compound derived from chromenone or a pharmaceutically acceptable salt thereof that has antitumor ac

专利摘要:
COMPOUND, USE OF A COMPOUND, DERIVED FROM CHROMENONE, AND METHOD FOR THE TREATMENT OR PREVENTION OF A HOT BLOOD ANIMAL HAVING TUMORS THAT ARE SENSITIVE TO THE INHIBITION OF PI3-KINASE ENZYMES. The invention relates to the chromenone derivatives of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R8, n and R9 have any of the defined meanings further up 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 proliferative cell disorders.
公开号:BR112012010124B1
申请号:R112012010124-2
申请日:2010-10-25
公开日:2021-02-17
发明作者:Bernard Christophe Barlaam；Sebastien Louis Degorce；Christine Marie Paul Lambert-Van Der Brempt；Remy Robert Morgentin；Patrick Ple
申请人:Astrazeneca Ab.；
IPC主号:

专利说明:

[0001] [0001] The invention relates to certain new derivatives of chromenone or its pharmaceutically acceptable salts, which have anti-cancer activity and are consequently useful in methods of treating the human or animal body. The invention also relates to processes for the manufacture of said chromenone derivatives, pharmaceutical compositions containing them and their use in therapeutic methods, for example in the manufacture of medicines for use in the prevention or treatment of cancers in a warm-blooded animal such as the human being, including its use in the prevention or treatment of cancer.
[0002] [0002] The present invention also relates to chromenone derivatives which are selective inhibitors of phosphoinositide (PI) 3-kinase β and are, for example, useful for antitumor therapy. In addition, the present invention also relates to the use of chromenone derivatives of the invention which are selective inhibitors of phosphoinositide (PI) 3-kinase β, in antitumor therapy. Inhibitors of PI 3-kinase β can be effective in the treatment of tumors that are deficient in the PTEN gene (phosphatase and tensin homologue deleted on chromosome 10) and this concerns another feature of the invention.
[0003] [0003] In the area of cancer, in recent years, it has been discovered that a cell can become cancerous due to the transformation of a portion of its DNA into an oncogene, that is, a gene that, upon activation, leads to the formation of cells malignant tumor (Bradshaw, Mutagenesis, 1986, 1, 91). Several of such oncogenes give rise to the production of peptides, which are receptors for growth factors. The activation of the growth factor receptor complex subsequently leads to an increase in cell proliferation. It is known, for example, that several oncogenes encode tyrosine kinase enzymes and that certain growth factor receptors are also tyrosine kinase enzymes (Yarden 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 arises from such viral oncogenes, for example pp60v-SRc tyrosine kinase (otherwise known as v-Src) and the corresponding tyrosine kinases in normal cells, for example pp60c-SRc tyrosine kinase (otherwise known as c-Src).
[0004] [0004] Receptor tyrosine kinases are important in the transmission of biochemical signals that initiate cell replication. These are large enzymes that cross the cell membrane and have an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion that functions as a kinase to phosphorylate tyrosine amino acids into proteins and consequently to influence the cell proliferation. Several classes of receptor tyrosine kinases are known (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based on families of growth factors, which bind to different receptor tyrosine kinases. The classification includes Class I receptor tyrosine kinases that comprise the EGF family of receptor tyrosine kinases such as the EGF, TGFα, Neu and erbB receptors.
[0005] [0005] It is also known that certain tyrosine kinases belong to the class of non-receptor tyrosine kinases that are located intracellularly and are involved in the transmission of biochemical signals such as those that influence tumor cell motility, dissemination and invasiveness and subsequently growth metastatic tumor. Several classes of non-receptor tyrosine kinases are known including the Src family such as Src, Lyn, Fyn and Yes tyrosine kinases.
[0006] [0006] Furthermore, it is also known that certain kinases belong to the class of serine / threonine kinases that are located intracellularly and downstream of the activation of tyrosine kinase and are involved in the transmission of biochemical signals such as those of enzymes that phosphorylate the position 3 of the phosphatidylinositol (PI) inositol ring. Three major groups of PI 3-kinase enzymes are known to be classified according to their physiological substrate specificity (Vanhaesebroeck et al., Trends in Biol. Sci., 1997, 22, 267). Class III PI 3-kinase enzymes phosphorylate PI alone. In contrast, PI 3-kinase Class II enzymes phosphorylate both PI and PI 4-phosphate [hereinafter referred to as PI (4) P]. The enzymes of PI 3-kinase Class I phosphorylate PI, PI (4) P and PI 4,5-bisphosphate [hereinafter referred to as PI (4,5) P2], although it is believed that only PI (4,5) P2 is the physiological cell substrate. Phosphorylation of PI (4,5) P2 produces PI 3,4,5-lipid secondary messenger [hereinafter referred to as PI (3,4,5) P3]. The most distantly related members of this superfamily are Class IV kinases such as mTOR and DNA-dependent kinase that phosphorylates serine / threonine residues within protein substrates. The most studied and understood of these lipid kinases are the PI 3 kinase enzymes of Class I.
[0007] [0007] Class I PI 3-kinase is a heterodimer consisting of a p110 catalytic subunit and a regulatory subunit and the family is further divided into Class Ia and Class Ib enzymes based on the regulatory partners and regulatory mechanism . Class Ia enzymes include PI 3-kinase β and consist of three distinct catalytic subunits (p110α, p110β and p110δ) that dimerize with five distinct regulatory subunits (p85α, p55α, p50α, p85β and p55γ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers. Enzymes of PI 3-kinase Class Ia are generally activated in response to stimulation by the receptor tyrosine kinase growth factor, through the interaction of the regulatory subunit SH2 domains with specific phospho-tyrosine residues of the activated receptor or adapter proteins such as as IRS-1. Both p110α and p110β are constitutively expressed in all cell types, whereas p110δ expression is more restricted to leukocyte populations and some epithelial cells. In contrast, the unique Class Ib enzyme consists of a p110γ catalytic subunit that interacts with a p101 regulatory subunit. In addition, Class Ib enzymes are activated in response to G protein-bound receptor systems (GPCR) as well as by the mechanisms described above.
[0008] [0008] There is now considerable evidence indicating that Class Ia PI 3-kinase enzymes, which include PI 3-kinase β, contribute to tumorigenesis in a wide variety of human cancers, directly or indirectly (Vivanco and Sawyers, Nature Reviews Cancer , 2002, 2, 489-501). For example, the p110 subunit is amplified in some tumors such as those of the ovary (Shayesteh et al., Nature Genetics, 1999, 21: 99-102) and cervix (Ma et al., Oncogene, 2000, 19: 2739- 2744). Activating mutations within the p110 catalytic site have been associated with several other tumors such as those in the colorectal region and breast and lung (Samuels et al., Science, 2004, 304, 554). P85α tumor-related mutations have also been identified in cancers such as those of the ovary and colon (Philp et al., Cancer Research, 2001, 61, 7426-7429). In addition to the direct effects, it is believed that the activation of PI 3-kinase Class Ia contributes to tumorigenic events that occur upstream in the signaling pathways, for example through ligand-dependent or ligand-independent activation of receptor tyrosine kinases, systems GPCR or integrins (Vara et al., Cancer Treatment Reviews, 2004, 30, 193-204). Examples of such upstream signaling pathways include overexpression of the Erb2 receptor tyrosine kinase in a variety of tumors leading to the activation of PI 3 kinase-mediated pathways (Harari et al., Oncogene, 2000, 19, 6102-6114) and the overexpression of the Ras oncogene (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). In addition, Class Ia PI 3-kinases may indirectly contribute to tumorigenesis caused by several signaling events downstream. For example, the loss of the effect of tumor suppressor phosphatase PTEN that catalyzes the conversion of PI (3,4,5) P3 back to PI (4,5) P2 is associated with a very wide range of tumors through deregulation the production mediated by PI 3-kinase of PI (3,4,5) P3 (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41). In addition, the increased effects of other signaling events mediated by PI 3- kinase are believed to contribute to a variety of cancers, for example by Akt activation (Nicholson and Anderson, Cellular Signalling, 2002, 14, 381-395 ).
[0009] [0009] In addition to a role in mediating proliferative and survival signaling in tumor cells, there is also good evidence that Class Ia enzymes of PI 3-kinase will also contribute to tumorigenesis through their function in associated stromal cells with tumor. 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. Vasc. Biol., 2004 , 24, 294-300). Since PI 3 kinase Class I enzymes are also involved in motility and migration (Sawyer, Expert Opinion Investig. Drugs, 2004, 13, 1-19), PI 3 kinase inhibitors must provide therapeutic benefit through inhibition of tumor cell invasion and metastasis.
[0010] [00010] Furthermore, PI 3-kinase Class I enzymes play an important role in regulating immune cells with PI 3-kinase activity contributing to pro-tumorigenic effects of inflammatory cells (Coussens and Werb, Nature, 2002, 420 , 860-867).
[0011] [00011] These findings suggest that pharmacological inhibitors of Class I PI 3-kinase enzymes should be of therapeutic value for the treatment of various forms of cancer disease comprising solid tumors such as carcinomas and sarcomas and lymphoid leukemias and malignancies. In particular, Class I PI 3-kinase inhibitors should be of therapeutic value for the treatment, for example, of breast cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchialalveolar cancer) and prostate and bile duct cancer, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva and leukemias (including ALL and CML), multiple myeloma and lymphomas.
[0012] [00012] In general, researchers have explored the physiological and pathological roles of the PI 3-kinase enzyme family using the previously mentioned PI 3-kinase inhibitors LY294002 and vortmanin. Although the use of those compounds may suggest a role for PI 3-kinase in a cellular event, they are not sufficiently selective within the PI 3-kinase family to allow dissection of the individual roles of family members. For this reason, more potent and pharmaceutically selective PI 3-kinase inhibitors would be useful to allow a more complete understanding of the function of PI 3-kinase and to provide therapeutic agents.
[0013] [00013] In addition to the effects of tumorigenesis, there is evidence that Class I PI 3-kinase enzymes play a role in other diseases (Wymann et al., Trends in Pharmacological Science, 2003, 24, 366-376). Both PI 3-kinase Class Ia enzymes and the unique Class Ib enzyme play important roles in immune system cells (Koyasu, Nature Immunology, 2003, 4, 313-319) and thus they are therapeutic targets for inflammatory and inflammatory indications. allergic. Inhibition of PI 3-kinase is also, as described earlier, useful for treating cardiovascular disease through anti-inflammatory effects or directly affecting cardiac myocytes (Prasad et al., Trends in Cardiovascular Medicine, 2003, 13, 206 -212). Inhibition of PI 3-kinase is also useful to treat thrombosis. WO2004016607 provides a method of disrupting platelet aggregation and adhesion that occurs under high shear conditions and a method to inhibit shear-induced platelet activation, where both methods comprise the administration of a PI 3-kinase β inhibitor selective. WO2004016607 also provides an antithrombotic method which comprises administering an effective amount of a selective PI 3 kinase β inhibitor. According to the method, specific thrombosis inhibition can be achieved without affecting normal hemostasis by marking PI 3-kinase β which is important for shear-induced platelet activation. The said antithrombotic method therefore does not involve side effects caused by the breakdown of normal hemostasis, such as prolonged bleeding time.
[0014] [00014] Thus, inhibitors of Class I PI 3 kinase enzymes, including PI 3-kinase β inhibitors, are expected to be of value in the prevention and treatment of a wide variety of diseases in addition to cancer.
[0015] [00015] The compounds, i.e., the chromenone derivatives, of the invention have now surprisingly been found to have potent anti-tumor activity, being useful in inhibiting the uncontrolled cell proliferation that arises from malignant disease. Without wishing to imply that the compounds disclosed in the present invention have pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds provide an anti-tumor effect through inhibition of Class 3 PI 3-kinase enzymes, particularly through inhibition of PI 3-kinase Class Ia enzymes and / or PI 3-kinase Class Ib enzyme, more particularly through inhibition of PI 3-kinase Class Ia enzymes, which include inhibition of PI 3-kinase β.
[0016] [00016] The compounds of the present invention are also useful in inhibiting the uncontrolled cell proliferation that arises from various non-malignant diseases such as inflammatory diseases (for example rheumatoid arthritis and inflammatory bowel disease), fibrotic diseases (for example liver cirrhosis and pulmonary fibrosis ), glomerulonephritis, multiple sclerosis, psoriasis, benign prostatic hypertrophy (BPH), skin hypersensitivity reactions, blood vessel diseases (eg atherosclerosis and restenosis), allergic asthma, insulin-dependent diabetes, diabetic retinopathy and diabetic nephropathy.
[0017] [00017] In general, the compounds of the present invention have potent inhibitory activity against Class Ia PI 3-kinase enzymes, particularly against Class Ia PI 3-kinase enzymes, including against PI 3-kinase β, although they have inhibitory activity less potent against tyrosine kinase enzymes such as receptor tyrosine kinases, for example EGF receptor tyrosine kinase and / or VEGF receptor tyrosine kinase or against non-receptor tyrosine kinases such as Src. In addition, certain compounds of the present invention, have substantially better potency against Class Ia PI 3-kinase enzymes, particularly against Class Ia PI 3-kinase enzymes, including against PI 3-kinase β, than against tyrosine EGF receptor kinase or tyrosine kinase VEGF receptor or tyrosine kinase non-Src receptor. Such compounds have sufficient potency against Class I PI 3-kinase enzymes so that they can be used in an amount sufficient to inhibit Class I PI 3-kinase enzymes, particularly to inhibit Class Ia PI 3-kinase enzymes, including PI 3-kinase β, although they demonstrate little activity against EGF receptor tyrosine kinase or VEGF receptor tyrosine kinase or Src non-receptor tyrosine kinase.
[0018] [00018] According to one aspect of the invention, a chromenone derivative of Formula I is provided
[0019] [00019] In this specification the generic term “alkyl (1-8C)” includes both straight- and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl and also cycloalkyl (3-8C) groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloeptyl and also cycloalkyl (3-6C) alkyl (1-2C) groups such as cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl and 2- cyclohexylethyl. However references to individual alkyl groups such as "propyl" are specific only to the straight chain version, references to individual branched chain alkyl groups such as "isopropyl" are specific only to the branched chain version and references to individual cycloalkyl groups such as "cyclopentyl" are specific only to the 5-membered ring. An analogous conversion applies other generic terms, for example alkoxy (1-6C) includes cycloalkyloxy groups (3-6C) and cycloalkylalkoxy groups having from 4 to 6 carbon atoms, for example methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, 2-cyclopropylethoxy, cyclo-butylmethoxy, 2-cyclobutyloxy and cyclopentylmethoxy; (1-6C) alkylamino includes (3-6C) cycloalkylamino groups and N- (cycloalkylalkyl) -amino groups having from 4 to 6 carbon atoms, for example methylamino, ethylamino, propylamino, cyclopropylamino, cyclobutylamino, cyclohexylamino-, cyclopropylmethyl- amino, 2-cyclopropylethylamino, cyclobutylmethylamino, 2-cyclobutylethylamino and cyclopentylmethylamino; and di- [(1-6C) alkyl] amino includes di- [cycloalkyl (3-6C)] amino groups and di- [cycloalkyl-alkyl] amino groups in which the cycloalkylalkyl moiety has 4 to 6 carbon atoms, for example example dimethylamino, diethylamino, dipropylamino, N-cyclopropyl-N-methylamino, N-cyclobutyl-N-methylamino, N-cyclohexyl-N-ethyl-amino, N-cyclopropylmethyl-N-methylamino, N- (2-cyclopropylethyl) -N -methyl-amino and N-cyclopentylmethyl-N-methylamino.
[0020] [00020] A person skilled in the art will assess that the terms "alkyl (1-6C)", "alkyl (1-4C)", "alkyl (1-3C)" and "alkyl (1-2C)" which are here used refer to any of the alkyl groups defined above which have from 1 to 6, 1 to 4, 1 to 3 and 1 to 2 carbon atoms respectively. The same convention applies to other terms used here, such as, for example, “alkoxy (1-6C)”, “alkoxy (1- 4C)”, “alkoxy (1-3C)” and “alkoxy (1-2C ) ”.
[0021] [00021] For the avoidance of doubt, when, as defined above, the groups R4 and R5 together form a phenyl ring or a 5- or 6-membered heterocyclyl ring or a 5- or 6-membered heteroaryl ring, said ring includes the carbon atoms of the phenyl group of nucleus to which groups R4 and R5 are attached. For example, when the groups R4 and R5 together form a phenyl ring, then the ring system directly linked to the N group (R3) would be a naphthyl ring:
[0022] [00022] Similarly, when, as defined above, the groups R4 and R5 together form a pyridine ring, then the ring system directly linked to the N (R3) group would be a quinolinyl or isoquinolinyl ring.
[0023] [00023] It should be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any one of such form optically active or racemic that has phosphoinositide (PI) 3-kinase inhibitory activity. The synthesis of optically active forms can be performed by standard techniques of organic chemistry well known in the art, for example by synthesizing optically active starting materials or by resolving a racemic form. Similarly, the activity mentioned above can be assessed using standard laboratory techniques.
[0024] [00024] A particular enantiomer of the compounds described herein can be more active than the other enantiomers of the compound. For example, the (+) enantiomer of the title compound of Example 3.06 (i.e., the compound of Example 3.06a, where (+) means the optical rotation measured using the conditions described in Example 3.06a) is the enantiomer having the activity weaker. For the avoidance of doubt, the chiral center in question is the carbon atom to which the methyl and -N (R3) phenyl- (R4) (R5) (R6) (R7) (R8) groups are attached.
[0025] [00025] Consequently, in another aspect of the invention, a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, wherein the chiral center to which the methyl and -N (R3) phenyl (R4) groups ( R5) (R6) (R7) (R8) are linked is in the stereochemical configuration (R). In another aspect of the invention, a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, wherein the chiral center at which the methyl and -N (R3) phenyl (R4) (R5) (R6) groups (R7) (R8) are linked is in the stereochemical configuration (S).
[0026] [00026] According to another aspect of the invention a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, which is a single enantiomer that in an enantiomeric excess (% ee) of ≥ 95, ≥ 98% or ≥ 99%. In one embodiment of this aspect of the invention, the chiral center to which the methyl group and -N (R3) phenyl (R4) (R5) (R6) (R7) (R8) are attached is in the stereochemical (R) configuration. In a further embodiment of this aspect of the invention, the chiral center to which the methyl group and -N (R3) phenyl- (R4) (R5) (R6) (R7) (R8) are attached is in the stereochemical configuration (S ).
[0027] [00027] According to another aspect of the invention there is provided a pharmaceutical composition, which comprises a chromenone derivative of Formula I, which is a single enantiomer that in an enantiomeric excess (% ee) of ≥ 95, ≥ 98% or ≥ 99% or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier. Conveniently, the single enantiomer is present in an enantiomeric excess (% ee) of ≥ 99%. In one embodiment of this aspect of the invention, the chiral center to which the methyl group and -N (R3) phenyl (R4) (R5) (R6) (R7) (R8) are attached is in the stereochemical (R) configuration. In a further embodiment of this aspect of the invention, the chiral center to which the methyl group and -N (R3) phenyl (R4) (R5) (R6) (R7) (R8) are attached is in the stereochemical (S) configuration .
[0028] [00028] Some compounds of Formula (I) may exhibit polymorphism. It should be understood that the present invention encompasses any polymorphic form or mixtures thereof, which form has properties useful in inhibiting the activity of phosphoinositide (PI) 3-kinase, being well known in the art how to determine the effectiveness of a polymorphic form for inhibition phosphoinositide (PI) 3-kinase activity by the standard testicles described below.
[0029] [00029] It is generally known that materials can be analyzed using conventional techniques such as powder X-ray diffraction analysis, differential scanning colorimetry (hereinafter DSC), thermal gravimetric analysis (hereinafter TGA), transform transform spectroscopy Diffuse Reflectance Infrared Fourier (DRIFT), Near Infrared spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.
[0030] [00030] As an example, the compound of Example 3.06b exhibits polymorphism and two crystalline forms have been identified
[0031] [00031] Consequently, another aspect of the invention is Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- chromene-6-carboxamide, where the (-) - in the chemical name means the optical rotation measured using the conditions described in Example 3.06b.
[0032] [00032] Consequently, another aspect of the invention is Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- chromene-6-carboxamide.
[0033] [00033] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least a specific peak of about 2-theta = 7.9o.
[0034] [00034] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least a specific peak of about 2-theta = 16.7o.
[0035] [00035] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks of about 2-theta = 7.9o and 16.7o.
[0036] [00036] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks of about 2-theta = 7.9, 16.7, 20.3, 19.3 , 13.2, 7.2, 19.5, 17.9, 23.0, 5.0o.
[0037] [00037] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in Figure A.
[0038] [00038] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak in 2-theta = 7.9o plus or minus 0.5o 2-theta.
[0039] [00039] In accordance with another aspect of the present invention, a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak on 2-theta = 16.7o plus or minus 0.5o 2-theta.
[0040] [00040] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks in 2-theta = 7.9o and 16.7o where said values can be plus or minus 0.5o 2-theta.
[0041] [00041] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks in 2-theta = 7.9, 16.7, 20.3, 19.3, 13 , 2, 7.2, 19.5, 17.9, 23.0, 5.0o. wherein said values can be plus or minus 0.5o 2-theta.
[0042] [00042] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta = 7.9 °.
[0043] [00043] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta = 16.7o.
[0044] [00044] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks in 2-theta = 7.9o and 16.7o.
[0045] [00045] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks in 2-theta = 7.9, 16.7, 20.3, 19.3, 13 , 2, 7.2, 19.5, 17.9, 23.0, 5.0o.
[0046] [00046] In accordance with another aspect of the present invention, there is provided a crystalline form, Form A of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern as shown in Figure A.
[0047] [00047] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least a specific peak of about 2-theta = 20.7o.
[0048] [00048] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least a specific peak of about 2-theta = 13.8o.
[0049] [00049] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks of about 2-theta = 20.7o and 13.8o.
[0050] [00050] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks of about 2-theta = 20.7, 13.8, 21.5, 19.6 , 12.8, 15.4, 10.7, 8.5, 22.4o.
[0051] [00051] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in Figure C.
[0052] [00052] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak in 2-theta = 20.7o plus or minus 0.5o 2-theta.
[0053] [00053] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak in 2-theta = 13.8o plus or minus 0.5o 2-theta.
[0054] [00054] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks in 2-theta = 20.7o and 13.8o where said values can be plus or minus 0.5o 2-theta.
[0055] [00055] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks in 2-theta = 20.7, 13.8, 21.5, 19.6, 12 , 8, 15.4, 10.7, 8.5, 22.4 o where said values can be plus or minus 0.5o 2-theta.
[0056] [00056] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta = 20.7o.
[0057] [00057] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta = 13.8o.
[0058] [00058] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks in 2-theta = 20.7o and 13.8o.
[0059] [00059] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks in 2-theta = 20.7, 13.8, 21.5, 19.6, 12 , 8, 15.4, 10.7, 8.5, 22.4 °.
[0060] [00060] In accordance with another aspect of the present invention, there is provided a crystalline form, Form B of (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern as shown in Figure C.
[0061] [00061] Another example of a compound that exhibits the polymorphism is the compound of Example 3.13b.
[0062] [00062] Consequently, another aspect of the invention is Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5-trifluorophenylamino) -ethyl) -4H-chromene-6-carboxamide, where the (-) - in the chemical name means the optical rotation measured using the conditions described in Example 3.13b.
[0063] [00063] Consequently, another aspect of the invention is Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5-trifluorophenylamino) -ethyl) -4H-chromene-6-carboxamide.
[0064] [00064] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least a specific peak of about 2-theta = 20.0o.
[0065] [00065] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least a specific peak of about 2-theta = 18.0 °.
[0066] [00066] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks of about 2-theta = 20.0o and 18.0o.
[0067] [00067] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks of about 2-theta = 20.0, 18.0, 14.0, 19.4 , 23.2, 23.8, 10.8, 19.1, 11.2, 27.8o.
[0068] [00068] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in Figure E.
[0069] [00069] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak in 2-theta = 20.0o plus or minus 0.5o 2-theta.
[0070] [00070] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak in 2-theta = 18.0o plus or minus 0.5o 2-theta.
[0071] [00071] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks at 2-theta = 20.0o and 18.0o where said values can be plus or minus 0.5o 2-theta.
[0072] [00072] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks in 2-theta = 20.0, 18.0, 14.0, 19.4, 23 , 2, 23.8, 10.8, 19.1, 11.2, 27.8 ° where said values can be more or less 0.5o 2-theta.
[0073] [00073] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta = 20.0o.
[0074] [00074] According to another aspect of the invention a crystalline form is provided, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta = 18.0o.
[0075] [00075] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks at 2-theta = 20.0o and 18.0o.
[0076] [00076] According to another aspect of the invention a crystalline form is provided, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks in 2-theta = 20.0, 18.0, 14.0, 19.4, 23 , 2, 23.8, 10.8, 19.1, 11.2, 27.8o.
[0077] [00077] According to another aspect of the invention a crystalline form, Form A of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern as shown in Figure E.
[0078] [00078] According to another aspect of the invention a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least a specific peak of about 2-theta = 6.2 °.
[0079] [00079] According to another aspect of the invention, a crystalline form is provided, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least a specific peak of about 2-theta = 7.0o.
[0080] [00080] According to another aspect of the invention a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks of about 2-theta = 6.2o and 7.0o.
[0081] [00081] According to another aspect of the invention a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks of about 2-theta = 6.2, 7.0, 10.3, 22.4 , 15.9, 20.4, 27.2, 12.4, 18.7, 12.8o.
[0082] [00082] According to another aspect of the invention a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has a powder X-ray diffraction pattern substantially the same as the powder X-ray diffraction pattern shown in Figure G.
[0083] [00083] According to another aspect of the invention, a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak in 2-theta = 6.2o plus 0.5o 2-theta.
[0084] [00084] According to another aspect of the invention a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak in 2-theta = 7.0 ° plus or minus 0.5 ° 2-theta .
[0085] [00085] According to another aspect of the invention a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks in 2-theta = 6.2o and 7.0o in which the said values can be plus or minus 0.5o 2-theta.
[0086] [00086] In accordance with another aspect of the invention there is provided a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3, 5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks in 2-theta = 6.2, 7.0, 10.3, 22.4, 15.9, 20.4, 27.2, 12.4, 18.7, 12.8o in which said values can be more or less 0.5o 2-theta.
[0087] [00087] According to another aspect of the invention a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta = 6.2o.
[0088] [00088] According to another aspect of the invention a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least one specific peak at 2-theta = 7.0o.
[0089] [00089] According to another aspect of the invention a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with at least two specific peaks in 2-theta = 6.2o and 7.0o.
[0090] [00090] According to another aspect of the invention, a crystalline form, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern with specific peaks in 2-theta = 6.2, 7.0, 10.3, 22.4, 15 , 9, 20.4, 27.2, 12.4, 18.7, 12.8o.
[0091] [00091] According to another aspect of the invention, a crystalline form is provided, Form B of (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5 -trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide, which has an X-ray powder diffraction pattern as shown in Figure G.
[0092] [00092] It will be understood that 2-theta values of the X-ray diffraction patterns in the powder may vary slightly from one machine to another or from one sample to another and thus the values quoted should not be interpreted as absolute.
[0093] [00093] It is known that an X-ray powder diffraction pattern can be obtained by having one or more measurement errors depending on the measurement conditions (such as equipment or machine used). In particular, it is generally known that the intensities in an X-ray powder diffraction pattern can fluctuate depending on the measurement conditions. Therefore it should be understood that the crystalline Forms of the present invention described above, unless otherwise stated, are not limited to crystals that provide powder X-ray diffraction patterns identical to the powder X-ray diffraction pattern shown in Figures A, CE and G and any crystals that provide X-ray powder diffraction patterns substantially the same as those shown in these Figures fall within the scope of the present invention. A person skilled in the powder X-ray diffraction technique is able to judge the substantial identity of the powder X-ray diffraction patterns.
[0094] [00094] People skilled in the powder X-ray diffraction technique will also find that the relative intensity of the peaks can be affected, for example, by grains over 30 microns in size and non-unitary aspect ratios, which can affect the analysis of the samples. The qualified person will also find that the position of the reflections can be affected by the precise height at which the sample is located on the diffractometer and the zero calibration of the diffractometer. The flatness of the surface of the atmosphere can also have a small effect. Consequently, the diffraction pattern data presented should not be understood as absolute values (see Jenkins, R & Snyder, RL 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons 1996; Bunn, CW (1948), Chemical Crystallography, Clarendon Press, London; Klug, HP & Alexander, LE (1974), X-Ray Diffraction Procedures).
[0095] [00095] In general, an error of measurement of a diffraction angle in an X-ray powder diffractogram is approximately plus or minus 0.5o 2-theta and such a degree of measurement error should be taken into account when considering of the X-ray diffraction data in the powder. In addition, it should be understood that intensities may fluctuate depending on experimental conditions and sample preparation (preferred orientation).
[0096] [00096] The particular compounds of the invention are each of the Examples and their pharmaceutically acceptable salt (s), each of which provides a further independent aspect of the invention.
[0097] [00097] According to another aspect of the invention, a chromenone derivative of Formula I is provided, which is obtainable by following any of the Examples as disclosed herein.
[0098] [00098] Another feature is any of the scopes defined here with the proviso that specific examples, such as Examples 1.00, 2.00, 3.00, 4.00 etc. are individually refused.
[0099] [00099] It should be understood that certain compounds of Formula I defined above can exhibit the phenomenon of tautomerism. It should be understood that the present invention includes in its definition any such tautomeric form or a mixture thereof, which has phosphoinositide (PI) 3-kinase inhibitory activity and should not be limited to any one tautomeric form used within the drawings of the formulas or names in the Examples. In general, only one of any such tautomeric forms is named in the Examples that follow or are presented in any of the drawings of the relevant formulas that follow.
[0100] [000100] The appropriate values for the generic radicals mentioned above include those presented below.
[0101] [000101] A suitable value for the 3- to 8-membered heterocyclyl ring system containing nitrogen formed by Formula I groups R1 and R2 is, for example, a non-aromatic ring containing unsaturated or partially saturated hydrogen of 3 to 8 members, which optionally contains 1 or 2 other heteroatoms selected from oxygen, nitrogen and sulfur, in which a ring sulfur atom is optionally oxidized to form the oxide (s). Suitable examples include azepanyl, oxazepanyl , aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, tetrahydro-1,4-thiazinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, piperidinyl, piperidinyl, homiperiperazin , tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl. In a particular group of compounds, particular examples of the heterocyclyl ring include azepanyl, oxazepanyl, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl and especially azepan-1-yl, 1,4-oxazepan-4-yl, azetidin- 1-yl, pyrrolidine-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl and piperazine-1-yl.
[0102] [000102] A suitable value for the 5- to 6-membered heterocyclyl ring formed by the Formula I groups R4 and R5 is, for example, a 5- or 6-membered unsaturated or partially saturated aromatic ring, containing 1, 2 or 3 heteroatoms selected from oxygen and nitrogen. Suitable examples include tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydrinidine, tetrahydropyridinyl, tetrahydridinyl, tetrahydrinidine, tetrahydropyridinyl, tetrahydridinyl, tetrahydrinidine, tetrahydridinyl, tetrahydrinin, tetrahydridinyl, tetrahydrinin, tetrahydroxylidine, tetrahydrinin, tetrahydridinyl, tetrahydrohydine, tetrahydridine, tetrahydrohydine.
[0103] [000103] A suitable value for the 5- to 6-membered heterocyclyl ring formed by the R4 and R5 groups of Formula I is, for example, a 5- or 6-membered aromatic monocyclic ring with 1, 2 or 3 ring hetero atoms selected from oxygen and nitrogen. Suitable examples include furanoyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl.
[0104] [000104] The appropriate values for any of the 'R' groups (R1 to R9), include, for example: - for fluorine, chlorine, bromine and iodine halogen; for (1-8C) alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, cyclohexylmethyl and 2-cyclopropylethyl; for alkenyl (2-8C): vinyl, isopropenyl, ally and but-2-enyl; for alkynyl (2-8C): ethynyl, 2-propynyl and but-2-inyl; for (1-6C) alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (1-6C) alkyl amino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di - [(1-6C alkyl)] amino: dimethylamino, diethylamino, N-ethyl-Nmethylamino and diisopropylamino; for halogen- (1-6C alkyl): chloromethyl, 2-fluoroethyl, 2-chloroethyl, 1-chloroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3,3- difluoropropyl and 3,3,3-trifluoropropyl; for hydroxy- (1-6C alkyl): hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; and for (1-6C) alkoxy - (1-6C alkyl): methoxymethyl, ethoxymethyl, 1-methoxy-ethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl.
[0105] [000105] A pharmaceutically acceptable salt of a compound of Formula I is, for example, an acid addition salt of a compound of Formula I, for example an acid addition salt with an organic or inorganic acid such as hydrochloric acid, hydrobromic, sulfuric, trifluoroacetic or citrus; or, for example, a salt of a compound of Formula I that is sufficiently acidic, for example an alkali or ferrous alkali metal salt such as a calcium or magnesium salt or an ammonium salt or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholino or tris- (2-hydroxyethyl) -amine. Another suitable pharmaceutically acceptable salt of a compound of Formula I is, for example, a salt formed within a human or animal body after administration of a compound of Formula I.
[0106] [000106] It is further understood that a suitable pharmaceutically acceptable solvent of a compound of Formula I also forms an aspect of the present invention. A suitable pharmaceutically acceptable solvent is, for example, a hydride such as a hemihydride, a monohydride, a dihydride or a trihydride or an alternative amount thereof.
[0107] [000107] It is further understood that a suitable pharmaceutically acceptable prodrug of a compound of Formula I also forms an aspect of the present invention. Consequently, the compounds of the invention can be administered in the form of a prodrug, which is a compound that is decomposed in the human or animal body to make a compound of the invention. A prodrug can be used to alter physical properties and / or pharmacokinetic properties of a compound of the invention. A prodrug can be formed when the compound of the invention contains a suitable group or substituent to which a property modifying group can be attached. Examples of prodrugs include ester derivatives cleavable in vivo that can be formed in a carboxy group or hydroxy group in a compound of Formula I and amide derivatives cleavable in vivo that can be formed in a carboxy group or an amino group in one compound of Formula I.
[0108] [000108] Accordingly, the present invention includes those compounds of Formula I as defined above when made available by organic synthesis and when made available within the human or animal body via the cleavage of a prodrug thereof. Accordingly, the present invention includes those compounds of Formula I that are produced by synthetic organic means and also such compounds that are produced in the human or animal body via the metabolism of a precursor compound, which is a compound of Formula I can be a compound synthetically produced or a metabolically produced compound.
[0109] [000109] A suitable pharmaceutically acceptable prodrug of a compound of Formula I is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
[0110] a) Methods in Enzymology, Vol. 42, p. 309-396, editado por K. Widder, et al. (Academic Press, 1985); b) Design de pro-drugs, editada por H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, editado por Krogsgaard-Larsen e H. Bundgaard, Capítulo 5 “Design and Application of pro-drugs”, pela H. Bundgaard p. 113-191 (1991); 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 e V. Stella, “Pro-drugs como Novel Delivery Systems”, A.C.S. Symposium Séries, Volume 14; e h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987. [000110] Various forms of prodrug have been described, for example in the following documents: - a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) The Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of pro-drugs”, by H. Bundgaard p. 113-191 (1991); 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 (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.
