THIOPHENE DERIVATIVES

Abstract

Compounds of the formula I

##STR00001##

are inhibitors of HIF-2α, and can be employed for the treatment of diseases such as cancer.

Claims

1: A compound of the formula I ##STR00060## wherein R.sup.1 denotes A, [C(R.sup.6).sub.2].sub.qAr, [C(R.sup.6).sub.2].sub.qCyc, [C(R.sup.6).sub.2].sub.qHet, or COA, R.sup.2 denotes SO.sub.2A, SOA, SA, SO.sub.2NHA, SO.sub.2NA.sub.2, S(═NH, ═O)A, S(═NH).sub.2A, NO.sub.2, Hal, CN, A, Het.sup.1, COOH, or COOA, R.sup.3 denotes H or Hal, R.sup.4 denotes H or Hal, R.sup.5 denotes H or Hal, R.sup.6 denotes H or A′, A denotes unbranched or branched alkyl having 1-8 C-atoms, in which 1-5 H atoms may be replaced by OH, OA, F, Cl, and/or Br, and/or in which one or two non-adjacent CH.sub.2 groups may be replaced by O and/or NH groups, A′ denotes unbranched or branched alkyl having 1, 2, 3, or 4 C-atoms, Cyc denotes cyclic alkyl with 3, 4, 5, 6, or 7 C-atoms, in which 1-5 H atoms may be replaced by OH, OA, F, and/or Cl, Ar denotes phenyl, which is unsubstituted or mono-, di-, or trisubstituted by Hal, A, NH.sub.2, NHA, NA.sub.2, COOH, COOA, CONH.sub.2, CONHA, CONA.sub.2, CONHAr, S(O).sub.pA, NHCH.sub.2Ar, CN, OH, and/or OA, Het denotes a mono- or bicyclic aromatic, unsaturated, or saturated heterocycle having 1 to 4 N, O, and/or S atoms, which may be unsubstituted or mono-, di-, or trisubstituted by Hal, A, NH.sub.2, NHA, NA.sub.2, COOH, COOA, CONH.sub.2, CONHA, CONA.sub.2, CONHAr, S(O).sub.pA, NHCH.sub.2Ar, CN, OH, and/or OA, Het.sup.1 denotes a mono- or bicyclic aromatic, unsaturated, or saturated heterocycle having 1 to 4 N, O, and/or S atoms, which may be unsubstituted or mono-, di-, or trisubstituted by Hal, A, COOA, NH.sub.2, NHA, and/or NA.sub.2, Hal denotes F, Cl, Br, or I, n denotes 1 or 2, m denotes 0, 1, 2, or 3, p denotes 1, 2, or 3, q denotes 0, 1, or 2, or a pharmaceutically acceptable solvate, salt, tautomer, or stereoisomer thereof, including a mixture thereof in all ratios.

2: The compound according to claim 1, wherein R.sup.1 denotes A, [C(R.sup.6).sub.2].sub.qAr, [C(R.sup.5).sub.2].sub.qCyc, or [C(R.sup.6).sub.2].sub.qHet, or a pharmaceutically acceptable solvate, salt, tautomer, or stereoisomer thereof, including a mixture thereof in all ratios.

3: The compound according to claim 1, wherein R.sup.2 denotes SO.sub.2A, or a pharmaceutically acceptable solvate, salt, tautomer, or stereoisomer thereof, including a mixture thereof in all ratios.

4: The compound according to claim 1, wherein R.sup.3 denotes H or F, R.sup.4 denotes H or F, R.sup.5 denotes H, or a pharmaceutically acceptable solvate, salt, tautomer, or stereoisomer thereof, including a mixture thereof in all ratios.

5: The compound according to claim 1, wherein A denotes unbranched or branched alkyl having 1-8 C-atoms, in which 1-5 H atoms may be replaced by OH and/or F, and/or in which one or two non-adjacent CH.sub.2 groups may be replaced by O and/or NH groups, or a pharmaceutically acceptable solvate, salt, tautomer thereof, including a mixture thereof in all ratios.

6: The compound according to claim 1, wherein Ar denotes phenyl, which is unsubstituted or mono-, di-, or trisubstituted by Hal and/or CN, or a pharmaceutically acceptable solvate, salt, tautomer, or stereoisomer thereof, including a mixture thereof in all ratios.

7: The compound according to claim 1, wherein Het denotes a monocyclic saturated heterocycle having 1 to 4 N, O, and/or S atoms, which may be unsubstituted or mono-, di-, or trisubstituted by Hal, A, CN, OH, and/or OA, or a pharmaceutically acceptable solvate, salt, tautomer, or stereoisomer thereof, including a mixtures thereof in all ratios.

8: The compound according to claim 1, wherein Het denotes tetrahydrofuryl, 1,3-dioxolanyl, tetrahydro-thienyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydro-pyranyl, or piperazinyl, or a pharmaceutically acceptable solvate, salt, tautomer, or stereoisomer thereof, including a mixture thereof in all ratios.

9: The compound according to claim 1, wherein R.sup.1 denotes A, [C(R.sup.6).sub.2].sub.qAr, [C(R.sup.6).sub.2].sub.qCyc, or [C(R.sup.6).sub.2].sub.qHet, R.sup.2 denotes SO.sub.2A, R.sup.3 denotes H or F, R.sup.4 denotes H or F, R.sup.5 denotes H, R.sup.6 denotes H or A′, A denotes unbranched or branched alkyl having 1-8 C-atoms, in which 1-5 H atoms may be replaced by OH and/or F, and/or in which one or two non-adjacent CH.sub.2 groups may be replaced by O and/or NH groups, A′ denotes unbranched or branched alkyl having 1, 2, 3, or 4 C-atoms, Cyc denotes cyclic alkyl with 3, 4, 5, 6, or 7 C-atoms, in which 1-5 H atoms may be replaced by OH, OA, F, and/or Cl, Ar denotes phenyl, which is unsubstituted or mono-, di-, or trisubstituted by Hal and/or CN, Het denotes tetrahydrofuryl, 1,3-dioxolanyl, tetrahydro-thienyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydro-pyranyl, or piperazinyl, Hal denotes F, Cl, Br, or I, n denotes 1 or 2, m denotes 0, 1, 2, or 3, p denotes 1, 2, or 3, q denotes 0, 1, or 2, or a pharmaceutically acceptable solvate, salt, tautomer, or stereoisomer thereof, including a mixture thereof in all ratios.

10: The compound according to claim 1, selected from the group consisting of: TABLE-US-00004 No. Structure  1a (4S)-1-(cyclohexyloxy)-5,5-difluoro-3-methanesulfonyl- 4H,5H,6H-cyclopenta[c]thiophen-4-ol,  2a (4S)-l-(2,2-dimethylpropoxy)-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol,  3a (4S)-1-cyclobutoxy-5,5-difluoro-3-methanesulfonyl- 4H,5H,6H-cyclopenta[c]thiophen-4-ol,  4a (4S)-5,5-difluoro-3-methanesulfonyl-1-(2-methylbutoxy)- 4H,5H,6H-cyclopenta[c]thiophen-4-ol,  5a (4S)-1-(2,2-difluoroethoxy)-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol,  6a (4S)-5,5-difluoro-3-methanesulfonyl-1-(3,3,3-trifluoro-2- methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol,  7a (4S)-5,5-difluoro-3-methanesulfonyl-1-(2,2,2- trifluoroethoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol,  8a (4S)-5,5-difluoro-3-methanesulfonyl-1-(2-methylpropoxy)- 4H,5H,6H-cyclopenta[e]thiophen-4-ol,  9a (4S)-5,5-difluoro-3-methanesulfonyl-1-{[1,1,1- trifluorobutan-2-yl]oxy}-4H,5H,6H-cyclopenta[c]thiophen- 4-ol, 10a (4S)-1-{[1,1-difluoropropan-2-yl]oxy}-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol, 11a (4S)-5,5-difluoro-3-methanesulfonyl-1-(3,3,3- trifluoropropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol, 12a (4S)-5,5-difluoro-3-methanesulfonyl-1-propoxy-4H,5H,6H- cyclopenta[c]thiophen-4-ol, 13a (4S)-1-(cyclopropylmethoxy)-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol, 14a (4S)-1-{[1,1-difluoropropan-2-yl]oxy}-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol, 15a (4S)-1-(2,2-difluoropropoxy)-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol, 16a (4S)-5,5-difluoro-3-methanesulfonyl-1-[(1- methoxycyclobuty])methoxy]-4H,5H,6H- cyclopenta[c]thiophen-4-ol, 17a (4S,5S)-5-fluoro-3-methanesulfonyl-1-(2,2,2- trifluoroethoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol, 18a (4S)-1-[(3,3-difluorocyclobuty])methoxy]-5,5-difluoro- 3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen- 4-ol, 19a (4S)-1-(cyclobutylmethoxy)-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol, 20a (4S)-1-(1-cyclobutylethoxy)-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol, 21a (4S)-1-(3,3-difluorobutoxy)-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol, 22a (4S)-5,5-difluoro-3-methanesulfonyl-1-(oxan-4-yloxy)- 4H,5H,6H-cyclopenta[c]thiophen-4-ol, 23a (4S)-5,5-difluoro-3-methanesulfonyl-1-[2- (trifluoromethoxy)ethoxy]-4H,5H,6H- cyclopenta[c]thiophen-4-ol, 24a 1-(3,4-difluorophenoxy)-5,5-difluoro-3-methanesulfonyl- 4H,5H,6H-cyclopenta[c]thiophen-4-ol, 25a (4S)-5,5-difluoro-3-methanesulfonyl-1-(propan-2-yloxy)- 4H,5H,6H-cyclopenta[c]thiophen-4-ol, 26a 3-chloro-5-{(4S)-5,5-difluoro-4-hydroxy-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-1- yl]oxy}benzonitrile, 27a (4S)-1-(3,5-difluorophenoxy)-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol, 26a 3-{[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl- 4H,5H,6H-cyclopenta[c]thiophen-1-yl]oxy}-5- fluorobenzonitrile, 29a (4S)-5,5-difluoro-1-(4-fluorophenoxy)-3-methanesulfonyl- 4H,5H,6H-cyclopenta[c]thiophen-4-ol, 30a (4S)-1-(3-chloro-5-fluorophenoxy)-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol, 31a 3-{[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl- 4H,5H,6H-cyclopenta[c]thiophen-1-yl]oxy}benzonitrile, 32a (4S)-1-ethoxy-5,5-difluoro-3-methanesulfonyl-4H,5H,6H- cyclopenta[c]thiophen-4-ol, 33a (4S)-5,5-difluoro-3-methanesulfonyl-1-(4,4,4- trifluorobutoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol, and 34a (4S)-1-(3,4-difluorophenoxy)-5,5-difluoro-3- methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol. or a pharmaceutically acceptable solvate, salt, tautomer or stereoisomer thereof, including a mixture thereof in all ratios.

