COMPOUND, PHARMACEUTICAL COMPOSITION, COMBINATION, AND USE OF A COMPOUND

专利摘要:
compound, pharmaceutical composition, combination, and, use of a compound a compound of formula (i), (i) or a pharmaceutically acceptable salt thereof, compositions, combinations and medicaments containing said compounds and processes for preparing the same. the invention also relates to the use of said compounds, combinations, compositions and medicaments, for example, as inhibitors of estrogen receptor activity, including estrogen receptor degradation, treatment of estrogen receptor-mediated diseases and conditions.
公开号:BR112015032623B1
申请号:R112015032623-4
申请日:2014-07-01
公开日:2022-01-11
发明作者:Sebastien Andre Campos；John David Harling；Afjal Hussain Miah；Ian Edward David Smith
申请人:Glaxosmithkline Intellectual Property Development Limited；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[001] The present invention relates to compounds, compositions, combinations and medicaments containing said compounds and processes for preparing the same. The invention also relates to the use of said compounds, combinations, compositions and medicaments, for example as inhibitors of estrogen receptor activity, including degrading the estrogen receptor, for the treatment of diseases and conditions mediated by the estrogen receptor, in particular for the treatment of breast cancer. FUNDAMENTALS OF THE INVENTION
[002] The estrogen receptor (ER) is a member of the nuclear hormone receptor family and functions as a ligand-activated transcription factor involved with the up- or down-regulation of gene expression. The natural hormones for the estrogen receptor are B17-estradiol (E2) and closely related metabolites. The binding of estradiol to the estrogen receptor causes a dimerization of the receptor and the dimer in turn binds to estrogen response elements (ERE's) in DNA. The ERDNA complex recruits other transcription factors responsible for transcription of DNA downstream of the ERE into mRNA that is eventually translated into protein. Alternatively, the interaction of ER with DNA may be indirect through the intermediation of other transcription factors, most notably fos and jun. Since the expression of a large number of genes is regulated by the estrogen receptor and since the estrogen receptor is expressed in many cell types, modulation of the estrogen receptor through the binding of natural hormones or synthetic ER ligands may have profound effects on the physiology and pathophysiology of the organism.
[003] A variety of diseases have their etiology and/or pathology mediated by the ER. Collectively these diseases are called estrogen dependent diseases. Estrogens are critical for sexual development in women. In addition, estrogens play an important role in maintaining bone density, regulating blood lipid levels, and appear to have neuroprotective effects. Consequently, decreased estrogen production in postmenopausal women is associated with various diseases such as osteoporosis, atherosclerosis, depression and cognitive disorders. In contrast, certain types of proliferative diseases such as breast and uterine cancer and endometriosis are stimulated by estrogens, and therefore antiestrogens (i.e., estrogen antagonists) have utility in the prevention and treatment of these types of disorders.
[004] There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene (ESR1 and ESR2, respectively).
[005] Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns. ERα is found in the endometrium, breast cancer cells, ovarian stromal cells, and the hypothalamus. In men, the ERα protein is found in the epithelium of the efferent ducts. ERβ protein expression has been documented in kidneys, brain, bone, heart, lungs, intestinal mucosa, prostate and endothelial cells. The development, therefore, of selective ligands can therefore preserve the beneficial aspects of estrogen.
[006] Breast cancer is the most common malignancy to affect women and worldwide, the incidence of the disease is increasing. Estrogens, in particular, act as an endocrine growth factor for at least a third of breast cancers, and depriving the tumor of this stimulus is a recognized therapy for advanced disease. In premenopausal women, this is achieved by ablating ovarian function through surgical, radiotherapeutic, or medical means and, in postmenopausal women, by the use of aromatase inhibitors.
[007] An alternative method for estrogen withdrawal is to antagonize estrogen with antiestrogens. These are drugs that bind to and compete for estrogen receptors (ER) present in estrogen-responsive tissue. Conventional nonsteroidal antiestrogens, such as tamoxifen, compete efficiently for ER binding, but their effectiveness is often limited by the partial agonism they demonstrate, which results in incomplete blockade of estrogen-mediated activity. A specific or “pure” anti-estrogen with high affinity for the ER and no agonist effect may have advantages over conventional non-steroidal anti-estrogens in the treatment of estrogen-dependent disease. Fulvestrant is the first in a new class of potent pure antiestrogens and is completely free of the estrogen-like partial agonist activity associated with currently available antiestrogens such as tamoxifen.
[008] It would be desirable to investigate other methods to antagonize the ER receptor.
[009] One method would be to develop selective ER downregulators or degraders that reduce ER expression to the transcript or protein level.
[0010] Several methods are available for manipulating protein levels, including chimeric molecules that target proteolysis (PROTACs) that contain a ligand that recognizes the target protein bound to a ligand that binds to a specific E3 ubiquitin ligase. It would be desirable to have a small molecule that could simultaneously bind ER and an E3 ubiquitin ligase and that promotes ER ubiquitination and leads to ER degradation by the Proteosome. A suitable E3 ubiquitin ligase is von Hippel-Lindau (VHL) tumor suppressor.
[0011] The present inventors have identified compounds that are capable of inhibiting estrogen receptor function including compounds that degrade the estrogen receptor.SUMMARY OF THE INVENTION
[0012] In one aspect there is provided a compound of formula (I):
wherein R1 is OH, C1-3 alkyl, halogen, HR2 is OH, C1-3X alkyl is O, COL is a linking group comprising a length of 8 to 16 atoms at the shortest length R3 is straight chain C1-6 alkyl or branched, C3-6R4 cycloalkyl is 4-methylthiazol-5-yl, oxazol-5-yl, haloor a pharmaceutically acceptable salt thereof.
[0013] In another aspect of the present invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in therapy, in particular in the treatment of diseases and conditions mediated by the estrogen receptor.
[0014] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.
[0015] In another aspect of the present invention, there is provided a method of treating estrogen receptor-mediated diseases and conditions in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
[0016] In another aspect of the present invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of diseases and conditions mediated by the estrogen receptor. .
[0017] In another aspect there is provided a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent.
[0018] In another aspect there is provided a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent for use in therapy, particularly to treat estrogen receptor-mediated diseases and conditions. .
[0019] In another aspect of the invention there is provided a combination comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent for use in the treatment of diseases and conditions mediated by the estrogen receptor.
[0020] In another aspect there is provided a method of treating diseases and conditions mediated by the estrogen receptor comprising administering to a human being in need thereof a therapeutically effective amount of a combination comprising the compound of formula (I) or a salt of the same. even pharmaceutically acceptable and at least one other therapeutic agent.
[0021] In another aspect there is provided the use of a combination comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent in the manufacture of a medicament for treating diseases and conditions mediated by the receptor mediated by estrogen.
[0022] In another aspect there is provided a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one antineoplastic agent.
[0023] In another aspect there is provided a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one antineoplastic agent, for use in therapy, in particular for diseases and conditions mediated by the estrogen receptor .
[0024] In another aspect there is provided a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one antineoplastic agent, for use in the treatment of diseases and conditions mediated by the estrogen receptor.
[0025] In another aspect there is provided the use of a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one antineoplastic agent, in the manufacture of a medicament for treating diseases and conditions mediated by the receptor mediated by estrogen.
[0026] In another aspect there is provided a method of treating diseases and conditions mediated by the estrogen receptor, comprising administering to a human being in need thereof a therapeutically effective amount of a combination comprising a compound of formula (I) or a salt pharmaceutically acceptable thereof and at least one antineoplastic agent.
[0027] In another aspect there is provided a pharmaceutical composition comprising a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent, particularly at least one antineoplastic agent and one or more of carriers , pharmaceutically acceptable diluents and excipients.
[0028] In another aspect there is provided a method of degrading the estrogen receptor comprising administering to a human being in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof DETAILED DESCRIPTION OF THE INVENTION
[0029] As used herein, "a compound of the invention" includes all solvates, complexes, polymorphs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (I) and salts thereof.
[0030] As used herein "halo" means fluorine (-F), chlorine (-Cl), bromine (-Br) or iodine (-I).
[0031] As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will evoke the biological or medical response of a tissue, system, animal, or human being that is being sought, for example, by a researched or physician. Furthermore, the term "therapeutically effective amount" means any amount that, when compared to a corresponding individual who has not received such amount, results in improved treatment, cure, prevention, or regeneration of a disease, disorder, or side effect, or a decrease the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
[0032] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissue. and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
[0033] The compounds of the invention can exist in solid or liquid forms. In solid form, the compound of the invention can exist in a continuous sequence of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long-range order at the molecular level and, depending on the temperature, can exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinct X-ray diffraction patterns and, although they exhibit the properties of a solid, are more formally described as a liquid. On heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically of second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has an internal structure of regular order at the molecular level and gives a distinct X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phage change, typically of the first order ('melting point').
[0034] The compound of formula (I) can exist in solvated and unsolvated forms. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. The skilled artisan will appreciate that pharmaceutically acceptable solvates can be formed from crystalline compounds in which solvent molecules are incorporated into the crystal lattice during crystallization. The incorporated solvent molecules can be water or non-aqueous molecules such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine and ethyl acetate molecules. The crystalline lattice incorporated with water molecules is typically referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing varying amounts of water. The present invention includes all such solvates.
[0035] The compounds of the invention may have the ability to crystallize in more than one form, one characteristic, which is known as polymorphism and it is understood that such polymorphic forms ("polymorphs") are within the scope of the invention. Polymorphism can usually occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as X-ray diffraction patterns, solubility and melting point.
[0036] It is also mentioned that compounds of formula (I) can form tautomers. It is understood that all tautomers and mixtures of tautomers of the compounds of the present invention are included within the scope of the compounds of the present invention.
[0037] As used herein, the term "estrogen receptor inhibitor", or "inhibitor" refers to any compound or treatment capable of inhibiting or reducing estrogen receptor expression or activity. The inhibitor is preferably selected.
[0038] In one aspect R4 is 4-methylthiazol-5-yl, oxazol-5-yl.In one aspect R4 is 4-methylthiazol-5-yl;In one aspect R4 is chloro;In one aspect R4 is oxazol-5 -yl;In one aspect R1 is OH, F, Br, OCH3 or H;In another aspect R1 is OH;In one aspect R2 is OH or OCH3;In one aspect R2 is OH;In one aspect the linking group is a straight chain alkylene group of 8 to 16 carbon atoms in which one or more carbon atoms are replaced by a group each independently selected from -O-, -NH-, -N(CH3)-,

[0039] In one aspect the linking group is of the formula (ii)-(R5CH2CH2)X OCH2(ii)
[0040] Wherein each R5 is independently selected from -O-, -NH-, -N(CH3)- or
ex is 2-4
[0041] In one aspect each R5 is O; In another aspect the linker is selected from (OCH2CH2)4 OCH2(OCH2CH2)3 OCH2(OCH2CH2)2 OCH2

