BENZOTHOPHENE DERIVATIVES AND COMPOSITIONS THEREOF AS SELECTIVE ESTOGEN RECEPTOR DEGRADATORS

专利摘要:
benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders. the present invention relates to compounds of formula i: wherein n, m, x, y1, r1, r2, r3, r4 and r5 are defined in the summary of the invention; capable of being both potent estrogen receptor antagonists and degraders. the invention also provides a process for preparing compounds of the invention, pharmaceutical preparations comprising such compounds, and methods of using such compounds and compositions in the control of diseases or disorders associated with aberrant estrogen receptor activity.
公开号:BR112015018882B1
申请号:R112015018882-6
申请日:2014-02-12
公开日:2021-09-14
发明作者:Heather Elizabeth Burks；Michael A. Dechantsreiter；Guo He；Jill NUNEZ；Stefan Peukert；Clayton SPRINGER；Yingchuan Sun；Noel Marie-France Thomsen；George Scott Tria；Bing Yu
申请人:Novartis Ag；
IPC主号:

专利说明:

BACKGROUND FIELD OF INVENTION
[0001] The present invention relates to compounds and compositions that are potent estrogen receptor signaling agonists and selective estrogen receptor degraders (SERDs). The invention also provides a process for preparing compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the control of diseases or disorders associated with aberrant estrogen receptor activity. BACKGROUND OF THE INVENTION
[0002] Estrogens play a critical role in the development of female and male reproductive tissues and contribute to the development and progression of estrogen receptor diseases or disorders such as breast, ovarian, colon, prostate, endometrial and cancers. uterine Estrogen receptor positive (ERα) diseases such as breast cancers are usually treated with a selective estrogen receptor modulator (SERM) or an aromatase inhibitor (AI). Although these therapies have proven effective in reducing the incidence of breast cancer progression, some patients exhibit treatment resistance and progress to advanced metastatic breast cancer.
[0003] Treatment resistance results, in part, from the evolution of tumors to a state of hypersensitivity to low estrogen levels (treatment with AI) or development of dependence on antiestrogen for transcription activation (treatment with SERM). SERDs degrade the receptor, effectively eliminating ERα expression and in so doing, engage the fundamental resistance mechanisms that develop to antiendocrine monotherapy. Furthermore, clinical and preclinical data show that a significant number of resistance reaction series can be avoided by using an antiestrogen that exhibits SERD activity.
[0004] The compounds of the present invention, as SERDs, can be used as therapies for the treatment of estrogen receptor diseases or disorders, for example, ovulatory dysfunction, uterine cancer, endometrial cancer, ovarian cancer, endometriosis, osteoporosis, prostate cancer, benign prostatic hypertrophy, estrogen receptor positive (ERα) breast cancer, in particular ERα-positive breast cancer exhibiting de novo resistance to existing antiestrogens and aromatase inhibitors. SUMMARY OF THE INVENTION
[0005] In one aspect, the present invention provides compounds of Formula

[0006] in which:
[0007] n is selected from 0, 1 and 2;
[0008] m is selected from 0, 1 and 2;
[0009] X is selected from O and NR6; wherein R6 is C1-4alkyl;
[0010] Y1 is selected from N and CR7; wherein R7 is selected from hydrogen and C1-4alkyl;
[0011] R1 is hydrogen;
[0012] R2 is selected from hydrogen and halo;
[0013] R3 is selected from -CH2CH2R8b and -CR8a=CR8aR8b; wherein each R8a is independently selected from hydrogen, fluorine and C1-4alkyl; and R8b is selected from -C(O)OR9a, -C(O)NR9aR9b, -C(O)NHOR9a, -C(O)X2R9a and a 5- to 6-membered heteroaryl selected from:

[0014] wherein the dotted line indicates the point of attachment with -CH2CH2 or -CR8a=CR8a of R3; wherein X2 is C1-4alkylene; R9a and R9b are independently selected from hydrogen, C1-4alkyl, C1-4alkyl substituted by hydroxy, C1-4alkyl substituted by halo and -X4R10; wherein X4 is selected from a bond and C1-3alkylene; and R10 is a 4- to 6-membered saturated ring containing 1 to 3 atoms independently selected from O, N and S; wherein said heteroaryl of R8b is unsubstituted or substituted with 1 to 3 groups independently selected from C1-4alkyl and C3-8cycloalkyl;
[0015] R4 is selected from hydrogen, C1-4alkyl, halo and C1-3alkoxy;
[0016] R5 is selected from C6-10aryl and a 5- to 6-membered heteroaryl selected from:

[0017] wherein the dotted line indicates the point of attachment with the benzothiophene nucleus; wherein said C6-10aryl or heteroaryl of R5 is substituted with 1 to 3 groups selected from -X3-R5a and R5a; where X3 is methylene; R5a is selected from hydroxy, amino, C1-4alkyl, halo, nitro, cyano, C1-4alkyl substituted by halo, C1-4alkyl substituted by cyano, C1-4alkyl substituted by hydroxy, C1-4alkoxy substituted by halo, C1- 4alkoxy, -SF5, -NRnaRnb, -C(O)Rna, C3-8Cycloalkyl and a 4- to 7-membered, saturated, unsaturated or partially saturated ring containing 1 to 4 heteroatoms or groups selected from O, NH, C( O) and S(O)0-2; wherein R11a and R11b are independently selected from hydrogen and C1-4alkyl; or R11a and R11b together with the nitrogen to which they are both attached form a 4- to 7-membered saturated ring containing another heteroatom or group selected from O, NH, and S(O)0-2; wherein said 4- to 7-membered ring of R5a may be unsubstituted or substituted with C1-4alkyl;
[0018] In a second aspect, the present invention provides a pharmaceutical composition containing a compound of Formula I or an N-oxide derivative, tautomer, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
[0019] In a third aspect, the present invention provides a method of treating a disease in an animal in which a combined selective estrogen receptor antagonist and estrogen receptor degrader can prevent, inhibit or ameliorate the pathology and/or symptomatology of diseases, wherein the method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or an N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof .
[0020] In a fourth aspect, the present invention provides the use of a compound of Formula I in the manufacture of a medicament to treat a disease in an animal in which estrogen receptor activity contributes to the pathology and/or symptomatology of the illness.
[0021] In a fifth aspect, the present invention provides a process for the preparation of compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof. Definitions
[0022] The general terms used hereinafter and hereinafter preferably have within the context of this description the following meanings, unless otherwise indicated, where the more general terms, whenever used, may independently of one another be replaced by more specific definitions or remain, thereby defining more detailed modalities of the invention:
[0023] "Alkyl" refers to a fully saturated, branched or unbranched hydrocarbon moiety having up to 20 carbon atoms. Unless otherwise provided, alkyl refers to hydrocarbon moieties having 1 to 7 carbon atoms (C 1-4 alkyl), or 1 to 4 carbon atoms (C 1-4 alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl , n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. A substituted alkyl is an alkyl group containing one or more, such as one, two or three substituents selected from halogen, hydroxy or alkoxy groups. Halo-substituted alkyl and halo-substituted alkoxy can be straight-chain or branched and include methoxy, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, and the like.
[0024] "Aryl" means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms. For example, aryl can be phenyl or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group.
[0025] "Heteroaryl" is as defined for aryl above where one or more of the ring members is a heteroatom. For example, C5-10heteroaryl is a minimum of 5 members as indicated by the carbon atoms, however these carbon atoms can be replaced by a heteroatom. Accordingly, C5-10heteroaryl includes pyridinyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[1,3]dioxol, imidazolyl, benzoimidazolyl, pyrimidinyl, furanyl, oxazolyl, triazolyl, isoxazolyl tetrazolyl, pyrazolyl, thienyl, etc.
"Cycloalkyl" means a saturated or partially saturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the indicated number of ring atoms. For example, C3-10cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
"Heterocycloalkyl" means cycloalkyl, as defined in this application, with the proviso that one or more of the indicated ring carbons is replaced by a moiety selected from -O-, -N=, -NR-, -C (O)-, -S-, -S(O) - or -S(O)2-, where R is hydrogen, C1-4alkyl or a nitrogen protecting group. For example, C3-8heterocycloalkyl, as used in this application, to describe compounds of the invention include morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylane, 1,4-dioxa-8-aza-spiro[ 4,5]dec-8-yl, thiomorpholino, sulphonomorpholino, sulphonomorpholino, etc.
[0028] "Halogen" (or halo) preferably represents chlorine or fluorine, but may also be bromine or iodine.
The compounds of Formula I may have different isomeric forms. For example, any asymmetric carbon atom can be present in the (R), (S) or (R,S) configuration, preferably in the (R) or (S) configuration. Substituents on a double bond or especially a ring may be present in cis- (=Z-) or trans (=E-) form. The compounds can thus be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
Compounds of Formula I have X defined as being selected from O and NR6; where R6 is C1-4alkyl. It is known that other groups such as a bond or a carbonyl at the X position are detrimental to the antagonist activity (IC50 of MCF7 M) and degradation potential (percentage of ER remaining) of the compounds. Compare below:

Compounds of Formula I have R3 defined as being selected from -CH2CH2R8b and -CR8a=CR8aR8b. It is known that, for example, where each R8a and R8b is hydrogen, a shorter or longer order of bond between phenyl and -C(O)OH is detrimental to antagonist activity (IC50 MCF7 μM) and potential for degradation (percentage of remaining ER) of the compounds. Compare below:

[0032] Where the plural form (eg compounds, salts) is used, this includes the singular (eg single compound, single salt). "A compound" does not exclude that (for example, in a pharmaceutical formulation) more than one compound of Formula I (or a salt thereof) is present, the "a(a)" merely representing the indefinite article . "A(a)" may therefore preferably be read as "one or more", less preferably and alternatively as "a(one)".
[0033] Whenever a compound or compounds of Formula I is mentioned, this is also meant to include N-oxides of such compounds and/or tautomers thereof.
[0034] The term "and/or an N-oxide thereof, a tautomer thereof and/or a (preferably pharmaceutically acceptable) salt thereof" especially means that a compound of Formula I may be present as such or in admixture with its N-oxide, as a tautomer (eg, due to tautomerism of keto-enol, lactam¬lactin, amide-imidic acid or enamine-imine) or in mixture (eg, equivalence reaction caused) with its tautomer, or as a salt of the compound of Formula I and/or any of these forms or mixtures of two or more of such forms.
The present invention also includes all suitable isotopic variations of the compounds of the invention, or pharmaceutically acceptable salts thereof. An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the mass generally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of hydrogen, carbon, nitrogen and oxygen such as 2H, 3H, 11C, 13C , 14C, 15N, 17O, 18O, 35S, 18F, 36Cl and 123I. Certain isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies. In particular examples, 3H and 14C isotopes can be used for their ease of preparation and detectability. In other examples, substitution with isotopes such as 2H may provide certain therapeutic advantages that result from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopic variations of the compounds of the invention or pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. For example, the compounds of the invention may exist in a deuterated form as shown below:
Description of Preferred Modalities
[0036] The present invention relates to selective estrogen receptor degraders. In one embodiment, with respect to the compounds of Formula I, the compounds of Formula Ia are:

[0037] wherein: n is selected from 0, 1 and 2; m is selected from 0, 1 and 2; Y1 is selected from N and CR7; wherein R7 is selected from hydrogen and C1-4alkyl; R1 is hydrogen; R2 is selected from hydrogen and halo; R3 is selected from -CH2CH2R8b and -CR8a=CR8aR8b; wherein each R8a is independently selected from hydrogen and C1-4alkyl; and R8b is selected from -C(O)OR9a, -C(O)NR9aR9b, -C(O)NHOR9a, -C(O)X2R9a, tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4 - triazolyl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2-oxo-pyrimidinyl and imidazolyl; wherein X2 is C1-4alkylene; R9a and R9b are independently selected from hydrogen, C1-4alkyl, C1-4alkyl substituted by hydroxy, C1-4alkyl substituted by halo and -X4R10; wherein X4 is selected from a bond and C1-3alkylene; and R10 is a 4 to 6 membered saturated ring containing 1 to 3 atoms independently selected from O, N and S; wherein said tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl, 2-oxo-pyrimidinyl or imidazolyl of R8b is unsubstituted or substituted with 1 to 3 groups independently selected from C1-4alkyl and C3 -8cycloalkyl; R4 is selected from hydrogen and C1-4alkyl; and each R5a is independently selected from hydroxy, C1-4alkyl, halo, nitro, cyano, C1-4alkyl substituted by halo, C1-4alkoxy substituted by halo, C1-4alkyl substituted by hydroxy, C1-4alkoxy, C3-8cycloalkyl, -NRiiaRiib, -C(O)Riia is a 4- to 7-membered, saturated, unsaturated or partially saturated ring containing 1 to 4 heteroatoms or groups selected from O, NH, C(O) and S(O)0- two; wherein X2 is selected from a methylene bond; wherein R11a and R11b are independently selected from hydrogen and C1-4alkyl; wherein said 4- to 7-membered ring of R5a may be unsubstituted or substituted with C1-4alkyl; X3 is selected from a methylene bond; or a pharmaceutically acceptable salt thereof.
[0038] In another embodiment, R3 is selected from -CH2CH2R8b and -CR8a=CR8aR8b; wherein each R8a is independently selected from hydrogen and C1-4alkyl; and R8b is selected from -C(O)OR9a, -C(O)NR9aR9b, -C(O)NHOR9a, and -C(O)X2R9a; wherein X2 is C1-4alkylene; R9a and R9b are independently selected from hydrogen, C1-4alkyl, C1-4alkyl substituted by hydroxy, C1-4alkyl substituted by halo and morpholino-ethyl.
[0039] In another embodiment, R3 is selected from -CH2CH2R8b and -CR8a=CR8aR8b; wherein each R8a is independently selected from hydrogen and C1-4alkyl; and R8b is independently selected from -C(O)OH, -C(O)CHs, -C(O)OCH3 and morpholino-ethyl.
[0040] In another embodiment, R5a is selected from hydroxy, fluoro, trifluoro-methyl and 1,1-difluoro-ethyl.
[0041] In another modality, they are compounds, or a pharmaceutically acceptable salt thereof, selected from:












[0042] In another modality, it is a compound, or the pharmaceutically acceptable salt thereof, selected from:


[0043] In another embodiment, R3 is selected from -CH2CH2R8b and -CR8a=CR8aR8b; wherein each R8a is independently selected from hydrogen and C1-4alkyl; and R8b is selected from tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2 -oxo-pyrimidinyl and imidazolyl; wherein said tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl, 2-oxo-pyrimidinyl or imidazolyl of R8b is unsubstituted or substituted with 1 to 3 groups independently selected from C1-4alkyl and C3 -8cycloalkyl; wherein said phenyl, pyrrolidinyl or indolizinyl of R3 is unsubstituted or substituted with a group selected from -C(O)ORπ; wherein R13 is selected from hydrogen and C1-4alkyl;
[0044] In another modality, it is a compound, or the pharmaceutically acceptable salt thereof, selected from:



[0045] In another embodiment are compounds of Formula Ib:

[0046] wherein: n is selected from 0, 1 and 2; m is selected from 0, 1 and 2; Y1 is selected from N and CR7; wherein R7 is selected from hydrogen and C1-4alkyl; R1 is hydrogen; R2 is selected from hydrogen and halo; R3 is selected from -CH2CH2R8b and -CR8a=CR8aR8b; wherein each R8a is independently selected from hydrogen and C1-4alkyl; and R8b is selected from -C(O)OR9a, -C(O)NR9aR9b, -C(O)NHOR9a, -C(O)X2R9a, tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4 - triazolyl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2-oxo-pyrimidinyl and imidazolyl; wherein X2 is C1-4alkylene; R9a and R9b are independently selected from hydrogen, C1-4alkyl, C1-4alkyl substituted by hydroxy and C1-4alkyl substituted by halo; wherein said tetrazolyl, 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl, 2-oxo-pyrimidinyl or imidazolyl of R 8b is unsubstituted or substituted with a group selected from C 1-4 alkyl and C3-8cycloalkyl; R4 is selected from hydrogen and C1-4alkyl; each R5a is independently selected from hydroxy, C1-4alkyl, halo, nitro, cyano, C1-4alkyl substituted by halo, C1-4alkoxy substituted by halo, C1-4alkyl substituted by hydroxy, C1-4alkoxy and -C(O)R11a; wherein R11a is selected from hydrogen and C1-4alkyl; and R6 is C1-4alkyl; or a pharmaceutically acceptable salt thereof.
[0047] In another embodiment, R3 is selected from -CH2CH2R8b and -CR8a=CR8aR8b; wherein each R8a is independently selected from hydrogen and C1-4alkyl; and R8b is selected from -C(O)OR9a, -C(O)NR9aR9b, -C(O)NHOR9a, and -C(O)X2R9a; wherein X2 is C1-4alkylene; R9a and R9b are independently selected from hydrogen, C1-4alkyl, hydroxy substituted C1-4alkyl and halo substituted C1-4alkyl.
[0048] In another modality it is a compound, or a pharmaceutically acceptable salt thereof, selected from:

[0049] In another embodiment it is a compound, or a pharmaceutically acceptable salt thereof, selected from:

Pharmacology and Utility
[0050] The present invention relates to compounds of Formula I' which decrease the effects of estrogen receptors and decrease concentrations of estrogen receptors and, therefore, are useful as agents for the treatment or prevention of diseases or conditions in which the actions of estrogens or estrogen receptors are involved in the aetiology or pathology of the disease or condition or contribute to at least one symptom of the disease or condition and where such actions of estrogens or estrogen receptors are undesirable. The compounds of the invention are potent both as estrogen receptor antagonists and selective estrogen receptor degraders (SERDS).
[0051] The estrogen receptor (ER) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. In both women and men, estrogens play an important role in regulating various physiological processes. In humans, two different ER subtypes are known: ERα and ERβ. Each subtype has a distinct tissue distribution and different biological roles. For example, ERα is highly present in endometrial, breast, ovarian stromal, and hypothalamic cancer cells. ERβ protein expression has been documented in kidney, brain, bone, heart, lung, intestinal mucosa, prostate, bladder, ovary, testes, and endothelial cells.
[0052] Pharmaceuticals such as tamoxifen, raloxifene and lasofoxifene are well known as estrogen receptor modulators. Tamoxifen, for example, acts as an estrogen on bone and endometrium, while it acts as an antiestrogen on breast tissue. Breast cancer is the predominant neoplastic disease in women. ERα is a regulator of breast cancer progression. Existing treatment multiples aim to reduce estrogen levels or block its binding to ERα, thereby minimizing tumor progression and further inducing tumor regression in ERα positive breast cancer. Tamoxifen is a first-generation treatment for ERα-positive breast cancer. However, efficacy in the treatment of breast cancer is seriously compromised by intrinsic or newly developed resistance to anti-hormonal therapy such as treatment with tamoxifen or aromatase inhibitors. Such resistance may exist or develop as a result of ERα phosphorylation or regulation of key components in hormone receptor and/or growth factor signal transduction arrays. Tamoxifen resistance is regulated by the residual agonist activity of tamoxifen. Second-generation treatments such as toremifene, droloxifene, idoxifene, arzoxifene, and raloxifene did not improve the efficacy of tamoxifen in the treatment of ERα-positive breast cancer and/or demonstrated cross-resistance to each other.
[0053] Fulvestranto is a pure ERα antagonist without the partial agonist activity that is typical for estrogen receptor modulators. It is the only marketed selective estrogen receptor degrader (SERD) and it is effective in second-line treatment of breast cancer. Fulvestrant antagonizes both estrogen receptors and effectively degrades or down-regulates ERα protein levels in cells. This SERD activity inhibits ERα-regulated proliferation and tumor growth. Fulvestrant, when given once a month at 250 mg, is equally effective as tamoxifen in the treatment of ERα-positive advanced breast cancer. In a second-line treatment of ERα-positive tamoxifen-resistant breast cancer, fulvestrant, when given once a month at 250 mg, is equally effective as aromatase inhibitors, despite relatively poor bioavailability and/or exposure. tion that limits its clinical effectiveness. Several other SERDs exist, for example: "ICI 164,384", an analogous structure of fulvestrant; "GW5638", a structural analogue of tamoxifen; and "GW7604", a structural analogue of 4-hydroxy tamoxifen.
[0054] Consequently, there is a need for new potent ERα antagonists, which may preferably have ER down-regulation or degradation activity in, for example, breast cancer cells without stimulation of proliferation in ERα positive, hormone-resistant breast cancer cells. Such compounds may be orally administrable and be useful in the treatment of, among other things, ERα-positive hormone-resistant breast cancer.
[0055] Estrogen receptor related diseases or conditions include, but are not limited to aberrant estrogen receptor activity associated with: cancer, eg bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian and uterine cancer; leiomyoma, for example, uterine leiomyoma; central nervous system defects, for example, alcoholism and migraine; cardiovascular system defects, for example, aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, and hypertension; defects of the hematological system, eg deep vein thrombosis; immune diseases and inflammation, for example Graves' disease, arthritis, multiple sclerosis and cirrhosis; susceptibility to infection, for example, hepatitis B and chronic liver disease; metabolic defects, for example, bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia and osteoporosis; neurological defects, for example Alzheimer's disease, Parkinson's disease, migraine, vertigo; psychiatric defects, eg anorexia nervosa, attention deficit hyperactivity disorder, dementia, major depressive disorder, and psychosis; and reproductive defects, eg age at menarche, endometriosis and infertility. In the context of cancer treatment, the compound of Formula I offers improved therapeutic activity characterized by complete or long-term tumor regression, a lower incidence or rate of development of treatment resistance, and/or a reduction in invasiveness. of tumor.
[0056] The present invention relates to compounds that are potent both as estrogen receptor antagonists and selective estrogen receptor degraders. The invention also provides a process for preparing compounds of the invention and pharmaceutical preparations comprising such compounds. Another aspect of the present invention relates to a method of treating disorders mediated by estrogen receptors comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I as defined in the Summary of the Invention.
[0057] In one embodiment, the compounds of the invention are used to treat breast cancer in a mammal.
[0058] In another modality, cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancers.
[0059] In another modality, the cancer is breast cancer.
[0060] In another modality, cancer is a hormone-dependent cancer.
[0061] In another modality, cancer is estrogen-dependent cancer.
[0062] In another modality, the cancer is an estrogen sensitive cancer.
[0063] In another modality, cancer is a cancer resistant to anti-hormonal treatment.
[0064] In another modality, cancer is an estrogen sensitive cancer or an estrogen receptor dependent cancer that is resistant to anti-hormonal treatment.
[0065] In another embodiment, the anti-hormonal treatment includes treatment with at least one agent selected from tamoxifen, fulvestrant, a steroidal aromatase inhibitor, and a non-steroidal aromatase inhibitor.
In another embodiment, compounds of the invention are used to treat hormone receptor positive metastatic breast cancer in a postmenopausal woman with disease progression following antiestrogen therapy.
[0067] In another embodiment, the compounds of the invention are used to treat a hormone-dependent malignant or benign disease of the breast or reproductive tract in a mammal.
[0068] In another embodiment, the malignant or benign disease is breast cancer.
[0069] In another embodiment, compounds of the invention are used to treat cancer in a mammal, where the mammal is not undergoing chemotherapy.
[0070] In another embodiment, compounds of the invention are used to treat cancer in a mammal, wherein the mammal is being treated for cancer with at least one anti-cancer agent.
[0071] In another modality, cancer is a hormone refractory cancer.
[0072] In another embodiment, compounds of the invention are used in the treatment of endometriosis in a mammal.
[0073] In another embodiment, compounds of the invention are used in the treatment of leiomyoma in a mammal.
[0074] In another modality, leiomyoma is selected from uterine leiomyoma, esophageal leiomyoma, cutaneous leiomyoma, and small bowel leiomyoma.
[0075] In another embodiment, the compounds of the invention are used in the treatment of fibroids, for example, uterine fibroids, in a mammal.
Compounds of the present invention may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from chemotherapy agents, for example , mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, and other anticancer agents, for example, cisplatin, 5-fluorouracil or 5-fluoro-2-4(1 H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine.
[0077] Such combinations can offer significant advantages, including synergistic activity, in therapy.
In certain embodiments, the present invention relates to the aforementioned method, wherein said compound is administered parenterally.
In certain embodiments, the present invention relates to the aforementioned method, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecally, topically, or intranasally.
In certain embodiments, the present invention relates to the aforementioned method, wherein said compound is administered systemically.
[0081] In certain embodiments, the present invention relates to the aforementioned method, wherein said patient is a mammal.
In certain embodiments, the present invention relates to the aforementioned method, wherein said patient is a primate.
[0083] In certain embodiments, the present invention relates to the aforementioned method, wherein said patient is a human.
[0084] In another aspect, the present invention relates to a method of treating a disorder mediated by estrogen receptors, comprising the step of: administering to a patient in need thereof a therapeutically effective amount of a chemotherapeutic agent in combination with a therapeutically effective amount of a compound of Formula I as defined in the Summary of the Invention. Pharmaceutical Compositions
[0085] In another aspect, the present invention provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or thinners. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, e.g., purgatives ( aqueous or non-aqueous solutions or suspensions), tablets, for example, those bleached for buccal, sublingual and systemic absorption, cakes, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous, or epidural injection as, for example, a sterile solution or suspension, or an extended-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) nasally; (9) pulmonary; or (10) intrathecally.
[0086] The phrase "therapeutically effective amount" as used herein means the amount of a compound, material, or composition comprising a compound of the present invention that is effective to produce some desired therapeutic effect in at least a subpopulation of cells in an animal at a reasonable risk/benefit ratio for any medical treatment.
[0087] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of safe medical judgment, suitable for use in contact with the tissues. of being humans and animals if excessive toxicity, irritation, response, or other problem or complication, commensurate with the risk/benefit ratio.
[0088] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, excipient, manufacturing aid (eg, lubricant, talcum magnesium, lime). calcium or zinc stearate, or stearic acid), or solvent encapsulating material, involved in carrying or transporting the object compound from one organ or portion of the body to another organ or portion of the body. Each vehicle must be "acceptable" in the sense that it is compatible with other ingredients in the formulation and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatine; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, peanut oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH-buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical formulations.
As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are thereby capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in this regard refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in vehicle administration or in the dosage form manufacturing process, or by separately reacting a purified compound of the invention in this free base form with a suitable organic or inorganic acid, and isolating the salt thereby formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, salts naphylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
[0090] The pharmaceutically acceptable salts of the subject compounds include the conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, of non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulphanilic , 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, disulfonic ethane, oxalic, isotionic, and the like.
In other cases, the compounds of the present invention may contain one or more acidic functional groups and thus are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these examples refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can also be prepared in situ in vehicle administration or in the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base such as hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary or tertiary organic amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra)
[0092] Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
[0093] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfide, sodium sulfide and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
[0094] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sub-lingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a therapeutic effect. Generally, within one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent active ingredient, preferably from about 5 percent to about 70 percent, more preferably from about 10 percent to about 30 percent.
[0095] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, for example, bile acids, and polymeric vehicles, for example ¬plum, polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation makes orally bioavailable a compound of the present invention.
[0096] Methods of preparing these formulations or compositions include the step of introducing in association a compound of the present invention with the vehicle and, optionally, one or more accessory ingredients. In general, formulations are prepared uniformly and intimately by bringing into association a compound of the present invention with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.
[0097] Formulations of the invention suitable for oral administration may be in the form of capsules, seals, pills, tablets, lo-sangos (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia) and/or as antiseptics and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention can also be administered as a cake, electuary or paste.
[0098] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, pills, powders, granules, troches and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as citrate. sodium or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds and surfactants such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and nonionic surfactants; (8) absorbents such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) pain agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in hard shell gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
[0099] A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binder (eg, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (eg, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfactant or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
Tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as tablets, capsules, pills and granules, may optionally be classified or prepared with coatings or shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation technique. They can also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymeric matrices, liposomes and/or microspheres. They can be formulated for quick release, eg freeze dried. They can be sterilized by, for example, filtering through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium. immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.
[00101] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, peanut, corn, olive, castor sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene leno glycols and sorbitan fatty acid esters, and mixtures thereof.
[00102] In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring, coloring, perfuming and preserving agents.
[00103] Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.
[00104] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or vehicles comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, which is solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.
The formulations of the present invention that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such vehicles are known in the art to be appropriate.
[00106] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The optical compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants that may be required.
[00107] Ointments, pastes, creams, and gels may contain, in addition to the active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
[00108] Powders and sprays may contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
[00109] Transdermal patches have the added advantage of providing controlled release of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flow can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.
[00110] Ophthalmic formulations, powder ointments, eye solutions, and the like, are also contemplated as being within the scope of this invention.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more sterile powders, emulsions, suspensions, dispersions or pharmaceutically acceptable isotonic, sterile aqueous or non-aqueous solutions that can be reconstituted. in sterile injectable solutions or dispersions immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that make the formulation isotonic with the blood in the intended container, or suspending or thickening agents.
[00112] Examples of suitable aqueous or non-aqueous vehicles that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, oils vegetables, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying and dispersing agents. The prevention of the action of microorganisms on the object compounds can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be caused by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.
[00114] In some cases, in order to prolong the effect of a drug, it is desirable to decrease the drug absorption from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material having poor water solubility. The drug's absorption rate then depends on its dissolution rate which, in turn, may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
[00115] Injectable deposit forms are made by forming microencapsulated matrices of the object compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug to polymer ratio, and the nature of the particular polymer employed, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by capturing the drug in liposomes or microemulsions that are compatible with body tissue.
[00116] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are, of course, provided in forms suitable for each route of administration. For example, they are administered in tablet or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., administration by injection, infusion, or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
[00118] The phrases "parenterally administered" and "parenterally administered" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, infusion and intravenous, intramuscular injection. , intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal.
[00119] The phrases "systemic administration," "systemically administered," "peripherally administered," and "peripherally administered" as used herein mean the administration of a compound, drug or other material directly into the central nervous system , so that it enters the patient's system and thereby undergoes metabolism and other similar processes, eg, subcutaneous administration.
These compounds can be administered to humans and other animals for therapy by any suitable administration routine, including orally, nasally, such as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as powders, ointments or drops, including buccally and sublingually.
[00121] Regardless of the selected route of administration, the compounds of the present invention, which can be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated in pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.
[00122] The actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention can be varied in order to obtain an amount of the active ingredient that is effective to obtain the desired therapeutic response for a particular patient, composition and mode of administration , without being toxic to the patient.
[00123] The selected dosage level will depend on a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof of routine administration, time of administration, rate excretion or metabolism of the particular compound being employed, rate and extent of absorption, duration of treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, age, sex, weight, condition, general health and past medical history of the patient being treated, and as factors well known in medical techniques.
[00124] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may initiate doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than those required in order to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is obtained.
In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the minimum effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention to a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day.
[00126] If desired, the effective daily dose of active compound may be administered as two, three, four, five, six or more subdoses administered separately at appropriate intervals throughout the day, in unit dosage forms, optionally, in unit dosage forms. The preferred dosage is one administration per day.
[00127] Although it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
The compounds according to the invention may be formulated for administration in any convenient manner for use in human or veterinary medicine, by analogy with other pharmaceutical products.
[00129] In another aspect, the present invention provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the object compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or thinners. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, purgatives (solutions or sus' aqueous or non-aqueous pensions), tablets, cakes, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin, lungs, or mucous membranes; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or (8) nasally.
[00130] The term "treatment" is intended to also encompass prophylaxis, therapy and cure.
The patient receiving this treatment is any animal in need thereof, including primates, in particular humans, and other mammals such as horses, cattle, swine and sheep; and poultry and pets in general.
The compound of the invention can be administered as is or in admixtures with pharmaceutically acceptable carriers and may also be administered in conjunction with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Conjunctive therapy, therefore, includes sequential, simultaneous, and separate administration of the active compound in such a way that the therapeutic effects of the first administered one do not entirely disappear when the subsequent one is administered.
[00133] Microemulsification technology can improve the bioavailability of some lipophilic (water-insoluble) pharmaceutical agents. Examples include Trimetrine (Dordunoo, SK, et al., Drug De-velopment and Industrial Pharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen, PC, et al., J Pharm Sci 80(7), 712-714, 1991). Among other things, microemulsification provides enhanced bioavailability by preferentially directing absorption into the circulatory system, which thereby bypasses the liver, and prevents the destruction of compounds in the hepatobiliary circulation.
[00134] Although all suitable amphiphilic vehicles are contemplated, the currently preferred vehicles are generally those which have been Generally-Recognized-As-Safe (GRAS), and which can either solubilize the compound of the present invention or microemulsify them into a later stage when the solution comes into contact with a complex water phase (such as that found in the human gastrointestinal tract). Usually, amphiphilic ingredients that meet these requirements have HLB (hydrophilic to lipophilic balance) values of 2 to 20, and their structures contain straight-chain aliphatic radicals in the range of C-6 to C-20. Examples are glycerides of polyethylene glycolized fat and polyethylene glycols.
[00135] Commercially available amphiphilic vehicles are particularly contemplated, including Gelucire-series, Labrafil, Labrasol, or Lauroglycol (all manufactured and distributed by Gattefosse Corporation, Saint Priest, France), PEG-mono-oleate, PEG-di -oleate, PEG-mono-laurate and di-laurate, Lecithin, Polysorbate 80, etc. (produced and distributed by several companies in the United States, America and all over the world).
[00136] Hydrophilic polymers suitable for use in the present invention that are readily soluble in water, can be covalently linked to a vesicular-forming lipid, and that are tolerated in vivo without toxic effects (i.e., they are biocompatible). Suitable polymers include polyethylene glycol (PEG), polylactic (also called polylactide), polyglycolic acid (also called polyglycolide), a polylactic-polyglycolic acid copolymer, and polyvinyl alcohol. Preferred polymers are those having a molecular weight from about 100 or 120 Daltons to about 5,000 or 10,000 Daltons, and more preferably from about 300 Daltons to about 5,000 Daltons. In a particularly preferred embodiment, the polymer is polyethylene glycol having a molecular weight of about 100 to about 5,000 Daltons, and more preferably having a molecular weight of about 300 to about 5,000 Daltons. In a particularly preferred embodiment, the polymer is 750 Dalton polyethylene glycol (PEG(750)). Polymers can also be defined by the number of monomers in them; a preferred embodiment of the present invention utilizes polymers of at least about three monomers, such PEG polymers consisting of three monomers (approximately 150 Daltons).
Other hydrophilic polymers which may be suitable for use in the present invention include polyvinylpyrrolidone, polymethoxazoline, polyethylaxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and cellulose derivatives such as hydroxymethylcellulose or hydroxyethylcellulose.
[00138] In certain embodiments, a formulation of the present invention comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, acrylic and methacrylic ester polymers, polyvinyl polymers, polyglycolides, polysilaxanes, polyurethanes and co -polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, lactic acid and glycolic acid polymers, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone) , polysaccharides, protein, polyhaluronic acids, polycyanoacrylates, and combinations, mixtures, or copolymers thereof.
[00139] Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8 glucose units, designated by the Greek letter .alpha., .beta. or .gamma., respectively. Cyclodextrins with a little more than six glucose units are not known to exist. Glucose units are linked by alpha-1,4-glycosidic bonds. As a consequence of the chair conformation of sugar units, all secondary hydroxyl groups (at C-2, C-3) are located on one side of the ring, although all primary hydroxyl groups at C¬6 are located on the other side. As a result, the outer faces are hydrophilic, making the cyclodextrins water soluble. In contrast, the cavities of cyclodextrins are hydrophobic, as they are aligned by the hydrogen of C-3 and C-5 atoms, and by oxygens such as ether. These matrices allow complexation with a variety of relatively hydrophobic compounds, including, for example, steroidal compounds such as 17.beta.-estradiol (see, for example, van Uden et al. Plant Cell Tiss. Org. Cult 38:1-3-113 (1994)). Complexation occurs through Van der Waals interactions and hydrogen bond formation. For an overview of the chemistry of cyclodextrins, see, Wenz, Agnew. Chem. Int. Ed. Engl., 33:803-822 (1994).
[00140] The physicochemical properties of cyclodextrin derivatives strongly depend on the species and the degree of substitution. For example, its solubility in water ranges from insoluble (eg, triacetyl-beta-cyclodextrin) to 147% soluble (weight/volume) (G-2-beta-cyclodextrin). Furthermore, they are soluble in most organic solvents. The properties of cyclodextrins allow control over the solubility of various formulation components by increasing or decreasing their solubility.
[00141] Numerous cyclodextrins and methods for their preparation have been described. For example, Parmeter (I), et al. (United States Patent No. 3,453,259) and Gramera, et al. (United States Patent No. 3,459,731) described electroneutral cyclodextrins. Other derivatives include cyclodextrins with cationic properties [Parmeter (II), US Patent No. 3,453,257], insoluble cross-linked cyclodextrins (Solms, US Patent No. 3,420,788), and cyclodextrins with anionic properties [Parmeter (III), United States Patent No. 3,426,011]. Among cyclodextrin derivatives with anionic properties, carboxylic acids, phosphorus acids, phosphinous acids, phosphonic acids, phosphoric acids, thiophosphonic acids, thiosulfinic acids, and sulfonic acids were attached to cyclodextri- in origin [see, Parmeter (III), supra ]. Furthermore, sulfoalkyl ether cyclodextrin derivatives have been described by Stella, et al. (United States Patent No. 5,134,127).
[00142] Liposomes consist of at least one lipid bilayer membrane surrounding an internal aqueous compartment. Liposomes can be characterized by membrane type and size. Small unilamellar vesicles (SUVs) have a simple membrane and typically range between 0.02 and 0.05 µM in diameter; large unimellar vesicles (LUVS) are typically larger than 0.05 µm oligolamellar vesicles and large multilamellar vesicles have multiple membrane layers, usually concentric and are typically larger than 0.1 µm. Liposomes with several non-concentric membranes, that is, several smaller vesicles contained within a larger vesicle, are called multivesicle vesicles.
One aspect of the present invention relates to formulations comprising liposomes containing a compound of the present invention, wherein the liposome membrane is formulated to provide a liposome with increased transport capacity. Alternatively or in addition, the compound of the present invention may be contained within, or absorbed into, the liposome bilayer of the liposome. The compound of the present invention can be aggregated with a lipid surfactant and transported within the liposome internal space; in these cases, the liposome membrane is formulated to resist the disruptive effects of the active-surfactant aggregate.
[00144] According to an embodiment of the present invention, the lipid bilayer of a liposome contains lipids derivatized with polyethylene glycol (PEG), such that the PEG chains extend from the inner surface of the lipid bilayer into the inner space encap¬ sullated by the liposome, and extended from outside the lipid bilayer into the surrounding environment.
[00145] Active agents contained within the liposomes of the present invention are in solubilized form. Aggregates of surfactant and active agent (such as emulsions or micelles containing the active agent of interest) can be trapped within the interior space of liposomes in accordance with the present invention. A surfactant acts to disperse and solubilize the active agent, and can be selected from any suitable aliphatic, cycloaliphatic or aromatic surfactant, including but not limited to biocompatible lysophosphatylcholines (LPCs) of varying chain lengths (eg from about C.sub.14 to about C.sub.20). Polymer-derived lipids such as PEG lipids can also be used for micelle formation, as they act to inhibit micelle/mebrane fusion, and since the addition of a polymer to the surfactant molecules lowers the CMC of the surfactant and helps in formation of micelles. Surfactants and micelle formation aids are preferred. Surfactants with CMCs in the micromolar range are preferred; high CMC surfactants can be used to prepare micelles trapped within the liposomes of the present invention, however, micelle surfactant monomers can affect the stability of the liposome bilayer and may be a factor in designating a liposome of a stability of ¬ wanted.
[00146] Liposomes in accordance with the present invention can be prepared by any of a variety of techniques that are known in the art. See, for example, United States Patent No. 4,235,871; Published PCT applications WO 96/14057; New RRC, Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33 to 104; Lasic DD, Liposomes from physics to applications, Elsevier Science Publishers BV, Amsterdam, 1993.
[00147] For example, liposomes of the present invention can be prepared by diffusing a lipid derived with a hydrophilic polymer into preformed liposomes, such as by exposing preformed liposomes to micelles composed of lipid-grafted polymers , at lipid concentrations corresponding to the final mole percent lipid derivative that is desired in the liposome. Liposomes containing a hydrophilic polymer can also be formed by homogenization, lipid field hydration, or extrusion techniques, as are known in the art.
[00148] In one aspect of the present invention, liposomes are prepared to have substantially homogenized sizes within a selected size range. An effective sizing method involves extruding an aqueous suspension of liposomes through a series of polycarbonate membranes having a selected uniform pore size; the pore size of the membrane will roughly correspond with larger sizes of liposomes produced by extrusion through that membrane. See, for example, United States Patent No. 4,37,323 (April 12, 1988).
[00149] The release characteristics of a formulation of the present invention depend on the encapsulating material, the concentration of the encapsulated drug, and the presence of release modifiers, for example, the release can be manipulated to be dependent on pH, for example, using a pH-sensitive coating that releases only at a low pH, such as in the stomach, or as in the intestine. An enteric coating can be used to prevent release from occurring even after passing through the stomach. Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to achieve an initial release in the stomach, followed by a delayed release in the intestine. Release can also be manipulated by including salts or pore-forming agents, which can increase water uptake or drug release by capsule diffusion. Excipients that modify drug solubility can also be used to control the rate of release. Agents that enhance matrix degradation or release from the matrix may also be incorporated. They can be added to the drug, added as a separate phase (ie, as particulates), or they can be co-dissolved in the polymer phase depending on the compound. In all cases, the amount must be between 0.1 and thirty percent (weight/weight of polymer). Types of degradation enhancers include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, sodium carbonate. calcium, zinc carbonate, zinc hydroxide, and organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine, and triethanolamine and surfactants such as Tween® and Pluronic®. Pore-forming agents that add microstructure to the matrices (ie, water-soluble compounds such as inorganic salts and sugars) are added as particulates. The range should be between one and thirty percent (weight/polymer weight).
[00150] The uptake can also be manipulated by changing the residence time of particulates in the intestine. This can be achieved, for example, by coating the particulate with, or selecting as the encapsulating material, a mucosal adhesive polymer. Examples include most polymers with free carboxyl groups, such as chitosan, celluloses, and especially polyacrylates (as used herein, polyacrylates refers to polymers including acrylate groups and modified acrylate groups such as cyanoacrylates and methacrylates). Pharmaceutical Compositions
The invention especially relates to the use of a compound of Formula I (or a pharmaceutical composition comprising a compound of Formula I) in the treatment of one or more diseases mentioned herein; where response to treatment is beneficial as demonstrated, for example, by partial or complete removal of one or more symptoms of the disease until completion of cure or remission.
[00152] Given the central role of ER-α in the development and progression of breast cancer, the compounds described here are useful in the treatment of breast cancer, alone or in combination with other agents used to treat breast cancer , including but not limited to aromatase inhibitors, anthracillins, platinums, nitrogen mustard alkylating agents, and taxanes. Agents used to treat breast cancer include, but are not limited to, paclita¬xel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vicitanorel Ixabepilan.
[00153] Furthermore, the compounds of the invention are useful in the treatment of breast cancer, alone or in combination with other agents that modulate other series of critical reactions in breast cancer including, but not limited to those that target IGF1R, EGFR , erB-B2 and the PI3K/AKT/mTOR axis, Rb axis including CDK4/6 and D-cyclins, HSP90, PARP and/or histone deacetylases.
[00154] A compound of the invention may therefore also be used in combination with the following:
[00155] Vascular Endothelial Growth Factor (VEGF) Receptor Inhibitors: Bevacizumab (sold under the trade name Avastin® by Genentech/Roche), axitinib, (N-methyl-2-[[3-[(E)-2 -pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No. WO 01/002369), Brivanib Alaninate ((S)-(( R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan -2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4 -pyridinylmethyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No. WO 02/066470), pasireotide (also known as SOM230, and described in PCT Publication No. WO 02/010192), sorafenib (sold under the trade name Nexavar®);
[00156] HER2 receptor inhibitors: Trastuzumab (sold under the trade name Herceptin® by Genentech/Roche), neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4- [(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described in PCT Publication No. WO 05/ 028443), lapatinib or lapatinib ditosylate (sold under the trade name Tykerb® by GlaxoSmithKline);
[00157] CD20 Antibodies: Rituximab (sold under the tradenames Riuxan® and MabThera® by Genentech/Roche), tositumomab (sold under the tradenames Bexxar® by GlaxoSmith¬Kline), ofatumumab (sold under the tradename Arzerra ® by GlaxoSmithKline);
[00158] Tyrosine kinase inhibitors: Erlotinib hydrochloride (sold under the trade name Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]- N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib malate (sold under the trade name Sutent® by Pfizer), bosutinib (4-[( 2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in Patent No. 6,780,996), dasatinib (sold under the tradename Sprycel® by Bristol-Myers Squibb), armala (also known as pazopanib, sold under the tradename Votrient® by GlaxoSmithKline), imatinib, and mesylate imatinib (sold under the trade names Gilvec® and Gleevec® by Novartis);
[00159] Bcr/Abl kinase inhibitors: nilatinib hydrochloride (sold under the trade name Tasigna® by Novartis);
[00160] DNA Synthesis Inhibitors: Capecitabine (sold under the trade name Xeloda® by Roche), gemcitabine hydrochloride (sold under the trade name Gemzar® by Eli Lilly and Company), Nelarabine ((2R,3S) ,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol, sold under the trade names Arranon® and Atriance® by GlaxoSmithKline);
Antineoplastic Agents: oxaliplatin (sold under the tradename Eloxatin® by Sanofi-Aventis and described in U.S. Patent No. 4,169,846);
[00162] Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (sold under the trade name Iressa®), N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3 ''S'')-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the trade name Tovok® by Boehringer Ingelheim), cetuximab (sold under the trade name Erbitux® by Bristol-Myers Squibb), panitumumab (sold under the trade name Vectibix® by Amgen);
[00163] HER dimerization inhibitors: Pertuzumab (sold under the tradename Omnitarg®, by Genentech);
[00164] Human Granulocyte Colony Stimulating Factor (G-CSF) Modulators: Filgrastim (sold under the trade name Neupogen® by Amgen);
[00165] Immunomodulators: Afutuzumab (available from Roche®), pegfilgrastim (sold under the tradename Neulasta® by Amgen), lenalidomide (also known as CC-5013, sold under the tradename Revlimid®), thalidomide (sold under the tradename commercial Thalomid®);
[00166] CD40 Inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc);
Pro-apoptotic receptor antagonists (PARAs): Dulanermin (also known as AMG-951, available from Amgen/Genentech);
Hedgehog Antagonists: 2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)-benzamide (also known as GDC-0449, and described in PCT Publication no. °WO 06/028958);
PI3K Inhibitors: 4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4 -yl]morpholine  (also known as GDC 0941 and described in PC T Publication Nos. WO 09/036082 and WO 09/055730), 2-Methyl-2-[4-[3-methyl-2-oxo-8 -(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in PCT Publication no. WO 06/122806));
[00170] Phospholipase Inhibitors: Anagrelide (sold under the trade name Agrylin®);
[00171] Inhibitors of BCL-2: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N- [[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386);
Mitogen-Activated Protein Kinase (MEK) Kinase Inhibitors: XL-518 (Cas No. 1029872-29-4, available from ACC Corp.);
Aromatase Inhibitors: Exemestane (sold under the tradename Aromasin® by Pfizer), letrozole (sold under the tradename Femara® by Novartis), anastrozole (sold under the tradename Arimidex®);
Topoisomerase I Inhibitors: Irinotecan (sold under the tradename Camptosar® by Pfizer), topotecan hydrochloride (sold under the tradename Hycamtin® by GlaxoSmithKline);
Topoisomerase II Inhibitors: etoposide (also known as VP-16 and etoposide phosphate, sold under the trade names Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradenames Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradenames trade name Vumon®);
[00176] mTOR Inhibitors: Tensirolimus (sold under the trade name Torisel® by Pfizer), ridapholimus (formally known as depherolimus, (1R,2R,4S)-4-[(2R)-2 [(1R) ,9S,12S,15R,16E,18R,19R,21R, 23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21, 23,29,35-hexamethyl- 2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30,3,1,04.9] hexatria-count-16,24,26, 28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03/064383), everolimus (sold under the trade name Afinitor® by Novartis);
[00177] Osteoclastic Bone Resorption Inhibitors: 1-Hydroxy-2-imidazol-1-yl-phosphonoethyl)phosphonic acid monohydrate (sold under the trade name Zometa® by Novartis);
CD33 Antibody Drug Conjugates: gentuzumab ozogamycin (sold under the tradename Milatarg® by Pfizer/Wyeth);
[00179] CD22 Antibody Drug Conjugates: inotuzumab ozogamycin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);
[00180] CD20 Antibody Drug Conjugates: ibritumomab tiuxetan (sold under the trade name Zevalin®);
[00181] Somatostatin analogues: octreotide (also known as octreotide acetate, sold under the trade names Sandostatin® and Sandostatin LAR®);
Synthetic interleukin-11 (IL-11): oprelvecin (sold under the tradename Neumega® by Pfizer/Wyeth);
[00183] Synthetic Erythropoietin: Darbepoetin alfa (sold under the trade name Aranesp® by Amgen);
[00184] Nuclear Factor K B (RANK) Activator Receptor Inhibitors: Denosumab (sold under the trade name Prolia® by Amgen);
Thrombopoietin mimetic peptibodies: Romiplostim (sold under the trade name Nplate® by Amgen;
[00186] Cell Growth Stimulators: Palifermin (sold under the tradename Kepivance® by Amgen);
Anti-Insulin-like Growth Factor 1 Receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751,871, available from ACC Corp), robatumumab (CAS No. 934235-44-6) ;
[00188] Anti-CS1 Antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3);
[00189] CD52 Antibodies: Alentuzumab (sold under the trade name Campath®);
[00190] CTLA-4 inhibitors: Tremelimumab (IgG2 monoclonal antibody available from Pfizer, formally known as ticilimumab, CP-675,206), ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9);
Histone Deacetylase (HDI) Inhibitors: Voninostate (sold under the trade name Zolinza® by Merck);
[00192] Alkylating agents: Temozolomide (sold under the trade names Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the trade name Cosmegen®), melphalan (also known as known as L-PAM, L-sarcolysine, and phenylalanine mustard, sold under the trade name Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the trade name Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Mileran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU , sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), cyclophosphamide (sold under the tradenames commercials Cytoxan® and Neosar®), dacarbazine (also know acidified as DTIC, DIC, and imidazole carboxamide, sold under the tradename DTIC-Dome®), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename Hexalen®), ifosfamide (sold under the tradename commercial Ifex®), procarbazine (sold under the trade name Matulane®), mechlorethamine (also known as nitrogen mustard, mustin, and mechloroethamine hydrochloride, sold under the trade name Mustargen®), streptozocin (sold under the trade name Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, sold under the trade name Thioplex®;
[00193] Biological Response Modifiers: bacilla calmette-guerin (sold under the trade names theraCys® and TICE® BCG), denileukin diftitox (sold under the trade name Ontak®);
[00194] Antitumor Antibiotics: doxorubicin (sold under the trade names Adriamycin® and Rubex®), bleomycin (sold under the trade name lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold It is sold under the tradename Cerubidine®), liposomal daunorubicin (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename DaunoXome®). the trade name Ellence™), idarubicin (sold under the trade names Idamycin®, Idamycin PFS®), mitomycin C (sold under the trade name Mutamycin®);
[00195] Anti-Microtubule Agents: Estramustine (sold under the trade name Emcyl®);
[00196] Cathepsin K Inhibitors: Odanacatib (also known as MK-0822, N-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4 '-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide, available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication No. WO 03/075836);
[00197] Epothilan B Analogs: Ixabepilan (sold under the tradename Lxempra® by Bristol-Myers Squibb);
[00198] Heat Shock Protein (HSP) Inhibitors: Tanespimycin (17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in U.S. Patent No. 4,261 .989);
[00199] TpoR Agonists: Eltrombopag (sold under the tradenames Promacta® and Revolade® by GlaxoSmithKline);
[00200] Antimitotic Agents: Docetaxel (sold under the trade name Taxotere® by Sanofi-Aventis);
[00201] Adrenal Steroid Inhibitors: aminoglutethimide (sold under the trade name Cytadren®);
[00202] Antiandrogens: Nilutamide (sold under the trade names Nilandron® and Anandron®), bicalutamide (sold under the trade name Casodex®), flutamide (sold under the trade name Fulexin™);
[00203] Androgens: Fluoxymesterone (sold under the trade name Halotestin®);
Proteasome Inhibitors: Bortezomib (sold under the trade name Velcade®);
[00205] CDK1 Inhibitors: Alvocidib (also known as flovopyrdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl -4-piperidinyl]-4-chromenone, and described in U.S. Patent No. 5,621,02);
Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (sold under the trade names Viadure® by Bayer AG, Eligard® by Sanofi-Aventis and Lupron® by Abbott Lab);
[00207] Taxane antineoplastic agents: Cabazitaxel (1-hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxitax-11 -ene-2α,4,13α-triyl-4-acetate- 2-benzoate- 13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate), larotaxel ((2α,3^4α,5β,7α,10β,13α)- 4,W-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-9-oxo-5 ,20-epoxy-7,19-cyclotax-11-en-2-yl benzoate);
5HT1a receptor agonists: Xaliproden (also known as SR57746, 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6- tetrahydropyridine, and described in U.S. Patent No. 5,266,573);
HPC Vaccines: Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck;
[00210] Iron Chelating Agents: Deferasinox (sold under the trade name Exjade® by Novartis);
[00211] Antimetabolites: Claribin (2-chlorodeoxyadenosine, sold under the tradename leustatin®), 5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed ( sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), liposomal cytarabine (also known as Liposomal Ara-C, sold under the tradename Cytosar-U® trade name Depo-Cyt™), decitabine (sold under the trade name Dacogen®), hydroxyurea (sold under the trade names Hydrea®, Droxia™ and Milacel™), fludarabine (sold under the trade name Fludara®) , floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename Leustatin™), methotrexate (also known as amethopterin, sodium methotrexate ( MTX), sold under the trade names Rheumatrex® and Trexall™), pentostatin (sold under the trade name l Nipent®);
[00212] Bisphosphonates: Pamidronate (sold under the trade name Aredia®), zoledronic acid (sold under the trade name Zometa®);
[00213] Demethylating agents: 5-azacytidine (sold under the trade name Vidaza®), decitabine (sold under the trade name Dacogen®);
[00214] Plant Alkaloids: Protein-bound paclitaxel (sold under the trade name Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the trade names Alkaban-AQ® and Velban®), vincristine ( also known as vincristine sulfate, LCR, and VCR, sold under the trade names Oncovin® and Vincasar Pfs®), vinorelbine (sold under the tradename Navelbine®), paclitaxel (sold under the tradenames Taxol and Onxal™);
[00215] Retinoids: Alitretinoin (sold under the trade name Panretin®), tretinoin (all trans retinoic acid, also known as ATRA, sold under the trade name Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the tradename Targretin®);
[00216] Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the trade names Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort ®), dexamethazone ((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl - 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]fenantren-3-one), prednisolone (sold under the trade names Delta-Cortel ®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the trade names Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (also known as 6-Methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, sold under the trade names Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®);
[00217] Cytokines: interleukin-2 (also known as aldes-leucine and IL-2, sold under the trade name Proleukin®), interleukin-11 (also known as oprevelcin, sold under the trade name Neumega®) , alpha interferon alpha (also known as IFN-alpha, sold under the trade names Intron® A, and Roferon-A®);
[00218] Luteinizing Hormone Releasing Hormone (LHRH) Agonists: Goserelin (sold under the trade name Zoladex®);
[00219] Progesterones: megestrol (also known as megestrol acetate, sold under the trade name Megace®);
[00220] Heterogeneous cytotoxic agents: arsenic trioxide (sold under the trade name Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the trade names Elspar® and Kidrolase®) ;
[00221] A compound of Formula (I) may also be used in combination with the following adjuvant therapies:
[00222] Anti-nausea drugs: NK-1 receptor antagonists: Casopitant (sold under the trade names Rezonic® and Zunrisa® by GlaxoSmithKline); and
[00223] Cytoprotective agents: Amifostine (sold under the trade name Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).
[00224] None of the quotations of references made in the present invention should be understood as an admission that the cited references are of prior art, which may negatively affect the patentability of the present invention. Processes for Preparing the Compounds of the Invention
The present invention also includes processes for the preparation of compounds of the invention. In the reactions described, it may be necessary to protect the reactive functional groups, for example, hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, for their unwanted participation in the reactions. Conventional protection groups can be used according to practice, eg see T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.
[00226] The compounds of Formula I, shown here where R8a is hydrogen, can be prepared by proceeding as in General Reaction Scheme I: General Reaction Scheme I:

[00227] wherein R1, R5 and R8b are as defined under Formula I in the Summary of the Invention. A compound of Formula I can be prepared by reacting a compound of Formula I (where R3 has a double bond as shown above) with a suitable reducing agent (such as H2, and the like) and a suitable catalyst (such as such as Palladium on carbon (Pd/C), or the like), under a suitable pressure (such as about 1 atm to about 5 atm). The reaction takes place at about 0 °C to 50 °C and can take from about 1 to about 24 hours to complete.
[00228] The compounds of Formula I, shown here R8a is hydrogen and R3 has a double bond, can be prepared by proceeding with the following General Reaction Scheme II: General Reaction Scheme II:

[00229] wherein R1, R5 and R8b are as defined under Formula I in the Summary of the Invention and Q is a leaving group such as a halogen or triflate. A compound of Formula I can be prepared by reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a suitable catalyst (such as Palladium, or the like), a suitable base (such as potassium carbonate , and the like), and a suitable acid (such as pivalic acid, or the like). The reaction takes place at about 120°C-200°C and can take from about 1 to about 18 hours to complete.
[00230] Detailed examples of the synthesis of compounds of Formula I can be found in the examples, infra. Additional Processes for Preparing the Compounds of the Invention
A compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
[00232] The compounds of Formula I can also be modified by attaching appropriate functionalities to enhance selective properties. Modifications of these species are known in the art and include those that increase penetration into a particular biological system (eg, blood, lymphatic system, central nervous system, testis), increase bioavailability, increase solubility to allow parenteral administration (eg injection, infusion), alter metabolism and/or alter secretion rate. Examples of such modifications include, but are not limited to, esterification with, for example, polyethylene glycols, derivatization with pivaloyloxy or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings and heteroatom substitution on aromatic rings. Whenever compounds of Formula I, and/or N-oxides, tautomers and/or salts (preferably pharmaceutically acceptable) thereof are mentioned, this comprises such modified Formulas, although preferably molecules of Formula I, their N-oxides, their tautomers and/or their salts are intended.
Alternatively, the salt forms of the compounds of the invention may be prepared using salts of the starting materials or intermediates. In view of the intimate relationship between the novel compounds of Formula I in free form and those in the form of their salts, including those salts which can be used as intermediates, for example, in the purification or identification of the novel compounds, any reference to the compounds or a compound of Formula I hereinafter and hereinafter is to be understood as referring to the compound in free form and/or also to one or more salts thereof, as appropriate and convenient, as well as one or more solvates, by example, hydrates.
Salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, of compounds of Formula I with a basic nitrogen atom, especially pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as acid like hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example, acetic acid, proionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, malonic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, acid methylmaleic, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane acid -1,2-disulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2- or 3-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid o, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propylsulfamic acid, or other organic protonic acids such as ascorbic acid.
[00235] For isolation or purification purposes, it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
[00236] The free acid or free base forms of the compounds of the invention can be prepared from the base addition salt or acid addition salt of, respectively, for example a compound of the invention in an addition salt form acid can be converted to the corresponding free base by treating with a suitable base (eg, ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (eg hydrochloric acid, etc.).
Compounds of the invention in unoxidized form can be prepared from N-oxides of compounds of the invention by treating with a reducing agent (eg sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, borohydride, sodium hydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.
[00238] Prodrug derivatives of the compounds of the invention can be prepared by methods known to those skilled in the art (eg, for further details see, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Volume 4, page 1985; Ferriz, JM et al., Current Pharmaceutical Design, 2010, 16, 2033-2052). Examples of prodrug derivatives of compounds of the invention may be:

[00239] Derivatives of the compounds of the invention can be made by methods known to those skilled in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.
The compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (eg hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
The compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers . Although resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (eg, crystalline diastereomeric salts). Diastereomers have distinct physical properties (eg melting points, solubilities, reactivity, etc.) and can be easily separated by taking advantage of these dissimilarities. Diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical method that may not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from your racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons , Inc., 1981.
[00242] In summary, the compounds of Formula I can be made by process A, which involves: (a) those of general reaction schemes I and II; and (b) optionally converting a compound of the invention into a pharmaceutically acceptable salt; (c) optionally converting a salt form of a compound of the invention to a non-salt form; (d) optionally converting an unoxidized form of a compound of the invention to a pharmaceutically acceptable N-oxide; (e) optionally converting an N-oxide form of a compound of the invention to its unoxidized form; (f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers; (g) optionally converting a non-derivative compound of the invention into a pharmaceutically acceptable prodrug derivative; and (h) optionally converting a prodrug derivative of a compound of the invention to its underivatized form.
[00243] As the production of the starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art in the art or as described in the examples hereinafter.
[00244] One of skill in the art will appreciate that the above transformations are only representative of methods for preparing the compounds of the present invention, and that other well-known methods can similarly be used. Examples
[00245] The following examples and intermediates serve to illustrate the invention without limiting its scope.
[00246] Some abbreviations used in the examples are as follows: aq. (aqueous); br (broad); °C (degrees Celsius); δ NMR chemical shift in ppm down-stream of tetramethylsilane; d (double); DCE (1,2-dichloroethane; DCM (dichloromethane); DIEA (N,N-diisopropylethylamine); DIBAL-H (diisobutylaluminum hydride); DMA (dimethyl-acetamide); DME (dimethoxyethane); DMF (N ,N-dimethylformamide); DMSO (dimethylsulfoxide); Et (ethyl); EtOAc (ethyl acetate); g (gram); h (hour); HATU (O-(7-azabenzotriazol-1-yl) hexafluorophosphate -N, N, N', N'- tetramethyluronium); HRMS (high resolution mass spectrometry); i-Pr (isopropyl); L (liter); LAH (lithium aluminum hydride); LC/MS (cro - liquid chromatography-mass spectrometry); M (molarity); m (multiplet); Me (methyl); mg (milligram); MHz (megahertz); min (minute); mL (milliliter); μL (microliter) ; mmol (millimole); N (normal); NBS (N-bromosuccinimide); n-Bu (normal butyl); n-BuLi (n-butyllithium); NMM (N-methylmorpholine); NMR (nuclear magnetic resonance); Ph (phenyl); pH (-log10H+ concentration); ppm (parts per million); q (quartet); s (singlet); sat. (saturated); t (triplet); t-Bu (tert-butyl); Tf (trifluorometa nosulfonyl); TFA (trifluoroacetic acid); Ts (p-toluenesulfonyl); TsOH (p-toluenesulfonic acid); TBS (tert-butyldimethylsilyl); TEA (triethylamine); THF (tetrahydrofuran); and TMS (trimethylsilyl).
[00247] All intermediates required for the preparation of compounds of Formula I can be prepared as described in scheme 1. Employing intermediates H, K, L, O, P, R, T, U, X, and Z provided the synthesis of compounds of Formula I using the transformations described in scheme 2. On occasion examples may be converted to additional examples as described in the experimental section. Reaction scheme I
Reaction scheme 2
Intermediates A 2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene (compound 1)

[00248] To a 5 ml microwave vial was added a solution of 6-methoxybenzo[b]thiophene (400 mg, 2.44 mmol) in anhydrous DMA (3 ml) followed by 1-bromo-4-fluorobenzene (448 mg, 2.56 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl][2 -(2-aminoethyl)phenyl]palladium(II) (BrettPhos paladacycle 1st generation, 97 mg, 0.12 mmol), trimethylacetic acid (746 mg, 7.31 mmol) and potassium carbonate (1.01 g, 7, 31 mmol). The microwave vial was sealed, purged with nitrogen and subjected to microwave irradiation at 150 °C for 2 hours. On completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were then washed with brine, dried over aqueous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by 2x trituration with heptane and the remaining triturate (containing some product) was concentrated and purified by column chromatography (SiO 2 , 0 to 30% EtOAc/Heptane) to provide 2- (4-fluorophenyl)-6-methoxybenzo[b]thiophene (340 mg, 1.32 mmol, 54% yield). 1H NMR (400 MHz, (CD3)2SO) δppm = 3.79-3.93 (m, 3H), 7.01 (dd, J = 8.59, 2.53Hz, 1H), 7 .24-7.42 (m, 2H), 7.56 (d, J = 2.53Hz, 1H), 7.67-7.86 (m, 4H). LC/MS (m/z, MH+): 258.8. 2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophene (compound 2)

[00249] To a 20 mL microwave vial, 6-methoxybenzo[b]thiophene (1 g, 6.09 mmol), 2-bromo-5-fluorotoluene (0.808 mL, 6.39 mmol), BrettPhos paladacyclo (1st generation) (0.243 g, 0.304 mmol), trimethylacetic acid (1.866 g, 18.27 mmol), and K2CO3 (2.52 g, 18.27 mmol) were suspended in DMA (10 mL). The reaction was heated for 90 minutes at 150 °C under microwave radiation. The reaction mixture was diluted with DCM and water. The organic layer was collected (phase separator) and concentrated to provide the crude product. The crude material was concentrated onto silica gel and purified by column chromatography (SiO 2 , 100% heptanes) to give 2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophene (730 mg, 2.68 mmol, 44% yield) as a white solid. 1H NMR (400 MHz, CDCl 3 ) δ ppm = 7.69 (d, J = 9.09 Hz, 1H), 7.43 (dd, J = 6.06, 8.59 Hz, 1H), 7.35 (d, J = 2.53 Hz, 1H), 7.14 (s, 1H), 7.00 - 7.10 (m, 2H), 6.90 - 7.00 (m, 1H), 3. 92 (s, 3H), 2.47 (s, 3H).
[00250] The following compounds were prepared in an analogous model using the appropriate bromide: Structure Name Physical data
Intermediates B 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (compound 7)

To a 500 mL round base flask containing 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (22 g, 81 mmol) in THF (250 mL) at 0 °C was added NBS ( 15 g, 84 mmol). The reaction mixture was stirred at 0°C for 60 minutes and then allowed to warm to room temperature and stirred for a further 2 hours. On completion, the reaction mixture was concentrated to 50% volume and quenched with saturated aqueous sodium thiosulfate solution. The resulting solution was extracted with diethyl ether 3x and the combined organic solvent was dried over aqueous MgSO4, filtered and concentrated in vacuo to give 3-bromo-6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene ( 27.5 g, 79 mmol, 97% yield). 1H NMR (400 MHz, CDCl3) δ ppm = 7.63 (d, J = 9.1 Hz, 1H), 7.55-7.61 (m, 2H), 7.19 (d, J = 2.5Hz, 1H), 6.96¬7.02 (m, 1H), 6.87-6.95 (m, 2H), 3.81 (s, 3H), 3.79 (s, 3H).
[00252] The following compounds were prepared by bromination of the corresponding starting materials as described above:
3-bromo-7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 3-bromo-5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b] thiophene (compounds 13 and 14)

[00253] To a round base flask, a separate mixture of 7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 5,7-difluoro-6-methoxy-2-(4- methoxyphenyl)benzo[b]thiophene (380 mg, 1.318 mmol) was dissolved in THF (10 mL) and the solution was cooled to 0°C. To the solution, NBS (237 mg, 1.331 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour then warmed to room temperature and stirred for a further 2 hours. The reaction mixture was concentrated to provide the raw product. The crude product was diluted with DCM and saturated Na2S2O3 (sodium thiosulfate). The organic layer was collected (phase separator) and concentrated. The reaction mixture was diluted with water and DCM. The organic phase was collected (phase separator) and concentrated to provide the crude product. The crude material was purified by column chromatography (SiO 2 , 0 to 5% heptanes/EtOAc) to give 3-bromo-7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (211 mg , 0.575 mmol, 43.6% yield) and 3-bromo-5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (125 mg, 0.324 mmol, 24.62 % of production). 3-bromo-7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene: 1H NMR (400 MHz, CDCl3) δ ppm = 7.56 - 7.66 (m, 2H), 7 .46 (dd, J = 1.01, 8.59 Hz, 1H), 7.11 (dd, J = 7.58, 8.59 Hz, 1H), 6.90 - 6.97 (m, 2H ), 3.92 (s, 3H), 3.79 (s, 3H). 3-bromo-5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene: 1H NMR (400 MHz, CDCl3) δ ppm = 7.53 - 7.68 (m, 2H) , 7.48 (d, J = 8.59 Hz, 1H), 7.15 - 7.27 (m, 1H), 7.07 (dt, J = 2.53, 8.59 Hz, 1H), 3.98 (s, 3H), 4.02 (s, 3H). Intermediates C 3-Bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (compound 15)

To a solution of 3-bromo-6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene (4 g, 11.45 mmol) in DCM (20.02 mL) at room temperature trifluoroacetic acid (20.02 ml) was added dropwise, the reaction turned from orange to dark brown in color. On addition, the resulting mixture was stirred at room temperature for 10 minutes and then hydrogen peroxide (30% aqueous wt.) (1.583 mL, 16.47 mmol) was added dropwise. After 90 minutes at room temperature the reaction mixture was quenched with sodium bisulfide (1.714 g, 16.47 mmol) (vigorous bubbling was observed) followed by 3.0 mL of water. The resulting suspension was stirred vigorously for 15 minutes and then concentrated in vacuo to remove DCM and most of the TFA. The residue was partitioned between DCM (40ml) and saturated aqueous NaHCO3 solution (40ml) and separated. The organic layer was collected (phase separator) and concentrated in vacuo to furnish the crude product, which was purified by column chromatography (SiO2, 1-40% EtOAc/Heptane) to furnish 3-bromo-6-1-oxide -methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (4.6 g, 10.08 mmol, 88% yield) as an orange solid. 1H NMR (400 MHz, CD3OD) δ ppm = 7.51-7.65 (m, 2H), 7.37-7.51 (m, 2H), 7.08 (dd, J = 2.27 , 8.34 Hz, 1H), 6.79-6.96 (m, 2H), 3.74 (s, 3H), 3.68 (s, 3H).
[00255] The following benzo[b]thiophene 1-oxides were prepared in an analogous model as described above:

Intermediates D 7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (compounds 24 and 25 )

[00256] To a 200 ml round base flask, 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (4.5 g, 16.7 mmol) was suspended in THF (60 ml) and the solution was cooled to -78 °C. To the cooled solution was added n-BuLi (2.5 M in hexanes, 11.65 mL, 29.1 mmol) dropwise. After 30 minutes the reaction mixture was warmed to 0°C and stirred for a further 1 hour causing the reaction mixture to go into solution and turn black. The reaction mixture was cooled to -78 °C and N-fluorobenzenesulfonimide (9.19 g, 29.1 mmol) was added causing the reaction mixture to turn light orange. After 20 minutes at -78 °C, the reaction mixture was allowed to gradually thank to room temperature over 1 hour. The reaction was quenched with MeOH and diluted with DCM and 1N NaOH. The organic phase was collected (phase separator) and concentrated to provide the crude product. The crude material was purified by column chromatography (SiO2, 100% Heptane). Fractions were concentrated to a white solid and triturated with cold MeOH. The precipitate was discarded and the filtrate was concentrated to give 7-fluoro-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene and 5,7-difluoro-6-methoxy-2-(4-methoxyphenyl)benzo [b]thiophene as an inseparable mixture (1.8g, ~35% yield). Intermediates E 2-Bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (compound 26)

To a solution of 2,3-dibromo-6-methoxybenzo[b]thiophene 1,1-dioxide (2.50 g, 7.06 mmol) in THF (100 mL) at room temperature was added 4-bromophenol (1.344 g, 7.77 mmol) and Cs2CO3 (6.90 g, 21.19 mmol). The reaction mixture turned green after ~1 minute of stirring. The mixture was stirred at room temperature for 18 hours, after which time the reaction was quenched with water and diluted with DCM. The organic layer was collected (phase separator) and concentrated to provide 2-bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (3.10 g, 6.95 mmol, 98% yield) as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δppm = 3.83 (s, 3H), 6.92-7.03 (m, 3H), 7.25-7.35 (m, 2H), 7 .39-7.50 (m, 2H). Intermediates F 3-(4-Bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (compound 27)
Step 1: To a solution of 2-bromo-3-(4-bromophenoxy)-6-methoxy-benzo[b]thiophene 1,1-dioxide (3.10 g, 6.95 mmol) in MeOH (10 mL) ) and DMSO (30 mL) was added NaBH4 (0.789 g, 20.85 mmol). The mixture was stirred at room temperature for 3 hours, after which time the reaction was quenched with water and diluted with DCM. The organic layer was collected (phase separator) and concentrated to provide 1,1- 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (2.47 g, 6.73 mmol, 97% production) as an off-white solid which was used without further purification. 1H NMR (400 MHz, CDCl 3 ) δ ppm = 3.85 (s, 3H), 5.38 (s, 1H), 7.02-7.08 (m, 3H), 7.22 (d , J = 2.53 Hz, 1H), 7.47¬7.60 (m, 3H). 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (compound 28)
Step 2: To a solution of 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (2.47 g, 6.73 mmol) in THF (90 mL) was added DIBAL -H (1.0 M in DCM, 33.6 mL, 33.6 mmol) in one portion. The mixture was heated to 75 °C for 2 hours, after which time the reaction was cooled to room temperature and quenched with EtO-Ac (32.9 mL, 336 mmol). The resulting solution was stirred for 10 minutes, before carefully adding 75 mL of water and potassium sodium tartrate (33.100 g, 117 mmol). The mixture was stirred vigorously for 10 minutes and diluted with 75 mL EtOAc. The organic layer was collected, dried over anhydrous MgSO4 and concentrated in vacuo to provide 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (1.9 g, 5.67 mmol, 84% yield ) as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm = 3.81 (s, 3H), 6.46 (s, 1H), 6.90 (d, J = 9.09Hz, 3H), 7. 16-7.22 (m, 1H), 7.31-7.40 (m, 2H), 7.46 (d, J = 9.09Hz, 1H). LC/MS (m/z, MH+): 336.8. Intermediates G (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 29)

[00258] To a microwave vial, 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (500 mg, 1.49 mmol), methyl acrylate (770 mg, 8.95 mmol), and Pd (PPh3)2Cl2 (157 mg, 0.22 mmol) were suspended in DMF (12 mL) and triethylamine (1.039 mL, 7.46 mmol). The reaction was heated for 60 minutes at 120 °C under microwave irradiation. The reaction mixture was diluted with DCM and water. The organic layer was collected (phase separator) and concentrated to obtain the crude product. The crude material was purified by column chromatography (SiO 2 , 1-20% EtOAc/Heptane) to give (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl ) acrylate (311 mg, 0.91 mmol, 61% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm = 1.46 (s, 3H), 3.73 (s, 3H), 6.28 (d, J = 16.17Hz, 1H), 6. 59 (s, 1H), 6.90 (dd, J = 8.59, 2.02 Hz, 1H), 7.00 (d, J = 8.59 Hz, 2H), 7.21 ( d, J=2.02Hz, 1H), 7.37-7.48 (m, 3H), 7.59 (d, J=16.17Hz, 1H). LC/MS (m/z, MH+): 341.1. (E) - tert -butyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 30)

[00259] To a microwave vial, 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (4 g, 11.93 mmol), tert-butyl acrylate (10.49 mL, 71.6 mmol), and Pd(PPh3)2Cl2 (1.256 g, 1.79 mmol) were suspended in DMF (12 mL) and triethylamine (8.32 mL, 59.7 mmol). The reaction was heated for 60 minutes at 120 °C under microwave irradiation. The reaction mixture was diluted with DCM and water. The organic layer was collected (phase separator) and concentrated to obtain the crude product. The crude material was purified by column chromatography (SiO 2 , 1x 20% EtOAc/Heptane) to give (E) 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate )-tert-butyl (3 g, 7.84 mmol, 66% yield) as a white solid. 1H NMR (CDCl3) δ ppm = 7.45-7.63 (m, 4H), 7.27-7.33 (m, 1H), 7.03-7.13 (m, 2H), 6.99 (dd, J = 8.8, 2.3 Hz, 1 H), 6.66 (s, 1 H), 6.30 (d, J = 16.2 Hz, 1 H), 3, 90 (s, 3H), 1.55 (s, 9H). Intermediates H 3-(4-((6-methoxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3yl)oxy)phenyl)acrylate (E) - tert-butyl (compound 31)

[00260] To a 5 mL microwave vial, a solution of (E)-tert 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate is added. - butyl (50 mg, 0.13 mmol) in anhydrous DMA (1.5 mL), followed by 1-bromo-4-(trifluoromethyl)benzene (35.3 mg, 0.16 mmol), chloro[2-( dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos paladacyclo 1st generation, 10.4 mg, 0.013 mmol), trimethylacetic acid (40.1 mg, 0.392 mmol) and potassium carbonate (54.2 mg, 0.392 mmol). The microwave vial was sealed, purged and re-charged with nitrogen. The reaction mixture is subjected to microwave irradiation for 2 hours at 150°C. On completion, the reaction was diluted with EtOAc, and washed with water and brine. The combined organic layer was dried over aqueous MgSO 4 , filtered and concentrated in vacuo to furnish a red-brown residue which was purified by column chromatography (SiO 2 , 0 to 30% EtOAc/heptane) to furnish (E)-tert-butyl 3-(4-((6-methoxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (59.4 mg, 0.11 mmol, 86% of production). 1H NMR (400 MHz, CD3OD) δppm = 1.42-1.61 (m, 9H), 3.77-3.98 (m, 3H), 6.31 (d, J = 15.66 Hz, 1H), 6.87-7.04 (m, 3H), 7.28 (d, J = 9.09 Hz, 1H), 7.46 (d, J = 2.53 Hz, 1H), 7.47-7.57 (m, 3H), 7.65 (d, J = 8.08Hz, 2H), 7.89 (d, J = 8.08Hz, 2H ). LC/MS (m/z, MH+): 471.40. (E)-methyl 3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 32)
To a flask containing (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (800 mg, 2.35 mmol) in anhydrous DMA (3 .0 mL) was added 1-iodo-2-isopropylbenzene (0.751 mL, 4.70 mmol) followed by chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-tri -i-propyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos paladacycle 1st generation, 188 mg, 0.24 mmol), trimethylacetic acid (0.818 mL, 7 .05 mmol) and potassium carbonate (974 mg, 7.05 mmol). The vial was sealed, purged and re-charged with nitrogen and the resulting mixture was heated to 150°C for 2 hours, after which time the reaction was diluted with EtOAc, and washed with water and brine. The combined organic layer was dried over aqueous MgSO4, filtered and concentrated in vacuo to furnish a red-brown residue which was purified by column chromatography (SiO2, 0 to 30% EtOAc/heptane) to furnish (E)-methyl 3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (675 mg, 1.48 mmol, 63% yield). 1H NMR (400 MHz, CDCl 3 ) δ ppm = 7.61 (d, J = 15.9 Hz, 1H), 7.42 - 7.29 (m, 7H), 7.15 (ddd, J = 8. 1.5.7, 2.8 Hz, 1H), 6.97 (dd, J = 8.8, 2.3 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.29 (d, J = 16.0 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 3.26 (p, J = 6.8 Hz, 1H), 1.19 (d, J = 6.9 Hz, 6H). LC/MS (m/z, MH+): 459.0.


Intermediários K 3-(4-((6-metóxi-2-(4-metoxifenil)benzo[ b ]tiofen-3-il)óxi)fenil)propanoato de terc- butila (composto 56)
[00262] The following intermediates H were prepared in a model similar to compound 31 using the appropriate intermediates G and the corresponding aryl bromide as starting materials:




Intermediates K tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propanoate (compound 56)

To a solution of (E)-tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (27 mg, 0.06 mmol) in 4:1 MeOH:DCM (2.5 mL) was added palladium on carbon (10 wt%, 0.59 mg, 5.53 µmol). The reaction was stirred at room temperature under a balloon of hydrogen for 12 hours, after which the reaction was purged with nitrogen and filtered through CeliteTM. The remaining palladium was washed with DCM (30 mL) and the resulting solution was concentrated in vacuo to give 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy tert-butyl)phenyl)propanoate (27mg, 0.06mmol, 100% yield) which was used without further purification. LC/MS (m/z, MH+): 491.3. Intermediates L (E)-2-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-1,3, 4-oxadiazole (compound 57)

To a 30 ml flask, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl) acid acrylic (100mg, 0.230mmol) and acetohydrazide (85mg, 1.151mmol) were dissolved in POCl 3 (2ml, 21.46mmol) and the mixture was heated to 100°C for 18 hours. The reaction mixture was cooled to room temperature poured onto ice. The solution was quenched with saturated sodium bicarbonate and diluted with DCM. The organic layer was collected (phase separator) and concentrated to provide the raw material. The crude product was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 30-100% CH3CN/H2O) to give (E)-2-(4-((2-(4-fluoro-) 2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-1,3,4-oxadiazole (83 mg, 0.176 mmol, 76% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δppm = 2.38 (s, 3H), 2.57 (s, 3H), 3.90 (s, 3H), 6.81-6.98 (m , 4H), 6.98-7.08 (m, 2H), 7.28-7.42 (m, 2H), 7.44-7.58 (m, 4H). LC/MS (m/z, MH+): 473.4,
[00265] The following intermediates were prepared in a similar model to the above intermediates, using the appropriate starting materials:
(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-4H-1,2 ,4-triazole (compound 59)

[00266] To a microwave flask, (E)-2-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styril) -5-methyl-1,3,4-oxadiazole (23 mg, 0.049 mmol) and ammonium trifluoroacetate (128 mg, 0.973 mmol) were suspended in toluene (2 mL). The reaction was heated for 18 hours at 180 °C under microwave irradiation. The reaction mixture was concentrated and the crude product was purified by reverse phase HPLC (neutral condition, 0.1% TFA in 20 to 100% CH3CN/H2O) to give (E)-3-(4-( (2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-4H-1,2,4-triazole (15mg, 0.032mmol, 65% production) as a white solid. LC/MS (m/z, MH+): 472.1. (E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2( 3 H )-one (compound 60)
Step 1: To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl) acid oxy)phenyl)acrylic (40mg, 0.092mmol) was dissolved in DMF (1ml). The vial was charged with hydrazine (5.90 mg, 0.184 mmol), HATU (52.5 mg, 0.138 mmol), and DIEA (0.048 mL, 0.276 mmol). The reaction mixture was stirred for 10 minutes at room temperature. The reaction was quenched with saturated aqueous NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated by vacuum to provide the raw product. The crude material was purified by column chromatography (SiO 2 , 1 to 20% MeOH/DCM) to give (E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[ b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one (38 mg, 0.085 mmol, 92% yield). LC/MS (m/z, MH+): 449.1 Step 2: To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)) -6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylhydrazide (38 mg, 0.085 mmol) was dissolved in THF (2 mL). The flask was charged with 1,1'-carbonyldiimidazole (16.49 mg, 0.102 mmol) and the reaction stirred at room temperature for 1 hour. The reaction mixture was acidified with 6N HCl which caused a precipitate to form. The mixture was diluted with DCM to dissolve the precipitate. The organic phase was collected (phase separator) and concentrated to give (E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl) )oxy)styryl)-1,3,4-oxadiazol-2(3H)-one (31 mg, 0.065 mmol, 77% yield) as an off-white solid which was used without further purification. LC/MS (m/z, MH): 473.0 (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy )phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (compound 61)

[00267] To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl) acid oxy)phenyl)acrylic (50mg, 0.115mmol) was dissolved in DMF (2ml). The vial was charged with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (27.0 mg, 0.230 mmol), HATU (65.6 mg, 0.173 mmol), and DIEA (0.060 mL, 0.345 mmol). The reaction mixture was stirred for 30 minutes at room temperature. The reaction was quenched with saturated NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to provide the crude product. The crude material was purified by column chromatography (SiO 2 , 1-80% heptanes/EtOAc) to provide (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6- methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (53 mg, 0.099 mmol, 86% yield). 1H NMR (400 MHz, CD3OD) δ ppm = 1.48¬1.73 (m, 3H), 1.73-1.96 (m, 3H), 2.36 (s, 3H), 3 .56-3.70 (m, 1H), 3.89 (s, 3H), 3.98-4.14 (m, 1H), 4.96 (br.s., 1H), 6.35 (d, J = 15.66 Hz, 1H), 6.79-6.95 (m, 3H), 6.95-7.07 (m, 2H), 7.26-7 .39 (m, 2H), 7.39-7.48 (m, 3H), 7.52 (d, J = 16.17 Hz, 1H). LC/MS (m/z, MH+): 534.1. Intermediates M 1 -3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene oxide (compound 62)