11: A process for the preparation of the compound of the formula I according to claim 1 or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the process comprising: reacting a compound of the formula II with NaBH.sub.4 or any other reducing agent, ##STR00061## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, n, and m have the meanings indicated in claim 1, and/or converting a base or acid of the formula I into one of its salts.

12: A medicament, comprising: at least one compound of the formula I according to claim 1 and/or, a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, including a mixture thereof in all ratios, and optionally, a pharmaceutically acceptable carrier, excipient, or vehicle.

13: A method for the treatment and/or prevention of cancer and/or von Hippel-Lindau disease (VHL), the method comprising: administering to a subject in need thereof, the compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, including a mixture thereof in all ratios.

14: The method according to claim 13, wherein the cancer is a cancer of head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, or central nervous system, or wherein the cancer is a solid tumor, blood-borne tumor, glioblastoma, renal cell carcinoma (RCC), or clear cell renal cell carcinoma (ccRCC).

15: A medicament, comprising: at least one compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, including a mixture thereof in all ratios, and at least one further medicament active ingredient.

16: A set (kit) consisting of separate packs of (a) an effective amount of the compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, including a mixture thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.

Description

USE

[0145] The present compounds are suitable as pharmaceutical active ingredients for mammals, especially for humans, in the treatment of cancer.

[0146] The present invention encompasses the use of the compounds of the formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof for the preparation of a medicament for the treatment or prevention of cancer.

[0147] Moreover, the present invention encompasses the compounds in formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof for treatment or prevention of cancer.

[0148] Also encompassed is the use of the compounds of the formula I and/or pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof for the preparation of a medicament for the treatment or prevention of a HIF-2α-induced disease or a HIF-2α-induced condition in a mammal, in which to this method a therapeutically effective amount of a compound according to the invention is administered to a sick mammal in need of such treatment. The therapeutic amount varies according to the specific disease and can be determined by the person skilled in the art without un-due effort.

[0149] The present invention specifically relates to compounds of the formula I and pharmaceutically acceptable salts, solvates. tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the use for the treatment of diseases in which the inhibition, regulation and/or modulation inhibition of HIF-2α plays a role.

[0150] The present invention specifically relates to compounds of the formula I and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the use for the inhibition of HIF-2α.

[0151] Representative cancers that compounds of formula I are useful for treating or preventing include, but are not limited to, cancer of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumors and blood-borne tumors.

[0152] Moreover, representative cancers that compounds of formula I are useful for treating or preventing include glioblastoma, renal cell carcinoma (RCC) and clear cell renal cell carcinoma (ccRCC).

[0153] Moreover, the present invention encompasses the compounds for use of the formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof for treatment or prevention of von Hippel-Lindau (VHL) disease.

[0154] Moreover, the present invention encompasses the compounds for use of the formula I and/or pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof for treatment or prevention of a cardiovascular disease.

[0155] Preferably, the present invention relates to a method of treating cancer comprising administering to a subject in need thereof an effective amount of a compound of formula I according to the invention.

[0156] Particularly preferable, the present invention relates to a method wherein the disease is a cancer, wherein administration is simultaneous, sequential or in alternation with administration of at least one other active drug agent.

[0157] The disclosed compounds of the formula I can be administered in combination with other known therapeutic agents, including anticancer agents. As used here, the term “anticancer agent” relates to any agent which is administered to a patient with cancer for the purposes of treating the cancer.

[0158] The anticancer treatment defined above may be applied as a monotherapy or may involve, in addition to the herein disclosed compounds of formula I, conventional surgery or radiotherapy or medicinal therapy. Such medicinal therapy, e.g. a chemotherapy or a targeted therapy, may include one or more, but preferably one, of the following anti-tumor agents:

Alkylating Agents

[0159] such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-302.sup.4, VAL-083.sup.4;

Platinum Compounds

[0160] such as carboplatin, cisplatin, eptaplatin, miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;

DNA Altering Agents

[0161] such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine;
amsacrine, brostallicin, pixantrone, laromustine.sup.1,3;

Topoisomerase Inhibitors

[0162] such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin;

Microtubule Modifiers

[0163] such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine;
fosbretabulin, tesetaxel;

Antimetabolites

[0164] such as asparaginase.sup.3, azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur;
doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur.sup.2,3, trimetrexate;

Anticancer Antibiotics

[0165] such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin;
aclarubicin, peplomycin, pirarubicin;

Hormones/Antagonists

[0166] such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol;
acolbifene, danazol, deslorelin, epitiostanol, orteronel, enzalutamide.sup.1,3;

Aromatase Inhibitors

[0167] such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone;
formestane;

Small Molecule Kinase Inhibitors

[0168] such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib;
afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib.sup.4, cabozantinib S-malate.sup.1,3, ibrutinib.sup.1,3, icotinib.sup.4, buparlisib.sup.2, cipatinib.sup.4, cobimetinib.sup.1,3, idelaisib.sup.1,3, fedratinib.sup.1, XL-647.sup.4;

Photosensitizers

[0169] such as methoxsalen.sup.3;
porfimer sodium, talaporfin, temoporfin;

Antibodies

[0170] such as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab.sup.2,3;
catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab.sup.1,2,3, onartuzumab.sup.1,3, racotumomab.sup.1, tabalumab.sup.1,3, EMD-525797.sup.4, avelumab, nivolumab.sup.1,3;

Cytokines

[0171] such as aldesleukin, interferon alfa.sup.2, interferon alfa2a.sup.3, interferon alfa2b.sup.2,3; celmoleukin, tasonermin, teceleukin, oprelvekin.sup.1,3, recombinant interferon beta-1a.sup.4;

Drug Conjugates

[0172] such as denileukin diftitox, ibritumomab tiuxetan, iobenguane I123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept;
cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab.sup.1,3, vintafolide.sup.1,3;

Vaccines

[0173] such as sipuleucel.sup.3; vitespen.sup.3, emepepimut-S.sup.3, oncoVAX.sup.4, rindopepimut.sup.3, troVax.sup.4, MGN-1601.sup.4, MGN-1703.sup.4;

Miscellaneous

[0174] alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel.sup.3, sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicine.sup.4, picibanil.sup.4, reolysin.sup.4, retaspimycin hydrochloride.sup.1,3, trebananib.sup.2,3, virulizin.sup.4, carfilzomib.sup.1,3, endostatin.sup.4, immucothel.sup.4, belinostat.sup.3, MGN-1703.sup.4;

PARP Inhibitors

Olaparib, Veliparib.