[0111] [000111] A suitable pharmaceutically acceptable prodrug of a compound of Formula I having a carboxy group is, for example, one in an in vivo cleavable ester. An in vivo cleavable ester of a compound of Formula I that contains a carboxy group is, for example, a pharmaceutically acceptable ester that is cleaved in the human or animal body to produce precursor acid. Pharmaceutically acceptable esters for carboxy include (1-6C alkyl) esters such as methyl, ethyl and tert-butyl, (1-6C) methyl alkoxy esters such as methoxymethyl esters, (1-6C) alkyl alkoxy esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C) carbonyloxy (1-6C alkyl) esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as esters methyl-2-oxo-1,3-dioxolen-4-ylmethyl and (1-6C) carbonyloxy (1-6C alkyl) esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.
[0112] [000112] A suitable pharmaceutically acceptable prodrug of a compound of Formula I having a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of Formula I that contains a hydroxy group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the human or animal body to produce the precursor hydroxy compound. The suitable pharmaceutically acceptable ester that forms groups for a hydroxy group includes inorganic esters such as phosphate esters (including cyclic phosphorimidic esters). In addition, the suitable pharmaceutically acceptable ester forming groups for a hydroxy group includes alkanoyl groups (1-10C) such as acetyl, benzoyl, phenylacetyl and suitable benzyl and phenylacetyl groups, alkoxy (1-10C) carbonyl groups such as ethoxycarbonyl , N, N- [di-alkyl (1-4C)] - carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of the ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N, Ndialkylaminomethyl, morpholino-methyl, piperazin-1-ylmethyl and 4-alkyl (1-4C) piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether that forms groups for a hydroxy group includes α-acyloxyalkyl such as acetoxymethyl and pivaloyloxymethyl groups.
[0113] [000113] A suitable pharmaceutically acceptable prodrug of a compound of Formula I having a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, (1-4C) alkyl amine such as methylamine, a di-alkyl (1-4C) amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, an alkoxy (1-4C) alkylamine (2-4C) such as 2-methoxyethylamine, a phenyl -alkyl (1-4C) amine such as benzylamine acid and amino acids such as glycine or an ester thereof.
[0114] [000114] A suitable pharmaceutically acceptable prodrug of a compound of Formula I having an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides of an amino group include, for example, an amide formed with alkanoyl groups (1-10C) such as an appropriate acetyl, benzoyl, phenylacetyl and benzyl and phenylacetyl groups. Examples of the ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N, N-dialkylaminomethyl, morpholino-methyl, piperazin-1-ylmethyl and 4-alkyl (1-4C) piperazin-1-ylmethyl.
[0115] [000115] The in vivo effects of a Formula I compound can be exerted in part by one or more metabolites that are formed within a human or animal body after administration of a Formula I compound. As stated above, the effects in vivo of a compound of Formula I can also be extracted via the metabolism of a precursor compound (a prodrug).
[0116] [000116] For the avoidance of doubt, it should be understood that where in this specification a group is qualified by 'more defined above' or 'defined more above', said group covers the definition that occurs first and the broadest as well as each and all the particular settings for this group.
[0117] [000117] Particular new compounds of the invention include, for example, chromenone derivatives of Formula I or their pharmaceutically acceptable salts, wherein, unless otherwise stated, each R1, R2, R3, R4, R5, R6, R7, R8, n and R9 have any of the meanings defined above or in paragraphs (a) to (ii) below: - (a) R1 is H or (1-4C) alkyl; (b) R1 is H; (c) R1 is (1-4C) alkyl; (d) R1 is methyl or ethyl; (e) R1 is H, methyl or ethyl; (f) R1 is methyl; (g) R2 is alkyl (1-4C) optionally substituted by halogen, hydroxy, alkoxy (1-3C), cyano, alkyl (1-3C) amino or di- [alkyl (1-3C)] amino; (h) R2 is (1-3C) alkyl optionally substituted by halogen, hydroxy, (1-3C) alkoxy or di- [alkyl (1-3C)] amino; (i) R2 is (1-3C) alkyl optionally substituted by halogen, hydroxy, methoxy or N, N-dimethylamino; (j) R2 is methyl, ethyl, propyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, cyclopropylmethyl or 1- (N, N-dimethylamino) -ethyl; (k) R2 is methyl; (l) R1 and R2 are both methyl; (m) R1 and R2 together form a 4- to 7-membered nitrogen-containing heterocyclyl ring system, which optionally contains 1 other heteroatom selected from oxygen, nitrogen and sulfur, in which a sulfur atom in the ring is optionally oxidized to form the oxide (s) S, said ring being optionally substituted by halogen, hydroxy, alkyl (1-3C), alkoxy (1-3C) or hydroxy-alkyl (1-3C); (n) R1 and R2 together form a nitrogen-containing heterocyclyl ring system, selected from azepanyl, oxazepanyl, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl and piperazinyl, said ring being optionally substituted by halogen, hydroxy, alkyl (1 -3C), alkoxy (1-3C) or hydroxy-alkyl (1-3C); (o) R1 and R2 together form a nitrogen-containing heterocyclyl ring system, selected from azepan-1-yl, 1,4-oxazepan-4-yl, azetidin-1-yl, pyrrolidine-1-yl, morpholin- 4-yl, thiomorpholin-4-yl, piperidine-1-yl and piperazine-1-yl, said ring being optionally substituted by halogen, hydroxy, alkyl (1-3C), alkoxy (1-3C) or hydroxy-alkyl (1-3C); (p) R3 is H or methyl; (q) R3 is H; (r) R3 is methyl; (s) R4 and R5 are independently selected from H, halogen, alkyl (1-3C), alkenyl (2-3C), alkynyl (2-3C), alkoxy (1-3C) and cyano; (t) R4 and R5 are independently selected from H, fluorine, chlorine, methyl, ethynyl, methoxy and cyano; (u) R4 and R5 are independently selected from H or halogen; (v) R4 and R5 are independently selected from H, fluorine or chlorine; (w) R6, R7 and R8 are independently selected from H, fluorine, chlorine, methyl, ethynyl, methoxy and cyano; (x) R6, R7 and R8 are independently selected from H or halogen; (y) R6 is H and R7 and R8 are independently selected from H, fluorine or chlorine; (z) and R8 are H and R4, R5 and R7 are halogen; (aa) R6 and R8 are H and R4, R5 and R7 are fluorine; (bb) R4, R6 and R8 are H and R5 and R7 are halogen; (cc) R4, R6 and R8 are H and R5 and R7 are fluorine; (dd) n is 0; (ee) n is 0 or 1; (ff) n is 1; (gg) R9 is methyl or ethyl; (hh) R9 is methyl; or (ii) n is 1 and R9 is a methyl group located at position 2 of the morpholino ring.
[0118] [000118] A particular group of the compounds of the invention are derived from chromenone of Formula I above in which: - R1 is H or (1-4C) alkyl; R2 is alkyl (1-4C) optionally substituted by halogen, hydroxy, alkoxy (1-3C), cyano, alkyl (1-3C) amino or di- [alkyl (1-3C)] amino; or R1 and R2 together form a 4- to 7-membered nitrogen-containing heterocyclyl ring system, which optionally contains 1 other heteroatom selected from oxygen, nitrogen and sulfur, in which a sulfur atom in the ring is optionally oxidized to form the (s ) oxide (s) S, said ring being optionally substituted by halogen, hydroxy, alkyl (1-3C), alkoxy (1-3C) or hydroxy-alkyl (1-3C); R3 is H or methyl; R4 and R5 are independently selected from H, halogen, alkyl (1-3C), alkenyl (2-3C), alkynyl (2-3C), alkoxy (1-3C) and cyano; R6, R7 and R8 are independently selected from H, halogen, alkyl (1-3C), alkenyl (2-3C), alkynyl (2-3C), alkoxy (1-3C) and cyano; n is 0; or a pharmaceutically acceptable salt thereof.
[0119] [000119] Another particular group of the compounds of the invention are derived from chromenone of Formula I above in which: - R1 is H, methyl or ethyl; R2 is alkyl (1-4C) optionally substituted by halogen, hydroxy, alkoxy (1-3C), cyano, alkyl (1-3C) amino or di- [alkyl (1-3C)] amino; or R1 and R2 together form a nitrogen-containing heterocyclyl ring system, selected from azepanyl, oxazepanyl, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl and piperazinyl, said ring being optionally substituted by halogen, hydroxy, alkyl (1-3C) , alkoxy (1-3C) or hydroxyalkyl (1-3C); R3 is H; R4 and R5 are independently selected from H, fluorine or chlorine; R6, R7 and R8 are independently selected from H or halogen; n is 0; or a pharmaceutically acceptable salt thereof.
[0120] [000120] Another particular group of the compounds of the invention are derived from chromenone of Formula I above in which: - R1 and R2 are suitably as defined in any of paragraphs (a) to (g) and (m) to (o) above; R3 is suitably as defined in any of paragraphs (p) to (q) above; R4 and R5 are suitably as defined in any of paragraphs (s), (u) to (v) above and are particularly as defined in any of paragraphs (u) to (v) above; R6, R7 and R8 are suitably as defined in any of paragraphs (x) to (y) above; and n is suitably as defined in paragraph (dd) above.
[0121] [000121] Another particular group of the compounds of the invention are chromenone derivatives of Formula I above or and their pharmaceutically acceptable salt (s), wherein: - R1 and R2 are suitably as defined in any of paragraphs (a) to (o) above, particularly as defined in paragraph (l) above; R3 is suitably as defined in any of paragraphs (p) to (r) above; R4 and R5 are suitably as defined in any of paragraphs (s) to (v) above and are particularly as defined in paragraph (v) above; R6, R7 and R8 are suitably as defined in any of paragraphs (w) to (cc) above and are particularly as defined in any of paragraphs (z) to (cc) above; and n and R9 are suitably as defined in any of paragraphs (dd) to (ii) above.
[0122] [000122] Another particular group of the compounds of the invention are derived from chromenone of Formula I above in which: - R1 is H, methyl or ethyl; R2 is methyl, ethyl, cyclopropylmethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl or 2- (dimethylamino) ethyl; or R1 and R2 together form a heterocyclyl ring system containing optionally substituted nitrogen, selected from azepan-1-yl, 1,4-oxazepan-4-yl, azetidin-1-yl, 3-fluoroazetidin-1-yl, 3 -hydroxy-azetidin-1-yl, pyrrolidin-1-yl, (2R) -2- (hydroxymethyl) pyrrolidin-1-yl, (2S) -2- (hydroxymethyl) pyrrolidin-1-yl, morpholin-4-yl , thiomorpholin-4-yl, piperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-methoxypiperidin-1-yl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is H or methyl; R4 and R5 are independently selected from H, fluorine or chlorine; R6, R7 and R8 are independently selected from H, fluorine or chlorine; n is 0; or a pharmaceutically acceptable salt thereof.
[0123] [000123] Another particular group of the compounds of the invention are derived from chromenone of Formula I above in which: - R1 is methyl; R2 is methyl; or R1 and R2 together form a pyrrolidin-1-yl ring; R3 is H; R4 and R5 are independently selected from H or fluorine; R6 is H; R7 and R8 are independently selected from H, fluorine or chlorine; n is 0; or a pharmaceutically acceptable salt of the same
[0124] [000124] A particular group of the compounds of the invention are derived from chromenone of Formula I above in which: - R1 is H or (1-4C) alkyl; R2 is alkyl (1-4C) optionally substituted by halogen, hydroxy, alkoxy (1-3C), cyano, alkyl (1-3C) amino or di- [alkyl (1-3C)] amino; or R1 and R2 together form a 4- to 7-membered nitrogen-containing heterocyclyl ring system, which optionally contains 1 other heteroatom selected from oxygen, nitrogen and sulfur, in which a sulfur atom in the ring is optionally oxidized to form the (s ) oxide (s) S, said ring being optionally substituted by halogen, hydroxy, alkyl (1-3C), alkoxy (1-3C) or hydroxy-alkyl (1-3C); R3 is H or methyl; R4 and R5 are independently selected from H, halogen, alkyl (1-3C), alkenyl (2-3C), alkynyl (2-3C), alkoxy (1-3C) and cyano; R6, R7 and R8 are independently selected from H, halogen, alkyl (1-3C), alkenyl (2-3C), alkynyl (2-3C), alkoxy (1-3C) and cyano; n is 0 or 1; each R9 group is methyl; or a pharmaceutically acceptable salt thereof.
[0125] [000125] A particular group of the compounds of the invention are derived from chromenone of Formula I above in which: - R1 is methyl; R2 is methyl or (2-hydroxy) ethyl; or R1 and R2 together form a heterocyclyl ring system containing 6-membered nitrogen, said ring system being optionally substituted by hydroxy; R3 is H or methyl; R4 and R5 are independently selected from H or halogen; R6, R7 and R8 are independently selected from H or halogen; n is 1; R9 is a methyl group located at position 2 of the morpholino ring; or a pharmaceutically acceptable salt thereof.
[0126] [000126] Another particular group of the compounds of the invention are derived from chromenone of Formula I above in which: - R1 is H, methyl or ethyl; R2 is alkyl (1-3C) optionally substituted by halogen, hydroxy, alkoxy (1-3C), cyano, alkyl (1-3C) amino or di- [alkyl (1-3C)] amino; or R1 and R2 together form a nitrogen-containing heterocyclyl ring system, selected from azepanyl, oxazepanyl, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl and piperazinyl, said ring being optionally substituted by halogen, hydroxy, alkyl (1-3C) , alkoxy (1-3C) or hydroxyalkyl (1-3C); R3 is H; R4 and R5 are independently selected from H, halogen, alkyl (1-3C), alkenyl (2-3C), alkynyl (2-3C), alkoxy (1-3C) and cyano; R6, R7 and R8 are independently selected from H, halogen, alkyl (1-3C), alkenyl (2-3C), alkynyl (2-3C), alkoxy (1-3C) and cyano; n is 0 or 1; each group R9 is alkyl (1-3C); or a pharmaceutically acceptable salt thereof.
[0127] [000127] Another particular group of the compounds of the invention are derived from chromenone of Formula I above in which: - R1 is H, methyl or ethyl; R2 is methyl, ethyl, cyclopropylmethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl or 2- (dimethylamino) ethyl; or R1 and R2 together form a heterocyclyl ring system containing optionally substituted nitrogen, selected from azepan-1-yl, 1,4-oxazepan-4-yl, azetidin-1-yl, 3-fluoroazetidin-1-yl, 3 -hydroxyazetidin -1-yl, pyrrolidin-1-yl, (2R) -2- (hydroxymethyl) pyrrolidin-1-yl, (2S) -2- (hydroxymethyl) pyrrolidin-1-yl, morfolin-4-yl, thiomorpholin -4-yl, piperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-methoxypiperidin-1-yl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is H or methyl; R4 and R5 are independently selected from H, fluorine, chlorine, methyl, ethynyl, methoxy and cyano; R6, R7 and R8 are independently selected from H, fluorine, chlorine, methyl, ethynyl, methoxy and cyano; n is 0 or 1; R9 is methyl; or a pharmaceutically acceptable salt thereof.
[0128] [000128] Another particular group of the compounds of the invention are derived from chromenone of Formula I above in which: - R1 is methyl; R2 is methyl; R3 is H or methyl; R4 and R5 are independently selected from H or fluorine; R6 is H; R7 and R8 are independently selected from H or fluorine; n is 0; or a pharmaceutically acceptable salt of the same
[0129] [000129] Particular compounds of the invention are, for example, the chromenone derivatives of Formula I which are disclosed within the Examples which are presented below.
[0130] [000130] For example, a particular compound of the invention is a chromenone derivative of Formula I selected from any of the following: - N- (2- (dimethylamino) ethyl) -8- (1- (4-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide; N- (2- (dimethylamino) ethyl) -8- (1- (3-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide; N- (2- (dimethylamino) ethyl) -2-morpholino-4-oxo-8- (1- (phenylamino) ethyl) -4H-chromene-6-carboxamide; 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -N- (2- (dimethylamino) ethyl) - 2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (4-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; N- (2- (dimethylamino) ethyl) -8- (1- (4-fluorophenylamino) ethyl) -N-methyl2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3-chloro-4-fluorophenylamino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8- (1- (3-chloro-4-fluorophenylamino) ethyl) -N- (2-hydroxyethyl) -Nomethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -N- (2-hydroxyethyl) -Nomethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -6- (morpholino-4-carbonyl) -2-morpholino-4H-chromen-4-one; N- (2- (dimethylamino) ethyl) -8- (1 - ((4-fluorophenyl) (methyl) amino) ethyl) - 2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1 - ((3,4-difluorophenyl) (methyl) amino) ethyl) -N- (2- (dimethylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide; N- (2- (dimethylamino) ethyl) -8- (1 - ((4-fluorophenyl) (methyl) amino) ethyl) - N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,4-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino4-oxo-4H-chromene-6-carboxamide; 8- (1- (3-chloro-4-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1 - ((4-fluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1 - (((3-chloro-4-fluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3-chlorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (2,3-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; N, N-dimethyl-2-morpholino-4-oxo-8- (1- (3,4,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide; 8- (1- (3-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-diethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-6- (pyrrolidine-1-carbonyl) -4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -6- (4-methylpiperazine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-6- (piperazine-1-carbonyl) -4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-6- (thiomorfoline4-carbonyl) -4H-chromen-4-one; 6- (azepano-1-carbonyl) -8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 6- (azetidine-1-carbonyl) -8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-6- (piperidino-1-carbonyl) -4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -N-ethyl-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -6- (3-hydroxyazetidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -6- (3-fluoroazetidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -N- (2-hydroxyethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -N- (2-methoxyethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4-oxo-N-propyl4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -N-ethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -N- (2-fluoroethyl) -2-morpholino4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -N- (3-methoxypropyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -6 - ((R) -2- (hydroxymethyl) pyrrolidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -6 - ((S) -2- (hydroxymethyl) pyrrolidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; N- (cyclopropylmethyl) -8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -N- (2-methoxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-6- (1,4-oxazepan-4-carbonyl) -4H-chromen-4-one; and 8- (1- (3,5-difluorophenylamino) ethyl) -6- (4-methoxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; or a pharmaceutically acceptable salt thereof.
[0131] [000131] According to another aspect of the invention, a particular compound of the invention is a chromenone derivative of Formula I selected from any of the following: - 8- (1- (4-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1- (4-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1S) -1- (4-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide, 8- (1- (3,4-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1- (3,4-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1S) -1- (3,4-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1S) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide; N, N-dimethyl-2-morpholino-4-oxo-8 - ((1R) -1- (2,3,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide; N, N-dimethyl-2-morpholino-4-oxo-8 - ((1S) -1- (2,3,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide; 8- (1- (3-chloro-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1- (3-chloro-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1S) -1- (3-chloro-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -Nmethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6 -carboxamide; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6 -carboxamide; 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((R) -2-methyl-morpholine) -4-oxo-4H-chromene-6-carboxamide ; 8 - ((1S) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((R) -2-methyl-morpholino) -4-oxo-4H-chromene-6-carboxamide ; 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -2-methyl-morpholine) -4-oxo-4H-chromene-6-carboxamide ; 8 - ((1S) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -2-methyl-morpholino) -4-oxo-4H-chromene-6-carboxamide ; 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2 - ((R) - 2-methyl-morpholino) -4-oxo-4H-chromene-6 -carboxamide; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2- ((R) -2-methylmorpholine) -4-oxo-4H-chromene -6-carboxamide; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2- ((R) -2-methylmorpholine) -4-oxo-4H-chromene -6-carboxamide; 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -Nmethyl-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene -6-carboxamide; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2 - ((R) -2-methylmorpholine) -4 -oxo-4H-chromene-6-carboxamide; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2 - ((R) -2-methylmorpholine) -4 -oxo-4H-chromene-6-carboxamide; 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2 - ((R) -2-methylmorpholine) -4H-chromen-4 -one; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2 - ((R) -2-methylmorpholine) -4H -chromen-4-one; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2 - ((R) -2-methylmorpholine) -4H -chromen-4-one; 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -3-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -3-methyl-morpholine) -4-oxo-4H-chromene-6-carboxamide ; and 8 - ((1S) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -3-methyl-morpholine) -4-oxo-4H-chromene-6-carboxamide ; or a pharmaceutically acceptable salt thereof.
[0132] [000132] According to yet another aspect of the invention, a particular compound of the invention is a chromenone derivative of Formula I selected from any of the following: - 8 - ((1R) -1- (4-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1- (3,4-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; N, N-dimethyl-2-morpholino-4-oxo-8 - ((1R) -1- (2,3,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide; 8 - ((1R) -1- (3-chloro-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6 -carboxamide; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8 - ((1R) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((R) -2-methyl-morpholine) -4-oxo-4H-chromene-6-carboxamide ; 8 - ((1R) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -2-methyl-morpholine) -4-oxo-4H-chromene-6-carboxamide ; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2- ((R) -2-methylmorpholine) -4-oxo-4H-chromene -6-carboxamide; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2 - ((R) -2-methylmorpholine) -4 -oxo-4H-chromene-6-carboxamide; 8 - ((1R) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2 - ((R) -2-methylmorpholine) -4H -chromen-4-one; and 8 - ((1R) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -3-methyl-morpholine) -4-oxo-4H-chromene-6-carboxamide ; or a pharmaceutically acceptable salt thereof.
[0133] [000133] Still according to another aspect of the invention, a particular compound of the invention is a chromenone derivative of Formula I selected from any of the following: - 8 - ((1S) -1- (4-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1S) -1- (3,4-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1S) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; N, N-dimethyl-2-morpholino-4-oxo-8 - ((1S) -1- (2,3,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide; 8 - ((1S) -1- (3-chloro-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6 -carboxamide; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one; 8 - ((1S) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((R) -2-methyl-morpholino) -4-oxo-4H-chromene-6-carboxamide ; 8 - ((1S) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -2-methyl-morpholino) -4-oxo-4H-chromene-6-carboxamide ; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2- ((R) -2-methylmorpholine) -4-oxo-4H-chromene -6-carboxamide; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2 - ((R) -2-methylmorpholine) -4 -oxo-4H-chromene-6-carboxamide; 8 - ((1S) -1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2 - ((R) -2-methylmorpholine) -4H -chromen-4-one; and 8 - ((1S) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -3-methyl-morpholine) -4-oxo-4H-chromene-6-carboxamide ; or a pharmaceutically acceptable salt thereof.
[0134] [000134] According to another aspect of the invention, a particular compound of the invention is the compound of Example 3.06b; or a pharmaceutically acceptable salt thereof.
[0135] [000135] According to another aspect of the invention, a particular compound of the invention is (-) - 8- (1- (3,5-difluorophenylamino) ethyl) - N, N-dimethyl -2-morpholino-4-oxo -4H-chromene-6-carboxamide; or a pharmaceutically acceptable salt thereof, where the (-) - in the chemical name means the optical rotation measured using the conditions described in Example 3.06b.
[0136] [000136] According to another aspect of the invention, a particular compound of the invention is 8 - ((1R) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo -4H-chromene-6-carboxamide; or a pharmaceutically acceptable salt thereof.
[0137] [000137] According to another aspect of the invention, a particular compound of the invention is 8 - ((1S) -1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo -4H-chromene-6-carboxamide; or a pharmaceutically acceptable salt thereof.
[0138] [000138] According to another aspect of the invention, a particular compound of the invention is the compound of Example 3.13b; or a pharmaceutically acceptable salt thereof.
[0139] [000139] According to another aspect of the invention, a particular compound of the invention is (-) - N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide; or a pharmaceutically acceptable salt thereof, where the (-) - in the chemical name means the optical rotation measured using the conditions described in Example 3.13b.
[0140] [000140] According to another aspect of the invention, a particular compound of the invention is N, N-dimethyl-2-morpholino-4-oxo-8- ((1R) -1- (2,3,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide; or a pharmaceutically acceptable salt thereof.
[0141] [000141] According to another aspect of the invention, a particular compound of the invention is N, N-dimethyl-2-morpholino-4-oxo-8- ((1S) -1- (2,3,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide; or a pharmaceutically acceptable salt thereof.
[0142] [000142] Another aspect of the present invention provides a process for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof. A suitable process is illustrated by the following representative process variants in which, unless otherwise stated, R1, R2, R3, R4, R5, R6, R7, R8, n and R9 have any of the meanings defined above. The necessary starting materials can be obtained by standard organic chemistry procedures. The preparation of such starting materials is described in conjunction with the following representative process variants and within the attached Examples. Alternatively, the necessary starting materials are obtainable by procedures analogous to those illustrated which are within the ordinary skill of an organic chemist.
[0143] [000143] Suitable process variants include, for example, the following: - (a) The reaction, conveniently in the presence of a suitable activating reagent, of a compound of Formula II
[0144] [000144] An activating reagent suitable for the reaction includes, for example, a Lewis acid such as tin (IV) tetrachloride, aluminum (III) tetrachloride or titanium (IV) tetrachloride.
[0145] [000145] Conveniently, the suitable catalyst is titanium (IV) tetrachloride.
[0146] [000146] Conveniently, the reaction is conducted in the presence of a suitable base such as an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine or N-methyl morpholine.
[0147] [000147] Conveniently, the suitable base is triethylamine.
[0148] [000148] The reaction is conveniently carried out in the presence of a suitable solvent or diluent such as, for example, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, halogenated solvents such such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example from -50 ° C to 100 ° C, preferably in the range 0 ° C to 30 ° C.
[0149] [000149] A suitable reducing reagent is a metal borohydride such as, for example, sodium cyanotrihydroborate. The reduction reaction is conveniently carried out in the presence of a suitable solvent or diluent, such as for example an alcohol such as methanol or ethanol or a mixture of solvents that contain alcohols, generally in the presence of a weak acid such as acetic acid. The reaction is conveniently carried out at a temperature in the range, for example, 0 ° C to 30 ° C.
[0150] [000150] Formula II compounds can be, for example, prepared by a cross-linking reaction of a Formula V compound:
[0151] [000151] The reaction is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethyl-aminopyridine, triethylamine, N-methylmorpholine, diazabicyclo- [5,4,0] undec-7-ene, diisopropylethylamine or, for example, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate or calcium carbonate.
[0152] [000152] The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent such as, for example, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol ethanol, halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example from -50 ° C to 100 ° C, preferably in the range of 0 ° C to 30 ° C.
[0153] [000153] The compounds of Formula III can be obtained by conventional procedures or are commercially available, known in the literature or they can be prepared standard processes known in the art.
[0154] [000154] The compounds of Formula V can be obtained by procedures analogous to those described in Example 1.00 here, where the method for preparing the starting material 8-acetyl-N- (2- (dimethylamino) -ethyl) -2 -morpholino-4-oxo-4H-chromene-6-carboxamide is given. In particular, the compounds of Formulas V can be obtained by the procedures according to the following scheme:
[0155] [000155] For example, compounds of Formula V can be prepared by reacting a compound of Formula VII:
[0156] [000156] A suitable catalyst for the reaction includes, for example, a metallic catalyst such as palladium (0), palladium (II) for example tetracis (triphenylphosphine) palladium (0), palladium (II) chloride, palladium bromide (II), bis (triphenylphosphino) palladium (II) chloride, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tris (dibenzylidene acetone) dipaladium. Optionally, the catalyst can be formed in situ by reacting one or more of the above catalysts with a trialkylphosphine, such as, for example, tri-N-butylphosphine or tricyclohexylphosphine.
[0157] [000157] The reaction is conveniently carried out in the presence of a suitable solvent or diluent such as, for example, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene and at a temperature in the range, for example from 20 ° C to 150 ° C, preferably in the range of 60 ° C to 120 ° C.
[0158] [000158] Formula VII compounds, for example, can be prepared by reacting a Formula VIII compound:
[0159] [000159] The reaction of the compounds of Formula VIII with that of Formula IX is conveniently carried out in the presence of a suitable solvent or diluent such as, for example, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane , benzene, toluene, xylene, halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example 20 ° C to 150 ° C, preferably in the range 60 ° C to 120 ° C.
[0160] [000160] The saponification reaction can be reduced for example by treatment with an alkali or alkaline earth metal hydroxide such as lithium, potassium or sodium hydroxide in a suitable solvent such as, for example, methanol or a mixture of ethanol and water or a water-miscible solvent, such as for example tetrahydrofuran or dioxane, at a temperature in the range, for example from 0 ° C to -100 ° C, preferably in the range of 20 to 40 ° C.
[0161] [000161] The compounds of Formula VIII have been described in the literature (Ger. Offen, DE 4318756, 1994 and Aust. J. Chem. 2003, 56, 1099) or they can be prepared by standard procedures known in the art.
[0162] [000162] The compounds of Formula VIIIa can alternatively be obtained by the procedures according to the following scheme, which was described in more detail in Example 1.00 here, where the method for preparing 8-bromo-2-morpholino-4- methyl oxo-4H-chromene-6-carboxylate using such a method is provided:
[0163] [000163] For example, Formula VIIIa compounds can be prepared by reacting a Formula VIII compound:
[0164] [000164] The reaction of the compounds of Formula VIII with that of Formula IXa is conveniently carried out in the presence of a suitable solvent or diluent such as, for example, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene or xylene and at a temperature in the range, for example from -100 ° C to temperature, preferably in the range of -80 ° C to 20 ° C.
[0165] [000165] The ring closing reaction to convert a compound of Formula VIIIb into a compound of Formula VIIIa can be conducted for example by treatment with a dehydrating agent, such as for example trifluoromethanesulfonic anhydride, in a suitable solvent such as for example dichloroethane at a temperature in the range, for example from 0 ° C to -100 ° C, conveniently in the range of 20 to 60 ° C.
[0166] [000166] Alternatively, the Compound of Formula VIIIa can be prepared according to the following scheme, which was described in more detail in Example 9.0 here, which describes the preparation of 8-bromo-2 - ((R) -2 -methylmorpholine) -4-oxo-4H-chromene-6-carboxylate:
[0167] [000167] Alternatively, compounds of Formula II can, for example, be prepared by reacting a compound of Formula XVI:
[0168] [000168] A catalyst suitable for the Stille reaction includes, for example, a metal catalyst such as palladium (0), palladium (II) for example tetracis (triphenylphosphino) palladium (0), palladium (II) chloride, bromide palladium (II), bis (triphenylphosphino) palladium (II) chloride, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tris (dibenzylidene acetone) -dipaladium. Optionally, the catalyst can be formed in situ by reacting one or more of the above catalysts with a trialkylphosphine, such as, for example, tri-N-butylphosphine or tricyclohexylphosphine.
[0169] [000169] The reaction is conveniently carried out in the presence of a suitable solvent or diluent such as, for example, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene in the range, for example from 20 ° C to 150 ° C, conveniently in the range of 60 ° C to 120 ° C.
[0170] [000170] Alternatively, compounds of Formula II can, for example, be prepared by reacting a compound of Formula XVI:
[0171] [000171] A catalyst suitable for the Heck reaction includes, for example, a metal catalyst such as palladium (0), palladium (II) for example tetracis (triphenylphosphino) palladium (0), palladium (II) chloride, bromide palladium (II), bis (triphenylphosphino) palladium (II) chloride, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tris (dibenzylidene acetone) -dipaladium; Optionally, the catalyst can be formed in situ by reacting one or more of the above catalysts with a trialkylphosphine, such as, for example, tri-N-butylphosphine or tricyclohexylphosphine.
[0172] [000172] Conveniently, the catalyst is palladium (II) acetate in the presence of bis (1,3-diphenylphosphino) propane.
[0173] [000173] The reaction is conveniently carried out in the presence of a suitable solvent or diluent such as, for example, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene or alcohols and a temperature in the range, for example from 20 ° C to 150 ° C. Conveniently ethylene glycol is used and the reaction is conducted at a temperature between 90 to 130 ° C.
[0174] [000174] An example of a process scheme that can be used for the synthesis of a compound of Formula XVI, such as for example 8-bromo-N, N-dimethyl-2- (morpholin-4-yl) -4- oxo-4H-chromene-6-carboxamide, is as follows:
[0175] [000175] The reaction is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethyl-aminopyridine, triethylamine, N-methylmorpholine, diazabicyclo- [5,4,0] undec-7-ene, diisopropylethylamine or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
[0176] [000176] The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent such as, for example, N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol, ethanol, halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example from -50 ° C to 100 ° C, preferably in the range 0 ° C to 30 ° C .
[0177] [000177] Formula X compounds can be, for example, prepared by a saponification reaction, of a Formula Xa compound:
[0178] [000178] The saponification reaction can be reduced for example by treating a compound of Formula Xa with an alkali or alkaline earth metal hydroxide such as lithium, potassium or sodium hydroxide in a suitable solvent such as for example an ethanol mixture and water or a water-miscible solvent, such as for example tetrahydrofuran or dioxane, at a temperature in the range, for example from 0 ° C to -100 ° C, preferably in the range of 20 to 40 ° C.
[0179] [000179] The compounds of Formula Xa can, for example, be prepared by the reaction, conveniently in the presence of a suitable catalyst as defined above, of a compound of Formula XI:
[0180] [000180] A suitable displaceable group L is, for example, a halogen group such as a chlorine, bromine, iodine, trifluoromethanesulfonyl or methanesulfonyl group. Conveniently, the displaceable group L is bromine.
[0181] [000181] The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent such as, for example, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol ethanol, halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example from -50 ° C to 100 ° C, preferably in the range 0 ° C to 30 ° C.
[0182] [000182] The compounds of Formulas XI can be obtained by procedures analogous to those described in Example 2.00 here, where the method for preparing the starting material is 8- (1- (3-chloro-2-fluorophenylamino) ethyl) acid ) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid is given. In particular, the compounds of Formulas XI can be obtained by the procedures according to the following scheme:
[0183] [000183] For example, Formula XI compounds can be prepared by reacting a Formula XII compound:
[0184] [000184] The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent such as, for example, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, halogenated solvents such as DCM, chloroform or carbon tetrachloride and at a temperature in the range, for example from -50 ° C to 100 ° C, preferably in the range of 0 ° C to 30 ° C.
[0185] [000185] Formula XII compounds can, for example, be prepared by reacting a Formula XIII compound:
[0186] [000186] The reaction is conveniently carried out in the presence of a suitable solvent or diluent such as for example alcohols (methanol, ethanol) or a mixture of solvents containing alcohols and at a temperature in the range, for example from -50 ° C to 50 ° C ° C, preferably in the range 0 ° C to 20 ° C.
[0187] [000187] The compounds of Formula XIII can be obtained by linking the compounds of Formula VIIIa with a suitable stanane such as, for example, tributyl (1-ethoxyvinyl) stanane under typical Stille conditions using conditions reported in process variants (a) . Alternatively, compounds of Formula XIII can be obtained by linking the compounds of Formula VIIIa with a suitable alkene such as, for example, (1-vinyloxy) butane under Heck-type conditions (see conditions reported in process variants (a)). (c) The reaction, conveniently in the presence of a suitable catalyst as defined above in process variant (b) above, of a compound of Formula XIV:
[0188] [000188] A suitable displaceable group L is, for example, a halogen group such as a chlorine, bromine, iodine group, a methanesulfonyl group or a trifluoromethanesulfonyl group. Conveniently, the displaceable group L is bromine.