[00268] To a solution of 4-bromophenol (469 mg, 2.71 mmol) in DMF (3 mL) was added sodium hydride (60% suspension in oil, 108 mg, 2.71 mmol), the resulting mixture was allowed to stir for 10 minutes at room temperature. To the solution, 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (900 mg, 2.46 mmol) was added as a solid. The reaction was heated to 80 °C for 18 hours. On completion, the reaction was cooled to room temperature, quenched with water and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to provide the crude product. The crude material was purified by column chromatography (SiO 2 , 0 to 60% EtOAc/Heptane) to give 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b] 1-oxide thiophene (980 mg, 2.14 mmol, 87% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm = 7.70-7.78 (m, 2H), 7.53 (d, J = 2.02 Hz, 1H), 7.41 (d, J = 8.59 Hz, 2H), 6.90-7.06 (m, 6H), 3.91 (s, 3H), 3.83 (s, 3H).
Intermediários N 3-(4-bromofenóxi)-6-metóxi-2-(4-metoxifenil)benzo[ b ]tiofeno (composto 65) [00269] The following intermediates were prepared in a model similar to the above intermediates, using the appropriate starting materials: Intermediates N 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (compound 65)
A solution of 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (970 mg, 2.12 mmol) in THF (5 mL) was cooled to 0 °C. To the cooled solution was added LAH (129 mg, 3.39 mmol) in one portion. The reaction mixture was stirred at 0°C for 30 minutes, after which the mixture was poured into 1M aqueous NaHSO 4 solution and extracted with DCM. The organic layer was collected (phase separator) and concentrated in vacuo to furnish the crude product which was purified by column chromatography (SiO 2 , 0 to 30% EtOAc/Heptane) to furnish 3-(4-bromophenoxy)-6- methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (850 mg, 1.93 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, CDCl 3 ) δ ppm = 3.83 (s, 3H), 3.90 (s, 3H), 6.80-6.99 (m, 5H), 7.22-7 .32 (m, 2H), 7.32-7.44 (m, 2H), 7.65 (d, J = 9.09Hz, 2H).
Intermediários O 3-(4-bromofenóxi)-2-(4-hidroxifenil)benzo[ b ]tiofen-6-ol (composto 68) [00271] The following intermediates were prepared in a similar model to the above intermediates, using the appropriate starting materials: Intermediates O 3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (compound 68)
To a 30 mL vial containing 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (100 mg, 0.23 mmol) in DCM (1 mL) was BBr3 (1M in hexanes, 0.680 ml, 0.68 mmol) is added and the reaction mixture was stirred for 1 hour at room temperature. On completion, the reaction was quenched with 4 mL of MeOH and stirred for 10 minutes. The mixture was concentrated in vacuo onto silica gel and the crude material was purified by column chromatography (SiO 2 , 1x100% EtOAc/Heptane) to give 3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo [b]thiophen-6-ol (72 mg, 0.17 mmol, 77% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm = 7.47¬7.57 (m, 2H), 7.35-7.45 (m, 2H), 7.20 (d, J = 2.02 Hz, 1H), 7.16 (d, J = 8.59 Hz, 1H), 6.73-6.90 (m, 5H). Intermediates P 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (E) - tert-butyl (compound 69)
To a solution of 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (79 mg, 0.18 mmol) in DMF (1.7 mL) was added triethylamine (0.125 mL, 0.90 mmol) followed by tert-butyl acrylate (0.184 mL, 1.25 mmol) and Pd(PPh3)2Cl2 (18.9 mg, 0.03 mmol). The mixture was then subjected to microwave irradiation for 1 hour at 120 °C, after which the reaction was diluted with water (15 ml) and extracted with EtOAc (4 x 10 ml). The combined organic layers were washed with brine (30 mL), passed through a phase separator to remove water and concentrated in vacuo to provide the crude product as an orange oil which was purified by column chromatography ( SiO 2 , 0-50% EtOAc/Heptane) to give (E) 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate - tert -butyl as a pale yellow oil (55 mg, 0.11 mmol, 63% yield). 1H NMR (400 MHz, CDCl 3 ) δ ppm = 1.44 (s, 9H), 3.71 (s, 3H), 3.78 (s, 3H), 6.13 (d, J = 15 .66 Hz, 1H), 6.76-6.83 (m, 3H), 6.86 (m, J = 8.59Hz, 2H), 7.14-7.19 (m, 2H) H), 7.31 (m, J = 8.59 Hz, 2H), 7.42 (d, J = 16.17 Hz, 1H), 7.54 (d, J = 8.59 Hz, 2H). (E)-4-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-imidazole (compound 70)
[00274] To a microwave vial, 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (50 mg, 0.113 mmol) was dissolved in DMF (2 mL) and triethyl amine (0.474 mL, 3.40 mmol). To the solution was added tert-butyl 4-vinyl-1H-imidazol-1-carboxylate (66.0 mg, 0.340 mmol) and Pd(PPh3)2Cl2 (7.95 mg, 0.011 mmol). The system was stimulated with nitrogen and heated to 150 °C for 1 hour under microwave radiation. The mixture was cooled to room temperature and diluted with DCM and saturated NH4Cl. The organic layer was collected (phase separator) and concentrated onto silica gel and the material was purified by column chromatography (SiO2, 0 to 30% DCM/MeOH) to provide (E)-4-( 4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-imidazole (41 mg, 0.090 mmol, 80% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.78 (d, J = 1.52 Hz, 1H), 7.51 - 7.62 (m, 2H), 7.46 - 7.51 (m, 1H) , 7.39 (d, J = 9.09 Hz, 2H), 7.32 (d, J = 2.53 Hz, 1H), 7.15 (d, J = 9.09 Hz, 1H), 7 .08 (d, J = 16.67 Hz, 1H), 6.76 - 6.95 (m, 6H), 3.77 (s, 3H), 3.69 (s, 3H). Intermediates Q (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 71)
To a solution of (E)-methyl 3-(4-hydroxyphenyl)acrylate (190 mg, 1.07 mmol) in DMF (5 mL) was added sodium hydride (60% suspension in oil, 42 .7mg, 1.07mmol). The resulting mixture was allowed to stir for 10 minutes at room temperature, after which 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (300 mg, 0.82 mmol ) was added, as a solid. The reaction was heated to 80 °C for 18 hours and on completion was cooled to room temperature, quenched with water and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to furnish the crude product which was purified by column chromatography (SiO2, 0 to 80% EtOAc/Heptane) to furnish 3-(4-((6) (E)-methyl -methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (370 mg, 0.80 mmol, 97% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm = 7.75 (d, J = 9.09 Hz, 2H), 7.65 (d, J = 15.66 Hz, 1H), 7.54 (d , J = 2.02 Hz, 1H), 7.43-7.52 (m, J = 9.09 Hz, 2H), 7.07-7.16 (m, J = 8.59 Hz, 2H), 6.98-7.07 (m, 1H), 6.93 (d, J = 9.09 Hz, 3H), 6.35 (d, J = 16.17 Hz, 1H ), 3.91 (s, 3H), 3.82 (d, J = 1.52 Hz, 6H). LC/MS (m/z, MH+): 463.4.
3-(4-((6-metóxi-2-(4-metoxifenil)-1-oxidobenzo[ b' tiofen-3-il)óxi)fenil)-2- metilacrilato de (E)-etila (composto 75) [00276] The following intermediates were prepared in a similar model to the above intermediates, using the appropriate starting materials: (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b'thiophen-3-yl)oxy)phenyl)-2-methylacrylate (compound 75)
To a solution of (E)-ethyl 3-(4-hydroxyphenyl)-2-methylacrylate (92 mg, 0.445 mmol) in DMF (2.0 mL) was added sodium hydride (60% suspension in oil, 17.79 mg, 0.445 mmol), the resulting mixture was allowed to stir for 30 minutes at room temperature. To the solution, 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (125 mg, 0.342 mmol) was added as a suspension in DMF (2.0 mL). The reaction was heated to 80 °C for 15 hours. On completion, the reaction was cooled to room temperature, quenched with water and extracted with EtOAc. The combined organic layers were then washed with water, saturated aqueous NaHCO3, brine and then collected (phase separator) and concentrated in vacuo to provide the crude product. The crude material was purified by column chromatography (SiO 2 , 0-70% EtOAc/Heptane) to give 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]) (E)-ethyl thiophen-3-yl)oxy)phenyl)-2-methylacrylate (144 mg, 0.294 mmol, 86% yield). LC/MS (m/z, MH+): 491.3 (E)-ethyl 3-(4-hydroxy-2-methylphenyl)acrylate (compound 76)
[00278] To a microwave vial containing 4-bromo-3-methylphenol (600 mg, 3.21 mmol) in anhydrous DMF (3.0 mL) was added ethyl acrylate (996 mg, 9.94 mmol), palladium(II) acetate (72.0 mg, 0.321 mmol), tri(o-tolyl)phosphine (146 mg, 0.481 mmol) and triethylamine (1.57 mL, 11.23 mmol). The resulting mixture was sealed and subjected to microwave irradiation at 120°C for 2 hours, after which time the reaction was diluted with EtOAc and filtered through Celite™. The filtrate was then washed with water, brine and dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to furnish the crude product as a brown oil which was purified by column chromatography (SiO 2 , 0 to 30% EtOAc/Heptane) to provide (E)-ethyl 3-(4-hydroxy-2-methylphenyl)acrylate (289.8 mg, 1.405 mmol, 44% yield). LC/MS (m/z, MH+): 207.2.
Intermediários R 3-(4-((6-metóxi-2-(4-metoxifenil)benzo[ b ]tiofen-3-il)óxi)fenil)acrilato de (E)-metila (composto 85) [00279] The following intermediates were prepared in a similar model to the above intermediates, using the appropriate starting materials:Intermediates R (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 85)
To a 30 mL vial containing (E) 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate -methyl (200mg, 0.43mmol) were added THF (5ml), triphenylphosphine(420mg, 1.60mmol) and TMS-Cl (0.553ml, 4.32mmol). The reaction was heated to 75 °C for 18 hours, after which time the mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3 and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to furnish the crude product which was purified by column chromatography (SiO2, 0 to 60% EtO-Ac/Heptane) to furnish 3-(4-((6) (E)-methyl -methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (110 mg, 0.25 mmol, 57% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm = 7.58-7.73 (m, 3H), 7.38-7.50 (m, J = 8.59 Hz, 2H), 7.28 ( t, J = 2.27 Hz, 2H), 6.96-7.05 (m, J = 8.59 Hz, 2H), 6.85-6.96 (m, 3H), 6, 32 (d, J = 15.66 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H).
3-(4-((6-metóxi-2-(4-metoxifenil)benzo[ b ]tiofen-3-il)óxi)fenil)-2- metilacrilato de (E)-etila (composto 89) [00281] The following intermediates were prepared in a model similar to the above intermediates, using the appropriate starting materials: Structure Name Physical data (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate (compound 89)
To a solution of 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate from (E) -ethyl (144 mg, 0.294 mmol) in THF (6.0 mL) were added triphenylphosphine (285 mg, 1.086 mmol) and TMS-Cl (0.375 mL, 2.94 mmol). The reaction was heated to 75 °C for 7 hours, after which time the mixture was cooled to room temperature, quenched with saturated aqueous NaHCO3 and extracted with EtOAc, the combined organic layers were collected (phase separator) and concentrated in vacuo to furnish the crude product which was purified by column chromatography (SiO 2 , 0¬40% EtOAc/Heptane) to furnish 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[ (E)-ethyl b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate (107 mg, 0.225 mmol, 77% yield). LC/MS (m/z, MH+): 475.3.
Intermediários S Ácido(E )-3-(4-((6-metóxi-2-(4-metoxifenil)benzo[ b ]tiofen-3- il)óxi)fenil)acrílico (composto 98) [00283] The following intermediates were prepared in a model similar to the above intermediates, using the appropriate starting materials: Intermediates S (E )-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (compound 98)
To a 30 mL vial containing (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate ( 110mg, 0.25mmol) was added THF (2.00ml), MeOH (1.00ml), H 2 O (1.00ml) and LiOH (29.5mg, 1.23mmol). The resulting mixture was stirred at room temperature for 60 minutes, after which the reaction was concentrated in vacuo, diluted with water, and acidified to pH 2 with 6M HCl causing a precipitate to form. The mixture was diluted with 20 mL of DCM and 2 mL of MeOH and the organic layer was collected (phase separator) and concentrated in vacuo to give (E)-3-(4-((6-methoxy-2-() acid. 4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic (98 mg, 0.23 mmol, 92% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm = 7.51-7.69 (m, 5H), 7.43 (d, J = 2.02 Hz, 1H), 7.25 (d, J = 9.09Hz, 1H), 6.88-7.02 (m, 5H), 6.37 (d, J = 15.66Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H). LC/MS (m/z, MH+): 433.0.
Ácido(E)-3-(4-((2-(4-fluoro-2-metilfenil)-6-metoxibenzo[ b ]tiofen-3- il)óxi)fenil)acrílico (composto 100) [00285] The following intermediates were prepared in a similar model to the above intermediates, using the appropriate starting materials: (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (compound 100)
[00286] To a 30 mL screw cap vial, 3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate of (E)-tert-butyl (100 mg, 0.204 mmol) was dissolved in 4M HCl in dioxane (153 µl, 0.612 mmol) and the reaction mixture was stirred for 10 minutes at room temperature. The reaction mixture was concentrated to dryness to give (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl) acid acrylic (88 mg, 0.202 mmol, 99% yield). 1H NMR (400 MHz, CD3OD) δ ppm = 2.25 (s, 3H) 3.78 (s, 3H) 6.21 (d, J=15.66 Hz, 1H) 6.68 - 6 .84 (m, 3H) 6.84 - 6.92 (m, 2H) 7.16 - 7.29 (m, 2H) 7.31 - 7.41 (m, 3H) 7.46 (d, J=16.17 Hz, 1H). Intermediates T (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (compound 101)
[00287] To a 30 ml flask, (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (98 mg, 0.23 mmol) was dissolved in DMF (2 mL). The flask was charged with HATU (129 mg, 0.34 mmol) and DIEA (0.119 mL, 0.68 mmol) and the mixture stirred for 10 minutes. A color change from light orange to dark orange was observed. To the solution, NH4Cl (24.24 mg, 0.45 mmol) was added, and the reaction mixture was stirred for 30 minutes at room temperature. The reaction was quenched with saturated aqueous NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated to provide the crude product. The crude material was purified by column chromatography (SiO 2 , 1-10% MeOH/DCM) to provide (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b) ]thiophen-3-yl)oxy)phenyl)acrylamide (77 mg, 0.18 mmol, 79% yield) as an off-white solid. 1H NMR (400 MHz, CD3OD) δppm = 8.00 (s, 4H), 7.59-7.70 (m, 2H), 7.45-7.55 (m, 2H), 7 .42 (d, J = 2.02 Hz, 1H), 7.24 (d, J = 8.59Hz, 1H), 6.84-7.02 (m, 4H), 6.52 (d, J = 15.66 Hz, 1H), 3.88 (s, 3H), 3.79 (s, 3H). LC/MS (m/z, MH+): 432.3. (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide ( compound 102)
[00288] To a 30 ml flask containing (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (41 mg, 0.10 mmol) was added DMF (3 mL), followed by 3,3,3-trifluoropropan-1-amine (13.94 mg, 0.12 mmol), HATU (54.1 mg, 0.14 mmol), and DIEA (0.050 mL, 0.28 mmol). The mixture was stirred at room temperature for 30 minutes, after which the reaction was quenched with saturated aqueous NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo on silica gel. The crude material was purified by column chromatography (SiO 2 , 0 to 30% EtO-Ac/heptane) to give (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b) ]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide (38 mg, 0.07 mmol, 72% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm = 7.64 (d, J = 9.09 Hz, 2H), 7.45-7.56 (m, 3H), 7.42 (d, J = 2.02Hz, 1H), 7.25 (d, J = 8.59Hz, 1H), 6.90-7.02 (m, 5H), 6.47 (d, J = 15, 66Hz, 1H), 3.88 (s, 3H), 3.74-3.85 (m, 3H), 3.54 (t, J = 7.07Hz, 2H), 2, 34-2.56 (m, 2H). LC/MS (m/z, MH+): 528.3.
(E)-3-(4-((2-(4-fluorofenil)-6-metoxibenzo[b]tiofen-3- il)óxi)fenil)acrilamida (composto 105) [00289] The following intermediates were prepared in a similar model to the above intermediates, using the appropriate starting materials: (E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (compound 105)
(E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (48 mg, 0.115 mmol) was dissolved in DMF (3.00 ml). The flask was charged with HATU (65.6 mg, 0.173 mmol), DIEA (0.060 mL, 0.345 mmol), and NH4Cl (6.16 mg, 0.115 mmol). The reaction mixture was stirred for 10 minutes at room temperature. The reaction was quenched with saturated NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to provide the crude product. The crude material was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1 to 100% CH3CN/H2O) to give (E)-3-(4-((2-(4-fluorophenyl)) -6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (41 mg, 0.098 mmol, 85% yield) as a light orange solid. 1H NMR (400 MHz, CD3OD) δppm = 3.77 (s, 3H) 6.40 (d, J=15.66Hz, 1H) 6.78 - 6.90 (m, 3H) 6 .95 - 7.06 (m, 2H) 7.16 (d, J=8.59 Hz, 1H) 7.29 - 7.49 (m, 4H) 7.55 - 7.69 (m , 2H). Intermediates U (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-tetrazol (compound 106)
[00291] To a microwave flask, (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (75 mg, 0.174 mmol) and Bu2SnO (4.33 mg, 0.02 mmol) were suspended in DME (3 mL). The flask was charged with TMSN3 (0.023 mL, 0.17 mmol) and the reaction was heated for 60 minutes at 180 °C under microwave irradiation. The reaction mixture was filtered to remove solids and concentrated onto silica gel. The crude material was purified by column chromatography (SiO 2 , 1 to 20% MeOH/DCM) to give (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene) -3-yl)oxy)styryl)-1-H-tetrazol (66 mg, 0.15 mmol, 83% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm = 7.45-7.61 (m, 5H), 7.32 (d, J = 2.02 Hz, 1H), 7.15 (d, J = 9.09Hz, 1H), 6.98 (d, J = 16.67Hz, 1H), 6.86-6.93 (m, 2H), 6.78-6.86 (m, 3H), 3.78 (s, 3H), 3.69 (s, 3H). LC/MS (m/z, MH+): 457.4. (E)-5-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1H-tetrazol (compound 107)
[00292] To a microwave flask, (E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (41 mg , 0.098 mmol) and Bu2SnO (2.433 mg, 9.77 µmol) were suspended in DME (3 mL). The vial was loaded with TMSN3 (0.013 mL, 0.098 mmol) and the reaction was heated for 60 minutes at 180 °C under microwave radiation. The reaction mixture was filtered to remove solids and concentrated on silica gel. The crude material was purified by column chromatography (SiO 2 , 1 to 20% DCM/MeOH) to give (E)-5-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen- 3-yl)oxy)styryl)-1H-tetrazol (31 mg, 0.070 mmol, 71.4% yield) as an orange solid. 1H NMR (400 MHz, , CD3OD) δppm = 3.78 (s, 3H) 6.80 - 6.91 (m, 3H) 6.96 - 7.07 (m, 3H) 7.19 (d, J=8.59 Hz, 1H) 7.34 (d, J=2.53Hz, 1H) 7.35 - 7.52 (m, 3H) 7.58 - 7.74 ( m, 2H). (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1-methyl-1H-tetrazol and (E)- 5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-2-methyl-2H-tetrazol (compounds 108 and 109)
To a 30 mL vial containing (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-2H- tetrazole (15 mg, 0.03 mmol) in DMF (2 mL) was added with iodomethane (2.260 µL, 0.04 mmol) and K2CO3 (13.62 mg, 0.10 mmol) and the reaction was stirred at tem room temperature for 18 hours. The reaction was quenched with saturated aqueous NH4Cl (15 mL) and extracted with DCM (25 mL). The organic phase was collected (phase separator) and concentrated in vacuo to provide the crude product. The crude product was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1 to 100% CH3CN/H2O) to give (E)-5-(4-((6-methoxy-2) -(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1-methyl-1H-tetrazol (8 mg, 0.08 mmol, 52% yield) and (E)-5- (4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-2-methyl-2H-tetrazol (6 mg, 0.01 mmol, 39% of production) both as a white solid.
[00294] (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1-methyl-1H-tetrazol: 1H NMR (400 MHz, CD3OD) δ ppm = 7.48 - 7.60 (m, 3H), 7.39 - 7.48 (m, 2H), 7.30 (d, J = 2.02 Hz, 1H ), 7.14 (d, J = 9.09 Hz, 1H), 6.95 (d, J = 16.67 Hz, 1H), 6.77 - 6.90 (m, 5H), 4.24 (s, 3H), 3.76 (s, 3H), 3.68 (s, 3H). LC/MS (m/z, MH+): 471.4.
[00295] (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-2-methyl-2H-tetrazol: 1H NMR (400 MHz, CD3OD) δ ppm = 7.75 (d, J = 16.17 Hz, 1H), 7.59 - 7.70 (m, 4H), 7.43 (d, J = 2.02 Hz, 1H), 7.27 (d, J = 8.59 Hz, 1H), 7.09 (d, J = 16.17 Hz, 1H), 6.97 - 7.05 (m, 2H), 6.90 - 6.97 (m, 3H), 4.14 (s, 3H), 3.89 (s, 3H), 3.80 (s, 3H). LC/MS (m/z, MH+): 471.4.
Intermediários V 5-((6-metóxi-2-(4-metoxifenil)-1-oxidobenzo[ b ]tiofen-3-il)óxi)picolinato de metila (composto 117)[00296] The following intermediates were prepared in a similar model to the above intermediates, using the appropriate starting materials:Intermediates V Methyl 5-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)picolinate (compound 117)
[00297] To a solution of methyl 5-hydroxypyridine-2-carboxylate (0.273 g, 1.78 mmol) in DMF (6.84 mL) at room temperature was added sodium hydride (60% suspension in oil, 0.043 g, 1.78 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. After 30 minutes at room temperature 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzothiophene 1-oxide (0.5 g, 1.37 mmol) was added and the reaction was heated to 80 °C for 18 hours. On completion, the reaction was cooled to room temperature, quenched with water and extracted with DCM. The organic layers were combined, passed through a phase separator and concentrated in vacuo to furnish the crude product, which was purified by column chromatography (SiO2, 0-75% EtOAc/heptane) to furnish 5- methyl ((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)picolinate (314 mg, 0.72 mmol, 52% yield). 1H NMR (400 MHz, CDCl 3 ) δ ppm = 3.73 (s, 3H), 3.84 (s, 3H), 3.90-3.92 (m, 3H), 6.79¬6 .86 (m, 2H), 6.91 (dd, J = 8.59, 2.53Hz, 1H), 7.03 (d, J = 8.59Hz, 1H), 7.30 (dd, J = 8.59, 3.03 Hz, 1H), 7.48 (d, J = 2.53Hz, 1H), 7.55-7.60 (m, 2H), 7 .95 (d, J = 8.59 Hz, 1H), 8.55 (d, J = 2.02 Hz, 1H). LC/MS (m/z, MH+): 438.2. Intermediates W (5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)methanol (compound 118)
[00298] Step 1: To a solution of methyl 5-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)picolinate (0.314 g, 0.718 mmol) in THF (5.98 mL) at 0 °C was added LAH (1.0 M in THF, 2.153 mL, 2.15 mmol) dropwise and the reaction was stirred at 0 °C for 1 hour. On completion, the reaction was quenched with water and aqueous saturated potassium sodium tartrate and the resulting mixture was stirred for 30 minutes and then extracted with EtOAc (3x). The organic layers were combined, passed through a phase separator and concentrated in vacuo to give (5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2 -yl) crude methanol which was used without further purification. LC/MS (m/z, MH+): 394.2. 5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)picolinaldehyde (compound 119)
[00299] Step 2: To a solution of (5-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)methanol (0.266 g, 0.676 mmol) in DCM (3.38 mL) was added manganese dioxide (1.176 g, 13.52 mmol) and the reaction was stirred at room temperature for 48 hours. On completion, the reaction was filtered over CeliteTM and concentrated in vacuo to furnish crude 5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)picolinaldehyde which was used without further purification. LC/MS (m/z, MH+): 392.2. Intermediates X (E)-methyl 3-(5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate (compound 120)
[00300] To a solution of 5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)picolinaldehyde (0.265 g, 0.68 mmol) in DCM (3.38 mL) at 0 °C was added methyl 2-(triphenylphosphoranylidene)acetate (0.543 g, 1.63 mmol) and the reaction was stirred at room temperature for 18 hours. On completion, the mixture was concentrated in vacuo to furnish the crude material which was purified by column chromatography (SiO2, 0-25% EtO-Ac/heptanes) to furnish 3-(5-((6-methoxy-) (E)-Methyl 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate (96mg, 0.22mmol, 32% yield). 1H NMR (400 MHz, CDCl3) δ ppm = 3.70-3.75 (m, 6H), 3.79-3.83 (m, 3H), 6.70 (d, J = 15.66 Hz, 1H), 6.77-6.88 (m, 3H), 7.02 (dd,J = 8.59, 3.03 Hz, 1H), 7.17 (s, 1H) , 7.18¬7.22 (m, 2H), 7.48-7.59 (m, 3H), 8.42 (d, J = 2.53Hz, 1H). LC/MS (m/z, MH+): 448.3. Intermediates Y (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)amino)phenyl)acrylate (compound 121)
To a large microwave vial (10-20 mL) was added 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (350 mg, 1.00 mmol) , ethyl 4-aminocinnamate (383 mg, 2.00 mmol) and K3PO4 (425 mg, 2.00 mmol). 1,4-dioxane (6.0ml) was then added followed by chloro-(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1' methyl-t-butyl ether adduct '-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (RuPhos paladacyclo, 73.0 mg, 0.10 mmol) and the reaction was subjected to microwave irradiation at 120 °C for 3 hours . On completion, the reaction mixture was transferred to a round base flask with EtOAc and concentrated in vacuo. The resulting material was partitioned between water and EtOAc and separated, the aqueous layer was then further extracted with EtOAc (3x) and the combined organic layers were passed through a phase separator to remove water and concentrated in vacuo. The crude material was purified by column chromatography (SiO 2 , 0 to 30% EtOAc/heptane) to give 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl) (E)-ethyl)amino)phenyl)acrylate (69.0 mg, 0.15 mmol, 15% yield) as a white solid. LC/MS (m/z, MH+): 460.3. Intermediates Z 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate (E )-ethyl of (compound 122)
To a solution of (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)amino)phenyl)acrylate (69.0) mg, 0.15 mmol) in DMF (6.0 mL) at room temperature was added NaH (60% suspension in oil, 139 mg, 3.48 mmol). After 15 minutes, methyl iodide (0.272 mL, 4.35 mmol) was added and the resulting solution was allowed to stir at room temperature for 45 minutes, after which time the reaction was quenched with brine and diluted with water. The resulting solution was then extracted with EtOAc (3x) and the combined organic layers were washed with brine (2X), passed through a phase separator and concentrated in vacuo to provide the crude product which was purified by phase HPLC. reverse (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to give (3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-) (E)-ethyl)(methyl)amino)phenyl)acrylate (25.5 mg, 0.05 mmol, 36% yield) as a white solid. LC/MS (m/z, MH+): 474, 4. Additional Intermediates: 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide (compound 123)
To a suspension of 2-bromo-5-fluorobenzoic acid (2.0 g, 9.13 mmol) in DCM (90 mL) at room temperature was added N,O-dimethylhydroxylamine hydrochloride (1.069 g, 10.96 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.276 g, 11.87 mmol), hydroxybenzotriazole (1.818 g, 11.87 mmol) and triethylamine (2.55 mL, 18.26 mmol). The resulting mixture was stirred at room temperature for 5.5 hours, after which time the reaction was quenched by addition of saturated aqueous NaHCO3 solution and the layers separated. The organic layer was then washed with brine, dried over aqueous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0 to 40% EtOAc/Hexanes) to provide 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide as a white solid. 1H NMR (400 MHz, CDCl 3 ) δ ppm 7.54 (dd, J = 8.8, 4.9 Hz, 1H), 7.05 (dd, J = 8.2, 3.0 Hz, 1H), 7.00 (td, J = 8.4, 3.0Hz, 1H), 3.50 (s, 2H), 3.38 (s, 3H). 1-(2-bromo-5-fluorophenyl)ethanone (compound 124)
To a solution of 2-bromo-5-fluoro-N-methoxy-N-methylbenzamide (1.54 g, 5.88 mmol) in THF (60 mL) at 0°C was added MeMgI (3 0.0M in diethyl ether, 1.998 mL, 5.99 mmol) dropwise over minutes, the reaction immediately turned bright yellow after a few drops, and then after continued addition the reaction lost yellow color and a significant amount of white precipitate precipitated out. After 15 minutes, the reaction was warmed to room temperature and stirred for 15 hours, after which an additional 3 x 0.5 equivalent of MeMgl (1.0 mL) was added every 3 hours, after up to 23 hours the reaction was quenched by addition of saturated aqueous NH4Cl solution and extracted with diethyl ether (3x). The combined organic layers were dried over aqueous MgSO 4 , filtered and concentrated in vacuo and the resulting crude material was purified by column chromatography (SiO 2 , 0 to 20% EtOAc/Hexanes) to provide 1-(2-Bromo-5-5. -fluorophenyl)ethanone (1.038 g, 4.78 mmol, 81% yield). 1H NMR (400 MHz, CDCl 3 ) δ ppm 7.57 (dd, J = 8.8, 4.79 Hz, 1H), 7.18 (dd, J = 8.4, 3.1 Hz, 1H), 7.07 - 6.99 (m, 1H), 2.63 (s, 3H). 1-bromo-4-fluoro-2-(prop-1-en-2-yl)benzene (compound 125)
To a suspension of methyltriphenylphosphonium bomide (5.69 g, 15.91 mmol) in diethyl ether (80 mL) at room temperature was added n-BuLi (2.5 M in hexanes, 6.37 mL) , 15.91 mmol) dropwise. The reaction immediately turned bright orange and the resulting solution was stirred for 35 minutes at room temperature, after which time a solution of 1-(2-bromo-5-fluorophenyl)ethanone (3.14 g, 14.47 mmol) in diethyl ether (20 ml) was added dropwise. The reaction lost its bright yellow color and became almost completely white with a significant amount of white precipitate, the reaction was stirred for 89 hours, then it was quenched by the addition of water and extracted with diethyl ether (3X). The combined organic layers were dried over aqueous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0 to 5% diethyl ether/hexanes) to provide 1-bromo-4-fluoro-2-(prop-1-en-2-yl)benzene. 1H NMR (400 MHz, CDCl 3 ) δ ppm 7.49 (dd, J = 8.8, 5.3 Hz, 1H), 6.92 (dd, J = 9.0, 3.1 Hz, 1H), 6.85 (t, J = 8.3, 3.1 Hz, 1H), 5.24 (t, J = 1.7 Hz, 1H), 4.96 (s, 1H), 2.08 (d, J = 1.4 Hz, 3H). 1-bromo-4-fluoro-2-isopropylbenzene (compound 126)
To a solution of 1-bromo-4-fluoro-2-(prop-1-en-2-yl)benzene (200 mg, 0.930 mmol) in DCM (5 mL) was added 5% rhodium on alumina (30mg, 0.015mmol). The resulting mixture was shaken under a hydrogen atmosphere (3.51 kg/cm2 (50 psi)) for 18 hours, after which time the reaction was filtered through Celite™ and concentrated in vacuo to provide 1-bromo-4-fluoro- 2-isopropylbenzene. 1H NMR (400 MHz, CD2Cl2) δppm 7.48 (dd, J = 8.6, 5.7 Hz, 1H), 7.01 (dd, J = 10.3, 3.1 Hz, 1H), 6. 82 - 6.75 (m, 1H), 3.38 - 3.25 (m, 1H), 1.21 (d, J = 6.9 Hz, 6H). 1-bromo-2-(1-fluoroethyl)benzene (compound 127)
To a solution of 1-(2-bromophenyl)ethanol (1 g, 4.97 mmol) in DCM (12 ml) was added triethylamine trihydrofluoride (1.621 ml, 9.95 mmol) and XtalFluor-E ® (1.708 g, 7.46 mmol) dropwise over 5 minutes. After addition, the resulting mixture was stirred at room temperature for 1 hour and then cooled to 0°C and quenched by addition of saturated aqueous NaHCO3 . The layers were separated and the aqueous was extracted with DCM (2x). The combined organic layers were dried over aqueous MgSO4, filtered and concentrated in vacuo to provide 1-bromo-2-(1-fluoroethyl)benzene. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.54 (dt, J = 8.0, 1.2 Hz, 1H), 7.50 (dd, J = 7.8, 1.8 Hz, 1H), 7.38 (td, J = 7.6, 1.3 Hz, 1H), 7.19 (td, J = 7.7, 1.7 Hz, 1H), 5.90 (dq, J = 46, 6, 6.4 Hz, 1H), 1.60 (dd, J = 24.2, 6.5 Hz, 3H). (E)-ethyl 2-(4-hydroxybenzylidene)butanoate (compound 128)
To a solution of ethyl 2-bromobutanoate (2.75 mL, 19.65 mmol) in DMF (15 mL) were added PPh3 (3.87 g, 14.4 mmol) and zinc (1.285 g, 19, 65 mmol). The resulting mixture was heated to 140°C for 3 hours, after which time the reaction was cooled to room temperature and filtered to remove solid. The filtrate was concentrated in vacuo and the resulting crude material was purified by column chromatography (SiO 2 , 0 to 30% EtOAc/Heptane) to provide (E)-ethyl 2-(4-hydroxybenzylidene)butanoate (820 mg). , 3.72 mmol, 38% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.95 (t, J=7.33 Hz, 3H), 1.12 (t, J=7.07Hz, 3H), 2.36 (q, J=7.58 Hz, 2H), 4.03 (q, J=7.07 Hz, 2H), 6.61 (m, J=8.59 Hz, 2H), 7.08 (m , J=8.59 Hz, 2H), 7.35 (s, 1H). LC/MS (m/z, MH+): 221.2. 1-((1-isocyano-2-methylpropyl)sulfonyl)-4-methylbenzene (compound 129)
