R₁₃And R₁₄Together form a chain that completes the ring, the chain being (CH₂)_4-5Or (CH₂)₂O (CH₂)₂And m is 1-4, n is 0-3, and p is 0-2. [0062] One embodiment of the compound of formula (III) is Ar₁But a) Cycloalkyl groups selected from cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, b) Cycloalkenyl groups selected from cyclopentenyl, cyclohexenyl, cycloheptenyl, c) Phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl, d) Pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, frill, isooxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indole, benzimidazolyl, benzofuranyl, benzoxazolyl Heteroaryl selected from zolyl, benzopyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, and indazolyl, or cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexano Pyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinolin, cyclohexanoquinolin, cyclopentanoisoquinoline, cyclohexanoisoquinolin, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzoimidazole, cyclo Condensed heteroaryl selected from pentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene, or e) Heterocycles selected from pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolydinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl and indolinyl. [0063] Ar above₁More than one R each need₁, R₂And R₃May be replaced by (as defined above) R_aIs H, C_1-6Alkyl, C_2-5Alkenyl, C_2-5Alkynyl, phenyl or heteroaryl (chosen from pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, frills, thiazolyl and thienyl), each R_aIf you need more than one phenyl, halogen, C_1-3Alkyl, C_1-3Alkoxy, OH, oxo, or NR₁₀R₁₁May be replaced with R_aIs in 4th place, R₃Is H, halogen, methyl, methoxy, hydroxymethyl or OH, R₆Is C_1-3Alkyl or H, R₇Is branched or non-branched C_1-6Alkyl or H, R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-6Alkyl, C_3-8Selected from cycloalkyl, benzyl and phenyl, said alkyl, cycloalkyl or phenyl is optionally OH, C_1-3Alkoxy, C_1-3Acyloxy, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄Or may be replaced with phenyl, or R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (each required C_1-3Alkyl, C_1-3Alkoxy, OH or-(CH₂)_nNR₁₃R₁₄May be replaced by) R₁₂Is H or C_1-6Alkyl (Phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with) R₁₃And R₁₄H and C independently_1-6Alkyl (C if necessary_1-3(May be substituted with alkoxy, OH or phenyl), or R₁₃And R₁₄Together form a chain that completes the ring, and the chain is (CH).₂)_4-5Or (CH₂)₂O (CH₂)₂Is a compound. [0064] Another embodiment of the compound of formula (III) is Ar₁Is phenyl or pyridyl, X is NH or N-CH₃And Y is NH and R_aIs H, hydroxy C_1-2Alkyl, 2-hydroxyethylaminomethyl, methoxybenzylaminomethyl, pyridyl (which may be halogenated if desired), phenyl, 3-hydroxy-2-oxo-propyl, vinyl or C_3-5Alkyne (C_1-3(Substituted with alkoxy or phenyl) R₁And R₂Are the same or different, halogen, C_1-3Alkyl (its C)_1-3Alkyl may be partially or completely halogenated if desired), NO₂, NR₁₃R₁₄Selected from R₃Is H, halogen, methoxy or methyl, R₁₀And R₁₁May be the same or different, H, OH, C independently_1-3Alkoxy, branched or non-branched C_1-3Alkyl (OH, C if necessary_1-3Alkoxy, C_1-3Acyloxy, CO₂R₁₂, NR₁₃R₁₄, O (CH₂)_2-4NR₁₃R₁₄Or may be replaced with phenyl) R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (each required C_1-3Alkyl, C_1-3(May be substituted with alkoxy or OH), R₁₂Is H or C_1-3Alkyl (Phenyl, OH, C as needed_1-3Alkoxy or NR₁₃R₁₄May be replaced with) R₁₃And R₁₄H and C independently_1-3Alkyl (C if necessary_1-3(May be substituted with alkoxy or OH), or R₁₃And R₁₄Together form a chain that completes the ring, and the chain is (CH).₂)_4-5Or (CH₂)₂O (CH₂)₂It is the compound described immediately before. [0065] Yet another embodiment of the compound of formula (III) is Ar₁Is phenyl R_aIs H or hydroxymethyl R₁And R₂Are the same or different, halogen, methyl (may be partially or fully halogenated if desired), NO₂And NH₂Selected from R₃Is H, chloro, fluoro, bromo or methoxy, R₁₀And R₁₁May be the same or different, each independently H, OH, methoxy, branched or unbranched C_1-3Alkyl (OH, NR if necessary₁₃R₁₄Or may be replaced with phenyl) R₁₀And R₁₁Together with morpholino, pyrrolidinyl, piperazinyl or piperidinyl (each required C_1-2(May be substituted by alkyl) and R₁₂May be replaced with morpholino if necessary C_1-3It is the compound described immediately before it is alkyl. [0066] In a further embodiment of the invention, compounds of formulas (I) and (Ia) below are provided. 2- (2,6-dichlorophenylamino) -6,7-dimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -3,5-dihydro-imidazole [4,5-i] phenanthridine-4-one; 2- (2,6-dichlorophenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -7-methyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-1,8-dihydro-imidazole [4,5-h] isoquinoline-6-ethyl acetate; 3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -methyl acrylate ester; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-6- (2-hydroxyethyl) -1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-1,8-dihydro-imidazole [4,5-h] isoquinoline-6-carboxylic acid methyl ester; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 3- [2- (2,6-dichlorophenylamino) -1-methyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -acrylate methyl ester; [0067] 3- [2- (2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-1,8-dihydro-imidazole [4,5-h] isoquinoline-6-yl] propionate ethyl ester N-Benzyl-N-Methyl-2-[(2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-1,8-dihydro-imidazole [4,5-h] isoquinoline-6-yl] Acetamide; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-6- (2-morpholine-4-ylethyl) -1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2-Chloro-6-methylphenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (4-Bromo-2-dichlorophenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 3- [2- (2,6-dichlorophenylamino) -1-methyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -N-methoxy-N -Methyl acrylamide; 2- (2-Chloro-6-nitrophenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; N-Benzyl-3- [2- (2,6-dichlorophenylamino) -1-methyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -acrylamide ; 3- [2- (2,6-dichlorophenylamino) -1-methyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -4-morpholine acrylate Amide; 2- (2,6-dichlorophenylamino) -1,7-dimethyl -6- [3- (4-morpholino) propyl] -1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -4-hydroxymethyl-1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-Dimethylphenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2-Ethyl-6-methylphenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-6- (3-phenylaminopropyl) -1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; [0068] 2- (2,6-dichlorophenylamino 6- {3- [4- (2-diethylaminoethoxy) -phenylamino] propyl} -1,7-dimethyl-1,8-dihydro-imidazole [4,5-h] Isoquinoline-9-on; 2- (2-Bromo-6-chloro-4-fluorophenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -4- (2-hydroxyethylaminomethyl) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -4- (4-methoxybenzylaminomethyl) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-vinyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -4- (2,6-difluoropyridin-3yl) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9 -on; 2- (2,6-dichlorophenylamino) -4- (3-methylphenyl) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-1,8-dihydro-imidazole [4,5-h] isoquinoline-6-carboxylic acid 2- (4-morpholino) ethyl ester ; 2- (2,6-dichlorophenylamino) -4- (3-hydroxy-2-oxo-propyl) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9 -on; N-4- (2-diethylaminoethoxy) phenyl-3- [2- (2,6-dichlorophenylamino) -1-methyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] Isoquinoline-7-yl] -acrylamide; 3- [2- (2,6-dichlorophenylamino) -1-methyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -N-methylacrylamide; 9-Hydroxy-2- (2,6-dichlorophenylamino) -3,5,6,7,8,9-Hexahydro-imidazole [4,5-i] Phenanthridine-4-one; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (3-hydroxypropen-1-yl) -1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one ; [0069] 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (2-phenylethenyl) -1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one; 2- (2-Amino-6-chlorophenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,6,7-trimethyl-4-vinyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -4- (3-methoxypropin-1-yl) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9 -on; 2- (2,6-dichlorophenylamino) -1,6,7-trimethyl-4- (5-phenylpent-1-inyl) -1,8-dihydro-imidazole [4,5-h] isoquinoline-9- on; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-oxazole-5-yl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1-methyl-7-vinyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (3-morpholine-4-yl-propen-1-yl) -1,8-dihydro-imidazole [4,5-h]- Isoquinoline-9-on; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-6- [2- (2-hydroxyethyl) aminoethyl] -1,8-dihydro-imidazole [4,5-h] isoquinoline-9- on; 3- [2- (2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -acrylonitrile; 2- (2-Chloro-6-methylphenylamino) -1,7-dimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1-methyl-7-oxazole-5-yl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-6- (3-hydroxypropyl) -1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -7- (3-hydroxypropen-1-yl) -1-methyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one; [0070] 2- (2-Chloro-6-methylphenylamino) -7- (3-hydroxypropen-1-yl) -1-methyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9- on; 2- (2,6-dichlorophenylamino) -7- (3-diethylaminopropen-1-yl) -1,6-dimethyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one ; 7- (3-Aminopropene-1-yl) -2- (2,6-dichlorophenylamino) -1,6-dimethyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one ; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (3-pyrrolidine-1-yl-propen-1-yl) -1,8-dihydro-imidazole [4,5-h]- Isoquinoline-9-on; 7- (3-Benzylmethylaminopropen-1-yl) 2- (2,6-dichlorophenylamino) -1,6-dimethyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9- on; 2- (2,6-dichloro-4-methoxyphenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichloro-4-methoxyphenylamino) -1,6-dimethyl-7-oxazole-5-yl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -7- (3-diethylaminopropen-1-yl) -1-methyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one; 