TW201002697A - Morpholino pyrimidine derivative used in diseases linked to mTOR kinase and/or PI3K - Google Patents

Abstract

A compound of formula (I) or a pharamaceutically acceptable salt thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by an mTOR kinase and/or one or more PI3K enzyme.

Description

201002697 IX. Description of the Invention: [Technical Field] The present invention relates to N-morpholinylpyrimidine compounds, processes for preparing the same, and pharmaceutical compositions thereof, and their use in therapy, for example, in the treatment of proliferative diseases such as cancer And, in particular, for use in diseases mediated by mTOR kinase and/or one or more PI3K enzymes. [Prior Art] It is now very clear that the imbalance between oncogenes and tumor-suppressor genes can contribute to the formation of malignant tumors, for example, by increased cell proliferation or increased cell survival. It is also known that signaling pathways mediated by the PI3K/mTOR population have a central role in many cellular processes, including proliferation and survival, and that these pathways are dysregulated in a wide range of human cancers and other diseases. Pathogenic factors. The macrolide antibacterial rapamycin (sirolimus) is labeled as the enzyme mTOR. This enzyme belongs to the lipid kinase inositol (PI) kinase-associated kinase (PIKK) population of protein kinases, which also includes ATM, ATR, <DNA-PK and hSMG-1. mTOR, like other members of the PIKK population, does not have measurable lipid kinase activity, but instead functions as a serine/threonine kinase. Much of the understanding of mTOR's messages is based on the use of rapamycin. Rapamycin first binds to the 12 kDa immunoglobulin FK506-binding protein (FKBP 12), and this complex inhibits mTOR signaling (Tee and Blenis, Cell and Development Biology Symposium, 2005, 16, 29 -37). The mTOR protein line contains a catalytic kinase functional site, a FKBP12-rapamycin binding (FRB) functional site, close to the C-terminus and up to 20 longitudinal rows. 137081 201002697 Repeated HEAT host at the N-terminus to infer the functional site, And FRAP-ATM-TRRAP (FAT) and FAT C-terminal functional sites (Huang and Houghton, Pharmacological Current Insights, 2003, 3, 3Ή-377). mTOR kinase is a key regulator of cell growth and has been shown to regulate a wide range of cellular functions including translation, transcription, mRNA conversion, protein stability, actin cytoskeletal reorganization and autologous consumption (Jacinto and Hall, Natural Review of Molecular and Cell Biology, 2005, 4, 117-126). The mTOR kinase system integrates information from growth factors (such as insulin or insulin-like growth factors) with C nutrients (such as amino acids and glucose) to regulate cell growth. The mTOR kinase is activated by growth factors through the PI3K-Akt pathway. The most well-characterized function of mTOR kinase in mammalian cells is to regulate translation through two pathways, meaning activation of ribosome S6K1 to enhance the 5'-terminal oligopyrimidine (TOP) Translation of mRNA, with inhibition of 4E-BP1, to allow CAP-dependent mRNA translation. In general, researchers have used the inhibition of rapamycin and related rapamycin analogues to explore the physiology of 111 011 based on the specificity of mTOR as an intracellular marker. Pathological role. However, recent data indicate that rapamycin has a mutable signaling effect on mTOR and indicates that direct inhibition of mTOR kinase functional sites is comparable to that achieved by rapamycin. Broad anticancer activity (Edinger et al., Cancer Researc H, 2003, 63, 8451-8460). Thus, potent and selective inhibitors of mTOR kinase activity can be used to allow for a more complete understanding of mTOR kinase function and to provide useful therapeutic agents.

There is considerable evidence that pathways upstream of mTOR, such as the PI3K 137081 201002697 pathway, are frequently activated in cancer (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501; Bjornsti and Houghton, Nature Reviews Cancer, 2004, 4, 335-348; Inoki et al, Nature Genetics, 2005, 37, 19-24). For example, components of the PI3K pathway are mutated in different human tumors, including activating mutations in growth factor receptors, and amplification and/or overexpression of Π3Κ and Akt. In addition, there is evidence that endothelial cell proliferation can also be based on mTOR signaling. Endothelial cell proliferation is stimulated by the activation of vascular endothelial growth factor (VEGF) by the ΡΒΚ-Akt-mTOR signaling pathway (Dancey, Expert Insights on Research Drugs, 2005, 14, 313-328). Furthermore, the mTOR kinase signaling message is influenced by factor-1 a (HIF-1 a), which is caused by hypoxia, and partially controls VEGF synthesis (Hudson et al., Molecular and Cell Biology, 2002). , 22, 7004-7014). Therefore, tumor angiogenesis can be determined in two ways, depending on the message from mTOR kinase, through tumor and stromal cells, synthesis by VEGF hypoxia, and VEGF stimulation through endothelial proliferation and survival, after ΡΒΚ-Akt- mTOR sends a message. These findings indicate that pharmacological inhibitors of mTOR kinase should have therapeutic value to treat various forms of cancer, including solid tumors such as carcinomas and sarcomas, and leukemias and lymphoid malignancies. In particular, inhibitors of mTOR kinase should have therapeutic value for the treatment of, for example, breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer, and bronchial pulmonary cell carcinoma) and cancer of the prostate, with bile ducts, bones, Bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, nest, membrane, skin, sputum, verrucous, uterus, cervix and vaginal cancer, and leukemia (including ALL and 137081 201002697 CML ), multiple myeloma and lymphoma. In addition to tumorigenesis, there is evidence that the mTOR kinase system plays a role in an array of defective tumor syndromes. Recent studies have confirmed that tumor suppressor gene proteins, such as TSC1, TSC2, PTEN, and LKB1, closely control mTOR kinase signaling. Loss of these tumor suppressor proteins results in a range of defective tumor symptoms due to elevated mTOR kinase signaling (Tee and Blenis, Cell and Development Biology Symposium, 2005, 16, 29-37) . Regulatory dysfunction of mTOR kinase has a cluster of established C-linked syndromes, including Peutz-Jeghers syndrome town (PJS), Cowden disease,

Bannayan-Riley-Ruvalcaba Syndrome (BRRS), Proteus Symptoms, Lhermitte-Duclos disease, and trochanteric induration (TSC) (Inoki et al, Nature Genetics, 2005, 37, 19-24). Patients with these syndromes develop characteristic benign tumor tumors in multiple sexual organs.

Recent research has revealed the role of mTOR kinase in other diseases (Easton & Houghton, Professional Insights on Therapeutic Subjects, 2004, 8, 551-564). Rapamycin has been inactivated as an effective immunosuppressive agent by inhibiting the proliferation of T \ cells and B cell antigens and antibody production (Sehgal, Transplantation Journal, 2003, 35, 7S-14S) And thus mTOR kinase inhibitors may also be useful immunosuppressive agents. Inhibition of the kinase activity of mTOR can also be used to prevent restenosis, which means controlling the undesired proliferation of normal cells in the distribution of blood vessels, which responds to the introduction of vascular stents in the treatment of vascular distribution diseases (Morice et al., New England Medicine) Journal, 2002, 346, 1773-1780). Furthermore, rapamycin analogues, everolimus, reduce the severity and incidence of cardiac allograft vascular disease (Eisen et al., New England Medical Journal 137081 201002697, 2003, 349, The 847-858 enhanced mT〇R kinase activity is associated with cardiac hypertrophy, which is of clinical importance as a major risk factor for heart failure and the result of increased cell size by cardiomyocytes (10) & BleniS, Seminar on Cell and Developmental Biology, 2〇〇5,16,29_37). Therefore, mTOR kinase inhibitors are expected to be valuable in the prevention and treatment of diseases other than cancer. It is also believed that many of these N-morphine (tetra) derivatives may have inhibitory activity against the phospholipid inositol (PI) 3 - kinase population of the kinase. 1 / #脂脂肌醇 (PI) 3_ kinase (ship) is a lipid kinase that exists everywhere, which is used as a ', downstream of the surface cell body of the field, and in the path of the intracellular cell membrane and protein pathway Transducer. All pi3K are bispecific enzymes with lipid kinase activity which phosphorylate phosphoinositides at the 3-meridyl position and less fully characterized protein kinase activity. Ϊ́3κ_ catalytic reaction of lipid products, including phospholipid inositol 3,4,5-triphosphate [ρ,4,5妁], phospholipid inositol 3,4-bisphosphate [ρι(3,4) Ρ2] and phospholipid creatinine 3_monophosphate II [ΡΙ(3)Ρ]' constitute a second messenger in a variety of message transduction pathways, including cell proliferation, adhesion, survival, cellular reorganization and cell The sac must pass the path. The ΡΙ(3) Ρ system is present in all cells in the composition, and its content is not significantly changed after the stimulant stimulation. Conversely, Dan (3,4疋2 and (3'4,5)P3 are not found in most cells, but they accumulate rapidly when stimulated by a stimulant. H3K-produces 3 - The downstream action of phosphoinositide second messenger, which is mediated by the target molecule. The molecule contains a 3-phosphoinositide-binding functional site, such as a pleckstrin homologous _ functional site, and recently confirmed 137083 - 10· 201002697 FYVE and phox functional sites. The well-characterized protein targets for PI3K include PDK1 and protein kinase B (PKB). In addition, tyrosine kinases such as Btk and Itk are dependent on PI3K activity. The PI3K population of lipid kinases can be classified into three groups based on their physiological specificity (Vanhaesebroeck et al., Trends in Biol. Sci., 1997, 22, 267). Class III PI3K enzymes alone make PI Phosphorylation. In contrast, the type II PI3K enzyme phosphorylates both PI and PI 4-phosphate [PI(4)P]. Type 1卩131<: enzyme system makes 1,1) and? 14,5-bisphosphate [?1 (4,5)? 2] Phosphoryl thiolation, only the PI (4,5) P2 is physiologically physiological. Phosphorylation of PI(4,5)P2 produces a lipid second messenger PI(3,4,5)P3. The far-relevant member of the lipid kinase supergroup is a class IV kinase, such as mTOR (discussed above), and a DNA-dependent kinase that causes the protein to undergo a serine/threonine residue. Chemical. The most studied and understood PI3K lipid kinase is the class I PI3K enzyme. Class I PI3K is a heterodimer comprising a pllO catalytic subunit and a regulatory subunit. This ethnic group is further divided into species la and species lb enzymes based on regulatory partners and regulatory mechanisms. The type la enzyme contains three different catalytic subunits (pllOa, pllOyS, and ρΙΙΟά), which are polymerized with five different regulatory subunits (ρ85 α, ρ55 α, ρ50 α, ρ85, and ρ55 7〇, in which all catalytic subunits It is capable of interacting with all regulatory subunits to form a variety of heterodimers. The species la ΡΙ3Κ generally regulates the subunit SH2 functional site and activates the receptor or conjugate or protein such as the specific phosphonium group of IRS-1 - The interaction of tyrosine residues is activated in response to growth factor stimulation of the receptor tyrosine kinase. Both pi 10 α and pi 100,000 are structurally represented by 137081 * 11 - 201002697 in all cell types. However, plio (5 expression is more restricted to white blood cell populations and some epithelial cells. In contrast, a single species of enzyme contains a pii〇r catalytic subunit that interacts with ρίοι regulatory subunits. Furthermore, species lb The enzyme is activated in response to the G-protein coupled receptor system (GPCR) and its performance is shown to be restricted by white blood cells and cardiomyocytes.

There is considerable evidence that the species la PI3K enzyme is involved in a wide variety of human cancers, either directly or indirectly, to promote tumorigenesis (Vivanco and Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, the pi 10 α subunit is a tumor of some tumors such as the ovary (Shayesteh et al, Nature Genetics, 1999, 21, 99-102) and the cervix (Ma et al, oncogene, 2000, 19, 2739-2744). It is enlarged. More recently, activating mutations in the catalytic position of the ρΙΙΟα catalytic subunit have been associated with various other tumors, such as the colorectal region and breast and lung tumors (Samuels et al., Science, 2004, 304, 554). Tumor-associated mutations in the ρ85 alpha regulatory subunit have also been identified in cancer, such as ovarian and colon cancers (Philp et al, Cancer Researc H, 2001, 61, 7426-7429). In addition to its direct effect, it is generally believed that the activation of the species la Π3Κ contributes to the tumorigenesis event, which occurs upstream of the signaling pathway, for example by receptor tyrosine kinase, GPCR system or ligand integrin dependence. Sex or ligand independent activation (Vara et al, Review of Cancer Therapy, 2004, 30, 193-204). Examples of such upstream signaling pathways include overexpression of the receptor tyrosine kinase erbB2 in a variety of tumors that result in activation of the PI3K vector pathway (Harari et al, Oncogene, 2000, 19, 6102-6114), Overexpression with ras oncogenes (Kauffmann-Zeh et al, Nature 1997, 385, 544-548). In addition, the category la PI3K 137081 -12- 201002697 can indirectly contribute to the development of tumors caused by various downstream signaling events. For example, it will catalyze the loss of PI (3,4,5)P3 conversion to PI(4,5)P2, and the loss of PTEN tumor suppressor gene lyase activity, and the production of PI via a wide range of PBK media (3) , 4, 5) P3 dysregulated tumors are associated (Simpson and Parsons, Exp.  Cell Res. , 2001, 264, 29-41). Furthermore, the enhancement of the role of other PI3K media signaling events can contribute to a variety of cancers, for example, through the activation of Akt (Nicholson and Anderson, Cell Signaling, 2002, 14, 381-395). In addition to its role in the message of proliferation and survival in vector tumor cells, there is evidence that the species la PI3K enzyme promotes tumorigenesis in tumor-associated stromal cells. For example, it is known that PI3K signaling plays an important role in mediating endothelium cells in response to angiogenic factors such as VEGF angiogenesis events (Abid et al., Arterioscler.  Thromb.  Vase.  Biol. , 2004, 24, 294-300). Because of the type I PI3K enzyme also involves mobility and migration (Sawyer, Expert Opinion Investig.  Drugs, 2004, 13, 1-19), PI3K enzyme inhibitors should provide therapeutic benefit by inhibiting tumor cell invasion and metastasis. In addition, the class I PI3K enzyme plays an important role in the regulation of immune cells that contribute to the pre-neoplastic action of inflammatory cells (Coussens and Werb, Nature, 2002, 420, 860-867). These findings indicate that the pharmacological inhibitors of the class I PI3K enzymes have therapeutic value in the treatment of various diseases, including various forms of cancer diseases, including solid tumors such as carcinomas and sarcomas, and leukemias and lymphoid malignancies. In particular, inhibitors of the species Κ3Κ enzymes should have therapeutic value for the treatment of, for example, the breast, colorectal, lung (including small cell lung cancer, non-small cells 137081 -13 - 201002697 lung cancer and bronchial lung cancer) and cancer of the prostate , with bile ducts, bones, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vaginal cancer, and leukemia (including ALL and CML), multiple myeloma and lymphoma. PI3K 7, species lb PI3K, was activated by GPCR, which was finally confirmed in mice lacking the enzyme. Therefore, neutrophils and macrophages derived from PI3K r-deficient animals fail to produce PI(3,4,5)P3 in response to various chemokines (such as IL-8, C5a, fMLP, and MIP). -la) stimulation, however, the signalling of the species la PI3K by the protein tyrosine kinase coupling receptor remains intact (Hirsch et al., Science, 2000, 287 (5455), 1049-1053; Li et al., Science, 2002, 287 (5455), 1046-1049; Sasaki et al., Science, 2002, 287 (5455), 1040-1046). Furthermore, the phosphorylation of PI(3,4,5)P3 by PKB was not initiated by such GPCR ligands in cells without PI3Kr. As a result, the results were noted, at least in resting hematopoietic cells, PI3K7 is a separate PI3K isoform recombinant, which is activated in vivo by GPCR. When wild-type and ΡΙ3ΚΤ+ mice bone marrow-derived neutrophils and peritoneal python cell lines were tested in vitro, reduced but not completely eliminated properties were found in the chemotaxis and adhesion assays. However, this translates into a sudden decrease in neutrophil infiltration by the IL-8-driven neutrophil (Hirsch et al., Science, 2000, 287 (5455), 1049-1053). Recent data indicate that the PI3Kr system is involved in the path-finding process, rather than the mechanical force generation of motility. 'The random migration has not diminished in cells lacking PI3K 7 (Hannigan et al., Proc.  Nat.  Acad, of Science of U. S. A. , 2002, 99 (6), 3603-8). The data linking PI3K τ to the pathology of respiratory diseases is accompanied by the injection of ρ〗 3Κ r 137081 -14- 201002697 in the lung infiltration and activation caused by the endotoxin that regulates neutrophils in acute lung injury. a central role (Yum et al., J.  Immunology, 2001, 167 (11), 6601-8). Although the ΡΙ3Κγ system is highly expressed in white blood cells, the loss does not seem to interfere with the fact of hematopoiesis, and the fact that the PI3K r-free mouse line can survive and fertility further implies that this PI3K isoform is a potential drug. Subject. Research work on mice that have been eliminated has also established PI3K 7 as an essential amplifier for mast cell activation (Laffargue et al., Immunity, 2002, 16 (3), 441-451). Therefore, in addition to tumorigenesis, there is evidence that the species I PI3K enzyme plays a role in other diseases (Wymann et al., Trends in Pharmacology, 2003, 24, 366-376). Both the la PI3K enzyme and the single species lb enzyme have important roles in the cells of the immune system (Koyasu, Nature Immunology, 2003, 4, 313-319), and therefore are related to the treatment of inflammatory and allergic indications. Subject. Recent reports have confirmed that mice lacking ΡΙ3ΚΤ and PI3K5 are viable, but have attenuated inflammatory and allergic responses (Ali et al, Nature, 2004, 431 (7011), 1007-11). Inhibition of PBK can also be used to treat cardiovascular disease via anti-inflammatory effects or directly by affecting cardiomyocytes (Prasad et al., Trends in Cardiovascular Medicine, 2003, 13, 206-212). Therefore, inhibitors of the class I PI3K enzyme are expected to be valuable in the prevention and treatment of a wide variety of diseases other than cancer. Several compounds that inhibit PI3K and phospholipid creatinine (PI) kinase-associated kinase (PI3KK) have been identified, including wortmannin and the ecdysteroid derivative LY294002. These compounds are rationally specific inhibitors of Π3Κ and PI3KK over other kinases, but they lack efficacy and show little selectivity in the PI3K population 137081 -15-201002697. Thus, it is generally desirable to provide further effective mTOR and/or PI3K inhibitors for the treatment of cancer, inflammatory or obstructive airway diseases, immunity or cardiovascular disease. N-?P-linyl, pyridine derivatives and PI3K inhibitors are known in the art. International Patent Application WO 2004/048365 discloses compounds which have PI3K enzyme inhibition/tongue and are useful in the treatment of cancer. These compounds are arylamino-" and heteroarylamino-substituted pyrimidines which differ from the compounds of the invention due to their arylamino- and heteroarylamino substituents. WO 2004/048365. Compounds having a substituent of the invention -XR1 are not disclosed. Inhibitors of PI3K activity that can be used to treat cancer are also disclosed in European patent applications! In 277 738, it refers to 4-N-morpholinyl-substituted bicyclic heteroaryl compounds, such as quinazoline p and pyrido[3,2-d]pyrimidine derivatives, and 4-N-? '#-substituted tricyclic heteroaryl compounds, but not monocyclic pyrimidine derivatives. W02007/080382, WO2008/023180 and W02008/023159 disclose compounds having mTOR and/or PI3K enzyme inhibitory activity and which are useful for treating cancer. Compounds comprising a thiourea substituent are not disclosed in WO2007/080382, WO2008/023180 and WO2008/023159. Many compounds, such as 4-morpholin-4-yl-6-(phenylsulfonylmethyl)-2-pyridin-4-yl-pyrimidine and 4-{6-[(phenylsulfonyl)methyl]- 2-Pyridin-2-ylpyrimidin-4-yl}morpholine has been registered in the Chemical Abstracts database, but utilization has not been pointed out, and it has not been pointed out that these compounds have mTOR and/or I>I3K inhibitory activity or are useful. The nature of treatment. 137081 -16- 201002697 Surprisingly, we have found that certain N_morpholinylpyrimidine derivatives have therapeutic properties that can be used. Without wishing to be bound by the theory, one

It is generally believed that the therapeutic utility of such derivatives is derived from their inhibitory activity against mT0R kinase and/or - or a variety of cytokines such as the species Ia enzyme and/or species still enzymes. Because of the signaling pathways mediated by the PI3K/mT〇R group, there are a number of cellular processes, including hyperplasia and survival, and because of these dysregulations, a wide range of human cancers and other diseases: Disease factors, it is expected that this material can be used for treatment: Temple 疋D 何 何 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物 生物. The compounds of the present invention are also useful for inhibiting uncontrolled cell proliferation, which occurs as a result of various non-WU diseases such as inflammatory or cardiovascular diseases. Shouting - disease, immune disease - 'The compound of the invention has an effective inhibition against mTOR kinase, and the compound can also have effective inhibition against one or more PI3K enzymes (such as the species la enzyme and / or species Ib enzyme) active. SUMMARY OF THE INVENTION According to one aspect of the invention, there is provided a compound of formula (I) η

Or a pharmaceutically acceptable salt thereof; wherein 137081 17 201002697 m is 0, 1, 2, 3 or 4; the 7 and Υ 2 lines are independently Ν or CR8, provided that one of Υ1 and γ2 is ν, and the other is CR8 ; X is a linking group selected from -CR4 =CR5 -, -CR4 =CR5 CR6 R7 -, -CR6 R7 CR5 = CR4-, -C three C-, -C three CCR6R7-, -CR6R7CeC-, -NR4CR6R7_, -OCR6R7-, -SCR6R7-, -S(〇)CR6R7-, -s(o)2cr6r7-, -c(o)nr4cr6r7-, -nr4c(o)cr6r7-, -nr4c(o)nr5cr6r7-, -NR4S (0) 2CR6R7-, -S(0)2NR4CR6R7-, -C(0)NR4-, -NR4C(0)-, '-NR4 C(〇)NR5 ·, -S(0)2 NR4 - and _NR4 s(0)2 _ ; R1 is selected from the group consisting of hydrogen, c]-6 alkyl, C2_6 alkenyl, (2-6 alkynyl, carbocyclyl, carbocyclyl q-6 alkyl, heterocyclyl and hetero a group of a cycloalkyl c16 alkyl group, which group is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, R9, -OR9, -SR9, _s〇R9, - S〇2R9, -COR9, -C02R9, -CONK Ri 〇, 视9 Ri 〇, tear 9 c〇Rl 〇, nr9 c〇2 Rl 〇, ·9 c〇nr1 〇r] 5 , -NR9COCONR10R15 and -NR9S〇 2R1〇;

- called , -CORH, -C〇2Ri 丨, _c〇NRl 丨 R1 2 nr1 i r1 &-NRnCOCONR12R16;

, cyano, nitro, -R13, -OR13, -COR13, _C〇2r13, _c〇nri3r14,

R4 and R5 are independently hydrogen or C, _NRl3C02R14 and -NR13S02R14; 1 - 6 formula; 137081 -18- 201002697 or R1 and R4 and their connected or a plurality of atoms together form 4_ to ι〇_ a slave or heterocyclic ring in which i, 2 or 3 ring carbon atoms are optionally replaced by deuterium or S' and the ring is optionally substituted by one or more substituents selected from halo, Cyano, nitro, hydroxy, keto, alkyl, C]-6 alkoxy,! ^alkyl, haloCi 6 alkoxy, hydroxy q 6 alkyl 'hydroxy C!-6 alkoxy, Ci6 alkoxy Q 6 alkyl, A, alkoxyalkoxy, amine , Cu alkylamino group, bis(Ci 6 alkyl)amino group, amino 6 alkyl group, (Ch alkyl)amino ci6 alkyl group, bis(Ci6 alkyl)amino group Ci6 alkyl group, gas-based leukosyl group, C1_6 alkylsulfonyl, c16 alkylsulfonylamino, q 6 alkylsulfonyl (CI. 6 alkyl) amine, amine sulfonyl, Cu alkyl sulfonyl, double (C! — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — R6 and R7 are independently selected from the group consisting of hydrogen, halo 'cyano, nitro and Cl 6 alkyl; R8 is selected from hydrogen, halo, cyano and alkyl; R9 and R1 G are independently hydrogen or are selected from a group of a Ci-6 alkyl group, a carbocyclic group, a carbocyclic group Cn alkyl group, a heterocyclic group and a heterocyclic group C]-6 alkyl group, which group is optionally substituted by one or more substituents, and a substituent Selected from -yl, cyano, nitro, thiol, C]-6 alkyl, (^_6 alkoxy, _yl Ck alkyl, halo Ck alkoxy, hydroxy C -6 Base, hydroxy Ck alkoxy, (^-6 alkoxy Ci_6 alkyl, C1-6 alkoxy Cu alkoxy, amine, Ch acryl, bis(c1-6 decyl)amine, amine Alkyl-6-6 alkyl, (C)·6 alkyl)aminoCh alkyl, bis(Cu alkyl)amino Ck alkyl, cyano Ci-6 alkyl, (^-6 alkylsulfonyl, C16 alkylsulfonylamino, q_6 alkylsulfonyl (c^alkyl)amine, amidoxime 137081 -19- 201002697, c]-6 alkylamine sulfonyl, bis(Ci 6 alkyl Aminesulfonyl, Ci 6 alkanoylamino, Cu alkylalkyl (Ch alkyl) amine, amine methyl sulfonyl, Ci6 alkyl amine fluorenyl and bis (Ch alkyl) amine carbaryl; R11 And R12, R17 and R18 are independently hydrogen or a group selected from the group consisting of a q-6 alkyl group, a carbocyclic group, a carbocyclic group q-6 alkyl group, a heterocyclic group and a heterocyclic group Ci 6 alkyl group. Optionally substituted with one or more substituents selected from halo, cyano, nitro, hydroxy, alkyl, Cl-6 alkoxy, haloCi6 alkyl, halo C!-6 alkoxy , hydroxy C!-6 alkyl, hydroxy Ci 6 alkoxy, Ci6 alkoxy Q 6 alkyl, Cm decyl c 6 alkoxy, amine ' Ci 6 alkylamino, double (c^6 alkyl)amino, amino Cualkyl, (Cl 6 alkyl)amino Ci 6 alkyl, bis(Ck alkyl)amino C!-6 alkyl, cyano Ci6 alkyl, Ci 6 alkylsulfonyl, C 6-6 alkanoyl, Ci 6 alkyl alkoxy (q 6 alkyl) amine, amine methyl sulfhydryl, C!-6 alkyl amine carbhydryl and bis (C !_6 alkyl)aminoindenyl; R13, RM, R1S, 6 and 圮9 are independently hydrogen or selected from Ci 6 alkyl, carbocyclyl, carbocyclyl Ci-6 alkyl, heterocyclic And a group of a heterocyclic group q _ 6 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, c^6 alkyl, Cl_6 Alkoxy, haloCi 6 alkyl, halo C^6 alkoxy, hydroxy C^6 alkyl, hydroxy ci6 alkoxy, Ci 6 alkoxy C!-6 alkyl, C^6 alkoxy (^_6 alkoxy group, amine group, C16 alkylamino group, bis(Cl-6 alkyl)amino group, amine Cu alkyl group, (c16 alkyl) amine group Ci6 alkyl 'double (C!-6 said Alkyl Ck alkyl, cyano q-6 alkyl, Cl 6 alkylsulfonyl, Q 6 alkylsulfonylamino, Ci-6 alkylsulfonyl (Ci 6 alkyl) amine, amine sulfonate Sulfhydryl, Ci_6 alkylamine sulfonate Base, bis(c1-6 alkyl)amine sulfonyl, ci 6 amide amino group, C -6 alkyl sulfonyl (q -6 hexyl) amine group, amine sulfhydryl group, Ci _ 6 137081 -20- 201002697 Hydrazinyl and bis(C!-6 alkyl)aminecarbamyl; or R18 together with R19 and the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring, wherein 1 or 2 rings The carbon atom is optionally replaced by N, hydrazine or S, and the ring is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, Ck alkyl, Cl-6 alkoxy , 匚 匚 烷基 alkyl, dentate Ci-6 emulsified base, thiol-based, light-base alkoxy, Ci-6 hexaoxy C!-6 alkyl, C! -6 alkoxy (^_6 alkoxy group, amine group, (^-6 alkylamino group, bis(Cu alkyl)amino group, amine cv6 alkyl group, (Cu alkyl) amino group Cu alkyl group, bis(c^alkyl group) Aminoalkyl, cyanoCl-6 alkyl, Cl-6 alkylsulfonyl, C -6 alkylsulfonylamino, Ci 6 alkylsulfonyl (Ci6 alkyl) amine, amine sulfonyl , C! _6 alkylamine sulfonyl, bis (Ci -6 alkyl sulfonyl, Ci -6 aryl amine, C)-6 alkyl alkyl (Cii alkyl) amine, amine Acyl '(Yue ^ _6 alkyl amines and bis acyl (C] _6 alkyl) carbamoyl acyl, be used as medicaments for the treatment of proliferative diseases. According to another aspect of the invention, there is provided a compound of formula (I)

Or (1) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; Y 14 Y is independently N or CR8, provided that one of Y and Y2 is N, and the other CR8; 137081 -21 - 201002697 X is a linking group selected from the group consisting of cr4=cr5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -CEC-, -C three CCR6R7-, -CR6R7CeC-, -NR4CR6R7-, -〇CR6R7-, -SCR6R7-, -S(0)CR6R7-, -s(o)2cr6r7-, -C(0)NR4CR6R7-, -NR4C(0)CR6R7-, -NR4C(0)NR5CR6R7-, - NR4S(0)2CR6R7-, -S(0)2NR4CR6R7-, -C(0)NR4-, -NR4C(0)-, -NR4 C(0)NR5 -, -s(0)2 NR4 - and -NR4 s(0)2-; R1 is selected from the group consisting of Q-6 alkyl, c: 2-6 alkenyl, c2-6 alkynyl, carbocyclyl, carbocyclyl C!-6 alkyl, heterocyclyl and heterocyclic A 6 a group of an alkyl group, which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, R9, -OR9, -SR9, -SOR9'-s〇2r9, _C0R9, -C〇2r9, c〇nr9r1〇-NR9Ri. -NR9COri. , _NR9c〇2Rl. NR9c〇NRi〇Rl5, -nr9coconr10r15A_nr9s〇2R10; or X-R1 is -CR6R70H; R2 is a group selected from the group consisting of a carbocyclic group and a heterocyclic group, and this group is

Substituting 17CSNR18R19, and optionally substituted by - or a plurality of substituents, the substituents are independently selected from the group consisting of dentate, cyano, schishyl, _R11, _0R11, _SRU, gu, -S02 R", -CORH, _C〇2 R1丨, _c〇NRl i R1 2 NR1 丨R1 2 Service "Caf 2 Each R3, when present, is independently selected from the group consisting of dentate, cyano hr13, _or13, -SR13, -SOR13, _s〇2R13, _c〇r13 , Γ -C〇2R , _C〇NR13R14, NR R '-NRl3c〇Rl4'-NR-co2RH^.NRl3s 14; R4 and lanthanide are independently hydrogen or alkyl; or R1 and R4 are connected to one of them Carbocyclic (tetra) heterocyclic n-shaped 丨m = + —_ into 4_ to ίο-member, 丨, 2 or 3 ring carbon atoms are replaced by 137081 -22· 201002697 N, Ο or S, and The ring is optionally substituted with one or more substituents, the substituents being far from the base, cyano, nitro, thiol, keto, 6 alkyl, C^-6 alkoxy, functional alkyl, south (^_6 alkoxy, hydroxy Ci 6 alkyl, hydroxy Q-6 alkoxy, Cl-6 alkoxy Ci6 alkyl, Ci 6 alkoxy q 6 alkoxy, amine, C!-6 alkylamine Base, bis(Cl_6 alkyl)amino, amine Ci 6 alkyl, (Q-6 alkyl) amine C l 6 alkyl 'bis(Ci 6 alkyl)amino-based Ci6 alkyl, cyano C^6 alkyl, Ck alkylsulfonyl, Cl-6 alkylsulfonylamino, Ci 6 alkyl thiol CH alkyl)amino, amidoxime, CV6 alkylamine sulfonyl, bis(C)-6 alkyl)sulfonyl, Cu alkanoyl, Cu alkyl sulfonyl (Ci-6 alkyl) An amine group, an amine sulfhydryl group, a C -6 alkylamine carbaryl group and a bis (Cu alkyl) amine aryl group; R6 and R7 are independently selected from the group consisting of hydrogen, a halogen group, a cyano group, a nitro group and a C16 alkane group; R8 is selected from the group consisting of hydrogen, halo, cyano and (^-6 alkyl; R9 and RW are independently hydrogen, or are selected from Ci 6 alkyl, carbocyclyl, carbocyclyl & 6 alkyl; a group of a cyclic group and a heterocyclic group q _6 alkyl group, which group is optionally substituted by one or more substituents selected from a group consisting of a functional group, a cyano group, a nitro group, a hydroxyl group, a Q 6 alkyl group, C! _6 alkoxy, halo Ck alkyl, halo (^_6 alkoxy, hydroxy <^_6 alkyl, hydroxy (^_6 alkoxy, (^_6 alkoxy (^_6 alkyl, C) _6 alkoxy (^_6 alkoxy, amine, Ck alkylamino, bis((^-6 alkyl)amine, amino Ck alkyl, (Ch alkyl)amino CV6 alkyl, double (CkAlkyl)amino CV6 alkyl, cyanoalkyl, q-6 alkylsulfonyl, CV6 alkyl aryl, Ci. 6 phenyl acid (Ci-6) amine, amine $ Yellow wine, alkylamine sulfonyl, bis(Ck alkyl)amine sulfonyl, Cu alkanoamine, q-6 alkyl alkyl (Ci-6 alkyl) amine, amine sulfhydryl, Ci-6 Alkylamine 137081 -23- 201002697 fluorenyl and bis(Cl-6 alkyl)amine carbenyl; RU, R12, R17 and R18 are independently hydrogen or selected from cl-6 cyclyl, anthracenyl, a group of a ruthenium-based Ch filament, a heterocyclic group, and a heterocyclic red oxime, which is optionally substituted with - or a plurality of substituents selected from a group selected from a group, a chloro group, a nitro group, a thio group, CH alkyl, decyloxy, i-based Cl.6 county 'halo-Cl.6 alkoxy, hydroxyalkyl, methoxy, Cl.6 alkoxy Q-6 alkyl Chaloxy C16 oxygenated Amino group, amine group, c 6 alkyl group, bis(c)-6 alkyl) amine group, amine Ci-6 alkyl group (Ci 6 alkyl) amino group Ch alkyl group, bis(Ch alkyl)amino group Cl_6 An alkyl group, a cyano Ci6 alkyl group, a Ci6 alkylsulfonyl group, a cv6 aromatine group, a cl 6 aryl group (c-6-6 alkyl) amine group, an amine methyl group,

Cu alkylamine-methyl fluorenyl and bis(Ci 6 alkyl)amine fluorenyl; R, R, Rls, R16 and R19 are independently hydrogen or selected from CH choline, anoindigo, and slave ruthenium C a group of a 6-alkyl group, a heterocyclic group and a heterocyclic group Ci_6 alkyl group, which group is optionally substituted by one or more substituents selected from a halogen group, a cyano group, a nitro group, a hydroxyl group, Ci 6 alkyl, Ci 6 alkoxy, halo ^ · alkyl, i group < ^ 6 alkoxy, hydroxy Ci 6 alkyl, hydroxy Ci 6 alkoxy, c 6 alkoxy C 丨6 alkyl, c 6 alkoxy C 6 alkoxy, amine, c] 6 alkylamino, bis(Cu alkyl)amine, amine c] 6 alkyl, (Ci 6 alkyl) Amino group c 6 hexyl, bis(Ch alkyl)amino Cb alkyl, cyanoCh alkyl, Cp6 alkyl group fluorenyl group, C _6 alkyl group hydrazino group, q _ 6 Sulfhydryl (Q -6 hexyl) amino group 'amine acid group, c _6 alkyl amide group, bis (c16 alkyl) amine hydrazino group, Cu alkanoamine group, q-6 alkyl fluorenyl group (C) _6 alkyl)amino, amine carbaryl, c]-6 alkylamine carbhydryl and bis(Cl-6 alkyl)amine fluorenyl; or R together with R19 and the nitrogen atom to which the temple is attached 3_至员杂137081 -24- 201002697 Ring wherein one or two ring carbon atoms are optionally replaced by N, hydrazine or S, and the ring is optionally substituted by one or more substituents selected from the group consisting of Halo, cyano, nitro, hydroxy' (ν6 alkyl, (V6 alkoxy, halo Cm alkyl, haloalkoxy, hydroxy (^_6 alkyl, hydroxyalkoxy, (^-6) Oxykk alkyl, (^_6 alkoxy C!-6 alkoxy, amine, Ck alkylamino, bis(C)-6 alkyl) amine, amine Cu alkyl, (Cw alkyl) Amino Cu alkyl, bis(Q-6 alkyl)amino (^-6 alkyl, cyano (^_6 alkyl' (^_6 alkylsulfonyl, Q -6 alkylsulfonylamino, q - 6 alkylsulfonyl-6 alkyl)amine, amine fluorenyl, Ck alkylamine sulfonyl, bis(Ci 6 alkyl)amine sulfonyl, Ci 6 alkanoyl, C!-6 An alkanoyl (Ci_6 alkyl)amino group, an amine methyl sulfhydryl group, a (methalinyl fluorenyl group, and a bis(Ck alkyl) amine carbaryl group, for use as a medicament for treating a proliferative disease. According to the present invention On the other hand, a compound of formula 1 is provided

Or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; 'provided that one of 1 and Υ2 is Ν, and the other 1Y and γ2 are independently N or CR8, provided that 1 - one is CR8;

-CR4 =CR5 CR6 R7 -, ' -CR6R7c = C- '

13708J -25- 201002697 -NR^CR^R^ - > -OCR^R^. . _SCR^R^ . -S(0)CR^R^ . -S(0)2CR6r7., -c(o) Nr4cr6r7-, _NR4C(0)nr5cr6r7·, s(〇)2Nr4cr6r7, -C(0)NR4 _, -NR4 C(O)-·, -NR4 C(0)NR5 -, -S(〇)2 NR4 _ And _nr4 s(〇)2; R is selected from the group consisting of a Cb6 group, a c2_6 alkenyl group, a c2-6 block group, a carbocyclic group, a carbocyclic group Q-6 alkyl group, a heterocyclic group and a heterocyclic group c]6 a group of an alkyl group, which is optionally substituted by one or more substituents selected from the group consisting of a group, a cyano group, a nitro group, R9, -OR9, -SR9, -SOR9, _S〇2R9, - C〇r9, _c〇2r9, c〇nr9r1〇-nr9r1g, -nr9corw, nr9c〇2R1G nr9c〇nrigr15 or X-R1 is -CR6R7〇H; R2 is selected from (ν6 alkyl, carbocyclic and heterocyclic groups) a group substituted by -NR17CSNR18R19' and optionally substituted by one or more substituents, the substituents being independently selected from halo, cyano, nitro, _R1 1, _〇Rl, 丨i , _s〇Rl], -S〇2 R11, -COR11 ' -C02 R", _C0NR11 Ri 2, _NRl i Rl 2, NRl) c〇Rl 2 and -(10) kiss (7) hidden 12!^; each R3' exists When independently selected from the group consisting of halo-cyano, nitro, _Rl3, _〇Rn, -SR13, -SOR13, _s〇2Rl3, c〇r]3, c〇2R]3 (ο·," -NR13R14, -NR13CORi4 ' _NRi3C〇2Ri4&_NRl3s〇2Rl4 ; R4 and R5 Is independently hydrogen or Ci6 alkyl; or R1 and R4 and one or more of the atoms to which they are attached form a 4_ to i〇_member carbon bad or heterocyclic ring, wherein 丨, 2 or 3 The ring carbon atom is optionally substituted by N, hydrazine or S, and the ring is optionally substituted by one or more substituents selected from the group consisting of ii, cyano, decyl, thiol, keto, & 6 burnt base, Ci _ 6 , elemental oxygen dentate c _6 yard base, dentate Ci 6 alkoxy group, via group Cl — alkyl group, 137081 -26- 201002697 via group Ch alkoxy, Ci 6 alkoxy Ci6 alkyl, Ci 6 alkoxy Ci 6 alkoxy, amine, 6 alkylamino, bis(Cl-6 alkyl)amine, amine c] 6 alkyl, (Ci-6 alkyl) amine Cl_6 Alkyl, bis(Ci-6 alkyl)amino-based Ci6 alkyl, cyano (^-6 alkyl, c16 alkylsulfonyl, Ci6 alkylsulfonylamino, alkylsulfonyl (C^6) Alkyl)amino, aminsulfonyl, c16 alkylamine sulfonyl, bis(Ch alkyl)amine sulfonyl, Cl-6 alkanoyl , Ci6 alkyl fluorenyl (Ci6 alkyl) amine group, amine methyl sulfhydryl group, C 6-6 alkyl carbamoyl group and bis (Cl 6 alkyl) amine carbaryl group; R6 and R7 are independently selected from hydrogen and halogen a group, a cyano group, a nitro group and a 6 alkyl group; R8 is selected from the group consisting of hydrogen, a halogen group, a cyano group and a C 6 alkyl group; R9 and rig are independently hydrogen or are selected from a Ci6 alkyl group, a carbocyclic group, a carbocyclic group. a group of Cl, an alkyl group, a heterocyclic group and a heterocyclic group C] _6 alkyl group, which group is optionally substituted by one or more substituents selected from a halogen group, a cyano group, a code group, and 1匚 匚 1-6 烧 〇 '〇! 1-6 alkoxy, 1 ^ base (^ 6 6 base, _ base (2 6 6 alkoxy, hydroxy C! 6 alkyl, hydroxy alkoxy , Cl_6 alkoxy q-6 alkyl, C]-6 alkoxy C!-6 alkoxy, amine, (^-6 alkylamino, bis-6 alkyl)amine, amine Ci_6 alkyl , (C!·6 alkyl)aminoc]-6 alkyl, bis(c16 alkyl)amine c _6 alkyl, cyanoCl-6 alkyl, Ci 6 alkylsulfonyl, Ci 6 alkyl sulfonate Merylamino, Cu alkylsulfonyl ((-6 alkyl) amine, amine sulfonyl, Ci-6 alkyl sulfonyl, bis(Cl-6 alkyl) amine sulfonyl, 6 hexane Amidino, C! _ 6 Burning thiol (C! -6 hexyl) amine group, amine mercapto group, q 6 alkyl amide group and bis (C! -6 alkyl) amine mercapto group; R, R, R17 and R18 series Is independently hydrogen, or a group selected from the group consisting of a q 6 alkyl group, a carbocyclic group, a carbocyclic group C!_6 alkyl group, a heterocyclic group, and a heterocyclic group Ci 6 alkyl group. This group is 137081 -27- 201002697 Optionally substituted with one or more substituents selected from halo, cyano, nitro, thio, Ci-6 alkyl, c16 alkyl fluorenyl, halo C 6 alkyl, halo c 6 alkoxy 'HydroxyCl_6 alkyl, hydroxy Ci 6 alkoxy, Ci 6 alkoxy c!-6 alkyl, q-6 alkoxy (^_6 alkoxy, amine, Ci 6 alkylamino, bis ( Ck alkyl)amino 'amino-Ci-6 alkyl, (Ci-6 alkyl) aminoalkyl, bis(Cw alkyl)amino Cu alkyl, cyano Ci 6 alkyl, Ci 6 alkyl Sulfonyl, q-6 alkanoyl 'Cl_6 alkyl fluorenyl (Ci 6 alkyl) amine group, amine fluorenyl group, c _ 6 alkyl amide thiol group and bis (Ci 6 alkyl) amine formazan R13, R14, R1S, Rl6 and Rl9 are independently hydrogen or a group selected from the group consisting of a hexyl group, a hexyl group, a carbocyclyl group, a heterocyclic group and a heterocyclic group c16 alkyl group. The group is optionally substituted by one or more substituents selected from the group consisting of benzyl, cyano, nitro, hydroxy, c]-6 alkyl, c16 alkoxy, _*C16 alkyl, halo C) _6 alkoxy group, hydroxy C 6 alkyl group, hydroxy Ci6 alkoxy group, (^ alkoxy C -6 alkyl group, c 6 alkoxy group C 6 alkoxy group, amine group, (^^ alkylamino group, Bis(C!-6 alkyl)amino, amino C1-6 alkyl, (Ci 6 alkyl)amine Ci 6 alkyl 'bis(Cl-6 alkyl)amino C]-6 alkyl, cyano Ch alkyl, (^_6 alkylsulfonyl, q_6 alkylsulfonylamino, Ci 6 alkylsulfonyl (C1 alkyl fluorenyl, sulfonyl, q-6 alkyl sulfonyl) , bis(C16 alkyl)amine sulfonyl, q 6 alkanoylamino, 6-alkylindenyl (Ci-6 alkyl)amine, aminemethanyl, Ci-6 alkylaminecarbamyl and bis (Ck Alkylamino hydrazide; or R18 together with R19 and the nitrogen atom to which they are attached form a 3 to 1 〇 member heterocyclic ring wherein 1 or 2 ring carbon atoms are optionally replaced by N, 0 or S And the ring is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, Ck alkyl, Cl-6 alkoxy, halo Q 6 alkyl, 】37081 -28- 201002697 i group (^_6 alkoxy group, hydroxy c!_6 alkyl group, hydroxy q_6 alkoxy group, (^_6 alkoxy Q_6 alkyl group, Ci-6 alkoxy alkane) Oxyl, amine, (^-6 alkylamino, bis(Ci-6 alkyl)amine, amine CP6 alkyl, (Ci-6 alkyl)amino-Ci alkyl, bis(C-6-alkane) Amino Cil alkyl, cyano Ci-6 alkyl, (^-6 alkylsulfonyl, q-6 alkylsulfonylamino, c16 alkylsulfonyl (Ci 6 alkyl) amine, amine Sulfonic acid group, C _6 alkylamine sulfonyl sulfonyl group, bis(Cl 6 alkyl)amine sulfonyl sulfonyl group, Cl_6 decylamino group, Ci-6 alkyl fluorenyl (C^alkyl) amine group, amine hydrazine The base, C!-6 alkylamine methyl thiol and bis((^-6 alkyl)amine methyl sulfhydryl are used as agents for the treatment of proliferative diseases. According to another aspect of the present invention, there is provided the use of a compound of formula 1 for the manufacture of a medicament for the treatment of a proliferative disorder

