WO2015092634A1 - 1,2,3,4-tetrahydroisoquinoline compounds and compositions as selective estrogen receptor antagonists and degraders - Google Patents

1,2,3,4-tetrahydroisoquinoline compounds and compositions as selective estrogen receptor antagonists and degraders Download PDF

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Publication number
WO2015092634A1
WO2015092634A1 PCT/IB2014/066813 IB2014066813W WO2015092634A1 WO 2015092634 A1 WO2015092634 A1 WO 2015092634A1 IB 2014066813 W IB2014066813 W IB 2014066813W WO 2015092634 A1 WO2015092634 A1 WO 2015092634A1
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substituted
methyl
4alkyl
mmol
halo
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PCT/IB2014/066813
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French (fr)
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Heather Elizabeth BURKS
Rajeshri Ganesh Karki
Christina Ann KIRBY
Jill NUNEZ
Stefan Peukert
Clayton SPRINGER
Yingchuan Sun
Noel Marie-France THOMSEN
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to compounds and compositions that are potent antagonists of estrogen receptor signaling and selective estrogen receptor degraders (SERDs).
  • SESDs selective estrogen receptor degraders
  • the invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with aberrant estrogen receptor activity.
  • estrogen receptor diseases or disorders such as breast, ovarian, colon, prostate, endometrial and uterine cancers.
  • Estrogen receptor (ERoc)-positive diseases such as breast cancer are usually treated with a selective estrogen receptor modulator (SERM) or an aromatase inhibitor (AI). While these therapies have proven effective at reducing the incidence of progression of breast cancer, some patients exhibit treatment resistance and progress to advanced metastatic breast cancer.
  • SERM selective estrogen receptor modulator
  • AI aromatase inhibitor
  • Treatment resistance results, in part, from the evolution of tumors to a state of hypersensitivity to low estrogen levels (AI treatment) or development of dependence upon the antiestrogen for activation of transcription (SERM treatment).
  • SERDs degrade the receptor, effectively eliminating ERoc expression and in so doing circumvent the underlying mechanisms of resistance that develop to antiendocrine monotherapy.
  • clinical and preclinical data show that a significant number of the resistance pathways can be circumvented by the use of an antiestrogen that exhibits SERD activity.
  • the compounds of the present invention can be used as therapies for the treatment of estrogen receptor diseases or disorders, for example, ovulatory dysfunction, uterine cancer, endometrium cancer, ovarian cancer, endometriosis, osteoporosis, prostate cancer, benign prostatic hypertrophy, estrogen receptor (ERoc)-positive breast cancer, in particular ERoc- positive breast cancer exhibiting denovo resistance to existing antiestrogens and aromatase inhibitors.
  • estrogen receptor diseases or disorders for example, ovulatory dysfunction, uterine cancer, endometrium cancer, ovarian cancer, endometriosis, osteoporosis, prostate cancer, benign prostatic hypertrophy, estrogen receptor (ERoc)-positive breast cancer, in particular ERoc- positive breast cancer exhibiting denovo resistance to existing antiestrogens and aromatase inhibitors.
  • n is selected from 0, 1 and 2;
  • X is selected from N and CR6; wherein R6 is selected from hydrogen and Ci- 4alkyl;
  • Ri is hydrogen
  • R21S selected from methyl, -CH 2 F, -CHF 2 , CF 3 and CD 3 ;
  • R3 is selected from -CH2CH2R8 and wherein each R7 is independently selected from hydrogen, fluoro and Ci-4alkyl; and Rs is selected from -C(0)ORsa, -
  • dotted line indicates the point of attachment with -CH2CH2 or - of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Re is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl;
  • R41S selected from hydrogen, Ci-4alkyl, halo and Ci-3alkoxy
  • R51S selected from C6-ioaryl, a 5-6 member heteroaryl containing 1 or 2 heteroatoms selected from O, S and N, and a partially saturated 9-10 member bicyclic ring containing 1 or two heteroatoms selected from O, S and N; wherein said C6-ioaryl, heteroaryl or bicyclic ring system of Rs is unsubstituted or substituted where chemically available with 1 to 3 R11 groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo- substituted-Ci-4alkyl, cyano-substituted-Ci-4alkyl, hydroxy-substituted-Ci-4alkyl, halo-substituted- Ci-4alkoxy, Ci-4alkoxy, -SFs, -NRi2aRi2b, -C(0)Ri2a, -S(0)o-2Ri2a, C3- 8 cycloalkyl-
  • the present invention provides a pharmaceutical composition which contains a compound of Formula I or a 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.
  • the present invention provides a method of treating a disease in an animal in which a combined selective estrogen receptor anatagonist and estrogen receptor degarder can prevent, inhibit or ameliorate the pathology and/or symptom ology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of a compound of
  • Formula I in the manufacture of a medicament for treating a disease in an animal in which estrogen receptor activity contributes to the pathology and/or symptomology of the disease.
  • the present invention provides a process for preparing 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.
  • Ester/acid pairs exist in the examples where the esters basically serve as prodrugs of the acids.
  • the seter in example 3 is
  • 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 (Ci -7 alkyl), or 1 to 4 carbon atoms (Ci -4 alkyl).
  • alkyl include, but are not limited to, methyl, ethyl, «-propyl, zso-propyl, «-butyl, sec- butyl, z ' sobutyl, ferr-butyl, «-pentyl, isopentyl, neopentyl, «-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, «-heptyl, «-octyl, «-nonyl, «-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 either straight-chained or branched and includes, methoxy, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, and the like.
  • Aryl means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms.
  • aryl may be phenyl or naphthyl, preferably phenyl.
  • Arylene means a divalent radical derived from an aryl group.
  • Heteroaryl is as defined for aryl above where one or more of the ring members is a heteroatom.
  • C 5- ioheteroaryl is a minimum of 5 members as indicated by the carbon atoms but that these carbon atoms can be replaced by a heteroatom.
  • C 5- i 0 heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated.
  • C 3- i 0 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • Heterocycloalkyl means cycloalkyl, as defined in this application, provided that one or more of the ring carbons indicated, are replaced by a moiety selected
  • C 3-8 heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, thiomorpholino, sulfanomorpholino, sulfonomo holino, etc.
  • Halogen (or halo) preferably represents chloro or fluoro, but may also be bromo or iodo.
  • Compounds of formula I may have different isomeric forms.
  • any asymmetric carbon atom may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.
  • the compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
  • the plural form e.g. compounds, salts
  • a compound does not exclude that (e.g. in a pharmaceutical formulation) more than one compound of the formula I (or a salt thereof) is present, the "a” merely representing the indefinite article.
  • A can thus preferably be read as “one or more", less preferably alternatively as “one”.
  • 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 the formula I may be present as such or in mixture with its N-oxide, as tautomer (e.g. due to keto-enol, lactam-lactim, amide-imidic acid or enamine-imine tautomerism) or in (e.g. equivalency reaction caused) mixture with its tautomer, or as a salt of the compound of the formula I and/or any of these forms or mixtures of two or more of such forms.
  • tautomer e.g. due to keto-enol, lactam-lactim, amide-imidic acid or enamine-imine tautomerism
  • equivalency reaction caused mixture with its tautomer
  • 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 atomic mass usually found in nature.
  • 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 as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S, 18 F, 36 C1 and 123 I.
  • isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies.
  • 3 H and 14 C isotopes may be used for their ease of preparation and detectability.
  • substitution with isotopes such as 2 H may afford certain therapeutic advantages resulting from greater 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.
  • compounds of the invention can exist in a deutorated form as shown below:
  • the present invention relates to selective estrogen receptor degraders.
  • compounds of Formula I are compounds of Formula la:
  • n is selected from 0 and 1 ;
  • X is selected from N and CH;
  • R2 is selected from methyl, -CH 2 F, -CHF 2 , CF 3 and CD 3 ;
  • R4 is methyl;
  • Rs is selected from Ce- and a 5-6 member heteroaryl or bicyclic ring selected from:
  • Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from O, N, NH, and S(0)o-2; wherein said C 3-8 cycloalkyl or 4-7 member ring of Rn can be unsubstituted or further substituted with a group selected from halo -substituted Ci -4 alkyl and Ci-4alkyl; or a pharmaceutically acceptable salt thereof.
  • R2 is selected from methyl, -
  • Rs is selected from C6-ioaryl unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from fluoro, methyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, isopropoxy, trifluoromethyl, hydroxy, methoxy-ethyl, methyl substituted pyrazolyl, trifluoro-ethyl, trifluoro-propyl, cyclobutyl, cyclopropyl-methyl, cyclopentyl, l-(trifluoromethyl)cyclopropyl, trifluoromethoxy and trifluoro-ethoxy; or a pharmaceutically acceptable salt thereof.
  • n is selected from 0 and 1 ;
  • R2 is selected from methyl, -CH 2 F, -CHF 2 , CF 3 and CD 3 ;
  • R4 is methyl; and
  • Rs is a 5-6 member heteroaryl or bicyclic ring selected from:
  • heteroaryl of Rs is unsubstituted or substituted with a group selected from methyl, isopropyl and methoxy; or a pharmaceutically acceptable salt thereof.
  • X is selected from N and CRJS; wherein R.6 is selected from hydrogen and Ci-4alkyl; Ri is hydrogen; R2 is selected from methyl, -CH 2 F, -CHF 2 , CF 3 and CD 3 ; R3 is selected from -CH2CH2R8 and wherein each R7 is independently selected from hydrogen, fluoro and Ci-4alkyl; and Rs is a 5-member heteroaryl selected from:
  • CR7 CR7 of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Re is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl; R 9 is selected from hydrogen, methyl, ethyl, trifluoro-ethyl, isobutyl, cyclopropyl, hydroxy-methyl and propyl; and Rio is selected from hydrogen and methyl;
  • Rs is selected from C6-ioaryl and a 5-6 member heteroaryl or bicyclic ring selected from:
  • n is selected from 0, 1 and 2;
  • X is selected from N and CR.6;
  • Rjds selected from hydrogen and Ci-4alkyl
  • Ri is hydrogen
  • R21S selected from methyl, -CH 2 F, - CHF 2 , CF 3 and CD 3
  • R3 is selected from -CfhCfbRs and wherein each R71S independently selected from hydrogen, fluoro and Ci-4alkyl
  • Rs is selected from -C(0)ORsa, - C(0)NR 8a R8b, -C(0)NHOR 8a , -C(0)YR 8a and a 5 -member heteroaryl selected from:
  • CR7 CR7 of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Re is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl;
  • R41S selected from hydrogen, Ci-4alkyl, halo and Ci-3alkoxy; Rsis selected from
  • C6-ioaryl a 5-6 member heteroaryl containing 1 or 2 heteroatoms selected from O, S and N, and a partially saturated 9-10 member bicyclic ring containing 1 or two heteroatoms selected from O, S and N; wherein said C6-ioaryl, heteroaryl or bicyclic ring system of R5 is unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo-substituted-Ci-4alkyl, cyano-substituted-Ci- 4alkyl, hydroxy-substituted-Ci-4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, -SF5, -NRi2aRi2b, - C(0)Ri2a, -S(O) 0 -2Ri2a, C 3-8 cycloalkyl and
  • n is selected from 0 and 1;
  • X is selected from N and CH;
  • R2 is selected from methyl, -CH 2 F, -CHF 2 , CF 3 and CD 3 ;
  • R4 is methyl;
  • Rs is selected from Ce- and a 5-6 member heteroaryl or bicyclic ring selected from:
  • R2 is selected from -CH 2 F, -
  • Rs is selected from C6-ioaryl unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from fluoro, methyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, isopropoxy, trifluoromethyl, hydroxy, methoxy -ethyl, methyl substituted pyrazolyl, trifluoro-ethyl, trifluoro -propyl, cyclobutyl, l-(trifluoromethyl)cyclopropyl, trifluoromethoxy and trifluoro -ethoxy; or a pharmaceutically acceptable salt thereof.
  • the present invention relates to compounds of Formula I that diminish the effects of estrogen receptors and lower the 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 etiology or pathology of the disease or condition or contribute to at least one symptom of the disease or condition and wherein such actions of estrogens or estrogen receptors are undesirable.
  • Compounds of the invention are both potent estrogen receptor antagonists and selective estrogen receptor degraders (SERDS).
  • the estrogen receptor (ER) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. In both females and males, estrogens play an important role in the regulation of a number of physiological processes. In humans, two different ER subtypes are known: ERoc and ER . Each subtype has a distinct tissue distribution and with different biological roles. For example, ERoc has high presence in endometrium, breast cancer cells, ovarian stroma cells and in the hypothalamus. The expression of the ER protein has been documented in kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, bladder, ovary, testis, and endothelial cells.
  • Tamoxifen for example, behaves like an estrogen in bone and endometrium, whereas it behaves like an anti-estrogen in breast tissue.
  • Breast cancer is the predominant neoplastic disease in women.
  • ERoc is a major driver of breast cancer progression.
  • Multiple existing treatment approaches aim to reduce estrogen levels or block its binding to ERoc thereby minimizing tumor progression or even inducing tumor regression in ERoc -positive breast cancer.
  • Tamoxifen is a first-generation treatment for ERoc-positive breast cancer.
  • Fulvestrant is a pure ERoc antagonist without the partial agonist activity which is typical for the estrogen receptor modulators. It is the only marketed selective estrogen receptor degrader (SERD) and it is efficacious in second-line treatment of breast cancer. Fulvestrant both antagonizes estrogen receptors and effectively degrades or down-regulates ERoc protein levels in cells. This SERD activity inhibits ERoc -driven proliferation and tumor growth. Fulvestrant, when administered once a month at 250 mg is equally effective to tamoxifen in treatment of ERoc- positive advanced breast cancer.
  • SESD selective estrogen receptor degrader
  • fulvestrant In second-line treatment of ERoc -positive tamoxifen-resistant breast cancer, fulvestrant, when administered once a month at 250 mg, is equally effective to aromatase inhibitors, despite relatively poor bioavailability and/or target exposure which limits its clinical efficacy.
  • SERDs include "ICI 164,384", a structural analog of fulvestrant; "GW5638”, a structural analog of tamoxifen; and "GW7604", a structural analogue of 4-hydroxy -tamoxifen.
  • ERoc antagonists which would preferably have ER degrading or down-regulating activity in, for example, breast cancer cells without stimulating proliferation in ERoc -positive, hormone treatment-resistant breast cancer cells.
  • Such compounds would be orally administrable and be useful in the treatment of, amongst other things, ERoc -positive, hormone treatment-resistant breast cancer.
  • Estrogen receptor-related diseases or conditions include, but are not limited to, aberrant estrogen receptor activity associated with: cancer, for example, 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
  • hematological system defects for example, deep vein thrombosis
  • immune and inflammation diseases for example, Graves' Disease, arthritis, mulitple 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 and vertigo
  • psychiatric defects for example, anorexia nervosa, attention deficity hyperactivity disorder, dementia, major depressive disorder and psychosis
  • reproductive defects for
  • the present invention relates to compounds that are both potent estrogen receptor anatagonists and selective estrogen receptor degraders.
  • the invention further provides a process for the preparation of 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
  • compounds of the invention are used to treat cancer in a mammal.
  • the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancers.
  • the cancer is breast cancer.
  • the cancer is a hormone dependent cancer.
  • the cancer is an estrogen receptor dependent cancer.
  • the cancer is an estrogen-sensitive cancer.
  • the cancer is resistant to anti-hormonal treatment.
  • the cancer is an estrogen-sensitive cancer or an estrogen receptor dependent cancer that is resistant to anti-hormonal treatment.
  • the anti-hormonal treatment includes treatment with at least one agent selected from tamoxifen, fulvestrant, a steroidal aromatase inhibitor, and a nonsteroidal aromatase inhibitor.
  • compounds of the invention are used to treat hormone receptor positive metastatic breast cancer in a postmenopausal woman with disease progression following anti-estrogen therapy.
  • compounds of theinvention are used to treat a hormonal dependent benign or malignant disease of the breast or reproductive tract in a mammal.
  • the benign or malignant disease is breast cancer.
  • compounds of the invention are used to treat cancer in a mammal, wherein the mammal is chemotherapy -naive.
  • 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.
  • the cancer is a hormone refractory cancer.
  • compounds of the invention are used in the treatment of endometriosis in a mammal.
  • compounds of the invention are used in the treatment of leiomyoma in a mammal.
  • the leiomyoma is selected from uterine leiomyoma, esophageal leiomyoma, cutaneous leiomyoma and small bowel leiomyoma.
  • 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.
  • a compound of the 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, e.g. cisplatin, 5-fluorouracil or 5-fluoro-2-4(l H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine.
  • chemotherapy agents for example, mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine
  • the present invention relates to the aforementioned method, wherein said compound is administered parenterally.
  • the present invention relates to the aforementioned method, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecally, topically or intranasally.
  • the present invention relates to the aforementioned method, wherein said compound is administered systemically.
  • the present invention relates to the aforementioned method, wherein said patient is a mammal.
  • the present invention relates to the aforementioned method, wherein said patient is a primate.
  • the present invention relates to the aforementioned method, wherein said patient is a human.
  • 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 chemothereutic agent in combination with a therapeutically effective amount of a compound of formula I as defined in the Summary of the Invention.
  • the present invention provides pharmaceutically acceptable compositions which comprise 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 diluents.
  • 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, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, 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 sustained- 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 intrarect
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transport
  • materials which 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) gelatin; (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, corn 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 hydrox
  • certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • a basic functional group such as amino or alkylamino
  • “pharmaceutically-acceptable salts” in this respect, 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 the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus 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, napthylate, mesylate, glucoheptonate, lactobionate, and
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • 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.
  • pharmaceutically-acceptable salts in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra)
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite 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.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), 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 which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety -nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 percent to about 30 percent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and poly anhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately 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.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes 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 may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate 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
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface -active 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.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as 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 polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which 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.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the 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, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • 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 nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an 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.
  • 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.
  • Powders and sprays can 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 can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • 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 flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may 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 into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given 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 given in forms suitable for each administration route. For example, they are administered in tablets 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.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • peripheral administration and “administered peripherally” as used herein mean the
  • administration of a compound, drug or other material other than directly into the central nervous system such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for 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.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
  • composition While 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
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • 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, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, 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.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue
  • treatment is intended to encompass also prophylaxis, therapy and cure.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
  • the compound of the invention can be administered as such or in admixtures with pharmaceutically acceptable carriers and can also be administered in conjunction with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides.
  • Conjunctive therapy thus includes sequential, simultaneous and separate administration of the active compound in a way that the therapeutical effects of the first administered one is not entirely disappeared when the subsequent is administered.
  • Microemulsification technology can improve bioavailability of some lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic
  • microemulsification provides enhanced bioavailability by preferentially directing absorption to the lymphatic system instead of the circulatory system, which thereby bypasses the liver, and prevents destruction of the compounds in the hepatobiliary circulation.
  • amphiphilic carriers While all suitable amphiphilic carriers are contemplated, the presently preferred carriers are generally those that have Generally-Recognized-as-Safe (GRAS) status, and that can both solubilize the compound of the present invention and microemulsify it at a later stage when the solution comes into a contact with a complex water phase (such as one found in human gastrointestinal tract).
  • GRAS Generally-Recognized-as-Safe
  • amphiphilic ingredients that satisfy these requirements have HLB (hydrophilic to lipophilic balance) values of 2-20, and their structures contain straight chain aliphatic radicals in the range of C-6 to C-20. Examples are polyethylene-glycolized fatty glycerides and polyethylene glycols.
  • amphiphilic carriers 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 a number of companies in USA and worldwide).
  • Hydrophilic polymers suitable for use in the present invention are those which are readily water-soluble, can be covalently attached to a vesicle-forming lipid, and which are tolerated in vivo without toxic effects (i.e., are biocompatible).
  • Suitable polymers include polyethylene glycol (PEG), polylactic (also termed polylactide), polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolic acid copolymer, and polyvinyl alcohol.
  • PEG polyethylene glycol
  • polylactic also termed polylactide
  • polyglycolic acid also termed polyglycolide
  • a polylactic-polyglycolic acid copolymer a polyvinyl alcohol.
  • Preferred polymers are those having a molecular weight of from about 100 or 120 daltons up to about 5,000 or 10,000 daltons, and more preferably from about 300 daltons to about 5,000 daltons.
  • the polymer is polyethyleneglycol having a molecular weight of from about 100 to about 5,000 daltons, and more preferably having a molecular weight of from about 300 to about 5,000 daltons.
  • the polymer is polyethyleneglycol of 750 daltons (PEG(750)).
  • Polymers may also be defined by the number of monomers therein; 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).
  • hydrophilic polymers which may be suitable for use in the present invention include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline,
  • polyhydroxypropyl methacrylamide polymethacrylamide, polydimethylacrylamide, and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.
  • a formulation of the present invention comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronic acids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.
  • a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and
  • Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8 glucose units, designated by the Greek letter .alpha., .beta, or .gamma., respectively. Cyclodextrins with fewer than six glucose units are not known to exist. The glucose units are linked by alpha- 1,4- glucosidic bonds. As a consequence of the chair conformation of the sugar units, all secondary hydroxyl groups (at C-2, C-3) are located on one side of the ring, while all the primary hydroxyl groups at C-6 are situated on the other side. As a result, the external faces are hydrophilic, making the cyclodextrins water-soluble.
  • the cavities of the cyclodextrins are hydrophobic, since they are lined by the hydrogen of atoms C-3 and C-5, and by ether-like oxygens.
  • These matrices allow complexation with a variety of relatively hydrophobic compounds, including, for instance, steroid compounds such as 17.beta. -estradiol (see, e.g., van Uden et al. Plant Cell Tiss. Org. Cult. 38: 1-3-113 (1994)).
  • the complexation takes place by Van der Waals interactions and by hydrogen bond formation.
  • the physico-chemical properties of the cyclodextrin derivatives depend strongly on the kind and the degree of substitution. For example, their solubility in water ranges from insoluble (e.g., triacetyl-beta-cyclodextrin) to 147% soluble (w/v) (G-2-beta-cyclodextrin). In addition, they are soluble in many organic solvents. The properties of the cyclodextrins enable the control over solubility of various formulation components by increasing or decreasing their solubility.
  • cyclodextrin derivatives with anionic properties carboxylic acids, phosphorous acids, phosphinous acids, phosphonic acids, phosphoric acids, thiophosphonic acids, thiosulphinic acids, and sulfonic acids have been appended to the parent cyclodextrin [see, Parmeter (III), supra]. Furthermore, sulfoalkyl ether cyclodextrin derivatives have been described by Stella, et al. (U.S. Pat. No. 5,134,127).
  • Liposomes consist of at least one lipid bilayer membrane enclosing an aqueous internal compartment. Liposomes may be characterized by membrane type and by size. Small unilamellar vesicles (SUVs) have a single membrane and typically range between 0.02 and 0.05 ⁇ in diameter; large unilamellar vesicles (LUVS) are typically larger than 0.05 ⁇
  • Oligolamellar large vesicles and multilamellar vesicles have multiple, usually concentric, membrane layers and are typically larger than 0.1 ⁇ . Liposomes with several nonconcentric membranes, i.e., several smaller vesicles contained within a larger vesicle, are termed multivesicular vesicles.
  • One aspect of the present invention relates to formulations comprising liposomes containing a compound of the present invention, where the liposome membrane is formulated to provide a liposome with increased carrying capacity.
  • the compound of the present invention may be contained within, or adsorbed onto, the liposome bilayer of the liposome.
  • the compound of the present invention may be aggregated with a lipid surfactant and carried within the liposome's internal space; in these cases, the liposome membrane is formulated to resist the disruptive effects of the active agent-surfactant aggregate.
  • 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 interior space encapsulated by the liposome, and extend from the exterior of the lipid bilayer into the surrounding environment.
  • PEG polyethylene glycol
  • Active agents contained within 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) may be entrapped within the interior space of liposomes according to the present invention.
  • a surfactant acts to disperse and solubilize the active agent, and may be selected from any suitable aliphatic, cycloaliphatic or aromatic surfactant, including but not limited to biocompatible lysophosphatidylcholines (LPCs) of varying chain lengths (for example, from about C. sub.14 to about C.sub.20).
  • Polymer-derivatized lipids such as PEG-lipids may also be utilized for micelle formation as they will act to inhibit micelle/membrane fusion, and as the addition of a polymer to surfactant molecules decreases the CMC of the surfactant and aids in micelle formation.
  • Liposomes according to the present invention may be prepared by any of a variety of techniques that are known in the art. See, e.g., U.S. Pat. No. 4,235,871; Published PCT applications WO 96/14057; New RRC, Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104; Lasic DD, Liposomes from physics to applications, Elsevier Science Publishers BV, Amsterdam, 1993.
  • liposomes of the present invention may be prepared by diffusing a lipid derivatized 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 of derivatized lipid which 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.
  • the liposomes are prepared to have substantially homogeneous sizes in a selected size range.
  • One effective sizing method involves extruding an aqueous suspension of the liposomes through a series of polycarbonate membranes having a selected uniform pore size; the pore size of the membrane will correspond roughly with the largest sizes of liposomes produced by extrusion through that membrane. See e.g., U.S. Pat. No. 4,737,323 (Apr. 12, 1988).
  • the release characteristics of a formulation of the present invention depend on the encapsulating material, the concentration of encapsulated drug, and the presence of release modifiers.
  • release can be manipulated to be pH dependent, for example, using a pH sensitive coating that releases only at a low pH, as in the stomach, or a higher pH, as in the intestine.
  • An enteric coating can be used to prevent release from occurring until after passage through the stomach.
  • Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to obtain an initial release in the stomach, followed by later release in the intestine.
  • Release can also be manipulated by inclusion of salts or pore forming agents, which can increase water uptake or release of drug by diffusion from the capsule.
  • Excipients which modify the solubility of the drug can also be used to control the release rate.
  • Agents which enhance degradation of the matrix or release from the matrix can also be incorporated. They can be added to the drug, added as a separate phase (i.e., as particulates), or can be co-dissolved in the polymer phase depending on the compound. In all cases the amount should be between 0.1 and thirty percent (w/w 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, calcium carbonate, zinc carbonate, and 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 which add microstructure to the matrices i.e., water soluble compounds such as inorganic salts and sugars
  • the range should be between one and thirty percent (w/w polymer).
  • Uptake can also be manipulated by altering residence time of the particles in the gut. This can be achieved, for example, by coating the particle with, or selecting as the encapsulating material, a mucosal adhesive polymer.
  • 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).
  • the invention especially relates to the use of a compound of the formula I (or a pharmaceutical composition comprising a compound of the formula I) in the treatment of one or more of the diseases mentioned herein; wherein the response to treatment is beneficial as demonstrated, for example, by the partial or complete removal of one or more of the symptoms of the disease up to complete cure or remission.
  • compounds disclosed herein are useful in the treatment of breast cancer, either alone or in combination with other agents used to treat breast cancer, including but not limited to aromatase inhibitors, anthracylines, platins, nitrogen mustard alkylating agents and taxanes.
  • Agents used to treat breast cancer include, but are not limited to, paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine and ixabepilone.
  • compounds of the invention are useful in the treatment of breast cancer, either alone or in combination with other agents that modulate other critical pathways in breast cancer, including but not limited to those that target IGF1R, EGFR, erB-B2 and the PI3 K/AKT/mTOR axis, Rb axis including CDK4/6 and D-cyclins, HSP90, PARP and/or histone deacetylases.
  • a compound of the invention can, therefore, also be used in combination with the following:
  • VEGF receptor inhibitors Bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methyl-2-[[3-[(£T)-2-pyridin-2- ylethenyl]-lH-indazol-6-yl]sulfanyl]benzamide, also known as AGO 13736, and described in PCT Publication No.
  • HER2 receptor inhibitors Trastuzumab (sold under the trademark Herceptin® by Genentech/Roche), neratinib (also known as HKI-272, (2iT)-N-[4-[[3-chloro-4-[(pyridin-2- yl)methoxy]phenyl] amino] -3 -cy ano-7-ethoxyquinolin-6-yl] -4-(dimethylamino)but-2-enamide, and described PCT Publication No. WO 05/028443), lapatinib or lapatinib ditosylate (sold under the trademark Tykerb® by Glaxo SmithKline);
  • CD20 antibodies Rituximab (sold under the trademarks Riuxan® and MabThera® by Genentech/Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline);
  • Tyrosine kinase inhibitors Erlotinib hydrochloride (sold under the trademark Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5- methylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib malate (sold under the tradename Sutent® by Pfizer), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in US Patent No.
  • dasatinib (sold under the tradename Sprycel® by Bristol-Myers Squibb), armala (also known as pazopanib, sold under the tradename Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (sold under the tradenames Gilvec® and Gleevec® by Novartis);
  • Bcr/Abl kinase inhibitors nilotinib hydrochloride (sold under the tradename Tasigna® by Novartis);
  • DNA Synthesis inhibitors Capecitabine (sold under the trademark Xeloda® by Roche), gemcitabine hydrochloride (sold under the trademark 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 tradenames Arranon® and Atriance® by GlaxoSmithKline);
  • Antineoplastic agents oxaliplatin (sold under the tradename Eloxatin® ay Sanofi- Aventis and described in US Patent No. 4,169,846);
  • Epidermal growth factor receptor (EGFR) inhibitors Gefitnib (sold under the tradename Iressa®), N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3- furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers
  • panitumumab sold under the tradename Vectibix® by Amgen
  • HER dimerization inhibitors Pertuzumab (sold under the trademark Omnitarg®, by
  • G-CSF modulators Filgrastim (sold under the tradename Neupogen® by Amgen);
  • 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 Thalomid®);
  • CD40 inhibitors Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc);
  • Pro-apoptotic receptor agonists PARAs: Dulanermin (also known as AMG-951, available from Amgen/Genentech); [00174] 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-(lH-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-l- yl]methyl]thieno[3,2-d]pyrimidin-4-yl]mo holine (also known as GDC 0941 and described in
  • Phospholipase A2 inhibitors Anagrelide (sold under the tradename Agrylin®);
  • BCL-2 inhibitors 4-[4-[[2-(4-chlorophenyl)-5 ,5 -dimethyl- 1 -cyclohexen- 1 -yl]methyl] - 1 - piperazinyl] -N- [ [4- [ [( 1 R)-3 -(4-morpholinyl)- 1 - [(phenylthio)methyl]propyl] amino] -3 -
  • Mitogen-activated protein kinase kinase (MEK) inhibitors XL-518 (Cas No. 1029872- 29-4, available from ACC Corp.);
  • Aromatase inhibitors Exemestane (sold under the trademark Aromasin® by Pfizer), letrozole (sold under the tradename Femara® by Novartis), anastrozole (sold under the tradename Arimidex®);
  • Topoisomerase I inhibitors Irinotecan (sold under the trademark Camptosar® by Pfizer), topotecan hydrochloride (sold under the tradename Hycamtin® by Glaxo SmithKline);
  • Topoisomerase II inhibitors also known as VP- 16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradename Vumon®);
  • mTOR inhibitors Temsirolimus (sold under the tradename Torisel® by Pfizer), ridaforolimus (formally known as deferolimus, (lR,2R,45)-4-[(2R)-2
  • CD33 Antibody Drug Conjugates Gemtuzumab ozogamicin (sold under the tradename Mylotarg® by Pfizer/Wyeth);
  • CD22 Antibody Drug Conjugates Inotuzumab ozogamicin (also referred to as CMC-
  • CD20 Antibody Drug Conjugates Ibritumomab tiuxetan (sold under the tradename
  • octreotide also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®
  • Sandostatin® also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®
  • Synthetic Interleukin-11 (IL-11): oprelvekin (sold under the tradename Neumega® by Pfizer/Wyeth);
  • Receptor Activator for Nuclear Factor ⁇ B (RANK) inhibitors Denosumab (sold under the tradename Prolia® by Amgen);
  • Thrombopoietin mimetic peptibodies Romiplostim (sold under the tradename Nplate® by Amgen;
  • Cell growth stimulators Palifermin (sold under the tradename Kepivance® by Amgen);
  • IGF-1R Anti-Insulin-like Growth Factor-1 receptor antibodies: Figitumumab (also known as CP-751,871, available from ACC Corp), robatumumab (CAS No. 934235-44-6);
  • Anti-CSl antibodies Elotuzumab (HuLuc63, CAS No. 915296-00-3);
  • CD52 antibodies Alemtuzumab (sold under the tradename Campath®);
  • CTLA-4 inhibitors Tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206), ipilimumab (CTLA-4 antibody, also known as
  • Histone deacetylase inhibitors (HDI): Voninostat (sold under the tradename Zolinza® by Merck); [00198] Alkylating agents: Temozolomide (sold under the tradenames Temodar® and
  • Temodal® by Schering-Plough Merck dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), 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®), cyclo
  • Biologic response modifiers bacillus calmette-guerin (sold under the tradenames theraCys® and TICE® BCG), denileukin diftitox (sold under the tradename Ontak®);
  • Anti-tumor antibiotics doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename EllenceTM), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), mitomycin C (sold under the tradename Mutamycin®);
  • Anti-microtubule agents Estramustine (sold under the tradename Emcyl®);
  • Cathepsin K inhibitors Odanacatib (also know as MK-0822, N-(l-cyanocyclopropyl)- 4-fluoro-N 2 - ⁇ (lS)-2,2,2-trifluoro-l-[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);
  • Epothilone B analogs Ixabepilone (sold under the tradename Lxempra® by Bristol- Myers Squibb);
  • HSP Heat Shock Protein
  • TpoR agonists Eltrombopag (sold under the tradenames Promacta® and Revolade® by Glaxo SmithKline) ;
  • Anti-mitotic agents Docetaxel (sold under the tradename Taxotere® by Sanofi- Aventis);
  • Adrenal steroid inhibitors aminoglutethimide (sold under the tradename Cytadren®);
  • Anti -androgens Nilutamide (sold under the tradenames Nilandron® and Anandron®), bicalutamide (sold under tradename Casodex®), flutamide (sold under the tradename FulexinTM);
  • Androgens Fluoxymesterone (sold under the tradename Halotestin®);
  • CDK1 inhibitors Alvocidib (also known as flovopirdol or HMR-1275, 2-(2- chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-l-methyl-4-piperidinyl]-4-chromenone, and described in US Patent No. 5,621,002);
  • GnRH Gonadotropin-re leasing hormone receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames Viadure® by Bayer AG, Eligard® by Sanofi-Aventis and Lupron® by Abbott Lab);
  • Taxane anti -neoplastic agents Cabazitaxel (l -hydroxy-7 ,10 -dimethoxy-9-oxo-5 ,20- epoxytax-1 l-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3- ⁇ [(tert- butoxy)carbonyl]amino ⁇ -2-hydroxy-3-phenylpropanoate), larotaxel ((2 ⁇ ,3 ⁇ ,4 ⁇ ,5 ⁇ ,7 ⁇ ,10 ⁇ ,13 ⁇ )- 4,10-bis(acetyloxy)-13-( ⁇ (2R,35)-3- [(fer?-butoxycarbonyl) amino]-2-hydroxy-3- phenylpropanoyl ⁇ oxy)-l- hydroxy -9-oxo-5, 20-epoxy-7, 19-cyclotax- 1 l-en-2-yl benzoate);
  • 5HTla receptor agonists Xaliproden (also known as SR57746, l-[2-(2-naphthyl)ethyl]- 4-[3-(trifluoromethyl)phenyl]-l,2,3,6-tetrahydropyridine, and described in US Patent No.
  • HPC vaccines Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck;
  • Iron Chelating agents Deferasinox (sold under the tradename Exjade® by Novartis);
  • Anti-metabolites Claribine (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®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCytTM), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, DroxiaTM and MylocelTM), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorode
  • Demethylating agents 5-azacitidine (sold under the tradename Vidaza®), decitabine (sold under the tradename Dacogen®);
  • Plant Alkaloids Paclitaxel protein-bound (sold under the tradename Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames Oncovin® and Vincasar Pfs®), vinorelbine (sold under the tradename Navelbine®), paclitaxel (sold under the tradenames Taxol and OnxalTM);
  • Retinoids Alitretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cz ' s- retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Claras®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the tradename Targretin®);
  • Glucocorticosteroids Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone ((8S,9R, 1 OS, 1 IS, 135, 14S, 16R, 17R)-9-fluoro- 11 , 17-dihydroxy- 17-(2-hydroxy acetyl)- 10,13,16- trimethyl-6,7,8,9,10,11,12,13, 14,15, 16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone
  • Cytokines interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename Proleukin®), interleukin-11 (also known as oprevelkin, sold under the tradename Neumega®), alpha interferon alfa (also known as IFN-alpha, sold under the tradenames Intron® A, and Pvoferon-A®);
  • LHRH Leutinizing hormone releasing hormone
  • megestrol also known as megestrol acetate, sold under the tradename
  • Trisenox® asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®);
  • a compound of formula (I) can also be used in combination with the following adjunct therapies:
  • Anti-nausea drugs NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and
  • Cytoprotective agents Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).
  • the present invention also includes processes for the preparation of compounds of the invention.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.
  • a compound of Formula I can be prepared by hydrolysing a compound of formula 2 in the presence of a suitable hydro lyzing agent (such as
  • ethanethiol/aluminum chloride and the like
  • a suitable solvent such as dichloromethane, or the like.
  • a compound of Formula I can be prepared by hydrolysing a compound of formula 2 in the presence of a suitable Lewis Acid (such as Boron tribromide, and the like) and a suitable solvent (such as dichloromethane, or the like) under a suitable pressure and atmosphere (such as -78°/Nitrogen, and the like). The reaction takes place at about 0°C from about 1 to about 4 hours to complete.
  • a suitable Lewis Acid such as Boron tribromide, and the like
  • a suitable solvent such as dichloromethane, or the like
  • a compound of Formula I can be prepared by reacting a compound of formula 3 with a compound of formula 4 in the presence of a suitable solvent (such as DMF and the like), a suitable catalyst (such as PdCl 2 (PPh 3 ) 2 , or the like), a suitable base (such as triethylamine, and the like). The reaction takes place at about 120 °C to about 200°C and can take from about 1 to about 18 hours to complete.
  • a suitable solvent such as DMF and the like
  • a suitable catalyst such as PdCl 2 (PPh 3 ) 2 , or the like
  • a suitable base such as triethylamine, and the like.
  • 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.
  • 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.
  • Compounds of the formula I can also be modified by appending appropriate functionalities to enhance selective biological properties. Modifications of this kind are known in the art and include those that increase penetration into a given biological system (e.g. blood, lymphatic system, central nervous system, testis), increase bioavailability, increase solubility to allow parenteral administration (e.g. injection, infusion), alter metabolism and/or alter the rate of secretion. Examples of this type of modifications include but are not limited to esterification, e.g. with polyethylene glycols, derivatisation with pivaloyloxy or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings and heteroatom substitution in aromatic rings.
  • esterification e.g. with polyethylene glycols, derivatisation with pivaloyloxy or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings and heteroatom substitution in aromatic rings.
  • the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
  • any reference to the compounds or a compound of the formula I hereinbefore 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 expedient, as well as to one or more solvates, e.g. hydrates.
  • Salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic 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, methylmaleic acid, 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-
  • the free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g., 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 (e.g., 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 (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • a suitable inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985; Ferriz, J.M. et al., Current Pharmaceutical Design, 2010, 16, 2033-2052).
  • Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill 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", 3 rd edition, John Wiley and Sons, Inc., 1999.
  • Compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., 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.
  • 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. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
  • the compounds of Formula I can be made by a process, which involves:
  • Method I To a vial, 6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (1.5 g, 8.47 mmol) was dissolved in DMF (10 mL) and charged with l-fluoro-4-iodobenzene (3.76 g, 16.93 mmol) and potassium carbonate (1.170 g, 8.47 mmol). The reaction mixture was flushed with nitrogen, charged with copper(I) iodide (161 mg, 847 ⁇ ), and heated at 150 °C for 16 h at which point starting material remained. The reaction mixture was charged with additional copper(I) iodide (161 mg, 847 ⁇ ) and heated for an additional 16 h.
  • LC/MS indicated 50% consumption of starting material.
  • the reaction vial was charged with additional copper(I) iodide (215 mg, 1.129 mmol) and heated at 150 °C for an additional 16 h.
  • LC/MS indicated no addition conversion.
  • the reaction mixture was cooled to ambient temperature and was diluted with dichloromethane and water.
  • the organic layer was passed through a phase separator and concentrated.
  • the crude product was purified by silica gel chromatography (80 g, 0-100% ethyl acetate/heptanes) to afford 2-(4-fluoro-2-methylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (1.1 g, 34% yield) as a beige solid.
  • Step 1 3-(4-bromophenyl)-lH-pyrazole (0.377 g, 1.690 mmol) was dissolved in THF (8.45 ml). 60% Sodium hydride in oil (0.101 g, 2.54 mmol) was added and the reaction was stirred at rt for 15 min. Methyl iodide (0.116 ml, 1.859 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated.
  • Step 2 6-methoxy-2-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one compound and 6-methoxy-2-(4-(l-methyl-lH-pyrazol-5- yl)phenyl)-3, 4-dihydroisoquinolin- l(2H)-one were prepared using method I from above in combination with aryl bromide highlighted in above intermediate example (248 mg, 0.744 mmol, 71.3 % yield) as a white solid.
  • Step 1 To 2-(4-(benzyloxy)-3-fluorophenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (0.341 g, 0.904 mmol) was added ethanol (4.52 mL). The compound did not dissolve completely therefore THF (9 mL) was added until compound dissolved. A scoop of Pd(OH) 2 was added, then the reaction solution was purged with hydrogen and left with a hydrogen balloon at room temperature overnight. The reaction was filtered through a syringe filter and concentrated to afford product (0.341 g, 0.904 mmol) as a white solid.
  • Step 2 To a microwave vial, 2-(3-fluoro-4-hydroxyphenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (0.039 g, 0.136 mmol), N-phenyltrifluoromethanesulfonimide (0.058 g, 0.163 mmol), and potassium carbonate (0.056 g, 0.407 mmol) were suspended in THF (0.679 mL). The reaction was microwaved for 8 min at 120 °C. The reaction was done via LC/MS, so the reaction was filtered and concentrated.
  • Step 3 To 2-fluoro-4-(6-methoxy-l-oxo-3,4-dihydroisoquinolin-2(lH)- yl)phenyl trifluoromethanesulfonate (0.024 g, 0.057 mmol), potassium trifluoro(prop-l-en-2- yl)borate (0.017 g, 0.114 mmol), and triethylamine (0.024 ml, 0.172 mmol) were dissolved in THF (0.143 ml).
  • Step 4 To 2-(3-fluoro-4-(prop-l-en-2-yl)phenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (0.015 g, 0.048 mmol) was added methanol (1.5 mL). THF (0.5mL) was added until compound was dissolved. A scoop of 10% palladium on carbon was added and the reaction mixture was purged with hydrogen. The reaction stirred at room temperature for 1 h. The reaction was filtered through a syringe filter and concentrated to afford (13.7 mg, 0.044 mmol, 91 % yield) as a clear oil.
  • Step 1 To a 100 mL round-bottomed flask, 1 -(benzyloxy)-4-bromobenzene
  • Step 2 In a 100 mL round bottomed flask, the oven -dried iminium salt was dissolved in THF (20 mL) and the reaction flask was cooled to 0 °C. A 3 M solution of methylmagnesium bromide in diethyl ether (2.56 mL, 7.67 mmol) was added dropwise to the reaction mixture. Upon stirring at 0 °C for 30 min, LC MS analysis of an aliquot indicated partial conversion. The mixture was charged with an additional 1.5 mL of a 3 M solution of methylmagnesium bromide in diethyl ether and stirred for 1 h at 0 °C.
  • Step 3 In a 30 mL vial, l-(4-(benzyloxy)phenyl)-2-(4-fluorophenyl)-6- methoxy-1 -methyl- 1, 2,3 ,4-tetrahydroisoquinoline (1.6 g, 3.53 mmol) dissolved in
  • Step 4 In a 30 mL vial, 4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenol (250 mg, 0.688 mmol) was dissolved in dichloromethane (3 mL). The vial was cooled to 0 °C and charged with triethylamine (115 ⁇ L, 825 ⁇ ) followed by trifluoromethanesulfonic anhydride (139 ⁇ L, 825 ⁇ ). The reaction mixture was warmed to room temperature and stirred for 2 h.
  • Step 1 To a 100 mL round bottomed flask was added l-(benzyloxy)-4- bromobenzene (1.522 g, 5.78 mmol) and tetrahydrofuran (20 mL). The reaction flask was cooled to -78 °C and charged with 1.6 M «-butyllithium in hexanes (3.98 mL, 6.36 mmol) over 10 min. The suspension was stirred at -78 °C for 40 min.
  • Step 2 In a 100 mL round bottomed flask, the iminium intermediate was dissolved in tetrahydrofuran (20 mL) and the reaction flask was cooled to 0 °C. The flask was charged with 3 M methymagnesium bromide in diethyl ether (2.056 mL, 6.17 mmol) dropwise. The reaction mixture stirred at 0 °C for 30 min at which time the reaction was monitored by LC MS, indicating 40% conversion. The reaction was charged with additional 3 M
  • Step 3 In a 30 mL vial, l-(4-(benzyloxy)phenyl)-2-(4-fluoro-2-methylphenyl)-
  • 6-methoxy-l -methyl- 1,2,3 ,4-tetrahydroisoquinoline (0.8 g, 1.711 mmol) was dissolved in dichloromethane (8 mL).
  • the reaction vial was charged with aluminum trichloride (684 mg, 5.13 mmol) and N,N-dimethylaniline (2.166 mL, 17.11 mmol) and stirred at room temperature for 2 h.
  • the reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (100 mL).
  • the mixture was treated with saturated sodium bicarbonate until pH 5 was obtained.
  • the layers were separated, the aqueous layer was extracted twice with dichloromethane.
  • Step 4 To a 30 mL vial, 4-(2-(4-fluoro-2-methylphenyl)-6-methoxy-l -methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenol (200 mg, 0.530 mmol), dichloromethane (2 mL), and triethylamine (89 ⁇ L, 636 ⁇ ) were added and the vial was cooled to 0 °C. The reaction mixture was charged with trifluoromethanesulfonic anhydride (107 ⁇ L, 0.636 mmol), warmed to room temperature and stirred for 2 h.
  • trifluoromethanesulfonic anhydride 107 ⁇ L, 0.636 mmol
  • Step 1 To a 250 mL round bottomed flask was added l-bromo-4-iodobenzene
  • Step 2 Iminium intermediate was dissolved in tetrahydrofuran (22.0 mL) and cooled to 0 °C. The reaction was charged with a 1.6 M solution of methylmagnesium bromide in diethyl ether (3.16 mL, 9.48 mmol) and the reaction mixture was stirred at 0°C for 1 h. The reaction was quenched with saturated ammonium chloride. The aqueous layer was separated and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude material.
  • Step 1 To a 40 mL vial was added l-bromo-4-iodo-2-methylbenzene (0.159 mL, 1.106 mmol) and pentanes (2.91 mL). The reaction vial was charged with a 2.5 M n- butyllithium in hexanes (444 ⁇ L, 1.110 mmol) and a white precipitate formed immediately.
  • Step 2 Iminium intermediate was dissolved in tetrahydrofuran (2.388 mL) and cooled to 0 °C. To this, 1 M methylmagnesium bromide in tetrahydrofuran (0.132 g, 1.106 mmol) was added dropwise and the reaction stirred at 0 °C for 1 h. The reaction was quenched with saturated ammonium chloride and extracted wth dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude product. Crude material was purified by silica gel chromatography (0-10% ethyl acetate/heptanes) to obtain product (157 mg, 97% yield) as a red-orange solid.
  • Step 1 To a 40 mL scintillation vial was added 5-bromo-2-iodopyridine (0.144 g, 0.508 mmol) and pentanes (1.335 mL). The reaction vial was charged with 2.5 M n- butyllithium (204 ⁇ L, 0.510 mmol) in hexanes and a precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C.
  • Step 2 To a cold solution of the iminium intermediate in tetrahydrofuran
  • Step 1 To a 40 mL scintillation vial was added 1 -bromo-4-iodobenzene (0.549 g, 1.939 mmol) and pentanes (2.55 mL). The reaction vial was charged with 2.5 M n-butyllithium (0.780 mL, 1.949 mmol) in hexanes and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C.
  • Step 2 Iminium intermediate was dissolved in tetrahydrofuran (2.094 ml) and cooled to 0 °C. The reaction was charged with a 1.4M solution of methylmagnesium bromide (0.693 ml, 0.970 mmol) in tetrahydrofuran and stirred at 0°C for 1 hour. The reaction appeared incomplete via LC/MS so the reaction was allowed to warm to room temperature overnight. The reaction was quenched with saturation ammonium chloride solution. The aqueous layer was separated and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated.
  • Step 1 To a 250 mL round bottomed flask was added l-bromo-4-iodobenzene
  • Step 2 The crude material was suspended in tetrahydrofuran (54.8 mL) and cooled to 0°C (ice-water). The reaction mixture was charged with 3.0 M methylmagnesium bromide (6.77 mL, 20.31 mmol) in diethylether dropwise and left to stir for 2 h with warming to ambient temperature. The reaction mixture was quenched with saturated ammonium chloride and diluted with dichloromethane. The layers were separated, the aqueous was washed 2 x with dichloromethane, the organic layers were pooled, washed with brine, passed through a phase separator, and condensed.
  • 3.0 M methylmagnesium bromide (6.77 mL, 20.31 mmol) in diethylether dropwise and left to stir for 2 h with warming to ambient temperature.
  • the reaction mixture was quenched with saturated ammonium chloride and diluted with dichloromethane. The layers were separated, the aqueous was washed 2
  • the reaction vial was flushed with nitrogen and heated at 80 °C for 16 h.
  • LC MS indicated partial conversion of starting material.
  • the reaction mixture was charged with additional methyl acrylate (160 ⁇ ,, 1776 ⁇ ) and Pd(PPh 3 ) 2 Cl 2 (15.58 mg, 0.022 mmol).
  • the vial was flushed with nitrogen and heated at 120 °C for 6 h.
  • the reaction mixture was cooled to ambient temperature and diluted with dichloromethane.
  • the organic layer was washed with water and brine then passed through phase separator and concentrated.
  • reaction mixture was heated for 1 h at 130 °C, LC MS indicated complete conversion to product.
  • the reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated.
  • the crude material was purified via silica gel chromatography using 0-50% ethyl acetate in heptanes to afford product (63 mg, 0.134 mmol, 52.8 % yield) as a yellow oil.
  • the crude reaction mixture was cooled to ambient temperature, diluted with dichloromethane and water. The layers were separated, the aqueous was washed 2 x with dichloromethane. The organic layers were pooled, washed with brine, passed through a phase separator, and condensed.
  • the crude material was purified by silica gel chromatography (0-70% ethyl acetate/heptanes) to afford the desired product as a pale yellow solid (1.18 g, 59% yield).
  • Step 1 2-(4-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-l(2H)-one.
  • Step 2 To a vial, 2-(4-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-l(2H)- one 420 mg, 1.633 mmol) was dissolved in dimethylformamide (3.27 mL). Tert- butylchlorodimethylsilane (369 mg, 2.449 mmol), N,N-dimethylpyridin-4-amine (40 mg, 0.327 mmol), and imidazole (500 mg, 7.35 mmol) were added and the reaction stirred at room temperature overnight. The reaction was quenched with water and extracted with
  • Step 1 To a 50 mL round bottomed flask was added l-bromo-4-iodobenzene
  • Step 2 To a cold solution of the iminium intermediate in tetrahydrofuran (6.50 mL) was added a 1.4 M solution of methylmagnesium bromide (2.140 mL, 3.00 mmol) in tetrahydrofuran. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated ammonium chloride. The aqueous layer was separated and extracted with
  • reaction mixture was cooled to -78 °C and quenched with methanol. Volatiles were removed and the pH of the resulting solution was adjusted with saturated sodium bicarbonate to pH 9. The mixture was diluted with dichloromethane and the layers were separated. The organic layer was washed with water and brine, passed through phase separator, and concentrated to afford the crude product.
  • Route B To a vial containing (£)-methyl 3-(4-(2-(4-fluorophenyl)-6-methoxy-
  • reaction mixture stirred at 0 °C for 1 h, the mixture was warmed to rt and stirred for 3 h.
  • the reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride, and diluted with dichloromethane.
  • the organic phase was collected, dried (sodium sulfate), filtered, and concentrated to afford crude product.
  • Enantiomers were separated using analytical SFC with an IC column (20% methanol, 0.1% trifluoroacetic acid in carbon dioxide) - Analytical SFC, IC column, 2.37 min and 2.51 min. resulted in (S,E)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid and (R,E)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l- methyl-l ,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid.
  • Iminium intermediate was dissolved in tetrahydrofuran (2.388 mL) and the reaction was cooled to 0 °C and a 1 M solution of l-methyl- 3 -magnesium iodide (1.106 mL, 1.106 mmol) in diethyl ether was added dropwise. The reaction stirred at 0 °C for 1 h at which time it was quenched with saturated ammonium chloride. The aqueous layer was extracted thrice with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated.
  • the vial was charged with a mixture of l-methyl-4 -vinyl- lH-imidazole and 1 -methyl-5 -vinyl- 1H- imidazole (1.455 mL, 0.728 mmol) and Pd(PPh 3 ) 2 Cl 2 (26 mg, 0.036 mmol).
  • the system was flushed with nitrogen and heated at 150 °C for 1 h under microwave radiation.
  • the mixture was cooled to room temperature and quenched with saturated ammonium chloride.
  • the reaction mixture was extracted three times with dichloromethane, the organic layers were combined, passed through a phase separator and concentrated to give crude material.
  • Example 20a LC MS (m/z, MH + ): 440.2 PI : 3 ⁇ 4 NMR (400 MHz,
  • Example 20b LC MS (m/z, MH + ): 440.2. P2: 3 ⁇ 4 NMR (400 MHz,
  • Step 1 3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin- 1 -yl)phenyl)propanoic acid.
  • Step 2 To a 30 mL vial, 3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)propanoic acid (0.036 g, 0.086 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0°C. Ethanethiol (118 ⁇ , 1.601 mmol) was added followed by aluminum trichloride (86 mg, 0.644 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and brought to pH 6 with saturated sodium bicarbonate.
  • the reaction mixture was stirred at 0 °C for 30 min, cooled at -78 °C and quenched with methanol and concentrated. Volatiles were removed and the solution was basified with saturated sodium bicarbonate to pH 9. The mixture was diluted with dichloromethane and the layers were separated. The organic layer was washed with water and brine, passed through phase separator and concentrated. The crude product was purified by reverse phase HPLC (15-95%
  • Step 1 In a vial, (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (Intermediate Fl) (40 mg, 0.096 mmol) was dissolved in dimethylformamide (958 ⁇ ). The reaction vial was charged with HATU (44 mg, 0.115 mmol), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.012 g, 0.105 mmol), and 4- methylmorpholine (53 ⁇ , 0.479 mmol) and stirred overnight at rt.
  • HATU 44 mg, 0.115 mmol
  • 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine 0.012 g, 0.105 mmol
  • 4- methylmorpholine 53 ⁇ , 0.479 mmol
  • Step 2 In a vial, (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (0.045 g, 0.087 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (120 ⁇ ⁇ , 1.625 mmol) and aluminum chloride (87 mg, 0.653 mmol) were added, the reaction vial was warmed to rt and stirred for 3 h.
  • the reaction was quenched with water and brought to pH 6 with saturated sodium bicarbonate.
  • the aqueous layer was extracted thrice with dichloromethane, the organic layers were combined, passed through a phase separator and concentrated but afforded no desired product.
  • the aqueous layer was acidified to pH 4 with 1 M hydrochloric acid and extracted thrice with dichloromethane.
  • the organic layers were combined, passed through a phase separator, and concentrated to give crude material.
  • the crude product was purified by reverse phase HPLC (5 mM NH 4 OH modifier, 15 -40% acetonitrile/water) the title compound as an orange solid (3 mg, 8% yield).
  • Step 1 To a 30 mL vial, (£)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-
  • Step 2 To a 2 mL microwave vial, (iT)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l- methyl-l ,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylamide (1.201 mL, 0.120 mmol) and dibutylstannanone (2.99 mg, 0.012 mmol) were suspended in 1,2-dimethoxyethane (1.201 mL). The vial was charged with azidotrimethylsilane (48 ⁇ ⁇ , 0.360 mmol) and the reaction was heated for 60 min at 180 °C under microwave radiation. LC MS showed partial conversion to product.
  • Step 3 To a vial containing, (£)-l-(4-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-2-(4- fluorophenyl)-6-methoxy-l -methyl- 1, 2,3 ,4-tetrahydroisoquino line (3.2 mg, 7.25 ⁇ ) was dissolved in dichloromethane (72 ⁇ ) and cooled to 0 °C. Ethanethiol (1 ⁇ , 0.135 mmol) was added followed by the addition of aluminum chloride (7.25 mg, 0.054 mmol). The reaction was warmed to rt and stirred for 3 h.
  • Step 1 To a 40 mL scintallation vial was added l-bromo-4-iodobenzene (0.718 g, 2.54 mmol) and pentanes (6.68 mL, Ratio: 1.4). The reaction vial was charged with a 2.5 M n- butyllithium (1.019 mL, 2.55 mmol) solution in hexanes and a white precipitate formed immediately.
  • reaction mixture was then quenched with water (10 mL) and ethyl acetate (10 mL) and warmed to rt perchloric acid (0.219 ml, 3.64 mmol, 70% in water) was added and the reaction mixture stirred for 30 min at rt.
  • the reaction was then diluted with water and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude iminium intermediate which was used crude in the next step.
  • Step 2 Iminium intermediate was dissolved in dimethylformamide (7 mL, 0.12
  • Step 3 Ethyl 2-(l-(4-bromophenyl)-2-(4-isopropylphenyl)-6-methoxy-l,2,3,4- tetrahydroisoquinolin-l-yl)-2,2-difluoroacetate (0.362 g, 0.648 mmol) was dissolved in 1,4- dioxanes (6.48 mL). To this was added 1 M lithium hydroxide (1.621 mL, 1.621 mmol) and the reaction was heated to 40 °C for 2 h. LC MS showed the reaction was complete and the reaction was acidified to pH 1 with 1 N hydrochloric acid and extracted with DCM three times.
  • Step 4 In a vial, 2-(l-(4-bromophenyl)-2-(4-isopropylphenyl)-6-methoxy- l,2,3,4-tetrahydroisoquinolin-l-yl)-2,2-difluoroacetic acid (0.1 g, 0.189 mmol) was dissolved in l-methyl-2-pyrrolidinone (9.43 mL) and cesium fluoride (0.143 g, 0.943 mmol) was added. The reaction was put under nitrogen and heated to 192 °C for 24 h. After cooling to rt, water was added to the reaction and the reaction mixture was extracted with diethyl ether three times.
  • Step 5 To a 40 mL vial was added 1 -(4-bromophenyl)- l-(difluoromethyl)-2-
  • 1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.011 g, 0.022 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. To this was added aluminum chloride (0.024 g, 0.179 mmol) followed by the addition of ethanethiol (0.033 mL, 0.448 mmol). The reaction was warmed to rt and stirred for 2 h. The reaction was quenched with saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane.