To a solution of toluenesulfonylmethyl isocyanide (53 mg, 0.271 mmol) in DMSO (0.27 mL) and diethyl ether (0.27 mL) at room temperature was added NaH (60% suspension in oil, 21 .71 mg, 0.543 mmol) in one portion as a solid. The resulting mixture was stirred for 20 minutes at room temperature, after which time 2-bromopropane (0.038 ml, 0.407 mmol) was added and the reaction was stirred for 1 hour and then quenched by the addition of water (8 ml) and extracted with EtOAc (8 mL). The organic layer was dried over aqueous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0 to 30% EtOAc/Heptane) to give 1-((1-isocyano-2-methylpropyl)sulfonyl)-4-methylbenzene (41 mg, 0.173 mmol , 64% production). 1H NMR (400 MHz, CDCl 3 ) δ ppm 7.87 (d, J = 7.1 Hz, 2H), 7.42 (d, J = 7.1 Hz, 2H), 4.34 (s, 1H) , 2.74 (s, 1H), 2.48 (s, 3H), 1.19 (dd, J = 19.1, 6.6 Hz, 6H). (E)-methyl 3-(4-((2-formyl-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 130)
To a solution of (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.088 mmol) in CHCl3 (1.5 mL) at 0°C was added POCl 3 (0.5 mL, 5.36 mmol) followed by DMF (0.5 mL, 6.46 mmol). The resulting mixture was stirred at 0°C for 5 min and then allowed to warm to room temperature over 2 hours, after which time the reaction was again cooled to 0°C and quenched by dropwise addition of water. The mixture was then partitioned between 1N aqueous NaOH and CH2Cl2. The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 3-(4-((2-formyl-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl) (E)-methyl acrylate (31 mg, 0.084 mmol, 95% yield) which was used without further purification. LC/MS (m/z, MH+): 369.0. (E)-methyl 3-(4-((2-(4-isopropylaxazol-5-yl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 131)
To a solution of (E)-methyl 3-(4-((2-formyl-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.081 mmol) and 1 -((1-isocyano-2-methylpropyl)sulfonyl)-4-methylbenzene (38.7 mg, 0.163 mmol) in MeOH (1.5 mL) at room temperature was added NaOMe (13.20 mg, 0.244 mmol) as a solid. The resulting mixture was heated to 80°C for 3 hours, after which time the reaction was quenched by the addition of brine and extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0 to 20% EtOAc/Heptane) to give 3-(4-((2-(4-isopropylaxazol-5-yl)-6-methoxybenzo[b] (E)-Methyl]thiophen-3-yl)oxy)phenyl)acrylate (10 mg, 0.022 mmol, 27% yield) as a yellow oil. LC/MS (m/z, MH+): 450.0. (E)-4-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2-one (compound 132)
To a microwave vial, 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (1.0 g, 2.98 mmol), but-3-en-2-one (0.483 mL) , 8.95 mmol), and Pd(PPh3)2Cl2 (209 mg, 0.298 mmol) were suspended in DMF (10 mL) and triethylamine (2.079 mL, 14.92 mmol). The reaction was heated for 60 minutes at 120 °C under microwave irradiation. The reaction mixture was diluted with EtOAc and brine and the layers were separated. The aqueous layer was then also extracted with EtOAc (2X), the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0 to 20% EtOAc/Heptane) to give (E)-4-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl )but-3-en-2-one (584 mg, 1,800 mmol, 60% yield) as a light brown solid. LC/MS (m/z, MH+): 325.0. (E)-4-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2-one (compound 133)
[00313] To a 5 mL microwave vial, added a solution of (E)-4-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)but-3 -en-2-one (90 mg, 0.277 mmol) in anhydrous DMA (3.0 mL), followed by 1-iodo-2-isopropylbenzene (137 mg, 0.555 mmol), chloro[2-(dicyclohexylphosphino)- 3,6-dimethoxy-2',4',6'-tri-i-propyl-1,r-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos Paladacycle 1st generation, 22.16 mg, 0.028 mmol), trimethylacetic acid (85 mg, 0.832 mmol) and potassium carbonate (115 mg, 0.832 mmol). The microwave vial was sealed, purged and re-charged with nitrogen. The reaction mixture subjected to microwave irradiation for 2 hours at 150°C. On completion, the reaction was diluted with EtOAc, and washed with water (2X) and brine (1x). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to furnish the crude product, which was purified by column chromatography (SiO2, 0¬20% EtOAc/heptane) to furnish (E)-4-(4 -((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2-one (71.3 mg, 0.161 mmol, 58% yield) . LC/MS (m/z, MH+): 443.0. (E)-methyl 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 134)
To a solution of (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (2.1 g, 6.17 mmol) in THF 201 mL) at room temperature was added N-bromosuccinimide (1.208 g, 6.79 mmol). The resulting solution was vigorously stirred at room temperature for 2 hours, after which time the reaction was quenched by addition of saturated aqueous sodium thiosulfate solution and extracted with EtOAc (3x). The combined organic layers were dried over aqueous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0 to 40% EtOAc/Heptane) to provide 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy (E)-methyl)phenyl)acrylate (2.4 g, 5.72 mmol, 93% yield). 1H NMR (400 MHz, CDCl3) δppm 7.65 (d, J = 16.0 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.9 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.91 (dd, J = 8. 8. 2.2 Hz, 1H), 6.31 (s, 1H), 3.86 (s, 3H), 3.79 (s, 3H). LC/MS (m/z, MH+): 420.9. (E)-methyl 3-(4-((2-bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (E)-3-(4-((2-bromo) -6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic (compounds 135 and 136)
To a solution of (E)-methyl 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (2.4 g, 5.72 mmol) in DCM (20 mL) at room temperature was added BBr3 (1.0 M in Heptane, 17.17 mL, 17.17 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 hours, after which time an aqueous buffer (pH 7.4, made of citric acid and dibasic sodium phosphate, 10 ml), cooled to 0°C, was slowly added into the reaction. The resulting mixture was then diluted with DCM (30 ml) and stirred at room temperature for 1 hour. The phases were then separated and the organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO 2 , 0 to 100% EtOAc/Heptane) to give 3-(4-((2-bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl) (E)-methyl acrylate (1.6 g, 3.95 mmol, 69% yield) as a pale yellow solid and (E)-3-(4-((2-bromo-6-hydroxybenzo[b]) acid ]thiophen-3-yl)oxy)phenyl)acrylic (370 mg, 0.946 mmol, 17% yield) as a yellow solid.
(E)-Methyl 3-(4-((2-bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate: 1H NMR (400 MHz, CD3OD) δ ppm 3, 76 (s, 3H), 6.43 (d, J=16.17Hz, 1H), 6.82 (dd, J=8.84, 2.27Hz, 1H), 6.90 - 6.97 (m, 2H), 7.17 (d, J=2.02 Hz, 1H), 7.22 (d, J=8.59 Hz, 1H), 7.53 - 7, 62 (m, 2H), 7.65 (d, J=15.66Hz, 1H). LC/MS (m/z, MH+): 406.8.
(E)-3-(4-((2-Bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid: 1H NMR (400 MHz, CD3OD) δ ppm 6.38 (d, J=16.17 Hz, 1H), 6.82 (dd, J=8.59, 2.02Hz, 1H), 6.89 - 6.97 (m, 2H), 7 .17 (d, J=2.02 Hz, 1H), 7.23 (d, J=8.59Hz, 1H), 7.53 - 7.60 (m, 2H), 7.63 (d, J=15.66 Hz, 1H). LC/MS (m/z, MH+): 392.8. (E)-methyl 3-(4-((2-(2-isopropyl-6-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 137)
To a solution of (E)-methyl 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (150 mg, 0.358 mmol) in dimethoxyethane - In (1.7 mL) and water (0.3 mL) (2-isopropyl-6-methylphenyl)boronic acid (127 mg, 0.715 mmol), barium hydroxide (123 mg, 0.715 mmol) and tetrakis( triphenylphosphine)palladium(0) (41.3 mg, 0.036 mmol). The mixture was subjected to microwave irradiation at 125 °C for 25 minutes, after which time the reaction was acidified to pH 2 by addition of concentrated HCl. The mixture was then extracted with DCM (3*) and the combined organic layers were dried over aqueous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0 to 30% EtOAc/Heptane) to give 3-(4-((2-(2-isopropyl-6-methylphenyl)-6-methoxybenzo[b] (E)-Methyl]thiophen-3-yl)oxy)phenyl)acrylate (151 mg, 0.304 mmol, 85% yield). 1H NMR (400 MHz, (CD3)2SO) δppm 7.65 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.56 (d , J = 16.0 Hz, 1H), 7.32 - 7.18 (m, 3H), 7.10 (d, J = 7.4 Hz, 1H), 7.00 (dd, J = 8. 7, 2.3 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 6.47 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H), 3 .69 (s, 3H), 2.94 (p, J = 6.8 Hz, 1H), 2.15 (s, 3H), 1.12 (d, J = 6.8 Hz, 3H), 0 .98 (d, J = 6.8 Hz, 3H). LC/MS (m/z, MH+): 473.0. (E) - tert -butyl 3-(4-((2-(2-(difluoromethyl)phenyl)-6-hydroxybenzo[ b ]thiophen-3-yl)oxy)phenyl)acrylate (compound 138)
To a solution of (E)-tert-butyl 3-(4-((2-(2-(difluoromethyl)phenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (133mg, 0262mmol) in N-Methyl-2-pyrrolidone (1.5ml) was added thiophenol (0.040ml, 0.392mmol) and K 2 CO 3 (36.1mg, 0.262mmol). The resulting mixture was subjected to microwave irradiation at 200°C for 1 hour, after which time the reaction was quenched by the addition of water and extracted with EtOAc (2x). The combined organic layers were dried over aqueous MgSO 4 , filtered and concentrated in vacuo and the resulting crude material was purified by column chromatography (SiO 2 , 0 to 20% EtOAc/Heptane) to give 3-(4-((2-( (E)-tert-butyl 2-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (100mg, 0.202mmol, 77% yield). LC/MS (m/z, M¬H): 493.1. (E)-methyl 3-(4-((2-(2-(1,1-difluoroethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 139)
To a solution of (E)-methyl 3-(4-((2-bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (95 mg, 0.234 mmol) in dimethoxyethane (3.0 mL) 2-(2-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (94 mg, 0.352 mmol) complex was added. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (19.14 mg, 0.023 mmol) and potassium carbonate (2.0 M aqueous solution, 0.469 mL, 0.938 mmol). The resulting mixture was subjected to microwave irradiation at 100°C for 20 minutes, after which time the reaction was diluted with EtOAc and washed with saturated aqueous NH 4 Cl solution (2x). The combined organic layers were dried over aqueous MgSO 4 , filtered and concentrated in vacuo and the resulting crude material was purified by column chromatography (SiO 2 , 0-40% EtOAc/Heptane) to give 3-(4-((2 (E)-methyl -(2-(1,1-difluoroethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (77 mg, 0.165 mmol, 70% yield). 1H NMR (400 MHz, CDCl 3 ) δ ppm 7.63 - 7.56 (m, 2H), 7.44 - 7.38 (m, 1H), 7.36 (d, J = 8.8 Hz, 2H ), 7.33 (d, J = 4.71 Hz, 2H), 7.28 - 7.24 (m, 2H), 6.90 - 6.81 (m, 3H), 6.28 (d, J = 16.1 Hz, 1H), 3.78 (s, 3H), 1.91 (t, J = 18.4 Hz, 3H). (E)-methyl 3-(4-((6-methoxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 140)
To a solution of (E)-methyl 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (100 mg, 0.238 mmol) in 1 ,2-dimethoxyethane (3.0 mL) (2-(methoxymethyl)phenyl)boronic acid (79 mg, 0.477 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.5) were added. mg, 0.024 mmol) and Na 2 CO 3 (2.0N aqueous, 0.358 mL, 0.715 mmol). The resulting mixture was subjected to microwave irradiation at 100°C for 20 minutes, after which time the reaction was diluted with EtOAc, anhydrous Na2SO4 added, filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO 2 , 0 to 20% EtO-Ac/Heptane) to give 3-(4-((6-methoxy-2-(2-(methoxymethyl)phenyl)benzo[b] (E)-methyl thiophen-3-yl)oxy)phenyl)acrylate (86.6 mg, 0.188 mmol, 79% yield). LC/MS (m/z, M+H2O): 478.0. (E)-3-(4-((6-methoxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (compound 141)
To a solution of (E)-methyl 3-(4-((6-methoxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate ( 86.6 mg, 0.188 mmol) in MeOH (3.0 mL) was added LiOH (2.0N aqueous, 0.564 mL, 1.128 mmol). The resulting mixture was stirred at room temperature for 48 hours, after which time the reaction was brought to pH 7 by addition of 1N HCl, the neutralized reaction was then concentrated in vacuo to give acid (E)-3-(4 -((6-methoxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic (45.9 mg, 0.103 mmol, 55% yield). LC/MS (m/z, MH+): 447.0. (R,E)-methyl 3-(4-((2-(2-(1-hydroxyethyl)phenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 142)
To a microwave vial vial containing (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (100mg, 0.294mmol) in DMA (2.5 mL) were added (R)-1-(2-bromophenyl)ethanol (118 mg, 0.588 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4 ',6'-tri-i-propyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos Paladacycle 1st generation, 23.47 mg, 0.029 mmol), trimethylacetic acid ( 90 mg, 0.881 mmol) and potassium carbonate (122 mg, 0.881 mmol) The microwave vial was sealed, purged and re-charged with nitrogen. The reaction mixture was subjected to microwave irradiation for 2 hours at 150°C. On completion, the reaction was diluted with EtOAc, and washed with water and brine. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0 to 30% EtOAc/heptane) to provide 3-(4-((2-(2-(1-hydroxyethyl)phenyl)-6-methoxybenzo[ (R,E)-methyl b]thiophen-3-yl)oxy)phenyl)acrylate (27.5 mg, 0.060 mmol, 20% yield). LC/MS (m/z, MH+): 459.0. (R,E)-methyl 3-(4-((6-hydroxy-2-(2-(1-hydroxyethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 143)
To a solution of 3-(4-((2-(2-(1-hydroxyethyl)phenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (R,E) -methyl (27.5 mg, 0.060 mmol) N-methyl-2-pyrrolidone (1.0 mL) was added thiophenol (0.00922 mL, 0.090 mmol) and K2CO3 (8.25 mg, 0.060 mmol). The resulting mixture was subjected to microwave irradiation at 190°C for 1 hour, after which time the reaction was diluted with EtOAc and washed with brine. The layers were separated and the aqueous layer was also extracted with EtOAc, the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0 to 30% EtOAc/heptane) to give 3-(4-((6-hydroxy-2-(2-(1-hydroxyethyl)phenyl)benzo[b] (R,E)-methyl]thiophen-3-yl)oxy)phenyl)acrylate (5 mg, 0.011, 19% yield). LC/MS (m/z, MH+): 445.0. (E)-3-(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (compound 144)
To a solution of (E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (100 mg, 0.232 mmol) in DCM (3 mL) at room temperature were added tert-butyldimethylsilyl chloride (88 mg, 0.581 mmol) and N,N-diisopropylethylamine (0.122 mL, 0.697 mmol). The resulting mixture was stirred at room temperature for 18 hours, after which time the reaction was quenched by the addition of water and extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the resulting crude material was then dissolved in THF (wet) and K2CO3 (32.1 mg, 0.232 mmol) was added and the mixture was added. stirred at room temperature for 2 hours. On completion, the reaction was quenched by addition of 1N HCl and extracted with EtOAc (2X), the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide acid (E)-3 -(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic (120 mg, 0.220 mmol, 95% yield ). 1H NMR (400 MHz, CDCl3) δppm 7.66 (d, J = 16.0 Hz, 1H), 7.37 (d, J = 8.8 Hz, 2H), 7.34 - 7.24 ( m, 5H), 7.17 - 7.09 (m, 1H), 6.90 - 6.82 (m, 3H), 6.26 (d, J = 15.9 Hz, 1H), 3.24 (p, J = 6.7 Hz, 1H), 1.17 (d, J = 6.7 Hz, 6H), 1.01 (s, 9H), 0.24 (s, 6H). (E)-isopropyl 3-(4-((6-(( tert -butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 145)
To a solution of (E)-3-(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl acid )acrylic (59.6 mg, 0.109 mmol) in DCM (2.5 mL) were added i-PrOH (0.034 mL, 0.438 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (84 mg, 0.438 mmol) and 4-dimethylaminopyridine (8.02 mg, 0.066 mmol). The resulting mixture was stirred at room temperature for 75 min after which time the reaction was quenched by addition of water and diluted with DCM. The phases were separated and the aqueous layer was also extracted with DCM (3x). The combined organic layers were dried over aqueous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0 to 30% EtOAc/Heptane) to give 3-(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl) (E)-isopropyl )benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (35mg, 0.060mmol, 55% yield). 1H NMR (400 MHz, CDCl 3 ) δ ppm 7.49 (d, J = 16.0 Hz, 1H), 7.32 - 7.17 (m, 7H), 7.10 - 7.03 (m, 1H) ), 6.79 (d, J = 8.8 Hz, 3H), 6.18 (d, J = 16.1 Hz, 1H), 5.05 (p, J = 6.2 Hz, 1H), 3.18 (p, J = 6.8 Hz, 1H), 1.23 (d, J = 6.4 Hz, 6H), 1.11 (d, J = 6.8 Hz, 6H), 0, 95 (s, 9H), 0.18 (s, 6H). (E)-tert-butyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 146)
To a solution of (E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (400 mg, 0.929 mmol) in toluene (10 mL) was added N,N-dimethylformamide di-tert-butyl acetal (0.891 mL, 3.72 mmol) dropwise, a large amount of precipitate immediately precipitated. The resulting mixture was heated to 80°C for 1 hour, after which time the reaction was cooled to room temperature, diluted with EtOAc, washed with water, saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried over aqueous MgSO 4 , filtered and concentrated in vacuo and the resulting crude material was purified by column chromatography (SiO 2 , 0-40% EtOAc/Heptane) to provide 3-(4-((6) (E)-tert-butyl-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (149 mg, 0.306 mmol, 88% yield). 1H NMR (400 MHz, CDCl 3 ) δ ppm 7.42 (d, J = 16.0 Hz, 1H), 7.30 - 7.18 (m, 7H), 7.10 - 7.03 (m, 1H) ), 6.81 (dd, J = 8.7, 2.3 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.14 (d, J = 15.9 Hz , 1H), 5.55 (br s, 1H), 3.17 (p, J = 6.8 Hz, 1H), 1.46 (s, 9H), 1.10 (d, J = 6.9 Hz, 6H). LC/MS (m/z, MH): 485.1. (E)-tert-butyl 3-(4-((6-acetoxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 147)
To a solution of (E)-tert-butyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (63 mg, 0.129 mmol) in DCM (2.5 mL) was added acetic acid (0.030 mL, 0.518 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (99 mg, 0.518 mmol) and 4-dimethylaminopyridine (9.49 mg, 0.078 mmol). The resulting mixture was stirred at room temperature for 16 hours, after which time the reaction was quenched by addition of 0.1N HCl and diluted with DCM. The phases were separated and the aqueous layer was also extracted with DCM (2x). The combined organic layers were dried over aqueous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0 to 40% EtOAc/Heptane) to provide 3-(4-((6-acetoxy-2-(2-isopropylphenyl)benzo[b]thiophene). (E)-tert-butyl 3-yl)oxy)phenyl)acrylate (65 mg, 0.123 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 12.9 Hz, 1H), 7.37 (d, J = 5.9 Hz, 1H), 7.28 - 7.22 (m, 4H), 7.22 - 7.18 (m, 1H), 7.11 - 7.02 (m, 1H), 6.98 (dd, J = 8.6, 2.1 Hz, 1H), 6.81 - 6.72 (m, 2H), 6.12 (d, J = 15.9 Hz, 1H), 3.11 (p, J = 6.8 Hz, 1H), 2.28 (s, 3H), 1.44 (s, 9H), 1.09 (d, J = 6.8 Hz, 6H). 3-(4-((6-((1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)methoxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3 (E)- tert-butyl (yl)oxy)phenyl)acrylate (compound 148)
To a solution of (E)-tert-butyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (68) mg, 0.140 mmol) in acetone (2 mL) was added 2-(chloromethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (32.4 mg, 0.140 mmol), carbonated carbon potassium (19.31 mg, 0.140 mmol) and potassium iodide (23.2 mg, 0.140 mmol). The resulting mixture was stirred at room temperature for 48 hours. The solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution followed by brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to furnish the crude product, which was purified by flash chromatography (SiO2, 0 to 30% EtOAc/Heptane) to furnish 3-(4-((6-( (1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)methoxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (E )- tert -butyl (67.4 mg, 0.099 mmol, 71% yield). 1H NMR (400MHz, (CD3)2SO ) δ 8.37 (d, J = 7.4 Hz, 1H), 8.18 (dd, J = 7.4, 1.3 Hz, 1H), 8. 11 (td, J = 7.7, 1.3 Hz, 1H), 8.04 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.48 - 7.34 (m, 3H), 7.34 - 7.30 (m, 2H), 7.23 - 7.15 (m, 2H ), 6.89 - 6.81 (m, 2H), 6.33 (d, J = 16.0 Hz, 1H), 5.90 (s, 2H), 3.13 (q, J = 6. 9 Hz, 1H), 1.45 (s, 9H), 1.13 (d, J = 6.8 Hz, 6H). Examples
[00330] For the synthesis of examples 1 to 55: the following examples were prepared from the corresponding intermediates removing the methyl group(s) from the phenolic ether(s) and in some cases also removing a tert-butyl group from a functionality of carboxylic ester in the same step. general method A
To a solution of the above-described intermediate in DCM (0.02-0.1 M) at 0 °C was added BBrs (1 M in DCM, 1.5 -3 equivalents per MeO- group) dropwise drop. The resulting dark mixture was stirred at 0°C for 1 to 3 hours, after which the reaction was quenched with ice water or saturated aqueous NaHCO3 solution. The mixture was allowed to warm to room temperature and extracted with 5% MeOH in EtOAc. The combined organic phases were concentrated and the crude product dissolved in MeOH and purified by RP-HPLC to provide the example. General Method B:
To a solution of the above-described intermediate in DCM (0.02-0.1 M) at 0 °C is added BBr3 (1 M in hexanes, 1.5 - 3 equivalents per MeO- group) dropwise . The resulting dark mixture was stirred at 0°C for 1 to 3 hours, after which the reaction was quenched with methanol. The mixture was concentrated to a small volume and purified by RP-HPLC to provide the example. Example 1 3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propanoic acid
To a solution of tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)propanoate (27mg, 0.055mmol) ) in DCM (1.7 mL) at 0°C was added BBr3 (1.0 M in DCM, 0.220 mL, 0.220 mmol) dropwise (the reaction turned brown in color and a solid immediately precipitated out). if the solution). The resulting mixture was stirred at 0°C for 1 hour, after which the reaction was quenched with ice water (3.0 ml) and allowed to warm to room temperature with vigorous stirring. The resulting mixture was concentrated in vacuo and dissolved in MeOH (2 mL) then purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to give 3-acid. (4-((6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)propanoic (7 mg, 0.02 mmol, 31% yield). LC/MS (m/z, MH+): 407.0943. Example 2 (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid
To a solution of (E)-tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)acrylate ( 40mg, 0.08mmol) in DCM (2.5ml) at 0°C was added BBr3 (1.0M in DCM, 0.33ml, 0.33mmol) dropwise, a solid immediately precipitated from solution. The resulting mixture was stirred at 0 °C for 100 minutes, after which the reaction was quenched by addition of saturated aqueous NaHCO 3 solution (4 mL) and a white precipitate was observed. The aqueous layer was then extracted with 5% MeOH/EtOAc (4 x 12 mL) and the combined organic layers were passed through a phase separator to remove water and concentrated in vacuo to furnish the crude product which dissolved. in MeOH (2 mL) and purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1 to 100% CH3CN/H2O) to give (E)-3-(4-((6-hydroxy) acid -2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic (17.5 mg, 0.04 mmol, 53% yield). LC/MS (m/z, MH+): 405.0790. Example 3 (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid
To a 2 drachma vial containing (E) 3-(4-((6-methoxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate -tert-butyl (59.4 mg, 0.113 mmol) in anhydrous DCM (1.5 mL) at 0 °C was added BBrs (1.0 M in DCM, 451 µL, 0.451 mmol) dropwise. The resulting mixture was stirred at 0°C for 1 hour, after which the reaction was quenched with 3 drops of water, diluted with DCM, and extracted with saturated aqueous NaHCO 3 (added a few drops of 2-propanol). The organic layer was dried over aqueous MgSO4, filtered, concentrated in vacuo to furnish the crude material which was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 10 to 100% CH3CN/H2O) to provide (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (33.8 mg, 0.074 mmol , 66% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm = 6.36 (d, J = 16.17 Hz, 1H), 6.78-6.89 (m, 1H), 6.98 (d, J = 8.59 Hz, 2H), 7.17-7.30 (m, 2H), 7.51-7.70 (m, 5H), 7.88 (d, J = 8.08 Hz, 2H). HRMS (m/z, MH+): 457.0710. Example 4 (E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid
Example 4 was prepared from the corresponding methyl ether/tert-butyl ester intermediates using method A. Example 4 was also prepared using the following hydrolysis reaction: to a solution of 3-(4- ((E)-Methyl ((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (25.8 mg, 0.058 mmol) in EtOH (1.5 mL) ) LiOH (2.0M aqueous, 0.290 mL, 0.580 mmol) was added. After 5 hours at room temperature, the reaction was acidified to pH 3 by addition of 1.0N aqueous HCl and extracted with 5% MeOH/EtOAc, the combined organic layers were passed through a phase separator and concentrated to vacuum to provide (E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (24.0 mg, 0.056 mmol, 96% production). 1H NMR (400 MHz, CD3OD) δ ppm = 7.57 (d, J = 15.9 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.37-7.21 (m, 5H), 7.15-7.08 (m, 1H), 6.88-6.82 (m, 3H), 6.31 (d, J = 15.9 Hz, 1H), 3. 27-3.18 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H). LC/MS (m/z, M-H): 429.0.
[00337] Alternatively, example 4 can also be prepared according to the following procedure:
Step 1: 2-Bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (compound 26). To a solution of 2,3-dibromo-6-methoxybenzo[b]thiophene 1,1-dioxide (12.5 g, 35.3 mmol) in THF (175 mL) at room temperature was added 4-bromophenol (6 .49 g, 37.1 mmol) and Cs2CO3 (34.5 g, 106 mmol). The resulting suspension was heated to 50°C and the reaction turned faintly yellowish green after a few minutes and then subsequently faintly pink, the mixture remained in the suspension. After 4 hours at 50 °C the mixture was cooled to room temperature, diluted with water (175 mL), and stirred for 15 minutes. The solution was transferred to a separatory funnel and the phases were separated. The aqueous layer was extracted with EtOAc (3*100 mL) and the combined organic layers were then washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1,1-dioxide 2 -bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (14.7 g, 33.0 mmol, 93% yield) as a faint pink solid which was used without further purification. 1H NMR (400 MHz, CDCl 3 ) δ ppm = 3.83 (s, 3H), 6.92-7.03 (m, 3H), 7.25-7.35 (m, 2H), 7.39- 7.50 (m, 2H).
[00339] Step 2: 3-(4-Bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (compound 27). To a solution of 2-bromo-3-(4-bromophenoxy)-6-methoxy-benzo[b]thiophene 1,1-dioxide (180 g, 403 mmol) in MeOH (150 mL) and DMSO (1300 mL) at 0°C (internal temperature was 5°C) the first portion of NaBH4 (15 g, 396.5 mmol) was added. The internal temperature rose rapidly to 40 °C and release of H2 gas was observed. The mixture was stirred in an ice bath for 30 minutes (internal temperature cooled to 10°C). The second portion of NaBH4 (15.5g, 409.7mmol) was added. The resulting mixture was stirred for 30 minutes, after which time the reaction was quenched with water (2000 ml) for 1 hour. The resulting precipitate was collected, air dried for 18 hours, then washed with heptane to give 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide as an off-white solid which was used without further purification. 1H NMR (400 MHz, CDCl 3 ) δ ppm = 3.85 (s, 3H), 5.38 (s, 1H), 7.02-7.08 (m, 3H), 7.22 (d , J = 2.53 Hz, 1H), 7.47-7.60 (m, 3H).
[00340] Step 3: 3-(4-Bromophenoxy)-6-methoxybenzo[b]thiophene (compound 28). To a solution of 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (230 g, 626 mmol) in THF (3450 mL) was added DIBAL-H (1.0 M in DCM, 3132 ml, 3132 mmol). The mixture was heated to 60°C for 18 hours. The mixture was cooled to 40°C. DIBAL-H (1.0 M in DCM or Toluene, 500 mL, 500 mmol) was added. The mixture was refluxed for 6 hours. DIBAL-H (1.0 M in DCM, 300 mL, 300 mmol) was added. The mixture was refluxed for 8 hours. After which time the reaction was cooled to 0°C for 2 hours. EtOAc (1226 mL) was added very slowly. Rochelle's salt solution (884 g, 626 mmol in 6000 mL water) was added slowly (over 3 hours). The resulting solution was aged at room temperature for 18 hours. The organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc(1000 ml). The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (149.8 g, 446.9 mmol, 71% yield) as a white solid that was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm = 3.81 (s, 3H), 6.46 (s, 1H), 6.90 (d, J = 9.09Hz, 3H), 7. 16-7.22 (m, 1H), 7.31-7.40 (m, 2H), 7.46 (d, J = 9.09Hz, 1H). LC/MS (m/z, MH+): 336.8.
Step 4: (E)-Methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 29). To a solution of 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (125 g, 373 mmol) and Pd(PPh3)2Cl2 (13.09 g, 18.64 mmol) in DMF (2500 mL) and di- isopropyl ethylamine (326 mL, 1864 mmol) at room temperature was added (subsurface) methyl acrylate (845 mL, 9322 mmol) over 3 to 4 hours. Once the addition started, the reaction was heated to 120°C for 13 hours. Methyl acrylate (150 mL, 1654.8 mmol) was added (subsurface). The reaction was heated to 120°C for 1 hour. The mixture was cooled to room temperature. Excess methyl acrylate and diisopropyl ethylamine was removed in vacuo. The resulting mixture was filtered through celite pad and the cake washed with EtOAc (2000 mL). The resulting mixture was washed with water (2x), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (SiO 2 , 5% to 50% EtOAc/Heptane) to give ((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate ( E)-methyl (81 g, 238 mmol, 64% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm = 1.46 (s, 3H), 3.73 (s, 3H), 6.28 (d, J = 16.17Hz, 1H), 6. 59 (s, 1H), 6.90 (dd, J = 8.59, 2.02 Hz, 1H), 7.00 (d, J = 8.59 Hz, 2H), 7.21 ( d, J=2.02Hz, 1H), 7.37-7.48 (m, 3H), 7.59 (d, J=16.17Hz, 1H). LC/MS (m/z, MH+): 341.1.
Step 5: (E)-Methyl 3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 32). To a solution of (E)-4-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2-one (45 g, 132 mmol) in anhydrous DMA (450 mL) at room temperature were added 1-iodo-2-isopropylbenzene (57 g, 231.6 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6' -tri-i-propyl-1,1'-biphenyl][2-(2-'aminoethyl)phenyl]palladium(II) (BrettPhos Paladacycle 1st generation, 6.34 g, 7.93 mmol), trimethylacetic acid (40, 5 g, 397 mmol) and potassium carbonate (55 g, 397 mmol). The resulting mixture was heated at 140°C for 1.5 hours. The reaction mixture was cooled to 50°C. The reaction was diluted with EtOAc (400 mL) and allowed to cool to room temperature. When the reaction cooled, a precipitate formed and was filtered off. The mother liquor was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to furnish the crude product, which was purified by column chromatography (SiO2, 10 to 20% EtOAc/heptane) to furnish 3-( (E)-Methyl 4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (47 g, 102.5 mmol). 1H NMR (400 MHz, CDCl 3 ) δ ppm = 7.61 (d, J = 15.9 Hz, 1H), 7.42 - 7.29 (m, 7H), 7.15 (ddd, J = 8. 1, 5.7, 2.8 Hz, 1H), 6.97 (dd, J = 8.8, 2.3 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.29 (d, J = 16.0 Hz, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 3.26 (p, J = 6.8 Hz, 1H), 1.19 (d, J = 6.9 Hz, 6H). LC/MS (m/z, MH+): 459.5.
Step 6: (E)-Methyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (Example 45). To a solution of (E)-methyl 3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (75 g, 164 mmol) in DCM (1000ml) at -2°C (internal temperature) was added tribromoborane (491ml, 491mmol) slowly via addition funnel to maintain the internal temperature below 2°C. The resulting mixture was kept at around 0 °C for 30 minutes. To a solution of sodium bicarbonate (Aqueous, 10%, 347 ml) at 5°C (internal temperature) was added the reaction mixture over 2 hours. The organic layer was separated from the aqueous layer. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The aqueous layer was extracted with EtOAc (500 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO 2 , 10 to 30% EtOAc/heptane) to give 3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl) (E)-methyl oxy)phenyl)acrylate (90 purity). The resulting product can be purified by suspension in acetonitrile for 1 hour or in EtOAc/Heptane (1:9) for 30 minutes. The solid was filtered and air dried for hours to give (E) 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate. )-methyl (68 g, 130 mmol, 79%). 1H NMR (400 MHz, CDCl3) δ ppm =7.60 (d, J = 15.9 Hz, 1H), 7.40 - 7.25 (m, 8H), 7.15 (ddd, J = 8. 1, 5.5, 3.0 Hz, 1H), 6.91 - 6.85 (m, 3H), 6.29 (d, J = 16.0 Hz, 1H), 3.80 (s, 3H) ), 3.25 (p, J = 6.8 Hz, 1H), 1.19 (d, J = 6.8 Hz, 6H). HR-MS (m/z, MH+): 445,1473.
