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Title:
DIHYDROBENZO[B][1]BENZOTHIEPIN COMPOUNDS USEFUL IN THERAPY
Document Type and Number:
WIPO Patent Application WO/2019/092044
Kind Code:
A1
Abstract:
The present invention relates to the use of a compound of formula (I), to decrease or inhibit, in vitro or ex vivo, the Patched receptor drug efflux activity, in particular the chemotherapeutic drug efflux activity and chemotherapy resistance. The present disclosure further relates to uses of such compounds, in particular to prepare a pharmaceutical composition to allow or improve the efficiency of a therapy of cancer in a subject in need thereof. The compound of the invention can indeed be advantageously used, in combination with at least one chemotherapeutic drug, for treating cancer, for preventing cancer metastasis and/or for preventing cancer recurrence in a subject.

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Inventors:
MUS-VETEAU ISABELLE (FR)
POINSARD CÉDRIC (FR)
PIGEON PIERRE (FR)
Application Number:
PCT/EP2018/080510
Publication Date:
May 16, 2019
Filing Date:
November 07, 2018
Export Citation:
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Assignee:
CENTRE NAT RECH SCIENT (FR)
UNIV NICE SOPHIA ANTIPOLIS (FR)
GENOCHEM (FR)
International Classes:
C07D337/14; A61K31/38; A61K31/4427; A61K31/497; A61K31/551; A61P35/00; C07D409/04
Domestic Patent References:
WO2009102864A12009-08-20
WO2014098932A12014-06-26
WO1994022846A11994-10-13
WO2016066594A12016-05-06
Foreign References:
US4243805A1981-01-06
DE2026027A11970-12-03
US3337554A1967-08-22
EP1553179A12005-07-13
Other References:
K SINDELAR ET AL: "POTENTIAL METABOLITES OF NEUROLEPTICS OF THE 10-PIPERAZINO-10,11-DIHYDRODIBENZO[b,f]THIEPIN SERIES: 2,3-DIHYDROXY DERIVATIVES OF PERATHIEPIN AND OCTOCLOTHEPIN AND SOME RELATED COMPOUNDS*", COLLECTION CZECHOSLOV. CHEM. COMMUN., vol. 41, 29 July 1975 (1975-07-29), pages 1396 - 1415, XP055447905
VLADIMIR VALENTA ET AL: "10-[4-(3-HYDROXYPROPYL)PIPERAZINO)-8-METHYLSULFONYL-10,11-DIHYDRODIBENZOl[b,f]THIEPIN AND SOME RELATED POTENTIAL METABOLITES OF THE NEUROLEPTIC AGENTS OXYPROTHEPIN AND METHIOTHEPIN*", COLLECTION CZECHOSLOV. CHEM. COMMUN., vol. 45, 1 January 1980 (1980-01-01), pages 529 - 538, XP055447901
VLADIMIR VALENTA ET AL: "POTENTIAL ANTIDEPRESSANTS: 10-AMINO-2-CHLORO-10,11-DIYDRODIBENZO[b,f]THIEPINS", COLLECT. CZECH. CHEM. COMMUN., vol. 54, 1 January 1989 (1989-01-01), pages 1979 - 1994, XP055447906
SZAKACS, G.; PATERSON, J.K.; LUDWIG, J.A.; BOOTH-GENTHE, C.; GOTTESMAN, M.M.: "Targeting multidrug resistance in cancer", NAT. REV. DRUG DISCOV., vol. 5, 2006, pages 219 - 234, XP002513064, DOI: doi:10.1038/nrd1984
LUQMANI, Y.A.: "Mechanisms of drug resistance in cancer chemotherapy", MED. PRINC. PRACT., vol. 14, no. 1, 2005, pages 35 - 48
BIDET, M.; TOMICO, A.; MARTIN, P.; GUIZOUARN, H.; MOLLAT, P.; MUS-VETEAU, I.: "The Hedgehog receptor Patched functions in multidrug transport and chemotherapy resistance", MOL. CANCER RES., vol. 10, 2012, pages 1496 - 508, XP055168279, DOI: doi:10.1158/1541-7786.MCR-11-0578
QUEIROZ, K.C.; RUELA-DE-SOUSA, R.R.; FUHLER, G.M.; ABERSON, H.L.; FERREIRA, C.V.; PEPPELENBOSCH, M.P.; SPEK, C.A.: "Hedgehog signaling maintains chemoresistance in myeloid leukemic cells", ONCOGENE, vol. 29, 2010, pages 6314 - 6322, XP002648970, DOI: doi:10.1038/onc.2010.375
SAZE, Z.; TERASHIMA, M.; KOGURE, M.; OHSUKA, F.; SUZUKI, H.; GOTOH, M.: "Activation of the sonic hedgehog pathway and its prognostic impact in patients with gastric cancer", DIG SURG., vol. 29, 2012, pages 115 - 123
BIDET, M.; TOMICO, A.; MARTIN, P.; GUIZOUARN, H.; MOLLAT, P.; MUS-VETEAU, I.: "The Hedgehog receptor patched functions in multidrug transport and chemotherapy resistance", MOL. CANCER RES., vol. 10, 2012, pages 1496 - 508, XP055168279, DOI: doi:10.1158/1541-7786.MCR-11-0578
TAYLOR, S.; SPUGNINI, E.P.; ASSARAF, Y.G.; AZZARITO, T.; RAUCH, C.; FAIS, S.: "Microenvironment acidity as a major determinant of tumor chemoresistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach", DRUG RESIST. UPDAT., vol. 23, 2015, pages 69 - 78, XP029347336, DOI: doi:10.1016/j.drup.2015.08.004
DAMAGHI, M.; WOJTKOWIAK, J.W.; GILLIES, R.J.: "pH sensing and regulation in cancer", FRONT. PHYSIOL., vol. 17, 2013, pages 370
FIORINI, L.; TRIBALAT, M.A.; SAUVARD, L.; CAZARETH, J.; LALLI, E.; BROUTIN, I.; THOMAS, O.P.; MUS-VETEAU, I.: "Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells", ONCOTARGET, vol. 6, 2015, pages 22282 - 97, XP055517434, DOI: doi:10.18632/oncotarget.4162
BIDET, M.; JOUBERT, O.; LACOMBE, B.; CIANTAR, M.; NEHME, R.; MOLLAT, P.; BRETILLON, L.; FAURE, H.; BITTMAN, R.; RUAT, M.: "The hedgehog receptor patched is involved in cholesterol transport", PLOS ONE, vol. 6, 2011, pages e23834, XP055305365, DOI: doi:10.1371/journal.pone.0023834
FIORINI, L.; TRIBALAT; M.A.; SAUVARD, L.; CAZARETH, J.; LALLI, E.; BROUTIN, I.; THOMAS, O.P.; MUS-VETEAU, I.: "Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells", ONCOTARGET, vol. 6, 2015, pages 22282 - 97, XP055517434, DOI: doi:10.18632/oncotarget.4162
Attorney, Agent or Firm:
COLOMBET, Alain et al. (PARIS CEDEX 09, PARIS CEDEX 09, FR)
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Claims:
CLAIMS

1 . A compound for use for treating cancer, said compound being chosen from compounds of formula (I) and their pharmaceutically acceptable salts and solvates:

(I)

wherein :

R1 , R2, R3, R4, R5, R6, R7 and R8 are independently selected from H, C1 -6 alkyl, C1 -6 alkoxy, C1 -6 haloalkyl, C1 -6 haloalkoxy, CN, -NH2, -NRaRb, halogen, -S-(C1 -6 alkyl), -S(0)-(C1 -6 alkyl), -S(0)2-(C1 -6 alkyl);

R9 and R10 are independently selected from H, C1 -6 alkyl, N-methyl-piperidin-4- yl, -(C1 -6 alkyl)-N(R')(R"), or R9 and R10, together with the nitrogen atom carrying them, form a heterocyclic group, wherein said heterocyclic group is optionally substituted by 1 , 2, 3 or 4 substituent(s) Rc ;

Ra and Rb are independently selected from H and C1 -6 alkyl, or Ra and Rb, together with the nitrogen atom carrying them, form a heterocyclic group, wherein said heterocyclic group is optionally substituted by 1 , 2, 3 or 4 substituents independently selected from C1 -6 alkyl and C1 -6 hydroxyalkyl;

Rc is C1 -6 alkyl; C1 -6 hydroxyalkyl; -N(R')(R"); or Rd-CO- wherein Rd is C1 -6 alkoxy, C1 -6 alkyl, C1 -6 hydroxyalkyl, methoxymethyl, aryl, aralkyl, -(C1 -6 alkyl)-CN, heteroaryl, heteroaralkyl, -CH2-0-(aryl) or 2-hydroxyethylethoxy,

R' and R" are each identical or different and represent H or C1 -6 alkyl, or R' and

R" form with the nitrogen atom carrying them a heterocyclic group,

with the proviso that R1 , R2, R3, R4, R5, R6, R7 and R8 do not simultaneously represent H,

wherein the cancer is one in which the cancer cells express Patched, and

wherein said compound decreases or inhibits Patched drug efflux activity in cancer cells. 2. The compound for use according to claim , for preventing cancer metastasis and/or for preventing cancer recurrence and/or for decreasing resistance to a chemotherapy in a subject.

3. A product comprising:

a) a compound according to any one of claims 1 to 2, and

b) at least one chemotherapeutic drug,

as combination product for a simultaneous, separate or sequential use for treating cancer, and/or for preventing cancer metastasis, and/or for preventing cancer recurrence, and/or for decreasing resistance to the chemotherapeutic drug b), in a subject.

4. The compound for use according to any one of claims 1 to 2 or the product according to claim 3, wherein at least one of the following conditions is fulfilled:

R1 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and - S02Me,

R2 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and - S02Me,

R3 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and - S02Me,

R4 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and - S02Me,

R5 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and - S02Me,

R6 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and - S02Me,

R7 is methyl, ethyl, isopropyl, (CI)3C-0-, -SMe, CI or MeO-, and/or

R8 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and - S02Me.

5. The compound for use according to any one of claims 1 to 2 or 4 or the product according to claim 3 or 4, wherein R9 and R10 form, together with the nitrogen atom carrying them, a piperazinyl group such as a 4-piperazinyl group, a diazepinyl group, a piperidinyl group or an azolyl group, optionally substituted by 1 , 2, 3 or 4 substituent(s) Rc.

6. The compound for use according to claims 1 to 2, 4 or 5, or the product according to any one of claims 3 to 5, wherein Rc is chosen from methyl, ethyl, isopropyl, -N(CH3)2, (CH3)3-C-0-CO-, CH3-CO-, CH3-CH2-CO-, CH2(OH)-CO-, CH3-0-CH2-CO-, benzoyl, benzyl-CO-, 4-methoxy-benzyl-CO-, 4-methoxyphenethyl, CN-CH2-CH2-, phenyl, pyridyl, 3-methylbenzyl, pyrrolidinyl, N,N-diethylamino, Ν,Ν-dimethylamino, CH2(OH)-CH2-, CH3- CH(CH3)-CO-, 2-methylbenzoyl, 3,5-dimethylbenzoyl, 3,4-dimethylbenzoyl, 3- chlorobenzoyl, 3-methoxybenzoyl, 3-cyanobenzoyl, 3-methylsulfonylbenzoyl, 3- trifluoromethylbenzoyl, 6-methyl-2-pyridyl-CO-, 5-methyl-3-pyridyl-CO-, 2-methylbenzyl, 3,5-dimethylbenzyl, 3,4-dimethylbenzyl, 3-chlorobenzyl, 3-methoxybenzyl, 3- methylsulfonylbenzyl, 5-methyl-3-pyridyl and 3-trifluoromethylbenzyl.

7. The compound for use according to claims 1 to 2, or 4 to 6, or the product according to any one of claims 4 to 7, wherein:

R1 = R2 = R3 = R4 = R8 = H,

R5 and R6 are independently chosen from H, C1 -6 alkyl and halogen,

R7 is chosen from H, C1 -6 alkyl, C1 -6 alkoxy, C1 -6 haloalkoxy, halogen and -S- (C1 -6 alkyl), preferably from C1 -6 alkyl, C1 -6 alkoxy, C1 -6 haloalkoxy, halogen and -S- (C1 -6 alkyl),

R9 and R10 together with the nitrogen atom carrying them, form a heterocyclic group, preferably a piperazine, 1 ,4-diazepinyl, piperidinyl, pyrrolidinyl, wherein said heterocyclic group is optionally substituted by one substituent Rc,

Rc is C1 -6 alkyl; C1 -6 hydroxyalkyi; -N(R')(R"); or Rd-CO- wherein Rd is C1 -6 alkoxy, C1 -6 alkyl, C1 -6 hydroxyalkyi, methoxymethyl, phenyl, benzyl, 2-methylphenyl, 3,5-dimethylphenyl, 3,4-dimethylphenyl, 3-chlorophenyl, 4-chlorophenyl, 3- methoxyphenyl, 3-cyanophenyl, 3-methylsulfonylphenyl, 3-trifluoromethylphenyl, 2- methylbenzyl, 3-methylbenzyl, 3,5-dimethylbenzyl, 3,4-dimethylbenzyl, 4- methoxyphenethyl, 3-chlorobenzyl, 3-methoxybenzyl, 3-methylsulfonylbenzyl, 3- trifluoromethylbenzyl, 5-methyl-3-pyridinemethyl, -(C1 -6 alkyl)-CN, pyridine, 6-methyl-2- pyridine, 5-methyl-3-pyridine, 4-chlorophenoxy-methyl or 2-hydroxyethylethoxy,

R' and R" are each identical or different and represent H or C1 -6 alkyl, or R' and

R" form with the nitrogen atom carrying them a heterocyclic group.

8. The compound for use according to claims 1 to 2, or 4 to 6, or the product according to any one of claims 3 to 6, wherein:

R1 = R2 = R3 = R4 = R5 = R6 = R8 = H,

R7 is chosen from C1 -6 alkyl,

R9 and R10 are independently selected from H, C1 -6 alkyl, N-methyl-piperidin-4- yl, -(C1 -6 alkyl)-N(R')(R"),

R' and R" are each identical or different and represent C1 -6 alkyl.

9. The compound for use according to claims 1 to 2, or 4 to 8, or the product according to any one of claims 4 to 9, wherein it is selected from:

1 -methyl-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

1 -(3-chloro-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-methyl-piperazine

1 -(3-methoxy-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-methyl-piperazine

1 -(1 ,2-dichloro-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-methyl-piperazine

1 -methyl-4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-1 ,4-diazepane 4-methyl-1 -(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperidine

N,N-dimethyl-1 -(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperidin-4- amine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

1 -ethyl-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

1 -isopropyl-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

N,N,N'-trimethyl-N'-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)ethane-1 ,2-diamine N,N,N'-trimethyl-N'-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)propane-1 ,3- diamine

3-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propanenitrile

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-phenyl-piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-(2-pyridyl)piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-(m-tolylmethyl)piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-pyrrolidin-1 -yl-piperidine

N,N-diethyl-1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperidin-4-amine 1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-1 ,4-diazepane

1 -[2-(4-methoxyphenyl)ethyl]-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazine

1 - methyl-N-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperidin-4-amine

2- [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]ethanol

2-[2-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]ethoxy]ethanol 1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-propyl-piperazine

1 -isobutyl-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-(o-tolylmethyl)piperazine

1 -[(3,5-dimethylphenyl)methyl]-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazine

1 -[(3,4-dimethylphenyl)methyl]-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazine

1 -[(3-chlorophenyl)methyl]-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine 1 - [(3-methoxyphenyl)methyl]-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-[(3- methylsulfonylphenyl)methyl]piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-[(5-methyl-3- pyridyl)methyl]piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-[(3- trifluoromethyl)phenyl]methyl]piperazine

tert-butyl 4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine-1 -carboxylate 1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]ethanone

2- hydroxy-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]ethanone 2-methoxy-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]ethanone [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-phenyl-methanone

1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-phenyl-ethanone 2-(4-methoxyphenyl)-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]-ethanone

tert-butyl 4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-1 ,4-diazepane-1 - carboxylate

1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one 2-(4-chlorophenoxy)-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]ethanone

2- methyl-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 - one

[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(o-tolyl)methanone (3,5-dimethylphenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]methanone

(3,4-dimethylphenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]methanone

(3-chlorophenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]methanone

(3-methoxyphenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]methanone

3- [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine-1 -carbonyl]benzonitrile [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(3- methylsulfonylphenyl)methanone [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-[3- (trifluoromethyl)phenyl]methanone

[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(6-methyl-2- pyridyl)methanone

[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(5-methyl-3- pyridyl)methanone

1 -[4-(3-isopropyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan- 1 -one

1 - [4-(3-ethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 - one

2- methyl-1 -[4-[3-(trichloromethoxy)-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl]piperazin-1 - yl]propan-1 -one

1 - [4-(1 ,3-dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl- propan-1 -one

1 -[4-(2,3-dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl- propan-1 -one

2- methyl-1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one. 10. The compound for use according to claims 1 to 2, or 4 to 8, or the product according to any one of claims 3 to 8, wherein the cancer is selected from a melanoma, a breast cancer, a thyroid cancer, a prostate cancer, a colorectal cancer, an ovarian cancer, a lung cancer, a pancreatic cancer, a glioma, a cervical cancer, an endometrial cancer, a head and neck cancer, a liver cancer, a renal cancer, a skin cancer, a stomach cancer, a testis cancer, an urothelial cancer, an adrenocortical carcinoma and non-solid cancers such as lymphoma.

1 1 . The product for use according to anyone of claims 3 to 10, wherein said at least one chemotherapeutic drug is selected from cisplatin, doxorubicin, docetaxel, methotrexate, temozolomide, 5-FU, dacarbazine and vemurafenib.

12. The product for use according to anyone of claims 3 to 1 1 , wherein the subject is a human suffering of a cancer and resistant to chemotherapy.

13. A compound chosen from compounds of formula (I) and their pharmaceutically acceptable salts and solvates:

(I)

wherein :

R1 , R2, R3, R4, R5, R6, R7 and R8 are independently selected from H, C1 -6 alkyl, C1 -6 alkoxy, C1 -6 haloalkyl, C1 -6 haloalkoxy, CN, -NH2, -NRaRb, halogen, -S-(C1 -6 alkyl), -S(0)-(C1 -6 alkyl), -S(0)2-(C1 -6 alkyl);

R9 and R10 are independently selected from H, C1 -6 alkyl, N-methyl-piperidin-4- yl, -(C1 -6 alkyl)-N(R')(R"), or R9 and R10, together with the nitrogen atom carrying them, form a heterocyclic group, wherein said heterocyclic group is optionally substituted by 1 , 2, 3 or 4 substituent(s) Rc ;

Ra and Rb are independently selected from H and C1 -6 alkyl, or Ra and Rb, together with the nitrogen atom carrying them, form a heterocyclic group, wherein said heterocyclic group is optionally substituted by 1 , 2, 3 or 4 substituents independently selected from C1 -6 alkyl and C1 -6 hydroxyalkyl;

Rc is C1 -6 alkyl; C1 -6 hydroxyalkyl; -N(R')(R"); or Rd-CO- wherein Rd is C1 -6 alkoxy, C1 -6 alkyl, C1 -6 hydroxyalkyl, methoxymethyl, aryl, aralkyl, -(C1 -6 alkyl)-CN, heteroaryl, heteroaralkyl, -CH2-0-(aryl) or 2-hydroxyethylethoxy,

R' and R" are each identical or different and represent H or C1 -6 alkyl, or R' and R" form with the nitrogen atom carrying them a heterocyclic group,

with the exception of methiothepin and its salts:

14. A composition comprising, in a pharmaceutically acceptable carrier, at least one compound according to claim 1 or 13, and at least one chemotherapeutic drug.

Description:
Dihydrobenzo[b][1]benzothiepin compounds useful in therapy FIELD OF THE INVENTION

This invention relates to Dihydrobenzo[b][1 ]benzothiepin compounds and their derivatives, which are useful in therapy, and to a process for their preparation. It also relates to intermediates used in the preparation of such compounds and derivatives, compositions containing them and their uses, for example their use in medicine. The compounds of the invention are useful as inhibitors or antagonists of the Patched receptor drug efflux activity, preferably in cancer treatment.

The invention also discloses methods for preventing or treating cancer, cancer metastasis and/or cancer recurrence in a subject.

BACKGROUND OF THE INVENTION

Eight million people die each year from cancer worldwide. Cancer is the second cause of death in the United States and in Europe. For many solid tumors, in spite of the reduction of the carcinoma by surgery and first-line chemotherapy, resistance to the drugs causing the death of patients is developed. This phenomenon of resistance to chemotherapeutic agents is a real public health problem. Multidrug resistance (MDR) has been intensively studied, and one of the most prominent mechanisms underlying MDR is overexpression of members of the family of ATP-binding cassette (ABC) transporters (Szakacs, G., Paterson, J.K., Ludwig, J.A., Booth-Genthe, C, and Gottesman, M.M. (2006). Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 5, 219-234). These transporters use energy derived from the hydrolysis of ATP to transport a wide range of substrates (endogenous toxicants and xenobiotics but also chemotherapeutic agents) across biological membranes against a concentration gradient. Since the discovery that the overexpression of ABC transporters in cancer cells can mediate resistance to anticancer drugs, research has been directed towards developing compounds that inhibit the efflux activity of ABC transporters and increase classical chemotherapy efficacy. However, to date, the Food and Drug Administration (FDA) has not approved the use of any ABC transporter inhibitor due to toxicity issues (Wang, Y.J., Zhang, Y.K., Kathawala, R.J., and Chen, Z.S. (2014).

It has long been postulated that the multidrug efflux transporter P-glycoprotein (P- gp/ABCB1/MDR1 ) mediates the main mechanism of resistance within cancer cells (Luqmani, Y.A. (2005) Mechanisms of drug resistance in cancer chemotherapy. Med. Princ. Pract. 14 Suppl 1 , 35-48)); however, it was recently shown that the Hedgehog receptor Patched 1 (referred to herein as "Patched"), which is overexpressed in many recurrent and metastatic cancers, pumps chemotherapeutic agents such as doxorubicin (dxr) out of cancer cells and also contributes to chemotherapy resistance (Bidet, M., Tomico, A., Martin, P., Guizouarn, H., Mollat, P., and Mus-Veteau, I. (2012). The Hedgehog receptor Patched functions in multidrug transport and chemotherapy resistance. Mol. Cancer Res. 10, 1496-508). Indeed, Patched is overexpressed in many cancers: lung, breast, basal cells of the skin, prostate, colon, brain (see the Human Protein Atlas website http://www.proteinatlas.ora/ENSG00000185920-PTCH1 /cancer) and myeloid leukemia (Queiroz, K.C., Ruela-de-Sousa, R.R., Fuhler, G.M., Aberson, H.L., Ferreira, C.V., Peppelenbosch, M.P., and Spek, C.A. (2010). Hedgehog signaling maintains chemoresistance in myeloid leukemic cells. Oncogene. 29, 6314-6322), and recent studies even suggest Patched as an early marker of gastric and thyroid cancers (Saze, Z., Terashima, M., Kogure, M., Ohsuka, F., Suzuki, H., and Gotoh, M. (2012). Activation of the sonic hedgehog pathway and its prognostic impact in patients with gastric cancer. Dig Surg. 29, 1 15-123).

