TW201245186A - Chromenone compounds - Google Patents

Abstract

The invention concerns chromenone compounds of Formula I; or pharmaceutically-acceptable salts thereof, wherein each of R1, R2, R3, R4, R5, n and R6 has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of cell proliferative disorders.

Description

201245186 VI. Description of the Invention: [Technical Field] The present invention relates to certain novel terpene compounds or pharmaceutically acceptable salts thereof, which have anticancer activity and are therefore useful in methods for treating human or animal bodies . The invention also relates to a method for the manufacture of such decenone compounds, a pharmaceutical composition containing the same, and its use in a method of treatment, for example for the manufacture of a cancer for the prevention or treatment of a warm-blooded animal such as a human (including drugs used to prevent or treat cancer). The present invention is also directed to terpene compounds which are selective inhibitors of phosphoinositide (PI) 3-kinase beta and which are useful, for example, in anti-tumor therapy. Further, the present invention relates to the use of the terpene compound of the present invention in antitumor therapy, which is a phosphoinositide (a selective inhibitor of PU 3 ·kinase J3. The inhibitor of ΡΙ3-kinase β is effective Therapeutic gene ρτΕΝ* is defective (chromosomes... phosphatase and tensin homolog) and is associated with yet another feature of the invention. The invention also relates to the selection of phosphoinositide (ΡΙ) 3·kinase δ Sexual inhibitors and, for example, ruthenone compounds for anti-tumor therapy; and decenone compounds which are selective inhibitors of both ΡΙ3-kinaseβ and ΡΙ3-kinase δ. 3-kinase β/δ inhibitors can also be used to treat tumors. [Prior Art] In the field of cancer, it has been found in recent years that cells can be converted into oncogenes due to a part of their DNA (that is, genes that cause malignant cells to be formed upon activation). It is cancerous (Bradshaw, Mutagenesis, 1986, 1, 91). Several of these oncogenes cause the production of peptides, which are receptors for growth factors. 16330S.doc 201245186 Growth factors are affected by Activation of complex subsequently leads to an increase in cell proliferation. For example, 'known in several oncogenes encode tyrosine kinase enzymes and certain growth factor receptors are also tyrosine kinase enzymes lines (Yar (Jen et al., Ann. Rev.

Biochem., 1988, 57, 443; Larsen et al., Ann·Reports in

Med·Chem. ’ 1989 ‘Chapter 13). The first group of tyrosine kinases to be identified are produced by such viral oncogenes, such as pp6〇v-src tyrosine kinase (or v-Src), and the corresponding tyrosine kinases in normal cells, for example PP6 (TSn: tyrosine kinase (or c_Src). Receptor-lanine kinase is critical in the propagation of biochemical signals that initiate cell replication. It is a large enzyme' that spans the cell membrane and has An extracellular binding domain of a growth factor (eg, epidermal growth factor (EGF)) and an intracellular portion that acts as a kinase to phosphorylate tyrosine amino acids in a protein and thereby affect cell proliferation. Based on binding to different receptor tyramines A family of growth factors for acid kinases 'known different classes of receptor tyrosine kinases (Wilks, Advances in Cancer Research, 1993, 60, 43-73) 〇 This classification includes class I receptor tyrosine kinases, which include The EGF family of receptor tyrosine kinases such as EGF, TGFa, and NeuAerbB receptors. It is also known that certain tyrosine kinases belong to non-receptor tyrosine kinases, which are located intracellularly and participate in biochemical signals. (eg, they affect the swelling Transmission of cell movement, spread and invasion, and subsequently affecting metastatic tumor growth. Different classes of non-receptor tyrosine kinases are known, including families such as Six, Lyn, Fyn, and Yes lysine kinases. It is also known that certain kinases belong to the class of serine/threonine kinases, which are located downstream of the cell and tyrosine kinase activation and are involved in the biologic 163305.doc 201245186 signal (eg, those who influence tumor cell growth) The spread of these serine/threonine signaling pathways, including the Raf_MEK-ERK cascade and PI 3-kinase (eg PDK-1, AKT and mTOR) downstream (Blume-jensen and Hunter, Nature, 2001, 411, 355) It is also known that certain other kinases belong to the class of lipid kinases, which are located intracellularly and are also involved in the spread of biochemical signals (eg, those that affect tumor cell growth and awareness). a class of lipid kinases, including the PI 3-kinase family described above, or referred to as the phospholipid inositol_3_kinase family. It is now well understood that the release of modulation of oncogenes and tumor suppressor genes may result in evil. Tumors, for example, 'by increasing cell proliferation or increasing cell survival. It is now also known that the signaling pathway mediated by the PI 3-kinase family plays a key role in many cellular processes, including proliferation and survival, and relies on 4 pathways. Regulation is the cause of many human cancers and other diseases (Katso et al., Annual Rev. Cell Dev. Biol) 2001, 17: 615-617 and Foster et al, J. Cell Science, 2003, 116: 3037-3040 The PI 3-kinase family of lipid kinases is a group of enzymes at the 3 position of the inositol ring of the acidified fat-filled inositol (PI). Three major groups of ρι 3_kinase enzymes are known to be classified according to their physiological specificity (Vanhaesebr〇eck et al., Trends in Biol. Sci., 1997, 22, 267). Class III pi 3-activase only phosphorylates PI. In comparison, 11 categories? 1 3_Kinase Enzyme Phosphorylation PI and PI 4-phosphate (hereinafter abbreviated as PI(4)P]. Class I PI 3_kinase enzyme phosphorylates PI, PI(4)P and PI 4,5-bisphosphate [hereinafter abbreviated as PI(4,5)P2] 'but is believed to be only PI(4,5)P2 Physiological cells are stressed. 163305.doc 6 201245186 Phosphorylation of PI(4,5)P2 produces a lipid second messenger ρι 3,4,5-triphosphate [hereinafter abbreviated as PI(3,4,5)P3]. Members of this superfamily that are further distant are members of the class 1 kinase, such as mTOR and DNA-dependent kinases of the serine/threonine residues in the phosphorylated protein. The most well-understood and well-known lipid kinase class I PI 3-kinase enzymes are studied. Class I PI 3-kinases are heterodimers composed of the pii〇 catalytic subunit and regulatory subunits and further classify the family into la-like and lb-like enzymes based on regulatory partners and regulatory mechanisms. _ kinase β and consists of three different catalytic subunits (ρ11〇α, ρ1丨叩, and ρ11〇δ) dimerized with five different regulatory subunits (ρ85α, ρ55α, ρ50α, ρ85β, and ρ55γ). All of the catalytic subunits are capable of interacting with all regulatory subunits to form various heterodimers. The la-like quinone 3-kinase is normally activated in response to growth factor stimulation by the receptor glutamine kinase, which is via a regulatory subunit SH2 domain with an activating receptor or a specific acid-filled tyrosine such as an adaptor protein such as IRS_i. Residue interaction. Both pll〇a and ρ11〇β are constitutively expressed in all cell types, while ρ11〇δ is more restricted to leukocyte populations and some epithelial cells. In contrast, a single lb-like enzyme consists of a p丨丨〇γ catalytic subunit that interacts with the p 101 regulatory subunit. In addition, lb-like enzymes are activated in response to the G protein coupled receptor (GPCR) system and by the above mechanisms. There is a large body of evidence indicating that la-type PI 3-kinase enzymes (which include pi 3-kinase β) directly or indirectly contribute to tumorigenesis in a variety of human cancers (Vivanc® and

Sawyers, Nature Reviews Cancer, 2002, 2, 489-501). For example, '卩110〇1 subunit in some tumors (eg ovary (31^3^, 11 et al. 163305.doc 201245186, Nature Genetics, 1999, 21: 99-102) and cervix (Ma et al, Oncogene) , 2000, 19: 2739-2744) The tumor was amplified. Mutations in the catalytic site of activated ρΐ 10α are associated with various other tumors (e.g., colorectal regions and tumors of the breast and lung) (Samuels et al, Science, 2004, 304, 554). Tumor-associated mutations in ρ85α have also been identified in cancers such as ovarian cancer and colon cancer (Philp et al, Cancer Research, 2001, 61, 7426-7429). PI 3 kinase-δ plays a key role in B cell function and has been shown to be a mediator of survival signaling in a variety of B cell malignancies. This includes, but is not limited to, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (Ikeda et al. Blood, 2010, 116, 1460-1468; Herman et al, Blood, 2010, 116, 2078-2088; Lannutti et al, Blood, 2011, 117, 591-594; Hoellenriegel et al, Blood, 2011, 118, 3603- 3612). In addition to the direct effect, it is believed that activation of the la-like PI 3-kinase also results in neoplastic events by, for example, receptor tyrosine kinase, GPCR system or ligand-dependent or ligand-independent activation of integrin. It occurs upstream of the signaling pathway (Vara et al., Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such upstream signaling pathways include overexpression of the receptor tyrosine kinase Erb2 in various tumors (which leads to PI 3-kinase mediated pathway activation (Harari et al, 〇nc〇gene, 2000, 19, 6102). -6114)) and overexpression of the oncogene Ras (Kauffmann-Zeh et al, Nature, 1997, 385, 544-548) » In addition, la-like PI 3 · kinases can indirectly contribute to tumorigenesis, which is caused by various downstream signaling Event caused. For example, the loss of the effect of PTEN tumor suppressor phosphatase, which catalyzes the retransformation of PI(3,4,5)P3 into PI(4,5)P2, by catalyzing the loss of PI 3-kinase-mediated PI (3, 4, 5) Regulation of P3 production is associated with a very large number of tumors (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41). In addition, it is believed that the increase in the effects of other PI 3-kinase-mediated signaling events leads to the elimination of multiple cancers by, for example, activation of Akt (Nicholson and Anderson, Cellular Signalling, 2002, 14, 381-395). There is also good evidence for the role of proliferation and survival signaling in tumor cells: The la-like PI 3-kinase enzyme will also contribute to tumorigenesis via its role in tumor-associated stromal cells. For example, 'PI 3 -kinase signaling is known to play an important role in mediating angiogenic events in endothelial cells in response to pro-angiogenic factors such as VEGF (Abid et al., Arterioscler. Thromb. Vase. Biol., 2004, 24, 294-300). Since Class I PI 3-kinase enzymes are also involved in exercise and migration (Sawyer, Expert Opinion Investig. Drugs, 2004 13 1- 1 9) 'The PI 3-kinase inhibitors should provide therapeutic benefit by inhibiting tumor cell invasion and metastasis. Class I PI 3-kinase enzymes play an important role in the regulation of immune cells with ΡΙ3·kinase activity, which leads to the pro-tumourigenic effect of inflammatory cells (c〇ussens&Werb , Nature, 2002, 420, 860-867) ° These findings indicate that pharmacological inhibitors of class I PI 3-kinase enzymes should be of therapeutic value to treat various forms of cancer disease, including solid tumors (eg, carcinomas and sarcomas) ) and leukemia and lymphoid malignancies. Specifically, the 163305.doc 201245186 inhibitor of PI 3-kinase should be of therapeutic value in the treatment of diseases such as breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and twig trachea). Alveolar cancer) and prostate cancer, and cholangiocarcinoma, lunar cancer, bladder cancer, brain cancer, head and neck cancer 'kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, Uterine, cervical and vulvar cancers and leukemias (including AL) L, CLL and CML [chronic myeloid leukemia], multiple myeloma and lymphoma (including non-Hodgkin, s lymphomas, For example, diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, and mantle cell lymphoma). In general, the PI 3-kinase inhibitors LY294002 and wortmannin have been used in the study to explore the physiological and pathological effects of the PI 3-kinase family. Although the use of these compounds may indicate an effect on PI 3-kinase in cellular events, it does not have sufficient selectivity in the pi 3_kinase family to isolate individual effects of family members. For this reason, more effective and selective pharmaceutical PI 3-kinase inhibitors can be used to more fully understand ρι 3_kinase function and provide useful therapeutics. In addition to tumorigenesis, the following evidence exists: Class 1 1 > 1 3 • Kinase enzymes play a role in other diseases (Wymann et al.' Trends in pharmaco丨Dgical

Science, 2003, 24, 366-376). Both the la-like PI 3-kinase enzyme and the mono-_Ib-like enzyme play an important role in the cells of the immune system (Koyasu, Nature Immunology, 2003, 4, 313-319) and thus are inflammatory and allergic indications. Therapeutic Targets As described above, inhibition of ρι 3·kinase is also used to treat the heart via anti-inflammatory effects or by directly affecting cardiomyocytes. 10 163305.doc 6 201245186 Vascular disease (Prasad et al., Trends in Cardi〇vascular Medicine 2003, U, 2〇6-212). Inhibition of PI 3-kinase is also used to treat thrombus formation. WO 2004016607 provides a method for disrupting platelet aggregation and adhesion under high shear conditions, and a method for inhibiting platelet activation induced by shear, both of which comprise administration of a selective PI 3-kinase p inhibitor. - w〇 2004016607 also provides an antithrombotic method which comprises administering an effective amount of a selective PI 3-kinase beta inhibitor. According to this method, specific inhibition of thrombosis can be obtained by targeting ΡΙ3_激_, which is essential for shear-induced platelet activation, without affecting normal hemostasis. Therefore, the anti-blood test formation method does not involve side effects caused by disrupting normal hemostasis, such as prolonging the withdrawal time. Therefore, expected job! Inhibitors of 3-kinase enzymes (including ρι 3· kinase β (4)) have the value of preventing and treating a variety of diseases other than cancer. 0 It is surprisingly found that the present sigma (ie, a ketene compound) is effective. Antitumor activity, which is used to inhibit uncontrolled cell proliferation. This uncontrolled proliferation is caused by a malignant disease. It is not intended to imply that the compounds disclosed in the present invention have only pharmacological activities due to the effects on a single biological process, and compounds such as traits are inhibited by inhibiting _Ι3_kinase, specific = kinase-like enzymes, and ... kinase enzymes. While 2 m13·(iv) provides an anti-(four) effect, the compounds of the invention are also caused by non-malignant diseases: and inflammatory bowel disease), in inhibiting uncontrolled cell proliferation, which are not caused by, for example, inflammatory diseases such as rheumatoid Arthritic fibrotic diseases (such as cirrhosis and lung fiber I63305.doc 201245186), glomerulonephritis, multiple sclerosis, psoriasis, benign prostatic hypertrophy (coffee), skin hypersensitivity, ▲ tube disease (such as arterial porridge Sclerotherapy and restenosis), allergic asthma, sputum-dependent diabetes, diabetic retinopathy, and diabetic nephropathy. Generally, the compounds of the present invention have specific targets for treatments. Kinase enzymes include acupuncture weights (iv) (iv) effective inhibitory activity of enzymes, and are directed against alanine kinase enzymes (eg, receptor lysine kinases, such as EGF receptors) Tyrosinase and /4 VEGF receptor tyrosine kinase) or non-receptor tyrosine kinases (eg, Src) have less potent inhibitory activity 14 In addition, certain compounds of the invention are directed against class I PI 3-kinase enzymes Specifically, it is essentially for "class!^3_kinase enzymes (including against ρι 3-kinase versus EGF receptor tyrosine kinase or VEGF receptor tyrosine kinase or Src non-receptor tyrosine kinase) Better potency "These compounds are potent against Class I PI 3-kinase enzymes in an amount sufficient to inhibit steroids, specifics, and inhibitors of IA-like η 3 -kinase enzymes (including ?! kinase beta) It was also confirmed that it has less activity against EGF receptor tyrosine kinase or VEgF receptor tyrosine kinase or Src non-receptor tyrosine kinase. In addition, the specific compound of the present invention was confirmed for PI 3_kinase p and ρι 3_ An effective inhibitory activity of kinase δ, directed against tyrosine kinase enzymes (eg, receptor tyrase kinases such as EGF receptor tyrosine kinase and/or VEGF receptor glutaminase), or against non-receptor tyramine Acid kinases (such as Src) have more effective inhibition In addition, certain compounds of the present invention are directed against both PI 3 -expressed 8$ β pj ^ h kinase δ than against EGF receptor tyrosine kinase or vegf orlane kinase or Src non-receptor tyrosine kinase It has a substantially better potency of 163305.doc β 12 201245186. These compounds have sufficient potency against both PI3·kinaseβ and PI 3-kinaseδ to be sufficient to inhibit ΡΙ3-kinase MPI3 kinases, while confirming the needle a EGF receptor glutaminase or VEGF receptor glutaminase or Src non-receptor tyrosine kinase has less activity. [Invention] According to one aspect of the present invention, a ketene derivative derived from the formula is provided. Object:

Wherein: R1 is optionally substituted by a hydroxy group (1_4 decyl group; R2 hydrazine or (1-4C) alkyl group; or R1 and R2 together form a 3 to 8 member nitrogen-containing heterocyclic ring system, as the case may be Containing 1 or 2 other heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring sulfur atom is optionally oxidized to form an S-oxide, which ring is optionally substituted by a hydroxyl group; R3 and R5 are independently selected from the group consisting of an anthracene and a halogen group. (^(^ alkoxy and cyano; R4 is hydrazine or fluoro; η is 0 or 1, and when η is 1, the R6 group is thiol; or a pharmaceutically acceptable salt thereof) The 'general term "(1-4C)alkyl" includes straight chain and has 163305.doc •13· 201245186 branched alkyl groups (eg propyl, isopropyl and tert-butyl), and (3-4C) a cycloalkyl group (for example, a cyclopropyl group and a cyclobutyl group), and a group such as a cyclopropylmethyl group. However, when referring to an individual alkyl group such as "propyl", it is exclusively used for a straight chain type, When referring to a single branched alkyl group such as "isopropyl", it is exclusively used for a branched type, and when referring to an individual cycloalkyl group such as "cyclopropyl", it is exclusively used for a 3-membered ring. Familiar with this The skilled artisan will appreciate that the terms "(i_4C) thiol" and "(1-3 C) alkyl" as used herein mean any of the alkyl groups defined above, and the knives have from 1 to 4 And 1 to 3 carbon atoms. The same conventions apply to other terms as used herein, such as "(1-3C) alkoxy", "(1_10C) alkoxycarbonyl, and "(1-10C) alkanoyl" It should be understood that although certain of the above formulae compounds as defined above may exist in optically active or racemic forms due to one or more asymmetric carbon atoms, the invention also includes inositol phosphate (PI) in its definition. Any of the optically active or racemic forms of 3-kinase inhibiting activity. Synthesis of the optically active form can be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by Resolution of racemic forms. Similarly, the above activities can be evaluated using standard laboratory techniques. The specific enantiomers of the compounds described herein can be more active than the other enantiomers of the compounds. The t+) enantiomer of the title compound of Q3 (ie, example ^ a compound wherein (+) indicates optical rotation as measured using the conditions described in Example 1. G3a) is an enantiomer having a weaker activity. To avoid doubt, the material core is attached to a carbon atom at the 2-position of the pyrrolidine ring of the decenone bicyclic ring. 163305.doc 201245186 Accordingly, in yet another aspect of the invention, there is provided a decenone derivative of formula j, or a pharmaceutically acceptable thereof a salt in which the palmar center at the 2-position of the pyrrolidine ring of the center of the ketenone ring is in the (R)-stereochemical configuration. In still another aspect of the invention, a formula I is provided. An enone derivative, or a pharmaceutically acceptable salt thereof, wherein the palmitic center at the 2-position of the pyrrolidine ring of the center of the ketene ring is in a (s)-stereochemical configuration. According to still another aspect of the present invention, there is provided a decenone derivative of the formula I, or a pharmaceutically acceptable salt thereof, which is an enantiomeric excess (% alpha weep %, = 8% or > 99%) a single enantiomer. In one embodiment of this aspect of the invention, the tetradental center at the 2-position of the central pyrrolidine ring attached to the decenone bicyclic ring is in a stereochemical configuration. In this consistent manner, in the consistent embodiment, the center of the ocalkenone ring is connected to the center of the bite of the bite ring in the (S)·stereochemical configuration. According to yet another aspect of the present invention, A pharmaceutical composition comprising a ketene derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier, the enantiomer of the decenone derivative of Formula 1 In bulk (%ee weep 95, > 98% or > 99% of the single enantiomer. Conveniently, the single enantiomer system is present in > 99% enantiomeric excess in the present invention In one embodiment of this aspect, the palmar center at the 2-position of the central pyrrolidine ring attached to the diazepam ring is in the (R)_stereochemical configuration. In another aspect of the invention, in the embodiment, the u is different from each other in the bile ring. The palmar center at the 2-position of the ring is in the (s)_stereochemical configuration. The polymorphism is exhibited. It will be appreciated that the present invention encompasses any of the polymorphic forms of I63305.doc -15 2012045186 or mixtures thereof, which have properties for inhibiting phosphoinositide (PI) 3 kinase activity, which are well known in the art. How to determine the potency of a polymorphic form for inhibiting phosphoinositide (3) kinase activity by standard tests as described below. It is well known that crystalline materials can be analyzed using conventional techniques such as: X-ray powder diffraction ( The following are XRPD) analysis, differential scanning calorimetry (hereinafter DSC), thermogravimetric analysis (hereinafter TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, near infrared ( NIR) spectroscopy, liquid and/or solid state nuclear magnetic resonance spectroscopy. The water content of these crystalline materials can be determined by Karl Fischer analysis. As an example, Example 1. The compound of 〇3b exhibits polycrystalline Sexual Three crystalline forms A, B and C have been identified. Specific crystalline forms may exhibit advantageous properties, such as improved stability' which makes them particularly suitable for pharmaceutical development. Thus, another aspect of the invention is fluorophenyl) pyrrolidine Form A of -2-yl]-6-(morpholine-4-carbonyl)-2-morpholinyl-nonene-4-one A 〇 According to still another aspect of the present invention, a fluorophenyl group is provided. a crystalline form (form A) of chitin-2-yl]-6-(morpholin-4·yl)-2-morpholinyl-octenoid-4' ketone, which has a ratio of about 2Θ=4·8 . An X-ray powder diffraction pattern having at least one characteristic peak. According to still another aspect of the present invention, 8-[(211)-1_(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholin-4-carbonyl)-2-morpholine is provided The crystalline form of the base-pinene_4__ (Form A) 'has about 20=8.1. The x-ray powder diffraction pattern β having at least one characteristic peak 163305.doc -16 - 201245186 is provided according to the still further aspect of the present invention, providing 8_[(2RM_(3,5^气phenyl) ratio bite-2 a crystallization form (form A) of the ketone -6- ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone ketone An X-ray powder diffraction pattern of two characteristic peaks. According to still another aspect of the present invention, -difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-ylcarbonyl)-2- a crystalline form (form Α) of morpholinyl-nonene-4-ketone having about 2Θ=4 8, 6.4, 8”, 9 6 , 15.8, 19_5, 20·3, 22·7, 23.4, 25.9 A x-ray powder diffraction pattern having a characteristic peak at °. According to still another aspect of the present invention, 8-[(2R)-l-(3,5-difluorophenyl) is provided as each of the ketone-2-yl]-6-(morphin-4-yl)- A crystalline form of 2-merinyl-benzophenone ketone (Form A) having an X-ray powder diffraction pattern that is substantially identical to the X-ray powder diffraction pattern shown in FIG. According to still another aspect of the present invention, 8_[(2R)-i_(3,5-difluorophenyl)pyrrolidine-2-yl]-6-(m-lin-4-yl)-2 is provided. - Crystalline form of morphine ketone -4-4 ketone (Form A) having a sigma of about 2 Θ = 4. 8 . An X-ray powder diffraction pattern having at least one characteristic peak at ±0.5 ° 2 Θ. According to still another aspect of the present invention, 'providing a fluorophenyl group' is more crystallized than each of the ketone-2-yl]-6-(morphin-4-yl)-2-morphinyl-p gram-4-gjg Form (Form A) 'It has a x-ray powder diffraction pattern having at least one characteristic peak at about 2 Θ = 8.10 ± 〇 502 θ. According to still another aspect of the present invention, 8_[(2R)-l-(3,5-difluoroιphenyl) ° is provided as 0 pyridine-2-yl]-6-(morpholin-4-carbonyl) Crystalline of -2-morpholinyl-decen-4-one 163305.doc -17- 201245186 Form (Form A) 'It has about 2Θ=48. And 8". An X-ray powder diffraction pattern having at least two characteristic peaks, wherein the equivalent value may be increased or decreased by 0.5 ο 2θ. According to still another aspect of the present invention, there is provided 8_[(2R)1(3,5 difluorophenyl)pyrrole-2-yl]-6-(Mallinomaki)_2·morpholinyl ketone The crystalline form (Form A) has about 2e = 4 8 , 6 4 , 8", 9 6 , 15 8 , 19.5, 20.3, 22.7, 23.4, 25.9. A ray-ray powder diffraction pattern having a characteristic peak, wherein the equivalent value may be added or subtracted by 5 〇 2Q. According to still another aspect of the present invention, 8 [(2R)1(3,5-difluorophenyl)pyrrolidin-2-yl]-6·(morpholin-4-carbonyl)-2·morpholinyl is provided. The crystalline form of the terpene·4-ketone (form A) 'has been at 2Θ=4.8. An X-ray powder diffraction pattern having at least one characteristic peak. According to still another aspect of the present invention, is provided 8-[(2R)_l-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholin-4-carbonyl)·2-? The crystalline form of the morphyl-nonene-4-one is in the form of 20 = 8.1. An X-ray powder diffraction pattern having at least one characteristic peak. According to still another aspect of the present invention, 8-[(2R)-l-(3,5-difluorophenyl)pyrrolidin-2-yl]·6·(morpholin-4-carbonyl)-2- The crystalline form of morpholinyl-nonen-4-one (Form A) 'has been at 2Θ=4_8. And 8.1. An X-ray powder diffraction pattern having at least two characteristic peaks. According to still another aspect of the present invention, 8-[(2R)-l-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholin-4-carbonyl)-2- A crystalline form of morpholinyl-decene-4- _ (Form A) having 2 Θ = 4.8, 6.4, 8.1, 9.6, 15.8, 19·5, 20.3, 22.7, 23.4, 25.9. X-ray powder with characteristic peaks 163305.doc Θ 201245186 End diffraction pattern. According to still another aspect of the present invention, there is provided 8-[(2R)-l-(3,5-difluorophenyl) ° ratio 0 octyl]-6-(morpholin-4-carbonyl)-2- A crystalline form of morpholinyl-decen-4-one (Form A) having an X-ray powder diffraction pattern as shown in FIG. Another aspect of the present invention is 8-[(2R)-i-(3,5-difluorophenyl)oxaridin-2-yl]-6-(Merline _4.carbonyl)_2_? The form b of the ketone 4-ketone. According to still another aspect of the present invention, 8-[(2R)-l-(3,5-difluorophenyl) < succinyl-2-yl]-6-(morpholin-4-carbonyl)- A crystalline form of 2-morpholinyl-decen-4-one (Form B) having a ratio of about 2 Å = 11.1. An X-ray powder diffraction pattern having at least one characteristic peak. According to still another aspect of the present invention, 8-[(2R)-l-(3,5-difluorophenyl) 0 is provided as a bite-2-yl]-6-(morpholin-4-carbonyl)- 2. Crystalline form of morpholinyl-decen-4-one (Form B) 'It has a ratio of about 20 = 6.9. And 11.1. An X-ray powder diffraction pattern having at least two characteristic peaks. According to still another aspect of the present invention, 8-[(2R)-l-(3,5-difluorophenyl) is provided in a ratio of 0 to 2-yl]-6-(ortho-4-yl) a crystalline form of -2-morphinyl- ketene-4-one (Form B) having about 2 Θ = 6.9, 9.4, 9.8, 11.1, 12.7, 13.1, 13.7, 17.8, 18.7, 19.7 . X-ray powder diffraction pattern having characteristic peaks according to another aspect of the present invention 'provides 8_[(2R)-l-(3,5-difluorophenyl) than each bit-2-yl]-6 a crystalline form (form B) of 2-merinyl-benzo-4-one having substantially the same X-ray powder diffraction pattern as shown in Figure 2. X-ray powder diffraction pattern. 163305.doc -19- 201245186 According to a still further aspect of the present invention, 8_[(2R) small (3 5 difluorophenyl) is provided as each pyridin-2-yl]-6-(morpholine-4-carbonyl) A crystalline form (form oxime) of 2-morpholinyl-nonene-4 ketone having an X-ray powder diffraction pattern having at least one characteristic peak at about 20 = 11 1 〇 ± 〇 5.20. According to still another aspect of the present invention, 8-[(2R) small (35 difluorophenyl) pyrrolidin-2-yl;]-6-(morpholin-4-carbonyl)_2-morpholinyl-hydrazine is provided. A crystalline form of the alkene-4-ketone (Form B) having a ratio of about 2 Θ = 69. And n丨. An X-ray powder diffraction pattern having at least two characteristic peaks, wherein the equivalent value can be added or subtracted by 0.55 ο 2θ. According to still another aspect of the present invention, there is provided a crystalline form of difluorophenyl)pyrrolidin-2-yl]-6-(morpholin-4-carbonyl)-2-morpholinyl-nonene-4-one Form B), which has about 2Θ=6 9 , 9.4, 9 8 , uj, 12.7, 13·1, 13.7, 17·8, 18.7, 19 7 . A ray line powder diffraction pattern having a characteristic peak, wherein the equivalent value may be increased or decreased by 5.2. According to still another aspect of the present invention, there is provided a crystalline form of • difluorophenyl)pyrrolidin-2-yl]·6·(morpholin-4-carbonyl)-2-morpholinyl-nonene_4_蜩(Form B), which has at (iv).i. There is at least one characteristic two-day X-ray powder diffraction pattern. According to still another aspect of the present invention, there is provided a difluorobenzopyrrolidin-2-yl]-6-(morpholin-4-carbonyl)-2-morpholinyl]nonene_4_ soil) W < crystalline form (Form B) 'It has 2在=6.90 and 11.1. The X-ray powder diffraction pattern of the two characteristic peaks of the right s + and the negative main. Crystal of fluorophenyl) According to still another aspect of the present invention, there is provided. Bilpyridin-2-yl]-6-(morpholin-4-carbonyl)-2-morpholinyl-decene_4_纲 •20· 163305.doc

S 201245186 Form (Form B) having 2Θ=6.9, 9.4, 9.8, u”, 12·7, 13”, 13.7, 17, 8, 18.7, 19.7. X-ray powder diffraction pattern having characteristic peaks According to a still further aspect of the present invention, 8. [(2R) small (35 difluorophenyl) pyrrolidine-2.yl]-6-(morpholine- a crystalline form of 4-carbonyl)-2-morpholinyl-nonene ketone (Form B) having an X-ray powder diffraction pattern as shown in Figure 2; another aspect of the invention is 8-[ (2RM_(3,5^fluorophenyl)β piroxime_2_yl]_6-(morpholin-4-carbonyl)-2-morpholinylcene-4-one ketone form c. According to the invention In another aspect, the nickname is phenyl) pyrrolebital-2-yl]-6·(morpholine·4_monoyl)_2_morpholinyl _ _4_ Ming crystallization form (form c) It has a value of about 2Θ=5.9. And 12 2. An X-ray powder diffraction pattern having at least two characteristic peaks. According to still another aspect of the present invention, 5 difluorophenyl) is provided. a specific crystalline form (form C) having a ratio of 2 Θ = 5 9 , 12 2 ' u 8 , 13 5, 15, 2 15 · 4, 17.1 < 3 X-ray powder diffraction round with characteristic peaks. According to still another aspect of the present invention, 8_[(2R)_1(3 5 difluorophenyl)-0 ratio is provided. a crystalline form of Form-2-yl]-6-(Mouthyl-4-yl)_2·morpholinyl-salt_____, which has a enthalpy of χ ray powder as shown in FIG. The X-ray powder diffraction pattern having substantially the same pattern is emitted. /, according to another aspect of the present invention, 8-[(2R)-l-(3,5-difluorophenyl) chin-2-yl] winter (Merlin _4_ syl)_2_琳琳基-say κ (iv) crystalline form (form c) 'which has a Θ=5 9 at about 2Θ. And 12 2. There are at least two 163305.doc •21 - 201245186 'where the value can be added or subtracted. Tepfeng # X-ray powder diffraction pattern 0·5ο2θ. . Bilo bite the "' aspect' provides 84 (called "(3,5_二11 phenyl) •2-yl]_6_(?琳_4_几基)·2_?琳基基小心嗣 crystal b (form C) having an X-ray powder diffraction pattern having characteristic peaks at about 2^=5.9, 12.2, 11.8, 13.5, 15·4 '17, 1 °, where the equivalent value can be added Or minus 5〇2β. Is H(2R) small (35 difluorophenyl), ordinated 2-yl]-6_(morpholine-4)carbonyl)_2 provided in accordance with the present invention? a crystalline form of the morphyl decenone (form c) having an X-ray powder diffraction pattern having at least two characteristic peaks at 20 = 59 and 12 2. According to yet another aspect of the present invention Crystalline form of 8_[(211)1(3,5•difluorophenyl)pyrrolidin-2-yl]_6-(morpholin-4·carbonyl)·2-morpholinyl-nonenone (Form C ' It has a parent ray powder diffraction pattern having characteristic peaks at 2 Θ = 5.9, 12.2, 11.8, 13.5, 15 々, 15.4, 17.1 °. According to still another aspect of the present invention, 8-[( Crystalline form of 2R)-l-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-ylcarbonyl)·2_morpholinylnonene-4-one (form C 'It has an X-ray powder diffraction pattern as shown in Figure 4. It should be understood that the 'Θ value of the X-ray powder diffraction pattern can vary slightly between machines or between samples, and therefore the quoted value is not It should be understood as an absolute value. It is known to obtain an X-ray powder diffraction pattern with one or more measurement errors, such as the equipment or machine used. In particular, it is well known in the 'X-ray powder diffraction pattern. The intensity can be varied according to the measurement conditions. 16330S.doc 22 201245186. Therefore, it should be understood that the crystalline forms of the invention described above are not limited to the ones shown in Figures 2, 4 and 4, unless otherwise stated. The ray powder is diffracted by a crystal of the same X-ray powder diffraction pattern, and any crystal providing a diffraction pattern of the X-ray powder substantially identical to those shown in Figures 1, 2 and 4 is within the scope of the present invention. The familiar ray powder diffraction technique can determine the diffraction pattern of the substantially identical X-ray powder. Those familiar with X-ray powder diffraction should also understand that the relative intensity of the peak can be affected by, for example, a size of 30 micro. The influence of the above and non-uniform aspect ratio crystal grains 'Shai and other crystal grains can affect the sample analysis. Those skilled in the art should also understand that the 'reflection position can be measured by the precise height and winding of the sample in the diffractometer. The effect of zero calibration of the ejector. The surface flatness of the sample can also have a small effect. Therefore, the diffraction pattern data provided should not be interpreted as an absolute value (see

Jenkins, R and Snyder, R.L. "Introduction to X-Ray Powder Diffractometry" John Wiley & Sons 1996; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London;

Klug > Η. P. & Alexander, LE (1974), X-Ray Diffraction Procedures) 〇 Usually 'the measurement error of the diffraction angle in the X-ray powder diffraction circle is about plus or minus 0.5° 2Θ 'and This measurement error should be considered when considering X-ray powder diffraction data. In addition, it should be understood that the strength may fluctuate depending on the experimental conditions and sample preparation (preferred orientation). Each of the specific compounds of the invention is an example of each of its pharmaceutically acceptable salts, each of which provides a further independent aspect of the invention. According to still another aspect of the present invention, a decenone derivative of the formula I is provided, which is obtained by an example according to the disclosure of the present invention, I63305.doc • 23-201245186. Yet another feature of the present invention is to abandon the specific examples (for example, the scope of the righteousness, the premise is a 1〇5 1〇ή 1Λ7 instance pair, 1.01, 1.03, 103b, 1.05, 1.06, 1.07, ι.〇8 .^ D ^ 2.00, 3.00, 3.02, 3.03, etc.). A further feature of the present invention is any range defined by ., a, or a text, provided that a specific instance is abandoned altogether (for example, 1.00 '1.01, 1.03, l.〇3b '1.05 '1.06 > 1 〇7, , 1.08, 2.00, 3·00, 3.02, 3.03, etc.). Thus, in a further aspect of the invention, 'providing a ketene derivative of formula I A/., ·

among them:

Rl is optionally substituted by a hydroxy group (1-4C) alkyl; R2 is hydrazine or (1-4C)alkyl; or R1 and R2 together form a 3 to 8 member nitrogen-containing heterocyclic ring system, as the case may be. Containing 1 or 2 other heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring sulfur atom is optionally oxidized to form an S-oxide, which ring is optionally substituted by a hydroxyl group; R3 and R5 are independently selected from the group consisting of an anthracene and a halogen group. (1-3C) alkoxy group and cyano group; 16330S.doc. 24 - e 201245186 R4 is hydrazine or fluorine; η is 0 or 1, and in the case of 11 system 1, the R6 group is methyl; or its medicine It can be used as a salt of the party, provided that the compound of formula I is not 8[(2R)丨difluorophenyl)pyrrolidin-2-yl]-6-(morpholin-4-carbonyl)-2·morpholinyl- Terpene _4_ ketone. It should be understood that certain compounds of the formula defined above exhibit tautomerism. It will be understood that the invention includes in its definition any such tautomeric form or mixture thereof which has phosphoinositide (gum) 3 kinase inhibitory activity and is not limited to the formula used in the formula or named in the examples The term is a tautomeric form. In general, only one of these tautomeric forms is named in the examples below or in the following figures. Values applicable to the ordinary groups mentioned above include those described below. A value suitable for a 3 to 8 membered nitrogen-containing heterocyclic ring system formed from a R1R2 group of formula I, for example, a nitrogen-containing non-aromatic saturated or partially saturated 3 to 8 membered ring / optionally containing 1 or 2 Other heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring sulfur atom is optionally oxidized to form a 5 oxide. Suitable examples include azacycloheptyl, oxazepine, aziridine, I-heteroalkyl, alkaloid, filament, and flavonoid. Specific salicyl, pyrazolyl, morpholinyl, thiomorpholinyl, tetrahydro q, 4 thiopyranyl, 1,1-di- oxytetrahydro-1,4 thiocyl, hexahydro Pyridyl, homohexahydropyridyl, piperidinyl, homopiperidinyl, dihydropyridinyl, tetrahydrogen. Pyridyl, dihydropyrimidinyl or tetrahydropyrimidinyl. Among the specific groups of the compound, specific examples of the heterocyclic ring include azetidinyl, morpholinyl, fluorene-tertiary tetrahydro-M-thiolinyl and hexahydropyridyl, and nitrogen Heterocyclic butyl _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -base. Suitable values for any of the "R" groups (R1 to R6) include, for example: - fluorine, gas, bromine and iodine for the halo; and (1-4C) alkyl: Base, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl and cyclobutyl; for (1-3C) alkoxy: methoxy, ethoxy, propoxy and iso Propoxy. Suitable pharmaceutically acceptable salts of the compounds of the formula I are, for example, acid addition salts of the compounds of the formula I, for example acids with inorganic or organic acids (for example hydrogen, hydrobromic, sulfuric, trifluoroacetic or citric) An addition salt; or, for example, a salt of a compound of formula I which is sufficiently acidic, such as an alkali or alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt, or with an organic base (eg, decylamine, dimethylamine, three) a salt of methylamine, hexahydropyridine, morpholine or 叁-(2-hydroxyethyl)amine. Still another suitable pharmaceutically acceptable salt of a compound of formula I is, for example, a salt formed after administration of a compound of formula I in a human or animal. It is further understood that suitable pharmaceutically acceptable solvates of the compounds of formula I also form an aspect of the invention. Suitable pharmaceutically acceptable solvates are, for example, hydrates such as hemihydrate, monohydrate, dihydrate or trihydrate or a substituted amount thereof. It is further understood that a suitable pharmaceutically acceptable prodrug of a compound of formula I also forms an aspect of the invention. Thus, the compound of the present invention can be administered in the form of a prodrug. The prodrug is decomposed in a human or animal body to release a compound of the present invention 163305.doc • 26-201245186. Prodrugs can be used to alter the physical and/or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the invention contain suitable groups or substituents to which the modifying group can be attached. Examples of prodrugs include in vivo dissociable ester derivatives which may be formed at the hydroxyl group of the compound of formula I and in vivo dissociable indoleamine derivatives which may be formed at the amine group of the compound of formula I. Accordingly, the present invention includes the same as defined above, which becomes useful by organic synthesis and becomes useful by dissociation of the prodrug in humans or animals. Thus, the present invention includes such compounds which are produced by organic synthesis and which are produced by metabolism of a precursor compound in humans or animals, that is, the compound of formula I may be a synthetically produced compound or produced by metabolism. Compound. Suitable pharmaceutically acceptable prodrugs of the compounds of formula I are those which are suitable for administration to humans or animals without undesired pharmacological activity and which are not excessively toxic based on sound medical judgment. Different forms of prodrugs are described in the following documents, for example, ία) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of drugs, by H. Bundgaard Editor (Elsevier, 1985); c) A Textbook of Drug Design and Development * by

Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5, "Design and Application of Pro-drugs", H. Bundgaard, pp. 113-191 (1991); 163305.doc -27- 201245186 d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard et al. > Journal of Pharmaceutical

Sciences, 77, 285 (1988); f) N. Kakeya et al., Chem. Pharm. Bull·, 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems” , ACS· Symposium Series, Volume 14; and h) E. Roche (ed.), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 ° Suitable pharmaceutically acceptable prodrugs of compounds of formula I having a hydroxy group (eg An ester or ether that is dissociable in vivo. An in vivo dissociable ester or ether of a compound of formula I containing a hydroxy group, for example, is cleaved in a human or animal body to produce a pharmaceutically acceptable ester or ether of the parent hydroxy compound. Pharmaceutically acceptable ester-forming groups suitable for use in the hydroxy group include inorganic esters such as phosphate esters (including phosphonium amide cyclic esters). Other pharmaceutically acceptable ester-forming groups suitable for use in the hydroxy group include (1-10C)alkyl fluorenyl groups (eg, ethyl hydrazino, benzhydryl, phenylethyl fluorenyl, substituted benzylidene and phenyl) Mercapto), (1_10C) alkoxycarbonyl (eg ethoxycarbonyl, [di-(1-4C)alkyl]aminecarbamyl, 2-dialkylaminoethyl) and 2-carboxyacetamidine Examples of the ring substituent on the phenyl phenyl fluorenyl group and the benzyl fluorenyl group include an aminomethyl group, an alkylaminomethyl group, a fluorenyl-dialkylaminomethyl group, a morpholinyl fluorenyl group, and a piperidine group. Plough-based thiol and 4-(1-4(1:)pyrylene-1'-1-ylmethyl. Pharmaceutically acceptable ether-forming groups suitable for hydroxy include a-methoxyalkyl, For example, ethoxylated fluorenyl and 163305.doc -28- 201245186 neopentyloxy fluorenyl. Suitable pharmaceutically acceptable prodrugs of the compounds of formula I having an amine group, for example, cleavable in vivo Amine derivatives. Suitable pharmaceutically acceptable guanamines from amine groups include, for example, (1-10C) alkyl sulfhydryl groups (e.g., ethenyl, benzhydryl, phenylethyl fluorenyl, and substituted phenyl) Mercapto and phenylethyl fluorenyl The formed guanamine. Examples of the ring substituent on the phenylethyl fluorenyl group and the benzyl fluorenyl group include an aminomethyl group, an alkylaminomethyl group, a dialkylamino fluorenyl group, a morpholinyl fluorenyl group, and a piperidine group. Cultivated 1-ylmethyl and 4-(l-4C)alkylpiped-1-ylindenyl. After administration of a compound of formula I, the in vivo effect of a compound of formula I may be partially in human or animal body Forming one or more metabolites for application. The in vivo effects of the compound of formula I can also be applied by means of the metabolism of the precursor compound (prodrug). To avoid doubt, it should be understood that in this specification The group is modified as defined above ("hereinbefore defined" or "defined hereinbefore"), and the group covers the first occurrence and the broadest definition of the group and each and all of the specific definitions. Particular novel compounds of the invention include, for example, a decenone derivative of formula j or a pharmaceutically acceptable salt thereof, wherein each of Ri, R, R, 114, 115, 11 and 1^, unless otherwise stated One of them has any of the above or defined in paragraphs (a) to (u) below (a) R1 is a (1-4C) alkyl group; (b) R is a methyl group, an ethyl group or a 2-hydroxyethyl group; (c) an R1 group methyl or ethyl group; 163305.doc •29· 201245186 ( d) R1 methyl; (e) R2 (1-4C) alkyl; (f) R2 methyl or ethyl; (g) R2 methyl; (h) R1 and R2 together form 4 to The nitrogen-containing heterocyclic ring system of the employee, which optionally contains one other hetero atom selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring-breaking atom is optionally oxidized to form an s-oxide, which ring is optionally substituted by a hydroxyl group; (l) R1 and R2 together form a nitrogen-containing heterocyclic ring system selected from the group consisting of azetidinyl, morphinyl, 1-sided oxytetrahydro-indole, 4-thiolinyl and hexahydropyridyl . The base is substituted by a radical; (1) R1 and R2 together form a nitrogen-containing heterocyclic ring system selected from the group consisting of azetidin-1-yl, morphin-4-yl, 1-sided oxytetrahydro _i, 4_ 〇 well _4-base and hexahydrogen. a pyridine-1-yl group which is optionally substituted with a hydroxy group; (k) R1 and R2 together form a nitrogen-containing heterocyclic ring system selected from azetidin-1-yl or oxime-4-yl; (1) R3 and R5 are independently selected from the group consisting of H, fluorine, methoxy and cyano; (m) R3 and R5 are independently selected from η and fluorine; (n) R3 and R5 are ruthenium; (〇) R3 and R5 are fluorine; (p) R4 system; (q) R3 and R4 are Η and R5 is fluorine; (r) R3 and R5 are fluorine and R4 is η; (s) η is 0; 163305.doc -30· 201245186 (t) n is 1; and (u) η is 1 and R6 is a fluorenyl group at the 2-position of the morpholine ring. (ν) R1 and R2 together form a nitrogen-containing heterocyclic ring system, and the ring is a linoleyl group; a specific group of the compound of the present invention is a ketene compound of the above formula I, wherein: - R1 is regarded as a hydroxy-substituted (1-4C)alkyl group; R2 is a (1-4C) alkyl group; or R1 and R2 together form a 4 to 6 membered nitrogen-containing heterocyclic ring system, optionally containing one selected from the group consisting of Other heteroatoms of oxygen, nitrogen and sulfur, wherein the ring sulfur atom is optionally oxidized to form an S-oxide' which is optionally substituted by a hydroxyl group; R3 and R5 are independently selected from fluorene or halo and R4 is η; 0 or 1 'and when the η system is 1 'the r6 group is a thiol group; or a pharmaceutically acceptable salt thereof. A further specific group of the compounds of the invention is a decenone compound of the above formula I, wherein: - R1 is optionally substituted by a radical (1 - 4C) aryl; R2 is (1-4C) alkyl; R1 and R2 together form a nitrogen-containing heterocyclic ring system selected from the group consisting of azetidinyl, morpholinyl, 1-oxotetrahydro-i, 4-thiolinyl and hexahydropyridyl, Cyclic conditions are substituted by a hydroxyl group; R and R are independently selected from fluorene or halo and r4 is η; η is 0 or 1, and when η is 1, the R6 group is methyl; or a pharmaceutically acceptable salt thereof . 163305.doc • 31- 201245186 A further specific group of the compounds of the invention is a ketene compound of the above formula i, wherein: - R is methyl, ethyl or 2-hydroxyethyl; R 2 is thiol or B Or R1 and R2 together form a nitrogen-containing heterocyclic ring system selected from the group consisting of azetidinyl, morpholinyl, 1-oxotetrahydro-indole, 4-thilyl and hexahydropyridine a ring which is optionally substituted with a radical; R and R5 are independently selected from fluorenyl or halo and R4 is H; η is 0 or 1, and in the case of J, the R6 group is methyl; or An acceptable salt. A further specific group of the compounds of the invention is a decenone compound of the above formula I, wherein: - R1 is fluorenyl or ethyl; R2 is decyl or ethyl; or R1 is R2 Forming a nitrogen-containing heterocyclic ring system selected from the group consisting of azetidin-buyl, morpholine-4-yl, 1-sideoxytetrahydro-1>4_thioglycol-4 and hexahydropyridin -1-yl' is optionally substituted with a hydroxy group; R3 and R5 are independently selected from fluorene or fluoro and R4 is η; η is 0 or 1, and when reading oxime, the r6 group is methyl; or it is pharmaceutically acceptable Accepted salt. Another specific group of the compound of the present invention is the above formula a terpene compound or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are suitably as defined in any one of the above paragraphs (4) to (k), especially as in paragraph (4), (g) above or (1) to (k); r3, R4 - 32 · 163305.doc Θ 201245186 and (d) are preferably as defined in any of the above paragraphs (1) to (Γ) and especially as in paragraph (1) or (4) above. And η and R6 are suitably as defined in any of the above paragraphs (s) to (u). A specific group is a ketene compound of the above formula I, a compound of the invention or a pharmaceutical thereof An acceptable salt, wherein: _ R1 and R2 are suitably as defined in the above paragraphs (&) to (1〇, or (v) above, especially as in paragraphs (4), (g) above. , as defined in (v) or (1) to (k), and more particularly as defined in paragraph (v) above; R3, R4 & R5 are suitably as defined in any of the above paragraphs (1) to (1) And especially as defined in the above paragraph (0 or (s); and η and R6 are suitably as defined in any of the above paragraphs (3) to (11) A specific group is a decenone compound of the above formula I, wherein: - R1 is a methyl group or a 2-hydroxyethyl group; R2 is a fluorenyl group; or R1 and R2 together form a nitrogen-containing heterocyclic ring system, It is selected from the group consisting of azetidin-yl, morphin-4-yl, 1-oxo-tetrahydro-1,4-1,4-pyridin-4-yl, hexahydropurine tb-l-yl and 4- R6 and R5 are independently selected from the group consisting of ruthenium, fluorine, decyloxy and cyano; R4 is ruthenium or fluorine; η is 0 or 1, and in the η system 1, R6 is A group methyl; or a pharmaceutically acceptable salt thereof. A further specific group of the compounds of the invention is a decenone compound of the above formula I, wherein: - 163305.doc - 33 - 201245186 R1 is methyl or 2-hydroxyethyl; R2 is methyl; or R1 and R2 Forming a nitrogen-containing heterocyclic ring system selected from the group consisting of azetidin-yl, morpholin-4-yl, 1-sided oxytetrahydro-1,4-thin-4-yl, hexahydro Pyridyl-1 and hydroxyhexahydropyridin-1-yl; R3 and R5 are independently selected from the group consisting of hydrazine, fluorine, methoxy and cyano; R4 is hydrazine or fluoro; η-system 0; A pharmaceutically acceptable salt. A further specific group of the compounds of the invention is a decenone compound of the above formula I, wherein: - R1 and R2 together form a nitrogen-containing heterocyclic ring system selected from the group consisting of azetidinyl-, morpholine 4-yl, iota-oxytetrahydro-i,4-thin-4-yl, hexahydropyridin-1-yl and 4-hydroxyhexahydropyridine_ι_yl; R3 and R5 are independently selected From H, fluorine, decyloxy and cyano; R4 is hydrazine or fluorine; η-system 0; or a pharmaceutically acceptable salt thereof. A further specific group of the compounds of the invention is a decenone compound of the above formula I, wherein: - R1 is methyl; R2 is methyl; or R1 and R2 together form a morpholine-4-yl ring; R3 and R5 is independently selected from η and fluorine; R4 is Η; η is 1' and the R6 group is fluorenyl; or a pharmaceutically acceptable salt thereof. 163305.doc 6 •34· 201245186 A further specific group of the compounds of the invention is a ketene compound of the above formula i, wherein: R 1 and R 2 together form a morpholin-4-yl ring; R 3 and R 5 independently It is selected from the group consisting of hydrazine and fluorine; R4 system; η system 1 ' and the R6 group is a fluorenyl group; or a pharmaceutically acceptable salt thereof. A further specific group of the compounds of the invention is a decenone compound of the above formula I, wherein: - R1 and R2 together form a morpholine-4-yl ring; R3 and R5 are hydrazine; R4 is Η; η-system 0; Or a pharmaceutically acceptable salt thereof. The specific compounds of the present invention are, for example, the ketene compounds of the formula I, which are disclosed in the examples described below. To avoid doubt, although the compounds have been named according to the IUPAC guidelines, there are still multiple correct names for a particular instance. For example, the compound of Example 1.03b can be named 8-[(211)-1-(3,5 -difluorophenyl)pyrrolidine_2_yl]_6_(morpholine_4_carbonyl)_2_morpholinyl-decene·4-one, or difluorophenyl)pyrrolidine_2_yl]-6-( Morpholine·4·carbonyl)·2_morpholinyl_4H decene·4-ketone. For example, the specific compound of the present invention is a ketamine derivative of the formula I selected from any one of the following: 8-(1_(3,5·difluorophenyl)pyrrolidin-2-yl) - hydrazine, hydrazine-dimethyl-2-morpholinyl-4-oxooxy-4-indolenecarboxamide; 8-(1-(3,5-difluorophenyl)-pyrrolidine-2- )--6-(morpholine-4-carbonyl)-2-morpholine 163305.doc -35· 201245186 base-4H-p gram -4-_ ; 8-[(2S)-l-(3,5 -difluorophenyl)indolepyridin-2-yl]-6-(morpholinylcarbonyl)_2_loryl-p-en-4-one; 8-[(2R)-i-(3,5_ Difluorophenyl) 0-pyridyl-2-yl]_6_(morpholine_4carbonyl oxime-yl-p gram _ 4 - _ ; 6-(azetidinylcarbonyl)_8·(1-( 3,5-difluorophenyl)pyrrolidinyl-2-yl)-2-ethyllinyl-4Η-bitite-4-_ ; 6_(azetidine-kappacarbonyldifluorophenyl)pyrrolidine·2_ ] -2- -2- 基 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克]-2-morpholinyl-nonene_4_one; 8 (1 (3-), "»Bilo-2-yl)-Ν, Ν-dimethyl-2-morphinyl _ 4-sided oxy-4-indole-nonene-6-formamide; 8 [(2S)-l-(3-fluorophenyl). slightly biting _2_yl]·ν, Ν-Dimethyl _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ base]-Ν, Ν-dimethyl 2 _ 琳 琳 _ 4 · side oxy-π gram -6-formamide; 8 (1-(3 - phenyl) <» Biha Bite_2-yl)-6-(Merlin·4·syl)_2_吗琳基_ 4Η-Ι1 克妇_4-ketone; 8-[(2S)-l-(3-fluorophenyl) Pyrrolidine-2-yl]-6-(morpholine································· _2_基]_6-(morpholine·4_carbonyl)_2_morpholinyl-** gram--4-_; 6 (azetidine·丨_carbonyl)·8·(ι·(3 -Fluorophenyl)pyrrolidine_2·yl)_2?163305.doc -36· 201245186 phenyl-4H-nonene-4·one; 6-(azetidin-1-carbonyl)-8-[ (2S)-l-(3-fluorophenyl)"pyrrolidin-2-yl]-2-morpholinyl-nonen-4-one; 6-(azetidin-1-carbonyl)- 8-[(2R)-l-(3-fluorophenyl)phosphonium-2-yl]-2-morpholinyl-nonen-4-one; 8-(1-(3-fluorophenyl) Pyrrrolidin-2-yl)-N,N-dimercapto-2-morpholinyl-4-oxo-4H-nonene-6-decylamine; 8-(1-(3,5-) Difluorophenyl)-doprolidin-2-yl)-2-((R)-2-methylmorpholinyl -6-(morpholine-4-carbonyl)-4H-nonen-4-one; 8-(1-(3-fluorophenylpyrrolidine-2-yl)_2_((R)-2-methyl Morpholinyl)_6_(morpholin-4-carbonyl)-4H-nonene_4-one: and 8-(1-(3-fluorophenyl)"pyrrolidine-2-yl)·Ν,Ν· Dimethyl·2_((8)_2-methylmorpholinyl)-4-oxooxy-4-indene-nonene-6-carbamimid; or a pharmaceutically acceptable salt thereof. According to still another aspect of the present invention, the specific compound of the present invention is a decenone derivative of the formula I selected from any one of the following: 8-(1·(3,5-difluorophenyl)対 bite _2•基)·ν,ν_dimethyl·2“Marinphyrin-sideoxy-4Η-bitite-6-cartoamine; 4 8-(1-(3,5·difluorophenyl)) „Bilo bite _2 base) 6 (Mu Lin collar base) base-4Η-bite thin · 4-_ ; ”'Lin 8-[(2 called 1-(3,5_difluorophenyl). _2 base]·6 (Merlin|Mallindi-bite _4-ketone; 6_(azetidinyl)-_8_(1_(3,5-difluorophenyl)吼 slightly bite 2-琳琳基-4H-bite _4-_ ; I63305.doc -37· 201245186 6'(gas heterocyclic butyl small rebel)-8-[(2R)-l-(3,5-dibenzene Base) 0-pyridyl-2-yl]-2-morphinyl_p gram _4-ketone; 8-(1-(3-fluorophenyl)pyrrolidinyl-2-yl)_N,N-diyl _ 2 morpholinyl ice-side oxy-4H-nonene _6. formamidine; [(R) 1 (3-fluorophenyl) „Bilo bite_2_yl]_N,N-dimethyl-2琳基_ 4-sideoxy-decenecarbamamine; 8-〇-(3·fluorophenyl).pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)_2_morpholinyl _ 4H-bitite · 4-ketone; 8-[(2R)-l-(3-fluorostyl base than bite · 2 · base] winter琳琳_4数基)-2·morpholinyl-biti-4-ketone; (azetidine _1·yl) fluorophenyl bilol bite baseline-4Η-Ρ克妇- 4-嗣; 6_(azetidinyl)-H(2R)-1 (3 笨 基 ^ 嘻 -2 -2 -2 -2 · · · · · · · · · 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 -(H3-fluorophenyl)ettB each bite_2_yl)_N,N_:f group_2.laninyl_4_sideoxy-4H-octenol-6-carbamimid; 8-(1 -(3,5-difluorophenyl)β-pyrrolidinyl 2yl)_2_((11)_2methylmorpholinyl X.(morpholin-4-yl)_4Η- octa- 4-ketone; 8 -(Η3-IIphenyl)吼 slightly bite 2_yl)_2-((R)_2·f quinolinyl•(morpholine-4-carbonyl)_4Η-decene·4-one; -2-((R)-2-methyl or its pharmaceutically acceptable 8-(1-(3-fluorophenyl)pyrrolidinyl)-indole, Ν_di-phenyl)_4_ side Oxy-4-indene-decene·6-nonylamine; salt. According to still another aspect of the present invention, the specific compound of the present invention is selected from the group consisting of 163305.doc

S •38· 201245186 The following is the ketene derivative of formula i: _ 8-(1-(3,5-difluorophenyl)pyrrolidine-2-yl)_;^,]^2 Mercapto-2-morpholinyl-4-sided oxy-4H-octahydro-6- decylamine; 8-(1-(3,5-difluorophenyl) "byridine-2-yl] Porphyrin_4_carbonyl)_2_morpholinyl-4Η- ketene-4-one; 8_[(2S)_1-(3,5·difluorophenyl)pyrrolidin-2-yl]-6-(啉-4-carbonyl)-2-morphinyl-bite _4_鲷; 6-(azetidin-1-carbonyl)-8-(1-(3,5-difluorophenyl)fluorene Bilo bit-2-yl)-2-morphinyl_4Η-ι» 克稀_4-ketone; 6-(azetidin-1·carbonyl)-8-[(2S)-l-( 3,5-difluorophenyl)pyrrolidin-2-yl b-2-morphinyl ketone _4-ketone; 8 (1 (3-fluoro-based). Bilo bite_2_base)_ν,Ν - Dimercapto-2-bromo--4-indolyl-4-indole-6-indenylamine; M(2S)-l-(3.fluorophenyl). Biloxidin·2·yl]-oxime, ν·dimethyl-2-ylmorpholinyl 4- 4-oxo-ρ-enk-6-carbamide; 8-0-(3-fluorophenyl) Pyrrolidine·2_yl)-6-(morpholine_4_carbonyl)_2_morpholinyl-4H-p gram _4-ketone; 8-[(2S)-l-(3 -1 phenyl) β-Byridine-2-yl]-6-(morpholine-4-ylcarbonyl)-2·morpholinyl-octenyl-4-one; 6 (azetidine·1-rebase)-8- (1-(3-fluorophenyl)"·Bilo bite_2_yl)-2-morphinyl-4H-p gram _4-ketone; ό-(azetidine-丨·carbonyl fluoride Phenyl)βpyrrolidinyl-2-yl]-2-merionyl ketone-4-one; 8-(1-(3-fluorophenyl)indolepyridin-2-yl)-:^, >1-Dimercapto-2-morpholinyl-4-sideoxy 163305.doc •39- 201245186 yl-4H-pinene-6-decylamine; 8-(1-(3,5-difluoro) Phenyl)pyrrolidine·2·yl)_2 (morphine-4-yl)-4Η>ketene-4-one; methylmorphinyl-6-8-(1-(3-fluorophenyl) Pyrrolidine 2_yl)_2_((11)_2 porphyrinyl)-4H-biting collar; and -methylmorphinyl)-6-(?8-(1 _(3_fluorophenyl)) Pyrrrolidine 2_yl)_N N_diindolyl) Winterside oxy-4H-bite.6_cartotenamine==)·2·methyl horse salt. Further, according to still another aspect of the present invention, the compound of the present invention (10) or a pharmaceutically acceptable salt thereof. Specific Compound Examples According to still another aspect of the present invention, the present invention 1. A compound of 5 or a pharmaceutically acceptable salt thereof. Specific Compound Examples According to still another aspect of the present invention, the compound of the present invention 1.06 or a pharmaceutically acceptable salt thereof.疋 疋 系 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据A compound of 3b or a pharmaceutically acceptable salt thereof. According to the invention, the state of the invention (W3 5 - prepared ^ '" special compound system (-)-8-14H two h base ... 琳琳 _4-base) · 2 · 琳琳--cut 4 Or a pharmaceutically acceptable salt thereof, wherein (i) of the chemical names refers to the optical rotation measured by the conditions described in Example 1 Money. According to still another aspect of the present invention, the specific compound of the present invention is (·) _8·((, fluorophenyl)-pyrrolidin-2-yl)-6-(morpholin-4-carbonyl)-2 - morpholine 163305.doc 201245186 base, dilute-4,; which gives (i) the chemical name the optical rotation measured using the conditions described in Example 1. 〇 3b. According to a still further aspect of the present invention, the compound of the present invention is (_) 8_ U-(3,5-di-suppressyl)pyrrolidin-2-yl)6 (morpholine-4)-benzylmorpholine a pharmaceutically acceptable salt; wherein (i) in the chemical name indicates the optical activity measured by the conditions described in the .G3b. According to still another aspect of the present invention, the present invention The specific compound is 8-[(2R)-l-(3,5-difluorophenyl). Bilo bite_2_yl] winter (Molin-___yl)·2_morpholinyl-decene- 4-ketone or a pharmaceutically acceptable salt thereof. According to the present invention, the specific compound of the present invention is 8-[(2R)-bu (3,5::fluorophenyl) bite·2 • base]_6 (Merlin|several base) winter 咐 -->» gram -4- ketone. According to another aspect of the present month, the specific compound of the present invention is Η 哪: fluorophenyl a pharmaceutically acceptable salt of a number of R morpholyl-decen-4-ones. According to still another aspect of the present invention, the specific compound of the present invention is a compound of the present invention. 8. [1] (3,5-difluorophenyl). The ratio of ...-based W?lin-4·yl)_2_morpholinyl-decen-4-one or a pharmaceutically acceptable salt thereof. this In the case of July, the specific compound of the present invention is H(2S)-1'(3,5.:fluorophenyl). Is it a _2 _ base] winter (nuenyl)? Orolinyl-4Η-nonene_4_one. According to still another aspect of the present invention, the specific compound of the present invention is called 1·0,5' difluorophenyl)° ratio is slightly determined. -6-(咐咐 collaryl)-2_morpholinyl-4H-spiro 4, a pharmaceutically acceptable salt. 163305.doc 201245186 According to still another aspect of the invention, the specific compound of the invention is 8 (-Fluorophenyl)anthracene (yl)methane (4)methyl is a group of 2, aryl- 4H-nonene 4-ketone or a pharmaceutically acceptable salt thereof. According to still another aspect of the present invention The specific compound of the present invention is 8_(ι·(3-fluorophenyl)°...·2·yl)-6-(4-methyl-l-carbon-based)-winterline--4H-p 克妇·4 _ ketone. According to a further aspect of the present invention, the specific compound of the present invention is 8 servant (3. fluorophenyl), biting _2•yl) winter (4-methyl maidenyl)·2_? A pharmaceutically acceptable salt of linco's 4-indole ketone. According to a further aspect of the invention, the particular compound of the invention is 8-[(2r)-i-(3-phenylphenyl). Bite_2_base)·6·(4 methyl piperine Bromocarbon)·2·morpholinyl-4H-nonene-4-one or a pharmaceutically acceptable salt thereof. According to a further aspect of the present invention, the specific compound of the present invention is 8-[(2RHl- (3 j stupid) 吼 (four) · 2 _ base)] _6_ (4 methyl ^ wells small base) -2- fluorenyl · 4 η _ _ _ _ ketone. According to the invention - The specific compound of the present invention 8-[(2RHl-(3_qiphenyl)" is more than „each bite·2_ base) b 6(4)methylpepropanyl)-2- oxazyl _4H-p gram roast - Pharmaceutically acceptable sleep of 4-ketones According to yet another aspect of the invention, the invention. r The ruthenium compound is M(2S)-(l-(3-fluorophenyl)pyrrolidine·2·yl)]·6·(4_甲|你基呢. Well·1·基基)·2- According to another aspect of the present invention, the present invention, the oxime compound, is 8-[(2S)-(l-(3-fluorine). Phenyl)pyrrolidin-2-yl)]_6_(4 审 | " , τ 丞 丞 · 1 -2- ) ) -2- -2- -2- -2- -2- -2- Η Η -4- 163 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 ·

S 201245186 According to the present invention, it is further separated from 8-[(2 0 0 ♦ fluoro phenyl). Specific; compound of each bite ^ ^ 琳 基 · 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 (3_Methoxy Am, the compound compound of the invention is 8-mer, the base of the milk base) n is more than 唆 唆_2 dragon. , 疋 疋 · 4 4 4 4 4 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其The specific compound is a group of 叩·(3-methoxy-based) 根据. According to the invention, the specific compound of the present invention is 叩·(3-methoxy-based) fluorene.毕洛唆_2箕1/:/ 川川古洛^ 2·基]-6_(Mallin _4_ aryl) 2 morpholinyl-4H-nonene·4 ketone pharmaceutically acceptable salt . According to the present invention, the specific compound of the present invention is 8-[(2R)-l-(3-methoxyphenyl) 芡2-yl]·6_(morpholine). 4-carbonyl)-2-morpholinyl-4H-nonen-4-one or its pharmaceutically acceptable sleep. According to still another aspect of the present invention, the present invention is characterized in that the compound is a compound called [1-(3. methoxyphenyl) 吼__2 yl] _6_(Merlin _4_ yl) 2 _ - 4H-*7 grams of diluted 4-class. According to a still further aspect of the present invention, the specific compound of the present invention is 8-[(egly oxyphenyl) fluorenyl]_6. (morphine (tetra)yl)-2_morpholinyl-4H-nonene-4 a pharmaceutically acceptable salt of a ketone. According to still another aspect of the present invention, the present invention is a specific compound system: 8 丨-丨-(3·methoxyphenyl) 吼 咬! Base] Winter (Merlin), _2_morpholinyl-4H-nonen-4-one or its pharmaceutically acceptable step. 163305.doc • 43- 201245186 According to still another aspect of the present invention, the specific compound of the present invention is 8-[(2S)-l-(3-decyloxyphenyl)oxaridin-2-yl]_6_( Morpholine _4 carbonyl morphine- 4 Η- 稀 嗣 嗣 嗣. According to still another aspect of the present invention, the specific compound of the present invention is 8-[(2S)-l-(3-methoxyphenyl) a pharmaceutically acceptable salt of pyrrolidine-2-yl]_6_(morpholine-.carbonyl X.morpholinyl-4H-nonene-4. ketone. Another aspect of the invention provides for the preparation of a formula [ The compound or its pharmaceutically acceptable (iv) m method method is illustrated by the following representative method variants, wherein unless otherwise stated, R1, R2, R3, R4, Rη and R have the meanings defined above. A meaning. The necessary starting materials can be obtained by standard organic chemistry procedures. The preparation of these starting materials is described in conjunction with the following representative method variants (iv) and in any case. Alternatively, the necessary starting materials can be They are interpreted by similar procedures, which are within the general techniques of organic chemists. Suitable method variants include, for example, the following: _ (a) Was

Wherein R3, R4, R5, or a heart has any of the meanings defined above, except that the functional group is present if it is desired to be protected; and the amine of formula m is I63305.doc 201245186 fork coupling reaction,

R III wherein R1 and R2 have any of the meanings defined above, except that any functional group is required to be protected. The reaction can be carried out in the presence of a suitable coupling agent such as TSTU (2-(2,5-di-oxypyrrolidinyl) tetrafluoroborate-1,1,3,3-tetradecyl). Isourea rust salt) or butyl 61'11 (tetrafluoroborate 2-(111-benzo[d][l,2,3]triazol-1-yl)·ΐ, ι,3,3-tetramethyl The isoururium sulfonium salt, or the i-propylphosphonic anhydride cyclic trimer' then removes any of the protecting groups present. This reaction is conveniently carried out in the presence of a suitable base. Suitable base (for example) organic amine test (for example, 0-bite, 2,6-dimethyl η than bite, methyl η than bite, 4-dimercaptoaminopyridine, triethylamine, fluorene-fluorenyl) Porphyrin, diazabicyclo[5.4.0]undec-7-dilute, diisopropylethylamine, or, for example, metal or soil metal hydroxide or hydroxide (eg sodium carbonate, carbonic acid) Potassium, carbonic acid, sodium hydroxide or hydrogen chloride). The reaction is conveniently carried out in a suitable inert solvent (for example; dimethyl decylamine, decyl pyrrolidone, tetrahydrofuran, i. 4 dioxane, !, 2 dimethyloxy ethane, stupid, fluorene, In the presence of xylene, methanol, ethanol, a halogenated solvent (such as dichloromethane, chloroform or tetra-carbonized carbon) and in the range of, for example, -5 (TC to 100 C (preferably 〇 to 3 ° C) Alternatively, the carboxylic acid compound of formula II can be converted to an activating species (e.g., helium), for example by treatment with grass mash, which can then be reacted with a hydrazine compound under conditions well known in the art. 163305.doc •45· 201245186 A compound of formula II can be prepared by, for example, a compoundation reaction of a compound of formula Ila.