  • 1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.009 g, 0.019 mmol) was dissolved in 1,4- dioxanes (1 mL) and lithium hydroxide (0.188 mL, 0.188 mmol) was added. The reaction was heated to rt for 3 h. The reaction was then quenched with aqueous 1 N hydrochloric acid and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated.

Abstract

The present invention relates to compounds of formula (I) in which n, R1, R2, R3, R4and R5 are as defined in the claims; capable of being both potent antagonists and degraders of estrogen receptors. Also described is a process for the preparation of compounds of the invention, and the invention further provides pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with aberrant estrogen receptor activity.

Description

1 ,2,3,4-TETRAHYDROISOQUINOLINE COMPOUNDS AND COMPOSITIONS AS SELECTIVE ESTROGEN RECEPTOR ANTAGONISTS AND DEGRADERS
BACKGROUND
FIELD OF THE INVENTION
[0001] The present invention relates to compounds and compositions that are potent antagonists of estrogen receptor signaling and selective estrogen receptor degraders (SERDs).
The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management 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 uterine cancers.
Estrogen receptor (ERoc)-positive diseases such as breast cancer are usually treated with a selective estrogen receptor modulator (SERM) or an aromatase inhibitor (AI). While these therapies have proven effective at reducing the incidence of progression of breast cancer, 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 (AI treatment) or development of dependence upon the antiestrogen for activation of transcription (SERM treatment). SERDs degrade the receptor, effectively eliminating ERoc expression and in so doing circumvent the underlying mechanisms of resistance that develop to antiendocrine monotherapy. Further, clinical and preclinical data show that a significant number of the resistance pathways can be circumvented by the use of 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, endometrium cancer, ovarian cancer, endometriosis, osteoporosis, prostate cancer, benign prostatic hypertrophy, estrogen receptor (ERoc)-positive breast cancer, in particular ERoc- positive breast cancer exhibiting denovo resistance to existing antiestrogens and aromatase inhibitors.
SUMMARY OF THE INVENTION
[0005] In one aspect , the present invention provides compounds of Formula I:
Figure imgf000003_0001
(I)
[0006] in which:
[0007] n is selected from 0, 1 and 2;
[0008] X is selected from N and CR6; wherein R6 is selected from hydrogen and Ci- 4alkyl;
[0009] Ri is hydrogen;
[0010] R21S selected from methyl, -CH2F, -CHF2, CF3 and CD3;
[0011] R3 is selected from -CH2CH2R8 and
Figure imgf000003_0002
wherein each R7 is independently selected from hydrogen, fluoro and Ci-4alkyl; and Rs is selected from -C(0)ORsa, -
C(0)NR8aR8b, -C(0)NHOR8a, -C(0)YR8a and a 5 -member heteroaryl selected from:
Figure imgf000004_0001
[0012] wherein the dotted line indicates the point of attachment with -CH2CH2 or - of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Re is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl;
[0013] R41S selected from hydrogen, Ci-4alkyl, halo and Ci-3alkoxy;
[0014] R51S selected from C6-ioaryl, a 5-6 member heteroaryl containing 1 or 2 heteroatoms selected from O, S and N, and a partially saturated 9-10 member bicyclic ring containing 1 or two heteroatoms selected from O, S and N; wherein said C6-ioaryl, heteroaryl or bicyclic ring system of Rs is unsubstituted or substituted where chemically available with 1 to 3 R11 groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo- substituted-Ci-4alkyl, cyano-substituted-Ci-4alkyl, hydroxy-substituted-Ci-4alkyl, halo-substituted- Ci-4alkoxy, Ci-4alkoxy, -SFs, -NRi2aRi2b, -C(0)Ri2a, -S(0)o-2Ri2a, C3-8cycloalkyl-Co-3alkyl and a 4-7 member ring containing one or two heteroatoms or groups selected from O, N, NH, and S(0)o- 2; wherein Ri2a and Ri2b are independently selected from hydrogen, Ci-4alkyl and C3-scycloalkyl; or Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from O, N, NH, and S(0)o-2; wherein said C3-8cycloalkyl or 4-7 member ring of R11 can be unsubstituted or further substituted with a group selected from halo-substituted Ci-4alkyl and Ci-4alkyl.
[0015] In a second aspect, the present invention provides a pharmaceutical composition which contains a compound of Formula I or a 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.
[0016] In a third aspect, the present invention provides a method of treating a disease in an animal in which a combined selective estrogen receptor anatagonist and estrogen receptor degarder can prevent, inhibit or ameliorate the pathology and/or symptom ology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
[0017] In a fourth aspect, the present invention provides the use of a compound of
Formula I in the manufacture of a medicament for treating a disease in an animal in which estrogen receptor activity contributes to the pathology and/or symptomology of the disease.
[0018] In a fifth aspect, the present invention provides a process for preparing 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. Ester/acid pairs exist in the examples where the esters basically serve as prodrugs of the acids. For example, the seter in example 3 is
Definitions
[0019] The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated, where more general terms whereever used may, independently of each other, be replaced by more specific definitions or remain, thus defining more detailed embodiments of the invention:
[0020] "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 (Ci-7alkyl), or 1 to 4 carbon atoms (Ci-4alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, «-propyl, zso-propyl, «-butyl, sec- butyl, z'sobutyl, ferr-butyl, «-pentyl, isopentyl, neopentyl, «-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, «-heptyl, «-octyl, «-nonyl, «-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 either straight-chained or branched and includes, methoxy, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, and the like.
[0021] "Aryl" means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms. For example, aryl may be phenyl or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group.
[0022] "Heteroaryl" is as defined for aryl above where one or more of the ring members is a heteroatom. For example C5-ioheteroaryl is a minimum of 5 members as indicated by the carbon atoms but that these carbon atoms can be replaced by a heteroatom. Consequently, C5-i0heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.
[0023] "Cycloalkyl" means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated. For example, C3-i0cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
[0024] "Heterocycloalkyl" means cycloalkyl, as defined in this application, provided that one or more of the ring carbons indicated, are replaced by a moiety selected
from -0-, -N=, -NR-, -C(O)-, -S-, -S(O) - or -S(0)2-, wherein R is hydrogen, Ci-4alkyl or a nitrogen protecting group. For example, C3-8heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, thiomorpholino, sulfanomorpholino, sulfonomo holino, etc.
[0025] "Halogen" (or halo) preferably represents chloro or fluoro, but may also be bromo or iodo.
[0026] Compounds of formula I may have different isomeric forms. For example, any asymmetric carbon atom may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration. Substituents at a double bond or especially a ring may be present in cis- (= Z-) or trans (= E-) form. The compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers. [0027] Where the plural form (e.g. compounds, salts) is used, this includes the singular
(e.g. a single compound, a single salt). "A compound" does not exclude that (e.g. in a pharmaceutical formulation) more than one compound of the formula I (or a salt thereof) is present, the "a" merely representing the indefinite article. "A" can thus preferably be read as "one or more", less preferably alternatively as "one".
[0028] Wherever a compound or compounds of the formula I are mentioned, this is further also intended to include N-oxides of such compounds and/or tautomers thereof.
[0029] 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 the formula I may be present as such or in mixture with its N-oxide, as tautomer (e.g. due to keto-enol, lactam-lactim, amide-imidic acid or enamine-imine tautomerism) or in (e.g. equivalency reaction caused) mixture with its tautomer, or as a salt of the compound of the formula I and/or any of these forms or mixtures of two or more of such forms.
[0030] 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 atomic mass usually 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 as 2H, 3H, nC, 13C, 14C, 15N, 170, 180, 35S, 18F, 36C1 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 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. In particular examples, 3H and 14C isotopes may be used for their ease of preparation and detectability. In other examples, substitution with isotopes such as 2H may afford certain therapeutic advantages resulting from greater 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, compounds of the invention can exist in a deutorated form as shown below:
Figure imgf000008_0001
Description of Preferred Embodiments
[0031] The present invention relates to selective estrogen receptor degraders. In one embodiment, with respect to compounds of Formula I, are compounds of Formula la:
Figure imgf000008_0002
[0032] in which: n is selected from 0 and 1 ; X is selected from N and CH; R2 is selected from methyl, -CH2F, -CHF2, CF3 and CD3; R4 is methyl; and Rs is selected from Ce- and a 5-6 member heteroaryl or bicyclic ring selected from:
Figure imgf000009_0001
[0033] wherein the dotted line indicates the point of attachment with the
tetrahydroisoquinoline core; wherein said C6-ioaryl or heteroaryl of Rs is unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo-substituted-Ci-4alkyl, cyano-substituted-Ci- 4alkyl, hydroxy-substituted-Ci-4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, -SFs, -NRi2aRi2b, - C(0)Ri2a, -S(0)o-2Ri2a, C3-8Cycloalkyl-Co-3alkyl and a 4-7 member ring containing one or two heteroatoms or groups selected from 0, N, NH, and S(0)o-2; wherein Rm and Ri2b are
independently selected from hydrogen and Ci-4alkyl; or Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from O, N, NH, and S(0)o-2; wherein said C3-8cycloalkyl or 4-7 member ring of Rn can be unsubstituted or further substituted with a group selected from halo -substituted Ci-4alkyl and Ci-4alkyl; or a pharmaceutically acceptable salt thereof.
[0034] In a further embodiment are compounds in which: R2 is selected from methyl, -
CH2F, -CHF2, CF3 and CD3; and Rs is selected from C6-ioaryl unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from fluoro, methyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, isopropoxy, trifluoromethyl, hydroxy, methoxy-ethyl, methyl substituted pyrazolyl, trifluoro-ethyl, trifluoro-propyl, cyclobutyl, cyclopropyl-methyl, cyclopentyl, l-(trifluoromethyl)cyclopropyl, trifluoromethoxy and trifluoro-ethoxy; or a pharmaceutically acceptable salt thereof.
[0035] In a further embodiment are compounds, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000010_0001
 OH
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0003
Figure imgf000012_0001
11
Figure imgf000013_0001

Figure imgf000014_0001

Figure imgf000015_0001

Figure imgf000016_0001
[0037] In another embodiment are compounds in which: n is selected from 0 and 1 ; R2 is selected from methyl, -CH2F, -CHF2, CF3 and CD3; R4 is methyl; and Rs is a 5-6 member heteroaryl or bicyclic ring selected from:
Figure imgf000016_0002
[0038] wherein the dotted line indicates the point of attachment with the
tetrahydroisoquinoline core; wherein said heteroaryl of Rs is unsubstituted or substituted with a group selected from methyl, isopropyl and methoxy; or a pharmaceutically acceptable salt thereof.
[0039] In a further embodiment are compounds, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000017_0001
Figure imgf000018_0002
In another embodiment are compounds of formula lb:
Figure imgf000018_0001
[0041] in which: X is selected from N and CRJS; wherein R.6 is selected from hydrogen and Ci-4alkyl; Ri is hydrogen; R2 is selected from methyl, -CH2F, -CHF2, CF3 and CD3; R3 is selected from -CH2CH2R8 and
Figure imgf000019_0001
wherein each R7 is independently selected from hydrogen, fluoro and Ci-4alkyl; and Rs is a 5-member heteroaryl selected from:
Figure imgf000019_0002
[0042] wherein the dotted line indicates the point of attachment with -CH2CH2 or -
CR7=CR7 of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Re is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl; R9 is selected from hydrogen, methyl, ethyl, trifluoro-ethyl, isobutyl, cyclopropyl, hydroxy-methyl and propyl; and Rio is selected from hydrogen and methyl;
[0043] Rs is selected from C6-ioaryl and a 5-6 member heteroaryl or bicyclic ring selected from:
Figure imgf000020_0001
[0044] wherein the dotted line indicates the point of attachment with the
tetrahydroisoquinoline core; wherein said C6-ioaryl or heteroaryl of Rs is unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo-substituted-Ci-4alkyl, cyano-substituted-Ci- 4alkyl, hydroxy-substituted-Ci-4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, -SFs, -NRi2aRi2b, - C(0)Ri2a, -S(O)0-2Ri2a, C3-8cycloalkyl and a 4-7 member ring containing one or two heteroatoms or groups selected from 0, N, NH, and S(0)o-2; wherein Ri2a and Ri2b are independently selected from hydrogen and Ci-4alkyl; or Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from O, N, NH, and S(0)o-2; wherein said C3-scycloalkyl or 4-7 member ring of Rn can be unsubstituted or further substituted with a group selected from halo-substituted Ci-4alkyl and Ci-4alkyl; or a pharmaceutically acceptable salt thereof.
[0045] In a further embodiment are compounds, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000024_0001

Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000025_0003
Figure imgf000026_0001
Figure imgf000027_0001
[0048] in which: n is selected from 0, 1 and 2; X is selected from N and CR.6; wherein
Rjds selected from hydrogen and Ci-4alkyl; Ri is hydrogen; R21S selected from methyl, -CH2F, - CHF2, CF3 and CD3; R3 is selected from -CfhCfbRs and
Figure imgf000028_0001
wherein each R71S independently selected from hydrogen, fluoro and Ci-4alkyl; and Rs is selected from -C(0)ORsa, - C(0)NR8aR8b, -C(0)NHOR8a, -C(0)YR8a and a 5 -member heteroaryl selected from:
Figure imgf000028_0002
[0049] wherein the dotted line indicates the point of attachment with -CH2CH2 or -
CR7=CR7 of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Re is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl;
[0050] R41S selected from hydrogen, Ci-4alkyl, halo and Ci-3alkoxy; Rsis selected from
C6-ioaryl, a 5-6 member heteroaryl containing 1 or 2 heteroatoms selected from O, S and N, and a partially saturated 9-10 member bicyclic ring containing 1 or two heteroatoms selected from O, S and N; wherein said C6-ioaryl, heteroaryl or bicyclic ring system of R5 is unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo-substituted-Ci-4alkyl, cyano-substituted-Ci- 4alkyl, hydroxy-substituted-Ci-4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, -SF5, -NRi2aRi2b, - C(0)Ri2a, -S(O)0-2Ri2a, C3-8cycloalkyl and a 4-7 member ring containing one or two heteroatoms or groups selected from O, N, NH, and S(0)o-2; wherein Ri2a and Ri2b are independently selected from hydrogen, Ci-4alkyl and C3-8cycloalkyl; or Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from 0, N, NH, and S(0)o-2; wherein said C3-8cycloalkyl or 4-7 member ring of Rii can be unsubstituted or further substituted with a group selected from halo-substituted Ci-4alkyl and Ci-4alkyl; or a pharmaceutically acceptable salt thereof.
[0051] In another embodiment are compounds of formula Id:
Figure imgf000029_0001
(Td)
[0052] in which: n is selected from 0 and 1; X is selected from N and CH; R2 is selected from methyl, -CH2F, -CHF2, CF3 and CD3; R4 is methyl; and Rs is selected from Ce- and a 5-6 member heteroaryl or bicyclic ring selected from:
Figure imgf000029_0002
[0053] wherein the dotted line indicates the point of attachment with the
tetrahydroisoquinoline core; wherein said C6-ioaryl or heteroaryl of Rs is unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo-substituted-Ci-4alkyl, cyano-substituted-Ci- 4alkyl, hydroxy-substituted-Ci-4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, -SFs, -NRi2aRi2b, - C(0)Ri2a, -S(O)0-2Ri2a, C3-8cycloalkyl and a 4-7 member ring containing one or two heteroatoms or groups selected from 0, N, NH, and S(0)o-2; wherein Ri2a and Ri2b are independently selected from hydrogen and Ci-4alkyl; or Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from O, N, NH, and S(0)o-2; wherein said C3-8cycloalkyl or 4-7 member ring of Rn can be unsubstituted or further substituted with a group selected from halo-substituted Ci-4alkyl and Ci-4alkyl; or a pharmaceutically acceptable salt thereof.
[0054] In a further embodiment are compounds in which: R2 is selected from -CH2F, -
CHF2 and CF3; and Rs is selected from C6-ioaryl unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from fluoro, methyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, isopropoxy, trifluoromethyl, hydroxy, methoxy -ethyl, methyl substituted pyrazolyl, trifluoro-ethyl, trifluoro -propyl, cyclobutyl, l-(trifluoromethyl)cyclopropyl, trifluoromethoxy and trifluoro -ethoxy; or a pharmaceutically acceptable salt thereof.
[0055] In a further embodiment are compounds, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000030_0001
Figure imgf000031_0001
Pharmacology and Utility
[0056] The present invention relates to compounds of Formula I that diminish the effects of estrogen receptors and lower the 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 etiology or pathology of the disease or condition or contribute to at least one symptom of the disease or condition and wherein such actions of estrogens or estrogen receptors are undesirable. Compounds of the invention are both potent estrogen receptor antagonists and selective estrogen receptor degraders (SERDS).
[0057] The estrogen receptor (ER) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. In both females and males, estrogens play an important role in the regulation of a number of physiological processes. In humans, two different ER subtypes are known: ERoc and ER . Each subtype has a distinct tissue distribution and with different biological roles. For example, ERoc has high presence in endometrium, breast cancer cells, ovarian stroma cells and in the hypothalamus. The expression of the ER protein has been documented in kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, bladder, ovary, testis, and endothelial cells.
[0058] Pharmaceuticals such as tamoxifen, raloxifene and lasofoxifene are well known estrogen receptor modulators. Tamoxifen, for example, behaves like an estrogen in bone and endometrium, whereas it behaves like an anti-estrogen in breast tissue. Breast cancer is the predominant neoplastic disease in women. ERoc is a major driver of breast cancer progression. Multiple existing treatment approaches aim to reduce estrogen levels or block its binding to ERoc thereby minimizing tumor progression or even inducing tumor regression in ERoc -positive breast cancer. Tamoxifen is a first-generation treatment for ERoc-positive breast cancer. However, efficacy in breast cancer treatment is seriously compromised by intrinsic or newly developed resistance to anti-hormonal therapy such as treatment with tamoxifen or aromatase inhibitors. Such resistance can exist or develop as a result of ERoc phoshorylation or regulation of key components in hormone receptor and/or growth factor signal transduction pathways. Tamoxifen resistance is driven by the residual agonist activity of tamoxifen. Second generation treatments such as toremifene, droloxifene, idoxifene, arzoxifene, and raloxifene have failed to improve upon the efficacy of tamoxifen in the treatment of ERoc-positive breast cancer and/or demonstrated cross-resistance with each other.
[0059] Fulvestrant is a pure ERoc antagonist without the partial agonist activity which is typical for the estrogen receptor modulators. It is the only marketed selective estrogen receptor degrader (SERD) and it is efficacious in second-line treatment of breast cancer. Fulvestrant both antagonizes estrogen receptors and effectively degrades or down-regulates ERoc protein levels in cells. This SERD activity inhibits ERoc -driven proliferation and tumor growth. Fulvestrant, when administered once a month at 250 mg is equally effective to tamoxifen in treatment of ERoc- positive advanced breast cancer. In second-line treatment of ERoc -positive tamoxifen-resistant breast cancer, fulvestrant, when administered once a month at 250 mg, is equally effective to aromatase inhibitors, despite relatively poor bioavailability and/or target exposure which limits its clinical efficacy. A number of other SERDs exist, for example: "ICI 164,384", a structural analog of fulvestrant; "GW5638", a structural analog of tamoxifen; and "GW7604", a structural analogue of 4-hydroxy -tamoxifen.
[0060] Hence, there is a need for new, potent ERoc antagonists, which would preferably have ER degrading or down-regulating activity in, for example, breast cancer cells without stimulating proliferation in ERoc -positive, hormone treatment-resistant breast cancer cells. Such compounds would be orally administrable and be useful in the treatment of, amongst other things, ERoc -positive, hormone treatment-resistant breast cancer.
[0061] Estrogen receptor-related diseases or conditions include, but are not limited to, aberrant estrogen receptor activity associated with: cancer, for example, 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; hematological system defects, for example, deep vein thrombosis; immune and inflammation diseases, for example, Graves' Disease, arthritis, mulitple 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 and vertigo; psychiatric defects, for example, anorexia nervosa, attention deficity hyperactivity disorder, dementia, major depressive disorder and psychosis; and reproductive defects, for example, age of menarche, endometriosis and infertility. In the context of treating cancers, the compound of Formula I offer improved therapeutic activity characterized by complete or longer-lasting tumor regression, a lower incidence or rate of development of resistance to treatment, and/or a reduction in tumor invasiveness.
[0062] The present invention relates to compounds that are both potent estrogen receptor anatagonists and selective estrogen receptor degraders. The invention further provides a process for the preparation of 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
[0063] In an embodiment, compounds of the invention are used to treat cancer in a mammal.
[0064] In a further embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancers.
[0065] In a further embodiment, the cancer is breast cancer.
[0066] In another embodiment, the cancer is a hormone dependent cancer.
[0067] In another embodiment, the cancer is an estrogen receptor dependent cancer.
[0068] In a further embodiment, the cancer is an estrogen-sensitive cancer. [0069] In another embodiment, the cancer is resistant to anti-hormonal treatment.
[0070] In a further embodiment, the cancer is an estrogen-sensitive cancer or an estrogen receptor dependent cancer that is resistant to anti-hormonal treatment.
[0071] In a further embodiment, the anti-hormonal treatment includes treatment with at least one agent selected from tamoxifen, fulvestrant, a steroidal aromatase inhibitor, and a nonsteroidal aromatase inhibitor.
[0072] 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 anti-estrogen therapy.
[0073] In another embodiment, compounds of theinvention are used to treat a hormonal dependent benign or malignant disease of the breast or reproductive tract in a mammal.
[0074] In a further embodiment, the benign or malignant disease is breast cancer.
[0075] In another embodiment, compounds of the invention are used to treat cancer in a mammal, wherein the mammal is chemotherapy -naive.
[0076] 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.
[0077] In a further embodiment, the cancer is a hormone refractory cancer.
[0078] In another embodiment, compounds of the invention are used in the treatment of endometriosis in a mammal.
[0079] In another embodiment, compounds of the invention are used in the treatment of leiomyoma in a mammal.
[0080] In a further embodiment, the leiomyoma is selected from uterine leiomyoma, esophageal leiomyoma, cutaneous leiomyoma and small bowel leiomyoma.
[0081] In another embodiment, compounds of the invention are used in the treatment of fibroids, for example, uterine fibroids, in a mammal.
[0082] 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 the 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, e.g. cisplatin, 5-fluorouracil or 5-fluoro-2-4(l H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine.
[0083] Such combinations may offer significant advantages, including synergistic activity, in therapy.
[0084] In certain embodiments, the present invention relates to the aforementioned method, wherein said compound is administered parenterally.
[0085] 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.
[0086] In certain embodiments, the present invention relates to the aforementioned method, wherein said compound is administered systemically.
[0087] In certain embodiments, the present invention relates to the aforementioned method, wherein said patient is a mammal.
[0088] In certain embodiments, the present invention relates to the aforementioned method, wherein said patient is a primate.
[0089] In certain embodiments, the present invention relates to the aforementioned method, wherein said patient is a human.
[0090] 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 chemothereutic agent in combination with a therapeutically effective amount of a compound of formula I as defined in the Summary of the Invention.
Pharmaceutical Compositions
[0091] In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise 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 diluents. 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, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, 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 sustained- 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.
[0092] The phrase "therapeutically-effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
[0093] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
[0094] The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which 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) gelatin; (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, corn 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 poly anhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.
[0095] As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids. The term
"pharmaceutically-acceptable salts" in this respect, 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 the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus 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, napthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).
[0096] The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like. [0097] 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 instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a
pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra)
[0098] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
[0099] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite 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.
[00100] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), 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 which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety -nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 percent to about 30 percent.
[00101] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and poly anhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.
[00102] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately 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.
[00103] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes 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 may also be administered as a bolus, electuary or paste.
[00104] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, touches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate 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 non-ionic 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) coloring 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 soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
[00105] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface -active 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.
[00106] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as 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 polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which 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 can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
[00107] 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, the 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, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
[00108] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
[00109] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
[00110] 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 nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
[00111] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
[00112] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
[00113] The ointments, pastes, creams and gels may contain, in addition to an 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.
[00114] Powders and sprays can 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 can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
[00115] Transdermal patches have the added advantage of providing controlled delivery 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 flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
[00116] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
[00117] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
[00118] Examples of suitable aqueous and nonaqueous carriers which 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, vegetable oils, 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 the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[00119] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may 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 into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
[00120] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon 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.
[00121] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
[00122] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given 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.
[00123] The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets 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.
[00124] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
[00125] The phrases "systemic administration," "administered systemically,"
"peripheral administration" and "administered peripherally" as used herein mean the
administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
[00126] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
[00127] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
[00128] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
[00129] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
[00130] 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 could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
[00131] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for 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.
[00132] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
[00133] While 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).
[00134] The compounds according to the invention may be formulated for
administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
[00135] In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. 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, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, 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.
[00136] The term "treatment" is intended to encompass also prophylaxis, therapy and cure.
[00137] The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
[00138] The compound of the invention can be administered as such or in admixtures with pharmaceutically acceptable carriers and can also be administered in conjunction with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Conjunctive therapy, thus includes sequential, simultaneous and separate administration of the active compound in a way that the therapeutical effects of the first administered one is not entirely disappeared when the subsequent is administered.
[00139] Microemulsification technology can improve bioavailability of some lipophilic
(water insoluble) pharmaceutical agents. Examples include Trimetrine (Dordunoo, S. K., et al., Drug Development and Industrial Pharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen, P. C, et al., J Pharm Sci 80(7), 712-714, 1991). Among other things, microemulsification provides enhanced bioavailability by preferentially directing absorption to the lymphatic system instead of the circulatory system, which thereby bypasses the liver, and prevents destruction of the compounds in the hepatobiliary circulation.
[00140] While all suitable amphiphilic carriers are contemplated, the presently preferred carriers are generally those that have Generally-Recognized-as-Safe (GRAS) status, and that can both solubilize the compound of the present invention and microemulsify it at a later stage when the solution comes into a contact with a complex water phase (such as one found in human gastrointestinal tract). Usually, amphiphilic ingredients that satisfy these requirements have HLB (hydrophilic to lipophilic balance) values of 2-20, and their structures contain straight chain aliphatic radicals in the range of C-6 to C-20. Examples are polyethylene-glycolized fatty glycerides and polyethylene glycols.
[00141] Commercially available amphiphilic carriers 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 a number of companies in USA and worldwide).
[00142] Hydrophilic polymers suitable for use in the present invention are those which are readily water-soluble, can be covalently attached to a vesicle-forming lipid, and which are tolerated in vivo without toxic effects (i.e., are biocompatible). Suitable polymers include polyethylene glycol (PEG), polylactic (also termed polylactide), polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolic acid copolymer, and polyvinyl alcohol. Preferred polymers are those having a molecular weight of from about 100 or 120 daltons up 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 polyethyleneglycol having a molecular weight of from about 100 to about 5,000 daltons, and more preferably having a molecular weight of from about 300 to about 5,000 daltons. In a particularly preferred embodiment, the polymer is polyethyleneglycol of 750 daltons (PEG(750)). Polymers may also be defined by the number of monomers therein; 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).
[00143] Other hydrophilic polymers which may be suitable for use in the present invention include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline,
polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.
[00144] In certain embodiments, a formulation of the present invention comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronic acids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.
[00145] Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8 glucose units, designated by the Greek letter .alpha., .beta, or .gamma., respectively. Cyclodextrins with fewer than six glucose units are not known to exist. The glucose units are linked by alpha- 1,4- glucosidic bonds. As a consequence of the chair conformation of the sugar units, all secondary hydroxyl groups (at C-2, C-3) are located on one side of the ring, while all the primary hydroxyl groups at C-6 are situated on the other side. As a result, the external faces are hydrophilic, making the cyclodextrins water-soluble. In contrast, the cavities of the cyclodextrins are hydrophobic, since they are lined by the hydrogen of atoms C-3 and C-5, and by ether-like oxygens. These matrices allow complexation with a variety of relatively hydrophobic compounds, including, for instance, steroid compounds such as 17.beta. -estradiol (see, e.g., van Uden et al. Plant Cell Tiss. Org. Cult. 38: 1-3-113 (1994)). The complexation takes place by Van der Waals interactions and by hydrogen bond formation. For a general review of the chemistry of cyclodextrins, see, Wenz, Agnew. Chem. Int. Ed. Engl., 33:803-822 (1994).
[00146] The physico-chemical properties of the cyclodextrin derivatives depend strongly on the kind and the degree of substitution. For example, their solubility in water ranges from insoluble (e.g., triacetyl-beta-cyclodextrin) to 147% soluble (w/v) (G-2-beta-cyclodextrin). In addition, they are soluble in many organic solvents. The properties of the cyclodextrins enable the control over solubility of various formulation components by increasing or decreasing their solubility.
[00147] Numerous cyclodextrins and methods for their preparation have been described. For example, Parmeter (I), et al. (U.S. Pat. No. 3,453,259) and Gramera, et al. (U.S. Pat. No. 3,459,731) described electroneutral cyclodextrins. Other derivatives include cyclodextrins with cationic properties [Parmeter (II), U.S. Pat. No. 3,453,257], insoluble crosslinked cyclodextrins (Solms, U.S. Pat. No. 3,420,788), and cyclodextrins with anionic properties [Parmeter (III), U.S. Pat. No. 3,426,011]. Among the cyclodextrin derivatives with anionic properties, carboxylic acids, phosphorous acids, phosphinous acids, phosphonic acids, phosphoric acids, thiophosphonic acids, thiosulphinic acids, and sulfonic acids have been appended to the parent cyclodextrin [see, Parmeter (III), supra]. Furthermore, sulfoalkyl ether cyclodextrin derivatives have been described by Stella, et al. (U.S. Pat. No. 5,134,127).
[00148] Liposomes consist of at least one lipid bilayer membrane enclosing an aqueous internal compartment. Liposomes may be characterized by membrane type and by size. Small unilamellar vesicles (SUVs) have a single membrane and typically range between 0.02 and 0.05 μιη in diameter; large unilamellar vesicles (LUVS) are typically larger than 0.05 μιη
Oligolamellar large vesicles and multilamellar vesicles have multiple, usually concentric, membrane layers and are typically larger than 0.1 μιη. Liposomes with several nonconcentric membranes, i.e., several smaller vesicles contained within a larger vesicle, are termed multivesicular vesicles.
[00149] One aspect of the present invention relates to formulations comprising liposomes containing a compound of the present invention, where the liposome membrane is formulated to provide a liposome with increased carrying capacity. Alternatively or in addition, the compound of the present invention may be contained within, or adsorbed onto, the liposome bilayer of the liposome. The compound of the present invention may be aggregated with a lipid surfactant and carried within the liposome's internal space; in these cases, the liposome membrane is formulated to resist the disruptive effects of the active agent-surfactant aggregate.
[00150] According to one 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 interior space encapsulated by the liposome, and extend from the exterior of the lipid bilayer into the surrounding environment.
[00151] Active agents contained within 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) may be entrapped within the interior space of liposomes according to the present invention. A surfactant acts to disperse and solubilize the active agent, and may be selected from any suitable aliphatic, cycloaliphatic or aromatic surfactant, including but not limited to biocompatible lysophosphatidylcholines (LPCs) of varying chain lengths (for example, from about C. sub.14 to about C.sub.20). Polymer-derivatized lipids such as PEG-lipids may also be utilized for micelle formation as they will act to inhibit micelle/membrane fusion, and as the addition of a polymer to surfactant molecules decreases the CMC of the surfactant and aids in micelle formation. Preferred are surfactants with CMCs in the micromolar range; higher CMC surfactants may be utilized to prepare micelles entrapped within liposomes of the present invention, however, micelle surfactant monomers could affect liposome bilayer stability and would be a factor in designing a liposome of a desired stability.
[00152] Liposomes according to the present invention may be prepared by any of a variety of techniques that are known in the art. See, e.g., U.S. Pat. No. 4,235,871; Published PCT applications WO 96/14057; New RRC, Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104; Lasic DD, Liposomes from physics to applications, Elsevier Science Publishers BV, Amsterdam, 1993.
[00153] For example, liposomes of the present invention may be prepared by diffusing a lipid derivatized 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 of derivatized lipid which 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.
[00154] In one aspect of the present invention, the liposomes are prepared to have substantially homogeneous sizes in a selected size range. One effective sizing method involves extruding an aqueous suspension of the liposomes through a series of polycarbonate membranes having a selected uniform pore size; the pore size of the membrane will correspond roughly with the largest sizes of liposomes produced by extrusion through that membrane. See e.g., U.S. Pat. No. 4,737,323 (Apr. 12, 1988).
[00155] The release characteristics of a formulation of the present invention depend on the encapsulating material, the concentration of encapsulated drug, and the presence of release modifiers. For example, release can be manipulated to be pH dependent, for example, using a pH sensitive coating that releases only at a low pH, as in the stomach, or a higher pH, as in the intestine. An enteric coating can be used to prevent release from occurring until after passage through the stomach. Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to obtain an initial release in the stomach, followed by later release in the intestine. Release can also be manipulated by inclusion of salts or pore forming agents, which can increase water uptake or release of drug by diffusion from the capsule. Excipients which modify the solubility of the drug can also be used to control the release rate. Agents which enhance degradation of the matrix or release from the matrix can also be incorporated. They can be added to the drug, added as a separate phase (i.e., as particulates), or can be co-dissolved in the polymer phase depending on the compound. In all cases the amount should be between 0.1 and thirty percent (w/w 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, calcium carbonate, zinc carbonate, and 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 which add microstructure to the matrices (i.e., water soluble compounds such as inorganic salts and sugars) are added as particulates. The range should be between one and thirty percent (w/w polymer).
[00156] Uptake can also be manipulated by altering residence time of the particles in the gut. This can be achieved, for example, by coating the particle 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 Combinations
[00157] The invention especially relates to the use of a compound of the formula I (or a pharmaceutical composition comprising a compound of the formula I) in the treatment of one or more of the diseases mentioned herein; wherein the response to treatment is beneficial as demonstrated, for example, by the partial or complete removal of one or more of the symptoms of the disease up to complete cure or remission.
[00158] Given the central role of ER-oc in breast cancer development and progression, compounds disclosed herein are useful in the treatment of breast cancer, either alone or in combination with other agents used to treat breast cancer, including but not limited to aromatase inhibitors, anthracylines, platins, nitrogen mustard alkylating agents and taxanes. Agents used to treat breast cancer, include, but are not limited to, paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine and ixabepilone.
[00159] Further, compounds of the invention are useful in the treatment of breast cancer, either alone or in combination with other agents that modulate other critical pathways in breast cancer, including but not limited to those that target IGF1R, EGFR, erB-B2 and the PI3 K/AKT/mTOR axis, Rb axis including CDK4/6 and D-cyclins, HSP90, PARP and/or histone deacetylases.
[00160] A compound of the invention can, therefore, also be used in combination with the following:
[00161] Vascular Endothelial Growth Factor (VEGF) receptor inhibitors: Bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methyl-2-[[3-[(£T)-2-pyridin-2- ylethenyl]-lH-indazol-6-yl]sulfanyl]benzamide, also known as AGO 13736, and described in PCT Publication No. WO 01/002369), Brivanib Alaninate ((5)-((R)-l-(4-(4-Fluoro-2-methyl-lH-indol- 5-yloxy)-5-methylpyrrolo[2,l- ][l,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-lH-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 tradename Nexavar®);
[00162] HER2 receptor inhibitors: Trastuzumab (sold under the trademark Herceptin® by Genentech/Roche), neratinib (also known as HKI-272, (2iT)-N-[4-[[3-chloro-4-[(pyridin-2- yl)methoxy]phenyl] amino] -3 -cy ano-7-ethoxyquinolin-6-yl] -4-(dimethylamino)but-2-enamide, and described PCT Publication No. WO 05/028443), lapatinib or lapatinib ditosylate (sold under the trademark Tykerb® by Glaxo SmithKline);
[00163] CD20 antibodies: Rituximab (sold under the trademarks Riuxan® and MabThera® by Genentech/Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline);
[00164] Tyrosine kinase inhibitors: Erlotinib hydrochloride (sold under the trademark Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5- methylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib malate (sold under the tradename Sutent® by Pfizer), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in US 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 imatinib mesylate (sold under the tradenames Gilvec® and Gleevec® by Novartis);
[00165] Bcr/Abl kinase inhibitors: nilotinib hydrochloride (sold under the tradename Tasigna® by Novartis);
[00166] DNA Synthesis inhibitors: Capecitabine (sold under the trademark Xeloda® by Roche), gemcitabine hydrochloride (sold under the trademark 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 tradenames Arranon® and Atriance® by GlaxoSmithKline);
[00167] Antineoplastic agents: oxaliplatin (sold under the tradename Eloxatin® ay Sanofi- Aventis and described in US Patent No. 4,169,846);
[00168] Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (sold under the tradename Iressa®), N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3- furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers
Squibb), panitumumab (sold under the tradename Vectibix® by Amgen);
[00169] HER dimerization inhibitors: Pertuzumab (sold under the trademark Omnitarg®, by
Genentech);
[00170] Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (sold under the tradename Neupogen® by Amgen);
[00171] 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 Thalomid®);
[00172] CD40 inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc);
[00173] Pro-apoptotic receptor agonists (PARAs): Dulanermin (also known as AMG-951, available from Amgen/Genentech); [00174] 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);
[00175] PI3K inhibitors: 4-[2-(lH-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-l- yl]methyl]thieno[3,2-d]pyrimidin-4-yl]mo holine (also known as GDC 0941 and described in
PCT 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-l-yl]phenyl]propionitrile (also known as BEZ
235 or NVP-BEZ 235, and described in PCT Publication No. WO 06/122806);
[00176] Phospholipase A2 inhibitors: Anagrelide (sold under the tradename Agrylin®);
[00177] BCL-2 inhibitors: 4-[4-[[2-(4-chlorophenyl)-5 ,5 -dimethyl- 1 -cyclohexen- 1 -yl]methyl] - 1 - piperazinyl] -N- [ [4- [ [( 1 R)-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);
[00178] Mitogen-activated protein kinase kinase (MEK) inhibitors: XL-518 (Cas No. 1029872- 29-4, available from ACC Corp.);
[00179] Aromatase inhibitors: Exemestane (sold under the trademark Aromasin® by Pfizer), letrozole (sold under the tradename Femara® by Novartis), anastrozole (sold under the tradename Arimidex®);
[00180] Topoisomerase I inhibitors: Irinotecan (sold under the trademark Camptosar® by Pfizer), topotecan hydrochloride (sold under the tradename Hycamtin® by Glaxo SmithKline);
[00181] Topoisomerase II inhibitors: etoposide (also known as VP- 16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradename Vumon®);
[00182] mTOR inhibitors: Temsirolimus (sold under the tradename Torisel® by Pfizer), ridaforolimus (formally known as deferolimus, (lR,2R,45)-4-[(2R)-2
[(1R,9S,12S,15R,16£,18R,19R,21R, 23S,24£,26£,28Z,30S,32S,35R)-l,18-dihydroxy-19,30- dimethoxy- 15, 17,21,23, 29,35-hexamethyl-2,3,10,14,20-pentaoxo-l l,36-dioxa-4- azatricyclo[30.3.1.04'9] hexatriaconta-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 tradename Afinitor® by Novartis); [00183] Osteoclastic bone resorption inhibitors: l-Hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradename Zometa® by Novartis);
[00184] CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename Mylotarg® by Pfizer/Wyeth);
[00185] CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-
544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);
[00186] CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (sold under the tradename
Zevalin®);
[00187] Somatostain analogs: octreotide (also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®);
[00188] Synthetic Interleukin-11 (IL-11): oprelvekin (sold under the tradename Neumega® by Pfizer/Wyeth);
[00189] Synthetic erythropoietin: Darbepoetin alfa (sold under the tradename Aranesp® by Amgen);
[00190] Receptor Activator for Nuclear Factor κ B (RANK) inhibitors: Denosumab (sold under the tradename Prolia® by Amgen);
[00191] Thrombopoietin mimetic peptibodies: Romiplostim (sold under the tradename Nplate® by Amgen;
[00192] Cell growth stimulators: Palifermin (sold under the tradename Kepivance® by Amgen);
[00193] 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);
[00194] Anti-CSl antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3);
[00195] CD52 antibodies: Alemtuzumab (sold under the tradename Campath®);
[00196] CTLA-4 inhibitors: Tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206), ipilimumab (CTLA-4 antibody, also known as
MDX-010, CAS No. 477202-00-9);
[00197] Histone deacetylase inhibitors (HDI): Voninostat (sold under the tradename Zolinza® by Merck); [00198] Alkylating agents: Temozolomide (sold under the tradenames Temodar® and
Temodal® by Schering-Plough Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), 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 Cytoxan® and Neosar®), dacarbazine (also known 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 Hex®), procarbazine (sold under the tradename Matulane®), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename Mustargen®), streptozocin (sold under the tradename Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, sold under the tradename Thioplex®;
[00199] Biologic response modifiers: bacillus calmette-guerin (sold under the tradenames theraCys® and TICE® BCG), denileukin diftitox (sold under the tradename Ontak®);
[00200] Anti-tumor antibiotics: doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename Ellence™), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), mitomycin C (sold under the tradename Mutamycin®);
[00201] Anti-microtubule agents: Estramustine (sold under the tradename Emcyl®);
[00202] Cathepsin K inhibitors: Odanacatib (also know as MK-0822, N-(l-cyanocyclopropyl)- 4-fluoro-N2-{(lS)-2,2,2-trifluoro-l-[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);
[00203] Epothilone B analogs: Ixabepilone (sold under the tradename Lxempra® by Bristol- Myers Squibb);
[00204] Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17- demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in US Patent No. 4,261,989);
[00205] TpoR agonists: Eltrombopag (sold under the tradenames Promacta® and Revolade® by Glaxo SmithKline) ;
[00206] Anti-mitotic agents: Docetaxel (sold under the tradename Taxotere® by Sanofi- Aventis);
[00207] Adrenal steroid inhibitors: aminoglutethimide (sold under the tradename Cytadren®);
[00208] Anti -androgens: Nilutamide (sold under the tradenames Nilandron® and Anandron®), bicalutamide (sold under tradename Casodex®), flutamide (sold under the tradename Fulexin™);
[00209] Androgens: Fluoxymesterone (sold under the tradename Halotestin®);
[00210] Proteasome inhibitors: Bortezomib (sold under the tradename Velcade®);
[00211] CDK1 inhibitors: Alvocidib (also known as flovopirdol or HMR-1275, 2-(2- chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-l-methyl-4-piperidinyl]-4-chromenone, and described in US Patent No. 5,621,002);
[00212] Gonadotropin-re leasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames Viadure® by Bayer AG, Eligard® by Sanofi-Aventis and Lupron® by Abbott Lab);
[00213] Taxane anti -neoplastic agents: Cabazitaxel (l -hydroxy-7 ,10 -dimethoxy-9-oxo-5 ,20- epoxytax-1 l-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{ [(tert- butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate), larotaxel ((2α,3ξ,4α,5β,7α,10β,13α)- 4,10-bis(acetyloxy)-13-({(2R,35)-3- [(fer?-butoxycarbonyl) amino]-2-hydroxy-3- phenylpropanoyl}oxy)-l- hydroxy -9-oxo-5, 20-epoxy-7, 19-cyclotax- 1 l-en-2-yl benzoate);
[00214] 5HTla receptor agonists: Xaliproden (also known as SR57746, l-[2-(2-naphthyl)ethyl]- 4-[3-(trifluoromethyl)phenyl]-l,2,3,6-tetrahydropyridine, and described in US Patent No.
5,266,573); [00215] HPC vaccines: Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck;
[00216] Iron Chelating agents: Deferasinox (sold under the tradename Exjade® by Novartis);
[00217] Anti-metabolites: Claribine (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®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt™), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, Droxia™ and Mylocel™), fludarabine (sold under the tradename 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, methotrexate sodim (MTX), sold under the tradenames Rheumatrex® and Trexall™), pentostatin (sold under the tradename Nipent®);
[00218] Bisphosphonates: Pamidronate (sold under the tradename Aredia®), zoledronic acid (sold under the tradename Zometa®);
[00219] Demethylating agents: 5-azacitidine (sold under the tradename Vidaza®), decitabine (sold under the tradename Dacogen®);
[00220] Plant Alkaloids: Paclitaxel protein-bound (sold under the tradename Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames Oncovin® and Vincasar Pfs®), vinorelbine (sold under the tradename Navelbine®), paclitaxel (sold under the tradenames Taxol and Onxal™);
[00221] Retinoids: Alitretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cz's- retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Claras®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the tradename Targretin®);
[00222] Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone ((8S,9R, 1 OS, 1 IS, 135, 14S, 16R, 17R)-9-fluoro- 11 , 17-dihydroxy- 17-(2-hydroxy acetyl)- 10,13,16- trimethyl-6,7,8,9,10,11,12,13, 14,15, 16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (also known as 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, sold under the tradenames Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®);
[00223] Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename Proleukin®), interleukin-11 (also known as oprevelkin, sold under the tradename Neumega®), alpha interferon alfa (also known as IFN-alpha, sold under the tradenames Intron® A, and Pvoferon-A®);
[00224] Leutinizing hormone releasing hormone (LHRH) agonists: Goserelin (sold under the tradename Zoladex®);
[00225] Progesterones: megestrol (also known as megestrol acetate, sold under the tradename
Megace®);
[00226] Miscellaneous cytotoxic agents: Arsenic trioxide (sold under the tradename
Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®);
[00227] A compound of formula (I) can also be used in combination with the following adjunct therapies:
[00228] Anti-nausea drugs: NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and
[00229] Cytoprotective agents: Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).
[00230] None of the quotations of references made within the present disclosure is to be understood as an admission that the references cited are prior art that would negatively affect the patentability of the present invention.
Processes for Making Compounds of the Invention [00231] The present invention also includes processes for the preparation of compounds of the invention. In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.
[00232] Compounds of Formula I can be prepared by proceeding as in the following
General Reaction Scheme I:
General Reaction Scheme I:
Figure imgf000060_0001
[00233] in which R1; R2, R3, R4, R5, n and X are as defined for Formula I in the
Summary of the Invention. A compound of Formula I can be prepared by hydrolysing a compound of formula 2 in the presence of a suitable hydro lyzing agent (such as
ethanethiol/aluminum chloride, and the like) and a suitable solvent (such as dichloromethane, or the like). The reaction takes place at about 0 °C to about 50 °C and can take from about 1 to about 24 hours to complete.
[00234] Compounds of Formula I can be prepared by proceeding as in the following
General Reaction Scheme II:
General Reaction Scheme II:
Figure imgf000060_0002
[00235] in which R1; R2, R3, R4, R5, n and X are as defined for Formula I in the
Summary of the Invention. A compound of Formula I can be prepared by hydrolysing a compound of formula 2 in the presence of a suitable Lewis Acid (such as Boron tribromide, and the like) and a suitable solvent (such as dichloromethane, or the like) under a suitable pressure and atmosphere (such as -78°/Nitrogen, and the like). The reaction takes place at about 0°C from about 1 to about 4 hours to complete.
[00236] Compounds of Formula I, where R3 is an acrylic acid or ester (Rsa) derivative, can be prepared by proceeding as in the following General Reaction Scheme III:
General Reaction Scheme III:
Figure imgf000061_0001
[00237] in which Ri, R2, R4, R5, Rsa, n and X are as defined for Formula I in the
Summary of the Invention. A compound of Formula I can be prepared by reacting a compound of formula 3 with a compound of formula 4 in the presence of a suitable solvent (such as DMF and the like), a suitable catalyst (such as PdCl2(PPh3)2, or the like), a suitable base (such as triethylamine, and the like). The reaction takes place at about 120 °C to about 200°C and can take from about 1 to about 18 hours to complete.
[00238] Detailed examples of the synthesis of compounds of Formula I can be found in the Examples, infra.
Additional Processes for Making Compounds of the Invention
[00239] 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.
[00240] Compounds of the formula I can also be modified by appending appropriate functionalities to enhance selective biological properties. Modifications of this kind are known in the art and include those that increase penetration into a given biological system (e.g. blood, lymphatic system, central nervous system, testis), increase bioavailability, increase solubility to allow parenteral administration (e.g. injection, infusion), alter metabolism and/or alter the rate of secretion. Examples of this type of modifications include but are not limited to esterification, e.g. with polyethylene glycols, derivatisation with pivaloyloxy or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings and heteroatom substitution in aromatic rings.
Whereever compounds of the formula I, and/or N-oxides, tautomers and/or (preferably pharmaceutically acceptable) salts thereof are mentioned, this comprises such modified formulae, while preferably the molecules of the formula I, their N-oxides, their tautomers and/or their salts are meant.
[00241] Alternatively, the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates. In view of the close relationship between the novel compounds of the formula I in free form and those in the form of their salts, including those salts that 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 the formula I hereinbefore 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 expedient, as well as to one or more solvates, e.g. hydrates.
[00242] Salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic 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, methylmaleic acid, 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- 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, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
[00243] 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.
[00244] The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., 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 (e.g., hydrochloric acid, etc.).
[00245] Compounds of the invention in unoxidized form can be prepared from N- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.
[00246] Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985; Ferriz, J.M. et al., Current Pharmaceutical Design, 2010, 16, 2033-2052).
[00247] Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill 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. [00248] Compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., 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.
[00249] 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. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
[00250] In summary, the compounds of Formula I can be made by a process, which involves:
(a) those of general reaction schemes I, II and III; 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 into 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-derivatized 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 non-derivatized form.
[00251] Insofar 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 or as disclosed in the Examples hereinafter.
[00252] One of skill in the art will appreciate that the above transformations are only representative of methods for preparation of the compounds of the present invention, and that other well known methods can similarly be used.
Examples
[00253] The following examples and intermediates serve to illustrate the invention without limiting the scope thereof.
[00254] Abbreviations used in the examples are as follows: aq. (aqueous); br (broad);
°C (degrees Celsius); δ NMR chemical shift in ppm downfield from tetramethyl-silane; d (doublet); DCE (1,2-dichloroethane; DCM (dichloromethane); DIEA (N,N- diisopropylethylamine); DIBAL-H (diisobutylaluminium hydride); DMA (dimethyl-acetamide); DME (dimethoxy ethane); DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); Et (ethyl); EtOAc (ethyl acetate); g (gram); h (hour); HATU (0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate); HRMS (high-resolution mass spectrometry); z'-Pr (isopropyl); L (liter); LAH (lithium aluminium hydride); LC MS (liquid chromatography-mass spectrometry); M (molarity); m (multiplet); Me (methyl); mg (milligram); MHz (megahertz); min (minute); mL (milliliter); μΕ (microliter); mmol (millimole); Ν (normal); NBS (N- bromosuccinimide); «-Bu (normal butyl); «-BuLi («-butyllithium); ΝΜΜ (N-methylmorpholine); NMR (nuclear magnetic resonance); Ph (phenyl); pH (-logioH+ concentration); ppm (parts per million); q (quartet); s (singlet); sat. (saturated); t (triplet); r-Bu (ferr-butyl); Tf
(trifluoromethanesulfonyl); TFA (trifluoroacetic acid); Ts (p-toluenesulfonyl); TsOH (p- tolunesulfonic acid); TBS (tert-butyldimethylsilyl); TEA (triethylamine); THF (tetrahydrofuran); TMS (trimethylsilyl); rt (room temperature); Si02 (silica); Pd(OH)2 (palladium hydroxide); Na2S04 (sodium sulfate); Pd(PPh3)2Cl2 (bis(triphenylphosphine)palladium(II) dichloride); HPLC (high-performance liquid chromatography); NH4OH (ammonium hydroxide); mM (millimolar); dd (doublet of doublet); dq (doublet of quartets); dt (doublet of triplets); spt (septet); td (triplet of doublets); ddd (doublet of doublet of doublets); tt (triplet of triplets); NMP (N-Methyl-2- pyrrolidone); BBr3 (boron tribromide); DMAP (4-Dimethylaminopyridine); TBSC1 (tert- Butyldimethylsilyl chloride); ACN (acetonitrile); A1C13 (aluminum trichloride); SFC (supercritical fluid chromatography); MeOH (methanol); HC1 (hydrochloric acid); C02 (carbon dioxide); IPA (isopropanol); CoCl2-6H20 (Cobalt(II) chloride hexahydrate); and HOBt (1- Hydroxybenzotriazole).
General Scheme for Intermediates
Figure imgf000066_0001
(where Rn and R9 are as defined in the Summary of the Invention) Preparation of Intermediates
4-iodo- 1 -isopropoxy-2-methylbenzene
Figure imgf000067_0001
[00255] To a 30 mL screw cap vial, 4-iodo-2-methylphenol (2 g, 8.55 mmol) was dissolved in DMF. The vial was charged with iodopropane (1.709 ml, 17.09 mmol) and potassium carbonate (1.181 g, 8.55 mmol). The reaction was stirred for 3 h at 50 °C. The reaction mixture was cooled to room temperature and filtered to remove solids. The filtrated was concentrated onto silica gel and purified by column chromatography (Si02, 0-20%
Heptanes EtOAc) to afford 4-iodo- l-isopropoxy-2-methylbenzene (2.12 g, 7.68 mmol, 90 % yield) as a colorless oil. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.34 (d, J=6.06 Hz, 6 H), 2.17 (s, 3 H), 4.49 (dt, J=12.13, 6.06 Hz, 1 H), 6.61 (d, J=8.08 Hz, 1 H), 7.33 - 7.54 (m, 2 H).
Preparation of A Intermediates
Intermediate Al
2-(4-fluorophenyl)-6-methoxy-3.4-dihvdroisoquinolin-l(2H)-one
Figure imgf000067_0002
[00256] Method I: To a vial, 6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (1.5 g, 8.47 mmol) was dissolved in DMF (10 mL) and charged with l-fluoro-4-iodobenzene (3.76 g, 16.93 mmol) and potassium carbonate (1.170 g, 8.47 mmol). The reaction mixture was flushed with nitrogen, charged with copper(I) iodide (161 mg, 847 μιηοΐ), and heated at 150 °C for 16 h at which point starting material remained. The reaction mixture was charged with additional copper(I) iodide (161 mg, 847 μιηοΐ) and heated for an additional 16 h. Residual starting material remained and the reaction mixture was cooled to ambient temperature, diluted with dichloromethane, and washed with water. The organic layer was passed through a phase separator and volatiles were removed. The crude product was purified by silica gel chromatography (40 g, 0-100% ethyl acetate/heptanes) to afford 2-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one as a white solid (1.3 g, 56% yield). LC MS (m/z, MH+): 272.4. ¾ NMR (400 MHz, CHLOROFORM-^ δ 3.11 (t, J=6.32 Hz, 2 H), 3.90 - 3.99 (m, 2 H), 6.72 (d, J=2.53 Hz, 1 H), 6.88 (dd, J=8.59, 2.53 Hz, 1 H), 7.02 - 7.14 (m, 2 H), 7.29 - 7.37 (m, 2 H), 8.09 (d, J=8.59 Hz, 1 H).
Intermediate A2
2-(4-fluoro-2-methylphenyl)-6-methoxy-3.4-dihvdroisoquinolin-l(2H)-one
Figure imgf000068_0001
[00257] Method II: To a 40 mL vial was added 6-methoxy-3,4-dihydroisoquinolin- l(2H)-one (2 g, 11.29 mmol), dimethylformamide (20 mL), followed by 4-fluoro-l-iodo-2- methylbenzene (5.33 g, 22.57 mmol), and ?ra«s-N,N'-dimethylcyclohexane-l,2-diamine (892 μL, 5.64 mmol). The reaction vial was flushed with nitrogen, charged with copper(I) iodide (215 mg, 1.129 mmol), and heated at 150 °C for 16 h. LC/MS indicated 50% consumption of starting material. The reaction vial was charged with additional copper(I) iodide (215 mg, 1.129 mmol) and heated at 150 °C for an additional 16 h. LC/MS indicated no addition conversion. The reaction mixture was cooled to ambient temperature and was diluted with dichloromethane and water. The organic layer was passed through a phase separator and concentrated. The crude product was purified by silica gel chromatography (80 g, 0-100% ethyl acetate/heptanes) to afford 2-(4-fluoro-2-methylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (1.1 g, 34% yield) as a beige solid. LC/MS (m/z, MH+): 286.4. ¾ NMR (400 MHz, CHLOROFORM-^ δ 2.28 (s, 3 H), 3.05 (dt, J=15.92, 5.18 Hz, 1 H), 3.21 (ddd, J=15.66, 10.11, 5.56 Hz, 1 H), 3.70 (dt, J=12.00, 5.87 Hz, 1 H), 3.88 (s, 3 H), 3.92 - 4.06 (m, 1 H), 6.75 (d, J=2.53 Hz, 1 H), 6.83 - 7.06 (m, 3 H), 7.17 (dd, J=8.59, 5.56 Hz, 1 H), 8.10 (d, J=8.59 Hz, 1 H). Intermediate A4
6-methoxy-2-(4-( 1 -methyl- 1 H-pyrazol-3 -yl)phenyl)-3.4-dihydroisoquinolin- 1 (2H)-one and 6-methoxy-2-(4-(l -methyl- lH-pyrazol-5-yl)phenyl)-3.4-dihydroisoquinolin-l(2H)-one
Figure imgf000069_0001
[00258] Step 1 : 3-(4-bromophenyl)-lH-pyrazole (0.377 g, 1.690 mmol) was dissolved in THF (8.45 ml). 60% Sodium hydride in oil (0.101 g, 2.54 mmol) was added and the reaction was stirred at rt for 15 min. Methyl iodide (0.116 ml, 1.859 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via silica gel chromatography using 0-50% ethyl acetate in heptanes to afford a 2: 1 mixture of products (370 mg, 1.561 mmol, 92 % yield) as a yellow solid. ¾ NMR (400 MHz, CHLOROFORM-^ δ ppm 3.86 - 3.95 (m, 3 H), 3.97 (s, 6 H), 6.34 (d, J=1.52 Hz, 1 H), 6.54 (d, J=2.02 Hz, 2 H), 7.30 - 7.33 (m, 2 H), 7.40 (d, J=2.53 Hz, 2 H), 7.49 - 7.56 (m, 5 H), 7.59 - 7.64 (m, 2 H), 7.66 - 7.72 (m, 4 H). LC MS (m/z, MH+): 238.9.
