Tetrahydroquinoline compounds as antitumor agents

Abstract

The present invention relates to a tetrahydroquinoline compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is a (C3-C7) cycloalkyl; a (C3-C7) heterocycloalkyl group comprising from 1 to 3 heteroatoms selected from the group consisting of O, N and S; (C1-C7) alkyl groups; a (C1-C7) heteroalkyl group comprising from 1 to 3 heteroatoms selected from the group consisting of O, N and S; an optionally substituted benzene ring or an optionally substituted (5-9) membered heteroaromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of O, N and S; r is H, (C1-C4) alkyl, (C1-C3) alkoxy (C1-C3) alkyl, (C3-C7) cycloalkyl; r1 and R2 are independently selected from the group consisting of H, NO2, CN, halogen, (C1-C4) alkyl, (C2-C4) alkenyl, (C1-C4) alkoxy (C1-C4) alkyl, (C3-C7) cycloalkyl (C1-C4) alkyl, (C1-C4) alkyl substituted by a (5-9) membered heteroaromatic ring comprising from 1 to 3 heteroatoms selected from O, N and S, amino optionally substituted by bis (dimethylamino) methylene, pyridyl, trifluoromethyl-SO2-, (C1-C3) alkyl-SO2-, a group NH-CO-R3, wherein R3 is selected from the group consisting of benzyl, (C3-C7) cycloalkyl (C1-C4) alkyl, phenyl, vinyl, halo-CH2-, (C1-C3) alkyl; a group NH-CH2-R4, wherein R4 is an optionally substituted benzene ring or an optionally substituted (5-9) membered heteroaromatic ring comprising from 1 to 3 heteroatoms selected from O, N and S; or R1 and R2 together form an optionally substituted aromatic ring comprising 6 carbon atoms. The tetrahydroquinoline compound according to the invention or a pharmaceutically acceptable salt thereof is a disrupting agent of the FANCM / BTR interaction in order to hinder the localization of FANCM at the telomere, preferably in the treatment of tumors. # imgabs0 #

Description

Field of the Invention

[0001] The present invention relates to novel antitumor agents.

[0002] background

[0003] Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism observed in many of the most refractory cancer subtypes. In ALT, telomeres are maintained through the influence of multiple homology-directed repair (HDR) mechanisms that allow DNA extension. Extensive data indicate that ALT-lengthened telomeres are characterized by a permissive chromatin state, stochastic DNA damage, and enhanced levels of replication stress. The latter can be attributed to the presence of variant repeats (e.g., TCAGGG, TGAGGG) in ALT telomeres resulting from recombination-mediated telomere replication. 1 Furthermore, replication stress in ALT cancers has been associated with unique nucleoprotein structures formed by mismanaged chromatin that promote cycles of DNA damage. 2

[0004] Normally, telomeres present a challenge to the replication machinery, leading to replication fork stalling. Fork flipping and restarting (mediated by FANCM3 and SMARCAL1)4 relieve replication stress at telomeres, leading to limitation of ALT activity. Conversely, unresolved replication stress leads to fork collapse, providing DSB substrates for ALT-mediated recombination and telomere synthesis. Therefore, proteins associated with ameliorating replication stress at telomeres are intrinsically involved in ALT regulation.

[0005] ALT is commonly found in cancers of mesenchymal origin, including cancers of the central nervous system as well as in many sarcomas, particularly osteosarcoma (OS). 5 This can be explained by the fact that telomerase expression is more tightly controlled in mesenchymal cells compared to epithelial cells. 4 The prevalence of ALT cancers (10%-15%) is underestimated, given the shortcomings of direct clinical diagnosis for ALT detection. In addition to OS (64% prevalence), pancreatic neuroendocrine (PanNET), and soft tissue tumors such as leiomyosarcoma, ALT is also prevalent in low-grade astrocytomas and secondary gliomas, as well as in several pediatric cancers such as neuroblastoma, diffuse intrinsic pontine glioma (DIPG), and glioblastoma. 2 To date, ALT activity has not been detected in normal cells, highlighting a unique cancer-selective therapeutic opportunity. However, despite this selectively associated feature with cancer, effective drugs that selectively kill ALT-positive cancer cells have yet to be discovered.

[0006] OS is the best example of ALT cancer. It is the most common type of primary malignant bone tumor, which is defined by the presence of malignant mesenchymal cells that produce osteoid or immature bone. OS accounts for 30%-80% of primary bone sarcomas. The affected population is mainly children, adolescents and young adults aged 10-30 years. 6 Males are more affected than females. The peak incidence of the most common type of OS (i.e., advanced central OS) occurs in the second decade of life during the adolescent growth spurt. If untreated, OS will progress locally and systemically and lead to death within a few months. The results of patients with OS before the use of effective chemotherapy are poor, with a 2-year overall survival rate of 15%-20% after surgical resection and / or radiotherapy. Neoadjuvant chemotherapy (including high-dose methotrexate with folinic acid rescue, doxorubicin, cisplatin, bleomycin, cyclophosphamide and dactinomycin) and subsequent definitive surgery have the advantage of promoting limb-saving surgery. Nearly all patients have microscopic metastases at diagnosis, as evidenced by the fact that 80%-90% develop metastatic recurrence if treated with surgical resection and / or radiation therapy. These patients have a particularly poor prognosis, with a five-year survival rate of only 20%-30%, compared with a five-year survival rate of 60%-66% for patients with localized disease.7

[0007] The findings described in this document are based on two major discoveries by the research team. First, in 2019, the Pickett lab discovered the Achilles' heel of ALT cells, allowing for the induction of ALT-specific cell death for the first time. This was achieved by inducing unconstrained replication stress at telomeres. They demonstrated that depletion of FANCM, a DNA translocase that functionally interacts with the BLM-TOP3A-RMI (BTR) complex and the Fanconi anemia (FA) core complex, resolved the replication stress that normally occurs at telomeres. ALT telomeres are characterized by unique structural aberrations that promote replication defects and are therefore highly sensitive to FANCM depletion. In the absence of FANCM, stalled forks deteriorate to form DSBs. These data demonstrate proof of concept for the toxic effects of exacerbated levels of telomere replication stress on ALT cells and suggest that the FANCM / BTR system is a promising target for the treatment of ALT cancer. Thus, patent publication WO2020 / 242330 describes methods for inhibiting the activity or expression of FANCM, such as inhibiting the interaction of FANCM with RMI and / or the ATPase activity of FANCM, to inhibit the growth and / or proliferation of ALT tumor cells and / or induce the death of ATL tumor cells.

[0008] The object of the present invention is to provide disruptors of FANCM / BTR interaction in order to hinder the localization of FANCM to telomeres and thereby treat tumors. SUMMARY OF THE INVENTION

[0010] The inventors have surprisingly discovered chemical disruptors of the FANCM / BTR interaction in order to hinder the localization of FANCM to telomeres.

[0011] Therefore, the present invention relates to a tetrahydroquinoline compound of formula (I) or a pharmaceutically acceptable salt thereof

[0012]

[0013] in

[0014] A is (C 3 -C 7 )cycloalkyl; containing from 1 to 3 heteroatoms selected from O, N and S (C 3 -C 7 )heterocycloalkyl; (C 1 -C 7 ) alkyl; containing from 1 to 3 heteroatoms selected from O, N and S (C 1 -C 7 )heteroalkyl; an optionally substituted benzene ring or an optionally substituted (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S;

[0015] R is H, (C 1 -C 4 ) alkyl, (C 1 -C 3 ) alkoxy (C 1 -C 3 ) alkyl, (C 3 -C 7 )cycloalkyl;

[0016] R 1 and R 2 Independently selected from the group consisting of: H, NO 2 , CN, halogen, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 ) alkyl, substituted by a (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S 1 -C 4 )alkyl,

[0017] Optionally bis(dimethylamino)methylene, pyridyl, (C 1 -C 3 )alkyl-SO 2 -substituted amino group,

[0018] NHSO 2 (C 1 -C 3 )alkyl;

[0019] Group N(SO 2 (C 1 -C 3 )alkyl) 2 ;

[0020] Group NH-CO-R 3 ,

[0021] Where R 3 Selected from the group consisting of: benzyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 ) alkyl, phenyl, vinyl, halogen -CH 2 -、(C 1 -C 3 )alkyl;

[0022] Group NH-CH 2 -R 4 ,

[0023] Where R 4 is an optionally substituted benzene ring or an optionally substituted (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S; or

[0024] R 1 and R 2 Together they form an optionally substituted aromatic ring containing 6 carbon atoms.

[0025] In a preferred and advantageous embodiment, R 1 or R 2 It is the group NH-CH 2 -R 4 , where R 4 is an optionally substituted aromatic ring or an optionally substituted (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S.

[0026] In a further aspect, the present invention relates to a tetrahydroquinoline compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0027] In still another aspect, the present invention relates to a tetrahydroquinoline compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a disruptor of FANCM / BTR interaction so as to hinder the localization of FANCM to telomeres, preferably for the treatment of tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Scheme 1 reports the general procedure for the synthesis of Compounds 1-6, 14, 19, and 20.

[0030] Figure 2 Scheme 2 reports the general procedure for the synthesis of Compound 8, Compound 9, Compound 11-Compound 13, Compound 16-Compound 18, and Compound 21-Compound 32.

[0031] Figure 3 Scheme 3 reports the general procedure for the synthesis of compound 7, compound 10, and compound 15.

[0032] Figure 4 In a), analysis of drug treatments for inhibition of 50% growth of U2OS cell lines (left) and induction of 50% cell death in the same cell lines (right) is reported. Error bars represent mean ± SEM from n = 3 experiments. In b), IC 50 (Left) and EC 50 (Right) Comparison of values. Each point represents the IC calculated from a drug that successfully inhibited growth or caused cell death in a cell line. 50 and EC 50 The bars represent the mean IC within each group. 50 and EC 50 In c) and d), co-immunoprecipitation was performed using RMI1 antibody to determine whether FANCM-BTR interaction was inhibited by compound 32. U2OS cells (IC 50 =15.51 μM). Western blots of co-immunoprecipitation products are shown (g), 5% input is shown in (top), and eluate is shown in (bottom). Eluate was normalized and expressed as a percentage of its corresponding input. Quantification was performed using ImageJ software.

[0033] Figure 5 Cell proliferation graphs for different cell lines treated with Compound 1, Compound 2, Compound 14, and Compound 32 are reported. Cells were treated with compounds at concentrations of 0 μM (0.5% DMSO), 0.625 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, 15 μM, 20 μM, and 25 μM. Cell proliferation was measured by % confluence. Error bars represent mean ± SEM from n = 3 experiments. DETAILED DESCRIPTION OF THE INVENTION

[0035] Therefore, the present invention relates to a tetrahydroquinoline compound of formula (I) or a pharmaceutically acceptable salt thereof

[0036]

[0037] in

[0038] A is (C 3 -C 7 )cycloalkyl; containing from 1 to 3 heteroatoms selected from O, N and S (C 3 -C 7 )heterocycloalkyl; (C 1 -C 7 ) alkyl; containing from 1 to 3 heteroatoms selected from O, N and S (C 1 -C 7 )heteroalkyl; an optionally substituted benzene ring or an optionally substituted (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S;

[0039] R is H, (C 1 -C 4 ) alkyl, (C 1 -C 3 ) alkoxy (C 1 -C 3 ) alkyl, (C 3 -C 7 )cycloalkyl;

[0040] R 1 and R 2 Independently selected from the group consisting of: H, NO 2 , CN, halogen, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 ) alkyl, substituted by a (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S 1 -C 4 )alkyl,

[0041] Optionally bis(dimethylamino)methylene, pyridyl, trifluoromethyl-SO 2 -、(C1 -C 3 )alkyl-SO 2 -substituted amino group,

[0042] Group NH-CO-R 3 ,

[0043] Where R 3 Selected from the group consisting of: benzyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 ) alkyl, phenyl, vinyl, halogen -CH 2 -、(C 1 -C 3 )alkyl;

[0044] Group NH-CH 2 -R 4 ,

[0045] Where R 4 is an optionally substituted benzene ring or an optionally substituted (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S; or

[0046] R 1 and R 2 Together they form an optionally substituted aromatic ring containing 6 carbon atoms.

[0047] When used in this invention, the following terms:

[0048] -“(C 1 -C 4 )alkyl" means a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl and isobutyl and the like;

[0049] -“(C 2 -C 4 )alkenyl" means an alkenyl group containing from 2 to 4 carbon atoms, such as vinyl, 1-propylene, 2-propylene, 1-butene, 1,2-butadiene and the like;

[0050] -“(C 1 -C 3 ) "alkoxy" means a straight or branched chain alkoxy group containing from 1 to 3 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like;

[0051] -“(C 3 -C 7) "Cycloalkyl" means a 3- to 7-membered all-carbon ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and cycloheptenyl;

[0052] - "containing from 1 to 3 heteroatoms selected from O, N and S (C 3 -C 7 )heterocycloalkyl" means a 3- to 7-membered all-carbon ring in which from 1 to 3 carbons are substituted by heteroatoms selected from O, N and S, such as oxiran-2-yl, oxiran-2-yl, aziridine-2-yl, 1H-aziridine-2-yl, 2H-aziridine-2-yl, 2H-aziridine-3-yl, thiirane-2-yl, thiirane-2-yl, thiol-2-yl, thiol-3-yl, thiol ... -2-yl, thietan-2-yl, 2H-thietan-3-yl, 2H-oxetan-3-yl, oxetan-3-yl, oxetan-2-yl, 2-pyrrolidinyl, 2-tetrahydrofuranyl, 2-tetrahydrothienyl, 2-piperidinyl, 2-tetrahydropyranyl, 2-thienyl, 2-azepanyl, 2-oxepanyl, 2-thiepanyl and the like;

[0053] - "containing from 1 to 3 heteroatoms selected from O, N and S (C 1 -C 7 )heteroalkyl” means a straight or branched alkyl group containing from 1 to 7 carbon atoms, wherein from 1 to 3 carbon atoms are substituted by heteroatoms selected from O, N and S, such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, pentyloxymethyl, butoxymethyl, propoxymethyl, ethoxymethyl, methoxymethyl, methylamino, ethylamino, propylamino, butylamino, pentylamino, methylthio, ethylthio, propylthio, butylthio, pentylthio and the like;

[0054] - "a (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S" means a 5- to 9-membered aromatic carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur; the heteroaromatic ring may optionally be further fused to an aromatic ring. Non-limiting examples of (5-9) membered heteroaromatic rings are, for example, pyrrol-2-yl, pyrrol-3-yl, furan-2-yl, furan-3-yl, thien-2-yl, thien-3-yl, imidazol-4-yl, 1,3-oxazol-5-yl, 1,3-oxazol-4-yl, 1,3-thiazol-5-yl, 1,3-thiazol-4-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-5-yl, pyridine- 2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, indol-2-yl, indol-3-yl, isoindol-1-yl, 1-benzofuran-3-yl, 1-benzofuran-2-yl, 2-benzofuran-1-yl, 2-benzothiophene-1-yl, 1-benzothiophene-3-yl, 2-benzothiophene-3-yl, benzimidazol-2-yl.