Or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; w and Y2 are independently N or CR8, provided that one of ΐγ and Y2 is N and the other is CR8; Is a linking group selected from _CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5 = CR, -C = C-, -C = CCR6R7-, (r6r7csc-, _nr4cr6R7-, OCR R - &gt; -SCR6R7- '-S(〇)CR6R7- ^ -S(0)2CR6R7- -C(0)NR4CR6R7-, -Nr4c(〇)cr6r7, nr4c(〇辉5cr6r7, 137081 -29- 201002697 -NR4S(〇)2CR6R7-, -S(〇)2nR4CR6R7_ , _C(〇)Nr4 Λ _NR4C(0)_ , -NR4c(0)NR5-, -s(o)2NR4_ and tear 4S(0)2_ · =1 is selected from hydrogen, Ch burn a group of a base group, an alkenyl group, a h block group, a carbocyclic group, a carbocyclic group C]_6 county, a heterocyclic group, and a heterocyclic group q_6, wherein the group is optionally substituted by - or a plurality of substituents, The substituent is selected from the group consisting of glutenyl, aryl, schwitz, -R9, -OR9, -SR9, 顾9, _s〇2R9, c〇R9, «, 'C〇NR9Rl° ' -NR9R1° ' -nr9c〇r1〇, _nr9c〇2R10 . -NR9CONR%5, tear 9c〇c〇nr1Gr14 NR9s〇2Ri〇; R2 is a group selected from the group consisting of a Cl-6 alkyl group, a carbocyclic group and a heterocyclic group, and this group is replaced by •NR17CSNR18RI9, And The case is substituted by - or a plurality of substituents independently selected from the group consisting of a dentate group, a cyano group, a nitro group, a _RU, a collar u, a _SR11, a _SORn, a -S〇2Ri 】, a -C0R1 】'c〇2r], R1 丨R1 2 NR1 丨R1 2 Coffee 1 (10) 2 &amp;-NR]1COCONR12r16; Each R3, when present, is independently selected from _ group, cyano group, nitro group, _r ! 3, _〇r 13, -SWSQR13 , _SQ2Rl3, fiber 13, c〇2Ri3 c〇nr13r14 丨4丨4, 视3C〇r14, 视13c〇2Rl^ NRi3s〇2Ri4 R and R are independently hydrogen or 6 alkyl; or (d)w and their are connected - or a plurality of atoms - forming a 4 to 10 member carbon ring or heterocyclic ring, wherein i, 2 or 3 ring carbon atoms are replaced by N, 〇 or S as appropriate - and the ring is optionally — or substituted with a plurality of substituents selected from the group consisting of a aryl group, a cyano group, a schlossyl group, a thiol group, a keto group, a Cl. 6 phenyl group, a hydracarbonyl group, a dentate C 1-6 alkyl ' m 6 alkoxy group, HydroxyCl_6 alkyl: via group Cl.W oxy, CH-laboxy Cw, ke_6 alkoxy Ci6 succinyl, cyclyl, cl6 acryl, bis(C16 alkyl)amine, amine Cl 6 137081 -30- 201002697 alkyl, (C1-6 alkyl)amino-based Ci_6 alkyl, (Cu alkyl)amino-Ch-alkyl, aryl 6-, Q -6-alkyl, Q-6, aryl, C!-6, alkyl (C) _6 Acryl group, amine group, amine acid group, Ci-6 alkyl sulfonate group, bis(C!-6 alkyl) amine sulfonyl group, Cu alkanoyl group, Cu sulphide group ((^_6 yard base) An amine group, a fluorenyl group, a c -6 alkyl group, and a bis (c -6 alkyl group) amine carbenyl group; R6 and R7 are independently selected from the group consisting of hydrogen, a halogen group, a cyano group, and a nitro group. And Ci 6 alkyl; R8 is selected from the group consisting of hydrogen, halo, cyano and Ck alkyl; R9 and R1C are independently hydrogen or are selected from Ci 6 alkyl, carbocyclyl, carbocyclic alkyl, heterocycle a group of a heterocyclic group C]-6 alkyl group, which group is optionally substituted by one or more substituents. 'Substituents are selected from the group consisting of _ group, cyano group, nitro group, hydroxyl group, CV6 alkyl group, c] _6 alkoxy, _*Cl 6 alkyl, dentyl 6 alkoxy, hydroxyalkyl, hydroxy C 6 alkoxy, Ci 6 alkoxy, monoalkyl, Ck alkoxy Ck alkoxy, amine , Ci 6 alkylamino, bis(Ci 6 alkyl)amine, amine c]-6 alkyl, (Cl-6 alkyl)amino Ci 6 alkyl, bis(Ci 6 alkyl)amine c]_6 , cyano Cl 6 alkyl, Ci 6 alkylsulfonyl, alkylsulfonylamino, q-6 alkylsulfonyl (Cl6 alkyl) amine, amidoxime, C!-6 Alkylamine sulfonyl, bis(Ci6 alkyl)amine sulfonyl, Ci6 alkanoyl, Cu alkyl fluorenyl (C-6 alkyl) amine, amine sulfhydryl, Ci6 alkylamine formazan And bis(C)-6 alkyl)aminocarboxamidine; R11, R12, R17 and R18 are independently hydrogen or selected from the group consisting of a pyridyl group, a carbocyclic group, a carbocyclic group, a c6 alkyl group, and a heterocyclic group. a group of a cyclic group and a heterocyclic group Ci 6 alkyl group, which group is optionally substituted by one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxyl group, a Cm alkyl group, and a Ci-6 an alkane group. Oxy group, _ group Ci 6 alkyl group, halogen group 137081 31 201002697 C!-6 alkoxy group, hydroxyl group _6 alkyl group, hydroxyl group (^_6 alkoxy group, (^_6 alkoxy Ci·6 alkyl group, C,-6 alkoxy C]·6 alkoxy group, amine group, acryl group, bis(C-6-6 alkyl)amino group, amine group C··6 alkyl group, (c1-6 alkyl group) AminoCh alkyl, bis(C!-6;/:complete)amine-based Ci-6, cyano c _6 alkyl, Ci-6 thiol thiol, C! -6 amide , C, -6 burning base (c) _ 6 decyl) amine group, amine sulfhydryl group, q-6 alkylamine carbhydryl group and bis < Α 6 alkyl) amine carbenyl group; R13, R14, Rls, "6 and 圮9 series a group independently of hydrogen or selected from the group consisting of a C 6 alkyl group, a carbocyclic group, a carbocyclic group cv6 alkyl group, a heterocyclic group and a heterocyclic group C 6 alkyl group, which group is optionally substituted by one or more Substituted, the substituent is selected from the group consisting of halo, cyano, nitro, hydroxy, C]-6 alkyl, q-6 alkoxy, functional q-6 alkyl, halo C!-6 alkoxy, Hydroxy C^6 alkyl, via q-6 alkoxy, alkoxy C]-6 alkyl, C -6 alkoxy q-6 alkoxy, amine, (^_6 acryl, Bis(C)-6 alkyl)amino, amine Q-6 alkyl, d6 alkyl)amino q-6 alkyl, bis(CV6 alkyl)amine C!-6 alkyl, cyano Ch alkyl group, Ck alkyl group &gt;6 xanthene, CV 6 alkylsulfonylamino group, (V 6 alkylsulfonyl (q 6 alkyl) amine group, amine sulfonyl group, Q · 6 alkyl group Amine thiol, bis(C! -6 alkyl)amine hydrazino, C! -6 alkyl alkanoyl, Cu alkyl alkino (Cu alkyl) amine, amine methyl sulfonyl, c] 6 alkyl Amine thiol and bis(Cu alkyl)amine Or R18 and R19 together with the nitrogen atom to which they are attached form a 3_ to 1〇 member heterocyclic ring, wherein 1 or 2 ring carbon atoms are optionally replaced by N, 〇 or s, and the ring system is The case is substituted by one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxyl group, a q -6 alkyl group, a q -6 alkoxy group, a halogen group q -6 alkyl group, a halogen group C^ -6 alkoxy group, a mercapto group (^_6 alkyl group, a transalkyl group Cn alkoxy group, a C^-6 alkoxy group C)-6 alkyl group, a Ci-6 alkoxy Q-6 alkoxy group, an amine group , q_6 alkylamino group, 137081 -32- 201002697 bis(Ch alkyl)amino group, amine Cu alkyl '(Cl6 alkyl)amino group Ci6 alkyl, bis(C-6-6)amino group C] -6 alkyl, cyano Ci6 alkyl, c] 6 alkylsulfonyl, alkylsulfonylamino, Cl6 alkylsulfonyl (Ci6 alkyl) amine, amine sulfonyl, C] _6 Alkylamine sulfonyl, bis(Ci 6 alkyl)amine sulfonyl, Ci 6 ruthenium, C! 6 alkyl alkyl (C) -6 alkyl) amine, amine methyl sulfhydryl, C _ 6 alkylamine carbenyl and bis(c^alkyl)amine fluorenyl. According to another aspect of the present invention, there is provided the use of a compound of formula 1 for the manufacture of a medicament for the treatment of a proliferative disorder

L 7~(R3)m N

Or (1) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; 1 Y and Y2 are independently N or CR8, provided that γ and Y2 are N and the other Is CR8; X is a linking group' selected from -CR4 = CR5 - , -CR4 =: (3⁄45 CR6 R7 -, -CR R CR5 = CR4 -, -C ξ C-, -C CCR6 R7 -, _cr6 r7 c = C-, -NR4CR6R7-, -〇Cr6R7-, -SCr6r7_, _s(0)cr6r7_, s(〇)2cr6r7 -c(0)nr4cr6r7-, -nr4c(0)cr6r7-, -nr4c(〇)NR5Cr6r7_ ' -nr4s(0)2cr6r7-, -s(0)2nr4cr6r7-, -C(0)NR4_, _NR4C(〇)_, -NR4 C(0)NR5 -, -s(0)2 NR4 _ and _NR4 S (0) 2 -; R1 is selected from C1-6 alkyl, C2-6 alkenyl, c: 2-6 alkynyl, carbocyclyl, carbocyclyl 137081 -33- 201002697 c]-6 alkyl, heterocyclic And a heterocyclic group of a Ci 6 alkyl group, which group is optionally substituted by one or more substituents selected from the group consisting of i group, cyano group, exact group, R OR SR, -SOR9, _s〇2r9 , _c〇R9, _c〇2R9, c〇nr9r1〇' NR R NR C0RlG, -NR9C02R1Q, -NR9CONR1QR15, -nr9coconrwrii_Nr9s〇2r10; or X-R1 is -CR6 R7 〇H; R2 is selected from a pyridyl group, a carbocyclic ring a group having a heterocyclic group, this group Retrieved by NR17CSNR18R19, substituted and optionally substituted by one or more substituents, the substituents are independently selected from halo-cyano-nitro, ^, ^^, ^^, S〇2 R 1 , _C0Rl1 —C〇2 R11, —CONR11R1 2, —NR1 1 R1 2, —NR11 c〇Ri 2 &-NRnCOCONR12R]6; each R3, when present, is independently selected from halo, cyano, nitro, _r13, _〇r13, -SR13, -SOR13, _s〇2r13, C0R13, _c〇2R13, c〇nr13r14, -NR13R!4 . -NRi3C〇R&gt;4 . -nr13co2r14a-nr13so2r14 ; R4 and Rs are independently hydrogen or Ci 6 alkyl; or R1 and R4 together with one or more of the atoms to which they are attached form a 4- to 10-membered carbon ring or heterocyclic ring wherein 丨, 2 or 3 ring carbon atoms are optionally N, hydrazine or s substitution, and the ring is optionally substituted by one or more substituents selected from the group consisting of ii, cyano, nitro 'hydroxy, keto, Ci 6 alkyl, Ci 6 alkoxy , haloq-6 alkyl, _*Cl_6 alkoxy, hydroxy Ci 6 alkyl, via c 6 alkoxy, Ci-6 alkoxy CV6 alkyl, (: 6 alkoxy Cp6 alkane Oxyl, amine, Cu alkylamino, bis(Ch alkyl)amine, amine Cl_6 Alkyl, (C!·6)ylamino-based Cl_6 alkyl, bis(Ci 6 alkyl)amino-based Ci 6 alkyl, aryl C^6 alkyl, Ci 6 alkylsulfonyl, Ci6 alkyl Sulfhydrylamino group, Ci6 137081 -34- 201002697 alkyl fluorenyl (Cl ' 6 alkyl) amine group, amine sulfonyl group, C! -6 alkyl sulfonyl group, bis (Ch alkyl) amine Sulfhydryl 'Ci_6 alkyl amidino' Ci6 alkyl fluorenyl (CH alkyl) amine group, amine methyl sulfonyl group, Ci_6 alkyl amine carbaryl group and bis (CH alkyl) amine aryl group; R and R series Independently selected from the group consisting of hydrogen, A group, cyano group, nitro group and Ci.6; R8 is selected from the group consisting of hydrogen, halogen, cyano and Ci 6 alkyl; R9 and R10 are independently hydrogen or selected from alkyl a group of a carbocyclic group, a carbocyclic group c^6 alkyl group, a heterocyclic group and a heterocyclic group C1-6 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of a dentate group, Cyano 'nitro, hydroxy, C^6 alkyl, Cl-6 alkoxy, 豳*Ci 6 alkyl, haloj alkoxy, hydroxy c]-6 alkyl, hydroxy c] 6 alkoxy, A, Alkoxy Ci 6 alkyl, Cm alkoxy c^6 alkoxy, amine, (^-6 alkylamino, bis((^-6 alkyl)amino, amine C] -6 alkyl, (C 】 6 alkyl)amine C! -6 alkyl, bis(q -6 alkyl)amino C!_6 alkyl, cyanoalkyl, (^_6 alkylsulfonyl, (^_6 alkyl) Sulfoamino group, q-6 alkylsulfonyl (CP6 alkyl) amine group, amine sulfonyl group, Ck alkylamine sulfonyl group, bis(c)-6 alkyl sulfonyl group, c] _6 alkyl amidino, Q 6 alkyl alkino (C!-6 alkyl) amine, amine methyl sulfonyl, Ci-6 alkyl amine carbaryl and bis-6 alkyl) amine fluorenyl; R11, R12 And R17 and R18 are independently hydrogen or a group selected from the group consisting of an alkyl group, a carbocyclic group, a carbocyclic group Q 6 alkyl group, a heterocyclic group and a heterocyclic group q -6 , which is optionally Substituted by one or more substituents selected from the group consisting of i, cyano, nitro, hydroxy, &amp; -6 alkyl, c)-6 alkoxy, _yl (^-6 alkyl, halo C!) 6 methoxy, thiol C^·6 alkyl, hydroxy Cn alkoxy, Ck oxyalkyl, C -6 saponin C]-6 alkoxy, amine, Ci_6 amine group, Double 137081 -35- 201002697 (c!-6 alkyl)amino group, amino Cu alkyl group, (Ci 6 alkyl)amino group Ci 6 alkyl group, bis(Ck alkyl)amine group core 6 group, Cyano C _6 burning base, q-6 Group; acyl yellow [epsilon], Cu alkanoyl group, C〗 _6 alkanoyl group (Ch alkyl) amino, acyl amine Yue,

Ci -6 Shao Yuan Ji Yue female A-based base and double (C〗 _6 yard base) amine-based base; R13, R14, R1S, R16 and R!9 series are independently hydrogen, or selected from Ch-based, stone-reverse a group of a cyclic group, a rabbit ring group C! _ g-heyl group, a heterocyclic group, and a heterocyclic group q -6 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of , cyano, nitro, hydroxy, C -6 alkyl, Ch alkoxy, _ *Ci 6 alkyl, halo Ck alkoxy, hydroxy (^ 6 alkyl, hydroxy Ci6 alkoxy, Ci 6 alkane Oxy C 6 alkyl, C!-6 alkoxy q-6 alkoxy, amine, Ci6 alkylamino, bis(Cu alkyl)amine, amine C1-6 alkyl, (C16 alkyl)amine Base c16 alkyl, bis(q-6 alkyl)amino C1-6 alkyl, cyano Ci6 alkyl, Ci 6 alkylsulfonyl, q-6 alkylsulfonylamino, c16 alkyl sulfonate Mercapto (c^alkyl)amine, amine% fluorenyl, q_6 alkylamine sulfonyl, bis(Ci-6 alkyl)amine sulfonyl, Ck alkanoyl, Cl-6 alkyl sulfonyl a Cb alkyl)amino group, an amine carbaryl group, a Ci6 alkylamine carbhydryl group, and a bis(C1-6 alkyl) amidino group; or R18 and R19 and a nitrogen atom to which they are attached Forming a 3 to 1 member heterocyclic ring in which 1 or 2 ring carbon atoms are optionally replaced by N, hydrazine or s, and the hydrazine is optionally substituted by one or more substituents selected from _ Base, cyano group, acetyl group, thiol group, Ch-yard group, (: diterpene oxy group, halo group & aryl group, fluorenyl group (^_6 alkoxy group, hydroxy Ci 6 alkyl group, hydroxy group 6 alkoxy group) , Ci 6 alkoxy q-6 alkyl, Cl 6 alkoxy Ci 6 alkoxy, amine, 6 alkylamino, bis(Ch alkyl)amine, amine Ci6 alkyl, (Ci6 alkyl) Aminoalkyl, bis(Cm alkyl)amino C 6 alkyl, cyano Ci6 alkyl, q 6 alkylsulfonium 137081 -36- 201002697, c!-6 alkylsulfonylamino, (^ _6 alkylsulfonyl (Ck alkyl) amine group, amine sulfonyl group, C! -6 alkyl amine sulfonyl group, bis (C! -6 alkyl) amine sulfonyl group, q -6 ruthenium amide group a Cu-based (C-6-6 alkyl)amino group, an amine sulfhydryl group, a Cu-based amine carbaryl group, and a bis(Ch alkyl)amino fluorenyl group. According to another aspect of the present invention, Use of a compound of formula 1 for the manufacture of a medicament for the treatment of a proliferative disease

.i~(R3L

N

Formula (I) or a pharmaceutically acceptable salt; wherein m is 0, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8, provided that one of 1 γ and γ2 is N, and the other Is CR8; X is a linking group' selected from -CR4 = CR5 - , -CR4 = CR5 CR_6 r7 _ , \ -CR6 R7 CR5 = CR4 -, -C ξ c-, -C ξ CCR6 R7 -, -CR6 R7 c Ξ C-, -NR4 CR6 R7 -, -0CR6 R7 ... SCr6 R7 _, _s(〇)cr6 r7 ' s(〇)2 cr6 r7, -c(o)nr4cr6r7-, -NR4C(0)NR5cR6R7_, _s( 〇) 2Nr4cr6r7, _C(0)NR4-, -NR4C(0)-, -NR4C(0)NR5-, -S(〇)2NR4- and _NR4S(0)2-; R1 is selected from Ci·6 alkane a group of C, 2-6 alkenyl, C2_6 alkynyl, carbocyclyl, carbocyclyl q -6 alkyl, heterocyclyl and heterocyclyl c! _6, which is optionally Or substituted with a plurality of substituents selected from the group consisting of halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9, _s〇2r9, _c〇r9, _c〇2r9, c〇nr9r10, 13708] -37- 201002697 -NR9 CONR1 0 Ri 5 , -NR9 R10 &gt; -NR9 COR10 xn , -nr9co2r10 -NR9COC〇NRi〇Ri5 and _Nr9s〇2ri〇 ;

Or X-R1 is -CR6 R7 OH R2 is a group selected from the group consisting of: (6 alkyl, 砀i hexamethenyl and heterocyclic groups, this group is substituted by -NR17CSNR18R]9, the day phase is reached and optionally Substituted by one or more substituents, the substituents are independently selected from halo, cyano, nitro, _Rl, _〇Rl, _SR1丨, !, S02 R '-COR ' -C02 Ri i Λ _C0NR11R12 Λ _NR11 R12 , _NRi ic〇Rl 2 and -NRHCOCONR12!^ ; each R3', when present, is independently selected from halo, cyano, nitro, -R^-ORl3, -SR, -SOR13, -S02Ri3, c〇 R13 c〇2Rl3 c〇nr13r14 -NR 3R14, -NR13COR14, _Ri3C〇2Ri4 and _NRi3S〇2Ri4 ; R4 and lanthanide are independently hydrogen or Cl6 alkyl; or R1 and R4 and one or more atoms to which they are attached Forming 4 to 1 member carbon-bad or heterocyclic ring together, wherein I 2 or 3 ring carbon atoms are optionally replaced by N, hydrazine or S' and the ring system is optionally substituted by one or more substituents a substituent selected from the group consisting of halo, cyano, nitro, hydroxy, keto, Ci 6 alkyl, alkoxy, halo-Ci-6 alkyl, functional C 6 alkoxy, hydroxy (^^alkyl, Base c]_6 alkoxy, Cl 6 alkoxy Ci 6 alkyl Ci 6 alkoxy Ci 6 alkoxy, amine, Cu alkylamino, bis(Cl 6 alkyl)amine, amine Ci6 alkyl, (Cu alkyl) amine C 6 alkyl, bis (Ci 6 Alkyl)amino-based Ci 6 alkyl 'cyano Ci_6 alkyl, (^-6 alkylsulfonyl, cv6 alkylsulfonylamino, Cy alkylsulfonyl (Cu alkyl) amine, amine sulfonate Sulfhydryl, q-6 alkylamine sulfonyl, bis(Ch alkyl)amine sulfonyl, Cl-6 alkyl amide, Cu alkyl hydrazino (Ch alkyl) amine, amine sulfhydryl, Cu alkyl Amidino and bis(CV6 alkyl)amine 137081 -38- 201002697 fluorenyl; R6 and R7 are independently selected from hydrogen, dentate, cyano, nitro and Ci.6 alkyl; R8 is selected from hydrogen , halo, cyano and Ci 6 alkyl; R9 and R1G are independently hydrogen or are selected from the group consisting of Ci-6 alkyl, carbocyclyl 'carbocyclyl q 6 alkyl, heterocyclic and heterocyclic C1-6 alkyl a group which is optionally substituted by one or more substituents selected from the group consisting of a group, a cyano group, a nitro group, a thiol group, a C. 6 alkyl group, a (6 alkoxy group, a halogen group) Alkyl, dentyl c -6 alkyl aryl, hydroxy c 1-6 alkyl, hydroxy c] 6 alkoxy, Ci decyloxy C 6 alkyl, Q 6 alkyl OxylCl 6 alkoxy, amine, Ci 6 alkylamino 'dialkyl) amine, amine C!-6 alkyl, (Cl 6 alkyl) amine Ci 6 alkyl, bis (Ci 6 alkyl) AminoCh alkyl, cyano (^ 6 alkyl, Ci-6 alkylsulfonyl 1 - 6 alkylsulfonylamino, C!-6 alkylsulfonyl (Cl 6 alkyl) amine, amine sulfonate Sulfhydryl, C!-6 alkylamine sulfonyl, bis(CH alkyl)amine sulfonyl, c]-6 alkyl amide, (V6 alkyl sulfonyl (Ch alkyl) amine, amine methyl fluorenyl a Ci 6 alkylamine ketone group and a bis((:!-6 alkyl)amine carbenyl group; R, R12, R17 and R18 are independently hydrogen or selected from an alkyl group, a carbocyclic group, a carbocyclic group. a group of a C!-6 alkyl group, a heterocyclic group and a heterocyclic group Ci 6 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, Hydroxy, C!_6 alkyl, Ci 6 alkoxy, halo Ci 6 alkyl, halo q-6 alkoxy, hydroxy (^-6 alkyl, hydroxy c) 6 alkoxy, c16 alkoxy C^6 Alkyl, C]-6 alkoxy Ci_6 alkoxy, amine, alkylamino, bis(C!.6 alkyl)amine, aminoChalkyl, (Ci 6 alkyl)amine Ci6 alkane Base, double (Ch Alkyl)amino C^6 alkyl, cyano Ci6 alkyl, Ci6 alkylsulfonyl, C-6-6 alkylamino, q-6 alkyl alkino (Ci-6 alkyl) amine, amine A Sulfhydryl, 137081 -39- 201002697 Q-6, alkylaminomethyl and bis(Cl_6 alkyl)amine fluorenyl; R13, R14, Ris, Ri6 and Ri9 are independently hydrogen or selected from Ci_6 alkyl, a group of a carbocyclic group, a carbocyclic group C]-6 alkyl group, a heterocyclic group and a heterocyclic group C1-6 alkyl group, the group being optionally substituted by one or more substituents selected from a halogen group, Cyano, acetyl, hydroxy, Ck alkyl, C]-6 alkoxy, _yl (^-6 alkyl, halo) &lt;^_6 alkoxy, hydroxyCl 6 alkyl, hydroxy & 6 alkoxy, q 6 alkoxy C!-6 alkyl, Ck alkoxy alkoxy, amine, Cl-6 alkylamine, Bis(C!-6 alkyl)amino, amino Ck alkyl, (Cu alkyl)amino Cu alkyl, bis(C!.6 alkyl)amine C!-6 alkyl, cyanoalkyl , Ck alkylsulfonyl, C!-6 alkylsulfonylamino, Cl 6 alkylsulfonyl (Ci 6 alkyl) amine, amine sulfonyl 'Ck alkylamine sulfonyl, double ( Ci 6 alkyl)amine sulfonyl, Ci 6 alkanoyl, Ck alkanoyl (CV6 alkyl) amine, amine sulfhydryl, (alkyl alkyl fluorenyl and bis (Ci-6 alkane) Or an amine group; or R18 and R19 together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclic ring, wherein 1 or 2 ring carbon atoms are optionally replaced by n, hydrazine or s, and The ring is optionally substituted by one or more substituents selected from the group consisting of benzyl, cyano, nitro, hydroxy, Ck alkyl, Ck alkoxy, halo cv6 alkyl, halo C!- 6 alkoxy, hydroxy C 6 alkyl, hydroxy ci 6 alkoxy, (^, alkoxy Ci-6 alkyl, c]-6 alkoxy C16 alkoxy, amine, Ci6 alkylamino , bis(Ch alkyl)amino group, amino Cu alkyl group, (Cu alkyl)amino Cu alkyl group, bis(C!-6 alkyl)aminoalkyl group, cyano C 6 alkyl group, c] 6 alkyl sulfonyl, c -6 alkyl amide, Ci 6 alkyl sulfonyl (Ci 6 alkyl) amine, amine sulfonyl, C! 6 alkyl sulfonyl, double (Ci 6 alkyl)amine sulfonyl, Ci 6 amidoxime, C!-6 alkino (C16 alkyl) amine, amine sulfhydryl, Ci 6 alkane 137081 • 40- 201002697 carbamine And bis(c)-6 alkyl)amine oxime. According to a further aspect of the invention, there is also provided a compound of formula (I) 4-(R3)m 1 γ·^&gt;γ2 R], γ人人X Ν Formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; W and Y2 are independently N or CR8, provided that one of 1Y and Y2 is N, and the other Is CR8; X is a linking group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -C tri-C-, -CeCCR6R7-, -CR6R7C = C-, -NR4CR6R7-, -OCR6R7 -, -scr6r7-, -s(o)cr6r7-, -s(o)2cr6r7-, -C(0)NR4CR6R7-, _NR4C(0)CR6R7-, -NR4C(0)NR5CR6R7_, -nr4s(o)2cr6r7 -, -s(o)2nr4cr6r7-, -C(0)NR4- -NR4C(0)-, -NR4 C(0)NR5 -, -(0)2 NR4 - and -NR4 S(〇)2 -; R1 is selected from hydrogen, Cu alkyl, C2_6 alkenyl, C2_6 alkynyl a group of a carbocyclic group, a carbocyclylalkyl group, a heterocyclic group and a heterocyclic group Ci-6 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of i groups and cyanogens Base, nitro, -R9, -OR9, SR9, -SOR9, -02R9, -COR9, -C02 R9, -CONR9 R1 〇, -NR9 R1 〇, -NR9 COR1 〇, -NR9 C02 R10, NR9 CONR1 0 R1 5, -NR9COCONR10R15 and NR9S02R10; R2 is a group selected from C! -6 alkyl, carbocyclic group and heterocyclic group, and this group is substituted by 137081 -41 - 201002697 -nr1 7CSNR] 8Ri 9 , and - brothers 4t and excellent substitution of one or more substituents, the substituents are independently selected from the group consisting of fluorenyl, cyano, nitro, _r11, _〇r11, _sr11, _s〇r1i, -S〇2R] -cor&quot;, -C〇2r1 1, c〇nrU R1 2, _nr1 〗 〖r1 2, nr1 丨c〇r1 2 and -NR1 1 COCONR1 2 R1 6 ; Each R3, when present, is independently selected from the group, Cyano, nitro, &amp; 3, _〇Ri3, -C02r!3, -C〇NR13R14 x -R13, -SOR13, -S02Ri3, _c〇Rl3, -NW4, _N R13c〇Rl4, _NRl3c〇2Rl4 and NNi3s〇; R4 and Rs are independently hydrogen or Ci 6 alkyl; or R1 and R4 are connected to them or a plurality of atoms to form 4_ to 1〇_ Carbocyclic or heterocyclic ring 'where!, 2 or 3 ring carbon atoms are optionally replaced by N, hydrazine or S, and the ring is optionally substituted by one or more substituents selected from li 'cyano, nitro, thiol, keto, Ci.6 alkyl, C!-6 alkoxy, _ group (: 1_6 alkyl, alkoxy, hydroxy Gy alkyl hydroxy C!-6 alkane Oxyl, Ci-6 alkoxy Ci 6 alkyl, a 6 alkoxy alkoxy, amine, Cl 6 alkyl amine, bis 6 hexyl) amine, amine 6 alkyl, (CH alkyl) Amino C1-6 alkyl, bis(Ch alkyl)amino Cualkyl, cyano q'6 alkyl, ·6 alkylsulfonyl, q-6 alkylsulfonylamino, q_6 An alkyl group (Cl -6 alkyl) amine group, an amine fluorenyl group, a C -6 hexyl amine fluorenyl group, a bis(CH alkyl) amine sulfonyl group, a C -6 olefin amidino group , Cu alkyl fluorenyl (C) -6 alkyl) amine group, amine methyl sulfhydryl group, C16 alkyl amine fluorenyl group and bis (c16 alkyl) amine carbaryl group; R6 and R7 are independently selected from Hydrogen, halo 'cyano, nitro and c 6 alkyl; R8 is selected from the group consisting of hydrogen, halo, cyano and cv6 alkyl; ' is independently hydrogen, or is selected from Ci_6 alkyl, carbocyclyl, a carbocyclic group ci-6 137081 -42- 201002697 A group of an alkyl 'heterocyclyl group and a heterocyclic group Ck alkyl group, the group being optionally substituted by one or more substituents selected from a halogen group, Cyano, acetyl, hydroxy, Ci-6 alkyl 'cv6 alkoxy 'haloalkyl, il-based C!-6 alkoxy, hydroxy Ck alkyl, hydroxy C!-6 alkoxy, c^6 Alkoxy Cu alkyl group, C].6 calcined base C 2 6 alkoxy group, amine group, C]_6 alkyl group, bis (c 6 group) amine group, amine Cu alkyl group, (CV6 Alkyl)aminoalkylalkyl, bis(Ci 6 alkyl)amino cv6 alkyl, cyano cv6 alkyl, 〇ν6 alkylsulfonyl, Cl 1 ~ 6 alkylsulfonylamino, cumane Alkyl sulfonyl (Cu alkyl) amine group, amine aryl group, c 6 alkyl sulfonyl bis (Cl 6 alkyl) amine sulfonyl group, Ci 6 alkanoyl group, C] -6 alkane oxime Alkyl (C 6 alkyl) aminylamine, c16 alkylamine decanoic acid and bis((1-6 alkyl)aminecarbamyl; RU, R12, R17 and R18 are independently hydrogen, or a group from c] 6 alkyl, carbocyclyl, carbocyclyl q-6 alkyl, heterocyclyl and heterocyclyl C1-6 alkyl, this group being optionally substituted by one or more substituents' The substituent is selected from the group consisting of halo, cyano, nitro, hydroxy, C^6 alkyl, Cl-6 alkoxy, hydroxy, alkyl, C1-6 alkoxy, hydroxy Ci-6 alkyl, hydroxy c!-6 alkane Oxyl, cv6 alkoxy C1-6 alkyl, C!, 6 alkoxy Ci_6 alkoxy, amine, acryl, bis(c-6 alkyl)amine, amine Ci-6 alkyl, (Ch alkyl)amino-based Ci 6 alkyl, bis(C-6-alkyl)amino C!-6 alkyl, cyanoalkyl, (^^alkylsulfonyl, q-6 alkyl amidino , C! -6 alkyl alkane (C: -6 alkyl) amine group, amine methyl sulfonyl group, C hexyl amide amine fluorenyl group and bis (C hexaalkyl) amine fluorenyl group; R13, R14, R1S, R16AR19 are independently hydrogen or a group selected from the group consisting of an alkyl group, a carbocyclic group, a carbocyclic group C 6 alkyl group, a heterocyclic group and a heterocyclic group Q6 alkyl group, which is optionally one or more Substituted by a substituent selected from the group consisting of 137081 -43- 201002697 halo, cyano, nitro, hydroxy, (V6 alkyl, 〇ν6 alkoxy, Base Cl_6 alkyl, dentate Ci-6 alkoxy, hydroxy Ck alkyl, hydroxy (^_6 alkoxy, C!-6 alkoxy Ci-6 alkyl, (ν6 alkoxy Ci-6 alkoxy) a group, an amine group, a (^_6 alkylamino group, a bis(CV6 alkyl)amino group, an amine Cu alkyl group, a (Ck alkyl)amino group cv6 alkyl group, a bis(cv6 alkyl)amino group Cu alkyl group, Cyano Cu alkyl, cv6 alkyl, &lt;^-6-Acetylamino, Ck-alkyl (Cj-6 alkyl) amine, amine sulfonyl, Ck alkylamine sulfonyl, bis(Ci_6 alkyl) amine sulfonate Sulfhydryl, (^_6 alkyl amidino, (^_6 alkyl fluorenyl (Ck alkyl) amine group, amine fluorenyl group, Ci-6 alkyl amine fluorenyl group and bis (Ck alkyl) amine mercapto group Or R18 and R19 together with the nitrogen atom to which they are attached form a 3 to 1 member heterocyclic ring, wherein 1 or 2 ring carbon atoms are optionally replaced by n, hydrazine or S, and the ring is optionally Substituted by one or more substituents selected from the group consisting of a benzyl group, a cyano group, a nitro group, a hydroxyl group, a CV6 alkyl group, a Ch alkoxy group, an i group (^-6 alkyl group, a halogenated Ck alkoxy group, a hydroxyl group ( ^_6 alkyl, hydroxy Ck alkoxy, Ck alkoxy Ck alkyl, (^_6 alkoxy (^_6 alkoxy, amine, C!-6 alkylamino, bis(C)-6 alkyl) Amino, amine cv6 alkyl, (q. 6 alkyl) amine CV6 alkyl 'bis(q-6 alkyl) amine C!-6 alkyl, cyano &lt;^_6 alkyl, Cu alkylsulfonyl, C^6 alkylsulfonylamino, Ci6 alkylsulfonyl (Ci6 alkyl) amine, amine sulfonyl, C! -6 alkyl Amine sulfonyl, bis(Ci 6 alkyl sulfonyl, C!-6 amidino, 〇ν6 alkyl sulfonate (Cu alkyl) amine, amine carbaryl, Cu alkyl amide And bis(Ck alkyl)amine oxime. According to a further aspect of the invention, a compound of formula 1 137081 -44 - 201002697 八N 1 is also provided.

Formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; 1Y and Y2 are independently N or CR8, provided that one of Y and Y2 is N, and One is CR8; X is a linking group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5=CR4-, -CEC-, -CeCCR6R7-, -CR6R7CsC-, -NR4CR6R7-, -OCR6R7-,- SCR6R7-, -s(o)cr6r7-, -s(o)2cr6r7-, -C(0)NR4CR6R7-, -nr4c(o)cr6r7-, -nr4c(o)nr5cr6r7-, -nr4s(o)2cr6r7- , -s(o)2nr4cr6r7-, -C(0)NR4-, -NR4C(0)-, -NR4 C(0)NR5 -, -(0)2 NR4 - and -NR4 S(0)2 -;

R1 is a group selected from the group consisting of C i -6 alkyl group, C 2 -6 fine group, C 2 - 6 fast group, a destructive group, a carbon-based alkyl group, a heterocyclic group and a heterocyclic group Ci_6 alkyl group. Substituted by one or more substituents selected from the group consisting of i, cyano, nitro, -R9, -OR9, -SR9, -SOR9, -02R9, -COR9, -C02R9, -CONR9R10, -NR9R10 , -NR9COR10, -NR9C02R10, -NR9CONR10R15, -NR9 COCONR1 0 R15 and NR9 S02 R1 0 ; or X-R1 is -CR6R7OH; R2 is a group selected from the group consisting of q_6 alkyl, carbocyclic and heterocyclic groups, The group is substituted by -NR17CSNR18R19, and is optionally substituted by one or more substituents, taking 137081 -45-201002697 algebra independently from halo, cyano, schwitz, _Rl丨, -OR, 1, _SRn, _S 〇Rl 1, S〇2 R, -COR, -CC^R11, -CONR11 R1 2, -nr1 1 R1 2, -NR11 COR1 2 A -NRnCOCONR, 2R16 ; each R3, when present, is independently selected from halogen Base, cyano, nitro, _Rl 3, _〇Rl 3, -R, -SOR13, -S〇2Ri3, _c〇Ri3, c〇2Rl3, c〇NR丨3r14 -NR R 4 ^ -NR1 3 COR1 4 x -NR1 3C02R14^ _NRi3S〇2Ri4 ; R4 and the oxime are independently hydrogen or Ci6 alkyl; R and R together with one or more of the atoms to which they are attached form a 4 to ι〇 member carbon cyclic or heterocyclic ring wherein 1, 2 or 3 ring carbon atoms are optionally N, 0 or S is substituted, and the ring is optionally substituted with one or more substituents, and the substituent is selected from! i group, cyano group, nitro group, thiol group, fluorenyl group, Ci 6 alkyl group, q. 6 alkoxy group, halogenyl Ci-6 alkyl group, halo C 6 alkoxy group, hydroxy C 6 alkyl group, thiol group Alkoxy, Ci 6 alkoxy Ci 6 alkyl, Ci 6 alkoxy^-6 alkoxyamino, Cl. 6 alkylamino, bis(c!-6 alkyl)amine, amine c] 6 alkyl (Ch alkyl) amine-based Ci_6 alkyl, dialkyl) amino-based Ci-6 alkyl, =, _ 1 0, aryl-based Cl-6 fluorenyl sulfhydryl, 匚 6 6 Amino group, 6 6 alkyl sulfonyl (Ch alkyl) amine group, amine sulfonyl group, c -6 alkyl sulfonyl sulfhydryl group, bis (CH alkyl) amine base, CH decylamine Base, Ch-based sulfhydryl (Cl.6)-based amine amine-branth, Cb 6-based amine thiol and bis (Ch-based brinic acid; R and R are independently selected from hydrogen, halogen , cyano, nitro and alkyl; R8 is selected from the group consisting of hydrogen, _, cyano and Ci6; R9 and R10 are independently hydrogen ' or selected from Ci 6 alkyl, carbocyclic, carbocyclic a group of a pyridyl group, a heterocyclic group and a heterocyclic group Ci_6 alkyl group, which is optionally substituted by one or more substituents, the substituent being selected from a group, a cyano group, and the like, as the case may be, 6 137081 - 46 - 201002697 Base, meridine, Ci-6 alkyl, Cl-6 alkoxy, ifi-based Ch alkyl, halo Ck alkoxy, hydroxy C!-6 alkyl, hydroxy Ci6 alkoxy, Ci6 alkoxy Ci 6 alkyl, q-6 alkyl fluorenyl C1_6 alkyl fluorenyl, amine, alkylamino, bis(C16 alkyl)amino, aminoCh alkyl, (Ci 6 alkyl)amine Ci6 alkyl, double (Ci 6 alkyl)amino C!-6 alkyl, cyano Ci6 alkyl, Ci6 alkylsulfonyl, Cij alkyl tertylamino, Cl-6 alkylsulfonyl (Ci-6 alkane) Amino group, amine sulfonyl group, Q 6 alkyl group, bis (Cu alkyl) amine sulfonyl group, alkyl amidino group, C 6 6 alkyl group (Ci-6 alkyl) amine group, amine A Anthracenyl, 6-alkylaminoindenyl and bis(C1 -6 alkyl)amine fluorenyl; R11, R12, R17 and R1S are independently hydrogen or selected from the group consisting of q 6 alkyl, carbocyclic, carbocyclic a group of a C 6 alkyl group, a heterocyclic group and a heterocyclic group Ci 6 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of a halogen group, a cyano group, a nitro group, Hydroxy, Cl-6 alkyl, C!-6 alkoxy, i-based cv6 alkyl, halo-Ci-6 alkoxy, hydroxy Ci-6 alkyl, hydroxy Ci6 alkoxy, c] 6 alkoxy C!-6 alkyl, (V6 alkoxy Cl-6 alkoxy, amine, Ci 6 alkylamino, bis(C!-6 alkyl)amine, amine Ci 6 alkyl, (Ci6 alkyl) Amino CH alkyl, bis(C!-6 alkyl)amino C1-6 alkyl, cyano Ci6 alkyl, alkylsulfonyl, C?-6 alkanoyl, Ci 6 alkyl fluorenyl ( CH alkyl)amino, amine mercapto, C!-6 alkyl amidino and bis(Ci 6 alkyl) amidamyl; R, R14, R1S, R16 and R19 are independently hydrogen, or a group selected from the group consisting of a thiol group, an anti-% group, a sulphonyl group, a 6-alkyl group, a heterocyclic group and a heterocyclic group 6 6 alkyl group, the group being optionally substituted by one or more substituents, a substituent Selected from fluorenyl, cyano, nitro, thiol, CH alkyl, c16 alkoxy, south base C16 137081 -47- 201002697 alkyl, halo &lt;^_6 alkoxy, hydroxy (^_6 alkyl , hydroxy c^6 alkoxy, Ci-6 alkoxy Q-6 alkyl, (^_6 alkoxy Ck alkoxy, amine, Cn acryl, bis(Ch alkyl)amine, amine Ch-alkyl, (Ci_6 alkyl)amino-Ci-6 alkyl, bis(Ch alkyl)amino Cu alkyl, cyano-Ch alkyl, CV6 alkylsulfonyl, Cil alkylsulfonylamine Base, Cl 6 alkylsulfonyl (Ci6 alkyl) amine group, amine sulfonyl group, q 6 alkyl sulfonyl group, bis(C! -6 alkyl) aminoxime group, Cu alkanoyl group, 6 An alkanoyl (cv6 alkyl)amino group, an amine fluorenyl group, an alkylamine carbhydryl group, and a bis(Cl-6 alkyl)amine carbhydryl group; or R18 together with R19 and the nitrogen atom to which they are attached form 3_ To a 10-membered heterocyclic ring, wherein 1 or 2 ring carbon atoms are optionally substituted by n, hydrazine or S, and the ring system is optionally substituted by one or more substituents selected from the group consisting of a benzyl group and a cyano group. , nitro, hydroxy, (V6 alkyl, Ck alkoxy, _yl Ck alkyl, halo) &lt;^_6 alkoxy, hydroxy C1-6 alkyl, hydroxy Ci6 alkoxy, (:: alkoxy Alkyl, alkoxy (^-6 alkoxy, amine, Ck alkylamino, bis(Cw alkyl)amine, amine Ck alkyl, (&lt;^6 alkyl)amine cv6 alkyl , bis(C!-6 alkyl)amino (^-6 alkyl, cyano Ci-6 alkyl, alkylsulfonyl, alkylsulfonylamino, C16 alkylsulfonyl (C16 alkyl) amine Base, acesulfame, CV6 alkylamine sulfonyl, bis(Cl 6 alkyl)amine sulfonyl, Cl 6 aryl amine, (6 6 alkyl fluorenyl (C^alkyl)amino group, amine carbaryl group, CV6 alkylamine carbaryl group and bis(Ch alkyl)aminocarbamyl group. According to a further aspect of the invention, there is also provided a compound of formula 1 137081 -48- 201002697 ο

(R3)m

R'

R2 Formula (I) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; α and Y2 are independently N or CR8, provided that one of 1Y and γ2 is N, and One is CR8;

X is a linking group selected from _CR4=CR5-, -CR4CR5CR6RB, -CR6R7CR5=CR4-, -CSC-, -CeCCR6R7-, _CR6R7C3C-NR4CR6R7-, -〇CR6r7_, _SCR6R7_, _S(〇)cr6r7, s( 〇) 2Cr6r7, -C(0)NR4CR6R7-, _NR4C(0)NR5CR6R7-, -S(〇)2NR4CR6R7-, -C(0)NR4-, -NR4C(0)-, -NR4C(0)NR5-, -S(0)2NR4j_NR4S(0)2-; R1 is selected from the group consisting of a CH group, a C2 6 alkenyl group, a C2 6 alkynyl group, a hindered ring group, a carbocyclic group q-6 alkyl group, a heterocyclic group and a heterocyclic group. a group of a Ci_6 alkyl group, the group being substituted by one or more substituents as appropriate. The substituent is selected from the group consisting of halo, cyano, nitro, -R9, -OR9, -SR9, -SOR9, 02R9, _c〇R9, _c〇2R9, c〇nr9r1〇, -NR R -NR9 COR1 〇. -NR9C02R10 &gt; -N^CONR1 °R15 . -NR9 COCONR10 Ri 5 and nr9 s〇2 Rl 0 ; or X- R1 is -CR6 R7 〇H; R2 is a base selected from the group consisting of a CH group, a carbocyclic group and a heterocyclic group, and this group is substituted by _NR17CSNR]8Rl 9 and optionally substituted by one or more substituents. The substituent is independently selected from the group consisting of a south group, a cyano group, a nitro group, a -R11, -OR11, -SR11, -SOR11, 137081 -49-201002697 -SC^R11, -COR11 ' _c〇2R&quot;, -CONR11 R12, -NR11 R1 2, -NR11 COR1 2 Each R3, when present, is independently selected from halo, cyano, nitro, _Ri3, _ORi3, -R13, -SOR13, _s〇2R13, _C〇R13, _c 〇2r13 ' _C〇NR13R14, -NR13R14, -NR13c〇R14, _NR13C02R14 and -NR13S02R14 ; 圮 and 妒 are independently hydrogen or c]_6 alkyl; or R1 and R4 together with one or more atoms to which they are attached Forming a 4- to 10-membered carbon cyclic or heterocyclic ring wherein 1; 2 or 3 ring carbon atoms are optionally replaced by N, hydrazine or S' and the ring is optionally substituted by one or more substituents Substituted, the substituent is selected from the group consisting of ii group 'cyano, nitro, hydroxy, keto, Ci6 alkyl, C -6 alkoxy, halo C 6 alkyl, functional c _ 6 alkoxy, hydroxy &amp; 6 alkyl, hydroxy Cm alkoxy, Ci 6 alkoxy Q 6 alkyl, q-6 alkoxy Ci 6 alkoxy, amine, Cli alkylamino, bis(Ci 6 alkyl)amine, amine Ci6 alkyl, (Ch alkyl)amino qj alkyl, bis(Ci6 alkyl)amino c 6 alkyl, cyanoalkyl, Cl 6 alkylsulfonyl, Ci 6 alkylsulfonylamino , base based on alkyl group (C! _6 yard base) amine group, amine base group, _ 6 alkyl group Alkyl, (q-6 alkyl)amine sulfonyl, Ci 6 alkanoyl, C]alkylalkylalkyl) aminyl fluorenyl, C! -6 alkyl amide thiol and double (C) -6 alkyl) anthracene; R and R are independently selected from the group consisting of hydrogen, a functional group, a cyano group, a nitro group and a q.6 alkyl group; and the R8 group is selected from the group consisting of hydrogen 'halo group, cyano group and Ci 6 alkyl; R and R are 'independently hydrogen' or a group selected from the group consisting of Ci 6 alkyl, carbocyclyl, carbocyclyl, and heterocyclyl c16 alkyl, which is a group Optionally substituted with - or a plurality of substituents selected from the group consisting of hydrazine, cyano, nitro, 137081 • 50- 201002697 hydroxy, (^-6 alkyl, (^_6 alkoxy, halo q-6 hexane) Base, halo group c _6 alkoxy group, hydroxy CP6 alkyl group, hydroxy group (:16 alkoxy group, Cl_6 alkoxy group C 6 alkyl group, C) _6 炫 • 乳-based Cl-6 emulsifier base, amine group, Cl -6 an amine group, a bis(Cl-6) group amine group, an amine group Ck alkyl group, a (Ci 6 alkyl)amino group C 6 alkyl group, a bis(Ci 6 alkyl)amino group CV6 alkyl group, a cyano group (^_6 alkyl, (^_6 alkylsulfonyl, (^_6 alkylsulfonylamino, Cu alkylsulfonyl (Ci 6 alkyl) amine, amine sulfonyl, Q_6 Amine sulfonyl, bis(Ci6 alkyl)amine sulfonyl, Ci6 alkanoyl, Q 6 alkyl alkane (C! -6 alkyl) amine, amine sulfhydryl, q -6 alkyl amide And bis(C -6-6 alkyl) amininyl; R11, R12, R17 and R18 are independently hydrogen or selected from Ci 6 alkyl, carbocyclyl, carbocyclyl c -6 alkyl, a group of a heterocyclic group and a heterocyclic group Ci 6 alkyl group, which group is optionally substituted by one or more substituents selected from a halogen group, a cyano group, a nitro group, a hydroxyl group, a Ck alkyl group, ^_6 alkoxy, haloCl 6 alkyl, haloalkoxy, hydroxy q-6 alkyl, hydroxy Ci 6 alkoxy, Ci 6 alkoxy c]-6 alkyl, c!-6 alkoxy Base q·6 alkoxy, amine, Ci 6 alkylamino, bis(C -6 alkyl)amine, amine Cl 4 alkyl, % 6 alkyl)amino Ci6 alkyl, double (c^ 6 alkyl)amino group c _6 alkyl, cyano Ci 6 alkyl, alkyl sulfonyl, Cu alkyl amide, Cl 6 alkyl cyano (Ci6 alkyl) amine, amine sulfhydryl, ci -6 alkylamine methyl hydrazino and bis(Ck alkyl) amine carbaryl; R13, R", Rls, Rl6 and Rl9 are independently hydrogen or selected from Ci6 alkyl, carbocyclyl, carbon a group of a C1_6 alkyl 'heterocyclyl group and a heterocyclic group C16 alkyl group, which is optionally taken as π by a substituent or a substituent selected from the group consisting of an anthracenyl group, a cyano group, a fluorenyl group, and a Base, c16 alkyl, C16 alkoxy, halo c&quot; alkyl, halo C1'oxy, C1_4, C1.6 alkoxy, !37〇81 -51 - 201002697

Ck alkoxy q-6 alkyl, Ck alkoxy Ci-6 alkoxy, amine, C -6 alkylamino, bis(Ck alkyl)amine, amine Q-6 alkyl, ( CV6 alkyl)amino cv6 alkyl, bis(Α_6 alkyl)amino c&quot; alkyl, cyano cv6 alkyl, Cn alkyl aryl, C^-6 alkyl thiol, Q- 6 alkyl thiol (Ci-6 alkyl) amine group, amine sulfonyl group, CP6 alkylamine sulfonyl group, bis((^_6 alkyl) sulfonyl group, alkanoyl group, CVe alkane a (CV6 alkyl)amino group, an amine methyl sulfhydryl group, a C!-6 alkyl amine fluorenyl group, and a bis(CV6 alkyl) amine carbaryl group; or R18 together with R19 and the nitrogen atom to which they are attached Wherein 1 or 2 ring carbon atoms are optionally substituted by n, hydrazine or S, and the ring is optionally substituted by one or more substituents selected from halo , I, nitro, hydroxy, Ch alkyl, Ch alkoxy, halo C 6 alkyl, halo q-6 alkoxy, hydroxy 6 alkyl, hydroxy c] -6 alkoxy, Ci 6 alkane Alkoxyalkyl, Cl_6 alkoxy Ci_6 alkoxy, amine, &amp; 6 alkylamino, bis(Ch alkyl)amine, amine Clj alkyl, (Ci 6 alkyl)amine Q 6 alkyl, bis(Cw alkyl)amino C 6 alkyl, cyano &amp; alkyl, &amp; alkylsulfonyl, A-6 alkylsulfonylamino, q 6 alkylsulfonyl ((:1 6 alkyl)amine group, amine sulfhydryl group, C]_69 group amine group, bis (Gi6 sinter base, Ci.6 saponin base, Cl.6 sulphonate group (CB alkyl group) Alkyl 1 mercapto, Cl.6 leucine carbhydryl and bis(Ch alkyl)aminocarbamyl. Certain compounds of formula (I) can exist in stereoisomeric forms. It should be understood that = It encompasses all geometric and optical isomers of the compound of formula (1), and:: racemates. The tautomers and mixtures thereof also constitute this aspect. The solvates and their compositions also form an aspect of the invention. For example, a suitable solvate of the compound of the formula (1) is, for example, a hydrate, 137081 - 52 - 201002697 - a hydrate or a trihydrate, or a compound such as a hemihydrate, a monohydrate, or a substituted amount. The compound of formula 1 as defined herein, and the salt used in the pharmaceutical composition are pharmaceutically acceptable salts, and are useful in the manufacture of a compound of formula 1 and a pharmaceutically acceptable salt thereof. For example, a pharmaceutically acceptable salt of the present invention may comprise an acid addition salt of a compound of formula (1) as defined herein, which is sufficient to form such a salt. Such acid addition salts include, but are not limited to, reverse a dibasic acid salt, a methyl sulphonate, a hydrochloride, a hydrobromide salt, a citrate salt and a succinic acid salt, and a salt formed with phosphoric acid and sulfuric acid. Further, a compound of the formula (1) is sufficient In the case of acidity, the salt is a salt test, and examples include, but are not limited to, metal ruthenium, such as sodium or a clock, a metal salt such as calcium or magnesium or an organic amine salt such as triethylamine, ethanolamine, ethanolamine, Triethanolamine, please. Lin, N-methyl six gas bites, N_ethylhexahydropyridine, diamine or amino acid, such as amidoxime. The compound of formula (I) may also be hydrolyzed in vivo (iv). An in vivo hydrolysable ester of a compound of formula (I) containing a thiol or hydroxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce a parent acid or alcohol. Such a test can be confirmed by, for example, administering a test compound to a test animal in an intravenous manner, followed by testing the body fluid of the test animal. Suitable pharmaceutically acceptable (4) for rebel, including C1.4 oxymethyl-branched 'e.g. methoxymethyl' C1_6 ethoxylated methyl acetonate, for example, dimethyl acetoxy A, mercaptoesters 'c38 cycloalkoxycarbonyloxy q-6 alkyl esters, for example, cyclohexylcarbonyloxyethyl, anthracene, 3-dioxolan-2-ylmethyl Vinegar, for example, 5-methyl-u_dioxanthene; 2_copper-based 137081-53-201002697 base, and c]-6-oxygen oxetyloxyethyl esters, such as 丨_methoxy A benzyloxyethyl group; and can be formed at any of the carboxyl groups in the compounds of the invention. Suitable pharmaceutically acceptable vinegars for hydroxy groups, including inorganic steroids, such as phosphates (including aminophosphate cyclic esters) and alpha methoxyalkyl ethers, and due to decomposition of vinegar to obtain the parent hydroxy group Related compounds caused by in vivo hydrolysis. Examples of the gadolinyloxyalkyl ethers include ethenyloxymethoxy and 2,2-dimethylpropoxyoxycarbonyl. For hydroxyl groups, a group capable of forming a hydrolyzable vinegar in vivo may be selected, and the selection includes a Cii decane fluorenyl group such as a methyl group, a thiol group, a benzamidine group, a phenethyl group, a substituted benzoyl group and a benzene group. Ethyl carbonyl; alkoxycarbonyl (for alkyl carbonates), such as ethoxycarbonyl; bis-Ch tyrosyl fluorenyl and n_(: _Ch-aminoethyl)-Nq-4 alkylamine a mercapto group (to obtain a urethane); a di(n-alkylaminoethyl fluorenyl group and a carboxyethyl fluorenyl group; an example of a ring substituent on the phenethyl fluorenyl group and the carbaryl group, including an aminomethyl group, CH acrylmethyl and bis 4 alkyl)aminomethyl, and N ♦ lin or hexahydro (tetra), which are attached to the benzhydryl ring from a ring nitrogen atom via a methylene linking group 3_ or 'position. Other interesting in vivo hydrolyzable species include, for example, $institutional-ca, wherein RA is, for example, a phenyl group or a phenyl group. In such a class, suitable substituents on the phenyl group include, for example, 4-CH hexahydropyridinyl-c&quot; alkyl, hexahydropyramyl-Ci4 alkyl and N-morpholinylalkyl. The compound of formula (I) can also be administered in the form of a prodrug which is decomposed in the body of a human to obtain a compound of formula 1. Various prodrug forms are known in the art. For a reference on such prodrug derivatives: , j 137081 -54- 201002697 a) Design of prodrugs, edited by H. Bundgaard (Elsevier, 1985), Enzymology, Vol. 42, vol. 396 pages, edited by K. Widder et al. (University, Press, 1985); b) Textbook on Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 &quot; Design and Application of Prodrugs &quot;, by η. Bundgaard, pp. 113-191 (1991); c) H. Bundgaard, Development of Drug Delivery Review, &amp; 1-38 (1992); d) H. Bundgaard et al., Medical Sciences Journal, 77, 285 (1988); and e) N_Kakeya et al., Chem Pharm Bull, 32, 692 (1984). In this patent specification, the generic term, Cpi alkyl" includes both straight-chain and branched-chain alkyl groups. However, the reference to individual alkyl groups, such as &quot;propyl,, is only 4 曰 straight chain Variants (ie, n-propyl and isopropyl), and references to individual branched alkyl groups, such as "third-butyl", are exclusively referred to as branched chain variants. In Cp_q alkyl and other terms The prefix CpV, where 卩 and ^ are integers, indicates the range of carbon atoms present in the group, such as &amp; *alkyl includes C]alkyl (methyl), C2 alkyl (ethyl), &amp;alkyl (propyl, such as n-propyl and isopropyl) and 04 alkyl (n-butyl, t-butyl, isobutyl and tert-butyl).

The term Cp-q alkoxy includes _〇_Cp _ q 炫. Cp-q alkyl-based, including -c(o)alkyl. Halo&quot; Division, including fluoro, chloro, bromo and iodo. Human bauxite is a saturated, unsaturated or partially saturated monocyclic, bicyclic or cyclic ring system containing from 3 to 14 ring atoms with a c=o group substitution. "Carbocyclyl, including, aryl" wherein the fluorenyl 12 group can be &quot;Cp-q cycloalkyl" and &quot;Cp-q 137081 -55 - 201002697 cycloalkenyl&quot;. The aryl '' is an aromatic monocyclic, bicyclic or tricyclic carbocyclic ring system.

Cp-q % alkenyl" is an unsaturated or partially saturated monocyclic, bicyclic or trisogenic n-based ring system containing at least one c=c bond, and wherein the ring group can be c=〇 Group replacement. 2 soil

The Cp - q cycloalkyl group '' is a saturated monocyclic, bicyclic or tricyclic carbocyclic ring system, and wherein the ring CH2 group can be replaced by a c= fluorene group. a heteronuclear group is saturated, partially saturated or partially saturated, monocyclic, bicyclic, tricyclic ring system 'containing 3 to 14 ring atoms' wherein (1) or 4 rings are originally derived from I, sulfur or oxygen 'The ring may be carbon or nitrogen linked, and wherein the ring nitrogen or "sub may be oxidized, and wherein the ring may be referred to as a (f)yl" heterocyclic group, including "heteroaryl", "," Base, and,,,,,,,,,,,,,,,,, , Θ aryl | | is (iv) a monocyclic, bis (tetra) or tricyclic heterocyclic group, fluorene has 5 to 10 ring atoms, wherein x private atoms are selected from nitrogen, 丨·• or oxygen The ring nitrogen or sulfur can be oxidized. &quot;cycloheteroalkenyl" is a system of non-fresh or partially saturated monocyclic heterocycles, particularly having a subunit selected from nitrogen, sulfur or oxygen, which may be a carbon or nitrogen linkage, and a group substitution. The ch2 group may be a C=indenyl ring compound, and a monocyclic or anthracene ring, and a monocyclic or tricyclic heterocyclic ring system, particularly having 5 to 10 ring atoms, Wherein I, A, 2, 3 or 4 ring atoms are selected from the group consisting of sulphur or sulphur, the sputum may be carbon or nitrogen linkage, and the dragon may be oxidized by Lu #々, and its titOi _ clothing see 3, stone melon Atomic m group substitution. 】]]] 37081 -56- 201002697 This patent specification can be used in conjunction with the term "_β^" to describe a group containing more than one official month b group. Unless the wooden female is ancient, there are 5 months, this term is intended to be interpreted as the singer of the art _ _ ^ ^, 喏 for example, the stone anti-% Cp _ q alkyl including Carbocyclyl substituted e | ih. m alkyl, heterocyclyl Cp q alkyl includes Cp-q alkyl group substituted by heterocyclic group and double (C&quot; alkyl) amine group includes 2 An amine group substituted with the same or different Cp_q alkyl group. The halo-based cp_q alkyl group is a cp_q alkyl group which is substituted with hydrazine or a plurality of halo substituents, and particularly substituted with 1' 2 or 3 i-substituents. Similarly, other generic terms containing a functional group, such as alkoxy, may contain one or more substituents, and in particular 1, 2 or 3 substituents. The hydroxy Cp _ q alkyl group is cp _ qalkyl' which is substituted by 1 or more hydroxy groups, and in particular by 1, 2 or 3 hydroxy substituents. Similarly, other generic terms containing hydroxyl groups, such as hydroxy Cp _ q alkoxy, may contain hydrazine or more, and in particular 1, 2 or 3 hydroxy substituents.

The Cp-q alkoxy Cp_q alkyl group is a Cpq alkyl group which is substituted with 1 or more alkoxy substituents, and particularly hydrazine, 2 or 3 Cp_q alkoxy substituents. Similarly, 'the other general term for (a, alkoxy, such as Cp q alkoxy Cp - q alkoxy) may contain 1 or more Cp. q alkoxy substituents, and especially 1,2 Or 3 Cp_q^oxy substituents. In the case where the substituent is selected from "1 or 2&quot;, "1, 2 or 3', or "1, 2' 3 or 4" groups or substituents In the following, it should be understood that this definition includes all substituents being selected from one of the specified groups, meaning that all substituents are the same, or the substituents are selected from two or more specified groups, ie substituents. 137081 -57- 201002697 The compounds of the present invention have been named by means of computer software (ACD/named version 8 。). Twin diseases include malignant diseases such as cancer, and non-malignant diseases, such as inflammatory diseases, Blocking airway disease, immune disease or cardiovascular disease. Suitable meanings for any R group or any part or substituent of such a group include: With respect to alkyl: methyl, ethyl, propyl, butyl, 2-methylpropyl and tert-butyl; about C1-6 alkyl: C1-4 alkyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and hexyl; with respect to c3_6 cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; about c3_6 cycloalkylCl_4 alkyl: ring Propylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; about aryl: phenyl and tea; about aryl Ci-4 alkyl: loyal, stupid a group, a naphthylmethyl group and a decylethyl group; a carbocyclic group: an aryl 'cyclohexenyl group and (: 3_6 cycloalkyl group; about a _ group: a fluoro group 'chloro group, a bromo group and an iodine group; -4 alkoxy group · methoxy, ethoxy, propoxy and isopropoxy; about Cil alkoxy: Cl 4 alkoxy, pentyloxy, ethyl propyl decyl and hexyloxy; 137081 -58- 201002697 About CI-6 alkanoyl group with regard to heteroaryl group: : ethyl hydrazino group, propyl fluorenyl group and 2-methyl propyl fluorenyl group; mouth ratio 疋 疋 group, imiline group, side „林基, pp Linji, mouth bite base 'σ塞 基, 峨 基, pyrazolyl, pyrazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl, furyl, hydrazine, pyrinic , sulfhydryl, stupid and biting α-nan, a benzo-t夫 喃 及 苯 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于 关于Azylmethyl, pyrazolylethyl, furylmethyl, furylethyl, pyrenyl fluorenyl, thienylethyl, P to dimethylmethyl, p ratio. Base, pyridylethyl, D-denylmethyl, thioethyl, dimethyl propyl, pyrimidinyl butyl, imidazolylpropyl, imidazolylbutyl, quinolylpropyl, 1 , 3,4-trisalpropyl and p. Heteromethyl; heterotetracycline, tetrahydropyrrolidyl, iso-tr-quinoline, fluorenyl, benzo-pyrazole, benzoxazolyl, hexahydropyridyl, hexahydropyrrole , nitrotetradecyl, N-morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, indanyl, diindole-2H-methyl and tetra 137081 -59- 201002697 hydrogen furan base. Not =: Yes 'About this statement... All of them are m, ^==Y2, x, Rl, x_Rl, R2, R3, R4, R5, R6, R7, R8R9, Ri meaning: R, R14 The specific meanings of R17, R18 and R]9 are as follows. This is intended to be used in conjunction with any embodiment of the invention, where appropriate. Any definition, claim, or m of the present invention, m is 0, 1, 2, or 3. In another aspect, 'm is 〇, 1 or 2. In the case of the advance step, m is 0 or 1. On the other hand, „1 is 〇, so R3 is absent. In yet another aspect, m is 1, and R3 is methyl.

In one aspect of the invention, 1 Υ is Ν and Υ 2 is CR8. In the other aspect, it is Ν, and Υ2 is CH. On the other hand, it is CR8, and Υ2 is Ν. In a further aspect, Ιγ is CH or CF and γ2 is Ν. In yet another aspect, ΐγ is CH and Υ2 is Ν.

X is in the aspect of the invention -OCR6R7-, 'X is a linking group selected from _NR4CR6R7--SCR6R7-, -S(0)CR6R7-, _s(〇)2CR6r7--C(0)NR4CR6R7_, _NR4C(〇 NR5CR6R7_, s(〇)2Nr4cr6r7 137081 •60- 201002697 -NR4C(0)_, -C(0)NR4-, -S(0)2NR4- and -NR4S(0)2-. In another aspect, X is a linking group selected from the group consisting of -NR4CR6R7-, -OCR6R7-, -SCR6R7-, -s(o)cr6r7-, -s(o)2cr6r7-, -c(o)nr4cr6r7-, -nr4c (o) nr5cr6r7-, -S(0)2NR4CR6R7, -C(0)NR4- and -nr4c(o)-. In a further aspect, x is a linking group selected from the group consisting of -NR4CR6R7 -, -OCR6R7-, -scr6r7-, -s(o)cr6r7-, -s(o)2cr6r7-, -C(0)NR4-, and -nr4c ( o)-. In a further aspect, x is a linking group selected from the group consisting of -NR4CR6R7-, -OCR6R7-, -scr6r7-, -s(o)cr6r7-, and -S(0)2CR6R7-. In still another aspect, X is a linking group selected from the group consisting of 4〇16117-, -3(0)〇16117-, and -s(o)2cr6r7-. In another aspect, X is a linking group selected from the group consisting of -NR4CH2-, -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -SCH2-, -SCH(CH3)-, -SC(CH3) )2-, -s(o)ch2-, -s(o)ch(ch3)-, -s(o)c(ch3)2-, -S(0)2CH2-, -S(0)2CH( CH3)-, -S(0)2C(CH3)2-, -C(0)NR4- and -NR4C(0)-. In another aspect, X is a linking group selected from the group consisting of -NR4CH2-, -OCH2-'-SCH2-, -S(0)CH2-, -S(0)2CH2-, -C(0)NR4-and- NR4 c(o)-. In another aspect, X is a linking group selected from the group consisting of -NR4CH2-, -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -SCH2-, -SCH(CH3)-, -SC(CH3) ) 2-, -S(0)CH2-, -S(0)CH(CH3)-, -S(0)C(CH3)r, -S(0)2CH2-, -s(o)2 ch( Ch3)- and -s(o)2 C(CH3)2 - 〇 On the other hand, X is a linking group selected from -NR4CH2-, -OCH2-, -SCH2-, -s(o)ch2- and - S(0)2CH2-. In a further aspect 'X is a linking group selected from -NHCH2-, -N(CH3)CH2-, -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -SCH2-, -SCH(CH3) )-, 137081 -61 - 201002697 -SC(CH3)2-, -S(0)CH2-, -S(0)CH(CH3)-, -S(0)C(CH3)2-, -S( 0) 2CH2-, -S(0)2CH(CH3)-, -S(0)2C(CH3)2-, -C(0)NH-, -C(0)N(CH3)-, -NHC( O)- and -N(CH3)C(0)-. In a further aspect, X is a linking group selected from the group consisting of -NHCH2-, -N(CH3)CH2-, -OCH2-, -SCH2-, -S(0)CH2-, -S(0)2CH2-, _C(0 NH_, -C(0)N(CH3)-, -NHC(O)-, and -N(CH3)C(0)-. In still a further aspect, X is a linking group selected from the group consisting of -NHCH2-, -N(CH3)CH2-, -0CH2-, -0CH(CH3)-, -OC(CH3)2_, -SCH2_, : -SCH ( CH3)-, -SC(CH3)2-, -s(o)ch2-, -s(o)ch(ch3)-, -S(0)C(CH3)2-, -S(0)2CH2- , -s(o)2ch(ch3)- and -s(o)2c(ch3)2-. In still a further aspect, X is a linking group selected from the group consisting of -NHCH2-, -N(CH3)CH2-, -OCH2-, -SCH2-, and -S(0)2CH2-. On the other hand, X is -sch2- or -s(o)2ch2-. In another aspect, X is -SCH2-, -SCH(CH3)- or -SC(CH3)2-. On the other hand, X is -s(o)ch2-, -s(o)ch(ch3)- or -s(o)c(ch3)2-. On the other hand, X is -S(0)2CH2-, -S(0)2CH(CH3)- or , -S(0)2C(CH3)2-. On the other hand, X is -s(o)2ch2-. On the other hand, X is -s(o)2c(ch3)2-. R1 In one aspect of the invention, R1 is selected from the group consisting of C 4 alkyl, (: 3-10 cycloalkyl, aryl, C3_1() cycloalkyl Cij alkyl, aryl Ci-4 alkyl, cycloheteroalkyl a heteroaryl group, a cycloheteroalkyl group (^-4 alkyl group, a heteroaryl group (^-4 alkyl group), the group being optionally substituted by one or more substituents selected from the group consisting of a dentate group, Cyano, 137081 -62- 201002697 Nitro, 119, -0-foot 9, -(:0119, _〇^119111(), to 1191^1() and ^1^9(:01110. On the other hand' R1 is selected from the group consisting of adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, ethyl, tetrahydrop Ratio 11 base, 峨 、, 米 σ 坐, p than salivation, 吱 基, 11 thiophene, fluorenyl, π 定 Ρ, Ρ VT well base, tetrahydropyrene , tetrahydropyrrolylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylhydrazino, pyrazolylethyl, furylmethyl, furylethyl , thiophene fluorenyl, thienylethyl, pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrimidine Ethyl, pyridylmethyl and pyridylethyl groups' This group is optionally substituted by 1, 2 or 3 substituents selected from halo, cyano, nitro, r9, _0R9, _c〇R9, _c〇nr9 Rl 〇, -NR9 R10 and -NR9 COR10. In a further aspect, R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, and second-butyl, Cyclopropyl, cyclopentyl, cyclohexyl, phenyl 'yryl, phenethyl, imidazolyl, tetrahydropyrrolyl, oxadiazolyl, pyrazolyl, glucosyl, pyrazolylethyl, furanyl a group of methyl, pyrenyl fluorenyl 'oxazolyl fluorenyl, pyrimidyl fluorenyl and pyridyl ethyl, which group is optionally substituted by 1 or 2 substituents. Amino, halo, cyano, benzyl, methyl, decyloxy, trifluoromethyl, trifluoromethoxy, _nhcoch3, -CONH2 and -conhch3. In yet another aspect, R1 is selected from the group consisting of hydrazine Base, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH-, -CH2CH2NC(0)CH3, -CH2CONH2, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluorodecylphenyl 2-oxophenyl, 2-methylbenyl, 4-ethylamino Benzo '4-aminophenyl, p-α--4-yl, p-bito-2_yl, 137081-63- 201002697 2-ketotetrahydropyrrole·3-yl, p-pyrazole-2-yl a group of 4 - mercaptocarbazolyl and methyl-1,3'4-oxodiazol-2-yl. In still another aspect, Ri is selected from the group consisting of fluorenyl, _CH2CH2〇H and phenyl. Further, in another aspect, R1 is a group selected from the group consisting of a methyl group and a phenyl group. In still another aspect, R1 is a methyl group. In still another aspect, R1 is _CH2CH2OH. In yet another aspect, Ri is phenyl. X-R1 In one embodiment, X-R is _C(CH3)2〇H or _CH2〇H. In a specific embodiment, X-R1 is &lt;Ή2〇Η. In one embodiment, 'X-R' is -C(CH3)2〇H. R2 In one aspect of the invention, R2 is selected from a carbocyclic or heterocyclic group, which is substituted by -NRUcsnrUrH, and optionally substituted with - or a plurality of substituents independently selected from halo, cyanide Base, nitro, _Rl], _〇Rl〗, !, • CONR〗 iR12, _NR11R12 and _NR11C0R12. In the aspect of the invention, r2 is selected from a carbocyclic group or a heterocyclic group, which is substituted by -NHCSNR1 8 R]9, and optionally substituted with - or a plurality of substituents independently selected from halogen Base, cyano group, nitro group, _R1 1, _〇Rll, i -CONR11 R1 2, -NR11 R]2 and _NRi lc〇Ri 2 . In the present invention, R2 is selected from a carbocyclic group or a heterocyclic group, and the group is substituted by -NHCSNHR19, and is optionally substituted by a substituent of the group, the substituent is independently selected from the group consisting of a dentate group. , cyano group, wall group, 1 ^ OR11 ' -COR11, 137081 • 64 - 201002697 -CONR11 R1 2, -NRH Ri 2 and _NR1 1 COR] 2 0 In one aspect of the invention, R2 is selected from 5 or 6 a carbocyclyl or heterocyclic group, this group is substituted by -NR17CSNR18R19, and optionally substituted by one or more earthy groups, the substituents are independently selected from the group consisting of _ group, fluorenyl group, nitro group, -Rl]i! C0Rn, -CONRll R1 2, _NRl ! Rl 2 and _NRl ! c〇Rl 2. In one aspect of the invention, the R2 is selected from a 5 or 6 membered carbocyclyl or heterocyclyl group, the group being substituted by -NHCSNRlsRi9, and optionally substituted by a substituent or a plurality of substituents. Halo, cyano, nitro, _Rll, hepta-COR1 1, -CONR11 Ri 2, _NRn Rl 2 and _NRl [c〇Rl 2 . In one aspect of the invention, the R2 is selected from a 5 or 6 membered carbocyclyl or heterocyclyl group, the group being substituted by -NHCSNHRH, and optionally substituted by - or a plurality of substituents, the substituents being independently selected from Halo, cyano, nitro, _Rll, _〇Rnt-COR11, -CONR1] Ri 2, _NRh Rl 2 and -NRl! c〇R] 2. In one aspect of the invention, the R2 is selected from the group consisting of a 6-membered aryl group and a 5 or 6-membered heteroaryl group, which group is substituted by -NRnCSNRl8Rl9 and optionally substituted with one or more earth-removing groups, the substituents being independent It is selected from the group consisting of halo, cyano, nitro, -Rll ', -COR11, -CONR1 丨R1 2, -NR11 Ri 2 and _NRl ic〇Rl 2. In one aspect of the invention, the R2 is selected from the group consisting of a 6 membered aryl group and a 5 or 6 membered heteroaryl group, the group being substituted by -NHCSNRURB, and optionally substituted with one or more substituents, the substituents being independently selected from Tooth group, fluorenyl group, nitro group, _Rll, _〇RU, -COR11, -CONRHR12 ' -Nr11r12 and nr&quot;c〇r12 In one aspect of the invention, R2 is selected from a 6-membered aryl group and a 5 or 6-membered Aryl group, this group is substituted by -NHCSNHRW, and optionally substituted by one or more substituents independently selected from _ group, cyano group, nitro group, _Rl], _〇Rll, 137081-65-201002697 -COR1 ], -CONR11 R] 2, _NR] 1 R1 2 and -nr1 1 COR1 2. In another aspect, R2 is selected from the group consisting of phenyl, tr-pyrrolyl, and imi. Sit, p-saltyl, pyrenyl, pyrenyl, pyridyl, pyrimidinyl, morphinyl, thiazolyl, this group is substituted by -NR1 YCSNR1 9 and optionally substituted by one or more substituents Substituted 'substituents are independently selected from halo, cyano, nitro, _RU, _〇Rl 1, -CORH'-CONRURn'-NRUm-NRiicoRK. In another aspect, R2 is selected from the group consisting of phenyl, hydrazine 11 , decyl sulphate, p-saltyl, cumyl, porphinyl-p-bityl, and biting. a oxime group, a peak α, which is substituted by -NHCSNR1 8 R1 9 and optionally substituted with one or more substituents. The substituents are independently selected from halo, cyano, nitro, _Rl 1, _〇Ri 1, -CORU'-CONRHrU'-NRUrI-nrIIcorU. In another aspect, R2 is selected from the group consisting of phenyl, p-pyrrolyl, imidazo, ρ than s-based, decyl, pyrenyl, pyridyl, pyrimidinyl, hydrazine-carbazolyl, The group is substituted by -NHCSNHR19 and is optionally substituted by one or more substituents independently selected from halo, cyano, nitro, -Ri 1, 〇Ri 1, _CC) Rl!, - CONR1 1 R1 2, -NR11 R1 2 and -NR11 COR1 2. In another aspect, R2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, p-saltyl, thiol, thienyl, pyridyl, pyrimidinyl , 嗒 基, 嗤 嗤, this group is substituted by -NR] 7CSNR] 8R19, and optionally substituted by one or more substituents 'Substituents are independently selected from fluoro, methyl, decyloxy, Sulfhydryl, gas sulfhydryl, -CONH2, -CONHCH3&amp;-CON(CH3)2. In another aspect, R2 is selected from the group consisting of phenyl, pyrrolyl, imidazolyl, indolyl, thiol, thienyl, P is substituted with pyridine, pyrimidinyl, taronic, or sigma. This group is replaced by -NHCSNR1 8 R1 9 and is optionally substituted by one or more substitutions 137081 -66- 201002697. Substituents are independently selected. Self-fluorine group , methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3 and -CON(CH3)2. On the other hand, R2 is selected from the group consisting of phenyl, p-p-group, σ-m. , σ 坐, furyl, thienyl, pyridyl, pyrimidinyl, hydrazine, pyrazolyl, this group is substituted by -NHCSNHR19, and optionally substituted by one or more substituents, substituents Independently selected from the group consisting of fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3, and -CON(CH3)2. On the other hand, R2 is phenyl or pyridyl, NR17CSNR18R19 is substituted, and optionally substituted by one or more substituents independently selected from fluoro, methyl, methoxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3, and -CON(CH3) 2. In another aspect, R2 is phenyl or pyridyl, substituted by -NHCSNR1 8R] 9 and optionally substituted with one or more substituents independently selected from fluoro, decyl, decyloxy, Hydroxonyl, cyanoguanidino, -CONH2, -CONHCH3, and -CON(CH3)2. In another aspect, R2 is phenyl or pyridyl, substituted by -NHCSNHR19, and optionally substituted by one or more base Substituents, the substituents are independently selected from the group consisting of fluoro, methyl, decyloxy, hydroxymethyl, cyanomethyl, -CONH2, -CONHCH3, and -CON(CH3)2. On the other hand, R2 is a stupid or pyridine. The base is optionally substituted by -NR17CSNR18R19. In another aspect, R2 is phenyl or pyridyl, optionally substituted by -NHCSNR1 SR1 9 . In another aspect, R2 is phenyl or pyridyl, optionally substituted by -NHCSNHR1 9 137081 •67- 201002697. On the other hand, R2 is