[00259] Step 2: 6-methoxy-2-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one compound and 6-methoxy-2-(4-(l-methyl-lH-pyrazol-5- yl)phenyl)-3, 4-dihydroisoquinolin- l(2H)-one were prepared using method I from above in combination with aryl bromide highlighted in above intermediate example (248 mg, 0.744 mmol, 71.3 % yield) as a white solid. ¾ NMR (400 MHz, CHLOROFORM-^ δ ppm 2.86 - 2.95 (m, 2 H), 3.64 - 3.67 (m, 3 H), 3.69 - 3.75 (m, 3 H), 3.75 - 3.85 (m, 2 H), 6.35 (br. s., 1 H), 6.50 - 6.57 (m, 1 H), 6.62 - 6.72 (m, 1 H), 7.16 - 7.32 (m, 4 H), 7.62 (d, J=8.59 Hz, 1 H), 7.84 - 7.91 (m, 1 H). LC MS (m/z, MH+): 334.1 Intermediate A5
2-(3-fluoro-4-isopropylphenyl)-6-methoxy-3.4-dihvdroisoquinolin-l(2HN)-one
Figure imgf000070_0001
[00260] Step 1. To 2-(4-(benzyloxy)-3-fluorophenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (0.341 g, 0.904 mmol) was added ethanol (4.52 mL). The compound did not dissolve completely therefore THF (9 mL) was added until compound dissolved. A scoop of Pd(OH)2 was added, then the reaction solution was purged with hydrogen and left with a hydrogen balloon at room temperature overnight. The reaction was filtered through a syringe filter and concentrated to afford product (0.341 g, 0.904 mmol) as a white solid. ¾ NMR (400 MHz, DMSO-< ) δ ppm 3.07 (t, J=6.32 Hz, 2 H), 3.81 - 3.88 (m, 5 H), 6.88 - 7.04 (m, 4 H), 7.22 (d, J=12.63 Hz, 1 H), 7.85 (d, J=9.09 Hz, 1 H), 9.84 (s, 1 H). LC MS (m/z, MH+): 288.3.
[00261] Step 2. To a microwave vial, 2-(3-fluoro-4-hydroxyphenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (0.039 g, 0.136 mmol), N-phenyltrifluoromethanesulfonimide (0.058 g, 0.163 mmol), and potassium carbonate (0.056 g, 0.407 mmol) were suspended in THF (0.679 mL). The reaction was microwaved for 8 min at 120 °C. The reaction was done via LC/MS, so the reaction was filtered and concentrated. The crude material was purified via silica gel chromatography using 0-50% ethyl acetate in heptanes to afford product (46 mg, 0.110 mmol, 81 % yield) as a white powder. ¾ NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 8.7 Hz, 1H), 7.42 (dd, J = 11.3, 2.5 Hz, 1H), 7.39 - 7.30 (m, 1H), 7.30 - 7.20 (m, 1H), 6.91 (dd, J = 8.7, 2.5 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H), 4.00 (t, J = 6.4 Hz, 2H), 3.89 (s, 3H), 3.14 (t, J = 6.3 Hz, 2H).
LC/MS (m/z, MH+): 420.4.
[00262] Step 3. To 2-fluoro-4-(6-methoxy-l-oxo-3,4-dihydroisoquinolin-2(lH)- yl)phenyl trifluoromethanesulfonate (0.024 g, 0.057 mmol), potassium trifluoro(prop-l-en-2- yl)borate (0.017 g, 0.114 mmol), and triethylamine (0.024 ml, 0.172 mmol) were dissolved in THF (0.143 ml). The reaction was purged with nitrogen then 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (4.67 mg, 5.72 μιηοΐ) was added to the reaction mixture. The reaction was heated to 80 °C overnight. The reaction was quenched with water and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via silica gel chromatography using 0-50% ethyl acetate in heptanes to afford product (15 mg, 84% yield) as a pink solid. 1H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 9.2 Hz, 1H), 7.38 - 7.30 (m, 1H), 7.19 - 7.10 (m, 2H), 6.91 (dd, J = 8.7, 2.5 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 5.29 - 5.21 (m, 2H), 4.02 - 3.97 (m, 2H), 3.89 (d, J = 2.9 Hz, 3H), 3.13 (t, J = 6.4 Hz, 2H), 2.18 - 2.14 (m, 3H). LC MS (m/z, MH+): 312.4.
[00263] Step 4. To 2-(3-fluoro-4-(prop-l-en-2-yl)phenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (0.015 g, 0.048 mmol) was added methanol (1.5 mL). THF (0.5mL) was added until compound was dissolved. A scoop of 10% palladium on carbon was added and the reaction mixture was purged with hydrogen. The reaction stirred at room temperature for 1 h. The reaction was filtered through a syringe filter and concentrated to afford (13.7 mg, 0.044 mmol, 91 % yield) as a clear oil. ¾ NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 8.7 Hz, 1H), 7.17 (t, J = 8.3 Hz, 1H), 7.07 - 6.95 (m, 2H), 6.81 (dd, J = 8.7, 2.6 Hz, 1H), 6.68 - 6.60 (m, 1H), 3.91 - 3.84 (m, 2H), 3.79 (s, 3H), 3.15 (p, J = 6.9 Hz, 1H), 3.02 (t, J = 6.4 Hz, 2H), 1.19 (d, J = 6.9 Hz, 6H). LC MS (m/z, MH+): 314.1.
Intermediate A6
2-(4-isobutylphenyl)-6-methoxy-3.4-dihvdroisoquinolin-l(2H)-one
Figure imgf000071_0001
[00264] In a vial, 6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.25 g, 1.411 mmol) was dissolved in N-dimethylformamide (2.82 ml). To this was added l-bromo-4-isobutylbenzene (0.451 g, 2.116 mmol) and potassium carbonate (0.390 g, 2.82 mmol). The reaction mixture was flushed with nitrogen, charged with copper(I) iodide (0.161 g, 0.847 mmol) and heated to 150 °C for 24 h. The reaction mixture was cooled to room temperature, quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via silica gel chromatography using 0-75% ethyl acetate in heptanes to afford the desired product (190 mg, 0.614 mmol, 43.5 % yield) as a light orange solid. ¾ NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 8.7 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.24 - 7.15 (m, 2H), 6.89 (dd, J = 8.7, 2.6 Hz, 1H), 6.77 - 6.65 (m, 1H), 3.96 (dd, J = 7.0, 6.0 Hz, 2H), 3.86 (s, 3H), 3.09 (t, J = 6.4 Hz, 2H), 2.50 (d, J = 7.1 Hz, 2H), 1.90 (dh, J = 13.5, 6.8 Hz, 1H), 0.94 (d, J = 6.6 Hz, 6H). LC MS (m/z, MH+): 310.4.
Intermediate A7
2-(4-isopropylphenvn-6-methoxy-3.4-dihvdroisoquinolin-l(2HN)-one
Figure imgf000072_0001
[00265] To a 200 mL recovery flask, 6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (8 g,
45.1 mmol) was dissolved in dimethylformamide (65 mL) and charged with l-iodo-4- isopropylbenzene (11.11 g, 45.1 mmol) and potassium carbonate (12.48 g, 90 mmol). The reaction mixture was charged with copper(I) iodide (5.16 g, 27.1 mmol), placed under an atmosphere of nitrogen and heated at 160 °C under nitrogen for 48 h. LC MS indicated product formation and starting material remained, the reaction vial was charged with copper(I) iodide (3 g) and stirred for an additional 24 h. Conversion did not change of starting material to product at this time. The reaction mixture was diluted with dichloromethane, filtered, and concentrated. The crude material partitioned between brine and ethyl acetate, the organic layer was washed 3x with brine. The organic layer was dried with magnesium sulfate, which was then fitlered, and concentrated. The material was suspended in dichloromethane and loaded onto celite for solid loading purification. The material was purified by silica gel chromatography (80 g column, 0-80% ethyl acetate/heptanes). DMF remains post column despite brine wash. The gummy solid was dissolved in ethyl acetate and washed with brine 3 x. The organic layer was dried (MgS04), filtered, and concentrated to afford the product as a light yellow soild (7.12 g, 53% yield). ¾ NMR (400 MHz, DMSO-< ) δ ppm 1.15 - 1.30 (m, 6 H), 2.91 (quin, J=6.95 Hz, 1 H), 3.08 (t, J=6.57 Hz, 2 H), 3.83 (s, 3 H), 3.90 (t, J=6.32 Hz, 2 H), 6.80 - 7.02 (m, 2 H), 7.16 - 7.39 (m, 4 H), 7.78 - 7.94 (m, 1 H). LC/MS (m/z, MH+): 296.4. Preparation of B Intermediates
Intermediate Bl
4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1.2.3.4-tetrahydroisoquinolin-l-yl)phenyl
trifluoromethanesulfonate
Figure imgf000073_0001
[00266] Step 1. To a 100 mL round-bottomed flask, 1 -(benzyloxy)-4-bromobenzene
(1.891 g, 7.19 mmol) was dissolved in tetrahydrofuran (20 mL) and the reaction flask cooled to - 78 °C. The reaction flask was charged with a 1.6 M solution of «-butyllithium (4.94 mL, 7.91 mmol) in hexanes over a period of 10 min and the reaction stirred at -78 °C for 40 min. The reaction mixture was charged with a solution of 2-(4-fluorophenyl)-6-methoxy-3,4- dihydroisoquinolin-l (2H)-one (Intermediate Al) (1.3 g, 4.79 mmol) in THF (5 mL) over 15 min and stirred at -78 °C for an additional 50 min. At this time, the reaction was poured into a water (45 mL) and ethyl acetate (45 mL) mixture and treated with perchloric acid (1 mL, 70% in water). After 20 min, the pH of the solution was adjusted with saturated sodium bicarbonate to pH 5. The layers were separated, the aqueous layer was washed twice with ethyl acetate. The organic layers were combined, dried (Na2S04), filtered, and concentrated to afford the iminium salt intermediate as a yellow solid. LC MS (m/z, M+): 438.4.
[00267] Step 2. In a 100 mL round bottomed flask, the oven -dried iminium salt was dissolved in THF (20 mL) and the reaction flask was cooled to 0 °C. A 3 M solution of methylmagnesium bromide in diethyl ether (2.56 mL, 7.67 mmol) was added dropwise to the reaction mixture. Upon stirring at 0 °C for 30 min, LC MS analysis of an aliquot indicated partial conversion. The mixture was charged with an additional 1.5 mL of a 3 M solution of methylmagnesium bromide in diethyl ether and stirred for 1 h at 0 °C. The suspension was poured into saturated ammonium chloride and stirred for 1 h. The layers were separated and the aqueous layer was extracted with dichloromethane (5 x), the organic extracts were combined, passed through a phase separator and concentrated. The crude reaction mixture was purified by silica gel chromatography (40 g column, 0-100% ethyl acetate/heptanes) to afford the title compound as a white solid (1.65 g, 76% yield). LC MS (m/z, MH+): 454.4. ¾ NMR (400 MHz,
CHLOROFORM-^ δ 1.64 (s, 3 H), 2.92 (dt, J=16.04, 4.36 Hz, 1 H), 3.09 - 3.20 (m, 1 H), 3.26 - 3.35 (m, 1 H), 3.38 - 3.47 (m, 1 H), 3.79 (s, 3 H), 5.04 (s, 2 H), 6.51 - 6.58 (m, 2 H), 6.61 - 6.67 (m, 2 H), 6.71 - 6.78 (m, 3 H), 6.79 - 6.84 (m, 2 H), 7.06 (q, J=5.05 Hz, 2 H), 7.29 - 7.46 (m, 5 H).
[00268] Step 3. In a 30 mL vial, l-(4-(benzyloxy)phenyl)-2-(4-fluorophenyl)-6- methoxy-1 -methyl- 1, 2,3 ,4-tetrahydroisoquinoline (1.6 g, 3.53 mmol) dissolved in
dichloromethane (10 mL) and the reaction flask was charged with aluminum chloride (1.411 g, 10.58 mmol) and N,N-dimethylaniline (4.47 mL, 35.3 mmol). The reaction mixture was stirred at room temperature for 2 h at which time consumption of starting material was observed by LC/MS. The reaction was quenched with water (10 mL) and dichloromethane (100 mL). The pH value of the aqueous layer was adjusted to pH 5 with saturated sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane, the combined organic phases were washed with brine, dried (Na2S04), filtered, and concentrated. The resultant crude oil was purified by silica gel chromatography (40 g column, 0-100% ethyl acetate/heptanes) to afford the title compound as a white foamy solid (780 mg, 60% yield). ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.63 (s, 3 H), 2.92 (dt, J=16.04, 4.36 Hz, 1 H), 3.08 - 3.20 (m, 1 H), 3.26 - 3.34 (m, 1 H), 3.37 - 3.47 (m, 1 H), 3.79 (s, 3 H), 4.58 (s, 1 H), 6.52 - 6.60 (m, 2 H), 6.61 - 6.69 (m, 4 H), 6.70 - 6.80 (m, 3 H), 6.96 - 7.09 (m, 2 H).
[00269] Step 4. In a 30 mL vial, 4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenol (250 mg, 0.688 mmol) was dissolved in dichloromethane (3 mL). The vial was cooled to 0 °C and charged with triethylamine (115 μL, 825 μιηοΐ) followed by trifluoromethanesulfonic anhydride (139 μL, 825 μιηοΐ). The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate and diluted with dichloromethane, the layers were separated, the organic layer was washed with water, passed through a phase separator, and concentrated. The crude product was purified by silica gel chromatography (24 g column, 0-100% ethyl acetate/heptanes) to afford the title compound as a colorless oil (280 mg, 82% yield). LC/MS (m/z, MH+): 496.4. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.68 (s, 3 H), 2.83 - 3.16 (m, 2 H), 3.19 - 3.31 (m, 1 H), 3.41 (ddd, J=12.13, 8.08, 4.04 Hz, 1 H), 3.80 (s, 3 H), 6.54 (dd, J=9.09, 5.05 Hz, 2 H), 6.62 - 6.82 (m, 5 H), 7.11 (d, J=9.09 Hz, 2 H), 7.24 (d, J=8.59 Hz, 2 H). iyF NMR (376 MHz, CHLOROFORM-J) δ - 118.76 (s), -72.76 (s).
Intermediate B2
4-(2-(4-fluoro-2-methylphenyl)-6-methoxy-l-methyl-1.2.3.4-tetrahvdroisoquinol^
trifluoromethanesulfonate
Figure imgf000075_0001
[00270] Step 1. To a 100 mL round bottomed flask was added l-(benzyloxy)-4- bromobenzene (1.522 g, 5.78 mmol) and tetrahydrofuran (20 mL). The reaction flask was cooled to -78 °C and charged with 1.6 M «-butyllithium in hexanes (3.98 mL, 6.36 mmol) over 10 min. The suspension was stirred at -78 °C for 40 min. To this, 2-(4-fluoro-2-methylphenyl)-6- methoxy-3,4-dihydroisoquinolin-l(2H)-one (Intermediate A2) (1.1 g, 3.86 mmol) in tetrahydrofuran (5 mL) was added over 15 min. The reaction mixture was stirred at -78 °C for 50 min at which time it was poured into a mixture of water (45 mL) and ethyl acetate (45 mL). Perchloric acid (1 mL, 70% in water) was added and the mixture stirred for 20 min. The solution was treated with saturated sodium bicarbonate to pH 5. The layers were separated, the aqueous layer was washed twice with ethyl acetate. The organic layers were combined, dried (Na2S04), filtered, concentrated, the resultant iminium intermediate was obtained as a yellow solid after being dried in a vacuum oven. LC MS (m/z, M+): 452.4.
[00271] Step 2. In a 100 mL round bottomed flask, the iminium intermediate was dissolved in tetrahydrofuran (20 mL) and the reaction flask was cooled to 0 °C. The flask was charged with 3 M methymagnesium bromide in diethyl ether (2.056 mL, 6.17 mmol) dropwise. The reaction mixture stirred at 0 °C for 30 min at which time the reaction was monitored by LC MS, indicating 40% conversion. The reaction was charged with additional 3 M
methylmagnesium bromide in diethyl ether (1.5 mL) and stirred at 0 °C for 1 h. Complete consumption of starting material was observed and the reaction mixture was quenched with saturated ammonium chloride. The layers were separated, the aqueous was extracted five times with dichloromethane, the organic layers were combined, passed through a phase separator, and condensed to afford the crude product. The crude material was purified by silica gel
chromatography (40 g column, 0-100% ethyl acetate/heptanes) to afford l-(4-(benzyloxy)phenyl)- 2-(4-fluoro-2-methylphenyl)-6-methoxy-l -methyl- 1, 2,3 ,4-tetrahydroisoquinoline as a white solid (800 mg, 44% yield). LC MS (m/z, MH+): 468.5. ¾ NMR (400 MHz, CHLOROFORM-J) δ 1.56 (s, 3 H), 2.40 (s, 3 H), 2.88 - 2.91 (m, 2 H), 3.24 - 3.27 (m, 2 H), 5.05 (s, 2 H), 6.63 - 6.66 (m, 1 H), 6.73 (d, J=2.53 Hz, 1 H), 6.82 - 6.96 (m, 4 H), 7.18 - 7.20 (m, 2 H), 7.34 - 7.46 (m, 6 H).
[00272] Step 3. In a 30 mL vial, l-(4-(benzyloxy)phenyl)-2-(4-fluoro-2-methylphenyl)-
6-methoxy-l -methyl- 1,2,3 ,4-tetrahydroisoquinoline (0.8 g, 1.711 mmol) was dissolved in dichloromethane (8 mL). The reaction vial was charged with aluminum trichloride (684 mg, 5.13 mmol) and N,N-dimethylaniline (2.166 mL, 17.11 mmol) and stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (100 mL). The mixture was treated with saturated sodium bicarbonate until pH 5 was obtained. The layers were separated, the aqueous layer was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried (Na2S04), filtered, and concentrated. The resultant oil was purified by silica gel chromatography (0-100% ethyl acetate/heptanes) to afford 4-(2-(4-fluoro-2-methylphenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenol (400 mg, 62% yield). LC MS (m/z, MH+): 378.2. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.55 (s, 3 H), 2.38 (s, 3 H), 2.84 - 2.91 (m, 2 H), 3.16 - 3.34 (m, 2 H), 3.86 (s, 3 H), 6.61 - 6.64 (m, 1 H), 6.68 - 6.71 (m, 3 H), 6.76 - 6.84 (m, 2 H), 6.89 - 6.92 (m, 1H), 7.10 - 7.20 (m, 2 H), 7.32 - 7.40 (m, 1 H).
[00273] Step 4. To a 30 mL vial, 4-(2-(4-fluoro-2-methylphenyl)-6-methoxy-l -methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenol (200 mg, 0.530 mmol), dichloromethane (2 mL), and triethylamine (89 μL, 636 μιηοΐ) were added and the vial was cooled to 0 °C. The reaction mixture was charged with trifluoromethanesulfonic anhydride (107 μL, 0.636 mmol), warmed to room temperature and stirred for 2 h. After starting material consumption, the reaction mixture was quenched with saturated sodium bicarbonate and diluted with dichloromethane. The layers were separated, the organic was washed with water, passed through phase separator, concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate/heptanes) to afford 4-(2-(4-fluoro-2-methylphenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 - yl)phenyl trifluoromethanesulfonate (240 mg, 89% yield) as a clear oil. LC MS (m/z, MH+): 510.2.
Preparation of Intermediates C Intermediate CI
(iT)-2-(4-fluorophenyl)-6-methoxy-l-methyl-l-(4-(2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazol-4-yl)vinyl)phenyl)-1.2.3.4-tetrahydroisoquinoline
Figure imgf000077_0001
[00274] To a 30 mL screw cap vial, 4-vinyl-lH- imidazole (260 mg, 2.76 mmol) was dissolved in dimethylformamide (4 mL) and charged with sodium hydride (60% dispersion in mineral oil, 331 mg, 8.29 mmol). The reaction mixture was stirred at room temperature for 15 min at which time. 2-(Trimethylsilyl)ethoxymethyl chloride (490 μL, 2.76 mmol) was added and the reaction mixture was left to stand for 90 min. The reaction mixture was cooled to 0 °C and quenched saturated ammonium chloride. The crude mixture was diluted with dichloromethane, the layers were separated, the organic layer was washed with water and brine. The organic layer was passed through phase separator and concentrated. The crude product was purified by silica gel chromatography (0%-100% ethyl acetate/heptanes) to afford a regioisomeric mixture of l-((2- (trimethylsilyl)ethoxy)methyl)-4-vinyl-lH-imidazole as a white solid (540 mg, 87%). LC MS (m/z, MH+): 225.4.
[00275] To a 30 mL screw cap vial, 4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin- l-yl)phenyl trifluoromethanesulfonate (90 mg, 0.023 mmol) was mixed with l-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl-lH-imidazole (82 mg, 0.363 mmol), dimethylformamide (2 mL), and triethylamine (760 μL, 5.45 mmol). The reaction mixture was charged with Pd(PPh3)2Cl2 (12.75 mg, 0.018 mmol), flushed with nitrogen, and heated at 80 °C for 16 h. The crude mixture was directly purified by silica gel chromatography (0-70% ethyl acetate/heptanes) to afford the title compound as a white solid (40 mg, 35%). LC MS (m/z, MH+): 570.6.
Preparation of D Intermediates Intermediate Dl
1 -(4-bromophenyl)-6-methoxy- 1 -methyl-2 -phenyl- 1.2.3.4-tetrahydroisoquinoline
Figure imgf000078_0001
[00276] Step 1. To a 250 mL round bottomed flask was added l-bromo-4-iodobenzene
(2.68 g, 9.80 mmol) and pentanes (27.0 mL). The reaction vial was charged with 2.5 M n- butyllithium in hexanes (3.8 mL, 9.51 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at room temperature for 1 h at which time the reaction mixture was cooled to -78 °C charged with a solution of 6-methoxy-2-phenyl-3,4-dihydroisoquinolin-l(2H)- one (0.80 g, 3.63 mmol) in tetrahydrofuran (19.0 mL). The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with water (40 mL) and diluted with ethyl acetate (40 mL). Perchloric acid (1.16 mL, 13.58 mmol, 70% in water) was added to the reaction mixture and stirred for 30 min at room temperature. The reaction mixture was further diluted with ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, passed through a phase separator, and concentrated to give crude iminium intermediate based on LC MS. The iminium intermediate was used directly in the next step. LC/MS (m/z, M+): 394.2.
[00277] Step 2. Iminium intermediate was dissolved in tetrahydrofuran (22.0 mL) and cooled to 0 °C. The reaction was charged with a 1.6 M solution of methylmagnesium bromide in diethyl ether (3.16 mL, 9.48 mmol) and the reaction mixture was stirred at 0°C for 1 h. The reaction was quenched with saturated ammonium chloride. The aqueous layer was separated and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude material. Crude product was purified by silica gel chromatography (0-30% ethyl acetate/heptanes) to obtain the title compound (1.59 g, quantative). LC MS (m/z, MH+): 410.3. 1H NMR (400 MHz, CHLOROFORM-^ δ 1.61 (s, 3 H), 2.80 - 2.93 (m, 1 H), 3.06 (m, J=5.60 Hz, 1 H), 3.27 - 3.36 (m, 1 H), 3.40 (m, J=8.10 Hz, 1 H), 3.72 (s, 3 H), 6.52 - 6.62 (m, 4 H), 6.62 - 6.69 (m, 2 H), 6.97 - 7.08 (m, 4 H), 7.26 (d, J=8.59 Hz, 2 H).
Intermediate D2
1 -(4-bromo-3 -methylphenyl)-2-(4-fluorophenyl)-6-methoxy- 1 -methyl- 1.2.3.4- tetrahydroisoquinoline
Figure imgf000079_0001
[00278] Step 1. To a 40 mL vial was added l-bromo-4-iodo-2-methylbenzene (0.159 mL, 1.106 mmol) and pentanes (2.91 mL). The reaction vial was charged with a 2.5 M n- butyllithium in hexanes (444 μL, 1.110 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at room temperature for 1 h at which time, the reaction mixture was cooled to -78 °C and a solution of 2-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)- one (Intermediate Al) (0.1 g, 0.369 mmol) in tetrahydrofuran (2.077 ml) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with water (4 mL) and ethyl acetate (4 mL). Perchloric acid (0.136 ml, 1.585 mmol, 70% in water) was added and the reaction mixture stirred for 30 min at rt. The reaction mixture was extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude iminium intermediate. LC MS (m/z, MH+): 425.8.
[00279] Step 2. Iminium intermediate was dissolved in tetrahydrofuran (2.388 mL) and cooled to 0 °C. To this, 1 M methylmagnesium bromide in tetrahydrofuran (0.132 g, 1.106 mmol) was added dropwise and the reaction stirred at 0 °C for 1 h. The reaction was quenched with saturated ammonium chloride and extracted wth dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude product. Crude material was purified by silica gel chromatography (0-10% ethyl acetate/heptanes) to obtain product (157 mg, 97% yield) as a red-orange solid. LC MS (m/z, MH+): 441.9. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.53 (s, 3 H), 2.20 (s, 3 H), 2.70 - 2.91 (m, 1 H), 2.96 - 3.09 (m, 1 H), 3.14 - 3.25 (m, 1 H), 3.25 - 3.36 (m, 1 H), 3.63 - 3.70 (m, 3 H), 6.42 - 6.58 (m, 4 H), 6.59 - 6.72 (m, 3 H), 6.76 (dd, J=8.34, 2.27 Hz, 1 H), 6.94 (d, J=2.02 Hz, 1 H), 7.24 (d, J=8.08 Hz, 1 H).
Intermediate D3
1 -(5 -bromopyridin-2-yl)-2-(4-isopropylphenyl)-6-methoxy- 1 -methyl- 1.2.3.4- tetrahydroisoquinoline
Figure imgf000080_0001
[00280] Step 1. To a 40 mL scintillation vial was added 5-bromo-2-iodopyridine (0.144 g, 0.508 mmol) and pentanes (1.335 mL). The reaction vial was charged with 2.5 M n- butyllithium (204 μL, 0.510 mmol) in hexanes and a precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C. A solution of 2-(4-isopropylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (Intermediate A7) (50 mg, 0.169 mmol) in tetrahydrofuran (0.954 mL) was added and the reaction mixture was stirred at -78 °C for 1 h. The reaction was warmed to -40 °C and stirred for an additional hour. The reaction mixture was then quenched with water (2 mL) and ethyl acetate (2 mL). Perchloric acid (0.063 ml, 0.728 mmol, 70% in water) was added to the reaction mixture and the reaction mixture was stirred for 30 min at rt. The quenched reaction mixture was diluted with
dichloromethane and water and the layers were separated. The aqueous layer was washed twice with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to give crude iminium intermediate based on LC MS as a yellow oil which was used directly in the next step. LC/MS (m/z, MH+): 437.4
[00281] Step 2. To a cold solution of the iminium intermediate in tetrahydrofuran
(1.097 mL) was added 1.4 M methyl magnesium bromide (363 μL, 0.508 mmol) in
tetrahydrofuran. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated ammonium chloride. The aqueous layer was separated and extracted with
dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude material. Crude material was purified via flash chromatography using 0-30% ethyl acetate in heptane to afford product (86 mg, 0.191 mmol, 113 % yield) as an orange oil. ¾ NMR (400 MHz, CHLOROFORM-J) δ ppm 1.04 - 1.11 (m, 6 H), 1.66 - 1.74 (m, 3 H), 2.69 (dt, J=13.77, 7.01 Hz, 1 H), 2.83 (dt, J=15.79, 3.22 Hz, 1 H), 3.17 (ddd, J=15.66, 9.09, 6.57 Hz, 1 H), 3.44 - 3.54 (m, 2 H), 3.67 (s, 3 H), 6.39 - 6.47 (m, 2 H), 6.49 - 6.55 (m, 1 H), 6.55 - 6.59 (m, 1 H), 6.65 - 6.70 (m, 1 H), 6.84 (m, J=8.59 Hz, 2 H), 7.24 - 7.30 (m, 1 H), 7.46 - 7.53 (m, 1 H), 8.44 (d, J=2.02 Hz, 1 H). LC/MS (m/z, MH+): 452.4.
Intermediate D4
1 -(4-bromophenyl)-2-(4-isobutylphenyl)-6-methoxy- 1 -methyl- 1.2.3.4-tetrahydroisoquinoline
Figure imgf000081_0001
[00282] Step 1. To a 40 mL scintillation vial was added 1 -bromo-4-iodobenzene (0.549 g, 1.939 mmol) and pentanes (2.55 mL). The reaction vial was charged with 2.5 M n-butyllithium (0.780 mL, 1.949 mmol) in hexanes and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C. A solution of 2-(4-isobutylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (Intermediate A6) (0.100 g, 0.323 mmol) in tetrahydrofuran (1.821 mL) was added and the reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was then quenched with water (4 mL) and diluted with ethyl acetate (4 mL). Perchloric acid (0.119 mL, 1.390 mmol, 70% in water) was added to the reaction mixture and stirred for 30 min at rt. The reaction mixture was further diluted with water and the aqueous layer was extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude iminium intermediate based on LC MS. The iminium intermediate was used directly in the next step. LC/MS (m/z, MH+): 448.4.
[00283] Step 2. Iminium intermediate was dissolved in tetrahydrofuran (2.094 ml) and cooled to 0 °C. The reaction was charged with a 1.4M solution of methylmagnesium bromide (0.693 ml, 0.970 mmol) in tetrahydrofuran and stirred at 0°C for 1 hour. The reaction appeared incomplete via LC/MS so the reaction was allowed to warm to room temperature overnight. The reaction was quenched with saturation ammonium chloride solution. The aqueous layer was separated and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated. Crude material was purified via silica gel chromatography using 0-30% ethyl acetate in heptane to afford product (118 mg, 0.254 mmol, 79 % yield) as a yellow oil. ¾ NMR (400 MHz, Chloroform-d) δ 7.26 - 7.20 (m, 2H), 7.03 - 6.95 (m, 2H), 6.80 - 6.74 (m, 2H), 6.63 (d, J = 8.6 Hz, 1H), 6.60 - 6.50 (m, 2H), 6.49 - 6.42 (m, 2H), 3.69 (s, 3H), 3.35 (ddd, J = 12.4, 8.6, 4.0 Hz, 1H), 3.26 (dt, J = 12.0, 5.0 Hz, 1H), 3.03 (ddd, J = 16.1, 8.5, 4.9 Hz, 1H), 2.84 (dt, J = 16.1, 4.5 Hz, 1H), 2.27 (d, J = 7.1 Hz, 2H), 1.69 (dp, J = 13.5, 6.7 Hz, 1H), 1.58 (s, 3H), 0.77 (d, J = 6.6 Hz, 6H). LC/MS (m/z, MH+): 466.5.
Intermediate D5
l-(4-bromophenyl)-2-(4-isopropylphenyl)-6-methoxy-l -methyl- 1.2.3.4-tetrahydroisoquinoline
Figure imgf000082_0001
[00284] Step 1. To a 250 mL round bottomed flask was added l-bromo-4-iodobenzene
(5.75 g, 20.31 mmol) and pentanes (67.2 mL). The reaction vial was charged with 2.5 M n- butyllithium (8.15 ml, 20.38 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C charged with a solution of 2-(4-isopropylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (Intermediate A7) (2 g, 6.77 mmol) in tetrahydrofuran (47.3 mL). The reaction mixture was stirred at -78 °C for 4 h. The reaction mixture was quenched with water and ethyl acetate, perchloric acid (2.502 ml, 29.1 mmol, 70% in water) was added to the reaction mixture which was stirred for 60 min. The quenched reaction mixture was diluted with ethyl acetate and water. A yellow precipitate was observed in the reaction mixture as well as the quenched reaction mixture. When the layers were separated, the aqueous was washed 2 x with ethyl acetate, the organic extracts were pooled and washed with brine. To keep the precipitate after the brine layer was removed the organic layer was not dried or filtered. The organic layer stood overnight at which time volatiles were removed to afford a yellow solid. LC MS (m/z, M+): 434.4.
[00285] Step 2. The crude material was suspended in tetrahydrofuran (54.8 mL) and cooled to 0°C (ice-water). The reaction mixture was charged with 3.0 M methylmagnesium bromide (6.77 mL, 20.31 mmol) in diethylether dropwise and left to stir for 2 h with warming to ambient temperature. The reaction mixture was quenched with saturated ammonium chloride and diluted with dichloromethane. The layers were separated, the aqueous was washed 2 x with dichloromethane, the organic layers were pooled, washed with brine, passed through a phase separator, and condensed. The crude material was purified by silica gel chromatography (80 g column, 0-60% ethyl acetate/heptanes) to afford the desired product as a white solid (1.99 g, 65% yield). ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.10 - 1.27 (m, 6 H), 1.67 (s, 3 H), 2.70 - 2.86 (m, 1 H), 2.92 (d, J=15.66 Hz, 1 H), 3.09 (d, J=5.56 Hz, 1 H), 3.30 - 3.54 (m, 2 H), 3.85 (s, 3 H), 6.56 (d, J=8.08 Hz, 2 H), 6.72 (d, J=8.08 Hz, 1 H), 6.94 (d, J=8.08 Hz, 2 H), 7.10 (d, J=8.08 Hz, 2 H), 7.33 (d, J=8.59 Hz, 2 H). LC MS (m/z, M+): 450.4.
Preparation of E Intermediates
Intermediate El
(j )-methyl-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-1.2.3.4-tetrahvdroisoquinolin-l- vDphenvDacrylate
Figure imgf000083_0001
[00286] To a 30 mL screw cap vial, 4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl trifluoromethanesulfonate (Intermediate Bl) (110 mg, 0.222 mmol) was dissolved in DMF (2 mL) and triethylamine (928 μΐ^, 666 μιηοΐ) was added. The reaction mixture was charged with methyl acrylate (160 μΐ^, 1776 μιηοΐ) and Pd(PPh3)2Cl2 (15.58 mg, 0.022 mmol). The reaction vial was flushed with nitrogen and heated at 80 °C for 16 h. LC MS indicated partial conversion of starting material. The reaction mixture was charged with additional methyl acrylate (160 μΐ,, 1776 μιηοΐ) and Pd(PPh3)2Cl2 (15.58 mg, 0.022 mmol). The vial was flushed with nitrogen and heated at 120 °C for 6 h. The reaction mixture was cooled to ambient temperature and diluted with dichloromethane. The organic layer was washed with water and brine then passed through phase separator and concentrated. The crude product was purified by silica gel chromatography (40 g column, 0-70% ethyl acetate/heptanes) to afford the title compound as a greasy solid (80 mg, 84% yield). LC MS (m/z, MH+): 432.4. ¾ NMR (400 MHz, METHANOL-^) δ 1.69 (s, 3 H), 2.90 - 2.98 (m, 1 H), 3.05 - 3.22 (m, 2 H), 3.38 - 3.53 (m, 1 H), 6.50 (d, J=15.66 Hz, 1 H), 6.60 - 6.69 (m, 4 H), 6.69 - 6.73 (m, 1 H), 6.74 - 6.83 (m, 2 H), 7.25 (d, J=8.59 Hz, 2 H), 7.46 (d, J=8.08 Hz, 2 H), 7.66 (d, J=16.17 Hz, 1 H).
Intermediate E2
(EVmethyl 3 -(4-(2-(4-fluoro-2-methylphenyl)-6-methoxy-l -methyl- 1.2.3.4-tetrahy droisoquinolin-
1 -vDphenvDacrylate
Figure imgf000084_0001
[00287] To a 30 mL vial, 4-(2-(4-fluoro-2-methylphenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl trifluoromethanesulfonate (intermediate B2) (60 mg, 0.118 mmol) was dissolved in dimethylformamide (2 mL) and treated with triethylamine (492 μΐ^, 3.53 mmol). The reaction vial was charged with methyl acrylate (85 μΐ^, 0.942 mmol) and
Pd(PPh3)2Ci2 (8.27 mg, 0.012 mmol). The system was flushed with nitrogen and heated at 80 °C for 16 h. Partial conversion of starting material was observed by LC MS. The reaction mixture was cooled to ambient temperature and charged with additional methyl acrylate (85 μL, 0.942 mmol) and Pd(PPh3)2Cl2 (8.27 mg, 0.012 mmol), the vial was flushed with nitrogen and heated at 80 °C for 16 h. Starting material was consumed and the reaction mixture was cooled to ambient temperature, diluted with dichloromethane and washed with water. The organic layer was passed through a phase separator and concentrated. The crude product was purified by silica gel chromatography (0-70% ethyl acetate/heptanes) to afford the product as a colorless oil (37 mg, 70% yield). LC/MS (m/z, MH+): 446.3.
Intermediate E3
(EVmethyl 3 -(4-(6-methoxy- 1 -methyl-2-phenyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylate
Figure imgf000085_0001
[00288] To a 5 mL microwave vial was added l-(4-bromophenyl)-6-methoxy-l-methyl-
2-phenyl-l,2,3,4-tetrahydroisoquinoline (Intermediate D2) (200 mg, 0.490 mmol), Pd(PPh3)2Cl2 (51.6 mg, 0.073 mmol), dimethylformamide (3.3 mL), triethylamine (341 μL, 2.449 mmol), and methyl acrylate (441 μL, 4.90 mmol). The reaction mixture was microwaved for 1 h at 150 °C. LC/MS indicated complete conversion to product. The reaction mixture was quenched with water and was extracted three times with dichloromethane. The organic layers were combined, washed with brine, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford the title compound (56 mg, 26% yield, 95% purity). LC/MS (m/z, MH+): 414.3. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.75 (s, 3 H), 2.91 - 3.03 (m, 1 H), 3.19 (d, J=5.56 Hz, 1 H), 3.39 - 3.60 (m, 2 H), 3.82 (s, 3 H), 3.83 (s, 3 H), 6.44 (d, J=16.17 Hz, 1 H), 6.64 - 6.74 (m, 4 H), 6.77 (d, J=8.59 Hz, 1 H), 6.94 - 7.02 (m, 1 H), 7.06 - 7.13 (m, 2 H), 7.27 - 7.33 (m, 2 H), 7.42 (d, J=8.08 Hz, 2 H), 7.70 (d, J=16.17 Hz, 1 H).
Intermediate E4
(E)-methyl 3-(4-(2-(4-isobutylphenyl)-6-methoxy-l-methyl-1.2.3.4-tetrahvdroisoquinolin-
1 -vDphenvDacrylate
Figure imgf000086_0001
[00289] To a 40 mL vial was added l-(4-bromophenyl)-2-(4-isobutylphenyl)-6- methoxy-1 -methyl- 1,2,3 ,4-tetrahydroisoquinoline (Intermediate D4) (0.118 g, 0.254 mmol), bis(triphenylphosphine)palladium dichloride (0.089 g, 0.127 mmol), N,N-dimethylformamide (1.694 ml), triethylamine (0.177 mL, 1.270 mmol), and methyl acrylate (0.460 mL, 5.08 mmol). The reaction mixture was heated for 1 h at 130 °C, LC MS indicated complete conversion to product. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via silica gel chromatography using 0-50% ethyl acetate in heptanes to afford product (63 mg, 0.134 mmol, 52.8 % yield) as a yellow oil. ¾ NMR (400 MHz, Chloroform-d) δ 7.63 - 7.55 (m, 1H), 7.33 - 7.25 (m, 2H), 7.16 (d, J = 8.2 Hz, 2H), 6.79 - 6.71 (m, 2H), 6.66 (d, J = 8.6 Hz, 1H), 6.61 - 6.51 (m, 2H), 6.49 - 6.42 (m, 2H), 6.32 (d, J = 16.0 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 3.41 - 3.21 (m, 2H), 3.06 (ddd, J = 14.0, 8.7, 5.0 Hz, 1H), 2.86 (dt, J = 16.0, 4.4 Hz, 1H), 2.27 (d, J = 7.1 Hz, 2H), 1.66 (d, J = 6.7 Hz, 1H), 1.61 (s, 3H), 0.77 (d, J = 6.6 Hz, 6H). LC/MS (m/z, MH+): 470.1. Intermediate E5
(E)-methyl 3 -(4-(2-(4-isopropylphenyl)-6-methoxy-l -methyl- 1.2.3.4-tetrahvdroisoquinolin-l- vDphenvDacrylate
[00290] To a 30 mL vial with magnetic stir bar was added l-(4-bromophenyl)-2-(4- isopropylphenyl)-6-methoxy-l -methyl- 1,2,3 ,4-tetrahydroisoquinoline (Intermediate D5) (1.99 g, 4.42 mmol), Pd(PPh3)2Cl2 (0.465 g, 0.663 mmol), triethylamine (3.08 ml, 22.09 mmol), dimethylformamide (22.09 mL), and methyl acrylate (4.00 mL, 44.2 mmol). The reaction mixture was heated at 120 °C for 12 h. LC MS indicated conversion to product. The crude reaction mixture was cooled to ambient temperature, diluted with dichloromethane and water. The layers were separated, the aqueous was washed 2 x with dichloromethane. The organic layers were pooled, washed with brine, passed through a phase separator, and condensed. The crude material was purified by silica gel chromatography (0-70% ethyl acetate/heptanes) to afford the desired product as a pale yellow solid (1.18 g, 59% yield). LC MS (m/z, MH+): 456.5. ¾ NMR (400 MHz, DMSO-t/6) δ 1.13 - 1.20 (m, 6 H), 1.70 (s, 3 H), 2.79 (dt, J=13.77, 7.01 Hz, 1 H), 2.93 (d, J=16.17 Hz, 1 H), 3.12 (d, J=5.56 Hz, 1 H), 3.30 - 3.52 (m, 2 H), 3.77 - 3.83 (m, 6 H), 6.40 (d, J=15.66 Hz, 1 H), 6.55 (d, J=8.59 Hz, 2 H), 6.60 - 6.69 (m, 2 H), 6.74 (d, J=8.59 Hz, 1 H), 6.91 (d, J=8.59 Hz, 2 H), 7.28 (s, 1 H), 7.38 (d, J=8.08 Hz, 2 H), 7.67 (d, J=16.17 Hz, 1 H).
Intermediate E6
(E)-methyl 3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 -yl)-2- methylphenvDacrylate
Figure imgf000088_0001
[00291] To a 2 mL microwave vial was added l-(4-bromo-3-methylphenyl)-2-(4- fluorophenyl)-6-methoxy-l-methyl-l,2,3,4-tetrahydroisoquinoline (Intermediate D2) (0.075 g, 0.170 mmol), Pd(PPh3)2Cl2 (18 mg, 0.026 mmol), dimethylformamide (1.217 mL), triethylamine (119 μL, 0.852 mmol), and methylacrylate (153 μL, 1.703 mmol). The reaction mixture was microwaved for 1 h at 150 °C. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel flash chromatography (0-10% ethyl acetate/heptanes) in to afford product (56.3 mg, 74% yield) as a yellow oil. LC MS (m/z,
MH+): 446.1. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.64 - 1.72 (m, 3 H), 2.39 (s, 3 H), 2.96 (dt, J=15.92, 4.17 Hz, 1 H), 3.09 - 3.23 (m, 1 H), 3.30 - 3.41 (m, 1 H), 3.45 (ddd, J=11.87, 8.59, 3.79 Hz, 1 H), 3.82 (s, 3 H), 3.83 (s, 3 H), 6.37 (d, J=15.66 Hz, 1 H), 6.57 - 6.72 (m, 4 H), 6.74 - 6.83 (m, 3 H), 7.04 - 7.11 (m, 2 H), 7.45 (d, J=8.08 Hz, 1 H), 7.98 (d, J=15.66 Hz, 1 H).
Preparation of F Intermediates
Intermediate Fl
(iT)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-1.2.3.4-tetrahvdroisoquinolin-l- vDphenvDacrylic acid
Figure imgf000089_0001
[00292] To a 30 mL screw cap vial, (i?)-methyl 3-(4-(2-(4-fluorophenyl)-6-methoxy-l- methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (10 mg, 0.023 mmol) was dissolved tetrahydrofuran (1 mL) and charged with 2 M lithium hydroxide (500 μL). The reaction mixture was heated at 60 °C for 30 min. The crude was concentrated and adjusted to pH 5 with citric acid. The mixture was diluted with dichloromethane and washed with water and brine, passed through phase separator, concentrated to afford the crude. The crude product was purified by reverse phase HPLC (20-100% acetonitrile in water with 3% «-propanol). The title compound was afforded as a white solid (2 mg, 20%). LC MS n/z, MH+): 418.4. ¾ NMR (400 MHz, methanol-^) δ 1.67 (s, 3 H), 2.91-2.97 (m, 1 H), 3.12-3.17 (m, 1 H), 3.33-3.35 (m, 1 H), 3.46- 3.49 (m, 1 H), 3.77 (s, 3 H), 6.62-6.79 (m, 7 H), 7.14 (d, J= 8.6 Hz, 2 H), 7.34 (d, J= 8.6 Hz, 2 H), 7.53 (m, 1 H).
Preparation of G Intermediates
Intermediate Gl
fi)-methyl 3 -(4-(6-hydroxy- 1 -methyl -2 -phenyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylate
Figure imgf000090_0001
[00293] In a 30 mL vial, (£)-methyl 3-(4-(6-methoxy-l-methyl-2-phenyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (Intermediate E3) (207 mg, 501 μιηοΐ) was dissolved in dichloromethane (5.0 mL). A I M solution of boron tribromide in heptanes (2.0 mL, 2.0 mmol) was added and the reaction stirred at room temperature for 30 min. The reaction was quenched with methanol (5 mL) and stirred for an additional 10 min at room temperature. The reaction volume was reduced by half. The reaction mixture was then directly purified on the reverse phase HPLC (3% «-propanol in 10-100% acetonitrile/water) to afford the title compound (81 mg, 41%). LC MS (m/z, MH+): 400.3. 1H NMR (400 MHz, CHLOROFORM-^ δ 1.63 (br. s., 3 H), 2.75 - 2.91 (m, 1 H), 2.96 - 3.10 (m, 1 H), 3.27 - 3.43 (m, 2 H), 3.70 - 3.74 (m, 3 H), 5.16 (br. s., 1 H), 6.32 (d, J=16.17 Hz, 1 H), 6.45 - 6.51 (m, 1 H), 6.51 - 6.62 (m, 4 H), 6.83 - 6.91 (m, 1 H), 6.94 - 7.02 (m, 2 H), 7.12 - 7.21 (m, 2 H), 7.29 (d, J=8.08 Hz, 2 H), 7.58 (d, J=16.17 Hz, 1 H).
Preparation of L Intermediates Intermediate LI
6-((tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)-3.4-dihvdroisoquinolin-l(2H)-one
Figure imgf000090_0002
[00294] Step 1. 2-(4-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-l(2H)-one.
[00295] To a flask, 2-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one
(Intermediate Al) (0.5 g, 1.843 mmol) was dissolved in dichloromethane (9.22 mL) and cooled to 0 °C. A solution of 1 M boron tribromide in heptane (7.37 mL, 7.37 mmol) was added and the reaction stirred at 0 °C for 1 h. The reaction mixture was quenched with methanol (5 mL) and stirred for 10 min at room temperature. To the mixture was added celite, volatiles were removed, and the crude material was purified by silica gel chromatography (0-75% ethyl acetate/heptanes) to obtain 2-(4-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-l(2H)-one (420 mg, 89% yield) as a white solid. LC MS (m/z, MH+): 258. ¾ NMR (400 MHz, DMSO-<4) δ 3.02 (t, J=6.32 Hz, 2 H), 3.88 (t, J=6.32 Hz, 2 H), 6.69 (s, 1 H), 6.74 (dd, J=8.59, 2.53 Hz, 1 H), 7.17 - 7.26 (m, 2 H), 7.34 . 7.44 (m5 2 H), 7.77 (d, J=8.59 Hz, 1 H), 10.14 (s, 1 H).
[00296] Step 2. To a vial, 2-(4-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-l(2H)- one 420 mg, 1.633 mmol) was dissolved in dimethylformamide (3.27 mL). Tert- butylchlorodimethylsilane (369 mg, 2.449 mmol), N,N-dimethylpyridin-4-amine (40 mg, 0.327 mmol), and imidazole (500 mg, 7.35 mmol) were added and the reaction stirred at room temperature overnight. The reaction was quenched with water and extracted with
dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel flash chromatography (0-10% ethyl acetate/heptanes) to obtain 6-((tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)-3,4- dihydroisoquinolin-l(2H)-one (371 mg, 61% yield). LC MS (m/z, MH+): 372.2. ¾ NMR (400
MHz, CHLOROFORM-d) δ 0.24 - 0.29 (m, 6 H), 1.03 (s, 9 H), 3.08 (t, J=6.32 Hz, 2 H), 3.93 (t, J=6.57 Hz, 2 H), 6.70 (d, J=2.02 Hz, 1 H), 6.83 (dd, J=8.59, 2.53 Hz, 1 H), 7.04 - 7.15 (m, 2 H), 7.30 - 7.38 (m, 2 H), 8.05 (d, J=8.59 Hz, 1 H).
Preparation of M Intermediates
Intermediate Ml
l-(4-bromophenyl)-2-(4-fluorophenyl)-l-methyl-1.2.3.4-tetrahydroisoquinolin-6-ol
Figure imgf000091_0001
[00297] Step 1. To a 50 mL round bottomed flask was added l-bromo-4-iodobenzene
(848 mg, 3.00 mmol) and pentanes (7.86 mL). The reaction vial was charged with 2.5 M n- butyllithium (1.202 mL, 3.01 mmol) in heptanes and a white precipitate formed immediately. The lithiation reaction stirred at room temperature for 1 h at which time the reaction mixture was cooled to -78 °C. A solution of 6-((tert-butyldimethylsilyl)oxy)-2-(4-fluorophenyl)-3,4- dihydroisoquinolin-l(2H)-one (Intermediate LI) (371 mg, 0.999 mmol) in tetrahydrofuran (5.61 mL) was added and the reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with water (12 mL) and ethyl acetate (12 mL). Perchloric acid (70% in water, 369 μL, 4.29 mmol) was added to the reaction mixture which stirred for 30 min. The quenched reaction mixture was diluted with ethyl acetate and water, the layers were separated and the aqueous layer was washed twice with ethyl acetate. The organic layers were combined, passed through a phase separator and concentrated to give crude iminium intermediate which was used directly in the next step. LC MS (m/z, MH+): 398.2.
[00298] Step 2. To a cold solution of the iminium intermediate in tetrahydrofuran (6.50 mL) was added a 1.4 M solution of methylmagnesium bromide (2.140 mL, 3.00 mmol) in tetrahydrofuran. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated ammonium chloride. The aqueous layer was separated and extracted with
dichloromethane thrice. The organic layers were combined, passed through a phase separator and concentrated to give crude material. The crude material was purified by silica gel
chromatography (0-20% ethyl acetate/heptanes) to l-(4-bromophenyl)-2-(4-fluorophenyl)-l- methyl-l,2,3,4-tetrahydroisoquinolin-6-ol (404 mg, 98% yield). LC MS (m/z, MH+): 414.1. ¾ NMR (400 MHz, CHLOROFORM-d) δ 1.75 (s, 3 H), 2.90 - 3.06 (m, 1 H), 3.06 - 3.24 (m, 1 H), 3.31 - 3.42 (m, 1 H), 3.49 (ddd, J=12.00, 8.21, 4.04 Hz, 1 H), 6.61 - 6.77 (m, 5 H), 6.88 (t, J=8.84 Hz, 2 H), 7.08 - 7.18 (m, 2 H), 7.38 - 7.44 (m, 2 H).
Preparation of N Intermediates Intermediate Nl
(E)-N'-acetyl-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-1.2.3.4 etrahvdroi
vDphenvDacrylohydrazide
Figure imgf000093_0001
[00299] (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (Intermediate Fl) (0.0349 g, 0.084 mmol) was dissolved in dimethylformamide (836 μΐ ). To this was added, HATU (38 mg, 0.100 mmol) followed by acetohydrazide (7.43 mg, 0.100 mmol) and 4-methylmorpholine (46 μΐ^, 0.418 mmol). The reaction stirred overnight at rt, at which time it was quenched with saturated ammonium chloride and extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-75% ethyl acetate/heptanes) to obtain product (31.2 mg, 79% yield). LC MS (m/z, MH+): 474.1. 1H NMR (400 MHz, CHLOROFORM-^ δ 1.66 (br. s., 3 H), 2.11 (s, 3 H), 2.97 - 3.03 (m, 1 H), 3.13 (d, J=6.06 Hz, 1 H), 3.33 (br. s., 1 H), 3.43 (br. s., 1 H), 3.78 (s, 3 H), 6.53 - 6.83 (m, 8 H), 7.16 (d, J=7.58 Hz, 2 H), 7.33 (d, J=8.59 Hz, 2 H), 7.64 (d, J=15.66 Hz, 1 H), 9.86 (d, J=7.07 Hz, 2 H).
Intermediate N2
(E)-N'-(3 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylovDbutyrohvdrazide
Figure imgf000094_0001
[00300] (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (Intermediate Fl) (0.359 ml, 0.072 mmol) was dissolved in DMF (0.719 mL). To this was added HATU (0.033 g, 0.086 mmol) followed by the addition of acetohydrazide (8.81 mg, 0.086 mmol) and 4-methylmorpholine (0.040 ml, 0.359 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to obtain the title compound (31.7 mg, 88% yield) as a clear oil. LC MS (m/z, MH+): 502.0. 1H NMR (400 MHz,
CHLOROFORM-^ δ 0.94 - 1.02 (m, 3 H), 1.60 - 1.82 (m, 5 H), 2.35 (t, J=7.33 Hz, 2 H), 2.96 (br. s., 1 H), 3.13 (br. s., 1 H), 3.33 (br. s., 1 H), 3.44 (br. s., 1 H), 3.73 - 3.83 (m, 3 H), 6.53 - 6.82 (m, 8 H), 7.17 (d, J=7.07 Hz, 2 H), 7.30 - 7.39 (m, 2 H), 7.67 (d, J=15.66 Hz, 1 H), 9.64 (d, J=6.06 Hz, 1 H), 9.89 (br. s., 1 H).
Intermediate N3
(E)-N'-(3 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 - yl)phenyl)acryloyl)-3-methylbutanehvdrazide
Figure imgf000095_0001
[00301] (£)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (Intermediate Fl) (0.359 ml, 0.072 mmol) was dissolved in DMF (0.719 ml). To this was added HATU (0.033 g, 0.086 mmol) followed by acetohydrazide (10.02 mg, 0.086 mmol) and 4- methylmorphline (0.040 ml, 0.359 mmol). The reaction was stirred overnight at rt. The reaction was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel flash chromatography (0-50% ethyl acetate/heptanes) to obtain the title compound (31.4 mg, 85% yield) as a clear oil. LC MS (m/z, MH+): 516.1. ¾ NMR (400 MHz, CHLOROFORM-^ δ 0.98 - 1.01 (m, 6 H), 1.29 - 1.38 (m, 1 H), 1.66 (br. s., 3 H), 2.23 - 2.30 (m, 2 H), 2.94 (d, J=16.17 Hz, 1 H), 3.11 (d, J=13.64 Hz, 1 H), 3.33 (br. s., 1 H), 3.44 (br. s., 1 H), 3.77 - 3.83 (m, 3 H), 6.53 - 6.81 (m, 8 H), 7.18 (d, J=7.58 Hz, 2 H), 7.32 - 7.41 (m, 2 H), 7.67 (d, J=15.66 Hz, 1 H), 9.88 (d, J=6.57 Hz, 1 H), 10.13 (d, J=6.06 Hz, 1 H).
Intermediate N4
(E)-N'-(3 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylovDcvclopropanecarbohydrazide
Figure imgf000096_0001
[00302] (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (Intermediate Fl) (0.359 mL, 0.072 mmol) was dissolved in DMF (0.719 mL). To this was added HATU (0.033 g, 0.086 mmol) followed by acetohydrazide (8.63 mg, 0.086 mmol) and 4-methylmorpholine (0.040 mL, 0.359 mmol). The reaction was stirred at rt overnight when it was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to obtain the title compound (35.4 mg, 99% yield) as a clear oil. LC MS (m/z, MH+): 500.0. 1H NMR (400 MHz, CHLOROFORM-^ δ 1.17 (br. s., 4 H), 1.52 - 1.66 (m, 4 H), 2.84 (d, J=10.61 Hz, 1 H), 3.02 (br. s., 1 H), 3.23 (br. s., 1 H), 3.34 (br. s., 1 H), 3.70 (s, 3 H), 6.43 - 6.73 (m, 8 H), 7.08 (br. s., 2 H), 7.23 (d, J=8.08 Hz, 2 H), 7.56 (d, J=15.66 Hz, 1 H), 9.93 (br. s., 2 H).
Intermediate N5
(E)-3 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 -yl)phenyl)-N'-
(2-methoxyacetyl)acrylohvdrazide
Figure imgf000097_0001
[00303] (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (Intermediate Fl) (0.359 ml, 0.072 mmol) was dissolved in dimethylformamide (719 μΐ ). To this was added, HATU (0.033 g, 0.086 mmol) followed by addition 2-methoxyacetohydrazide (8.98 mg, 0.086 mmol) and 4-methylmorpholine (0.040 ml, 0.359 mmol). The reaction was stirred overnight at rt. The reaction was quenched with saturated ammonium chloride and extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to obtain product (27.5 mg, 76% yield) as a clear oil. LC MS (m/z, MH+): 504.1. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.68 (br. s., 3 H), 2.90 - 2.96 (m, 1 H), 3.14 (br. s., 1 H), 3.35 (br. s., 1 H), 3.39 - 3.51 (m, 4 H), 3.80 (s, 3 H), 4.08 (s, 2 H), 6.51 - 6.80 (m, 8 H), 7.18 (d, J=8.08 Hz, 2 H), 7.33 (d, J=8.59 Hz, 2 H), 7.64 (d, J=15.66 Hz, 1 H), 9.22 (d, J=5.56 Hz, 1 H), 9.47 (d, J=5.05 Hz, 1 H). Intermediate N6
(E)-N'-(3-(4-(2-(4-isopropylphenyl)-6-methoxy-l-mem^
vDphenvDacrylovDbutyrohvdrazide
Figure imgf000098_0001
[00304] (E)-3-(4-(2-(4-isopropylphenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (0.0623 g, 0.141 mmol) was dissolved in DMF (1.411 mL). To this was added HATU (0.064 g, 0.169 mmol) followed by butyric acid hydrazide (17 mg, 0.169 mmol) and 4-methylmorpholine (78 μΐ^, 0.705 mmol). The reaction was stirred overnight at rt. The reaction was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to obtain product (74 mg, 100% yield) as a clear oil. LC MS (m/z, MH+): 526.2. ¾ NMR (400 MHz, CHLOROFORM-^ δ ppm 0.98 (t, J=7.58 Hz, 3 H), 1.17 (dd, J=6.82, 1.26 Hz, 6 H), 1.62 - 1.69 (m, 3 H), 1.69 - 1.82 (m, 2 H), 2.38 (t, J=7.33 Hz, 2 H), 2.71 - 2.85 (m, 1 H), 2.87 - 2.98 (m, 1 H), 3.05 - 3.17 (m, 1 H), 3.30 - 3.50 (m, 2 H), 3.74 - 3.83 (m, 3 H), 6.56 (m, J=8.59 Hz, 2 H), 6.59 - 6.76 (m, 4 H), 6.92 (m, J=8.59 Hz, 2 H), 7.21 (m, J=8.08 Hz, 2 H), 7.35 (m, J=8.08 Hz, 2 H), 7.69 (d, J=15.66 Hz, 1 H), 10.02 (d, J=6.57 Hz, 1 H), 10.15 (d, J=6.57 Hz, 1 H). Intermediate N7
(E)-2-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1.2.3.4-tetrahvdroisoquinolin-l-yl)styryl)-5- methyl- 1.3.4-oxadiazole
Figure imgf000099_0001
[00305] (E)-N'-acetyl-3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylohydrazide (Intermediate Nl) (0.0312 g, 0.066 mmol) was dissolved in acetonitrile (1.318 mL). Triphenylphosphine (31 mg, 0.119 mmol) and
diisopropylethylamine (67 μΐ^, 0.382 mmol) were added and the reaction mixture was stirred for 5 min at rt. Hexachloroethane (20 mg, 0.086 mmol) was added and the reaction stirred at rt for 4 h. The reaction mixture was concentrated and diluted with water and dichloromethane. The aqueous layer was extracted twice with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-20% ethyl acetate/heptanes) to afford the desired product as a clear oil (26 mg, 0.057 mmol, 87% yield). LC MS (m/z, MH+): 456.1. ¾ NMR (400 MHz,
CHLOROFORM-d) δ ppm 1.66 (br. s., 3 H), 2.55 (s, 3 H), 2.85 - 3.01 (m, 1 H), 3.12 (br. s., 1 H), 3.32 (br. s., 1 H), 3.42 (br. s., 1 H), 3.77 (s, 3 H), 6.52 - 6.80 (m, 7 H), 6.89 - 6.98 (m, 1 H), 7.15 - 7.24 (m, 2 H), 7.37 (d, J=8.59 Hz, 2 H), 7.40 - 7.47 (m, 1 H).
