Compounds containing a hydroxyphenyl moiety and uses thereof

Abstract

The present inventors have succeeded in developing urea, oxalamide, amide, thiourea, carbamate or ester compounds, particularly urea compounds having two side groups, one of which has a hydroxyphenyl or phenyl moiety, particularly a hydroxyphenyl moiety. These compounds have the advantage of inhibiting IRE1 RNase activity and sensitizing cancer cells, particularly GB cells, to chemotherapy. The present invention relates to urea, oxalamide, amide, thiourea, carbamate or ester compounds, particularly urea compounds containing a hydroxyphenyl or phenyl moiety, particularly a hydroxyphenyl moiety, including their pharmaceutically acceptable salts and solvates, which are useful as sensitizing agents for chemotherapy of cancer cells, particularly glioblastoma, and are particularly useful as therapeutic compounds in the treatment of cancers that can be treated by alkylating agents such as temozolomide.

Description

[Technical field]

[0001] The present invention relates to urea, oxalamide, amide, thiourea, carbamate or ester compounds, particularly urea compounds containing a hydroxyphenyl or phenyl moiety, especially a hydroxyphenyl moiety, including pharmaceutically acceptable salts and solvates thereof, which are useful as sensitizing agents for chemotherapy of cancer cells, particularly glioblastoma, and particularly useful as therapeutic compounds in the treatment of cancers which may be treated with alkylating agents such as temozolomide. [Background technology]

[0002] Glioblastoma (GB) is the most common primary central nervous system (CNS) tumor and exhibits high levels of malignancy, recurrence and heterogeneity; traits that contribute to a poor prognosis with a median survival of 1.5 years after diagnosis. Standard treatment involves maximal safe resection of the tumor followed by a combination of radiation and the alkylating agent temozolomide. However, all of the patients succumb to the disease (R. Stupp et al., N. Engl. J. Med., 2005, 352, 987-996). GB cells, like most solid tumors, survive in a harsh environment that includes hypoxia, nutrient deprivation, necrosis and immune infiltration, as well as the need to tolerate high turnover and protein synthesis demands (D. Doultsinos et al., SLAS Discov. Adv. Life Sci. R&D, 2017, 22, 787-800). Thus, the unfolded protein response (UPR) is inextricably linked to GB pathophysiology (J. Obacz et al., Sci.Signal, 2017, 10, eaal2323). In particular, the major unfolded protein response (UPR) transducer, inositol-requiring enzyme 1 (IRE1), has been shown to play a crucial role in tumorigenesis and malignancy, as it promotes tumor invasion, angiogenesis and invasion by immune cells via XBP1 signaling. GB tumors exhibiting high levels of IRE1 / XBP1 activity have a worse prognosis than tumors with low activity (S. Lhomond et al., EMBO Mol. Med., 2018, 10, pp. 139-308). This is relevant to the possibility that, when IRE1 activity is reduced, GB cells exhibit a reduced ability to withstand a harsh environment, which could result in tumor sensitization to current therapies. Indeed, such studies have been performed in triple-negative breast cancer (TNBC), showing that inhibition of IRE1 RNase activity with the salicylaldehyde MKC8866 augments paclitaxel-dependent attenuation of TNBC pathogenesis in mouse xenograft models (SE Logue et al., Nat. Commun., 2018, 9, 3267).

[0003] In addition to the above, in breast cancer PDX models, MKC8866 treatment significantly increases the efficacy of docetaxel in regressing MYC-overexpressing tumors (N. Zhao et al., J. Clin. Invest., 2018, 128, 1283-1299). This inhibitor is currently being tested against other types of cancer.

[0004] Inhibition of IRE1 activity can be mediated by compounds that target either the ATP-binding kinase domain or the RNase domain. Direct RNase pharmacological inhibitors include 4μ8c, STF-083010, toyocamycin, and a series of MKC compounds, all of which rely on a hydroxy-arylaldehyde (HAA) motif, while kinase pharmacological inhibitors that in turn inhibit RNase include, among others, 1-(4-(8-amino-3-isopropylimidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-(trifluoromethyl)phenyl)urea (CAS# 1414938-21-8), 1-(4-(8-amino-3-(tert-butyl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-(trifluoromethyl)phenyl)urea (CAS# 1589527-65-0), 1-(4-(8-amino-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-fluorophenyl)urea (CAS# 1937235-76-1), 6-chloro-3-(6-fluoro-2-(phenylamino)-1H-benzo[d]imidazol-5-yl)-N-((1-methylpiperidin-4-yl)methyl)imidazo[1,2-b]pyridazin-8-amine (CAS# 2328097-41-0), 2-(3,4-dichlorobenzyl)-N-(4-methylbenzyl)-2-azaspiro[4.5]decane-8-carboxamide (CAS# 2121989-91-9), 2-chloro-N-(6-methyl-5-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)naphthalen-1-yl)benzenesulfonamide (CAS# 1630086-20-2) (T. Langlais, Biochem. J., 2021, 478, 2953-2975; D. Pelizzari-Raymundo et al. Trends in Cancer, 2020, 6, 1018-1030), and, although unknown regarding its effect on IRE1 activity, sunitinib (C. Hetz et al., Nat. Rev. Drug Discov., 2013, 12, 703-719).The discovery of Kinase Inhibitory RNase Attenuators (KIRAs) has described a mechanism of allosteric IRE1 RNase inhibition by ATP-competitive ligands, indicating that inhibition of the kinase site can have an inhibitory effect on RNase activity (L. Wang et al., Nat. Chem. Biol., 2012, 8, 982-989; H. C. Feldman et al., CS Chem. Biol., 2016, 11, 219-2205).

[0005] Other studies have shown that large (18-50 amino acids long) peptides derived from the cytoplasmic domain of IRE1 can affect its oligomerization and subsequent RNase activity (M. Bouchecareilh et al., FASEB J., 2011, 25, 3115-3129). However, such peptides, even in their reduced 18 amino acid form, present many problems when considered for use in the in vivo CNS environment, including bioavailability, proteasomal degradation, sheer size, crossing the blood-brain barrier, and stability. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] R. Stupp et al., N. Engl. J. Med., 2005, 352, 987-996 [Non-Patent Document 2] D. Doultsinos et al., SLAS Discov. Adv. Life Sci. R&D, 2017, 22, pp. 787-800 [Non-Patent Document 3] J. Obacz et al., Sci.Signal, 2017, 10, eaal2323 [Non-Patent Document 4] S. Lhomond et al., EMBO Mol. Med., 2018, 10, 139-308 [Non-Patent Document 5] S. E. Logue et al., Nat. Commun., 2018, 9, 3267

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[0007] However, there remains a need for compounds that have the ability to inhibit IRE1 RNase activity and sensitize cancer cells, particularly GB cells, to anti-cancer drugs, particularly alkylating agents, which may be of therapeutic value in the treatment of cancers that can be treated by alkylating agents. [Means for solving the problem]

[0008] The present inventors have now succeeded in developing urea, oxalamide, amide, thiourea, carbamate or ester compounds, in particular urea compounds having two side groups, one of which has a hydroxyphenyl or phenyl moiety, in particular a hydroxyphenyl moiety, which have the advantage of inhibiting IRE1 RNase activity and sensitizing cancer cells, in particular GB cells, to chemotherapy.

[0009] Thus, the present invention relates to compounds of general formula I, their pharma- ceutically acceptable salts and solvates, and methods of using such compounds or compositions containing such compounds as sensitizing agents for chemotherapy of malignant tumors.

[0010] In a general aspect, the present invention provides a compound of general formula I:

[0011] [ka]

[0012] A pharma- ceutically acceptable salt or solvate thereof [In the formula, A is selected from -NH-, -N(Me)- and -O-; L is

[0013] [ka]

[0014] or LA is

[0015] [ka]

[0016] and Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH 2- and -C(O)NH-, or a single bond; Z is O or S; R 1 and R 2 is independently selected from H and OH, with the proviso that R 1 and R 2 At least one of is H, and R 1 and R 2 is not simultaneously H, Cy:

[0017] [ka]

[0018] (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen, R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, R 5 is H or C1-C4-alkyl, R 6 is H, C1-C4-alkyl, C3-C4-cycloalkyl, halogen, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 is selected from R 8 and R 9 are independently selected from hydrogen, C1-C4-alkyl and C3-C4-cycloalkyl, R 9 is C1-C4-alkyl, R 10 is selected from H and C1-C4-alkyl, R 7 is H or C1-C4-alkyl, However, R 3 , R 4 , R 5 , R 6 and R 7(Provided that all of are not H at the same time)

[0019] [ka]

[0020] (In the formula, R 11 and R 12 are independently selected from hydrogen and C1-C4-alkyl.

[0021] [ka]

[0022] is selected from However, Cy is

[0023] [ka]

[0024] If R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are not all H at the same time. Provide The compound of formula I is: (R)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,4-dimethylbenzamide; (R)-4-Fluoro-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)benzamide; (S)-N-Ethyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (S)-N-Cyclopropyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (S)-N1-(5-carbamoyl-2-fluorophenyl)-N2-(4-(4-hydroxyphenyl)butan-2-yl)oxalamide; (R)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,4-dimethylbenzamide; (S)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)acetamide; (S)-1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(5-iodo-2-methylphenyl)urea; (S)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)propionamide; (S)-3-acetamido-N-(4-(4-hydroxyphenyl)butan-2-yl)-4-methylbenzamide; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)benzamide; (R)-N-Ethyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; Methyl (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzoate; (R)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)isobutyramide; (S)-1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,N,4-trimethylbenzamide; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (R)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)acetamide; (R)-N1-(5-carbamoyl-2-methylphenyl)-N2-(4-(4-hydroxyphenyl)butan-2-yl)oxalamide; N-Ethyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; 3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,4-dimethylbenzamide; 3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; 3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,2-dimethylbenzamide; 4-Fluoro-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)benzamide; 4-Fluoro-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N-methylbenzamide; N-cyclopropyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)phenyl)isobutyramide; N-(5-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-2-methylphenyl)acetamide; (S)-1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(m-tolyl)urea; 1-(2,5-dimethylphenyl)-3-(4-phenylbutan-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-hydroxyphenethyl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(2-fluorophenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(2-ethyl-6-methylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; N-(2,5-dimethylphenyl)-4-(3-hydroxyphenyl)piperazine-1-carboxamide; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-phenylurea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(m-tolyl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(p-tolyl)urea; 1-Cyclohexyl-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; and 1-(benzo[d][1,3]dioxol-5-yl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea None of the above.

[0025] The present invention also relates to a compound of formula I:

[0026] [ka]

[0027] Pharmaceutically acceptable salts or solvates thereof [In the formula, A is selected from -NH-, -N(Me)- and -O-; L is

[0028] [ka]

[0029] or LA is

[0030] [ka]

[0031] and Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH 2 - and -C(O)NH-, or a single bond; Z is O or S; R 1 and R 2 is independently selected from H, OH, and OMe, with the proviso that R 1 and R 2 At least one of the following is H: Cy:

[0032] [ka]

[0033] (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen, R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, R 5 is H or C1-C4-alkyl, R 6 is H, C1-C4-alkyl, C3-C4-cycloalkyl, halogen, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 is selected from R 8 and R 9 are independently selected from hydrogen, C1-C4-alkyl and C3-C4-cycloalkyl, R 9 is C1-C4-alkyl, R 10is selected from H and C1-C4-alkyl, R 7 is H or C1-C4-alkyl.

[0034] [ka]

[0035] (In the formula, R 11 and R 12 are independently selected from hydrogen and C1-C4-alkyl.

[0036] [ka]

[0037] [Selected from].

[0038] The present invention futher relates to a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, for use in increasing the sensitivity of cancer cells to anticancer agents, particularly alkylating agents, in the treatment of cancer, particularly glioblastoma, triple negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer.

[0039] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I as defined above, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable carrier, diluent, excipient and / or adjuvant.

[0040] In another aspect, the present invention provides a compound comprising 1-(2,5-dimethylphenyl)-3-(6-(3-hydroxyphenyl)pyridin-3-yl)urea; 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-pyrrol-3-yl)urea; 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-2-(prop-1-en-2-yl)-1H-indol-3-yl)urea; 1-(3,5-difluorophenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(3-methyl-5-(trifluoromethyl)phenyl)urea; and 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; or a hydroxyphenyl compound selected from the group consisting of: 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; or a pharma- ceutically acceptable salt or solvate thereof.

[0041] In another aspect, the present invention relates to a pharmaceutical composition comprising a hydroxyphenyl compound as defined above, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient.

[0042] In another aspect, the invention relates to a hydroxyphenyl compound as defined above, in combination with an anti-cancer agent, for use in the treatment of cancer.

[0043] In another aspect, the invention relates to a compound comprising a hydroxyphenyl moiety as defined above for use in increasing the sensitivity of cancer cells to anti-cancer agents in the treatment of cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] As detailed above, the present invention relates to compounds of formula I, and pharma- ceutically acceptable salts or solvates thereof.

[0045] A preferred compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, is 1 , R 2 and one or more of Cy are defined as follows: A is selected from -NH-, -N(Me)- and -O-, in particular A is -NH-; L is

[0046] [ka]

[0047] In particular, L is selected from

[0048] [ka]

[0049] and more particularly, L is selected from

[0050] [ka]

[0051] For example, L is selected from

[0052] [ka]

[0053] In another example, L is selected from

[0054] [ka]

[0055] or LA is

[0056] [ka]

[0057] and Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH 2 - and -C(O)NH-, in particular Y is -NH-, -N(Me)-, -NH-CH 2 -, -O- and -CH 2-, more particularly Y is selected from -NH-, -NH-CH 2 -, -O- and -CH 2 -, and even more particularly, Y is -NH-, Z is O or S, in particular Z is O, R 1 and R 2 is independently selected from H and OH, with the proviso that R 1 and R 2 At least one of is H, and R 1 and R 2 is not H at the same time, in particular, R 1 is OH and R 2 is H, Cy:

[0058] [ka]

[0059] (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen, in particular R 3 is selected from H, C1-C4-alkyl and F, more particularly R 3 is H or C1-C4-alkyl, and even more particularly, R 3 is Me or t-Bu, R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 4 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 4 is H or C1-C3-alkyl, and even more particularly, R 4 is H, R 5 is H or C1-C4-alkyl, in particular R 5 is H or C1-C3-alkyl, more particularly R 5 is H or Me, and even more particularly, R 5 is H, R6 is H, C1-C4-alkyl, C3-C4-cycloalkyl, halogen, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 In particular, R 6 is H, C1-C3-alkyl, I, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 More particularly, R 6 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, and even more particularly R 6 is selected from H, C1-C3-alkyl and cyclopropyl, and even more particularly R 6 is H or C1-C3-alkyl, R 8 and R 9 are independently selected from hydrogen, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 8 and R 9 are independently selected from hydrogen, C1-C3-alkyl and cyclopropyl; R 9 is C1-C4-alkyl, in particular R 9 is C1-C3-alkyl, R 10 is selected from H and C1-C4-alkyl, in particular R 10 is selected from H and C1-C3-alkyl, R 7 is H or C1-C4-alkyl, in particular R 7 is H or C1-C3-alkyl, more particularly R 7 is H or Me, and even more particularly, R 7 is H, However, R 3 , R 4 , R 5 , R 6 and R 7 (Provided that all of are not H at the same time)

[0060] [ka]

[0061] (In the formula, R 11 and R 12 are independently selected from hydrogen and C1-C4-alkyl, in particular R 11 and R 12 are independently selected from hydrogen and C1-C3-alkyl, more particularly R 11 and R 12 is H or Me, and even more particularly, R 11 and R 12 is Me)

[0062] [ka]

[0063] is selected from However, Cy is

[0064] [ka]

[0065] If R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are not all H at the same time, In particular, Cy

[0066] [ka]

[0067] (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen, in particular R 3is selected from H, C1-C4-alkyl and F, more particularly R 3 is H or C1-C4-alkyl, and even more particularly, R 3 is Me or t-Bu, R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 4 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 4 is H or C1-C3-alkyl, and even more particularly, R 4 is H, R 5 is H or C1-C4-alkyl, in particular R 5 is H or C1-C3-alkyl, more particularly R 5 is H or Me, and even more particularly, R 5 is H, R 6 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 6 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 6 is H or C1-C3-alkyl, R 7 is H or C1-C4-alkyl, in particular R 7 is H or C1-C3-alkyl, more particularly R 7 is H or Me, and even more particularly, R 7 is H, However, R 3 , R 4 , R 5 , R 6 and R 7 (Provided that all of are not H at the same time)

[0068] [ka]

[0069] (In the formula, R 11 and R12 are independently selected from hydrogen and C1-C4-alkyl, in particular R 11 and R 12 are independently selected from hydrogen and C1-C3-alkyl, more particularly R 11 and R 12 is H or Me, and even more particularly, R 11 and R 12 is Me)

[0070] [ka]

[0071] is selected from However, Cy is

[0072] [ka]

[0073] If R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are not all H at the same time, More specifically, Cy is

[0074] [ka]

[0075] (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen, in particular R 3 is selected from H, C1-C4-alkyl and F, more particularly R 3 is H or C1-C4-alkyl, and even more particularly, R 3 is Me or t-Bu, R 4is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 4 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 4 is H or C1-C3-alkyl, and even more particularly, R 4 is H, R 5 is H or C1-C4-alkyl, in particular R 5 is H or C1-C3-alkyl, more particularly R 5 is H or Me, and even more particularly, R 5 is H, R 6 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 6 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 6 is H or C1-C3-alkyl, R 7 is H or C1-C4-alkyl, in particular R 7 is H or C1-C3-alkyl, more particularly R 7 is H or Me, and even more particularly, R 7 is H, However, R 3 , R 4 , R 5 , R 6 and R 7 (Provided that all of are not H at the same time)

[0076] [ka]

[0077] is selected from However, Cy is

[0078] [ka]

[0079] If R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are not all H at the same time, The compound of formula I is: (R)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,4-dimethylbenzamide; (R)-4-Fluoro-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)benzamide; (S)-N-Ethyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (S)-N-Cyclopropyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (S)-N1-(5-carbamoyl-2-fluorophenyl)-N2-(4-(4-hydroxyphenyl)butan-2-yl)oxalamide; (R)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,4-dimethylbenzamide; (S)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)acetamide; (S)-1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(5-iodo-2-methylphenyl)urea; (S)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)propionamide; (S)-3-acetamido-N-(4-(4-hydroxyphenyl)butan-2-yl)-4-methylbenzamide; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)benzamide; (R)-N-Ethyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; Methyl (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzoate; (R)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)isobutyramide; (S)-1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,N,4-trimethylbenzamide; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (R)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)acetamide; (R)-N1-(5-carbamoyl-2-methylphenyl)-N2-(4-(4-hydroxyphenyl)butan-2-yl)oxalamide; N-Ethyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; 3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,4-dimethylbenzamide; 3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; 3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,2-dimethylbenzamide; 4-Fluoro-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)benzamide; 4-Fluoro-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N-methylbenzamide; N-cyclopropyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)phenyl)isobutyramide; N-(5-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-2-methylphenyl)acetamide; (S)-1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(m-tolyl)urea; 1-(2,5-dimethylphenyl)-3-(4-phenylbutan-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-hydroxyphenethyl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(2-fluorophenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(2-ethyl-6-methylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; N-(2,5-dimethylphenyl)-4-(3-hydroxyphenyl)piperazine-1-carboxamide; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-phenylurea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(m-tolyl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(p-tolyl)urea; 1-Cyclohexyl-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; and 1-(benzo[d][1,3]dioxol-5-yl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea None of the above.

[0080] Halogen includes fluorine, iodine, chlorine and bromine atoms.

[0081] C1-C4-Alkyl includes butyl, in particular n-butyl, isobutyl, sec-butyl or tert-butyl; propyl, in particular n-propyl or isopropyl; ethyl or methyl.

[0082] C3-C4-Cycloalkyl includes cyclopropyl and cyclobutyl.

[0083] In one embodiment, the compounds of formula I may be racemic or optically active.

[0084] In one embodiment, the compound of formula I may be racemic.

[0085] In one embodiment, the compounds of formula I may be optically active.

[0086] In one embodiment, the compounds of formula I are those where A is -NH-.

[0087] In one embodiment, the compounds of formula I are those where A is -N(Me)-.

[0088] In one embodiment, the compounds of formula I are those where A is -O-.

[0089] In one embodiment, the compound of formula I is one in which L is

[0090] [ka]

[0091] In particular, L is selected from

[0092] [ka]

[0093] The compound is selected from the group consisting of:

[0094] In one embodiment, the compound of formula I is one in which L is

[0095] [ka]

[0096] The compound is selected from the group consisting of:

[0097] In one embodiment, the compound of formula I is one in which L is

[0098] [ka]

[0099] The compound is selected from the group consisting of:

[0100] In one embodiment, the compound of formula I is one in which L is

[0101] [ka]

[0102] The compound is selected from the group consisting of:

[0103] In one embodiment, the compound of formula I is one in which L is

[0104] [ka]

[0105] It is a compound wherein

[0106] In one embodiment, the compound of formula I is one in which L is

[0107] [ka]

[0108] It is a compound wherein

[0109] In one embodiment, the compound of formula I is one in which L is

[0110] [ka]

[0111] It is a compound wherein

[0112] In one embodiment, the compound of formula I is one in which L is

[0113] [ka]

[0114] It is a compound wherein

[0115] In one embodiment, the compound of formula I is one in which L is

[0116] [ka]

[0117] It is a compound wherein

[0118] In one embodiment, the compound of formula I is one in which L is

[0119] [ka]

[0120] It is a compound wherein

[0121] In one embodiment, the compound of formula I is one in which L is

[0122] [ka]

[0123] It is a compound wherein

[0124] In one embodiment, the compound of formula I is one in which L is

[0125] [ka]

[0126] It is a compound wherein

[0127] In one embodiment, the compound of formula I is one in which L is

[0128] [ka]

[0129] It is a compound wherein

[0130] In one embodiment, the compound of formula I is one in which L is

[0131] [ka]

[0132] It is a compound wherein

[0133] In one embodiment, the compound of formula I is one in which L is

[0134] [ka]

[0135] It is a compound wherein

[0136] In one embodiment, the compound of formula I is one in which L is

[0137] [ka]

[0138] It is a compound wherein

[0139] In one embodiment, the compound of formula I is one in which L is

[0140] [ka]

[0141] It is a compound wherein

[0142] In one embodiment, the compound of formula I is one in which L is

[0143] [ka]

[0144] It is a compound wherein

[0145] In one embodiment, the compound of formula I is one in which L is

[0146] [ka]

[0147] It is a compound wherein

[0148] In one embodiment, the compound of formula I is one in which L is

[0149] [ka]

[0150] It is a compound wherein

[0151] In one embodiment, the compound of formula I is one in which L is

[0152] [ka]

[0153] It is a compound wherein

[0154] In one embodiment, the compound of formula I is one in which L is

[0155] [ka]

[0156] It is a compound wherein

[0157] In one embodiment, the compound of formula I is a compound wherein LA is

[0158] [ka]

[0159] It is a compound wherein

[0160] In one embodiment, the compound of formula I is a compound in which Y is -NH-, -N(Me)-, -NH-CH 2 -, -O- and -CH 2 In particular, Y is selected from -NH-, -NH-CH 2 -, -O- and -CH 2 - is a compound selected from the group consisting of

[0161] In one embodiment, the compounds of formula I are those where Y is -NH-.

[0162] In one embodiment, the compounds of formula I are those where Y is -N(Me)-.

[0163] In one embodiment, the compound of formula I is a compound in which Y is -NH-CH 2 - is a compound.

[0164] In one embodiment, the compounds of formula I are those where Y is -O-.

[0165] In one embodiment, the compound of formula I has the structure 2 - is a compound.

[0166] In one embodiment, the compounds of formula I are those where Z is O.

[0167] In one embodiment, the compound of formula I is a compound where Z is S.

[0168] In one embodiment, the compound of formula I is R 1 is OH and R 2 is H.

[0169] In one embodiment, the compound of formula I is R 1 is H and R 2 is a compound in which

[0170] In one embodiment, the compound of formula I is a compound wherein Cy is

[0171] [ka]

[0172] (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen, in particular R 3 is selected from H, C1-C4-alkyl and F, more particularly R 3 is H or C1-C4-alkyl, and even more particularly, R 3 is Me or t-Bu, R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 4 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 4 is H or C1-C3-alkyl, and even more particularly, R 4 is H, R 5 is H or C1-C4-alkyl, in particular R 5 is H or C1-C3-alkyl, more particularly R 5 is H or Me, and even more particularly, R5 is H, R 6 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 6 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 6 is H or C1-C3-alkyl, R 7 is H or C1-C4-alkyl, in particular R 7 is H or C1-C3-alkyl, more particularly R 7 is H or Me, and even more particularly, R 7 is H, However, R 3 , R 4 , R 5 , R 6 and R 7 (Provided that all of are not H at the same time) It is a compound wherein

[0173] In one embodiment, the compound of formula I is a compound wherein Cy is

[0174] [ka]

[0175] (In the formula, R 11 and R 12 are independently selected from hydrogen and C1-C4-alkyl, in particular R 11 and R 12 are independently selected from hydrogen and C1-C3-alkyl, more particularly R 11 and R 12 is H or Me, and even more particularly, R 11 and R 12 is Me) It is a compound wherein

[0176] In one embodiment, the compound of formula I is a compound wherein Cy is

[0177] [ka]

[0178] It is a compound wherein

[0179] In one embodiment, the compound of formula I is a compound wherein Cy is

[0180] [ka]

[0181] It is a compound wherein

[0182] In one embodiment, the compound of formula I is a compound wherein Cy is

[0183] [ka]

[0184] It is a compound wherein

[0185] In one embodiment, the compound of formula I is a compound wherein Cy is

[0186] [ka]

[0187] It is a compound wherein

[0188] In one embodiment, the compound of formula I is a compound wherein Cy is

[0189] [ka]

[0190] It is a compound wherein

[0191] In one embodiment, the compound of formula I is a compound wherein Cy is

[0192] [ka]

[0193] The compound is selected from the group consisting of:

[0194] In one embodiment, the compound of formula I is a compound wherein Cy is

[0195] [ka]

[0196] It is a compound wherein

[0197] In one embodiment, the compound of formula I is a compound of formula II:

[0198] [ka]

[0199] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, Y and Cy are as defined above with respect to formula I, and any of its embodiments.

[0200] In one embodiment, the compound of formula I is a compound of formula IIa:

[0201] [ka]

[0202] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A and Y are as defined above with respect to formula I, and any of its embodiments.

[0203] Certain compounds of formula IIa are 1 , R 2 , L, A and Y are defined as follows: R 1 and R 2 is independently selected from H and OH, with the proviso that R 1 and R 2 At least one of is H, and R 1 and R 2 is not H at the same time, in particular, R 1 is OH and R 2 is conditioned on H.

[0204] In one embodiment, the compound of formula I is a compound of formula IIb:

[0205] [ka]

[0206] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, Y and Cy are as defined above with respect to formula I, and any of its embodiments.

[0207] In one embodiment, the compound of formula I is a compound of formula IIc:

[0208] [ka]

[0209] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A and Y are as defined above with respect to formula I, and any of its embodiments.

[0210] In one embodiment, the compound of formula I is a compound of formula III:

[0211] [ka]

[0212] or a pharma- ceutically acceptable salt or solvate thereof; wherein L, A, Z, Y and Cy are as defined above for formula I, and any of its embodiments.

[0213] In one embodiment, the compound of formula I is a compound of formula IIIa:

[0214] [ka]

[0215] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, L, A, Z and Y are as defined above with respect to formula I, and any of its embodiments.

[0216] In one embodiment, the compound of formula I is a compound of formula IIIb:

[0217] [ka]

[0218] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, A, Z, Y and Cy are as defined above with respect to formula I, and any of its embodiments.

[0219] In one embodiment, the compound of formula I is a compound of formula IIIc:

[0220] [ka]

[0221] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, A, Z and Y are as defined above with respect to formula I, and any of its embodiments.

[0222] In one embodiment, the compound of formula I is a compound of formula IV:

[0223] [ka]

[0224] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, Y and Cy are as defined above with respect to formula I, and any of its embodiments.

[0225] In one embodiment, the compound of formula I is a compound of formula IVa:

[0226] [ka]

[0227] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L and Y are as defined above with respect to formula I, and any of its embodiments.

[0228] In one embodiment, the compound of formula I is a compound of formula IVb:

[0229] [ka]

[0230] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , Y and Cy are as defined above with respect to Formula I, and any of its embodiments.

[0231] In one embodiment, the compound of formula I is a compound of formula IVc:

[0232] [ka]

[0233] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and Y are as defined above with respect to formula I, and any of its embodiments.

[0234] In one embodiment, the compound of formula I is a compound of formula V:

[0235] [ka]

[0236] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A and Cy are as defined above with respect to formula I, and any of its embodiments.

[0237] In one embodiment, the compound of formula I is a compound of formula Va:

[0238] [ka]

[0239] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R2 , L and A are as defined above with respect to formula I, and any of its embodiments.

[0240] In one embodiment, the compound of formula I is a compound of formula Vb:

[0241] [ka]

[0242] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A and Cy are as defined above with respect to formula I, and any of its embodiments.

[0243] In one embodiment, the compound of formula I is a compound of formula Vc:

[0244] [ka]

[0245] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and A are as defined above with respect to formula I, and any of its embodiments.

[0246] In one embodiment, the compound of formula I is a compound of formula VI:

[0247] [ka]

[0248] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2, L and Cy are as defined above with respect to formula I, and any of its embodiments.

[0249] In one embodiment, the compound of formula I is a compound of formula VIa:

[0250] [ka]

[0251] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and L are as defined above with respect to formula I, and any of its embodiments.

[0252] In one embodiment, the compound of formula I is a compound of formula VIb:

[0253] [ka]

[0254] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and Cy are as defined above with respect to Formula I, and any of its embodiments.

[0255] In one embodiment, the compound of formula I is a compound of formula VIc:

[0256] [ka]

[0257] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2and Cy are as defined above with respect to Formula I, and any of its embodiments.

[0258] In one embodiment, the compound of formula I is a compound of formula VId:

[0259] [ka]

[0260] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 and R 2 is as defined above with respect to formula I, and any of its embodiments.

[0261] In one embodiment, the compound of formula I is a compound of formula VII:

[0262] [ka]

[0263] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, Z, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0264] In one embodiment, the compound of formula I is a compound of formula VIIa:

[0265] [ka]

[0266] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, Z and Y are as defined above with respect to formula I, and any of its embodiments.

[0267] In one embodiment, the compound of formula I is a compound of formula VIIb:

[0268] [ka]

[0269] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, Z, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0270] In one embodiment, the compound of formula I is a compound of formula VIIc:

[0271] [ka]

[0272] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, Z and Y are as defined above with respect to formula I, and any of its embodiments.

[0273] In one embodiment, the compound of formula I is a compound of formula VIII:

[0274] [ka]

[0275] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0276] A preferred compound of formula VIII, or a pharma- ceutically acceptable salt or solvate thereof, is 1 , R 2 , L, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is a compound defined as follows: R 1 and R 2 is independently selected from H and OH, with the proviso that R 1 and R 2 At least one of is H, and R 1 and R 2 is not H at the same time, in particular, R 1 is OH and R 2 is H, A is selected from -NH-, -N(Me)- and -O-, in particular A is -NH-; L is

[0277] [ka]

[0278] In particular, L is selected from

[0279] [ka]

[0280] and more particularly, L is selected from

[0281] [ka]

[0282] or LA is

[0283] [ka]

[0284] and Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH 2 - and -C(O)NH-, in particular Y is -NH-, -N(Me)-, -NH-CH 2 -, -O- and -CH 2 -, more particularly Y is selected from -NH-, -NH-CH 2 -, -O- and -CH 2 -, and even more particularly, Y is -NH-, R 3 is selected from H, C1-C4-alkyl and halogen, in particular R 3 is selected from H, C1-C4-alkyl and F, more particularly R 3 is H or C1-C4-alkyl, and even more particularly, R 3 is Me or t-Bu, R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 4 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 4 is H or C1-C3-alkyl, and even more particularly, R 4 is H, R 5 is H or C1-C4-alkyl, in particular R 5 is H or C1-C3-alkyl, more particularly R5 is H or Me, and even more particularly, R 5 is H, R 6 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 6 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 6 is H or C1-C3-alkyl, R 7 is H or C1-C4-alkyl, in particular R 7 is H or C1-C3-alkyl, more particularly R 7 is H or Me, and even more particularly, R 7 is H, However, R 3 , R 4 , R 5 , R 6 and R 7 The condition is that not all of are H at the same time.