[0175] .sup.1 Prop. INN (Proposed International Nonproprietary Name)
.sup.2 Rec. INN (Recommended International Nonproprietary Names)

.SUP.3 .USAN (United States Adopted Name)

.SUP.4 .no INN.

[0176] The following abbreviations refer respectively to the definitions below:

aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz (Megahertz), min (minute), mm (millimeter), mmol (millimole), mM (millimolar), m.p. (melting point), eq (equivalent), mL (milliliter), μL (microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl.sub.3 (deuterated chloroform), CD.sub.3OD (deuterated methanol), C-hex (cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane), DIC (diisopropyl carbodiimide), DIEA (diisopropylethyl-amine), DMF (dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d.sub.6 (deuterated dimethylsulfoxide), EDC (1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electrospray ionization), EtOAc (ethyl acetate), Et.sub.2O (diethyl ether), EtOH (ethanol), HATU (dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate), HPLC (High Performance Liquid Chromatography), i-PrOH (2-propanol), K.sub.2CO.sub.3 (potassium carbonate), LC (Liquid Chromatography), MeOH (methanol), MgSO.sub.4 (magnesium sulfate), MS (mass spectrometry), MTBE (methyl tert-butyl ether), NaHCO.sub.3 (sodium bicarbonate), NaBH.sub.4 (sodium borohydride), NMM (N-methyl morpholine), NMR (Nuclear Magnetic Resonance), PE (petroleum ether) PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), RT (room temperature), Rt (retention time), SPE (solid phase extraction), TBTU (2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoro borate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet), WL (wavelength).

[0177] Above and below, all temperatures are indicated in ° C. In the following examples, “conventional work-up” means: water is added if necessary, the pH is adjusted, if necessary, to values between 2 and 10, depending on the constitution of the end product, the mixture is extracted with EtOAc or DCM, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallisation. Rf values on silica gel; eluent: EtOAc/MeOH 9:1.

[0178] .sup.1H NMR was recorded on Bruker DPX-300, DRX-400, AVII-400 or on a 500 MHz spectrometer, using residual signal of deuterated solvent as internal reference. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (δ=2.49 ppm for .sup.1H NMR in DMSO-d.sub.6). .sup.1H NMR data are reported as follows: chemical shift (multiplicity, coupling constants, and number of hydrogens). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

Analytical Methods

LCMS

Method A

[0179] Column: Ascentis Express C18, 3.0×50 mm, 2.7 μm

[0180] Mobile phase: A: water with 0.05% TFA, B: ACN with 0.05% TFA

[0181] Gradient: 5% B to 100% B till min 2.1, hold till min 2.8 min, 100% B to 5% B till min 2.85, stop after 3.00

[0182] Flow: 1.5 mL/min

[0183] Wave length: 254 nm

Method B

[0184] Column: Kinetex EVO C18, 3.0×50 mm, 2.6 μm

[0185] Mobile phase: A: water with 0.04% NH.sub.4OH, B: ACN

[0186] Gradient: 10% B to 95% B till min 2.1, hold till min 2.7 min, 95% B to 10% B till min 2.75, stop after 3.00

[0187] Flow: 1.2 mL/min

[0188] Wave length: 254 nm

Method C

[0189] Column: Ascentis Express C18, 3.0×50 mm, 2.7 μm

[0190] Mobile phase: A: water with 0.05% TFA, B: ACN with 0.05% TFA

[0191] Gradient: 5% B to 60% B till min 3.0, 60% B to 100% B till min 4.2 min, hold till min 5.2, 100% B to 5% B till min 5.3, stop after 5.60

[0192] Flow: 1.5 mL/min

[0193] Wave length: 254 nm

Method D

[0194] Column: Kinetex EVO C18, 3.0×50 mm, 2.6 μm

[0195] Mobile phase: A: water with 0.04% NH.sub.4OH, B: ACN

[0196] Gradient: 10% B to 60% B till min 3.0, 60% B to 95% B till min 4.0 min, hold till min 4.8, 95% B to 10% B till min 4.9, stop after 5.20

[0197] Flow: 1.2 mL/min

[0198] Wave length: 254 nm

Method E

[0199] Column: Cortecs C18+, 2.1×50 mm, 2.7 μm

[0200] Mobile phase: A: water with 0.1% FA, B: ACN with 0.1% FA

[0201] Gradient: 10% B to 100% B till min 2.0, hold till min 2.6, 100% B to 10% B till min 2.7, stop after 2.90

[0202] Flow: 1.0 mL/min

[0203] Wave length: 254 nm

Method F

[0204] Column: Shim-pack GIST C18, 3.0×50 mm, 2.0 μm

[0205] Mobile phase: A: water with 5 mM NH.sub.4CO.sub.3, B: ACN

[0206] Gradient: 10% B to 95% B till min 2.1, hold till min 2.7 min, 95% B to 10% B till min 2.75, stop after 3.00

[0207] Flow: 1.2 mL/min

[0208] Wave length: 254 nm

Method G

[0209] Column: Durashell C18, 3.0×50 mm, 2.1 μm

[0210] Mobile phase: A: water with 0.04% NH.sub.4OH, B: ACN

[0211] Gradient: 10% B to 95% B till min 2.1, hold till min 2.7 min, 95% B to 10% B till min 2.75, stop after 3.00

[0212] Flow: 1.2 mL/min

[0213] Wave length: 254 nm

Method H

[0214] Column: Titank C18, 3.0×50 mm, 3.0 μm

[0215] Mobile phase: A: water with 5 mM NH.sub.4CO.sub.3, B: ACN

[0216] Gradient: 10% B to 95% B till min 2.1, hold till min 2.7 min, 95% B to 10% B till min 2.75, stop after 3.00

[0217] Flow: 1.2 mL/min

[0218] Wave length: 254 nm

Method I

[0219] Column: Poroshell HPH-C18, 3.0×50 mm, 2.7 μm

[0220] Mobile phase: A: water with 0.04% NH.sub.4OH, B: ACN

[0221] Gradient: 10% B to 95% B till min 2.1, hold till min 2.7 min, 95% B to 10% B till min 2.75, stop after 3.00

[0222] Flow: 1.2 mL/min

[0223] Wave length: 254 nm

Method J

[0224] Column: Cortecs C18+, 2.1×50 mm, 2.7 μm

[0225] Mobile phase: A: water with 0.1% FA, B: ACN with 0.1% FA

[0226] Gradient: 10% B to 60% B till min 3.0, 60% B to 100% B till min 4.0, hold till min 4.7, 100% B to 10% B till min 4.8, stop after 5.00

[0227] Flow: 1.0 mL/min

[0228] Wave length: 254 nm

Method K

[0229] Column: Cortecs C18+, 2.1×50 mm, 2.7 μm

[0230] Mobile phase: A: water with 0.1% FA, B: ACN with 0.1% FA

[0231] Gradient: 10% B to 100% B till min 1.10, hold till min 1.60, 100% B to 10% B till min 1.61, stop after 1.90

[0232] Flow: 1.0 mL/min

[0233] Wave length: 254 nm

Method L

[0234] Column: Cortecs C18+, 2.1×50 mm, 2.7 μm

[0235] Mobile phase: A: water with 0.1% FA, B: ACN with 0.1% FA

[0236] Gradient: 5% B to 100% B till min 2.0, hold till min 2.6, 100% B to 5% B till min 2.7, stop after 2.90

[0237] Flow: 1.0 mL/min

[0238] Wave length: 254 nm

HPLC

Method A

[0239] Column: XSELECT HSS T3 100×4.6 mm

[0240] Mobile phase: A=Water+0.05% TFA, B=ACN+0.05% TFA

[0241] Gradient: start 5% B, after 8 min 95% B, after 10.2 min 5% B, stop after 12 min

[0242] Flow: 1.2 mL/min

[0243] Wave length: 254 nm

Method B

[0244] Column: Ascentis Express C18 2.7 μm, 100×4.6 mm

[0245] Mobile phase: A=Water+0.05% TFA, B=ACN+0.05% TFA

[0246] Gradient: start 5% B, after 8 min 95% B, after 10.2 min 5% B, stop after 12 min