Intermediate N8
(E)-2-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1.2.3.4-tetrahvdroisoquinolin-l-yl)styryl)-5- propyl- 1.3.4-oxadiazole
Figure imgf000100_0001
[00306] (E)-N'-(3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1,2,3 , 4- tetrahydroisoquinolin-l-yl)phenyl)acryloyl)butyrohydrazide (Intermediate N2) (0.0317 g, 0.063 mmol) was dissolved in dry acetonitrile (1.264 mL). Triphenylphosphine (0.030 g, 0.114 mmol) and diisopropylethylamine (0.064 ml, 0.367 mmol) were added and the reaction mixture stirred for 5 min at rt. Hexachloroethane (0.019 g, 0.082 mmol) was added and the reaction stirred for 4 h at rt. The reaction mixture was concentrated, diluted with water and dichloromethane. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-20% ethyl acetate/heptanes) to afford the title compound as a clear solid (25 mg, 82% yield). LC MS (m/z, MH+): 484.1. ¾ NMR (400 MHz, CHLOROFORM-^ δ ppm 0.98 (t, J=7.33 Hz, 3 H), 1.55 - 1.65 (m, 3 H), 1.80 (sxt, J=7.38 Hz, 2 H), 2.79 (t, J=7.33 Hz, 2 H), 2.87 (d, J=15.66 Hz, 1 H), 3.00 - 3.17 (m, 1 H), 3.19 - 3.31 (m, 1 H), 3.32 - 3.45 (m, 1 H), 3.72 (s, 3 H), 6.48 - 6.73 (m, 7 H), 6.90 (d, J=16.67 Hz, 1 H), 7.16 (d, J=7.58 Hz, 2 H), 7.32 (d, J=8.59 Hz, 2 H), 7.35 - 7.43 (m, 1 H) Intermediate N9
(E)-2-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1.2.3.4-tetrahvdroisoquinolin-l-yl)styryl)-5- isobutyl- 1.3.4-oxadiazole
Figure imgf000101_0001
[00307] (£)-N'-(3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1 ,2,3 , 4- tetrahydroisoquinolin-l-yl)phenyl)acryloyl)-3-methylbutanehydrazide (Intermediate N3) (0.0314 g, 0.061 mmol) was dissolved in dry acetonitrile (1.218 mL). Triphenylphosphine (0.029 g, 0.110 mmol) and diisopropylethylamine (0.062 ml, 0.353 mmol) were added and the reaction mixture was stirred for 5 min at rt. Hexachloroethane (0.019 g, 0.079 mmol) was added and the reaction stirred at rt for 4 h. The reaction mixture was concentrated, and diluted with water and dichloromethane. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-20% ethyl acetate/heptanes) to afford the title compound as a clear oil (19.3 mg, 63% yield). LC MS (m/z, MH+): 498.1. ¾ NMR (400 MHz,
CHLOROFORM-^ δ 1.07 (d, J=6.57 Hz, 6 H), 1.60 - 1.78 (m, 3 H), 2.19 - 2.30 (m, 1 H), 2.79 (d, J=7.58 Hz, 2 H), 2.97 (d, J=15.66 Hz, 1 H), 3.17 (br. s., 1 H), 3.37 (br. s., 1 H), 3.47 (br. s., 1 H), 3.82 (s, 3 H), 6.57 - 6.84 (m, 7 H), 7.01 (d, J=16.67 Hz, 1 H), 7.20 - 7.28 (m, 2 H), 7.42 (d, J=8.59 Hz, 2 H), 7.45 - 7.52 (m, 1 H). Intermediate N10
(E)-2-cvclopropyl-5-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1.2.3.4-tetrahvdroisoquinolin-l- vDstyryl)- 1.3.4-oxadiazole
Figure imgf000102_0001
[00308] (E)-N'-(3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1 , 2,3,4- tetrahydroisoquinolin- 1 -yl)phenyl)acryloyl)cyclopropanecarbohydrazide (Intermediate N4) (0.0354 g, 0.071 mmol) was dissolved in dry acetonitrile (1.417 mL). Triphenylphosphine (0.033 g, 0.128 mmol) and diisopropylethylamine (0.072 mL, 0.411 mmol) were added and the reaction mixture stirred for 5 min at rt. Hexachloroethane (0.022 g, 0.092 mmol) was added and the reaction was stirred for 4 h at rt. The reaction mixture was concentrated and diluted with water and dichloromethane. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-20% ethyl acetate/heptanes) to afford (E)-2- cyclopropyl-5 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 - yl)styryl)-l,3,4-oxadiazole as a clear oil (24.2 mg, 70% yield). LC MS (m/z, MH+): 482.0. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.16 - 1.24 (m, 4 H), 1.71 (br. s., 3 H), 2.21 (tt, J=8.21, 5.18 Hz, 1 H), 2.97 (d, J=16.17 Hz, 1 H), 3.17 (br. s., 1 H), 3.27 - 3.41 (m, 1 H), 3.41 - 3.55 (m, 1 H), 3.82 (s, 3 H), 6.56 - 6.84 (m, 7 H), 6.97 (d, J=16.67 Hz, 1 H), 7.20 - 7.28 (m, 2 H), 7.37 - 7.49 (m, 3 H). Intermediate Nil
(E)-2-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1.2.3.4-tetrahvdroisoquinolin-l-yl)styryl)-5-
(methoxymethyl)- 1.3.4 -oxadiazole
Figure imgf000103_0001
[00309] (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)-N'-(2-methoxyacetyl)acrylohydrazide (Intermediate N5) (27.5 mg, 0.055 mmol) was dissolved in acetonitrile (1.092 mL). Triphenylphosphine (26 mg, 0.098 mmol) and diisopropylethylamine (55 μΐ^, 0.317 mmol) were added and the reaction mixture stirred for 5 min at rt. Hexachloroethane (17 mg, 0.071 mmol) was added and the reaction stirred for 4 h at rt. The reaction mixture was concentrated, diluted with water and dichloromethane. The aqueous layer was extracted twice with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-20% ethyl acetate/heptanes) to afford the desired product as a clear oil (23 mg, 87 % yield). LC MS (m/z, MH+): 486.0. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.71 (s, 3 H), 2.97 (d, J=15.66 Hz, 1 H), 3.11 - 3.23 (m, 1 H), 3.35 (d, J=13.64 Hz, 1 H), 3.46 (d, J=8.08 Hz, 1 H), 3.51 (s, 3 H), 3.82 (s, 3 H), 4.70 (s, 2 H), 6.59 - 6.73 (m, 4 H), 6.73 - 6.83 (m, 3 H), 7.02 (d, J=16.67 Hz, 1 H), 7.23 - 7.32 (m, 2 H), 7.43 (d, J=8.08 Hz, 2 H), 7.59 (d, J=16.17 Hz, 1 H) Intermediate N12
(E)-2-(4-(2-(4-isopropylphenyl)-6-methoxy-l-methyl-L^
5 -propyl- 1.3.4 -oxadiazole
Figure imgf000104_0001
[00310] (E)-N'-(3 -(4-(2-(4-isopropylphenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acryloyl)butyrohydrazide (Intermediate N6) (0.074 g, 0.141 mmol) was dissolved in acetonitrile (2.82 mL). Triphenylphosphine (66 mg, 0.253 mmol) and diisopropylethylamine (143 μΐ^, 0.816 mmol) were added and the reaction mixture stirred for 5 min at rt. Hexachloroethane (43 mg, 0.183 mmol) was added and the reaction was stirred at rt for 3 h. The reaction mixture was concentrated and diluted with water and dichloromethane. The aqueous layer was extracted twice with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-20% ethyl acetate/heptanes) to afford the title compound as a clear oil (82.5 mg, quantative yield). LC MS (m/z, MH+): 508.0. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.06 - 1.12 (m, 3 H), 1.16 - 1.24 (m, 6 H), 1.74 (s, 3 H), 1.90 (sxt, J=7.38 Hz, 2 H), 2.82 (dt, J=13.52, 7.14 Hz, 1 H), 2.86 - 2.92 (m, 2 H), 2.97 (dt, J=16.04, 4.11 Hz, 1 H), 3.12 - 3.25 (m, 1 H), 3.35 - 3.54 (m, 2 H), 3.77 - 3.84 (m, 3 H), 6.60 (m, J=8.08 Hz, 2 H), 6.65 - 6.72 (m, 2 H), 6.79 (d, J=8.59 Hz, 1 H), 6.95 (m, J=8.08 Hz, 2 H), 7.01 (d, J=16.67 Hz, 1 H), 7.32 (m, J=8.59 Hz, 2 H), 7.43 (m, J=8.59 Hz, 2 H), 7.50 (d, J=16.67 Hz, 1 H). Preparation of Q Intermediates
Intermediate Ql
1 -(4-bromophenyl)-2-(4-fluorophenyl)-6-methoxy- 1 -(trifluoromethyl)- 1.2.3.4- tetrahydroisoquinoline
Figure imgf000105_0001
[00311] To a 100 mL round bottomed flask was added l-bromo-4-iodobenzene (782 mg, 2.76 mmol) and pentanes (7.27 mL). The reaction flask was placed under an inert atmosphere and charged with 2.5 M «-butyllithium in hexanes (1.110 mL, 2.77 mmol) and a white precipitate formed immediately. The reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C and charged with 2-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)- one (Intermediate Al) (250 mg, 0.922 mmol) in tetrahydrofuran (5.19 mL). The reaction mixture was stirred at -78 °C for 1 h at which time it was quenched with water (12 mL) and diluted with ethyl acetate (12 mL). Perchloric acid (341 μL, 3.96 mmol, 70% in water) was added to the mixture and was stirred for 30 min at rt. The quenched reaction mixture was diluted with dichloromethane and water. The layers were separated and the aqueous layer was washed twice with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to give the crude iminium intermediate. LC MS (m/z, MH+): 412.1
[00312] Iminium intermediate was dissolved in DMF (6.0 mL), sodium acetate (0.227 g, 2.76 mmol) was added followed by the dropwise addition of 0.5 M trimethyl(trifluoromethyl)- silane in THF (3.69 mL, 1.843 mmol). The reaction was stirred at room temperature for 30 min. The reaction was quenched with saturated sodium bicarbonate. The aqueous layer was separated and extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to give crude material. Crude material was purified by silica gel (0-10% ethyl acetate/heptanes) to afford l-(4-bromophenyl)-2-(4-fluorophenyl)-6-methoxy-l- (trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline (338 mg, 76 % yield) as a yellow oil. LC MS (m/z, MH+): 482.0. ¾ NMR (400 MHz, CHLOROFORM-^ δ 2.93 - 3.04 (m, 1 H), 3.13 (s, 1 H), 3.36 - 3.47 (m, 1 H), 3.79 (s, 3 H), 3.80 - 3.89 (m, 1 H), 6.55 - 6.83 (m, 3 H), 7.07 (d, J=8.08 Hz, 2 H), 7.29 - 7.34 (m, 2 H), 7.64 - 7.69 (m, 2 H), 7.69 - 7.76 (m, 2 H).
Intermediate Q2
(E)-methyl 3 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 -(trifluoromethyl)- 1.2.3.4-tetrahvdroisoquinolin-
1 -vDphenvDacrylate
Figure imgf000106_0001
[00313] To a 2 mL microwave vial was added l-(4-bromophenyl)-2-(4-fluorophenyl)-6- methoxy-l-(trifluoromethyl)-l,2,3,4-tetrahydroisoquinoline (Intermediate Ql) (886 μΐ^, 0.208 mmol), Pd(PPh3)2Cl2 (22 mg, 0.031 mmol), dimethylformamide (1.388 mL), triethylamine (145 μΐ^, 1.041 mmol), and methylacrylate (187 μΐ^, 2.082 mmol). The reaction mixture was microwaved for 1 h at 150 °C, LC MS indicates conversion to product. The reaction mixture was quenched with water and extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel (0-50% ethyl acetate/heptanes) to afford (E)-methyl 3-(4-(2-(4-fluorophenyl)-6- methoxy-1 -(trifluoromethyl)- 1, 2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (22 mg, 22% yield) as a yellow oil. LC/MS (m/z, MH+): 486.2. ¾ NMR (400 MHz, CHLOROFORM-^ δ 3.00 - 3.10 (m, 1 H), 3.18 (d, J=9.60 Hz, 1 H), 3.44 - 3.53 (m, 1 H), 3.83 (s, 3 H), 3.84 (s, 3 H), 3.89 (br. s., 1 H), 6.44 (d, J=16.17 Hz, 1 H), 6.55 - 6.74 (m, 3 H), 6.76 (d, J=3.03 Hz, 1 H), 6.86 (dd, J=9.09, 2.02 Hz, 1 H), 7.24 - 7.32 (m, 2 H), 7.39 (d, J=8.08 Hz, 2 H), 7.63 - 7.78 (m, 2 H), 7.89 - 7.96 (m, 1 H). Intermediate Q3
(E)-methyl 3-(4-(6-methoxy-l-methyl-2-(3-methyl-4-(((trifl^
1.2.3.4-tetrahvdroisoquinolin-l-yl)phenyl)acrylate
Figure imgf000107_0001
[00314] To a 30 mL screw cap vial, (E)-methyl 3-(4-(2-(4-hydroxy-3-methylphenyl)-6- methoxy-1 -methyl- 1, 2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (100 mg, 0.225 mmol) was dissolved in dichloromethane (3 mL) and charged with triethylamine (38 μΐ^, 0.271 mmol). The solution was cooled to 0 °C and charged with trifluoromethanesulfonic anhydride (0.046 mL, 0.271 mmol). The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated sodium bicarbonate and diluted with dichloromethane. The organic layer was collected using a phase separator and concentrated to provide the crude product. The crude material was purified by column chromatography (Si02, 0-30% ethyl acetate/heptanes) to afford (E)-methyl 3-(4-(6-methoxy-l -methyl -2-(3-methyl-4-(((trifluoromethyl)sulfonyl)oxy )phenyl)- l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (95 mg, 0.165 mmol, 73.2 % yield) as a yellow solid. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.73 (s, 3 H), 2.17 (s, 3 H), 2.91 - 3.04 (m, 1 H), 3.12 - 3.31 (m, 1 H), 3.34 - 3.63 (m, 2 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 6.37 - 6.57 (m, 3 H), 6.62 - 6.79 (m, 3 H), 6.91 (d, J=9.09 Hz, 1 H), 7.28 - 7.35 (m, 2 H), 7.43 (d, J=8.08 Hz, 2 H), 7.69
(d, J=16.17 Hz, 1 H). LC MS (m/z, MH+): 576.1.
Preparation of R Intermediates
Intermediate Rl
(E)-l-(4-(2-(2-ethyl-2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fb^
1.2.3.4-tetrahydroisoquinoline
Figure imgf000108_0001
[00315] (E)-l-(4-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluorophenyl)-6-methoxy-l- methyl-l,2,3,4-tetrahydroisoquinoline (647 μΐ^, 0.123 mmol) was dissolved in
dimethylformamide (2.460 mL). Potassium carbonate (51.0 mg, 0.369 mmol) was added followed by iodoethane (10.93 μΐ^, 0.135 mmol). The reaction mixture was stirred overnight at rt, at which time it was quenched with saturated ammonium chloride and extracted thrice with
dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (5 mM NH4OH in 55-80% acetonitrile/water) to afford product (10 mg, 0.021 mmol, 17.31 % yield) as a yellow oil. LC MS (m/z, MH+): 470.1. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.66 - 1.76 (m, 6 H), 2.97 (d, J=15.66 Hz, 1 H), 3.17 (br. s., 1 H), 3.37 (br. s., 1 H), 3.49 (d, J=19.71 Hz, 1 H), 3.82 (s, 3 H), 4.64 - 4.73 (m, 2 H), 6.54 - 6.73 (m, 4 H), 6.77 (d, J=8.59 Hz, 4 H), 7.14 (d, J=16.67 Hz, 1 H), 7.24 (d, J=6.57 Hz, 1 H), 7.44 (d, J=8.08 Hz, 2 H), 7.72 (d, J=16.67 Hz, 1 H). Intermediate R2
(E)-l-(4-(2-(2-bu -2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluo^^
1.2.3.4-tetrahydroisoquinoline
Figure imgf000109_0001
[00316] (E)-l-(4-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluorophenyl)-6-methoxy-l- methyl-l,2,3,4-tetrahydroisoquinoline (647 μΐ, 0.123 mmol) was dissolved in dimethylformamide (2.460 mL). Potassium carbonate (51.0 mg, 0.369 mmol) was added followed by iodobutane (15.40 μΐ^, 0.135 mmol). The reaction was stirred overnight at rt. The reaction was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated to afford crude product. The crude material was purified by reverse phase HPLC (5 mM NH4OH in 55-80% acetonitrile/water) to afford product (18 mg, 29% yield) as a yellow oil. LC MS (m/z, MH+): 498.1. ¾NMR (400 MHz, CHLOROFORM-^ δ 0.90 (t, J=7.33 Hz, 3 H), 1.31 (dt, J=14.78, 7.52 Hz, 2 H), 1.61 (br. s., 3 H), 1.94 - 2.00 (m, 2 H), 2.87 (d, J=15.16 Hz, 1 H), 3.08 (d, J=7.07 Hz, 1 H), 3.28 (br. s., 1 H), 3.37 (br. s., 1 H), 3.72 (s, 3 H), 4.53 (t, J=7.33 Hz, 2 H), 6.49 - 6.64 (m, 5 H), 6.67 (d, J=8.08 Hz, 3 H), 7.04 (d, J=16.67 Hz, 2 H), 7.14 (br. s., 1 H), 7.34 (d, J=8.59 Hz, 1 H), 7.62 (d, J=16.17 Hz, 1 H). Intermediate R3
(E)-2-(4-fluorophenyl)-6-methoxy-l -methyl- l-(4-(2-(2-methyl-2H-tetrazol-5-yl)vinyl)phenyl)- 1.2.3.4-tetrahydroisoquinoline and (E)-2-(4-fluorophenyl)-6-methoxy-l-methyl-l-(4-(2-(l- methyl- 1 H-tetrazol-5 -yl)vinyl)phenyl)- 1.2.3.4-tetrahydroisoquinoline
Figure imgf000110_0001
[00317] (E)-l-(4-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluorophenyl)-6-methoxy-l- methyl- 1,2,3, 4-tetrahydroisoquinoline (0.058 g, 0.131 mmol) was dissolved in DMF (2.63 mL). Potassium carbonate (0.054 g, 0.394 mmol) was added followed by iodomethane (9.04 μΐ , 0.145 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride. The reaction mixture was extracted three times with
dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to afford crude product. The crude material was purified by reverse phase HPLC (5 mM NH4OH modifier, 45-70% acetonitrile/water) to afford (E)-2-(4-fluorophenyl)-6-methoxy-l- methyl-l-(4-(2-(l -methyl- lH-tetrazol-5-yl)vinyl)phenyl)- 1,2,3, 4-tetrahydroisoquinoline (5 mg, 8% yield) and (E)-2-(4-fluorophenyl)-6-methoxy-l -methyl- 1-(4-(2-(2 -methyl-2H-tetrazol-5 - yl)vinyl)phenyl)- 1,2,3, 4-tetrahydroisoquinoline (13 mg, 21% yield). LC MS (m/z, MH+): 456.1.
Intermediate R4
(EV2-(4-fluorophenylV6-methoxy-l-m
yl)vinyl)phenyl)-1.2.3.4-tetrahydroisoquinoline
Figure imgf000111_0001
[00318] (E)-l-(4-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluorophenyl)-6-methoxy-l- methyl-l,2,3,4-tetrahydroisoquinoline (679 μΐ^, 0.129 mmol) was dissolved in
dimethylformamide (2580 μΚ). Potassium carbonate (53.5 mg, 0.387 mmol) was added followed by the addition of l,l,l-trifluoro-3-iodopropane (16.63 μΐ, 0.142 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride. The reaction mixture was extracted three times with dichloromethane, the organic layers were combined, passed through a phase separator and concentrated to afford crude product. The crude material was purified by reverse phase HPLC (5 mM NH4OH in 55-80% acetonitrile/water) to afford product (8.6 mg, 12% yield) as a yellow oil. LC MS (m/z, MH+): 538.1. ¾NMR (400 MHz, METHANOL-^) δ ppm 1.58 (s, 3 H), 2.78 - 2.88 (m, 1 H), 2.88 - 2.99 (m, 2 H), 3.00 - 3.10 (m, 1 H), 3.24 (br. s., 1 H), 3.32 - 3.41 (m, 1 H), 3.66 (s, 3 H), 4.85 (t, J=6.57 Hz, 2 H), 6.49 - 6.62 (m, 5 H), 6.62 - 6.70 (m, 2 H), 7.07 (d, J=16.17 Hz, 1 H), 7.13 (d, J=8.08 Hz, 2 H), 7.37 (d, J=8.59 Hz, 2 H), 7.58 (d, J=16.17 Hz, 1 H).
[00319] The following intermediates of Table 1 were prepared, using appropriate starting materials, according to the above methods: Table 1
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
2 H), 6.62 - 6.70 (m, 2 H),
6.71 - 6.83 (m, 1 H), 6.94 (d, J=8.59 Hz, 2 H), 7.07 - 7.20 (m, 2 H), 7.27 - 7.43 (m, 2 H)
LC/MS (m/z, MH+): 464.5
1 -(4-bromophenyl)-6- 1H NMR (400 MHz, methoxy-l-methyl-2-(4-
D CHLOROFORM-d) δ 1.67
(3,3,3- (s, 3 H), 2.18 - 2.43 (m, 2
Br trifluoropropyl)phenyl)- H), 2.67 - 2.85 (m, 2 H),
1,2,3,4- 2.88 - 3.01 (m, 1 H), 3.06 - tetrahydroisoquinolin 3.21 (m, 1 H), 3.37 (dt,
J=12.00, 4.86 Hz, 1 H), 3.41 - 3.54 (m, 1 H), 3.80 (s, 3 H), 6.48 - 6.62 (m, 2 H), 6.62 - 6.69 (m, 2 H), 6.69 - 6.75 (m, 1 H), 6.91 (m, 2 H), 7.01 - 7.14 (m, 2 H), 7.30 - 7.41 (m, 2 H)
LC/MS (M/Z, MS+1): 506.5
1 -(4-bromophenyl)-6- 1H NMR (400 MHz, methoxy-l-methyl-2-(4- CHLOROFORM-d) δ 1.65
D
Br (2,2,2- (s, 3 H), 2.90 - 2.97 (m, 1 trifluoroethoxy)phenyl)- H), 3.03 - 3.18 (m, 1 H), 1,2,3,4- 3.22 - 3.35 (m, 1 H), 3.35 - tetrahydroisoquinoline 3.61 (m, 1 H), 3.80 (s, 3 H),
4.27 (q, J=8.08 Hz, 2 H), 6.52 - 6.76 (m, 7H), 6.96 - 7.11 (m, 2 H), 7.29 - 7.39 (m, 2 H)
LC/MS (M/Z, MS+1): 508.5
Br 1 -(4-bromophenyl)-6- methoxy-l-methyl-2-(4-
D
(trifluoromethoxy)phen
yl)-l,2,3,4- LC/MS (M/Z, MS+1): 494.4 tetrahydroisoquinoline
1 -(4-bromophenyl)-2- 1H NMR (400 MHz,
Br (3-fluoro-4- Chloroform-d) δ 7.32 - 7.24
D
isopropylphenyl)-6- (m, 2H), 7.10 - 7.01 (m, methoxy- 1 -methyl- 2H), 6.82 (t, J = 8.6 Hz, 1,2,3,4- 1H), 6.64 (d, J = 8.1 Hz, tetrahydroisoquinoline 1H), 6.56 (d, J = 8.3 Hz,
2H), 6.31 - 6.18 (m, 2H), 3.70 (s, 3H), 3.40 - 3.26 (m,
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
(E)-methyl 3-(4-(2-(2- 'HNMR (400 MHz,
fluoro-4- CHLOROFORM-J) δ ppm
E
isopropoxyphenyl)-6- 1.22 (d,J=6.06 Hz,6H), methoxy- 1 -methyl- 1.66 (d, J=1.52 Hz, 3 H),
1 1,2,3,4- 2.86 (dt,J=l 1.37, 5.94 Hz, 2 tetrahydroisoquinolin- 1 - H), 3.13 -3.33 (m,2H), yl)phenyl)acrylate 3.70 - 3.73 (m, 3 H), 3.73 - 3.76 (m, 3 H), 4.27 - 4.39 (m, 1H), 6.18 -6.25 (m, 1 H), 6.26 - 6.34 (m, 2 H), 6.45 (dd,J=13.14,2.53 Hz, 1 H), 6.59 - 6.65 (m, 2 H), 6.74 - 6.80 (m, 1 H), 7.12 (d, J=8.59 Hz, 2 H), 7.28 (d, J=8.08 Hz,2H), 7.58 (d, J=16.17Hz, 1 H)
LCMS(m/z, MH+): 490.1
(E)-methyl 3-(4-(6-
1
methoxy-l-methyl-2-(4-
E
( 1 -methyl- 1 H-pyrazol- 'HNMR (400 MHz, 3-yl)phenyl)-l,2,3,4- CHLOROFORM-(/) δ ppm tetrahydroisoquinolin- 1 - 1.70 - 1.82 (m, 3 H), 3.15 - yl)phenyl)acrylate 3.29 (m, 1 H), 3.40 - 3.60 compound and (E)- (m, 2 H), 3.65 -3.70 (m, 1 methyl 3-(4-(6- H), 3.77- 3.83 (m, 6 H), methoxy-l-methyl-2-(4- 3.83 - 3.94 (m, 3 H), 6.15 -
1 ( 1 -methyl- 1 H-pyrazol- 6.49 (m, 2 H), 6.62 - 6.80
5-yl)phenyl)-l,2,3,4- (m,4H), 7.06- 7.16 (m, 1 tetrahydroisoquinolin- 1 - H), 7.30 - 7.52 (m, 6 H), yl)phenyl)acrylate 7.62 - 7.73 (m, 2 H)
NMR shows ratio of products to be 1:1.35 LCMS(m/z, MH+): 494.1
(E)-methyl 3-(4-(6- 'HNMR (400 MHz, methoxy-l-methyl-2-(4- CHLOROFORM-(/) δ ppm
E 1
pentylphenyl)- 1 ,2,3 ,4- 1.04- 1.10 (m, 6 H), 1.68- tetrahydroisoquinolin- 1 - 1.78 (m, 3 H), 2.34 -2.42 yl)phenyl)acrylate (m, 1 H), 2.80 - 2.90 (m, 1
H),3.20(ddd,J=15.66, 10.11, 5.56 Hz, 1 H),3.43 - 3.56 (m, 2 H), 3.66 - 3.70 (m, 3 H), 3.71 -3.75 (m, 3 H), 6.31 -6.40 (m, 1 H), 6.40 - 6.46 (m, 2 H), 6.52 (dd,J=8.59,2.53 Hz, 1 H),
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Example 1
(EV3-(4-(2-(4-fluorophenylV6-methoxy-l-methyl-1.2.^^
vDphenvDacrylic acid
Figure imgf000134_0002
[00320] Route A: To a 30 mL screw cap vial, (£)-methyl 3-(4-(2-(4-fluorophenyl)-6- methoxy-1 -methyl- 1, 2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (80 mg, 0.185 mmol) was dissolved in dichloromethane (2 mL). The reaction vial was charged with 1 M boron tribromide in dichloromethane (742 μΐ^, 742 μιηοΐ) at -78 °C under a nitrogen atmosphere. The reaction mixture was placed in a 0 °C bath and stirred for 30 min. When the reaction was complete, the reaction mixture was cooled to -78 °C and quenched with methanol. Volatiles were removed and the pH of the resulting solution was adjusted with saturated sodium bicarbonate to pH 9. The mixture was diluted with dichloromethane and the layers were separated. The organic layer was washed with water and brine, passed through phase separator, and concentrated to afford the crude product. The crude product was purified by silica gel chromatography (24 g column, 0-100% ethyl acetate/heptanes) to afford (E)-methyl 3-(4-(2-(4-fluorophenyl)-6-hydroxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate as a white solid (70 mg, 91%). LC MS (m/z, MH+): 418.4.
[00321] Route B: To a vial containing (£)-methyl 3-(4-(2-(4-fluorophenyl)-6-methoxy-
1 -methyl- 1, 2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (107 mg, 0.248 mmol) was dissolved in dichloromethane (2.480 mL) and cooled to 0 °C. To this was added ethanethiol (183 μΐ^, 2.480 mmol) was added followed by the addition of aluminum chloride (132 mg, 0.992 mmol). The reaction stirred at 0 °C for 1 h at which time it was warmed to room temperature and stirred for 3 h. The reaction was quenched with water and brought to pH 6 with saturated sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel flash chromatography (0-50% ethyl acetate/hetpanes) to afford (£T)-methyl 3-(4-(2-(4- fluorophenyl)-6-hydroxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl)acrylate (54 mg, 52.2 % yield). LC MS (m/z, MH+): 418.3. ¾ NMR (400 MHz, DMSO-t/6) δ 1.60 (s, 3 H) 2.80 (d, J=16.67 Hz, 1 H) 3.07 (br. s., 1 H) 3.20 - 3.28 (m, 1 H) 3.41 (d, J=8.59 Hz, 1 H) 3.72 (s, 3 H) 6.39 - 6.50 (m, 1 H) 6.50 - 6.66 (m, 5 H) 6.88 (t, J=8.84 Hz, 2 H) 7.26 (d, J=8.59 Hz, 2 H) 7.56 - 7.67 (m, 3 H) 9.22 (s, 1 H).
Example 2
(E)-methyl 3 -(4-(6-hydroxy-2-(4-isobutylphenyl)-l -methyl- 1.2.3.4-tetrahvdroisoquinolin-l- vDphenvDacrylate
Figure imgf000135_0001
[00322] (E)-methyl 3-(4-(2-(4-isobutylphenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (Intermediate E4) (0.063 g, 0.134 mmol) was dissolved in dichloromethane (1.342 mL) and cooled to 0 °C. Aluminum chloride (0.143 g, 1.073 mmol) was added followed by the addition of ethanethiol (0.198 mL, 2.68 mmol). The reaction was stirred at 0 °C for 1 hour. The reaction was quenched with saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via silica gel chromatography using 0-100% ethyl acetate in heptanes to afford product (38 mg, 62% yield) as a yellow oil. ¾ NMR (400 MHz, Chloroform-d) δ 7.69 (d, J = 16.0 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.28 - 7.23 (m, 2H), 6.90 - 6.83 (m, 2H), 6.70 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 6.62 - 6.51 (m, 3H), 6.42 (d, J = 16.0 Hz, 1H), 3.83 (s, 3H), 3.50 - 3.30 (m, 2H), 3.12 (ddd, J = 16.0, 8.6, 5.0 Hz, 1H), 2.99 - 2.83 (m, 1H), 2.37 (d, J = 7.2 Hz, 2H), 1.78 (dt, J = 13.2, 6.5 Hz, 1H), 1.71 (s, 3H), 0.87 (d, J = 6.6 Hz, 6H). LC MS (m/z, MH+): 456.5.
Example 3
(E)-methyl 3 -(4-(6-hydroxy-2-(4-isopropylphenyl)- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylate
Figure imgf000136_0001
[00323] To a 30 mL vial, (E)-methyl 3-(4-(2-(4-isopropylphenyl)-6-methoxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (Intermediate E5) (2.51 g, 5.51 mmol) was dissolved in dichloromethane (10 mL). To this was added aluminum chloride (5.88 g, 44.1 mmol) followed by ethanethiol (8.15 mL, 110 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with water and dichloromethane. The organic phase was collected by filtration through a phase separator and concentrated to afford the crude product. The crude material was purified by column chromatography (1-30% Heptanes/ethyl acetate) to afford the desired product (1.8 g, 74% yield) as a white solid. ¾ NMR (CHLOROFORM-d) δ: 7.70 (d, J=16.2 Hz, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.29 (d, J=3.5 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 6.73 (d, J=8.6 Hz, 1H), 6.62-6.67 (m, 1H), 6.58 (d, J=8.6 Hz, 3H), 6.43 (d, J=16.2 Hz, 1H), 3.83 (s, 3H), 3.32-3.52 (m, 2H), 3.03-3.22 (m, 1H), 2.92 (dt, J=15.9, 4.2 Hz, 1H), 2.81 (dt, J=13.8, 7.0 Hz, 1H), 1.71 (s, 3H), 1.19 (d, J=7.1 Hz, 6H). LC MS (m/z, MH+): 442.1.
Example 4
(E)-3-(4-(6-hvdroxy-2-(6-isopropylpyridin-3-yl)-l -methyl- 1.2.3.4-tetr ahydroisoquinolin-l-yl)- phenvDacrylic acid
Figure imgf000137_0001
[00324] 2-(6-isopropylpyridin-3-yl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.133 g, 0.449 mmol) was dissolved in dichloromethane (4.49 ml). To this 1 M BBr3 in heptanes (4.49 ml, 4.49 mmol) was added dropwise and the reaction was stirred at rt for 30 min. LC MS showed some product so more BBr3 (4.49 ml, 4.49 mmol) was added and the reaction stirred an additional hour at rt. The reaction was quenched with an aqueous saturated solution of sodium bicarbonate and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The material was mostly starting material so the crude material was dissolved in NMP (4.5 mL) and transfered to a microwave vial.
Thiophenol (0.046 ml, 0.449 mmol) and potassium carbonate (0.093 g, 0.673 mmol) were added and the reaction was microwaved for 20 min at 200 °C. The reaction was quenched with water and extracted with ethyl acetate three times and dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to afford product. The product was in NMP so was taken on crude to the next reaction. LC MS (m/z, MH+): 283.1.
[00325] 6-hydroxy-2-(6-isopropylpyridin-3-yl)-3,4-dihydroisoquinolin-l(2H)-one (127 mg, 0.449 mmol) was dissolved in DMF (1 mL). To this was added imidazole (138 mg, 2.021 mmol) and DMAP (10.97 mg, 0.090 mmol) followed by TBSC1 (102 mg, 0.674 mmol). The reaction was stirred at rt for 4 h. The reaction was then quenched with water and extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purfied via silica gel chromatography (0-50% ethyl acetate/heptanes) to afford product (102 mg, 0.257 mmol, 57.3 % yield) as a beige solid. ¾ NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 2.6 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.4, 2.6 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 8.4, 2.4 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 3.73 (d, J = 6.4 Hz, 2H), 3.04 - 2.72 (m, 3H), 1.07 (d, J = 6.9 Hz, 6H), 0.76 (s, 9H), -0.00 (s, 6H). LC MS (m/z, MH+): 397.1.
[00326] To a 40 mL vial was added l-(4-bromophenyl)-2-(6-isopropylpyridin-3-yl)-l- methyl-l,2,3,4-tetrahydroisoquinolin-6-ol (0.047 g, 0.107 mmol), PdCl2(PPh3)2 (0.038 g, 0.054 mmol), DMF (1.075 ml), triethylamine (0.150 ml, 1.075 mmol), and acrylic acid (0.074 ml, 1.075 mmol). The reaction mixture was microwaved for 1 hour at 150 °C, LC/MS indicated conversion to product. The reaction mixture was quenched with water and extracted with dichloromethane (3x). The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via basic mass triggered HPLC (15-40% ACN in water with 5 mM NH4OH as modifier) to afford product (3 mg, 6.44 μιηοΐ, 5.99 % yield) as a white solid. ¾ NMR (400 MHz, Methanol-d4) δ 7.64 (d, J = 2.7 Hz, 1H), 7.56 (d, J = 16.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.15 (dd, J = 8.5, 2.7 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.61 (d, J = 8.6 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 6.52 - 6.42 (m, 2H), 3.60 - 3.52 (m, 1H), 3.43 - 3.37 (m, 1H), 3.15 (d, J = 5.2 Hz, 1H), 2.95 - 2.84 (m, 2H), 1.71 (s, 3H), 1.19 (dd, J = 6.9, 1.7 Hz, 6H). LC/MS (m/z, MH+): 429.4. Example 5
(E)-methyl 3 -(4-(6-hydroxy-2-(4-isopropoxyphenyl)-l -methyl- 1.2.3.4-tetrahvdroisoquinolin-l- vD-phenvDacrylate
Figure imgf000139_0001
[00327] 6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.21 g, 1.185 mmol) was dissolved dichloromethane (5.93 ml). A I M solution of BBr3 (5.93 ml, 5.93 mmol) in heptanes was added dropwise and the reaction stirred for 30 min at rt. LC MS indicates the reaction was 50% complete, additional 1 M BBr3 in heptanes (5.93 ml, 5.93 mmol) was added. The reaction stirred for 1 h at rt. The reaction was then quenched with saturated sodium bicarbonate. The reaction was extracted with DCM but DCM extract did not contain any product. The product precipitated out on the reaction flask and was collected. The crude product was used without purification in the next reaction. ¾ NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 8.4, 2.4 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 3.31 (t, J = 6.1 Hz, 2H), 2.79 (t, J = 6.6 Hz, 2H). LC/MS (m/z, MH+): 164.1.
[00328] 6-hydroxy-3,4-dihydroisoquinolin-l(2H)-one (193 mg, 1.185 mmol) was dissolved in DMF (2370 μΐ). Potassium carbonate (328 mg, 2.370 mmol) and benzyl bromide (155 μΐ, 1.304 mmol) were added and the reaction was sitrred at rt for 24 h. The reaction was quenched with water and extracted with dichloromethane (3x). The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatograph with 0-100% ethyl acetate in heptanes to afford product (64 mg, 0.253 mmol, 21.32 % yield over two steps) as a light yellow solid. ¾ NMR (400 MHz, Chloroform-d) δ 8.07 - 7.99 (m, 2H), 7.48 - 7.30 (m, 4H), 6.93 (dd, J = 8.6, 2.5 Hz, 1H), 6.82 - 6.75 (m, 1H), 6.08 (s, 1H), 5.11 (s, 2H), 3.59 - 3.50 (m, 2H), 3.02 - 2.93 (m, 2H). LC MS (m/z, MH+): 254.3.
[00329] 6-(benzyloxy)-3,4-dihydroisoquinolin-l(2H)-one (0.064 g, 0.253 mmol) was dissolved in DMF (0.505 ml), l-bromo-4-isopropoxybenzene (0.082 g, 0.379 mmol) and potassium carbonate (0.070 g, 0.505 mmol) were added. The reaction mixture was flushed with nitrogen and then copper(I) iodide (0.029 g, 0.152 mmol) was added. The reaction mixture was heated to 150 °C and stirred at 150 °C for 72 h. The reaction was quenched with water and extracted with dichloromethane (3x). The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography using 0- 75% ethyl acetate in heptanes to give the desired product (23 mg, 0.059 mmol, 23.49 % yield) as a beige solid. ¾ NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 8.6 Hz, 1H), 7.52 - 7.34 (m, 5H), 7.31 - 7.25 (m, 2H), 6.97 (dd, J = 8.6, 2.5 Hz, 1H), 6.95 - 6.90 (m, 2H), 6.82 (d, J = 2.4 Hz, 1H), 5.15 (s, 2H), 4.56 (hept, J = 6.1 Hz, 1H), 3.94 (dd, J = 7.0, 5.9 Hz, 2H), 3.10 (dd, J = 7.9, 5.0 Hz, 2H), 1.37 (d, J = 6.1 Hz, 6H). LC MS (m/z, MH+): 388.1.
[00330] 6-(benzyloxy)-2-(4-isopropoxyphenyl)-3,4-dihydroisoquinolin-l(2H)-one (0.023 g, 0.059 mmol) was dissolved in ethanol (1.187 ml). The compound was not completely soluble, therefore THF was added to dissolve all compound (2 mL). A scoop of Pd(OH)2 was added and the reaction solution was purged with hydrogen and left with a hydrogen balloon overnight. The reaction was filtered through a syring filter and concentrated to afford product (18 mg, 0.059 mmol, quantative yield) as a white solid. Reaction was pure enough to carry on crude to the next reaction. ¾ NMR (400 MHz, CHLOROFORM-^ δ ppm 1.22 - 1.27 (m, 6 H), 2.92 (t, J=6.57 Hz, 2 H), 3.76 - 3.84 (m, 2 H), 4.37 - 4.48 (m, 1 H), 6.51 (d, J=2.53 Hz, 1 H), 6.62 - 6.68 (m, 1 H), 6.75 - 6.85 (m, 2 H), 7.11 - 7.18 (m, 2 H), 7.85 (d, J=8.08 Hz, 1 H). LC/MS (m/z, MH+): 298.4.
[00331] To a 40 mL vial was added l-(4-bromophenyl)-2-(4-isopropoxyphenyl)-l- methyl-l,2,3,4-tetrahydroisoquinolin-6-ol (0.0213 g, 0.047 mmol), PdCl2(PPh3)2 (0.017 g, 0.024 mmol), DMF (0.314 ml), triethylamine (0.05 ml, 0.359 mmol), and methyl acrylate (0.085 ml,
0.942 mmol). The reaction mixture was heated for 1 h at 130 °C, LC/MS indicates only starting material. Added more methyl acrylate (0.085 ml, 0.942 mmol), triethylamine (0.05 ml, 0.359 mmol), and PdCl2(PPh3)2 (0.017 g, 0.024 mmol) and stirred for 2 h at 130 °C. Reaction still incomplete so more methyl acrylate (0.085 ml, 0.942 mmol), triethylamine (0.05 ml, 0.359 mmol), and PdCl2(PPh3)2 (0.017 g, 0.024 mmol) were added and reaction was microwaved at 150 °C for 2 h. Still incomplete so more methyl acrylate (0.085 ml, 0.942 mmol), triethylamine (0.05 ml, 0.359 mmol), and PdCl2(PPh3)2 (0.017 g, 0.024 mmol) were added and the reaction was microwave an additional 1 h at 150 °C. LC MS showed no more starting material. The reaction mixture was quenched with water and extracted three times with 10% methanol in ethyl acetate. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via silica gel chromatography using 0-25% ethyl acetate in heptanes to afford product (20 mg, 0.044 mmol, 93 % yield) as a yellow oil. LC/MS (m/z, MH+): 458.1
[00332] (E)-3-(4-(6-hydroxy-2-(4-isopropoxyphenyl)-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid was formed using the general hydrolysis procedure resulting in the final product (1.48 mg, 3.17 μιηοΐ, 6.04 % yield) as a cream solid. ¾ NMR (400 MHz, Methanol-d4) δ 7.60 (d, J = 15.9 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 6.64 - 6.54 (m, 6H), 6.50 (dd, J = 8.6, 2.7 Hz, 1H), 6.44 (d, J = 15.9 Hz, 1H), 4.44 (p, J = 6.0 Hz, 1H), 3.40 (ddd, J = 12.3, 8.5, 4.2 Hz, 1H), 3.29 - 3.22 (m, 1H), 3.05 (ddd, J = 13.6, 8.5, 4.9 Hz, 1H), 2.89 (dt, J = 16.1, 4.8 Hz, 1H), 1.67 (s, 3H), 1.24 (d, J = 6.0 Hz, 6H). LC/MS (m/z, MH+): 444.5.
Example 6
(E)-methyl 3 -(4-(6-hydroxy- 1 -methyl-2-(2-methylthiophen-3 -yl)- 1.2.3.4-tetrahvdroisoquinolin- 1 - vDphenvDacrylate
Figure imgf000141_0001
[00333] To a 30 mL screw cap vial, (E)-methyl 3 -(4-(6-methoxy-l -methyl -2-(2- methylthiophen-3-yl)-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (90 mg, 0.208 mmol) was dissolved in dichloromethane (3 mL) and the mixture was cooled to 0 °C. The vial was charged with ethanethiol (150 μΕ, 2.076 mmol) and AICI3 (111 mg, 0.83 mmol) under nitrogen. The reaction mixture stirred at 0 °C for 1 h, the mixture was warmed to rt and stirred for 3 h. The reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride, and diluted with dichloromethane. The organic phase was collected, dried (sodium sulfate), filtered, and concentrated to afford crude product.
[00334] Part of the crude material was purified by normal phase Isco flash
chromatography systems (0-100% EtO Ac/Heptane) to afford product. The product was further triturated with acetonitrile, the suspension was filtered. The solid was collected and dried to afford a light yellow solid (35 mg), which is brought to the next step. The filtrate was purified by reverse phase HPLC (modifier: 5 mM NH3) to afford product (5 mg), which is submitted for assays. LC MS (m/z, MH+): 420.2. ¾ NMR (400 MHz, METHANOL-d4) δ 1.65 (s, 3 H), 2.18 (s, 3 H), 2.46 - 2.65 (m, 1 H), 2.83 - 3.06 (m, 2 H), 3.08 - 3.26 (m, 1 H), 3.77 (s, 3 H), 6.32 (d, J=3.03 Hz, 1 H), 6.49 (d, J=15.66 Hz, 1 H), 6.62 (d, J=2.53 Hz, 1 H), 6.68 (dd, J=8.34, 2.78 Hz, 1 H), 6.90 (dd, J=3.03, 1.01 Hz, 1 H), 7.00 (d, J=8.08 Hz, 1 H), 7.33 (d, J=8.59 Hz, 2 H), 7.47 (d, J=8.08 Hz, 2 H), 7.66 (d, J=16.17 Hz, 1 H).
Example 7
(E)-methyl 3-(4-(6-hydroxy-2-(4-hvdroxy-3 -methylphenvD-1 -methyl- 1.2.3.4- tetrahydroisoquinolin- 1 -vDphenvDacrylate
Figure imgf000142_0001
[00335] To a 30 mL vial, (E)-methyl 3-(4-(2-(4-isopropoxy-3-methylphenyl)-6- methoxy-1 -methyl- 1, 2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (550 mg, 1.133 mmol) was dissolved in dichloromethane (1 mL) and the solution was cooled to 0 °C. To the cold solution was added 1 M boron tribromide in heptanes (1.699 mL, 1.699 mmol). The reaction was stirred at 0 °C for 1 h. The reaction mixture was quenched with 4 mL MeOH at 0 °C. The solution was concentrated by 50% volume and purified by reverse phase HPLC (basic condition, 0.1% NH4OH in CH3CN H20) to afford (E)-methyl 3-(4-(6-hydroxy-2-(4-hydroxy-3-methylphenyl)-l-methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (110 mg, 22% yield), and (E)-methyl 3-(4-(6- hydroxy-2-(4-isopropoxy-3 -methylphenyl)- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 - yl)phenyl)acrylate (21 mg, 0.045 mmol, 3.93 % yield) all as off white solids. LC MS (m/z, MH+): 472.1.
Example 8
(E)-methyl 3 -(4-(2-(4-fluorophenyl)-6-hvdroxy-l -methyl- 1.2.3.4-tetrahydroisoquinolin-l-yl)-2- methylphenvDacrylate
Figure imgf000143_0001
[00336] (E)-methyl 3 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4- tetrahydroisoquinolin- l-yl)-2-methylphenyl)acrylate (Intermediate E6) (56 mg, 0.126 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (0.186 mL, 2.51 mmol) was added followed by aluminum chloride (134 mg, 1.006 mmol). The reaction was warmed to room temperature and stirred for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-30% ethyl acetate/heptanes) to afford product (38.4 mg, 70% yield) as a yellow oil. LC MS (m/z, MH+): 432.1. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.67 (br. s., 3 H), 2.26 - 2.44 (m, 3 H), 2.84 - 2.98 (m, 1 H), 3.04 - 3.21 (m, 1 H), 3.34 (br. s., 1 H), 3.43 (br. s., 1 H), 3.83 (s, 3 H), 6.37 (d, J=16.17 Hz, 1 H), 6.65 (s, 2 H), 6.61 (s, 2 H), 6.71 (d, J=8.59 Hz, 1 H), 6.78 (t, J=8.34 Hz, 2 H), 6.98 - 7.12 (m, 2 H), 7.43 (d, J=8.08 Hz, 1 H), 7.97 (d, J=16.17 Hz, 1 H). Example 9
^-l-(4- -(lH-imidazol-4-yl)vmyl)phenyl)-2-(4-fluorophenyl)-l-methyl-1.2.3.4- tetrahvdroisoquinolin-6-ol
Figure imgf000144_0001
[00337] screw cap vial, (iT)-2-(4-fluorophenyl)-6-methoxy- 1 -methyl- 1 -(4-
(2-( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-imidazol-4-yl)vinyl)phenyl)- 1 ,2,3 ,4- tetrahydroisoquinoline (Intermediate CI) (40 mg, 0.070 mmol) was dissolved in dichloromethane (2 mL), cooled at -78 °C, charged with 1 M boron tribromide in dichloromethane (281 μΐ^, 0.281 mmol). The reaction mixture was stirred at 0 °C for 30 min and stored at 4 °C for 16 h. The reaction mixture was cooled to -78 °C and quenched with methanol and concentrated immediately. The resultant solution was basified with saturated sodium bicarbonate to pH 9 and diluted with dichloromethane. The layers were separated, the organic layer was collected, passed through phase separator and concentrated. The crude product was purified by reverse phase HPLC (15-100% acetonitrile/water with 3% «-propanol modifier). The title compound was afforded as a white solid (14 mg, 46%). LC MS (m/z, MH+): 426.4. ¾ NMR (400 MHz, methanol-^) δ 1.66 (s, 3 H), 2.85-2.91 (m, 1 H), 3.05-3.13 (m, 1 H), 3.25-3.33 (m, 1 H), 3.41- 3.47 (m, 1 H), 6.48 -6.52 (m, 1 H), 6.57-6.58 (m, 1 H), 6.62-6.67 (m, 3 H), 6.74-6.78 (m, 2 H), 7.02 (m, 2 H), 7.13-7.15 (m, 3 H), 7.33-7.35 (m, 2 H), 7.67 (m, 1 H).
Example 10
(E)-3 -(4-(2-(4-fluorophenyl)-6-hvdroxy- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylic acid
Figure imgf000145_0001
[00338] screw cap vial, (£)-methyl 3-(4-(2-(4-fluorophenyl)-6-hydroxy-l- methyl-l ,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (50 mg, 0.12 mmol) was dissolved in THF (1 mL) and treated with 2 M lithium hydroxide (927 μΐ^, 1854 μιηοΐ). The reaction mixture was heated at 60 °C for 30 min. The reaction vial was cooled to ambient temperature, volatiles were removed, and the resultant solution was treated with citric acid to pH 5. The aqueous mixture was diluted with dichloromethane and the layers were separated. The organic layer was washed with water and brine, passed through a phase separator, and concentrated. The crude product was purified by reverse phase HPLC (20-100% acetonitrile in water, 3% «-propanol modifier). The title compound was afforded as a white solid (60 mg, 79% yield).
[00339] Enantiomers were separated using analytical SFC with an IC column (20% methanol, 0.1% trifluoroacetic acid in carbon dioxide) - Analytical SFC, IC column, 2.37 min and 2.51 min. resulted in (S,E)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid and (R,E)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l- methyl-l ,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid. LC MS (m/z, MH+): 404.3. ¾ NMR (400 MHz, methanol-^) δ 1.69 (s, 3 H), 2.85-2.91 (m, 1 H), 3.07-3.13 (m, 1 H), 3.35-3.41 (m, 1 H), 3.46-3.52 (m, 1 H), 6.45 (d, J= 15.7 Hz, 1 H), 6.49-6.51 (m, 1 H), 6.57-6.67 (m, 4 H), 6.75-6.79 (m, 2 H), 7.24 (d, J= 8 Hz, 2 H), 7.45 (d, J= 8 Hz, 2 H), 7.62 (d, J= 16.2 Hz, 1 H). Example 11
(E)-3 -(4-(2-(4-fluoro-2-methylphenyl)-6-hydroxy- 1 -methyl- 1.2.3.4-tetrahvdroisoquinolin- 1 - vDphenvDacrylic acid
Figure imgf000146_0001
[00340] To a 30 mL screw cap vial, (i*T)-methyl 3-(4-(2-(4-fluorophenyl)-6-methoxy-l- methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (10 mg, 0.023 mmol) was dissolved in tetrahydrofuran (1 mL) and charged with 2 M lithium hydroxide (0.5 mL). The reaction mixture was heated at 60 °C for 30 min. The crude reaction was concentrated and adjusted to pH 5 with saturated sodium bicarbonate. The mixture was diluted with dichloromethane and the layers were separated. The organic layer was washed with water and brine, passed through phase separator, concentrated. The crude product was purified by reverse phase HPLC (20-100%
acetonitrile/water with 3% «-propanol modifier). The title compound was obtained as a white solid (2 mg, 20% yield). LC MS (m/z, MH+): 418.3. ¾ NMR (400 MHz, methanol-^) δ 1.59 (s, 3 H), 2.41 (s, 3 H), 2.75-2.96 (m, 2 H), 3.13-3.19 (m, 1 H), 3.33-3.35 (m, 1 H), 6.45 (d, J= 15.7 Hz, 1 H), 6.63-7.12 (m, 8 H), 7.46 (d, J= 8.1 Hz, 2 H), 7.61 (d, J= 16.2 Hz, 1 H).
Example 12
(E)-3 -(4-(6-hydroxy- 1 -methyl-2-phenyl- 1.2.3.4-tetrahvdroisoquinolin- 1 -vDphenvDacrylic acid
Figure imgf000146_0002
[00341] In a 30 mL vial, (£)-methyl 3-(4-(6-hydroxy-l-methyl-2-phenyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (Intermediate Gl) (48 mg, 120 μιηοΐ) was dissolved in 1,4-dioxanes (1 mL). To this, 1 M lithium hydroxide (2.52 mL, 2.52 mmol) was added. The reaction mixture stirred at room temperature for 5 h. The reaction mixture was then acidified to pH 1 with aqueous 1 M hydrochloric acid. The reaction mixture was extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated to afford the title compound (42 mg, 88%). LC MS (m/z, MH+): 386.3. ¾ NMR (400 MHz, METHANOL-^) δ 1.69 (s, 3 H), 2.88 (dt, J=15.92, 4.42 Hz, 1 H), 3.04 - 3.16 (m, 1 H), 3.38 (dt, J=12.00, 4.86 Hz, 1 H), 3.45 - 3.56 (m, 1 H), 6.44 (d, J=15.66 Hz, 1 H), 6.47 - 6.52 (m, 1 H), 6.57 (d, J=2.53 Hz, 1 H), 6.62 (d, J=8.59 Hz, 1 H), 6.64 - 6.69 (m, 2 H), 6.87 - 6.95 (m, 1 H) 6.98 - 7.06 (m, 2 H) 7.27 (d, J=8.59 Hz, 2 H) 7.44 (d, J=8.59 Hz, 2 H) 7.64 (d, J= 15.66 Hz, 1 H).
Example 13
(E)-3-(4-(2-(4-fluorophenyl)-6-hvdroxy-l-methyl-1.2.3.4-tetrahvdroisoquinolin-l-yl)-2- methylphenvDacrylic acid
Figure imgf000147_0001
[00342] (E)-methyl 3-(4-(2-(4-fluorophenyl)-6-hydroxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)-2-methylphenyl)acrylate (38.4 mg, 0.089 mmol) was dissolved in 1,4- dioxanes (4 mL). A I M solution of lithium hydroxide (0.890 mL, 0.890 mmol) was added. The reaction stirred at 40 °C for 6 h. The reaction mixture was then cooled to room temperature and acidified to pH 1 with 1 N hydrochloric acid. The reaction mixture was extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to afford pure product (31 mg, 80 % yield) as an off-white solid. LC MS (m/z, MH+): 418.5. ¾ NMR (400 MHz, METHANOL-^) δ ppm 1.52 (s, 3 H), 2.21 (s, 3 H), 2.74 (dt, J=15.92, 4.17 Hz, 1 H), 2.90 - 3.02 (m, 1 H), 3.12 - 3.23 (m, 1 H), 3.24 - 3.38 (m, 1 H), 6.24 (d, J=15.66 Hz, 1 H), 6.36 - 6.43 (m, 1 H), 6.44 - 6.57 (m, 4 H), 6.59 - 6.69 (m, 2 H), 6.91 - 6.98 (m, 2 H), 7.31 - 7.39 (m, 1 H), 7.84 (d, J=16.17 Hz, 1 H.
Example 14
(E)-3-(4-(6-hydroxy-2-(4-isobutylphenyl)- 1 -methyl- 1.2.3.4-tetrahvdroisoquinolin- 1 - vDphenvDacrylic acid
Figure imgf000148_0001
[00343] (E)-methyl 3 -(4-(6-hydroxy-2-(4-isobutylphenyl 1 -methyl- 1 ,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (Example 2) (0.038 g, 0.083 mmol) was dissolved in dioxane (0.834 mL) and aqueous 1 M lithium hydroxide (0.417 mL, 0.417 mmol) was added. The reaction was heated to 40 °C for 2 h. The reaction was quenched with 1 N hydrochloric acid and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to afford pure product (26 mg, 0.059 mmol, 70.6 % yield) as a light yellow powder. ¾ NMR (400 MHz, Methanol-d4) δ 7.63 (d, J = 16.0 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.22 (d, J = 8.3 Hz, 2H), 6.87 - 6.76 (m, 2H), 6.60 (d, J = 8.6 Hz, 1H), 6.59 - 6.52 (m, 3H), 6.49 (dd, J = 8.5, 2.7 Hz, 1H), 6.42 (d, J = 16.0 Hz, 1H), 3.44 (ddd, J = 16.2, 8.5, 4.3 Hz, 1H), 3.34 (t, J = 5.2 Hz, 1H), 3.07 (ddd, J = 13.9, 8.5, 4.8 Hz, 1H), 2.87 (dt, J = 15.9, 4.6 Hz, 1H), 2.33 (d, J = 7.2 Hz, 2H), 1.75 (dt, J = 13.4, 6.7 Hz, 1H), 1.67 (s, 3H), 0.83 (d, J = 6.6 Hz, 6H). LC MS (m/z, MH+): 442.4.
