TW201136930A - Bridged morpholino substituted purines - Google Patents

Abstract

The present invention relates to purine compounds that are useful as kinase inhibitors. More particularly, the present invention relates to purine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative conditions or disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative conditions or disorders including tumours and cancers as well as other disorders or conditions related to or associated with PI3K and/or mTOR kinases.

Description

201136930 VI. Description of the Invention: [Technical Field to Which the Invention Is Ascribed] The present invention relates to an anthraquinone compound which can be used as a kinase inhibitor. More specifically, the present invention relates to an anthracene derivative substituted with 2 ((morpholine-4-yl), 6-(pyrazine-2-yl), a preparation method thereof, and a pharmaceutical composition containing the same And the use of such compounds in the treatment of certain medical conditions, such as kinase-related disorders/conditions. [Prior Art] The exploration of kinase inhibitors has proven to be an effective field for the development of suitable pharmaceutical active substances. A kinase, or phosphotransferase, is an enzyme that transfers a phosphate group from a high energy donor molecule (e.g., ATP) to a specific target molecule (commonly referred to as a substrate) in a process known as phosphorylation. One of the largest group kinases is a protein kinase that acts on specific proteins and alters their activity. Because of this activity, these kinases are involved in many cellular processes, such as signal transduction and the biochemical reactions that trigger cells in metabolism. It has been suggested that certain cellular signaling processes are critical for effective inhibition of many medical conditions and certain cellular signaling processes, and thus may delay the progression of such conditions. Thus, kinases represent an attractive target for medicinal chemical furniture because the provision of kinase inhibitors may allow certain signaling processes to be controlled, thereby allowing certain medical conditions to be controlled. A family of kinases associated with inappropriate medical conditions in the body is the kinase of the phosphoinositide 3-excited 6|(PI3) family, which interacts with such things as cell migration, cell proliferation, & cancer transformation, cell survival, signal transduction, and protein. Various cellular events involved in intracellular transport. In recent years, this family of kinases has become the focus of much research aimed at developing therapies for the various diseases of 152948.doc 201136930. The enzyme in the group of acid inositol 3-kinase (PI3) family produces the phospholipid inositol "second messenger" enzyme. This trait is followed by various philosophical (four) Μα signaling pathways through which a wide variety of physiological processes are regulated, which are essential for many aspects of cell growth and survival, such as cell cycle progression, differentiation, Transcription, translation and apoptosis. The constitutive activation of the ρΐ3κ pathway is associated with the onset and progression of various cancers and is now largely evidenced by the rapid accumulation of evidence! > 13-foot signaling is often dysregulated in cancer. It is believed that the dysregulation of ΡΙ3Κ signaling occurs in two different ways. The first is the activation gene mutation, amplification and overexpression of the upstream receptor from ΡΙ3Κ or activated ΡΙ3Κ, resulting in increased ΡΙ3Κ signaling. For example, the ρΙ3Κα catalytic subunit is amplified and overexpressed in ovarian cancer and cervical cancer. Similarly, the upstream receptor for the activation of ΡΙ3Κ typically mutates, amplifies, and overexpresses EGFR, such as breast cancer, ovarian cancer, and lung cancer. In addition, activation of the effector downstream of the ΡΙ3Κ can also cause dysregulation of the ρΐ3κ pathway. For example, Akt/PKB (protein kinase Β) is particularly expressed and activated in breast cancer, pancreatic cancer, and ovarian cancer. Furthermore, members of the Ras family involved in PI3K activation are often mutated, for example, in colorectal cancer and pancreatic cancer. The second PI3K dysregulation mechanism involves the loss of the tumor suppressor phosphatase, which occurs in many invasive brain tumors, endometrial cancer, and breast cancer and melanoma. A specific cellular signaling pathway mediated by the ΡΙ3 family of kinases is the phospholipid 醯 inositol 3-kinase (PI3K)/Akt pathway. This pathway is decisively related to cell survival and is a major signaling component downstream of the growth factor receptor tyrosine kinase (RTK) "growth factor RTK binding to laPI3K," 52948.doc 201136930 which contains p85 regulation And the heterodimeric beta small gtp enzyme Ras of the pllO catalytic subunit can also recruit and activate pi3K via direct binding to p110. At the cell membrane, PI3K catalyzes the production of lipid second messenger 璘5,4,5·three-acid ester (PIP3). Subsequently, PIP3 recruits other downstream molecules (especially the serine-threonine kinases Akt and PDK1) via binding to its platelet-leukocyte C kinase pleckstrin homology (PH) domain. At the membrane, Akt is partially activated by phosphorylation of threonine 308 in its activation loop via PDK1. The additional acidification of the C-terminal serine 473 of Akt results in complete activation. This second structuring is carried out by the mammalian target of rapamycin (mir〇R). Akt regulates a variety of standard dry proteins, one of which is mTOR. Therefore, mTOR plays a key role in the downstream signaling of ΡΙ3Κ and Akt and has received much attention as a potential therapeutic target for various conditions. The amount of PIP3 in the cells is tightly regulated and several liposteric enzymes are used to quickly remove them. Of particular interest is the phosphatase PTEN, which converts PIP3 back to PIP2 and thereby disrupts PI3K signaling. The PI3K-Akt signaling pathway regulates many normal cellular processes, including cell proliferation, survival, growth, and movement, which are critical processes for tumor formation. The role of the PI3K/Akt pathway in tumorigenesis has also been extensively studied and mutations or alterations in most of the pathway components have been commonly associated with many cancers. In some cases of human ovarian cancer, gene amplification of pll〇 occurs, and Akt amplification is found in ovarian cancer, breast cancer, and colon cancer. In addition, activating mutations of p85 have been identified in ovarian cancer and colon cancer. Most importantly, PTEN has been identified as a major tumor suppressor of humans and loss of functional mutations in the pTEN gene is extremely common in occasional glioblastoma, melanoma, prostate cancer, and uterine 152948.doc 201136930 Membrane cancer, and is quite Large percentages of breast tumors, lung cancer, and lymphoma also carry PTEN mutations. Thus, a high percentage of human cancers have activated PI3K signaling via various mechanisms. Obviously, it has been shown that (mTOR) is important for the carcinogenic transformation induced by PI3K and Akt. In addition to the compelling and relevant information presented above, direct evidence of dysregulated PI3K signaling in cancer comes from the mouse genetic model. For example, mice with constitutively activated PI3K p85 regulatory subunits develop malignant lymphoma after hybridization with p53 knockout mice. In addition, the introduction of retroviruses of Akt and Ras causes mice to develop glioblastoma. In summary, all of this information provides a powerful validation of the novel anti-cancer strategy targeted by this pathway. mTOR is a 289 kDa serine/threonine kinase and is a PI3K-like kinase that is involved in mitotic stimulation and nutritional status associated with cell growth and division. mTOR acts as a key enzyme in the PI3K-Akt pathway as discussed above. mTOR was discovered during a study conducted to understand the mechanism of action of rapamycin. Upon entry into the cell, rapamycin binds to its intracellular standard FKBP12, and then the complex binds to mTOR and specifically inhibits mTOR. Therefore, mTOR is also known as FKBP-RAP related protein (FRAP), RAP FKBP12 target (RAFT1) and RAP target (RAPT1). The cells responsible for organ rejection stop growing due to the ability of rapamycin to inhibit the assimilation of signals coordinated by mTOR. Since inhibition of cell growth represents an effective target for the treatment of cancer, designing new drugs that inhibit mTOR will potentially be of therapeutic value. In humans, mTOR mediates the signaling signals from two sources, namely the nutrient and the activated growth factor receptors that enter the cell 152948.doc 201136930. It is present in at least two different complexes: a rapamycin-sensitive complex, called mTOR complex l (mTORCl), defined by its interaction with the accessory protein raptor (a regulatory protein associated with mTOR). Normal activation of mTOR results in increased protein translation as mTORC 1 phosphorylates and activates the translational regulatory factor eukaryotic initiation factor 4E-binding protein 1 and ribosomal p70 S6 kinase. Therefore, by inhibiting mTOR, rapamycin reduces the phosphorylation of these effectors and reduces protein synthesis, thereby effectively blocking the growth of mTOR. The second complex, mTOR complex 2 (mTORC2), is rapamycin non-sensitive and is defined by its interaction with rictor (the rapamycin non-sensitive counterpart of mTOR). mTORC2 is involved in the regulation of the intact living kinase Akt/PKB by phosphorylation of S473. Phosphorylation of S473 and PDK1 phosphorylation of T308 are required for complete Akt activation. Recent reports indicate that treatment with rapamycin for a prolonged period of time also inhibits the assembly and function of mTORC2 to inhibit Akt and that this property of rapamycin contributes to the anti-apoptotic effect of the drug. mTOR is also one of the major downstream effectors of the phospholipid inositol 3-kinase (PI3K)/Akt pathway and thus inhibition of mTOR provides another chance to inhibit (at least in part) the PI3K/Akt pathway. Another pathway that is affected by mTOR and appears to be particularly important in renal cell carcinoma involves hypoxia inducible factor (HIF). The oxygen-sensitive transcription factors HIF-1 and HIF-2 are accumulated in the absence of the Von Hippel-Lindau (VHL) gene function in clear cell renal cell carcinoma. The accumulation of these factors increases the stimulation of vascular endothelial growth factor (VEGF), platelet-derived growth factor and transforming growth factor. This effect is enhanced by activating mTOR by adding 152948.doc 201136930, which stimulates protein stabilizing function and protein translation function, and thereby increases HIF-1 activity. The complex gene products TSC丨 and TSC2 of tuberous sclerosis have also been identified to act together to inhibit mTOR-mediated downstream signaling. Mutations in these genes occur in tuberous sclerosis and loss of function results in another pathway that results in increased activity of mTOR and induces VEGF production. TSC2 also regulates HIF. Thus, studies evaluating the effects of TSC1ATSC2 mutations demonstrated an association between increased VEGF and activated imT0 pathways and angiogenesis. Rapamycin, also known as sirolimus, is a natural antibiotic produced by Streptomyces hygroscopicus. It was originally developed as an antifungal against Candida albicans, Cryptococcus ne0f0rmans, and Aspergillus (9) (10). Subsequently, rapamycin was developed as an immunosuppressive agent and their research helped to understand the mechanism of action of this agent. As an anticancer agent, rapamycin has been shown to inhibit the growth of several murine and human cancer cell lines in a tissue-culture and xenograft model in a concentration-dependent manner. In the sixty tumor cell lines screened by the National Cancer Institute in the USA, the general sensitivity to drugs can be seen at doses below 2000 ng/ml in leukemia, ovarian cancer, breast cancer. It is more obvious in central nervous system cancer and small cell lung cancer cell lines. In addition, rapamycin inhibits the oncogenic transformation of human cells induced by ρΐ3κ or Akt and has shown metastatic tumor growth inhibition and anti-angiogenic effects in an in vivo mouse model. Based on these clinical findings, a clinical trial using rapamycin as an anticancer drug was conducted and a rapamycin analogue having more favorable drug properties was developed. 152948.doc 201136930 CCI-779 (Temsir〇limus), a more water-soluble ester derivative of rapamycin, identified by Wyeth Ayerst as an in vitro inhibitor of tumor cell proliferation. Non-cytotoxic agent. In animals, CCI_779 demonstrates anti-tumor activity alone or in combination with cytotoxic agents in various human cancer models, such as glioma, rhabdomyosarcoma, and primitive neuroectoderm, at several non-toxic doses. Tumors (such as neural tube blastoma), head and neck cancer, prostate cancer, pancreatic cancer, and breast cancer cells. Treatment of mice with CCI-779 inhibited P70S6K activity and reduced neoplastic hyperplasia. Like rapamycin, human tumors lacking PTEN are more sensitive to CCI-779-mediated growth inhibition than cells expressing pTEN. Specifically, 3, an in vitro study of a group of eight human breast cancer cell lines showed that six of the eight cancer cell lines studied were inhibited by CCI-779, and their IC50 was found in the low nanomolar range. Two cell lines are resistant with an IC5 〇 > l μΜ. The sensitive cell line is estrogen receptor positive or overexpressing HER-2/Neu, or has lost the tumor suppressor gene product ΡΤΕΝ. The main toxicity of CCI-779 includes dermal toxicity and mild myelosuppression (mainly thrombocytopenia). CCI-779 has been evaluated in many clinical trials for a large number of cancer indications. In recent years, 'CCI-779 has been approved by the FDA for the treatment of advanced renal cell carcinoma (rCC) by intravenous infusion (sold as TORISELtm). The most common adverse reactions reported with Torisel have been rash, fatigue, mucositis, nausea, edema, and anorexia. In addition, clinical trials are ongoing. RAD001 (Everolimus), 40-0-(2-transethylethyl)-rapamycin, is another analog of rapamycin that can be administered orally. It has been evaluated in different human cancer cell lines in vitro and in in vivo xenograft models. 152948.doc 201136930 Its anti-neoplastic activity. The p70S6K inhibition and anti-hypergenic effects have been shown in these models. Similarly, RAD001 demonstrated concentration-dependent anti-tumor activity in a homologous rat pancreatic cancer model with intermittent dosing schedule. RAD001 has also been shown to have anti-angiogenic activity and inhibit proliferation of human vascular endothelial cells (HUVEC). Toxicity reported for RAD001 includes hypercholesterolemia, hypertriglyceridemia, mild white jk reduction, and thrombocytopenia. RAD001 is evaluated in a number of clinical trials in a single agent and in combination with other therapeutic agents. Like CCI-779, it is now approved by the FDA for RCC. Therefore, many studies have demonstrated that mT〇R inhibitors can improve survival in cancer patients. However, rapamycin and its analogs did not show general anti-tumor activity in early clinical trials. In cancer types, the rate of response varies from a low value of less than 10% in patients with glioblastoma and advanced renal cell carcinoma to a high value of about 40% in patients with mantle cell lymphoma. Knowledge of the PTEN and PI3K/Akt/mTOR related pathways can help select the type of tumor that will respond to mTOR inhibitors. In addition, because many tumor types remain unresponsive to single agent therapy with rapamycin derivatives, it is important to continue to look for factors that predict resistance or sensitivity to mT〇R inhibitors. Molecules that directly inhibit mTOR kinase activity will be of interest, the theory being that these molecules will inhibit both mTORCl and mTORC2. The inhibitor may be useful in the treatment of tumors with high Akt phosphorylation and which may be associated with growth, proliferation and survival associated with Akt activation. If mTOR-rictor is a key activator of the Akt-dependent survival process, the drug promotes apoptosis of tumor cells suitable for Akt-dependent regulatory mechanisms. There is now considerable effort to develop mTOR 152948.doc •10·201136930 enzyme inhibitors and more advanced compounds such as OSI-Ol 7 and AZD8055 have entered Phase 1 clinical trials. Thus, an mTOR inhibitor may further provide a biologically active compound that will be expected to be specifically adapted for use in a therapeutic regimen of a kinase-associated condition or disorder. In particular, mTOR inhibitors can potentially be used to treat a variety of cancers and related hyperproliferative disorders. In addition, the latest research involves mTOR in many non-oncological diseases, including inflammation, cardiovascular disease, and certain metabolic and neurological disorders. SUMMARY OF THE INVENTION The present invention provides a compound of formula (I):

Formula (1) wherein: Η, 自 and optionally substituted R1 are selected from the group consisting of Η C 1 -Cs alkyl; fresh: hydrazine, halogen, OH, N02, CN, -C12 alkyl, The substituted c2_c12 CyC 2 alkynyl group, optionally substituted c2-R is selected from the group consisting of Η, ^ ΝΗ 2, optionally substituted Ci_Ci2 alkyl, alkenyl, as the case may be replaced Formula 152948.doc 201136930 c] 2 heteroalkyl, optionally substituted C3_Ci2 cycloalkyl, optionally substituted C3_C丨2 cycloalkenyl, optionally substituted C2_C12 heterocycloalkyl, optionally substituted Cz-C, 2 heterocycloalkenyl, optionally substituted C6_C18 aryl, optionally substituted C丨-c 18 heteroaryl, optionally substituted c丨_Cu alkoxy, optionally substituted C2_Ci2 alkenyloxy, optionally substituted C2-C丨2 alkynyloxy, optionally substituted c2_c丨2 heteroalkoxy, optionally substituted C^-C! 2 cycloalkoxy, optionally Substituted C3_C12 cycloalkenyloxy, optionally substituted C: 2-Cl2 heterocycloalkoxy, optionally substituted Cz-Cu heterocycloalkenyloxy, optionally substituted Aryloxy, optionally substituted C^-Cu heteroaryloxy, optionally substituted Ci_Ci2 alkylamino, SR8, S03H, S02NR8R9, S〇2r8, s〇nr8r9, SOR8, COR8, COOH, COOR8 , c〇NR8R9, NR8COR9, NR8COOR9, nr«S〇2r9, NR8C〇nr8r9, nr8r9a fluorenyl, or R2 is a group of the formula:

Each ruler 2!1 is independently selected from the group consisting of H, halogen, 〇HN〇2, CN, NH2, substituted c2-c12 alkenyl, optionally substituted 2C1_C12 alkyl, optionally, by visual a substituted G-Ci2 alkynyl group, optionally substituted c^c] 2 heteroalkyl, optionally substituted c3_c丨2 cycloalkyl,

152948.doc •12- 201136930 q-CH Heteroaryl, optionally substituted Ci_Ci2 alkoxy, optionally substituted C2-Cu alkenyloxy, optionally substituted CyCu alkynyloxy, optionally substituted Qc, 2 heteroalkoxy, optionally substituted c3-Ci2 cycloalkoxy, optionally substituted C: 3_Cl2 cycloalkenyloxy, optionally substituted Ci-C丨2 heterocycloalkoxy , optionally substituted C2_C12 heterocycloalkenyloxy, optionally substituted C0-Cl8 aryloxy, optionally substituted Cl.C1S heteroaryloxy, optionally substituted Ci_Ci2 alkylamine, SR8 , S03H, S02NH2, S02R8, SONH2, SOR8, COR8, COOH, COOR8, CONR8r9, NR8C0R9, nr8c〇〇r9, nr8so2r9, NR8c〇NR8R9, NR8R9 and sulfhydryl; r is selected from the group consisting of 1, 2 and 3. Integer