2- (2,6-Dimethylphenylamino) -1,7-dimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (4-methylpiperazin-1-yl-propen-1-yl) -1,8-dihydro-imidazole [4,5-h] -Isoquinoline-9-on; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-(3-piperidin-1-yl-propen-1-yl) -1,8-dihydro-imidazole [4,5-h]- Isoquinoline-9-on; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-{3- [ethyl (2-hydroxyethyl) amino] propene-1-yl} -1,8-dihydro-imidazole [4,5 -h]-isoquinoline-9-on; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- [3- (3-hydroxypyrrolidin-1-yl) -propen-1-yl] -1,8-dihydro-imidazole [4, 5-h]-isoquinoline-9-on; 7- (3-Dibutylaminopropen-1-yl) -2- (2,6-dichlorophenylamino) -1,6-dimethyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9- on; [0071] 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-{3-[(2-methoxyethyl) methylamino] propene-1-yl} -1,8-dihydro-imidazole [4,5 -h]-isoquinoline-9-on; 7- (3-Diethylaminopropen-1-yl) -1,6-dimethyl-2- (2,6-dimethylphenylamino) -1,8-dihydro-imidazole [4,5-h] -isoquinoline-9- on; 2- (2,6-dichlorophenylamino) -7- {3-[(2-diethylaminoethyl) methylamino] -propene-1-yl} -1,6-dimethyl-1,8-dihydro-imidazole [4, 5-h]-isoquinoline-9-on; 7- (3-Diethylaminopropen-1-yl) -1,6-dimethyl-2- (2,4,6-trichlorophenylamino) -1,8-dihydro-imidazole [4,5-h] -isoquinoline- 9-on 2- (2,6-dichlorophenylamino) -6-methyl-7-oxazole-5-yl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-[3- (2-pyrrolidine-1-ylmethylpyrrolidin-1-yl) -propene-1-yl] -1,8-dihydro -Imidazo [4,5-h]-Isoquinoline-9-On 7- [3- (2S-aminomethylpyrrolidine-1-yl) -propene-1-yl] -2- (2,6-dichlorophenylamino) -1,6-dimethyl-1,8-dihydro-imidazole [4 , 5-h]-isoquinoline-9-on 1-{3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenyl} -L-proline carboxamide 1-{3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenil} -Piperidine-3-carboxamide 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (methylhydrazonomethyl) -1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one 7- [3- (3-Aminopyrrolidine-1-yl) -propene-1-yl] -2- (2,6-dichlorophenylamino) -1,6-dimethyl-1,8-dihydro-imidazole [4, 5-h]-isoquinoline-9-on 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-[3- (3-acetamidopyrrolidine-1-yl) -propene-1-yl] -1,8-dihydro-imidazole [4, 5-h]-isoquinoline-9-on [0072] 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- [3- (3-dimethylaminopyrrolidine-1-yl) -propene-1-yl] -1,8-dihydro-imidazole [4] , 5-h]-isoquinoline-9-on 1-{3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenil} -Piperidine-2-carboxamide 7- [3- (3-Aminomethylpiperidine-1-yl) -propen-1-yl] -2- (2,6-dichlorophenylamino) -1,6-dimethyl-1,8-dihydro-imidazole [4 , 5-h]-isoquinoline-9-on 1-{3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenyl} -piperidine-3-carboxylic acid diethylamide 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-ethynyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one 1-{3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenyl} -3-methylurea Cyclohexanecarboxylic acid {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -propenyl} Amide 2- (2,6-dichlorophenylamino) -1-methyl-7-phenyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one N- {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenyl} Methane Sulfonamide 3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -propenylurea 1-Cyclohexyl-3- {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7 -Il]-Propenil} -Urea N- {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenyl} Benzene Sulfonamide [0073] 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (3-ethylaminopropen-1-yl) -1,8-dihydro-imidazole [4,5-h] -isoquinoline-9- on N- {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenil} -guanidine Piperidine-3-carboxylic acid {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7 -Il]-Propenyl} amide L-Proline {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -Propenyl} amide D-Proline {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -propenyl} Amide 3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -benzoamide L-azetidine-2-carboxylic acid {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline -7-Il] -Propenyl} amide Piperidine-2-carboxylic acid {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7 -Il]-Propenyl} amide; and These pharmaceutically acceptable derivatives. [0074] In yet another embodiment of the invention, compounds of formulas (I) and (Ia) below are provided. 2- (2,6-dichlorophenylamino) -3,5-dihydro-imidazole [4,5-i] phenanthridine-4-one; 2- (2,6-dichlorophenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-6- (2-hydroxyethyl) -1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-1,8-dihydro-imidazole [4,5-h] isoquinoline-6-carboxylic acid methyl ester; 3- [2- (2,6-dichlorophenylamino) -1-methyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -acrylate methyl ester; 2- (2-Chloro-6-methylphenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 3- [2- (2,6-dichlorophenylamino) -1-methyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -N-methoxy-N -Methyl acrylamide; 2- (2-Chloro-6-nitrophenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; N-Benzyl-3- [2- (2,6-dichlorophenylamino) -1-methyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -acrylamide ; 3- [2- (2,6-dichlorophenylamino) -1-methyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -4-morpholine acrylate Amide; 2- (2,6-dichlorophenylamino) -4-hydroxymethyl-1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-vinyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-1,8-dihydro-imidazole [4,5-h] isoquinoline-6-carboxylic acid 2- (4-morpholino) ethyl ester ; [0075] 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (3-hydroxypropen-1-yl) -1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one ; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-oxazole-5-yl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1-methyl-7-vinyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (3-morpholine-4-yl-propen-1-yl) -1,8-dihydro-imidazole [4,5-h]- Isoquinoline-9-on; 3- [2- (2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -acrylonitrile; 2- (2-Chloro-6-methylphenylamino) -1,7-dimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1-methyl-7-oxazole-5-yl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -7- (3-hydroxypropen-1-yl) -1-methyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one; 2- (2-Chloro-6-methylphenylamino) -7- (3-hydroxypropen-1-yl) -1-methyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9- on; 2- (2,6-dichlorophenylamino) -7- (3-diethylaminopropen-1-yl) -1,6-dimethyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one ; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (3-pyrrolidine-1-yl-propen-1-yl) -1,8-dihydro-imidazole [4,5-h]- Isoquinoline-9-on; 2- (2,6-dichlorophenylamino) -7- (3-diethylaminopropen-1-yl) -1-methyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (4-methylpiperazin-1-yl-propen-1-yl) -1,8-dihydro-imidazole [4,5-h] -Isoquinoline-9-on; 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-(3-piperidin-1-yl-propen-1-yl) -1,8-dihydro-imidazole [4,5-h]- Isoquinoline-9-on; [0076] 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-{3- [ethyl (2-hydroxyethyl) amino] propene-1-yl} -1,8-dihydro-imidazole [4,5 -h]-isoquinoline-9-on; 7- (3-Diethylaminopropen-1-yl) -1,6-dimethyl-2- (2,6-dimethylphenylamino) -1,8-dihydro-imidazole [4,5-h] -isoquinoline-9- on; 2- (2,6-dichlorophenylamino) -7- {3-[(2-diethylaminoethyl) methylamino] -propene-1-yl} -1,6-dimethyl-1,8-dihydro-imidazole [4, 5-h]-isoquinoline-9-on; 7- (3-Diethylaminopropen-1-yl) -1,6-dimethyl-2- (2,4,6-trichlorophenylamino) -1,8-dihydro-imidazole [4,5-h] -isoquinoline- 9-on 2- (2,6-dichlorophenylamino) -6-methyl-7-oxazole-5-yl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-[3- (2-pyrrolidine-1-ylmethylpyrrolidin-1-yl) -propene-1-yl] -1,8-dihydro -Imidazo [4,5-h]-Isoquinoline-9-On 7- [3- (2S-Phenylmethylpyrrolidine-1-yl) -propene-1-yl] -2- (2,6-dichlorophenylamino) -1,6-dimethyl-1,8-dihydro-imidazole [4 , 5-h]-isoquinoline-9-on 1-{3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenyl} -L-proline carboxamide 1-{3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenil} -Piperidine-3-carboxamide 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (methylhydrazonomethyl) -1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one 7- [3- (3-Aminopyrrolidine-1-yl) -propene-1-yl] -2- (2,6-dichlorophenylamino) -1,6-dimethyl-1,8-dihydro-imidazole [4, 5-h]-isoquinoline-9-on 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-[3- (3-acetamidopyrrolidine-1-yl) -propene-1-yl] -1,8-dihydro-imidazole [4, 5-h]-isoquinoline-9-on [0077] 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- [3- (3-dimethylaminopyrrolidine-1-yl) -propene-1-yl] -1,8-dihydro-imidazole [4] , 5-h]-isoquinoline-9-on 1-{3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenil} -Piperidine-2-carboxamide 7- [3- (3-Aminomethylpiperidine-1-yl) -propen-1-yl] -2- (2,6-dichlorophenylamino) -1,6-dimethyl-1,8-dihydro-imidazole [4 , 5-h]-isoquinoline-9-on 1-{3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenyl} -piperidine-3-carboxylic acid diethylamide 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-ethynyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one 1-{3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenyl} -3-methylurea Cyclohexanecarboxylic acid {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -propenyl} Amide 2- (2,6-dichlorophenylamino) -1-methyl-7-phenyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one N- {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenyl} Methane Sulfonamide 3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -propenylurea 1-Cyclohexyl-3- {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7 -Il]-Propenil} -Urea [0078] N- {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenyl} Benzene Sulfonamide 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (3-ethylaminopropen-1-yl) -1,8-dihydro-imidazole [4,5-h] -isoquinoline-9- on N- {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl]- Propenil} -guanidine Piperidine-3-carboxylic acid {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7 -Il]-Propenyl} amide L-Proline {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -Propenyl} amide D-Proline {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -propenyl} Amide 3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -benzoamide