[0285] In one embodiment, the compound of formula I is a compound of formula VIIIb:

[0286] [ka]

[0287] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0288] In one embodiment, the compound of formula I is a compound of formula VIIIc:

[0289] [ka]

[0290] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A and Y are as defined above with respect to formula I, and any of its embodiments.

[0291] In one embodiment, the compound of formula I is a compound of formula IX:

[0292] [ka]

[0293] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, L, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0294] In one embodiment, the compound of formula I is a compound of formula IXa:

[0295] [ka]

[0296] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, L, A and Y are as defined above with respect to formula I, and any of its embodiments.

[0297] In one embodiment, the compound of formula I is a compound of formula IXb:

[0298] [ka]

[0299] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0300] In one embodiment, the compound of formula I is a compound of formula IXc:

[0301] [ka]

[0302] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, A and Y are as defined above with respect to formula I, and any of its embodiments.

[0303] In one embodiment, the compound of formula I is a compound of formula X:

[0304] [ka]

[0305] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0306] In one embodiment, the compound of formula I is a compound of formula Xa:

[0307] [ka]

[0308] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L and A are as defined above with respect to formula I, and any of its embodiments.

[0309] In one embodiment, the compound of formula I is a compound of formula Xb:

[0310] [ka]

[0311] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0312] In one embodiment, the compound of formula I is a compound of formula Xc:

[0313] [ka]

[0314] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and A are as defined above with respect to formula I, and any of its embodiments.

[0315] In one embodiment, the compound of formula I is a compound of formula XI:

[0316] [ka]

[0317] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0318] In one embodiment, the compound of formula I is a compound of formula XIa:

[0319] [ka]

[0320] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L and A are as defined above with respect to formula I, and any of its embodiments.

[0321] In one embodiment, the compound of formula I is a compound of formula XIb:

[0322] [ka]

[0323] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, R 3 , R 4 , R5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0324] In one embodiment, the compound of formula I is a compound of formula XIc:

[0325] [ka]

[0326] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and A are as defined above with respect to formula I, and any of its embodiments.

[0327] In one embodiment, the compound of formula I is a compound of formula XII:

[0328] [ka]

[0329] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0330] In one embodiment, the compound of formula I is a compound of formula XIIa:

[0331] [ka]

[0332] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0333] In one embodiment, the compound of formula I is a compound of formula XIIb:

[0334] [ka]

[0335] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0336] In one embodiment, the compound of formula I is a compound of formula XIIc:

[0337] [ka]

[0338] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and A are as defined above with respect to formula I, and any of its embodiments.

[0339] In one embodiment, the compound of formula I is a compound of formula XIII:

[0340] [ka]

[0341] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0342] In one embodiment, the compound of formula I is a compound of formula XIIIa:

[0343] [ka]

[0344] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L and A are as defined above with respect to formula I, and any of its embodiments.

[0345] In one embodiment, the compound of formula I is a compound of formula XIIIb:

[0346] [ka]

[0347] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, R 3 , R 4 , R 5 , R 6 and R7 is as defined above with respect to formula I, and any of its embodiments.

[0348] In one embodiment, the compound of formula I is a compound of formula XIIIc:

[0349] [ka]

[0350] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and A are as defined above with respect to formula I, and any of its embodiments.

[0351] In one embodiment, the compound of formula I is a compound of formula XIV:

[0352] [ka]

[0353] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L and Cy are as defined above with respect to formula I, and any of its embodiments.

[0354] In one embodiment, the compound of formula I is a compound of formula XIVa:

[0355] [ka]

[0356] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2and L are as defined above with respect to formula I, and any of its embodiments.

[0357] In one embodiment, the compound of formula I is a compound of formula XIVb:

[0358] [ka]

[0359] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and Cy are as defined above with respect to Formula I, and any of its embodiments.

[0360] In one embodiment, the compound of formula I is a compound of formula XIVc:

[0361] [ka]

[0362] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 and R 2 is as defined above with respect to formula I, and any of its embodiments.

[0363] Particularly preferred compounds of the invention are those listed in Table 1 below:

[0364] [Table 1A]

[0365] [Table 1B]

[0366] [Table 1C]

[0367] [Table 1D]

[0368] [Table 1E]

[0369] The present invention further relates to the hydroxyphenyl compounds listed in Table 1b below.

[0370] The term "hydroxyphenyl compound," as used herein, means a compound that contains a hydroxyphenyl moiety.

[0371] [Table 2]

[0372] The compounds of the invention can be prepared in a variety of ways using reactions known by those skilled in the art. Exemplary routes of synthesis are described hereinafter.

[0373] The compounds of the present invention (i.e., the compounds of formula I above and its subformulas, as well as the hydroxyphenyl compounds of Table 1b above) can indeed inhibit IRE RNase activity and sensitize cancer cells to anticancer drugs. The compounds of the present invention further have the advantage of sensitizing cancer cells, particularly GGM cells, to anticancer drugs, particularly alkylating agents. Thus, the present invention also provides the use of the compounds of the present invention or pharma- ceutically acceptable salts or solvates thereof, as sensitizing agents for chemotherapy of cancer cells.

[0374] Thus, the present invention relates to the use of the compounds of the present invention, or a pharma- ceutically acceptable salt or solvate thereof, for treating cancer, in particular as sensitizing agents for chemotherapy of cancer cells.

[0375] Purpose Unexpectedly, the inventors have discovered that compounds of the present invention, including compound 41 listed in the provisos above, can be used as inhibitors of IRE1 RNase activity and have the potential to increase the sensitization of cancer cells to anti-cancer drugs in the treatment of cancer.

[0376] Indeed, and without wishing to be bound by any theory, the inventors believe that the particular structure of the compounds of the present invention enables them to interact with the ATP kinase binding pocket of IRE1.

[0377] The compounds of the present invention are capable of inhibiting IRE1 RNase activity and increasing the sensitivity of cancer cells to anti-cancer drugs in the treatment of cancer, particularly glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer.

[0378] The compounds of the invention as defined above can be used to treat cancer, in particular as sensitizing agents for chemotherapy of cancer cells, with the aim of improving the efficacy of chemotherapy in cancer treatment, preventing resistance and reducing toxic and adverse effects.

[0379] Thus, the present invention provides For use in the treatment of cancer, Combined with anticancer drugs Compounds of Formula I:

[0380] [ka]

[0381] With respect to a pharma- ceutically acceptable salt or solvate thereof, wherein A is selected from -NH-, -N(Me)-, and -O-; L is

[0382] [ka]

[0383] or LA is

[0384] [ka]

[0385] and Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH 2 - and -C(O)NH-, or a single bond; Z is O or S; R 1 and R 2 is independently selected from H and OH, with the proviso that R 1 and R 2 At least one of the following is H: Cy:

[0386] [ka]

[0387] (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen, R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, R 5 is H or C1-C4-alkyl, R 6 is H, C1-C4-alkyl, C3-C4-cycloalkyl, halogen, C(O)NR 8 R9 , NHC(O)R 10 and C(O)OR 11 is selected from R 8 and R 9 are independently selected from hydrogen, C1-C4-alkyl and C3-C4-cycloalkyl, R 9 is C1-C4-alkyl, R 10 is selected from H and C1-C4-alkyl, R 7 is H or C1-C4-alkyl, However, R 3 , R 4 , R 5 , R 6 and R 7 (Provided that all of are not H at the same time)

[0388] [ka]

[0389] (In the formula, R 11 and R 12 are independently selected from hydrogen and C1-C4-alkyl.

[0390] [ka]

[0391] is selected from.

[0392] In one embodiment, the compounds for use of formula I may be racemic or optically active.

[0393] In one embodiment, the compounds for use of formula I may be racemic.

[0394] In one embodiment, the compounds for use of formula I are in optically active form.

[0395] In one embodiment, a particular compound for use according to the invention is a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, wherein A, L, Y, Z, R 1 , R 2 and Cy is defined as follows: A is selected from -NH-, -N(Me)- and -O-, in particular A is -NH-; L is

[0396] [ka]

[0397] In particular, L is selected from

[0398] [ka]

[0399] and more particularly, L is selected from

[0400] [ka]

[0401] and even more particularly, L is selected from

[0402] [ka]

[0403] or LA is

[0404] [ka]

[0405] and Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH2 - and -C(O)NH- or a single bond, in particular Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH 2 - and -C(O)NH-, more particularly Y is selected from -NH- or -C(O)NH-; Z is O or S, in particular Z is O, R 1 and R 2 is independently selected from H and OH, with the proviso that R 1 and R 2 is H, in particular R 1 is OH and R 2 is H, Cy:

[0406] [ka]

[0407] (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen, in particular R 3 is selected from H, C1-C4-alkyl and F, more particularly R 3 is C1-C4-alkyl or F, and even more particularly, R 3 is Me or F, R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 4 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 4 is H or C1-C3-alkyl, and even more particularly, R 4 is H, R 5 is H or C1-C4-alkyl, in particular R 5 is H or C1-C3-alkyl, more particularly R 5 is H or Me, and even more particularly, R 5 is H, R 6 is H, C1-C4-alkyl, C3-C4-cycloalkyl, halogen, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 In particular, R 6 is H, C1-C3-alkyl, I, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 More particularly, R 6 is C1-C3-alkyl, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 and even more particularly selected from R 6 is C1-C3-alkyl and C(O)NR 8 R 9 is selected from R 8 and R 9 are independently selected from hydrogen, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 8 and R 9 are independently selected from hydrogen, C1-C3-alkyl and cyclopropyl; R 9 is C1-C4-alkyl, in particular R 9 is C1-C3-alkyl, R 10 is selected from H and C1-C4-alkyl, in particular R 10 is selected from H and C1-C3-alkyl, R 7 is H or C1-C4-alkyl, in particular R 7 is H or C1-C3-alkyl, more particularly R 7 is H or Me, and even more particularly, R 7 is H)

[0408] [ka]

[0409] (In the formula, R 11 and R 12 are independently selected from hydrogen and C1-C4-alkyl, in particular R 11 and R 12 are independently selected from hydrogen and C1-C3-alkyl, more particularly R 11 and R 12 is H or Me, and even more particularly, R 11 and R 12 is Me)

[0410] [ka]

[0411] is selected from In particular, Cy

[0412] [ka]

[0413] (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen, in particular R 3 is selected from H, C1-C4-alkyl and F, more particularly R 3 is C1-C4-alkyl or F, and even more particularly, R 3 is Me or F, R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 4 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 4 is H or C1-C3-alkyl, and even more particularly, R 4 is H, R 5 is H or C1-C4-alkyl, in particular R 5is H or C1-C3-alkyl, more particularly R 5 is H or Me, and even more particularly, R 5 is H, R 6 is H, C1-C4-alkyl, C3-C4-cycloalkyl, halogen, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 In particular, R 6 is H, C1-C3-alkyl, I, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 More particularly, R 6 is C1-C3-alkyl, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 and even more particularly selected from R 6 is C1-C3-alkyl and C(O)NR 8 R 9 is selected from R 8 and R 9 are independently selected from hydrogen, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 8 and R 9 are independently selected from hydrogen, C1-C3-alkyl and cyclopropyl; R 9 is C1-C4-alkyl, in particular R 9 is C1-C3-alkyl, R 10 is selected from H and C1-C4-alkyl, in particular R 10 is selected from H and C1-C3-alkyl, R 7 is H or C1-C4-alkyl, in particular R 7 is H or C1-C3-alkyl, more particularly R 7 is H or Me, and even more particularly, R 7 is H) It is.

[0414] In one embodiment, the compounds for use of formula I are those where A is -NH-.

[0415] In one embodiment, the compounds for use of formula I are those where A is -N(Me)-.

[0416] In one embodiment, the compounds for use of formula I are those where A is -O-.

[0417] In one embodiment, the compound for use of formula I is

[0418] [ka]

[0419] In particular, L is selected from

[0420] [ka]

[0421] The compound is selected from the group consisting of:

[0422] In one embodiment, the compound of formula I is a compound wherein LA is

[0423] [ka]

[0424] It is a compound wherein

[0425] In one embodiment, the compound for use of formula I is one in which Y is -NH-, -N(Me)-, -NH-CH 2 -, -O- and -CH 2 In particular, Y is selected from -NH-, -NH-CH 2 -, -O- and -CH 2- is a compound selected from the group consisting of

[0426] In one embodiment, the compounds for use of formula I are those where Y is -NH-.

[0427] In one embodiment, the compounds for use of formula I are those where Y is -N(Me)-.

[0428] In one embodiment, the compound for use of formula I is 2 - is a compound.

[0429] In one embodiment, the compounds for use of formula I are those where Y is -O-.

[0430] In one embodiment, the compound for use of formula I is 2 - is a compound.

[0431] In one embodiment, the compounds for use of formula I are those where Z is O.

[0432] In one embodiment, the compounds for use of formula I are those where Z is S.

[0433] In one embodiment, the compound for use of formula I is R 1 is OH and R 2 is H.

[0434] In one embodiment, the compound for use of formula I is R 1 is H and R 2 is a compound in which

[0435] In one embodiment, the compound for use of formula I is a compound of formula II:

[0436] [ka]

[0437] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, Y and Cy are as defined above with respect to formula I, and any of its embodiments.

[0438] In one embodiment, the compound for use of formula I is a compound of formula IIa:

[0439] [ka]

[0440] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A and Y are as defined above with respect to formula I, and any of its embodiments.

[0441] In one embodiment, the compound for use of formula I is a compound of formula IIb:

[0442] [ka]

[0443] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, Y and Cy are as defined above with respect to formula I, and any of its embodiments.

[0444] In one embodiment, the compound for use of formula I is a compound of formula IIc:

[0445] [ka]

[0446] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A and Y are as defined above with respect to formula I, and any of its embodiments.

[0447] In one embodiment, the compound for use of formula I is a compound of formula III:

[0448] [ka]

[0449] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, L, A, Z, Y and Cy are as defined above for formula I, and any of its embodiments.

[0450] In one embodiment, the compound for use of formula I is a compound of formula IIIa:

[0451] [ka]

[0452] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, L, A, Z and Y are as defined above with respect to formula I, and any of its embodiments.

[0453] In one embodiment, the compound for use of formula I is a compound of formula IIIb:

[0454] [ka]

[0455] or a pharma- ceutically acceptable salt or solvate thereof; wherein A, Z, Y and Cy are as defined above for formula I, and any of its embodiments.

[0456] In one embodiment, the compound for use of formula I is a compound of formula IIIc:

[0457] [ka]

[0458] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, A, Z and Y are as defined above with respect to formula I, and any of its embodiments.

[0459] In one embodiment, the compound for use of formula I is a compound of formula IV:

[0460] [ka]

[0461] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, Y and Cy are as defined above with respect to formula I, and any of its embodiments.

[0462] In one embodiment, the compound for use of formula I is a compound of formula IVa:

[0463] [ka]

[0464] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2, L and Y are as defined above with respect to formula I, and any of its embodiments.

[0465] In one embodiment, the compound for use of formula I is a compound of formula IVb:

[0466] [ka]

[0467] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , Y and Cy are as defined above with respect to Formula I, and any of its embodiments.

[0468] In one embodiment, the compound for use of formula I is a compound of formula IVc:

[0469] [ka]

[0470] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and Y are as defined above with respect to formula I, and any of its embodiments.

[0471] In one embodiment, the compound for use of formula I is a compound of formula V:

[0472] [ka]

[0473] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2, L, A and Cy are as defined above with respect to formula I, and any of its embodiments.

[0474] In one embodiment, the compound for use of formula I is a compound of formula Va:

[0475] [ka]

[0476] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L and A are as defined above with respect to formula I, and any of its embodiments.

[0477] In one embodiment, the compound for use of formula I is a compound of formula Vb:

[0478] [ka]

[0479] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A and Cy are as defined above with respect to formula I, and any of its embodiments.

[0480] In one embodiment, the compound for use of formula I is a compound of formula Vc:

[0481] [ka]

[0482] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2and A are as defined above with respect to formula I, and any of its embodiments.

[0483] In one embodiment, the compound for use of formula I is a compound of formula VI:

[0484] [ka]

[0485] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L and Cy are as defined above with respect to formula I, and any of its embodiments.

[0486] In one embodiment, the compound for use of formula I is a compound of formula VIa:

[0487] [ka]

[0488] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and L are as defined above with respect to formula I, and any of its embodiments.

[0489] In one embodiment, the compound for use of formula I is a compound of formula VIb:

[0490] [ka]

[0491] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2and Cy are as defined above with respect to Formula I, and any of its embodiments.

[0492] In one embodiment, the compound for use of formula I is a compound of formula VIc:

[0493] [ka]

[0494] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and Cy are as defined above with respect to Formula I, and any of its embodiments.

[0495] In one embodiment, the compound for use of formula I is a compound of formula VId:

[0496] [ka]

[0497] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 and R 2 is as defined above with respect to formula I, and any of its embodiments.

[0498] In one embodiment, the compound for use of formula I is a compound of formula VII:

[0499] [ka]

[0500] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, Z, Y, R3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0501] In one embodiment, the compound for use of formula I is a compound of formula VIIa:

[0502] [ka]

[0503] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, Z and Y are as defined above with respect to formula I, and any of its embodiments.

[0504] In one embodiment, the compound for use of formula I is a compound of formula VIIb:

[0505] [ka]

[0506] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, Z, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0507] In one embodiment, the compound for use of formula I is a compound of formula VIIc:

[0508] [ka]

[0509] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, Z and Y are as defined above with respect to formula I, and any of its embodiments.

[0510] In one embodiment, the compound for use of formula I is a compound of formula VIII:

[0511] [ka]

[0512] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0513] Preferred compounds for use in formula VI, or a pharma- ceutically acceptable salt or solvate thereof, are 1 , R 2 , L, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is a compound defined as follows: R 1 and R 2 is independently selected from H and OH, with the proviso that R 1 and R 2 is H, in particular R 1 is OH and R 2 is H, A is selected from -NH-, -N(Me)- and -O-, in particular A is -NH-; L is

[0514] [ka]

[0515] In particular, L is selected from

[0516] [ka]

[0517] and more particularly, L is selected from

[0518] [ka]

[0519] or LA is

[0520] [ka]

[0521] and Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH 2 - and -C(O)NH- or a single bond, in particular Y is -NH-, -N(Me)-, -NH-CH 2 -, -O- and -CH 2 -, more particularly Y is selected from -NH-, -NH-CH 2 -, -O- and -CH 2 -, and even more particularly, Y is -NH-, R 3 is selected from H, C1-C4-alkyl and halogen, in particular R 3is selected from H, C1-C4-alkyl and F, more particularly R 3 is H or C1-C4-alkyl, and even more particularly, R 3 is Me or t-Bu, R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 4 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 4 is H or C1-C3-alkyl, and even more particularly, R 4 is H, R 5 is H or C1-C4-alkyl, in particular R 5 is H or C1-C3-alkyl, more particularly R 5 is H or Me, and even more particularly, R 5 is H, R 6 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl, in particular R 6 is selected from H, C1-C3-alkyl and cyclopropyl, more particularly R 6 is H or C1-C3-alkyl, R 7 is H or C1-C4-alkyl, in particular R 7 is H or C1-C3-alkyl, more particularly R 7 is H or Me, and even more particularly, R 7 is H, However, R 3 , R 4 , R 5 , R 6 and R 7 The condition is that not all of are H at the same time.

[0522] In one embodiment, the compound for use of formula I is a compound of formula VIIIb:

[0523] [ka]

[0524] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0525] In one embodiment, the compound for use of formula I is a compound of formula VIIIc:

[0526] [ka]

[0527] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A and Y are as defined above with respect to formula I, and any of its embodiments.

[0528] In one embodiment, the compound for use of formula I is a compound of formula IX:

[0529] [ka]

[0530] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, L, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0531] In one embodiment, the compound for use of formula I is a compound of formula IXa:

[0532] [ka]

[0533] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, L, A and Y are as defined above with respect to formula I, and any of its embodiments.

[0534] In one embodiment, the compound for use of formula I is a compound of formula IXb:

[0535] [ka]

[0536] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0537] In one embodiment, the compound for use of formula I is a compound of formula IXc:

[0538] [ka]

[0539] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, A and Y are as defined above with respect to formula I, and any of its embodiments.

[0540] In one embodiment, the compound for use of formula I is a compound of formula X:

[0541] [ka]

[0542] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0543] In one embodiment, the compound for use of formula I is a compound of formula Xa:

[0544] [ka]

[0545] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L and A are as defined above with respect to formula I, and any of its embodiments.

[0546] In one embodiment, the compound for use of formula I is a compound of formula Xb:

[0547] [ka]

[0548] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, R 3 , R4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0549] In one embodiment, the compound for use of formula I is a compound of formula Xc:

[0550] [ka]

[0551] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and A are as defined above with respect to formula I, and any of its embodiments.

[0552] In one embodiment, the compound for use of formula I is a compound of formula XI:

[0553] [ka]

[0554] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0555] In one embodiment, the compound for use of formula I is a compound of formula XIa:

[0556] [ka]

[0557] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L and A are as defined above with respect to formula I, and any of its embodiments.

[0558] In one embodiment, the compound for use of formula I is a compound of formula XIb:

[0559] [ka]

[0560] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0561] In one embodiment, the compound for use of formula I is a compound of formula XIc:

[0562] [ka]

[0563] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and A are as defined above with respect to formula I, and any of its embodiments.

[0564] In one embodiment, the compound for use of formula I is a compound of formula XII:

[0565] [ka]

[0566] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0567] In one embodiment, the compound for use of formula I is a compound of formula XIIa:

[0568] [ka]

[0569] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0570] In one embodiment, the compound for use of formula I is a compound of formula XIIb:

[0571] [ka]

[0572] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, R 3 , R4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0573] In one embodiment, the compound for use of formula I is a compound of formula XIIc:

[0574] [ka]

[0575] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and A are as defined above with respect to formula I, and any of its embodiments.

[0576] In one embodiment, the compound for use of formula I is a compound of formula XIII:

[0577] [ka]

[0578] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0579] In one embodiment, the compound for use of formula I is a compound of formula XIIIa:

[0580] [ka]

[0581] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L and A are as defined above with respect to formula I, and any of its embodiments.

[0582] In one embodiment, the compound for use of formula I is a compound of formula XIIIb:

[0583] [ka]

[0584] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , A, R 3 , R 4 , R 5 , R 6 and R 7 is as defined above with respect to formula I, and any of its embodiments.

[0585] In one embodiment, the compound for use of formula I is a compound of formula XIIIc:

[0586] [ka]

[0587] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and A are as defined above with respect to formula I, and any of its embodiments.

[0588] In one embodiment, the compound for use of formula I is a compound of formula XIV:

[0589] [ka]

[0590] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 , L and Cy are as defined above with respect to formula I, and any of its embodiments.

[0591] In one embodiment, the compound for use of formula I is a compound of formula XIVa:

[0592] [ka]

[0593] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and L are as defined above with respect to formula I, and any of its embodiments.

[0594] In one embodiment, the compound for use of formula I is a compound of formula XIVb:

[0595] [ka]

[0596] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 , R 2 and Cy are as defined above with respect to Formula I, and any of its embodiments.

[0597] In one embodiment, the compound for use of formula I is a compound of formula XIVc:

[0598] [ka]

[0599] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 1 and R 2 is as defined above with respect to formula I, and any of its embodiments.

[0600] Thus, compounds for use according to the invention include compounds and sub-formulas of formula I defined above, in particular the compounds in Table 2 below.

[0601] [Table 3A]

[0602] [Table 3B]

[0603] [Table 3C]

[0604] [Table 3D]

[0605] [Table 3E]

[0606] [Table 3F]

[0607] [Table 3G]

[0608] The present invention also relates to the hydroxyphenyl compounds listed in Table 2b below in combination with anti-cancer agents for use in the treatment of cancer.

[0609] [Table 4]

[0610] The present invention also relates to the compounds of the present invention as described above for use in the treatment of cancer, in increasing the sensitivity of cancer cells to anti-cancer agents.

[0611] In one embodiment, the compound for use according to the invention is selected from compounds 2, 3, 4, 5, 6, 7, 9, 11, 12, 14, 16, 17, 18, 20, 22, 23, 24, 27, 28, S-28, R-28, 30, 31, 32, 40, 41, 42, 43, 44, 46, 47, 50, 52, 54, 57, 58, 59, 63, 64 and 66 in Tables 2 and 2b above.

[0612] In one embodiment, the compound for use according to the invention is selected from compounds 2, 3, 4, 5, 6, 7, 9, 11, 12, 14, 16, 17, 18, 20, 22, 23, 24, 27, 28, S-28, R-28, 30, 31, 32, 40, 41, 42, 43, 44, 46, 47, 50, 52, 54, 63, 64 and 66 in Table 2 above.

[0613] In one embodiment, the compound for use according to the invention is selected from compounds 57, 58 and 59 in Table 2b above.

[0614] In one embodiment, the compounds for use according to the invention are selected from compounds 28, 33, 34, 35, 36, 37 and 38 in Table 2 above, in particular compounds 28 and 33 in Table 2 above.

[0615] In one embodiment, the compound for use according to the invention is compound 28 in Table 2 above.

[0616] Cancer treatment, particularly chemotherapy, is a type of treatment that uses one or more anti-cancer drugs. Anti-cancer or cytotoxic drugs within the meaning of the present invention include, but are not limited to, alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti-angiogenic agents. Preferably, the anti-cancer drug is an alkylating agent. A preferred alkylating agent is temozolamide.

[0617] The compounds of the present invention are therefore useful for the treatment of cancer, particularly cancers that can be treated by anti-cancer agents selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti-angiogenic agents, more particularly cancers that can be treated by alkylating agents.

[0618] Within the meaning of the present invention, cancers that may be treated by anti-cancer agents selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti-angiogenic agents include, but are not limited to, glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer. A preferred cancer to be treated by alkylating agents is glioblastoma.

[0619] Thus, in one embodiment there is provided a compound of the invention, or a pharma- ceutically acceptable salt or solvate thereof, in combination with an anti-cancer agent for use in the treatment of cancer.

[0620] The present invention therefore also relates to a compound of the present invention, i.e. a compound of formula I as defined above or any of its subformulas, in particular a compound of Table 2 or a hydroxyphenyl compound of Table 2b above, or a pharmaceutically acceptable salt or solvate thereof, in combination with an anticancer agent, in particular an anticancer agent selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly a cancer selected from glioblastoma (GB), triple negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly a cancer that can be treated by an alkylating agent, even more particularly a cancer selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an alkylating agent, even more particularly, temozolomide, for use in the treatment of cancer, preferably a cancer that can be treated by an anticancer agent selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly a compound of the present invention, i.e. a compound of formula I as defined above or any of its subformulas, in particular a compound of Table 2 or a hydroxyphenyl compound of Table 2b above, or a pharmaceutically acceptable salt or solvate thereof.

[0621] In other words, the present invention also relates to a method for treating cancer, particularly cancer that can be treated by an anti-cancer agent selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti-angiogenic agents, more particularly cancer selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly cancer that can be treated by an alkylating agent, even more particularly glioblastoma, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof in combination with an anti-cancer agent, particularly an anti-cancer agent selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti-angiogenic agents, more particularly alkylating agents, even more particularly temozolomide, to a patient in need of such treatment.Preferably, the patient is a warm-blooded animal, more preferably a human.The cancer that can be treated by an alkylating agent is preferably a cancer as defined above.

[0622] The present invention further provides the use of the compound of the present invention or a pharma- ceutically acceptable salt or solvate thereof in combination with an anticancer agent, in particular an anticancer agent selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an anticancer agent selected from glioblastoma, triple-negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly an anticancer agent that can be treated by an alkylating agent, even more particularly an alkylating agent, even more particularly temozolomide, for the manufacture of a medicament for use in the treatment of cancer, in particular a cancer that can be treated by an alkylating agent, in particular a cancer that can be treated by an alkylating agent, in particular a cancer that can be treated by an alkylating agent, even more particularly ...

[0623] By "in combination" is intended a combination preparation in which the active ingredients are either physically together in the same preparation or physically separate, for use in combination therapy by simultaneous or sequential administration to a patient.

[0624] Thus, according to the present invention, a compound of the present invention or a pharma- ceutically acceptable salt or solvate thereof and an anti-cancer drug are administered to a patient, either simultaneously or sequentially, in the same formulation or in separate forms, to treat cancer.

[0625] According to a further aspect of the invention there is provided a compound of the invention, or a pharma- ceutically acceptable salt or solvate thereof, for use in increasing the sensitivity of cancer cells to anti-cancer agents in the treatment of cancer.

[0626] The present invention therefore relates to a compound of the invention, i.e. a compound of formula I and any of its embodiments as defined above, or any of the subformulas of formula I, in particular the hydrophenyl compounds of Table 2 (Table 3) or Table 2b (Table 4), or a pharmaceutically acceptable salt or solvate thereof, for use in increasing the sensitivity of cancer cells to anticancer agents, in particular anticancer agents selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly to alkylating agents, even more particularly to temozolomide, in the treatment of cancer, in particular cancers that can be treated by anticancer agents selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly to alkylating agents, even more particularly to temozolomide, in the treatment of cancer, in particular cancers that can be treated by anticancer agents selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly to alkylating agents, even more particularly to temozolomide.

[0627] In other words, the present invention also relates to a method for increasing the sensitivity of cancer cells to anticancer agents, in particular anticancer agents selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly anticancer agents selected from glioblastoma, triple negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, even more particularly anticancer agents selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly alkylating agents, even more particularly temozolomide, in the treatment of cancer, in particular cancers that can be treated by anticancer agents selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly alkylating agents, even more particularly temozolomide, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, i.e. a compound of formula I and any of its embodiments as defined above, or any of its subformulas, or a compound of Table The present invention relates to a method comprising administering to a patient in need thereof a hydrophenyl compound of formula 2b (Table 4), or a pharma- ceutically acceptable salt or solvate thereof, in combination with an anti-cancer agent, in particular an anti-cancer agent selected from alkylating agents, anti-microtubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and anti-angiogenic agents, more particularly an alkylating agent, and even more particularly temozolomide. Preferably, the patient is a warm-blooded animal, more preferably a human.

[0628] The present invention further provides the use of a compound of the present invention, i.e. a compound of formula I and any of its embodiments as defined above, or any of its subformulas, or a hydrophenyl compound of Table 2b (Table 4), or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for use in sensitizing cancer cells to an anticancer agent, in particular an anticancer agent selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an anticancer agent selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly an alkylating agent, even more particularly temozolomide, in the treatment of cancer, in particular a cancer that can be treated by an anticancer agent selected from alkylating agents, antimicrotubule agents, antimetabolites, topoisomerase inhibitors, cytotoxic antibiotics and antiangiogenic agents, more particularly a cancer that can be treated by an alkylating agent, even more particularly a cancer that can be treated by an alkylating agent, in particular ...