R3 is selected from the group consisting of ruthenium, F, Cl, Br, 〇H, optionally substituted Ci Q alkyl, OR8, OCOR8, Ch2〇H, NH2, NR8R9, NR8c〇R4 nr8so2r9; R6 is selected from Η , OH, 0R8, 〇Pg〇, 〇c〇r8, CH2〇H NH2, NR8R9, NR8PgN, N(PgN)2, nr8c〇r9, nr8c〇nr8r9 and nr8so2r9; R7 is selected from Η, F, Each of R8 and R9 is independently selected from the group consisting of C1, Br, 0H, 〇r8, 〇c〇r8, ch2oh, nh2, NRV, nr8c〇r9, and nr8s〇2R^. Substituted CVCu alkyl, optionally substituted C2_Ci2 dilute, optionally substituted c2-c12 alkynyl, optionally substituted c2_Ci2 heteroalkyl, optionally substituted C3_C12 cycloalkyl, optionally Substituted W-following alkenyl substituted heterocycloalkyl, optionally substituted 152948.doc • 13· 201136930 Heterocycloalkenyl, optionally substituted C6_Ci8 aryl and optionally substituted C !-Ci8 heteroaryl, or R and R together with the atom to which they are attached form an optionally substituted cyclic moiety; pgQ is a protecting group for oxygen; each PgN is independently nitrogen Base 2; each ruler 2 is independently selected from the group consisting of C "C6 alkyl, dentyl G-C6 alkyl, hydroxyCl_c6 alkyl, Ci_c6 alkoxy Ci_C6 alkyl, cyano" (: 6 alkyl, amino Ci_C6 alkyl, Ci_C6 alkylamino^-^alkyl, and di(C丨-C6 alkyl)amino C丨-c6 alkyl; q is selected from 0, 1, An integer of the group consisting of 2, 3, and 4; x is a group of formula (CR102) m2; each R is independently selected from the group consisting of: c-c6 alkyl; An integer of the group consisting of G, 1, 2, 3, and 4; or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof. As with any structurally related compound having a specific utility, the variable of the compound of formula (1) Certain embodiments are particularly suitable for their end use. In various embodiments 'q is an integer selected from the group consisting of 〇, 1, 2, 3, and 4. In some embodiments, q is 4. In - In some embodiments, frame 3. j is in the embodiment where 'q is 2. In some embodiments, 9 is ^. In this embodiment, q is 〇. In some embodiments of trifluoromethyl, each can be a group of free F, CM, Br groups and ethyl groups. The 1^ substituent may be attached to any available position on the ring of 7 member 152948.doc 201136930. In the presence of multiple R/substituents, each Rz substituent The position is independent of the other substituents. In some embodiments 'q is 1 and the Rz substituent is at the alpha position of the ring nitrogen. This provides a compound of formula (la). R6

Or a pharmaceutically acceptable salt or prodrug thereof, wherein R, R, r3, R6, r7, m X are as defined above. In some embodiments, (} is 〇. This provides a compound of formula (Ib): R6

Or a pharmaceutically acceptable salt or prodrug thereof wherein R丨, R2, R3, R6, R7 and X are as defined above 152948.doc -15· 201136930 In some embodiments, R is selected from Η, OR8 And optionally substituted Ci-C6 alkyl group in some embodiments 'R3 is OR8' wherein R8 is optionally substituted

CrC6 alkyl. Examples of R3 groups of this type include methoxy, trifluoromethoxy, ethoxy, isopropoxy, propoxy and butoxy. In some embodiments, R3 is methoxy. In some embodiments 'R3 is an optionally substituted Ci_c6 alkyl group. Examples of R3 groups of this type include methyl, trifluoromethyl, ethyl, propyl, isopropyl and butyl. In some embodiments, R3 is a fluorenyl group. In some embodiments, R3 is selected from the group consisting of ruthenium, osmiumoxy, and methyl. In some embodiments, R3 is deuterium. In some embodiments, R7 is selected from the group consisting of ruthenium, F, Cl, Br, 〇11, and NH2. In some embodiments, R7 is deuterium. In some embodiments, both R3 and R7 are deuterium. In some embodiments 'q=0, R3 is Η and R7 is Η. This provides a compound of formula (Ic):

Or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R6 and X are as defined above. In some embodiments of the compound containing group R8, R8 is selected from the group consisting of hydrazine and C,-C6 alkyl. In some embodiments, R8 is methyl. In some embodiments, R8 is Η. In some embodiments of the compound containing a group R9, R9 is selected from the group consisting of C6 alkyl. In some embodiments, R9 is a fluorenyl group. In some embodiments, R9 is Η. As previously stated, X is a group of formula (CR1G2)m. In some embodiments, m is selected from the group consisting of 0, 1, and 2. In some embodiments, m is 0 or 1. In some embodiments, m is zero. In some embodiments, m is 1 °. In some embodiments, q = 0, R3 is Η, R7 is Η and m is 〇. This provides a compound of formula (II):

(Formula II) or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2 and R6 are as defined above. 152948.doc -17- 201136930. This provides, in some embodiments, q = 〇, R3 is Η, R7 is H and m is 1 a compound of formula (III):

Or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, 6 and 6 are as defined above. In some embodiments of the compounds of formula (I), (la), (lb), (Ic), and (ΙΠ), each R10 is deuterium. In some embodiments, each R] is independently a C-C6-based group that is optionally substituted. In some embodiments, one R10 is H and the other R1Q is deuterium or optionally substituted C1-C6 alkyl. In some embodiments, one R10 is Η and the other is CH3. In some embodiments of the compounds of formula (I), (la), (lb), (Ic), and (in), one R10 is deuterium and X is therefore a group of the formula:

In some embodiments, 'R3 and R7 are Η' m is 1, q is 〇 and one r1 〇 is Η. This product provides the compound of formula (IV): 152948.doc •18· 201136930 R6

Or a pharmaceutically acceptable salt or prodrug thereof, wherein R1, R2, R6 and R10 are as defined above. In some embodiments, Ri is selected from the group consisting of hydrazine, fluoro, carbyl, bromo, decylethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl A group consisting of butyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-indenyl, pentyl and hexyl. In some embodiments, R1 is Η. In some embodiments the 'R6 is selected from the group consisting of ruthenium, osmium 2, and NR8R9 wherein R8 and R9 are as defined above. In some embodiments, R6 is NH2. In some embodiments, R 2 is selected from the group consisting of hydrazine, an aryl group, optionally substituted Ci-Cu alkyl, optionally substituted c 2 —c^, and optionally substituted C 2 -C 1 2 miscellaneous, optionally substituted c 3 _ C 2 cycloalkyl, optionally substituted QC, 2 heterocycloalkyl, optionally substituted C6-C18 aryl, and optionally substituted (^-(:18heteroaryl. In some embodiments, R2 is optionally substituted C6_C]8 aryl. In some embodiments of 152948.doc -19·201136930 R, Ce_Ci8 is optionally substituted The aryl group (and thus R2) is a group of the formula:

Wherein P is an integer selected from the group consisting of (^^, ^); each R is independently selected from the group consisting of H, halogen, OH, N〇2, CN, NH2, optionally substituted iCi_Ci2 Substituted, optionally substituted C2-cu alkenyl, optionally substituted Q-Cu alkynyl, optionally substituted c^-Ci2 heteroalkyl, optionally substituted C3_Ci2 cycloalkyl, optionally Substituted C2_Cl2 heterocycloalkyl, optionally substituted heterocyclic dilute, optionally substituted C6_C丨8 aryl, optionally substituted CrC, 8 heteroaryl, optionally substituted CI_C Oxyl, optionally substituted C^-C, 2 alkenyloxy, optionally substituted QC 2 alkynyloxy, optionally substituted C2_C] 2 heteroalkoxy, optionally substituted C3_C12 ring Alkoxy, optionally substituted 2-cycloalkenyloxy, optionally substituted C^c丨2 heterocycloalkoxy, optionally substituted C2_Ci2 heterocycloalkenyloxy, optionally substituted c^ c] 8 aryloxy, optionally substituted C1_heteroaryloxy, optionally substituted c _Ci2 alkylamine, SR8, S〇3H, S02NH2, S02R8, SONH2, SOR8, COR8, COOH , COOR8, c〇NR8R9, nr8cor9, nr8coor9, NR8S02R9, NR8CONR8R9, NR8R9 and fluorenyl, or any two adjacent R13 may form a cyclic moiety together with each other and the carbon atom to which they are attached 152948.doc -20-201136930; Wherein R 8 and R 9 are as defined above. The phenyl group may be unsubstituted or optionally substituted with one or more suitable substituents. If the phenyl group is substituted, i, 2, 3, 4 or 5 substituents may be present. In some embodiments, p is 〇, 丨 or 2. In some embodiments P is 1. In some embodiments, p is 2. In some embodiments, R1 is Η ' R3 is H, 6 is 1^2, R7 is η, X is (CH2)m 'where m is 〇, and r2 is a group of the formula:

This provides a compound of formula (V):

Or a pharmaceutically acceptable salt or prodrug thereof, wherein R13 and p are as defined above. 152948.doc • 21· 201136930 In some embodiments, R1 is deuterium, R3 is H, r^NH2, R, H, X is (CR102)m, wherein m is 1, and R2 is a group of the formula:

This provides a compound of formula (Va):

Or a pharmaceutically acceptable salt or prodrug thereof, wherein R, R13 and p are as defined above. In some embodiments containing only 10 compounds, R10 is selected from the group consisting of hydrazine, Ci-C6 acetonide, C1-C6 hydroxyalkyl, and c-C6 alkyl. In some embodiments, the D<10>dry'R is selected from the group consisting of methyl, ethyl, propyl, isopropyl and butyl. In some embodiments, it is selected from the group consisting of ruthenium, osmium, and ethyl. ▲ In the examples, R2 is selected from a C1-C丨2 alkyl group substituted by a cyano group, as the case may be, or a C3-C12 cycloalkyl group substituted by a C. striatum, as the case may be, 152948.doc • 22- 201136930 The group consisting of Gc, 2 heterocycloalkyl and optionally substituted C2_Ci2 heteroalkyl. In some embodiments, R2 is selected from the group consisting of cyano, optionally substituted CrC!2 alkyl, and optionally substituted C2_Ci2 heteroalkyl. In some embodiments, R 2 is selected from the group consisting of methyl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-methyl-propyl, butyl, isobutyl, 3 a group consisting of 3-methyl-butyl, 2-ethyl-butyl, pentyl, 2-hydrazino, pentyl, hexyl, heptyl and octyl. In some embodiments 'R2 is a methyl group substituted as appropriate in the following formula:

Wherein R 0, R21 and R22 are each independently selected from the group consisting of ruthenium, ci, Br, F, OH, N02, CN, NH2, optionally substituted Cl_Cl2 alkyl, and optionally substituted CrCu heteroalkyl. In some embodiments, each R20, R2, and R22 are independently selected from the group consisting of hydrazine, Cl, Br, F, OH, N 〇 2, CN, NH 2, methyl, ethyl, propyl, Isopropyl, butyl, pentyl, methoxyindenyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, amine , 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, decylaminomethyl, 2-methylaminoethyl, 3-mercapto Aminopropyl, 4-mercaptoaminobutyl, 5-methylaminopentyl, ethylaminoindenyl, 2-ethylaminoethyl, 3-ethylaminopropyl, 4- Ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl 152948.doc -23- 201136930, 3-dimethylaminopropyl, 4. Dimethylaminobutyl, 5-dimethylaminopentylpentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4- Diethylaminobutyl and 5-diethylaminopentyl. In some embodiments, R 2 is optionally substituted C 3 —Ci 2 cycloalkyl. In some embodiments, R2 is selected from the group consisting of optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl. In some embodiments, R2 is cyclopropyl. In some embodiments, the optionally substituted c3_Ci2 cycloalkyl is selected from the group consisting of:

Wherein R23 is independently selected from the group consisting of H, optionally substituted qc, 2 alkyl, optionally substituted C2_Ci2 alkenyl, optionally substituted qc 2 alkynyl, optionally substituted C2_Ci2 heteroalkyl, optionally substituted C3-C, 2 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted (: 2_Cl2 heterocycloalkyl, optionally substituted c2_) C12 heterocycloalkenyl, optionally substituted MW group, optionally substituted Ci-C 8 heteroaryl 'Ci_c substituted as appropriate 2 alkoxy, optionally substituted qc, 2 olefin Substituted C2_C 2 alkenyloxy as appropriate - C2-C1Q heteroalkoxy substituted, optionally substituted C3_C12 cycloalkoxy, optionally substituted wuoxy, optionally Substituted C-heterocyclic fluorenyloxy, as appropriate, I12, which is substituted by a Ce-C!8 aryloxy group, optionally substituted c · 152948.doc •24 · 201136930 cls heteroaryloxy, optionally substituted Ci_c 2 alkyl amine based so2nr24r25, SOR24, so2r24, sonr24r25, S〇R24, c〇r2 COOH, COOR24 and CONR24R25; Each of R24 and R25 is independently selected from the group consisting of H.subst. H, optionally substituted ^/^alkyl, optionally substituted C2_c 2 alkenyl, optionally substituted c2-c, 2 fast Substituted C2_CiG heterocyclyl, optionally substituted C3_Cl2 cycloalkyl, optionally substituted, cycloalkenyl, optionally substituted C2_Ci2 heterocyclic alkyl, optionally substituted C2 -cls heterocycloalkenyl, optionally substituted aryl and optionally substituted CrC 丨 8 heteroaryl.

In some embodiments, the C3_C12 ring hospital, as appropriate, is replaced by the following group: H R23

Wherein R23 is as defined above. In some embodiments r2 is a group of the formula:

152948.doc •25· 201136930 wherein each Μ is independently N or CR 2a ; each R is independently selected from the group consisting of H, halogen, N02, CN, NH2, optionally substituted alkyl, optionally Substituted c^-c, 2 alkenyl, optionally substituted C2_Ci2 alkynyl, optionally substituted Cz-Cn heteroalkyl, optionally substituted. /. Cycloalkyl, optionally substituted Gc, 2 heterocycloalkyl, optionally substituted c2_Ci2 heterocycloalkenyl, optionally substituted Q-Cu aryl, optionally substituted G-Cu heteroaryl , as the case may be substituted c] _c〗 2 alkoxy, optionally substituted Cz-Cn alkenyloxy, optionally substituted C2_Ci2 alkynyloxy, optionally substituted CyCu heteroalkoxy, optionally Substituted, optionally substituted c^c丨2 cycloalkoxy, optionally substituted c3_c] 2 cycloalkenyloxy, optionally substituted qc 2 heterocycloalkoxy, optionally substituted C2_C〗 2 Heterocyclic alkenyloxy, optionally substituted C6_Ci8 aryloxy, optionally substituted C]-C〗 8 heteroaryloxy, optionally substituted c _Ci2 alkylamine, SR8, S03H, S02NH2, S02R8, SONH2, SOR8, COR8, COOH, COOR8, CONR8R9, NR8COR9, NR8COOR9, NR8so2R9, NR8c〇NR8R9, nr8r9 and fluorenyl; wherein R8 and R9 are as defined above; r is selected from 1, 2 and 3 integers of the group. In some embodiments 'r is 丄 and the rule 2 is a group of the formula:

Wherein each m is as described above. 152948.doc •26· 201136930 In some embodiments, 1* is 2 and R2 is a group of the formula:

Each of them is as defined above. In some embodiments, each oxime is CR2. In some embodiments, one oxime group is oxime and the other oxime group is CR2a. In some embodiments, R 2 is a group of the formula:

Wherein R2aW is as defined above; s is an integer selected from the group consisting of 0, 1, 2, 3 and 4; r is an integer selected from the group consisting of 1, 2 and 3. In some embodiments, each oxime is CR2a, r is 1 and R2 is a group of the formula:

Where R2aW is as defined above. In some embodiments, each Μ is CR2a, r is 2 and R2 is a group of the formula: 152948.doc •27·201136930 R2a

Wherein R2a is as defined above. In some embodiments, one Μ is N and the other is CR2a « In one embodiment, R2 is a group of the formula: R2a

Where 1123 and r are as defined above. In some embodiments, r is selected from the group consisting of ruthenium and 2. In this embodiment, r is 1. In some embodiments, Hung 2 is. Each R2a substituent may be selected from any suitable substituents as appropriate. In some embodiments, each line is independently selected from the group consisting of H, f, CH2CH3, OCH3, CN, 0CF3, c〇2CH3, N〇2, and nhcoch3. , nhso2ch3, NHCH2CH3 and CI?3 group.

In some embodiments, R2 is 葙悴M and A is replaced by CVC12 heterocyclic uneyl 0 / in some embodiments 'R2 is selected from the group consisting of: Base, depending on the situation, the bite _2_ base is replaced, as appropriate. More than ...-based, depending on the situation, the dioxetane _ 2- base, depending on the situation: oxygen ^ m as appropriate to replace 152948.doc -28- 201136930 tetrahydrofuran-2-yl, depending Substituted tetrahydrofuran-3-yl, optionally substituted piperidin-1-yl, optionally substituted piperidinyl-2-yl, optionally substituted piperidin-3-yl, optionally Substituted piperidine-4-yl, optionally substituted morpholin-1-yl, optionally substituted morpholin-2-yl, optionally substituted morphin-3-yl, optionally substituted Thereafter, 4_dioxol-2-yl, optionally substituted thiomorpholine _ 丨 _ group, optionally substituted thiomorpholine-2 group, optionally substituted sulfur a morpholine _3• group, optionally substituted thiomorpholine _4_ group, optionally substituted piperazine _ 丨 _ group and optionally substituted piperazine 2 - group. In some embodiments, the optionally substituted C2_Ci2 heterocycloalkyl is selected from the group consisting of: nn^N, r26, wherein R26 is independently selected from the group consisting of: H, optionally substituted QC, 2 alkyl, optionally substituted C2_Ci2 alkenyl, optionally substituted C2-cu alkynyl, optionally substituted heteroalkyl, optionally substituted c^c, 2 cycloalkyl, visual a substituted C3_Ci2 cycloalkenyl group I24 substituted heterocyclic ring, optionally substituted c2_CI2 heterocyclic group, (d) a substituted α6·(:18 aryl group, optionally substituted CVC1S heteroaryl group, Substituted Ci_c] 2 hospitaloxy, optionally substituted ic2-c12 diloxy, optionally substituted C2-Ci2 loxy, C2_Cl nonyloxy substituted according to conditions, as appropriate Substituted cyclohexyloxy, optionally substituted C3_Ci2 epoxide, as appropriate 2 152948.doc •29· 201136930 substituted c^c, 2 heterocycloalkoxy, optionally substituted C2_C 〖2 heterocycloalkenyloxy, optionally substituted QC] 8 aryloxy, optionally substituted C! 8 heteroaryloxy, optionally substituted Ci_Ci2 Alkylamino, S02NR27R28 > SOR27 ' S02R27 . SONR27R28 , SOR27 COR27, COOH, COOR27 and CONR27R28 ; each R27 and R28 are independently selected from the group consisting of: h, optionally substituted (VCW based, optionally) Substituted Μ" County, optionally substituted C2-C12 alkynyl, optionally substituted c2_c丨. Heteroalkyl, optionally substituted C3-C" ring-based, optionally substituted c3_c12 ring , a C2-CI2 heterocycloalkyl group substituted, optionally substituted c2-Ci2 heterolyzed group, optionally a substituted I-based group, and optionally a substituted CrCu heteroaryl group. Wherein, the C-heterocyclic ring-burning group is optionally selected from the group consisting of:

, 0 where R26 is as defined above. In a group embodiment, R26 is selected from the group consisting of ruthenium, COR27, and COOR28. In some embodiments, R27 private. Α Α 1 Γ p. R k is selected from C, - 11 2葙格, cc P , substituted CpC丨8 aryl and optionally substituted CVC丨8 heteroaryl group Ά. Group. In some embodiments, R27 is a C丨-C6 alkyl group. In some embodiments, R27 is methyl. 152948.doc 201136930 In some embodiments, R2 is optionally substituted C2-C12 heteroalkyl. In some embodiments, the C^-Cn heteroalkyl group is selected from the group consisting of a hydroxyalkyl group, a C1-C6 alkoxy C1-C6 alkyl group, an amine C1-C6 alkyl group, and a C1-C6 group. A group consisting of an alkylamino-based Ci-C6 or a di-(Ci-C6 alkyl)-based Ci-C6 alkyl group. Examples of possible meanings of r2 as a Cz-C!2 heteroalkyl group include hydroxymethyl, transethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, methoxymethyl, 2-methoxyethyl , 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, aminoguanidino, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl , 5-Aminopentyl, methylaminoindenyl, 2-decylaminoethyl, 3-methylaminopropyl, 4-decylaminobutyl, 5-decylaminopentyl , ethylamino fluorenyl, 2-ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, diammonium methyl , 2-dimethylaminoethyl, 3-didecylaminopropyl, 4-didecylaminobutyl, 5-didecylaminopentyl, diethylaminoindenyl, 2 2-Diethylaminoethyl, 3-diethylaminopropyl, 4·diethylaminobutyl and 5-diethylaminoindenyl. In some embodiments, 'R is selected from the group consisting of sulfhydryl, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, and ring. Propyl, cyclopentyl, butyl, isobutyl, 3,3-didecyl-butyl, 2-ethylbutyl, pentyl, 2-indenyl, pentyl, hexyl, heptyl, octyl A cyano group, a cyano group, a decyl fluorenyl group and a butoxy fluorenyl group. Many, if not all, of the variables discussed above may be superseded. If the variables are substituted as appropriate, in some embodiments, each of the substituents present as appropriate is independently selected from the group consisting of: self, 〇, =s ' CN, -N〇2, -CF3, - off 3, alkyl, dilute, alkynyl, dentate, 152948.doc • 31 - 201136930 haloalkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, hetero Cycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, aralkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylene , heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkane Alkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkoxy, naphthenic Oxyl, cycloalkenyloxy, heterocycloalkoxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkoxy, amine, alkylamine Base, mercaptoamine, aminoalkyl, arylamine, Sulfonic acid amine, sulfinylamino, sulfonyl, alkylsulfonyl, aryl sulfhydryl, amine fluorenyl, sulfhydryl, alkylsulfinyl, aryl Sulfonyl, aminosulfinylaminoalkyl, _C( =(7)〇H, _c(= 〇)Ra, -C( = 〇)〇Ra, C( = 〇)NRaRb, c(=N〇 H) Ra, c (= NRa) NRbRC, NRaR, NRaC (= 〇) Rb, NRaC (=0) 〇 Rb,

-ORa, NRaC(=0)NRbRc, wherein R, R, Rc and Rd are each independently selected from the group consisting of: C2-C12 dilute, block, C3-C12 ring dilute group, Ci_c attached atomic one

, the substituents present as the case may be independently selected from H, CVCu alkyl, Ci_Ci2, alkyl, qc, ..., c3_Ci2 cycloalkyl, heterocycloalkyl, C 1 decyl, or Ra, In some embodiments, 152948.doc •32· 201136930 is a group consisting of F, CM, Br, =0, =S, -CN, -N〇2, alkyl, alkenyl, heteroalkyl, Alkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino, aminoalkyl, decylamino, phenoxy Alkoxyalkyl 'benzoxyloxy, alkylsulfonyl, arylsulfonyl, aminosulfonyl, -C(0)0Ra, COOH, SH and mercapto. In some embodiments, each optionally present substituent is independently selected from the group consisting of F, Br, C1, = 0, =S, -CN, fluorenyl, trifluoromethyl, ethyl '2 , 2,2-difluoro^ethyl, isopropyl, propyl, 2-ethylpropyl, 3,3-dimercapto-propyl, butyl, isobutyl, 3,3_di -butyl, 2-ethyl-butyl, pentyl, 2-decyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, nh2, -no2, phenoxy , hydroxy, decyloxy, trifluoromethoxy, ethoxy and fluorenyldioxy. Alternatively, two optionally present substituents on the same moiety may be joined together to form a fused cyclic substituent attached to the optionally substituted moiety. Thus, the term optionally substituted includes fused rings such as cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings. The disclosed embodiments of the present invention are also directed to pharmaceutically acceptable salts of such compounds, pharmaceutically acceptable N-oxides, pharmaceutically acceptable prodrugs and pharmaceutically active metabolites, and A pharmaceutically acceptable salt of such metabolites. The invention also relates to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient. In another aspect, the invention provides a method of inhibiting a protein kinase, a fragment thereof 152948.doc • 33·201136930 or a complex or a functional equivalent thereof, the method comprising: the protein kinase or a fragment or complex thereof or The functional equivalent and/or its cofactor are contacted with an effective amount of a compound of formula (I) as described herein. The compounds disclosed herein act directly and exclusively on kinase molecules or complexes or fragments thereof to inhibit biological activity. However, it should be understood that these compounds may also act, at least in part, on the cofactors involved in the phosphorylation process. The kinase cofactors are known to include ionic species (e.g., zinc and calcium), lipids (e.g., phospholipid lysine), and dimercaptoglycerol. In some embodiments, the protein kinase is a serine/threonine protein kinase or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the serine/threonine protein kinase or a fragment or complex thereof is its mTOR protein kinase or fragment, or a complex thereof, or a functional equivalent thereof, in some embodiments, a silk amine The acid/threonine protein kinase is mTORC 1 or a fragment or complex thereof or a functional equivalent thereof. In one embodiment of the method, contacting the one or more protein kinases with a compound comprises administering a compound to a mammal comprising one or more protein kinases. In another aspect, the invention provides the use of a compound of formula (I) for inhibiting one or more protein kinases. In some embodiments, the protein kinase is a serine/threonine protein kinase or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the serine/threonine protein kinase or fragment or complex thereof is its mT〇R protein kinase or fragment, or a complex thereof or a functional equivalent thereof. In some embodiments the 'serine/threonine protein kinase is mTORC 1 or a fragment thereof, or a functional equivalent thereof. 152948.doc • 34· 201136930 In another aspect, the invention provides a method of treating or preventing a condition in a mammal, wherein inhibition of one or more protein kinases or fragments or complexes thereof or functional equivalents thereof Preventing, inhibiting or ameliorating the pathology or symptoms of the condition, the method comprising administering a therapeutically effective amount of a compound of formula (I). In some embodiments, the protein kinase is a serine/threonine protein kinase or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the serine/threonine protein kinase or fragment or complex thereof is a 111 〇11 protein kinase or a sheet slave, or a complex thereof or a functional equivalent thereof. In some embodiments, The serine/threonine protein kinase is mT〇RC1 or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, adrenitis, multiple sclerosis, self Immunity disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic sac syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease ( Alzheimerls disease), Huntington's disease, Parkinson's disease (4) heart, insulin-dependent diabetes, obesity, diabetic retinopathy, cardiac hypertrophy, and autologous dominant polycystic kidney disease. In some cases, the condition is cancer. In some embodiments, the cancer is selected from the group consisting of a hematological cancer, such as a myeloproliferative disorder (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), Bone marrow cell metaplasia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, acute red blood cell 152948.doc • 35. 201136930 Cell leukemia, Hodgkin's and Non Hodgkin's disease, B cell lymphoma, acute tau cell leukemia, myelodysplastic syndrome, plasma cell disease, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, ovarian cancer, cervical cancer, Vaginal cancer and vulvar cancer, endometrial hyperplasia; gastrointestinal cancer 'such as colorectal cancer, polyps, liver cancer, stomach cancer, pancreatic cancer, gallbladder cancer; urinary tract cancer, such as prostate cancer, kidney cancer; urinary bladder cancer, urinary tract cancer , penile cancer; skin cancer, such as melanoma; brain tumors, such as glioblastoma, neurogenic Tumor, astrocytoma, ependymoma, brain stem glioma, neural tube blastoma, meningioma, astrocytoma, oligodendroglioma; head and neck cancer, such as nasopharyngeal carcinoma, laryngeal cancer Respiratory cancer, such as lung cancer (1^8(:1^(: and 3(:1^(:), mesothelioma; eye disease, such as retinoblastoma; musculoskeletal diseases such as osteosarcoma, musculoskeletal tumors; Squamous cell carcinoma and fibroids. In another aspect, the invention provides the use of a compound of formula (1) for the manufacture of a medicament for treating a condition in an animal, wherein - or a plurality of protein kinases or fragments or complexes thereof, or functions thereof, etc. Inhibition of the agent prevents, inhibits or ameliorates the pathology or symptoms of the condition. In another example, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, an N-oxide or a former The use of a medicament for the treatment of a condition in which inhibition of one or more protein kinases or fragments or complexes thereof or a functional equivalent thereof prevents, inhibits or ameliorates the pathology or symptoms of the condition. Or a method of treating an individual's increase in sexual condition The method of administering the therapeutically effective amount of the formula (1) is 152948.doc * 36 - 201136930. In another aspect, the invention provides a compound of formula (1) for use in the preparation of a medicament for treating a proliferative condition in a subject Uses. In some embodiments, the protein kinase is a serine/threonine protein kinase or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the serine/threon protein kinase or a fragment or complex thereof is its mT〇R protein kinase or fragment, or a complex thereof or a functional equivalent thereof. In some embodiments, the serine/threonine protein kinase is 111 〇11 (: 1 or a fragment or complex thereof or a functional equivalent thereof. In some embodiments, the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory Enteropathy, adrenitis, multiple sclerosis, autoimmune disease, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyomas, polycystic inoculation syndrome, hamartoma , tuberous sclerosis, Alzheimer Disease, Huntington's disease, Parkinson's disease 'aunt Insulin-dependent diabetes mellitus, obesity, sugar show retinopathy, cardiac hypertrophy and autosomal dominant polycystic kidney disease. In the case of the case, the condition is cancer. In some embodiments, the cancer is selected from the group consisting of a hematological cancer, such as a f-proliferative disorder (idiopathic myelofibrosis, polycythemia vera, primary to hyperplasia, chronic myeloid leukemia) ), bone marrow cell metaplasia, chronic bone marrow saponin leukemia 'acute lymphocytic leukemia, acute red blood cell line leukemia, Hodgkin's and non-Hodgkin's disease, B cell lymphoma, acute tau cell leukemia, Myelodysplastic syndrome, sputum cell disease, 152948.doc -37· 201136930 hairy cell leukemia, Kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, ovarian cancer, cervical cancer, vaginal cancer and vulvar cancer, uterus Endometrial neoplasia, gastrointestinal cancer 'such as colorectal cancer, polyp, liver cancer, stomach cancer, sputum cancer, gallbladder cancer; urinary tract cancer 'such as prostate cancer, kidney cancer; urinary bladder cancer, urinary tract cancer, penile cancer; skin cancer, Such as melanoma; brain tumors such as glioblastoma, neuroblastoma, astrocytoma, ependymoma, brain stem glioma, god Transectoblastoma, meningioma, astrocytoma, oligodendroglioma; head and neck cancer, such as nasopharyngeal carcinoma, laryngeal cancer; respiratory cancer, such as lung cancer (NSCLC and SCLC), mesothelioma; eye disease 'such as retina Germ cell tumor; musculoskeletal diseases such as osteosarcoma, musculoskeletal tumors; squamous cell carcinoma and fibroids. These and other features of the present teachings are set forth herein. [Embodiment] In the present specification, a number of terms that are well known to those skilled in the art are used. However, for the sake of clarity, many terms will be defined. As used herein, the term "unsubstituted" means that no substituent is present or the only substituent is hydrogen. As used throughout the specification, the term "optionally substituted" means that the group may or may not be further substituted or fused (to form a fused polycyclic system) without one or more non-hydrogen substituents. In certain embodiments, the substituents are one or more groups independently selected from the group consisting of: halogen, = 〇, =S, -CN, -N02, -CF3, -0CF3, alkyl , alkenyl, alkynyl, haloalkyl, i alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocyclo, heterocycloalkenyl, aryl, heteroaryl, naphthenic Alkyl, heterocycloalkyl 152948.doc -38· 201136930 alkyl, heteroarylalkyl, aralkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylene , cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl,heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxy ring Alkyl, alkoxyheterocycloalkyl, alkoxyaryl, alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkoxy, cyclooxyl, cycloalkoxy , heterocyclic alkoxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkoxy, amine, alkylamino, decylamino , aminoalkyl, arylamine, sulfonylamino, sulfinyl , sulfonyl, alkylsulfonyl, arylsulfonic acid, aminosulfonyl, sulfinyl, alkylsulfinyl, aryl sulfhydryl, amino sulfhydryl Base group, _C(=〇)〇H, _C(=〇)Ra ' -C(=0)0Ra . C(=〇)NRaRb > C(=NOH)Ra > C(=NRa)NRbRc &gt ; NR R, NRaC (= 〇) Rb, NRaC (=0) 0Rb, NRaC (=0) NRbRc, NRaC (= NRb) NReRd, NRaS02Rb, _SRa, S02NRaRb, -〇R_a, 〇C(=0)NRaRb, 〇c(=〇)Ra and fluorenyl, wherein R, Rb, rc and Rd are each independently selected from the group consisting of: Η, CVC12 炫, Cl_Ci2 _ alkyl, C2_Ci2, C2_Ci2 fast, c2- Cl^, G3_Ci2, C3_Ci2 cycloalkenyl, C2_Ci2 heterocycloalkyl, C2-Cl2 heterocycloalkenyl, C6_Cis aryl, Ci_Ci8 heteroaryl and fluorenyl, or Ra, Rb, RC & Rd Any two or more of them together with the atoms to which they are attached form a heterocyclic ring system having from 3 to 12 ring atoms. In some embodiments, each of the optionally present substituents is independently selected from the group consisting of: _ prime, =0, = s, _CN, _N 〇 2, _Cf3, • 〇 CF3, cyclized, ligated, Fast group, halogenated group, (tetra) group, tooth block group, 152948.doc •39· 201136930 compound, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, Hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, heterocycloalkane Oxyl, heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, arylalkoxy, amine, alkylamino, decylamino, aminoalkane Alkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, _COOH, -SH and fluorenyl. Examples of substituents that are particularly suitable, as the case may be, include F, C1.

