TW200800919A - Substituted pyrimidinyl oxime kinase inhibitors - Google Patents

Abstract

The present invention is directed to substituted pyrimidine compounds of formula (I): and forms thereof, their synthesis and use for treating, preventing or ameliorating a chronic or acute protein kinase mediate disease, disorder or condition.

Description

200800919 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention is a substituted gypsum compound, a form thereof, a process for its preparation, and its use as a kinase inhibitor. 5 [Prior Art] In general, protein kinases are the largest group of structurally related phosphonyl transferases with highly retained structure and catalytic functions, which can be phosphorylated (eg protein-tyrosine, protein-serine) Acid/threonine, histidine, and the like are divided into several families and are responsible for controlling a wide variety of cells 10 signaling processes. Examples of protein-tyrosine kinases include, but are not limited to, Irk, IGFR], Zap-70, Bmx, Btk, CHK (Csk homologous kinase), CSK (C-terminal Src kinase), Itk-1, Src (c- Src, Lyn, Fyn, Lck, Syk, Hck, Yes, Blk, Fgr and Frk), Tec, Txk/Rlk, Abl, EGFR is (EGFR-l/ErbB-B ErbB-2/NEU/HER-2, ErbB -3 and ErbB-4), FAK, FGF1R (and FGFR1 or FGR-1), FGF2R (and _FGR-2), MET (and Met-1 or c-MET), PDGFR (α and β), Tie- Bu Tie-2 (and Tek-1 or Tek), VEGFRI (and FLT-1), VEGFR2 (and KDR), FLT-3, FLT-4, c-fine KIT, JAKJ, JAK2, 20 JAK3, TYK2, LOK, RET, TRKA, PYK2, ALK (inter-variable i-lymphoma kinase), EPHA (1-8), EPHB (1-6), RON, Fes, Fer or EPHB4 (and EPHB4-1). Examples of protein-serine/threonine kinases include, but are not limited to, Ark, ATM (1-3), CamK (I-IV), CamKK, Chkl, and 2 (detection 5 200800919 dot kinase), CKI, CK2. Erk, IKK-I (and ΙΚΚ-ALPHA or CHUK), IKK-2 (and IKK-BETA), Ilk, Jnk (1-3), LimK (1 and 2), MLK3Raf (A, B, and C), CDK (1-10), PKC (including all PKC isoforms), Plk (1-3), NIK, Pak (1-3), PDK1, PKR, 5 RhoK, RIP, RIP-2, GSK3 (a and β ), PKA, P38, Erk (1·3), PKB (including all PKB isoforms) (and AKT-1, AKT-2, AKT-3 or AKT3-1), IRAKI, FRK, SGK, TAK1 or Tpl- 2 (and

COT) 〇 I Protein kinase plays a very important role in the regulation of normal cell growth. However, as a result of abnormal regulation of tyrosine kinase (receptor or non-receptor) or receptor tyrosine-induced S# ligands, message transmission becomes dysregulated, leading to uncontrolled cell proliferation, resulting in cancer or related diseases. , illness or syndrome. Protein kinases catalyze and regulate the process of phosphorylation. Kinases then bind the acid ester group to proteins or lipid targets according to various extracellular forms: hormones, neurotransmitters, growth and differentiation factors, cell cycle events, _ environment Stress, nutritional stress and the like. Phosphorylation regulates or modulates various cellular processes such as proliferation, growth, differentiation, metabolism, apoptosis, activity, transcription, translation, and other processes. Protein phosphorylation insufficiency due to unregulated cell mitosis, sputum-adjusted cells, and increased kinase activity is associated with several diseases and conditions, such as osteoarthritis, rheumatoid arthritis/ , Guan Yanzhong, synovial spasm, multiple sclerosis, myasthenia gravis, diabetes, diabetic angiopathy, diabetic retinopathy, retinal vascular proliferation, inflammatory bowel disease, Crohns disease, ulcerative knot ^ 6 200800919 m disease shellfish 16 bloody shock, fibrosis and differentiated skin disease, middle sacral nervous system disease, neurodegenerative disease in the wide 3; after C injury and nerve damage and axonal degeneration of the disease = such as the Ministry or ridge Listen two::;: Department of disease, viral infection, heart disease, lung or lung disease = or disease. Therefore, the kinase inhibitor has the potential as a therapeutic agent. 10 15 = "Heavy Wei Wei Li" silk (4) There are specific diseases that are characterized by repeated a::: points. The muscles of the face or upper body are especially prosperous (maybe all). The disease is caused by the anti-acetylation of the muscles in the society. This animal is immunized with the receptor protein and has a body with a myasthenia gravis, disease (taken from the Internet: gravis & action = Search + OMD >). Regarding "invasion of synovial sputum in arthritis", the procedure is "segment: ί; 寻 =: Γ, lymphocytes and giant sputum cells are abundant;" granulation tissue from the synovial membrane to form rheumatoid arthritis The bearing surface of the joint is overgrown and related to damage (from the network: <huP://caneerweb.nchac gi_bin/〇md? (4)) (4) Amino acid kinase can be further classified into a receptor A valine acid kinase or a non-synthesis citrate kinase. The receptor gibberellic acid uses a ligand-interacting functional site from the cell, uses a hydrophobic transmembrane functional site, and contains catalytically active enzyme functional sites and other regulatory sequences. The cytoplasmic functional site spans the cell membrane across 7 20 200800919. Non-receptor tyrosine kinases are often immobilized on the cell membrane by the addition of other hydrophobic moieties via the nutrients. Epidermal growth factor receptor (EGFR) The tyrosine-kinase family includes the receptor EGFR (also known as EGFR-1 or Erb-Bl), HER-2 (or neu), 5 EGFR3 and EGFR 4. Epidermal growth factor (EGF), transforming growth factor-α (TGF-α) and HER-2 ligand herregulin A ligand that binds to an EGFR receptor. For example, EGFR overexpression or mutation in one or more members of the EGFR kinase family generally involves cancer and other diseases characterized by uncontrolled or abnormal cell growth. EGFR abnormalities are also associated with Have also been associated with epidermoid tumors, head and neck tumors, breast tumors, and tumors associated with other major organs, such as the lungs and gastrointestinal tract. Cancers that are clinically prevalent in EGFR include the lungs, stomach, and head. And neck cancer (Klijn JG, Berns PM, Schmitz PI and Foekens JA; The 15 clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patients, ^ Endocr. Rev., 1992 , 13, 3-17; Salomon DA Gullick W; The erbB family of receptors and their ligands: Multiple targets for therapy, and /, 2001, 2, 4-11). 20 When treating head cancer such as brain cancer and the like, The ability of small molecule EGFR inhibitors to penetrate the blood-brain barrier can have therapeutic advantages because EGFR is involved in primary brain tumors and breast cancer and small cells that are often transferred to the brain. Lung cancer is often overexpressed (Eckstrand AJ, Sugawa N, James CD and Collins VP; Amplified and rearranged epidermal growth 200800919 factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N-and/or C-termal tails, Proc. Acad NatL Sci. USA, 19925 89, 4309-4313; and Wickstrand CJ, Hale LP, Batra SK, Hill ML, 5 Humphrey PA, Kurpad SN, McLendon RE, Moscatello D, Pegram CN, Reist CJ, Traweek ST, Wong AJ , Zalutsky MR and Bigner, DD; Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas, Cflwcer iies·, 1995, 55, 3140-3148) o ίο Diseases associated with increased EGFR performance include proliferation Glomerulonephritis, kidney disease induced by diabetes, and chronic pancreatitis. EGFR inhibitors are tested in axonal product tests to promote axonal activity in both cerebellar granule cells and sciatic ganglion neurons, presumably by acting directly on neurons to block neurons for pith 15 Inhibition of sphincter inhibitors, EGFR inhibitors may have the potential to promote axonal regeneration after brain & spinal cord injury (V. Koprivica et al., EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans, Science, 2005, 310, 106) 〇20 HER1 and HER2 overexpression has been implicated in various cancers such as bladder, breast, colorectal, endometrium, esophagus, stomach, glioma head and neck, lungs (non-small Cell lung cancer), ovary, pancreas, kidney and prostate cancer. According to the prevalence of HER1 and HER2 in the tumor over-expressed, HER1 over-expressed in the breast, kidney cells, lung, colon straight 9 200800919 intestine, head and neck, ovary, pancreas, glioma, bladder, esophagus , stomach, endometrium, and cervical cancer; relatively, HER2 overexpression occurs in the esophagus, head and neck, lungs, stomach, kidney cells, breast, bladder, ovary and colorectal, prostate and endometrium Horizons in 5 Cancer Therapeutics: From Bench to Bedside, Signa Transduction Inhibitors, 2001, 2(2), ISSN 1532-3048). Although HER2 is not as overexpressed in breast and ovarian cancer as some other cancers, HER2 has been found to be the cause of clinically common cancers (Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A ίο and McGuire WL; Human breast cancer: Correlation of relapse and survival with amplification of HER-2/neu oncogene, Science, 1987, 235, 177-82; Slamon DJ,

Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE et al; Studies of the HER-2/neu proto-oncogene in human breast 15 and ovarian cancer, Science, 1989? 244, 707-712; Hetzel DJ5, Wilson TO, Keeney GL, Roche PC, Cha SS and Podrantz KC; HER-2/neu expression: A major prognostic factor in endometrial cancer, Gpeco/· (9 «co/·, 1992, 47, 179-85) o Breast cancer patients with HER-2 overexpression often metastasize to brain 20 (Kirsch DG and Hochberg FH; Targeting HER-2 in brain metastases from breast cancer, Clin. Can. Res., 2003? 9, 5435_5436). The prognosis of these patients is extremely poor and tumors in the brain often lead to death. Post-mortem showed that 20 to 30% of patients who died of breast cancer had brain metastases (Grossi PM, Ochiai H, Archer GE, McLendon RE, Zalutsky 200800919 MR, Friedman AH, Friedman HS, Bigner DD and Sampson JH; Efficacy of intracerebral microinfusion of trastuzumab In an a a a a a a a a a a a a a a a Accepting a transplant causes a serious and fatal disease. CMV is also a major cause of arteriosclerosis and viral-mediated birth defects. Human CMVs use EGFR to enter cells during infection, EGFR autophosphorylates, and downstream signaling pathway components are activated; however, EGFR ίο specific inhibitor tyrphostin AG1478 is clearly reduced in tyrphostin Viral load in infected cells in the presence (Wang X et al, Nature, 24 July 2003, Vol 424, 456-461). Therefore, potent EGFR selective inhibitors can be used in anti-CMV therapy. The specific purine-substituted pyrimidine is recorded by the Chemical Abstracts Association (CAS), such as 4,6-diamino-5-pyrimidinefurfural (CAS Registry Number: 109831-69-8) and N,Nf- Dimercapto-5-[(decamimidino)methyl]-4,6-pyrimidine> Diamine (CAS Registry Number: 14160-97-5) and described in 1987, 25(1), 343-5 . Specific references describe substituted pyrimidine compounds such as U.S. Patent Nos. 6,080,750, 6,107,301 and 2,6,833,378, which require one or more EGFR, HER-1, HER-2 kinase proteins and the like to have anti-tumor cells. Proliferatively potent potent small molecule kinase inhibitors, which are thus useful for treating or ameliorating diseases mediated by EGFR, HER-1 or HER-2 kinase receptors, mediated or hyperproliferative by gold tube formation 11 200800919 The invention relates to a compound of formula (1)

R2, VNH

R4, R5, R6, r7, L and y and their forms, wherein Ra, R2, 5

JO is as defined in the present invention. For the egg (four) Na to compose its form, its system. ^ ^ ^ ^A (iMb ^ ^ ^ . Horse protein kinase inhibitor. Its shape is: as a protein kinase inhibitor. The present invention is a protein 敫醢: a compound of formula (1) and In the form of an inhibitor of such a type, one person, fiER-2 and a driver are in contact with the compound. ά3 makes the functional site of the protein kinase and the medicinal system of the present invention Rate (1) A compound, a form thereof, or a medicament for use in the treatment, prevention, or improvement of a kinase-mediated disease, disorder, or condition. One example of the invention includes (1) Combination, which is used as a medicament. Forms of Use One example of the present invention includes the use of a prodrug of a compound of the formula (1) as a pharmaceutical composition, a drug or an agent, 'use,:, form preventive or Amelioration of a kinase-mediated disease, disorder or condition. An example of the invention is the use of a compound of formula (1) prior to use as a medicament. μ and its form are additionally related to the treatment, Prevent or change the chronic or individual A sexual protein kinase mediated disease, disorder or disease comprising administering to the individual an effective amount of a compound of formula (1) and a form thereof. The present invention - the case includes a chronic condition for treating, preventing or modifying an individual in need thereof Or an acute protein kinase mediated disease, disorder, disease, method comprising administering to the individual an effective amount of a compound of formula (1) and a form thereof. These and other aspects of the invention may be apparent from the following detailed description. The aspects and advantages are achieved by the use of the compounds of the invention. DETAILED DESCRIPTION OF THE INVENTION The invention relates to a compound of formula (1): 13 20 200800919

And a form thereof, wherein: • L is selected from the group consisting of a bond, a Cl-6 alkyl group or a serogroup 6 alkyl group; a lanthanide group, an aryl group, a heteroaryl group, a stupid and fused group, a heterocyclic group or a stupid 5 Wherein the benzene ring moiety/linker of the benzofused ring system

Ra is selected from ON-0-R! or cyano;

The JO h is selected from the group consisting of hydrogen, Cl.8 filament, Cl.8_, Ci 8 alkoxy, c-oxo-Cw alkyl, hydroxy-Cl_s alkyl, hydroxy-Cy alkoxy, amine alkyl, cv8 Anthracenyl-amino-Cl_d-based, Ci 8-burning oxygen_c"8 alkyl-monoamine-C"-8 alkyl, C!8 alkyl-sulfonyl-8 alkyl, Cu alkyl sulfonate Oxy-Cw alkyl, aryl, aryl-Ci8 alkyl, aryloxy 2, heterocyclyl-Cw alkyl, heterocyclyl-carbonyl-Ci 8 alkyl or heteroaryl-C 1 · 8 An alkyl group, wherein the aryl-Cw alkyl group is optionally substituted on the aryl group by one, two, three, four or five substituents each selected from the group consisting of hydroxyl groups, C18 alkyl groups, C! An oxy group, an amine group, a Cw alkyl-amino group or a Ci 8 alkoxycarbonyl group, and 14 15 200800919 10 15 wherein the heterocyclic group _C!·8 alkyl group is optionally one, two or three on the heterocyclic group. Or four substituents each selected from the group consisting of: a hydroxyl group, a Ci 8 alkyl group, a C!-8 alkoxy group, an amine group, a Cw alkyl-amino group or a Ci 8 alkoxycarbonyl group; , CV8 alkyl or cN8 alkoxy; and Rule 3, Rule 4, R5, R6 and R7 are each selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, C -8 alkoxy, c -8 alkoxyalkyl, -Cl 8 alkyl, halo <1-8 alkyl, hydroxy-Cl.8 alkoxy, cyclyl-Ci 8 alkoxy, amine, Cw alkyl-amine, amine-Cl s alkyl , Ci 8 alkyl-amino-8 alkyl, carboxyl, CNS decyl, c!-8 alkoxycarbonyl, c312 cycloalkyl, aryl, aryloxy, aryl-Cw alkyl, aryl-Ci 8 alkane Oxy, aryl-nonylamino, heteroaryl, heteroaryloxy, heteroaryl &lt;1-8 alkoxy or heterocyclic group, wherein aryl, aryloxy, arylalkyl and aryl-Ci The 8 alkoxy group is optionally substituted on the aryl group with one, two, three, four or five substituents selected from the group consisting of cyano, halogen, hydroxy, Ci 8 alkyl, Ci 8 alkoxy, amine a Cw alkyl-amino group, an aminoalkyl group, a ci 8 alkyl-amino-Cw alkyl group or a C8 alkoxycarbonyl group, and wherein the heteroaryl group and the heteroaryloxy group are each optionally a heteroaryl group. Substituted by one, two, three, four or five substituents selected from the group consisting of: Cls alkyl, amino-Cw alkyl, Cl-8 alkyl-amino-Ci-8 alkyl, carboxyl, Ci 8 decyl or C 1 - 8 氧元氧禄基. Examples of the compound of the formula (1) and its form include those in which the RA system is C=N-0-Ri Examples of the compound of the formula (I) and its form include compounds wherein the ~ is a nitrogen group 15 20 200800919. The compound of the formula (1) and examples thereof include a compound wherein &amp; is selected from hydrogen, c]- 8 alkyl, Ci8 alkenyl, Ci8 alkoxy, c&quot;oxygen &amp; alkyl, hydroxy-CN8 alkyl, hydroxy-Ci8 alkoxy, amino-C18 alkyl, C]-8 alkyl-amine --Cl-8 fluorenyl, Cl-8 oxy-Ci8 alkyl-amino _Ci-8 alkyl, C -8, complete-branched-Cl-8@yl, Ci 8 alkyl sulfonate Acidoxy-Ci 8 alkyl, aryl, aryl-8, aryloxyfluorenyl, heterocyclyl·c18 alkyl, heterocyclyl-carbonyl-Cualkyl or heteroaryl-Ci8 The aryl-Ci-8 alkyl group is optionally substituted on the aryl group with a substituent selected from the group consisting of a hydroxyl group, a C-alkyl group, a Cw alkoxy group, an amine group, and a Ci 8 alkyl group. An amine group or a CK8 alkoxycarbonyl group, and wherein the heterocyclic group -C-8-8 alkyl group is optionally substituted on the heterocyclic group with a substituent selected from the group consisting of a hydroxyl group, a Cw alkyl group, a Ci 8 alkoxy group, Amine,

Ci-8 alkyl-amino or Cw alkoxycarbonyl. Examples of compounds of formula (I) and forms thereof include a compound wherein Ri is selected from the group consisting of hydrogen, Cw alkyl, c!-8 alkenyl, Cw alkoxy, c1-8 alkoxy-Ci 8 alkyl, hydroxy- Cw alkyl, hydroxy-c!_8 alkoxy, amino-8 alkyl, Cw alkyl-amino-Cw alkyl, Cw alkoxy-Cl-8 alkyl-aminoalkyl, Cw alkyl-sulfonyl -Cw alkyl, Cl_8 alkyl-sulfonyloxy_18 alkyl, aryl, aryl-C!-8 alkyl, aryloxy-Ci_8 alkyl, heterocyclyl-Cy alkyl, heterocyclic a benzyl-Cw-alkyl or a heteroaryl-c1-8 alkyl group, wherein the aryl-Cι-g fluorene group is optionally substituted on the aryl group by a c--8 alkoxy group, and wherein the heterocyclic ring The thiol-C 1 -8 alkyl group is optionally substituted on the heterocyclic group via a thiol group or a c ^ 16 20 200800919 oxycarbonyl group. Examples of compounds of formula (I) and forms thereof include a compound wherein Ri is selected from the group consisting of hydrogen, Ci-8 alkyl, CK8 alkenyl, Ci 8 alkoxy-Ci 8 alkyl, hydroxy-Cu:!: aryl, hydroxy -C!·8 alkoxy, cKs alkyl-amino-c1-8 alkyl, 5 Cw alkoxy-Cw alkyl-amino-C-8 alkyl, Ci8 alkyl __sulfonyloxy _〇18 alkyl, aryl, aryl-C!-8 alkyl, aryloxy-Cw alkyl, heterocyclyl-Ci8 alkyl, heterocyclyl-poly-Cw-based or heteroaryl 8 An alkyl group, wherein the aryl-Cm alkyl group is optionally substituted with a Ci 8 alkoxy group on the aryl group, and wherein the heteroalkyl group/"alkyl group is optionally a hydroxyl group or an alkoxycarbonyl group on the heterocyclic group Examples of compounds of formula (1) and forms thereof include a compound wherein & is selected from hydrogen or Cw alkyl. 15 Examples of compounds of formula (I) and forms thereof include a compound wherein R3 R4 R5, R6i R7 Each line is selected from the group consisting of hydrogen, halogen, thiol, C&quot; alkyl, Cb8 alkoxy, Cl-8 alkoxyalkyl, thio-Ci 8 alkyl, halo, ^, C1, ♦ Amino-C&quot; mercapto, Ci 8 alkyl, amine 8 alkyl, ruthenium, 20 fluorenyl, C1.8 oxygenated m 'Cycloalkyl, aryl, aryloxy, formula: 々8 alkyl, aryl hydrazine 8 alkoxy, aryl-nonylamino, heteroaryl, hetero-aryl, heteroaryl-C1·8 The alkoxy or heterocyclic group, /, the middle = yl-aryl-Cl-8 alkyl group and the aryl-Cw alkoxy group are each optionally substituted by the aromatic earth H or two substituents each selected from the following: ·Aromatic group, dentate base group, CN8 alkyl group, Ci 8 alkoxy group, amine group, C1_8 alkyl group-amine 17 200800919 group, amino group-〇1-8 alkyl group, 1-8 alkyl group-amino group _€!1-8 alkyl or 01 alkoxycarbonyl, and wherein the heteroaryloxy group is optionally substituted on the heteroaryl group with a substituent selected from the group consisting of Cw alkyl, amino-Cw alkyl, cle8 An alkyl-amino-CK8 5 alkyl group, a thiol group, a Ci_8 aryl group or a Cu oxynitride group. Examples of the compound of the formula (I) and its form include a compound wherein R3, R4, 5, and 6 Each of R7 is selected from the group consisting of hydrogen, halogen, transbasic, Ch-based,

10 15

Cu alkoxy, C 〖8 burnt oxygen _C〗 _8 alkyl, hydroxy-Cu alkyl, halo·α18 alkyl, trans-C!_8 alkoxy, halo-Ci-8 alkoxy , amine group, Cu alkyl group-amino group, amine group-C!_s alkyl group, C!-8 alkyl group-amino group _C^8 alkyl group, carboxyl group, Ci_8 fluorenyl group, C _8 alkoxycarbonyl group, C3_ !2 cycloalkyl, aryl, aryloxy, aryl-Cw alkyl, aryl-cN8 alkoxy, aryl-nonylamino, heteroaryl, heteroaryloxy, heteroaryl alkoxy Or a heterocyclic group, wherein the aryl group, the aryl-Cw alkyl group and the aryl-Ci_8 alkoxy group are each optionally substituted on the aryl group with one or two substituents selected from the group consisting of: cyano, halogen Or a Ci-8 alkoxy group, and wherein the heteroaryloxy group is optionally substituted with a C1.8 alkyl group. Examples of the compound of the formula (1) and its form include a compound wherein each of the compounds is selected from the group consisting of hydrogen, *, hydroxy, Ci.8 alkyl, I-8 alkyl lactyl, g-Cl-8 alkoxy, aryl, aryloxy Mercaptan, aryl-Cb8 alkoxy, aryl 1-8-C "8 alkoxy or heterocyclic group, aryl, heterocyclic, heteroaryl wherein aryl, aryl _c18 alkyl And the base or the two, each of the 乳 乳 基 取代 各 各 各 各 芳 芳 芳 芳 芳 芳 芳 芳 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : The heteroaryl group is optionally substituted with a Cm substituent. Examples of the compound of the formula (I) and its form include a compound wherein the L is selected from the group consisting of a bond, a C. 6 alkyl group or a -6 alkyl group; Ar is selected from the group consisting of an aryl group, a heteroaryl group, a benzo-fused hexacyclic ring, or a benzo-fused ～2 cycloalkyl group, wherein the benzene ring moiety of the benzo-fused ring system is linked to the L variable; It is selected from ON-0-R! or cyano; R is selected from the group consisting of hydrazine, alkyl, Cl.8 alkenyl, Ci 8 alkoxylate, 10 hydroxy-C1-8 alkyl, hydroxy·c 1 ·8 alkoxy, c 1 _s alkyl, amine _ci -s alkyl, Cw alkoxy-Cw alkyl-amine _ Ci s alkyl, Ci 8 alkyl-sulfonyloxy-C!·8 alkyl, aryl, aryl-Ci8 alkyl, aryloxy-Cl′ alkyl, heterocyclyl-C 8 alkyl , heterocyclyl-carbonyl 8 alkyl or heteroaryl-C 1 -8 alkyl' is wherein the aryl-Cm alkyl group is optionally taken on the aryl group via a Ci8 alkoxy group, and wherein Cyclo-C--8-alkyl is optionally substituted on the heterocyclic group via a hydroxy group or a c-alkoxycarbonyl group; 8 70 R2 is selected from hydrogen, C!-8 alkyl or (:)-8 alkoxy And 20 R3, R4, R5, R6 and R7 are each selected from the group consisting of hydrogen, halogen, hydroxy, Ci 8 alkyl, CN8 alkoxy, halo-C-8 alkoxy, aryl, aryloxy, Aryl::: aryl, aryl-C^8 alkoxy, aryl-arylamino, heteroaryloxy, heteroaryl-Ci _8; J: oxy or heterocyclic, wherein aryl , aryl-c^8 alkyl and aryl-c^8 alkoxy are each substituted on the aryl 19 200800919 by one or two substituents each selected from the group consisting of cyano, dentate or Cl · 8 alkoxy, and wherein the heteroaryloxy group is optionally substituted with a heteroaryl group via a cl-8 alkyl group. Examples of less compounds of the formula (I) and forms thereof include a compound wherein 5 L is selected from the group consisting of a bond, c]-6 alkyl or halo 6 alkyl;

Ar is selected from the group consisting of phenyl group, butyl group, silky &quot; sulphate, dextro, benzoxanthyl, benzoxanyl, benzo[L3]dioxol, 2, 3-Dihydro-w-yl or hydroquinone, wherein oxazolyl, fluorenyl, benzene, quaternary, benzimidazolyl, benzodioxole, 1U-oxyl 71 The benzene ring portion of the air enthalpy is attached to the iron number; ... RA is selected from ΟΝ-0% or cyano; R! is selected from hydrogen, Cw alkyl, Cl-8 alkenyl, Ci 8 alkoxyalkyl , hydroxy-cN8 alkyl, hydroxy-Cl.8 alkoxy, Ci_8 alkyl-amino-c^15 alkyl, Cl-8 alkoxy-alkyl-amino-Cw alkyl, Cu8 alkyl-sulfonate. oxy-C〗 8-alkyl, aryl, phenyl-Ci.8 alkyl, phenoxy&lt;8&gt; decyl, hydrazin-4-yl-C!^, hexahydro-n-bit Carboxyl group, sulphonyl-4-yl-carbonyl-Cw alkyl or pyridyl-Ci 8 alkyl, wherein phenyl-Cw alkyl is optionally taken from the phenyl group via an alkoxy group. Generation, and the soil of the six rats σ is more than the bite base _C ! _8 is based on the hexahydro carbene group by the hydrazine Ci-8 aerobic group; R2 is selected from hydrogen, Cle8 alkyl or c!_8 alkoxy And R3, R4, R5, R6, and R7 is selected from argon faculties, a halogen, by group, C! 8 they burn, 20200800919

Cw alkoxy, halo-Cu alkoxy, phenyl, phenoxy, phenyl-Cw k-based, phenyl-C _8 alkoxy, phenyl-nonylamino, pyridyloxy, hetero aryl-Ch8:!: complete lactation or ruthenium 0 _' base, wherein phenyl, phenyl-C&quot; alkyl and phenyl-Ci s alkoxy groups are optionally treated on the aryl 5 group. Two substituents each selected from the group consisting of a cyano group, a halogen or a CN8 alkoxy group, and wherein the thiol group 1 is optionally substituted on a thiol group by a C18 alkyl group. The invention further relates to a compound of the formula (la): R2, ο, ΝΗ Ν,

And its form, wherein it is selected from the group consisting of a bond, a C 6 alkyl group or a halo-cK6 alkyl group; R 1 is selected from the group consisting of hydrazine, Cw alkyl, Cw alkenyl, Cl 8 alkoxy, Ci8 alkoxyl_1 · 8 alkyl, hydroxy-C1_8 alkyl, hydroxy_C1_8 alkoxy, amino fluorenyl, C _8 alkyl-amino-c] _8 alkyl, c!_8 alkoxyalkylamine 1 base &quot ;^1·8 alkyl, Cl-8, and fluorenyl:): complete, cK8 alkyl-sulfonyloxy-C!-8 alkyl, aryl, aryl-Ci_8 alkyl, aromatic Oxy-alkyl, heterocyclyl-Cw alkyl, heterocyclyl-carbonyl-Ci 8 alkyl or hetero 21 200800919 aryl-cN8 alkyl, wherein aryl-C -8·8 is based on the case Substituted by one, two, three, four or five substituents each selected from the group consisting of: hydroxy, c18 alkyl, C!-8 alkoxy, amine, cNS alkyl-amino or Ci 8 alkane Oxycarbonyl, 5 and wherein the heterocyclyl-Ch alkyl group is optionally substituted on the heterocyclic group with one, two, three or four substituents each selected from the group consisting of hydroxyl groups, Ci 8 alkyl groups, C! -8 alkoxy, amino, Cu alkyl-amino or Ci 8 alkoxycarbonyl; R 2 is selected from hydrogen, c!·8 alkyl or cN8 alkoxy; and 10 K3, K4, R5, and R7 each Selected from hydrogen, halogen 'hydroxy' Cw alkyl, Cw alkoxy, Ci-8 alkoxy-Cw alkyl, hydroxy-Cl 8 alkyl, halo-Cw alkyl, hydroxy-Cl-8 alkoxy, halo-Ci 8 alkoxy, amino, Cw alkyl-amino, amino-Ci-8 alkyl, Cw alkyl-aminoalkyl, carboxyl, c1-8 mercapto, Ci 8 alkoxycarbonyl, Cm 15 cycloalkyl , aryl, aryloxy, aryl-Cw alkyl, aryl-Cl-8 alkoxy, aryl-nonylamino, heteroaryl, heteroaryloxy, heteroaryl / alkoxy Or a heterocyclic group, wherein the aryl group, the aryloxy group, the aryl-Cm alkyl group, and the aryl-CN8 alkoxy group are each selected from the following on the aryl group by one, two, three, four or five Substituted by: cyano, halogen, hydroxy, CN8 alkyl, Cw alkoxy, amine, Cw alkyl-amine, amine-Ci-8 alkyl, Ci-8 alkyl-amino-C!·8 An alkyl or c1-8 alkoxycarbonyl group, and wherein the heteroaryl and heteroaryloxy groups are each optionally substituted on the heteroaryl group with one, two, three, four or five substituents selected from C18 Alkyl, amine group 22 200800919 C1-8 纟 基, C1-8 alkyl-amino _Ci-8 alkyl, ruthenium, Cu, or C! _8 j A few oxygen bases. Benben is additionally related to a compound of formula (lb):

And a form thereof, wherein 5 L is selected from a bond, a c1-6 alkyl or a haloalkyl group; and the -X-Y-Z- is a radical selected from the group consisting of -N(R3)_N=C(R3)...