L-azetidine-2-carboxylic acid {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline -7-Il] -Propenyl} amide Piperidine-2-carboxylic acid {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7 -Il]-Propenyl} amide; as well as These pharmaceutically acceptable derivatives. [0079] Compounds of the invention containing one or more asymmetric carbon atoms can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are clearly included in the present invention. Each stereoisomeric carbon may have an R configuration, an S configuration, or a combination of these configurations. Some of the compounds of the invention may be present in more than one tautomeric form. The present invention includes all such tautomers. The compounds of the present invention are only those compounds intended to be "chemically stable" as will be appreciated by those skilled in the art. For example, a compound having a "dangling valence" or "carbanion" is not a compound intended by the present invention. All terms used herein should be understood in their usual sense as known in the art, unless otherwise noted. For example, "C_1-6Alkoxy "has terminal oxygen C_1-6Alkyl, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkylene or alkynyl groups should be understood to be branched or non-branched unless otherwise noted. Other more specific definitions are as follows. [0080] [0080] The term "halogen" as used herein should be understood to mean bromine, chlorine, fluorine or iodine. The term "heteroaryl" refers to a stable 5- to 8-membered (preferably 5- or 6-membered) monocyclic or 8- to 11-membered bicyclic aromatic heterocyclic group. Each heterocycle consists of a carbon atom and 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Heterocycles may be bonded by any atom of the ring, which results in the formation of a stable structure. Examples of "heteroaryl" groups are pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, frill, isooxazolyl, isothiazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indrill, benzimidazolyl, benzofuranyl. Oxazolyl, benzoisooxazolyl, benzopyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, 2,4-dioxo-quinazolinyl, imidazole [4,5-c] pyridinyl and indazolyl, or condensed heteroaryl, such as cyclo Pentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyridine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinolin, cyclohexanoquinolin, cyclopentanoisoquinolin, cyclohexyl Sanoisoquinolin, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzoimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexano Thiophene is mentioned. [0081] The term "heterocycle" refers to a stable 4--8 (preferably 5- or 6-membered) monocyclic or 8--11-membered bicyclic heterocyclic group (which may be saturated or unsaturated). , Also non-aromatic). Each heterocycle consists of a carbon atom and 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Heterocycles may be bonded by any atom of the ring, which results in the formation of a stable structure. Examples of "heterocyclic" groups are azetidinyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolydinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl, indolinyl, 2,3-dihydrobenzoimidazolyl and 2,3-dihydro-1H-imidazole [ 4,5-c] Pyridinyl can be mentioned. As used herein and as used herein, the terms "nitrogen" and "sulfur" and their respective element symbols include all oxidized forms of nitrogen and sulfur as well as quaternized forms of any basic nitrogen. The term "aryl" should be understood to mean a 6-10 member aromatic carbocyclic ring, where "aryl" includes, for example, phenyl and naphthyl, and other terms including "aryl" are aryl components. Examples of these parts include arylalkyl, aryloxy or arylthio. [0082] The term "carbon ring" should be understood to mean a 3-10-membered aromatic or non-aromatic cyclic carbon chain. Examples of non-aromatic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl and the like. Examples of aromatic carbocyclic rings include the above "aryl" compounds. The term "acyl" should be understood to mean the R- (C = O) -part (where R is alkyl). Examples of R are saturated or unsaturated, branched or unbranched C_1-10It may be alkyl, or R may be the previously defined "aryl". "Acyloxy" is R-CO₂-It should be understood to mean a group (in the formula, R is as defined in this section). The present invention includes pharmaceutically acceptable derivatives of the compounds of the present invention. A "pharmaceutically acceptable derivative" is any pharmaceutically acceptable salt or ester of a compound of the invention, or a compound of the invention, a pharmacologically active metabolite or a pharmacologically active residue thereof after administration to a patient. Represents any other compound that can be given (directly or indirectly). [0083] Pharmaceutically acceptable salts of the compounds of the present invention include pharmaceutically acceptable salts derived from inorganic and organic acids and bases. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, etc. Examples thereof include acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid. Other acids, such as oxalic acid, are not pharmaceutically acceptable on their own, but may also be used in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Good. Salts derived from suitable bases include alkali metal (eg sodium) salts, alkaline earth metal (eg magnesium) salts, ammonium salts and N- (C).₁-C₄Alkyl)₄⁺Salt is mentioned. In addition, examples of the compound of the present invention include prodrugs of the compound of the present invention. Prodrugs include compounds that are modified to produce the compounds of the invention after a simple chemical conversion. Simple chemical conversions include hydrolysis, oxidation and reduction (enzymatic, metabolic or other). Specifically, when the prodrug of the invention is administered to a patient, the prodrug may be converted to a compound of the invention, thereby conferring the desired pharmacological effect. [0084]<u style="single">General synthesis method</u>The compounds of the present invention can be prepared by the methods described below. Optimal reaction conditions and reaction times can vary depending on the particular reactants used. Unless otherwise specified, the solvent, temperature, pressure and other reaction conditions can be readily selected by one of ordinary skill in the art. A special operation is shown in the section of Synthesis Examples. Typically, reaction progress can be monitored by thin layer chromatography (TLC) if desired. If desired, the intermediates and products can be purified by silica gel chromatography and / or recrystallization. Starting materials and reagents are commercially available or can be prepared by one of ordinary skill in the art using the methods described in the chemical literature. A general procedure (method A) that can be used to synthesize the compound of formula (I) is shown in Scheme I. Scheme I (Method A) [0085] [Chemical 29]<img file="JP5036112B2_D0012.tif" />[0086] The diamine II, which may be optionally substituted, is reacted with the arylisothiocyanate in a suitable solvent such as EtOAc, DMF or THF at about ambient to reflux temperature for about 3 to 24 hours to give thiourea III. It can also be started with a salt of II and reacted with arylisothiocyanates in pyridine or a neutral solvent, eg, in THF in the presence of a suitable base such as triethylamine. Thiourea is reacted with a suitable activator in a suitable solvent, eg, THF or DMF, at approximately ambient to reflux temperatures, eg, 1,3-dicyclohexylcarbodiimide (DCC) or mercury oxide (II) to I or A precursor of I is obtained, which may undergo further chemical conversion to obtain the desired compound. If desired, the two steps may be carried out by adding DCC or mercury (II) oxide to the reaction of II with arylisothiocyanate without isolating thiourea. Alternatively, a benzothiazole (formula I, X = S) may be prepared by Method A, starting with a similar aminothiophenol. It is also preferred to use Method B as shown in Scheme II and described below. Scheme II (Method B) [0087] [Chemical 30]<img file="JP5036112B2_D0013.tif" />[0088] In this method, an appropriately substituted aniline is reacted with an arylisothiocyanate as in Method A to give thiourea V. V is reacted under cyclization conditions, eg, in the presence of bromine, in a suitable solvent such as chloroform at approximately reflux temperature to give I (X = S) or a precursor of I. The starting diamine (II) in Method A can be prepared, for example, by reducing nitroaniline in a suitable solvent such as EtOAc or HOAc in the presence of a suitable catalyst such as palladium / carbon in a hydrogen atmosphere. One operation (method C) for preparing the starting nitroaniline is shown in Scheme III and described below. Scheme III (Method C) [0089] [Chemical 31]<img file="JP5036112B2_D0014.tif" />[0090] In Method C, 2,6-dichloro-3-nitrobenzonitrile (VI) is reacted with the amine in a suitable solvent, such as EtOH, THF or EtOAc, optionally in a pressurized flask at about 0-80 ° C. And get VII. VII is a suitable base, eg K₂CO₃, Potassium t-butoxide or 1,8-diazabicyclo [5.4.0] Undeca-7-ene (DBU) in the presence of a suitable solvent, eg, react with keto-ester VIII at about ambient temperature in DMF or DMSO. And get IX. Hydrolyzing and cyclizing IX to give X is carried out by reaction with an aqueous acid, such as a mixture of acetic acid, sulfuric acid and water, at approximately reflux temperature. Nitroaniline X is reduced as described above in a suitable solvent, preferably acetic acid and / or trifluoroacetic acid to give XI. In the modification of Method C, the above intermediate IX may be reduced to the corresponding diamine to produce benzimidazole by Method A prior to the production of isoquinolinone. R_AThe procedure for introducing a compound of formula (I) into the compound is shown in Scheme IV. Scheme IV [0091] [Chemical 32]<img file="JP5036112B2_D0015.tif" />[0092] Intermediate XII (subsequently prepared by reduction as described in Scheme III for the preparation of IX) is reacted with bromine in a suitable solvent such as chloroform at ambient temperature to give XIII. Convert Intermediate XIII to XIV according to Method A. Carbon can be introduced in place of bromine using cross-coupling chemistry. For example, (PPh₃)₂PdCl₂In the presence of a suitable