Wherein A1 and A2 are selected from CH or N, provided that at least one of A1 or A2 is CH. On the other hand, R2 is

R 19 wherein A1 and A2 are selected from CH or N, provided that at least one of A1 or A2 is CH. On the other hand, R2 is

19 wherein A1 and A2 are selected from CH or N, provided that at least one of A1 or A2 is CH. On the other hand, R2 is

Wherein A1 and A2 are CH. R4 In one aspect of the invention, R4 is ruthenium or osmium. On the other hand, R4 is hydrogen. 137081 -68- 201002697 R4 and R1 In another aspect of the invention, when X is -nr4cr6r7-, -nr4c(o)cr6r7_'-NR4C(0)NR5 cr6r7-, -NR4S(0)2CR6R7-, -nr4c( o)-, -NR4 C(0)NR5 - or -NR4 S(O)2 -, R1 and R4 together with one or more of the atoms to which they are attached form a 4- to 10-membered heterocyclic ring, wherein , 2 or 3 ring-blocking atomic systems are optionally replaced by N, hydrazine or S, and the ring system is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, thiol, Keto group, alkyl group, Ci_6 oxy group, haloalkyl group, halo group C]_6 alkoxy group, light-based Ci·6 leukoyl group, trans-base Ck alkoxy group, Ch-laboxy group Ci-6 alkyl group, Ch alkoxy Ck alkoxy, amine, (^-6 alkylamino, bis(q-6 alkyl)amine, urethral Cu alkyl, (C)·6 alkyl) amine (^_6) Anthracenyl, bis(c)-6 carbyl)amino group q·6 alkyl, cyano C -6 —alkyl, C]-6 calcinyl, (^6 calcinyl amine, Ci- 6 alkylsulfonyl (c)-6 alkyl)amine, aminsulfonyl, Ci6 alkylamine sulfonyl, bis(Ck alkyl)amine sulfonyl, c 6 octadecylamine, Ci 6 Alkyl (C)-6 alkyl) amine , Aminomethyl thiol, Ci 6 alkylamine sulfhydryl and bis(Q-6 alkyl)amine carbamide. In another aspect of the invention, when X is _NR4CR6R7_, _Nr4c(〇)cr6r7_-NR4C( 0) NR5CR6R7- ^ -NR4S(0)2CR6R7- ^ -NR4C(0)- ' -NR4C(0)NR5· or _NR4S(0)2_, one or more of 圮和记 and their connected The atoms together form a 5_,6_ or 7_membered heterocyclic ring wherein [the ring carbon atom is optionally substituted by N or (3) and ^(iv) is optionally substituted with a plurality of substituents selected from a halogen group. , cyano, nitro, hydroxy, yl, alkyl, ch-oxygen, i-based cw fluorenyl, halo-CH-oxyl, hydroxy-Ch alkyl, trans-cvw oxy, Ci 6 thiol Ci -6 yard base, Ci 6 methoxy 137081 &gt;69· 201002697

Cl-6 alkoxy, amino, C^6 alkylamino, bis(Ci-6 alkyl)amine, amine C]-6 alkyl, (Ch alkyl)amino q-6 alkyl, Bis(Ch alkyl)amino Cu alkyl, cyano q-6 alkyl, C 6 alkylsulfonyl, q 6 alkylsulfonylamino, -6 alkyl base (q _ 6 alkyl) aminyl, amine sulfonyl, Ci -6 alkyl sulfonyl sulfonyl, bis (Ch alkyl) amine sulfonyl, (: 6 alkyl amidino, c16 alkyl (c) _6 An alkyl group, an amine carbenyl group, a Ci 6 alkyl amide group, and a bis (Ch alkyl) amine carbenyl group. In another aspect of the invention 'When 乂 is _NR4 cr6 R7 -, _NR4 c (〇) CR6 R7 _ , -nr4c(o)nr5cr6r7-, -nr4s(o)2cr6r7_, _NR4C(0)_, -NR C(0)NR5 - or -NR4 S(O)2 -, R1 and R4 Forming a 5- or 6-membered heterocyclic ring together with one or more of the atoms to which they are attached, wherein one ring carbon atom is optionally replaced by N or hydrazine, and the ring is optionally substituted by one or more substituents. Substituted, the substituent is selected from the group consisting of a keto group, a cyano group, a nitro group, a hydroxyl group, a ketone group, a q 6 group, a C 6 · alkoxy group, a halogen group C! 6 alkyl group, a _ group (^ 6 alkoxy group) Subbasic c1-6 alkyl, hydroxy Ch alkoxy, Cl 6 alkoxy Cl 6 alkyl, Ci 6 alkoxy Ci 6 alkoxy, amine, cv 6 alkylamino, bis(Cw alkyl)amine, amine Ci 6 alkyl, Cj-6 alkyl)amino q·6 alkyl, bis(Ch alkyl)amino C 6 alkyl, cyano Ci-6 alkyl, q·6 alkylsulfonyl, Ck alkylsulfonylamino , Ci6 alkyl group sulfhydryl group (Ci _6 alkyl group) amine group, amine sulfhydryl group, q -6 alkyl amide hydrazine group, bis (Ch alkyl) amine fluorenyl group, q-6 amide group, Ck saponin (Cu-based) amine group, amine methyl sulfhydryl group, C!-6 alkyl amine carbaryl group and bis (C 6 alkyl) amine carbaryl group. R5 is an aspect of the invention, R5 Is a hydrogen or a mercapto group. 137081 -70- 201002697 In another aspect, R5 is hydrogen. In another aspect, R5 is fluorenyl. R6 In one aspect of the invention, R6 is hydrogen or methyl. R6 is hydrogen. In another aspect, R6 is methyl. R7 In one aspect of the invention, R7 is hydrazine or methyl. On the other hand, R7 is hydrogen. On the other hand, 'R7 is methyl. R8 In one aspect of the invention, R8 is hydrogen or a south group. On the other hand, 'R8 is hydrogen or a fluorine group. In the aspect of the invention, R8 is hydrogen. R9 In one aspect of the invention, R9 is a salt, -, p-horse A or an alkyl group, optionally substituted by 1, 2 or 3 substituents. The substituent is selected from the group consisting of a benzyl group and a nitrogen group. , an exact group, a trans group, a CH alkoxy group, an amine group, (: a 4-alkylamino group and a bis(Ci4 alkyl) amine group. On the other hand, 'R9 is hydrogen, or Ci_4 alkyl, optionally substituted by hydrazine, 2 or 3 halo substituents. In a further aspect: R9 is hydrogen, methyl or trifluoromethyl.

Rl In one aspect of the invention, R10 is hydrogen. R11 137081 -71 - 201002697 In one aspect of the invention, Ru is hydrogen, or a group selected from the group consisting of -4 alkyl, aryl and heteroalkyl, which groups are optionally i, 2 or 3 Substituents selected from the group consisting of a picture group, a hydroxyl group and a cyano group. On the other hand, R11 is an alkyl group, a strepyl or a tetrahydropyrrolyl group, which is optionally substituted with a hydroxy group or a cyano group. In another aspect, R1] is hydrogen or methyl. R12 In one aspect of the invention, R]2 is hydrogen or methyl. R17 In the aspect of the invention, R" is hydrogen, or a group selected from the group consisting of aq 4 alkyl, an aryl group and a cycloalkyl group. This group is optionally selected from 1, 2 or 3 groups, a hydroxyl group and a cyano group are substituted. The other φ R is hydrogen, optionally substituted by a base or an aryl group, a phenyl group or a tetrahydro P group. On the other hand, R17 is hydrogen or A. base.

On the other hand, 'Rl 7 is hydrogen. R18 In one aspect of the invention, R]8 is hydrogen or methyl. In one aspect of the invention, R]8 is hydrogen. R19 In one aspect of the invention, Ri9 is a gas, a bucket, a yang, and a surface is R, or is selected from the group consisting of a Ci 6 alkyl group, a core 6 ring alkyl group, an aryl group, a heteroaryl group, and a ruthenium. The base of the group C.6 and the heteroaryl group: the group of the group 6 is substituted by _ or a plurality of substituents, and the substituent is selected from the group consisting of: ※# nitro, encapsulation, Ci_6 Affiliation, k alkoxy, functional group h 137081 -72- 201002697 alkyl, i-based (^_6 alkoxy, hydroxy 6 alkyl 'hydroxy oxime ^ 6 alkoxy, 匚 1-6 alkoxy (21 —6 alkyl, (^1_6, oxime (31-6 alkoxy, amine, (11-6 alkyl), bis(Ch alkyl)amine, amine Cu alkyl, (Cw alkyl)amine Chyryl, bis(CV6 alkyl)amino C1-6 alkyl, cyanoCl6 alkyl, Ci6 alkylsulfonyl, C^6 alkylsulfonylamino, Cl-6 alkylsulfonyl ( (^-6 alkyl)amino, aminsulfonyl, Cu alkylamine sulfonyl, bis(Cu alkyl)amine sulfonyl, q-6 alkanoyl, c -6 alkyl alkyl (Ci a -6 alkyl)amino group, an amine fluorenyl group, a C -6 alkyl sulfhydryl fluorenyl group, and a bis(C) -6 group amide group. In one aspect of the invention, 'R19 is hydrazine, or From Cb6 alkyl, c3_6 cycloalkyl, phenyl, decyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidinyl, hydrazine, hydrazine Base, fluorenyl, quinolyl, benzimidazolyl, benzofuranyl, dibenzofuranyl, benzopyrhenyl, phenyl Q-6 alkyl, fluorenyl Ci-6 alkyl, pyrrolyl An alkyl group, an imidazolyl Ck alkyl group, an isoxazolylalkyl group, a pyrazolyl group (^_6 alkyl group, a furyl group (^_6 alkyl group, a thienyl group, a ^6 alkyl group, a pyridyl group, a ^6 alkyl group,疋 疋 Cl Cl - - - - 、 、 、 、 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl a group of stupid and imidazolyl C1_6 alkyl, benzofuranyl C! : 6 alkyl 'dibenzofuranyl q -6 alkyl, benzothienyl C]-6 alkyl group, this group Optionally substituted with one or more substituents selected from halo, cyano, nitro, hydroxy 'CV6 alkyl, Ci-6 alkoxy, ii-based CV6 alkyl, halo (^-6 alkoxy, Hydroxy (^_6 alkyl, light hydrazine &quot; condensed base 'C〗. 6 alkoxy Ck alkyl, Ci-6 alkoxy Ci-6 burning" Base, amine group, Cu alkylamino group, bis(Cu alkyl)amino group, amine Cu alkyl group, (Ch alkyl) amino group Ci-6 alkyl group, bis(Ch alkyl)amino group Ch alkyl group, 137081 - 73- 201002697 Cyano-Cl-6 alkyl, ci-6 alkylsulfonyl, q-6 alkylsulfonylamino, c]-6 alkylsulfonyl (C1-6 alkyl)amine, Aminesulfonyl, Cu alkylamine sulfonyl, bis(Ch alkyl)amine sulfonyl, c]-6 alkyl amide, Ci6 alkino (CH alkyl) amine, amine methyl sulfhydryl, C ] _ 6 alkylamine carbenyl and bis (Ci -6 alkyl) amine carbenyl. In one aspect of the invention, it is hydrogen or is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl a group of a group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a porphinyl group, an imidazolylmethyl group, an iso-p-saltyl group, a decyl group, a pyridyl group, and a pyrimidinyl group, which is optionally one or more Substituent substituted 'substituent is selected from the group consisting of dentate, cyano, nitro, light, C!-6 alkyl, Ck alkoxy, halo-Ci-6 alkyl, dentate (^_6 alkoxy, ZH Alkyl Ck alkyl, hydroxy (^_6 alkoxy, Ci-6 alkoxy (^-6 alkyl, Ci. 6 alkoxy alkoxy, amine, &lt;^_6 alkylamino, double (C! -6 alkyl)amine, amine CV6 alkyl, (Cu alkyl)amino Cu alkyl, bis(cv6 alkyl)amino Ck alkyl, cyano Ci-6 alkyl, (^-6 alkyl sulfonate) Mercapto, Ci_6 alkyl decylamino, C! -6 alkyl thiol (Ci-6 alkyl) amine, amine sulfonyl, Q-6 alkyl sulfonyl, bis (Ck alkane) Aminesulfonyl, Cu alkanoyl, C -6 alkyl alkino (Cu alkyl) amine, amine sulfhydryl, Cu alkyl amine fluorenyl and bis ((^ 6 alkyl) Amine group. In one aspect of the invention, R1 9 is hydrogen or is selected from the group consisting of decyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2(cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2 oh '-C(CH3 )2 CH2 OH ' -CH2 CH2 OH ' - Ch2 ch2 ch2 oh , 4-mercaptophenyl, 4-chlorophenyl, 4-trifluorodecylphenyl, 4-fluorophenyl, 4-137081 -74- 201002697 methoxyphenyl, 3,4-di Fluorophenyl, phenyl, porphin-2-yl, -CH2 p-mazole-2-yl), -CH2 (p-salt-3-yl), iso-p-saltyl-3-yl, 6-keto Base-out-? ratio bit-2-yl, 5-methylisoxazol-3-yl, -CH2 (1-methylpyrazolyl), 1-methylpyrazolone, 6-methoxy a group of pyridin-3-yl, 5-fluoropyridin-2-yl, pyrimidin-2-yl and 1H-pyrazol-3-yl. In one aspect of the invention, Ri 9 is hydrogen or is selected from the group consisting of Base, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl'cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, _CH2 (cyclopropyl ),_CH2CH2NMe2, -CH(CH3)CH2 oh ' -C(CH3 )2 ch2 oh &gt; -ch 2 ch2 oh &gt; -ch2 ch2 ch2 oh , 4-methylphenyl, 4-chlorophenyl, 4-trifluorodecylphenyl, 4-fluorophenyl, 4-methoxyphenyl, 3,4-di Fluorophenyl, thiophen-2-yl, -CH2 (azizol-2-yl), -CH2 (miquivalent 3 base), isoindole π-spinyl-3-yl, ketone-out-oxime _ 2_based, 5-mercaptoisosine 3-based CH2 (1-methylpyrazole ice-based), μ-mercaptopyrazole-4-yl, 6-methoxypyridin-3-yl, 5-fluoro a group of a pyridyl-2-yl group, a pyrimidinyl group, and an iota-pyrazole group. In the aspect of the invention, Rl9 is a group selected from the group consisting of methyl, ethyl, cyclopropyl, CH2CH2NMe2, _Ch2CH2〇h, 4-fluorophenyl, 4-oxophenyl and phenyl. X is a square Φ, and Rl9 is hydrogen or a group selected from the group consisting of ethyl, cyclopropyl, fluorophenyl, 4-methoxyphenyl and phenyl. In the aspect of the invention, 'R19 is _CH2CH2OH. R1 8 and Rl 9 In the present invention, R8 and R 9 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring ^ /, a ring carbon atom is optionally N or 137 137081 -75- 201002697, and the hydrazine is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, decyl, thiol, Cl_6, cyclyl, Ci 6 】 6 alkyl, halo c 6 alkoxy, hydroxy Q 6 alkyl, hydroxy Q 6 alkoxy, Q-6 alkoxy Cm alkyl, Cl 6 alkoxy Ci6 alkoxy, amine, [Μ Alkylamino, bis(Ch alkyl)amino, amino Ci-6 alkyl, (c) 6 alkyl)amino C]-6 alkyl, bis(Cu alkyl)amino C 6 alkyl, cyano q 6 alkyl, alkylsulfonyl, Q 6 alkylsulfonylamino ' c16 alkylsulfonyl (CI 6 alkyl) amine, amine sulfonyl, Cl 6 alkyl sulfonyl, double (CH Alkyl) sulfonyl, Cl_6 alkanoyl, Ci-6 alkyl alkoxy (Ci 6 alkyl) amine, amine methyl sulfonyl, Cu alkyl amine methyl thiol and bis (Ci 6 alkyl) amine formazan base. In one aspect of the invention, 8 is combined with "9 and the nitrogen atom to which they are attached to form a morpholine ring. In one aspect of the invention, a subset of a compound of formula 1 or a pharmaceutically acceptable salt thereof; 0, 1 or 2; 1Y and Y2 are independently N or CR8, provided that one of 1 γ and Y2 is N and the other is CR8; X is a linking group selected from _NR4CR6R7-, -0CR6R7-, _SCR_6R7_ -S(0)CR6R7-, -S(0)2CR6r7-, _c(0)NR4CR6R7-'-NR4C(0)NR5-CR6R7 -, -S(0)2NR4CR6R7 ... NR4c(0)_, _s(〇 2nr4 and _nr4s(〇)2; R is a group selected from the group consisting of C!-6 alkyl, carbocyclyl, carbocyclyl Ci-6 alkyl, heterocyclic and heterocyclic C!-6 alkyl 'This group is optionally substituted by one or more substituents' substituents selected from halo, cyano, nitro, R9, _〇R9, _c〇r9, -CONR9 R1 0, -NR9 R1 0 and - NR9 COR1 0 ; 137081 •76- 201002697 or X_Rl is -C(CH3)2 OH or -Ch2 〇H; R is selected from aryl and heteroaryl, this group is replaced by _nr1 7 CSNRl s Rl 9 And optionally substituted by one or more substituents, the substituents are independently selected from the group consisting of a group, a cyano group, a nitro group, -Rn, _0R11, _c〇Rll ' C〇nr11r12, nr11r12 and -NR11 COR] 2 ; each R3, when present, is a fluorenyl group; R4 and R5 are independently hydrogen or Ci6 alkyl; or when X is -NR4CR6R7_, _NR4C(〇)nr5cr6r7, nr4c (〇) or -NR4S(0)2- when '圮 and R4 together with one or more of the atoms to which they are attached form a 5-, 6- or 7-membered heterocyclic ring, wherein one ring carbon atom is optionally Substituted by N or hydrazine, and the ring is optionally substituted by one or more substituents selected from the group consisting of a dentate group, a cyano group, a schlossyl group, a thiol group, a hexyl group, a Ci 6 alkyl group, an oxy group, a halogen group. c -6 alkyl, dentate Ci-6 alkoxy, hydroxy c] 6 alkyl 'hydroxy A 6 alkoxy, c 6 alkoxy Ci-6 alkyl, Ci 6 alkoxy Ci 6 alkoxy, amine Base, Cl-6 alkylamino group, bis(ch alkyl)amino group, amino Cu alkyl group, (Ch hexyl) amine alkyl group, bis(Ch alkyl)amino group C 6 alkyl group, cyano Ci 6 Alkyl, Ck alkylsulfonyl, Ci-6 alkylsulfonylamino, q 6 alkylsulfonyl (C!-6 alkyl) amine, amine sulfonyl, Ci-6 alkyl sulfonyl, Bis(Cl·6 alkyl)amine sulfonyl, Ch alkyl amide, Cl 6 alkyl alkyl (Ci-6 alkyl) amine, A a C, -6 alkylalkyl fluorenyl group and a bis (Ci -6 alkyl) amine carbaryl group; R6 and R7 are independently selected from the group consisting of hydrogen, a halogen, a cyano group, a nitroalkyl group; , halo, cyano and Cl 6 alkyl; R 9 and R 1 G are independently hydrogen or a group selected from the group consisting of c 6 alkyl, carbocyclic and heterocyclic groups. This group is optionally one or more Substituted substituents, substituents selected 137081 -77- 201002697 from halo, cyano, deradyl, light, Cl-6, alkoxy, halo C!-6 alkyl, functional group Cl_6 alkoxy, hydroxy C 6 alkyl, hydroxy cl 6 alkoxy, alkoxy (^-6 alkyl, Ci-6 alkoxy Ci-6 alkoxy, amine, C!-6 alkylamino group and Bis(Ch alkyl)amino group; R11, R12, R17 and R1S are independently hydrogen or a group selected from the group consisting of a C1-6 alkyl group, a carbocyclic group and a heterocyclic group, which group is optionally one or more Substituted by a substituent, the substituent is selected from the group consisting of i group, cyano group, nitro group, hydroxyl group, Cl 6 alkyl group, Cl 6 alkoxy group, halo 〇 6 alkyl group, _ group C 6 alkoxy group, hydroxy C 6 alkyl group, hydroxyl group Q-6 alkoxy, C]-6 alkoxy Cyalkyl, Ch alkoxy Ci-6 alkoxy, amine, Ci-6 alkylamino Bis(Cl_6 alkyl)amino group; and R19 is hydrogen ' or selected from (^-6 alkyl, c3-6 cycloalkyl, aryl, heteroaryl, aryl q-6 alkyl and heteroaryl C1-6 alkyl) a group which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano 'nitro, hydroxy, c]-6 alkyl, c]-6 alkoxy, halo (^ _6 alkyl, halo (^_6 alkoxy, transalkyl, hydroxyCl 6 alkoxy, Ci 6 alkoxy c] 6 alkyl, C]-6 alkoxy CV6 alkoxy, amine , Ci 6 alkylamino, bis(c) 6 alkyl)amino, amine C!-6 alkyl, (Cl-6 alkyl)amino Ci 6 alkyl, bis(Ci 6 alkyl)amine Ci_6 alkane , cyano Cl6 alkyl, Ci6 alkylsulfonyl, Ci 6 alkyl decylamino, c 6 alkylsulfonyl (Ci 6 alkyl) amine, amidoxime, C! 6 alkylamine sulfonyl, bis(c16 alkyl)amine sulfonyl, Ci 6 alkanoyl, C!-6 alkyl fluorenyl (C -6 alkyl) amine, amine methyl sulfhydryl, Ci a 6-membered heterocyclic ring, wherein R18 and R19 together with the nitrogen atom to which they are attached, wherein 137081-78-201002 697 1 ring carbon atom is optionally substituted by N or hydrazine, and the ring is optionally substituted by one or more substituents selected from the group consisting of a dentate group, a cyano group, a nitro group, a hydroxyl group, and a Q-6 alkyl group. , Ch alkoxy, from a group c] 6 alkyl, halo Ci 6 alkoxy, via Q 6 alkyl, hydroxy C 6 alkoxy, Ci 6 alkoxy Ci 6 alkyl, Ci 6 alkoxy Ck Alkoxy, amine, Cl 6 alkylamino, bis(Ci 6 alkyl)amine, amine CV6 alkyl, (Cl-6 alkyl)amine Ci 6 alkyl, bis(Ci 6 alkyl)amine c -6 alkyl, cyano &lt;^·6 alkyl, cv6 alkylsulfonyl, (^_6 alkylsulfonylamino, Ci -6 alkyl ketone (Cj -6 alkyl) amine Base, amine amine, Cj -6 alkyl sulfonyl sulfonate, bis (Cu alkyl) amine sulfonyl group, Cu hydrazinyl group, Cn decyl group (Ci -6 alkyl) amine group, amine hydrazine a base, a Ci-6 alkyl decanoic acid group and a bis(C-6-6)aminoindenyl group. In another aspect of the invention, there is provided a subset of a compound of formula (I) or a pharmaceutically acceptable salt thereof; m is 0, 1 or 2; W and Y2 are independently N or CR8, provided that 1Y and Y2 are One is n and the other is CR8; X is a linking group selected from ^114012-, -〇〇12-, -001(013)-, -〇(:(0^)2-, -SCH2-, - Sch(ch3)-, -SC(CH3)2-, -S(0)CH2-, -S(0)CH(CH3)-, -s(0)c(ch3)2-, -s(o) 2CH2-, -S(0)2CH(CH3)-, -S(0)2C(CH3)2-, -C(0)NR4- and -NR4C(0)-; R is selected from the group consisting of Base, ethyl, propyl, butyl, isobutyl, second-butyl, cyclodecyl, bad hexyl, phenyl, thiol, phenethyl, tetranitroxanthene, thiol, taste基基' P is succinyl, succinyl, phenyl, quinone. Alkyl, pyrimidinyl, pyridinyl, tetrahydropyrrolylmethyl, tetrahydropyrrolyl 137081 -79- 201002697, pyrrolyl , pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furylmethyl, furylethyl, pyrenylmethyl, pyrenylethyl , pyridyl fluorenyl, pyridylethyl, pyrimidinylmethyl, a group of a pyridylethyl group, a pyridylmethyl group and a pyridylethyl group, which group is optionally substituted with 2 or 3 substituents selected from a halogen group, a cyano group, a nitro group, R9, _〇r9, c〇r9, _c〇nr9 r1 〇^ 〇 and -NR9 COR10; or X-R1 is -C(CH3)2 OH or -CH2 OH; R is selected from 5 or 6 member aryl groups and a heteroaryl group, this group being substituted by _NHCSNRl 8Rl 9 and optionally substituted by one or more substituents independently selected from halo, cyano, nitro, -RH, _0R11, _C〇Rll, _CC)NRllRl2, nr11r12 and -NR11 cor1 2 ; each R3, when present, is methyl; R4 is hydrogen or Ck alkyl; or when X is -NR4CH2· or -NR4C(0)·, R1 and R4 Forming a 5- or 6-membered heterocyclic ring together with one or more of the atoms to which they are attached, wherein one ring carbon atom is optionally replaced by N or 0, and the ring is optionally substituted by one or more substituents. Substituted, the substituent is selected from the group consisting of a halogen 'cyano group, a nitro group, a hydroxyl group, a Ci 6 alkyl group, an alkoxy group, a aryl group, a 6-alkyl group, a halogen-based Ci6 alkoxy group, a hydroxyalkyl group, and a thiol group. Alkoxy, C 6 alkoxy c 6 alkyl, alkoxy 6 alkoxy, amine , Cu alkylamino, bis(Ci 6 alkyl)amino, amino q 6 alkyl, (Ch alkyl)amino C 6 alkyl, bis (Cl 6 alkyl) amine Ci 6 alkyl, cyano Cl 6 Alkyl, C1_6 alkylsulfonyl, Ci-6 alkylsulfonylamino, q_6 alkyl 4-mercapto (C! -6 alkyl) amine, amine hydrazino, Ci -6 alkyl amide Sulfhydryl, 137081 -80- 201002697 bis(C _6 alkyl)amine sulfonyl, Ci 6 alkyl amide, Ci 6 alkyl sulfonyl π &quot;alkyl) amine, amine carbaryl, Cl-6 alkylamine Anthracenyl and bis(Ch alkyl)aminecarbamyl; R8 is selected from the group consisting of hydrogen, halo, cyano and Cl-6; R9 and R are independently hydrogen or are selected from Ci 6 alkyl, carbocyclyl And a group of a heterocyclic group which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, Cl-6 alkyl, Ci 6 alkoxy, and functional group Q-6 alkyl, haloC〗 6 alkoxy, hydroxy C1-6 alkyl, hydroxy Ci 6 &amp; oxy, C!-6 alkoxy C] _6 alkyl, c]-6 alkoxy C _6 alkoxy, amine, c, ^ 1 - 6 alkylamino and bis (CV6 alkyl) amine; R11, R12 and R18 are independently hydrogen, or selected from a group of a Cl_6 alkyl group, a carbocyclic group and a heterocyclic group, which group is optionally substituted by one or more substituents selected from the group consisting of a halogen group, a cyano group, a nitro group, a thiol group, and (^_6 Alkyl, oxy, haloalkyl, halooxy, via Ci_6^, via c, &lt; alkoxy, Ck alkoxy Cn alkyl, C^-6 alkoxy Cn a group, an amine group, a Cu alkylamino group and a bis(Ch alkyl)amino group; and R19 is hydrogen ' or a CV6 alkyl group, a c3-6 cycloalkyl group, an aryl group, a heteroaryl group, an aryl C]-6 alkane And a heteroaryl group (^-6 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of ii groups, cyano groups, nitro groups, thio groups, Cn alkyl groups, Ck alkoxy, functional fluorenyl, halocytyloxy, hydroxyalkyl, hydroxy C^6 alkoxy, Ci-6 alkoxy&lt;^-6 alkyl, Ci-6 alkane Oxyl (^_6 alkoxy group, amine group, CV6 alkylamino group, bis(Ck alkyl)amino group, amine CV6 alkyl group, (Ch alkyl)amino group C!-6 alkyl group, bis(Cl_6 alkane) Amino-Ci-6 alkyl, cyano q-6 alkyl, Ci-6 alkylsulfonyl, Ch alkane 137081 -81 - 201002697 sulfonylamino group, c _6 alkyl sulfonate (Ci 6 alkyl)amino group, amine sulfonyl group, C!_6 alkylamine sulfonyl group, bis(Ci_6 alkyl)amine sulfonyl group, 6-alkylamino group, q-6 alkyl fluorenyl group (C !_6 alkyl)amino, amidino, Ci 6 alkylamine, mercapto and bis((1-6)aminocarbamyl; or R18 together with R19 and the nitrogen atom to which they are attached a 6-membered heterocyclic ring, wherein t 1 ring carbon atoms are optionally substituted by hydrazine or hydrazine, and the ring system is optionally substituted by one or more substituents selected from the group consisting of a picture group, a cyano group, a nitro group, Hydroxy, Ci-6 alkyl, (V6 alkoxy, dentyl Ci 6 alkyl, dentyl Ci 6 alkoxy, hydroxy Ck alkyl, hydroxy CCl alkoxy, Ci 6 alkoxy Ci 6 alkyl, Ci 6 alkoxy C!_6 alkoxy, amine, Ci 6 alkylamino, bis(Ci 6 alkyl)amine, amine C]-6 alkyl, (Ch alkyl)amine Ci6 alkyl, Bis(Ci6 alkyl)amino Cm alkyl, cyano q-6 alkyl, Ck alkylsulfonyl, cv6 alkylsulfonylamino, C]-6 alkylsulfonyl (Ci6 alkyl)amine Alkyl sulfonyl, Ci 6 alkyl sulfonyl aryl, bis(Ci-6 alkyl) amine sulfonyl, Cu alkyl amide, CV 6 alkyl sulfhydryl (Ch alkane) ) Amino, acyl amine Yue, CI6 alkyl amine and bis acyl (c ^ alkyl) amine Yue acyl. In another specific class of the compound of formula (I) or a pharmaceutically acceptable salt thereof; m is 0 or 1; iY is CH, and Y2 is N; X is a linking group selected from -S(0)2CH2-, -s(o)2ch(ch3)- and -s(o)2c(ch3)2-; R1 is selected from the group consisting of decyl, ethyl, propyl, butyl, isobutyl, tert-butyl, ring Propyl, cyclopentylcyclohexyl, phenyl, benzyl, phenethyl, pyridyl, pyrazolylethyl, furyl fluorenyl, pyrenyl fluorenyl, pyrazolyl fluorenyl, hydrazine 137081 -82- 201002697 A group of oxadiazomethyl and pyrylethyl, which is optionally substituted with 1 or 2 substituents. The substituent is selected from the group consisting of an amine group, a functional group, a cyano group, a decyl group, and a fluorenyl group. , trifluoromethyl, trifluoromethoxy, _NHC0CH3, -C〇Nh2 and -conhch3; or -XR1 is -C(CH3)2 OH or -CH2 OH; R is distant from the base, P is slightly base, °m D sitting base, P ratio σ sitting base, biting σ south base, p thiophene group, p ratio σ base, biting base, tower P well base,? a group of α, which is substituted by -NHCSNHR19, and optionally substituted by one or more substituents independently selected from halo, cyano, fluorenyl, _R] 1, 〇Rl 1, _C〇Rl 1, -CONR11 R1 2, -NR11 R1 2 and -NR11 COR1 2 ; R3 ', when present, is a fluorenyl group; R11, R12 and R18 are independently hydrogen or are selected from Ci 6 alkyl a group of a carbocyclic group and a heterocyclic group. This group is optionally substituted by one or more substituents selected from the group consisting of a halogen 'cyano group, a nitro group, a hydroxyl group, a C 6 alkyl group, and a Ci 6 alkane. Oxy, haloq-6 alkyl, _yl Ci6 alkoxy, hydroxy Ci6 alkyl, hydroxy Ci6 alkoxy, C^6 alkoxy (^-6 alkyl, Ci-6 alkoxy Ci_6 courtyard oxygen a group, an amine group, a C!·6 alkylamino group and a bis(Ci6 alkyl)amino group; and R19 is hydrogen or selected from a Cu alkyl group, a c3-6 cycloalkyl group, an aryl group, a heteroaryl group, an aryl group a group of a C!-6 alkyl group and a heteroaryl C16 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxyl group, and a CV6 alkyl group. , c^6 alkoxy, haloCl_6 alkyl, haloCi 6 alkoxy, via Cn alkyl, hydroxy Ci_^ , Ci 6 alkoxy Ci 6 alkyl, Ck alkoxy C!-6 alkoxy, amine, Ci6 alkylamino, bis(Ci6 alkyl)amine, amine Cu alkyl, (Ci 6 Alkyl)amino-Ci6 alkyl, bis(CH alkane 137081-83-201002697)aminocv6 alkyl, cyano Ck alkyl, (^-6 alkylsulfonyl, cv6 alkylsulfonylamino, Cu alkylsulfonyl (Ch alkyl) amine group, amine sulfonyl group, C! 6 alkyl amine sulfonyl group, bis (C! -6 alkyl) amine sulfonyl group, Ci -6 alkyl amidino group, a Cu alkylalkyl (Cu alkyl) amine group, an amine sulfhydryl group, a Cu alkyl amine fluorenyl group, and a bis (Cu alkyl) amine fluorenyl group. The compound of the formula (I) or a pharmaceutically acceptable salt thereof Further specific species; m is 1; X is a linking group selected from -S(0)2CH2-, -S(0)2CH(CH3)-, and -s(o)2c(ch3)2-; W is CH And Y2 is N. R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentylcyclohexyl, phenyl, benzyl, phenylethyl a group of a pyridyl group, a pyridyl group, a pyridylethyl group, a furylmethyl group, a thexyl fluorenyl group, a pyrazolyl fluorenyl group, a thiadiylmethyl group, and a pyridylethyl group. The group is optionally substituted by 1 or 2 substituents selected from the group consisting of an amine group, a functional group, a cyano group, a methyl group, a methoxy group, a trifluorodecyl group, a trifluoromethoxy group, -NHCOCH3, -CONH2, and -CONHCH3; R2 is phenyl or pyridyl, substituted by -NHCSNHR19, and optionally substituted by one or more substituents independently selected from fluoro, decyl, methoxy, hydroxymethyl, cyanoguanidine a group, -C〇NH2, -CO, CH3 and -CON(CH3)2; R3 is a methyl group; and R19 is hydrogen or is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso _ butyl, tert-butyl 'pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrenyl, imidazolylmethyl, isos-zolyl, pyrazolyl, Pyridyl 137081 -84- 201002697 The group of a pyridyl and pyrimidinyl group. This group is optionally substituted by one or more substituents. The substituent is selected from the group consisting of halo, cyano, nitro, hydroxy, q -6 alkyl. , C!-6-yard oxy, halo Q-6 alkyl, 13⁄4-based Crg alkoxy, via-based Cpg-dyl, hydroxy c _6 alkoxy, q-6 alkoxy C!_6 alkyl, Cv6 alkoxy Ck alkano group, amine group, alkylamino group, bis(CV6 alkyl)amine , Amino Cm alkyl, (Cu alkyl) amine CV6 alkyl, bis(Ck alkyl)amino Cu alkyl, murine C]-6 alkyl, Ci-6 alkyl, Ci -6 Indeed, alkylamino, Ci alkylsulfonyl (Ci-6 alkyl) amine, amine sulfonyl, C! 6 alkyl sulfonyl, bis (Ch alkyl) amine sulfonyl, ( V6 alkanoguanamine, Cu alkylalkyl (Ch alkyl) amine group, amine methyl sulfonyl group, Cu alkyl amine methyl sulfonyl group and bis (Cu alkyl) amine methyl group. In a further specific class of the compound of formula (I) or a pharmaceutically acceptable salt thereof; m is 1; X is a linking group selected from the group consisting of -s(o)2ch2-, -s(o)2ch(ch3)-and- s(o)2c(ch3)2-; W is CH and Y2 is N. R1 is selected from the group consisting of decyl, isopropyl, cyclopropyl, cyclohexyl, -ch2ch2oh-, -CH2CH2NC(0)CH3, -CH2CONH2, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-tri Fluorinyl phenyl, 2-decyloxyphenyl, 2-mercaptophenyl, 4-ethylamidophenyl, 4-aminophenyl, p-pyridin-4-yl, pyridin-2-yl 2-ketotetrahydrop-pyrrol-3-yl'pyrazol-2-yl, 4-mercaptothiazol-2-yl and 3-mercapto-1,3,4-pyrazol-2-yl Group; R2 is 137081 -85· 201002697

Wherein A1 and A2 are selected from CH or N, provided that at least one of Αι or a2 is CH; R17 is hydrogen; R18 is hydrogen; R19 is hydrogen, or is selected from decyl, ethyl, propyl, iso-propenyl Base, butyl, iso-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, _CH2 (cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH , _C(CH3)2CH2OH, -CHzCI^OH, -CH2CH2CH2OH, 4-nonylphenyl, 4-phenylphenyl, 4-difluoromethylphenyl, 4-fluorophenyl, 4-oxophenyl, 3 ,4-difluorophenyl, thiophene-2-yl, _CH2 (imidazolium-2-yl), -03⁄4 (taste. -3-yl), isoxazolyl-3-yl, 6-keto-pyridine 2-yl-5methyliso-salt-3-yl, 1-indolyl p-w w- 4-yl, _CH2 (1m-spin-4-yl), 6-methoxy sulphate _3_yl, 5_ gas radical Hey. a group of a fluoren-2-yl group, a mouth bite a _2 _ group and a m 峨唆 group; and R 3 is a methyl group. Telling a subset of the compounds of formula (Ia) or (Ib)

In one aspect of the invention, it is similar to L

137081 -86- 201002697 or a pharmaceutically acceptable salt thereof; 1 ¥ and ¥2 are independently N or CR8, provided that one of ΐγ and γ2 is n and the other is CR8; X is a linking group selected from _NR4CR6R7-, 〇cr6r7, Scr6r7 _, -S(0)CR6R7- &gt; -S(0)2CR6R7- ' -C(0)NR4CR6R7- ' -NR4C(0)NR5-CR6R7-, _S(〇)2NR4Cr6r7_ , _nr4c(〇), s(〇)2Nr4 and -NR4S(0)2-; R is a radical from Ci -6 alkyl, carbocyclyl, carbocyclyl Ci -6 alkyl, heterocyclyl and hetero fluorenyl c a 4-alkyl group which is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, R9, _R9, _c〇R9, -CONR9 R1 0 , -NR9 R1 0 and _nr9 COR1 0 ; or X-R1 is -C(CH3)2 〇H or -CH2 OH; R is from aryl and heteroaryl, this group is _NRl 7 CSNRl s rI 9 is substituted, and optionally substituted by - or a plurality of substituents, the substituents are independently selected from the group consisting of halo, cyano, nitro, -R1!, _QR1 1, _Cqr1 i, c〇NRl ! Rl 2, coffee 1 2 And -NR11 COR1 2 ; R3 is a fluorenyl group; only 4 is independently hydrogen or Ci6 alkyl with lanthanide or X is -NR4CR6R7_, _NR4C(0) cis 5cr6r7, nr4c(〇) or -NR S( 0) 2 a Temple, R and R4 together with one or more of the atoms to which they are attached form a 5-, 6- or 7-membered heterocyclic ring, the +(10) ring carbon atom of which is optionally replaced by n or 〇 Substituted substituents, oxy, schlossyl, filbert (3⁄4, ganyl steel, alkyl, Ck alkoxy, halo-Cl-6 alkyl, dentate &amp; Μ^ , hydroxy Ci-6 alkyl, hydroxy Ch 137081 • 87· 201002697 alkyl fluorenyl, Cm alkoxy Cm alkyl, c _ 6 alkoxy Cl 6 alkoxy, geminyl, c -6 alkylamine, double (Ch alkyl)amino group, amino Cu alkyl group, (Ci 6 alkyl)amino group q·6 alkyl group, bis(Cu alkyl)amino group CV6 alkyl group, cyano cl 6 alkyl group, c]_6 Substrate-based, cv6-based aryl-based amine group, alkyl sulfonyl group (C! -6 alkyl) amine group, amine base, Cl -6 alkyl group, bis (Q alkane) Amine sulfonyl, Ci_6 alkyl amide, C! 6 alkyl alkyl (Cl 6 alkyl) amine, amine sulfhydryl, c 6 alkyl amidino and bis (c alkyl) amine Mercapto; R6 and R7 are independently selected from the group consisting of hydrazine, halo, cyano, nitro and ^^alkyl; R8 is selected from the group consisting of hydrogen, halo, cyano and (^ _6 alkyl) R9 and R1G are independently hydrogen or a group selected from a C1-6 alkyl group, a carbocyclic group and a heterocyclic group, and the group is optionally substituted by one or more substituents selected from a halogen group and a cyano group. , nitro, hydroxy, Cl-6 alkyl, fluorenyl 16 alkoxy, _yl Ci-6 alkyl, seroyl q_6 alkoxy, hydroxy c!-6 alkyl, hydroxy Ci6 alkoxy, q·6 Oxy C16 alkyl, c]-6 alkoxy c16 alkoxy, amine, C1-6 acryl and bis(Ch alkyl)amine; R11, R12, Ri7&amp;Ri8 are independently hydrogen, or a group derived from a Cu alkyl group, a carbocyclic group and a heterocyclic group, which group is optionally substituted by one or more substituents selected from the group consisting of a yl group, a cyano group, a nitro group, a hydroxyl group, and a q-6 alkane group. Alkoxy group, alkoxy group, li group (^_6 alkyl group, halo group, 6 alkoxy group, hydroxy Ci 6 alkyl group, trans group (^_6 alkoxy group, q_6 alkoxyalkyl group, alkoxy group c) Alkoxy, amino, Cu alkylamino and bis(Cl6 alkyl)amine; and R9 is nitrogen ' or selected from C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, a group of an aryl Q-6 alkyl group and a heteroaryl Q decyl group, which group is optionally substituted by one or more substituents The substituent is selected from the group consisting of halo, cyano, nitro, hydroxy 137081-88-201002697, c]-6 alkyl, cv6 alkoxy, i-based cv6 alkyl, _yl (^-6 alkoxy, hydroxy Ck alkane Base, hydroxy c!_6 alkoxy, c _6 alkoxy (^_6 alkyl, Ci-6 alkoxy C^-6 alkoxy, amine, Cn leucine, bis (Ck alkyl) Amino, amine cv6 alkyl, (Cu alkyl) amine cv6 alkyl, bis(Cl-6 alkyl)amino Ck alkyl, cyano (^-6 alkyl, (^-6 alkylsulfonyl, Cu) Alkyl fluorenylamino, C! -6 alkyl thiol (C! -6 alkyl) amine, amine acid group, Cl-6 alkyl amine &amp; base, bis(Q -6 alkyl) amine Further sulfhydryl, C] _ 6 burnt amine, Ci-6 alkyl alkane (Ch alkyl) amine group, amine methyl sulfhydryl group, Cu alkyl amine fluorenyl group and bis (C! -6 alkyl) amine fluorenyl group Or R18 together with R19 and the nitrogen atom to which they are attached form a 6-membered heterocyclic ring wherein one ring carbon atom is optionally replaced by N or hydrazine, and the ring is optionally substituted with one or more substituents. The substituent is selected from the group consisting of a cyano group, a cyano group, a nitro group, a thiol group, a Cj-6 alkyl group, a Ci-6 alkoxy group, a halogenyl Cl-6 alkyl group, a dentate Ci 6 alkoxy group. Hydroxy C]-6 alkyl, hydroxy q-6 alkoxy, Ci 6 alkoxy Ci 6 alkyl, C 6 alkoxy Ci-6 alkoxy, amine, Ci-6 alkylamino 'bis(Ci 6 alkyl) Amine group, amine group Q·6 alkyl group, (Ch alkyl group) amine group Ci 6 alkyl group, bis(Cu alkyl)amino group C1-6 alkyl group, cyano C]-6 alkyl group, (^-6 alkyl group) Sulfonyl, Ci6 alkylsulfonylamino, c]-6 alkylsulfonyl (Cl-6 alkyl) amine, aminesulfonyl, Ci 6 alkylamine sulfonyl, bis(Ch alkyl)amine Sulfonyl, Cl 6 alkanoyl, Cl-6, (c)-6 alkyl) amine, amine oxime, Ci 6 alkylamine thiol and bis(Ci-6 alkyl)amine Hyperthyroidism. In another aspect of the invention, there is provided a subset of the compounds of formula (Ia) or (Ib) 137081 -89- 201002697 ο R3 , n/^R3