Br, I, CH3, CH2CH3, OH, OCH3, CF3, OCF3, N〇2, NH2 and CN. Alternatively, two optionally present substituents on the same moiety may be joined together to form a fused cyclic substituent attached to the optionally substituted moiety. Thus, the term optionally substituted includes fused rings such as cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings. In the definition of many substituents below, it is stated that "the group may be an end group or a bridging group". This intention is intended to mean that the term is intended to cover the case where the group is a linking group between two other moieties of the molecule and that it is an end portion. The use of the term alkyl is exemplified. 'Some publications will use the term "extension base" for a bridging group and thus, in these other publications, the terms 'alkyl' (end group) and "extension base" (bridge base) There is a difference between them. This distinction is not mentioned in the slaughter of the present application and most of the groups may be bridging or terminal groups. "Amidino" means an R-C(=0)- group in which the R group can be a succinyl group, a ring-based group, a heterocyclic alkyl group, an aryl group or a heteroaryl group as defined herein. Examples of brewing bases include ethyl and styrene. This group can be an end group or a bridging group. If the group is terminal & 152948.doc -40- 201136930, then 纟 is bonded to the rest of the molecule via a few base carbons. "Hydrazolylamino" means an r_C(=〇)_nh_ group, wherein the genomic group may be as defined herein; a thiol group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group It can be an end group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a nitrogen atom. As a group or a part of a group, "alkenyl" means having at least one carbon-carbon double bond and may preferably have 2 to 12 carbon atoms in the positive chain of 'better 2_H) carbon atoms, preferably 2·. A linear or branched aliphatic hydrocarbon group of 6 carbon atoms. The group may have a plurality of double bonds in the normal chain and the orientation of each bond is independently Ε or an exemplary dilute group including, but not limited to, vinyl, propylene butenyl, pentenyl, and Alkenyl, heptenyl, octenyl and decenyl. This group can be an end group or a bridging group. "Alkenyloxy" means an alkenyl group wherein alkenyl is as defined herein. Preferably, the alkenyloxy group is Cl_c6;)#-based oxy group. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an oxygen atom. Unless otherwise noted, "alkyl" refers to a straight or branched aliphatic hydrocarbon group, preferably a cyanoalkyl group, more preferably a Ci-Cio alkyl group, as part of a group or a group. Examples of the alkyl-based Ci-Ce-based substituent include a methyl group, a group, a n-butyl group, a second butyl group, a third butyl group, and the group may be a terminal group or a bridging group. Base, n-propyl, 2-propylhexyl and the like. Unless otherwise specified, "amino" "monoalkylaminoalkylamino" includes monoalkylamino and dialkyl means -NH- group 'where alkyl is as defined above in 152948.doc • 41- 201136930. "Dialkylamino" means an alkyl hN- group in which each fluorenyl group may be the same or different and each is as defined herein with respect to an alkyl group. The alkyl group is preferably a .--alkyl group. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a nitrogen atom. "Institutional amine carbonyl" means the formula (Alkyl) x (H) yNC (= a group of 0)-, wherein the alkyl group is as defined herein, and the sum of χ+γ = 2. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded via a carbonyl carbon. The remainder of the molecule. "Alkoxy" means an alkyl-hydrazone group wherein alkyl is as defined herein. S-saltoxy is preferably a c rC6 alkoxy. Examples include (but are not limited to) Alkoxy and ethoxy. The group may be a terminal group or a bridging group. "Alkoxy group" means an alkoxy-alkyl group, wherein the alkoxy group and the alkyl moiety are as herein As defined, the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via an alkyl group. "Alkoxyaryl" means an alkoxy-aryl group. a group of alkoxy groups And an aryl moiety is as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via an aryl group. "Alkoxycarbonyl" means an alkyl group. a group of _〇_(:(=〇)_, wherein alkyl is as defined herein. The alkyl group is preferably oxime, -alkyl. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a carbonyl carbon. "Alkoxycycloalkyl" means an alkoxy-cycloalkyl group. a group wherein the alkoxy and cycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remaining 152948 of the molecule via a cycloalkyl group. .doc • 42- 201136930 part. "Alkoxyheteroaryl" is a (tetra)oxy.heteroaryl group wherein the decyloxy and heteroaryl moieties are as defined herein. The group may be a terminal group. Or bridge. 纟. If the group is a terminal group, it is bonded to the rest of the molecule via a (iv) group. "Alkoxyheterocycloalkyl" means an alkoxy-heterocycloalkyl- group, Wherein the alkoxy and heterocycloalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a heterocycloalkyl group. "Alkylsulfinyl" means an alkyl group S_(= 〇)- group wherein alkyl is as defined herein. Preferably, the alkyl group is an alkyl group exemplified alkyl sulfinic acid/fluorenyl group. (but not limited to) methylsulfinyl and ethylsulfinyl. The group may be a terminal or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a sulfur atom. "Alkylsulfonyl" means an alkyl group -S(=0)2. group wherein alkyl is as defined above. The alkyl group is preferably fluorene alkyl. Examples include (but are not limited to) Methylsulfonyl and ethylsulfonyl. This group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a sulfur atom. 'As a group or a part of a group, "alkynyl" means having one carbon-, carbon-bonded and preferably having from 2 to 12 carbon atoms, more preferably from 2 to 10 carbon atoms in the normal chain, More preferably, the linear or branched aliphatic hydrocarbon group of 2 to 6 carbon atoms. Exemplary structures include, but are not limited to, ethynyl and propynyl. This group can be an end group or a bridging group. "Alkynyloxy" means an alkynyl-fluorene group wherein the alkynyl group is as defined herein 152948.doc -43·201136930. Preferably, the alkynyloxy group is a Cl_c6 fast oxy group. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via an oxygen atom. Aminoalkyl" means an NH;j-alkyl- group wherein the alkyl group is as defined herein. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a burn group. The amine-based sulfhydryl group J means an NH2_S(=0)2· group. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a sulfur atom. As a group or a part of a group, "aryl" means (1) a monocyclic or fused polycyclic aromatic carbocyclic ring (optional ring structure having a ring atom of carbon) which is optionally substituted. It has 5 to 12 atoms. Examples of the aryl group include a phenyl group, a naphthyl group and the like; (ii) a partially saturated bicyclic aromatic carbocyclic moiety which is optionally substituted, wherein the phenyl group and the C5·7 cycloalkyl group or the cycloalkenyl group are thick. Together, they form a cyclic structure such as tetrahydronaphthyl 'fluorenyl or indanyl. This group can be an end group or a bridging group. The aryl group is usually a C6_Ci8 aryl group. "Arylalkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein. Exemplary arylalkenyl groups include phenyl allyl groups. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an alkenyl group. "Arylalkyl" means an aryl-homo-based group wherein the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain an alkyl moiety. Exemplary aralkyl groups include benzyl, phenethyl, 丨-naphthylmethyl and 2-naphthylmethyl. The group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a 152948.doc 201136930. "Arylalkoxy" means an aryl-alkyl-0- group wherein the alkyl and aryl are as defined herein. This group can be an end group or a bridging group. If the group is a sulfhydryl group, it is bonded to the remainder of the molecule via an oxygen atom. Unless otherwise specified, "arylamino" includes monoarylamine and diarylamine. A monoarylamine group means a group of the formula aryl NH- wherein aryl is as defined herein. The diarylamine group means a group of the formula (aryl) wherein each aryl group may be the same or different and each is as defined herein for an aryl group. The group may be a terminal group or a bridging group. The group is bonded to the remainder of the molecule via an atomic atom. The arylheteroalkyl group means an aryl-heteroalkyl- group, wherein the aryl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, then the (four) pure group is bonded to the rest of the molecule. "Aryloxy" means an aryl group, wherein the aryl group is as defined herein Preferably, the aryloxy group is Ce-C, 8 aryloxy group, more preferably c6_CiQ aryloxy group. The group may be a terminal group or a bridging group 4, wherein the group is a silk, and then it is bonded to the molecule via an oxygen atom. The remainder of the phrase "arylsulfonyl" means an aryl-S(=〇)2. group, wherein the aryl group is as defined herein. The group may be a terminal group or a bridging group. If the (d) is The terminal group is bonded to the rest of the molecule via a sulfur atom. A "bond" is a bond between a compound or each atom in a molecule. The bond can be a single bond, a double bond, or a bond. "Cycloalkenyl" A non-tetracyclic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and preferably having 5 to 10 carbon atoms per ring. Exemplary monocyclic ring 152948.doc • 45- 201136930 Alkenyl ring including cyclopentane Alkenyl, cyclohexenyl or cycloheptenyl. The cycloalkenyl group may be substituted by one or more substituents. The cycloalkenyl group is typically a C3_Ci2 alkenyl group. The group may be a terminal group or a bridging group. Unless otherwise specified, Otherwise "cycloalkyl" means a saturated monocyclic or fused or spiro polycyclic carbocyclic ring, preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The group includes a monocyclic system such as a cyclopropyl group and a cyclohexyl group, a bicyclic system such as decalin, and a system such as adamantane. The cycloalkyl group is usually a Cs-C! 2 alkyl group. It may be a terminal group or a bridging group. "A ring-based alkyl group" means a ring-based group and a alkyl group, wherein the cyclohexyl and alkyl moieties are as defined herein. Exemplary monocyclic alkylalkyl groups include a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and a cycloheptyl fluorenyl group. The group may be a terminal group or a bridging group. If the group is a terminal group, it is via The alkyl group is bonded to the rest of the molecule. "Cycloalkylalkenyl" means a cycloalkyl-alkenyl- group wherein the cycloalkyl and alkenyl moieties are as defined herein. a group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via an alkenyl group. "Cycloalkylheteroalkyl" means a cycloalkyl-heteroalkyl- group, wherein The cycloalkyl and heteroalkyl moieties are as defined herein. The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a heteroalkyl group. "A" refers to a cycloalkyl-hydrazine group wherein cycloalkyl is as defined herein. The cycloalkoxy group is preferably a Cl_C6 cycloalkoxy group. Examples include, but are not limited to, cyclopropoxy and cyclobutoxy The group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via an oxygen atom. "N-alkenyloxy" means a cycloalkenyl group, wherein the cyclol group is preferably a q-oxy group as defined herein (: a cardinyloxy group. The group may be a terminal group or a bridging group. The group is a terminal group' which is bonded to the rest of the moiety via an oxygen atom. 77 "Haloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms are selected from the group consisting of fluorine, a, The halogen atom of the group consisting of bromine and iodine is substituted. The halogen group usually has the formula CnH(2n+im)Xm, and each of the X groups is independently selected from the group consisting of F, Cb, and I. The group 'n is usually from 10 to 10, more preferably from 1 to 6, most preferably u3em is usually from 丨 to 6, more preferably from work to 3. Examples of the alkyl group include fluoromethyl, difluoromethyl and Fluoromethyl. "(4)", refers to an alkenyl group as defined herein, "middle- or multiple gas atoms are replaced by a group of atoms independently selected from the group consisting of F, α, ~, and !" "A" refers to an alkynyl group, as defined herein, wherein - or a plurality of hydrogen atoms are independently replaced by a group of (tetra) atoms consisting of F, C1, B, ... "i" means chlorine, fluorine, bromine or iodine "Hybrid" means a straight or branched chain of a chain preferably having from 2 to 12 carbons, more preferably from 2 to 6 carbons, wherein - one carbon atom (and any associated hydrogen atom) is independent The ground is selected from the hetero atomic group (4), which is selected from the group of sighs, where R is selected from the C.C12 ring group substituted by H, as the case may be substituted, and the C3.C12 ring leunt group substituted by the case. And a group of substituted Cl_Cl8 heteroaryl groups as appropriate. Exemplary miscellaneous s 152948.doc • 47· 201136930 includes alkyl ethers, secondary and tertiary alkylamines, decylamines, alkyl sulfides and the like Examples of the compound base include hydroxyCl-c6 alkyl, Ci-Cs alkoxy cvc6 alkyl, amine CrC6 alkyl, (^-(^alkylamino c-c6 alkyl and two ( C^-C: 6 alkyl)amino C" (: 6 alkyl. The group may be a terminal group or a bridging group. "Heteroalkoxy J means a heteroalkyl-0- group in which a heteroalkyl group The heteroalkoxy group is preferably a C2_C: 6 heteroalkoxy group. The group may be a terminal group or a bridging group. Separately or as part of a group, "heteroaryl" means containing Have one or more in the ring A group in which an atom is a ring atom and the remaining ring atoms are an aromatic ring of a carbon atom (preferably a 5- or 6-membered aromatic ring). Suitable hetero atoms include nitrogen, oxygen and sulfur. Examples of heteroaryl groups include thiophene and stupid. And thiophene, benzopyrene, benzopyrene, benzoxazole, benzothiazole, stupid and scorpion saliva, Cai 幷 [2,3-b] thiophene, furan, isooxazine, dibenzopyrazine Orphan, morphine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, hydrazine, 3%, nitrone, tetrazole, hydrazine, isoindole, 1H-carbazole, stupid triazole , 呤, quinoline, isoquinoline, pyridazine, acridine, quinoxaline, porphyrin, oxazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole Oxazole, 1,2,3-oxadiazole, 丨'2,4-oxadiazole, 1,2,3-triazole, triazole, 1,2,4-thiadiazole, thiadiazole, furazan , phenoxazine, indole pyridyl, 3-pyridyl or 4-pyridyl, 2-quinolinyl, 3-quinolyl, 4-quinolinyl, 5-quinolinyl or 8-quinolinyl, 1 -isoquinolyl, 3-isoquinolinyl, 4 isoindolyl or 5-isoquinolinyl, 1 fluorenyl, 2-indenyl or 3_ι β 2-thienyl group and a thienyl group or 3_. The heteroaryl group is usually a gCi_Cu heteroaryl group. This group can be an end group or a bridging group. 152948.doc •48·201136930 Heteroarylalkyl” means a heteroaryl-alkyl group wherein the heteroaryl and alkyl moieties are as defined herein. Preferably, the heteroarylalkyl group contains a lower alkyl moiety. Exemplary non-heteroarylalkyl groups include pyridylmethyl. This group can be an end group or a bridging group. If the group is terminal &, it is bonded to the remainder of the molecule via the nodal group. "Heteroarylalkenyl" means a heteroaryl.thenyl group wherein the heteroaryl and dilute moieties are as defined herein. This group can be an end group or a bridging group. If "Hai, the group is a terminal group", its (4) group is bonded to the rest of the molecule. "Heteroaryl" means "heteroaryl-heteroalkyl-group" where the impurity = and miscellaneous The base moiety is as defined herein. The group may be a terminal group or a bridge group. The group is a terminal group, and then it is bonded to a part of the molecule via a miscellaneous group. The "heteroaryloxy group" means a heteroaryl group - 0- group, and the heteroaryl group such as the quinone heteroaryloxy group is preferably a Ci_c]8 heteroaryloxy group. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an oxygen atom. "Heterocyclic" means a heterocyclic ring containing at least one selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom, a double «polyunsaturated or fully unsaturated monocyclic and heteroaryl group. Examples of the clothes portion include a heterocycloalkyl group, a heterocycloalkylene group, and a hetero-alkyl group which is defined by the sth' θ θ but contains at least one double bond. Heterocyclenyl end group or bridging group. Is a heterocyclenyl group. The group may be "heterocycloalkyl" means at least one hetero atom selected from the group consisting of 152948.doc -49·201136930 nitrogen, sulfur, oxygen, preferably to a hetero atom. Saturated monocyclic, bicyclic or polycyclic. Each ring is preferably from 3 to 10 members, more preferably from 4 to 7 members. Examples of suitable heterocycloalkyl substituents include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 13-diazacycloheptane, 1 , 4-diazacycloheptane, i, 4-oxocycloheptane and anthracene, 4-oxothioheptane. The heterocycloalkyl group is usually C: 2_C 2 heterocycloalkyl. This group can be an end group or a bridging group. "Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl- group wherein the heterocycloalkyl and alkyl moieties are as defined herein. Exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuranyl)methyl and (2. tetrahydrothiofuranyl)methyl. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via an alkyl group. "Heterocycloalkylalkenyl" means a heterocycloalkyl-alkenyl- group wherein the heterocycloalkyl and alkenyl moieties are as defined herein. This group can be an end group or a bridging group. If the group is a terminal group', it is bonded to the remainder of the molecule via an alkenyl group. "Heterocycloalkylheteroalkyl" means a heterocycloalkyl-heteroalkyl- group wherein the heterocycloalkyl and heteroalkyl moieties are as defined herein. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a heteroalkyl group. "Heterocycloalkoxy" means a heterocycloalkyl-indenyl group, wherein the heterocycloalkyl is as defined herein. The heterocycloalkoxy group is preferably a Cl-C6 heterocycloalkoxy group. This group can be an end group or a bridging group. If the base ring is a terminal group, it is bonded to the rest of the molecule via an oxygen atom. 152948.doc • 50·201136930 Hetero-l-oxyloxy” means a heterocycloalkenyl-G group, the heterocyclic ring of which is defined herein as a heterocyclic oxime group, preferably a ^_C6 heterocyclic oxy group. This group can be an end group or a bridging group. If the group is a terminal group', it is bonded to the rest of the molecule via an oxygen atom. "Hydroxyl" means a radical as defined herein, wherein one or more hydrogen atoms are replaced by an OH group. The base group usually has the formula _) just. In this type of group +, n is usually preferably (1) and most is '1 to 3. ;^ is usually from 1 to 6, more preferably from 丨 to 3. Unless otherwise specified, as a group, "low carbon yard" means an aliphatic hydrocarbon group which may be a straight or branched chain having from 1 to 6 carbon atoms, more preferably from 4 to 4 carbon atoms in the chain, such as Base, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tert-butyl). This group can be an end group or a bridging group. "Alkyl" means an R-S(=〇)- group, wherein the r group can be OH, alkyl, cycloalkyl, heterocycloalkyl, as defined herein; aryl or heteroaryl. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule via a sulfur atom. "Sulphonylamino" means an RS(=0)-NH- group, wherein the R group can be OH, alkyl, cycloalkyl, heterocycloalkyl as defined herein; aryl or hetero Aryl. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a nitrogen atom. "Sulphonyl" means an R-S(=0)2- group wherein the R group can be OH, alkyl, cycloalkyl, heterocycloalkyl, as defined herein; aryl or heteroaryl. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a 152948.doc • 51-201136930 sulfur atom. "Sulfonylamino" means an R-S(=〇)2_NH- group. This group can be an end group or a bridging group. If the group is a terminal group, it is bonded to the rest of the molecule via a nitrogen atom. It is to be understood that the steroids of the formula (I) include diastereomers, enantiomers, tautomers and mixtures of the "Ej or ΓΖ" configuration or the oxime isomers. Heterogeneous forms of geometric isomers. It will also be appreciated that some isomeric forms such as diastereomers, enantiomers and geometric isomers may be separated by physical and/or chemical methods by those skilled in the art. Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or as mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter recited. Further, if appropriate, formula (I) is intended to cover the solvation of the compounds and the unsolvated form S. Thus, each 4 includes a compound' having the indicated structure' including both hydrated and non-hydrated forms. The term "pharmaceutically acceptable salts", refers to salts which retain the desired biological activity of the compounds identified above, and includes pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acids for the compounds of formula (1) Addition salts can be prepared from inorganic acids or from organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid and scaly acid. Suitable organic acids may be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, heterocyclic and acid acids of organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, apples. Acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, aryl 152948.doc -52·201136930 sulfonic acid. Additional information regarding pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of solid pharmaceuticals, it will be understood by those skilled in the art that the compounds, reagents and salts of the present invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and the specified formula. "Prodrug" means a compound that undergoes conversion to a compound of formula (I), usually by metabolic means (e.g., by hydrolysis, reduction or oxidation), within a biological system. For example, a prodrug containing a compound of formula (I) can be converted to a parent molecule by in vivo hydrolysis. Suitable esters of the compound of formula (I) containing a hydroxy group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates , fumarate, maleate, methylene-bis-β-hydroxynaphthalate, gentisate, isethionate, di-p-quinone-based tartrate, hydrazine Alkane sulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylaminosulfonate, and quinate. As another example, an ester prodrug of a compound of formula (I) containing a carboxyl group can be converted to a parent molecule by hydrolysis in vivo. (Examples of prodrugs are F.J. Leinweber, Drug Metab. Res., 1 8:379, 1987, their prodrugs). Similarly, a sulfhydryl prodrug of a compound of formula (I) containing a hydroxy group can be converted to a parent molecule by in vivo hydrolysis. (Many examples of prodrugs used in these and other functional groups (including amines) are described in Prodrugs: Challenges and Rewards (Parts 1 and 2); V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag and J Tilley; Springer, 2007). The term "protecting group for oxygen" means a group which prevents the oxygen moiety from reacting during further derivatization of the protected compound 152948.doc •53·201136930 and which can be easily removed as needed. In one embodiment, the protecting group is removed under physiological conditions by a natural metabolic process and the substantially protected compound acts as a prodrug for the active unprotected material. Examples of the protecting group for oxygen include a mercapto group (such as an ethylidene group), an ether (such as methoxy fluorene scale (MOM), anthracene-methoxy ethoxy oxime (ΜΕΜ), p-methoxy anisole ( ΡΜΒ), methylthiomethyl ether, pentyl (piv), tetrahydropyran (THP)) and the stone burial mystery (such as triterpene (tms), t-butyl dimethyl Teddy base (TBDMS) and triisopropyl sylvestris. The term "nitrogen protecting group" means a group which prevents the nitrogen moiety from reacting during further derivatization of the protected compound and which can be easily removed when needed. In one embodiment, the protecting group is removed under physiological conditions by a natural metabolic process and the substantially protected compound acts as a prodrug for the unprotected substance. A suitable nitrogen protecting group can be used. Examples include mercapto, trityl, phthalimidoethylamino, triethylene sulfonyl, acetophenone, sulphate, sulphate; urethane type Blocking groups, such as stupid methoxy group ("CBz"), 4-phenylbenzoquinone oxo, 2-mercaptobenzoxanyl, 4-decyl benzoyl Carbonyl, 4·fluorobenzyloxycarbonyl, 4-acetomethoxycarbonyl, 3-oxobenzyloxycarbonyl, 2-p-benzophenoxycarbonyl, 2,4-dioxamethyloxycarbonyl, 4-bromobenzyl Oxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitro-p-methoxycarbonyl, 4-cyanobenzyloxycarbonyl, tert-butoxycarbonyl ("tBoc"), 2-(4-biphenyl)- Isopropyloxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylpropan-1-yloxycarbonyl, 2-phenylpropan-2-yloxycarbonyl, 2· (p-tolylmethyl)-propan-2-yloxycarbonyl, cyclopentyloxycarbonyl, 1-methylcyclopentoxycarbyl, cyclohexyloxycarbonyl, 1-methylcyclohexyloxycarbonyl, 2-indenyl Cyclohexyloxyl charcoal 152948.doc • 54· 201136930 base, 2-(4-methyl carbaryl sulfonyl) ethoxycarbonyl, 2-(methylsulfonyl) ethoxylate ' 2- (three Phenylphosphine) · ethoxycarbonyl, fluorenyl oxycarbonyl ("FMOC"), 2 - (trimethyl decyl) ethoxycarbonyl, allyloxycarbonyl, 1 - (trimethyldecylmethyl) propyl Ethoxycarbonyl, 5-benzoxazole, oxacarbonyl, 4-ethyloxybenzoquinoneoxycarbonyl, 2,2,2•trichloroethoxycarbonyl '2-ethylidene-2-propoxycarbonyl Cyclopropyl Methoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1 ·piperidinyloxycarbonyl and the like; benzhydrylsulfonyl, 2-nitrobenzene The sulfenyl group, the diphenylphosphine oxide and the like. The actual nitrogen protecting group used is not critical as long as the nitrogen group derived is stable under subsequent reaction conditions and can be selectively removed as needed Substantially destroy the rest of the molecule (including any other nitrogen protecting groups). Other examples of such groups are found in: Greene, τ. W. and Wuts, Ρ·G. Μ., Protective Groups in Organic Synthesis,