Two NN(R3)-C(R3)=, -N(R3)-C(R3)=C(R3)-, -C(R3)2-C(R3)2-C(R3)2-,- 〇-C(R3)2-〇-, -N(R3)-C(R3)=N-, -OC(R3)diC(R3)- or -N(R3)-C(R3)2-C (R3)2-; wherein the dotted line in the formula (lb) represents the position when one or two double bonds are present in the atomic group; R1 is selected from the group consisting of ruthenium, Cu alkyl, C!-8 alkenyl, cumane Oxy, CN8 alkoxy-C _8 alkyl, hydroxy-Cw alkyl, hydroxy 8 alkoxy, amine *_Ci 8 alkyl, Cu alkylamino-Cw alkyl, Cl 8 alkoxy-Cl 8 alkane Amine 5 group, 1·8 alkyl, Cl·8 alkyl-sulfonyl group _c _8 alkyl, C1-8 alkyl sulfonyloxy-Cu alkyl, aryl, aryl *_Ci 8 Alkyl, aryloxy-Ci_8 23 200800919 alkyl, heterocyclyl-Cw alkyl, heterocyclyl-carbonyl-cN8 alkyl or heteroaryl-Cu alkyl, wherein aryl-CN8 alkyl is optionally The aryl group is substituted with one, two, three, four or five substituents each selected from the group consisting of hydroxyl, C!-8 alkyl, 5 alkoxy, amine, Cw alkyl-amine or C! a -8 alkoxycarbonyl group, wherein the heterocyclic group &lt;1-8 alkyl group is optionally substituted on the heterocyclic group with one, two, three or four substituents each selected from the group consisting of: , Ci-8 alkyl, &gt; cKS alkoxy, amine, Cl 8 alkyl-amino or cle8 alkoxycarbonyl; 10 R2 is selected from hydrogen, Ci-8 alkyl or (:!-8 alkoxy; And R3 is selected from the group consisting of hydrogen, halogen, hydroxy, cN8 alkyl, Cw alkoxy, CN8 oxy-Ci-8 alkyl, hydroxy-Cw alkyl, halo-Cu alkyl, hydroxy-C!-8 alkoxy , halo-Cl 8 alkoxy, amine, cl 8 alkyl-amino, amino-Cw alkyl, Cl-8 alkyl-amino-Ci-8 alkyl, carboxyl, Cl 8 15 decyl, Cl-8 Alkoxycarbonyl, C3_12 cycloalkyl, aryl, aryloxy, 0-aryl-Cw alkyl, aryl-Ci 8 alkoxy, aryl-nonylamino, heteroaryl, heteroaryloxy, hetero Aryl-C^ alkoxy or heterocyclic group, wherein aryl, aryloxy, aryl-c18 alkyl and aryl·cl-8 alkoxy are each optionally substituted on the aryl group by one, two or three , four or five substituents selected from the group consisting of: cyano, halogen, hydroxy, CK8 alkyl, Cl-8 alkoxy, amine, C&quot; alkyl-amino, amine-Cm alkyl, Cl.8 alkyl-amino-C丨_8 alkyl or Ci8 alkoxycarbonyl, and wherein the heteroaryl and heteroaryloxy groups are optionally one or two on the heteroaryl group Three, four or five substituents selected from the group consisting of: c]-8 alkyl, silk 24 200800919 alkyl, Ci·8 alkyl-amino-Cw alkyl, carboxyl, c^8, or C !_8 alkoxycarbonyl. The invention further relates to a compound of formula (Ic):

NH

_ and its form, wherein 5 J0 L is selected from the group consisting of a bond, a c6·6 alkyl group or a halo group _c!_6 alkyl group;

Ar is selected from the group consisting of an aryl group, a heteroaryl group, a benzo-fused-heterocyclic group or a stupid and fused {bad alkyl group, wherein the benzene ring moiety L· variable of the benzofused ring system; R2 is selected from the group consisting of hydrogen, C..8 alkyl or (^-8 alkoxy; and R3, R4, R5, R6&amp; R7 are each selected from the group consisting of hydrogen, _, hydroxy, cc "8 alkoxy, Cl" .8 炫氧.Cl.8 alkyl, hydroxy^7&quot; base, yl-c-8 alkyl, hydroxy-Cl8 alkoxy, dentate _c" * amine, cNS alkyl-amine, amine Base 8 alkyl, 70 ram, "·8 焼, 叛 醯 醯 、, Ci 8 alkoxy = amine, aryl, aryloxy, aryl / η alkyl, # 3, 〗 2 Oxy, aryl, decylamino, heteroaryl*, heteroaryloxy, hetero = t C].8 alkoxy or heterocyclic, ', aryl 25 15 200800919 wherein aryl, aryloxy, The aryl-Cw alkyl group and the aryl-Ci 8 alkoxy group are each optionally substituted on the aryl group with one, two, three, four or five substituents selected from the group consisting of cyano, halogen, hydroxy, C18. An alkyl group, a C18 alkoxy group, an amine group, a CNS alkyl-amino group, an amine group -Ci 8 alkyl group, an 8-alkyl-amino group-C!8 alkyl group or a cN8 alkoxycarbonyl group, and wherein The aryl and heteroaryloxy groups are each optionally substituted on the heteroaryl group with one, two, three, four or five substituents selected from Cw alkyl, aminoalkyl, cN8 alkyl-amino -Ci 8 alkyl, carboxy, ci 8 fluorenyl or oxy-oxyl. Examples of compounds of formula (1C) and forms thereof include a compound wherein R 2 is selected from hydrogen. 15 20 Compound of formula (Ic) and its form Examples include a compound wherein R4, R5, 116 and R7 are each selected from the group consisting of hydrogen, halogen, hydroxy, c&quot;alkyl, c]8 methoxy, C1·8 alkoxy-alkyl, via VIII, aryl-8 oxane, Λ ι 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧 烧·8-alkylamino group _C1·8 alkyl, carboxy, :yl, bis-"peroxy" 'C3_12 cycloalkyl, aryl, aryloxy, aryl 8 -q8 alkyl, aryl 々8 Alkoxy, aryl, arylamino, oxy-f, hetero-f-C丨-8 alkoxy or heterocyclic, hetero-, H-aryl _Ci.8 fluorenyl and aryl _Ci·8 The alkoxy groups are each substituted with one or two substituents selected from the group consisting of: cyano, Ϊ^-based to silk. , A. with an oxy group, an amine group, a k-alkyl-amine group, a compound of the formula (Ic), and a form thereof, including a compound wherein R3, R4, R5, R6 and r7 are each selected from the group consisting of Hydrogen, halogen, hydroxyl, C18 alkyl, Cw alkoxy, C!8 alkoxy-Cw alkyl, hydroxy-c1-8 alkyl, halo-Cu alkyl, hydroxy-Cw alkoxy, halo _Cl_8 alkoxy group, amine group, 8-alkyl-amino group, amino group-C!_8 alkyl group, Cw alkyl group-amino group_c〗 _8 alkyl group, carboxyl group, C -8 mercapto group, CNS alkoxy group Carbonyl, C3-12 cycloalkyl, aryl, aryloxy, aryl-C!-8 alkyl, aryl-C!-8 alkoxy, aryl-nonylamino, heteroaryl, heteroaryl Oxy, heteroaryl-CN8 alkoxy or heterocyclic, in 15 20 wherein aryl, aryl-C1-8 alkyl and aryl-C1-8 alkoxy are each optionally present on the aryl group by one or two Substituted by a substituent selected from the group consisting of cyano, halogen or C!-8 alkoxy. Examples of compounds of the formula (Ic) and forms thereof include a compound wherein R4, R5, R6 and r7 are each selected from the group consisting of hydrogen, dentate, hydroxyl, Ci8 alkyl, di-alkoxy, halo-cl -8 alkoxy, aryl, aryloxy, aryl-c18 alkyl, 8-aryl-Cw alkoxy, aryl-nonylamino, heteroaryloxy, heteroaryl- alkoxy or hetero a cyclic group, i wherein aryl, aryl-8, and aryl-8 alkoxy are each optionally taken from one or two substituents selected from the group consisting of dentate or c,-8 alkane on the aryl group. Oxygen. Examples of the compound of the formula ' / (1C) and a form thereof include a compound selected from the group consisting of a bond, a C 6 alkyl group or a dentate group _c 丨 · "based, · /,

Ar is selected from the group consisting of aryl, base, fused. heterocyclic or benzene. The benzene ring moiety of the benzoxene ring system; 27 200800919 5

R2 is selected from the group consisting of hydrogen, Ci_8 alkyl or Cu alkoxy; and R3, FU, Rs, R6 and R? are each selected from the group consisting of hydrogen, halogen, hydroxyl, Cw alkyl, methoxy, halo-C^8 Alkoxy, aryl, aryloxy, aryl-Cb8 alkyl, aryl-C!.8 alkoxy, aryl-nonylamino, heteroaryl-1,heteroaryl-Ci-8 alkoxy Or a heterocyclic group, wherein the aryl group, the aryl-Cm alkyl group and the aryl-Ci.8 alkoxy group are each optionally substituted on the aryl group with one or two substituents selected from the group consisting of: cyano, Halogen or Cu alkoxy. The invention further relates to a compound of formula (Id):

And a form thereof, wherein L is selected from the group consisting of a bond, a c 1 -6 alkyl group or a halo _c K6 alkyl group; the R 2 system is selected from the group consisting of hydrogen, Ci 8 alkyl or Cu alkoxy; and h'R 5 'R 6 &amp; R 7 Is selected from the group consisting of chlorine, 4, thiol, Ci8 alkyl, Cw alkoxy, CNS alkoxy-Cl_s alkyl, hydroxy-Ci 8 alkyl, halo-Cm alkyl, hydroxy-Cm alkoxy, ^ Alkoxy group, amine group, Cw alkyl-amino group, amino-Cl-8 alkyl group, Ci 8 alkyl-amino group-Cu alkyl group, carboxyl group, Cw fluorenyl group, Cl_8 alkoxycarbonyl group, ring Alkyl, 28 15 200800919 aryl, aryloxy, aryl-Cu alkyl, aryl-Ci 8 alkoxy, aryl-nonylamino, heteroaryl, heteroaryloxy, heteroaryl-Cw The oxy group, wherein the aryl group, the aryloxy group, the aryl fluorene group and the aryl group oxime are each substituted on the aryl group with one, two, three, four or five substituents selected from the group consisting of : cyano, halogen, hydroxy, Cw alkyl, C18 alkoxy, amine, Cw alkyl-amino, amino-Ci-8 alkyl, alkyl-amino-C-8 alkyl or cumane An oxycarbonyl group, and wherein the heteroaryl group and the heteroaryloxy group are optionally one, two, three, four or five selected from the following on the heteroaryl group Substituents are substituted: c18 alkyl, amino-CN8 alkyl, CN8 alkyl-amino-Cu alkyl, carboxyl, cK8 fluorenyl or Ci_8 oxy group. The invention further relates to a compound of formula (le):

And a form thereof, wherein 15 L is selected from the group consisting of a bond, a Ck alkyl group or a halo-Ci 6 alkyl group; and is an atomic group selected from the group consisting of -N(R3)_N;=C(R 士, , -N (R3)-C(R3)=, -N(R3)-C(R3)=C(R3)-, -c(r3)2-c( 29 200800919 R3)2_C(R3)2-,-0- C(R3)2-0-, _N(R3)-C(R3)=N-,_0-C (R3)=C(R3)· or -N(R3)-C(R3)2_C(R3)2_ Wherein the dotted line in the formula (ie) indicates the position when one or two double bonds are present in the atomic group; 5 R2 is selected from hydrogen, Ci_8 alkyl or Ch alkoxy; and R3 is selected from hydrogen, halogen , hydroxy, Cw alkyl, Cl_8 alkoxy, Cl-8 alkoxyalkyl, hydroxy-CU8 alkyl, halo-Cu alkyl, hydroxy-Ci_8 alkoxy, halo-Cw alkoxy, amine , c^8 alkyl-amino, amino-Ci_8 alkyl, C!-8 alkyl-amino-Cw alkyl, carboxyl, Cl_8 10 fluorenyl, Cns alkoxycarbonyl, C3-; 2 cycloalkyl , aryl, aryloxy, aryl-Cm alkyl, aryl-CK8 alkoxy, aryl-nonylamino, heteroaryl, heteroaryloxy, heteroaryl-C1-8 alkoxy or heterocyclic a group, wherein the aryl group, the aryloxy group, the aryl group _Cl 8 alkyl group, and the aryl group _Ci 8 alkoxy group are optionally subjected to one, two, three, respectively, on the aryl group. Or five subunits selected from the group consisting of: cyano, halogen, hydroxy, Cw alkyl, Cl-8 alkoxy, amine, CV8 alkyl-amine, amine _c18 alkyl, alkyl -Amino-C!.8 alkyl or Ci_8 alkoxycarbonyl, and wherein the heteroaryl and heteroaryloxy are each optionally substituted on the heteroaryl group by one, two, three, four or five selected from Substituted by: c18, amino group 20 ^ 丨 · 8 alkyl, Cl-8 alkyl-amino-C -8 alkyl, carboxyl, Ci 8 fluorenyl or c1 > 8 oxygenated groups Examples of the compound of the formula (I) include a compound and (*): ^R2:k3:R.R5.^, the configuration of the 15 knives relative to the double bond; in addition, R3, r4, r5, 30 200800919 When one or more of r6 or r7 is hydrogen, the hydrogen is omitted from the table below):

Cpd (*)-Ra r2 L (R3-R4*Rs&quot;^6~^7)^^ 1 (£)-CH=N-OCH3 H Bonding (3-C1-4-F) Stupid 2 (£ )-CH = N-OCH3 H bond l-(3-F-benzyl)oxazol-5-yl 3 (£)-CH=N-OCH3 H bond (3-C1-4-F) phenyl 4 (£)-CH = N-OCH3 H bond [3-Cl-4-(3-F-benzyloxy)] stupid 5 (£)-CH = N-OCH3 H bond 2-(3 -F-benzyl)carbazol-5-yl 6 (£)-CH=N-0CH2C(0)-morpholine-4-yl H-bonded 1-(3-F-benzyl)carbazole-5 -Base 7 (£)-CH = N-OCH3 H bond (3-OCH3-4-phenoxy)phenyl 8 (£), CH=N-0CH2C(0)-morpholine-4-yl H Bonding (3-OCH3-4-stupoxy) Stupid 9 • (£)-CH=N-OCH3 H Bonding (3-C1-4-benzyloxy) Stupid 10 (£)-CH= N-OCH2CH3 H bonded l-(3-F-benzyl)oxazol-5-yl 11 (£&gt;CH = N-OCH2CH = CH2 H bonded 1-(3-F-benzyl)carbazole- 5-Base i (£)-CH=N-0-C(CH3)3 H Bonding l-(3-F-Benzyl)oxazol-5-yl 13 (£)-CH=N-OCH3 H bond (3-CH3-4-Pyridin-3-yloxy)phenyl 14 (£)-CH = N-0CH2CH3 H -CH (hole-CH3)-phenyl 15 (Z)-CH=N-OH H Bonding l-(3-F·benzyl)oxazol-5-yl 16 (£hCH=N-OCH2CH3 H -CH(S-CH3)-stupyl 17 (E)-CH=N-OCH2C H3 H bond n n d ο 1,5 -yl 18 (£)-CH = N-OCH2CH3 H bond [3-Cl-4-(3-F-benzyloxy)]phenyl 31 200800919

Cpd 19 20 21 22 23 r 25 26 27 2 8 29

31 32 33 34 35 36 (*)-Ra r2 L (R3 - ruler 4-R5-R6 - ruler 7) Ar (£)-CH = N-0(CH2)2-norfosolin-4-yl H bond 1-(3-F-Benzyl)carbazol-5-yl (£)-CH = N-OCH3 H bonded nitrogen node-5-yl (£)-CH = N-OCH3 H bonded 4-OCHF2 -phenyl (£)-CH=N-OCH3 H bonded carbazole-5-yl (£)-CH = N-OCH3 H bonded benzo[1,3]dioxetene-5- :(£)-CH = N-OCH3 H bond (4-phenyloxy)phenyl (£&gt;CH=N-OCH5 H bonded (4-benzyloxy)phenyl (£)-CH = N-OCH3 H Bonding 4-CH(CH3)CH2CH3-Phenyl (£)-CH = N-OCH3 H Bonding 4-C(CH3)3-Phenyl (£)-CH = N-OCH3 H Bonding (3.benzyloxy)phenyl (£)-CH = N-OCH3 H bonded [3-CH3-4-(6-CH3-pyridin-3-yloxy)] phenyl (£)-CH = N-OCH2CH(CH3)2 H bond l-(3-F-benzyl)carbazol-5-yl (£)-CH = N-0(CH2)2-phenoxy H bond l-( 3-F-benzyl)carbazole-5-yl (£)-CH=N-0CH3 H bond (3-CI-4-pyridin-2-yloxy)phenyl (£)-CH = N- OCH2CH3 H bond l-(3-F-benzyl)indole-5-yl (£)-CH = N-OCH3 H bonded l-(3-F-benzyl)indole-5-yl (E )-CH = N-0CH3 H -ch2cf2- 6-CH3-pyridin-2-yl (£)-CH = N-0CH3 H Bonding 3-Br-phenyl 32 200800919

Cpd (*)-Ra r2 L 37 (£)-CH = N-OCH2CH3 H Bonding 38 (£)-CH=N-OCH3 H Bonding 39 (£)-CH=N-OCH3 ch3 Bonding 40 (£ )-CH=N-OCH3 ch2ch3 Bonding 41 (£)-CH=N-OCH2CH3 ch2ch3 Bonding I42 (£)-CH = N-OCH3 ch2ch3 Bonding 43 (£)-CH=N-OCH2CH3 ch2ch3 Bonding 44 (£)-CH = N-(4-OCH3-benzylindenyl) H bond junction 45 (£:)-CH = N-(2-OCH3-benzyloxy) H bond junction 46 (£)-CH = N-benzyloxy H bond 47 (£)-CH=N-OCH(CH3)2 H bond 48 (£)-CH = N-OCH3 H bond turtle (£)-CH=N-OCH2CH3 H Bond junction 50 (£)-CH = N-OCH3 H Bond junction 51 (£)-CH=N-OCH2CH3 H Bond junction 52 (e)-ch=n-och2ch3 H Bond junction 53 (£)-CH = N , OCH3 ch3 bond 54 (£)-CH=N-OCH3 H bond (1^3-4, reverse 5--6-foot 7) eight "(3-C Bu 4 · benzyloxy) stupid Base (3-C1-4-b ratio -3-yl-lactyl)phenyl[3-Cl_4-(3-F-benzyloxy)]phenyl 1-(3-F-benzyl)carbazole -5-yl-l-(3-F-benzyl)oxazol-5-yl[3-Cl-4-(3-F-benzyloxy)]phenyl [3_C1_4-(3-F-benzyl) Oxyl)]phenyl 1-(3-F-benzyl)oxazol-5-yl-l-(3-F-benzyl)oxazol-5-yl-l-(3-F-benzyl)carbazole -5-based l-(3-F -benzyl)carbazol-5-yl 1-octyl-, salin-5-yl-1 benzyl-oxazol-5-yl 1-(3-CN-benzyl)indazole-5-yl 1- (3-CN-benzyl)oxazol-5-yl 2-benzyl-oxazol-5-yl-l-(3-F-benzyl)indazol-5-yl-l-(3-Cl-benzyl ) carbazole-5-based 33 200800919

Cpd (*)-Ra R2 L (R3-R4-R5-R6-R7)Ar

55 (£)-CH = N-OCH2CH3 H

56 (£)-CH = N-OCH3 H 57 (£)-CH = N-OCH2CH3 H 58 (£)-CH=N-OCH2CH3 ' H 59 (£)-CH=N-OCH3 H ,60 (£) -CH=N-OCH3 H 61 (£)-CH=N-OCH3 H 62 (£)-CH=N-OCH2CH3 H 63 (£)-CH=N-OCH3 H 64 (£)-CH = N-OCH3 H m (£)-CH = N-stupyl H 6 6 (E)-CH = N-OCH3 H 67 (£)-CH = N-0CH2CH3 H 6 8 (£)-CH=N-0 (CH2 ) 20CH3 H 69 (z)-ch=no(ch2)3oh H 70 (£)-CH = N-0(CH2)3N(CH3)2 H 71 (£)-CH = N-0(CH2)20CH3 H Bonded l-(3-Cl-benzyl)oxazol-5-yl-bonded 1-(3-OCH3-benzyl)carbazole-5-yl-bonded 1-(3-0CH3-benzyl)carbazole -5-yl-bonded 2-(3-F-benzyl)benzimidazole-5-yl-bonded 3-C1-phenyl-bonded 2-(3-F-benzyl)benzimidazole-5-yl Bonded [3-OCH3-4-(3-F-benzyloxy)] phenyl bond [3-OCH3-4-(3-F-benzyloxy)]phenyl bond (3-Cn -4-OCH3) phenyl bond (3-C1-4-norfosolin-4-yl) stupyl bond l-(3-F-benzyl)carbazole-5-yl bond l-(4 -F·benzyl)carbazole-5-yl-bonded 1-(4-F-benzyl)oxazol-5-yl-bonded l-(3-F-benzyl)carbazole·5-yl bond L-(3-F-benzyl)oxazol-5-yl-bonded 1-(3-F-benzyl Base) carbazole-5-yl bond (3-C1-4-benzyloxy)phenyl 34 200800919

Cpd (*)-Ra r2 L (R3-R4-Rs_R6,R7)Ar 72 (£)-CH=N-OCH3 H Bonded 2-(3-F-phenyl) benzofuran-5-yl 73 ( £)-CH = N-OCH3 H bonded 2-benzyl-benzofuran-5-yl 74 (£:&gt;CH=N-OCH3 H bonded 1-(3-F-benzyl)-2, 3. Dihydro-indole-5-yl 75 (£:)-CH = N-0(CH2)30H H bonded [3-Cl-4-(3-F-benzyloxy)]phenyl 76 ) (£)-CH = N-0(CH2)30H H Bonding (3-C1-4-benzyloxy)phenyl 77 (£)-CH = N-OH H Bonding (3-CN4-Benzyl) Alkyl) stupyl 78 (£), CH = N-0(CH2)2-isfos-4-yl H bond (3-C1-4-benzyloxy)phenyl 79 (£)- CH = N-OH H bonded [3-Cl-4-(3-F-benzyloxy)]phenyl 80 (£)-CH = N-OCH3 H bonded (2-F-4-C1) Phenyl 81 (Z)-CH = N-OCH3 H bond (2-F-4-C1)phenyl 82 (£)-CH = N-OCH3 H bond (2-F-4-Br) phenyl i (Z)-CH = N-OCH3 H bond (2-F-4-Br)phenyl 84 (£)-CH = N-OH H bond l-(3-F-benzyl)carbazole- 5-based 85 (£:)-CH = N-0(CH2)30H H bonded N(3-F-benzyl)carbazol-5-yl 86 (£)-CH=N-OCH3 ch3 bond ( 2-F-4-Br)phenyl 87 (E)-CH = N-0(CH2)3·morpholine-4-yl H-bonded 1-(3-F·benzyl ) carbazole-5-yl 88 (£)-CH = N-OH H bonded l-(3-F·benzyl)吲哚-5-yl 89 (£)-CH = N-OCH3 H bond ( 4-C1-2-F-5-OH)phenyl 35 200800919

Cpd (*)-Ra r2 L 9 0 (z)-ch=n-och3 Η Bonding (4-C1-2-F-5-OH)phenyl 91 (£)-CH = N-0(CH2) 30H Η bond l-(3-F-benzyl)indole-5-yl 92 (£)-CH = N-0(CH2)3-hexahydropyridine.-1-yl hydrazone bond l-(3 -F-benzyl)carbazol-5-yl 93 (£)-CH = N-0(CH2)2·?福咁-4-ylΗ linkage [3-(:1-4-(3*^ -benzyloxy)] stupid 94 (£)-CH=N-0(CH2)2-hexahydropyridin-1-ylindole bonded [3-Cl-4-(3-F·benzyloxy) )] Stupid I95 (£)-CH = N-0(CH2)2-hexahydropyridin-1-ylindole Bonded (3-C1-4-benzyloxy)phenyl 96 (£)-CH = N-0(CH2)2-hexahydropyridin-1-ylindole bonded l-(3-F-benzyl)carbazol-5-yl 97 (£)-CH = N, OCH3 Η bonded [341- 4-(3,542-benzyloxy)]phenyl 98 (£)-CH-N-OH Η bonded [3-Cl-4-(3,5-F2-benzyloxy)]phenyl 99 ( £)-CH=N-0(CH2)2-??咁-4-ylΗ Bonding [3-C〖-4-(3,5-F2-benzyloxy)]phenyl 100 (£) -CH = N-OH Η -CE(S-CUj)- Stupid 101 (£)-CH = N-0(CH2)2-??咁-4-ylΗ Bonding l-(3-F-Benzyl吲哚)-5-yl•&gt;2 (£)-CH=N-0(CH2)2-hexahydropyridin-1-ylindole Bonding l-(3-F-benzyl)indole-5 -Base 103 (E)-CH=N-0(CH2)2-??咁-4-ylindole-CU(S-CU3)-phenyl 104 (£)-CH=N-OCH3 Η Bonding [4-NHC( 0)-phenyl]phenyl 105 (£)-CH = N-OH Η bonded [4-NHC(0)-phenyl]phenyl 106 (£&gt;CH = N-0(CH2)2_6 Hydropyridin-1-ylindole-CH(5^CH3)-phenyl107(£)-CH=N-0(CH2)2-isfene-4-ylindole Bonding [4-NHC(0)- Phenyl]phenyl 36 200800919 (*)-Ra r2 L (£)-CH = N-0(CH2)2-??咁-4-ylΗ Bonding (3-C1-4-F)phenyl ( £)-CH = N-0(CH2)2-Isofosin-4·ylindole Bonding (4-phenoxy)phenyl (£)-CH = N-OCH3 Η Bonding [2-NHC(0 )-stupyl]pyrimidin-5-yl (£)-CH=N-OH Η bonded (4-phenoxy)phenyl (£)-CH = N-0(CH2)3-morpholine-4 ·Based on a bond (3-C1-4-benzyloxy)phenyl (£)-CH = N.〇(CH2)3〇.S02CH3 Η bond (3-C1-4-benzyloxy) Phenyl (£)-CH=N-OCH2-pyridine·2·yl hydrazide bonded (3-C1-4·benzyloxy)phenyl (£)-CH = N-0(CH2)3-NH( CH2)2-0CH3 Η bond (3-C1-4·benzyloxy) phenyl (£)-CH = N-0(CH2)3, (4-0H-hexahydropyridinium bond (3- CI-4-benzyloxy) phenyl-1 -yl) (£)-CH = N-0CH2-(lC(0) 0-C(CH3)3 Η bond (3-C1-4-benzyloxy)phenyl-hexanitrozide ratio bit-4 group) CN Η bond (3-C1-4-benzyloxy) Phenyl

Cpd 108 109 I 10 111 112 • 113 114 115 116 117

Examples of the compound of the formula (I) include a compound selected from the group consisting of: 37 200800919

Compound 1 compound 2 compound 3 compound 4

Compound 5 Compound 6 Compound 7 Compound 8 38 200800919

Compound 13 Compound 14 Compound 15 Compound 16 39 200800919

Compound 17 compound 18 compound 19 compound 20

Compound 21 Compound 22 Compound 23 Compound 24 40 200800919

Compound 25 Compound 26 Compound 27 Compound 28

Compound 29 compound 30 compound 31

Compound 32 41 200800919

Compound 33 compound 34 compound 35 compound 36

Compound 37 Compound 38 Compound 39 Compound 40

42 200800919

Compound 45 Compound 46 Compound 47 Compound 48 43

200800919

NH2 n N

N, NH, 0 Ό

N-n

NH2 N N

N NH

N-N

NC

Compound 49 compound 50 compound 51

Compound 53 compound 54

Compound 52 compound 5 5

44 200800919

Compound 57 compound 58 compound 59 compound 60

N

i

N, NH

〇 I .0

NH2 N

N

Cl nh2 n N k

N, NH

N NH

01 ,0

N ^NH

Cl

M

Compound 61 Compound 62 Compound 63 Compound 64 45 200800919

Compound 65 Compound 66 Compound 67 Compound 68

Compound 69 Compound 70 Compound 71 Compound 72 46 .200800919

F 化合物 compound 73 compound 74

0.

Compound 7 5

Compound 7 7 Compound 7 8 Compound 7 9 Compound 8 0 47 200800919

Compound 81

Br Br is called νΓ〇Η

Compound 82 Compound 83

Compound 85 Compound 86 Compound 87 Compound 88 48 200800919

Compound 89 compound 90 compound 91 compound 92

Compound 93 Compound 94 Compound 95 Compound 96 49 200800919

Compound 101 Compound 102 Compound 103 Compound 104 50 200800919

ο

IN

Cl

F compound 105 compound 106 compound 107 compound 108

Compound 109 Compound 110 Compound 111 Compound 112 51 200800919 〇=S=〇

Cl 0.

Cl 0.

Cl 0. Compound 113 Compound 114 Compound 115 Compound 116

Compound 117 Compound 118 Chemical Definition &amp; Name The bond line drawn from the substituent variable into the ring system indicates that the substituent may be attached to any substitutable ring atom. 52 200800919 The following terms used by Shame have the following definitions. The present invention is intended to have a specific chemical formula. The specifics provided are intended to illustrate the term. The term itself / the scope of the ambiguity includes variations encompassed by a number of general practitioners. Chemical 5 term, read from right to left, wherein the rightmost group is attached to the core group and the group on the left is the terminal group. The chemical formula of the term is used to read from left to right, wherein the leftmost group is attached to the core molecule (as indicated by the broken apostrophe) and the rightmost group is the terminal group. The "C!-8 alkyl" group means a saturated aliphatic branched chain or a linear hydrocarbon group or a bonding group having a quinone to 8 straight or branched chain atoms, wherein the =1 group is derived from The carbon atom is derivatized by removing a hydrogen atom and the bond group is derived by removing one hydrogen atom from each of the two slave atoms in the chain. The term "C!-8 alkyl" also includes "Cw alkyl" and "Cl $alkyl" groups or bonding groups, such as 15 A, each having 1 to 6 carbon atoms and 1 to 4 stone anti-atoms. Base, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, decyltributyl, _^pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2 -hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 1-octyl, 2-octyl, 3-octyl and the like may be located via a terminal carbon atom or via The carbon atoms in the chain are attached to the core molecule. Similarly, a substituent variable can be attached to an alkyl bond group of an effective valence of 20. The term "C2_8 alkenyl" means an alkyl group or a bonding group having 2 to 8 linear or branched chain carbon atoms and having at least one carbon-carbon double bond. The term "C2_8 alkenyl" also includes "C2-4 dilute" groups or bonding groups having 2 to 4 carbon atoms, such as ethylene (also known as vinyl (viny 1)), 53 200800919 / , allyl allyl (also known as propylene), propylene, and the like. The deduction of Ci.s alkoxy" means having up to 8 linear or branched = disc atomic (tetra) or bonding groups, wherein the group or bonding group 1 = bonding atom is attached, as follows: -〇-Cw base. The term "cN8 'meta-milk=" also includes individual groups having up to 6 carbon atoms and up to 4 carbon atoms, Cl.6 alkoxy groups and "°1.4 alkoxy groups" or bonding groups, such as ruthenium. Oxy, ethoxy, propoxy, butoxy and the like. The alkoxy group can be attached to the core molecule and further substituted as shown by the bonding group. 1 r\ 1 u 15 The term “〇3-] 2 ring-burning group means a saturated or partially unsatisfactory group. The term "C3_12 cycloalkyl" also includes C3 8 cycloalkyl, ^10% alkyl, C5-6 cycloalkyl, C58 cycloalkyl, C5iyf alkyl, q η ^ complete or benzo fused · ^ (d) Base ring system groups and the like 2 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloheptyl 4, hydrogen, 9-, u, 3, 4. , adamantyl and the like. Benzene condensed _&lt;:3·12 bad filaments" means a C3_12 cyclofilament (tetrazed) group having a benzene ring fused to an adjacent carbon atom of a cyclonic system. Examples of the '12 cycloalkyl group include those which are fused to &lt; 5·6 cycloalkyl ring system groups and the like, such as a group, a hydroquinone group, and the like. ρ The term "aryl" means an unsaturated aromatic smog system group. The nuclear system includes phenyl, naphthyl, azulenyl, i-based, and the like. Examples of aryl groups in representative compounds of the present invention include phenyl ruthenium, the term "hetero", when used as the prefix of the ring system, ^ table t ring system 54 20 10 15 20 200800919 === selected 2 from / :0,? (.) or called a hetero atom. Or the ring may have a b 2 red or a 4 carbon atom member placed by a nitrogen atom or a ring may have! One: a nitrogen member and an oxygen or sulfur atom. ; for heteroatoms, scorpion scorpion. Or up to two adjacent ring members can be 〇 or 〇. , the first hetero atom is nitrogen, and the other hetero atom is selected from N, s spray (also known as 4,5d^^), 3_dioxolanyl, 2-imidazopyridinyl ,四峻其|β, waki), imidazolidinyl, 2_pyrazolyl, 咐f咐, yl, tetrazolidinyl, hexahydropyridyl, M-dioxane, 啐二叫ill Base, , = ruthenyl, hexachloro 0 (tetra), ruthenyl, tetrahydro 1 phenanthrene A, hydrazine, /, hydrogen - 1,4-oxazinyl, tetrahydro-furan. The term "hetero", tetrachloro-tower 0, and the like, and the like, includes: a benzo-fused-heterocyclyl ring system group and a fluorene, 3, an anthracene group (also known as 2). , 3 · dihydrogen, yl), benzo- to: amylamine, the term "cage, one 虱 酞 酞 及 及 及 = = = 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻 相邻It is a heterocyclic ring system group having a benzo group fused to a ring system. Representative of the present invention is a conjugated group and an exemplified group.单价 示 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Azolyl, isoindole, oxazolyl, triazolyl, thiadiazolyl, pyridyl, pyridinium, and the like. * fluorenyl (4) "heteroaryl" also includes benzo-fused fused-heteroaryl ring system groups and such as L-base, 吲σ-based, aza-based, argon = benzopyrene Benzyl, benzoxenyl" fluorenyl, aza-sodium, benzoimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxyl, phenylenyl, benzodiazepine Base, sulfhydryl, 4Η_4 _yl” 奎咐基, 10 15 20 :/圭咐基, 十林基, (四)基, 4唾“&quot;奎十林基, u.Naphthalene, acridinyl and Such as. '丁相来β, ° "T-opened heteroaryl" means a heteroaryl ring system group having a benzene ring bonded to the ring system. Examples of the present fused heteroaryl group in the representative compounds of the present invention include a +sodium group, a aryl group, a benzofuranyl group, and a benzo-saltyl group.