[0055] According to the present invention and unless otherwise provided, when any of the above mentioned groups is optionally substituted, it may be replaced at any free position thereof by one or more straight or branched (C 1 -C 4 ) is substituted with an alkyl group or a halogen atom.

[0056] The term "pharmaceutically acceptable salts" of compounds of formula (I) refers to those salts that retain the biological effectiveness and properties of the compounds, and thus pharmaceutically acceptable salts of compounds of formula (I) include acid addition salts with inorganic or organic acids, such as nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, (D) lactic acid or (L) lactic acid, oxalic acid, ascorbic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, isethionic acid, succinic acid and salicylic acid.

[0057] In a preferred and advantageous embodiment, R 1 or R 2 It is the group NH-CH 2 -R 4 , where R 4 is an optionally substituted aromatic ring or an optionally substituted (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S.

[0058] Without being bound by any theory, the inventors believe that the compound of formula (I) can inhibit the activity or expression of FANCM due to its specific structure, such as inhibiting the interaction between FANCM and RMI and / or the ATPase activity of FANCM, so as to inhibit the growth and / or proliferation of ALT tumor cells and / or induce the death of ATL tumor cells.

[0059] According to the present invention, A is (C 3 -C 7 )cycloalkyl; containing from 1 to 3 heteroatoms selected from O, N and S (C 3 -C 7 )heterocycloalkyl; (C 1 -C 7 ) alkyl; containing from 1 to 3 heteroatoms selected from O, N and S (C 1 -C 7 )heteroalkyl; an optionally substituted benzene ring or an optionally substituted (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S.

[0060] In a preferred embodiment, A is (C 3 -C 7 )cycloalkyl, more preferably A is cyclopentyl.

[0061] When A is (C 3 -C 7 ) cycloalkyl, it is preferably selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, more preferably A is cyclopentyl.

[0062] When A is (C 3 -C 7 ) is heterocycloalkyl, it is preferably selected from the group consisting of pyrrolidin-2-yl, tetrahydrofuran-2-yl, tetrahydrothiophen-2-yl.

[0063] When A is (C 1 -C 7 )alkyl, it is preferably selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, propan-2-yl, but-2-yl, pent-2-yl, hex-2-yl, pent-3-yl, 2-methylpent-3-yl, 2,4-dimethylpent-3-yl, tert-butyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl and 4-methylpentyl.

[0064] When A is (C 1 -C 7 ) is preferably selected from the group consisting of methoxy, propoxy, butoxy, pentyloxy, hexyloxy, pentyloxymethyl.

[0065] When A is a (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S, it is selected from the group consisting of pyrrolyl, pyrrol-2-yl, pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, imidazol-4-yl, 1,3-oxazol-5-yl, 1,3-oxazol-4-yl, 1,3-thiazol-5-yl, 1,3-thiazol-4-yl, 1,2,3-triazol-4-yl, 1 , 2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, indol-2-yl, indol-3-yl, isoindol-1-yl, 1-benzofuran-3-yl, 1-benzofuran-2-yl, 2-benzofuran-1-yl, 2-benzothiophene-1-yl, 1-benzothiophene-3-yl, 2-benzothiophene-3-yl and benzimidazol-2-yl.

[0066] R is H, (C 1 -C 4 ) alkyl, (C 1 -C 3 ) alkoxy (C 1 -C 3 ) alkyl or (C 3 -C 7 )cycloalkyl.

[0067] In a preferred embodiment, R is (C 1 -C 4 ) alkyl, more preferably R is ethyl.

[0068] When R is (C 1 -C 4 ) alkyl, it is preferably selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl and isobutyl, more preferably ethyl.

[0069] When R is (C 1 -C 3 ) alkoxy, it is preferably methoxy.

[0070] When R is (C 1 -C 3 ) alkyl, it is preferably ethyl.

[0071] When R is (C 3 -C 7 ) is cycloalkyl, it is preferably cyclopropyl.

[0072] According to the present invention, R 1 and R 2 Independently selected from the group consisting of: H, NO2 , CN, halogen, (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, a (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S,

[0073] Optionally bis(dimethylamino)methylene, pyridyl, trifluoromethyl-SO 2 -、(C 1 -C 3 )alkyl-SO 2 -substituted amino group,

[0074] NHSO 2 (C 1 -C 3 )alkyl;

[0075] Group N(SO 2 (C 1 -C 3 )alkyl) 2 ;

[0076] Group NH-CO-R 3 ,

[0077] Where R 3 Selected from the group consisting of: benzyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 ) alkyl, phenyl, vinyl, halogen -CH 2 -、(C 1 -C 3 )alkyl;

[0078] Group NH-CH 2 -R 4 ,

[0079] Where R 4 is an optionally substituted benzene ring or an optionally substituted (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S; and

[0080] R 1 and R 2Together they form an optionally substituted aromatic ring containing 6 carbon atoms.

[0081] In a preferred embodiment, R 1 or R 2 One of them is H.

[0082] In a more preferred embodiment, R 1 and R 2 One of them is H and the other is the group NH-CH 2 -R 4 , where R 4 is an optionally substituted benzene ring or an optionally substituted (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S.

[0083] In a still more preferred embodiment, R 4 Selected from the group consisting of pyrrol-2-yl, pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, imidazol-4-yl, 1,3-oxazol-5-yl, 1,3-oxazol-4-yl, 1,3-thiazol-5-yl, 1,3-thiazol-4-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridine-3-yl, imidazol-4-yl, 1,3-oxazol-5-yl, 1,3-thiazol-4-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridine-3-yl, pyridine-4-yl, pyridine-5-yl, pyridine-6-yl, pyridine-7-yl, pyridine-8-yl, pyridine-9-yl, pyridine-10-yl, pyridine-11-yl, pyridine-12-yl, pyridine-13-yl, pyridine-14-yl, pyridine-15-yl, pyridine-16-yl, pyridine-17-yl, pyridine-18-yl, pyridine-19-yl, pyridine-1 In a still more preferred and advantageous embodiment, R 4 It is imidazol-4-yl.

[0084] R 4 It may be an optionally substituted benzene ring. Preferably, it is a phenyl group substituted by halogen, more preferably a phenyl group substituted by bromine.

[0085] When R 1 or R 2 When halogen, it is preferably bromine.

[0086] When R 1 or R 2 Yes (C 1 -C 4 )alkyl, it is preferably selected from butan-2-yl (or sec-butyl) or propan-2-yl (or isobutyl).

[0087] When R 1 or R 2 Yes (C 2 -C 4) alkenyl, it is preferably vinyl.

[0088] When R 1 or R 2 Yes (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl, it is preferably methoxyethyl.

[0089] When R 1 or R 2 is substituted by a (5-9) membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S 1 -C 4 )alkyl, it is preferably furan-2-ylmethyl.

[0090] When R 1 or R 2 Yes (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, it is preferably 3-(cyclopentyl)methyl.

[0091] When R 1 or R 2 is optionally bis(dimethylamino)methylene, pyridyl, trifluoromethyl-SO 2 -、(C 1 -C 3 )alkyl-SO 2 -substituted amino, it is preferably selected from bis(dimethylamino)methylene, pyridyl, trifluoromethyl-SO 2 -, methyl-SO 2 -substituted amino.

[0092] R 1 or R 2 It can be the group NH-CO-R 3 , where R 3 Selected from the group consisting of: benzyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 ) alkyl, phenyl, vinyl, halogen -CH 2 -、(C 1 -C 3 ) alkyl. Preferably, R 3 Selected from benzyl, cyclopentylethyl, phenyl, vinyl, bromo-CH 2 - and ethyl group.

[0093] R 1and R 2 They may also together form an optionally substituted aromatic ring containing 6 carbon atoms.

[0094] In a preferred embodiment, the compound of formula (I) is selected from the group consisting of:

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] Preferably, the tetrahydroquinoline compound of formula (I) or a pharmaceutically acceptable salt thereof is Compound 32, Compound 1, Compound 2 and Compound 14. More preferably, it is Compound 32.

[0103] Compound 1-Compound 6, Compound 14, Compound 19 and Compound 20 are as shown in Scheme 1 ( Figure 1 ) as reported in .

[0104] Compound 8, Compound 9, Compound 11-Compound 13, Compound 16-Compound 18 and Compound 21-Compound 32 were prepared by following Scheme 2 ( Figure 2 ) was obtained according to the general procedure reported in .

[0105] Compound 7, compound 10 and compound 15 follow Scheme 3 ( Figure 3 ) was obtained through the method reported in .

[0106] Preferably, the compounds of the present invention are present in pharmaceutical compositions together with pharmaceutically acceptable carriers and excipients.

[0107] Therefore, in a further aspect, the present invention relates to a composition of the present invention and at least one pharmaceutically acceptable excipient.

[0108] Therefore, the composition may also contain a pharmaceutically acceptable excipient and may be administered in a pharmaceutical form suitable for the desired administration route.

[0109] Pharmaceutically acceptable additives may be excipients, ligands, dispersants, colorants and wetting agents, and are typically used to prepare tablets, capsules, pills, solutions, suspensions and emulsions for oral administration. Injectable solutions for parenteral administration are also contemplated, including subcutaneous, spinal and transdermal administration.

[0110] The compound of formula (I) can be used in free alkali or salt form. Preferably, the salt is a salt selected from the group consisting of hydrochloride, hydrobromide, phosphate, sulfate, bisulfate, alkyl sulfonate, aryl sulfonate, acetate, citrate, oxalate, maleate, fumarate, succinate, lactate and tartrate. Salt can also be formed between a cation and a negatively charged group. Suitable cations include potassium ions, magnesium ions, calcium ions and ammonium cations such as tetramethylammonium ions. Examples of some suitable substituted ammonium ions are those derived from ethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, piperazine, choline, meglumine and tromethamine and amino acids such as lysine and arginine.

[0111] The pharmaceutical composition according to the present invention is preferably for intra-articular, intravenous, oral, transdermal, intrathecal, intranasal, intraperitoneal or intramuscular administration, more preferably oral administration.

[0112] The compounds of formula (I) of the present invention are preferably administered at a dosage ranging from 1 nM to 20000 nM, more preferably at a dosage ranging from 1 nM to 1000 nM.

[0113] In a further aspect, the present invention relates to a tetrahydroquinoline compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0114] In still another aspect, the present invention relates to a tetrahydroquinoline compound of formula (I) or a pharmaceutically acceptable salt thereof, used as a disruptor of FANCM / BTR interaction to hinder FANCM localization at telomeres, preferably for treating tumors, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancers, Kaposi's sarcoma (soft tissue sarcoma), AIDS-related lymphoma (lymphoma), primary CNS lymphoma (lymphoma), anal cancer, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma of the skin, bile duct cancer, bladder cancer, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma (Burkitt lymphoma). Lymphoma, Carcinoid tumor (gastrointestinal), Cancer of unknown primary, Cardiac (heart) tumors, Central nervous system tumors, Atypical teratoid / rhabdoid tumors, Medulloblastoma and other CNS embryonal tumors, Germ cell tumors, Primary CNS lymphoma, Cervical cancer, Childhood cancer, Cholangiocarcinoma, Chondrosarcoma, Chordoma, Chronic lymphocytic leukemia (CLL), Chronic myelogenous leukemia (CML), Leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma and other central nervous system cancers, endometrial cancer, childhood ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, central nervous system germ cell tumors in children, extracranial germ cell tumors in children, extragonadal germ cell tumors, ovarian germ cell tumors, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, cardiac tumors, childhood hepatocellular carcinoma, Langerhans cell histiocytosis (Histiocytosis,Langerhans Cell, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, Kaposi's sarcoma, renal cancer, Langerhans cell histiocytosis Cell Histiocytosis), laryngeal cancer, leiomyoma, leukemia, lip and oral cancer, liposarcoma, liver cancer, lung cancer (including non-small cell, small cell, pleuropulmonary blastoma, inflammatory myofibroblastic tumor of the lung and tracheobronchial tumor), leiomyosarcoma, lymphoma, male breast cancer, malignant fibrous histiocytoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma (skin cancer), mesothelioma, malignant metastatic cancer, occult primary metastatic squamous neck cancer, midline tract cancer with NUT gene alteration, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, chronic myelogenous leukemia (CML), acute myeloid leukemia (Myeloid Leukemia, Acute, AML), Chronic Myeloproliferative Neoplasms, Nasal and Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Lip and Oral Cavity Cancer, and Oropharyngeal Cancer, Osteosarcoma, Osteoclastoma, Ovarian Cancer, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (PanNET), Papillomatosis, Paraganglioma, Sinus and Nasal Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumors, Plasma Cell Neoplasms / Multiple Myeloma, Pleuropulmonary Blastomycin, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Primary Peritoneal Cancer, Prostate Cancer, Inflammatory Myofibroblastic Tumor of the Lung, Rare Cancers in Children, Rectal Cancer, Recurrent Cancers, Renal Cell Carcinoma, Retinoblastoma, Rhabdomyosarcoma, Childhood, Salivary Gland Cancer, Sarcoma, Rhabdomyosarcoma, Childhood Rhabdomyosarcoma), childhood vascular tumors, Ewing sarcoma, Kaposi sarcoma, osteosarcoma, soft tissue sarcoma, uterine sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, cutaneous squamous cell carcinoma, metastatic occult primary squamous neck cancer, gastric cancer, T-cell lymphoma, testicular cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma and thymic cancer, thyroid cancer, tracheobronchial tumor, transitional cell carcinoma of the renal pelvis and ureter, cancer of unknown primary, undifferentiated pleomorphic sarcoma, transitional cell carcinoma of the ureter and renal pelvis, urethral cancer, uterine cancer, endometrial cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, Wilms tumor and other childhood kidney tumors. ,

[0115] The present inventors have found that the compound of formula (I) can inhibit the activity or expression of FANCM due to its specific structure, such as inhibiting the interaction between FANCM and RMI and / or the ATPase activity of FANCM, so as to inhibit the growth and / or proliferation of ALT tumor cells and / or induce the death of ATL tumor cells, such as chondrosarcoma, osteoclastoma, osteosarcoma, breast cancer, CNS cancer, neuroblastoma, pancreatic neuroendocrine tumor (PanNET), angiosarcoma, leiomyoma, leiomyosarcoma, liposarcoma, undifferentiated pleomorphic sarcoma.