Example 15
(E)-3 -(4-(6-hydroxy-2-(4-isopropylphenyl)- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylic acid
Figure imgf000149_0001
[00344] To a 30 mL screw cap vial, (E)-methyl 3-(4-(6-hydroxy-2-(4-isopropylphenyl)-
1 -methyl- 1,2,3, 4-tetrahydroisoquinolin- l-yl)phenyl)acrylate (Example 3) (1.8 g, 4.08 mmol) was dissolved in tetrahydrofuran (8 mL), methanol (4 mL), and water (4 mL). The vial was charged with lithium hydroxide (0.488 g, 20.38 mmol) and the reaction mixture was stirred for 60 min at room temperature. The reaction mixture was concentrated by vacuum, diluted with water, and acidified with citric acid causing a percipitate to form. The mixture was diluted with
dichloromethane (25 mL) and MeOH (5 mL). The organic layer was collected and concentrated to afford the crude product. The crude material was purified by column chromatography (1-20% methanol/dichloromethane) to afford the title compound (1.68 g, 96% yield) as a white solid. ¾ NMR (CHLOROFORM-d) δ: 7.68 (d, J=16.2 Hz, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 6.62 (d, J=8.6 Hz, 1H), 6.54 (d, J=2.5 Hz, 1H), 6.48 (d, J=8.6 Hz, 3H), 6.33 (d, J=16.2 Hz, 1H), 3.21-3.48 (m, 2H), 2.92-3.10 (m, 1H), 2.76-2.92 (m, 1H), 2.71 (dt, J=13.8, 7.0 Hz, 1H), 1.62 (s, 3H), 1.09 (dd, J=7.1, 1.0 Hz, 6H). LC MS (m/z, MH+): 428.1.
[00345] Preparative Chiral OJH column (40% methanol, 10 mM ammonium hydroxide in CO2); retention times of the enantiomers on chiral OJ-H column: phase:5-55% MeOH with 20 mM NH4OH in C02: 2.61 min and 3.09 min.
Example 16
(E)-3-(4-(2-(4-fluorophenyl)-6-hvdroxy-l-(trifluoromethyl^^
vDphenvDacrylic acid
Figure imgf000150_0001
[00346] (E)-methyl 3 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 -(trifluoromethyl)- 1 ,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (Intermediate Q2) (22.2 mg, 0.046 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0°C. Ethanethiol (68 μΐ , 0.915 mmol) was added followed by aluminum trichloride (49 mg, 0.366 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel (0-50% ethyl acetate/heptanes) to afford (E)-methyl 3-(4-(2-(4-fluorophenyl)-6-hydroxy-l- (trifluoromethyl)-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (14 mg, 65 % yield) as a clear oil. LC/MS (m/z, MH+): 472.0. ¾ NMR (400 MHz, CHLOROFORM-^ δ ppm 3.02 (dt, J=16.04, 4.36 Hz, 1 H), 3.12 - 3.24 (m, 1 H), 3.44 - 3.52 (m, 1 H), 3.81 - 3.85 (m, 3 H), 3.85 - 3.93 (m, 1 H), 6.44 (d, J=16.17 Hz, 1 H), 6.58 - 6.66 (m, 3 H), 6.66 - 6.74 (m, 3 H), 6.78 - 6.85 (m, 1 H), 7.25 - 7.32 (m, 2 H), 7.36 - 7.43 (m, 2 H), 7.67 (d, J=15.66 Hz, 1 H).
[00347] (E)-methyl 3-(4-(2-(4-fluorophenyl)-6-hydroxy-l-(trifluoromethyl)-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (14 mg, 0.030 mmol) was dissolved in 1,4-dioxane (4 mL). To this, 1 M lithium hydroxide (800 μΕ, 0.800 mmol) was added and the reaction stirred at 40 °C for 6 h. The reaction mixture was then cooled to rt and acidified to pH 1 with 1 M HC1. The reaction mixture was extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to afford pure product as a white solid (10.7 mg, 0.023 mmol, 79% yield). LC MS (m/z, MH+): 458.0. ¾ NMR (400 MHz, METHANOL-^) δ 2.85 (s, 1 H), 3.01 (br. s., 1 H), 3.33 - 3.43 (m, 1 H), 3.69 (br. s., 1 H), 6.37 (d, J=16.17 Hz, 1 H), 6.42 (dd, J=8.84, 2.78 Hz, 1 H), 6.55 - 6.62 (m, 6 H), 7.17 (d, J=8.59 Hz, 2 H), 7.36 (d, J=8.08 Hz, 2 H), 7.52 (d, J=16.17 Hz, 1 H). 19F NMR (376 MHz, METHANOL-^) δ - 120.98 (s, 1 F), -64.01 (s, 3 F).
[00348] (E)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l-(trifluoromethyl)-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid was purified by SFC on an AD-H (35% IPA with 10 mM NH4OH in C02) to afford (S,E)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l-(trifluoromethyl)- 1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (14 mg, 0.029 mmol, 24% yield, 94% pure) as a white solid and (R,E)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l-(trifluoromethyl)-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (14 mg, 0.031 mmol, 25% yield, 100% pure) as a white solid. PI LC MS (m/z, MH+): 458.4 AD-H column, 5-55% IPA with 20 mM NH4OH in C02, 2.5 min (analytical); 1.8 min prep. P2: LC/MS (m/z, MH+): 458.4 5-55% IPA with 20 mM NH4OH in C022.75 min (analytical); 2.8 min for prep.
Example 17
(E)-3-(4-(2-(4-fluorophenyl)-6-hvdroxy-l-(methyl-d3)-1.2.3.4-tetrahvdroisoquinolin-l- vDphenvDacrylic acid
Figure imgf000151_0001
Figure imgf000152_0001
[00349] To a 40 mL vial was added l-bromo-4-iodobenzene (0.313 g, 1.106 mmol) and pentanes (2.91 mL). The reaction vial was charged with 2.5 M «-butyllithium in hexanes (444 μL, 1.110 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C and a solution of 2-(4-fluorophenyl)-6- methoxy-3,4-dihydroisoquinolin-l(2H)-one (Intermediate Al) (0.1 g, 0.369 mmol) in tetrahydrofuran (2.077 mL) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with water (5 mL) and ethyl acetate (5 mL). Perchloric acid (0.136 ml, 1.585 mmol, 70% in water) was added to the reaction mixture which was stirred for 30 min at rt. The quenched reaction mixture was diluted with dichloromethane and water. The layers were separated and the aqueous layer was washed twice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated to give crude iminium intermediate based on LC MS which was used directly in the next step. LC MS (m/z, MH+): 411.8.
[00350] Iminium intermediate was dissolved in tetrahydrofuran (2.388 mL) and the reaction was cooled to 0 °C and a 1 M solution of l-methyl- 3-magnesium iodide (1.106 mL, 1.106 mmol) in diethyl ether was added dropwise. The reaction stirred at 0 °C for 1 h at which time it was quenched with saturated ammonium chloride. The aqueous layer was extracted thrice with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-10% ethyl acetate/heptanes) to afford product (91 mg, 57% yield). LC MS (m/z, MH+): 430.9. ¾ NMR (400 MHz, CHLOROFORM-J) δ 2.78 - 2.91 (m, 1 H), 2.97 - 3.08 (m, 1 H), 3.16 - 3.24 (m, 1 H), 3.27 - 3.36 (m, 1 H), 3.68 - 3.72 (m, 3 H), 6.50 (dd, J=9.09, 5.05 Hz, 2 H), 6.53 - 6.60 (m, 2 H), 6.60 - 6.64 (m, 1 H), 6.64 - 6.73 (m, 2 H), 6.96 (d, J=8.08 Hz, 2 H), 7.20 - 7.27 (m, 2 H).
[00351] To a 20 mL microwave vial was added l-(4-bromophenyl)-2-(4-fluorophenyl)-
6-methoxy-l-methyl-t/3-l,2,3,4-tetrahydroisoquinoline (0.091 g, 0.212 mmol), Pd(PPh3)2Cl2 (22 mg, 0.032 mmol), dimethylformamide (1.413 mL), triethylamine (148 μΐ^, 1.060 mmol), and methyl acrylate (192 μΐ^, 2.120 mmol). The reaction mixture was microwaved for 1 h at 150 °C. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-10% ethyl acetate/heptanes) to afford product (10 mg, 10% yield). LC MS (m/z, MH+): 435.5. ¾ NMR (400 MHz, CHLOROFORM- d) δ 2.83 - 2.92 (m, 1 H), 3.06 (br. s., 1 H), 3.27 (br. s., 1 H), 3.36 (br. s., 1 H), 3.71 - 3.75 (m, 6 H), 6.33 (d, J=15.66 Hz, 1 H), 6.45 - 6.75 (m, 7 H), 7.14 (d, J=6.57 Hz, 2 H), 7.31 (d, J=8.59 Hz, 2 H), 7.59 (d, J=15.66 Hz, 1 H).
[00352] (E)-methyl 3 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 -methyl-^- 1 ,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (10 mg, 0.023 mmol) was dissolved in
dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (0.034 mL, 0.460 mmol) was added followed by aluminum chloride (24.55 mg, 0.184 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford product (8.1 mg, 84% yield) as a clear oil. LC MS (m/z, MH+): 421.0. ¾ NMR (400 MHz, METHANOL-^) δ 2.89 (br. s., 1 H), 2.98 - 3.15 (m, 1 H), 3.27 - 3.53 (m, 2 H), 3.61 - 3.73 (m, 3 H), 6.27 - 6.47 (m, 2 H), 6.47 - 6.71 (m, 4 H), 6.74 (br. s., 2 H), 7.11 (d, J=8.08 Hz, 2 H), 7.38 (d, J=8.08 Hz, 2 H), 7.56 (d, J=16.17 Hz, 1 H).
[00353] (E)-methyl 3 -(4-(2-(4-fluorophenyl)-6-hydroxy- 1 -methyl-^- 1 ,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (8.1 mg, 0.019 mmol) was dissolved in 1,4-dioxanes (2 mL). To this was added 1 M lithium hydroxide (193 μΕ, 0.193 mmol) and the reaction stirred at 40 °C for 6 h. The reaction mixture was cooled to rt and acidified to pH 1 with 1 M HC1. The reaction mixture was extracted thrice with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated to afford crude product. The crude material was purified by reverse phase HPLC (15-40% acetonitrile/water with 5 mM NH4OH) to afford product (2.6 mg, 33% yield) as a white solid. LC MS (m/z, MH+): 407.1. ¾ NMR (400 MHz, METHANOL-^) δ 2.78 (dt, J=16.04, 4.36 Hz, 1 H), 2.91 - 3.03 (m, 1 H), 3.10 - 3.19 (m, 1 H), 3.34 (ddd, J=12.00, 8.46, 3.79 Hz, 1 H), 6.35 (d, J=16.17 Hz, 1 H), 6.38 - 6.43 (m, 1 H), 6.48 (d, J=2.53 Hz, 1 H), 6.51 (d, J=8.59 Hz, 1 H), 6.53 - 6.59 (m, 2 H), 6.63 - 6.70 (m, 2 H), 7.13 (d, J=8.08 Hz, 2 H), 7.34 (d, J=8.59 Hz, 2 H), 7.50 (d, J=16.17 Hz, 1 H).
Example 18
(E)-3-(4-(l-(difluoromethyl)-2-(4-fluorophenvD^
vDphenvDacrylic acid
Figure imgf000154_0001
[00354] To a 40 mL scintallation vial was added 4-bromo-2-fluoro-l-iodobenzene
(0.469 g, 1.659 mmol) and pentanes (4.36 ml). The reaction vial was charged with a 2.5 M n- butyllithium in hexanes (0.666 mL, 1.664 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C and a solution of 2-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (Intermediate Al)
(0.15 g, 0.553 mmol) in tetrahydrofuran (3.12 mL) was added. The reaction mixture was stirred at
-78 °C for 1 h. The reaction mixture was quenched with water (6.5 mL) and ethyl acetate (6.5 mL) and warmed to rt. Perchloric acid (143 μΐ^, 2.378 mmol, 70% in water) was added and the reaction mixture stirred for 30 min at rt. The reaction was diluted with water and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give iminium intermediate which was used crude in the next step. LC MS (m/z, MH+): 411.9.
[00355] Iminium intermediate was dissolved in dimethylformamide (4.5 mL) and potassium fluoride (96 mg, 1.659 mmol) was added. A solution of ethyl 2,2-difluoro-2- (trimethylsilyl)acetate (0.217 g, 1.106 mmol) in dimethylformamide (3.0 mL) was added dropwise and the reaction stirred at rt for 30 min. The reaction was quenched with saturated sodium bicarbonate and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-10% ethyl acetate/heptanes) to afford product (240 mg, 81 % yield) as a brown oil. LC MS (m/z, MH+): 535.8. ¾ NMR (400 MHz, CHLOROFORM-^ δ 0.90 (t, J=7.33 Hz, 3 H), 2.62 (dt, J=15.66, 3.28 Hz, 1 H), 2.78 - 2.90 (m, 1 H), 2.94 (dt, J=12.00, 4.11 Hz, 1 H), 3.19 - 3.31 (m, 1 H), 3.63 (s, 3 H), 3.87 (qd, J=7.24, 2.02 Hz, 2 H), 6.49 - 6.58 (m, 6 H), 6.77 (dd, J=8.59, 4.55 Hz, 1 H), 6.96 (d, J=8.59 Hz, 2 H), 7.11 - 7.18 (m, 2 H). 19F NMR (376 MHz, CHLOROFORM-^ δ -117.02 (s, 1 F), -100.52 - -97.72 (m, 2 F).
[00356] Ethyl 2-(l-(4-bromophenyl)-2-(4-fluorophenyl)-6-methoxy-l,2,3,4- tetrahydroisoquinolin-l-yl)-2,2-difluoroacetate (0.240 g, 0.449 mmol) was dissolved in 1,4- dioxanes (4 mL). To this, 1 M lithium hydroxide (1.123 mL, 1.123 mmol) was added and the reaction was heated to 40 °C for 2 h. The reaction was cooled to ambient temperature and acidified to pH 1 with 1 M HC1 and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated. The material was taken on crude as a brown oil to the next reaction. LC/MS (m/z, MH+): 507.8. ¾ NMR (400 MHz, CHLOROFORM-^ δ 2.86 (d, J=16.67 Hz, 1 H), 3.06 (d, J=10.11 Hz, 1 H), 3.27 - 3.49 (m, 2 H), 3.73 - 3.78 (m, 3 H), 6.47 - 6.58 (m, 2 H), 6.62 - 6.72 (m, 3 H), 6.72 - 6.79 (m, 2 H), 6.94 - 7.00 (m, 2 H), 7.24 - 7.28 (m, 1 H), 7.33 (d, J=8.59 Hz, 1 H). 19F NMR (376 MHz, CHLOROFORM- d) δ -114.50 (s, 1 F), -110.78 - -109.47 (m, 1 F), -100.12 - -99.00 (m, 1 F).
[00357] 2-(l-(4-Bromophenyl)-2-(4-fluorophenyl)-6-methoxy-l,2,3,4- tetrahydroisoquinolin-l-yl)-2,2-difluoroacetic acid (113 mg, 0.224 mmol) was dissolved in 1- methyl-2-pyrrolidinone (11.0 mL) and cesium fluoride (170 mg, 1.120 mmol) was added. The reaction was placed under nitrogen and heated to 192 °C for 24 h. After cooling to rt, water was added and the reaction mixture was extracted with diethyl ether three times. The organic layers were combined, passed through a phase separator and concentrated to give crude material which was purified by silica gel chromatography (0-10% ethyl acetate/heptanes) to afford product (53 mg, 51% yield) as a clear oil. LC MS (m/z, MH+): 463.8. ¾ NMR (400 MHz, CHLOROFORM- d) δ 2.92 - 3.01 (m, 2 H), 3.19 - 3.32 (m, 1 H), 3.52 - 3.62 (m, 1 H), 3.73 (s, 3 H), 6.29 - 6.63 (m, 4 H), 6.66 (d, J=2.53 Hz, 1 H), 6.67 - 6.75 (m, 2 H), 6.82 (dd, J=8.59, 3.54 Hz, 1 H), 6.85 - 6.92 (m, 2 H), 7.23 - 7.29 (m, 2 H). 19F NMR (376 MHz, CHLOROFORM-^ δ -126.73 - -124.96 (m, 1 F), -122.01 - -120.53 (m, 1 F), -117.40 (s, 1 F).
[00358] (E)-methyl 3-(4-(l-(difluoromethyl)-2-(4-fluorophenyl)-6-methoxy-l,2,3,4- tetrahydroisoquinolin- 1 -yl)phenyl)acrylate
Figure imgf000156_0001
[00359] To a microwave vial was added l-(4-bromophenyl)-l-(difluoromethyl)-2-(4- fluorophenyl)-6-methoxy-l,2,3,4-tetrahydroisoquinoline (0.053 g, 0.115 mmol), Pd(PPh3)2Cl2 (12 mg, 0.017 mmol), dimethylformamide (0.764 mL), triethylamine (80 iL, 0.573 mmol), and methylacrylate (103 iL, 1.146 mmol). The reaction mixture was microwaved for 1 h at 150 °C. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford product (13.3 mg, 25% yield) as a yellow oil. LC MS (m/z, MH+): 468.1. ¾ NMR (400 MHz, CHLOROFORM-^ δ 2.92 - 3.06 (m, 2 H), 3.33 (s, 1 H), 3.59 - 3.65 (m, 1 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 6.28 - 6.40 (m, 2 H), 6.53 - 6.58 (m, 2 H), 6.61 (dd, J=8.84, 2.78 Hz, 1 H), 6.65 - 6.72 (m, 3 H), 6.81 - 6.86 (m, 1 H), 7.05 (d, J=8.08 Hz, 2 H), 7.30 (d, J=8.08 Hz, 2 H), 7.57 (d, J=15.66 Hz, 1 H). 19F NMR (376 MHz, CHLOROFORM-^ δ -126.73 - -124.79 (m, 1 F), - 122.05 - -120.53 (m, 1 F), -117.34 (br. s., 1 F). [00360] (E)-methyl 3-(4-(l-(difluoromethyl)-2-(4-fluorophenyl)-6-methoxy-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (16.7 mg, 0.036 mmol) was dissolved in
dichloromethane (2 mL) and cooled to 0°C. Ethanethiol (0.053 mL, 0.714 mmol) was added followed by aluminum chloride (38.1 mg, 0.286 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to give product as a green-yellow oil. The material was used crude in the next reaction. LC MS (m/z, MH+): 454.0. ¾ NMR (400 MHz,
CHLOROFORM-^ δ 2.92 - 3.08 (m, 2 H), 3.25 - 3.37 (m, 1 H), 3.63 (td, J=6.82, 3.54 Hz, 1 H), 3.74 (s, 3 H), 6.22 - 6.43 (m, 2 H), 6.50 - 6.63 (m, 3 H), 6.63 - 6.74 (m, 3 H), 6.78 (dd, J=8.84, 3.28 Hz, 1 H), 7.06 (m, J=8.08 Hz, 2 H), 7.29 (m, J=8.08 Hz, 2 H), 7.57 (d, J=16.17 Hz, 1 H). 19F NMR (376 MHz, CHLOROFORM-^ δ -126.16 - -124.07 (m, 1 F), -122.30 - -120.62 (m, 1 F), - 116.78 (br. s., 1 F).
[00361] (E)-methyl 3-(4-(l-(difluoromethyl)-2-(4-fluorophenyl)-6-hydroxy-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (16.32 mg, 0.036 mmol) was dissolved in 1,4-dioxanes (4 mL). To this, 1 M lithium hydroxide (90 μΕ, 0.090 mmol) was added. The reaction stirred at 40 °C for 6 h. The reaction mixture was cooled to rt and acidified to pH 1 with 1 M HC1. The reaction mixture was extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to afford crude material which was purified by reverse phase HPLC (5 mM NH4OH as modifier, 15-40% acetonitrile/water). Pure product (4.2 mg, 26% yield) was obtained as a white solid. LC MS (m/z, MH+): 440.2. ¾ NMR (400 MHz, METHANOL-^) δ 2.75 - 2.99 (m, 2 H), 3.31 (dt, J=11.37, 5.43 Hz, 1 H), 3.45 - 3.59 (m, 1 H), 6.30 - 6.76 (m, 9 H), 7.05 (d, J=8.08 Hz, 2 H), 7.34 (d, J=8.59 Hz, 2 H), 7.48 (d, J=15.66 Hz, 1 H). 19F NMR (376 MHz, METHANOL-^) δ -128.06 - -126.57 (m, 1 F), -123.52 - -122.10 (m, 1 F), -120.43 (s, 1 F).
Example 19
(E)-4-(4-(2-(4-fluorophenyl)-6-hvdroxy- 1 -methyl- 1.2.3.4-tetrahvdroisoquinolin- 1 -vDphenvDbut-
3-en-2-one
Figure imgf000158_0001
[00362] To a 2 mL microwave vial was added l-(4-bromophenyl)-2-(4-fluorophenyl)-l- methyl-l,2,3,4-tetrahydroisoquinolin-6-ol (Intermediate Ml) (0.1 g, 0.243 mmol), Pd(PPh3)2Cl2 (26 mg, 0.036 mmol), dimethylformamide (1.617 mL), triethylamine (169 μΐ^, 1.213 mmol), and but-3-en-2-one (197 μΐ^, 2.425 mmol). The reaction mixture was microwaved for 1 h at 150 °C. The reaction mixture was quenched with water and extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified via SFC (mobile phase 10% isopropyl alcohol with 10 mM ammonium hydroxide in carbon dioxide) to afford (E)-4-(4-(2-(4-fluorophenyl)-6-hydroxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)but-3-en-2-one (14 mg, 0.035 mmol, 14.38 % yield) as an off white solid. LC MS (m/z, MH+): 402.2. ¾ NMR (400 MHz, METHANOL-^) δ 1.57 (s, 3 H), 2.26 (s, 3 H), 2.73 - 2.82 (m, 1 H), 2.93 - 3.03 (m, 1 H), 3.14 - 3.19 (m, 1 H), 3.30 - 3.39 (m, 1 H), 6.37 - 6.44 (m, 1 H), 6.46 - 6.60 (m, 4 H), 6.61 - 6.70 (m, 3 H), 7.11 - 7.20 (m, 2 H), 7.39 (m, J=8.59 Hz, 2 H), 7.51 (d, J=16.67 Hz, 1 H).
Example 20
(E)-2-(4-fluorophenyl)- 1 -methyl- 1 -(4-(2-(l -methyl- 1 H-imidazol-4-yl)vinyl)phenyl)- 1.2.3.4- tetrahvdroisoquinolin-6-ol and (EN)-2-(4-fluorophenvn-l-methyl-l-(4-(2-(l -methyl-lH-imidazol- 5-yl)vinyl)phenyl)-1.2.3.4-tetrahvdroisoquinolin-6-ol
Figure imgf000159_0001
[00363] To a 30 mL vial, 4-vinyl-lH-imidazole (357 mg, 3.79 mmol) was dissolved in tetrahydrofuran (2 mL) and the solution was cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 152 mg, 3.79 mmol) was added and the mixture was stirred for 10 min at 0°C. The reaction mixture was charged with iodomethane (237 μΐ^, 3.79 mmol) and stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride (15 mL) and dichloromethane (25 mL) was added. The organic phase was collected, passed through a phase separator and concentrated to give crude product. Crude material was purified by silica gel chromatography (0-20% methanol/dichloromethane) to afford a mixture of 1 -methyl -4-vinyl-lH- imidazole and l-methyl-5 -vinyl- lH-imidazole (290 mg, 71% yield) as a yellow oil. ¾ NMR (400 MHz, CHLOROFORM-^ δ 3.51 (s, 3 H), 3.49 (s, 3 H), 4.97 (dd, J=11.12, 1.52 Hz, 1 H), 5.09 (dd, J=11.12, 1.01 Hz, 1 H), 5.44 (dd, J=17.68, 1.01 Hz, 1 H), 5.67 (dd, J=17.43, 1.77 Hz, 1 H), 6.25 - 6.49 (m, 2 H), 6.62 - 6.73 (m, 1 H), 7.04 (s, 1 H), 7.25 (d, J=7.58 Hz, 2 H).
[00364] To a 5 mL microwave vial, l-(4-bromophenyl)-2-(4-fluorophenyl)-l-methyl- l,2,3,4-tetrahydroisoquinolin-6-ol (Intermediate Ml) (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1.617 mL) and triethylamine (169 μΐ^, 1.213 mmol) was added. The vial was charged with a mixture of l-methyl-4 -vinyl- lH-imidazole and 1 -methyl-5 -vinyl- 1H- imidazole (1.455 mL, 0.728 mmol) and Pd(PPh3)2Cl2 (26 mg, 0.036 mmol). The system was flushed with nitrogen and heated at 150 °C for 1 h under microwave radiation. The mixture was cooled to room temperature and quenched with saturated ammonium chloride. The reaction mixture was extracted three times with dichloromethane, the organic layers were combined, passed through a phase separator and concentrated to give crude material. The crude material was purified on an achiral C4 waters Atlantis Hilic 19 x 150mm 5um column with a mobile phase of 5-10% methanol with 10 mM ammonium hydroxide at a flow rate of 80 g/min to obtain (E)-2-(4- fluorophenyl)- 1 -methyl- 1 -(4-(2-( 1 -methyl- 1 H-imidazol-4-yl)vinyl)phenyl)- 1 ,2,3 ,4- tetrahydroisoquinolin-6-ol (2.4 mg, 2% yield) as a yellow solid and (E)-2-(4-fluorophenyl)-l- methyl-l-(4-(2-(l -methyl- lH-imidazol-5-yl)vinyl)phenyl)-l, 2,3 ,4-tetrahydroisoquinolin-6-ol (4 mg, 3% yield) as a white solid.
[00365] Example 20a: LC MS (m/z, MH+): 440.2 PI : ¾ NMR (400 MHz,
METHANOLS) δ 1.56 (s, 3 H), 2.78 (d, J=16.17 Hz, 1 H), 2.92 - 3.05 (m, 1 H), 3.16 (br. s., 1 H), 3.30 - 3.40 (m, 1 H), 3.65 (s, 3 H), 6.36 - 6.41 (m, 1 H), 6.44 - 6.59 (m, 4 H), 6.63 - 6.71 (m, 2 H), 6.92 (s, 2 H), 7.07 (d, J=8.59 Hz, 2 H), 7.15 (s, 1 H), 7.29 (d, J=8.59 Hz, 2 H), 7.50 (s, 1 H).
[00366] Example 20b: LC MS (m/z, MH+): 440.2. P2: ¾ NMR (400 MHz,
METHANOLS) δ 1.64 - 1.70 (m, 3 H), 2.84 - 2.95 (m, 1 H), 3.05 - 3.17 (m, 1 H), 3.26 - 3.31 (m, 1 H), 3.41 - 3.49 (m, 1 H), 3.73 (s, 3 H), 6.49 - 6.56 (m, 1 H), 6.56 - 6.70 (m, 4 H), 6.73 - 6.81 (m, 2 H), 6.94 - 7.01 (m, 1 H), 7.06 - 7.18 (m, 4 H), 7.34 (d, J=8.08 Hz, 2 H), 7.60 (s, 1 H).
Example 21
3 -(4-(2-(4-fluorophenyl)-6-hvdroxy-l -methyl- 1.2.3.4-tetrahydroisoquinolin-l- vDphenvDpropanoic acid
Figure imgf000160_0001
[00367] Step 1. 3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin- 1 -yl)phenyl)propanoic acid. (E)-3 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 - methyl- 1, 2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acry lie acid (Intermdeiate Fl) (0.04 g, 0.096 mmol) was dissolved in ethanol (958 μΐ^) and stirred for 30 min at rt. To this was added
CoCl2-6H20 (0.456 mg, 1.916 μιηοΐ) and the reaction was cooled to 0 °C. Sodium borohydride (7.25 mg, 0.192 mmol) was added; the reaction was warmed to rt, and stirred overnight. Partial conversation was observed; additional CoCl2-6H20 (0.456 mg, 1.916 μιηοΐ) and sodium borohydride (7.25 mg, 0.192 mmol) were added. The reaction stirred for 1 h at rt at which time it was quenched with saturated sodium bicarbonate and extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated to give 3-(4-(2- (4-fluorophenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl)propanoic acid (36 mg, 90% yield) which was carried forward without further purification. LC MS (m/z, MH+): 420.2. ¾ NMR (400 MHz, METHANOL-^) δ ppm 1.53 (s, 3 H), 2.79 (d, J=16.17 Hz, 2 H), 2.93 - 3.06 (m, 1 H), 3.11 - 3.23 (m, 1 H), 3.23 - 3.36 (m, 3 H), 3.58 - 3.75 (m, 4 H), 6.40 - 6.52 (m, 3 H), 6.52 - 6.67 (m, 4 H), 6.99 (d, J=7.07 Hz, 2 H), 7.21 (br. s., 2 H).
[00368] Step 2. To a 30 mL vial, 3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)propanoic acid (0.036 g, 0.086 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0°C. Ethanethiol (118 μΐ , 1.601 mmol) was added followed by aluminum trichloride (86 mg, 0.644 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and brought to pH 6 with saturated sodium bicarbonate. The aqueous layer was extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (5 mM NH4OH modifier, 15 -40% acetonitrile/water) to afford 3- (4-(2-(4-fluorophenyl)-6-hydroxy- 1 -methyl- 1 ,2,3,4-tetrahydroisoquinolin- 1 -yl)phenyl)propanoic acid (13 mg, 37% yield) as a white solid. LC MS (m/z, MH+): 406.2. ¾ NMR (400 MHz, METHANOL-^) δ 1.53 (s, 3 H), 2.44 (t, J=7.83 Hz, 2 H), 2.71 - 2.81 (m, 3 H), 2.90 - 3.01 (m, 1 H), 3.14 - 3.20 (m, 1 H), 3.27 - 3.35 (m, 1 H), 6.36 - 6.42 (m, 1 H), 6.44 - 6.52 (m, 4 H), 6.61 - 6.68 (m, 2 H), 6.92 - 7.00 (m, 4 H)LC/MS (m/z, MH+): 442.2. Example 22
(E)-3 -(4-(2-(4-fluorophenyl)-6-hvdroxy- 1 -methyl- 1.2.3.4-tetrahvdroisoquinolin- 1 -yl)phenyl)-N- methylacrylamide
Figure imgf000162_0001
[00369] In a 30 mL vial, (£)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (24 mg, 0.059 mmol) was dissolved in dichloromethane (1 mL) and charged with HATU (33.9 mg, 0.089 mmol) and triethylamine (25 μΐ^, 0.178 mmol). The mixture stirred for 30 min at room temperature at which time it was charged with methylamine hydrochloride (12.05 mg, 0.178 mmol). The reaction mixture stirred at room temperature for 16 h at which time it was diluted with dichloromethane. The organic layer was washed with water and brine, passed through phase separator, and concentrated. The crude product purified by reverse phase HPLC (20-100% acetonitrile/water with 3% «-propanol modifier) to afford the title compound as a white solid (6 mg, 24%). LC MS (m/z, MH+): 417.3. ¾ NMR (400 MHz, methanol-^) δ 1.67 (s, 3 H), 2.84 (s, 3 H), 2.87-2.91 (m, 1 H), 3.06-3.12 (m, 1 H), 3.27-3.41 (m, 1 H), 3.42-3.48 (m, 1 H), 6.48-6.51 (m, 1 H), 6.52-6.67 (m, 5 H), 6.74-6.79 (m, 2 H), 7.22 (d, J= 8.6 Hz, 2 H), 7.41 (d, J= 8.6 Hz, 2 H), 7.49 (d, J= 8.6 Hz, 1 H).
Example 23
(E)-3 -(4-(2-(4-fluorophenyl)-6-hvdroxy- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 -yl)phenyl)-N-
(3.3.3 -trifluoropropyDacrylamide
Figure imgf000163_0001
[00370] (£)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l -methyl- 1 ,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (0.053 g, 0.131 mmol) was dissolved in dimethylformamide (1.314 mL). To this solution, l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-¾]pyridinium 3-oxid hexafluorophosphate (60 mg, 0.158 mmol) was added followed by the addition of 3,3 ,3 -trifluoropropan-l -amine (14 μΐ^, 0.145 mmol). The reaction vessel was charged with 4-methylmorpholine (72 μΐ^, 0.657 mmol) and was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel flash chromatography (0-50% ethyl acetate/heptanes) to obtain (ii)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide (32 mg, 48% yield).
LC MS (m/z, MH+): 499.2. ¾ NMR (400 MHz, METHANOL-^) δ 1.66 (s, 3 H), 2.47 (qt, J=10.95, 7.07 Hz, 2 H), 2.83 - 2.91 (m, 1 H), 3.02 - 3.13 (m, 1 H), 3.24 - 3.31 (m, 1 H), 3.39 - 3.48 (m, 1 H), 3.56 (t, J=7.07 Hz, 2 H), 6.48 - 6.53 (m, 1 H), 6.56 (d, J=15.66 Hz, 1 H), 6.59 - 6.67 (m, 4 H), 6.72 - 6.79 (m, 2 H), 7.22 (m, J=8.59 Hz, 2 H), 7.41 (m, J=8.59 Hz, 2 H), 7.53 (d, J=15.66 Hz, 1 H). Example 24
^-N- .2-dffluoroethyl) -(4- -(4-fluorophenyl)-6-hvdroxy-l -methyl-1.2.3.4- tetrahydroisoquinolin- 1 -vDphenvDacrylamide
Figure imgf000164_0001
[00371 ] (E)-3 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (Intermediate Fl) was suspended in
dichloromethane (2 mL) and the reaction flask was charged with HATU (52.9 mg, 0.139 mmol), triethylamine (26 μL, 0.185 mmol) and 2,2-difluoroethanamine (15.02 mg, 0.185 mmol). The reaction mixture was stirred at room temperature for 16 h. The crude reaction mixture was diluted with dichloromethane, the organic extract was washed with water and brine. The organic layer was passed through phase separator and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate/heptanes) to afford the title compound as a white solid (40 mg, 90%). LC MS (m/z, MH+): 481.4.
[00372] To a 30 mL cap vial, (£)-N-(2,2-difluoroethyl)-3-(4-(2-(4-fluorophenyl)-6- methoxy-1 -methyl- 1, 2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylamide (40 mg, 0.083 mmol) was dissolved in dichloromethane (2 mL) and cooled at -78 °C. The reaction mixture was charged with 1 M boron tribromide in dichloromethane (250 μL, 0.250 mmol). The reaction mixture was stirred at 0 °C for 30 min, cooled at -78 °C and quenched with methanol and concentrated. Volatiles were removed and the solution was basified with saturated sodium bicarbonate to pH 9. The mixture was diluted with dichloromethane and the layers were separated. The organic layer was washed with water and brine, passed through phase separator and concentrated. The crude product was purified by reverse phase HPLC (15-95%
acetonitrile/water with 3% «-propanol modifier). The title compound was obtained as a white solid (15 mg, 38%). LC MS (m/z, MH+): 467.4. ¾ NMR (400 MHz, methanol-^) δ 1.67 (s, 3 H), 2.86-2.91 (m, 1 H), 3.06-3.12 (m, 1H), 3.26-3.29 (m, 1H), 3.42-3.48 (m, 1H), 6.49-6.51 (m, 1H), 6.51-6.66 (m, 5H), 6.74-6.79 (m, 2H), 7.23 (d, J= 8.6 Hz, 2H), 7.42 (d, J= 8.6 Hz, 2H), 7.55 (d, J= 15.7 Hz, 1H).
Example 25
(E)-3 -(4-(2-(4-fluorophenyl)-6-hvdroxy- 1 -methyl- 1.2.3.4-tetrahvdroisoquinolin- 1 -yl)phenyl)-N- hydroxyacrylamide
Figure imgf000165_0001
[00373] Step 1. In a vial, (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (Intermediate Fl) (40 mg, 0.096 mmol) was dissolved in dimethylformamide (958 μΐ ). The reaction vial was charged with HATU (44 mg, 0.115 mmol), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.012 g, 0.105 mmol), and 4- methylmorpholine (53 μΕ, 0.479 mmol) and stirred overnight at rt. The reaction mixture was quenched with saturated ammonium chloride and extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to obtain (E)- 3 -(4-(2-(4-fluorophenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl)-N- ((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (45 mg, 91% yield). LC MS (m/z, MH+): 571.3. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.58 - 1.74 (m, 6 H), 1.80 - 1.95 (m, 4 H), 2.92 - 3.02 (m, 1 H), 3.15 (br. s., 1 H), 3.35 (br. s., 1 H), 3.46 (br. s., 1 H), 3.64 - 3.73 (m, 1 H), 3.81 (s, 3 H), 4.00 (t, J=9.35 Hz, 1 H), 6.55 - 6.84 (m, 8 H), 7.22 (d, J=6.06 Hz, 2 H), 7.33 - 7.48 (m, 2 H), 7.73 (d, J=15.66 Hz, 1 H).
[00374] Step 2. In a vial, (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (0.045 g, 0.087 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (120 μΐ^, 1.625 mmol) and aluminum chloride (87 mg, 0.653 mmol) were added, the reaction vial was warmed to rt and stirred for 3 h. The reaction was quenched with water and brought to pH 6 with saturated sodium bicarbonate. The aqueous layer was extracted thrice with dichloromethane, the organic layers were combined, passed through a phase separator and concentrated but afforded no desired product. The aqueous layer was acidified to pH 4 with 1 M hydrochloric acid and extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated to give crude material. The crude product was purified by reverse phase HPLC (5 mM NH4OH modifier, 15 -40% acetonitrile/water) the title compound as an orange solid (3 mg, 8% yield). LC MS (m/z, MH+): 419.2. ¾ NMR (400 MHz, METHANOL-^) δ 1.57 (s, 3 H), 2.78 (d, J=16.17 Hz, 1 H), 2.97 (d, J=8.59 Hz, 1 H), 3.25 - 3.29 (m, 1 H), 3.28 - 3.40 (m, 1 H), 6.34 - 6.44 (m, 2 H), 6.44 - 6.59 (m, 4 H), 6.62 - 6.71 (m, 2 H), 7.04 - 7.15 (m, 2 H), 7.23 - 7.34 (m, 2 H), 7.44 (d, J=14.65 Hz, 1 H).
Example 26
(£)-l-(4-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluorophenyl)-l -methyl- 1.2.3.4- tetrahvdroisoquinolin-6-ol
Figure imgf000166_0001
[00375] Step 1. To a 30 mL vial, (£)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (Intermediate Fl) (113 mg, 0.271 mmol) was dissolved in DMF (2.71 mL). To this was added HATU (124 mg, 0.325 mmol) followed by the addition of ammonium chloride (16 mg, 0.298 mmol). The reaction vial was charged with 4- methylmorpholine (149 μΐ , 1.353 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (3% «-propanol, 30-100% acetonitrile/water) to afford (iT)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1 ,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylamide (83 mg, 74% yield). LC MS (m/z, MH+): 417.3. ¾ NMR (400 MHz, METHANOL-^) δ 1.65 (s, 3 H), 2.86 - 2.94 (m, 1 H), 3.06 - 3.16 (m, 1 H), 3.22 - 3.30 (m, 1 H), 3.39 - 3.47 (m, 1 H), 3.74 (s, 3 H), 6.50 - 6.71 (m, 6 H), 6.71 - 6.79 (m, 2 H), 7.20 (d, J=8.59 Hz, 2 H,) 7.40 (d, J=8.08 Hz, 2 H), 7.52 (d, J=15.66 Hz, 1 H).
[00376] Step 2. To a 2 mL microwave vial, (iT)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l- methyl-l ,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylamide (1.201 mL, 0.120 mmol) and dibutylstannanone (2.99 mg, 0.012 mmol) were suspended in 1,2-dimethoxyethane (1.201 mL). The vial was charged with azidotrimethylsilane (48 μΐ^, 0.360 mmol) and the reaction was heated for 60 min at 180 °C under microwave radiation. LC MS showed partial conversion to product. Additional azidotrimethylsilane (96 μΐ^, 0.720 mmol) was added to the microwave vial and the reaction was microwaved for 1 h at 180 °C. LC/MS showed additional conversion to product with residual starting material remaining. The vial was charged with azidotrimethylsilane (96 μΐ^, 0.720 mmol) and the reaction was microwaved for 2 h at 180 °C. LC/MS indicated complete conversion to product. The reaction mixture was filtered to remove solids and concentrated. The crude material was purified by reverse phase HPLC (0.1% trifluoroacetic acid modifier, 10-100%) toi afford (£)- 1 -(4-(2-(2H-tetrazol-5 -yl)vinyl)phenyl)-2-(4-fluorophenyl)- 1 -methyl- 1 ,2,3 ,4- tetrahydroisoquinolin-6-ol (3.2 mg, 6% yield). LC/MS (m/z, MH+): 442.1. ¾ NMR (400 MHz, METHANOL-^) δ 1.93 - 1.96 (m, 3 H), 3.21 - 3.29 (m, 1 H), 3.38 - 3.43 (m, 1 H), 3.71 (d, J=6.57 Hz, 1 H), 3.83 (s, 3 H), 3.88 (br. s., 1 H), 6.74 - 6.82 (m, 2 H), 6.86 (d, J=2.53 Hz, 3 H), 6.97 - 7.04 (m, 2 H), 7.22 (d, J=8.59 Hz, 2 H), 7.27 (d, J=16.67 Hz, 1 H), 7.60 (d, J=8.59 Hz, 2 H), 7.68 (d, J=16.17 Hz, 1 H).
[00377] Step 3. To a vial containing, (£)-l-(4-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-2-(4- fluorophenyl)-6-methoxy-l -methyl- 1, 2,3 ,4-tetrahydroisoquino line (3.2 mg, 7.25 μιηοΐ) was dissolved in dichloromethane (72 μΕ) and cooled to 0 °C. Ethanethiol (1 μΕ, 0.135 mmol) was added followed by the addition of aluminum chloride (7.25 mg, 0.054 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and brought to pH 6 with saturated sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (acidic conditions, 30-100% acetonitrile/water) to afford (£)-l-(4-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluorophenyl)-l- methyl-l ,2,3,4-tetrahydroisoquinolin-6-ol (0.85 mg, 21% yield). LC MS m/z, MH+): 428.1. ¾ NMR (400 MHz, METHANOL-^) δ 1.69 (s, 3 H), 2.87 - 2.97 (m, 1 H), 3.10 (br. s., 1 H), 3.38 (t, J=1.52 Hz, 1 H), 3.54 (br. s., 1 H), 6.43 - 6.49 (m, 1 H), 6.52 - 6.58 (m, 2 H), 6.66 (br. s., 2 H), 6.77 (t, J=8.59 Hz, 2 H), 7.08 - 7.18 (m, 3 H), 7.45 (d, J=8.59 Hz, 2 H), 7.55 (d, J=16.67 Hz, 1 H).
Example 27
(E)-3-(4-(l-(difluoromethyl)-6-hvdroxy^
vDphenvDacrylic acid
Figure imgf000168_0001
[00378] Step 1. To a 40 mL scintallation vial was added l-bromo-4-iodobenzene (0.718 g, 2.54 mmol) and pentanes (6.68 mL, Ratio: 1.4). The reaction vial was charged with a 2.5 M n- butyllithium (1.019 mL, 2.55 mmol) solution in hexanes and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C charged with a solution of 2-(4-isopropylphenyl)-6-methoxy-3,4- dihydroisoquinolin-l (2H)-one (Intermediate A7) (0.25 g, 0.846 mmol) in tetrahydrofuran (4.77 mL). The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was then quenched with water (10 mL) and ethyl acetate (10 mL) and warmed to rt perchloric acid (0.219 ml, 3.64 mmol, 70% in water) was added and the reaction mixture stirred for 30 min at rt. The reaction was then diluted with water and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude iminium intermediate which was used crude in the next step.
[00379] Step 2. Iminium intermediate was dissolved in dimethylformamide (7 mL, 0.12
M) and potassium fluoride (0.148 g, 2.54 mmol) was added. A dimethylformamide (4.5 mL, 0.18 M) solution of ethyl 2,2-difluoro-2-(trimethylsilyl)acetate (0.332 g, 1.693 mmol) was added dropwise and the reaction stirred at rt for 30 min. The reaction was quenched with saturated sodium bicarbonate and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-10% ethylacetate/ heptanes) to afford ethyl 2-(l-(4-bromophenyl)-2- (4-isopropylphenyl)-6-methoxy-l,2,3,4-tetrahydroisoquinolin-l-yl)-2,2-difluoroacetate (362 mg, 77 % yield) as a yellow oil.
[00380] LC/MS (MH+): 559.8 1H NMR (400 MHz, CHLOROFORM-d) δ 1.05 (t,
J=7.33 Hz, 3 H), 1.09 - 1.18 (m, 6 H), 2.69 - 2.87 (m, 2 H), 2.97 (ddd, J=15.03, 9.98, 4.29 Hz, 1 H), 3.14 - 3.27 (m, 1 H), 3.40 - 3.51 (m, 1 H), 3.76 (s, 3 H), 4.00 (q, J=7.07 Hz, 2 H), 6.60 - 6.69 (m, 4 H), 6.85 (d, J=8.59 Hz, 2 H), 6.90 (dd, J=8.34, 3.79 Hz, 1 H), 7.15 (d, J=8.59 Hz, 2 H), 7.27 (d, J=8.59 Hz, 2 H) 19F NMR (376 MHz, CHLOROFORM-d) δ -100.37 - -99.10 (m, 1 F), -98.23 - -96.89 (m, 1 F).
[00381] Step 3. Ethyl 2-(l-(4-bromophenyl)-2-(4-isopropylphenyl)-6-methoxy-l,2,3,4- tetrahydroisoquinolin-l-yl)-2,2-difluoroacetate (0.362 g, 0.648 mmol) was dissolved in 1,4- dioxanes (6.48 mL). To this was added 1 M lithium hydroxide (1.621 mL, 1.621 mmol) and the reaction was heated to 40 °C for 2 h. LC MS showed the reaction was complete and the reaction was acidified to pH 1 with 1 N hydrochloric acid and extracted with DCM three times. The organic layers were combined, passed through a phase separator and concentrated to afford product 2-(l-(4-bromophenyl)-2-(4-isopropylphenyl)-6-methoxy-l,2,3,4-tetrahydroisoquinolin-l- yl)-2,2-difluoroacetic acid (346 mg, quantitative) as a yellow solid. The material was forward without further purification. LC MS (MH+): 531.8 1H NMR (400 MHz, CHLOROFORM-d) δ 0.98 - 1.08 (m, 6 H), 2.61 - 2.74 (m, 1 H), 2.74 - 2.85 (m, 1 H), 3.04 (d, J=8.08 Hz, 1 H), 3.22 - 3.34 (m, 1 H), 3.34 - 3.44 (m, 1 H), 3.64 - 3.70 (m, 3 H), 6.40 (d, J=6.57 Hz, 2 H), 6.54 - 6.66 (m, 2 H), 6.81 (d, J=8.59 Hz, 2 H), 6.89 (dd, J=8.59, 5.56 Hz, 2 H), 7.21 (d, J=8.08 Hz, 2 H), 7.25 - 7.30 (m, 1 H). 19F NMR (376 MHz, CHLOROFORM-d) δ -111.97 - -104.47 (m, 1 F), -99.55 - - 94.12 (m, 1 F).
[00382] Step 4. In a vial, 2-(l-(4-bromophenyl)-2-(4-isopropylphenyl)-6-methoxy- l,2,3,4-tetrahydroisoquinolin-l-yl)-2,2-difluoroacetic acid (0.1 g, 0.189 mmol) was dissolved in l-methyl-2-pyrrolidinone (9.43 mL) and cesium fluoride (0.143 g, 0.943 mmol) was added. The reaction was put under nitrogen and heated to 192 °C for 24 h. After cooling to rt, water was added to the reaction and the reaction mixture was extracted with diethyl ether three times. The organic layers were combined, passed through a phase separator and concentrated to give crude material which was purified by silica gel chromatography (0-10% ethyl acetate/ heptanes) to afford product 1 -(4-bromophenyl)- 1 -(difluoromethyl)-2-(4-isopropylphenyl)-6-methoxy- 1 ,2,3 ,4- tetrahydroisoquinoline(73 mg, 80% yield) as a yellow oil. LC/MS (MH+): 487.8. ¾ NMR (400 MHz, CHLOROFORM-d) δ 1.07 - 1.13 (m, 6 H), 2.71 (dt, J=13.77, 7.01 Hz, 1 H), 2.86 - 3.07 (m, 2 H), 3.29 (dt, J=11.37, 5.43 Hz, 1 H), 3.60 (ddd, J=11.75, 6.95, 5.05 Hz, 1 H), 3.71 (s, 3 H), 6.21 (s, 1 H), 6.44 - 6.52 (m, 2 H), 6.59 (dd, J=8.84, 2.78 Hz, 1 H), 6.65 (d, J=2.53 Hz, 1 H), 6.79 - 6.94 (m, 5 H), 7.20 - 7.28 (m, 2 H). 19F NMR (376 MHz, CHLOROFORM-d) δ -126.77 - - 125.26 (m, 1 F), -121.73 - -120.22 (m, 1 F).
[00383] Step 5. To a 40 mL vial was added 1 -(4-bromophenyl)- l-(difluoromethyl)-2-
(4-isopropylphenyl)-6-methoxy-l,2,3,4-tetrahydroisoquinoline (0.073 g, 0.150 mmol),
Pd(PPh3)2Cl2 (0.053 g, 0.075 mmol), dimethylformamide (1.001 mL), triethylamine (0.105 mL, 0.750 mmol), and methylacrylate (0.270 ml, 3.00 mmol). The reaction mixture was heated for 1 hour at 130 oC, LC/MS indicates conversion to product. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford (E)-methyl 3-(4-(l-(difluoromethyl)-2- (4-isopropylphenyl)-6-methoxy-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (11 mg, 15% yield) as a yellow oil. LC/MS (MH+): 492.1. ¾ NMR (400 MHz, CHLOROFORM-d) δ 1.17 - 1.21 (m, 6 H), 2.81 (dt, J=13.89, 6.69 Hz, 1 H), 3.00 - 3.18 (m, 2 H), 3.35 - 3.48 (m, 1 H), 3.66 - 3.78 (m, 1 H), 3.81 - 3.86 (m, 6 H), 6.34 - 6.53 (m, 2 H), 6.56 - 6.66 (m, 2 H), 6.70 (dd, J=8.84, 2.78 Hz, 1 H), 6.78 (d, J=2.53 Hz, 1 H), 6.90 - 7.00 (m, 3 H), 7.17 (d, J=8.08 Hz, 2 H), 7.39 (d, J=8.59 Hz, 2 H), 7.69 (d, J=16.17 Hz, 1 H). 19F NMR (376 MHz, CHLOROFORM-d) δ -126.53 - -125.58 (m, 1 F), -121.42 - -120.38 (m, 1 F). [00384] Step 6. (E)-methyl 3-(4-(l-(difluoromethyl)-2-(4-isopropylphenyl)-6-methoxy-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.011 g, 0.022 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. To this was added aluminum chloride (0.024 g, 0.179 mmol) followed by the addition of ethanethiol (0.033 mL, 0.448 mmol). The reaction was warmed to rt and stirred for 2 h. The reaction was quenched with saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to afford product (E)-methyl 3-(4- ( 1 -(difluoromethyl)-6-hydroxy-2-(4-isopropylphenyl)- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 - yl)phenyl)acrylate (9 mg, 84% yield) as a yellow oil. Reaction was carried on without purification. LC MS (MH+): 478.5 1H NMR (400 MHz, CHLOROFORM-d) δ 1.04 - 1.12 (m, 6 H), 2.71 (dt, J=13.77, 7.01 Hz, 1 H), 2.91 - 3.03 (m, 2 H), 3.27 - 3.30 (m, 1 H), 3.50 - 3.69 (m, 1 H), 3.73 (s, 3 H), 6.20 - 6.43 (m, 2 H), 6.48 (d, J=8.59 Hz, 2 H), 6.55 (dd, J=8.59, 2.53 Hz, 1 H), 6.66 (d, J=2.53 Hz, 1 H), 6.79 (dd, J=8.59, 3.54 Hz, 1 H), 6.84 (d, J=8.59 Hz, 2 H), 7.07 (d, J=7.58 Hz, 2 H), 7.29 (d, J=8.59 Hz, 2 H), 7.58 (d, J=16.17 Hz, 1 H).
[00385] Step 7. (E)-methyl 3-(4-(l-(difluoromethyl)-6-hydroxy-2-(4-isopropylphenyl)-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.009 g, 0.019 mmol) was dissolved in 1,4- dioxanes (1 mL) and lithium hydroxide (0.188 mL, 0.188 mmol) was added. The reaction was heated to rt for 3 h. The reaction was then quenched with aqueous 1 N hydrochloric acid and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via basic HPLC (5 mM NH4OH, 15-40% acetonitrile in water) to afford product (E)-3-(4-(l-(difluoromethyl)-6-hydroxy- 2-(4-isopropylphenyl)-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (3.8 mg, 43.5% yield) as a white solid. LC MS (MH+): 464.5. ¾ NMR (400 MHz, METHANOL-d4) δ 1.05 (dd, J=6.82, 2.27 Hz, 6 H), 2.66 (dt, J=13.77, 7.01 Hz, 1 H), 2.82 - 2.97 (m, 2 H), 3.30 (dd, J=11.87, 5.31 Hz, 1 H), 3.54 (d, J=6.06 Hz, 1 H), 6.31 - 6.67 (m, 7 H), 6.82 (d, J=8.59 Hz, 2 H), 7.04 (d, J=7.58 Hz, 2 H), 7.28 - 7.37 (m, 2 H), 7.47 (d, J=15.66 Hz, 1 H). 19F NMR (376 MHz,
METHANOLS) δ -128.08 - -127.17 (m, 1 F), -122.75 - -121.85 (m, 1 F). Example 27a
(S JV3-(4-(l-(difluoromethylV6-hvdroxy-2-^
vDphenvDacrylic acid
Figure imgf000172_0001
Example 27b
(RJ)-3-(4-(l-(difluoromethyl)-6-hvdroxy-2-(4-isopropylphenyl)-1.2.3.4 etrahvdroisoquinolin-l- vDphenvDacrylic acid
Figure imgf000172_0002
[00386] Preparative Chiral AD-H column (40% isopropanol in C02); retention times of the enantiomers on chiral AD-H column: phase:5-55% isopropanol in CO2: 2.71 min and 3.11 min. Example 27b is 2.71 min and Example 27a is 3.11 min.
Example 28
(E)-2-(4-fluorophenyl)-l-methyl-l-(4-(2-(l -propyl- lH-tetrazol-5-yl)vinyl)phenyl)-1.2.3.4- tetrahvdroisoquinolin-6-ol
Figure imgf000173_0001
[00387] To a 20 mL microwave vial was added l-(4-bromophenyl)-2-(4-fluorophenyl)-
6-methoxy-l -methyl- 1, 2,3 ,4-tetrahydroisoquinoline (400 mg, 0.938 mmol), Pd(PPh3)2Cl2 (99 mg, 0.141 mmol), dimethylformamide (6.26 ml), triethylamine (654 μΐ^, 4.69 mmol), and acrylonitrile (618 μΐ^, 9.38 mmol). The reaction mixture was microwaved for 1 h at 150 °C, LC MS indicated complete conversion to product. The reaction mixture was quenched with water and extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-20% ethyl acetate/heptanes) to afford product (173 mg, 0.434 mmol, 46% yield). LC/MS (m/z, MH+): 399.2. 'HNMR (400 MHz, CHLOROFORM-^ δ 1.69 - 1.75 (m, 3 H), 2.93 - 3.03 (m, 1 H), 3.12 - 3.25 (m, 1 H), 3.28 - 3.39 (m, 1 H), 3.47 (td, J=8.08, 4.55 Hz, 1 H), 3.80 - 3.84 (m, 3 H), 5.86 (d, J=16.67 Hz, 1 H), 6.59 - 6.85 (m, 7 H), 7.25 - 7.36 (m, 3 H), 7.40 (d, J=16.67 Hz, 1 H), 7.71 (d, J=8.59 Hz, 1 H).
[00388] To a microwave vial, (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylonitrile (173 mg, 0.434 mmol) was dissolved in 1,2-dimethoxyethane (4.34 mL). Dibutylstannanone (10.81 mg, 0.043 mmol) and
azidotrimethylsilane (346 μΐ^, 2.60 mmol) were added and the reaction mixture was microwaved for 2 h at 180 °C. The reaction mixture was filtered to remove solids and concentrated; the material was not purified. LC/MS (m/z, MH+): 442.2.
[00389] (E)-l-(4-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluorophenyl)-6-methoxy-l- methyl- 1,2,3 ,4-tetrahydroisoquinoline (0.040 g, 0.091 mmol) was dissolved in DMF (1.812 mL); and potassium carbonate (38 mg, 0.272 mmol) was added followed by 1-iodopropane (9.72 μΐ^, 0.100 mmol). The reaction was stirred at rt overnight when it was quenched with saturated ammonium chloride. The reaction mixture was extracted thrice with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated to afford crude product. The crude material was purified by reverse phase HPLC (5 mM NH4OH modifier, 15- 40% acetonitrile/water) to afford (E)-2-(4-fluorophenyl)-6-methoxy-l-methyl-l-(4-(2-(2-propyl- 2H-tetrazol-5-yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinoline (12.7 mg, 29% yield) and (E)-2-(4- fluorophenyl)-6-methoxy- 1 -methyl- 1 -(4-(2-( 1 -propyl- 1 H-tetrazol-5 -yl)vinyl)phenyl)- 1 ,2,3 ,4- tetrahydroisoquinoline (4.4 mg, 10% yield).
[00390] (E)-2-(4-fluorophenyl)-6-methoxy-l -methyl- 1 -(4-(2-(2-propyl-2H-tetrazol-5 - yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinoline: LC/MS (m/z, MH+): 484.2. ¾ NMR (400 MHz, CHLOROFORM-^ δ 0.91 (t, J=7.33 Hz, 3 H), 1.62 (br. s., 3 H), 1.95 - 2.05 (m, 2 H), 2.89 (br. s., 1 H), 3.07 (br. s., 1 H), 3.28 (br. s., 1 H), 3.39 (br. s., 1 H), 3.72 (s, 3 H), 4.50 (t, J=7.33 Hz, 2 H), 6.61 (br. s., 4 H), 6.68 (br. s., 3 H), 6.99 - 7.08 (m, 2 H), 7.14 (br. s., 1 H), 7.34 (d, J=8.08 Hz, 2 H), 7.61 (d, J=16.67 Hz, 1 H).
[00391] (E)-2-(4-fluorophenyl)-6-methoxy-l-methyl-l-(4-(2-(l-propyl-lH-tetrazol-5- yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinoline: LC/MS (m/z, MH+): 484.2. ¾ NMR (400 MHz, CHLOROFORM-^ δ 0.87 - 0.96 (m, 3 H), 1.63 (br. s., 3 H), 1.90 (dq, J=14.65, 7.41 Hz, 2 H), 2.91 (br. s., 1 H), 3.08 (br. s., 1 H), 3.27 (br. s., 1 H), 3.40 (br. s., 1 H), 3.72 (s, 3 H), 4.24 - 4.31 (m, 2 H), 5.34 (d, J=12.13 Hz, 1 H), 6.52 - 6.78 (m, 7 H), 7.02 (s, 1 H), 7.37 (d, J=8.59 Hz, 2 H), 7.56 - 7.62 (m, 2 H), 7.83 (d, J=15.66 Hz, 1 H).