The term "Cl-8 fluorenyl" means a group of the formula: _c(〇)H ^(〇κν8 alkyl group or a bonding group of the formula: -c(〇)_Ci8 alkyl-end group. δ# "Cl·8 filaments_Cl.8 filaments" means a group of the formula: -Cu, a terroir-o-Cm alkyl group, or a bonding group of the formula: _Ci-8 alkyl group-end group The term "Cw aerobic-Cl_8 fluorenylamino group _Ci 8 alkyl group" means the following formula: soil group: _Cl·8 alkyl group-Ci-8 alkyl-O-Cw alkyl group, -Cl -8垸=[Α·8 alkyl base) (C1.8 alkyl 7々8垸 base)] or _C18 burnt base C18 Luo o-Cm base) 2, or the following bond: _c&quot; Erythril Ci 8 56 200800919 alkyl-O-Cw alkyl-terminal group, -Cw alkyl-NKCw alkyl) ((^_8 alkyl-0-C!.8 alkyl-terminal group)] , -Cw alkyl-N [(CK8 alkyl terminal group) (Cb8-based -O-Cu alkyl)] or -Cu alkyl group / NI ^Cu alkyl) (C!_8 alkyl-O-- Cu base* &quot;end group]]. The term "C"-8 alkoxycarbonyl" means a group of the formula: _c(0)_0_Ci 8 'membered' or a bonding group of the following formula: -C(〇)-〇_Ci-8 alkyl-end Group. The term "C!.8 alkyl-amino" refers to a group of the formula: an NH-Ci_8 alkyl or -Νβυalkyl)2. 10 15 The term "Cu-alkyl-amino-Cw alkyl" means a group of the formula: -Cb8 alkyl-NH-Ch alkyl or -Cu alkyl-N (Cr8 alkyl) 2, or the following formula Bonding group: _C!_8 alkyl-ΝΗ-(^8 alkyl terminal group or -Cl_8 aryl group)-Cu group-end group. The term "c"-8-alkyl-sulfonyl-Cl 8 alkyl" means a group of the formula: -Ci.8 alkyl-sore!-8 alkyl, or a bonding group of the formula: -Ci 8-alkyl-S Ο 2 _ C 1 -8 alkyl group · terminal group. The term "C"-8 alkyl-sulfonyloxy-Ci_8 alkyl" means a group of the formula: -Cw alkyl-O-sCVCu alkyl, or a bonding group of the formula: alkyl-o- Scvcw alkyl-terminal group. The term "amino" refers to a group of the formula: -nh2. The term "amino-Cw alkyl" means a group of the formula: _Ci 8 alkyl-NH 2 , or a bonding group of the formula: _c 1 8 alkyl · NH terminal group or _c Μ alkyl group - Ν (end group) 2. The maryl-nonylamino group means a group of the formula: _nhc(o)-aryl. 57 20 200800919 The term base-aryl. The term "alkyl-Cks alkyl" means a group of the formula: lauranyl-Ci.8 alkoxy" means a group of the formula: _〇_Ci 8 ^oxy "" means a group of the formula: Ο·aryl. The arylarylaryl group-alkyl group means a group of the formula: ^ _ mcarboxy group means a group of the following formula: {(Ο)ΟΙί. Nt" or "function" means a group of chlorine, actin, fluorine or broken. l※土七1·8 alkoxy" means a group of the following formula: c alkoxy group (dental group h 17,1Φ 々 々 插 広 広 広 広 広 · · · · · · · · · · _ _ CN CN CN CN And includes mono- and tri-methyl hydro-hydrogen, a &quot; methyl lactyl, dimethoxy methoxy, latex-murine ethoxy, and the like. 垸oxy_Cl·6 silk group means the following formula Group: -Cw m -1 Soil M3, wherein one or more deuterium atoms may be substituted on the cv6 alkoxy group allowed by the effective valence. ~, effective mussel number 4 "halo-c18 alkyl" The group of the formula (halo) 1-17, and the C, / (tetra) atom of the 1-8 alkyl group in the middle one can be substituted with the effective valence of the alkyl group and includes monofluoromethyl, difluoromethyl Base, 20 dioxyl ethyl and the like. The term "halo-C!-6 alkyl" is used to mean the formula (halo) M3, one of which is a CW-based group of the .-CK6 alkyl group. The above-mentioned tooth atom may be substituted for the effective valence. The term "heterocyclyl 々8 phenotype" means a group of the formula: ' 10 15 6 58 200800919 alkyl-heterocyclyl. The term "heterocyclyl" Base_ρ }ιΧ&gt; alkyl-c(o)- The group "base group" means a group of the following formula: a group of 5 aryl aryl group - 嶋" means a group of the following formula (10) · 8 alkyl group 1 base group - alkyl group means a group of the formula: &amp; _ _ _ aryloxy" means a group of the formula: -0-heteroaryl. 10 is a C8 alkoxy group which is represented by an effective carbon chain atom of the cN8 alkoxy group. a group which may be substituted by one or more hydroxyl groups. The group which is substituted by a group -Cl.8 alkyl group means a group in which an effective carbon chain atom of a Ci-8 alkyl group may be substituted by one or more hydroxyl groups. The term "substituted" means independently replacing one or more hydrogen atoms with a substituent which is tolerated by the effective valence. 15 The term "dependently selected" means that the structural variable is specified in the combination shown. "Group" means an atomic group attached to a bonding group substituent at a position bonded to a bonding group to a core molecule. The atomic group is used to terminate the structural variable. In general, the present invention uses the IUPAC nomenclature. "Form" means that, for the compounds of the present invention, there may be (non-limiting) salts, stereo a form, a tautomer, a crystal, a polymorph, an amorphous, a solvate, a hydrate, an ester, a prodrug or a metabolite. 59 20 200800919 本发=盖:: The form and presence of such compounds Substantially pure substance form: (for the compound of the invention) its spinable mixture, geometric isomers: such as (non-limiting) mirror image isomers, elimination 5 10 15

What is a mixture of isomers (tetra) stereoisomers), a combination of forms, and mixtures thereof. The present invention contemplates that all such compounds of the present invention may be present in a pharmaceutically acceptable manner as described in the "Pharmaceutical" of the compounds of the present invention; Form: The salt form includes acid addition salts which can be formed by mixing the present invention with a solution of the following acids: such as acetic acid, adipic acid, the present acid, carbonic acid, citric acid, anti-daily Diacid, glycolic acid, hydrochloric acid, cis-butene: acid, malonic acid, phosphoric acid, saccharic acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid, and the like. Further, when the compound of the present invention has an acidic atomic group, Suitable salts may include metal salts such as sodium or potassium salts; soil metal salts such as the word or magnesium salts; and salts formed using suitable organic ligands, such as quaternary ammonium salts. Thus, representative salts include The following: acetate, adipate, benzenesulfonate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, calcium, CamSylate (or Camphor sulfonate), carbonate, chlorination , clavulanate, citrate, dihydrochloride, edetate, fumarate, gluconate, glutamate, gluconate, hydrabamine , hydrobromide, hydrochloride, iodide, isethionate, lactate, malate, cis-sebacate, malonic acid 20 200800919 salt, mandelate, methanesulfonate, nitric acid Salt, oleate, pamoate, palmitate, phosphate/dihydrochloride, saccharate, salicylate, stearate, sulfate, succinate, tartrate, toluene Sulfonates, trigas acetates, trifluoroacetates, and the like. Examples of salt forms of representative compounds of the invention include monohydrochloride salts. In any of the processes of the compounds of the invention, it may be required and/or It is desirable to protect sensitive or reactive groups on any of the molecules of interest. This can be achieved by customary protecting groups such as in 10 15 ed JFW McNmie, Plenum Press 1973; and T w & Wuts, ^ll^ , 3r Edition, John Wiley & Sons, 1999. These protecting groups can be used in appropriate subsequent stages Removal by methods known in the art: wood hair n covers all filament form and mixtures thereof. The invention includes various isomers of the compound and mixtures thereof. Pepper isomers are meant to indicate that the compounds have the same composition and You are different in ° and / or chemical properties. In these things, - the physic, but the structure is 昱...: #1 2 and the type is the ability to rotate the plane of polarization (optical isomers). (4) isomers or groups: m isomers means that the same structure is present, and only the isomers of the two diagrams are arranged differently. The value has its direction to turn in different directions. The term "optical rotation::: the degree to which the object will be in the plane of the plane of polarization." 糸There is no optical isomer rotation. The term "racemate" or "disappearance, 曰人 y this mouth" means two mirror images. Iso 20 200800919 Mixtures in which each of the individual materials rotates the plane of polarization in the opposite direction so that the mixture does not have optical rotation. The term "mirrible isomer" means having a mirror that cannot be overlapped = the term "non-mirrored isomer" means a stereoscopic image of a non-image isomer. 10 15 于德Γ# "对掌" is shown in the figure The configuration τ cannot overlap and mirror the molecules. This is different from the non-pairing molecules that can overlap with their mirror image. The two different mirror patterns of the palm of the hand are also called left-handed (left, upper or right-handed (right hand)', which is simply referred to as D, depending on the way of rotating the polarized light:: "R" and "S" A group representing a group of carbon atoms (etc.) surrounding a stereogenic source. The singular form of a palm or non-palm mixing mixture is substantially free of the form of a mirror image molecule. The substantially pure form includes one of the mirror images of the mixture. There is a range of less than 25%, less than 1%, less than 5, or less than 1%. Examples of isolated forms of the fY mixture include right-hand mirror image isomers, wherein the mixture is substantially free L-isomers. In this case, substantially free of the system means that the L-isomer can be less than 25%, less than 10%, less than 5%, less than 2% or low according to the following formula In the range of i %: left-handed %=~~-, It quantity, X100 (right-handed mass) + (left-handed mass) Similarly, examples of isolated forms of non-pivoting mixtures include left-handed mirror-isomers, Wherein the mixture is substantially free of dextrorotatory isomers. As far as 62 20 200800919 is concerned, substantially free of the system The dextrorotatory isomer can be occupied according to the following formula: 25%, less than 10%, less than 5%, less than 2% or less than 1% dry circumference: dextrorotatory %=- (dextrorotatory mass) + (left-handed mass), and "what isomer" means that the substituent atom is different from the carbon-carboniferous double-dense to the ring-burning ring or to the bridged double-ring system. Each key of the key ^ 10 15 20 is spread in the heart, E" configuration, the substituent is relative to carbon · carbon: two I: on the side. In the "Z" configuration, the substituent is opposite to the carbon_石The double bond system is oriented on the same side. The fire state. On the side of the connection: the base _^^; the plane of the sub-base phase of the base is located on the same opposite side. It has a "cis heart and a 'substrate relative to the ring plane Is a heterogeneous descriptor of a compound located in a mixture of the "cis/reverse" and "quot;" trans-types ("R", Γ 「 "D r state and used in the literature.", £" and Z ") means that the atomic group of the compound can be isolated and prepared into individual structures: material: specific synthesis or self-isomeric mixed photoacid (or test) binding display The long-term separation technique includes the use of spin to form optical rotation a (after = free test of each isomer (or free acid), appropriate reaction to palmitic adjuvant crystallization and regeneration of the free base), by means of Indoleamine (subsequently divided into + cents to form an isomer to the ester of each isomer or V...曰曰 or chromatographic separation and removal of the palmitic adjuvant) or use 63 _ 10 15 20 200800919 The chromatographic method separates the isomeric mixture of the intermediate or the final product. Further, the compound of the present invention may have one or more polymorphic or amorphous forms, and the oral form is included in the scope of the present invention. Certain compounds: co-water (ie, hydrates) or general organic solvents (such as organic esters, such as B = and the like) form solvates, which are also encompassed by the present invention. For protein kinases * EGFR m, = 2 = inhibitors of this type, have a low of 5 _ or less at about 25 μΜ or lower, about 15 M ^ human feet, about! μΜ or lower: about ^ - or lower, about coffee or lower or about 〇 1 〇. 5 μΜ or lower, about 0.25 or EC50 (1% (50% inhibition in the range of 50% effective concentration) Concentration) The composition of the compound of the formula (1) and its form, and the preparation of the compound of the formula (1), as the preparation of the product, is as follows: a metabolite form and a form thereof as a protein kinase*^1)^, which is a compound of the formula (1) and a form thereof, which is a form of the egg white hair = enzyme package, and is a form of 64 200800919 for inrt type (1) A compound or a form thereof, wherein the ligand of the nostalgic is labeled 'and wherein - the system is a radioligand selected from the group consisting of those in which the substance is blocked. 5 10 15 20 protein comprising the use of a compound of formula (1) and a form thereof for use as a sputum, such as EGFR, sputum, sacral muscle 2, and the like, such that the protein # kinase functional site and receptor The present invention includes the use of a compound of the formula (1) and a form thereof, which is a composition, a drug or an agent for treating a disease, a disorder or a drug of the neotide. I (d) or an improved kinase-mediated agent. A compound of the formula (1) and a form thereof, which comprises the prodrug of the compound of the formula (I) and a form thereof, a composition, a medicament or a medicament for treating, preventing or ameliorating a kinase; The present invention relates to a chronic or acute protein kinase-mediated disease for treating or preventing the compound of the formula (1), which comprises a prodrug of the compound of the formula (1) and a form thereof. And the method of administering an effective amount of the compound of the formula (1) and a form thereof to the individual, the method of the present invention further comprising administering the compound to the individual. Premedication And its form. The formula (I) further comprises the treatment, prevention or amelioration of a chronic or acute R, HER-i only Leg-2-mediated disease, disorder or condition. 65 200800919 The disease, disorder or condition is associated with increased or unadjusted protein kinase activity, performance or signaling, and the like of the individual. The method of the invention further comprises administering to the individual an effective amount of the formula (1) Its pharmaceutical composition, drug or pharmaceutical form.

In the method of the present invention, the disease, disorder or condition is an individual's E (3FR^enzyme-mediated head or brain cancer, and wherein the compound penetrates the blood brain P early wall. 10 15 20

The method of the invention further comprises treating or damaging and promoting axonal regeneration after brain or spinal cord injury, wherein the compound is EGFR EGFR, and the method comprises the step of treating, preventing or ameliorating the kinase-mediated cytomegalovirus in the individual. Virus infection. A chronic or acute protein kinase mediated disease, disorder, or condition includes, but is not limited to, a disease, disorder, or condition associated with unadjusted kinase activity and a condition concomitant with the activity. The collateral is not = protein, performance, or message transmission" kinase expression or message transmission, increased delivery leads to unregulated cell proliferation, 3) increased kinase signaling, two-cell lean, or 4) mutation leading to compositional kinase activity set. The presence of kinase activity can be determined by methods well known in the art

"Yuwu" is not covered with a steel Μ &gt; A damage to the body (such as mf) means one or more of the multicellular organic 66 10 15 20 200800919 body due to multiple cells, or a longer life expectancy The cell population of the cell population. Tumor cells derived from the proliferation of non-differentiated cells use a number of mechanisms to survive and spread, often with high proliferation rates due to defects in the growth control of normal cells. Many tumor cells secrete autologous growth, or increase the growth rate of other cells secreted by the cells, and the growth and spread of tumor cells by the movement of the tumor. The matrix diffuses in response to the movement factor, allowing it to preferentially move to a specific tissue that is attached to a new site and grows. This affects the residual tumor of the tumor::: The lethality of the tumor. Kinase inhibitors can not be molded by kinase inhibitors;:: This can be used for treatment. Or knowing or not yet clearing the special tumor residual mechanism, but it can still be used for treatment by affecting tumor residual by the mechanism. Or change the second = indication = substance or its form can be used to treat, prevent rheumatoid arthritis, intermediate C, brother production ° (unrestricted) osteoarthritis, myasthenia gravis, diabetes,: urinary disease, • ulceration Colitis, osteointestinal disease, Crohn's disease (c_ns lupus, chronic pancreatitis, sub-disease: 7, transplant or (4) transplant rejection, differentiated skin disease or disease: disease; pivot: ; disease: in the brain or spinal cord injury Post-neural; bad = sudden: = sexual condition or condition, acute or slow, exhibition and glazed degeneration related diseases, lung or lung disease or kidney disease 1 disease, viral infection, heart 67 200800919 chronic cancer, selected From bladder cancer, brain ''including (non-restrictive): acute or colorectal cancer, endometrial fistula cancer, breast cancer, knot 5 10 15 20 Kaposi's meat-like cancer; and 盥痗广古关), leukemia, lymphoma or nipple cells are mutated. Abnormal cell proliferation, unregulated, broad a#, growth, tumor vascular disease, tumor angiogenesis, stagnation or metastatic cancer cell invasion and movement. Progressive or disease progression includes (non-restrictive): fiber-enhanced skin disease or The condition is selected from the group consisting of papilloma formation, psoriasis dermatitis, wet therapy, seborrhea or chemotherapy-induced perfusion; medium ==, selected from Alzheimer's disease (Alzhei Saki, s dise), or glaucoma Viral infection, selected from fungal infections, from 2 2 = cytomegalovirus; heart disease '€ from arteriosclerosis, neovascular vascular disease, such as arterial restenosis; lung or sexual obstruction: pulmonary sensitivity, pulmonary fibrosis , pulmonary fibrosis or chronic ":?: kidney or kidney disease, selected from acute, subacute or slow sclerosing or membrane proliferative glomerulonephritis, glomerular dysplasia, congenital polycystic kidney Dysplasia or f-fibrosis. Cancer, two-kinase-mediated cancer includes (non-restricted) bladder: ;: / or neck cancer, breast cancer, cervical cancer, colorectal cancer, Teng: two:: tumor : Cancer, endometrial cancer, esophageal cancer, lung cancer, Indian cancer, urinary urea or renal cell carcinoma. 68 200800919 Endometrial cancer, esophageal cancer:;, cancer, ,,,,,,,,,,,,,,,,,,, Gas, lung cancer, nest cancer, prostate cancer or kidney. "Table-based diseases without the use of a compound of formula ⑴ syndrome or anti embodiment of the present invention, the specific condition: Ϊ enclosed within the scope of the present invention, only for those not specifically disclosed for the compounds of Patent piece goods. _ Λ Λ Λ 方法 方法 在 在 在 在 在 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法 方法The combination form is administered at the same time. Sexual t: two prodrugs means a form of a compound of formula (1) or a form thereof which can be converted into a therapeutic biological activity: "what organism, wherein the converted form can be: 1) a form of relative activity; 2) a form that is relatively inert; 3) a form of relative activity; or 4) any form that is directly or indirectly derived from transformation in the body. When the compound may be too toxic to be administered systemically, digestive tract, ... The prodrug can be used when it is destroyed by the body before reaching the destination. The method for selecting the appropriate pre-drug derivative is described, for example, in ed. H. Bundgaard, Elsevier, 1985 〇. The term "metabolite" is used to mean A prodrug form of a compound of formula (1) or a form thereof that is converted to a less active functional derivative of the compound by in vivo metabolism or metabolic processes. &gt; The term "individual" in the context of the present invention means a patient, such as an animal, a gift or a human, which is the target of treatment, observation or experiment and is at (or easy to) 69 20 200800919 development related to unadjusted kinase activity The disease or condition is at risk of having the disease or condition. The term "effective amount" means an amount of a compound of formula (1) or a form, pharmaceutical composition, medicament or agent thereof that produces a biological or medical response (such as inhibition of activation of unadjusted kinase activity) in a tissue system, animal or human, It is sought by researchers, veterinarians, doctors, or other clinical personnel, including symptomatic relief of the disease or condition being treated. ^ The effective amount of the compound is from about 0.001 mg/kg/day to about 300 mg/kg/曰. A "mineral composition" means a product containing a compound of the formula (1) or a form thereof, such as a product comprising a specific amount of a specific component, and any product which directly or indirectly combines a specific component from a specific amount. 15 Technique: "Pharmaceutical" or "drug" means a compound containing formula (1) or a table ‘ . The invention includes the use of such an agent for the treatment, prevention or treatment of a disease, disorder or condition mediated by an acute or acute kinase. Sufficient to indicate that the molecule itself and the composition are of a quality, and that no negative or allergic occurs when the purity of the drug or drug is properly applied or the other is not. Veterinary use "samples: including human use (clinical and over-the-counter use) and including the scope of the invention, pharmaceutically acceptable::: Π: way of medicine, pharmaceutical composition, drugs" Correction: not included ( a compound, or a form thereof, for use in treating, pre-treating, a combination of products of a therapeutic agent that causes a 'γ 忮 Q 忮 or acute protein kinase mediated 70 200800919 disease, disorder, or condition. Protein ί and r, f combined products for the treatment, prevention or improvement of chronic or acute = treatment, prevention or improvement of the disease = = = = amount of any kind or two compounds or therapeutic agents before the administration of the drug Or afterwards the drug is administered to the individual. Chemotherapy is called iL, and it is not used to treat cytomegalovirus antiviral agents for the treatment of kinase-mediated cancer. The chemotherapeutic agent includes 10 permanent:: a generator, an antitumor agent, a cytotoxic agent, P 1 4 for cell proliferation, radiation therapy, and the like or a combination thereof. "Traditional therapy, prevention or improvement" means that (unrestricted) helps to eliminate, enter into the course of an acute kinase-mediated disease, disorder or condition, or to induce radiation therapy. Are the individuals in need exposed to the body? Therapy. The present invention includes a method of administering a compound of the formula (1) or a form thereof, a sputum, a drug, a drug, or an agent in combination with radiation therapy. The procedure for administering this therapy is known to those skilled in the art. The appropriateness of radiation therapy is as if it has been used in clinical therapy, where radiation therapy is used alone or in combination with other chemotherapeutic agents. 20. The invention includes a pharmaceutical composition comprising a compound of formula (1) or a blend thereof in one form with one or more pharmaceutically acceptable excipients. The invention includes a method of making a pharmaceutical composition, medicament or medicament comprising mixing a compound of formula (I) or a form thereof, and optionally a pharmaceutically acceptable carrier. The invention includes a pharmaceutical composition, medicament or medicament 71 200800919 which is formed by a method of mixing a compound of formula (i) or a form thereof, and optionally an acceptable carrier. Period # - Articles and non-study (four) learning techniques. The method of making the method (4) includes the practice that the pharmaceutical composition, drug or agent may take various forms: the model includes (and is not limited to) intravenous (four) 10 15 Han r tendon, intratumor, intracerebral Or cranial meat, main body _, product, drug or medicament may be a dosage form for use in such a mode of administration: , and, tablets, pills, capsules, powders, granules, sterile parenteral suspension = , metered aerosol or liquid spray, automatic ejector device or tester's sputum, product, music or pharmaceutical system including solids, tablets, capsules (including immediate release, time-sharing release: type Formulations, granules and powders; and liquid tank forms = two emulsions and suspensions. Forms for parenteral administration = gluten, emulsions and suspensions. Or the pharmaceutical composition, drug or music (4) may be suitable a form that is administered once a week or every month; for example, a live (4) salt can be used to provide intramuscular injection&gt;, 2 a dosage form of the pharmaceutical composition, drug or medicament (tablet, gel injection, suppository, Teaspoon and the like) contain an effective amount of pre-preventive effect Active ingredient. The pharmaceutical composition,

Lr to Le can contain from about 0.001 mg to about 5 mg (preferably about, ', 500 pg) of the compound of formula (1) or its form and can be adapted to suit the mode of administration for the individual in need thereof. Form. ',, ' 72 20 200800919 The expected effective amount of the pharmaceutical composition, medicament or medicament of the present invention is, == about 3. . Within the range of mg/kg body weight/曰. Another example = the distance range may be from about 0.003 to about 100 mg/kg body weight per day from about _ to about 15 mg/kg body weight/twist.匕 = drug or agent can be administered from about 1 to about 5 times per sputum: especially by oral administration, S, the pharmaceutical composition, f5tV, H〇°·01'0*05' 0 0 10 is: In the form of sputum sputum, it is possible to use the mode of administration of sputum and sputum in the treatment of severe sputum treatment according to the symptom, and:::::: The treatment method and pharmaceutical composition, drug or The compound or its form includes a group selected from the group consisting of (5-Fanta-4-amino group, 6 ♦ gas, 4 gas, phenylamine, acetal, aldehyde, aldehyde, aldehyde, aldehyde, aldehyde, aldehyde, aldehyde, aldehyde, aldehyde, aldehyde, aldehyde, aldehyde Amino-6Κ3 Icarboxaldehyde oxime-fluorenyl 肟, (5-5)-4-amino i[3-chloro-5-carbaldehyde oxime-fluorenyl _ _ _ _ fluoro-benzyl)-1 Η-carbazole 5-ylamino]-pyrimidine 4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine 73 200800919 (5-5)-4-amino-6-(3-decyloxy- 4-phenoxy-phenylamino)pyrimidine-5-formaldehyde 0-methyl-yl-indole, (5-5)-4-amino- 6-(4-+-yloxy-3-chloro-phenyl Amino-deny-5-formic acid: 〇-fluorenyl·month-deficient, (5-5)-4-amino-6-[1-(3-fluoro-nodoxy)-m-indazol-5-ylamine Pyrimidine-5-nonanal oxime-ethyl-oxime, (5£)-4-amino-7-[1-(3-fluoro-octyl)-111-, 嗤-5-yl Base]-mouth 唆, -5 - 曱 〇 烤 - roasted propyl _ month deficiencies, (5 5)-4-amino-6-[1-(3-fluoro-indolyl)·1 Η-carbazole-5 -ylamino]-pyrimidin-5-furald oxime-t-butyl-hydrazine, (5Ε)-4-amino-6-[(lS)-l-phenyl-ethylamino] -曱盘(1) Ethyl-moon loss, (5-5)-4-amino-6-(1Η_弓卜朵_5·ylamino)-mouth bite _5曱 〇-ethyl-month loss , 10(5五)_4_Amino-6_[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-indole-ethyl-moon loss, (5£)-4-amino-6-[l-(3-fluoro-benzyl)-1Η-carbazole-5-ylamino]•pyrimidine-5-曱曱·(2-? Lin-4-yl-ethyl)-month-deficient, (5Ε)-4-amino-6-(4-phenoxy-phenylamino)_唆唆巧_曱搭〇_曱基-月亏, 74 200800919 (5 5)-4-Amino-6·(4-Pheptyloxy-phenylamino) "Bite bite 〇 甲基 _ methyl-month loss" (5£)·4_Amino- 6-[l-(3-fluoroH)-1HH5-ylamino]] 唆-5-furfural 0-isobutyl-hydrazine, (5-5)-4-amino-6-[l-(3 - gas-based) -111-, salino-5-ylamino]" dense. dimethyl-5-furfural 0-(2-phenoxy-ethyl)-indole, (5-5)-4-amino-6 ·[3_氯_4_( 口比基基曱oxy)_phenylamino]_ Isopyridine-5-furfural 0-mercapto-purine, (5£)-4-amino-6-[1-(3-fluoro-aryl)-1Η-decylamino]bit-5 -furfural 0-ethyl-hydrazine, (5-5)-4.amino-6_[1-(3-indolyl-indenyl)-1Η-吲u-d-5-ylamino]-pyrimidine- 5-furfural 0-methyl-hydrazine, (5-5)-4-amino-6-(3-di-phenylamino π-decanoic acid 〇-曱-肟-, # (5£)-' Amino-6-(4-benzyloxy-3_a-phenylamino)-pyrimidine_5_furfural oxime-ethyl-moon-deficient (5-5)-4-amino-6-[ 3-chloro-4-(pyridin-3-yloxy)-phenylamino]-pyrimidine-5-furfural 0-fluorenyl-hydrazine, (5-5)-4-amino-6-[l- (3-Fluorobenzyl)_1H_indazole_5-gastriaminopyrimidine-5-indole 0-(4-decyloxy-indolyl)-fat, 75 200800919 (5-5)-4-amino -6·[1-(3-敦_ +基基)_m "引瓦基基基基]• Mouthidine-5-furald oxime-(2-methoxy-benzyl)·monthly loss, (5 five )-4-amino-6-[l-(3-fluoro-indolyl azole-5-ylamino) ♦-5-carboxylic acid oxime-segment group·monthly loss, (5-5)-4•amine 6·[1-(3-Fluoro)·1Η"Azozolylamino-p-pyridin-5-carboxamidine-isopropyl-indole, (5-5)-4-amino-6-(1 -benzyl-1Η-carbazole-5-ylamino)pyrimidine-formaldehyde' fluorenyl-hydrazine (5-5)-4-Amino-6-(1-benzyl-1Η-indazole-5-ylamino)-pyrimidinecarboxaldehyde 0-ethyl-moon-deficient, 3-{5-[6-amino group -(5-5)-5-(methoxyimino-indenyl)pyrimidin-4-ylamino]pyran-1-ylmethyl}•octonitrile, 3-{5-[6-amino group -(5-5)-5-(ethoxyimine-methyl) "Midine 4-amino group]----------------------- -6-Π-(3'-gas 4 yl)-1H prasin-5-ylamino]] 密-5-aldehyde oxime-methyl-hydrazine, (5 quinone·amino-6-[1 -(3- gas fluorenyl)]^ azole _5: arylamino group] "Misquito-5-formaldehyde oxime-ethyl-oxime, (5-5)-4-amino-6-[2-(3 -fluoro-benzyl)~1Η-benzimidazole_5-ylaminopyrimidine-5-furfural 0-ethyl·肟, 76 200800919 (5£)·4-amino- 6·(3-chloro- Phenylamino 唆_5·甲甲曱基_月亏' (5五)-4-amino-6-[2-(3· It-+)- 1Η-benzo-α-ηη-5 -aminoamino]-pyrimidine-5-furfural 0-mercapto-purine, (5-5)-4-amino-6-[ 1-(3-fluoro-benzyl)-1Η-oral sputum-5 -ylamino]^ 密口定-5-formaldehyde 0-phenyl-indole, (5-5)-4-amino-6-[1-(3-fluoro-n-carbazole-5-ylamino) -pyrimidine&gt; -5-furfural 0-(2-methoxy-ethyl)-indole, (5Z)-4-amino-6-[ 1-(3-Fluoro-octyl)-1Η"Thrazole_5.ylamino]pyrimidine-5-decanoic acid 0-(3-propanyl-propyl)-moon loss, (5-5)-4- Amino-6-[1-(3-fluoro-+yl)-111-carbazole-5-ylamino]-pyrimidine-5-carbaldehyde 0-(3-didecylamino-propyl)-oxime , (5-5)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)&gt;pyrimidine-5-nonanal 0-(2-methoxy-ethyl)-肟, _ (5 5)·4·Amino-6-indole-(3-fluoro-benzyl)-2,3-dihydro-1H-indol-5-ylamino]•pyrimidine-5-曱Aldehyde 0-fluorenyl-hydrazine, (5-5)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy) phenylamino]pyrimidine-5-carboxylic acid -(3-carbyl-propyl)-monthly loss, (5-5)-4-amino-6-(4-octyloxy-3-chloro-phenylamino)-pyrimidinecarboxaldehyde 0-(3 -transcarbyl-propyl)-monthly loss, 77 200800919 (5-5)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-formaldehyde, (5-5)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine_5-formaldehyde 0 - (2 · phlophine π-lin-4-yl-ethyl Base)-month loss, ♦ (5-5)-4-amino-6-(4-benzyloxy_3.chloro-phenylamino)pyrimidinecarboxaldehyde (9-(2-) 4-yl-ethyl)-lunol hydrochloride, (5£)-4-amino-6-[3- -4_(3j; oxy)-phenylamino]•心定-5 -曱月月亏' (10)-4-Amino-6-[Η3-Fluorosin-5-ylamino]+ 5-formaldehyde oxime, __4_amine-based winter [H3_fluoroyl)_1Η^5·ylamine bromide-5-indole 0-(3-propionyl-propyl)-month-deficient, (5-anthranamine Radix [H3|MHh, salivation _5.ylamino]·-5-furfural 0-(3-morpholine_4_yl-propyl)_yield, mouth-nosed-5-ylamino ]-- u定(5五)-4-Amino-6-[l-(3-fluoro-aryl)_ι only... -5-formaldehyde oxime, towyl-HH3-fluoro- gekib this + Dicamide-5-formaldehyde 〇·(3-hydroxypropyl)_肟, soil makeup soil J hawthorn (5 external 4-amino-HH3·fluoroanthryl)_1Η^5_ylamino]_feeding -5-Meta 0·(3·hexahydropurine small base_propyl)·monthly loss, 78 200800919 (5£)-4-amino-6-[3-chloro-4-(3-fluoro- Benzyloxy)-phenylamino]-pyrimidine-5-purine 0 - (2 · morphine sulphate-4 -yl-ethyl)-moon-deficient (5-5)-4-amino-6 -[3 gastric chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine-5-methyl-2-(2-hexazone σ ratio-1 -yl-ethyl) -month-deficient '(5-5)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine-5-carboxaldehyde oxime - (2 - six squirrels -1 - base-b )-月月夫(5-5)-4-Amino-6-[1-(3.fluoro-benzyl)-1Η-oxazol-5-ylamino]-pyrimidine, -5 -曱路0 - (2 - six rat ° ratio σ set -1 - base - ethyl) - monthly loss, (5 5)-4-aminochloro-4·(3,5·difluoro-benzyloxy)·phenyl Amino]-pyrimidine-5-furfural 0-fluorenyl-hydrazine, (5-5)·4-amino group·6-[3- gas- 4·(3,5-di-halo-yloxy)- Phenylamino]-pyrimidine-5-furald oxime, (5jE)-4-amino-6-[3-chloro-4_(3,5-dioxa-decyloxy)-phenylamino] _. dense.定-5 - 曱藤Ο - (2 · 咐福咐-4 -yl-ethyl)-月亏' (5-5)-4-amino- 6- [(lS)-l-phenyl-ethyl Amino]·Miao Bite-5-曱路月亏' (5-5)-4-Amino-6-[l-(3-fluoro-benzyl)-1Η-吲哚-5-ylamino]- Pyrimidine-5-ruthenate bismuth - (2-ifu.lin-4-yl-ethyl)_月亏' (5-5)-4-amino-6-[l-(3-fluoro-benzyl) ·1Η-吲哚-5-ylamino]-pyrimidine-5-曱-Ο - (2 - six mouse bites-1-yl-ethyl)-month-deficient '(5-5)-4-amino- 6-(4-Benzyloxy-3-chloro-phenylamino)-pyrimidine-5-furfural oxime - (3-Isofolin-4-yl-propyl)-monthly loss 79 200800919 (10) 4-Amino_6_(4_γ-yloxy_3_gas_phenylindole-[3|methoxy-ethylamino)-propyl]_月亏, or) Hawthorn 5~甲骏4 -Amino-6-(4-octyloxy_3_chloro-phenylamino)-feeding. Fixed·$• guess. [Embodiment] Synthesis method