[0629] According to a further feature of the present invention, there is provided a use of a compound of the present invention, i.e. a compound of formula I and any of its embodiments as defined above, or any of its subformulas, or a hydrophenyl compound of Table 2b (Table 4), or a pharma- ceutically acceptable salt or solvate thereof, for inhibiting IRE1 RNase activity in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of the present invention, or a pharma- ceutically acceptable salt or solvate thereof. In other words, the present invention also provides a method of inhibiting IRE1 RNase activity in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of the present invention, i.e. a compound of formula I and any of its embodiments as defined above, or a hydrophenyl compound of Table 2b (Table 4), or any of its subformulas, or a pharma- ceutically acceptable salt or solvate thereof. Preferably, the patient is a warm-blooded animal, even more preferably a human.

[0630] According to the present invention, the compounds of the invention, or for use according to the present invention, may be administered in a therapeutically effective amount as a pharmaceutical formulation by any of the accepted modes of administration, preferably by intravenous or oral routes.

[0631] The therapeutically effective amount ranges from 0.1 to 50,000 μg per kg of body weight per day, preferably 1,000 to 40,000 μg per kg of body weight per day, depending on a number of factors such as the severity of the disease being treated, the age and relative health of the subject, the potency of the compound, the route and form of administration, the indication for which administration is intended, and the preferences and experience of the physician involved. Those skilled in the art of treating such diseases can rely on their personal knowledge to research the therapeutically effective amount of the anticancer agent of the present invention for a given cancer.

[0632] According to one embodiment, the compound of the present invention, its acceptable pharmaceutical salt or solvate may be administered as part of combination therapy.Therefore, within the scope of the present invention are included the co-administration of compositions and medicaments that contain, in addition to the compound of the present invention, its pharmaceutically acceptable salt or solvate as active ingredient, additional therapeutic agent and / or active ingredient, and the embodiments that include said compositions and medicaments.Such multi-drug regimens, often referred to as combination therapy, may be used in the treatment of cancer, particularly the treatment of those defined above.

[0633] Thus, the treatment methods and pharmaceutical compositions of the present invention can use the compounds of the present invention, or their acceptable pharmaceutical salts or solvates, in the form of monotherapy, but the methods and compositions can also be used in the form of multitherapy, in which one or more compounds of the present invention, or their pharma- ceutically acceptable salts or solvates, are co-administered in combination with one or more other therapeutic agents. Such additional therapeutic agents include, but are not limited to, alkylating agents, preferably temozolomide.

[0634] In one embodiment, the treatment method and pharmaceutical composition of the present invention may use the compound of the present invention, or its acceptable pharmaceutical salt or their solvate in combination with radiation therapy.According to this embodiment, the compound of the present invention, its acceptable pharmaceutical salt or solvate may be administered in combination with radiation therapy.Therefore, there is provided a compound of formula I and any of its embodiments, or any of its subformulas, or a hydrophenyl compound of Table 2b (Table 4) as defined above, for use in treating cancer as defined above in combination with radiation therapy.Such radiation therapy includes, but is not limited to, external beam radiation therapy, brachytherapy and total body radioisotope therapy.

[0635] The present invention also provides a pharmaceutical composition comprising a compound of the invention, i.e. a compound of formula I and any of its embodiments as defined above, or any of its subformulas, or a hydrophenyl compound of Table 2b (Table 4), or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable carrier, diluent, excipient and / or adjuvant.

[0636] As noted above, the present invention also encompasses pharmaceutical compositions that contain, in addition to a compound of the present invention as an active ingredient, a pharma- ceutically acceptable salt or solvate thereof, additional therapeutic agents and / or active ingredients, particularly anti-cancer agents.

[0637] The present invention also provides a compound of the invention, or a pharma- ceutically acceptable salt or solvate thereof, for use in therapeutic treatment in the human or animal body.

[0638] Another object of the invention is a medicament comprising, as active ingredient, at least one compound according to the invention or a pharma- ceutically acceptable salt or solvate thereof.

[0639] Generally, for pharmaceutical uses, the compounds of the present invention may be formulated as pharmaceutical preparations comprising at least one compound of the present invention, as well as at least one pharma- ceutically acceptable carrier, diluent, excipient and / or adjuvant, and optionally one or more further pharma- ceutically active compounds.

[0640] By way of non-limiting example, such formulations may be in a form suitable for administration orally, parenterally (such as by intravenous, intramuscular, or subcutaneous injection or intravenous infusion), topically (including ocular), intracerebrally, by inhalation, skin patch, implant, suppository, etc. Such suitable dosage forms (which may be solid, semi-solid, or liquid, depending on the method of administration), as well as methods for their preparation, and carriers, diluents, and excipients will be apparent to those skilled in the art. Reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[0641] For example, the compounds of the present invention, or pharmaceutical compositions containing the compounds of the present invention, may be administered orally in the form of tablets, coated tablets, pills, capsules, soft gelatin capsules, oral powders, granules, ovules, elixirs, solutions or suspensions, which may contain flavorings or colorants for immediate, delayed, modified, sustained, pulsed or controlled release applications.

[0642] Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium, and binders such as certain complex silicates, polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, etc. Similar types of solid compositions may also be used as fillers in hard gelatin capsules. Preferred excipients in this regard include lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. The hard gelatin capsules may contain granules of the compound of the present invention.

[0643] Soft gelatin capsules may be prepared using capsule agents containing the compounds of the present invention, vegetable oils, waxes, fats, or other vehicles suitable for soft gelatin capsules.As an example, an acceptable vehicle may be an oily vehicle such as a long-chain triglyceride vegetable oil (e.g., corn oil).

[0644] Dispersible powders and granules suitable for preparation of an aqueous suspension by adding water may contain the active ingredient in a mixture with a dispersing agent, a wetting agent, and a suspending agent, and one or more preservatives. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

[0645] Liquid dosage forms for oral administration may include pharma- ceutically acceptable solutions, emulsions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water or oily vehicles. Liquid dosage forms may be supplied as a dry product for constitution with water or other suitable vehicle before use. Such compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, complexing agents, such as 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, and sweeteners, flavoring agents, fragrances, coloring substances or dyes, together with diluents, such as water, ethanol, propylene glycol, and glycerin, and combinations thereof. These compositions may be preserved by the addition of an antioxidant, such as butylated hydroxyanisol or alpha-tocopherol.

[0646] Finely divided powders of the compounds of the invention can be prepared, for example, by micronization or by methods known in the art. The compounds of the invention may be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for tablet formation and other formulation types.

[0647] When the compounds of the invention are administered parenterally, examples of such administration include one or more of administering the agent intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternal, intracranially, intramuscularly or subcutaneously, and / or by use of infusion techniques.

[0648] The compounds of the present invention can be administered by the parenteral route using readily available formulations or depot type formulations.

[0649] Pharmaceutical compositions for parenteral administration of readily available formulations may be in the form of a sterile injectable aqueous or oily solution or suspension in a non-toxic parenterally acceptable diluent or solvent and may contain formulatory agents such as suspending, stabilizing, dispersing, wetting agents and / or complexing agents (cyclodextrins, e.g., 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, and the like).

[0650] Depot-type formulations for parenteral administration may be prepared by conventional techniques using pharma- ceutically acceptable excipients, including, but not limited to, biocompatible and biodegradable polymers (e.g., poly(β-caprolactone), poly(ethylene oxide), poly(glycolic acid), poly[(lactic acid)-co-(glycolic acid)...], poly(lactic acid)...), non-biodegradable polymers (e.g., ethylene vinyl acetate copolymers, polyurethanes, polyester(amides), polyvinyl chloride...), aqueous and non-aqueous vehicles (e.g., water, sesame oil, cottonseed oil, soybean oil, castor oil, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils, propylene glycol, DMSO, THF, 2-pyrrolidone, N-methylpyrrolidinone, N-vinylpyrrolidinone...).

[0651] Alternatively, the active ingredient may be in a dry form, such as a powdered, crystalline, or lyophilized solid, for constitution with a suitable vehicle. The preparation of suitable parenteral formulations is readily accomplished under sterile conditions by standard pharmaceutical techniques well known to those skilled in the art.

[0652] As indicated, the compounds of the present invention can be administered intranasally or by inhalation, conveniently delivered in the form of a dry powder inhaler or aerosol spray supply from a pressurized container, pump, spray or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, (e.g., from Ineos Fluor), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer can contain a solution or suspension of the active compound. It may also be formulated into capsules and cartridges (e.g., made of gelatin) containing a powder mix of the compound and a suitable powder base, such as lactose or starch, for use in an inhaler or insufflator. For compositions suitable and / or compatible with inhalation administration, the compounds or salts of the present invention are preferably in a form having reduced particle size, more preferably obtained or obtainable by micronization. The preferred particle size of the reduced size (eg, micronized) compound or salt or solvate is defined by a D50 value of from about 0.5 to about 50 microns (eg, as measured using laser diffraction).

[0653] Alternatively, the compound of the present invention may be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder.The compound of the present invention may also be administered dermally or transdermally, for example, by using a skin patch.The compound of the present invention may also be administered by pulmonary or rectal route.The compound of the present invention may also be administered by ocular route.For ophthalmic use, the compound may be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or preferably as a solution in isotonic pH-adjusted sterile saline, optionally combined with a preservative such as benzylalkonium chloride.Alternatively, the compound may be formulated in an ointment such as petrolatum.

[0654] For topical application to the skin, the agent of the present invention may be formulated as a suitable ointment containing the active compound suspended or dissolved in a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the agent of the present invention may be formulated as a suitable lotion or cream suspended or dissolved in a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0655] definition The following definitions and explanations are for terms used throughout this specification, including both the specification and claims.

[0656] Unless otherwise stated, any reference herein to a compound of the invention means the compound, and thus, the pharma- ceutically acceptable salts and solvates thereof.

[0657] When describing the compounds of the present invention, the terms used, unless otherwise indicated, should be construed in accordance with the following definitions.

[0658] The term "unsubstituted" as used herein means that a radical, group or residue has no substituents. The term "substituted" means that a radical, group or residue has one or more substituents.

[0659] The term "halo" or "halogen" refers to atoms of group 17 of the periodic table (the halogens) and includes in particular fluorine, chlorine, bromine and iodine atoms. Preferred halo groups in the context of the present invention are fluoro and iodo, with fluoro being particularly preferred.

[0660] The term “alkyl,” alone or as part of another substituent, refers to a group of the formula C n H 2n+1 where n is a number equal to or greater than 1. Thus, an alkyl group can contain one or more carbon atoms, and generally, according to the present invention, contains 1 to 12, more preferably 1 to 8, and even more preferably 1 to 6 carbon atoms. An alkyl group within the meaning of the present invention may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, isopentyl, sec-pentyl, tert-pentyl, n-hexyl, neohexyl, isohexyl, sec-hexyl, and tert-hexyl. Particular examples of alkyl groups in the context of the present invention include methyl, ethyl, isopropyl, and tert-butyl.

[0661] The term "haloalkyl", alone or in combination, refers to an alkyl group as defined above, in which one or more hydrogens are replaced by halogens as defined above. Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.

[0662] The term "cycloalkyl" as used herein refers to a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbyl group. Cycloalkyl groups can contain 3 or more carbon atoms in the ring, and generally, according to the present invention, contain 3 to 10, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0663] The term "heteroatom" as used herein refers to any atom that is not carbon or hydrogen. Non-limiting examples of such heteroatoms include nitrogen, oxygen, sulfur, and phosphorus. Preferred heteroatoms according to the present invention are nitrogen, oxygen, and sulfur.

[0664] The terms "heterocyclyl", "heterocycloalkyl" or "heterocyclo", as used herein, alone or as part of another group, refer to a non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., 3-7 membered monocyclic, 7-11 membered bicyclic, or containing a total of 3-10 ring atoms) having at least one heteroatom in at least one carbon atom-containing ring. Each ring of a heteroatom-containing heterocyclic group can have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, the nitrogen and sulfur heteroatoms being optionally oxidized and the nitrogen heteroatom being optionally quaternized. A heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, valence permitting. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, morpholinyl.

[0665] The term "aryl" as used herein refers to a polyunsaturated aromatic hydrocarbyl group, usually containing 5 to 12 atoms, preferably 6 to 10 atoms, having a single ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl), in which at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, 1-naphthyl (or naphthalene-1-yl), 2-naphthyl (or naphthalene-2-yl), anthracenyl, indanyl, indenyl, and 1,2,3,4-tetrahydronaphthyl.

[0666] The term "heteroaryl," as used herein, alone or as part of another group, refers to, including but not limited to, an aromatic ring or ring system of 5 to 12 carbon atoms containing one to two rings fused together, each ring typically containing 5 to 6 atoms, at least one of the rings being aromatic, one or more carbon atoms in one or more of the rings being replaced by oxygen, nitrogen and / or sulfur atoms, the nitrogen and sulfur heteroatoms optionally being oxidized, and the nitrogen heteroatom optionally being quaternized. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, furanyl, benzofuranyl, pyrrolyl, indolyl, thiophenyl, benzothiophenyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiazolyl, and benzothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, and tetrazolyl.

[0667] The compounds of the present invention containing a basic functional group may be in the form of a pharma- ceutically acceptable salt. The pharma- ceutically acceptable salts of the compounds of the present invention containing one or more basic functional groups include, in particular, the acid addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, cinnamate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide ion, isethione. Salts in the form of 1-methyl-2-propanediol, ...

[0668] Pharmaceutically acceptable salts and subformulas of the compounds of formula I, or the hydrophenyl compounds of Table 2b, can be prepared, for example, as follows: (i) reacting a compound of formula I or any of its subformulas, or a hydrophenyl compound of Table 2b, with the desired acid; or (ii) Converting one of the salts of the compound of formula I or any of its subformulas, or the hydrophenyl compounds of Table 2b, into another by reaction with an appropriate acid or by a suitable ion exchange column.

[0669] All of these reactions are usually carried out in solution. The salts can precipitate from the solution and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the salt can vary from completely ionized to almost non-ionized.

[0670] The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharma- ceutically acceptable solvent molecules, such as ethanol, and the term "hydrate" is used where said solvent is water.

[0671] The compounds of the present invention include the compounds of the present invention as defined hereinabove, including all polymorphs and crystal habits thereof, prodrugs thereof, and isomers (including optical isomers, geometric isomers and tautomers), and isotopically labeled compounds of the present invention.

[0672] Furthermore, generally, with regard to salts of the compounds of the present invention, pharma- ceutically acceptable salts are preferred, although it should be noted that the invention in its broadest sense also includes non-pharmaceutically acceptable salts, which may be used, for example, for the isolation and / or purification of the compounds of the present invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts, which may facilitate the separation of the optically active isomers of the compounds of the present invention.

[0673] The term "patient" refers to a warm-blooded animal, more preferably a human, currently awaiting or receiving medical care, or being or will be the subject of a medical procedure.

[0674] The term "human" refers to subjects of both genders and at any stage of development (i.e., newborn, infant, child, adolescent, adult). In one embodiment, the human is an adolescent or adult, preferably an adult.

[0675] The terms "treat," "treating" and "treatment," as used herein, are intended to include alleviating or arresting a condition or disease and / or its attendant symptoms.

[0676] The term "therapeutically effective amount" (or, more simply, "effective amount"), as used herein, means an amount of an active agent or ingredient sufficient to realize a desired therapeutic or prophylactic effect in the individual to whom it is administered.

[0677] The term "administration" or its derivatives (e.g., "administering") means providing an active agent or ingredient, alone or as part of a pharma- ceutically acceptable composition, to a patient whose condition, symptom, or disease is to be treated.

[0678] By "pharmaceutically acceptable" it is meant that the components of a pharmaceutical composition are compatible with each other and not harmful to the patient.

[0679] The term "excipient" as used herein means a substance that is formulated together with an active agent or active ingredient in a pharmaceutical composition or medicament. Excipients acceptable for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, 21st Edition 2011. The choice of excipient may be selected with respect to the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense of not being harmful to its recipient. The at least one pharma- ceutically acceptable excipient may be, for example, a binder, diluent, carrier, lubricant, disintegrant, wetting agent, dispersant, suspending agent, and the like.

[0680] The term "pharmaceutical vehicle" as used herein means a carrier or inert medium used as a solvent or diluent in which a pharma- ceutical active agent is formulated and / or administered. Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.

[0681] The term "cancer," as used herein, refers to a physiological condition in a subject that is characterized by unregulated or deregulated cell growth that has the potential to invade or spread to other parts of the body. The term "cancer" includes solid tumors and blood-borne tumors, whether malignant or benign.

[0682] Examples of cancer include, but are not limited to: Acinar adenocarcinoma, Acinar carcinoma, Acral lentigo melanoma, Actinic keratosis, Adenocarcinoma, Adenoid cystic carcinoma, Adenosquamous carcinoma, Adnexal carcinoma, Adrenal rest tumor, Adrenal cortical carcinoma, Aldosterone-secreting carcinoma, Alveolar soft part sarcoma, Amelanotic melanoma, Thyroid enamel cell carcinoma carcinoma), angiosarcoma, apocrine carcinoma, Askin tumor, astrocytoma, basal cell carcinoma, basaloid carcinoma, basal squamous cell carcinoma, biliary tract cancer, bone cancer, bone marrow cancer, botryoid sarcoma, brain cancer, breast cancer, pulmonary bronchioloalveolar carcinoma, bronchial adenocarcinoma, bronchogenic carcinoma, malignant pleomorphic adenoma, cervical cancer, chloroma, cholangiocellular carcinoma, chondrosarcoma, choriocarcinoma, choroid plexus papilloma, clear cell adenocarcinoma, colon cancer, colorectal cancer, comedonal carcinoma, cortisol-producing carcinoma, columnar cell carcinoma, dedifferentiated fat Liposarcoma, ductal adenocarcinoma of the prostate, ductal carcinoma, ductal carcinoma in situ, duodenal cancer, eccrine adenocarcinoma, embryonal carcinoma, endometrial carcinoma, endometrial stromal sarcoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, exophytic carcinoma, fibroblastic sarcoma, fibrocarcinoma, fibrous lamellar carcinoma, fibrosarcoma, follicular thyroid carcinoma, gallbladder cancer, gastric adenocarcinoma, giant cell carcinoma, giant cell sarcoma, giant cell tumor of bone, glioma, glioblastoma or glioblastoma multiforme, granulose cell carcinoma carcinoma), head and neck cancer, hemangioma, angiosarcoma, hepatoblastoma, hepatocellular carcinoma, Hürthle cell carcinoma, ileal cancer, invasive lobular carcinoma, inflammatory breast cancer, intraductal carcinoma, intraepidermal carcinoma, jejunal cancer, Kaposi's sarcoma, Krukenberg's tumor, Krutzycki cell carcinoma, Kupffer cell sarcoma, large cell carcinoma, laryngeal cancer, lentigo maligna melanoma, liposarcoma, liver cancer, lobular carcinoma, lobular carcinoma in situ, lung cancer, lymphoepithelioma, lymphosarcoma, malignant melanoma, medullary carcinoma, medullary thyroid carcinoma, medulloblastoma, meningeal carcinomatosis, Merkel cell carcinoma, micropapillary carcinoma, mixed cell sarcoma, mucinous carcinoma, mucocutaneous carcinoma Skin cancer, mucosal melanoma, myxoid liposarcoma, myxosarcoma, nasopharyngeal carcinoma, nephroblastoma, neuroblastoma, nodular melanoma, non-clear cell renal carcinoma, non-small cell lung carcinoma, oat cell carcinoma, intraocular melanoma, oral carcinoma, osteoid carcinoma, osteosarcoma, ovarian carcinoma, Paget's carcinoma, pancreatic carcinoma, pancreatoblastoma, papillary adenocarcinoma, papillary carcinoma, papillary thyroid carcinoma, pelvic carcinoma, periampullary carcinoma, phyllodes tumor, pituitary carcinoma, pleomorphic liposarcoma, pleuropulmonary blastoma, primary intraosseous carcinoma, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, round cell liposarcoma, scar carcinoma, schistosomal bladder cancercancer, Schneider's carcinoma, sebaceous carcinoma, signet ring cell carcinoma, skin cancer, small cell lung cancer, small cell osteosarcoma, soft tissue sarcoma, spindle cell carcinoma, spindle cell sarcoma, squamous cell carcinoma, gastric cancer, superficial spreading melanoma, synovial sarcoma, telangiectatic sarcoma, terminal ductal carcinoma, testicular cancer, thyroid cancer, transitional cell carcinoma, tubular carcinoma, oncogenic melanoma, undifferentiated carcinoma, urachal adenocarcinoma, bladder cancer, uterine cancer, endometrial cancer, uveal melanoma, aginal cancer, cerrucous carcinoma, choriocarcinoma, well-differentiated liposarcoma, Wilm's tubor or intracranial yolk sac tumor. Preferred cancers according to the present invention are glioblastoma, triple negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer, and more preferred cancer is glioblastoma.

[0683] The terms "anticancer agent", "anticancer drug", "chemotherapeutic agent" or "cytotoxic agent" as used herein refer to chemical agents used to treat cancer that are administered in one or more cycles of regimens, alone or in combination with one or more other agents, over a period of days to weeks. Such agents are toxic to cells with high proliferation rates, such as cancer cells.

[0684] Examples of anti-cancer drugs include, but are not limited to: alkylating agents such as, for example, cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine, nitrosoureas or temozolomide; - antifolates, such as methotrexate, pemetrexed, pralatrexate or trimetrexate; pyrimidine analogues, such as azacitidine, capecitabine, cytarabine, decitabine, floxurinine, fluorouracil, gemcitabine or trifluridine; antimetabolites, including purine analogues, such as azathioprine, cladribine, fludarabine, mercaptopurine or tioguanine (formerly thioguanine). - anti-microtubule agents, including taxanes, such as paclitaxel, docetaxel, abraxane or taxotere; and vinca alkaloids, such as vinblastine, vincristine, vindesine or vinorelbine. - cytotoxic antibiotics, including anthracyclines such as, for example, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone or valrubicin; and peptide antibiotics such as, for example, bleomycin or actinomycin. - topoisomerase inhibitors, including inhibitors of topoisomerase I, such as, for example, irinotecan or topotecan; inhibitors of topoisomerase II, such as, for example, etoposide, teniposide or tafluposide. - Epothilones histone deacetylase inhibitors, such as, for example, vorinostat, romidepsin, panobinostat or quisinostat - kinase inhibitors such as, for example, afatinib, avitinib, bortezomib, carfilzomib, dabrafenib, erlotinib, gefitinib, imatinib, osimertinib, vemurafenib or vismodegib - Platinum-based drugs such as carboplatin, cisplatin or oxaliplatin - proteasome inhibitors, such as, for example, bortezomib, carfilzomib or ixazomib; - Retinoids such as tretinoin, alitretinoin or bexarotene.

[0685] A preferred anti-cancer drug according to the present invention is an alkylating agent. A preferred anti-cancer drug according to the present invention is temozolomide.

[0686] The present invention will be better understood with reference to the following examples and drawings, which are intended to be representative of specific embodiments of the invention and are not intended to limit the scope of the invention. [Brief description of the drawings]

[0687] [Figure 1A]In vitro inhibition of IRE1 Activity by compounds of the invention. Measurement of IRE1 activity in vitro in the presence of increasing concentrations of MKC(A). FRET signal was measured upon cleavage of the fluorescent probe over a 25 minute incubation. IC50 calculated from the fitting process is shown in the figure. Symbols and error bars represent the mean ± standard deviation. [Figure 1B] In vitro inhibition of IRE1 Activity by compounds of the invention. Measurement of IRE1 activity in vitro in the presence of increasing concentrations of compound 34 (Z4A). FRET signal was measured upon cleavage of the fluorescent probe over a 25 minute incubation. IC50s calculated from the fitting process are shown in the figure. Symbols and error bars represent the mean ± standard deviation. [Figure 1C] In vitro inhibition of IRE1 Activity by compounds of the invention. Measurement of IRE1 activity in vitro in the presence of increasing concentrations of compound 35 (Z4B). FRET signal was measured upon cleavage of the fluorescent probe over a 25 minute incubation. IC50s calculated from the fitting process are shown in the figures. Symbols and error bars represent the mean ± standard deviation. [Figure 1D] In vitro inhibition of IRE1 Activity by compounds of the invention. Measurement of IRE1 activity in vitro in the presence of increasing concentrations of compound 36 (Z4C). FRET signal was measured upon cleavage of the fluorescent probe over a 25 minute incubation. IC50s calculated from the fitting process are shown in the figures. Symbols and error bars represent the mean ± standard deviation. [Figure 1E] In vitro inhibition of IRE1 Activity by compounds of the invention. Measurement of IRE1 activity in vitro in the presence of increasing concentrations of compound 37 (Z4D). FRET signal was measured upon cleavage of the fluorescent probe over a 25 minute incubation. IC50s calculated from the fitting process are shown in the figures. Symbols and error bars represent the mean ± standard deviation. [Figure 1F]In vitro inhibition of IRE1 Activity by compounds of the invention. Measurement of IRE1 activity in vitro in the presence of increasing concentrations of 38(Z4E)(BF). FRET signal was measured upon cleavage of the fluorescent probe over a 25 minute incubation. IC50s calculated from the fitting process are shown in the figure. Symbols and error bars represent the mean ± standard deviation. [Figure 2A] Compound 33 (Z4) and Compound 28 (Z4P) inhibit IRE1 activity in a cellular model. Protein levels of IRE1 and phospho-IRE1 in U87 cells treated with Compound 33 (Z4) and Compound 28 (Z4P) for 24 hours. The fold change in protein expression between IRE1 and phospho-IRE1 is presented in bar graph form normalized to untreated U87 cells. Nonlinear regression was calculated using GraphPad Prism software. Symbols and error bars represent the mean ± standard deviation. [Figure 2B] In a cell model, compound 33 (Z4) and compound 28 (Z4P) inhibit IRE1 activity. Quantification of XBP1 mRNA levels upon treatment with 1 μg / mL tunicamycin for 24 hours in the presence or absence of pretreatment with 25 μM compound 33 (Z4) or compound 28 (Z4P) normalized to untreated U87 cells. Nonlinear regression was calculated using GraphPad Prism software. Symbols and error bars represent the mean ± standard deviation. [Figure 2C] In a cellular model, compound 33 (Z4) and compound 28 (Z4P) inhibit IRE1 activity. Quantification of SPARC mRNA levels in the presence of 5 μg / mL actinomycin D and in the presence of 10 μg / mL tunicamycin and 9 μg / mL compound 33 (Z4) or compound 28 (Z4P) for 4 hours in U87 cells. Nonlinear regression was calculated using GraphPad Prism software. Symbols and error bars represent the mean ± standard deviation. [Figure 2D]In a cellular model, compound 33 (Z4) and compound 28 (Z4P) inhibit IRE1 activity. Cell viability of U87 cells as a function of TMZ concentration in the presence of increasing concentrations of compound 33 (Z4) and compound 28 (Z4P). Nonlinear regression was calculated using GraphPad Prism software. Symbols and error bars represent the mean ± standard deviation. [Figure 3A] Compounds of the invention mediate the increase in TMZ toxicity in U87 cells. Cell viability assay performed using U87 cells treated with increasing concentrations of compound 34 (Z4A) during TMZ treatment. Nonlinear regression was calculated using GraphPad Prism software. Symbols and error bars represent the mean ± standard deviation. [Figure 3B] Compounds of the invention mediate the increase in TMZ toxicity in U87 cells. Cell viability assay performed using U87 cells treated with increasing concentrations of compound 35 (Z4B) during TMZ treatment. Nonlinear regression was calculated using GraphPad Prism software. Symbols and error bars represent the mean ± standard deviation. [Figure 3C] Compounds of the invention mediate the increase in TMZ toxicity in U87 cells. Cell viability assay performed using U87 cells treated with increasing concentrations of compound 36 (Z4C) during TMZ treatment. Nonlinear regression was calculated using GraphPad Prism software. Symbols and error bars represent the mean ± standard deviation. [Figure 3D] Compounds of the invention mediate the increase in TMZ toxicity in U87 cells. Cell viability assay performed using U87 cells treated with increasing concentrations of compound 37 (Z4D) during TMZ treatment. Nonlinear regression was calculated using GraphPad Prism software. Symbols and error bars represent the mean ± standard deviation. [Figure 3E]Compounds of the invention mediate the increase in TMZ toxicity in U87 cells. Cell viability assay performed using U87 cells treated with increasing concentrations of compound 38 (Z4E) during TMZ treatment. Nonlinear regression was calculated using GraphPad Prism software. Symbols and error bars represent the mean ± standard deviation. [Figure 3F] Compounds of the invention mediate the increase in TMZ toxicity in U87 cells. Cell viability assay performed using U87 cells treated with increasing concentrations of compound 28 (Z4P) during TMZ treatment. Nonlinear regression was calculated using GraphPad Prism software. Symbols and error bars represent the mean ± standard deviation. [Figure 4A] In vivo effect of compound 28 (Z4P). Weight tracing of animals treated with three different concentrations of compound 28 (Z4P) over 7 days. Symbols and error bars represent mean ± standard error (number of animals is indicated in the method section of biological evaluation). [Figure 4B] In vivo effect of Compound 28 (Z4P). Kaplan-Meier representation of survival rate of mice under this regimen (black: control; red: Compound 28 (Z4P); blue: TMZ; yellow: Compound 28 (Z4P) + TMZ). [Figure 4C] In vivo effect of compound 28 (Z4P). Quantitative analysis of bioluminescence imaging signals for control (PBS) and compound 28 (Z4P) groups over 35 days of experiment. Symbols and error bars represent mean ± standard error (number of animals is shown in the method section of biological evaluation). [Figure 5A] Compound 28 (Z4P) crosses the BBB and delays recurrence in vivo under TMZ treatment. Treatment time series for compound 28 (Z4P) in the GB model over 34 days. The period of tumor monitoring is represented as dot marks. [Figure 5B]Compound 28 (Z4P) crosses the BBB and delays recurrence in vivo under TMZ treatment. Quantification of XBP1 mRNA levels from tumors in vivo upon treatment with compound 28 (Z4P) versus control. Symbols and error bars represent the mean ± standard error. [Figure 5C] Compound 28 (Z4P) crosses the BBB and delays recurrence in vivo under TMZ treatment. Treatment time series for the combination of compound 28 (Z4P) (upper arrow) and TMZ (shaded area) in the GB model over 186 days. The period of tumor monitoring is represented as dot marks. [Figure 5D] Compound 28 (Z4P) crosses the BBB and delays relapse in vivo under TMZ treatment. Quantitative analysis of bioluminescence imaging signals over 186 days of experiments for groups treated with TMZ alone or in combination with Z4P (COMBO). Symbols and error bars represent the mean ± standard error. EXAMPLES

[0688] Abbreviation anh: anhydrous; CAN: acetonitrile; DCC: N,N'-dicyclohexylcarbodiimide; DCM: dichloromethane; DIAD: diisopropyl azodicarboxylate; DiPE: diisopropyl ethyl ether; DIPEA: diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMSO: dimethyl sulfoxide; DPPA: diphenylphosphoryl azide; equiv.: equivalent; ESI: electrospray ionization; HPLC: high performance liquid chromatography; HRMS: high-resolution mass spectrometry; MS: mass spectrometry; NMR: nuclear magnetic resonance; PE: petroleum ether; ppm: parts per million; rt or rt: room temperature; SCC: silica-gel column chromatography; TFA: trifluoroacetic acid; THF: tetrahydrofurane; TLC: Thin Layer Chromatography

[0689] synthesis General Information - Commercially available reagents and solvents were purchased from Enamine, Fluorochem, Sigma-Aldrich, Alfa Aesar, and Acros and used as received. All reactions under inert atmosphere were carried out under argon. Petroleum ether (PE) refers to petroleum ether with a temperature between 40 and 60°C. Thin layer chromatography (TLC) was performed on TLC silica gel 60 F254 aluminum plates. Compounds were visualized by exposure to UV light (254 nm) or by immersion of the plates in potassium permanganate or phosphomolybdic acid solutions followed by heating. Silica-gel column chromatography (SCC) was performed using silica gel (particle size 40-63 μm) with isocratic or stepwise gradient elution as indicated. Automated flash column chromatography was performed on an Interchim PuriFlash450 using FlashPure Ecoflex silica cartridges (irregular particle size 50 μm). NMR spectra were obtained on a 300 / 400 / 500 MHz spectrometer and referenced to residual solvent. All chemical shifts are reported in parts per million (ppm). The abbreviations used to describe the resonances are s (singlet), d (doublet), t (triplet), q (quartet), sept (septet), a (distinct), bs (broad singlet) and m (multiplet). Coupling constants (J) are expressed in 0.1 Hz. HPLC-MS analysis was performed on a Shimadzu Prominence system using Thermoscientific Hypersil Gold aQ column chromatography (5μ, 250×4.6 mm) coupled to an Advion ESI mass spectrometer [Method: binary gradient, solvent A=H 2 O + 0.1% TFA, solvent B = MeCN + 0.1% TFA, flow rate = 1 mL / min, A / B from 20 to 100%].