OCH2CH2N(CH3)CH2CH2OCH2CH2OCH2OCH2CH2N(CH3) (CH2)3(OCH2CH2)2OCH2

[0042] Although aspects for each variable have generally been listed above separately for each variable this invention includes those compounds wherein several or each aspect in formula (I) is selected from each of the aspects listed above. Accordingly, this invention is intended to include all combinations of aspects for each variable.
[0043] Examples of compounds of the present invention include the following:(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-((6-hydroxy-2-(4) -hydroxy-phenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2S,4R)-4-Hydroxy-1-((S)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl) )-benzo[b]thiophen-3-yl)oxy)phenoxy)-2-isopropyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-( 4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2S,4R)-1-((S)-2-(tert-butyl)-14-(4-((6-hydroxy-2-( 4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4 -(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2S,4R)-1-((S)-2-(tert-butyl)-14-(4-((2-(4-hydroxyphenyl)) -6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4) -methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2S,4R)-1-((S)-2-(tert-butyl)-14-(4-((6-hydroxy-2-phenylbenzo[ b]thiophen-3-yl)oxy)phenoxy) -4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S ,4R)-1-((S)-14-(4-((2-(4-bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)-2-(tert-butyl) -4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S ,4R)-1-((S)-2-(tert-butyl)-14-(4-((2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy) -4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S ,4R)-1-((S)-2-(tert-butyl)-14-(4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy) -4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S ,4R)-4-hydroxy-1-((S)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-2-methyl-4 -oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-Ethyl-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophene-3-carbonyl)phenoxy)-4- oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R) -4-hydroxy-1-((S)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophene-3-carbonyl)phenoxy)-2-isopropyl-4-oxo -6,9,12-trioxa-3-azatetra-decan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1- ((S)-2-cyclopropyl-14-(4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12 -trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S) -2-cyclopentyl-14-(4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3 - azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-1-((S) -14-(4-(6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophene-3-carbonyl)phenoxy)-2-isobutyl-4-oxo-6,9,12-trioxa-3- azatetra-decan-1-oil)-N -(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-1-((S)-17-(4-(6-hydroxy-2- (4-hydroxyphenyl)-benzo[b]thiophene-3-carbonyl)phenoxy)-2-isopropyl-4-oxo-6,9,12,15-tetraoxa-3-azaeptadecan-1-oyl)-N-(4 -(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-butyl)-17-(4-(6-hydroxy-2) -(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-aza-heptadecan-1-oyl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(2 -(4-Hhydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N -(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(6- hydroxy-2-(4-methoxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N -(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-butyl)-17-(4-(6- hydroxy-2-(4-methoxy-phenyl)benzo[b]thi ofene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-aza-eptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(6-hydroxy-2-(4-hydroxy-phenyl)) benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(oxazol-5-yl) benzyl)pyrrolidine-2-carboxamide; (2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(2-(4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene) -3-carbonyl)phenoxy)ethoxy)ethoxy)acetamido)-3,3-dimethyl-butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl) phenoxy)-12-methyl-4-oxo-6,9-dioxa-3,12-diaza-tetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl) pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-butyl)-18-(4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b] thiophene-3-carbonyl)phenoxy)-16-methyl-4-oxo-6,9,12-trioxa-3,16-diazaoctadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(2-(4-(4-(6-hydroxy)) -2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy)ethoxy)-acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazole) -5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(4-(2-(4-(6-)) hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)piperazin-1-yl)ethoxy)-acetamido)-3,3-dimethylbutanoyl)-N-(4-(4- methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(1-(4-(6-hydroxy-) 2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)fe nyl)piperidin-4-yl)piperazin-1-yl)-acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S, 4R)-4-hydroxy-1-((S)-2-(2-(9-(4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenyl) )-3,9-diazaspiro[5.5]undecan-3-yl)-acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ,;(2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(9-(4-(6-hydroxy-2-(4-hydroxy-phenyl))benzo[b ]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)-ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5) -yl)benzyl)-pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-butyl)-17-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo [b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-azaeptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazole-5) -yl)benzyl)pyrrolidine-2-carboxamide ;(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-((6-hydroxy-2-(4-hydroxy- phenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-chlorobenzyl)-4-hydroxypyrrolidine- 2-carb pharmaceutically acceptable salt thereof xamidae
[0044] The compounds of formula (I) may be in the form of a salt. Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to the non-toxic salts of the compounds of this invention. For a review of suitable salts see Berge et al, J. Pharm. Sci. 1977, 66, 1-19.
[0045] Suitable pharmaceutically acceptable salts may include acid addition salts. A pharmaceutically acceptable acid addition salt may be formed by reacting a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, p-toluenesulfonic, benzenesulfonic, methanesulfonic , ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallization and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) may comprise or be, for example, a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate salt. (eg 2-naphthalenesulfonate).
[0046] Other non-pharmaceutically acceptable salts, for example trifluoroacetates, may be used, for example in the isolation of compounds of the invention and included within the scope of this invention.
[0047] The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the compounds of formula (I).
[0048] While it is possible that, for use in therapy, the compound of the invention may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable carriers, diluents or excipients. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to its recipient. According to another aspect of the invention there is also provided a process for preparing a pharmaceutical composition comprising the agent, or pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The pharmaceutical composition may be for use in the treatment and/or prophylaxis of any of the conditions described herein.
[0049] Pharmaceutical compositions may be presented in unit dosage forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Such unit doses may accordingly be administered once or more than once a day. Such pharmaceutical compositions may be prepared by any of the methods well known in the pharmaceutical art.
[0050] The pharmaceutical compositions may be adapted for administration by any suitable route, for example, orally (including buccal or sublingual), rectal, inhaled, intranasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal). Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing the active ingredient into association with the carrier(s) or excipient(s).
[0051] Pharmaceutical compositions adapted for oral administration may be presented as separate units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whipped creams; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
[0052] For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by reducing the compound to a suitable fine size and mixing with a similarly prepared pharmaceutical carrier such as an edible carbohydrate, such as, for example, starch or mannitol. Flavoring, preservative, dispersant and coloring agent may also be present.
[0053] Capsules are manufactured by preparing a powder mixture as described above and filling the formed gelatin capsules. Gliders and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture prior to the filling operation. A disintegrating or solubilizing agent such as agar, calcium carbonate or sodium carbonate may also be added to improve drug availability when the capsule is ingested.
[0054] In addition, when desired or necessary, suitable binders, glidants, lubricants, sweetening agents, flavors, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium acetate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or grinding, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably ground, with a diluent or base as described above and optionally, with a binder such as carboxymethyl cellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a retardant solution such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture may be granulated by moistening with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and straining through a sieve. As an alternative to granulation, the powder mixture can be driven through the tablet machine and the result is imperfectly formed pieces broken into granules. The granules can be lubricated to prevent them from sticking to the matrices that form the tablet by adding stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulation or milling steps. A clear or opaque protective coating consisting of a sealant coating of shellac, a coating of sugar or polymeric material, and a coating of wax polish can be provided. Dyes can be added to these coatings to distinguish different unit dosages.
[0055] Oral fluids such as solution, syrups and elixirs can be prepared in unit dosage form so that a given amount contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions may be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or natural sweeteners or saccharin or other natural sweeteners and the like may also be added.
[0056] Where appropriate, dosage unit compositions for oral administration may be microencapsulated. The composition can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
[0057] The compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
[0058] Pharmaceutical compositions adapted for transdermal administration may be presented as separate patches intended to remain in intimate contact with the epidermis of the recipient for an extended period of time.
[0059] Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
[0060] For treatments of the eye or other external tissues, for example mouth and skin, the compositions are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be used with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil oily base.
[0061] Pharmaceutical compositions adapted for topical administration to the eye include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
[0062] Pharmaceutical compositions adapted for topical administration in the mouth include tablets, lozenges and mouthwashes.
[0063] Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or as enemas.
[0064] Dosage forms for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspensions, drops, gels or dry powders.
[0065] Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
[0066] Pharmaceutical compositions adapted for parenteral administration include sterile aqueous and non-aqueous injection solutions which may contain antioxidants, buffers, bacterostats and solutes which render the composition isotonic with the blood of the intended recipient; and sterile aqueous and non-aqueous suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately before of use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.
[0067] It should be understood that in addition to the ingredients particularly mentioned above, the compositions may include other agents conventional in the art considering the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
[0068] A therapeutically effective amount of the agent will depend on a number of factors including, for example, age and weight, the exact condition requiring treatment and its severity, the nature of the formulation, the route of administration and ultimately will be at the discretion of the physician. or veterinary attendants. In particular, the subject to be treated is a mammal, particularly a human.
[0069] The agent can be administered in a daily dose. This amount may be given in a single dose per day or in several (such as two, three, four, five or six) sub-doses per day such that the total daily dose is the same.
[0070] Suitably, the amount of the compound of the invention administered in accordance with the present invention will be an amount selected from 0.01 mg to 1 g per day (calculated as the free or desalted compound).
[0071] We have found that the compounds defined in the present invention, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions containing them, are capable of degrading the estrogen receptor.
[0072] Accordingly, the compounds of the present invention are expected to be potentially useful agents in the treatment of diseases or medical conditions mediated alone or in part by the estrogen receptor.
[0073] Methods of treating or preventing diseases, disorders and conditions mediated by the estrogen receptor are provided herein. A method may comprise administering to a subject, for example a subject in need thereof, a therapeutically effective amount of a compound of the invention.
[0074] Thus in one aspect there is provided a compound of the invention for use in therapy
[0075] Thus in one aspect there is provided a compound of the invention for use in the treatment of diseases, disorders or conditions mediated by the estrogen receptor
[0076] Thus in one aspect there is provided the use of a compound of the invention in the manufacture of a medicament for treating diseases, disorders or conditions mediated by the estrogen receptor.
[0077] In another aspect there is provided a method of treating diseases, disorders or conditions mediated by the estrogen receptor in a mammal comprising administering a therapeutically effective amount of a compound of the invention.
[0078] The compound of the invention is useful in the treatment of conditions associated with the estrogen receptor. A "conditions associated with estrogen receptor," as used herein, denotes a condition or disorder that can be treated by modulating the function or activity of an estrogen receptor in a subject, wherein the treatment comprises partial prevention, alleviation, or cure of the condition. condition or disorder. The modulation can occur locally, for example, within certain tissues of the individual, or more extensively throughout an individual being treated for such a condition or disorder.
[0079] In one respect the estrogen-mediated disease or condition is breast cancer.
[0080] The compounds of the present invention may be used in combination with or include one or more other therapeutic agents and may be administered sequentially or simultaneously by any convenient route separately or in combination with pharmaceutical compositions.
[0081] The therapeutically effective amount of the other therapeutic agents of the present invention will depend on a number of factors including, for example, the age and weight of the mammal, the exact condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of delivery. administration. Ultimately, the therapeutically effective amount will be at the discretion of the attending physician or veterinarian. The relative timings of administration will be selected to achieve the desired combined therapeutic effect.
[0082] The compounds of the present invention and other therapeutic agent(s) may be used in combination by administration simultaneously in a unitary pharmaceutical composition comprising both compounds. Alternatively, the combination may be administered separately in separate pharmaceutical compositions, each comprising one of the compounds in a sequential manner whereby, for example, the compound of the invention is administered first and the other second and vice versa. Such sequential administration may be close in time (e.g., simultaneously) or distant in time. Furthermore, it is not important whether the compounds are administered in the same dosage form, for example, one compound can be administered topically and the other compound can be administered orally. Suitably, both compounds are administered orally.
[0083] Combinations can be presented as a combination kit. By the terms "combination kit" "or kit of parts" as used herein is intended the pharmaceutical composition or compositions that are used to administer the combination according to the invention. When both compounds are administered simultaneously, the combination kit may contain both compounds in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. When the compounds are not administered simultaneously, the combination kit will contain each compound as separate pharmaceutical compositions in a single pack or as separate pharmaceutical compositions in separate packs.
[0084] The combination kit may also be provided with instruction such as dosage and administration instructions. Such dosage and administration instructions may be of the type that are provided to a physician, for example by a drug product label, or they may be of the type that are provided by a physician, such as instructions to a patient.
[0085] When the combination is administered separately in a sequential manner whereby one is administered first and the other second or vice versa, such sequential administration may be close in time or distant in time. For example, administration of another agent from several minutes to several dozen minutes after administration of the first agent and administration of another agent from several hours to several days after administration of the first agent included, where the time interval is not limited For example, one agent can be administered once a day and the other agent can be administered 2 or 3 times a day, or one agent can be administered once a week and the other agent can be administered once a day and the similar.
[0086] It will be apparent to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, for example as a metal alkali or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimize activity and/or stability and/or physical characteristics such as solubility, of the therapeutic ingredient. It will also be apparent that, where appropriate, therapeutic ingredients may be used in optically pure form.
[0087] When combined in the same composition it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the composition and can be formulated for administration. When formulated separately they may be provided in any convenient composition, conveniently in such a manner as is known for such compounds in the art.
[0088] When the compound of formula (I) is used in combination with a second therapeutic agent active against the same disease, condition or disorder, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
[0089] In the embodiment, the compound of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used with other therapeutic methods of treating cancer. In particular, in antineoplastic therapy, combination therapy with another chemotherapeutic, hormonal, antibody agents as well as surgical and/or radiation treatments other than those mentioned above are considered.
[0090] As indicated, the therapeutically effective amount of the compound of the compound of formula (I) or a pharmaceutically acceptable salt thereof are discussed above. The therapeutically effective amount of the other therapeutic agents of the present invention will depend on a number of factors including, for example, the age and weight of the mammal, the exact condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the therapeutically effective amount will be at the discretion of the attending physician or veterinarian. The relative timings of administration will be selected to achieve the desired combined therapeutic effect.
[0091] In one modality, the other anticancer therapy is surgical and/or radiation therapy.
[0092] In one embodiment, the other anticancer therapy is at least one additional antineoplastic agent.
[0093] Any antineoplastic agent that has activity against a susceptible tumor to be treated can be used in combination. Typical useful antineoplastic agents include, but are not limited to, antimicrotubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas and triazenes; antibiotic agents such as anthracyclines, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and antifoliate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormone analogues; signal transduction pathway inhibitors; non-receptor tyrosine angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors.
[0094] Antimicrotubule or antimitotic agents:
[0095] Antimicrotubule or antimitotic agents are phase-specific agents active against the microtubules of tumor cells during M-phase or cell cycle mitosis. Examples of antimicrotubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
[0096] Diterpenoids, which are derived from natural sources, are phase-specific anticancer agents that operate in the G2/M phases of the cell cycle. Diterpenoids are believed to stabilize the β-tubulin subunit of microtubules by binding to this protein. Protein disassembly appears to be then inhibited with mitosis being stopped and cell death ensuing. Examples of diterpenoids include, but are not limited to, paclitaxel and its analogue docetaxel.
[0097] Paclitaxel, 5β,20-epoxy-1,2α,4,7β,10β,13α-hexa-hydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S )-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as a TAXOL® injectable solution. The same is a member of the terpene taxane family. Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann. Intem. Med., 111: 273, 1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83: 1797, 1991). It is a potential candidate for the treatment of skin neoplasms (Einzig et al., Proc. Am. Soc. Clin. Oncol., 20:46) and carcinomas of the head and neck (Forastire et al., Sem. Oncol. , 20: 56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et al., Nature, 368: 750, 1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lines, Ignoff, RJ et al, Cancer Chemotherapy Pocket Guide, 1998) related to duration of dosing above a threshold concentration (50 nM) (Kearns, CM et al., Seminars in Oncology, 3(6) pp. 16-23, 1995).
[0098] Docetaxel is a semi-synthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree.
[0099] Vinca alkaloids are phase-specific antineoplastic agents derived from the myrtle plant. Vinca alkaloids act in the M phase (mitosis) of the cell cycle by specifically binding to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is thought to be stopped at metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine and vinorelbine.
[00100] Vinblastine, vincaleucoblastine sulfate, is commercially available as VELBAN® as a solution for injection. Although it has a possible indication as a second-line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocystic lymphomas. Myelosuppression is the dose-limiting side effect of vinblastine.
[00101] Vincristine, vincaleucoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN® as a solution for injection. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for malignant Hodgkin's and non-Hodgkin's lymphomas. Alopecia and neurological effects are the most common side effects of vincristine and to a lesser degree myelosuppression and gastrointestinal mucositis effects occur.
[00102] Vinorelbine, 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)], commercially available as a solution for injection of vinorelbine tartrate (NAVELBINE®), it is a semi-synthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of a variety of solid tumors, particularly non-small cell lung, advanced breast, and hormone-refractory prostate cancers. Myelosuppression is the most common dose-limiting side effect of vinorelbine.Platinum coordination complexes:
[00103] Platinum coordination complexes are non-phase-specific anticancer agents that interact with DNA. Platinum complexes enter tumor cells, undergo water addition and form intra- and inter-strand cross-links with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, oxaliplatin, cisplatin and carboplatin.
[00104] Cisplatin, cis-diaminodichloroplatinum, is commercially available as PLATINOL® as a solution for injection. Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
[00105] Carboplatin, platinum, diamine [1,1-cyclobutane-dicarboxylate(2-)-O,O'], is commercially available as PARAPLATIN® as an injectable solution. Carboplatin is primarily indicated in first- and second-line treatments of advanced ovarian carcinoma.Alkylating Agents:
[00106] Alkylating agents are non-phase specific anticancer agents and strong electrolytes. Typically, alkylating agents form covalent bonds, by alkylation, to DNA through nucleophilic portions of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
[00107] Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of malignant lymphomas, multiple myeloma and leukemias.
[00108] Melphalan, 4-[bis(2-chloroethyl)amino]-phenylalanine, is commercially available as a solution for injection or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-operable epithelial ovarian carcinoma. Bone marrow suppression is the most common dose-limiting side effect of melphalan.
[00109] Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma and Hodgkin's disease.
[00110] Busulfan, 1,4-butanediol dimethanesulfonate, is commercially available as MILERAN® TABLETES. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia.
[00111] Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commercially available as individual vials of lyophilized material as BiCNU®. Carmustine is indicated for palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease and non-Hodgkin's lymphomas.
[00112] Dacarbazine, 5-(3,3-dimethyl-1-triazene)-imidazole-4-carboxamide, is commercially available as single vials of material such as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second-line treatment of Hodgkin's Disease. Antineoplastic antibiotics:
[00113] Antineoplastic antibiotics are non-phase specific agents that bind or intercalate with DNA. Typically, such an action results in stable DNA complexes or strand breakage, which disrupts the common function of nucleic acids leading to cell death. Examples of antibiotic antineoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclines such as daunorubicin and doxorubicin; and bleomycins.
[00114] Dactinomycin, also known as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma.
[00115] Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-lixohexopyranosyl)oxy]-7,8,9 hydrochloride, 10-Tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedione, is commercially available as an injectable liposomal form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for the induction of remission in the treatment of acute non-lymphocytic leukemia and advanced HIV-associated Kaposi's sarcoma.
[00116] Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-α-lixo-hexopyranosyl)oxy]-8-glycoyl, 7,8,9,10 hydrochloride -tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12naphthacenedione, is commercially available as an injectable form as RUBEX® or ADRIAMICIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas.
[00117] Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas.Topoisomerase II Inhibitors:
[00118] Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
[00119] Epipodophyllotoxins are phase-specific antineoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing the DNA strand to break. Filament breaks accumulate and cell death ensues. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
[00120] Etoposide, 4'-desmethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene-eD-glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16 . Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers.
[00121] Teniposide, 4'-desmethyl-epipodophyllotoxin 9[4,6-0-(R)-tenylidene-and-D-glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Neoplastic antimetabolite agents:
[00122] Neoplastic antimetabolite agents are phase-specific antineoplastic agents that act in the S-phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine- or pyrimidine-based synthesis and thereby limiting the synthesis of DNA. Consequently, S phase does not proceed and cell death ensues. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
[00123] 5-fluorouracil, 5-fluoro-2,4-(1H,3H)pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result is typically cell death. 5-Fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach, and pancreas. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
[00124] Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. Cytarabine is believed to exhibit cell-phase specificity in S-phase by inhibiting DNA strand elongation by incorporating terminal cytarabine into the growing DNA strand. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2',2'-difluorodeoxycytidine (gemcitabine).
[00125] Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits S-phase cell-phase specificity by inhibiting DNA synthesis by a hitherto unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. A useful mercaptopurine analogue is azathioprine.
[00126] Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits S-phase cell-phase specificity by inhibiting DNA synthesis by a hitherto unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other purine analogues include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate and cladribine.
[00127] Gemcitabine, 2'-deoxy-2',2'-difluoro-cytidine monohydrochloride (β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell-phase specificity in S-phase and blocking the progression of cells across the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.
[00128] Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl)methyl]methyl-amino]benzoyl]-glutamic acid, is commercially available as sodium methotrexate. Methotrexate exhibits cell-phase effects specifically in S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dihydrofolic acid reductase which is required for the synthesis of purine and thymidylate nucleotides. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma and carcinomas of the breast, head, neck, ovary and bladder. Topoisomerase I inhibitors:
[00129] Camptothecins, including camptothecin and camptothecin derivatives are available or under development as topoisomerase I inhibitors. The cytotoxic activity of camptothecins is believed to be related to their topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan and the various optical forms of 7-(4-methylpiperazine-methylene)-10,11-ethylenedioxy-20-camptothecin described below.
[00130] Irinotecan HCl, (4S)-4,11-Diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3',4',6,7]indolizino[1] hydrochloride ,2-b]quinoline-3,14(4H,12H)-dione, is commercially available as CAMPTOSAR® solution for injection. Irinotecan is a camptothecin derivative that binds, together with its active metabolite SN-38, to the topoisomerase I - DNA complex. Cytotoxicity is believed to occur as a result of irreparable double-stranded breaks caused by the interaction of the ternary topoisomerase I : DNA : irinotecan or SN-38 complex with replication enzymes. Irinotecan is indicated for the treatment of metastatic cancer of the colon or rectum.
[00131] Topotecan HCl, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4',6,7]indolizino[1,2] monohydrochloride -b]quinoline-3,14-(4H,12H)-dione, is commercially available as HYCAMTIN® solution for injection. Topotecan is a camptothecin derivative that binds to the topoisomerase I - DNA complex and prevents the rewiring of single-stranded breaks caused by Topoisomerase I in response to the twisting effort of the DNA molecule. Topotecan is indicated for the second-line treatment of metastatic carcinoma of the ovary and small cell lung cancer. Hormones and hormone analogues:
[00132] Hormones and hormone analogues are compounds useful for treating cancers in which there is a relationship between the hormone(s) and the development and/or lack of development of the cancer. Examples of hormones and hormone analogues useful in the treatment of cancer include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazol and exemestane useful in the treatment of adrenocortical carcinoma and hormone-dependent mammary carcinoma containing estrogen receptors; progestins such as megestrol acetate useful in the treatment of hormone-dependent breast cancer and endometrial carcinoma; estrogens, estrogens and antiestrogens such as fulvestrant, flutamide, nilutamide, bicalutamide, cyproterone acetate and 5α-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; antiestrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, as well as selective estrogen receptor modulators (SERMS) such as those described in U.S. Patent Nos. 5,681,835, 5,877,219 and 6,207,716 useful in the treatment of hormone-dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof that stimulate the release of luteinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment of prostatic carcinoma, e.g. LHRH agonists and antagonists such as acetate of goserelin and leuprolide.Signal transduction pathway inhibitors:
[00133] Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process that evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Inhibitors of signal transduction useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphatidyl inositol-3 kinases, myo-inositol signaling, and Ras oncogenes. .
[00134] Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell development. Such protein tyrosine kinases can be broadly classified as either receptor or non-receptor kinases.
[00135] Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are commonly referred to as growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e., aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Consequently, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases would provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), erbB2, erbB4, ret, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like domains and homology with epidermal growth factor (TIE-2), insulin growth factor I receptor (IGFI), macrophage colony stimulating factor (cfms) receptors, BTK, ckit , cmet, fibroblast growth factor (FGF), Trk receptors (TrkA, TrkB and TrkC), ephrin receptors (eph) and the protooncogene RET. Several growth inhibitor receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors, and antisense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for example, in Kath, John C., Exp. Opin. The R. Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2, February 1997; and Lofts, F.J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
[00136] Tyrosine kinases, which are not growth factor receptor kinases are called non-receptor tyrosine kinases. Non-receptor tyrosine kinases useful in the present invention, which are targets or potential targets of anticancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Bruton's tyrosine kinase, and Bcr-Abl. Such non-receptor kinases and agents that inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research 8(5): 465-80; and Bolen, J.B., Brugge, J.S., (1997) Annual review of Immunology. 15: 371-404.
[00137] SH2/SH3 domain blockers are agents that disrupt the binding of SH2 or SH3 domains in a variety of enzymes or adapter proteins including, the PI3-K p85 subunit, Src family kinases, adapter molecules (Shc, Crk , Nck, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anticancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.
[00138] Inhibitors of Serine/Threonine Kinases including blockers of the MAP kinase cascade which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs) and Extracellular Regulated Kinases (ERKs); and protein kinase C family member blockers including PKC blockers (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). The IkB kinase family (IKKa, IKKb), the PKB family kinases, members of the akt kinase family, and TGF beta receptor kinases. Such Serine/Threonine kinases and their inhibitors are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A. and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P.A. and Harris, A. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6,268,391; and Martinez-Iacaci, ., et al, Int. J. Cancer (2000), 88(1), 44-52.
[00139] Inhibitors of members of the Phosphotidyl Inositol-3 Kinase family including PI3-kinase, ATM, DNA-PK and Ku blockers are also useful in the present invention. Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7): 935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545.
[00140] Also useful in the present invention are inhibitors of Myo-inositol signaling such as phospholipase C blockers and Myo-inositol analogues. Such signal inhibitors are described in Powis, G. and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
[00141] Another group of inhibitors of the signal transduction pathway are inhibitors of the Ras Oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase and CAAX proteases as well as antisense oligonucleotide, ribozymes and immunotherapy. Such inhibitors have been shown to block the activation of ras in cells containing wild-type mutant ras, thereby acting as anti-proliferation agents. Inhibition of the Ras oncogene is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3): 19-30.
[00142] As mentioned above, antibody antagonists for receptor kinase ligand binding can also serve as inhibitors of signal transduction. This group of inhibitors of the signal transduction pathway includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example the EGFR-specific antibody Imclone C225 (see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286 ); Herceptin ® erbB2 antibody (see Tyrosine Kinase Signaling in Breast cancer: erbB Family Receptor Tyrosine Kinases, Breast Cancer Res., 2000, 2(3), 176-183); and 2CB specific antibody VEGFR2 (see Brekken, R. A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124 ). Antiangiogenic agents:
[00143] Anti-angiogenic agents including inhibitors of non-receptor MEK angiogenesis may also be useful. Anti-angiogenic agents such as those that inhibit the effects of vascular endothelial growth factor, (e.g. the antivascular endothelial cell growth factor antibody bevacizumab [Avastin®] and compounds that function by other mechanisms (e.g. linomide, inhibitors of vascular function) αvβ3 integrin, endostatin and angiostatin); Immunotherapeutic agents:
[00144] Agents used in immunotherapeutic regimens may also be useful in combination with compounds of formula (I). Immunotherapy methods, including for example ex vivo and in vivo methods for increasing the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, methods for decreasing the T-cell energy, methods using transfected immune cells such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cell lines, and methods using anti-idiotypic antibodies Proapoptic agents:
[00145] Agents used in proapoptotic regimens (eg, bcl-2 antisense oligonucleotides) can also be used in the combination of the present invention. Cell cycle signaling inhibitors
[00146] Cell cycle signaling inhibitors inhibit molecules involved in cell cycle control. A family of protein kinases called cyclin-dependent kinases (CDKs) and their interaction with a family of proteins called cyclins controls progression through the eukaryotic cell cycle. Coordinated activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several cell cycle signaling inhibitors are under development. For example, examples of cyclin-dependent kinases, including CDK2, CDK4, and CDK6, and inhibitors thereof are described, for example, in Rosania et al, Exp. Opin. The R. Patents (2000) 10(2): 215-230.
[00147] In one embodiment, the combination of the present invention comprises a compound of formula I or a salt or solvate thereof and at least one antineoplastic agent selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents , topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor MEK tyrosine angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors.
[00148] In one embodiment, the combination of the present invention comprises a compound of formula I or a salt or solvate thereof and at least one antineoplastic agent which is an antimicrotubule agent selected from diterpenoids and vinca alkaloids.
[00149] In another embodiment, at least one antineoplastic agent is a diterpenoid.
[00150] In another embodiment, at least one antineoplastic agent is a vinca alkaloid.
[00151] In one embodiment, the combination of the present invention comprises a compound of formula I or a salt or solvate thereof and at least one antineoplastic agent, which is a platinum coordination complex.
[00152] In another embodiment, at least one antineoplastic agent is paclitaxel, carboplatin, or vinorelbine.
[00153] In another embodiment, at least one antineoplastic agent is carboplatin.
[00154] In another embodiment, at least one antineoplastic agent is vinorelbine.
[00155] In another embodiment, at least one antineoplastic agent is paclitaxel.
[00156] In one embodiment, the combination of the present invention comprises a compound of formula I and salts or solvates thereof and at least one antineoplastic agent which is an inhibitor of the signal transduction pathway.
[00157] In another embodiment the signal transduction pathway inhibitor is an inhibitor of a growth factor receptor kinase VEGFR2, TIE2, PDGFR, BTK, erbB2, EGFr, IGFR-1, TrkA, TrkB, TrkC, or c -fms.
[00158] In another embodiment the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase rafk, akt, or PKC-zeta.
[00159] In another embodiment the signal transduction pathway inhibitor is an inhibitor of a non-receptor tyrosine kinase selected from the src family of kinases.
[00160] In another embodiment the signal transduction pathway inhibitor is a c-src inhibitor.
[00161] In another embodiment the signal transduction pathway inhibitor is a Ras oncogene inhibitor selected from farnesyl transferase and geranylgeranyl transferase inhibitors.
[00162] In another embodiment the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the group consisting of PI3K.
[00163] In another embodiment the signal transduction pathway inhibitor is a dual inhibitor of EGFr/erbB2, for example N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5 -({[2-(methanesulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (structure below):