[0247] Flow: 1.5 mL/min

[0248] Wave length: 254 nm

Analytical Chiral Separation

Method A

[0249] Method: HPLC

[0250] Column: ChiralPak IG-3, 0.46×5 cm, 3 μm

[0251] Mobile phase: Hex(0.1% DEA)/EtOH=7:3

[0252] Wave length: 254 nm

[0253] Flow: 1.0 mL/min

Method B

[0254] Method: HPLC

[0255] Column: ChiralPak IG-3, 0.46×5 cm, 3 μm

[0256] Mobile phase: Hex(0.1% DEA)/EtOH=8:2

[0257] Wave length: 254 nm

[0258] Flow: 1.0 mL/min

Method C

[0259] Method: HPLC

[0260] Column: ChiralPak IC-3, 0.46×5 cm, 3 μm

[0261] Mobile phase: Hex(0.1% DEA)/EtOH=7:3

[0262] Wave length: 254 nm

[0263] Flow: 1.0 mL/min

Method D

[0264] Method: HPLC

[0265] Column: ChiralPak IF-3, 0.46×5 cm, 3 μm

[0266] Mobile phase: Hex(0.1% DEA)/EtOH=7:3

[0267] Wave length: 254 nm

[0268] Flow: 1.0 mL/min

Method E

[0269] Method: HPLC

[0270] Column: ChiralPak IG-3, 0.46×5 cm, 3 μm

[0271] Mobile phase: Hex(0.1% DEA)/EtOH=9:1

[0272] Wave length: 254 nm

[0273] Flow: 1.0 mL/min

Method F

[0274] Method: HPLC

[0275] Column: ChiralPak IG-3, 0.46×5 cm, 3 μm

[0276] Mobile phase: Hex(0.1% DEA)/EtOH=6:4

[0277] Wave length: 254 nm

[0278] Flow: 1.0 mL/min

Method G

[0279] Method: HPLC

[0280] Column: ChiralPak IC-3, 0.46×5 cm, 3 μm

[0281] Mobile phase: Hex(0.1% DEA)/IPA=1:1

[0282] Wave length: 254 nm

[0283] Flow: 1.0 mL/min

Method H

[0284] Method: HPLC

[0285] Column: ChiralPak IF-3, 0.46×5 cm, 3 μm

[0286] Mobile phase: Hex(10 mmol NH.sub.3)/EtOH=5:5

[0287] Wave length: 254 nm

[0288] Flow: 1.0 mL/min

Method I

[0289] Method: HPLC

[0290] Column: Chiral Cellulose-SB, 0.46×10 cm, 3 μm

[0291] Mobile phase: Hex(0.1% DEA)/IPA=3:1

[0292] Wave length: 254 nm

[0293] Flow: 1.0 mL/min

Method J

[0294] Method: HPLC

[0295] Column: ChiralPak IG-3, 0.46×5 cm, 3 μm

[0296] Mobile phase: Hex(0.1% DEA)/EtOH=1:1

[0297] Wave length: 254 nm

[0298] Flow: 1.0 mL/min

Method K

[0299] Method: HPLC

[0300] Column: ChiralPak IE-3, 0.46×5 cm, 3 μm

[0301] Mobile phase: Hex(0.1% DEA)/EtOH=85:15

[0302] Wave length: 254 nm

[0303] Flow: 1.0 mL/min

Method L

[0304] Method: HPLC

[0305] Column: ChiralPak IC-3, 0.46×5 cm, 3 μm

[0306] Mobile phase: Hex(0.1% DEA)/IPA=65:35

[0307] Wave length: 254 nm

[0308] Flow: 1.0 mL/min

Biological Activity

[0309] Alphascreen Protein protein interaction assay:

[0310] For the assessment of functional disruption of the interaction of the PAS B domains of HIF-2α and HIF-1β an AlphaScreen assay was set-up. The assay was performed in 384 well light gray Perkin Elmer microtiter plates in a total volume of 7 μl. Human rec His6Gb1-TEV-GEFKGL-HIF2α (240-350aa)-G (fc 143 nM) and human rec ARNT His6Gb1-TEV-GEFKGL-ARNT (356-470aa)-FLAG-E362R (fc 143 nM) were incubated with the compound (fc 1 nM to 30 μM) of interest in 20 mM Hepes, 150 mM NaCl, 0.05% Tween 20, 2 mM DTT, 0.1% (w/v) BSA, 0.3% DMSO, pH 7.5 for 15 min at 23° C. The detection of the protein protein interaction was performed by adding AlphaLISA® Anti-FLAG Acceptor beads (fc 20 μg/mL) and AlphaScreen® Nickel Chelate Donor beads (fc 9 μg/mL) (both Perkin Elmer) and the reaction was incubated for 240 min at 23° C. in the dark. If donor and acceptor beads get in close proximity to each other caused by interaction of HIF2alpha PAS B with HIF-1ß PAS B domain it results in a luminescence signal at 615 nm after excitation at 680 nm. The PPI disruption activity of a compound was calculated directly from the loss in Alphascreen signal. The AlphaScreen signal was measured with an Envision multimode reader (Perkin Elmer LAS Germany GmbH). The control value used was the inhibitor-free reaction. The pharmacological zero value used was determined in the absence of HIF-1ß. The inhibitory values (IC50) were calculated using Assay analyser from GeneData.

[0311] The compounds inhibit HIF-2α in the assay with an IC.sub.50 of A<50 nM, 50≤B≤1000 nM, and C>1000 nM as shown in the following table:

TABLE-US-00001 Example AlphaScreen  1a A  2a A  3a A  4a A  5a A  6a A  7a A  8a A  9a A 10a A 11a A 12a A 13a A 14a A 15a A 16a A 17a A 18a A 19a A 20a A 21a A 22a A 23a A 24a C 25a B 26a B 27a B 28a B 29a C 30a C 31a C 32a C 33a A 34a B

ITC

[0312] ITC measurements were performed with a VP-ITC microcalorimeter from MicroCal/Malvern (UK). For all titration experiments the protein and the respective compounds were formulated in 30 mM HEPES buffer pH 7.5, 150 mM NaCl and 5 mM ß-mercaptoethanol. The protein, HIF2a (240-350)-G, was prepared by recombinant overexpression and multistep chromatography purification. Compounds were used from concentrated DMSO stock solutions. The final protein concentration in the injection syringe was 100 μM. Ligand stock solutions of 10 mM in DMSO were diluted to 10 μM concentrations with buffer and loaded into the sample cell. All buffers were adjusted to a final concentration of 1% (v/v) DMSO. Both, the titrate and titrant solutions were degassed prior to loading the calorimeter cell and injection syringe. ITC titrations were conducted at a constant temperature of 303 K. ITC data analysis was performed using the Origin 7 (OriginLab Cooperation Northampton, USA)-based calorimetry customization supplied as standard instrument software by MicroCal/Malvern (UK). The integrated heat data were fit with a one-site binding model to determine the apparent values for affinity, enthalpy and stoichiometry of binding.

[0313] The compounds bind HIF-2α in the assay with an K.sub.D of A<100 nM, 100≤B≤1000 nM, and C>1000 nM as shown in the following table:

TABLE-US-00002 Example ITC  1a B  3a B  5a B  7a A  8a B  9a B 12a B 13a B 16a B 19a A 20a B 22a B 24a C 25a C 26a C 27a B 28a B 29a C 30a C 31a C

Cellular Mechanistic Assay: 786-O HRE-luc2P Reporter Assay

[0314] This reporter assay was designed to monitor binding of the HIF2α-HIF1β complex to specific DNA fragment called hypoxia response element (HRE) in physiologically relevant cell line. 786-O HRE-luc2P cells were derived from 786-O human renal cell adenocarcinoma cell line by stable integration of a HRE Luc reporter construct (pGL4.42 [luc2P/HRE/Hygro] Vector, Promega, cat no. E4001) driving the expression of luciferase under the control of HRE sequence. HRE is present in promoters of various genes regulated by hypoxia inducible factors. 786-O cells express only HIF2α. As a result, this reporter assay allows monitoring of HIF2α-HIF1β activity by determining the activity of produced luciferase. Cell culture is performed in RPMI media supplemented with 10% FBS, Sodium Pyruvate, Penicillin/Streptomycin, Glutamine, 200 μg/mL Hygromycin Gold.

[0315] The assay was performed in 384 well white, opaque microtiterplate with transparent bottom (Greiner Bio-one, Frickenhausen). 786-O HRE-luc2P cells were resuspended at 4×104 cells/mL in fresh, pre-warmed medium (RPMI, 10% FBS, SP, P/S, Q) w/o hygromycin. 50 μl of cell suspension (2000 cells) per well were dispensed in microtiter plates and incubated over night at 37° C. in a 5% CO.sub.2 incubator. Compounds were added with Labcyte Echo dispenser (fc 0.3% DMSO, 9 concentrations dilution raw starting at 30 μM). Plates were incubated for 48 h at 37° C. in a 5% CO.sub.2 incubator. After this 45 μl of prewarmed ONE-Glo™ EX Reagent were added per well. Plates were placed on an orbital shaker at 1200 rpm for 3 minutes. Plates were sealed and luminescence was measured a Tecan Spark 20M microplate reader (end-point measurement with 0.1 second reading time). Values were normalized to DMSO ctrl and wells without cells (only medium ctrl). Decrease in luminescence directly correlates with inhibition of HIF2α activity. EC50 values and % of effect values were calculated fitting a variable-slope sigmoidal function using Ryvu Therapeutics (formerly Selvita S.A.) DRC application or GraphPad Prism software.