Representative compounds of the invention can be synthesized according to the following description and are described in more detail in the specific synthesis examples below. Section - 』 = The process and material examples are for illustrative purposes; the invention should not;; the chemical reactions and conditions. Description Unless otherwise stated, the materials and intermediates used in the flowcharts and examples are stupid and prepared by methods known to those skilled in the art. None of the #10 reactions attempted to optimize the yield. Those skilled in the art also increase the yield via materials, solvents, reagents, reaction conditions, and the like. 4 &lt;Example tampering &gt; The compound of the present invention may also be used as an intermediate to be converted to other compounds representing the present invention via a functional group. 15 • DSC analysis was performed on a TA Instruments Q100. The calibration standard is surrounded by indium. The sample (approx. 2 mg) was placed in a TA DSC weighing pan and recorded for re-use of the crimped disc for analysis. The sample was heated to a final temperature of 25 Torr at a rate of 1 Torr in nitrogen (5 〇 ml/min). c. The data was processed using a thermal analyzer (Universal Analyzer 2000, ta Instruments). 20 The terminology used in the description of the present invention is generally known to those skilled in the art using 200800919. The following abbreviations used in the present invention have the indicated meanings: cPd compound dichloromethane N,N-monomethylformamide - methyl sulphate ethyl acetate hour/minute

DCM DMF DMSO EtOAc hr(s)/min(s) LCMS Rt RT/rt/r.t. tea or Et3N High Pressure Liquid Chromatography Mass Spectrometry Retention Time Room Temperature Triethylamine

Flowchart A

Compound Ai &gt;~ one) reacts with appropriate gas in a suitable solvent such as f benzene and the like A2 under conditions, to produce a compound

81 200800919 Compound A2 (a mixture with an chelating agent such as triethylamine and the like in a suitable solvent such as DMSO and the like) is reacted with compound A3 to produce compound A4.

i ::::A4 (reacted in the appropriate solvents ~DMS〇 &amp;such ice-likes react with NH20H hydrochloride to produce hydrazine) = representative of the substance. Formula (1) compound

Compound A5 (in a suitable solvent such as 1), a pharmaceutically acceptable reagent (such as a carbonic acid, and the like) and a compound = a member, are de-bonded, such as a tooth atom and a compound A7, a representative of the compound of formula W. This latter) reaction, produced 82 10 200800919

A solution of δA7 (in a suitable solvent such as swollen and the like) is reacted with compound 4, A8 (the towel Q2 is a cleavage group such as a functional atom and the like) to produce compound A9, formula (I) Representative of the compound.

R2, nh

AID ^ The compound of formula (I) is metabolized to give a representative of compound A10, a compound of formula (1).

Flowchart B

83 200800919 A mixture of compound B1 (in a suitable solvent such as THF and the like) and a reagent such as triethylamine and the like is reacted with compound A3 to yield compound B2.

Reaction of a suspension of compound B2 in N(R2)H2 (in a suitable solvent such as MeOH and the like) yields compound B3, a representative of the compound of formula (I). Example 1 10 (5-5)-4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-mouth °-5-A to (9-(2-? °Lin-4-yl-ethyl)-monthly loss (compound 78)

NH3 (g) a solution of 4,6-dichloro-pyrimidine-5-furfural compound la (50 g, 282.5 mmol) in toluene (565 ml, 0.5 M) 15 using a 12C glass frit. After 3 mins, the mixture was warmed at 60 °C under stirring. 30 mii^NH3 (g) The second blowing was passed through the reaction mixture over 3 min 84 200800919 and the reaction was heated for 30 mins. The third blow of NH3 (g) was passed through the reaction mixture for 3 min and the reaction was heated for the last 20 mins. The reaction mixture was diluted with H.sub.2 (1 L) and EtOAc (EtOAc (EtOAc) The organic extract was washed with brine (4×) and dried (Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.). NMR (300 MHz, DMSO-m) δ 10.27 (s, 1H), 8·74 (br s5 1 Η), 8·58 (br s, 1 Η), 8·42 (s, 1 Η) 〇

10

4-Benzyloxy-3-chloro-phenylamine compound (8.9 g, 38 mmol) added to compound lb (6.0 g, 38 mmol) and Et3N (10.6 mL, 76 Mole) in DMSO (38 ml, 1 M) in solution. The mixture was warmed at 100 QC for 3 hrs. The reaction mixture was cooled, then diluted with EtOAc (EtOAc) The organic extract was washed with EtOAc (4×), EtOAc (EtOAc) 4-Amino-6-(4-carbyloxy-3-chloro-phenylamino)H5-Methylamine U (8.29 g, 61%) as a yellow solid.屯NMR (400 MHz, CD30D, temperature) δ 10.15 (s, 1H), 8.05 (s, 1H), 7.77 (d, J 2·4 Ηζ, 1 Η), 7·48 (d, J =: 7· 6 Ηζ, 2 Η), 7·38 (m, 85 15 200800919 4H), 7·11 (d, J 2.8 Hz, 1H), 5.18, (s, 2H) 〇

A solution of compound Id (3.98 g, 10.9 mmol) and NH20H hydrochloride (3. 02 g, 43.6 mmol) was warmed in DSMO at 90 °C for 4 hours. The reaction mixture was cooled with EtOAc (EtOAc)EtOAc. The combined organic extracts were washed with H20 (4×) then dried (Na.sub.2SO.sub.4) and concentrated on EtOAc (12 g). The residue was purified by column chromatography ( Horizon 65+, 70 to 100%EtOAc /hexane) to afford 4-amino-6-(4-benzyloxy-3-chloro-phenylamino)-pyrimidine- 5-nonanal oxime compound le (2.65 g (66%) ίο yellow solid. 1H NMR (300 MHz, DMSO-m) δ 11.26 (s, 1H), ' 9,82 (s, 1 Η), 8.64 (s ,1Η),8.03 (s,1Η),7.81 (d,J = 2·4 Ηζ, 1H), 7·45 (m,6H), 7:23 (m,3H),5·20 (s,2H) ) 86 200800919

4-(2-Chloro-ethyl)·Foufodine hydrochloride (1·6 g, 8·9 mmol) was added to compound le (3.3 g, 8.9 mmol) and carbonic acid planer (8.6 Gram, 26.7 g) in a suspension in DMF (90 mL, 0.1 Μ). The mixture was warmed at 5 〇 〇 c 5 for 6 hrs. The reaction mixture was cooled, then diluted with EtOAc & EtOAc (EtOAc). The combined organic extracts were washed with Η &quot; (4 χ), dried (NajO4) and concentrated on Si〇2 (12 g). The residue was purified by column chromatography (Horizon 4 Ό + Μ, 0-6% MeOH / DCM) to yield compound 78

(3.58 g, 83%) of a yellow solid. hNMRpOOMI^DMSO-M) 10 δ 9.60 (s,m),8·72 (s,1H),8·03 (s,1H),7·83 (d,J = 2·7 Hz, 1Η),7 ·49-7·39 (m,6Η),7·28 (s,2Η),7·18 (d,Bu 9·0 Ηζ,1Η), 5·20 (s,2Η),4·30 (t , J = 5·6 Ηζ, 2Η), 3·58 (m, 4Η), 2·6ό (t, J 2·5 6, 2Η), 2·47 (m, 4Η); MS (ESI) m /z 383 (ΜΗ+) ; DSC temperature record: At 175 〇C, there is a single endothermic wave 15 due to melting. The maximum temperature is 174.66 CC and 176.28 0C, respectively, and 142.9 87 • 200800919 J/g. Compound 78 is further conjugated to monohydrochloride HCl to give the monohydrochloride salt of compound 78. 4 NMR (300 MHz, DMSO·) δ 10.78 (br s, 1H), 9·52 (s, 1Η), 8·79 (s, 1Η), 8·06 (s5 1Η), 7·84 (d , J = 5 2.7 Hz, 1 H), 7.51-7.19 (m, 9 H), 7.20 (d, J = 9 Hz, 1H), 5·22 (s, 2H), 4·56 (br s, 2 H), 4·03·3·82 (m, 4H), 3·58-3·18 (m, 13H); analytical calculation C24H28C12N603: C, 55.50; H, 5·43; N, _ 16·18 ; C1, 13.65; Experimental values: C, 55·08; H, 5.41; N, 15.94;

Cl, 13.17 〇 10 Using the method of Example 1, other representative compounds of the invention were prepared:

Cpd name and data 1 (5) _4-amino chloride _4_fluoro-phenylamino; l. pyrimidine-5-formaldehyde 〇 曱 _ _ monthly loss H NMR (DMSO- must) δ 9.68 (br, 1H), 8.71 (br 1H) 8·〇6 (S, 1H), 7·99 (dd, J = 6.78 and 2.80 Hz, 1Η), 7·, 49 • (m5 1H)? 7.35 ( Br5 2H)? 7.34 (m9 1H)5 3.96 (s? 3H). LC-MS Rt = 1.08 min? m/z 296.3 (MH+) 88 200800919

Cpd name and data 2 (5-5)-4-amino-6-[l-(3-fluoro-benzyl)_1Η-indazol-5-ylamino]-pyrimidine_5_furfural 0-methyl - NMR (DMSO, δ 9·75 (s, 1H), 8.73 (s, 1H), 8.09 (t, J = 0·86 Ηζ, 1 Η), 8.06 (d, J = 1.86 Ηζ, 1Η), 8·00 (s, 1H), 7·64 (d, J = 9·07 Hz, 1H), 7·44 (dd, J = 8·88 and 1.93 Hz, 1H), 7.34 ( m,1H), 7.21 (s, 2H), 7·09 (m,

I 1H), 7.04 (m, 2H), 5·67 (s, 2H), 3.95 (s, 3H)· LC-MS

Rt = 1.19 min, m/z 392·4 (MH+) 3 (5£)-4-amino-6-(3-chloro-4-d-octylamino)-, π-but-5-methyl 〇-Methyl-肟MS m/z 310.1 (MH+) 4 (5-5)-4-amino-6-[3_chloro-4-(3-fluoro-benzyloxy)-phenylamino] _ pyrimidine-5-formaldehyde 0-fluorenyl-indole 1h NMR (CD3OD) δ 8·56 (s, 1H), 7·96 (s, 1H), 7.68 (d, J = 2·50 Ηζ, 1Η), 7·39 (td, J = 7·98 and 5.58 Ηζ, 1Η), 7·28 (dd, J = 8·85 and 2.61 Ηζ, 2 Η), 7·23 (m, 1 Η), 7· 08 (d, J = 8·92 Ηζ, 1Η), 7·〇2 (m, 1Η), 5·18 (s, 2Η), 3·98 (s, 3Η)· LC-MS Rt = 1.41 min, m/ζ 402·1 (ΜΗ+) 89 200800919

Cpd name and data 5 (5 5)-4-amino-6-[2-(3-1 ·octyl)-2Η-, 嗤-5-ylamino] hydrazide _5_formaldehyde 0-fluorenyl -肟lU NMR (CDC13) δ 9.60 (s, 1H)5 8.34 (d? J = 0.50 Hz, 1H), 8·18 (s, 1H), 8·03 (dd, J = 1.83 and 〇·45 Hz , 1H), 7·91 (br, 1H), 7.71 (dd, J = 9·20 and 0·65 Hz, 1H), 7·31 (m, 1H), 7·23 (m, 1H), 7 ·02 (dd, J = 7.88 and 1.96 Hz, I 2H), 6.96 (m, 1H), 5·72 (br, 2H), 5.58 (s, 2H), 4·03 (s , 3H)· LC-MS Rt = 1.12 min, m/z 392·2 (MH+) 6 (5-5)-4-amino-6-[1·(3-fluoro-benzyl)-lH-carbazole _5-ylamino]-pyrimidine-5-furaldehyde aldehyde 0-(2-morphol-4-yl-2-keto-ethyl)-oxime NMR (CD3OD) δ 8.73 (s, 1H), 8.13 (d, J 〇 · 92 Hz, 1H), 8·12 (s, 1H), 7.94 (dd, J = 1.91 and 〇·66 Hz, 1H), 7·63 (d, J = 9 · 0 Hz, 1H), 7·44 (dd, J = 8·92 and 1.97 Hz, 1Η), 7·32 (dt, J = 7.98 and 5.75 Hz, 1H), 7·02 (m , 2H), Lu 6·89 (dt, J = 9.66 and 1.79 Hz, 1H), 5·69 (s, 2H), 5·00 (s, 2H), 3·67 (t, J = 4·52 Hz, 2H), 3·60 (m5 4H) 3 · 53 (t, J = 4 · 85 Hz, 2H) · LC-MS Rt = 1 · 00 min, m / z 505 · 1 (MH +) .200800919

Cpd designation and data - amidino-6-(3-decyloxy-4-phenoxy-benzaldehyde oxime-methyl-肟iH NMR (CDC13) δ 9.40 (s, 1H), 8.30 (s, 1 Η) ,8·22 (s, 1Η), 7·51 (t, J = 1.24 Ηζ, 1Η), 7·29 (m, 2Η), 7·03 (tt, J = 7.31 and 1.11 Hz, 1H),6·96 (m,4H),5·36 (s,2H), 4.03 (s,3H),3,86 (s,3H)· LC-MS Rt 2·27 min,m/z 366.1 (MH+) 8 (5E)-4-Amino-6-(3-decyloxy-4-phenoxy-phenylamino)-pyrimidine-5-decanoic acid 0-(2-? 4·yl-2-mercapto-ethyl)-monthly NMR (CDC13) δ 9·33 (br,1H), 8.46 (s,1H), 8.22 (s, 1H), 7·49 (d, J = 2·49 Hz, 1H), 7.28 (td, J = 7.44 and 1·23 Hz, 2H), 7·13 (dd, J = 8.68 and 2.46 Hz, 1H), 7·03 (tt, J 2.34 and 1.07 Hz, 1Η), 6.95 (m, 3H), 5·50 (br, 2H), 4.84 (s, 2H), 3.88 (s, 3H), 3.68 (t, J = 4.80 Hz, 2H), 3·64 (4H), 3.53 (t, J = 4·80 Hz, 2H)· LC-MS Rt = 1·06 min, m/z 379·2 (MH+ ) 91 200800919

Cpd name and data 9 (5 5)·4 -amino- 6-(4-fluorenyloxy-3-gas-phenylamino)-ΐJ-succinyl-5-formaldehyde 0-fluorenyl-ruthenium NMR (CDC13) δ 9·34 (s, 1Η), 8.27 (s, 1Η), 8·18 (s, 1Η), 7.66 (d, J = 2·60 Ηζ, 1Η), 7·46 (m , 2Η), 7·32, 7·42 (4Η), 6·94 (d, J = 8·87 Hz, 1 Η), 5·33 (br, 2Η), 5·16 (s, 2Η), 4·01 (s,3Η). LC-MS Rt = 1·4Ό min, I m/z 384.1 (ΜΗ+) 10 (5£)·4-Amino-6-[1-(3-fluoro-benzyl) Base)-1Η-oxazol-5-ylamino]-pyrimidine·5 -曱Ο-ethyl-monthly NMR (CDC13) δ 10.39 (s,1H), 8.42 (s,1H),8· 10 (m, 1Η), 8·08 (s, 1Η), 7·89 (s, 1Η), 7·35 (d, J = 1.3 Ηζ, 1H), 7·24-7·33 (4H), 6·83-7·01 (3H),5·60 (s,2H), 4.28 (q,J 2·7·06 Hz, 2H), 1.37 (t, J 27.04 Hz, 3H)· LC-MS Rt = 1.27 min, m/z 406.1 (MH+) 92 200800919

Cpd name and data 11 (5Ε)·4-amino-6-[l-(3-fluoro-benzyl)-m·carbazole·5·ylamino]-pyrimidine-5-carboxamoxime-allyl -肟NMR (CDC13) δ 9·52 (br,1Η), 8.36 (s,1Η),8·17 (s, 1Η),8·04 (d,J = 0·88 Ηζ,1Η),7· 97 (m,1Η),7·41 (dd, J = 9.05 and 2.1 Hz, 1H), 7·23-7·32 (2H), 6·83-6·98 (3Η), 6.06 (m ,1Η),5.58 (s,2Η),5·45 (br,2Η),5·39, (dq,J=17·29 and 1.52 Hz,1H),5.31 (m,1H),4· 69 (dt, J = 5·98 and 1·35 Hz, 2H). LC-MS Rt = 1.32 min, m/z 418.1 (MH+) 12 (5-5)-4-amino- 6-[l-( 3-fluoro-indenyl)-1H-,salt-5-ylamino]-m-pyridine-5-furaldehyde- 0-t-butyl-slip NMR (CDC13) δ 8·30 (s,1H) , 8.18 (s, 1H), 8·04 (m, 1Η), 8·00 (m, 1Η), 7·21-7·36 (4Η), 6.84-6·98 (3Η), 5.58 ( s,2H),1.41 (s,9H)· LC-MS Rt is called ·45 min,m/zw 434.1 (MH+) 93 200800919

Cpd name and data 13 (5-5)-4-amino-6-[3_mercapto-4-(pyridine-3-yloxy)-phenylamimidyl]-pyrimidine-5-furaldehyde 0-methyl -肟&amp; 4 NMR (CDC13) δ 9·42 (br,1H) A36 (10),:=2 81 and 0·60 Hz, 1H), 8·31 (dd, Bu 4·41 and h6, 1H ), 8 3〇(s,1H),8·20 (s,1H),7·48 (d,J = 2·37 Hz,m),^4〇(dd, J = 8·64 and 2· 74 Hz, 1H), 7·23 (ddd, Bu 8·39, _ 4.37, and 0.80 Hz, 1H), 7· 17 (ddd, J = 8.40, 2 75 and 1 65

Hz, 1H), 6.93 (d, J = 8·68 Hz, 1H), 5·45 (br, 2H), 4·〇〇(s, 3H), 2·24 (s, 3H)· LC -MS Rt ; ······· Ο-ethyl-month-loss NMR (CDC13) δ 8·24 (s,1Η), 8.09 (s,1Η),7·71 (d, J = 6·85 Ηζ,1Η), 7.31-7.38 (3Η) ,7·22-7·28 (2Η),5·45 (m,1Η),5·29 (br,2Η),4·18 (q,J=7·1〇Hz, 2Η),1·57 (d, J = 6·85 Ηζ, 3Η), 1·31 (t, J = 7·05 Ηζ, 3Η)· LC-MS Rt = 1.19 min, m/z 286.0 (ΜΗ+) 94 200800919

Cpd name and data 15 (52)-4-amino-6-[1-(3-fluoro-indenyl)-111-bamboo-5-ylamino]-glycine-5-furald oxime! H NMR (CD3OD) δ 8.54 (s? 1H)? 8.05 (d, J - 0.87 Hz, 1H), 7.92 (dd, J = 1.90 and 0.72 Hz, 1H), 7.90 (s, 1H), 7· 51 (dt, J 2·8·89 and 0·81 Hz, 1H), 7·41 (dd, J = 8.96 and 1.93 Hz, 1H), 7·30 (td, J = 7.94 and 5· 84 Hz, 1H), 7·01 (m, 1H), 6.97 (m, 1H), 6.88 (dt, J = 9.79 and 2.27 Hz, 1H), 5·65 (s, 2H)· LC-MS Rt 2·98 min, m/z 378.1 (MH+) 16 (5 £)-4-amino-6-[(l S)-l-phenyl-ethylamino]- Pyrimidine-5-formaldehyde oxime-ethyl-monthly lR NMR (CDCI3) δ 8.92 (d, J = 7.11 Hz, 1H), 8.42 (s, 1H), 8.02 (s, 1H), 7·28-7· 39 (5H),7·23 (br,2H),5·47 (m,1H),4·17 (q,J = 7·02 Hz, 2H),1·61 (d, J = 6.87) ... Hz, 3H), 1·28 (t, J = 7·04 Hz, 3H)· LC-MS Rt = 1·19 min, m/z 286.1 (MH+) 95 200800919

Cpd name and data 17 (5 cores)-4-amino-6-(1Η-^ ϋ-5-ylamine-based nibble-5-decanoic acid 0·ethyl-moon loss towel NMR (CDC13) δ 9.42 (br,1Η),8·33 (s,1Η), 8.15 (s, 1H), 7.76 (d, J = 2·03 Hz, 1H), 7.39 (d, J = 8·69 Hz, 1H), 7.24 (m, 2H), 6.55 (m, 1H), 5, 65 (br, 2H), 4·26 (q, J = 7·05 Hz, 2H), 1·37 (t, J = 7·08) Hz,3H)· LC-MS Rt = 0.96 min, m/z 297.0 (MH+) 18 (5E)-4-amino-6-[3- gas-4-(3-fluoro-benzyloxy)- Phenylamino]-pyrimidine-5-furfural 0. Ethyl-hydrazine NMR (CDC13) δ 9·56 (br, 1H), 8.30 (s, 1H), 8. Π (s, 1 Η), 7.66 ( d, J = 2·64 Ηζ, 1Η), 7·34 (m, 2Η), 7·21 (m, 2H), 7·02 (td, J = 8·20 and 2·37 Hz, 1H), 6.93 (d, J = 8,81 Hz, 1H), 5.62 (br, 2H), 5.14 (s, 2H), 4.27 (q, J = 7·05 Hz, 2H), 1.37 (t, J = 7.07 Hz, 3H). LC-MS Rt = 1.56 min, m/z 416.1 (MH+) 96 200800919

Cpd name and data 19 (5£)-4-amino-6-[l-(3-fluoro-benzyl)-1Η-indazol-5-ylamino]-pyrimidine-5-曱(2 - 福福 林林-4-yl-ethyl)-monthly loss ln NMR (CD3〇D) δ 8.63 (s, 1H), 8.05 (d, J = 0.91 Hz, 1H), 7.92 (m , 2H), 7.50 (m, 1H), 7·42 (dd, J = 8.95 and 1.92 Hz, 1H), 7·30 (m, 1H), 7·00 (m, 2H), 6·87 (m, 1H), 5·65 (s, 2H), 4.38 (t, J = 5·45 Hz, 2H), 3·71 (t, J i 2·65 Hz, 4H), 2·83 ( t, J = 5·46 Hz, 2H), 2.64 (t, J = 4·54 Hz, 4H). LC-MS Rt = 0.84 min, m/z 491·2 (MH+) 20 (5£)-4 -Amino-6-(hydroquinone-5-ylamino)-pyrimidine-5-carboxaldehyde 0-methyl-month-loss lH NMR (CDC13) δ 9.51 (br, 1H), 8.33 (s? 1H), 8.14 (s? 1H), 7·40 (m, 1H), 7·20 (m, 2H), 6.00 (br, 2H), 4.01 (s, 3H), 2.96 (t, J = 7.79 Hz, 2H ), 2.90 (t5 J = 7.35 Hz, 2H)? 2.10 (m? 2H). LC-MS Rt - 1.15 min, m/z 284.1 ® (MH+) 21 (5E)-4-Amino·6·(4 Difluoromethoxy-phenylamino)-pyrimidine-5-furfural 0-fluorenyl-indole 1H NMR (CDC13) δ 10.06 (br,1H),8·40 (s,1Η),8·14 (s, 1Η), 7.52 (d, J = 8·93 Ηζ, 2Η), 7·16 (d, J = 8·97 Ηζ, 2Η), 6.74 (br, 2Η), 6.38 (d, J = 73.68 Ηζ ,1Η),4·04 (s, 3Η). Rt = 1.03 min, m/z 310.1 (MH+) 97 200800919

Cpd name and data 22 (5-5)-4. Amino-6-(1Η-, σ-s--5-ylamino)_. Σσ定巧_曱 〇 〇 曱 肟 肟 肟 NMR (CDC13) δ 8.61 (s, 1 Η), 8.02 (d, J = 〇 · 96 Ηζ, 1 Η), 7·94 (s, 1 Η), 7.92 (dd, J = 1.96 and 〇·81 Ηζ, 1Η), 7·53 (dt, J = 8·94 and 0·81 Ηζ, 1Η), 7.42 (dd, J = 8·91 and 1.96) Ηζ,1Η),4·00 (s,3Η)· LC-MS Rt = 〇·60 min, im/z 284.0 (ΜΗ+) 23 (5-membered)-4-amino- 6-(benzo[1] , 3] Dioxetane _5-ylamino group: l. Pyrimidine-5-furfural 0. Methyl-hydrazine! H NMR (CDC13) δ 10.20 (br, 1H), 8.33 (s, 1H ), 8·1〇(s,1H),7.07 (m,1H),6·92 (d,J=3·14 Hz,1H),6·82 (br,2H),6·81 (d, J = 1·85 Hz, 1H), 6.03 (s, 2H), 4·04 (s, 3H)· LC-MS Rt = 0.65 min (22·93%), m/z 288·1 (MH+); Rt = 0.85 min (77.Ό7%), m/z 288.0 (MH+) 24 (5-5)-4-amino-6-(4-phenoxy-phenylamine-based nibble-5-曱 O- Methyl-肟!Η NMR (CDC13) δ 8.36 (s,1H),8·12 (s,1H),7.43 (m, 2Η),7·36 (m,3Η),7·14 (m,1Η) ), 7·04 (m, 3Η), 4.05 (s, 3H). LC-MS Rt = 1.30 min, m/z 336·1 (MH+) 98

P 200800919

Cpd name and data 25 (5 5)-4-Aminopurine-fluorenyl-肟4 NMR (CDC13) δ 9·31 (br,1Η),8·31 (s,1H),8 15 (s, 1H ), 7.28-7.46 (7H), 6·99 (m, 2H), 5·54 (br, 2H), 5·(Π (s, 2H), 4.00 (s, 3H)· LC-MS Rt 29 min, m/z 35〇2 (MH+) 26 (5-5)-4-amino- 6-(4-dibutyl-phenylamino)_injection ^·method 0-methyl- Monthly Loss NMR (CDC13) δ 9.72 (s, 1H), 8.33 (s, 1H), 8.16 (s, 1Η), 7·43 (d, J 2·8 Ηζ, 2Η), 7·20 (d , J = 8·44 Hz 1Η), 6·21 (br, 2Η), 4·02 (s, 3Η), 2·59 (m, 1Η), 1.58 (dq, J 2: 7.28 and 7.25 Hz, 2H), 1.23 (d, J = 6·94 Hz, 3H), 0·83 (t, J = 7·31 Hz, 3H)· LC-MS Rt = 1.35 min, m/z 300.2 ( MH+) 27 (5-5)-4-amino-6-(4-butytyl-2-ylamino)-oxime. _5-formic acid hydrazine-mercapto- sulphate NMR (CDC13) δ 8·36 (s,1H),8J4 (s,1H),7·42 (s,4Η),4·02 (s,3Η),1·33 (s,9Η). LC-MS Rt = 1 ·32 min, m/z 300·1 (MH+) 99 200800919