[0690] Typical Procedure 1 - Synthesis of N-phthalimide derivatives [J. Med. Chem., 2007, 50, 1076] In a dry flask equipped with a magnetic stir bar under argon, PPh 3(1.5 equiv.) and phthalimide (1.0 equiv.) in dry THF (10 mL / 3 mmol) were added. The mixture was cooled to 0° C. and the alcohol derivative (1.0 equiv.) was added. After 10 min at 0° C., DIAD (1.5 equiv.) was added dropwise, keeping the temperature below 5° C. After 15 min, the ice bath was removed and the mixture was stirred at room temperature for several hours. The reaction was cooled to 0° C. and the alcohol derivative (1.0 equiv.) was added. After 10 min at 0° C., DIAD (1.5 equiv.) was added dropwise, keeping the temperature below 5° C. After 15 min, the ice bath was removed and the mixture was stirred at room temperature for several hours. 1 HNMR was used for monitoring.

[0691] Once the alcohol was completely consumed, the THF was evaporated under vacuum. The residue was dissolved in Et 2 The mixture was dissolved in 1H2O and stored in the refrigerator overnight. Triphenylphosphine oxide precipitated. The mixture was filtered and the powder was separated by rinsing with cold Et 2 The crude product was purified by column chromatography on silica (SCC).

[0692] Each product was compared to the library. 1 Confirmed by 1 H NMR.

[0693] Typical Procedure 2 - Sonogashira reaction [Chem. Commun., 2013, 49, 4157] In a dry flask equipped with a magnetic stir bar under argon, the alkyne derivative (1 equiv.), 4-iodoanisole (1 equiv.), CuI (4% mol) and PdCl 2 (PPh 3 ) 2 (2% mol). Dry acetonitrile (3 mL / 0.5 mmol) was added under argon, and the solution was degassed with argon (10-15 min). After degassing, dry NEt 3 (5.0 equiv.) was added and the solution was stirred at room temperature for several hours. The reaction was monitored by TLC.

[0694] Once both N-phthalimide and 4-iodoanisole were consumed, the solvent was evaporated and the crude was triturated in DiPE (diisopropyl ether) and filtered to give the product in good yield or purified using SCC.

[0695] Exemplary Procedure 3: Deprotection of N-phthalimide derivates using hydrazine [Org. Lett., 2020, 22, pp. 194-198] In a dry flask equipped with a magnetic stir bar, the N-phthalimide derivative (1 equiv.) was dissolved in EtOH (18 mL / 2 mmol), and hydrazine hydrate (10 equiv.) was added dropwise to the solution. The resulting mixture was heated to reflux for a minimum of 4 h. The reaction was monitored by TLC.

[0696] The pasty precipitate that formed was then filtered through a plug of Celite, washed with cold EtOH and the solvent evaporated under reduced pressure (T<35° C.). A small amount of DCM was added to precipitate a second product. The filtration and filtrate were concentrated under reduced pressure and purified using SCC, DCM / MeOH to give the desired pure product.

[0697] Typical procedure 4: Complete reduction of triple bonds to single bonds [J. Med. Chem., 2010, 53, 8679] In a dry flask equipped with a magnetic stir bar, the alkyne substrate (1 equiv.) was dissolved in EtOH. Then, 10% Pd / C was added (1 / 4 of the mass of the alkyne substrate) and the reaction mixture was stirred at room temperature under hydrogen pressure (1 atm). The reaction was monitored by TLC.

[0698] The mixture was then filtered through a pad of Celite, the catalyst was rinsed three times with EtOH, and the resulting filtrate was then evaporated in vacuo to give the alkane product without further purification.

[0699] Typical Procedure 5: Urea formation using 2-isocyanato-1,4-dimethylbenzene In a dry reaction flask under argon, the amine derivative (1 eq.) in dry DCM was added. 2-Isocyanato-1,4-dimethylbenzene (1 eq.) was dissolved in dry DCM and added dropwise to the reaction tube. The mixture was stirred at room temperature overnight. The precipitate that formed was filtered and washed with cold DCM to often give the pure desired product.

[0700] Typical Procedure 5Bis: Urea formation using triphosgene [Org. Lett., 2004, 6, pp. 3111-3114] In a dry reaction flask under argon, the amine derivative (1 equiv.) and NEt 3 (2 eq.) was added. The mixture was cooled to 0° C. and triphosgene (0.5 eq.) diluted in DCM was added dropwise. The mixture was allowed to warm to room temperature and heated at 40° C. for 6 hours. Upon completion, the solution was cooled to room temperature and concentrated in vacuo. Freshly dried DCM was added to the crude and the second amide derivative (1 eq.) was added. The mixture was stirred overnight and the reaction was monitored by TLC or 1 Monitored by 1 H NMR.

[0701] The solvent was removed and the crude was purified using SCC, DCM / MeOH to give the pure product. Fractions (10-20 mg) were purified by semi-preparative HPLC to give sufficient pure compound for identification and biological assays.

[0702] Typical Procedure 6: BBr 3 [Bioorg. Med. Chem. 2016, p. 2318] In a dry flask equipped with a magnetic stir bar, the urea derivative (1 equiv.) was dissolved in DCM (2 mL / 0.1 mmol). The solution was cooled to -78°C and diluted with BBr 3 (1M in DCM, 4.0 eq.) was added dropwise. The mixture was left under vigorous stirring while slowly warming to room temperature until the starting material was completely consumed. The reaction was monitored by TLC.

[0703] The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give sufficient pure compound for identification and biological assays.

[0704] Exemplary procedure 7: Acyl azide formation from carboxyl derivatives In a dry flask equipped with a magnetic stir bar, the carboxyl derivative (1 equiv.) was dissolved in dry toluene (2 mL / 100 mg) and NEt 3 (1.05 eq.) was added at room temperature. After 15 min, DPPA (1.05 eq.) was added slowly. The mixture was stirred until complete consumption of the starting material and monitored by TLC.

[0705] Water was added and the solution was extracted twice with EtOAc. The combined organic layers were washed with brine and MgSO 4 The crude material was used without purification or purified using SCC, cyclohexane / EtOAc to give the pure product.

[0706] Exemplary procedure 8: Urea formation from acyl azide derivatives via Curtius rearrangement In a dry flask equipped with a magnetic stir bar, the acyl azide derivative (1 equiv.) was dissolved in dry toluene (2 mL / 100 mg) and heated to reflux overnight. The mixture was allowed to warm to room temperature and 2,5-dimethylaniline (1 equiv.) was added. The mixture was stirred at room temperature overnight. The precipitate was filtered and washed with toluene to give the desired compound or water was added and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine and MgSO 4 The crude material was used without purification or purified using SCC, DCM / MeOH to give the pure product.

[0707] Exemplary Procedure 9: Ullmann reaction of piperidine [G. Tang et al., Bioorg. Med. Chem. Lett., 2010, 20, 6020-6023] In an oven-dried Schlenk tube under argon, iodine derivative (1 equiv.), piperidine derivative (1.2 equiv.), K 2 CO 3 (2.0 equiv.), CuI (10% mol) and L-proline (20% mol) were added. The mixture was heated at 90° C. overnight and complete consumption of the iodine derivative was followed by TLC. The solution was allowed to warm to room temperature and partitioned between water and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and diluted with MgSO 4 The crude was purified using column chromatography on silica (100% cyclohexane to 80 / 20 cyclohexane / EtOAc in all cases).

[0708] Exemplary Procedure 10: BOC Deprotection using HCl Solution In an oven-dried flask under argon, a solution of HCl in dioxane (4 M, 2 mL per 100 mg of carbamate) was added to the carbamate derivative. The mixture was stirred at room temperature for 2 hours until complete consumption of the starting material. Evaporation of the solvent afforded the corresponding chlorinated salt of the desired product in quantitative yield.

[0709] Typical Procedure 11: Suzuki reaction In an oven-dried flask under argon, add the bromide derivative (1 equiv.), arylboronic acid (1.2 equiv.), Na 2 CO 3 (1.2 equiv.) in 2M water and a catalytic amount of Pd(PPh 3 ) 4 (5% mol) (6.5 mL per 300 mg of bromide derivative) was added. The reaction mixture was stirred at reflux overnight. The solution was allowed to warm to room temperature, diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine and MgSO 4The crude was purified using column chromatography on silica, cyclohexane / EtOAc to give the pure product.

[0710] Typical Procedure 12: Reductive amination of 4-(4-hydroxyphenyl)butan-2-one derivatives [adapted from ACS Chem. Neurosci., 2017, 8, pp. 486-500]

[0711] [ka]

[0712] To a 500 mL round bottom flask charged with methanol (150 mL) was added the ketone starting material (28.05 mmol, 1 equiv.) and ammonium acetate (12.97 g, 168.3 mmol, 6 equiv.). The reaction mixture was stirred at room temperature for 30 min, after which the temperature was lowered to 0° C. using an ice bath. Sodium cyanoborohydride (2.64 g, 42.07 mmol, 1.5 equiv.) was then added in small portions. After the addition, the ice batch was removed and the reaction was stirred at room temperature overnight. TLC monitoring showed complete consumption of the starting material, and the reaction was subsequently quenched at 0° C. by adding HCl 1M (200 mL). After 15 min of stirring, the reaction mixture was concentrated by rotary evaporation to remove most of the methanol, and then extracted with diethyl ether (2×100 mL). The aqueous layer was isolated and made basic by adding concentrated NaOH until pH > 10, then sodium chloride was added until saturated, then extracted with DCM (3 x 100 mL). The combined organic layers were washed with anhydrous MgSO 4 The crude products were usually pure enough to be used without further purification, but if necessary, purification could be achieved by silica gel column chromatography using gradient elution (100:0 to 90:10 DCM / MeOH).

[0713] Typical Procedure 13 - Urea Synthesis Using 1-(3-Isocyanatobutyl)-4-Methoxybenzene Intermediate

[0714] [ka]

[0715] Process 1 4-(4-Methoxyphenyl)butan-2-amine - inert atmosphere, NEt 3 To a solution of 4-(4-methoxyphenyl)butan-2-amine (0.5 g, 2.79 mmol, 1 equiv.) in anhydrous dichloromethane was added 4-(4-methoxyphenyl)butan-2-amine (0.282 g, 2.79 mmol, 3 equiv.) and the mixture was cooled to 0-5° C. in an ice bath. Triphosgene (0.414 g, 1.395 mmol, 0.5 equiv.) was added and the mixture was allowed to warm to room temperature. The reaction was monitored by TLC and stopped upon complete consumption of the amine derivative (approximately 5 h). The reaction mixture was concentrated in vacuo and then extracted with Et 2 Filtration with O (3×30 mL) and concentration of the organic layer in vacuo afforded the pure isocyanate product (425 mg, 74%) which was pure enough to be used directly in the next step without further purification. 1 H NMR (300 MHz, CDCl 3 , 20℃), δ = 7.08 (dd, J = 3 Hz, CH Ar ×2), 6.82 (dd, J = 3 Hz, CH Ar ×2), 3.77 (s, O-CH 3 ), 3.53 (m, CH), 2.62 (m, CH 2 ), 1.76 (m, CH 2 ), 1.29 (dd, J = 6 Hz, CH 3 ) ppm.

[0716] Process 2

[0717] [ka]

[0718] In an oven-dried 25 mL round-bottom flask, a solution of anhydrous dichloromethane (6 mL) was added with 1-(3-isocyanatobutyl)-4-methoxybenzene (1 eq.) and the corresponding aniline derivative (1 eq.) at room temperature under an argon atmosphere. The reaction mixture was stirred overnight at room temperature and monitored by TLC, and stopped when the aniline derivative was completely consumed. The treatment is specific to each compound: see the protocol for each analogue.

[0719] Typical Procedure 14 - Urea synthesis using isocyanatobenzene derivatives

[0720] [ka]

[0721] In an oven-dried 25 mL round-bottom flask, a solution of anhydrous dichloromethane (6 mL) was added with 4-(4-methoxyphenyl)butan-2-amine (1 eq.) and the corresponding isocyanatobenzene derivative (1 eq.) at room temperature under an argon atmosphere. The reaction mixture was stirred overnight at room temperature, monitored by TLC, and stopped upon complete consumption of the amine derivative. The treatment is specific to each compound: see the protocol for each analog.

[0722] Typical Procedure 15 - Saponification of Ester Group

[0723] [ka]

[0724] A solution of the acetyl-protected compound (1.0 equiv.) in THF (3 mL / 0.1 mmol) was added to H 2 LiOH (4.0 equiv.) in 20 (1.5 mL / 0.1 mmol) was added. The reaction was stirred at room temperature (monitored by TLC). The reaction mixture was then diluted with H 2The biphasic reaction mixture was quenched with O and extracted three times with EtOAc. The combined organic layers were washed with MgSO 4 Drying at 40° C. and concentration gave the crude product, which was purified by SCC and / or a crude fraction (10–20 mg) was purified by semi-preparative HPLC / preparative TLC to give sufficient pure compound for identification and biological assays.

[0725] Exemplary Procedure 16 - Deprotection of benzyl protecting group

[0726] [ka]

[0727] To a solution of the benzyl-protected compound (1.0 equiv.) in MeOH (10 mL / 0.2 mmol) under argon was added 10% Pd / C (1 / 4 of the mass of the alkyne substrate). The flask was evacuated and filled with hydrogen gas via a balloon. The mixture was stirred at room temperature for 2 h. The Pd / C was removed by vacuum filtration through Celite, and the Celite layer was washed with MeOH (3×10 mL). The filtrate was concentrated to give the crude product, which was purified by SCC and / or crude fractions (10-20 mg) were purified by semi-preparative HPLC / preparative TLC to give sufficient pure compound for identification and biological assays.

[0728] Scheme 1. General synthetic scheme for Examples 1-3.

[0729] [ka]

[0730] Example 1: 1-(2,5-dimethylphenyl)-3-(4-hydroxybenzyl)urea 2,5-Dimethylaniline (1.624 mmol, 1.0 equiv, 0.2 mL) and 4-(aminomethyl)phenol (1.624 mmol, 1.0 equiv, 200 mg) as primary amine were reacted according to the typical procedure 5Bis. The crude was purified by SCC (100% DCM to 95 / 5 DCM / MeOH) to give the desired compound 1, 104 mg, yield: 22.8%.

[0731] Fractions of the crude mixture (10-20 mg) were purified by semi-preparative HPLC to give sufficient pure compound for identification and biological assays.

[0732] [ka]

[0733] 1 H NMR (300 MHz, DMSO-d 6 , 20℃), δ = 9.29 (s, 1H), 7.74 - 7.58 (m, 2H), 7.11 (m, 2H), 6.97 (d, 1H), 6.90 (t, 1H), 6.78 - 6.63 (m, 3H), 4.16 (d, 2H), 2.21 (s, 3H), 2.11 (s, 3H) ppm. 13 C NMR (75 MHz, DMSO-d 6 , 20℃), δ = 156.26, 155.28, 138.01, 134.85, 130.24, 129.79, 128.61, 123.45, 122.40, 120.91, 115.05, 42.46, 20.94, 17.46 ppm. HRMS (M+Na) + : - Calculated value: 309.0999 - Measured value: 309.1005.

[0734] (Example 2) 1-(2,5-dimethylbenzyl)-3-(4-hydroxybenzyl)urea (2,5-Dimethylphenyl)methanamine (1.624 mmol, 1.0 equiv, 0.23 mL) and 4-(aminomethyl)phenol (1.624 mmol, 1.0 equiv, 200 mg) as a primary amine were reacted according to the typical procedure 5Bis. The crude was purified by SCC (100% DCM to 98 / 2 DCM / MeOH) to give compound 2, 75 mg, yield: 16.2%.

[0735] Fractions of the crude mixture (10-20 mg) were purified by semi-preparative HPLC to give sufficient pure compound for identification and biological assays.

[0736] [ka]

[0737] 1 H NMR (300 MHz, DMSO-d 6 , 20℃), δ = 9.23 (s, 1H), 7.10 - 7.01 (m, 2H), 7.06 - 6.97 (m, 3H), 6.98 - 6.90 (m, 1H), 6.76 - 6.64 (m, 2H), 6.21 (dt, 2H), 4.16 (d, 2H), 4.11 (d, J = 5.9 Hz, 2H), 2.24 (s, 3H), 2.20 (s, 3H). 13 C NMR (75MHz, DMSO-d 6 , 20℃), δ = 157.97, 156.11, 138.15, 134.45, 132.17, 131.01, 129.82, 128.33, 127.86, 127.11, 114.96, 42.56, 41.04, 30.71, 20.74, 18.09. HRMS (M+Na) + Calculated value: 307.1417 - Measured value: 307.1416.

[0738] (Example 3) 1-(2,5-dimethylbenzyl)-3-(4-hydroxyphenethyl)urea 2,5-Dimethylphenyl)methanamine (1.458 mmol, 1.0 equiv, 0.21 mL) and 4-(2-aminoethyl)phenol (1.458 mmol, 1.0 equiv, 200 mg) as a primary amine were reacted according to the typical procedure 5Bis. The crude was purified by SCC (100% DCM to 98 / 2 DCM / MeOH) to give compound 3, 107 mg, yield: 24.6%.

[0739] Fractions of the crude mixture (10-20 mg) were purified by semi-preparative HPLC to give sufficient pure compound for identification and biological assays.

[0740] [ka]

[0741] 1 H NMR (300 MHz, DMSO-d 6 , 20℃), δ = 9.16 (s, 1H), 7.05 - 6.90 (m, 6H), 6.72 - 6.64 (m, 2H), 6.19 (t, 1H), 5.82 (t, 1H), 4.13 (d, 2H), 3.24 - 3.14 (m, 2H), 2.57 (t, 2H), 2.24 (s, 3H), 2.20 (s, 3H) ppm. 13 C NMR (75 MHz, DMSO-d 6 , 20℃), δ = 157.83, 155.55, 138.12, 134.39, 132.18, 129.77, 129.70, 129.45, 127.98, 127.08, 115.05, 41.23, 40.96, 35.29, 20.69, 18.04 ppm. HRMS (M+H) + Calculated value: 299.1754 - Measured value: 299.1756. Scheme 2. General synthetic scheme for Examples 4-5.

[0742] [ka]

[0743] (Example 4) 1-(2,5-dimethylphenyl)-3-(3-(4-hydroxyphenyl)propyl)urea Process 1 2-(Prop-2-yn-1-yl)isoindoline-1,3-dione (A1) - Typical procedure 1 was followed using prop-2-yn-1-ol (0.107 mol, 1.0 equiv, 6.2 mL) as the alcohol. The crude was purified by SCC (100% DCM) to give A1, 11.7 g, yield: 59%.

[0744] [ka]

[0745] 1 H NMR (300 MHz, CDCl 3 , 20℃), δ = 7.94 - 7.82 (m, 2H), 7.80 - 7.68 (m, 2H), 4.45 (d, J = 2.5 Hz, 2H), 2.22 (t, J = 2.5 Hz, 1H) ppm. 13 C NMR (75 MHz, CDCl 3 , 20℃), δ = 167.11, 134.36, 132.13, 123.72, 76.74, 71.62, 27.13 ppm.

[0746] Process 2 2-(3-(4-Methoxyphenyl)prop-2-yn-1-yl)isoindoline-1,3-dione (A2) - Typical procedure 2 was followed using 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (A1) (5.40 mmol, 1.0 equiv, 1.0 g) as the N-phthalimide derivative. The mixture was stirred overnight. The solvent was removed and the crude was triturated with cold EtOAc, filtered and dried. The resulting powder was sonicated in distilled water, filtered and dried to give A2, 1.2 g, yield: 76.3%. A2 was used in the next step without further purification.

[0747] [ka]

[0748] 1 H NMR (400 MHz, DMSO-d 6 , 20℃), δ = 7.98 - 7.83 (m, 4H), 7.40 - 7.31 (m, 2H), 6.95 - 6.87 (m, 2H), 4.60 (s, 2H), 3.75 (s, 3H) ppm. 13 C NMR (101 MHz, DMSO-d 6 , 20℃), δ = 166.82, 159.52, 134.70, 133.08, 131.49, 123.35, 114.25, 113.51, 82.43, 82.04, 55.21, 27.48 ppm.

[0749] Process 3 3-(4-Methoxyphenyl)prop-2-yn-1-amine (A3) - N-phthalimide derivative, 2-(3-(4-methoxyphenyl)prop-2-yn-1-yl)isoindoline-1,3-dione (A2) (3.43 mmol, 1.0 equiv, 1.0 g) and hydrazine hydrate (34.33 mmol, 10.0 equiv, 1.08 mL) were used following typical procedure 3. The crude was purified by SCC (100% DCM to 98 / 2 DCM / MeOH) to give A3, 0.45 g, yield: 81%.

[0750] [ka]

[0751] 1 H NMR (400 MHz, DMSO-d 6 , 20℃), δ = 7.36 - 7.28 (m, 2H, 1, 3), 6.97 - 6.87 (m, 2H, 4, 6), 3.76 (s, 3H, 8), 3.47 (s, 2H, 11) ppm. 13 C NMR (101 MHz, DMSO-d 6 , 20℃), δ = 158.96, 132.59, 114.98, 114.19, 90.47, 81.11, 55.16, 31.32 ppm.

[0752] Process 4 3-(4-Methoxyphenyl)propan-1-amine (A4) - Typical procedure 4 was followed using 3-(4-methoxyphenyl)prop-2-yn-1-amine (A3) (1.613 mmol, 1.0 equiv, 260 mg) as the alkyne derivative. Work-up afforded A4, 244 mg, yield: 91.6%. The crude was used in the next step without purification.

[0753] [ka]

[0754] 1 H NMR (400 MHz, CDCl 3 , 20℃), δ = 7.14 - 7.06 (m, 2H), 6.87 - 6.79 (m, 2H), 3.79 (s, 3H), 2.76 - 2.68 (m, 2H), 2.60 (dd, 2H), 1.74 (dtd, 2H) ppm. 13 C NMR (101 MHz, CDCl 3 , 20℃), δ = 157.90, 134.37, 129.38, 113.93, 55.41, 41.92, 35.81, 32.48 ppm.

[0755] Process 5 1-(2,5-Dimethylphenyl)-3-(3-(4-Methoxyphenyl)propyl)urea (A5) - Followed typical procedure 5Bis using 2,5-dimethylaniline (0.303 mmol, 1.0 equiv, 37 μL) and 4-(4-Methoxyphenyl)but-3-yn-2-amine (A4) (0.303 mmol, 1.0 equiv, 50 mg) as the primary amine. After solvent evaporation, trituration with DiPE, filtration and purification of the crude by SCC (100% DCM to 99 / 1 DCM / MeOH) gave A5, 59 mg, yield: 62.4%.

[0756] [ka]

[0757] 1 H NMR (400 MHz, DMSO-d 6, 20℃), δ = 7.66 - 7.61 (m, 1H), 7.50 (s, 1H), 7.17 - 7.09 (m, 2H), 6.98 (d, 1H), 6.89 - 6.81 (m, 2H), 6.71 - 6.64 (m, 1H), 6.53 (t, 1H), 3.72 (s, 3H), 3.07 (q, 2H), 2.59 - 2.51 (m, 2H), 2.21 (s, 3H), 2.12 (s, 3H), 1.69 (p, 2H) ppm. 13 C NMR (101 MHz, DMSO-d 6 , 20℃), δ = 157.39, 155.36, 138.02, 134.85, 133.51, 129.79, 129.17, 123.52, 122.41, 121.05, 113.72, 54.95, 38.60, 31.72, 31.58, 20.94, 17.45 ppm.

[0758] Process 6 1-(2,5-Dimethylphenyl)-3-(3-(4-hydroxyphenyl)propyl)urea (4) - Typical procedure 6 was followed using 1-(2,5-dimethylphenyl)-3-(3-(4-methoxyphenyl)propyl)urea (A5) (0.08 mmol, 1.0 equiv, 25 mg) as the methoxy-protected urea. The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction (10-20 mg) of the crude mixture was purified by semi-preparative HPLC to give pure compound 4 in sufficient quantity for identification and biological assays.

[0759] [ka]

[0760] 1 H NMR (300 MHz, acetone-d 6, 20 °C), δ = 8.10 (s, 1H, OH 19), 7.74 (d, J = 1.8 Hz, 1H, CH 8), 7.15 (s, 1H, NH 9), 7.08 - 6.97 (m, 2H, CH 17), 6.97 (d, J = 7.6 Hz, 1H, CH 4), 6.74 (m, 2H, CH 16), 6.71 (dd, J = 7.6, 1.8 Hz, 1H, CH 3), 6.08 (t, J = 5.8 Hz, 1H, NH 11), 3.22 (td, J = 7.0, 5.8 Hz, 2H, CH 2 12), 2.56 (t, J = 7.0 Hz, 2H, CH 2 14), 2.24 (s, 3H, CH 3 1), 2.15 (s, 3H, CH 3 6), 1.77 (quintet, J = 7.0 Hz, 2H, CH 2 13) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20 °C), δ = 156.44 (CO 10), 156.37 (COH 18), 139.06 (C 15), 136.33 (C 5), 133.49 (C 2), 130.73 (CH 4), 130.08 (CH 17), 125.20 (C 7), 123.90 (CH 3), 122.87 (CH 8), 115.97 (CH 16), 40.09 (CH 2 12), 33.26 (CH 2 13), 32.93 (CH 2 14), 21.31 (CH 3 1), 17.68 (CH 3 6) ppm. HRMS (M+Na) + : Calculated: 321.15735 - Measured: 321.1574. MS (ESI+): m / z (%) 299.1 (100) [M+H + .

[0761] (Example 5) Synthesis of 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)-2-methylbutan-2-yl)urea Process 1 4-(4-Methoxyphenyl)-2-methylbut-3-yn-2-amine (B1) - Typical procedure 2 was followed using 2-methylbut-3-yn-2-amine (6.015 mmol, 1.0 equiv, 0.5 g, 0.6 mL) as the amine derivative and distilled THF as the solvent. The mixture was stirred overnight. The solvent was removed and NH 4 A saturated aqueous solution of Cl was added, and Et 2 The organic phase was washed with brine and MgSO 4 The solution was concentrated in vacuo and the crude product was purified by SCC (PE / EtOAc / NEt 3 -2 / 1 / 0.01) to give B1, 0.9 g, yield: 71.9%.

[0762] [ka]

[0763] 1 H NMR (300 MHz, CDCl 3 , 20℃), δ = 7.37 - 7.26 (m, 2H), 6.86 - 6.75 (m, 2H,), 3.79 (s, 3H), 1.48 (s, 6H) ppm. 13 C NMR (75 MHz, CDCl 3 , 20℃), δ = 159.39, 133.00, 115.66, 113.97, 95.65, 79.91, 55.38, 45.82, 32.07 ppm.

[0764] Process 2 4-(4-Methoxyphenyl)-2-methylbutan-2-amine (B2) - Followed typical procedure 4 using 4-(4-Methoxyphenyl)-2-methylbut-3-yn-2-amine (B1) (0.528 mmol, 1.0 equiv, 100 mg) as N-phthalimide derivative. The crude was used without purification: B2, 96 mg, yield: 94%.

[0765] [ka]

[0766] 1 H NMR (400 MHz, CDCl 3 , 20℃), δ = 7.15 - 7.07 (m, 2H), 6.87 - 6.78 (m, 2H), 3.78 (s, 3H), 2.64 - 2.55 (m, 2H), 1.69 - 1.60 (m, 2H), 1.16 (s, 6H) ppm. 13 C NMR (101 MHz, CDCl 3 , 20℃), δ = 157.88, 134.97, 129.28, 114.01, 55.43, 49.70, 47.41, 30.54, 30.29 ppm.

[0767] Process 3 1-(2,5-Dimethylphenyl)-3-(4-(4-methoxyphenyl)-2-methylbutan-2-yl)urea (B3) - Followed typical procedure 5Bis using 2,5-dimethylaniline (0.259 mmol, 1.0 equiv, 32 μL) and 4-(4-methoxyphenyl)-2-methylbutan-2-amine (B2) (0.259 mmol, 1.0 equiv, 50 mg) as the primary amine. Evaporation of the solvent, trituration with DCM and filtration gave B3, 59 mg, yield: 67%.

[0768] [ka]

[0769] 1 H NMR (400 MHz, CDCl 3 , 20℃), δ = 7.72 - 7.66 (m, 1H), 7.43 (s, 1H), 7.14 - 7.05 (m, 2H), 6.97 (d, 1H), 6.87 - 6.78 (m, 2H), 6.65 (ddd, 1H), 6.40 (s, 1H), 3.70 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 1.95 - 1.86 (m, 2H), 1.30 (s, 7H) ppm. 13 C NMR (101 MHz, CDCl 3 , 20℃), δ = 157.26, 154.47, 138.18, 134.83, 134.36, 129.77, 129.03, 123.05, 122.08, 120.62, 113.69, 54.96, 51.83, 42.30, 29.19, 27.32, 20.98, 17.54 ppm.

[0770] Process 4 1-(2,5-Dimethylphenyl)-3-(4-(4-hydroxyphenyl)-2-methylbutan-2-yl)urea (5) - Followed typical procedure 6 using 1-(2,5-dimethylphenyl)-3-(4-(4-methoxyphenyl)-2-methylbutan-2-yl)urea (B3) (0.073 mmol, 1.0 equiv, 25 mg) as the methoxy-protected urea.

[0771] The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give pure compound 5 in sufficient quantity for identification and biological assays.

[0772] [ka]

[0773] 1 H NMR (300 MHz, acetone-d 6 , 20℃), δ = 8.06 (s, 1H, OH 20), 7.79 (d, J = 1.8 Hz, 1H, CH 8), 7.15 (s, 1H, NH 9), 7.01 (m, 2H, CH 17), 6.96 (d, J = 7.6 Hz, 1H, CH 4), 7.73 (m, 2H, CH 18), 6.69 (dd, J = 7.6, 1.8 Hz, 1H, CH 3), 5.93 (s, 1H, NH 11), 2.55 (m, 2H, CH 2 14 / 15), 2.24 (s, 3H, CH 3 1), 2.15 (s, 3H, CH 3 6), 2.00 (m, 2H, CH 2 14 / 15), 1.36 (s, 6H, CH 3 13) ppm. 13 C NMR (101 MHz, CDCl 3 , 20℃), δ = 156.19 (COH 19), 155.55 (CO 10), 139.19 (C 5), 136.28 (C 2), 134.34 (C 16), 130.68 (CH 4), 130.00 (CH 2 17), 124.80 (C 7), 123.60 (CH 3), 122.52 (CH 8), 115.91 (CH 2 18), 53.15 (C 12), 43.71 (CH 2 14), 30.51 (CH 2 15), 27.92 (CH 3 13), 21.35 (CH 3 1), 17.80 (CH 3 6) ppm. HRMS (M+Na) + Calculated value: 349.18865 - Measured value: 349.1888. Purity at HPLC λ = 254 nm: 95%. MS (ESI+): m / z (%) 327.2 (100) [M+H + ]. Scheme 3. General synthetic scheme for Examples 6-8.