[00164] In one embodiment, the combination of the present invention comprises a compound of formula I or a salt or solvate thereof and at least one antineoplastic agent which is an inhibitor of cell cycle signaling.
[00165] In another embodiment, the inhibitor of cell cycle signaling is an inhibitor of CDK2, CDK4 or CDK6.
[00166] Particular components of combination therapy include combinations with other antiestrogens including tamoxifen and/or fulvestrant.
[00167] In one embodiment the mammal in the methods and uses of the present invention is a human. General Synthetic Methods
[00168] The compounds of general formula (I) can be prepared by methods known in the art of organic synthesis as shown in the specific examples described below. In all methods, it is well understood that protecting groups for sensitive or reactive groups can be used where necessary in accordance with general principles of chemistry. Protective groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a convenient stage of compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and the order of their execution must be compatible with the preparation of compounds of formula (I).Experimental Abbreviations:DCM: dichloromethane.DIPEA: N,N-diisopropylethylamine.DMF: N, N-dimethylformamide.h: hour.HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.HPLC: high performance liquid chromatography.LCMS: liquid chromatography -mass spectrometryMin: minutes.NMR: Nuclear magnetic resonance.RT: retention time.tBu: tert-butoxide.TFA: trifluoroacetic acid.THF: tetrahydrofuran.TMSCl: trimethylsilyl chloride.LCMS Method:
[00169] The analysis was conducted on an Acquity UPLC BEH C18 column (50 mm x 2.1 mm internal diameter 1.7 μm packing diameter) at 40°C.
[00170] The solvents used were: A = 0.1% v/v solution of formic acid in water.B = 0.1% v/v solution of formic acid in acetonitrile.
[00171] The gradient used was as follows:

[00172] The UV detection was a signal averaged over the wavelength from 210 nm to 350 nm and the mass spectra were recorded on a mass spectrometer using electrospray ionization in positive and negative alternating scan mode.
[00173] The following illustrates the mobile phases and gradients used when compounds underwent purification by Mass Directed Autoprep HPLC. Mass Directed Autoprep HPLC (Formic Acid Modifier)
[00174] HPLC analysis was conducted on a Sunfire C18 column (150 mm x 30 mm inner diameter, 5 μm packing diameter) at room temperature.
[00175] The solvents used were: A = 0.1% v/v solution of formic acid in water.B = 0.1% v/v solution of formic acid in acetonitrile. Ammonium Bicarbonate)
[00176] HPLC analysis was conducted on an XBridge C18 column (150 mm x 30 mm internal diameter, 5 μm packing diameter) at room temperature.
[00177] The solvents used were: A = 10 mM ammonium bicarbonate in water adjusted to pH 10 with the ammonia solution. B = acetonitrile.
[00178] For each of the for each of the mass-directed autoprep purifications, regardless of the modifier used, the gradient used was dependent on the retention time of the particular compound undergoing purification as recorded in analytical LCMS and was as follows:
[00179] For compounds with an analytical LCMS retention time below 0.6 minutes the following gradient was used:

[00180] For compounds with an analytical LCMS retention time between 0.6 and 0.9 minutes the following gradient was used:

[00181] For compounds with an analytical LCMS retention time between 0.9 and 1.2 minutes the following gradient was used:

[00182] For compounds with an analytical LCMS retention time between 1.2 and 1.4 minutes the following gradient was used:


[00183] For compounds with an analytical LCMS retention time greater than 1.4 minutes (LCMS method A) or greater than 3.6 minutes (LCMS method B) the following gradient was used:

[00184] UV detection was a signal averaged over the wavelength from 210 nm to 350 nm and mass spectra were recorded on a mass spectrometer using electrospray ionization in positive and negative alternate scan mode.
[00185] Chemical names were generated using ACD Name Pro version 6.02 from Advanced Chemistry Development, Inc.

[00186] 4-((6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenol can be prepared according to the process described by Palkowitz, Alan David, US 5492922A.

[00187] 3-Bromo-2-(4-bromophenyl)-6-methoxybenzo[b]thiophene-1-oxide can be prepared according to the process described by Zhihui Qin et al. J. Med. Chem. 2007, 50, 2682-2692.

[00188]oxide can be prepared according to the process described by Hong Liu et al. Chem. Res. Toxicol. 2005, 18, 162-173.
[00189] tert-Butyl 2-(2-(benzyloxy)ethoxy)acetate

[00190] KOtBu (3.24 g, 29 mmol) was added to a stirred solution of 2-(benzyloxy)ethanol (commercially available e.g. from Aldrich) (4 g, 26 mmol) in tBuOH (30 mL) and the mixture was stirred at room temperature for 2 hours. Tert-butyl bromoacetate (commercially available eg from Aldrich) (7 ml, 47 mmol) was then added and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM (50 ml) and washed with water (2 x 50 ml) and then brine (2 x 50 ml). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica (330 g cartridge) using a gradient elution of 0% to 100% tert-butyl methyl ether in cyclohexane to give the title compound (724 mg, 2.3 mmol, 9 % yield). LCMS RT = 1.10 min, ES+ve m/z 267.4 [M + H]+ tert-butyl 2-(2-hydroxyethoxy)acetate

[00191] A mixture of tert-butyl 2-(2-(benzyloxy)ethoxy)acetate (724 mg, 2.3 mmol) and 10% w/w palladium on carbon (365 mg, 0.34 mmol) in Ethanol (10 ml) was stirred at room temperature under an atmosphere of hydrogen for 1.5 hours. Palladium on carbon was filtered through celite and the filtrate evaporated under reduced pressure to give the title compound (349 mg, 1.8 mmol, 78% yield). LCMS RT = 0.61 min, ES+ve m/z 263.4 [M + H]+ tert-butyl .2-(2-(tosyloxy)ethoxy)acetate

[00192] Tosyl chloride (578 mg, 3.0 mmol) was added to a cold (0°C) solution of tert-butyl 2-(2-hydroxyethoxy)acetate (349 mg, 1.8 mmol) in pyridine (4 ml). The reaction was stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate (50 ml) and 2M aqueous HCl (40 ml). The organic extract was separated, washed with 2M aqueous HCl (40 ml), followed by saturated sodium bicarbonate (50 ml) and brine (50 ml). The organic extract was then dried (hydrophobic frit) and concentrated under reduced pressure to give the title compound (618 mg, 1.50 mmol, 84% yield). LCMS RT = 1.14 min, ES+ve m/z 348.0 [M + NH4]+ tert-butyl .2-(2-(2-(benzyloxy)ethoxy)ethoxy)acetate

[00193] KOtBu (20 ml, 20 mmol) was added to a stirred solution of 2-(2-(benzyloxy)ethoxy)ethanol (commercially available e.g. from Aldrich) (2.74 ml, 15 mmol) in tBuOH (30 ml ) and the mixture was stirred under an atmosphere of nitrogen at room temperature for 2 hours. The reaction mixture was cooled to 0°C, tert-butyl bromoacetate (commercially available eg from Aldrich) (4 ml, 28 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was then concentrated and partitioned between water (50 ml) and DCM (50 ml). The organic layer was separated and the aqueous layer was further extracted with DCM (50 ml). The combined organic layers were dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0% to 100% tert-butyl methyl ether in cyclohexane to give the title compound (3.56 g, 11 mmol, 74% yield). LCMS RT = 1.11 min, ES+ve m/z 311.4 [M + H]+, 328.4 [M + NH4] + tert-.2-(2-(2-hydroxyethoxy)ethoxy)acetate butyl

[00194] A mixture of tert-butyl 2-(2-(2-(benzyloxy)ethoxy)ethoxy)acetate (7.97 g, 25 mmol) and 10% w/w palladium on carbon (2.68 g, 2.5 mmol) in ethanol (100 ml) was stirred at room temperature under an atmosphere of hydrogen for 1.5 hours. The mixture was filtered through celite and the filtrate evaporated under reduced pressure to give the title compound (5.45 g, 22 mmol, 88% yield). LCMS RT=0.65min, ES+ve m/z 238.1 [M+NH4]+. 1H NMR (400 MHz, CDCl 3 ) □ = 3.98 (s, 2H), 3.74 - 3.64 (m, 6H), 3.62 - 3.55 (m, 2H), 2.77 (t , J = 6.0 Hz, 1H), 1.44 (s, 9H). tert-Butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate

[00195] Tosyl chloride (commercially available e.g. from Aldrich) (3.60 g, 19 mmol) was added to a cold (0°C) solution of 2-(2-(2-hydroxyethoxy)ethoxy)acetate. tert-butyl (2.72 g, 11 mmol) in pyridine (25 ml). The reaction was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was partitioned between ethyl acetate (30 ml) and 2M aqueous HCl (30 ml). The organic extract was separated, washed with 2M aqueous HCl (30 ml), dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica (330 g cartridge) using a gradient elution of 0% to 100% tert-butyl methyl ether in cyclohexane to give the title compound (1.71 g, 4.5 mmol, 40% yield). LCMS RT = 1.13 min, ES+ve m/z 375.3 [M + H]+ tert-butyl α1-phenyl-2,5,8,11-tetraoxatridecan-13-oate

[00196] Potassium tert-butoxide (commercially available e.g. from Aldrich) (7.71 g, 69 mmol) was added to a stirred solution of 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethanol ( commercially available e.g. from Fluorochem) (15 g, 62 mmol) in tert-butanol (200 ml) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, tert-butyl bromoacetate (commercially available eg from Aldrich) (17 ml, 112 mmol) was added and the mixture was stirred overnight. DCM (300 ml) was added washed with water (300 ml) and then brine (2 organic was dried using a hydrophobic frit at reduced pressure to give the crude product as a yellow oil. The product was purified by chromatography on silica using an elution 0% to 100% methyl tert-butyl ether in cyclohexane gradient to give the title compound (13.3 g, 38 mmol, 60% yield) LCMS RT = 1.10 min, ES+ve m/ z 372.4 [M + NH4]+.2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate tert-butyl

[00197] tert-butyl (13.3 g, 38 mmol) and palladium on carbon (10% w/w, 11.4 g, 11 mmol) in ethanol (200 ml) was stirred at room temperature under an atmosphere of hydrogen for 1.5 hours. The mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give the title compound (9.74 g, 37 mmol, 98% yield) as a yellow oil. 1H NMR (400MHz, DMSO-d6) = 4.54 (s, 1H), 3.99 (s, 2H), 3.60 - 3.40 (m, 12H), 1.43 (s, 9H). tert-Butyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate

[00198] Tosyl chloride (commercially available e.g. from Aldrich) (11.9 g, 63 mmol) was added to a cold (0°C) solution of 2-(2-(2-(2-hydroxyethoxy)ethoxy) tert-butyl)ethoxy)acetate (9.74 g, 37 mmol) in pyridine (150 ml). The reaction was stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate (300 ml) and aqueous HCl (2M, 300 ml). The organic extract was washed with more aqueous HCl (2M, 300 ml), saturated K2CO3 (100 ml) and brine (100 ml). The organic extract was dried using MgSO4 and concentrated under reduced pressure to give the title compound (10.3 g, 25 mmol, 67% yield) as a yellow oil. LCMS RT = 1.14 min, ES+ve 436.2 [M + NH4]+.2-(2-(3-(Benzyloxy)propoxy)ethoxy)ethanol

[00199] Sodium hydride (60% w/w in mineral oil) (350 mg, 8.8 mmol) was added to a mixture of 2,2'-oxydiethanol (commercially available e.g. from Aldrich) (2.32 g, 22 mmol) and ((3-bromopropoxy)methyl)benzene (commercially available e.g. from Aldrich) (0.77 ml, 4.4 mmol) in DMF (10 ml). The reaction mixture was stirred at room temperature for 3 hours. An additional aliquot of sodium hydride, (60% w/w in mineral oil) (350 mg, 8.8 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was separated, dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica (50 g cartridge) using a gradient elution of 0% to 25% MeOH in DCM to give the title compound (648 mg, 2.6 mmol, 58% yield). LCMS RT = 0.78 min, ES+ve m/z 255.1 [M + H]+ tert-butyl 1-phenyl-2,6,9,12-tetraoxatetradecan-14-oate