catalyst such as 1-methyl-2-pyrrolidinone (NMP), it is reacted with vinyl tributyltin at about 100 ° C. to obtain XV. Also, (PPh₃)₂PdCl₂, And in the presence of a suitable catalyst such as CuI and a suitable base such as triethylamine, react with the terminal alkyne in a solvent such as THF at approximately ambient temperature._aGet an alkyne as. Other R_aThese Rs by methods known to those skilled in the art_aObtained by the conversion of. Some of these transformations are illustrated below. R₄And R₅A method for preparing a compound of the present invention in which the ring B is represented (which is based on the procedure described in J. Heterocyclic Chem., 1970, 7, 615) is shown in Scheme V. Scheme V [0093] [Chemical 33]<img file="JP5036112B2_D0016.tif" />[0094] Intermediate XVI (prepared according to Method A or Method B) is reacted with a reducing agent such as sodium hydride at about 0 ° C to ambient temperature in a suitable solvent such as THF or dioxane to make Intermediate XVII (its). One carbonyl of the imide is selectively reduced). Treatment of XVII with a strong acid such as sulfuric acid at ambient temperature results in dislocation to isoquinolone XVIII. This method is R₆, R₇, R₈And R₉Will be found to be optimal for compounds in which are all of the same group, preferably methyl. In this modification of the method, the reduction of the imide and the rearrangement to isoquinolone can be done before forming the benzimidazole ring. R of compound or intermediate of formula (I) prepared as shown in the above scheme₈Or R₉The functional groups at can also be converted by methods known to those of skill in the art to prepare additional compounds of the invention. Some of these transformations are also illustrated below. [0095]<u style="single">Therapeutic usage</u>The compounds of the present invention are beneficial in suppressing the activity of src family kinases and PDGFR kinases. In doing so, these compounds are effective in blocking disease processes mediated by these kinases. For example, by suppressing p56lck, these compounds block downstream signaling events after T cell activation by the antigen. Activation of antigen-specific T cells is required for the induction and progression of diseases, including autoimmune diseases, allergic diseases and graft rejection (JH Hanke et al., Inflamm. Res., 1995, 44, 357). Therefore, the compounds of the present invention are beneficial in treating such diseases. These include rheumatoid arthritis, multiple sclerosis, Guillain-Barré syndrome, Crohn's disease, ulcerative colitis, psoriasis, transplant-to-host disease, systemic lupus erythematosus, insulin-dependent diabetes mellitus and asthma. Not limited to. [0096] In view of their inhibitory effect on src family kinases and PDGFR kinases, the compounds of the present invention are beneficial in treating cancer. For example, the compounds of the present invention are beneficial in treating src-dependent tumors such as breast cancer, colon cancer, melanoma and sarcoma, and PDGF-dependent tumors such as ovarian cancer, prostate cancer and glial blastoma. Beneficial to treat. By suppressing p60src, the compounds of the present invention may also be beneficial in treating osteoporosis, Paget's disease, bone inflammation and arthritis. By suppressing PDGFR kinase, the compounds of the invention may also be beneficial in treating adenomyosis, restenosis and atherosclerosis. By suppressing lyn kinase, the compounds of the invention may also be beneficial in enhancing or enhancing the effectiveness of radiation therapy. For therapeutic use, the compounds of the invention can be administered in any conventional form and in any conventional manner. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrabursa, infusion, sublingual, transdermal, oral, rectal, topical or inhalation. The preferred route of administration is oral and intravenous. Compositions containing the compounds of the invention for each of the above routes of administration will be apparent to those of skill in the art. For example, one embodiment of the present invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the present invention. Such pharmaceutical compositions will further include pharmaceutically acceptable carriers and adjuvants as described below. [0097] The compounds of the present invention alone or enhance the stability of the inhibitors, promote administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity and assist. It can be administered in combination with an adjuvant (including other active ingredients) such as giving therapy. Advantageously, such combination therapies utilize low doses of conventional therapeutic agents, thus avoiding possible toxicity and side effects that occur when these agents are used as a single therapy. The compounds of the present invention may be physically combined with conventional therapeutic agents or other adjuvants in a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. In certain embodiments, a pharmaceutical composition comprising a combination of such compounds comprises at least about 5%, more preferably at least about 20% of the compound (w / w) of formula (I) or a combination thereof. The optimum% (w / w) of the compound of formula (I) may vary and is within the skill of ordinary skill in the art. The compounds may also be administered separately (sequentially or in parallel). Separate administration allows great flexibility in the dosing regimen. [0098] As mentioned above, dosage forms of the compounds of the invention include pharmaceutically acceptable carriers and adjuvants known to those of skill in the art. Examples of these carriers and adjuvants include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include tablets, capsules, capsules, liquids, solutions, suspensions, emulsions, lozenges, syrups, reclaimed powders, granules, suppositories and transdermal patches. Methods for preparing such dosage forms are known (eg, HC Ansel and NG). See Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, Volume 5, Lea and Febiger (1990)). Dosage levels and requirements are well recognized in the art and can be selected by one of ordinary skill in the art from available methods and techniques suitable for the particular patient. In certain embodiments, the dosing level is in the range of about 1-1000 mg / dosing for a 70 kg patient. One dose daily may be sufficient, but up to five doses daily may be given. For oral medication, up to 200 mg / day may be required. As those skilled in the art will appreciate, lower or higher doses may be required depending on the particular factor. For example, the particular dose and treatment regimen will depend on factors such as the patient's general health profile, the severity and course of the patient's disability or its temperament, and the judgment of the treating physician. [0099] (Example)<u style="single">Synthesis Example</u>Example 1: Synthesis of 2- (2,6-dichlorophenylamino) -6,6-dimethyl-1H, 6H-imidazole [4,5-h] isoquinoline-7,9-dione [0100] [Chemical 34]<img file="JP5036112B2_D0017.tif" />[0101] 4,4-Dimethyl-7-nitro-2H, 4H-isoquinoline-1,3-dione in methanol (50 ml) (prepared as described in US Pat. No. 4,666923 (1987)) (1.0 g, 4.5 mmol) was hydrogenated at 3.5 kg / cm2 (50 psi) for 1.5 hours at 10% Pd / C (30 mg). The catalyst was removed by filtration and the solvent was removed to give 8-amino-4,4-dimethyl-2H, 4H-isoquinoline-1,3-dione (0.90 g, 98%). The amine (1.5 g, 7.35 mmol) was stirred in acetic anhydride (9 ml) at room temperature for 3 hours and then poured onto ice. The precipitate was filtered, washed with water and dried to give 7-acetamide-4,4-dimethyl-2H, 4H-isoquinoline-1,3-dione (1.55 g, 86%). The amide was converted to 7-acetamido-4,4-dimethyl-8-nitro-2H, 4H-isoquinoline-1,3-dione as described in US Pat. No. 4,176184 (1979). 90% H of 7-acetamide-4,4-dimethyl-8-nitro-2H, 4H-isoquinoline-1,3-dione (4.0 g, 13.7 mmol)₂SO₄And heated at 70 ° C for 8 hours. The cooled mixture was poured onto ice. The precipitate is collected, dissolved in ethyl acetate, washed with water, dried and evaporated to 7-amino-4,4-dimethyl-8-nitro-2H, 4H-isoquinoline-1,3-dione (3.38 g, 99). %) Was obtained. Melting point 259-263 ° C; MS (CI) 250 (MH +). [0102] 3.5 kg / cm solution of the above amine (1.5 g, 6.0 mmol) in methanol (50 ml)²Hydrogenated with platinum oxide (30 mg) for 1.25 hours at (50 psi). The mixture was filtered through diatomaceous earth and evaporated to give 7,8-diamino-4,4-dimethyl-2H, 4H-isoquinoline-1,3-dione (1.31 g, 100%). MS (CI) 220 (MH +). As described in Method A, 2,6-dichlorophenylisothiocyanate (1.16 g, 5.7 mmol) in ethyl acetate (40 ml) 7,8-diamino-4,4-dimethyl-2H, 4H-isoquinoline-1, It was added to a suspension of 3-dione (1.31 g, 6.0 mmol) and the mixture was stirred overnight. The solid was filtered and dried to give thiourea (1.55 g, 61%). Melting point&gt; 300 ° C; MS (CI) 423,425 (MH +). A solution of thiourea (2.23 g, 5.28 mmol) in THF (50 ml) and dicyclohexylcarbodiimide (1.11 g, 5.4 mmol) was heated under reflux with stirring for 4 hours. The cooled solution is stirred overnight, filtered and the crystals CH₂Cl₂The title compound (1.20 g) was obtained by washing with. Evaporate the filtrate and CH₂Cl₂Grinding was further obtained as a product (0.7 g, total yield 93%). Melting point 290-292 ° C; MS (EI) 388, 390 (M +). Example 2: Synthesis of 2- (2,6-dichlorophenylamino) -6,6-dimethyl-7,8-dihydro-1H, 6H-imidazole [4,5-h] isoquinoline-9-one [0103] [Chemical 35]<img file="JP5036112B2_D0018.tif" />[0104] NaBH in a solution of the product of Example 1 (90 mg, 0.23 mmol) in THF (5 ml)₄(90 mg, 2.3 mmol) followed by water (4 drops). The reaction mixture was stirred at ambient temperature for 1 hour. Subsequently, 1N HCl (5 ml) was added dropwise and the reaction mixture was stirred for an additional 15 minutes, LVDS.