[0116] Furthermore, the present invention relates to a tetrahydroquinoline compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a disruptor of FANCM / BTR interaction in order to hinder the localization of FANCM to telomeres for the treatment of human disorders such as Bloom syndrome, dyskeratosis congenita and possibly age-related diseases.

[0117] The present invention will now be described in detail with reference to examples of preparation of the compounds of the present invention and examples for testing antitumor activity, which are for illustrative purposes rather than for limiting purposes.

[0118] Experimental Section

[0119] The compounds of the invention were prepared according to the synthetic schemes reported below.

[0120] Materials and methods.

[0121] Final compounds were analyzed by analytical HPLC (Shimadzu Prominance HPLC system) equipped with a C18-bound analytical RP-HPLC column (Phenomenex Kinetex, 4.6 mm×150 mm, 5 μm) using gradient elution (10% to 90% acetonitrile (0.1% TFA) in water in 20 min; flow rate = 1.0 mL / min; diode array UV detector). Molecular weights of compounds were confirmed by ESI-mass spectrometry (MS) using a Q Exactive Orbitrap LC-MS / MS system (Thermo Fisher Scientific, Waltham, MA, USA). Spectrometers were recorded on a Varian INOVA 500 MHz spectrometer. 1 HNMR and 13 C NMR spectroscopy and measurement of CDCl 3 (7.26 / 77.16ppm) or DMSO-d 6(2.50 / 39.52 ppm). Multiplicity abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, hept = septet, dd = doublet of doublet, td = doublet of triplet, m = multiplet, and bs = broad signal. Coupling constant J values ​​are measured in Hertz (Hz), and chemical shift values ​​are in parts per million (ppm).

[0122] Example 1

[0123] A) Preparation of N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-nitrobenzenesulfonamide.

[0124]

[0125] A stirred solution of (1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methanamine (570 mg, 3 mmol, 1 eq) and DIPEA (548 μL, 3.15 mmol, 1.05 eq) in anhydrous DCM (9 mL) was cooled to 0 °C in an ice bath, then a solution of 3-nitrobenzenesulfonyl chloride (1183 mg, 3.15 mmol, 1.05 eq) in anhydrous DCM (2 mL) was added dropwise, and the resulting mixture was allowed to stir at room temperature overnight. The organic solvent was evaporated under reduced pressure, the reaction was extracted in EtOAc and washed with 0.1 M HCl (2 × 30 mL) and NaHCO 3 The saturated solution (2×50 mL) was washed. Each aqueous aliquot was back extracted with 2 aliquots of EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and the volatiles were evaporated under vacuum to obtain the desired product as a light yellow powder (1010 mg, 92%), which was used in the next step without any further purification.

[0126] 1 H NMR (400 MHz, CDCl 3 )δ8.52(d,J=2.0Hz,1H),8.37-8.31(m,1H),8.11(dq,J=7.8,1.2Hz,1H),7.65( t,J=8.0Hz,1H),6.74(dd,J=8.3,2.2Hz,1H),6.63(d,J=2.2Hz,1H),6.35(d,J=8 .4Hz,1H),4.93(s,1H),4.08(d,J=5.9Hz,2H),3.26(q,J=7.0Hz,2H),3.20(t,J= 5.7Hz, 2H), 2.57 (t, J = 6.4Hz, 2H), 1.86 (p, J = 6.1Hz, 2H), 1.07 (t, J = 7.0Hz, 3H).

[0127] 13C NMR (101 MHz, CDCl 3 )δ148.15,144.90,143.07,132.71,130.20,129.28,127.31,126.72,122 .57,121.40,110.28,110.14,48.37,47.47,45.35,28.10,22.12,10.87.

[0128] The following intermediates were prepared according to the scheme mentioned above:

[0129] N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-vinylbenzenesulfonamide

[0130]

[0131] 1 H NMR (400 MHz, CDCl 3 )δ7.80(d,J=8.4Hz,2H),7.51(d,J=8.3Hz,2H),6.83-6.73(m,2H),6.68(d,J=2 .2Hz,1H),6.45(d,J=8.4Hz,1H),5.88(d,J=17.6Hz,1H),5.43(d,J=10.9Hz,1H ),4.53(t,J=5.9Hz,1H),3.97(d,J=5.9Hz,3H),3.29(q,J=7.1Hz,2H),3.21(t, J=5.7Hz,2H),2.62(t,J=6.4Hz,2H),1.96-1.87(m,2H),1.09(t,J=7.0Hz,3H).

[0132] 13 C NMR (101 MHz, CDCl 3 )δ144.87,141.77,139.08,135.57,129.27,127.65,127.15,126.78,122 .72,122.34,117.33,110.47,48.44,47.27,45.40,28.15,22.22,10.81.

[0133] N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-isopropylbenzenesulfonamide

[0134]

[0135] 1 H NMR (400 MHz, CDCl 3)δ7.73(s,1H),7.69(dd,J=6.5,2.2Hz,1H),7.43(s,2H),6.81(dd,J=8.4,2.2Hz,1H),6.71(d,J=2.2Hz,1H),6.49(d,J=8.4Hz,1H),4.86(t,J=5.9Hz,1H),3.98(d,J=5.9Hz,2H),3.30(q,J=7.1Hz,2H),3.23(t,J=5.6Hz,2H),2.97(hept,J=7.0Hz,1H),2.63(t,J=6.4Hz,2H),1.90(p,J=6.1Hz,2H),1.27(d,J=6.9Hz,6H),1.10(t,J=7.0Hz,3H)。

[0136] 13 C NMR(101MHz,CDCl 3 )δ150.19,140.07,133.72,130.77,129.74,129.17,129.04,127.02,125.07,124.68,118.25,113.54,48.30,47.07,45.70,34.12,27.90,23.83,21.87,10.70。

[0137] N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)naphthalene-2-sulfonamide

[0138]

[0139] 1 H NMR(400MHz,CDCl 3 )δ8.39(d,J=1.8Hz,1H),7.93-7.85(m,3H),7.82(dd,J=8.6,1.9Hz,1H),7.65-7.54(m,2H),6.84(dd,J=8.4,2.2Hz,1H),6.68(d,J=2.2Hz,1H),6.48(d,J=8.4Hz,1H),5.29(s,1H),4.03(d,J=5.9Hz,2H),3.21(q,J=7.1Hz,2H),3.15(t,J=5.7Hz,2H),2.47(t,J=6.4Hz,2H),1.79(p,J=6.2Hz,2H),1.07(t,J=7.0Hz,3H)。

[0140] 13 C NMR(101MHz,CDCl 3)δ137.14,134.69,132.12,130.45,130.32,129.92,129.31,129.28,128.96,128.63,128.48,128.19,127.87,127.40,127.11,122.52,48.14,47.10,46.10,27.50,21.38,10.65。

[0141] N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-(2-methoxyethyl)benzenesulfonamide

[0142]

[0143] 1 H NMR(400MHz,CDCl 3 )δ7.78(d,J=8.2Hz,2H),7.35(d,J=8.3Hz,2H),6.81(dd,J=8.4,2.3Hz,1H),6.71(d,J=2.2Hz,1H),6.45(d,J=8.4Hz,1H),4.77(t,J=5.8Hz,1H),3.95(d,J=5.8Hz,2H),3.63(t,J=6.7Hz,2H),3.35(s,3H),3.29(q,J=7.1Hz,2H),3.21(t,J=5.7Hz,2H),2.94(t,J=6.7Hz,2H),2.63(t,J=6.4Hz,2H),1.97-1.83(m,2H),1.09(t,J=7.0Hz,3H)。

[0144] 13 C NMR(101MHz,CDCl 3 )δ144.69,144.38,137.97,129.49,129.15,127.27,127.02,122.58,122.49,110.38,72.77,58.74,48.33,47.08,45.29,36.03,28.06,22.15,10.71。

[0145] 4-Cyano-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide

[0146]

[0147] 1 H NMR(400MHz,CDCl 3)δ7.86(d,J=8.0Hz,2H),7.69(d,J=8.0Hz,2H),6.76(d,J=7.6Hz,1H),6.61(s,1H),6.39(d,J=7.6Hz,1H),5.15(t,J=5.8Hz,1H),4.01(d,J=5.8Hz,2H),3.29(q,J=7.1Hz,2H),3.22(t,J=5.7Hz,2H),2.57(t,J=6.4Hz,2H),1.88(p,J=6.1Hz,2H),1.10(t,J=5.7Hz,3H)。

[0148] 13 C NMR(101MHz,CDCl 3 )δ144.87,144.79,132.67,129.22,127.77,127.21,122.44,121.73,117.55,115.80,110.25,48.31,47.24,45.29,28.06,22.08,10.73。

[0149] N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-2-nitrobenzenesulfonamide

[0150]

[0151] 1 H NMR(400MHz,CDCl 3 )δ7.99(dd,J=7.2,1.9Hz,1H),7.80(d,J=7.4Hz,1H),7.70-7.57(m,2H),6.83(dd,J=8.4,2.2Hz,1H),6.73(s,1H),6.39(d,J=8.3Hz,1H),5.19(s,1H),4.14(d,J=5.8Hz,2H),3.28(q,J=7.1Hz,2H),3.20(t,J=5.7Hz,2H),2.59(t,J=6.5Hz,2H),1.87(p,J=6.1Hz,2H),1.08(t,J=7.1Hz,3H)。

[0152] 13 C NMR(101MHz,CDCl 3 )δ147.72,144.78,134.13,133.20,132.67,131.20,129.14,127.13,125.10,122.41,121.83,110.25,48.31,47.85,45.26,28.03,22.11,10.73。

[0153] B) Preparation of N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-nitrobenzenesulfonamide (Compound 1).

[0154]

[0155] To N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-nitrobenzenesulfonamide (722 mg, 2.102 mmol, 1 eq), PPh 3 To the stirred solution of cyclopentanol (1652mg, 6.306mmol, 3 equivalents) and cyclopentanol (572 μ L, 6.306mmol, 3 equivalents) in anhydrous toluene, activated molecular sieves are added, and the mixture is allowed to stir for 15 minutes at 0 ° C. Diethyl azodicarboxylate solution (40% in toluene) (1528 μ L, 8.390mmol, 3 equivalents) is added dropwise under an inert atmosphere. The mixture is stirred at room temperature overnight. The mixture is evaporated under reduced pressure, and then the desired product (930mg, 100%) as a light orange solid is purified by flash chromatography (hexane / EtOAc 9:1).

[0156] LC-MS: t R 17.98 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 23 H 30 N 3 O 4 S[M+H] + , HRMS calculated value: 444.19515, measured value: 444.19452.

[0157] 1 H NMR (400 MHz, CDCl 3 )δ8.38(t,J=2.1Hz,1H),8.32-8.25(m,1H),8.02-7.95(m,1H),7.59(t,J=8.0Hz,1H),6 .86(d,J=8.3Hz,1H),6.74(s,1H),6.39(d,J=8.4Hz,1H),4.37(p,J=8.4Hz,1H),4.25(s, 2H),3.27(q,J=7.1Hz,2H),3.21(d,J=6.4Hz,2H),2.60(t,J=6.4Hz,2H),1.88(d,J=6.4 Hz, 2H), 1.84-1.70 (m, 3H), 1.68-1.57 (m, 2H), 1.57-1.46 (m, 4H), 1.09 (t, J = 7.0Hz, 3H).

[0158] 13 C NMR (101 MHz, CDCl 3 )δ148.30,144.45,132.73,130.24,129.35,127.43,126.49,122.67,1 10.44,60.27,48.66,47.75,45.72,30.24,28.46,23.84,22.52,11.23.

[0159] according to Figure 2 The following final compounds were prepared according to the general procedure reported in:

[0160] 3-Bromo-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-benzenesulfonamide (Compound 3)

[0161]

[0162] Purification (hexane / EtOAc 92:8). Yield = 82%. LC-MS: t R 18.60 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 23 H 30 Bn 2 O 2 S[M+H] + , HRMS calculated value: 477.12059, found value: 477.12050. For C 23 H 30 Bn 2 O 2 S[M+H] + , calculated value: 479.11854, measured value: 479.11868.