[00392] (E)-2-(4-fluorophenyl)-6-methoxy-l-methyl-l-(4-(2-(l-propyl-lH-tetrazol-5- yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinoline (4.4 mg, 9.10 μιηοΐ) was dissolved in dichloromethane (2 mL) and cooled to 0°C. Ethanethiol (13 μΕ, 0.170 mmol) was added followed by the addition of aluminum chloride (9.10 mg, 0.068 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and brought to a pH 6 with saturated solution of sodium bicarbonate. The aqueous layer was extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (5mM NH4OH modifier, 35-60% acetonitrile/water) to afford the title compound as a white solid (1.2 mg, 28% yield). LC/MS (m/z, MH+): 470.5. ¾ NMR (400 MHz, DMSO-< ) δ 0.84 - 0.90 (m, 3 H), 1.62 (d, J=3.54 Hz, 3 H), 1.83 (dd, J=14.40, 7.33 Hz, 2 H), 2.82 (br. s., 1 H), 3.09 (br. s., 1 H), 3.24 (s, 1 H), 3.41 (br. s., 1 H), 4.50 (t, J=7.07 Hz, 2 H), 5.83 (d, J=12.13 Hz, 1 H), 6.47 (d, J=8.08 Hz, 1 H), 6.51 - 6.66 (m, 4 H), 6.85 - 6.93 (m, 2 H), 7.27 - 7.40 (m, 2 H), 7.69 (t, J=8.59 Hz, 2 H), 7.76 (d, J=16.17 Hz, 1 H).
Example 29
(E)-2-(4-fluorophenyl)-l -methyl- 1-(4-(2-(2^
tetrahydroisoquinolin-6-ol
Figure imgf000175_0001
[00393] To a 20 mL microwave vial was added l-(4-bromophenyl)-2-(4-fluorophenyl)-
6-methoxy-l -methyl- 1, 2,3 ,4-tetrahydroisoquinoline (400 mg, 0.938 mmol), Pd(PPh3)2Cl2 (99 mg, 0.141 mmol), dimethylformamide (6.26 ml), triethylamine (654 μΐ^, 4.69 mmol), and acrylonitrile (618 μΐ^, 9.38 mmol). The reaction mixture was microwaved for 1 h at 150 °C, LC MS indicated complete conversion to product. The reaction mixture was quenched with water and extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-20% ethyl acetate/heptanes) to afford product (173 mg, 0.434 mmol, 46% yield). LC/MS (m/z, MH+): 399.2. 'HNMR (400 MHz, CHLOROFORM-^ δ 1.69 - 1.75 (m, 3 H), 2.93 - 3.03 (m, 1 H), 3.12 - 3.25 (m, 1 H), 3.28 - 3.39 (m, 1 H), 3.47 (td, J=8.08, 4.55 Hz, 1 H), 3.80 - 3.84 (m, 3 H), 5.86 (d, J=16.67 Hz, 1 H), 6.59 - 6.85 (m, 7 H), 7.25 - 7.36 (m, 3 H), 7.40 (d, J=16.67 Hz, 1 H), 7.71 (d, J=8.59 Hz, 1 H).
[00394] To a microwave vial, (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylonitrile (173 mg, 0.434 mmol) was dissolved in 1,2-dimethoxyethane (4.34 mL). Dibutylstannanone (10.81 mg, 0.043 mmol) and azidotrimethylsilane (346 μΐ^, 2.60 mmol) were added and the reaction mixture was microwaved for 2 h at 180 °C. The reaction mixture was filtered to remove solids and concentrated; the material was not purified. LC MS (m/z, MH+): 442.2.
[00395] (E)-l-(4-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluorophenyl)-6-methoxy-l- methyl-l,2,3,4-tetrahydroisoquinoline (0.040 g, 0.091 mmol) was dissolved in DMF (1.812 mL); and potassium carbonate (38 mg, 0.272 mmol) was added followed by 1-iodopropane (9.72 μΐ^, 0.100 mmol). The reaction was stirred at rt overnight when it was quenched with saturated ammonium chloride. The reaction mixture was extracted thrice with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated to afford crude product. The crude material was purified by reverse phase HPLC (5 mM NH4OH modifier, 15- 40% acetonitrile/water) to afford (E)-2-(4-fluorophenyl)-6-methoxy-l-methyl-l-(4-(2-(2-propyl- 2H-tetrazol-5-yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinoline (12.7 mg, 29% yield) and (E)-2-(4- fluorophenyl)-6-methoxy- 1 -methyl- 1 -(4-(2-( 1 -propyl- 1 H-tetrazol-5 -yl)vinyl)phenyl)- 1 ,2,3 ,4- tetrahydroisoquinoline (4.4 mg, 10% yield).
[00396] (E)-2-(4-fluorophenyl)-6-methoxy-l -methyl- 1 -(4-(2-(2-propyl-2H-tetrazol-5 - yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinoline: LC MS (m/z, MH+): 484.2. ¾ NMR (400 MHz, CHLOROFORM-^ δ 0.91 (t, J=7.33 Hz, 3 H), 1.62 (br. s., 3 H), 1.95 - 2.05 (m, 2 H), 2.89 (br. s., 1 H), 3.07 (br. s., 1 H), 3.28 (br. s., 1 H), 3.39 (br. s., 1 H), 3.72 (s, 3 H), 4.50 (t, J=7.33 Hz, 2 H), 6.61 (br. s., 4 H), 6.68 (br. s., 3 H), 6.99 - 7.08 (m, 2 H), 7.14 (br. s., 1 H), 7.34 (d, J=8.08 Hz, 2 H), 7.61 (d, J=16.67 Hz, 1 H).
[00397] (E)-2-(4-fluorophenyl)-6-methoxy-l-methyl-l-(4-(2-(l-propyl-lH-tetrazol-5- yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinoline: LC/MS (m/z, MH+): 484.2. ¾ NMR (400 MHz, CHLOROFORM-^ δ 0.87 - 0.96 (m, 3 H), 1.63 (br. s., 3 H), 1.90 (dq, J=14.65, 7.41 Hz, 2 H), 2.91 (br. s., 1 H), 3.08 (br. s., 1 H), 3.27 (br. s., 1 H), 3.40 (br. s., 1 H), 3.72 (s, 3 H), 4.24 - 4.31 (m, 2 H), 5.34 (d, J=12.13 Hz, 1 H), 6.52 - 6.78 (m, 7 H), 7.02 (s, 1 H), 7.37 (d, J=8.59 Hz, 2 H), 7.56 - 7.62 (m, 2 H), 7.83 (d, J=15.66 Hz, 1 H).
[00398] (E)-2-(4-fluorophenyl)-6-methoxy- 1 -methyl- 1 -(4-(2-(2-propyl-2H-tetrazol-5 - yl)vinyl)phenyl)-l, 2,3 ,4-tetrahydroisoquino line (12.7 mg, 0.026 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0°C. Ethanethiol (36 μΕ, 0.490 mmol) was added followed by aluminum chloride (26.3 mg, 0.197 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and brought to a pH 6 with saturated sodium bicarbonate. The aqueous layer was extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (5 mM NH4OH modifier, 45-70% acetonitrile/water) to afford the title compound as a white solid (1.5 mg, 12% yield). LC/MS (m/z, MH+): 470.5. ¾ NMR (400 MHz, DMSO-t/6) δ 0.88 (t, J=7.33 Hz, 3 H), 1.61 (s, 3 H), 1.96 (sxt, J=7.28 Hz, 2 H), 2.81 (d, J=16.67 Hz, 1 H), 3.02 - 3.12 (m, 1 H), 3.21 - 3.29 (m, 1 H), 3.38 - 3.47 (m, 1 H), 4.64 (t, J=6.82 Hz, 2 H), 6.44 - 6.50 (m, 1 H), 6.51 - 6.66 (m, 4 H), 6.84 - 6.91 (m, 2 H), 7.25 (d, J=8.08 Hz, 2 H), 7.29 (d, J=16.67 Hz, 1 H), 7.57 - 7.66 (m, 3 H).
Example 30
(E)-l-(4-(2-(2-ethyl-2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluorophenyl)-l-methyl-1.2.3.4- tetrahydroisoquinolin-6-ol
Figure imgf000177_0001
[00399] (E)-l-(4-(2-(2-ethyl-2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluorophenyl)-6- methoxy-1 -methyl- 1, 2,3 ,4-tetrahydroisoquinoline (Intermediate Rl) (10 mg, 0.021 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (32 μΐ , 0.426 mmol) was added followed by aluminum chloride (22.72 mg, 0.170 mmol). The reaction was then warmed to rt and stirred for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (0.1% TFA modifier, 35-60% acetonitrile/water) to afford product (3.9 mg, 40% yield) as a white solid. LC/MS (m/z, MH+): 456.4. ¾ NMR (400 MHz, METHANOL-^) δ 1.53 (t, J=7.33 Hz, 3 H), 1.76 (br. s., 3 H), 2.96 - 3.08 (m, 1 H), 3.12 - 3.19 (m, 1 H), 3.51 (br. s., 1 H), 3.65 (br. s., 1 H), 4.61 (q, J=7.24 Hz, 2 H), 6.47 - 6.54 (m, 1 H), 6.56 - 6.63 (m, 2 H), 6.72 (br. s., 2 H), 6.80 - 6.90 (m, 2 H), 7.06 - 7.17 (m, 3 H), 7.45 (d, J=8.08 Hz, 2 H), 7.59 (d, J=16.17 Hz, 1 H).
Example 31
(E)- 1 -(4-(2-(2-butyl-2H-tetrazol-5 -yl)vinyl)phenyl)-2-(4-fluorophenyl)- 1 -methyl- 1.2.3.4- tetrahvdroisoquinolin-6-ol
Figure imgf000178_0001
[00400] (E)-l-(4-(2-(2-butyl-2H-tetrazol-5-yl)vinyl)phenyl)-2-(4-fluorophenyl)-6- methoxy-1 -methyl- 1, 2,3 ,4-tetrahydroisoquinoline (Intermediate R2) (18 mg, 0.036 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (54 μΐ , 0.723 mmol) was added followed by aluminum chloride (38.6 mg, 0.289 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (0.1% TFA modifier, 35-60% acetonitrile/water) to afford product (5.1 mg, 27% yield) as a white solid. LC/MS (m/z, MH+): 442.1. ¾ NMR (400 MHz, METHANOL-^) δ 0.85
- 0.92 (m, 3 H), 1.27 (dq, J=14.84, 7.35 Hz, 2 H), 1.79 - 1.86 (m, 3 H), 1.91 (dt, J=14.78, 7.01 Hz, 2 H), 3.11 (d, J=16.67 Hz, 2 H), 3.65 (br. s., 1 H), 3.79 (br. s., 1 H), 4.58 (t, J=6.82 Hz, 2 H), 6.50
- 6.57 (m, 1 H), 6.57 - 6.64 (m, 2 H), 6.77 (br. s., 2 H), 6.92 (t, J=8.08 Hz, 2 H), 7.06 (d, J=8.08 Hz, 2 H), 7.15 (d, J=16.67 Hz, 1 H), 7.47 (d, J=8.59 Hz, 2 H), 7.59 (d, J=16.67 Hz, 1 H). Example 32
(E)-2-(4-fluorophenyl)- 1 -methyl- 1 -(4-(2-(l -methyl- 1 H-tetrazol-5 -yl)vinyl)phenyl)- 1.2.3.4- tetrahvdroisoquinolin-6-ol
Figure imgf000179_0001
[00401] (E)-2-(4-fluorophenyl)-6-methoxy-l-methyl-l-(4-(2-(l-methyl-lH-tetrazol-5- yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinoline (Intermediate R3) (5 mg, 10.98 μιηοΐ) was dissolved in dichloromethane (2 mL) and cooled to 0°C. Ethanethiol (0.015 mL, 0.205 mmol) was added followed by aluminum trichloride (10.98 mg, 0.082 mmol). The reaction was warmed to room temperature and stirred at room temperature for 3 h. The reaction was quenched with water and brought to pH of 6 with saturated sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via by reverse phase HPLC (0.1% TFA modifier, 25-50% acetonitrile/water) to afford product (1 mg, 20% yield) as a white film. LC MS (m/z, MH+): 442.3. ¾ NMR (400 MHz, METHANOL-^) δ 1.72 (s, 3 H), 3.02 (d, J=7.07 Hz, 1 H), 3.09 - 3.17 (m, 1 H), 3.47 (br. s., 1 H), 3.60 (d, J=19.20 Hz, 1 H), 3.74 (s, 3 H), 6.45 - 6.52 (m, 2 H), 6.52 - 6.58 (m, 2 H), 6.70 (br. s., 2 H), 6.87 (t, J=8.59 Hz, 2 H), 6.97 - 7.07 (m, 4 H), 7.19 (d, J=12.13 Hz, 1 H.
Example 33
(E)-2-(4-fluorophenyl)- 1 -methyl- 1 -(4-(2-(2-methyl-2H-tetrazol-5 -yl)vinyl)phenyl)- 1.2.3.4- tetrahvdroisoquinolin-6-ol
Figure imgf000180_0001
[00402] (E)-2-(4-fluorophenyl)-6-methoxy-l -methyl- 1 -(4-(2-(2-methyl-2H-tetrazol-5 - yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinoline (Intermediate R3) (13 mg, 0.029 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0°C. Ethanethiol (0.039 mL, 0.532 mmol) was added followed by the addition of aluminum trichloride (28.5 mg, 0.214 mmol). The reaction was warmed to room temperature and stirred for 3 h. The reaction was quenched with water and brought to pH of 6 with saturated sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via SFC (10% isopropanol with 10 mM NH4OH in carbon dioxide) to afford product (4 mg, 29% yield). LC MS (m/z, MH+): 442.2. ¾ NMR (400 MHz, METHANOL-^) δ 1.57 (s, 3 H), 2.74 - 2.83 (m, 1 H), 2.94 - 3.04 (m, 1 H), 3.13 - 3.19 (m, 1 H), 3.31 - 3.40 (m, 1 H), 4.24 - 4.28 (m, 3 H), 6.37 - 6.43 (m, 1 H), 6.46 - 6.61 (m, 4 H), 6.63 - 6.70 (m, 2 H), 7.03 - 7.08 (m, 1 H), 7.11 - 7.15 (m, 2 H), 7.32 - 7.40 (m, 2 H), 7.55 (d, J=16.17 Hz, 1 H).
Example 34
(EV2-( -fluorophenylVl -methy ^
yl)vinyl)phenyl)-1.2.3.4-tetrahvdroisoquinolin-6-ol
Figure imgf000181_0001
[00403] (E)-2-(4-fluorophenyl)-6-methoxy-l -methyl- 1-(4-(2-(2-(3 ,3,3 -trifluoropropyl)-
2H-tetrazol-5-yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinoline (Intermediate R4) (8.6 mg, 0.016 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0°C. Ethanethiol (0.024 mL, 0.320 mmol) was added followed by aluminum chloride (17.07 mg, 0.128 mmol). The reaction was warmed to room temperature and stirred at for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by reverse phase HPLC (0.1% TFA modifier, 45-70% acetonitrile in water) to afford product (5.4 mg, 39% yield) as a white solid. LC MS (m/z, MH+): 524.5. ¾ NMR (400 MHz, METHANOL-^) δ ppm 1.75 (s, 3 H), 2.86 - 3.07 (m, 3 H), 3.14 (br. s., 1 H), 3.51 (br. s., 1 H), 3.63 (br. s., 1 H), 4.87 (t, J=6.57 Hz, 2 H), 6.46 - 6.53 (m, 1 H), 6.55 - 6.61 (m, 2 H), 6.72 (br. s., 2 H), 6.80 - 6.89 (m, 2 H), 7.09 (m, J=8.08 Hz, 2 H), 7.14 (d, J=16.67 Hz, 1 H), 7.45 (m, J=8.08 Hz, 2 H), 7.61 (d, J=16.67 Hz, 1 H). Example 35
(E)-2-(4-fluorophenyl)- 1 -methyl- 1 -(4-(2-( 1 -propyl- lH-imidazol-4-yl)vinyl)phenyl)- 1.2.3.4- tetrahvdroisoquinolin-6-ol
Figure imgf000182_0001
[00404] To a 30 mL vial, 4-vinyl-lH-imidazole (400 mg, 4.25 mmol) was dissolved in
THF (2 mL) and the solution was cooled to 0 °C. The reaction vial was charged with 60% sodium hydride in mineral oil (170 mg, 4.25 mmol) and the reaction mixture stirred for 10 min at 0 °C. To the mixture was added 1-iodopropane (0.415 mL, 4.25 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride (15 mL) and diluted with dichloromethane (25 mL). The organic phases were combined, passed through a phase separator and concentrated to afford the crude product. The crude material was purified by column chromatography (1-10% dichloromethane/methanol) to afford a mixture of l-propyl-4-vinyl-lH-imidazole and l-propyl-5-vinyl-lH-imidazole (511 mg, 3.72: 1). l-propyl-4-vinyl-lH-imidazole: ¾ NMR (400 MHz, CHLOROFORM-^ δ 0.83 - 0.91 (m, 3 H), 1.66 - 1.82 (m, 2 H), 3.74 - 3.90 (m, 2 H), 5.11 (dd, J=11.12, 1.52 Hz, 1 H), 5.73 - 5.87 (m, 1 H), 6.52 (dd, J=17.18, 11.12 Hz, 1 H), 6.80 (s, 1 H), 7.58 (s, 1 H). l-propyl-5-vinyl-lH-imidazole: ¾ NMR (400 MHz, CHLOROFORM-^ δ 0.78 - 0.93 (m, 3 H), 1.63 - 1.82 (m, 2 H), 3.76 - 3.90 (m, 2 H), 5.22 (d, J=11.12 Hz, 1 H), 5.57 (d, J=17.18 Hz, 1 H), 6.41 (dd, J=17.43, 11.37 Hz, 1 H), 7.17 (s, 1 H), 7.63 (s, 1 H).
[00405] To a microwave vial, l-(4-bromophenyl)-2-(4-fluorophenyl)-6-methoxy-l- methyl- 1, 2,3 ,4-tetrahydroisoquinoline (0.13 g, 0.305 mmol) was dissolved in DMF (2 mL) and triethylamine (213 μΐ^, 1.525 mmol). To the solution was added a mixture of 1 -propyl -4-vinyl- lH-imidazole and l-propyl-5 -vinyl- lH-imidazole (125 mg, 0.915 mmol) and Pd(PPh3)2Cl2 (0.032 g, 0.046 mmol). The system was flushed with nitrogen and heated at 150 °C for 1 h under microwave radiation. The mixture was cooled to room temperature and quenched with saturated ammonium chloride. The reaction mixture was extracted with dichloromethane (3 x), the organic layers were combined, passed through a phase separator, and concentrated to give crude material. The crude material was purified by silica gel chromatography (0-75% ethyl acetate/heptanes) to afford mixture of two isomers (141 mg, 0.293 mmol, 96% yield). LC MS (m/z, MH+): 482.1.
[00406] A mixture of (E)-2-(4-fluorophenyl)-6-methoxy-l-methyl-l-(4-(2-(l-propyl- lH-imidazol-4-yl)vinyl)phenyl)- 1,2,3 ,4-tetrahydroisoquinoline and (E)-2-(4-fluorophenyl)-6- methoxy- 1 -methyl- 1 -(4-(2-( 1 -propyl- 1 H-imidazol-5-yl)vinyl)phenyl)- 1 ,2,3 ,4- tetrahydroisoquinoline (0.141 g, 0.293 mmol) was dissolved in dichloromethane (2.93 mL) and cooled to 0 °C. Ethanethiol (404 μΐ , 5.46 mmol) was added followed by aluminum chloride (293 mg, 2.196 mmol). The reaction was warmed to room temperature and stirred for 3 h. The reaction was quenched with water and brought to pH 6 with saturated sodium bicarbonate. The aqueous layer was extracted thrice with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-75% ethyl acetate/heptanes) to afford a mixture of the two isomer products (69 mg). This mixture was urified via SFC (25% methanol with 10 mM ammonium hydroxide in carbon dioxide) to provide one single isomer (E)-2-(4-fluorophenyl)- 1 -methyl- l-(4-(2-(l -propyl- lH-imidazol-4-yl)vinyl)phenyl)-l,2,3,4-tetrahydroisoquinolin-6-ol as a white solid (17 mg, 12% yield). LC MS (m/z, MH+): 468.2. ¾ NMR (400 MHz, METHANOL-^) δ 0.86 (t, J=7.33 Hz, 3 H), 1.56 (s, 3 H), 1.78 (sxt, J=7.28 Hz, 2 H), 2.73 - 2.84 (m, 1 H), 2.93 - 3.05 (m, 1 H), 3.09 - 3.17 (m, 1 H), 3.31 - 3.40 (m, 1 H), 3.96 (t, J=7.07 Hz, 2 H), 5.39 (s, 1 H), 6.37 - 6.44 (m, 1 H), 6.45 - 6.61 (m, 5 H), 6.62 - 6.70 (m, 2 H), 6.85 - 6.95 (m, 1 H), 7.00 - 7.11 (m, 3 H), 7.27 (d, J=8.08 Hz,
2 H). Example 36
(E)-2-(4-fluorophenyl)- 1 -methyl- 1-(4-(2-(5 -methyl- 1.3.4-oxadiazol-2-yl)vinyl)phenyl)- 1.2.3.4- tetrahvdroisoquinolin-6-ol
Figure imgf000184_0001
[00407] (E)-2-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)styryl)-5 -methyl- 1,3 ,4-oxadiazole (Intermediate N7) (0.026 g, 0.057 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0°C. Ethanethiol (0.084 mL, 1.142 mmol) was added followed by aluminum trichloride (0.061 g, 0.457 mmol). The reaction was warmed to room temperature and stirred for three hours. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with
dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by reverse phase HPLC (5 mM NH4OH modifier, 35-60% acetonitrile/water) to afford product (9.6 mg, 38% yield) as a white solid. LC MS (m/z,
MH+): 442.1. ¾ NMR (400 MHz, METHANOL-^) δ 1.58 (s, 3 H), 2.48 (s, 3 H), 2.78 (dt, J=15.92, 4.17 Hz, 1 H), 2.94 - 3.05 (m, 1 H), 3.14 - 3.19 (m, 1 H), 3.32 - 3.40 (m, 1 H), 6.40 (dd, J=8.59, 2.53 Hz, 1 H), 6.48 (d, J=2.53 Hz, 1 H), 6.51 (d, J=8.59 Hz, 1 H), 6.55 - 6.60 (m, 2 H), 6.63 - 6.71 (m, 2 H), 6.97 (d, J=16.67 Hz, 1 H), 7.17 (d, J=8.59 Hz, 2 H), 7.41 (d, J=8.59 Hz, 2 H), 7.48 (d, J=16.17 Hz, 1 H).
Example 37
(E)-2-(4-fluorophenyl)-l -methyl- l-(4-(2-(5 -propyl- 1.3.4-oxadiazol-2-yl)vinyl)phenyl)-1.2.3.4- tetrahvdroisoquinolin-6-ol
Figure imgf000185_0001
[00408] (E)-2-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)styryl)-5 -propyl- 1, 3 ,4-oxadiazole (Intermediate N8) (0.025 g, 0.052 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (0.076 mL, 1.034 mmol) was added followed by aluminum chloride (0.055 g, 0.414 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane, the organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via by reverse phase HPLC (5mM NH4OH modifier, 45-70% acetonitrile/water) to afford product (12 mg, 49% yield) as a white solid. LC/MS (m/z, MH+): 470.4. ¾ NMR (400 MHz, DMSO-<4) δ 0.97 (t, J=7.33 Hz, 3 H), 1.60 (s, 3 H), 1.76 (sxt, J=7.38 Hz, 2 H), 2.76 - 2.90 (m, 3 H), 3.01 - 3.14 (m, 1 H), 3.19 - 3.29 (m, 1 H), 3.38 - 3.47 (m, 1 H), 6.40 - 6.50 (m, 1 H), 6.50 - 6.66 (m, 4 H), 6.88 (t, J=8.84 Hz, 2 H), 7.12 - 7.31 (m, 3 H), 7.49 (d, J=16.67 Hz, 1 H), 7.63 (d, J=8.59 Hz, 2 H), 9.21 (br. s., 1 H).
Example 38
(E)-2-(4-fluorophenyl)- 1 -(4-(2-(5 -isobutyl- 1.3.4-oxadiazol-2-yl)vinyl)phenyl)- 1 -methyl- 1.2.3.4- tetrahvdroisoquinolin-6-ol
Figure imgf000186_0001
[00409] (E)-2-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)styryl)-5 -isobutyl- 1, 3 ,4-oxadiazole (Intermediate N9) (19.3 mg, 0.039 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (0.057 mL, 0.776 mmol) was added followed by aluminum chloride (41 mg, 0.310 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (5 mM NH4OH modifier, 45-70% acetonitrile/water) to afford product (9.3 mg, 49% yield) as a white solid. LC MS (m/z, MH+): 484.5. ¾ NMR (400 MHz, DMSO-<4) δ 0.98 (d, J=6.57 Hz, 6 H), 1.60 (s, 3 H), 2.02 - 2.19 (m, 1 H), 2.73 - 2.86 (m, 3 H), 3.02 - 3.17 (m, 1 H), 3.20 - 3.28 (m, 1 H), 3.38 - 3.49 (m, 1 H), 6.46 (dd, J=8.59, 2.53 Hz, 1 H), 6.50 - 6.66 (m, 4 H), 6.88 (t, J=8.59 Hz, 2 H), 7.17 - 7.30 (m, 3 H), 7.49 (d, J=16.17 Hz, 1 H), 7.63 (d, J=8.59 Hz, 2 H), 9.20 (br. s., 1 H).
Example 39
(E)-l-(4-(2-(5-cvclopropyl-1.3.4-oxadiazol-2-yl)vin^
1.2.3.4-tetrahvdroisoquinolin-6-ol
Figure imgf000187_0001
[00410] (E)-2-cyclopropyl-5-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1,2,3 , 4- tetrahydroisoquinolin-l-yl)styryl)-l,3,4-oxadiazole (Intermediate N 10) (24.2 mg, 0.050 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (74 μΐ^, 1.005 mmol) was added followed by aluminum chloride (0.054 g, 0.402 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (5 mM NH4OH modifier, 45-70% acetonitrile/water) to afford product (11.4 mg, 48% yield) as a white solid. LC MS (m/z, MH+): 468.5. ¾ NMR (400 MHz, DMSO-< ) δ ppm 1.00 - 1.22 (m, 4 H), 1.60 (s, 3 H), 2.16 - 2.31 (m, 1 H), 2.80 (d, J=16.17 Hz, 1 H), 3.01 - 3.15 (m, 1 H), 3.17 - 3.28 (m, 1 H), 3.37 - 3.50 (m, 1 H), 6.41 - 6.50 (m, 1 H), 6.50 - 6.69 (m, 4 H), 6.88 (t, J=8.84 Hz, 2 H), 7.19 (d, J=16.67 Hz, 1 H), 7.26 (m, J=8.08 Hz, 2 H), 7.46 (d, J=16.17 Hz, 1 H), 7.61 (m, J=8.08 Hz, 2 H), 9.21 (br. s., 1 H).
Example 40
(E) -2 -(4 -fluorophenyl)- 1 -(4-(2-(5-(hvdroxymethyl)- 1.3.4-oxadiazol-2-yl)vinyl)phenyl)- 1 -methyl-
1.2.3.4-tetrahvdroisoquinolin-6-ol
Figure imgf000188_0001
[00411] (E)-2-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)styryl)-5-(methoxymethyl)-l,3,4-oxadiazole (Intermediate Ni l) (0.227 mL, 0.023 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (34 μΕ, 0.453 mmol) was added followed by aluminum chloride (24 mg, 0.181 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (5 mM NH4OH modifier, 45-70%
acetonitrile/water) to afford product (4.2 mg, 40% yield) as a white fluffy solid. LC MS (m/z, MH+): 458.4. ¾ NMR (400 MHz, METHANOL-^) δ 1.59 (s, 3 H), 2.79 (d, J=16.67 Hz, 1 H), 2.94 - 3.05 (m, 2 H), 3.32 - 3.40 (m, 1 H), 4.68 (s, 2 H), 6.38 - 6.43 (m, 1 H), 6.46 - 6.54 (m, 2 H), 6.57 (dd, J=9.09, 5.05 Hz, 2 H), 6.67 (t, J=8.84 Hz, 2 H), 7.01 (d, J=16.17 Hz, 1 H), 7.18 (d, J=8.59 Hz, 2 H), 7.43 (d, J=8.08 Hz, 2 H), 7.54 (d, J=16.17 Hz, 1 H). Example 41
(E)-2-(4-isopropylphenyl)- 1 -methyl- 1 -(4-(2-(5 -propyl- 1.3.4-oxadiazol-2-yl)vinyl)phenyl)- 1.2.3.4- tetrahvdroisoquinolin-6-ol
Figure imgf000189_0001
[00412] (E)-2-(4-(2-(4-isopropylphenyl)-6-methoxy- 1 -methyl- 1 ,2,3,4- tetrahydroisoquinolin-l-yl)styryl)-5 -propyl- 1, 3 ,4-oxadiazole (Intermediate N12) (82.5 mg, 0.163 mmol) was dissolved in dichloromethane (6 mL) and cooled to 0 °C. Ethanethiol (240 μΐ , 3.25 mmol) was added followed by aluminum chloride (173 mg, 1.300 mmol). The reaction was then warmed to rt and stirred for 1 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-100% ethyl acetate/heptanes) to afford the title compound (44 mg, 54% yield) as a white solid. LC MS (m/z, MH+): 494.6. ¾ NMR (400 MHz, CHLOROFORM-^ δ 0.84 - 0.93 (m, 3 H), 0.96 - 1.03 (m, 6 H), 1.46 - 1.60 (m, 3 H), 1.71 (sxt, J=7.48 Hz, 2 H), 2.62 (dt, J=13.64, 6.82 Hz, 1 H), 2.71 (t, J=7.58 Hz, 3 H), 2.90 (d, J=6.57 Hz, 1 H), 3.10 - 3.35 (m, 2 H), 6.31 - 6.55 (m, 5 H), 6.69 - 6.83 (m, 3 H), 7.11 (d, J=7.58 Hz, 2 H), 7.21 (d, J=8.08 Hz, 2 H), 7.32 (d, J=16.17 Hz, 1 H). Example 42
(E) -(4-(2-(4 -dimethyl-4H-1.2.4 riazol-3^^^
1.2.3.4-tetrahvdroisoquinolin-6-ol
Figure imgf000190_0001
[00413] (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (Intermediate Fl) (1.078 mL, 0.216 mmol) was suspended in acetonitrile (0.431 mL) and DMF (0.5 mL) at rt. To this was added, HOBt (40 mg, 0.259 mmol) and N-(3-Dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride (50 mg, 0.259 mmol) and the reaction stirred at rt for 2.5 h. The reaction mixture was cooled to 0 °C and a solution of hydrazine hydrate (21 μΐ^, 0.431 mmol) in acetonitrile (1.0 mL) was added dropwise. The reaction mixture stirred at 0 °C for 30 min. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layers were combined and washed with saturated sodium bicarbonate. The organic layer was passed through a phase separator and concentrated to give (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylohydrazide as a yellow oil which was used crude in the next reaction (quantative yield). LC MS (m/z, MH+): 432.1. ¾ NMR (400 MHz,
CHLOROFORM- ) δ 1.59 (s, 3 H), 2.83 - 2.87 (m, 1 H), 3.00 - 3.12 (m, 1 H), 3.19 - 3.28 (m, 1 H), 3.30 - 3.40 (m, 1 H), 3.70 (s, 3 H), 6.34 (d, J=15.66 Hz, 1 H), 6.47 - 6.72 (m, 7 H), 7.10 (m, J=8.08 Hz, 2 H), 7.28 (m, J=8.08 Hz, 2 H), 7.56 (d, J=15.66 Hz, 1 H)
[00414] Under nitrogen, N-methylacetamide (10.70 μΐ^, 0.139 mmol) was dissolved in dichloromethane (0.695 mL) and the reaction vial was cooled to 0 °C. The vial was charged with 2,6-lutidine (32 μΐ^, 0.278 mmol) and oxalyl chloride (12 μΐ^, 0.139 mmol) was added dropwise. The reaction mixture stirred at 0 °C for 40 min at which time, (E)-3-(4-(2-(4-fluorophenyl)-6- methoxy-l-methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylohydrazide (60 mg, 0.139 mmol) was added and the reaction was warmed to rt and stirred for 2 h. The reaction was concentrated, the residue dissolved in saturated sodium bicarbonate (3 mL) and heated to 90 °C for 2 h. The reaction was cooled to rt and the water layer was extracted thrice with
dichloromethane. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by reverse phase HPLC (5 mM NH4OH in 45-70% acetonitrile/water) to afford (E)-l-(4-(2-(4,5-dimethyl-4H-l,2,4-triazol-3-yl)vinyl)phenyl)-2-(4- fluorophenyl)-6-methoxy-l -methyl- 1, 2,3 ,4-tetrahydroisoquinoline (17 mg, 26% yield) as a clear oil. LC MS (m/z, MH+): 469.5. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.67 - 1.74 (m, 3 H), 2.49 (s, 3 H), 2.91 - 3.07 (m, 1 H), 3.10 - 3.25 (m, 1 H), 3.29 - 3.40 (m, 1 H), 3.40 - 3.52 (m, 1 H), 3.62 (s, 3 H), 3.78 - 3.83 (m, 3 H), 6.58 - 6.72 (m, 4 H), 6.72 - 6.85 (m, 4 H), 7.22 (d, J=8.59 Hz, 2 H), 7.41 (d, J=8.08 Hz, 2 H), 7.73 (d, J=16.17 Hz, 1 H).
[00415] (E)-l-(4-(2-(4,5-dimethyl-4H-l,2,4-triazol-3-yl)vinyl)phenyl)-2-(4- fluorophenyl)-6-methoxy-l -methyl- 1,2,3 ,4-tetrahydroisoquinoline (17 mg, 0.036 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (0.054 mL, 0.726 mmol) was added followed by aluminum chloride (38.7 mg, 0.290 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated. The crude material was pure by analytical methods and not further purified to obtain the title compounds (13 mg, 79% yield) as a red solid. LC/MS (m/z, MH+): 455.5. ¾ NMR (400 MHz, DMSO-t/6) δ 1.61 (s, 3 H), 2.38 (s, 3 H), 2.81 (d, J=16.17 Hz, 1 H), 3.02 - 3.15 (m, 1 H), 3.26 (dt, J=l 1.49, 4.36 Hz, 1 H), 3.39 - 3.49 (m, 1 H), 3.62 (s, 3 H), 6.44 - 6.50 (m, 1 H), 6.52 - 6.59 (m, 2 H), 6.63 (dd, J=8.59, 5.05 Hz, 2 H), 6.88 (t, J=8.84 Hz, 2 H), 7.14 (d, J=16.17 Hz, 1 H), 7.25 (m, J=8.08 Hz, 2 H), 7.52 (d, J=16.17 Hz, 1 H), 7.58 (m, J=8.08 Hz, 2 H), 9.23 (s, 1 H).
[00416] The following Examples of Table 2 were prepared, using appropriate starting materials, according to the above methods:
Table 2
Figure imgf000192_0001
Figure imgf000193_0001
(E)-methyl 3-(4-(2-(3-
1 fluorophenyl)-6- ¾ NMR (400 MHz,
hydroxy- 1 -methyl- CHLOROFORM-rf) δ 1.65 (s, 3 H), 1,2,3,4- 2.82 (d, J=16.17 Hz, 1 H), 2.99 - 3.15 (m, 1 H), 3.29 - 3.44 (m, 2 H), tetrahydroisoquinolin- 1 - 3.72 (s, 3 H), 6.20 - 6.36 (m, 3 H), yl)phenyl)acrylate 6.42 - 6.50 (m, 1 H), 6.50 - 6.58 (m,
2 H), 6.60 (d, J=8.59 Hz, 1 H), 6.89 (q, J=8.08 Hz, 1 H), 7.21 (d, J=8.59 Hz, 2 H), 7.32 (d, J=8.59 Hz, 2 H), 7.58 (d, J=15.66 Hz, 1 H)
LC/MS (m/z, MH+): 418.1
(E)-methyl 3-(4-(6-
COOCH3 hydroxy- 1 -methyl -2 - LC/MS (m/z, MH+): 406.2
¾ NMR (400 MHz, METHANOL - (thiophen-3-yl)-l,2,3,4- d4) δ 1.66 (s, 3 H), 2.84 (dt, tetrahydroisoquinolin- 1 - J=15.92, 3.41 Hz, 1 H), 3.19 (ddd, yl)phenyl)acrylate J=15.79, 9.47, 6.57 Hz, 1 H), 3.38 - 3.66 (m, 2 H), 3.78 (s, 3 H), 6.06 (dd, J=5.05, 1.52 Hz, 1 H), 6.34 (dd, J=3.03, 1.52 Hz, 1 H), 6.41 - 6.70 (m, 4 H), 6.97 (dd, J=5.31, 3.28 Hz, 1 H), 7.43 (m, J=8.59 Hz, 2 H), 7.50 (m, J=8.59 Hz, 2 H), 7.68 (d, J=16.17 Hz, 1 H)
(E)-methyl 3-(4-(6-
1 hydroxy- 1 -methyl -2-(4- (trifluoromethyl)phenyl
)-l,2,3,4- tetrahydroisoquinolin- 1 - yl)phenyl)acrylate LC/MS (m/z, MH+): 468.5
(E)-methyl 3-(4-(2-(2-
1 fluoro-4- ¾ NMR (400 MHz, METHANOL - hy droxypheny 1) -6 - c¾) δ ρρπι 1.55 - 1.63 (m, 3 H), 2.65 hydroxy- 1 -methyl- - 2.84 (m, 2 H), 3.07 - 3.19 (m, 2 H), 1,2,3,4- 3.66 (s, 3 H), 6.07 (dd, J=9.35, 2.78
Hz, 1 H), 6.19 (t, .7=9.09 Hz, 1 H), tetrahydroisoquinolin- 1 - 6.23 - 6.31 (m, 1 H), 6.35 (d, yl)phenyl)acrylate J=16.17 Hz, 1 H), 6.42 - 6.52 (m, 2
H), 6.60 (d, J=8.59 Hz, 1 H), 6.98
HoAA (s, 2 H), 7.28 (d, J=8.59 Hz, 2 H),
F 7.53 (d, J=15.66 Hz, 1 H)
LC/MS (m/z, MH+): 433.9
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Examples 77a & b:
(R.E)-3-(4-(6-hydroxy-l -methyl -2-(2-methylthiophen-3-ylN)-1.2.3.4-tetrahvdroisoquinolin-l - vDphenvDacrylic acid and (S.EN)-3-(4-(6-hydroxy-l-methyl-2-(2-methylthiophen-3-ylN)-1.2.3.4- tetrahydroisoquinolin- 1 -yl)phenyl)acrylic acid
Figure imgf000206_0002
[00417] To a 30 mL screw cap vial, (E)-methyl 3-(4-(6-hydroxy-l-methyl-2-(2- methylthiophen-3-yl)-l,2,3,4-tetrahydroisoquinolin-l -yl)phenyl)acrylate (Example 6) (100 mg, 0.238 mmol) was dissolved in tetrahydrofuran (2 mL). The vial was charged with 2M lithium hydroxide aqueous solution (0.477 mL, 0.953 mmol) and the reaction mixture was heated at 60 °C for 30 min. The reaction mixture was concentrated by vacuum, diluted with water, and acidified with citric acid to pH 5. The mixture was diluted with dichloromethane (20 mL). The organic layer was collected and concentrated to afford the crude product. The crude material was purified by running through the preparative chiral OJH column (21 X 250 mm), mobile phase was 45% methanol in CO2 over 4.5 min at 75 g/ min flow rate. Enantiomer 1 was collected at 2.87 min and enantiomer 2 was collected at 3.57 min. Absolute configuration of enantiomer was not determined. First eluted peak (enantiomer 1) was randomly assigned as R and second eluted peak (enantiomer 2) as S. LC MS (m/z, MH+): 406.5
Examples 100, 100a & b
(E)-3 -(4-(6-hydroxy-2-(5 -isopropylthiophen-2-vD- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylic acid
(R.EN)-3-(4-(6-hydroxy-2-(5-isopropylthiophen-2-ylN)-l -methyl- 1.2.3.4-tetr ahydroisoquinolin-l- vDphenvDacrylic acid
(S.E)-3 -(4-(6-hydroxy-2-(5 -isopropylthiophen-2-vD- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylic acid
Figure imgf000207_0001
[00418] Step 1 : 6-Methoxy-2-(5(prop-l-en-2-yl)thiophen-2-yl)-3,4-dihydroisoquinolin- l(2H)-one. To a 30 mL screw cap vial, 2-(5-bromothiophen-2-yl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (770 mg, 2.277 mmol) was dissolved in MeCN (Volume: 1 mL) and degassed water (Volume: 1.000 mL). The mixture was charged with 4,4,5,5-tetramethyl-2- (prop-l-en-2-yl)-l,3,2-dioxaborolane (0.856 mL, 4.55 mmol), K2C03 (944 mg, 6.83 mmol). The reaction mixture was flushed with nitrogen, charged with XPhos Pd cycle (84 mg, 0.114 mmol). The mixture was heated at 80 °C for 16 hr. The mixture was diluted with DCM, washed with water and brine. The organic phase was collected, dried (sodium sulfate), filtered, and concentrated to afford crude product. The crude material was purified by normal phase Isco flash chromatography systems (0-100% EtO Ac/Heptane) to afford product as an off white solid (570 mg, 1.904 mmol, 84 % yield). LC MS (m/z, MH+): 300.1. ¾ NMR (400 MHz, CHLOROFORM-d) δ ppm 2.14 (s, 3 H), 3.14 (t, J=6.57 Hz, 2 H), 3.88 (s, 3 H), 4.11 (t, J=6.57 Hz, 2 H), 4.90 (s, 1 H), 5.37 (s, 1 H), 6.60 (d, J=4.04 Hz, 1 H), 6.73 (d, J=2.53 Hz, 1 H), 6.85 (d, J=4.04 Hz, 1 H), 6.91 (dd, J=8.59, 2.53 Hz, 1 H), 8.12 (d, J=9.09 Hz, 1 H)
[00419] Step 2: 2-(5-Isopropylthiophen-2-yl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)- one:
Figure imgf000208_0001
[00420] To a 250 mL round bottom flask, 6-methoxy-2-(5-(prop-l-en-2-yl)thiophen-2- yl)-3,4-dihydroisoquinolin-l(2H)-one (570 mg, 1.904 mmol) was dissolved in MeOH (50 mL) and the mixture was charged with 10% palladium on carbon (203 mg, 0.190 mmol). The reaction mixture was flushed with H2 for three time, and stirred under H2 for 1 h. The mixture was filtered through celite, the filtrate was conentrated to afford a crude product. The crude material was purified by normal phase Isco flash chromatography systems (0-100% EtOAc Heptane) to afford a off white solid (250 mg, 0.829 mmol, 43.6 % yield). LC MS (m/z, MH+): 302.1. 1H NMR (400 MHz, CHLOROFORM-J) δ ppm 1.35 (d, J=7.07 Hz, 6 H), 3.04 - 3.22 (m, 3 H), 3.88 (s, 3 H), 4.08 (t, J=6.57 Hz, 2 H), 6.55 (d, J=4.04 Hz, 1 H), 6.62 (d, J=3.54 Hz, 1 H), 6.72 (s, 1 H), 6.84 - 7.02 (m, 1 H), 8.11 (d, J=8.59 Hz, 1 H).
[00421] Step 3: l-(4-Bromophenyl)-2-(5-isopropylthiophen-2-yl)-6-methoxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinoline:
Figure imgf000208_0002
[00422] To a 250 mL round bottomed flask was added l-bromo-4-iodobenzene (704 mg, 2.49 mmol) and pentanes (2 mL). The reaction vial was charged with 2.5 M n-butyllithium in hexanes (1 mL, 2.50 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at room temperature for 1 h at which time the reaction mixture was cooled to -78 °C charged with a solution of 2-(5-isopropylthiophen-2-yl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one (250 mg, 0.829 mmol) in tetrahydrofuran (2.0 mL). The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with water (40 mL) and diluted with ethyl acetate (40 mL). Perchloric acid (0.3 mL, 3.57 mmol, 70% in water) was added to the reaction mixture and stirred for 30 min at room temperature. The reaction mixture was further diluted with ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, passed through a phase separator, and concentrated to give crude iminium intermediate based on LC MS. The iminium intermediate was used directly in the next reaction. LC MS (m/z, M+): 441.9.
[00423] Iminium intermediate was dissolved in tetrahydrofuran (2.0 mL) and cooled to
0 °C. The reaction was charged with a 1.4 M solution of methylmagnesium bromide in diethyl ether (1.78 mL, 2.49 mmol) and the reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated ammonium chloride. The aqueous layer was separated and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude material. Crude product was purified by silica gel chromatography (0-30% ethyl acetate/heptanes) to obtain the title compound (200 mg, 53% yield). LC MS (m/z, MH+): 457.9. ¾ NMR (400 MHz, CHLOROFORM-^ δ ppm 1.21 (dd, J=7.07, 3.03 Hz, 6 H), 1.74 (s, 3 H), 2.79 - 2.99 (m, 2 H), 3.06 - 3.23 (m, 1 H), 3.33 - 3.57 (m, 2 H), 3.79 (s, 3 H), 5.87 (d, J=3.54 Hz, 1 H), 6.33 (dd, J=3.54, 1.01 Hz, 1 H), 6.56 - 6.70 (m, 2 H), 6.70 - 6.81 (m, 1 H), 7.20 - 7.30 (m, 2 H), 7.34 - 7.40 (m, 2 H).
[00424] Step 4: (E)-tert-Butyl 3-(4-(2-(5-isopropylthiophen-2-yl)-6-methoxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate:
Figure imgf000209_0001
[00425] To a 40 mL screw cap vial, l-(4-bromophenyl)-2-(5-isopropylthiophen-2-yl)-6- methoxy-1 -methyl- 1, 2,3 ,4-tetrahydroisoquino line (190 mg, 0.416 mmol) was dissolved in DMF (Volume: 2ml) and TEA (0.464 ml, 3.33 mmol). The reaction mixture was added with tert-butyl acrylate (0.488 ml, 3.33 mmol) and Pd(PPh3)2Cl2 (29.2 mg, 0.042 mmol). The system was flushed with nitrogen and heated at 100 °C for 16 h. The mixture was diluted with DCM, organic was washed with water. Organic passed through phase separator, concentrated and dry loaded on column. The crude product was purified via Isco (0% EtOAc in hexane to 70% EtOAc; isco 40 g gold column). Fractions containing the desired product were concentrated to afford a sticky yellow solid (130 mg, 0.258 mmol, 62.0 % yield). LC MS (m/z, MH+): 504.1.
[00426] Step 5: (Example 100) (E)-3-(4-(6-hydroxy-2-(5-isopropylthiophen-2-yl)-l- methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl)acrylic acid :
Figure imgf000210_0001
[00427] To a 30 mL screw cap vial, (E)-tert-butyl 3-(4-(2-(5-isopropylthiophen-2-yl)-6- methoxy-1 -methyl- 1, 2,3 ,4-tetrahydroisoquinolin- l-yl)phenyl)acrylate (130 mg, 0.258 mmol) was dissolved in DCM (Volume: 1 mL) and the mixture was cooled to -78 °C. The vial was charged with 1M BBr3 in hexane (0.774 mL, 0.774 mmol) dropwise under nitrogen. The reaction mixture was warmed to room temperature and the mixture was stirred for 30 min. The reaction mixture was cooled to 0 °C, quenched with saturated Sodium bicarbonate aqueous solution, and diluted with DCM. The organic phase was collected, dried (sodium sulfate), filtered, and concentrated to afford crude product. The crude material was purified by normal phase Isco flash
chromatography systems (0-100% EtO Ac/Heptane) to afford product as a white solid (30 mg, 0.067 mmol, 26.0 % yield). LCMS: m/z 434.1. ¾ NMR (400 MHz, METHANOL-d4) δ ppm 1.02 - 1.20 (m, 6 H), 1.73 (s, 3 H), 2.77 - 2.97 (m, 2 H), 2.99 - 3.16 (m, 1 H), 3.37 - 3.54 (m, 2 H), 5.91 (d, J=3.54 Hz, 1 H), 6.31 (dd, J=3.54, 1.01 Hz, 1 H), 6.38 - 6.59 (m, 3 H), 6.66 (d, J=8.59 Hz, 1 H), 7.39 (d, J=8.59 Hz, 2 H), 7.48 (d, J=8.59 Hz, 2 H), 7.65 (d, J=16.17 Hz, 1 H).
[00428] Step 6: (Examples 100a & b) (R,E)-3-(4-(6-hydroxy-2-(5-isopropylthiophen-
2-yl)-l -methyl- 1, 2,3 ,4-tetrahydroisoquinolin- l-yl)phenyl)acrylic acid and (S,E)-3-(4-(6-hydroxy- 2-(5 -isopropylthiophen-2-yl)- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl)acrylic acid:
Figure imgf000210_0002
[00429] (E)-3-(4-(6-hydroxy-2-(5 -isopropylthiophen-2-yl)- 1 -methyl- 1 ,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid was purified by running through the preparative chiral IC column (21 X 250 mm), mobile phase was 20% methanol: DCM (7:3) in CO2 over 8 min at 75 g/ min flow rate. Enantiomer 1 was collected at 4.7 min and enantiomer 2 was collected at 6.0 min. Absolute configuration of enantiomer is not determined. First eluted peak
(enantiomer 1) was randomly assigned as R and second eluted peak (enantiomer 2) as S. LC MS (m/z, MH+): 434.2.
Examples 101, 101a & b
(E)-3-(4-(l -(difluoromethyl)-6-hvdroxy-2-(4-isobutylphenyl)- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylic acid; (R.E)-3-(4-(l-(difluoromethyl)-6-hvdroxy-2-(4-isobutylphenyl)-1.2.3.4- tetrahydroisoquinolin-l -vDphenvDacrylic acid; and (S.E)-3-(4-(l-(difluoromethyl)-6-hvdroxy-2- (4-isobutylphenvD- 1.2.3.4-tetrahydroisoquinolin- 1 -vDphenvDacrylic acid :
Figure imgf000211_0001
[00430] Step 1 : Ethyl 2-(l-(4-bromophenyl)-2-(4-isobutylphenyl)-6-methoxy-l,2,3,4- tetrahydroisoquinolin-l-yl)-2,2-difluoroacetate: To a 40 mL scintallation vial was added 1- bromo-4-iodobenzene (0.864 g, 3.05 mmol) and pentanes (8.03 ml). The reaction vial was charged with a 2.5 M n-butyllithium in hexanes (1.226 ml, 3.06 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C and a solution of 2-(4-isobutylphenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one (0.315 g, 1.018 mmol) in tetrahydrofuran (5.74 ml) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was then quenched with water (12 mL) and ethyl acetate (12 mL) and warmed to r.t. Perchloric acid (0.263 ml, 4.38 mmol) was added and the reaction mixture stirred for 30 minutes at r.t. The reaction was diluted with water and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give iminium intermediate which was used crude in the next step. LC/MS (m/z, MH+): 448.4. [00431] Iminium intermediate was dissolved in dimethylformamide (8.5 mL) and potassium fluoride (0.177 g, 3.05 mmol) was added. A solution of ethyl 2,2-difluoro-2- (trimethylsilyl)acetate (0.400 g, 2.036 mmol) in dimethylformamide (5.5 mL) was added dropwise and the reaction stirred at r.t. for 30 minutes. The reaction was quenched with saturated sodium bicarbonate and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel flash chromatography (0-10% ethyl acetate/heptanes) to afford product (516 mg,89 % yield) as a yellow oil. LC MS (m/z, MH+): 572.5. ¾ NMR (400 MHz, Chloroform-d) δ 7.28 - 7.20 (m, 2H), 7.16 - 7.09 (m, 2H), 6.90 (dd, J = 9.5, 4.4 Hz, 1H), 6.78 - 6.73 (m, 2H), 6.67 - 6.58 (m, 4H), 4.00 (q, J = 7.2 Hz, 2H), 3.75 (s, 3H), 3.45 (ddd, J = 12.6, 9.7, 3.4 Hz, 1H), 3.22 (dt, J = 12.0, 4.5 Hz, 1H), 2.97 (ddd, J = 14.7, 9.6, 4.5 Hz, 1H), 2.80 (dt, J = 15.7, 3.8 Hz, 1H), 2.30 (dd, J = 7.2, 1.6 Hz, 2H), 1.72 (dp, J = 13.5, 6.7 Hz, 1H), 1.04 (t, J = 7.1 Hz, 3H), 0.80 (dd, J = 6.6, 2.9 Hz, 6H). 19F NMR (376 MHz, Chloroform-d) δ -97.62 (d, J = 246.9 Hz, 2F), -99.67 (d, J = 247.0 Hz, 2F).
[00432] Step 2: 2-(l-(4-Bromophenyl)-2-(4-isobutylphenyl)-6-methoxy-l,2,3,4- tetrahydroisoquinolin-l-yl)-2,2-difluoroacetic acid: Ethyl 2-(l-(4-bromophenyl)-2-(4- isobutylphenyl)-6-methoxy-l,2,3,4-tetrahydroisoquinolin-l-yl)-2,2-difluoroacetate (1.86 g, 3.25 mmol) was dissolved in 1,4-dioxane (32.5 ml). To this, 1 M lithium hydroxide (8.12 ml, 8.12 mmol) was added and the reaction was heated to 40 °C for 2 h. The reaction was cooled to ambient temperature and acidified to pH 1 with 1 M HC1 and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated. The material was taken on crude as a yellow oil to the next reaction. LC MS (m/z, MH+): 544.5. ¾ NMR (400 MHz, Chloroform-d) δ 7.20 (d, J = 8.5 Hz, 2H), 6.90 (dt, J = 14.6, 7.5 Hz, 3H), 6.74 (d, J = 8.4 Hz, 2H), 6.65 - 6.57 (m, 2H), 6.45 - 6.35 (m, 2H), 3.67 (s, 3H), 3.44 - 3.35 (m, 1H), 3.28 (ddd, J = 17.2, 12.0, 4.8 Hz, 1H), 3.12 - 3.03 (m, 1H), 2.84 - 2.77 (m, 1H), 2.30 - 2.18 (m, 2H), 1.64 (dq, J = 13.5, 6.8 Hz, 1H), 0.70 (dd, J = 6.6, 4.9 Hz, 6H). Cannot obtain a fluorine NMR.
[00433] Step 3 : 1 -(4-Bromophenyl)- 1 -(difluoromethyl)-2-(4-isobutylphenyl)-6- methoxy-l,2,3,4-tetrahydroisoquinoline: 2-(l-(4-Bromophenyl)-2-(4-isobutylphenyl)-6-methoxy- l,2,3,4-tetrahydroisoquinolin-l-yl)-2,2-difluoroacetic acid (7.00 ml, 3.29 mmol) was dissolved in l-methyl-2-pyrrolidinone (65.8 ml) and cesium fluoride (2.497 g, 16.44 mmol) was added. The reaction was placed under nitrogen and heated to 192 °C for 24 h. After cooling to rt, water was added and the reaction mixture was extracted with diethyl ether three times. The organic layers were combined, passed through a phase separator and concentrated to give crude material which was purified by silica gel chromatography (0-10% ethyl acetate/heptanes) to afford product (1.29 g, 78 % yield) as a yellow oil. LC MS (m/z, MH+): 502.0. ¾ NMR (400 MHz, Chloroform-d) δ 7.28 - 7.21 (m, 2H), 6.93 - 6.82 (m, 3H), 6.82 - 6.76 (m, 2H), 6.67 (d, J = 2.8 Hz, 1H), 6.61 (dd, J = 8.8, 2.8 Hz, 1H), 6.55 - 6.22 (m, 3H), 3.74 (s, 3H), 3.61 (dtd, J = 11.7, 6.7, 5.8, 3.6 Hz, 1H), 3.33 (dt, J = 11.4, 5.5 Hz, 1H), 2.99 (q, J = 5.3 Hz, 2H), 2.29 (d, J = 7.2 Hz, 2H), 1.70 (dp, J = 13.5, 6.7 Hz, 1H), 0.80 - 0.75 (m, 6H). 19F NMR (376 MHz, Chloroform-d) δ -121.09 (d, J = 279.9 Hz, IF), -125.97 (d, J = 280.6 Hz, IF).
[00434] Step 4: (E)-Methyl 3-(4-(l-(difluoromethyl)-2-(4-isobutylphenyl)-6-methoxy-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate: To a 40 mL vial was added l-(4- bromophenyl)- 1 -(difluoromethyl)-2-(4-isobutylphenyl)-6-methoxy- 1 ,2,3 ,4-tetrahydroisoquinoline (0.197 g, 0.394 mmol), Pd(PPh3)2Cl2 (0.138 g, 0.197 mmol), dimethylformamide (2.62 ml), triethylamine (0.274 ml, 1.968 mmol), and methylacrylate (0.709 ml, 7.87 mmol). The reaction mixture was heated for 1 h at 120 °C. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford product (89 mg, 44.7 % yield) as an orange oil. LC MS (m/z, MH+): 506. ¾ NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 16.0 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.02 (d, J = 8.0 Hz, 2H), 6.84 (dd, J = 8.8, 3.5 Hz, 1H), 6.79 - 6.71 (m, 2H), 6.67 (d, J = 2.8 Hz, 1H), 6.59 (dd, J = 8.8, 2.8 Hz, 1H), 6.56 - 6.24 (m, 4H), 3.71 (d, J = 2.1 Hz, 6H), 3.63 - 3.54 (m, 1H), 3.33 (dt, J = 11.3, 5.3 Hz, 1H), 2.98 (q, J = 5.6, 4.1 Hz, 2H), 2.26 (d, J = 7.1 Hz, 2H), 1.69 (dt, J = 13.5, 6.7 Hz, 1H), 0.75 (dd, J = 6.6, 1.9 Hz, 6H).19F NMR (376 MHz, Chloroform-d) δ -121.00 (d, J = 279.6 Hz, IF), -126.34 (d, J = 279.8 Hz, IF).
[00435] Step 5: (E)-Methyl 3-(4-(l-(difluoromethyl)-6-hydroxy-2-(4-isobutylphenyl)-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate: (E)-Methyl 3-(4-(l-(difluoromethyl)-2-(4- isobutylphenyl)-6-methoxy-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.089 g, 0.176 mmol) was dissolved in dichloromethane (3.52 ml) and cooled to 0°C. Aluminum chloride (0.188 g, 1.408 mmol) was added followed by ethanethiol (0.260 ml, 3.52 mmol). The reaction was warmed to rt and stirred for 2 h. The reaction was quenched with saturated ammonium chloride.