(la) (lb) or a pharmaceutically acceptable salt thereof; 1Y and Y2 are independently N or CR8, provided that one of Y and Y2 is N and the other is CR8; X is a linking group selected from -NR4CH2-, -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -SCH2-, -SCH(CH3)-, -sc(ch3)2-'-s(o)ch2-, -s(o)ch(ch3)-, -s(o)c(ch3)2-, -s(o)2ch2-, -S(0)2CH(CH3)-, -S(0)2C(CH3 2-, -C(0)NR4- and -NR4C(0)-; R1 is selected from the group consisting of adamantyl, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, ring Pentyl, cyclohexyl, phenyl, benzyl, phenethyl, tetra argon P than B groups, succinyl, imidinyl, P, β, thiol, far phenyl, P Base, ° dense σ base, Q b well, tetrahydro ρ than radyl fluorenyl, tetrahydrofuroyl ethyl, pyrrolyl fluorenyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, s Ratio α 坐 曱 、, ρ 唆 乙基 乙基 ethyl, butyl thiol thiol ethyl, thiophenethyl, phenophenethyl, ρ butyl thiol, p ratio α Stationary ethyl, ° α 定 曱 曱 °, ° σ 定 乙基 ethyl, Ρ ratio ρ well base methyl and ρ ratio 11 well base ethyl , the group is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halo 'cyano, nitro, R9, -OR9, -COR9, -CONR9R10, -NR9R10 and -NR9 COR10; X-R1 is -C(CH3)2OH or -CH2OH; 137081 -90- 201002697

R2 is selected from the group consisting of 5 or 6 berylates and heteropoly I"" squares. This group is substituted by _NHCSNR] 8r1 9 and optionally substituted by one or more substituents independently selected from halo. , cyano', argyl, -R11, _〇ri 1, f ~C〇R ' -CONR11 R1 2 x -NR1 1 R1 2 and -NR11 COR1 2 ; R3 is methyl; R4 is hydrogen or C! - 6 Or an alkyl group; or when X is -nr4〇v or _nr4c(〇), R1 and r4 are bonded to one or more of the atoms to form a 5- or 6-membered heterocyclic ring, wherein the "solid ring carbon atom" It is optionally replaced by N or Q, and the ring is optionally substituted with - or a plurality of substituents: the substituent is selected from the group consisting of _ group, cyano m group, q_old group, h alkoxy group, halogen group CV6 *, tooth base ^ 6 alkoxy, via ^ 6 alkyl, via alkoxylate, Cl. 6 alkoxy Ci6 alkyl, oxy lactyl, amine, benzylamine, double ((: 6 alkyl)amino group, amine group. &quot;alkyl, (C)-6 alkyl)amino C1-6 alkyl, bis(Ci 6 alkyl)amino q 6 alkyl, cyano C ^6 alkyl, C _ 6 alkyl sulfonyl, Q 6 alkyl sulfonylamino, Cl 炫 • 醯 ( (C) _6 alkyl) amine, amine continued,, and 6 burning base Amine, bis (C -6 alkyl) aminoxasulfonyl, Ci 6 alkanoylamino, Ci6 alkyl fluorenyl (Ch alkyl) amine, amine sulfhydryl, Ci-6 alkylamine fluorenyl And bis(c _6 alkyl)aminocarboxamidine; R8 is selected from the group consisting of hydrogen, halo, cyano and C16 alkyl; R9 and R10 are independently hydrogen or are selected from Ci 6 alkyl, carbocyclyl and The group of the heterocyclic group 'This group is optionally substituted by one or more substituents selected from the group consisting of dentate, cyano, nitro, hydroxy, C16 alkyl, C1-6 alkoxy, haloCl —6 calcinyl, functional Ck alkoxy, hydroxy (^6 alkyl, hydroxy cv6 alkoxy 137081 -91 - 201002697 base, C^-6 alkoxy-chromic group, C]-6 activating base (^ _6 methoxy, amine, CV6 alkylamino and bis(Ch alkyl)amine; R11, R12 and R18 are independently hydrogen or a group selected from a C1-6 alkyl, a carbocyclic group and a heterocyclic group. This group is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, Ci-6 alkyl, cl6 alkoxy, halo Q-6 alkyl, halo Base q, 6 alkoxy, hydroxy C!-6 alkyl, via Ci 6 alkoxy, Ck alkoxy Cl-6 a Ck alkoxy Cl-6 alkoxy group, an amine group, a Ci-6 alkylamino group and a bis(Cl-6 alkyl)amino group; and R19 is hydrogen or is selected from C]-6 alkyl, C3_6 cycloalkyl, aryl a heteroaryl group, an aryl c]-6 alkyl group, and a heteroaryl Cl_0 alkyl group, the group being optionally substituted by one or more substituents selected from the group consisting of an anthracenyl group, a cyano group, and a nitro group , mercapto, C!_6 alkyl, q.6 alkoxy, halo C]-6 alkyl, haloCi6 alkoxy, trans-C!-6 alkyl, hydroxyCl-6 alkoxy, Ci 6 alkane Oxyl Ci 6 alkyl, Q-6 alkoxy C]-6 alkoxy, amine, C] 6 alkylamino, bis(Ci 6 alkyl) amine, amino Cu alkyl, (Cl 6 alkyl Amino-Ci6 alkyl, bis(CH-alkyl)amino C -6 alkyl, cyano C^6 alkyl, q-6 alkylsulfonyl, alkylsulfonylamino, (^_6) Alkylsulfonyl (C16 alkyl) amine, amine sulfonyl, C!-6 alkyl sulfonyl, bis(c^6 alkyl)amine sulfonyl, q alkanoyl, Cu Mercapto(Ch alkyl)amino, amidino, Ci 6 alkylamine, and bis(A-6 alkyl)amine hydrazino; or R18 together with R19 and the nitrogen atom to which they are attached form a 6-membered heterocyclic ring in which one ring carbon atom is optionally substituted by N or 0, and the ring is optionally substituted with - or a plurality of substituents. The substituent is selected from the group consisting of a ke group, a cyano group, a nitro group, and a hydroxy group. , Cj-6 alkyl, C _6 oxime, dentate q_6 alkyl, dentate C -6 calcinyl, 137081 • 92- 201002697 hydroxy (ν6 alkyl, hydroxy Ck alkoxy, (v6 alkane) Oxycv6 alkyl, Ch alkyl fluorenyl c!_6 alkoxy, amine, (^-6 alkylamino, bis(c^6 alkyl)amine, amine Q-6 alkyl, (&lt;^ -6 alkyl)amino c 6 alkyl, bis(Ck alkyl)amino c 6 alkyl, cyano (^-6 alkyl, Cil alkylsulfonyl, (^-6 alkylsulfonyl) Amino group, Cu alkylsulfonyl (Cu alkyl) amine group, amine sulfonyl group, cv6 alkyl amine sulfonyl group, bis(C!-6 alkyl) amine sulfonyl group, Ck alkanoguanidino group Ch Chalkonyl (C! -6 alkyl)amino, amine mercapto, C! 6 alkylamine formazan and bis(Cu alkyl) amidamyl. In another specific species of the compound of formula (la) or (lb),

Or a pharmaceutically acceptable salt thereof; iY is CH, and Y2 is N; X is a linking group selected from the group consisting of -S(0)2CH2-, -S(0)2CH(CH3)-, and -S(0)2C (CH3)2-; R1 is selected from the group consisting of decyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentylcyclohexyl, phenyl, decyl, phenyl a group of a pyridyl group, a pyrazolylethyl group, a furylmethyl group, a pyrenylmethyl group, a thiazolylmethyl group, an oxadiazolylmethyl group, and a pyridylethyl group. This group is optionally Substituted by 1 or 2 substituents selected from the group consisting of amino, halo, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -NHCOCH3, -CONH2 and -conhch3; 137081 - 93- 201002697 or -XR1 is -C(CH3)2 〇H or -CH2 OH; R2 is selected from the group consisting of a benzyl group, a ton 11 group, a salivyl group, a p-saltyl group, a decyl group, a thiophene group, a pyridine group. a group, a pyrimidinyl group, a hydrazine group, a pyrazolyl group, this group is substituted by -NHCSNHR19, and optionally substituted by one or more substituents independently selected from a halogen group, a cyano group, a nitro group, Rl 1, 〇 〇 Rl 丨, _c 〇 RU, -CONR11 R1 2, -NR11 R1 2 and _nr1 1 COR1 2 ; R3 is fluorenyl; R11 R12 and R18 are independently hydrogen or a group selected from the group consisting of a q-6 cyclyl, a carbocyclic group and a heterocyclic group, the group being optionally substituted by one or more substituents selected from the group consisting of i groups, Cyano, nitro, hydroxy, q-6 alkyl, Cl6 alkoxy, halo-Ci-6 alkyl, halo-Ck alkoxy, via c-1-6 alkyl, via q6 alkoxy, C! _6 alkoxy Cl-6 alkyl, C _ 6 alkoxy Cl 6 alkoxy, amine, c -6 alkylamine and bis (c alkyl) amine; and R is hydrogen ' or selected from c a group of a 6-alkyl group, a c3- 6 cyclodextyl group, an aryl group, a heteroaryl group, a C group, a 6-alkyl group, and a heteroaryl group Q -6, which is optionally one or more Substituted by a substituent selected from a halogen group, a cyano group, a nitro group, a hydroxyl group, a Cl -6 alkyl group, a C!-6 alkoxy group, a _ group (^-6 alkyl group, a dentate group C! _ 6 burnt) Oxyl, hydroxy C -6 alkyl, hydroxy C 6 alkoxy, Cl 6 alkoxy c 6 alkyl, c] -6 alkoxy c 6 alkoxy, amine, cv 6 alkylamino, bis ( ^_6 alkyl) Amino, aminoCh alkyl, (q-6 alkyl)amino Cualkyl, bis(cv6 alkyl)amino C!-6 alkyl, cyanoalkyl, CV6 alkyl Sulfhydryl, alkylsulfonylamino, q-6 alkylsulfonyl (C!-6 alkyl)amine, aminesulfonyl, C!-6 alkylamine sulfonyl, bis(Ch alkyl) Aminesulfonyl, Cu alkanoyl, c 6-6 alkyl (c-6 alkyl) amine, amine sulfhydryl, Cu alkylamine carbaryl 137081 -94- 201002697 and double (C !-6 alkyl)amine mercapto group. In a further specific class of compounds of formula (la) or (lb)

R

R2 or a pharmaceutically acceptable salt thereof; X is a linking group selected from the group consisting of -s(o)2ch2-, -s(o)2ch(ch3)-, and -s(o)2c(ch3)2-; iY is CH, and Y2 is N. R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentylcyclohexyl, phenyl, benzyl, phenethyl, pyridyl, anthracene a group of a decylethyl group, a bromomethyl group, a far phenylmethyl group, a discidylmethyl group, an oxadiazolylhydryl group, and a pyridylethyl group, which is optionally 1 or 2 Substituted by a substituent, the substituent is selected from the group consisting of an amino group, a ii group, a cyano group, a decyl group, a methoxy group, a trifluoromethyl group, a trifluoromethoxy group, -NHCOCH3, -CONH2, and -conhch3; R2 is a phenyl group or a pyridine group. a group, substituted by -NHCSNHR19, and optionally substituted with one or more substituents independently selected from fluoro, decyl, decyloxy, hydroxymethyl, cyanoguanidino, -CONH2, -CONHCH3, and CON(CH3)2; R3 is a fluorenyl group; and R19 is hydrogen or is selected from the group consisting of decyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, P-sequenyl, succinylmethyl, isosaki sigma, p-α-sitting, p-137081 -95- 201002697 pyridine a group based on a pyrimidinyl group, which is optionally one or more Substituted by a substituent, the substituent is selected from the group consisting of a halogen group, a cyano group, a nitro group, a hydroxyl group, a q_6 alkyl group, an alkoxy group, a halogen group C^-6 alkyl group, a halogen group C^_6 a gas group, a base group, Hydroxy cv6 alkoxy, cv6 alkoxy c!_6 alkyl, Ck alkoxy (^_6 alkoxy, amine, (^-6 alkylamino, bis((^-6 alkyl))amine, amine (^_6 alkyl, (Cu alkyl) amino Cu alkyl, bis(Ch alkyl)amino CV6 alkyl, gas based Ci-6 alkyl, Ci -6 alkyl base, Ci-6 alkyl Continuing arylamino, Ci -6 alkylsulfonyl (Ch alkyl) amine, amine sulfonyl, c 6 alkyl sulfonyl, bis (Cu alkyl) amine sulfonyl, C! _6 An alkalamine group, a CV6 alkanoyl (Ch alkyl) amine group, an amine fluorenyl group, a q_6 alkylamine carbhydryl group, and a bis(CV6 alkyl) amine carbaryl group. In the formula (la) or (lb) Further specific species of compounds in R3 human R3

(la) (lb) or a pharmaceutically acceptable salt thereof; m is 1; X is a linking group selected from the group consisting of -S(0)2CH2-, -S(0)2CH(CH3)-, and -s(o) 2c(ch3)2-; iY is CH and Y2 is N; R1 is selected from decyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, -CH2CH2NC(0)CH3, -CH2CONH2, phenyl, 4-fluorophenyl, 2-phenylphenyl, 2-trifluorodecylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-ethylamidobenzene 137081-96-201002697 base, 4 - an amine base, a pyridinyl group, a pyridin-2-yl group, an anthranilyl tetrapyrrole group, a dish of a pyridin-2-yl group, a 4-methylpyrazole-2-yl group, and a 3-methyl_ι, a group of 3,4-dioxazol-2-yl; R2 is

R17 R18 wherein A1 and A2 are selected from CH or N, provided that at least one of A1 or A2 is CH; R17 is hydrogen; R18 is hydrogen; and R19 is hydrogen or is selected from methyl, ethyl, propyl, Isopropyl, butyl, iso-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, _Ch2 (cyclopropyl), -CH2CH2NMe2, -CH ( CH3)CH2OH, -C(CH3)2CH2OH, _CH2CH2OH, -(:Η2(:Η2ΟΉ2(Μ, 4-mercaptophenyl, 4-phenylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl) , 4_nonyloxyphenyl, 3,4-fluorobenzol, sulphate-2-yl, -CH2 (D-sodium-2-yl), -CH:2 (m-sodium-3-yl), Iso-zazolyl-3-yl, 6-keto-1H-pyridin-2-yl, 5-nonyliso-π-azole _3_yl, 1-hydrazinopyrazole-4-yl, -CH2(1 -methylpyrazolyl), 6-methoxypyridine _3_yl, 5_ gas group 17 to σ疋-2-yl, σ岔 bit_2_yl and 1H-U ratio a--3-yl a group; and R3 is a fluorenyl group. In a further specific class of the compound of formula (la) or (lb) 137081 -97- 201002697

Or a pharmaceutically acceptable salt thereof; m is 1; iY is CH, and Y2 is N; X is a linking group selected from -S(0)2CH2-, -S(0)2CH(CH3)-, and -S (0) 2C(CH3)2-; and R1 is selected from the group consisting of methyl, isopropyl, cyclopropyl, cyclohexyl, _CH2CH2OH, -CH2CH2NC(0)CH3, -CH2CONH2, phenyl, 4-fluorobenzene Base, 2-chlorophenyl, 2-trifluorodecylphenyl, 2-decyloxyphenyl, 2-methylphenyl, 4-ethylaminophenyl, 4-aminophenyl, pyridine-4 -yl, pyridin-2-yl, 2-ketotetrahydropyrrol-3-yl, p-conazole-2-yl, 4-methyloxazol-2-yl and 3-methyl-1,3,4 a group of -oxadiazol-2-yl; or -XR1 is C(CH3)2OH; R2 is

Wherein A1 and A2 are selected from CH or N, provided that at least one of eight or eight is CH; R17 is hydrogen; R18 is hydrogen; and 137081-98-201002697 R19 is hydrogen' or is selected from methyl, Base, propyl, iso-propyl, butyl, iso-butyl, second-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -ch2 (cyclopropyl), -CH2CH2NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2CH2OH, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4- Fluorophenyl, 4-methoxyphenyl, 3,4-monopropenyl, p-cephen-2-yl, -CH? (taste-2-yl), -CH2 (isox-3-yl) , isoxazolyl-3-yl, 6-keto-1H-pyridin-2-yl, 5-methylisoxazole _3_yl, μmethylpyrazole _4_yl, -CH2(1- a group of a thiol p-but-4-yl), a 6-fluorenyloxy-3-yl group, a 5-fluoropyridin-2-yl group, a pyrimidin-2-yl group, and a 1H-pyrazol-3-yl group And R3 is a methyl group. In a further specific class of compounds of formula (la) or (lb)

(10) (lb) or a pharmaceutically acceptable salt thereof; m is 1; W is CH, and Y2 is N; X is a linking group selected from -S(0)2CH2-, -S(0)2CH(CH3) - and -S(0)2C(CH3)2-; and R1 is selected from the group consisting of methyl, isopropyl, cyclopropyl, cyclohexyl, -CH2CH2OH, 137081-99-201002697-CH2CH2NC(0)CH3, -CH2CONH2, phenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-methylphenyl, 4-ethylamidophenyl 4-aminophenyl, pyridine-4-yl, pyridin-2-yl, 2-ketotetrahydropyrrol-3-yl, thiazol-2-yl, 4-methyloxazol-2-yl and 3- a group of methyl-1,3,4-pyrazol-2-yl; or XR1 is C(CH3)2 OH; R2 is

Wherein A1 and A2 are CH; R17 is hydrogen; R18 is hydrogen; and R19 is hydrogen' or is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, and tert-butyl. , pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2 (cyclopropyl), L-CH2 CH2 NMe2, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2OH, -CH2CH2Oi2OH, phenyl, 4-methylphenyl, 4-phenylphenyl, 4-trifluorodecylphenyl, 4-fluorophenyl, tolyloxyphenyl, 3,4-difluorobenzene Base, thiophene-2-yl, -CH2 (isoxazole-2-yl), -CH2 (salt-3-yl), iso-indenyl-3-yl, carbyl-2-yl, 5-methyl The base is different from the _3_ base and 1-曱 base p ratio. Sit, -CH2 (1-methylpyrazole-4-yl), 6-methoxypyridine-3-yl, 5-fluoropyridin-2-yl, pyrimidine_2-yl and 1H-pyrazole-3 a group based on; 137081 -100- 201002697 and R3 is a sulfhydryl group. In a further specific class of compounds of formula (la) or (lb) R3 k human R3

Or a pharmaceutically acceptable salt thereof; m is 1; iY is CH, and Y2 is N; X is a linking group selected from -S(0)2CH2-, -S(0)2CH(CH3)- and -S(0)2 C(CH3)2 -; and R1 is a group selected from the group consisting of fluorenyl, -CH2CH2OH and phenyl; or -XR1 is C(CH3)2OH; R2 is

/R19 R17 R18 wherein A1 and A2 are selected from CH or N, provided that at least one of A1 or A2 is CH; R17 is hydrogen; R18 is hydrogen; and R19 is selected from decyl, ethyl, cyclopropyl, a group of -CH2CH2NMe2, -CH2CH2OH, phenyl, 4-fluorophenyl and 4-anthraceneoxyphenyl; 137081 201002697 and R3 is a fluorenyl group. In a further specific class of compounds of formula (la) or (lb),

R

R2 or a pharmaceutically acceptable salt thereof; m is 1; 1Y is CH, and Y2 is N; X is a linking group selected from -S(0)2CH2-, -S(0)2CH(CH3)- and - S(0)2C(CH3)2-; and R1 is a group selected from the group consisting of fluorenyl, -CH2CH2OH and phenyl; or XR1 is C(CH3)2OH; R2 is

R17 R18 wherein A1 and A2 are CH; R17 is hydrogen; R18 is hydrogen; and R19 is selected from the group consisting of methyl, ethyl, cyclopropyl, -CH2CH2NMe2, -CH2CH2OH, phenyl, 4-fluorophenyl and 4-methyl a group of oxyphenyl groups; and R3 is a methyl group. 137081 -102- 201002697 In a further specific class of compounds of formula (la) or (lb) .0, /0, R&gt;-

1 γ-^^-γ2

R! Λ / R2 , x &gt; r da) or a pharmaceutically acceptable salt thereof; m is 1; 1Y is CH, and Y2 is N; X is a linking group -S(0)2 C(CH3)2 - And R1 is a group selected from a methyl group and a phenyl group; or XR1 is -C(CH3)2OH; R2 is

R 19 wherein A1 and A2 are CH; R17 is hydrogen; R18 is hydrogen; and R19 is -CH2CH2OH; and R3 is a fluorenyl group. Another aspect of the invention provides a compound or combination of compounds selected from any one of the Examples, or a pharmaceutically acceptable salt thereof. Another aspect of the present invention provides a compound or a combination of compounds selected from the group consisting of 137081 - 103 - 201002697 3-ethyl-l-[4-[4-[(3S)-3-indolyl ylyl yl]_6_ (曱 酿 酿 曱 成 -2- -2- -2- -2- 基 基 基 苯基 苯基 , , , , , ,, 3-cyclopropyl-l-[4-[4-[(3S)-3-indolylmorpholine·4] (Methanesulfonyl fluorenyl) pyrimidine-2-yl] stupid] sulfur vein, 3-(4-fluorophenyl)-l-[4-[4-[(3S)-3-methylmorpholine Ice-based]_6_(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]thiourea, H4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(A Sulfhydrylmethyl)pyrimidinyl]pyridyl]-3-phenyl-thiourea, 3-(4-methoxyphenyl)_i_[4-[4-[(3S)-3-methylmorpholine _4_基]_6-(methylsulfonyl aryl) 3⁄4'. 1,4-yl]phenyl]sulfur, 3-cyclopropyl-l-[4-[4-[(3S)-3 -methylmorpholine_4_yl]_6_(2_methylsulfonylpropan-2-yl)pyrimidin-2-yl]phenyl]thiourea, 3 methyl-l-[4-[4-[(3S曱-3-mercapto-4-yl]-6-(2-methyl lithosperylpropan-2-yl) aceton-2-yl]phenyl]sulfurate, 3-ethyl-l- [4-[4-[(3S)-3-indolyl]-4-yl]-6-(2-methylglycosylpropan-2-yl). , 3-(2-3⁄4ethyl)-i_[4-[4-[(3S)-3-indenyl]p- 4-yl]-6-(2-fluoridylxanthylpropan-2-yl)pyrimidine-2-yl]phenyl]thiourea, 3-(2-diguanylamino)_H4-[4-[( 3S)-3-methylmorpholin-4-yl]-6-(2-methyl-bromopropan-2-yl&gt;-mididin-2-yl]phenyl]thiourea, 1-[4-[ 4-[2-(phenylsulfonyl)propan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine_2_yl]phenyl]-3-methylsulfide Urea, 1-[4-[4-[2-(phenylphosphonate)propan-2-yl]-6-[(3S)-3-methylhblin_4_yl]. _2 yl]phenyl]-3-cyclopropylthiourea, 137081 -104- 201002697 1-[4-[4-[2-(本四四醯基)propyl-2-yl]-6-[(3S )-3-曱基?ι»林-4-基]t&gt; dense bite_2_yl]phenyl]-3-ethylthiourea, 1-[4-[4-[2-(本石页醯基) )C 2 —yl]_6-[(3S)-3-indenyl p-phenyl-4-yl]«密α定_2_yl]phenyl]-3-(2-ethyl)thiourea, 3-(2-Ethyl)-1-[4-[4-[2-(3-hydroxypropylsulfonyl)propan-2-yl]-6-[(3S)-3-methyl? Physo-4-yl&gt;-mididin-2-yl]phenyl]thiourea, 1-[4-[4-[2-(3-propylsulfonyl)propan-2-yl]_6_[( 3S) each methylmorpholine·4yl]pyrimidin-2-yl]phenyl]-3-methylthiourea, 3-cyclopropyl-1-[4-[4-[2-(3-hydroxypropyl) Sulfomethyl)propan-2-yl]_6_[(3s)_3_methylmorpholin-4- &gt;Mididine-2-yl]phenyl]thiourea, 3-ethyl small [4-[4-[2-(3-hydroxypropylsulfonyl)propan-2-yl] winter [(3S) _3_Methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea, 3-(2-hydroxyethyl) small [4-[4-(2-hydroxypropan-2-yl)- 6-[(3S)-3-indolylmorpholine-4-yl]pyrimidin-2-yl]phenyl]thiourea, 1-[4-[4-(2-hydroxypropan-2-yl)_6_[ (3S) each methylmorpholinopyrimidin]pyrimidin-2-yl]phenyl]-3-methylthiourea, 3-cyclopropyl small [4-[4-(2-hydroxypropan-2-yl)- 6-[(3S)-3-methylmorpholineyl]pyrimidin-2-yl]phenyl]thiourea, and 3-ethyl-l-[4-[4-(2-hydroxyprop-2-) Base)_6_[(3S) each methylmorpholino). Michidine-2-phenyl]thiourea or a pharmaceutically acceptable salt thereof. The invention also provides a process for the preparation of a compound of formula (1) or a pharmaceutically acceptable salt thereof. The compound of the formula (I) wherein X = _S(〇)2Cr6r7_ can be obtained by reacting a compound of the formula (I) wherein 乂 = 137081 • 105 - 201002697 SCR6R7 - for example, using 〇x〇ne@, in a mixed solvent system with ethanol Made by oxidation.

At room temperature, in the compound of formula (I), wherein R1 X = R1 〇CR6R7 _, by the compound of formula (I) wherein Rlx = HOCR6R7-, and the compound of formula (9) wherein ^ is a leaving group (such as a tooth) Base, toluenesulfonyl, methanesulfonyl, etc., if appropriate, in the presence of a suitable test, such as triethylamine, and a solvent such as tetraziridine or N,N-dimercaptocarbamide .

A compound of the formula (I) wherein R1 X = R1 R4NCR6R7 - may be obtained by a compound of the formula (I) wherein R is x = HR4 NCR6R7-, and a compound of the formula (II) wherein L1 is a cleavage group (eg iii group, hydrazine) Benzene-based brewing base, toxin-branching base, etc.) 'Reacts in the presence of a suitable base, such as triethylamine, with a solvent such as tetranitrofuran or n,n-dimethyldecylamine; or 1^乂= hr4ncr6r7_ Formula (1) A compound prepared by reacting a compound of the formula (ΠΙ) with a suitable reducing agent such as NaCNBH3.

A compound of formula (I), wherein X1 = -s(o)2cr6r7_, -scr6r7_, _ocr6r7_, -R4NCR6R7-, -S(0)CR6R7-' can be liberated via a compound of formula (IV) wherein L1 is 137081 • 106- 201002697 a base (such as a halo group, a toluenesulfonyl group, a decanesulfonyl group, etc.), and a compound of the formula (v) 'optional base, such as triethylamine, with a solvent such as tetrahydrofuran or hydrazine, hydrazine-dimethyl It is prepared by reacting in the presence of formamide. η 八 R1—Χ'Η (V)

A compound of formula (I), wherein X = -SCR6R7-, can be prepared as a compound of formula (IV) wherein L1 is a leaving group (e.g., halo, acesulfonyl, methanesulfonyl, etc.), Thiourea, reacted in a suitable solvent such as ethanol to produce a compound of formula (VI) which is then subsequently combined with a compound of formula (11) in a suitable base, such as sodium hydroxide, with a solvent such as hydrazine, hydrazine-dimethyl The reaction is carried out in the presence of carbamide.

The compound of the formula (I) wherein X = _R4NC(0)- can be prepared in the following manner, the reaction of the compound of the formula (VII) with the amine of the formula Rir4nh 'subsequently the appropriate activation of the carboxylic acid' is known from the literature Methods such as the use of a coupling agent, such as HATU, or conversion to barium chloride.

A compound of formula (I), wherein X = _s(〇)2CR6R7_, can be prepared in the following manner, a compound of formula (I) wherein X = 4(〇)2〇^_, and a continuous compound of formula (vm) 137081 - 107 - 201002697 where L1 is a leaving group (such as a halogen group,

The reaction is followed by a compound of the formula (ιχ), a genus, and a thiophanate.

a compound of formula (I), wherein R1 X = H〇CR6R7_, can be reacted in a suitable bath with a suitable organometallic reagent of formula (ΧΙ) and formula (ΧΠ), such as a Grignard reagent, via a compound of formula (χ) production. In the case where R6 and R7 are different, a technique known in the literature may be used, such as conversion of a compound of the formula (χ) into a composition of Wemreb and a reaction with an organometallic reagent of the formula (χι), followed by a subsequent step. Reacts with an organometallic reagent of the formula π (XII).

The compound of the formula (I) can be prepared from a compound of the formula (I) wherein L2 is a leaving group (e.g., halo, fluorene sulfonyl, methanesulfonyl, _SMe, -S(〇) 2Me, etc.), using an appropriate organometallic Reagents (such as dihydroxyborane r2B(OH)2 or dihydroxyboronic vinegar R2B(OR)2, etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent such as 1,4- Dioxane. Alternatively, in the case where R2 is attached to the pyrimidine ring via a nitrogen, oxygen or a hydrophobic atom, the compound of formula 1 can be prepared from a compound of formula (XIII) wherein L2 is a leaving group (e.g., halo, indolyl sulfonyl, methane sulfonate) Base, -SMe, -S(0)2Me, etc., in the form of a desired amine, 137081 •108-201002697 potassium carbonate, in the appropriate solvent sterol or sulphur fresh in the presence of an appropriate test, such as N, Reaction in N-dimethylformamide.

(XIII)

It should be understood that the compound can be converted to another compound of the formula (藉) by any of the techniques listed above or known in the literature, such as oxidation, alkylation, reductive amination. Wait. a compound of the formula (XIII), wherein χΐ=-s(〇)2C:r6r7-, _seR6R7_, -OCR6R7-, -R4NCR6R7-, -S(0)CR6R7_, wherein L1 is a leaving group (such as a halogen group, a compound of the formula (V), optionally in the presence of a suitable base such as triethylamine, in the presence of a solvent such as tetrahydrofuran or N,N-didecylguanamine Made by reaction. [&gt;(吭 ^Χ1Η (V)

L2 Re R7 (XIV)

L5 R6'V (XIII)

A compound of the formula (XIII) wherein X = -SCR6 R7 - can be prepared as a compound of the formula (XIV) wherein L1 is a leaving group (e.g., halo, toluenesulfonyl, decanesulfonyl) Etc., reacting with thiourea in a suitable solvent such as ethanol to produce a compound of formula (XV), which is then subsequently reacted with a compound of formula (II), such as sodium hydroxide, with a solvent such as hydrazine, hydrazine- In the presence of dimercaptoamine

137081 -109- 201002697 A compound of formula (XIII) wherein x = -r4nc(o)- can be prepared by reacting a compound of formula (XVI) with an amine of formula R1 R4NH followed by appropriate activation of the carboxylic acid, By means of methods known in the literature, such as the use of coupling agents, such as HATU, or conversion to gasified hydrazine.

A compound of the formula (XIII), wherein X = -s(o)2cr6r7-, can be prepared in the following manner, a compound of the formula (XIII) wherein X = _s(o)2 CH2 -, a continuous reaction with a compound of the formula (VIII) 'Subsequent to the compound of formula (IX), wherein Li is a leaving group (such as halo, fluorenyl sulfonyl, decane sulfonyl, etc.), in the presence of a suitable base, such as a mouse or a di-di The alcohol clock is reacted in a suitable solvent such as tetrazolium or hydrazine, hydrazine-dimethylformamide.

A compound of the formula (XIII), wherein R1X = HOCR6R7_, can be produced by reacting a compound of the formula (XVII) with a suitable organometallic reagent of the formula (XI) and the formula (e.g., Gngnard reagent) in a suitable solvent. In the case where R6 and R7 are different, then a technique known in the literature can be used, such as conversion of a compound of the formula (χνπ) into Weinreb decylamine, and reaction with an organometallic reagent of the formula (ΧΙ), followed by a subsequent step. . Reacts with an organometallic reagent of formula (XII).

137081 -110- 201002697 The compound of the formula (ιν) can be prepared from a compound of the formula (XIV) wherein L2 is a leaving group (such as a halogen group, a sulfonyl group, a methanesulfonyl group, a _SMe, a ss(〇) 2Me, etc.), And L1 is a leaving group (such as a functional group, toluenesulfonyl group, ▼ alkanesulfonyl group, etc.), using a suitable organometallic reagent (such as dihydroxyborane R2B (〇H) 2 or dihydroxyborane R2B (OR) 2, etc., in the presence of a suitable metal catalyst (such as palladium or copper), in a suitable solvent, such as dioxane. Or 'in the case where R2 is attached to the pyrimidine ring via a nitrogen, oxygen or sulfur atom, the compound of formula (IV) can be prepared from the formula (XIV), wherein L2 is a leaving group (such as a halo, a pyrolyl xanthine, Alcohol or thiol, such as -SMe, -s(〇)2 Me, in the presence of an appropriate test: such as N,N-didecyl decylamine. 'The way is Amine, such as potassium carbonate, in a suitable solvent

(XIV)

The compound of the formula (X) can be produced from a compound of the formula (XVII), wherein L2 is a leaving group (milk, halo, sulfonyl, sulfonyl, s-SMe, -S(0)2Me, etc.), and R For hydrogen or C^4, use appropriate organometallic reagents (such as the second base of r2b (〇h) 2 or two (four) Shi Pengyuan, r2b (〇r) 2), etc., in the appropriate metal catalyst In the presence of palladium or copper, in a suitable solvent, such as I 〆 - dioxane. Alternatively, in the case where R2 is bonded to the t-ring through a nitrogen, oxygen or sulfur atom, the compound of formula (X) can be prepared from a compound of formula _), wherein it is a cleavage group (for example, a dentate group: toluene continuation base, a plant performance) Stuffed base, _SMe, _s(〇)2Me#), in the form of an amine, an alcohol or a mercaptan, in the presence of a suitable test, such as potassium sulphate, in a suitable solvent such as N,N-dimethylhydrazine Reaction in the amine. 137081 -111 - 201002697

The compound of the formula (XVIII) can be produced from a compound of the formula (XIX) wherein L2 is a leaving group (e.g., halo, toluenesulfonyl, decanesulfonyl, -SMe, -S(0)2Me, etc.), using an appropriate organic a metal reagent (such as dihydroxyborane r2B(OH)2 or dihydroxypyrrolidine R2B(OR)2, etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent, such as 1,4- Dioxane. Alternatively, in the case where R2 is bonded to the pyrimidine ring via a nitrogen, oxygen or sulfur atom, the compound of formula (XVIII) can be prepared from a compound of formula (XIX) wherein L2 is a leaving group (eg, halo, fluorene sulfonyl, hydrazine) Burning sulfhydryl, -SMe, _S(0)2Me, etc.) in the presence of the desired amine, alcohol or thiol in the presence of an appropriate test, such as carbonic acid, in a suitable solvent such as N, N-di Reaction in carbamide.

The compound of the formula (XX) can be produced from a compound of the formula (XXI) wherein L2 is a leaving group (e.g., halo, indenesulfonyl, methanesulfonyl, -SMe, _s (〇\ Me, etc.), using an appropriate organic metal a reagent (such as dihydroxyborane r2B (〇h) 2 or dihydroxyborane R2B (〇R) 2, etc.) in the presence of a suitable metal catalyst (such as palladium or copper) in a suitable solvent, such as 1, 4-dioxanthine. Or, in R2 through nitrogen,

Alcohol or mercaptan in the presence of a suitable base. Eight w 丞, 丫 + ~|, A ' is obtained by reacting with the desired amine, such as potassium citrate, in a suitable solvent 137 137081 -112- 201002697 such as N,N-dimethylformamide.

a compound of the formula (I), wherein L1 is a leaving group (such as a functional group, a terpene sulfonyl group, a methanesulfonyl group, etc.), which may be present via a compound of the formula (XXII) and a compound of the formula (ΧΧΠΙ), optionally in the presence of a suitable base. It is prepared by reacting, for example, triethylamine in a suitable solvent such as N,N-methylmethylamine.

It will be appreciated that a compound of formula (ΧΧΠ) can be converted to another compound of formula (ΧΧΠ) by techniques such as those listed above or known in the literature, such as oxidation, alkylation, reductive amination. Function and so on. The compound of the formula (IV) wherein Li is a leaving group (such as a halogen group, a pyridone group, a methanesulfonyl group, etc.) can be appropriately detected by a compound of the formula (χχιν) and a compound of the formula (χχιπ). The following is prepared by reacting, for example, triethylamine in a suitable solvent such as hydrazine or hydrazine-dimercaptocaramine. ·

a compound of the formula (X), wherein L1 is a leaving group (e.g., halo, fluorene sulfonyl, methane, fluorenyl, etc.), and R is hydrogen or a Ci-4 alkyl group, which can be via the formula (χχν) compound ' and formula (XXIII) The compound, if appropriate, is prepared by reacting in the presence of a suitable base such as triethylamine in a suitable solvent such as ν,ν-didecylguanamine. 137081 -113- 201002697

[V N

A compound of the formula (XVIII), wherein L1 is a leaving group (e.g., halo, indene, decanesulfonyl, etc.), via a compound of formula (XXVI), and a compound of formula (XXIII), optionally with a suitable base In the presence of, for example, triethylamine, it is prepared by reacting in a suitable solvent such as hydrazine, hydrazine-dimethylamine.

a compound of the formula (XX), wherein L1 is a leaving group (e.g., halo, fluorene sulfonyl, fluorene, etc.), and L2 is a leaving group (e.g., halo, hydrazine, methanesulfonyl, -SMe, -S(0)2Me, etc., via a compound of formula (XXVII), and a compound of formula (XXIII), optionally in the presence of a suitable base, such as triethylamine, in a suitable solvent such as N,N-dimethyl It is prepared by reacting with carbamide. η

[&gt; compound of formula (XIII) wherein L1 is a leaving group (e.g., halo, fluorenyl sulfonyl, decanesulfonyl, etc.), and L2 is a leaving group (e.g., halo, toluenesulfonyl, methane) Sulfosyl, -SMe, -S(〇)2 Me, etc., via a compound of formula (XXVIII), and a compound of formula (XXIII), optionally in the presence of a suitable reagent, such as triethylamine, in a suitable solvent such as N It is prepared by reacting with N-dimercaptodecylamine. 137081 -114- 201002697

It will be appreciated that a compound of formula (XIII) can be converted to another compound of formula (ΧΙΙΙ) by techniques such as those listed above or known in the literature, such as oxidation, alkylation, reductive amination. Function and so on. a compound of the formula (XIV), wherein L1 is a leaving group (such as a halogen group, a toluene xanthyl group, a methanesulfonyl group, etc.), and L2 is a leaving group (such as a benzyl group, a fluorenyl group, a scutane sulphate group, a -SMe , -S(O)2 Me, etc.) can be passed through a compound of formula (XXIX), and a compound of formula (XXIII), as appropriate, in the presence of a suitable test, such as triethylamine, in a suitable solvent such as N,N-di It is prepared by reacting with carbamide.

A compound of the formula (XVII), wherein L1 is a leaving group (e.g., ij group, hydrazine sulfhydryl, methoxantine, etc.), and L2 is a leaving group (e.g., benzyl, tolylxanthyl, decanesulfonyl, - SMe, -S(0)2Me, etc.) and R is hydrogen or a Ci 4 building group, via a compound of formula (XXX), and a compound of formula (XXIII), optionally in the presence of a suitable base, such as triethylamine, It is prepared by reacting a suitable solvent such as hydrazine or hydrazine-dimethyl decylamine.