[0316] The compounds inhibit HIF-2α in the assay with an IC50 of A<50 nM, 50≤B≤1000 nM, and C>1000 nM as shown in the following table:

TABLE-US-00003 Example HRE-luc2P reporter assay  1a B  2a B  3a B  4a B  5a B  6a A  7a B  8a B  9a C 10a C 11a B 12a B 13a C 14a B 15a B 16a C 17a B 18a B 19a B 20a B 21a B 23a C 24a C 25a C 26a C 27a C 28a C 29a C 30a C 31a C 32a C 33a B 34a C

Synthesis

General Procedure

[0317] ##STR00005## ##STR00006## ##STR00007##

Synthesis of 3-(2,5-dichlorothiophen-3-yl)propanoic acid (2)

[0318] ##STR00008##

[0319] To 3-(thiophen-3-yl)propanoic acid (6.00 g, 36.49 mmol, 95%) in a 250 mL round-bottom flask was added toluene (70 mL) and SO.sub.2Cl.sub.2 (11.92 g, 83.90 mmol, 95%). The resulting solution was stirred at 69° C. for 4 h. The reaction was then quenched by the addition of 100 mL of water/ice and extracted with 4×100 mL of EtOAc. The combined organic layer was dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified via column chromatography eluting with 0-8% EtOAc in PE to afford 8.89 g of 3-(2,5-dichlorothiophen-3-yl)propanoic acid as a colorless solid.

[0320] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.00 (s, 1H), 7.07 (s, 1H), 2.75-2.70 (m, 2H), 2.54-2.48 (m, 2H); LC-MS (method D): [M−H].sup.−=222.75, Rt=0.89 min.

Synthesis of 3-(2,5-dichlorothiophen-3-yl)propanoyl chloride (3)

[0321] ##STR00009##

[0322] To 3-(2,5-dichlorothiophen-3-yl)propanoic acid (8.89 g, 36.89 mmol, 93.4%) in a 250 mL round-bottom flask purged with nitrogen was added thionyl chloride (80.00 mL, 1.05 mol, 95%). The resulting solution was stirred at 25° C. for 3 h. The mixture was then concentrated under reduced pressure to afford 8.32 g of 3-(2,5-dichlorothiophen-3-yl)propanoyl chloride as orange oil which was used without further purification.

Synthesis of 1,3-dichloro-5H,6H-cyclopenta[c]thiophen-4-one (4)

[0323] ##STR00010##

[0324] 3-(2,5-dichlorothiophen-3-yl)propanoyl chloride (8.32 g, 32.04 mmol, 93.8%) was dissolved in DCM (80 mL) in a 500 mL round-bottom flask purged with nitrogen and the solution was cooled to 0-5° C. AlCl.sub.3 (35.98 g, 256.3 mmol, 95%) was added slowly. The resulting mixture was stirred at 25° C. for 5 h. It was then poured into 1 L of water/ice and extracted with 3×300 mL of EtOAc. The combined organic layer was dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified via column chromatography eluting with EtOAc (0-10%) in PE to afford 4.02 g 1,3-dichloro-5H,6H-cyclopenta[c]thiophen-4-one as a light yellow solid.

[0325] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 3.01-2.95 (m, 2H), 2.87-2.81 (m, 2H); LC-MS (Method D): [M+H].sup.+=206.80, Rt=0.95 min.

Synthesis of 1-chloro-3-(methylsulfanyl)-4H,5H,6H-cyclopenta[c]thiophen-4-one

[0326] ##STR00011##

[0327] Into a 250-mL round-bottom flask purged with nitrogen, was placed 1,3-dichloro-5H,6H-cyclopenta[c]thiophen-4-one (4.57 g, 21.10 mmol), tetrahydrofuran (97 mL) and (methylsulfanyl)sodium (1.77 g, 23.99 mmol). The resulting solution was stirred for 4 h at 25° C. The reaction was then quenched by the addition of H.sub.2O. The resulting solution was extracted with 100 mL of ethyl acetate. The organic layer was dried, filtered and the solvent evaporated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20) to gain 3.3 g (71%) of 1-chloro-3-(methylsulfanyl)-4H,5H,6H-cyclopenta[c]thiophen-4-one as a red solid. LC-MS (Method K): [M+H].sup.+=218.85, Rt=0.92 min.

Synthesis of 1-chloro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one

[0328] ##STR00012##

[0329] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-chloro-3-(methylsulfanyl)-4H,5H,6H-cyclopenta[c]thiophen-4-one (3.3 g, 15.0 mmol), dichloromethane (31 mL) and m-CPBA (17.2 g, 74.75 mmol, 75%). The resulting solution was stirred for 2 h at 25° C. and quenched with water. The resulting solution was extracted with 4×50 mL of ethyl acetate and the organic layers combined, dried over sodium sulfate, filtered and concentrated under vacuum to afford 3.3 g (85%) of 1-chloro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one as white solid. LC-MS (Method K): [M+H].sup.+=250.85, Rt=0.71 min.

Synthesis of 1-chloro-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2′[1,3]dioxolane]

[0330] ##STR00013##

[0331] Into a 250-mL round-bottom flask purged with nitrogen, was placed 1-chloro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one (3.00 g, 10.0 mmol), ethane-1,2-diol (1.30 g, 20.0 mmol), TsOH (0.36 g, 1.996 mmol), toluene (100 mL). The resulting solution was stirred for 16 h at 125° C. The resulting mixture was concentrated and the residue purified via column chromatography (ethyl acetate:petroleum ether=1:3). This resulted in 2.8 g (94%) of 1-chloro-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2′-[1,3]dioxolane] as a yellow solid. LC-MS (Method K): [M+H].sup.+=294.95, Rt=0.94 min.

Synthesis of 3-methanesulfonyl-1-(2-methylpropoxy)-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2′-[1,3]dioxolane]

[0332] ##STR00014##

[0333] Into a 20-mL vial purged nitrogen, was placed 2-methylpropan-1-ol (1286 mg, 16.5 mmol), DMF (20 mL). This was followed by the addition of potassium isobutoxide (1.04 g, 8.8 mmol). The mixture was stirred for 20 min at 0° C. To this was added 1-chloro-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2′[1,3]dioxolane] (900 mg, 2.75 mmol), 15-crown-5 (955.71 mg, 4.1 mmol). The resulting solution was stirred for 3 h at 55° C. in an oil bath, cooled to room temperature and quenched with water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined, filtered and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 566 mg (53%) of 3-methanesulfonyl-1-(2-methylpropoxy)-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2′[1,3]dioxolane] as a brown solid. LC-MS (Method K): [M+H].sup.+=333.05, Rt=1.06 min.

Synthesis of 3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-one

[0334] ##STR00015##

[0335] Into a 100-mL round-bottom flask was placed 3-methanesulfonyl-1-(2-methylpropoxy)-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2-[1,3]dioxolane] (556 mg, 1.5 mmol), DCM (10 mL) and TFA (1.5 mL, 19.2 mmol). The resulting solution was stirred for 3 h at 25° C. The reaction was then quenched by the addition of 30 mL of NaHCO.sub.3. The resulting solution was extracted with ethyl acetate, the combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. This resulted in 500 mg (74.9% pure, 86%) of 3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-one as a brown solid. LC-MS (Method K): [M+H].sup.+=288.95, Rt=0.94 min.

Synthesis of 5-fluoro-3-methanesulfonyl-4,4-dimethoxy-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophene

[0336] ##STR00016##

[0337] Into a 20-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-one (560 mg, 1.45 mmol, 74.9%), MeOH (10 mL), selectfluor (1376 mg, 3.7 mmol), H.sub.2SO.sub.4 (0.25 mL, 4.5 mmol). The resulting solution was stirred for 3 h at 60° C. in an oil bath. The resulting solution was extracted with 3×30 mL ethyl acetate and the organic layers were combined, filtered and concentrated under vacuum. This resulted in 550 mg (39% pure, 42%) of 5-fluoro-3-methanesulfonyl-4,4-dimethoxy-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophene as a brown solid. LC-MS (Method K): [M+H—CH.sub.3—OCH.sub.3].sup.+=306.95, Rt=1.09 min.