[00200] KOtBu (315 mg, 2.8 mmol) was added to a stirred solution of 2-(2-(3-(benzyloxy)propoxy)ethoxy)ethanol (648 mg, 2.6 mmol) in tBuOH (8 mL) and the mixture was stirred at room temperature for 2 hours. Tert-butyl bromoacetate (commercially available eg from Aldrich) (0.68 ml, 4.6 mmol) was added and the mixture was stirred at room temperature overnight. More aliquots of KOtBu (315 mg, 2.8 mmol) and tert-butyl bromoacetate (0.68 ml, 4.6 mmol) were added and the reaction was stirred at room temperature for 6 hours. A final aliquot of tert-butyl bromoacetate (0.68 ml, 4.6 mmol) was added and the reaction was stirred for 16 hours. The reaction mixture was partitioned between water (50 ml) and DCM (70 ml). The organic layer was separated, dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0% to 100% tert-butyl methyl ether in cyclohexane, followed by 0% to 20% MeOH in cyclohexane to give the title compound (438 mg, 1 .2 mmol, 47% yield). LCMS RT = 1.16 min, ES+ve m/z 369.5 [M + H]+ tert-butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)acetate

[00201] A mixture of tert-butyl 1-phenyl-2,6,9,12-tetraoxatetradecan-14-oate (418 mg, 1.13 mmol) and 10% w/w palladium on carbon (0.05 g, 0.47 mmol) in ethanol (5 ml) was stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered through celite and the filtrate evaporated under reduced pressure to give the title compound (314mg, 1.1mmol, 99% yield). 1H NMR (400 MHz, CDCl3) □ = 4.03 (s, 2H), 3.84 - 3.75 (m, 2H), 3.74 - 3.58 (m, 10H), 2.58 - 2 .43 (m, 1H), 1.87 - 1.78 (m, 2H), 1.48 (s, 9H). 2-(2-(2-(3-(tosyloxy)propoxy)ethoxy)ethoxy) tert-butyl acetate

[00202] Tosyl chloride (commercially available e.g. from Aldrich) (430 mg, 2.3 mmol) was added to a cold (0°C) solution of 2-(2-(2-(3-hydroxypropoxy)ethoxy tert-butyl)ethoxy)acetate (314mg, 1.1mmol) in pyridine (5ml). The reaction was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was partitioned between ethyl acetate (30 ml) and saturated aqueous sodium bicarbonate (30 ml). The organic extract was washed with additional aqueous saturated sodium bicarbonate (2 x 30 ml), brine (30 ml), dried using a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica using a gradient elution of 0% to 100% tert-butyl methyl ether in cyclohexane to give the title compound (310 mg, 0.72 mmol, 64% yield). LCMS RT = 1.14 min, ES+ve m/z 450.3 [M + NH4]+.2-((4-bromobenzyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (2S,4R)-tert -butyl

[00203] An ice-cold mixture of butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid available e.g. from Aldrich) (7.95 g, 34 mmol) and (4-bromophenyl)methanamine (commercially available e.g. from FluroChem) (6, 4 g, 34 mmol) in DMF (200 ml) was treated with DIPEA (18 ml, 103 mmol) and then with HATU (14.4 g, 38 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched with water (200 ml) and extracted with ethyl acetate (2 x 200 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (2 x 300 ml), water (100 ml), brine (200 ml), dried over magnesium sulfate and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution of 0% to 10% methanol in DCM to give the title compound (12.9 g, 32 mmol, 94% yield). LCMS RT = 0.87 min, ES+ve m/z 399.2/401.2 [M + H]+ α4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl )- (2S,4R)-tert-butyl pyrrolidine-1-carboxylate

[00204] A mixture of (2S,4R)-tert-butyl 2-((4-bromobenzyl)carbamoyl)-4-hydroxy-pyrrolidine-1-carboxylate (12.9 g, 32 mmol), 4- methyl thiazole (commercially available e.g. from Aldrich) (5.9 ml, 65 mmol), palladium (II) acetate (commercially available e.g. from Aldrich) (0.145 g, 0.65 mmol) and potassium acetate (6 .34 g, 65 mmol) in N-methyl-2-pyrrolidone (80 ml) was stirred at 120°C under nitrogen for 18 hours. Water (100 ml) was added and the product was extracted with ethyl acetate (4 x 300 ml). The combined organic phase was washed with brine (5 x 200 ml), dried over magnesium sulfate and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution of 0% to 10% methanol in DCM to give the title compound (8 g, 19 mmol, 59% yield). LCMS RT = 0.75 min, ES+ve m/z 418.4 [M + H]+.(2S,4R)-4-Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl) pyrrolidine-2-carboxamide, hydrochloride

[00205] (2S,4R)-tert-Butyl 4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)-pyrrolidine-1-carboxylate (8 g, 19 mmol) was dissolved in methanol (30 ml) and DCM (20 ml) and treated with HCl in dioxane (4 M, 8 ml, 32 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was triturated with DCM, filtered and dried under reduced pressure to give the title compound (6.7 g, 19 mmol, 99% yield). LCMS RT = 0.49 min, ES+ve m/z 318.3 [M + H]+.((S)-1-((2S,4R)-4-hydroxy-2-((4-(4) tert-butyl)-methylthiazol-5-yl)benzyl)-carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

[00206] A stirred mixture of (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (125mg, 0.35mmol ) and (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (commercially available e.g. from Aldrich) (77 mg, 0.35 mmol) in DMF (0.9 ml) was treated with DIPEA (0.22 ml, 1.3 mmol) and then with HATU (134 mg, 0.35 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (120 mg, 0.23 mmol, 72% yield). LCMS RT = 0.87 min, ES+ve m/z 517.3 [M + H]+ .(2S,4R)-1-((S)-2-Amino-3-methylbutanoyl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride

[00207] A solution of ((S)-1-((2 S ,4 R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl tert-Butyl)-3-methyl-1-oxobutan-2-yl)carbamate (287mg, 0.56mmol) in THF (5ml) was treated with HCl in 1,4-dioxan (4M, 10ml). , 40 mmol) and stirred at room temperature for 2 hours. The mixture was evaporated to dryness to give the title compound (224mg, 0.49mmol, quantitative). LCMS RT = 0.55 min, ES+ve m/z 417.3 [M+H]+. ((S)-1-cyclopentyl-2-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-2- tert-butyl oxoethyl) carbamate

[00208] HATU (260 mg, 0.68 mmol) was added to a solution of (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide , hydrochloride (200 mg, 0.57 mmol), (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetic acid (commercially available e.g. from Fluorochem) (180 mg, 0.74 mmol) and DIPEA (0.40 ml, 2.3 mmol) in DMF (2 ml). The reaction was stirred at room temperature for 30 min and directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (200 mg, 0.37 mmol, 65% yield). LCMS RT = 0.94 min, ES+ve m/z 543.4 [M + H]+ .(2S,4R)-1-((S)-2-Amino-2-cyclopentylacetyl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride OH

tert-Butyl [00209]((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate (200 mg, 0.37 mmol) was suspended in DCM (1 ml) and treated with HCl in dioxane (4M, 1 ml, 4.0 mmol), followed by MeOH (0.5 ml). The reaction mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness to give the title compound (160mg, 0.33mmol, 89% yield). LCMS RT = 0.61 min, ES+ve m/z 443.6 [M+H]+. (2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride

[00210] A stirred mixture of (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (70mg, 0.20mmol ) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (commercially available e.g. from Fluka) (50 mg, 0.22 mmol) in DMF (1 ml) was treated with DIPEA (0.14 ml, 0.79 mmol) and then with HATU (90 mg, 0.24 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was subjected directly to mass-directed automated preparative HPLC purification (formic acid modifier) to give the boc-protected intermediate product. The intermediate was then dissolved in a mixture of dichloromethane (0.5 ml) and methanol (0.1 ml) and treated with HCl in 1,4-dioxane (4M, 0.25 ml, 1.0 mmol). After stirring at room temperature for 1 hour, the reaction mixture was evaporated to dryness and the residue triturated to a solid with dichloromethane and dried under vacuum to give the title compound (76 mg, 0.16 mmol, 82% Yield). LCMS RT = 0.58 min, ES+ve m/z 431.2 [M + H]+.4-(Oxazol-5-yl)benzonitrile

[00211] A mixture of 4-formylbenzonitrile (commercially available e.g. from Aldrich) (5.32 g, 41 mmol), 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (commercially available e.g. from Aldrich) (8, 83 g, 45 mmol) and potassium carbonate (7.3 g, 53 mmol) in methanol (200 ml) was stirred at room temperature for 80 minutes. The mixture was then evaporated to dryness; the residue was treated with saturated aqueous sodium bicarbonate (100 ml) and extracted with dichloromethane (3 x 100 ml). The combined organics were washed with brine (75 ml), passed through a hydrophobic frit and then evaporated to dryness to yield the title compound (7.19 g, 42 mmol, quantitative). LCMS RT = 0.75 min, ES+ve m/z 171 [M + H]+.(4-(Oxazol-5-yl)phenyl)methanamine

[00212] Under an atmosphere of nitrogen, an ice-cold mixture of 4-(oxazol-5-yl)benzonitrile (900 mg, 5.29 mmol) and cobalt (II) chloride hexahydrate (commercially available e.g. from Aldrich) (1 .8 g, 7.9 mmol) in methanol (50 ml) was treated portionwise over 5 minutes with sodium borohydride (1 g, 26 mmol). The mixture was stirred for 30 minutes and then treated with water (50 ml) and concentrated aqueous ammonia (20 ml). The mixture was extracted with chloroform (3 x 150 ml), the combined organics were evaporated to dryness and the product was purified by chromatography on silica using a gradient elution of 0% to 30% methanol in dichloromethane (+0.1 % triethylamine) to give the title compound (580 mg, 3.3 mmol, 63% yield). LCMS RT = 0.35 min, ES+ve m/z 175 [M + H]+ α4-hydroxy-2-((4-(oxazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate ( 2S,4R)-tert-butyl

[00213] To a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (0.66g, 2.9mmol) in dry DMF (20ml) (4-(oxazol-5-yl)phenyl)methanamine (0.5g, 2.9mmol) and DIPEA (1ml, 5.7mmol) were added. This solution was ice-cooled and HATU (1.09 g, 2.9 mmol) was added. The reaction mixture was stirred with cooling for an additional hour then treated with water (30 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic phase was washed with saturated aqueous sodium bicarbonate (60 ml), brine (60 ml), dried over magnesium sulfate, filtered and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution of 0% to 25% methanol in dichloromethane to give the title compound (758 mg, 1.96 mmol, 68% yield). LCMS RT = 0.73 min, ES+ve m/z 388 [M + H]+ .(2S,4R)-4-Hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2- carboxamide, hydrochloride

[00214] A solution of (2S,4R)-tert-butyl 4-hydroxy-2-((4-(oxazol-5-yl)benzyl)carbamoyl)-pyrrolidine-1-carboxylate (2.74 g , 7.1 mmol) in methanol (10 ml) and dichloromethane (15 ml) was treated with hydrochloric acid (4 M in 1,4-dioxane) (8.8 ml, 35 mmol) and the mixture was stirred at room temperature. for 24 hours. The mixture was evaporated to dryness. The residue was suspended in methanol, filtered and dried under vacuum to give the title compound (2.24 g, 6.9 mmol, 98% yield). LCMS RT = 0.44 min, ES+ve m/z 288 [M + H]+ .(2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4-hydroxy- N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride

[00215] HATU (141 mg, 0.371 mmol) was added to a solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (86 mg, 0.37 mmol), (2S ,4R)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (100mg, 0.31mmol) and DIPEA (0.162ml, 0.93mmol) in DMF (4 ml). The reaction was stirred for 45 minutes at room temperature. The reaction mixture was partitioned between EtOAc (20 ml) and water (20 ml). The aqueous phase was back-extracted with EtOAc and the organic phase washed with brine (10 ml). The combined organic extracts were dried using a hydrophobic frit and concentrated under reduced pressure. The residue was purified by chromatography on silica using a gradient elution of 0% to 10% methanol in dichloromethane to give the required intermediate (132 mg). HCl in dioxane (4M, 0.386 ml, 1.54 mmol) was added to a solution of the intermediate (132 mg) dissolved in DCM (2 ml) and MeOH (2 ml). The mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure to give the title compound (95 mg, 0.22 mmol, 70% yield) as a beige solid. LCMS RT = 0.53 min, ES+ve m/z 401.4 [M + H]+.2-(2-(2-(2-(4-((6-methoxy-2-(4-methoxyphenyl) )benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy) tert-butyl acetate

[00216] A mixture of 4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenol (200 mg, 0.53 mmol), 2-(2-( tert-Butyl 2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (265mg, 0.63mmol), K 2 CO 3 (219mg, 1.59mmol) in DMF (3ml) was heated to 85°C. °C for 16 hours. Another aliquot of tert-butyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (265 mg, 0.63 mmol) was added and the reaction heated to 85°C for a further 24 hours. The reaction was cooled to room temperature and partitioned between EtOAc (25 ml) and water (25 ml). The organic extract was washed with brine (25 ml), dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0% to 50% EtOAc in cyclohexane to give the title compound (245 mg, 0.39 mmol, 74% yield). LCMS RT = 1.48 min, ES+ve m/z 625.4 [M+H]+. 2-(2-(2-(2-(4-((6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetic acid

[00217] Under a nitrogen atmosphere, an ice cold solution of 2-(2-(2-(2-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl) tert-butyl oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate (245 mg, 0.39 mmol) in dry dichloromethane (5 ml) was treated with propane-1-thiol (commercially available e.g. from Aldrich) (0.178 ml , 1.97 mmol) and then with aluminum chloride (commercially available e.g. from Aldrich) (418 mg, 3.1 mmol). The reaction mixture was stirred at room temperature for 16 hours. Another aliquot of propane-1-thiol (0.178 ml, 1.96 mmol) and aluminum chloride (418 mg, 3.1 mmol) were added and the reaction was stirred at room temperature for a further 24 hours. Aqueous HCl (2M, 20 ml) was added and the product was extracted with EtOAc (2 x 25 ml). The organic extracts were combined, dried using a hydrophobic frit and concentrated under reduced pressure. The residue was purified by SPE in aminopropyl (NH2): the column was first washed with MeOH (3 column volumes) and the product released by elution with ammonia in methanol (2M, 3 column volumes). The ammonia fraction was concentrated under reduced pressure. The product undergoes purification by automated bulk directed preparative HPLC (formic acid modifier) to yield the title compound (33 mg, 0.061 mmol, 16% yield) as a colorless glass. LCMS RT = 0.90 min, ES+ve m/z 541.2 [M + H]+.Example 1:(2S,4R)-1-((S)-2-(tert-butyl)-14- (4-((6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1 -oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00218] HATU (commercially available e.g. from Aldrich) (19 mg, 0.050 mmol) was added to a mixture of 2-(2-(2-(2-(4-((6-hydroxy-2-( 4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetic acid (22 mg, 0.041 mmol), (2S,4R)-1-((S)-2-amino- 3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (23 mg, 0.049 mmol) and DIPEA (commercially available e.g. from Aldrich ) (0.05 ml, 0.29 mmol) in DMF (0.8 ml). The reaction was allowed to stand at room temperature for 25 minutes. The reaction mixture was directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (8 mg, 0.008 mmol, 21% yield) as a colorless glass. LCMS RT = 1.02 min, ES+ve m/z 953.5 [M + H]+.Example 2;(2S,4R)-4-Hydroxy-1-((S)-14-(4-( (6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenoxy)-2-isopropyl-4-oxo-6,9,12-trioxa-3-aza-tetradecan- 1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00219] HATU (20 mg, 0.053 mmol) was added to a mixture of 2-(2-(2-(2-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]) thiophen-3-yl)oxy)-phenoxy)ethoxy)ethoxy)ethoxy)acetic acid (20 mg, 0.037 mmol) (2S,4R)-1-((S)-2-amino-3-methylbutanoyl)-4-hydroxy -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (20 mg, 0.044 mmol) and DIPEA (0.05 ml, 0.29 mmol) in DMF (0.8 ml). The reaction was allowed to stand at room temperature for 25 minutes. The reaction mixture was directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (9 mg, 0.0096 mmol, 26% yield) as a colorless glass. LCMS RT = 0.98 min, ES+ve m/z 939.5 [M + H]+.Example 3: (2S,4R)-1-((S)-2-(tert-Butyl)-14 Acid -(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-aza-tetradecan- 1-oyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00220] HATU (16 mg, 0.042 mmol) was added to a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(oxazol-5-yl)-benzyl)pyrrolidine-2-carboxamide, hydrochloride (18 mg, 0.041 mmol), 2-(2-(2-(2-(4-((6-hydroxy-2) -(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)-ethoxy)ethoxy)acetic acid (15 mg, 0.028 mmol) and DIPEA (0.024 ml, 0.14 mmol) in DMF (0 .8 ml). The reaction was stirred for 45 minutes at room temperature. The reaction mixture was directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (3 mg, 0.003 mmol, 12% yield) as a white solid. LCMS RT = 0.98 min, ES+ve m/z 923.2, 924.3 [M+H]+. Example 4:(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-((2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophen-3-yl )oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2 -carboxamide

[00221] Under an atmosphere of nitrogen, an ice cold solution of 2-(2-(2-(2-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl) tert-butyl oxy)phenoxy)ethoxy)-ethoxy)ethoxy)acetate (290mg, 0.46mmol) in dry dichloromethane (15ml) was treated with propane-1-thiol (0.210ml, 2.3mmol) and aluminum chloride (495 mg, 3.7 mmol). The reaction was stirred at room temperature for 6 hours. Aqueous HCl (1M, 10 ml) was added and the product was extracted with EtOAc (50 ml). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure. The residue was purified by SPE in aminopropyl (NH2): the column was first washed with MeOH (3 column volumes) and the product released by elution with ammonia in methanol (2M, 4 column volumes). The ammonia fraction was concentrated under reduced pressure and the residue was partitioned between EtOAc (25 ml) and aqueous HCl (1M, 25 ml). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure to give a yellow residue as (130 mg).
[00222] 70mg of the obtained residue was dissolved in DMF (0.8ml) and treated with (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (73mg, 0.16mmol) and DIPEA (0.15ml, 0.859mmol). HATU (60 mg, 0.16 mmol) was added to the stirred reaction mixture and the reaction was allowed to stand at room temperature for 25 minutes. The solution was directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (20 mg, 0.021 mmol, 5% yield) as a yellow solid. LCMS RT = 1.19 min, ES+ve m/z 967.4 [M + H]+.4-((6-Methoxy-2-phenylbenzo[b]thiophen-3-yl)oxy)phenol