[0774] [ka]

[0775] (Example 6) 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)but-3-yn-2-yl)urea Process 1 2-(But-3-yn-2-yl)isoindoline-1,3-dione (C1) - Typical procedure 1 was followed using but-3-yn-2-ol (0.107 mol, 1.0 equiv, 8.5 mL) as the alcohol. The crude was purified by SCC (mobile phase: 100% cyclohexane to 9:1 cyclohexane:EtOAc). Fractions were collected and solvent evaporated to give the crude, which was purified by SCC (100% cyclohexane to 9 / 1 cyclohexane:EtOAc) to give C1, 13.8 g, yield: 65.7%.

[0776] [ka]

[0777] 1 H NMR (400 MHz, CDCl 3 , 20℃), δ = 7.85 (dd, 2H), 7.72 (dd, 2H), 5.20 (qd, 1H), 2.34 (d, 1H), 1.70 (d, 3H) ppm. 13 C NMR (101 MHz, CDCl 3 , 20℃), δ = 166.99, 134.25, 131.98, 123.56, 81.22, 71.32, 36.98, 20.17 ppm.

[0778] Process 2 2-(4-(4-hydroxyphenyl)but-3-yn-2-yl)isoindoline-1,3-dione (C2) - Typical procedure 2 was followed using 2-(but-3-yn-2-yl)isoindoline-1,3-dione (C1) (1.255 mmol, 1.0 equiv, 250 mg) as the N-phthalimide derivative. The mixture was stirred overnight. The solution was diluted with water, extracted twice with EtOAc, washed with brine, and purified with MgSO 4 The organic layer was filtered and concentrated under vacuum. The crude was triturated with DiPE and filtered to give C2, 350 mg, yield: 95.7%. C2 was used in the next step without further purification.

[0779] [ka]

[0780] 1 H NMR (300 MHz, CDCl 3 , 20℃), δ = 7.86 (dd, 2H), 7.73 (dd, 2H), 7.35 - 7.27 (m, 2H), 6.80 - 6.71 (m, 2H), 5.41 (q, 1H), 1.78 (d, J = 7.1 Hz, 3H) ppm.

[0781] Process 3 4-(4-Hydroxyphenyl)but-3-yn-2-amine (C3) - N-phthalimide derivative, 2-(4-(4-hydroxyphenyl)but-3-yn-2-yl)isoindoline-1,3-dione (C2) (1.202 mmol, 1.0 equiv, 350 mg) and hydrazine hydrate (12.015 mmol, 10.0 equiv, 0.38 mL) were used following typical procedure 3. The crude was purified by SCC (100% DCM to 98 / 2 DCM / MeOH) to give C3, 61 mg, yield: 31%.

[0782] [ka]

[0783] 1 H NMR (400 MHz, DMSO-d 6 , 20℃), δ = 7.23 - 7.14 (m, 2H), 6.76 - 6.68 (m, 2H), 3.81 (q, J = 6.7 Hz, 1H), 1.29 (d, J = 6.7 Hz, 3H) ppm. 13 C NMR (400 MHz, DMSO-d 6 , 20℃), δ = 157.41, 132.64, 115.53, 113.02, 92.47, 81.08, 69.78, 38.62, 24.47 ppm.

[0784] Process 4 1-(2,5-Dimethylphenyl)-3-(4-(4-hydroxyphenyl)but-3-yn-2-yl)urea (6) - Followed typical procedure 5 using 2-isocyanato-1,4-dimethylbenzene (1 eq.) and 4-(3-aminobut-1-yn-1-yl)phenol (C3) (1 eq.). The solvent was evaporated and the crude was triturated with DiPE and filtered to give compound 6.

[0785] Fractions of the crude mixture (10-20 mg) were purified by semi-preparative HPLC to give sufficient pure compound for identification and biological assays.

[0786] [ka]

[0787] 1 H NMR (300 MHz, acetone-d 6, 20℃), δ = 8.78 (s, 1H, OH 20), 7.83 - 7.76 (d, J = 2.1 Hz, 1H, CH 8), 7.25 (m, 2H, CH 18), 7.21 (s, 1H, NH 9), 6.98 (d, J = 7.7 Hz, 1H, CH 4), 6.84 - 6.76 (m, 2H, CH 17), 6.77 - 6.68 (dd, J = 7.7, 2.1 Hz, 1H, CH 3), 6.43 (d, J = 8.0 Hz, 1H, NH 11), 4.88 (dq, J = 8.0, 6.8 Hz, 1H, CH 12), 2.29 - 2.19 (s, 3H, CH 3 6), 2.17 (s, 3H, CH 3 1), 1.46 (d, J = 6.8 Hz, 3H, CH 3 13) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃), δ = 158.59 (COH 19), 155.24 (CO 10), 138.78 (C 16), 136.40 (C 5), 133.88 (CH 18), 130.76 (CH 4), 124.98 (C 2), 124.00 (CH 3), 122.53 (CH 8), 116.34 (CH 17), 114.69 (C 7), 89.58 (CC 14 / 15), 82.42 (CC 14 / 15), 38.70 (CH 12), 23.53 (CH 3 13), 21.32 (CH 3 1), 17.65 (CH 3 6) ppm. HRMS (M+Na) + Calculated value: 331.1417 - Measured value: 331.1415. Purity by HPLC λ = 254 nm: 96%. MS (ESI+): m / z (%) 309.1 (100) [M+H + ].

[0788] (Example 7) 1-(2,5-dimethylphenyl)-3-(3-(4-hydroxyphenyl)prop-2-yn-1-yl)urea Step 1: 1-(2,5-Dimethylphenyl)-3-(prop-2-yn-1-yl)urea (D1) - Followed typical procedure 5 using 2-isocyanato-1,4-dimethylbenzene (2.27 mmol, 1 equiv, 334 mg) and prop-2-yn-1-amine (2.27 mmol, 1.0 equiv, 144 μL) as primary amine. The solvent was evaporated and the crude was triturated with DiPE and filtered to give D1, 345 mg, yield: 75%.

[0789] [ka]

[0790] 1 H NMR (400 MHz, CDCl 3 , 20℃), δ = 7.19 - 7.14 (m, 1H), 7.13 (d, 1H), 6.98 (dd, 1H), 5.95 (s, 1H), 4.70 (s, 1H), 4.04 (dd, 2H), 2.32 (s, 3H), 2.24 (s, 3H), 2.21 (t, 1H) ppm. 13 C NMR (101 MHz, CDCl 3 , 20℃), δ = 199.31, 155.95, 137.27, 135.27, 131.17, 127.72, 126.97, 80.47, 77.48, 77.16, 76.84, 71.42, 30.24, 21.06, 17.55 ppm.

[0791] Process 2 1-(2,5-Dimethylphenyl)-3-(3-(4-hydroxyphenyl)prop-2-yn-1-yl)urea (7) - Typical procedure 2 was followed using 1-(2,5-dimethylphenyl)-3-(prop-2-yn-1-yl)urea (D1) (0.494 mmol, 1.0 equiv, 100 mg) as the alkyne derivative and 4-iodophenol (0.494 mmol, 1.0 equiv, 109 mg) as the iodine derivative. The mixture was stirred overnight. The solution was diluted with water, extracted twice with EtOAc, washed with brine and purified with MgSO 4 The organic layer was filtered and concentrated in vacuo. The crude was purified by SCC (100% DCM to 98 / 2 DCM / MeOH) to give compound 7, 95 mg.

[0792] Fractions of the crude mixture (10-20 mg) were purified by semi-preparative HPLC to give sufficient pure compound for identification and biological assays.

[0793] [ka]

[0794] 1 H NMR (300 MHz, acetone-d 6 , 20℃), δ = 8.71 (s, 1H, OH 19), 7.76 (d, J = 2.0 Hz, 1H, CH 8), 7.28 (s, 1H, NH 9), 7.26 (m, 2H, CH 17), 6.99 (d, J = 7.9 Hz, 1H, CH 4), 6.86 - 6.75 (m, 2H, CH 16), 6.78 - 6.68 (m, J = 7.9, 2.0 Hz, 1H, CH 3), 6.34 (t, J = 5.5 Hz, 1H, NH 11), 4.21 (d, J = 5.5 Hz, 2H, CH 2 12), 2.25 (s, 3H, CH 3 1), 2.18 (s, 3H, CH 3 6) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃), δ = 158.58 (COH 18), 155.88 (CO 10), 138.72 (C 15), 136.42 (C 5), 133.91 (CH 17), 130.79 (CH 4), 125.35 (C 2), 124.21 (CH 3), 122.89 (CH 8), 116.35 (CH 16), 114.77 (C 7), 85.60 (CC 13 / 14), 83.00 (CC 13 / 14), 30.71 (CH 2 12), 21.30 (CH 3 1), 17.65 (CH 3 6) ppm. Purity at HPLC λ = 254 nm: 95%. MS (ESI+): m / z (%) 295.3 (100) [M+H + ].

[0795] (Example 8) 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)-2-methylbut-3-yn-2-yl)urea Process 1 1-(2,5-Dimethylphenyl)-3-(2-methylbut-3-yn-2-yl)urea (E1) - Followed typical procedure 5 using 2-isocyanato-1,4-dimethylbenzene (1.205 mmol, 1.0 equiv, 178 mg) and 2-methylbut-3-yn-2-amine (1.203 mmol, 1.0 equiv, 119 μL) as the primary amine. The solvent was evaporated and the crude was triturated with DiPE and filtered to give E1, 208 mg, yield: 75%.

[0796] [ka]

[0797] 1 H NMR (400 MHz, CDCl 3, 20℃), δ = 7.40 - 7.35 (m, 1H), 7.08 (d, 1H), 6.93 - 6.86 (m, 1H), 6.42 (s, 1H), 4.74 (s, 1H), 2.43 (s, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 1.63 (s, 6H) ppm. 13 C NMR (101 MHz, CDCl 3 , 20℃), δ = 155.16, 136.92, 136.13, 130.75, 128.00, 126.23, 125.09, 87.51, 70.40, 47.34, 30.10, 21.17, 17.81 ppm.

[0798] Process 2 1-(2,5-Dimethylphenyl)-3-(4-(4-hydroxyphenyl)-2-methylbut-3-yn-2-yl)urea (8) - Typical procedure 2 was followed using 1-(2,5-dimethylphenyl)-3-(2-methylbut-3-yn-2-yl)urea (E1) (0.434 mmol, 1.0 equiv, 100 mg) as the alkyne derivative and 4-iodophenol (0.434 mmol, 1.0 equiv, 96 mg) as the iodine derivative. The mixture was stirred overnight. The solution was diluted with water, extracted twice with EtOAc, washed with brine and purified with MgSO 4 The organic layer was filtered and concentrated in vacuo. The crude was purified by SCC (100% DCM to 98 / 2 DCM / MeOH) to give compound 8, 94 mg, yield: 67%.

[0799] Fractions of the crude mixture (10-20 mg) were purified by semi-preparative HPLC to give sufficient pure compound for identification and biological assays.

[0800] [ka]

[0801] 1H NMR (300 MHz, acetone-d 6 , 20℃), δ = 8.65 (s, 1H, OH 20), 7.87 - 7.80 (d, J = 2.0 Hz, 1H, CH 8), 7.30 - 7.19 (m, 2H, CH 18), 7.16 (s, 1H, NH 9), 6.97 (d, J = 7.4 Hz, 1H, CH 4), 6.85 - 6.74 (m, 2H, CH 17), 6.75 - 6.65 (dd, J = 7.4, 2.0 Hz, 1H, CH 3), 6.28 (s, 1H, NH 11), 2.25 (s, 3H, CH 3 1), 2.15 (s, 3H, CH 3 6), 1.71 (s, 6H, CH 3 13) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃), δ = 158.42 (COH 19), 155.01 (CO 10), 139.01 (C 16), 136.38 (C 5), 133.89 (CH 18), 130.72 (CH 4), 124.61 (C 2), 123.73 (CH 3), 122.31 (CH 8), 116.29 (CH 17), 115.12 (C 7), 92.89 (CC 14 / 15), 81.42 (CC 14 / 15), 48.52 (C 12), 30.19 (CH 3 13), 21.35 (CH 3 1), 17.72 (CH 3 6) ppm. HRMS (M+Na) + Calculated value: 348.16825 - Measured value: 348.1683. Purity at HPLC λ = 254 nm: 99%. MS (ESI+): m / z (%) 323.0 (100) [M+H + ].

[0802] (Example 9) 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-indol-3-yl)urea

[0803] [ka]

[0804] Process 1 Methyl 1-(4-methoxyphenyl)-1H-indole-3-carboxylate (F1) - In an oven-dried round-bottom flask under argon, prepare methyl 1H-indole-3-carboxylate (1.71 mmol, 1.0 equiv, 300 mg), 4-iodoanisole (2.23 mmol, 1.3 equiv, 521 mg), CuI (10% mol, 33 mg), K in 1,4-dioxane (4 mL). 3 PO 4 (3.423 mmol, 2.0 equiv, 693 mg) and trans-1,2-diaminocyclohexane (10% mol, 20 μL) were added. The mixture was stirred at reflux overnight. After completion of the reaction, the mixture was allowed to warm to room temperature. It was quenched with water (5 mL) and extracted with EtOAc (2×5 mL). The organic layer was filtered through Celite and concentrated under vacuum. The resulting residue was triturated with DiPE and filtered to give F1, 410 mg, yield: 85%.

[0805] [ka]

[0806] 1 H NMR (400 MHz, MeOD, 20℃), δ = 8.23 ​​- 8.13 (m, 1H), 8.09 (s, 1H), 7.54 - 7.45 (m, 2H), 7.43 (ddt, 1H), 7.35 - 7.24 (m, 2H), 7.21 - 7.13 (m, 2H), 3.95 (s, 3H), 3.92 (s, 3H) ppm. 13C NMR (101 MHz, MeOD, 20℃), δ = 167.27, 160.91, 138.62, 135.91, 132.52, 127.99, 127.47, 124.45, 123.34, 122.42, 116.08, 112.03, 109.18, 56.12, 51.56 ppm.

[0807] Process 2 1-(4-Methoxyphenyl)-1H-indole-3-carboxylic acid (F2) - To a solution of methyl 1-(4-methoxyphenyl)-1H-indole-3-carboxylate F1 (0.35 mmol, 1.0 equiv, 100 mg) in THF (1 mL) and MeOH (0.5 mL) was added 1N aqueous NaOH (0.9 mmol, 2.5 equiv, 0.9 mL) at room temperature. The resulting solution was stirred overnight at 50 °C. After completion of the reaction, the mixture was allowed to warm to room temperature and acidified using 1N aqueous HCl. The aqueous layer was extracted with EtOAc (3 x 3 mL) and the combined organic layers were washed with anhydrous MgSO 4 After drying at rt, filtration and evaporation of the solvent, F2, 95 mg, yield: <99%.

[0808] [ka]

[0809] 1 H NMR (400 MHz, CDCl 3 , 20℃), δ = 8.34 - 8.27 (m, 1H), 8.07 (s, 1H), 7.47 - 7.39 (m, 3H), 7.39 - 7.25 (m, 2H), 7.11 - 7.03 (m, 2H), 3.90 (s, 3H) ppm. 13 C NMR (101 MHz, CDCl 3, 20℃), δ = 169.96, 159.45, 137.55, 135.82, 131.40, 127.05, 126.54, 123.61, 122.79, 122.05, 115.12, 111.21, 107.98, 55.81 ppm.

[0810] Process 3 1-(4-Methoxyphenyl)-1H-indole-3-carbonyl azide (F3) - 1-(4-Methoxyphenyl)-1H-indole-3-carboxylic acid F2 (0.37 mmol, 1.0 equiv, 100 mg) in dry toluene (2 mL) was added in an oven-dried flask at room temperature under argon. Triethylamine (0.39 mmol, 1.05 equiv, 55 μL) was added and the solution was stirred for 15 min, followed by DPPA (0.39 mmol, 1.05 equiv, 84 μL). After stirring for 5 h at room temperature, the solvent was removed and the mixture was purified on silica column chromatography to give F3, 95 mg, yield: 87%.

[0811] [ka]

[0812] 1 H NMR (300 MHz, CDCl 3 , 20℃), δ = 8.31 (m, 1H), 7.97 (s, 1H), 7.43 - 7.38 (m, 2H), 7.36 - 7.29 (m, 2H), 7.26 (s, 1H), 7.09 - 7.03 (m, 2H), 3.90 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl 3 , 20℃), δ = 168.29, 159.59, 137.80, 135.75, 131.00, 126.60, 126.51, 124.06, 123.26, 122.01, 115.13, 111.34, 110.21, 55.81 ppm.

[0813] Process 4 1-(2,5-Dimethylphenyl)-3-(1-(4-methoxyphenyl)-1H-indol-3-yl)urea (F5) - In an oven-dried flask under argon, the isolated 1-(4-methoxyphenyl)-1H-indole-3-carbonyl azide (F3) (0.36 mmol, 1.0 equiv, 95 mg) dissolved in toluene (2 mL) was added and heated to reflux overnight, resulting in the formation of the isocyanate compound via Curtius rearrangement F4 (not isolated). The mixture was allowed to warm to room temperature and 2,5-dimethylaniline (0.36 mmol, 1.0 equiv, 44 μL) was added and stirred overnight. The mixture was filtered and the white powder was washed with cold toluene to give F5, 85 mg, 61% yield.

[0814] [ka]

[0815] 1 H NMR (300 MHz, DMSO-d 6 , 20℃), δ = 9.04 (s, 1H), 7.94 (s, 1H), 7.83 - 7.76 (m, 1H), 7.74 (s, 1H), 7.73 - 7.63 (m, 1H), 7.54 - 7.41 (m, 3H), 7.30 - 7.07 (m, 4H), 7.05 (d, 1H), 6.79 - 6.70 (m, 1H), 3.83 (s, 3H), 2.24 (d, 6H) ppm. 13 C NMR (75 MHz, DMSO-d 6 , 20℃), δ = 157.42, 152.64, 137.49, 135.06, 133.09, 132.21, 129.94, 125.04, 123.63, 122.88, 122.75, 121.74, 120.91, 119.23, 117.58, 117.21, 116.31, 114.95, 110.16, 55.41, 20.94, 17.49 ppm.

[0816] Process 5 1-(2,5-Dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-indol-3-yl)urea (9) - Typical procedure 6 was followed using 1-(2,5-dimethylphenyl)-3-(1-(4-methoxyphenyl)-1H-indol-3-yl)urea (F5) (65 μmol, 1.0 equiv, 25 mg) in dry DCM (2 mL). The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and fractions (10-20 mg) of the crude mixture were purified by semi-preparative HPLC to give pure compound 9 in sufficient quantity for identification and biological assays.

[0817] [ka]

[0818] 1 H NMR (500 MHz, acetone, 20℃), δ = 8.60 (s, 1H, OH 24), 8.55 (s, 1H, NH 9), 7.93 - 7.89 (d, J = 1.5 Hz, 1H, CH 8), 7.84 (s, 1H, NH 11), 7.78 - 7.70 (d, J = 8.2 Hz, 1H, CH 15), 7.65 (s, 1H, CH 13), 7.46 (d, J = 8.2 Hz, 1H, CH 18), 7.44 - 7.38 (m, 2H, CH 21), 7.20 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H, CH 17), 7.10 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H, CH 16), 7.09 - 7.02 (m, 2H, CH 22), 7.04 (d, J = 7.6 Hz 1H, CH 4), 6.77 (dd, J = 7.6, 1.5 Hz 1H, CH 3), 2.30 (s, 3H, CH 3 1), 2.25 (s, 3H, CH 3 6) ppm. 13 C NMR (126 MHz, acetone, 20℃), δ = 209.16 (CO 10), 156.31 (COH 23), 136.00 (C 2), 134.54 (C 19), 131.87 (C 20), 129.88 (CH 4), 125.67 (CH 21), 123.56 (C 5), 123.13 (CH 3), 122.34 (CH 17), 121.64 (CH 8), 119.13 (CH 16), 117.67 (CH 15), 116.24 (CH 22), 110.04 (CH 18), 20.43 (CH 3 1), 16.91 (CH 3 6) ppm. Purity at HPLC λ = 254 nm: 100%. MS (ESI+): m / z (%) 371.8 (100) [M+H + ].

[0819] Example 10: N-(2,5-dimethylphenyl)-4-(4-hydroxyphenyl)piperazine-1-carboxamide

[0820] [ka]

[0821] N-(2,5-Dimethylphenyl)-4-(4-hydroxyphenyl)piperazine-1-carboxamide (10) - Typical procedure 5 was followed using 2-isocyanato-1,4-dimethylbenzene (0.281 mmol, 1 equiv, 41 mg) and 4-(piperazin-1-yl)phenol (0.281 mmol, 1.0 equiv, 50 mg) in dry DCM (3 mL). The precipitate was filtered and washed with cold DCM to give compound 10, 69 mg. Fractions of the crude mixture (10-20 mg) were purified by semi-preparative HPLC to give sufficient pure compound 10 for identification and biological assays.

[0822] [ka]

[0823] 1 H NMR (300 MHz, acetone-d 6 , 20℃), δ = 7.93 (s, 1H, OH 17), 7.35 (s, 1H, NH 9), 7.25 (d, J = 1.9 Hz, 1H, CH 8), 7.03 (d, J = 7.7 Hz, 1H, CH 4), 6.94 - 6.83 (m, 2H, CH 15), 6.87 - 6.77 (dd, J = 7.7, 1.9 Hz, 1H, CH 3), 6.81 - 6.70 (m, 2H, CH 14), 3.70 - 3.61 (m, 4H, CH 2 12), 3.09 - 2.98 (m, 4H, CH 2 11), 2.28 - 2.21 (m, 3H, CH 3 1), 2.20 (s, 3H, CH 3 6) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃), δ = 156.34 (CO 10), 152.59 (COH 16), 145.94 (C 13), 138.80 (C 5), 136.04 (C 2), 130.76 (CH 4), 129.35 (C 7), 126.08 (CH 8), 125.63 (CH 3), 119.71 (CH 15), 116.44 (CH 14), 51.83 (CH 2 12), 45.29 (CH 2 11), 21.04 (CH 3 1), 17.81 (CH 3 6) ppm. HRMS (M+Na) + Calculated value: 348.16825 - Measured value: 348.1683. Purity at HPLC λ = 254 nm: 100%. MS (ESI+): m / z (%) 326.1 (32) [M+H+ ].

[0824] (Example 11) 1-(2,5-dimethylphenyl)-3-(3'-hydroxy-[1,1'-biphenyl]-4-yl)urea Process 1 1-(2,5-Dimethylphenyl)-3-(3'-methoxy-[1,1'-biphenyl]-4-yl)urea (G1) - Following typical procedure 5 using 2-isocyanato-1,4-dimethylbenzene (1 mmol, 1.0 equiv, 148 mg) and 4'-methoxy-[1,1'-biphenyl]-4-amine (1 mmol, 1.0 equiv, 200 mg) in dry DCM (6 mL). The solvent was evaporated and the residue was triturated with DiPE and filtered to give G1, 357 mg, 103% yield, which was used directly in the next step without further purification.

[0825] [ka]

[0826] MS(ESI+): m / z(%) 347.0(100) [M+H + ].

[0827] Process 2 1-(2,5-Dimethylphenyl)-3-(3'-hydroxy-[1,1'-biphenyl]-4-yl)urea (11) - Typical procedure 6 was followed using 1-(2,5-dimethylphenyl)-3-(3'-methoxy-[1,1'-biphenyl]-4-yl)urea G1 (72 μmol, 1.0 equiv, 25 mg) in dry DCM (2 mL). The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction (10-20 mg) of the crude mixture was purified by semi-preparative HPLC to give pure compound 11 in sufficient quantity for identification and biological assays.

[0828] [ka]

[0829] 1 H NMR (300 MHz, acetone-d 6 , 20 °C), δ = 8.51 (s, 1H, OH 22), 8.42 (s, 1H, NH 11), 7.82 - 7.75 (m, 1H, CH 7), 7.66 - 7.59 (m, 2H, CH 2 13), 7.57 - 7.51 (m, 2H, CH 2 14), 7.49 (s, 1H, NH 9), 7.24 (t, 1H, dd, 1H, CH 18), 7.09 (d dd, 1H, CH 19), 7.09 (t, 1H, CH 21), 7.04 (d, 1H, CH 3), 6.79 (m, 1H, CH 4), 6.79 (dd, 1H, CH 17), 2.29 (s, 3H, CH 3 6), 2.23 (s, 3H, CH 3 1) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20 °C), δ = 158.77 (CO 10), 153.55 (COH 20), 143.05 (C 16), 140.65 (C 15), 138.27 (C 2), 136.49 (C 5), 135.42 (C 12), 130.88 (CH 3), 130.66 (CH 18), 127.92 (CH 2 14), 125.89 (C 8), 124.67 (CH 4 / 17), 123.27 (CH 7), 119.50 (CH 2 13), 118.50 (CH 19 / 21), 114.64 (CH 19 / 21), 114.13 (CH 4 / 17), 21.30 (CH 3 6), 17.69 (CH 3 1) ppm. Purity at HPLC λ = 254 nm: 100%. MS (ESI+): m / z (%) 333.0 (100) [M+H+ ].

[0830] (Example 12) 1-(2,5-dimethylphenyl)-3-(4'-hydroxy-[1,1'-biphenyl]-4-yl)urea Process 1 1-(2,5-Dimethylphenyl)-3-(4'-methoxy-[1,1'-biphenyl]-4-yl)urea (H1) - Following typical procedure 5 using 2-isocyanato-1,4-dimethylbenzene (1 mmol, 1.0 equiv, 148 mg) and 4'-methoxy-[1,1'-biphenyl]-4-amine (1 mmol, 1.0 equiv, 200 mg) in dry DCM (6 mL). The solvent was evaporated and the residue was triturated with DiPE and filtered to give H1, 304 mg, yield: 87%.

[0831] [ka]

[0832] 1 H NMR (400 MHz, DMSO-d 6 , 20℃), δ = 9.05 (s, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 7.61 - 7.48 (m, 6H), 7.05 (d, J = 7.6 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.77 (d, J = 7.6 Hz, 1H), 3.79 (s, 3H), 2.25 (s, 3H), 2.20 (s, 3H) ppm. 13 C NMR (101 MHz, DMSO-d 6 , 20℃), δ = 158.43, 152.60, 138.75, 137.16, 135.07, 133.20, 132.32, 129.98, 127.14, 126.47, 124.37, 123.33, 121.61, 118.36, 114.31, 55.13, 20.92, 17.45 ppm.

[0833] Process 2 1-(2,5-Dimethylphenyl)-3-(4'-hydroxy-[1,1'-biphenyl]-4-yl)urea (12) - Typical procedure 6 was followed using 1-(2,5-dimethylphenyl)-3-(4'-methoxy-[1,1'-biphenyl]-4-yl)urea H1 (72 μmol, 1.0 equiv, 25 mg) in dry DCM (2 mL). The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and fractions (10-20 mg) of the crude mixture were purified by semi-preparative HPLC to give pure compound 12 in sufficient quantities for identification and biological assays.

[0834] [ka]

[0835] 1 H NMR (300 MHz, acetone-d 6 , 20℃), δ = 8.50 (s, 1H, OH 20), 8.39 (s, 1H, NH 9), 7.79 (d, J = 1.2 Hz, 1H, CH 7), 7.65 - 7.55 (m, 2H, CH 17), 7.50 (m, 2H, CH 18), 7.49 (s, 1H, NH 11), 7.46 (m, 2H, CH 14), 7.03 (d, J = 7.7 Hz, 1H, CH 3), 6.96 - 6.85 (m, 2H, CH 13), 6.83 - 6.74 (dd, J = 7.7, 1.2 Hz, 1H, CH 4), 2.29 (s, 3H, CH 3 6), 2.23 (s, 3H, CH 3 1) ppm. 13 C NMR (75 MHz, acetone-d 6, 20℃), δ = 157.59 (CO 10), 139.85 (COH 19), 138.38 (C 8), 136.47 (C 5), 135.53 (C 16), 132.99 (C 12), 130.86 (CH 3), 128.32 (CH 14), 127.35 (CH 18), 125.78 (C 2), 124.56 (CH 4), 123.19 (CH 7), 119.59 (CH 17), 116.52 (CH 13), 103.18 (C 15), 21.31 (CH 3 6), 17.73 (CH 3 1) ppm. Purity at HPLC λ = 254 nm: 97.5%. MS (ESI+): m / z (%) 333.0 (100) [M+H + ].

[0836] (Example 13) 1-(2,5-dimethylphenyl)-3-(4'-hydroxy-[1,1'-biphenyl]-3-yl)urea Process 1 1-(2,5-Dimethylphenyl)-3-(4'-methoxy-[1,1'-biphenyl]-3-yl)urea (I1) - Typical procedure 5 was followed using 2-isocyanato-1,4-dimethylbenzene (1 mmol, 1.0 equiv, 148 mg) and 4'-methoxy-[1,1'-biphenyl]-3-amine (1 mmol, 1.0 equiv, 200 mg) in dry DCM (6 mL). The solvent was evaporated and the residue was triturated with DiPE and filtered to give I1, 276 mg, yield: 79%.

[0837] [ka]

[0838] 1 H NMR (400 MHz, DMSO-d 6, 20℃), δ = 9.08 (s, 1H), 7.87 (s, 1H), 7.77 (m, 1H), 7.70 (s, 1H), 7.56 (d, 2H), 7.33 (m, 2H), 7.20 (m, 1H), 7.04 (m, 2+1H), 6.77 (d, 1H), 3.80 (s, 3H), 2.25 (s, 3H), 2.20 (s, 3H) ppm. 13 C NMR (101 MHz, DMSO-d 6 , 20℃), δ = 158.91, 152.68, 140.49, 140.41, 137.14, 135.06, 132.67, 129.96, 129.30, 127.67, 124.34, 123.32, 121.60, 119.68, 116.40, 115.77, 114.34, 55.16, 20.90, 17.44 ppm.

[0839] Process 2 1-(2,5-Dimethylphenyl)-3-(4'-hydroxy-[1,1'-biphenyl]-3-yl)urea (13) - Typical procedure 6 was followed using 1-(2,5-dimethylphenyl)-3-(4'-methoxy-[1,1'-biphenyl]-3-yl)urea I1 (72 μmol, 1.0 equiv, 25 mg) in dry DCM (2 mL). The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction (10-20 mg) of the crude mixture was purified by semi-preparative HPLC to give pure compound 13 in sufficient quantity for identification and biological assays.

[0840] [ka]

[0841] 1 H NMR (300 MHz, acetone-d 6, 20 °C), δ = 8.48 (s, 1H, OH 22), 8.47 (s, 1H, NH 9), 7.83 (t, J = 2.0 Hz, 1H, CH 17), 7.83 - 7.76 (d, J = 1.4 Hz, 1H, CH 8), 7.54 - 7.46 (m, 2H, CH 19), 7.49 (s, 1H, NH 11), 7.44 (ddd, J = 7.8, 2.0, 1.1 Hz, 1H, CH 13), 7.30 (t, J = 7.8 Hz, 1H, CH 14), 7.20 (ddd, J = 7.8, 2.0, 1.1 Hz, 1H, CH 15), 7.03 (d, J = 7.7 Hz, 1H, CH 4), 6.98 - 6.87 (m, 2H, CH 20), 6.84 - 6.74 (dd, J = 7.7, 1.4 Hz, 1H, CH 3), 2.29 (s, 3H, CH 3 1), 2.23 (s, 3H, CH 3 6) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20 °C), δ = 158.08 (CO 10), 153.65 (COH 21), 142.46 (C 12), 141.60 (C 12), 138.31 (C 5), 136.50 (C 2), 133.26 (C 18), 130.87 (CH 4), 129.95 (CH 14), 128.81 (CH 19), 125.80 (C 7), 124.62 (CH 3), 123.23 (CH 8), 120.88 (CH 15), 117.40 (CH 13), 117.26 (CH 17), 116.53 (CH 20), 21.30 (CH 3 1), 17.69 (CH 3 6) ppm. Purity at HPLCλ = 254 nm: 100%. MS (ESI+): m / z (%) 333.0 (100) [M+H + .