Synthesis of 5-fluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-one

[0338] ##STR00017##

[0339] Into a 100-mL round-bottom flask, was placed 5-fluoro-3-methanesulfonyl-4,4-dimethoxy-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophene (550 mg, 0.858 mmol, 39%), DCM (10 mL), TFA (2 mL, 25.580 mmol). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of water. The resulting mixture was extracted with 3×20 mL of ethyl acetate and the organic layers combined, filtered and concentrated under vacuum. This resulted in 520 mg (45% pure, 89%) of 5-fluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-one as a solid. LC-MS (Method K): [M+H].sup.+=306.95, Rt=1.10 min.

Synthesis of tert-butyl({[5-fluoro-1-methanesulfonyl-3-(2-methylpropoxy)-4H-cyclopenta[c]thiophen-6-yl]oxy})dimethylsilane

[0340] ##STR00018##

[0341] Into a 50-mL 3-necked round-bottom flask purged with nitrogen, was placed 5-fluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-one (100 mg, 0.29 mmol), DCM (5 mL), TEA (160 mg, 1.50 mmol, 95%), TBSOTf (252 mg, 0.91 mmol). The resulting mixture was stirred for 3 h at room temperature and then concentrated under vacuum. The residue was purified via column chromatography (ethyl acetate:petroleum ether=1:5). This resulted in 100 mg (74%) of tert-butyl({[5-fluoro-1-methanesulfonyl-3-(2-methylpropoxy)-4H-cyclopenta[c]thiophen-6-yl]oxy})dimethylsilane as yellow oil. LC-MS (Method K): [M+H].sup.+=421.10, Rt=1.36 min.

Synthesis of 5,5-difluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-one

[0342] ##STR00019##

[0343] Into a 25-mL round-bottom flask, was placed tert-butyl({[5-fluoro-1-methanesulfonyl-3-(2-methylpropoxy)-4H-cyclopenta[c]thiophen-6-yl]oxy})dimethylsilane (90 mg, 0.19 mmol), MeCN (4 mL), selectfluor (151.5 mg, 0.41 mmol). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 2×30 mL of aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. This resulted in 60 mg (86%) of 5,5-difluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-one as a yellow solid. LC-MS (Method K): [M+H].sup.+=325.05, Rt=0.97 min.

Synthesis of 5,5-difluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol

[0344] ##STR00020##

[0345] Into a 25-mL round-bottom flask, was placed 5,5-difluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-one (30 mg, 0.08 mmol), THF (4 mL), NaBH.sub.4 (7.0 mg, 0.18 mmol). The resulting solution was stirred for 2 h at room temperature and diluted with 30 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated. 5,5-difluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol was obtained as a white solid.

Chiral resolution of 5,5-difluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (8)

[0346] ##STR00021##

[0347] 5,5-difluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (8) were separated by Chiral-Prep-HPLC under the following condition: HPLC Column: ChiralPak IG-3, 0.46×5 cm, 3 μm mobile phase: Hex(0.1% DEA)/EtOH=9:1, wave length: 254 nm, flow: 1.0 mL/min. This resulted in 30.3 mg of (4S)-5,5-difluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (8a) as a white solid with a melting point of 65-68° C.

[0348] 8a: .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.04 (dd, J=11.6, 2.8 Hz, 1H), 3.97 (d, J=6.5 Hz, 2H), 3.25 (s, 3H), 3.24-3.12 (m, 2H), 2.18-2.00 (m, 1H), 1.03 (d, J=6.7 Hz, 6H); LC-MS (method E): Rt=1.24 min, [M+HCOO].sup.−=370.75; HPLC (method B): purity 99.1%, Rt 5.28 min; chiral HPLC (method E): 98.0% er, Rt 3.95 min, (8b: Rt=3.53 min).

[0349] Following compounds have been obtained analogously:

(4S)-1-(cyclohexyloxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (1a)

[0350] ##STR00022##

[0351] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.06-5.02 (m, 1H), 4.31-4.23 (m, 1H), 3.27 (s, 3H), 3.21-3.08 (m, 2H), 2.06 (m, 2H), 1.80-1.74 (m, 2H), 1.66-1.58 (m, 3H), 1.52-1.35 (m, 3H); LC-MS (method A): Rt=1.47 min, [M+Na].sup.+=274.9; HPLC (method A): purity 99.7%, Rt 6.70 min; chiral HPLC (method A): >99.5% ee, Rt 2.2 min.

[0352] The (4R)-enantiomer has been obtained analogously.

(4S)-1-(2,2-dimethylpropoxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (2a)

[0353] ##STR00023##

[0354] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.06 (dd, J=11.5, 2.9 Hz, 1H), 3.88 (s, 2H), 3.28 (s, 3H), 3.23 (ddd, J=16.2, 9.0, 5.4 Hz, 2H), 1.06 (s, 9H); LC-MS (method B): Rt=1.66 min, [M+NH.sub.4].sup.+=358.1; HPLC (method B): purity 98.6%, Rt 5.72 min; chiral HPLC (method B): >99.5% ee, Rt 1.53 min.

[0355] The (4R)-enantiomer has been obtained analogously.

(4S)-1-cyclobutoxy-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (3a)

[0356] ##STR00024##

[0357] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.06-5.02 (m, 1H), 4.80-4.73 (m, 1H), 3.26-3.14 (m, 5H), 2.55-2.45 (m, 2H), 2.31-2.18 (m, 2H), 1.95-1.85 (m, 1H), 1.78-1.68 (m, 1H); LC-MS (method A): Rt=1.52 min, [M+Na].sup.+=346.9; HPLC (method A): purity 99.5%, Rt 6.0 min; chiral HPLC (method B): 99.8% er, Rt 2.26 min.

[0358] The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-(2-methylbutoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (4a)

[0359] ##STR00025##

[0360] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.06 (dd, J=11.4, 2.7 Hz, 1H), 4.08-3.96 (m, 2H), 3.31 (s, 3H), 3.22-3.14 (m, 2H), 1.94-1.83 (m, 1H), 1.62-1.48 (m, 1H), 1.36-1.21 (m, 1H), 1.03-0.93 (m, 6H); LC-MS (method C): Rt=2.75 min, [M+Na].sup.+=363.0; HPLC (method A): purity 97.4%, Rt 6.75 min; chiral HPLC (method C): >99.5% ee, Rt 1.24 min.

[0361] The (4R)-enantiomer has been obtained analogously.

(4S)-1-(2,2-difluoroethoxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (5a)

[0362] ##STR00026##

[0363] Prepared according to general procedure; .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ=6.69 (m, 1H), 6.56-6.21 (m, 1H), 4.97 (m, 1H), 4.62-4.52 (m, 2H), 3.44-3.28 (m, 5H); LC-MS (method A): Rt=1.06 min, [M+Na].sup.+=356.8; HPLC (method A): purity 99.9%, Rt 5.16 min; chiral HPLC (method A): 99.5% ee, Rt 1.9 min.

[0364] The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-(3,3,3-trifluoro-2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (6a)

[0365] ##STR00027##

[0366] Prepared according to general procedure; .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ=6.69 (d, J=7.1 Hz, 1H), 5.03-4.87 (m, 1H), 4.34 (d, J=5.4 Hz, 2H), 3.28 (d, J=5.6 Hz, 5H), 2.97 (d, J=7.6 Hz, 1H), 1.18 (d, J=7.1 Hz, 3H); LC-MS (method D): Rt=2.52 min, [M+NH.sub.4].sup.+=398.1; HPLC (method A): purity 99.5%, Rt 6.20 min; chiral HPLC (method B): >99.5% ee, Rt 2.13 min.

[0367] The (4R)-stereoisomers have been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-(2,2,2-trifluoroethoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (7a)

[0368] ##STR00028##

[0369] Prepared according to general procedure; .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ=5.08 (d, J=6.9 Hz, 1H), 5.07-4.99 (m, 3H), 3.40-3.35 (m, 5H); LC-MS (method E): Rt=1.14 min, [M+HCOO].sup.−=396.7; HPLC (method A): purity 99.6%, Rt 5.6 min; chiral HPLC (method D): >99.5% ee, Rt 1.22 min.

[0370] The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-(2-methylpropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (8a)

[0371] ##STR00029##

[0372] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.04 (dd, J=11.6, 2.8 Hz, 1H), 3.97 (d, J=6.5 Hz, 2H), 3.25 (s, 3H), 3.24-3.12 (m, 2H), 2.18-2.00 (m, 1H), 1.03 (d, J=6.7 Hz, 6H); LC-MS (method E): Rt=1.24 min, [M+HCOO].sup.−=370.75; HPLC (method B): purity 99.1%, Rt 5.28 min; chiral HPLC (method E): 98.0% er, Rt 3.95 min.