Wherein R, R, R, n and R have any of the meanings defined above and R7 is (1-6C)alkyl, conveniently fluorenyl or ethyl. The saponification reaction can be carried out, for example, in a suitable solvent (for example, a mixture of ethanol and water, or water and water at a temperature of, for example, 〇 ° C to 1 Torr (preferably in the range of 20 ° C to 40 ° C). The compound of the formula Ila is treated with a metal or alkaline earth metal hydroxide such as lithium oxynitride, potassium hydroxide or sodium hydroxide in a miscible solvent such as tetrahydrocarbamate or dioxane. The compound of formula Ila can be prepared, for example, by the following means: conveniently bringing the IV compound in the presence of a suitable catalyst,

Wherein η and R6 have any of the meanings defined above, and the R7 system (丨_6(:)alkyl group is conveniently methyl or ethyl; reacts with a compound of formula V, 163305.doc • 46· 201245186

fT v wherein R3, R4 and R5 have any of the meanings defined above, except that any functional group is required to be protected, and 1^(} is a suitable leaving group such as a dentate group (eg, gas, bromine, An iodine group, conveniently bromine or iodine, is subsequently removed from any of the protecting groups present. Suitable catalysts for the reaction include, for example, metal catalysts such as palladium (iridium), such as four (three stupid) Palladium (〇); or palladium („) salt (such as palladium acetate (π), vaporized palladium (II), palladium bromide (11), bis(triphenylphosphine) gasified palladium (11) , H, · bis(diphenylphosphino)ferrocene]digas palladium (II), or hydrazine (dibenzylidenepropyl) diphosphine, and phosphine ligands (eg (9,9-dioxin) Base-9H·. ton of _4,5-diyl) bis(monophosphine)) Catalyst formed in situ. The reaction is conveniently carried out in a suitable solvent (eg #, flu dimethylformamide, tetrahydrofuran) , 1,4-dioxane i, 2-dimethoxyethane, benzene, toluene or diphenylbenzene) and in the range of, for example, 2:0 ° C to 150 t (preferably 6 (rC) The reaction is carried out at a temperature of up to 120 ° C. The reaction is also conveniently carried out in a base (example) The implementation of this type of reaction is described as "Metal-Catalyzed Cross Coupling Reactions" (2nd edition 'edited by Armin Meijere, Fran9〇is Diederich, Wiley Buchwald type coupling reaction in -VCH, 2004, Vol. 1, p. 699. 163305.doc -47- 201245186 Starting material in example 1.00 _8_(1_(3,5_ difluoro stupyl) An example of the reaction is illustrated in Step 4 of the preparation of pyrrolidine·2·yl)-2-morpholinyl-4-oxooxy-4-indole-6-carboxylic acid. Alternatively, the compound of the formula Ila can be obtained by chan. -Lam coupling type reaction, wherein a compound of formula IV is reacted with a compound of formula Va,

Wherein R3, R4 and R5 have any of the meanings defined above, except that if any functional group is desired to be protected, and R8 is (UC)alkyl or Ηβ, the reaction is conveniently carried out at a copper source (eg copper acetate (π) )) exists in the 〇 (: 1 ^ implementation ' and is exposed to atmospheric oxygen by means of ambient temperature (Tetrahedr〇n

Letters, 1998, 2933). The compound of formula 1V can be prepared by hydrogenating a compound of formula VI,

Wherein η and R6 have any of the meanings defined above, and the R7-based (16C)alkyl group is conveniently methyl or ethyl' and the lanthanide protecting group map (e.g., amine group 163305.doc -48·

S 201245186 acid ester, such as a third butoxycarbonyl group, after which Pl is removed. The reaction is conveniently carried out in a suitable solvent (for example, an alcohol such as methanol, #, octadecylcarbamide, tetrahydrofuran, 1,4-di, fensin, 1,2,2- methoxyl In the presence of alkane, benzene, methyl or diphenylbenzene; conveniently in methanol and in the range of, for example, 20 ° C to 100 ° C (preferably in the range of 50 ° (: to 80 ° C) At a temperature of from 1 to 100 atm (preferably about 5 atm), it is carried out in the presence of a catalyst (for example, ruthenium, rhodium, platinum, preferably 5% alumina). Tributoxycarbonyl' can be conveniently removed by using hydrogenated hydrogen (dissolved in, for example, dioxane) in a solvent such as DCM at room temperature. Alternatively, the compound of formula iv can be used Prepared in the following manner: Compound I of formula VI (wherein η and R6 have any of the meanings defined above, and r7 is (ι 6 C)alkyl is conveniently methyl or ethyl) and a compound of formula via ,

Wherein P! is a protecting base ring, preferably an alkoxycarbonyl group, such as a third butoxy group; reacting under Heck coupling conditions, then removing the protecting group, and then reducing the resulting isomer dihydrogen % (or vice versa). For additional details on Heck coupling conditions, see, for example, "Meul_ Catalyzed Cross-Coupling Reactions", edited by Francois Diederich and P.J. Stang, Wiley-VCH, 1998, p. 99. Suitable catalysts for the ahai reaction include, for example, metal catalysts (for example, (I), such as dichlorobis(triphenylphosphine)palladium(II)); or palladium (11) salts (such as palladium acetate). (II), gasification (II), > odorization (II)) Catalyst β which is conveniently formed in situ in the presence of a phosphine ligand (for example, triphenyl 163305.doc • 49- 201245186 phosphine) The reaction is conveniently carried out in a suitable solvent (for example, #, dimethyl dimethyl carbamide, tetrahydrofuran, 1,4-dioxin, 1,2-dimethoxyethane, stupid, anthracene or xylene) and It is carried out, for example, at a temperature ranging from 2 Torr to 150 ° C (preferably 6 Torr. Torr to 120 ° C). The reaction is also conveniently carried out in the presence of a test such as carbonic acid, potassium carbonate or sodium carbonate, conveniently carbonated off. In the case of a third butoxycarbonyl group, p 1 can be conveniently removed by using hydrogenated hydrogen (dissolved in, for example, dioxane) in a solvent (e.g., DCM) at room temperature. The reaction to carry out the reduction of the isomer dihydropyrrole is conveniently carried out in a suitable solvent (for example, an alcohol such as methanol, dimethylformamide, tetrahydro hydrazine, hydrazine-dioxane, 1,2-dioxyloxy group). In the presence of ethane, benzene, toluene or xylene; conveniently in the sterol and in the range of, for example, 20 ° C to 100 ° C (preferably in the range of 20 ° C to 60 ° C) The temperature is at a hydrogen pressure (ι_100 atm) (preferably about 5 atm) in the presence of a catalyst such as palladium, rhodium or platinum, preferably 5% palladium on carbon. A compound of formula VI can be prepared, for example, by the following: a compound of formula VII

Wherein η and R6 have any of the meanings defined above, and R7 is (1-6C) 163305.doc • 50- 201245186 is preferably a thiol or ethyl group;

Wherein P1 is a protecting group (e.g., an amino formate vinegar such as a third butoxy group) and the R is a (1 - 3C) or a hydrazine; the reaction is carried out under Suzuki coupling conditions. For additional details on Suzuki coupling conditions, see (for example): "Meul_ Catalyzed Cross-Coupling Reactions" by Francois

Edited by Diederich and P.J. Stang, Wiley-VCH, 1998, p. 49, after which P is removed. Catalysts suitable for use in the S-H reaction include, for example, a metal catalyst such as a ruthenium, such as tetrakis(diphenylphosphine), or a salt of (II), such as acetic acid (II), Palladium (II) chloride, palladium (II) bromide, bis(triphenylphosphine) gasification (n), [U, · bis(monophosphinyl)ferrocene] II gas (Π) Or hydrazine (dibenzylideneacetone) dipalladium) conveniently present in the phosphine ligand (eg (9,9-dimercapto-9H-purine·4 5-diyl) bis(monophosphine)) The catalyst formed in situ. The reaction is conveniently carried out in a suitable solvent (for example from dimethyl dimethyl amide, tetraterpene, flurane, 1,4 -1 ° smoldering, 1,2-dimethoxy ethoxy, stupid, toluene or _ Benzene) is carried out at a temperature of, for example, 2.0 ° C to 15 (in the range of TC (preferably in the range of 6 Torr to 120 ° C). The reaction is also conveniently carried out in a base (for example, cesium carbonate, carbonic acid) It is carried out in the presence of an aqueous solution of sodium carbonate or sodium carbonate conveniently. 163305.doc 51 201245186: The compound of the formula VII of the formula IX can be obtained from the following method.

CH

Wherein R7 is a (1-6C)alkyl group conveniently referred to as methyl or ethyl;

Wherein π and R have any of the meanings defined above; coupling in the presence of a suitable activator (e.g., Lewis acid, such as boron trifluoride diethyl ether complex). The reaction of a compound of the formula IX with a compound of the formula X is conveniently carried out in a suitable solvent (for example dimethylformamide, tetrahydrofuran, 1 44 dioxin?*-"fly methoxyethane, benzene, toluene, xylene or halogenated The solvent (for example, dichlorohydrazine, gas-form or tetra-carbonized carbon) is present in the presence and at a temperature of from 2 ° C to 15 (in the range (preferably in the range of from 601 to 1201). The compound can be prepared, for example, as shown in the synthesis of methyl bromide-2-morpholinyl-4-oxo-4H-nonene-6-carboxylate used as a starting material in the example. The compound of formula IX is also described in the literature (Ger. 〇ffen, DE 4318756 1994 and Aust. J. Chem. 2003, 56, 1099), or it can be prepared by standard methods known in the art. 163305.doc

S • 52- 201245186 In particular, a compound of formula VII can be obtained by a procedure according to the following scheme:

8-Bromo-2·morpholinyl-4-oxo-4H-nonene decanoic acid methyl ester of the compound of formula VII or may be obtained in more detail by the procedure according to the following scheme in Example 1 herein. , which provides a method for preparing 8 > odor _2 · linalyl side gas base - 4H-17 gram -6 - formic acid methyl vinegar using the route:

Pd(OAc)j dppf.TEA EiOH

I63305.doc -53- 201245186 where ΒιΆ, / 臭 ' Pd(〇Ac) 2 is acetic acid, (π), DCM is a gas, and LiHMDS is bis(dimethylformamido) guanamine lithium, Et〇 H is ethanol, Dppf is 1,1-bis(diphenylphosphino)ferrocene, tau is triethylamine, thf is tetranitrofuran and TGO is trifluoromethanesulfonic anhydride. The compound of formula VII can also be obtained in a large scale procedure according to the following scheme, which is described in more detail in Example 100.

MeO

〇

The compound of the formula VII can also be obtained by the following formula:

Wherein R is a (1-6C) alkyl group, conveniently a methyl or ethyl group;

Xa 163305.doc •54·201245186 wherein η and R6 have any of the meanings defined above; reacting with a suitable activator (for example a strong base such as bis(trimethylformamidine) lithium amide) Providing a compound of formula IXa:

A ring closure reaction is then carried out to form a compound of formula VII. The reaction of a compound of the formula IX with a compound of the formula Xa is conveniently carried out in the presence of a suitable solvent or diluent (for example tetrahydrofuran, hydrazine-dioxane, ι, 2-dimethoxyethane, benzene, toluene, diphenyl) And at (for example) _丨〇〇. 〇 to ambient temperature range (preferably at a temperature of 8 (Γ to 2 〇t)). For example, in a suitable solvent (such as di-ethane), for example, 〇 In the range of 〇c to i〇〇°c, a ring closure reaction is preferably carried out by treatment with a dehydrating agent (for example, trifluoromethanesulfonic anhydride) at a temperature in the range of 2 〇t to 6 (rc) to convert the compound of formula IXa into a compound of formula XI, in the above process variant (a), conveniently in the presence of a suitable catalyst as defined above,

163305.doc -55· 201245186 wherein R, R, π and R6 have any of the meanings defined above, only if it is desired to protect any of the functional groups present;

Wherein R 3 , R 4 , R 5 have any of the meanings defined above and the LG is suitably a leaving group such as a halo group, such as a gas, bromine, iodine group (preferably bromine or iodine), followed by removal Any protecting group present. The appropriate response for this type is described as "Metal-Catalyzed Cross-

The Coupling Reactions (2nd Edition, edited by Annin Meijere, Francois Diederich, Wiley-VCH, 2004, Vol. 1, p. 699) couples the Buchwald reaction. The conditions applicable to such reactions are set forth in the above process variations. The compound of formula XI can be prepared, for example, by first saponifying a hydrazine compound,

Wherein n, R6 & P have any of the meanings defined above. A (1-6C)alkyl group, conveniently a decyl or ethyl group, and if desired to protect any of the functional groups present; and then conveniently utilized in the presence of a suitable base and coupling agent -56-163305.doc

S 201245186 Amine of formula III subjects the resulting acid to guanamine formation

R III wherein R1 and R2 have any of the meanings defined above, except where appropriate, in a suitable coupling agent (eg TSTU (2-(2,5-di-oxypyrrolidin-1-yl) )-1,1,3,3-tetradecylisourea rust salt) or TBTU (tetrafluoroborate 2-(111-benzo[(1][1,2,3]triazol-1-yl)- 1,1,3,3-tetramethylisourea rust salt)) protects any functional group in the presence of 'subsequent removal of P! and any other protecting group present. The saponification reaction can be by (for example) a suitable solvent (for example, a mixture of ethanol and water, or a water and water miscible solvent) at a temperature of, for example, 0 ° C to 100 ° (in the range of preferably 20 ° C to 40 ° C) In the case of, for example, tetrahydrofuran or two chews, the metal or argon metal arsenide (for example, argon oxide, potassium hydroxide or sodium hydroxide) is used to treat the compound of formula XII. The indole coupling reaction is conveniently carried out. It is suitable to be carried out in the presence of a suitable base. For example, an organic amine test (for example, n-bite, 2,6-dimethylpyrene-bite, methyl beta-bite, 4-didecylamine-based pyridine, tri-B. Amine, decylmorpholine, diazabicyclo [5.4.0] eleven-7-ene, diisopropylethylamine), or, for example, an alkali metal or alkaline earth metal carbonate or hydroxide (eg, sodium carbonate, carbonic acid, carbonic acid, sodium hydroxide) Or hydration _). The reaction is conveniently carried out in a suitable inert solvent or diluent (eg #, decyl decyl decylamine, hydrazine methyl pyrrolidone, tetrahydrofuran, hydrazine, 4 _ 2. 院, 1, 2 - Dimethoxyethane, Benzene, Toluene, Diphenyl, Methanol, Ethanol, Letter 163305.doc • 57· 201245186 Chemical/Valent (eg dioxane, gas or carbonized carbon) And can be carried out at a temperature of, for example, -50 C to loot: (preferably 〇. 匚 to 3 〇〇c) or for guanamine coupling to convert carboxylic acid to an activating substance ( For example, helium is suitably treated by treatment with grass mash, and then it is conveniently reacted with a hydrazine compound in the presence of an organic base such as triethylamine. If Pi is a third butoxycarbonyl group, Easily remove ρι with gaseous hydrogen (dissolved in, for example, dioxane) in a solvent such as DCM at room temperature. The compound of formula XI can be obtained by the following formula: R\

Wherein R1, R2, η and R6 have any of the meanings defined above-only if it is desired to protect any of the functional groups present; by reacting with a compound of formula ν by a Suzuki reaction,

Wherein P! is a protecting group (e.g., an amino formate vinegar ' such as a third butoxy group 163305.doc • 58-201245186 base)' and R8 is a (1-3C) alkyl group or a hydrazine; ! Hydrogenation and removal of the protecting group. Catalysts suitable for use in the Suzuki reaction include, for example, metal catalysts such as (0), such as tetrakis(triphenylphosphine)palladium(0); or from palladium(II) salts (eg, acetate (II), gas Palladium (II), palladium (II) bromide, bis(triphenylphosphine)palladium chloride (π), [1,1·-bis(diphenylphosphino)ferrocene] digas (II) ), roll (dipyridinyl acetonide) dipalladium) conveniently in a phosphine ligand (eg (9,9-dimethyl-9Η-咕 -4-4,5-diyl) bis(diphenylphosphine)) There is a catalyst formed in situ. The reaction is conveniently carried out in a suitable solvent (for example dimethylformamide, tetrahydrofuran, 1,4-dioxin, 1,2-dimethoxymethoxy, stupid, toluene or xylene) It is carried out at a temperature in the range of, for example, 20 ° C to 150 ° C (preferably in the range of 60 ° C to 120 ° C). The reaction is also conveniently carried out in the presence of an aqueous solution (usually carbonic acid, carbonic acid dehydrated or sodium carbonate; preferably sodium carbonate). If P! is a tert-butoxycarbonyl group, the removal of the protecting group can be conveniently carried out by using a vaporized hydrogen (dissolved in, for example, dioxane) in a solvent (e.g., DCM) at room temperature. The hydrogenation reaction is conveniently carried out in a suitable solvent (for example, an alcohol such as decyl alcohol; or #, ΑΓ-dimethyl decylamine, tetrahydro hexane, ι, 4-dioxalate, 1,2-dimethyl In the presence of oxyethane, benzene, toluene or dinonylbenzene; preferably decyl alcohol, and in the range of, for example, 20 ° C to 10 ° C (preferably in the range of 50 ° (: to 8 CTC) And at a temperature of hydrogen (1-100 atm) (preferably about 5 atm) in the presence of a catalyst such as palladium, rhodium or platinum 'preferably 5% alumina. The XI compound can be obtained by the following method: ΧΙΠ compound 163305.doc • 59- 201245186 (wherein R1, R2, η and R6 have any of the meanings defined above only if it is desired to protect any of the functional groups present ) and formula Villa compound

Villa wherein P is a protecting group 'preferably an alkoxycarbonyl group, such as a third butoxycarbonyl group; after reacting under Heek coupling conditions, the & group is removed from the protecting group, and then the resulting isomer dihydrogen is reduced. Pyrrole (or vice versa). For additional details on Heck coupling conditions, see (for example): "River 6^· Catalyzed Cross-Coupling Reactions^ * Edited by Fran9ois Diederich and PJ Stang, Wiley-VCH, 1998, page 99. Catalysts suitable for this reaction include (for example) a metal catalyst (for example palladium (π), such as di- gas bis(triphenylphosphine)palladium („)); or from palladium (ΙΙ) salt (such as palladium(II) acetate, palladium chloride (II) Palladium bromide (11)) is conveniently formed in situ in the presence of a phosphine ligand such as triphenylphosphine. The reaction is conveniently carried out in a suitable solvent (for example; dimethyl decylamine, tetrahydrofuran, 1,4-dioxane, 1> 2-dimethoxyethane, benzene, toluene or xylene) For example) 2〇. It is carried out at a temperature of 150 〇c (preferably 6 〇β (: to 120 ° C). The reaction is also conveniently carried out in a base such as cesium carbonate, potassium carbonate or sodium carbonate, conveniently potassium carbonate If it is a third butoxycarbonyl group, it can be conveniently used in a solvent (for example, DCM) at room temperature with hydrogenated hydrogen (dissolved in, for example, dioxane) or trifluoroacetic acid. Remove P 1. • 60- 163305.doc

S 201245186 The reduction reaction of the obtained isomer dihydro d is preferably in a suitable solvent (for example, an alcohol such as decyl alcohol, dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1, 2) In the presence of -dimethoxyethane, benzene, toluene or diphenylbenzene; conveniently in methanol and in the range of, for example, 20 ° C to 10 ° C (preferably at 20 ° C to At a temperature of 60 ° C, at a hydrogen pressure (1-100 atm) (preferably about 5 atm) in a catalyst (eg, granules, bonds, turns, such as oxidized turn (IV), preferably 5%) It is carried out in the presence of palladium on carbon. An example of a process scheme that can be used to synthesize a compound of formula XIII (e.g., 8-bromodimethyl-2-(morpholin-4-yl)-4-yloxy-4open-nonene-6-nonylamine) as follows:

Among them, NaOH is sodium hydroxide, Me2NH is dimethylamine, DCM is dichlorodecane, LiHMDS is bis(trimethylcarbenyl) guanamine lithium, EtOH is ethanol, DIPEA is diisopropylethylamine. THF is tetrahydrofuran, Tf20 is trifluorodecanesulfonic anhydride and TBTU is 2-(1Η-benzo[d;l[l,2,3]triazol-1-yl)-l,l,3, tetrafluoroborate. 3-tetramethylisourea sulfonium salt. Alternatively, a compound of formula XIII can be prepared by reacting a compound of formula III with a compound of formula XIV in a guanamine coupling reaction: 163305.doc -61 - 201245186

The XIV type XIV chemical substance can be obtained by the procedure according to the following scheme.

ΗνΟ

Compounds of formula XIV can be prepared, for example, by saponifying a compound of formula VII

VII wherein η and R6 have any of the meanings defined above, and the R7 system (16C) is conveniently referred to as methyl or ethyl. •62· 163305.doc

S 201245186 The saponification reaction can be carried out, for example, in a suitable solvent (for example, a mixture of ethanol and water) at a temperature of, for example, 〇 ° C to 1 oo ° C (preferably in the range of 20 ° C to 40 ° C). Or a water and water miscible solvent, such as tetrahydrofuran or dioxin, to treat the compound of formula VII with an alkali metal or alkaline earth metal hydroxide such as lithium hydroxide, potassium hydroxide or sodium hydroxide. Implementation. It will be understood that several steps can be combined without isolation or purification of the intermediate. For example, a compound of formula XIII can be obtained directly from a compound of formula VII, as illustrated in Example 1, 03b (large scale procedure), wherein a compound of formula XIV is obtained from a compound of VII. Here, the formate salt of the compound of the formula (ν (obtained from saponification of vil without isolation) is directly reacted with an activator (for example 2-chloro-4,6-dimethoxy-1,3,5-dihole). To form an activating species ("activation g"), the amine of formula HI is then reacted to form a hydrazine compound. It will be appreciated that other pre-mutations of the process steps in the variations of the above methods are also possible. For example, a compound of formula I can be prepared using procedures analogous to those described in variants (a) through (匕), but wherein the final step in the procedure introduces a morpholine-(R6)n group. It will be understood that any of the compounds of formula I obtained by any of the above methods may be converted to another compound of formula I, if desired. When a pharmaceutically acceptable salt (e.g., an acid addition salt) of a ketene derivative of the formula is desired, it can be obtained, for example, by reacting the decenone derivative with a suitable acid. When a pharmaceutically acceptable prodrug of a ketene derivative of formula I is desired, it can be obtained using conventional procedures. For example, an in vivo dissociable vinegar of a decenone derivative can be obtained, for example, by reacting a hydroxy-containing compound 163305.doc-63 - 201245186 with a pharmaceutically acceptable carboxylic acid. For example, an in vivo dissociable guanamine of the decenone derivative of formula i can be obtained, for example, by reacting an amine-containing pharmaceutically acceptable compound of the formula I with a pharmaceutically acceptable carboxylic acid. Those skilled in the art of organic synthesis will also appreciate that certain ring substituents in the compounds of the invention may be introduced by standard aromatic substitution reactions or by conventional functional group modification methods before or immediately after the methods mentioned above. And it is itself included in the method aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, a substituent reduction method, a substituent alkylation method, a substituent deuteration method, a substituent amidation method, and a substituent oxidation method. The reagents and reaction conditions used in such procedures are well known in the art. Specific examples of the aromatic substitution reaction include introduction of a nitro group using concentrated nitric acid under Friedel-Crafts conditions, introduction of ruthenium using, for example, ruthenium-based teeth and Lewis acid (for example, aluminum tri-aluminum). Base; introduction of an alkyl group using an alkyl tooth and a Lewis acid (for example, aluminum tri-aluminum) under Fried Krafts conditions; and introduction of a dentate group. Specific examples of the modification include reduction of a nitro group to an amine group by, for example, catalytic argonization using a recording medium or treatment with iron in the presence of hydrochloric acid and under heating; oxidation of an alkylthio group to an alkane A sulfinyl group or an alkylsulfonyl group. It should also be understood that "in some of the reactions mentioned above, it may be necessary or desirable to protect any sensitive groups in the compound. Conditions that are necessary or necessary to be protected and suitable methods of protection are known to those skilled in the art. Conventional protecting groups are used according to standard procedures (for a description see TW Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Therefore, if the reactants include, for example, an amine group, a carboxyl group or a warp group

163305.doc -64-S 201245186 and other groups' may require a protecting group in some of the reactions mentioned herein. Suitable protecting groups for amine or alkylamine groups are, for example, mercapto groups (e.g., alkanoyl groups such as ethyl hydrazino), alkoxycarbonyl groups (e.g., decyloxycarbonyl, ethoxycarbonyl or butyl) Oxycarbonyl), arylmethoxycarbonyl (e.g., benzyloxycarbonyl), or arylalkyl (e.g., benzhydryl). Removal of the above protecting groups The protecting group conditions necessarily vary with the protecting group selected. Thus, for example, a thiol group (e.g., an alkano group) or an alkoxy group can be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. Or ^ brewing base. Alternatively, the thiol group (eg, a third butoxycarbonyl group) can be removed by, for example, treatment with a suitable acid (eg, hydrochloric acid, sulfuric acid, phosphoric acid, or difluoroacetic acid) and can be, for example, by a catalyst (eg, Hydrogenation is carried out on carbon or by treatment with Lewis acid (for example, boron tris(trifluoroacetate) to remove the aryl methoxy group (10) such as benzoquinone. A suitable alternative protecting group for the filaments, for example, o-xanthene, which can be removed by treatment with an alkylamine (e.g., dimethylaminopropylamine) or with hydrazine. Suitable protecting groups for a hydroxy group are, for example, a fluorenyl group (for example, an alkano group such as an ethyl fluorenyl group; an aryl fluorenyl group such as a benzylidene group) or an arylmethyl group (for example, a protecting group above a benzyl group) In addition to the protecting group conditions necessarily vary with the choice of protecting group. Thus, for example, -r can be transferred by, for example, using a suitable metal oxide such as a metal oxide (for example, oxyhydrogen or hydrogen (IV)). The saccharide group such as a burnt base or an aryl fluorenyl group is removed. Alternatively, the arylmethyl group (e.g., benzyl group) can be removed, for example, by hydrogenation over a catalyst (10) such as palladium on carbon. The protecting group can be removed using the techniques well known in the art of chemistry in the synthesis - convenient stage 163305.doc -65 - 201245186. Certain intermediates (e.g., compounds of Formula II, Ila, IV, VI, VII, IXa, XI, XIII, and XIV) as defined herein are novel and provide such intermediates as a further feature of the invention. For example, a compound of formula VII, wherein η and R6 have any of the meanings defined above, can be used as an intermediate in the preparation of a particular compound of the invention:

VII Bioassay The following assays can be used to measure the effects of the compounds of the invention as inhibitors of ΡΙ3 kinase, a live inhibitor of phosphorylated AKT (ser473) in MDA-MB-468 cells, Swiss athymic In vivo inhibitors of phosphorylated AKT (ser473) in nu/nu mice, and in vivo inhibitors of tumor growth in Swiss athymic nu/nu mice transplanted with human prostate adenocarcinoma cell line (PC3). {M., In vitro enzyme inhibition assay The inhibition of ΡΙ3Κβ, ΡΙ3Κα, ΡΙ3Κγ, and ΡΙ3Κδ was evaluated using human recombinant enzymes in Kinase Glo-based enzyme activity assays. This assay measures the absence of sputum after incubation with enzymes, ΡΙΡ2 and guanidine plus compounds. The reaction at the end of the reaction was detected by the addition of Kinase Glo reagent, in which Ultra GloTM Luciferase (Promega) uses ATP as a substrate to catalyze

163305.doc -66- S 201245186 Single oxidation of luciferin and generation of light. There is a direct relationship between the luminescence measured by the Kinase-Glo plus reagent and the amount of ATP remaining in the competitive kinase reaction, and the luminescence is inversely related to the kinase activity. Twelve different compound concentrations were tested and plots of the original data for inhibition of ΡΙ3Κβ, ΡΙ3Κα, ΡΙ3Κγ, and ΡΙ3Κδ versus inhibitor concentration. Method Details: The compound in 100% DMSO was added to the assay plate by acoustic dispensing. ΡΙ3Κβ was added to Tris buffer (50 mM Tris pH 7.4, 0.05% CHAPS, 2.1 mM DTT, and 10 mM MgCl2) and pre-incubated with the compound for 20 min before addition of the substrate containing ΡΙΡ2 and ATP. After 80 min, the enzyme reaction was stopped by adding a Kinase Glo detection solution. The plate was allowed to stand at room temperature for 30 min and then the gain setting for the largest well was read on a Pherastar instrument (Luminescence ATP 384 program). The final concentrations of DMSO, ATP and PIP2 in the assay were 1%, 8 μΜ and 80 μΜ, respectively. Data analysis: IC5G values were calculated using a logarithmic curve fitted to a non-linear regression kit and fitting the raw data to the inhibitor concentration. The IC5G value is the test compound inhibition of 5 〇 ° /. The concentration of enzyme activity. (b) Detection of phosphorylated AKT (ser473) in MDA-MB-468 cells MDA-MB-468 cells (human breast cancer ATCC HTB 132) were inoculated to Greiner 3 84 by automated cell culture robot (Selec T) The hole is black in the flat bottom plate. Cells can also be maintained manually and inoculated into the plate using multidrop or Wellmate 163305.doc •67- 201245186. The cells were seeded at 1500 cells/well in 40 μM DMEN containing 10% FCS and 1% glutamine. The cell plates were incubated for 18 hours in a 37 ° C incubator. The compound is administered to the cells using an Echo acoustic dispenser which dispenses an amount of the compound or DMSO. Compounds were administered at a concentration of 12 points from the highest dose of 30 μΜ, and 28 compounds were administered on one plate. Each plate has 17 DMSO-only control wells and 16 negative control wells that have been administered a concentration of a reference compound that will knock out the ρΑΚΤ signal. The plates were incubated at 37 °C for 2 hours, and the cells were fixed by adding a 3.7% furfural solution to a fume hood using Wellmate. After fixing for 30 min, the fixative and media were removed and the plates were washed with Proclin PBS/A using a Tecan PW3 84 plate washer in a fume hood. The wells were blocked and infiltrated with 40 μM PBS containing 0.5% Tween 20 and 1% marvel using Wellmate and incubated for 60 min at room temperature. The permeation and blocking buffer was removed using a Tecan PW384 plate washer, followed by the addition of 20 μΐ-grade antibody solution using Wellmate. The primary antibody solution was rabbit anti-phospho-AKT Ser 473 (Cell Signaling Technology, Cat. No. 3787) in a 1:500 dilution of 1% marvel in PBS/T (dried milk powder) and incubated at 4 °C. overnight. The plates were washed three times with phosphate buffered saline + 0.05% (v/v) polysorbate vinegar 20 and Proclin 300 (Supelco) using a Tecan PW384 plate washer. Subsequently, 20 μM of the secondary antibody solution was added to each well using Wellmate and incubated for 1 hour at room temperature. The secondary antibody solution was diluted with Alexa Fluor 488 anti-rabbit (Molecular Probes, Cat. No. A11008) containing 1%

I63305.doc -68 - S 201245186 marvel phosphate buffered saline + 0. 05% (v/v) 1:1000 dilution of polysorbate 2〇. The plates were washed three times as described above, then 20 μM PBS was added to each well and the plates were sealed with a black plate sealer. Read the plate as quickly as possible on the Acumen Reader. Using this system can generate ICso values and determine the amount of plates by control wells. The reference compounds were run once each to detect analytical performance. (c) Detection of phosphorylated AKT in Swiss athymic nu/nu mice (ser473>

Swiss athymic nu/nu mice can be transplanted subcutaneously with the human prostate adenocarcinoma cell line pC3 (ATCC CRL143 5) to determine the antitumor activity of PI3 kinase inhibitors. On day 0, 106 cells in 50% MatrigelTM (BD Biosciences No. 354234) were injected subcutaneously into the left abdomen of the animals. When the tumor reached a volume of about 400-600 mm3, the animals were randomized to the desired group size (usually 5 per treatment group) and treatment started. Tumors were taken at the end and snap frozen in liquid nitrogen at -80. (: Store until analysis. Add 1 ml of lysis buffer plus phosphatase inhibitor Sigma P2850, Sigma P5726 (diluted 1:100) and protease inhibitor Sigma to each tumor in the Fastprep tube. P8340 (released at 1:200). The tumor was homogenized on a Fastprep machine for 1 minute and then allowed to stand on ice for 10 min. The sample was spun in a refrigerated centrifuge at 13,000 rpm for 10 min. The cleaned lysate was placed in a fresh tube and analyzed for protein assay using 5 μΐ. All tumor samples were diluted to the same concentration so that at 140 volts each on a 4-15% NuPAGE Bis-Tris gel (Invitrogen) The lanes were run for 90 min with 163305.doc -69 - 201245186 15 pg. Randomize the samples to minimize the gel effect. After blotting onto the Nitrocellulose membrane, block it for 1 hour, followed by total AKT (CST No. 9272) Or a 1:500 dilution of antibody to phosphorylated AKT-ser 473 (CST No. 9271) overnight. A 1:2,000 dilution of antibody (CST No. 7074) linked to anti-rabbit secondary HRP at room temperature Cultivate together 1 hour before 'will imprint in P The BST was washed three times. The blocking and antibody incubation buffer was stored in 5% dry milk powder in 0.05% polysorbate pbs. The blot was washed three times in PBS/T, followed by the Pierce West Dura ECL kit and ChemiGenius visualized "Quantify the bands and obtain the ratio of acid-filled to total signal for each sample. The controls were averaged and each treated sample was normalized to the mean control value. (d) Detection of human prostate gland Tumor growth in Swiss athymic nu/nu mice transplanted with PC3 cancer cells Swiss athymic nu/nu mice can be transplanted subcutaneously with human prostate adenocarcinoma cell line pC3 (ATCC CRL143 5) to determine pi3 kinase inhibitors Antitumor activity. On day 0, 1〇6 cells in 50% Matrigel (BDM) were injected subcutaneously into the left abdomen of the animal. When the tumor reached a volume of about 2〇〇_3〇〇mm3 The animals are randomized into 10-15 groups and treatment begins. The animals are administered a compound in a suitable vehicle at a defined dose by the oral, intravenous or intraperitoneal route (and optionally a Cyp inhibitor, 1 -amine) Benzo benzophenone 11 sitting) For 2 to 4 weeks, the tumor is usually measured twice a week by a caliper and the volume of the tumor is calculated using the ellipse formula (pi/6x width X width X length). (4) Detection of phosphorylated AKT (ser473) in Jeko cells 163305.doc •70-

S 201245186 Add the compound at the final concentration of xlO in 10 μΐ 1% (Wv) DMSO to the well of a Greiner V bottom 96-well plate. The compound was administered at a concentration of 10 points from the highest dose of 1 μΜ, and 8 compounds were administered on one plate. Each plate has 8 DMSO positive control wells that have been administered vehicle and anti-IgM, and 8 negative control wells that have been administered vehicle and assay buffer. The final vehicle concentration was 0.1% DMSC^ per round including the reference ΡΙ3Κδ-selective compound. Jeko sputum cells (human coat cell lymphoma, ATCC CRL-3006) were seeded into a Greiner 96-well V-bottom plate containing the compound. The cells were seeded at 100,000 cells/well in 70 μΐ RPMI containing 1% glutamine. The cell plates were incubated for 1 hour in a 37 ° C incubator. After pre-incubation of this compound, anti-IgM (F(ab')2 fragment goat anti-human IgM, Stratech 109-006-129) at a final concentration of x5 in 20 μL assay buffer (RPMI with 1% face amidoxime) ) added to the board. The final anti-IgM concentration is 0.06 pg/ml or equivalent EC90 dose. The plates were incubated for 10 min at 37 ° C, then the plates were immediately placed on ice and centrifuged at 12000 rpm for 4 min. On ice, carefully remove the supernatant with a manual pipette and add 40 μL of Lysis Buffer. The plates were incubated on ice for 5 min and stored at -801 until the phosphor (ser473)/ according to the manufacturer's instructions (Mesoscale Diagnostics, K11100D-3)

All Akt whole cell lysate kits were analyzed. While the pharmacological properties of the compounds of formula I vary with the desired structural change, in general, one or more of the above tests (a) and (b) can be used to confirm that the compound of formula I has the following concentration or dosage. Activity: - Test (a): - IC50 for ΡΙ3Κβ 'in (for example) 1 ηΜ-25 μΜ range 163305.doc -71- 201245186; test (a wide-targeted!>131^1 (::5) 〇, in (for example, μ ηΜ -25 μΜ; s) (b): - IC50' for the acid-filled strontium (ser473) in MDA-MB-468 cells, for example, in the range of 1 η Μ -25 μΜ Test; (e): - IC50 for cell phosphorylation of AKT (ser473) in Jeko cells, in the range of, for example, 1 nM-25 μΜ; conveniently 'specific compounds of the invention in the above test (a) and (b) is active in one or more of the following concentrations or doses: - Test (a): - IC50 for ΡΙ3Κβ, in the range of, for example, 1 ηΜ-10 μΜ; Test (a): PI3KS2IC5〇, in the range of, for example, 丨-ΙΟ μΜ; Test (b): - Targeting cell phosphorylation in Mda-MB-468 cells IC (ser473) IC50, in the range of, for example, 1 ηΜ-20 μΜ; Test (e): - IC5〇 for cell phosphorylation of AKT (ser473) in jek〇 cells, for example, 1 ηΜ-20 Within the range of μΜ; conveniently 'specific compounds of the invention are active in one or more of the above tests (a), (b), (c) and (d) at the following concentrations or doses:-test (a ): - for ic50 of ρΙ3Κβ, in the range of (for example) ι ηΜ-10 μΜ; test (a): - IC50 for ΡΙ3Κδ, in the range of (eg) 1 ηΜ-10 μΜ16330S.doc

S-72·201245186; Test S (b): - IC50 for cells filled with acidified sputum (ser473) in MDA-MB-468 cells, in the range of, for example, 1 ηΜ-20 μΜ; ): - 50% inhibition of phosphorylated AKT (ser473) in vivo, in the range of, for example, 1-200 mg/kg/day; beta (d) · · xenograft activity 'at (for example) 1 -200 mg/kg/day. Test (e): - IC50 for cell phosphorylation of AKT (ser473) in Jek〇 cells, in the range of, for example, 1 ηΜ-20 μΜ; for example, έ 'as shown in Example 1. The J compound has the following activity: IC50 for ΡΙ3Κβ having about 11 ηΜ in Test U); ICS0 for ΡΙ3Κδ of about 24 nM in test (a); and about 5 ηΜ in test (b) The activity of IC50 of cells phosphorylated AKT (ser473) in MDA-MB-468 cells.