[0163] 1 H NMR (400 MHz, CDCl 3)δ7.87-7.79(m,1H),7.68(dd,J=7.7,2.2Hz,1H),7.62(dt,J=8.6,2.1Hz,1H),7.30(td,J =8.0,2.7Hz,1H),6.98-6.89(m,1H),6.84(s,1H),6.48(dd,J=8.5,2.7Hz,1H),4.31-4.18 (m,3H),3.31(q,J=7.1Hz,2H),3.23(t,J=6.5Hz,2H),2.68(t,J=6.5Hz,2H),1.92(p,J=6. 5Hz,2H),1.74-1.61(m,2H),1.61-1.50(m,2H),1.50-1.37(m,4H),1.12(t,J=7.1Hz,3H).

[0164] 13 C NMR (101 MHz, CDCl 3 )δ144.42,143.45,135.03,130.37,130.18,128.64,126.59,125.65,124.21,122.8 3,122.50,110.37,59.75,48.47,47.46,45.51,29.61,28.28,23.57,22.40,10.96.

[0165] N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-vinylbenzenesulfonamide (compound Object 4)

[0166]

[0167] Purification (hexane / EtOAc 92:8). Yield = 91%. LC-MS: t R 18.34 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 25 H 33 N 2 O 2 S[M+H] + , HRMS calculated value: 425.22572, measured value: 425.22558.

[0168] 1 H NMR (400 MHz, CDCl 3)δ7.73(d,J=8.1Hz,2H),7.46(d,J=8.1Hz,2H),7.06-6.94(m,1H),6.88(s,1H),6.73(dd,J=17. 6,10.9Hz,1H),6.50(d,J=8.4Hz,1H),5.86(d,J=17.6Hz,1H),5.40(d,J=10.9Hz,1H),4.24(s,2H ),4.19-3.99(m,1H),3.31(q,J=7.1Hz,2H),3.22(t,J=5.6Hz,2H),2.68(t,J=6.4Hz,2H),1.93( q,J=6.3Hz,2H),1.79-1.58(m,4H),1.58-1.47(m,2H),1.47-1.35(m,2H),1.11(t,J=7.0Hz,3H).

[0169] 13 C NMR (101 MHz, CDCl 3 )δ144.28,141.23,140.30,135.64,128.47,127.54,126.58,126.34,124.98,122.5 3,116.95,110.42,59.61,48.46,47.37,45.48,29.41,28.26,23.54,22.43,10.87.

[0170] N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-isopropylbenzenesulfonamide (compound Object 5 )

[0171]

[0172] Purification (hexane / EtOAc 92:8). Yield = 44%. LC-MS: t R 19.16 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 26 H 37 N 2 O 2 S[M+H] + , HRMS calculated value: 441.25702, found value: 441.25732. For C 26 H 36 N 2 NaO 2 S[M+Na] + , calculated value: 463.23952, measured value: 463.23831.

[0173] 1 H NMR (400 MHz, CDCl 3 )δ7.65(s,1H),7.63(dd,J=6.0,2.7Hz,1H),7.46-7.35(m,2H),6.99(dd,J=8.3,2.2Hz,1H),6 .91(d,J=2.2Hz,1H),6.51(d,J=8.4Hz,1H),4.28-4.18(m,3H),3.32(q,J=7.1Hz,2H),3.23(t, J=5.7Hz,2H),2.96(hept,J=6.9Hz,1H),2.70(t,J=6.4Hz,2H),1.93(p,J=6.1Hz,2H),1.67-1. 57(m,2H),1.55-1.47(m,2H),1.46-1.34(m,4H),1.26(d,J=6.9Hz,6H),1.12(t,J=7.0Hz,3H).

[0174] 13 C NMR (101 MHz, CDCl 3 )δ149.97,144.25,141.16,130.39,128.88,128.45,126.32,125.17,125.12,124.68,122. 48,110.38,59.61,48.45,47.27,45.46,34.17,29.32,28.28,23.90,23.56,22.42,10.89.

[0175] N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)naphthalene-2-sulfonamide (Compound 6 )

[0176]

[0177] Purification (hexane / EtOAc 93:7). Yield = 61%. LC-MS: t R 18.85 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 27 H 33 N 2 O 2 S[M+H] + , HRMS calculated value: 449.22572, measured value: 449.22597.

[0178] 1 H NMR (400 MHz, CDCl 3)δ8.29(s,1H),7.97-7.83(m,3H),7.82-7.72(m,1H),7.64-7.51(m,2H),7.00 (d,J=8.7Hz,1H),6.87(d,J=2.6Hz,1H),6.48(dd,J=8.4,2.2Hz,1H),4.40-4.2 5(m,3H),3.29(q,J=2.2Hz,2H),3.18(t,J=5.6Hz,2H),2.61(t,J=6.4Hz,2H),1 .92-1.82(m,2H),1.73-1.62(m,2H),1.56-1.35(m,6H),1.10(t,J=2.1Hz,3H).

[0179] 13 C NMR (101 MHz, CDCl 3 )δ144.24,138.32,134.60,132.27,129.30,129.06,128.55,128.45,128.37,127.87,127.31,126.5 0,124.70,122.74,122.40,110.29,59.65,48.39,47.41,45.44,29.55,28.18,23.55,22.34,10.92.

[0180] N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-(2-methoxy-ethyl)benzenesulfonyl Amide (Compound 14)

[0181]

[0182] Purification (hexane / EtOAc 9:1). Yield = 75%. LC-MS: t R 18.20 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 26 H 36 N 2 NaO 3 S[M+H] + , HRMS calculated value: 479.23443, measured value: 479.23481.

[0183] 1 H NMR (400 MHz, CDCl 3)δ7.64-7.58(m,2H),7.39-7.30(m,2H),6.98(dd,J=8.4,2.2Hz,1H),6.91(d,J=2.2Hz,1H),6 .51(d,J=8.4Hz,1H),4.29-4.19(m,3H),3.32(q,J=7.1Hz,2H),3.23(t,J=5.6Hz,2H),2.70(t ,J=6.4Hz,2H),2.65(d,J=7.5Hz,2H),2.07(hept,J=7.7Hz,1H),1.93(p,J=6.1Hz,2H),1.73- 1.56(m,7H),1.56-1.45(m,4H),1.45-1.31(m,4H),1.21-1.15(m,1H),1.11(t,J=7.0Hz,3H).

[0184] 13 C NMR (101 MHz, CDCl 3 )δ144.21,143.56,140.91,132.70,128.77,128.44,127.40,126.27,125.18,124.51,122.50,110 .38,59.55,48.46,47.26,47.22,45.49,41.93,32.47,29.28,28.28,25.03,23.52,22.41,10.87.

[0185] 4-Cyano-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (Compound 19)

[0186]

[0187] Purification (hexane / EtOAc 9:1). Yield = 66%. LC-MS: t R 17.27 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 24 H 32 N 3 NaO 2 S[M+Na] + , HRMS calculated value: 446.18782, measured value: 446.18698.

[0188] 1 H NMR (400 MHz, CDCl 3)δ7.78(d,J=8.3Hz,2H),7.67(d,J=8.4Hz,2H),6.89(dd,J=8.4,2.4Hz,1H),6 .75(d,J=2.3Hz,1H),6.45(d,J=8.4Hz,1H),4.34-4.18(m,3H),3.31(q,J=7.0 Hz,2H),3.23(t,J=5.6Hz,2H),2.63(t,J=6.3Hz,2H),1.92(p,J=6.1Hz,2H),1 .76-1.63(m,2H),1.63-1.53(m,2H),1.53-1.38(m,4H),1.12(t,J=7.0Hz,3H).

[0189] 13 C NMR (101 MHz, CDCl 3 )δ145.92,144.40,132.53,128.76,127.62,126.80,123.47,122.35,117.62,1 15.44,110.23,59.85,48.39,47.47,45.39,29.71,28.22,23.43,22.30,10.82.

[0190] N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-2-nitrobenzenesulfonamide (Compound 20)

[0191]

[0192] Purification (hexane / EtOAc 85:15). Yield = 72%. LC-MS: t R 17.57 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 23 H 30 N 3 O 4 S[M+H] + , HRMS calculated value: 444.19515, found value: 444.19482. For C 23 H 29 N 3 NaO 4 S[M+Na] + , calculated value: 466.17765, measured value: 466.17715.

[0193] 1 H NMR (400 MHz, CDCl 3)δ7.69(d,J=7.9Hz,1H),7.58-7.50(m,2H),7.41(ddd,J=8.5,6.1,2.7Hz,1 H),6.89(dd,J=8.5,2.3Hz,1H),6.77(d,J=2.3Hz,1H),6.38(d,J=8.4Hz,1H ),4.46-4.20(m,3H),3.28(q,J=7.0Hz,2H),3.19(t,J=5.6Hz,2H),2.57(t, J=6.4Hz,2H),1.98-1.76(m,4H),1.62-1.46(m,6H),1.08(t,J=7.1Hz,3H).

[0194] 13 C NMR (101 MHz, CDCl 3 )δ147.65,144.34,135.11,132.55,131.27,131.03,128.98,127.03,123.79,123.4 4,122.33,110.26,59.94,48.41,47.63,45.37,29.66,28.12,23.56,22.33,10.79.

[0195] Example 2

[0196] A) Preparation of N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-nitrobenzenesulfonamide.

[0197]

[0198] A stirred solution of (1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methanamine (570 mg, 3 mmol, 1 eq.) and DIPEA (548 μL, 3.15 mmol, 1.05 eq.) in anhydrous DCM (8 mL) was cooled to 0 °C in an ice bath, then a solution of 4-nitrobenzenesulfonyl chloride (1183 mg, 3.15 mmol, 1.05 eq.) in anhydrous DCM (2 mL) was added dropwise, and the resulting mixture was allowed to stir at room temperature overnight. The organic solvent was evaporated under reduced pressure, the reaction was extracted in EtOAc and washed with 0.1 M HCl (2 × 30 mL) and NaHCO 3 The saturated solution (2×50 mL) was washed. Each aqueous aliquot was stripped with 2 aliquots of EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The desired product (1070 mg, 95%) was obtained as a light yellow powder after evaporation of the organic solvent and used in the next step without any further purification.

[0199] LC-MS: tR 10.12 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 18 H 22 N 3 O 4 S[M+H] + , LRMS calculated value: 376.13, measured value: 376.50.

[0200] 1 H NMR (400 MHz, CDCl 3 )δ8.39-8.16(m,2H),8.03-7.86(m,2H),6.77(dd,J=8.4,2.3Hz,1H),6.63(d,J=2.3Hz,1H),6.40(d,J=8.4Hz,1H),4.82(t,J=5.6Hz,1H) ,4.06(d,J=5.7Hz,2H),3.28(q,J=7.1Hz,2H),3.21(d,J=6.4Hz,2H),2.58(t,J=6.4Hz,2H),1.87(p,J=6.4Hz,2H),1.09(t,J=7.1Hz,3H).

[0201] 13 C NMR (101 MHz, CDCl 3 )δ146.52,145.00,129.31,128.49,127.32,124.20,122.61,121.53,110.34,48.40,47.47,45.37,28.17,22.13,10.77.

[0202] B) Preparation of N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-nitrobenzenesulfonamide (Compound 2).

[0203]

[0204] To N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-nitrobenzenesulfonamide (1050 mg, 2.797 mmol, 1 eq), PPh 3To the stirring solution of cyclopentanol (2200mg, 8.390mmol, 3 equivalents) and cyclopentanol (762 μ L, 8.390mmol, 3 equivalents) in anhydrous toluene, activated molecular sieves are added, and the mixture is allowed to stir for 15 minutes at 0 ° C. Diethyl azodicarboxylate solution (40% in toluene) (1528 μ L, 8.390mmol, 3 equivalents) is added dropwise under an inert atmosphere. The mixture is stirred at room temperature overnight. The mixture is evaporated under reduced pressure, and then the desired product (1005mg, 81%) as a light yellow liquid is purified by flash chromatography (hexane / EtOAc 7:3 to 1:1).

[0205] LC-MS: t R 12.15 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 23 H 30 N 3 O 4 S[M+H] + , HRMS calculated value: 444.19515, measured value: 444.19567.

[0206] 1 H NMR (400 MHz, CDCl 3 )δ8.21(d,J=8.4Hz,2H),7.82(d,J=8.3Hz,2H),6.89(d,J=8.3Hz,1H),6.74(s ,1H),6.44(d,J=8.4Hz,1H),4.32(p,J=8.5Hz,1H),4.26(s,2H),3.30(q,J=7.1 Hz,2H),3.22(t,J=5.7Hz,2H),2.60(t,J=6.4Hz,2H),1.89(p,J=6.0Hz,2H),1 .80-1.67(m,3H),1.67-1.55(m,2H),1.55-1.42(m,4H),1.11(t,J=7.1Hz,3H).

[0207] 13 C NMR (101 MHz, CDCl 3 )δ149.50,147.59,144.48,128.92,128.22,127.01,123.96,123.31,122.3 8,110.25,59.95,48.41,47.51,45.41,29.81,28.24,23.47,22.29,10.79.

[0208] C) Preparation 4-Amino-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide

[0209]

[0210] A stirred solution of N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-nitrobenzenesulfonamide (990 mg, 2.223 mmol, 1 eq) in anhydrous MeOH (12 mL) was flushed with nitrogen, and then a suspension of Pd / C (10% w / w) (99, 10% by weight relative to substrate) in anhydrous MeOH (3 mL) was added. The mixture was gently stirred under nitrogen atmosphere for 10 minutes. When the conversion was complete, H 2 (g) stream was bubbled through the suspension at room temperature for 3 hours. The mixture was filtered through a celite pad and eluted with a mixture of MeOH / THF (1: 1). The solvent was evaporated under reduced pressure, and a light yellow viscous oil (813 mg, 89%) was obtained, which was used for the following synthesis steps without any other purification.