₃Neutralized with EtOAc and extracted with EtOAc. The extract is washed with saline, dried and evaporated to allow alcohol 2- (2,6-dichlorophenylamino) -6,6-dimethyl-7-hydroxy-7,8-dihydro-1H, 6H-imidazo [4]. , 5-h] Isoquinoline-9-one (90 mg, 99%) was obtained. This intermediate was used immediately due to its instability. It was characterized as methyl ether and the product was prepared by dissolving it in MeOH / HCl and stirring for several hours. After evaporation, leave the residue in EtOAc / LVDS₃Distributed between aqueous solutions. The organic phase was washed with brine, dried and evaporated to give a methyl ether derivative. Melting point 278-280 ° C (decomposition); MS (ES) 405 (MH +). The previous alcohol (100 mg, 0.26 mmol) was dissolved in TFA (2 ml), followed by this solution at 0 ° C from sodium tristrifluoroacetoxyborohydride (sodium hydride 160 mg, 4.2 mmol and TFA 3 ml in- It was added to the solution (produced in situ). The reaction mixture is stirred at ambient temperature for 4 hours, the solvent is evaporated, the residue is ground with water and the resulting mixture is LVDS.₃Neutralized with, and filtered to give the title compound (85 mg, 92%). 4% MeOH / CH as eluent₂Cl₂Use this product to SiO₂Purified by flash chromatography and recrystallization from EtOAc. Melting point 287-290 ° C; MS (CI) 375 (MH)⁺). Example 3a: Synthesis of 2- (2,6-dichlorophenylamino) -6,7-dimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one [0105] [Chemical 36]<img file="JP5036112B2_D0019.tif" />[0106] 2- (2,6-dichlorophenylamino) -6,6-dimethyl-7-hydroxy-7,8-dihydro-1H, 6H-imidazole [4,5-h] isoquinoline-9-one (from Example 2) (45 mg, 0.11 mmol) was suspended in concentrated sulfuric acid (1 ml) and the resulting mixture was stirred at ambient temperature for 15 minutes. Pour the solution into ice and LVDS₃Neutralized with and filtered. The filtrate was ground with water (10 ml) and centrifuged. The liquid was decanted, the residual solid was ground with methanol and centrifuged. The supernatant was decanted and the residue was dried to give the title compound (35 mg, 84%). Melting point&gt; 300 ° C; MS (ES) 373 (MH)⁺). Example 3b: Synthesis of 2- (2,6-dichlorophenylamino) -6,7-dimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one (Method C) [0107] [Chemical 37]<img file="JP5036112B2_D0020.tif" />[0108] A 500 ml pressure flask was charged with a 5.1 M solution of 2,6-dichloro-3-nitrobenzonitrile (30.0 g, 138 mmol) and ammonia in EtOH (170 ml). The flask was sealed and heated at 80 ° C. with stirring in an oil bath for 1.5 hours. The cooled solution was filtered, the crystals were washed with water and dried to give 2-amino-6-chloro-3-nitrobenzonitrile (18.4 g, 68%). Melting point 181-184 ° C; MS (ES)^-) 196, 198 (MH^-). Fine powder K in a solution of 2-amino-6-chloro-3-nitrobenzonitrile (1.97 g, 10 mmol) and ethyl 2-methylacetacetate (3.6 g, 25 mmol) in DMF (10 ml).₂CO₃Was added and the mixture was vigorously stirred for 24 hours. The dark red mixture was diluted with EtOAc and washed successively with 2M HCl, water and brine. The evaporated residue was purified by flash chromatography in hexane / EtOAc 3: 1 to oil 2- (3-amino-2-cyano-4-nitrophenyl) -2-methyl-3-oxobutyrate ethyl ester in oil (1.39). g, obtained as 46%). MS (NH)₃ CI) 323 (M + NH₄⁺), 293 (M + NH₄-NO⁺). Ester (1.39 g, 4.56 mmol) from the above, acetic acid (20 ml), H₂SO₄It was added to a mixture of (3 ml) and water (2 ml) and the solution was heated at 100 ° C. for 3 hours. The cooled solution is diluted with water (30 ml), the precipitate is collected, washed with water and MeOH, dried and dried with 8-amino-3,4-dimethyl-7-nitro-2H-isoquinoline-1-one (0.76). g, 72%) was obtained. Melting point&gt; 300 ° C. [0109] A solution of aminoisoquinoline-1-one (0.20 g, 0.86 mmol) from the tip in trifluoroacetic acid (11 ml) and acetic acid (7 ml) at 3.5 kg / cm with 10% palladium / carbon (21 mg).²Hydrogenated at (50 psi) for 2 hours. The solution is filtered through diatomaceous earth, washed with acetic acid and the filtrate is evaporated to give 7,8-diamino-3,4-dimethyl-2H-isoquinoline-1-one ditrifluoroacetate (310 mg, 83%). It was. Suspension of diaminoisoquinoline-1-one ditrifluoroacetate (1.15 g, 2.67 mmol) and 2,6-dichlorophenylisothiocyanate (0.60 g, 2.93 mmol) in pyridine (16 ml) at room temperature for 18 hours. Stirred (Method A). The solution was diluted with toluene, evaporated and residual pyridine was removed by toluene azeotrope. The residue was ground with EtOAc to give thiourea (1.17 g). A portion of this material (0.50 g, 1.23 mmol) and dicyclohexylcarbodiimide (0.375 g, 1.84 mmol) were heated together in DMF under an argon atmosphere at 80 ° C. for 4 hours. The cooled solution was evaporated and ground first with cold MeOH and then with boiling MeOH to give the title compound as a light brown solid (0.309 g, 73%), the same as the sample obtained in Example 3a. .. Example 4: Synthesis of 2- (2,6-dichlorophenylamino) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one [0110] [Chemical 38]<img file="JP5036112B2_D0021.tif" />[0111] A solution of 2,6-dichloro-3-nitrobenzonitrile (98.7 g, 0.455 mol) in EtOAc (910 ml) was cooled to 5 ° C. A 40% aqueous solution of methylamine (79.5 ml, 1.14 mol) was added with vigorous mechanical stirring to keep the temperature at 10-15 ° C. After the addition was complete, stirring was continued at the same temperature for 3 hours. Methylamine (16 ml, 0.23 mol) was further added and the mixture was stirred at room temperature for an additional 1.5 hours. Water (300 ml) was added, followed by hexane (450 ml). The mixture was stirred for 15 minutes, filtered and the solid was washed with water and MeOH to give 6-chloro-2-methylamino-3-nitrobenzonitrile (80.3 g, 83%). Melting point 167-170 ° C. [0112] Ethyl2-methylacetoacetate (34.3 g, 233 mmol) was added dropwise over 5 minutes to a stirred solution of potassium t-butoxide (24.3 g, 206 mmol) in DMSO (500 ml). The temperature rose to 30 ° C. 6-Chloro-2-methylamino-3-nitrobenzonitrile (43.6 g, 190 mmol) was added in small portions over 15 minutes. The temperature rose to 40 ° C. The solution was stirred for 1 hour without external heating or cooling. The mixture is 10% NH₄It was poured into Cl (500 ml) and extracted with EtOAc (2x500 ml). The combined extracts were washed with water (2x250 ml) and saline and evaporated. MeOH (200 ml) was added to the residue and stirred for 1.5 hours. The yellow solid is filtered, washed with cold MeOH (25 ml) and dried to dry 2- (2-cyano-3-methylamino-4-nitrophenyl) -2-methyl-3-oxobutyrate ethyl ester (36.2 g). , 60%). Melting point 87-91 ° C. A solution of the above ester (10.5 g, 32.5 mmol) in EtOAc (130 ml) with 10% palladium / carbon (0.5 g) 3.5 kg / cm²Hydrogenated at (50 psi) for 24 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. A mixture of EtOAc / Hexanes (1: 1, 10 ml) was added to the residue and the resulting mixture was stirred for 0.5 hours. The crystals were filtered and washed with hexane to give 2- (4-amino-2-cyano-3-methylaminophenyl) -2-methyl-3-oxobutyric acid ethyl ester (7.74 g, 81%). Melting point 118-123 ° C. [0113] A solution of the above amino ester (7.7 g, 26.6 mmol) and 2,6-dichlorophenyl isothiocyanate (5.43 g, 26.6 mmol) in THF (150 ml) was stirred at room temperature for 5 hours. Mercury (II) oxide (6.34 g, 29.3 mmol) was then added all at once and stirring was continued overnight. The mixture was filtered through diatomaceous earth and washed well with THF. Evaporate the filtrate and grind the residue with ether to 2- [4-cyano-2- (2,6-dichlorophenylamino) -3-methyl-3H-benzimidazol-5-yl] -2-methyl-3- Ethyl oxobutyrate was obtained as an off-white solid (7.7 g, 63%). In a stirred mixture of concentrated sulfuric acid (40 ml), HOAc (40 ml) and water (40 ml) at 60 ° C, 2- [4-cyano-2- (2,6-dichlorophenylamino) -3-methyl-3H-benzimidazole -5-Il] -2-Methyl-3-oxobutyrate ethyl ester (7.7 g, 16 mmol) was added at once. The solution was heated at 100 ° C. for 2.5 hours and then stirred at room temperature overnight. Pour the reaction mixture into ice and concentrate NH while cooling with ice.₄Neutralized with OH. The precipitate was filtered and washed well with water. The solid was slurried in MeOH, stirred well, filtered, washed with MeOH until the wash was colorless and dried. The title compound was obtained as a gray solid (5.48 g, 88%). Melting point&gt; 300 ° C; MS (NH)₃ CI) 387, 389 (MH +). Example 5: Synthesis of 2- (2,6-dichlorophenylamino) -6,6-dimethyl-6H-thiazolo [4,5-h] isoquinoline-7,9-dione (Method B) [0114] [Chemical 39]<img file="JP5036112B2_D0022.tif" />[0115] 2,6-Dichlorophenylisothiocyanate (223 mg, 1.1) in a suspension of 7-amino-4,4-dimethyl-2H, 4H-isoquinoline-1,3-dione (204 mg, 1 mmol) in EtOAc (25 ml). Millimole) was added in 3 portions and the mixture was stirred overnight. The solid was filtered and dried to give thiourea (380 mg, 93%). Melting point 142-144 ° C; MS (CI) 408 (MH)⁺). CHCl₃In a suspension of thiourea (140 mg, 0.34 mmol) in (20 ml), CHCl₃Br in (2 ml)₂(60 mg, 0.37 mmol) was added dropwise. The solution was heated to reflux for 1 hour. Evaporate the solvent and saturate the residue LVDS₃Grinded with (50 ml). The solid was filtered, washed with water and dried to give the title compound (114 mg, 82%). Melting point&gt; 300 ° C; MS (CI) 406 (MH +). Example 6: Synthesis of 2- (2,6-dichlorophenylamino) -6,7-dimethyl-8H-thiazolo [4,5-h] isoquinoline-9-one (Method B) [0116] [Chemical 40]<img file="JP5036112B2_D0023.tif" />[0117] NaBH in a solution of 7-nitro-4,4-dimethyl-2H, 4H-isoquinoline-1,3-dione (1.0 g, 4.3 mmol) from Example 1 in THF (50 ml).₄(330 mg, 8.7 mmol) followed by water (10 drops). The reaction mixture was stirred at room temperature for 2.5 hours, cooled in an ice bath and treated with 1N HCl until a pale yellow color was maintained. After 10 minutes, saturate the reaction mixture.₃Neutralized with EtOAc and extracted with EtOAc. The extract was washed with saline, dried and evaporated to give the alcohol, which was immediately absorbed into concentrated sulfuric acid (8 ml). Stir this mixture until completely dissolved (10 minutes), pour into ice and 10% NH₄Neutralized with OH, left for several hours, filtered and dried to give 3,4-dimethyl-7-nitro-isoquinoline-1-one (780 mg, 83%). MS (CI) 219 (MH)⁺). A solution of 3,4-dimethyl-7-nitro-isoquinoline-1-one (750 mg, 3.4 mmol) in MeOH (250 ml) at Pd / C (25 mg) 4.2 kg / cm²Hydrogenated at (60 psi) for 24 hours. The reaction mixture was filtered through diatomaceous earth and washed well with MeOH. The filtrate was evaporated to give an amine (554 mg, 85%), which was immediately dissolved in EtOAc (60 ml) and treated with 2,6-dichlorophenyl isothiocyanate (663 mg, 3.3 mmol). The mixture was stirred at ambient temperature for 48 hours, refluxed for 4 hours and stirred at ambient temperature for an additional 72 hours. Thiourea was filtered and washed with EtOAc (850 mg, 74%). Melting point 220 ° C (decomposition). A portion of thiourea (490 mg, 1.25 mmol) is suspended in CHCl3 (50 ml) and CHCl3 (50 ml) is suspended.