Indeed, it was shown that the human Patched protein expressed in yeast confers resistance to various chemotherapeutic agents used to treat many metastatic cancers (doxorubicin, methotrexate, temozolomide, 5-FU) and effluxes doxorubicin. This yeast model has been extended to different human cancer cell lines endogenously overexpressing Patched such as the melanoma cell lines Mewo (WT BRAF) and A375 (BRAF mutated) (Bidet, M., Tomico, A., Martin, P., Guizouarn, H., Mollat, P., and Mus- Veteau, I. (2012). The Hedgehog receptor Patched functions in multidrug transport and chemotherapy resistance. Mol. Cancer Res. 10, 1496-508).

Patched is not part of the ABC transporters family. Indeed, it was previously shown that Patched uses the proton motive force to efflux drugs similarly to the bacterial efflux pumps from the RND family (Bidet, M., Tomico, A., Martin, P., Guizouarn, H., Mollat, P., and Mus- Veteau, I. (2012). The Hedgehog receptor patched functions in multidrug transport and chemotherapy resistance. Mol. Cancer Res. 10, 1496-508). This may seem surprising; however, the alteration of energy metabolism that occurs in hypoxic conditions in cancer cells has been shown to lead to lactate accumulation and intracellular acidification (Taylor, S., Spugnini, E.P., Assaraf, Y.G., Azzarito, T., Rauch, C, and Fais, S. (2015). Microenvironment acidity as a major determinant of tumor chemoresistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach. Drug Resist. Updat. 23, 69-78). Accordingly, rapidly dividing cancer cells produce and release large amounts of protons into the extracellular compartment due to heightened glucose utilization. This pattern of acidic extracellular environment and the alkaline cytosol is considered a hallmark of malignant cancers and is referred to as a "reversed pH gradient" (Damaghi, M., Wojtkowiak, J.W., and Gillies, R.J. (2013). pH sensing and regulation in cancer. Front. Physiol. 17, 370). Therefore, in cancer cells, Patched can function as an efflux pump using the proton gradient.

This makes Patched a particularly relevant therapeutic target for recurrent and metastatic cancers. Compounds inhibiting the drug efflux activity of Patched have been described for example in Fiorini et al (Fiorini, L, Tribalat, M.A., Sauvard, L, Cazareth, J., Lalli, E., Broutin, I., Thomas, O.P., and Mus-Veteau, I. (2015). Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells. Oncotarget 6, 22282-97) and in WO2016/066594. However, their efficacy has to be improved.

There is thus a need for providing compounds which would be efficient inhibitors of the drug efflux activity of Patched, and which may be used in cancer therapy. SUMMARY OF THE INVENTION

Surprisingly, the inventors have discovered that specific molecules may be useful for preventing and/or decreasing Patched drug efflux in cancer cells. As shown in the examples, these molecules particularly decrease Patched chemotherapeutic drug efflux in cancer cells, such as doxorubicin efflux in cancer cells, notably in adrenocortical carcinoma, melanoma, breath cancer and colorectal cancer cells. Doxorubicin consequently can exert its cytotoxic effects, leading to a decrease in cancer cell proliferation.

Thus, said molecules may be able to increase the effectiveness of chemotherapeutic treatments directed against any cancer which expresses Patched, by decreasing resistance to chemotherapy and restoring sensibility.

The present invention therefore relates to the use of a dihydrobenzo[b][1 ]benzothiepin compound of formula (I), or one of its derivatives:

(I)

wherein R1 to R10 are as described below,

for treating cancer.

Specifically, the dihydrobenzo[b][1 ]benzothiepin compounds of formula (I) of the invention are able to decrease or inhibit Patched drug efflux activity in cancer cells, specifically in cancer cells which express Patched.

Another object of the invention is a dihydrobenzo[b][1 ]benzothiepin compound of formula (I), or one of its derivatives, for use for preventing cancer metastasis and/or for preventing cancer recurrence and/or for decreasing resistance to a chemotherapy in a subject.

Another object of the invention is a product comprising:

a) a dihydrobenzo[b][1 ]benzothiepin compound of formula (I), or one of its derivatives, and

b) at least one chemotherapeutic drug,

as combination product for a simultaneous, separate or sequential use for treating cancer, and/or for preventing cancer metastasis, and/or for preventing cancer recurrence, and/or for decreasing resistance to the chemotherapeutic drug b), in a subject.

Preferably the invention relates to a product comprising:

a) a dihydrobenzo[b][1 ]benzothiepin compound of formula (I), or one of its derivatives, and

b) at least one chemotherapeutic drug,

as combination product for a simultaneous, separate or sequential use for treating cancer, and/or for decreasing resistance to the chemotherapeutic drug b), in a subject.

Another object of the invention is a composition comprising, in a physiologically acceptable medium, at least one dihydrobenzo[b][1 ]benzothiepin compound of formula (I) or one of its derivatives. Preferably said composition further comprises at least one chemotherapeutic drug. Another object of the invention is a compound chosen from compounds of formula (I), their pharmaceutically acceptable salts and solvates, prodrugs of said compounds, and pharmaceutically acceptable salts and solvates of said rodrugs:

(I)

wherein :

R1 , R2, R3, R4, R5, R6, R7 and R8 are independently selected from H, C1 -6 alkyl, C1 -6 alkoxy, C1 -6 haloalkyl, C1 -6 haloalkoxy, CN, -NH2, -NRaRb, halogen, -S-(C1 -6 alkyl), -S(0)-(C1 -6 alkyl), -S(0)2-(C1 -6 alkyl);

R9 and R10 are independently selected from H, C1 -6 alkyl, N-methyl-piperidin-4- yl, -(C1 -6 alkyl)-N(R')(R"), or R9 and R10, together with the nitrogen atom carrying them, form a heterocyclic group, wherein said heterocyclic group is optionally substituted by 1 , 2, 3 or 4 substituent(s) Rc ;

Ra and Rb are independently selected from H and C1 -6 alkyl, or Ra and Rb, together with the nitrogen atom carrying them, form a heterocyclic group, wherein said heterocyclic group is optionally substituted by 1 , 2, 3 or 4 substituents independently selected from C1 -6 alkyl and C1 -6 hydroxyalkyl;

Rc is C1 -6 alkyl; C1 -6 hydroxyalkyl; -N(R')(R"); or Rd-CO- wherein Rd is C1 -6 alkoxy, C1 -6 alkyl, C1 -6 hydroxyalkyl, methoxymethyl, aryl, aralkyl, -(C1 -6 alkyl)-CN, heteroaryl, heteroaralkyl, -CH2-0-(aryl) or 2-hydroxyethylethoxy,

R' and R" are each identical or different and represent H or C1 -6 alkyl, or R' and R" form with the nitrogen atom carrying them a heterocyclic group,

with the exce tion of methiothepin and its salts:

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound for use for treating cancer, said compound being chosen from compounds of formula (I), their pharmaceutically acceptable salts and solvates, prodrugs of said compounds, and pharmaceutically acceptable salts and solvates of said prodrugs:

wherein :

R1 , R2, R3, R4, R5, R6, R7 and R8 are independently selected from H, C1 -6 alkyl, C1 -6 alkoxy, C1 -6 haloalkyl, C1 -6 haloalkoxy, CN, -NH2, -NRaRb, halogen, -S-(C1 -6 alkyl), -S(0)-(C1 -6 alkyl), -S(0)2-(C1 -6 alkyl);

R9 and R10 are independently selected from H, C1 -6 alkyl, N-methyl-piperidin-4- yl, -(C1 -6 alkyl)-N(R')(R"), or R9 and R10, together with the nitrogen atom carrying them, form a heterocyclic group, wherein said heterocyclic group is optionally substituted by 1 , 2, 3 or 4 substituent(s) Rc ;

Ra and Rb are independently selected from H and C1 -6 alkyl, or Ra and Rb, together with the nitrogen atom carrying them, form a heterocyclic group, wherein said heterocyclic group is optionally substituted by 1 , 2, 3 or 4 substituents independently selected from C1 -6 alkyl and C1 -6 hydroxyalkyl;

Rc is C1 -6 alkyl; C1 -6 hydroxyalkyl; -N(R')(R"); or Rd-CO- wherein Rd is C1 -6 alkoxy, C1 -6 alkyl, C1 -6 hydroxyalkyl, methoxymethyl, aryl, aralkyl, -(C1 -6 alkyl)-CN, heteroaryl, heteroaralkyl, -CH2-0-(aryl) or 2-hydroxyethylethoxy,

R' and R" are each identical or different and represent H or C1 -6 alkyl, or R' and R" form with the nitrogen atom carrying them a heterocyclic group. Preferably the compound of the invention is of formula (I), with the proviso that R1 , R2, R3, R4, R5, R6, R7 and R8 do not simultaneously represent H. In other words, the proviso excludes compounds for which R1 =R2=R3=R4=R5=R6=R7=R8=H.

The compounds of formula (I), their pharmaceutically acceptable salts and solvates, prodrugs of said compounds, and pharmaceutically acceptable salts and solvates of said prodrugs, are inhibitors of the drug efflux activity of Patched. They may be used as medicines. Specifically, the dihydrobenzo[b][1 ]benzothiepin compounds of formula (I) of the invention are able to decrease or inhibit Patched drug efflux activity in cancer cells, specifically in cancer cells which express Patched.

Preferably said compound of formula (I), or one of its derivatives, is useful for preventing cancer metastasis and/or for preventing cancer recurrence and/or for decreasing resistance to a chemotherapy in a subject.

Another object of the invention is a product comprising:

a) a dihydrobenzo[b][1 ]benzothiepin compound of formula (I), or one of its derivatives, and

b) at least one chemotherapeutic drug,

as combination product for a simultaneous, separate or sequential use for treating cancer, and/or for preventing cancer metastasis, and/or for preventing cancer recurrence, and/or for decreasing resistance to the chemotherapeutic drug b), in a subject.

The "drug efflux activity of Patched" is the use of the proton motive force by Patched to efflux drugs from cells expressing Patched. Said activity may be measured as disclosed in the examples.

The compound according to the invention is preferably in substantially pure form.

By "pharmaceutically acceptable salts", it is meant any acid addition salts with inorganic or organic acids, such as the hydrochloride, mesylate, hydrobromide, acetate, fumarate, sulfate, succinate, citrate, phosphate, maleate, tartrate, lactate, benzoate or carbonate salt. Preferably, the salt is mesylate or maleate.

The compounds of the invention may also be isolated in association with solvent molecules or can form complexes with solvents in which they are reacted or from which they are precipitated, crystallized or isolated; theses are called solvates. Solvates include hydrates, organic solvates and mixed hydrates/organic solvates.

By "prodrug", it is meant a compound which is chemically processed to obtain a compound of formula (I). The compound of formula (I) may also comprise at least one isotope, particularly chosen from 3 H, 11 C, 14 C, 18 F, 15 0 and 13 N.

By "C1 -6 alkyl", it is meant a is a linear hydrocarbon group comprising from 1 to 6 carbon atoms, in particular from 1 to 3 carbon atoms, or a branched or cyclic hydrocarbon group comprising from 3 to 6 carbon atoms. Examples of alkyl groups include methyl (Me), ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and cyclohexyl groups, and preferably methyl or isopropyl. A "C1 -6 alkoxy" is an -O-alkyl group wherein the alkyl moiety is as defined above.

By "C1 -6 haloalkyl" and "C1 -6 haloalkoxy", it is meant respectively C1 -6 alkyl or C1 -6 alkoxy as defined above, which is substituted on at least one of its hydrogen atoms by one or more halogen atoms.

The halogen atom is preferably chosen from F, Br, I and CI.

A "C1 -6 hydroxyalkyl" is a C1 -6 alkyl group as defined above, in which at least one hydrogen atom has been substituted by a hydroxyl (OH). Preferably the hydroxyalkyl group is CH2(OH)- or CH2(OH)-CH2-.

A "heterocyclic group" is refers to a monocyclic or polycyclic saturated hydrocarbon group, in which at least one hydrogen atom has been substituted by a heteroatom, and which may be optionally substituted. The heteroatom may be N, O, P or S. Preferably, the heterocyclic group is chosen from azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepinyl, morpholinyl and piperazinyl groups. Preferably, it may be substituted by 1 , 2, 3 or 4 substituents. Said substituents may be selected from C1 -6 alkyl, C1 -6 hydroxyalkyl, methylamino and dimethylamino.

Preferably the heterocyclic group is piperazinyl, piperidinyl, 1 ,4-diazepanyl, or pyrrolidinyl. More preferably it is 4-methyl-piperazinyl, 4-methyl-piperidinyl, 4-(N,N-dimethylamino)- piperidine, 4-methyl-1 ,4-diazepinyl or pyrrolidinyl.

By "aryl", it is meant a monocyclic or polycyclic aromatic hydrocarbon group, which may be optionally substituted. Preferably, the aryl group is a phenyl. The aryl may be not substituted, or substituted by at least one C1 -6 alkyl group, and/or by at least one C1 -6 hydroxyalkyl, and/or by at least one halogen, and/or by at least one cyano group (-CN), and/or by at least one methylsulfonyl group, and/or by at least one C1 -6 halokalkyl group. Examples of aryl groups include phenyl, 2-methylphenyl, 3,5-dimethylphenyl, 3,4- dimethylphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 3-cyanophenyl, 3- methylsulfonylphenyl, 3-trifluoromethylphenyl. By "aralkyi", it is meant an aryl group as described above, linked to the compound of formula (I) by an alkyl group. Preferably, the aralkyi group is a benzyl or phenethyl. The aralkyi may be substituted on the aryl group by at least one C1 -6 alkyl group, and/or by at least one C1 -6 hydroxyalkyl, and/or by at least one C1 -6 alkoxy, and/or by at least one halogen, and/or by at least one methylsulfonyl group, and/or by at least one C1 -6 halokalkyl group. Preferably the aralkyi is benzyl, 2-methylbenzyl, 3-methylbenzyl, 3,5- dimethylbenzyl, 3,4-dimethylbenzyl, 4-methoxyphenethyl, 3-chlorobenzyl, 3- methoxybenzyl, 3-methylsulfonylbenzyl, 3-trifluoromethylbenzyl.

By "heteroaryl", it is meant an aryl group in which at least one carbon atom of the aromatic ring is substituted by a heteroatom, and which may be optionally substituted. The heteroatom may be nitrogen, oxygen, phosphorus or sulfur. Preferably the heteroatom is nitrogen. Examples of heteroaryl groups include pyridine, pyrrole, thiophene, furane, pyrimidine, pyrazine, triazine, imidazole, thiazole, oxazole, and isoxazole groups. Preferably, the heteroaryl group is a pyridine group such as 2- or 3-pyridino. The heteroaryl may be substituted by at least one C1 -6 alkyl group. Preferably the heteroaryl is 6-methyl-2-pyridine, 5-methyl-3-pyridine.

By "heteroaralkyl", it is meant an aralkyi group in which at least one carbon atom of the aromatic ring is substituted by a heteroatom, and which may be optionally substituted. The heteroatom may be nitrogen, oxygen, phosphorus or sulfur. Preferably the heteroatom is nitrogen. Examples of heteroaralkyl groups include 3-pyridinemethyl. It may be substituted by at least one C1 -6 alkyl group. Preferably, the heteroaralkyl group is 5-methyl-3- pyridinemethyl. Preferably R1 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and -S02Me.

More preferably R1 is H.

Preferably R2 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and -S02Me.

More preferably R2 is H. Preferably R3 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and -S02Me.

More preferably R3 is H.

Preferably R4 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and -S02Me.

More preferably R4 is H.

Preferably R5 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and -S02Me.

More preferably R5 is H, Me or CI.

Preferably R6 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and -S02Me.

More preferably R6 is H, Me or CI.

Preferably R7 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and -S02Me.

More preferably R7 is methyl, ethyl, isopropyl, (CI)3C-0-, -SMe, CI or MeO-.

Preferably R8 is chosen from H, F, CI, Br, CN, CF3, OCF3, C1 -6 alkyl, C1 -6 alkoxy, -SMe and -S02Me.

More preferably R8 is H. Preferably R9 and R10 form, together with the nitrogen atom carrying them, a piperazinylgroup such as a 4-piperazinyl group, a diazepinyl group, a piperidinyl group, a pyrrolidinylgroup or an azolyl group, optionally substituted by 1 , 2, 3 or 4 substituent(s) Rc.

Preferably Rc is chosen from methyl, ethyl, isopropyl, -N(CH3)2, (CH3)3-C-0-CO-, CH3- CO-, CH3-CH2-CO-, CH2(OH)-CO-, CH3-0-CH2-CO-, benzoyl, benzyl-CO-, 4-methoxy- benzyl-CO-, 4-methoxyphenethyl, CN-CH2-CH2-, phenyl, pyridyl, 3-methylbenzyl, pyrrolidinyl, N,N-diethylamino, Ν,Ν-dimethylamino, CH2(OH)-CH2-, CH3-CH(CH3)-CO-, 2-methylbenzoyl, 3,5-dimethylbenzoyl, 3,4-dimethylbenzoyl, 3-chlorobenzoyl, 3- methoxybenzoyl, 3-cyanobenzoyl, 3-methylsulfonylbenzoyl, 3-trifluoromethylbenzoyl, 6- methyl-2-pyridyl-CO-, 5-methyl-3-pyridyl-CO-, 2-methylbenzyl, 3,5-dimethylbenzyl, 3,4- dimethylbenzyl, 3-chlorobenzyl, 3-methoxybenzyl, 3-methylsulfonylbenzyl, 5-methyl-3- pyridyl and 3-trifluoromethylbenzyl.

The compounds of formula (I) for which R9 and R10, together with the nitrogen atom carrying them, form a non-substituted 4-piperazinyl group, are compounds of formula (IA):

(ΙΑ)

The compounds of formula (I) for which R9 and R10, together with the nitrogen atom carrying them, form a 4-piperazinyl group substituted by one substituent Rc, with Rc being Rd- -, are compounds of formula (IB):

(IB)

The compounds of formula (I) for which R9 and R10, together with the nitrogen atom carrying them, form a 4-piperazinyl group substituted by one substituent Rc, with Rc being C1 -6 alkyl; C1 -6 hydroxyalkyl; or -N(R')(R"), are compounds of formula (IC):

(IC)

Another object of the invention is a compound chosen from compounds of formula (I), their pharmaceutically acceptable salts and solvates, prodrugs of said compounds, and pharmaceutically acceptable salts and solvates of said prodrugs:

(I)

wherein :

R1 , R2, R3, R4, R5, R6, R7 and R8 are independently selected from H, C1 -6 alkyl, C1 -6 alkoxy, C1 -6 haloalkyl, C1 -6 haloalkoxy, CN, -NH2, -NRaRb, halogen, -S-(C1 -6 alkyl), -S(0)-(C1 -6 alkyl), -S(0)2-(C1 -6 alkyl);

R9 and R10 are independently selected from H, C1 -6 alkyl, N-methyl-piperidin-4- yl, -(C1 -6 alkyl)-N(R')(R"), or R9 and R10, together with the nitrogen atom carrying them, form a heterocyclic group, wherein said heterocyclic group is optionally substituted by 1 , 2, 3 or 4 substituent(s) Rc ;

Ra and Rb are independently selected from H and C1 -6 alkyl, or Ra and Rb, together with the nitrogen atom carrying them, form a heterocyclic group, wherein said heterocyclic group is optionally substituted by 1 , 2, 3 or 4 substituents independently selected from C1 -6 alkyl and C1 -6 hydroxyalkyl;

Rc is C1 -6 alkyl; C1 -6 hydroxyalkyl; -N(R')(R"); or Rd-CO- wherein Rd is C1 -6 alkoxy, C1 -6 alkyl, C1 -6 hydroxyalkyl, methoxymethyl, aryl, aralkyl, -(C1 -6 alkyl)-CN, heteroaryl, heteroaralkyl, -CH2-0-(aryl) or 2-hydroxyethylethoxy,

R' and R" are each identical or different and represent H or C1 -6 alkyl, or R' and R" form with the nitrogen atom carrying them a heterocyclic group,

with the exception of methiothepin and its salts:

Preferably in this embodiment, the proviso that R1 , R2, R3, R4, R5, R6, R7 and R8 do not simultaneously represent H is also applicable.

Methiothepin is the compound of formula (I) with R1 =R2=R3=R4=R5=R6=R8=H, R7= Me- S-, and R9 and R10 together with the nitrogen atom carrying them, form a piperazine group substituted by one Rc in position 4 and which is methyl. Preferably the compound of formula (I) for use according to the invention is chosen from methiothepin, methiothepin mesylate and methiothepin maleate. Preferably, according to another embodiment, the compound of formula (I) for use according to the invention is chosen from compounds of formula (I) in which:

R1 = R2 = R3 = R4 = R8 = H,

R5 and R6 are independently chosen from H, C1 -6 alkyl and halogen,

R7 is chosen from H, C1 -6 alkyl, C1 -6 alkoxy, C1 -6 haloalkoxy, halogen and -S- (C1 -6 alkyl), preferably from C1 -6 alkyl, C1 -6 alkoxy, C1 -6 haloalkoxy, halogen and -S- (C1 -6 alkyl),

R9 and R10 together with the nitrogen atom carrying them, form a heterocyclic group, preferably a piperazine, 1 ,4-diazepinyl, piperidinyl, pyrrolidinyl, wherein said heterocyclic group is optionally substituted by one substituent Rc,

Rc is C1 -6 alkyl; C1 -6 hydroxyalkyl; -N(R')(R"); or Rd-CO- wherein Rd is C1 -6 alkoxy, C1 -6 alkyl, C1 -6 hydroxyalkyl, methoxymethyl, phenyl, benzyl, 2-methylphenyl, 3,5-dimethylphenyl, 3,4-dimethylphenyl, 3-chlorophenyl, 4-chlorophenyl, 3- methoxyphenyl, 3-cyanophenyl, 3-methylsulfonylphenyl, 3-trifluoromethylphenyl, 2- methylbenzyl, 3-methylbenzyl, 3,5-dimethylbenzyl, 3,4-dimethylbenzyl, 4- methoxyphenethyl, 3-chlorobenzyl, 3-methoxybenzyl, 3-methylsulfonylbenzyl, 3- trifluoromethylbenzyl, 5-methyl-3-pyridinemethyl, -(C1 -6 alkyl)-CN, pyridine, 6-methyl-2- pyridine, 5-methyl-3-pyridine, 4-chlorophenoxy-methyl or 2-hydroxyethylethoxy,

R' and R" are each identical or different and represent H or C1 -6 alkyl, or R' and R" form with the nitrogen atom carrying them a heterocyclic group.

Preferably, according to another embodiment, the compound of formula (I) for use according to the invention is chosen from compounds of formula (I) in which:

R1 = R2 = R3 = R4 = R5 = R6 = R8 = H,

R7 is chosen from C1 -6 alkyl,

R9 and R10 are independently selected from H, C1 -6 alkyl, N-methyl-piperidin-4- yl, -(C1 -6 alkyl)-N(R')(R"),

R' and R" are each identical or different and represent C1 -6 alkyl.