Step 7: (E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (Example 4). To a solution of (E)-methyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (50 g, 112 mmol) in MeOH (1000 mL) at 0 °C was added lithium hydroxide (2N, 281 mL, 562 mmol). The resulting mixture was stirred at room temperature for 5 hours. Lithium hydroxide (2N, 281 mL, 562 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction mixture was cooled in an ice bath and HCl (0.5N, 3500 mL, 1750 mmol) was added over 30 minutes. A precipitate formed when HCl was added to the reaction mixture. The precipitate was collected by vacuum filtration and washed with water and heptane. The resulting mass was air-dried for 22 hours. The resulting pasty solid was dried in a vacuum oven (local vacuum) at 45°C for 24 hours. The vacuum was exchanged for high vacuum, the temperature was increased to 50°C. A beaker containing molecular and a beaker containing P2O5 were placed in the vacuum oven. After a few hours, the beaker containing P2O5 was removed. The product was dried in a vacuum oven (high vacuum) at 50°C for 18 hours to give (E)-3-(4-((6-hydroxy-2-(2-isopropylphenyl))benzo[b] acid thiophen-3-yl)oxy)phenyl)acrylic (50 g, 114 mmol). 1H NMR (400 MHz, CD3OD) δ ppm = 7.57 (d, J = 15.9 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.37-7.21 (m, 5H), 7.15-7.08 (m, 1H), 6.88-6.82 (m, 3H), 6.31 (d, J = 15.9 Hz, 1H), 3. 27-3.18 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H).
Exemplo 26 Ácido (E)-3-(4-((6-hidróxi-2-(4-metoxifenil)benzo[ b ]tiofen-3- il)óxi)fenil)acrílico [00345] The following examples were prepared from the corresponding methyl ether/tert-butyl ester intermediates using Method A: Table 1 Example 26 (E)-3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid
[00346] Step 1: To a 30 ml vial containing (E) 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate -methyl (100mg, 0.22mmol) in DCM (1ml) was added BBr3 (1M in heptane, 0.224ml, 0.22mmol) and the reaction was stirred for 1 hour at room temperature. The reaction mixture was quenched with 4 mL of MeOH and stirred for 10 minutes at room temperature. The crude material was concentrated onto silica gel and purified by column chromatography (SiO 2 , 1-100% EtOAc/Heptane) to give 3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b ) (E)-methyl]thiophen-3-yl)oxy)phenyl)acrylate (11 mg, 0.03 mmol, 12% yield), and a mixture of 3-(4-((2-(4-hydroxyphenyl) (E)-methyl )-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate and 3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-) (E)-methyl 3-yl)oxy)phenyl)acrylate (32 mg, 0.07 mmol, 33% yield). LC/MS (m/z, MH+): 433.2.
[00347] Step 2: To a 30 mL vial containing a mixture of 3-(4-((2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate ( E)-methyl and (E)-methyl 3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (32mg, 0, 07 mmol) in THF (3 mL), MeOH (1 mL), and H 2 O (2 mL) was added LiOH (9.14 mg, 0.38 mmol). The reaction mixture was stirred for 60 minutes at room temperature then concentrated in vacuo, diluted with water, and acidified to pH 2 with 6M HCl causing a precipitate to form. The mixture was diluted with 20 mL of DCM and 2 mL of MeOH. The organic layer was collected (phase separator) and concentrated in vacuo to provide the crude product. The sample was purified by supercritical fluid chromatography (CHIRALCEL® OJ-H column, 45% MeOH in CO2) to give (E)-3-(4-((6-hydroxy-2-(4-methoxyphenyl)) acid benzo[b]thiophen-3-yl)oxy)phenyl)acrylic (17 mg, 0.04 mmol, 53% yield) as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ ppm = 7.64 (d, J = 8.59 Hz, 2H), 7.55-7.62 (m, 2H), 7.51 (d , J = 16.17 Hz, 1H), 7.30 (d, J = 2.02Hz, 1H), 7.13 (d, J = 8.59Hz, 1H), 6.90¬ 7.04 (m, 4H), 6.83 (dd, J = 2.02, 8.59Hz, 1H), 6.38 (d, J = 16.17Hz, 1H), 3. 75 (s, 3H). LC/MS (m/z, MH): 417.5. Example 27 (E)-3-(4-((2-(4-(Difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid
[00348] Step 1: To a microwave vial containing 3-(4-((2-(4-(difluoromethyl)phenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (E)- tert -butyl (50mg, 0.098mmol) in N-methyl-2-pyrrolidone (1.0ml) was added thiophenol (0.015ml, 0.147mmol) followed by K 2 CO 3 (14mg, 0.098mmol). The resulting mixture was subjected to microwave irradiation for 1 hour at 200°C, after which time the reaction was quenched with brine and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to furnish the crude material which was purified by column chromatography (SiO2, 0 to 30% EtOAc/Heptane) to furnish 3-( (E)-tert-butyl 4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30mg, 0.061mmol, 62% of production). LC/MS (m/z, M-H): 493.5
Step 2: To a vial containing (E)- 3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate tert-butyl (30mg, 0.061mmol) in THF (1.0ml) was added HCl (4.70N in dioxane, 0.4ml, 1.600mmol). The resulting mixture was stirred at 50°C for 12 hours, after which time the reaction was concentrated in vacuo and purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 10-100% of CH3CN/H2O) to give (E)-3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (21 mg, 0.048 mmol, 79% yield). LC/MS (m/z, MH): 437.5. Example 28 (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylic acid
To a solution of (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate (107 mg, 0.225 mmol) in DCM (5.0 mL) at 0 °C was added BBr3 (1.0 M in DCM, 0.902 mL, 0.902 mmol) dropwise. The resulting mixture was stirred at 0 °C for 100 minutes, after which the reaction was quenched by addition of saturated aqueous NaHCO3 (4 mL) and acidified to pH 3 by addition of concentrated HCl. The aqueous layer was then extracted with 5% MeOH/EtOAc (4 x 12 mL) and the combined organic layers were passed through a phase separator to remove water and concentrated in vacuo to furnish the crude product which dissolved. in MeOH and purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to give (E)-3-(4-((6-hydroxy-2-() acid 4-hydroxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylic (32.4 mg, 0.078 mmol, 34% yield). HRMS (m/z, MH+): 419.0872. Example 29 (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylic acid
[00351] Step 1: To a solution of 3-(5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate (E )-methyl (0.096 g, 0.215 mmol) in DCM (2.145 mL) at room temperature was added BBr3 (1.0 M in heptane, 0.858 mL, 0.86 mmol) and the reaction was stirred at room temperature for 30 minutes. On completion, the reaction was quenched with MeOH (2.0 mL) and stirred for 10 minutes at room temperature then concentrated in vacuo on silica gel, then purified by column chromatography (SiO2, 0-20 % MeOH/DCM) to give 3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate (E)- methyl. LC/MS (m/z, MH+): 420.3.
[00352] Step 2: To a solution of 3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylate (E )-methyl (0.118 g, 0.28 mmol) in THF (2.00 mL) and water (2.00 mL) was added lithium hydroxide (1.0 M aqueous, 0.844 mL, 0.84 mmol) and the reaction was stirred at room temperature for 2 hours. On completion, the reaction was quenched with water, diluted with DCM and acidified to pH 1 with 1N HCl. The mixture was extracted with DCM (3x) and the combined organic layers were passed through a phase separator and concentrated in vacuum to furnish the crude product which was purified by reverse phase HPLC (acidic condition, 3% TFA in 10 to 100% CH3CN/H2O) to furnish (E)-3-(5-((6-hydroxy) acid -2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylic (14 mg, 0.03 mmol, 9% yield). 1H NMR (400 MHz, (CD3)2SO) δ ppm = 6.66 (d, J = 15.66 Hz, 1H), 6.77-6.81 (m, 2H), 6.84 (dd , J = 8.59, 2.02 Hz, 1H), 7.17 (d, J = 8.59 Hz, 1H), 7.22 (dd, J = 8.59, 3.03 Hz, 1H), 7.31 (d, J = 2.02 Hz, 1H), 7.44-7.49 (m, 2H), 7.52 (d, J = 15.66 Hz, 1H ), 7.64 (d, J = 8.59 Hz, 1H), 8.45 (d, J = 2.53 Hz, 1H). LC/MS (m/z, MH+): 406.2. Example 30 (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylic acid
[00353] Step 1: To a solution of 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate from (E) -ethyl (25.5 mg, 0.05 mmol) in DCM (1.5 mL) at 0 °C was added BBr3 (1.0 M in DCM, 0.215 mL, 0.21 mmol) dropwise. After 4 hours at 0 °C the reaction was quenched with saturated aqueous NaHCO 3 and extracted with 5% MeOH/EtOAc, the combined organic layers were passed through a phase separator and concentrated in vacuo to provide 3-( crude (E)-ethyl 4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate which was used without further purification. LC/MS (m/z, MH+): 446.5.
Step 2: To a crude solution of 3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate (E) )-ethyl (25 mg, 0.06 mmol) in EtOH (1.5 mL) at room temperature was added LiOH (2N aqueous, 0.168 mL, 0.34 mmol), the reaction was allowed to stir at room temperature for 18 hours, after which time the reaction was quenched with 1N HCl (4 mL) and concentrated in vacuo to remove EtOH. The resulting suspension was extracted with 5% MeOH/EtOAc (3X), dried, and concentrated in vacuo to furnish the crude product which was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% of CH3CN/H2O) to give (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylic acid (4 .98 mg, 0.01 mmol, 21% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm = 3.12 (s, 3H), 6.11 (d, 1H, J = 15.66 Hz), 6.56 (d, 2H, J = 8 .59 Hz), 6.65 (d, 2H, J = 9.09 Hz), 6.69 (dd, 1H, J = 8.59, 2.02 Hz), 6.98 (d, 1 H, J = 8.59 Hz), 7.11 (d, 1 H, J = 2.02 Hz), 7.24 (d, 2 H, J = 9.09 Hz), 7.30 (d, 2H, J = 9.09 Hz), 7.48 (d, 1H, J = 16.17 Hz). HRMS (m/z, MH+): 418.1065. Example 31 (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl) acrylamide
To a 30 mL vial containing (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-( 3,3,3- trifluoropropyl)acrylamide (38 mg, 0.07 mmol) in DCM (1 mL) was added BBr3 (1 M in heptane, 0.072 mL, 0.07 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with 4 mL of MeOH and stirred for 10 minutes at room temperature after which time the resulting mixture was concentrated to 50% volume and the crude product was purified by reverse phase HPLC (acidic condition, 0.1 %TFA in 1-100% CH3CN/H2O) to give (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl )-N-(3,3,3-trifluoropropyl)acrylamide (31 mg, 0.06 mmol, 86% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm = 7.40-7.63 (m, 5H), 7.21 (d, J = 2.02 Hz, 1H), 7.15 (d, J = 8.59Hz, 1H), 6.88-6.98 (m, 2H), 6.68-6.87 (m, 3H), 6.45 (d, J = 15.66Hz, 1H), 3.54 (t, J = 7.07Hz, 2H), 2.46 (tq, J = 6.82, 10.95Hz, 2H). LC/MS (m/z, MH+): 500.4. Example 32 (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-hydroxyacrylamide
[00356] To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy )phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (53 mg, 0.099 mmol) was dissolved in DCM (1 mL). The flask was charged with BBr3 (1.0 M in hexanes, 0.298 mL, 0.298 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with 4 mL of MeOH and stirred for 10 minutes. The mixture was concentrated onto silica gel and the crude material was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 30 to 100% CH3CN/H2O) to give (E)-3-(4- ((2-(4-fluoro-2-methylphenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-hydroxyacrylamide (16 mg, 0.037 mmol, 37% yield) as a white solid . 1H NMR (400 MHz, CD3OD) δppm = 2.25 (s, 3H) 6.19 (d, J = 16.17Hz, 1H), 6.66-6.84 (m, 4H) ), 6.88 (dd, J = 9.85, 2.78 Hz, 1H), 7.06-7.26 (m, 3H), 7.26-7.45 (m, 3H) . LC/MS (m/z, MH+): 436.1.
Exemplo 45 3-(4-((6-hidróxi-2-(2-isopropilfenil)benzo[ b ]tiofen-3-il)óxi)fenil)acrilato de (E)-metila[00357] The following examples were prepared using the procedures described in the examples above using appropriate starting materials: Table 2 Example 45 (E)-Methyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate
To a solution of (E)-methyl 3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30mg, 0.065) mmol) in DCM (1.5 mL) at 0 °C was added BBr3 (1.0 M in heptane, 0.196 mL, 0.196 mmol) dropwise. After 1 hour at 0°C the reaction was quenched with saturated aqueous NaHCO 3 and extracted with EtOAc, the combined organic layers were passed through a phase separator and concentrated in vacuo to furnish the crude product which was purified by column chromatography (SiO2, 0 to 30% EtO-Ac/heptane) to provide 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (E)-methyl (25.8 mg, 0.058 mmol, 89% yield). 1H NMR (400 MHz, CDCl3) δ ppm =7.60 (d, J = 15.9 Hz, 1H), 7.40 - 7.25 (m, 8H), 7.15 (ddd, J = 8. 1, 5.5, 3.0 Hz, 1H), 6.91 - 6.85 (m, 3H), 6.29 (d, J = 16.0 Hz, 1H), 3.80 (s, 3H) ), 3.25 (p, J = 6.8 Hz, 1H), 1.19 (d, J = 6.8 Hz, 6H). LC/MS (m/z, M¬H): 443.0. Example 46 (E)-2-(4-fluoro-2-methylphenyl)-3-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)vinyl)phenoxy)benzo[b ]thiophen-6-ol
To a 30 mL screw cap vial, (E)-2-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy )styryl)-5-methyl-1,3,4-oxadiazole (12 mg, 0.025 mmol) was dissolved in DCM (0.5 mL). The flask was charged with BBr3 (1.0 M in hexanes, 0.076 ml, 0.076 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with 2 mL of MeOH and stirred for 10 minutes. The mixture was concentrated onto silica gel and the crude material was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 30 to 100% CH3CN/H2O) to give (E)-2-(4- fluoro-2-methylphenyl)-3-(4-(2-(5-methyl-1,3,4-oxadiazol-2-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol (3mg, 6 .54 µmol, 26% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δppm = 2.26 (s, 3H), 2.45 (s, 3H), 6.73-6.86 (m, 5H), 6.88 (dd , J = 9.85, 2.78 Hz, 1H), 7.08-7.30 (m, 3H), 7.34-7.45 (m, 3H). LC/MS (m/z, MH+): 459.4.
Exemplo 48 (E)-5-(4-((2-(4-fluoro-2-metilfenil)-6-hidroxibenzo[ b ]tiofen-3-il)óxi)estiril)- 1,3,4-oxadiazol-2(3 H )-ona [00360] The following examples were prepared using procedures described in the examples above using appropriate starting materials: Table 3 Example 48 (E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol- 2(3H)-one
To a 30 mL screw cap vial, (E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy )styryl)-1,3,4-oxadiazol-2(3H)-one (15 mg, 0.032 mmol) was dissolved in DCM (1 mL). The flask was charged with BBr3 (1.0 M in hexanes, 0.095 ml, 0.095 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with 4 mL of MeOH and stirred for 10 minutes. The mixture was concentrated on silica gel and the crude material was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 30-100% CH3CN/H2O) to give (E) -5-(4-((2-(4-fluoro-2-methylphenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)- one (6 mg, 0.013 mmol, 41% yield) as a white solid. LC/MS (m/z, MH-): 459.0. Example 49 (E)-2-(4-fluoro-2-methylphenyl)-3-(4-(2-(5-methyl-4H-1,2,4-triazol-3-yl)vinyl)phenoxy) benzo[b]thiophen-6-ol
To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy )styryl)-5-methyl-4H-1,2,4-triazole (15 mg, 0.032 mmol) was dissolved in DCM (1 mL). The flask was charged with BBr3 (1.0 M in hexanes, 0.095 ml, 0.095 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with 4 mL of MeOH and stirred for 10 minutes. The mixture was concentrated to 50% volume and purified by reverse phase HPLC (acidic condition, 0.1% TFA in 30 to 100% CH3CN/H2O) to give (E)-2-(4-fluoro -2-methylphenyl)-3-(4-(2-(5-methyl-4H-1,2,4-triazol-3-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol (7mg, 0.015 mmol, 48% yield) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm = 2.26 (s, 3H), 2.42 (s, 3H), 6.72-6.83 (m, 5H), 6.88 (dd , J = 10.11, 2.53 Hz, 1H), 7.14 (d, J = 2.02Hz, 1H), 7.16-7.26 (m, 2H), 7.29 -7.41 (m, 3H). LC/MS (m/z, MH+): 458.1.
Exemplo 54 (E)-2-(4-hidroxifenil)-3-(4-(2-(1 -metil-1 H-tetrazol-5-il)vinil)- fenóxi)benzo[ b ]tiofen-6-ol [00363] The following examples were prepared from the corresponding methyl ether intermediates using method B: Table 4 Example 54 (E)-2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-tetrazol-5-yl)vinyl)-phenoxy)benzo[b]thiophen-6-ol
To a 30 mL vial containing (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1-methyl -1-H-tetrazol (12 mg, 0.03 mmol) in DCM (1 mL) was added BBr3 (1 M in heptane, 0.077 mL, 0.08 mmol) and the reaction was stirred for 1 hour at room temperature environment. The reaction mixture was quenched with 4 mL of MeOH  and stirred for 10 minutes at room temperature. The reaction mixture was concentrated to 50% volume and the crude product was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 1¬100% CH3CN/H2O) to give (E) -2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-tetrazol-5-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol (4mg, 9, 04 µmol, 35% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm = 7.52 (d, J = 16.67 Hz, 1H), 7.38¬7.48 (m, 4H), 7.09 (d, J = 2.02 Hz, 1 H), 7.06 (d, J = 8.59 Hz, 1 H), 6.96 (d, J = 16.67 Hz, 1 H), 6.81-6.90 (m, 2H), 6.61-6.73 (m, 3H), 4.24 (s, 3H). LC/MS (m/z, MH+): 443.3.
[00365] The following examples were prepared using procedures described in the examples above using appropriate starting materials: Table 5
[00366] Examples 56-62 were prepared from the corresponding methyl- or ethyl ester intermediates by ester hydrolysis using general method C: The corresponding methyl- or ethyl ester was dissolved in ethanol (0.05 - 0.1M), 2M aqueous LiOH solution (5-10 eq.) was added and the mixture stirred at room temperature for 16 hours. The solution was acidified with 4N HCl and the precipitate extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to yield the product. The following examples were prepared using method C from the appropriate starting materials: Table 6
Exemplo 70 (E)-3-(4-((6-hidróxi-2-(4-(trifluorometil)fenil)benzo[b]tiofen-3-il)óxi)fenil)- N-metilacrilamida Examples 63 to 71 were prepared from the corresponding acid by amide formation. General Method D: The corresponding acid was dissolved in DMF (0.03 - 0.1 M), HATU (1.5 equivalents) was added and the mixture stirred for 5 minutes. DIEA (5 equivalents) and the corresponding amine (3 equivalents) were added and the mixture stirred at room temperature 16 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated to yield the crude which was purified by RP-HPLC. The following examples were prepared using method D: Table 7Example 70 (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-methylacrylamide
To a vial containing (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid ( 15.9 mg, 0.035 mmol) was added DMF (1.0 mL), followed by methylamine hydrochloride (7.1 mg, 0.105 mmol), HATU (19.9 mg, 0.052 mmol), and DIEA (0.030 mL, 0.174 mmol). The mixture was stirred at room temperature for 12 hours, after which the reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to furnish the crude product which was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1 to 100% CH3CN/H2O) to provide (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-methylacrylamide (13, 8 mg, 0.029 mmol, 84% yield). 1H NMR (400 MHz, CD3OD) δppm = 2.82 (s, 3H), 6.43 (d, J = 15.66 Hz, 1H), 6.82 (dd, J = 8.59, 2.02 Hz, 1H), 6.89-7.02 (m, 2H), 7.13-7.30 (m, 2H), 7.37-7.52 (m, 3H) , 7.61 (d, J = 8.08 Hz, 2H), 7.85 (d, J = 8.08 Hz, 2H). HRMS (m/z, MH+): 470.1018. Example 71 (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)-N-methylacrylamide
To a solution of (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylic acid ( 0.057 g, 0.14 mmol) in DMF (1.406 mL) were added HATU (0.064 g, 0.17 mmol), methylamine hydrochloride (10.45 mg, 0.16 mmol) and NMM (0.077 mL, 0.70 mmol). The resulting mixture was stirred at room temperature for 48 hours, after which time the reaction was quenched with saturated aqueous 4N HCl and extracted with EtOAc (3x). The combined organic layers were passed through a phase separator and concentrated in vacuo to furnish the crude product which was purified by reverse phase HPLC (acidic condition, 3% TFA in 10¬100% CH3CN/H2O) to provide (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)-N-methylacrylamide (30mg, 0 .05 mmol, 37% production). 1H NMR (400 MHz, (CD3)2SO) δ ppm = 2.67-2.72 (m, 3H), 6.77-6.90 (m, 4H), 7.14-7.23 ( m, 2H), 7.30 (d, J = 2.02 Hz, 1H), 7.36 (d, J = 15.16 Hz, 1H), 7.44-7.51 (m, 3H) ), 8.42 (d, J = 3.03 Hz, 1H). LC/MS (m/z, MH+): 419.3.
[00370] Examples 72 to 75 were prepared from the corresponding bromide (Intermediate O) by Heck reaction. General method E: Bromide (intermediate O) was dissolved in DMF (0.02 - 0.1 M), triethyl amine (10% DMF), the corresponding terminal alkene (3 equivalents) and Pd(PPh3)2Cl2 (0.1 eq.) was added and the system purged with nitrogen. The mixture was heated at 150 °C for 1 to 3 hours under microwave irradiation. The mixture was cooled to room temperature and diluted with DCM and saturated aqueous NH4Cl. The organic layer was collected (phase separator), concentrated in vacuo and purified by reverse phase HPLC. Example 72 (E)-3-(4-(2-(1H-imidazol-4-yl)vinyl)phenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol
To a microwave vial containing 3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (20 mg, 0.05 mmol) in DMF (2 mL) triethyl amine (0.202 mL, 1.45 mmol), tert-butyl 4-vinyl-1H-imidazole-1-carboxylate (28.2 mg, 0.15 mmol) and Pd(PPh3)2Cl2 (3,) were added. 40mg, 4.84µmol). The system was stimulated with nitrogen and heated to 150 °C for 1 hour under microwave irradiation. The mixture was cooled to room temperature and diluted with DCM and saturated aqueous NH4Cl. The organic layer was collected (phase separator), concentrated in vacuo and purified by reverse phase HPLC (basic condition, 0.1% NH4OH in 1 to 100% CH3CN/H2O) to give (E)-3 -(4-(2-(1-H-imidazol-4-yl)vinyl)phenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (3mg, 7.03μmol, 15% production) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm = 7.57 (s, 1H), 7.43 (d, J = 8.59 Hz, 2H), 7.30 (d, J = 8.59 Hz , 2H), 6.96-7.14 (m, 3H), 6.74-6.96 (m, 4H), 6.53-6.74 (m, 3H). LC/MS (m/z, MH+): 427.3. Example 73 (E)-2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-imidazol-4-yl)vinyl)phenoxy)-benzo[b]thiophen-6-ol
To a microwave vial, 3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (50 mg, 0.121 mmol) was dissolved in DMF (2 ml) and triethyl amine (0.506 ml, 3.63 mmol). To the solution were added 4-vinyl-1-methyl imidazole (39.2 mg, 0.363 mmol) and Pd(PPh3)2Cl2 (8.49 mg, 0.012 mmol). The system was stimulated with nitrogen and heated to 150 °C for 1 hour under microwave radiation. The mixture was cooled to room temperature and diluted with DCM and saturated NH4Cl. The organic layer was collected (phase separator) and purified by reverse phase HPLC (acidic condition, 0.1% TFA in 1 to 100% CH3CN/H2O) to provide (E)-2-(4-hydroxyphenyl) -3-(4-(2-(1-methyl-1H-imidazol-4-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol (31mg, 0.070mmol, 58.2% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm = 3.82 (s, 3H) 6.57 - 6.74 (m, 3H) 6.75 - 6.93 (m, 3H) 6.98 - 7.14 (m, 3H) 7.32 - 7.54 (m, 5H) 8.73 (s, 1H). LC/MS (m/z, MH+): 441.3.
[00373] The following examples were prepared using the E method: Table 8
Exemplo 78 (E)-4-(4-((6-hidróxi-2-(2-isopropilfenil)benzo[ b ]tiofen-3-il)óxi)fenil)but-3- en-2-ona [00374] The following examples were prepared using procedures described in the above examples 1 to 75 using appropriate starting materials: Table 9 Example 78 (E)-4-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2-one
To a solution of (E)-4-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2- One (71.3 mg, 0.161 mmol) in DCM (2.5 mL) at 0°C was added BBr3 (1.0 M in Heptane, 0.403 mL, 0.403 mmol) dropwise. The resulting mixture was stirred at 0°C for 1 hour, after which time the reaction was quenched by addition of saturated aqueous NaHCO3 solution and extracted with 10% i-PrOH/DCM (3X). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 45-70% CH3CN/H2O) to give (E)-4-(4-((6-hydroxy-2-( 2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)but-3-en-2-one (11.1 mg, 0.026 mmol, 16%). 1H NMR (400 MHz, CD3OD) δ ppm = 7.55 (d, J = 16.3 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.37 - 7.19 (m, 5H), 7.14 - 7.08 (m, 1H), 6.86 (d, J = 8.8 Hz, 3H), 6.63 (d, J = 16.3 Hz, 1H) , 3.23 (p, J = 6.9 Hz, 1H), 2.33 (s, 3H), 1.16 (d, J = 6.8 Hz, 6H). HRMS (m/z, MH+): 429.1509. Example 79 (E)-3-(4-((2-(2-(Difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid
To a solution of (E)-tert-butyl 3-(4-((2-(2-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (100mg, 0.202mmol) in 1,4-dioxane (3.0ml) was added aqueous 4.0M HCl (0.202ml, 0.809mmol). The resulting mixture was heated to 50°C and stirred at that temperature for 2 hours, after which time the reaction was quenched by addition of saturated aqueous NaHCO 3 and extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the resulting crude material was purified by reverse phase HPLC (basic conditions, 0.1% NH4OH in CH3CN/H2O) to give acid ( E)-3-(4-((2-(2-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic (16.7 mg, 0.037 mmol, 19% of production). 1H NMR (400 MHz, CD3OD) δ ppm = 7.72 - 7.64 (m, 1H), 7.54 - 7.42 (m, 4H), 7.39 (d, J = 8.7 Hz, 2H), 7.33 - 7.24 (m, 2H), 7.00 (d, J = 55.2 Hz, 1H), 6.88 (dd, J = 8.7, 2.2 Hz, 1H), 6.81 (d, J = 8.9 Hz, 2H), 6.30 (d, J = 16.0 Hz, 1H). HRMS (m/z, MH+): 439.0776. Example 80 (E)-3-(4-((6-hydroxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid
To a solution of (E)-3-(4-((6-methoxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (45 0.9mg, 0.103mmol) in N-methyl-2-pyrrolidone (1.0ml) was added thiophenol (0.016ml, 0.154mmol) and K 2 CO 3 (14.21mg, 0.103mmol). The resulting mixture was subjected to microwave irradiation at 200°C for 90 minutes, after which time the reaction was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo and the crude material was purified by was purified by reverse phase HPLC (basic condition, 0.1% NH4OH in CH3CN/H2O) to give (E)-3-(4-((6-) acid. hydroxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic (3.0 mg, 0.00645 mmol, 6% yield). 1H NMR (400 MHz, CD3OD) δ ppm = 7.47 (d, J = 7.7 Hz, 1H), 7.40 - 7.31 (m, 4H), 7.31 - 7.21 (m, 4H), 6.86 (dd, J = 8.7, 2.1 Hz, 1H), 6.79 (d, J = 8.4 Hz, 2H), 6.35 (d, J = 15.9 Hz, 1H), 4.53 (s, 2H), 3.29 (s, 3H). HRMS (m/z, M+H2O): 450.1355. Example 81 (E)-isopropyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate
To a solution of 3-(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate of (E )-isopropyl (35mg, 0.060mmol) in THF (2.0ml) at 0°C was added tetra-n-butylammonium fluoride (1.0M in THF, 0.089ml, 0.089mmol) dropwise , the reaction immediately turned bright yellow in color. Stirring was continued at 0°C for 45 minutes, after which the reaction was warmed to room temperature for 15 minutes and then quenched by addition of saturated aqueous NaHCO3 . The aqueous layer was extracted with EtOAc (4x) and the combined organic layers were dried over aqueous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0-20% EtOAc/Heptane) to give 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-) (E)-isopropyl yl)oxy)phenyl)acrylate (14.0 mg, 0.029 mmol, 49% yield). 1H NMR (400 MHz, CD3OD) δ ppm = 7.55 (d, J = 16.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.37 - 7.20 (m, 5H), 7.11 (td, J = 7.6, 1.5 Hz, 1H), 6.89 - 6.81 (m, 3H), 6.32 (d, J = 16.0 Hz, 1H), 5.05 (p, J = 6.2 Hz, 1H), 3.23 (p, J = 6.9 Hz, 1H), 1.28 (d, J = 6.2 Hz, 6H), 1.16 (d, J = 6.8 Hz, 6H). HRMS (m/z, MH+): 473.1774. Example 82 (E)-3-(4-((6-Acetoxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid
To a solution of (E)-tert-butyl 3-(4-((6-acetoxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (65 mg, 0.123 mmol) in DCM (3.0 mL) at 0°C was added TFA dropwise over 5 minutes. The reaction was stirred at 0°C for 1 hour, after which time it was warmed to room temperature for a further 55 minutes. The mixture was then diluted with DCM and concentrated in vacuo to remove both DCM and TFA. The crude material was then also azeotroped with DCM (3x) to make sure all TFA was removed and provided a pale yellow solid. The resulting crude material was dissolved in MeOH (3 mL) and purified by reverse phase HPLC (acidic conditions, 0.1% TFA in 45-70% CH3CN/H2O) to give acid (E)-3-(4 -((6-acetoxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic (39.1 mg, 0.083 mmol, 67% yield). 1H NMR (400 MHz, CD3OD) δ ppm = 7.69 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 15.9 Hz, 1H), 7.45 (dd, J = 8.7, 6.4 Hz, 3H), 7.40 - 7.26 (m, 3H), 7.18 - 7.10 (m, 2H), 6.86 (d, J = 8.8 Hz, 2H), 6.32 (d, J = 16.0 Hz, 1H), 3.20 (p, J = 6.9 Hz, 1H), 2.32 (s, 3H), 1.17 ( d, J = 6.9 Hz, 6H). HRMS (m/z, MH+): 473.1399. Example 83 (E)-3-(4-((2-(2-Isopropylphenyl)-6-((3-methoxypropanoyl)oxy)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid
[00380] Step 1: To a solution of (E)-tert- 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate Butyl (42 mg, 0.086 mmol) in DCM (3 mL) at room temperature was added 3-methoxypropanoyl chloride (15.87 mg, 0.129 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (0.030 ml, 0.172 mmol). The resulting mixture was stirred at room temperature for 2 hours, after which time an additional amount of methoxypropanoyl chloride (15.87 mg, 0.129 mmol) was added and stirring was continued at room temperature for 18 hours. . On completion, the reaction was concentrated in vacuo and used in the next step without further purification.
[00381] Step 2: The resulting crude product was taken up in DCM (3 ml) and trifluoroacetic acid (3 ml). The mixture was stirred at room temperature for 1 hour, after which the reaction was concentrated in vacuo and the resulting crude material was purified by reverse phase HPLC (acidic condition, 0.1% formic acid as the modifier , 55-80% CH3CN/H2O) to give (E)-3-(4-((2-(2-isopropylphenyl))-6-((3-methoxypropanoyl)oxy)benzo[b]thiophen-3-acid yl)oxy)phenyl)acrylic (15mg, 0.029mmol, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 2.1 Hz, 1H), 7.61 - 7.56 (m, 2H), 7.51 - 7.33 (m, 6H), 7.21 (td, J = 7.3, 1.6 Hz, 1H), 7.15 (dd, J = 8.7, 2.1 Hz, 1H), 6.93 - 6.86 (m, 2H), 6.35 (d, J = 16.0 Hz, 1H), 3.69 (t, J = 6.1 Hz, 2H), 3.30 (s, 3H), 3.14 (p, J = 6.8 Hz, 1H), 2.87 (t, J = 6.0 Hz, 2H), 1.14 (d, J = 6.8 Hz, 6H). HRMS (m/z, MH+): 517.1689. Example 84 (E)-3-(4-((6-((1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)methoxy)-2-(2-isopropylphenyl) acid benzo[b]thiophen-3-yl)oxy)phenyl)acrylic
To a solution of 3-(4-((6-((1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)methoxy)-2-(2-isopropylphenyl)benzo (E)-tert-butyl [b]thiophen-3-yl)oxy)phenyl)acrylatoin (67.4 mg, 0.099 mmol) in DCM (2 mL) at room temperature was added trifluoroacetic acid (0.227 mL, 2.97 mmol). The resulting mixture was stirred at room temperature for 1 hour, after which the reaction was concentrated in vacuo. The resulting crude material was purified by reverse phase HPLC (acidic condition, 0.1% formic acid as the modifier, 55-80% CH3CN/H2O) to give (E)-3-(4-((6) acid -((1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)methoxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic ( 41.4 mg, 0.066 mmol, 66% yield). 1H NMR (400 MHz, (CD3)2SO) δ 12.33 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.18 (d, J = 7.5 Hz, 1H), 8.11 (t, J = 7.5 Hz, 1H), 8.04 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H) , 7.60 - 7.54 (m, 2H), 7.47 (d, J = 16.0 Hz, 1H), 7.44 - 7.29 (m, 4H), 7.24 - 7.15 (m, 2H), 6.92 - 6.84 (m, 2H), 6.35 (d, J = 16.0 Hz, 1H), 5.90 (s, 2H), 3.14 (h, J = 6.9 Hz, 1H), 1.13 (d, J = 6.9 Hz, 6H). HRMS (m/z, MH+): 626.1207. Example 85 (S,E)-3-(4-((6-((2-amino-3-methylbutanoyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy) acid phenyl) acrylic
A solution of (S,E)-3-(4-(3-(tert-butoxy)-3-oxoprop-1-en-1) 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate - yl)phenoxy)-2-(2-isopropylphenyl)benzo[b]thiophen-6-yl (106.8 mg, 0.156 mmol) in HCl (2.0 mL, 4N in 1,4-dioxane) was stirred in at room temperature for 18 hours, after which time the mixture was concentrated in vacuo to remove the HCl and 1,4-dioxane. The resulting crude material was then triturated with heptane (2X) to obtain (S,E)-3-(4-((6-((2-amino-3-methylbutanoyl)oxy)-2-(acid hydrochloride) 2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic (54.1 mg, 0.094 mmol, 85% yield). 1H NMR (400 MHz, CD3OD) δ ppm = 7.81 (d, J = 2.02 Hz, 1H), 7.42 - 7.62 (m, 4H), 7.25 - 7.42 (m, 3H), 7.09 - 7.26 (m, 2H), 6.86 (d, J=8.59 Hz, 2H), 6.32 (d, J=15.66 Hz, 1H), 4.29 (d, J=5.05Hz, 1H), 3.18 (s, 1H), 2.44 - 2.60 (m, 1H), 1.12 - 1.35 (m, 12H) HRMS (m/z, MH+): 530.1988.