[00223] Hydroquinone (commercially available e.g. from Aldrich) (133 mg, 1.207 mmol) was dissolved in DMF (2 ml). NaH (60% w/w in mineral oil) (20 mg, 0.5 mmol) was added slowly followed by 3-bromo-2-(4-bromophenyl)-6-methoxybenzo[b]thiophene-1-oxide (100 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water (10 ml) was added and the product was extracted with EtOAc (30 ml). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure. The residue was purified by chromatography on silica using a gradient elution of 0% to 100% ethyl acetate in cyclohexane followed by a 0% to 20% methanol in ethyl acetate gradient elution to yield a yellow solid (186 mg). This solid was dissolved in THF (5 ml) and treated with LiAlH4 in THF (1 M, 1.3 ml, 1.3 mmol). The reaction was stirred at room temperature for 1 hour. Aqueous NaOH (50%, 50 ml) was carefully added and the mixture was partitioned between EtOAc (50 ml) and water (50 ml). 2M HCl was added to reach pH 1 in the aqueous phase. The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0% to 100% ethyl acetate in cyclohexane to give the title compound (90 mg, 0.26 mmol, 80% pure, 86% yield) as a white solid. LCMS RT = 1.29 min, ES+ve m/z 349.3 [M + H]+.2-(2-(2-(2-(4-((6-methoxy-2-phenylbenzo[b]) thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy) tert-butyl acetate

[00224] A mixture of 4-((6-methoxy-2-phenylbenzo[b]thiophen-3-yl)oxy)-phenol (90 mg, 0.26 mmol), 2-(2-(2-(2) - tert-butyl (tosyloxy)ethoxy)ethoxy)ethoxy)acetate (216 mg, 0.517 mmol), K 2 CO 3 (107 mg, 0.78 mmol) in DMF (2 mL) was heated at 85°C for 16 hours. The reaction was cooled to room temperature and partitioned between EtOAc (30 ml) and water (30 ml). The organic layer was dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0% to 50% ethyl acetate in cyclohexane to give the title compound (104 mg, 0.18 mmol, 68% yield) as a yellow oil. LCMS RT = 1.50 min, ES+ve m/z 617.3 [M + Na]+.Example 5(2S,4R)-1-((S)-2-(tert-butyl)-14-( 4-((6-hydroxy-2-phenylbenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy- N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00225] Under an atmosphere of nitrogen, an ice cold solution of 2-(2-(2-(2-(4-((6-methoxy-2-phenylbenzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy tert-butyl)ethoxy)ethoxy)acetate (104mg, 0.175mmol) in dry dichloromethane (10ml) was treated with propane-1-thiol (0.048ml, 0.525mmol) followed by aluminum chloride (117mg, 0 .87 mmol). The reaction was stirred at room temperature for 3 hours. Another aliquot of propane-1-thiol (0.048 ml, 0.53 mmol) and aluminum chloride (117 mg, 0.874 mmol) was added and the suspension was sonicated for 10 minutes to help solubilize the reactions. The reaction was then stirred at room temperature for 3 hours. Aqueous HCl (1M, 10 ml) was added and the product was extracted with EtOAc (50 ml). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure. The residue was purified by SPE in aminopropyl (NH2): the column was first washed with MeOH (3 column volumes) and the product released by elution with ammonia in methanol (2M, 4 column volumes). The ammonia fraction was concentrated under reduced pressure and the residue was partitioned between EtOAc (25 ml) and aqueous HCl (1M, 25 ml). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure to give a yellow residue (44 mg). This residue was dissolved in DMF (0.8 ml) and treated with (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4) -methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (59mg, 0.13mmol) and DIPEA (0.1ml, 0.57mmol). HATU (47 mg, 0.12 mmol) was added to the solution which was stirred at room temperature for 10 min. The solution was then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier gradient) to yield the title compound (10 mg, 10.7 µmol, 6% yield) as a colorless glass. LCMS RT = 1.20 min, ES+ve m/z 937.6 [M + H]+.2-(4-Bromophenyl)-3-(4-(tert-butoxy)phenoxy)-6-methoxybenzo[b ] thiophene-1-oxide

[00226] 4-(tert-Butoxy)phenol (2.56 g, 15.41 mmol) was dissolved in DMF (70 ml). NaH, in mineral oil (60% w/w, 0.840 g, 21 mmol) was added slowly followed by 3-bromo-2-(4-bromophenyl)-6-methoxy-benzo[b]thiophene-1-oxide (commercially available e.g. from Aldrich) (5.8 g, 14 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water (100 ml) followed by aqueous HCl (2M, 20 ml) were added and the product was extracted with EtOAc (200 ml). The organic extract was dried using MgSO4 and concentrated under reduced pressure to give the title compound (5.8 g, 11.6 mmol, 83% yield). LCMS RT = 1.41 min, ES+ve m/z 499.1/501.1 [M + H]+.4-((2-(4-Bromophenyl)-6-methoxybenzo[b]thiophen-3- yl)oxy)phenol

[00227] TMSCl (commercially available e.g. from Aldrich) (3.84 ml, 30 mmol) was added to a solution of 2-(4-bromophenyl)-3-(4-(tert-butoxy)phenoxy)-6- methoxybenzo[b]thiophene-1-oxide (1.5 g, 3 mmol) and triphenylphosphine (2.75 g, 10.5 mmol) in THF (30 ml). The reaction mixture was stirred under reflux conditions for 3 hours. The reaction was cooled to room temperature and water (100 ml) was added. The intermediate was extracted with EtOAc (200 ml). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure. The intermediate was purified by chromatography on silica using a gradient elution of 0% to 50% ethyl acetate in cyclohexane to yield a yellow oil. The oil was dissolved in DCM (15 ml) and treated with HCl in dioxane (4 M, 7.5 ml, 30 mmol). The reaction was heated for 3 hours at 40°C. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (150 ml) and brine (150 ml). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0% to 35% ethyl acetate in cyclohexane to give the title compound (1 g, 2.3 mmol, 78% yield) as a white solid. LCMS RT = 1.41 min, ES+ve m/z 427.1/429.1 [M + H]+α2-(2-(2-(2-(4-((2-(4-bromophenyl) tert-butyl)-6-methoxybenzo[b]thiophen-3-yl)-oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate

[00228] A mixture of 4-((2-(4-bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenol (1 g, 2.340 mmol), 2-(2-(2-( tert-Butyl 2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (2g, 4.8mmol), K2CO3 (1g, 7.2mmol) in DMF (2ml) was heated at 85°C for 48 hours. The reaction was cooled to room temperature and partitioned between EtOAc (100 ml) and water (100 ml). The organic layer was dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0% to 50% ethyl acetate in cyclohexane to give the title compound (1.41 g, 2.1 mmol, 89% yield) as an oil. yellow. LCMS RT = 1.61 min, ES+ve m/z 690.4/692.4 [M + NH4]+.Example 6(2S,4R)-1-((S)-14-(4-(( 2-(4-bromophenyl)-6-hydroxybenzo[b]-thiophen-3-yl)oxy)phenoxy)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecan- 1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00229] Under an atmosphere of nitrogen, an ice cold solution of 2-(2-(2-(2-(4-((2-(4-bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy tert-butyl)phenoxy)ethoxy)ethoxy)ethoxy)acetate (225mg, 0.33mmol) in dry DCM (10ml) was treated with propane-1-thiol (0.091ml, 1.0mmol) followed by aluminum chloride (223 mg, 1.7 mmol). The reaction was then stirred at room temperature for 5 hours. Aqueous HCl (1M, 10 ml) was added and the product was extracted with EtOAc (50 ml). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure. The residue was dissolved in DMF (3 ml) and treated with DIPEA (0.3 ml, 1.718 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamide, hydrochloride (234 mg, 0.5 mmol). HATU (191 mg, 0.5 mmol) was added and the reaction was stirred at room temperature for 10 min. The solution was then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (72 mg, 0.071 mmol, 21% yield) as a white solid. LCMS RT = 1.30 min, ES+ve m/z 1015.3/1017.3 [M + H]+.3-(4-(tert-Butoxy)phenoxy)-2-(4-fluorophenyl)-6 -methoxybenzo[b]-thiophene-1-oxide

[00230] 4-(tert-Butoxy)phenol (393 mg, 2.37 mmol) was dissolved in DMF (15 ml). NaH in mineral oil (60% w/w, 172 mg, 4.3 mmol) was added slowly followed by 3-bromo-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene-1-oxide (760 mg , 2.2 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. Water (200 ml) was added and the product was extracted with EtOAc (200 ml). Aqueous HCl (2M) was added until the pH of the aqueous phase was 1 and the aqueous phase was extracted with EtOAc (200 ml). The combined organic extracts were washed with brine (300 ml), dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0% to 50% ethyl acetate in dichloromethane to give the title compound (815 mg, 1.86 mmol, 86% yield) as a yellow solid. LCMS RT = 1.32 min, ES+ve m/z 439.3 [M + H]+.3-(4-(tert-Butoxy)phenoxy)-2-(4-fluorophenyl)-6-methoxybenzo[b ] thiophene

[00231] LiAlH4 in THF (1M, 3.72 ml, 3.7 mmol) was added to a mixture of 3-(4-(tert-butoxy)phenoxy)-2-(4-fluorophenyl)-6-methoxybenzo[ b] thiophene-1-oxide (815 mg, 1.86 mmol) in THF (15 ml). The reaction was stirred at room temperature for 1.5 hours. Aqueous NaOH (50%, 10 ml) was carefully added and the mixture was partitioned between EtOAc (100 ml) and water (100 ml). The aqueous phase was further extracted with EtOAc (3 x 100 ml). The organic extracts were combined, dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0% to 50% dichloromethane in cyclohexane to give the title compound (560 mg, 1.33 mmol, 71% yield) as a colorless gum. LCMS RT = 1.61 min, ES+ve m/z 423.0 [M + H]+.4-((2-(4-Fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy) phenol

[00232] 3-(4-(tert-Butoxy)phenoxy)-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene (560 mg, 1.33 mmol) was dissolved in 1,4-dioxane (5 ml). HCl in dioxane (4M, 5 ml, 20 mmol) was added and the reaction mixture was stirred overnight at 60°C. The mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile and concentrated under reduced pressure to give the title compound (450 mg, 1.2 mmol, 93% yield). LCMS RT = 1.30 min, ES+ve m/z 367.2 [M + H]+.2-(2-(2-(2-(4-((2-(4-fluorophenyl)-6- methoxybenzo[b]thiophen-3-yl)-oxy)phenoxy)ethoxy)ethoxy)ethoxy) tert-butyl acetate

[00233] A mixture of 4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenol (450 mg, 1.228 mmol), 2-(2-(2-( tert-Butyl 2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (1.028 g, 2.46 mmol), K 2 CO 3 (509 mg, 3.68 mmol) in DMF (6 ml) was heated to 80°C for 72 hours. The reaction was cooled to room temperature and partitioned between EtOAc (50 ml) and water (50 ml). The organic extract was washed with brine (50 ml), dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0% to 50% ethyl acetate in cyclohexane to give the title compound (600 mg, 0.98 mmol, 80% yield) as a colorless gum. LCMS RT = 1.51 min, ES+ve m/z 635 [M + Na]+Example 7(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-( (2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00234] Under a nitrogen atmosphere, an ice cold solution of 2-(2-(2-(2-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy tert-Butyl )phenoxy)ethoxy)-ethoxy)ethoxy)acetate (240mg, 0.39mmol) in dry DCM (10ml) was treated with propane-1-thiol (0.107ml, 1.18mmol) followed by aluminum chloride (261 mg, 1.96 mmol). The reaction was then stirred at room temperature for 4 hours. Another aliquot of aluminum chloride (130 mg, 0.98 mmol) was added and the reaction was stirred at room temperature for an additional hour. Aqueous HCl (1M, 10 ml) was added and the product was extracted with EtOAc (50 ml). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure. The residue was purified by SPE in aminopropyl (NH2): the column was first washed with MeOH (3 column volumes) and the product released by elution with ammonia in methanol (2M, 4 column volumes). The ammonia fraction was concentrated under reduced pressure and the residue was partitioned between EtOAc (25 ml) and aqueous HCl (1M, 25 ml). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure to give a yellow residue (126 mg). This residue was dissolved in DMF (1.6 ml) and treated with DIPEA (0.342 ml, 1.96 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)- 4-hydroxy-N-(4-(4-methyl-thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (163 mg, 0.35 mmol). HATU (132 mg, 0.347 mmol) was added and the reaction was stirred at room temperature for 10 min. The solution was then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (47 mg, 0.049 mmol, 13% yield) as a white-yellow solid. LCMS RT = 1.21 min, ES+ve m/z 955.6 [M + H]+ .(4-Fluorophenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl ) - methanone

[00235] Under an atmosphere of nitrogen, an ice-cooled suspension of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (commercially available e.g. from Aldrich) (10 g, 37 mmol) in anhydrous dichloromethane ( 250 ml) was treated with aluminum chloride (5.9 g, 44 mmol) and then with 4-fluorobenzoyl chloride (commercially available e.g. from Aldrich) (5.2 ml, 44 mmol). The mixture was stirred at 0°C for 3 days and then treated with 1M aqueous hydrochloric acid (200 ml) and stirred for 20 minutes. The mixture was subsequently treated with dichloromethane (200 ml) and 1M aqueous hydrochloric acid (200 ml) and separated. The aqueous phase was extracted with additional dichloromethane (2 x 150 ml) and the organics were combined and evaporated to dryness. The product was purified by chromatography on silica using a gradient elution of 0% to 25% ethyl acetate in cyclohexane to give the title compound (12.7 g, 32 mmol, 87% yield). LCMS RT = 1.40 min, ES+ve m/z 393.3 [M + H]+.(4-(2-(2-(2-Hydroxyethoxy)ethoxy)ethoxy)phenyl)(6-methoxy-2 -(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone

[00236] Sodium hydride (60% w/w in mineral oil) (64 mg, 1.6mmol) was added to an ice-cold solution of 2,2'-(ethane-1,2-diylbis(oxy) )-diethanol (commercially available eg from Aldrich) (670 mg, 4.5 mmol) in DMF (3.5 ml). The reaction was stirred at 0°C for 15 min and (4-fluorophenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone (350 mg, 0.89 mmol) was then added. The reaction mixture was warmed to room temperature and stirred for a further 3 hours. The reaction mixture was partitioned between DCM (40 ml) and water (40 ml). The mixture was separated and the aqueous phase was extracted with additional DCM (40 ml). The combined organic extracts were evaporated to dryness and the product was purified by chromatography on silica (50 g cartridge) using a gradient elution of 0% to 25% MeOH in DCM to yield the title compound (453 mg, 0 .87 mmol, 93% yield). LCMS RT = 1.17 min, ES+ve m/z 523.3 [M + H]+.(4-(2-(2-(2-(2-Hydroxyethoxy)ethoxy)ethoxy)ethoxy)phenyl)( 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone

[00237] Under an atmosphere of nitrogen, an ice-cold solution of (4-fluorophenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone (1.72 g, 4.4 mmol) and 2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))diethanol (commercially available e.g. from Aldrich) (4.26 g, 22 mmol) in dry DMF (20 ml ) was treated with sodium hydride (60% w/w in mineral oil) (316 mg, 7.9 mmol) and the mixture was stirred with ice-cooling for 15 minutes then allowed to warm to room temperature. After 2 hours the mixture was treated with water (50 ml) and dichloromethane (70 ml). The mixture was separated and the aqueous phase was extracted with dichloromethane (20 ml). The combined organics were evaporated to dryness and the product was purified by chromatography on silica using a gradient elution of 0% to 25% methanol in dichloromethane to give the title compound (2.34 g, 4.1 mmol, 94 % yield). LCMS RT = 1.18 min, ES+ve m/z 567 [M + H]+.2-(2-(2-(2-(4-(6-methoxy-2-(4-methoxyphenyl)benzo[ b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy) tert-butyl acetate

[00238] Sodium hydride, 60% w/w in mineral oil (69 mg, 1.7 mmol) was added to an ice-cold solution of (4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy) phenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone (450 mg, 0.86 mmol) in DMF (3.3 ml). The reaction was stirred at 0°C for 1 hour and tert-butyl bromoacetate (commercially available eg from Aldrich) (0.25 ml, 1.7 mmol) was added. The reaction was warmed to room temperature and stirred for an additional 3 hours. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was separated, washed with brine (30 ml), passed through a hydrophobic frit and evaporated to dryness. The product was purified by chromatography on silica (50 g cartridge) using a gradient elution of 0% to 100% ethyl acetate in cyclohexane to give the title compound (330 mg, 0.52 mmol, 60% yield ). LCMS RT = 1.40 min, ES+ve m/z 637.3 [M + H]+, 659.3 [M + Na]+. 2-(2-(2-(2-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thio-phene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)acetic acid, 2 -(2-(2-(2-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thio-phene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)acetic acid, 2- (2 -(2-(2-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thio-phen-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)acetic