Preferably the compound of formula (I) according to the invention is chosen from:

1 -methyl-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

1 -(3-chloro-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-methyl-piperazine 1 -(3-methoxy-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-methyl-piperazine

1 -(1 ,2-dichloro-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-methyl-piperazine

1 -methyl-4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-1 ,4-diazepane 4-methyl-1 -(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperidine

N,N-dimethyl-1 -(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperidin-4- amine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

1 -ethyl-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

1 -isopropyl-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

N,N,N'-trimethyl-N'-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)ethane-1 ,2-diamine N,N,N'-trimethyl-N'-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)propane-1 ,3- diamine

3-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propanenitrile 1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-phenyl-piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-(2-pyridyl)piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-(m-tolylmethyl)piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-pyrrolidin-1 -yl-piperidine

N,N-diethyl-1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperidin-4-amine 1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-1 ,4-diazepane

1 -[2-(4-methoxyphenyl)ethyl]-4-(3-methyl-5,6-dihydrobenzo[b][ 1 ]benzothiepin-5- yl)piperazine

1 - methyl-N-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperidin-4-amine

2- [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]ethanol

2-[2-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]ethoxy]ethanol 1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-propyl-piperazine

1 -isobutyl-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-(o-tolylmethyl)piperazine

1 -[(3,5-dimethylphenyl)methyl]-4-(3-methyl-5,6-dihydrobenzo[b ][1 ]benzothiepin-5- yl)piperazine

1 -[(3,4-dimethylphenyl)methyl]-4-(3-methyl-5,6-dihydrobenzo[b ][1 ]benzothiepin-5- yl)piperazine

1 -[(3-chlorophenyl)methyl]-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazi

1 -[(3-methoxyphenyl)methyl]-4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-[(3- methylsulfonylphenyl)methyl]piperazine 1 - (3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-[(5-methyl-3- pyridyl)methyl]piperazine

1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-[(3- trifluoromethyl)phenyl]methyl]piperazine

tert-butyl 4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine-1 -carboxylate 1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]ethanone

2- hydroxy-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]ethanone 2-methoxy-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]ethanone [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-phenyl-methanone 1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-phenyl-ethanone 2-(4-methoxyphenyl)-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]-ethanone

tert-butyl 4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-1 ,4-diazepane-1 - carboxylate

1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one

2-(4-chlorophenoxy)-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]ethanone

2- methyl-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 - one

[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(o-tolyl)methanone (3,5-dimethylphenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]methanone

(3,4-dimethylphenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]methanone

(3-chlorophenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]methanone

(3-methoxyphenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]methanone

3- [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine-1 -carbonyl]benzonitrile [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(3- methylsulfonylphenyl)methanone

[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-[3- (trifluoromethyl)phenyl]methanone

[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(6-methyl-2- pyridyl)methanone [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(5-methyl-3- pyridyl)methanone

1 -[4-(3-isopropyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-

1 - one

1 -[4-(3-ethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 - one

2- methyl-1 -[4-[3-(trichloromethoxy)-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl]piperazin-1 - yl]propan-1 -one

1 -[4-(1 ,3-dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl- propan-1 -one

1 - [4-(2,3-dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl- propan-1 -one

2- methyl-1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one

More preferably, the compound of formula (I) is chosen from methiothepin, methiothepin mesylate, methiothepin maleate, 2-methyl-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one, 2-methyl-1 -[4- (3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, [4- (3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(5-methyl-3- pyridyl)methanone, 1 -(3-methyl-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)-4-[(3- methylsulfonylphenyl)methyl]piperazine, 1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin- 5-yl)-4-[(5-methyl-3-pyridyl)methyl]piperazine, 1 -[4-(3-isopropyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one, 1 -[4-(3-ethyl- 5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one, 1 -(3- methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-(m-tolylmethyl)piperazine, (3- chlorophenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]methanone, [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-[3- (trifluoromethyl)phenyl]methanone and 1 -[(3,4-dimethylphenyl)methyl]-4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine.

More preferably, the compound of formula (I) is chosen from methiothepin, methiothepin mesylate, methiothepin maleate, 2-methyl-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one and 2-methyl- 1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 - one.

More preferably, the compound of formula (I) is chosen from 2-methyl-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one and 2-methyl- 1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 - one.

Preparation of the compounds of the invention

The compounds of formula (I) according to the present invention may be prepared as follows:

In a typical procedure, a solution of compounds (II) and (III) in a suitable solvent like water or N-methylpyrrolidone may be heated to a temperature between 25°C and 250°C in a conventional vessel or in a microwave oven, in the presence of a base like sodium or potassium hydroxide, and optionally with a catalyst like copper powder to yield compound (IV).

Compound (I) can be prepared by reductive amination, in the presence of an amine HNR9R10 and a suitable reducing agent like for example sodium borohydride.

Compound (I) can also be prepared from compound (IV) by reduction to the alcohol (V) followed by conversion to the activated intermediate compound (VI), for example by chlorination with a chlorinating agent like thionyl chloride. Compound (VI) can then be reacted with an amine HNR9R10 in a suitable solvent at a temperature between 25°C and 250°C.

These processes are illustrated by the following scheme:

Y= CI, Br, OMs, OTs

More specifically, as illustrated by the scheme below: The compounds of formula (IA) (i.e. compounds of formula (I) in which R9 and R10, together with the nitrogen atom carrying them, form a 4-piperazinyl group) can be converted to compounds of formula (IB) by treatment with an acid of formula RaCOOH or with an acid derivative in typical reactions of amide bond formations.

Compounds of formula (IA) can also be alkylated with an alkylation agent like for example propyl iodide, to obtain the corresponding compounds of formula (IC). More specifically compounds of formula (IB) can be converted to compounds of formula (IC) by reduction with a suitable reducing agent like for example lithium aluminium hydride.

(IC)

Therapeutic applications of the compounds of the invention

As explained above, and as shown in the examples, the inventors demonstrated that Dihydrobenzo[b][1 ]benzothiepin compounds of formula (I) and their derivatives according to the invention are able to inhibit the growth of Patched-overexpressing yeasts in the presence of doxorubicin, and to inhibit the doxorubicin efflux. They further show that Dihydrobenzo[b][1 ]benzothiepin compounds of formula (I) and their derivatives according to the invention significantly increase the sensitivity to doxorubicin of different cancer cell lines which endogenously over-express Patched, such as adrenocortical carcinoma, melanoma, breath cancer and colon cancer cell lines. As shown below, the cytotoxicity of doxorubicin on the melanoma, breath cancer, colon cancer and adrenocortical carcinoma cell lines was significantly increased when doxorubicin was used in combination with Dihydrobenzo[b][1 ]benzothiepin compounds and their derivatives according to the invention.

The invention also relates to the use of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof for increasing the sensitivity of a cancer to a chemotherapeutic drug. A further object of the invention is the use of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof for decreasing the resistance of a cancer with respect to a chemotherapeutic drug. Preferably, the invention relates to the use of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof for decreasing the resistance of a cancer with respect to a chemotherapeutic drug, wherein the cancer cells express Patched.

Another object of the invention is a product comprising:

a) a dihydrobenzo[b][1 ]benzothiepin compound of formula (I), or one of its derivatives, and

b) at least one chemotherapeutic drug,

as combination product for a simultaneous, separate or sequential use for treating cancer, and/or for preventing cancer metastasis, and/or for preventing cancer recurrence, and/or for decreasing resistance to the chemotherapeutic drug b), in a subject.

Preferably the product is for decreasing resistance of a cancer to the chemotherapeutic drug b), in a subject, wherein the cancer cells express Patched.

The term "subject" refers to any subject and typically designates a patient, in particular a subject undergoing a treatment of cancer such as chemotherapy and/or radiotherapy, or a subject at risk, or suspected to be at risk, of developing a cancer.

The subject is preferably a mammal, even more preferably a human being, for example a human being suffering of a cancer and resistant to chemotherapy.

The subject is typically a cancer patient, preferably a patient whose tumor cells express the Patched receptor.

The subject may have been exposed to part of a complete conventional treatment protocol, for example to at least one cycle of the all treatment protocol, for example two cycles of the all treatment protocol. By "treatment" is meant the curative treatment of cancer. A curative treatment is defined as a treatment that completely treat (cure) or partially treat (induces tumor growth stabilization, retardation or regression) cancer.

The cancer may be any kind of cancer or neoplasia in which the tumor or cancer cells express or overexpress the Patched receptor. The cancer is Patched-positive.

A typical cancer is a cancer resistant to the first-line chemotherapy.

The cancer is for example selected from a melanoma, a breast cancer, a thyroid cancer, a prostate cancer, a colorectal cancer, an ovarian cancer, a lung cancer, a pancreatic cancer, a glioma, a cervical cancer, an endometrial cancer, a head and neck cancer, a liver cancer, a renal cancer, a skin cancer, a stomach cancer, a testis cancer, an urothelial cancer or an adrenocortical carcinoma, but also non solid cancers such as lymphoma. This cancer can be a metastatic cancer or not.

In a particular embodiment of the present invention, the chemotherapeutic drug is selected from an anthracycline, an antitumor antibiotic, an alkylating agent, an antimetabolite, an alkaloid, a topoisomerase inhibitor, an anti-mitotic agent such as a spindle poison, a DNA-intercalating agent, a taxane, a platin-based component, a specific kinase inhibitor, an androgen receptor antagonist, an hormone, a cytokine, an antiangiogenic agent, an antibody, in particular a monoclonal antibody, a modulator of the immunity system, an oncolytic virus and a TLR (Toll-like receptor)-3 ligand.

The treatment may include several chemotherapeutic drugs and will be selected by the cancerologist depending on the specific cancer to be prevented or treated.

Anthracyclins include for example doxorubicin, daunorubicin, epirubicin, pirarubicin, idarubicin, zorubicin, aclarubicin, nemorubicin, sabarubicin or valrubicin.

Antitumor antibiotics include for example Bleomycin, hydroxyurea, Mitomycin C or

Mitoxantrone.

Alkylating agents include for example dacarbazine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, ifosfamide, melphalan, mechlorethamine, oxaliplatin, uramustine or temozolomide.

Examples of antimetabolites are Azathioprine, Capecitabine, Cytarabine, Floxuridine, Fludarabine, Fluorouracil, Gemcitabine, Methotrexate, Fluorouracil (5-FU) or Pemetrexed; Akaloids include for example vinblastine, or vincristine (Vinorelbine); Topoisomerase inhibitors include, for example Irinotecan, Topotecan or Etoposide; Spindle poisons are for example selected from Vinblastine, Vincristine and Vinorelbine; Taxanes are for example selected from docetaxel, larotaxel, cabazitaxel, paclitaxel (PG- paclitaxel and DHA-paclitaxel), ortataxel, tesetaxel, and taxoprexin.

Examples of platin-based components are CDDP and OXP.

Examples of specific kinase inhibitors are for example BRAF kinase inhibitors such as vemurafenib and dabrafenib, or MEK inhibitors such as trametinib, or Plk1 inhibitors such as volasertib.

Androgen receptor antagonists are for example bicalutamide or enzalutamide.

Tamoxifen and anti-aromatase drugs are typically used in the context of hormonotherapy. Examples of cytokines usable in the context of an immunotherapy are IL-2 (lnterleukine-2) and IFN (Interferon) alpha (IFNa).

Antiangiogenic agents are for example VEGF inhibitors such as itraconazole, bevacizumab or ranibizumab.

Anti-CD20 (pan B-Cell antigen) and anti-Her2/Neu (Human Epidermal Growth Factor Receptor-2/NEU) are examples of monoclonal antibodies. Monoclonal antibodies also include anti-immune checkpoint antibodies, such as anti-PD1 , anti-PDL1 , anti-CTLA4, anti-OX40L, anti-PDL2, anti-CD73, anti-CD80, anti-CD86, anti-TIGIT, anti-Galactin-3 or anti-HVEM antibodies.

Anti-PD1 antibodies include pembrolizumab or nivolumab.

Immunity system modulators are for example ID01 , ID02 or TD02 inhibitors, A2a antagonists or STING agonists.

Oncolytic viruses are for exemple Talimogene laherparepvec.

In a preferred embodiment, the chemotherapeutic drug is selected from anthracyclins, alkylating agents, taxanes, topoisomerase inhibitors, antimetabolites and BRAF kinase inhibitors.

In a preferred embodiment, the chemotherapeutic drug is selected from cisplatin, doxorubicin, docetaxel, cyclophosphamide, oxaliplatin, irinotecan, methotrexate, temozolomide, 5-FU, dacarbazine and vemurafenib.

In a preferred embodiment, the chemotherapeutic drug is selected from cisplatin, doxorubicin, methotrexate, temozolomide, 5-FU, dacarbazine and vemurafenib. In particular embodiments of the invention: - Methiothepin or methiothepin mesylate or methiothepin maleate, is used in combination with at least one of cisplatin, doxorubicin, docetaxel, cyclophosphamide, oxaliplatin, irinotecan, dacarbazine or vemurafenib, or

- Methiothepin or methiothepin mesylate or methiothepin maleate, is used in combination with at least one of cisplatin, doxorubicin, dacarbazine or vemurafenib, or

- 2-methyl-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan- 1 -one is used in combination with at least one of cisplatin, doxorubicin, dacarbazine or vemurafenib, or

- 1 -[4-(2,3-dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl- propan-1 -one is used in combination with at least one of cisplatin, doxorubicin, dacarbazine or vemurafenib, or

- 2-methyl-1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one is used in combination with at least one of cisplatin, doxorubicin, dacarbazine or vemurafenib, or

- Cisplatin is used in combination with at least one of methiothepin, methiothepin mesylate, methiothepin maleate, 2-methyl-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl- 5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one or 2- methyl-1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one, or

- Doxorubicin is used in combination with at least one of methiothepin, methiothepin mesylate, methiothepin maleate, 2-methyl-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl- 5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one or 2- methyl-1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one, or

- Docetaxel is used in combination with at least one of methiothepin, methiothepin mesylate, methiothepin maleate, 2-methyl-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl- 5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one or 2- methyl-1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one, or

- Cyclophosphamide is used in combination with at least one of methiothepin, methiothepin mesylate, methiothepin maleate, 2-methyl-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl- 5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one or 2- methyl-1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one, or

- Oxaliplatin is used in combination with at least one of methiothepin, methiothepin mesylate, methiothepin maleate, 2-methyl-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl-

5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one or 2- methyl-1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one, or

- Irinotecan is used in combination with at least one of methiothepin, methiothepin mesylate, methiothepin maleate, 2-methyl-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl- 5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one or 2- methyl-1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one, or

- Dacarbazine is used in combination with at least one of methiothepin, methiothepin mesylate, methiothepin maleate, 2-methyl-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl- 5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one or 2- methyl-1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one, or

- Vemurafenib is used in combination with at least one of methiothepin, methiothepin mesylate, methiothepin maleate, 2-methyl-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl- 5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-2-methyl-propan-1 -one or 2- methyl-1 -[4-(3-methylsulfanyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one.

The present invention further relates to a pharmaceutical composition or medicament, comprising a compound of formula (I) as described above. The compound of the invention can in particular be advantageously used in combination with at least one chemotherapeutic drug, for treating cancer, for preventing cancer metastasis and/or for preventing cancer recurrence in a subject.

Thus the present invention further relates a product comprising:

a) a dihydrobenzo[b][1 ]benzothiepin compound of formula (I), or one of its derivatives, and

b) at least one chemotherapeutic drug, as combination product for a simultaneous, separate or sequential use for treating cancer, and/or for preventing cancer metastasis, and/or for preventing cancer recurrence, and/or for decreasing resistance to the chemotherapeutic drug b), in a subject.

The chemotherapeutic drug b) is preferably as described above.

Herein described are also (i) a method for preventing or treating cancer, (ii) a method for increasing the sensitivity of a cancer to a chemotherapeutic agent, and (iii) a method for decreasing the resistance of a cancer with respect to a chemotherapeutic drug, each of said methods comprising administering to a subject in need thereof with an effective amount of at least one compound of formula (I) as defined above, preferably together with a chemotherapeutic drug.

As used herein, "a therapeutically effective amount or dose" refers to an amount of the compound of the invention which prevents, removes, slows down the cancer or reduces or delays one or several symptoms or disorders caused by or associated with said disease in the subject, preferably a human being. The effective amount, and more generally the dosage regimen, of the compound of the invention and pharmaceutical compositions thereof may be determined and adapted by the one skilled in the art. An effective dose can be determined by the use of conventional techniques and by observing results obtained under analogous circumstances. The therapeutically effective dose of the compound of the invention will vary depending on the disease to be treated or prevented, its gravity, the route of administration, any co-therapy involved, the patient's age, weight, general medical condition, medical history, etc.

Typically, the amount of the compound to be administrated to a patient may range from about 0.01 to 500 mg/kg of body weight for a human patient. In a particular embodiment, the pharmaceutical composition according to the invention comprises 0.01 mg/kg to 300 mg/kg of the compound of the invention, preferably from 0.01 mg/kg to 3 mg/kg, for instance from 25 to 300 mg/kg.

In a particular aspect, the compounds of the invention can be administered to the subject by parenteral route, topical route, oral route or intravenous (IV) injection. The compound or the nanoparticle of the invention may be administered to the subject daily (for example 1 , 2, 3, 4, 5, 6 or 7 times a day) during several consecutive days, for example during 2 to 10 consecutive days, preferably from 3 to 6 consecutive days. Said treatment may be repeated during 1 , 2, 3, 4, 5, 6 or 7 weeks, or every two or three weeks or every one, two or three months. Alternatively, several treatment cycles can be performed, optionally with a break period between two treatment cycles, for instance of 1 , 2, 3, 4 or 5 weeks. The compound or the nanoparticle of the invention can for example be administered as a single dose once a week, once every two weeks, or once a month. The treatment may be repeated one or several times per year.

Doses are administered at appropriate intervals which can be determined by the skilled person. The amount chosen will depend on multiple factors, including the route of administration, duration of administration, time of administration, the elimination rate of the selected compound of formula (I), or of the various products used in combination with said compound, the age, weight and physical condition of the patient and his/her medical history, and any other information known in medicine.

The administration route can be oral, topical or parenteral, typically rectal, sublingual, intranasal, intra-peritoneal (IP), intra-venous (IV), intra-arterial (IA), intra-muscular (IM), intra-cerebellar, intrathecal, intratumoral and/or intradermal. The pharmaceutical composition is adapted for one or several of the above-mentioned routes. The pharmaceutical composition is preferably administered by injection or by intravenous infusion of suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal.

The formulations of the present invention comprise a compound of formula (I) in a pharmaceutically acceptable carrier. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.

The pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as gels, oils, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or vehicles, or as pills, tablets, capsules, powders, suppositories, etc. that contain solid vehicles in a way known in the art, possibly through dosage forms or devices providing sustained and/or delayed release. For this type of formulation, an agent such as cellulose, lipids, carbonates or starches are used advantageously.

Agents or vehicles that can be used in the formulations (liquid and/or injectable and/or solid) are excipients or inert vehicles, i.e. pharmaceutically inactive and non-toxic vehicles. Mention may be made, for example, of saline, physiological, isotonic and/or buffered solutions, compatible with pharmaceutical use and known to those skilled in the art. The compositions may contain one or more agents or vehicles chosen from dispersants, solubilizers, stabilizers, preservatives, etc. Particular examples are methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, cyclodextrins, polysorbate 80, mannitol, gelatin, lactose, liposomes, vegetable oils or animal, acacia, etc. Preferably, vegetable oils are used.

Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.

Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Every such formulation can also contain other pharmaceutically compatible and non-toxic auxiliary agents, such as, e.g. stabilizers, antioxidants, binders, dyes, emulsifiers or flavouring substances. Further aspects and advantages of the present invention will be disclosed in the following experimental section which shall be considered as illustrative only.

LEGENDS TO THE FIGURES

In the following figures and example, P375 designates methiothepin maleate.

P298 designates Fipexide hydrochloride.

PSC833 designates Valspodar.

Figure 1. P375 inhibits yeast expressing Patched resistance to doxorubicin.

(A) Yeast expressing Patched or control yeast were grown in the presence of 10 μΜ of each molecule to be tested, and in the presence or the absence of doxorubicin (dxr) (10 μΜ for yeast expressing Patched and 5 μΜ for control yeast). DMSO was used as control. The growth of yeast was measured by absorbance at 600 nm. (B) Yeast expressing wild- type Patched and control yeast were incubated with dxr for 2 hours and fixed for dxr loading control, or resuspended in buffer supplemented with DMSO, 10 μΜ P375 or 2.5 μΜ PSC833 for 10 min. and fixed. Histograms represent the intracellular dxr fluorescence quantification which was carried out using Image J software on more than 100 yeast from 3 different fields for each condition on 3 independent experiments. Data are represented as mean ± SEM and were analyzed using Anova multiple comparison test and Bonferroni correction. Significance is attained at P < 0.05 ( * ) ( *** : P < 0.0005).

Figure 2. Patched is expressed in Adrenocortical carcinoma. (A) Patched and Smoothened proteins are expressed in ACC tumor tissues at a variable extent of intensity and distribution. For each protein, an example of weak and intense expression is shown. (B) Western blotting showing Patched protein expression in total extracts from ACC cell lines H295R and MUC-1 . Beta-tubulin was used as loading control. Histogram reports the quantification of Patched protein obtained from 3 western blots performed on 3 extracts of each cell line.

Figure 3. P375 enhances the cytotoxic effect of doxorubicin on ACC cells over- expressing Patched.

(A) Treatment-dependent quantification of cell viability of H295R (left) and MUC-1 (right) cells upon addition of 2 μΜ doxorubicin (dxr) and different concentrations of P375. Stars represent statistical significance over cells incubated with 2 μΜ dxr. (B) Cell viability was measured after 48 hours treatment with serial dilutions of dxr with or without P375 on H295R cells. (C) dxr IC50 values calculated on H295R cells and H295R cells rendered resistant to dxr (H295R dxr R). (D) Western blotting showing Patched protein expression in total extracts from H295R and H295RdoxR cells. Beta-tubulin was used as loading control. (E) P375 IC50 on H295R cell viability was measured after 48 hours treatment with serial dilutions of P375 with or without 2 μΜ dxr.

IC50 values were calculated from the mean of at least three experiments using Prism6 software.

Figure 4. P375 enhances the pro-apoptotic, anti-proliferative and anti-clonogenic effect of doxorubicin.

(A) Cell apoptosis was evaluated using the luminescent assay Caspase-Glo 3/7 after 48 hours treatment with medium alone or with medium containing dxr alone, P375 alone, or dxr and P375 together. Histograms represent the mean ± SEM of 3 independent experiments and data were analyzed using Anova multiple comparison test and Bonferroni correction. Significance is attained at P < 0.05 (*) (**:P < 0.005, ***: P < 0.0005). (B) For proliferation tests, cells were seeded in 96 well-plates and treated with medium containing serial dilutions of dxr in the presence or the absence of P375. After 7 days, Neutral Red was used for quantification of living cells. Data are represented as mean ± SEM. IC50 were calculated from the mean of at least three independent experiments using Prism6 software. (C) For clone formation tests, cells were seeded in 24 well-plates and treated with DMSO as control, dxr alone, P375 alone or a combination of dxr and P375. After 14 days, clones were revealed with crystal violet solution, pictures were taken and absorbance was read at 550 nm after solubilisation. Histograms represent the mean ± SEM of at least three independent experiments for each cell line and were analyzed using Anova multiple comparison test and Bonferroni correction. Significance is attained at P < 0.05 ( * ) ( *** : P < 0.0005). Figure 5. P375 inhibits the doxorubicin efflux activity of Patched.

(A) Cells were seeded on coverslips and incubated with dxr. After 2 hours, three coverslips were fixed for dxr loading control. The other coverslips (a triplicate per condition) were incubated with DMSO, P375 or the P-gp antagonist PSC833 for 30 min. and fixed. (B) Cells were seeded on coverslips and incubated with Hoechst. After 2 hours, three coverslips were fixed for Hoechst loading control. The other coverslips (a triplicate per condition) were incubated with DMSO, P375 or PSC833 for 30 min. and fixed. (C) H295R cells were transfected with Patched siRNA or negative control siRNA. Patched protein expression (right panel) and dxr efflux (left panel) were analyzed 16 hours after transfection. (D) H295R cells were transfected with P-gp siRNA or negative control siRNA. P-gp protein expression (right panel) and dxr efflux (left panel) were analyzed.