Exemplo 139 Ácido (E)-3-(4-((2-(2-(1,1-difluoroetil)-4-fluorofeml)-6- hidroxibenzo[ b ]tiofen-3-il)óxi)fenil)acrílico
[00384] The following examples were prepared using procedures described in the above examples 1-85 using appropriate starting materials:
















Example 139 (E)-3-(4-((2-(2-(1,1-Difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid

Step 1: 2-Bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (compound 26). To a solution of 2,3-dibromo-6-methoxybenzo[b]thiophene 1,1-dioxide (2.50 g, 7.06 mmol) in THF (100 mL) at room temperature was added 4-bromophenol (1.344 g, 7.77 mmol) and Cs2CO3 (6.90 g, 21.19 mmol). The reaction mixture turned green after ~1 minute of stirring. The mixture was stirred at room temperature for 18 hours, after which time the reaction was quenched with water and diluted with DCM. The organic layer was collected (phase separator) and concentrated to give 2-bromo-3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (3.10 g, 6.95 mmol, 98% yield) as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δppm = 3.83 (s, 3H), 6.92¬7.03 (m, 3H), 7.25-7.35 (m, 2H), 7 .39-7.50 (m, 2H).
Step 2: 3-(4-Bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (compound 27). To a solution of 2-bromo-3-(4-bromophenoxy)-6-methoxy-benzo[b]thiophene 1,1-dioxide (3.10 g, 6.95 mmol) in MeOH (10 mL) and DMSO (30 mL) was added NaBH4 (0.789 g, 20.85 mmol). The mixture was stirred at room temperature for 3 hours, after which time the reaction was quenched with water and diluted with DCM. The organic layer was collected (phase separator) and concentrated to provide 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (2.47 g, 6.73 mmol, 97% yield ) as an off-white solid that was used without further purification. 1H NMR (400 MHz, CDCl 3 ) δ ppm = 3.85 (s, 3H), 5.38 (s, 1H), 7.02-7.08 (m, 3H), 7.22 (d , J = 2.53 Hz, 1H), 7.47-7.60 (m, 3H).
[00387] Step 3: 3-(4-Bromophenoxy)-6-methoxybenzo[b]thiophene (compound 28). To a solution of 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene 1,1-dioxide (2.47 g, 6.73 mmol) in THF (90 mL) was added DIBAL-H ( 1.0 M in DCM, 33.6 mL, 33.6 mmol) in one portion. The mixture was heated to 75 °C for 2 hours, after which time the reaction was cooled to room temperature and quenched with EtO-Ac (32.9 mL, 336 mmol). The resulting solution was stirred for 10 minutes, before carefully adding 75 mL of water and potassium sodium tartrate (33.100 g, 117 mmol). The mixture was stirred vigorously for 10 minutes and diluted with 75 mL EtOAc. The organic layer was collected, dried over anhydrous MgSO4 and concentrated in vacuo to provide 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (1.9 g, 5.67 mmol, 84% yield ) as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ ppm = 3.81 (s, 3H), 6.46 (s, 1H), 6.90 (d, J = 9.09Hz, 3H), 7. 16-7.22 (m, 1H), 7.31-7.40 (m, 2H), 7.46 (d, J = 9.09Hz, 1H). LC/MS (m/z, MH+): 336.8.
Step 4: (E)-Methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 29). To a microwave vial, 3-(4-bromophenoxy)-6-methoxybenzo[b]thiophene (500 mg, 1.49 mmol), methyl acrylate (770 mg, 8.95 mmol), and Pd( PPh3)2Cl2 (157 mg, 0.22 mmol) were suspended in DMF (12 mL) and triethylamine (1.039 mL, 7.46 mmol). The reaction was heated for 60 minutes at 120 °C under microwave irradiation. The reaction mixture was diluted with DCM and water. The organic layer was collected (phase separator) and concentrated to obtain the crude product. The crude material was purified by column chromatography (SiO 2 , 1-20% EtOAc/Heptane) to give (E) 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate )-methyl (311 mg, 0.91 mmol, 61% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm = 1.46 (s, 3H), 3.73 (s, 3H), 6.28 (d, J = 16.17Hz, 1H), 6. 59 (s, 1H), 6.90 (dd, J = 8.59, 2.02 Hz, 1H), 7.00 (d, J = 8.59 Hz, 2H), 7.21 ( d, J=2.02Hz, 1H), 7.37-7.48 (m, 3H), 7.59 (d, J=16.17Hz, 1H). LC/MS (m/z, MH+): 341.1.
Step 5: (E)-Methyl 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 134). To a solution of (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (2.1 g, 6.17 mmol) in THF 201 mL) in At room temperature, N-bromosuccinimide (1.208 g, 6.79 mmol) was added. The resulting solution was vigorously stirred at room temperature for 2 hours, after which time the reaction was quenched by addition of saturated aqueous sodium thiosulfate solution and extracted with EtOAc (3x). The combined organic layers were dried over aqueous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0-40% EtOAc/Heptane) to provide 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy (E)-methyl)phenyl)acrylate (2.4 g, 5.72 mmol, 93% yield). 1H NMR (400 MHz, CDCl3) δppm 7.65 (d, J = 16.0 Hz, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.9 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.91 (dd, J = 8. 8. 2.2 Hz, 1H), 6.31 (s, 1H), 3.86 (s, 3H), 3.79 (s, 3H). LC/MS (m/z, MH+): 420.9.
[00390] Step 6: (E)-Methyl 3-(4-((2-bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate and (E)-3-(4 acid) -((2-bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic (compounds 135 and 136). To a solution of (E)-methyl 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (2.4 g, 5.72 mmol) in DCM (20 mL) at room temperature was added BBr3 (1.0 M in Heptane, 17.17 mL, 17.17 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 hours, after which time an aqueous buffer (pH 7.4, made of citric acid and dibasic sodium phosphate, 10 ml), cooled to 0°C, was slowly added into the reaction. The resulting mixture was then diluted with DCM (30 ml) and stirred at room temperature for 1 hour. The phases were then separated and the organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography (SiO 2 , 0-100% EtOAc/Heptane) to give 3-(4-((2-bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy) (E)-methyl phenyl)acrylate (1.6 g, 3.95 mmol, 69% yield) as a pale yellow solid and (E)-3-(4-((2-bromo-6-hydroxybenzoic) acid [b]thiophen-3-yl)oxy)phenyl)acrylic (370 mg, 0.946 mmol, 17% yield) as a yellow solid.
(E)-Methyl 3-(4-((2-bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate: 1H NMR (400 MHz, CD3OD) δ ppm 3, 76 (s, 3H), 6.43 (d, J=16.17Hz, 1H), 6.82 (dd, J=8.84, 2.27Hz, 1H), 6.90 - 6.97 (m, 2H), 7.17 (d, J=2.02 Hz, 1H), 7.22 (d, J=8.59 Hz, 1H), 7.53 - 7, 62 (m, 2H), 7.65 (d, J=15.66Hz, 1H). LC/MS (m/z, MH+): 406.8.
(E)-3-(4-((2-Bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid: 1H NMR (400 MHz, CD3OD) δ ppm 6.38 (d, J=16.17 Hz, 1H), 6.82 (dd, J=8.59, 2.02Hz, 1H), 6.89 - 6.97 (m, 2H), 7 .17 (d, J=2.02 Hz, 1H), 7.23 (d, J=8.59Hz, 1H), 7.53 - 7.60 (m, 2H), 7.63 (d, J=15.66 Hz, 1H). LC/MS (m/z, MH+): 392.8.
Step 7: 1-bromo-2-(1,1-difluoroethyl)-4-fluorobenzene (compound 149). To a solution of DeoxoFluor® (8.49 ml, 46.1 mmol) and MeOH (2 drops) was added 1-(2-bromo-5-fluorophenyl)ethanone (5.0 g, 23.04 mmol). The resulting mixture was heated to 70°C for 18 hours, after which time the reaction was quenched by slow addition to 50 ml of ice water and diluted with diethyl ether. The organic layer was collected and washed with saturated aqueous NaHCO3 solution (2X), citric acid, and brine. The organic layers were concentrated in vacuo and purified by column chromatography (SiO 2 , 0-20% EtO-Ac/Heptane) to give 1-bromo-2-(1,1-difluoroethyl)-4-fluorobenzene (3 .83 g, 16.02 mmol, 69.6% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD) δppm 1.98 - 2.11 (m, 3H), 7.15 (td, J=8.21, 3.28 Hz, 1H), 7.39 (dd, J =9.60, 3.03 Hz, 1H), 7.71 (dd, J=8.59, 5.05 Hz, 1H). 19F NMR (376 MHz, CD3OD) δppm -115.63 (s, 1F), -88.94 (s, 2F).
Step 8: 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 150). To a solution of 1-bromo-2-(1,1-difluoroethyl)-4-fluorobenzene (3.83 g, 16.02 mmol) in 1,4-dioxane (15 mL) was added Bis(pinacolato)diborone ( 5.29 g, 20.83 mmol), potassium acetate (3.15 g, 32.0 mmol) and PdCl2(PPh3)2 (1.125 g, 1.602 mmol). The resulting mixture was heated to 80°C and stirred under a nitrogen atmosphere for 18 hours, after which time the mixture was cooled to room temperature and concentrated onto silica gel. The crude material was then purified by column chromatography (SiO 2 , 0-15% EtOAc/Heptane) to give 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5 ,5-tetramethyl-1,3,2-dioxaborolane (2.90 g, 10.14 mmol, 63% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD) δppm 1.37 (s, 12H), 2.01 (t, J=18.44 Hz, 3H), 7.18 (td, J=8.34, 2 .53Hz, 1H), 7.25 (dd, J=10.11, 2.53Hz, 1H), 7.62 (dd, J=8.08, 6.57Hz, 1H).
Step 9: 3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate ( E)-methyl (compound 151). To a solution of (E)-methyl 3-(4-((2-bromo-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (1.6 g, 3.95 mmol) in toluene (20 ml) and water (2 ml) was added 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.259 g, 7.90 mmol), K2CO3 (2.73 g, 19.74 mmol), and Pd(PPh3)4 (0.456 g, 0.395 mmol). The resulting mixture was heated to 90°C for 18 hours, after which time the reaction was cooled to room temperature and filtered to remove solids. The filtrate was acidified with HCl (1N aqueous) and extracted with DCM, the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO 2 , 0-60% EtOAc/Heptane) to give 3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6 (E)-methyl-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (1.4 g, 2.89 mmol, 73.2% yield) as a light orange solid. The product was dissolved in DCM and treated with Pd scavenger for two hours at room temperature then filtered, and the filtrate collected and concentrated in vacuo to provide the final product. 1H NMR (400 MHz, CD3OD) δ ppm 1.89 (t, J=18.69 Hz, 3H), 3.75 (s, 3H), 6.37 (d, J=16.17 Hz, 1H), 6 .80 - 6.89 (m, 3H), 7.11 (td, J=8.21, 2.78 Hz, 1H), 7.17 - 7.25 (m, 2H), 7.31 - 7 .42 (m, 2H), 7.44 - 7.51 (m, 2H), 7.59 (d, J=16.17 Hz, 1H).
[00396] Step 10: (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy) acid phenyl)acrylic (example 140). To a solution of 3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate from (E) -methyl (1.4 g, 2.89) in THF (5 mL) and water (3 mL) was added 56% LiOH monohydrate (371 mg, 8.67 mmol). The resulting mixture was stirred at room temperature for 18 hours, after which time the reaction was concentrated in vacuo to remove THF and the resulting solution was diluted with water and acidified by addition of HCl (1N aq.), causing a precipitate to precipitate. up. The resulting precipitate was filtered to provide (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl acid )oxy)phenyl)acrylic as a white solid which was not purified again (980 mg, 2.021 mmol, 69.9% yield). 1H NMR (400 MHz, CD3OD) δ ppm = 1.80 (t, J=18.44 Hz, 3H), 6.23 (d, J=16.17Hz, 1H), 6.71 - 6 .81 (m, 3H), 7.03 (td, J=8.21, 2.78 Hz, 1H), 7.08 - 7.14 (m, 2H), 7.22 - 7. 32 (m, 2H), 7.37 (d, J=8.59Hz, 2H), 7.47 (d, J=16.17Hz, 1H). LC/MS (m/z, M-H): 468.9. Essay
The compounds of the invention were evaluated for their ability to be potent both as estrogen receptor agonists and to degrade estrogen receptors. The antagonistic and degrading properties of the compounds of the invention described herein can be evidenced by testing in the ER transcription and ERα degradation assays, respectively. ER Transcription Assay (MCF7 cells)
The ER transcription assay is a reporter assay that is based on the ability of ER to induce transcription of a luciferase reporter gene containing estrogen response elements (EREs) in the promoter/enhancer region. When the reporter gene is transfected into MCF7 cells (containing endogenous ER), transcription is reflected by the level of luciferase expression.
MCF7 cells are maintained in DMEM/F12 (Gibco, catalog number 11330) supplemented with 10% fetal bovine serum (FBS) (Gemini Bio-Products, catalog number 100-106). A previous transfection, cells are split into a T75 flask at a density of 300,000 cells/mL (10 mL total) and allowed to attach overnight in a humidified 37°C CO2 incubator.
[00400] The next day, before transfection, the media are exchanged for DMEM/F12 (Gibco, catalog number 21041) supplemented with 10% charcoal extracted serum (Gemini Bio-Products, catalog number 100-119). MCF7 cells are then transfected in bulk using Lipofectin (Invitrogen, catalog number 18292) with the following plasmids: 7x-TK-ERE-Luc3 (ER reporter gene) and pCMV-Renilla (normalization control). Briefly, for each vial of T75, 32.5 µL of Lipofectin is added 617.5 µL of OptiMEM (Gibco #11058) and incubated for 30 minutes at 37°C. Approximately 20 ug of DNA is mixed in OptiMEM (Invitrogen) for a total volume of 650 μL. After incubation, the OptiMEM-DNA mixture is added to the OptiMEM-Lipofectin mixture and incubated for 15 minutes at 37°C. The DNA-Lipofectin mix is then added directly to the T75 vial and the vial is returned to the incubator.
[00401] After overnight incubation, the compound is added to the individual wells of a 96-well plate in a volume of 10 µL of media at a concentration of 10x together with 17β estradiol whose final concentration is 0.1 nM. Typically, DMSO (used as a vehicle) is included to obtain a final concentration of 0.1% when added to cells. Transfected cells are trypsinized, resuspended in DMEM/F12/10% charcoal extracted serum and added to 96-well plates at 25,000 cells/well in 90 µL of media. The plate is then returned to the incubator for 24 hours.
[00402] After incubation with compounds for 24 hours, firefly and Renilla luciferase activities are measured to determine ER transcriptional activity. Media are removed from 96-well plates by decanting and blotting onto paper towels. Cells are lysed with 40ul/well of 1X passive lysis buffer (25 mM Tris phosphate, 2 mM CDTA, 10% Glycerol, 0.5% Triton X-100 and 2 mM DTT before use) and allowed to incubate at room temperature for 10 minutes.
Luciferase firefly activity is measured by adding 30 ul of luciferase firefly assay buffer (20 mM Tricine, 0.1 mM EDTA, (MgCO3)4 Mg(OH)2 to 1.07 mM • 5H2O, 2.67 mM MgSO4, 33.3 mM DTT, 270 μM Coenzyme A, 470 μM luciferin, 530 μM Ade TP, reconstituted) per well, followed by light unit evaluation using a luminometer ( BMG labtech FLUOstar OPTIMA). A total read time of one second after one second of delay.
Renilla luciferase activity is measured by adding 50 ul of Renilla luciferase assay buffer (1.1M NaCl, 2.2mM Na2EDTA, 0.22M KxPO4 (pH 5.1), 0 .44 mg/ml BSA, 1.3 mM NaN3, 1.43 µM coelenterazine, pH adjusted to pH 5.0), per well, followed by light unit evaluation using using a luminometer. A total read time of one second after one second of delay. If the luciferase firefly signal is elevated, the Renilla test should be done one hour after the firefly test due to incomplete termination of the firefly signal. Degradation of ERα (MCF7 cells)
Plate MCF7 cells at 0.3 million cells/ml (100 µl/well) in 96-well, clear base, black plates (Grei¬ner, catalog number 655090) in DMEM/F12 media ( Gibco, catalog number 11330) supplemented with 10% charcoal extracted serum (Gemini Bio-Products, catalog number 100-119), and incubate them at 37°C, 5% CO2 for 24-36 hours. The next day, prepare 10x solutions of ligands in DMSO and add the solution to the cells to obtain a final concentration of 10 µM. A DMSO control is required for relative calculations, and fulvestrant is used as a positive control for ER degradation. Cells are subjected to in-cell Western assay after incubation of cells with ligand for 18 to 24 hours.
[00406] The media are removed from the plates by decantation, and the cells are immediately fixed with 100 µl of 3.7% formaldehyde in PBS using a multichannel pepitor. Add formaldehyde to the sides of the wells to prevent cell breakage. Plates are incubated at room temperature for 20 minutes without shaking. The fixed solution is then removed and the cells are permeabilized with 100 µL/well of 0.1% Triton X-100 in PBS. The lysate is then blocked by adding 50 uL/well of blocking solution (3% goat serum, 1% BSA, 0.1% cold fish skin gelatin and 0.1% of Triton X-100 in PBS, pH 7.4) and allowed to stir at room temperature for 2 hours, or alternatively at 4°C overnight.
[00407] After blocking, 40 μL/well of primary antibody against ERα (HC-20) (Santa cruz, catalog number 543) diluted 1:3000 in blocking buffer diluted 1:3 with PBS is added to each well, except for the negative control wells (which are used for base subtraction) and the plate is sealed and incubated overnight at 4°C. The next day, the primary antibody solution is removed and the wells are washed three times with 0.1% TWEEN in PBS, with each wash lasting 5 minutes. 40μL/well of secondary antibody (Goat Anti-Rab Biotium CF770 1:2000, catalog number 20078) and DRAQ5 (DNA staining, 5mM, Thermo Scientific, catalog number 62251) diluted to 1:10000 in diluted blocking buffer 1:3 with PBS is then added to all wells, including the negative control wells, and the plate is allowed to incubate on the shaker at room temperature for 2 hours. The secondary antibody solution is then removed and the plates washed three times as described above. The plate is then washed once with PBS just to minimize autofluorescence. The plate is then cleaned and read on a LiCor Odyssey imager.
[00408] For % of response calculations, please divide the intensities integrated as to channel 700 (ER) by intensities integrated as to channel 800 (DNA normalization); 700 (ER)/800 (DNA). This will be referred to as the normalized value. Then subtract the mean of the negative control wells (no primary antibody) from all normalized values. This corresponds to negative subtraction. % Response = (Unknown Value / DMSO Control Value) *100.
The data describing the antagonist and degradation properties for the examples are compiled in table 11. The column titled IC50 of MCF7 reports the inflection point of inhibition of transcription in MCF7 cells as described above. Percent remaining ERα reports remaining ERα protein measured at 10 µM ligand concentration as described above. The ERα IC50 column reports the inflection point of degradation in response to binder concentration, eg (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene) acid -3-yl)oxy)phenyl)acrylic (example 2), inhibits 50% of ERα-induced transcriptions in MCF7 cells at a concentration of 0.748 μM and degrades the ERα receptor, at a concentration of 10μM in 59 %. Half of the observed degradation occurs at a concentration of 0.026 µM. Table 11






[00410] It is understood that the examples and modalities described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to persons skilled in the art and shall be included in the spirit and competence of this application and scope of the claims attached.