Cpd name and data 28 29 (5 5)-4-amino-6-(3 · aryloxy-phenylamino)-mouth bite-5-carboxylic acid ^ Ο - fluorenyl-month-deficiency NMR (CDC13 δ 9·73 (br,1H), 8.32 (s,1H),8·16 (s 1H),7·24-7·47 (7H),7·06 (m,1H),6·79 ( Ddd,J = δ 〇' 2·33 and 0·65 Hz,1H),6·12 (br,2H),5·09 (s,2H),4 (s,3H)· LC-MS Rt = 1 · 32 min, m/z 350·1 (MH+) (5£)-4-amino-6-[3-methyl-4-(6-methyl-acridin-3-yloxy)· stupid Amino]pyrimidin-5-furfural 0-fluorenyl-肟4 NMR (CDC13) δ 9.41 (s,1H),8·31 (s,1H),8·25 (dd,J = 2·59 And 0·75 Ηζ,1Η),8·19 (s,1Η),7·45 (d,J=2·61 Ηζ,1Η),7·35 (dd,J=8·59 and 2.71 Ηζ ,1Η),7·12 (dd,J=8·52 and 2.67 Ηζ,1Η),7·09 (t,J=8·43 Ηζ, 1Η), 6.87 (d,J 2·8·62 Ηζ ,1Η),5·53 (br,2Η),4·02 (s, 3Η), 2·50 (s,3Η),2·26 (s,3Η)· LC-MS Rt = 〇·58 min, m/z 365·1 (ΜΗ+) 100 200800919

Cpd name and data 3〇(5£)-4amino-6-[1-(3·fluoro·benzyl)-1Η-oxazol-5-ylamino]-pyrimidine_5_furfural 0- Butyl-hydrazine 1H NMR (CD3OD) δ 8.62 (s, 1H), 8.05 (d, J = 0·97 Hz, 1 Η), 7.92 (dd, J = 1.91 and 0·78 Hz, 1 Η) ,7·91 (s,1Η), 7·52 (dt, J 2:9·01 and 0·83 Hz, 1H), 7·41 (dd, J 2·8·98 and 1.95 Hz, 1H), 7·30 (m, 1H), 6·99 (m, 2H), 6·87 (m, I 1H), 5, 66 (s, 2H), 3.97 (d, J = 6.72 Hz, 2H) , 2·05 (m, 1H), 0.99 (d, J = 6.73 Hz, 6H)· LOMS Rt ii 1.67 min, m/z 485.1 (MH+) 31 (5-5)-4-amino _ 6-[ 1-(3-Fluoro-benzyl)-1 H-indazol-5-ylamino-1·pyrimidine-5-carboxaldehyde 0-(2-phenoxy-ethyl)-indole NMR (CDC13) δ 8.47 (s,1H),8.10 (m,1H),8·〇5 (s, 1H),7·85 (m,1H), 7.21-7·36 (5H),6·84-7·01 ( 6H), 5·59 (s, 2H), 4.58 (t, J = 4·42 Hz, 2H), 4.28 (t, Bu 4·30 • Hz, 2H)· LC-MS Rt = 1.47 min, m/ z 498.2 (MH+) 101 200800919

Cpd name and data 32 (5-5)-4-amino-6-[3-chloro-4-pyran-2-ylmethoxy)-phenylamino]-bit-5-decanoate Ο Base-month deficit NMR (DMSO-do) δ 9·58 (s, 1H), 8.69 (s, 1H), 8.58 (m, 1 Η), 8·02 (s, 1 Η), 7·87 (td, J = 8·21 and 1.72 Ηζ, 2Η), 7·56 (d, J = 7·89 Ηζ, 1Η), 7·37 (m, 2Η), 7·27 (br, 2Η), 7.17 ( d, J = 9·08 Ηζ, 1Η), 5·25 (s, 2Η), 3·94 (s, , 3Η)· LC-MS Rt = 0·73 min, m/z 385.1 (ΜΗ+) 33 (5 5) _4-Amino- 6-[1·(3-1·卞基)-1Η- 口口口--5-ylamino]- 口密口定-5 -甲藤Ο -Ethyl- Monthly deficient NMR (CDC13) δ 9.68 (br, 1H), 8.34 (s, 1H), 8.12 (s, 1H), 7·76 (br, 1H), 7·28 (m, 1H), 7·22 ( m, 2H), 7·16 (d, J 2·3 Hz, 1H), 6.96 (dt, J = 8.74 and 2.75 Hz, 1H), 6·89 (m, 1H), 6·77 (dt, J = 9.55 and 2.27 Hz, 1H), 6.56 (d, J = 3.13 Hz, 1H), 6·11 (br, 2H), 5.32 (s, 2H), 4·26 (q, J = 7.09 Hz, 2H), 1·36 (t, J = 7·06 Hz, 3H)· LC-MS Rt = 1.44 min, m/z 405·2 (MH+) 102 200800919

Cpcl name and data 34 (5-5)-4-amino-6-[1-(3.fluoro-benzyl)-1Η-indol-5-ylamino]-pyrimidine-5-nonanal oxime-oxime Base-肟 NMR (CD3OD) δ 8·59 (s, 1H), 7·85 (s, 1H), 7·64 (dd, J = 2·02 and 0·57 Ηζ, 1Η), 6·91· 6·98 (3Η), 7·11 (dd, J 2·8·74 and 2·01 Ηζ, 1Η), 6.93 (m, 2Η), 6.78 (dt, J 29.95 and 2.18 Ηζ ,1Η),6·51 (dd,J=3·16 and 0·82 Ηζ, _ 1Η), 5·41 (s,2Η), 3.96 (s,3Η)· LC-MS Rt = 1·34 min , m/z 391.1 (ΜΗ+) 35 (5£&gt; 4-amino-6-[2,2-difluoro-2-(6·decyl-pyridin-2-yl)-ethylamino] -pyrimidine-5-furfural 0-methyl-肟4 NMR (CD3OD) δ 8·41 (s,1H),7·85 (s,1H),7·79 (t, J = 7.81 Ηζ, 1Η),7·49 (t, J = 7.79 Ηζ, 1Η), 7·35 (d, J = 7·74 Hz, 1Η), 4·44 (t, J = 13·98 Hz, 2H), 3 · 81 (s, 3H), 2.56 (s? 3H). LC-MS Rt = 0.59 min (32.36%), m/z sin 323.2 (MH+); Rt = 0.88 min (67.64%), m/z 323.2 ( MH+) 36 (5E)-4-Amino- 6-(3·Di-phenylamino)-,·σ定·5-A 〇-〇-肟 肟iH NMR (CDC13) δ 8·31 (br 1Η), 8.17 (s, 1Η), 7·78 (m, 1Η), 7.34-7.44 (3Η), 4.07 (s, 3Η)· LC-MS Rt = 1.07 min, m/z 322.0 (MH+). 103 200800919

Cpd name and data 37 (5-5) 4-amino-6-(4-benzyloxy-3-a-phenylamino)-pyrimidine-5-formaldehyde 0-ethyl-oxime 1h NMR (CDC13 ) δ 9.59 (br,1H), 8.30 (s5 1 Η), 8·16 (s,1Η), 7·65 (d, J 2 2.64 Ηζ, 1 Η), 7.30-7.48 (6Η), 6.95 ( d, J = 8·87 Hz, 1H), 5·73 (br, 2H), 5·16 (s, 2H), 4·27 (q, J = 7·05 Hz, 2 H), 1.37 (t , J = 7·06 Hz, 3H)· _ LC-MS Rt = 1.49 min, m/z 398·1 (MH+) 38 (5-5)-4-amino-6-[3- gas-4-( Oral ratio 嚏3_yloxy)-phenylamino]-pyrimidine-5-furfural 0-fluorenyl-hydrazine! H NMR (CDC13) δ 10.14 (br, 1H), 8.41 (s, 1 Η), 8·38 (m, 2H), 8·19 (s, 1H), 7·81 (d, JT = 2·79 Hz, 1H), 7·42 (dd, J = 8.97 and 2.63 Hz, 1H ),7·29 (m,2H),7·07 (d,J=8·84 Hz,1H), 6.68 (br,2H),4·06 (s5 3H). LC-MS Rt =〇·55 Min,m/z 371.0 (MH+) 39 (5-5)-4_[3_Gas-4-(3-Fluoro-yloxy)-phenylamino]-6-methylamino-pyrimidine-5 -furfural 0-methyl·肟!H NMR (300 Hz? CDC13) δ 8.99 (bs? 1Η)? 8.31 (bs, 1Η),8·26 (s,1Η),7·54 (d,J = 2.5 Ηζ, 1 Η) 7·38-7·17 (m,4H),7·04-6·90 (m,2H),5·13 (s,2H),3·97 (s,3H), 3·13 (d, J 2·9 Hz, 3H) ; LC/MS (m/z) (MH+) 416·1 (calculated C2〇H19C1FN502, 415.85) 104 200800919

Cpd name and data 40 (5-5)-4-ethylamino-6-[l-(3-fluoro-benzyl)-1Η-oxazol-5-ylamino]-pyrimidine-5-furaldehyde -Methyl-肟lB NMR (300 Hz, CDC13) δ 8.97 (bs5 1Η), 8.23 (s, 1H),8·21 (bs,1H),8·02 (s,1H),7·83 (s ,1H), 7·37-7·23 (m,4H), 6.97-6.95 (m,2H), 6.86-6.81 (m, 1H), 5.58 (s,2H),3·95 (s,3H) , 3.63-3.59 (m, 2H), , 1.29 (t, J = 7.2 Hz, 3H); LC/MS (m/z) (MH+) 420.1 (calc. C22H22FN70, 419.46) 41 (5E)-4-ethyl Amino-6·[1_(3-fluoro-benzyl)-lH-indazol-5-ylamino]-pyrimidine-5-carboxaldehyde 0-ethyl-oxime! H NMR (300 Hz, CDC13) δ 9 ·07 (bs,1H),8·24 (s,1Η),8.22 (bs,1Η),8·02 (s,1Η),7.83 (s,1Η), 7.34-7.23 (m,4Η),6 ·97·6·95 (m, 2Η), 6·86-6·82 (m, 1Η), 5·58 (s, 2Η), 4·19 (q, J = 7·05, 2Η), 3 ·64·3·57 (m, • 2Η), 1·33-1·27 (m, 6Η); LC/MS (m/z) (ΜΗ+) 434·2 (calculation C23H24FN70, 433.48) 105 200800919

Cpd name and data 42 (5 5) _4 · [3 · chloro · 4 · (3-fluoro _ + yloxy) · stupylamino] _ 6 - ethyl amino - pyrimidine - 5 - furfural 0 - 曱肟 肟 A NMR (300 Hz, CDC13) δ 8.86 (bs, 1H), 8.24 (s, 2Η), 7.56 (d, J = 2.61 Ηζ, 1 Η), 7·39-7·37 (m, 4 Η) , 7·17-7·03 (m,1H),6·93-6·90 (m,1H), 6.44 (bs,1H), 5.13 (s,2H),3.98 (s,3H),3· 59 (m, 2H), 1.28 (t5 J _ 7·23 Hz, 3H) ; LC/MS (m/z) (MH+) 430.1 (calc. C21H21C1FN502, 429.88) 43 (5 5)-4-[3 - Chloro-4-(3-fluoro-octyloxy)-phenylamino]-6-ethylamino-0-dimethylindole-5-methyl 0-ethyl-month-deficient NMR (300 Hz, CDC13 ) δ 8.75 (bs, 1Η), 8.25 (s, 1Η), 8·24 (s, 1Η), 7·59 (d, J = 2·57 Ηζ, 1Η), 7.35-7.18 (m, 4Ή), 7·04-6·98 (m,1H),6·91-6·88 (m,1H),6·18 (bs,1H), 5.12 (s,2H),4·23 (q,J = 7·05 Hz, 2H), 3·56 • (m, 2H), 1.35 (t, J 27.05 Hz, 3H), 1.26 (t, J = 7·14 Hz, 3H) ; LC/MS (m/ z) (MH+) 444·1 (calculation C22H23C1FN502, 443.90) 106 200800919

Cpd name and data 44 (5-5)·4-Amino- 6-[1·(3-fluoro-indolyl)_ιη·5Bus_5_ylamino]-. Midine-5-furaldehyde 0-(4-decyloxy-benzyl)_肟1h NMR (CD3OD) δ 8·60 (s,1H),8·05 (d,J = 〇·96 Hz, 1Η ), 7.89 (s, 1Η), 7·76 (m, 1Η), 7·47 (d, J = 8·93 Ηζ, 1H), 7.22-7.36 (4H), 6·94-7·03 (3H ),6·85 (m,2H), 5·66 (s,2H),5·11 (s,2H),3·68 (s,3H). LC-MS Rt = 1.41 min, m/ z 498·1 (MH+) 45 (5-5)·4-Amino-6-[l-(3-fluoro-aryl)-lH-Bus-5-ylamino]---------------------- 0-(2-methoxy-octyl)-monthly loss! H NMR (CD3OD) δ 8.60 (s, 1H), 8.05 (d, J = 0.92 Hz, 1H), 7·89 (s, 1H) , 7,80 (dd, J = 1·94 and 0·73 Hz, 1H), 7·49 (d, J = 8·97 Hz, 1H), 7·37 (dd, J = 7.43 and 2.09 Hz,1H),7·29 (m,3H),6·94-7·03 (3H),6·88 (m,2H), 5·66 (s,2H),5·22 (s,2H ),3·77 (s,3H)· LC-MS Rt = 1.46 min, m/z 498.0 (MH+) 107 200800919

Cpd name and data 46 (5E)-4-amino-6-[l-(3-fluoro-benzyl)-1Η-indazol-5-ylamino]-pyrimidine-5-formate hydrazine-卞Base-month loss! NMR (CD3OD) δ 8.64 (s, 1H), 8.04 (d, J 20.88 Hz, 1Η), 7·90 (s, 1H), 7·77 (m, 1H), 7·41-7·47 (3H), 7·27-7·36 (4H), 7.22 (dd, J = 8.96 and 1.96 Hz, 1H), 6·95-7·02 ( 2H),6·87 (dt, J = 9.58 and 2·01 Hz, 1Η), 5·65 (s, 2H), 5.19 (s, 2H)· LC-MS Rt = 1.42 min, m/z 468.1 (MH+). 47 (5£)-4-amino-6-[l-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carboxylic acid hydrazine - Isopropyl-monthly lB NMR (CD3OD) δ 8.57 (s, 1H)? 8.05 (d, J = 0.88 Hz? 1H), 7·94 (dd, J = 1.92 and 0·82 Hz, 1H) ,7·92 (s,1H), 7·51 (d, J = 8.92 Hz, 1H), 7·42 (dd, Bu 8·99 and 1.95 Hz, 1Η), 7·30 (td, J = 7.98 and 5.73 Hz, 1Η), 6·94-7·02 (2H), 6·87 (dt, J = 9·66 and 2·01 Hz, 1H), 5.65 (s, 2H), 4.46 (m,1H),1·32 (d,J = 6·24 Hz,6H)· LC-MS Rt = 1.34 min, m/z 420.2 (MH+) 108 200800919

Cpd name and data 48 (5-5)-4-amino-6-(1-benzyl-1H-indazol-5-ylamino)-pyrimidine-5-furald oxime 曱 曱 肟 肟 NMR CD3OD) δ 8.60 (s,1H), 8.03 (d, J = 0·91 Hz, 1Η), 7.92 (d, J = 0.77 Ηζ, 1Η), 7.91 (s, 1Η), 7·50 (dt, J =8·96 and 0·74 Hz, 1H), 7.40 (dd, J 2·8·93 and 1.91 Hz, 1Η), 7.16-7.32 (5Η), 5·64 (s, 2Η), 3.98 (s,3Η)· LC-MS Rt = 1·12 min, m/z 374.1 (MH+) 49 (5-5)-4-amino-6-(1-benzyl-1H-indazol-5-yl Amino)-pyrimidine-5-furfural 0-ethyl-hydrazine 5H NMR (CD3〇D) δ 8.59 (s? 1H)? 8.03 (d, J = 0.89 Hz, 1H), 7·93 (dd, J = 1·90 and 0.73 Hz, 1H), 7·91 (s, 1H), 7·51 (dt, J = 9·01 and 0·78 Hz, 1H), 7·40 (dd, J = 8· 94 and 1.94 Hz, 1H), 7·16-7·32 (5H), 5.64 (s, 2H), 4·23 (q, JT = 7·07 Hz, 2H), 1.34 (t, J = 7·04 Hz, 3H)· LC-MS Rt =1.21 min, m/z 388·1 (MH+) 109 200800919

Cpd name and data 5〇3_{5-[6-amino-(5penta)·5·(methoxyiminomethyl) "mididin-4-ylamino]-oxazol-1-ylindole }}-Benzonitrile H NMR (CD3OD) δ 8.60 (Sy 1H)? 8.07 (d5 J - 0.91 Hz, 1H), 7.93 (dd, J = 1.92 and 〇·71 Hz, 1H), 7 92 (s, 1H), 7·63 (td, J 2·5·39 and 1.81 Hz, 1H), 7·54 (dt, J 2.90 and 0·86 Hz, 1H), 7.53 (s, 1H) , 7.48 (m, 2H), 7.44 (dd, J = 8.95 and 1.94 Hz, 1H), 5·71 (s, 2H), 3·98 (s, 3H)· LC_MS Rt = 1.08 min, m/z 399·2 (MH+) 51 Amino-(5-5)-5-(ethoxyimino-indenyl)-pyrimidin-4-ylamino]-P-indolyl-1 -ylindolyl辛猜1U NMR (CD3〇D) δ 8.60 (s? 1H)? 8.07 (d? J - 〇.91 Hz, 1H), 7·94 (dd, J = L92 and 0·73 Hz, 1H), 7.92 (s, 1H), 7·62 (td, J = 5.25 and 1.61 Hz, 1H), 7·54 (dt, J 2·8·97 and 0·86 Hz, 1H), 7·53 (m, 1H),7·48 (m,2H),7·43 (dd, J = 8.95 and 1.96 Hz, 1H), 5·70 (s, 2H), 4·24 (q, J 2:7.07) Hz, 2H), 1·34 (t, J = 7.08 Hz, 3H)· LC-MS Rt 2 l·16 min, m/z 413.3 (MH+) no 200800919

Cpd name and data 52 (5-penta-amino-6-(2-indolyl 2Η_, oxazol-5-ylaldehyde 0-ethyl- 肟 NMR (CD3OD) δ 8.59 (s, 1 Η), 8· 22 (d, J = 〇·73 Ηζ 1H), 7·95 (s, 1H), 7·93 (dd, J = 1·98 and 0·76 Hz, 1H) 7·58 (dt, J = 9 ·21 and 0.85 Hz, 1H), 7·27-7·37 (6H), 5·62 (s, 2H), 4·24 (q, J = 7.10 Hz, 2H), 1·35 (t, J = _ 7.05 Hz, 3H). LC-MS Rt = 1 · 16 min, m/z 388·2 (MH+) 53 (5 5)-4-[l-(3•fluoro-benzyl; MH-carbazole -5-ylamino]_6-methylamino-pyrimidine-5-furfural 0.methyl-ray towel NMR (300 Hz, CDC13) δ 8.65 (bs, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8·01 (s, 1H), 7.85 (d, J = 1.74 Hz, 1H), 7·39·7·22 (m, 3H), 6.97-6.94 (m, 2H) , 6.41-6.37 (m, 1H), 5·57 (s, 2H), 3.97 (s, 3H), 3·09 (d, J = 4.80 Hz, 3H) ; LC/MS (m/z) (MH+ ) 406·1 (Calculation _ C21H20FN7O? 405.43) 111 200800919

Cpd name and data 54 (5 5)-4•Amino- 6-[l -(3 - gas-octyl)·ιη_ 口引嗤_5·ylamino]-°Midine-5-furfural 0-Methyl-肟 NMR (300 Hz, CDC13) δ 9.88 (bs, 1Η), 8.44 (bs, 1H), 8·13 (s, 1Η), 8·06 (s, 1H), 7·93 ( s,1H),7.39-7.05 (m,6H),6.37 (bs,1H),5·57 (s,2H),4·〇2 (s,3H);); LC/MS (m/z) (MH+) 408·1 (calculate c2〇Hl8C1N7〇, i 407.86) 55 (5-5)-4-amino-6-[1-(3-gas-+yl)_1;^-,嗤_5-yl Amino]---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ,8·04 (s,1H), 7.96 (m,1H), 7.43-7.04 (m,6H), 5.68 (bs,1H),5·30 (s,2H),4·26 (q, J II 7.05 Hz, 2H), 1·37 (t, J = 7.05 Hz, 3H); LC/MS (m/z) (MH+) 422.1 (calc. C21H20ClN7O, 421.88) 56 (5-5)-4-Amino-6 -[ 1-(3-decyloxy-octyl)-1H-sodium succin-5-ylamino]-pyrimidine-5-nonanal oxime-fluorenyl 肟 (NMR) (300 Hz, CDC13) δ 9.89 (bs,1Η),8·43 (s, 1Η),8·12 (s,1H),8·04 (s,1H),7·91 (bs,1Η), 7.36-7.19 (m,2 H),6·82·6·6·44 (m,2H), 5.57 (s,2H), 4·02 (s,3H), 3.74 (s,3H) ; LC/MS (m/z) ( MH+) 404·2 (calculation C21H21N702, 403.44) 112 200800919

Cpd name and data 57 (5-5; Μ-amino-6-[1-(3·曱-oxy-benzyl)_iH-indazol-5-ylamino]·0 σ 定 -5 -5 - Ο-ethyl·moon loss towel NMR (300 Hz, CDC13) δ 10·45 (bs, 1Η), 8.40 (s, 1Η), 8·069 (s, 1Η), 8.067 (s, 1Η), 7· 85 (s,1Η),7·55 (bs,1H),7.36-7.27 (m,3H),6·74 (m,3H),5.58 (s, 2H),4·28 (q,J = 7.08 Hz, 2H), 3·75 (s, 3H), 1.37 (t, J _ = 7.08 Hz, 3H) ; LC/MS (m/z) (MH+) 418.2 (calc. C22H23N702, 417·46) 58 (5 5)-4-Amino-6-[2-(3-carbo-indenyl)-1Η·benzophenamimid-5-ylamino]·σ密α定-5-甲搭0-Ethyl- Monthly loss NMR (CD3OD) δ 8.64 (s, 1Η), 8.13 (s, 1Η), 8.11 (d, J = 1·83 Ηζ, 1Η), 7·68 (d, J = 8·77 Ηζ, 1Η ), 7·49 (dd, J = 8·82 and 1·86 Ηζ, 1Η), 7·43 (m, 1Η), 7.07-7.24 (3H), 4·52 (s, 2H), 4·30 (q, J = 7·1〇Hz, 2H), 1·36 (t, J • = 7·07 Hz, 3H). LC-MS Rt = 0.28 min (68.74%), m/z 406.0 (MH+) ; Rt = 0.76 min (31.26%), m/z 406.2 (MH+) 113 200800919

Cpd name and data 59 (5-5)-4-amino-6-(3-chloro-phenylamino).定_5-曱搭〇-Methyl-monthly loss 4 NMR (CDC13) δ 9.82 (br,1Η),8·28 (s,1Η),8·21 (s, 1Η),7·41 (m, 1Η), 7·30 (m, 1Η), 7.13 (m, 1Η), 5·96 (br, 2Η), 4·05 (s, 3Η)· LC-MS Rt = 〇·56 min (51.88%) , m/z 278.0 (ΜΗ+) ; Rt = 1.02 min (48.12%), m/z 278.1 I (MH+) 60 (5-5)-4-amino-6·[2·(3_fluoro-benzyl _1H-benzimidazol-5-ylamino]-pyrimidine-5-carboxaldehyde 0-methyl-oxime NMR (CD3OD) δ 8·59 (s, 1H), 7·94 (s, 1H), 7.83 (dd, J = 1·99 and 0·54 Ηζ, 1Η), 7·50 (dd, J = 8·59 and 0.53 Ηζ, 1Η), 7·34 (dt, J = 6·Ό9 and 7.96) Ηζ,1Η),7·23 (dd,J=8·60 and 2·01 Ηζ,1Η),7·14 (dt,J=7·60 and 0.75 Ηζ, 1Η),7·06 (dt,J = 9·98 and 1.94 Ηζ, 1Η), 6.99 (td, J = ❿ 8·84 and 2.87 Hz, 1H), 4·27 (s, 2H), 3.99 (s, 3H)· LC- MS Rt = 0.55 min, m/z 392.1 (MH+) 114 200800919

Cpd name and data 61(10)-4·amino-[4-(3-fluoro'yloxy)·3_methoxy-phenylamino]-pyrimidine-5-formaldehyde 0-fluorenyl-monthly lRNMR ^ 3〇〇H^CDCl3&gt;S ^.32 (bs?1H)? 8.32^ 1H)? 8.16 (s, 1H), 7.36-7.02 (m5 4H)5 6.91-6.82 (m, 3H), 5.62 (bs, 1H), 5.13 (s, 2H), 3·998 (s, 3H), 3.91

(s,3H) ; LC/MS (m/z) (MH+) 398·1 (calc. C2〇H2〇FN5〇39 397.40) 62 (5-5)-4-amino-6-[4_(3·Fluorine -octyloxy)-3-methoxy-phenylamino]-pyrimidine-5-furaldehyde. 0-ethyl-hydrazine NMR (300 Hz, CDC13) δ 9·51 (bs, 1H), 8· 32 (s, 1Η), 8·15 (s, 1Η), 7·36·7·16 (m·4Η), 7·02-6·82 (m, 3Η), 5·80 (bs, 1Η) ,5·13 (s,2Η), 4.25 (q, J = 7·06 Ηζ, 2Η), 3.91 (s, 3Η), 1.36 (t, J = 7·06 Ηζ, 3Η);) LC/MS (m/z) (ΜΗ+) 412.2 (calculated C21H22FN5〇3, 411.43) 115 200800919

Cpd name and data 63 (5-5)-4·Amino-6-(3-chloro-4-methoxy-phenylamino)·, gnat-5-formaldehyde 〇 曱 肟-肟 NMR NMR (CDC13 ) δ 9.32 (br,1H), 8.28 (s,1H),8·18 (s, 1Η),7·61 (d,J = 2·63 Ηζ,1Η), 7·39 (dd, J = 8 ·85 and 2·63 Ηζ,1Η),6·93 (d,J 2·8·86 Ηζ,1Η),5·39 (br,2Η), 4·02 (s,3Η),3·90 (s ,3Η)· LC-MS Rt = 1·00 min, m/z _ 308.1 (MH+) 64 (5-membered)-4-amino group _6-(3 - gas-4-? Phenylamino)-. dense. -5-5-nonanal 0-fluorenyl-ruthenium NMR (CDC13) δ 9.43 (br, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 7.66 (d, J = 2·51 Hz, 1Η), 7·41 (dd, J = 8·71 and 2.66 Hz, 1H), 7·04 (d, J = 8·68 Hz, 1Η), 5.45 (br, 2H), 4·02 ( s,3H),3·88 (t,J 2·4·59 Hz, 4H), 3·04 (t, J = 4·55 Hz, 4H). LC-MS Rt = 1.02 min, m/z 363.1 ( MH+) _ 65 (5-5)-4-amino-6-[1-(3-fluoro-indenyl)-111-bine sitting _5-ylamino]-metamididine_5_formaldehyde O- Phenyl 肟 NMR (CDC13) δ 8.70 (s5 1Η), 8·21 (s, 1Η), 8·04 (s, 1H), 7·99 (s, 1H), 6·81-7·44 (10H),5·58 (s,2H). LC-MS Rt = 1.44 min, m/z 454.2 (MH+) 116 200800919

Cpd name and data 66 (5 5)_4·Amino-6-[l_(4-fluoro-benzyl)-1Η-oxazol-5-ylamino]•pyrimidine-5-furaldehyde 0-fluorenyl-肟]H NMR (300 Hz, CDC13) δ 9.64 (bs? 1Η)? 8.38 (s? 1Η), 8·14 (s, 1Η), 8·02 (s, 1Η), 7·93 (s, 1Η) ),7·42·7·16 (m,4H),7·01-6.95 (m,2H),5·92 (bs,2H),5·56 (s, 2H),4·01 (s, 3H) ; LC/MS (m/z) (MH+) 392·2 (calc. i C20H18FN7O, 391·40) 67 (5-5)-4-amino-6·[1-(4-fluoro-benzyl) -1Η-吲嗤_5-ylamino]_-minopyridine-5-furaldehyde 0-ethyl·肟NMR (300 Hz, CDC13) δ 9.73 (bs,1Η),8·37 (s, 1Η) , 8.15 (s, 1Η), 8·02 (s, 1Η), 7·93 (s, 1Η), 7·41-7·16 (m, 4H), 7.01-6.95 (m, 2H), 5.94 ( Bs,1H),5·56 (s, 2H),4·25 (q,J 2·7·06 Hz, 2H), 1.36 (t, J = 7.06 Hz, 3H) ; LC/MS (m/z) (MH+) 406·2 (calculated C21H20FN7O, _ 405.43) 117 200800919

Cpd name and data 68 (5 5)·4·Amino-6-[1_(3·fluoro-benzyl)·1Η-indazol-5-ylamino]-pyrimidin-5-decanoate Ο (2 -decyloxy-ethyl)-monthly lR NMR (CD3OD) δ 8.60 (s. 1H), 8,05 (d, J - 0.89 Hz, 1H), 7.93 (dd, J 2 1.91 and 0.75 Hz , 1H), 7.92 (s, 1H), 7·51 (dt, J 28.97 and 0·76 Hz, 1H), 7·43 (dd, J = 8·94 and 1.93 Hz, 1H) , 7.30 (td, J = 7.97 and 5.95 Hz, 1H), § 7.01 (m, 1H), 6.96 (m, 1H), 6.87 (dt, J = 9.70 and 1.71)

Hz, 1H), 5.65 (s, 1H), 4·32 (t, J 2·49 Hz, 2H), 3·71 (t, J 2·60 Hz, 2H), 3·35 (s, 3H)· LC-MS Rt = 1.13 min, m/z 436.2 (MH+) 69 ( 5 Z) - 4-amino 6-[l-(3 - gas-fluorenyl]-5-ylamino] -. Bite · 5 - Preparation Ο - (3 - thiol-propyl) - Moon Deficit 4 NMR (CD3OD) δ 8·62 (s, 1H), 8·05 (d, J 20.089 Hz , 1H), 7·93 (dd, J = 1.91 and 0·75 Hz, 1H), 7·91 (s, 1H), 10 7·46 (m, 2H), 7·30 (m, 1H), 7·01 (m,1H),6·87-6·96 (2H),5·65 (s,2H),4·28 (t,J = 6·48 Hz, 2H), 3.69 (t, J =6·35 Hz, 2H),1·94 (m,2H)· LC-MS Rt = 0.55 min, m/z 436.3 (MH+) 118 200800919

Cpd name and data 7 ❹(5 5)_4-amino-indolyl)-1Η_ϋ·5_ylamino]m-pyridine-5-formaldehyde 0-(3-didecylamino-propyl)_肟Ln NMR (CDC13) δ 9.38 (br, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 8.03 (d, J = 0.73 Hz, 1H), 7.97 (d, J - 1.92 Hz, 1H) , 7.42 (dd, J = 8·87 and 1.91 Hz, 1H), 7·23·7·37 (2H), 6·91-6·98 (2H), 6.86 (m, 1H), 5.58 ( s,2H),5·21 , (br,2H),4·26 (t,J 2 6.51 Hz, 2H), 2·41 (t, J = 7.05)

Hz, 2H), 2·24 (s, 6H), 1.92 (m, 2H)· LC-MS Rt = 0.29 min (37.41%), m/z 463.2 (MH+) ; Rt = 0.76 min (62.59%) ), m/z 463.2 (MH+) 71 (5-5)-4-Amino-6-(4-indolyloxy-3-chloro-phenylamino)-density furfural 0-(2-oxime NMR (CD3OD) δ 8.56 (s, 1H), 7.95 (s, 1H), 7.66 (d, J = 2.58 Ηζ, 1 Η), 7.47 (m, 2 Η), 7.28-7.40 ( 4Η), • 7.08 (d, J = 8·89 Hz, 1Η), 5.16 (s, 2H), 4.32 (t, Bu 4, 45 Hz, 2H), 3·71 (t, J = 4·58 Hz , 2H), 3·36 (s, 3H). LC-MS Rt = 1.36 min, m/z 428.1 (MH+) 119 200800919