Images were acquired with a fluorescence microscope using a 40X objective. Dxr or Hoechst fluorescence was quantified using ImageJ software for about 100 cells per condition per experiment. All data presented are the mean ± SEM of 3 independent experiments and were analyzed using Anova multiple comparison test and Bonferroni correction. Significance is attained at P < 0.05 ( * ).

Figure 6. P375 enhances the cytotoxic effect of doxorubicin on other cancer cells expressing Patched.

(A) Western blotting showing Patched protein expression in total extracts from colorectal carcinoma (HCT1 16), breast adenocarcinoma (MCF7), and melanoma (A375) cell lines. Beta-tubulin was used as loading control. (B) P375 inhibited dxr efflux. Cells from each cell line were seeded on coverslips and incubated with dxr. After 2 hours, three coverslips of each cell line were fixed for dxr loading control. The other coverslips (a triplicate per cell line) were incubated with DMSO or P375 for 30 min, and then fixed. Images were acquired with a fluorescence microscope using a 40X objective. Dxr fluorescence was quantified using ImageJ software for about 100 cells per condition per experiment. (C) Cell viability was measured after 24 hour treatments with serial dilutions of dxr with or without P375 on each cell line. Dxr IC50 values reported are the mean value of 3 independent experiments for each cell line, and were calculated using Prism 6 software. Figure 7. P375 enhances the efficiency of doxorubicin on H295R tumor bearing mice.

(A) Quantification of TUNEL positive cells in tumor slides after one therapeutic cycle. Stars denote significant differences compared with controls. (B) Dxr quantification in mice tumors after one therapeutic cycle was performed using fluorescence microscopy analysis of tissue slides and ImageJ software. Data presented are mean ± SEM and were analyzed using Student's /-test. Significance is attained at P < 0.05 ( * ). (C) Evolution of the tumor size for the 4 groups of mice treated with two therapeutic cycles with different treatment modalities. The two-way repeated measures ANOVA analysis showed a significant difference between the group control and the group treated with P375 and lipdxr. (D) Dxr in mice tumors and hearts after two therapeutic cycles was quantified using fluorescence microscopy analysis of tissue slides and ImageJ software. Data presented are mean ± SEM and were analyzed using Student's /-test. Significance is attained at P < 0.05 ( * ) ( ** : P < 0.005).

Figure 8. Methiothepin increases docetaxel cytotoxicity on pancreatic cancer cell line PC3.

A. Addition of 30μΜ of methiothepin increases docetaxel sensitivity of pancreatic cancer cells by a factor of 5 after 48 hours treatment. IC50 of docetaxel in the presence of 30μΜ of methiothepin is about 39μΜ, whereas the IC50 of docetaxel alone was greater than 200μΜ.

B. IC50 of methiothepin in the presence of 75μΜ of docetaxel is about 8μΜ.

Figure 9. Methiothepin increases docetaxel cytotoxicity on breast cancer cell line MDA-MB-231.

A. Addition of 20μΜ of methiothepin increases more than 4 times the sensitivity of breast cancer cells to docetaxel after 48 hours treatment. IC50 of docetaxel in the presence of 20μΜ of methiothepin is about 31 μΜ, whereas the IC50 of docetaxel alone was around 129μΜ.

B. IC50 of methiothepin in the presence of 50μΜ of docetaxel is about 8μΜ.

EXAMPLES

Example 1 : Synthesis of different compounds according to the invention Chemical Material

The following Intermediates and Compounds illustrate the preparation of the compounds of formula (I) and certain derivatives thereof.

1 H Nuclear Magnetic Resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (delta) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: eg. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

Compound 1j 1-methyl-4-(3-methyl-5,6-dihvdrobenzorbiri1benzothiepin-5- vDpiperazine

Intermediate 1 : 2-[2-(p-tolylsulfanyl)phenyl]acetic acid 500 mg of 2-iodophenylacetic acid (1 .9 mmol), 261 mg of p-thiocresol (2.10 mmol, 1 .1 eq), 18 mg of copper powder (0.29 mmol, 0.15 eq) and 535 mg of potassium hydroxide (9.54 mmol, 5 eq) were mixed in 12 ml of water and heated in a microwave oven at 170°C for 20 mn. The reaction mixture was acidified to pH = 2 with concentrated HCI and extracted three times with 20 ml of dichloromethane. The organic phases were separated with an hydrophobic membrane, further washed with 10ml of 1 N HCI and concentrated to dryness, yielding 473 mg of clear oil solidifying on standing and used as a crude in the next step.

LCMS: m/z = 276 [M+NH4+], 534 [2M+NH4+] Intermediate 2: 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one

A mixture of 450 mg of 2-[2-(p-tolylsulfanyl)phenyl]acetic acid (1 .74 mmol) and 4.74 g of polyphosphoric acid was heated to 120°C for 3 h. 20 ml of water was added dropwise to the reaction mixture and the crude product was extracted three time with 20 ml of dichloromethane, separating the organic phase with an hydrophobic membrane, yielding 360 mg of dark oil after concentration to dryness used as a crude in the next step.

1 H NMR (in CDCI3): δ 8.02 (m, 1 H), 7.14-7.66 (m, 6H), 4.37 (s, 2H), 2.34 (s, 3H)

Intermediate 3: 1-methyl-4-(3-methylbenzo[b][1 ]benzothiepin-5-yl)piperazine 55 μΙ of TiCI4 (0.5 mmol, 1 .5 eq) was added to a solution of 80 mg of 3-methyl-6H- benzo[b][1 ]benzothiepin-5-one (0.33 mmol) and 185 μΙ of 1 -methylpiperazine (1 .66 mmol, 5 eq) in 1 .3 ml of toluene and the reaction mixture was stirred at 1 10°C for 7h. The reaction mixture was cooled down to 0°C and 5 ml of water was added slowly. The white precipitate was filtered off and washed with 5 ml of tetrahydrofuran. The aqueous phase was extracted twice with 10 ml of ethyl acetate. The combined organic layers were concentrated to dryness yielding 77 mg of brown oil used as a crude in the next step. LCMS: m/z = 323 [M+H+] Compound 1 : 1-methyl-4-(3-methyl-5,6-dihydrobenzo[b][1]benzothiepin-5- yl)piperazine

77 mg (0.24 mmol) of 1 -methyl-4-(3-methylbenzo[b][1 ]benzothiepin-5-yl)piperazine was solubilized in 1 .5 ml of acetic acid and cooled down to 0°C. 135 mg of sodium borohydride (3.6 mmol, 15 eq) was then added portionwise (gas emission noticed). The brown slurry was then stirred at room temperature. After 5 mn, 2 ml of acetic acid was added to facilitate the stirring and the reaction mixture was stirred for 16h. Sodium hydroxide 10N was then added until pH=12. The crude product was extracted three time with 10ml of ethyl acetate. The combined organic layers were washed with 10ml of water and concentrated under vacuum. The residue was purified by flash chromatography on silica (from 100% dichloromethane to a 2/3 mixture of dichloromethane and dichloromethane/methanol/ammonium hydroxide 90/10/1 ) yielding the product as a yellowish solid.

LCMS: m/z = 325 [M+H+]

1 H NMR (in CDCI3): δ 7.37-7.51 (m, 2H), 7.23-7.32 (m, 2H), 7.03-7.21 (m, 2H), 6.88 (dd, 1 H), 3.82-4.01 (m, 2H), 3.17 (dd, 1 H), 2.45-2.80 (br m, 8H), 2.29 (s, 3H), 2.26 (s, 3H)

Compound 2: tert-butyl 4-(3-methyl-5,6-dihvdrobenzorbiri 1benzothiepin-5- yl)piperazine-1-carboxylate

Intermediate 4: 2-[2-(p-tolylsulfanyl)phenyl]acetic acid

2.00 g of 2-iodophenylacetic acid (7.63 mmol), 1 .04 g of p-thiocresol (8.40 mmol, 1 .1 eq), 73 mg of copper powder (1 .14 mmol, 0.15 eq) and 2.14 g of potassium hydroxide (38.1 mmol, 5 eq) were mixed in 49 ml of water and heated in a microwave oven at 170°C for 20 mn. The reaction mixture was acidified to pH = 2 with concentrated HCI and extracted three times with 100 ml of dichloromethane. The organic phases were separated with an hydrophobic membrane, further washed with 50ml of 1 N HCI and concentrated to dryness, yielding 1 .93 g of beige solid and used as a crude in the next step.

LCMS: m/z = 276 [M+NH4+]

Intermediate 5: 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one

5 drops of DMF were added to a solution of 1 .70 g of 2-[2-(p-tolylsulfanyl)phenyl]acetic acid (6.58 mmol) and 835 μΙ of oxalyl chloride (9.87 mmol, 1 .5 eq) in 17 ml of dichloromethane (gas emission noticed) and the reaction mixture was stirred for 1 h. Residual oxalyl chloride and dichloromethane were evaporated under vacuum. The residue was dissolved in 20 ml of dichloromethane and 2.63 g of aluminium chloride (19.7 mmol, 3 eq) was added by portion at 0°C. The suspension was stirred at RT for 16h. 30 ml of water was added slowly at 0°C and product was extracted four times with 15 ml of dichloromethane. The combined organic layers were washed successively with 30 ml of a saturated aqueous solution of sodium bicarbonate and 20 ml of water and concentrated under vacuum. The residue was purified by flash chromatography on silica (from a 95:5 mixture of cyclohexane and dichloromethane to 100% dichloromethane) yielding 1 .33 g of beige powder.

Compound 2: tert-butyl 4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazine-1-carboxylate

205 μΙ of TiCI4 (1 .87 mmol, 1 .5 eq) was added to a solution of 300 mg of 3-methyl-6H- benzo[b][1 ]benzothiepin-5-one (1 .25 mmol) and 1 .16 g of 1 -N-Boc-piperazine (6.24 mmol, 5 eq) in 4.9 ml of toluene and the reaction mixture was stirred at 1 10°C for 1 h. Toluene was evaporated under vacuum. The residue was dissolved in 3.6 ml of acetic acid and 236 mg of sodium borohydride (6.24 mmol, 5 eq) was added (exotherm and gas emission noticed). The suspension was stirred at RT for 16h. Sodium hydroxide 10N was then added until pH=12. The white precipitate was filtered off and washed with 15 ml of dichloromethane. The biphasic mixture was separated and aqueous layer was extracted again with dichloromethane (5 x 10 ml). The combined organic layers were washed successively with 50 ml of a saturated aqueous solution of sodium bicarbonate and 40 ml of water and concentrated under vacuum. The residue was purified by flash chromatography on silica (from 100% dichloromethane to a 9:1 mixture of dichloromethane and ethyl acetate) yielding the product as a white powder. LCMS: m/z = 41 1 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.38 (d, 1 H), 7.17-7.32 (m, 3H), 7.08 (dt, 1 H), 6.88 (dd, 1 H), 3.82-4.03 (m, 2H), 3.40 (br m, 4H), 3.13 (d, 1 H), 2.60 (br m, 4H), 2.26 (s, 3H), 1 .45 (s, 9H)

Compound 3: 1-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)piperazin e

5.20 ml of a solution of HCI 4N in dioxane (20.8 mmol, 22 eq) was added to a solution of 388 mg of Compound 2 (0.94 mmol) in 6 ml of dioxane and the suspension was stirred for 20h. The suspension was filtered and washed twice with 3 ml of dioxane. The solid was dissolved in 6 ml of water and the resulting solution was basified with a solution of NaOH 10N. Product was extracted three times with 10 ml of dichloromethane. The combined organic layers were washed successively with 20 ml of a saturated aqueous solution of sodium bicarbonate and 15 ml of water and concentrated to dryness, yielding the product as a yellow solid.

LCMS: m/z = 31 1 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.38 (d, 1 H), 7.17-7.32 (m, 3H), 7.08 (dt, 1 H), 6.88 (dd, 1 H), 3.82-3.99 (m, 2H), 3.16 (d, 1 H), 2.66-2.99 (br m, 8H), 2.26 (s, 3H) Compound 4: 1 -r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)piperaz in-1- yllethanone

14 μΙ of acetic anhydride (0.14 mmol, 1 .5 eq) was added to a solution of 30 mg of 1 -(3- methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.10 mmol) and 59 μΙ of N,N- diisopropylethylamine (0.34 mmol, 3.5 eq) in 1 ml of dimethylformamide and the reaction mixture was stirred for 4h. 3 ml of a saturated aqueous solution of sodium bicarbonate was added and the product was extracted three times with 5 ml of dichloromethane. The combined organic layers were washed successively with 5 ml of a saturated aqueous solution of sodium bicarbonate and 5 ml of water and concentrated to dryness. The residue was purified by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate) yielding the product as a white powder.

LCMS: m/z = 353 [M+H+], 416 [M+ACN+Na+], 727 [2M+Na+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.17-7.34 (m, 4H), 7.08 (dt, 1 H), 6.90 (dd, 1 H), 3.82- 4.03 (m, 2H), 3.61 (t, 2H), 3.40 (m, 2H), 3.13 (dd, 1 H), 2.46-2.72 (m, 4H), 2.27 (s, 3H), 2.06 (s, 3H) Compound 5: 2-hvdroxy-1 -r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5- yl)piperazin-1-vnethanone A solution of 10 mg of glycolic acid (0.13 mmol, 1 .3 eq), 56 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.17 mmol, 1 .8 eq) and 59 μΙ of N,N- diisopropylethylamine (0.34 mmol 3.5 eq) in 1 ml of dimethylformamide was stirred at RT for 15 mn. 30 mg of 1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.10 mmol) was added and the reaction mixture was stirred for 16h. 3 ml of a saturated aqueous solution of sodium bicarbonate was added and the product was extracted three times with 5 ml of dichloromethane. The combined organic layers were washed successively with 5 ml of a saturated aqueous solution of sodium bicarbonate and 5 ml of water and concentrated to dryness. The residue was purified by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate) yielding the product as a beige powder.

LCMS: m/z = 369 [M+H+], 432 [M+ACN+Na+], 759 [2M+Na+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.20-7.34 (m, 4H), 7.08 (dt, 1 H), 6.90 (dd, 1 H), 4.13 (d, 2H), 4.02 (dd, 1 H), 3.87 (t, 1 H), 3.65 (m, 3H), 3.09-3.25 (m, 3H), 2.48-2.73 (m, 4H), 2.26 (s, 3H)

Compound 6: 1-(3-chloro-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)-4-methyl - piperazine

Intermediate 6: 2-[2-(4-chlorophenyl)sulfanylphenyl]acetic acid

Intermediate 6 was prepared according to the procedure used for Intermediate 1 from 500 mg of 2-iodophenylacetic acid (1 .91 mmol), 304 mg of 4-chlorothiophenol (2.10 mmol, 1 .1 eq), 18 mg of copper powder (0.29 mmol, 0.15 eq) and 535 mg of potassium hydroxide (9.54 mmol, 5 eq) in 10 ml of water.

520 mg of clear oil was obtained and used as a crude in the next step.

LCMS: m/z = 323 [M+HCOO-]

Intermediate 7: 3-chloro-6H-benzo[b][1]benzothiepin-5-one Intermediate 7 was prepared according to the procedure used for Intermediate 2 from 450 mg of 2-[2-(4-chlorophenyl)sulfanylphenyl]acetic acid (1 .61 mmol) and 4.74 g of polyphosphoric acid. Heating was performed at 120°C during 5.5h.

332 mg of beige oil solidifying on standing was obtained and used as a crude in the next step.

Intermediate 8: 1-(3-chlorobenzo[b][1]benzothiepin-5-yl)-4-methyl-piperazine

Intermediate 8 was prepared according to the procedure used for Intermediate 3 from 100 mg of 3-chloro-6H-benzo[b][1 ]benzothiepin-5-one (0.38 mmol), 63 μΙ of TiCI4 (0.58 mmol, 1 .5 eq) and 213 μΙ of 1 -methylpiperazine (1 .92 mmol, 5 eq) in 1 .6 ml of toluene.

127 mg of brown oil was obtained and used as a crude in the next step.

LCMS: m/z = 343 [M+H+], 384 [M+ACN+H+] Compound 6: 1-(3-chloro-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-methyl- piperazine

Compound 6 was prepared according to the procedure used for Compound 1 from 1 10 mg of 1 -(3-chlorobenzo[b][1 ]benzothiepin-5-yl)-4-methyl-piperazine (0.32 mmol) and 182 mg of sodium borohydride (4.81 mmol, 15 eq) in 2.1 ml of acetic acid.

A brown oil was obtained after purification by flash chromatography on silica (from 100% dichloromethane to a 6/4 mixture of dichloromethane and dichloromethane/methanol/ammonium hydroxide 90/10/1 ).

LCMS: m/z = 345 [M+H+]

1 H NMR (in CDCI3): δ 7.66 (d, 1 H), 7.49 (d, 1 H), 7.24-7.36 (m, 3H), 7.01 -7.21 (m, 2H),

3.81 -3.98 (m, 2H), 3.15 (dd, 1 H), 2.48-2.71 (br m, 8H), 2.32 (s, 3H)

Compound 7: 2-methoxy-1 -r4-(3-methyl-5,6-dihvdrobenzorb1H lbenzothiepin-5- yl)piperazin-1-vnethanone

Compound 7 was prepared according to the procedure used for Compound 5 from 1 1 mg of methoxyacetic acid (0.13 mmol, 1 .3 eq), 56 mg of 0-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.17 mmol, 1 .8 eq), 59 μΙ of N,N- diisopropylethylamine (0.34 mmol 3.5 eq) and 30 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.10 mmol) in 1 ml of dimethylformamide. The reaction mixture was stirred for 4h. A yellowish powder was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate)

LCMS: m/z = 383 [M+H+], 446 [M+ACN+Na+], 787 [2M+Na+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.19-7.34 (m, 4H), 7.08 (dt, 1 H), 6.90 (dd, 1 H), 3.82- 4.08 (m, 4H), 3.31 -3.64 (m, 7H), 3.12 (dd, 1 H), 2.47-2.80 (m, 4H), 2.26 (s, 3H)

Compound 8: 1 -r4-(3-isopropyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)pipe razin-1 - νΠ-2-methyl-propan-l -one Intermediate 9: 2-[2-(4-isopropylphenyl)sulfanylphenyl]acetic acid

500 mg of 2-iodophenylacetic acid (1 .91 mmol), 320 mg of 4-isopropylbenzenethiol (2.10 mmol, 1 .1 eq), 109 mg of copper iodide (0.57 mmol, 0.30 eq) and 535 mg of potassium hydroxide (9.54 mmol, 5 eq) were mixed in 3 ml of water and stirred for 24h at 100°C in a sealed vial. 12.1 mg of copper powder (0.19 mmol, 0.1 eq) was added and the reaction mixture was stirred at 100°C for 3h in a sealed vial. The reaction mixture was filtered. The mother liquors were acidified to pH = 2 with concentrated HCI and extracted three times with 20 ml of dichloromethane. The organic phases were separated with an hydrophobic membrane, further washed with 20ml of 1 N HCI and concentrated to dryness, yielding 453 mg of orange solid and used as a crude in the next step.

LCMS: m/z = 304 [M+NH4+], 590 [2M+NH4+]

Intermediate 9 : 3-isopropyl-6H-benzo[b][1]benzothiepin-5-one 5 drops of DMF were added to a solution of 440 mg of 2-[2-(4- isopropylphenyl)sulfanylphenyl]acetic acid (1 .54 mmol) and 195 μΙ of oxalyl chloride (2.30 mmol, 1 .5 eq) in 4.4 ml of dichloromethane (gas emission noticed) and the reaction mixture was stirred for 30 min. Residual oxalyl chloride and dichloromethane were evaporated under vacuum. The residue was dissolved in 5 ml of dichloromethane and 615 mg of aluminium chloride (4.61 mmol, 3 eq) was added at RT. The suspension was stirred for 2.5h. 15 ml of water was added slowly and product was extracted four times with 10 ml of dichloromethane. The combined organic layers were washed successively with 25 ml of a saturated aqueous solution of sodium bicarbonate and 20 ml of water and concentrated under vacuum. The residue was purified by flash chromatography on silica (from a 95:5 mixture of cyclohexane and dichloromethane to 100% dichloromethane) yielding 268 mg of orange oil. Intermediate 10: tert-butyl 4-(3-isopropyl-5,6-dihydrobenzo[b][1]benzothiepin-5- yl)piperazine-1 -carboxylate 279 μΙ of a solution of TiCI4 1 M in toluene (0.28 mmol, 1 .5 eq) was added to a solution of 50 mg of 3-isopropyl-6H-benzo[b][1 ]benzothiepin-5-one (0.19 mmol) and 174 mg of 1 -N- Boc-piperazine (0.93 mmol, 5 eq) in 0.5 ml of toluene and the reaction mixture was stirred at 70°C for 2h. Toluene was evaporated under vacuum. The residue was dissolved in 0.8 ml of acetic acid and 35 mg of sodium borohydride (0.93 mmol, 5 eq) was added (exotherm and gas emission noticed). The suspension was stirred at RT for 1 .5h. Sodium hydroxide 10N was then added until pH=12. The crude product was extracted five time with 5 ml of dichloromethane, separating the organic phase with an hydrophobic membrane. The combined organic layers were washed successively with 10 ml of a saturated aqueous solution of sodium bicarbonate and 5 ml of water and concentrated under vacuum yielding 82 mg of dark gum and used as a crude in the next step.

Intermediate 11 : 1-(3-isopropyl-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)piper azine

1 .40 ml of a solution of HCI 4N in dioxane (5.61 mmol, 30 eq) was added to a solution of 82 mg of tert-butyl 4-(3-isopropyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine-1 - carboxylate (0.19 mmol) in 2 ml of dichloromethane and the suspension was stirred for 20h. 5 ml of water was added and the product was washed twice with 4 ml of dichloromethane. Aqueous layer was basified with a solution of NaOH 10N. Product was extracted three times with 5 ml of dichloromethane. The combined organic layers were washed successively with 5 ml of a saturated aqueous solution of sodium bicarbonate and 3 ml of water and concentrated to dryness, yielding 20 mg of yellow oil and used as a crude in the next step.

LCMS: m/z = 339 [M+H+] Compound 8: 1 -[4-(3-isopropyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1- yl]-2-methyl-propan-1 -one

Compound 8 was prepared according to the procedure used for Compound 5 from 7 mg of isobutyric acid (0.077 mmol, 1 .3 eq), 34 mg of 0-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.1 1 mmol, 1 .8 eq), 36 μΙ of N,N- diisopropylethylamine (0.21 mmol 3.5 eq) and 20 mg of 1 -(3-isopropyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.059 mmol) in 1 ml of dimethylformamide.