Second edition; Wiley-Interscience: 1991; Chapter 7; McOmie JFW (ed.), Protective Groups in Organic Chemistry, Plenum Press, 1973; and Kocienski, PJ, pr〇tecting Groups, Second Edition, Theime Medical Pub, 2000 . The term "therapeutically effective amount" or "effective amount" is an amount sufficient to achieve a beneficial or desired clinical result. An effective amount can be administered by one or more administrations. The effective amount is usually sufficient to alleviate, improve, stabilize, reverse, slow or delay the progression of the disease state. The term "functional equivalent" is intended to include variants of the specified protein kinase species described herein. It will be appreciated that kinases may have isoforms such that when a particular kinase has a grade, secondary, tertiary or quaternary structure different from the prototype kinase 152948.doc • 55· 201136930 Knife maintains biological activity as a protein kinase. Isoforms can be produced from normal dual gene variations in a population and include mutations such as amino acid extraction, loss of addition, truncation or repetition. The term "functional equivalent" is also included in the transcription of t, including alteration of post-transformation variants. Other functional equivalents (4) Post-repair (eg, brewing) kinases. Specific compounds of the invention include the following:

ΝΗ-

152948.doc •56· 201136930

152948.doc -57- 201136930

152948.doc •58- 201136930

NH-

Or a pharmaceutically acceptable salt or prodrug thereof. The ability of such compounds to inhibit the activity of certain protein kinases can be a direct and singular activity of the compound. The inhibition of biological activity by sputum inhibition and the early action of kinase molecules should be understood. The compound may also act as a cofactor for the kinase in question involved in the phosphorylation process. /Chemicals may have activity against certain serine/threonine kinases, such as mTOR or fragments or complexes or functional equivalents thereof. The inhibition of protein kinases may be in the manner well known in the art. 152948.doc • 59-201136930. For example, if an in vitro inhibition of protein kinase is required, an appropriate amount of the compound can be added to the solution containing the kinase. Inhibition of kinase activity in mammals is required. Inhibition of kinases typically involves the administration of a compound to a mammal containing a kinase. Thus, a compound can have a variety of applications where it can be used to inhibit the ability of a protein kinase of the above type. For example, a compound can be used to inhibit serine/thorn Amino acid protein kinase. The compound can also be used to treat or prevent a condition in a mammal, wherein inhibition of the protein kinase and/or its cofactor can prevent, inhibit or ameliorate the pathology or symptoms of the condition. It is expected that the compound of the present invention will be applied. For treating various conditions associated with (7) (10) kinase, including a condition selected from the group consisting of inflammation, rheumatoid Tube inflammation, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, adrenitis, multiple sclerosis, autoimmune disease, lupus, allergic encephalomyelitis, transplant rejection, endometriosis Symptoms, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, 胄-dependent diabetes, obesity, diabetic retinopathy , cardiac hypertrophy, autologous dominant polynephrosis"" The compounds of the invention are expected to be suitable for the treatment of various cancers including, but not limited to, bone cancer, brain and CNS tumors, breast cancer, colorectal cancer, endocrine cancer (including the adrenal gland) Cortical cancer), pancreatic cancer, pituitary cancer, thyroid cancer, accessory squamous adenocarcinoma, thymic carcinoma, intestinal cancer, liver cancer, extrahepatic cholangiocarcinoma, gastrointestinal cancer, gallbladder cancer, genitourinary cancer, gynecological cancer, head and neck Cancer, leukemia, myeloma, hematological disease, lung cancer, lymphoma, eye cancer, skin 152948.doc -60- 201136930 Cancer, soft tissue sarcoma 'adult soft tissue sarcoma, Kaposi's meat Tumor, urinary tract cancer. Exemplary cancers that can be treated by the compounds of the invention include hematological cancers, such as myeloproliferative disorders (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic myeloid leukemia) ), bone marrow cell metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute red blood cell blastin, Hodgkin's and non-Hodgkin's disease, b-cell lymphoma, acute tau cell leukemia, bone Zhao dysplasia syndrome, plasma cell disease, hairy cell leukemia, Kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, Indian cancer, cervical cancer, vaginal cancer and vulvar cancer, endometrial hyperplasia; gastrointestinal tract Cancer, such as colorectal cancer, polyp, liver cancer, stomach cancer, smear cancer, gallbladder cancer; urinary tract cancer, such as prostate cancer, kidney cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer, such as melanoma; brain tumor , such as glioblastoma, neuroblastoma, astrocytoma, ependymoma, brain stem glioma, nerve Germ cell tumor, meningioma, astrocytoma, oligodendrocyte head and neck; such as nasal cancer, laryngeal cancer; respiratory cancer, such as lung cancer SCLC), fa's skin tumor; eye disease 'such as retinoblastoma; musculoskeletal; Such as sarcoma, musculoskeletal tumors; squamous cell carcinoma and fibroids. The s substance can also be used for the preparation of an agent for treating an animal condition, wherein protein inhibition inhibits, inhibits or ameliorates the pathology or symptoms of the condition. The compounds are also useful in the preparation of a medicament for the treatment or prevention of a kinase-related disorder. Administration of a compound of formula (1) to humans can be by any acceptable enteral dosage form (e.g., oral or rectal), or by parenteral administration (such as subcutaneous, intramuscular, Intravenous and intradermal routes). The injection can be a bolus or via continuous or intermittent infusion. The active compound will usually be included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient. In various embodiments, the inhibitor compound can be rapidly associated with, for example, a cancerous tumor as compared to normal cells. Proliferating cells are more selective or more toxic. When a compound is used, it can be administered in any form or mode that renders the compound bioavailable. Those skilled in the art of formulating preparations may select the appropriate dosage form and mode according to the specific characteristics of the selected compound, the condition to be treated, the stage of the condition to be treated, and other related conditions. For reference, refer to RemingtonsPh-like (5) coffee, (4) version , CkPubhshingCo. (1995) to obtain further funding1. The compound can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient. Although the compound itself = yang, it is usually formulated and administered in the form of its pharmaceutically acceptable salt: because these forms are generally more stable, easier to crystallize and have a higher solubility, however, the compounds are usually in the desired mode of administration. It is used in the form of a formulated pharmaceutical composition. Thus, in some embodiments, the ', and the pharmaceutically acceptable carrier comprises a pharmaceutical group of formula (1) #释剂 or excipient. Things. This proprietary composition is prepared by techniques well known in the art. In other embodiments, the present teachings provide a pharmaceutical package or kit that includes one or more of the benefits of a pharmaceutical composition or ingredients. In the package or kit, there may be a volume of 152948.doc • 62·201136930 with a dose of the early dose. The kits can include compositions (including lyophilized compositions) comprising an effective pharmaceutical agent in the form of a concentrate, which can be further diluted prior to use, or can be provided in a concentration of use wherein the vial can include - or multiple doses . Conveniently, in such kits, a single dose can be provided from a sterile vial to allow the physician to directly utilize the vials, wherein the vials will have the desired amount and concentration of the medicament. Various written materials such as instructions for use or precautions in the form prescribed by government agencies that regulate the manufacture, use or sale of drugs or biological products may be provided with the container, which reflects the approval of the institution for human administration. Manufacture, use or sale. The compound can be used or administered in combination with one or more other drugs that treat the mentioned condition/disease. The components may be administered in the same formulation or in the form of separate formulations. If administered in separate formulations, the compound can be administered sequentially or simultaneously with other drugs. In addition to being administered in combination with - or a combination of other drugs, the compounds may also be used in combination therapy. When so carried out, the compounds are usually administered in combination with each other: Alternatively, one or more of the compounds may be simultaneously (in the form of a combined formulation) or phase = -, to achieve the desired effect. When the material form of each compound is different, such that the combination of the two drugs provides a pharmaceutical composition of the present invention which is modified by parenteral injection comprising a medically acceptable sterile aqueous or non-aqueous solution, medical music. On τ ^ ^ Knife Liquid, Suspension Liquid or Emulsion, 乂 and ... 籾 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Examples of vehicles include water, ethanol, poly (pan such as glycerol, propylene glycol, polyethyl 152948.doc-63-201136930 diols and the like) and suitable mixtures thereof, vegetable oils (such as eucalyptus oil) and injectables. Organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, in the case of a dispersion, by maintenance of the desired particle size, and by the use of a surfactant.曰 These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Microbial action can be prevented by including various antibacterial and antifungal agents (e.g., benzoic acid vinegar, chlorobutanol, benzoate, sorbic acid, and the like). It may also be desirable to include an isotonic agent such as a sugar, sodium vaporate, and the like. Injectable pharmaceutical forms can be extended by the inclusion of delayed absorbents such as monostearate and gelatin. If desired, and for more efficient distribution, the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by combining the sterilizing agents in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use. Solid dosage forms for oral administration include capsules, lozenges, pills, powders and granules. In such solid dosage forms the 'active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dibasic calcium phosphate) and/or the following: filler or increment Agents such as powder, lactose, vegetable sugar, glucose, mannitol, and aspartic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyethylene beta-pyrrolidone, sucrose, and gum arabic ; C) humectant, such as glycerin; d) disintegrant, for example, 152948.doc -64 - 201136930 Qiongyue, calcium carbonate, horse yam or wood. Powder, alginic acid, certain citrate and sodium citrate , e) solution blockers such as paraffin; f) absorption enhancers, such as quaternary compounds; g) ' 'such as cetyl alcohol and glyceryl monostearate, Η) adsorbents, such as kaolin and doors Soil, and 1) lubricants such as talc, calcium stearate 'stearic acid ^ solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of gelatine, Yujie 隹 capsules and pills, the dosage form may also contain a buffer. A similar type of solid group is referred to as π m . 々 can also be used as a filler in soft-filled and hard-filled gelatin capsules, such as lactose (lactose/milk sputum excipients and high molecular weight polyethylene glycols and the like). 0 匕 及 及 ( ( ( ( ( ( ( ( ( ( ( ( ( ( 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体 固体The delayed method is only or preferably in the intestines, a combination of Qiu Renyue, You Shi, and 4 minutes to release the active ingredient. The embedding can be used, and the composition of the composition includes the polymerization #质和蜡. The active compound may also be in microencapsulated form with or a plurality of the above-mentioned excipients. Liquid dosage forms for mouthwash administration include pharmaceutically acceptable emulsions, solutions, suspensions, sugars and ugly agents. The liquid dosage form may contain inert dilute (4) commonly used in the art, such as water or other solvents, co-solvents and emulsifiers, such as ethanol, isopropanol, ethylene carbonate, ethyl acetate, benzoquinone benzene benzoate Oxime ester, C Glycol, hydrazine, 3-butanediol, dimercaptoamine, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, poly 152948 .doc -65- 201136930 Fatty acid esters of ethylene glycol and sorbitan and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetters, lotions, emulsifiers and suspending agents, sweetness Agents, flavoring agents and flavoring agents. In addition to the active compounds, the suspension may also contain suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose. , aluminum partial aluminum hydroxide, bentonite, agar and tragacanth and mixtures thereof. 0 The composition for rectal or vaginal administration is preferably a suppository, which can be prepared by combining the compound of the present invention with a non-irritating excipient or carrier. Prepared by mixing, such as cocoa butter, polyethylene glycol or wax, which is solid at room temperature but liquid at body temperature and thus melts in the rectum or vaginal cavity and Release of the active compound. For use in the present invention Dosage forms for topical administration of the compounds include powders, patches, sprays, ointments and inhalants. The active compounds are mixed under sterile conditions withpharmaceutically acceptable carriers and any required preservatives, buffers or propellants which may be required. Preferably, the amount of the compound administered will treat and reduce or slow the condition. The therapeutically effective amount can be readily determined by the attending diagnostician using known techniques and observing the results obtained under similar circumstances. In determining the therapeutically effective amount, many should be considered. Factors include, but are not limited to, the species of the animal, its size, age, and the overall condition involved in the health of the condition, the severity of the condition, the specific compound to which the patient responds to the treatment, the mode of administration, and the mode of administration. Bioavailability of the formulation, selected dosing regimen, use of other agents, and other relevant conditions. 152948.doc •66- 201136930 The preferred dose will range from about 0.01 mg to 300 mg per kilogram of body weight per day. The preferred agent will be from 1 mg to 100 mg per kilogram of body weight per day, more preferably from 0.2 mg to 80 mg per kilogram of body weight per day, and more preferably from 0.2 mg to 50 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day. Synthesis of Compounds of the Invention The agents of the various embodiments can be prepared using the reaction routes and synthetic procedures described below using techniques readily available in the art using readily available starting materials. The preparation of specific compounds of the examples is described in detail in the following examples, but the skilled artisan will recognize that the chemical reactions can be readily adapted to the preparation of many other agents of various embodiments. For example, the synthesis of a non-exemplified compound can be successfully carried out by modifications apparent to those skilled in the art, for example, by appropriate protection of the interfering group, by becoming other suitable reagents known in the art or by The reaction conditions were routinely modified. One of the organic synthesis suitable for protecting groups can be found in Tw Greeneis

Protective Groups, 〇rganic Synthesis, 3rd edition, John Wiley & Sons, 1991. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for the preparation of other compounds of the various embodiments. Suitable reagents for the synthesis of the compounds can be obtained or prepared according to techniques known in the art. General Synthetic Process Various - Substituted 嘌呤 can be prepared in a straightforward three-step procedure using 2,6-dichloropurine as a starting material. The 2,6-dichloro(tetra) is purchased from many sources or can be obtained from 嘌呤_2,6 - Diketone or Astragalus itself, using, for example, phosphonium chloride (Indian Journal 〇f Chemistry, ^B: Organic Chemistry 152948.doc •67- 201136930

Including Medicinal Chemistry·, 23; 12; 1984; 1286-1288). A generic representative procedure is shown in Flow 1. Process 1

As shown, the initial reaction of 2,6-dioxane with an alkyl halide produces alkylation at the 9 position, 2〇〇1, 20(4-7), 1067). In a typical procedure, the alcohol can be reacted with 2,6·dione in the presence of a phosphine and an activator such as diethyl azodicarboxylate. Alternatively, the alkyl halide can be reacted with the starting oxime in the presence of a suitable base such as potassium carbonate to achieve a similar alkylation. Me Mountain.cz.wa/ CTzewzjir;; 2004, 14(11), 2955) . Subsequent palladium catalyzed coupling with a suitable aryl-p-acid or ester followed by the production of an intermediate 1995, 36, 1 1, 1945, Collect. Czech. Chem. Commun. 2002 67, 325). Addition of oxa-3-aza-bicyclo[3.2.1]octane Process Research & Development 2010, 14, 459) can then be carried out at elevated temperatures or using microwave radiation in suitable solvents (such as DMA, 152948) .doc -68 - 201136930 NMP, DMF or THF) is carried out to produce the desired trisubstituted enthalpy. Process 2

The R1 substituent can be changed by using 8-substituted dihalogen as a starting material (Scheme 1) or can be introduced later in the synthesis sequence (Scheme 2). For example, a chemical reaction can be performed at 8 positions after the sequence described in the above Scheme 1 is completed. For example, the 4-8 position can be brominated to produce 5. The bromide can then be replaced by, for example, an organometallic agent such as organozinc to mount R1 as in 6. Scheme 3 describes three variations in the three-step procedure in which the first step 152948.doc -69-201136930 uses different conditions to introduce different substituents at the 9 position of the anthracene skeleton. However, the 'principle' skilled attainment can modify the general reaction scheme shown in Scheme 1, in which the nitrogen portion of the 9-position of the ruthenium can react with a portion of the reactant containing a suitable leaving group (such as a _ compound). The nitrogen is displaced from the leaving group to form a nitrogen at the 9 position followed by a functionalized compound. Derivatives suitable for use in this type of reaction and which may be replaced by nitrogen in such reactions are those known in the art and which generally contain a portion of this type of leaving group for use in such types of reactions. As is well known to those skilled in the art, as shown in Scheme 3, the three simplest ways to obtain a compound of the invention involve dichloropurine with an aryl group (such as a benzyl group) or a heteroaryl group. a base halide (to introduce an aryl or heteroaryl substituted methyl" alcohol at the 9 position (to introduce a disubstituted fluorenyl group at the 9 position) or an aryl or heteroaryl § acid (to directly introduce an aryl group) Or heteroaryl) reaction. 152948.doc •70· 201136930 Process 3 jrSrN^ CI^N^N Η

In the examples described below, all temperatures in the following description are in degrees Celsius unless otherwise indicated and all parts and percentages are by weight unless otherwise indicated. Various starting materials and their domain agents are from, for example, Aldrich

The chemical supplier of Company or Lancaster Synthesis Ltd., and unless otherwise indicated, these materials can be used without further purification. Tetrahydrofuran (THF) and N,N-di-f-carboxamide (DMF) are constructed from a bottle

Aldrich is used as received. All solvents were purified by standard methods in the art, unless otherwise indicated. The reaction described below is carried out under a positive pressure of nitrogen, g ^ ^ 虱 rolling or using a dry 152948.doc • 71- 201136930 tube, at ambient temperature (unless otherwise specified), in an anhydrous solvent, and The reaction flask was equipped with a rubber septum for introduction of the receptor and reagent via a syringe. The glassware is dried by oven and/or dried by heating. The analytical thin layer was carried out on a glass bottom silicone 60 F 254 plate (E MerCk (0.25 mm)) and dissolved at a suitable solvent ratio (v/v). The reaction is terminated by TLC and as judged by the depletion of the starting material. The TLC plate was examined by UV absorption or by using an anisaldehyde spray reagent or a phosphomolybdic acid reagent (Aldrich Chemica 20 wt% ethanol solution) which was heat activated or by staining in an iodine chamber. The treatment volume is usually treated by doubling the reaction volume with a reaction solvent or an extraction solvent, followed by washing with the indicated aqueous solution using a 25% by volume extraction volume (unless otherwise indicated). The product solution was dried over anhydrous sodium sulfate, followed by filtration under reduced pressure on a rotary evaporator and evaporation of solvent and was taken care of. Unless otherwise specified, flash column chromatography [Still et al, J. Org. Chem., 43, 2923 (1978)] uses E Merck grade sputum (40-63 μιη) and approximately 20:1 to 5 〇. :1 Shishi gum: The crude material ratio is carried out. Hydrogenolysis is carried out under the indicated pressure or at ambient pressure. NMR spectra were recorded on a Bruker instrument at 400 MHz and nC-NMR spectra were recorded at 1 〇〇 MHz. NMR spectra were obtained as CDC13 solutions using chloroform as a reference standard (7 27 ppm and 77.00 ppm) or using CD3OD (3.4 and 4.8 ppm and 49.3 ppm) or, if appropriate, internal tetradecyl decane standards (〇.00 ppm) (Reported in ppm). Use other NMR solvents as needed. When reporting peak diversity, the following abbreviations are used: s = singlet, doublet, t = triplet, m = multiplet, br = wide, 152948.doc -72 · 201136930 dd = doublet, dt == The double peak of the triplet. The coupling constant (when given) is reported in Hertz. Mass spectra were obtained using ESI or APCI using LC/MS. All melting points are unresolved The reaction requiring microwave irradiation is carried out in a CEM Discover s-c/au reactor. All final products were more than 90% pure (obtained at 220 nm and 254 nm according to HPLC). The following examples are intended to illustrate the disclosed embodiments and are not to be construed as limiting. Other compounds than the compounds described below can be prepared using the reaction schemes described below or their appropriate changes or modifications. General procedure