[0373] The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-{[1,1,1-trifluorobutan-2-yl]oxy}-4H,5H,6H-cyclopenta[c]thiophen-4-ol (9a)

[0374] ##STR00030##

[0375] Prepared according to general procedure; .sup.1H NMR (400 MHz, CD.sub.3OD): δ=5.08 (dd, J=11.1, 3.0 Hz, 1H), 4.74-4.65 (m, 1H), 3.28 (s, 3H), 3.26-3.18 (m, 2H), 2.01-1.83 (m, 2H), 1.13 (t, J=7.6 Hz, 3H); LC-MS (method E): Rt=1.44 min, [M+HCOO].sup.−=424.75; HPLC (method B): purity 99.6%, Rt 5.44 min; chiral HPLC (method B): 99.8% er, Rt 2.36 min.

[0376] In the formula “or” means unknown configuration.

[0377] The stereoisomers have been obtained analogously.

(4S)-{[1,1-difluoropropan-2-yl]oxy}-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (10a)

[0378] ##STR00031##

[0379] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=6.18-5.81 (m, 1H), 5.08-5.03 (m, 1H), 4.62-4.47 (m, 1H), 3.29-3.14 (m, 5H), 1.45 (s, 3H); LC-MS (method D): Rt=2.14 min, [M+NH.sub.4].sup.+=366.0; HPLC (method B): purity 96.5%, Rt 4.50 min; chiral HPLC (method A): >99.5% ee, Rt 2.17 min.

[0380] In the formula “or” means unknown configuration.

[0381] The stereoisomers have been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-(3,3,3-trifluoropropoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (11a)

[0382] ##STR00032##

[0383] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.07 (dd, J=11.5, 3.0 Hz, 1H), 4.44 (t, J=5.8 Hz, 2H), 3.29 (s, 3H), 3.26-3.19 (m, 2H), 2.86-2.71 (m, 2H); LC-MS (method B): Rt=1.41 min, [M+NH.sub.4].sup.+=384.0; HPLC (method A): purity 96.1%, Rt 4.74 min; chiral HPLC (method B): >99.5%, Rt 1.61 min.

[0384] The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-propoxy-4H,5H,6H-cyclopenta[c]thiophen-4-ol (12a)

[0385] ##STR00033##

[0386] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.08 (m, 2H), 4.19-4.15 (m, 2H), 3.25-3.11 (m, 5H), 1.91-1.80 (m, 2H), 1.08-1.06 (m, 3H); LC-MS (method F): Rt=1.77 min, [M−H].sup.−=311.0; HPLC (method A): purity 98.9%, Rt 5.91 min; chiral HPLC (method F): >99.5% ee, Rt 1.10 min.

[0387] The (4R)-enantiomer has been obtained analogously.

(4S)-1-(cyclopropylmethoxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (13a)

[0388] ##STR00034##

[0389] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.08 (dd, J=11.1, 3.0 Hz, 1H), 4.05 (d, J=7.2 Hz, 2H), 3.27-3.15 (m, 5H), 1.39-1.26 (m, 1H), 0.71-0.60 (m, 2H), 0.45-0.39 (m, 2H); LC-MS (method G): Rt=1.41 min, [M+NH.sub.4].sup.+=342.1; HPLC (method A): purity 99.8%, Rt 5.79 min; chiral HPLC (method B): >99.5% ee, Rt 5.45 min.

[0390] The (4R)-enantiomer has been obtained analogously.

(4S)-1-{[1,1-difluoropropan-2-yl]oxy}-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (14a)

[0391] ##STR00035##

[0392] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=6.19-5.81 (m, 1H), 5.08-5.03 (m, 1H), 4.62-4.47 (m, 1H), 3.30-3.14 (m, 5H), 1.44 (s, 3H); LC-MS (method D): Rt=2.14 min, [M+NH.sub.4].sup.+=366.1; HPLC (method B): purity 96.8%, Rt 4.52 min; chiral HPLC (method A): >99.5% ee,

[0393] Rt 1.74 min.

[0394] In the formula “or” means unknown configuration.

[0395] The stereoisomers have been obtained analogously.

(4S)-1-(2,2-difluoropropoxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (15a)

[0396] ##STR00036##

[0397] Prepared according to general procedure; .sup.1H NMR (400 MHz, CDCl.sub.3): 5.24 (dd, J=11.5, 4.8 Hz, 1H), 4.28-4.20 (t, J=11.2 Hz, 2H), 3.40-3.14 (m, 6H), 1.78 (t, J=18.8 Hz, 3H); LC-MS (method H): Rt=1.62 min, [M−H].sup.−=346.9; HPLC (method B): purity 99.5%, Rt 4.7 min; chiral HPLC (method A): >99.5% ee, Rt 2.21 min.

[0398] The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-[(1-methoxycyclobutyl)methoxy]-4H,5H,6H-cyclopenta[c]thiophen-4-ol (16a)

[0399] ##STR00037##

[0400] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.08 (dd, J=11.4, 2.7 Hz, 1H), 4.33 (s, 2H), 3.36-3.30 (m, 4H), 3.28-3.17 (m, 4H), 2.30-2.19 (m, 2H), 2.11-2.03 (m, 2H), 1.90-1.67 (m, 2H); LC-MS (method E): Rt=1.09 min, [M+COO].sup.−=412.8; HPLC (method A): purity 99.8%, Rt 5.71 min; chiral HPLC (method A): >99.5% ee, Rt 1.55 min.

[0401] The (4R)-enantiomer has been obtained analogously.

(4S,5S)-5-fluoro-3-methanesulfonyl-1-(2,2,2-trifluoroethoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (17a)

[0402] ##STR00038##

[0403] Prepared according to general procedure; .sup.1H NMR (400 MHz, CD.sub.3OD): δ=5.39-5.19 (m, 2H), 4.79-4.73 (m, 2H), 3.37-3.32 (m, 3H), 3.15-3.03 (m, 2H); LC-MS (method B): Rt=1.24 min, [M−H].sup.−=332.9; HPLC (method B): purity 98.0%, Rt 4.08 min; chiral HPLC (method A): >99.5% ee, Rt 3.67 min.

[0404] The stereoisomers have been obtained analogously.

(4S)-1-[(3,3-difluorocyclobutyl)methoxy]-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (18a)

[0405] ##STR00039##

[0406] Prepared according to general procedure; .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ=6.68 (d, J=7.0 Hz, 1H), 5.06-4.88 (m, 1H), 4.28 (d, J=6.0 Hz, 2H), 3.29 (d, J=16.1 Hz, 5H), 2.83-2.57 (m, 3H), 2.49 (s, 2H); LC-MS (method B): Rt=1.49 min, [M+NH.sub.4].sup.+=392.1; HPLC (method B): purity 99.5%, Rt 4.98 min; chiral HPLC (method A): >99.5% ee, Rt 1.42 min.

[0407] The (4R)-enantiomer has been obtained analogously.

(4S)-1-(cyclobutylmethoxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (19a)

[0408] ##STR00040##

[0409] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.08 (dd, J=2.7 Hz, 1H), 4.18 (d, J=6.3 Hz, 2H), 3.27 (s, 3H), 3.24-3.16 (m, 2H), 2.88-2.78 (m, 1H), 2.21-2.09 (m, 2H), 2.06-1.80 (m, 4H); LC-MS (method E): Rt=1.28 min, [M+Na].sup.+=362.0; HPLC (method A): purity 99.8%, Rt 6.47 min; chiral HPLC (method A): >99.5% ee, Rt 2.20 min.

[0410] The (4R)-enantiomer has been obtained analogously.

(4S)-1-(1-cyclobutylethoxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (20a)

[0411] ##STR00041##

[0412] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.08 (dd, J=11.7, 2.7 Hz, 1H), 4.31-4.23 (m, 1H), 3.29-3.06 (m, 5H), 2.64-2.51 (m, 1H), 2.07-1.77 (m, 6H), 1.28 (d, J=6 Hz, 3H); LC-MS (method E): Rt=1.41 min, [2M+H].sup.+=705.1; HPLC (method A): purity 99.4%, Rt 6.78 min; chiral HPLC (method B): 99.2% er, Rt 1.45 min.

[0413] The stereoisomers have been obtained analogously.

(4S)-1-(3,3-difluorobutoxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (21a)

[0414] ##STR00042##

[0415] Prepared according to general procedure; .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ=6.71 (d, J=7.0 Hz, 1H), 5.06-4.92 (m, 1H), 4.43-4.32 (m, 2H), 3.34 (s, 3H), 3.31-3.19 (m, 2H), 2.49-2.36 (m, 2H), 1.76-1.61 (m, 3H); LC-MS (method H): Rt=2.86 min, [M+NH.sub.4].sup.+=380.0; HPLC (method B): purity 97.4%, Rt 4.71 min; chiral HPLC (method A): >99.5% ee, Rt 1.25 min.