[0189] [000189] The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent such as, for example, N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy ethane, benzene , toluene, xylene, methanol, ethanol, halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example from -50 ° C to 100 ° C, preferably in the range of 0 ° C to 50 ° C Conveniently, the suitable inert solvent is N, Ndimethylformamide.
[0190] [000190] The compounds of Formula XIV can, for example, be prepared by the reaction, conveniently in the presence of a suitable catalyst as defined above, of a compound of Formula XV:
[0191] [000191] The compounds of Formula XV can be, for example, prepared by a cross-linking reaction, conveniently in the presence of a suitable catalyst as defined above in the variant of process (b) above, of a compound of Formula XVa:
[0192] [000192] The reaction is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethyl-aminopyridine, triethylamine, N-methylmorpholine, diazabicyclo- [5,4,0] undec-7-ene, diisopropylethylamine or, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.
[0193] [000193] The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent such as, for example, N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, methanol, ethanol, halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example from -50 ° C to 100 ° C, preferably in the range of 0 ° C to 30 ° C .
[0194] [000194] Formula XVa compounds can be, for example, prepared by a saponification reaction, of a Formula XII compound:
[0195] [000195] The saponification reaction can be reduced for example by treating a compound of Formula XII with an alkali or alkaline earth metal hydroxide such as lithium, potassium or sodium hydroxide in a suitable solvent such as for example methanol or a mixture of ethanol and water or a water-miscible solvent, such as for example tetrahydrofuran or dioxane, at a temperature in the range, for example from 0 ° C to -100 ° C, preferably in the range of 20 to 40 ° C.
[0196] [000196] Alternatively, compounds of Formula XV can be, for example, prepared by a reduction reaction of a compound of Formula II, where a suitable reducing reagent is used, such as for example a metal borohydride such as for example borohydride sodium. The reaction is conveniently carried out in the presence of a suitable solvent or diluent, such as for example an alcohol such as methanol or ethanol or a mixture of solvents containing alcohols, generally in the presence of a weak acid such as acetic acid. The reaction is conveniently carried out at a temperature in the range, for example, 0 ° C to 30 ° C. (d) The reaction of a compound of Formula XVII:
[0197] [000197] Suitable reactions of this type are described as Buchwald reactions of palladium binding in 'Metal-Catalyzed Cross-Reactions Coupling', Second Edition, Edited by Armin Meijere, François Diederich, Wiley-VCH, 2004, Volume 1, p699).
[0198] [000198] Alternatively, compounds of Formula I can be prepared by reactions of the type of Chan-Lam bond, in which a compound of Formula XVII is reacted with a compound of Formula IIIb:
[0199] [000199] Formula XVII compounds can, for example, be prepared by a reductive amination reaction of a Formula II compound:
[0200] [000200] Where the compound of Formula I is a single optically active enantiomer (chiral center being the carbon atom to which the methyl group and -N-phenyl (R4) (R5) (R6) (R7) (R8) are attached ), procedures analogous to those outlined in the following scheme can be used to prepare the compounds of Formula XVII (for more details on a particular example of this, see Example 8.00 here):
[0201] [000201] For example, a single optically active enantiomer of Formula XVII can, can be prepared by reacting a compound of Formula II with a chiral equivalent of R3NH2 such as a chiral sulfonamide eg (R) -2-methylpropane- 2- sulfinamide, to give a corresponding imine. This reaction is conveniently carried out in the presence of a Lewis acid such as titanium (IV) tetraethoxide. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent such as, for example, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, halogenated solvents such as dichloromethane , chloroform or carbon tetrachloride and at a temperature in the range, for example from -50 ° C to 100 ° C, preferably in the range of 0 ° C to 30 ° C.
[0202] [000202] The reduction of the corresponding imine is then carried out using a reducing agent such as a borohydride, for example, sodium cyanoborohydride, hereinafter any protecting group that is present is removed. The reaction is conveniently carried out in the presence of a weak acid. A suitable weak acid is, for example, acetic acid. The reaction is conveniently carried out in the presence of an alcohol such as methanol or ethanol or a mixture of an alcohol and a suitable inert solvent or diluent such as, for example, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, 1,2 -dimethoxyethane, benzene, toluene, xylene, halogenated solvents such as dichloromethane, chloroform or carbon tetrachloride and at a temperature in the range, for example from -50 ° C to 20 ° C, preferably around -15 ° C
[0203] [000203] It should be understood that other changes in the process steps in the process variants described above are also possible. For example, a Compound of Formula I can be prepared using procedures analogous to those described in process variants (a) to (d), but in which the final step in the procedure is the introduction of the morpholino- (R9) group n.
[0204] [000204] It is to be understood that any compound of Formula I obtained by any of the processes described above can be converted into another compound of Formula I if required. For example, a compound of Formula I in which R3 is H can be converted to a compound of Formula I in which R3 is alkyl (1-3C) by alkylation with an alkylating agent. For example, where R3 is methyl, a suitable alkylating agent such as dimethyl sulfate or methyl iodide can be used. The reaction can be carried out in the presence of a strong base, such as for example sodium bis (trimethylsilyl) amide optionally in the presence of a suitable crown ether (for example 1,4,7,10,13-pentaoxacyclopentadecane, also known as 15 -crown-5 for sodium) at low temperature (-78 ° C to 0 ° C) in an inert solvent such as for example THF.
[0205] [000205] When a pharmaceutically suitable salt of a chromenone derivative of Formula I is required, for example an acid addition salt, it can be obtained, for example, by reacting said chromenone derivative with a suitable acid.
[0206] [000206] When a pharmaceutically acceptable prodrug of a chromenone derivative of Formula I is required, it can be obtained using a conventional procedure. For example, an in vivo cleavable ester of a Formula I chromenone derivative can be obtained, for example, by reacting a Formula I compound containing a carboxy group with a pharmaceutically acceptable alcohol or by reacting a Formula I compound which contains a hydroxy group with a pharmaceutically acceptable carboxylic acid. For example, an in vivo cleavable amide of a Formula I chromenone derivative can be obtained, for example, by reacting a Formula I compound containing a carboxy group with a pharmaceutically acceptable amine or by reacting a Formula I compound that contains an amino group with a pharmaceutically acceptable carboxylic acid.
[0207] [000207] It should also be assessed by the person skilled in the techniques of organic synthesis that certain of the ring substituents in the compounds of the present invention can be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications before or immediately following the processes mentioned above and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents, acylation of substituents, amidation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminum trichloride) under Friedel conditions Crafts; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of the modifications include the reduction of a nitro group to an amino group, for example, by catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.
[0208] [000208] It should also be assessed that, in some of the reactions mentioned above, it may be necessary or desirable to protect any sensitive groups in the compounds. Cases where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protection groups can be used according to standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if the reagents include groups such as amino, carboxy or hydroxy, they may be desirable to protect the group in some of the reactions mentioned herein.
[0209] [000209] A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, arylmethoxycarbonyl, for example benzyloxycarbonyl or an aroyl group, for example benzoyl. The deprotection conditions for the above protection groups will necessarily vary with the choice of the protection group. Thus, for example, an acyl group such as an alkanoyl group or alkoxycarbonyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tbutoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be removed, for example, by hydrogenation in a catalyst such as palladium on carbon or by treatment with a Lewis acid for example tris (trifluoroacetate) boron. An alternative protecting group suitable for a primary amino group is, for example, a phthaloyl group that can be removed by treatment with an alkylamine, for example dimethylaminopropylamine or hydrazine.
[0210] [000210] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl or an arylmethyl group, for example benzyl. The deprotection conditions for the above protection groups will necessarily vary with the choice of the protection group. Thus, for example, an acyl group such as an alkanoyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group can be removed, for example, by hydrogenation in a catalyst such as palladium on carbon.
[0211] [000211] A suitable protecting group for a carboxy group is, for example, an esterification group, for example a methyl group or an ethyl group that can be removed, for example, by hydrolysis with a base such as sodium hydroxide or by example a t-butyl group that can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid or for example a benzyl group that can be removed, for example, by hydrogenation in a catalyst such as palladium on carbon.
[0212] [000212] The protecting groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
[0213] [000213] Certain of the intermediates (for example, compounds of Formulas II, IV, V, VII, VIIIa, VIIIb, X, Xa, XI, XII, XIII, XIV, XV, XVa, XVI, XVII) defined herein are new and these are provided as another feature of the invention. For example, compounds of Formula VIIIa (where n, R9 and R10 have any of the meanings defined above) may be useful as intermediates in the preparation of the particular compounds of the invention:
[0214] [000214] In addition, the following compound can be useful as an intermediate in the preparation of the particular compounds of the invention:
[0215] [000215] The following assays can be used to measure the effects of the compounds of the present invention as inhibitors of PI3 kinase enzymes, as in vitro inhibitors of phosphorus AKT (ser473) in MAD-MB-468 cells, as in vivo inhibitors of phospho AKT (ser473) in athymic nu / nu Swiss mice and as in vivo tumor growth inhibitors in athymic nu / nu Swiss mice transplanted with the human prostate adenocarcinoma cell line PC3. (a) In vitro enzyme inhibition assay
[0216] [000216] The inhibition of PI3Kβ, PI3Kα, PI3Kγ and PI3Kδ was evaluated in an enzyme activity assay based on Kinase Glo using human recombinant enzymes. The assay measures ATP depletion after incubation with enzyme, PIP2 and ATP plus compound. ATP at the end of the reaction is detected by the addition of the Kinase Glo reagent, in which the Ultra Glo® luciferase (Promega) uses ATP as a substrate to catalyze the luciferin mono-oxygenation and the generation of light. A direct relationship exists between the luminescence measured with the Kinase-Glo Plus Reagent and the amount of ATP that remains in a completed kinase reaction and the luminescence is inversely related to the kinase activity. Twelve different compound concentrations were tested and the raw data for PI3Kb, PI3Kα, PI3Kγ and PI3Kδ inhibition were plotted versus the inhibitor concentration. Method Details:
[0217] [000217] The compounds in 100% DMSO were added to the assay plates by the acoustic dispensing.
[0218] [000218] PI3Kβ was added in a Tris buffer (50 mM Tris pH 7.4, 0.05% CHAPS, 2.1 mM DTT and 10 mM MgCl2) and allowed to pre-incubate with the compound for 20 minutes before adding substrate solution containing PIP2 and ATP. The enzymatic reaction was stopped after 80 minutes by the addition of Kinase Glo detection solution. The plates were left for 30 minutes at room temperature and then read on a Pherastar Instrument (ATP 384 luminescence program) gain adjustment in the maximum reservoir. The final concentration of DMSO, ATP and PIP2 in the assay was 1%, 8 μM and 80 μM respectively. Data analysis
[0219] [000219] IC50 values were calculated using a log curve fit to a nonlinear regression package, adjusting the raw data for the inhibitor concentration. The IC50 value is the concentration of test compound that inhibited 50% of the enzyme activity. (b) Protocol for the detection of AKT phospho (ser473) in MADMB-468 cells
[0220] [000220] MDA-MB-468 cells (human breast adenocarcinoma ATCC HTB 132) are seeded on black flat-bottomed plates of 384 Greiner reservoirs by the automated cell culture robot (Selec T). The cells can also be maintained manually and seeded in plates using multigout or Wellmate. Cells seeded at 1500 cells / reservoir in 40 μl DMEN containing 10% FCS and 1% glutamine. The cell plates are incubated for 18 hours in a 37 ° C incubator.
[0221] [000221] The compounds are dosed in the cells using an Echo acoustic dispenser, which dispenses nl quantities of compound or DMSO. The compounds are dosed in a 12 point concentration range of 30 μM top dose, 28 compounds are dosed on a plate. There are only 17 positive DMSO control reservoirs per plate and 16 negative control reservoirs that have been dosed with a reference compound concentration that will silence the pAKT signal.
[0222] [000222] The plates are incubated at 37 ° C for 2 hours, the cells are fixed by adding 10 μl of a 3.7% formaldehyde solution in a fume hood using a Wellmate.
[0223] [000223] After 30 minutes to allow fixation, the fixative and the medium are removed and the plates washed with Proclin PBS / A using a Tecan PW384 plate washer in a chapel.
[0224] [000224] The reservoirs are blocked and permeabilized with the addition of 40 µl of PBS containing 0.5% Tween 20 and 1% marvel using a Wellmate and incubated for 60 minutes at room temperature.
[0225] [000225] The permeabilization and blocking plugs removed using Tecan PW384 plate washer, after 20 l of primary antibody solution added using a Wellmate. The primary antibody solution is a 1: 500 dilution of rabbit AKT Ser 473 antiphosphate (Cell signalling technologies catalog number # 3787) in PBS / T containing 1% marvel (dry milk powder) and incubated overnight at 4 ° C.
[0226] [000226] The plates are washed using a Tecan PW384 plate washer three times with Phosphate Buffered Saline Solution + 0.05% (v / v) Polysorbate 20 and Proclin 300 (Supelco). 20 μl of secondary antibody solution is then added to the reservoir using a Wellmate and incubated for 1 hour at room temperature. The secondary antibody solution is a 1: 1000 dilution of Alexa Fluor 488 antiCoelho (Molecular Probes cat no A11008) diluted in Phosphate Buffered Saline + 0.05% (v / v) Polysorbate 20 containing 1% marvel. The plates are washed three times as before after 20 μl of PBS added to the reservoir and the plates sealed with the black plate sealer.
[0227] [000227] The plates are read in an Acumen reader as soon as possible. Using this system IC50 values can be generated and the quality of the plates determined by the control reservoirs. The reference compounds are conducted each time to monitor the performance of the assay. (c) Protocol for the detection of AKT phosphorus (ser473) in nu / nu athymic Swiss mice
[0228] [000228] Swiss athymic nu / nu mice can be transplanted s.c with human prostatic adenocarcinoma cell line PC3 (ATCC CRL1435) to determine the anti-tumor activity of PI3 kinase inhibitors. On day 0, 1X10 6 cells in Matrigel® 50% (BD Biosciences # 354234) are injected s.c. into the animals' left flank. Animals are randomized into the required group sizes (typically 5 per treatment group) when the tumors reach a volume of ~ 400 to 600 mm3 and treatment begins. Tumors are removed at the end and suddenly frozen in liquid nitrogen and stored at -80 ° C until analysis.
[0229] [000229] 1 ml of lysis buffer plus Sigma # P2850, Sigma # P5726 phosphate inhibitors (diluted 1: 100) and Sigma # P8340 protease inhibitors (diluted 1: 200) are added to each tumor in a Fastprep tube. The tumors are homogenized for 1 minute in the Fastprep machine and then left on ice for 10 minutes. The samples are spun for 10 minutes at 13,000 rpm in a cold centrifuge. The purified lysates are then taken into fresh tubes and 5 μl used for a protein determination assay. All tumor samples are diluted to the same concentration so that 15 μg are conducted per line on a 4 to 15% NuPAGE Bis-Tris gel (Invitrogen) for 90 minutes at 140 Volts. The samples are randomized so that the effects of the gel are minimized. After staining on nitrocellulose membranes they are blocked for one hour then incubated overnight with a 1: 500 dilution of antibody to AKT (CST # 9272) or phosphorus AKT-ser 473 (CST # 9271) in total ether. The spots are washed three times in PBST before incubation for one hour at room temperature with a 1: 2,000 dilution of HRP-linked secondary anti-rabbit antibody (CST # 7074). Blocking and antibody incubation buffers are 5% dry milk powder in PBS with 0.05% Polysorbate. The spots are washed three times in PBS / T then visualized using the Pierce West Dura ECL kit and ChemiGenius. The ranges are quantified and a ratio of phospho to total signal is obtained for each sample. Controls are averaged and each treatment sample is normalized to the control value averaged. (d) Protocol for the detection of tumor growth inhibition in PC3 human prostatic adenocarcinoma cell line transplanted to the athymic nu / nu Swiss mice
[0230] [000230] Swiss athymic nu / nu mice can be transplanted s.c with the human prostatic adenocarcinoma cell line PC3 (ATCC CRL1435) to determine the anti-tumor activity of PI3 kinase inhibitors. On day 0, 1X10 6 cells in 50% Matrigel (BDM) are injected s.c. into the animals' left flank. The animals are randomized into groups of 10 to 15 when the tumors reach a volume of ~ 200 to 300 mm3 and treatment begins. The animals are dosed for 2 to 4 weeks via the peroral, intravenous or intraperitoneal routes with the compound (and optionally a cyp inhibitor such as 1-aminobenzotriazole) in a defined vehicle at defined doses. Tumors are usually measured twice a week by caliber and the volume of the tumors is calculated using the elliptical formula (pi / 6 x width x width x length).
[0231] [000231] Although the pharmacological properties of Formula I compounds vary with structural change as expected, in general the activity possessed by Formula I compounds can be demonstrated at the following concentrations or doses in one or more of tests (a) and (b ) above:- Test (a): - IC50 versus PI3Kβ in the range, for example, from 1 nM to 25 µM; Test (b): - IC50 versus phosphorus AKT cellular AKT (ser473) in MAD-MB-468 cells, in the range, for example, from 1 nM to 25 µM; Conveniently, the particular compounds of the invention have activity at the following concentrations or doses in one or more of the tests (a) and (b) above: - Test (a): - IC50 versus PI3Kβ in the range, for example, from 1 nM to 10 µM; Test (b): - IC50 versus AKT cell phospho AKT (ser473) in MAD-MB-468 cells, in the range, for example, from 1 nM to 20 µM; Conveniently, the particular compounds of the invention have activity at the following concentrations or doses in one or more of the tests (a), (b), (c) and (d) above: - Test (a): - IC50 versus PI3Kβ in the range, for example, from 1 nM to 10 µM; Test (b): - IC50 versus AKT cell phospho AKT (ser473) in MAD-MB-468 cells, in the range, for example, from 1 nM to 20 µM; Test (c): - inhibition> 50% of phosphorus AKT in vivo (ser473) in the range, for example, from 1 to 200 mg / kg / day; Test (d): - xenograft activity in the range, for example, from 1 to 200 mg / kg / day.
[0232] [000232] For example, the chromenone compound disclosed as Example 1.00 has activity in Test (a) with an IC50 versus PI3Kβ of approximately 2 nM; and activity in Test (b) with an IC50 versus cell phosphorus AKT cell AKT (ser473) in MAD-MB-468 cells of approximately 9 nM.
[0233] [000233] For example, the chromenone compound disclosed as Example 2.05 has activity in Test (a) with an IC50 versus PI3Kβ of approximately 5 nM; and activity in Test (b) with an IC50 versus cell phospho AKT cell AKT (ser473) in MAD-MB-468 cells of approximately 17 nM.
[0234] [000234] For example, the chromenone compound disclosed as Example 3.03 has activity in Test (a) with an IC50 versus PI3Kβ of approximately 9 nM; and activity in Test (b) with an IC50 versus cell phosphorus AKT cell AKT (ser473) in MAD-MB-468 cells of approximately 35 (37) nM. The value given in parentheses is an average IC50 value calculated from a larger number of duplicates than was used to calculate the first quoted value for the given Example compound.
[0235] [000235] For example, the chromenone compound disclosed as Example 3.04 has activity in Test (a) with an IC50 versus PI3Kβ of approximately 11 nM; and activity in Test (b) with an IC50 versus cell phosphorus AKT cell AKT (ser473) in MAD-MB-468 cells of approximately 12 nM.
[0236] [000236] For example, the chromenone compound disclosed as Example 3.06 has activity in Test (a) with an IC50 versus PI3Kβ of approximately 6 nM; and activity in Test (b) with an IC50 versus cell phosphorus AKT cell AKT (ser473) in MAD-MB-468 cells of approximately 9 nM.
[0237] [000237] For example, the chromenone compound disclosed as Example 3.06a has activity in Test (a) with an IC50 versus PI3Kβ of approximately 3.7 μM; and activity in Test (b) with an IC50 versus cell phosphorus AKT cell AKT (ser473) in MADMB-468 cells of approximately 13.5 μM.
[0238] [000238] For example, the chromenone compound disclosed as Example 3.06b has activity in Test (a) with an IC50 versus PI3Kβ of approximately 2 nM; and activity in Test (b) with an IC50 versus cell phospho AKT cell AKT (ser473) in MAD-MB-468 cells of approximately 5 (3) nM. The value given in parentheses is an average IC50 value calculated from a greater number of duplicates than were used to calculate the first quoted value for the given Example compound.
[0239] [000239] For example, the chromenone compound disclosed as Example 3.07 has activity in Test (a) with an IC50 versus PI3Kβ of approximately 29 nM; and activity in Test (b) with an IC50 versus cell phospho AKT cell AKT (ser473) in MAD-MB-468 cells of approximately 0.58 μM.
[0240] [000240] For example, the chromenone compound disclosed as Example 3.11 has activity in Test (a) with an IC50 versus PI3Kβ of approximately 4 nM; and activity in Test (b) with an IC50 versus cell phospho AKT cell AKT (ser473) in MAD-MB-468 cells of approximately 27 nM.
[0241] [000241] For example, the chromenone compound disclosed as Example 4.02 has activity in Test (a) with an IC50 versus PI3Kβ of approximately 4 nM; and activity in Test (b) with an IC50 versus cell phosphorus AKT cell AKT (ser473) in MAD-MB-468 cells of approximately 1 (2) nM. The value given in parentheses is an average IC50 value calculated from a larger number of duplicates than was used to calculate the first quoted value for the given Example compound.
[0242] [000242] For example, the chromenone compound disclosed as Example 3.13a has activity in Test (a) with an IC50 versus PI3Kβ of approximately 4.5 μM; and activity in Test (b) with an IC50 versus cell phospho AKT cell AKT (ser473) in MADMB-468 cells of approximately 4.3 μM.
[0243] [000243] For example, the chromenone compound disclosed as Example 5.0a has activity in Test (a) with an IC50 versus PI3Kβ of approximately 5 nM; and activity in Test (b) with an IC50 versus cell phospho AKT cell AKT (ser473) in MADMB-468 cells of approximately 15 nM.
[0244] [000244] For example, the chromenone compounds disclosed within the Examples have activity in Test (a) at the levels illustrated in Table A.
[0245] [000245] According to another aspect of the invention there is provided a pharmaceutical composition, which comprises a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above in combination with a pharmaceutically acceptable diluent or carrier.
[0246] [000246] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for use topical (for example as creams, ointments, gels or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely powder) divided) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intraperitoneal or intramuscular dosing) or as a suppository for rectal dosing.
[0247] [000247] The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.
[0248] [000248] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the treated host and the particular route of administration. For example, a formulation intended for oral administration to humans in general will contain, for example, from 1 mg to 1 g of active agent (more suitably from 1 to 250 mg, for example from 1 to 100 mg) combined with an amount appropriate and convenient number of excipients that can vary from about 5 to about 98 weight percent of the total composition.
[0249] [000249] The dose size for the therapeutic or prophylactic purposes of a compound of Formula I 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 well-known principles of medicine.
[0250] [000250] When using a compound of Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, from 1 mg / kg to 100 mg / kg of body weight, given if required in divided doses. In general, lower doses will be administered when a parenteral route is used. Thus, for example, for intravenous administration, a dose in the range, for example, from 1 mg / kg to 25 mg / kg of body weight in general will be used. Similarly, for administration by inhalation, a dose in the range, for example, from 1 mg / kg to 25 mg / kg of body weight will be used. Oral administration is, however, preferred, particularly in tablet form. Typically, unit dosage forms will contain from about 10 mg to 0.5 g of a compound of this invention.
[0251] [000251] As stated above, PI 3-kinase enzymes are known to contribute to tumorigenesis by one or more of the effects of mediating the proliferation of cancer and other cells, mediating angiogenic events and mediating motility, migration and invasiveness of cancer cells. We have found that the chromenone derivatives of the present invention have potent antitumor activity that is believed to be obtained by inhibiting one or more of the Class Ia PI 3-kinase enzymes (such as the Class Ia and / or PI 3-kinase enzymes) or the PI 3-kinase Class Ib enzyme) that are involved in the signal transduction steps that lead to tumor cell proliferation and survival and the invasiveness and migratory ability to metastasize tumor cells.
[0252] [000252] Consequently, the derivatives of the present invention are of value as antitumor agents, in particular as selective inhibitors of the proliferation, survival, motility, dissemination and invasiveness of mammalian cancer cells that lead to inhibition of tumor growth and survival and inhibition of metastatic tumor growth. In particular, the chromenone derivatives of the present invention are of value as antiproliferative and antiinvasive agents in the containment and / or treatment of solid tumor disease. In particular, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumors that are sensitive to the inhibition of one or more of the multiple PI 3-kinase enzymes such as the PI 3 -kinase Class Ia enzymes and the PI 3- enzyme Class Ib kinase that are involved in the signal transduction steps that lead to tumor cell proliferation and survival and the migratory and invasive ability of metastatic tumor cells. In addition, the compounds of the present invention are expected to be useful in preventing or treating those tumors that are mediated alone or in part by inhibiting PI 3-kinase enzymes such as PI 3-kinase Class Ia enzymes and the PI 3- enzyme Class Ib kinase, that is, the compounds can be used to produce an inhibitory effect of the PI 3-kinase enzyme in a warm-blooded animal in need of such treatment.
[0253] [000253] As stated above, inhibitors of PI 3-kinase enzymes should be of therapeutic value for the treatment, for example, of breast, colorectal, lung cancer (including small cell lung cancer, cell lung cancer not small and bronchialveolar cancer) and prostate and bile duct cancer, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva and leukemias [including acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML)], multiple myeloma and lymphomas.
[0254] [000254] According to another aspect of the invention, a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, as defined above for use as a medicament in a warm-blooded animal such as a human.
[0255] [000255] According to another aspect of the invention, a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, as defined above for use in producing an antiproliferative effect in a warm-blooded animal such as the human being.
[0256] [000256] According to another feature of this aspect of the invention, a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above for use in a warm-blooded animal such as a human being as a human being, is provided. anti-invasive agent in the containment and / or treatment of solid tumor disease.
[0257] [000257] According to another aspect of the invention, the use of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above for the production of an antiproliferative effect in a warm-blooded animal, is provided like the human being.
[0258] [000258] In accordance with another feature of this aspect of the invention, the use of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above in the manufacture of a medicament for use in producing an effect, is provided. antiproliferative in a warm-blooded animal such as humans.
[0259] [000259] According to another feature of this aspect of the invention, the use of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above in the manufacture of a medicament for use in a blood animal, is provided hot as human as an anti-invasive agent in the containment and / or treatment of solid tumor disease.
[0260] [000260] According to another feature of this aspect of the invention, a method is provided to produce an antiproliferative effect in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above.
[0261] [000261] According to another feature of this aspect of the invention, a method is provided to produce an anti-invasive effect by containing and / or treating solid tumor disease in a warm-blooded animal, such as a human, in need of such a treatment comprising administering to said animal an effective amount of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, solvate or prodrug, as defined above.
[0262] [000262] According to another aspect of the invention, a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, as defined above for use in preventing or treating cancer in a warm-blooded animal such as the human being.
[0263] [000263] According to another aspect of the invention, the use of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, as defined above in the manufacture of a medicament for use in the prevention or treatment of cancer in a warm-blooded animal just like a human being.
[0264] [000264] In accordance with another characteristic of this aspect of the invention, a method is provided for the prevention or treatment of cancer in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal a quantity efficacy of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above.
[0265] [000265] According to another aspect of the invention, the use of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, as defined above in the manufacture of a medicament for use in the prevention or treatment of disease of solid tumor in a warm-blooded animal such as a human.
[0266] [000266] According to another feature of this aspect of the invention, a method is provided for the prevention or treatment of solid tumor disease in a warm-blooded animal, such as a human, in need of such treatment which comprises administering to said animal an effective amount of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above.
[0267] [000267] According to another aspect of the invention, a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, as defined above for use in the prevention or treatment of those tumors that are sensitive to inhibition of PI 3 enzymes. -kinase (such as Class Ia enzymes and / or the PI 3 -kinase Class Ib enzyme) that are involved in the signal transduction steps that lead to the proliferation, survival, invasiveness and migratory capacity of tumor cells.
[0268] [000268] According to another feature of this aspect of the invention, the use of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above in the manufacture of a medicament for use in preventing or treating those, is provided. tumors that are sensitive to inhibition of PI 3-kinase enzymes (such as Class Ia enzymes and / or the PI 3-kinase Class Ib enzyme) that are involved in the signal transduction steps that lead to proliferation, survival, invasiveness and migratory capacity of tumor cells.
[0269] [000269] In accordance with another feature of this aspect of the invention, a method is provided for the prevention or treatment of those tumors that are sensitive to the inhibition of PI 3-kinase enzymes (such as Class Ia enzymes and / or the PI 3 enzyme Class Ib kinase) that are involved in the signal transduction steps that lead to the proliferation, survival, invasiveness and migratory capacity of tumor cells which comprises administering to said animal an effective amount of a Formula I chromenone derivative or a pharmaceutically salt acceptable, as defined above.
[0270] [000270] According to another aspect of the invention a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, as defined above for use in providing an inhibitory effect of the enzyme PI 3-kinase (such as an inhibitory effect of the PI 3-kinase Class Ia enzyme or PI 3-kinase Class Ib enzyme).
[0271] [000271] In accordance with another feature of this aspect of the invention, use is made of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above in the manufacture of a medicament for use in providing an effect inhibitor of the enzyme PI 3-kinase (such as an inhibitory effect of the enzyme PI 3-kinase Class Ia or enzyme PI 3-kinase Class Ib).
[0272] [000272] According to another aspect of the invention there is also provided a method for providing an inhibitory effect of the PI 3 kinase enzyme (such as an inhibitory effect of the PI 3 kinase Class Ia enzyme or PI 3 3 kinase Class Ib enzyme) which comprises administering an effective amount of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above.
[0273] [000273] As stated above, certain compounds of the present invention have substantially better potency against PI 3-kinase Class Ia enzymes than against PI 3-kinase Class Ib enzyme or against EGF receptor tyrosine kinase, tyrosine kinase VEGF receptor or non-Src receptor tyrosine kinase enzymes. Such compounds have sufficient potency against PI 3-kinase Class Ia enzymes so that they can be used in an amount sufficient to inhibit PI 3-kinase Class Ia enzymes while showing little activity against PI 3-kinase Class Ib enzyme or against the EGF receptor tyrosine kinase, the VEGF receptor tyrosine kinase or non-receptor tyrosine kinase enzymes Src. Such compounds are likely to be useful for the selective inhibition of PI 3 -kinase Class Ia enzymes and are likely to be useful for the effective treatment, for example of tumors induced by the PI 3 -kinase Class Ia enzyme.
[0274] [000274] According to this aspect of the invention, a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, as defined further above for use in providing a selective PI 3-kinase Class Ia inhibitory effect.
[0275] [000275] In accordance with another feature of this aspect of the invention, use is made of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above in the manufacture of a medicament for use in providing an effect selective PI 3-kinase Class Ia inhibitor.
[0276] [000276] In accordance with another aspect of the invention there is also provided a method for providing an inhibitory effect of the selective PI 3 kinase Class Ia enzyme which comprises administering an effective amount of a chromenone derivative of Formula I or a pharmaceutically acceptable salt of the same, as defined above.
[0277] [000277] By "a selective inhibitory effect of the PI 3-kinase Class Ia enzyme" it is intended that the chromenone derivatives of Formula I are more potent against PI 3-kinase Class Ia enzymes than against other kinase enzymes. In particular, some of the compounds according to the invention are more potent against PI 3 -kinase Class Ia enzymes than against other kinases such as receptor or non-receptor tyrosine kinases or serine / threonine kinases. For example a selective PI 3-kinase Class Ia inhibitor according to the invention is at least 5 times more potent, conveniently at least 10 times more potent, more conveniently at least 100 times more potent, against PI 3-kinase Class enzymes More than against other kinases.
[0278] [000278] According to another feature of the invention, a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof is provided, as defined above for use in the treatment of breast, colorectal, lung (including lung cancer) small cell, non-small cell lung cancer and bronchialveolar cancer) and prostate.
[0279] [000279] According to another characteristic of this aspect of the invention, a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above for use in the treatment of cancer of the bile duct, bone, bladder, head, is provided and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva and leukemias (including ALL and CML), multiple myeloma and lymphomas.
[0280] [000280] According to another feature of this aspect of the invention, the use of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above in the manufacture of a medicament for use in the treatment of breast cancer, is provided. breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer and bronchialveolar cancer) and prostate.
[0281] [000281] In accordance with another feature of this aspect of the invention, use is made of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above in the manufacture of a medicament for use in the treatment of cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid, uterus, cervix and vulva and leukemias (including ALL and CML), multiple myeloma and lymphomas.
[0282] [000282] According to another feature of this aspect of the invention a method is provided for treating breast, colorectal, lung (including small cell lung cancer, non-small cell lung cancer and bronchialveolar cancer) and prostate cancer in one warm-blooded animal such as a human in need of such treatment which comprises administering an effective amount of a chromenone derivative of Formula I or a pharmaceutically acceptable salt thereof, as defined above.
[0283] [000283] According to another feature of this aspect of the invention there is provided a method for treating cancer of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, pancreas, skin, testicles, thyroid , uterus, cervix and vulva and leukemias (including ALL and CML), multiple myeloma and lymphomas in a warm-blooded animal such as humans who are in need of such treatment which comprises administering an effective amount of a chromenone derivative from Formula I or a pharmaceutically acceptable salt thereof, as defined above.
[0284] [000284] As stated above, the in vivo effects of a Formula I compound can be exerted in part by one or more metabolites that are formed within a human or animal body after administration of a Formula I compound.
[0285] [000285] The particular compounds of the invention have better potency against PI 3-kinase β than against the other isoforms of PI 3-kinase class I such as α, γ and δ.
[0286] [000286] The present invention therefore also considers a method for inhibiting phosphoinositide 3-kinase β in a patient, which comprises administering to a patient an amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, effective in inhibiting the fosfoinositide 3-kinase β in the patient.
[0287] [000287] The compound of Formula (I) or a pharmaceutically acceptable salt thereof, which is an inhibitor of PI 3-kinase, also has potential therapeutic uses in a variety of other disease states. For example, PI 3-kinase plays an important role in promoting smooth muscle proliferation in the vascular tree, that is, vascular smooth muscle cells, Thyberg, 1998, European Journal of Cell Biology 76 (1): 33-42 and in the lungs (airway smooth muscle cells), Krymskaya, VP, BioDrugs, 2007. 21 (2): 85-95. The excessive proliferation of vascular smooth muscle cells plays an important role in the formation of atherosclerotic plaques and in the development of neoplasm hyperplasia following invasive vascular procedures, Scwartz et al., 1984, Progress in Cardiovascular Disease 26: 355-372; Clowes et al., 1978, Laboratory Investigations 39: 141-150. In addition, excessive proliferation of airway smooth muscle cells leads to the development of COPD in the environment of asthma and chronic bronchitis. Inhibitors of PI 3-kinase activity can therefore be used to prevent vascular restenosis, atherosclerosis and COPD.
[0288] [000288] PI 3-kinases also play an important role in regulating tumor cells and in the propensity of these cells to undergo the development of apoptosis (Sellers et al., 1999, The Journal of Clinical Investigation 104: 1655-1661). Additionally, the uncontrolled regulation of PI 3-kinase PI (3,4,5) P3 and PI (3,4) P2 lipid products by lipid phosphatase PTEN plays an important role in the progression of various malignant tumors in humans (Leevers et al., 1999, Current Opinion in Cell Biology 11: 219-225). A specific role for the phosphoinositide 3-kinase β (PI3Kβ) isoform has been described in these types of cancers (Jia S et al., 2008, Nature 454 (7205): 776-9; Wee et al., 2008, PNAS 105 ( 35): 13057-62). Therefore, the 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.