2,6-dioxane (1 equivalent), alcohol (丨_3 equivalent), and triphenylphosphine (丨·〗) are dissolved in a suitable organic solvent (for example, THF) to 〇·ι_〇·2 The intensity of Μ. Dialkyl azodicarboxylate (1-2 equivalents) or an equivalent coupler was added dropwise to the solution at room temperature over about 30 minutes. The reaction mixture was stirred at around 6 Torr for about 12-24 hours. Transformation was monitored by TLC and/or LC/MS. The reaction mixture was then quenched with ice cold water. The aqueous layer is extracted with an organic solvent such as ethyl acetate or methylene chloride to give a crude material. Purification can then be carried out on a silicone column 152948.doc -73-201136930 using a suitable solvent system to give an iv-substituted oxime. Suzuki Coupling

Cl xV'〉

Cl human 〆^ R, substituted digas (1 equivalent), 5-aminopyrazine-2-lemonic acid pinacol ester (1 equivalent) and palladium (II) catalyst complex (5·1〇 M〇1%) dissolved in a peroxide-free organic solvent (0·05·0·1 M) (such as dioxane, DME or THF) with the addition of 2 Μ sodium carbonate or potassium carbonate aqueous solution (4 equivalents) Thereafter, the reaction mixture was degassed and purged with nitrogen. The reaction mixture was then stirred for 1 to 5 hours on an oil bath maintained at 6 〇 1 Torr. Regarding the disappearance of the starting mash, the transformation was monitored by LC/MS. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic phase was separated and the aqueous layer was extracted with several portions of ethyl acetate. Drying over sodium sulfate: organic layer and removing the solvent under vacuum, yielding 5 _alkyl groups. 不 令 · ) ) “ 粗 粗 粗 粗 粗 粗 粗 粗 粗 粗 粗 粗 粗 粗 粗 粗 粗 粗The next stage. 8_oxa-3·aza-bicyclic 丨^"octane addition 152948.doc •74· 201136930

In the sealed vial, use microwave radiation at 5〇18〇(>c will contain 5_

Suitable polar microwave active solvents (such as Nmp, DMA or DMF) of 3-aza-bicyclo[3.2.1]octane hydrochloride (5_1 〇 equivalent) and triethylamine (5 +1 (eq) equivalent) (0.05-1 M) Heat for 20-40 minutes. Regarding product formation, the conversion can be monitored by LCMS. The crude material was purified by chromatography to give the desired tri-substituted. Example 1, Compound 6 Synthesis of 2,6-dioxa-9-(1-ethyl-propyl)·9Η嘌呤

2,6·Dichloro oxime (10.58 mm 〇l, 1 eq.), 3 pentanol (15.87 mm 〇l, 1.5 eq.) and triphenylphosphine (15.87 mmol, 1.5 eq.) were dissolved in 80 ml of anhydrous four. Diisopropyl azodicarboxylate (1587 mm 〇 1, 15 equivalents) was added dropwise thereto at room temperature over 3 minutes in argon. The reaction mixture was stirred at room temperature for 24 hours. Transformation was measured by TLC or LC/MSg. The reaction mixture was poured into a beaker containing ice-cold water. The aqueous layer was extracted with 3 portions of 1 〇〇 mi 152948.doc -75·201136930 ethyl acetate to give a crude product. This product was purified on a silica gel column (5-6 % ethyl acetate in petroleum ether, gradient elution) to yield the desired compound yield of 75% (2.4 g). NMR CDC13 (ppm): 8.12 (s, 1H); 4.46 (m, 1H); 2.05 (m, 4H); 0.96 (t, 6H). Synthesis of 5-[2-gas-9-(1-ethyl-propyl)·9η·嘌呤·6-yl]-pyrazin-2-ylamine

To 2,6-dichloro-9-(1-ethyl-propyl)_9Η-嘌呤 (1 mm〇1,i equivalent), 5-aminopyrazine-2-carboxate pinacol ester (1 mm 〇1,i equivalent) and ^,-bis(diphenylphosphino)ferrocene gasified palladium (11) complex with diqi methane (7) i mmo b 10 mol%) in peroxide-free dioxane (Add 2 Μ aqueous sodium carbonate solution (4 mm. Bu 4# amount) to the solution in 2 。. The reaction mixture was then stirred on an oil bath maintained at 8 Torr.

Amine. Degas and purify the mixture with nitrogen for 3 hours. Make anti-deer mix; 4

152948.doc -76- 201136930

In a sealed vial, using microwave irradiation, 5_[2_gas_9-(1-ethyl-propyl)-9H-indole-6-yl)pyrazine-2-amine is contained at 165 〇c ( 〇163 mmol, 1 equivalent), 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (0.817 mmol '5 equivalents) and triethylamine (114 mm〇i, 7 equivalents) 3 mi NMP was heated for 25 minutes. The contents were allowed to cool to room temperature and for product formation, the conversion was monitored by LCMS. After 25 minutes, the reaction was complete with little or no decomposition. The crude material was purified by reverse phase HPLC to give the desired compound (yield: 14%). NMR DMSO-d6 (ppm): 9,17 (s, 1H), 9.00 (bs5 1H), 8.10 (s, 1H), 7.32 (bs, 2H), 4.47-4.34 (m, 5H), 3.20-3.1 ( m, 2H), 2.10-1.90 (m, 4H), 1.80 (m, 2H), 1.70 (m, 2H), 0.65 (t, 6H). m/z: 395.21 [MH+]. Example 2, Compound 10 Synthesis of tert-butyl 4-(2,6-dichloro-indol-9-yl)-piperidinecarboxylate

152948.doc 77- 201136930 2,6-dioxane (2.0 mmol, 1 equivalent), 4-carbyl-nitopic bite-1-carboxylic acid tert-butyl vinegar (1 ·3 mmol '0_65 equivalent) and triphenyl The phosphine (2.4 mmol, 1.2 eq.) was dissolved in 16 ml of anhydrous tetrahydrofuran, and diethyl azodicarboxylate (2.2 mmol, 1.1 eq.) was added dropwise at room temperature over 30 min. The reaction mixture was stirred at 60-70 ° C for 24 hours. The reaction mixture was poured into a beaker containing ice-cold water. The aqueous layer was extracted with 3 portions of 25 ml of ethyl acetate to give a crude material. This product was purified on a silica gel column (20-50% ethyl acetate in petroleum ether, gradient elution) to give 4-(2,6-di- s- -9 yl)-piperidine-1 - decanoic acid. Third butyl ester. Synthesis 4·[6-(5-Aminopyridin-2-yl)-2-azepine-9-yl]-Phenan-1-indole

To 2,6-dioxanthone (1)ethyl.propyl)_9Η·嗓呤(〇83 _〇i,i equivalent), 5-amino group,pyrazine·2·camate acid pinanol vinegar (125 〇丨, η当幻 and U'-bis(diphenylphosphino)ferrocene chlorination _) complex with two gas smoldering (8 mom ' 0.07 mmol) in a peroxide-free bismuth (10) 甽A 2 M aqueous solution of carbonic acid was added to the solution (2.49 _. Bu 3 equivalents). The reaction mixture was degassed and purged with an atmosphere. Then search for the 152948.doc •78- 201136930 oil bath on the oil bath for four hours. Regarding the disappearance of the initial enthalpy, the transformation was monitored by lc/ms. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and water. The organic phase was separated and the aqueous layer was further extracted with three portions of 200 ml of ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo to yield 4-[6·(5-amino-pyrazine-2-yl)-2-chloroin-9-yl]-piperidine-indole-carboxylic acid Tributyl ester. The crude material was purified by silica gel chromatography using ethyl acetate petroleum ether to give the desired product 4-[6-(5-amino-pyrazin-2-yl)_2_(8•oxa~3 Azabicyclo[3.2.1]oct-3-yl)-purine-9-yl]-bite-1·carboxylic acid tert-butyl vinegar (1〇)

4-[6-(5-Amino-pyrazine-2-yl)_2_gas__〇9-yl]•piperidine-1-carboxylic acid tert-butyl ester was added to a 150 ° C oil bath ( 〇.〇7 mm〇l, 1 equivalent), 8-oxa-3-azino-bicyclo[3.2.1]octane hydrochloride (〇.7〇mm〇l, 1〇 equivalent) and =ethylamine (0.35 2 ml of DMA of mmol '5 equivalents) was heated for 12 hours. The contents were allowed to cool to room temperature and for product formation, the conversion was monitored by LCMS. Purification of the crude material by reverse phase HPLC produces the desired product (1.16 rngp iH NMr

MeOD (ppm): 9.30 (s, 1H), 9.10 (s, 1H), 8·15 (s, 1H) 4 95 152948.doc -79- 201136930 (m, 1H), 4.55-4.45 (m, 4H) , 4.30 (d, 2H), 3.35-3.30 (m 2H), 3.15-3.00 (m, 2H), 2.30-2.15 (m, 4H), 2.05-1.95 (m 2H), 1.80-1.70 (m, 2H) , 1.52 (s, 9H). m/z: 508.27 [MH+]. Example 3, Compound 11 Synthesis of 2,6-dioxa-9-isopropyl-9H-indole

CI

CI

Add 2-iodopropane (1.62 g, 9 52 κπ〇3 (ι.32 g, 9) to a solution of 2,6-diox-9H-indole (1.00 g, 5.29 mmol) dissolved in 40 mL of DMSO. • 52 mmol). The solution was stirred for 1 hour at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and ethyl acetate. The organic layer was separated and extracted twice with ethyl acetate. Purification by chromatography (EtOAc, EtOAc/EtOAc: EtOAc) Ppm): 8·17 (d, 1H), 4·86-4.97 (seven peaks, 1h) 1 64 1 66 (mountain 6H) m/z: 231 [MH+] Synthesis 5-(2-gas-9- Isopropyl-9H-嘌呤·6•yl)_pyrazine·2_ylamine

152948.doc -80- 201136930

Add 5-amino-lysine to a solution of 2,6-dioxa-9-isopropyl·9Η-D 吟 (0.50 g, 2.16 mmol) dissolved in 15 mL of anhydrous dioxane. An alcohol ester (〇·48 g, 2.28 mmol) and a complex of 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride with dichloromethane (018 g, 〇22 mmol). A saturated aqueous solution of K2CO3 (〇_6〇 g, 4.33 mmol) was then added to the solution. The solution was mixed for 4 hours at 9 °C. After cooling, the solvent was evaporated and the reaction mixture was dissolved in HsO and DCM. The organic layer was separated and the aqueous phase was extracted twice with DCM. Purification by flash column chromatography (2% decyl alcohol in DCM) to give 5-(2-chloro-9-isopropyl-9H-purin-6-yl)-pyrazine as a white solid. 2-ylamine (41% / yield). NMR CDC13 (ppm): 9.48 (s, 1H), 8.27 (d, 1H), 8.21 (s, 1H), 5.03 (s, 2H), 4.94-5.03 (seven peak, 1H), 1.65-1.66 (d, 6H). m/z: 290 [MH+] Synthesis 5-[9-isopropyl-2-(8•oxa-3-aza-bicycloindole 3.2.1]oct-3-yl)-9H-indole-6- Bisylazine 2-ylamine (11)

Add 8 to a solution of 5-(2-chloro-9.isopropyl-9Η-嘌呤·6-yl)-0-pyrazin-2-ylamine (0.46 g, 1.60 mm〇i) dissolved in 15 mL of DMA _oxa~3_aza-bicyclo[3.2.1]octane (〇.81§, 719111111〇1) and 7 mL of triethylamine. The brown solution was heated using microwave irradiation for 3 minutes. The reaction mixture was dissolved in H.sub.2 and ethyl acetate and organic layer was separated. The aqueous layer was extracted with ethyl acetate 152948.doc 201136930 times. Purification by flash column chromatography (silica gel, 2% methanol in DCM) afforded 5-[9-isopropyl-2-(8-oxa-3-aza-bicyclo[ 3.2.1] Oct-3-yl)-9^1-indol-6-yl]-pyrazine-2-ylamine (51% yield). 11^ NMR CDC13 (ppm): 9·21 (d, 1H), 8.25 (d, 1H), 7.88 (s, 1H), 4.84 (s, 2H), 4.74-4.82 (seven peak, 111), 4.51 ( 111, 211), 3.26-3.30 (dd, 4H), 1.87-1.97 (m, 4H), 1.59-1.60 (d, 6H). m/z: 367.22 [MH+] Example 4, Compound 19 Synthesis 5-[8-bromo-9-isopropyl-2(8-oxa-3-aza-bicyclo[3·2·ι]辛_3_ Base)-9H-嘌呤-6·yl] "比嗓-2-ylamine (19)

5-[9-isopropyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9H- dissolved in 15 mL of gas at 5 °C N-bromobutanediamine (0.18 g '1.03 mmol) was slowly added to a solution of indole-6-yl]-pyrazine-2-amine (11) (0.32 g' 0.86 mmol). The brown solution was stirred at this temperature for 2 hours. Thereafter, the reaction mixture was dissolved in DCM and H 2 hydrazine and the organic layer was separated. The aqueous layer was extracted twice with DCM. Purification by preparative HPLC to give 5-[8----9-isopropyl- 2(8-oxa-3-aza-bicyclo[3 2 1]oct-3-yl) as a color solid. -9H-indol-6-yl]pyrazin-2-ylamine (23% yield). iH Nmr MeOD (ppm): 9.18 (s, 1H), 9.01 (s, 1H), 4.90 (m, 1H), 4 36 152948.doc -82· 201136930 (m, 4H), 3.28 (m, 1H), 3.13 (m,1Η),1·88 (m,2H), 1.72 (m, 2H), 1.58 (d, 6H); m/z: 445/447 [MH+] Example 5, Compound 20 Synthesis 5-[8 -95-(1-ethyl-propyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-9H-indol-6-yl] Biazin-2-ylamine (20)

5-[9-(1-ethyl-propyl)_2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3 dissolved in 10 mL of gas at 5 °C Base)-9H-°Pan-6-yl]-n-pyrazine·2_ylamine (6) (40 mg '0.1 mmol) solution was slowly added with bismuth-bromobutaneimide (20 mg '〇·12 Mm). The brown solution was stirred at this temperature for 2 hours. Subsequently, the reaction mixture was dissolved in DCM and Ηβ and the organic layer was separated. The aqueous layer was extracted twice with DCM. Purification by preparative HPLC to give 5-[8----9-(1-ethyl-propyl)-2-(8-oxa-3-aza-bicyclo[3.2.1] as a color solid. Oct-3-yl)-9H-indol-6-yl]pyridin-2-ylamine (18 mg, 38% yield). 4 NMR MeOD (ppm): 9.11 (s, 1H), 9.03 (s, 1H), 4.52 (m, 1H), 4.46 (m, 4H), 3.25 (m, 2H), 2.12 (m, 4H), 1.98 (m, 2H), 1.80 (m, 2H), 0.86 (m, 6H); m/z: 473/475 [MH+] Example 6, Compound 9 Synthesis of 9-benzoinyl-2,6-di--9H -嘌呤152948.doc •83· 201136930

Add anhydrous potassium carbonate (6.34 mmol, 1.2 eq.) and benzyl at room temperature to a stirred solution of 2,6-dioxane (5·3 〇mm〇l, 1 eq. Bromine (6.34 mmol, 1.2 eq.). The reaction mixture was maintained at this temperature for 20 hours. The reaction can be monitored using tlc or LC/MS. The reaction mixture was poured into a beaker containing ice-cold water. The aqueous layer was acidified to pH 5-6. The aqueous layer was extracted with 3 portions of 75 ml of ethyl acetate to give a crude material. The product was purified on a gum column (10-70% ethyl acetate petroleum ether, gradient) to yield the desired compound. Synthesis of 5-(9-benzyl-2-ox-9H-indol-6-yl)-®pyrazine-2-yl-amine

9-Benzenyl-2,6-dioxane (〇159 mm〇1,i equivalent), 5-aminopyrazine-2·guanic acid pinacol ester (0.159 mm〇1,i equivalent) and hydrazine , a complex of bis(diphenylphosphino)ferrocene gasified palladium (11) and dioxane (〇〇15 mmol, 1〇m〇l%) dissolved in the added peroxide-free Dioxane ml) in a mixture with 2 Μ aqueous sodium carbonate solution (0.636 _ 〇 1, 4 eq.). The reaction mixture was degassed and purged with nitrogen. The reaction mixture was then allowed to stand for 3 hours while maintaining the oil name of 152948.doc •84-201136930. Regarding the disappearance of the starting enthalpy, the reaction was monitored by LC/MS. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and water. The organic phase was separated and the aqueous layer was further extracted with 3 portions of 50 ml of ethyl acetate. The combined ethyl acetate layer was washed once with a brine solution (1 mL). The organic layer was dried over sodium sulfate and the solvent was removed in vacuo to yield <RTI ID=0.0>> This material was passed to the next stage without further purification. Synthesis of 5-[9-phenylindole-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-9H-indol-6-yl]·" ratio. Qin-2-yl-amine (9)

In a sealed vial 'Using microwave radiation, containing 5-(9-benzoin-2-chloro-9H-indol-6-yl)-pyrazin-2-ylamine (0.1 mm〇1) at 165 °C , 1 equivalent), 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (0.5111111〇1,5 equivalents) and triethylamine (0.7 mmol '7 equivalents) of 3 ml NMP heating 25 minutes. The contents were allowed to cool to room temperature and for product formation, conversion was monitored by Lcms. After 2 minutes, 'reaction completed' no decomposition was observed. The crude material was purified by reverse phase HPLC to give 5-[9-m-methyl-2-(8-oxa-3-aza-bicyclo[3-2.1]oct-3-yl)-purity with a purity of 98%. 9H-嘌呤-6-based]·. Bisazine_2_yl - 152948.doc -85 - 201136930