Cpd name and data 72 (5-5)·4-Amino-6-[2·(3-fluoro-phenyl)-benzofuran-5-ylamino]-pyrimidine-5-formaldehyde 0-methyl_肟4 NMR (300 Hz, CDC13) δ 9·80 (bs, 1H), 8.44 (s, 1Η), 8.15 (s, 1Η), 7·82 (d, J = 2·16 Ηζ, 1Η), 7 ·64-7·26 (m,5H),7·09-7·03 (m,2H),6·24 (bs,1H),4·03 (s, 3H) ; LC/MS (m/z ) (MH+) 378·2 (Calculate C2〇H16FN502, i 377.37) 73 (5£*)- 4-Amino- 6-(2-indolyl-benzopyran-5-ylamino)- shout定-5_ Formaldehyde 0-fluorenyl-肟lH NMR (300 Hz? CDC13) δ 9.35 (bs, 1Η), 8.33 (s5 1H), 8.14 (s, 1H), 7·69 (d, J = 2·12 Hz,1H), 7.38-7.21 (m,8H),5·55 (bs,1H),4.10 (s,2H),3·99 (s,3H); LC/MS (m/z) (MH+) 374.1 (Calculate C21H19N502, 373.41)

120 200800919

Cpd name and data 74 (5£:)-4-amino-6-[1-(3.fluoro-octyl)-2,3-dihydro·1Η-, indol-5-ylamino]-pyrimidine -5-furfural 0_mercapto- 肟!H NMR (CDC13) δ 9·07 (s,1Η), 8.29 (s,1Η),8·13 (s, 1Η),7·29 (td,J 2,7·55 and 5·49 Ηζ,1Η),7·24 (m,1Η), 7·14 (d,J=8·01 Ηζ,1Η),7·09 (dd,J=9·89 and 2.23 Ηζ,1Η),7·04 (dd,J 2·8·71 and 2·05 Ηζ,1Η),6·96 (td,J i = 8·11 and 2·65 Ηζ,1Η), 6.42 (d , J = 8·31 Ηζ, 1Η), 5·42 (br, 2Η), 4·23 (s, 2Η), 3·98 (s, 3Η), 3.36 (t, J = 8·19 Hz, 2H ), 3·01 (t, J = 8·29 Hz, 2H); LC-MS Rt = 1.48 min, m/z 393.3 (MH+) 75 (5 5)-4-amino- 6-[3 - gas - 4-(3-Fluoro-octyloxy)-phenylamino]_ 唯, σ定-5 -甲备Ο - (3 - thio-propyl)-moon shawl NMR (300 Hz, CDC13 ) δ 8.56 (s, 1Η), 7.96 (s, 1Η), 7·70 (d, J 22.55 Ηζ, 1Η), 7.01-7.00 (m, 6Η), 5·17 (s — 2Η), 4· 29 (t, J = 6·35 Ηζ, 2Η), 3·70 (d, J = 6·35 Hz, 2Η), 1.96 (m, 2Η); LC/MS 〇/ζ) 44 6·2 (ΜΗ+) (calculation C21H21C1FN503, 445·87). 121 200800919

Cpd name and data 76 (5-5)-4-amino-6-(4-benzyloxy-3-a-phenylamino)-pyrimidine-5-methyl 0-(3-carbyl-propyl Base)-month deficient NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7·97 (s, 1Η), 7.67 (d, j=2.5, 1Η), 7·46 (d, j= 7.1,2Η), 7·38-7·25(ηι,4Η),7·06 (d,j = 8.9, 1Η), 5.15 (s,2H), 4·28 (t,j 2:12,5, 2H), 3.70 (t, Bu 12.7, 2H), 1.97-1.94 _ (m, 2H) ; MS (ESI) m/z 427, 428 (MH+), 426 (ΜΗ-) 77 (5 5)-4- Amino-6-(4-+-yloxy-3-chloro-phenylamino)-carcinoma- 5-nonanal oxime NMR (300 MHz, CD3OD) δ 8.52 (s, 1H), 7.96 (s , 1Η),7·66 (d,J 2·2 4, 1Η), 7·50-7·29 (m,6Η), 7·10 (d, J = 9 Ηζ, 1Η), 5.17 (s , 2Η); MS (ESI) m/z 370 (MH+) 79 (5-5)-4·Amino-6·[3-Gas-4-(3-F-Octyloxy)-phenylamino ]_ 嘧啶pyrimidine-5-carboxaldehyde oxime! H NMR (300 MHz, CD3OD) δ 8.51 (s9 1Η)? 7.95 (s? 1Η), 7·66 (d, J 2·4 Ηζ, 1Η), 7· 40-7·04 (m,7Η),5·17 (s,2Η) 80 (5-5)-4-amino-6-(4-chloro-2- gas·phenylamino) "Bite bite_ 5-A disk Methyl-oxime MS m / z 296 · 1 (MH +) 122 200800919

Cpd name and data 81 (5Z)-4-amino-6-(4-chloro-2-fluoro-phenylamino)-pyrimidine _5_decanoic acid thiol-monthly MS m/z 296.1 (MH+ 82 (^幻-'amine-based winter (4) desert--fluoro-phenylamine group ^ 密^^^- citric acid. · Methyl-肟MS m/z 340 (MH+) 83 (5Z)-4- Amino- 6-(4-&gt; odor-2 -fluoro-phenylamino)_isophilic % 曱 〇 _ methyl-肟MS m/z 340 (MH+) 84 (5 5)-4- Amino-6·[1_(3-fluoro-octyl)pyridin-5-ylamino]-m-pyridine-5-furaldehyde NMR (300 MHz, DMSO, δ 11.22 (s, 1 Η), 9.92 (s, 1Η), 8·65 (s, 1Η), 8.09 (s, 1Η), 8·04 (d, J = 1·8 Ηζ, 1H), 7.97 (s, 1H), 7·65 (d , J = 9·0 Hz, 1H), 7·44-7·36 (m, 2H), 7·11-7.03 (m, 5H), 5·66 (s, 2H); MS (ESI) m/ z 376 (MH+) 85 (5-5)-4-amino-6-[1-(3-fluoro-benzyl)_1H-indazol-5-ylamine-biting-5-decanoic acid 0-(3 -基-propyl)-month loss NMR (300 MHz, CDC13) δ 9·40 (s, 1H), 8.34 (s, 1Η), 8·18 (s, 1Η), 8·04 (s, 1Η) ),7·94 (s,1Η),7·40-7·25 (m,2H),6·98-6·84 (m,3H),5·58 (s,2H),5.33 (br s , 2H), 4.37 (t, J two 5.7 Hz, 2H), 3·83 (t, J = 12.3 Hz, 2H), 2.04 (m, 2H) ; MS (ESI) m/z 434 (MH+) 123 200800919

Cpd name and data 86 (5-5)-4-(4-bromo-2-fluoro-phenylamino)_6-methoxyamino-pyrimidinecarboxaldehyde 0-methyl-monthly MS m/z 370 (MH+ ) 87 (5 5) _4_&amp;c base - 6-[l-(3-fluoro)-lH-mouth 嗤-5-ylamino]-moutidine _5_furfural 0-(3-? Phenanthroline-propyl)-肟it! NMR (300 ΜΠζ, CDC13) δ 9·37 (s,1H),8·34 (s, 1Η), 8.17 (s,1Η),8·03 (s ,1Η),7·96 (s,1Η),7·42 (dd, J 2,9·0,1·8 Ηζ,1Η), 7·30-7.24 (m,#Η), 6.97-6·83 (m, 3Η), 5·57 (s, 2Η), 5.34 (s, 2Η), 4·26 (t, 6.3 Ηζ, 2Η), 3·72 (m, 4Η), 2·52 (m, 6Η),1·95 (m,2Η); MS (ESI) m/z 505 (MH+) 88 (5£)-4-amino group·6_[1_(3_fluoro-octyl)·1Η-吲哚_5-ylamino]-pyrimidine-5-decanoic acid smear NMR (300 MHz, DMSO, δ 11.18 (s, 1H), 9.89 (s, 1 Η), 8.65 (s, 1 Η), 7 ·95 (s,1Η),7·81 (d,J = 1.5 Ηζ, 1H), 7.52 (d,J 2·3 Hz, 1H), 7·42-7.02 (m,7H),6·48 (d, J = 2·7 Hz, 1H), 5·44 (s, 2H); MS (ESI) m/z 377 (MH+) 89 (5-5)-4-amino-6-(4-chloro -2-fluoro-5-pyridyl-benzene Amino)-, σ定_5_ furfural 0_methyl-肟MS m/z 312.1 (MH+) 90 (5Z)-4-amino-6-(4-chloro-2-fluoro-5-hydroxy-benzene Amino) pyrimidine-5-furfural 0-methyl-indole MS m/z 312·1 (MH+) 124 200800919

Cpd name and data 91 (5 5)·4·Amino-6-[l-(3-fluoro-benzyl)-1Η·吲哚-5-ylamino]-pyrimidine.定-5 -曱搭Ο - (3 - mercapto-propyl)-monthly loss 4 NMR (300 MHz, DMSO-state δ 9.74 (s, 1H), 8.74 (s, 1 Η), 7·98 ( s,1Η), 7.86 (d, J = 1·8 Ηζ, 1Η), 7·53 (d, J = 3·3 Hz, 1H), 7·38-7·34 (m, 2H), 7· 20-7·00 (m,6H), 6.49 (d, J two 3.0 Hz, 1H), 5.78 (s, 2H), 4.56 (t, J = 5·1 , Hz, 1H), 4·24 (t , J = 6·3 Hz, 2H), 3.55 (m, 2H), 1·86 (m, 2H); MS (ESI) m/z 435 (MH+) 92 (5-5)-4. Amino- 6 - [l-(3 - gas-fluorenyl)-lH-oral °°-5-ylamino]-mouth 唆-5·carboxylic acid 0-(3 - six mice 11 to bite-1-yl-propyl NMR) (300 MHz, CD3OD) δ 8.62 (s, 1H), 8.05 (s, 1Η), 7.92 (s, 1Η), 7·52 (m, 2Η), 7·40 (m ,1Η), 7·02-6·85 (m,3H),5·65 (s,2H),4·23 (t,J=6·3 Hz, 2H), 2.60 (m,6H), 2.00 (m, 2H), 1.61 (m, 4H), 1.47 10 (m, 2H); MS (ESI) m/z 503 (MH+) 125 200800919

Cpd name and data 93 (5-5)-4-amino-6-[3-chloro-4-(3-1-benzyloxy)-phenylamino]pyrimidine-5-formaldehyde 0-(2 -Fofu-4-yl-ethyl)_monthly NMR (300 MHz, CD3OD) δ 8·59 (s, 1Η), 7·98 (s, 1Η), 7·68 (d, J = 2 ·7 Ηζ,1Η),7·42-7·26 (m,4Η), 7.10-7.06 (m,2Η),5·20 (s,2Η),4·38 (t,J = 5·7 Ηζ , 2Η), 3·71 (t, J = 4·8 Ηζ, 4Η), 2·78 (t, J = 5.7 Ηζ, 2Η), , 2·59 (t, J = 4·5 Hz, 4Η) MS (ESI) m/z 499 (ΜΗ+) 94 (5£)-4-amino-6-[3-chloro-4-(3-fluoro-benzyloxy) phenylamino] 0-(2-hexahydroindole-1-yl-ethyl)·moon loss*H NMR (300 MHz, DMSO-&lt;i^) δ 9.63 (s? 1Η), 8.72 ( s, 2H),8·03 (s,1H), 7.85 (d5 J = 3·0 Hz, 1H), 7·49_7·17 (m,7H), 5.23 (s,3H), 4.27 (t,J = 6·0 Hz, 2H), 2·61 (t, J = 5·4 Hz, 2H), 2·50 (m, 4H), 1·51-1·37 (m, 6H); MS (ESI m/z 499 (MH+) 95 (5-5)-4•Amino- 6-(4-+-yloxy-3-a-phenylamino)-, π- -- 5-曱路Ο - ( 2 - six sputum 吼 ° -1 -yl · ethyl) - monthly deficient NMR (300 MHz DMSO-state δ 9.63 (s, 1H), 8.72 (s, 1 Η), 8·03 (s, 1 Η), 7·85 (d, J = 3·0 Ηζ, 1 Η), 7·50-7 ·18 (m,9H),5·21 (s,2H),4·28 (t,J = 6·0 Hz, 2H), 2·61 (t, J = 6·0 Hz, 2H), 2.39 (m,4H),1·49 (m5 4Ή),1·39 (m, 2H) ; MS (ESI) m/z 481 (MH+) 126 200800919

Cpd name and data 96 (5-5)-4-amino-6-[1·(3-fluoro-benzyl)-1Η-oxazol-5-ylamino]-pyrimidine-5-曱 0- (2 - hexanitrogen. 唆-1-yl-ethyl)-month loss NMR (400 MHz, DMSO, δ 9.78 (s, 1H), 8.74 (s, 1 Η), 8.08 (d, j = 302, 2Η),7·99 (s,1Η),7·64 (d,j=9.〇, 1H),7·44-7·32 (m,2H),7.19(s,2H),7.11 -7·01 (m, 3H), 5·67 (s, 2H), 4·27 (t, j = 11.6, 2H), 2·61 (t, j = 11.5, , 2H), 2.49-2.39 ( m,4H),1·50-1.45 (m,4H),1·35 (d, j = 5.0,2H) 97 (5-5)-4-amino-6-[3-chloro-4_(3, 5-Difluoro-benzyloxy)-phenylamino]-pyrimidine-5-carboxamoxime-fluorenyl-ray towel NMR (300 MHz, DMSO, δ 9·60 (s, 1H), 8.71 ( s, 1Η),8·04 (s,1Η),7·88 (d,J=2·7 Ηζ,1Η),7·42 (dd,J=9·3, 2·7 Ηζ,1Η), 7·3〇-7·16 (m,6Η), 5.25 (s,2Η), 3.98 (s,3Η); MS (ESI) m/z 420 (ΜΗ+) Xin 98 (5-5)-4-amine -6-[3-Chloro-4-(3,5-difluoro-benzyloxy)-phenylamino]-°-bite-5-A valence loss *H NMR (300 MHz? DMSO- i/5) δ 11.25 (s, ΙΗ)? 9.81 (s,1Η),8·62 (s ,1Η),8·01 (s,1Η),7·82 (d,J = 2·4 Ηζ, 1H), 7·42 (dd, J = 9·0, 2·7 Hz, 1H), 7 ·23·7.17 (m,6H), 5.23 (s, 2H) ; MS (ESI) m/z 406 (ΜΉ+) 127 200800919

Cpd name and data 99 (5-5)-4-amino-6-[3-chloro-4-(3,5-difluoro-octyloxy)-phenylamino]•Nursing-5-曱备0·(2-?福口林-4-yl-ethyl)· 月亏巾 NMR (300 MHz, DMSO, δ 9.61 (s, 1Η), 8.73 (s, 1Η), 8· 04 (s, 1Η), 7·87 (d, J = 2.7 Ηζ, 1Η), 7·42 (dd, J = 8·7, 2·7 Hz, 1H), 7·29-7·16 (m ,6H),5·24 (s,2H), 4.30 (t,J = 5·7 Hz, 2H), 3.58 (m, 4H), 2.66 (t, J = 5·7 I Hz, 2H), 2.45 (m,4H); MS (ESI) m/z 519 (MH+) 100 (5-5)-4-amino-6-[(lS)-l-phenyl-ethylamino]-pyrimidine-5- Formaldehyde oxime MS m/z 258·1 (MH+) 101 (5-5)-4-amino-6-[1-(3-fluoro-octyl)-1Η-indole-5-ylamino]-pyrimidine- 5-furfural 0-(2-isofazin-4-yl-ethyl)-oxime NMR (400 MHz, DMSO-π) δ 9.72 (s, 1H), 8.73 (s, 1 Η), 7· 95 (s, 1Η), 7·83 (d, j = L7, 1Η), 7·50 (d, j=3.0, 1H), 7·38-7·32 (m, 2H), 7.18-6.97 ( m,6H),6·46 (d5 j2·2,9H),5·43 (s,2H),4·27 t,j = 11.3, 2H),3·55 (t, j=9.0, 4H), 2.65 (t, j = 11.3, 2H), 2·50-2·44 (m, 4H); MS (ESI) m/ z 490 (MH+), 488 (MH-) 128 200800919

Cpd name and data 102(5£)-4-amino-6-[1-(3-fluoro-yl)-111_5-p--5-ylamino]------------- · (2 - Six rat bites -1 -yl-ethyl) · Monthly deficient NMR (400 MHz, CD3〇D) δ 8.61-8.59 (m, 1Η), 7·86-7·83 (m, 1Η) , 7.64-7.62 (m, 1Η), 7·32-7·25 (m, 3H), 7·12-7·08 (m, 1H), 6·96-6·94 (m, 2H), 6 · 77 (d, j=9.3, 1H), 6.51-6.48 (m, lH), 5·41-5·38 (m, 2H), , 4.35-4.31 m, 2H), 2·77·2·74 (m, 2H), 2·53 (s, 1H), 1.59 (s, 4H), 1·45 (s, 2H); MS (ESI) m/z 488 (MH+), 486 (MH-) 103 ( 5£^)_4_Amino- 6-[(lS)-l-phenyl-ethylamino]-n-mp π-carboxylic acid 0-(2-morpholin-4-yl-ethyl)-oxime MS m/z 371.2 (MH+) 104 N-{4-[6-Amino-(5-penta)-5-(methoxyimino-indenyl)-pyrimidine-4-ylamino]-stupylbenzene Indoleamine MS m/z 363.2 (MH+) 10 105 ν·{4_[6-Amino-(5Ε)-5-(1ιγίΐΓ〇χγ-imide-methyl)·Uridylsylamino]Phenyl Benzoylamine MS m/z 349·1 (ΜΗ+) 106 (5-5)-4-amino-6-[(lS)-l-phenyl-ethylamino]Minidine-5- Bismuth citrate-(2-hexahydropyridin-1-yl-ethyl )-肟MS m/z 369.2 (MH+) 107 N-(4-{6-Amino-(5-penta)-5-[(2-hofolin-4-yl-ethoxyimine)-A ]]-pyrimidin-4-ylamino}}-phenyl)-benzimidamide MS m/z 462.2 (MH+) 129 200800919

Cpd name and data 108 (5-5)-4-amino-6-(3-phenylphenylamino)-mouth-densidine-5-formic acid; Ο_(2 _?福福林-4_基-乙Base), monthly loss NMR (400 MHz, CD3OD) δ 8·58 (d, j=2.6, ιΗ) 8·00 (d, j=2.2, 1H), 7·82-7·80 (m, lH) ,7·4(Κ7·36 ' (m,lH),7·20-7·16 (m,1H), 4.37 (t,j = 12.1,2H) 3·71-3·69 (m,4H) , 2·77 (t, j = lM, 2H), 2·58 (d, j=4 g I 4H) ; MS (ESI) m/z 394, 395 (MH+) 396 ' · 109 (5 five) _4-Amino-6-(4-phenoxy-phenylaminodin_5_ formazan-4-yl-ethyl)·monthly loss 4 NMR (400 MHz, DMSO-state δ 8· 12 (s,1H) 7.42-7.34 (m,4H),7.13-7.05 (m,6H),4·02 3 2H)? 3.50 (dj=4.0, 4H), 2.52-2.50 (m, 2H)? 2.33 4H) S' 110 N-{5-[6-Amino-(5-penta)-5-(methoxyimino-methyl)"Midine"4-yl10-amino]-densidine--2 -Base}•Benzamidine MS m/z 365·1 (MH+) 111 (5-5)-4-amino-6-(4-phenoxy-phenylamino)-pyrimidine-5-formaldehyde oxime MS m/z 322.1 (MH+) 130 200800919

Cpd name and data 112 (5Ϊ5_-aminopyrimidine_5·formaldehyde 0-(3_morpholine*4-yl-propyl)_monthly loss iH NMR (400 MHz, CD3〇D) δ 8.56 (s, 1Π ), 7.95 (s, 1Η), 7.66 (d, j=2.5, 1Η), 7·46 (d, j=7.1, 2Η), 7·38-7·26 (m, 4H), 7· 06 (d,j=28.9, 1H),5·15 (s,1H), 4.23 (t,j = 12.5, 2H),3·67 (t5 j=9.6, 4H), 2.53-2.46 (m, I 6H), 2·00-1·90 (m, 2H); MS (ESI) m/z 497 (MH+) 113 methanesulfonic acid (5 £)-3-[4-amino-6-(4-benzyl Oxy-3-chloro-phenylamino)-pyrimidin-5-ylfluorenylaminooxy]-propyl ester NMR (400 MHz, CD3OD) δ 8·58 (s, 1H), 7.95 (s, 1Η), 7.67 (d, j=2.4, 1Η), 7·47-7.45 (m, 2Η), 7·38-7·23 (m, 4H), 7·07-7·04 (m ,1Η),5·14 (s,2Η),4·38 (t,j212·4, 2Η), 4·30 (t,j = 12.2, 2Η), 3·07 (s,3Η), 2.18-2.15 (m,2Η) _ 114 (5-5)-4-amino-6-(4-benzyloxy-3_gas-phenylaminopyrimidine-5-furaldehyde 0·pyridine-2_ Methyl-hydrazine NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 8·52·8·49 (m5 1Η), 7.92 (s, 1Η), 7·85-7·80 (m ,1Η),7·58-7.55 (m,1Η), 7.49-7.42 (m,3Η),7·40-7·28 (m,4H), 7·16-7·12 (m,lH),7·05-7·01 (m ,lH),5·28 (s,2Η), 5·16 (s,2Η) 131 200800919

Cpd name and data 115 (5 £&gt;4-amino-6-(4.benzyloxy-3-a-phenylamino)&gt;pyrimidine-5-formaldehyde 0-[3-(2-methoxy- Ethylamino)-propyl]-肟H NMR (400 MHz, CD3OD) δ 8.56 (s, 1 Η), 7.95 (s, 1 Η), 7·66 (d, j=2.4, 1 Η), 7.46 (d, j=7.6, 2Η),

7·38-7·24 (m, 4H), 7.05 (d, j 2:8, 9H), 5.14 (s, 2H), 4·25 (t, j = 12.3, 2H), 3·49- 3·47 (m, 2H), 3.31-3.29 i (m, 3H), 2.80-2.76 (m, 4H), 1·99-1·92 (m, 2H); MS (ESI) m/z 512, 485 (MH+),483 (MH-) 116 (5E)-4-Amino- 6-(4-Alkyloxy-3-a-phenylamino thiophene _5_ furfural 0-[3- (4-Hydroxy-hexahydropyridin-1-yl)-propyl]-oxime NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.95 (s, 1 Η), 7·66 (d, 卜2·4, 1Η), 7·47-7·25 (m, 6H), 7·05 (d, j = 8.9, 1Η), 5·14 (s, 2Η), 4·21 (t, j = 12.0, 2Η), 3·62 (s, 1Η), 2.84-2.81 (m, 2H), 2·54-2·50 (m, 2H), 2·22-2·18 • (m, 2H), 1·98-1·91 (m, 2H), 1.87-1.83 (m, 2Η), 1.60-1.51 (m, 2H) ; MS (ESI) m/z 511,512 (MH+), 513, 509, 510 (MH-) 132 200800919

Cpd name and data 117 (5-5)-4-[4-amino-6-(4-benzyloxy-3-a-phenylamino)-pyrimidine-5-ylarylene-based oxygen Benzyl]-hexahydropyridine-1-carboxylic acid tert-butyl ester*H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.95 (s, 1 Η), 7·65 (d, j=2.6 , 1Η), 7·48-7·45 (m, 2H), 7.39-7.35 (m, 2H), 7·34-7·23 (m, 2H), 7.09-7.05 (m? 1H), 5.15 I (s, 2H), 4·06 (d, j=6.4, 4H), 2·82-2·75 (m, 2H), 1.81-1.74 (m, 2H), 1·44 (s, 9H), 1.30-1.17 (m,2H); MS (ESI) m/z 567 (MH+), 565 (MH·) Example 2 4-amino-6-(4-benzyloxy-3-chloro-phenyl Amino)-pyrimidin-5-nitrile (Compound 118)

A milk no-胼 compound 2a (82 grams, 〇47 really talk ((M3 ml, 0.94 millimolar) and 4_wulkoxy: hair-benzene =) amine compound 2MU0 mg, 0.47 millimolar) THF (47 ml) = 133 200800919 The solution was stirred at 25 ° C for 3 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. (175 mg, 100%) of off-white solid; 1H NMR (300 MHz, CD3OD) δ 8.42 (S, 1 Η), 7·63 (s, 1 Η), 7·52-7·40 (m, 7 Η), 7· 12 (m,1Η),5·22 (s, 2H),5·19 (s,2) ; MS (ESI) m/z: 373 (MH+)〇

Hz 15 2)

A suspension of compound 2e (10 oz, 0.027 mmol) in MeOH (2······ The reaction mixture was cooled and concentrated. The resulting residue was dissolved in Et 〇Ac (25 mL) and washed with water (15 liters). The organic layer was dried with EtOAc (EtOAc m.) iH NMR (4 〇〇 MHz, CD3OD) δ 8.05 (s, 1H), 7.57 (s, ΐΗ), 7·48 (d, J = 7.2)

Other representative compounds of the invention can be prepared using the W 2 formula: 134 200800919 designation 4-amino-6-[3- gas-4-(3-fluoro-benzyloxy)-phenylamino]-pyrimidine -5-carbonitrile 4-amino-6-[2-(3-fluoro-indolylbenzoxazole·5-ylkamino]-pyrimidine-5-carbonitrile 4_amino-6-Π-(3-fluoro -benzyl)_1H-indol-5-ylamino]-bt-but-5-carbonitrile 4-amino-6-(4-oxo-phenylamino)&gt;pyrimidine-5-carbonitrile 4-amino Use of the following method for the treatment, prevention or amelioration of chronic or acute kinase-mediated diseases, disorders or conditions by -6-(3-a-4-fluoro-phenylaminopyrimidine-5-carbonitrile biologically active compounds Dec. Example 1 Fusion of EGFR kinase glutathione-S-transferase (GST) and EGFR PCR amplification of intracellular portion (NM_005228) used in EGFR kinase assay. The intracellular portion of EGFR begins at the nucleus Glycoside 2189 (corresponding to amino acid 667) and ending with a stop codon. This part was PCR amplified with primers, adding 10 λ attB sequences to each end, recombined into the entry vector, and then to the GST destination vector. Inside (eg Gateway Technologies Manual by Inyitrogen Corporation, Carlsbad, California) 135 200800919 The target vector is recombinantly produced into a shuttle vector in the bacteria of DH1 OB AC strain. The shuttle vector is transfected into Sf 9 cells and the supernatant containing baculovirus is collected. The GSTEGFR protein is infected with the original The large sf 9 cell culture of the virus was purified. After a suitable period of time, the fine 5 cells were collected and dissolved. The GSTEGFR was subsequently purified from the lysate on the glutathione-Sepharose column ( For example, Amersham Biosciences, Buckinghamshire, United Kingdom, EGFR The EGFR substrate was biotinylated by polyGluTyr (128 mg) (Sigma, St. Louis, Missouri) in IX PBS buffer on ice. Prepared by incubating with 12 times molar excess of sulfo-NHS-LC-biotin for at least 2 hours. Free biotin was separated from biotinylated polyGluTyr on a gel filtration column. 10X Kinase Buffer (500 mM Tris, pH 8.0, 100 mM magnesium chloride and 1 mM sodium hypotrophy), DTT (final 1 mM from 500 mM stock), 15 ATP (final 5 μΜ from 10 mM stock), biotinylated polyGluTyr (10 micrograms) /μl stock solution), γ-33Ρ ATP (10 μΟΜ/μΕ stock solution) &gt; and water mixture was added to each well (90 μL/well) of Streptavidin Flashplate (Perkin Elmer, Wellesley, MA). The test compound (2 μL) in 100% DMSO was added to the appropriate 2 wells. Diluted GSTEGFR (diluted 1:300 in 50 mM Tris, pH 8·0 and 0.1% bovine serum albumin) (10 μl) was added to the well to initiate the reaction. The plate was incubated for 1 hour at 30 QC with shaking. The reaction contents were taken out, and the plate was sequentially washed with IX PBS buffer (300 μl, magnesium-free 136 200800919 and other ^GmMEDTA three times. After the last time, the same, the same, the end, the 爰Punching j (2GG soar) was added to the wells. The plates were then sealed and read on a TopCount scintillation counter. The test compounds were tested repeatedly at 16 concentrations on a half log 5 dilution starting at 2 〇〇μΜ. The maximum and minimum signals are determined on each plate. The percent inhibition of the test compound is calculated according to the following formula: • (maximum signal - test compound) · '(maximum signal - minimum signal), j (100) = % inhibition - For the concentration of the test, ICm is generated by plotting the percentage of inhibition on the logarithm of the concentration tested for the particular compound. The EGFR Ic front 10 fruit line is shown in Table 1. π'% Table 1 EGFR IC5〇(MM) Cpd ic50 Cpd IC5〇Cpd ic5〇1 0.07 36 0.02 70 0.02 2 0.008 37 0.02 71 0.01 3 1.1 38 0.1 74 0.06 4 0.01 41 0.4 75 0.008 5 0.5 42 7.8 76 0.01 7 0.05 43 1.4 77 0.02 9 0.02 44 0.07 78 0.02 137 200800919

Cpd IC5〇Cpd IC5〇Cpd IC5〇10 0.005 45 0.05 79 0.008 11 0.008 46 0.02 80 0.3 12 0.04 47 0.01 82 0.2 13 0.2 48 0.04 84 0.01 14 0·1 49 0.03 85 0.02 16 0.01 50 0.02 87 0.03 17 0.02 51 0.04 88 0.009 18 0.03 54 0.02 91 0.007 19 0.02 55 0.04 92 0.05 20 1·2 56 0·3 93 0.02 21 1.5 57 0.2 94 0.02 22 0.3 58 0.03 95 0.05 23 1.9 59 0.05 96 0.06 24 0.09 60 0.05 97 0.03 25 0.03 61 0.2 98 0.02 28 0.9 62 0.2 99 0.07 29 0.2 63 1.2 100 0.02 30 0.03 65 0.04 102 0.04 138 200800919

Cpd IC5〇Cpd IC5〇Cpd ic50 31 0.02 66 0.1 108 0·2 32 0.01 67 0.1 111 0.1 33 0.02 68 0.01 112 0.02 34 0.01 69 0.01 118 0.03 Example 2 HER-2 kinase assay HER_2 kinase used in Proqinase (Freiburg, Germany) consisting of a fusion of GST (Glutathione-S-transferase), HIS6-thrombin, and a nucleotide encoding 679 to 1255 of HER-2 5 (Accession No. M11730) Structural purification. 10X Kinase Reaction Buffer (600 mM Hepes, pH 7.5, 30 mM Magnesium Chloride, 0.03 mM Sodium Vanadate and 500 μg/ml PEG 2 〇, 〇〇〇), DTT (final 1.2 mM, obtained from 10 mM stock), ATP (1 μΜ, obtained from 10 ίο 10 mM stock), biotinylated polyGluTyr (final 1.25 ng/μl, obtained from 1 μg/μl stock), Upstate Biotechnol〇gies, Lake

a mixture of chlorinated (final 3 mM from 1 M stock), γ-33Ρ-ΑΤΡ (10 pCiy^L stock) and water (70 μL/well) added to Streptavidin In each hole of the Flashplate (Cat. # SMPI03, NEN, 15 Boston, ΜΑ). A test compound stock solution (1 microliter) was added to the appropriate wells. Add diluted GSTHER2 kinase (6. 7 ng/μl diluted to 50 mM Tris-Ηα, pH 8.0 and 0.1% bovine serum albumin) (30 μl) (total volume 139 200800919 200 ng/well) Start the reaction. The reaction plate was incubated at 30 ° C for 1 hour. The reaction was terminated by aspirating the reaction mixture from the wells and washing the wells three times with IX PBS stop buffer (3 μL) and 1QQ mM EDTA. After the last wash, 5 identical stop buffer (200 microliters) was again added to the wells. The plate was then sealed and read on a TopCount scintillation counter. The test compound was repeatedly tested three times at a concentration of 8 μg from a single pair of _ number dilutions at 8 concentrations. The maximum and minimum number of tests are determined on each board. The percent inhibition of the test compound is calculated according to the following formula: ° (maximum signal - test compound) 1 10 - ' (maximum ( 1 (100) = % inhibition. For a list of test concentrations, IC5 〇 is by inhibition of the percentage compound The logarithmic value of the tested concentration is plotted. The Her_2 mimetic system is shown in Table 2. C5g results Table 2 HER2 IC5〇(MM)

Cpd ic50 Cpd ic5〇 Cpd — IC5〇 1 0.2 36 0.6 77 0.1 2 0.01 37 0.09 78 0.06 3 5.2 38 0.05 79 0.01 4 0.02 39 14.8 80 100 5 3.7 40 10.6 81 100 140 200800919

Cpd IC5〇Cpd ICso Cpd IC5〇6 0.1 41 3.6 82 100 7 0.1 42 100 83 100 8 0.7 43 10.4 84 0.04 9 0.2 44 1.6 85 0.02 10 0.007 45 0.4 86 100 11 0.01 46 0.1 87 0.07 12 0.05 47 0.03 88 0.02 13 0.1 48 0.02 89 10.0 14 3.1 49 0.01 90 100 15 100 X 50 0.04 91 0.03 16 0.01 51 0.04 92 0.03 17 0.6 52 4.5 93 0.008 18 0.04 53 10.0 94 0.04 19 0.05 54 0.03 95 0.2 20 14.1 55 0.03 96 0.1 21 5.3 60 0.08 97 1.0 22 4.1 63 1.0 98 0.1 23 28,5 64 100 99 0.2 141 200800919

Cpd ic5〇Cpd ------ ICso Cpd ic5〇24 0.2 65 0.2 100 10.0 25 0.3 66 0·2 101 0·06 26 100 67 0·2 102 0.14 27 100 68 0.006 103 100 28 5.5 69 0.004 104 100 29 0.2 70 0.02 105 100 30 0.2 71 0.05 106 100 31 0·3 72 100 107 10.0 32 0.09 73 2.9 108 1·1 33 0.1 74 0·3 109 100 34 0.03 75 0.009 110 10.0 35 100 76 0.03 111 0.3 118 0.1 Example 3 In vitro cell proliferation inhibition assay The ability of a test compound to inhibit unadjusted in vitro cell proliferation can be achieved by measuring the incorporation of i4C-labeled thymidine into a newly constructed DNA within a cell line derived from several tissue-derived carcinomas. The situation is decided. Thus, the ability of the test compound to multiply the proliferation of various phenotypic cells can be determined. The cancer cell lines used include the American Germplasm Conservation Center (the 142 200800919)

American Type Culture Collection) HeLa cervical adenocarcinoma (ATCC Cat. #CCL2), SK-OV-3 ovarian cancer (ATCC Cat· #ΗΤΒ·77), MCF-7 breast cancer (ATCC Cat· # HTB-22), BT474 breast cancer (ATCC Cat· #HTB-20), SKBR3 breast cancer (ATCC Cat. #HTB-30), A431 epidermal 5-like carcinoma (ATCC Cat. #CRL-1555) and NCI-N87 gastric cancer (ATCC Cat· #CRL- 5822) Sputum cancer cells are trypsinized and counted. Cells (3000-8000 counts) were added to each well of a 96-well CytoStar tissue culture treated flash-count microplate (Amersham #RPNQ0160) in complete medium (100 liters), which was then at 37 QC was incubated in complete medium for 24 hours in an inert atmosphere containing 5% CO 2 . Test compounds (1 microliter) in 100% DMSO were added to the plate wells and only DMSO was added to the control wells. The plate was incubated in complete medium at 37 ° C for 24 hours in a 5% CO 2 atmosphere. 15 part of methyl 14C-thymidine (56 mC/mmol) (NEN #NEC568 or

Amersham #CFA532) and complete medium (20 microliters, yielding 0.2 μ(Μ/well) were added to each well and the plate was incubated at 37 ° C for a third 24 hours in a 5% (: 02 atmosphere). The contents of the plate were discarded, the plate was washed twice with PBS (200 μl), and PBS (200 μl) was added to each well after 2 。. The plate was sealed, and the degree of methyl 14C-thymidine incorporation was Quantify on the Packard Top count.