₃Br in (5 ml)₂It was treated with a solution of (200 mg, 1.25 mmol) and the resulting mixture was refluxed for 1 hour. Evaporate the solvent and remove the residue from NaHSO₃Suspended in saturated solution of, filtered, then LVDS₃Was treated in the same manner with a saturated solution of. Silica column chromatography (CH)₂Cl₂Purification with 0-5% MeOH in eluent) gave the title compound (281 mg, 58%). Melting point&gt; 300 ° C, MS (CI) 390 (MH)⁺). Example 7: 2- (2,6-dichlorophenylamino) -1,7-dimethyl-6- (2-morpholine-4-yl-2-oxoethyl) -1,8-dihydro-imidazole [4,5-h ] Isoquinoline-9-one synthesis [0118] [Chemical 41]<img file="JP5036112B2_D0024.tif" />[0119] 2- (2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-1,8-dihydro-imidazo [4,5-h] isoquinoline-6-ylacetic acid in DMF (7 ml) (Method C) O-Benzotriazole-1-yl-N, N, N', N'-tetramethyluronium tetrafluoroborate (TBTU) (TBTU) in a solution of (1.0 g, 2.3 mmol) prepared using and A. 0.82 g, 2.6 mmol) and morpholine (0.24 ml, 2.8 mmol) were added and the mixture was stirred at room temperature for 18 hours. Ice water was added, the precipitate was collected, washed with water and dried to give the title compound (0.97 g, 84%). Melting point&gt; 300 ° C; MS (ES) 500, 502 (MH +). Example 8: 2- (2,6-dichlorophenylamino) -1,7-dimethyl-6- (2-morpholine-4-yl-ethyl) -1,8-dihydro-imidazole [4,5-h] isoquinoline -9-on synthesis [0120] [Chemical 42]<img file="JP5036112B2_D0025.tif" />[0121] A stirred suspension of the product of Example 7 (85 mg, 0.17 mmol) in THF (9 ml) was heated to reflux and borane-methyl sulfide (0.09 ml, 0.9 mmol) was added. Stirring was continued overnight at room temperature for 3.5 hours at reflux. 6M HCl was added and the solution was stirred for 2 hours. Apply the solution to a Varian SCX column and apply MeOH / CH₂Cl₂ Wash at 50:50, then MeOH / CH the product₂Cl₂/ NH₄Eluted with OH 50:50: 1. The product is further purified on a silica column and CH₂Cl₂Elution with / MeOH 98: 2 gave the title compound (32 mg, 39%). Melting point 285-290 ° C; MS (ES) 486, 488 (MH +). Example 9: Synthesis of 2- (2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-1,8-dihydro-imidazole [4,5-h] isoquinoline-6-ylacetate ethyl ester [0122] [Chemical 43]<img file="JP5036112B2_D0026.tif" />[0123] 2- (2,6-dichlorophenylamino) -1,7-dimethyl-9-oxo-1,8-dihydro-imidazole [4,5-h] isoquinoline-6-ylacetic acid to ethanol and H₂SO₄Prepared by refluxing in. Melting point 280-285 ° C (decomposition); MS (CI) 459, 461 (MH +). Example 10: 2- (2,6-dichlorophenylamino) -1,7-dimethyl-6- (2-hydroxyethyl) -1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one Synthetic [0124] [Chemical 44]<img file="JP5036112B2_D0027.tif" />[0125] A solution of lithium aluminum hydride (1 M, 0.25 ml, 0.25 mmol in THF) was added to a stirred solution of the product (25 mg, 0.05 mmol) of Example 9 in THF (2 ml) under a nitrogen atmosphere. The mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added, followed by water, which was then acidified with 1N HCl. Apply the entire mixture to the Varian SCX cartridge and apply 1N HCl, water, acetone, MeOH, and MeOH / CH.₂Cl₂Washed in order with (1: 1). Then the product is MeOH / CH₂Cl₂/ NH₄It was eluted with OH (49: 49: 2). The eluent was evaporated to give the title compound (15 mg, 72%). Melting point&gt; 300 ° C; MS (ES) 417, 419 (MH +). Example 11: Synthesis of 2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-carbaldehyde The methods described below are useful for preparing intermediate compounds such as 11 with an aldehyde moiety at the 7-position. [0126] [Chemical 45]<img file="JP5036112B2_D0028.tif" />[0127] Selenium dioxide (430 mg, 3.9 mmol) was added to a suspension of the product (521 mg, 1.3 mmol) from Example 4 in dioxane (30 ml) and the mixture was heated at 100 ° C. for 5 hours. The reaction is then cooled to room temperature and 10% MeOH-CH.₂Cl₂Was filtered through diatomaceous earth and then concentrated in vacuo. CH crude material₂Cl₂Grinding to give the title compound (476 mg, 92%). Melting point&gt; 300 ° C; MS (CI) 401, 403 (MH +). Example 12: 3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -Synthesis of methyl acrylate ester [0128] [Chemical 46]<img file="JP5036112B2_D0029.tif" />[0129] Suspension of the product of Example 11 (329 mg, 0.82 mmol) in THF (5 ml) with trimethylphosphonoacetate (164 mg, 0.90 mmol), lithium hydroxide monohydrate (76 mg, 1.8 mmol) and water. (0.9 ml) was added continuously. The dark red solution was stirred for 2 hours, the reaction was stopped with water, the resulting solid was recovered and dried in vacuo. Column chromatography (5% MeOH-CH₂Cl₂) To obtain the title compound (300 mg, 80%). Melting point&gt; 300 ° C; MS (ES) 457, 459 (MH +). Example 13: 3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-yl] -Synthesis of propionate methyl ester [0130] [Chemical 47]<img file="JP5036112B2_D0030.tif" />[0131] PtO in a solution of the product of Example 12 (30 mg, 0.06 mmol) in EtOH (3 ml) and AcOH (4 ml) in a pearl reactor.₂(2 mg, 0.007 mmol) was added. 3.5kg / cm for the pearl reactor²(50psi) H₂Was prepared and shaken for 12 hours. The crude reaction solution was filtered through diatomaceous earth using EtOH and concentrated in vacuo. Column chromatography (2% MeOH-CH₂Cl₂) To obtain the title compound (9 mg, 30%). Melting point 268 ° C (decomposition); MS (ES) 459, 461 (MH +). Example 14: 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (3-hydroxy-propen-1-yl) -1,8-dihydro-imidazole [4,5-h] isoquinoline -9-on synthesis [0132] [Chemical 48]<img file="JP5036112B2_D0031.tif" />[0133] A suspension of the product of Example 12 (100 mg, 0.22 mmol) in THF (7 ml) was cooled to -78 ° C. Sodium bis (trimethylsilyl) amide (1 M in THF, 0.44 mmol) was added dropwise. The bright red solution was warmed to 0 ° C. for 15 minutes, then lithium aluminum hydride (1 M in THF, 2.6 mmol) was added and the orange solution was warmed to room temperature for 0.5 hours. The mixture was cooled to 0 ° C., the reaction was terminated with saturated ammonium chloride, and the mixture was extracted with ethyl acetate. Column chromatography (3-6% MeOH-CH₂Cl₂) To obtain the title compound (32 mg, 34%). Melting point 298-300 ° C; MS (ES) 429, 431 (MH +). Example 15: Synthesis of 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-vinyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one [0134] [Chemical 49]<img file="JP5036112B2_D0032.tif" />[0135] Trimethylsilylmethylmagnesium chloride (2 ml, 2 mmol) was added to a suspension of the product of Example 11 (100 mg, 0.25 mmol) in THF (5 ml) at -78 ° C. The reaction was warmed to room temperature for 1 hour, then cooled to 0 ° C., stopped with water and extracted with ethyl acetate to give silyl alcohol (85 mg, 70%). CH crude silyl alcohol₂Cl₂Suspended in and cooled to 0 ° C. Boron trifluoride etherate (42 μl, 0.32 mmol) was added and the slurry was warmed to room temperature for 1 hour. Stop the reaction with water and CH₂Cl₂Was removed in vacuum. Collect the resulting solid, followed by CH₂Cl₂Grinding to give the title compound (17 mg, 61%). Melting point&gt; 300 ° C; MS (Es) 399, 401 (MH +). Example 16: 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (1-hydroxyprop-2-en-1-yl) -1,8-dihydro-imidazole [4,5- h] Isoquinoline-9-one synthesis [0136] [Chemical 50]<img file="JP5036112B2_D0033.tif" />[0137] 2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7-carbaldehyde in THF (3 ml) 2) The suspension of (100 mg, 0.25 mmol) was cooled to -78 ° C. Vinyl magnesium bromide (1 M in THF, 2.0 mmol) was added dropwise and the brown suspension was gradually warmed to -10 ° C over 2 hours. The solution was terminated with saturated ammonium chloride, extracted with ethyl acetate and concentrated in vacuo to give the title compound, which was used in the next step without purification. Melting point 235-236 ° C, MS (ES) 429 (MH +). Example 17: 2- (2,6-dichlorophenylamino) -7- (1-acetoxyprop-3-en-1-yl) -1,6-dimethyl-1,8-dihydro-imidazole [4,5- h] Isoquinoline-9-one synthesis [0138] [Chemical 51]<img file="JP5036112B2_D0034.tif" />[0139] Acetic anhydride (1 ml) was added to a solution of the product of Example 16 (106 mg, 0.25 mmol) in THF (1 ml). Triethylamine (35 μl, 0.25 mmol) was added and the reaction was stirred for 14 hours and then concentrated in vacuo. Column chromatography (2% MeOH-CH₂Cl₂) To obtain the title compound (85 mg, 79%). Melting point 169-171 ° C; MS (ES) 471 (MH +). Example 18: 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (3-morpholine-4-yl-propen-1-yl) -1,8-dihydro-imidazole [4,5 -h]-Isoquinoline-9-one synthesis [0140] [Chemical 52]<img file="JP5036112B2_D0035.tif" />[0141] Tris (dibenzylideneacetone) dipalladium (0) (1.8 mg, 0.002 mmol) and triphenylphosphine (1.6 mg, 0.006 mmol) are inactive in THF (0.5 ml) for 20 minutes until the red solution turns yellow. Stirred in atmosphere. The product of Example 17 (20 mg, 0.04 mmol), triethylamine (17 μl, 0.12 mmol) and morpholine (11 μl, 0.12 mmol) in THF (0.5 ml) were added sequentially to this solution. The solution was stirred for 14 hours and then concentrated to give an oil. Column chromatography (10% MeOH-CH₂Cl₂) To obtain the title compound (10 mg, 50%). Melting point 175-177 ° C; MS (ES) 498 (MH +). Example 19: Synthesis of 7-benzylaminomethyl-2- (2,6-dichlorophenylamino) -1,6-dimethyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline-9-one [0142] [Chemical 53]<img file="JP5036112B2_D0036.tif" />[0143] Benzylamine (54 mg, 0.50 mmol) was added to a suspension of the product of Example 11 (50 mg, 0.12 mmol) in THF (4 ml). The reaction was stirred for 12 hours and then concentrated in vacuo. Crude imine was suspended in MeOH (2 ml), sodium hydride (21 mg, 0.55 mmol) was added and the reaction was stirred for 3 hours. The reaction was stopped with water and the resulting solid was recovered and dried to give the title compound (11 mg, 39%). Melting point 231-234 ° C; MS (ES) 492 (MH +). Example 20: Synthesis of 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7-oxazole-5-yl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one [0144] [Chemical 54]<img file="JP5036112B2_D0037.tif" />[0145] The product of Example 11 (40 mg, 0.10 mmol), tosylmethyl isocyanide (21 mg, 0.11 mmol) and K in methanol (2 ml).