1H), 8.30 (s, 1H), 7.76 (s, 1H), 7.46-7.30 (m, 4ti), 7 37 (bs 2H), 5.39 (m, 2H), 4.56 (m, 2H), 4.34 (d , 2H), 3·34 (d, 2H) 2.11-1.85 (m, 4H), m/z: 415.20 [MH+]. Example 7 'Compound 27 Synthesis of 5-(2-gas-9-isopropyl-8-methyl-9H-indol-6-yl)indole-2-ylamine

2,6-diox_9_isopropyl_8-methyl-9Η-嘌呤 was purchased and used with the above for 5-(2-isopropyl _8-fluorenyl -9 Η嘌呤 _6• group) Pyrazinylamine The same procedure was used to convert to 5-(2-gas-9-isopropyl-9Η-嘌呤_6-yl)pyridin-2-ylamine. The crude product was used in the next step without purification. 〇成丨9-isopropyl-8-methyl-2-(8-oxa-3-aza-bicyclo[3 2]octyl)_9H-indole+pyrazine-2_ylamine η)

Use the same as described above for 5_[9_isopropyl-2-(8-oxaaza-bicyclo]oct-3-yl)_9Η-嗓呤_6_yl] than the 2-aminoamine (11) 152948.doc -86 - 201136930 The procedure 'to make 5-(2-gas-9-isopropyl-8-fluorenyl-9H-indol-6-yl)_〇 ratio. Conversion of Qin-2-ylamine to 5_[9-isopropyl_8-methyl_2_(8-oxaaza-bicyclo[3.2.1] osin-3-yl)-9H-嘌呤-6-yl ]-Pyrazine-2-ylamine (27). Isolation 5_ [9-isopropyl-8-methyl-2-(8-oxa-3-aza-bicyclo[3.2.1]octyl-3-yl)·9H_嗓吟-6-yl]- π is a two-step yield of _2_ylamine-[Delta gel chromatography] after commercialization of 2 6 diox-9-isopropyl-8-mercapto-9H-indole as starting material It is 22%. NMR d6-DMSO (ppm): 9.01 (s, 1H). 8 〇9 (s, 1H); 7.42 (bs, 2H); 4.81 (q, 1H); 4.45 (m, 2H), 4.35 (m 2H) , 3.18 (m, 2H), 2.83 (s, 3H), 1.83 (m, 2H), 1.70 (m, 2H) 1.63 (s, 6H), 1.60 (s, 6H) ; m/z: 381.18 [MH+] The compounds outlined in Table 1 were synthesized according to the procedures outlined above or variations thereof. Table 1 synthesized compounds

*HNMR a|m/z — DMSO-d6 (ppm): 9.17 (s, 1H), 395 Γδ 9.00 (bs, 1H), 8.10 (s, 1H), 7.32 (bs, 2H), 4.50-4.30 (m , 5H), 3.20-3.10 (m, 2H), 2.30 (m, 1H), 1.80 (m, 2H), 1.70 (m, 2H), 1.60 (d, 3H), 1.00 (d, 3H), 0.70 ( d,3H)» _--- 152948.doc 87- 201136930 No. Structure ^NMR m/z 2 nh2 ό CDC13 (ppm): 9.14 (s, 1H), 8.93 (s, 1H), 8.59 (s, 1H) , 4.62-4.65 (m, 2H), 4.41-4.55 (bs, 2H), 3.38 (d, 2H), 2.17-2.21 (m, 2H), 2.02-2.10 (m, 6H), 1.79-1.88 (m, 8H), 1.54 (q, 2H), 0.99 (t, 3H). 435.24 3 νη2 Λ k/N CDC13 (ppm): 9.14 (s, 1H), 8.89 (s, 1H), 8.62 (s, 1H), 4.58-4.60 (m, 2H), 4.30-4.46 (bs, 2H) , 3.38 (d, 2H), 2.05-2.10 (m, 8H), 1.78-1.87 (m, 8H). 449.24 4 FIFl^ Λ CDC13 (ppm): 9.15 (s, 1H), 8.56 (bs, 1H), 8.34 (s, 1H), 5.23 (m, 2H), 4.70 (m, 1H), 4.56 (m, 2H) ), 4.44 (m, 2H), 3.30 (m, 2H), 2.58 (m, 1H), 2.20 (m, 1H), 1.10-1.90 (m, 6H), 1.30 (m, 2H), 1.01 (t, 3H). 421.21 5 nh2 Λ Wn DMSO-d6 (ppm): 9.19 (s, 1H), 9.00 (bs, lH), 8.10(s, 1H), 7.30 (bs, 2H), 7.20 -7.10 (m, 4H), 4.92 (m, 1H), 4.44-4.32 (m, 4H), 3.5-2.90 (m, 6H), 2.30 (m, 2H), 1.90-1.70 (m, 4H) 〇455.20 152948.doc -88 - 201136930 No. Structure 'hnmr m/z 6 (mh2 Λ ^ΝΧ^ΙΧ) (Ο Ν ^ DMSO-d6 (ppm): 9.17 (s, 1H), 9.00 (bs, 1H), 8.10 (s, 1H), 7.32 (bs, (H, 2H) 395.21 7 νη2 [Ί\ xXNy MeOD (ppm): 9.18 (s, 1H), 8.96 (s, 1H), 8.06 (s, 1H), 4.95 (m, 1H), 4.42 (m, 4H), 3.18 ( m, 2H), 2.28 (m, 2H), 2.12 (m, 2H), 1.88 (m, 4H), 1.75 (m, 4H). 393.16 8 νη2 Λ Wn χχΝ> Ν V DMSO-d6 (ppm): 9.18 (s, 1H), 8.90 (bs, 1H), 8.10 (s, lH), 7.29 (bs, 2H), 4.47-4.38 (m, 4H), 4.04 (s, 2H), 3.18-3.14 (m, 2H) ), 1.80 (m, 2H), 1.70 (m, 2H), 1.00 (d, 9H). 395.21 9 νη2 ? il ^γΝ ^χΝ> CDC13 (ppm): 9.76 (d, 1H), 8.38 (s, 1H) ), 8.30 (s, 1H), 7.76 (s, 1H), 7.46-7.30 (m, 4H), 7.37 (bs, 2H), 5.39 (m, 2 H), 4.56 (m, 2H), 4.34 (d, 2H), 3.34 (d, 2H), 2.11-1.85 (m, 4H). 415.20 152948.doc 89- 201136930 No. Structure! hnmr m/z 10 nh2 Λ Ν Λ MeOD (ppm): 9.30 (s, 1 Η), 9.10 (s, lH), 8.15 (s, 1H), 4.95 (m, 1H), 4.55-4.45 (m, 4H), 4.30 (d, 2H), 3.35-3.30 (m, 2H), 3.15-3.00 (m, 2H), 2.30-2.15 (m, 4H), 2.05-1.95 ( m, 2H), 1.80-1.70 (m, 2H), 1.52 (s, 9H) 508.27 11 νη2 Λ XjC> θ' DMSO-d6 (ppm): 9.17 (s, 1H), 9.00 (bs, 1H), 8.11 (s, 1H), 7.32 (bs, 2H), 4.88 (m, 1H), 4.48 (m, 2H), 4.37 (d, 2H), 3.18 (d, 2H), 1.86 (m, 2H), 1.73 ( m, 2H), 1.59 (d,6H) 〇367.22 12 νη2 ψ χχ> , <0 Ν DMSO-d6 (ppm): 9.11 (s, 1H), 9.00 (s, 1H), 8.48 (s, 1H) , 4.92-4.97 (m, 1H), 4.58 (d, 2H), 4.43 (bs, 2H), 3.37 (dd, 2H), 2.01-2.08 (m, 3H), 1.87 (d, 2H), 1.74-1.77 (m,1H), 1.68 (d,3H), 1.45 (q, 1H), 1.02 (d,3H), 0.97 (d,3H) 409.26 13 νη2 6 ΧΤΝ> DMSO-d6 (ppm): 9.04 (s, (H, 3H) (s, 1H), 2.02-2.07 (m, 4H), 1.87 (d, 2H), 1.16-1.20 (m, 2H), 1.10 (d, 3H), 4 结构 d d d 423 423 423 423 423 423 423 423 423 423 , 1H), 8.10 (s, 1H), 7.28 (bs, 2H), 5.25 (m, 1H), 4.48-4.36 (m, 4H), 4.15 (q, 2H), 4.08-4.00 (m, 2H), 3.92-3.87 (m, 2H), 3.17 (d, 2H), 1.86-1.84 (m, 2H), 1.77-1.71 (m, 2H). 395.21 15 νη2 Λ Wn χΧΝ} 0 Ν, DMSO-d6 (ppm): 9.18 (s, 1H), 8.95 (bs, 1H), 8.10 (s, 1H), 7.31 (bs, 2H), 4.48 (m, 2H) ), 4.39 (d, 2H), 4.24 (dd, 2H), 3.17 (d, 2H), 1.87-1.85 (m, 2H), 1.74-1.69 (m, 2H), 1.48 (t, 3H). 353.17 16 ΝΗ〇Λ Wn ^ 6 MeOD (ppm): 9.21 (s, 1H), 8.95 (s, 1H), 8.05 (s, 1H), 4.68 (m, 1H), 4.38 (m, 4H), 4.05 ( m, 1H), 3.1-3.3 (m, 4H), 2.75 (m, 1H), 2.20 (m, 4H), 2.08 (s, 3H), 1.86 (m, 2H), 1.72 (m, 2H) 450.24 17 ΝΗ〇Λ Wn (Ο Ν, CDC13 (ppm): d 9.69 (s, 2H), 8.36-8.35 (m, 1H), 8.25 (d, 1H), 7.98 (s, 1H), 4.51 (brs, 2H) , 4.27 (d, 2H), 4.18 (t, 2H), 3.29 (d, 2H), 1.96-2.09 (m, 2H), 1.68-1.92 (m, 9H), 1.29-1.18 (m, 4H), 1.03 -0.98 (m, 2H) 435.27 152948.doc -91- 201136930 No. Structure *HNMR m/z 18 nh2 Λ (Ο ^ CDC13 (ppm): 9.02 (s, 1H), 8.99 (s, 1H), 8.42 (s , 1H), 6.06 (s, 2H), 4.69-4.72 (m, 1H), 4.53-4.54 (m, 2H), 4.37-4.38 (m, 2H), 3.33 (dd, 2H), 3.14 (sextet, 1H ), 1.60-1.68 (m, 4H), 1.33 (t, 3H), 1.24-1.26 (m, 3H), 0.85-0.99 (m, 5H) 409.18 19 νη2 Λ XjCVer (Ο Ν \ MeOD (ppm): 9.18 (s, 1H), 9.01 (s, 1H), 4.90 (m, 1H), 4.36 (m, 4H), 3.28 (m, 1H), 3.13 (m, 1H), 1.88 (m, 2H), 1.72 ( m, 2H), 1.58 (d, 6H) 447.41 20 νη2 Λ fVVer (0Ν Ν ^ MeOD (ppm): 9.11 (s, 1H), 9.03 (s , 1H), 4.52 (m, 1H), 4.46 (m, 4H), 3.25 (m, 2H), 2.12 (m, 4H), 1.98 (m, 2H), 1.80 (m, 2H), 0.86 (m, 6H) 474.38 21 νη2 Λ fVvci (Ο仏MeOD (ppm): 9.30 (s, 1H), 9.08 (s, 1H), 4.58 (m, 1H), 4.47 (m, 4H), 3.32 (m, 1H), 3.25 (m, 1H), 2.12 (m, 4H), 1.98 (m, 2H), 1.79 (m, 2H), 0.89 (m, 6H) 429.11 152948.doc 92- 201136930 No. Structure!hnmr m/z 22 nh2 Λ CDC13 (ppm): 8.96 (s, 2Η), 8.45 (s, 1H), 6.35 (s, 2H), 4.54-4.55 (m, 2H), 4.26-4.42 (m, 3H), 3.33 (d, 2H ), 2.31 (sextet, 1H), 2.0-2.11 (m, 4H), 1.81-1.83 (m, 2H), 1.06 (d, 3H), 0.80-0.85 (m, 6H) 409.17 23 νη2 Λ χΎΛ CDCI3 (ppm ): 9.02 (s, 2H), 8.39 (s, 1H), 5.86 (s, 2H), 4.53-4.55 (m, 3H), 4.39 (d, 2H), 3.32 (dd, 2H), 2.49 (sextet, 1H), 1.96-2.03 (m, 4H), 1.83-1.85 (m, 2H), 1.69-1.79 (m, 2H), 1.64 (d, 3H), 1.52-1.56 (m, 2H), 1.32-1.37 ( m, CH), 1.12-1.16 (m, 1H) 421.18 24 νη2 Λ Wn X ]ΓΝ"> (Ο ρ- CDCI3 (ppm): 9.00 (s, 1H), 8.94 (s, 1H), 8.41 (s , 1H), 6.05 (s, 2H), 4.53-4.58 (m, 3H), 4.32-4.42 (m, 2H), 3.33 (dd, 2H) , 1.90-1.98 (m, 2H) 25 ΝΗ2 Λ χίΛ CDCI3 (ppm): 9.04 (s, 1H), 8.91 (s, 1H), 8.52 (s, 1H), 6.72-6.96 (bs, 2H), 4.52-4.60 (m, 3H), 4.31- 4.44 (m, 2H), 3.34 (dd, 2H), 1.95-2.12 (m, 6H), 1.81-1.83 (m, 2H), 1.21-1.41 (m, 4H), 1.09-1.19 (m, 1H), 0.84-0.91 (m, 6H) 423.20 152948.doc 93- 201136930 No. NMR m/z 26 nh2 ψ DMSO-d6 (ppm): 9.11 (s, 1H), 9.0 (bs, 1H), 8.05 (s, 1H ), 7.29 (bs, 2H), 4.61 (m, 1H), 4.44 (m, 2H), 4.35 (m, 2H), 3.15 (m, 2H), 2.11-2.06 (m, 4H), 1.81-1.57 ( m,12H) 421.18 27 Λ (013⁄4 DMSO-d6(ppm): 9.01 (s, 1H), 8.09 (s, 1H), 7.42 (bs, 2H), 4.81 (q, 1H), 4.45 (m, 2H) , 4.35 (m, 2H), 3.18 (m, 2H), 2.83 (s, 3H), 1.83 (m, 2H), 1.70 (m, 2H), 1.63 (s, 6H), 1.60 (s, 6H) 38U8 ' 28 Λ DMSO-d6 (ppm): 9.13 (s, 1H), 9.0 (bs, 1H)} 8.05 (s, 1H), 7.29 (bs, 2H), 4.42 (m, 2H), 4.35 (m, 2H) ), 4.05 (m, 2H), 3.15 (m, 2H), 1.81 (m, 2H), 1.68 (m, 2H), 1.38 (m, 1H), 0.55-0.48 (m, 4H) 379J4 Biology MTOR assay laboratory test 4eBPl generating full-length mTOR kinase and His tag of. [γ33Ρ]_ ATP was purchased from Amersham (GE Healthcare). All chemicals were from Sigma-Aldrich unless otherwise stated. Phosphorylation assays were initially performed in 384 well polypropylene plates (Greiner) in a final volume of 20 pL. Compounds were tested in 8-stage dilutions, usually in the range of 1 〇〇 μΜ to 0.006 μΜ, in duplicate. First, each well 1 μμι - 质 质 谷 谷 谷 谷 谷 谷 谷 谷 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 .doc • 94- 201136930 10 mM MnCl2) was added to a sample culture plate containing 1 μl of test compound in pure DMSO solution per well. The reaction was initiated by adding 10 μί of 20 μΜ ATP solution per well (final assay concentration of 10 μΜ ATP and 0.4 gCi [γ33Ρ]-ΑΤΡ per well). After incubation at room temperature for 1 hour, the reaction was stopped with 40 μM of 20 mM EDTA/1 mM ATP solution per well. The 50 μί stop reaction mixture per well was then transferred to a 384-well MultiScreen HTS-PH filter plate (Millipore) pre-added with 50 μί of 1% acid per well. Filter through vacuum using 120 μί 0.5 °/ per well. The plate was washed 4 times with phosphoric acid. Finally, 10 pL of OptiphaseTM SuperMix liquid scintillation cocktail (Perkin Elmer) per well was added. After a minimum of 1 hour of incubation, the Wallac MicroBeta TriLux scintillation counter was counted using a coincidence counting mode with mutual interference correction. IC5Q is defined as the concentration of the compound required for 50% inhibition of kinase enzyme activity. The IC5〇 data is shown in Table 2 below. Table 2 - In vitro mTOR inhibitory activity assay IC5G data Compound number IC50 (mTOR) · Compound number IC5〇(mTOR)* 1 -Η-+ 15 ++ 2 -ΗΗ- 16 ++ 3 17 + 4 ++ 18 -Η - 5 +++ 19 ++ 6 +-Η- 20 -Η- 7 +++ 21 -Η- 8 +++ 22 +-Η- 9 + 23 +++ 10 -Ι-+ 24 -Η- 11 -Hf 25 12 ++ 26 13 27 +++ 14 ++ 28 ++ <0.1 μΜ 0.1 μΜ-1 μΜ >1 μΜ

152948.doc -95- 201136930 The details of the specific embodiments described herein are not to be construed as limiting. Various equivalents and modifications can be made without departing from the spirit and scope of the invention, and it is understood that the equivalent embodiments are part of the invention. 152948.doc -96-

Claims (1)