[0289] [000289] PI 3-kinase also plays an important role in leukocyte function (Fuller et al., 1999, The Journal of Immunology 162 (11): 6337-6340; Eder et al., 1998, The Journal of Biological Chemistry 273 (43): 28025-31) and lymphocytic function (VicenteManzanares et al., 1999, The Journal of Immunology 163 (7): 4001- 4012). For example, leukocyte adhesion to the inflamed endothelium involves the activation of endogenous leukocyte integrins by a PI 3-kinase-dependent signaling process. In addition, oxidative burst (Nishioka et al., 1998, FEBS Letters 441 (1): 63-66 and Condliffe, AM, et al., Blood, 2005. 106 (4): 1432-40) and cytoskeletal reorganization ( Kirsch et al., 1999, Proceedings National Academy of Sciences USA 96 (11): 6211-6216) in neutrophils seems to involve PI 3-kinase signaling. Neutrophil migration and directional movement are also dependent on PI 3-kinase activity (Camps, M., et al., Nat Med, 2005. 11 (9): p. 936-43 and Sadhu, C., et al. , J Immunol, 2003. 170 (5): 2647-54). Thus, PI 3-kinase inhibitors may be useful in reducing leukocyte adhesion and activation at sites of inflammation and therefore can be used to treat acute and / or chronic inflammatory disorders. PI 3-kinase also plays an important role in lymphocyte proliferation and activation, Fruman et al., 1999, Science 283 (5400): 393-397. Given the important role of lymphocytes in autoimmune diseases, an inhibitor of PI 3-kinase activity can be used in the treatment of such disorders.
[0290] (i) outros medicamentos antiproliferativos/antineoplásticos e combinações destes, como usado na oncologia médica, tais como agentes de alquilação (por exemplo cisplatina, oxaliplatina, carboplatina, ciclofosfamida, mostarda nitrogenada, melfalan, clorambucila, busulfan, temozolamida e nitrosouréias); antimetabólitos (por exemplo gencitabina e antifoliatos tais como fluoropirimidinas como 5-fluorouracila e tegafur, raltitrexed, metotrexato, citosina arabinosídeo e hidroxiuréia); antibióticos antitumor (por exemplo antraciclinas como adriamicina, bleomicina, doxorrubicina, daunomicina, epirrubicina, idarrubicina, mitomicina-C, dactinomicina e mitramicina); agentes antimitóticos (por exemplo alcalóides vinca como vincristina, vinblastina, vindesina e vinorrelbina e taxóides como taxol e taxotere e inibidores da polocinase); e inibidores da topoisomerase (por exemplo epipodofilotoxinas como etoposídeo e teniposídeo, ansacrina, topotecano e camptotecina); (ii) agentes citostáticos tais como antiestrogênios (por exemplo tamoxifeno, fulvestrant, toremifeno, raloxifeno, droloxifeno e iodoxifeno), antiandrogênios (por exemplo bicalutamida, flutamida, nilutamida e acetato de ciproterona), antagonistas de LHRH ou agonistas de LHRH (por exemplo goserelina, leuprorelina e buserelina), progestogênios (por exemplo acetato de megestrol), inibidores de aromatase (por exemplo como anastrozol, letrozol, vorazol e exemestano) e inibidores da 5α-redutase tais como finasterida; (iii) Agentes antiinvasão [or exemplo inibidores da família da c-Src cinase como 4-(6-cloro-2,3-metilenodioxianilino)-7-[2-(4-metilpiperazin-1-il)etóxi]-5-tetraidropiran-4-iloxiquinazolina (AZD0530; Pedido de Patente Internacional WO 01/94341), N-(2-cloro-6-metilfenil)-2-{6-[4-(2-hidroxietil)piperazin-1-il]-2-metilpirimidin-4-ilamino}- tiazol-5-carboxamida (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) e bosutinib (SKI-606) e inibidores da metaloproteinase como marimastat, inibidores da função do receptor ativador de plasminogênio da urocinase ou anticorpos para a Heparanase]; (iv) inibidores da função do fator de crescimento: por exemplo tais inibidores incluem anticorpos do fator de crescimento e anticorpos do receptor do fator de crescimento (por exemplo o anticorpo antierbB2 trastuzumab [Herceptina®], o anticorpo antiEGFR panitumumab, o anticorpo antierbB1 cetuximab [Erbitux, C225] e qualquer fator de crescimento ou anticorpos do receptor do fator de crescimento divulgados por Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, pp11-29); tais inibidores também incluem os inibidores da tirosina cinase, por exemplo inibidores da família do fator de crescimento epidérmico (por exemplo inibidores da tirosina cinase da família de EGFR tais como N-(3-cloro-4-fluorofenil)- 7-metóxi-6-(3-morfolinopropóxi)quinazolin-4-amina (gefitinib, ZD1839), N-(3-etinil-fenil)-6,7-bis(2-metoxietóxi)quinazolin-4-amina (erlotinib, OSI-774) e 6-acrilamido-N-(3-cloro-4-fluorofenil)-7-(3- morfolinopropóxi)-quinazolin-4-amina (CI 1033), inibidores da tirosina cinase de erbB2 tais como lapatinib); inibidores da família do fator de crescimento de hepatócito; inibidores da família do fator de crescimento de insulina; inibidores da família do fator de crescimento derivada de plaqueta tais como imatinib e/ou nilotinib (AMN107); inibidores das serina/treonina cinases (por exemplo inibidores da sinalização de Ras/Raf tais como inibidores da farnesil transferase, por exemplo sorafenib (BAY 43-9006), tipifarnib (R115777) e lonafarnib (SCH66336)), inibidores da sinalização de célula através da MEK e/ou AKT cinases, inibidores de c-kit, inibidores da abl cinase, inibidores da PI3 cinase, inibidores da Plt3 cinase, inibidores da CSF-1R cinase, inibidores da receptor de IGF (fator de crescimento como insulina) cinase; inibidores da aurora cinase (por exemplo AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 E AX39459) e inibidores da cinase dependente de ciclina tais como inibidores de CDK2 e/ou CDK4; (v) Agentes antiangiogênicos tais como aqueles que inibem os efeitos do fator de crescimento endotelial vascular, [or exemplo o anticorpo do fator de crescimento de célula endotelial antivascular bevacizumab (Avastina®) e por exemplo, um inibidor da tirosina cinase receptora de VEGF tal como vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) e 4-(4-fluoro-2-metilindol-5-ilóxi)-6-metóxi-7-(3-pirrolidin-1- ilpropóxi)-quinazolina (AZD2171; Exemplo 240 dentro da WO 00/47212), compostos tais como aqueles divulgados nos Pedidos de Patente Internacional WO97/22596, WO 97/30035, WO 97/32856 e WO 98/13354 e compostos que funcionam por outros mecanismos (por exemplo linomida, inibidores da função da integrina αvβ3 e angiostatina)]; (vi) Agentes de dano vascular tais como Combretastatina A4 e compostos divulgados nos Pedidos de Patente Internacional WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 e WO 02/08213; (vii) um antagonista do receptor de endotelina, por exemplo zibotentan (ZD4054) ou atrasentan; (viii) Terapias de anti-sentido, por exemplo aquelas que são direcionadas aos alvos listados acima, tais como ISIS 2503, um antisentido anti-ras; (ix) Métodos de terapia de gene, incluindo por exemplo métodos para substituir genes aberrantes tais como p53 aberrante ou BRCA1 aberrante ou BRCA2, métodos de GDEPT (terapia de prodroga de enzima direcionada ao gene) tais como aqueles usando a citosina desaminase, timidina cinase ou uma enzima de nitrorredutase bacteriana e métodos para aumentar a tolerância do paciente à quimioterapia ou radioterapia tais como terapia de gene de resistência a medicamento múltiplo; e (x) Métodos de imunoterapia, incluindo por exemplo métodos ex vivo e in vivo para aumentar a imunogenicidade de células de tumor do paciente, tais como transfecção com citocinas tais como interleucina 2, interleucina 4 ou fator estimulador de colônia de granulócito-macrófago, métodos para diminuir a energia de célula T, métodos usando células imunes transfectadas tais como células dendríticas transfectadas com citocina, métodos usando linhagens de célula de tumor transfectada com citocina e métodos usando anticorpos antiidiotípicos. [000290] The anticancer treatment defined above may be applied as a single therapy or may involve, in addition to the effects of the compound of the invention, conventional surgery or radiation therapy or chemotherapy. Such chemotherapy may include one or more of the following categories of antitumor agents: - (i) other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifoliators such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); anti-tumor antibiotics (for example anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mitramycin); antimitotic agents (for example vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins such as etoposide and teniposide, ansacrine, topotecan and camptothecin); (ii) cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxifene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists (LHRH or agonists) , leuprorelin and buserelin), progestogens (eg megestrol acetate), aromatase inhibitors (eg as anastrozole, letrozole, vorazole and exemestane) and 5α-reductase inhibitors such as finasteride; (iii) Anti-invasion agents [for example inhibitors of the c-Src kinase family such as 4- (6-chloro-2,3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy] -5- tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), N- (2-chloro-6-methylphenyl) -2- {6- [4- (2-hydroxyethyl) piperazin-1-yl] - 2-methylpyrimidin-4-ylamino} - thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606) and metalloproteinase inhibitors such as marimastat, inhibitors of urokinase plasminogen activating receptor function or antibodies to Heparanase]; (iv) growth factor function inhibitors: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the antierbB2 antibody trastuzumab [Herceptina®], the antiEGFR antibody panitumumab, the antierbB1 cetuximab antibody [Erbitux, C225] and any growth factor or growth factor receptor antibodies released by Stern et al. Critical reviews in oncology / haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example tyrosine kinase inhibitors of the EGFR family such as N- (3-chloro-4-fluorophenyl) - 7-methoxy-6 - (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynyl-phenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) -quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; platelet-derived growth factor family inhibitors such as imatinib and / or nilotinib (AMN107); serine / threonine kinase inhibitors (eg Ras / Raf signaling inhibitors such as farnesyl transferase inhibitors, eg sorafenib (BAY 43-9006), tipifarnib (R115777) and canvasfarnib (SCH66336)), cell signaling inhibitors via MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF (insulin growth factor) kinase inhibitors; aurora kinase inhibitors (e.g. 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) Antiangiogenic agents such as those that inhibit the effects of vascular endothelial growth factor, [for example the antivascular endothelial cell growth factor antibody bevacizumab (Avastina®) and for example, a VEGF receptor tyrosine kinase inhibitor such such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7 - (3-pyrrolidin-1-ylpropoxy) -quinazoline (AZD2171; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications WO97 / 22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, αvβ3 integrin function inhibitors and angiostatin)]; (vi) Vascular damage agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or tardentan; (viii) Antisense therapies, for example those that target the targets listed above, such as ISIS 2503, an anti-ras antisense; (ix) Methods of gene therapy, including for example methods to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, methods of GDEPT (gene directed enzyme prodrug therapy) such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and methods for increasing the patient's tolerance of chemotherapy or radiation therapy such as multiple drug resistance gene therapy; and (x) Immunotherapy methods, including for example ex vivo and in vivo methods to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, methods to decrease T cell energy, methods using transfected immune cells such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cell lines and methods using antiidiotypic antibodies.
[0291] [000291] According to this aspect of the invention there is provided a combination suitable for use in the treatment of cancer comprising a compound of Formula I as defined above or a pharmaceutically acceptable salt thereof and any of the antitumor agents listed under (i ) to (ix) above.
[0292] [000292] Therefore in another aspect of the invention a compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided in combination with an antitumor agent selected from one listed under (i) to (ix) above.
[0293] [000293] In another aspect of the invention there is provided a combination suitable for use in the treatment of cancer comprising a compound of Formula I as defined above or a pharmaceutically acceptable salt thereof and any of the antitumor agents listed under (i) above.
[0294] [000294] In another aspect of the invention there is provided a combination suitable for use in the treatment of cancer comprising a compound of Formula I as defined above or a pharmaceutically acceptable salt thereof and a taxoid, such as for example taxol or taxotere , conveniently taxotere.
[0295] [000295] Here, where the term "combination" is used it should be understood that it refers to simultaneous, separate or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In another aspect of the invention, "combination" refers to sequential administration. Where administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
[0296] [000296] According to another aspect of the invention there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an antitumor agent selected from one listed under (i) to (ix) herein above, in combination with a pharmaceutically acceptable diluent or carrier.
[0297] [000297] According to another aspect of the invention there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an antitumor agent selected from one listed under (i) to (ix) here above, in combination with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
[0298] [000298] According to another feature of the invention, the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an antitumor agent selected from one listed under (i) to (ix) above, is provided, in the manufacture of a drug for use in cancer in a warm-blooded animal, such as a human being.
[0299] [000299] Therefore, in a further feature of the invention, a method of treating cancer in a warm-blooded animal, such as a human being, is in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof in combination with an antitumor agent selected from the one listed under (i) - (ix) here above.
[0300] [000300] In accordance with another aspect of the present invention, a kit is provided which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an antitumor agent selected from one listed under (i) to (ix) up here.
[0301] a) um composto da Fórmula (I) ou um sal farmaceuticamente aceitável do mesmo em uma primeira forma de dosagem unitária; b) um agente antitumor selecionado de um listado sob (i) a (ix) aqui acima; em uma segunda forma de dosagem unitária; e c) meios recipientes para conter as ditas primeira e segunda formas de dosagem. [000301] In accordance with another aspect of the present invention, a kit is provided which comprises: a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof in a first unit dosage form; b) an anti-tumor agent selected from one listed under (i) to (ix) here above; in a second unit dosage form; and c) container means for containing said first and second dosage forms.
[0302] [000302] Although the compounds of Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including humans), they are also useful whenever it is required to inhibit the effects of the PI 3-kinase enzyme of Class I, particularly one of the PI 3-kinase Class Ia enzymes and / or PI 3-kinase Class Ib enzyme, more particularly one of the PI 3-kinase Class Ia enzymes, which include PI 3-kinase β. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
[0303] (i) as operações foram realizadas em temperatura ambiente, isto é, na faixa de 17 a 25º C e sob uma atmosfera de um gás inerte tal como nitrogênio a menos que de outro modo estabelecido; (ii) as evaporações foram realizadas pela evaporação rotativa ou utilizando equipamento de Genevac a vácuo e procedimentos de trabalho foram realizados depois da remoção de sólidos residuais pela filtração; (iii) As purificações pela cromatografia cintilante foram realizadas em um Armen Glider Flash : Spot II Ultimate automatizado (Armen Instrument, Saint-Ave, França) usando cartuchos de sílica Si60 de fase normal Merck pré empacotados (granulometria : 15 a 40 ou 40 a 63 µm) obtidos da Merck, Darmstad, Alemanha; (iv) A cromatografia preparativa foi realizada em um instrumento Waters (600/2700 ou 2525) adaptado com um dos espectrômetros de massa ZMD ou ZQ ESCi e um Waters X-Terra ou um Waters X-Bridge ou uma coluna de fase reversa Waters SunFire (C-18, sílica de 5 mícrons, 19 mm de diâmetro, 100 mm de comprimento, taxa de fluxo de 40 ml / minuto) usando misturas decrescentemente polares de água (que contém 0,2 % de carbonato de amônio) e acetonitrila como eluente; (v) os rendimentos, onde presentes, não são necessariamente o máximo atingível; (vi) no geral, as estruturas de produtos finais da Fórmula I foram confirmados pela espectroscopia magnética nuclear (RMN); valores de mudança química de RMN foram medidos na escala delta [espectros de ressonância magnética de próton foram determinados usando um instrumento Bruker Avance 500 (500 MHz)]; as medições foram tomadas em temperatura ambiente a menos que de outro modo especificado; as seguintes abreviações foram usadas: s, singleto; d, dubleto; t, tripleto; q, quarteto; m, multipleto; dd, dubleto de dubletos; ddd, dubleto de dubleto de dubleto; dt, dubleto de tripletos; bs, sinal amplo; (vii) no geral, os produtos finais da Fórmula I foram também caracterizados pela espectroscopia de massa a seguir da cromatografia líquida (LCMS); LCMS foi realizada usando um Waters Alliance HT (2790 & 2795) adaptado com um espectrômetro de massa Waters ZQ ESCi ou ZMD ESCi e uma coluna X Bridge 5 μm C-18 (2,1 x 50 mm) em uma taxa de fluxo de 2,4 ml/min, usando um sistema de solvente de 95 % de A + 5 % de C a 95 % de B + 5 % de C em 4 minutos, onde A = água, B = metanol, C = metanol:água 1:1 (que contém 0,2 % de carbonato de amônio); (viii) intermediários no geral não foram totalmente caracterizados e a pureza foi avaliada pelas análises cromatográficas de camada fina, espectral de massa, HPLC e/ou RMN; (ix) os espectros de difração de raio X no pó foram determinados (usando um Bruker D4 Analytical Instrument) pela montagem de uma amostra do material cristalino em uma montagem de bolacha de cristal de silício único Bruker (SSC) e espalhando a amostra em uma camada fina com a ajuda de uma lâmina de microscópio. A amostra foi girada a 30 revoluções por minuto (para melhorar as estatísticas de contagem) e irradiada com raios X gerados por um tubo de foco fino longo de cobre operado a 40 kV e 40 mA com um comprimento de onda de 1,5418 ângstroms. A fonte de raio X colimado foi passada através de uma fenda de divergência variável automática ajustada em V20 e a radiação refletida direcionada através de uma fenda antidispersão de 5,89 mm e uma fenda de detetor de 9,55 mm. A amostra foi exposta por 0,03 segundos por incremento de 0,00570° 2-teta (modo de varredura contínua) na faixa de 2 graus até 40 graus 2-teta no modo nata-teta. O tempo de condução foi de 3 minutos e 36 segundos. O instrumento foi equipado com um detetor sensível à posição (Lynxeye). Os dados de controle e captura foram por meio de um Dell Optiplex 686 NT 4.0 Workstation operando com o software Diffrac+. As pessoas habilitadas na técnica da difração do raio X no pó constatará que a intensidade relativa dos picos podem ser afetados, por exemplo, pelos grãos acima de 30 mícrons no tamanho e razões de aspecto não unitárias que podem afetar as análises das amostras. A pessoa habilitada também constatará que a posição das reflexões pode ser afetada pela altura precisa na qual a amostra se situa no difratômetro e a calibração do zero do difratômetro. A planaridade da superfície da atmosfera também pode ter um efeito pequeno. Consequentemente os dados de padrão de difração apresentados não devem ser entendidos como valores absolutos; (x) A Colorimetria de Varredura Diferencial foi realizada usando um instrumento de DSC Q1000 da TA Instruments. Tipicamente menos do que 5 mg de material contido em um cadinho de alumínio padrão adaptado com uma tampa foi aquecido na faixa de temperatura de 25° C a 300° C a uma taxa de aquecimento constante de 10° C por minuto. Um gás de purga usando nitrogênio foi usado em uma taxa de fluxo de 50 ml por minuto; e (xi) as seguintes abreviações foram usadas:- aq. aquosoCDCl3 deutero-clorofórmioCHCl3 clorofórmioDCM diclorometanoDEA dietilaminaDIPEA N-etil-N-isopropilpropan-2-aminaDMF N,N-dimetilformamidaDMSO sulfóxido de dimetilaDSC Colorimetria de Varredura DiferencialDTAD Diazeno-1,2-dicarboxilato de (E)-di-terc-butilaEDCI Cloridreto de 1-(3-dimetilaminopropil)-3-etilcarbodiimidaÉter éter dietílico%ee % de excesso enantioméricoHOPO 2-hidróxi-piridina n-óxidoIPA álcool isopropílicoMeCN acetonitrilaMeOH metanolMTBE éter metil terc-butílicoNMP 1-metil-2-pirrolidonasat. saturadosol. soluçãoTHF tetraidrofuranoTEA trietil aminaTBTU tetrafluoroborato de 2-(1H-benzo[d][1,2,3] triazol-1-il)-1,1,3,3-tetrametilisourônioTSTU tetrafluoroborato de 2-(2,5-dioxopirrolidin-1-il)-1,1,3,3-tetrametilisourônio.[000303] The invention will now be illustrated in the following Examples in which, in general: (i) operations were carried out at room temperature, that is, in the range of 17 to 25º C and under an atmosphere of an inert gas such as nitrogen unless otherwise established; (ii) evaporations were carried out by rotary evaporation or using Genevac vacuum equipment and work procedures were carried out after the removal of residual solids by filtration; (iii) Purifications by sparkling chromatography were performed in an automated Armen Glider Flash: Spot II Ultimate (Armen Instrument, Saint-Ave, France) using pre-packaged Merck normal phase Si60 silica cartridges (granulometry: 15 to 40 or 40 to 63 µm) obtained from Merck, Darmstad, Germany; (iv) Preparative chromatography was performed on a Waters instrument (600/2700 or 2525) adapted with one of the ZMD or ZQ ESCi mass spectrometers and a Waters X-Terra or a Waters X-Bridge or a Waters SunFire reverse phase column (C-18, 5 micron silica, 19 mm in diameter, 100 mm in length, flow rate 40 ml / minute) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent; (v) yields, where present, are not necessarily the maximum attainable; (vi) in general, the final product structures of Formula I were confirmed by nuclear magnetic spectroscopy (NMR); chemical change values of NMR were measured on the delta scale [roton magnetic resonance spectra were determined using a Bruker Avance 500 (500 MHz) instrument]; measurements were taken at room temperature unless otherwise specified; the following abbreviations were used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doublet of triplets; bs, broad signal; (vii) in general, the final products of Formula I were also characterized by mass spectroscopy following liquid chromatography (LCMS); LCMS was performed using a Waters Alliance HT (2790 & 2795) adapted with a Waters ZQ ESCi or ZMD ESCi mass spectrometer and a 5 μm C-18 (2.1 x 50 mm) X Bridge column at a flow rate of 2 , 4 ml / min, using a solvent system of 95% A + 5% C to 95% B + 5% C in 4 minutes, where A = water, B = methanol, C = methanol: water 1 : 1 (which contains 0.2% ammonium carbonate); (viii) intermediates in general were not fully characterized and purity was assessed by thin layer chromatographic, mass spectral, HPLC and / or NMR analyzes; (ix) the X-ray powder diffraction spectra were determined (using a Bruker D4 Analytical Instrument) by assembling a sample of the crystalline material in a single Bruker silicon crystal wafer assembly (SSC) and spreading the sample on a thin layer with the help of a microscope slide. The sample was rotated at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays generated by a long fine-focus copper tube operated at 40 kV and 40 mA with a wavelength of 1.5418 angstroms. The collimated X-ray source was passed through an automatic variable divergence slot set at V20 and the reflected radiation directed through a 5.89 mm anti-scatter slot and a 9.55 mm detector slot. The sample was exposed for 0.03 seconds by an increment of 0.00570 ° 2-theta (continuous scan mode) in the range of 2 degrees to 40 degrees 2-theta in cream-theta mode. The driving time was 3 minutes and 36 seconds. The instrument was equipped with a position sensitive detector (Lynxeye). The control and capture data were through a Dell Optiplex 686 NT 4.0 Workstation operating with Diffrac + software. People skilled in the X-ray powder diffraction technique will find that the relative intensity of the peaks can be affected, for example, by grains over 30 microns in size and non-unitary aspect ratios that can affect sample analyzes. The qualified person will also find that the position of the reflections can be affected by the precise height at which the sample is located on the diffractometer and the zero calibration of the diffractometer. The flatness of the surface of the atmosphere can also have a small effect. Consequently, the diffraction pattern data presented should not be understood as absolute values; (x) Differential Scan Colorimetry was performed using a DS Instruments Q1000 instrument from TA Instruments. Typically less than 5 mg of material contained in a standard aluminum crucible fitted with a lid was heated in the temperature range of 25 ° C to 300 ° C at a constant heating rate of 10 ° C per minute. A purge gas using nitrogen was used at a flow rate of 50 ml per minute; and (xi) the following abbreviations have been used: - aq. aqueous CDCl3 deutero-chloroform CHCl3 chloroform DCM dichloromethane DEA diethylamine DIPEA N-ethyl-N-isopropylpropan-2-amine DMF N, N-dimethylformamide DMSO dimethyl sulfoxide DSC Differential Scan Colorimetry DTAD (E) -di-tert-butyl diazene-1,2-dicarboxylate EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Ether diethyl ether % and and% of enantiomeric excess HOPO 2-hydroxy-pyridine n-oxide IPA isopropyl alcohol MeCN acetonitrile MeOH methanol MTBE tert-butyl methyl ether NMP 1-methyl-2-pyrrolidone sat. saturated Sun. solution THF tetrahydrofuran TEA triethyl amine TBTU 2- (1H-benzo [d] [1,2,3] triazol-1-yl) -1,1,3,3-tetramethylisouronium tetrafluoroborate TSTU 2- (2,5-dioxopyrrolidin-1-yl) -1,1,3,3-tetramethylisouronium tetrafluoroborate.
[0304] [000304] Titanium chloride (ILOTES) (0.129 ml, 0.13 mmol) was added to a stirred suspension of 8-acetyl-N- (2- (dimethylamino) ethyl) -2-morpholino-4-oxo-4H- chromene-6-carboxamide (100 mg, 0.26 mmol), 4-fluoroaniline (0.042 ml, 0.44 mmol) and triethylamine (0.108 ml, 0.77 mmol) in DCM (2 ml) under nitrogen at 10 ° C The resulting solution was stirred at 23 ° C for 2 days. A saturated sodium carbonate solution was added and extracted with DCM. The organic phase was washed with water, brine, dried over magnesium sulfate and concentrated to produce the crude imine. The imine was diluted with DCM and MeOH and acetic acid (0.030 ml, 0.52 mmol) and sodium cyanotrihydroborate (32.4 mg, 0.52 mmol) were added. The resulting solution was stirred at room temperature for 30 min. A solution of the sodium carbonate was added and extracted with DCM. The organic phase was washed with water, brine, dried over magnesium sulfate and concentrated to dryness. The crude product was purified by silica gel scintillation chromatography eluting with 5% methanol in DCM followed by 5% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness and a second purification was done on a preparative HPLC using a Waters X-earth reverse phase column (C-18, 5 micron silica, 19 mm diameter, 100 mm long, flow rate 40 ml / minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. Fractions containing the desired compound were evaporated to dryness to give a white solid which was triturated in MTBE then dried under vacuum to produce N- (2- (dimethylamino) ethyl) -8- (1- (4-fluorophenylamino) -ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide (73.0 mg, 58.6%). Mass spectrum: M + H + 483. NMR spectrum: (CDCl3) 1.60 (d, 3H), 2.25 (s, 6H), 2.50 (t, 2H), 3.45 - 3.58 (m, 6H), 3.79 - 3.89 (m, 4H), 4.02 (bs, 1 H), 4.88 - 4.98 (m, 1 H), 5.56 (s, 1 H), 6.40 (dd, 2H), 6.81 (dd, 2H), 6.91 (bs, 1 H), 8.27 (d, 1 H), 8.34 (d, 1 H) . The 8-acetyl-N- (2- (dimethylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide used as a starting material was made as follows: -
[0305] [000305] To a stirred suspension of methyl 4-hydroxybenzoate (180 g, 1183 mmol) in DCM (3 liters) was added to the bromine drops (64 ml, 1242 mmol) under nitrogen and at 0 ° C and the reaction mixture was allowed to stir at room temperature for 36 hours. A solution of sodium thiosulfate (500 ml of a 10% solution) was then added while maintaining the temperature at around 15 ° C followed by the addition of MeOH (250 ml). The organic layer was washed with water, then brine, dried over magnesium sulfate, filtered and concentrated to dryness to yield methyl 3-bromo-4-hydroxybenzoate (290 g) as a white solid. Mass spectrum: [M - H] - 229. Step 2
[0306] [000306] To a stirred suspension of methyl 3-bromo-4-hydroxybenzoate (270 g, 1168 mmol) in DCM (1.5 liter) was added pyridine (150 ml). Acetyl chloride (87 ml, 1227 mmol) was then added to the drops at room temperature and under nitrogen. The mixture was allowed to stir for 2 hours at room temperature. The water (1 liter) was then added followed by 2 N HCl to pH 1. The organic layer was then washed with water, brine, dried over magnesium sulfate, filtered and evaporated to dryness to produce 4-acetoxy3-bromobenzoate methyl (300 g, 94%) as a white powder. NMR spectrum: (DMSOd6) 2.34 (s, 3H), 3.87 (s, 3H), 7.47 (d, 1 H), 8.01 (dd, 1 H), 8.20 (d , 1 H). Step 3
[0307] [000307] To the methyl 4-acetoxy-3-bromobenzoate (150 g, 549.3 mmol) was added aluminum trichloride (220 g, 1647.9 mmol) and the mixture was heated to 140 ° C in the absence of solvent for 3 hours. Upon cooling to room temperature the solid was ground and cautiously added to the water (1.5 liters) with stirring. The HCl (250 ml of 12 N) was then added and stirring was continued for 30 minutes. The obtained solid was collected by filtration, washed with water (2 x 2 liters) and dried overnight to produce 3-acetyl-5-bromo-4-hydroxybenzoic acid (120 g, 84%) as a yellow powder. Mass spectrum: [M - H] - 258. Step 4
[0308] [000308] To a stirred suspension of 3-acetyl-5-bromo-4-hydroxybenzoic acid (240 g, 926 mmol) in MeOH (2 liters) was added to the drops sulfurous dichloride (68 ml, 926.5 mmol) under nitrogen and the mixture was heated to 80 ° C for 3 hours. The reaction mixture was cooled to concentrated room temperature, diluted with DCM. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to produce the crude compound, which was purified on silica, eluting with 70% DCM in petroleum ether. The solvents were evaporated to dryness to produce methyl 3-acetyl-5-bromo-4-hydroxy-benzoate (108 g, 42.7%) as a white powder. Mass spectrum: [M - H] - 229. Step 5
[0309] [000309] To the stirred solution of morpholino (201 ml, 2295 mmol) in water (2 liters) was added carbon disulfide (0.138 liter, 2295.67 mmol) under nitrogen. Sodium hydroxide (96 g, 2410 mmol in the solution in 1 liter of water) was then added to the drops. The resulting mixture was stirred at room temperature for 1 hour, then cooled to 5 ° C with an ice bath and dimethyl sulfate (217 ml, 2295 mmol) was added to the drops. The mixture was stirred for 1 hour at room temperature, the obtained solid was collected by filtration, washed with water (2 x 1 liter) and dried under vacuum in phosphorus pentoxide at 50 ° C to give methyl morpholino-4-carbodithioate ( 360 g, 88%). NMR spectrum: (CDCl3): 2.68 (s, 3H), 3.71 - 3.84 (m, 4H), 4.02 (bs, 2H), 4.30 (bs, 2H). Step 6
[0310] [000310] Chloride gas (455 g, 6417 mmol) was bubbled through a solution of methyl morpholino-4-carbodithioate (170 g, 959 mmol) in DCM (1.5 liter) over a period of 2 hours, while the temperature is maintained at around 10 to 15 ° C. Once the addition of chloride has been completed, stirring was continued for an additional 1.5 hours while precipitation occurred. The nitrogen was then passed through the mixture for 30 minutes. The solid was collected by filtration under nitrogen, washed with DCM and stored under nitrogen in the refrigerator. There was thus obtained 4- (dichloromethylene) morpholin-4-io chloride (180 g, 92%) as a white hygroscopic solid. Step 7
[0311] [000311] To a stirred solution of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (106 g, 388 mmol) in toluene (1 liter) was added to the drops (diethyloxon) trifluoroborate (0.201 liter, 1630 mmol), under nitrogen. The resulting solution was allowed to stir overnight at room temperature, then 4- (dichloromethylene) morpholin-4-io chloride (143 g, 698 mmol) was added and the mixture heated to 90 ° C for 12 hours. Upon cooling to room temperature, diethyl ether (1.5 liters) was added and the solid was collected by filtration. This solid was then suspended in MeOH (1 liter) and the mixture was heated to 50 ° C for 2 hours.