A compound of the formula (XIX), wherein L1 is a leaving group (such as a benzyl group, a methanesulfonyl group, a methanesulfonyl group, etc.), and L2 is a leaving group (eg, a dentate group, a sulfonyl group, 137081 • 115·201002697) a decanesulfonyl group, -SMe, -S(0)2Me, etc., may be via a compound of the formula (χχχι), and a compound of the formula (XXIII), optionally in the presence of a suitable reagent, such as triethylamine, in a suitable solvent, for example It is prepared by reacting N,N-dimethylformamide.

A compound of the formula (XXI) wherein L1 is a leaving group (e.g., halo, fluorene sulfonyl, methanesulfonyl, etc.) and L2 is a leaving group (e.g., halo, toluenesulfonyl, decanesulfonyl) , -SMe, -S(0)2 Me, etc., via a compound of the formula (χχχπ), and a compound of the formula (XXIII) as appropriate in the presence of a suitable test, such as triethylamine, in a suitable solvent such as N, N- It is prepared by reacting in dimethylformamide.

A compound of formula (I) wherein Rlx = h2NCh2_ can be prepared from a compound of formula (xvm) by hydrogen (reduced) with a suitable catalyst, such as palladium on carbon, in a suitable solvent such as ethanol, such as hydrogenation.

Compounds of formula (I) wherein Rlx = H2NC(0)_ can be prepared from a compound of formula (XVIII) by hydrolysis, for example, sodium hydroxide in a suitable solvent such as a mixture of water and ethanol. 137081 -116- 201002697

(XVIU)

In the formula (I), "R X = H2NCr6r7 _" can be obtained by reacting with an organometallic reagent (xi). (Individual reaction 1 from a compound of the formula (XVIU).

NC Ν R (XVlil) tr Ο 〔 ν „ R R R R R R R R R R R R R R R R R R R The method is to use hydrogen as a suitable catalyst, such as palladium/carbon, in a suitable solvent, such as the reduction of B. *, such as hydrogenation. [) (R3) m C3 &lt; rx

R

NC^N^L2 (XIX)

H2N

N*^L2 (X1H) A compound of the formula (XIII) wherein R1X = H2NC(0)_, which may be a compound of the formula (XIX) in a mixture of a suitable solvent such as a water-ethanol mixture.

(XIX) (XIII) A compound of formula (XIII) wherein Ι^Χ = Η2Ναΐ6Ι17-, which is a reaction of reagents (XI) with (XII), is prepared from a compound of formula (XIX). Via with organic gold R^-Μ (Χ〇 *(R )m ο

, 〇, Ν R

R-M T| (XII) ncAn^l2 (XIX)

R

Re R7 (XIH) 137081 201002697 ’ first with carbon ring or

It should be understood that the 'R2 group can be at any stage, a heterocyclic ring...- ι under the nitro moiety, whether it is an amine or an oxazole, and other methods. It will be appreciated that certain different ring substituents in the compounds of the invention may be introduced by standard aromatic substitution reactions, or by functional group modification, either prior to or immediately prior to the methods mentioned above. Thereafter, and thus are included in the method aspect of the invention. For example, the compound of formula 1 can be converted to other compounds of formula (1) by standard aromatic substitution reactions or by functional group modification. Such reactions and modifications include, for example, the introduction of a substituent by an aromatic substitution reaction, the reduction of a substituent, the alkylation of a substituent, and the oxidation of a substituent. The reagents and reaction conditions for such procedures are well known in the art of chemistry. Specific examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of a sulfhydryl group, the use of, for example, a ruthenium halide and a Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions; the introduction of an alkyl group, the use of an alkyl group Halides and Lewis acids (such as aluminum trichloride) under Friedel Crafts conditions; and introduction of halogen groups. Specific examples of upgrading, including reduction of the nitro group to an amine group, by catalytic hydrogenation with, for example, a nickel catalyst, or treatment with iron in the presence of hydrochloric acid, and heating; oxidation of the alkylthio group to an alkylsulfinyl group Or alkylsulfonyl. 137081 -118- 201002697 It should also be understood that in the reactions mentioned herein, it is necessary/need to protect any sensitive groups in the compound. The circumstances in which the protection must be or need to be protected 1 and the appropriate party of the poem (4) are known as (4). Conventional protecting groups can be used according to standard practice (for instructions, see T.W. Green, Protective Base for Organic Synthesis, John Wiley &amp; ΐ ΐ 99ι). Thus = if the reactant contains a group such as an amine group, a carboxyl group or a hydroxyl group, it is generally expected that the group will be protected in some of the reactions mentioned herein. Suitable protecting groups for an amine group or an aroma group are, for example, anthracenyl groups such as an alkano group, such as an ethyl group, an oxycarbonyl group such as a methoxycarbonyl group, a hexyloxy group or a third-butoxy group. An aryl methoxy group, for example; an oxycarbonyl group, or a fluorenyl group, for example, a benzylidene group. The need for a protecting group above will vary with the choice of protecting group. Thus, for example, == such as a decyl or a m group, or a (iv) group can be removed, for example, by a suitable hydrolysis, such as a metal hydroxide such as a hydrazine or a sodium or a hydrazine. The base '#, such as a second-butoxyl group, can be removed, for example, by treatment with a suitable acid, such as hydrochloric acid, sulfuric acid or squaric acid or trifluoroacetic acid, and the methoxyl group, such as an oxo group, It may be removed, for example, by chlorination on the catalyst, such as carbon residue, or by treatment with Lewis acid, such as ginseng (tri-I acetic acid (tetra)'. Suitable replacement protecting groups for the -amino group are For example, a sulfhydryl group, which may be removed by treatment with a deuteroamine such as dimethylaminopropylamine, or with hydrazine. The appropriate protecting group for the thiol group is, for example, a fluorenyl group, such as a (iv) group, and a A fluorenyl group, such as a benzylidene group, or an arylmethyl group, such as a lower group. With regard to the removal protection conditions of the above protecting group, it will have to be changed with the choice of the protection 137081 201002697. Thus, for example,醯基, 譬如院 Sac, or 芳基基, can be tested, for example, by appropriate It is removed by hydrolysis, such as a metal hydroxide such as lithium hydroxide or sodium. Alternatively, an arylmethyl group, such as a sulfhydryl group, can be removed, for example, by hydrogenation on a catalyst, such as carbon. A suitable protecting group for a carboxyl group is, for example, an esterifying group, such as a mercapto group or an ethyl group, which may be removed, for example, by hydrolysis, such as sodium hydroxide, or, for example, a third-butyl group. It can be removed, for example, by treatment with an acid, such as an organic acid, such as tri-II acetic acid, or, for example, a genomic group, which can be removed, for example, by hydrogenation on a catalyst, such as palladium on carbon. At any convenient stage in the synthesis, it is removed using conventional techniques known in the art. Many of the intermediates defined herein are novel, and such are provided as further features of the invention. It can be used to measure the compounds of the present invention as mTOR kinase inhibitors, as PI3 kinase inhibitors, as a live inhibitor of the activation of the signaling pathway of PI3 kinase, and as a MDA-MB-468 human breast cancer cell. The role of in vitro inhibitors of hyperplasia. (8) (1) In vitro mTOR kinase assay This assay uses the AlphaScreen technique (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine the inhibition of the test compound by the phosphorylation of mTOR The ability of deuteration. The C-terminal fragment of mTOR covering amino acid residues 1362 to 2549 of mTOR 137081 - 120 - 201002697 The head (EMBL acceptance number L34075) is stably expressed in HEK293 cells with FLAG-labeled fusions. , as described by Vilella-Bach et al., J. Biol. Chem., 1999, 274, 4266-4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line is routinely accompanied by 5% C02. Containing 10% heat-inactivated bovine fetal serum (FCS; Sigma, Poole, Dorset, UK, Cat. No. F0392), 1% L-glutamate (Gibco, Cat. No. 25030-024) and 2 mg at 37 °C /lb-based factor (G418 sulfate; Invitrogen, UK catalog number 10131-027) in Dulbecco's Denature Eagle Growth Medium (DMEM; Invitrogen, Paisley, UK catalog number 41966-029), reaching 70-90% Convergence. Following expression in the mammalian HEK293 cell line, the expressed protein is labeled using the FLAG epitope and purified using standard purification techniques. The test compound was prepared as a 10 mM stock solution in DMSO and diluted in water as needed to give a range of final assay concentrations. The aliquot of each compound dilution (2 microliters) was placed in a Greiner 384-well low volume (LV) white polystyrene (Greiner Bio-one) well. Recombinant purified mTOR enzyme, 1 biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val- phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala-Pro- Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH2; Bachem UK), ATP (20 //Μ) and buffer solution [containing Tris-HCl ρΗ7·4 buffer (50 mM), EGTA ( A 30 μl mixture of 0.1 mM), bovine serum albumin (0.5 mg/ml), DTT (1.25 mM) and manganese chloride (10 mM) was stirred at room temperature for 90 minutes. A control well that produces the highest message corresponding to the highest enzyme activity is produced by replacing the test compound with 5% DMSO. A control well that produces the lowest message corresponding to the complete enzyme 137081 -121 - 201002697 is produced by adding EDTA (83 mM) instead of the test compound. These test solutions were incubated at room temperature for 2 hours. 10 μL of a mixture containing EDTA (50 mM), bovine serum albumin (BSA; 0.5 mg/ml) and Tris-HCl pH 7.4 buffer (50 mM) containing p70 S6 kinase (T389) 1A5 Monoclonal antibody (cell signaling technology, catalog number 9206B), and added AlphaScreen streptavidin donor and protein A acceptor beads (200 ng; Perkin Elmer, catalog numbering 6760002B and 6760137R individually), The reaction was stopped and the assay plate was left in the dark for about 20 hours at room temperature. The resulting signal, which was generated by excitation of the laser light at 680 nm, was read using a Packard Envision instrument. The phosphonylated biotinylated peptide system is formed on the spot due to the phosphonium mediated by mTOR. Phosphonylated biotinylated peptide associated with AlphaScreen streptavidin donor beads, forming a complex with p70 S6 kinase (T389) 1A5 monoclonal antibody, and the anti-system and AlphaScreen protein A receptor Bead association. The donor bead: acceptor bead complex produces a signal that can be measured when excited by a laser light at 680 nanometers. Therefore, the presence of mT〇R kinase activity causes a detection signal. In the presence of mTOR kinase inhibitors, signal strength is reduced. The mTOR enzyme inhibition system for the compound to be tested is expressed by the IC5 enthalpy value. (a) (ii) In Vitro MTOR Kinase Assay (Echo) This assay uses AlphaScreen technology (Gray et al., Analytical Biochemistry 2003, 313: 234-245) to determine the inhibition of test compounds by recombination of mT〇R scales. The ability to S disk. The C-terminal cut of mT〇R covering amino acid residues 1362 to 2549 of mTOR is 137081-122-201002697. The head (EMBL accepting number L34075) is stably expressed in HEK293 cells as a FLAG-tagged fusion. Vilella-Bach et al., J. Biol. Chem., 1999, 274, 4266-4272. The HEK293 FLAG-tagged mTOR (1362-2549) stable cell line was routinely maintained at 37 ° C with 5% C02 in serum containing 10% heat-inactivated bovine fetal serum (FCS; Sigma, Poole, Dorset, UK, catalog number F0392), 1% L-brutamine (Gibco, Cat. No. 25030-024) and 2 mg/ml base factor (G418 sulfate; Invitrogen, UK catalog number 10131-027) Dulbecco's denaturation Eagle growth medium (DMEM; Invitrogen, Paisley, UK catalog number 41966-029) reached 70-90% confluence. Following expression in the mammalian HEK293 cell line, the expressed protein is labeled using the FLAG epitope and purified using standard purification techniques. The test compound was prepared as a 10 mM stock solution in DMSO and diluted in water-DMSO as needed to give a range of final assay concentrations. The aliquot of each compound dilution (120 ng, 2 μl) was placed in a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one) using a Labcyte Echo 550 dispense. In the well. Recombinant purified mTOR enzyme, 1 biotinylated peptide substrate (Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala-Pro- Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH2; Bachem UK), ATP (20 μΜ) and buffer solution [containing Tris-HCl pH 7.4 buffer (50 mM), EGTA (0.1 A mixture of 1230 microliters of mM), bovine serum albumin (0.5 mg/ml), DTT (1.25 mM) and manganese chloride (1 mM) was stirred at room temperature for 12090 minutes. A control well that produces the highest message corresponding to the highest enzyme activity, 137081 -123- 201002697 is produced by replacing 100 mg of DMSO with the test compound. A control well that produces the lowest message corresponding to the complete inhibition of the enzyme is produced by adding LY294002EDTA (100 uM, 83 mM) instead of the test compound. These test solutions were incubated at room temperature for 2 hours. 510 μl of a mixture containing EDTA (50 mM), bovine serum albumin (BSA; 0.5 mg/ml) and Tris-HCl ρΗ7·4 buffer (50 mM) containing p70 S6 kinase (T389) 1A5 Monoclonal antibody (cell signaling technology, catalog number 9206B), and added AlphaScreen chain amino acid donor and protein A receptor beads (200 ng; Perkin Elmer, catalog numbering 6760002B and 6760137R individually) The reaction was stopped and the assay plate was left overnight in the dark at room temperature. The resulting signal, which was generated by excitation of the laser light at 680 nm, was read using a Packard Envision instrument. The wall-based biotinylated peptide system was formed on the spot due to the filling effect of mTOR. Phosphonylated biotinylated peptide associated with AlphaScreen streptavidin donor beads, forming a complex with p70 S6 kinase (T389) 1A5 monoclonal antibody, and the anti-system and AlphaScreen protein A receptor Bead association. When excited by laser light at 680 nm, the donor bead: acceptor bead complex produces a signal that can be measured. Therefore, the presence of mTOR kinase activity results in a detection signal. In the presence of mTOR kinase inhibitors, signal strength is reduced. The mTOR enzyme inhibitory line for the compound to be tested is expressed by the IC50 value. (b) (i) In vitro PI3K enzyme assay This assay uses AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313: 234-245) to determine inhibition of test compounds by lipid PI(4,5)P2 137081 -124- 201002697 The ability of the recombinant type I PI3K enzyme to phosphorylate. The human PI3K catalyzes and modulates the subunit-encoded DNA fragment, which is isolated from the cDNA gene pool using standard molecular biology and PCR asexual propagation techniques. Selected DNA fragments are used to generate a baculovirus expression vector. Specifically, the full-length DNA of each of the pllOo;, pll0/3, and ρ11〇5 type la human PI3K pllO isomeric recombinants (the EMBL acceptor numbers for pllOa, pllOyS, and pll0&lt;5 are individually HSU79143, S67334, Y10055) Subsequent asexual reproduction into the pDESTIO vector (Invitrogen, Inc., Fountain Drive, Paisley, UK). This vector is a channel adaptation variant of Fastbacl containing the 6-His epitope tag. Corresponding to the truncated form of the type lb human PI3K pllO T isomeric recombinant (EMBL accepting number X8336A) of amino acid residues 144-1102, and the full-length human ρ85 α regulatory subunit (EMBL accepting number HSP13KIN), also by the second generation Asexually propagated into the pFastBacl vector containing the 6-His epitope tag. The type la pllO construct is co-expressed with the ρ85 α regulatory subunit. After expression in a baculovirus system using standard baculovirus expression techniques, the expressed protein is labeled with His epitope and purified using standard purification techniques. The DNA corresponding to the amino acid 263 to 380 of the human general receptor for the functional site of phosphoinositide (Grpl) PH was isolated from the cDNA gene pool using standard molecular biology and PCR asexual reproduction techniques. The resulting DNA fragment was sub-proliferatively propagated into the pGEX 4T1 E. coli expression vector (Amersham Pharmacia Biotech, Rainham, Essex, UK) containing the GST epitope tag, as analyzed by Gray et al., Biochemistry, 2003, 313: 234-245). The GST-tagged Grpl PH functional site was expressed and purified using standard techniques. 137081 -125 - 201002697 The test compound was prepared as a 10 mM stock solution in DMSO and diluted to water as needed to give a range of final assay concentrations. A aliquot of each compound dilution (2 microliters) was placed in a well of Greiner 384-well low volume (LV) white polystyrene board (Greiner Bio-one, Brunei Way, Stonehouse, Gloucestershire, UK catalog number 784075). . Each selected recombinant purified PI3K enzyme (15 ng), DiC8-PI (4,5) P2 substrate (40 _; Cell Information Corporation, Kinnear Road, Columbus, USA, catalog number 901), adenine triphosphate (ATP; 4 //Μ) and buffer solution [containing Tris-HCl pH 7.6 buffer (40 mM, 10 μl), 3-[(3-cholestyrylpropyl) decylammonium]- A mixture of 1-propanesulfonate (CHAPS; 0.04%), dithiothreitol (DTT; 2 mM) and magnesium sulfide (10 mM) was stirred at room temperature for 20 minutes. A control well that produces the lowest message corresponding to the highest enzyme activity is produced by replacing the test compound with 5% DMSO. A control well that produces the highest message corresponding to the complete inhibition of the enzyme is replaced by the addition of wortmannin (6 //Μ; Calbiochem/Merck Biotech, Padge Road, Beeston, Nottingham, UK catalog number 681675) Produced by the test compound. These test solutions were also stirred at room temperature for 20 minutes. Each reaction was stopped by the addition of 10 microliters of a mixture of EDTA (100 mM), bovine serum albumin (BSA, 0.045%) and Tris-HCl ρΗ7·6 buffer (40 mM). Add biotinylated-DiC8-PI(3,4,5)P3 (50 nM; Cell Signaling, catalog number 107), recombinant purified GST-Grpl PH protein (2.5 nM) and AlphaScreen anti-GST donor and acceptor Beads (100 ng; Packard Biotech Co., Ltd., Station Road, Pangbourne, Berkshire, UK, catalog number 6760603M) ' 137081 •126- 201002697 and leave the test plate at room temperature for about 5 to 20 hours in the dark . The resulting signal, which was generated by excitation of the laser light at 680 nm, was read using a Packard AlphaQuest instrument. PI(3,4,5)P3 is formed in the field due to the phosphorylation of PI3K by PI(4,5)P2. The GST-Gq)l PH functional site protein associated with AlphaScreen anti-GST donor beads forms a complex with biotinylated PI(3,4,5)P3 associated with Alphascreen Streptavidn acceptor beads. The PI(3,4,5)P3 line produced by the enzyme competes with the biotinylated PI(3,4,5)P3 to bind to the PH functional site protein. When excited by laser light at 680 nm, the donor bead: acceptor bead complex produces a signal that can be measured. Therefore, PI3K enzyme activity to form PI (3,4,5) P3 and subsequent competition with biotinylated I (3,4,5) P3 will cause a signal of decrease. The signal intensity was restored in the presence of a PI3K enzyme inhibitor. The P13K enzyme inhibitory line for the compound to be tested is expressed by the IC5 〇 value. (9) (6) In vitro PI3K enzyme assay (Echo) This assay uses AlphaScreen technology (Gray et al., Analytical Biochemistry, 2003, 313 · 234-245) to determine inhibition of test compounds by lipid PI(4,5)P2 The ability to recombine the phospholipidation of type I PI3K enzymes. The human PI3K catalyzes and modulates the subunit-encoded DNA fragment, which is isolated from the cDNA gene pool using standard molecular biology and PCR asexual propagation techniques. Selected DNA fragments are used to generate a baculovirus expression vector. Specifically, the full-length DNA of each of the pllOa, pllO/S, and pll05 type la human PI3K pllO isomeric recombinants (the EMBL acceptor numbers for pllOa, pllOyS, and pll0 5 are individually HSU79143, S67334, Y10055) is secondary to the asexual Reproduced into the pDESTIO vector (Invitrogen, Inc., Fountain Drive, Paisley, UK) 137081 -127- 201002697. This vector is a channel adaptation variant of Fastbacl containing the 6-His epitope tag. Corresponding to the truncated form of the type lb human PI3K pllO T isomeric recombinant (EMBL accepting number X8336A) of amino acid residues 144-1102, and the eclipse ρ85 α regulatory subunit (EMBL accepting number HSP13KIN), also The second generation is asexually propagated into the pFastBacl vector containing the 6-His epitope tag. The type la pllO construct is co-expressed with the Ρ85α regulatory subunit. After expression in a baculovirus system using standard baculovirus expression techniques, the expressed protein is labeled with His epitope and purified using standard purification techniques. The DNA corresponding to the amino acid 263 to 380 of the human general receptor for the functional site of phosphoinositide (Grpl) PH was isolated from the cDNA gene pool using standard molecular biology and PCR asexual reproduction techniques. The resulting DNA fragment was sub-proliferatively propagated into the pGEX 4T1 E. coli expression vector (Amersham Pharmacia Biotech, Rainham, Essex, UK) containing the GST epitope tag, as analyzed by Gray et al., Biochemistry, 2003, 313: 234-245). The GST-tagged Grpl PH functional site was expressed and purified using standard techniques. The test compound was prepared as a 10 mM stock solution in DMSO and the solution in DMSO was diluted to water as needed to give a range of final assay concentrations. Aliquots of each compound dilution (120 ng, 2 μl) were dispensed acoustically using a Labcyte Echo 550 dispensing in a Greiner 384-well low volume (LV) white polystyrene plate (Greiner Bio-one, Brunei Way) , Stonehouse, Gloucestershire, UK catalog number 784075). Each of the selected recombinant purified I&gt;I3K enzyme (15 ng), DiC8-PI(4,5)P2 was primed (40 _; Cell Information Company, Kinnear Road, Columbus, USA, catalog number 901), gland: y: 137081 -128 - 201002697 Triphosphate (ATP; 4 //Μ) and buffer solution [containing Tris-HCl pH 7.6 buffer (40 mM, 10 μl), 3-[(3-cholestyramine) a mixture of propyl)didecylammonium]-1-propane sulfonate (CHAPS; 0.04%), dithiothreitol (DTT; 2 mM) and magnesium hydride (10 mM) at room temperature Stir for 20 minutes. A control well that produces the lowest message corresponding to the highest enzyme activity is produced by replacing the test compound with 1005% DMSO. A control well that produces the highest message corresponding to complete inhibition of the enzyme is replaced by the addition of wortmannin (6; Calbiochem/Merck Biotech, Padge Road, Beeston, Nottingham, UK catalog number 681675) And produced. These test solutions were also incubated at room temperature for 20 minutes with stirring. Each reaction was stopped by the addition of 10 microliters of a mixture of EDTA (100 mM), bovine serum albumin (BSA, 0.045%) and Tris-HCl ρΗ7·6 buffer (40 mM). Add biotinylated-DiC8-PI(3,4,5)P3 (50 nM; Cell Signaling, catalog number 107), recombinant purified GST-Grpl PH protein (2.5 nM) and AlphaScreen anti-GST donor and acceptor Beads (100 ng; Packard Biotech Co., Ltd., Station Road, Pangbourne, Berkshire, UK, catalog number 6760603 M), and leave the assay plate in the dark for about 5 to overnight for 20 hours at room temperature. The resulting signal, which was generated by excitation of the laser light at 680 nm, was read using a Packard AlphaQuest instrument. PI(3,4,5)P3 is formed in the field due to the dendification of PI(3,5)P2 by PI3K. The GST-Grpl PH functional site protein associated with AlphaScreen anti-GST donor beads forms a complex with biotinylated ruthenium (3,4,5)Ρ3 associated with Alphascreen Streptavidn acceptor beads. The PI(3,4,5)P3 line produced by the enzyme method 137081 -129- 201002697 competes with the biotinylated PI(3,4,5)P3 to bind to the PH functional site protein. When excited by laser light at 680 nm, the donor bead: acceptor bead complex produces a signal that can be measured. Therefore, PI3K enzyme activity to form PI (3,4,5) P3 and subsequent competition with biotinylated PI (3,4,5) P3 will result in a reduced signal. The signal intensity was restored in the presence of a PI3K enzyme inhibitor. The P13K enzyme inhibitory line for the compound to be tested is expressed by the IC5 〇 value. (6) In vitro phosphonium-Ser473 Akt assay This assay measures the ability of a test compound to inhibit the phosphorylation of serine 473 in Akt using Acumen Explorer technology (Acumen Bioscience, Inc.), one available A plate reader that quickly quantifies the characteristics of images produced by laser scanning. The MDA-MB-468 human breast cancer cell line (LGC Promochem, Teddington, Middlesex, UK, Cat. No. HTB-132) was routinely maintained at 37 ° C with 5% c〇2, containing 10% heat 70-90% confluence of inactivated FCS and 1% L-faced decylamine in DMEM. For this test, 'Using &quot;Accutase&quot; (Innovative Cell Technology, San Diego, CA, USA; Cat. No. AT104) 'Using standard tissue culture methods, the cells are detached from the culture flask and resuspended in the medium to obtain each 1.7xl05 cells in milliliters. Inoculate a aliquot (90 μl) into each of the 60 internal wells of a black Packard 96 well plate (PerkinElmer, Boston, MA, USA; catalog number 6005182) to obtain a density of ~15000 cells per well. The aliquot of the medium (9 μL) was placed in an external well to prevent edge effects. The cells were incubated overnight at 37 ° C with 5% CO 2 to allow them to adhere. On day 2, the cells were incubated. Treated with the test compound and cultured for 2 hours at 37% (with 5% 137081 -130-201002697 C02. The test compound was made into a 10 mM stock solution in DMSO and grown as needed for growth medium continuity) Diluted to a range of concentrations, which is 10 times the final concentration required. Place the aliquot of each compound dilution (10 microliters) in the well (in triplicate) to obtain the final desired concentrated As the lowest response control, each plate contained wells with a final concentration of 100 //M LY294002 (Calbiochem, Beeston, UK, catalog number 440202). As the highest response control, the well system contained 1% DMSO in place of the test compound. After incubation, the contents of the plates were fixed by treatment with 1.6% formic acid in water (Sigma, Poole, Dorset, UK, Cat. No. FI635) for 1 hour at room temperature. All subsequent aspiration and washing steps were performed using Tecan 96. The well plate scrubber (sucking speed 10 mm/sec) was carried out. The fixing solution was removed and the contents of the plate were washed with phosphate buffered saline (PBS; 50 μl; Gibco, Cat. No. 10010015). The contents were treated with a one-part (50 μl) cell osmosis buffer containing PBS and 0.5% Tween-20 mixture for 10 minutes at room temperature. The "osmotic" buffer was removed and non-specific The sexual binding site was blocked by a one-part (50 microliter) blocking buffer containing 5% dry skim milk [&quot;Marvel" (registered trademark). ); Premier drink , Stafford, GB] in a mixture of PBS and 0.05% Tween-20. Remove the "blocking" buffer and dilute the cells at room temperature with a 1:500 buffer in the "blocking" buffer. The rabbit anti-phospho-Akt (Ser473) antibody solution (50 microliters per well; cells sent a message, Hitchin, Herts, UK, catalog number 9277) was incubated for 1 hour. The cells were washed three times in a mixture of PBS and 0.05% Tween-20. Next, the cells were labeled with Alexafluor 488 labeled with Alexafluor 488 in a &lt;blocking buffer 137081 -131 * 201002697 at room temperature, 50 microliters per well; Molecular Probes Invitrogen Co., Ltd. , Paisley, UK, Cat. No. A11008) Incubate for 1 hour. Wash cells 3 times with a mixture of PBS and 0.05% Tween-20. Add one serving of PBS (50 μL) to each well and block with a black plate. The plate is sealed and the fluorescent signal is detected and analyzed. The fluorescence dose response data obtained for each compound is analyzed, and the degree of inhibition of serine 473 in Akt is expressed as the IC5 enthalpy. (d) Living body Extra MDA-MB-468 Human Breast Cancer Proliferation Test This test measures the ability of a test compound to inhibit cell proliferation, which is assessed using the Cellomics array scanning technique. MDA-MB-468 Human Breast Cancer Cell Line (LGC Promochem, catalog number HTB-132) was maintained in a routine manner as described in Biological Test (b) herein. For this proliferation assay, cells were detached from the culture flask using Accutase and inoculated into the black Packard 96 well. In the inner 60 wells, at a density of 8000 cells per well, in 100 μl of complete growth medium. The external well contained 100 μl of sterile PBS. The cells were incubated at 37 ° C with 5% CO 2 overnight to allow They adhered. On day 2, the cells were treated with the test compound and cultured for 48 hours at 37 ° C with 5% CO 2 . The test compound was prepared as a 10 mM stock solution in DMSO and pressed It is necessary to continuously dilute with the growth medium to obtain a range of test concentrations. A liquid fraction (50 μL) of each compound release solution is placed in the well, and the cells are cultured at 37 ° C for 2 days at 5% CO 2 . Each plate contained a control well that did not have a test compound. On day 4, the BrdU labeling reagent 137081-132-201002697 (Sigma, catalog number B9285) was added at a final dilution of 1:1000, and the cells were at 37 °C. The cells were cultured for 2 hours. The medium was removed, and the cells in each well were treated with a 100 μl mixture of ethanol and glacial acetic acid (90% ethanol, 5% glacial acetic acid, and 5% water) for 30 minutes at room temperature. Fix. Wash the cells in each well twice with PBS (1 (8) microliters). Aqueous hydrochloric acid (2M, 100 μL) was added to each well. After 20 min at room temperature, the cells were washed twice with PBS. Hydrogen peroxide (3%, 50 μl; Sigma, Cat. No. H1009) was added to In each well, after 10 minutes at room temperature, the well was washed again with PBS.

BrdU was incorporated by a mouse anti-BrdU antibody (50 μL; Caltag, Burlingame, CA, US; diluted 1:40 in PBS containing 1% BSA and 0.05% Tween-20 at room temperature; The catalog number MD5200) was cultured for 1 hour and was detected. The unbound anti-system was removed with two washes of PBS. For imaging of BrdU incorporated, cells were PBS (50 μl) and 0.05% Tween-20 buffer containing 1 : 1000 dilution of Alexa Fluor 488-labeled goat anti-mouse IgG at room temperature. Handle for 1 hour. For nuclear visualization, a 1:1000 dilution of Hoechst dye (Molecular Probes, catalog number H3570) was added. The plates were washed sequentially with PBS. Next, PBS (1 (8) microliters) was added to each well and scanned using a Cellomics array to analyze the plates to assess the total number of cells and the number of BrdU positive cells. The fluorescence dose response data obtained for each compound was analyzed, and the degree of inhibition of MDA-MB-468 cell growth was expressed as IC5 〇 value. While the pharmacological properties of the compounds of formula (I) are expected to vary with structural changes, in general, the activity possessed by the compounds of formula (I) may be in one or more of the above tests (8) to (6). , at the following concentrations or doses 137081 -133- 201002697 Real:- Test (8)(1):-IC5 〇 for mTOR kinase, below 10 /zM, especially 0Ό01-0.5 //M, for many compounds; for example lb , the system measures IC50, the value is 0.55 / Μ. Test (b)(i): - IC5〇 for pllOr type lb human PI3K, below 10 Μ, especially 0.001-0.5 //M, for many compounds; and IC5〇 for ρΙΙΟα type la human ΡΙ3Κ, in Below 10 /iM, especially 0.001-0.5 / M, for many compounds; for the example lb, IC50 is measured in three cases, the values are 39.75, 11.74 and 3.20.

Test (c): - IC5 0 for alkine 473 in Akt, below 10 //M, especially 0.1-20 for many compounds; for example lb, IC50 is measured in two cases, value It is 1.93 and 1.74 //M. Test (d): - IC5 〇 is below 20//Μ; The following examples are tested in the enzyme test (8) (ii): Example number test (8) (ii) IC5 〇 ( &quot;M) Example number test (8) (ii) IC5〇( fM) Example number test (8)(ϋ) IC5 0 ( fM) la 0.0177 2c 0.000828 4b 0.154 1 0.0197 2d 0.305 4 0.161 Id 0.0215 3 0.011 4c 0.0585 lb 0.0816 3a 0.00717 5 0.0079 lc 0.0688 3b 0.0124 5a 0.0367 2 0.00477 3c 0.00308 5b 0.0384 2a 0.0051 4a 0.0155 5c 0.0374 2b 0.0068 137081 -134- 201002697 The present invention is advantageous because of its pharmacological activity. Specifically, the compound of the present invention modulates (particularly inhibits) mT〇R kinase and/or phospholipid 醯 inositol-3-kinase (PI3K) enzyme, such as pBK enzymes (eg, ΡΙ3Κα, ΡΙ3Κ /5, and ΡΙ3Κ ( 5) with the species ib ΡΙ3Κ enzyme (pi3K r). More specifically, the compounds of the invention modulate (particularly inhibit) mT〇R kinase. More specifically, the compounds of the invention modulate (particularly inhibit) one or more PI3K Enzymes. The inhibitory properties of the compounds of formula (I) can be demonstrated using the test procedures presented herein and in the experimental paragraphs. Thus, the compounds of formula 1 are useful in the treatment (treatment or prevention) of symptoms/diseases in humans and non-human animals. , which is mediated by mTOR kinase and/or one or more pi3K enzymes, and in particular by the time (10) kinase. The invention also provides a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharmaceutical thereof An acceptable salt, accompanied by a pharmaceutically acceptable diluent or carrier. The compositions of the present invention may be in a form suitable for oral use (for example, as tablets, lozenges, hard or soft). Capsules, aqueous or oily suspensions, emulsions, knife powders or granules, syrups or elixirs), topical use (for example as creams, ointments, gels or aqueous or oily solutions or suspensions), by inhalation ( For example, subdivided powder or liquid aerosol), by insufflation (for example, preparation, turf) or parenteral administration (for example, as a sterile aqueous or oily solution, ', # ί endothelium, intraperitoneal cavity or muscle Oral administration, or as a pick-up for rectal administration. The composition of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients known in the art. Therefore, a group intended for oral use 137081 135 - 201002697 There are, for example, one or more colouring, sweetening, bridging and/or preservatives. One or a combination of excipients to produce a single-dose active ingredient, the amount will depend on the host to be treated and the specific (4) Pathway changes. Example /, the formula intended for oral administration to humans 'usually will contain an alpha agent (more suitably 1 to, milligrams 'eg 1 to gram of milligrams), suitable! Match The weight percentage is changed from about 5 of the total composition. The dosage size for the therapeutic or prophylactic purpose of the compound of formula I, the nature and severity of the disease state, the age of the animal or the patient = the route of administration, according to conventional knowledge Changes in the principle of medicine. In the use of a compound of formula (I) for therapeutic or prophylactic purposes, it is administered in a sputum-like manner such that it takes, for example, from 1 mg/kg to 100 mg/kg body weight, "If necessary, it is administered in a separate dose. Generally, Lu's is administered at a lower dose when using a parenteral grip. Therefore, for example, for intravenous administration, for example, i mg / kg to 25 mg is used. Dosage in the range of /kg body weight. Similarly, for the administration of drugs by the inhaler, the second dose uses, for example, a dose ranging from 1 g/kg to 25 mg/kg body weight. Typically, the unit dosage form will contain from about 10 mg to about 0.5 g of the compound of the invention. σ As stated herein, mT0R kinase and ΡΙ3Κ enzyme are known to have roles in tumorigenesis and many other diseases. It has been found that the compound of formula (1) has potent antitumor activity and is generally believed to be obtained by inhibiting mTOR kinase and/or one or more PI3K enzymes. The compounds of the invention are valuable as antitumor agents. Specific words 137081 -136- 201002697 This vitamin compound is used to inhibit and/or treat solid and/or liquid tumors :: as an anti-proliferative, cellular zero and/or anti-invasive agent. It is expected that the compound of the present invention can be used for the prevention or treatment of tumors which are sensitive to mTOR and/or or genus PI3K enzymes (such as the species Ia ρι; 3Κ enzyme and the species of yeast). Furthermore, the compounds of the present invention are expected to be useful for Pre-protection or treatment of tumors that are mediated alone or in part by mTOR and / or - or more # ΡΙ 3 Κ enzymes (such as the species IaPI3K enzyme and the species Ibpi3K enzyme). Therefore, compounds can be used to treat the blood in need of such treatment. Order (10) enzyme inhibition in animals. Certain compounds can be used to produce pi3K enzyme inhibition in warm-blooded animals in need of such treatment. As stated herein, mT〇R kinase and/or one or more inhibitors of ρΐ3κ enzyme It should have therapeutic value to treat proliferative diseases such as cancer, and especially oral tumors such as carcinomas and sarcomas, and leukemias and lymphoid malignancies, and especially treatments such as breast, colorectal, lung (including small cell lung cancer, Non-small cell lung cancer and bronchial tuberculosis) and prostate cancer, with gallbladder, bones, bladder, head and neck, kidney, liver, gastrointestinal Weaving, esophagus, ovarian 'pancreas, skin, testicles, thyroid, uterus, sputum and female genital cancer, and leukemia [including acute lymphoblastic leukemia (all) and myelogenous leukemia (CML)], multiple myeloma And lymphoma. According to a further aspect of the invention there is provided a steroid or a pharmaceutically acceptable salt thereof of formula (1) as defined herein for use as a medicament in a warm-blooded animal such as a human. In a further aspect, there is provided a compound of formula 1 as defined herein, or a tactically acceptable salt thereof, for use in a warm-blooded animal, such as a human, to produce an anti-proliferative effect using 13708]-137.201002697. Further aspects of the invention Or a pharmaceutically acceptable salt thereof to produce a cell dying effect. The further step according to the invention or a pharmaceutically acceptable salt thereof