A yellowish powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 45/55 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 409 [M+H+]

1 H NMR (in CDCI3): δ 7.47-7.53 (m, 2H), 7.18-7.35 (m, 3H), 7.10 (dt, 1 H), 6.94 (dd, 1 H), 3.81 -4.07 (m, 2H), 3.31 -3.70 (m, 4H), 3.12 (dd, 1 H), 2.49-2.89 (m, 6H), 1 .18 (d, 6H), 1 .10 (d, 6H) Compound 9: 1 -(3-methoxy-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)-4-methyl - piperazine

Intermediate 12: 2-[2-(4-methoxyphenyl)sulfanylphenyl]acetic acid Intermediate 12 was prepared according to the procedure used for Intermediate 1 from 500 mg of 2-iodophenylacetic acid (1 .91 mmol), 258 μΙ of 4-methoxybenzenethiol (2.10 mmol, 1 .1 eq), 18 mg of copper powder (0.29 mmol, 0.15 eq) and 535 mg of potassium hydroxide (9.54 mmol, 5 eq) in 10 ml of water.

504 mg of orange oil solidifying on standing was obtained and used as a crude in the next step.

LCMS: m/z = 292 [M+NH4+], 571 [2M+Na+], 547 [2M-H+]

Intermediate 13: 3-methoxy-6H-benzo[b][1]benzothiepin-5-one Intermediate 13 was prepared according to the procedure used for Intermediate 2 from 450 mg of 2-[2-(4-methoxyphenyl)sulfanylphenyl]acetic acid (1 .64 mmol) and 4.74 g of polyphosphoric acid.

238 mg of dark oil was obtained and used as a crude in the next step. Intermediate 14: 1-(3-methoxybenzo[b][1 ]benzothiepin-5-yl)-4-methyl-piperazine

Intermediate 14 was prepared according to the procedure used for Intermediate 3 from 100 mg of 3-methoxy-6H-benzo[b][1 ]benzothiepin-5-one (0.39 mmol), 64 μΙ of TiCI4 (0.59 mmol, 1 .5 eq) and 216 μΙ of 1 -methylpiperazine (1 .95 mmol, 5 eq) in 1 .6 ml of toluene. 123 mg of brown oil was obtained and used as a crude in the next step.

LCMS: m/z = 339 [M+H+] Compound 9: 1 -(3-methoxy-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-methyl- piperazine 1 10 mg (0.32 mmol) of 1 -(3-methoxybenzo[b][1 ]benzothiepin-5-yl)-4-methyl-piperazine was solubilized in 3.9 ml of acetic acid and cooled down to 0°C. 184 mg of sodium borohydride (4.87 mmol, 15 eq) was then added portionwise (gas emission noticed). The brown slurry was then stirred at room temperature for 16h. Sodium hydroxide 10N was then added until pH=12. The crude product was extracted three time with 10ml of ethyl acetate. The combined organic layers were washed with 10ml of water and concentrated under vacuum. The residue was purified by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ) yielding the product as a yellowish solid.

LCMS: m/z = 341 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (d, 1 H), 7.21 -7.69 (m, 4H), 7.04-7.17 (m, 1 H), 6.64 (dd, 1 H), 3.78-4.03 (m, 2H), 3.75 (s, 3H), 3.17 (dd, 1 H), 2.48-2.76 (br m, 8H), 2.32 (s, 3H)

Compound 10: 1-(1 ,2-dichloro-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)-4-methyl - piperazine

Intermediate 15: 2-[2-(2,3-dichlorophenyl)sulfanylphenyl]acetic acid

Intermediate 15 was prepared according to the procedure used for Intermediate 1 from 500 mg of 2-iodophenylacetic acid (1 .91 mmol), 376 mg of 2,3-dichlorothiophenol (2.10 mmol, 1 .1 eq), 18 mg of copper powder (0.29 mmol, 0.15 eq) and 535 mg of potassium hydroxide (9.54 mmol, 5 eq) in 12 ml of water.

585 mg of beige solid was obtained and used as a crude in the next step. Intermediate 16: 1 ,2-dichloro-6H-benzo[b][1]benzothiepin-5-one

Intermediate 16 was prepared according to the procedure used for Intermediate 2 from 550 mg of 2-[2-(2,3-dichlorophenyl)sulfanylphenyl]acetic acid (1 .76 mmol) and 5.79 g of polyphosphoric acid. Heating was performed at 120°C during 16h.

213 mg of beige solid was obtained after purification by flash chromatography on silica (from a 95:5 mixture of cyclohexane and dichloromethane to 100% dichloromethane) Compound 10: 1-(1 ,2-dichloro-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)-4-methy l- piperazine

56 μΙ of TiCI4 (0.51 mmol, 1 .5 eq) was added to a solution of 100 mg of 1 ,2-dichloro-6H- benzo[b][1 ]benzothiepin-5-one (0.34 mmol) and 188 μΙ of 1 -methylpiperazine (1 .69 mmol, 5 eq) in 1 .6 ml of toluene and the reaction mixture was stirred at 1 10°C for 16h. Sodium borohydride (5.08 mmol, 15 eq) and acetic acid (1 .45 ml) were added in five portions in 5h. The brown suspension was stirred at RT for 4 days. 10 ml of water was added dropwise to the reaction mixture and the crude product was extracted three time with 20 ml of dichloromethane, separating the organic phase with an hydrophobic membrane. The combined organic layers were washed successively with 20 ml of a saturated aqueous solution of sodium bicarbonate and 20 ml of water and concentrated under vacuum. The residue was purified by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ) yielding the product as a brown powder.

LCMS: m/z = 379 [M+H+]

1 H NMR (in CDCI3): δ 7.55 (d, 1 H), 7.43 (d, 1 H), 7.21 -7.26 (m, 3H), 7.10-7.16 (m, 1 H), 4.09 (dd, 1 H), 3.78 (t, 1 H), 3.19 (dd, 1 H), 2.54-2.74 (br m, 8H), 2.34 (s, 3H) Compound UJ (3^-dimethylphenylH4-(3-methyl-5,6- dihydrobenzorbiri1benzothiepin-5-yl)piperazin-1 -vHmethanone

Compound 16 was prepared according to the procedure used for Compound 8 from 38 mg of 3,4-dimethylbenzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide.

A beige powder was obtained after purification by flash chromatography on silica (from a

70/30 to a 25/75 mixture of dichloromethane and ethyl acetate)

LCMS: m/z = 443 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (br d, 1 H), 6.84-7.37 (m, 9H), 3.69-4.1 1 (br m, 4H), 3.30-3.52

(br m, 2H), 3.14 (br d, 1 H), 2.43-2.88 (br m, 4H), 2.26 (s, 9H).

Compound 13: 1-methyl-4-(3-methylsulfanyl-5,6-dihvdrobenzorb1fnbenzothiep in-5- yl)-1 ,4-diazepane First step: 36 μΙ of TiCI4 (0.33 mmol, 1 .5 eq) was added to a solution of 60 mg of 3- methylsulfanyl-6H-benzo[b][1 ]benzothiepin-5-one (0.22 mmol) and 137 μΙ of 1 - methylhomopiperazine (1 .10 mmol, 5 eq) in 1 ml of toluene and the reaction mixture was stirred at 1 10°C for 3h. Toluene was evaporated under vacuum.

Second step: The residue was dissolved in 1 .6 ml of acetic acid and 83 mg of sodium borohydride (2.20 mmol, 10 eq) was added (exotherm and gas emission noticed). The suspension was stirred at RT for 16h. Sodium hydroxide 10N was then added until pH=12. The white precipitate was filtered off and washed with 5 ml of dichloromethane. The biphasic mixture was separated and aqueous layer was extracted again with dichloromethane (2 x 3 ml). The combined organic layers were washed successively with 5 ml of a saturated aqueous solution of sodium bicarbonate and 4 ml of water and concentrated under vacuum. The residue was purified by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ) yielding the product as a beige powder.

LCMS: m/z = 371 [M+H+]

1 H NMR (in CDCI3): δ 7.67 (d, 1 H), 7.50 (d, 1 H), 7.23-7.32 (m, 3H), 7.09 (dt, 1 H), 6.95 (dd, 1 H), 3.92-4.07 (m, 2H), 3.13 (m, 1 H), 2.46-2.95 (m, 8H), 2.44 (s, 3H), 2.37 (s, 3H), 1 .82 (q, 2H)

Compound 14: 4-methyl-1-(3-methylsulfanyl-5,6-dihvdrobenzofb1fnbenzothiep in-5- vDpiperidine

Compound 14 was prepared according to the procedure used for Compound 13 from 50 mg of 3-methylsulfanyl-6H-benzo[b][1 ]benzothiepin-5-one (0.18 mmol), 30 μΙ of TiCI4

(0.28 mmol, 1 .5 eq) and 109 μΙ of 4-methylpiperidine (0.92 mmol, 5 eq) in 0.8 ml of toluene and from 35 mg of sodium borohydride (0.92 mmol, 5 eq) in 1 ml acetic acid.

A beige solid was obtained after purification by preparative LCMS.

LCMS: m/z = 356 [M+H+]

1 H NMR (in CDCI3): δ 7.63 (d, 1 H), 7.50 (dd, 1 H), 7.04-7.35 (m, 4H), 6.96 (dd, 1 H), 3.73-

4.07 (m, 2H), 2.90-3.25 (br m, 2H), 2.26-2.73 (br m, 7H), 1 .54-1 .70 (br m, 3H), 0.85-0.98

(m, 4H)

Compound 15: r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)piperazi n-1-vn- (5-methyl-3-pyridyl)methanone Compound 15 was prepared according to the procedure used for Compound 5 from 34 mg of 5-methyl-nicotinic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. An orange solid was obtained after purification by flash chromatography on silica (from a 70/30 mixture of dichloromethane and ethyl acetate to 100% of ethyl acetate)

LCMS: m/z = 430 [M+H+]

1 H NMR (in CDCI3): δ 8.46 (br m, 2H), 7.47-7.55 (m, 2H), 7.18-7.36 (m, 4H), 7.10 (dt, 1 H), 6.93 (br d, 1 H), 3.82-4.16 (br m, 4H), 3.17-3.52 (br m, 3H), 2.46-2.90 (br m, 4H), 2.37 (s, 3H), 2.28 (s, 3H).

Compound 16j N,N-dimethyl-1 -(3-methylsulfanyl-5,6- dihvdrobenzorbirnbenzothiepin-5-yl)piperidin-4-amine

Compound 16 was prepared according to the procedure used for Compound 13 from 50 mg of 3-methylsulfanyl-6H-benzo[b][1 ]benzothiepin-5-one (0.18 mmol), 30 μΙ of TiCI4 (0.28 mmol, 1 .5 eq) and 1 18 mg of 4-dimethylaminopiperidine (0.92 mmol, 5 eq) in 0.8 ml of toluene and from 35 mg of sodium borohydride (0.92 mmol, 5 eq) in 1 ml acetic acid. An orange solid was obtained after purification by preparative LCMS.

LCMS: m/z = 385 [M+H+]

1 H NMR (in CDCI3): δ 7.58 (d, 1 H), 7.50 (d, 1 H), 7.04-7.33 (m, 4H), 6.96 (dd, 1 H), 3.81 - 3.97 (m, 2H), 2.99-3.20 (m, 2H), 2.70-2.77 (m, 1 H), 2.50-2.61 (m, 1 H), 2.42 (s, 3H), 2.31 (s, 6H), 2.13 (m, 1 H), 1 .51 -1 .96 (m, 4H), 1 .37 (m, 1 H)

Compound 17: r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)piperazi n-1-vn- f3-(trifluoromethyl)phenvnmethanone

Compound 17 was prepared according to the procedure used for Compound 5 from 48 mg of 3-(trifluoromethyl)benzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of 0-(benzotriazol-1 -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. An off-white powder was obtained after purification by flash chromatography on silica (from a 70/30 to a 25/75 mixture of dichloromethane and ethyl acetate)

LCMS: m/z = 483 [M+H+] 1 H NMR (in CDCI3): δ 7.47-7.70 (m, 5H), 7.06-7.34 (m, 5H), 6.91 (br d, 1 H), 3.70-4.07 (br m, 4H), 3.36 (br m, 2H), 3.15 (br d, 1 H), 2.43-2.92 (br m, 4H), 2.27 (s, 3H).

Compound 18j 2-(4-chlorophenoxy)-1-i4-(3-methyl-5,6- dihydrobenzorbirnbenzothiepin-5-yl)piperazin-1 -vnethanone

Compound 18 was prepared according to the procedure used for Compound 5 from 23 mg of 4-chlorophenoxyacetic acid (0.13 mmol, 1 .3 eq), 56 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.17 mmol, 1 .8 eq), 59 μΙ of N,N- diisopropylethylamine (0.34 mmol 3.5 eq) and 30 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.10 mmol) in 1 ml of dimethylformamide. An off-white powder was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate)

LCMS: m/z = 479 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (d, 1 H), 7.04-7.38 (m, 7H), 6.74-6.98 (br m, 3H), 4.59-4.70 (m, 2H), 2.41 -4.37 (br m, 1 1 H), 2.27 (s, 3H)

Compound 19j 1 -ethyl-4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5- vDpiperazine

Compound 19 was prepared according to the procedure used for Compound 13 from 50 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.21 mmol), 34 μΙ of TiCI4 (0.31 mmol, 1 .5 eq) and 132 μΙ of 1 -ethylpiperazine (1 .04 mmol, 5 eq) in 0.8 ml of toluene. The reaction mixture was stirred at 75°C for 4h. The second step was performed with 39 mg of sodium borohydride (1 .04 mmol, 5 eq) in 1 ml acetic acid.

A yellow powder was obtained after purification by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ),

LCMS: m/z = 339 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.38 (d, 1 H), 7.16-7.32 (m, 3H), 7.07 (dt, 1 H), 6.87 (dd, 1 H), 3.83-4.02 (m, 2H), 3.17 (dd, 1 H), 2.37-2.82 (br m, 10H), 2.26 (s, 3H), 1 .09 (t, 3H)

Compound 20: 1-isopropyl-4-(3-methyl-5,6-dihvdrobenzorbiri1benzothiepin-5 - vDpiperazine Compound 20 was prepared according to the procedure used for Compound 13 from 40 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.17 mmol), 27 μΙ of TiCI4 (0.25 mmol, 1 .5 eq) and 107 mg of 1 -isopropylpiperazine (0,83 mmol, 5 eq) in 0.7 ml of toluene. The reaction mixture was stirred at 75°C for 4h. The second step was performed with 31 mg of sodium borohydride (0,83 mmol, 5 eq) in 0,48 ml acetic acid.

A yellow powder was obtained after purification by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ),

LCMS: m/z = 353 [M+H+]

Compound 21 : N.N.N'-trimethyl-N'-O-methyl-S.B-dihvdrobenzorblfnbenzothiep in-S- yl)ethane-1 ,2-diamine

Compound 21 was prepared according to the procedure used for Compound 13 from 50 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.21 mmol), 34 μΙ of TiCI4 (0.31 mmol,

1 .5 eq) and 132 μΙ of N,N',N'-trimethylethane-1 ,2-diamine (1 .04 mmol, 5 eq) in 0.8 ml of toluene. The reaction mixture was stirred at 75°C for 5h. Second step was performed with

39 mg of sodium borohydride (1 .04 mmol, 5 eq) in 1 ml acetic acid.

A light brown oil was obtained after purification by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ).

LCMS: m/z = 327 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (dd, 1 H), 7.41 (d, 1 H), 7.16-7.30 (m, 3H), 7.06 (dt, 1 H), 6.85 (dd, 1 H), 3.91 -4.07 (m, 2H), 3.01 -3.16 (m, 1 H), 2.65-2.72 (m, 2H), 2.36-2.47 (m, 5H), 2.24 (s, 3H), 2.19 (s, 6H)

Compound 22: (3.5-dimethylphenylH4-(3-methyl-5.6- dihvdrobenzorbirilbenzothiepin-5-yl)piperazin-1 -yllmethanone Compound 22 was prepared according to the procedure used for Compound 5 from 38 mg of 3,5-dimethylbenzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. An off-white powder was obtained after purification by flash chromatography on silica (from a 70/30 to a 25/75 mixture of dichloromethane and ethyl acetate) LCMS: m/z = 443 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (d, 1 H), 6.84-7.37 (m, 9H), 3.65-4.06 (m, 4H), 3.38 (br m, 2H), 3.14 (br d, 1 H), 2.40-2.84 (br m, 4H), 2.31 (s, 6H), 2.17 (s, 3H). Compound 23: N,N,N'-trimethyl-N'-(3-methyl-5,6-dihvdrobenzorbirnbenzothie pin-5- yl)propane-1 ,3-diamine

Compound 23 was prepared according to the procedure used for Compound 21 from 50 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.21 mmol), 34 μΙ of TiCI4 (0.31 mmol, 1 .5 eq) and 152 μΙ of N,N,N'-Trimethyl-1 ,3-propanediamine (1 .04 mmol, 5 eq) in 0.8 ml of toluene and from 39 mg of sodium borohydride (1 .04 mmol, 5 eq) in 1 ml acetic acid. A light brown oil was obtained after purification by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ),

LCMS: m/z = 341 [M+H+]

1 H NMR (in CDCI3): δ 7.51 (dd, 1 H), 7.41 (d, 1 H), 7.17-7.30 (m, 3H), 7.07 (dt, 1 H), 6.86 (dd, 1 H), 3.89-4.08 (m, 2H), 2.97-3.13 (m, 1 H), 2.49-2.72 (m, 2H), 2.1 1 -2.45 (m, 14H), 1 .66 (qt, 2H) Compound 24: 3-r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)pipera zin-1- yllpropanenitrile

Compound 24 was prepared according to the procedure used for Compound 21 from 50 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.21 mmol), 34 μΙ of TiCI4 (0.31 mmol, 1 .5 eq) and 145 mg of 3-piperazinopropionitrile (1 .04 mmol, 5 eq) in 0.8 ml of toluene and from 39 mg of sodium borohydride (1 .04 mmol, 5 eq) in 1 ml acetic acid.

An orange powder was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate).

LCMS: m/z = 364 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.17-7.36 (m, 4H), 7.07 (dt, 1 H), 6.89 (dd, 1 H), 3.82-

4.07 (m, 2H), 3.16 (br dd, 1 H), 2.41 -2.86 (br m, 10H), 2.27 (s, 3H), 1 .25-1 .30 (m, 2H)

Compound 25: 2-methyl-1 -r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5- yl)piperazin-1-vnpropan-1 -one Compound 25 was prepared according to the procedure used for Compound 5 from 24 μΙ of isobutyric acid (0.26 mmol, 1 .3 eq), 1 14 mg of 0-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 120 μΙ of N,N- diisopropylethylamine (0.69 mmol 3.5 eq) and 61 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.20 mmol) in 1 ml of dimethylformamide. A red solid was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate)

LCMS: m/z = 381 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (d, 1 H), 7.17-7.36 (m, 4H), 7.08 (dt, 1 H), 6.90 (d, 1 H), 3.82- 4.05 (m, 2H), 3.35-3.71 (m, 4H), 3.13 (d, 1 H), 2.45-2.85 (m, 5H), 2.27 (s, 3H), 1 .10 (d, 6H).

Compound 26: 1-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)-4-phenyl - piperazine

Compound 26 was prepared according to the procedure used for Compound 19 from 50 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.21 mmol), 34 μΙ of TiCI4 (0.31 mmol, 1 .5 eq) and 169 mg of 1 -phenylpiperazine (1 .04 mmol, 5 eq) in 0.8 ml of toluene and from 39 mg of sodium borohydride (1 .04 mmol, 5 eq) in 1 ml acetic acid.

An orange powder was obtained after purification by flash chromatography on silica (from 100% dichloromethane to a 85/15 mixture of dichloromethane and methanol) , .

LCMS: m/z = 387 [M+H+]

1 H NMR (in CDCI3): δ 7.52 (dd, 1 H), 7.43 (m, 1 H), 7.18-7.36 (m, 5H), 7.10 (dt, 1 H), 6.82- 6.96 (m, 4H), 3.87-4.1 1 (m, 2H), 3.10-3.34 (m, 5H), 2.70-3.00 (m, 4H), 2.27 (s, 3H)

Compound 27j 1 -(3-methyl-5,6-dihvdrobenzorb1H 1benzothiepin-5-yl)-4-(2- pyridvDpiperazine

Compound 27 was prepared according to the procedure used for Compound 13 from 40 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.17 mmol), 27 μΙ of TiCI4 (0.25 mmol, 1 .5 eq) and 136 mg of 1 -(2-pyridyl)piperazine (0.83 mmol, 5 eq) in 0.7 ml of toluene. The reaction mixture was stirred at 90°C for 4h. Second step was performed with 31 mg of sodium borohydride (0.83 mmol, 5 eq) in 0.9 ml acetic acid.

An orange solid was obtained after purification by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ), LCMS: m/z = 388 [M+H+]

1 H NMR (in CDCI3): δ 8.18 (m, 1 H), 7.42-7.52 (m, 3H), 7.17-7.35 (m, 3H), 7.08 (dt, 1 H), 6.90 (dd, 1 H), 6.57-6.65 (m, 2H), 3.44-4.1 1 (m, 6H), 3.19 (dd, 1 H), 2.58-2.87 (m, 4H), 2.27 (s, 3H)

Compound 28: 1-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)-4-(m- tolylmethvDpiperazine

Compound 28 was prepared according to the procedure used for Compound 19 from 50 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.21 mmol), 34 μΙ of TiCI4 (0.31 mmol, 1 .5 eq) and 198 mg of 1 -(3-methylbenzyl)piperazine (1 .04 mmol, 5 eq) in 0.8 ml of toluene and from 39 mg of sodium borohydride (1 .04 mmol, 5 eq) in 1 ml acetic acid.

A white solid was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate).

LCMS: m/z = 415 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.39 (d, 1 H), 7.03-7.32 (m, 8H), 6.87 (dd, 1 H), 3.82- 4.01 (m, 2H), 3.48 (s, 2H), 3.17 (dd, 1 H), 2.40-2.80 (m, 8H), 2.35 (s, 3H), 2.27 (s, 3H)

Compound 29: 1-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)-4-pyrrol idin-1 - yl-piperidine

Compound 29 was prepared according to the procedure used for Compound 19 from 50 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.21 mmol), 34 μΙ of TiCI4 (0.31 mmol, 1 .5 eq) and 161 mg of 4-(1 -pyrrolidinyl)piperidine (1 .04 mmol, 5 eq) in 0.8 ml of toluene. The reaction mixture was stirred at 75°C for 3h for the first step. The second step was performed with 39 mg of sodium borohydride (1 .04 mmol, 5 eq) in 1 ml acetic acid and the reaction mixture was stirred for 1 h at RT.

A yellow powder was obtained after purification by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 85/15/1 ),

1 H NMR (in CDCI3): δ 7.48-7.52 (m, 2H), 7.17-7.29 (m, 3H), 7.07 (dt, 1 H), 6.87 (dd, 1 H), 3.77-3.97 (m, 2H), 2.90-3.18 (br m, 2H), 2.44-2.75 (br m, 6H), 2.30-2.37 (m, 1 H), 2.22 (s, 3H), 1 .30-2.04 (br m, 9H).

Compound 30: 1 -r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)piperaz in-1 - νΠ-2-phenyl-ethanone Compound 30 was prepared according to the procedure used for Compound 5 from 29 mg of phenylacetic acid (0.21 mmol, 1 .3 eq), 93 mg of 0-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.29 mmol, 1 .8 eq), 98 μΙ of N,N- diisopropylethylamine (0.56 mmol 3.5 eq) and 50 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.16 mmol) in 1 ml of tetrahydrofurane + 5 drops of dimethylformamide.