[0211] LC-MS: t R 11.35 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 23 H 32 N 3 O 2 S[M+H] + , calculated value: 414.59, measured value: 414.49.

[0212] 1 H NMR (400 MHz, CDCl 3 )δ8.02(d,J=8.3Hz,2H),7.57(d,J=8.3Hz,2H),6.87(d,J=8.3Hz,1H),6.69(s,1H ),6.43(d,J=8.3Hz,1H),5.93(bs,2H),4.32(p,J=8.5Hz,1H),4.24(s,2H),3.28(q ,J=7.1Hz,2H),3.21(t,J=5.7Hz,2H),2.60(t,J=6.4Hz,2H),1.87(p,J=6.0Hz,2H ),1.81-1.69(m,3H),1.65-1.57(m,2H),1.54-1.44(m,4H),1.09(t,J=7.1Hz,3H).

[0213] The following intermediates were prepared according to the scheme mentioned above:

[0214] 3-Amino-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide

[0215]

[0216] Yield = 80%. LC-MS: t R 9.88 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 23 H 32 N 3 O 2 S[M+H] + , calculated value: 414.22, measured value: 414.27.

[0217] 1 H NMR (400 MHz, CDCl 3 )δ8.37(t,J=2.0Hz,1H),8.31-8.26(m,1H),7.99-7.94(m,1H),7.59(t,J=8.0Hz,1H),6.84 (d,J=8.3Hz,1H),6.75(s,1H),6.34(d,J=8.3Hz,1H),6.74(bs,2H),4.36(p,J=8.4Hz,1H),4 .25(s,2H),3.25(q,J=7.0Hz,2H),3.18(d,J=6.5Hz,2H),2.59(t,J=6.4Hz,2H),1.85(d,J= 6.5Hz,2H),1.82-1.68(m,3H),1.66-1.59(m,2H),1.54-1.43(m,4H),1.07(t,J=7.0Hz,3H).

[0218] D) Preparation of N-(4-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)- Phenyl)-2-phenylacetamide (Compound 8 )

[0219]

[0220] Phenylacetic acid (25 mg, 0.182 mmol, 1.5 eq) and HBTU (69 mg, 0.182 mmol, 1.5 eq) were charged into a round bottom flask and then dissolved in anhydrous DMF (1 mL) in the presence of DIPEA (63 μL, 0.364 mmol, 3 eq). After stirring at room temperature for 30 minutes, a solution of 4-amino-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (50 mg, 0.121 mmol, 1 eq) in anhydrous DMF (0.5 mL) was added and the reaction was stirred at room temperature overnight. The mixture was extracted in EtOAc and washed with 0.5 M HCl and NaHCO 3 The saturated solution was washed twice, and the aqueous solution was back-extracted with an aliquot of EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and the volatiles were evaporated under vacuum to obtain a crude product, which was purified by column chromatography (Hex / EtOAc 7:3). The title compound (28 mg, 29%) was obtained as a light yellow foam.

[0221] LC-MS: t R 17.88 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 31 H 38 N 3 O 3 S[M+H] + , HRMS calculated value: 532.26284, measured value: 532.26251.

[0222] 1 H NMR (400 MHz, CDCl 3 )δ7.67(d,J=8.5Hz,2H),7.61(s,1H),7.54(d,J=8.6Hz,2H),7.44-7.36(m,2H),7.36-7.29( m,3H),6.97(dd,J=8.7,2.0Hz,1H),6.89(s,1H),6.50(d,J=8.4Hz,1H),4.19(d,J=8.2Hz,3H) ,3.74(s,2H),3.30(q,J=7.1Hz,2H),3.21(t,J=5.6Hz,2H),2.67(t,J=6.5Hz,2H),1.91(p,J =6.1Hz,2H),1.66-1.54(m,2H),1.53-1.45(m,2H),1.41-1.29(m,4H),1.10(t,J=7.0Hz,3H).

[0223] 13 C NMR (101 MHz, CDCl 3 )δ169.62,141.35,136.00,134.10,129.60,129.37,128.84,128.34,128.31,127.90,126.16,122. 63,119.27,110.59,110.10,59.52,48.40,47.21,45.57,44.87,29.33,28.20,23.54,22.27,10.81.

[0224] The following compounds were prepared according to the above mentioned procedure:

[0225] 3-Cyclopentyl-N-(4-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)-methyl)sulfamoyl 1-(4-(4-(4-phenyl)propionamide) (Compound 9 )

[0226]

[0227] Purification (hexane / EtOAc 8:2). Yield = 40%. LC-MS: t R 19.44 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 31 H 44 N 3 O 3 S[M+H] + , HRMS calculated value: 538.30979, measured value: 538.30955.

[0228] 1 H NMR (400 MHz, CDCl 3 )δ7.82(s,1H),7.70(d,J=8.6Hz,2H),7.63(d,J=8.6Hz,2H),6.98(dd,J=8.5,2.4Hz,1H),6 .90(d,J=2.3Hz,1H),6.51(d,J=8.5Hz,1H),4.30-4.13(m,3H),3.31(q,J=7.1Hz,2H),3.22 (t,J=5.6Hz,2H),2.69(t,J=6.4Hz,2H),2.43-2.32(m,4H),1.92(p,J=6.2Hz,2H),1.84-1. 68(m,6H),1.68-1.56(m,6H),1.54-1.46(m,3H),1.41-1.31(m,2H),1.10(t,J=7.0Hz,3H).

[0229] 13 C NMR (101 MHz, CDCl 3 )δ179.93,172.35,144.19,141.84,135.53,128.37,126.12,125.15,122.60,119.24,110.54,59.53,48.41,47 .25,45.51,39.77,39.66,37.16,33.50,32.58,32.48,31.73,30.99,28.25,25.25,25.21,23.56,22.34,10.80.

[0230] N-(3-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl) Benzamide (Compound 11).

[0231]

[0232] Purification (hexane / EtOAc 85:15). Yield = 57%. LC-MS: t R 17.02 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 30 H 36 N 3 O 3 S[M+H] + , HRMS calculated value: 518.24719, measured value: 518.24698.

[0233] 1 H NMR (400 MHz, CDCl 3 )δ8.70(s,1H),8.36(d,J=8.1Hz,1H),8.04-7.95(m,2H),7.80(d,J=2.1Hz,1H),7.60-7.40(m ,5H),6.81(dd,J=8.5,2.3Hz,1H),6.74(d,J=2.3Hz,1H),6.32(d,J=8.4Hz,1H),4.28(p,J=8.5 Hz,1H),4.14(s,2H),3.20(q,J=7.1Hz,2H),3.13(t,J=5.7Hz,2H),2.50(t,J=6.4Hz,2H),1.87 -1.74(m,2H),1.69-1.54(m,2H),1.54-1.39(m,2H),1.39-1.20(m,4H),1.04(t,J=7.0Hz,3H).

[0234] 13 C NMR (101 MHz, CDCl 3 )δ166.13,144.09,140.98,139.33,134.30,132.15,129.78,128.83,128.25,127.58,126.23,124.54,1 23.95,122.40,122.13,118.68,110.32,59.68,48.28,47.27,45.37,29.44,28.05,23.56,22.20,10.75.

[0235] N-(3-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)- 2-Phenylacetamide (Compound 12).

[0236]

[0237] Purification (hexane / EtOAc 85:15). Yield = 35%. LC-MS: t R 17.18 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 31 H 38 N 3 O 3 S[M+H] + , HRMS calculated value: 532.26284, measured value: 532.26303.

[0238] 1 H NMR (400 MHz, CDCl 3 )δ8.07(s,1H),7.99(d,J=8.1Hz,1H),7.70(s,1H),7.47(d,J=7.9Hz,1H),7.40-7.27(m,6H) ,6.96(dd,J=8.5,2.2Hz,1H),6.87(d,J=2.2Hz,1H),6.47(d,J=8.4Hz,1H),4.30-4.15(m,3H) ,3.72(s,2H),3.29(q,J=7.1Hz,2H),3.21(t,J=5.6Hz,2H),2.62(t,J=6.4Hz,2H),1.89(p,J =6.0Hz,2H),1.68-1.54(m,2H),1.54-1.42(m,2H),1.42-1.30(m,4H),1.10(t,J=7.0Hz,3H).

[0239] 13 C NMR (101 MHz, CDCl3 )δ169.80,143.95,141.19,138.89,134.41,129.81,129.59,129.13,128.31,127.60,126.20,125.25,123. 49,122.73,122.22,118.07,110.76,59.66,48.35,47.41,45.67,44.62,29.37,28.09,23.57,22.14,10.80.

[0240] 3-Cyclopentyl-N-(3-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)-methyl)-sulfonamide Acyl)phenyl)propanamide (Compound 13).

[0241]

[0242] Purification (hexane / EtOAc 8:2). Yield = 26%. LC-MS: t R 17.25 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 31 H 44 N 3 O 3 S[M+H] + , HRMS calculated value: 538.30979, measured value: 538.30997.

[0243] 1 H NMR (400 MHz, CDCl 3 )δ8.08(d,J=8.1Hz,1H),7.89(s,1H),7.64(s,1H),7.47(d,J=7.9Hz,1H),7.39(t,J=8.0Hz,1H),6.9 5(dd,J=8.4,2.2Hz,1H),6.84(d,J=2.1Hz,1H),6.47(d,J=8.4Hz,1H),4.32-4.13(m,3H),3.30(q,J= 7.0Hz,2H),3.21(t,J=5.6Hz,2H),2.64(t,J=6.4Hz,2H),2.39(t,J=6.5Hz,2H),1.90(p,J=6.1Hz,2H ),1.82-1.70(m,6H),1.67-1.56(m,6H),1.54-1.46(m,4H),1.42-1.33(m,3H),1.10(t,J=7.0Hz,3H).

[0244] 13 C NMR (101 MHz, CDCl3 )δ172.25,144.24,141.32,139.09,129.81,128.44,126.36,124.80,123.40,122.47,121.97,117.96,11 0.37,59.68,48.43,47.41,45.47,39.85,37.06,32.62,31.78,29.45,28.23,25.28,23.57,22.36,10.81.

[0245] E) Preparation of N-(4-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl) Phenyl)acrylamide (Compound 25).

[0246]

[0247] To a stirred solution of 4-amino-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (50 mg, 0.121 mmol, 1 eq) and DIPEA (63 μL, 0.364 mmol, 3 eq) in anhydrous DCM (2 mL) was added a solution of acryloyl chloride (20 μL, 0.242 mmol, 2 eq) in anhydrous DCM (0.5 mL) dropwise at 0 °C. When the conversion was complete, the resulting solution was allowed to stir at room temperature for 4 hours. The mixture was extracted in EtOAc and washed with 0.5 M HCl. The aqueous phase was back extracted with an aliquot of EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and the volatiles evaporated under vacuum to obtain a crude mixture, which was purified by column chromatography (hexane / EtOAc 7:3). The product was obtained as an off-white solid (49 mg, 86%).

[0248] LC-MS: t R 16.30 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 26 H 34 N 3 O 3 S[M+H] + , HRMS calculated value: 468.23154, measured value: 468.23112.

[0249] 1 H NMR (400 MHz, CDCl 3)δ8.53(s,1H),7.74(d,J=8.5Hz,2H),7.69(d,J=8.5Hz,2H),6.98(dd,J=8.4,2.2Hz,1H),6.89(d,J=2. 2Hz, 1H), 6.51 (d, J=8.4Hz, 1H), 6.44 (dd, J=16.9, 1.7Hz, 1H), 6.33 (dd, J=16.8, 9.9Hz, 1H), 5.73 (dd, J= 9.9,1.7Hz,1H),4.27-4.14(m,3H),3.29(q,J=7.1Hz,2H),3.21(t,J=5.6Hz,2H),2.67(t,J=6.4Hz,2H) ,1.90(p,J=6.1Hz,2H),1.66-1.55(m,2H),1.55-1.44(m,2H),1.42-1.31(m,4H),1.10(t,J=7.0Hz,3H).

[0250] 13 C NMR (101 MHz, CDCl 3 )δ164.26,144.07,142.05,135.62,130.98,128.68,128.26,128.24,126.11,125.32,1 22.73,119.70,110.76,59.60,48.37,47.35,45.65,29.36,28.18,23.57,22.21,10.84.

[0251] The following compounds were prepared according to the above mentioned procedure:

[0252] N-(3-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl) Acrylamide (Compound 17).

[0253]

[0254] Purification (hexane / EtOAc 9:1). Yield: 32%. LC-MS: t R 16.38 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 26 H 34 N 3 O 3 S[M+H] + , HRMS calculated value: 468.23154, found value: 468.23123. For C 26 H 33 N 3 NaO3 S[M+Na] + , HRMS calculated value: 490.21403, measured value: 490.21350.

[0255] 1 H NMR (400 MHz, CDCl 3 )δ8.23(d,J=8.0Hz,1H),8.16(s,1H),7.63(s,1H),7.49(d,J=8.0Hz,1H),7.42(t,J=7.8Hz,1H),6 .97-6.86(m,1H),6.81(s,1H),6.53-6.37(m,2H),6.30(dd,J=16.8,10.2Hz,1H),5.77(d,J=10.0H z,1H),4.33-4.13(m,3H),3.28(q,J=7.0Hz,2H),3.20(t,J=5.8Hz,2H),2.61(t,J=6.4Hz,2H),1.8 8(p,J=6.1Hz,2H),1.76-1.58(m,2H),1.58-1.46(m,2H),1.46-1.32(m,4H),1.09(t,J=7.0Hz,3H).