[0842] (Example 14) 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)cyclohexyl)urea

[0843] [ka]

[0844] Process 1 4-(4-Methoxyphenyl)cyclohexanone (J1) - 4-(4-Hydroxyphenyl)cyclohexanone (5.26 mmol, 1.0 equiv, 1 g) in dry acetone (13 mL) in an oven-dried flask under argon was dissolved in CS 2 CO 3 (7.88 mmol, 1.5 equiv, 2.57 g). Iodomethane (excess, 15.0 equiv) was added dropwise and the mixture was refluxed for 1 h. After completion, monitored using TLC, the solvent was removed, water was added (25 mL) and the aqueous phase was extracted with DCM (3 x 25 ml). The combined organic layers were washed with Na 2 SO 4 The solid residue was purified using chromatography to give J1, 0.95 g, yield: 88%.

[0845] [ka]

[0846] 1 H NMR (300 MHz, MeOD, 20℃), δ = 7.19 (m, 2H), 6.85 (m, 2H), 3.76 (s, 3H), 3.01 (tt, 1H), 2.61 (td, 2H), 2.39 (ddt, 2H), 2.24 - 2.08 (m, 1H), 2.08 - 1.79 (m, 3H), 1.78 - 1.49 (m, 1H) ppm.

[0847] Process 2 4-(4-Methoxyphenyl)cyclohexane-1-amine (J2) - Typical procedure 2 was followed using 4-(4-methoxyphenyl)cyclohexanone J1 (1.22 mmol, 1.0 equiv, 250 mg). After 36 h reaction, work-up afforded J2, 210 mg, yield: 83.6%. The amine derivative was used without purification.

[0848] Process 3 1-(2,5-Dimethylphenyl)-3-(4-(4-methoxyphenyl)cyclohexyl)urea (J3) - Typical procedure 5 was followed using 2-isocyanato-1,4-dimethylbenzene (0.925 mmol, 1.0 equiv, 136 mg) and 4-(4-methoxyphenyl)cyclohex-1-amine J2 (1 mmol, 1.0 equiv, 200 mg) in dry DCM (5 mL). The solvent was evaporated and the residue was triturated and washed with cold DCM to give J3, 151 mg, yield: 66%.

[0849] [ka]

[0850] 1 H NMR (300 MHz, DMSO-d 6 , 20℃), δ = 7.70 (s, 1H), 7.45 (s, 1H), 7.19 - 7.12 (m, 2H), 6.97 (d, 1H), 6.87 - 6.81 (m, 2H), 6.66 (dd, 1H), 6.49 (d, 1H), 3.71 (s, 3H), 3.56 - 3.40 (m, 1H), 2.44 (dt, 1H), 2.21 (s, 3H), 2.12 (s, 3H), 2.00 (dd, 2H), 1.79 (d, 2H), 1.50 (qd, 2H), 1.35 - 1.18 (m, 2H) ppm. 13 C NMR (75 MHz, DMSO-d 6, 20℃), δ = 157.46, 154.64, 138.80, 138.13, 134.87, 129.82, 127.54, 123.10, 122.20, 120.60, 113.67, 54.97, 48.08, 42.03, 33.49, 33.06, 21.01, 17.49 ppm.

[0851] Process 4 1-(2,5-Dimethylphenyl)-3-(4-(4-hydroxyphenyl)cyclohexyl)urea (14) - Typical procedure 6 was followed using 1-(2,5-dimethylphenyl)-3-(4-(4-methoxyphenyl)cyclohexyl)urea J3 (71 μmol, 1.0 equiv, 25 mg) in dry DCM (2 mL). The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give pure compound 14 in sufficient quantity for identification and biological assays.

[0852] [ka]

[0853] 1 H NMR (400 MHz, DMSO-d 6, 20℃), δ = 9.10 (s, 1H, OH 20), 7.68 (d, 1H, J ≦ 2 Hz, CH 7), 7.43 (s, 1H, NH 9), 7.02 (m, 2H, CH 17), 6.97 (d, 1H, J = 8.3 Hz, CH 3), 6.66 (m, 2H, CH 18), 6.66 (dd, 1H, J = 8.3, ≦ 2 Hz, CH 4), 6.46 (d, J = 7.6 Hz, 1H, NH 11), 3.45 (tdt, J (approximate value) = 12.0 (eq-eq), 7.6 (NH), 3.5 (eq-ax) Hz, 1H, CH 12), 2.38 (tt, J (approx.) = 12.0 (eq-eq), 3.5 (eq-ax) Hz, 1H, CH 15), 2.20 (s, 3H, CH 3 6), 2.11 (s, 3H, CH 3 1), 1.98 (dq, J (approximate value) = 12.0 (gem), 3.5 (ax-eq / ax-ax), 2H, CH ax 13), 1.77 (dq, J (approximate value) = 12.0 (gem), 3.5 (ax-eq / ax-ax), 2H, CH ax 14), 1.47 (tdd, J (approximate) = 12.0 (eq-eq), 12.0 (gem), 3.5 (eq-ax) Hz, 2H, CH eq 14), 1.25 (tdd, J (approximate) = 12.0 (eq-eq), 12.0 (gem), 3.5 (eq-ax) Hz, 2H, CH eq 13) ppm. 13 C NMR (101 MHz, DMSO-d 6, 20℃), δ = 155.39 (CO 10), 154.68 (COH 20), 138.12 (CH 2), 137.04 (CH 16), 134.88 (CH 5), 129.83 (CH 3), 127.43 (CH 17), 123.19 (CH 8), 122.26 (CH 4), 120.69 (CH 7), 114.99 (CH 18), 48.15 (CH 12), 42.06 (CH 15), 33.54 (CH 13), 33.15 (CH 14), 21.01 (CH 3 6), 17.48 (CH 3 1) ppm. Purity at HPLC λ = 254 nm: 100%. MS (ESI+): m / z (%) 338.9 (100) [M+H + ].

[0854] (Example 15) 1-(2,5-dimethylphenyl)-3-(1-(3-hydroxyphenyl)piperidin-3-yl)urea Process 1 tert-Butyl (1-(3-methoxyphenyl)piperidin-3-yl)carbamate (K1) - Typical procedure 9 was followed using 1-iodo-3-methoxybenzene (1.068 mmol, 1.0 equiv, 250 mg) as the iodine derivative and tert-butyl piperidin-3-ylcarbamate (1.282 mmol, 1.2 equiv, 257 mg) as the piperidine derivative. The crude was purified using column chromatography on silica (100% cyclohexane to 80 / 20 cyclohexane / EtOAc) to give K1, 194 mg, yield: 49%.

[0855] [ka]

[0856] 1H NMR (400 MHz, MeOD, 20℃), δ = 7.11 (t, J = 8.2 Hz, 1H), 6.56 (dd, J = 8.2, 2.3 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 6.40 (dd, J = 8.2, 2.3 Hz, 1H), 3.75 (s, 3H), 3.68 - 3.55 (m, 2H), 3.42 (dt, 1H), 2.75 (ddd, 1H), 2.59 (dd,1H), 1.90 (dt, 1H), 1.80 (dp, 1H), 1.67 (dtt, 1H), 1.45 (s, 9+1H) ppm. 13 C NMR (101 MHz, MeOD, 20℃), δ = 162.07, 157.80, 154.32, 130.84, 130.70, 110.75, 105.97, 104.30, 80.11, 56.59, 55.55, 51.03, 49.64, 49.43, 49.21, 49.00, 48.79, 48.57, 48.36, 31.44, 28.78, 24.71 ppm.

[0857] Process 2 1-(3-Methoxyphenyl)piperidin-3-amine dihydrochloride (K2) - Followed typical procedure 10 using tert-butyl (1-(3-methoxyphenyl)piperidin-3-yl)carbamate K1 (0.163 mmol, 1.0 equiv, 50 mg). Evaporation of the solvent afforded K2 in quantitative yield.

[0858] [ka]

[0859] 1H NMR (400 MHz, MeOD, 20℃), δ = 7.48 - 7.40 (m, 1H), 7.22 (t, 1H), 7.22 - 7.16 (m, 1H), 7.01 - 6.96 (m, 1H), 3.88 (tt, 1H), 3.86 (s, 3H), 3.81 - 3.71 (m, 1H), 3.59 (td, 3H), 2.20 (m, 3H), 1.87 (m, 1H) ppm.

[0860] Process 3 1-(2,5-Dimethylphenyl)-3-(1-(3-methoxyphenyl)piperidin-3-yl)urea (K3) - Following typical procedure 5 using 2-isocyanato-1,4-dimethylbenzene (0.143 mmol, 1.0 equiv, 21 mg) and 1-(3-methoxyphenyl)piperidin-3-amine dihydrochloride K2 (0.143 mmol, 1.0 equiv, 40 mg) in dry DCM (2 mL), followed by triethylamine (0.287 mmol, 2.0 equiv, 40 μL). The mixture was stirred at room temperature overnight. The precipitate was filtered and washed with cold DCM to give K3, 42 mg, yield: 83%.

[0861] [ka]

[0862] 1 H NMR (300 MHz, DMSO-d 6, 20℃), δ = 7.72 (s, 1H), 7.62 (s, 1H), 7.10 (t, J = 8.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 6.71 - 6.64 (m, 1H), 6.54 (ddd, J = 8.3, 2.4, 0.8 Hz, 1H), 6.46 (t, J = 2.3 Hz, 1H), 6.34 (ddd, J = 8.1, 2.4, 0.8 Hz, 1H), 3.71 (s, 3+1H), 3.49 (dd, 1H), 3.00 (m, 2H), 2.81 (dd, 1H), 2.21 (s, 3H), 2.12 (s, 3H), 1.85 - 1.70 (m, 1H), 1.65 - 1.38 (m, 1H), 1.15 (t, 2H) ppm. 13 C NMR (75 MHz, DMSO-d 6 , 20℃), δ = 160.24, 154.76, 152.45, 138.01, 134.90, 129.84, 123.16, 122.31, 120.66, 108.62, 103.88, 101.92, 54.39, 48.87, 45.65, 45.09, 29.95, 28.03, 22.66, 21.02, 17.55 ppm.

[0863] Process 4 1-(2,5-Dimethylphenyl)-3-(1-(3-hydroxyphenyl)piperidin-3-yl)urea (15) - Typical procedure 6 was followed using 1-(2,5-dimethylphenyl)-3-(1-(3-methoxyphenyl)piperidin-3-yl)urea K3 (71 μmol, 1.0 equiv, 25 mg) in dry DCM (2 mL). The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give pure compound 15 in sufficient quantity for identification and biological assays.

[0864] [ka]

[0865] 1 H NMR (300 MHz, acetone-d 6 , 20℃), δ = 8.08 (s, 1H, OH 24), 7.84 (d, J = 1.8 Hz, 1H, CH 8), 7.28 (s, 1H, NH 9), 7.03 (d, J = 8.0 Hz, 1H, CH 4), 6.98 (t, J = 8.0 Hz, 1H, CH 20), 6.75 - 6.66 (dd, J = 8.0, 2.2 Hz, 1H, CH 3), 6.44 - 6.39 (ddd, J = 8.0, 2.2, 0.8 Hz, 1H, CH 21), 6.42 (t, J = 0.8 Hz, 1H, CH 23), 6.28 (ddd, J = 8.0, 2.2, 0.8 Hz, 1H, CH 19), 6.20 (d, 1H, NH 11), 3.94 (m, 1H, CH 12), 3.57 - 3.46 (m, 1H, CHpiperidine), 3.28 - 3.14 (m, 1H, CHpiperidine), 2.99 (m, 1H, CHpiperidine), 2.91 - 2.82 (m, 2H, CHpiperidine), 2.25 (s, 3H, CH 3 1 / 6), 2.14 (s, 3H, CH 3 1 / 6), 1.91 - 1.46 (m, 3H, CH piperidine) ppm. 13 C NMR (300 MHz, acetone-d 6, 20℃), δ = 159.12 (COH 22), 155.70 (C 18), 154.20 (CO 10), 139.07 (C 7), 136.34 (C 2), 130.73 (CH 4), 130.48 (CH 20), 124.69 (C 5), 123.72 (CH 3), 122.41 (CH 8), 108.77 (CH 21), 107.21 (CH 19), 104.44 (CH 23), 56.26 (CH 2 Piperidine), 50.22 (CH 2 piperidine), 46.70 (CH 12), 30.92 (CH 2 piperidine), 23.77 (CH 2 piperidine), 21.36 (CH 3 1), 17.70 (CH 3 6) ppm. Purity at HPLC λ = 254 nm: 100%. MS (ESI+): m / z (%) 340.0 (100) [M+H + ]. HRMS (M+Na) + Calculated value: 362.1839 - Measured value: 362.1840.

[0866] (Example 16) 3-(2,5-dimethylphenyl)-1-(4-(4-hydroxyphenyl)butan-2-yl)-1-methylurea (B3-1)

[0867] [ka]

[0868] Process 1 4-(4-(benzyloxy)phenyl)-N-methylbutan-2-amine (L1) - To a 100 mL round bottom flask charged with methanol (30 mL) was added 4-(4-(benzyloxy)phenyl)butan-2-one (500 mg, 1.966 mmol, 1 equiv) and aqueous methylamine (40% by weight in water, 680 μL, 7.864 mmol, 4 equiv). After stirring at room temperature for 30 min, sodium cyanoborohydride (148.2 mg, 2.359 mmol, 1.2 equiv) was added and stirring was continued for 18 h. Saturated NaHCO 3 (20 mL) was added to quench the reaction, and the reaction mixture was extracted with DCM (3×20 mL). The organic phase was washed with anhydrous MgSO 4 The mixture was dried over 1000 ml, filtered and evaporated to dryness by rotary evaporation. The residue was redissolved in EtOAc and extracted with 0.1 M HCl solution (3×10 mL). The isolated acidic aqueous phase was then made basic by adding 1 M NaOH until pH ∼10 and then extracted with EtOAc (3×10 mL). The organic phase was washed with anhydrous MgSO 4 The mixture was dried at 40° C. for 1 hour, filtered, evaporated to dryness by rotary evaporation, and dried under high vacuum to give 178 mg of crude product L1, pure enough to be used in the next step without further purification. Yield 34%.

[0869] [ka]

[0870] 1 H NMR (300 MHz, acetone-d 6 , 20℃): δ = 7.52 - 7.26 (m, 6H), 7.19 - 7.07 (m, 2H), 6.96 - 6.86 (m, 2H), 5.08 (s, 2H), 2.64 - 2.46 (m, 3H), 2.33 (s, 3H), 1.78 - 1.43 (m, 2H), 1.04 (d, J = 6.3 Hz, 3H) ppm.

[0871] Process 2 1-(4-(4-(benzyloxy)phenyl)butan-2-yl)-3-(2,5-dimethylphenyl)-1-methylurea (L2) - A 10 mL round bottom flask charged with anhydrous DCM (6 mL) and equipped with a condenser was charged with 4-(4-(benzyloxy)phenyl)-N-methylbutan-2-amine L1 (178 mg, 0.661 mmol, 1 equiv) and triethylamine (101.3 μL, 0.727 mmol, 1.1 equiv) under argon atmosphere. After stirring for 20 min at room temperature, 4-nitrophenyl(2,5-dimethylphenyl)carbamate (208 mg, 0.727 mmol, 1.1 equiv) was added and the reaction was heated to 35 °C and stirred for 72 h. The reaction mixture was washed with 0.1 M NaOH (2 × 10 mL) and the organic phase was washed with anhydrous MgSO 4 The mixture was dried at 40° C. for 1 hour, filtered, evaporated to dryness by rotary evaporation, then concentrated to dryness and the residue was dried under high vacuum to give 220 mg of crude product. The solid was loaded and purified by silica gel column chromatography (25 g of silica) with isocratic elution (80:20 PE / acetone) to give the pure desired product L2, 145 mg, yield: 46%, R f The yield was (PE / acetone 80:20): 0.265.

[0872] [ka]

[0873] 1 H NMR (300 MHz, acetone-d 6 , 20℃): δ = 7.51 - 7.24 (m, 6H), 7.21 - 7.09 (m, 2H), 7.03 (d, J = 7.9 Hz, 2H), 6.97 - 6.87 (m, 2H), 6.87 - 6.74 (m, 1H), 5.06 (s, 2H), 4.57 - 4.40 (m, 1H), 2.54 (t, J = 7.9 Hz, 2H), 2.29 - 2.11 (m, 6H), 1.92 - 1.58 (m, 2H), 1.13 (d, J = 6.7 Hz, 3H) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃) δ = 157.90, 156.76, 139.12, 138.54, 135.93, 135.30, 130.61, 130.08 (2C), 129.19 (2C), 128.76, 128.65, 128.46, 128.29 (2C), 125.60, 125.19, 115.46 (2C), 70.31, 50.01, 37.16, 32.76, 30.60, 27.64, 21.16, 18.65, 17.82 ppm.

[0874] Process 3 3-(2,5-dimethylphenyl)-1-(4-(4-hydroxyphenyl)butan-2-yl)-1-methylurea (16) - To a 10 mL round bottom flask charged with MeOH (5 mL) was added 1-(4-(4-(benzyloxy)phenyl)butan-2-yl)-3-(2,5-dimethylphenyl)-1-methylurea L2 (145 mg, 0.303 mmol, 1 equiv) and palladium on charcoal 10% by weight (22 mg, 15% by weight). The reaction mixture was then diluted with H 2 Place under atmosphere, stir and monitor by TLC. After 3 h, TLC showed complete deprotection and the reaction mixture was filtered over a Celite pad to remove Pd / C and rinsed with methanol (10 mL) to give 122 mg of crude product. Purification by silica gel column chromatography (12 g silica) with solid loading and isocratic elution (85:15 PE / acetone) gave pure desired compound 16, 98 mg, yield: 99%, R f The yield was (PE / acetone 70:30): 0.67.

[0875] [ka]

[0876] 1 H NMR (300 MHz, acetone-d 6, 20℃): δ = 8.09 (s, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.10 - 6.98 (m, 3H), 6.94 (s, 1H), 6.83 - 6.76 (m, 1H), 6.75 - 6.69 (m, 2H), 4.56 - 4.38 (m, 1H), 2.92 (s, 3H), 2.51 (t, 2H), 2.28 - 2.16 (m, 6H), 1.92 - 1.59 (m, 2H), 1.14 (d, J = 6.7 Hz, 3H) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃) δ = 156.78, 156.35, 139.18, 136.02, 133.77, 130.65, 130.07 (3C), 128.66, 125.53, 125.17, 115.95 (2C), 50.15, 37.38, 32.85, 27.69, 21.12, 18.65, 17.76 ppm.

[0877] (Example 17) 2-(2,5-dimethylphenyl)-N-(4-(4-hydroxyphenyl)butan-2-yl)acetamide

[0878] [ka]

[0879] Process 1 2-(2,5-Dimethylphenyl)-N-(4-(4-Methoxyphenyl)butan-2-yl)acetamide (M1) - To a 25 mL round bottom flask charged with dry DCM (12 mL) under argon atmosphere was added 2-(2,5-dimethylphenyl)acetic acid (80 mg, 0.487 mmol, 1 equiv), 1,3-diisopropylcarbodiimide (115 μL, 0.731 mmol, 1.5 equiv), 1-hydroxybenzotriazole (112 mg, 0.731 mmol, 1.5 equiv) and DIPEA (127 μL, 0.731 mmol, 1.5 equiv). After stirring at room temperature for 30 min, 4-(4-methoxyphenyl)butan-2-amine (105 mg, 0.585 mmol, 1.2 equiv) was added and stirring was continued for 18 h. The reaction mixture was evaporated to dryness by rotary evaporation, the residue was dissolved in ethyl acetate (15 mL) and filtered on a fritted funnel (por. 4). The filtrate was washed with 0.1 M citric acid (15 mL), 0.1 M sodium hydroxide and water (15 mL) and the organic layer was diluted with anhydrous MgSO 4 The mixture was dried at 40° C. for 1 hour, dried at 40° C. for 1 hour, filtered and evaporated to dryness by rotary evaporation, and the residue was dried under high vacuum to give 185 mg of crude product. The solid was loaded and purified by silica gel column chromatography (12 g silica, ratio 1:65) with gradient elution (95:5 to 85:25 PE / EtOAc) to give the pure desired product M1, 124 mg, yield: 78%, R f (PE / EtOAc 80:20): 0.23 was obtained.

[0880] [ka]

[0881] 1 H NMR (300 MHz, acetone-d 6, 20℃): δ = 7.10-7.00 (m, 4H), 6.94 (dd, 1H), 6.81 (dt, 2H), 3.92 (septet, 1H), 3.74 (s, 3H), 3.46 (s, 2H), 2.53 (m, 2H), 2.27 (s, 3H), 2.24 (s, 3H), 1.68 (m, 2H) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃) δ = 170.13, 163.08, 162.43, 160.41, 158.83, 135.77, 134.93, 134.53, 131.68, 130.78, 130.06, 128.13, 114.50, 55.38, 45.32, 41.82, 39.66, 32.24, 21.28, 20.96, 19.38 ppm.

[0882] Process 2 2-(2,5-Dimethylphenyl)-N-(4-(4-hydroxyphenyl)butan-2-yl)acetamide (17) - 2-(2,5-Dimethylphenyl)-N-(4-(4-methoxyphenyl)butan-2-yl)acetamide M1 (0.384 mmol, 1.0 equiv, 124 mg) was reacted according to typical procedure 6. The crude residue (169 mg) was purified by silica gel flash chromatography (4 g silica) with liquid deposition and gradient elution (DCM / MeOH from 100:0 to 92:8) to give the pure desired compound 17, 61 mg, yield: 51%, R f (DCM / MeOH 96:4): 0.27 was obtained.

[0883] [ka]

[0884] 1 H NMR (300 MHz, acetone-d 6, 20℃): δ = 8.18 (s, 1H), 7.10 - 6.89 (m, 6H), 6.87 (s, 1H), 6.77 - 6.66 (m, 2H), 4.04 - 3.84 (m, 1H), 3.47 (s, 2H), 2.61 - 2.39 (m, 2H), 2.27 (s, 3H), 2.24 (s, 3H), 1.76 - 1.57 (m, 2H), 1.10 (d, J = 6.6 Hz, 3H) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃) δ = 170.13, 158.83, 135.77, 134.93, 134.53, 131.68, 130.78, 130.06, 128.13, 114.50, 55.38, 45.32, 41.82, 39.66, 32.24, 21.28, 20.96, 19.38 ppm.

[0885] (Example 18) 2,5-Dimethylphenyl (4-(4-hydroxyphenyl)butan-2-yl)carbamate

[0886] [ka]

[0887] Process 1 4-Nitrophenyl(4-(4-methoxyphenyl)butan-2-yl)carbamate (N1) - In a 250 mL round bottom flask, a solution of 4-(4-methoxyphenyl)butan-2-amine (2.568 g, 14.326 mmol, 1 equiv) and DIPEA (4.99 mL, 28.611 mmol, 2 equiv) in anhydrous DCM (60 mL) was maintained at 0 °C with an ice bath under argon atmosphere, and a solution of 4-nitrophenyl chloroformate (2.887 g, 28.611 mmol, 2 equiv) in anhydrous DCM (40 mL) was added. 30 min after the addition was complete, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for 18 h. TLC monitoring indicated complete consumption of the amine and the reaction mixture was transferred to a 500 mL separatory funnel and washed with saturated NaHCO3 (120 mL) and brine (2×100 mL). The organic layer was washed with anhydrous MgSO 4 The crude residue was purified by silica gel flash chromatography with liquid deposition and gradient elution (PE / DCM from 50:50 to 0:100) to give the pure desired product N1, 2.237 g, yield: 55%, R f (PE / DCM25:75):0.43 was obtained.

[0888] [ka]

[0889] 1 H NMR (300 MHz, CDCl 3 , 20℃): δ = 8.30 - 8.18 (dt, 2H), 7.37 - 7.26 (dt, 2H), 7.17 - 7.06 (dt, 2H), 6.89 - 6.78 (dt, 2H), 4.96 (d, J = 8.6 Hz, 1H), 3.92 - 3.72 (m, 1H), 3.78 (s, 3H), 2.66 (t, J = 7.9 Hz, 2H), 1.95 - 1.72 (m, 2H), 1.28 (d, J = 6.6 Hz, 3H) ppm. 13 C NMR (75 MHz, chloroform-d 1 , 20℃) δ = 158.06, 156.12, 152.52, 144.78, 133.41, 129.33, 125.24, 122.05, 114.06, 77.36, 55.39, 47.64, 38.91, 31.59, 21.22 ppm.

[0890] Process 2 2,5-Dimethylphenyl(4-(4-methoxyphenyl)butan-2-yl)carbamate (N2) - To a solution of 2,5-dimethylphenol (37.4 mg, 0.305 mmol, 1 equiv) in anhydrous THF (4 mL) in a 10 mL round bottom flask maintained at 0 °C with an ice bath under argon, NaH (0.367 mmol, 1.2 equiv, 60 wt% in oil) was added. The reaction was stirred at 0 °C until gas evolution ceased. A solution of 4-nitrophenyl(4-(4-methoxyphenyl)butan-2-yl)carbamate N1 (126 mg, 0.367 mmol, 1.2 equiv) in anhydrous THF (3 mL) was then added and the reaction mixture immediately turned from light yellow to orange. The ice bath was then removed and the reaction was monitored by TLC, which showed complete conversion after 3 h. The reaction mixture was evaporated to dryness by rotary evaporation, and the residue was resuspended in DIPE (7 mL), sonicated, and filtered on a fritted funnel (por. 4). The filtrate was evaporated to dryness by rotary evaporation to give 115 mg of crude product N2, which was used in the next step without further purification. Rf (PE / acetone 70:30): 0.48.

[0891] [ka]

[0892] 1 H NMR (300 MHz, acetone-d 6 , 20℃): δ = 7.16 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.88 - 6.81 (m, 3H), 6.68 (d, J = 8.6 Hz, 1H), 3.75 (s, 3H), 2.77 - 2.56 (m, 2H), 2.27 (s, 3H), 2.14 (s, 3H), 1.94 - 1.72 (m, 2H), 1.23 (d, J = 6.6 Hz, 3H) ppm.

[0893] Process 3 2,5-Dimethylphenyl(4-(4-hydroxyphenyl)butan-2-yl)carbamate (18) - 2,5-Dimethylphenyl(4-(4-methoxyphenyl)butan-2-yl)carbamate N2 (115 mg, 0.334 mmol, 1.0 equiv.) was reacted according to typical procedure 6 to give 121 mg of crude product as a yellow oil. The crude residue was purified by silica gel flash chromatography (4 g FlashPure ID HP silica column) with liquid deposition and gradient elution (PE / acetone from 100:0 to 30:70) to give the pure desired compound 18, 32 mg, yield: 31%.

[0894] [ka]

[0895] 1 H NMR (300 MHz, acetone-d 6 , 20℃): δ = 8.05 (s, 1H), 7.07 (dd, J = 8.0, 4.6 Hz, 4H), 6.95 - 6.80 (m, 2H), 6.83 - 6.69 (m, 2H), 6.65 (d, J = 8.6 Hz, 1H), 3.72 (h, J = 6.9 Hz, 1H), 2.75 - 2.52 (m, 2H), 2.27 (s, 3H), 2.13 (s, 3H), 1.92 - 1.66 (m, 2H), 1.23 (d, J = 6.6 Hz, 3H) ppm. 13 C NMR (75 MHz, chloroform-d 1 , 20℃) δ = 156.36, 156.26, 154.70, 150.86, 137.15, 133.62, 131.22, 130.13, 128.34, 126.60, 123.84, 115.98, 115.89, 47.69, 39.77, 32.34, 21.46, 20.81, 15.85, 1.10 ppm. Purity at HPLC λ = 210 nm: 96.5%. MS (ESI+): m / z (%) 314.1 (100) [M+H + ].

[0896] (Example 19) 4-(4-hydroxyphenyl)butan-2-yl 2-(2,5-dimethylphenyl)acetate

[0897] [ka]

[0898] Process 1 4-(4-Methoxyphenyl)butan-2-yl 2-(2,5-dimethylphenyl)acetate (O1) - In a 25 mL round bottom flask under argon, to a solution of 2-(2,5-dimethylphenyl)acetic acid (80 mg, 0.487 mmol, 1 equiv), N,N'-dicyclohexylcarbodiimide (110.6 mg, 0.536 mmol, 1.1 equiv) and 4-dimethylaminopyridine (9 mg, 0.073 mmol, 0.15 equiv) in anhydrous DCM (8 mL) was added 4-(4-methoxyphenyl)butan-2-ol (96.6 mg, 0.536 mmol, 1.1 equiv). The reaction was stirred at room temperature and TLC monitoring indicated the reaction was complete after 4.5 h. After completion, N,N'-dicyclohexylurea was filtered off through a fritted funnel (porosity 4) and the filtrate was washed with water (15 mL), 0.1 M citric acid (15 mL), 0.1 M NaOH (15 mL) and water (15 mL). The organic layer was washed with anhydrous MgSO 4 The mixture was dried at 40° C. for 1 hour, filtered, evaporated to dryness by rotary evaporation, and the residue was dried under high vacuum to give 206 mg of crude product. Purification by silica gel flash chromatography (10.3 g silica, ratio 1:50) with liquid deposition and gradient elution (PE / EtOAc from 100:0 to 96:4) gave the pure desired product O1, 147 mg, yield: 97%, R f (PE / EtOAc 95:5): 0.39 was obtained.

[0899] [ka]

[0900] 1 H NMR (300 MHz, acetone-d 6 , 20℃): δ = 6.91 - 6.71 (m, 5H), 6.66 - 6.54 (m, 2H), 4.70 - 4.53 (m, 1H), 3.53 (s, 3H), 3.39 (d, J = 3.1 Hz, 2H), 2.40 - 2.16 (m, 2H), 2.09 - 1.94 (m, 5H), 1.68 - 1.47 (m, 2H), 0.99 (d, J = 6.3 Hz, 3H) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃) δ = 171.39, 158.91, 135.94, 134.48, 134.35, 134.27, 131.79, 130.87, 130.05, 128.54, 114.55, 71.00, 55.39, 39.91, 38.69, 31.27, 20.90, 20.23, 19.23 ppm.

[0901] Process 2 4-(4-Hydroxyphenyl)butan-2-yl 2-(2,5-dimethylphenyl)acetate (19) - 4-(4-Methoxyphenyl)butan-2-yl 2-(2,5-dimethylphenyl)acetate O1 (147 mg, 0.450 mmol, 1.0 equiv.) was reacted according to typical procedure 6 to give 174 mg of crude product. The crude residue was purified by silica gel flash chromatography (4 g FlashPure ID HP silica column) with liquid deposition and gradient elution (PE / DCM from 100:0 to 20:80) to give the pure desired compound 19, 23 mg, yield: 16%.

[0902] [ka]

[0903] 1 H NMR (300 MHz, acetone-d 6 , 20℃): δ = 7.35 - 7.18 (m, 2H), 7.16 - 6.96 (m, 5H), 4.26 - 4.07 (m, 1H), 3.89 (s, 2H), 2.94 - 2.66 (m, 2H), 2.33 (s, 3H), 2.28 (q, J = 0.7 Hz, 3H), 2.15 - 2.02 (m, 2H), 1.72 (d, J = 6.6 Hz, 3H) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃) δ = 170.62, 150.27, 139.47, 136.12, 134.63, 133.57, 131.91, 130.99, 130.17, 128.84, 122.45, 52.19, 43.48, 39.52, 33.93, 26.78, 20.89, 19.19 ppm. Purity at HPLC λ = 254 nm: 99.4%.