A light brown powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 6/4 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 429 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.16-7.36 (m, 9H), 7.08 (dt, 1 H), 6.90 (dd, 1 H), 3.54-

4.04 (m, 6H), 3.25-3.49 (m, 2H), 3.07 (dd, 1 H), 2.31 -2.67 (m, 4H), 2.25 (s, 3H)

Compound 31 : N.N-diethyl-l -O-methyl-S.B-dihydrobenzorbirnbenzothiepin-S- yl)piperidin-4-amine

Compound 31 was prepared according to the procedure used for Compound 29 from 50 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.21 mmol), 34 μΙ of TiCI4 (0.31 mmol,

1 .5 eq) and 163 mg of 4-diethylamino-piperidine (1 .04 mmol, 5 eq) in 0.8 ml of toluene and from 39 mg of sodium borohydride (1 .04 mmol, 5 eq) in 1 ml acetic acid.

An off-white powder was obtained after purification by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 85/15/1 ).

1 H NMR (in CDCI3): δ 7.50 (dd, 1 H), 7.42 (d, 1 H), 7.16-7.30 (m, 3H), 7.07 (dt, 1 H), 6.88 (dd, 1 H), 3.83-3.99 (m, 2H), 3.01 -3.19 (m, 2H), 2.44-2.78 (m, 7H), 2.29-2.36 (m, 1 H), 2.26 (s, 3H), 1 .35-1 .90 (m, 4H), 1 .05 (t, 6H).

Compound 32: N.N-dimethyl-l -O-methyl-S.B-dihvdrobenzorbirnbenzothiepin-S- yl)pyrrolidin-3-amine

Compound 32 was prepared according to the procedure used for Compound 13 from 40 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.17 mmol), 27 μΙ of TiCI4 (0.25 mmol, 1 .5 eq) and 107 mg of N,N-dimethylpyrrolidine-3-amine (0,83 mmol, 5 eq) in 0.7 ml of toluene. The reaction mixture was stirred at 80°C for 4h. The second step was performed with 31 mg of sodium borohydride (0,83 mmol, 5 eq) in 0,48 ml acetic acid. An oily residue crystalizing on standing was obtained after purification by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ).

LCMS: m/z = 339 [M+H+]

Compound 33: tert-butyl 4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)-1 ,4- diazepane-1 -carboxylate

Compound 33 was prepared according to the procedure used for Compound 2 from 68 μΙ of TiCI4 (0.62 mmol, 1 .5 eq), 100 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.42 mmol) and 1 .16 g of 1 -N-Boc-piperazine (2.08 mmol, 5 eq) in 1 .6 ml of toluene. The reaction mixture was stirred at 75°C for 4h. The next step was performed with 79 mg of sodium borohydride (2.08 mmol, 5 eq) in 2 ml of acetic acid.

An orange powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 25/75 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 425 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (m, 2H), 7.05-7.31 (m, 4H), 6.87 (d, 1 H), 3.93-4.07 (m, 2H), 2.69-3.57 (m, 9H), 2.26 (s, 3H), 1 .71 (br m, 2H), 1 .47 (s, 9H) Compound 34: 1 -(3-methyl-5,6-dihvdrobenzoib1H 1benzothiepin-5-yl)-1 ,4-diazepane

Compound 34 was prepared according to the procedure used for Compound 3 from 120 mg of tert-butyl 4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-1 ,4-diazepane-1 - carboxylate (0.28 mmol) and 1 .41 ml of a solution of HCI 4N in dioxane in 2 ml of dioxane. The suspension was stirred for 3h at RT.

A light yellow powder was obtained.

LCMS: m/z = 325 [M+H+]

1 H NMR (in CDCI3): δ 7.49-7.53 (m, 2H), 7.18-7.30 (m, 3H), 7.08 (dt, 1 H), 6.88 (dd, 1 H), 3.92-4.10 (m, 2H), 2.67-3.25 (m, 9H), 2.27 (s, 3H), 1 .70-1 .92 (m, 2H).

Compound 35: r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)piperazi n-1-vn- (3-methylsulfonylphenyl)methanone

Compound 35 was prepared according to the procedure used for Compound 5 from 50 mg of 3-(methylsulfonyl)benzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of 0-(benzotriazol-1 -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. A yellowish powder was obtained after purification by flash chromatography on silica (from a 70/30 mixture of cyclohexane and ethyl acetate to 100% of ethyl acetate)

LCMS: m/z = 493 [M+H+], 556 [M+ACN+Na+], 985 [2M+H]

1 H NMR (in CDCI3): δ 7.97-8.01 (m, 2H), 7.59-7.70 (m, 2H), 7.50 (br d, 1 H), 6.88-7.35 (m, 6H), 3.70-4.07 (br m, 4H), 3.34 (br m, 2H), 3.14 (br d, 1 H), 3.07 (s, 3H), 2.43-2.92 (br m, 4H), 2.28 (s, 3H). Compound 36j 1-r2-(4-methoxyphenyl)ethyl1-4-(3-methyl-5.6- dihvdrobenzorbiri1benzothiepin-5-yl)piperazine

Intermediate 19: 2-(4-methoxyphenyl)-1-[4-(3-methyl-5,6- dihydrobenzo[b][1]benzothiepin-5-yl)piperazin-1 -yl]-ethanone

A solution of 35 mg of 4-methoxyphenylacetic acid (0.21 mmol, 1 .3 eq), 93 mg of O- (benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.29 mmol, 1 .8 eq) and 98 μΙ of N,N-diisopropylethylamine (0.56 mmol 3.5 eq) in 1 ml of dimethylformamide was stirred at RT for 15 mn. 50 mg of 1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazine (0.16 mmol) was added and the reaction mixture was stirred for 4h. 3 ml of a saturated aqueous solution of sodium bicarbonate was added and the product was extracted three times with 5 ml of dichloromethane. The combined organic layers were washed successively with 5 ml of a saturated aqueous solution of sodium bicarbonate and 5 ml of water and concentrated to dryness. The residue was purified by flash chromatography on silica (from a 95/5 to a 5/95 mixture of cyclohexane and ethyl acetate) yielding 46 mg of light yellow powder.

LCMS: m/z = 459 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (d, 1 H), 7.03-7.32 (m, 7H), 6.82-6.91 (m, 3H), 3.60-4.01 (m, 9H), 3.27-3.49 (m, 2H), 3.07 (dd, 1 H), 2.31 -2.67 (m, 4H), 2.25 (s, 3H)

Compound 36: 1-[2-(4-methoxyphenyl)ethyl]-4-(3-methyl-5,6- dihydrobenzo[b][1]benzothiepin-5-yl)piperazine

A solution of 20 mg of 2-(4-methoxyphenyl)-1 -[4-(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-ethanone (0.044 mmol) in 0.5 ml of tetrahydrofurane was slowly added to a suspension of 17 mg of LJAIH4 (0.44 mmol, 10 eq) and the resulting mixture was stirred at 60°C for 4h. The reaction mixture was cooled to RT and a solution of NaOH 2N was slowly added until pH=12. The resulting solution was stirred for 10 min at RT. The product was extracted three times with 3 ml of dichloromethane. The combined organic layers were washed successively with 4 ml of a saturated aqueous solution of sodium bicarbonate and 3 ml of water and concentrated to dryness. The residue was purified by flash chromatography on silica (from 100% of cyclohexane to 100% of a mixture of cyclohexane/ethyl acetate/triethylamine 50/50/1 ) yielding the product as a light brown powder.

1 H NMR (in CDCI3): δ 7.50 (dd, 1 H), 7.38 (d, 1 H), 7.24-7.33 (m, 2H), 7.03-7.21 (m, 4H), 6.79-6.90 (m, 3H), 3.84-4.03 (m, 2H), 3.79 (s, 3H), 3.19 (dd, 1 H), 2.47-2.87 (m, 12H), 2.26 (s, 3H)

Compound 37: r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)piperazi n-1-vn- (o-tolyl)methanone

Compound 37 was prepared according to the procedure used for Compound 5 from 35 mg of 2-methylbenzoic acid (0.26 mmol, 1 .3 eq), 1 14 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 120 μΙ of N,N- diisopropylethylamine (0.69 mmol 3.5 eq) and 61 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.20 mmol) in 1 ml of dimethylformamide. A white powder was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate)

LCMS: m/z = 429 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (d, 1 H), 7.02-7.36 (m, 9H), 6.92 (br m, 1 H), 3.70-4.10 (br m, 4H), 3.02-3.31 (br m, 3H), 2.40-2.90 (br m, 4H), 2.17-2.31 (br m, 6H).

Compound 38: 1 -methyl-N-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5- yl)piperidin-4-amine Intermediate 20: 3-methyl-5,6-dihydrobenzo[b][1]benzothiepin-5-ol

55 mg of sodium borohydride (1 .46 mmol, 3.5 eq) was added by portions to a solution of 100 mg of 3-methyl-6H-benzo[b][1 ]benzothiepin-5-one (0.42 mmol) in 2 ml of ethanol and 0.2 ml of water and the reaction mixture was stirred at reflux for 1 h. Ethanol was evaporated under vacuum, 2 ml of water was added and the product was extracted three times with 3 ml of dichloromethane. The combined organic layers were washed with 5 ml of an aqueous solution of HCI 4N and concentrated to dryness, yielding 95 mg of yellow oil used as a crude in the next step.

Intermediate 21 : 5-chloro-3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepine

244 μΙ of thionyl chloride (3.34 mmol, 9 eq) was slowly added to a solution of 90 mg of 3- methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-ol (0.37 mmol) in 1 ml of dichloromethane and the reaction mixture was stirred ar RT for 16h. 500 μΙ of thionyl chloride (6.87 mmol, 18.5 eq) was added again and the reaction mixture was stirred at 35°C for 4h. Thionyl chloride was removed by azeotropic distillation with toluene under vacuum and the residue was dried under vacuum yielding 105 mg of a dark gum used as a crude in the next step.

Compound 38: 1 -methyl-N-(3-methyl-5,6-dihydrobenzo[b][1]benzothiepin-5- yl)piperidin-4-amine

A solution of 30 mg of 5-chloro-3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepine (0.12 mmol) and 80 mg of 4-amino-1 -methylpiperidine (0.70 mmol, 6.1 eq) was stirred at 1 10°C in a sealed vial for 45 min. 3 ml of a saturated aqueous solution of sodium bicarbonate was added and the product was extracted three times with 3 ml of dichloromethane. The combined organic layers were washed successively with 5 ml of a saturated aqueous solution of sodium bicarbonate and 4 ml of water and concentrated to dryness. The residue was purified by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ) yielding the product as a brown solid.

LCMS: m/z = 339 [M+H+]

1 H NMR (in CDCI3): δ 7.36-7.51 (m, 4H), 6.96-7.19 (br m, 3H), 2.90-3.61 (br m, 7H), 2.69 (s, 3H), 2.03-2.50 (m, 8H) Compound 39: 1-r4-(3-ethyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)piperaz in-1-vn- 2-methyl-propan-1 -one

Intermediate 22: 2-[2-(4-ethylphenyl)sulfanylphenyl]acetic acid 500 mg of 2-iodophenylacetic acid (1 .91 mmol), 290 mg of 4-ethylthiophenol (2.10 mmol, 1 .1 eq), 36 mg of copper powder (0.57 mmol, 0.30 eq) and 535 mg of potassium hydroxide (9.54 mmol, 5 eq) were mixed in 3 ml of water and stirred for 3h at 100°C in a sealed vial. 36 mg of copper iodide (0.19 mmol, 0.1 eq) was added and the reaction mixture was stirred at 100°C for 16h in a sealed vial. 36 mg of copper iodide (0.19 mmol, 0.1 eq) was added again and the reaction mixture was stirred at 100°C for 7h in a sealed vial. The reaction mixture was filtered. The mother liquors were acidified to pH = 2 with concentrated HCI and extracted three times with 20 ml of dichloromethane. The organic phases were separated with an hydrophobic membrane, further washed with 20ml of 1 N HCI and concentrated to dryness, yielding 430 mg of yellow solid and used as a crude in the next step.

LCMS: m/z = 290 [M+NH4+], 567 [2M+Na+]

Intermediate 23: 3-isopropyl-6H-benzo[b][1]benzothiepin-5-one

Intermediate 23 was prepared according to the procedure used for Intermediate 5 from 400 mg of 2-[2-(4-ethylphenyl)sulfanylphenyl]acetic acid (1 .47 mmol), 186 μΙ of oxalyl chloride (2.20 mmol, 1 .5 eq) in 4 ml of dichloromethane and 587 mg of aluminium chloride (4.41 mmol, 3 eq) in 5 ml of dichloromethane.

166 mg of an orange oil was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% of ethyl acetate)

LCMS: m/z = 254 [M+H+]

Intermediate 24: tert-butyl 4-(3-ethyl-5,6-dihydrobenzo[b][1]benzothiepin-5- yl)piperazine-1-carboxylate Intermediate 24 was prepared according to the procedure used for compound 2 from 354 μΙ of a solution of TiCI4 1 M in toluene (0.35 mmol, 1 .5 eq), 60 mg of 3-isopropyl-6H- benzo[b][1 ]benzothiepin-5-one (0.24 mmol) and 220 mg of 1 -N-Boc-piperazine (1 .18 mmol, 5 eq) in 0.6 ml of toluene and from 45 mg of sodium borohydride (1 .18 mmol, 5 eq) in 1 ml of acetic acid. Reduction was made during 16h at RT.

100 mg of a dark gum was isolated and used as a crude in the next step.

LCMS: m/z = 425 [M+H+]

Intermediate 25: 1-(3-ethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine 1 .71 ml of a solution of HCI 4N in dioxane (6.84 mmol, 30 eq) was added to a solution of 100 mg of tert-butyl 4-(3-ethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine-1 - carboxylate (0.23 mmol) in 2.5 ml of dichloromethane and the suspension was stirred for 20h. The reaction mixture was basified with a solution of NaOH 10N. Product was extracted three times with 5 ml of dichloromethane. The combined organic layers were washed successively with 5 ml of a saturated aqueous solution of sodium bicarbonate and 3 ml of water and concentrated to dryness, yielding 76 mg of orange oil and used as a crude in the next step.

LCMS: m/z = 325 [M+H+]

Compound 39: 1-[4-(3-ethyl-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)pipera zin-1-yl]- 2-methyl-propan-1-one

Compound 39 was prepared according to the procedure used for Compound 5 from 28 μΙ of isobutyric acid (0.30 mmol, 1 .3 eq), 135 mg of 0-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.42 mmol, 1 .8 eq), 143 μΙ of N,N- diisopropylethylamine (0.82 mmol 3.5 eq) and 76 mg of 1 -(3-ethyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.23 mmol) in 1 ml of dimethylformamide.

An orange powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 45/55 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 395 [M+H+]

1 H NMR (in CDCI3): δ 7.51 (br d, 1 H), 7.18-7.41 (m, 4H), 7.09 (br t, 1 H), 6.93 (br d, 1 H),

3.81 -4.07 (m, 2H), 3.31 -3.70 (m, 4H), 3.13 (br d, 1 H), 2.50-2.83 (m, 7H), 1 .09-1 .25 (m,

9H)

Compound 40: 2-r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)pipera zin-1- yllethanol

A solution of 30 mg of 5-chloro-3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepine (0.12 mmol) and 150 mg of 1 -piperazineethanol (1 .15 mmol, 10 eq) in 0.3 ml of chloroform was stirred at 75°C in a sealed vial for 3h. 3 ml of a saturated aqueous solution of sodium bicarbonate was added and the product was extracted three times with 3 ml of dichloromethane. The combined organic layers were washed successively with 5 ml of a saturated aqueous solution of sodium bicarbonate and 4 ml of water and concentrated to dryness. The residue was purified by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ) yielding the product as a yellowish solid.

LCMS: m/z = 355 [M+H+] 1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.17-7.37 (m, 4H), 7.08 (dt, 1 H), 6.89 (dd, 1 H), 3.81 - 4.03 (m, 2H), 3.69 (t, 2H), 3.18 (dd, 1 H), 2.99 (br s, 1 H), 2.58-2.87 (br m, 10H), 2.27 (s, 3H). Compound 41 : 2-methyl-1-f4-(3-methylsulfanyl-5,6-dihvdrobenzofb1fnbenzoth iepin- 5-yl)piperazin-1 -yllpropan-1 -one

Compound 41 was prepared according to the procedure used for Compound 5 from 23 μΙ of isobutyric acid (0.25 mmol, 1 .3 eq), 1 1 1 mg of 0-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 17 μΙ of N,N- diisopropylethylamine (0.67 mmol 3.5 eq) and 66 mg of 1 -(3-methylsulfanyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. An orange solid was obtained after purification by flash chromatography on silica (from a 95/5 to a 45/55 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 413 [M+H+]

1 H NMR (in CDCI3): δ 7.49-7.53 (m, 2H), 7.19-7.36 (m, 3H), 7.1 1 (br t, 1 H), 6.98 (br d, 1 H), 3.80-4.04 (m, 2H), 3.33-3.68 (br m, 4H), 3.1 1 (dd, 1 H), 2.57-2.84 (br m, 5H), 2.43 (s, 3H), 1 .1 1 (d, 6H) Compound 42j 1 -r4-(1 ,3-dimethyl-5,6-dihydrobenzorb1H1benzothiepin-5- yl)piperazin-1-vn-2-methyl-propan-1 -one

Intermediate 26: 2-[2-(2,4-dimethylphenyl)sulfanylphenyl]acetic acid Intermediate 26 was prepared according to the procedure used for Intermediate 9 from 500 mg of 2-iodophenylacetic acid (1 .91 mmol), 290 mg of 2,4-dimethylthiophenol (2.10 mmol, 1 .1 eq), 109 mg of copper iodide (0.57 mmol, 0.30 eq) and 535 mg of potassium hydroxide (9.54 mmol, 5 eq) in 3 ml of water. The reaction was stirred for one week at 100°C.

237 mg of a white solid was obtained after purification by flash chromatography on silica (from a 95/5 to a 50/50 mixture of cyclohexane and a mixture of cyclohexane/ethyl acetate acetic acid 50/50/1 ).

LCMS: m/z = 290 [M+NH4+], 314 [M+ACN+H+], 567 [2M+Na+], 583 [2M+K+]

Intermediate 27: 1 ,3-dimethyl-6H-benzo[b][1]benzothiepin-5-one Intermediate 27 was prepared according to the procedure used for Intermediate 5 from 230 mg of 2-[2-(2,4-dimethylphenyl)sulfanylphenyl]acetic acid (0.84 mmol), 107 μΙ of oxalyl chloride (1 .27 mmol, 1 .5 eq) in 3 ml of dichloromethane and 338 mg of aluminium chloride (2.53 mmol, 3 eq) in 5 ml of dichloromethane.

149 mg of a yellowish solid was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and dichloromethane to 100% of dichloromethane)

Intermediate 28: tert-butyl 4-(1 ,3-dimethyl-5,6-dihydrobenzo[b][1]benzothiepin-5- yl)piperazine-1-carboxylate

Intermediate 28 was prepared according to the procedure used for Compound 2 from 354 μΙ of a solution of TiCI4 1 M in toluene (0.35 mmol, 1 .5 eq), 60 mg of 1 ,3-dimethyl-6H- benzo[b][1 ]benzothiepin-5-one (0.24 mmol) and 220 mg of 1 -N-Boc-piperazine (1 .18 mmol, 5 eq) in 0.6 ml of toluene and from 45 mg of sodium borohydride (1 .18 mmol, 5 eq) in 1 ml of acetic acid.

100 mg of a beige solid was isolated and used as a crude in the next step.

LCMS: m/z = 425 [M+H+] Intermediate 29: 1-(1 ,3-dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

Intermediate 29 was prepared according to the procedure used for Compound 3 from 1 .77 ml of a solution of HCI 4N in dioxane (7.07 mmol, 30 eq) and 100 mg of tert-butyl 4-(1 ,3- dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine-1 -carboxylate (0.24 mmol) in 2.5 ml of dichloromethane

70 mg of an orange oil was isolated and used as a crude in the next step.

LCMS: m/z = 325 [M+H+]

Compound 42 : 1 -[4-(1 ,3-dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazin-1-yl]-2-methyl-propan-1 -one

Compound 42 was prepared according to the procedure used for Compound 9 from 26 μΙ of isobutyric acid (0.28 mmol, 1 .3 eq), 125 mg of 0-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.39 mmol, 1 .8 eq), 132 μΙ of N,N- diisopropylethylamine (0.76 mmol 3.5 eq) and 70 mg of 1 -(1 ,3-dimethyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.22 mmol) in 1 ml of dimethylformamide. A light brown powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 45/55 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 395 [M+H+]

1 H NMR (in CDCI3): δ 7.47 (br d, 1 H), 7.01 -7.31 (m, 4H), 6.88 (br m, 1 H), 4.15-4.23 (m, 1 H), 3.43-3.79 (br m, 5H), 3.22 (dd, 1 H), 2.52-2.84 (br m, 5H), 2.49 (s, 3H), 2.23 (s, 3H), 1 .09 (d, 6H)

Compound 43: 3-r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)pipera zine-1- carbonyllbenzonitrile

Compound 43 was prepared according to the procedure used for Compound 5 from 37 mg of 3-cyanobenzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. A yellowish powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 25/75 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 440 [M+H+]

1 H NMR (in CDCI3): δ 7.49-7.72 (m, 5H), 6.90-7.35 (m, 6H), 3.70-4.07 (br m, 4H), 3.36 (br m, 2H), 3.15 (br d, 1 H), 2.43-2.92 (br m, 4H), 2.28 (s, 3H).

Compound 44j 2-(4-methoxyphenyl)-1 -i4-(3-methyl-5,6- dihydrobenzorbiri1benzothiepin-5-yl)piperazin-1 -yl1-ethanone Compound 44 was prepared according to the procedure used for Compound 9 from 35 mg of 4-methoxyphenylacetic acid (0.21 mmol, 1 .3 eq), 93 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.29 mmol, 1 .8 eq), 98 μΙ of N,N- diisopropylethylamine (0.56 mmol 3.5 eq) and 50 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.16 mmol) in 1 ml of dimethylformamide. A light yellow powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 5/95 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 459 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (d, 1 H), 7.03-7.32 (m, 7H), 6.82-6.91 (m, 3H), 3.60-4.01 (m, 9H), 3.27-3.49 (m, 2H), 3.07 (dd, 1 H), 2.31 -2.67 (m, 4H), 2.25 (s, 3H) Compound 45: 2-r2-r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)pip erazin-

1 -yllethoxylethanol

Compound 45 was prepared according to the procedure used for Compound 40 from 40 mg of 5-chloro-3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepine (0.15 mmol) and 267 mg of 1 -[2-(2-hydroxyethoxy)ethyl]piperazine (1 .53 mmol, 10 eq) in 0.4 ml of chloroform.

An orange solid was obtained after purification by flash chromatography on silica (from 100% dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90/10/1 ),

LCMS: m/z = 399 [M+H+]

1 H NMR (in CDCI3): δ 7.48 (dd, 1 H), 7.38 (d, 1 H), 7.20-7.31 (m, 3H), 7.08 (dt, 1 H), 6.89 (dd, 1 H), 3.81 -4.02 (m, 2H), 3.59-3.78 (m, 6H), 3.18 (dd, 1 H), 2.99 (br s, 1 H), 2.58-2.87 (br m, 10H), 2.26 (s, 3H). Compound 46: (3-chlorophenyl)-r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothie pin-5- yl)piperazin-1-vnmethanone

Compound 46 was prepared according to the procedure used for Compound 5 from 39 mg of 3-chlorobenzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide.