[0256] 13 C NMR (101 MHz, CDCl 3 )δ163.99,144.33,141.37,139.05,131.17,129.90,128.45,128.30,126.43,124.59,123.58,1 22.53,122.13,118.22,110.40,59.79,48.43,47.53,45.49,29.55,28.23,23.62,22.37,10.92.

[0257] 2-Bromo-N-(3-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-sulfamoyl) phenyl)acetamide (Compound 18).

[0258]

[0259] Purification (hexane / EtOAc 8:2). Yield = 20%. LC-MS: t R 16.68 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 25 H 33 Bn 3 O 3 S[M+H]+ , HRMS calculated value: 534.14205, found value: 534.14262. For C 25 H 33 Bn 3 O 3 S[M+H] + , HRMS calculated value: 536.14000, measured value: 536.14032.

[0260] 1 H NMR (400 MHz, CDCl 3 )δ8.60(s,1H),7.88(d,J=8.1Hz,1H),7.82(s,1H),7.54(d,J=8.0Hz,1H),7.42(t,J=8.0Hz,1H ),6.97(dd,J=8.4,2.3Hz,1H),6.88(s,1H),6.56(d,J=8.3Hz,1H),4.24(s,2H),4.19(s,2H),4 .18-4.11(m,2H),3.32(q,J=7.1Hz,2H),3.24(t,J=5.7Hz,2H),2.67(t,J=6.5Hz,2H),1.91(p, J=6.1Hz,4H),1.72-1.61(m,2H),1.56-1.47(m,2H),1.46-1.36(m,4H),1.12(t,J=7.1Hz,3H).

[0261] 13 C NMR (101 MHz, CDCl 3 )δ164.30,152.30,143.48,141.94,137.52,129.70,128.40,126.28,125.76,123.37,123. 13,118.37,111.28,59.59,48.21,47.27,45.93,42.89,29.37,29.05,23.41,22.99,10.64.

[0262] N-(3-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl) Propionamide (Compound 21).

[0263]

[0264] Purification (hexane / DCM / EtOAc 5:4:1). Yield = 53%. LC-MS: t R16.42 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 26 H 36 N 3 O 3 S[M+H] + , HRMS calculated value: 470.24719, measured value: 470.24689.

[0265] 1 H NMR (400 MHz, CDCl 3 )δ8.14(d,J=8.1Hz,1H),8.08(s,1H),7.67(t,J=2.0Hz,1H),7.47(d,J=8.2Hz,1H),7.39(t,J=8.0Hz,1 H),6.95(dd,J=8.4,2.3Hz,1H),6.84(d,J=2.2Hz,1H),6.46(d,J=8.4Hz,1H),4.31-4.15(m,3H),3.30( q,J=7.0Hz,2H),3.21(t,J=5.6Hz,2H),2.63(t,J=6.3Hz,2H),2.40(q,J=7.6Hz,2H),1.95-1.85(m,2H) ,1.69-1.56(m,2H),1.56-1.45(m,2H),1.44-1.31(m,4H),1.23(t,J=7.5Hz,3H),1.10(t,J=7.0Hz,3H).

[0266] 13 C NMR (101 MHz, CDCl 3 )δ172.83,144.31,141.23,139.31,129.82,128.38,126.32,124.80,123.42,122.50,121.77, 117.93,110.38,59.72,48.43,47.53,45.47,30.66,29.44,28.24,23.59,22.37,10.88,9.64.

[0267] N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-(methylsulfonylamino)benzenesulfonyl Amide (Compound 22)

[0268]

[0269] Purification (hexane / EtOAc 75:25). Yield = 58%. LC-MS: t R17.06 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 24 H 34 N 3 O 4 S 2 [M+H] + , HRMS calculated value: 492.19852, measured value: 492.22903.

[0270] 1 H NMR (400 MHz, CDCl 3 )δ7.87(dt,J=7.5,1.7Hz,1H),7.79(t,J=1.9Hz,1H),7.59-7.48(m,2H),6.98(dd,J=8. 4,2.3Hz,1H),6.90(d,J=2.3Hz,1H),6.51(d,J=8.4Hz,1H),4.34-4.15(m,3H),3.38(s, 3H),3.32(q,J=7.0Hz,2H),3.23(t,J=5.7Hz,2H),2.70(t,J=6.4Hz,2H),1.98-1.88(m, 2H),1.69-1.59(m,2H),1.56-1.47(m,2H),1.40(q,J=4.9Hz,4H),1.12(t,J=7.0Hz,3H).

[0271] 13 C NMR (101 MHz, CDCl 3 )δ144.39,142.98,134.20,134.19,130.23,129.59,128.92,128.53,126.43,124.49,1 22.57,110.47,59.82,48.44,47.36,45.46,42.89,29.38,28.23,23.48,22.39,10.89.

[0272] N-cyclopentyl-N-((1-ethyl-1,2,3,4 - tetrahydroquinolin-6-yl)methyl)-4-(N-(methylsulfonyl)methyl Sulfonylamino)benzenesulfonamide (Compound 24).

[0273]

[0274] Purification (hexane / EtOAc 75:25). Yield = 40%. LC-MS: t R17.06 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 25 H 36 N 3 O 6 S 3 [M+H] + , HRMS calculated value: 570.17607, measured value: 570.17644.

[0275] 1 H NMR (400 MHz, CDCl 3 )δ7.85(d,J=8.6Hz,2H),7.44(d,J=8.6Hz,2H),6.94(dd,J=8.4,2.3Hz,1H),6.9 0(d,J=2.3Hz,1H),6.51(d,J=8.3Hz,1H),4.32-4.16(m,3H),3.41(s,6H),3.32( q,J=7.1Hz,2H),3.23(t,J=5.7Hz,2H),2.71(t,J=6.4Hz,2H),2.00-1.86(m,2H) ,1.72-1.61(m,2H),1.57-1.50(m,2H),1.50-1.37(m,4H),1.12(t,J=7.0Hz,3H).

[0276] 13 C NMR (101 MHz, CDCl 3 )δ144.44,143.61,136.64,131.33,128.55,128.49,126.42,124.40,122.64,1 10.52,59.87,48.46,47.64,45.49,42.89,29.58,28.27,23.53,22.43,10.87.

[0277] 2-Bromo-N-(4-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-sulfamoyl) phenyl)acetamide (Compound 26).

[0278]

[0279] Purification (hexane / DCM / EtOAc 5:4:1). Yield = 22%. LC-MS: t R 16.79 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 25 H33 Bn 3 O 3 S[M+H] + , HRMS calculated value: 534.14205, found value: 534.14186. For C 25 H 33 Bn 3 O 3 S[M+H] + , HRMS calculated value: 536.14000, measured value: 536.13979.

[0280] 1 H NMR (400 MHz, CDCl 3 )δ8.46(s,1H),7.79-7.72(m,2H),7.71-7.62(m,2H),6.97(dd,J=8.4,2.3Hz,1 H),6.89(d,J=2.3Hz,1H),6.51(d,J=8.4Hz,1H),4.30-4.12(m,5H),3.32(q,J=7 .0Hz,2H),3.23(t,J=5.7Hz,2H),2.69(t,J=6.4Hz,2H),1.93(p,J=6.1Hz,2H), 1.65-1.57(m,2H),1.57-1.45(m,2H),1.45-1.34(m,4H),1.12(t,J=7.0Hz,3H).

[0281] 13 C NMR (101 MHz, CDCl 3 )δ164.26,144.30,140.24,137.34,128.54,128.44,126.31,124.97,122.62,119. 65,110.54,59.64,48.48,47.39,45.55,43.01,29.44,28.29,23.57,22.41,10.90.

[0282] N-(4-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl) Propionamide (Compound 27)

[0283]

[0284] Purification (hexane / EtOAc 7:3). Yield = 52%. LC-MS: t R 16.69 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 26 H36 N 3 O 3 S[M+H] + , HRMS calculated value: 470.24719, measured value: 470.24683.

[0285] 1 H NMR (400 MHz, CDCl 3 )δ8.16(s,1H),7.80-7.63(m,4H),6.98(dd,J=8.5,2.3Hz,1H),6.89(d,J=2.2Hz,1H ),6.50(d,J=8.4Hz,1H),4.21(s,3H),3.30(q,J=7.1Hz,2H),3.21(t,J=5.6Hz,2H),2 .67(t,J=6.4Hz,2H),2.38(q,J=7.5Hz,2H),1.90(p,J=6.1Hz,2H),1.66-1.55(m,2H) ,1.53-1.45(m,2H),1.43-1.32(m,4H),1.19(t,J=7.5Hz,3H),1.10(t,J=7.0Hz,3H).

[0286] 13 C NMR (101 MHz, CDCl 3 )δ173.03,144.28,142.20,135.22,128.25,128.19,126.08,125.00,122.52,119.29, 110.42,59.56,48.38,47.34,45.44,30.69,29.31,28.24,23.54,22.34,10.83,9.56.

[0287] N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-(trifluoromethyl-sulfonylamino) Benzenesulfonamide (Compound 30)

[0288]

[0289] Purification (hexane / EtOAc 6:4). Yield = 32%. LC-MS: t R 16.33 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 24 H 31 F 3 N 3 O 4 S 2 [M+H] +, HRMS calculated value: 546.17026, measured value: 546.16990.

[0290] 1 H NMR (400 MHz, CDCl 3 )δ7.70(d,J=8.3Hz,2H),7.30-7.22(m,2H),6.94(d,J=8.5Hz,1H),6.87(s,1H ),6.52(d,J=8.4Hz,1H),5.86-5.52(m,1H),4.29-4.14(m,3H),3.32(q,J=7.1 Hz,2H),3.23(t,J=5.6Hz,2H),2.67(t,J=6.5Hz,2H),1.92(p,J=6.1Hz,2H),1 .67-1.56(m,2H),1.54-1.46(m,2H),1.46-1.34(m,5H),1.11(t,J=7.0Hz,3H).

[0291] 13 C NMR (101 MHz, CDCl 3 )δ143.97,139.56,138.28,128.64,128.39,126.23,125.52,123.14,122.13,111.18, 59.71,48.44,47.37,45.71,31.73,29.45,28.13,23.59,22.79,22.19,14.26,10.65.

[0292] Example 3

[0293] A) Preparation of N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-(furan-2-ylmethyl) Benzenesulfonamide (Compound 10)

[0294]

[0295] 3-Bromo-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-benzenesulfonamide (96 mg, 0.2 mmol, 1 eq), K 3 PO 4 (84 mg, 0.4 mmol, 2 eq.) and (furan-2-ylmethyl)boronic acid (124 mg, 0.6 mmol, 3 eq.) were charged into a vial and a mixture of water and toluene (3.0 mL, 1:10) was added. The mixture was allowed to stir at room temperature for 20 min while undergoing different vacuum and argon flushing cycles. Pd(OAc) was added under argon atmosphere. 2To the solution of 4-(4-(2-nitro-1-yl)-2-nitro-2-nitro-1-yl)-2-nitro-1-nitro-2-nitro-1-nitro-2-nitro-1-nitro-2-nitro-2-nitro-1-nitro-2-nitro-2-nitro-1-nitro-2-nitro-2-nitro-2-nitro-2-nitro-2-nitro-2-nitro-2-nitro-2-nitro-2-nitro-3 ...3-nitro-2-nitro-3-nitro-2-nitro-

[0296] LC-MS: t R 16.33 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 28 H 35 N 2 O 3 S[M+H] + , HRMS calculated value: 479.23629, measured value: 479.23667.

[0297] 1 H NMR (400 MHz, CDCl 3 )δ7.65(d,J=5.6Hz,2H),7.39(d,J=4.6Hz,2H),7.32(d,J=1.8Hz,1H),6.97(dd,J=8.5,2.3Hz,1H) ,6.89(d,J=2.2Hz,1H),6.52(d,J=8.4Hz,1H),6.30(t,J=2.5Hz,1H),6.03(d,J=3.1Hz,1H),4.30- 4.16(m,3H),4.00(s,2H),3.32(q,J=7.1Hz,2H),3.23(t,J=5.6Hz,2H),2.69(t,J=6.4Hz,2H),1.9 3(p,J=6.1Hz,2H),1.61-1.53(m,2H),1.53-1.45(m,2H),1.42-1.30(m,4H),1.12(t,J=7.0Hz,3H).

[0298] 13 C NMR (101 MHz, CDCl 3)δ153.37,144.03,141.93,141.34,139.45,132.49,129.12,128.45,127.40,126.29,125.40,122.69,1 10.68,110.51,110.12,106.90,59.59,48.43,47.24,45.66,34.32,29.29,28.19,23.53,22.27,10.85.

[0299] N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-isobutyl-benzenesulfonamide (Chemical Compound 7 )

[0300]

[0301] Purification (hexane / EtOAc 95:5). Yield = 82%. LC-MS: t R 20.07 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 27 H 39 N 2 O 2 S[M+H] + , HRMS calculated value: 455.27267, measured value: 455.27228.

[0302] 1 H NMR (400 MHz, CDCl 3 )δ7.62(d,J=7.6Hz,1H),7.58(s,1H),7.36(t,J=7.7Hz,1H),7.30(d,J=7.5Hz,1H),6.98(d, J=8.3Hz,1H),6.91(s,1H),6.51(d,J=8.4Hz,1H),4.28-4.17(m,3H),3.32(q,J=7.0Hz,2H), 3.23(t,J=5.7Hz,2H),2.70(t,J=6.4Hz,2H),2.52(d,J=7.2Hz,2H),1.98-1.82(m,3H),1.68 -1.56(m,2H),1.50(s,2H),1.45-1.32(m,4H),1.12(t,J=7.0Hz,3H),0.90(d,J=6.7Hz,7H).

[0303] 13 C NMR (101 MHz, CDCl 3)δ144.29,142.87,141.05,132.97,128.70,128.48,127.70,126.34,125.18,124.63,122.53, 110.42,59.60,48.49,47.35,45.51,45.25,30.30,29.34,28.30,23.54,22.46,22.36,10.93.