[0312] [000312] On cooling to room temperature, the solid was collected by filtration and then solubilized in DCM (1 liter) and washed with water and a saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness to produce methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (68.0 g, 47.6% ) as a yellowish white solid. Mass spectrum: M + H + 368. This intermediate can also be prepared by an alternative route (see below) Step 8
[0313] [000313] Sodium hydroxide (4.35 ml, 8.69 mmol) was added to a stirred suspension of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (1.6 g, 4.35 mmol) dissolved in MeOH (30 ml). The resulting suspension was stirred at 23 ° C for 16 hours. The mixture was diluted with water and the pH adjusted to 3 with 2 N HCl. The precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide overnight to give 8-bromo-2-morpholino-4- acid oxo-4H-chromene-6-carboxylic (1.30 g, 84%) as a beige solid. Mass spectrum: M + H + 356 Step 9
[0314] [000314] Bis (triphenylphosphino) palladium (II) chloride (12.78 mg, 0.02 mmol) was added to a stirred mixture of 8-bromo-2-morpholino-4-oxo-4H-chromene-6- acid carboxylic (215 mg, 0.61 mmol) and tributyl (1-ethoxyvinyl) stannane (0.226 ml, 0.67 mmol) in 1,4-dioxane (5 ml) and the mixture was purged with nitrogen. The resulting mixture was stirred at 100 ° C for 3 hours. 2N HCl (0.5 ml) was added and the reaction mixture was stirred at 50 ° C for 25 minutes then allowed to cool to room temperature and concentrated in vacuo. The product was diluted with diethyl ether and pentane to produce a solid, which was collected by filtration and washed with ether / pentane to give 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid ( 200 mg, 104%) as a beige solid. Mass spectrum: M + H + 318. Step 10
[0315] [000315] To a suspension of 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (470 mg, 1.48 mmol) in DCM (10 ml) at room temperature, DIPEA was added (0.284 ml, 1.63 mmol) and TSTU (491 mg, 1.63 mmol). The mixture was stirred for 15 minutes, N1, N1-dimethylethane-1,2-diamine (0.171 ml, 1.56 mmol) was added and stirring was continued for an additional hour. The mixture was absorbed on silica gel and purified by silica gel scintillation chromatography eluting with 5 to 10% methanol in DCM then with 10% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness to produce 8-acetyl-N- (2- (dimethylamino) ethyl) - 2-morpholino-4-oxo-4H-chromene-6-carboxamide (352 mg, 61.3%) as a beige solid. Mass spectrum: M + H + 388. Alternative route to prepare methyl 8-bromo-2-morpholino-4-oxo-4H-chromene6-carboxylate:
[0316] [000316] Dibromo (0.185 liter, 3614.92 mmol) was added to the drops to a stirred suspension of methyl 4-hydroxybenzoate (500 g, 3286 mmol) in DCM (4 liters) at 0 ° C under N2. The mixture was allowed to stir for 24 hours at room temperature under N2 (necessary to trap HBr). A solution of sodium metabisulfate (62.5 g, 329 mmol) in 2 liters of water was then added, while maintaining the temperature at around 15 ° C, followed by 500 ml of MeOH. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and concentrated to dryness to yield methyl 3-bromo-4-hydroxybenzoate (710 g, 94%) as a white solid. NMR spectrum (CDCl3): 3.89 (s, 3H), 5.95 (s, 1 H), 7.05 (d, 1 H), 7.92 (dd, 1 H), 8.19 ( d, 1 H). Step 2
[0317] [000317] To a degassed solution of methyl 3-bromo-4-hydroxybenzoate (350 g, 1514.87 mmol) in ethanol (3 liters) were added triethylamine (0.528 liter, 3787.17 mmol), 1- (vinyloxy) butane (0.588 liter, 4544.60 mmol), 1,1'-bis (diphenylphosphino) ferrocene (33.1 g, 60.6 mmol) and diacethoxipaladium (8.50 g, 37.9 mmol) under nitrogen. The mixture was heated to 70 ° C overnight. The reaction was cooled, filtered and the filtrate concentrated. The resulting solid was solubilized with DCM (2 liters) and 4 N HCl (1.14 liter, 4544 mmol) was added with stirring. Stirring was continued for 2 hours, the organic phase was separated, dried over magnesium sulfate, filtered and concentrated to produce a solid that was stirred in diethyl ether (5 liters) for 2 hours. The solid was filtered off and the filtrate concentrated to dryness to yield methyl 3-acetyl-4-hydroxybenzoate (240 g, 82%) as a beige powder. Mass spectrum: [M - H] - 193. Step 3
[0318] [000318] To a stirred solution of methyl 3-acetyl-4-hydroxybenzoate (240 g, 1236 mmol) in DCM (2 liters) was added pyridine (0.400 liter, 4944 mmol) followed by an addition to the dibromo drops (0.070 liter, 1360 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours then cooled to 5 ° C and 4 N HCl (0.927 liter, 3708 mmol) was added to the drops. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated to produce the brown solid which was stirred in ether / petroleum ether (1: 1, 1 liter) for 1 hour. The solid was collected by filtration and dried to produce methyl 3-acetyl-5-bromo-4-hydroxybenzoate (270 g, 80%) as a beige powder. Step 4
[0319] [000319] To a solution of lithium bis (trimethylsilyl) amide (1.41 liter, 1406 mmol) at -65 ° C under nitrogen was added to the methyl 3-acetyl-5-bromo-4-hydroxybenzoate drops (120 g , 439 mmol) in THF (1.2 LITER). The solution was allowed to warm up to 0 ° C and maintained at this temperature for 1 hour. The cooled solution back to -65 ° C and morpholino-4-carbonyl chloride (0.055 liter, 483 mmol) was added. The mixture was stirred at room temperature for 2 hours then cooled to -30 ° C, DCM (1.5 liter) and water (1 liter) were added followed by the addition of 6 N HCl drops (500 ml) then HCl 2 N (300 ml) until pH 7, the aqueous solution was extracted with DCM (3 X). The combined extracts were dried over magnesium sulfate and evaporated. The crude product was triturated in MTBE to obtain methyl 3-bromo-4-hydroxy-5- (3-morpholino-3-oxopropanoyl) benzoate (153 g, 90%) as a beige solid. Mass spectrum: M + H + 388. Step 5
[0320] [000320] Trifluoromethanesulfonic anhydride (0.755 liter, 4487 mmol) was added to a stirred solution of methyl 3-bromo-4-hydroxy-5- (3-morpholino-3-oxopropanoyl) benzoate (433 g, 1122 mmol, material from several batches) dissolved in 1,2-dichloroethane (1 liter) at room temperature under nitrogen (exotherm). The resulting solution was stirred at 50 ° C overnight. The mixture was partially evaporated and the residue was diluted with MeOH (1.6 liter) at 0 ° C (exotherm) and stirred for 1 hour at room temperature. The solvent was evaporated again and the residue was diluted in DCM, quenched with a saturated aqueous solution of sodium carbonate and extracted with DCM. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to produce the crude product. The crude was ground under MTBE (2x), ethyl acetate (1x) and MTBE (1x). The solid was dried to produce methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (208 g, 50%) as a beige solid. Mass spectrum: M + H + 370. Example 1.01 N- (2- (dimethylamino) ethyl) -8- (1- (3-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0321] [000321] N- (2- (dimethylamino) ethyl) -8- (1- (3-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide was prepared using a procedure analogous to that described in Example 1.00 (28.0 mg, 18.7%). Mass spectrum: M + H + 483. NMR spectrum: (CDCl3) 1.62 (d, 3H), 2.27 (s, 6H), 2.52 (t, 2H), 3.44 - 3.58 (m, 6H), 3.78 - 3.89 (m, 4H), 4.55 (bs, 1 H), 4.92 - 5.02 (m, 1 H), 5.56 (s, 1 H), 6.14 (ddd, 1 H), 7.27 (dd, 1 H), 7.36 (ddd, 1 H), 6.95 (bs, 1 H), 7.03 (dd, 1 H), 8.28 (d, 1 H), 8.35 (d, 1 H). Example 1.02 N- (2- (dimethylamino) ethyl) -2-morpholino-4-oxo-8- (1- (phenylamino) ethyl) -4H-chromene-6-carboxamide
[0322] [000322] N- (2- (dimethylamino) ethyl) -2-morpholino-4-oxo-8- (1- (phenylamino) -ethyl) -4H-chromene-6-carboxamide was prepared using a procedure analogous to that described in Example 1.00 (36.0 mg, 25%). Mass spectrum: M + H + 465. NMR spectrum: (CDCl3) 1.62 (d, 3H), 2.25 (s, 6H), 2.49 (t, 2H), 3.44 - 3.57 (m, 6H), 3.75 - 3.86 (m, 4H), 4.09 (d, 1 H), 4.95 - 5.05 (m, 1 H), 5.56 (s, 1 H), 6.58 (d, 2H), 6.68 (t, 1 H), 6.90 (bs, 1 H), 7.11 (dd, 2H), 8.30 (d, 1 H) , 8.34 (d, 1 H). Example 2.00 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -N- (2- (dimethylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0323] [000323] 2- (1H-benzo [d] [1,2,3] triazol-1-yl) -1,1,3,3 -tetramethylisouronium tetrafluoroborate (73.3 mg, 0.23 mmol) was added to a stirred solution of 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (85 mg, 0.19 mmol), 4- methylmorpholine (0.052 ml, 0.48 mmol) and N1, N1-dimethylethane-1,2-diamine (0.025 ml, 0.23 mmol) dissolved in NMP (1.2 ml) at room temperature. The resulting solution was stirred for 2 hours. The reaction mixture was purified by preparative HPLC using a Waters SunFire reverse phase column (C-18, 5 micron silica, 19 mm in diameter, 100 mm in length, 40 ml / minute flow rate) and the mixtures decreasingly polar water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. Fractions containing the desired compound were evaporated, triturated with diethyl ether and dried to produce 8- (1- (3-chloro-2-fluorophenylamino) -ethyl) -N- (2- (dimethylamino) ethyl) -2- morpholino-4-oxo-4H-chromene-6-carboxamide (59.2 mg, 60.2%) as a white solid. Mass spectrum: M + H + 517. NMR spectrum: (DMSOd6) 1.57 (d, 3H), 2.15 (s, 6H), 2.37 (t, 2H), 3.26 - 3.34 (m partially hidden by H2O, 2H), 3.50 - 3.62 (m, 4H), 3.70 - 3.79 (m, 4H), 5.03 - 5.12 (m, 1 H), 5.61 (s, 1 H), 6.34 (dd, 1 H), 6.49 (d, 1 H), 6.64 (ddd, 1 H), 6.82 (d, 1 H), 8.10 (d, 1 H), 8.32 (d, 1 H), 8.61 (t, 1 H).
[0324] [000324] The 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid used as starting material was as follows: -
[0325] [000325] To a stirred suspension of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (40 g, 108 mmol, as described in Example 1.00) in dioxane (300 ml) tributyl (1-ethoxyvinyl) stannane (38.5 ml, 114 mmol) and bis (triphenylphosphino) palladium (II) chloride (3.05 g, 4.35 mmol) were added. The mixture was purged with nitrogen and heated to 90 ° C overnight. More tributyl (1-ethoxyvinyl) stannane (20 ml) and bis (triphenylphosphino) palladium (II) chloride (1.5 g) were added and the reaction mixture heated for an additional 3 hours. The mixture was cooled to room temperature, 2 N HCl (81 ml, 163 mmol) was added and the dark suspension heated to 45 ° C for 30 min. dioxane was evaporated in vacuo, the residue was dissolved in DCM and a saturated sodium bicarbonate solution was added to pH 4. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to produce a crude compound which was triturated in diethyl ether, filtered and dried to produce methyl 8-acetyl2-morpholino-4-oxo-4H-chromene-6-carboxylate (25.0 g, 69.5%) as a yellowish white solid. Mass spectrum: M + H + 332.
[0326] [000326] Sodium tetrahydroborate (82 mg, 2.16 mmol) was added to a solution of methyl 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylate (650 mg, 1.96 mmol ) in methanol (20 ml) and DCM (10 ml) at - 10 ° C. After 15 minutes of stirring at -10 ° C, the reaction mixture was quenched with water (25 ml). The volatiles were removed and the aqueous layer extracted twice with DCM. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was triturated with diethyl ether and the solid collected by filtration to give methyl 8- (1-hydroxyethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylate (500 mg, 76%) as brown solid , that the next step was used without further purification. Mass spectrum: M + H + 334.
[0327] [000327] Tribromophosphine (1.65 ml, 1.65 mmol) was added to a stirred suspension of methyl 8- (1-hydroxyethyl) -2-morpholino-4-oxo-4H-chromene6-carboxylate (500 mg, 1 , 50 mmol) in DCM (10 ml) in an ice bath under nitrogen. The resulting solution was stirred at room temperature for 24 hours. The reaction was incomplete and in addition, tribromo-phosphine (0.300 ml, 0.30 mmol) was added and the reaction mixture stirred for an additional 12 hours. The solvent was evaporated, the residue was suspended in water and ice and a sodium carbonate solution was carefully added to pH 6. The precipitate was collected by filtration, washed with water then with diethyl ether and dried to produce the 8 - Methyl (1-bromoethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylate (470 mg, 79%) as a dark beige solid. Mass spectrum: M + H + 398.
[0328] [000328] 3-chloro-2-fluoroaniline (0.239 ml, 2.17 mmol) was added to a stirred suspension of 8- (1-bromoethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylate methyl (215 mg, 0.54 mmol) dissolved in DCM (3 ml) at room temperature. The resulting suspension was stirred for 16 hours then the temperature was raised to 50 ° C for 16 hours. The crude product was purified by silica gel scintillation chromatography eluting with 5% methanol in DCM. The solvent was evaporated to dryness to produce methyl 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylate (206 mg, 82% ) as a white solid. Mass spectrum: M + H + 461.
[0329] [000329] Sodium hydroxide (0.217 ml, 0.43 mmol) was added to a stirred solution of 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H- methyl chromene-6-carboxylate (200 mg, 0.43 mmol) dissolved in MeOH (2 ml). The resulting solution was stirred at room temperature for 16 hours. THF was added and the resulting solution was stirred at 50 ° C for 8 hours. The pH was adjusted to 3 with 2N HCl, the solvent was removed in vacuo and the residue diluted with H2O. The solid was collected by filtration, washed with water and dried to give 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (171 mg, 88%) as a white solid. Mass spectrum: M + H + 447. Example 2.01 8- (1- (4-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0330] [000330] 8- (1- (4-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (82 mg, 0.20 mmol) was reacted with dimethylamine (0.119 ml, 0.24 mmol) using a procedure similar to that described in Example 2.00 to produce 8- (1- (4-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene -6-carboxamide (53 mg, 60.7%) as a white solid. Mass spectrum: M + H + 440.
[0331] [000331] NMR spectrum: (DMSOd6) 1.50 (d, 3H), 2.66 (s, 3H), 2.92 (s, 3H), 3.50 - 3.65 (m, 4H), 3.70 - 3.81 (m, 4H), 4.92 - 5.02 (m, 1 H), 5.60 (s, 1 H), 6.27 (d, 1 H), 6.46 (dd, 2H), 6.84 (dd, 2H), 7.56 (d, 1 H), 7.77 (d, 1 H).
[0332] [000332] The 8- (1- (4-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid used as starting material was manufactured using a procedure similar to that described in Example 2 , 00. Mass spectrum: M + H + 413. Example 2.02 N- (2- (dimethylamino) ethyl) -8- (1- (4-fluorophenylamino) ethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0333] [000333] 8- (1- (4-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (80 mg, 0.19 mmol) was reacted with N1, N1, N2 - trimethylethane-1,2-diamine (0.030 ml, 0.23 mmol) using a procedure similar to that described in Example 2.00 to produce N- (2- (dimethyl-amino) ethyl) -8- (1- (4-fluorophenylamino) ethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (15.0 mg, 15.6%) as a white solid. Mass spectrum: M + H + 497. NMR spectrum: (DMSOd6) 1.49 (d, 3H), 1.74 (bs, 3H), 2.01 (bs, 1 H), 2.18 (s, 3H), 2.66 (bs, 1.5 H), 2.89 (bs, 2H), 3.05 (bs, 1.5H), 3.47 (bs, 1 H), 3.50 - 3 , 64 (m, 4H), 3.71 - 3.79 (m, 4H), 4.93 - 5.01 (m, 1 H), 5.59 (s, 1 H), 6.29 (bs , 1 H), 6.46 (dd, 2H), 6.84 (dd, 2H), 6.54 (d, 1 H), 6.73 (d, 1 H). Example 2.03 8- (1- (3-chloro-4-fluorophenylamino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) - 2-morpholino-4H-chromen-4-one
[0334] [000334] 8- (1- (3-chloro-4-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.28 mmol) was reacted with piperidine -4-ol (34.0 mg, 0.34 mmol) using a procedure similar to that described in Example 2.00 to produce 8- (1- (3-chloro-4-fluorophenylamino) ethyl) -6- ( 4-hydroxypiperidine-1-carbonyl) -2-morpholino-4Hcromen-4-one (110 mg, 74.2%) as a white solid. Mass spectrum: M + H + 530. NMR spectrum: (DMSOd6) at 323 ° K: 1.24 (bs, 2H), 1.51 (d, 3H), 2.99 (bs, 2H), 3, 30 (bs, 2H), 3.37 (bs, 2H), 3.49 - 3.63 (m, 4H), 3.63 - 3.72 (m, 1 H), 3.72 - 3.82 (m, 4H), 4.62 (d, 1 H), 4.92 - 5.02 (m, 1 H), 5.56 (s, 1 H), 6.36 - 6.46 (m, 2H), 6.59 (dd, 1 H), 7.01 (dd, 1 H), 7.51 (d, 1 H), 7.76 (d, 1 H).
[0335] [000335] The 8- (1- (3-chloro-4-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid used as a starting material was manufactured using a procedure similar to that described in Example 2.00. Mass spectrum: M + H + 447. Example 2.04 8- (1- (3-chloro-4-fluorophenylamino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0336] [000336] 8- (1- (3-chloro-4-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (78 mg, 0.17 mmol) was reacted with 2 - (methylamino) ethanol (0.017 ml, 0.21 mmol) using a procedure similar to that described in Example 2.00 to give 8- (1- (3-chloro-4-fluorophenyl-amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (60.0 mg, 68.2%) as a white solid. Mass spectrum: M + H + 504. NMR spectrum: (DMSOd6) at 323 ° K: 1.51 (d, 3H), 2.82 (bs, 1.5H), 2.90 (bs, 1.5H ), 3.42 (bs, 4H), 3.49 - 3.63 (m, 4H), 3.69 - 3.79 (m, 4H), 4.60 (bs, 1 H), 4.92 - 5.01 (m, 1 H), 5.56 (s, 1 H), 6.37 (dd, 1 H), 6.42 (ddd, 1 H), 6.61 (dd, 1 H) , 7.02 (dd, 1 H), 7.57 (d, 1 H), 7.80 (d, 1 H).
[0337] [000337] The 8- (1- (3-chloro-4-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid used as starting material was manufactured using a procedure similar to that described in Example 2.0. Mass spectrum: M + H + 447. Example 2.05 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0338] [000338] 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (130 mg, 0.29 mmol) was reacted with 2 - (methylamino) ethanol (0.028 ml, 0.35 mmol) using a procedure similar to that described in Example 2.00 to produce 8- (1- (3-chloro-2-fluoro-phenylamino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (65.0 mg, 44.3%) as a white solid. Mass spectrum: M + H + 504. NMR spectrum: (DMSOd6) 1.57 (d, 3H), 2.76 (s, 1.5H), 2.94 (s, 1.5H), 3.07 (bs, 1 H), 3.27 (bs, 1 H), 3.45 (bs, 1 H), 3.51 - 3.64 (m, 5H), 3.70 - 3.78 (m, 4H), 4.69 (bs, 0.5H), 4.78 (ns, 0.5H), 5.08 (bs, 1 H), 5.60 (s, 1 H), 6.33 - 6 , 47 (bs, 2H), 6.65 (ddd, 1 H), 6.83 (dd, 1 H), 7.60 (bs, 0.5H), 7.61 (bs, 0.5H), 7.79 (bs, 0.5H), 7.81 (bs, 0.5H).
[0339] [000339] The 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid used as starting material was manufactured using a procedure similar to that described in Example 2.00. Mass spectrum: M + H + 447. Example 2.06 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) - 2-morpholino-4H-chromen-4-one
[0340] [000340] 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (130 mg, 0.29 mmol) was reacted with piperidine -4-ol (35.3 mg, 0.35 mmol) using a procedure similar to that described in Example 2.00 to give 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -6- ( 4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one (101 mg, 65.5%) as a white solid. Mass spectrum: M + H + 530. NMR spectrum: (DMSOd6) at 323 ° K: 1.24 (bs, 2H), 1.62 (d, 3H), 1.63 (bs, 2H), 2, 99 (bs, 2H), 3.19 (bs partially hidden by H2O, 2H), 3.49 - 3.63 (m, 4H), 3.65 - 3.72 (m, 1 H), 3.72 - 3.78 (m, 4H), 4.62 (d, 1 H), 5.04 - 5.13 (m, 1 H), 5.56 (s, 1 H), 6.28 (d, 1 H), 6.33 (dd, 1 H), 6.64 (ddd, 1 H), 6.82 (ddd, 1 H), 7.57 (d, 1 H), 7.77 (d, 1 H). Example 2.07 8- (1- (3,5-difluorophenylamino) ethyl) -6- (morpholino-4-carbonyl) -2-morpholino-4H-chromen-4-one
[0341] [000341] TSTU (84 mg, 0.28 mmol) at 25 ° C, was added to 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene6- carboxylic (100 mg, 0.14 mmol) and DIPEA (0.049 ml, 0.28 mmol) dissolved in DCM (1 ml). The resulting solution was stirred at 25 ° C for 2 hours. Morpholino (0.037 ml, 0.42 mmol) was then added, the resulting solution was stirred at 25 ° C for 30 minutes then concentrated. The crude was diluted with 1 ml of DMA and purified by preparative HPLC using a Waters XBridge reverse phase column (C-18, 5 micron silica, 19 mm in diameter, 100 mm in length, flow rate 40 ml / minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. Fractions containing the desired compound were evaporated to dryness, crushed in diethyl ether and collected by filtration to produce 8- (1- (3,5-difluorophenylamino) tyl) -6- (morpholino-4-carbonyl) -2 -morpholino-4H-chromen4-one (63.0 mg, 90%) as a yellow solid. Mass spectrum: M + H + 500. NMR spectrum: (DMSOd6) 1.53 (d, 3H), 3.11 (bs, 2H), 3.37 - 3.71 (m, 10H), 3.71 - 3.80 (m, 4H), 4.98 - 5.07 (m, 1 H), 5.62 (s, 1 H), 6.15 (dd, 2H), 6.25 (ddd, 1 H), 6.97 (d, 1 H), 7.51 (d, 1 H), 7.82 (d, 1 H).
[0342] [000342] The 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid used as the starting material was manufactured using a procedure similar to that described in Example 2.00. Example 2.08 8- (1- (3,5-difluorophenylamino) ethyl) -6 - ((S) -3-hydroxypyrrolidine-1-carbonyl) -2-morpholino-4H-chromen-4-one (enantiomer 2)
[0343] [000343] EDCI (102 mg, 0.53 mmol) was added in one portion to 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6- acid carboxylic (200 mg, 0.35 mmol, enantiomer 2 ([α] D20 ° - 102 °, described as a starting material in Example 7.0a), (S) - pyrrolidin-3-ol (0.043 ml, 0, 53 mmol) and HOPO (47.1 mg, 0.42 mmol) dissolved in DCM (2 ml) in a screw cap vial The resulting solution was stirred at room temperature for 5 minutes then 50 ° C for 30 minutes. EDCI (~ 50 mg) was added to complete the reaction.The solution was washed with a 10% aqueous citric acid solution, water, brine and dried over magnesium sulfate.The solvent was evaporated and the crude product purified by flash chromatography on silica gel (40 g) eluting with 0 to 10% MeOH in DCM The solvent was evaporated to dryness to yield 8- (1- (3,5-difluorophenylamino) ethyl) -6 - ((S) -3-hydroxypyrrolidine-1-carbonyl) -2-morpholino-4H-chromen-4-one (95%) as a white foam relayed. Mass spectrum: M + H + 500. NMR spectrum (CDCl3): 1.60 (d, 3H), 1.89 - 2.11 (m, 1 H), 2.54 (bs, 0.5H), 2.81 (bs, 0.5H), 3.29 - 3.43 (m, 2H), 3.51 (bs, 4H), 3.64 - 3.78 (m, 2H), 3.79 - 3.91 (m, 5H), 4.42 (bs, 0.5H), 4.54 (bs, 0.5H), 4.59 (bs, 0.5H), 4.70 (bs, 0, 5H), 4.87 - 4.95 (m, 1 H), 5.54 (bs, 1 H), 5.89 - 6.01 (m, 2H), 6.09 (dd, 1 H), 7.85 (s, 0.5H), 7.87 (s, 0.5H), 8.18 (bs, 0.5H), 8.25 (bs, 0.5H). Example 3.00 N- (2- (dimethylamino) ethyl) -8- (1 - ((4-fluorophenyl) (methyl) amino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0344] [000344] An 8- (1-bromoethyl) -N- (2- (dimethylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrochloride solution (85 mg, 0.16 mmol ) and 4-fluoro-N-methylaniline (0.077 ml, 0.64 mmol) in NMP (1 ml) was stirred at room temperature for 4 hours then at 45 ° C for 1 hour. The reaction mixture was allowed to cool to room temperature and purified by preparative HPLC using a Waters X-Bridge reverse phase column (C-18, 5 micron silica, 19 mm in diameter, 100 mm in length, flow rate 40 ml / minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. Fractions containing the desired compound were evaporated to dryness. The residue was triturated in diethyl ether, collected by filtration and dried to produce N- (2- (dimethylamino) ethyl) -8- (1 - ((4-fluorophenyl) (methyl) amino) ethyl) -2-morpholino- 4-oxo-4H-chromene-6-carboxamide (42.0 mg, 53.1%) as a white solid. Mass spectrum: M + H + 497. NMR spectrum: (CDCl3) 1.66 (d, 3H), 2.33 (s, 6H), 2.33 (bs, 2H), 2.60 (bs, 2H ), 2.61 (s, 3H), 3.09 - 3.24 (m, 4H), 3.44 - 3.57 (m, 4H), 3.57 - 3.66 (m, 2H), 5.36 (q, 1 H), 5.48 (s, 1 H), 6.75 (dd, 2H), 6.77 (dd, 2H), 7.14 (bs, 1 H), 8, 33 (s, 1 H), 8.44 (s, 1 H). The 8- (1-bromoethyl) -N- (2- (dimethylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide used as starting material was made as follows: -
[0345] [000345] To a suspension of methyl 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylate (193 mg, 0.41 mmol, as described in Example 2.00) in methanol (2 ml ) was added at -15 ° C sodium tetrahydroborate (15.4 mg, 0.41 mmol). The resulting suspension was stirred at -15 ° C for 20 minutes. The reaction mixture was quenched with a 2 N aqueous NaOH solution (0.408 ml, 0.82 mmol) and allowed to warm to room temperature for 1 hour. More NaOH (0.408 ml, 0.82 mmol) was added and stirring was continued for an additional 15 minutes. HCl (0.917 ml, 1.83 mmol) was added to adjust the pH from 2 to 3. The resulting precipitate was diluted with about 1 ml of water, collected by filtration, washed with ethyl acetate, diethyl ether and dried to a constant weight to produce 8- (1-hydroxyethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (122 mg, 94%) as an orange solid that was used without further purification. Mass spectrum: M + H + 320.
[0346] [000346] TSTU (104 mg, 0.34 mmol) at 25 ° C, was added portion-wise to 8- (1-hydroxyethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (110 mg, 0.34 mmol) and DIPEA (0.066 ml, 0.38 mmol) suspended in DCM (1 ml) under nitrogen. The resulting mixture was stirred at 25 ° C for 1.5 hours. N1, N1-dimethylethane-1,2-diamine (0.038 ml, 0.34 mmol) was then added and the mixture stirred at 25 ° C for 30 minutes. The mixture was poured into a column on silica gel and purified by sparkling chromatography eluting with 5% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness, the residue was triturated in diethyl ether, collected by filtration and dried to produce N- (2- (dimethyl-amino) ethyl) -8- (1-hydroxyethyl) -2-morpholino-4 -oxo-4H-chromene-6-carboxamide (80 mg, 0.205 mmol, 59.6%) as a yellowish white solid. Mass spectrum: M + H + 390.
[0347] [000347] A solution of tribromophosphine 1 M in DCM (0.154 ml, 0.15 mmol) at 25 ° C, was added to the drops to N- (2- (dimethylamino) ethyl) - 8- (1-hydroxyethyl) -2 -morpholino-4-oxo-4H-chromene-6-carboxamide (60 mg, 0.15 mmol) suspended in DCM (1 ml). This suspension was stirred at 25 ° C for 4 days. The resulting precipitate was collected by filtration, washed with diethyl ether and dried to produce 8- (1-bromoethyl) -N- (2- (dimethylamino) ethyl) -2-morpholino-4-oxo-4H-chromene- hydrobromide 6-carboxamide (98 mg,> 100%) as a white solid, which was used without further purification. Mass spectrum: M + H + 454. Example 3.01 8- (1 - ((3,4-difluorophenyl) (methyl) amino) ethyl) -N- (2- (dimethylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0348] [000348] 3,4-difluoro-N-methylaniline (161 mg, 1.13 mmol) was reacted with 8- (1-bromoethyl) -N- (2- (dimethylamino) ethyl) -2-morpholino-4 hydrobromide -oxo-4H-chromene-6-carboxamide (150 mg, 0.28 mmol) using a procedure similar to that described in Example 3.00 to give 8- (1- ((3,4-difluorophenyl) (methyl) amino ) ethyl) -N- (2- (dimethylamino) ethyl) -2-morpholino4-oxo-4H-chromene-6-carboxamide (66.0 mg, 45.6%). Mass spectrum: M + H + 515. NMR spectrum: (DMSOd6) 1.56 (d, 3H), 2.18 (s, 6H), 2.41 (t, 2H), 2.63 (s, 3H ), 3.21 - 3.28 (m, 2H), 3.34 - 3.41 (m partially hidden by H2O, 4H), 3.41 - 3.49 (m, 2H), 3.49 - 3 , 56 (m, 2H), 5.53 (q, 1 H), 5.55 (s, 1 H), 6.61 (d, 1 H), 6.87 (ddd, 1 H), 7, 24 (dd, 1 H), 8.09 (d, 1 H), 8.43 (d, 1 H), 8.74 (t, 1 H). Example 3.02 N- (2- (dimethylamino) ethyl) -8- (1 - ((4-fluorophenyl) (methyl) amino) ethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0349] [000349] 4-fluoro-N-methylaniline (82 mg, 0.66 mmol) was reacted with 8- (1-bromoethyl) -N- (2- (dimethylamino) ethyl) -N-methyl-2-morpholinohydride -4-oxo-4H-chromene-6-carboxamide (90 mg, 0.16 mmol) using a procedure similar to that described in example 3.00 to give N- (2- (dimethylamino) ethyl) -8- (1 - (((4-fluorophenyl) (methyl) amino) ethyl) - N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (39.0 mg, 46.4%) as a white solid. Mass spectrum: M + H + 511. NMR spectrum: (DMSOd6) at 323 ° K: 1.55 (d, 3H), 2.04 (bs, 6H), 2.40 (bs, 2H), 2, 68 (s, 3H), 2.93 (s, 3H), 3.22 - 3.36 (m, 4H), 3.37 (bs, 2H), 3.44 - 3.58 (m, 4H) , 5.45 (q, 1 H), 5.50 (s, 1 H), 6.82 (dd, 2H), 7.01 (dd, 2H), 7.56 (d, 1 H), 7 , 83 (d, 1 H).
[0350] [000350] The 8- (1-bromoethyl) -N- (2- (dimethylamino) ethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide was used as a starting material using a procedure similar to that described for the starting material in Example 3.00 except that N1, N1, N2-trimethylethane-1,2-diamine was used instead of N1, N1-dimethylethane-1,2-diamine. Example 3.03 8- (1- (3,4-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0351] [000351] 3,4-difluoroaniline (0.105 ml, 1.06 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6- hydrobromide carboxamide (130 mg, 0.27 mmol) using a procedure similar to that described in Example 3.00 to give 8- (1- (3,4-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino- 4-oxo-4H-chromene-6-carboxamide (35.0 mg, 28.8%) as a white solid. Mass spectrum: M + H + 458. NMR spectrum: (DMSOd6) 1.50 (d, 3H), 2.70 (s, 3H), 2.94 (s, 3H), 3.50 - 3.63 (m, 4H), 3.71 - 3.79 (m, 4H), 4.92 - 5.01 (m, 1 H), 5.60 (s, 1 H), 6.25 (d, 1 H), 6.46 (ddd, 1 H), 6.54 (d, 1 H), 7.05 (dd, 1 H), 7.54 (d, 1 H), 7.78 (d, 1 H).
[0352] [000352] A larger batch of the racemic compound above was resolved by chiral preparative HPLC using the following conditions:
[0353] [000353] First enantiomer to evolve 1100 mg (Example 3.03a) [α] D20 °: + 119 ° (99.1% ee) in MeCN
[0354] [000354] Second enantiomer to evolve 1090 mg (Example 3.03b) [α] D20 °: -120 ° (99.3% ee) in MeCN
[0355] [000355] The 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide used as starting material was made as follows:
[0356] [000356] TSTU (108 mg, 0.36 mmol) was added to the portions with 8- (1-hydroxyethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (115 mg, 0.36 mmol, as described in Example 3.00) and DIPEA (0.069 ml, 0.40 mmol) suspended in DCM (1 ml) at 25 ° C under nitrogen. The resulting mixture was stirred at 25 ° C for 1.5 hours. Dimethylamine (0.180 ml, 0.36 mmol) was then added and stirring was continued for an additional 30 minutes. The mixture was poured into a column on silica gel and purified by scintillation chromatography eluting with 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness. The residue was triturated in diethyl ether, collected by filtration and dried to produce 8- (1-hydroxyethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (123 mg, 0.355 mmol, 99%) as a yellowish white solid. Mass spectrum: M + H + 347.
[0357] [000357] A 1M solution of tribromophosphine of CH2Cl2 (0.346 ml, 0.35 mmol) at 25 ° C, was added to the drops at 8- (1-hydroxyethyl) -N, N-dimethyl-2-morpholino-4- oxo-4H-chromene-6-carboxamide (120 mg, 0.35 mmol) suspended in DCM (1 ml). The resulting suspension was stirred at 25 ° C for 4 days. The resulting gum was triturated in ether to give a precipitate which was collected by filtration, washed with ether and dried to a constant weight to produce 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4- hydrobromide oxo-4H-chromene-6-carboxamide (140 mg, 82%) as a white solid, which was used without further purification. Mass spectrum: M + H + 409. Example 3.04 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0358] [000358] 3-Chloro-2-fluoroaniline hydrobromide (0.179 ml, 1.63 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene -6-carboxamide (200 mg, 0.41 mmol, as described in Example 3.03) using a procedure similar to that described in Example 3.00 to give 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (121 mg, 62.6%) as a white solid. Mass spectrum: M + H + 474. NMR spectrum: (DMSOd6) 1.58 (d, 3H), 2.70 (s, 3H), 2.94 (s, 3H), 3.50 - 3.64 (m, 4H), 3.70 - 3.80 (m, 4H), 5.05 - 5.15 (m, 1 H), 5.60 (m, 1 H), 6.37 (dd, 1 H), 6.44 (d, 1 H), 6.65 (ddd, 1 H), 6.83 (dd, 1 H), 7.60 (d, 1 H), 7.78 (d, 1 H).
[0359] [000359] A larger batch of the racemic compound above was resolved by the chiral preparative HPLC using the following conditions:
[0360] [000360] 3-Chloro-4-fluoroaniline hydrobromide (238 mg, 1.63 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene -6-carboxamide (200 mg, 0.41 mmol, as described in Example 3.03) to give 8- (1- (3-chloro-4-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino -4-oxo-4H-chromene-6-carboxamide (122 mg, 63.1%) as a white solid. Mass spectrum: M + H + 474. NMR spectrum: (DMSOd6) 1.51 (d, 3H), 2.70 (s, 3H), 2.94 (s, 3H), 3.50 - 3.64 (m, 4H), 3.69 - 3.81 (m, 4H), 4.94 - 5.05 (m, 1 H), 5.60 (m, 1 H), 6.47 (ddd, 1 H), 6.52 (d, 1 H), 6.67 (dd, 1 H), 7.05 (dd, 1 H), 7.55 (d, 1 H), 7.79 (d, 1 H). Example 3.06 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0361] [000361] To a suspension of 8- (1-bromoethyl) -N, Ndimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (3.63 g, 7.41 mmol, as described in Example 3.03) in DMF (35 ml) under nitrogen, 3,5-difluoroaniline (3.82 g, 29.62 mmol) was added. The resulting yellow solution was stirred at 50 ° C for 5 hours. The reaction mixture was concentrated to dryness, then purified by silica gel scintillation chromatography eluting with 1 to 7% methanol in DCM. The solvent was evaporated to dryness to produce 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2,32 g, 68.5%) as a light yellow solid. Mass spectrum: M + H + 458. NMR spectrum: (DMSOd6) 1.52 (d, 3H), 2.74 (s, 3H), 2.95 (s, 3H), 3.50 - 3.64 (m, 4H), 3.70 - 3.79 (m, 4H), 4.97 - 5.05 (m, 1 H), 5.60 (m, 1 H), 6.15 (dd, 2H ), 6.22 (tt, 1 H), 6.96 (d, 1 H), 7.54 (d, 1 H), 7.81 (d, 1 H).
[0362] [000362] This racemic compound was resolved by chiral preparative HPLC using the following conditions: Gilson Prep Instrument (200 ml heads) Merck column 50 mm 20 μm Chiralpak IC Eluent MeCN / MeOH / DEA 90/10 / 0.2 Ambient greenhouse temperature Flow 60 ml / min Wavelength 254 nm Sample conc 12 mg / ml in MeCN / MeOH / DEA 90/10 / 0.5 Injection volume 30 ml Driving time 50 min
[0363] [000363] First enantiomer to evolve (room temperature: 10.8 min) 0.820 g (Example 3.06a) [α] D 20 = + 121.8 ° in EtOH.