[0904] (Example 20) 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)thiourea

[0905] [ka]

[0906] Process 1 1-(2,5-Dimethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)thiourea (P1) - 2,5-dimethylphenylisothyanate (60 mg, 0.368 mmol, 1 equiv.) was weighed out under a fume hood into a 5 mL oven-dried round-bottom flask due to its toxicity, quickly placed under argon atmosphere, and to this was added anhydrous DCM (2 mL). A solution of 4-(4-methoxyphenyl)butan-2-amine (69 g, 0.386 mmol, 1.05 equiv.) in anhydrous DCM (1 mL) was then added and the reaction was stirred at room temperature. TLC monitoring indicated complete conversion after 1.5 h. The reaction mixture was evaporated to dryness by rotary evaporation and the residue P1 (126 mg) was used directly in the next step without further purification. 1 H NMR (300 MHz, acetone-d 6 , 20℃): δ = 8.34 (s, 1H), 7.19 - 6.97 (m, 5H), 6.87 - 6.77 (m, 2H), 4.60 (bs, 1H), 3.74 (s, 3H), 2.60 (m, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 1.89 - 1.63 (m, 2H), 1.17 (d, J = 6.6 Hz, 3H) ppm.

[0907] Process 2 1-(2,5-Dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)thiourea (20) - 1-(2,5-Dimethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)thiourea P1 (126 mg, 0.368 mmol, 1.0 equiv.) was reacted according to typical procedure 6 to give 160 mg of crude product. The crude residue was purified by silica gel flash chromatography using solid loading on Celite and isocratic elution (75:25 PE / acetone) to give pure compound 20, 87 mg, yield: 72%. 1 H NMR (300 MHz, acetone-d 6, 20℃): δ = 8.30 (s, 1H), 8.03 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.08 - 6.97 (m, 4H), 6.78 - 6.67 (m, 2H), 6.50 (s, 1H), 4.59 (s, 1H), 2.64 - 2.48 (m, 2H), 2.32 - 2.15 (m, 5H), 2.09 (s, 2H), 1.90 - 1.62 (m, 2H), 1.29 (s, 1H), 1.17 (d, J = 6.6 Hz, 3H) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃) δ = 182.05, 156.29, 137.20, 136.98, 133.70, 133.32, 131.66, 130.05 (2C), 129.39, 128.88, 115.93 (2C), 51.42, 39.45, 32.46, 20.83, 20.71, 17.58 ppm. Purity at HPLC λ = 254 nm: 99.3%. MS (ESI+): m / z (%) 329.2 (100) [M+H + ].

[0908] (Example 21) 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(o-tolyl)urea

[0909] [ka]

[0910] Process 1 1-(4-(4-Methoxyphenyl)butan-2-yl)-3-(o-tolyl)urea (Q1) - Followed typical procedure 13 part 2 using 1-(3-isocyanatobutyl)-4-methoxybenzene (80 mg, 0.390 mmol, 1 equiv.) and o-toluidine (41.77 mg, 0.390 mmol, 1 equiv.). The crude product was purified by SCC using solid deposition and gradient elution (dichloromethane / methanol from 98:2 to 95:5) to give pure desired product Q1: 40 mg, 33%. 1 H NMR (300 MHz, CDCl 3 , 20℃), δ = 7.43 (d, J = 6 Hz, CH Ar) , 7.18 (t, J = 6 Hz, CH Ar ×2), 7.09 (d, J = 9 Hz, CH Ar ), 7.05 (d, J = 9 Hz, CH Ar ×2), 6.79 (dd, J = 9 Hz, CH Ar ×2), 6.37 (s, NH), 3.91 (q, J = 6 Hz, CH), 3.75 (s, CH 3 ), 2.57 (t, J = 6 Hz, CH 2 ), 2.24 (s, CH 3 ), 1.66 (m, CH 2 ), 1.13 (d, J = 6 Hz, CH 3 ) ppm.

[0911] Process 2 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(o-tolyl)urea (21) - 1-(4-(4-methoxyphenyl)butan-2-yl)-3-(o-tolyl)urea Q1 (40 mg, 0.128 mmol, 1 equiv.) and BBr 3(192.46 mg, 0.768 mmol, 6 equiv.) was used following typical procedure 6. The crude product was purified by SCC using solid deposition and gradient elution (petroleum ether / acetone from 95:5 to 8:2) to give the pure desired compound 21:32 mg, 32%. 1 H NMR (300 MHz, acetone- d6 , 20℃), δ = 8.09 (s, OH), 7.93 (d, NH), 7.2 (s, CH Ar ), 7.09 (t, CH Ar ×2), 7.01 (dd, CH Ar ×2), 6.85 (t, CH Ar ), 6.73 (dd, CH Ar ×2), 5.96 (d, J = 9 Hz, NH), 3.87 (m, CH), 2.59 (m, CH 2 ), 2.2 (s, CH 3 ), 1.7 (m, CH 2 ), 1.17 (d, J = 6 Hz, CH 3 ) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃), δ = 156.33, 155.88, 139.42, 133.74, 130.87, 130.05, 127.83, 127.02, 122.97, 121.83, 115.95, 45.99, 40.34, 32.30, 21.84, 18.10 ppm.

[0912] (Example 22) 1-(3,5-dimethyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea

[0913] [ka]

[0914] Process 1 1-(3,5-Dimethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea (R1) - Followed typical procedure 13 part 2 using 4-(4-methoxyphenyl)butan-2-amine (80 mg, 0.446 mmol, 1 equiv.) and isocyanato-3,5-dimethylbenzene (59.7 mg, 0.446 mmol, 1 equiv.). The crude product was purified by SCC (petroleum ether / acetone from 95:5 to 8:2) to give the pure desired product R1: 123 mg, 88%. 1 H NMR (300 MHz, CDCl 3 , 20℃), δ = 7.22 (s, NH), 7.02 (d, J = 9 Hz, CH Ar ×2), 6.90 (s, CH Ar ×2), 6.77 (d, J = 9 Hz, CH Ar ×2), 6.63 (s, CH Ar ), 5.29 (s, NH), 3.89 (m, CH), 3.74 (s, CH 3 ), 2.56 (m, CH 2 ), 2.20 (s, CH 3 ), 1.65 (m, CH 2 ), 1.13 (d, J = 6 Hz, CH 3 ) ppm.

[0915] Process 2 1-(3,5-dimethyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea (22) - 1-(3,5-dimethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea R1 (123 mg, 0.377 mmol, 1 equiv.) and BBr 3 (566.36 mg, 2.261 mmol, 6 equiv.) was used following typical procedure 6. The crude product was purified by SCC (dichloromethane / methanol from 99:1 to 95:5) to give the pure desired compound 22:98 mg, 52%. 1 H NMR (300 MHz, CDCl 3, 20℃), δ = 7.28 (s, NH), 6.88 (d, J = 9 Hz, CH Ar ×2), 6.78 (m, CH Ar ×2), 6.76 (m, CH Ar ×3), 6.44 (s, NH), 3.91 (m, J = 6 Hz, CH), 2.58 (t, J = 6 Hz, CH 2 ), 2.29 (s, CH 3 ×2), 1.44 (m, CH 2 ), 1.16 (d, J = 6 Hz, CH 3 ) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃), δ = 156.33, 155.83, 141.51, 138.71, 133.72, 130.04, 123.83, 116.80, 115.96, 45.95, 40.32, 32.30, 21.83, 21.50 ppm. Purity at HPLC λ = 254 nm: 100%. MS (ESI+): m / z (%) 313.0 (100) [M+H + ].

[0916] (Example 23) 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(3-isopropylphenyl)urea

[0917] [ka]

[0918] Process 1 1-(4-(4-(benzyloxy)phenyl)butan-2-yl)-3-(3-isopropylphenyl)urea (S1) - Following typical procedure 13 part 2 using 1-(benzyloxy)-4-(3-isocyantobutyl)benzene (95 mg, 0.336 mmol, 1 equiv.) and 3-isopropylaniline (50 mg, 0.370 mmol, 1.1 equiv.). The crude product was purified by SCC (petroleum ether / ethyl acetate from 95:5 to 85:15) with solid deposition to give the pure desired product S1: 47 mg, 34%. 1 H NMR (300 MHz, acetone-d 6, 20℃), δ = 7.80 (s, NH), 7.47 (m, CH Ar ×2), 7.38 (m, CH Ar ×3), 7.32 (m, CH Ar ×2), 7.13 (m, CH Ar ×3), 6.91 (m, CH Ar ×2), 6.81 (m, CH Ar ) 5.07 (s, CH 2 ), 3.88 (m, CH), 2.83 (m, CH), 2.63 (m, CH 2 ), 1.72 (m, CH 2 ), 1.20 (d, J = 6 Hz, CH 3 ) ppm.

[0919] Process 2 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(3-isopropylphenyl)urea (23) - A mixture of 1-(4-(4-(benzyloxy)phenyl)butan-2-yl)-3-(3-isopropylphenyl)urea S1 (47 mg, 0.113 mmol, 1 equiv.) and Pd / C (10% by weight) in MeOH (10 mL) was evacuated and filled with hydrogen gas via a balloon. The mixture was stirred at room temperature for 2 h. The Pd / C was removed by vacuum filtration through Celite and the Celite layer was washed with MeOH (10 mL x 3). The mixture was concentrated to give the crude product, which was purified by SCC using solid deposition and gradient elution (petroleum ether / acetone from 95:5 to 8:2) to give the pure desired compound 23: 32 mg, 87%. 1 H NMR (300 MHz, acetone-d 6, 20℃), δ = 8.17 (s, OH), 8.03 (s, NH), 7.38 (m, CH Ar ), 7.32 (m, CH Ar ), 7.14 (t, J = 9 Hz, CH Ar ), 7.02 (d, J = 9 Hz, CH Ar ×2), 6.80 (d, J = 6 Hz, CH Ar ), 6.74 (dd, J = 3 Hz, CH Ar ×2), 5.88 (d, J = 9 Hz, NH), 3.87 (m, CH), 2.85 (m, CH), 2.58 (m, CH 2 ), 1.71 (m, CH 2 ), 1.20 (d, J = 6 Hz, CH 3 ), 1.17 (d, J = 6 Hz, CH 3 ) ppm. 13 C NMR (75 MHz, acetone-d 6, 20℃), δ = 155.40, 154.81, 149.18, 140.94, 132.90, 129.29, 129.17, 128.44, 119.17, 115.99, 115.55, 115.04, 113.76, 45.02, 44.91, 39.46, 34.04, 31.42, 23.42, 20.97 ppm.

[0920] (Example 24) 1-(benzo[d]thiazol-6-yl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea

[0921] [ka]

[0922] Process 1 6-Isocyanatobenzo[d]thiazole (T1) - under inert atmosphere, NEt 3 To a solution of (161.69 mg, 1.598 mmol, 3 equiv) in anhydrous dichloromethane (6 mL) was added benzo[d]thiazol-6-amine (80 mg, 0.533 mmol, 1 equiv) and the mixture was cooled to 0-5 °C in an ice bath. Triphosgene (79 mg, 0.266 mmol, 0.5 equiv) was added and the mixture was allowed to warm to room temperature. The reaction was monitored by TLC and stopped upon complete consumption of the amine derivative (overnight). The reaction mixture was concentrated in vacuo and then extracted with Et 2 The organic layer was concentrated in vacuo to give the pure isocyanate product T1 (62 mg, 66%), which was of sufficient purity to be used directly in step 3 without further purification.

[0923] Process 2 4-(3-aminobutyl)phenylacetate (T2) - synthesized according to the typical procedure: reductive amination of 4-(4-hydroxyphenyl)butan-2-one derivative - to a solution of anhydrous dichloromethane (8 mL) and TFA (trifluoroacetic acid - 8 mL) was added acetic anhydride (810 mg, 7.93 mmol, 4 equiv.) and 4-(4-hydroxyphenyl)butan-2-aminium chloride (400 mg, 1.98 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred for 4 hours, monitored by TLC and stopped upon complete consumption, then the solution was concentrated by rotary evaporation to give the crude product, which was purified by SCC (dichloromethane / methanol from 95:5 to 50 / 50) to give the pure desired compound T2: 388 mg, 80%. 1 H NMR (300 MHz, CDCl 3 , 20℃), δ = 7.78 (s, NH 3+ ), 7.09 (d, J = 9 Hz, CH Ar ×2), 6.92 (d, J = 9 Hz, CH Ar ×2), 3.14 (m, CH), 2.57 (m, J = 9 Hz, CH 2 ), 2.23 (s, CH 3 ), 1.92 (bs, CH 2 ), 1.70 (bs, CH 2 ), 1.21 (d, J = 6 Hz, CH 3 ) ppm.

[0924] Process 3 4-(3-(3-benzo[d]thiazol-6-yl)ureido)butyl)phenylacetate (T3) - In an oven-dried 25 mL round-bottom flask, under argon at room temperature, add 6-isocyanatobenzo[d]thiazole T1 (62 mg, 0.352 mmol, 1 equiv.), NEt 3(42.7 mg, 0.422 mmol, 1.2 equiv.) and 4-(3-aminobutyl)phenylacetate T2 (80 mg, 0.387 mmol, 1.1 equiv.) were added. The reaction mixture was stirred overnight at room temperature and monitored by TLC and stopped upon complete consumption of the amine derivative. The resulting mixture was solvent evaporated by rotary evaporation and the crude product was purified by SCC (97:3 dichloromethane / methanol) to give pure desired product T3: 55 mg, 40%. 1 H NMR (300 MHz, acetone-d 6, 20℃), δ = 9.15 (s, CH), 8.40 (d, J = 3 Hz, CH Ar ), 8.11 (s, NH), 7.91 (d, J = 9 Hz, CH Ar ), 7.54 (dd, J = 3 Hz, CH Ar ), 7.24 (d, J = 9 Hz, CH Ar ×2), 7.00 (d, J = 9 Hz, CH Ar ×2), 5.81 (d, J = 9 Hz, NH), 3.95 (m, CH), 2.71 (m, CH 2 ), 2.23 (s, CH 3 ), 1.78 (m, CH 2 ), 1.20 (d, J = 9 Hz, CH 3 ) ppm.

[0925] Process 4 1-(benzo[d]thiazol-6-yl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea (24) - A solution of 4-(3-(3-benzo[d]thiazol-6-yl)ureido)butyl)phenylacetate T3 (55 mg, 0.143 mmol, 1 equiv.) in tetrahydrofuran (6 mL) was added to the reaction mixture at room temperature with H 2 LiOH (13.74 mg, 0.574, 4 equiv) in 2 mL of O was added. The reaction was stirred for 24 h. The reaction mixture was then diluted with H 2The biphasic reaction mixture was quenched with O (4 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with MgSO 4 Drying at rt and concentration gave the crude product which was purified by SCC (dichloromethane / methanol from 99:1 to 95:5) to give the pure desired compound 24:31 mg, 63%. 1 H NMR (300 MHz, acetone-d 6, 20℃), δ = 9.16 (s, CH Ar ), 8.40 (s, OH), 8.16 (s, NH), 8.13 (s, CH Ar ), 7.89 (d, J = 6 Hz, CH Ar ), 7.54 (dd, J = 3 Hz, CH Ar ), 7.02 (d, J = 9 Hz, CH Ar x 2), 6.73 (d, J = 9 Hz, CH Ar x 2), 5.81 (d, J = 9 Hz, NH), 3.91 (s, J = 6 Hz, CH), 2.60 (m, CH 2 ), 1.72 (m, CH 2 ), 1.18 (d, J = 6 Hz, CH 3 ) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃), δ = 156.33, 155.86, 155.74, 155.42, 140.65, 133.75, 130.08, 127.10, 122.51, 118.42, 115.97, 112.59, 46.05, 40.29, 32.31, 21.82 ppm. Purity at HPLC λ = 254 nm: 98 %. MS (ESI+): m / z (%) 341.9 (100) [M+H + ].

[0926] (Example 25) 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(quinolin-7-yl)urea

[0927] [ka]

[0928] Process 1 7-Isocyanatoquinoline (U1) - under inert atmosphere, NEt 3 To a solution of quinolin-7-amine (309.9 mg, 0.613 mmol, 5 equiv.) in anhydrous dichloromethane (6 mL) was added quinolin-7-amine (133 mg, 0.613 mmol, 1 equiv.) and cooled to 0-5° C. in an ice bath. Triphosgene (181.8 mg, 0.613 mmol, 1 equiv.) was added and the mixture was allowed to warm to room temperature. Upon complete consumption of the amine derivative (overnight), the reaction was monitored by TLC. The reaction mixture was concentrated in vacuo and then diluted with Et 2 The organic layer was concentrated in vacuo to give the pure isocyanate product U1 (80 mg, 68%) which was of sufficient purity to be used directly in step 3 without further purification.

[0929] Process 2 4-(3-aminobutyl)phenylacetate (U2) - synthesis by typical procedure: reductive amination of 4-(4-hydroxyphenyl)butan-2-one derivative - to a solution of anhydrous dichloromethane (8 mL) and TFA (trifluoroacetic acid - 8 mL) was added acetic anhydride (810 mg, 7.93 mmol, 4 equiv.) and 4-(4-hydroxyphenyl)butan-2-aminium chloride (400 mg, 1.98 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred for 4 h and upon complete consumption was monitored by TLC, the solution was then concentrated by rotary evaporation to give the crude product which was purified by SCC (dichloromethane / methanol from 95:5 to 50 / 50) to give the pure desired product U2: 388 mg, 80%. 1 H NMR (300 MHz, CDCl 3 , 20℃), δ = 7.78 (s, NH 3+), 7.09 (d, J = 9 Hz, CH Ar ×2), 6.92 (d, J = 9 Hz, CH Ar ×2), 3.14 (m, CH), 2.57 (m, J = 9 Hz, CH 2 ), 2.23 (s, CH 3 ), 1.92 (bs, CH 2 ), 1.70 (bs, CH 2 ), 1.21 (d, J = 6 Hz, CH 3 ) ppm.

[0930] Process 3 4-(3-(3-(quinolin-7-yl)ureido)butyl)phenylacetate (U3) - In an oven-dried 25 mL round-bottom flask, under argon atmosphere, at room temperature, a solution of 7-isocyanatoquinoline U1 (80 mg, 0.47 mmol, 1 equiv.), NEt 3 (95.14 mg, 0.94 mmol, 2 equiv.) and 4-(3-aminobutyl)phenylacetate U2 (97.44 mg, 0.47 mmol, 1 equiv.) were added. The reaction mixture was stirred at room temperature overnight and complete consumption of the amine derivative was monitored by TLC. The resulting mixture was solvent evaporated by rotary evaporation and the crude product was purified by SCC (dichloromethane / acetone from 95:5 to 7:3) to give pure desired product U3: 23 mg, 13%. 1 H NMR (300 MHz, acetone-d 6, 20℃), δ = 7.94 (m, CH Ar ), 7.39 (m, CH Ar ×2), 7.22 (m, CH Ar ×3), 7.17 (m, CH Ar ), 6.99 (d, J = 9 Hz, CH Ar ×2), 6.85 (dd, J = 3 Hz, CH Ar ), 5.63 (d, J = 6 Hz, NH), 3.92 (m, CH), 2.70 (m, CH 2), 2.23 (s, CH 3 ), 1.76 (m, CH 2 ), 1.20 (d, J = 9 Hz, CH 3 ) ppm.

[0931] Process 4 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(quinolin-7-yl)urea (25) - A solution of 4-(3-(3-(quinolin-7-yl)ureido)butyl)phenylacetate U3 (23 mg, 0.061 mmol, 1 equiv.) in tetrahydrofuran (6 mL) was added to the reaction mixture at room temperature with H 2 LiOH (5.838 mg, 0.244 mmol, 4 equiv) in 2 mL of O was added. The reaction was stirred for 24 h. The reaction mixture was then diluted with H 2 The biphasic reaction mixture was quenched with O (4 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with MgSO 4 Drying at 40° C. and concentration gave the crude product, which was purified by SCC (petroleum ether / acetone from 9:1 to 7:3) to give the pure desired compound 25:18 mg, 88%. 1 H NMR (300 MHz, acetone-d 6, 20℃), δ = 8.15 (s, NH), 8.09 (s, CH Ar ), 7.31 (dd, J = 3 Hz, CH Ar ), 7.02 (d, J = 6 Hz, CH Ar ×2), 6.73 (m, CH Ar ×3), 6.67 (d, J = 6 Hz, NH), 5.90 (s, CH 2 ), 3.82 (m, CH), 2.58 (m, CH 2 ), 1.70 (m, CH 2 ), 1.14 (d, J = 6 Hz, CH 3 ) ppm. 13 C NMR (75 MHz, acetone-d 6, 20℃), δ = 156.39, 155.53, 142.88, 136.17, 133.77, 130.13, 129.02, 121.28, 120.88, 116.01, 115.01, 46.11, 40.29, 32.35, 21.83 ppm. Purity at HPLC λ = 254 nm: 99 %. MS (ESI+): m / z (%) 335.9 (100) [M+H + ].

[0932] (Example 26) 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(2-methylnaphthalen-1-yl)urea

[0933] [ka]

[0934] Process 1 1-(4-(4-Methoxyphenyl)butan-2-yl)-3-(2-methylnaphthalen-1-yl)urea (V1) - Following typical procedure 14 using 1-(3-isocyanatobutyl)-4-methoxybenzene (50 mg, 0.244 mmol, 1 equiv.) and 2-methylnaphthalen-1-amine (38.2 mg, 0.244 mmol, 1 equiv.). The crude product was purified by SCC (7:3 petroleum ether / acetone) with solid deposition to give the pure desired product V1: 40 mg, 45%. 1 H NMR (300 MHz, CDCl 3 , 20℃), δ = 8.08 (d, J = 9 Hz, CH Ar ), 7.82 (m, CH Ar ×2), 7.51 (m, CH Ar ×2), 7.41 (d, J = 6 Hz, CH Ar ), 6.96 (d, J = 9 Hz, CH Ar ×2), 7.76 (d, J = 6 Hz, CH Ar×2), 6.06 (s, NH), 3.99 (m, CH), 3,76 (s, CH 3 ), 2.50 (s, CH 3 ), 2.45 (m, CH 2 ), 1.52 (m, CH 2 ), 1.03 (d, J = 9 Hz, CH 3 ) ppm.

[0935] Process 2 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(2-methylnaphthalen-1-yl)urea (26) - 1-(4-(4-methoxyphenyl)butan-2-yl)-3-(2-methylnaphthalen-1-yl)urea (40 mg, 0.110 mmol, 1 equiv.) and BBr 3 (110.58 mg, 0.441 mmol, 4 equiv.) was used following typical procedure 6. The crude product was purified by SCC using solid deposition and gradient elution (dichloromethane / methanol from 99:1 to 95:5) to give the pure desired compound 26:37 mg, 96%. 1 H NMR (300 MHz, acetone-d 6 , 20℃), δ = 8.24 (s, NH), 8.04 (d, J = 9 Hz, NH), 7.80 (d, J = 6 Hz, CH Ar ), 7.60 (t, J = 6 Hz, CH Ar ×2), 7.42 (m, CH Ar x 2), 7.29 (d, J = 9 Hz, CH Ar ), 6.99 (d, J = 9 Hz, CH Ar ×2), 6.73 (d, J = 9 Hz, CH Ar ×2), 5.88 (s, OH), 3.87 (m, CH), 2.55 (m, J = 6 Hz, CH 2 ), 2.40 (s, CH 3 ), 1.64 (m, CH 2 ), 1.11 (d, J = 6 Hz, CH 3) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃), δ = 156.95, 156.30, 133.92, 133.04, 130.10, 129.74, 128.68, 126.87, 125.85, 124.00, 115.94, 46.18, 40.39, 32.39, 22.00, 18.80 ppm. Purity at HPLC λ = 254 nm: 100%. MS (ESI+): m / z (%) 348.9 (100) [M+H + ].

[0936] (Example 27) 1-(2-(tert-butyl)phenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea

[0937] [ka]

[0938] Process 1 1-(4-(4-(benzyloxy)phenyl)butan-2-yl)-3-(2-(tert-butyl)phenyl)urea (W1) - Following typical procedure 14 using 1-(benzyloxy)-4-(3-isocyanatobutyl)benzene (70 mg, 0.249 mmol, 1 equiv.) and 2-(tert-butyl)aniline (40.84 mg, 0.273 mmol, 1.1 equiv.). The crude product was purified by SCC (8:2 petroleum ether / acetone) with solid deposition to give the pure desired product W1: 88 mg, 82%. 1 H NMR (300 MHz, acetone-d 6 , 20℃), δ = 7.47 (m, CH Ar ×2), 7.37 (m, CH Ar ×5), 7.12 (m, CH Ar ×4), 6.92 (m, CH Ar ×2), 6.83 (m, CHAr ), 5.82 (d, J = 9 Hz, NH), 5.07 (s, CH 2 ), 3.89 (m, CH), 2.63 (m, CH 2 ), 1.71 (m, CH 2 ), 1.41 (s, CH 3 ×3), 1.14 (d, J = 6 Hz, CH 3 ) ppm.

[0939] Process 2 1-(2-(tert-butyl)phenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea (27) - A mixture of 1-(4-(4-(benzyloxy)phenyl)butan-2-yl)-3-(2-(tert-butyl)phenyl)urea W1 (88 mg, 0.204 mmol, 1 equiv.) and Pd / C (10% by weight) in MeOH (10 mL) was evacuated and filled with hydrogen gas via a balloon. The mixture was stirred at room temperature for 2 h. The Pd / C was removed by vacuum filtration through Celite and the Celite layer was washed with MeOH (10 mL x 3). The mixture was concentrated to give the crude product which was purified by SCC using solid deposition and gradient elution (99:1 to 95:5 dichloromethane / methanol) to give the pure desired compound 27: 65 mg, 93%. 1 H NMR (300 MHz, CDCl 3 , 20℃), δ = 7.6 (s, NH), 7.16 (m, CH Ar ×2), 7.07 (m, CH Ar ), 6.88 (d, J = 9 Hz, CH Ar ×2), 6.70 (d, J = 9 Hz, CH Ar ×2), 6.06 (s, NH), 3.88 (m, CH), 2.44 (m, J = 6 Hz, CH 2 ), 1.56 (m, CH 2 ), 1.32 (s, CH 3 ×3), 1.02 (d, J = 6 Hz, CH3 ) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃), δ = 155.94, 155.46, 144.17, 137.15, 132.90, 129.89, 129.15, 126.23, 125.14, 115.08, 45.29, 39.51, 34.52, 31.47, 30.18, 21.11 ppm. Purity at HPLC λ = 254 nm: 100%. MS (ESI+): m / z (%) 341.0 (100) [M+H + ].

[0940] (Example 28) 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea

[0941] [ka]

[0942] 4-(4-Methoxyphenyl)butan-2-amine (W1) - 4-(4-Methoxyphenyl)butan-2-one (5 g, 28.05 mmol, 1 eq.) and ammonium acetate (12.97 g, 168.3 mmol, 6 eq.) were added to a 250 mL round bottom flask charged with methanol (150 mL) and the reaction mixture was stirred at room temperature for 30 min. The temperature was then lowered to 0° C. using an ice bath and sodium cyanoborohydride (2.64 g, 42.07 mmol, 1.5 eq.) was added in small portions. The ice batch was then removed and the reaction was stirred overnight at room temperature. TLC monitoring showed complete consumption of the starting material and the reaction was subsequently quenched at 0° C. by adding HCl 1M (200 mL). After stirring for 15 min, the reaction mixture was concentrated by rotary evaporation to remove most of the methanol, then extracted with diethyl ether (2×100 mL). The aqueous layer was separated and made basic by adding concentrated NaOH until pH≧10, then sodium chloride was added until saturated, then extracted with DCM (3×100 mL). The combined organic layers were washed with anhydrous MgSO 4 The mixture was dried at 37° C. for 1 hour, filtered, evaporated to dryness by rotary evaporation, and the residue was dried under high vacuum to give 4.2 g of crude product W1 (83% yield, average 80-85% yield). The crude product W1 was pure enough to be used without further purification, but if necessary, purification can be carried out by silica gel column chromatography using gradient elution (100:0-90:10 DCM / MeOH).

[0943] [ka]

[0944] 1 H NMR (300.16 MHz, CDCl 3 , 20℃): δ = 7.10 (dt, 2H, CH 7,8); 6.82 (dt, 2H, CH 9,10); 3.78 (s, 3H, CH 312); 2.90 (h, 1H, CH 2); 2.60 (qdd, 2H, CH 2 5); 1.62 (m, 2H, CH 2 4); 1.10 (d, 3H, CH 3 1) ppm. 13 C NMR (75.47 MHz, CDCl 3 , 20℃): δ = 157.86 (C 11); 134.51 (C 6); 129.32 (CH 9,10); 113.93 (CH 7,8); 55.40 (CH 3 12); 46.65 (CH2); 42.24 (CH 2 4); 32.05 (CH 2 5); 24.21 (CH 3 1) ppm.

[0945] 4-Nitrophenyl(2,5-dimethylphenyl)carbamate (W2) - To a 250 mL round bottom flask charged with dry EtOAc (100 mL) under argon atmosphere, 4-nitrophenyl chloroformate (2.0 g, 9.9 mmol, 1.1 equiv), potassium carbonate (1.37 g, 9.9 mmol, 1.1 equiv) and 2,5-dimethylaniline (1.12 mL, 9.0 mmol, 1 equiv) were added successively. The reaction was stirred at room temperature and followed by TLC. After 2 h, the reaction mixture was diluted with EtOAc (100 mL), transferred to a separatory funnel and washed successively with 1 M citric acid (100 mL), saturated sodium carbonate (100 mL) and brine (100 mL). The organic layer was separated using anhydrous MgSO 4 The mixture was dried at rt, filtered, evaporated to dryness by rotary evaporation, and the residue dried under high vacuum to give 1.9 g of W2 (74% yield) as a pale beige solid which was used without further purification.

[0946] [ka]

[0947] 1H NMR (300.16 MHz, CDCl 3 , 20℃): δ = 8.29 (dt, 2H, CH 14,15); 7.64 (bs, 1H, NH 9); 7.41 (dt, 2H, CH 12,13); 7.11 (d, 1H, CH 3); 6.93 (d, 1H, CH 4); 6.78 (bs, 1H, CH 7); 2.32 (d, 6H, CH 3 1,6) ppm.

[0948] 1-(2,5-Dimethylphenyl)-3-(4-(4-Methoxyphenyl)butan-2-yl)urea (W3) - To a 25 mL round bottom flask charged with dry DCM (12 mL) under argon atmosphere was added 4-nitrophenyl(2,5-dimethylphenyl)carbamate W2 (639 mg, 2.231 mmol, 1 equiv) and triethylamine (311 μL, 2.231 mmol, 1 equiv), followed by 4-(4-methoxyphenyl)butan-2-amine W1 (400 mg, 2.231 mmol, 1 equiv). The reaction was stirred at room temperature and TLC monitoring showed complete conversion after 1 h. The reaction mixture was then concentrated to dryness by rotary evaporation and the solid residue was triturated and sonicated in diisopropyl ether (10 mL) and then filtered. The solid was collected, resuspended in cold water (10 mL), sonicated, and then filtered (two replicates). Finally, the solid was collected and dried under high vacuum to give 564 mg of W3 (77% yield) as an off-white solid that was used without further purification.