₂CO₃The suspension was heated to 40 ° C for 90 minutes. The mixture was diluted with water (3 ml) and the solid was collected by filtration to give the title compound (26 mg, 60%). Melting point&gt; 300 ° C; MS (ES) 440, 442 (MH +). Example 21: 2- (2,6-dichlorophenylamino) -1,6-dimethyl-7- (3-methyl-3H-imidazol-4-yl) -1,8-dihydro-imidazole [4,5-h ] Isoquinoline-9-one synthesis [0146] [Chemical 55]<img file="JP5036112B2_D0038.tif" />[0147] A suspension of the product of Example 11 (50 mg, 0.13 mmol) and methylamine (2 M, 2 ml, 4 mmol in THF) in dry THF (2 ml) was stirred at room temperature for 12 hours. Evaporate THF and the resulting imine is tosylmethylisicianide (27 mg, 0.14 mmol), K₂CO₃It was mixed with (31 mg, 0.23 mmol) and dry DMSO (2 ml). The suspension was stirred at room temperature for 5 days. Water (5 ml) was added and the precipitate was collected by filtration. CH₂Cl₂Flash chromatography in / MeOH (98: 2) gave the title compound (8 mg, 14%). Melting point&gt; 300 ° C; MS (ES) 453, 455 (MH +). Example 22: Synthesis of 2- (2,6-dichlorophenylamino) -1,6,7-trimethyl-4-vinyl-1,8-dihydro-imidazole [4,5-h] isoquinoline-9-one [0148] [Case 56]<img file="JP5036112B2_D0039.tif" />[0149] CHCl₃Bromine in a solution of 2- (4-amino-2-cyano-3-methylaminophenyl) -2-methyl-3-oxobutyric acid ethyl ester (9.02 g, 31.2 mmol) from Example 4 in (90 ml). (4.98 g, 31.2 mmol) was added dropwise at ambient temperature. After the addition of bromine, the reaction mixture was diluted with ethyl acetate (800 ml). Saturate this solution LVDS₃It was washed continuously with solution and saline and dried. The residue after evaporation is purified by flash chromatography in hexane / EtOAc 2: 1 and ethyl 2- (4-amino-5-bromo-2-cyano-3-methylaminophenyl) -2-methyl-3-oxobutyrate. The ester was obtained as an oil (6.06 g, 53%). In a solution of the above ester (3.32 g, 9.02 mmol) in 1,4-dioxane (45 ml), 2,6-dichlorophenyl isothiocyanate (2.02 g, 9.92 mmol) and mercury oxide (II) (2.54 g) under a nitrogen atmosphere. , 11.7 mmol) was added. The resulting mixture was stirred and heated at 95 ° C. overnight. Cool the reaction mixture to room temperature, diatomaceous earth and SiO₂Filtered with a short pad. The filtrate is concentrated and the residue is purified by flash chromatography in hexane / EtOAc 2: 1 for 2- [8-bromo-4-cyano-2- (2,6-dichlorophenylamino) -3-methyl-3H-benzo. Imidazole-5-yl] -2-methyl-3-oxobutyric acid ethyl ester was obtained as a brown solid (3.44 g, 71%). [0150] The above bromoesters (600 mg, 1.11 mmol) in NMP (4 ml), (PPh₃)₂PdCl₂A mixture of (78 mg, 0.11 mmol) and tributyl (vinyl) tin (0.49 ml, 1.67 mmol) was degassed and heated at 100 ° C. under an argon atmosphere for 3 days. The mixture is concentrated and the residue is purified by flash chromatography in hexane / EtOAc 3: 1 to 2- [4-cyano-2- (2,6-dichlorophenylamino) -3-methyl-8-vinyl-3H- Benzimidazole-5-yl] -2-methyl-3-oxobutyric acid ethyl ester was obtained as an oil (530 mg, 98%). H₂SO₄A solution of the above ketoester (66 mg, 0.14 mmol) in a mixture of (0.6 ml), acetic acid (0.6 ml) and water (0.6 ml) was heated at 100 ° C. for 2 hours. The resulting mixture was cooled to room temperature and diluted with water (10 ml) . The solution was adjusted to pH 8 with 10% NaOH solution. Filter the precipitated brown solid and CH₂Cl₂Purification by flash chromatography in / MeOH 30: 1 gave the title compound (15 mg, 27%). Melting point above 250 ° C (decomposition); MS (CI) 413 (MH +). Example 23: Synthesis of 2- (2,6-dichlorophenylamino) -1,6,7-trimethyl-9-oxo-1,8-dihydro-imidazole [4,5-h] isoquinoline-4-carbaldehyde [0151] [Chemical 57]<img file="JP5036112B2_D0040.tif" />[0152] 2- [4-Cyano-2- (2,6-dichlorophenylamino) -3-methyl-8-vinyl-3H-benzimidazol-5-yl] -2-methyl-3-oxobutyric acid in THF (30 ml) A solution of ethyl ester (see Example 22) (538 mg, 1.11 mmol) in 2.5% OsO in tBuOH (3.0 ml).₄Solution, NaIO₄Treated with (712 mg, 3.33 mmol) and water (3 ml). After stirring at room temperature for 1.5 hours, the mixture was diluted with EtOAc. The organic solution was washed with saline, dried and concentrated. The residue was purified by flash chromatography in hexane / EtOAc 4: 1 and 2- [4-cyano-2- (2,6-dichlorophenylamino) -8-formyl-3-methyl-3H-benzimidazol-5-yl ] -2-Methyl-3-oxobutyric acid ethyl ester was obtained as an oil (345 mg, 64%). H₂SO₄A solution of the above aldehyde (35 mg, 0.07 mmol) in a mixture of (0.6 ml), acetic acid (0.6 ml) and water (0.6 ml) was heated at 100 ° C. for 1.5 hours and cooled to room temperature. The resulting mixture was diluted with water (10 ml) and the pH was adjusted to 7 with an ammonium hydroxide solution. The precipitated orange powder was filtered to give the title compound as an orange solid (18 mg, 60%). Example 24: 2- (2,6-dichlorophenylamino) -4- (2-hydroxyethylaminomethyl) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h] isoquinoline- 9-on synthesis [0153] [Chemical 58]<img file="JP5036112B2_D0041.tif" />[0154] Suspension of product (30 mg, 0.07 mmol) of Example 23 in MeOH (5 ml) with ethanolamine (44 μl, 0.72 mmol) and NaBH₃It was treated with CN (14 mg, 0.22 mmol) and stirred at room temperature for 16 hours. The resulting mixture was concentrated and the residue was diluted with water. The precipitated solid was filtered to give the title compound (12 mg, 36%). Melting point above 250 ° C (decomposition); MS (CI) 460 (MH +). Example 25: 2- (2,6-dichlorophenylamino) -4- (3-methoxypropin-1-yl) -1,6,7-trimethyl-1,8-dihydro-imidazole [4,5-h ] Isoquinoline-9-one synthesis [0155] [Chemical 59]<img file="JP5036112B2_D0042.tif" />[0156] Et₃2- [8-Bromo-4-cyano-2- (2,6-dichlorophenylamino) -3-methyl-3H-benzimidazol-5-yl] -2-methyl in N (1 ml) and THF (1 ml) -3-oxobutyrate ethyl ester (see Example 22) (50 mg, 0.09 mmol), methylpropargyl ether (16 μl, 0.19 mmol), (PPh₃)₂PdCl₂A mixture of (6.5 mg, 0.009 mmol) and CuI (3.5 mg, 0.02 mmol) was stirred at room temperature for 5 days under an argon atmosphere. The resulting mixture is concentrated and the residue is purified by flash chromatography in hexane / EtOAc 3: 1 with 2- [4-cyano-2- (2,6-dichlorophenylamino) -8- (4-methoxypropine-). 1-Il) -3-methyl-3H-benzimidazol-5-yl] -2-methyl-3-oxobutyric acid ethyl ester was obtained as an oil (30 mg, 61%). H₂SO₄A solution of the above ketoester (29 mg, 0.006 mmol) in a mixture of (0.4 ml), acetic acid (0.4 ml) and water (0.4 ml) was heated at 100 ° C. for 2 hours. The resulting mixture was cooled to room temperature and diluted with water (10 ml). The pH of this solution was adjusted to 8 with 10% NaOH solution. The precipitated solid was filtered to give the title compound (17 mg, 68%). Melting point above 250 ° C (decomposition); MS (CI) 455 (MH +). Example 26: Synthesis of 2- (2,6-dichlorophenylamino) -3,5-dihydro-imidazole [4,5-i] phenanthridine-4-one [0157] [Chemical 60]<img file="JP5036112B2_D0043.tif" />[0158] 30 solutions of t-BuLi (2.7 M, 26 ml, 25.88 mmol in pentane) to a solution of N- (t-butoxycarbonyl) aniline (2.0 g, 10.35 mmol) in dry THF (50 ml) at -78 ° C. It was added dropwise over a minute. The resulting yellow solution was warmed to -20 ° C and stirred at this temperature for 2.5 hours. N-Bu in dry THF (10 ml)₃SnCl (4.2 ml, 15.52 mmol) was added over 20 minutes and the solution was stirred at -20 ° C for 2 hours and then at room temperature for 12 hours. The reaction mixture is LVDS₃It was poured into a solution and extracted with ether. The extract is washed with water and saline, and DDL is used.₄It was dried with. The solvent was evaporated and the resulting oil was purified by flash chromatography in hexane / ether (20: 1) to give 2-tributylstanylphenylcarbamic acid t-butyl ester (2.42 g, 54%). Tin (II) chloride (46.67 g, 206.84 mmol) was added dropwise to a solution of 2-bromo-5-nitrobenzoic acid (12.71 g, 49.9 mmol) in dry ethanol (200 ml). The mixture was heated at 70 ° C. for 45 minutes and then the ethanol was evaporated. The residue was cooled to 0 ° C. acetic anhydride (43 ml) and pyridine (26 ml) were added. The solution was stirred at room temperature for 14 hours and evaporated. The residue was partitioned between 2M aqueous HCl and ethyl acetate (400ml). The organic phase was washed with saline and DDL₄It was dried with. The residue from the evaporation was crystallized in water to give 5-acetylamino-2-bromobenzoic acid (12.4 g, 96%). [0159] 5-Acetylamino-2-bromobenzoic acid (6.81 g, 26.39 mmol) was added dropwise to fuming nitric acid (90%, 11 ml) at 0 ° C (H. Goldstin, G. Preitner. Helv. Chim. As described by Acta 1944, 27, 888). The ice bath was removed and the solution was stirred at room temperature for 1.5 hours and then poured into ice water. 3-Acetylamino-6-bromo-2-nitro-benzoic acid was recovered by filtration (5.07 g, 63%). A solution of (trimethylsilyl) diazomethane in hexane to a solution of 3-acetylamino-6-bromo-2-nitro-benzoic acid (3.86 g, 14.96 mmol) in dry THF (42 ml) and dry methanol (18 ml) (2M). , 24 ml, 48 mmol) was added. The solution was stirred at room temperature for 3 hours and evaporated. The residue was purified by flash chromatography in hexane / ethyl acetate (6: 1) to give 3-acetylamino-6-bromo-2-nitrobenzoic acid methyl ester (2.45 g, 52%). 3-Acetylamino-6-bromo-2-nitrobenzoic acid methyl ester (1.3 g, 11 mmol) and Pd (PPh) in dry toluene (15 ml)₃)₄The solution (0.31 g, 0.27 mmol) was stirred at room temperature for 10 minutes. To this orange solution was added a solution of 2-tributylstanylphenylcarbamic acid t-butyl ester (2.10 g, 4.94 mmol) in dry toluene (10 ml) and the mixture was heated to reflux for 14 hours. During that time a precipitate formed. 8-Acetamide-7-nitro-6-oxo-5,6-dihydro-phenanthridine-6-one was collected by filtration as an off-white solid (1.07 g, 88%). [0160] Solution of 8-acetamide-7-nitro-6-oxo-5,6-dihydro-phenanthridine-6-one (770 mg, 2.66 mmol) and NaOMe (25% w / w in MeOH) in dry methanol (15 ml) , 3.5 ml, 6.64 mmol) was heated and refluxed for 3 hours. The methanol was evaporated and the residue was ground with water and filtered to give 8-amino-7-nitro-5H-phenanthridine-6-one (500 mg, 74%). 