[0364] [000364] Second enantiomer to evolve (room temperature: 15.4 min) 0.923 g (Example 3.06b) [α] D 20 = - 122.6 ° in EtOH.
[0365] [000365] Retention times (room temperature) are from chiral separation after analytical HPLC (1 ml / min, 20 μm Chiralpak AD MeCN / MeOH / DEA 90/10 / 0.5).
[0366] [000366] The second enantiomer to evolve (Example 3.06b) crystallized in ethanol, before drying under environmental conditions to produce the Form A material. This form was determined to be crystalline by XRPD (see Figure A) and has the following peaks X-ray powder diffraction characteristics:
[0367] [000367] DSC analysis of Form A was also performed (Figure B) and showed an initial event with a start at 125.8 ° C and a peak at 129.2 ° C, followed by an exothermic event before a fusion with a start of 223.8 ° C and a peak at 226.7 ° C.
[0368] [000368] Form B material was produced by pasting Form A in acetonitrile, ethyl acetate or methanol. as each of the solvents given approximately 20 mg of the original material was placed in a flask with a magnetic flea and approximately 2 ml of solvent added, the flask was then tightly sealed with a stopper and allowed to stir on a magnetic stirring plate. After 3 days, the sample was removed from the plate, the lid removed and the slurry allowed to dry under environmental conditions before it was analyzed by XRPD and DSC. This form (Form B) was determined to be crystalline by XRPD (Figure C) and observed to be different for Form A. This form has the following characteristic X-ray Diffraction peaks in the powder:
[0369] [000369] DSC analysis (Figure D) showed that the Form B material has a melting point of 225.8 ° C (start). Example 3.07 8- (1 - ((4-fluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0370] [000370] 4-Fluoro-N-methylaniline hydrobromide (204 mg, 1.63 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene -6-carboxamide (200 mg, 0.41 mmol, as described in Example 3.03), using a procedure analogous to that described in Example 3.00, to produce 8- (1 - ((4-fluorophenyl) ( methyl) amino) ethyl) - N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (96 mg, 51.9%) as a white solid. Mass spectrum: M + H + 454. NMR spectrum: (DMSOd6) 1.55 (d, 3H), 2.65 (s, 3H), 2.89 (s, 3H), 3.00 (s, 3H ), 3.20 - 3.27 (m, 2H), 3.27 - 3.33 (m partially hidden by H2O, 2H), 3.42 - 3.48 (ms, 2H), 3.48 - 3 , 56 (m, 2H), 5.48 (q, 1 H), 5.54 (s, 1 H), 6.83 (dd, 2H), 7.04 (dd, 1 H), 7.65 (d, 2H), 7.86 (d, 1 H). Example 3.08 8- (1 - ((3-chloro-4-fluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0371] [000371] 3-chloro-4-fluoro-N-methylaniline (260 mg, 1.63 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo hydrobromide -4H-chromene-6-carboxamide (200 mg, 0.41 mmol, as described in Example 3.03), using a procedure analogous to that described in Example 3.00, to produce 8- (1 - ((3 -chloro-4-fluorophenyl) (methyl) amino) -ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (107 mg, 53.7%) as a white solid . Mass spectrum: M + H + 488. NMR spectrum: (DMSOd6) 1.55 (d, 3H), 2.63 (s, 3H), 2.91 (s, 3H), 3.01 (s, 3H ), 3.20 - 3.29 (m, 2H), 3.30 - 3.37 (m partially hidden by H2O, 2H), 3.42 - 3.49 (ms, 2H), 3.49 - 3 , 57 (m, 2H), 5.54 (s, 1 H), 5.55 (q, 1 H), 6.79 (dd, 1 H), 6.98 (dd, 1 H), 7, 23 (dd, 1 H), 7.68 (d, 1 H), 7.87 (d, 1 H). Examples 3.09 to 3.13
[0372] [000372] For the preparation of the compounds of Examples 3.09 to 3.13 (shown in Table I), the appropriate aniline (1.20 mmol) and 8- (1-bromoethyl) -N, N-dimethyl hydrobromide -2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.123 g, 0.3 mmol) were suspended in NMP (1.0 ml) and sealed in a tube. The reaction was purged with argon and heated to 75 ° C over a period of 15 hours. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse phase column (C-18, 5 micron silica, 19 mm in diameter, 100 mm in length, 40 ml / minute flow rate) and the decreasingly polar mixtures of water (which contains 0.2% ammonium carbonate and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness.
[0373] [000373] NMR spectrum: (CDCl3) 1.62 (d, 3H), 2.85 (s, 3H), 3.06 (s, 3H), 3.42 - 3.55 (m, 4H), 3.76 - 3.77 (m, 4H), 4.14 (d, 1 H), 4.90 - 5.00 (m, 1 H), 5.54 (s, 1 H), 6.34 (dd, 1 H), 6.45 (dd, 1 H), 6.64 (dd, 1 H), 7.01 (dd, 1 H), 7.71 (d, 1 H), 8.12 (d, 1 H). Example 3.10:
[0374] [000374] NMR spectrum: (CDCl3) 1.67 (d, 3H), 2.86 (s, 3H), 3.07 (s, 3H), 3.44 - 3.57 (m, 4H), 3.79 - 3.88 (m, 4H), 4.38 (bs, 1 H), 4.94 - 5.02 (m, 1 H), 5.55 (s, 1 H), 6.08 (dd, 1 H), 6.48 (dd, 1 H), 6.74 (dd, 1 H), 7.71 (d, 1 H), 8.12 (d, 1 H). Example 3.11:
[0375] [000375] NMR spectrum: (CDCl3) 1.56 (d, 3H), 2.91 (s, 3H), 3.07 (s, 3H), 3.45 - 3.59 (m, 4H), 3.78 - 3.92 (m, 4H), 4.39 (d, 1 H), 4.77 - 4.88 (m, 1 H), 5.55 (s, 1 H), 6.01 (dd, 2H), 7.70 (d, 1 H), 8.12 (d, 1 H). Example 3.12:
[0376] [000376] NMR spectrum: (CDCl3) 1.60 (d, 3H), 2.85 (s, 3H), 3.06 (s, 3H), 3.45 - 3.55 (m, 4H), 3.76 - 3.87 (m, 4H), 4.22 (d, 1 H), 4.89 - 4.99 (m, 1 H), 5.55 (s, 1 H), 6.13 (ddd, 1 H), 6.26 (dd, 1 H), 6.36 (ddd, 1 H), 7.04 (dd, 1 H), 7.73 (d, 1 H), 8.11 (d, 1 H). Example 3.13:
[0377] [000377] NMR spectrum: (CDCl3): 1.67 (d, 3H), 2.92 (s, 3H), 3.09 (s, 3H), 3.46 - 3.58 (m, 4H) , 3.81 - 3.90 (m, 4H), 4.53 (bs, 1 H), 4.88 - 4.96 (m, 1 H), 5.56 (s, 1 H), 5, 80 - 5.88 (m, 1 H), 6.17 - 6.27 (m, 1 H), 7.71 (d, 1 H), 8.13 (d, 1 H).
[0378] [000378] A larger batch of this compound was prepared and the enantiomers separated as follows:
[0379] [000379] 4.2 g of the compound of Example 3.13 were subjected to chromatography on 2 injections using the conditions above. Each enantiomer was dissolved in MeOH and added to an SCX column. The column was flowed with MeOH then the product eluted with 7 M ammonia in MeOH. The solvents were evaporated, giving a glass that was pasted with MTBE (75 ml) for 48 hours until the whole was transformed into a white powdery solid. This was collected by filtration, washed with MTBE and dried under vacuum at 50 ° C.
[0380] [000380] First eluted enantiomer: 2.0 g isolated [α] D20 °: + 50 ° in DCM (enantiomer 1) Example 3.13a.
[0381] [000381] Second eluted enantiomer: 1.9 g isolated [α] D20 °: -50 ° in DCM (enantiomer 2) Example 3.13b.
[0382] [000382] The second enantiomer to evolve (Example 3.13b) crystallized in DCM, before drying under environmental conditions to produce the Form A material. This form was determined to be crystalline by XRPD (see Figure E) and has the following peaks X-ray powder diffraction characteristics:
[0383] [000383] DSC analysis of Form A was also performed (Figure F) and showed that this material has a melting point of 156.0 ° C (start).
[0384] [000384] Form B material was produced by pasting Form A in a water / methanol mixture. Approximately 20 mg of the original material was placed in a bottle with a magnetic flea and approximately 100 ml of methanol and 2 ml of water added, the bottle was then tightly sealed with a lid and allowed to stir on a magnetic stirring plate. After 3 days, the sample was removed from the plate, the lid removed and the slurry allowed to dry under environmental conditions before it was analyzed by XRPD and DSC. This form (Form B) was determined to be crystalline by XRPD (Figure G) and observed to be different for Form A. The form has the following characteristic X-ray Diffraction peaks in Powder:
[0385] [000385] This material has a start of desolvation at 98.6 ° C (start) (see Figure H) and the thermogravimetric analysis showed that the material had a loss of mass compatible with a solvate in methanol 1: 1 (Figure I) . Example 3.14 8- (1- (3-chloro-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0386] [000386] 3-Chloro-5-fluoroaniline hydrobromide (0.074 ml, 0.73 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene -6-carboxamide (0.09 g, 0.18 mmol)) using a procedure analogous to that described in Example 3.03 to give 8- (1- (3-chloro-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.065 g, 75%) as a white solid. Mass spectrum: M + H + 474. NMR spectrum (CDCl3): 1.61 (d, 3H), 2.90 (bs, 3H), 3.09 (bs, 3H), 3.46 - 3.55 (m, 4H), 3.80 - 3.88 (m, 4H), 4.35 (d, 1 H), 4.88 - 4.96 (m, 1 H), 5.56 (s, 1 H), 6.03 (ddd, 1 H), 6.27 (dd, 1 H), 6.39 (ddd, 1 H), 7.70 (d, 1 H), 8.12 (d, 1 H). Example 3.15 8- (1- (2,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0387] [000387] 2,5-difluoroaniline (0.074 ml, 0.73 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene- hydrobromide 6-carboxamide (0.09 g, 0.18 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (2,5-difluorophenylamino) -ethyl) -N, N-dimethyl- 2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.055 g, 66%) as a white solid. Mass spectrum: M + H + 458. NMR spectrum (DMSOd6): 1.57 (d, 3H), 2.72 (bs, 3H), 2.94 (bs, 3H), 3.51 - 3.64 (m, 4H), 3.71 - 3.78 (m, 4H), 5.02 - 5.11 (m, 1 H), 5.61 (s, 1 H), 6.19 - 1.33 (m, 2H), 6.43 (d, 1 H), 7.01 - 7.09 (m, 1 H), 7.60 (d, 1 H), 7.79 (d, 1 H). Example 3.16 8- (1- (3-fluoro-5-methylphenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0388] [000388] 3-fluoro-5-methylaniline (0.091 ml, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (0.1 g, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (3-fluoro-5-methyl-phenylamino) ethyl) - N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.053 g, 57%) as a white solid. Mass spectrum: M + H + 454.
[0389] [000389] NMR spectrum (CDCl3): 1.60 (d, 3H), 2.20 (s, 3H), 2.87 (bs, 3H), 3.07 (bs, 3H), 3.45 - 3.54 (m, 4H), 3.79 - 3.85 (m, 4H), 4.11 (d, 1 H), 4.90 - 4.97 (m, 1 H), 5.55 ( s, 1 H), 5.92 (ddd, 1 H), 6.12 (s, 1 H), 6.20 (d, 1 H), 7.73 (d, 1 H), 8.12 ( d, 1 H). Example 3.17 8- (1- (3-cyano-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0390] [000390] 3-Amino-5-fluorobenzonitrile (0.111 g, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (0.1 g, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (3-cyano-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.052 g, 55%) as a white solid. Mass spectrum: M + H + 465. NMR spectrum (CDCl3): 1.62 (d, 3H), 2.92 (bs, 3H), 3.08 (bs, 3H), 3.45 - 3.58 (m, 4H), 3.82 - 3.91 (m, 4H), 4.61 (d, 1 H), 4.88 - 4.97 (m, 1 H), 5.57 (s, 1 H), 6.36 (ddd, 1 H), 6.49 (dd, 1 H), 6.65 (ddd, 1 H), 7.70 (d, 1 H), 8.14 (d, 1 H). Example 3.18 8- (1- (3-cyanophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0391] [000391] 3-Aminobenzonitrile (96 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6- hydrobromide carboxamide (0.1 g, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (3-cyanophenylamino) ethyl) -N, N-dimethyl-2-morpholino- 4-oxo-4H-chromene-6-carboxamide (44 mg, 48%) as a white solid. Mass spectrum: M + H + 447.
[0392] [000392] NMR spectrum (CDCl3): 1.63 (d, 3H), 2.88 (bs, 3H), 3.07 (bs, 3H), 3.45 - 3.58 (m, 4H), 3.81 - 3.88 (m, 4H), 4.35 (d, 1 H), 4.91 - 4.99 (m, 1 H), 5.57 (s, 1 H), 6.64 (s, 1 H), 6.70 (dd, 1 H), 6.96 (d, 1 H), 7.19 (dd, 1 H), 7.71 (d, 1 H), 8.13 (d, 1 H). Example 3.19 8- (1- (2,3-dichlorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0393] [000393] 2,3-dichloroaniline (0.097 ml, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene- hydrobromide 6-carboxamide (0.1 g, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (2,3-dichlorophenylamino) ethyl) -N, N-dimethyl-2 -morpholino-4-oxo-4H-chromene-6-carboxamide (51 mg, 51%) as a white solid. Mass spectrum: M + H + 490.
[0394] [000394] NMR spectrum (CDCl3): 1.69 (d, 3H), 2.85 (s, 3H), 3.07 (s, 3H), 3.47 - 3.56 (m, 4H), 3.79 - 3.88 (m, 4H), 4.86 (d, 1 H), 4.93 - 5.02 (m, 1 H), 5.56 (s, 1 H), 6.19 (d, 1 H), 6.78 (dd, 1 H), 6.89 (dd, 1 H), 7.66 (d, 1 H), 8.12 (d, 1 H). Example 3.20 8- (1- (3-ethynylphenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0395] [000395] 3-Ethinylaniline (0.083 ml, 0.73 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6- hydrobromide carboxamide (0.09 g, 0.18 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (3-ethynylphenylamino) ethyl) -N, N-dimethyl-2-morpholino- 4-oxo-4H-chromene-6-carboxamide (52 mg, 64%) as a white solid. Mass spectrum: M + H + 446.
[0396] [000396] NMR spectrum (DMSOd6): 1.52 (d, 3H), 2.68 (bs, 3H), 2.93 (bs, 3H), 3.50 - 3.64 (m, 4H), 3.69 - 3.79 (m, 4H), 3.99 (s, 1 H), 4.98 - 5.06 (m, 1 H), 5.60 (s, 1 H), 6.46 - 6.54 (m, 2H), 6.57 - 6.63 (m, 2H), 7.00 (dd, 1 H), 7.56 (d, 1 H), 7.78 (d, 1 H). Example 3.21 8- (1- (5-cyano-2-methylphenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0397] [000397] 3-Amino-4-methylbenzonitrile (108 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (5-cyano-2-methylphenylamino) ethyl) -N, N-dimethyl -2-morpholino-4-oxo-4H-chromene-6-carboxamide (50 mg, 53%) as a white solid. Mass spectrum: M + H + 461. NMR spectrum (DMSOd6): 1.62 (d, 3H), 2.30 (s, 3H), 2.69 (bs, 3H), 2.93 (bs, 3H ), 3.51 - 3.64 (m, 4H), 3.70 - 3.80 (m, 4H), 5.00 - 5.08 (m, 1 H), 5.56 (d, 1 H ), 5.61 (s, 1 H), 5.96 (dd, 1 H), 6.24 (ddd, 1 H), 6.96 (dd, 1 H), 7.58 (d, 1 H ), 7.79 (d, 1 H). Example 3.22 8- (1- (5-fluoro-2-methylphenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0398] [000398] 5-fluoro-2-methylaniline (102 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene hydrobromide -6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (5-fluoro-2-methylphenyl-amino) ethyl) -N, N- dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (56 mg, 61%) as a white solid. Mass spectrum: M + H + 454. NMR spectrum (DMSOd6): 1.60 (d, 3H), 2.20 (s, 3H), 2.69 (bs, 3H), 2.93 (bs, 3H ), 3.53 - 3.65 (m, 4H), 3.72 - 3.80 (m, 4H), 5.08 - 5.18 (m, 1 H), 5.62 (s, 1 H ), 5.73 (d, 1 H), 6.52 (d, 1 H), 6.92 (dd, 1 H), 7.18 (dd, 1 H), 7.58 (d, 1 H ), 7.80 (d, 1 H). Example 3.23 8- (1- (3-cyano-5-methylphenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0399] [000399] 3-Amino-5-methylbenzonitrile (108 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using an analogous procedure similar to that described in Example 3.03 to give 8- (1- (3-cyano-5-methylphenylamino) ethyl) -N, N -dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (45 mg, 48%) as a white solid. Mass spectrum: M + H + 461. NMR spectrum (DMSOd6): 1.53 (d, 3H), 2.16 (s, 3H), 2.71 (bs, 3H), 2.94 (bs, 3H ), 3.51 - 3.64 (m, 4H), 3.69 - 3.80 (m, 4H), 5.00 - 5.10 (m, 1 H), 5.61 (s, 1 H ), 6.60 (s, 1 H), 6.67 (s, 1 H), 6.73 (d, 1 H), 6.74 (s, 1 H), 7.54 (d, 1 H ), 7.79 (d, 1 H). Example 3.24 8- (1- (5-fluoro-2-methoxyphenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0400] [000400] 5-fluoro-2-methoxyaniline (115 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene hydrobromide -6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (5-fluoro-2-methoxyphenylamino) ethyl) -N, N-dimethyl -2-morpholino-4-oxo-4H-chromene-6-carboxamide (54 mg, 56%) as a white solid. Mass spectrum: M + H + 470. NMR spectrum (DMSOd6): 1.58 (d, 3H), 2.71 (bs, 3H), 2.94 (bs, 3H), 3.51 - 3.64 (m, 4H), 3.70 - 3.78 (m, 4H), 3.82 (s, 3H), 4.97 - 5.06 (m, 1 H), 5.61 (s, 1 H ), 6.60 (s, 1 H), 6.67 (s, 1 H), 6.73 (d, 1 H), 6.74 (s, 1 H), 7.54 (d, 1 H ), 7.79 (d, 1 H). Example 3.25 8- (1- (5-cyano-2-methoxyphenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0401] [000401] 3-Amino-4-methoxybenzonitrile (121 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (5-cyano-2-methoxyphenylamino) ethyl) -N, N- dimethyl-2-morpholino-4-oxo-4H-Romanian-6-carboxamide (50 mg, 51%) as a white solid. Mass spectrum: M + H + 477. NMR spectrum (DMSOd6): 1.60 (d, 3H), 2.72 (bs, 3H), 2.94 (bs, 3H), 3.51 - 3.65 (m, 4H), 3.71 - 3.80 (m, 4H), 3.92 (s, 3H), 5.05 - 5.13 (m, 1 H), 5.61 (s, 1 H ), 5.86 (d, 1 H), 6.57 (d, 1 H), 6.98 (d, 1 H), 7.03 (dd, 1 H), 7.57 (d, 1 H ), 7.79 (d, 1 H). Example 3.26 8- (1- (2-chloro-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0402] [000402] 2-chloro-5-fluoroaniline (119 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (2-chloro-5-fluoro-phenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (45 mg, 47%) as a white solid. Mass spectrum: M + H + 474. NMR spectrum (DMSOd6): 1.62 (d, 3H), 2.74 (bs, 3H), 2.94 (bs, 3H), 3.51 - 3.65 (m, 4H), 3.69 - 3.79 (m, 4H), 5.06 - 5.16 (m, 1 H), 5.61 (s, 1 H), 5.99 (d, 1 H), 6.27 (dd, 1 H), 6.40 (ddd, 1 H), 7.30 (dd, 1 H), 7.59 (d, 1 H), 7.80 (d, 1 H). Example 3.27 N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2,3,6-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide
[0403] [000403] 2,3,6-trifluoroaniline (0.086 ml, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give N, N-dimethyl-2-morpholino-4-oxo-8- (1- (2, 3,6-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide (42 mg, 43%) as a white solid. Mass spectrum: M + H + 476. NMR spectrum (DMSOd6): 1.56 (d, 3H), 2.75 (bs, 3H), 2.97 (bs, 3H), 3.50 - 3.59 (m, 4H), 3.69 - 3.80 (m, 4H), 5.38 - 5.47 (m, 1 H), 5.57 (s, 1 H), 6.05 (d, 1 H), 6.60 - 6.70 (m, 1 H), 6.86 - 6.96 (m, 1 H), 7.73 (d, 1 H), 7.76 (d, 1 H) . Example 3.28 8- (1- (5-chloro-2-methylphenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0404] [000404] 5-chloro-2-methylaniline (0.098 ml, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (5-chloro-2-methyl-phenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (56 mg, 58%) as a white solid. Mass spectrum: M + H + 470. NMR spectrum (DMSOd6): 1.61 (d, 3H), 2.21 (s, 3H), 2.71 (bs, 3H), 2.93 (bs, 3H ), 3.52 - 3.65 (m, 4H), 3.70 - 3.80 (m, 4H), 5.03 - 5.11 (m, 1 H), 5.55 (d, 1 H ), 5.62 (s, 1 H), 6.19 (d, 1 H), 6.49 (dd, 1 H), 6.97 (d, 1 H), 7.62 (d, 1 H ), 7.79 (d, 1 H). Example 3.29 8- (1- (3-cyano-2-methylphenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0405] [000405] 3-Amino-2-methylbenzonitrile (108 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (3-cyano-2-methylphenylamino) ethyl) -N, N- dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (52 mg, 55%) as a white solid. Mass spectrum: M + H + 461.
[0406] [000406] NMR spectrum (DMSOd6): 1.61 (d, 3H), 2.45 (s, 3H), 2.65 (bs, 3H), 2.92 (bs, 3H), 3.50 - 3.64 (m, 4H), 3.70 - 3.79 (m, 4H), 5.05 - 5.14 (m, 1 H), 5.61 (s, 1 H), 5.81 ( d, 1 H), 6.46 (d, 1 H), 6.92 (d, 1 H), 7.02 (dd, 1 H), 7.56 (d, 1 H), 7.78 ( d, 1 H). Example 3.30 8- (1- (3-fluoro-5-methoxyphenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0407] [000407] 3-fluoro-5-methoxyaniline (115 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (3-fluoro-5-methoxyphenylamino) ethyl) -N, N- dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (60 mg, 63%) as a white solid. Mass spectrum: M + H + 470. NMR spectrum (DMSOd6): 1.50 (d, 3H), 2.74 (bs, 3H), 2.94 (bs, 3H), 3.50 - 3.63 (m, 4H), 3.61 (s, 3H), 3.68 - 3.79 (m, 4H), 4.94 - 5.03 (m, 1 H), 5.60 (s, 1 H ), 5.87 (dd, 1 H), 5.88 (s, 1 H), 5.93 (ddd, 1 H), 6.63 (d, 1 H), 7.57 (d, 1 H ), 7.79 (d, 1 H). Example 3.31 8- (1- (3-fluoro-2-methoxyphenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0408] [000408] 3-fluoro-2-methoxyaniline (115 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (3-fluoro-2-methoxyphenylamino) ethyl) -N, N- dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (57 mg, 60%) as a white solid. Mass spectrum: M + H + 470. NMR spectrum (DMSOd6): 1.59 (d, 3H), 2.70 (bs, 3H), 2.93 (bs, 3H), 3.50 - 3.63 (m, 4H), 3.71 - 3.79 (m, 4H), 3.83 (s, 3H), 5.02 - 5.11 (m, 1 H), 5.60 (s, 1 H ), 5.95 (d, 1 H), 6.11 (d, 1 H), 6.39 (dd, 1 H), 6.72 (ddd, 1 H), 7.59 (d, 1 H ), 7.78 (d, 1 H). Example 3.32 8- (1- (3-chloro-2,6-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0409] [000409] 3-chloro-2,6-difluoroaniline (133 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo- hydrobromide 4H-chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (3-chloro-2,6-difluorophenylamino) ethyl) - N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (47 mg, 47%) as a white solid. Mass spectrum: M + H + 492. NMR spectrum (DMSOd6): 1.56 (d, 3H), 2.74 (bs, 3H), 2.97 (bs, 3H), 3.50 - 3.58 (m, 4H), 3.70 - 3.80 (m, 4H), 5.37 - 5.46 (m, 1 H), 5.57 (s, 1 H), 5.99 (d, 1 H), 6.81 (ddd, 1 H), 6.94 (ddd, 1 H), 7.72 (d, 1 H), 7.76 (d, 1 H). Example 3.33 8- (1- (3,5-dichlorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0410] [000410] 3,5-dichloroaniline (132 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene- hydrobromide 6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (3,5-dichlorophenylamino) -ethyl) -N, N-dimethyl-2 -morpholino-4-oxo-4H-chromene-6-carboxamide (75 mg, 75%) as a white solid. Mass spectrum: M + H + 490. NMR spectrum (DMSOd6): 1.52 (d, 3H), 2.75 (bs, 3H), 2.95 (bs, 3H), 3.51 - 3.63 (m, 4H), 3.70 - 3.78 (m, 4H), 5.01 - 5.09 (m, 1 H), 5.61 (s, 1 H), 6.50 (s, 2H ), 6.61 (s, 1 H), 6.91 (d, 1 H), 7.54 (d, 1 H), 7.81 (d, 1 H) Example 3.34 8- (1- (3-ethynyl-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0411] [000411] 3-Ethynyl-5-fluoroaniline (165 mg, 1.22 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (3-ethynyl-5-fluorophenylamino) ethyl) -N, N- dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (80 mg, 56%) as a white solid. Mass spectrum: M + H + 464. NMR spectrum (DMSOd6): 1.52 (d, 3H), 2.72 (bs, 3H), 2.94 (bs, 3H), 3.50 - 3.63 (m, 4H), 3.69 - 3.78 (m, 4H), 4.12 (s, 1 H), 4.98 - 5.07 (m, 1 H), 5.66 (s, 1 H), 6.31 (d, 1 H), 6.40 (d, 1 H), 6.46 (s, 1 H), 6.81 (d, 1 H), 7.54 (d, 1 H), 7.80 (d, 1 H). Example 3.35 8- (1- (2-cyano-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0412] [000412] 2-Amino-4-fluorobenzonitrile (111 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1- (2-cyano-5-fluorophenylamino) ethyl) -N, N- dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (40 mg, 42%) as a white solid. Mass spectrum: M + H + 465. NMR spectrum (DMSOd6): 1.62 (d, 3H), 2.76 (bs, 3H), 2.96 (bs, 3H), 3.49 - 3.64 (m, 4H), 3.67 - 3.79 (m, 4H), 5.12 - 5.22 (m, 1 H), 5.61 (s, 1 H), 6.35 (dd, 1 H), 6.52 (ddd, 1 H), 6.88 (d, 1 H), 7.61 (dd, 1 H), 7.68 (d, 1 H), 7.82 (d, 1 H). Example 3.36 8- (1- (2-cyano-3-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0413] [000413] 2-Amino-6-fluorobenzonitrile (111 mg, 0.82 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H- hydrobromide chromene-6-carboxamide (100 mg, 0.20 mmol) using a procedure analogous to that described in Example 3.03.
[0414] [000414] The crude product was purified by silica gel scintillation chromatography eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness. The resulting oil was crystallized from ethyl acetate to give 8- (1- (2-cyano-3-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6 -carboxamide (45.0 mg, 64.3%) as a white solid. Mass spectrum: M + H + 465. NMR spectrum (DMSOd6): 1.61 (d, 3H), 2.74 (bs, 3H), 2.95 (bs, 3H), 3.49 - 3.62 (m, 4H), 3.69 - 3.77 (m, 4H), 5.17 - 5.26 (m, 1 H), 5.61 (s, 1 H), 6.33 (d, 1 H), 6.56 (dd, 1 H), 6.99 (d, 1 H), 7.32 (dd, 1 H), 7.69 (d, 1 H), 7.81 (d, 1 H). Example 3.37 8- (1 - ((3-chloro-5-fluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0415] [000415] 3-chloro-5-fluoro-N-methylaniline (195 mg, 1.22 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4- hydrobromide oxo-4H-chromene-6-carboxamide (150 mg, 0.31 mmol) using a procedure analogous to that described in Example 3.03 to give 8- (1 - ((3-chloro-5-fluorophenyl) (methyl ) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (38 mg, 25%) as a white solid. Mass spectrum: M + H + 488. NMR spectrum (DMSOd6): 1.55 (d, 3H), 2.61 (s, 3H), 2.93 (bs, 3H), 3.01 (bs, 3H ), 3.20 - 3.27 (m, 2H), 3.33 - 3.37 (m partially hidden by H2O, 2H), 3.42 - 3.48 (m, 2H), 3.49 - 3 , 55 (m, 2H), 5.55 (s, 1 H), 5.61 (q, 1 H), 6.61 (d, 1 H), 6.66 (d, 1 H), 6, 75 (s, 1 H), 7.71 (d, 1 H), 7.89 (d, 1 H). Example 3.38 N, N-dimethyl-8- (1- (methyl (3,4,5-trifluorophenyl) amino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0416] [000416] 3,4,5-trifluoro-N-methylaniline (197 mg, 1.22 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4- hydrobromide oxo-4H-chromene-6-carboxamide (150 mg, 0.31 mmol) using a procedure analogous to that described in Example 3.03 to give N, N-dimethyl-8- (1- (methyl (3,4, 5-trifluorophenyl) amino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide (54.0 mg, 36.1%) as a white solid. Mass spectrum: M + H + 490. NMR spectrum (DMSOd6): 1.54 (d, 3H), 2.62 (s, 3H), 2.91 (bs, 3H), 3.00 (bs, 3H ), 3.24 - 3.31 (m partially hidden by H2O, 2H), 3.33 - 3.42 (m partially hidden by H2O, 2H), 3.45 - 3.52 (m, 2H), 3 , 52 - 3.60 (m, 2H), 5.55 q, 1 H), 5.56 (s, 1 H), 6.73 (d, 1 H), 6.75 (d, 1 H) , 7.67 (d, 1 H), 7.89 (d, 1 H). Example 3.39 N, N-dimethyl-8- (1- (methyl (2,3,5-trifluorophenyl) amino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0417] [000417] 2,3,5-trifluoro-N-methylaniline (197 mg, 1.22 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4- hydrobromide oxo-4H-chromene-6-carboxamide (150 mg, 0.31 mmol) using a procedure analogous to that described in Example 3.03 to give N, N-dimethyl-8- (1- (methyl (2,3 , 5-trifluorophenyl) amino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide (12 mg, 8%) as a white solid. Mass spectrum: M + H + 490. NMR spectrum (DMSOd6): 1.63 (d, 3H), 2.67 (s, 3H), 2.92 (bs, 3H), 3.02 (bs, 3H ), 3.18 - 3.26 (m, 2H), 3.22 - 3.37 (m partially hidden by H2O, 2H), 3.49 - 3.56 (m, 2H), 3.56 - 3 , 63 (m, 2H), 5.38 (q, 1 H), 5.53 (s, 1 H), 6.68 - 6.75 (m, 1 H), 6.88 - 6.96 ( m, 1 H), 7.78 (d, 1 H), 7.86 (d, 1 H). Example 3.40 N, N-dimethyl-8- (1- (methyl (phenyl) amino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0418] [000418] N-Methylaniline (153 mg, 1.43 mmol) was reacted with 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6- hydrobromide carboxamide (175 mg, 0.36 mmol) using a procedure analogous to that described in Example 3.03 to give N, N-dimethyl-8- (1- (methyl (phenyl) -amino) ethyl) -2-morpholino -4-oxo-4H-chromene-6-carboxamide (57 mg, 37%) as a white solid. Mass spectrum: M + H + 436. NMR spectrum (DMSOd6): 1.57 (d, 3H), 2.65 (s, 3H), 2.90 (bs, 3H), 3.00 (bs, 3H ), 3.16 - 3.22 (m, 2H), 3.23 - 3.31 (m partially hidden by H2O, 2H), 3.36 - 3.42 (m, 2H), 3.42 - 3 , 49 (m, 2H), 5.52 (s, 1 H), 5.55 (q, 1 H), 6.66 (t, 1 H), 6.84 (d, 2H), 7.19 (t, 2H), 7.67 (d, 1 H), 7.87 (d, 1 H). Example 3.41 8- (1 - ((3-ethynyl-5-fluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0419] [000419] A 8- (1-bromoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (185 mg, 0.37 mmol), N, N-diethylaniline (174 µl, 1.10 mmol) and 3-ethynyl-5-fluoro-N-methylaniline (60 mg, 0.40 mmol) in DMF (1043 µl) were stirred at 50 ° C for 2 days.
[0420] [000420] Purification was done using a procedure analogous to that described in Example 3.03 to give 8- (1 - ((3-ethynyl-5-fluorophenyl) - (methyl) amino) ethyl) -N, N- dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (60 mg, 34%) as a white solid. Mass spectrum: M + H + 478. NMR spectrum (DMSOd6): 1.55 (d, 3H), 2.62 (s, 3H), 2.92 (bs, 3H), 3.01 (bs, 3H ), 3.18 - 3.27 (m, 2H), 3.28 - 3.33 (m partially hidden by H2O, 2H), 3.40 - 3.48 (m, 2H), 3.48 - 3 , 57 (m, 2H), 4.21 (s, 1 H), 5.54 (q, 1 H), 5.62 (s, 1 H), 6.52 (d, 1 H), 6, 73 (d, 1 H), 6.80 (s, 1 H), 7.72 (d, 1 H), 7.89 (d, 1 H). Examples 4.01 to 4.26
[0421] [000421] 0.17 mmol of a previously prepared solution of 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylate of 2,5-dioxopyrrolidin -1-yl was introduced into 26 vials, each containing the appropriate amine (0.51 mmol) for each Example compound (as shown under the column named 'Reagent Name' in Table II). The resulting solution was stirred at 35 ° C for 2 hours, concentrated to dryness and diluted with DMF (1.5 ml). The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse phase column (C-18, 5 micron silica, 19 mm in diameter, 100 mm in length, 40 ml / minute flow rate) and the decreasingly polar mixtures of water (which contains 0.2% ammonium carbonate) and acetonitrile as eluent. Fractions containing the desired compound were evaporated to dryness to produce the desired product.
[0422] [000422] Example 4.01: NMR spectrum: (DMSOd6) at 353 ° K: 1.01 (t, 6H), 1.56 (d, 3H), 3.25 (bs, 4H), 3.52 - 3.65 (m, 4H), 3.73 - 3.81 (m, 4H), 4.98 - 5.06 (m, 1 H), 5.55 (s, 1 H), 6.11 -6.22 (m, 3H), 6.72 (d, 1 H), 7.54 (d, 1 H), 7.78 (d, 1 H).
[0423] [000423] Example 4.02: NMR spectrum: (DMSOd6) at 323 ° K: 1.52 (d, 3H), 1.66-1.78 (m, 2H), 1.78-1.91 ( m, 2H), 3.07 - 3.23 (m, 2H), 3.37 - 3.49 (m partially hidden by H2O, 2H), 3.51 - 3.64 (m, 4H), 3, 69 - 3.81 (m, 4H), 4.98 - 5.08 (m, 1 H), 5.61 (s, 1 H), 6.16 (dd, 2H), 6.24 (ddd, 1 H), 6.97 (d, 1 H), 7.67 (d, 1 H), 7.93 (d, 1 H).