For example, the decenone compound as disclosed in Example 2. has the following activity: IC5〇 for ΡΙ3Κβ having about 9 ηΜ in test (a); ΡΙ3Κδ having about 12 ηΜ in test (a) ICS0; and in test (b) have about 2 nM of IC50 activity against cell phosphorylated AKT (ser473) in MDA-MB-468 cells.

For example, the decenone compound as disclosed in Example 1 has the following activity: IC5() for ΡΙ3Κβ having about 7 ηΜ in test (a); ΡΙ3Κδ having about 9 ηΜ in test (a) ICso; and ICw activity of AKT I63305.doc-73-201245186 (ser473) against MDA-MB-468 cells in test (b); and in test (e) There is an activity of about 7 nM of IC50 for phosphorylation of AKT (ser473) in cells in Jeko cells. For example, the ketene compound disclosed in Example 1.03 has the following activity: ICso for ΡΙ3Κβ of about 12 nM in test (a); IC5〇 for ΡΙ3Κδ of about 22 nM in test (4); The activity of IC5(R) having about 2 nM of cell phosphorylation Ακτ (ser473) in MDA-MB-468 cells was tested in (b). For example, the decenone compound as disclosed in Example 1.3a has the following activity: IC5〇 for ΡΙ3Κβ having about 0.198 μΜ in test (a); ΡΙ3Κδ having about 0.282 μΜ in test (a) ICso; and in test (b) has an activity of about 27 nM of IC5〇 against the cell deacidified AKT (ser473) in MDA-MB-468 cells. For example, the terpene compound disclosed in Example 1.05 has the following activity: IC5〇 for ΡΙ3Κβ having about 7 nM in test (a); ICso for ΡΙ3Κδ having about 9 nM in test (a); And in test (b) there is about 1 nM of activity against IC5〇 of cytosine AKT (ser473) in MDA-MB-468 cells. For example, the decenone compound as disclosed in Example 1.06 has the following activity: IC5 for ΡΙ3Κβ having about 7 nM in test (a). There was about 7 nM of ICso for ΡΙ3Κδ in test (a); and IC50 activity of about 1 nM against cell phosphorylated AKT (ser473) in MDA-MB-468 cells in test (b). For example, the decenone compound as disclosed in Example 1.07 has the following activity: IC5G for ΡΙ3Κβ of about 6 nM in test (4); ICso for Ρΐ3Κδ of about 5 nM in test 16330S.doc 201245186 (a) And the activity of IC5Q with about 2 nM of the cell-acidified Ακτ (ser473) in MDA-MB-468 cells in test (b). For example, the decenone compound as disclosed in Example 1. 〇8 has the following activity: ICm of about 6 nM for ΡΙ3Κβ in test (a); Ρΐ3Κδ with about 6 nM in test (a) ICm; and the activity of IC50 of about 2 nM against cell phosphorylated AKT (ser473) in MDA-MB-468 cells in test (b). For example, the decenone compound as disclosed in Example M0 has the following activity: IC5C for ΡΙ3Κβ having about 8 nM in test (a); IC5 ΡΠΚ for ΡΠΚδ of about 21 nM in test (a) And having about 4 nM of IC5〇 activity against cell phosphorylation (ser473) in MDA_MB_468 cells in test (b). For example, the decenone compound as disclosed in the Examples has the following activity: about 9 nM in test (a) for ρΐ3Κρ2Ι (:5〇; in test (a) having about 15 nM for ΡΙ3Κδ ICso; and having about 8 nM of IC5〇 activity against cell phosphorylation (ser473) in MDA_MB_468 cells in test (b). For example, the terpene compound disclosed in Example 3.00 has the following activity: in the test (a) has about 丨丨nM for pi3Kp2iC5Q; in test U) has about 18 nM for ? 131^1 (:5〇; and having about 3 nM of IC5〇 activity against cell phosphorylation akt (ser473) in MDA_MB_468 cells in test (b), for example, as disclosed in Example 3.02 The terpene-compound has the following activity 163305.doc -75- 201245186: IC5Q for ΡΙ3Κβ with about 14 nM in test (a); IC50 for ΡΙ3Κδ of about 10 nM in test (a); Test (b) has about 3 nM of activity against IC5〇 of cell phosphorylated AKT (ser473) in MDA-MB-468 cells. For example, the terpene compound disclosed in Example 3.03 has the following activity: Test (a) with about 10 nM of IC5G for ΡΙ3Κβ; IC50 with 73Κδ of about 7 nM in test (a); and MDA-MB-468 cells with about 1 nM in test (b) The activity of the cells of the AKT (ser473) is phosphorylated. For example, the terpene compound disclosed in the examples has the activity in Table A in the test (a).

Table A Example No. ΡΙ3Κβ inhibition, IC5〇(μΜ) ΡΙ3Κ$ inhibition, IC5〇(μΜ) 1.00 0.013 0.015 1.01 0.016 0.016 1.02 0.015 0.014 1.03 0.012 0.022 1.03a 0.198 0.282 1.03b 0.007 0.009 1.04 0.011 0.024 1.05 0.007 0.009 1.06 0.007 0.007 1.07 0.006 0.005 1.08 0.006 0.006 1.09 0.007 0.014 1.10 0.008 0.021 163305.doc -76- 201245186

• Example 3. (The compound disclosed in H has about 6% of the squamous Ακτ (10) 473) in the MDA-MB-468 cells in test (9). ΡΙ3Κβ inhibition ' ICjoO^M). 0.015 0.032 sex. According to still another aspect of the present invention, there is provided a pharmaceutical composition comprising a decenone derivative of the formula I as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier . The composition of the present invention may be in a form suitable for oral use (for example, as a tablet, a diamond, a hard or soft capsule, an aqueous or oily suspension, an emulsion, a dispersible powder or granule, a syrup or an elixir), suitable for use. Form for topical use (for example as a cream, ointment, gel, or aqueous or oily solution or suspension), in a form suitable for administration by inhalation (for example as a fine powder or liquid 163305.doc •77·201245186 Aerosol), in a form suitable for administration by insufflation (for example as a fine powder) or in a form suitable for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intraperitoneal or Intramuscular administration or as a suppository for rectal administration) The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients, which are well known in the art. Thus, compositions intended for oral use can have, for example, one or more coloring agents, sweeteners, terminal odorants, and/or preservatives. The amount of active ingredient which may be combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the subject being treated and the particular route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, from 丨mg to 18 active agents (more preferably from 1 mg to 250 mg, such as from 1 mg to 100 mg), in combination with the total composition. A suitable and convenient amount of excipient can be mixed between about 5% and about 98% by weight. For therapeutic or prophylactic purposes, the dosage of the compound will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient, and the route of administration, according to conventional medical principles. When a formula is used for therapeutic or prophylactic purposes, it is usually administered in such a way as to receive a daily dose in the range of, for example, 1 01 §/1^ to 1 〇〇mg/kg body weight, if needed They are administered in separate doses. In general, lower doses should be administered when the parenteral route is used. Thus, for example, in the case of intravenous administration, the dosage of, for example, 丨mg/kg to 25 mg/kg body weight should generally be used. Similarly, for administration by inhalation, a dose in the range of, for example, 1 mg/kg to 25 mg/kg body weight should be used. However, 163305.doc

S • 78 · 201245186 Oral administration in the form of lozenges is preferred. Generally, unit dosage forms will contain from about 10 mg to 0.5 g of a compound of the invention. As noted above, PI 3-kinase enzymes are known to contribute to tumorigenesis by mediating the proliferation of cancer and other cells, mediating angiogenic events, and mediating the movement, migration, and 'invasion of cancer cells. It has been found that the bismuth compound of the present invention has potential anti-tumor activity and is believed to act by inhibiting a class I PI 3-kinase enzyme (e.g., "class!^3_kinase enzyme and/or specific class-3 kinase enzyme) Obtained by one or more of these enzymes involved in a signal transduction step that leads to tumor cell proliferation and survival and metastasis to the invasion and migration ability of tumor cells. Therefore, the present invention has the following value: an antitumor agent, specifically A selective inhibitor of proliferation, survival, movement, spread, and invasion of mammalian cancer cells, which results in inhibition of tumor growth and survival and inhibition of metastatic tumor growth. 9 body and f 'the acne ketone compound of the present invention has anti- Proliferative and anti-invasive agents to protect against and/or treat the value of solid tumor diseases. In particular, it is expected that the compounds of the invention may be used to prevent or treat such multiple PI 3-kinase enzymes (eg, Ia_3_kinase and Ib_3 kinase) Inhibitoryly sensitive tumors of - or more of the enzymes involved in the proliferation and survival of tumor cells and the migration and migration of cells In addition, it is expected that the compounds of the present invention can be used to prevent or treat the oncogene mediated by inhibition of PI3•kinase enzymes (eg, • agonistic enzymes with 3·kinase enzymes) alone or in part. That is, the compound can be used to produce a Η3 enzyme inhibitory effect in a warm gold animal in need of the treatment. 163305.doc 201245186 As described above, the PI 3-kinase inhibitor should have various forms of cancer disease ( Including the therapeutic value of solid tumors (such as carcinomas and sarcomas) and leukemias and lymphoid malignancies. In particular, inhibitors of steroidal kinases should have therapeutic value in the treatment of, for example, breast cancer, colorectal Cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and tibial airway alveolar cancer) and prostate cancer, and cholangiocarcinoma, bone cancer, bladder cancer, brain cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophagus Cancer, Insect Cancer, Pancreatic Cancer, Skin Cancer, Testicular Cancer, Thyroid Cancer, Uterine Cancer, Cervical and Vulvar Cancer, and Leukemia (including ALL, CLL, and cML), Multiple Bone Tumors and lymphomas (including non-Hodgkin's lymphomas, such as diffuse large 8-cell lymphoma [DLBCL], follicular lymphoma, and mantle cell lymphoma). According to yet another aspect of the present invention, provided as defined above A decyl methoxide derivative or a pharmaceutically acceptable salt thereof, which is a pharmaceutically acceptable agent for a warm-blooded animal (e.g., human). According to still another aspect of the present invention, a ketene having a hydrazine as defined above is provided. a derivative or a pharmaceutically acceptable salt thereof for use in producing an antiproliferative effect in a warm-blooded animal such as a human. According to still another feature of the present invention, there is provided a terpene net derivative of the formula a pharmaceutically acceptable salt for use as an anti-invasive agent in a warm-blooded animal such as a human for the prevention and/or treatment of a solid tumor disease. According to still another aspect of the present invention, there is provided a bite as defined above Use of an enone derivative or a pharmaceutically acceptable salt thereof for producing an antiproliferative effect in a warm-blooded animal such as a human.

According to still another feature of this aspect of the invention, Formula I 163305.doc as defined above is provided

S-80-201245186 The ketene derivative _ is used for the use of a salt of ruthenium, which is used for the production of an anti-proliferative effect by using π such as human isothermal, ^ γ. According to the present invention, the J-agent feature provides a ketone derivative as defined above or a pharmaceutically acceptable olefin thereof, such as a human ruthenium, which is produced in a warm-blooded animal such as a human># As an anti-snoring agent for the prevention of tumor diseases.祀久匕飞(7) The treatment of another blood animal towel according to this aspect of the invention produces an anti-proliferative effect, 4 treatment / dish ^ ^ ^ ^ . . method, the method comprises administering the animal: The terpene derivative of formula 1 or a pharmaceutically acceptable salt thereof is defined herein. In a further aspect of the invention, there is provided a method for preventing and/or treating a solid tumor disease in an anti-invasive effect in a blood-containing animal in need thereof, the method comprising administering an effective amount of the animal as above A sessile derivative of the formula or a pharmaceutically acceptable compound or prodrug thereof. According to a further aspect of the invention, an ambiguity as above is provided! A smear derivative or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer in a warm-blooded animal such as a human. According to a further aspect of the present invention, there is provided a bite derivative derivative of C as defined above or a pharmaceutically acceptable salt thereof for use in the manufacture of a heart preventing or treating cancer of a warm-blooded animal such as a human. Pharmacy. According to still another feature of this aspect of the invention, a method of preventing or treating cancer in a warm-blooded animal (e.g., a human) in need of such treatment, comprising administering to the animal an effective amount of a ketene as defined above Derivatives or their medicines 163305.doc • 81 - 201245186 Acceptable salts. According to still another aspect of the present invention, there is provided a use of a decenone derivative of the formula or a pharmaceutically acceptable salt thereof as defined above for the manufacture or prevention of a warm-blooded animal (e.g., a human) An agent for solid tumor disease. According to still another feature of this aspect of the invention, there is provided a method of preventing or treating a solid tumor disease in a warm-blooded animal (e.g., a human) in need of such treatment, comprising administering to the animal an effective amount of a formula as defined above A ketene derivative or a pharmaceutically acceptable salt thereof. According to still another feature of this aspect of the invention, there is provided a decenone derivative, or a pharmaceutically acceptable salt thereof, as defined above, for use in preventing or treating such a PI 3-kinase enzyme (for example Inhibitoryly sensitive tumors of 1 & enzymes and/or class 3 kinases, which are involved in signal transduction steps leading to tumor cell proliferation, survival, invasion and migration. According to still another feature of this aspect of the invention, there is provided the use of a ketene derivative of the formula I as defined above, or a pharmaceutically acceptable salt thereof, for use in the manufacture or in the treatment of PI 3_ An agent for inhibiting sensitive tumors of a kinase enzyme (eg, a class 13 enzyme and/or a lb type PI 3 -exciting enzyme) that is involved in a signal transduction step that results in the ability of tumor cells to proliferate, survive, invade, and migrate. Yet another feature of this aspect of the invention provides methods of preventing or treating such tumors that are inhibitory to PI 3-kinase enzymes (eg, class 13 enzymes and/or class 3 kinases), which are involved in A signal transduction step of tumor cell proliferation, survival, invasion, and migration capability, the method comprising administering to the animal an effective amount of a decenone derivative as defined above or I63305.doc • 82 · 201245186 Accept the salt. According to still another feature of the present invention, there is provided a smear derivative derivative or a pharmaceutically acceptable salt thereof as defined above for use in providing a ρι 3_kinase inhibitory effect (for example, _ΡΙ3·kinase or pI 3_kinase fermentation effect). According to still another feature of this aspect of the invention, there is provided the use of a decenone derivative or a pharmaceutically acceptable salt thereof, as defined above, for use in the manufacture to provide a PI 3 inhibitory effect (eg An agent of la-like PI 3-kinase or lb-like PI3_kinase inhibitory effect). According to a further aspect of the present invention, there is also provided a method for providing a ρι % kinase enzyme inhibitory effect (for example, _PI 3 • kinase enzyme or _ρι 3 • kinase enzyme efficacies, the method comprising administering an effective amount as above A defined ketamine derivative or a pharmaceutically acceptable salt thereof. As described above, certain compounds of the present invention are directed against h-yan kinase, compared to lb-like PI 3-kinase or to VEGF against EGF. The heterozygous (tetra) acid kinase or the non-heteropathic amine 竣 kinase enzyme t== good performance. These compounds have a sufficient needle for the _PI3. kinase enzyme: I: 吏1 is sufficient to inhibit 1 赖3_kinase enzyme , at the same time, the syndrome = ΡΙ 3 · kinase enzyme or against the EGF receptor glutaminase, : tropase kinase or Src non-receptor glutamate kinase compounds may be TM 3 - kinase enzyme selectivity (for example) Ia Jane 3 _ Kinase-driven tumors according to this aspect of the invention, providing a smear 163305.doc-83 · 201245186 of the formula I as defined above, or a pharmaceutically acceptable salt thereof, for providing a selection Sex type η 3-kinase inhibitory effect. According to this issue A further feature of the present invention is the use of a hydrazine derivative or a pharmaceutically acceptable salt thereof as defined above for the manufacture of a medicament for providing a selective _PI3_kinase inhibitory effect. According to the invention, it is also mentioned (iv) that a method for providing a selective 3-nose enzyme inhibitor (IV) comprising administering an effective amount of a decenone derivative of the formula I as defined above or a pharmaceutically acceptable amount thereof "Selective (four) 3-converting enzyme inhibitory effect" means that the xenonone compound of the formula is more effective against la ΡΙ 3 • _ 素 than for other _ enzymes. Specifically - 'the present invention - Some of the compounds are more potent against _ρι 3-kinase than against other kinases (eg, receptors or non-tetra (4) kinases or serine/threonine kinases. For example, the selective la-type PI 3 of the present invention. The kinase inhibitor has a potency against _ρι 3•kinase enzymes that is at least 5 times more potent than other kinases, conveniently at least 1 fold more potent, and more conveniently at least 100 fold more potent. According to still another feature of the invention, the above is provided Terpene derivatives as defined A pharmaceutically acceptable salt thereof for use in the treatment of breast cancer, colorectal cancer, lung cancer (including small cell lung cancer 'non-small cell lung cancer and tibial tracheal alveolar carcinoma) and prostate cancer. Further features of this aspect of the invention Providing a decenone derivative of the formula J as defined above or a pharmaceutically acceptable salt thereof for the treatment of cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer , ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, I63305.doc _ ^ _

S 201245186 Sub-cancer, cervical cancer and vulvar cancer, and white disease (including all and CML), multiple myeloma and lymphoma. According to still another feature of this aspect of the invention, there is provided a ketal derivative or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, kidney Cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, and leukemia (including all, CLL and CML), multiple bone marrow Tumors and lymphomas (including non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma [DLBCL] 'follicular lymphoma and mantle cell lymphoma). According to yet another feature of this aspect of the invention, Use of the ketene derivative of formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and bronchioloalveolar carcinoma) ) and agents for prostate cancer. According to still another feature of this aspect of the invention, there is provided the use of a decenone derivative of the formula or a pharmaceutically acceptable salt thereof, as defined above, for the manufacture of a medicament for the treatment of cholangiocarcinoma , bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, colon tissue, esophageal cancer ovarian cancer, adenocarcinoma skin cancer, testicular cancer, verrucous adenocarcinoma, uterine cancer, cervical cancer and vulvar cancer' Leukemia (including ALL and CML), multiple myeloma and lymphoma. According to still another feature of this aspect of the invention, there is provided a use of a decenone derivative or a pharmaceutically acceptable salt thereof as defined above for the manufacture of a medicament for the treatment of cholangiocarcinoma , bone cancer, bladder cancer, head 163305.doc •85· 201245186 squamous cell carcinoma, kidney cancer, liver cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical Cancer and vulvar cancer, and leukemia (including ALL, CLL, and CML), multiple myeloma, and lymphoma (including non-Hodgkin's lymphoma, such as diffuse large 3-cell lymphoma [DLBCL], follicular lymphoma, and coat Cell lymphoma). According to still another feature of this aspect of the invention, there is provided a method for treating the following diseases, such as human and other warm-blooded animals, in need of such treatment: breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and fine Branched tracheal alveolar carcinoma) and prostate cancer, the method comprising administering an effective amount of a decenone derivative of formula I as defined above, or a pharmaceutically acceptable salt thereof. According to still another feature of this aspect of the invention, there is provided a method for treating the following diseases such as human and other warm-blooded animals in need of such treatments: cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, gastrointestinal Tissue cancer, esophageal cancer 1 nest cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical cancer and vulvar cancer, and leukemia (including sputum and cml), multiple bone tumors and lymphoma, financial The method comprises administering an effective amount of a decenone derivative of formula I as defined above, or a pharmaceutically acceptable salt thereof. According to the aspect of the present invention, the method for treating the following diseases such as human and other warm-blooded animals is required: cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, and gastrointestinal Tissue cancer, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, 睪Α β ^ & ^ 芊 癌 cancer, squamous adenocarcinoma, uterine cancer, cervical cancer and vulvar cancer, and white blood ^ ^ α τ into (b) Blood diseases (including ALL, CLL and CML), multiple myeloma and lymphoma (Bao Dian, Basil non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma [DLBCL1, au J 'bubble lymphoma And jacket fine -86- 163305.doc

S 201245186 Lymphoma), the method involves administering an effective amount as defined above! A terpene derivative or a pharmaceutically acceptable salt thereof. As described above, after administration of a hydrazine compound, the in vivo effect of the compound of formula (1) can be exerted in part by the formation of one or more metabolic products in a human or animal body. As indicated above, certain compounds of the invention have better potency against certain isoforms of the ρι 3-kinase enzyme than others. For example, a particular compound of the invention has a better potency against PI 3-kinase β and ρι 3·kinase 5 than against other kinase isoforms (e.g., alpha and gamma). Accordingly, the present invention also encompasses a method for inhibiting phosphoinositide 3-kinase β in a patient' method comprising administering to a patient an amount of a sputum compound which is effective for inhibiting the amount of acid inositol 3-kinase β in a patient or a pharmaceutical thereof Acceptable salt. Similarly, the present invention also encompasses a method for inhibiting phosphoinositide 3-kinase δ in a patient' method comprising administering to a patient a compound which is effective to inhibit the amount of phosphoinositide 3-kinase S in a patient or The pharmaceutically acceptable salt hydrazone, a compound of formula j or an pharmaceutically acceptable salt thereof, which is an inhibitor of PI 3-kinase, also has potential therapeutic utility in a variety of other disease states. For example, PI 3-kinase promotes vascular trees (ie, vascular smooth muscle cells) (Thyberg, 1998, v (10) Heart 76(1).33-42), and lung (airway smooth muscle cells) (Krymskaya, vp, 2007 · 21(2): 85·95) plays an important role in smooth muscle proliferation. The 4th thinning of vascular smooth muscle cells plays an important role in the formation of atherosclerotic plaques and invasive vascular procedures after bloody endothelium hyperplasia I63305.doc -87- 201245186, Scwartz et al., 1984 , ZVogre·?·? Cari/i.ovascM/ar Dz.jeaje 26:355-372; Clowes et al., 1978, Laboratory Investigations 39:141-150 In addition, excessive proliferation of airway smooth muscle cells leads to asthma and chronic branches COPD occurs in the context of bronchitis. Therefore, inhibitors of PI 3-kinase activity can be used to prevent vascular restenosis, atherosclerosis, and COPD. PI 3-kinase also plays an important role in regulating tumor cells and their tendency to undergo apoptosis (Sellers et al, 1 999, 〇 / 104: 1655-1661). In addition, the uncontrolled regulation of the PI 3-kinase primordial products PI(3,4,5)P3 and PI(3,4)P2 by the lipid hydratase PTEN plays an important role in a large number of malignancies in humans. (Leevers et al., 1999, Cwrre/ϊί Ce" Less 1: 1:219-225). The specific role of the phosphoinositide 3-kinase β (ΡΙ3Κβ) isoform has been described in these types of cancer (Jia S et al, 2008, Waiwre 454 (7205): 776-9; Wee# Λ » 2008, PNAS 105(35):13057-62) 〇0 ilb » A compound of formula I or a pharmaceutically acceptable salt thereof, which is an inhibitor of PI 3-kinase, can be used to treat neoplasms in humans. PI 3-kinase is also in leukocyte function (Fuller et al., 1999, 77ze Journal of Immunology 162(11): 6337-6340; Eder ^ A > 1998, The Journal of Biological Chemistry 273(43):28025-3 1) And lymphocyte function (Vicente-Manzanares et al. '1999, The • 7 owr «a / skin y 163 (7): 4001-4012) plays an important role. For example, leukocyte adhesion to inflammatory endothelial tissue involves the activation of endogenous leukocyte integrins by a PI 3-kinase-dependent signaling process. In addition, the hobby -88- 163305.doc

S 201245186 {The oxidized hair in the granulocytes (Nishi〇ka et al., ι998

Letters 441(1): 63-66 and Condliffe, α.Μ. et al. 2005. 106(4): 1432-40) and cytoskeletal recombination (Kirsch et al., ι 999. Proceedings National Academy of Sciences USA 96(11) : 6211-6216) appears to be involved in pi 3_kinase signaling. Neutrophil migration and directional movement also depend on ΡΙ 3·kinase activity (Camps, M et al, Md, 2005. 11(9): p. 936·43 and Sadhu, c et al, j / m (10)/, 2003, 170(5): 2647-54). Thus, PI 3-kinase inhibitors can be used to reduce leukocyte adhesion and activation at the site of inflammation and are therefore useful in the treatment of acute and/or chronic inflammatory conditions. PI 3_kinase also plays an important role in lymphocyte proliferation and activation, Fruman et al., 1999, Sconce 283 (5400): 393-397. Inhibitors of PI 3-kinase activity are useful in the treatment of such conditions due to the important role of lymphocytes in autoimmune diseases. The anti-cancer treatment as defined above may be applied as the sole therapy or in addition to the compounds of the invention to conventional surgical or radiation therapy or chemotherapy. The chemotherapy may include one or more of the following classes of anti-tumor agents: - (i) other anti-proliferative/anti-tumor drugs and combinations thereof, such as those used in medical oncology, for example, alkylating agents (eg, cis Uranium, oxaliplatin, carb〇platin, cyclopamine, nitrogen mustard, melphalan, chlorambucil, busulfan ( Busulfan), bendamustine, temozolamide, and adenosine; anti-metabolites (eg, gemcitabine and antifolate preparations such as 'fluoropyrimidines, eg 5-fluorouracil and tegafur, tifi 163305.doc •89· 201245186 raltitrexed, methotrexate, cytosine arabinoside and transgland; anti-tumor Antibiotics (eg, anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, ida Idarubicin, mitomycin-C (mitomycin- C), dactinomycin and mithramycin; anti-mitotic agents (eg, periwinkle bioassay, such as vincristine, vinblastine, vindesine) And vinorelbine and yew, such as taxol and taxotere and polo kinase inhibitors; and topoisomerase inhibitors (eg, poor ghosts) (epipodophyllotoxins), such as etoposide and teniposide, amsacrine, topotecan and camptothecin; (ii) cells Growth inhibitors, for example, anti-estrogens (eg, tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene) Droloxifene) and iodoxyfene, anti-androgens (eg, bicalutamide, flutamide, nilutamide, and cyproterone acetate) ), the androgen receptor antagonist MDV3100 or ARN-509 (which Nuclear translocation of androgen receptor and its binding to DNA or coactivator proteins), inhibitors of CYP17A1 (such as abiraterone [ZYTIGATM]), and mixed inhibitors of androgen receptor function and CYP17A1 (eg TOK-001, Garrett-90-163305.doc

S 201245186 Dragon (galeterone)). LHRH antagonists or LHRH agonists (eg, goserelin, leUproreiin, and buserelin), progestogens (eg, megestrol acetate) 〇1 acetate)), ^• aromatase inhibitors (for example, anastroxo 0 sit (anastr〇z〇ie), comet 0 sit (letrozole), volts beta (voraz〇ie) and exemestane ( Exemestane)) and 5α-reductase inhibitors (eg finasteride); (iii) anti-invasive agents [eg, C-Src kinase family inhibitors such as 4-(6-gas-2,3) -methylenedioxyaminoamino)_7_[2-(4-methylpipephin-1-yl)ethoxy]- 5-tetrahydropyran-4-yloxyquinazoline (AZD〇 53〇; International Patent Application WO 01/94341), N-(2-Ga-6-methylphenyl)_2_{6_[4_(2·hydroxyethyl)piped-1-yl]-2-A Pyrimidine-4-ylamino}thiazole·5·carbamamine (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib Osutinib) (SKI 6〇6), and metalloproteinase inhibitors such as marimastat, urokinase plasminogen activator receptor function Inhibitors or antibodies against heparanase]; (iv) Growth factor function inhibitors: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (eg, anti-erbB2 antibody trastuzumab (trastuzumab) [HerceptinTM], anti-EGFR antibody panitumumab, anti-erbB1 antibody, cilostazumab ((10) like ^[Erbhux' C225] and by stern et al, & 〇nc〇i〇gy/haematology, 2005 , Vol. 54, pp. U 29, Rev.-Growth Factor or Growth Factor Receptor Antibody); & Inhibitors also include tyrosine kinase inhibitors such as epidermal growth factor + family inhibitors (10) 163305. Doc •91- 201245186 For example, an EGFR family of tyrosine kinase inhibitors, such as iV-(3-a-4-fluorophenyl)-7-methoxy-6-(3-morpholinylpropoxy)quine Oxazoline-4-amine (gefitinib, ZD1839), iV-(3-ethynylphenyl)-6,7-bis(2-decyloxyethoxy)quinazolin-4- Amine (erlotinib, OSI-774) and 6-acrylamido-#-(3- gas-4-fluorophenyl)-7-(3-morpholinylpropoxy)-quine Oxazolin-4-amine (CI 1033), erbB2 tyrosine Enzyme inhibitors (eg, lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the membrane growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib fnilotinib) (AMN107); inhibitor of serine/threonine kinase (eg Ras/Raf signaling inhibitors such as farnesyl transferase inhibitors such as sorafenib (sorafenib) (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336), cell signaling inhibitors via MEK and/or AKT kinase, c- Kit inhibitor, abl kinase inhibitor, PI3 kinase inhibitor, Plt3 kinase inhibitor, CSF-1R kinase inhibitor, IGF receptor (insulin-like growth factor) kinase inhibitor; aurora kinase inhibitor (eg AZD1152, PH739358, VX) -680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors, such as CDK2 and/or CDK4 inhibitors; (V) anti-angiogenic agents, for example, They can suppress jk An effector of endothelial growth factor [eg, the anti-vascular endothelial growth factor antibody bevacizumab (AvastinTM) and, for example, a VEGF receptor glutaminase inhibitor, such as vandetanib (vandetanib) ( ZD6474), Vata 163305.doc • 92·

S 201245186 Nie (vatalanib) (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4- (4-^-2-fluorenyl 0-doped 0--5-yloxy)-6-decyloxy-7-(3-0-pyridin-1-ylpropoxy)quinazoline (AZD2171; Examples of WO 00/47212, such as those disclosed in International Patent Application Nos. WO 97/22596, WO 97/30035, WO 97/32856, and WO 98/13354, and compounds which act by other mechanisms (eg, linomide, integrin ανβ3 functional inhibitors and angiostatin); (vi) vascular damaging agents, such as Cobeta > (Combretastatin) A4 and disclosed in international patents Compounds of WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan; (viii) antisense therapeutics, for example, those directed to the above listed targets, eg, ISIS 2503, anti-ras antisense; (ix) to Gene therapy agents, including, for example, methods for replacing abnormal genes such as aberrant p53 or abnormal BRCA1 or BRCA2, such as GDEPT using cytosine deaminase, thymidine kinase or bacterial nitroreductase (gene-directed enzyme prodrug therapy) methods and methods for improving patient tolerance to chemotherapy or radiation therapy (eg, multi-drug resistant anti-gene therapy); and (X) agents for immunotherapy, such Immunotherapy includes, for example, in vitro and in vivo methods for increasing the immunogenicity of a patient's tumor cells, for example, 163305.doc •93· 201245186 using cytokines such as interleukin 2, interleukin 4 or granulocyte-maize cell colony stimulating factor Transfection; methods for reducing T-cell anergy; methods of using transfected immune cells (eg, cytokine-transfected dendritic cells); methods of using cytokine transfected tumor cell lines; Methods for anti-individual genotype antibodies; methods for anti-T cell enhancement, including CTLA4 antibodies and for CD137, PD-1 or B7-H1, toll-receptor agonism Antibodies; agonistic antibodies against CD40 (eg, SGN-40 (Dacetuzumab) or Tweak receptor (eg, PDL-192); agonistic antibodies against FAS; methods using antibodies to tumor associated antigens; And antibodies that lack target cell types (eg, unconjugated anti-CD20 antibodies (eg, Rituximab, ofatumumab, Obinutuzumab), anti-CD 19 Antibodies (eg, MEDI-551), anti-CD52 antibodies (eg, Alemtuzumab), anti-CD37 antibodies (eg, TRU-016), anti-CD22 antibodies (eg, Inotuzumab, radiolabeled) Anti-CD20 antibodies Bexxar and Zevalin, and anti-CD54 antibody Campas; immunotoxins, such as moxetumumab pasudotox; use A method of anti-individual genotype antibody; a method of enhancing the function of killing cells; and a method of using an antibody-toxin conjugate (for example, an anti-CD33 antibody Mylotarg). An immunomodulator such as Revlimid (Lenalidomide). According to this aspect of the invention, there is provided a combination suitable for the treatment of cancer comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and an antitumor agent as set forth above under (i)-(x) Any of them. 163305.doc • 94· 201245186 Thus, in a further aspect of the invention, there is provided a compound of formula i or a pharmaceutically acceptable salt thereof, and an antitumor selected from the group consisting of those listed under (i)-(x) above Combination of agents. In a further aspect of the invention, 'providing a combination suitable for the treatment of cancer, which is a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and the antibiotics listed above (0 (()) In a further aspect of the invention, there is provided a combination suitable for the treatment of cancer comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, and a sage (eg purple Cedar or yew, conveniently yew.) In the present context, when the term "combination" is used, it is to be understood that it refers to simultaneous, separate or sequential administration. In one aspect of the invention "Combination" means simultaneous administration. In another aspect of the invention, "combination" means separate administration. In another aspect of the invention, '"combination" means sequential administration. In a sequential or separate administration, the administration of the second component should not be delayed to avoid loss of the beneficial effects of the combination. According to yet another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutical thereof An acceptable salt and a group selected from the group consisting of the antitumor agents listed under (1)-(4) above And a pharmaceutically acceptable diluent or a • • 一 一 一 一 一 一 一 一 一 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物a combination, and a pharmaceutically acceptable dilute "carrier for the treatment of cancer beta. According to another feature of the invention, a compound of formula (I) or a pharmaceutically acceptable compound thereof is provided. 163305.doc • 95· 201245186 The use of a combination of anti-tumor agents as set forth in (1)-(χ) above is used to manufacture a cancer agent for a warm-blooded animal, such as a human. Thus, 'providing treatment in additional features of the invention A method of treating cancer of a warm-blooded animal (e.g., a human) in the treatment comprising administering to the animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, selected from the group consisting of those enumerated above (... (4) A combination of anti-tumor agents. According to still another aspect of the present invention, there is provided a kit comprising a compound of the formula "or a pharmaceutically acceptable salt thereof and an antitumor agent selected from the group consisting of (1) (8) above. According to another aspect of the present invention, a a group comprising: a) a compound of formula I or a pharmaceutically acceptable salt thereof, in a first unit dosage form; b) an antitumor agent selected from the group consisting of the above, in a second unit dosage form; a trough member 'which is used to contain the first and second dosage forms. Although the compounds of formula I are primarily of value as therapeutic agents for use in warm-blooded animals, including humans, there is a need to inhibit class 1] 13-kinase enzymes, specifically la-type PI 3-kinase enzymes and/or ratios. It can also be used in the case of the effect of a 3-kinase enzyme, more specifically an IA-like PI 3-kinase enzyme, which includes PI 3_kinase p. Therefore, it is used as a pharmacological standard for the development of new biological tests and the search for new pharmacological agents. [Embodiment] The present invention will now be explained in the following examples, in which usually: (〇 unless otherwise stated, at ambient temperature (i.e., at 17 ° C to 25 ° (: 163305.doc)