A light orange powder was obtained after purification by flash chromatography on silica

(from a 95/5 to a 50/50 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 449 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (br d, 1 H), 6.88-7.37 (m, 10H), 3.69-4.05 (br m, 4H), 3.36 (br m, 2H), 3.15 (br d, 1 H), 2.43-2.88 (br m, 4H), 2.28 (s, 3H).

Compound 47: 1-isobutyl-4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5- vDpiperazine

Intermediate 30: 2-methyl-1-[4-(3-methyl-5,6-dihydrobenzo[b][1]benzothiepin-5 - yl)piperazin-1-yl]propan-1 -one Intermediate 30 was prepared according to the procedure used for Intermediate 19from 24 μΙ of isobutyric acid (0.26 mmol, 1 .3 eq), 1 14 mg of 0-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 120 μΙ of N,N- diisopropylethylamine (0.69 mmol 3.5 eq) and 61 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.20 mmol) in 1 ml of dimethylformamide. The reaction mixture was stirred at RT for 16h.

45 mg of a red solid was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate)

LCMS: m/z = 381 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (d, 1 H), 7.17-7.36 (m, 4H), 7.08 (dt, 1 H), 6.90 (d, 1 H), 3.82- 4.05 (m, 2H), 3.35-3.71 (m, 4H), 3.13 (d, 1 H), 2.45-2.85 (m, 5H), 2.27 (s, 3H), 1 .10 (d, 6H).

Compound 47: 1-isobutyl-4-(3-methyl-5,6-dihydrobenzo[b][1]benzothiepin-5- yl)piperazine Compound 47 was prepared according to the procedure used for Compound 36 from 25 mg of 2-methyl-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]propan-1 -one (0.066 mmol) in 0.5 ml of tetrahydrofurane and 25 mg of LiAIH4 (0.66 mmol, 10 eq) in 0.5 ml of tetrahydrofurane.

A yellow oil was obtained after purification by flash chromatography on silica (from 100% of cyclohexane to 100% of a mixture of cyclohexane/ethyl acetate/triethylamine 50/50/1 ).. LCMS: m/z = 367 [M+H+]

1 H NMR (in CDCI3): δ 7.48 (dd, 1 H), 7.41 (d, 1 H), 7.16-7.32 (m, 3H), 7.07 (dt, 1 H), 6.88 (dd, 1 H), 3.78-4.00 (m, 2H), 3.17 (dd, 1 H), 2.33-2.79 (br m, 8H), 2.26 (s, 3H), 2.1 1 (d, 2H), 1 .79 (m, 1 H), 0.90 (d, 6H).

Compound 48j 1 -r4-(2,3-dimethyl-5,6-dihvdrobenzorb1H lbenzothiepin-5- yl)piperazin-1-vn-2-methyl-propan-1 -one

Intermediate 31 : 2-[2-(2,3-dimethylphenyl)sulfanylphenyl]acetic acid

Intermediate 31 was prepared according to the procedure used for Intermediate 19 from 500 mg of 2-iodophenylacetic acid (1 .91 mmol), 283 μΙ of 3,4-dimethylthiophenol (2.10 mmol, 1 .1 eq), 109 mg of copper iodide (0.57 mmol, 0.30 eq) and 535 mg of potassium hydroxide (9.54 mmol, 5 eq) in 3 ml of water. 1 week stirring at 100°C and addition of 2 x 12.1 mg of copper powder (0.19 mmol, 0.1 eq) and 129 μΙ of 3,4-dimethylthiophenol (0.95 mmol, 0.5 eq) were performed. 455 mg of a light brown solid was isolated and used as a crude in the next step.

LCMS: m/z = 290 [M+NH4+], 567 [2M+Na+]

Intermediate 32: 2,3-dimethyl-6H-benzo[b][1]benzothiepin-5-one

Intermediate 32 was prepared according to the procedure used for Intermediate 5 from 450 mg of 2-[2-(2,3-dimethylphenyl)sulfanylphenyl]acetic acid (1 .65 mmol), 210 μΙ of oxalyl chloride (2.48 mmol, 1 .5 eq) in 4.5 ml of dichloromethane and 661 mg of aluminium chloride (4.96 mmol, 3 eq) in 7 ml of dichloromethane.

200 mg of a yellowish solid was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and dichloromethane to 100% of dichloromethane)

Intermediate 33: tert-butyl 4-(2,3-dimethyl-5,6-dihydrobenzo[b][1]benzothiepin-5- yl)piperazine-1-carboxylate

Intermediate 33 was prepared according to the procedure used for Compound 2 from 354 μΙ of a solution of TiCI4 1 M in toluene (0.35 mmol, 1 .5 eq), 60 mg of 2,3-dimethyl-6H- benzo[b][1 ]benzothiepin-5-one (0.24 mmol) and 220 mg of 1 -N-Boc-piperazine (1 .18 mmol, 5 eq) in 0.6 ml of toluene and from 45 mg of sodium borohydride (1 .18 mmol, 5 eq) in 1 ml of acetic acid.

100 mg of a beige solid was isolated and used as a crude in the next step.

LCMS: m/z = 425 [M+H+] Intermediate 34: 1-(2,3-dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine

Intermediate 34 was prepared according to the procedure used for Compound 3 from 1 .77 ml of a solution of HCI 4N in dioxane (7.07 mmol, 30 eq) and 100 mg of tert-butyl 4-(2,3- dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine-1 -carboxylate (0.24 mmol) in 2.5 ml of dichloromethane

76 mg of an orange oil was isolated and used as a crude in the next step.

LCMS: m/z = 325 [M+H+]

Compound 48: 1 -[4-(2,3-dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazin-1-yl]-2-methyl-propan-1 -one Compound 48 was prepared according to the procedure used for Compound 5 from 28 μΙ of isobutyric acid (0.30 mmol, 1 .3 eq), 135 mg of 0-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.42 mmol, 1 .8 eq), 143 μΙ of N,N- diisopropylethylamine (0.82 mmol 3.5 eq) and 76 mg of 1 -(2,3-dimethyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.23 mmol) in 1 ml of dimethylformamide. An off-white powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 45/55 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 395 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (br d, 1 H), 7.16-7.31 (m, 4H), 7.07 (dt, 1 H), 3.81 -4.02 (m, 2H), 3.33-3.70 (br m, 4H), 3.10 (dd, 1 H), 2.49-2.83 (br m, 5H), 2.17 (s, 6H), 1 .1 1 (d, 6H)

Compound 49j 1 -(3-methyl-5,6-dihvdrobenzorbiri1benzothiepin-5-yl)-4-(o- tolylmethvDpiperazine Intermediate 35: [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1- yl]-(o-tolyl)methanone

Intermediate 35 was prepared according to the procedure used for Intermediate 19 from 35 mg of 2-methylbenzoic acid (0.26 mmol, 1 .3 eq), 1 14 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 120 μΙ of N,N- diisopropylethylamine (0.69 mmol 3.5 eq) and 61 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.20 mmol) in 1 ml of dimethylformamide. 61 mg of a white powder was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate)

LCMS: m/z = 429 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (d, 1 H), 7.02-7.36 (m, 9H), 6.92 (br m, 1 H), 3.70-4.10 (br m, 4H), 3.02-3.31 (br m, 3H), 2.40-2.90 (br m, 4H), 2.17-2.31 (br m, 6H).

Compound 49: 1 -(3-methyl-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)-4-(o- tolylmethyl)piperazine

Compound 49 was prepared according to the procedure used for Compound 36 from 30 mg of [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(o- tolyl)methanone (0.070 mmol) in 0.5 ml of tetrahydrofurane and 27 mg of LJAIH4 (0.70 mmol, 10 eq) in 0.5 ml of tetrahydrofurane. An off-white powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 50/50 mixture of cyclohexane and ethyl acetate).

LCMS: m/z = 415 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.41 (d, 1 H), 7.00-7.34 (m, 8H), 6.89 (dd, 1 H), 3.82- 4.03 (m, 2H), 3.50 (br s, 2H), 3.17 (dd, 1 H), 2.46-2.83 (br m, 8H), 2.37 (s, 3H), 2.27 (s, 3H).

Compound 50j 2-methyl-1 -r4-r3-(trichloromethoxy)-5,6- dihvdrobenzorbinibenzothiepin-5-yllpiperazin-1 -yllpropan-1 -one

Intermediate 36: 2-[2-[4-(trifluoromethoxy)phenyl]sulfanylphenyl]acetic acid

Intermediate 36 was prepared according to the procedure used for Intermediate 22 from 500 mg of 2-iodophenylacetic acid (1 .91 mmol), 408 mg of 4-(trifluoromethoxy)thiophenol (2.10 mmol, 1 .1 eq), 36 mg of copper powder (0.57 mmol, 0.30 eq), 535 mg of potassium hydroxide (9.54 mmol, 5 eq) and 2 x 36 mg of copper iodide (0.19 mmol, 0.1 eq) in 3 ml of water.

550 mg of a yellow solid was isolated and used as a crude in the next step. Intermediate 37: 3-(trichloromethoxy)-6H-benzo[b][1]benzothiepin-5-one

Intermediate 37 was prepared according to the procedure used for Intermediate 5 from 525 mg of 2-[2-[4-(trifluoromethoxy)phenyl]sulfanylphenyl]acetic acid (1 .60 mmol), 203 μΙ of oxalyl chloride (2.40 mmol, 1 .5 eq) in 5.3 ml of dichloromethane and 640 mg of aluminium chloride (4.80 mmol, 3 eq) in 8 ml of dichloromethane.

364 mg of a yellowish solid was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and dichloromethane to 100% of dichloromethane) Intermediate 38: tert-butyl 4-[3-(trichloromethoxy)-5,6- dihydrobenzo[b][1]benzothiepin-5-yl]piperazine-1-carboxylate

Intermediate 38 was prepared according to the procedure used for Compound 2 from 290 μΙ of a solution of TiCI4 1 M in toluene (0.29 mmol, 1 .7 eq), 60 mg of 3-(trichloromethoxy)- 6H-benzo[b][1 ]benzothiepin-5-one (0.17 mmol) and 180 mg of 1 -N-Boc-piperazine (0.97 mmol, 5.8 eq) in 0.6 ml of toluene and from 37 mg of sodium borohydride (0.97 mmol, 5.8 eq) in 0.9 ml of acetic acid.

93 mg of a dark gum was isolated and used as a crude in the next step.

LCMS: m/z = 529 [M+H+]

Intermediate 39: 1-[3-(trichloromethoxy)-5,6-dihydrobenzo[b][1]benzothiepin-5 - yljpiperazine

Intermediate 39 was prepared according to the procedure used for Compound 3 from 1 .45 ml of a solution of HCI 4N in dioxane (5.81 mmol, 33 eq) and 93 mg of tert-butyl 4-[3- (trichloromethoxy)-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl]piperazine-1 -carboxylate (0.18 mmol) in 2.3 ml of dichloromethane

67 mg of an orange oil was isolated and used as a crude in the next step.

LCMS: m/z = 429 [M+H+]

Compound 50: 2-methyl-1 -[4-[3-(trichloromethoxy)-5,6- dihydrobenzo[b][1]benzothiepin-5-yl]piperazin-1 -yl]propan-1 -one

Compound 50 was prepared according to the procedure used for Compound 5 from 21 μΙ of isobutyric acid (0.23 mmol, 1 .45 eq), 102 mg of 0-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.32 mmol, 2 eq), 107 μΙ of N,N- diisopropylethylamine (0.62 mmol 3.9 eq) and 67 mg of 1 -(3-ethyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.16 mmol) in 1 ml of dimethylformamide. A light brown solid was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate)

LCMS: m/z = 499 [M+H+]

1 H NMR (in CDCI3): δ 7.83 (br d, 1 H), 7.43-7.56 (m, 2H), 7.28 (m, 2H), 7.10-7.18 (m, 2H), 3.81 -4.05 (m, 2H), 3.34-3.73 (br m, 4H), 3.1 1 (br d, 1 H), 2.60-2.84 (m, 5H), 1 .12 (d, 6H) Compound 51j 1-r(3.5-dimethylphenyl)methvn-4-(3-methyl-5.6- dihvdrobenzorbiri1benzothiepin-5-yl)piperazine

Intermediate 40: (3,5-dimethylphenyl)-[4-(3-methyl-5,6- dihydrobenzo[b][1]benzothiepin-5-yl)piperazin-1 -yl]methanone Intermediate 40 was prepared according to the procedure used for Intermediate 19 from 38 mg of 3,5-dimethylbenzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. 68 mg of an off-white powder was obtained after purification by flash chromatography on silica (from a 70/30 to a 25/75 mixture of dichloromethane and ethyl acetate)

LCMS: m/z = 443 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (d, 1 H), 6.84-7.37 (m, 9H), 3.65-4.06 (m, 4H), 3.38 (br m, 2H), 3.14 (br d, 1 H), 2.40-2.84 (br m, 4H), 2.31 (s, 6H), 2.17 (s, 3H).

Compound 51 : 1-[(3,5-dimethylphenyl)methyl]-4-(3-methyl-5,6- dihydrobenzo[b][1]benzothiepin-5-yl)piperazine Compound 51 was prepared according to the procedure used for Compound 36 from 20 mg of (3,5-dimethylphenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazin-1 -yl]methanone (0.045 mmol) in 0.5 ml of tetrahydrofurane and 17 mg of LiAIH4 (0.45 mmol, 10 eq) in 0.5 ml of tetrahydrofurane. The reaction mixture was stirred for 45 min at 60°C.

A yellowish powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 40/60 mixture of cyclohexane and ethyl acetate) , .

LCMS: m/z = 429 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (br d, 1 H), 7.37 (br d, 1 H), 7.16-7.31 (m, 3H), 7.07 (dt, 1 H), 6.85-6.97 (br m, 4H), 3.82-4.03 (m, 2H), 3.52 (br s, 2H), 3.17 (dd, 1 H), 2.40-2.86 (br m, 8H), 2.30 (s, 6H), 2.26 (s, 3H).

Compound 52: 1-r(3.4-dimethylphenyl)methvn-4-(3-methyl-5.6- dihvdrobenzorbirnbenzothiepin-5-yl)piperazine Intermediate 41 : (3,4-dimethylphenyl)-[4-(3-methyl-5,6- dihydrobenzo[b][1]benzothiepin-5-yl)piperazin-1 -yl]methanone

Intermediate 41 was prepared according to the procedure used for Intermediate 19 from 38 mg of 3,4-dimethylbenzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. 63 mg of a beige powder was obtained after purification by flash chromatography on silica (from a 70/30 to a 25/75 mixture of dichloromethane and ethyl acetate)

LCMS: m/z = 443 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (br d, 1 H), 6.84-7.37 (m, 9H), 3.69-4.1 1 (br m, 4H), 3.30-3.52 (br m, 2H), 3.14 (br d, 1 H), 2.43-2.88 (br m, 4H), 2.26 (s, 9H).

Compound 52: 1-[(3,4-dimethylphenyl)methyl]-4-(3-methyl-5,6- dihydrobenzo[b][1]benzothiepin-5-yl)piperazine

Compound 52 was prepared according to the procedure used for Compound 36 from 20 mg of (3,4-dimethylphenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazin-1 -yl]methanone (0.045 mmol) in 0.5 ml of tetrahydrofurane and 17 mg of LiAIH4 (0.45 mmol, 10 eq) in 0.5 ml of tetrahydrofurane.

An off-white powder was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate).

LCMS: m/z = 429 [M+H+]

1 H NMR (in CDCI3): δ 7.47 (br d, 1 H), 6.86-7.37 (m, 9H), 3.87-4.03 (m, 2H), 3.47-3.74 (br m, 2H), 3.19 (dd, 1 H), 2.40-2.96 (br m, 8H), 2.25 (s, 9H).

Compound 53: (3-methoxyphenyl)-r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothi epin- 5-yl)piperazin-1 -yllmethanone Compound 53 was prepared according to the procedure used for Compound 5 from 38 mg of 3-methoxybenzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. A beige powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 25/75 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 445 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (br d, 1 H), 6.88-7.37 (m, 10H), 3.75-4.06 (br m, 7H), 3.36 (br m, 2H), 3.15 (br d, 1 H), 2.43-2.92 (br m, 4H), 2.28 (s, 3H). Compound 54: 1 -r(3-chlorophenyl)methvn-4-(3-methyl-5,6- dihydrobenzorbirilbenzothiepin-5-yl)piperazine

Intermediate 42: (3-chlorophenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1]benzothi epin- 5-yl)piperazin-1 -yl]methanone

Intermediate 42 was prepared according to the procedure used for Intermediate 19 from 39 mg of 3-chlorobenzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. 69 mg of a light orange powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 50/50 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 449 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (br d, 1 H), 6.88-7.37 (m, 10H), 3.69-4.05 (br m, 4H), 3.36 (br m, 2H), 3.15 (br d, 1 H), 2.43-2.88 (br m, 4H), 2.28 (s, 3H).

Compound 54: 1 -[(3-chlorophenyl)methyl]-4-(3-methyl-5,6- dihydrobenzo[b][1]benzothiepin-5-yl)piperazine

Compound 54 was prepared according to the procedure used for Compound 36 from 35 mg of (3-chlorophenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 - yl]methanone (0.078 mmol) in 0.5 ml of tetrahydrofurane and 30 mg of LiAIH4 (0.78 mmol, 10 eq) in 0.5 ml of tetrahydrofurane.

A light grey powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 40/60 mixture of cyclohexane and ethyl acetate),,

LCMS: m/z = 435 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (br d, 1 H), 7.38 (br s, 1 H), 7.16-7.33 (m, 7H), 7.07 (dt, 1 H), 6.88 (br d, 1 H), 3.82-4.01 (m, 2H), 3.48 (s, 2H), 3.17 (dd, 1 H), 2.40-2.77 (br m, 8H), 2.27 (s, 3H).

Compound 55: 1-r(3-methoxyphenyl)methvn-4-(3-methyl-5.6- dihvdrobenzorbiri1benzothiepin-5-yl)piperazine Intermediate 43: (3-methoxyphenyl)-[4-(3-methyl-5,6- dihydrobenzo[b][1]benzothiepin-5-yl)piperazin-1 -yl]methanone Intermediate 43 was prepared according to the procedure used for Intermediate 19 from 38 mg of 3-methoxybenzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. 72 mg of a beige powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 25/75 mixture of cyclohexane and ethyl acetate)

LCMS: m/z = 445 [M+H+]

1 H NMR (in CDCI3): δ 7.50 (br d, 1 H), 6.88-7.37 (m, 10H), 3.75-4.06 (br m, 7H), 3.36 (br m, 2H), 3.15 (br d, 1 H), 2.43-2.92 (br m, 4H), 2.28 (s, 3H).

Compound 55: 1-[(3-methoxyphenyl)methyl]-4-(3-methyl-5,6- dihydrobenzo[b][1]benzothiepin-5-yl)piperazine

Compound 55 was prepared according to the procedure used for Compound 36 from 30 mg of (3-methoxyphenyl)-[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin- 1 -yl]methanone (0.067 mmol) in 0.5 ml of tetrahydrofurane and 26 mg of LiAIH4 (0.67 mmol, 10 eq) in 0.5 ml of tetrahydrofurane. The reaction mixture was stirred for 1 .5h at 60°C.

A white powder was obtained after purification by flash chromatography on silica (from a 95/5 to a 40/60 mixture of cyclohexane and ethyl acetate)..

LCMS: m/z = 431 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (br d, 1 H), 7.37 (br d, 1 H), 7.16-7.34 (m, 4H), 7.07 (dt, 1 H), 6.79-7.00 (br m, 4H), 3.88-4.02 (m, 2H), 3.82 (s, 3H), 3.56 (br s, 2H), 3.17 (dd, 1 H), 2.39- 2.84 (br m, 8H), 2.26 (s, 3H).

Compound 56: 1-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)-4-r(3- methylsulfonylphenvDmethyllpiperazine

Intermediate 44: [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1- yl]-(3-methylsulfonylphenyl)methanone

Intermediate 44 was prepared according to the procedure used for Intermediate 19 from 50 mg of 3-(methylsulfonyl)benzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of 0-(benzotriazol-1 - yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. 82 mg of a yellowish powder was obtained after purification by flash chromatography on silica (from a 70/30 mixture of cyclohexane and ethyl acetate to 100% of ethyl acetate) LCMS: m/z = 493 [M+H+], 556 [M+ACN+Na+], 985 [2M+H]

1 H NMR (in CDCI3): δ 7.97-8.01 (m, 2H), 7.59-7.70 (m, 2H), 7.50 (br d, 1 H), 6.88-7.35 (m, 6H), 3.70-4.07 (br m, 4H), 3.34 (br m, 2H), 3.14 (br d, 1 H), 3.07 (s, 3H), 2.43-2.92 (br m, 4H), 2.28 (s, 3H). Compound 56: 1-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-[(3- methylsulfonylphenyl)methyl]piperazine

Compound 56 was prepared according to the procedure used for Compound 36 from 35 mg of [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(3- methylsulfonylphenyl)methanone (0.071 mmol) in 0.5 ml of tetrahydrofurane and 27 mg of LiAIH4 (0.71 mmol, 10 eq) in 0.5 ml of tetrahydrofurane.

An off-white powder was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% of ethyl acetate).

LCMS: m/z = 479 [M+H+]

1 H NMR (in CDCI3): δ 7.81 -7.91 (m, 2H), 7.65 (br d, 1 H), 7.48-7.55 (m, 2H), 7.38 (br s, 1 H), 7.16-7.32 (m, 3H), 7.07 (dt, 1 H), 6.88 (br dd, 1 H), 3.83-4.01 (m, 2H), 3.58 (s, 2H), 3.17 (dd, 1 H), 3.06 (s, 3H), 2.39-2.77 (br m, 8H), 2.27 (s, 3H).

Compound 57: 1-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)-4-r(5-me thyl-3- pyridyDmethyllpiperazine

Intermediate 45: [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1- yl]-(5-methyl-3-pyridyl)methanone Intermediate 45 was prepared according to the procedure used for Intermediate 19 from 34 mg of 5-methyl-nicotinic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. 73 mg of an orange solid was obtained after purification by flash chromatography on silica (from a 70/30 mixture of dichloromethane and ethyl acetate to 100% of ethyl acetate) LCMS: m/z = 430 [M+H+]

1 H NMR (in CDCI3): δ 8.46 (br m, 2H), 7.47-7.55 (m, 2H), 7.18-7.36 (m, 4H), 7.10 (dt, 1 H), 6.93 (br d, 1 H), 3.82-4.16 (br m, 4H), 3.17-3.52 (br m, 3H), 2.46-2.90 (br m, 4H), 2.37 (s, 3H), 2.28 (s, 3H).

Compound 57: 1-(3-methyl-5,6-dihydrobenzo[b][1]benzothiepin-5-yl)-4-[(5-m ethyl-3- pyridyl)methyl]piperazine

Compound 57 was prepared according to the procedure used for Compound 36 from 30 mg of [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-(5-methyl-3- pyridyl)methanone (0.070 mmol) in 0.5 ml of tetrahydrofurane and 27 mg of LiAIH4 (0.70 mmol, 10 eq) in 0.5 ml of tetrahydrofurane.