201136930 VII. Patent application scope: 1 · A compound of formula (I): R is selected from the group consisting of H, _ and optionally substituted c 1 -C6 alkyl; R is selected from the group consisting of: 11, 画, 〇Η, ν 〇 2, CN, ΝΑ, Optionally substituted Ci_Ci2 alkyl, optionally substituted hc! 2 alkenyl, optionally substituted C2_Ci2 alkynyl, optionally substituted Cs-Cu heteroalkyl, optionally substituted C3_C12 cycloalkyl , optionally substituted C^-C!2 cycloalkenyl, optionally substituted c2_Ci2 heterocycloalkyl, optionally substituted C^-C!2 heterocycloalkenyl, optionally substituted Q- Cu aryl, optionally substituted Ci_c-8 heteroaryl, optionally substituted qC丨2 alkoxy, optionally substituted C2_Ci2 alkenyloxy, optionally substituted C^-Cn alkynyloxy , as the case may be substituted C2_C〗 G heteroalkoxy, optionally substituted Cs-C 2 ring alkoxy, optionally substituted C3-C! 2 cycloalkenyloxy, optionally substituted C2_C ] 2 heterocycloalkoxy, optionally substituted C 2 — CU heterocycloalkenyloxy, optionally substituted C 6 —Ci 8 152948.doc 201136930 aryloxy, optionally substituted Ci-Cu heteroaryloxy, optionally Substituted c!-c丨2 alkylamino group, SR8, so3h, S02NR8R9, S02R8, SONR8R9, s〇r8, c〇r8, C00H, c〇〇r8 c〇nr8r9 NR8C〇r9, nr8c〇〇r9 , nr8s〇2r9 nr8c〇nr8r9, nr8r9 and fluorenyl, or R is a group of the formula: Wherein each of the oximes is independently N or CR2a, and each of the spurs 23 is independently selected from the group consisting of hydrazine, halogen, hydrazine H, N 〇 2, CN, NH 2, optionally substituted alkyl, optionally substituted Qc 2 alkenyl, optionally substituted C2_Ci2 alkynyl, optionally substituted C2_Cl2 heteroalkyl, optionally substituted cycloalkyl, substituted C2_C丨2 heterocycloalkyl, optionally Substituted C2-C_cycloalkenyl, optionally substituted C6_Ci8 aryl, optionally substituted c丨_c, 8 heteroaryl, optionally substituted C丨-C丨2 alkoxy, Optionally substituted C2-C-2-alkenyloxy, optionally substituted C2-Cl2 alkynyloxy, substituted C2_C!2 heteroalkoxy, optionally substituted cvc12m alkoxy, visually Substituted C3_C4 alkenyloxy, optionally as defined, C^-C!2 heterocycloalkoxy, optionally substituted heterocycloalkenyloxy, optionally substituted c6_Ci8 aryloxy, optionally Substituted heteroaryloxy, optionally substituted Ci_Ci2 alkylamine, SR, S03H, S02NH2, S02R8, s〇NH2, SOR8, COR8, COOH, COOR8, c〇NR8R9, nr8c 〇r9, nr8c〇〇r9, 152948.doc 201136930 nr8so2r9, nr8conr8r9, nr8r9 and fluorenyl; r is an integer selected from the group consisting of 1, 2 and 3; R3 is selected from Η, F, Cl, Br, OH, a group consisting of Cl_C6 alkyl, OR8, OCOR8, CH2OH, nh2, nr8r9, nr8cor9 and nr8so2r9, as appropriate; R is selected from Η, oh, OR8, 〇Pg0, OCOR8, CI^OH, NH2, NR8R9, a group consisting of NR8PgN, N(PgN)2, nr8c〇r9, NR8c〇NR8R9 and nr8so2r9; R is selected from the group consisting of ruthenium, F, Cl, Br, OH, OR8, 〇c〇R8, CH2OH, NH2, NR8R9, NR8COR9 and a group consisting of NR8S02R9; each R and R9 are independently selected from the group consisting of H, optionally substituted C1-C丨2 alkyl, optionally substituted C^-Ci2 alkenyl, optionally substituted c ^-Cu alkynyl, optionally substituted C2_Cig heteroalkyl, optionally substituted C3_cn cycloalkyl, optionally substituted C3_Ci2 ring dilute, optionally substituted C2_Cn heterocyclic, optionally substituted Qc] 2 heterocycloalkenyl, optionally substituted C6_Ci8 aryl and optionally substituted <^-(:18 heteroaryl, or R and R together with the atom to which they are attached form an optionally substituted cyclic moiety; Pg^ is a protecting group for oxygen; each pgN is independently a protecting group for nitrogen; each inverse 2 is independently selected from the group consisting of :Ci_c6 alkyl, dentyl-q-C6 alkyl, hydroxy Ci_Ce alkyl, Ci_C6 alkoxy 446 alkylcyano-Ci-C6 alkyl, amine c "C6 alkyl, c]-C6 alkylamino匸广152948.doc 201136930 c6 leucoyl, and di(Cl_C6 alkyl)amino-based Cl_C6 alkyl; q is an integer selected from the group consisting of ruthenium, 1, 2, 3 and 4; X is a group; each Rl (&gt; is independently selected from the group consisting of hydrazine and optionally substituted Ci-C6 alkyl; m is an integer selected from the group consisting of ruthenium, 1, 2, 3, and 4; or its medicinal Acceptable salts, antioxidants or prodrugs. 2. The compound of claim 1 wherein q is hydrazine. 3. A compound according to claim 1 or 2, wherein R3 is selected from the group consisting of ruthenium, OR8 and, optionally, a Cl-(:6 alkyl group, wherein r8 is as defined in claim 1. The compound of claim 1 or 2, wherein R3 is H. 5. The compound of claim 1 or 2, wherein R7*He 6. The compound of claim 4, wherein the claw is selected from the group consisting of ruthenium, ruthenium and ruthenium 7. The compound of claim 1 or 2, wherein „1 is 〇 or 1. 8. The compound of claim 1 or 2, wherein (7) is ^. 9. The compound of claim 1 or 2, wherein m is 1»1〇·, as the compound of claim 9, wherein one R10 is Η&amp;χ is a group of the formula: 11 wherein R10 is as claimed in claim 1 As defined in 1. ' wherein the compound is a compound of the formula 152948.doc 201136930 ΛΛ卜 R10 12. 13. 14. 15. 16. 17. 18. Where R1, R2, R6 K R IOl, c ^ R K and R are as defined in the request. The compound of claim 10, wherein the group consisting of R1 is a free radical, a C-C6 halocarbon hydroxyalkyl group, and a c丨-C6 alkyl group. The compound of claim 1G, wherein R, G is selected from the group consisting of hydrazine, methyl, ethyl, propyl, isopropyl and butyl. The compound of claim 1 wherein R1° is selected from the group consisting of ruthenium, osmium and ethyl. The compound of any one of the items 2 and U, wherein. A compound according to any one of the preceding claims, wherein the compound is selected from the group consisting of muscle and her', wherein rir9 is as defined in claim 1 and the compound of any one of claims 1, 2 and 11 Wherein R6 is NH2. The compound of any one of claims 1, 2, and 11, wherein R2 is selected from the group consisting of hydrazine, cyano, optionally substituted Ci_c 2 alkyl, optionally substituted Cs-C Alkenyl, optionally substituted C2_Ci2 heteroalkyl, optionally substituted C3_C12 cycloalkyl, optionally substituted c2-cu heterocycloalkyl, optionally substituted C6-C18 aryl and Substituted Ci-C! 8 heteroaryl. 152948.doc 201136930 where R2 is the formula below. 19. If the claim 丨 ': and any of the compounds in the group: Each of the ridges is independently N or CR2a, and each of the ridges 23 is independently selected from the group consisting of: H, dentate, OH, N〇2, CN, nh2, optionally substituted Μ&quot;alkyl, depending on the situation Substituted q-cu alkenyl, optionally substituted C2_Ci2 alkynyl, optionally substituted C: 2_C 2 heteroalkyl, optionally substituted C3_c&quot; cycloalkyl, optionally substituted c^ c] 2 heterocycloalkyl, optionally substituted QC 2 heterocyclenyl, optionally substituted Q_c 8 aryl, optionally substituted qc 8 heteroaryl, optionally substituted Ci_Ci2 Alkoxy, substituted C2-Ci2 alkenyloxy, optionally substituted C2_Ci2 alkynyloxy, optionally substituted C: 2_Cl2 heteroalkoxy, optionally substituted, optionally substituted Cs-C! 2 cycloalkoxy, optionally substituted c3_Ci2 cycloaliphaticoxy, optionally substituted C1_C12 heterocycloalkoxy, optionally substituted C^C 2 heterocycloalkenyloxy, optionally Substituted C6_Ci8 aryloxy, optionally substituted (^-(: with heteroaryloxy, optionally substituted Ci-C丨2 alkylamino, SR8, s〇3H, S02NH2 , SO2R8, SONH2, SOR8, COR8, COOH, COOR8, CONR8R9, NR8COR9, NR8C00R9, NR8S02R9, nr8conr8r9, NR8R9 and fluorenyl; wherein r8 and r9 are as defined in claim 1; 152948.doc • 6 - 201136930 r is selected An integer of the group consisting of free i, 2, and 3. 20. 21. The compound of claim 19, wherein &gt; is 1 or 2. The compound of claim 19, wherein the compound has the formula: Where R2a&amp;r is as defined in claim 19. 22. 23. The compound of claim 19, wherein each of the lines is independently selected from the group consisting of H, F, 〇CH3, CN, 0Cf3, C〇2CH3, Ν〇2, ΝΗ2 nhcoCH3, NHS〇2CH3, NHCH2CH3, CH3 and Cf [composed of groups. The compound of claim 18, wherein r2 is selected from the group consisting of cyano, optionally substituted C^-C!2 alkyl, optionally substituted C3_Ci2 cycloalkyl, optionally substituted CrCu heterocycloalkyl, and A group of C2_Cu heteroalkyl groups which are optionally substituted. The compound of claim 23, wherein R2 is an alkyl group substituted as appropriate: Wherein R20, R21 and R22 are each independently selected from the group consisting of ruthenium, Cl, Br, F, OH, NO:, CN, NH2, optionally substituted q-Cu alkyl, optionally substituted C2_Ci2 Heteroalkyl, optionally substituted Ca-C!2 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted Ce-C 8 aryl and optionally substituted Ci_Ci8 heteroaryl 152948 .doc 201136930 The base 'or any two or more of R ° , R 21 and R 22 together with the carbon atom to which they are attached form a cyclic moiety. The compound of claim 24, wherein each of the ruthenium, RZ1 and r22 is independently selected from the group consisting of ruthenium, Cl, Br, F, on, N02, CN, NH2, methyl, ethyl, Propyl, isopropyl, butyl, pentyl, methoxyindenyl, 2-decyloxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl , aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, methylaminomethyl, 2-methylaminoethyl, 3 -Methylaminopropyl, 4-methylaminobutyl, 5•methylaminopentyl, ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminopropyl , 4-ethylaminobutyl, 5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethyl Aminobutyl, 5-dimethylaminopentyl, diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl, 4-diethylaminobutyl And 5-diethylaminopentyl. 26. The compound of claim 23, wherein R2 is selected from the group consisting of thiol, ethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl , cyclopropyl, cyclopentyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-indenyl, pentyl, pent-4- Alkenyl, hexyl, heptyl, octyl, cyano, decyloxymethyl and butoxycarbonyl. 27. The compound of any one of claims 1, 2, and 11, wherein the optionally present substituent is selected from the group consisting of F, Br, C1, = 0, =S, -CN, methyl , trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimercapto-propyl, butyl, iso 152948.doc 201136930 Butyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, decyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl Base, phenyl, NH2, -N02, phenoxy, hydroxy, methoxy, trifluoromethoxy, ethoxy and fluorenyldioxy. 28. The compound of claim 1 which is selected from the group consisting of: 152948.doc -9- 201136930 152948.doc • 10· 201136930 152948.doc • 11 - 201136930 Or a pharmaceutically acceptable salt or prodrug thereof. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 and a pharmaceutically acceptable diluent, excipient or carrier. A method of inhibiting a protein kinase in vitro, the method comprising contacting the protein kinase or a fragment or complex thereof or a functional equivalent thereof and/or a cofactor thereof with an effective amount of a compound according to any one of claims 1 to 28 . The method of claim 30 wherein the protein kinase is serine/threonine kinase or a fragment or complex thereof or a functional equivalent thereof. The method of claim 31, wherein the serine/threonine protein kinase or a fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof, or a functional equivalent thereof The method of claim 31 or 32, wherein the serine/threonine protein kinase is mTORC 1 or a fragment or complex thereof or a functional equivalent thereof. 34. Use of a compound according to any one of claims 1 to 28 which is for the manufacture of a medicament for inhibiting one or more protein kinases. 35. The use of claim 34, wherein the protein kinase is serine/threonuclease or a fragment or complex thereof or a functional equivalent thereof. 36. The use of claim 35, wherein the serine/threonine protein kinase or fragment or complex thereof is an mTOR protein kinase or a fragment thereof, or a complex thereof, or a functional equivalent thereof. 37. The use of claim 35 or 36, wherein the serine/threonine protein kinase is mTORCl or a fragment or complex thereof or a functional equivalent thereof. The use of a compound according to any one of claims 1 to 28 for the manufacture of a medicament for treating or preventing a condition in a mammal, wherein the inhibition of one or more protein kinases or fragments or complexes thereof or functions thereof Equivalents may prevent, inhibit or ameliorate the pathology or symptoms of the condition. The use of the protein kinase is a serine/threonine egg white kinase or a fragment or complex thereof or a functional equivalent thereof. The use of claim 39, wherein the serine/threonine protein kinase or a fragment or complex thereof is mTOR protein kinase or a fragment thereof, or a complex thereof or a functional equivalent thereof. 41. The use of claim 39 or 40, wherein the serine/threonine protein kinase 152948.doc •13·201136930 is mTORCl or a fragment or complex thereof or a functional equivalent thereof β 42. The use according to any one of the preceding claims, wherein the condition is selected from the group consisting of inflammation, rheumatoid arthritis, psoriasis, atherosclerosis, colitis, inflammatory bowel disease, pancreatitis, multiple sclerosis Symptoms, autoimmune disorders, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovarian syndrome, hamartoma, tuberous sclerosis, Alzheimer's Disease (Alzheimer, s disease), Huntington's disease, Parkinson's disease, insulin-dependent diabetes, obesity, diabetic retinopathy, cardiac hypertrophy, and autologous dominant polycystic kidney disease . The use of any one of claims 38 to 40, wherein the condition is cancer. 44. The use of claim 43, wherein the cancer is selected from the group consisting of a blood cancer, such as a myeloproliferative disorder (idiopathic myelofibrosis, true polycythemia, essential thrombocythemia, chronic bone marrow) Leukemia), bone marrow cell metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute red blood cell line leukemia, Hodgkin's and non-Hodgkin's disease, B-cell lymphoma, acute D-cell white matter month Symptoms of medullary dysplasia, plasma cell disease, hairy cell leukemia Kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, Indian cancer, child lung cancer, vaginal cancer and vulvar cancer, endometrial hyperplasia; Cancer, such as colorectal cancer, polyp, liver cancer, stomach cancer, pancreatic cancer, gallbladder cancer; urinary tract cancer, such as prostate cancer, kidney cancer; urinary bladder cancer, urethral cancer, penile cancer; skin cancer 'such as melanoma; brain Tumors such as glioblastoma, neuroblastoma, astrocytes 152948.doc 201136930 tumor, ependymoma, brain stem glioma Neural tube blastoma, meningioma, astrocytoma, oligodendroglioma; head and neck cancer, such as nasopharyngeal carcinoma, laryngeal cancer; respiratory cancer, such as lung cancer (NSCLC &amp; SCLC), mesothelioma; eye disease, Such as retinal blastoma; musculoskeletal disorders, such as osteosarcoma, musculoskeletal tumors; squamous cell carcinoma and fibroids. 45. Use of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, N-oxide or prodrug thereof, for the manufacture of a medicament for treating a condition, wherein inhibition A variety of protein kinases or complexes thereof or functional equivalents thereof can prevent, inhibit or ameliorate the pathology or symptoms of the condition. 46. The use of claim 45, wherein the protein kinase is serine/threonine kinase or a fragment or complex thereof or a functional equivalent thereof. 47. The use of claim 46, wherein the serine/threonine protein kinase or fragment or complex thereof is mTOR protein kinase or a fragment thereof, or a complex thereof, or a functional equivalent thereof. 48. The use of claim 46 or 47, wherein the serine/threonine protein kinase is mTORCl or a fragment or complex thereof or a functional equivalent thereof. 49. The use of any one of claims 45 to 47, wherein the condition is selected from the group consisting of: inflammation, rheumatoid arthritis, psoriasis, arterial* atherosclerosis, colitis, inflammatory bowel Disease, pancreatitis, multiple sclerosis, autoimmune disease, lupus, allergic encephalomyelitis, transplant rejection, endometriosis, leiomyoma, polycystic ovary syndrome, hamartoma, nodular Sclerosis, Alzheimer's disease, Huntington's disease, Parkinson's disease, insulin-dependent diabetes, obesity, diabetes 152948.doc •15-201136930 Retinopathy, cardiac hypertrophy, and autologous dominant polycystic kidney disease. The use of any one of claims 45 to 47, wherein the condition is cancer. 51. The use of claim 50, wherein the cancer is selected from the group consisting of a blood cancer, such as a myeloproliferative disorder (idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia, chronic bone marrow) Leukemia), bone marrow cell metaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia, acute red blood cell line leukemia, Hodgkin's disease, and Non-Hodgkin's disease, B cell lymphoma, acute tau cell leukemia, myelodysplastic syndrome, plasma cell disease, hairy cell leukemia, kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, ovarian cancer, cervical cancer, Vaginal cancer and vulvar cancer, endometrial hyperplasia; Gastrointestinal cancer such as colorectal cancer, polyps, liver cancer, stomach cancer, visceral cancer, gallbladder cancer; urinary tract cancer such as prostate cancer, kidney cancer; urinary bladder cancer, urinary tract cancer , penile cancer; skin cancer, such as melanoma; brain tumors such as glioblastoma, neuroblastoma, star Tumor, ependymoma, brain stem glioma, neural tube blastoma, meningioma, astrocytoma, oligodendroglioma; head and neck cancer, such as nasopharyngeal carcinoma, laryngeal cancer; respiratory cancer, such as Lung cancer (NSCLC and SCLC), mesothelioma; eye diseases such as retinoblastoma; musculoskeletal diseases such as osteosarcoma, musculoskeletal tumors; squamous cell carcinoma and fibroids. 52. Use of a compound according to any one of claims 1 to 28 for the manufacture of a medicament for preventing or treating a proliferative condition in an individual. 53. The use of claim 52 wherein the condition is cancer. 152948.doc -16- 201136930 54. The use of claim 53, wherein the cancer is selected from the group consisting of: a blood cancer such as a myeloproliferative disorder (idiopathic myelofibrosis, polycythemia vera, original Thrombotic thrombocytosis, chronic myeloid leukemia), f cytochemistry ±, chronic myelomonocytic leukemia =, acute lymphoblastic leukemia, acute red blood cell line leukemia, 隹奇金氏和非霍奇金病, B Cellular lymphoma, acute T cell leukemia, myelodysplastic syndrome, polycytosis, hairy cell leukemia, Kaposi's sarcoma, lymphoma; gynecological cancer, such as breast cancer, ovarian cancer 'cervical cancer, vaginal cancer and vulvar cancer , endometrial hyperplasia; gastrointestinal cancer, such as colorectal cancer, polyps, liver cancer, stomach cancer, pancreatic cancer, gallbladder cancer; urinary tract cancer, such as prostate cancer, kidney cancer; urinary bladder cancer, urethral cancer, penile cancer; skin Cancer, such as melanoma; brain tumors, such as glioblastoma, neuroblastoma, astrocytoma, ependymoma, brainstem glial Tumor, blastocystoma, meningioma, astrocytoma, oligodendroglioma; head and neck cancer, such as nasopharyngeal carcinoma, laryngeal cancer; respiratory cancer, such as lung cancer (NSCLC and sclc), mesothelioma, eye disease , such as retinoblastoma; musculoskeletal disorders, such as osteosarcoma, musculoskeletal tumors; squamous cell carcinoma and fibroids. 55. A compound according to any one of clauses 2, 11 and 28, or a pharmaceutically acceptable salt, N-oxide or prodrug thereof, for the treatment of a proliferative condition. 152948.doc •17· 201136930 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 152948.doc