[00239] A cooled (0°C) solution of 2-(2-(2-(2-(4-(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy) tert-butyl ethoxy)ethoxy)acetate (330 mg, 0.518 mmol) in dry DCM (7 ml) was treated with propane-1-thiol (commercially available e.g. from Aldrich) (0.188 ml, 2.1 mmol) and then with aluminum chloride (commercially available eg from Aldrich) (290 mg, 2.2 mmol). The reaction was warmed to room temperature and stirred for 3 hours. Another aliquot of aluminum chloride (290 mg, 2.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was cautiously treated with 2M aqueous HCl (10 ml) and THF (20 ml). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 20 ml). The combined organic layers were dried using a hydrophobic frit and concentrated under reduced pressure. The crude product was dissolved in DMSO (4 ml) and subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the three products:
[00240] 2-(2-(2-(2-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thio-phene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy) acid acetic acid (140 mg, 0.25 mmol, 49% yield). LCMS RT = 0.84 min, ES+ve m/z 553.3 [M+H]+.
[00241] 2-(2-(2-(2-(4-(6-Hydroxy-2-(4-methoxyphenyl)benzo[b]thio-phene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy) acid acetic acid (16 mg, 0.028 mmol, 5% yield). LCMS RT = 0.99 min, ES+ve m/z 567.3 [M+H]+.
[00242] 2-(2-(2-(2-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thio-phen-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)acetic acid (58 mg, 0.10 mmol, 20% yield). LCMS RT = 1.04 min, ES+ve m/z 567.3 [M + H]+.14-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3- acid carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oic acid, 14-(4-(6-Hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)- 3,6,9,12-tetraoxatetradecan-1-oic acid, 14-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9, 12-tetraoxatetradecan-1-oic

[00243] Under an atmosphere of nitrogen, an ice cold solution of tert-butyl 14-(4-(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-3,6, 9,12-tetraoxatetradecan-1-oate (480 mg, 0.71 mmol) in dry dichloromethane (10 ml) was treated with propane-1-thiol (commercially available e.g. from Aldrich) (0.319 ml, 3.5 mmol) and then with aluminum chloride (564 mg, 4.2 mmol). After 3 hours the mixture was cautiously treated with 2M aqueous hydrochloric acid (10 ml) and then evaporated to dryness. The product was subjected directly to mass-directed automated preparative HPLC purification (formic acid modifier) to yield the three title compounds:
[00244] 14-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oic acid (220 mg , 0.37 mmol, 52% yield). LCMS RT = 0.87 min, ES+ve m/z 597 [M+H]+.
[00245] 14-(4-(6-Hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oic acid (24 mg , 0.039 mmol, 5.6% yield). LCMS RT = 0.99 min, ES+ve m/z 610 [M+H]+.
[00246] 14-(4-(2-(4-Hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oic acid (53 mg, 0.087 mmol, 12% yield). LCMS RT = 1.05 min, ES+ve m/z 610 [M + H]+.Example 8(2S,4R)-1-((S)-2-(tert-butyl)-14-(4- (6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00247] HATU (27 mg, 0.071 mmol) was added to a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (38 mg, 0.081 mmol), 2-(2-(2-(2-(4-(6-hydroxy-2-(4)) -hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-ethoxy)ethoxy)ethoxy)acetic acid (30 mg, 0.054 mmol) and DIPEA (0.095 ml, 0.54 mmol) in DMF (0.8 ml). The reaction was stirred at room temperature for 30 min and then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (16 mg, 0.017 mmol, 31% yield). LCMS RT = 0.97 min, ES+ve m/z 966.4 [M+H]+.
[00248] Using a method analogous to that for (2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[ b]thiophene-3-carbonyl)-phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methyl-thiazol-5) -yl)benzyl)pyrrolidine-2-carboxamide the following compounds were prepared:

Example 15(2S,4R)-4-Hydroxy-1-((S)-17-(4-(6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophene-3-carbonyl)phenoxy)- 2-isopropyl-4-oxo-6,9,12,15-tetraoxa-3-azaeptadecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00249] A solution of 14-(4-(6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1- acid Olic acid (18mg, 0.030mmol) in DMF (0.7ml) was treated with DIPEA (0.021ml, 0.12mmol) and (2S,4R)-1-((S)-2-amino-3-methylbutanoyl )-4-hydroxy-N-(4-(4-methyl-thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (22 mg, 0.048 mmol) and then with HATU (14 mg, 0.036 mmol) and the mixture was stirred for 30 minutes. The product was subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (25 mg, 0.025 mmol, 83% yield). LCMS RT = 0.94 min, ES+ve m/z 995.5 [M + H]+.Example 16(2S,4R)-1-((S)-2-(tert-butyl)-17-( 4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-aza-eptadecan-1 -oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00250] A solution of 14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oic acid (18mg, 0.030mmol) in DMF (0.7ml) was treated with DIPEA (0.021ml, 0.12mmol) and (2S,4R)-1-((S)-2-amino-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (23 mg, 0.048 mmol) and then with HATU (14 mg, 0.036 mmol) and the mixture was stirred for 30 minutes. The product was subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (22 mg, 0.022 mmol, 72% yield). LCMS RT = 0.98 min, ES+ve m/z 1009.5 [M + H]+.Example 17(2S,4R)-1-((S)-2-(tert-butyl)-14-( 4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-aza-tetradecan-1-oyl)-4 -hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00251] HATU (27 mg, 0.071 mmol) was added to a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride) (38 mg, 0.081 mmol), 2-(2-(2-(2-(4-(2-(4-hydroxyphenyl)) acid -6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-ethoxy)ethoxy)ethoxy)acetic acid (31 mg, 0.054 mmol) and DIPEA (0.095 ml, 0.54 mmol) in DMF (0.8 ml). The reaction was stirred at room temperature for 30 min and then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (15 mg, 0.015 mmol, 28% yield). LCMS RT = 1.14 min, ES+ve m/z 979.5 [M + H]+.Example 18(2S,4R)-1-((S)-2-(Tert-butyl)-14-( 4-(6-hydroxy-2-(4-methoxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)- 4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00252] HATU (11 mg, 0.028 mmol) was added to a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (15 mg, 0.032 mmol), 2-(2-(2-(2-(4-(6-hydroxy-2-(4)) -methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-ethoxy)ethoxy)ethoxy)acetic acid (13 mg, 0.022 mmol) and DIPEA (0.038 ml, 0.22 mmol) in DMF (0.6 ml). The reaction was stirred at room temperature for 30 min and then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (9 mg, 0.009 mmol, 43% yield). LCMS RT = 1.09 min, ES+ve m/z 979.5 [M + H]+.Example 19 (2S,4R)-1-((S)-2-(tert-butyl)-17-( 4-(6-hydroxy-2-(4-methoxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-aza-eptadecan-1 -oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00253] A mixture of 14-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oic acid ( 20 mg, 0.033 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl )pyrrolidine-2-carboxamide, hydrochloride (23 mg, 0.049 mmol) in DMF (0.7 mL) was treated with DIPEA (0.023 mL, 0.13 mmol) and then with HATU (15 mg, 0.039 mmol) and stirred in room temperature for 15 minutes. The product was directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (14 mg, 0.014 mmol, 42% yield). LCMS RT = 1.09 min, ES+ve m/z 1023.5 [M + H]+.Example 20(2S,4R)-1-((S)-2-(tert-butyl)-14-( 4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)- 4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00254] HATU (21 mg, 0.056 mmol) was added to a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (oxazol-5-yl)-benzyl)pyrrolidine-2-carboxamide, hydrochloride (29 mg, 0.065 mmol), 2-(2-(2-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl) )benzo[b]thiophene-3-carbonyl)phenoxy)-ethoxy)ethoxy)ethoxy)acetic acid (24 mg, 0.043 mmol) and DIPEA (0.076 ml, 0.43 mmol) in DMF (0.8 ml). The reaction was stirred at room temperature for 30 min and then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (26 mg, 0.028 mmol, 64% yield). LCMS RT = 0.94 min, ES+ve m/z 935.6 [M + H]+ .(4-Fluorophenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl )methanone

[00255] Under a nitrogen atmosphere, an ice-cold solution of (4-fluorophenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone (5 g, 13 mmol) in DCM Dry (50 ml) was treated cautiously with boron tribromide in DCM (1 M, 38 ml, 38 mmol) and the mixture was stirred with cooling for 2 hours. The mixture was cautiously treated with water (100 ml) and then with DCM (50 ml) and MeOH (15 ml). The mixture was partitioned and the aqueous phase was extracted with 10% MeOH in DCM (100 ml). The combined organic extracts were evaporated to dryness and the product was purified by chromatography on silica using a gradient elution of 0% to 100% ethyl acetate in DCM to yield the title compound (3.95 g, 11 mmol, 85% yield). LCMS RT = 0.98 min, ES+ve m/z 365.2 [M+H]+. (6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-fluorophenyl)methanone

[00256] A solution of (4-fluorophenyl)(6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophen-3-yl)methanone (2.58 g, 7.1 mmol) in DMF (25 ml) was treated with sodium carbonate (3.00 g, 28.3 mmol) and then with benzyl bromide (2.53 ml, 21 mmol). The mixture was gradually heated to 75°C and heated at this temperature for 6 hours, then at 60°C overnight. The cooled mixture was treated with DCM (150 ml) and water (100 ml) and the organic phase was separated. The aqueous phase was extracted with additional DCM (50 ml) and the combined organic layers were evaporated to dryness. The product was purified by chromatography on silica using a gradient elution of 0% to 20% ethyl acetate in cyclohexane to give the title compound (2.97 g, 5.5 mmol, 77% yield). LCMS RT = 1.59 min, ES+ve m/z 545.2 [M + H]+ .(6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl )(4-(2-(2-hydroxyethoxy)ethoxy)phenyl)methanone

[00257] Sodium hydride, 60% w/w in mineral oil (40mg, 0.99mmol) (commercially available e.g. from Aldrich) (292mg, 2.8mmol) in dry DMF (3ml) and the mixture was stirred for 30 minutes. (6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-fluorophenyl)methanone (300 mg, 0.55 mmol) was added and the reaction mixture was warmed to room temperature and stirred for a further 18 hours. The mixture was treated with water (50 ml) and DCM (50 ml) and the organic phase was separated. The aqueous phase was extracted with additional DCM (50 ml). The combined organic extracts were evaporated to dryness and the product was purified by chromatography on silica (50 g cartridge) using a gradient elution of 0% to 25% MeOH in DCM to yield the title compound (260 mg, 0 .41 mmol, 75% yield). LCMS RT = 1.45 min, ES+ve m/z 631.4 [M + H]+.2-(2-(2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)) phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy) tert-butyl acetate

[00258] Sodium hydride, 60% w/w in mineral oil (25mg, 0.634mmol) was added to a cold (0°C) solution of (6-(benzyloxy)-2-(4-(benzyloxy) phenyl)benzo[b]thiophen-3-yl)(4-(2-(2-hydroxyethoxy)ethoxy)phenyl)-methanone (200 mg, 0.32 mmol) in DMF (1.2 ml). The reaction was stirred at 0°C for 1 hour and tert-butyl bromoacetate (commercially available eg from Aldrich) (0.094 ml, 0.63 mmol) was added. The reaction was warmed to room temperature and stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was separated, washed with brine (30 ml), dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica (50 g cartridge) using a gradient elution of 0% to 100% ethyl acetate in cyclohexane to give the title compound (200 mg, 0.23 mmol, 74% yield ). LCMS RT = 1.59 min, ES+ve m/z 745.5 [M + H]+.2-(2-(2-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[ b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)acetic

[00259] A mixture of 2-(2-(2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy) tert-butyl acetate (200 mg, 0.27 mmol), 10% w/w palladium on carbon (29 mg, 0.027 mmol), ammonium formate (339 mg, 5.4 mmol) and water (0.19 ml , 11 mmol) in DMF (2.6 ml) was heated at 50°C for 2 hours. The reaction mixture was filtered through celite, washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude material was dissolved in TFA (1.5 ml) and stirred at room temperature for 10 min. The reaction mixture was concentrated and a 1:1 mixture of 25% aqueous HCl/THF (3 ml) was added. The crude mixture was then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (51 mg, 0.10 mmol, 37% yield). LCMS RT = 0.84 min, ES+ve m/z 509.3 [M + H]+.Example 21 (2S,4R)-4-hydroxy-1-((S)-2-(2-(2) -(2-(4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)acetamido)-3,3-dimethyl-butanoyl)-N -(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00260] HATU (25 mg, 0.066 mmol) was added to a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-( 4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (31 mg, 0.066 mmol), 2-(2-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzoic acid) [b]thiophene-3-carbonyl)phenoxy)ethoxy)-ethoxy)acetic acid (26 mg, 0.051 mmol) and DIPEA (0.089 ml, 0.51 mmol) in DMF (0.6 ml). The reaction was stirred at room temperature for 30 min and then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (33 mg, 0.035 mmol, 69% yield) LCMS RT = 0.96 min, ES+v and m/z 921.4 [M + H]+.(2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene- tert-butyl 3-carbonyl)phenoxy)ethyl)(methyl)carbamate

[00261] Sodium hydride, 60% w/w in mineral oil (54 mg, 1.35 mmol) was added to a cold (0°C) solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate (commercially available e.g. from Chem-impex) (225 mg, 1.29 mmol) in DMF (3 ml) and the mixture was stirred at 0°C for 15 min. (6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-fluorophenyl)methanone (350 mg, 0.64 mmol) was added and the reaction was slowly heated to room temperature and stirred for 18 hours. The mixture was cautiously treated with water (40 ml) and ethyl acetate (40 ml). The organic phase was separated and the aqueous phase was extracted with additional ethyl acetate (40 ml). The combined organic extracts were washed with water (40 ml), brine (40 ml) and evaporated under reduced pressure to give the title compound (445 mg, 0.64 mmol, 99% yield). LCMS RT = 1.63 min, ES+ve m/z 700.5 [M + H]+, 722.3 [M + Na]+.(6-(Benzyloxy)-2-(4-(benzyloxy)phenyl )benzo[b]thiophen-3-yl)(4-(2-(methylamino)ethoxy)phenyl)methanone, hydrochloride

[00262] HCl in dioxane (4M, 1.6 ml, 6.4 mmol) was added to a solution of (2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo tert-butyl [b]thiophene-3-carbonyl)phenoxy)ethyl)(methyl)carbamate (445 mg, 0.64 mmol) in DCM (2 ml) and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced to give the title compound (400mg, 0.63mmol, 98% yield). LCMS RT = 1.16 min, ES+ve m/z 600.3 [M + H]+.2-(2-(2-((2-(4-(6-(benzyloxy)-2-(4) -(benzyloxy)phenyl)benzo[b]-thiophene-3-carbonyl)phenoxy)ethyl)(methyl)amino)ethoxy)ethoxy) tert-butyl acetate

[00263] A vial was charged with (6-(benzyloxy)-2-(4-(benzyloxy)-phenyl)benzo[b]thiophen-3-yl)(4-(2-(methylamino)ethoxy)phenyl)methanone , tert-butyl hydrochloride (140 mg, 0.22 mmol), 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate (99 mg, 0.26 mmol), DIPEA (0.15 ml, 0 .88 mmol) and DMF (1.5 ml). The vial was sealed and the reaction was heated at 80°C for 18 hours. Additional tert-butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate (99 mg, 0.26 mmol) was added and the reaction was stirred at 80°C for a further 24 hours. The reaction was cooled to room temperature and the mixture was then subjected directly to mass-directed automated preparative HPLC purification (Ammonium Bicarbonate Modifier) to yield the title compound (85 mg, 0.11 mmol, 48% yield ). LCMS RT = 1.31 min, ES+v and m/z 802.4 [M + H]+ 2-(2-(2-((2-(4-(6-hydroxy-2-(4-)) hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)(methyl)amino)ethoxy)ethoxy)acetic, hydrochloride

[00264] A mixture of 2-(2-(2-((2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy tert-Butyl)ethyl)(methyl)amino)ethoxy)ethoxy)acetate (80 mg, 0.1 mmol), 10% w/w palladium on carbon (11 mg, 0.01 mmol), ammonium formate (126 mg, 2 mmol) and water (0.072 ml, 4 mmol) in DMF (1 ml) was heated at 50°C for 1 hour. The reaction mixture was filtered through celite, washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude material was then dissolved in TFA (1 ml) and stirred at room temperature for 10 min. The reaction mixture was concentrated and a 1:1 mixture of 25% aqueous HCl/THF (3 ml) was added. The crude mixture was then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (37 mg, 0.061 mmol, 62% yield). LCMS RT = 0.68 min, ES+ve m/z 566.3 [M + H]+.Example 22(2S,4R)-1-((S)-2-(tert-butyl)-14-( 4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-12-methyl-4-oxo-6,9-dioxa-3,12-diaza-tetradecan -1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00265] HATU (25 mg, 0.066 mmol) was added to a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (35 mg, 0.075 mmol), 2-(2-(2-((2-(4-(6-hydroxy-2-() 4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-ethyl)(methyl)amino)ethoxy)ethoxy)acetic acid, hydrochloride (30 mg, 0.050 mmol) and DIPEA (0.087 ml, 0.5 mmol) in DMF (0.8 ml). The reaction was stirred at room temperature for 30 min and was then subjected directly to mass directed automated preparative HPLC purification (formic acid modifier). The product containing a small amount of impurity was consequently dissolved in a 1:1 mixture of MeOH and DMSO (1 ml) and subjected to mass directed automated preparative HPLC purification using an ammonium bicarbonate modifier to yield the title compound (24 mg, 0.025 mmol, 49% yield). LCMS RT = 0.80 min, ES+ve m/z 978.5 [M + H]+.15-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b] tert-butyl thiophene-3-carbonyl)phenoxy)-13-methyl-3,6,9-trioxa-13-azapentadecan-1-oate