A yellowish powder was obtained after purification by flash chromatography on silica (from 100% of dichloromethane to 100% of a mixture of dichloromethane/methanol/ammonium hydroxide 90:10:1 ),

LCMS: m/z = 416 [M+H+]

1 H NMR (in CDCI3): δ 8.35 (br m, 2H), 7.76 (br m, 1 H), 7.48 (br d, 1 H), 6.89-7.34 (m, 6H), 3.83-4.05 (m, 2H), 3.68 (br s, 2H), 3.24 (br dd, 1 H), 3.06 (s, 3H), 2.39-3.00 (br m, 8H), 2.35 (s, 3H), 2.27 (s, 3H).

Compound 58: r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)piperazi n-1-vn- phenyl-methanone

Compound 58 was prepared according to the procedure used for Compound 5 from 15 mg of benzoic acid (0.13 mmol, 1 .3 eq), 56 mg of 0-(benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (0.17 mmol, 1 .8 eq), 59 μΙ of N,N- diisopropylethylamine (0.34 mmol 3.5 eq) and 30 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.10 mmol) in 1 ml of dimethylformamide. A white powder was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate)

LCMS: m/z = 415 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 7.39 (s, 5H), 7.17-7.36 (m, 4H), 7.08 (dt, 1 H), 6.90 (dd, 1 H), 3.72-4.08 (m, 4H), 3.39 (br m, 2H), 3.15 (dd, 1 H), 2.47-2.83 (br m, 4H), 2.27 (s, 3H) Compound 59: 1-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)-4-r(3- trifluoromethyDphenyllmethyllpiperazine

Intermediate 46: [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1- yl]-[3-(trifluoromethyl)phenyl]methanone

Intermediate 46 was prepared according to the procedure used for Intermediate 19 from 48 mg of 3-(trifluoromethyl)benzoic acid (0.25 mmol, 1 .3 eq), 1 12 mg of 0-(benzotriazol-1 - yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. 77 mg of an off-white powder was obtained after purification by flash chromatography on silica (from a 70/30 to a 25/75 mixture of dichloromethane and ethyl acetate)

LCMS: m/z = 483 [M+H+]

1 H NMR (in CDCI3): δ 7.47-7.70 (m, 5H), 7.06-7.34 (m, 5H), 6.91 (br d, 1 H), 3.70-4.07 (br m, 4H), 3.36 (br m, 2H), 3.15 (br d, 1 H), 2.43-2.92 (br m, 4H), 2.27 (s, 3H).

Compound 59: 1-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)-4-[(3- trifluoromethyl)phenyl]methyl]piperazine

Compound 59 was prepared according to the procedure used for Compound 36 from 20 mg of [4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]-[3- (trifluoromethyl)phenyl]methanone (0.041 mmol) in 0.5 ml of tetrahydrofurane and 16 mg of LiAIH4 (0.41 mmol, 10 eq) in 0.5 ml of tetrahydrofurane.

A white powder was obtained after purification by flash chromatography on silica (from 100% of dichloromethane to a 95/5 mixture of dichloromethane and ethyl acetate).

LCMS: m/z = 469 [M+H+]

Compound 60: 1-r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)pipera zin-1- yllpropan-1 -one

Compound 60 was prepared according to the procedure used for Compound 5 from 19 μΙ of propionic anhydride (0.14 mmol, 1 .5 eq), 30 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.10 mmol) and 59 μΙ of N,N- diisopropylethylamine (0.34 mmol, 3.5 eq) in 1 ml of tetrahydrofuran. A brown solid was obtained after purification by flash chromatography on silica (from a 95/5 mixture of cyclohexane and ethyl acetate to 100% ethyl acetate)

LCMS: m/z = 367 [M+H+]

1 H NMR (in CDCI3): δ 7.49 (dd, 1 H), 6.80-7.34 (m, 6H), 3.18-4.53 (br m, 8H), 2.67 (br m, 3H), 2.32 (m, 5H), 1 .12 (t, 3H)

Compound 61 : r4-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)piperazi n-1-vn- (6-methyl-2-pyridyl)methanone Compound 61 was prepared according to the procedure used for Compound 5 from 34 mg of 6-methylpicolinic acid (0.25 mmol, 1 .3 eq), 1 12 mg of O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (0.35 mmol, 1 .8 eq), 1 18 μΙ of N,N- diisopropylethylamine (0.68 mmol 3.5 eq) and 60 mg of 1 -(3-methyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.19 mmol) in 1 ml of dimethylformamide. A pinkish powder was obtained after purification by flash chromatography on silica (from a 70/30 mixture of dichloromethane and ethyl acetate to 100% of ethyl acetate)

LCMS: m/z = 430 [M+H+]

1 H NMR (in CDCI3): δ 7.66 (br t, 1 H), 7.50 (br d, 1 H), 7.06-7.39 (m, 7H), 6.92 (br m, 1 H), 3.83-4.07 (br m, 4H), 3.50 (br m, 2H), 3.15 (br d, 1 H), 2.75-2.90 (br m, 2H), 2.43-2.72 (br m, 5H), 2.28 (s, 3H).

Compound 62: 1-(3-methyl-5,6-dihvdrobenzorbirnbenzothiepin-5-yl)-4-propyl - piperazine A suspension of 40 mg of 1 -(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazine (0.13 mmol), 15 μΙ of iodopropane (0.15 mmol, 1 .2 eq) and 27 mg of potassium carbonate (0.19 mmol, 1 .5 eq) in 2 ml of tetrahydrofurane was stirred at RT for 10 days. 5 ml of water was added and the product was extracted three times with 5 ml of dichloromethane. The combined organic layers were washed successively with 5 ml of a saturated aqueous solution of sodium bicarbonate and 4 ml of water and concentrated to dryness. The residue was purified by flash chromatography on silica (from 100% cyclohexane to 100% of a mixture of cyclohexane/ethyl acetate/triethylamine 25/75/1 ) yielding the product as a light brown powder.

LCMS: m/z = 353 [M+H+] 1 H NMR (in CDCI3): δ 7.48 (br d, 1 H), 7.38 (br s, 1 H), 7.15-7.32 (m, 3H), 7.05 (dt, 1 H), 6.87 (br dd, 1 H), 3.82-4.01 (m, 2H), 3.17 (dd, 1 H), 2.40-2.81 (br m, 8H), 2.29-2.34 (m, 2H), 2.26 (s, 3H), 1 .42-1 .60 (m, 2H), 0.89 (t, 3H).

Example 2: IC50 of the compounds of the invention on adrenocortical carcinoma cell line (AAC) and on melanoma cells, with or without doxorubicin (Dxr)

The IC50 of the compounds of the invention (cited in example 1 ) on adrenocortical carcinoma cell line (AAC) and on melanoma cells, with or without doxorubicin (Dxr), were measured as follows:

Cells were seeded in 96-well plates in triplicate and grown in medium to achieve 70% to 80% confluence. Medium was then removed and replaced with 100 μΙ_Λ/νβΙΙ of complete medium containing the compound or DMSO as control. After 2 hours, 100 μΙ_ of complete medium containing serial dilutions of doxorubicin was added. Plates were incubated at 37°C and 5% C0 2 . After 24 or 48 hours, plates were incubated 3 hours at 37°C with 100 μΙ_/ννβΙΙ neutral red (NR) solution (50 μg/mL in medium) following the manufacturer's protocol. Measurements were made in microplate readers (Multiskan Go Microplate Spectrophotometer from Thermo Scientific and SPECTRA from Tecan).

IC50 was defined as the concentration that resulted in a 50% decrease in the number of live cells, and IC50 values were calculated using GraphPad Prism 6 software.

The results are in Table 1 below:

IC50 on ACC IC50 + Dxr on ACC IC50 on IC50 + Dxr on

Compound

cells cells melanoma melanoma

Methiothepine 13μΜ 3,5μΜ 15 7

1 15 - 20 μΜ 5μΜ ΝΑ ΝΑ

3 10-15μΜ 7,2μΜ 9μΜ 13μΜ

4 »20μΜ 3,2μΜ ΝΑ ΝΑ

5 »20μΜ 1 1 μΜ ΝΑ ΝΑ

6 15 - 20 μΜ 6,5μΜ ΝΑ ΝΑ

7 >20μΜ 6,2μΜ ΝΑ ΝΑ 10μΜ 0,8μΜ

15-20 μΜ 6,8μΜ ΝΑ ΝΑ

4,6μΜ ΝΑ ΝΑ

7μΜ 3,3μΜ 20μΜ 15μΜ

3,8μΜ 11μΜ 7μΜ

10μΜ ΝΑ ΝΑ

20μΜ 1,5μΜ >20μΜ 3,7μΜ

3,6μΜ 13μΜ 11μΜ

>10μΜ 1,8μΜ >20μΜ >20μΜ

»20μΜ >20μΜ ΝΑ

15-20μΜ 6,1μΜ >20μΜ 15μΜ

15-20μΜ 4,3μΜ ΝΑ ΝΑ

>20μΜ 12μΜ ΝΑ ΝΑ

10μΜ 6,5μΜ »20μΜ 12μΜ

15-20μΜ 5-1 ΟμΜ 13μΜ 10μΜ

>20μΜ 7,5μΜ ΝΑ ΝΑ

20μΜ 1μΜ »20μΜ 5μΜ

»20μΜ >20μΜ ΝΑ ΝΑ

20μΜ 7μΜ ΝΑ ΝΑ

10μΜ 1μΜ ΝΑ ΝΑ

»20μΜ >20μΜ ΝΑ ΝΑ

>15μΜ 5,6μΜ

>20μΜ 6,4μΜ »20μΜ 15μΜ

10μΜ 5,5μΜ ΝΑ ΝΑ 7μΜ 3μΜ

15μΜ 3,5μΜ >20μΜ >20μΜ

10μΜ 2,3μΜ »20μΜ 20μΜ

»20μΜ 20μΜ ΝΑ

10-20μΜ 0,5μΜ >20μΜ >20μΜ

»20μΜ >20μΜ ΝΑ

>20μΜ 0,8μΜ >20μΜ >20μΜ

>20μΜ 2,6μΜ >20μΜ >20μΜ

>20μΜ 2,7μΜ >20μΜ >20μΜ

15μΜ >20μΜ ΝΑ ΝΑ

»20μΜ 20μΜ ΝΑ

>10μΜ 1 ,9μΜ >20μΜ >20μΜ

15μΜ 7μΜ ΝΑ ΝΑ

20μΜ 0,9-1 μΜ >20μΜ >20μΜ

>10μΜ 2.5μΜ ΝΑ ΝΑ

>20μΜ 2,8μΜ >20μΜ >20μΜ

10μΜ 2μΜ ΝΑ ΝΑ

7μΜ 1 ,8μΜ ΝΑ ΝΑ

7,5μΜ 5μΜ >20μΜ 20μΜ

10μΜ 2,6μΜ ΝΑ ΝΑ

10μΜ 2μΜ ΝΑ ΝΑ

10-20μΜ 4μΜ ΝΑ ΝΑ

>20μΜ 15μΜ ΝΑ ΝΑ

»20μΜ 10μΜ ΝΑ 61 >10μΜ 3,7μΜ >20μΜ 7,5μΜ

62 >20μΜ 15μΜ ΝΑ ΝΑ

Table 1: IC50 results

NA = not measured

Example 3: Use of methiothepin maleate (P375) according to the invention Biological Material

Methiothepin maleate (P375) was purchased from Santa Cruz: CAS number: 20229-30-5 ; MW: 472.62 ; molecular formula: C20H24N2S2.C4H4O4. Doxorubicin hydrochloride, Hoechst 33342, cisplatin and temozolomide were purchased from Sigma-Aldrich. PSC 833 was purchased from Tocris. 2-methyl-1 -[4-(3-methyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazin-1 -yl]propan-1 -one, 1 -[4-(2,3-dimethyl-5,6-dihydrobenzo[b][1 ]benzothiepin-5- yl)piperazin-1 -yl]-2-methyl-propan-1 -one and 2-methyl-1 -[4-(3-methylsulfanyl-5,6- dihydrobenzo[b][1 ]benzothiepin-5-yl)piperazin-1 -yl]propan-1 -one were prepared as disclosed above.

K699 Saccharomyces cerevisiae yeast strain (Mata, ura3 and leu 2-3, kindly donated by R. Arkowitz) was transformed with pYEP-hPtc-MAP (human Patched) or pYEP-mMyo- MAP (control) expression vector and grown as described (Bidet, M., Joubert, O., Lacombe, B., Ciantar, M., Nehme, R., Mollat, P., Bretillon, L.,Faure, H., Bittman, R., Ruat, M., and Mus-Veteau, I. (201 1 ). The hedgehog receptor patched is involved in cholesterol transport. PLoS One 6, e23834) at 18°C until OD 600 5-7.

The human adrenocortical carcinoma cell line H295R was cultured in DMEM/F12 supplemented with 2% NuSerum (BD), 1 % ITS+ (BD) and penicillin/streptomycin (Invitrogen) at 37°C in a 5% C0 2 /95% air water-saturated atmosphere.

The human colorectal carcinoma (HCT1 16), breast adenocarcinoma (MCF7) and melanoma (A375) cell lines were purchased from ATCC, and cultured in DMEM medium supplemented with 10% fetal bovine serum and penicillin/streptomycin (Invitrogen) at 37°C in a 5% C0 2 /95% air water-saturated atmosphere. The effect of methiothepin on the resistance of yeast-expressing Patched to doxorubicin was performed as described in (Fiorini, L, Tribalat, M.A., Sauvard, L, Cazareth, J., Lalli, E., Broutin, I., Thomas, O.P., and Mus-Veteau, I. (2015). Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells. Oncotarget 6, 22282-97). In a previous study, the inventors reported that the expression of human Patched allowed yeast to grow in the presence of a concentration of doxorubicin (dxr) that inhibits the growth of control yeast, indicating that Patched confers resistance to dxr (Bidet et al 2012). From these results, the inventors developed a screening test in 96-well plates to identify compounds capable of inhibiting the resistance of yeast expressing human Patched to dxr. 1200 drug molecules were added at a final concentration of 10 μΜ to yeast expressing Patched in a medium supplemented or not with dxr. The inventors observed that molecule P375 significantly inhibited the growth of yeast expressing Patched in the presence of dxr contrary to the majority of the molecules tested such as P298 which had no effect (Fig. 1 A). P375 had no effect on the growth of yeast expressing Patched in the absence of dxr and did not inhibit the growth of control yeast in the presence of small amounts of dxr, suggesting that this molecule inhibits specifically dxr resistance conferred by Patched activity.

The effect of methiothepin on doxorubicin efflux from yeast expressing Patched was performed as already described in (Fiorini, L, Tribalat, M.A., Sauvard, L, Cazareth, J., Lalli, E., Broutin, I., Thomas, O.P., and Mus-Veteau, I. (2015). Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells. Oncotarget 6, 22282-97).

The inventors took advantage of the natural fluorescence properties of dxr to carry out dxr efflux measurements, and tested the effect of P375 on dxr efflux. 2-deoxy-D-glucose was added in buffer during dxr loading and efflux in order to de-energize yeast and inhibit ATP-binding cassette (ABC) transporters which also contribute to dxr efflux in yeast. This enabled us to selectively study the dxr efflux activity of Patched. Dxr fluorescence measured in yeast expressing Patched after efflux in buffer containing DMSO was significantly lower than that measured in control yeast, consistently with the dxr efflux activity of Patched already described (Bidet, M., Tomico, A., Martin, P., Guizouarn, H., Mollat, P., and Mus-Veteau, I. (2012). The Hedgehog receptor patched functions in multidrug transport and chemotherapy resistance. Mol. Cancer Res. 10, 1496-508) (Fig 1 B). Dxr fluorescence in yeast expressing Patched was significantly higher when P375 was present in the efflux buffer while this molecule had no significant effect on the dxr fluorescence of control yeasts, indicating that P375 specifically inhibited Patched dxr efflux activity. Note that PSC833 had no significant effect on dxr efflux from yeast expressing Patched suggesting that Patched is not sensitive to this P-glycoprotein (P-gp) inhibitor. The effect of methiothepin on the cytotoxicity of doxorubicin on adrenocortical carcinoma, melanoma, breath cancer and colorectal cancer cells was performed as described in (Fiorini, L, Tribalat, M.A., Sauvard, L, Cazareth, J., Lalli, E., Broutin, I., Thomas, O.P., and Mus-Veteau, I. (2015). Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells. Oncotarget 6, 22282-97).

Two melanoma cell lines were chosen to measure the effect of P375 on dxr cytotoxicity. The MEWO cell line is derived from a melanoma metastatic site (lymph node tissue), and the A375 cell line is derived from a human malignant melanoma and carries the BRAFV600E mutation. The human colorectal carcinoma (HCT1 16) and breast adenocarcinoma (MCF7) cell lines were purchased from ATCC. These four cell lines express the protein Patched as shown by western-blotting (Fig. 6A). Adrenocortical carcinoma (ACC) is a rare cancer which presents strong resistance to the best treatment available at the present time composed of a mixture of chemotherapeutic agents (etoposide, doxorubicin and cisplatin) combined with the adrenolytic substance mitotane (EDP-M). As Patched is strongly expressed in the human ACC cell line H295R (Fig. 2A and 3D) and in ACC patients tumors (Fig. 2A), and dxr is used in ACC treatment, the inventors decided to use also this cell line to test the effect of P375 on the dxr cytotoxicity. Cells were treated separately with increasing concentrations of dxr, with or without P375, during 24 or 48 hours before cell viability measurement. Experiments show that P375 increased cell mortality induced by dxr on all cell lines, and induced a significant decrease of the dxr IC50 (Fig. 3B, 3C, 6B, 6C). Dose-response of P375 on cell viability have been performed providing IC50 values in the presence of dxr of about 10 μΜ and 3 μΜ on melanoma and ACC cells respectively.

In agreement with the results of cytotoxicity, apoptosis experiments based on caspase 3/7 activation measurements indicated that the addition of P375 to dxr treatment significantly increased the percentage of apoptotic cells (Fig. 4A). The inventors also observed that the presence of P375 in the culture medium significantly increased the anti-proliferative effect of dxr on ACC cells, dxr-IC50 on cell proliferation being reduced nearly 10 times with 2 μΜ of P375 (Fig. 4B). Moreover, the combination of dxr and P375 inhibited the ability of H295R cells to form clones to a significantly greater extent than dxr alone (P<0.05) (Fig. 4C). The effect of methiothepin on doxorubicin efflux from cancer cells was performed as described in (Fiorini, L, Tribalat, M.A., Sauvard, L, Cazareth, J., Lalli, E., Broutin, I., Thomas, O.P., and Mus-Veteau, I. (2015). Natural paniceins from mediterranean sponge inhibit the multidrug resistance activity of Patched and increase chemotherapy efficiency on melanoma cells. Oncotarget 6, 22282-97).

As for yeast, epifluorescence microscopy was used to measure the effect of P375 on dxr efflux in melanoma and ACC cells. As shown in Fig. 5 and 6, incubation of cells with dxr induced a strong accumulation of dxr in the nuclei which was drastically reduced after 30 min of incubation with the efflux buffer. Measurements indicated that 60 to 70% of the dxr amount was transported out of cells. The presence of P375 in the efflux buffer allowed retaining part of the dxr in the nuclei. The effect is stronger in ACC cells in which about 60% of dxr was retained showing that P375 strongly inhibited the efflux of dxr in these cells. Note that P375 has no effect on Hoechst efflux contrary to the P-gp antagonist PSC833, suggesting that P375 inhibited specifically dxr efflux. Remarkably, the reduction of 60% of Patched expression using silencing Patched RNA induces about 60% inhibition of dxr efflux in ACC cells suggesting that Patched is the major dxr efflux pump in these cells (Fig. 5C). Accordingly, PSC833 has no effect on the dxr efflux on ACC cells while dxr is a well-known P-gp substrate. This is in good agreements with experiments showing that a 70% decrease of P-gp expression using silencing RNA inhibited only 10% of the dxr efflux, and suggests that P-gp does not contribute much to the dxr efflux in these ACC cells.

Effect of methiothepin on doxorubicin efficacy in vivo

For therapeutic experiments female athymic NMRI nu/nu mice (6 - 8 weeks) were purchased from Charles River (Sulzfeld, Germany) and housed under pathogen-free conditions. All experiments were carried out following protocols approved by the Regierung von Oberbayern and in accordance with the German guidelines for animal studies. H295R xenografts were induced as described before (Hantel et al 2014). Tumor- bearing mice (n= 7-8) were treated with two therapeutic cycles which consisted of either liposomal doxorubicin (6 mg/kg body weight, intravenously on days 4 and 10), P375 (2 mg/kg body weight, intraperitoneal^ on days 1 to 19) or a combination of liposomal doxorubicin and P375 (P375: 2 mg/kg body weight, intraperitoneal^ on days 1 to 19 plus liposomal doxorubicin 6 mg/kg body weight, intravenously on days 4 and 10). Animals were monitored daily and tumor sizes measured every second day (as tumor length x width [cm 2 ]). At day 40 after tumor induction, when first tumors reached a longest tumor diameter of 1 .5 cm, the therapeutic study was terminated.

This Experiments showed a highest therapeutic efficacy for the combined administration of P375 + lipdxr (p<0.01 vs. controls on day 39; Figure 7 A and C). Mice showed no obvious signs of side effects caused by the drugs (no weight loss or abnormal behavior). Epifluorescence images taken from ACC xenograft tumor slides showed that tumors from mice treated with lip-dxr accumulated dxr, and that co-administration of P375 with lip-dxr enhanced significantly (about 3 times) dxr content in tumors (Fig. 7B and D). This observation is in very good agreement with in vitro studies showing that P375 prevented dxr from being transported out of cells. In contrast, epifluorescence images from heart slides showed that P375 did not enhance the amounts of dxr in mice hearts where Patched is not expressed (Fig. 7D).

Example 4: Use of methiothepin maleate (P375) for increasing docetaxel cytotoxicity on pancreatic cancer cell line PC3 and on breast cancer cell line MDA- MB-231 Docetaxel is one of the gold standard treatment of prostate and breast cancers. Experiments measuring the IC50 of docetaxel cytotoxicity were performed on two different cancer cell lines: pancreatic cancer cells PC3 and breast cancer cells MDA-MB-231 .

PC3 and MDA-MB-231 cells have been seeded in 96 well-plates and treated separately with increasing concentrations of docetaxel with or without methiothepin, during 48 hours before cell viability measurement using neutral red. Experiments show that methiothepin increased cell mortality induced by docetaxel on both cell lines, and induced a significant decrease of the docetaxel IC50 (Fig. 8A and 9A). Dose-response of methiothepin on cell viability have been performed providing IC50 values in the presence of docetaxel of about 8 μΜ on both cell lines (Fig. 8B and 9B).

The results presented in Figure 8 on prostate cancer cells show that the IC50 of docetaxel in the presence of 30μΜ of methiothepin is about 39μΜ, whereas the IC50 of docetaxel alone was greater than 200μΜ. Thus, the addition of 30μΜ of methiothepin increases docetaxel sensitivity of pancreatic cancer cells by a factor of 5 after 48 hours treatment (Fig. 8A).

The IC50 of methiothepin in the presence of 75μΜ of docetaxel is about 8μΜ (Fig. 8B).

The results presented in Figure 9 on breast cancer cells show that the IC50 of docetaxel in the presence of 20μΜ of methiothepin is about 31 μΜ, whereas the IC50 of docetaxel alone was around 129μΜ. Thus, the addition of 20μΜ of methiothepin increases more than 4 times the sensitivity of breast cancer cells to docetaxel after 48 hours treatment (Fig. 9A).

The IC50 of methiothepin in the presence of 50μΜ of docetaxel is about 8μΜ (Fig. 9B).