The aqueous layer was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. Crude material was purified by silica gel chromatography (0-25% ethyl acetate/hepanes) to afford product (72 mg, 83 % yield) as a yellow oil. LC/MS (m/z, MH+): 492.5. ¾ NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 16.1 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.13 (d, J = 7.9 Hz, 2H), 6.91 (dd, J = 8.7, 3.5 Hz, 1H), 6.88 - 6.82 (m, 2H), 6.74 (d, J = 2.7 Hz, 1H), 6.68 - 6.60 (m, 1H), 6.60 - 6.54 (m, 2H), 6.54 - 6.35 (m, 2H), 3.84 (s, 3H), 3.69 (dt, J = 11.5, 5.9 Hz, 1H), 3.43 (dt, J = 11.2, 5.3 Hz, 1H), 3.06 (q, J = 5.2, 4.4 Hz, 2H), 2.37 (d, J = 7.1 Hz, 2H), 1.78 (dt, J = 13.5, 6.8 Hz, 1H), 0.86 (dd, J = 6.6, 1.8 Hz, 6H). 19F NMR (376 MHz, Chloroform-d) δ -121.05 (d, J = 279.9 Hz, IF), -126.34 (d, J = 279.8 Hz, IF).
[00436] Step 6: (Example 101) (E)-3-(4-(l-(Difluoromethyl)-6-hydroxy-2-(4- isobutylphenyl)-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid: (E)-Methyl 3-(4-(l- (difluoromethyl)-6-hydroxy-2-(4-isobutylphenyl)- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 - yl)phenyl)acrylate (0.072 g, 0.146 mmol) was dissolved in 1,4-dioxane (1.465 ml). To this, 1 M lithium hydroxide (1.465 ml, 1.465 mmol) was added. The reaction was stirred at r.t. for 1 hour. The reaction mixture acidified to pH 1 with 1 M HC1. The reaction mixture was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by reverse phase HPLC (5 mM NH4OH modifier, 25-50% acetonitrile/water). Pure product (9 mg, 12.87 % yield) was obtained as a white solid. LC MS (m/z, MH+): 378.5. ¾ NMR (400 MHz, Methanol-d4) δ 7.51 (d, J = 15.9 Hz, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.86 - 6.78 (m, 2H), 6.73 (dd, J = 8.6, 3.3 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.63 - 6.38 (m, 5H), 3.60 (dt, J = 11.5, 5.6 Hz, 1H), 3.44 (dt, J = 11.6, 5.6 Hz, 1H), 3.00 (t, J = 5.7 Hz, 2H), 2.33 (d, J = 7.2 Hz, 2H), 1.74 (dt, J = 13.4, 6.7 Hz, 1H), 0.82 (dd, J = 6.7, 2.0 Hz, 6H). 19F NMR (376 MHz, Methanol-d4) δ -122.52 (d, J = 279.2 Hz, IF), -128.10 (d, J = 278.9 Hz, IF).
[00437] Step 7: (Examples 101a and b) (R,E)-3-(4-(l-(difluoromethyl)-6-hydroxy-2-
(4-isobutylphenyl)-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid and (S,E)-3-(4-(l- (difluoromethyl)-6-hydroxy-2-(4-isobutylphenyl)- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 - yl)phenyl)acrylic acid: Preparative Chiral AD-H column (35% isopropanol in C02); retention times of the enantiomers on chiral AD-H column: phase:5-55% isopropanol in CO2: 2.95 min and 3.32 min. Each enantiomer was further purified by achiral SFC Princeton DIOL column (15-25% CCVmethanol) with the system back pressure 120 bar, flow rate 30.0ml/min, and column oven temperature at 40 °C to afford 100% pure enantiomers. The first eluting enantiomer was randomly assigned R stereochemistry, the later eluting one S stereochemistry. Example 102
(E)-3-(4-(2-(2-Fluoro-4-isobu phenyl)-6-hvdroxy-l -methyl- 1.2.3.4-tetrahvdroisoquinolin-l- vDphenvDacrylic acid:
Figure imgf000215_0001
Step 1 : 2-(4-(BenzyloxyN)-2-fluorophenylN)-6-methoxy-3.4-dihvdroisoquinolin-l(2HN)-one
[00438] Step 1 : 2-(4-(Benzyloxy)-2-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one: 6-Methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.5 g, 2.82 mmol) was dissolved in dimethylformamide (5.64 ml). 4-(benzyloxy)-l-bromo-2-fluorobenzene (1.190 g, 4.23 mmol) and potassium carbonate (0.780 g, 5.64 mmol) were added. The reaction mixture was flushed with nitrogen and copper(I) iodide (0.322 g, 1.693 mmol) was added. The reaction mixture was heated to 150 °C and stirred at 150 °C for 36 h. The reaction was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-75% ethyl acetate/heptanes) to give desired product (618 mg, 58.0 % yield) as a light orange solid. LC MS (m/z, MH+): 378.1. 1H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 8.6 Hz, 1H), 7.49 - 7.33 (m, 5H), 7.30 (d, J = 8.7 Hz, 1H), 6.90 (dd, J = 8.7, 2.6 Hz, 1H), 6.87 - 6.77 (m, 2H), 6.75 (d, J = 2.5 Hz, 1H), 5.08 (s, 2H), 3.87 (d, J = 3.2 Hz, 5H), 3.12 (t, J = 6.5 Hz, 2H).
[00439] Step 2: 2-(2-Fluoro-4-hydroxyphenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one: To 2-(4-(benzyloxy)-2-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.618 g, 1.637 mmol) was added in ethanol (4.09 ml). The compound did not dissolve completely therefore tetrahydropyran (9.00 mL) was added until the compound dissolved. A scoop of Pd(OH)2 was added, then the reaction solution was purged with hydrogen and left with a hydrogen balloon at r.t. for 3 h. The reaction was filtered through a syringe filter and concentrated to afford product (0.618 g, 1.637 mmol) as an off-white solid. LC MS (m/z, MH+): 288.3. ¾ NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.88 - 7.77 (m, 1H), 7.22 (td, J = 8.9, 1.4 Hz, 1H), 6.97 - 6.87 (m, 2H), 6.70 - 6.58 (m, 2H), 3.83 (s, 3H), 3.76 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 6.4 Hz, 2H). 19F NMR (376 MHz, DMSO-d6) δ -118.86 (d, J = 11.1 Hz, IF).
[00440] Step 3 : 3-Fluoro-4-(6-methoxy-l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)phenyl trifluoromethanesulfonate: 2-(2-fluoro-4-hydroxyphenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one (0.2 g, 0.696 mmol), N-phenyltrifluoromethanesulfonimide (0.298 g, 0.835 mmol), and potassium carbonate (0.289 g, 2.089 mmol) were added to a microwave vial and tetrahydropyran (3.48 ml) was added. The reaction was microwaved for 1 h at 120 °C.The reaction was filtered and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford product (308 mg, quantative yield) as a white solid. LC MS (m/z, MH+): 420.0. ¾ NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 8.7 Hz, 1H), 7.56 - 7.46 (m, 1H), 7.21 - 7.11 (m, 2H), 6.91 (dd, J = 8.6, 2.5 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.89 (s, 3H), 3.16 (t, J = 6.4 Hz, 2H). 19F NMR (376 MHz, Chloroform-d) δ -74.08 (d, J = 1087.6 Hz, 3F), -112.88 (s, IF).
[00441] Step 4: 2-(2-fluoro-4-(2-methylprop-l-en-l-yl)phenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one: To a microwave vial, 3-fluoro-4-(6-methoxy-l-oxo-3,4- dihydroisoquinolin-2(lH)-yl)phenyl trifluoromethanesulfonate (0.144 g, 0.343 mmol), 4,4,5,5- tetramethyl-2-(2-methylprop-l-en-l-yl)-l,3,2-dioxaborolane (0.106 ml, 0.515 mmol), XPhos Pd cycle (0.025 g, 0.034 mmol) and potassium carbonate (0.142 g, 1.030 mmol) were added and dissolved in acetonitrile (2.289 ml) and water (1.145 ml). The reaction mixture was microwaved for 30 minutes at 150 °C. The reaction mixture was filtered to remove solids and concentrated. The crude product was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford impure product (48 mg, 43.0 % yield) as a light yellow solid. LC MS (m/z, MH+): 326.3. ¾ NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 8.6 Hz, 1H), 7.31 (t, J = 8.2 Hz, 1H), 7.09 - 6.99 (m, 2H), 6.90 (dd, J = 8.7, 2.6 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H), 6.24 (s, 1H), 3.92 (q, J = 6.1 Hz, 2H), 3.89 (s, 3H), 3.14 (t, J = 6.5 Hz, 2H), 1.92 (dd, J = 12.2, 1.4 Hz, 6H). 19F NMR (376 MHz, Chloroform-d) δ -120.57 (s, IF).
[00442] Step 5: 2-(2-Fluoro-4-isobutylphenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one: To 2-(2-fluoro-4-(2-methylprop-l-en-l-yl)phenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one (0.048 g, 0.148 mmol) was added methanol (1 mL). Tetrahydropyran (l.OmL) was added until compound was dissolved. A scoop of 10% palladium on carbon was added, then the reaction solution was purged with hydrogen and left with a hydrogen balloon at rt for 1 h. The reaction was filter through a syringe filter and concentrated to afford product (52 mg, quantative
% yield) as a clear oil. LC/MS (m/z, MH+): 328.1. ¾ NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 8.6 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 6.93 - 6.84 (m, 2H), 6.80 (dd, J = 8.7, 2.6 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 3.79 (d, J = 9.3 Hz, 5H), 3.03 (t, J = 6.4 Hz, 2H), 2.40 (d, J = 7.2 Hz, 2H), 1.85 - 1.79 (m, 1H), 0.85 (d, J = 6.6 Hz, 6H). 19F NMR (376 MHz, Chloroform-d) δ -119.82 - - 122.63 (m, IF).
[00443] Step 5: l-(4-Bromophenyl)-2-(2-fluoro-4-isobutylphenyl)-6-methoxy-l- methyl-l,2,3,4-tetrahydroisoquinoline: To a 40ml scintillation vial was added l-bromo-4- iodobenzene (0.153 g, 0.541 mmol) and pentanes (1.421 ml). The reaction vial was charged with 2.5 M n-butyllithium in hexanes (0.218 ml, 0.546 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C and solution of 2-(2-fluoro-4-isobutylphenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one (0.059 g, 0.180 mmol) in tetrahydrofuran (1.015 ml) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was then quenched with water (2.2 mL) and ethyl acetate (2.2 mL) and warmed to rt. Perchloric acid (0.067 ml, 0.775 mmol) was added and the reaction mixture was stirred for 30 minutes at rt. The reaction was diluted water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to give iminum intermediate which was used crude in the next step. LC MS (m/z, MH+): 469.4.
[00444] Iminium intermediate was dissolved in tetrahydrofuran (1.168 ml) and cooled to 0 °C. A 1.4M solution of methylmagnesium bromide in tetrahydrofuran (0.386 ml, 0.541 mmol) was added dropwise. The mixture was brought to rt and stirred for lhr. The reaction was quenched with saturation ammonium chloride. And extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated. Crude material was purified by silica gel chromatography (0-25% ethyl acetate/heptane) to afford product (70 mg, 81 % yield) as an orange oil. LC MS (m/z, MH+): 484.4. ¾ NMR (400 MHz, Chloroform-d) δ 7.24 - 7.18 (m, 2H), 7.00 - 6.93 (m, 2H), 6.77 (d, J = 8.3 Hz, 1H), 6.70 (dd, J = 12.5, 2.0 Hz, 1H), 6.62 (d, J = 8.3 Hz, 2H), 6.49 (dd, J = 8.1, 2.0 Hz, 1H), 6.32 (t, J = 8.4 Hz, 1H), 3.73 (s, 3H), 3.36 - 3.14 (m, 2H), 2.83 (tq, J = 16.2, 8.0, 5.7 Hz, 2H), 2.29 (d, J = 7.1 Hz, 2H), 1.73 (dq, J = 13.5, 6.8 Hz, 1H), 1.65 (d, J = 1.9 Hz, 3H), 0.81 - 0.78 (m, 6H). 19F NMR (376 MHz, Chloroform-d) δ -118.57 (s, IF).
[00445] Step 6: (E)-Methyl 3-(4-(2-(2-fluoro-4-isobutylphenyl)-6-methoxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate: To a 40 mL vial l-(4-bromophenyl)-2-(2- fluoro-4-isobutylphenyl)-6-methoxy-l -methyl- 1, 2,3 ,4-tetrahydroisoquinoline (0.070 g, 0.145 mmol), PdCl2(PPh3)2 (0.051 g, 0.073 mmol), dimethylformamide (0.967 ml), triethylamine (0.101 ml, 0.725 mmol), and methyl acrylate (0.131 ml, 1.451 mmol) were added. The reaction mixture was heated for 1 h at 130 °C. The reaction was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford product (23 mg, 32.5 % yield) as a light yellow oil. LC MS (m/z,
MH+): 488.5. ¾ NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 16.0 Hz, 1H), 7.30 - 7.24 (m,
2H), 7.16 - 7.08 (m, 2H), 6.79 (dt, J = 8.8, 1.2 Hz, 1H), 6.69 (dd, J = 12.5, 2.0 Hz, 1H), 6.63 (d, J
= 7.5 Hz, 2H), 6.46 (dd, J = 8.2, 2.0 Hz, 1H), 6.36 - 6.26 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 3.37 -
3.27 (m, 1H), 3.27 - 3.18 (m, 1H), 2.85 (dtt, J = 16.2, 10.5, 5.7 Hz, 2H), 2.28 (d, J = 7.2 Hz, 2H),
1.77 - 1.63 (m, 4H), 0.80 - 0.77 (m, 6H). 19F NMR (376 MHz, Chloroform-d) δ -118.65 (s, IF).
[00446] Step 7: (E)-Methyl 3-(4-(2-(2-fluoro-4-isobutylphenyl)-6-hydroxy-l-methyl-
1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl)acrylate : (E)-m ethyl 3 -(4-(2-(2-fluoro-4- isobutylphenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl) acrylate (0.023 g,
0.047 mmol) was dissolved in dichloromethane (0.472 ml) and cooled to 0 °C. Aluminum chloride (0.050 g, 0.377 mmol) was added followed by the addition of ethanethiol (0.070 ml,
0.943 mmol). The reaction was stirred at 0°C for 2 h. The reaction was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-30% ethyl acetate/heptanes) to afford product (21 mg, 94 % yield) as a light yellow oil. LC MS (m/z, MH+): 474.5. ¾ NMR (400 MHz, Chloroform-d) δ 7.69 (dd, J =
16.2, 4.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.32 - 7.19 (m, 2H), 6.82 (dd, J = 17.3, 10.1 Hz, 2H),
6.67 (q, J = 8.5, 7.9 Hz, 2H), 6.56 (d, J = 8.4 Hz, 1H), 6.50 - 6.34 (m, 2H), 3.83 (d, J = 3.4 Hz,
3H), 3.37 (d, J = 25.1 Hz, 2H), 2.92 (d, J = 12.3 Hz, 2H), 2.38 (d, J = 7.5 Hz, 2H), 1.89 - 1.72 (m,
4H), 0.90 (dd, J = 11.4, 6.8 Hz, 6H). 19F NMR (376 MHz, Chloroform-d) δ -118.64.
[00447] Step 8: (Example 102) (E)-3-(4-(2-(2-Fluoro-4-isobutylphenyl)-6-hydroxy-l- methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid: (E)-Methyl 3-(4-(2-(2-fluoro-4- isobutylphenyl)-6-hydroxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl)acrylate (0.021 g,
0.044 mmol) was dissolved in 1,4-dioxane (1.5 ml). To this, 1 M lithium hydroxide (0.222 ml,
0.222 mmol) was added. The reaction was heated to 40 °C for 2 h. The reaction was cooled to rt and acidified to pH 1 with 1 M HC1. The reaction mixture was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to afford product (12.6 mg, 61.8 % yield) as a cream solid. LC/MS (m/z, MH+):
460.5. ¾ NMR (400 MHz, Methanol-d4) δ 7.62 (d, J = 16.0 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.25 - 7.16 (m, 2H), 6.79 (dd, J = 12.6, 2.0 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.62 - 6.54 (m, 3H), 6.48 - 6.37 (m, 2H), 3.41 - 3.33 (m, 1H), 3.29 - 3.22 (m, 1H), 2.91 - 2.80 (m, 2H), 2.36 (d, J = 7.2 Hz, 2H), 1.79 (dq, J = 13.6, 6.7 Hz, 1H), 1.74 - 1.66 (m, 3H), 0.86 (d, J = 6.6 Hz, 6H). 19F NMR (376 MHz, Methanol-d4) δ -119.93 (s, IF).
Example 103
(E)-3-(4-(2-(2-fluoro-4-isopropylphenyl)-6-hydrox
vDphenvDacrylic acid:
Figure imgf000219_0001
Step 1 : 2-(2-Fluoro-4-isopropylphenylN)-6-methoxy-3.4-dihvdroisoquinolin-l(2HN)-one
Figure imgf000219_0002
[00448] To 2-(2-fluoro-4-(prop-l-en-2-yl)phenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one (0.069 g, 0.222 mmol) was added methanol (1 mL). Tetrahydropyran (1.5mL) was added until compound was dissolved. A scoop of 10% palladium on carbon was added, then the reaction solution was purged with hydrogen and left with a hydrogen balloon at rt for 1 h. The reaction was filter through a syringe filter and concentrated to afford product (69 mg, 99 % yield) as a clear oil. LC MS (m/z, MH+): 314.4. ¾ NMR (400 MHz, Chloroform-d) δ 8.03 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.00 - 6.92 (m, 2H), 6.81 (dd, J = 8.7, 2.6 Hz, 1H), 6.71 - 6.62 (m, 1H), 3.80 (s, 5H), 3.04 (t, J = 6.4 Hz, 2H), 2.85 (hept, J = 6.9 Hz, 1H), 1.18 (d, J = 6.9 Hz, 6H). 19F NMR (376 MHz, Chloroform-d) δ -120.45 (s, IF).
[00449] Step 2: l-(4-bromophenyl)-2-(2-fluoro-4-isopropylphenyl)-6-methoxy-l- methyl- 1 ,2,3 ,4-tetrahydroisoquinoline :
Figure imgf000220_0001
[00450] To a 40ml scintillation vial was added l-bromo-4-iodobenzene (0.187 g, 0.661 mmol) and pentanes (1.737 ml). The reaction vial was charged with 2.5 M n-butyllithium in hexanes (0.267 ml, 0.667 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C and a solution of 2-(2-fluoro-4-isopropylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.069 g, 0.220 mmol) in tetrahydrofuran (1.241 ml) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was then quenched with water (2.7 mL) and ethyl acetate (2.7 mL) and warmed to rt. Perchloric acid (0.081 ml, 0.947 mmol) was added and the reaction mixture stirred for at r.t for 30 minutes. The reaction was diluted water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to give to give iminium intermediate which was used crude in the next step. LC MS (m/z, MH+): 454.4.
[00451] Iminium intermediate was dissolved in tetrahydrofuran (1.427 ml) and cooled to 0 °C. A 1.4 M solution of methylmagnesium bromide in tetrahydrofuran (0.472 ml, 0.661 mmol) was added dropwise to the reaction mixture. The reaction mixture was then warmed to rt and stirred for 1 h. The reaction was quenched with a saturation ammonium chloride and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated. Crude material was purified by silica gel chromatography (0-25% ethyl acetate )heptane to afford product (78 mg, 76 % yield) as a yellow oil. LC/MS (m/z, MH+): 470.4. ¾ NMR (400 MHz, Chloroform-d) δ 7.23 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.1 Hz, 2H), 6.81 - 6.74 (m, 2H), 6.67 - 6.52 (m, 3H), 6.36 (s, 1H), 3.74 (s, 3H), 3.38 - 3.14 (m, 2H), 2.84 (q, J = 14.4, 11.3 Hz, 2H), 2.73 (h, J = 6.8 Hz, 1H), 1.66 (s, 3H), 1.12 (dd, J = 7.0, 1.5 Hz, 6H). 19F NMR (376 MHz, Chloroform-d) δ -118.17 (s, IF).
[00452] Step 3: (E)-Methyl 3-(4-(2-(2-fluoro-4-isopropylphenyl)-6-methoxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate:
Figure imgf000221_0001
[00453] To a 40 mL vial was added l-(4-bromophenyl)-2-(2-fluoro-4-isopropylphenyl)-
6-methoxy-l -methyl- 1,2,3 ,4-tetrahydroisoquinoline (0.078 g, 0.167 mmol), PdCl2(PPh3)2 (0.058 g, 0.083 mmol), dimethylformamide (1.110 ml), triethylamine (0.116 ml, 0.833 mmol), and methyl acrylate (0.151 ml, 1.665 mmol). The reaction mixture was heated for 1 h at 130 °C. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford product (55 mg, 69.7 % yield) as a light yellow oil. LC MS (m/z, MH+): 474.5. ¾ NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 16.0 Hz, 1H), 7.29 (s, 2H), 7.15 (t, J = 8.4 Hz, 2H), 6.83 - 6.73 (m, 2H), 6.62 (d, J = 8.6 Hz, 2H), 6.53 (dd, J = 8.3, 2.1 Hz, 1H), 6.39 - 6.25 (m, 2H), 3.72 (d, J = 7.1 Hz, 6H), 3.37 - 3.15 (m, 2H), 2.80 (dddd, J = 41.3, 20.7, 10.6, 5.7 Hz, 3H), 1.67 (d, J = 1.8 Hz, 3H), 1.10 (dd, J = 6.9, 1.8 Hz, 6H). 19F NMR (376 MHz, Chloroform-d) δ -118.20 (s, IF).
[00454] Step 4: (E)-Methyl 3-(4-(2-(2-fluoro-4-isopropylphenyl)-6-hydroxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate:
Figure imgf000221_0002
[00455] (E)-Methyl 3-(4-(2-(2-fluoro-4-isopropylphenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.055 g, 0.116 mmol) was dissolved in
dichloromethane (1.161 ml) and cooled to 0 °C. Aluminum chloride (0.124 g, 0.929 mmol) was added followed by the addition of ethanethiol (0.172 ml, 2.323 mmol). The reaction was stirred at 0°C for 2 h. The reaction was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-30% ethyl acetate/heptanes) to afford product (41 mg, 77 % yield) as a light brown oil. LC MS (m/z, MH+): 460.5. 'HNMR (400 MHz, Chloroform-d) δ 7.49 (d, J = 16.0 Hz, 1H), 7.18 (d, J = 8.1 Hz, 2H), 7.04 (d, J = 7.9 Hz, 2H), 6.72 - 6.61 (m, 2H), 6.51 - 6.40 (m, 3H), 6.30 - 6.18 (m, 2H), 3.63 (s, 3H), 3.26 - 3.04 (m, 2H), 2.68 (dtd, J = 40.4, 15.0, 13.8, 6.3 Hz, 3H), 1.57 (s, 3H), 1.01 (dd, J = 6.8, 1.9 Hz, 6H). 19F NMR (376 MHz, Chloroform-d) δ -118.23 (s, IF).
[00456] Step 5: (Example 103) (E)-3-(4-(2-(2-fluoro-4-isopropylphenyl)-6-hydroxy-l- methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid: (E)-m ethyl 3-(4-(2-(2-fluoro-4- isopropylphenyl)-6-hydroxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl)acrylate (0.041 g, 0.089 mmol) was dissolved in 1,4-dioxane (1.5 ml). To this, 1 M lithium hydroxide (0.446 ml, 0.446 mmol) was added. The reaction was heated to 40 °C and stirred for 2 h. The reaction was cooled to rt and acidified to pH 1 with 1 M HC1. The reaction mixture was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to afford product (27 mg, 0.057 mmol, 63.9 % yield) as a cream colored solid. LC MS (m/z, MH+): 446.5. ¾ NMR (400 MHz, Methanol-d4) δ 7.61 (d, J = 16.0 Hz, 1H), 7.39 (d, J = 8.3 Hz, 2H), 7.25 - 7.17 (m, 2H), 6.86 (dd, J = 12.7, 2.0 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.65 - 6.55 (m, 3H), 6.50 - 6.36 (m, 2H), 3.26 (q, J = 6.2 Hz, 2H), 2.88 - 2.69 (m, 3H), 1.70 (d, J = 2.0 Hz, 3H), 1.16 (dd, J = 6.8, 1.9 Hz, 6H). 19F NMR (376 MHz, Methanol-d4) δ -119.38 (s, IF).
Example 104
(E)-3-(4-(2-(4-(sec-Butyl)phenyl)-6-hvdroxy-l-methyl-1.2.3.4-tetrahvdroisoquinolin-l- vDphenvDacrylic acid:
Figure imgf000222_0001
[00457] Step 1 : 2-(4-Acetylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one: 6-
Methoxy-3,4-dihydroisoquinolin-l(2H)-one (1 g, 5.64 mmol) was dissolved in
dimethylformamide (14.11 ml). l-(4-iodophenyl)ethanone (2.92 g, 11.85 mmol) and potassium carbonate (1.560 g, 11.29 mmol) were added. The reaction mixture was flushed with nitrogen and copper(I) iodide (0.645 g, 3.39 mmol) was added. The reaction mixture was heated to 150 °C for 72 h. The reaction mixture was diluted with dichloromethane, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-70% ethyl acetate/heptanes) to afford a white-brown solid containing a large amount of DMF. The material was transferred to a 30 mL vial and DMF was removed on the VI 0 evaporator through 5 rounds of evaporation with dilution of the sample with aceonitrile and water to afford product (942 mg, 56.5 % yield). LC MS (m/z, MH+): 296.4. ¾ NMR (400 MHz, CHLOROFORM-d) δ 2.61 (s, 3 H), 3.13 (t, J=6.32 Hz, 2 H), 3.88 (s, 3 H), 4.04 (d, J=6.57 Hz, 2 H), 6.74 (d, J=2.53 Hz, 1 H), 6.90 (dd, J=8.59, 2.53 Hz, 1 H), 7.44 - 7.55 (m, 2 H), 7.96 - 8.03 (m, 2 H), 8.11 (d, J=8.59 Hz, 1 H).
[00458] Step 2: (E)-2-(4-(But-2-en-2-yl)phenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one and (Z)-2-(4-(but-2-en-2-yl)phenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one: Under nitrogen, bromo(ethyl)triphenylphosphorane (0.0719 g, 0.194 mmol) was dissolved in ether (0.775 ml). A 2.5M solution of n-butyllithium in hexanes (0.085 ml, 0.213 mmol) was added dropwise and the reaction stirred at rtfor 2 h. A solution of 2-(4-acetylphenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (0.063 g, 0.213 mmol) in tetrahydropyran (1 mL) was added. The reaction was then heated to 50 °C for 4 h and to 60 °C overnight. The reaction was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatographys (0-50% ethyl acetate/heptanes) to afford a 1 : 1 mixture of E:Z. products (29 mg, 0.094 mmol, 48.7 % yield) as an orange solid. LC MS (m/z, MH+): 308.4. ¾ NMR (400 MHz, Chloroform-d) δ 7.93 (dd, J = 8.7, 2.6 Hz, 1H), 7.25 - 7.10 (m, 3H), 7.11 - 7.01 (m, 1H), 6.71 (dt, J = 8.7, 2.7 Hz, 1H), 6.55 (t, J = 2.5 Hz, 1H), 5.55 (dqd, J = 114.8, 6.6, 1.6 Hz, 1H), 3.80 (dt, J = 10.4, 6.5 Hz, 2H), 3.73 - 3.64 (m, 3H), 2.92 (td, J = 6.4, 4.2 Hz, 2H), 1.85 (p, J = 1.6 Hz, 3H), 1.68 - 1.41 (m, 3H).
[00459] Step 3: 2-(4-(sec-Butyl)phenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one:
To (E)-2-(4-(but-2-en-2-yl)phenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one and (Z)-2-(4- (but-2-en-2-yl)phenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.029 g, 0.094 mmol) was added methanol (1.5 mL). Tetrahydropyran (0.5mL) was added until starting material was dissolved. A scoop of 10% palladium on carbon was added, then the reaction solution was purged with hydrogen and left with a hydrogen balloon at rt for 1 h . The reaction was filter through a syringe filter and concentrated to afford product (30 mg, 103 % yield) as a yellow solid. LC/MS (m/z, MH+): 310.1. ¾ NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 8.7 Hz, 1H), 7.26 - 7.19 (m, 2H), 7.16 - 7.04 (m, 2H), 6.80 (dd, J = 8.6, 2.5 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 3.92 - 3.84 (m, 2H), 3.78 (s, 3H), 3.01 (t, J = 6.4 Hz, 2H), 2.53 (h, J = 7.0 Hz, 1H), 1.52 (pd, J = 7.3, 1.8 Hz, 2H), 1.16 (d, J = 7.0 Hz, 3H), 0.77 (t, J = 7.4 Hz, 3H).
[00460] Step 4: l-(4-Bromophenyl)-2-(4-(sec-butyl)phenyl)-6-methoxy-l-methyl-
1,2,3,4-tetrahydroisoquinoline: To a 40ml scintillation vial was added l-bromo-4-iodobenzene (0.362 g, 1.280 mmol) and pentanes (1.682 ml). The reaction vial was charged with 2.5 M n- butyllithium in hexanes (0.515 ml, 1.286 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C and a solution of 2-(4-(sec-butyl)phenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.066 g, 0.213 mmol) in tetrahydrofuran (1.202 ml) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was then quenched with water (2.6 mL) and ethyl acetate (2.6 mL) and warmed to rt. Perchloric acid (0.079 ml, 0.917 mmol) was added and the reaction mixture was stirred at rt for 30 minutes. The reaction was diluted water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to give iminum intermediate which was used crude in the next step. LC MS (m/z, MH+): 451.4.
[00461] Iminium intermediate was dissolved in tetrahydrofuran (1.382 ml) and cooled to 0 °C. A 1.4M solution of methylmagnesium bromide in tetrahydrofuran (0.457 ml, 0.640 mmol) was added dropwise and the reaction was stirred at 0°C for 1 hour. The reaction was quenched with saturation ammonium chloride and extracted with dichloromethane three times.
The organic layers were combined, passed through a phase separator and concentrated. Crude material was purified by silica gel chromatography (0-25% ethyl acetate/heptane) to afford product (68 mg, 68.6 % yield) as a light green oil. LC MS (m/z, MH+): 465.9. ¾ NMR (400
MHz, Chloroform-d) δ 7.26 - 7.20 (m, 2H), 7.03 - 6.97 (m, 2H), 6.83 - 6.77 (m, 2H), 6.64 (d, J =
8.4 Hz, 1H), 6.59 - 6.52 (m, 2H), 6.50 - 6.43 (m, 2H), 3.69 (s, 3H), 3.41 - 3.23 (m, 2H), 3.02 (ddd,
J = 16.0, 8.6, 5.0 Hz, 1H), 2.84 (dt, J = 16.1, 4.6 Hz, 1H), 2.40 (h, J = 7.0 Hz, 1H), 1.63 - 1.55 (m,
3H), 1.43 (p, J = 7.3 Hz, 2H), 1.08 (d, J = 7.0 Hz, 3H), 0.69 (td, J = 7.4, 1.5 Hz, 3H).
[00462] Step 5: (E)-Methyl 3-(4-(2-(4-(sec-butyl)phenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate: To a 40 mL vial, l-(4-bromophenyl)-2-(4-(sec- butyl)phenyl)-6-methoxy-l -methyl- 1, 2,3 ,4-tetrahydroisoquinoline (0.068 g, 0.146 mmol),
PdCl2(PPh3)2 (0.051 g, 0.073 mmol), dimethylformamide (0.976 ml), triethylamine (0.102 ml,
0.732 mmol), and methyl acrylate (0.265 ml, 2.93 mmol) were added. The reaction mixture was heated for 1 h at 130 °C. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford product (38 mg, 55.3 % yield) as a yellow oil. LC MS (m/z, MH+): 470.5. 'HNMR (400 MHz, Chloroform-d) δ 7.59 (d, J = 16.0 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.21 - 7.13 (m, 2H), 6.82 - 6.75 (m, 2H), 6.67 (d, J = 8.6 Hz, 1H), 6.61 - 6.53 (m, 2H), 6.50 - 6.43 (m, 2H), 6.32 (d, J = 16.0 Hz, 1H), 3.71 (d, J = 6.1 Hz, 6H), 3.43 - 3.25 (m, 2H), 3.05 (ddd, J = 16.2, 8.6, 5.2 Hz, 1H), 2.86 (dt, J = 16.1, 4.5 Hz, 1H), 2.39 (h, J = 7.0 Hz, 1H), 1.62 (s, 3H), 1.42 (pd, J = 7.3, 1.1 Hz, 2H), 1.08 (d, J = 6.9 Hz, 3H), 0.69 (td, J = 7.4, 1.5 Hz, 3H).
[00463] Step 6: (E)-methyl 3-(4-(2-(4-(sec-butyl)phenyl)-6-hydroxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate: (E)-Methyl 3-(4-(2-(4-(sec-butyl)phenyl)-6-methoxy- 1 -methyl- 1, 2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.038 g, 0.081 mmol) was dissolved in dichloromethane (0.809 ml) and cooled to 0°C. Aluminum chloride (0.086 g, 0.647 mmol) was added followed by the addition of ethanethiol (0.120 ml, 1.618 mmol). The reaction was stirred at 0°C for 2 h. The reaction was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-30% ethyl acetate/heptanes) to afford product (20.6 mg, 55.9 % yield) as a yellow oil. LC MS (m/z, MH+): 456.6 'HNMR (400 MHz, Chloroform-d) δ 7.70 (d, J = 16.0 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.27 (d, J = 7.9 Hz, 2H), 6.89 (d, J = 8.1 Hz, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 2.7 Hz, 1H), 6.62 - 6.52 (m, 3H), 6.43 (d, J = 16.0 Hz, 1H), 3.83 (s, 3H), 3.44 (ddt, J = 22.3, 12.2, 5.5 Hz, 2H), 3.11 (ddd, J = 14.5, 8.5, 5.4 Hz, 1H), 2.93 (dt, J = 16.8, 4.4 Hz, 1H), 2.50 (h, J = 7.0 Hz, 1H), 1.72 (s, 3H), 1.53 (pd, J = 7.5, 1.1 Hz, 2H), 1.18 (d, J = 6.9 Hz, 3H), 0.79 (td, J = 7.4, 1.6 Hz, 3H).
[00464] Step 7: (Example 104) (E)-methyl 3-(4-(2-(4-(sec-butyl)phenyl)-6-hydroxy-l- methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.0206 g, 0.045 mmol) was dissolved in 1,4-dioxane (Volume: 1 mL). To this, 1 M lithium hydroxide (0.226 mL, 0.226 mmol) was added. The reaction was heated to 40 °C for 2 h. The reaction was cooled to rt and acidified to pH 1 with 1 M HC1. The reaction mixture was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to afford product (13.9 mg, 67.5 % yield) as a cream colored solid. LC/MS (m/z, MH+): 442.6. ¾ NMR (400 MHz, Methanol-d4) δ 7.64 (d, J = 16.1 Hz, 1H), 7.47 - 7.38 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.90 - 6.81 (m, 2H), 6.65 - 6.55 (m, 4H), 6.50 (dd, J = 8.5, 2.6 Hz, 1H), 6.44 (d, J = 16.0 Hz, 1H), 3.51 - 3.42 (m, 1H), 3.39 - 3.33 (m, 1H), 3.14 - 3.02 (m, 1H), 2.88 (dt, J = 16.1, 4.5 Hz, 1H), 2.45 (p, J = 6.9 Hz, 1H), 1.68 (s, 3H), 1.57 - 1.46 (m, 2H), 1.15 (dd, J = 7.0, 1.4 Hz, 3H), 0.76 (t, J = 7.4 Hz, 3H). Example 105
(E)-3 -(4-(6-Hydroxy-2-(4-isopentylphenyl)- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylic acid:
Figure imgf000226_0001
[00465] Step 1 : 4-(6-Methoxy-l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)benzaldehyde: 6-
Methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.75 g, 4.23 mmol) was dissolved in dimethyl- formamide (8.47 ml). 4-iodobenzaldehyde (1.473 g, 6.35 mmol) and potassium carbonate (1.170 g, 8.47 mmol) were added. The reaction mixture was flushed with nitrogen and copper(I) iodide (0.484 g, 2.54 mmol) was added. The reaction mixture was heated to 150 °C for 18 h. The reaction was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-75% ethyl acetate/heptane) to afford product (887 mg, 74.5 % yield) as a light yellow solid. LC MS (m/z, MH+): 282.3. ¾ NMR (400 MHz,
Chloroform-d) δ 9.82 (s, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.80 - 7.69 (m, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.74 (dd, J = 8.8, 2.6 Hz, 1H), 6.60 (d, J = 2.8 Hz, 1H), 3.90 (t, J = 6.4 Hz, 2H), 3.72 (s, 3H), 2.98 (t, J = 6.3 Hz, 2H).
[00466] Step 2: (E)-6-Methoxy-2-(4-(3-methylbut-l-en-l-yl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one and (Z)-6-methoxy-2-(4-(3-methylbut-l-en-l-yl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one: Under nitrogen, bromo(isobutyl)triphenylphosphorane (0.170 g,
0.427 mmol) was dissolved in tetrahydropyran (0.7M, 0.6 ml). A 2.5M solution of n-butyllithium in heptanes (0.185 ml, 0.462 mmol) was added dropwise and the reaction stirred at rt for 2 h. A solution of 4-(6-methoxy-l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)benzaldehyde (0.1 g, 0.355 mmol) in tetrahydropyran (0.5 mL) was added and the reaction was stirred at rt overnight. The reaction was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatographys (0-100% ethyl acetate/heptanes) to afford a 3: 1 E:Z ratio product (99 mg, 0.308 mmol, 87 % yield) as a white solid. LC MS (m/z, MH+): 322.4. ¾ NMR
(400 MHz, Chloroform-d) δ 8.13 (dd, J = 8.6, 2.6 Hz, 1H), 7.45 - 7.25 (m, 4H), 6.90 (dd, J = 8.6, 2.4 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.41 - 6.27 (m, 1H), 6.25 - 5.45 (m, 1H), 3.98 (dt, J = 9.8,
6.5 Hz, 2H), 3.88 (s, 3H), 3.15 - 3.07 (m, 2H), 3.03 - 2.88 (m, 1H), 1.10 (dd, J = 19.6, 6.7 Hz, 6H).
[00467] Step 3 : 2-(4-Isopentylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one:
To (E)-6-methoxy-2-(4-(3-methylbut-l-en-l-yl)phenyl)-3,4-dihydroisoquinolin-l(2H)-on^ and (Z)-6-methoxy-2-(4-(3 -methylbut- 1 -en- 1 -yl)phenyl)-3 ,4-dihydroisoquinolin- 1 (2H)-one (0.099 g, 0.308 mmol) was added methanol (3.08 ml). Tetrahydropyran (0.5mL) was added until compound was dissolved. A scoop of 10% palladium on carbon was added and the reaction mixture was purged with hydrogen and left with a hydrogen balloon at rt for 3h. The reaction was filter through a syringe filter and concentrated to afford product (96 mg, 96 % yield) as a yellow solid. LC MS (m/z, MH+): 324.4. ¾ NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 8.6 Hz, 1H), 7.22 - 7.15 (m, 2H), 7.15 - 7.08 (m, 2H), 6.78 (dd, J = 8.6, 2.5 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 3.85 (t, J = 6.4 Hz, 2H), 3.76 (s, 3H), 2.99 (t, J = 6.4 Hz, 2H), 2.58 - 2.47 (m, 2H), 1.53 (dq, J = 13.1, 6.6 Hz, 1H), 1.46 - 1.38 (m, 2H), 0.85 (d, J = 6.5 Hz, 6H).
[00468] Step 4: l-(4-Bromophenyl)-2-(4-isopentylphenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinoline: To a 40ml scintillation vial was added l-bromo-4-iodobenzene (0.504 g, 1.781 mmol) and pentanes (2.341 ml). The reaction vial was charged with 2.5 M n-butyllithium in hexanes (0.716 ml, 1.790 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 hour at which time, the reaction mixture was cooled to -78 °C and a solution of 2-(4-isopentylpheny l)-6-methoxy -3 ,4-dihydroisoquinolin- l(2H)-one (0.096 g, 0.297 mmol) in tetrahydrofuran (1.672 ml) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was then quenched with water (3.7 mL) and ethyl acetate (3.7 mL) and warmed to rt. Perchloric acid (0.110 ml, 1.276 mmol) was added and the reaction mixture was stirred for 30 minutes at rt. The reaction mixture was diluted with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to give iminum intermediate which was used crude in the next step. LC MS (m/z, MH+): 465.5.
[00469] Iminium intermediate was dissolved in tetrahydrofuran (1.923 ml) and cooled to 0 °C. A 1.4M solution of methylmagnesium bromide in tetrahydrofuran (0.636 ml, 0.890 mmol) was added dropwise. The mixture was warmed to rt and stirred for 1 h. The reaction was quenched with saturation ammonium chloride and extracted with dichloromethane three times.
The organic layers were combined, passed through a phase separator and concentrated. Crude material was purified by silica gel chromatography (0-25% ethyl acetate/heptane) to afford product (76 mg, 53.5 % yield) as a brown oil. LC MS (m/z, MH+): 480.5. ¾ NMR (400 MHz, Chloroform-d) δ 7.24 (dd, J = 8.5, 1.8 Hz, 2H), 7.00 (dd, J = 8.5, 1.9 Hz, 2H), 6.85 - 6.77 (m, 2H), 6.64 (d, J = 8.6 Hz, 1H), 6.56 (dt, J = 10.7, 2.5 Hz, 2H), 6.46 (dd, J = 8.2, 1.8 Hz, 2H), 3.70 (d, J = 1.6 Hz, 3H), 3.35 (ddd, J = 12.5, 8.4, 3.8 Hz, 1H), 3.26 (dt, J = 11.6, 5.0 Hz, 1H), 3.03 (ddd, J = 14.1, 8.6, 4.9 Hz, 1H), 2.84 (dt, J = 16.1, 4.5 Hz, 1H), 2.47 - 2.35 (m, 2H), 1.58 (s, 3H), 1.51 - 1.41 (m, 1H), 1.39 - 1.31 (m, 2H), 0.83 (dd, J = 6.5, 1.7 Hz, 6H).
[00470] Step 5: (E)-methyl 3 -(4-(2-(4-isopentylphenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate: To a 40 mL vial l-(4-bromophenyl)-2-(4- isopentylphenyl)-6-methoxy-l -methyl- 1, 2,3 ,4-tetrahydroisoquinoline (0.076 g, 0.159 mmol), PdCl2(PPh3)2 (0.056 g, 0.079 mmol), dimethylformamide (1.059 ml), triethylamine (0.111 ml, 0.794 mmol), and methyl acrylate (0.288 ml, 3.18 mmol) were added. The reaction mixture was heated for 1 h at 130 °C. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford product (33 mg, 43.0 % yield) as a yellow oil. LC MS (m/z, MH+): 484.6. ¾ NMR (400 MHz, Chloroform-d) δ 7.63 - 7.55 (m, 1H), 7.34 - 7.26 (m, 2H), 7.17 (dd, J = 7.2, 1.5 Hz, 2H), 6.83 - 6.76 (m, 2H), 6.66 (d, J = 8.6 Hz, 1H), 6.61 - 6.53 (m, 2H), 6.49 - 6.43 (m, 2H), 6.32 (d, J = 16.0 Hz, 1H), 3.72 (d, J = 5.6 Hz, 6H), 3.38 (ddd, J = 12.5, 9.0, 4.1 Hz, 1H), 3.29 (dt, J = 11.9, 4.9 Hz, 1H), 3.06 (ddd, J = 14.2, 8.7, 4.8 Hz, 1H), 2.86 (dt, J = 16.2, 4.4 Hz, 1H), 2.47 - 2.36 (m, 2H), 1.62 (s, 3H), 1.46 (p, J = 6.8 Hz, 1H), 1.39 - 1.31 (m, 2H), 0.85 - 0.81 (m, 6H).
[00471] Step 6: (E)-Methyl 3-(4-(6-hydroxy-2-(4-isopentylphenyl)-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate: (E)-methyl 3-(4-(2-(4-isopentylphenyl)-6-methoxy-l- methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.033 g, 0.068 mmol) was dissolved in dichloromethane (0.682 ml) and cooled to 0 °C. Aluminum chloride (0.073 g, 0.546 mmol) was added followed by the addition of ethanethiol (0.101 ml, 1.365 mmol). The reaction was stirred at
0 °C for 2 h. The reaction was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-30% ethyl acetate/heptanes) to afford product (29.5 mg, 92 % yield) as a yellow oil. LC/MS (m/z, MH+):
570.6. ¾ NMR (400 MHz, Chloroform-d) δ 7.51 (d, J = 16.0 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H),
7.14 - 7.03 (m, 2H), 6.70 (d, J = 8.0 Hz, 2H), 6.51 (d, J = 8.6 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H),
6.43 - 6.33 (m, 3H), 6.24 (d, J = 15.9 Hz, 1H), 3.64 (s, 3H), 3.32 - 3.13 (m, 2H), 2.92 (ddd, J = 14.1, 8.6, 4.9 Hz, 1H), 2.77 - 2.68 (m, 1H), 2.36 - 2.26 (m, 2H), 1.52 (s, 3H), 1.36 (dt, J = 13.1, 6.6 Hz, 1H), 1.30 - 1.21 (m, 2H), 0.75 - 0.72 (m, 6H).
[00472] Step 7: (Example 105) (E)-3-(4-(6-Hydroxy-2-(4-isopentylphenyl)-l-methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid: (E)-Methyl 3-(4-(6-hydroxy-2-(4- isopentylphenyl)-l-methyl-l,2,3,4 etrahydroisoquinolin-l-yl)phenyl)acrylate (0.0295 g, 0.063 mmol) was dissolved in 1,4-dioxane (0.628 ml). To this, 1 M lithium hydroxide (0.314 ml, 0.314 mmol) was added. The reaction was heated to 40 °C for 2 h. The reaction was cooled to rt and acidified to pH 1 with 1 M HC1. The reaction mixture was extracted three times with
dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to afford product (17.4 mg, 59.0 % yield) as a light yellow solid. LC MS (m/z, MH+): 456.5. ¾ NMR (400 MHz, Methanol-d4) δ 7.63 (d, J = 16.0 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.6 Hz, 1H), 6.59 - 6.53 (m, 3H), 6.49 (dd, J = 8.6, 2.7 Hz, 1H), 6.44 (d, J = 16.0 Hz, 1H), 3.44 (td, J = 8.6, 4.4 Hz, 1H), 3.35 (d, J = 5.0 Hz, 1H), 3.08 (ddd, J = 14.2, 8.7, 5.0 Hz, 1H), 2.88 (dt, J = 15.9, 4.5 Hz, 1H), 2.52 - 2.44 (m, 2H), 1.67 (s, 3H), 1.51 (dq, J = 13.2, 6.6 Hz, 1H), 1.46 - 1.37 (m, 2H), 0.90 (d, J = 6.5 Hz, 6H).
Example 106
(E)-3 -(4-(2-(4-(Cvclopropylmethyl)phenyl)-6-hvdroxy- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylic acid
Figure imgf000229_0001
[00473] Step 1 : 2-(4-(Cyclopropylidenemethyl)phenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one: Under nitrogen, bromo(3-bromopropyl)triphenylphosphorane (0.091 g, 0.196 mmol) was dissolved in tetrahydropyran (0.889 ml). Potassium tert-butoxide (0.391 ml, 0.391 mmol) was added in two portions and the reaction stirred at 60 °C for 10 mins. The preformed ylide was then added to a solution of 4-(6-methoxy-l-oxo-3,4-dihydroisoquinolin- 2(lH)-yl)benzaldehyde (0.05 g, 0.178 mmol, see previous example 104) in tetrahydropyran (1 mL). The reaction mixture was heated to 60 °C for 4 h. The reaction was concentrated and purified by silica gel chromatographys (0-50% ethyl acetate/heptanes) to afford product (18 mg, 33.2 % yield) as a white solid. LC MS (m/z, MH+): 306.4. ¾ NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 8.6 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.40 - 7.32 (m, 2H), 6.90 (dd, J = 8.7, 2.6 Hz, 1H), 6.80 - 6.70 (m, 2H), 3.99 (dd, J = 7.0, 6.0 Hz, 2H), 3.89 (s, 3H), 3.12 (t, J = 6.4 Hz, 2H), 1.44 (ddd, J = 9.8, 5.7, 2.2 Hz, 2H), 1.21 (ddd, J = 9.8, 5.7, 1.8 Hz, 2H).
[00474] Step 2: 2-(4-(Cyclopropylmethyl)phenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one and 2-(4-butylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one: To 2-(4- (cyclopropylidenemethyl)phenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.03 g, 0.098 mmol) was added methanol (1.5 mL). Tetrahydropyran (2.0 mL) was added until compound was dissolved. A scoop of 10% palladium on carbon was added and the reaction mixture was purged with hydrogen and left with a hydrogen balloon at rt for 3 h. The reaction was filtered through a syringe filter and concentrated to afford a 1 : 1 mixture of products (29 mg, 96 % yield) as a white solid. LC MS (m/z, MH+): 308.3. ¾ NMR (400 MHz, Chloroform-d) δ 7.88 (dd, J = 8.6, 1.5 Hz, 1H), 7.06 (d, J = 11.6 Hz, 3H), 7.01 - 6.95 (m, 1H), 6.66 (dd, J = 8.8, 2.5 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 3.74 (td, J = 6.4, 3.3 Hz, 2H), 3.64 (s, 3H), 3.56 - 3.50 (m, 1H), 2.87 (td, J = 6.5, 1.8 Hz, 2H), 2.43 - 2.36 (m, 1H), 2.33 (d, J = 6.9 Hz, 1H), 1.67 - 1.61 (m, 1H), 1.44 - 1.34 (m, 1H), 1.15 (dq, J = 14.6, 7.3 Hz, 1H), 0.71 (t, J = 7.3 Hz, 2H), 0.35 - 0.28 (m, 1H).
[00475] Step 3 : l-(4-Bromophenyl)-2-(4-(cyclopropylmethyl)phenyl)-6-methoxy-l- methyl- 1 ,2,3 ,4-tetrahydroisoquinoline and 1 -(4-bromophenyl)-2-(4-butylphenyl)-6-methoxy- 1 - methyl- 1, 2,3 ,4-tetrahydroisoquinoline: To a 40ml scintillation vial was added l-bromo-4- iodobenzene (0.160 g, 0.566 mmol) and pentanes (0.744 ml). The reaction vial was charged with 2.5 M n-butyllithium in hexanes (0.228 ml, 0.569 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C and a solution of 2-(4-(cyclopropylmethyl)phenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one and 2-(4-butylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)- one (0.029 g, 0.094 mmol) in tetrahydrofuran (0.532 ml) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was then quenched with water (1.1 mL) and ethyl acetate (1.1 mL) and warmed to rt. Perchloric acid (0.035 ml, 0.406 mmol) was added and the reaction mixture was stirred for 30 minutes at rt. The reaction mixture was diluted with water and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give iminum intermediate which was used crude in the next step. LC/MS (m/z, MH+): 448.3. [00476] Iminium intermediate was dissolved in tetrahydrofuran (0.611 ml) and was cooled to 0 °C. A 1.4 M solution of methylmagnesium bromide in tetrahydrofuran (0.202 ml, 0.283 mmol) was added dropwise. The mixture was warmed to rt and stirred for 1 h. The reaction was quenched with saturation ammonium chloride and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated. Crude material was purified by silica gel chromatography (0-25% ethyl acetate/heptanes) to afford a 1 :1 mixture products (42 mg, 96 % yield) as a clear oil. LC MS (m/z, MH+): 462.4 and 466.4. ¾ NMR (400 MHz, Chloroform-d) δ 7.17 (dd, J = 8.6, 2.8 Hz, 2H), 6.97 - 6.89 (m, 2H), 6.82 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.56 (dd, J = 8.6, 2.2 Hz, 1H), 6.53 - 6.45 (m, 2H), 6.43 - 6.34 (m, 2H), 3.63 (s, 3H), 3.28 (ddt, J = 12.7, 8.5, 4.1 Hz, 1H), 3.19 (dq, J = 10.9, 5.1 Hz, 1H), 2.95 (ddd, J = 16.1, 8.7, 4.9 Hz, 1H), 2.77 (dt, J = 16.0, 4.5 Hz, 1H), 2.38 - 2.31 (m, 1H), 2.29 (d, J = 6.8 Hz, 1H), 1.51 (d, J = 4.3 Hz, 3H), 1.38 (tt, J = 8.0, 6.3 Hz, 1H), 1.21 - 1.12 (m, 3H), 0.37 - 0.30 (m, 1H), -0.01 (q, J = 4.9 Hz, 1H).
[00477] Step 4: (E)-Methyl 3-(4-(2-(4-(cyclopropylmethyl)phenyl)-6-methoxy-l- methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate and (E)-methyl 3-(4-(2-(4- butylphenyl)-6-methoxy-l-methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate: To a 40 mL vial 1 -(4-bromophenyl)-2-(4-(cyclopropylmethyl)phenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4- tetrahydroisoquinoline and 1 -(4-bromophenyl)-2-(4-butylphenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4- tetrahydroisoquinoline (0.042 g, 0.091 mmol), PdCl2(PPh3)2 (0.032 g, 0.045 mmol),
dimethylformamide (0.91 mL), triethylamine (0.063 ml, 0.454 mmol), and methyl acrylate (0.082 ml, 0.908 mmol) were added. The reaction mixture was heated for 1 h at 130 °C. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford 1 : 1 mixture of products (19 mg, 0.041 mmol, 44.7 % yield) as a yellow oil. LC MS (m/z, MH+): 468.5 and 470.5. ¾ NMR (400 MHz, Chloroform-d) δ 7.53 (d, J = 16.0 Hz, 1H), 7.24 (dd, J = 8.2, 2.9 Hz, 2H), 7.17 - 7.08 (m, 2H), 6.85 - 6.78 (m, 1H), 6.76 - 6.68 (m, 1H), 6.59 (dd, J = 8.6, 2.5 Hz, 1H), 6.56 - 6.45 (m, 2H), 6.45 - 6.34 (m, 2H), 6.26 (d, J = 15.8 Hz, 1H), 3.65 (d, J = 5.5 Hz, 6H), 3.37 - 3.19 (m, 2H), 2.99 (ddd, J = 15.3, 8.6, 5.0 Hz, 1H), 2.79 (dt, J = 16.1, 4.5 Hz, 1H), 2.37 - 2.31 (m, 1H), 2.29 (d, J = 6.8 Hz, 1H), 1.55 (d, J = 4.4 Hz, 3H), 1.46 - 1.30 (m, 1H), 1.23 - 1.10 (m, 2H), 0.75 (td, J = 7.3, 4.5 Hz, 2H), 0.37 - 0.28 (m, 1H), 0.15 - -0.13 (m, 1H). [00478] Step 5: (E)-Methyl 3-(4-(2-(4-(cyclopropylmethyl)phenyl)-6-hydroxy-l- methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate and (E)-methyl 3-(4-(2-(4- butylphenyl)-6-hydroxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl)acrylate:
[00479] (E)-methyl 3-(4-(2-(4-(cyclopropylmethyl)phenyl)-6-methoxy-l-methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate and (E)-methyl 3-(4-(2-(4-butylphenyl)-6- methoxy-l-methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.019 g, 0.041 mmol) were dissolved in dichloromethane (0.406 ml). 1M BBr3 in heptanes (0.203 ml, 0.203 mmol) was added and the reaction stirred at rt for 30 minutes. The reaction was carefully quenched with saturated sodium bicarbonate and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to afford product as a brown oil. The material was taken on crude to the next step. LC MS (m/z, MH+): 454.1 and 456.2
[00480] Step 6: (Example 106) (E)-3-(4-(2-(4-(Cyclopropylmethyl)phenyl)-6-hydroxy-
1 -methyl- 1, 2,3 ,4-tetrahydroisoquinolin- l-yl)phenyl)acrylic acid: (E)-Methyl 3-(4-(2-(4- (cyclopropylmethyl)phenyl)-6-hydroxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 - yl)phenyl)acrylate and (E)-methyl 3 -(4-(2-(4-butylphenyl)-6-hydroxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin- l-yl)phenyl)acrylate (18.60 mg, 0.041 mmol) were dissolved in 1,4-dioxane (Volume: 1 ml). To this, 1 M lithium hydroxide (0.205 ml, 0.205 mmol) was added. The reaction was heated to 40 °C for 2 h. The reaction was cooled to rt and acidified to pH 1 with 1 M HCl. The reaction mixture was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by reverse phase HPLC (0.1% TFA modifier in 25-50% acetonitrile/water) to afford product (4.6 mg, 8.06 μιηοΐ, 19.66 % yield) as a white solid. LC MS (m/z, MH+): 440.5. ¾ NMR (400 MHz, DMSO-d6) δ 7.59 - 7.50 (m, 3H), 7.29 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 6.61 - 6.43 (m, 6H), 3.31 (s, 1H), 3.08 (s, 2H), 2.83 (s, 1H), 2.35 (d, J = 7.0 Hz, 2H), 1.62 (s, 3H), 0.87 (q, J = 7.6, 6.5 Hz, 1H), 0.47 - 0.34 (m, 2H), 0.11 (q, J = 5.0 Hz, 2H).
Example 107
(E)-3 -(4-(6-hvdroxy-2-(4-isobutyl-3 -methylphenyl)- 1 -methyl- 1.2.3.4-tetrahydroisoquinolin- 1 - vDphenvDacrylic acid:
Figure imgf000233_0001
[00481] Step 1 : l-(Benzyloxy)-4-bromo-2-methylbenzene: 4-Bromo-2-methylphenol
(0.5 g, 2.67 mmol) was dissolved in dimethy If orm amide (5.35 ml). Potassium carbonate (0.739 g, 5.35 mmol) was added followed by benzyl bromide (0.350 ml, 2.94 mmol). The reaction was stirred at rt for 72 h. The reaction was quenched with water and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purfied by silica gel chromatography (0-30% ethyl acetate/heptanes) to afford product (732 mg, 2.64 mmol, 99 % yield) as a clear oil. ¾ NMR (400 MHz, Chloroform-d) δ 7.49 - 7.32 (m, 5H), 7.31 (dd, J = 2.6, 0.9 Hz, 1H), 7.26 (ddd, J = 8.6, 2.5, 0.7 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 5.08 (s, 2H), 2.28 (s, 3H).