Performing operations under an inert gas (eg nitrogen) atmosphere under S 201245186; (ii) performing a process by rotary evaporation or evaporation using a Genevac apparatus in a vacuum and removing residual solids by filtration (iii) Pre-filled Merck Normal Phase Si60 Ceria cartridges (particle size measurement: 15-40 or 40-63 μηι) obtained from Merck, Darmstad, Germany in automated Armen Glider Flash : Spot II Ultimate (Armen Instruments' Purification by flash chromatography on Saint-Ave, France). (iv) using a mixture of water (containing 〇.2% ammonium carbonate) and a decreasing mixture of acetonitrile as an eluent in a ZMD or ZQ ESCi mass spectrometer and Waters X-Terra or Waters X-Bridge or Waters SunFire (C-18) Preparative chromatography was performed on a Waters instrument (600/2700 or 2525) with a 5 micron oxidized '19 mm diameter, 100 mm length, flow rate of 4 〇 mL/min); (v) Yield (if present) may not be (vi) In general, the structure of the end product is confirmed by nuclear magnetic resonance (NMR) spectroscopy; the NMR chemical shift value is measured by the δ scale [using Bruker Avance 500 (500) The MHz instrument measures the proton magnetic resonance spectrum]; unless otherwise stated 'otherwise measured at ambient temperature; the following abbreviations have been used: 3, singlet; £1, doublet; 1' triplet; 9, quadruple ; 111, multiple peaks; dd, double peaks of double bees; ddd, double peaks of double peaks; dt, double peaks of triple peaks; bs, wide signal; (vii) - generally speaking, the final product of formula I It can be characterized by mass spectrometry after liquid chromatography (LCMS); using a Waters ZQ ESCi or ZMD ESCi mass spectrometer and XB Waters Alliance HT (2790 and 2795) with a ridge 5 μπι C-18 column (2.1x50 mm) at a flow rate of 2.4 mL/min, using 4 163305.doc •97-201245186 min 95. /〇A+5% C to 95% B + 5% C solvent system for LCMS, where A = water, B = methanol, 01:1 methanol: water (containing 〇 · 2 〇 / 0 ammonium carbonate); The intermediate is usually not fully characterized and the purity is assessed by thin layer chromatography, mass spectrometry, HPLC and/or NMR analysis; (ix) X-ray powder diffraction spectroscopy using a Bruker D4 instrument by mounting a sample of the crystalline material to Bruker Single-arc crystal (SSC) wafer holders were mounted and developed by thin-film slide specimens into thin layers. The sample was spun at 3 rpm (in improved count statistics) and X-rays with a wavelength of 1.541 8 angstroms produced by a copper elongated focus tube operating at 40 kV and 40 mA. The collimated X-ray source is passed through an automatically variable divergence slit set at V20 and reflects the radiation directly through the 5.89 mm anti-scatter slit and the 9.55 mm gauge slit. The sample was exposed in the Θ-Θ mode from 2 degrees to 40 degrees 2 〇. 〇 3 sec / 0·00570 ° 2 Θ increment (continuous scanning mode) ^ running time is 3 minutes and 36 seconds. The instrument is equipped with a position sensitive detector (Lynxeye). Use

Diffrac + software running Dell Optiplex 686 NT 4.0 Workstation for control and data capture. Those skilled in the art of X-ray powder diffraction should also understand that the relative intensity of the peaks can be affected by, for example, grains having a size above 30 microns and a non-uniform aspect ratio, and the relative intensity of the peaks can affect sample analysis. Those skilled in the art should also appreciate that the position of the reflection can be affected by the precise height of the sample in the diffractometer and the zero correction of the diffractometer. The surface flatness of the sample may also have a small effect. Therefore, the diffraction pattern data presented should not be considered as an absolute value. (X) Differential scanning calorimetry was performed using a TA Instruments Q1000 DSC instrument. The standard 163305.doc •98·201245186 disc containing less than 5 mg of material and equipped with a lid is typically heated to a temperature range of 25°C to 300°c at a constant heating rate of 10 °C /min. Using a purge gas (using nitrogen) at a flow rate of 50 mL/min; and (xi) using a Bruker APEX-II CCD diffractometer at 200 K to monochromate Mo/:c with graphite (radiation (λ=0.71073 A) The single crystal X-ray diffraction is collected and analyzed. The structure is analyzed by direct method and refined for all reflections. Geometry: Calculate the key distance, angle, etc. using rounded fraction coordinates. According to (full) variance - The variance of the covariance matrix is used to evaluate all su values. The unit cell standard deviation (esd) is taken into account in the evaluation of distance, angle and torsion angle. Intensive: F2 refinement for all reflections. Weighted R factor wR and The goodness S is based on F2, and the conventional Rfactors R is based on F, where F is set to zero for negative F2. The threshold expression F2>2a(F2) is only used to calculate Rfactors(gt), etc. and is used for fine The choice of retouching is irrelevant. The R factor based on F2 is statistically about twice as large as that based on F, and the R-factor based on ALL data is even larger. Computer program: Data collection: Bruker V X? Cell refinement: Bruker with /iVr; data reduction: Bruker for structure Analytical program: (Sheldrick, 2008); Program for refining structures: (Sheldrick, 2008); Molecular Graphics: (Johnson, 1976), (Spek, 2007); used. Software for preparing materials for publication: PLJTOA^Spek, 2007). Waterborne hour Deuterated chloroform Dichlorodecane (xii) The following abbreviations have been used: -aq. h

CDC1 DCM 163305.doc •99- 201245186 DIPEA Ethyl-W-Isopropylpropan-2-amine DMF Dimethylguanamine DSC Differential Scanning Calorimetry DMA Dimercaptoacetamide DMSO Dimethyl Yafeng Diethyl ether EtAc Ethyl acetate HC1 Hydrogen acid HPLC High performance liquid chromatography MeCN Acetonitrile MeOH Sterol MgS〇4 Magnesium sulphate Min Min MTBE Methyl third butyl ether TBME Mercapto third butyl ether NaHC03 Sodium bicarbonate NaOH Sodium hydroxide nh3 ammonia NMP 1-mercapto-2-pyrrolidone P2〇5 phosphorus pentoxide (V) rt room temperature THF tetrahydrofuran TEA triethylamine TFA trifluoroacetic acid • 100· 163305.doc s 201245186 TBTU tetrafluoro 2-(1Η-benzo[d][l,2,3]triazole-yl)-1,1,3,3-tetradecylisourea rust salt TSTU tetrafluoroborate 2-(2,5- Bis-oxyl-pyrrolidin-1-yl)-1,1,3,3-tetramethylisourea rust salt HATU hexafluorophosphate 2-(3Η-[1,2,3]triazolo[4 ,5- 15]°pyridin-3-yl)-1,1,3,3-tetramethylisourea rust salt (V) Example 1.00 8-[l-(3,5-difluorophenyl)pyrrole Pyridyl]_N,N-dimethyl_2_morpholinyl-4· pendant oxy-4Η-nonene-6-formamide

Under the condition of gas to 8_(1·(3,5-difluorophenyl)pyrrolidin-2-yl)2·Mallinyl-4-sideoxy·4Η-bite dilute formic acid (6〇mg) 〇13 _ Add DlpEA(7)〇46 to 悬浮%mm〇〇 in the suspension in DMF (1 mL), then add TSTU(4)5, 〇14 ❶丨), and mix overnight. Dimethylamine (2N, 131 mL in THF, 〇% mmol) was then added and the mixture was stirred for an additional hour. The reaction mixture was purified by preparative HpLc. The fractions were evaporated to dryness. EtOAc m. Pyrrrolidine_2·yl)-N,N_-indenyl_2·norpolyl-4-lateral oxy-4H- octa--6- decylamine (43 163305.doc • 101 * 201245186 mg, 68% » Quality error: m/z [M+H]+=484. Proton NMR spectrum: (DMSO-d6) 1.75-1.88 (m, iH), i 97_2 〇9 (m, 2H), 2.45-2.57 (m, partially hidden by DMSO-d5, 1H), 2.7 〇 (s, 3H) ), 2.92 (s, 3H), 3.33-3.41 (m, 1H), 3.50-3.57 (m, 2H), 3.37-3.64 (m, 2H), 3.71-3.80 (m, 5H), 5.25 (d, 1H) ), 5.61 (s, 1H), 6.13 (d, 2H), 6.32 (t, 1H), 7.11 (d, 1H), 7.80 (d, 1H) 8-(1-(3,) used as starting material 5-Di-Itphenyl)>Bile-bite_2_yl)-2-morpholinyl-4-o-oxy-4H-nonene-6-carboxylic acid is prepared as follows:

Step 1 To a solution of 8-bromo-2-morpholinyl-4-oxo-4H-nonene-6-carboxylate (23 g, 62.47 mmol) in DME (300 mL) and water (30 mL) Add 1-(t-butoxycarbonyl)·1Η-pyrrol-2-ylboronic acid (14.50 g, 68.72 mmol), Na2C〇3 (19.87 g '187.41 mmol) and bis(triphenylphosphine) to the stirred suspension. ) Gasification (11) (0.877 g, 1.25 mmol). The mixture was degassed with argon and heated to 80 ° C for 7 h. The reaction was cooled and concentrated, and the residue I63305.doc • 102- 201245186 was taken in 300 mL DCM and 300 water. The organic phase was decanted and washed with brine, then dried over MgSO4, filtered and concentrated to afford crude material which was purified on silica gel eluting with 8 </ Evaporation of the solvent' to give a white powder as a white powder of 2-(6-(methoxy yl) 2-phenylolyl 4 oxo- 4H-nonene -8 base) · 1 &amp; pyrrole _ 1 · decanoic acid Tributyl ester (20 g, 70. Mass spectrum: m/z [M+H]+ = 455. Step 2 in a hydrogen atmosphere at 5 bar and 65 deaths will be stored in sMe〇H (2 of 175 (6 -(methoxycarbonyl)·2-morpholinyl_4_sideoxy_4H_decene_8_yl)_ih-吼-l-carboxylic acid tert-butyl ester (17.1 g ' 37.63 mmol) And 5% alumina on hydrazine (50%, wet) (3.4 g, 〇.8 〇 mmol) was stirred for 7 h. Filtered on a diatomaceous earth pad and the catalyst was removed from the reaction and washed with Me〇H. The diatomaceous earth and the catalyst were slurried in 500 mL of 10% MeOH in DCM and again. The organic solution was combined and evaporated to give a pale-brown solid (6-(methoxycarbonyl)-2- Morpholinyl·4-tertiaryoxy-4H-octadec-8-yl)pyrrolidine-1-decanoic acid tert-butyl ester (14.4 g, 83%). Mass Spectrum: m/z [M+H]+ =459 〇Step 3 to 2-(6.(Methoxycarbonyl)-2-morpholinyl-4-oxooxy-4Η-indole-8-yl)pyrrolidine-1-carboxylic acid at room temperature Tributyl ester (44〇mg, 〇% solution Add a gasified argon (4 Torr in dioxane) (2.4 mL, 9.6 mmol) to a stirred solution of dioxane (3 mL) and DCM (3 mL). The residue was azeotroped twice with MeCN and dried at 163 305* doc </ s> </ s> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2-morpholinyl _4_. oxo-8-(. than slightly bit-2-yl)-4Η-«» gram -6-carboxylic acid vinegar (286 mg, 83%) « Mass Spectrometry: m/z [M+H]+=359. Step 4 to 2-infrared base 4-side oxy-8-(° than slightly bit-2-yl)-4H-p gram -6-carboxylic acid decyl ester ( 27〇1^,0.75 111111〇1), 1-bromo-3,5-difluorobenzene (〇.〇95 111卜0.83 mmol) and carbonic acid (368 mg, 1.13 mmol) dissolved in ι,4-二Add the chaser complex (33 mg, 〇.〇4 mmol 'see below) to the succulent mixture (5 mL). The resulting suspension was degassed with argon and then stirred at 8 〇»c for 23 h. The reaction mixture was cooled to room temperature, filtered and concentrated. EtOAc (EtOAc) The OH was eluted to purify the crude product. The solvent is evaporated to dryness to give a clear yellow foamy 8-(1-(3,5-di-Phenylphenyl)~heptan-2-yl)-2-oxazyl-4-yloxy -4H·decene-6-carboxylic acid methyl ester (206 mg, 58%). Mass spectrum: m/z [M+H]+ = 471. The palladium complex used as a reactant was prepared as follows: - (9,9-dimethyl-9H-.sup.4,5.diyl)bis(diphenylphosphine) (256 mg, 0.44) Methyl), hydrazine (dibenzylideneacetone) dipalladium (184 mg, 0.20 mmol) and 1-bromo-3,5-difluorobenzene (0.213 mL, 1.85 mmol) in benzene (10 mL) Stir at room temperature for 96 h. The mixture was then filtered through a pad of Celite and concentrated in vacuo. A gorge (1 〇 mL) was added to the residue and a yellow crystalline solid formed after standing for 4 h. The solid was collected by filtration, washed with ether and dried in vacuo to give the desired palladium complex (139 mg, 163305.doc •104 - 201245186 3 9%) ° Step 5

Add 2-N NaOH aqueous solution (0.622 mL, i 24 mm 〇1) to bis-morpholino-4-oxo- 4H-nonene _6-carboxylic acid decyl ester (195 mg, 〇41 mmol) The reaction mixture was stirred at 4 (TC) for 6 h. The mixture was cooled to &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&&& Add water to the slurry and extract with DCM. Wash the organic phase with water~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Drying to give 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholinyl-4-oxo-4H-nonene as a light gray-brown solid. 6-carboxylic acid (67 mg '35%). Mass spectrum: m/z [M+H]+= 457. In the above 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl) Preparation of -2-morpholinyl-4-oxo-4H-nonene-6·•carboxylic acid 8-bromo-2-morpholinyl-4-side used as starting material in step 1 of the process Methyl oxy-4H-nonene-6-carboxylate is prepared as follows:-

〇〇 ^5:γΟ clyN〇

163305.doc • 105- 201245186 Step 1 Drop by dropwise to a suspension of methyl 4-hydroxybenzoate (18〇g, 1183 mm〇i) in DCM (3 L) at nitrogen and 〇 °C Bromine (64 mL, 1242 mmol) was added and the mixture was stirred at room temperature for 36 h. Sodium thiosulfate solution (500 mL of 10% solution) was then added while maintaining the temperature at about 15 °C, after which MeOH (250 mL) was added. The organic layer was washed with EtOAc (EtOAc m.) Mass spectrum: m/z [M-H]-= 229. Step 2 To a stirred suspension of methyl 3-bromo-4-hydroxybenzoate (270 g, 1168 mmol) in DCM (1.5 L) was added EtOAc (15 mL). Ethyl chloride (87 mL, .1227 mmol) was then added dropwise at room temperature under nitrogen. The mixture was stirred at room temperature for 2 h. Water (1 L) was added followed by 2 N HC1 until pH 1. The organic layer was then washed with water, brine, dried EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Proton NMR spectrum: (DMSO-d6) 2.34 (s, 3H), 3.87 (s, 3H), 7.47 (d, 1H), 8.01 (dd, 1H), 8.20 (d, 1H). Step 3 To the methyl 4-acetoxy-3-bromobenzoate (150 g, 549.3 mmol) was added dimethyl sulphate (220 g ' 1647.9 mmol) and the mixture was heated at 140 ° C in the absence of solvent. 3 h. After cooling to room temperature, the solid was pulverized and carefully added to water (1.5 L) with stirring. Then HC1 was added (250 mL, 163305.doc)

S • 106· 201245186 12N) and stirring was maintained for 30 min » The obtained solid was collected by filtration, washed with water (2×2 L) and dried overnight to give a yellow powder of 3-ethylamino-5_ &gt; Citrate (120 g, 84%). Mass spectrum: m/z [M-H]- = 258. Step 4 A gasified sulfoxide (68) was added dropwise to a stirred suspension of 3-ethylindolyl-5-bromo-4-hydroxybenzoic acid (24 g, 926 mmol) in Me0H (2 L) under nitrogen. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The crude compound was obtained, which was purified by chromatography eluting with EtOAc EtOAc EtOAc EtOAc EtOAc Ethyl hydroxybenzoate (108 g, 42 7%) Mass Spectrum: m/z [M_H]-= 229. Step 5 Under MeOH, morpholine (201 mL, 2295 mmol) in water (2 L) Carbon disulfide (0.138 L, 2295 67 mm 〇1) was added to the stirred solution, followed by dropwise addition of sodium hydroxide (96 g, 241 〇mmol, in a solution of 1 l of water). The resulting mixture was stirred at room temperature.丨h, then cooled to 5 ° C with an ice bath and diamyl sulfate (217 mL, 2295 mm 〇i) was added dropwise. The mixture was stirred at room temperature for 1 h and collected by filtration. The mixture was washed with water (2×1 L) and dried with pentoxide pentoxide under vacuum at 5 ° C under vacuo to yield methyl morpholine-4-dithio decanoate (36 〇g, 88%). Proton nmr spectrum: (CDC13): 2.68 (s, 3H), 3.71-3.84 (m, 4H), 4.02 (bs, 2H), 4.30 (bs, 2H) 〇' I63305.doc •107- 201245186 Step 6 ventilate over 2 h The gas (455 g, 6417 mmol) was bubbled through a solution of morpholine-4-dithiodecanoate (170 g, 959 mmol) in DCM (1.5 L) while maintaining the temperature at about 1 〇〇. c to 丨. After completion of the gas addition, stirring was continued for 1.5 h, at which time precipitation occurred. Nitrogen was then passed through the mixture for 30 min. The solid was collected by filtration under nitrogen, washed with dcm and stored in a refrigerator under nitrogen. Thus, a white hygroscopic solid gasified 4 (diqimethylene)? ♦ -4- wrong salt (180 g, 92%) was obtained. Step 7 Under nitrogen to 3-ethylinden-5-bromo- Addition of (diethyloxy ion) monofluoroborate (0.201 L, 1630 mmol) dropwise to a stirred solution of dimethyl 4-hydroxybenzoate (06 g, 388 mmol) in toluene (1 L). The resulting solution was stirred at room temperature overnight and then added Gasification 4_(diqi-indenyl)morpholine_4_rust salt (143 g, 698 mmol) and the mixture was at 9 Torr. The mixture was heated 12 〇 under cooling to add to ether (丨5 L) and the solid was collected by filtration. This solid was then suspended in MeOH (1 L) and the mixture was heated at 50 °C for 2 h. After cooling to temperature, the solid was collected by filtration, then dissolved in dcm (1 L) and washed with water and a saturated solution of sodium bicarbonate. The organic layer was dried over MgSO 4 , filtered and evaporated to dryness. 8-bromo-2-morpholinyl·4_sideoxy_4H_decene_6 methyl formate (68 〇g, 47.6%) as a white solid. Mass spectrometry: m/z [M+H]+= 368 » The alternative pathway for the preparation of 8-bromomorpholinyl-4·t-oxy-4H-nonene-6-decanoate was as follows: 163305.doc

S -108- 201245186 Step 14

Step 1 Add bromine (0.185 L, 3614.92 mmol) dropwise to a stirred suspension of 4-pyridylbenzoic acid vinegar (500 g, 3286 mmol) in DCM (4 L). The mixture was stirred at room temperature under N 2 for 24 h. A solution of sodium metabisulfite (62.5 g, 329 mmol) in 2 L of water was then added while maintaining the temperature at about 15 . 〇, then add 500 mL of MeOH. The organic layer was washed with water and brine, dried over EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Proton NMR spectrum (CDC13): 3.89 (s, 3H), 5.95 (s, 1H), 7.05 (d, 1H), 7.92 (dd, 1H), 8.19 (d, 1H). Step 2 Add triethylamine (〇528 L) to a degassed solution of methyl 3-bromo-4-hydroxybenzoate (35 〇g, 1514 87 mm〇1) in ethanol (3 L) under nitrogen. , 3 787.17 mmol), 1-(vinyloxy)butane (〇588 L, 4544 6〇mmol), 1,1'-bis(diphenylphosphino)ferrocene (33)g, 6〇 6 mm 〇丨) and ethoxylated palladium (8·5 〇g, 37, 9 mm 〇i). The mixture was heated at 7 ° C overnight. The reaction was cooled, filtered and the filtrate was concentrated. The resulting solid was dissolved in DCM (2 L) and 4 N EtOAc ( 丨 14 L, 4454 mm 〇 1) was added with stirring. Stirring was continued for 2 h, the organic phase was separated, dried over EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc The solid was filtered and concentrated to dryness to give crystals: mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Step 3 Add pyridine (〇4〇〇L, to a stirred solution of methyl 3-acetamido-4-hydroxybenzoate (24〇g, 1236 mmol) in DCM (2 L) at 〇°C. 4944 mmol) 'After adding bromine (〇〇7〇l, 1360 mm〇l). The reaction mixture was stirred at room temperature for 2 h then cooled to EtOAc (EtOAc) (EtOAc) It was stirred in ether/petroleum (1:1 '1 L) for 1 hr. The solid was collected by filtration and dried to give ethyl 3-ethyl-ethyl-5-bromo-4-hydroxybenzoate (270 g, 80%). Mass spectrum: m/z [m+H]+= 273. Step 4: 3-ethyl fluorenyl group added to thf (1.2 L) was added dropwise to a solution of lithium bis(trimethylmethane alkyl) guanamine (14i l, 1406 mmol) at -65 ° C under nitrogen. Ethyl 5-5-bromo-4-hydroxybenzoate (12 〇g, 439 mm 〇丨). The solution was warmed to 0 ° C and maintained at this temperature for 1 h. The solution was cooled back to -651 and morpholine-4-carbonylindole chloride (0.055 L, 483 mmol) was added. The mixture was stirred at room temperature for 2 h then cooled to _3 〇 ° C and DCM (1.5 L) was added. Water (1 L), then 6 N HCl (500 mL) was added dropwise, followed by 2 N HCl (300 mL) until pH s. The combined extracts were dried over MgS 4 and evaporated. The crude product was ground in MTBE from 163305.doc

S-110·201245186 gave decyl 3-bromo-4-hydroxy-5-(3-morpholinyl-3-p-oxypropenyl)benzoate as a beige solid (153 g, 90%). Mass spectrometry: m/z [m+h]+= 388 » Step 5 to 3-bromo-4-ylidene-5-(3·········· Ethyl benzoate (433 g '1122 min〇l, material from several batches) was dissolved in 1,2·diethylene b (1 l) and the solution was added with trifluorodecanesulfonic anhydride ( 0.755 L, 4487 mmol) (exothermic). The resulting solution was stirred at 50 ° C overnight. Partially evaporate the mixture, the residue was diluted with EtOAc &lt;(&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; The saturated aqueous solution of sodium carbonate was quenched and extracted with DCM. EtOAc EtOAc (EtOAc). The solid was dried to give the title compound as m.p., </RTI> <RTIgt; </RTI> <RTIgt; M+H]+=370. The same route for the preparation of 8-de-2-methylin-4-yloxy-4H-»» gram-6-carboxylic acid methyl vinegar is carried out on a larger scale as follows:

Step 1 163305.doc 201245186 A vessel A was charged with methane (1060 Kg) and 4-hydroxybenzoate (1 〇〇 Kg) under a nitrogen purge (10 L/min). The reaction was cooled to -2 ° C (starting temperature 3.3 ° C, final temperature - 1.7 ° C, time 1 hour 45 min). The bromine (115 Kg) was charged with nitrogen pressure and the temperature was maintained at +2 C (starting temperature - i.7 ° C, final temperature - 〇.l ° C, high temperature i. 2 ° C, time 4 h) Inside. The reaction was stirred for 24 h while warming to 2 (rc (starting temperature - O.rc, final temperature 18.2 ° C). 0 charged sodium metabisulfite (12.5 Kg) in demineralized water (400 Kg) Solution (starting temperature 175 ° C, termination &gt; 11.0 C, temperature 28.2 C 'addition time 3 h 30 min). The resulting suspension was filtered in two approximately equal portions. Filter load 1 and use Mineral water (200 Kg) was washed 'after washing with heptane (272 Kg) to yield 204 Kg of load 1 wet cake. Filter 2 was filtered and washed with demineralized water (213 Kg). Filter cake (162 Kg) was reloaded The vessel A was reconstituted with heptane (274 Kg) and subsequently re-twisted to produce a 132 Kg load 2 wet cake. The load 1 was dried at 50 ° C in a double cone vacuum dryer to produce 67.2 Kg. Dry weight. To vessel B was charged with 3-bromo-4-hydroxybenzoic acid methyl S under a nitrogen purge (10 L/min) to load 2 (132 Kg) and water (1200 Kg). To 15 ° C to 20 ° C (starting temperature 11.3 ° C, final temperature 15.0 ° C, time 20 min) and stir for 75 min. Filter the resulting suspension on a stainless steel filter. The resulting wet cake (194 Kg) was refilled into vessel b under a sweep (10 L/min), followed by water (600 Kg) » The temperature of the reaction was raised to 15. (: to 20. (: (starting temperature) U.7 ° C 'final temperature 15.0 ° C 'time 20 min) and mix for 30 min. Filter the resulting suspension on a non-recorded steel filter. At 5 〇. The resulting wet cake -112· 163305.doc

S 201245186 (2〇0 Kg) was dried in a Slurry Pan Drier to produce 50.2 Kg dry weight. A total of methyl 3-bromo-4-hydroxybenzoate (117.4 kg, 77.3%) was obtained. This procedure was carried out four times with minor differences in reaction conditions and separation procedures to yield a total of 429.2 kig of methyl 3-bromo-4-hydroxybenzoate (yield ranging from 62.3% to 77.3%). Step 2 To a vessel A, 3-bromo-4-hydroxyindole methyl ester (200 Kg) and ethanol (1250 Kg) were charged under a nitrogen purge (10 L/min). The vessel was evacuated to a vacuum and released into nitrogen twice. Triethylamine (220 Kg) was charged and then rinsed with ethanol (15 Kg). Vinyl butyl ether (266 Kg) was charged and then rinsed with ethanol (15 Kg). Charged with 1, bis-bis(diphenylphosphino)ferrocene (18.9 Kg), followed by palladium diethyloxypalladium (4.96 Kg), and the reaction was heated to 70 ° C (starting temperature 17.9 °) C, final temperature 70.1 ° C, time 2 h 30 min). The reaction was stirred for 13 h. The reaction was cooled to 5 (TC (starting temperature 68.7 ° C, final temperature 53.5 ° C, time 40 min). The reaction was hot filtered through a glass-lined mild steel filter with a 3-cylinder filter on the inlet. After that, rinse with ethanol (120 Kg), then distill off the ethanol solvent at 50 ° (maximum jacket temperature (maximum substrate temperature = 50.7 ° C, time 7 h 25 min, distillate 1010 Kg). At 20 ° C to 25 ° C, the container A was charged with dilute hydrogen acid (680 Kg, prepared from 90 Kg of 36% HCl and 590 Kg of water) (initial temperature 35 ° C, final temperature 24.9 ° C, time 1 The reaction was stirred for 2 h 30 min »The resulting suspension was filtered on a filter over 2 loads and the filter cake was washed with demineralized water (2500 Kg). Container A was charged with sterol (2150 Kg) and Wet filter cake (326 Kg). Heat the reaction to 60 ° C (starting temperature 163305.doc • 113· 201245186 10.7^, final temperature 59.3 ° C, time 3 h 45 min). Reaction via hot pressure filter The material was filtered from vessel A to vessel B and filtered through a 3-cartridge filter to vessel B, followed by dilution with methanol (1 20 Kg). Demineralized water (815 Kg) was charged in vessel B. The reaction was cooled to 20 ° C and the reaction was stirred for 8 h. The resulting suspension was filtered on a filter and decyl alcohol (105 Kg) and demineralized water (60) The mixture was washed with a mixture of Kg), and the wet product (162 Kg) was dried at 45 ° C to give U6.5 Kg of methyl 3-acetamido-4-hydroxybenzoate (99.6% HPLC purity, yield 69.3%) This procedure was carried out three times with minor differences in reaction conditions and separation procedure' resulting in a total of 25 1.4 kg of methyl 3-ethylindol-4-hydroxybenzoate (yield ranging from 69.3% to 71,7%). Step 3 In a nitrogen purge (10 L/min), vessel A was charged with methyl 3-ethyl-bromo-4-hydroxybenzoate (80 Kg) and di-methane (660 Kg). 98 Kg) 'After the gas purge (13 Kg), the reaction was cooled to _2 ° C (starting temperature 7.6 ° C 'final temperature - 4.0 eC, time 2 h). Loading bromine (73.5 Kg) Maintain the temperature between _5 ° C and 0 ° C (starting temperature -4.0 ° C, final / melon - 2.5 C '咼 - -2.0. 〇, time 5 1135 111 丨 11). Mix for 1 hour. Load sodium arsenite sulphate (1 2.8 Kg) The solution stored in demineralized water (168 Kg) 'maintains temperature at 〇. (: to 5 ° C (starting temperature -7.2 ° C, termination / dish -4.0 C 'warm · 4.0 β) (3 'add time 30 min). 30 minutes of mixing

The layers were separated and the lower organic layer (8 〇 8 Kg) was discarded. » A gas methane (111 Kg) was charged to vessel a and stirred for 30 minutes, the layers were separated and the lower organic layer (126 Kg) was discarded. The upper aqueous phase was discarded and wasted (3〇1 Kg). To container A 114 16330S.doc

The combined organic phase (86*7 Kg) was loaded in S 201245186. After charging 4 M hydrogen acid (336 Kg) and stirring for 30 minutes, the layers were separated and the lower organic layer (856 Kg) was discarded. Dioxane (111 Kg) was charged and stirred for 30 minutes, the layers were separated and the lower organic layer (106 Kg) was discarded. Dioxide methane (ill Kg) was charged to vessel A and stirred for 30 minutes, the layers were separated and the lower organic layer (113 Kg) was discarded. The upper aqueous phase was discarded and wasted (404 Kg). Three combined organic layers (1075 Kg) were charged to vessel A. The demineralized water (168 Kg) was charged and stirred for 30 minutes, and the layers were separated and the lower organic layer (1050 Kg) was discarded. The upper aqueous phase was discarded and wasted (195 Kg). The vessel B was charged with an organic layer which was assembled for distillation and distilled off under atmospheric pressure (high substrate temperature 47.8. (:, distillate 500 Kg). Charged with decyl alcohol (531 Kg), The vessel was assembled for distillation and the solvent was distilled off at atmospheric pressure at a maximum substrate temperature of 65 ° C (high substrate temperature 65.8 ° C 'high vapor temperature 62.9 ° C, distillate 685 Kg). The reaction was cooled to 20 °C to 25 ° C (starting temperature 65.8 ° C, final temperature 23 (:, time 2 h). Fill the demineralized water (504 Kg) and filter the resulting suspension under filter pressure and water: methanol The filter cake was washed with a 2:1 mixture (84 Kg). The wet product (129 Kg) was dried at 45 ° C to give methyl 3-ethyl-decyl-5-bromo-4-hydroxy acetonate (dry weight: 99.7 Kg , HPLC purity 98%, yield 88·60 / 〇). This procedure was carried out three times with minor differences in reaction conditions and separation procedures, resulting in a total of 313 kg of 3-ethenyl-5-bromo-4-hydroxybenzoic acid. Methyl ester (yield ranging from 87.6% to 89.5%). Step 4: To a vessel a, 3-acetamido-5-bromo-4-I63305.doc -1 under nitrogen purge (10 L/min) 15- 201245186 Methyl hydroxybenzoate (75.3 Kg) and tetrahydrofuran (640 Kg) »The mixture was stirred for 15 min to ensure complete dissolution. The solution (714.5 Kg) was placed in a nitrogen purged cylinder and tetrahydrofuran rinsed (10 Kg) The vessel a was charged with a 20% solution (726 Kg) of lithium bis(trimethylformamidine) guanamine in THF under nitrogen purge (1 〇L/min), followed by THF rinse (1). 〇Kg). Cool the contents of the vessel to between -1 (TC and -15 ° C (starting temperature I2.8t, final temperature -15.6 ° C, time 45 min). Add 3-ethyl fluorenyl- a solution of 5-methyl-4-carbylbenzoic acid methyl ester in THF (743 Kg), maintained at a temperature between -10 ° C and -15 ° (between starting temperature -15.6 ° C, finally Temperature - i2.9t, still temperature -11.4. (: 'time 1 hour 10 min), then tetrahydrogenate rinse (1 〇 Kg). Mix the reaction at -i ° °c to -15 ° C 1 Hour 30 min (starting temperature -12.9 (:, final temperature - 12_1 &lt;&gt; 〇. Loaded with linal-4-carbonyl oxime (45.2 Kg), maintained at -5 ° C to -10 ° C (from Starting temperature -U.7t, final temperature -5.6 C '咼温-2.1 C, time 30 min), after Furans hydrogen squeak rinsed (5 Kg). The reaction was allocated 5C mix to 10 ° C 9 h. The reaction was taken at 5.搅拌 Stir for another 2 h. The demineralized water (375 Kg) was charged and the temperature was kept below l〇°C (starting temperature 7YC, final temperature 6.4. 〇, high temperature 6 lt, time 34 min). Digested with methane (7〇〇Kg), maintaining the temperature below l〇°C (starting temperature 6.5°C, final temperature 1〇丨, high temperature 1〇Γ (:, time 40 min). The reaction mixture Transfer from vessel a to vessel with 2 gas (48 Kg) rinse. Adjust pH by adding 4 M hydrogen acid solution (459 and become i-helic acid (32 6 Kg) near the target pH. Start pH 12·07 'End pH 1.8 'Starting temperature 6 α 'Final temperature 60%, high temperature HUTC, addition time 4 h). Separate layers and discard lower water layer (983 •116· 163305.doc

S 201245186

Kg) and then loaded into vessel R103 for re-extraction. Dioxane methane (124 Kg) was charged to vessel c and stirred for 15 min, and the layers were separated, and the lower organic layer (43 5 Kg) was discarded and then charged into vessel D. Discard the upper water layer and waste (618 Kg). Hexane (1105 Kg) was charged over 2 h, maintaining the temperature at 5 〇c to 10 ° C (starting temperature 6.4. (:, final temperature 5.8 t). The mixture was cooled to -8 ° C (starting) Temperature 5.8 (:, final temperature - 7.1. 〇, seeded at -3 ° C. The resulting suspension was filtered on a stainless steel filter in two loads and the wet cake was washed with cyclohexane (240 Kg) Total (load 1 wet cake = 12 〇 Kg and load 2 wet cake = 3 12 Kg) at 50. (: The combined wet cake (432 Kg) was dried in a Slurry Pan Drier for 9 days. (Day 1 And Day 2: Dry under vacuum. Days 3 and 4: Heat and vacuum were turned off and kept under nitrogen. Days 5 to 7: Dry under vacuum. Day 7: Products by grinding Crush and reload into the dryer _) to produce 3_bromo-4_hydroxy_5_[3_(morpholine-4-yl)-3-oxooxypropyl] benzoic acid decyl ester (dry weight = 79 84 Kg, HPLC purity 93.4%, yield 75°/.). This procedure was carried out 5 times. The slight difference was in the reaction conditions and the separation procedure, resulting in a total of 308.2] &lt;^3-bromo-4-hydroxy-5- [3-(morpholin-4-yl)-3-yloxypropyl]benzol Methyl ester (yield range from 66 〇/〇 to 75 〇/〇). Step 5 Load container 3 with bromine_4_hydroxy_5_[3_ (II) under II purge (10 L/min) Porphyrin-4_yl)-3-indolyl propyl hydrazide] decyl decanoate (7 〇 Kg) and gas stupid (77 〇 Kg) ° added trifluorodecane sulfonic anhydride (205 Kg), maintained below After 25C (starting temperature 11.7t, final temperature in generations, high temperature 19.8*&gt;C, time 30 min), the chlorine is flushed (6 Kg). The reaction is heated to 163305.doc •117· 201245186 70°C Starting temperature 19.8 ° C, final temperature 71.0 ° C, time 2 h). The reaction was stirred at 70 ° C for 6 h. The reaction was cooled to 5 ° C (starting temperature 71 〇 ° C, final temperature 5 °C, time 3 h). Charge methanol (250 Kg) and maintain the temperature below 15 °C (starting temperature 5 ° C, final temperature 13.9 ° C, high temperature 14.1 ° C, time 2 h 10 min). The reaction was stirred at 20 ° C to 25 ° C for 20 h. A 20% sodium carbonate solution (403 Kg) was added until pH 7.5, maintaining the temperature below 25 ° C (starting ρ Η &lt; 1, ending pH 7.55, starting from Starting temperature 12.0 ° C, final temperature 19.3 ° C, high temperature 20.6 ° C, adding time 2 hours 5 min). Dioxane (371 Kg). The reaction was stirred for 5 h. After charged with demineralised water (280 Kg) and stirred for 1 hour, the layers were separated. Discard the lower organic layer (1259 Kg). Container A was charged with dioxane (371 Kg). After stirring for 30 min, the layers were separated. The lower organic layer (394 Kg) was discarded and combined with the previous organics. The upper aqueous layer (1031 Kg) was discarded and wasted. The combined organic matter (1689 Kg) was placed in the vessel A, followed by demineralized water (280 Kg). After stirring for 30 min, the layers were separated. The lower organic layer (1538 Kg) was discarded. Discard the upper water layer (390 Kg) and waste it. The organics (1538 Kg) were returned to vessel A, which was assembled for distillation and the solvent was distilled at as low as 100 mbar and at 50 ° C until the DCM content of the reaction mixture was below 3.5%. Cool to 〇 ° C to 5 ° C (starting temperature 54.4 ° C, final temperature 5.0 ° C), stir for 1 hour and then filter on a stainless steel filter. The filter cake was washed with ethyl acetate (2 x 63 Kg) and the wet cake (3 8.2 Kg) was dried in a vacuum oven at 50 ° C to give 8-bromo-2 morpholinyl-4- oxo-4H- Terpene-6-formic acid methyl ester (dry weight = 34.5 Kg 'HPLC purity 98.1%, yield 51.7%) » 163305.doc -118· 201245186 This procedure was carried out several times with minor differences in reaction conditions and separation procedures' A total of 112.6 kg of 8-bromo-2-morpholinyl-4-isooxy-4H-octenol-6-decanoate was produced. Example 1.01 8-(1_(3,5-Difluorophenyl)pyrrolidin-2-yl)-N-(2-hydroxyethyl)-N•methyl 2-morphinyl-4-yloxy-4H -p gram-6-aramin