The cell proliferation of the Hela cell line was measured using the ATP-Lite method as described in ATP Lite Kit (Perkin-Elmer Kit Number 6106941) or the aforementioned C14 method. Cell proliferation of other cell lines was measured using the c14 method. 143 200800919 The 1 Csg values of the compounds tested in various cell lines are shown in Tables 3 and 4. The term "NT" means that the compound shown is not tested in a particular cell line. The absence of this test does not mean that the compound is not active in a particular cell line or any other untested cell line. table 3

Hela IC5〇 (μΜ)

Cpd —— 1C50 Cpd IC5〇Cpd IC5〇9 35.0 83 3.6 97 100 19 10.0 84 4.9 98 100 34 3.5 85 15.6 99 100 46 100 86 100 100 10.0 60 10.0 87 4.9 101 25.1 70 10.0 88 10.9 102 1.4 75 40.1 89 10.0 103 10.0 76 59.4 90 10.0 104 10.0 77 10.0 91 9.4 105 100 78 19.6 92 4.7 106 10.0 79 100 93 22.1 107 100 80 100 94 6.1 108 10.0 81 10.0 95 12.1 109 100 144 200800919

Cpd ic5〇 Cpd IC50 Cpd IC5〇 82 100 96 14.7 110 33.1 118 100 Table 4 IC5〇 (MM)

Cpd SK-OV-3 MCF-7 BT474 SKBR3 N87 A431 9 100 86.6 NT NT 0.7 NT 19 19.1 2.5 0.03 0.1 0.04 1.1 34 3.2 3.8 NT NT 0.2 NT 46 NT NT 0·1 0.3 10.0 100 60 10.0 10.0 NT NT 0.6 NT 70 NT NT 0.1 0.4 0.3 14.2 75 10.0 30.7 NT NT 0.001 NT 76 24.1 10.0 0.2 0.3 0.3 1.8 78 100 100 0.06 0.2 0.2 0.8 87 NT NT 0.3 0.5 0.3 3.6 91 5.4 10.0 0.2 0.3 0.2 1.3 92 NT NT 0.2 0.4 0.2 3.1 93 100 100 0.04 0.02 0.07 0.6 145 200800919

Cpd SK-OV-3 MCF-7 BT474 SKBR3 N87 A431 94 1.0 1.0 0.5 0.5 0.4 NT 95 2.4 1.0 10.0 10.0 1.1 100 96 15.3 2.1 0.2 0.4 0.2 0.8 99 NT NT 10.0 100 100 100 101 NT NT 0.05 0.06 0.03 0.009 102 NT NT 0.9 0.7 0.2 0.001 118 NT NT 100 100 100 100 Example 4 N87 human tumor xenograft model N87 gastric cancer cell line overexpresses HER-2 and forms tumors due to gene amplification in nude mice (Kasprzyk PG, Song SU, Di Fiore PP, 5 King CR? Therapy of an animal model of human gastrc cancer using a combination of anti-erbB-2 monoclonal antibodies, Cancer Res., 1992, 52, 2771-2776). Nu/nu female rats (Charles River; 8 to 9 weeks old) were implanted with 320 to 530 N87 gastric cancer cells subcutaneously in the flank. Animals were weighed two times a week during the study and were checked frequently. Tumor size was measured twice a week and was detected every time the neoplasm reached its target weight range (approximately 75 mg). Animals were paired when the tumors were in the range of 62 to 126 mg (average tumor size per group, 70 to 74 mg). The tumor weight was estimated using the following formula: 146 200800919 (Kuan Ling 1) (length) Tumor weight = __ 2 4 The test compound was taken daily after the tumor reached the target weight. In the treatment of 纟日彳Λ u α only + π武 &quot;, the test compound was administered once a day for 3 5 days. In treatment group 2, arsenic bismuth w &gt; ★ The test compound was administered once a day for 30 days. In the treatment group 2, each dose of the test compound was administered once a day through 3 曰 / oral therapy, and 3, each dose of the test compound was administered once a day for 36 days. In the treatment group 5 to 1 ,, the test compound was administered once a day for 30 days. &amp; Tumor weight of the individual (n=8) of the paired test group (n=8) and the adjuvant-treated group. Tumor growth inhibition (in percent) was calculated on the last day of the study using the following formula: Tumor growth inhibition (width 1) (length)

15 147 1 The test compound is administered daily after the tumor reaches the target weight, and the test is performed in the 2 pi adjuvant group. "The average tumor in the test group, tumor growth inhibition = Xl%%__", weight / 3 1 The average tumor weight study results of the adjuvant group are shown in Table 5. The statistical significance was evaluated using the two-tailed Student's t test comparing the adjuvant group with the experimental group. The term "(::" means uncalculated The P value of the treatment group is shown. The lack of this calculation does not indicate that the activity of the compound is not statistically significant in this particular cell line or any other untested cell line. 20 200800919 N87 Tumor Growth Inhibition Treatment Group Cpd Dose ( Mg/kg) TGI P value 1 78 100 71.0% 0.006 2 78 100 69.4% 0.003 3 78 100 59.56% 0.044 3 78 50 50.56% 0.025 3 78 25 41.29% 0.023 4 78 100 49.3% 0.007 4 78 50 33.9% 0.02 4 78 25 6.5% 0.04 5 93 100 59.9% NC 6 94 100 47.1% NC 7 101 100 66% NC 8 112 100 48.6% NC 9 114 100 47% NC 10 115 100 50.2% NC Example 5 A431 Human Tumor Xenograft Model A431 epidermoid carcinoma cell line in nude mice EGFR, activating guide 148 200800919 drives the path of cell proliferation, invasion and retention of cancer cells and forms tumors (Giard DJ, Aaronson SA, Todaro GJ, Arnstein P, Jersey JH, Dosik H, Parks WP, In vitro cultivation of human tumors : establishment of cell lines derived from a series of solid 5 tumors, J. Nai/.Cancer / i, 1973, 51, 1417-1423; and Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J,Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor ίο monoclonal antibody, Proc, Natl Acad. Sci. USA, 1983? 80? 1337-1341) The test compound was orally administered to the test treatment group daily after the tumor reached the target weight. In treatment groups 1 and 2, each dose of the test compound was administered once a day for 25 days. In treatment group 3, each dose of the test compound was administered twice daily for 25 days. In treatment group 4, the test compound φ was administered twice daily for 30 days. In the treatment group 5 to 1 ,, the test compound was administered once a day for 30 days. 20 Using the formula of Example 4, the tumor weight of the individual of the test group and the paired individual of the drug treatment group were measured daily. Tumor growth inhibition was calculated using the isoform of Example 4 on the last day of the study (the results of the study are shown in Table 6. The statistical significance was compared with the adjuvant group and the test_evaluation using the two-tailed incineration. The term % The silky indication does not calculate the value of r::nrp. The lack of this measurement does not indicate that the activity of the compound is significant in this specific sputum or any other untreated cells. (iv) The material growth is inhibited. 149 200800919 Table 6 A431 tumor growth inhibition Treatment group Cpd dose (mg/kg) TGI P value 1 78 100 66.8% 0.025 1 78 30 10.6% 0.553 2 78 100 34.6% 0.216 2 78 50 14.3% 0.571 3 78 100 51.1% 0.038 3 78 50 45.12% 0.106 4 78 100 52% 0.048 5 93 100 64.0% NC 6 94 100 66% NC 7 101 100 51 % NC 8 112 100 33% NC 9 114 100 -3% NC 10 115 100 4% NC Example 6 BT474 Human Tumor Xenograft Model 5 BT474 human tumor cell line overexpresses HER-2 and forms tumor in immunodeficient mice (Rabindran SK, Discafani CM, Rosfjord EC, 150 200800919

Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF and Wissner A, Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the 5 HER-2 Tyrosine Kinase, Cfl/icer 2004, 64, 3958-3965) o Immunodeficiency CB.17 SCID female mice were implanted subcutaneously into BT474 breast cancer cells in the posterior flank. Animals were weighed twice a week during the study and were checked frequently. After the tumor reached the target weight, the test compound was orally administered to the test treatment group daily. In treatment group 1, each dose of the test compound was administered once every one day for 25 days. In treatment group 2, each dose of the test compound was administered twice daily for 25 weeks. Using the formula of Example 4, the tumor weight of the individual in the test group (n=8) and the paired individual (n=8) in the adjuvant-treated group was measured daily. Tumor growth inhibition (in percent) was calculated at the last sigma of the study using the formula of Example 4. 15 The results of the study are shown in Table 7. Statistical significance was assessed using the two-tailed Student's t-test comparing the adjuvant group with the experimental group. Cpd dose (mg/kg) of BT474 tumor growth inhibition treatment group TGI P value 1 78 50 27% 0.100 2 78 100 52% 0.004 3 78 200 56% 0.019 151 200800919 i brain barrier penetrating compound 7 8 blood brain barrier wear, The name of the class, such as the postal beta, is in the vein of the Sprague Dawley male (3 g/kg) or a test.乂,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ! The composition samples were taken after 25 hours, 〇5 hours, and ι small % after administration. 10 Oral (PO) formula consists of 1 mg / 3⁄4 liter in the adjuvant (〇 5% 曱-based cellulose), after the injection, 丄 n 尺 only ϋ ϋ · 5 hours, 1 hour and 2 hours Blood water samples were taken. ^ Plasma samples (0.5 ml) were collected and centrifuged (2000 rpm, 3 min), and stored at -60 °C until LC analysis was performed. Brain samples were collected immediately after the last blood collection. The sample was dried with 〇·9% Ν&amp;α Run 15 and weighed and placed in a propylene round bottom tube containing Falcon ι4 φ ^ liter containing 3 ml of methanol. The sterol mixture was homogenized with OMNI ΤΗ 115 homogenized and centrifuged at 7,000 rpm for 10 minutes. The supernatant was removed and stored frozen in a 15 liter polyethylene test tube at 6 ° C until LC-MS/MS analysis. 152 200800919 Table 8 Concentrations in plasma (ng/ml) and brain (ng/g) 60·〇. 60 minutes (plasma) mean itSEM brain/gold slurry ratio------- 73.6 + 16.4

120 minutes (brain) P.o. 120 minutes (brain) i · v. 6 0 minutes (jk pulp) i·v· 60 minutes (brain) 46.1 + 17.4 51.16 + 13.71 124.1 + 5.5 306.9 + 55

。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Incorporate various publications listed in Γ 。. These publications are generally described in the present specification in the present specification. 153 10

Claims (1)