[0424] [000424] Example 4.03: NMR spectrum: (DMSOd6) 1.52 (d, 3H), 1.93 (bs, 1 H), 2.08 (bs, 1 H), 2.14 (s, 3H), 2.41 (bs, 2H), 3.05 (bs, 2H), 3.50 - 3.64 (m, 5H), 3.68 (bs, 1 H), 3.72 - 3, 80 (ms, 4H), 4.98 - 5.06 (m, 1 H), 5.62 (s, 1 H), 6.15 (dd, 2H), 6.25 (ddd, 1 H), 6.98 (d, 1 H), 7.46 (d, 1 H), 7.78 (d, 1 H).
[0425] [000425] Example 4.04: NMR spectrum: (DMSOd6) 1.52 (d, 3H), 2.43 (bs, 2H), 2.69 (bs, 2H), 3.00 (bs, 2H) , 3.46 (bs partially hidden by H2O, 2H), 3.50 - 3.65 (m, 5H), 3.70 - 3.79 (m, 4H), 4.97 - 5.05 (m, 1 H), 5.61 (s, 1 H), 6.14 (dd, 2H), 6.24 (ddd, 1 H), 6.98 (d, 1 H), 7.47 (d, 1 H), 7.78 (d, 1 H).
[0426] [000426] The removal of the tert-butyl carboxylate protection group was carried out as follows:
[0427] [000427] The crude solution was washed with a 10% citric acid solution (pH ~ 4), water, dried over magnesium sulfate and concentrated. HCl (4 N in dioxane; 1066 µl, 4.27 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The volatiles were removed under vacuum and the residue dissolved in 10% methanolic ammonia in DCM (5 ml). Insolubles were removed by filtration, the filtrate was concentrated and the crude product was purified by preparative HPLC as described above.
[0428] [000428] Example 4.05: NMR spectrum: (DMSOd6) 1.52 (d, 3H), 2.32 (bs, 2H), 2.66 (bs, 2H), 3.45 (bs partially hidden by H2O, 1 H), 3.50 - 3.64 (m, 5H), 3.68 (bs, 1 H), 3.70 - 3.81 (m, 4H), 3.96 (bs, 1 H ), 4.96 - 5.06 (m, 1 H), 5.61 (s, 1 H), 6.14 (dd, 2H), 6.25 (ddd, 1 H), 6.96 (d , 1 H), 7.51 (d, 1 H), 7.80 (d, 1 H).
[0429] [000429] Example 4.06: NMR spectrum: (DMSOd6) 1.11 - 1.22 (m, 1 H), 1.22 - 1.32 (m, 1 H), 1.32 - 1.43 (m, 2H), 1.44 - 1.55 (m, 2H), 1.52 (d, 3H), 1.62 - 1.73 (m, 2H), 3.03 - 3.12 (m , 2H), 3.37 - 3.45 (m partially hidden by H2O, 1 H), 3.51 - 3.70 (m, 5H), 3.71 - 3.79 (m, 4H), 4, 97 - 5.06 (m, 1 H), 5.61 (s, 1 H), 6.14 (dd, 2H), 6.23 (ddd, 1 H), 6.98 (d, 1 H) , 7.45 (d, 1 H), 7.73 (d, 1 H).
[0430] [000430] Example 4.07: NMR spectrum: (DMSOd6) at 323 ° K: 1.54 (d, 3H), 2.90 (bs, 3H), 3.20 (bs partially hidden by H2O, 2H) , 3.47 (bs, 2H), 3.51 - 3.64 (m, 4H), 3.71 - 3.79 (m, 4H), 4.61 (bs, 1 H), 4.97 - 5.05 (m, 1 H), 5.58 (s, 1 H), 6.15 (dd, 2H), 6.20 (ddd, 1 H), 6.83 (d, 1 H), 7 , 58 (d, 1 H), 7.84 (d, 1 H).
[0431] [000431] Example 4.08: NMR spectrum: (DMSOd6) 1.51 (d, 3H), 2.17 - 2.28 (m, 2H), 3.49 - 3.64 (m, 4H), 3.70 - 3.79 (m, 4H), 3.97 - 4.09 (m, 2H), 4.09 - 4.20 (m, 2H), 4.97 - 5.06 (m, 1 H), 5.62 (s, 1 H), 6.15 (dd, 2H), 6.23 (ddd, 1 H), 7.04 (d, 1 H), 7.79 (d, 1 H ), 8.03 (d, 1 H).
[0432] [000432] Example 4.09: NMR spectrum: (DMSOd6) at 323 ° K: 1.27 (bs, 2H), 1.54 (d, 3H), 1.64 (bs, 2H), 3.04 (bs, 2H), 3.49 (bs, 1 H), 3.52 - 3.62 (m, 4H), 3.63 (bs, 1 H), 3.66 - 3.74 (bs, 1 H), 3.72 - 3.80 (m, 4H), 4.66 (d, 1 H), 4.97 - 5.05 (m, 1 H), 5.58 (s, 1 H), 6.15 (dd, 2H), 6.20 (ddd, 1 H), 6.86 (d, 1 H), 7.53 (d, 1 H), 7.80 (d, 1 H).
[0433] [000433] Example 4.10: NMR spectrum: (DMSOd6) at 323 ° K: 1.39 (bs, 4H), 1.54 (d, 3H), 1.54-4.64 (m, 2H) , 3.31 (bs partially hidden by H2O, 4H), 3.49 - 3.66 (m, 4H), 3.68 - 3.84 (m, 4H), 4.96 - 5.07 (m, 1 H), 5.58 (s, 1 H), 6.14 (dd, 2H), 6.20 (ddd, 1 H), 6.86 (d, 1 H), 7.52 (d, 1 H), 7.79 (d, 1 H).
[0434] [000434] Example 4.11: NMR spectrum: (DMSOd6) at 323 ° K: 0.96 (bs, 3H), 1.54 (d, 3H), 2.85 (bs, 3H), 3.23 (bs partially hidden by H2O, 2H), 3.51 - 3.65 (m, 4H), 3.75 - 3.82 (m, 4H), 4.97 - 5.06 (m, 1 H), 5.58 (s, 1 H), 6.15 (dd, 2H), 6.20 (ddd, 1 H), 6.86 (d, 1 H), 7.54 (s, 1 H), 7 , 79 (d, 1 H).
[0435] [000435] Example 4.12: NMR spectrum: (DMSOd6) at 323 ° K: 1.53 (d, 3H), 3.51 - 3.64 (m, 4H), 3.71 - 3.80 ( m, 4H), 3.84 (bs, 2H), 4.19 - 4.32 (m, 2H), 4.43-4.52 (m, 1 H), 4.97 - 5.06 (m , 1 H), 5.59 (s, 1 H), 5.63 (d, 1 H), 6.16 (dd, 2H), 6.20 (ddd, 1 H), 6.92 (d, 1 H), 7.80 (s, 1 H), 8.05 (d, 1 H).
[0436] [000436] Example 4.13: NMR spectrum: (DMSOd6) 323 ° K: 1.53 (d, 3H), 3.52 - 3.66 (m, 4H), 3.71 - 3.82 (m , 4H), 4.04 - 4.24 (m, 2H), 4.29 - 4.51 (m, 2H), 4.98 - 5.09 (m, 1 H), 5.39 (ddddd, 1 H), 5.59 (s, 1 H), 6.17 (dd, 2H), 6.20 (ddd, 1 H), 6.91 (d, 1 H), 7.81 (s, 1 H), 8.06 (d, 1 H).
[0437] [000437] Example 4.14: NMR spectrum: (DMSOd6) 1.53 (d, 3H), 3.27 - 3.33 (m, 2H), 3.47 - 3.52 (m, 2H), 3.52 - 3.63 (m, 4H), 3.70 - 3.79 (m, 4H), 4.73 (t, 1 H), 4.96 - 5.04 (m, 1 H), 5.62 (s, 1 H), 6.15 (dd, 2H), 6.22 (ddd, 1 H), 7.03 (d, 1 H), 8.08 (s, 1 H), 8 , 38 (d, 1 H), 8.69 (t, 1 H).
[0438] [000438] Example 4.15: NMR spectrum: (DMSOd6) 1.52 (d, 3H), 3.26 (s, 3H), 3.35 - 3.42 (m partially hidden by H2O, 2H), 3.42 - 3.48 (m, 2H), 3.50 - 3.64 (m, 4H), 3.70 - 3.79 (m, 4H), 4.96 - 5.05 (m, 1 H), 5.62 (s, 1 H), 6.14 (dd, 2H), 6.22 (ddd, 1 H), 7.03 (d, 1 H), 8.07 (s, 1 H ), 8.37 (d, 1 H), 8.78 (t, 1 H).
[0439] [000439] Example 4.16: NMR spectrum: (DMSOd6) 0.88 (t, 3H), 1.47 - 1.58 (m, 2H), 1.52 (d, 3H), 3.13 - 3.24 (m, 2H), 3.50 - 3.64 (m, 4H), 3.70 - 3.79 (m, 4H), 4.96 - 5.05 (m, 1 H), 5 , 62 (s, 1 H), 6.14 (dd, 2H), 6.22 (ddd, 1 H), 7.03 (d, 1 H), 8.07 (s, 1 H), 8, 36 (d, 1 H), 8.73 (t, 1 H).
[0440] [000440] Example 4.17: NMR spectrum: (DMSOd6) 1.11 (t, 3H), 1.51 (d, 3H), 3.21 - 3.30 (m, 2H), 3.50 - 3.64 (m, 4H), 3.69 - 3.80 (m, 4H), 4.96 - 5.04 (m, 1 H), 5.62 (s, 1 H), 6.14 ( dd, 2H), 6.22 (ddd, 1 H), 7.03 (d, 1 H), 8.07 (s, 1 H), 8.35 (d, 1 H), 8.74 (t , 1 H).
[0441] [000441] Example 4.18: NMR spectrum: (DMSOd6) 1.52 (d, 3H), 3.48 - 3.64 (m, 6H), 3.70 - 3.78 (m, 4H), 4.53 (dt, 2H), 4.96 - 5.04 (m, 1 H), 5.62 (s, 1 H), 6.14 (dd, 2H), 6.22 (ddd, 1 H ), 7.03 (d, 1 H), 8.09 (d, 1 H), 8.39 (d, 1 H), 8.96 (t, 1 H).
[0442] [000442] Example 4.19: NMR spectrum: (DMSOd6) 1.52 (d, 3H), 1.70 - 1.79 (m, 2H), 3.23 (s, 3H), 3.24 - 3.30 (m, 2H), 3.36 - 3.42 (m partially hidden by H2O, 2H), 3.50 - 3.63 (m, 4H), 3.71 - 3.78 (m, 4H ), 4.96 - 5.04 (m, 1 H), 5.62 (s, 1 H), 6.14 (dd, 2H), 6.22 (ddd, 1 H), 7.03 (d , 1 H), 8.06 (d, 1 H), 8.35 (d, 1 H), 8.73 (t, 1 H).
[0443] [000443] Example 4.20: NMR spectrum: (DMSOd6) 1.54 (d, 3H), 1.56 - 1.98 (m, 4H), 2.75 - 3.47 (m, 2H), 3.48 - 3.65 (m, 6H), 3.68 - 3.82 (m, 4H), 4.11 (bs, 1 H), 4.76 - 4.86 (m, 1 H), 4.95 - 5.07 (m, 1 H), 5.61 (s, 1 H), 6.15 (dd, 2H), 6.23 (ddd, 1 H), 6.93 - 7.02 (m, 1 H) 7.64 (s, 0.5H), 7.68 (s, 0.5H), 7.95 (s, 1 H).
[0444] [000444] Example 4.21: NMR spectrum: (DMSOd6) 1.54 (d, 3H), 1.56 - 1.98 (m, 4H), 2.75 - 3.47 (m, 2H), 3.48 - 3.65 (m, 6H), 3.68 - 3.82 (m, 4H), 4.11 (bs, 1 H), 4.76 - 4.86 (m, 1 H), 4.95 - 5.07 (m, 1 H), 5.61 (s, 1 H), 6.15 (dd, 2H), 6.23 (ddd, 1 H), 6.93 - 7.02 (m, 1 H) 7.64 (s, 0.5H), 7.68 (s, 0.5H), 7.95 (s, 1 H).
[0445] [000445] Example 4.22: NMR spectrum: (DMSOd6) 1.51 (d, 3H), 1.75 (d, 3H), 3.51 - 3.62 (m, 4H), 3.71 - 3.78 (m, 4H), 4.96 - 5.04 (m, 1 H), 5.61 (s, 1 H), 6.14 (dd, 2H), 6.22 (ddd, 1 H ), 7.03 (d, 1 H), 8.07 (d, 1 H), 8.33 (d, 1 H), 8.67 (q, 1 H).
[0446] [000446] Example 4.23: NMR spectrum: (DMSOd6) 0.18 - 0.27 (m, 2H), 0.39 - 0.48 (m, 2H), 0.98 - 1.08 (m , 1 H), 1.51 (d, 3H), 3.08 - 3.16 (m, 2H), 3.51 - 3.64 (m, 4H), 3.71 - 3.80 (m, 4H), 4.97 - 5.06 (m, 1 H), 5.63 (s, 1 H), 6.15 (dd, 2H), 6.23 (ddd, 1 H), 7.05 ( d, 1 H), 8.09 (d, 1 H), 8.38 (d, 1 H), 8.86 (t, 1 H).
[0447] [000447] Example 4.24: NMR spectrum: (DMSOd6) at 323 ° K: 1.52 (d, 3H), 2.89 (s, 3H), 3.02 - 3.50 (m partially hidden by H2O, 7H), 3.50 - 3.68 (m, 4H), 3.71 - 3.80 (m, 4H), 5.01 (bs, 1 H), 5.63 (s, 1 H) , 6.14 (dd, 2H), 6.23 (ddd, 1 H), 6.98 (d, 1 H), 7.52 (d, 1 H), 7.78 (d, 1 H).
[0448] [000448] Example 4.25: NMR spectrum: (DMSOd6) at 323 ° K: 1.43 (bs, 2H), 1.55 (d, 3H), 1.87 (bs, 1 H), 3, 27 - 3.89 (m, 15H), 4.97 - 5.06 (m, 1 H), 5.59 (s, 1 H), 6.15 (dd, 2H), 6.21 (ddd, 1 H), 6.87 (d, 1 H), 7.54 (d, 1 H), 7.80 (d, 1 H).
[0449] [000449] Example 4.26: NMR spectrum: (DMSOd6) at 323 ° K: 1.34 (bs, 2H), 1.51 (d, 3H), 1.72 (bs, 2H), 3.08 (bs, 2H), 3.25 (s, 3H), 3.36 - 3.44 (m, 1 H), (m, 4H), 3.67 (bs, 2H), 3.69 - 3, 82 (m, 4H), 4.97 - 5.07 (m, 1 H), 5.58 (s, 1 H), 6.15 (dd, 2H), 6.21 (ddd, 1 H), 6.86 (d, 1 H), 7.52 (d, 1 H), 7.80 (d, 1 H).
[0450] [000450] The 2,5-dioxopyrrolidin-1-yl 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylate used as starting material for the preparation of the compounds of Examples 4.01 to 4.26 was carried out as follows: -
[0451] [000451] TSTU (2.098 g, 6.97 mmol) was added at room temperature to 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6- carboxylic (manufactured using a procedure similar to that described for the synthesis of 8- (1- (3-chloro-2-fluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid in Example 2 .00; 2.5 g, 3.49 mmol) and DIPEA (1.214 ml, 6.97 mmol) in DCM (25 ml). The resulting solution was stirred for 2 hours. This intermediate solution was used as such in the next step. Example 5.0 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0452] [000452] 2- (2,5-dioxopyrrolidin-1-yl) -1,1,3,3-tetramethylisouronium tetrafluoroborate (2.134 g, 7.09 mmol), was added in one portion to a stirred acid solution 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic (2.1 g, 4.73 mmol) and N- ethyl-N-isopropylpropan-2-amine (1.646 ml, 9.45 mmol) in DCM (20 ml) at room temperature and stirred at room temperature for 90 minutes. Dimethylamine (4.73 ml, 9.45 mmol) was then added and the reaction mixture was stirred at room temperature for 30 minutes. Water and DCM were added, the organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash silica gel chromatography eluting with DCM / MeCN (1: 1) after 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to produce a foam that crystallized from ethyl acetate (10 ml). The ether (10 ml) was added to complete the crystallization and the white solid was collected by filtration and dried to give 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N, N- dimethyl-2-morpholino4-oxo-4H-chromene-6-carboxamide (1.65 g, 74%). Mass spectrum: M + H + 472. NMR spectrum (DMSOd6): 1.55 (d, 3H), 2.63 (s, 3H), 2.92 (bs, 3H), 3.01 (bs, 3H ), 3.21 - 3.29 (m, 2H), 3.31 - 3.39 (m partially hidden by H2O, 2H), 3.41 - 3.49 (m, 2H), 3.49 - 3 , 57 (m, 2H), 5.55 (s, 1 H), 5.58 (q, 1 H), 6.40 (t, 1 H), 6.53 (d, 2H), 7.70 (d, 1 H), 7.89 (d, 1 H).
[0453] [000453] This racemic compound was resolved by the chiral preparative HPLC using the following conditions:
[0454] [000454] The 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid used as starting material was made as follows : -
[0455] [000455] Potassium iodide (1.521 g, 9.16 mmol) was added to a suspension of methyl 8- (1-bromoethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylate (3.3 g, 8.33 mmol, as described in Example 2.00) and 3,5-difluoro-N-methylaniline (3.58 g, 24.99 mmol) in CHCl3 (16 ml) and MeOH (4 ml). The mixture was stirred at room temperature over the weekend. The reaction mixture was concentrated to dryness and the resulting dark oil was triturated with diethyl ether to give a solid that was collected by filtration. This solid was suspended in water and the pH was adjusted to 6 to 7 with 2N NaOH. The crude product was filtered and washed with ether, dried and purified by silica gel scintillation chromatography eluting with 0 to 10% water. MeOH in DCM. The solvent was evaporated to dryness to produce the methyl 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylate (3 , 1 g, 81%) as a white solid. Mass spectrum: M + H + 459.
[0456] [000456] NaOH 2 N NaOH (6.54 ml, 13.1 mmol), was added dropwise to a stirred suspension of 8- (1 - ((3,5-difluorophenyl) (methyl) amino) -ethyl) - Methyl 2-morpholino-4-oxo-4H-chromene-6-carboxylate (3 g, 6.54 mmol), in THF (30 ml) / MeOH (30 ml). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with water, the pH was adjusted to 3 with a sol. 2 M aq. of HCl. The solvents were removed and the white precipitate was collected by filtration, washed with water and dried after washing with ethyl acetate and ether to produce 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl acid ) -2-morpholino-4-oxo-4H-chromene-6-carboxylic (2.5 g, 86%) which was used without further purification. Mass spectrum: M + H + 445.
[0457] [000457] The compound of Example 5.0a can also be manufactured using the following alternative method:
[0458] [000458] Lithium bis (trimethylsilyl) amide (1 N in THF) (26.2 ml, 26.23 mmol) was added to a stirred solution of 8- (1- (3,5-difluorophenylamino) -ethyl) - N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (6 g, 13.12 mmol, prepared as described in Example 3.06b; [α] D20 = -122.6 ° in EtOH) dissolved in anhydrous THF (60 ml) at - 60 ° C under argon. The light red solution was allowed to warm to -10 ° C over a period of 15 minutes then cooled to -60 ° C before adding dimethyl sulfate (2.482 ml, 26.23 mmol). The resulting yellow solution was allowed to warm to 0 ° C and stirred for 15 minutes.
[0459] [000459] The reaction mixture cooled back to -10 ° C before adding a saturated aqueous solution of NH4Cl (30 ml) followed by extraction with DCM. The crude product (7 g) was purified by silica gel scintillation chromatography eluting with 0 to 15% EtOH in DCM / ethyl acetate (1/1) then 15% EtOH in DCM. The solvent was evaporated to dryness to produce the (4.2 g, 8.91 mmol, 67.9%) as a yellowish white foam. Example 5.01 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one
[0460] [000460] 2- (1H-benzo [d] [1,2,3] triazol-1-yl) - 1,1,3,3-tetramethylisouronium tetrafluoroborate (113 mg, 0.35 mmol) was added to a stirred solution of 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (130 mg, 0.29 mmol) , 4-methyl-morpholino (0.080 ml, 0.73 mmol) and piperidin-4-ol (36 mg, 0.35 mmol) dissolved in NMP (1.2 ml). The resulting solution was stirred at 23 ° C for 2 hours. The reaction mixture was purified by preparative HPLC using a Waters SunFire system. Fractions containing the desired compound were evaporated, triturated with ether and dried to produce 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one (90 mg, 58%) as a white solid. Mass spectrum: M + H + 528. NMR spectrum (DMSOd6 at 323 ° K): 1.38 (bs, 2H), 1.57 (d, 3H), 1.75 (bs, 2H), 2.66 (s, 3H), 3.23 - 3.30 (m, 2H), 3.30 - 3.38 (m, 2H), 3.61 (m, 4H), 3.65 (bs, 4H), 3.71 - 3.79 (m, 1 H), 4.66 (d, 1 H), 5.52 (s, 1 H), 5.54 (q, 1 H), 6.36 (t, 1 H), 6.50 (d, 2H), 7.62 (d, 1 H), 7.87 (d, 1 H). Example 5.02 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (3-hydroxypyrrolidine-1-carbonyl) -2-morpholino-4H-chromen-4-one
[0461] [000461] This compound was prepared using a procedure analogous to that described in Example 5.01. Pyrrolidin-3-ol (0.028 ml, 0.35 mmol) was used in place of piperidin-4-ol to give 8- (1 - ((3,5-difluorophenyl) - (methyl) amino) ethyl) -6 - (3-hydroxypyrrolidine-1-carbonyl) -2-morpholino-4H-chromen-4-one (80 mg, 53%) as a white solid. Mass spectrum: M + H + 514. NMR spectrum (DMSOd6 at 323 ° K): 1.57 (d, 3H), 1.82 (bs, 1 H), 1.96 (bs, 1 H), 2 , 63 (s, 1.5H), 2.65 (s, 1.5H), 3.22 - 3.62 (m, 12H), 4.25 (bs, 0.5H), 4.33 (bs , 0.5H), 4.86 (bs, 0.5H), 4.92 (bs, 0.5H), 5.51 (s, 1 H), 5.56 (q, 1 H), 6, 36 (t, 1 H), 6.51 (d, 2H), 7.76 (d, 0.5H), 7.78 (bs, 0.5H), 8.02 (bs, 1 H). Example 5.03 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6 - ((R) -2- (hydroxymethyl) pyrrolidine -1-carbonyl) -2-morpholino-4H-chromen-4- ona
[0462] [000462] This compound was prepared using a procedure similar to that described in Example 5.01. (R) -pyrrolidin-2-ylmethanol (0.035 ml, 0.35 mmol) was used in place of piperidin-4-ol to give 8- (1 - ((3,5-difluoro-phenyl) (methyl) amino ) ethyl) -6 - ((R) -2- (hydroxymethyl) pyrrolidino1-carbonyl) -2-morpholino-4H-chromen-4-one (81 mg, 53%) as a white solid. Mass spectrum: M + H + 528. NMR spectrum (DMSOd6 at 323 ° K): 1.57 (d, 3H), 1.72 (bs, 1 H), 1.83 - 2.01 (m, 3H ), 2.61 (s, 1.5H), 2.65 (s, 1.5H), 3.22 - 3.68 (m, 12H), 4.17 (bs, 1 H), 4.68 (bs, 1 H), 5.51 (s, 0.5H), 5.52 (s, 0.5H), 5.53 - 5.60 (m, 1 H), 6.36 (t, 1 H), 6.47 - 6.55 (m, 2H), 6.74 (s, 0.5H), 6.78 (s, 0.5H), 8.01 (bs, 1 H). Example 6.0 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -2-morpholino-6- (pyrrolidine-1-carbonyl) -4H-chromen-4-one
[0463] [000463] 3,5-difluoro-N-methylaniline (222 mg, 1.55 mmol), 8- (1-bromoethyl) -2-morpholino-6- (pyrrolidine-1-carbonyl) -4H-chromene 4- one (200 mg, 0.39 mmol) and potassium iodide (64.3 mg, 0.39 mmol) in CHCl3 (0.8 ml) and MeOH (0.2 ml) were stirred at 20 ° C for 25 hours. The reaction mixture was concentrated to dryness, diluted with DCM (30 ml), washed with water, brine, dried over magnesium sulfate and concentrated to produce the crude product. Purification was done by flashing silica gel chromatography eluting with 2 to 4% MeOH in DCM. The solvent was evaporated to dryness to produce a foam which was dissolved in acetonitrile-water and concentrated in vacuo to give 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -2-morpholino- 6- (pyrrolidino-1-carbonyl) -4H-chromen-4-one (115 mg, 60%) as a white solid. Mass spectrum: M + H + 498. NMR spectrum (DMSOd6): 1.56 (d, 3H), 1.78 - 1.93 (m, 4H), 2.62 (s, 3H), 3.23 - 3.29 (m, 2H), 3.35 - 3.56 (m, 10H), 5.55 (s, 1 H), 5.59 (q, 1 H), 6.40 (t, 1 H), 6.53 (d, 2H), 7.79 (d, 1 H), 8.01 (d, 1 H).
[0464] [000464] The 8- (1-bromoethyl) -2-morpholino-6- (pyrrolidine-1-carbonyl) -4H-chromen-4-one hydrobromide used as starting material was made as follows: -
[0465] [000465] 2- (2,5-dioxopyrrolidin-1-yl) -1,1,3,3-tetramethylisouronium tetrafluoroborate (3.34 g, 11.09 mmol) at 25 ° C was added to the portions to the acid 8- (1-hydroxyethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic (1.77 g, 5.54 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.028 ml, 11.64 mmol) suspended in DCM (15 ml) under nitrogen. The resulting mixture was stirred at 25 ° C for 5 hours. Pyrrolidine (1.388 ml, 16.63 mmol) was then added to the mixture and the resulting mixture was stirred at 25 ° C overnight. The mixture was poured into a column on silica gel and purified by sparkling chromatography eluting with 2 to 7% metallic ammonium (7 N) in DCM. The solvent was evaporated to dryness, the residue was triturated in ethyl acetate (10 ml), collected by filtration and dried to produce 8- (1-hydroxyethyl) -2-morpholino-6- (pyrrolidine-1-carbonyl) -4H-chromen-4-one (1.66 g, 80%) as a beige solid. Mass spectrum: M + H + 373.
[0466] [000466] A solution of tribromophosphine (0.491 ml, 5.22 mmol) in 1,2-dichloroethane (4 ml) at 10 ° C, was added to the 8- (1-hydroxyethyl) -2-morpholino-6- drops. (pyrrolidine-1-carbonyl) -4H-chromen-4-one (1.62 g, 4.35 mmol) suspended in 1,2-dichloroethane (18 ml) under nitrogen. The resulting suspension was stirred at 50 ° C for 1 hour. The reaction mixture was allowed to cool to room temperature with stirring and diluted with diethyl ether (18 ml). The precipitate was collected by filtration, washed with diethyl ether and dried to a constant weight to produce 8- (1-bromoethyl) -2-morpholino-6- (pyrrolidine-1-carbonyl) -4H-chromen-4-one ( 2.45 g, 100%) hydrobromide as a white solid, which was used without further purification. NMR spectrum (DMSOd6): 1.79 - 1.93 (m, 4H), 2.11 (d, 3H), 3.37 - 3.44 (m, 2H), 3.46 - 3.53 ( m, 2H), 3.57 - 3.70 (m, 4H), 3.73 - 3.80 (m, 4H), 5.66 (s, 1 H), 5.92 (q, 1 H) , 7.99 - 8.03 (m, 2H). Example 7.0 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide
[0467] [000467] TBTU (108 mg, 0.34 mmol) was added in one portion to a stirred solution of 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -2-morpholino- 4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.28 mmol), N-ethyl-N-isopropylpropan-2-amine (0.103 ml, 0.59 mmol) and 2- (methylamino) ethanol (0.027 ml, 0.34 mmol) in DMF (1 ml). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was filtered and purified by preparative HPLC using a reverse phase column (C-18, 5 micron silica, 19 mm in diameter, 100 mm in length, flow rate 40 ml / minute) and the mixtures decreasing polar water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. Fractions containing the desired compound were evaporated to dryness to yield 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide (90 mg, 64%) as a yellowish white solid. Mass spectrum: M + H + 502. NMR spectrum (DMSOd6 at 323 ° K): 1.58 (d, 3H), 2.65 (s, 3H), 3.01 (s, 3H), 3.23 - 3.40 (m, 5H), 3.4 - 3.71 (m, 7H), 4.74 (bs, 1 H), 5.52 (s, 1 H), 5.57 (q, 1 H), 6.38 (t, 1 H), 6.53 (d, 2H), 7.74 (bs, 1 H), 7.93 (s, 1 H). Example 7.0a 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (enantiomer 1)
[0468] [000468] Tetrabutylammonium fluoride (0.568 ml, 0.57 mmol) was added to a stirred solution of N- (2- (tert-butyldiphenylsilyloxy) ethyl) - 8- (1 - ((3,5-difluorophenyl) ( methyl) amino) ethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide enantiomer 1 (210 mg, 0.28 mmol) dissolved in THF (2 ml) at room temperature under nitrogen and the resulting solution stirred for 16 hours. The mixture was evaporated to dryness, diluted with DCM and washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel scintillation chromatography eluting with 5 to 7% MeOH in DCM. The solvent was evaporated to dryness, the gum was triturated in ether / pentane, the solid was collected by filtration and dried to give 8- (1 - ((3,5-difluorophenyl) - (methyl) amino) ethyl) - N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide enantiomer 1 (79 mg, 56%) as a white solid. Mass spectrum: M + H + 502. [α] D20 °: -9 ° in MeCN.
[0469] [000469] N- (2- (tert-butyldiphenylsilyloxy) ethyl) -8- (1 - ((3,5-difluorophenyl) - (methyl) amino) ethyl) -N-methyl-2-morpholino-4-oxo -4H-chromene-6-carboxamide enantiomer 1 used as starting material was made as follows: -
[0470] [000470] To a solution of 2- (methylamino) ethanol (2.14 ml, 26.6 mmol) in DCM (60 ml) was added triethylamine (4.1 ml, 29.3 mmol), N, N-dimethylpyridine -4-amine (1.63 g, 13.3 mmol) and tert-butylchlorodiphenylsilane (7.6 ml, 29.3 mmol). The reaction was stirred overnight at 40 ° C. After cooling to room temperature, the reaction was quenched with water (20 ml) and ether (100 ml). The organic phase was washed with water, brine, dried over magnesium sulfate and concentrated to produce the crude product which was purified by silica gel scintillation chromatography eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to produce 2- (tert-butyldiphenylsilyloxy) -N-methylethylamine (4.4 g, 53%) as a colorless oil. NMR spectrum (DMSOd6): 0.99 (s, 9H), 2.27 (s, 3H), 2.63 (t, 2H), 3.68 (t, 2H), 7.40 - 7.49 (m, 6H), 7.60 - 7.65 (m, 4H).
[0471] [000471] 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic acid was prepared as described in Example 2.00 and the two enantiomers were separated by chiral preparative HPLC using the following conditions:
[0472] [000472] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (135 mg, 0.71 mmol) was added in one portion to 8- (1- (3,5-difluorophenylamino) ethyl) -2- acid morpholino-4-oxo-4H-chromene-6-carboxylic (200 mg, 0.35 mmol, enantiomer 1; [α] D20 °: + 115 °), 2- (tert-butyldiphenylsilyloxy) -N-methylethylamine (221 mg, 0 , 71 mmol) and 2-hydroxypyridine N-oxide (78 mg, 0.71 mmol) dissolved in DCM (2 ml) under argon. The resulting solution was stirred at room temperature overnight. The solution was evaporated to dryness, water was added and the product was extracted with DCM. The organic phase was washed with brine and dried over magnesium sulfate, the solvent was evaporated to produce N- (2- (tert-butyl-diphenylsilyloxy) ethyl) -8- (1- (3,5-difluorophenylamino) ethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (94%) as a white solid. Mass spectrum: M + H + 726.
[0473] [000473] Lithium bis (trimethylsilyl) amide (0.539 ml, 0.54 mmol) was added to a stirred solution of N- (2- (tert-butyldiphenylsilyloxy) ethyl) - 8- (1- (3,5-difluorophenylamino ) ethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (230 mg, 0.32 mmol) dissolved in dry THF (3 ml). The solution was stirred for 10 minutes at -20 ° C under nitrogen. Dimethyl sulfate (0.051 ml, 0.54 mmol) was added to the mixture and the resulting suspension was allowed to rise to room temperature for 1 hour and 30 hours under nitrogen. A saturated aqueous solution of NH4Cl was added and the reaction mixture was extracted with DCM. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The crude product was diluted with DCM and purified by silica gel scintillation chromatography eluting with 4% ethyl alcohol in DCM. The solvent was evaporated to dryness to produce N- (2- (tert-butyldiphenylsilyloxy) ethyl) -8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N-methyl-2-morpholino- 4-oxo-4H-chromene-6-carboxamide enantiomer 1 (210 mg, 90%) as a white solid. Mass spectrum: M + H + 740. Example 7.0b 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (enantiomer two)
[0474] [000474] This compound was prepared using a procedure analogous to that described for example 7.0a but isolated using enantiomer 2 of 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4-oxo-4H acid -chromene-6-carboxylic ([α] D20 °: -102 °). Thus N- (2- (tert-butyldiphenylsilyloxy) ethyl) -8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N-methyl-2-morpholino-4-oxo-4H-chromene- 6-carboxamide enantiomer 2 (1.8 g, 2.43 mmol) gave 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -N- (2-hydroxyethyl) -N-methyl- 2-morpholino-4-oxo-4H-chromene-6-carboxamide enantiomer 2 (0.985 g, 80%) as a white solid [α] D20 °: + 10 ° in MeCN. Mass spectrum: M + H + 502. NMR spectrum (DMSOd6): 1.54 (bs, 3H), 2.61 (s, 3H), 2.96 (s, 1.5H), 3.01 (s , 1.5H), 3.20 - 3.30 (m, 4H), 3.41 - 3.58 (m, 7H), 3.65 (bs, 1 H), 4.68 (bs, 1 H ), 5.54 (s, 1 H), 5.58 (q, 1 H), 6.40 (d, 2H), 6.54 (t, 1 H), 7.70 (bs, 0.5H ), 7.77 (bs, 0.5H), 7.90 (bs, 0.5H) 7.93 (bs, 0.5H). Example 7.01a 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one (enantiomer 2)
[0475] [000475] Tetrabutylammonium fluoride (1 N in THF) (7.83 ml, 7.83 mmol) was added to the drops to a stirred solution of 6- (4- (tert-butyldi-phenylsilyloxy) piperidine-1-carbonyl) - 8- (1 - ((3,5-difluorophenyl) (methyl) amino) -ethyl) -2-morpholino-4H-chromen-4-one (3 g, 3.92 mmol, enantiomer 2 in Example 7.0a, [α] D20 °: -102 °) dissolved in THF (20 ml) at room temperature under nitrogen and stirred for 2 hours. The mixture was evaporated to dryness, diluted with DCM, washed with water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel scintillation chromatography (80 g) eluting with 3 to 7% MeOH in DCM. The solvent was evaporated to dryness to give a foam which was ground in ether (2 to 5 ml). The resulting white solid was collected by filtration and dried to give 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino- 4H-chromen-4-one enantiomer 2 (1.7 g, 82%) as a white solid. Mass spectrum: M + H + 528. [α] D20 °: + 7 ° in MeCN.