To 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)·2·morpholinyl-4•oxy-4-indole-6-carboxylic acid (105 mg, 0.21 mm) 〇i), 4_曱 carbaryl (0.070 mL, 0.63 mmol) and 2-(decylamino)ethanol (〇〇22 m]L, 0.28 mmol) were dissolved in ΝΜΡ (1 · 5 mL). The solution was stirred at room temperature for 16 h, then was purified by preparative HPLC eluting to dryness and tris. This material was collected by filtration, washed with diethyl ether and dried in vacuo and 5 (EtOAc) toield. ......methyl 2-morpholinyl-4-sided oxy-4H-nonene-6-carboxamide (77 mg, 7 μ%). Mass Spectrum: m/z [M+H]+=5] .4. f ^NMRIf : (DMS〇.-d6) 1.77-1.92 (m, 1H), 1.97-2.09 (m, 2H)' 2.51-2.60 (m, partially hidden by DMSO-d5, 1H), 2 78 (s, 163305.doc •119- 201245186 1.2H), 2.93 (s, 1.8H), 3.00-3.09 (m, 0.8H), 3.13-3.23 (m, 0.8H), 3.33-3.49 (m, by H20 Partially hidden, 2 4H), 3 5〇_3 66 (m, 5H), 3. 70-3.81 (m, 5H), 4.77 (t, 0.6H), 4.78 (t, 0.4H), 5.25 (d, 1H), 5.62 (s, 1H), 6.06-6.18 (m, 2H), 6.32 ( t, 1H), 7.13 (s, 0.4H), 7.23 (s, 0.6H), 7.80 (s, 0.6H), 7.84 (s, 〇.4H) Example 1.02 8-(1-(3,5-one gas) Phenyl)e than fluorenyl-yl)-6-(4-carbylhexanitro-Otto)-morpholino-4-indole-4-one

The title compound was prepared using a procedure similar to that described in Example 1. 〇 1. 8-(1-(3,5-Difluorophenyl)pyrrolidin-2-yl)-2-morpholinyl-4- oxo-4H-p gram -6-decanoic acid (105 mg, 0.21 mmol) was reacted with hexahydro 0-biti-4-ol (22.48 mg, 0.22 mmol) to give 8-(1-(3,5-difluorophenyl)indolepyridin-2-yl as a white solid. - 6-(4-Hydroxyhexahydropyridin-1-carbonyl)-2-morphinyl-4H-bitter-4-one (75 mg, 66%). Mass spectrum: m/z [M+H]+= 540. Proton NMR spectrum: (DMSO-d6) 1.02 (bs, 0.5H), 1.19-1.50 (m, 2.5H), 1.74 (bs, 1H), 1.79-1.89 (m, 1H), 1.99-2.13 (m, 2H) ), 2.52-2.61 (m, partially hidden by DMSO-d5, 1H), 2.89 (bs, 1H), 163305.doc • 120·s 201245186 2.94 (bs' 0.5H), 3.26 (bs, ΐΗ), 3 31_3 · 43 (m, hidden by H20 '1.5H), 3.50-3.66 (m, 4H), 3 67 (bs, 1H), 3 71_3 86 (m, 5.5H), 4.00 (bs, 0.5H), 4.75 (d&gt; 1H), 5.22-5.30 (m, 1H), 5.63 (s, 1H), 6.14 (d5 2H), 6.34 (t, 1H), 4.07 (d, 1H), 7.80 • (d, 1H) 1.03 8_(l-(3,5-Difluorophenyl)pyrrolidinyl-2-yl)-6-(morpholine-4-carbonyl) 2 morpholinyl-4H-nonen-4-one

To 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholinyl-4-o-oxy-4H·nonene·6_ under nitrogen at room temperature Ni-((B) was added in portions with a solution of citric acid (85 mg, 〇19 mmoi), 2% ketone 1-oxide (41.4 mg, 0.37 mmol) and morphine (0.033 mL '0.37 mmol). Imino)methylene)-N3,N3-dimethylpropane-L3-diamine hydrochloride (71 4 mg, 0.37 mmol) and stirred for 4 h. The reaction mixture was diluted with DCM and washed with water and brine. 'Dry and concentrate with MgSCU. The reaction mixture was purified by preparative hplc. The fractions were evaporated to dryness and the residue was takenjjjjjjjjjj The remaining solid was triturated with diethyl light, filtered, washed with diethyl ether and dried under vacuum at 50 ° C, 163305.doc • 121 · 201245186 to give a light gray-brown solid 8-(1-(3) ,5-difluorophenyl)β piroxime-6-(morphin-4-yl)-2-methoxy-4Η-ρ克埽_4-ketone (58.0 mg, 59.3 %). Mass spectrum: m/z [M+H]+= 526. Proton NMR spectrum: (DMSO-d6) 1.74-1.89 (m, 1H), 1.98-2.09 (m, 2H), 2.50-2.57 (m, partially hidden by DMSO-d5, iH), 3.07 (bs, 3H), 3.24 (bs, 1H), 3.74-3.41 (m, 2H), 3.45 (bs, 2H), 3.49. 3.67 (m, 5H)} 3.70-3.81 (m, 5H), 5.22-5.29 (m, 1H), 5.62 (s, 1H), 6.13 (d, 2H), 6.34 (t, 1H), 7.07 (d, 1H), 7.82 (d, 1H) Example 1.03a 8-[(2S)-l-(3,5 -difluorophenyl)w than butyl-2-yl]-6-(wherein-4-mercapto-based-4H-&gt;* gram-4-one

To 8-[(2S)-(l-(3,5-difluorophenyl)) at room temperature. Compared with D each pyridine-2-yl)]_2-morpholinyl-4-sideoxy-4H- Terpene-6-formic acid (1〇2 mg, 0.21 mm〇i, &gt; 98% enantiomeric purity from 2-(6-(methoxycarbonyl)_2_morpholinyl_4_ pendantoxy -4H-decene-8-yl)pyrrolidine-1·carboxylic acid tert-butyl ester for the first eluting ester enantiomeric separation of the palm of the hand (see below) and dipea (0.041 mL, 0.23 mmol) Add tstu once in the stirred solution

163305.doc -122 * S 201245186 (75.0 mg ’ 23 · 23 mmol) 〇 The resulting condiment was mixed at room temperature for 1 h. Ik is added to the reaction &gt; chelating compound (〇 〇37 red, 〇 42 _〇1) and stirring is continued throughout the weekend. The reaction mixture was purified by preparative hplc. The fractions were evaporated to dryness <RTI ID=0.0> The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum and 5[deg.] C. to give a pale yellow solid of 8-[(2S)-l-(3,5- Difluorophenyl)pyrrolidinyl-2-yl]_6_(morpholine-4-carbonyl)-2-morphinyl-4H-octen-4-one (64 mg, 57%). Mass spectrum: m/z [M+H]+= 526. Optical rotation · [a] D20. : 3·4. (16.7 mg in 2 mL of acetonitrile), enantiomeric purity: 95% proton NMR spectrum (CDC13) 1.96-2.17 (m,3H)' 2.45-2.57 (m,1H), 3.07-3.83 (m , 14H), 3,, 83-3.95 (m, 4H), 5.07 (d, 1H), 5.58 (s, 1H), 5.92 (dd, 2H), 6.11 (ddt, 1H), 7.24 (d, 1H) , 8.15 (s, 1H) Example 1.03b 8-[(2R)-l-(3,5-Difluorophenyl)pyrrolidin-2-yl]-6-(morpholin-4·carbonyl)-2-琳琳基-咬烯-4-辋

To 8-[(2R)-(l-(3,5-difluorophenyl)pyrrolidin-2-yl)]-2- 16330S.doc •123- 201245186 at room temperature

Your 4--4-oxo-4H-decene decanoic acid (144 mg, 0.30 mmol &gt;&gt; 98% enantiomeric purity from 2-(6-(methoxycarbonyl)_2-morpholinyl _4_ side oxy-4H-*» gram -8-yl)" piroxime-1-decanoic acid tert-butyl ester of the second eluting ester enantiomeric separation of the palm of the hand - see Add TSTU (106 mg, 〇 '33 mmol) to the stirred solution of DIpEA (0.057 mL '0.33 mmol) and stir the mixture 丨5. Then add the methion to the reaction mixture (0.052 mL, 0.60) Mm) and continue to mix the entire weekend. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness. The residue was dissolved in DCM, dried and concentrated with EtOAc. The remaining solid was triturated with diethyl ether, filtered, and washed with diethyl ether and evaporated and evaporated. Dry under the crucible to give a pale yellow solid [(2R)-l-(3,5-difluorophenyl)"» η η η _ _ _ _ _ _ -6 -6 -6 -6 -6 2-??-based-p-g-butyl-4-steel (69 mg, 44%). Mass spectrum: m/z [M+H]+= 526. Optical rotation. [a] D2 〇. : _4 5. (14 8 mg in 2 mL of acetonitrile), enantiomeric purity: 970/. Proton NMR spectrum (CDC13) 1.96-2.17 (m, 3H), 2.45-2.57 (m, 1H) 3.07-3.83 (m, 14H), 3.83-3.95 (m, 4H), 5.07 (d, 1H), 5.58 ( s,1H), 5.92 (dd,2H), 6.11 (ddt,1H), 7.24 (d,1H), 8.15 (s 1H) ,. (S' used as starting material 8_(1_(3,5_) Difluorophenyl)pyrrolidinyl 2,morpholinyl-4·sideoxy·4Η•decene·6·decanoic acid (R) and (s)_enantiomers were prepared as follows: - '' Step 1 163305.doc

S 124- 201245186

Separation of palms Step 1

First eluting enantiomer (enantiomer 1) second eluting enantiomer i#-p- isomer 2) for palm preparative HPLC conditions: instrument Prochrom column Prochrom 200 mm 20 Ιιη Chiralpak ΙΑ Eluent TBME/MeOH 80/20 Flow rate 1000 ml/min Wavelength 254 nm Sample concentration 3.75 g/400 ml TBME/MeOH 80/20 Injection volume 400 ml Run time 20 min by palmar HPLC 5 15 g of 2-(6-(decyloxycarbonyl)-2-ylmorpholinyl-4-oxo-4H-nonenyl-8-yl)pyrrolidine-1-carboxylic acid tert-butyl ester was isolated by secondary injection (as above Prepared as described in Example 1.00). The first eluting enantiomer: 6.32 g, strength = 91%, ctD = -72.7. Second eluting enantiomer: 6.94 g, strength = 89% ' aD = +69.4°. The enantiomeric purity of each enantiomer was &gt; 98%. Alternative to palm-form preparative HPLC conditions: Instrument Kronlab column Merck 100 mm 20 μιη Chiralpak IC eluent MeOH/TEA 99.9/0.1 flow rate 1 ml/min wavelength 225 nm, 254 nm sample concentration 20 mg/ml, stored Injection volume in EtOH 50 ml Run time 40 min 163305.doc -125- 201245186 Separate 6 by 5 injections 1 g 2_(6·(曱oxycarbonyl)_2•morpholinyl_4 pendantoxy-4Η- Terpene-8-yl)pyrrolidine-1-decanoic acid tert-butyl ester. The first eluting enantiomer: 1.88 g; the second eluting enantiomer: l98 g. The enantiomeric purity of each enantiomer was &gt; 98 Å/〇. The 2-(6-(decyloxycarbonyl)-2-morphinyl 4-sideoxy-4H-bito-8-yl) obtained after palmitic HPLC was established according to the following procedure: Absolute stereochemistry of the two enantiomers of tert-butyl citrate.

Enantiomer 1 Unknown Absolute Stereoscopic Absolute Stereochemistry 2-Mermanyl-4-Sideoxy-8-(.Bilobitone-2·yl)-4Η-ρ克稀-6-carboxylic acid oxime ester pair Isomer 1 from 2-(6-(methoxycarbonyl)-2-morpholinyl-4-oxo-4H-nonen-8-yl)pyrrolidine-1-carboxylic acid tert-butyl Ester enantiomer 1 is obtained by acidic removal of the protecting group with hydrogenated hydrogen (see similar procedure below 8_[(2 ft)-1-(3,5-di-phenyl)) ratio of 1 each 11 Step 1) of the preparation of din-2-yl]-6-(morphin-4-yl)_2-morpholinyl-decen-4-one (i.e., Example 1.03b). Subsequently will be -126- 163305.doc

S 201245186 obtained 2_morpholinyl-4·sideoxy-8-(pyrrolidin-2-yl)-4H-nonene_6_carboxylic acid methyl acetate enantiomer tartaric acid (〇·5 equivalent) mixed, Thus producing 2-morpholinyl·4·sideoxy_8•(pyrrolidine_2_yl)_4Η_nonene·6•methyl formate (2S,3S)-2,3-dihydroxy succinate It is crystallized from a decyl alcohol/isopropanol using a vapor diffusion method. A small amount of the sample was dissolved in methanol in a vial and placed inside a larger vial containing a small volume of isopropanol anti-solvent. The diffusion of the isopropanol antisolvent into the methoxide solution over time causes crystallization, and the absolute configuration of the resulting crystal was determined by single crystal X-ray diffraction. According to the Cahn-Ingold-Prelog sequence rule, 2- morpholinyl 4-4-oxo-8-(pyrrolidin-2-yl;)_4H_nonene_6-formic acid methyl ester (2S, 3S) 2 was determined. The 3 dihydroxy moiety succinate has a (s)-configuration for the palmitic carbon atom. Therefore, the pair of 2_(6-(methoxycarbonyl)_2-morpholinyl-4-oxo-4H-nonene-8-yl)"pyrrolidin-1-decanoic acid second butyl ester Isomer 2 is assigned the (r)-configuration. The following private sequence illustrates the second eluting ester enantiomer from above (ie (2R)_2_(6-(decyloxycarbonyl)_2_morpholinyl·4-sideoxy-4H•pinene_8 H(2R)_W3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholin-4-carbonyl)-2-? Preparation of morphyl-nonene-4-one (ie, Example 1.03b). The first eluted ester enantiomer (i.e., (2S).-2-(6-(methoxy))-2- morpholinyl _4_ oxo group was extracted from the above step using a similar procedure. -4H-decene-8-yl)pyrrolidine-i-decanoic acid tert-butyl ester) Synthesis of 8_[(2S)_ 1-(3,5-difluorophenyl)pyrrolidin-2-yl] Morpholine_4_carbonyl)_2_morpholinyl-nonene-4-one (ie, Example 1. 〇3a). 163305.doc •127· 201245186

Pd(OAc)2 Step 2 Step 1 To (2R)-2-(6-(methoxycarbonyl)-2-morpholinyl-4-oxo-4H-indole-8-yl)pyrrolidine- A solution of 1-butylic acid tert-butyl ester (1.90 g, 3.52 mmol) dissolved in DCM (15 mL) was added argon (4 Μ, stored in dioxane) (8.81 mL ' 3 5.22 mmol) The reaction mixture was stirred at room temperature for 8 h. After concentration, '10% methanol ammonia (7 N) in DCM was added, and the reaction mixture was adsorbed onto silica gel and then subjected to flash chromatography on silica gel with 0 to 8% methanol ammonia (7 N) in DCM. Elute to purify. The solvent was evaporated to dryness to give 2-morpholinyl-4-oxo-8-[(2R)-pyrrolidin-2-yl]nonene as a pale orange crystalline solid after trituration with diethyl ether. Methyl -6-decanoate (1.11 g, 88%). Mass Spectrum: m/z [M+H]+ = 359. &lt;EMI ID=9.1&gt;&gt; Ethrolidin-2-yl]nonene-6-carboxylic acid oxime ester (0.9 g '2.51 mmol), 1-bromo-3,5-difluorobenzene (0.361 ml, 3.14 mmol), (9,9-dimethyl Base-9H-. ton-4,5-diyl) bis(diphenylphosphine) (145-128-163305.doc

S 201225186 mg, 0·25 mmol) and cesium carbonate (1.227 g, 3.77 mm 〇1) were added to a stirred mixture of 14· dioxane (16 mL), and diethylphosphonium palladium (〇〇28 g, 0.13 mmol). The resulting suspension was degassed with argon and then stirred in EtOAc (H.sub.2: EtOAc). The reaction mixture was cooled to room temperature, concentrated in the presence of silica gel and flash chromatographed on EtOAc. Purification by elution with Me 〇 H. The solvent was evaporated to dryness to give a yellow foamy product of 8-[(2R)-l-(3,5-difluorophenyl)lahydroidyl]-2-morpholine. Methyl 4-ethyloxy-decene·6-methyl formate (0.792 g, 67%). Mass: m/z [M+H]+= 471 〇 Step 3 MeOH (9 mL) and DCM 8_[(2R)-l-(3,5-difluorophenyl)"pyrrolidin-2-yl]-2-morpholinyl-4-oxo-octenoid in a mixture of (6 mL) -6-Methyl decanoate (〇·79 g, 1 68 mm〇i) was added 2 NaOH aqueous solution (2.5 5 ml '5·10 mmol) and the reaction mixture was stirred at room temperature overnight. To a solution of 2 N HCI (2.5 mL, 5.0 mmol) was added dropwise to a mixture of the mixture and the mixture was diluted with water (9 mL) and the mixture was concentrated to half volume. The aqueous phase 'concentrates the organic phase to dryness, produces a foam, which is ground in EtAc by filtration The mixture was washed with EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjjj 2-yl]-2-morpholinyl-4-oxooxy-decene-6-carboxylic acid (0.638 g, 83%). Mass: m/z [M+H]+= 457. Large-scale synthesis example 1 ·〇3a and 1 .〇3b : Step 1 163305.doc •129- 201245186

KOH (0.419 L, • methyl methacrylate (900 g, 2444 mmol) in 4889 mmol) was added. The resulting suspension was mixed at 20 ° C for 4 hours until the completion of the crystallization. The reactants were passed through to remove insoluble particles and transferred to an aqueous (2 L) vessel (container crucible). Morpholine (〇639 L, 7333 mmol) was added and stirring was continued. The vessel 2 was charged with 2 gas_46 dimethoxy-1,3,5-di 11 well (1931 g, iiooo mm〇i) and water (8 L) and the temperature was adjusted to about 7 ° C to Anal methylmorpholine (134 mL, 1222 mmol) was charged at a rate to maintain the contents at 10. The contents were stirred and the contents were stirred for 4 hours. The contents of vessel 2 were transferred to a vessel crucible and stirred at room temperature overnight. Then DCM (5 L) was added and the mixture was transferred to a 3 liter separator. The organic extract was extracted with a further portion of DCM and dried (Na.sub.4) and evaporated to dry. The solid was stirred in ethyl acetate and filtered to give a pale-yellow solid of 8----6-((::::::::) 520 g, 50.3 %). Mass spectrum: m/z [M+H]+= 425. Step 2

〇

DMF (4 L) was degassed by bubbling through a stream of nitrogen for 15 minutes. To 1 • • 130- 163305.doc

S 201245186 Jacketed vessel was filled with one part of DMF (600 mL) followed by 8_bromo-6-(morpholine-4-carbonyl)-2-morpholinyl-4-indene-4-one (440) g,1〇4〇mmol), 2,3-dihydro-1H-&quot;birol-1_carboxylic acid tert-butyl ester (246 g, 1455 mmol), di-based phosphine (27.3 g, 1〇4 mmol) And carbonic acid unloading (43 1 g, 3119 mmol). The remainder of the DMF (3 L) was added followed by diethyldimethoxypalladium (11.67 g, 52 mmol). The resulting suspension was stirred under nitrogen and heated at 100 ° C for 16 hours. The mixture was cooled to room temperature and diluted with dcM (4 L). The mixture was filtered through celite, and the filtrate and washings were poured into water (38 L) and further DCM (2_5 L) was added. The organic layer was separated and the aqueous phase was extracted with other DCM (2.5 L). The organic phase was dried over magnesium sulfate, filtered and concentrated to give a brown gum. The gel was purified by flash column chromatography on silica gel eluting with DCM and EtOAc EtOAc/EtOAc. The forerunner containing ph3p contains a large amount of product. The first effluent is concentrated to obtain an impurity. The pure fraction produced 442 g of pure product. The first effluent (75 〇 g ceria column) was repurified as above, resulting in 24 g of pure product. Combine the two harvests to give 2-(6-(N-Phen-4-carbonyl)-2-morphinyl_4-sideoxy_4H-p keene_8·yl)_2,5 as a yellow solid - Dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (466 g, 88%). Mass Spectrum: m/z [M+H]+=512 » Step 3

163305.doc 131 201245186 To 2-(6-(morpholine-4-carbonyl)-2-morpholinyl·4_sideoxy_4H_nonene_8_yl)-2,5-dihydro-1H- Trifluoroacetic acid (1 6 [) was added to a solution of the pyridin-1-decanoic acid tert-butyl ester (444 g, 867 92 mmol) in DCM (3 L). The mixture was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure. The residue was diluted with DCM (2.5 L) and added to a vigorously stirred mixture of DCM (1L) and concentrated aqueous ammonia (4 L). The aqueous solution was washed with other DCM (2 L). The combined organic solution was dried with MgSO4, filtered and evaporated. Step 4 〇0

〇

〇 will be stored in MeOH (3500 mL), which is 8-(2,5-dihydro-1H-pyrrol-2-yl)-6·(morpholin-4-yl)-2-morpholinyl·4Η- Terpene-4- _ (353 g, 858 111111 (^) and 5% JL-type 87 L palladium on carbon (70 g, 16 mmol) was stirred in a hydrogen atmosphere at 5 bar and 45 ° C for 3 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. &lt;RTI ID=0.0&gt;&gt;&gt; /DCM) Purify the residue. The desired product 6-(morpholin-4-carbonyl)-2-morpholinyl-8-(pyrrolidin-2-yl)-4indole-2-one (187) g, 53%) is separated into a colorless dry film. More materials are obtained by repeating this reaction. • 132· I63305.doc

S 201245186 Step 5

6-(morpholine-4-carbonyl)-2-morpholinyl-8-(pyrrolidin-2-yl)-4Η-nonene-4·one (296) suspended in dioxane (3 L) g, 716 mm 〇 1), bromide quinone difluorobenzene (173 g' 895 mmol) and carbonate planer (7 〇〇g, 2148 mmol) were bubbled with air for 10 minutes. Add diethyl p-methoxy palladium (8 〇 4 g, % mmol) and (9,9-dimethyl-911-. ton.-4,5-diyl) bis(diphenylphosphine) (41.4 § , 72 mmol) and the mixture was bubbled with nitrogen for 2 minutes, followed by 10 Torr. The mixture was heated for 2 hours. After cooling to room temperature, the mixture was partitioned between DCM (500 mL) and water (250 mL). The organic phase was washed with brine and dried over magnesium sulfate. To produce a brown gum. The gel was purified by flash column chromatography on silica gel using gradient elution (〇% methanol/DCM to 5% methanol/DCM). The desired product 8-(1-( 3,5-Difluorophenyl)pyrrolidin-2-yl)·6·(morpholine-4-carbonyl)-2-morpholinyl-4H-nonen-4-one (282 g, 75%) It is a pale yellow dry film. Mass Spectrum: m/z [M+H]+ = 526. More material is obtained by repeating this reaction. Step 6 163305.doc -133- 201245186

Separation of each enantiomer by preparative plastic HPLC as follows: racemic 8-(1-(3,5-&lt;1 phenyl)° 洛洛-2-yl)-6- (Merlin A solution of 2-carboyl-2-merinyl-4H-dibenzo-4-one (325 g) was dissolved in a 50% v/v mixture of methanol in ethanol. An 800 mL sample of the compound (each containing 12 g of the racemate) was sequentially injected onto a Prochrom 200 mm 20 μιη Chiralpak AD column (5 kg CSP) using a Prochrom HPLC instrument. The enantiomer was eluted at room temperature using an eluent containing 25% heptane: 37.5% methanol: 37.5% ethanol at a flow rate of 1.2 L min-1 and a run time of 25 minutes. The eluted first enantiomer had a retention time of 6.5 min and after 10 minutes the second enantiomer began to elute. The first eluting enantiomer (143 g, 272 mmol, 50.7 0/〇) was obtained as a solid in the form of a cream and the second eluting enantiomer (59 g) was recovered as a brown film. Analysis conditions for palm purification:

Chiralpak ID 4.6x250 mm 5 μπι column. Use 1 ml/min 163305.doc •134· s 201245186

EtOH: MeOH (5〇*5〇\ j, 〇&gt;&gt;, -. • 5〇) eluted. The running time is 3 〇 minutes at 25 °C. First, the retention of the enantiomer eluted from the separation of the above step 6_ (IV) 17·73 mhl. This was compared with the real sample of Example 103b prepared according to the above method, and identified as the case 1 bird, ie 8-[(2R)-l-(3,5-difluoro-phenyl) bite_ 2•基]·6 (the enantiomeric isomer of morpholinopyrene-4'. The retention time of the second eluting enantiomer is 13.52 min', which is identified as an example 丨〇3a, Enantiomeric enantiomers of 8_[(28) small (3'5-difluorophenyl) pyrrolidine·2_yl]_6_(morpholine-4)carbonyl)_2•morpholinyl-decen-4-one Estimating the relative enantiomers in the first eluting enantiomer of step 6 above for palm chromatography (ie, example l. 〇3b 8-[(2R)-l-(3,5 - difluorophenyl) pyrrolidin-2-yl]-6-(morpholine-4-ylcarbonyl)-2·morpholinyl-nonene-4 enketone enantiomer) content is about 〇· 7%, yielding an enantiomeric purity of 99 3% and an enantiomeric excess of 98.6%. The crystalline form of the compound of Example 103b (Form A) was also produced according to the following procedure: 8-[(2R)- 1-(3,5-Difluorophenyl)pyrrolidin-2-yl]-6-(morpholin-4-carbonyl)-2-morpholinyl-nonene-4-one (9 g) in ether ( Slurry was made in 180 mL) for 72 hours. The resulting off-white powder was dried and then analyzed by XRPD and shown as crystals (Figure 1) with the following 2 使用 values measured using CuKa radiation: 163305.doc -135- 201245186 Angle 2-θ (2Θ ) Strength ° / 〇 4.8 37.0 6.4 18.9 8.1 53.6 9.6 49.0 15.8 32.3 19.5 1 100.0 20.3 20.3 22.7 27.0 23.4 29.6 25.9 13.9 Another crystalline form of the compound of Example 1 〇3b (Form B) is also produced according to the following method: -[(2R)-l-(3,5-difluorophenyl)pyrrolidinyl-2-yl]_6_(morpholine_4•carbonyl)-2-morpholinyl-nonene-4-one (1.77 g The slurry was made into ether (4 mL) for 12 hours. The obtained off-white powder (72 〇mg) was isolated by filtration and dried. It was analyzed by XRPD (Fig. 2) and shown as different crystalline forms to Form A' uses the CuKa radiation to measure the following 20 values: - Angle 2-θ (2Θ) Strength % 6.9 74.2 __ 9.4 47.0 9.8 27.7 __ 11.1 35.2 12.7 56.4 13.1 30.7 13.7 28.1 __ 17.8 64.6 18.7 100.0 __ 19.7 62.4 163305.doc

S • 136– 201245186 A DSC analysis (Fig. 3) was also performed on Form B, which showed a melting point of 180.2 ° C (start). A further crystalline form (Form C) of the compound of Example i.〇3b was also produced by slurrying Form B in methanol. Approximately 20 mg of Form B material was placed in a vial with a magnetic stir bar and approximately 2 ml of methanol was added. The vial was then tightly sealed with a lid and stirred on a magnetic stir plate. After 3 days, the sample was removed from the plate, the lid was opened and the paddle was dried under ambient conditions and then subdivided by XRPD. 4) 4. Form (form as 晶体 by xRpD as crystal and found to be The following two values were found for different quantities found: : CuKa radiation angle 2-θ(2θ) 5.9 27.6 11.8 15^6 12.2 ------ _13.5 ΐοαο 15.2 ------- ^-- - 64.5 15.4 ------ ^22 17.1 1---~ 22.3 Example 1.04 Karinyl-6-[(l-epoxysulfur-8] 1(3,5-fluorophenyl) ton slightly bite _2 yl] phenyl-4-yl)carbonyl] _4H_decene _4 threshold

163305.doc -137- 201245186

To 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2.morpholinyl-4-oxooxy-4-indolene terephthalic acid (125 mg, at room temperature TBTU (176 mg, 0.55 mmol) was added in one portion to a stirred solution of 0.27 mmol) and DIPEA (0·286 mL '1·64 mmol) and stirred for 2.5 h. Thiomorpholine 1-oxide hydrochloride (85 mg, 0.55 mmol) was added to the reaction mixture and stirring was continued for 3 h. The reaction mixture was diluted with DCM, washed with EtOAc EtOAc. The residue was purified by preparative HPLC. The residue was evaporated to dryness. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50 ° C to give 8-[1-(3,5 - Base) β is more than 嘻. 2-(2-yl)-2 -l-yl-6-(1-oxo-[1,4-propane-4-carbonyl]nonen-4-one (87 mg, 57%). Mass spectrum: m/z [M+H]+ = 558. Proton NMR spectrum: (DMSO-d6) 1.75-1.86 (m, 1H), 1.98-2.08 (m, 2H), 2.14 (bs, 0.5H), 2·51·2.58 (m, partially hidden by DMSO-d5, 1H), 2.64 (bs, 1H), 2.81 (bs, 1.5H), 2.98 (bs, 1H), 3.27 (bs, 1H), 3.40 (bs, 1H), 3.49-3.65 (m, 5H), 3.64- 3.83 (m, 6H), 4.21 (bs, 0.5H), 4.34 (bs, 0.5H), 5.25 (d, 1H), 5.62 (s, 1H), 6.13 (d, 2H), 6.34 (t, 1H) , 7.18 (s, 1H), 7.87 (d, 1H) Example 1.05 6-(Heterocyclic butyrol-1-yl)-8-[(2R)-(l-(3,5-difluorophenyl) ) Blow bite · 2-base)]-2-Nolyl-4H-P 克稀萌163305.doc

•138

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Under nitrogen to 8-[(2R)-l-(3,5-difluorophenyl)n-pyridin-2-yl]_2-morphinyl-4-yloxy-p-gly-6-carboxylic acid (1 50 mg, 0.33 mmol, &gt; 98% enantiomeric purity, see Example 1 for details of preparation, 〇3b), DIPEA (0.229 mL, 1.31 mmol) dissolved in CHC13 (2 mL) TBTU (211 mg '0.66 mmol) was added to the mixture. The resulting solution was stirred at room temperature for 30 min » azetidine hydrochloride (61 5 mg, 0.66 mmol) was added and the mixture was stirred at 50 ° C for 2-3 h. The solution was cooled to room temperature, quenched with 10% aqueous citric acid and extracted with hexanes. The combined organic phase was washed with a saturated aqueous solution of sodium bicarbonate, brine, dried over EtOAc and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in EtAc/DCM (1/1). The solvent was evaporated to dryness, the dry film was triturated in diethyl ether and the slabs were collected by filtration, washed with diethyl diethyl hydrazine and dried to a weight of . . . to give a solid 6-( Azetidine-1-carbonyl)-8_[(2R)-(l-(3,5-difluorophenyl) °heptin-2-yl)]-2-morphinyl-4H-p Kedi-4-indole (126 mg, 0.254 mmol, 77 〇/〇). Mass spectrum: m/z [M+H]+= 495. Proton NMR spectrum: (DMSO - ci6) 1.74-1.88 (m, 1H), 1.97-2.08 (m, 2H), 2.13 - 2.24 (m, 2H), 2.43-2.51 (m, partially hidden by DMSO-d5, 1H ), 3.33 - 3.39 (m, partially hidden by H20, 1H), 3.49-3.66 (m, 4H), 3.70-3.81 (m, 5H), 3.93-4.09 (m, 4H), 5.25 (d, 1H), 5.62 (s, 1H), 6.15 (d, 2H), 6.33 (t, 1H), 7.30 (d, 1H), 8.04 (d, 1H) Example 1.06 163305.doc -139· 201245186 8-[(2R)- (l_(3-Fluorophenyl)nfcrrolidin-2-yl)]-N,N-dimethyl-2-morpholinyl-4-oxo-4H-nonene-6-carboxamide

To 8-[(2R)-1-(3-fluorophenylpyrrolidin-2-yl)-2·morphinyl-4-yloxy-p-en-6-oxime at room temperature under nitrogen Acid (488 mg, 1.11 mmol, &gt; 98% enantiomeric purity), decylamine hydrochloride (127 mg, 1.56 mmol), and DIPEA (0.582 mL, 3.34 mmol) dissolved in DCM (5 mL) TSTU (429 mg, 1.34 mmol) was added in one portion of the mixture. The resulting suspension was stirred at room temperature for 20 min. The reaction mixture was quenched with water and extracted with DCM (1×40 mL). Drying over MgSO4 and EtOAc (EtOAc) elute elute eluting eluting eluting The foam was triturated in diethyl ether (10 mL), and the obtained solid was evaporated and dried under reduced pressure to give 8-[(2HHl-(3-fluorophenyl) as a yellow solid. ]]-N,N-dimethyl-2-morphinyl-4-sided oxy-4H-nonene-6-decylamine (276 mg, 53%). Fault: m/z [M+ H]+=466. Proton NMR spectrum: (DMSO-d6) 1.78-1.92 (m, 1H), 1.96-2.09 (m, 2H), 2.46-2.56 (m, from DMSO-d5 part Hidden, 1H), 2·68 (s, 3Η), 2.90 (s, 3Η), 3.33-3.42 (m, hidden by Η20, iH), -140· 163305.doc s 201245186 3.50-3.66 (m, 4H ), 3.70-3.81 (m, 5H), 5·23 (d lu, , '1H), 5.61 (s, 1H)' 6.21-6.29 (m, 2H), 6.36 (ddd, 1H), 7, 〇9 (1) Northern iH), (d, 1H), 7.80 (d, 1H) 8-[(2R)-(l-(3·fluorophenyl) barbium _2 base)]·2 used as starting material · Methyl sulfonyl 4-ylidene-4-indole-6-carboxylic acid is prepared as follows: Step 1

To 2,morpholinyl sideoxy_8_[(2R)·pyrrolidinyl]nonene_6 formic acid vinegar (121 mg ' 〇_34 mmol), (9,9-dimethyl-9H-咕 ridicule _4,5-diyl) bis(diphenylphosphine) (16.61 mg, 0,03 mmol), _3_ gas benzene (0.047 mL '0.42 mmol) and carbonate planer (165 mg, 0.51 mm 〇1) suspension To a stirred mixture of 1,4-dioxane (3.3 mL) was added diethylphosphonium palladium (3.3 mg, 〇. 〇 1 mmol), and the resulting suspension was degassed with argon and then at AI. Stir for 20 h at C. The reaction mixture was cooled to room temperature, and the crude product was purified eluting from EtOAc EtOAc EtOAc The solvent was evaporated to dryness to give 8-[(2RH1(3-fluorophenyl)pyrrolidin-2-yl)]-2·morpholinyl·4_sideoxy·4H_decene_6•carboxylic acid as a yellow oil. Methyl vinegar (120 mg, 79%) was allowed to stand for curing. Mass Spectrum: _ [M+H]+= 453 〇 Step 4 • Ml - 163305.doc 201245186