[0304] N-Cyclopentyl-3-(cyclopentylmethyl)-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)-methyl)benzenesulfonyl Amine (Compound 15)

[0305]

[0306] Purification (hexane / EtOAc 95:5). Yield = 41%. LC-MS: t R 17.22 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 29 H 41 N 2 O 2 S[M+H] + , HRMS calculated value: 481.28832, measured value: 481.28808.

[0307] 1 H NMR (400 MHz, CDCl 3 )δ7.71(d,J=7.8Hz,2H),7.31(d,J=7.9Hz,2H),6.98(d,J=8.4Hz,1H),6.90(s, 1H),6.50(d,J=8.4Hz,1H),4.33-4.06(m,3H),3.61(t,J=6.7Hz,2H),3.41-3.27 (m,5H),3.22(t,J=5.6Hz,2H),2.93(t,J=6.8Hz,2H),2.69(t,J=6.4Hz,2H),1.9 2(p,J=6.1Hz,2H),1.69-1.46(m,4H),1.43-1.30(m,4H),1.11(t,J=7.0Hz,3H).

[0308] 13 C NMR (101 MHz, CDCl 3)δ144.17,143.91,139.03,129.38,128.36,127.31,126.18,125.15,122.48,110.38, 72.92,59.52,58.87,48.42,47.27,45.45,36.11,29.31,28.24,23.51,22.39,10.81.

[0309] Example 4

[0310] A) Preparation of N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-(pyridin-2-ylamino) Benzenesulfonamide (Compound 16)

[0311]

[0312] 3-Amino-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (71 mg, 0.172 mmol, 1 eq), 2-bromopyridine (18 μL, 0.189 mmol, 1.1 eq) and Cs 2 CO 3 (112 mg, 0.344 mmol, 2 eq) was charged into a vial in the presence of anhydrous toluene (1 mL) as solvent. The mixture was stirred at room temperature while undergoing different vacuum and argon flushing cycles. Pd(OAc) was added under argon atmosphere 2 (3mg, 0.014, 8% mol) and 4,5-bis (diphenylphosphino) -9,9- dimethylxanthene (Xantphos) (16mg, 0.028mmol, 16% mol) in anhydrous toluene, and the resulting solution was heated at 60 ° C. After 1 hour, the reaction was complete, and the mixture was distributed between EtOAc and water. The organic phase was washed twice with water, and then the combined water layer was stripped with an aliquot of EtOAc. The organic layer was collected, dried over anhydrous sodium sulfate, filtered and the volatiles were evaporated under vacuum to obtain a crude product, which was purified by column chromatography (Hex / EtOAc 8:2). The title compound (25mg, 30%) was obtained as a light yellow solid.

[0313] LC-MS: t R 14.77 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 28 H 35 N 4 O 2 S[M+H] +, HRMS calculated value: 491.24752, found value: 491.24727. For C 28 H 34 N 4 NaO 2 S[M+H] + , calculated value: 513.23002, measured value: 513.22925.

[0314] 1 H NMR (400 MHz, CDCl 3 )δ8.22(dd,J=5.0,1.9Hz,1H),7.78(d,J=2.1Hz,1H),7.69(dt,J=7.2,2.2Hz,1H),7.57-7.46(m,1H) ,7.43-7.32(m,2H),7.00-6.93(m,1H),6.93-6.83(m,2H),6.83-6.75(m,2H),6.49(d,J=8.4Hz,1H),4 .26(s,2H),4.21-4.15(m,1H),3.30(q,J=7.0Hz,2H),3.21(t,J=5.6Hz,2H),2.67(t,J=6.4Hz,2H),1 .90(p,J=6.1Hz,2H),1.71-1.61(m,2H),1.61-1.47(m,2H),1.47-1.35(m,4H),1.10(t,J=7.0Hz,3H).

[0315] 13 C NMR (101 MHz, CDCl 3 )δ155.13,148.23,144.29,142.00,141.58,137.91,129.73,128.55,126.42,125.10,122.54,122.31,1 20.17,117.43,115.96,110.42,109.87,59.75,48.46,47.49,45.50,29.47,28.28,23.56,22.43,10.91.

[0316] Preparation of N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-(pyridin-2-ylamino) Benzenesulfonamide (Compound 28)

[0317]

[0318] Purification (hexane / EtOAc 7:3). Yield = 57%. LC-MS: t R14.86 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 28 H 35 N 4 O 2 S[M+H] + , HRMS calculated value: 491.24752, found value: 491.24766. For C 28 H 34 N 4 NaO 2 S[M+H] + , calculated value: 513.23002, measured value: 513.23019.

[0319] 1 H NMR (400 MHz, CDCl 3 )δ8.22(dd,J=5.0,1.9Hz,1H),7.78(d,J=2.1Hz,1H),7.69(dt,J=7.2,2.2Hz,1H),7.57-7.46(m,1H) ,7.43-7.32(m,2H),7.00-6.93(m,1H),6.93-6.83(m,2H),6.83-6.75(m,2H),6.49(d,J=8.4Hz,1H),4 .26(s,2H),4.21-4.15(m,1H),3.30(q,J=7.0Hz,2H),3.21(t,J=5.6Hz,2H),2.67(t,J=6.4Hz,2H),1 .90(p,J=6.1Hz,2H),1.71-1.61(m,2H),1.61-1.47(m,2H),1.47-1.35(m,4H),1.10(t,J=7.0Hz,3H).

[0320] 13 C NMR (101 MHz, CDCl 3 )δ155.13,148.23,144.29,142.00,141.58,137.91,129.73,128.55,126.42,125.10,122.54,122.31,1 20.17,117.43,115.96,110.42,109.87,59.75,48.46,47.49,45.50,29.47,28.28,23.56,22.43,10.91.

[0321] Example 5

[0322] A) Preparation of 3-((bis(dimethylamino)methylene)amino)-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydro Quinolin-6-yl)methyl)benzenesulfonamide (Compound 23)

[0323]

[0324] To a stirred solution of 4-amino-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (50 mg, 0.121 mmol, 1 eq) and DIPEA (63 μL, 0.364 mmol, 3 eq) in anhydrous DMF (1.3 mL) was added N,N,N′,N′-tetramethylchloroformamidine hexafluorophosphate (TCFH) (68 mg, 0.242 mmol, 2 eq) and the reaction was stirred at room temperature overnight. The mixture was extracted in EtOAc and eluted with NaHCO 3 The saturated solution was washed twice with water. The aqueous solution was back extracted with an aliquot of EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and the volatiles were evaporated under vacuum to obtain a crude mixture, which was purified by column chromatography (DCM / MeOH from 99:1 to 97:3 with an additive of 1% NH 3 The product was obtained as an off-white solid (53 mg, 90%).

[0325] LC-MS: t R 14.73 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 28 H 42 N 5 O 2 S[M+H] + , HRMS calculated value: 512.30537, measured value: 512.30542.

[0326] 1 H NMR (400 MHz, CDCl 3)δ7.33-7.25(m,2H),7.09(d,J=2.2Hz,1H),6.99(dd,J=8.3,2.2Hz,1H),6 .96-6.88(m,2H),6.50(d,J=8.3Hz,1H),4.28-4.14(m,3H),3.30(q,J=7.0 Hz,2H),3.21(t,J=5.6Hz,2H),2.71(s,14H),1.92(p,J=6.1Hz,2H),1.65- 1.54(m,2H),1.53-1.43(m,2H),1.43-1.31(m,4H),1.10(t,J=7.0Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ164.40,160.81,144.24,141.52,129.39,128.38,126.18,125.68,125.61,122.56,119. 85,118.49,110.45,59.56,48.48,47.49,45.51,39.84,29.31,28.30,23.51,22.47,10.91.

[0327] 4-((Bis(dimethylamino)methylene)amino)-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinoline- 6-yl)methyl)benzenesulfonamide (Compound 29)

[0328]

[0329] Purification (DCM / MeOH 99:1 to 97:3, additive 1% NH 3 ). Yield = 63%. LC-MS: t R 14.80 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 28 H 42 N 5 O 2 S[M+H] + , HRMS calculated value: 512.30537, measured value: 512.30522.

[0330] 1 H NMR (400 MHz, CDCl 3)δ7.62(d,J=8.3Hz,2H),6.98(d,J=8.4Hz,1H),6.92(s,1H),6.69(d,J=8. 2Hz,2H),6.50(d,J=8.4Hz,1H),4.26-4.09(m,3H),3.30(q,J=7.1Hz,2H), 3.21(t,J=5.6Hz,2H),2.76-2.62(m,14H),1.91(p,J=6.1Hz,2H),1.64-1. 52(m,2H),1.51-1.42(m,2H),1.35(d,J=5.0Hz,4H),1.10(t,J=7.0Hz,3H).

[0331] 13 C NMR (101 MHz, CDCl 3 )δ160.86,156.07,144.09,130.96,128.49,128.26,126.05,125.76,122.44,121. 37,110.39,59.35,48.41,47.15,45.44,39.80,29.19,28.24,23.57,22.42,10.85.

[0332] Example 6

[0333] A) Preparation of 4-(((1H-imidazol-4-yl)methyl)amino)-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinoline (6-Methyl)benzenesulfonamide (Compound 32)

[0334]

[0335] To a stirred solution of 4-amino-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (60 mg, 0.145 mmol, 1 eq) in anhydrous MeOH (2 mL) was added imidazole-4-carbaldehyde (42 mg, 0.434 mmol, 3 eq) and a catalytic amount of acetic acid (5 μL). The reaction was stirred under an inert atmosphere overnight until complete formation of the imine was observed. NaBH was then added 4 To 4-(4-(2-(4-(2-(4-(2-nitro-1-yl)-2-yl)-1-yl)-2-nitro ...

[0336] LC-MS: t R11.96 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 27 H 36 N 5 O 2 S[M+H] + , HRMS calculated value: 494.25842, found value: 494.25878. For C 27 H 37 N 5 O 3 S[M+2H] 2+ / 2, calculated value: 511.26171, measured value: 511.26202.

[0337] 1 H NMR (400 MHz, CDCl 3 )δ11.36(s,1H),7.66(s,1H),7.50(d,J=8.4Hz,2H),7.00(dd,J=8.5,2.3Hz,1H),6.88(s,1H),6. 72(s,1H),6.56(d,J=8.5Hz,2H),6.52(d,J=8.5Hz,1H),5.15(t,J=6.5Hz,1H),4.45(d,J=6.3Hz, 2H),4.24-4.09(m,3H),3.31(q,J=7.0Hz,2H),3.23(t,J=5.6Hz,2H),2.68(t,J=6.4Hz,2H),1.91 (p,J=6.0Hz,2H),1.68-1.58(m,2H),1.58-1.46(m,2H),1.42-1.31(m,4H),1.11(t,J=7.0Hz,3H).

[0338] 13 C NMR (101 MHz, CDCl 3 )δ150.53,144.31,136.33,134.90,129.14,127.96,127.67,125.85,125.52,122.70,116. 56,112.42,110.58,59.55,48.44,47.08,45.52,38.11,29.41,28.30,23.74,22.36,10.91.

[0339] 4-((2-bromobenzyl)amino)-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzene Sulfonamide (Compound 31)

[0340]

[0341] Purification (hexane / EtOAc 85:15). Yield = 48%. LC-MS: t R 12.50 min, (Analytical HPLC, 10% to 90% acetonitrile (0.1% TFA) in water (0.1% TFA) in 20 min, flow rate 1.0 mL / min). For C 30 H 37 Bn 3 O 2 S[M+H] + , HRMS calculated value: 582.17844, found value: 582.17832. For C 30 H 37 Bn 3 O 2 S[M+H] + , calculated value: 584.17639, measured value: 584.17625.

[0342] 1 H NMR (400 MHz, CDCl 3 )δ7.60-7.52(m,3H),7.32(d,J=7.7Hz,1H),7.25(t,J=7.4Hz,1H),7.14(t,J=7.6Hz,1H),6.99(d ,J=8.4Hz,1H),6.91(s,1H),6.55(d,J=8.3Hz,2H),6.51(d,J=8.4Hz,1H),4.78(s,1H),4.42(s,2 H),4.23-4.13(m,3H),3.31(q,J=7.1Hz,2H),3.21(t,J=5.7Hz,2H),2.69(t,J=6.5Hz,2H),1.92( p,J=6.0Hz,2H),1.67-1.55(m,2H),1.54-1.44(m,3H),1.44-1.32(m,4H),1.11(t,J=7.0Hz,3H).

[0343] 13 C NMR (101 MHz, CDCl 3 )δ150.81,144.11,137.10,133.03,129.20,129.09,129.03,128.63,128.31,127.75,126.10,125.76,1 23.30,122.51,112.05,110.47,59.41,48.43,47.89,47.17,45.50,29.30,28.25,23.62,22.43,10.88.

[0344] Example 7

[0345] Activity of Compound 1, Compound 2, Compound 14 and Compound 32

[0346] U2OS cells were treated with Compound 1, Compound 2, Compound 14, and Compound 32 at concentrations of 0 μM, 0.625 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, 15 μM, 20 μM, and 25 μM. Live cell imaging platform to assess cell proliferation (confluence) and cytotoxicity (CellTox TM Green confluence). Use CellTox TM Green confluence is the percentage of total cell confluence, and cell death is calculated as the percentage of total confluence. Cytotoxicity measurement is carried out at the time point when cells reach complete confluence and reaches the upper limit (capped). This is the cell death caused by excessive confluence of cells, rather than the result of compound action. The same experiment was also performed on the list of ALT positive cell lines, telomerase positive cell lines, ALT and telomerase positive cell lines and normal cell lines. For ALT positive cell lines, GM847, SK-N-FI, HuO9, Saos-2, CAL72, IIICF / c and HS729 were used. For telomerase positive cells, HCT116, HeLa, HT1080, SK-N-Be2 and SK-N-AS and KELLY were used. For ALT positive / telomerase positive and lethal cell lines, GM847, hTERT, MRC-5 and IMR-90 were used.