[00482] Step 2: 2-(4-(Benzyloxy)-3-methylphenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one: 6-Methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.31 g, 1.749 mmol) was dissolved in dimethylformamide (3.50 ml). l-(benzyloxy)-4-bromo-2-methylbenzene (0.727 g, 2.62 mmol) and potassium carbonate (0.484 g, 3.50 mmol) were added. The reaction mixture was flushed with nitrogen and copper(I) iodide (0.200 g, 1.050 mmol) was added. The reaction mixture was heated to 150 °C for 48h. The reaction was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-75% ethyl acetate/heptanes) to afford product (498 mg, 76 % yield) as a light orange solid. LC MS (m/z, MH+):374.4. ¾ NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.46 - 7.38 (m, 2H), 7.38 - 7.32 (m, 1H), 7.23 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.6, 2.7 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.74 (d, J = 2.4 Hz, 1H), 5.11 (s, 2H), 3.91 (t, J = 6.4 Hz, 2H), 3.86 (s, 3H), 3.08 (t, J = 6.5 Hz, 2H), 2.35 (s, 3H).
[00483] Step 3: 2-(4-Hydroxy-3-methylphenyl)-6-methoxy-3,4-dihydroisoquinolin-
1 (2H)-one: 2-(4-(Benzyloxy)-3 -methylphenyl)-6-methoxy-3 ,4-dihydroisoquinolin- 1 (2H)-one (0.341 g, 0.913 mmol) was dissolved in ethanol (4.57 ml). Tetrahydropyran (9.0 ml) was added until compound was dissolved. A scoop of Pd(OH)2 was added. The reaction solution was purged with hydrogen and left with a hydrogen balloon at rt for 6 h. The reaction was filtered through a syringe filter and concentrated to afford product (0.341 g, quantative yield) as a white solid. LC MS (m/z, MH+): 284.3. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 6.99 - 6.88 (m, 3H), 6.76 (dd, J = 8.4, 2.0 Hz, 1H), 3.82 (d, J = 4.8 Hz, 5H), 3.05 (t, J = 6.5 Hz, 2H), 2.12 (s, 3H).
[00484] Step 4: 4-(6-Methoxy-l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)-2-methylphenyl trifluoromethanesulfonate: 2-(4-Hydroxy-3-methylphenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one (0.2 g, 0.706 mmol), N-phenyltrifluoromethanesulfonimide (0.303 g, 0.847 mmol), and potassium carbonate (0.293 g, 2.118 mmol) were added to a microwave vial followed by the addition of tetrahydropyran (3.53 ml). The reaction was microwaved for 1 hr at 120°C. The reaction was filtered and concentrated. The crude material was purified by silica gel
chromatography (0-50% ethyl acetate/heptanes) to afford product (300 mg, quantative % yield) as a white powder. LC MS (m/z, MH+): 416.4. ¾ NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 8.7 Hz, 1H), 7.38 (dt, J = 1.8, 1.0 Hz, 1H), 7.30 - 7.25 (m, 2H), 6.90 (dd, J = 8.7, 2.5 Hz, 1H), 6.79 - 6.69 (m, 1H), 3.97 (dd, J = 6.9, 6.0 Hz, 2H), 3.88 (s, 3H), 3.11 (t, J = 6.4 Hz, 2H), 2.39 (d, J = 0.8 Hz, 3H). 19F NMR (376 MHz, Chloroform-d) δ -73.78 (s, 3F).
[00485] Step 5: 6-Methoxy-2-(3-methyl-4-(2-methylprop-l-en-l-yl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one: To a microwave vial, 4-(6-methoxy-l-oxo-3,4-dihydroisoquinolin- 2(lH)-yl)-2-methylphenyl trifluoromethanesulfonate (0.052 g, 0.125 mmol), 4,4,5,5-tetramethyl- 2-(2-methylprop-l-en-l-yl)-l,3,2-dioxaborolane (0.039 ml, 0.188 mmol), XPhos Pd cycle (9.25 mg, 0.013 mmol) and potassium carbonate (0.052 g, 0.376 mmol) were dissolved in acetonitrile (0.835 ml) and water (0.417 ml). The reaction was microwaved for 30 min at 150 °C. The reaction mixture was filtered to remove solids and concentrated. The crude product was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford product (46 mg, 114 % yield) as a white solid. LC/MS (m/z, MH+): 322.1. ¾ NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 1.9 Hz, 1H), 7.20 - 7.13 (m, 2H), 6.90 (dd, J = 8.7, 2.6 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.21 (s, 1H), 3.97 (q, J = 6.4 Hz, 2H), 3.88 (s, 3H), 3.11 (t, J = 6.4 Hz, 2H), 2.26 (s, 3H), 1.94 (s, 3H), 1.75 (s, 3H).
[00486] Step 6: 2-(4-Isobutyl-3-methylphenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one: To 6-methoxy-2-(3-methyl-4-(2-methylprop-l-en-l-yl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one (0.107 g, 0.333 mmol) was added methanol (1 mL). Tetrahydropyran (l.OmL) was added until compound was dissolved. A scoop of 10% palladium on carbon was added. The reaction solution was purged with hydrogen and left with a hydrogen balloon at rt for 1 h. The reaction was filtered through a syringe filter and concentrated to afford product (110 mg, quantative % yield) as a clear oil. LC MS (m/z, MH+): 324.1. ¾ NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 7.02 (d, J = 2.3 Hz, 2H), 6.78 (dd, J = 8.8, 2.6 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 3.85 (t, J = 6.4 Hz, 2H), 3.77 (s, 3H), 2.99 (t, J = 6.5 Hz, 2H), 2.38 (d, J = 7.2 Hz, 2H), 2.22 (s, 3H), 1.85 - 1.78 (m, 1H), 0.86 (d, J = 6.5 Hz, 6H).
[00487] Step 7: l-(4-Bromophenyl)-2-(4-isobutyl-3-methylphenyl)-6-methoxy-l- methyl-1, 2,3 ,4-tetrahydroisoquino line: To a 40 ml scintillation vial was added l-bromo-4- iodobenzene (0.281 g, 0.992 mmol) and pentanes (2.61 ml). The reaction vial was charged with 2.5 M n-butyllithium in hexanes (0.401 ml, 1.002 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 hour at which time, the reaction mixture was cooled to -78 °C and a solution of 2-(4-isobutyl-3-methylphenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (0.107 g, 0.331 mmol) in tetrahydrofuran (1.864 ml) was added. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was then quenched with water (4 mL) and ethyl acetate (4 mL) and warmed to rt. Perchloric acid (0.122 ml, 1.423 mmol) was added and the reaction mixture was stirred for 30 minutes at rt. The reaction mixture was diluted water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to give iminum intermediate which was used crude in the next step. LC MS (m/z, MH+): 465.4.
[00488] Iminium intermediate was dissolved in tetrahydrofuran (2.143 ml) and cooled to 0 °C. A 1.4M solution of methylmagnesium bromide in tetrahydrofuran (0.709 ml, 0.992 mmol) was added dropwise. The reaction mixture was warmed to rt and stirred 1 h. The reaction was quenched with saturation ammonium chloride and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated.
Crude material was purified by silica gel chromatography (0-25% ethyl acetate/heptane) to afford product (108 mg, 68.2 % yield) as a light yellow oil. LC/MS (m/z, MH+): 480.0. ¾ NMR (400
MHz, Chloroform-d) δ 7.28 - 7.19 (m, 2H), 7.04 - 6.96 (m, 2H), 6.69 (d, J = 8.1 Hz, 1H), 6.64 (d,
J = 8.5 Hz, 1H), 6.60 - 6.51 (m, 2H), 6.30 (d, J = 2.3 Hz, 1H), 6.26 (dd, J = 8.1, 2.4 Hz, 1H), 3.69
(s, 3H), 3.33 (ddt, J = 12.9, 8.4, 4.2 Hz, 1H), 3.26 (dt, J = 12.0, 4.9 Hz, 1H), 3.02 (ddd, J = 15.9,
8.6, 4.9 Hz, 1H), 2.84 (dt, J = 15.9, 4.6 Hz, 1H), 2.27 (d, J = 7.2 Hz, 2H), 2.01 (s, 3H), 1.69 (dp, J
= 13.6, 6.7 Hz, 1H), 1.58 (s, 3H), 0.79 (d, J = 6.7 Hz, 6H). [00489] Step 8: (E)-Methyl 3-(4-(2-(4-isobutyl-3-methylphenyl)-6-methoxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate: To a 40 mL vial, l-(4-bromophenyl)-2-(4- isobutyl-3-methylphenyl)-6-methoxy-l-memyl-l,2,3,4 etrahydroisoquinoline (0.108 g, 0.226 mmol), PdCl2(PPh3)2 (0.079 g, 0.113 mmol), dimethylformamide (1.505 ml), triethylamine (0.157 ml, 1.129 mmol), and methyl acrylate (0.205 ml, 2.257 mmol) were added. The reaction mixture was heated for 1 h at 130 °C. The reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford product (54 mg, 49.5 % yield) as a light yellow oil. LC MS (m/z, MH+): 484.5. ¾ NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 16.0 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.16 (d, J = 6.3 Hz, 2H), 6.67 (t, J = 8.7 Hz, 2H), 6.61 - 6.52 (m, 2H), 6.36 - 6.25 (m, 3H), 3.72 (s, 3H), 3.70 (s, 3H), 3.41 - 3.24 (m, 2H), 3.06 (ddd, J = 14.6, 8.9, 5.0 Hz, 1H), 2.85 (dt, J = 16.0, 4.4 Hz, 1H), 2.27 (d, J = 7.2 Hz, 2H), 1.98 (s, 3H), 1.69 (dt, J = 13.4, 6.7 Hz, 4H), 0.80 (t, J = 3.5 Hz, 6H).
[00490] Step 9: (E)-Methyl 3-(4-(6-hydroxy-2-(4-isobutyl-3-methylphenyl)-l-methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate: (E)-methyl 3-(4-(2-(4-isobutyl-3- methylphenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl)acrylate (0.054 g, 0.112 mmol) was dissolved in dichloromethane (1.117 ml) and cooled to 0 °C. Aluminum chloride (0.119 g, 0.893 mmol) was added followed by the addition of ethanethiol (0.165 ml, 2.233 mmol). The reaction was stirred at 0°C for 2 h. The reaction was quenched with saturated ammonium chloride and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-30% ethyl acetate/heptanes) to afford product (39 mg, 74.4 % yield) as a light yellow oil. LC MS (m/z, MH+): 470.5. ¾ NMR (400 MHz, Chloroform-d) δ 7.71 (dd, J = 15.9, 3.6 Hz, 1H), 7.40 (dd, J = 8.3, 3.6 Hz, 2H), 7.27 (dd, J = 8.3, 4.9 Hz, 2H), 6.79 (dd, J = 8.4, 3.8 Hz, 1H), 6.72 (dd, J = 8.4, 3.7 Hz, 1H), 6.65 (d, J = 3.3 Hz, 1H), 6.62 - 6.55 (m, 1H), 6.48 - 6.33 (m, 3H), 3.84 (d, J = 3.6 Hz, 3H), 3.42 (dtt, J = 25.4, 10.8, 4.4 Hz, 2H), 3.24 - 3.06 (m, 1H), 2.92 (dd, J = 14.8, 5.0 Hz, 1H), 2.38 (dd, J = 7.2, 3.6 Hz, 2H), 2.08 (d, J = 3.6 Hz, 3H), 1.85 - 1.65 (m, 4H), 0.91 (td, J = 7.6, 3.7 Hz, 6H).
[00491] Step 10: (Example 107) (E)-3-(4-(6-hydroxy-2-(4-isobutyl-3-methylphenyl)-l- methyl-l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid: (E)-Methyl 3-(4-(6-hydroxy-2-(4- isobutyl-3 -methylphenyl)- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- 1 -yl)phenyl)acrylate (0.039 g,
0.083 mmol) was dissolved in 1,4-dioxane (Volume: 1.5 ml). To this, 1 M lithium hydroxide (0.415 ml, 0.415 mmol) was added. The reaction was heated to 40 °C for 2 h. The reaction was cooled to rt and acidified to pH 1 with 1 M HCl. The reaction mixture was extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated to afford product (24 mg, 61.5 % yield) as a light orange solid. LC MS (m/z, MH+): 456.5. ¾ NMR (400 MHz, Methanol-d4) δ 7.64 (d, J = 16.0 Hz, 1H), 7.48 - 7.40 (m, 2H), 7.23 - 7.14 (m, 2H), 6.83 (d, J = 8.2 Hz, 1H), 6.67 - 6.60 (m, 2H), 6.54 (dd, J = 8.6, 2.7 Hz, 1H), 6.45 (dd, J = 17.0, 3.7 Hz, 3H), 3.62 - 3.53 (m, 1H), 3.53 - 3.42 (m, 1H), 3.24 - 3.09 (m, 1H), 3.07 - 2.93 (m, 1H), 2.38 (dd, J = 7.1, 1.1 Hz, 2H), 2.07 (s, 3H), 1.82 - 1.70 (m, 4H), 0.87 (dd, J = 6.6, 2.2 Hz, 6H).
Example 108
(E)-3-(4-(2-(4-cvclopentylphenyl)-6-hvdroxy-l -methyl- 1.2.3.4-tetr ahydroisoquinolin-l- vDphenvDacrylic acid:
Figure imgf000237_0001
[00492] Step 1 : 2-(4-Cyclopentylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one:
According to the methods for intermediates A, the title compound was prepared (899 mg, 2.80 mmol, 99 % yield) as a white solid. LC MS (m/z, MH+): 322.1. ¾ NMR (400 MHz,
METHANOL-^) δ ppm 1.52 - 1.70 (m, 2 H), 1.70 - 1.80 (m, 2 H), 1.80 - 1.96 (m, 2 H), 2.04 - 2.19 (m, 2 H), 2.97 - 3.12 (m, 1 H), 3.15 (t, J=6.57 Hz, 2 H), 3.89 (s, 3 H), 3.96 (t, J=6.82 Hz, 2 H), 6.88 (d, J=2.53 Hz, 1 H), 6.94 (dd, J=8.59, 2.53 Hz, 1 H), 7.24 - 7.41 (m, 4 H), 7.96 (d, J=8.59 Hz, 1 H).
[00493] Step 2: l-(4-Bromophenyl)-2-(4-cyclopentylphenyl)-6-methoxy-l-methyl-
1,2,3,4-tetrahydroisoquinoline: According to the methods for intermediates D, the title compound was prepared (354 mg, 0.743 mmol, 26.6 % yield) as a yellow solid. LC/MS (m/z, MH+): 476.0. ¾ NMR (400 MHz, CHLOROFORM-^ δ ppm 1.36 - 1.46 (m, 2 H), 1.53 - 1.63 (m, 5 H), 1.64 - 1.74 (m, 2 H), 1.87 - 1.98 (m, 2 H), 2.69 - 2.93 (m, 2 H), 2.96 - 3.10 (m, 1 H), 3.21 - 3.32 (m, 1 H), 3.32 - 3.44 (m, 1 H), 3.71 (s, 3 H), 6.48 (m, J=8.59 Hz, 2 H), 6.51 - 6.60 (m, 2 H), 6.61 - 6.69 (m, 1 H), 6.87 (m, J=8.59 Hz, 2 H), 6.99 - 7.08 (m, 2 H), 7.21 - 7.28 (m, 2 H). [00494] Step 3: (E)-Methyl 3 -(4-(2-(4-cyclopentylphenyl)-6-methoxy-l -methyl- 1,2,3 , 4- tetrahydroisoquinolin-l-yl)phenyl)acrylate: According to the methods for intermediates E, the title compound was prepared (80 mg, 0.166 mmol, 79 % yield) as a white solid. LC MS (m/z, MH+): 482.1. ¾ NMR (400 MHz, METHANOL-^) δ ppm 1.43 - 1.59 (m, 2 H), 1.59 - 1.73 (m, 5 H), 1.73 - 1.85 (m, 2 H), 1.93 - 2.06 (m, 2 H), 2.80 - 3.04 (m, 2 H), 3.10 - 3.24 (m, 1 H), 3.36 - 3.41 (m, 1 H), 3.45 - 3.55 (m, 1 H), 3.78 (s, 3 H), 3.80 (s, 3 H), 6.51 (d, J=16.17 Hz, 1 H), 6.55 - 6.67 (m, 3 H), 6.67 - 6.75 (m, 2 H), 6.94 (d, J=8.59 Hz, 2 H), 7.28 (m, J=8.08 Hz, 2 H), 7.47 (m, J=8.08 Hz, 2 H), 7.68 (d, J=16.17 Hz, 1 H).
[00495] Step 4: (E)-Methyl 3-(4-(2-(4-cyclopentylphenyl)-6-hydroxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate: According to the methods for intermediates G, the title compound was prepared (60 mg, 0.128 mmol, 77 % yield) as a pale yellow solid. LC MS (m/z, MH-): 466.2. ¾ NMR (400 MHz, METHANOL-^) δ ppm 1.41 - 1.58 (m, 2 H), 1.58 - 1.71 (m, 5 H), 1.71 - 1.85 (m, 2 H), 1.90 - 2.05 (m, 2 H), 2.79 - 2.93 (m, 2 H), 3.01 - 3.16 (m, 1 H), 3.34 (d, J=4.04 Hz, 1 H), 3.40 - 3.52 (m, 1 H), 3.77 (s, 3 H), 6.43 - 6.53 (m, 2 H), 6.54 - 6.65 (m, 4 H), 6.91 (d, J=8.59 Hz, 2 H), 7.26 (d, J=8.08 Hz, 2 H), 7.45 (d, J=8.08 Hz, 2 H), 7.66 (d, J=15.66 Hz, 1 H).
[00496] Step 5: (Example 108) (E)-3-(4-(2-(4-cyclopentylphenyl)-6-hydroxy-l-methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid: According to the general methods for examples, the title compound was prepared (35 mg, 0.077 mmol, 72.2 % yield) as a white solid. LC/MS (m/z, MH-): 452.1. ¾ NMR (400 MHz, METHANOL-^) δ ppm 1.32 - 1.46 (m, 2 H), 1.49 - 1.62 (m, 5 H), 1.62 - 1.76 (m, 2 H), 1.82 - 1.93 (m, 2 H), 2.70 - 2.84 (m, 2 H), 2.92 - 3.07 (m, 1 H), 3.24 - 3.30 (m, 1 H), 3.36 (ddd, J=12.13, 8.59, 3.54 Hz, 1 H), 6.35 (d, J=15.66 Hz, 1 H), 6.38 - 6.44 (m, 1 H), 6.44 - 6.56 (m, 4 H), 6.83 (d, J=8.59 Hz, 2 H), 7.16 (d, J=8.59 Hz, 2 H), 7.35 (d, J=8.59 Hz, 2 H), 7.54 (d, J=15.66 Hz, 1 H).
Example 109
(E)-3-(4-(2-(3-chloro-4-isopen phenyl)-6-hvdroxy-l-mem^
vDphenvDacrylic acid
Figure imgf000239_0001
[00497] To a 30 mL vial was added 4-bromo-2-chloro-l-iodobenzene (1 g, 3.15 mmol) and DMF (3.15 mL). To this, under a nitrogen atmosphere was added phosphazene P4-tBu (0.079 mL, 0.079 mmol) as a 1.0 M solution in hexanes followed by diethylzinc (3.78 mL, 3.78 mmol) in a 1.0 M heptanes solution. The reaction mixture stirred for 4 h at rt at which time it was charged with allyl bromide and stirred overnight. The reaction mixture was quenched with water and saturated ammonium chloride. The quenched reaction mixture was diluted with ethyl acetate and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed 3 x with ethyl acetate. The organic layers were pooled, washed with brine, dried (MgS04), and filtered. The crude material was purified by silica gel chromatography (12 g column, 0-30% ethyl acetate/heptanes) to afford 4-bromo-2-chloro-l-(3-methylbut-2-en-l-yl)benzene (750 mg, 92% yield). ¾ NMR (400 MHz, CHLOROFORM-^ δ 3.27 - 3.57 (m, 2 H), 4.95 - 5.21 (m, 2 H), 5.83 - 6.03 (m, 1 H), 7.11 (s, 1 H), 7.34 (d, J=2.02 Hz, 1 H), 7.52 (d, J=2.02 Hz, 1 H).
[00498] Step 2: 2-(3-Chloro-4-(3-methylbut-2-en-l-yl)phenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one: To a vial, 6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (512 mg, 2.89 mmol) was dissolved in DMF (7.2 mL) and charged with 4-bromo-2-chloro-l-(3-methylbut- 2-en-l-yl)benzene (750 mg, 2.89 mmol) and potassium carbonate (799 mg, 5.78 mmol). The reaction mixture was charged with copper(I) iodide (330 mg, 1.734 mmol) and heated at 160 °C for 24 h. LC MS indicated product formation with starting material remaining, the reaction mixture was charged with additional copper(I) iodide (330 mg, 1.734 mmol) and stirred for an additional 48 h. The reaction mixture was diluted with dichloromethane, filtered, and concentrated. The crude material was purified by silica gel chromatography (40 g, 0-70% ethyl acetate/heptanes) to afford 2-(3-chloro-4-(3-methylbut-2-en-l-yl)phenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one as a yellow solid (620 mg, 60% yield). LC MS (m/z, MH+): 356.4. [00499] Step 3: 2-(3-Chloro-4-isopentylphenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one: To a 30 mL vial containing 2-(3-chloro-4-(3-methylbut-2-en-l-yl)phenyl)-6-methoxy-
3,4-dihydroisoquinolin-l(2H)-one (620 mg, 1.742 mmol) and ethanol (9.457 mL) was added platinum(IV) oxide (39.6 mg, 0.174 mmol). The reaction vial was charged with hydrogen and heated gently at 50 °C. The reaction was complete when the solution turned clear, LC MS confirmed conversion of starting material to product. The reaction mixture was filtered through celite, washed with dichloromethane, and concentrated. The crude material was purified by silica gel chromatography (0-70% ethyl acetate/heptanes) to obtain 2-(3-chloro-4-isopentylphenyl)-6- methoxy-3,4-dihydroisoquinolin-l(2H)-one (611 mg, 98% yield) as a yellow solid. 1H NMR (400
MHz, CHLOROFORM-^ δ 0.93 - 1.01 (m, 6 H), 1.41 - 1.55 (m, 2 H), 1.64 (dt, J=13.14, 6.57 Hz,
1 H), 2.66 - 2.76 (m, 2 H), 3.02 - 3.14 (m, 2 H), 3.87 (s, 3 H), 3.91 - 4.02 (m, 2 H), 6.72 (s, 1 H),
6.82 - 6.93 (m, 1 H), 7.19 - 7.24 (m, 2 H), 7.37 (s, 1 H), 8.09 (d, J=8.59 Hz, 1 H).
[00500] Step 4: l-(4-Bromophenyl)-2-(3-chloro-4-isopentylphenyl)-6-methoxy-l- methyl-l,2,3,4-tetrahydroisoquinoline: To a 250 mL round bottomed flask was added l-bromo-4- iodobenzene (1450 mg, 5.13 mmol) and pentanes (18.400 mL). The reaction flask was charged with 2.5 M n-butyllithium (2.058 mL, 5.14 mmol) and a white precipitate formed immediately.
The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C charged with a solution of 2-(3-chloro-4-isopentylphenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one (611.6 mg, 1.709 mmol) in tetrahydrofuran (12.95 mL). The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with water and ethyl acetate, 70% perchloric acid in water (0.632 mL, 7.35 mmol) was added to the reaction mixture which was stirred for 60 min. The quenched reaction mixture was diluted with ethyl acetate and water, the layers were separated, the aqueous was washed 2 x with ethyl acetate, the organic extracts were pooled, washed with brine, dried (MgS04), filtered, and concentrated. The crude material was suspended in tetrahydrofuran (14.99 mL) and charged with 1.4 M methylmagnesium bromide
(3.66 mL, 5.13 mmol) in toluene/tetrahydrofuran. The reaction mixture stirred overnight at room temperature and the addition to the iminium ion was not complete. The reaction mixture was charged with an additional methylmagnesium bromide (3.66 mL, 5.13 mmol) (1.4 M in toluene/tetrahydrofuran) and stirred at room temperature until complete. The reaction mixture was quenched with saturated ammonium chloride and diluted with dichloromethane. The layers were separated, the aqueous was washed 2 x with dichloromethane, the organic layers were pooled, washed with brine, passed through a phase separator, and condensed. The crude material was purified by silica gel chromatography (0-60% ethyl acetate/heptanes) to afford l-(4- bromophenyl)-2-(3 -chloro-4-isopentylphenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4- tetrahydroisoquinoline as a yellow solid (653 mg, 75% yield). LC MS (m/z, M+): 512.4. 1H NMR (400 MHz, CHLOROFORM-J) δ 0.82 - 0.99 (m, 6 H) 1.37 - 1.46 (m, 2 H) 1.47 - 1.64 (m, 2 H) 1.68 (br. s., 2 H) 2.49 - 2.67 (m, 2 H) 2.92 (d, J=14.15 Hz, 1 H) 3.14 (br. s., 1 H) 3.26 - 3.55 (m, 2 H) 3.72 - 3.84 (s, 3 H) 6.32 (br. s., 1 H) 6.56 - 6.76 (m, 4 H) 6.86 (d, J=8.08 Hz, 1 H) 7.10 (d, J=7.58 Hz, 2 H) 7.31 - 7.40 (m, 2 H).
[00501] Step 5 : (E)-Methyl 3-(4-(2-(3-chloro-4-isopentylphenyl)-6-methoxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate: To a 30 mL vial with magnetic stir bar was added l-(4-bromophenyl)-2-(3-chloro-4-isopentylphenyl)-6-methoxy-l -methyl-l , 2,3,4- tetrahydroisoquinoline (653 mg, 1.273 mmol), Pd(PPh3)2Ci2 (134 mg, 0.191 mmol), triethylamine (887 μΐ, 6.37 mmol), DMF (6.3 mL), and methyl acrylate (1.15 mL, 12.73 mmol). The reaction mixture was heated at 120 °C for 5 h. LC/MS indicated conversion to product. The crude reaction mixture was cooled to ambient temperature, diluted with dichloromethane and water. The layers were separated, the aqueous was washed 2 x with dichloromethane. The organic layers were pooled, washed with brine, passed through a phase separator, and condensed. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to afford (E)-methyl 3- (4-(2-(3-chloro-4-isopentylphenyl)-6-methoxy-l-methyl-l,2,3,4-tetrahydroisoquinolin-l- yl)phenyl)acrylate (301 mg, 46% yield). LC/MS (m/z, MH+): 518.5.
[00502] Step 6: (E)-Methyl 3-(4-(2-(3-chloro-4-isopentylphenyl)-6-hydroxy-l -methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate: To a 30 mL vial with magnetic stir bar was added (E)-methyl 3 -(4-(2-(3-chloro-4-isopentylphenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (301 mg, 0.581 mmol) and dichloromethane (5.8 mL). To this was added aluminum chloride (655 mg, 4.91 mmol) followed by ethanethiol (900 μΕ, 12.17 mmol). The reaction progress was monitored by LC/MS and complete conversion was observed in 4 h. The reaction mixture was quenched with water and diluted with dichloromethane. The layers were separated, the aqueous layer was washed 2 x with dichloromethane, the organic layers were pooled, washed with brine, dried (MgS04), filtered, and concentrated. Purification was conducted by normal phase silica gel chromatography (24 g column, 0-60% ethyl acetate/heptanes) to afford (E)-methyl 3-(4-(2-(3-chloro-4-isopentylphenyl)-6-hydroxy-l-methyl- 1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate as a yellow sticky solid (244 mg, 83% yield). LC/MS (m/z, M+): 504.5.
[00503] Step 7: (Example 109) (E)-3-(4-(2-(3-chloro-4-isopentylphenyl)-6-hydroxy-l- methyl-l ,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid: To a 30 mL vial with magnetic stir bar was added (E)-methyl 3 -(4-(2-(3-chloro-4-isopentylphenyl)-6-hydroxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (244 mg, 0.484 mmol) and ethanol (968 μΐ^). The reaction vial was charged with 3 M lithium hydroxide (484 μΐ^, 1.452 mmol) and stirred overnight at room temperature. The reaction was complete by LC MS, the reaction mixture was quenched with saturated citric acid and diluted with ethyl acetate. The layers were separated, the aqueous was washed 3 x with ethyl acetate. The organic layers were pooled, dried (MgS04), filtered, and concentrated. The crude material was purified by reverse phase HPLC with 5 mM ammonium hydroxide as a modifier, 25-50% acetonitrile/water, collecting at a wavelength of 288 nM to obtain (E)-3-(4-(2-(3-chloro-4-isopentylphenyl)-6-hydroxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (68 mg, 29% yield). HRMS: (m/z, M+): 490.2178. min. ¾ NMR (400 MHz, DMSO-<4) δ 0.87 (d, J=6.57 Hz, 6 H), 1.24 - 1.38 (m, 2 H), 1.50 (dt, J=13.52, 6.63 Hz, 1 H), 1.64 (s, 3 H), 2.79 (d, J=15.66 Hz, 1 H), 3.00 - 3.19 (m, 1 H), 3.27 - 3.59 (m, 4 H), 6.34 - 6.64 (m, 6 H), 6.95 (d, J=8.59 Hz, 1 H), 7.31 (d, J=8.08 Hz, 2 H), 7.43 - 7.64 (m, 3 H).
Example 110
(E)-3-(4-(2-(3-Chloro-4-propylphenyl)-6-hvdroxy-l-methyl-1.2.3.4-tetrahvdroisoquinolin-l- vDphenvDacrylic acid:
Figure imgf000242_0001
[00504] Step 1 : l-Allyl-4-bromo-2-chlorobenzene: To a 30 mL vial was added 4- bromo-2-chloro-l-iodobenzene (500 mg, 1.576 mmol) and DMF (1.576 mL). To this, under a nitrogen atmosphere was added Phosphazene P4-tBu (39.4 μΐ, 0.039 mmol) as a 1.0 M solution in hexanes followed by diethyl zinc in a 1.0 M heptanes solution. The reaction mixture stirred for 4 h at rt at which time it was charged with allyl bromide and stirred overnight. LC/MS indicates conversion of product. The reaction mixture was quenched with water and saturated ammonium chloride. The quenched reaction mixture was diluted with ethyl acetate and transferred to a separatory funnel. The layers were separated, the aqueous layer was washed 3 x with ethyl acetate. The organic layers were pooled, washed with brine, dried (MgS04), and filtered. 1H NMR of the crude material confirms desired product along with dimethylformamide. The crude material was purified by silica gel chromatography (0-50% ethyl acetate/heptanes) to obtain 1- allyl-4-bromo-2-chlorobenzene (300 mg, 82% yield). ¾ NMR (400 MHz, CHLOROFORM-^ δ 3.27 - 3.57 (m, 2 H), 4.95 - 5.21 (m, 2 H), 5.83 - 6.03 (m, 1 H), 7.11 (s, 1 H), 7.34 (d, J=2.02 Hz, 1 H), 7.52 (d, J=2.02 Hz, 1 H).
[00505] Step 2: 2-(4-Allyl-3-chlorophenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)- one: To a vial, 6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (230 mg, 1.296 mmol) was dissolved in DMF (3.240 mL) and charged with 1 -allyl-4-bromo-2-chlorobenzene (300 mg, 1.296 mmol) and potassium carbonate (358 mg, 2.59 mmol). The reaction mixture was charged with copper(I) iodide (148 mg, 0.777 mmol), and heated at 160 °C for 24 h. LC MS indicated product formation but starting material remaining. The reaction vial was charged with additional copper(I) iodide (148 mg, 0.777 mmol) and heated for an additional 24 h. The reaction mixture was diluted with dichloromethane, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-70% ethyl acetate/heptanes) to afford 2-(4-allyl-3-chlorophenyl)-6-methoxy- 3,4-dihydroisoquinolin-l(2H)-one (163 mg, 38% yield) as a yellow solid. LC/MS (m/z, MH+): 328.4. ¾ NMR (400 MHz, CHLOROFORM-^ δ 1.93 (dd, J=6.57, 1.52 Hz, 1 H), 3.04 - 3.17 (m, 1 H), 3.82 - 3.89 (m, 1 H), 3.92 - 4.03 (m, 1 H), 6.22 (dd, J=15.66, 6.57 Hz, 1 H), 6.67 - 6.80 (m, 1 H), 6.88 (dd, J=9.09, 2.53 Hz, 1 H), 7.20 - 7.31 (m, 2 H), 7.22 - 7.30 (m, 2 H), 7.33 - 7.39 (m, 1 H), 7.33 - 7.40 (m, 1 H), 7.51 (s, 1 H), 7.48 - 7.55 (m, 1 H), 8.05 - 8.15 (m, 1 H), 8.06 - 8.14 (m, 1 H).
[00506] Step 3 : 2-(3-Chloro-4-propylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)- one: To a 30 mL vial containing 2-(4-allyl-3-chlorophenyl)-6-methoxy-3,4-dihydroisoquinolin- l(2H)-one and ethanol (4.9 mL) was added platinum(IV) oxide (11.29 mg, 0.050 mmol). The reaction vial was sparged with hydrogen and heated gently at 50 °C. The reaction was complete when the solution turned clear, LC/MS confirmed conversion of starting material to product. The reaction mixture was filtered through celite, washed with dichloromethane, and concentrated. The crude material was purified by silica gel chromatography (0-40% ethyl acetate/heptanes) to obtain 2-(3-chloro-4-propylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (157 mg, 96% yield) as a white solid. LC/MS (m/z, MH+): 330.4. ¾ NMR (400 MHz, CHLOROFORM-^ δ 0.99 (t, J=7.33 Hz, 3 H), 1.58 - 1.75 (m, 2 H), 2.65 - 2.77 (m, 2 H), 3.10 (t, J=6.32 Hz, 2 H), 3.87 (s, 3 H), 3.91 - 3.99 (m, 2 H), 6.72 (d, J=2.53 Hz, 1 H), 6.88 (dd, J=8.59, 2.53 Hz, 1 H), 7.21 - 7.24 (m, 2 H), 7.35 - 7.40 (m, 1 H), 8.09 (d, J=8.59 Hz, 1 H). [00507] Step 4: l-(4-Bromophenyl)-2-(3-chloro-4-propylphenyl)-6-methoxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinoline: To a 250 mL round bottomed flask was added l-bromo-4- iodobenzene (1168 mg, 4.13 mmol) and pentanes (13.700 mL). The reaction flask was charged with 2.5 M n-butyllithium in hexanes (1.657 mL, 4.14 mmol) and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C and charged with a solution of 2-(3-chloro-4-propylphenyl)-6-methoxy-3,4- dihydroisoquinolin-l (2H)-one (454 mg, 1.377 mmol) in tetrahydrofuran (9.64 mL). The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with water and ethyl acetate, 70% perchloric acid in water (0.509 mL, 5.92 mmol) was added to the reaction mixture which was stirred for 60 min. The quenched reaction mixture was diluted with ethyl acetate and water, the layers were separated, the aqueous was washed 2 x with ethyl acetate, the organic extracts were pooled, washed with brine, dried (MgS04), filtered, and concentrated. The crude material was suspended in tetrahydrofuran (11.16 mL) and charged with 3.0 M
methylmagnesium bromide (2.95 mL, 4.13 mmol) in diethylether. The reaction mixture stirred overnight at room temperature. The reaction mixture was quenched with saturated ammonium chloride and diluted with dichloromethane. The layers were separated, the aqueous was washed 2 x with dichloromethane, the organic layers were pooled, washed with brine, passed through a phase separator, and condensed. The crude material was purified by silica gel chromatography (0- 40% ethyl acetate/heptanes) to afford l-(4-bromophenyl)-2-(3-chloro-4-propylphenyl)-6- methoxy-1 -methyl- 1,2,3 ,4-tetrahydroisoquinoline as a white solid (344 mg, 52% yield). LC MS (m/z, MH+): 486.4.
[00508] Step 5 : (E)-Methyl 3-(4-(2-(3-chloro-4-propylphenyl)-6-methoxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate: To a 30 mL vial with magnetic stir bar was added l-(4-bromophenyl)-2-(3-chloro-4-propylphenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinoline (344 mg, 0.709 mmol), Pd(PPh3)2Cl2 (74.7 mg, 0.106 mmol), triethylamine (494 μΐ,, 3.55 mmol), DMF (3.547 mL), and methyl acrylate (643 μΐ,, 7.09 mmol). The reaction mixture was heated at 120 °C for 12 h. LC/MS indicated conversion to product. The crude reaction mixture was cooled to ambient temperature, diluted with dichloromethane and water. The layers were separated, the aqueous was washed 2 x with dichloromethane. The organic layers were pooled, washed with brine, passed through a phase separator, and condensed. The crude material was purified by silica gel chromatography (0-70% ethyl acetate/heptanes) to afford (E)-methyl 3 -(4-(2-(3 -chloro-4-propylphenyl)-6-methoxy- 1 -methyl- 1 ,2,3 ,4-tetrahydroisoquinolin- l-yl)phenyl)acrylate (199 mg, 57% yield). LC/MS (m/z, M+): 490.5. [00509] Step 6: (E)-Methyl 3-(4-(2-(3-chloro-4-propylphenyl)-6-hydroxy-l-methyl-
1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate: To a 30 mL vial with magnetic stir bar was added (E)-methyl 3 -(4-(2-(3-chloro-4-propylphenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (199 mg, 0.406 mmol) and dichloromethane (4.061 mL). To this was added aluminum chloride (162 mg, 1.218 mmol) followed by ethanethiol (601 μΐ^, 8.12 mmol). The reaction progress was monitored by LC MS and complete conversion was not observed in 2 h. An additional amount of aluminum chloride (162 mg, 1.218 mmol) and ethanethiol (601 μΐ^, 8.12 mmol) was added and the reaction was complete within 3 h of this addition. The reaction mixture was quenched with water and diluted with dichloromethane. The layers were separated, the aqueous layer was washed 2 x with dichloromethane, the organic layers were pooled, washed with brine, dried (MgS04), filtered, and concentrated. Purification was conducted by normal phase silica gel chromatography (0-60% ethyl acetate/heptanes) to afford (E)-methyl 3-(4-(2-(3-chloro-4-propylphenyl)-6-hydroxy-l-methyl-l,2,3,4-tetrahydroisoquinolin- l-yl)phenyl)acrylate as a yellow waxy solid (163 mg, 84% yield). LC/MS (m/z, M+): 476.5.
[00510] Step 7: (Example 110) (E)-3-(4-(2-(3-Chloro-4-propylphenyl)-6-hydroxy-l- methyl-l ,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid: To a 30 mL vial with magnetic stir bar was added (E)-methyl 3 -(4-(2-(3-chloro-4-propylphenyl)-6-methoxy-l -methyl- 1 ,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylate (163 mg, 0.342 mmol) and ethanol (1 mL). The reaction vial was charged with 3 M lithium hydroxide (0.342 mL, 1.027 mmol) and stirred overnight at room temperature. The reaction was complete by LC/MS, the reaction mixture was quenched with saturated citric acid and diluted with ethyl acetate. The layers were separated, the aqueous was washed 3 x with ethyl acetate. The organic layers were pooled, dried (MgS04), filtered, and concentrated. The crude material was purified by reverse phase HPLC with 5 mM ammonium hydroxide as a modifier with 25-50% acetonitrile/water as the mobile phase, collecting at a wavelength of 288 nM to obtain (E)-3-(4-(2-(3-chloro-4-propylphenyl)-6-hydroxy- 1 -methyl- 1, 2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (47 mg, 28% yield). HRMS (m/z,
M+): 461.1865. ¾ NMR (400 MHz, METHANOL-d4) δ 0.91 (t, J=7.33 Hz, 3 H), 1.48 - 1.62 (m, 2 H), 1.65 - 1.72 (m, 3 H), 2.47 - 2.62 (m, 2 H), 2.87 (dt, J=16.04, 3.85 Hz, 1 H), 3.03 - 3.21 (m, 1 H), 3.34 - 3.54 (m, 2 H), 6.38 - 6.54 (m, 3 H), 6.55 - 6.66 (m, 3 H), 6.90 (d, J=8.08 Hz, 1 H), 7.23 - 7.34(m, 2 H), 7.46 (d, J=8.59 Hz, 2 H), 7.61 (d, J=16.17 Hz, 1 H). Assays
[00511] Compounds of the invention were assessed for their ability to be both potent estrogen receptor antagonists and to degrade estrogen receptors. The antagonist and degrading properties of the compounds of the invention described herein can be evidenced by testing in the ER transcription and ERoc degradation assays, respectively.
ER transcription assay (MCF7 Cells)
[0001] The ER transcription assay is a reporter assay that is based on the ability of ER to induce transcription from a luciferase reporter gene containing estrogen response elements (EREs) in the promoter/enhancer region. When the reporter gene is transfected in MCF7 cells (containing endogenous ER), transcription is reflected by the level of luciferase expression.
[0002] 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 day before transfection, cells are split into a T75 flask at a cell density of 300,000 cells/mL (lOmL total) and allowed to attach overnight in a humidified C02 incubator at 37°C.
[0003] Next day, prior to transfection, media is switched to DMEM F12 (Gibco, catalog number 21041) supplemented with 10% charcoal-stripped serum (Gemini Bio-Products, catalog number 100-119). MCF7 cells are then bulk transfected, 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 T75 flask, 32.5 μΐ of Lipofectin is added to 617.5 uL of OptiMEM (Gibco #11058) and incubated for 30 min at 37C. Approximately 20 ug DNA is mixed in OptiMEM (Invitrogen) to a total volume of 650 μΐ . Following incubation, the OptiMEM-DNA mixture is added to the OptiMEM-Lipofectin mix and incubated for 15 minutes at 37°C. The DNA-Lipofectin mixture is then added directly to the T75 flask and the flask is returned to the incubator.
[0004] After overnight incubation, compound is added to individual wells of a 96-well plate in a 10 μΐ volume of media at lOx concentration along with 17β estradiol whose final concentration is 0.1 nM. Normally, DMSO (used as a vehicle) is included to achieve a final concentration of 0.1% when added to the cells. Transfected cells are trypsinized, resuspended in DMEM F12/10% charcoal-stripped serum and added to the 96-well plate at 25,000 cells/well in 90μΕ of media. The plate is then returned to the incubator for 24 hours. [0005] After incubation with compounds for 24 hours, Firefly and Renilla luciferase activities are measured to determine ER transcriptional activity. Media is removed from 96-well plates by decanting and blotting on paper towels. Cells are lysed with 40ul/well of IX passive lysis buffer (25mM Tris Phospate, 2mM CDTA, 10% Glycerol, 0.5% Triton X-100 and 2mM DTT before use) and allowed incubate at room temperature for 10 minutes.
[0006] Firefly luciferase activity is measured by adding 30 ul Firefly luciferase assay buffer (20mM Tricine, 0.1 mM EDTA, 1.07 mM (MgC03)4 Mg(OH)2 · 5H20, 2.67 mM MgS04, 33.3 mM DTT, 270 μΜ Coenzyme A, 470 μΜ luciferin, 530 μΜ ATP, reconstituted) per well, followed by measuring light units using a luminometer (BMG labtech FLUOstar OPTIMA). One second total read time after a one second delay.
[0007] Renilla luciferase activity is measured by adding 50 ul Renilla luciferase assay buffer (1.1M NaCl, 2.2 mM Na2EDTA, 0.22 M KxP04 (pH 5.1), 0.44 mg/mL BSA, 1.3 mM NaN3, 1.43 uM coelenterazine, final pH adjusted to 5.0), per well, followed by measuring light units using a luminometer. One second total read time after one second delay. If Firefly luciferase signal is high, Renilla assay must be done an hour after the Firefly assay due to incomplete squelching of Firefly signal.
ERa degradation (MCF7 cells)
[0008] Plate MCF7 cells at 0.3 million cells/mL (100 μΐ/well) in black, clear-bottom
96-well plates (Greiner, catalog number 655090) in DMEM F12 media (Gibco, catalog number 11330) supplemented with 10% charcoal-stripped serum (Gemini Bio-Products, catalog number 100-119), and incubate them at 37°C, 5% C02 for 24-36 hours. Next day, make lOx solution of ligands in DMSO and add the solution to the cells to achieve a final concentration of lOuM. A DMSO control is required for relative calculations, and fulvestrant is used as a positive control for ER degradation. The cells are subjected to the in-cell Western assay after incubating cells with ligand for 18-24 hours.
[0009] Media is removed from the plates by decanting, and cells are immediately fixed with 100 μΐ of 3.7% formaldehyde in PBS using a multi-channel pipettor. Add formaldehyde to the sides of the wells to avoid cell disruption. Plates are incubated at room temperature for 20 minutes without shaking. The fix solution is then removed and cells are permeabilized with 100 μΕ/well of 0.1% Triton X-100 in PBS. The lysate is then blocked by adding 50uL/well of blocking solution (3% goat serum, 1% BSA, 0.1% cold fish skin gelatin and 0.1% Triton X-100 in PBS, H 7.4) and allowed to shake at room temperature for 2 hr, or alternatively, at 4°C overnight.
[0010] After blocking, 40 μΙ ΛνεΙΙ of the primary antibody against ERa (HC-20)
(Santa cruz, catalog number 543) diluted at 1 :3000 in blocking buffer diluted 1 :3 with PBS is added to each well, except the negative control wells (which are used for background subtraction) and the plate is sealed and incubated overnight at 4°C. 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. 40μΕΛνε11 of secondary antibody (Biotium CF770 goat anti-rabbit 1 :2000, catalog number 20078) and DRAQ5 (DNA stain, 5mM, Thermo Scientific, catalog number 62251) diluted at 1 : 10000 in blocking buffer diluted 1 :3 with PBS is then added to all the well, including the negative control wells, and the plate is allowed to incubate on shaker at room temperature for 2 hr. The secondary antibody solution is then removed and the plates are washed three times as described above. The plate is then washed one final time with PBS alone to minimize auto- fluorescence. The plate is then cleaned and read on LiCor Odyssey imager.
[0011] For % response calculations, first divide integrated intensities for 700 channel
(EPv) by integrated intensities for 800 channel (DNA normalization); 700 (ER)/800 (DNA). This will be referred to as the normalized value. Then subtract average of negative control wells (no primary antibody) from all normalized values. This corresponds to negative subtraction. % response = (V alue unknown Value DMSO control) * 100.
[0012] The data describing the antagonist and degradation properties for the examples is compiled in table 3. The column titled MCF7 IC50 reports the inflection point of the inhibition of transcription in MCF7 cells as described above. Percentage ERa remaining reports the remaining ERa protein measured at 10 μΜ concentration of the ligand as described above. The column ERa IC50 reports the inflection point of the degradation in response to the ligand concentration. For example, (E)-3-(4-(6-hydroxy-2-(4-isopropylphenyl)-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (example 15), inhibits 50% of the ERa induced transcriptions in MCF7 cells at a concentration of 0.0301 μΜ and degrades the ERa receptor, at 3ΐ0μΜ concentration, by 85%. Half of the observed receptor degradation occurs at a concentration of 0.0010 μΜ. Table 3
Figure imgf000249_0001
0.4720 32
0.3847 35
1 .4090 63
0.1 133 39
0.0152 42
0.0710 34 0.0270
0.1313 28 0.0048
0.0564 30 0.0056
0.1069 43
0.0886 25 0.0028
0.0434 38
0.0301 46
0.0268 38
0.6203 17 0.0506
0.2067 21
0.3019 16
0.0227 13 0.0013
0.4632 13
0.7125 21
0.1 106 14 0.0147
0.5050 14
0.5134 15 0.0150a 0.341 14
b 0.477 14
0.1 193 15
0.4990 24
2.2750 26
0.7291 25
0.2732 20 0.01 17
0.0549 17 0.0055
0.1098 19
2.3380 18 0.0287 86 0.0390 16 0.0004
87 0.0266 19 0.0005
88 0.0670 15 0.0023
89 0.0530 14 0.0006
90 0.0360 22
91 0.0540 17
92 0.4656 22 0.0125
93 0.0360 17
94 0.1080 25
96 0.1393 24 0.0058
96a 0.1250 13 0.0029
96b 1 .1380 1 1
97 0.0253 21
99 0.7120 21
100 0.045 13 0.003
100a 0.024 1 1 0.003
100b 0.603 1 1 0.021
101 0.055 21 0.005
101 a 0.220 17 0.391
101 b 0.938 7 0.403
102 0.007 12 0.0004
103 0.262 14 0.374
104 0.1 12 25 0.005
105 0.036 18 0.004
106 0.006 12 0.0006
107 0.064 16 0.004
108 0.056 21 0.001
109 0.249 14 0.409
1 10 0.055 15 0.004
[0001] It is understood that the examples and embodiments 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 are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

Figure imgf000253_0001
in which:
n is selected from 0, 1 and 2;
X is selected from N and CR6; wherein R6 is selected from hydrogen and Ci-4alkyl; Ri is hydrogen;
R2 is selected from methyl, -C¾F, -CHF2, CF3 and CD3;
R3 is selected from -CH2CH2R8 and
Figure imgf000253_0002
wherein each R7 is independently selected from hydrogen, fluoro and Ci-4alkyl; and Rs is selected from -C(0)ORsa, - C(0)NR8aR8b, -C(0)NHORsa, -C(0)YRsa and a 5-member heteroaryl selected from:
Figure imgf000253_0003
wherein the dotted line indicates the point of attachment with -CH2CH2 or - CR7=CR7 of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Rs is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl;
R4 is selected from hydrogen, Ci-4alkyl, halo and Ci-3alkoxy;
Rs is selected from C6-ioaryl, a 5-6 member heteroaryl containing 1 or 2 heteroatoms selected from O, S and N, and a partially saturated 9-10 member bicyclic ring containing 1 or two heteroatoms selected from O, S and N; wherein said C6-ioaryl, heteroaryl or bicyclic ring system of R5 is unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo-substituted-Ci- 4alkyl, cyano-substituted-Ci-4alkyl, hydroxy-substituted-Ci-4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, -SFs, -NRi2aRi2b, -C(0)Ri2a, -S(O)0-2Ri2a, C3-8cycloalkyl-Co-3alkyl and a 4-7 member ring containing one or two heteroatoms or groups selected from O, N, NH, and S(0)o- 2; wherein Rmand Ri2b are independently selected from hydrogen, Ci-4alkyl and C3_ scycloalky 1; or Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from O, N, NH, and S(0)o-2; wherein said C3.8cycloalkyl or 4-7 member ring of R11 can be unsubstituted or further substituted with a group selected from halo-substituted Ci_4alkyl and Ci-4alkyl; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 of formula la:
Figure imgf000254_0001
(la) in which:
n is selected from 0 and 1;
X is selected from N and CH; R2 is selected from methyl, -CH2F, -CHF2, CF3 and CD3;
R4 is methyl; and
Ri is selected from C6-ioaryl and a 5-6 member heteroaryl or bicyclic ring selected from:
Figure imgf000255_0001
wherein the dotted line indicates the point of attachment with the tetrahydroisoquinoline core; wherein said C6-ioaryl or heteroaryl of Rs is unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo-substituted-Ci-4alkyl, cyano-substituted-Ci-4alkyl, hydroxy-substituted-Ci- 4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, -SFs, -NRi2aRi2b, -C(0)Ri2a, -S(O)0-2Ri2a, C3_ 8cycloalkyl-C0-3alkyl and a 4-7 member ring containing one or two heteroatoms or groups selected from O, N, NH, and S(0)o-2; wherein Ri2a and Ri2b are independently selected from hydrogen and Ci-4alkyl; or Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from O, N, NH, and S(0)o-2; wherein said C3_8cycloalkyl or 4-7 member ring of Rn can be unsubstituted or further substituted with a group selected from halo-substituted Ci_4alkyl and Ci-4alkyl; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 in which:
R2 is selected from methyl, -CH2F, -CHF2, CF3 and CD3; and
Rs is selected from C6-ioaryl unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from fluoro, methyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, isopropoxy, trifluoromethyl, hydroxy, methoxy -ethyl, methyl substituted pyrazolyl, trifluoro-ethyl, trifluoro-propyl, cyclobutyl, cyclopropyl-methyl, cyclopentyl, 1- (trifluoromethyl)cyclopropyl, trifluoromethoxy and trifluoro-ethoxy; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000256_0001
Figure imgf000257_0001
256
Figure imgf000258_0001
Figure imgf000258_0002
Figure imgf000258_0003
Figure imgf000259_0001
258
Figure imgf000260_0001
259
Figure imgf000261_0001
260
Figure imgf000262_0001
261
5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000263_0001
6. The compound of claim 2 in which:
n is selected from 0 and 1;
R2 is selected from methyl, -CH2F, -CHF2, CF3 and CD3;
R4 is methyl; and
Ri is a 5-6 member heteroaryl or bicyclic ring selected from:
Figure imgf000264_0001
wherein the dotted line indicates the point of attachment with the tetrahydroisoquinoline core; wherein said heteroaryl of Rs is unsubstituted or substituted with a group selected from methyl and methoxy; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000264_0002
Figure imgf000265_0001
Figure imgf000265_0002
Figure imgf000265_0003
Figure imgf000265_0004
The compound of claim 1 of formula lb:
Figure imgf000266_0001
(lb) in which:
X is selected from N and CR6; wherein R6 is selected from hydrogen and Ci-4alkyl;
Ri is hydrogen;
R2 is selected from methyl, -CH2F, -CHF2, CF3 and CD3;
R3 is selected from -CH2CH2R8 and
Figure imgf000266_0002
wherein each R7 is independently selected from hydrogen, fluoro and Ci-4alkyl; and Rs is a 5-member heteroaryl selected from:
Figure imgf000266_0003
wherein the dotted line indicates the point of attachment with -CH2CH2 or - CR7=CR7 of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Rs is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl; R9 is selected from hydrogen, methyl, ethyl, trifluoro-ethyl, isobutyl, cyclopropyl, hydroxy -methyl and propyl; and Ri0 is selected from hydrogen and methyl; R5 is selected from C6-ioaryl and a 5-6 member heteroaryl or bicyclic ring selected from:
Figure imgf000267_0001
wherein the dotted line indicates the point of attachment with the tetrahydroisoquinoline core; wherein said C6-ioaryl or heteroaryl of Rs is unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo-substituted-Ci-4alkyl, cyano-substituted-Ci-4alkyl, hydroxy-substituted-Ci- 4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, -SFs, -NRi2aRi2b, -C(0)Ri2a, -S(O)0-2Ri2a, C3_ scycloalkyl and a 4-7 member ring containing one or two heteroatoms or groups selected from O, N, NH, and S(0)o-2; wherein Ri2a and Ri2b are independently selected from hydrogen and Ci-4alkyl; or Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from O, N, NH, and S(0)o-2; wherein said C3.8cycloalkyl or 4-7 member ring of R11 can be unsubstituted or further substituted with a group selected from halo-substituted Ci_4alkyl and Ci-4alkyl; or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000268_0001
Figure imgf000269_0001
268
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000271_0002
Figure imgf000272_0001
271
Figure imgf000273_0001
Figure imgf000273_0002
272 in which:
n is selected from 0, 1 and 2;
X is selected from N and CR6; wherein R6 is selected from hydrogen and Ci-4alkyl;
Ri is hydrogen;
R2 is selected from methyl, -C¾F, -CHF2, CF3 and CD3;
R3 is selected from -CH2CH2R8 and
Figure imgf000274_0001
wherein each R7 is independently selected from hydrogen, fluoro and Ci-4alkyl; and Rs is selected from -C(0)ORsa, - C(0)NR8aR8b, -C(0)NHORsa, -C(0)YRsa and a 5-member heteroaryl selected from:
Figure imgf000274_0002
wherein the dotted line indicates the point of attachment with -CH2CH2 or - CR7=CR7 of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Rs is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl; R4 is selected from hydrogen, Ci-4alkyl, halo and Ci-3alkoxy;
R5 is selected from C6-ioaryl, a 5-6 member heteroaryl containing 1 or 2 heteroatoms selected from O, S and N, and a partially saturated 9-10 member bicyclic ring containing 1 or two heteroatoms selected from O, S and N; wherein said C6-ioaryl, heteroaryl or bicyclic ring system of R5 is unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo-substituted-Ci- 4alkyl, cyano-substituted-Ci-4alkyl, hydroxy-substituted-Ci-4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, -SFs, -NRi2aRi2b, -C(0)Ri2a, -S(O)0-2Ri2a, C3_8cycloalkyl and a 4-7 member ring containing one or two heteroatoms or groups selected from O, N, NH, and S(0)o-2; wherein Ri2aand Ri2b are independently selected from hydrogen, Ci-4alkyl and C3-8cycloalkyl; or Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from O, N, NH, and S(0)o-2; wherein said C3-8cycloalkyl or 4-7 member ring of Rn can be unsubstituted or further substituted with a group selected from halo-substituted Ci_4alkyl and Ci-4alkyl; or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 of formula Id:
Figure imgf000275_0001
(Id) in which:
n is selected from 0 and 1;
X is selected from N and CH;
R2 is selected from methyl, -CH2F, -CHF2, CF3 and CD3;
R4 is methyl; and
Ri is selected from C6-ioaryl and a 5-6 member heteroaryl or bicyclic ring selected from:
Figure imgf000275_0002
wherein the dotted line indicates the point of attachment with the tetrahydroisoquinoline core; wherein said C6-ioaryl or heteroaryl of Rs is unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo-substituted-Ci-4alkyl, cyano-substituted-Ci-4alkyl, hydroxy-substituted-Ci- 4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, -SFs, -NRi2aRi2b, -C(0)Ri2a, -S(O)0-2Ri2a, C3- scycloalkyl and a 4-7 member ring containing one or two heteroatoms or groups selected from O, N, NH, and S(0)o-2; wherein Ri2a and Ri2b are independently selected from hydrogen and Ci-4alkyl; or Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from O, N, NH, and S(0)o-2; wherein said C3.8cycloalkyl or 4-7 member ring of Rn can be unsubstituted or further substituted with a group selected from halo-substituted Ci_4alkyl and Ci-4alkyl; or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 in which:
R2 is selected from -CH2F, -CHF2 and CF3; and
Rs is selected from C6-ioaryl unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from fluoro, methyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, isopropoxy, trifluoromethyl, hydroxy, methoxy -ethyl, methyl substituted pyrazolyl, trifluoro-ethyl, trifluoro-propyl, cyclobutyl, l-(trifluoromethyl)cyclopropyl, trifluoromethoxy and trifluoro-ethoxy; or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000276_0001
Figure imgf000277_0001
15. A pharmaceutical composition comprising a compound of claim 1 admixed with at least one pharmaceutically acceptable excipient.
16. The pharmaceutical composition of claim 15, wherein the excipient is selected from corn starch, potato starch, tapioca starch, starch paste, pre-gelatinized starch, sugars, gelatin, natural gums, synthetic gums, sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium
carboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium aluminum silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, agar-agar, sodium carbonate, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, clays, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, hydrogenated vegetable oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, silica, and combinations thereof.
17. The pharmaceutical composition of claim 15, further comprising an additional therapeutic agent.
18. The pharmaceutical composition of claim 17, wherein the additional therapeutic agent is selected from an anticancer compound, an analgesic, an antiemetic, an antidepressant, and an anti-inflammatory agent.
19. A method to treat cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1.
20. The method of claim 19, wherein the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancers.
21. The method of claim 20, further comprising administering to the subject an additional therapeutic agent.
22. The method of claim 21, wherein the additional therapeutic agent comprises an anticancer drug, a pain medication, an antiemetic, an antidepressant or an anti-inflammatory agent.
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