Ο —

To a mixture of THF (2.4 mL) and MeOH (2.4 mL), 8_[(2R)-(1 -(3-fluorophenyl).bibr.din-2-yl)]-2- 2·N-NaOH (0.398 mL, 0.80 mmol) was added to the methyl group _4 η </ RTI> decyl-6-carboxylate (120 mg, 0.27 mmol). The resulting solution was stirred at 25 ° C throughout the week. The aqueous HCl solution was added until the pH was about 2. The solvent was removed under vacuum and a yellow solid was collected by filtration &lt;[&quot;&quot;&quot;&quot;&quot;&quot;&quot; ]-2·Molinyl-4-sided oxy- 4H-p-gram-6-decanoic acid (100 mg, 86 〇/〇). Mass spectrum: m/z [M+H]+ = 439. Example 1.07 8-[(2R)-(l-(3-Fluorophenyl)pyrrolidin-2-yl)]-6-(morpholin-4-carbonyl)-2-morphinyl ketone-4-嗣

To 8-[(2R)-(l-(3-fluorophenylpyrrolidin-2-yl)]-2-morpholinyl-4-oxo-4H-nonene at room temperature under nitrogen 6-decanoic acid (250 mg, 0.57 mmob &gt; 98% enantiomeric purity, see Example 1.06 for details of preparation), morpholine (0.075 mL, 0.86 mmol) and DIPEA (0.149 mL, 163305.doc) s • 142- 201245186 0.86 mmol) TSTU (220 mg, 0.68 mmol) was added in one portion to a stirred suspension of DCM (5 mL). The obtained suspension was stirred at room temperature for 10 h. The reaction mixture was purified. The fractions were evaporated to dryness. The obtained foam was dissolved in DCM (0.5 mL) and diethyl ether (1 mL) was added. The obtained crystalline solid was collected by filtration and dried under vacuum. 8-[(2RHl-(3-fluorophenyl)pyrrolidin-2-yl)]-6-(morpholine-4·.carbonyl)-2-morpholinyl-4H-nonene_4 -ketone (126 mg '44〇/〇). [a]D20.: -I5.20 (19.8 mg in 2 mL of acetonitrile). MS: m/z [M+H]+=508. Spectrum: (DMSO-d6) 1.81-1.93 (m, 1H), 1.97-2.10 (m, 2H), 2.50-2.59 (m, partially hidden by DMSO-d5, 1H), 3. 19-3.24 (m, partially hidden by H20, 1H), 3.34-3.42 (m, 4H), 3.44 (bs, 4H), 3.50-3.64 (m, 4H), 3.71-3.81 (m, 5H), 5.23 ( d, 1H), 5- 58 (S, 1H), 6.21-6.28 (m, 2H), 7.36 (ddd, 1H), 7.〇8 (dd, 1H), 7.10 (d, 1H), 7.82 (d , 1H) Example 1.08 6- (a gas-heterocyclic d-h-i-repo)-8-[(2R)-(1-(3-fluorophenyl)nt slightly bite_2_ base)]-2-Merlin基-4Η-Ρ克稀_4·明

Under nitrogen to 8-[(2R)-(l-(3-fluorophenyl)"pyrrolidin-2-yl)]·2·morpholine 163305.doc -143- 201245186

4--4-oxo-4H-nonene-6-carboxylic acid (212 mg, 0.48 mm 〇1 > 98 〇 / 〇 enantiomeric purity, for details of preparation, see Example i 〇 6) &amp; DIpEA (0.674 mL, 3.87 mmol) HATU (3 68 mg, 0.97 mmol) was added to a stirred solution of DCM (1 mL). The resulting solution was stirred at room temperature for 1 h. Azetidine hydrochloride (271 mg, 29.9 mmol) was added and the mixture was stirred at room temperature for 15 h. The fractions were evaporated to dryness by preparative HpLC purification to give a pale yellow foamy 6-(azetidin-1-carbonyl)-8-[(2R)-(l-(3- Fluoryl) tIpyrrolidine-2-yl)]-2-morpholinyl-4H-nonen-4-one (28 mg, 12%). Mass spectrum: m/z [M+H]+= 478. Proton NMR spectrum (CDC13) 1.97-2.14 (m,3H), 2.18-2.33 (m,2H), 2-40-2.52 (m5 1H), 3.37-3.46 (m, 1H), 3.48-3.61 (m, 4H) ), 3.75-3.82 (m, 1H), 3.82-3-92 (m, 4H), 4.02-4.10 (m, 1H), 4.12-4.20 (m, 2H), 4.21-4.30 (m, 1H), 5.08 (d, 1H), 5.57 (s, 1H), 6.14 (ddd, 1H), 6.21 (dd, 1H), 6.37 (ddd, 1H), 7.08 (dd, 1H), 7.64 (d, 1H), 8.26 ( d, 1H) Example 1.09 8-[(2R)-(l-(3,5-Difluorophenyl)pyrrolidin-2-yl)]·6-(4-methylpiperidin-1-carbonyl)- 2-morpholinyl-4Η-nonene-4-one 163305.doc

-144-

S 201245186 8-[(2R)-l-(3,5-difluorophenyl)"&gt; ratio 11 each _2. base]_2_morpholinyl-4-sideoxy- at room temperature Terpene-6-formic acid (for preparation, see example i.〇3b, 97 mg, 0.21 mmol), DIPEA (0.185 mL, 1.06 mmol) and 1-indole base (0.047 mL, 0-43 mmol) mixed with DCM (3 mL). Subsequently, a N-propylphosphonic anhydride cyclic trimer (50 wt% solution in EtAc) (0.633 mL' 1.08 mmol) was added and the reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was purified by preparative HPLC to give 8-[(2R)-(l-(3,5-difluorophenyl)"pyrrolidin-2-yl)]_6·(4) as a white foam. -Methylpyrazine-1-indolyl-2-pyrimyl- 4Η-17 g dilute-4-indole (67 mg, 59%). Mass spectrum·· m/z [M+H]+=539. Proton NMR spectrum: (DMSO-d6): 1.76-1.89 (m, 2 H), 1.98-2.07 (m, 2 Η), 2.11 (s, 3 Η), 2.13-2.22 (m, 2 Η), 2.36 ( Br, 2 Η) 2.93-3.13 (br,2 Η), 3.35-3.42 (m, hidden by Η20, 2 Η) 3.51-3.67 (m,4 Η), 3.70-3.78 (m,6 Η), 5.26 (d,1 Η), 5 62 (s,1 H), 6.14 (d,2 H), 6.33 (m,1 H), 7.02 (d,1 H),7 78 (d,1 H) Example 1.10 8-[(2R)-(l-(3-fluorophenyl)°*rhodin-2-yl)]-6-(4-methylpiperidinylcarbonyl)-2-morpholinyl-4H-indole Alkene-4-_

Using a procedure similar to that described in Example 100, 8-[(2R)"(3 163305.doc •145- 201245186 fluorophenyl)pyrrolidin-2-yl)]-2·morpholinyl-4- The pendant oxy-4H-nonene-6-carboxylic acid (for the preparation 'see example 1.06; 100 mg, 0.23 mmol) was reacted with 1-methylpiperazine (0.076 ml, 0.68 mmol) to give 8-[(2R) )-(l-(3-fluorophenyl)&quot;pyrrolidin-2-yl)]-6-(4-methylpiped-1-carbonyl)-2-morpholinyl-4H-nonene- 4-ketone (39 mg, 33 ° / 〇). Mass spectrum: m/z [M+H]+= 521. Proton NMR spectrum: (CDC13): 1.97-2.13 (m, 4 H), 2.24 (br s, 3 Η), 2.29-2.54 (m, 4 Η), 3.00-3.28 (m, 2 Η), 3.40-3.47 (m, 1 Η), 3.49-3.61 (m, 4 Η), 3.69-3.81 (m, 3 Η), 3.81-3.94 (m, 4 Η), 5.10 (d, 1 Η), 5.57 (s, 1 Η), 6.12 (d, 1 Η), 6.20 (d, 1 Η), 6.33-6.41 (m,1 Η), 7.06-7.11 (m,1 Η), 7.26 (s, hidden by gas imitation, 1 Η ),8·12 (d,1 Η) Example 1.11 8-[(2R)-(l-(3-Methoxyphenyl)carinol-2-yl)]-6-(morpholin-4- Carbonyl)-2-morpholinyl-4H-nonene-4-one

8-[(2R)-(1-(3-methoxyphenyl)°-pyridin-2-yl)-2-morpholinyl-4- side was used using procedures similar to those described in Example 1.04 oxy-4H-nonene-6-carboxylic acid (63 mg, 0.14 mmol) and morpholine (0.12 mL, 0.14 mmol) anti-163305.doc • 146·s 201245186 should be produced to give a white foamy 8-[( 2R)-(i_(3-decyloxyphenyl)pyrrole0 each 2-yl-2-yl)]-6-(molin-4-yl)-2-ylyl _4H-p gram _4 _ Ming (37 mg, 51 〇 / 〇). Mass spectrum: m/z [M+H]+=520. Proton NMR spectrum: (DMSO-A): 1.78-1.91 (m, 1 H), 1.95-2.06 (m, 2 H), 2.50-2.56 (m' is partially hidden by DMSO-d5, 1 printed, 2.96- 3.26 ( Ms 4 Η), 3.35-3.42 (m, 2 H)} 3.50-3.62 (m, 6 H), 3.63 (s, 3 H), 3.71-3.79 (m, 6 H), 5.20 (d, 1 H) , 5.61 (s, 1 H), 5.94-5.98 (m, 1 H), 6.01 (dd5 1 H), 6.21 (dd, 1 H), 6.99 (dd, 1 H), 7.12 (d, 1 H), 7.81 (d, 1 Η) MMA-04957-98-01-109269 8-(1-(3-decyloxyphenyl)n 洛 咬_2_yl)_2-morpholinyl used as starting material -4-Sideoxy-4H-nonene-6-carboxylic acid was prepared using a procedure similar to that described in Example 1-5, in which 1-bromo-3-indolyl benzene was substituted for 1-bromo-3. _fluorobenzene: Step 1

Using a procedure similar to that described in Example 1.0, 2-morpholinyl-4 et al. oxo-8-[(2R)-pyrrolidin-2-yl]nonene-6 methyl formate (example i 〇 Prepared as described in 3b, 125 mg, 0.35 mmol) was reacted with 1 · bromo-3-oxooxy stupid (0.049 163305.doc • 147· 201245186 m b 0.38 mmol) to give a yellow gum-like oxyphenyl) hydrazine. Than a bite-2-yl)]-2-morphinyl-4-indolyl-4H-bitite_6·methyl formate (90 mg, 56%). Mass spectrum: m/z [μ+Η]+=465. Step 2

8-[(2R)-(l-(3-decyloxyphenyl)indolepyrrolidin-2-yl)]-2-morpholinyl-4-yloxy-4H-p gram-6 - 曱 曱 旨 90 (90 mg, 0.19 mmol) and sodium hydroxide (38.7 mg, 0.97 mmol) reacted to give a beige solid [[2R)-(1-(3-methoxyphenyl)&lt;;»Bilo bites-2-yl)]-2-morphinyl-4-sideoxy_ 4Η-bite _6-formic acid (64 mg, 73%). Quality error: m/z [Μ+Η]+=451. Example 1.12 8-(1-(4-Fluorophenyl)pyrrolidin-2-yl)-6-(morpholin-4-carbonyl)-2·morpholinyl_ 4 Η - 〃克稀4 -明163305. Doc

To 6-(morpholine-4·carbonyl)-2-morpholinyl-8-(pyrrolidin-2-yl)-4Η-nonen-4-one (250 mg, 〇.6〇mmol), biphenyl _2_dicyclohexylphosphine (21 mg, • 148·)

S 201245186 0.06 mmol), 1-di-4-pyrene (0.083 ml, 0.76 mmol) and cesium carbonate (296 mg, 0.91 mmol) were dissolved in 1,4-dioxane (5 mL). Diethoxymethyl (6.79 mg, 0.03 mmol). The resulting suspension was degassed with argon and then stirred at 10 ° C for 15 h. The reaction mixture was purified by preparative HPLC. The fractions containing the desired compound are evaporated to dryness to give the title compound, 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-6-(morpholin-4-carbonyl)-2-morpholinyl -4H-nonen-4-one (140 mg, 46%). Mass spectrum: m/z [M+H]+=5 () 8. Proton NMR spectrum (DMSO-A): 1.79-1.92 (m, 1 H), 1.95-2.07 (m, 2 H), 2.52-2.57 (m, partially hidden by DMSO-d5, 1 H), 2.92-3.28 ( m, 4 Η), 3.39-3.67 (m, 1 Η), 3.48-3.67 (m, 6 Η), 3.70-3.80 (m, 6 Η), 5.17 (d, 1 Η), 5.61 (s, 1 Η ), 6.41 (dd, 2 Η), 6.95 (dd, 2 H), 7.13 (d, 1 H), 7.81 (d, 1 H). Purification of the above racemic mixture via palmitic HPLC: Instrument Gilson Prep (200 ml head) Column Merck 50 mm 20 μιη Chiralpak IC Eluent MeCN/MeOH/TEA 90/10/0.1 Flow rate 100 ml/min Wavelength 254 Nm sample concentration 88 mg / 30 ml, stored in MeCN, injection volume 30 ml, run time 40 min, the sample is obtained as a transparent film, and then ground with diethyl ether 163305.doc -149- 201245186 Produces a creamy white solid. The materials were dried overnight at 40 ° C in vacuo. First eluting enantiomer: 30 mg (99% enantiomeric purity) Example 1.12a Second eluting enantiomer: 26 mg (99% enantiomeric purity) Example 1.12b Example 1.12a 8-(1-(4-Fluorophenyl)"pyrrolidin-2-yl)-6-(morpholin-4-carbonyl) -2-morpholinyl·4H-nonen-4-one (enantiomer 1) Analytical conditions: Instrument HP1100 Column 3 μπι Chiralpak IC 4.6x50 mm Eluent MeCN/MeOH/TEA 90/10/0.1 Flow rate 1 ml/min Wavelength 254 nm Sample concentration 1 mg/ml, stored in EtOH Injection volume 10 ul Run time 5 min First eluting enantiomer: Example 1.12a, retention time 2.92 min, 99.7% pure . Example 1.12b 8-(1-(4-Fluorophenyl)"pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholinyl-4H-nonen-4-one (enantiomer 2) Analytical conditions: 163305.doc - 150-

S 201245186 Instrument HP1100 Column 3μιη Chiralpak IC 4.6x50 mm Eluent MeCN/MeOH/TEA 90/10/0.1 Flow rate 1 ml/min Wavelength 254 nm Sample concentration 1 mg/ml, stored in EtOH Injection volume 10 ul Run Time 5 min Second eluting enantiomer: Example 1.12b, retention time 3.56 min, 99.6°/. Pure. 6-(morpholine-4-carbonyl)-2-morpholinyl-8·(pyrrolidin-2·yl)-4Η-nonene-4-one used as a starting material was prepared as follows: - Step 1

To a solution of 8-bromo-2-morpholinyl-4-oxo-4H-nonene-6-decanoate (10 g, in a mixture of methanol (225 mL,) and DCM (75 mL) 2 N NaOH (40..7 mL, 81.48 mmol) was added to 27.2 mmol). The slurry was stirred at room temperature for 16 h. The solvent was evaporated, water (150 mL) was added to the mixture, the solution was cooled to 0 &lt;0&gt;C and 6N HCl solution (15 mL, 89.6 mmol) was added dropwise to the mixture until the pH was about 3.4. The solid formed was collected by hydrazine, washed with water (3×50 mL), then toluene (3×50 mL), then diethyl ether (3×50 mL), dried at 55 ° C under vacuum, and then dried over EtOAc. Doc-151 - 201245186 Obtained 8-bromo-2-morpholinyl-4-4-oxo-4H-nonene-6-carboxylic acid as a beige solid (9.47 g, 98%). The crude product was used without further purification. Mass Spectrum: m/z [M+H]+=354 〇 Step 2

To 8-bromo-2-morpholinyl-4-yloxy-4H-nonene-6-carboxylic acid (2 g, 5.65 mmol), DIPEA (4.9 mL, 28.2 mmol) and morpholine (0.543) Add N-propylphosphonic anhydride cyclic trimer (5 〇 wt% solution, stored in the heart) in a stirred solution of mL, 6.2 mmol) in DCM (14 mL) (8.57 ml ' 14.68 mmol) . The mixture was stirred for 1 h at room temperature then water (1 mL) was added. The reaction mixture was stirred for 15 min and extracted with dCM. The combined organic layers were washed with EtOAc (EtOAc m.). -p ketene-4-one (1·90 g, 79%). Mass Spectrum: m/z [M+H]+=423 ° Step 3

Under nitrogen to 8-bromo-6-(indol-4-carbonyl)-2-l- propyl ketone-4-one (1.79 g, 4.23 mmol), 2,3-dihydro-1H-pyrrole carboxylic acid Third butyl

I63305.doc . J52 - S 201245186 Ester (1.431 g, 8_46 mm〇i), triphenylphosphine (〇222 g, 〇85 mm〇1) and potassium acetate (1.245 g, 12.69 mmol) dissolved in DMF (24.88 ml) The stirred suspension was added with diethyl p-methoxy palladium (〇〇95 g, 〇42. The resulting suspension was degassed under nitrogen and stirred at 1 ° C for 16 h. The mixture was evaporated and adsorbed onto silica gel. And purify by 5% to 8% decyl alcohol in a flash chromatography on a silica gel. The solvent is evaporated to dryness to give 2-(6-(morpholin-4-carbonyl)-2- as an orange oil. L-butyl-4-oxo-4H-decene-8-yl)-2,5-dihydro-1H-pyrrole-1-decanoic acid tert-butyl ester and 2_(6_(morpholine-4)carbonyl )-2-morpholinyloxy-4H-nonene_8-yl)-2,3-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (2.20 g, 1.2%) Mass spectrum: m/z [M+H]+=512. Step 4

2-(6-(morpholine-4-yl)-2-morphinyl winterside oxy- 4Η-ρ克 diluted in ethanol (3〇mi) at 1.2 atm at room temperature 8-yl)-2,3·dihydro·iH-indolepyr-1-carboxylic acid tert-butyl ester compound and 2-(6-(morpholine-4-ylcarbonyl)·2_morpholinyl-4-side Oxy-4Η-ρ克稀-8-yl)-2,5-dihydro-1Η-0 ratio ρ each-1-carboxylic acid: butyl (1:1) of the above mixture (2"g, 2.05 Mrnol) and oxidized New Zealand (IV) (0.093 g, 0.41 _〇1) were hydrogenated for 4 h. The resulting solution was filtered, and the filtrate was concentrated to dryness to give a crude brown crystals (yield: 6-( morpho </ br </ br </ br </ br </ br> 《»比洛咬·ι_曱酸第r 163305.doc -153· 201245186 Butyl vinegar (1.60 g, 76%). Mass spectrometry: m/z [m+h卜=514 step 5

第三 to 2-(6-(morpholine-4-carbonyl)-2-morpholinyl_4-o-oxy-4H-nonen-8-yl)pyrrolidine_1-carboxylic acid tributyl at room temperature The base ester (2 g, 3 89 mm 〇i) was dissolved in DCM (15 mL). EtOAc (EtOAc) After concentration, dcm (15 mL) and MeOH (15 mL) were added, followed by a 10 〇 / hydrazine ammonia (7 N) solution in DCM (1 〇 mL). The crude product was adsorbed onto silica gel and purified by flash chromatography on silica gel eluting with 0 to 10% methanol in DCM. The solvent was evaporated to dryness to give a solid and dried in vacuo to yield 6-(morpholin-4-carbonyl)-2-morpholinyl-8-(pyrrolidin-2-yl)-4? Terpene-4-one (1.0 g, 62%) » Mass Spectrum: m/z [Μ+Η]+=414. Example 2.00 8-(1-(3-Fluorophenyl)pyrrolidin-2-yl)-indole, fluorenyl-dimethyl-2-morpholinyl-4-oxo-4-indene-6-A Guanamine

163305.doc •154· S 201245186 To N,N-monomethyl-2-infrared-4-yloxy- 8-(° ratio ° bit-2-yl)_4H_ 11 克稀-6- Amine (130 mg, 0.35 mmol), 1-bromo-3-fluorobenzene (〇〇49 m, 0.44 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl) Add bis(diphenylphosphine) (20.25 mg '0.03 mmol) and carbonated (171 mg, 〇52 mmol) to a stirred mixture of ι,4-dioxane (4 mL) (3·9 mg, 0.02 mrnoip The resulting suspension was degassed with argon and stirred at 10 ° C for 16 h then cooled to room temperature, filtered and concentrated. The crude product was dissolved in DMA (2 mL) Purification by preparative hplc. Evaporation of the fractions containing the desired compound to dryness to give a solid 8-(j-(3-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2.啉 侧 _ _ 4H-decene-6-formamide (67 mg, 41%). Mass Spectrum: m/z [M+H]+= 466. Proton NMR spectrum: (DMSO..d6) 1.78+ 90 (m, iH), mos (m 2H), 2.52-2.60 (m, partially hidden by DMSO-d5, 1H), 2 68 (s 3H), 2·90 (s, 3H), 3, 33-3.39 (m, hidden by H2〇, m 5H), 3.50-3.57 (m, 2H), 3.57-3.64 (m, 2H), 3 713 79 (m, 5.23 (d, 1H), 5.61 (s, 1H), 6.22-6 oo / ..., ) , / 6.29 (m, 2H), 6.37 (ddd 1H), 7.09 (dd, 1H), 7.14 (d, 1H), 7, 8 〇 (d, 1H). The N,N-dimethylmorphinyl group I side is used as a starting material. Ding-2-yl)_4H-p gram-6-ylamine is prepared as follows. Step 1

201245186 Ethyl 8-bromomorpholinyl-4-oxo-4H-nonene-6-carboxylate (8 g '21.73 mmol) dissolved in MeOH (42 mL) and THF (21 mL) Sodium hydroxide (32.6 mL, 65.19 mmol) was added to the stirred suspension. The resulting suspension was stirred at room temperature for 1 h. Then MeOH (60 mL), THF (10 mL) and water (1 mL) were added to facilitate stirring. Upon completion, the reaction was added to 〇 ° C and 2 N HCl was added to the suspension until pH 2. The solid was collected by filtration, washed with water, AcOEt, diethyl ether and dried with P205 under vacuum at 50 ° C to give 8-bromo-2-morpholinyl-4-oxo-4H-decene. -6-carboxylic acid (7.0 g '91〇/〇). Mass spectrum: m/z [m+H]+= 354. Step 2

To a solution of 8-bromo-2-morpholinyl-4-oxo-4H-nonene-6-carboxylic acid (7 g, 19.77 mmol) and DIPEA (3.79 mL, 21.74 mmol) in DCM (100 mL) TSTU (6.55 g, 21.74 mmol) was added to the stirred solution. The resulting suspension was stirred at room temperature for 4 h. Add more TSTU (6.55 g, 21.74 mmol) and DIPEA (3·79 mL, 21.74 mmol) and carry out the mixing for another 16 h. The reaction mixture was quenched with aq. aq. The combined organics were dried with EtOAc EtOAc EtOAc EtOAc EtOAc. ·

S 201245186 Physic 8-bromo-N,N-dimethyl-2-morpholinyl-4-oxo-4H-nonene-6-indoleamine (7.70 g, 102%). Mass spectrum: m/z [M+H]+=381. The 8-bromo-indole, indole-dimethyl-2-morpholinyl-4-oxooxy-4-indole-2-eneamine was also synthesized on a large scale according to the following procedure. 8-bromo-2-morpholinyl in water (572 mL) in a 3 liter jacketed vessel (container 1) equipped with an overhead air agitator at 22 ° C for 30 min at a constant rate Potassium hydroxide (39.8 mL, 518.37 mmol) was added to -4- oxo-4H-nonene-6-carboxylate (99.3 g, 259.18 mmol). The resulting mixture was stirred at 22 ° C for 4 h. Water (286 mL) was added in one portion and the mixture was stirred at 22 ° C for 2 h until saponification was completed. The reactants were filtered to remove insoluble particles, water (95 mL) was charged as a screen filter, and the combined filtrate was transferred to a 3 liter jacketed container (container 1). To the vessel 1, a solution of dimethylamine hydrochloride (64.4 g, 777.55 mmol) in hydrazine (91 mL) was added and stirring was continued. In a separate 2 liter jacketed vessel (container 2), vessel 2 was charged with 2_gas_4,6·dimethoxy-1,3,5-three tillage (2〇8 g, 1.17 mol) And water (978 mL) and adjust the temperature to about 8 °C. 4· Mercaptomorpholine (214 mL, 1.94 mol) was charged at a rate to maintain the contents of container 2 &lt;12〇c and at 12. The contents were stirred for 2.5 h under the armpits. The contents of vessel 2 were transferred to vessel 2' via a dropping funnel at a constant rate over 3.5 h and stirred at 22 °C for 6 h. The reaction mixture was then subjected to the following temperature-carrying protocol. 163305.doc *157· 201245186 Duration of operation for container 2 contents heating/cooling operation (min) Heating to 75t 30 Maintaining at 75°C 60 Cooling to 60°C 90 Maintaining at 60°C 30 Heating to 75 °C 30 Maintain at 75 °C 60 Cool to 60 °C 90 Hold at 60 °C 30 Heat to 75 °C 30 Hold at 75 °C 60 Cool to 20 °C 400 Keep at 20 °C 60 Filter The reaction mixture was washed with water (381 mL). The solid was washed with water (381 mL) and dried <RTI ID=0.0></RTI> to <RTI ID=0.0> Ace-6-nonylamine (78 g, 78%). Mass spectrum: m/z [M+H] 381. Proton NMR spectrum: (400 MHz, DMSO, 30 ° C) 2.93 (3H, br. s), 2.99 (3H, br. s), 3.57-3.60 (4H, m), 3.74-3.76 (4H, m), 5.61 (1H, s), 7.87 (1H, d, J=1.9Hz), 7.99 (1H, d, J=1.9Hz); Step 3

163305.doc -158- s 201245186 to 8-bromo-N,N-dimethyl-2-morphinyl-4-yloxy·4Η-ρg-6-carbamide (3.15 g' 8.26 mmol , 1-(T-butoxycarbonyl)·1Η_pyrrole_2_ylboronic acid (2.1 g, 9.92 mmol) and sodium carbonate (2.63 g, 24.79 mmol) in DME (50 mL) and water (10 mL) Bis(triphenylphosphine)palladium chloride (11) (0.116 g, 0.17 mmol) was added in one portion to the stirred slurry. The resulting mixture was stirred at 80 ° C for 8 h. After cooling, water was added to the reaction mixture and extracted with DCM. The combined organic phases were washed with water and brine, dried over sodium sulfate and evaporated. The crude product was purified by flash chromatography eluting with EtOAc EtOAc The solvent was evaporated to dryness to give 2-(6-(didecylaminoindolyl)-2-morpholinyl-4-oxo-4H-nonen-8-yl)·1H-pyrrole-1 - Tert-butyl formate (2.40 g, 62%). Mass spectrum: m/z [M+H]+ = 468. Step 4

2-(6-(Dimethylaminocarbamoyl)-2-morpholinyl-4-oxo-4H-nonene-8- at a flow rate of 10 bar, 50 ° C and 1 mL/min a solution of tert-butyl-lH-pyrrole-l-carboxylic acid tert-butyl ester (0.6 g, 1.28 mmol) in MeOH (1 mL) 5% RI 1 / AI 2 O 3 (NanoThales CatCartii, 枉, product ID THS 02118) Hydrogenation was carried out using a Η-Cube (continuous flow hydrogenation unit HC-2.SS, from THALES Nanotechnology, Budapest H-1031; Zahony u.7.; Hungaria) for 3.5 h while continuously recycling. Replace the 163305.doc •159· 201245186 with a 10% Pd/c stem and perform hydrogenation at 60 bar and 6 (rc). The mixture is evaporated to dryness to give a solid which is taken in diethyl ether. Medium-grind Y transition and dry under vacuum and thief to give pure (monomethylamine-mercapto)-2·morpholinyl_4_sideoxy-4H_nonene_8-yl)pyrrole as a white solid The crude pyridine carboxylic acid tert-butyl vinegar (0.30 g, 5 %) was used in the next step as it was. Mass spectrum: m/z [M+H]+=472. Step 5

To the tert-butyl 2-(6-(didecylaminoindenyl)_2•morpholinyl·4·oxy-4-indene-8-yl)pyrrolidine]•carboxylic acid at room temperature (85 〇 mg, 丨 8 〇 mmol) Add the HCi (45 〇mL, 18 mmol, 4 M solution) to a stirred solution of DCM (10 mL) and stir. And MeOH (5 mL), then add j 〇0/ in DCM. Sterol ammonia (7 N, 5 mL). The solid was filtered and washed with DCM and Me 〇Hi i: mixture. The solvent was evaporated to dryness and triturated with diethyldiethyl ether to give N,N-dimethyl-di-l- </ br> -2-yl)-4H-nonene-6-carboxamide (675 mg, 1 〇 1 〇 /. mass spectrum: m/z [M+H]+=372. Example 2.01 8-(1-(3 -Methoxyphenyl)carinol-2-yl)-1^ with dimethyl-; 2-morpholinyl-4-oxo-4H-nonene-6-formamide•160· 163305 .doc

S 201245186

The title compound was prepared using a procedure similar to that described in Example 2. </ RTI> using only 1-bromo-3-methoxybenzene (0.055 ml, 0.44 mmol) instead of 1-bromo-3-fluorobenzene. Produces 8-(1-(3-decyloxyphenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholinyl-4-oxo-4H-nonene as a solid - 6-Artemisamine (46 mg, 28%). Mass spectrum: m/z [M+H]+= 478. Proton NMR spectrum. (DMSO-d6) 1.78-1.90 (m, 1H), 1.94-2.07 (m 2H), 2.46-2.55 (m' is partially hidden by DMSO-d5, iH), 2.70 (s, 3H), 2 · 90 (s, 3H), 3.33 - 3.39 (m, partially hidden by H20, 1H), 3.49-3.57 (m, 2H), 3.57-3.63 (m, 2H), 3.64 (s, 3H), 3.69-3.79 (m, 5H), 5.19 (d, 1H), 5.61 (s, 1H), 5.98 (s, 1H), 6.02 (dd, 1H), 6.20 (dd, 1H), 6.98 (dd, 1H), 7.17 ( d,1H),7.79 (d, 1H) Example 2.02 8-(1-(3-Cyano-5-fluorophenyl)pyrrolidine-2-yl)_N,N•Dimethyl-2-morpholine Base-4-sided oxy-4H-»» 克稀·6_甲甲胺

F 163305.doc -161 - 201245186 The title compound was prepared using a procedure similar to that described in Example 2.00 'only using 3-bromo-5-oxo-cause (88 mg, 0.44 indole-3·gas benzene) to produce 8-(W3_Cyano-phenyl)β-l-butyl-2-yl)-indole, fluorenyl-dimethyl-2-morphinyl-4-yloxy_4Η·decene_6• Amine (90 mg, 52%). Mass spectrum: m/z [M+H]+ = 491. Proton NMR spectrum: (DMSO-d6) 1.74-1.88 (m, iH), 1 99 2 1 〇 2H), 2.45-2.56 (m, partially hidden by DMSO-d5, iH), 2 68 (s 3H), 2.90 (s, 3H), 3.35-3.43 (m, partially hidden by H20, 1H) 3.49-3.58 (m, 2H), 3.58-3.66 (m, 2H), 3.71-3.77 (m, 4H) 3.77-3.85 (m , 1H), 5.31 (d, 1H), 5.62 (s, lH), 6.61 (d, 1H), 6.75 (s, 1H), 6.92 (s, 1H), 7.07 (d, 1H), 7.80 (d, 1H) Example 2.03 N,N-·Methyl-2 -Nylidene-4 -trisyl-8-(1-phenylindole-based)·4H-decene-6-carboxamide

The title compound was prepared using a procedure similar to that described in the procedure of Example 2.0 except that bromobenzene (0.046 ml, 0.44 mmol) was used instead of 1-bromo-3-fluorobenzene to give a solid N,N-dimethyl- 2-morpholinyl-4-oxo-8-(1-phenylpyrrolidin-2-yl)-4H-nonene-6-carboxamide (59 mg, 38%). Mass spectrum: m/z [M+H]+=448 ° 163305.doc 201245186 Proton NMR spectrum: (DMSO-d6) 1.80-1.93 (m,1H), 1.95-2.10 (m, 2H), 2.45-2.56 (m) , partially hidden by DMSO-d5, 1H), 2.67 (s, 3H), 2.89 (s, 3H), 3.33-3.40 (m, partially hidden by H20, 1H), 3.50-3.57 (m5 2H), 3.57 -3.65 (m, 2H), 3.70-3.81 (m, 5H), 5.20 (d, 1H), 5.61 (s, 1H), 6.44 (d, 2H), 6.58 (t, 1H), 7.10 (dd, 2H ), 7.17 (d, 1H), 7.79 (d, 1H) Example 2.04 8-(1-(4-Fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholinyl -4-Sideoxy-4H-pinene-6-formamide

The title compound was prepared using a procedure similar to that described in Example 2.20 except that 1-bromo-4-fluorobenzene (0.048 ml, 0.44 mmol) was used instead of 1-bromo-3·fluorobenzene to give a solid. (1-(4-Fluorophenyl)pyrrolidin-2-yl)-N,N-dimercapto-2-morpholino-4-oxo-4H-nonene-6-carboxamide (3 1 mg, 19%). Mass spectrum: m/z [M+H]+ = 466. Proton NMR spectrum: (DMSO_d6) 1.79-1.91 (m, 1H), 1.93-2.07 (m, 2H), 2.45-2.56 (m, partially hidden by DMSO-d5, 1H), 2.68 (s, 3H), 2.90 (s, 3H), 3.32-3.42 (m, partially hidden by H20, 1H), 3.49-3.57 (m, 2H), 3.57-3.64 (m, 2H), 3.70-3.80 (m, 5H), 5.16 (d , 1H), 5.61 (s, 1H), 6.42 (dd, 2H), 6.94 (dd, 2H), 163305.doc -163· 201245186 7.18 (d, 1H), 7.79 (d, 1H) by the palm of the hand Separation of racemic 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholinyl-4-oxo-4H-nonene by HPLC 6-decylamine (200 mg, real J 2.04), thus obtained as J 2.04a and 2.04b: Instrument Gilson Prep (200 ml head) Column Merck 50 mm 20 μιη Chiralpak IC Eluent MeCN/MeOH 80/20 Flow rate 100 ml/min Wavelength 254 nm Sample concentration 140 mg/25 ml MeCN Injection volume 25 ml Run time 25 min Samples are obtained as a transparent film, which is then ground with diethyl ether to produce solid. The materials were dried overnight at 40 ° C in a vacuum. First eluting enantiomer: 63 mg (99.7% enantiomeric purity), iH 2.04a, second eluting enantiomer: 58 mg (99.0% enantiomeric purity) Example 2.04 b Example 2.04a 8-[(2S)-l-(4-Fluorophenyl)pyrrolidin-2-yl]-N,N-dimethyl-2-morpholinyl-4- oxo-4H- Terpene-6-carbamide mass spectrum: m/z [M+H]+ = 466. Proton NMR spectrum (CDC13): 1.95-2.12 (m,3 H), 2.40-2.52 (m,1 -164- 163305.doc s 201245186 Η), 2.78 (s, 3 Η), 3.03 (s, 3 Η) , 3.30-3.43 (m, 1 Η), 3.46 3.81-3.93 (m, 4 Η), 5.04 3.60 (m, 4 Η), 3.71-3.80 (m, 1 Η), (d, 1 Η), 5.57 ( s, 1 Η), 6.36 (dd, 2 Η), 6.86 (dd, 2 Η), 7.40 (d, 1 Η), 8.11 (d, 1 Η) 〇 Example 2.04b 8-[(2R)-l- (4-Fluorophenyl)pyrrolidin-2-ylpyridyl N,N-dimethylmorpholinyl-4- 4-oxo-4H-nonene-6-carbenamide Mass spectrum: m/z [M+H ]+=466 〇 proton NMR spectrum (CDC13) : (m,3 Η), 2 4〇·2 52 (m,i Η), 2.78 (s, 3 Η), 3.03 (s, 3 Η), 3.30- 3.43 (m, 1 Η), 3.46- 3.60 (m, 4 Η), 3.71-3.80 (m, 1 Η), 3.81-3.93 (m, 4 Η), 5.04 (d, 1 Η), 5.57 (s, 1 Η), 6.36 (dd, 2 Η), 6.86 (dd, 2 Η), 7.40 (d, 1 Η), 8.11 (d, 1 Η) 实例 Example 2 by enantioselective synthesis in the following manner 〇 The absolute stereochemistry of each of the eclipses and 2 〇牝. Example 2 〇4b is a pair of palmitic starting materials of known absolute chemistry (ie, 2_morpholinyl_4_sideoxy_8_[(2r)-pyrrolidin-2-yl]nonene-6· Methyl formate, prepared as described in Example 1), was prepared. By analogy, instance 2 〇 4a is assigned the (s)_ configuration. The details of the enantioselective synthesis of Example 2.04b are as follows:

Using a procedure similar to that described in Example 1·〇4, 163305.doc 201245186 fluorophenyl)pyrrolidinyl-2-yl)]-2-morpholinyl-4-oxo-4H-nonene-6 -Citric acid (56 mg '0.13 mmol, for preparation, see example 1.03b) was reacted with dimethylamine hydrochloride (52 mg, 0.64 mmol) to give 8-(1-(4-fluorophenyl)° Bilpyridin-2-yl)-N,N-dimethyl-2-morpholinyl-4-oxo-4H-chito-6-carboxamide (9 mg, 15%), analytical data as above . 8-[(2R)-(l-(4-Fluorophenyl)pyrrolidin-2-yl)]-2-oxalin-4-yloxy-4H-nonene-6 as starting material - The formic acid was prepared using a procedure similar to that described in Example 1.05, in which bromo-4 fluorobenzene was used instead of 1 bromo-3-phenylbenzene: Step 1

2-morpholinyl-4-oxo-8-[(2R)-pyrrolidin-2-yl]nonene-6-carboxylic acid methyl (130 mg, 〇·36 mm〇l) and 1-bromo -4-fluorobenzene (0.239 ml, 2.18 mmol) was reacted to give a gray-brown solid of 8_[(2Κ)·(1·(4-fluorophenyl). than slightly bita-2-yl)]-2-? Methylolinyl-4-oxo-4-decene-6-decanoate (enantiomer 2 '24 mg '15%). Mass spectrum: m/z [Μ+Η]+=453. Step 2

I63305.doc

S-166- 201245186 8-[(2R)-(l-(4-Fluorophenyl)β-pyrrolidin-2-yl)l- 2-morpholinyl-cardiyloxy-4H-bite- 6-Methyl decanoate (1) 9 mg, 0.26 mmol from 2 different batches) was reacted with sodium hydroxide to give phenyl as a yellow solid. Bilpyridin-2-yl)-2-morpholinyl-4-oxo-4H-nonene-6-carboxylic acid (enantiomer 2, 95 mg, 82%). Mass spectrum: m/z [M+H]+ = 439. Example 3.00 8-(1-(3,5-Difluorophenyl)pyrrolidin-2-yl)-2-((11)-2-methylmorpholinyl)-6-(morpholin-4-carbonyl )-4H-nonen-4-one

To the 8-(1-(3,5-di-phenylphenyl) ring slightly under the nitrogen, 2_yl)_2_((尺)_2_methylmorpholinyl)-4-oxo-4H-pinene -6-carboxylic acid (9 〇 mg, 0.19 mmol) 'DIPEA (0.083 mL '0.48 mmol) was dissolved in DMA (2 m[) to add TBTU (154 mg, 〇.48 mm 〇〇. The solution was stirred at room temperature for 30 min»added morpholine (〇〇5〇mL, 〇57 m-) and the mixture was mixed for ih at room temperature. The reaction mixture 1 was prepared by preparative tendon containing (4) part of the compound Evaporate to dryness to give a yellow solid. (W3,5.: fluorophenylw Μ _2 yl)_2_ (W-2·曱 吗 吗 ) )) _6• (? mouth, 4, base)· 4η• benzophenone (10) mg, 66%). 163305.doc 167- 201245186 Quality error: m/z [M+H]+=540. Proton NMR spectrum: (DMSO-d6) 1.17 (d, 3H), 1.75-1.88 (m, 1H), 1.99-2.08 (m, 2H), 2.45-2.57 (m, partially hidden by DMSOd6, 1H), 2.77- 2.86 (m,1H),3·06 (bs,2H), 3.09-3.19 (m, 1H), 3.23 (bs,2H),3.33-3.41 (m, partially hidden by H20, 1H), 3.44 (bs, 2H), 3.55 (bs, 2H), 3.58-3.71 (m, 2H), 3.73-3.80 (m, 1H), 3.85-4.06 (m, 3H), 5.26 (d, 1H), 5.64 (s, 1H) , 6.13 (d, 2H), 6.34 (t, 1H), 7.06 (d, 0.5H), 7.07 (d, 0.5H), 7.82 (d, 1H) 8-(1-(3) used as starting material ,5-difluorophenyl)pyrrolidin-2-yl)-2-((R)-2-mercapto-l-yl)_4·Sideoxy-4H-bitite-6-decanoic acid was prepared as follows :· step 1

To a suspension of 3-ethylindolyl-5-bromo-4-hydroxybenzoate (7 g, 243.52 mmol) in THF (700 mL) at -50 ° C under nitrogen A flask with a bleach trap was added with lithium bis(trimethylmethane) guanamine (828 ml, 828 mmol). The dark solution was warmed to _5t and stirred for 2 h. Carbon disulfide (22 mL, 365 mmol) was added in one portion to the solution at -20 ° C. The mixture was then stirred at room temperature overnight. Water (7 〇〇 mL) was added and the THF layer was washed with water (2×350 mL). Combine the aqueous phase and cool to 〇〇c -168 - 163305.doc

S 201245186 and formed by neutralization with H2S〇4 (1〇8 mi, 1948 mm〇1) in a vessel equipped with a bleach trap. The mixture was stirred at room temperature for 3 h EtOAc (EtOAc)EtOAc. The aqueous phase was extracted with DCM (2x). The organic phases were combined, washed with brine &apos; dried, filtered and evaporated to give an orange solid. The solid was triturated in diethyl ether and allowed to dry to give a yellow/purified solid of bromo-4-hydroxy-2-thio-2H-decene-6-carboxylic acid methyl ester (48.7 g, 63% ). Mass spectrum: m/z [M+H]+=317 » Step 2

To a solution of methyl 8-bromo-4-hydroxy-2-thioxo-2H-nonene-6-carboxylate (48.69 g, 154.5 mmol) and potassium carbonate (2135 g, 154 5 〇mm〇i) in acetone (490) Ethyl iodide (I) ^ 463.5 i mmol) was added in one portion to the stirred suspension in mL). The resulting suspension was stirred under nitrogen for 1 h in a flask equipped with a bleach trap. The reaction mixture was concentrated, and the residue was diluted with DCM (98 mL) / water (49 mL). The phases were separated and the aqueous layer was extracted with DCM (49 mL). The residue is triturated with petroleum ether, filtered and dried under vacuum to give a succulent solid. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Ester (52.9 g, 1%). Mass Spectrum: _ [M+H]+=345 163305.doc -169· 201245186 Step 3

White 8 / odor-2-(ethylthio)_4_ oxoxy ketone-6-formic acid vinegar (47·35 g '132.45 mmol) was stored in ice-cooled DCM (420 mL) The mixed solution was added with 3 - chlorobenzo-peroxyacid (76 g, 264.90 mm 〇l). The resulting mixture was then stirred at room temperature for 2 h under nitrogen. The suspension was cooled to -15 ° C and filtered, and the solid was washed with cold DCM, followed by a solution of sodium succinate (16.44 g, 66.23 mmol) in water (290 mL), followed by NaHC. 3 Saturated solution (2x3 00 mL) of washing solution. The organic layer was decanted and dried by means of MgS 4 and evaporated to give a red powder which was triturated with diethyl ether to give a solid which was collected and dried by the transition to give a white material as a bromine. (Ethylsulfonyl)-4-oxooxy-4Η-ρ克妇-6-carboxylic acid toluene (44.6 g, 90%). Mass spectrum: m/z [M+H]+= 375. Step 4 163305.doc

Methyl 8 bromo-2-(ethylsulfonyl)-4. oxo-4H-nonene-6-carboxylate (44.56 g, 118.77 mmol) and (R) at 5 ° C under nitrogen _2-mercaptomorpholine salt 170·

S 201245186 醆 salt (22.88 g' 166.27 mmol) DIPEA (51.7 mL, 296.91 mm 〇l) was added dropwise to the solution of DCM (430 mL). The resulting suspension was stirred at room temperature for 1 h.. The reaction mixture was diluted with water and slowly quenched with &lt;RTI ID=0.0&gt;&gt; The phases were separated and the organic phase was washed with water, brine, dried over MgSO 4 and concentrated. Will be crude

The material was triturated in EtAc for 1 h, and the solid was collected by filtration and dried to give 8-bromo-2-((R)-2·methylmorpholinyl)-4. -6·decyl decanoate (32.6 g, 67%). Mass spectrum: m/z [M+H]+=384. Step S

To (R)-8- &gt; odor-2-(2-methylmorphinyl)-4-side oxy aceton-6-decanoate (10.06 g '25 mmol), 1-(third Mixture concentrate of butoxycarbonylpyrrolidine (6.46 g '30.00 mmol) and sodium carbonate (7.95 g, 75,00 mmol) in DME (140 mL) and water (28 mL) Add bis(triphenylphosphine) gasified palladium (Π) (0·448 g, 0.63 mmol) in one time. Degas the mixture with argon for 15 min, then heat at 80 ° C. 6 Evaporate the solvent 'to the residue Water was added and the combined organic phases were washed with water and brine using DC1V [extraction mixture], dried and concentrated with &lt;RTI ID=0.0&gt;&gt; _2·(2·Methylaryl)-4-oxo-4Η-decene-8-yl)-1Η-pyrrole-1-carboxylic acid tert-butyl 163305.doc -171 - 201245186 Ester (13.98 g Mass spectrometry: m/z [M+H]+=469. Step 6

(R)-2-(6-(decyloxycarbonylmethylmorphinyl)-4- oxo-4H- sulphate-8-yl)-1 hydrazine in MeOH (50 mL) .略1_carboxylic acid = butyl ester (2 g, 4.27 mmol) and 5% alumina on 铑 (5 〇%, wet) (〇4 g' 0.09 mmol) under hydrogen atmosphere at 5 bar and Stir at 65 ° C for 2 h. Add more catalyst and continue to stir overnight. Subsequently, 2 g of 5% Rh/C was added, after which the same amount was added after j h and then another 2 h. The catalyst was filtered through diatomaceous earth and washed with MeOH/DCM and solvent was evaporated. The crude product was purified by flash chromatography eluting with EtOAc (EtOAc) Evaporation of the solvent to dryness afforded 2-(m.p.p. oxycarbonyl)-2-((R)-2-indolyl morpholinyl)-4-yloxy _4 Η decene-8 as a white solid. -Base) Pyrrole bite-1-decanoic acid second butyl (1.18 g, 59%). Mass spectrum: m/z [Μ+Η]+=473. Step 7 163305.doc

-172

S 201245186 to 2-(6-(methoxycarbonyl)-2-((R)-2-methylmorpholinyl)-4-4-oxo-4H-nonen-8-yl)pyrrole at room temperature Butyl-1-decanoic acid tert-butyl ester (118 g,

2.50 mmol) 4 N HCl (6.24 mL ' 24.97 mmol) was added to a stirred solution of DCM (10 mL) and stirred for 16 h. The solvent was evaporated and dCM (5 mL) and MeOH (5 mL) was then evaporated. /〇Methanol ammonia (7 N). The solid was filtered and washed with a 1:1 mixture of DCM and MeOH. The solvent was evaporated to dryness and the crude material was purified eluting eluting eluting eluting eluting Collected by filtration and dried under vacuum to give a white solid, 2-((()))- </RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Vinegar (0.760 g, 82%). Mass spectrum·· m/z [M+H]+=373. Step 8

To 2-((R)-2-indolylmorpholinyl)·4-sideoxy_8·(ΪΙ比咯咬_2•基克克稀-6-carboxylic acid vinegar (190 mg, 0.5 1 mmol) ), (9,9-dimethyl 9h B octopus-4,5-diyl) bis(diphenylphosphine) (25.09 mg, 0.04, bromo-3,5-difluoro stupid (73.4 μΐ, 0.64) Methyldimethoxy palladium (4.58 mg, 0. 02 mmol) was added to a stirred mixture of EtOAc EtOAc (EtOAc (EtOAc). The resulting suspension was degassed with argon 163305.doc -173 - 201245186 and then stirred for 20 h under loot. The reaction mixture was cooled to room temperature, the insoluble material was removed by filtration and the filtrate was concentrated. The mixture was purified by flash chromatography on EtOAc (EtOAc) eluting with EtOAc EtOAc EtOAc. Phenyl). σ 各 基 -2-yl)-2-((R)-2-methyl 吓 _ _ _)_4_ oxo-4H-nonene-6-carboxylic acid methyl ester (150 mg, 61%) Mass Spectrum: m/z [M+H]+=485. Step 9

To 2-((R)-2-indolylmorpholinyl)-4-oxooxy-8-(1-pyl.pyrrolidin-2-yl)-4Η-bitite-6-decanoate Add a solution of the ester (136 mg, 0.28 mmol) in MeOH (2 mL) / water (2 mL). The mixture was stirred at room temperature for 18 h, then at 50 ° C to complete the reaction. At 5. (: The reaction was acidified to pH 2-3 with 2 N EtOAc (EtOAc EtOAc EtOAc EtOAc EtOAc) (1-(3,5-Difluorophenyl)pyrrolidin-2-yl)-2-((R)-2-indolylmorpholinyl)-4-yloxy-4H-nonene-6- Citrate (95 mg, 72%), which was used without further purification. Mass Spectrum: m/z [M+H]+= 471. (R)-2-A used as starting material in step 4 above. The morpholine hydrochloride system 163305.doc -174- 201245186 is prepared as follows: - Step 1

2-(Benzylamino)ethanol (207(6), 1454 97 mmol) and (R)-2-methyloxirane (153 nU' 2182.46 mmol) were mixed together and passed through a 150 ° C flow chemistry system The heated 1 〇 mL loop was pumped at [mL/min rate] to adjust the back pressure regulator to achieve a pressure of 25 psi inside the loop. Excess propylene oxide was removed under vacuum to give a colorless liquid (RW-(benzyl(2-hydroxyethyl)amino)propan-2-ol (3 〇〇g, 99%). Mass Spectrum: m/ z [M+H]+=210° Step 2

Stirring of (R)-l-(benzyl(2-hydroxyethyl)amino)propan-2-ol (11 〇g, 525.60 mmol) in dioxane (5 〇〇 mL) under nitrogen Potassium hydroxide powder (88 g, 1576.80 mmol) and volume (2-(2-methoxyethoxy)ethyl)amine (1.681 mL, 5.26 mmol) were added continuously to the solution. The mixture was cooled to 〇t: and a solution of 4-methylbenzene·5 sulfonate 5 g, 551 88 mm 〇i) in dioxane (500 mL) was added dropwise. The reaction mixture was stirred for 45 min then stirred at room temperature for a further 4 h. The mixture was filtered and the filtrate was evaporated. I63305.doc -175- 201245186 The residue was dissolved in DCM and purified eluting with EtOAc EtOAc. The solvent was evaporated to give an oil which was diluted (250 mL). A solution of 4 n hc in a dioxin (0.066 L' 262.8 mmol) was then added dropwise with stirring. After 3 〇 _, the solid formed was collected by filtration, washed with diethyl ether and dried to give (R)-4-benzyl-2-mercapto morpholine hydrochloride (4 g, 33%). Proton NMR spectrum: (DMSO-d6): 1·〇9 (d, 3H), 2.67_2.77 (m, 1H), 2.93-3.04 (m, 1H), 3.14-3.23 (m, 2H), 3.83- 4.00 (m, 3H), 4.29-4.34 (m, 2H), 7.43-7.49 (m, 3H), 7.60-7.68 (m, 2H), 11.62 (bs, 1H). Step 3

HCI HCI cr oxr (R)-4-benzyl·2·decylmorpholine hydrochloride in the presence of palladium 10%/C (3 g, 28.19 mmol) at room temperature and i &amp; 4〇g, 175 65 mm〇1) The solution in ethanol (1 L) was hydrogenated overnight. The mixture was filtered and the filtrate was concentrated to dryness to afford (D) </RTI> <RTIgt; Proton NMR spectrum: (DMSO-d6): 1.10 (d, 3H), 2.62 (dd, 1H), 2.85-2.95 (m, 1H), 3.08-3.20 (m, 2H), 3.70-3.77 (m, 1H) , 3.78-3.83 (m, 1H), 3.90 (dd, 1H), 9.49 (bs, 2H). Example 3.01 2-((R)-2-methylmorpholinyl)_6·(morpholine-4-ylcarbonyl)_8-(1-phenylpyrrolidin-2-yl)·4Η-nonene-4-one 163305 .doc s -176- 201245186

Under nitrogen to 2-((R)-2-indolylmorpholinyl)_4_sideoxy-8-(1-phenyl. than octyl-2-yl)-4Η-ρ ketene-6- TBTU (148 mg, 0.46 mmol) was added to a stirred solution of decanoic acid (8 mg, 0.18 mmol), DIPEA (0-080 mL '0.46 mmol) dissolved in DMA (2 mL). The resulting solution was stirred at room temperature for 30 min. Morpholine (0.048 mL, 0.55 mmol) was added to the mixture and stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC. The fraction containing the desired compound is evaporated to dryness to give 2-((R)-2-methylmorpholinyl)- 6 (morpholine-4-carbonylphenylpyrrole _ 2-yl) as a viscous solid. 4-indole-4-one (60 mg, 65%). Mass spectrum: m/z [M+H]+= 504. Proton NMR spectrum: (DMS0-d6) Ll7 (d, 3H), i π] 93 (m, lH), ^98-2.09 (m, 2H), 2.47-2.57 (m, partially hidden by DMSOd6, 1H), 2.77-2.86 (m5 1H), 3.02 (bs, 2H), 3.09-3.18 (m, 1H), 3"9 (bs, 2H), 3.34-3.40 (m 'hidden by H20, 1H), 3 42 ( Bs&gt; 2H), 3.55 (bs, 2H), 3.58-3.71 (m, 2H), 3.72-3.81 (m, !Η), 3.85-4.07 (m, 3H), 5.22 (d, 1H), 5.64 (s , 1H), 6.44 (d, 2H), 6.53 (t} 1H), 7.10 (t, 2H), 7.12 (d, 1H), 7.81 (d, 1H) 2-((R) used as starting material -2-Methylmorpholinyl)_4_sideoxyl (Phenylpyroxypyrene-2-carbenyl-6-carboxylic acid) was prepared as follows: _ Step 1 163305.doc 201245186 ο

To 2-((R)-2-indolyl)-4-yloxy-8-(η ratio η „ _2 _ _ _ _ _ 190 190 190 190 -6 -6 -6 190 190 190 190 Mg, 0.5 1 mmol), (9,9-dimethyl 9 Η -4 -4,5-diyl) bis(diphenylphosphine) (25.09 mg, 〇〇4 mm 〇^, bromobenzene (67 μΐ, 0.64 mmol) and a carbonated planer (249 mg, 0.77 mm 〇1) were added to a stirred mixture of 1,4-bis &quot; ward (5 mL) to add diethyl ethoxylate (4.58 mg, 0.02 mmol). The resulting suspension was degassed with argon and stirred at EtOAc &lt;t&gt; for 20 h. After cooling to room temperature, the insoluble material was removed by filtration and the filtrate was concentrated. Purification by flash chromatography on 0-6% MeOH in EtAc. Evaporation of solvent to dryness to give 2-((())) Alkyloxy·8-(1·Phenylpyrrolidine-2-yl)-4H-bitite-6-carboxylic acid methyl vinegar (H2 mg, 49%). Mass Spectrum: m/z [M+H]+ =449. Step 2

To 2-((R)-2-methylmorpholinyl)-4-oxo-8-(1-phenylpyrrolidin-2-yl)-4H-nonene-6 as described in Example 3.00 - Add methyl formate (105 mg, 0.23 mmol) in MeOH (2 mL) / water (2 mL)

163305.doc -178- S 201245186 Sodium hydroxide (2 N, stored in water) (0.293 mL, 〇·59 mm〇i), thus obtaining ((R)-2-methylmorphinyl)_4-side Oxy-8-(1-phenyl η 洛 咬 _2 _ _ _ _ _ Η 咣 咣 咣 _ 曱 曱 。 ( ( 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Mass spectrum: m/z [M+H]+= 435. Example 3.02 MM3·fluorophenyl)"Bilo bite_2_yl)_2-((R)_2_f-based phenanthrenyl)6 (morphine-4-carbonyl)-4H-bitite-4·.one

To 8-(1-(3-fluorophenyl)"pyrrolidin-2-yl)-2-((R)-2-methyl?-based M-sideoxy-4H-pinene under nitrogen Add TBTU (138 mg, 0.43 mmol) to a stirred solution of -6-decanoic acid (97 mg, 0.21 mmol), DIPEA (0.075 mL, 0.43 mmol) in DMF (1_5 mL). After stirring for 1.5 h, morpholine (28 mL, 0.32 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was purified by preparative HP lc. In DCM, it is dried by MgS〇4 and evaporated to dryness to give a yellow foamy form of 8-(丨_(3_fluorophenyl)pyrrolidin-2-yl)~2-((R)-2-methyl? Phenyl)-6-(morpholine-4-carbonyl)-4H-dibenzo-4-one (63 mg, 56%). MS: m/z [M+H]+= 533. DMSO- d6) 1.17 (d, 3H), 1.77-1.90 (m, 1H), 163305.doc 179- 201245186 1.98-2·1〇(m, 2H), 2 47_2 57 (m, hidden by DMS〇d6) , 1H), 2.78-2.86 (m, 1H), 3.04 (bs, 2H), 3.09-3.18 (m, 1H), 3.22 (bs, 2H), 3.34-3.41 (m, hidden by H20, 1H), 3.42 (bs, 2H), 3.54 (bs, 2H), 3 .58-3.70 (m, 2H), 3.73-3.80 (m, 1H), 3.85-4.06 (m, 3H), 5.25 (d, 1H), 5.63 (s, 0.5H), 3.64 (s, 〇.5H ), 6.19-6.29 (m, 2H), 6.38 (ddd, 1H), 7.05-7.13 (m&gt; 2H), 7.81 (d, 1H). 8-(1-(3-Fluoro) used as starting material The pyrrolidine-2-yl)2-((r)_2.methylmorpholinyl)-4-oxo-4H-nonene-6-carboxylic acid is prepared as follows: _ Step 1 〇

2-((R)-2-methylindolyl)-4-yloxy·8_(η ratio slightly bit_2_yl)·4η_decene-6-decanoate (0·35) g, 〇.94 mm〇1), (9 9_ dimethyl_9Η 咕 mock _4,5_diyl) bis(diphenylphosphine) (0.046 g, 0.08 mmol), 1-di·3_fluoro Benzene (0.131 ml, 1.17 mmol) and a carbonic acid planing (0.459 g, 1.41 _ 〇ι) were added to a stirred mixture of 1,4-dioxane (9 mL), and diethylphosphonium palladium (8.44 mg, 0.04) was added. Mm〇l) » The resulting suspension was degassed with argon and then dropped for 20 h at 10 0 C. The reaction mixture was cooled to room temperature, the insoluble material was removed by filtration and the filtrate was concentrated. The crude product was adsorbed onto the ground gel and purified by flash chromatography on silica gel eluting with Et. Evaporating the solvent to dryness to obtain a gray-brown foam

163305.doc • 180 · S 201245186 (3-Fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholinyl)_4-sideoxy-4H-p keene- Methyl 6-carboxylate (〇 279 g, 640/〇). Mass Spectrum: m/z [m+H]+= 467 ° Step 2

To 8-(1-(3-fluorophenyl)pyrrolidinyl-2-yl)-2-((R)-2-methylmorphinyl)-4-yloxy in suspension in MeOH (4 mL) -4Η-Diluted methyl butyrate (0·25 g '0.54 mmol) was added 2 N NaOH aqueous solution (〇8〇4 ml, 1.61 mmol)·»The solution was stirred at 4 ° C overnight, then After cooling to 〇 ° 〇 and 2 N HCl aqueous solution (0, 670 ml, 1.34 mmol) was added dropwise to the reaction mixture until pH was about 3. The resulting sinks were collected by rubbing, washed with water and under vacuum and 50. (: Dry to a constant weight in the presence of P2 〇 5 to give 8-(1-(3-fluorophenyl)pyrrolidinium-2-yl)-2-((R)-2-A as a beige solid吗 morpholinyl) 4-4-oxo-4H-nonene-6-decanoic acid (201 mg, 83%) 〇 Mass Spectrum: m/z [M+H]+=453. Example 3.03 8-(1-( 3-fluorophenyl)oxaridin-2-yl)-N,N-dimethyl-2-((R)-2-methylmorpholinyl)-4. oxo-4H-pinene- 6-carbamide 163305.doc -181 - 201245186

F 8-(1-(3-Fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-indolyl)-4-yloxy- as described in Example 3.02 4H-P gram -6-decanoic acid (102 mg, 0.23 mmol) was reacted with dimethylamine (2N in THF) (0.169 ml, 0.34 mmol) to give a pale yellow foam. (1-(3-Fluorophenyl)°b-pyridin-2-yl)-N,N-dimethyl-2-((R)-2-methylmorpholinyl)-4-sideoxy- 4H·decene-6-formamide (51 mg, 47%). Mass spectrum: m/z [M+H]+= 480. Proton NMR spectrum: (DMSO-d6) 1.17 (d, 3H), 1.77-1.90 (m, 1H), 1.98-2.08 (m, 2H), 2.45-2.58 (m, partially hidden by DMSOd6, 1H), 2.69 ( s, 3H), 2.78-2.86 (m, 1H), 2.90 (s, 3H), 3.09-3.18 (m, 1H), 3.33-3.39 (m, partially hidden by H20, 1 printed, 3.58-3.70 (m, 2H), 3.72-7.79 (m, 1H), 3.85-4.07 (m, 3H), 6.24 (d, 1H), 5.63 (s, 0.5H), 5.64 (s, 0.5H), 6.21-6.29 (m, 2H), 6.33-6,40 (m, 1H), 7·04 (ddd, 1H), 7.13 (d, 0.5H), 7.14 (d, 〇.5H), 7.80 (d, 1H). BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: X-ray powder diffraction pattern of Example 1.03b Form A; Figure 2: Example l. 〇3b Form B X-ray powder diffraction pattern; Figure 3: Example l. 〇3b Form B DSC heat Analytical map; and Figure 4: Example 1. X-ray powder diffraction pattern of Form 3b Form C.

163305.doc -182 · S

Claims (1)

201245186 VII. Patent application scope: 1 · A compound of formula I, Wherein: R1 is optionally substituted by a hydroxy group (1-4C) alkyl; R2 is a hydrazine or (1-4C) alkyl group; or R1 and R2 together form a 3 to 8 member nitrogen-containing heterocyclic ring system, Depending on the case, it contains 1 or 2 other heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring sulfur atom is optionally deuterated to form an S-oxide, which is optionally substituted by a hydroxyl group; R3 and R5 are independently selected from hydrazine. , halo, (1-3C)alkoxy and cyano; R4 is hydrazine or fluoro; η is 0 or 1 ' and when η is 1, the R6 group is methyl; or pharmaceutically acceptable salt. 2. A compound of formula I according to claim 1, wherein: R1 is optionally substituted by a hydroxy group (i.sub.4 alkyl; R2 (1-4C)alkyl; or R1 and R2 form 4 to 6 members a nitrogen-containing heterocyclic ring system, which optionally contains one other hetero atom selected from the group consisting of oxygen, nitrogen and sulfur, wherein the ring sulfur atom is oxidized to form an s-oxide according to 163305.doc 201245186. Or a pharmaceutically acceptable salt thereof. 3. The compound of formula j of claim 1 or 2 wherein the rule 3 and the rule 5 are independently selected from the group consisting of H 'fluoro, methoxy and cyano; or 4. The compound of formula I, wherein R4 is η; or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3. 5. The formula I of any one of claims 1 to 4 And a pharmaceutically acceptable salt thereof. The compound of formula I according to any one of claims 1 to 4, wherein the η is a methyl group; or a pharmaceutically acceptable salt thereof. A compound of formula I according to claim 1, wherein: R1 is optionally substituted by a hydroxy group (1-4C) alkyl; R2 is (1-4C)alkyl; or R1 and R2 together form 4 to 6 members a nitrogen heterocyclyl ring system optionally containing one other hetero atom selected from the group consisting of oxygen, nitrogen and sulfur, wherein the t-ring sulfur atom is optionally oxidized to form an S-oxide, which is optionally substituted by a hydroxyl group; R3 and R5 Is independently selected from the group consisting of - and R4 is H; η is 0 or 1, and when in !, the R6 group is a thiol group; or a pharmaceutically acceptable salt thereof. ' 8. As in claim 1 a compound, wherein: R is a fluorenyl group, an ethyl group or a 2-hydroxyethyl group; R2 is a fluorenyl group or an ethyl group; or R and R form a nitrogen-containing heterocyclic ring system selected from the group consisting of azetidine Base, morpholinyl, W, oxytetrahydro, M, thiophene and hexahydropyridine 163305.doc 201245186 The group 'is optionally substituted with a hydroxy group; R3 and R5 are independently selected from hydrazine or a halogen group and the R4 system η ; η 〇 or 1, and when η is 1, the R 6 group is a sulfhydryl group; or a pharmaceutically acceptable salt thereof. 9. The compound of the formula I according to claim 1, wherein: R1 is a thiol group or 2-hydroxyethyl; r2 methyl; or R1 and R2 together form a nitrogen-containing heterocyclic ring system selected from the group consisting of azetidin-1-yl, morphin-4-yl, 1-side oxygen Tetrahydro-1,4-indole-4-yl, hexahydropyridyl Pyridin-1-yl and 4-hydroxyhexafluoropyridin-1-yl; R3 and R5 are independently selected from H, fluoro, decyloxy and cyano; R4 is hydrazine or fluoro; η is 0 or 1, and When the η system is 1, the R6 group is a methyl group; or a pharmaceutically acceptable salt thereof. 1 A compound of the formula I according to claim 1 which is selected from any one of the following: 8-(1- (3,5-difluorophenyl)pyrrolidin-2-yl)-indole, indole-dimethyl-2-morpholinyl-4-oxooxy-4-indole-2-enecarbamamine; -(1-(3,5-difluorophenyl). Bilobidine-2-yl)-6-(morpholin-4-carbonyl)-2-morpholinyl-4H-nonen-4-one; 8-[(2S)-l-(3,5-di Fluorophenyl)pyrrolidin-2-yl]-6-(morpholin-4-carbonyl)-2-morphinyl ketone-4-one; 8-[(2R)_l-(3,5-difluoro Phenyl)pyrrolidin-2-yl]-6-(morpholin-4-carbonyl)-2-morphinyl-πglyl-4-indole; 6-(azetidin-1-carbonyl)- 8-(1-(3,5-Difluorophenyl)pyrrolidine-2· 163305.doc 201245186 base)-2-morpholinyl-4H-nonen-4-one; 6-(azetidine -1-carbonyl)-8-[(2S)-l-(3,5-difluorophenyl)°bipiridin-2-yl]-2-morpholinyl-nonen-4-one; 6- (Azetidine-1-carbonyl)-8-[(2R)-l-(3,5-difluorophenyl). Bilobidine-2-yl]-2-morpholinyl-decen-4-one; 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl- 2-morpholinyl-4-sided oxy-4H-nonene-6-carboxamide; 8-[(2S)-l-(3-indolyl)pyrrolidin-2-yl]-N,N -dimercapto-2-morpholinyl-4-o-oxy-decene-6-formamide; 8-[(2R)-l-(3-fluorophenyl)pyrrolidin-2-yl]- Ν,Ν·Dimercapto-2-morpholinyl-4-sideoxy-decene-6-formamide; 8_(1-(3-fluorophenyl)pyrrolidin-2-yl)-6-( Morpholine-4-carbonyl)-2-morpholinyl-4H-P gram--4-indole; 8-[(2S)-l-(3-acrobasic)»»比洛咬·2-base] -6-(Nupip-4-pyryl)-2-morphinyl-p-cyano-4-one; 8-[(2R)-l-(3-fluorophenyl)-l-r- yl-2-yl -6-(morpholine-4-carbonyl)-2-morphinyl ketone-4-one; 6-(azetidin-1-carbonylfluorophenyl)pyrrolidine-2-yl 2-line -4H-»1 克稀-4-_ ; 6-(azetidine·ι·carbonyl)fluorophenyl)pyrrolidine_2_yl]-2-morphinyl-bite; 6-( Azetidine-1·carbonylfluorophenyl)pyrrolidine·2_yl]-2-morphine·octenylene_4-ketone; 8-(1-(3-fluorophenyl)pyrrolidine·2_* )_Ν,Ν·Dimethyl_2•morpholinyl heart 16330 5.doc 201245186 oxo-4H-pinene-6-carbamide; 8-(1-(3,5-difluorophenyl)"pyrrolidine_2•yl)_2_((r)_2A吗 morpholinyl)-6-(norpoline-4 -yl)_-4H-p gram-keto; 8_(1-(3-fluorophenyl)pyrrolidine-2-yl)_2·(( κ)_2_Methylmorpholinyl)6_ (?--4-yl)-411-17g dilute-4-?; and 8-(1-(3-fluorophenyl)pyrrolidine_2_ () ΝΝ 曱 曱 _2 2 ((R) 2 - fluorenyl morpholinyl)-4- oxo-4H-nonene _ 6 _ _ _ _ _ _ _ _ 11. As requested by the Ϊ compound, it is 8_[(2R)_H3 5-diphenyl) pyrrole bite-2·^]-6_(?,林_4_几基)·2? Rare · 4 嗣; or its pharmaceutically acceptable salt. 12. For example, the compound of the formula '8-[(2r) small (3,% difluorophenyl) is more than 嘻2-yl]_6_(?啦·4_基基)·2_?琳基- Bite thin · 4 · 嗣. 13. A pharmaceutically acceptable salt of the compound of the formula 1 of claim 1, which is 8-succinate (3,5.difluoro-phenyl)bite·2_yl]·6·(Maylin·4· Base)_2·morpholinyl-decene_4_鲷. Μ 2 ^ ¥ 11 ^ 1 compound 'its system 8_[叫吼5·二气phenyl) than each d base (Merlin, base)_2_琳琳基_余4•嗣; or Dan Emirates is acceptable Salt. The compound of the formula 1 (the) (IV) p-difluorobenzene (tetra)-en-4-one. 2 ge morpholinyl)-6 (morpholino-4) carbonyl, hydrazine, or a pharmaceutically acceptable salt thereof . 16. A pharmaceutical preparation 化合物 Compound 2 The pharmaceutically acceptable salt of formula 1 as claimed in claims 1 to 15, and any pharmaceutically acceptable salt 163305.doc 201245186 release or formulation. 17. 18. 19. 20. The compound of any one of items 1 to 15 or a pharmaceutically acceptable salt thereof for use in therapy β 2 as claimed in any one of claims 1 to 15 The use of a hydrazine compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a tumor which is inhibitory to the inhibition of ρι 3 kinase enzyme. The acne derivative of the formula 1 of any one of 1 to 15 or the pharmaceutical salt thereof is used for the prevention or treatment of a tumor which is sensitive to the inhibition of the ΡΙ3·kinase enzyme. A method for treating or preventing a warm-blooded animal having a tumor against PI3-, wherein the inhibitory sensitivity is as described in any one of claims 1 to 15 There are acceptable salts for the administration. Compound or its medicine 163305.doc