权利要求:
Claims (20)
[0001]
na qual: n é selecionado entre 0, 1 e 2; m é selecionado entre 0, 1 e 2; X é selecionado a partir de O e NR 6 ; em que R 6 representa C 1-4 alquila; Y 1 é selecionado dentre N e CR 7 ; em que R 7 selecionado dentre hidrogênio e C 1-4 alquila; R 1 hidrogêio; R 2 é selecionado dentre hidrogênio e halo; R 3 é selecionado dentre -CH 2 CH 2 R 8b e -CR 8a = CR 8a R 8b ; em que cada R8a é independentemente selecionado a par¬tir de hidrogênio, fluoro e C1-4alquil; e R 8b é selecionado a partir de -C (O) OR 9a , - C (O) NR 9a R 9b , -C (O) NHOR 9a , -C (O) X 2 R 9a e um heteroaril com 5-6 membros selecionado a partir de :  sendo que a linha a tracejado indica o ponto de ligação com -CH 2 CH 2 ou -CR 8a = CR 8a de R 3 ; em que X 2 representa C 1¬4 alquileno; R 9a e R 9b s independentemente selecionados de hidrogê¬nio, C 1-4 alquila, hidroxi-substituído-C 1-4 alquila, halo-substituído-C 1¬4 alquila e -X 4 R 10 ; em que X 4 é selecionado dentre uma ligao e C 1¬3 alquileno; e R wé um anel saturado de 4-6 membros contendo 1 a 3 átomos selecionados independentemente de O, N e S; em que o refe¬rido heteroaril de R8b é não substituído ou substituído com 1 a 3 grupos selecionados independentemente de C1-4alquil e C3-8 cicloalquil; R 4 selecionado dentre hidrogênio, C 1-4 alquila, halo e C 1¬3 alcoxi; R 5 selecionado de C 6-10 arila e um heteroarila de 5-6 membros selecionado dentre: sendo que a linha tracejada indica o ponto de ligação com o núcleo do benzotiofeno; onde os referidos C 6-10 arila ou heteroarila de R 5 é substituído por 1 a 3 grupo selecionado a partir de -X 3 -R 5a e R 5a ; em que X 3 representa um grupo metileno; R 5a selecionado de hidroxila, amino, C 1-4 alquila, halo, nitro, ciano, halo-substituído-C 1¬4 alquila, substituo-C-ciano 1-4 alquila, hidroxi-substituído-C 1-4 alquil , halo-substituído-C 1-4 alcoxi, C 1 - 4 alcoxi, -SF 5 , -NR 11a Rub , -C (O) R11a , cicloalquil C3-8 e um anel saturado, insaturado ou parcialmente saturado com 4-7 membros contendo um a 4 heteroátomos ou grupos selecionados dentre O, NH, C (O) e S (O) 0-2 ; em que R11a e RIW são selecionados independentemente a partir de hidrogênio e alquil CI- 4 ; ou R11a e R11b, juntamente com o nitrogênio ao qual ambos estão li¬gados, formam um anel saturado de 4 a 7 membros contendo um ou¬tro heteroátomo ou grupo selecionado dentre O, NH e S (O) 0-2 ; em que o referido anel de 4-7 membros de R5a pode ser não substituído ou substituído por c1-4alquila; ou um seu sal farmaceuticamente aceitável.1. Compound, characterized by the fact that it has the Formula I: in which: n is selected from 0, 1 and 2; m is selected from 0, 1 and 2; X is selected from O and NR 6 ; wherein R 6 represents C 1-4 alkyl; Y 1 is selected from N and CR 7 ; wherein R 7 is selected from hydrogen and C 1-4 alkyl; R 1 hydrogen; R 2 is selected from hydrogen and halo; R 3 is selected from -CH 2 CH 2 R 8b and -CR 8a = CR 8a R 8b ; wherein each R8a is independently selected from hydrogen, fluoro and C1-4alkyl; and R 8b is selected from -C(O) OR 9a , - C(O) NR 9a R 9b , -C(O) NHOR 9a , -C(O) X 2 R 9a and a heteroaryl with 5-6 members selected from: the broken line indicating the point of attachment with -CH 2 CH 2 or -CR 8a = CR 8a of R 3 ; wherein X 2 represents C 1-4 alkylene; R 9a and R 9b are independently selected from hydrogen, C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, halo-substituted-C 1-4 alkyl and -X 4 R 10 ; wherein X 4 is selected from a bond and C 1¬3 alkylene; and R w is a 4-6 membered saturated ring containing 1 to 3 atoms selected independently from O, N and S; wherein said heteroaryl of R 8b is unsubstituted or substituted with 1 to 3 groups independently selected from C 1-4 alkyl and C 3-8 cycloalkyl; R 4 is selected from hydrogen, C 1-4 alkyl, halo and C 1¬3 alkoxy; R 5 selected from a C 6-10 aryl and a 5-6 membered heteroaryl selected from: the dashed line indicating the point of attachment to the benzothiophene nucleus; wherein said C 6-10 aryl or heteroaryl of R 5 is substituted by 1 to 3 group selected from -X 3 -R 5a and R 5a ; wherein X 3 represents a methylene group; R 5a is selected from hydroxy, amino, C 1-4 alkyl, halo, nitro, cyano, halo-substituted-C 1-4 alkyl, substituted-C-cyano 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, halo-substituted-C 1-4 alkoxy, C 1-4 alkoxy, -SF 5 , -NR 11a Rub , -C(O)R11a , C 3-8 cycloalkyl and a 4-7 membered saturated, unsaturated or partially saturated ring containing one to 4 heteroatoms or groups selected from O, NH, C(O) and S(O) 0-2 ; wherein R11a and RIW are independently selected from hydrogen and C1-4 alkyl; or R11a and R11b, together with the nitrogen to which they are both attached, form a 4- to 7-membered saturated ring containing another heteroatom or group selected from O, NH and S(O) 0-2; wherein said 4-7 membered ring of R5a may be unsubstituted or substituted by 1-4alkyl; or a pharmaceutically acceptable salt thereof.
[0002]
na qual: n é selecionado entre 0, 1 e 2; m é selecionado entre 0, 1 e 2; Y i é selecionado dentre N e CR 7 ; em que R 7 selecionado dentre hidrogênio e C 1-4 alquila; R 1 hidrogênio; R 2 é selecionado dentre hidrogênio e halo; R 3 é selecionado dentre -CH 2 CH 2 R 8b e -CR 8a = CR 8a R 8b ; em que cada R8a é independentemente selecionado a partir de hidrogênio e alquil C1-4 ; e R 8b é selecionado a partir de -C (O) OR 9a , -C (O) NR 9a R 9b , - C (O) NHOR 9a , -C (O) X 2 R 9a , 1,3,4- oxadiazolil, 4H-1,2,4-triazolil, 5-oxo-4,5-di-hidro-1,3,4-oxadiazol-2-il, 2- oxo-pirimidinil e imidazolil; em que X 2 representa C 1-4 alquileno; R 9a e R9b são selecionados independentemente a partir de hidrogênio, C 1¬4 alquila, hidroxi-substituído-C 1-4 alquila, halo-substituído-C 1 - 4 alquila e X 4 R 10 ; em que X 4 é selecionado dentre uma ligao e C 1¬3 alquileno; e R 10 representa um anel saturado de 4-6 membros con¬tendo 1 a 3 átomos selecionados independentemente a partir de O, N e S; em que o referido 1,3,4-oxadiazolila, 4H-1,2,4-triazolila, 2-oxo- pirimidinila ou imidazolila de R 8b é não substituído ou substituído com 1 a 3 grupos selecionados independentemente de C 1-4 alquila e C 3 - 8 cicloalquil; R 4 selecionado dentre hidrogênio e C 1-4 alquila; e cada R 5a é selecionado independentemente dentre hidroxi, C 1¬4 alquila, halo, nitro, ciano, halo-substituído-C 1 - 4 alquila, halo- substituído-C 1-4 alcoxi, hidroxi-substituído-C 1-4 alquila, Alcoxi C 1¬ 4 , cicloalquil C 3-8 , - NR 11a R 11b , -C (O) R 11a e um anel saturado, in- saturado ou parcialmente saturado com 4-7 membros contendo um a 4 heteroátomos ou grupos selecionados de O, NH , C (O) e S (O) 0- 2 ; em que Riia e Riib são selecionados independentemente a partir de hidrogênio e ci-4alquila; em que o referido anel de 4-7 membros de R5a pode ser não substituído ou substituído com alquil CI-4 ; X 3 é selecionado dentre uma ligao e metileno; ou um seu sal farmaceuticamente aceitável.2. Compound, according to claim 1, characterized by the fact that it has the Formula Ia: in which: n is selected from 0, 1 and 2; m is selected from 0, 1 and 2; Y i is selected from N and CR 7 ; wherein R 7 is selected from hydrogen and C 1-4 alkyl; R 1 hydrogen; R 2 is selected from hydrogen and halo; R 3 is selected from -CH 2 CH 2 R 8b and -CR 8a = CR 8a R 8b ; wherein each R8a is independently selected from hydrogen and C1-4 alkyl; and R 8b is selected from -C(O) OR 9a , -C(O) NR 9a R 9b , -C(O) NHOR 9a , -C(O) X 2 R 9a , 1,3,4- oxadiazolyl, 4H-1,2,4-triazolyl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2-oxo-pyrimidinyl and imidazolyl; wherein X 2 represents C 1-4 alkylene; R 9a and R9b are independently selected from hydrogen, C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, halo-substituted-C 1 - 4 alkyl and X 4 R 10 ; wherein X 4 is selected from a bond and C 1¬3 alkylene; and R 10 represents a 4-6 membered saturated ring containing 1 to 3 atoms independently selected from O, N and S; wherein said 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl, 2-oxo-pyrimidinyl or imidazolyl of R 8b is unsubstituted or substituted with 1 to 3 groups independently selected from C 1-4 alkyl and C 3 - 8 cycloalkyl; R 4 is selected from hydrogen and C 1-4 alkyl; and each R 5a is independently selected from hydroxy, C 1-4 alkyl, halo, nitro, cyano, halo-substituted-C 1-4 alkyl, halo-substituted-C 1-4 alkoxy, hydroxy-substituted-C 1-4 alkyl, C 1' 4 alkoxy, C 3-8 cycloalkyl, -NR 11a R 11b , -C(O)R 11a and a 4-7 membered saturated, unsaturated or partially saturated ring containing one to 4 heteroatoms or groups selected from O, NH, C(O) and S(O) 0-2; wherein Riia and Riib are independently selected from hydrogen and cy-4alkyl; wherein said 4-7 membered ring of R5a may be unsubstituted or substituted with C1-4 alkyl; X 3 is selected from a bond and methylene; or a pharmaceutically acceptable salt thereof.
[0003]
3. Compound according to claim 2, characterized in that R 3 is selected from -CH 2 CH 2 R 8b and -CR 8a = CR 8a R 8b ; wherein each R8a is independently selected from hydrogen and C1-4 alkyl; and R 8b is selected from -C(O) OR 9-A , -C(O) NR 9a R 9b , -C(O) NHOR 9a and -C(O) X 2 R 9a ; wherein X 2 represents C 1-4 alkylene; R 9a and R 9b are independently selected from hydrogen, C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, halo-substituted-C 1-4 alkyl and morpholino-ethyl.
[0004]
4. Compound according to claim 3, characterized in that R 3 is selected from -CH 2 CH 2 R 8b and -CR 8a = CR 8a R 8b ; wherein each R8a is independently selected from hydrogen and C1-4 alkyl; and R 8b is independently selected from -C(O)OH and -C(O)OCH 3 .
[0005]

[0006]
6. A compound, according to claim 1, or its pharmaceutically acceptable salt, characterized in that it is selected from:
[0007]
7. Compound according to claim 2, characterized in that: R 3 is selected from -CH 2 CH 2 R 8b and - CR 8a = CR 8a R 8b ; wherein each R8a is independently selected from hydrogen and C1-4 alkyl; and R 8b is selected from 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2- oxo-pyrimidinyl and imidazolyl; wherein said 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl, 2-oxo-pyrimidinyl or imidazolyl of R 8b is unsubstituted or substituted with 1 to 3 groups selected independently of C 1-4 alkyl and C 3 -8 cycloalkyl.
[0008]
8. Compound, according to claim 1, or its pharmaceutically acceptable salt, characterized in that it is selected from:
[0009]
na qual: n é selecionado entre 0, 1 e 2; m é selecionado entre 0, 1 e 2; Y 1 é selecionado dentre N e CR 7 ; em que R 7 selecionado dentre hidrogênio e C 1-4 alquila; R 1 hidrogênio; R 2 é selecionado dentre hidrogênio e halo; R 3 é selecionado dentre -CH 2 CH 2 R 8b e -CR 8a = CR 8a R 8b ; em que cada R8a é independentemente selecionado a partir de hidrogênio e alquil CI-4 ; e R 8b é selecionado a partir de -C (O) OR 9a , —C (O) NR 9a R 9b , — C (O) NHOR 9a , —C (O) X 2 R 9a , 1,3,4— oxadiazolil, 4H-1,2,4-triazolil, 5-oxo-4,5-di-hidro-1,3,4-oxadiazol-2-il, 2— oxo—pirimidinil e imidazolil; em que X 2 representa C 1-4 alquileno; R 9a e R9b são selecionados independentemente a partir de hidrogênio, C 1— 4 alquila, hidroxi-substituído-C 1-4 alquila e halo-substituído-C 1¬4 alquila; em que o referido 1,3,4-oxadiazolil, 4H-1,2,4-triazolil, 2-oxo- pirimidinil ou imidazolil de R8b é não substituído ou substituído por um grupo selecionado dentre CI-4 alquil e c3-8 cicloalquil ; R 4 selecionado dentre hidrogênio e C 1-4 alquila; cada R 5a é selecionado independentemente dentre hidroxi, C 1¬4 -C halo-substituído alquila, halo, nitro, ciano, CI-4 alquila, halo- substituído-C 1-4 alcoxi, C-hidroxi-substituído 1-4 alquila, C 1-4 alcoxi e C (O) R 11a ; em que R11a é selecionado a partir de hidrogênio e alquil CI- 4 ; e R 6 representa C 1-4 alquila; ou um seu sal farmaceutica- mente aceitável.9. Compound, according to claim 1, characterized by the fact that it has the Formula Ib: in which: n is selected from 0, 1 and 2; m is selected from 0, 1 and 2; Y 1 is selected from N and CR 7 ; wherein R 7 is selected from hydrogen and C 1-4 alkyl; R 1 hydrogen; R 2 is selected from hydrogen and halo; R 3 is selected from -CH 2 CH 2 R 8b and -CR 8a = CR 8a R 8b ; wherein each R8a is independently selected from hydrogen and C1-4 alkyl; and R 8b is selected from -C(O) OR 9a , —C(O) NR 9a R 9b , — C(O) NHOR 9a , —C(O) X 2 R 9a , 1,3,4— oxadiazolyl, 4H-1,2,4-triazolyl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 2-oxo-pyrimidinyl and imidazolyl; wherein X 2 represents C 1-4 alkylene; R 9a and R 9b are independently selected from hydrogen, C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl and halo-substituted-C 1-4 alkyl; wherein said 1,3,4-oxadiazolyl, 4H-1,2,4-triazolyl, 2-oxo-pyrimidinyl or imidazolyl of R8b is unsubstituted or substituted by a group selected from C1-4 alkyl and C3-8 cycloalkyl ; R 4 is selected from hydrogen and C 1-4 alkyl; each R 5a is independently selected from hydroxy, C 1-4 -C halo-substituted alkyl, halo, nitro, cyano, C 1-4 alkyl, halo-substituted-C 1-4 alkoxy, C-hydroxy-substituted 1-4 alkyl , C 1-4 alkoxy and C(O)R 11a ; wherein R11a is selected from hydrogen and C1-4 alkyl; and R 6 represents C 1-4 alkyl; or a pharmaceutically acceptable salt thereof.
[0010]
10. Compound according to claim 9, characterized in that R 3 is selected from -CH 2 CH 2 R 8b and - CR 8a = CR 8a R 8b ; wherein each R8a is independently selected from hydrogen and C1-4 alkyl; and R 8b is selected from — C(O) OR 9a , -C(O) NR 9a R 9b , -C(O) NHOR 9a , and -C(O) X 2 R 9a ; wherein X 2 represents C 1-4 alkylene; R 9a and R 9b are independently selected from hydrogen, C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl and halo-substituted-C 1-4 alkyl.
[0011]
11. A compound, according to claim 10, or its pharmaceutically acceptable salts, characterized in that it is selected from:
[0012]
12. Compound, or its pharmaceutically acceptable salts, characterized in that it is selected from:
[0013]
13. A compound, according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it has the structure:
[0014]
14. Compound, according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it has the structure:
[0015]
15. Pharmaceutical composition, characterized in that it comprises a compound, as defined in claim 1, mixed with at least one pharmaceutically acceptable excipient.
[0016]
16. Pharmaceutical composition according to claim 15, characterized in that it further comprises an additional therapeutic agent.
[0017]
17. A compound, according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is in combination with another pharmacologically active compound or with two or more other pharmacologically active compounds.
[0018]
18. Compound according to claim 17, characterized in that said pharmacologically active compounds are one or more chemotherapeutic agents.
[0019]
19. Use of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is for the manufacture of a medicine to treat cancer in an individual.
[0020]
20. Use according to claim 19, characterized in that the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancers.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US10058534B2|2018-08-28|Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders

---

US10774065B2|2020-09-15|1-pyridazin-/triazin-3-yl-piper|/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2

---

ES2741746T3|2020-02-12|Compounds and compositions to inhibit SHP2 activity

---

EP3310771B1|2020-07-22|Compounds and compositions for inhibiting the activity of shp2

---

ES2810852T3|2021-03-09|Compounds and compositions to inhibit shp2 activity

---

ES2699354T3|2019-02-08|Derivatives of 1- | -piper | idine and compositions thereof to inhibit the activity of SHP2

---

WO2015092634A1|2015-06-25|1,2,3,4-tetrahydroisoquinoline compounds and compositions as selective estrogen receptor antagonists and degraders

同族专利:

---

公开号 | 公开日

---

TWI612040B|2018-01-21|

---

HUE039052T2|2018-12-28|

---

US9931317B2|2018-04-03|

---

US10058534B2|2018-08-28|

---

MA38325A3|2018-05-31|

---

CU24337B1|2018-04-03|

---

PE20151428A1|2015-09-24|

---

PL2958907T3|2018-07-31|

---

KR20150119385A|2015-10-23|

---

AU2014219283B2|2015-10-29|

---

IL240131D0|2015-09-24|

---

CR20150424A|2015-10-19|

---

JO3494B1|2020-07-05|

---

NZ710385A|2016-10-28|

---

TW201443034A|2014-11-16|

---

GEP201706638B|2017-03-10|

---

KR102279999B1|2021-07-22|

---

CY1120155T1|2018-12-12|

---

EA201591537A1|2015-12-30|

---

NO3077717T3|2018-07-21|

---

US20140235660A1|2014-08-21|

---

DK2958907T3|2018-06-06|

---

CA2899030C|2021-03-09|

---

UY35334A|2014-09-30|

---

US20170112805A1|2017-04-27|

---

HK1211941A1|2016-06-03|

---

EP3360870A1|2018-08-15|

---

US9561211B2|2017-02-07|

---

DOP2015000202A|2015-11-30|

---

PH12015501832A1|2015-11-09|

---

US9321746B2|2016-04-26|

---

US8877801B2|2014-11-04|

---

AP2015008618A0|2015-07-31|

---

HK1251227A1|2019-01-25|

---

ES2671516T3|2018-06-06|

---

JP2016509022A|2016-03-24|

---

WO2014130310A1|2014-08-28|

---

GT201500233A|2016-01-21|

---

US20180169063A1|2018-06-21|

---

MX359471B|2018-09-28|

---

RS57106B1|2018-06-29|

---

CU20150090A7|2016-04-25|

---

MY174888A|2020-05-20|

---

EP2958907A1|2015-12-30|

---

US20160184265A1|2016-06-30|

---

TN2015000323A1|2017-01-03|

---

BR112015018882A2|2017-07-18|

---

CA2899030A1|2014-08-28|

---

MA38325A2|2016-12-30|

---

AU2014219283C1|2016-10-27|

---

SG11201505697VA|2015-09-29|

---

SI2958907T1|2018-05-31|

---

JP6364028B2|2018-07-25|

---

IL240131A|2018-11-29|

---

AU2014219283A1|2015-08-13|

---

EP2958907B1|2018-02-28|

---

MA38325B1|2019-03-29|

---

CN105008343A|2015-10-28|

---

PH12015501832B1|2015-11-09|

---

NI201500106A|2015-10-20|

---

EA028032B1|2017-09-29|

---

AR094704A1|2015-08-19|

---

CN105008343B|2017-12-08|

---

HRP20180816T1|2018-06-29|

---

MX2015010752A|2015-11-30|

---

PT2958907T|2018-03-23|

---

CL2015002098A1|2015-11-13|

---

TR201806882T4|2018-06-21|

---

ME03061B|2019-01-20|

---

ZA201505305B|2016-09-28|

---

LT2958907T|2018-04-25|

---

US20150361065A1|2015-12-17|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

CH445129A|1964-04-29|1967-10-15|Nestle Sa|Process for the preparation of high molecular weight inclusion compounds|

---

US3459731A|1966-12-16|1969-08-05|Corn Products Co|Cyclodextrin polyethers and their production|

---

US3453257A|1967-02-13|1969-07-01|Corn Products Co|Cyclodextrin with cationic properties|

---

US3426011A|1967-02-13|1969-02-04|Corn Products Co|Cyclodextrins with anionic properties|

---

US3453259A|1967-03-22|1969-07-01|Corn Products Co|Cyclodextrin polyol ethers and their oxidation products|

---

JPS6041077B2|1976-09-06|1985-09-13|Yoshinori Kitani|

---

US4235871A|1978-02-24|1980-11-25|Papahadjopoulos Demetrios P|Method of encapsulating biologically active materials in lipid vesicles|

---

US4261989A|1979-02-19|1981-04-14|Kaken Chemical Co. Ltd.|Geldanamycin derivatives and antitumor drug|

---

ZA822247B|1981-04-03|1983-11-30|Lilly Co Eli|Benzothiophene compounds and process for preparing them|

---

US4418068A|1981-04-03|1983-11-29|Eli Lilly And Company|Antiestrogenic and antiandrugenic benzothiophenes|

---

US4737323A|1986-02-13|1988-04-12|Liposome Technology, Inc.|Liposome extrusion method|

---

US5266573A|1989-08-07|1993-11-30|Elf Sanofi|Trifluoromethylphenyltetrahydropyridines for the treatment and/or prophylaxis of intestinal motility disorders|

---

KR0166088B1|1990-01-23|1999-01-15|.|Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof|

---

EP0647450A1|1993-09-09|1995-04-12|BEHRINGWERKE Aktiengesellschaft|Improved prodrugs for enzyme mediated activation|

---

US6756388B1|1993-10-12|2004-06-29|Pfizer Inc.|Benzothiophenes and related compounds as estrogen agonists|

---

US6562862B1|1994-10-20|2003-05-13|Eli Lilly And Company|Methods of inhibiting physiological conditions associated with an excess of neuropeptide Y|

---

IL115849D0|1994-11-03|1996-01-31|Merz & Co Gmbh & Co|Tangential filtration preparation of liposomal drugs and liposome product thereof|

---

US5589482A|1994-12-14|1996-12-31|Pfizer Inc.|Benzo-thiophene estrogen agonists to treat prostatic hyperplasia|

---

US5998441A|1995-02-28|1999-12-07|Eli Lilly And Company|Benzothiophene compounds, intermediates, compositions, and methods|

---

AT207913T|1995-02-28|2001-11-15|Lilly Co Eli|BENZOTHIOPHENES, INTERMEDIATE PRODUCTS, COMPOSITIONS AND METHODS|

---

US5510357A|1995-02-28|1996-04-23|Eli Lilly And Company|Benzothiophene compounds as anti-estrogenic agents|

---

US6417199B1|1995-03-10|2002-07-09|Eli Lilly And Company|3-benzyl-benzothiophenes|

---

WO1997001549A1|1995-06-26|1997-01-16|Eli Lilly And Company|Benzothiophene compounds|

---

US5731342A|1996-02-22|1998-03-24|Eli Lilly And Company|Benzothiophenes, formulations containing same, and methods|

---

US5827876A|1996-04-09|1998-10-27|American Home Products Corporation|Inhibition of bone loss by 3- benzo b!-thiophenes|

---

US5886025A|1997-03-06|1999-03-23|Baylor University|Anti-mitotic agents which inhibit tubulin polymerization|

---

ZA982877B|1997-04-09|1999-10-04|Lilly Co Eli|Treatment of central nervous system disorders with selective estrogen receptor modulators.|

---

ZA982819B|1997-04-09|1999-10-04|Lilly Co Eli|Treatment or prophylaxis of prostatic cancer and benign prostatic hyperplasia with selective estrogn receptor modulators.|

---

ZA982818B|1997-04-09|1999-10-04|Lilly Co Eli|Prevention of breast cancer using selective estrogen receptor modulators.|

---

US6166069A|1998-05-12|2000-12-26|American Home Products Corporation|Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia|

---

AU3791799A|1998-05-12|1999-11-29|American Home Products Corporation|Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia|

---

PE20010306A1|1999-07-02|2001-03-29|Agouron Pharma|INDAZOLE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM USEFUL FOR THE INHIBITION OF PROTEIN KINASE|

---

NZ521225A|2000-03-09|2004-08-27|Aventis Pharma Gmbh|Therapeutic uses of PPAR mediators|

---

US7091240B2|2000-03-10|2006-08-15|Oxigene, Inc.|Tubulin binding ligands and corresponding prodrug constructs|

---

GB0018891D0|2000-08-01|2000-09-20|Novartis Ag|Organic compounds|

---

US6995162B2|2001-01-12|2006-02-07|Amgen Inc.|Substituted alkylamine derivatives and methods of use|

---

US7425565B2|2002-05-09|2008-09-16|Cedars-Sinai Medical Center|Use of benzothiopenes to treat and prevent prostate cancer|

---

BR0307544A|2002-02-01|2004-12-07|Ariad Gene Therapeutics Inc|Phosphorus-containing compounds, components and composition as well as their use by treatment methods|

---

DK1482924T3|2002-03-05|2008-09-29|Merck Frosst Canada Ltd|Cathepsin cysteine protease inhibotorer|

---

TWI275390B|2002-04-30|2007-03-11|Wyeth Corp|Process for the preparation of 7-substituted-3- quinolinecarbonitriles|

---

CA2490580C|2002-07-22|2012-12-11|Eli Lilly And Company|Selective estrogen receptor modulators containing a naphthalene group|

---

DE602004016331D1|2003-06-10|2008-10-16|Lilly Co Eli|PENTAFLUOROALKYLSULFIN-NAPHTHALINE AND ASSOCIATED ESTROGEN RECEPTOR MODULATORS|

---

US7399865B2|2003-09-15|2008-07-15|Wyeth|Protein tyrosine kinase enzyme inhibitors|

---

US20070066595A1|2004-01-22|2007-03-22|Dodge Jeffrey A|Selective estrogen receptor modulators|

---

EP1709022A1|2004-01-22|2006-10-11|Eli Lilly And Company|Selective estrogen receptor modulators|

---

US20080227814A1|2004-01-29|2008-09-18|Jeffrey Alan Dodge|Selective Estrogen Receptor Modulators|

---

KR20190072678A|2004-09-02|2019-06-25|제넨테크, 인크.|Pyridyl inhibitors of hedgehog signalling|

---

WO2006094235A1|2005-03-03|2006-09-08|Sirtris Pharmaceuticals, Inc.|Fused heterocyclic compounds and their use as sirtuin modulators|

---

GB0510390D0|2005-05-20|2005-06-29|Novartis Ag|Organic compounds|

---

KR20090112758A|2007-03-16|2009-10-28|일라이 릴리 앤드 캄파니|Process and intermediates for preparing arzoxifene|

---

AR068402A1|2007-09-12|2009-11-18|Genentech Inc|COMBINATIONS OF 3-QUINASA PHOSFOINOSITIDA INHIBITING COMPOUNDS AND CHEMOTHERAPEUTIC AGENTS AND METHODS OF USE|

---

US20090069380A1|2007-09-12|2009-03-12|Protia, Llc|Deuterium-enriched aroxifene|

---

WO2009055730A1|2007-10-25|2009-04-30|Genentech, Inc.|Process for making thienopyrimidine compounds|

---

US8168784B2|2008-06-20|2012-05-01|Abbott Laboratories|Processes to make apoptosis promoters|

---

CN102477033A|2010-11-23|2012-05-30|苏州波锐生物医药科技有限公司|Benzothiophene compound and application thereof in preventive and/or treatment medicine for breast cancer and osteoporosis|

---

WO2012084711A1|2010-12-24|2012-06-28|Msd Oss B.V.|N-substituted azetidine derivatives|

---

EA028032B1|2013-02-19|2017-09-29|Новартис Аг|Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders|EA028032B1|2013-02-19|2017-09-29|Новартис Аг|Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders|

---

KR20170118687A|2015-02-19|2017-10-25|제이엔씨 주식회사|Liquid crystalline compound having benzothiophene, liquid crystal composition and liquid crystal display element|

---

TWI708770B|2015-06-08|2020-11-01|日商捷恩智股份有限公司|Liquid crystal compound having benzothiophene, liquid crystal composition and liquid crystal display device|

---

MX2018007079A|2015-12-09|2018-11-12|The Board Of Trustees Of Univ Of Illinois|Benzothiophene-based selective estrogen receptor downregulators.|

---

RU2738646C2|2016-04-01|2020-12-15|РЕКЬЮРИУМ АйПи ХОЛДИНГС, ЛЛС|Estrogen receptor modulators|

---

WO2018081168A2|2016-10-24|2018-05-03|The Board Of Trustees Of The University Of Illinois|Benzothiophene-based selective mixed estrogen receptor downregulators|

---

EA201991622A1|2017-01-06|2020-01-23|Г1 Терапьютикс, Инк.|COMPLEX THERAPY FOR TREATMENT OF CANCER|

---

JP2020507566A|2017-02-10|2020-03-12|ジー１ セラピューティクス， インコーポレイテッド|Benzothiophene estrogen receptor modulator|

---

BR112020008888A2|2017-11-16|2020-10-20|Novartis Ag|combination therapies|

---

EP3709997A1|2017-11-16|2020-09-23|Novartis AG|Pharmaceutical combination comprising lsz102 and ribociclib|

---

WO2019106604A1|2017-12-01|2019-06-06|Novartis Ag|Pharmaceutical combination comprising lsz102 and alpelisib|

---

AR116109A1|2018-07-10|2021-03-31|Novartis Ag|DERIVATIVES OF 3-PIPERIDINE-2,6-DIONA AND USES OF THE SAME|

---

WO2020037251A1|2018-08-16|2020-02-20|G1 Therapeutics, Inc.|Benzothiophene estrogen receptor modulators to treat medical disorders|

---

BR112021011874A2|2018-12-20|2021-09-08|Novartis Ag|DOSAGE SCHEME AND PHARMACEUTICAL COMBINATION INCLUDING DERIVATIVES OF 3-PIPERIDINE-2,6-DIONE|

---

CN113329792A|2019-02-15|2021-08-31|诺华股份有限公司|Substituted 3-piperidine-2, 6-dione derivatives and uses thereof|

---

KR20210129671A|2019-02-15|2021-10-28|노파르티스 아게|3-isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof|

---

AU2020279979A1|2019-05-20|2021-11-25|Les Laboratoires Servier|Mcl-1 inhibitor antibody-drug conjugates and methods of use|

---

TW202135858A|2019-12-20|2021-10-01|瑞士商諾華公司|USES OF ANTI-TGFβ ANTIBODIES AND CHECKPOINT INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE DISEASES|

---

CN111057065B|2019-12-24|2021-04-23|沈阳药科大学|Preparation method and application of thienopyrimidine compound|

---

CN111646972B|2020-06-12|2021-06-29|上海皓元医药股份有限公司|Preparation method of selective estrogen receptor degradation agent and intermediate thereof|

---

WO2021260528A1|2020-06-23|2021-12-30|Novartis Ag|Dosing regimen comprising 3-piperidine-2,6-dione derivatives|

---

WO2022010937A1|2020-07-06|2022-01-13|Tactogen Inc|Advantageous benzothiophene compositions for mental disorders or enhancement|

---

WO2022029573A1|2020-08-03|2022-02-10|Novartis Ag|Heteroaryl substituted 3-piperidine-2,6-dione derivatives and uses thereof|

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

---

2019-08-20| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

---

2019-10-01| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2021-07-13| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2021-09-14| 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 12/02/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201361766439P| true| 2013-02-19|2013-02-19|

---

US61/766,439|2013-02-19|

---

PCT/US2014/015938|WO2014130310A1|2013-02-19|2014-02-12|Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders|

---