[0476] [000476] The preparation of 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one racemic is described in Example 5.01.
[0477] [000477] A 6- (4- (tert-butyldiphenylsilyloxy) piperidine-1-carbonyl) -8- (1- ((3,5-difluorophenyl) (methyl) amino) ethyl) -2-morpholino-4H-chromen 4-one enantiomer 2 used as a starting material was manufactured using a procedure analogous to that described for the synthesis of the starting material in Example 7.0a. Mass spectrum: M + H + 766. Example 7.01b 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one (enantiomer 1)
[0478] [000478] This compound was prepared using a procedure analogous to that described in Example 7.01a except that the chiral acid starting material was 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino- 4-oxo-4H-chromene-6-carboxylic enantiomer 1 ([α] D20 °: + 115 °) of Example 7.0a. It was thus obtained: 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -6- (4-hydroxypiperidine-1-carbonyl) -2-morpholino-4H-chromen-4-one enantiomer 1 (45 mg, 69%) as a white solid. [α] D20 °: -3 ° in MeCN. Mass spectrum: M + H + 528. Example 7.02 6- (azetidine-1-carbonyl) -8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4H-chromen-4-one (enantiomer 2)
[0479] [000479] 2- (2,5-dioxopyrrolidin-1-yl) -1,1,3,3-tetramethylisouronium tetrafluoroborate (409 mg, 1.36 mmol) was added to the portions in a suspension of the enantiomer 2 of the acid 8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4-oxo-4H-chromene-6-carboxylic ([α] D20 °: -102 °, enantiomer 2, see Example 7.0a) (450 mg, 1.05 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.310 ml, 1.78 mmol) in DCM (5 ml) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 4 hours. Azetidine (0.211 ml, 3.14 mmol) was then added to the mixture and stirring was continued overnight. The mixture was diluted with DMF and concentrated to remove DCM. The reaction mixture was purified by preparative HPLC in a Waters X-Bridge system. The fractions were evaporated to dryness to produce a white solid of 6- (azetidine-1-carbonyl) -8- (1- (3,5-difluorophenylamino) ethyl) -2-morpholino-4Hcromen-4-one (300 mg , 61%). Mass spectrum: M + H + 470. [α] D20 °: -113 ° in MeCN. NMR spectrum (DMSOd6): 1.50 (d, 3H), 2.18 - 2.28 (m, 2H), 3.50 - 3.63 (m, 4H), 3.69 - 3.78 ( m, 4H), 3.98 - 4.07 (m, 2H), 4.09 - 4.19 (m, 2H), 4.97 - 5.05 (m, 1 H), 5.61 (s , 1 H), 6.15 (d, 2H), 6.21 (t, 1 H), 7.03 (d, 1 H), 7.79 (d, 1 H), 8.02 (d, 1 H). Example 8.0 8- (1- (3-chloro-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (single enantiomer)
[0480] [000480] To a mixture of 8- (1-aminoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (350 mg, 1.01 mmol, single enantiomer, [α ] D20 °: + 35 ° in acetonitrile), cesium carbonate (1288 mg, 3.95 mmol), (9.9-dimethyl-9H-xanthan-4,5-diyl) bis (diphenylphosphine) (147 mg, 0 , 25 mmol) and 1-bromo-3-chloro-5-fluorobenzene (467 mg, 2.23 mmol) in degassed 1,4-dioxane (2 ml), tris (dibenzylidenoacetone) dipaladium (70 mg, 0, 08 mmol). The suspension was heated in a sealed container at 95 ° C for 16 hours. The reaction mixture was filtered through a short dicalite pad and concentrated under reduced pressure. The crude product was purified by silica gel scintillation chromatography eluting with 0 to 8% isopropanol in DCM. The solvent was evaporated to dryness, the product triturated with diethyl ether - DCM (9: 1), collected by filtration and dried to produce 8- (1- (3-chloro-5-fluorophenylamino) ethyl) -N, Ndimethyl -2-morpholino-4-oxo-4H-chromene-6-carboxamide (320 mg; 67%) as a light yellow solid. Mass spectrum: M + H + 474. [α] D20 °: -138 °. NMR spectrum (DMSOd6): 1.52 (d, 3H), 2.75 (bs, 3H), 2.95 (bs, 3H), 3.49 - 3.63 (m, 4H), 3.70 - 3.79 (m, 4H), 4.98 - 5.07 (m, 1 H), 5.60 (s, 1 H), 6.23 (d, 1 H), 6.42 (d, 1 H), 6.43 (ddd, 1 H), 6.94 (d, 1 H), 7.54 (d, 1 H), 7.80 (d, 1 H).
[0481] [000481] The 8- (1-aminoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (single enantiomer, [α] D20 °: + 35 ° in acetonitrile) used as starting material it was made as follows: -
[0482] [000482] N-ethyl-N-isopropylpropan-2-amine (9.4 ml, 53.9 mmol) was added to 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (5 , 7 g, 18 mmol) in DCM (100 ml). Five minutes later, dimethylamine hydrochloride (2.9 g, 35.9 mmol) and 2- (1H-benzo [d] - [1,2,3] triazol-1-yl) -1,1 tetrafluoroborate, 3,3-tetramethylisouronium (6.92 g, 21.6 mmol) were added. The mixture was diluted with DCM, washed with NaHCO3, dried over magnesium sulfate and concentrated to produce the crude product which was purified by silica gel flash chromatography eluting with 0 to 5% MeOH / DCM. The solvent was evaporated to dryness to produce 8-acetyl-N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2.75 g, 46%) as a yellow solid. Mass spectrum: M + H + 345.
[0483] [000483] Tetraethoxytitanium (12.5 g, 46.5 mmol) was added to a stirred solution of 8-acetyl-N, N-dimethyl-2-morpholino-4-oxo-4H-chromene6-carboxamide (4 g, 11.6 mmol) and (R) -2-methylpropane-2-sulfinamide (2.48 g, 20.4 mmol) in THF (100 ml) under nitrogen. The resulting mixture was stirred at reflux for 24 hours. The reaction mixture was allowed to cool to room temperature, quenched with brine (100 ml) and diluted with ethyl acetate. The precipitate was removed by filtration over celite and washed with ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water (twice), brine, dried over magnesium sulfate and concentrated to dryness to produce 2 g of the desired product. More product (2.8 g) was removed from the aqueous phase by extracting DCM. The 2 batches were combined to give 8- (1- (tert-butylsulfinylimino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (4.5 g, 87%) as a yellow foam, which was used in the next step without further purification. Mass spectrum: M + H + 448.
[0484] [000484] The 8- (1- (tert-butylsulfinylimino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide was diluted in DCM (35 ml) and MeOH (35 ml), acetic acid (4.6 ml, 80.4 mmol) and sodium cyanotrihydroborate (1.9 g, 30.2 mmol) were added at -15 ° C. The resulting mixture was stirred at -15 ° C by 5 hours later allowed to warm to 0 ° C. A saturated solution of Na2CO3 was added at 0 ° C until pH ~ 8 to 9 and extracted with DCM (x 2). The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel scintillation chromatography (SiO2 column, 15 to 40 µm -150 g Merck) eluting with 5 to 15% EtOH in DCM. Fractions containing impure product were concentrated and repurified using the same system. The fractions containing 8- (1- ((R) -1,1-dimethylethylsulfinamido) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide were combined and the solvent it was evaporated to dryness to produce 2.48 g, (5.52 mmol, 54.9%) as a white foam. Fractions containing a mixture of diastereoisomers were combined, concentrated and purified by preparative HPLC in a Waters X-Bridge system. Fractions containing the desired compound were evaporated to dryness to produce an additional yield of 8- (1 - ((R) -1,1-dimethylethylsulfinamido) ethyl) -N, N-dimethyl-2-morpholino-4-oxo -4H-chromene6-carboxamide (0.25 g, 0.556 mmol, 5.53%) as a white foam. These 2 batches (2.48 g) and (0.25 g) were combined to give 8- (1 - ((R) -1,1-dimethylethylsulfinamido) ethyl) -N, N-dimethyl-2-morpholino-4 -oxo-4H-chromene-6-carboxamide (2.73 g, 60%, diastereomeric excess> 95%). Mass spectrum: M + H + 450.
[0485] [000485] Hydrogen chloride in 4 M dioxane (15 ml, 60.1 mmol) was added to 8- (1 - ((R) -1,1-dimethylethylsulfinamido) ethyl) -N, N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide (2.7 g, 6.0 mmol) dissolved in dioxane (40 ml). The resulting white suspension was stirred at room temperature for 1 hour, collected by filtration, washed with diethyl ether and dried. It was dissolved in a 5% (7 N) methanolic ammonia solution in DCM (200 ml) and stirred for 5 minutes. The precipitate (NH4Cl) was removed by filtration and the filtrate was concentrated to dryness to produce 8- (1-aminoethyl) - N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide ( single enantiomer, 1.85 g, 89%) as a yellowish white solid. Mass spectrum: M + H + 346. [α] D20 °: + 35 ° in acetonitrile. Example 8.01 8- (1- (3-cyano-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (single enantiomer)
[0486] [000486] 8- (1-aminoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene6-carboxamide (300 mg, 0.87 mmol, [α] D20 °: + 35 ° in acetonitrile ) was reacted with 3-bromo-5-fluorobenzonitrile (382 mg, 1.91 mmol) using a procedure similar to that described in Example 8.00. Purification was done by silica gel scintillation chromatography eluting with 0 to 5% MeOH in DCM followed by preparative HPLC in a Waters X-Bridge system. Fractions containing the desired compound were evaporated to dryness to produce 8- (1- (3-cyano-5-fluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene- 6-carboxamide (330 mg, 82%) as a light white solid. Mass spectrum: M + H + 465.
[0487] [000487] [α] D20 °: -128 ° in MeCN. NMR spectrum (CDCl3): 1.51 (d, 3H), 2.91 (s, 3H), 3.09 (s, 3H), 3.44 - 3.60 (m, 4H), 3.78 - 3.93 (m, 4H), 4.85 - 4.94 (m, 1 H), 5.17 (d, 1 H), 5.56 (s, 1 H), 6.38 (ddd, 1 H), 6.51 (s, 1 H), 6.61 (d, 1 H), 7.70 (d, 1 H), 8.12 (d, 1 H). Example 8.02 N, N-dimethyl-2-morpholino-4-oxo-8- (1- (3,4,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide (single enantiomer)
[0488] [000488] 8- (1-aminoethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene6-carboxamide (232 mg, 0.67 mmol, [α] D20 °: + 35 ° in acetonitrile ), 3,4,5-trifluorophenylboronic acid (236 mg, 1.34 mmol), diaceto-copper hydride (148 mg, 0.74 mmol) and 4A molecular sieves (1 g) were weighed in a flask. Dichloroethane (4 ml) then pyridine (0.109 ml, 1.34 mmol) were added and the resulting mixture was stirred at room temperature for 2 days under an oxygen atmosphere. The mixture was diluted with DCM, filtered through a pad of celite, the filtrate was washed with a 0.5 N aqueous solution of NaOH and the aqueous phase extracted with DCM. The combined organics were dried over magnesium sulfate and concentrated. The crude product was purified by silica gel scintillation chromatography eluting with 0 to 10% MeOH in ethyl acetate / DCM (1: 1). The solvent was evaporated to dryness to produce the single enantiomeric N, N-dimethyl-2-morpholino-4-oxo-8- (1- (3,4,5-trifluorophenylamino) ethyl) -4H-chromene-6-carboxamide (100 mg, 31%) as a white foam. Mass spectrum: M + H + 476. [] D20 °: -108 ° in MeCN. NMR spectrum (CDCl3): 1.56 (d, 3H), 2.91 (s, 3H), 3.09 (s, 3H), 3.47 - 3.56 (m, 4H), 3.82 - 3.90 (m, 4H), 4.35 (d, 1 H), 4.79 - 4.88 (m, 1 H), 5.56 (s, 1 H), 6.03 (dd, 2H), 7.70 (d, 1 H), 8.12 (d, 1 H). Example 9.0 8- (1- (4-fluorophenylamino) ethyl) -N, N-dimethyl-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide
[0489] [000489] 8- (1-Bromoethyl) -N, N-dimethyl-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.30 mmol) and 4-fluoroaniline (0.113 ml, 1.19 mmol) in DMA (1 ml) were stirred at room temperature for 4 hours. The reaction mixture was filtered and purified by preparative HPLC using a reverse phase column (C-18, 5 micron silica, 19 mm in diameter, 100 mm in length, flow rate 40 ml / minute) and the mixtures decreasing polar water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. An additional purification was done by silica gel scintillation chromatography eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to produce an oil which was triturated with pentane to give 8- (1- (4-fluorophenylamino) ethyl) -N, N-dimethyl-2 - ((R) -2-methylmorpholine) - 4-oxo-4H-chromene-6-carboxamide (80 mg, 59%) as a white solid. NMR spectrum (DMSOd6): 1.16 (d, 3H), 1.50 (d, 3H), 2.66 (bs, 3H), 2.81 (ddd, 1 H), 2.93 (bs, 3H), 3.14 (ddd, 1 H), 3.57 - 3.70 (m, 2H), 3.87 - 4.03 (m, 3H), 4.93 - 5.01 (m, 1 H), 5.62 (s, 1 H), 6.24 - 6.29 (m, 1 H), 6.43 - 6.50 (m, 2H), 6.85 (t, 2H), 7 , 55 (d, 0.5H), 7.56 (d, 0.5H), 7.77 (d, 1 H).
[0490] [000490] The 8- (1-bromoethyl) -N, N-dimethyl-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide hydrobromide used as starting material was made as Follow:-
[0491] [000491] To a suspension of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (75 g, 258 mmol) in THF (350 ml) at -50 ° C under nitrogen was added sodium bis (trimethylsilyl) amide ( 1 M in THF) (904 ml, 903.58 mmol) over a period of 15 minutes. The dark solution was allowed to warm to -5-0 ° C and stirred for 1 hour. Carbon disulfide (24.8 ml, 413 mmol) was added in one portion to the solution at -20 ° C. The mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was cooled to -50 ° C, slowly quenched with a 15% aqueous solution of H2SO4 (750 ml) (necessary to trap the formed H2S). The reaction was extracted 3 times with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. This residue was triturated with DCM (500 ml), collected by filtration, washed with ether and dried under vacuum to give methyl 8-bromo-4-hydroxy-2-thioxo-2H-chromene-6-carboxylate (33.5 g , 41%) as a yellow solid. The filtrate was evaporated and the resulting dark gum was triturated with ethyl acetate (300 ml) to give a solid which was collected by filtration, washed with ether and dried under vacuum to give a second batch of 8-bromo-4-hydroxy-2- methyl thioxo-2H-chromene-6-carboxylate (17.5 g, 22%) as an orange solid. Mass spectrum: [M - H] - 314 for both batches.
[0492] [000492] Iodoethane (2.04 ml, 25.54 mmol), was added to a stirred suspension of methyl 8-bromo-4-hydroxy-2-thioxo-2H-chromene-6-carboxylate (2.3 g , 7.30 mmol) and potassium carbonate (1.21 g, 8.76 mmol) in acetone (100 ml) under nitrogen. The resulting mixture was stirred at 60 ° C for 2 hours. The mixture was concentrated in vacuo and the residue was partitioned between water and DCM. The aqueous layer was extracted in DCM and organic extracts were combined, washed with brine, dried over magnesium sulfate and evaporated. The crude product was purified by silica gel scintillation chromatography eluting with 0 to 10% ethyl acetate in DCM. The solvent was evaporated to dryness to produce methyl 8-bromo-2- (ethylthio) -4-oxo-4H-chromene-6-carboxylate (1.8 g, 72%) as an orange solid. Mass spectrum: M + H + 343.
[0493] [000493] To a stirred solution of methyl 8-bromo-2- (ethylthio) -4-oxo-4H-chromene-6-carboxylate (1.8 g, 5.24 mmol) in DCM (40 ml) in drops the 3-chlorobenzoperoxic acid (2.59 g, 10.49 mmol) while maintaining the temperature at around 20 ° C with a cold bath then allowed to stir at room temperature for 2 hours. The solution was cooled to -15 ° C, the solid was filtered off and rinsed with cold DCM. The filtrate was then washed with a solution of the sodium pentahydride sulfothioate (0.651 g, 2.62 mmol) in 30 ml H2O and twice with a solution of NaHCO3. The organic was dried over magnesium sulfate and evaporated to produce methyl 8-bromo-2- (ethylsulfonyl) -4-oxo-4H-chromene-6-carboxylate (1.85 g, 94%) as a red powder that it consists approximately of a 70:30 sulfone / sulfoxide mixture that was used as such in the next step.
[0494] [000494] A mixture of (R) -2-methylmorpholine hydrochloride (0.436 g, 3.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.184 ml, 6.80 mmol) in DCM (5 ml ) was added dropwise to a stirred solution of methyl 8-bromo-2- (ethylsulfonyl) -4-oxo-4H-chromene-6-carboxylate (0.85 g, 2.27 mmol) in DCM (10 ml) at 10 ° C under nitrogen. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was quenched with 1 M HCl, the phases were separated, the organic phase was washed with brine, dried over magnesium sulfate and concentrated to produce the crude product which was purified by silica gel scintillation chromatography eluting with 0 to 10 % MeOH in DCM. The solvent was evaporated to dryness to produce a trituration with ether, methyl 8-bromo-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxylate (0.760 g, 88% ) as a light yellow foam. Mass spectrum: M + H + 382. The reaction was repeated on a similar scale before proceeding to the next step.
[0495] [000495] Methyl 8-bromo-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxylate (1.45 g, 3.79 mmol), bis (triphenylphosphine) chloride palladium (II) (0.107 g, 0.15 mmol) and tributyl (1-ethoxyvinyl) stannane (1.346 ml, 3.98 mmol) in 1,4-dioxane (20 ml) were degassed, purged with argon and heated to 90 ° C for 4 hours. After cooling to room temperature, 2 N HCl (1.9 ml, 3.79 mmol) was added and the mixture was allowed to stir for 1 hour. The reaction mixture was concentrated, suspended in water, neutralized with NaHCO3 and extracted with DCM. The combined organic phases were washed with water, brine, dried over magnesium sulfate and concentrated. The crude product was triturated with nheptane, filtered and triturated with ether, filtered and dried to give methyl 8-acetyl-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxylate (1 , 15 g, 88%) as a gray solid. Mass spectrum: M + H + 346.
[0496] [000496] To a solution of methyl 8-acetyl-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxylate (1.15 g, 3.33 mmol) in MeOH ( 20 ml) / DCM (10 ml) Sodium tetrahydroborate (0.139 g, 3.66 mmol) was added at -10 ° C. The reaction mixture was quenched with water (50 ml) 15 min later. The volatiles were removed and the aqueous layer was extracted twice with DCM. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The residue was triturated with MTBE / DCM (9/1) and collected by filtration to give 8- (1-hydroxyethyl) -2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxylate of methyl (1.0 g, 86%) as a gray solid, which was used in the next step without further purification. Mass spectrum: M + H + 348.
[0497] [000497] NaOH (3.56 ml, 7.11 mmol) was added to a stirred suspension of 8- (1-hydroxyethyl) -2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene- Methyl 6-carboxylate (988 mg, 2.84 mmol) in MeOH (10 ml) / water (10 ml). The resulting mixture was stirred at room temperature for 1 hour then acidified to pH 2 to 3 with 2 N aq. (7.68 ml, 7.68 mmol). The resulting precipitate was collected by filtration, washed with diethyl ether and dried to produce 8- (1-hydroxyethyl) -2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxylic acid ( 900 mg, 95%) as a gray solid, which was used without further purification. Mass spectrum: M + H + 334.
[0498] [000498] 2- (2,5-dioxopyrrolidin-1-yl) -1,1,3,3-tetramethylisouronium tetrafluoroborate (2.38 g, 3.96 mmol) was added to the 8- (1- hydroxyethyl) -2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxylic (0.88 g, 2.64 mmol) and N-ethyl-N-isopropylpropan-2-amine ( 1.380 ml, 7.92 mmol) suspended in DCM (15 ml) at 10 ° C under nitrogen. The resulting mixture was stirred at room temperature for 2 hours. Dimethylamine (3.96 ml, 7.92 mmol) was then added at 10 ° C and the resulting mixture was stirred at room temperature overnight. The mixture was poured into a column on silica gel and purified by sparkling chromatography eluting with 0 to 10% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness to produce a foam that crystallized from ethyl acetate, the solid was collected by filtration and dried to a constant weight in a vacuum oven to produce 8- (1-hydroxyethyl) -N, N-dimethyl-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide (0.800 g, 84%) as a white solid. Mass spectrum: M + H + 361.
[0499] [000499] A solution of tribromophosphine (0.215 ml, 2.29 mmol) in 1,2-dichloroethane (1 ml) at 10 ° C was added to the drops at 8- (1-hydroxyethyl) -N, N-dimethyl-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide (750 mg, 2.08 mmol) suspended in 1,2-dichloroethane (9 ml) under nitrogen. The resulting suspension was stirred at 50 ° C for 1 hour. The reaction mixture was allowed to cool to room temperature with stirring and diluted with diethyl ether (40 ml). The precipitate was collected by filtration, washed with diethyl ether and dried to a constant weight to produce 8- (1-bromoethyl) -N, N-dimethyl-2 - ((R) -2-methyl-morpholino) hydrobromide - 4-oxo-4H-chromene-6-carboxamide (1.3 g, 124%) as a white solid, which was used without further purification. Mass spectrum: M + H + 424. Example 9.01 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((R) -2-methylmorpholine) -4- oxo-4H-chromene-6-carboxamide
[0500] [000500] 8- (1-bromoethyl) -N, N-dimethyl-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide hydrobromide (1 g, 1.98 mmol) and 3,5-difluoroaniline (1.024 g, 7.93 mmol) in DMA (5 ml) were reacted as described in Example 9.0 to give 8- (1- (3,5-difluorophenylamino) ethyl) - N, N-dimethyl-2 - ((R) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide (0.550 g, 57%). Mass spectrum: M + H + 472. NMR spectrum (DMSOd6): 1.16 (d, 3H), 1.52 (d, 3H), 2.74 (bs, 3H), 2.75 - 2.84 (m, 1 H), 2.95 (bs, 3H), 3.08 - 3.16 (m, 1 H), 3.56 - 3.68 (m, 2H), 3.86 - 4.04 (m, 3H), 4.97 - 5.08 (m, 1 H), 5.62 (s, 1 H), 6.12 - 6.19 (m, 2H), 6.22 (t, 1 H), 6.93 (d, 0.5H), 6.94 (d, 0.5H), 6.54 (d, 0.5H), 6.55 (d, 0.5H), 7.81 (s, 1 H).
[0501] [000501] The above mixture of diastereoisomers (495 mg) was purified by the chiral preparative HPLC using the following conditions:
[0502] [000502] A solution of 8- (1-bromoethyl) -N, N-dimethyl-2 - ((S) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide (670 mg, 1.42 mmol) and 3,5-difluoroaniline (736 mg, 5.70 mmol) in DMA (4 ml) was stirred at 50 ° C for 4 hours later at room temperature over the weekend. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, water, brine, dried over magnesium sulfate and concentrated to produce the crude product, which was purified by silica gel flash chromatography. eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness and the obtained foam was triturated with diethyl ether to give a white solid which was collected by filtration and dried under vacuum to give 8- (1- (3,5- difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide (400 mg, 60%). Mass spectrum: M + H + 472. NMR spectrum (CDCl3): 1.25 (d, 3H), 1.61 (d partially hidden by H2O, 3H), 2.83 (ddd, 1 H), 2, 90 (bs, 3H), 3.08 (bs, 3H), 3.18 (dddd, 1 H), 3.63 - 3.82 (m, 4H), 4.02 (ddd, 1 H), 4 , 37 (bs, 1 H), 4.88 - 4.97 (m, 1 H), 5.55 (s, 1 H), 5.97 (d, 2H), 6.13 (t, 1 H ), 7.72 (d, 1 H), 8.12 (d, 1 H).
[0503] [000503] The above mixture of diastereoisomers (370 mg) was purified by the chiral preparative HPLC using the following conditions:
[0504] [000504] 8- (1-bromoethyl) -N, N-dimethyl-2 - ((S) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide (110 mg, 0.20 mmol) and 4-fluoroaniline in DMA (1 ml) were stirred at 50 ° C for 5 hours. The reaction mixture was purified by preparative HPLC in a Waters X-Bridge system. Fractions containing the desired compound were concentrated. The obtained gum was triturated in diethyl ether and petroleum ether, the resulting solid was collected by filtration and dried to produce 8- (1- (4-fluorophenyl-amino) ethyl) -N, N-dimethyl-2 - (( S) -2-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide (45 mg, 51%) as a white solid. Mass spectrum: M + H + 545. NMR spectrum (CDCl3): 1.25 (d, 1.5H), 1.26 (d, 1.5H), 1.61 (d, 3H), 2.77 - 2.88 (m, 1 H), 2.83 (bs, 3H), 3.06 (bs, 3H), 3.13 - 3.22 (m, 1 H), 3.64 - 3.82 (m, 4H), 3.97 (bs, 1 H), 3.98 - 4.06 (m, 1 H), 4.91 (q, 1 H), 5.56 (s, 1 H), 6.37 - 6.43 (m, 2H), 6.82 (t, 2H), 7.73 (d, 1 H), 8.11 (d, 1 H). Example 10.0
[0505] [000505] For the preparation of the compounds of Examples 10.01 to 10.03 (shown in Table III), TBTU (96 mg, 0.30 mmol) was added in one portion to a stirred solution of the desired amine reagent (- , 0.30 mmol), 8- (1 - ((3,5-difluorophenyl) (methyl) amino) ethyl) -2 - ((R) -2-methyl-morpholino) -4-oxo-4H-chromene -6-carboxylic (125 mg, 0.27 mmol) and 4-methylmorpholine (0.066 ml, 0.60 mmol) in DMF (1 ml). The resulting solution was stirred at room temperature overnight. The reaction mixture was filtered and purified by preparative HPLC in a Waters XBridge system. Fractions containing the desired compound were evaporated to dryness.
[0506] [000506] Example 10.01: DMSOd6 at 323 ° K: 1.01 (d, 1.5H), 1.02 (d, 1.5H), 1.57 (d, 3H), 2.63 (s , 1.5H), 2.67 (s, 1.5H), 2.65 - 2.71 (m, 0.5H), 2.74 - 2.83 (m, 0.5H), 2.98 (bs, 6H), 3.31 - 3.55 (m, 2H), 3.61 - 3.81 (m, 4H), 5.56 (s, 1 H), 5.59 (q, 1 H ), 6.37 (t, 1 H), 6.57 (d, 2H), 7.70 (s, 1 H), 7.92 (s, 1 H).
[0507] [000507] Example 10.02: DMSOd6 at 323 ° K: 1.01 (d, 1.5H), 1.02 (d, 1.5H), 1.56 (d, 3H), 2.46 - 2 , 51 (m, 0.5H), 2.61 (s, 1.5H), 2.64 (s, 1.5H), 2.64 - 2.71 (m, 0.5H), 2.74 - 2.82 (m, 0.5H), 2.94 - 3.00 (m, 0.5H), 3.00 (bs, 3H), 3.27 - 3.90 (m, 9H), 4 , 74 (t, 1 H), 5.55 (s, 1 H), 5.59 (q, 1 H), 6.37 (t, 1 H), 6.55 (d, 2H), 7, 74 (bs, 1 H), 7.93 (s, 1 H).
[0508] [000508] Example 10.03: DMSOd6 at 323 ° K: 1.02 (d, 1.5H), 1.05 (d, 1.5H), 1.39 (bs, 2H), 1.58 (d , 3H), 1.79 (bs, 2H), 2.48 - 2.55 m partially hidden by DMSOd6, 0.5H), 2.64 (s, 1.5H), 2.66 - 2.71 ( m, 0.5H), 2.67 (s, 1.5H), 2.76 - 2.84 (m, 0.5H), 2.95 - 3.03 (m, 0.5H), 3, 21 (bs partially hidden by H2O, 2H), 3.31 - 3.56 (m, 2H), 3.63 - 3.81 (m, 4H), 3.84 (bs, 2H), 4.69 ( d, 1 H), 5.56 (s, 1 H), 5.58 (q, 1 H), 6.37 (t, 1 H), 6.53 (d, 2H), 7.64 (bs , 1 H), 7.89 (s, 1 H). Example 11 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - ((S) -3-methylmorpholine) -4- oxo-4H-chromene-6-carboxamide
[0509] [000509] 2- (1H-benzo [d] [1,2,3] triazol-1-yl) - 1,1,3,3-tetramethylisouronium tetrafluoroborate (55.6 mg, 0.17 mmol), was added in one portion to a stirred solution of 8- (1- (3,5-difluorophenylamino) ethyl) -2 - ((S) -3-methylmorpholine) -4-oxo-4H-chromene-6-carboxylic acid ( 70 mg, 0.16 mmol), dimethylamine (0.095 ml, 0.19 mmol) and 4-methylmorpholine (0.038 ml, 0.35 mmol) in DMF (1 ml). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was purified by preparative HPLC using a reverse phase column (C-18, 5 micron silica, 19 mm in diameter, 100 mm in length, 40 ml / minute flow rate) and the decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. Fractions containing the desired compound were evaporated to dryness to produce a residue which was triturated with Et2O, filtered and dried to give 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2 - (((S) -3-methylmorpholine) -4-oxo-4H-chromene-6-carboxamide (45 mg, 61%) as a light orange solid. Mass spectrum: M + H + 471. NMR spectrum (CDCl3): 1.37 (d, 1.5H), 1.41 (d, 1.5H), 1.59 (d, 1.5H), 1 , 60 (d, 1.5H), 2.89 (s, 1.5H), 2.91 (s, 1.5H), 3.08 (s, 3H), 3.35 - 3.43 (m , 1 H), 3.52 - 3.69 (m, 2H), 3.75 - 3.83 (m, 2H), 3.98 - 4.09 (m, 2H), 4.52 (d, 1 H), 4.85 - 4.96 (m, 1 H), 5.53 (s, 1 H), 5.97 (d, 2H), 6.11 (t, 1 H), 7.71 (d, 0.5H), 7.73 (d, 0.5H), 8.13 (d, 1 H). The 8- (1- (3,5-difluorophenylamino) ethyl) -2 - ((S) -3-methyl-morpholino) -4-oxo-4H-chromene-6-carboxylic acid used as starting material was made as Follow:-
[0510] [000510] Methyl 8-bromo-2- (ethylthio) -4-oxo-4H-chromene-6-carboxylate (850 mg, 2.29 mmol, prepared as described in Example 9) and 3,5-difluoroaniline ( 621 mg, 4.81 mmol) in DMA (10 ml) were stirred at 50 ° C overnight. The reaction mixture was diluted with water / ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by silica gel scintillation chromatography eluting with 0 to 25% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to produce methyl 8- (1- (3,5-difluorophenyl-amino) ethyl) -2- (ethylthio) -4- oxo-4H-chromene-6-carboxylate (550 mg, 57%) as a yellowish white solid. Mass spectrum: M + H + 420.
[0511] [000511] 3-Chlorobenzoperoxic acid (326 mg, 1.13 mmol) was added in one portion to a stirred suspension of 8- (1- (3,5-difluoro-phenylamino) ethyl) -2- (ethylthio) - Methyl 4-oxo-4H-chromene-6-carboxylate (475 mg, 1.13 mmol) in DCM (5 ml) cooled with a water / ice rinse. The resulting mixture was stirred at room temperature for 1 hour. The suspension was cooled to -15 ° C and filtered, the solid was washed with cold DCM (5 ml). The filtrate was then washed with a sun. aq. of sodium thiosulfate pentahydride in water (10 ml) and with a mixture of a saturated solution of NaHCO3 and water (1: 1, 15 ml). The organic layer was decanted, dried over MgSO4 and evaporated to produce the crude product of 8- (1- (3,5-difluorophenylamino) ethyl) -2- (ethylsulfinyl) -4-oxo-4H-chromene-6-carboxylate methyl (500 mg, 100%) as a reddish foam. Mass spectrum: M + H + 436.
[0512] [000512] (S) -3-methylmorpholine (87 mg, 0.86 mmol) was added to a stirred solution of 8- (1- (3,5-difluorophenylamino) ethyl) -2- (ethylsulfinyl) - 4-oxo Methyl -4H-chromene-6-carboxylate (250 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.150 ml, 0.86 mmol) in acetonitrile (3 ml) at room temperature. The resulting brown mixture was stirred at 75 ° C for 7 hours. The reaction mixture was concentrated, diluted with DCM, washed with 1 M hydrochloric acid, brine, dried over magnesium sulfate and concentrated to produce the crude product which was purified by silica gel flash chromatography eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to produce methyl 8- (1- (3,5-difluorophenylamino) ethyl) -2 - ((S) -3-methylmorpholine) -4-oxo-4H-chromene-6-carboxylate (90 mg, 34%) as a yellow foam. Spectrum: [M - H] - 457.
[0513] [000513] 2 N NaOH (0.206 ml, 0.41 mmol) was added to a stirred suspension of 8- (1- (3,5-difluorophenylamino) ethyl) -2 - ((S) -3-methylmorpholine) -4 methyl oxo-4H-chromene-6-carboxylate (90 mg, 0.20 mmol) in MeOH (1 ml) / THF (1 ml) and cooled with an ice water bath. The resulting suspension was stirred at room temperature for 2 hours. The reaction was incomplete so the temperature was raised to 35 ° C and stirred for an additional one hour. The reaction mixture was cooled with an ice bath, the pH was adjusted to 2 to 3 with 1 M hydrochloric acid and the volatiles were evaporated. The resulting precipitate was collected by filtration, dried, triturated with diethyl ether, collected by filtration and dried again under vacuum to give 8- (1- (3,5-difluorophenyl-amino) ethyl) -2 - (( S) -3-methylmorpholine) -4-oxo-4H-chromene-6-carboxylic (75 mg, 86%). Mass spectrum: M + H + 445.

权利要求:
Claims (2)
[0001]
Compound, characterized by the fact that it is (-) - 8- (1- (3,5-difluorophenylamino) ethyl) -N, N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide:
[0002]
Compound or a pharmaceutically acceptable salt thereof, according to claim 1, characterized in that the compound is a single (-) - 8- (1- (3,5-difluorophenylamino) ethyl) - N, N- enantiomer dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide which is in an enantiomeric excess (% ee) of ≥ 95.

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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2019-04-24| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-05-21| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2020-09-08| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-12-15| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-02-17| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 10 (DEZ) ANOS CONTADOS A PARTIR DE 17/02/2021, OBSERVADAS AS CONDICOES LEGAIS. |

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2021-05-25| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 25/10/2010 OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |

优先权:

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申请号 | 申请日 | 专利标题

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