[0347] To determine whether the compounds disrupt FANCM-BTR interaction, co-immunoprecipitation experiments were performed using RMI1 antibody in the presence and absence of compound 1, compound 2, compound 14, compound 32 and the reported compound PIP-199 treatment as well as scrambled siFANCM and DMSO. This method provides information indicating direct protein binding and is highly specific and easy to perform. U2OS cells were seeded at 50% confluence on 150 cm 2 After 24 h, cells were treated with scrambled siFANCM and DMSO (0.3%, determined by the maximum DMSO concentration present in the drug) and at their IC 50The cells were treated with 2, 14, 32, and PIP-199 at 4 °C concentrations. After 72 h, the cells were washed once with warm PBS, trypsinized at 37 °C for 5 min, resuspended in medium and counted using a Beckman Coulter cell counter. The cells were collected in a pellet in a Protein Lobind tube (Eppendorf) by centrifugation at 200 × g at 4 °C and the supernatant was discarded. Lysis buffer B (20 mM HEPES-KOH pH 7.9, 200 mM NaCl, 2 mM MgCl 2 , 10% v / v glycerol, 0.1 v / v Triton X-100) with 1 mM PMSF (Sigma), 1 mM DTT (Sigma) and Fresh pellets were lysed with protease inhibitor cocktail (Roche) and then incubated at 4°C on a rotating rack for 1 hour. Lysates were centrifuged at 13,000 rpm for 40 minutes at 4°C and the supernatant was collected. Protein G (Life Technologies) was prepared by washing the beads twice with 1× PBST. Resuspend in anti-RMI1 antibody (Rb, Proteintech: 14630-1-AP, 0.25 mg / mL) at a concentration of 0.8 μg / mg lysate. Use 5% lysate. Incubate at room temperature with rotation for 10 minutes, place the tube on a magnetic stand and remove the supernatant to remove unbound antibody. The antibody-bound beads are then washed once in 1× PBST. The supernatant is removed from the cell pellet and the lysate is added to the antibody-bound beads and then incubated overnight at 4°C on a rotator. The next day, the beads are separated on a magnetic stand and the supernatant (flow-through) is transferred to a clean tube for subsequent immunoprecipitation efficiency analysis. For each wash, wash with 200 μL of ice-cold lysis buffer B. -Ab-protein complex three times. Separate the beads on a magnetic stand between each wash, remove the supernatant, and resuspend the beads by gentle pipetting. Add 1× LDS buffer to -Ab-protein complex, then heated at 70 ° C for 10 minutes. On a magnetic stand, the eluate was transferred to a new tube. The eluate was analyzed by Western blotting, and the data were quantified using ImageJ software (National Institutes of Health). The eluate is expressed as a percentage of its corresponding lysate to show the relative differences between treatments.

[0348] Preliminary cell-based assays indicated that the best compound 32 showed inhibition of U2OS cell viability and promising lead properties (i.e., satisfied all of Lipinski's five rules). IC of compound 32 against U2OS 50 (i.e., the drug concentration that inhibits cell growth by 50%) and EC 50 The values ​​(i.e., the concentration effective to cause 50% cell death) were 15.52 μM and 1.36 μM, respectively ( FIG. 6 a ). In addition, the IC values ​​of a group of cell lines treated with compound 32 ( FIG. 6 b ) were 50 and EC 50 The comparison of the values ​​demonstrated that the compound showed selective induction of ALT cell death. In addition, compound 1 and compound 14 caused concentration-dependent toxicity to the ALT cell line partially selectively ( Figure 5 ).

[0349] Finally, immunoprecipitation experiments using anti-RMI1 (RMI1 of BTR complex) antibody on ALT cancer cell line U2OS demonstrated that compound 32 treatment indeed induced the expression of IC in U2OS cells. 50 The decrease in FANCM levels at the concentration of 1:1 was 1:1 (Figure 6c and Figure 6d). This suggests that compound 32 and its analogs described herein directly inhibit FANCM / BTR interaction. Most interestingly, FANCM protein levels in the input were quantified, indicating that compound 32 may also induce FANCM degradation by binding to the BTR complex.

Claims

1. A tetrahydroquinoline compound of formula (I) or a pharmaceutically acceptable salt thereof Wherein A is (C 3 -C 7 ) cycloalkyl; (C 3 -C 7 ) heterocycloalkyl containing from 1 to 3 heteroatoms selected from O, N, and S; (C 1 -C 7 ) alkyl; (C 1 -C 7 ) heteroalkyl containing from 1 to 3 heteroatoms selected from O, N, and S; an optionally substituted benzene ring or an optionally substituted (5-9)-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N, and S; R is H, (C 1 -C 4 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, (C 3 -C 7 )cycloalkyl; R 1 and R 2 are each independently selected from the group consisting of: H, NO 2 , CN, halogen, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl substituted by a (5-9)-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N, and S, Optionally substituted by bis(dimethylamino)methylene, pyridyl, trifluoromethyl-SO 2 -, (C 1 -C 3 )alkyl-SO 2 -substituted amino, The group NH-CO-R 3 , wherein R 3 is selected from the group consisting of: benzyl, (C 3 -C 7 ) cycloalkyl (C 1 -C 4 ) alkyl, phenyl, vinyl, halogen-CH 2 -, (C 1 -C 3 ) alkyl; group NH-CH 2 -R 4 , wherein R 4 is an optionally substituted benzene ring or an optionally substituted (5-9)-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S; or R 1 and R 2 together form an optionally substituted aromatic ring containing 6 carbon atoms.

2. The tetrahydroquinoline compound according to claim 1, wherein R 1 or R 2 is the group NH-CH 2 -R 4 , wherein R 4 is an optionally substituted aromatic ring or an optionally substituted (5-9)-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N and S.

3. The tetrahydroquinoline compound according to claim 1 or claim 2, wherein A is a (C 3 -C 7 ) cycloalkyl group, and preferably A is a cyclopentyl group.

4. The tetrahydroquinoline compound according to claim 1, wherein A is a (C 3 -C 7 ) cycloalkyl group, preferably selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and more preferably A is cyclopentyl.

5. The tetrahydroquinoline compound according to claim 1, wherein A is (C 1 -C 7 ) alkyl, preferably selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, propan-2-yl, butan-2-yl, pentan-2-yl, hexan-2-yl, pentan-3-yl, 2-methylpentan-3-yl, 2,4-dimethylpentan-3-yl, tert-butyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl and 4-methylpentyl.

6. The tetrahydroquinoline compound according to claim 1, wherein A is a (5-9)-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N, and S, preferably selected from the group consisting of pyrrolyl, pyrrol-2-yl, pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, imidazol-4-yl, 1,3-oxazol-5-yl, 1,3-oxazol-4-yl, 1,3-thiazol-5-yl, 1,3-thiazol-4-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, indol-2-yl, indol-3-yl, isoindol-1-yl, 1-benzofuran-3-yl, 1-benzofuran-2-yl, 2-benzofuran-1-yl, 2-benzothiophen-1-yl, 1-benzothiophen-3-yl, 2-benzothiophen-3-yl, and benzimidazol-2-yl.

7. The tetrahydroquinoline compound according to any one of claims 1-6, wherein R is (C 1 -C 4 ) alkyl, preferably R is ethyl.

8. The tetrahydroquinoline compound according to any one of claims 1-7, wherein R 1 or R 2 one of them is H.

9. The tetrahydroquinoline compound according to claim 1, wherein one of R 1 and R 2 is H, and the other is the group NH-CH 2 -R 4 , wherein R 4 is an optionally substituted benzene ring or an optionally substituted (5-9)-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N, and S.

10. The tetrahydroquinoline compound according to claim 9, wherein R 4 is selected from the group consisting of pyrrol-2-yl, pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, imidazol-4-yl, 1,3-oxazol-5-yl, 1,3-oxazol-4-yl, 1,3-thiazol-5-yl, 1,3-thiazol-4-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, indol-2-yl, indol-3-yl, isoindol-1-yl, 1-benzofuran-3-yl, 1-benzofuran-2-yl, 2-benzofuran-1-yl, 2-benzothiophen-1-yl, 1-benzothiophen-3-yl, 2-benzothiophen-3-yl, benzimidazol-2-yl.

11. The tetrahydroquinoline compound according to claim 10, wherein R 4 is imidazol-4-yl.

12. The tetrahydroquinoline compound according to claim 9, wherein R 4 is a phenyl group substituted by a halogen, preferably a phenyl group substituted by bromine.

13. The tetrahydroquinoline compound according to claim 1, wherein when R 1 or R 2 is a halogen, it is bromine.

14. The tetrahydroquinoline compound according to claim 1, wherein when R 1 or R 2 is (C 1 -C 4 ) alkyl, it is selected from butan-2-yl (or sec-butyl) and propan-2-yl (or isobutyl).

15. The tetrahydroquinoline compound according to claim 1, wherein when R 1 or R 2 is (C 2 -C 4 ) alkenyl, it is vinyl.

16. The tetrahydroquinoline compound according to claim 1, wherein when R 1 or R 2 is (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl, it is methoxyethyl.

17. The tetrahydroquinoline compound according to claim 1, wherein when R 1 or R 2 is a (C 1 -C 4 )alkyl group substituted with a (5-9)-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from O, N, and S, it is furan-2-ylmethyl.

18. The tetrahydroquinoline compound according to claim 1, wherein when R 1 or R 2 is (C 3 -C 7 ) cycloalkyl (C 1 -C 4 ) alkyl, it is 3-(cyclopentyl)methyl.

19. The tetrahydroquinoline compound according to claim 1, wherein when R 1 or R 2 is an amino group optionally substituted by bis(dimethylamino)methylene, pyridyl, trifluoromethyl-SO 2 -, (C 1 -C 3 )alkyl-SO 2 -, it is selected from amino groups substituted by bis(dimethylamino)methylene, pyridyl, trifluoromethyl-SO 2 -, methyl-SO 2 -.

20. The tetrahydroquinoline compound according to claim 1, wherein R 1 or R 2 is the group NH-CO-R 3 , and R 3 is selected from the group consisting of: benzyl, (C 3 -C 7 ) cycloalkyl(C 1 -C 4 ) alkyl, phenyl, vinyl, halogen-CH 2 -, (C 1 -C 3 ) alkyl, preferably R 3 is selected from the group consisting of: benzyl, cyclopentylethyl, phenyl, vinyl, bromo-CH 2 -, ethyl.

21. The tetrahydroquinoline compound according to claim 1, wherein R 1 and R 2 together further form an optionally substituted aromatic ring containing 6 carbon atoms.

22. The tetrahydroquinoline compound according to claim 1, wherein the compound of formula (I) is selected from the group consisting of N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-nitrobenzenesulfonamide (Compound 1); N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-nitrobenzenesulfonamide (Compound 2); 3-bromo-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (Compound 3); N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-vinylbenzenesulfonamide (Compound 4); N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-isopropylbenzenesulfonamide (Compound 5); N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)naphthalene-2-sulfonamide (Compound 6); N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-isobutylbenzenesulfonamide (Compound 7); N-(4-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)-2-phenylacetamide (Compound 8); 3-cyclopentyl-N-(4-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)propanamide (Compound 9); N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-(furan-2-ylmethyl)benzenesulfonamide (Compound 10); N-(3-(N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)benzamide (Compound 11); N-(3-(N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)-2-phenylacetamide (Compound 12); 3-Cyclopentyl-N-(3-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)propanamide (Compound 13); N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-(2-methoxyethyl)benzenesulfonamide (Compound 14); N-Cyclopentyl-3-(cyclopentylmethyl)-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (Compound 15); N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-(pyridin-2-ylamino)benzenesulfonamide (Compound 16); N-(3-(N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)acrylamide (Compound 17); 2-Bromo-N-(3-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)acetamide (Compound 18); 4-Cyano-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (Compound 19); N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-2-nitrobenzenesulfonamide (Compound 20); N-(3-(N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)propanamide (Compound 21); N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-3-(methylsulfonamido)benzenesulfonamide (Compound 22); 3-((Bis(dimethylamino)methylene)amino)-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (Compound 23); N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-(N-(methylsulfonyl)methylsulfonamido)benzenesulfonamide (Compound 24); N-(4-(N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)acrylamide (Compound 25); 2-Bromo-N-(4-(N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)acetamide (Compound 26); N-(4-(N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)sulfamoyl)phenyl)propanamide (Compound 27); N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-(pyridin-2-ylamino)benzenesulfonamide (Compound 28); 4-((Bis(dimethylamino)methylene)amino)-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (Compound 29); N-Cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-4-(trifluoromethylsulfonamido)benzenesulfonamide (Compound 30); 4-((2-Bromobenzyl)amino)-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (Compound 31); 4-(((1H-Imidazol-4-yl)methyl)amino)-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (Compound 32).

23. The tetrahydroquinoline compound according to claim 22, wherein the compound is 4-(((1H-imidazol-4-yl)methyl)amino)-N-cyclopentyl-N-((1-ethyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl)benzenesulfonamide (Compound 32).

24. A pharmaceutical composition comprising the tetrahydroquinoline compound according to any one of claims 1-23 and at least one pharmaceutically acceptable excipient.

25. The tetrahydroquinoline compound according to any one of claims 1-23 or a pharmaceutically acceptable salt thereof, for use as a medicament.

26. The tetrahydroquinoline compound according to any one of claims 1-23 or a pharmaceutically acceptable salt thereof, for use as a disruptor of the FANCM / BTR interaction to prevent FANCM from localizing to telomeres.

27. The tetrahydroquinoline compound according to claim 26 or a pharmaceutically acceptable salt thereof, for the treatment of tumors.

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