[00266] A vial was charged with (6-(benzyloxy)-2-(4-(benzyloxy)-phenyl)benzo[b]thiophen-3-yl)(4-(2-(methylamino)ethoxy)phenyl)methanone , tert-butyl hydrochloride (150 mg, 0.24 mmol), 2-(2-(2-(3-(tosyloxy)propoxy)ethoxy)ethoxy)acetate (143 mg, 0.33 mmol), DIPEA (0.165 ml, 0.94 mmol) and DMF (1.4 ml). The vial was sealed and the reaction was heated at 80°C for 18 hours. The reaction was cooled to room temperature and the mixture was then subjected directly to mass-directed automated preparative HPLC purification (ammonium bicarbonate modifier) to yield the title compound (90 mg, 0.11 mmol, 44% yield ). LCMS RT = 1.32 min, ES+ve m/z 860.5 [M + H]+.15-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3- acid carbonyl)phenoxy)-13-methyl-3,6,9-trioxa-13-azapentadecan-1-oic, hydrochloride

[00267] A mixture of 15-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-13-methyl-3,6,9 tert-butyl-trioxa-13-azapentadecan-1-oate (90 mg, 0.11 mmol), 10% w/w palladium on carbon (11 mg, 0.01 mmol), ammonium formate (132 mg, 2 .1 mmol) and water (0.075 ml, 4.2 mmol) in DMF (1 ml) was heated at 50°C for 1 hour. The reaction mixture was filtered through celite, washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude material was dissolved in TFA (1 ml) and stirred at room temperature for 10 min. The reaction mixture was concentrated and a 1:1 mixture of 25% aqueous HCl/THF (2 ml) was added. The crude mixture was then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (60 mg, 0.091 mmol, 87% yield). LCMS RT = 0.69 min, ES+ve m/z 624.4 [M + H]+.Example 23(2S,4R)-1-((S)-2-(tert-butyl)-18-( 4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-16-methyl-4-oxo-6,9,12-trioxa-3,16-diazaoctadecan -1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00268] HATU (37 mg, 0.098 mmol) was added to a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-( 4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (53 mg, 0.11 mmol), 15-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene acid -3-carbonyl)phenoxy)-13-methyl-3,6,9-trioxa-13-azapentadecan-1-oic acid, hydrochloride (50 mg, 0.076 mmol) and DIPEA (0.132 ml, 0.76 mmol) in DMF ( 0.8 ml). The reaction was stirred at room temperature for 30 min and was then subjected directly to mass directed automated preparative HPLC purification (formic acid modifier). The product containing a small amount of impurity was consequently dissolved in a 1:1 mixture of MeOH and DMSO (1 ml) and subjected to mass directed automated preparative HPLC purification using an ammonium bicarbonate modifier to yield the title compound (38 mg, 0.037 mmol, 48% yield). LCMS RT = 0.82 min, ES+ve m/z 1036.5 [M + H]+.(6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl )(4-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)phenyl)methanone

[00269] A solution of (6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-fluorophenyl)methanone (320 mg, 0.59 mmol) in NMP (3 ml) was sealed and heated in a Biotage “Initiator” microwave at 160°C for 1 hour. The cooled product was subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (181 mg, 0.26 mmol, 44% yield). LCMS RT = 1.19 min, ES+ve m/z 699 [M+H]+. 2-(2-(2-(4-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy )ethoxy) tert-butyl acetate

[00270] Under a nitrogen atmosphere, a solution of (6-(benzyl-oxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-(4-(2-) (2-hydroxyethoxy)ethyl)piperazin-1-yl)phenyl)methanone (120mg, 0.17mmol) in DMF (5ml) was treated with tert-butyl bromoacetate (0.1ml, 0.69mmol) ) and then with sodium hydride (60% in mineral oil) (41 mg, 1.03 mmol) and stirred at room temperature overnight. The mixture was treated with 5% aqueous ammonium chloride (30 ml) and extracted with dichloromethane (30 ml). The organic fraction was evaporated to dryness and the product was subjected to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (80 mg, 0.098 mmol, 57% yield). LCMS RT = 1.28 min, ES+v and m/z 813 [M + H]+.2-(2-(2-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl))benzoic acid [b] thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy)ethoxy)acetic

[00271] A solution of 2-(2-(2-(4-(4-(6-(benzyloxy)-2-(4-(benzyloxy)-phenyl)benzo[b]thiophene-3-carbonyl)phenyl) tert-butyl piperazin-1-yl)ethoxy)ethoxy)acetate (80 mg, 0.098 mmol) in a mixture of DMF (2 ml) and water (0.2 ml) was treated with ammonium formate (62 mg, 0 .98 mmol) and palladium on carbon (10% degussa type) (18 mg, 0.017 mmol) and stirred at 50°C for 1 hour. The cooled mixture was filtered and evaporated to dryness. The residue was treated with TFA (5 ml), stirred for 1 hour and then evaporated to dryness. The product was subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (34 mg, 0.059 mmol, 60% yield). LCMS RT = 0.67 min, ES+ve m/z 577 [M + H]+.Example 24(2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-( 2-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy)ethoxy)-acetamido)-3,3- dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00272] A mixture of 2-(2-(2-(4-(4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1 acid -yl)ethoxy)ethoxy)acetic acid (25 mg, 0.036 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-( 4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (26mg, 0.055mmol) in DMF (0.7ml) was treated with DIPEA (0.045ml, 0.26mmol) and then with HATU ( 17 mg, 0.044 mmol) and stirred at room temperature for 15 minutes. The product was subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (12 mg, 0.012 mmol, 33% yield). LCMS RT = 0.84 min, ES+ve m/z 989 [M + H]+.(6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)( 4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)phenyl)methanone

[00273] Under a nitrogen atmosphere, a solution of (6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-fluorophenyl)methanone (300 mg, 0 .55 mmol) in DMF (1 ml) was treated with 2,2'-(piperazine-1,4-diyl)diethanol (384 mg, 2.2 mmol) and then with sodium hydride (60% in mineral oil ) (44 mg, 1.1 mmol) and the mixture was heated at 50°C overnight. The cooled mixture was treated with 4M HCl in 1,4-dioxane (0.1 ml) and then the product was subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound ( 177 mg, 0.25 mmol, 46% yield). LCMS RT = 1.21 min, ES+ve m/z 699 [M + H]+.2-(2-(4-(2-(4-(6-(benzyloxy)-2-(4-(benzyloxy) )phenyl)benzo[b]-thiophene-3-carbonyl)phenoxy)ethyl)piperazin-1-yl)ethoxy) tert-butyl acetate

[00274] Under a nitrogen atmosphere, a solution of (6-(benzyl-oxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-(2-(4-) (2-hydroxyethyl)piperazin-1-yl)ethoxy)phenyl)methanone (120mg, 0.17mmol) in DMF (3ml) was treated with tert-butyl bromoacetate (0.051ml, 0.34mmol) and then with sodium hydride (60% in mineral oil) (28 mg, 0.69 mmol) and stirred at room temperature overnight. The mixture was treated with 5% aqueous ammonium chloride (20 ml) and extracted with dichloromethane (30 ml). The organic phase was evaporated to dryness and the product was subjected to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (88 mg, 0.11 mmol, 63% yield). LCMS RT = 1.30 min, ES+v and m/z 813 [M + H]+.2-(2-(4-(2-(4-(6-Hydroxy-2-(4-hydroxyphenyl))benzoic acid [b] thiophene-3-carbonyl)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetic

[00275] A solution of 2-(2-(4-(2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy) tert-butyl ethyl)piperazin-1-yl)ethoxy)acetate (80 mg, 0.098 mmol) in a mixture of DMF (2 ml) and water (150 μl) was treated with ammonium formate (62 mg, 0.98 mmol) and palladium on carbon (10% degussa type) (18 mg, 0.017 mmol) and stirred at 50°C for 1 hour. The cooled mixture was filtered and the filtrate evaporated to dryness. The residue was treated with TFA (5 ml), stirred for 1 hour and then evaporated to dryness. The product was subjected to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (22 mg, 0.038 mmol, 39% yield). LCMS RT = 0.67 min, ES+ve m/z 577 [M+H]+. Example 25(2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(4-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl))benzo[ b]thiophene-3-carbonyl)phenoxy)ethyl)piperazin-1-yl)ethoxy)-acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2 -carboxamide

[00276] A mixture of 2-(2-(4-(2-(4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)piperazin acid -1-yl)ethoxy)acetic acid (25 mg, 0.036 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-( 4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (26mg, 0.055mmol) in DMF (0.7ml) was treated with DIPEA (0.045ml, 0.26mmol) and then with HATU ( 17 mg, 0.044 mmol) and stirred at room temperature for 15 minutes. The product was subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to the title compound (18 mg, 0.018 mmol, 50% yield). LCMS RT = 0.91 min, ES+ve m/z 989 [M + H]+.4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3- tert-butyl carbonyl)phenyl)piperidin-4-yl)piperazine-1-carboxylate

[00277] A solution of (4-fluorophenyl)(6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophen-3-yl)methanone (300 mg, 0.82 mmol) in N-methyl-2 - pyrrolidone (4 ml) was sealed and heated in a Biotage “Initiator” microwave at 140°C for 90 min. The product was subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (221 mg, 0.36 mmol, 44% yield). LCMS RT = 0.81 min, ES+ve m/z 614 [M + H]+.(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-(4- (piperazin-1-yl)piperidin-1-yl)phenyl)methanone, hydrochloride

[00278] 4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carboml)phenyl)piperidm-4-yl)piperazmo-1-carboxylate tert-butyl ( 221 mg, 0.36 mmol) was dissolved in trifluoroacetic acid (4 ml). After 30 minutes the solution was evaporated to dryness, the residue taken up in THF (10 ml), treated with 4M HCl in 1,4-dioxane (2 ml) and evaporated to dryness to give the title compound ( 174 mg, 0.32 mmol, 89% yield). LCMS RT = 0.64 min, ES+ve m/z 514 [M + H]+.2-(4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene) tert-butyl -3-carbonyl)phenyl)piperidin-4-yl)piperazin-1-yl)acetate

[00279] A solution of (6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)methanone (300mg, 0.58mmol) in DMF (1ml) was treated with sodium bicarbonate (245mg, 2.9mmol) and tert-butyl bromoacetate (0.129ml, 0.88mmol) and the mixture was stirred at room temperature for 3 days. The product was subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (160 mg, 0.26 mmol, 44% yield). LCMS RT = 0.79 min, ES+v and m/z 628 [M + H]+. 2-(4-(1-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]) thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazin-1-yl)acetic acid, 3 hydrochloride

[00280] A solution of 2-(4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazin- tert-Butyl 1-yl)acetate (160 mg, 0.26 mmol) in THF (10 ml) and treated with 25% aqueous HCl (5 ml) and after 1 hour blown to dryness in a stream of nitrogen to produce the title compound (164 mg, 0.24 mmol, 92% yield). LCMS RT = 0.65 min, ES+ve m/z 572 [M + H]+.Example 26(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-( 1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazin-1-yl)-acetamido)-3,3-dimethylbutanoyl )-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00281] A mixture of 2-(4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazin acid -1-yl)acetic acid, 3-hydrochloride (37 mg, 0.054 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethyl-butanoyl)-4-hydroxy-N-( 4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (38mg, 0.081mmol) in DMF (0.7ml) was treated with DIPEA (0.066ml, 0.38mmol) and then with HATU (25 mg, 0.065 mmol) and stirred at room temperature for 15 minutes. The product was subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (22 mg, 0.022 mmol, 41% yield). LCMS RT = 0.83 min, ES+ve m/z 984 [M + H]+.9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)- tert-butyl phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[00282] A mixture of (4-fluorophenyl)(6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophen-3-yl)methanone (200 mg, 0.55 mmol) and 3,9-diazaspiro - tert-butyl [5,5]undecane-3-carboxylate (commercially available eg from Matrix Scientific) (279 mg, 1.1 mmol) was heated in a Biotage microwave at 130°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with DMF (3 ml) and then subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (215 mg, 0. 36 mmol, 65% yield). LCMS RT = 1.22 min, ES+ve m/z 599.5 [M+H]+. (4-(3,9-Diazaspiro[5.5]undecan-3-yl)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone, 2 hydrochloride

[00283] HCl in dioxane (4M, 1.5 ml, 6.0 mmol) was added to a solution of 9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3- tert-butyl carbonyl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (215mg, 0.36mmol) in a mixture of DCM (1ml) and MeOH (0.5ml) and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced to give the title compound (190mg, 0.33mmol, 93% yield). LCMS RT = 0.72 min, ES+ve m/z 499.1 [M + H]+.2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene- tert-butyl 3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)acetate, acid salt

[00284] A vial was charged with (4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3- yl)methanone, 2-hydrochloride (43mg, 0.075mmol), tert-butyl bromoacetate (commercially available e.g. from Aldrich) (0.013ml, 0.09mmol) and sodium bicarbonate (32mg,0.38mmol) in DMF (0.6 ml). The vial was sealed and the reaction was heated at 50°C for 2 hours. The reaction was cooled to room temperature, filtered and subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (37 mg, 0.056 mmol, 75% yield). LCMS RT = 0.84 min, ES+ve m/z 613.4 [M + H]+.2-(9-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene) acid -3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)acetic, 2-hydrochloride

[00285] 2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3- tert-butyl yl)acetate, formic acid salt (37mg, 0.056mmol) was cautiously treated with TFA (0.5ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, treated with HCl in dioxane (4M, 2 ml) and stirred at room temperature for 30 minutes. The solvent was removed under reduced to give the title compound (35mg, 0.056mmol, 100% yield). LCMS RT = 0.74 min, ES+ve m/z 557.1 [M + H]+.Example 27(2S,4R)-4-Hydroxy-1-((S)-2-(2-(9) -(4-(6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)-acetamido) -3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, formic acid salt

[00286] HATU (24 mg, 0.062 mmol) was added to a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (33 mg, 0.071 mmol), 2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]) ]thiophene-3-carbonyl)phenyl)-3,9-diaza-spiro[5.5]undecan-3-yl)acetic acid, 2-hydrochloride (30 mg, 0.048 mmol) and DIPEA (0.083 ml, 0.476 mmol) in DMF (0.6 ml). The reaction was stirred at room temperature for 30 min and then directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (20 mg, 0.02 mmol, 41% yield) . LCMS RT = 0.85 min, ES+ve m/z 969.4 [M + H]+.2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b) tert-butyl ]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethoxy)acetate, diazaspiro[5.5]undecan-3-yl) formic acid salt phenyl)(6-hydroxy-2-(4-

[00287] A vial was charged with (4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3- yl)methanone, 2-hydrochloride (43mg, 0.075mmol), tert-butyl 2-(2-(tosyloxy)ethoxy)acetate (0.028ml, 0.11mmol) and sodium bicarbonate (32mg, 0.38mmol ) in DMF (0.6 ml). The vial was sealed and the reaction was heated at 60°C for 20 hours. The reaction was cooled to room temperature, filtered and subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (34 mg, 0.048 mmol, 64% yield). LCMS RT = 0.88 min, ES+ve m/z 657.4 [M + H]+.2-(2-(9-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[ b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethoxy)acetic acid, 2 hydrochloride

[00288] 2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan tert-butyl-3-yl)ethoxy)acetate, formic acid salt (34 mg, 0.048 mmol) was cautiously treated with TFA (0.5 ml) and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated, treated with HCl in dioxane (4M, 2 ml) and stirred at room temperature for 30 minutes. The solvent was removed under reduced to give the title compound (32mg, 0.048mmol, 100% yield). LCMS RT = 0.77 min, ES+ve m/z 601.3 [M + H]+.Example 28 (2S,4R)-4-Hydroxy-1-((S)-2-(2-(2) -(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethoxy) acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamide, 2 formic acid salt

[00289] HATU (13 mg, 0.035 mmol) was added to a mixture of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4- (4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (16 mg, 0.035 mmol), 2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl) acid) benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethoxy)acetic acid, 2-hydrochloride (18 mg, 0.027 mmol) and DIPEA (0.047 ml, 0. 27 mmol) in DMF (0.6 ml). The reaction was stirred at room temperature for 30 min and was then subjected directly to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (3.3 mg, 3.0 μmol, 11% yield), LCMS RT = 0.84 min, ES+ve m/z 1013.5 [M + H]+, 507.7 [M/2 + H]+.Example 29(2S,4R)-1-( (S)-2-(tert-butyl)-17-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12 ,15-tetraoxa-3-aza-heptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[00290] A mixture of 14-(4-(6-hydroxy-2-(4-methoxyphenyl)-benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1- oic acid (20 mg, 0.033 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) )benzyl)pyrrolidine-2-carboxamide, hydrochloride (23mg, 0.049mmol) in DMF (0.7ml) was treated with DIPEA (0.023ml, 0.13mmol) and then with HATU (15mg, 0.039mmol) and stirred at room temperature for 15 minutes. The product was directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to give the title compound (12 mg, 0.014 mmol, 36% yield). LCMS RT = 1.14 min, ES+ve m/z 1023.5 [M+H]+.
3-Bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene can be prepared according to the process described by Palkowitz, Alan David, US 5492922A.3-Bromo-2-(4-hydroxyphenyl)benzo [b]thiophen-6-ol (N27880-20-4 -GSK3184105A)

[00291] BBr3 (commercially available e.g. from Aldrich) (2.274 ml, 24.05 mmol) was added to a suspension of 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (2, 8 g, 8.02 mmol) in dichloromethane (100 ml) stirred at 0°C under an atmosphere of nitrogen. The reaction was stirred for 2 hours at this temperature. Water (100 ml) was carefully added and the product was extracted with ethyl acetate (200 ml). The aqueous layer was washed with ethyl acetate (200 ml) and the organic fractions were then combined, washed with brine (2 x 200 ml), dried over MgSO4 and concentrated under reduced pressure to give the title compound (2.34 g , 7.29 mmol, 91% yield) as a beige solid. LCMS RT = 0.97 min, ES+ve m/z 320.5/322.1 [M + H]+.6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-3-bromobenzo[b ]thiophene-1-oxide (N27880-24-P1 - not registered)