[0416] The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-(oxan-4-yloxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (22a)

[0417] ##STR00043##

[0418] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.08-5.04 (m, 1H), 4.55-4.47 (m, 1H), 3.99-3.91 (m, 2H), 3.63-3.55 (m, 2H), 3.32-3.14 (m, 5H), 2.14-2.08 (m, 2H), 1.86-1.75 (m, 2H); LC-MS (method F): Rt=1.35 min, [M+Na].sup.+=376.9; HPLC (method A): purity 99.9%, Rt 4.96 min; chiral HPLC (method G): >99.5% ee, Rt 2.07 min.

[0419] The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-[2-(trifluoromethoxy)ethoxy]-4H,5H,6H-cyclopenta[c]thiophen-4-ol (23a)

[0420] ##STR00044##

[0421] Prepared according to general procedure; .sup.1H NMR (400 MHz, CD.sub.3OD): δ=5.07 (dd, J=11.4, 3.0 Hz, 1H), 4.48-4.42 (m, 2H), 4.42-4.35 (m, 2H), 3.29 (s, 3H), 3.36-3.15 (m, 2H); LC-MS (method B): Rt=2.42 min, [M+NH.sub.4].sup.+=400.0; HPLC (method B): purity 99.0%, Rt 4.90 min; chiral HPLC (method E): >99.5% ee, Rt 2.71 min.

[0422] The (4R)-enantiomer has been obtained analogously.

1-(3,4-difluorophenoxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (24a)

[0423] ##STR00045##

[0424] Prepared according to general procedure; .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.23-7.17 (m, 1H), 7.05-6.98 (m, 1H), 6.93-6.87 (m, 1H), 5.27-5.21 (m, 1H), 3.49 (s, 1H), 3.26 (s, 3H), 3.19-2.96 (m, 2H); LC-MS (method E): Rt=1.24 min, [M+H].sup.+=404.9; HPLC (method A): purity 99.3%, Rt 6.44 min; racemic.

(4S)-5,5-difluoro-3-methanesulfonyl-1-(propan-2-yloxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (25a)

[0425] ##STR00046##

[0426] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.05 (m, 1H), 4.53 (m, 1H), 3.28-3.25 (s, 3H), 3.24-3.13 (m, 2H), 1.42 (d, 6H); LC-MS (method I): Rt=1.37 min, [M+NH.sub.4].sup.+=330.0; HPLC (method B): purity 99.8%, Rt 4.4 min; chiral HPLC (method G): >99.5% ee, Rt 1.38 min.

[0427] The (4R)-enantiomer has been obtained analogously.

3-chloro-5-{[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-1-yl]oxy}benzonitrile (26a)

[0428] ##STR00047##

[0429] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=7.69 (t, 1H), 7.59-7.54 (m, 2H), 5.14 (m, 1H), 3.34 (s, 3H), 3.11 (m, 2H); LC-MS (method E): Rt=1.29 min, [M+Na].sup.+=429.0; HPLC (method A): purity 99.9%, Rt 6.45 min; chiral HPLC (method G): >99.5% ee, Rt 1.70 min.

[0430] The (4R)-enantiomer has been obtained analogously.

(4S)-1-(3,5-difluorophenoxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (27a)

[0431] ##STR00048##

[0432] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=7.00-6.73 (m, 3H), 5.15 (dd, J=11.2, 3.2 Hz, 1H), 3.35 (s, 3H), 3.23-2.95 (m, 2H); LC-MS (method I): Rt=1.61 min, [M+NH.sub.4].sup.+=400.2; HPLC (method A): purity 9.74%, Rt 6.5 min; chiral HPLC (method H): >99.5% ee, Rt 1.35 min.

[0433] The (4R)-enantiomer has been obtained analogously.

3-{[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-1-yl]oxy}-5-fluorobenzonitrile (28a)

[0434] ##STR00049##

[0435] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=7.52-7.42 (m, 2H), 7.38 (m, 1H), 5.16 (m, 1H), 3.36 (s, 3H), 3.13 (m, 2H); LC-MS (method I): Rt=1.50 min, [M−H].sup.−=367.9; HPLC (method A): purity 99.1%, Rt 6.09 min; chiral HPLC (method A): >99.5% ee, Rt 2.87 min.

[0436] The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-1-(4-fluorophenoxy)-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (29a)

[0437] ##STR00050##

[0438] Prepared according to general procedure; .sup.1H NMR (400 MHz, CD.sub.3OD): δ=7.36-7.09 (m, 4H), 5.10 (dd, J=11.3, 3.1 Hz, 1H), 3.30 (s, 3H), 3.19-2.87 (m, 2H); LC-MS (method B): Rt=1.55 min, [M+NH.sub.4].sup.+=382.2; HPLC (method A): purity 99.7%, Rt 6.29 min; chiral HPLC (method C): >99.5% ee, Rt 1.53 min.

[0439] The (4R)-enantiomer has been obtained analogously.

(4S)-1-(3-chloro-5-fluorophenoxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (30a)

[0440] ##STR00051##

[0441] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=7.19-7.09 (m, 2H), 7.00 (m, 1H), 5.16 (m, 1H), 3.36 (s, 3H), 3.12 (m, 2H); LC-MS (method J): Rt=2.71 min, [M+Na].sup.+=420.8; HPLC (method A): purity 99.4%, Rt 7.26 min; chiral HPLC (method I): >99.5% ee, Rt 2.31 min.

[0442] The (4R)-enantiomer has been obtained analogously.

3-{[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-1-yl]oxy}benzonitrile (31a)

[0443] ##STR00052##

[0444] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=7.67-7.58 (m, 3H), 7.53 (m, 1H), 5.14 (dd, 1H), 3.14 (d, 3H), 3.12-3.00 (m, 2H); LC-MS (method E): Rt=1.16 min, [M+H].sup.+=371.9; HPLC (method A): purity 98.7%, Rt 5.90 min; chiral HPLC (method J): >99.5% ee, Rt 1.35 min.

[0445] The (4R)-enantiomer has been obtained analogously.

(4S)-1-ethoxy-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (32a)

[0446] ##STR00053##

[0447] Prepared according to general procedure; .sup.1H NMR (300 MHz, CD.sub.3OD): δ=5.05 (dd, J=11.4, 2.7 Hz, 1H), 4.27-4.20 (m, 2H), 3.31 (s, 3H), 3.22-3.14 (m, 2H), 1.43 (t, J=6.9 Hz, 3H), LC-MS (method L): Rt=1.05 min, [M+H].sup.+=299.00; HPLC (method B): purity 99.2%, Rt 4.15 min; chiral HPLC (method L): >99.5% ee, Rt 1.30 min.

[0448] The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-(4,4,4-trifluorobutoxy)-4H,5H,6H-cyclopenta[c]thiophen-4-ol (33a)

[0449] ##STR00054##

[0450] Prepared according to general procedure; .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ=6.68 (d, J=7.2 Hz, 1H), 4.97-4.95 (m, 1H), 4.26 (t, J=6.3 Hz, 2H), 3.29-3.22 (m, 5H), 2.44-2.38 (m, 2H), 1.99-1.93 (m, 2H); LC-MS (method D): Rt=2.63 min, [M+NH.sub.4].sup.+=398.1; HPLC (method B): purity 99.5%, Rt 5.18 min; chiral HPLC (method K): >99.5% ee, Rt 2.31 min.

[0451] The (4R)-stereoisomer has been obtained analogously.

(4S)-1-(3,4-difluorophenoxy)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol (34a)

[0452] ##STR00055##

[0453] Prepared according to general procedure; .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.23-7.17 (m, 1H), 7.05-6.98 (m, 1H), 6.93-6.87 (m, 1H), 5.27-5.21 (m, 1H), 3.49 (s, 1H), 3.26 (s, 3H), 3.19-2.96 (m, 2H); LC-MS (method E): Rt=1.24 min, [M+H].sup.+=404.85; HPLC (method A): purity 99.3%, Rt 6.44 min.

[0454] The (4R)-stereoisomer has been obtained analogously.

[0455] The following compounds can be prepared in an analogous manner:

##STR00056## ##STR00057## ##STR00058## ##STR00059##

[0456] The following examples relate to medicaments:

Example A: Injection Vials

[0457] A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

Example B: Suppositories

[0458] A mixture of 20 g of an active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: Solution

[0459] A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH.sub.2PO.sub.4.2H.sub.2O, 28.48 g of Na.sub.2HPO.sub.4.12 H.sub.2O and 0.1 g of benzalkonium chloride in 940 mL of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment

[0460] 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

Example E: Tablets

[0461] A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in a conventional manner to give tablets in such a way that each tablet contains 10 mg of active ingredient.

Example F: Dragees

[0462] Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: Capsules

[0463] 2 kg of active ingredient of the formula I are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.

Example H: Ampoules

[0464] A solution of 1 kg of active ingredient of the formula I in 60 l of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.