200800919 X. Patent application scope: 1. A compound of formula (I) And a form thereof, wherein L is selected from the group consisting of a bond, a Ci 6 alkyl group or a halo 6 alkyl group; 5 Ar system, a self-aryl group, a heteroaryl group, a benzo-fused heterocyclic group or a stupid fused 匸3^% alkyl, wherein the stupid ring portion of the benzofused ring system is attached to the L variable; Ra is selected from the group consisting of ΟΝ-Ο-ΐ or cyano; Ri is selected from the group consisting of =, Cl_8 alkyl, Ci 8 olefin , Ci 8 alkoxy, Cw alkoxy oxime I·8 k group, fluorenyl-CNS alkyl, trans-Cu alkoxy, amine _ci 8 alkyl, Cw alkyl-amine _Ci· 8-alkyl, Ci 8 alkoxy-Ci 8 alkyl-amine f alkyl, Cw alkylsulfonyl &lt;18 alkyl, alkyl-sulfonate:oxy-Cw alkyl, aryl, aryl Alkyl, aryloxy_heart 1_8 alkane f, heterobasic eCl 8 alkyl, heterocyclyl-carbonyl-Cw alkyl or hetero 15 aryl-Cw alkyl, wherein the aryl-Cw alkyl group is as appropriate Substituted by one, two, three, four or five substituents each from the following: thiol, alkyl, 154 200800919 Cl-8 alkoxy, amine, Cl.8 alkyl-amine or CN8 alkoxycarbonyl, and wherein the heterocyclyl-C!.8 alkyl group is optionally selected from the following on the heterocyclic group by one, two, three or four Substituted by a substituent: hydroxy, Cw alkyl, /Cw alkoxy, amine, C!-8 alkyl-amino or Cw alkoxycarbonyl; R2 is selected from hydrogen, Cw alkyl or Ci-8 alkoxy; R3, R4, R6, R6 and R7 are each selected from the group consisting of hydrogen, halogen, hydroxy, Cw alkyl, 匕8 alkoxy, Cl-8 alkoxy-Ci 8 alkyl, hydroxy 8 alkyl, _yl-Cw alkyl , hydroxy-Ci_8 alkoxy, halo-Ci_8 alkoxy, amine, Cu alkyl-amino, amino-Ci8 alkyl, alkyl-aminoalkyl, carboxyl, C!_8 fluorenyl, C 8-alkoxycarbonyl, C3-l2 cycloalkyl, aryl, aryloxy, aryl-Cm alkyl, aryl-8 alkoxy, aryl-nonylamino, heteroaryl, heteroaryloxy , heteroaryl/(alkoxy) or heterocyclic, 15 Wherein aryl, aryloxy, aryl-Cl8 alkyl and aryl.CM alkoxy are each viewed on the aryl group by one, two, three, four or five selected from the group consisting of Substitution: cyano, pixel, hydroxy, -8 alkyl, CM alkoxy, amine, Cw alkyl-amine, amine-Ci 8 alkyl, Ci 8 alkyl-amino-Cw alkyl or Cl · 8 alkoxycarbonyl, and wherein the heteroaryl and heteroaryloxy are each optionally substituted on the heteroaryl by one, two, three, = or five substituents selected from the group consisting of Ci_8 alkyl, amine _Ci_8 anthracene, Cw alkyl-amino-Cw alkyl, fluorenyl, Cw decyl or c18 alkoxycarbonyl. 2. A compound of the scope of the patent application, wherein the Ra system is 155 20 200800919 C^N-O-R!. 3. If you apply for a patent scope! A compound of the formula wherein the Ra is a cyano group. 4. The compound of claim 1, wherein Ri is selected from the group consisting of hydrogen, (: -8 alkyl, cN8 alkenyl, cle8 alkoxy, c -8 alkoxyalkyl, hydroxy_Cl-8 alkyl, hydroxy _Ci8 alkoxy group, amine group _Ci8 oligo group, C!·8 alkyl group _amino group · Cl · 8 alkyl group, Ci 8 alkoxy 8 alkyl group amine group - C ^ 8j element base, C!- 8-alkyl group-continuation hydrazino group, c1-8 alkyl group-sulfonyloxy-Cw alkyl group, aryl group, aryl-Ci 8 alkyl group, aryloxyalkyl group, heterocyclic group-Cw alkyl group, a heterocyclyl-carbonyl-Ci 8 alkyl or heteroaryl-Cu alkyl group, wherein the aryl-C decyl group is optionally substituted on the aryl group with a substituent selected from the group consisting of a hydroxyl group, a Cw alkyl group, Cl_8 alkoxy group, amine group, Ci 8 alkyl group-amino group or Cu alkoxy group, and wherein the heterocyclic group -C 8 alkyl group is optionally substituted on the heterocyclic group with a substituent selected from the group consisting of Substituting a hydroxyl group, a C!-8 alkyl group, a cN8 alkoxy group, an amine group, a Cw alkyl-amino group or a Cw alkoxycarbonyl group. 5. A compound according to claim 1, wherein the Ri is selected from the group consisting of argon , Cw alkyl, Cl-8 alkenyl, Cl-8 alkoxy, Cl-8 alkoxy-Cu alkyl, hydroxy-C!-8 alkyl, hydroxy-Cw alkoxy, --cK8 alkyl, Cw alkyl-amino-Cw alkyl, Cl-8 alkoxy-Ci 8 alkyl-amino-C!-8 alkyl, C -8 alkyl-sulfonyl-Ch alkyl , 〇ν8 alkyl-sulfonyloxy-C-8 alkyl, aryl, aryl_cN8 alkyl, aryloxy-c-8 alkyl, heterocyclic-C-8 alkyl, hetero Cyclo-carbonyl-C 8 alkyl or heteroaryl-C1-8 ;): complete, 156 200800919 wherein the aryl-c -8-alkyl group is optionally substituted on the aryl group with a C 8 alkoxy group, And wherein the heterocyclic-C 1 -8 alkyl group is optionally substituted on the heterocyclic group by the O, Y, Y, Y, Y, Y,,,,,,,,,,,,, 5. A compound according to claim 1, wherein Ri is selected from the group consisting of hydrogen, Cw alkyl, cK8 alkenyl, Cl-8 alkoxy-Cl 8 alkyl, hydroxy-Cw alkyl, hydroxy-Cw alkoxy, Cw alkyl-amino-Ci 8 alkyl, Ci·8 oxy-Ci·8-alkyl-amino-Cu alkyl, cK8 alkyl _ shi oxime-C!·8 alkyl, aryl , aryl-C ???8 alkyl, aryloxy 0 alkyl, heterocyclyl-C1·8 alkyl, heterocyclyl-carbonyl-Cw alkyl or heteroaryl-Ci_8 alkyl, "wherein aryl The -Cu alkyl group is optionally substituted on the aryl group with a Ci-8 alkoxy group, and wherein the heterocyclic group -C!_8 alkyl group is optionally substituted on the heterocyclic group via a hydroxyl group or a Cu-fired 5-oxo-trans group. 7. The compound of claim 1, wherein the compound is selected from the group consisting of hydrogen or a C 1 -8 alkyl group. 8. The compound of claim 1 wherein R3, r4, r5, r6 and r7 are each Selected from hydrogen, halogen, carboxyl, c18 alkyl, -Ci-d-oxyl, Cu-oxygen-Ch-alkyl, trans-Cu-based, halo-Cw alkyl, hydroxy-Cl-8 alkoxy , halo-Ci_8 alkoxy, amine, C!-8 alkyl-amino, amine-Cl 8 alkyl, Ci 8 alkyl-aminoalkyl Carboxyl, Cw fluorenyl, CK8 alkoxycarbonyl, C3-12 cycloalkyl, aryl, aryloxy, aryl-C-8 alkyl, aryl-C!-8 alkoxy, aryl 157 200800919 - amidino, heteroaryl, heteroaryloxy, heteroaryl- or heterocyclyl, U from a lactyl group, an aryl group, an aryl 'alkyl group, and an aryl fluorene 8 methoxy group - or two Each of the following substituents is substituted for the paste = square = ? cCl; l group, Cl · 8 alkoxy group, amine group, c two material &quot; alkylamino group ~ alkyl group or k 10 15 9 · Rs among them The consumption basis is on the basis of the material _ self-replacement of τ ^ ^ CN8 alkyl, amine _Ci.8 alkyl, c (10) based - amine I, ground, carboxyl, C! · 8 fluorenyl Or a C1-s aerobic carbonyl group. The compound of claim 1, wherein each of R4, R5, and jUR7 is selected from the group consisting of hydrogen, halogen, thiol, Ci_8 alkyl, Cu alkoxy, (:, ·8 silk) _cv8 alkyl, via _Ci 8 alkyl, dentate 4-8 alkyl, via _Ci_8 alkoxy, functional group alkoxy group, amine group, CN8 alkyl group, amine group, amine group _Ci 8 alkyl, Ci 8 alkylamino-Cl.8 alkyl, carboxyl, Cw fluorenyl, CN8 alkoxycarbonyl, c3 12 cycloalkyl, aryl, aryloxy , aryl-Ci8 alkyl, aryl decyloxy, aryl-nonylamino, heteroaryl, heteroaryloxy, heteroaryl-Ci_8 alkoxy or heterocyclic, wherein aryl, aryl -Cw and aryl 8 alkoxy groups are optionally substituted on the aryl group with one or two substituents each selected from the group consisting of cyano, halogen or Cu alkoxy, and wherein the heteroaryloxy group The heteroaryl group is optionally substituted with a c alkyl group. 10. The compound of claim 1, wherein 158 20 200800919 ~, ^6 and !17 are each selected from the group consisting of hydrogen, tooth C]-8 alkoxy, and dentate. Alkyl, aryl, aryloxy = -Cw alkyl, aryl_Cl_8 alkoxy squary, heteroaryl-cN8 alkoxy or heterocyclic ketone W, heteroaryloxy', H, : and aryl-Ci_8 alkoxy are each optionally substituted with a substituent selected from the group consisting of a nitrogen atom or a C -8 alkoxy group, and Wherein the heteroaryloxy group is optionally substituted with a heteroaryl group via an alkyl group. 10 11. The compound of claim 1, wherein L is selected from the group consisting of a bond, a Cw alkyl group or a _ group-(:1_6 alkyl group; and the Ar system is selected from the group consisting of an aryl group, a heteroaryl group, and a benzo-fused _ a heterocyclic group or a benzo-fused cycloalkyl group, wherein the benzene ring portion of the benzofused ring system is σ = L variable; 'RA is selected from ON-O-Ri or cyano; 15 R! is selected from Hydrogen, Cw alkyl, Cw alkenyl, Cl 8 alkoxyalkyl, I hydroxy-Cw alkyl, hydroxy-cK8 alkoxy, Cw alkyl-amino-Cu alkyl, Cu oxygenated-Cu alkyl- Amino 々·8 alkyl, Cl 烧 _ 石 醯 醯 - - C C C C C C 院 院 院 院 院 院 院 院 院 院 院 院 院 院 院 院 院 院 院 院 院 院Alkyl, heterocyclyl-carbonyl-Ci &amp; alkyl or hetero 20 aryl-Ci-8 alkyl, 'wherein aryl-C -8 alkyl is optionally on the aryl via C!·8 Substituted by a methoxy group, and wherein the heterocyclyl-C1 -8 alkyl group is optionally substituted on the heterocyclic group via a thiol or c oxacarbonyl group; 200800919 5 R2 is selected from the group consisting of hydrogen, CV8 alkyl or Ci 8 alkoxy; and I is selected from the group consisting of hydrogen, halogen, thiol, alkyl, 8 兀 sheep i aryl -8 alkoxy, aryl, aromatic Its -C1-8 alkyl, aryl seven U burnt, ~ soil base, heteroaryl ~ alkoxy or heterocyclic, soil - based, hetero-milk base: 1: burnt base and shape ^ 2 : or substituted with a substituent selected from the group consisting of cyano, halogen or C!-8 alkoxy, and 10 15 Wherein the heteroaryloxy group is optionally substituted with a heteroaryl group. 12) The compound of claim 2, wherein the L is selected from the group consisting of a bond, a C. 6 alkyl or a halo-Cl 6 alkyl group; and the Ar is selected from the group consisting of a phenyl "t-based κ group, a +-based group. "(4) base, benzoheptinyl: benzo-flavor, benzo-, π, 3] dioxacyclo, 2.3-dihydro-sinyl or hydroquinone, wherein carbazolyl, fluorenyl , benzofuranyl, benzimidazolyl, benzo(1) anthracene dioxolane, 2.3-dihydro-sinyl and fluorenyl benzene ring moieties linked to l variables; From ON-OR" or cyano; R! is selected from the group consisting of hydrogen, Cw alkyl, Cw alkenyl, Cl-8 alkoxy-Ci 8 alkyl, trans-Cu alkyl, hydroxy-Cw alkoxy, cN8 Alkyl-amino-Ci s alkyl, C 8 · 8 alkoxy-C -8 alkyl-amino-Cw alkyl, Cl 8 alkyl _ sulphur oxy-CN8 alkyl, aryl, benzene --Cm alkyl, phenoxy-Ci8 alkyl, phoxet-4_yl-Cl·8 alkyl, hexahydropurine s-butyl _C18 alkyl, safflower-4-yl-syl-Ci · 8 alkyl or 吼 base _cN8 alkyl, 160 .200800919 wherein phenyl-Cw alkyl is optionally substituted with Gy alkoxy on the phenyl group, and the hexahydropyridyl-Cy alkane Optionally substituted on the hexahydropyridyl group via a hydroxyl group or a C!_8 alkoxy group; 5 R2 is selected from the group consisting of hydrogen, C.8 alkyl or oxime-8 alkoxy; and R3 R4 R6 and R7 are each Is selected from the group consisting of hydrogen, _, thiol, Cu alkyl, CM alkane, aryl-Ci.8 alkoxy, phenyl, phenoxy, phenyl ^本基C〗 · 8 纟 氧基 oxy, phenyl-branched amine, fluorenyloxy, 隹 基 -Cw alkoxy or oxime _4_ base, where = phenyl phenyl. The w group and the phenyl group to the silk group are each optionally substituted with a substituent selected from the group consisting of cyano, leucovorin or Cl.8 alkoxy, and 10 wherein the pyridyloxy group is optionally a pyridyl group.上经13· A compound of formula (la): Re and its form, wherein L is selected from the group consisting of a bond, c 161 15 200800919 R! is selected from the group consisting of hydrogen, c!_8 alkyl, CK8 alkenyl, Ci-8 alkoxy, Ci 8 alkoxyalkyl, hydroxy-Cw , hydroxy-Ci8 alkoxy, amino-Ci8 alkyl, Cw alkyl-amino-Cl.8 alkyl, χΐ8 alkoxy-Ci 8 alkyl-amino-C!·8 alkyl, C !-8 alkyl sulfoalkyl, alkyl sulfo 5 decyloxy, aryl, aryl-CV8 alkyl, aryloxy-Ci-8 alkyl, heterocyclyl-Cw alkyl a heterocyclic group -carbonyl-Ci 8 alkyl or a heteroaryl-Cu alkyl group, wherein the aryl-Cw alkyl group is optionally one, two, three, four or five each selected from the group consisting of aryl groups Substituted by a substituent: a hydroxy group, a C18 alkyl group, a 10 Cl.8 alkoxy group, an amine group, a Cw alkyl-amino group or a Cw alkoxycarbonyl group, and wherein the heterocyclic alkyl group is optionally subjected to a heterocyclic group. One, two, three or four substituents each selected from the group consisting of a hydroxyl group, a Ci 8 alkyl group, a Cl 8 alkoxy group, an amine group, a Ci-8 alkyl-amino group or an 8-alkoxycarbonyl group; R2 is selected from hydrogen, Cw alkyl or cN8 alkoxy; and &gt; R3, Rule 4, R5, H R7 are each selected from the group consisting of hydrogen, halogen, hydroxyl, ci 8-alkyl, C!-8 alkoxy, Cw alkoxy-Ci-8 alkyl, hydroxyalkyl, halogen Gw alkyl, hydroxy-Ci-8 alkoxy, halo-Ci8 alkoxy, amine, Cw alkane Amino-amino, amino-Ci 8 alkyl, 8-alkyl-amine 20-alkyl, carboxyl, Cu sulfhydryl, alkoxycarbonyl, c3-12 cycloalkyl, aryl, aryloxy, aryl-C18 alkane Alkyl, aryl-c18 alkoxy, aryl-nonylamino, heteroaryl, heteroaryloxy, heteroaryl-c alkoxy or heterocyclic, wherein aryl, aryloxy, aryl C18 alkyl and aryl_C1_8 alkoxy each 162 200800919 two, three, four or five selected from the group consisting of halogen, hydroxy, Cw alkyl, Cw alkane, substituted on the aryl group by a substituent : cyano, oxy, amine, Cw alkyl-amino, aminoalkyl, Ci 8 alkyl-amino-Cw alkyl or Ci 8 alkoxycarbonyl, and wherein heteroaryl and heteroaryloxy Each of the heteroaryl groups is optionally substituted with one, two, three, four or five substituents selected from the group consisting of C18 alkyl, amino-cN8 alkyl, CK8 alkyl-amino-Ci8 alkyl , carboxyl group, Cl 8 fluorenyl group or C!_8 alkoxy group. 14. A compound of formula (lb): And a form thereof, wherein L is selected from the group consisting of a bond, a cN6 alkyl group or a halo-Ck alkyl group; and is an atomic group selected from the group consisting of -N(R(n=c(R3)_, =NN(R3) )-C(R3)= , -n(r3)-c(r3)=c(r3)- , -c(r3)2_c(r3)2-c(r3)2_ , 15 -〇_c(r3) 2,o- , -n(r3)-c(r3)=n-, -0-C(R3)=C(R3)- or -N(R3)-C(R3)2-C(R3)2 - wherein the dotted line in formula (lb) 163 200800919 indicates the position when one or two double bonds are present in the atomic group; h is selected from the group consisting of hydrogen, cN8 alkyl, Cl-8 alkenyl, Ci-8 alkoxy, Ci 8 alkoxy•c^alkyl, hydroxy-Cls alkyl, hydroxyalkoxy, amino-Cw 5 alkyl, Cw alkyl-amino-Cw alkyl, Cl-8 alkoxy-Ci 8 alkyl-amine --Ci·8 alkyl, Cl-8 alkyl sulfonyl -8 alkyl, Cw alkyl-decyloxy-Cw alkyl, aryl, arylalkyl, aryloxyalkyl, heterocyclyl- Cw alkyl, heterocyclyl-carbonyl-Ci 8 alkyl or heteroaryl-CK8 alkyl, 10 wherein aryl-Cw alkyl is optionally one, two, three, four or five on the aryl group Substituted by a substituent selected from the group consisting of hydroxy, C18 alkyl, C!-8 alkoxy, amine, Cw alkyl-amine or 8-alkoxycarbonyl And wherein the heterocyclyl-Cw alkyl group is optionally substituted on the heterocyclic group with one, two, three or 15 substituents each selected from the group consisting of a hydroxyl group, a cl-8 alkyl group, a CNS alkoxy group, An amine group, a Ci-8 alkyl-amino group or a Cy alkoxycarbonyl group; R2 is selected from hydrogen, Cu alkyl or Cw alkoxy; and R3 is selected from the group consisting of hydrogen, dentate, hydroxyl, Cn8 alkyl, Ci 8 Alkoxy, Ci_8 oxime-CN8 alkyl, hydroxy-(^8 alkyl, halo-cN8 alkyl, hydroxy 0-Cl.8 alkoxy, halo-Cw alkoxy, amine, cK8 alkyl _Amino, Amino-C!·8 alkyl, C!·8-alkyl-amino-CN8 alkyl, carboxyl, cN8 酉&amp; base, Cl_8^oxycarbonyl 'C3 — !2 Cycloalkyl, aromatic , aryloxy, arylalkyl, aryl_Cl_8 alkoxy, aryl-nonylamino, heteroaryl, heteroaryloxy, heteroaryl-C!-8 alkoxy or heterocyclic , 164 200800919 wherein an aryl group, an aryloxy group, an aryl-Cw alkyl group, and an aryl-C_8 alkoxy group are each a hindered member having one, two, two, four or five substituents selected from the group consisting of Substituted: cyano, halogen, hydroxy, c1-8 alkyl, Cl 8 alkoxy, amine, Cw alkyl-amine, amine _Cl -8 alkyl, cl 8 alk-5-amino-Cl-8 alkyl or cN8 alkoxycarbonyl, and wherein the heteroaryl and heteroaryloxy groups are optionally substituted on the heteroaryl group by one, two, three, Substituted by four or five substituents selected from the group consisting of Cw alkyl, amino-C-8 alkyl, Cw alkyl-amino-Ci-8 alkyl, carboxyl, Ci-8 thiol or C 1-8 oxygenated A few bases. 10 15. Compound of formula (Ic): NH And its form, where T / 么, 职人 κ," 八 L variable; a heterocyclic group or a benzo-fused-C3_12 I benzene ring moiety attached to a C 8 alkyl group, 165 200800919 Cw alkoxy, Cw alkoxy _(^_8 alkyl, hydroxy_Cl-8 alkyl , halo-Cm alkyl, hydroxy-Cl-8 alkoxy, halo-Ci 8 alkoxy, amine, C.8 alkyl-amino, amine-Ci_8 alkyl, C&quot;alkyl-amine -Cw alkyl, carboxyl, Cl-8 fluorenyl, Ci 8 alkoxycarbonyl, C312 cycloalkyl, aryl, aryloxy, aryl-c18 alkyl, arylalkoxy, aryl-decylamine Alkyl, heteroaryl, heteroaryloxy, heteroaryl-c18 alkoxy or heterocyclic, wherein aryl, aryloxy, aryl-Cualkyl and aryl-Cl8 alkoxy are optionally used The aryl group is substituted with one, two, three, four or five substituents selected from the group consisting of cyano, spectrin, hydroxyl, CN8 alkyl, C18 alkoxy, amine, Cw alkyl-amine, Amino-Cl 8 alkyl, Cl-8 alkyl-amino-Cl.8 alkyl or C!-8 alkoxycarbonyl, and wherein the heteroaryl and heteroaryloxy groups are optionally one or two on the heteroaryl group. , three, four or five substituents selected from the following: C1_8 alkyl, amino-C!·8 alkyl, Cw alkylamine a C?-8 alkyl group, a carboxyl group, a C!-8 fluorenyl group or a Ci_8 alkoxy group. The compound of claim 15 wherein R2 is selected from the group consisting of hydrogen. A compound according to item 15, wherein each of R3, R4, R5, R6 and R7 is selected from the group consisting of hydrogen, halogen, hydroxy, Cl-8 alkyl, Ci.8 alkoxy, C-8 oxy-Cu-based, and thio- Cw alkyl, halo-Ci-8 alkyl, hydroxy-Cw alkoxy, halo-Cw alkoxy, amine 'C»·8 alkyl·amine, amine-Cw alkyl, cN8 alkane Alkyl-amino-cle8 alkyl, carboxyl, CN8, Cw alkoxycarbonyl, c3-12 cycloalkyl, aryl, aryloxy, aryl-Cw alkyl, aryl-Cw alkoxy, aryl 166 200800919 benzyl-nonylamino, heteroaryl, heteroaryloxy, heteroaryl fluorene or heterocyclic group, &amp; 5 wherein aryl, monoaryl-Cw alkyl and aryl hydrazine are optionally used Substituted on the aryl group by one or two substituents selected from the group consisting of: cyano, dentate, thiol, cN8 alkyl, cl 8 alkoxy, amine, Ci 8 alkyl-amine, amine Alkyl-C!-8 alkyl, Cl-8 alkyl-amino-Ci8 alkyl or alkoxycarbonyl. A compound according to Item 15, wherein each of R3, R4, R5, &amp; 6 and R7 is selected from the group consisting of hydrazine, halogen, hydroxy, alkyl, 1 〇Ci-8 alkoxy, Cw alkoxy _Cl-8 alkyl , hydroxy 8 alkyl, halo-Cw alkyl, hydroxy-Cl.8 alkoxy, _yl-〇1-8 alkoxy, amine, Cw alkyl-amino, amine-Ci.8 alkyl, Ci8alkyl-amino-Cy, yl, syllabic, cN8 fluorenyl, cN8 alkoxy group, C312 cycloalkyl, aryl, aryloxy, aryl-C-8 alkyl, aryl_Ci · 8 alkoxy, aryl 15-yl-nonylamino, heteroaryl, heteroaryloxy, heteroaryl-Cw alkoxy> or heterocyclic group, &gt; wherein aryl, -aryl-Cl. The alkyl group and the aryl group _Ci8 are optionally substituted on the aryl group with one or two substituents each selected from the group consisting of a cyano group, a halogen or a cN8 alkoxy group. 20 19. The compound of claim 15, wherein each of R3, R4, R5, R6&amp; r7 is selected from the group consisting of hydrogen, dentate, hydroxyl, Cw alkyl, Cukoxy, halo-C!-8 Oxy, aryl, aryloxy, aryl-C!-8 alkyl, aryl_Cl-8 alkoxy, aryl-nonylamino, heteroaryloxy, heteroaryl-Cl -8 alkoxy or Heterocyclyl, 167 200800919 ', the Chinese radical, the -aryl-Ci_8 alkyl and the aryl-Ci.8 oxime are each substituted on the aryl group with one or two substituents each selected from the group consisting of: Cyano, halogen or cN8 alkoxy. 2〇\"A compound of claim 15 wherein L is selected from the group consisting of a bond, a Ci-6 alkyl group or a halo-CN6 alkyl group; a fluorene f ^ group, a heteroaryl group, a benzo fused group Heterocyclyl or benzo-fused -C3.i2 % fluorenyl, wherein the benzene ring moiety of the benzofused ring system is attached to the L variable; the reverse watt R2 is selected from hydrogen, Cl.8 alkyl or CK8 Alkoxylate; and 10 15 ^, ^^ and each of the cores are selected from the group consisting of hydrogen to halogen^yloxyalkyl, ^alkoxy, fluorenyl-Cl-8 alkoxy, aryl, aryloxy = -8 a aryl group, a aryl group, a heteroaryl group, a heteroaryl-Ci»8 alkoxy group or a heterocyclic group, wherein = group, aryl group - alkyl group and aryl group The c18 alkoxy group is optionally substituted with one or two substituents each selected from the group consisting of halogen or cK8 alkoxy. 2L a compound of formula (Id): Re 168 200800919 and its form, wherein L is selected from the group consisting of a bond, C!-6 alkyl or halo-Cl_6 alkyl; R2 is selected from hydrogen, Cw alkyl or Cl-8 alkoxy; and R3, R4 , R5, R, and R7 are each selected from the group consisting of hydrogen, halogen, hydroxy, ci 8 alkyl, Cw alkoxy, C!-8 alkoxy-Cw alkyl, hydroxy-Cw alkyl, halo-C!-8 alkane a group, a hydroxy-Cw alkoxy group, a halo-Ci8 alkoxy group, an amine group, a C?8 alkyl-amino group, an amine group-cU8 alkyl group, a c!-8 alkyl-amino group-CK8 alkyl group, Carboxyl group, Cw fluorenyl group, C 8 ·8 alkoxycarbonyl group, c3_12 cycloalkyl group, aryl group, aryloxy group, aryl-Cl_8 alkyl group, aryl group -cN8 alkoxy group, aryl group amide group, heteroaryl group a heteroaryloxy group, a heteroaryl*C18 alkoxy group or a heterocyclic group, wherein the aryl group, the aryloxy group, the aryl-CN8 alkyl group and the aryl-Cl8 alkoxy group are each optionally bonded to an aryl group. , two, three, four or five substituents selected from the group consisting of: cyano, halogen, hydroxy, C18 alkyl, alkoxy, amine, C!-8 alkyl-amino, amine _cN8 An alkyl group, an alkyl-amino group-C!·8 alkyl group or a Cu alkoxy group, wherein the heteroaryl group and the heteroaryloxy group are each optionally substituted on the heteroaryl group. Two, three, four or five substituents selected from the group substituted: CN8 alkyl group, an alkyl group -CK8, Cw alkyl - -CK8 alkyl group, a carboxyl group, Cl_8 Cw acyl or alkoxycarbonyl group. 22. A compound of formula (le): 169 .200800919 And a form thereof, wherein the IL is selected from the group consisting of a bond, a Cw alkyl group or a halo-Cl 6 alkyl group; and the XYZ-line is an atomic group selected from the group consisting of -N(r3)_n=c(R3), =nn( R3).c(r3)= , -n(r3)-c(r3)=c(r3)· , 5 -C(R3)2-C(R3)2-C(R3)r , -〇-C (R3)2_〇_, -N(R3)-C(R3)=N-, 0-c(r3)=c(r3)· or,Ν(Ρ:3χ(Κ3ν€:(κ士; The dotted line in the formula (10) indicates the position when one or two double bonds are present in the atomic group; the _ rule 2 is derived from hydrogen, Cu alkyl or Cb8 alkoxy; and the core is selected from nitrogen, halogen, and thiol. , c18 alkyl, c18 alkoxy, h alkoxy-Cw alkyl, hydroxy-Ci-8 alkyl, halo-Ci 8 alkyl, hydroxyalkoxy, halo-C1-8 alkoxy, amine, C18 alkyl-amino, amino-C!.8 alkyl, Cl.8 alkyl-amino-Ci.8 alkyl, carboxy, Cw= group, Cw alkoxycarbonyl 'C3·!2 cycloalkyl , aryl, aryloxy, aryl-C1_8 alkyl, aryl_C1_8 alkoxy, aryl-nonylamino, heteroaryl, heteroaryloxy, heteroaryl_C1_8 alkoxy or heterocyclic Base, 170 200800919 wherein aryl, aryloxy, aryl-cN8 alkyl and aryl-Cl8 alkoxy Substituted on the aryl group by one, two, three, four or five substituents selected from the group consisting of cyano, halogen, hydroxy, C18 alkyl, Cw alkoxy, amine, Cw alkyl-amino , amino-Ci_8 alkyl, 8-alkyl-amine 5-yl-Cl.8 alkyl or C!-8 alkoxycarbonyl, and wherein the heteroaryl and heteroaryloxy groups are optionally subjected to a heteroaryl group. Two, three, four or five substituents selected from the group consisting of Cw alkyl, amine I _Cl 8 alkyl, Cl 8 alkyl-amino-Ci-8 alkyl, carboxyl, Cw decyl or Cu The compound of any one of claims 1 to 22, wherein the bean is selected from the group consisting of: ~(5-5)-4-amino-6-(3-chloro-4.fluoro -phenylamino)-pyrimidine_5-formaldehyde oxime-methyl-month-deficient, (5-5)-4'-amino-6-[1-(3-fluoro-octyl)]Hn5-ylamino Pyrimidine-5-carboxaldehyde oxime_methyl_moon loss, • (5 pentaamino-6·[3·gas-4·(3-fluoro-n-yloxy)-phenylamino]-pyrimidine-5-formaldehyde 〇-曱基_月亏, (10)_4·Amino _6_(3·methoxy-4 phenoxy-phenylamino W-pyridin-5-carboxaldehyde oxime- fluorenyl group, monthly loss, (5 5)-4 -amino group 6_(4_decyloxy_3_chlorophenylamine) Midine-5-nonanal oxime-mercapto-fat, (10)-4-amino-6-[1♦fluorooctyl)_1Η_ρ引唾_5_ylamino]· 171 200800919 Pyridine-5-decanoic acid 〇-ethyl-month-deficient, (5-5)-4-amino-6-[1-(3-fluoro-octyl)_1Η"Thrazole_5-ylamino]· 口密咬-5-carboxylic acid 〇-Lactyl _ _ _ _, (5 5) 4-amino-6-[1-(3-fluoro-benzyl) Η 吲 吲 _ 5 5 _ _ 甲醛 甲醛 甲醛 甲醛 甲醛 甲醛·Third butyl-fat, (5-5)-4-amino-6-[(lS)-L-phenyl-ethylamino]-pyrimidine_5_曱 Ο -ethyl-monthly loss , (5 5)-4-amino-6-(lHH5-ylamino)·pyrimidine oxime 0-ethyl-moon-deficient (5-5)-4amino-6-[3-chloro-4 -(3·fluoro-n-yloxy)-phenylamino]-a-densitidine-5-carboxylic acid 0-ethyl-month-deficient, (5-5)-4·amino-6·[1-( 3-fluoro-indolyl-5-ylamino]-pyrimidine-5-furfural 0-(2-norfosolin-4-yl-ethyl)_yield, (5-5)-4-amino -6-(4-phenoxy-phenylamino)- 密密咬_5-曱 〇-φ 曱-肟, (5E)-4-amino-6-(4-octyloxy- Phenylamino-based biting Ο-曱-------(5£)-4-amino- 6·[1 -(3·fluoro). Sodium-5-ylamino]-pyrimidine-5-carboxaldehyde 0-isobutyl-indole, (5-5)-4-amino-6-[1-(3-fluoro-)-yl--- -5-ylamino]-pyrimidine-5-carboxaldehyde 0-(2-phenoxy-ethyl)-indole, 172 200800919 (5£)-4-amino-6-[3-chloro-4-(pyridine -2-yl decyloxy)-phenylamino]pyrimidine-5-furfural 0-fluorenyl-hydrazine, (5£*)-4-amino-6-[1-(3-fluoro-fluorene) Base)-111-0 引-5-ylamino] pyrimidine-5-furfural 0-ethyl-hydrazine, (5-5)-4-amino- 6- [l-(3 - gas-卞Phyto-5-ylamino]pyrimidine-5-furfural 0-methyl-hydrazine, (5-5)-4-amino-6-(3-&gt;odor-phenylamino)-0唆-5-曱搭〇-曱望基-月亏, (5五)-4-amino- 6·(4-fluorenyloxy_3_gas-phenylamino)-mouth bite-5 _甲 Ο 乙基 -ethyl-monthly loss '(5 5)-4-amino- 6- [3- gas-4-(° ratio bite 3-yl lactyl)-phenylamino]-pyrimidine-5 -Formaldehyde 0-methyl-indole, (5-5)-4-amino-6-[1-(3-fluoro-benzyl)-1Η-indazol-5-ylamino]·pyrimidine-5-formaldehyde 0-(4-decyloxy-benzyl)-indole, φ (5E)-4-amino-6-[1-(3-fluoro-benzyl)-1Η-indazol-5-ylamino] · Pyrimidine-5-formaldehyde 0-(2-methoxy-benzyl)-indole, (5£)·4-amino-6 [1-(3-Fluoro-benzyl)-1Η-oxazol-5-ylamino]-pyrimidine-5-furfural 0-benzyl-indole, (5-5)-4·amino group_6-[ 1-(3-Fluoro-benzyl)-1Η-indazol-5-ylamino]-pyrimidine-5-furfural 0-isopropyl-hydrazine, (5-5)-4-amino-6-( 1-benzyl-1Η-indazol-5-ylamino)-pyrimidine 173 200800919 -5-nonanal oxime-methyl-oxime, (5-5)-4•amino-6-(1········· 1Η-, azole _5_ylamino)-pyrimidine-5-carboxaldehyde-ethyl-hydrazine, {5-[6-amino-(5-penta)-5-(methoxyimine-oxime Base)-pyrimidine_4_ylamino]-indazole-1_ylmethylbubenzonitrile, 3-{5-[6-amino-(5-penta)-5-(ethoxyimine-methyl ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Oxazol-5-ylamino]pyrimidine-5-furfural 0-methyl-indole, (5-5)-4-amino-6-[1-(3-a-octyl)-1 oxazole -5-ylamino]-pyrimidine-5-carboxaldehyde-ethyl-fat, (5-5)-4-amino-6-[2_(3-fluoro-indolyl)-iH-benzimidazole_5 _ 胺 基 ] 唆 · · · · · 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基5 5)-4-Amino-6-[2-(3-fluoro-indolyl)-1Η-benzo嗤_5_ylamino]pyrimidine-5-carboxaldehyde-methyl-oxime, (5-5)-4-amino-6-[1·(3-fluoro-benzyl)-1H-carbazole- 5-aminoamino]-pyrimidine-5-nonanal oxime _phenyl_yellow, (5-5)-4-amino-6-[1-(3_fluoro-benzyl)·1Η_carbazole _ 5_ylamino]_'biting-5-formaldehyde oxime_(2_methoxy-ethyl)_肟, 174 200800919 (5z)-4-amino-hk (3|segment base)·1Η_^_5_ Amino]pyrimidine-5-furfural 0-(3-hydroxy-propyl&gt; oxime, (5-5)-4-amino-6-[indolyl(3-fluoro,+yl)]Hn5-yl Amino] pyrimidine-5-formaldehyde 0-(3-dimethylamino-propyl)-indole, (5-5)-4-amino-6-(4-benzyloxy_3_chloro_ Phenylamino)-pyrimidine-5-methyl 0 (2-methoxy-ethyl)-yield, (5E)-4-amino-6-[l-(3-fluoro-indolyl)- 2,3-Dihydro, -1H-port 〇 〇-5-ylamino]-, π _ _ _ 曱 〇 曱 曱 曱 · · 月 月 , , , , , , , , , , , , , 3-Gas-4-(3-Fluorobenzyloxy)-phenylamino]-O-Methoxy-5-indole 0-(3-Ph-propyl-propyl)-monthly loss, (5 )-4-amino-6-(4-+-oxy-3-hydro-phenylamine-based nib-5-decanoic acid 0-(3-carbyl-propyl)-monthly loss, (5-5) 4-amino-6-(4-benzyloxy_3_chloro-phenylamino)-pyrimidine-5-oxime Aldehyde oxime, _(5-5)-4_amino-6-(4-benzyloxy-3-a-phenylamino)-pyrimidine-5·曱(9-(2-? 4-yl-ethyl)-monthly, (5-5)-4-amino-6-(4-+-yloxy-3-chloro-phenylamino)-,.定-5 -曱(9-(2-Isofos-4-yl-ethyl)-moon-salt hydrochloride, (5E)-4_amine·6-[3_气-4-( 3-fluorooxy)-phenylamino]-pyrimidine-5-carboxamidine, (5-5)_4_amino-6-[1-(3-fluoro-octyl)pyridin-5-ylamine基]· 175 200800919 Pyrimidine-5-furald oxime, (5 5) _4_ Amino-6-[l-(3-fluoro-azetidine-formaldehyde 0-(3+-soil)] H-mouth-salting- 5-aminoamino]-yl, internal group)-hydrazine, (5-5)-4_amino group, 6-[1-(3_fluoro, *5-methyl benzophenanthene: ylamino)· 5 5)-4-Amino-6-[1-(3_fluoropyrimidine-5-carboxammine, lower group)-1Η-吲5-5-ylamino]_ I (5E) 4-amino-6 -[1-(3_气_笔喷咬_5·甲搭〇_(3_经基心_1H-+朵_5·ylamino)-土-内基)_月亏, (5 five )-4-amino,6-[1-(3_a pyrimidine-formaldehyde oxime-(3_丄气土oxazol-5-ylamino)-(3,, acridine-fluorenyl-yl- Propyl)_肟, (5五)-4-amino-6-[3_chloro-4 n &gt; base l·q-5-A disk 〇·(2·„( I· 基 氧基 oxy) Phenylamine 1 horse brown-4-yl-ethyl) 肟, (5 5)-4-amino-6-[3- gas ^ ^ base] marriage-5·甲盘广基氧)_ Phenylamine d, pyridin-1-yl- Base)·肟, (5五)·4-Amino-6-(4-benzyl 4, Q &gt;· w , » ^ n „ base gas · phenylamino)-pyrimidine-5-aconel -(2-hexahydropurine + base · ethyl),, amine IK3 · gas 4 base sit _5 · ylamino]_ 〇疋 〇 〇 〇 · (2-hexahydro nHl-yl-ethyl )·Yue loss, (5 5)-4-amino-6-[3- gas-4-(3,5-difluoro-Jimei M, #盆胺基]•,唆-5-曱〇·Methyl·monthly loss, earthy soil)-based 176 200800919 (5-5)-4·Amino·6-[3-chloro-4-(3,5-difluoro-benzyloxy)_ Phenylamino]-11-densidine-5-A stagnation, (5-5)-4-amino-6-[3-chloro-4-(3,5-difluoro-benzyloxy) Phenylamino]-pyrimidine-5-formaldehyde 0-(2-morpholino-ethyl)·肟, (5£&gt; 4-amino-6-[(lS)-l-phenyl_ Ethylamine; μpyrimidine-5-formaldehyde oxime, (5£&gt; 4-Amino-6-[1-(3-fluoro-benzyl)-1Η-吲哚巧_ylamino]_ When pyridine-5-carboxaldehyde 〇(2_morpholine_ 4_基_乙)_肟, (5五)冰胺基)-1Η-十五-5-ylamino]_ 唯定定-5-甲骏〇_(2_六氢吼小小Base ethyl ester, (5-5)-4-amino-6-(4.octyloxy_3_chloro-p-stylaminopyridin-5-carboxaldehyde 〇_(3_?福咐_4 _基·propyl)·monthly loss, , 丄-amine * Μ 4 · lower oxy - 3 · chloro - phenylamino) - shout.定_甲〇〇·[%·methoxyethylamino)-propyl]_yield or 4 nitrileamino-o-octyloxy-31phenylamino)_ remaining 5· The compound is a compound of the protein-promoting substance in the range of the first to the second of the patent application, and the second enzyme is selected from the group consisting of EGFR, HER q 4 , and the chemical substance. The protein is stimulated by a 1 or HER-2. 26. The compound of any one of the preceding paragraphs, wherein the compound is a compound of any one of the preceding claims, wherein the compound is a compound of any one of the preceding claims. It is in its singular form. 28. A compound as claimed in the scope of patent application, wherein the compound is in the form of its metabolite. A compound according to any one of claims 1 to 27, wherein the "Haihuakou" is labeled with a ligand as a label and is selected from a gas or gas radioligand. ^ Ligand 30 · A composition of medical music, the pot contains the compound on the right side of the 27th. There is a pharmaceutical composition of the scope of the application of the patent scope 10 15 20: 1. For example, the pharmaceutical composition of claim 30, wherein the compound::: the effectiveness is between about 〇. Xie gram / kg to about In the range of kilograms of body weight. I 32· A method for preparing a pharmaceutical composition, which comprises a compound of #人4^#27 and a pharmaceutically acceptable compound of the two-species agent, which comprises an effective amount as claimed in the patent scope 27 items 34. If the drug is in the scope of patent application, the drug is in the range of about mg/kg, =/, and the medium compound. The amount is up to 300 g/kg. Body weight 35. A method according to claims 1 to 27, which is an inhibitor selected from the group consisting of EGFR, coffee or -=:=: chymase, the method comprising the egg and the receptor The compound is contacted. The beta kinase function of this department • The method of claim 35, wherein the method is 178 y 200800919 = the compound is used as a pharmaceutical composition, a drug or (4) for treating =, preventing or A disease-causing disease, disorder, or condition that is mediated by a good kinase. The method of 5, wherein the method further uses the compound as a medicament. 3 8· A chronic or urgent person for treating, preventing, or improving an individual in need from the pI# I Gube kinase mediated a pharmaceutical composition for a disease, condition or condition, comprising: an effective amount of a compound as claimed in any one of the claims of claim 7 10 10 15 20 3 8 as claimed in claim 38 a pharmaceutical composition further comprising a disease, a condition or a condition for improving chronic or acute egfr, her_i or her_2) V. The pharmaceutical composition of claim 38 of the patent scope, wherein The compound and the film are in the range of about 1 gram per kilogram to about 30 milligrams per kilogram per day. The medicinal composition of 38 parts of the patent range 毛Wherein the disease = or condition is associated with an increased or unadjusted protein kinase transmission of the individual and the like. = is a pharmaceutical composition such as /2, surrounding item /8, wherein the compound ', ', Use in the form of western medicine, medicine, or pharmaceutical preparations. For example, in the scope of patent application, 38 medical compositions, wherein the disease::= condition is osteoarthritis, rheumatoid arthritis, synovial spasm in arthritis, administration & 1 person &quot; evening ^ Sexual sclerosis, myasthenia gravis, diabetes, diabetic angiopathy, association, diabetic retinopathy, retinal vascular proliferation, cerebrovascular disease, Crohn's disease, ulcerative colon Yan, 179 200800919 Skeletal disease, transplantation or bone marrow transplant rejection, septic shock, fibroproliferative and sub-growth; f pancreatitis, central nervous system diseases, neurodegenerative skin diseases or conditions, post-neural damage And diseases related to axonal degeneration: or = or spinal orbital damage to cancer, eye diseases, viral infections, acute or chronic or kidney disease. Rickets, lung or lung disease or kidney 2; Shi Guang as in the patent scope of the 43rd medical composition, 1 each mu-sex cancer is selected from the sputum, the birth, the sputum and the sputum acute or intestinal Rectal, Lu, Head or Neck Cancer, Breast Cancer, Society 10 15 20 Colloid: Pulmonary Epidermoid Cancer, Esophageal Cancer, Gastric Cancer, God: Card 2: ί: Pancreatic Cancer, Prostate Cancer... Renal Cell Carcinoma, Carcinoma ; and disk: wide:: 1 two:. Ma), leukemia, lymphoma or nipple, cancer-related lesions, selected from abnormal cell proliferation, tumor growth, tumor vascular disease, tumor angiogenesis: / s or metastatic cancer cell invasion and movement. 180 1 2 2 2 2 2 2 2 2 2 2 2 2 2 180 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病 疾病Alzheimer's disease (Alzhei s, s disease), selection ==rkinson, s disease) or stagnation camp; among them, ocular diseases are mold infections: autologous] glaucoma; among them, the virus infection is selected, the pulse is changed, Vascular lesions caused by neointimal formation or transplantation, such as hyperkinesis, where the lung or lung disease is selected from allergic asthma, pulmonary fibrosis, pulmonary fibrosis, or chronic obstructive pulmonary disease; and its renal or renal disease 200800919 2Acute or chronic forms of glomerulonephritis or membranous hyperplasia, 'prosciutitis, glomerular sclerosis, congenital polycystic kidney development $ _ or renal fibrosis.襄 襄 『 『 『 『 『 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 46 The endometrium is a drug composition of cancer, lung cancer, nest cancer, 10 disease, sputum::: patent dry circumference* 38 items, which is mediated by 2 kinases. Cancer, selected from the bladder t 1: two; breast cancer, colorectal cancer, stomach cancer, 48 in the uterus by bite, nest cancer, prostate cancer or renal cell carcinoma. 48. For example, the medical and medical group of the 38th item of the patent scope, the disease, illness or condition is an individual, ,, shouting 15 20 cancer, and the compound or the brain contains the compound In the brain or spinal plexus 2: 2 3 2 ~ "Life, 苴 亨 亨 仆 必 η η 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 善 善 善 善 善 善 善 善 善 善 善2. For example, the pharmaceutical composition of the patent application scope 3 &gt; oral therapy, prevention or improvement of viral infections in individuals and baboons. The tympanic kinase-mediated cytomegalovirus is a pharmaceutical composition of claim 38, and the human body can be used as an aid to chemotherapy and radiation therapy. 52 52. The pharmaceutical composition of claim 38, which is used in combination with at least 181 200800919 a therapeutic agent. 53. If the application is in the 52nd section of the patent application, it is a chemotherapeutic agent for treating cancer. And the composition of the invention, wherein the therapeutic agent 54. Two are in the same. The effective amount of the therapeutic agent used to treat, prevent or ameliorate the condition is a reduced amount. , / ^ Γ华之^ Please (4) the medicine and composition of the 52nd item, which is administered to the individual during or after the parting of the agent. A process for the preparation of a compound according to any one of the preceding claims, comprising the steps of: a. reacting a compound of formula 与1 with a base to produce a compound of formula :2: C1 〇 CI ΝΗ, Α2 C1 . 15 b· reacting a mixture of a compound of formula Α2 with an alkaline reagent with a compound of formula A3 to produce a compound of formula A4: NH Nh2 c. reacting a compound of formula A4 with NH2OH hydrochloride to yield a compound of formula A5 which is representative of the compound of claim 1 of the patent: 182 200800919 /OH d - reacting a mixture of a compound of formula A 5 and an inert reagent with a compound of formula a 6 (Q! in the pot is a halogen-free group) to give a compound of formula A7, which is a compound of claim 1 representative: e. A compound of formula A7 and a compound of formula A8 (the towel Q2 is a halogen-free group) Inversely, a compound of the formula A9 is produced, which is representative of the compound of the first application of the patent scope: f• Metabolizes the substance 9 to produce a compound of the formula A10, 10 which is a compound of the compound of claim 1 of the 183 200800919 patent range. The method of preparing a compound according to the scope of the patent application comprises the steps of: a. a. mixing a compound of the formula B1 with an alkaline reagent to produce a compound of the formula B2: A A3 b. reacting a compound of formula B2 with a compound of formula N(R2)H2 to produce a compound of formula B3 which is representative of a compound of claim 1 of the scope of the patent application. 184 10 200800919 VII. Designation of representative representatives: (1) The representative representative of the case is: (No). (2) A brief description of the component symbols of this representative figure: None 10 VIII. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention. 4