3.5 kg / cm mixture of 8-amino-7-nitro-5H-phenanthridine-6-one (412 mg, 1.62 mmol), Pd / C (10 wt%, 234 mg) in TFA²Hydrogenated at (50 psi) for 50 minutes. The catalyst was filtered through a diatomaceous earth stopper and rinsed with ethanol. The solvent was evaporated to give 7,8-diamino-5H-phenanthridine-6-ontrifluoroacetate (520 mg, 71%). Add 2,6-dichlorophenylisothiocyanate (93 mg, 0.46 mmol) to a solution of 7,8-diamino-5H-phenanthridine-6-ontrifluoroacetate (200 mg, 0.44 mmol) in pyridine (3 ml). did. The suspension was stirred at room temperature for 14 hours. Pyridine was evaporated using toluene azeotrope. The residue was ground with ethanol to give thiourea (150 mg, 79%). A mixture of thiourea (146 mg, 0.34 mmol) and dicyclohexylcarbodiimide (83 mg, 40.80 mmol) in dry THF (2 ml) and dry DMF (0.9 ml) was heated to 80 ° C. for 8 hours. The solvent was removed under high vacuum and the residue was ground with hot ethanol to give the title compound (82 mg, 61%). Melting point&gt; 300 ° C; MS (CI) 395, 397 (MH +). Example 27: 2- (2,6-dichlorophenylamino) -3-methyl-5,6,7,8-tetrahydro-3H-1,3,5-triaza-dicyclopenta [a, f] naphthalene-4-one Synthesis of [0161] [Chemical 61]<img file="JP5036112B2_D0044.tif" />[0162] 6-Chloro-2-methylamino-3-nitrobenzonitrile (200 mg, 0.95 mmol) (Example 4), ethyl 2-oxocyclopentane carboxylate (177 mg, 1.13 mmol) and K in DMF (5 ml).₂CO₃The mixture (287 mg, 2.07 mmol) was stirred at room temperature for 60 hours. Saturate the mixture NH₄It was diluted with Cl solution and extracted with ether. The ether layer is washed with water and saline and dried (Na).₂SO₄), Filtered and concentrated. The residue was purified by silica chromatography (hexane: EtOAc = 3: 1) and ethyl 1- (2-cyano-3-methylamino-4-nitrophenyl) -2-oxo-cyclopentanecarboxylate (127 mg, 40). %) Was obtained as a yellow solid. [0163] A solution of tin (II) chloride dihydrate (681 mg, 3.0 mmol) in concentrated hydrochloric acid (0.5 ml) at room temperature was added to a solution of the above compound (100 mg, 0.30 mmol) in acetic acid (1 ml). The resulting mixture is stirred at room temperature for 2 hours and saturated with LVDS.₃The reaction was stopped with the solution. PH of the mixture₃Adjusted to 8. The product is extracted with EtOAc and the organic layer is washed with water and brine and dried (Na).₂SO₄), Concentrated to give ethyl 1- (4-amino-2-cyano-3-methylaminophenyl) -2-oxo-cyclopentanecarboxylate (76 mg, 84%) as a yellow oil. A mixture of the above diamine (140 mg, 0.46 mmol), 2,6-dichlorophenyl isothiocyanate (104 mg, 0.51 mmol) and HgO (110 mg, 0.51 mmol) in THF (5 ml) was refluxed for 8 hours. The cooled mixture was filtered through diatomaceous earth and concentrated. The residue is diluted with EtOAc, washed with water and saline and dried (Na).₂SO₄), Filtered and evaporated. The residue was purified by silica chromatography in hexane / EtOAc (1: 1) and ethyl 1- [4-cyano-2- (2,6-dichlorophenylamino) -3-methyl-3H-benzimidazol-5- Il] -2-oxo-cyclopentane carboxylate (200 mg, 92%) was obtained as a bright yellow solid. Water, acetic acid and H₂SO₄A solution of the above benzimidazole (195 mg, 0.41 mmol) in a 1: 1: 1 mixture (1.5 ml) was heated at 100 ° C. for 3 hours. The reaction mixture was cooled and diluted with water. The precipitate was collected and washed with water. CH the recovered yellow solid₂Cl₂SiO in / MeOH (20: 1)₂Purification by chromatography according to the above gave the title compound (70 mg, 43%) as a bright yellow solid. Melting point&gt; 300 ° C (decomposition), MS (CI) m / z 399 (M)⁺+ H). Example 28: 7- (3-aminopropen-1-yl) -2- (2,6-dichlorophenylamino) -1,6-dimethyl-1,8-dihydro-imidazole [4,5-h] -isoquinoline -9-on synthesis [0164] [Chemical 62]<img file="JP5036112B2_D0045.tif" />[0165] A suspension of tris (dibenzylideneacetone) dipalladium (0) (185 mg, 0.25 mmol) and triphenylphosphine (320 mg, 1.2 mmol) in THF (40 ml) was stirred under a nitrogen atmosphere for 20 minutes. A solution of the product (1.88 g, 4.0 mmol) from Example 17 in THF (5 ml) was added and the mixture was stirred for 20 minutes. Sodium azide (280 mg, 4.4 mmol) and water (4.0 ml) were added and the reaction solution was heated at 60 ° C. for 3 hours. The solution was cooled to room temperature and triphenylphosphine (1.0 g, 3.8 mmol) was added. After stirring for 45 minutes, ammonium hydroxide (4 ml) was added and stirring was continued overnight. Divide the resulting solution₄It was dried in, and then concentrated to obtain an oil. Column chromatography with silica, CH₂Cl₂Elution with / MeOH (increasing from 90:10 to 50:50) gave the title compound (1.2 g, 70%). Melting point&gt; 300 ° C; MS (ES) 428 (MH +). Example 29: 1- {3- [2- (2,6-dichlorophenylamino) -1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazole [4,5-h] isoquinoline-7 -Il] -Propenyl} -3-Synthesis of phenylurea [0166] [Chemical 63]<img file="JP5036112B2_D0046.tif" />[0167] A solution of the product of Example 28 (50 mg, 0.12 mmol) and phenylisocyanate (17 mg, 0.13 mmol) in DMF (2 ml) was heated at 60 ° C. for 10 hours. Filter the resulting precipitate and MeOH / CH₂Cl₂Grinding at (90:10) and drying to give the title compound (57 mg, 89%). Melting point&gt; 290 ° C; MS (ES) 547 (MH +).<u style="single">Other examples</u>The following compounds of the present invention (Table 1-3) were prepared using the same method as described above. [0168] [table 1]<img file="JP5036112B2_D0047.tif" />[0169] [Table 2]<img file="JP5036112B2_D0048.tif" />[0170] [Table 3]<img file="JP5036112B2_D0049.tif" />[0171] [Table 4]<img file="JP5036112B2_D0050.tif" />[0172] [Table 5]<img file="JP5036112B2_D0051.tif" />[0173] [Table 6]<img file="JP5036112B2_D0052.tif" />[0174] [Table 7]<img file="JP5036112B2_D0053.tif" />[0175] [Table 8]<img file="JP5036112B2_D0054.tif" />[0176] [Table 9]<img file="JP5036112B2_D0055.tif" />[0177] [Table 10]<img file="JP5036112B2_D0056.tif" />[0178] [Table 11]<img file="JP5036112B2_D0057.tif" />[0179] [Table 12]<img file="JP5036112B2_D0058.tif" />[0180] [Table 13]<img file="JP5036112B2_D0059.tif" />[0181] [Table 14]<img file="JP5036112B2_D0060.tif" />[0182] [Table 15]<img file="JP5036112B2_D0061.tif" />[0183] [Table 16]<img file="JP5036112B2_D0062.tif" />[0184] [Table 17]<img file="JP5036112B2_D0063.tif" />[0185] [Table 18]<img file="JP5036112B2_D0064.tif" /> 【0186】<u style="single">Evaluation of biological properties</u>Tyrosine kinase suppression assay The suppression of tyrosine kinase by the compound of the present invention was measured by the following assay. Kinase reaction buffer 50 mM Hepes, pH 7.5, 50 mM KCl, 25 mM MgCl₂, 5mM MnCl₂, 100 μM Na₃VO₄, 0.01% CHAPS, 1 mM DTT, and 50 mg / ml BSA, 100 mM adenosine 5'-triphosphate (ATP) solution, pH 7.5 γ33P-ATP, 10 μCi / μl 2000 Ci / mmol, -poly (L-glutamic acid-L) -Tyrosine, 4: 1) or 10 mg / ml in water (E4Y)_n.. Assay: Routine test compound at 5 mg / ml in 100% DMSO was appropriately diluted in complete kinase assay buffer containing 10% DMSO, and 10 μl of 6X compound solution was dispensed into each assay well and IC.₅₀The final compound concentration for measurement was in the range of 200 to 1 μg / ml. [Γ33P] -ATP labeling was prepared as a 10 Ci / mmol working solution in complete kinase assay buffer. Protein kinase was started by adding 10 to 50 ng of diluted enzyme stock solution. The plates were incubated at 30 ° C for 30 minutes. During the incubation period, the multi-screen recovery plate was pre-wet with 10% TCA / 5% Ppi. 150 μl of TCA / PPi was added to all multiscreen plate wells after pre-wetting. The kinase reaction was stopped by replica transfer of polypropylene reaction wells to a multi-screen plate. The plates were incubated at room temperature for 5 minutes, then vacuum collected, washed 3-4 times with 200 μl TCA / PPi per well, and then 100 μl cocktail was added per well. [0187] Experimental data consisted of 8 compound doses in double repeats using 10 enzyme control reaction wells (so-called totals) and 6 background wells. Results were obtained as suppression% (mean with SD) over the entire compound dose range. IC with Floating Suppression Maximum (Imax)₅₀Estimates of efficacy were measured. Using a kinase such as p56lck, all compounds in the above synthesis examples and tables were evaluated in the above tyrosine kinase assay and ICs &lt;10 μM₅₀Was found to have. Representative compounds from previous examples were evaluated using the tyrosine kinase assay above using p60src and ICs &lt;10 μM₅₀Was found to have. Using PDGFR kinase, representative compounds from previous examples were evaluated in the tyrosine kinase assay above and ICs &lt;10 μM₅₀Was found to have. [0188] Suppression of IL-2 production Inactivation of T cells resulting from suppression of the tyrosine kinase p56lck can be measured by suppression of IL-2 production in Jarkat cells. A 96-well flat bottom plate was coated with 4 μg / ml anti-CD3, clone UCHT1 (Immunotech Catalog # 1304) in 100 μl / well saline phosphate buffer (PBS). The solution was prepared by collecting 200 μl of 200 μg / ml anti-CD3 stock solution / 10 ml of PBS. The plate was then incubated at 37 ° C for 2 hours. Jarkat cells were pelleted and counted. Cells in RPMI, 10% FBS (complete medium) 2.5x10⁶Resuspended at cells / ml. The test compound was diluted directly from 5 mg / ml DMSO stock solution into complete medium. [0189] 10 μl of 20X compound / well was added to separate plates, followed by 100 μl of cell suspension added in 3 iterations, the plate being pre-incubated at 37 ° C for 30 minutes. A 96-well plate containing anti-CD3 was aspirated and cells and compounds were transferred to this plate. 100 μl of 20 ng / ml PMA (Folbol 12-millistate 13-acetate, Sigma Catalog # P-8139) was added and the plates were incubated overnight at 37 ° C (1 mg / ml PMA stock solution in ethanol, in complete medium). Dilute to 10 μl / ml with, then dilute to 20 μl / 10 ml in complete medium (final concentration of 100 μl / well = 10 ng / ml). The next day, the plate was centrifuged at 1500 rpm at room temperature for 5 minutes to remove the supernatant. The supernatant was tested using the R &amp; D Systems Quantikin Human IL-2 Kit (Cat. # 2050). Samples were diluted 1: 5 in RPMI 1640 and 100 μl / well was used in ELISA. The optical densities of each well were measured using a microplate reader set at 450 nm. EC by plotting absorbance vs. compound concentration using origin (nonlinear regression) or SAS₅₀The value was measured. Representative compounds from the above synthetic examples and tables were screened in this assay for ICs below 10 μM.₅₀Had.