[00292] 3-Bromo-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (2.12 g, 6.60 mmol) was dissolved in N,N-dimethylformamide (50 ml) and stirred at 0°C. °C NaH, 60% w/w in mineral oil (0.792 g, 19.80 mmol) was added and the reaction was stirred at 0°C for 10 minutes. (Bromomethyl)benzene (commercially available eg from Aldrich) (2.4 ml, 20.18 mmol) was added and the reaction stirred at room temperature overnight. A saturated solution of NH4Cl (10 ml) was added cautiously followed by water (100 ml). The product was extracted with ethyl acetate (200 ml). The organic phase was washed with brine (100 ml) and concentrated. The intermediate was purified by chromatography on silica using a gradient elution of 0% to 50% ethyl acetate in cyclohexane. The appropriate fraction was evaporated to give the required crude intermediate (2g). To a solution of the obtained compound (2 g) in dichloromethane (20 ml) was added trifluoroacetic acid (20 ml). The reaction was cooled to 0°C and after 5 minutes of stirring, H2O2, 30% w/w in water (0.489 mL, 4.79 mmol) was added. The resulting mixture was stirred at 0°C for 30 minutes and at room temperature for 1 hour. Solid sodium bisulfate (0.265 g) was cautiously added to the dark solution followed by 3 ml of water. The mixture was stirred vigorously for 15 minutes and then concentrated in vacuo. The residue was partitioned between dichloromethane (80 ml) and saturated NaHCO3 solution (80 ml). The layers were separated and the organic phase was extracted with saturated NaHCO3 solution. The organic phase was then dried using a hydrophobic frit and concentrated in vacuo. The solid obtained was triturated with Et2O/EtOAc and the brown solid was filtered to give the title compound (780 mg, 1.507 mmol, 23% yield). LCMS RT = 1.47 min, ES+ve m/z 517.2/519.1 [M + H]+α6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-3-(4- (tert-butoxy)phenoxy)benzo[b]thiophene (N27880-28-4 - GSK3186003A)

[00293] 4-(tert-Butoxy)phenol (302mg, 1.815mmol) was dissolved in N,N-dimethylformamide (15ml). NaH, 60% w/w in mineral oil (132 mg, 3.30 mmol) was added slowly followed by 6-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-bromobenzo[b]thiophene-1 -oxide (854 mg, 1.650 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. Water (300 ml) was added and the product was extracted with EtOAc (300 ml). 2M aqueous HCl was added until the pH of the aqueous phase was 1 and the aqueous phase was extracted with EtOAc (400 ml). The combined organic extracts were washed with brine (300 ml), dried using a hydrophobic frit and concentrated under reduced pressure to give the crude intermediate (1.08 g) as a brown solid. LiAlH4 in THF (1M, 4.48 ml, 4.48 mmol) was added to a mixture of the obtained intermediate (1.08 g) in tetrahydrofuran (20 ml). The reaction was stirred at room temperature for 1.5 hours. Aqueous NaOH (50%, 15 ml) was carefully added and the mixture was partitioned between EtOAc (100 ml) and water (100 ml). The aqueous phase was further extracted with EtOAc (3 x 100 ml). The organic extracts were combined, dried using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0% to 50% dichloromethane in cyclohexane followed by a 100% dichloromethane wash of the column to give the title compound (440 mg, 0.75 mmol, 45% of income). LCMS RT = 1.71 min, ES+ve m/z 587.3 [M + H]+.4-((6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen- 3-yl)oxy)phenol (N27880-29-10 - GSK3186439A)

[00294] 6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-3-(4-(tertbutoxy)phenoxy)-benzo[b]thiophene (440 mg, 0.750 mmol) was dissolved in 1,4- dioxane (20 ml). HCl in dioxane (4M, 1.875 ml, 7.50 mmol) was added and the reaction was stirred at 40°C for 60 hours. Another aliquot of HCl in dioxane (4M, 1.875 ml, 7.50 mmol) was added and the reaction was stirred at 60°C for 4 hours. The reaction mixture was evaporated under reduced pressure to give the title compound (405mg, 0.763mmol, >100% yield). LCMS RT = 1.53 min, ES+ve m/z 531.2 [M + H]+ 2-(2-(2-(2-(4-((6-(benzyloxy)-2-(4-) (benzyloxy)phenyl)benzo[b]-thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy) (N27880-78-1 - GSK3187620A) tert-butyl acetate

[00295] A mixture of 4-((6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)oxy)phenol (4.03 g, 7.59 mmol) , tert-butyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (5.40 g, 12.91 mmol), K2CO3 (316 mg, 2.290 mmol) in N,N -dimethylformamide (60 ml) was heated at 85°C for 48 hours. The reaction was cooled to room temperature and partitioned between EtOAc (600 ml) and water (600 ml). The organic extract was dried over MgSO4, filtered using a hydrophobic frit and concentrated under reduced pressure. The product was purified by chromatography on silica using a gradient elution of 0 to 50% TBME in cyclohexane to give the title compound (2 g, 2.57 mmol, 34% yield) as a brown oil. LCMS RT = 1.64 min, ES+ve m/z 799.6 [M + Na]+ 2-(2-(2-(2-(4-((6-hydroxy-2-(4-hydroxyphenyl)) benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate (N28770-80-4 - GSK3203216A)detert-butyl

[00296] A mixture of 2-(2-(2-(2-(4-((6-(benzyloxy)-2-(4-(benzyloxy)-phenyl)benzo[b]thiophen-3-yl)oxy )phenoxy)ethoxy)ethoxy)ethoxy) tert-butyl acetate (2 g, 2.57 mmol) and palladium on carbon (10% w/w, 1.096 g, 1.030 mmol) in ethyl acetate (100 ml) and HCl in EtOH (1%, 15.67 ml, 5.16 mmol) was stirred at room temperature overnight under an atmosphere of hydrogen. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting oil was evaporated under high vacuum overnight to give the title compound (1.478 g, 2.477 mmol, 96% yield). LCMS RT = 1.12 min, ES+ve m/z 619.3 [M + Na]+.Example 1 (alternative synthesis)(2S,4R)-1-((S)-2-(tert-butyl) -14-(4-((6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3- azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (N28770-81-9 - GSK3176165A)

[00297] 2-(2-(2-(2-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)-oxy)phenoxy)ethoxy)ethoxy)ethoxy ) tert-butyl acetate (100 mg, 0.168 mmol) was dissolved in 1,4-dioxane (2 ml). HCl in dioxane (4M, 0.210 ml, 0.840 mmol) was added and the reaction mixture was stirred at 40°C for 3 hours. Another aliquot of HCl in dioxane (4M, 0.210 ml, 0.840 mmol) was added and the reaction mixture was stirred at 40°C overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile and concentrated under reduced pressure (this process was carried out twice) to give the carboxylic acid intermediate (80 mg). HATU (77 mg, 0.203 mmol) was added to a solution of the obtained intermediate (80 mg), DIPEA (0.2 ml, 1.145 mmol) and (2S,4R)-1-((S)-2-amino-3 ,3-dimethyl-butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (94 mg, 0.218 mmol) in N,N-dimethylformamide (1.5 ml). The reaction mixture was stirred for 45 minutes at room temperature. The crude mixture was directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (50 mg, 0.052 mmol, 31% yield). LCMS RT = 1.04 min, ES+ve m/z 953.7 [M + H]+ .(2S,4R)-N-(4-Chlorobenzyl)-4-hydroxypyrrolidine-2-carboxamide,hydrochloride (N28770- 83-7 - unregistered)

[00298] HATU (1676 mg, 4.41 mmol) was added portionwise to a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (commercially available e.g. from Aldrich ) (1.019 g, 4.41 mmol), (4-chlorophenyl)methanamine (commercially available e.g. from Aldrich) (520 mg, 3.67 mmol) and DIPEA (1.924 ml, 11.02 mmol) in DMF (20 ml ). The reaction was stirred at room temperature for 3 hours. The reaction mixture was partitioned between EtOAc (100 ml) and water (100 ml). The aqueous phase was back-extracted with EtOAc (100 ml) and the organic phase was dried over MgSO4. The combined organic extracts were dried using a hydrophobic frit and concentrated under reduced pressure. The residue was purified by chromatography on silica using a gradient elution of 0 to 50% MeOH in TBME to yield the required intermediate (1.053 g). The obtained compound was dissolved in HCl in dioxane (4M, 10 ml, 40 mmol) and the solution was stirred for 30 minutes. MeOH (10 ml) was added to solubilize the white suspension and the reaction mixture was stirred for a further 30 minutes. The solvent was concentrated under reduced pressure to give a white solid. MeOH was added and the product was concentrated under reduced pressure (this process was carried out twice) to give the title compound (895 mg, 3.07 mmol, 84% yield) as a white solid. LCMS RT = 0.54 min, ES+ve m/z 255.2 [M + H]+ .(2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-N- (4-chloro-benzyl)-4-hydroxypyrrolidine-2-carboxamide, hydrochloride (N28770-84-6 -GSK3204451A)

[00299] HATU (1.603 g, 4.22 mmol) was added portionwise to a solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (975 mg, 4.22 mmol ), (2S,4R)-N-(4-chlorobenzyl)-4-hydroxypyrrolidine-2-carboxamide, hydrochloride (895 mg, 3.07 mmol) and DIPEA (1.841 ml, 10.54 mmol) in DMF (40 ml ). The reaction was stirred for 45 minutes at room temperature. The reaction mixture was partitioned between EtOAc (200 ml) and water (200 ml). The aqueous phase was back-extracted with EtOAc (200 ml) and the combined organic phases were washed with brine (200 ml). The organic phase was dried using a hydrophobic frit and concentrated under reduced pressure. The residue was purified by chromatography on silica using a gradient elution of 0 to 25% MeOH in methyl tert-butyl ether to yield the required intermediate (500 mg). The obtained compound was stirred in HCl in dioxane (4M, 10 ml, 40 mmol) at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dried under high vacuum for 48 hours to give the title compound (396 mg, 0.979 mmol, 32% yield) as a white solid. LCMS RT = 0.63 min, ES+ve m/z 368.2 [M + H]+.Example 30(2S,4R)-1-((S)-2-(tert-butyl)-14-( 4-((6-hydroxy-2-(4-hydroxy-phenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1- oil)-N-(4-chlorobenzyl)-4-hydroxypyrrolidine-2-carboxamide (N27880-88-5, GSK3205879A)

[00300] 2-(2-(2-(2-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy) tert-butyl acetate (100mg, 0.168mmol) was dissolved in HCl in dioxane (4M, 2ml, 8mmol). The reaction was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile then concentrated under reduced pressure (this process was carried out twice) to give the carboxylic acid intermediate (80 mg). HATU (70 mg, 0.184 mmol) was added to a solution of the obtained intermediate (80 mg), DIPEA (0.2 ml, 1.145 mmol) and (2S,4R)-1-((S)-2-amino-3 ,3-dimethylbutanoyl)-N-(4-chlorobenzyl)-4-hydroxy-pyrrolidine-2-carboxamide, hydrochloride (70 mg, 0.173 mmol) in DMF (1.5 ml). The mixture was stirred at room temperature overnight. The crude mixture was directly subjected to mass directed automated preparative HPLC purification (formic acid modifier) to yield the title compound (50 mg, 0.056 mmol, 34% yield). LCMS RT = 1.11 min, ES+v and m/z 889.0 [M - H]-.Estrogen Receptor Alpha (ERa) Degradation and Cell Count Imaging Assay
[00301] Compounds were evaluated for ERa degradation and cell count effects on an MCF-7 cell line using high-grade imaging. 50 µl of MCF-7 cell suspension in medium was dispensed into each well of PDL-coated, clear-walled, black-walled plates containing a defined concentration of test compound dissolved in DMSO spanning the concentration range of 0.03 µM to 30 µM. Cells were incubated in the presence of compound for 24 hours at 37oC, 5% CO2 before cells were fixed. After incubation with the fixative solution (4% formaldehyde) the reservoirs were aspirated and a solution containing detergent was added to permeabilize the cells followed by the addition of blocking solution containing 1% BSA (bovine serum albumin) to block the sites of non-specific binding. After an additional 1 hour incubation this solution was aspirated from the wells and the ERA specific antibody diluted in blocking solution at a concentration of 1 µg/ml (anti ERA, cat no sc-543, Santa Cruz) was added. Following incubation with the antibody for 2 hours the cells were washed with a PBS-based solution before the addition of a secondary goat anti-rabbit antibody fluorescently labeled with Alexa Fluor 488 at a concentration of 2 µg/ml (cat no11008, Invitrogen) and a Hoechst33342 nuclear dye dye at a concentration of 1 µg/ml (cat no H3570, Invitrogen). Following an additional 1 hour incubation the cells were once again washed with the PBS-based solution. Plaques were then imaged and the ERa staining intensity in the nucleus and cell count measured. The degradation of ERa activity was expressed relative to DMSO, giving 0% degradation and a self-degrading molecule classified as giving 100% activity. Cell reduction count was expressed relative to DMSO, classified as 0% reduction.
[00302] The examples showed evidence of ERa degradation in this assay relative to DMSO control at 1 uM concentration.

权利要求:
Claims (21)
[0001]
1. Compound, characterized by the fact that it has formula (I):
[0002]
2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R4 is 4-methylthiazol-5-yl, or oxazol-5-yl.
[0003]
3. A compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that R4 is 4-methylthiazol-5-yl.
[0004]
4. A compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R4 is chlorine.
[0005]
5. A compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that R4 is oxazol-5-yl.
[0006]
6. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that R1 is OH, F, Br, OCH3 or H.
[0007]
7. A compound or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that RI is OH.
[0008]
8. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that R2 is OH or OCH3.
[0009]
9. A compound or a pharmaceutically acceptable salt thereof according to claim 8, characterized in that R2 is OH.
[0010]
10. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, characterized in that the linking group is a straight chain alkylene group of 8 to 16 carbon atoms, in which one or more atoms carbon is(are) substituted by each independently selected group of
[0011]
11. A compound or a pharmaceutically acceptable salt thereof according to claim 10, characterized in that the linking group is of formula (II)-(R5CH2CH2)XOCH2(ii) wherein: each R5 is independently selected from -O -, -NH-, -
[0012]
12. Compound or a pharmaceutically acceptable salt thereof according to claims 1 to 9, characterized in that the ligand is selected from: [OCH2CH2)4OCH2 ;(OCH2CH2)4OCH2(OCH2CH2)3OCH2(OCH2CH2)2OCH2
[0013]
13. Compound of formula (I) according to claim 1, characterized in that it is: (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(( 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy -N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-14-(4-((6-hydroxy) -2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-2-isopropyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6- hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy-N -(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((2-( 4-hydroxyphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy-N-( 4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy) -2-phenylbenzo[b]thiophen n-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-14-(4-((2-(4-Bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy) phenoxy)-2-(tert-Butyl)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((2-(4-fluorophenyl)-6-hydroxybenzo[b] thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl) pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl) phenoxy)-2-methyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-2-Ethyl-14-( 4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-14-(4-(6-hydroxy) -2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-2-isopropyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-N-(4 -(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-Cyclopropyl-14-(4-(6-hydroxy-2-(4- hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazole- 5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-Cyclopentyl-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl) pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl) phenoxy)-2-isobutyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-N-(4-(4-methylthiazol-5-yl)benzyl 1)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-17-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3- carbonyl)phenoxy)-2-isopropyl-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oxyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-17-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3- carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine- 2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(2-(4-Hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl )phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy )-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;( 2S,4R)-1-((S)-2-(tert-Butyl)-17-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)- 4-oxo-6.9 ,12,15-tetraoxa-3-azaheptadecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1- ((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9 ,12-trioxa-3-azatetradecan-1-oxyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1- ((S)-2-(2-(2-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)acetamido)- 3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)- 14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-12-methyl-4-oxo-6,9-dioxa-3,12-diazatetradecan- 1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl) )-18-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-16-methyl-4-oxo-6,9,12-trioxa-3, 16-diazaoctadecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S )-two -(2-(2-(2-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy)ethoxy) acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-2 -(2-(2-(4-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)Ethyl)piperazin-1-yl)ethoxy) acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-2 -(2-(4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazin-1-yl)acetamido )-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-2- (2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)acetamido) -3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-2-( 2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3 - yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)- 2-(tert-Butyl)-17-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa -3-azaheptadecan-1-oxyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2 -(tert-Butyl)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12- trioxa-3-azatetradecan-1-oxyl)-N-(4-chlorobenzyl)-4-hydroxypyrrolidine-2-carboxamide; and pharmaceutically acceptable salts thereof.
[0014]
14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, characterized in that it is for use in the treatment of proliferative disease or conditions mediated by increased estrogen receptor alpha activity.
[0015]
15. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 13 and one or more pharmaceutically acceptable carriers, diluents and excipients.
[0016]
16. A compound according to claim 14, characterized in that the proliferative disease or condition is selected from breast cancer, uterine cancer, or endometriosis.
[0017]
17. Combination, characterized in that it comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 13 and at least one antineoplastic agent.
[0018]
18. Combination according to claim 19, characterized in that it is for use to treat proliferative diseases and conditions mediated by increased estrogen receptor alpha activity.
[0019]
19. Pharmaceutical composition, characterized in that it comprises a combination as defined in claim 19 and one or more pharmaceutically acceptable carriers, diluents and excipients.
[0020]
20. Use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 13, characterized in that it is for the manufacture of a drug to degrade the estrogen receptor in a human in need the same.
[0021]
21. Combination according to claim 18, characterized in that the proliferative disease or condition is selected from breast cancer, uterine cancer, or endometriosis.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-02-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-10-15| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2019-11-19| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-07-20| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2021-10-26| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2022-01-11| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 01/07/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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GBGB1311888.0A|GB201311888D0|2013-07-03|2013-07-03|Novel compounds|

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GB1311888.0|2013-07-03|

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PCT/EP2014/063899|WO2015000867A1|2013-07-03|2014-07-01|Benzothiophene derivatives as estrogen receptor inhibitors|

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