The system provides M as defined in this article to use the sputum in the formula (I) of the warm-blooded animal, such as the formula (I), to provide the formula as P; And/or treating proliferative diseases such as cancer. In humans, according to the further aspect of the invention, it is used as an extracting agent. Or a pharmaceutically acceptable salt thereof, the use of the formula (I) in the production of an anti-proliferative effect in a warm-blooded animal. In human sputum, in accordance with this aspect of the invention, the feature is provided A compound of the formula (I), or a pharmaceutically acceptable pharmaceutically acceptable agent thereof, is used in a warm-blooded animal such as a human: in a further aspect according to the invention, in &amp; antibiotic &amp; ^ Providing the use of 々rn as defined herein or a pharmaceutically acceptable compound thereof, in a blood-stained animal such as a human, for the purpose of producing a cell dying effect. In this aspect, the advancement characteristic of Niuyi is to provide a compound of the formula 1 as defined herein or a pharmaceutically acceptable salt thereof for use in the manufacture of an agent, which is in a warm-blooded animal such as a human^ Negative for the purpose of producing a cell dying effect. According to a further feature of the present invention, there is provided a use of a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof, which is in the form of a warm blood. Animals such as human cards, Yu, ' ρ And/or for the treatment of proliferative diseases such as cancer as an anti-invasive agent. According to a further feature of this aspect of the invention, there is provided a warm-blooded animal wall such as Λ #s山士 in need of treatment 137081 &gt; 138-201002697 For example, a method for producing an anti-proliferative effect in humans, 1 administering an effective amount to the animal, including a salt of a scientifically acceptable salt, a compound of the formula (!), or a drug thereof according to this aspect of the invention - The characteristics of the step are the warm-blooded animals such as humans in the treatment of ^ 要 要 要 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Administration of an effective amount of a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, in accordance with the aspect of the invention, in the form of formula (I) as defined herein. The use of a salt which is acceptable for the manufacture of a medicament for the prevention or treatment of a proliferative disease, such as cancer, in a warm-blooded animal such as a human. According to a further feature of this aspect of the invention, there is provided Need treatment A method of preventing or treating a proliferative disease, such as cancer, in a warm-blooded animal, such as a human, comprising administering to the animal an effective amount of a compound of formula 1 as defined herein or a pharmaceutically acceptable salt thereof. In a step, a compound of formula (1), or a pharmaceutically acceptable salt thereof, as defined herein, for use in the prevention or treatment of a grasping (10) kinase and/or one or more PI3 K enzymes (such as species Ia enzymes and/or species) The inhibition of PI3K enzymes is a sensitive tumor involving a message transduction step that results in the ability of tumor cells to develop, survive, invade and migrate. A further feature of this aspect of the invention provides a definition as defined herein Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis or treatment of mT0R kinase and/or one or more PI3K enzymes (eg, species la enzyme and/or species Ib ΡΙ3Κ) The inhibition of the enzyme is a sensitive tumor of 137081-139-201002697, which is involved in a signal transduction step that leads to the proliferation, survival, invasion and migration of tumor cells. According to a further feature of this aspect of the invention, there is provided a method of preventing or treating a tumor which is sensitive to inhibition of mTOR kinase and/or one or more PI3K enzymes, such as the species 匕 匕 enzyme and/or the species lb PI3K enzyme, A signal transduction step involving the ability to cause proliferation, survival, invasion and migration of tumor cells, the method comprising administering to the animal an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof . According to a further aspect of the invention there is provided a pharmaceutically acceptable salt of formula (1), or a pharmaceutically acceptable salt thereof, as defined herein, for use in providing mTOR kinase inhibition and/or PI3K enzyme inhibition (eg, species Ia pi3K enzyme or species) Than 3 Κ enzyme inhibition). According to a further feature of this aspect of the invention, there is provided the use of a compound of formula 0), or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament, wherein the KX drug regimen is for providing mTOR kinase inhibition and/or Enzyme inhibition (such as the species IapI3K enzyme or species IbpI3K enzyme inhibition). According to the further steps of the present invention, there is also provided a method for providing (10) kinase inhibition and/or PI3K enzyme inhibition (such as species L-enzyme or enzyme inhibition), which comprises administering an effective amount such as A compound of formula I or a pharmaceutically acceptable salt thereof. According to a further feature of the invention, there is provided a compound as defined herein, or a pharmaceutically acceptable pharmaceutically acceptable salt thereof, for use in the treatment of cancer, disease, inflammatory disease, stomata , immune disease or cardiovascular disease. According to a further feature of the present invention, there is provided a chemical compound 137081 '140-201002697 or a pharmaceutically acceptable salt thereof as defined herein for use in the treatment of solid tumors, such as carcinoma human sarcoma, and leukemia and lymphoid malignancy. Illness. According to a further feature of the present invention, there is provided a compound as defined herein, a compound of the formula & H, which can be used to treat breast, colorectal, lung (i small cell lung cancer, # small cell lung cancer and branches). Tracheal lung cancer) and cancer of the prostate. A further feature according to the invention is a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of the bile duct, bones, bladder and kidney, kidney, liver, gastrointestinal Tissue, esophagus, nest, pancreatic skin, testicular, thyroid, uterus, cervix and vaginal cancer, disease (including ALL and CML), multiple myeloma and lymphoma. A further feature according to the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of cancer, inflammatory diseases, obstructive airway diseases , immune disease or cardiovascular disease. According to a further feature of the invention there is provided a use of a compound of formula 1 as defined herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a solid tumor, chain ~ 腥翩 3 such as carcinoma and sarcoma , and leukemia and lymphoid malignant disorders. A further feature according to the invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for the treatment of breast 'colon I, lung (including Small cell lung cancer, non-small cell lung cancer and bronchial tuberculosis) and cancer of the prostate. According to a further feature of the invention, there is provided a method for the manufacture of a medicinal salt of the formula 137081 • 141 - 201002697 as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a biliary, bone, Bladder, head and neck, kidney, liver, intestine group: esophagus, nest, pancreas, skin, sputum, thyroid, sylvestre, and vaginal cancer, and leukemia (including ALL and multiple) Sexual myeloma and lymphoma. According to the further feature of the present invention, it is provided to treat cancer, inflammatory diseases, obstructive airway diseases, immune diseases or cardiovascular diseases in warm animals 3 such as humans in need of treatment; A method of cultivating a genus, which comprises administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined. A method of treating solid tumors, such as carcinomas and sarcomas, and leukemias and lymphoid malignancies, in a warm-blooded animal in need of treatment, such as in humans, comprising administering an effective amount of a compound of formula (I) as hereinbefore defined, or A pharmaceutically acceptable salt. According to a further feature of the present invention, a breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer, and a branch) is provided in a warm-blooded animal such as a human in need of treatment. A method of cancer of the tracheal lung cell carcinoma and a prostate comprising 'administering an effective amount of a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof. According to further features of the invention, there is provided a need Treated warm-blooded animals such as human towels' treatment of bile ducts, bones, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, nest, pancreas, skin, testicles, thyroid, uterus, cervix and women A method of vaginal cancer, and white ▲ disease (including ALL and CML), multiple myeloma, and lymphoma, comprising administering an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof 137081 -142· 201002697 As stated herein, the in vivo action of a compound of formula (i) can be formed by one or more compounds in a human or animal body after administration of a compound of formula 1 The invention relates to a combination therapy, wherein the compound of the formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising the compound of the formula (I), and another compound for controlling an oncological disease The treatment is administered simultaneously or sequentially or in combination. In particular, the treatment as defined herein may be administered alone or in addition to a compound of the invention, may involve conventional surgery or radiation therapy or chemotherapy. It can be used in combination with existing therapeutic agents to treat cancer. Suitable agents for use in combination include: _ (i) anti-proliferative/anti-tumor drugs and combinations thereof, such as those used in medical oncology, such as alkyl Chemical agents (such as cisplatin, chloramphenicol, cyclophosphamide, nitrogen mustard, amphetamine, chlorambucil, chulphan, and nitrosourea) Antimetabolites (eg, antifolates, such as pyrimidines, such as 5-fluorouracils) and tegafur, mlmrexed, amines, arab Cytidine, hydroxyurea, and gemdtabine; anti-tumor antibiotics (eg, anthracyclines such as adriamycin, bleomycin, dextromycin, doxorubicin, erythromycin) , idadamycin, mitomycin-C, dydtinmycin and mithramycin); anti-silk knife cracking sword (such as periwinkle plant test, such as vincristine, periwinkle test, vinca , with vin〇relbine and yew-like substances, such as pachtaxel (pachtaxel) and yew sage (garby); and topoisomerase inhibitor 137081 201002697 (eg Epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan, and euphorbia; (ii) cytostatics, Such as anti-estrogen (such as tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptor a lower regulator (such as fulvestrant), an antiandrogen (such as dicamtoin (bicalutami) De), flutamide, nilutamide and progesterone acetate, LHRH antagonists or LHRH activators (eg goserelin, suri) Lin (leuprorelin) and buserelin (buserelin), progesterone (such as megestrol acetate), aromatase inhibitors (such as anastrozole, letrozole, glass Inhibitors such as vorazole and exemestane and 5 α-reductase, such as finasteride; (iii) anti-invasive agents (eg c-Src kinase family inhibitors) , for example, 4-(6-chloro-2,3-indenyldioxyanilino)-7-[2-(4-mercaptohexahydropyrylene-1-yl)ethoxy]-5-tetra Hydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-nonylphenyl)-2-{6-[4-( 2-Hydroxyethyl)hexahydropyrrolidin-1-yl]-2-mercaptopyrimidin-4-ylamino p-pyrazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors, such as marimastat and urine (iv) inhibitor of the function of the enzyme plasminogen activator receptor; (iv) inhibitor of growth factor function: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (eg, anti-erbB2 antibody history) Tumma 137081 - 144- 201002697 Erstuzumab [HerceptinTM] and anti-erbBl antibodies some cetuximab [C225]); such inhibitors also include, for example, glutamate kinase inhibitors, such as epidermal growth Inhibitors of factor populations (eg, EGFR group tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-N-morpholinylpropoxy) ) quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-decyloxyethoxy quinine sitting _4_amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-carbyl-4-fluorophenyl)-7-(3-? Linke propoxy quinidine p-lin-4-amine (CI 1033), and erbB2 glutamine kinase inhibitors, such as lapatinib, inhibitors of hepatocyte growth factor population, small plate Inhibitors of derived growth factor populations, For example, imatinib is an inhibitor of serine/threonine kinase (eg, Ras/Raf signaling inhibitors such as farnesyltransferase inhibitors such as sorafenib (BAY) 43-9006)), and inhibitors of cells signaling through MEK and/or Akt kinase; (v) anti-angiogenic agents, such as those that inhibit vascular endothelial growth factor [eg, anti-vascular endothelial growth factor] The antibody bevacizumab (AvastinT M), and the VEGF receptor glycinate kinase inhibitor, such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7- (1-methylhexahydropyridin-4-ylindoleoxy)quinazoline (ZD6474; Example 2 in WO 01/32651), 4-(4-fluoroyl-2-indenyl-5-- Benzyl)-6-decyloxy-7-(3-tetrahydropyrrol-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00/47212), Vitalanib ( Vatalanib) (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds that act by other mechanisms (eg, linomide, integrin αν) /53 functional inhibitors and blood production 137081 -145 - 201002697 tubulogenin); (vi) vascular injury agents, such as the windmill bacteriocin A4, and international patent application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224 a compound disclosed in WO 02/04434 and WO 02/08213; (vii) an anti-significant therapeutic agent, for example, for the subject matter listed above, such as ISIS 2503, an anti-ras anti-significant; (viii) Gene therapy pathways, including pathways to replace the amnestic gene, such as the p53 or the BRCA1 or BRCA2, GDEPT (gene-guided enzyme prodrug therapy) pathway, such as the use of cytosine deaminase, thymidine kinase or Bacterial nitroreductase, and ways to increase patient tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; and (ix) immunotherapeutic approaches, including increasing the immunity of tumor cells in vitro In vivo pathways, such as infection by cytokines, such as interleukocytokinin 2, interleukocytokinin 4 or granulocyte-maize cell colony stimulating factor, reducing T-cell energy pathway, using transfection immunity fine (For example, cytokine transfected dendritic cells) of the pathway, using cytokine transfected K. Pathway of transfected tumor cell lines and anti-genetic pathways of antibody used. [Embodiment] The present invention will now be further explained with reference to the following illustrative examples. Unless otherwise stated, the starting materials are commercially available. All solvents and commercially available reagents are laboratory grade and are used as soon as they are received. In these examples, the 1 H NMR spectra were recorded on a Bruker DPX 300 (300 MHz), Bruker DRX 400 (400 MHz) instrument, or Brnker DRX 500 (500 MHz) instrument. The central absorption peak of chloroform-d (δΗ7·27 ppm), dimethyl hydrazine _d6 (5H2.50 ppm) or C 137081 201002697 ketone-d6 (5h 2.05 ppm) was used as an internal reference. The following abbreviations have been used: s, singlet; d, doublet; t, triple bee; q, quadruple; m, multiplet; br, broad. Column chromatography was performed using tannin (0.04-0.063 mm, Merck). In general, a Kromasil KR-100-5-C18 reverse phase column (250 X 20 mm, Akzo Nobel) was used in the preparative HPLC using a mixture of ethyl acetate f and water [containing 0.1% trifluoroacetic acid ( TFA)] as a dissolving agent at a flow rate of 10 ml/min. The following methods were used for liquid chromatography (LC) / mass spectrometry (MS) analysis: -HPLC: Agilent 1100 or Waters Alliance HT (2790 &amp; 2795) mass spectrometer: standard HPLC used in Waters ZQ ESCi HPLC column The column is Phemonenex Gemini C18 5 microns, 50 x 2 mm. The mobile phase used in the acidic HPLC method is: mobile phase A: water mobile phase B: acetonitrile mobile phase C: 1% citric acid at 50: 50 water:

The MeCN (v/v) method was then quickly balanced, using a flow rate of 5 ml for 0.45 minutes. Four general HPLC methods are available: 5 minutes to monitor the acid method 137081 -147- 201002697 time / minute mobile phase A : mobile phase B : mobile phase C : curve flow rate / ml / min 0.00 95 0 5 1 1.1 4 0 95 5 6 1.1 4.5 0 95 5 6 1.1 Early Acidic Method for Early Dissolved Compounds Time/Min Mobile Phase A: Mobile Phase B: Mobile Phase C · Curved Flow Rate / mL/min 0.00 95 0 5 1 1 1.1 4 57.5 37.5 5 6 1.1 4.5 57.5 37.5 5 6 1.1 Intermediate Acidity Method for Intermediate Dissolved Compounds Time/Min Mobile Phase A: Mobile Phase B: Mobile Phase C · Curved Flow Rate / mL/min 0.00 95 0 5 1 1.1 0.01 67.5 27.5 5 6 1.1 4.5 27.5 67.5 ~ 5 6 1.1 Late Acidic Method for Late Dissolved Compounds Time/Min Mobile Phase A: Mobile Phase B: Mobile Phase C: Curved Flow Rate / mL/min 0.00 95 0 5 1 1.1 0.01 27.5 67.5 5 6 1.1 4.5 5 95— g- 6 1.1 137081 -148- 201002697 Alkaline HPLC method In some cases, the compound ionization pseudo-alkaline HPLC method is a standard acidic method may not be suitable for either Chromatographic separation. In this case, four can be used. Mobile phase A ·· Water The mobile phase used is mobile phase B: Mobile phase D: Rapid equilibrium is achieved, using a flow rate of 5 ml, followed by 0.45 minutes for each method. Acetonitrile in 0.1% 880 ammonia in acetonitrile. Alkaline method - -. / min. mobile phase A: mobile phase B: mobile phase C: curve flow rate / - one 0.00 λ ml / min 95 0 5 1 1.1 4 0 95 1 5 6 1.1 4.5 0 95 5 6 1.1 Early alkaline method for early dissolution of compounds Time / minute Mobile phase A : Mobile phase B : Mobile phase C : Curve flow rate / ml / min 0.00 ' ----- --- — 95 0 5 1 1.1 4 57.5 37.5 5 6 1.1 4.5 57.5 37.5 5 6 1.1 Intermediate intermediate method for intermediate dissolved compounds

137081 -149- 201002697 time / minute

5 5 5 Late Alkaline Square Curve for Late Dissolved Compounds Mobile Phase C : 6 6

Method Time/minute Mobile phase A: Mobile phase B: Mobile phase C: 0.00 95 0 0.01 5 27.5 4.5 67.5 6 5 95 5 The following method is used for liquid chromatography (LQ/quality and 6 curves)

_ [S) Analysis: - State: Agilent 1100; Column: Waters „Symmetry&quot; 21 x 3〇mm; Bayer 曰, using chemical ionization (APCI); flow rate: 0.7 ml/min; absorption wavelength .254 nm; solvent A: water + 〇1% TFA; solvent b: bra 0.1% TFA, solvent gradient: 15_95% solvent B' over 2 7 minutes, followed by 95% solvent B over 3 minutes. The following methods were used for LC analysis: _ Method A: - Instrument: Agilentll 〇〇; Column: Cardiac also (10) Reverse phase gel, Qing X 3 house rice, 5 micron particle size; Solvent a: 〇 1% TFA/ Water, solvent & please % acetonitrile; material: 1 ml / min; solvent gradient: KM00% cold d B, after 20 minutes 'then 1% solvent B, after 丨 minute; absorption wavelength · 220, 254 And 280 nm. In general, the retention time of the product is noted. 137081 -150- 201002697 Method B: - Instrument: Agilent 1100; Column: Waters &quot;Xterra&quot; C8 reverse phase silicone, 100 x 3 mm, 5 micron particle size; solvent A: 0.015 M ammonia in water, solvent B: acetonitrile: flow rate: 1 ml/min, solvent gradient 10-100% solvent B over 20 minutes followed by 100% solvent B over 1 minute; absorption wavelengths: 220, 254 and 280 nm. In general, the retention time of the product is noted. Or in the following illustrative examples: -HPLC high performance liquid chromatography HBTU hexafluorophosphate 0-(benzotriazol-1-yl)-N,N,N',N'-tetradecylhydrazine; HATU hexafluorophosphate 0-(7-azabenzotriazol-1-yl) Changfan 1^,1^'-tetradecylhydrazine; HOBT 1-hydroxybenzotriazole; HOAT 1-hydroxy-7-nitrogen Benzotriazole; NMP N-methyltetrahydroindole-2-one; DMSO diterpenoid; DMF hydrazine, hydrazine-dimercaptoamine; DMA hydrazine, hydrazine-dimethylacetamide; THF tetrahydro ρ is deactivated; DME 1,2-dimethoxy ethane; DCCI dicyclohexylcarbodiimide;

MeOH methanol;

MeCN acetonitrile; DCM di-methane; DIPEA N,N-diisopropylethylamine; DBU 1,8-diazabicyclo[5.4.0]undec-7-ene; 137081 -151 - 201002697 RT room temperature ( Approximately 17 to 25 ° C); tR residence time; m / z mass / charge ratio.

Chemical names are generated by software using Lexichem ToolKit (version 1.60) from OpenEye Scientific Software (www.eyesopen.com) to produce IUPAC suitable names. Example 1: 3-Cyclopropyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl] Phenyl]thiourea

Diimidazole-1-yldecanethione (55 mg, 0.28 mmol) was dissolved in DCM (1 mL) and the solution was added to 4-[4-[(3S)-3- Methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenylamine (100 mg, 0.28 mmol) in a stirred solution in DCM ( 1.5 mL). After stirring for 90 minutes, triethylamine (0.039 ml, 0.28 mmol) and cyclopropylamine (0.096 ml, 1.38 mmol) were added, and the mixture was stirred at room temperature for 2 hr. The reaction was evaporated to dryness and purified by flash chromatography eluting with EtOAc EtOAc This material was further purified by preparative HPLC to give the desired material as a white solid (60 mg). NMR spectrum: NMR (400.13 MHz, DMSO-d6) 5 0.58-0.62 (2H, m), 0.74-0.79 (2H, m), 1.25 (3H, d), 3.21 (3H, s), 3.23-3.28 (1H , m), 3.48-3.54 (1H, m), 3.64-3.68 (1H, m), 3.78 (2H, d), 3.97-4.01 (2H, m), 4.18 (1H, d), 4.51 (2H, s ), 6.83 (1H, s), 7.62-7.65 (2H, m), 8.25-8.29 (2H, m), 9.52 (1H, 137081 -152- 201002697 S) LCMS spectrum: MH+ 462, retention time 165 minutes, method Monitoring of Acids The following compounds were prepared in a similar manner from 4_[4-[(3s)_3-pyringyl]4-4-yl]-6-(methylsulfonylfluorenyl) σ-mididine-2-yl]aniline Suitable amine. Example structure name LCMS MH+ _____ Residence time (minutes) la* a Η H 3-ethyl-l-[4-[4-[(3s)-3_methylmorpholin-4-yl]-6-(曱石Astragalus sulfhydryl-pyridyl-2-yl]phenyl]thiourea 450 1.70 lb [X Qp jfS Η H l-[4-[4-[(3S)-3-methylmorphin-4-yl]- 6-(Methyl decyl) hydrazin-2-yl]phenyl]-3-phenyl-thiourea 498 2.07 lc [X ' slAaAj〇r. Η H 3-(4-曱-Oxophenyl)-1-[4-[4-[(3S)-3-indolylmorpholin-4-yl]-6-(indolyl sulfhydryl)pyrimidine -2-yl]phenyl]thiourea 528 2.01 Id Ow Η H 3-(4-fluorophenyl)-1-[4-[4-[(3S)-3-indolylmorpholin-4-yl] -6-(nonylsulfonylmethyl)pyrimidin-2-yl]phenyl]thiourea 516 2.09 *Unpurified HPLC purification example la ·· 1 H NMR (400.13 MHz, DMSO-d6) &lt;5 1.14 (3Η,〇, 1.25 (3Η, d), 3.21 (3H, s), 3.23-3.27 (1H, m), 3.48-3.53 (2H, m), 3.50-3.54 (1H, m), 3.64-3.67 ( 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.15-4.19 (1H, m), 4.50 (3H, s), 6.82 (1H, s), 7.56-7.59 (2H, m), 7.89 (1H, s), 8.25-8.29 (2H, m), 9.63 (1H, s) 137081 -153- 201002697 Example lb: 1 H NMR (400.13 MHz, DMSO-d6) 5 1.25 (3H, d ),3·21 (3H, s), 3.24 (1H, m), 3.48-3.54 (1H, m), 3.64-3.68 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m ), 4.18 (1H, d), 4.50 (2H, s), 4.51 (1H, s), 6.83 (1H, s), 7.12-7.17 (1H, m), 7.32-7.37 (2H, m), 7.51 ( 2H, s), 7.66 (2H, s), 8.27-8.30 (2H, m), 9.89 (1H, s), 9.98 (1H, s) Example lc : 1 H NMR (400.13 MHz, DMSO-d6) 5 1 .25 (3H,d), 3.21 (3H, s), 3.24 (1H, m), 3.48-3.54 (1H, m), 3.64-3.68 (1H, m), 3.76 (3H, s), 3.78 (1H , d), 3.97-4.01 (1H, m), 4.18 (1H, d), 4.50 (2H, s), 4.51 (1H, s), 6.82 (1H, s), 6.90-6.94 (2H, m), 7.36 (2H, d), 7.65 (2H, d), 8.28 (2H, d), 9.71 (1H, s), 9.83 (1H, s) Example Id: 1 H NMR (400.13 MHz, DMSO-d6) &lt; 5 1.25 (3H, d), 3-21 (3H, s), 3.24 (1H, d), 3.48-3.54 (1H, m), 3.64-3.68 (1H, m), 3.77 (1H, d), 3.97 -4.01 (1H, m), 4.18 (1H, d), 4.51 (2H, s), 4.51 (1H, s), 6.83 (1H, s), 7.15-7.21 (2H, m), 7.46-7.52 (2H , m), 7.63-7.69 (2H, m), 8.28-8.32 (2H, m), 9.85 (1H, s), 9.99 (1H, s) 4-[4-[(3S)-3-曱?淋-4_基]_6_(甲石黄醯基 methyl). The preparation of succinyl-2-phenylaniline is described below. 4-[4-[(3S)-3.methylmorphin-4-yl]·6-(methyl mercaptomethyl) gnat_2_yl]aniline

Making N-[4-[4-[(3S)-3-methylmorpholine_4_yl]_6_(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]carbamic acid tert-butyl ester (1,09 g, 2.35 mmol) was dissolved in methanol (5 mL) and EtOAc (5 mL). The solution was 137081 - 154 - 201002697 伩' and the mixture was evaporated to a dark brown oil and dissolved in ethyl acetate (10 I, EtOAc, EtOAc). Water (5 ml) was added, followed by the addition of the carbonated air-span until the neutral pH was reached (~2 mL). The liquid phase was separated and washed with water (10 ml); The organic layer was dried over magnesium sulfate and evaporated to a pale yellow foam (8 EtOAc). NMR ^ ^ : « H NMR (399.9 MHz, DMSO-d6) 5 1.23 (3H, d), 3.31 (3H, s), 3.5 (1H, m), 3.64 (1H, m), 3.78 (1H, m) , 4.13 (1H, m), 4.49 (2H, m), 5.57 (2H, s), 6.61 (2H, d), 6.68 (1H, s), 8.08 (1H, d) LCMS spectrum: MH+ 363, residence time (10) minutes, method 5 minutes acid N. [4-[4-[(3S)-3-methyl phenanthrene _4_yl]_6. (Aminomethyl) epoxide-yl]phenyl]amine Third vinegar

\ 2-Benzyl-4-[(3S)-3-methylmorpholine-4-yl]_6_(nonylsulfonylmethyl)pyrimidine (1.0 g, 3.27 mmol) dissolved in 18% DMF 7:3:2 DME: water: ethanol ml) in the solution in the mixture. Then '[4-7-methylpropan-2-ylcarbonylcarbonylamino)phenyl]dihydroxyborane (1.165 g, 4.91 mmol), 2 m sodium carbonate solution (4 ml) and two Chlorobis(triphenylphosphine)palladium catalyst (115 mg, 016 mmol) was added to the solution and refluxed for 5 hours under nitrogen atmosphere and 9 (rc. The reaction was allowed to cool to room temperature) followed by ethyl acetate The liquid is treated with water. The organic matter is dehydrated and dried with magnesium sulfate, filtered, and concentrated to dry wine. The crude oil/valley is burned in a milk emulsion and filtered to remove insoluble matter. The yellow solid precipitated from the filtrate and the filtrate was filtered again. The solid was analyzed, 137081 - 155 - 201002697 and excess dihydroxyborane was found and the filtrate contained the product and a portion of the impurities. Purification by chromatography, eluting with 〇4 〇% ethyl acetate to give the desired compound as orange oil (530 mg). LCMS spectrum: MH+ 463 </ </ RTI> retention time 2.23 minutes, method 5 minutes acid 2-Alkyl-4-[(3S)-3.indolylmorpholine-4-yl]-6-(methylsulfonylfluorenyl)pyrimidine

2,4-Dichloro-6-(methylsulfonylmethyl)glycine (3 g, 〇13 mol) was dissolved in dioxane and dropped (under nitrogen). Triethylamine (17.4 mL, 0.13 mol) was added to give a clear brown solution. (3S)_3 methylmorpholine was dissolved in methylene chloride and added dropwise, keeping the reactant below _5 °C. Then, the cooling bath was removed, and the mixture was stirred for 1 hour. The reaction mixture was heated to 2% by volume under reflux, and then the reaction mixture was washed with water, dried over water, and evaporated. The crude material was purified by preparative HPLC to give the desired material (19.3 g). NMR spectrum: NMR (400.13 MHz, DMSO-d6) 5 1.21-1.23 (m, 3H), 3.11 (s, 3H), 3.19-3.26 (m, 1H), 3.42-3.49 (m, 1H), 3.58-3.62 (1H, m), 3.73 (d, 1H), 3.92-3.96 (m, 2H), 4.27-4.31 (m, 1H), 4.45 (s, 2H), 6.92 (s, 1H) LCMS spectrum: MH+ 306, Retention time L42 minutes, method 5 minutes acid 2,4-digas·6·(methylsulfonyl fluorenyl) pyrimidine bite

6-(Methanesulfonylfluorenyl)-1 fluorenyl-2,4-dione (132 g, 0.65 mol) was added to a chlorinated dish (1.2 L), and the mixture was heated to reflux. w 137081 -156- 201002697 hours, then cool to room temperature. The excess chlorinated dish was removed in vacuo and the residue was azeotroped with toluene (2 x 500 mL) and dissolved in dichloromethane. Next, the mixture was slowly poured onto ice (4 L) and stirred for 2 min, then with dichloromethane (3 x liters) (filtering out insoluble black material and discarding) with ethyl acetate (2) X 丨)) extraction. The extracts were combined, dehydrated and dried, then the residue was taken to give a desired material. This material was used without further purification. NMR spectrum: η 职 (micro 13 jobs, DMS 〇d6) accounted for 3 13 &amp;, Qiu, * 79 (s, 2H), 7.87 (s, 1H) ' LCMS spectrum: MH+ 239, residence time (3) minutes, method 5 minutes acid 6-(Aminomethyl)-ιη·Umidine 2,4_dione

6-(Chloromethyl)_1 Η pyrimidine _2 piperidinone (175 g, 丨〇 9 mol) was dissolved in DMF (2 liters), and added copper sulphate (1) gram, (3) Mo ear). The reaction was heated to 12 Torr for 2 hours, then allowed to cool, and the suspension was dried and concentrated in vacuo to afford a yellow solid. The crude material was washed with water &apos;filtered&apos; (d) developed in toluene. The solid was filtered and then triturated with isohexane to leave the desired compound as a yellow solid (g). This material was used without further purification. 6-(Gasylmethyl)-1 Heart-biting-2,4_2 is a commercially available substance. 2_Chloro-based winter coffee)-3-methylmorphine-based] Winter (methyl hydrazinomethyl (tetra) pyridine can also be produced by the method described below. 2-Alkylmethyl lining_4_ Base (methyl group) (four) 137081 -157- 201002697

Stir under 24 hours. The organic layer *3 ' was combined and the resulting solution was washed at 85 ° C with water (3 X 1 mL) to

The MgS(R) 4 was dehydrated, filtered, and the solvent was removed by evaporation to give a crude product as a dark brown oil which solidified (36g). The crude solid was purified by flash chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) 2.·Air-based 4-(mothylmethyl)-6-[(3S)-3-methyl-line.4·yl] pain bite Ο

Yu Yu. (: and under nitrogen, chlorinated methane sulfonate (0.245 ml, 3.14 mmol) was added dropwise to diethylene (〇, 875 ml, 6.28 mmol) and [2- gas-based-6-[( 3S)-3-Methylmorpholin-4-yl]pyrimidinyl]nonanol (51 mg, 2 〇9 mmol) in DCM (30 mL) over a period of 5 min. The resulting solution was stirred at room temperature for 45 minutes. The reaction mixture was diluted with water (20 mL). The organic layer was dried and dried (MgS04) and filtered. Sodium iodide (1569 KK ' 10.46 house Moule) was added and The reaction was heated to 5 ° C for 2 hrs. The reaction mixture was filtered and evaporated to give the desired material (761 mg). NMR Spectrum: NMR (400.132 MHz, DMSO) 5 1.19-1.25 (3H, m), 3.18-3.22 (1H, m), 3.40-3.47 (1H, m), 3.57-3.60 (1H, m), 3.71 (1H, d), 3.90-3.94 (1H, m), 3.96-3.98 (1H, m ), 4.28-4.32 (3H, m), 6.94 (1H, s). 137081 -158- 201002697 LCMS Spectrum: m/z (ESI+) (M+H)+ = 354 ; HPLC tR = 2.10 min 2-chloro -4-(Butylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]-pyridine can also be made in the following manner' [0-Chloryl winter [C3S&gt;3. Mercaptoin turf base] is added dropwise to gasification methane (91 ml, 1169.52 mmol) to DCM (2293 ml) at 0 °C under air. ; pyridine-4-yl] sterol (190 g, 779.68 mmol) and triethylamine (163 ml, 1169.52 mmol). The resulting solution was slowly warmed to room temperature for 4 hours. During the period, the reaction mixture was quenched with water, and the mixture was taken up in DCM and the organic layer was dehydrated and dried with &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&& -Methyl-P-Phen-4-yl]»Mispin-4-yl]methyl ester as a yellow gum (251 g). Add sodium iodide (234 g, 1567.07 mmol) to acetone (3679 ml) In the material, and the resulting suspension was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness and redissolved in DCM and then washed with th. The organic layer was dried over MgSO4, filtered, and evaporated to give the crude product (270 g) which was purified by chromatography to give an off-white solid. The preparation was carried out to obtain the desired substance, which was the same as the aforementioned sample. [2·Gas-6-[(3S)-3-methyl?vrlin_4·yl]]- pyridine. 4-yl]methanol

2-Chloro-6-[(3S)-3-methylmorphin_4_yl]. Bite-4-Resinolate (3.15 g) was dissolved in dry THF (20 mL) and cooled to EtOAc. The hydride solution (2.0 M in THF, 6.09 ml) was added dropwise, and the solution was warmed to room temperature and stirred for 1 hour. The reaction was quenched with water (20 mL) then evaporated EtOAc EtOAc EtOAc 〇 ml) wash. The organic material was evaporated and dried to give the desired material as white solid (2.44 g). NMR spectrum: NMR (400.132 MHz' DMSO) 5 1.20-1.21 (3H, m), 3.18-3.22 (1H, m), 3.40-3.47 (1H, m), 3.56-3.60 (1H, m), 3.71 (1H , 3.91-3.94 (1H, m), 3.98 (1H, d), 4.35 (3H, d), 5.51 (1H, t), 6.74 (1H, s). Mass spectrometry; M+H+244.

[2-Chloro-6-[(3S)-3-methyl?4-4-yl]n-melidine_4_yl]methanol can also be prepared by the following method: at 0 ° C, added dropwise Lithium borohydride (2M in THF) (454 mL, 908.17 mmol) to 2-carbyl-6-[(3S)-3-methylmorpholinopiperidin-4-carboxylic acid oxime ester ( 235 g, 864.92 mmoles in a solution of THF (4701 mL) over a period of 15 min. The mixture was stirred at room temperature for 2 hours, then water (1500 ml) was slowly added. A white solid formed which was decanted to facilitate removal of the THF under vacuum. More water (5 mL) was added to the residue and extracted with ethyl acetate (3×EtOAc). The combined organic materials were washed with brine and dried over <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2-Alkyl-6-[(3S)-3-methyloran·4·yl] mouth bite-4-carboxylic acid methyl vinegar

Methyl 2,6-di-pyrimidine-4-carboxylate (5 g) was dissolved in DCM (120 mL). (3S)_3-methylmorpholine (2.49 g), which had been dissolved in triethylamine (3. 70 ml) and DCM (10 ml), was added dropwise to the solution over 10 min. The reaction was left to stir at room temperature for 1 hour. The reaction was then evaporated to dryness and EtOAc EtOAc EtOAc (EtOAc) The organic material was washed once with water (150 mL) and dried (MgSO4), filtered and evaporated. The crude material was chromatographed on EtOAc EtOAc (EtOAc) NMR spectrum: 1 H NMR (400.132 MHz, DMSO) 5 1.22-1.24 (3H, m), 3.25 (1H, d), 3.41-3.48 (1H, m), 3.57-3.61 (1H, m), 3.71 (1H , d), 3.87 (3H, s), 3.91-3.95 (1H, m), 4.25 (1H, s), 4.45 (1H, s), 7.29 (1H, s). Mass spectrum; M+H+ 272. 2- Ethyl chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate can also be prepared in the following manner by adding 2,6-di-pyrimidine-4-carboxylic acid Methyl ester (250 g, 1207.65 mmol) to DCM (2500 mL). Triethylamine (185 mL, 1328.41 mmol) was added and the reaction was cooled to 0 °C. (3S)-3-Methylmorpholine (128 g, 1268.03 mmol) dissolved in DCM (300 mL) was added dropwise over 30 min and the mixture was stirred overnight at 5°. Water (800 ml) was added, the mixture was separated, and then aqueous layer was evaporated with DCM The combined organics were washed with brine (300 mL) dried over Et. The crude solid was dissolved in hot ethyl acetate (3 parts by volume), then isohexane (5 parts by volume) was added, and the mixture was left to cool and stirred over the weekend to obtain the desired material as a solid. the same. Example 2: 3-Cyclopropyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidine- 2-yl]phenyl]thiourea

137081 201002697 4-[4-[(3S)-3-indolylmorpholin-4-yl](2-methylsulfonylpropionyl)pyrimidin-2-yl]phenylamine (100 mg, 0.26 mmol) In a solution of 〇〇^ (2 ml), a solution of bis(.moxazol-1-yl)decanethione (5 〇·2 mg, 〇28 mmol) in (ml) The solution was stirred at room temperature for 2 hours. Cyclopropylamine (0.089 cfe liter, 1.28 mmol) was added followed by triethylamine (36 ml, 〇26 mmol) and the solution was stirred at room temperature overnight. The crude product was purified by preparative HPLC using EtOAc (EtOAc: EtOAc) NMR spectrum: W NMR (400.13 MHz, DMSO-d6) (5 0.59-0.62 (2H, m), 0.74-0.79 (2H, m), 1.24 (3H, d), 1.78 (6H, s), 2.90-2.95 (1H, m), 3.04 (3H, s), 3.19-3.25 (1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.96-4.00 (1H, m), 4.22-4.26 (1H, m), 4.59-4.66 (1H, m), 6.78 (1H, s), 7.62 (2H, d), 8.14 (1H, s), 8.29 (2H, d ), 9.51 (1H, s) LCMS Spectrum: m/z (ESI+) (M+H)+ = 490; HPLC tR = 2.08 min. The following compounds are used in a similar manner using the appropriate amine from 4_[4_[( 3S)_3_methylmorpholin-4-yl]-6-(2-oxasulfonylpropan-2-yl)pyrimidin-2-yl]aniline. Example structure name LCMS MH+ residence time (minutes) 2a 3-曱-l-[4-[4-[(3S)-3- 464 h96~~~ Λ 曱 吗 吗 -4- -4-yl]-6-(2- oxasulfonylpropan-2-yl)pyrimidine- 2-yl]phenyl]thiourea 137081 -162- 201002697 2b 0, &quot;A^N1NJ Η H 3-ethyl-l-[4-[4-[(3S)-3-indenyl]3- 4-yl]-6-(2_nonylsulfonylpropan-2-yl)pyrimidin-2-yl]phenyl]thiourea 478 2.14 2c Η H 3-(2-hydroxyethyl)-i_[4- [4-[(3S)-3-indolyl p-Phen-4-yl]-6-(2-oxasulfonylpropan-2-yl) Acridin-2-yl]phenyl]thiourea 494 1.78 2d a 〇. p ii V i human Η H 3-(2-dimethylaminoethyl)_ H4-[4-[(3S)- 3-methylmorphin-4-yl]-6-(2-indigo yellow-propionyl-2-yl)pyrimidin-2-yl]phenyl]thiourea 521 2.08 Example 2a: 1 H NMR ( 400.13 MHz, DMSO-d6) (5 1.24 (3H, d), 1.78 (6H, s), 2.95 (3H, d), 3.04 (3H, s), 3.17-3.25 (1H, m), 3.48-3.53 ( 1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-3.99 (1H, m), 4.24 (1H, d), 4.60-4.65 (1H, m), 6.78 (1H, s), 7.55 (2H, d), 7.85 (1H, s), 8.30 (2H, d), 9.73 (1H, s) Example 2b: 1 H NMR (400.13 MHz, DMSO-d6) &lt;5 1.14 (3H , t), 1.24 (3H, d), 1.77 (3H, s), 1.78 (3H, s), 3.03 (3H, s), 3.18-3.25 (1H, m), 3.47-3.52 (3H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.22-4.25 (1H, m), 4.59-4.65 (1H, m), 6.77 (1H, s), 7.56 (2H, d), 7.88 (1H, s), 8.30 (2H, d), 9.63 (1H, s) Example 2c : 1H NMR (400.13 MHz, DMSO-d6) δ 1.24 (3H,d), 1.78 ( 6H, s), 3.04 (3H, s), 3.17-3.25 (1H, m), 3.47-3.53 (1H, m), 3.57 (4H, s), 3.63-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 ( 1H, m), 4.24 (1H, d), 4.59-4.65 (1H, m), 4.81 (1H, s), 6.78 (1H, s), 7.63 (2H, d), 7.87 (1H, s), 8.30 (2H, d), 9.81 (1H, s) 137081 -163- 201002697 Example 2d: 1 H NMR (400.13 MHz, DMSO-d6) (5 1.24 (3H, d), 1.78 (6H, s), 2.21 (6H , s), 2.45 (2H, t), 3.04 (3H, s), 3.18-3.25 (1H, m), 3.47-3.57 (3H, m), 3.63-3.67 (1H, m), 3.77 (1H, d ), 3.96-4.00 (1H, m), 4.22-4.25 (1H, m), 4.59-4.65 (1H, m), 6.78 (1H, s), 7.65 (2H, d), 7.77 (1H, s), 8.30 (2H, d), 9.90 (1H, s) 4-[4-[(3S)-3-indolylmorpholin-4-yl]-6-(2-oxasulfonylpropan-2-yl) The preparation of phen-2-yl]aniline is described below: 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-oxasulfonylpropan-2- Pyrimido-2-yl]aniline η

Add bis (triphenylphosphine) red (ΙΙ) (〇·287 g, 〇41 mmol) to DMF (15 ml), DME (15 ml), ethanol (15 ml) at room temperature under nitrogen. 2_Chloryl winter [(3S)_3_indolyl morpholine ice-based]_6_(2_methanesulfonylpropan-2-yl)-octidine (2.73 g, 8.18 mmol) in water (37.5 ml) Ear), 4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)aniline (2.329 g, 10.63 mmol) and 2M aqueous sodium carbonate solution ( 15 ml '29.44 millimoles' inside. The reaction was purged with nitrogen for 15 min and the resulting mixture was stirred at 8 ° C for 3 h. The reaction mixture was diluted with ethyl acetate (300 mL) and washed twice with water (15 mL) and saturated brine (15 liters). The organic layer was dried (MgSO.sub.4), filtered, and evaporated to give a crude material. The crude product was purified by EtOAc EtOAc (EtOAc) NMR spectroscopy. NMR (400.13 MHz, DMSO-d6) &lt;5 1.33 (3H, d), 1.87 137081 -164 - 201002697 (6H, s), 2.93 (3H, s), 3.28-3.35 (1H, m), 3.56-3.63 (1H, m), 3.72-3.76 (1H, m), 3.82 (1H, d), 3.90 (2H, s), 4.01-4.05 (1H, m), 4.11-4.15 (1H, m), 4.46-4.53 (1H, m), 6.55 (1H, s), 6.71 (2H, d), 8.21 (2H, d) LCMS Spectrum: m/z (ESI+) (M+H)+ = 391 ; HPLC tR = 2.05 min. 2-Chloro-4-[(3S)-3-methylmorpholine_4_yl]-6·(2_methylsulfonylpropan-2-yl(tetra)pyridine

Add sodium tributoxide (278 mg, 2 89 mmol) to 2-chloro-4-[(3S)-3-methyl in DMF (25 mL). Morpholin-4-yl]-6-(methylsulfonylmethyl)-alkidine (883 mg, 2.89 mmol). Iododecane (0.180 ml, 2.89 mmol) was added and the resulting solution was applied to hydrazine. Stir under the arm for 15 minutes. Additional third sodium butoxide (278 mg, 2 89 mmol) was added followed by methyl iodide (0.180 mL, 2.89 mmol) and the resulting solution was stirred at 0 °C for 1 hour. The reaction was diluted with DCM (100 mL) and washed water (100 mL) The organic layer was dehydrated and dried (MgS 4 ), filtered, and the solvent was evaporated to give a gum, which was slowly dried. The crude product was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) NMR spectrum: H NMR (400.13 MHz, DMSO-d6) (5 1.26 (3H, d), 1.72 (6H, s), 2.87 (3H, s), 3.19-3.27 (1H, m), 3.44-3.51 ( 1H, m), 3.60-3.63 (1H, m), 3.72 (1H, d), 3.92-3.96 (2H, m), 4.23-4.32 (1H, m), 6.53 (1H, s) LCMS Spectrum: m/ z (ESI+) (M+H)+ = 334 ; HPLC tR = 1.95 min. 2-Chloro-4-[(3S)-3-methyloxa-4-yl]-6-(曱石黄醯基甲The basis of the system is 137081 -165 - 201002697. The description is described above. Example 3: 1_[4-[4-[2-(phenylsulfonyl)propan-2-yl]-6-[(3S)- 3.Methylmorpholin-4-yl]pyridin-2-yl]phenyl]-3-methylthiourea

4-[4-[2-(Benzenesulfonyl)propan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (0.091 A solution of bis-(indol-2-yl)methanethione (0.050 g, 0.28 mmol) in DCM (1.0 mL). Inside 'and the resulting solution is shameful. Stir for 3 〇 minutes at C. A solution of the guanamine (2.0 M in THF, 0.5 mL, 1.0 mmol) was then applied and the mixture was stirred at 40 &lt;0&gt;C for 30 min and solvent evaporated. The crude material was purified by preparative HPLC to give the desired material (yield: 63 mg). NMR spectrum: NMR (300.13 MHz, DMSO-d6) 5 1.20 (3H, d), 1.77 (3H, s), 1.78 (3H, s), 2.93 (3H, d), 3.11-3.20 (1H, m), 3.45-3.52 (1H, m), 3.61-3.66 (1H, m), 3.76 (1H, d), 3.94-3.98 (1H, m), 4.14 (1H, d), 4.50-4.59 (1H, m), 6.69 (1H, s), 7.40 (2H, d), 7.46-7.53 (4H, m), 7.61-7.68 (1H, m), 7.78-7.88 (3H, m), 9.73 (1H, s) LCMS Spectrum: m/z (ESI+) (M+H) + 526, HPLC tR = 2.41 min The compound below was prepared in a similar manner using the appropriate amine. -166- 137081 201002697 Example structure name LCMS MH+ residence time (minutes) 3a O', σνΑαΛ force Η Η 1-[4-[4-[2-(cyclosulfonyl)propan-2-yl]-6-[ (3S)-3-methylmorpholine 4-yl]pyrimidin-2-yl]phenyl]-3-cyclopropylthiourea 526 2.55 3b σς'ΑαΛ" Η Η 1-[4-[4-[2 -(stupyl)-propan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-ethylthiourea 540 2.57 3c 0, σ°^Αχι/Η Η Η 1-[4-[4-[2-(phenylsulfonyl)propan-2-yl]-6-[(3S)-3-indenyl]^-4 -yl]0^ ** 1,4-yl]phenyl]-3-(2-hydroxyethyl)thiourea 556 2.16 Example 3a: ]H NMR (300.13 MHz, DMSO-d6) (5 0.56-0.62 ( 2H,m), 0.72-0.78 (2H, m), 1.21 (3H, d), 1.77 (3H, s), 1.78 (3H, s), 2.81-2.99 (1H, m), 3.11-3.22 (1H, m), 3.45-3.52 (1H, m), 3.61-3.66 (1H, m), 3.76 (1H, d), 3.94-3.99 (1H, m), 4.13-4.17 (1H, m), 4.514.59 ( 1H, m), 6.70 (1H, s), 7.40-7.53 (6H, m), 7.62-7.68 (1H, m), 7.84 (2H, d), 8.14 (1H, s), 9.48 (1H, s) Example 3b: 1H NMR (300.13 MHz, DMSO-d6) (5 1.13 (3H, t), 1.20 (3H, d), 1.77 (3H, s), 1.78 (3H, s), 3.11, 3.22 (1 H, m), 3.43-3.51 (3H, m), 3.61-3.66 (1H, m), 3.76 (1H, d), 3.94-3.99 (1H, m), 4.11-4.16 (1H, m), 4.51- 4.58 (1H, m), 6.69 (1H, s), 7.41 (2H, d), 7.46-7.53 (4H, m), 7.62-7.68 (1H, m), 7.85 (3H, d), 9.62 (1H, s) Example 3c: 1H NMR (300.13 MHz, DMSO-d6) δ 1.20 (3H, d), 1.77 (3H, s), 1.78 (3H, s), 3.11-3.21 (1H, m), 3.44-3.50 ( 1H, m), 3.52-3.58 (4H, m), 137081 -167- 201002697 3.60-3.67 (1H, m), 3.76 (1H, d), 3.94-3.98 (1H, m), 4.08-4.16 (1H, m), 4.50-4.59 (1H, m), 4.84 (1H, s), 6.69 (1H, s), 7.46-7.52 (6H, m), 7.62-7.68 (1H, m), 7.83-7.87 (3H, m), 9.79 (1H, s) 4-[4-[2-(phenylsulfonyl)propan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine- The preparation of 2-yl]aniline is described below: 4-[4-[2·(phenylsulfonyl)propan-2-yl]-6-[(3S)-3-methylmorpholine-4-yl Octa-2-yl]aniline

Add sodium carbonate (2M in water) (3.21 mL, 6.43 mmol) to a mixture of DME (8.0 mL), ethanol (4 mL), DMF (4 mL) and water (4.0 mL) 4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)aniline (391 mg, 1.79 mmol) and 4_[2_(phenylsulfonate) Base) propioni-2-yl]_2-chloro-6-[(3S)-3-methylmorphin-4-yl]» 密α定 (7〇7 mg, 1.79 mmol). The mixture was degassed and purged with nitrogen three times. (11) (63 mg, 0.09 mmol) of bis(triphenylphosphine) chloride was added and the mixture was degassed and repurified three times with nitrogen. The resulting suspension was stirred at 8 ° C for 3 minutes. The reaction mixture was concentrated and diluted with EtOAc EtOAc (EtOAc) The organic layer was dehydrated with MgS 4 to give a crude product. The crude product was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) '〇 i-33 (3H, d), 1.85 (3H, s), (1H, m), 3.74-3.85 (4H, m),

NMR spectrum: 1 H NMR (300.13 MHz, CDC13) d 1.33 (3H

1·85 (3H, s), 3.25-3.35 (1H, m), 3.58-3.67 (1H 137081 -168- 201002697 4.02-4.07 (1H, m), 4.10-4.15 (1H, m), 4.47-4.50 ( 1H, m), 6.55-6.59 (2H, m), 6.63 (1H, s), 7.30-7.36 (2H, m), 7.45-7.51 (1H, m), 7.53-7.57 (2H, m), 7.74- 7.78 (2H, m) LCMS spectroscopy: m/z (ESI+) (M+H)+ = 453; HPLC tR = 2.22 min 4·[2-(Benzene)propan-2-yl]-2· Carbo 6-[(3S)-3·methyl-p-lin-4-yl] cancer bite

Methyl iodide (0.156 mL, 2-50 mmol) was added to 4-(phenylsulfonylhydrazino)-2-chloro-6-[(3S) in DMF (14 mL) cooled to 0 °C. 3-methylmorpholin-4-yl]pyrimidine (0.920 g, 2.5 mmol) and sodium tributoxide (0.240 g, 2.50 mmol). The reaction mixture was stirred for 10 minutes, then a second equivalent of sodium tris-butoxide (0.240 g, 2.50 mmol) and methyl iodide (0.156 mL, 2.50 mmol). The reaction was allowed to warm to room temperature then stirred for 1 hour. The mixture was diluted with water (50 mL) and DCM (50 mL). The organic layer was separated and washed sequentially with water (2 X 50 mL) and brine (2 X 50 mL). Then, the organic layer was dried (MgS04), filtered, and evaporated to give a crude product. The crude product was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) NMR spectrum: iH NMR (300.13 MHz, CDC13) 5 1.34 (3H,d), 1.75 (3H, s), 1.75 (3H, s), 3.26-3.35 (1H, m), 3.53-3.62 (1H, m) , 3.69-3.74 (1H, m), 3.79-3.83 (1H, m), 4.00-4.05 (2H, m), 4.34 (1H, d), 6.76 (1H, s), 7.45-7.50 (2H, m) , 7.56-7.65 (3H, m) LCMS Spectrum: m/z (ESI+) (M+H) + = 396 ; HPLC tR = 2.46 min 137081 -169- 201002697

4-(phenylsulfonylmethyl)-2·carbyl-6-[(3S)-3^-base morpholino] mouth bite 0 sodium benzenesulfinate (4.22 g, 25.74 mmol) 2-Chloryl ice (iodomethyl)-6-[(3S)_3_indolyl morpholine] was added to B. (2 〇 毫升 ml) (= gram, 19.80 mmol) The resulting mixture was stirred under a nitrogen atmosphere at 8 Torr for 20 hours. The reaction was allowed to cool and the solvent was removed. Add and wash the solution with water. The DCM was dehydrated to dryness (MgS 4), filtered, and solvent removed. The crude product was purified by flash chromatography eluting with EtOAc (EtOAc:EtOAc) NMR spectrum: NMR (400.132 MHz, DMSO-d6) 5 1.15-1.16 (3H,d), 3.11-3.18 (1H, td), 3.38-3.45 (1H, td), 3.55-3.58 (1H, dd), 3.70 -3.73 (1H, d), 3.85-3.94 (2H, m), 4.15 (1H, bs), 4.64 (2H, s), 6.67 (1H, s), 7.63-7.66 (2H, m), 7.74-7.80 (3H, m). LCMS Spectrum: m/z (ES+) (M+H)+ = 368; HPLC tR = 2.05 min · 2-chloro-4-(indolyl)-6-[(3S) -3-indolyl-4-yl]. The preparation of pyridine is described in the previous section. Example 4: 3-Cyclopropyl-1·[4·[4-[2-(3·hydroxypropylsulfonyl)propan-2-yl]-6-[(3S)-3-indolylmorpholine -4-yl]pyrimidin-2yl]phenyl]thiourea

137081 -170· 201002697 Add bis(σ米唆-1-yl)decanethione (46 mg, 0 20 mmol) to 3_[2_[2_ in DCM (2 mL) and THF (1 mL) (4Aminophenyl)6-[(3S) 3_indolylmorpholin-4-yl]pyrimidinyl]propan-2-ylsulfonyl]propanol (1 mg, 0.17 mmol) 'The reaction was stirred at room temperature for 3 hours. Cyclopropylamine (1.20 mmol) was added followed by triethylamine (43 mL, EtOAc &lt;RTI ID=0.0&gt;&gt; The mixture was cooled and purified by preparative EtOAc (EtOAc) NMR spectrum: 4 NMR (400.132 MHz, DMSO-d6) 5 0.57-0.65 (2H, m), 0.72-0.82 (2H, m), 1.24 (3H, d), 1.72-1.85 (8H, m), 3.21- 3.35 (4H, m), 3.41-3.54 (3H, m), 3.65 (1H, d), 3.77 (1H, d), 3.98 (1H, d), 4.24 (1H, d), 4.56-4.66 (2H, m), 6.79 (1H, s), 7.62 (2H, d), 8.16 (1H, s), 8.29 (2H, d), 9.51 (1H, s). LCMS Spectrum: m/z (ES+) (M+ H) + = 534 ; HPLC tR = 1.94 min. The following compounds were prepared in a similar manner from 3-[2-[2-(4-aminophenyl)-6-[(3S)-3-indenyl] Polin-4-yl]pyrimidin-4-yl]propan-2-ylsulfonyl]propan-1-ol and the appropriate amine. Example structure name LCMS MH+ retention time · (minutes) 4a Η Η 3-(2-hydroxyethyl)-1-[4-[4-[2-(3-hydroxypropylsulfonyl)propan-2-yl ]-6-[(3S)-3-indolylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea 538 1^68~~ 137081 -171 - 201002697 4b Άν Η Η 1-[4 -[4-[2-(3-|^-propyl-decyl)propan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]benzene ]]-3-methylthiourea 508 1.82 4c cx Ά Ν Η Η 3-ethyl-l-[4-[4-[2-(3-hydroxypropylsulfonyl)propan-2-yl] -6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea 522 1.97 Example 4a: 1H NMR (400.mMHz, DMSO-d6) (5 1.24 (3H) , d), 1.70-1.81 (8H, m), 3.17-3.34 (6H, m), 3.41-3.46 (2H, m), 3.47-3.55 (1H, m), 3.65 (1H, d), 3.77 (1H , d), 3.98 (1H, d), 4.24 (1H, d), 4.56-4.63 (2H, m), 4.81 (1H, s), 6.79 (1H, s), 7.63 (2H, d), 7.87 ( 1H, s), 8.30 (2H, d), 9.81 (1H, s) 1.82 (8H, m), 2.96 (3H, s), 3.16-3.34 (3H, m), 3.42-3.55 (3H, m), 3.65 (1H, d), 3.77 (1H, d), 3.98 (1H, d), 4.23 (1H, d), 4.56-4.64 (2H, m), 6.79 (1H, s), 7.55 (2H, d) , 7.85 (1H, s), 8.30 (2H, d), 9.73 (1H, s) Example 4c: 1H NMR (400.132 MHz, DMSO-d6) δ 1.14 (3H, t), 1.24 (3H, d), 1.74-1.82 (8H, m), 3.19-3.34 (5H, m), 3.39- 3.57 (3H, m), 3.65 (1H, d), 3.77 (1H, d), 3.98 (1H, d), 4.22 (1H, d), 4.57-4.64 (2H, m), 6.79 (1H, s) , 7.57 (2H, d), 7.89 (1H, s), 8.30 (2H, d) 3-[2-[2-(4-Aminophenyl)-6-[(3S)-3-indenyl] The preparation of phenyl 4-yl]pyrimidin-4-yl; i-prop-2-ylsulfonyl]propan-1-ol is described below. 3-[2-[2_(4-Aminophenyl)-6-[(3S),3-methylmorpholine-4-yl]pyrimidin-4-yl]propan-2-ylsulfonyl]propene- 1-alcohol 137081 -172- 201002697

Adding (II) (0176 g, 0.25 mmol) of bis(triphenylphosphine) chloride to a solvent of DMF (5 L), DME (8 mL), water (2 mL) and ethanol (15 mL) 3-[2-[2-Chloro-6-[(3S)-3-methylmorpholineyl]&gt;Methylene-4-yl]propan-2-ylsulfonyl]propoxy Tris(Cypto-2-yl) Shixi (2 g, millimolar), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborin-2-yl Aniline (11 〇 7 g, 5 〇 5 mmol) and 2M sodium carbonate solution (3 mL of &lt;RTI ID=0.0&gt; The reaction mixture was diluted with ethyl acetate (EtOAc) (EtOAc) The organic layer was dehydrated and dried over Na.sub.2SO.sub.4, filtered, and evaporated. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The organic layer was dried over Na 2 s 〇 4, filtered, and then evaporated to give a crude product. The crude product was purified by flash chopping chromatography. The elution gradient was 2 〇 to 1 〇〇% ethyl acetate in isohexane, then 4% methanol in ethyl acetate, and the material was obtained by ion exchange. Chromatography, further purification using a s. s. column, eluting with 7N ammonia in methanol to give the desired material as a beige solid (1 g). NMR spectrum: NMR (400.132 MHz, DMSO-d6) 5 1.21 (3H, d), 1.72-1.81 (8H, m), 3.14-3.22 (1H, m), 3.26-3.35 (3H, m), 3.41-3.52 (3H, m), 3.64 (1H, d), 3.76 (1H, d), 3.97 (1H, d), 4.19 (1H, d), 4.50-4.60 (2H, 137081 -173- 201002697 m), 5.54 ( 2H, d), 6.58-6.69 (3H, m), 8.06 (2H, d) LCMS spectrum: none. 3 仰-气基-6-[卿 3-methyl 琳琳_4. base] (four) butterfly C 2 Base-based brewing base] propoxy-tris(propan-2-yl)

Adding sodium tributoxide (5.93 mmol) to _5t to 3_[[2-chloro-6-[(3S)-3-indolylmorpholin-4-yl]pyrimidine-4-yl Methanesulfonyl]propoxy-tris(propyl)-naphthene (3 g, 5.93 mol) in a solution in DMF (1 mL), followed by dropwise at -5 °C Methyl iodide (0. 33 ml) was added. The addition of the third sodium butoxide and the methyl iodide was repeated, and the reaction was stirred at _5 ° C for 1 hour and then at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with water The organic layer was dried with EtOAc (EtOAc)EtOAc. NMR spectrum: 1H NMR (400.132 MHz, DMSO-d6) 5 0.96-1.04 (21H, m), 1.20 (3H, d), 1.79-1.89 (2H, m), 3.12-3.22 (3H, m), 3.39- 3.48 (1H, m), 3.58 (1H, d), 3.69-3.78 (3H, m), 3.94 (1H, d), 4.08 (1H, s), 6.88 (1H, s) LCMS Spectrum: m/z ( ES+) (M+H)+ = 534 ; HPLC tR = 3.98 min. 3·[[2·6-[(3S)-3-methylmorpholin-4-yl]c-pyridin-4-yl Methanesulfonyl]propoxy•tris(propyl-2-yl)

137081 -174- 201002697 3-[[2-Chloro-6-[(3S)-3-methylmorpholin-4-yl; h-pyridine-4] in DMF (25 mL) -yl]methanesulfonyl]propanol (5 〇 4 g, 14.41 mmol), added to DMF (25 mL) in chlorotriisopropyl oxime (3.70 at room temperature) l ' 17.29 love Moore) with. The rice alpha sits (2.354 grams, 34.58 millimoles) within a period of 5 minutes. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was evaporated to dryness EtOAc (EtOAc) The organic layer was dehydrated and dried (MgS 〇 4), and evaporated to give the desired material (yield: 7.29 g). NMR spectrum: NMR (400.132 MHz, CDC13) (5 0.99-1.07 (21H, m), 1.33 (3H, d), 2.06-2.13 (2H, m), 3.20-3.24 (2H, m), 3.26-3.34 ( 1H, m), 3.50-3.57 (1H, m), 3.66-3.70 (1H, m), 3.77-3.83 (3H, m), 3.99-4.03 (2H, m), 4.16 (2H, s), 4.25- 4.37 (1H, m), 6.54 (1H, s) 0,

LCMS spectroscopy: m/z (ESI+) (M+H)+ = 506; HPLC tR = 3.42 min. 3-[[2-[sup.6-[(38)·3-methyl? ] pyrimidine-4.yl]methyl hydrazinyl] propyl alcohol 3-chloroperoxybenzoic acid (4.00 g ' 23.16 mmol) was added to DCM (1 mL) at room temperature -[[2-Chloro-6-[(3S)-3-methylmorphin-4-yl)] dimethyl-4-yl]methylthio]propanol (3.68 g, 11.58 mmol) Inside, after 5 minutes. The resulting solution was scrambled for 3 hours at room temperature. Another '- part 3_chloroperoxybenzoic acid (2.00 g, 11.58 mmol) was added, and the resulting solution was stirred at room temperature for further 1 hour. The reaction mixture was washed successively with 10% aqueous sodium hydrogensulfite solution (2×100 mL), saturated aqueous sodium hydrogen carbonate (1 mL) and 137081 - 175 - 201002697 and brine (100 ml). The organic layer was dried (MgSO.sub.4), filtered and evaporated to give the desired material. NMR spectrum: 1 H NMR (400.132 MHz, CDC13) 5 1.34 (3H, d), 2.12-2.18 (2H, m), 3.27 (2H, t), 3.31-3.35 (1H, m), 3.51-3.57 (1H , m), 3.67-3.70 (1H, m), 3.77-3.82 (3H, m), 3.99-4.03 (1H, m), 4.18 (2H, s), 4.26-4.37 (1H, m), 6.51 (1H , s) LCMS spectrum: m/z (ESI+) (M+H)+ = 350; HPLC tR = 1.30 min. 3-[[2-chloro-6-[(3S)-3-methylmorpholine- 4-yl]pyrimidin-4-yl]methylthio]propan-1-ol

2-Alkyl-4-(iodomethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (12.4 g, 35.07 mmol) in DCM under nitrogen atmosphere (50 ml) solution was added to 3-mercapto-1-propanol (3.64 mL, 42.08 mmol) and DIPEA (9.77 mL, 56.11 mmol) in DCM (100 mL) The stirred solution was over a period of 40 minutes. The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with aq. EtOAc (EtOAc) The organic layer was dried (MgSO.sub.4), filtered and evaporated. The crude product was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) NMR spectrum: NMR (400.132 MHz, CDC13) 5 1.32 (3H, d), 1.84-1.90 (2H, m), 1.94 (1H, s), 2.69 (2H, t), 3.24-3.32 (1H, m), 3.51-3.58 (1H, m), 3.61 (2H, s), 3.67-3.71 (1H, m), 3.73-3.80 (3H, m), 3.98-4.04 (2H, m), 4.28-4.34 (1H, m ), 6.45 (1H, s) 137081 -176- 201002697 LCMS Spectrum: m/z (ESI+) (M+H)+ = 318; HPLC tR = 1.55 min · 2-chloro-4-(E-methyl) The preparation of -6-[(3S)-3-methylmorpholin-4-yl]pyrimidine is described above. Example 5: 3·(2-Hydroxyethyl)-1-[4·[4-(2·hydroxypropyl-2-yl)-6-[(3S)_3-indolylmorpholinyl]pyrimidine 2- Phenyl]thiourea

Add a solution of dimethoprim (84 mg, 0.46 mmol) in DCM (2 mL) under nitrogen to 2_[2-(4-aminophenyl)_6_ [(3S)-3-methylmorpholino]. Methyl 4-methyl-propan-2-ol (100 mg, 0.3 mmol) in a stirred solution of DCM (2 mL) and THF (1 mL) over a period of 2 min. The resulting solution was stirred at room temperature for 2 hours. Ethanolamine (91. 5 mg, 0.46 mmol) and triethylamine (1 mL) were added to the reaction mixture. The resulting solution was stirred at room temperature for 4 hours. The reaction mixture was evaporated to dry/solid and sub-dissolved in DMF. The crude product was purified by preparative HpLC to give the desired material as a white solid. NMR spectroscopy · 1 H NMR (399 9 〇 2 MHz, dms 〇) 5 [23 ie, mountain, 丄% paper s), 3.20 (1H, m), 3.50 (1H, m), 3.57 (4H, m), 3.64 (1H, m), 3.77 (1H, m), 3.98 (1H, m), 4.16 (1H, m), 4.54 (1H, m), 4.84 (1H, m), 5.24 (1H, s), 6.84 (1H, s), 7.59 (2H, d), 7.85 (1H, s), 8.29 (2H, d), 9.81 (1H, s) LCMS spectrum. She (ESI+) (M+H)+ = 432 ; The following compound was obtained in a similar manner using a suitable amine from Μ2#aminophenyl&gt;6-[(3S&gt;3-methylmorpholino]pyrimidinyl]propan-2-ol. • 177- 201002697 Example structure name LCMS MH+ retention time (minutes) 5a Η Η 1-[4-[4-(2-hydroxypropan-2-yl)-6-[(3S)-3-methylmorpholine _ 4-yl]pyrimidin-2-yl]phenyl]-3-methylthiourea 402 1.97 5b Η°Αχ meaning, Η Η 3-cyclopropyl-1-[4-[4-(2- via propyl-2) -yl)-6-[(3S)-3-indolylmorpholin-4-yl]pyrimidin-2-yl]phenyl]thiourea 428 2.12 5c Cx, H0A〇ninj Η Η 3-ethyl-l- [4-[4-(2-Hydroxypropan-2-yl)-6-[(3S)-3-indolylmorpholine]pyrimidin-2-yl]phenyl]thiourea 416 2.17 Example 5a: 1 H NMR (399.902 MHz, DMSO) 6 1.29 (3H,d), 1.52 (6H, s ), 3.00 (3H, d), 3.28 (1H, m), 3.55 (1H, m), 3.70 (1H, m), 3.83 (1H, m), 4.03 (1H, m), 4.22 (1H, m) , 4.59 (1H, m), 5.30 (1H, m), 6.90 (1H, s), 7.56 (2H, d), 7.87 (1H, s), 8.35 (2H, d), 9.83 (1H, s) 5b : 1 H NMR (399.902 MHz, DMSO) &lt;5 0.60 (2H, m), 0.76 (2H, m), 1.24 (3H, d), 1.46 (6H, s), 2.93 (1H, m), 3.22 (1H, m), 3.50 (1H, m), 3.65 (1H, m), 3.77 (1H, m), 3.98 (1H, m), 4.16 (1H, m), 4.54 (1H, m), 5.24 ( 1H, s), 6.85 (1H, s), 7.57 (2H, d), 8.10 (1H, s), 8.29 (2H, d), 9.52 (1H, s) Example 5c: 1 H NMR (399.902 MHz, DMSO &lt;5 1.14 (3H, t), 1.24 (3H, d), 1.46 (6H, s), 3.21 (1H, m), 3.50 (3H, m), 3.65 (1H, m), 3.77 (1H, m), 3.98 (1H, m), 4.16 (1H, m), 4.54 (1H, m), 5.24 (1H, s), 6.84 (1H, s), 7.52 (2H, d), 7.88 (1H, s ), 8.30 (2H, d), 9.65 (1H, s) 2-[2-(4-Aminophenyl)-6-[(3S)-3-indolylmorpholin-4-yl]pyrimidine-4 Preparation of -yl]propan-2-ol 137081 178· 201002697 is described below: 2_[2-(4-Aminophenyl)6_[(3S)methylmorpholine-4-yl]pyrimidin-4-yl ] propionate

Adding (η) (〇·492 g, 〇7〇 mmol) to dioxane (triphenylphosphine) under nitrogen to 2_[2 chloro group in DME (80 ml) and water (20.00 ml) _6 [(3S) 3_ Methylmorpholine] σMidine-4-yl]propan-2-ol (3.81 g, 14.02 mmol), 4-(4,4,5,5-tetramethyl Base_1,3,2_dioxaboron-2-yl)aniline (3 38 g, 15 42 mmol) and sodium carbonate (4.46 g, 42.06 mmol). The resulting solution was stirred at 8 ° C for 6 hours. The reaction mixture was diluted with DCM (2 mL) and washed twice with water (400 mL). The organic layer was dehydrated and dried with MgS〇4, filtered, and treated to give a crude product. The crude product was purified by flash chromatography, and the eluted gradient was from 2 to 6 % ethyl acetate in isohexane to obtain the material, which was further purified by ion exchange chromatography using a scx column. The 2M ammonia in the formazan was dissolved, and the desired substance was obtained as a pink gum (2.78 g). ' NMR spectrum: 1 H NMR (399 9〇2 test, DMS〇) accounted for! 2l (3h, [43 fine, s), 3.17 (1H, m), 3.47 (1H, m), 3.63 (1H, m), 3.76 (1H, m), 3.97 (1H, m), 4.13 (1H , m), 4.48 (1H, m), 5.18 (1H, s), 5.50 (2H, m), 6.59 (2H, d), 6.71 (1H, s), 8.07 (2H, d) LCMS Spectrum: m/ z qing+) (M+H)+ = 329 ; HpLC tR = [% min 2-[2-carbyl-6-[(3S)-3_methylmorpholine_4_yl]pyrimidin-4-yl] C- 2 - alcohol 137081 • 179- 201002697

Methyl 2-carbyl-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate (300 mg) was dissolved in dry THF and cooled to EtOAc. Methylmagnesium bromide (3.0 M ' in ether < 0.74 mL) was added dropwise over 2 min then the reaction was stirred at -78 °C for 20 min then, then warmed to room temperature. The reaction was stirred for a further 20 min then quenched with water (2 mL). Reduce the volume of the reaction to dryness and separate the mixture between ethyl acetate (50 ml) and water (50 ml) and allow the organic layer to dry with magnesium sulfate and vacuum to dry to the desired material. , as a white solid (291 mg). NMR spectrum: (400.13 MHz, DMSO-d6) (5 1.16-1.23 (3H, m), 1.36 (6H, s), 3.15-3.23 (1H, m), 3.40-3.47 (1H, m), 3.56-3.60 (1H, m), 3.71 (1H, d), 3.91-3.94 (2H, m), 4.34 (1H, s), 5.28 (1H, s), 6.87 (1H, s). MS; M+H+272 . Preparation of 2-Chloro-6-[(3S)-3-methyl?11-lin-4-yl]-bite-4-reo-acidic hydrazine is described in the previous section. 137081 180-

Claims (1)

201002697 X. Patent application scope: 1. A compound of formula (I) VIII - (R3) m N Or (1) or a pharmaceutically acceptable salt thereof; wherein m is 0, 1, 2, 3 or 4; W and Y2 are independently N or CR8, provided that one of Y and Y2 is N and the other is CR8 ; X is a linking group selected from -CR4=CR5-, -CR4=CR5CR6R7-, -CR6R7CR5 =CR4-, -C = C-, -CsCCR6R7-, -CR6R7CeC-, -NR4CR6R7-, -OCR6R7-, - SCR6R7---S(0)CR6 R7 -, -S(0)2CR6R7-, -C(0)NR4CR6R7-, -NR4C(0)CR6R7-, -NR4C(0)NR5CR6R7 -, -NR4S(0)2CR6R7 -, -S(0)2NR4CR6R7-, -C(0)NR4-, -NR4C(0)-, -NR4 C(0)NR5 -, -S(0)2 NR4 - and -NR4 S(0)2 R1 is a group selected from the group consisting of hydrogen, Ch alkyl, C2_6 alkenyl, (: 2-6 alkynyl, carbocyclyl, carbocyclylalkyl, heterocyclyl and heterocyclic (^-6 alkyl) groups The group is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, R9, -OR9, -SR9, -SOR9, -S02R9, -COR9, -C02R9, -CONR9 R10, -NR9R10, -NR9 COR10, -NR9C02R10, -NR9CONR10R15, -NR9COCONR10R15 and -NR9S02R10; R2 is a group selected from the group consisting of CV6 alkyl, carbocyclic and heterocyclic groups, which is 137081 201002697 =:::r Replace 'and The situation is replaced by - or a plurality of substituents, the substituents being independently selected from the group consisting of halo, cyano, nitro, _R11-NR COR1 2 and _nriiCC)CC)nr12Rl6; each R3', when present, is independently selected from the group consisting of 'Cyano, nitro, π, -OR '-SR13&gt;-sor^_s〇2R]3_c〇r13^ -C〇2r]3, c〇nr13rI4, Guangchang, Juyi 3, 4, 13c〇2R1 , nr13s〇2r14 f R and R are independently hydrogen or C 6 alkyl; y together with one or more atoms to which they are attached form a 'to 10' carbon ring or a heterocyclic ring' Or 3 ring carbon atoms are optionally substituted by N, hydrazine or S, and the ring system is optionally substituted by - or a plurality of substituents selected from the group consisting of a south group, a cyano group, a nitro group, a thio group, and a group. , Ci_6 alkyl, Cm alkoxy, haloCl_6 alkyl, _yl-6 alkoxy, hydroxy^alkyl, via C 6 alkoxy, Cl 6 alkoxy Ci-6 alkyl, alkoxy Alkoxy, amino, C 6-6 alkyl, bis(Cl 6 alkyl)amine, amine Ci6 alkyl, (Ch alkyl)amino C 6 alkyl, bis (CH alkyl) amine CI 6 alkyl, cyano ς-6 alkyl, ¢^-6 alkylsulfonyl, (^_6 alkyl sulfonate) Amino group, c!_6-mercaptosulfonic acid (c)-6 alkyl)amino group, aminesulfonyl group, c] 6 alkylamine sulfonyl group, bis(c!-6 alkyl)amine sulfonyl group , Ci 6 alkanoguanamine, Ci 6 alkyl fluorenyl (C 1-6 alkyl) amine group, amine sulfhydryl group, Cu alkyl amine fluorenyl group and bis (Ch alkyl) amine carbhydryl group; R6 and R7 Is independently selected from the group consisting of hydrogen, halo, cyano, nitro and Cu alkyl; R8 is selected from the group consisting of hydrogen, halo, cyano and C!-6 alkyl; R and R1 G are independently hydrogen or are selected from _ 6 alkyl group, hinder ring group, carbocyclic group 137081 201002697 alkyl group, heterocyclic group and heterocyclic group c] 6 alkyl group, this group is attached. The case is substituted by one or more substituents, substituents Selected from the group consisting of cyano, cyano, nitro, oxindole, Ck alkyl, Cl-6 alkoxy, _*Cl_6 alkyl, haloCl-6 alkoxy, hydroxy Cj-6 alkyl, hydroxy c]-6 alkoxy , Ch alkoxy C!-6 alkyl, C!-6 alkoxy (^_6 alkoxy, amine, (^-6 alkylamino, bis(Q-6 alkyl) amine, amine q_6 Alkyl, (Cu alkyl)amino cv6 alkyl, bis(C-6-6 alkyl)amino c]-6 alkyl, cyanoCl-6 alkyl, Ci 6 alkylsulfonyl, cumane Sulfosylamino group, Ci 6 alkylsulfonyl (Ci 6 alkyl) amine group, amine sulfonyl group, Q 6 alkyl group, fluorenyl group, bis(q -6 alkyl) amine hydrazino group, Alkylamino 'Ci-6 alkyl fluorenyl (Cw alkyl) amine group, amine methyl sulfonyl group, Ci6 alkyl amine carbhydryl group and bis (Cu alkyl) amine carbaryl group; R11, R12, R17 and Rl8 Is independently a nitrogen ' or a group selected from the group consisting of Ci6, carbocyclyl, carbocyclyl C -6 alkyl, heterocyclic and heterocyclyl Ci 6 alkyl, which is optionally one or more Substituted by a substituent selected from a halogen group, a cyano group, a nitro group, a hydroxyl group, a cl-6 alkyl group, a C1_6 alkoxy group, a halogenated c16 alkyl group, a functional group c1-6 alkoxy group, a hydroxy C16 alkyl group , hydroxy Ci 6 alkoxy, C]-6 alkoxy Ck alkyl, alkoxy Ci6 alkoxy, amine, Ci6 alkylamino, bis(Cw alkyl)amine, amine Ci 6 alkyl (Ci 6 alkyl)amino c]-6 alkyl, bis(Cl·6 alkyl)amino Ci 6 alkyl, cyanoalkyl, C!-6 alkyl fluorenyl, C -6-6 Amidino group, Ci6 alkyl fluorenyl group (c)j alkyl fluorenyl group, amine mercapto group, Ch typhobyl amine aryl group and bis((:66 alkyl) amide group; 13: Rl4 , Rls, R14R19 are independently hydrogen, or a group selected from the group consisting of c]-6 alkyl, saponin 5, sulfonyl C -6 alkyl, heterocyclic and heterocyclic C 6 alkyl. The group is optionally substituted with - or a plurality of substituents selected from 137081 201002697 halo, cyano, nitro, hydroxy, Ci 6 alkyl, Ci 6 alkoxy, halo c^6 alkyl, tooth Base c -6 alkoxy, hydroxy Ci 6 alkyl, hydroxy Ci oxy, Ci-6 alkoxy Cu alkyl, c16 alkoxy Ci 6 alkoxy, amine, Ch acryl, bis (Ch alkane) Amino group, amine group Ci6 alkyl group, (Ci6 alkyl group) amine group C]_6 alkyl group, bis(Ch alkyl)amino group Ci6 alkyl group, cyano Ci6 alkyl group, Ci-6 alkylsulfonyl group , alkylsulfonylamino, Cl 6 alkylsulfonyl (Cu alkyl) amine, amine sulfonyl, Ci6 alkyl amine sulfonyl, bis (Ci6 alkyl) amine sulfonyl, cv6 alkane Amidino, (^_6 alkylalkyl (Ck alkyl) amine, amine methyl sulfonyl, alkyl amine sulfhydryl and bis (Cl 6 alkyl) amine carbaryl; or Rl8 and Rl9 and their The nitrogen atoms of the bond together form a 3- to 10-membered heterocyclic ring. One or two of the ring carbon atoms are optionally placed by N, 〇 or s. And wherein the ring is optionally substituted with one or more substituents selected from the group consisting of halo, nitro, nitro, hydroxy, q-6 alkyl, Α-6 alkoxy, haloCl-6 alkyl, halo Base Cl - 6 :): alkoxy, light-based Q -6 burnt, ketone, benzyl group 6 alkoxy, - 6 oxaalkyl, Cl 6 alkyl C 6 alkoxy, amine, Ci 6 alkylamino group, bis(C1-6 alkyl)amino group, amino Cu alkyl group, (Ch alkyl)amino group CV6 alkyl group, bis(Ci-6 alkyl)amino group Cu alkyl group, cyano group Cu alkyl, CV6 alkyl fluorenyl, c16 alkylsulfonylamino, C1-6 alkylsulfonyl (C16 alkyl) amine, amine fluorenyl, Ci-6 alkylamine hydrazino, Bis(Ch-alkyl) amine fluorenyl-based Cl-6-branched amine group, C]·6 bristles (Cl-6)-based amine group, amine-branched group, Cl-6 alkylamine-methyl group and Bis(C!-6 alkyl)amine carbenyl. 2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein 1 Y is CH ' and Y 2 is N. 3. A compound of the formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein 137081 201002697 is -X-R1 is -C(CH3)2OH, or X is -S(0)2CH2 -, -S(0)2CH(CH3)- or -S(0)2C(CH3)2-; and R1 is selected from the group consisting of decyl, ethyl, propyl, butyl, isobutyl, tert-butyl , cyclopropyl, cyclopentylcyclohexyl, phenyl, benzyl, phenethyl, pyridyl, pyrazolylethyl, furyl fluorenyl, thienyl fluorenyl, thiazolylmethyl, thiadiazolyl a group of a fluorenyl group and a pyridyl group, the group being optionally substituted by 1 or 2 substituents selected from the group consisting of an amine group, a halogen group, a cyano group, a methyl group, a decyloxy group, and a trifluoroantimony group. Base, trifluoromethoxy, -nhcoch3, -CONH2 and -CONHCH3. 4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 3, wherein -X-R1 is -C(CH3)2OH, or X is -S(0)2CH2-, -S( 0) 2CH(CH3)- or -S(0)2C(CH3)2-; and R1 is a group selected from a methyl group, -CH2CH2OH, and a phenyl group. 5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein R2 is Η Η wherein A1 and A2 are selected from CH or N, provided that at least one of A1 or A2 is CH. 137081 201002697 6. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 5, wherein A1 and A2 are CH. 7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 5, wherein R1 9 is hydrogen or is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso -butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, stupyl, thienyl, imidazolyl, isoxazolyl, pyrazolyl, a group of a thiol group and a pyrimidinyl group, the group being optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, Ci 6 alkyl, C]-6 Mercapto, _yl (^_6 alkyl, _yl^, alkoxy, hydroxy C 6 alkyl, trans-c]-6 alkoxy, Cl-6 alkoxy Cl-6 alkyl, Ci 6 alkoxy Ci 6 Oxy group, amine group, Cm alkylamino group, bis((6-alkyl)amino group, amino group Cl 6 leuoleyl group, (Cl-6 alkyl)amino group C -6 alkyl group, double (C!- 6 alkyl)amino (^_6 alkyl, cyano C _6 alkyl, (^_6 alkylsulfonyl, alkylsulfonylamino, Cu alkylsulfonyl (c)-6 alkyl) Amine, sulfonamide, Ci 6 alkylamine sulfonate &amp; base, bis(Cj_6 alkyl) amine yokoic acid group, Cu succinylamine group, (^_6 saponin group (C!-6 alkyl group) Amino, amine f yl, q 纟 基 胺 胺 及 及 及 及 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. 8. a salt, wherein Ri 9 is a group selected from the group consisting of methyl, ethyl, cyclopropyl, -CH 2 CH 2 NMe 2 ' -CH 2 CH 2 OH, 4-fluorophenyl, 4-methoxyphenyl and phenyl. a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which is selected from any one of the following 3-ethyls[4-[4-[(3S)-3-methylmorphin-4-yl]- 6-(Metholinylmethyl) „Mididin-2-yl]phenyl]thiourea, 137081 201002697 Continuation of mercaptomethyl) 3-cyclopropyl-l-[4-[4-[(3S)- 3-methylmorpholine_4_yl]_6_(pyrimidin-2-yl)phenyl]thiourea, H4-fluorophenyl H_[4_[4_[(3S)methylmorpholine·4_yl] _6_(Methanesulfonylmethyl)pyrimidin-2-yl]phenyl]thiourea, soil H4-[4-[(3S)_3-methyl?, 林冰基]_6_(甲石黄醯基 methyl)m base] 3-phenyl-sulfur pulse, 3-(4-methoxyphenyl)-H4-[4-[(3S)-3-methylmorpholino]6((methylsulfonyl) Methyl) dimethyl-2-methyl]phenyl]thiourea, 3-cyclopropyl-H4-[4-[(3S)-3-indolylmorpholine-4-yl]_6_(2 Methylsulfonylpropan-2-ylpyrimidin-2-yl]phenyl]thiourea, 3-methyl-l-[4-[4-[(3S)-3-methylmorpholin-4-yl] -6-(2-oxasulfonylpropylpropanyl)pyrimidin-2-yl]phenyl]thiourea, 3-ethyl-l-[4-[4-[(3S)-3-methylmorpholine · 4-yl]_6_(2_methylsulfonylpropan-2-yl)pyrimidin-2-yl]phenyl]guanidine, 3-(2-hydroxyethyl)-i_[4-[4-[( 3S)-3-indolylmorpholine_4_yl]-6-(2-sulfonylsulfanylpropionate -2-yl) "Mididine-2-yl]phenyl]thiourea, 3-(2-methylaminoethyl) small [4-[4-[(3S)-3-methyl 淋 _ 4-(4-[2-[4-(phenylsulfonyl)propanyl) _2_yl]_6-[(3S)-3-methylmorpholine_4_yl]pyrimidin-2-yl]phenyl]-3-indolethiourea, 1-[4-[4-[2- (Benzenesulfonyl)propyl]_6_[(3S)_3_methylmorpholine-4-yl]pyrimidin-2-yl]benzyl]-3-cyclopropylthiol, 1-[4-[4- [2-(phenylsulfonyl)propan-2-yl]·6·[(35)methylmorpholine-4-yl]pyrimidin-2-yl]phenyl]-3-ethylthiourea, 137081 201002697 l -[4-[4-[2-(phenylsulfonyl)propan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl] 3-(2-hydroxyethyl)thiourea, 3-(2-hydroxyethyl)-1-[4-[4-[2-(3-hydroxypropyl acid))-2-yl] _6_[(3s)_3-曱基吗琳-4-yl]σ密σ定-2-yl]phenyl]sulfur, 1-[4-[4-[2-(3-hydroxypropylsulfonate) Benzyl-2-yl]_6_[(cutylmethylmorpholino).Mididine-2-yl]phenyl]-3-methylthiourea, 3-cyclopropyl-1-[4-[ 4-[2-(3-propylsulfonyl)propan-2-yl]_6_[(3S)_3·methyl?#林-4-yl], 1,4--2-yl]phenyl] Urea, 3- Base-l-[4-[4-[2-(3-hydroxypropylsulfonyl)propan-2-yl]-6-[(35) 3-methyl-no-indolyl-4-yl]- 2_yl]phenyl] sulfonylurea, 3-(2-hydroxyethylhydroxypropan-2-yl)_6_[(3S)_3·methylmorpholino] α-Bitter-2-yl]phenyl] Thiourea, 1-[4-[4-(2-hydroxypropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]- 3-methylthiourea, 3-cyclopropyl-H4-[4-(2-hydroxypropan-2-yl-W(3S)methylmorpholino), pyridin-2-yl]phenyl]thiourea And 3-ethyl-1-[4_[4_(2-hydroxypropionyl)_6_[(3S)3methylmorpholinyl). Michidine-yl]phenyl]thiourea, or its pharmaceutically The compound of the formula 1 according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof is used as a medicament for the treatment of a proliferative disease. U. species as claimed in claims 1 to 9. A compound of the formula (I) wherein the pharmaceutically acceptable salt is used in the manufacture of a medicament for the treatment of a proliferative disorder 137081 201002697. 12. A claim 1 to 9&quot; Use of a compound of the formula σ) or a pharmaceutically acceptable salt thereof for producing an anti-proliferative effect in a warm-blooded animal such as a human . 13. Use of a compound of the formula (1) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the production of an antiproliferative effect in a warm-blooded animal such as a human. A method of producing an anti-proliferative effect in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of formula (I) as claimed in claim 丨9, or a pharmaceutically acceptable compound thereof salt. 15. A method of treating cancer, an inflammatory disease, a blocker-based airway disease, an immune disease or a cardiovascular disease in a warming animal, such as a human, to be treated, comprising administering an effective amount such as a inflammatory A compound of the formula (I) according to any one of 1 to 9, or a pharmaceutically acceptable salt thereof. 16. A group of medicines, including gamma and sigma, containing m compounds, or 1 huabubu I ^ (1) /, accepted salt, as described in any one of claims 1 to 9 I. pharmaceutically acceptable i. diluent or carrier. 7', as in the formula (1), any of the formula (I), compound 4, or a pharmaceutically acceptable salt thereof, is used as a medicament. 137081 201002697 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention. : Formula (I) 137081