[0949] [ka]

[0950] 1 H NMR (300.16 MHz, DMSO-d 6, 20℃): δ = 7.81 (s, 1H, NH 9); 7.67 (s, 1H, CH 8); 7.12 (dt, 2H, CH 17,18); 6.95 (d, 2H, CH 3,4); 6.83 (dt, 2H, CH 19, 20); 6.64 (d, 1H, NH 11); 3.70 (s, 3H, CH 3 22); 3.55 (m, 1H, CH 12); 2.56 (m, 2H, CH2 15); 2.20 (s, 3H, CH 3 1); 2.14 (s, 3H, CH 3 6); 1.64 (septet, 2H, CH 2 14); 1.08 (d, 3H, CH 3 13) ppm. Purity at HPLC λ = 210 nm: 98.9%. MS (ESI+): m / z (%) 327.3 (100) [M+H + ].

[0951] 1-(2,5-Dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea (28, Z4P) - To a 100 mL round bottom flask charged with dry DCM (30 mL) under argon atmosphere was added 1-(2,5-dimethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea W3 (300 mg, 0.92 mmol, 1 equiv). After cooling to 0° C., boron tribromide (1M in DCM, 4.6 mL, 5 equiv) was added slowly over several minutes. The reaction mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred overnight. TLC monitoring indicated complete consumption of starting material and the reaction was quenched by addition of ice (20 g) and stirred for 30 min before being transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with DCM (2×40 mL) and EtOAc (2×40 mL). The combined organic layers were washed with anhydrous MgSO 4The mixture was dried at 40° C., filtered, evaporated to dryness by rotary evaporation, and the residue was dried under high vacuum to give 258 mg of crude product. 50 mg of the crude product was purified by silica gel column chromatography (3 g silica, ratio 1:60) with solid loading and isocratic elution (75:25 PE / acetone) to give 47 mg of compound 28 (Z4P) as a white powder.

[0952] [ka]

[0953] 1 H NMR (300.16 MHz, acetone-d 6 , 20℃): δ = 8.10 (bs, 1H, OH 22); 7.80 (s, 1H, NH 9); 7.09 (s, 1H, CH 8); 7.03 (dt, 2H, CH 17,18); 6.97 (d, 1H, CH 4); 6.74 (dt, 2H, CH 19,20); 6.69 (d, 1H, CH 3); 5.92 (d, 1H, NH 11); 3.87 (septet, 1H, CH 12); 2.60 (m, 2H, CH 2 15); 2.24 (s, 3H, CH 3 1); 2.15 (s, 3H, CH 3 6); 1.71 (m, 2H, CH 2 14); 1.16 (d, 3H, CH 3 13) ppm. 13 C NMR (75.47 MHz, (CD 3 ) 2 136.3 (C 2); 133.8 (C 7); 130.7 (CH 4); 130.1 (CH 17,18); 124.8 (C 5); 123.7 (CH 3); 122.5 (C 8); 115.92 (CH 19,20); 46.0 (CH 12); 40.4 (CH2 14); 32.3 (CH 2 15); 21.8 (CH 3 13); 21.3 (CH 3 1); 17.7 (CH 3 6) ppm. Purity at HPLC λ = 254 nm: 100%. MS (ESI+): m / z (%) 313.2 (100) [M+H + ].

[0954] Chiral HPLC Separation - Chiral preparative HPLC separation was performed on an Agilent 1260 Infinity unit (pump G1311C, autosampler G1329B, DAD G1365D and fraction collector G1364C) and monitored by Agilent OpenLAB CDS Chemstation LC. Samples were dissolved in a mixture of ethanol and hexane (50 / 50) and eluted on a Chiralpak ID (250 x 10 mm) column with hexane / ethanol / dichloromethane (80 / 10 / 10) as mobile phase (flow rate = 5 mL / min, UV detection at 254 nm) to give two enantiomers (RT A = 7.28 min and RT B = 9.12 min) was obtained.

[0955] Spontaneous Optical Rotation Measurements - The absolute stereochemistry of enantiomers A and B was determined by measuring their spontaneous optical rotations and comparing them to the enantiomer of compound 28 of known stereochemistry Z4P-R (in-house synthesis). Measurements were performed on a Perkin Elmer polarimeter 341 at 20°C using 0.5 mg / mL solutions of enantiomer A, enantiomer B and Z4P-R in acetonitrile with a sodium lamp (589 nm) and a 1-dm path. Results are the average of three measurements (1 s integration time). Enantiomer A: average optical rotation -0.023°, [α] D =-46; Enantiomer B: average optical rotation +0.021°, [α] D =+42;Z4P-R: Average optical rotation +0.023°, [α] D= + 46. Enantiomer A = compound S-28 and Enantiomer B = compound R-28.

[0956] [ka]

[0957] (Example 29) 1-(2,5-dimethylphenyl)-3-(4-phenylbutan-2-yl)urea

[0958] [ka]

[0959] 1-(2,5-Dimethylphenyl)-3-(4-phenylbutan-2-yl)urea (29) - To a 5 mL round bottom flask charged with dry DCM (2 mL) under argon atmosphere was added 4-nitrophenyl(2,5-dimethylphenyl)carbamate (96 mg, 0.335 mmol, 1 equiv.) and triethylamine (47 μL, 0.335 mmol, 1 equiv.) followed by 4-phenylbutan-2-amine (50 mg, 0.335 mmol, 1 equiv.). The reaction was stirred at room temperature and TLC monitoring showed complete conversion after 1 h. The reaction mixture was then concentrated to dryness by rotary evaporation and the solid residue was triturated and sonicated in diisopropyl ether (8 mL), filtered and rinsed with diisopropyl ether (4 mL). The solid was collected, resuspended in cold water (4 mL), sonicated, then filtered and rinsed with cold water (2 x 2 mL). Finally, the solid was collected and dried under high vacuum to give compound 29, 84 mg, 85% yield, in excellent purity. Purity at HPLC λ = 254 nm: 97.4%. MS (ESI+): m / z (%) 297.2 (100) [M+H + ]. 1 H NMR (300 MHz, acetone-d 6, 20℃), δ (ppm) = 7.81 (d, J = 1.8 Hz, 1H), 7.32 - 7.11 (m, 5H), 7.09 (s, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.70 (dd, J = 7.5, 1.8 Hz, 1H), 5.93 (d, J = 8.2 Hz, 1H), 3.99 - 3.79 (m, 1H), 2.79 - 2.59 (m, 2H), 2.25 (s, 3H), 2.16 (s, 3H), 1.76 (m, 2H), 1.17 (d, J = 6.6 Hz, 3H) ppm. 13 C NMR (75 MHz, acetone-d 6 , 20℃), δ (ppm) = 155.81, 143.25, 136.34, 130.70, 129.20 (3C), 129.14 (3C), 126.50, 123.65, 46.03, 40.06, 33.22, 21.82, 21.35, 17.69 ppm.

[0960] (Example 30) 1-(2,5-dimethylphenyl)-3-(4-hydroxyphenethyl)urea

[0961] [ka]

[0962] 1-(2,5-Dimethylphenyl)-3-(4-hydroxyphenethyl)urea (30) - 2,5-Dimethylaniline (1,458 mmol, 1.0 equiv, 0.18 mL) and 4-(2-aminoethyl)phenol (1.458 mmol, 1.0 equiv, 200 mg) as the primary amine were reacted according to typical procedure 5. The crude was purified by SCC (100% DCM to 98 / 2 DCM / MeOH) to give compound 30, 297 mg, yield: 71.6%.

[0963] Fractions of the crude mixture (10-20 mg) were purified by semi-preparative HPLC to give sufficient pure compound for identification and biological assays.

[0964] [ka]

[0965] 1 H NMR (300 MHz, DMSO-d 6 , 20℃), δ = 9.17 (s, 1H), 7.63 (d, 1H), 7.55 (s, 1H), 7.05 - 6.99 (m, 2H, 1), 6.97 (d, 1H), 6.73 - 6.65 (m, 3H), 6.46 (t, 1H), 3.30 - 3.22 (m, 2H), 2.62 (t, 2H), 2.21 (s, 3H), 2.10 (s, 3H) ppm. 13 C NMR (75 MHz, DMSO-d 6 , 20℃), δ = 155.61, 155.29, 137.95, 134.82, 129.77, 129.58, 129.48, 123.65, 122.47, 121.24, 115.10, 40.95, 35.03, 20.91, 17.43 ppm. HRMS (M+H) + Calculated value: 285.1597 - Measured value: 285.1573.

[0966] Example 31: N-(2,5-dimethylphenyl)-4-(3-hydroxyphenyl)piperazine-1-carboxamide

[0967] [ka]

[0968] Process 1 N-(2,5-dimethylphenyl)-4-(3-methoxyphenyl)piperazine-1-carboxamide (Z1) - Following typical procedure 5 using 2-isocyanato-1,4-dimethylbenzene (0.219 mmol, 1.0 equiv, 32 mg) and 1-(3-methoxyphenyl)piperazine hydrochloride (0.219 mmol, 1.0 equiv, 50 mg) in dry DCM (3 mL), followed by triethylamine (0.219 mmol, 1.0 equiv, 30 μL). The mixture was stirred at room temperature overnight. The precipitate was filtered and washed with cold DCM to give Z1, 47 mg, yield: 63%.

[0969] [ka]

[0970] 1 H NMR (400 MHz, DMSO-d 6 , 20℃), δ = 8.05 (s, 1H), 7.13 (t, 1H), 7.08 - 6.99 (m, 2H), 6.89 - 6.82 (m, 1H), 6.57 (ddd, 1H), 6.50 (t, 1H), 6.40 (ddd, 1H), 3.73 (s, 3H), 3.56 (t, 4H), 3.15 (t, 4H), 2.23 (s, 3H), 2.11 (s, 3H) ppm. 13 C NMR (101 MHz, DMSO-d 6 , 20℃), δ = 160.20, 155.60, 152.34, 137.62, 134.65, 129.91, 129.83, 129.64, 126.63, 125.25, 108.36, 104.55, 101.89, 54.89, 48.30, 43.74, 20.51, 17.50 ppm.

[0971] Process 2 N-(2,5-dimethylphenyl)-4-(3-hydroxyphenyl)piperazine-1-carboxamide (31) - Typical procedure 6 was followed using N-(2,5-dimethylphenyl)-4-(3-methoxyphenyl)piperazine-1-carboxamide Z1 (74 μmol, 1.0 equiv, 25 mg) in dry DCM (2 mL). The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and fractions (10-20 mg) of the crude mixture were purified by semi-preparative HPLC to give pure compound 31 in sufficient quantity for identification and biological assays.

[0972] [ka]

[0973] 1 H NMR (400 MHz, DMSO-d 6 , 20℃), δ = 9.14 (s, 1H, OH 19), 8.04 (s, 1H, NH 9), 7.02 (t, J = 8.0 Hz, 1H, CH 15), 7.03 (d, J = 2.0 Hz, 1H, CH 8), 7.02 (d, J = 2.0 Hz, 1H, CH 4), 6.89 - 6.82 (dd, J = 8.0, 2.0 Hz, 1H, CH 3), 6.42 (dd, J = 8.0, 2.2 Hz, 1H, CH 16), 6.34 (t, J = 2.2 Hz, 1H, CH 18), 6.24 (dd, J = 8.0, 2.2 Hz, 1H, CH 14), 3.56 (t, J = 5.0 Hz, 4H, CH 2 12), 3.10 (t, J = 5.0 Hz, 4H, CH 2 11), 2.23 (s, 3H, CH 3 1), 2.11 (s, 3H, CH 3 6) ppm. 13 C NMR (101 MHz, DMSO-d 6, 20℃), δ = 158.10, 155.60, 152.34, 137.62, 134.64, 129.89, 129.82, 129.55, 126.60, 125.23, 106.95, 106.52, 102.80, 48.37, 43.76, 20.51, 17.50 ppm. HRMS (M+Na) + Calculated value: 348.16825 - Measured value: 348.1683. Purity at HPLC λ = 254 nm: 99%. MS (ESI+): m / z (%) 326.0 (63) [M+H + ].

[0974] (Example 32) 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(p-tolyl)urea

[0975] [ka]

[0976] Process 1 1-(4-(4-Methoxyphenyl)butan-2-yl)-3-(p-tolyl)urea (AA1) - Followed typical procedure 13 part 2 using 1-(3-isocyanatobutyl)-4-methoxybenzene (50 mg, 0.244 mmol, 1 equiv.) and p-toluidine (26.04 mg, 0.244 mmol, 1 equiv.). The crude product was purified by SCC (75:25 petroleum ether / acetone) using solid deposition to give the pure desired product AA1: 40 mg, 52%. 1 H NMR (300 MHz, acetone-d 6 , 20 ℃), δ = 7.67 (s, NH), 7.35 (d, J = 9 Hz, CH Ar ×2), 7.13 (d, J = 9 Hz, CH Ar ×2), 7.03 (d, J = 9 Hz, CH Ar ×2), 6,82 (d, J = 9 Hz, CHAr ×2), 5,59 (d, J = 9 Hz, NH), 3.86 (m, CH), 3.74 (s, CH 3 ), 2.52 (m, CH 2 ), 2.23 (s, CH 3 ), 1.73 (m, CH 2 ), 1.15 (d, J = 6 Hz, CH 3 ) ppm.

[0977] Process 2 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(p-tolyl)urea (32) - 1-(4-(4-methoxyphenyl)butan-2-yl)-3-(p-tolyl)urea AA1 (40 mg, 0.128 mmol, 1 equiv.) and BBr 3 (192.46 mg, 0.768 mmol, 6 equiv.) was used following typical procedure 6. The crude product was purified by SCC using solid deposition and gradient elution (dichloromethane / methanol from 99:1 to 95:5) to give the pure desired compound 32:38 mg, 97%. 1 H NMR (300 MHz, acetone-d 6 , 20℃), δ = 8.1 (s, NH), 7.68 (s, OH), 7.3 (d, J = 9 Hz, CH Ar ×2), 7.01 (dd, J = 9 Hz, CH Ar ×2), 6.74 (d, J = 9 Hz, CH Ar ×2), 5.59 (d, J = 9 Hz, NH), 3.86 (m, J = 9 Hz, CH), 2.58 (m, CH 2 ), 2.23 (s, CH 3 ), 1.68 (m, CH 2 ), 1.15 (d, J = 6 Hz, CH 3 ) ppm. 13 C NMR (75 MHz, acetone-d 6, 20℃), δ = 155.42, 154.90, 138.31, 132.88, 130.26, 129.17, 118.15, 115.06, 45.04, 39.44, 31.41, 20.96, 19.78 ppm.

[0978] (Example 39) 1-(2,5-dimethylbenzyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea Process 1 1-(2,5-Dimethylbenzyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea (AB1) - 2,5-Dimethylphenyl)methanamine (0.75 mmol, 1.0 equiv, 0.1 mL) and 4-(4-methoxyphenyl)butan-2-amine W1 (0.75 mmol, 1.0 equiv, 101 mg) were used following typical procedure 5Bis. The crude product was purified by SCC (DCM / Et 2 O-80:20) to give 1-(2,5-dimethylbenzyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea AB1, 135 mg, yield: 53% as a white solid. 1 H NMR (300MHz, chloroform-d 1 , 20℃), δ (ppm): 7.04 - 6.98 (m, 4H), 6.94 - 6.91 (m, 1H), 6.78 - 6.75 (m, 2H), 5.15 (s, 1H), 4.95 (s, 1H), 4.20 (s, 2H), 3.76 - 3.66 (m, 1H), 3.75 (s, 3H), 2.57 - 2.50 (m, 2H), 2.23 (s, 3H), 2.21 (s, 3H) 1.66 - 1.58 (m, 2H), 1.08 (d, 3H). 13 C NMR (75MHz, chloroform-d 1 , 20℃), δ (ppm): 158.2, 157.8, 136.9, 135.5, 134.2, 133.0, 130.3, 129.2, 128.8, 128.0, 113.8, 55.3, 45.8, 42.5, 39.6, 31.6, 30.9, 21.8, 21.0, 18.5.

[0979] Process 2 1-(2,5-Dimethylbenzyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea (39) - 1-(2,5-Dimethylbenzyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea AB1 (0.159 mmol, 1.0 equiv, 54 mg) as the methoxy-protected urea in DCM (3 mL) with BBr 3 (1M in DCM, 0.635 mmol, 4.0 equiv, 0.635 mL) was used as in typical procedure 6. The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM. The solvent was removed and the SCC (DCM / Et 2 Purification by HPLC (HPLC: 0-60:40) gave 1-(2,5-dimethylbenzyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea 15, 38 mg, yield: 73%. Fractions of the crude mixture (10-20 mg) were purified by semi-preparative HPLC to give sufficient pure compound for identification and biological assays.

[0980] [ka]

[0981] 1 H NMR (300MHz, chloroform-d 1, 20℃), δ (ppm): 8.06 (s, 1H, OH 21), 7.09 (d, J = 1.9 Hz, 1H, CH 1), 7.06 - 7.00 (m, 2H, CH 18), 7.02 (d, J = 7.9 Hz, 1H, CH 5), 6.93 (dd, J = 7.6, 1.9 Hz, 1H, CH 4), 6.75 - 6.70 (m, 2H, CH 19), 5.57 (t, 1H, NH 10), 5.39 - 5.36 (d, J = 8.4 Hz, 1H, NH 12), 4.35 - 4.22 (m, 2H, CH 2 9), 3.88 - 3.74 (m, 1H, CH 13), 2.60 - 2.53 (m, 2H, CH 2 16), 2.25 (s, 3H, CH 3 ), 2.24 (s, 3H, CH 3 ), 1.71 - 1.63 (m, 2H, CH 2 15), 1.11 (d, J = 6.5 Hz, 3H, CH 3 14). 13 C NMR (75MHz, クロロホルム-d 1 , 20℃), δ (ppm): 158.5 (COH 20), 156.3 (CO 11), 139.2 (C 8), 135.8 (CH 4), 133.9 (C 2), 133.5 (C 6), 130.8 (CH 5), 130.1 (CH 18), 129.3 (C 17), 128.2 (CH 1), 115.9 (CH 19), 46.1 (CH 13), 42.4(CH 2 9), 40.6 (CH 2 15), 32.3 (CH 2 16), 22.1 (CH 3 3), 21.1 (CH 3 14), 18.5 (CH 3 7). HRMS (ESI+): m / z C 20 H 26 N 2 O 2 Na+ (M+Na) + Calculated value 349.18865; measured value 349.18860. Purity at HPLC λ = 254 nm: 74% (general conditions, R t = 17.13 minutes). MS (ESI+): m / z (%) 327.1 (100) [M+H + ].

[0982] (Example 40) 1-(2,5-dimethylphenyl)-3-(3-(3-hydroxyphenyl)prop-2-yn-1-yl)urea 1-(2,5-Dimethylphenyl)-3-(3-(3-hydroxyphenyl)prop-2-yn-1-yl)urea (40) - Typical procedure 2 was followed using 1-(2,5-dimethylphenyl)-3-(prop-2-yn-1-yl)urea D1 (0.227 mmol, 1.0 equiv, 46 mg) as the alkyne derivative and 3-iodophenol (0.227 mmol, 1.0 equiv, 50 mg) as the iodine derivative. The mixture was stirred overnight. The solution was diluted with H 2 Dilute with 20O (4 mL), extract twice with EtOAc, wash with brine, and rinse with MgSO 4 The organic layer was filtered and concentrated under vacuum. The crude was triturated with DiPE and filtered to give crude 1-(2,5-dimethylphenyl)-3-(3-(3-hydroxyphenyl)prop-2-yn-1-yl)urea 40, 52 mg. A fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give sufficient pure compound as a white solid for identification and biological assays.

[0983] [ka]

[0984] 1 H NMR (300MHz, acetone-d 6, 20 °C), δ (ppm): 8.60 (s, 1H, OH 21), 7.76 (d, J = 2.0 Hz, 1H, CH 8), 7.30 (s, 1H, NH 9), 7.17 (t, J = 8.1 Hz, 1H, CH 17), 7.00 (d, J = 7.6 Hz, 1H, CH 4), 6.89 (ddd, J = 8.2, 2.4, 1.2 Hz, 1H, CH 18), 6.87 (t, J = 2.4 Hz, 1H, CH 20), 6.83 (ddd, J = 8.2, 2.4, 1.2 Hz, 1H, CH 16), 6.74 (dd, J = 7.6, 2.0 Hz, 1H, CH 3), 6.38 (t, J = 5.5 Hz, 1H, NH 11), 4.23 (d, J = 5.5 Hz, 2H, CH 2 12), 2.25 (s, 3H, CH 3 1), 2.18 (s, 3H, CH 3 6). 13 C NMR (75 MHz, acetone-d 6 , 20 °C), δ (ppm): 156.9 (COH 19), 154.8 (CO 10), 137.8 (C 5), 135.5 (C 2), 129.9 (CH 4), 129.6 (CH 17), 124.5 (C 7), 124.1 (C 15), 123.3 (CH 3), 122.8 (CH 16), 122.0 (CH 8), 118.0 (CH 20), 115.8 (CH 18), 86.5 (CC 14), 81.8 (CC 13), 29.7 (CH 2 12), 20.4 (CH 3 1), 16.8 (CH 3 6). HRMS (ESI+): m / z C 18 H 18 N 2 O 2 Na + (M + Na) + calculated value 317.12605; measured value 317.12580. Purity at HPLC λ = 254 nm: 99% (general conditions, R t = 18.90 minutes). MS (ESI+): m / z (%) 295.2 (100) [M+H + ].

[0985] (Example 41) 1-(2,5-dimethylphenyl)-3-(4-(3-hydroxyphenyl)but-3-yn-2-yl)urea Process 1 But-3-yn-2-yl methanesulfonate (AC1) - Triethylamine (21.40 mmol, 1.5 equiv, 2.98 mL) was added to a solution of but-3-yn-2-ol (14.27 mmol, 1.0 equiv, 1.129 mL, 1.0 g) in DCM (10 mL). The resulting solution was cooled to 0° C. and mesyl chloride (17.12 mmol, 1.2 equiv, 1.33 mL, 1.96 g) was added dropwise. The mixture was allowed to reach ambient temperature and stirred for 4 h. DCM (10 mL) and H 2 O (10 mL) was added, the organic layer was separated, washed with brine (10 mL), dried and concentrated to give crude but-3-yn-2-yl methanesulfonate, 2.17 g, yield: 68%. The product was used in the next step without purification.

[0986] [ka]

[0987] 1 H NMR (300MHz, chloroform-d 1 , 20℃), δ (ppm): 5.29 (qd, J = 6.7, 2.2 Hz, 1H), 3.12 (s, 3H), 2.70 (d, J = 2.2 Hz, 1H), 1.66 (d, J = 6.7 Hz, 3H). 13 C NMR (75MHz, chloroform-d 1 , 20℃), δ (ppm): 80.3, 76.4, 67.6, 39.3, 22.6.

[0988] Process 2 But-3-yn-2-amine hydrochloride (AC2) - But-3-yn-2-yl methanesulfonate AC1 (14.62 mmol, 1.0 equiv, 2.16 g) was dissolved in aqueous NH 3 (5.3 mL) for 18 h. The resulting mixture was diluted with DCM (10 mL) and HO (10 mL), and the organic layer was separated and washed with MgSO 4 The organic layer was placed at reflux for 2 hours and 30 minutes until the vapor above the double condenser no longer gave a positive alkali test. After adding 4N HCl in dioxane, the solution was stirred for 24 hours, filtered, and then extracted with cold Et 2 Washing with O afforded but-3-yn-2-amine hydrochloride AC2, 445 mg, yield: 29% as an impure white solid.

[0989] [ka]

[0990] 1 H-NMR (300MHz, DMSO-d 6 , 20℃), δ (ppm): 8.63 (s, 3H), 4.24 (s, 1H), 3.66 (d, 1H, J = 2.1 Hz), 1.42 (d, 3H, J = 6.9 Hz).

[0991] Process 3 1-(But-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea (AC3) - Impure but-3-yn-2-amine hydrochloride AC2 (0.947 mmol, 1.0 equiv, 100 mg) in dry DCM (5 mL) was added. Dry triethylamine (0.974 mmol, 1.0 equiv, 0.133 μL) was added and the resulting solution was filtered under argon using a syringe and filter adapter to remove non-soluble powder. Following typical procedure 5, 2-isocyanato-1,4-dimethylbenzene (0.947 mmol, 1.0 equiv, 139 mg) in dry DCM (2 mL) was added. The resulting precipitate was filtered to give 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea AC3, 105 mg, yield: 51%, as a pale white solid. Melting point: 200 °C.

[0992] [ka]

[0993] 1 H-NMR (300MHz, DMSO-d 6 , 20℃), δ (ppm): 7.67 (d, J = 1.8 Hz, 1H), 7.55 (s, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.69 (dd, J = 7.6, 1.8 Hz, 1H), 4.55 - 4.39 (dtd, J = 7.9, 6.9, 2.3 Hz, 1H), 3.22 (d, J = 2.3 Hz, 1H), 2.21 (s, 3H), 2.11 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H). 13 C NMR (75MHz, DMSO-d 6 , 20℃), δ (ppm): 154.2, 137.7, 135.0, 129.9, 123.4, 122.7, 120.8, 85.8, 72.3, 36.5, 22.5, 21.0, 17.5.

[0994] Process 4 1-(2,5-Dimethylphenyl)-3-(4-(3-hydroxyphenyl)but-3-yn-2-yl)urea (41) - Typical procedure 2 was followed using 1-(but-3-yn-2-yl)-3-(2,5-dimethylphenyl)urea AC3 (0.227 mmol, 1.0 equiv, 46 mg) as the alkyne derivative and 3-iodophenol (0.227 mmol, 1.0 equiv, 50 mg) as the iodine derivative. The mixture was stirred overnight. The solution was diluted with H 2 Dilute with 2×O (3 mL), extract with EtOAc (2×3 mL), wash with brine (3 mL), and add MgSO 4 The mixture was dried at rt. The organic layer was filtered and concentrated under vacuum. The crude was triturated with DiPE and filtered to give crude 1-(2,5-dimethylphenyl)-3-(4-(3-hydroxyphenyl)but-3-yn-2-yl)urea 41, 55 mg. A fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give sufficient pure compound as a white solid for identification and biological assays.

[0995] [ka]

[0996] 1 H NMR (300MHz, acetone-d 6, 20℃), δ (ppm): 8.62 (s, 1H, OH 22), 7.80 (d, J = 2.1 Hz, 1H, CH 8), 7.22 (s, 1H, NH 9), 7.17 (t, J = 8.1 Hz, 1H, CH 18), 6.99 (d, J = 7.6 Hz, 1H, CH 4), 6.88 (ddd, J = 8.1, 2.4, 1.1 Hz, 1H, CH 19 / 17), 6.86 (t, J = 2.4 Hz, 1H, CH 21), 6.83 (ddd, J = 8.1, 2.4, 1.1 Hz, 1H, CH 19 / 17), 6.73 (d, J = 7.6, 2.1 Hz, 1H, CH 3), 6.46 (d, J = 8.1 Hz, 1H, NH 11), 4.90 (dq, J = 8.1, 6.9 Hz, 1H, CH 12), 2.25 (s, 3H, CH 3 1), 2.17 (s, 3H, CH 3 6), 1.47 (d, J = 6.9 Hz, 3H, CH 3 13). 13 C NMR (75MHz, アセトン-d 6 , 20℃), δ (ppm): 158.2 (COH 20), 155.2 (CO 10), 138.7 (C 5), 136.4 (C 2), 130.8 (CH 4), 130.5 (CH 18), 125.0 (C 7), 124.9 (C 16), 124.0 (CH 3), 123.6 (CH 21), 122.5 (CH 8), 118.9 (CH 17), 116.6 (CH 19), 91.3 (CC 14), 82.2 (CC 15), 38.6 (CH 12), 23.3 (CH 3 13), 21.3 (CH 3 1), 17.6 (CH 3 6). HRMS (ESI+): m / z C 19 H 20 N 2 O 2 Na + (M+Na) +Calculated value 331.1417; measured value 331.1421. Purity at HPLC λ = 254 nm: 100% (general conditions, R t = 19.94 minutes). MS (ESI+): m / z (%) 309.2 (100) [M+H + ].

[0997] (Example 42) 1-(2,5-dimethylphenyl)-3-(4-(3-hydroxyphenyl)-2-methylbut-3-yn-2-yl)urea 1-(2,5-Dimethylphenyl)-3-(4-(3-hydroxyphenyl)-2-methylbut-3-yn-2-yl)urea (44) - Typical procedure 2 was followed using 1-(2,5-dimethylphenyl)-3-(2-methylbut-3-yn-2-yl)urea E1 (0.227 mmol, 1.0 equiv, 52 mg) as the alkyne derivative and 3-iodophenol (0.227 mmol, 1.0 equiv, 50 mg) as the iodine derivative. The mixture was stirred overnight. The solution was diluted with H 2 Dilute with 20O (4 mL), extract twice with EtOAc, wash with brine, and rinse with MgSO 4 The organic layer was filtered and concentrated under vacuum to give crude 1-(2,5-dimethylphenyl)-3-(4-(3-hydroxyphenyl)-2-methylbut-3-yn-2-yl)urea 42, 55 mg, yield: 75%. A fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give the pure compound as a white solid in sufficient quantity for identification and biological assays.

[0998] [ka]

[0999] 1 H NMR (300MHz, acetone-d 6, 20℃), δ (ppm): 8.50 (s, 1H, OH 22), 7.85 (d, J = 1.8 Hz, 1H, CH 8), 7.17 (s, 1H, NH 9), 7.15 (t, J = 8.0 Hz, 1H, CH 18), 6.97 (d, J = 7.6 Hz, 1H, CH 4), 6.86 (ddd, J = 8.2, 2.5, 1.1 Hz, 1H, CH 19), 6.87 (t, J = 1.8Hz, 1H, CH 21), 6.81 (ddd, J = 8.2, 2.5, 1.1 Hz, 1H, CH 17), 6.70 (d, J = 7.6, 1.8 Hz, 1H, CH 3), 6.35 (s, 1H, NH 11), 2.25 (s, 3H, CH 3 1), 2.15 (s, 3H, CH 3 6), 1.71 (s, 6H, CH 3 13). 13 C NMR (75MHz, acetone-d 6 , 20℃), δ (ppm): 157.2 (COH 20), 157.1 (CO 10), 138.1 (C 5), 135.5 (C 2), 129.8 (CH 4), 129.5 (CH 18), 124.4 (C 16), 123.5 (C 7), 122.8 (CH 3), 122.7 (CH 19), 121.2 (CH 8), 118.1 (CH 21), 115.5 (CH 17), 93.7 (CC 14), 80.2 (CC 15), 47.4 (C 12), 29.1 (CH 3 13), 20.4 (CH 3 1), 16.8 (CH 3 6). HRMS (ESI+): m / z C 20 H 22 N 2 O 2 Na + (M+Na) + Calculated value 345.15735; measured value 345.15760. Purity at HPLC λ = 254 nm: 98% (general conditions, Rt = 20.91 minutes). MS (ESI+): m / z (%) 323.2 (100) [M+H + ].

[1000] (Example 43) 1-(2,5-dimethylphenyl)-3-(6-(4-hydroxyphenyl)pyridin-2-yl)urea Process 1 1-(6-Bromopyridin-2-yl)-3-(2,5-dimethylphenyl)urea (AD1) - To a solution of triphosgene (1.45 mmol, 0.5 equiv, 429 mg) in dry DCM (12 mL) under argon at 0° C., 6-bromopyridin-2-amine (2.89 mmol, 1.0 equiv, 500 mg) was slowly added followed by triethylamine (5.78 mmol, 2.0 equiv, 806 μL). The mixture was stirred at room temperature for a minimum of 6 h. The solvent was then removed under reduced pressure to give the isocyanate derivative as a yellow / green solid. The residue was dissolved in dry toluene (6 mL) and 2,5-dimethylaniline (2.89 mmol, 1.0 equiv, 358 μL) and triethylamine (5.78 mmol, 2.0 equiv, 806 μL) were added successively under argon. The resulting mixture was heated to reflux and maintained for 36 hours. The solvent was evaporated under reduced pressure, and the residue was triturated in DCM and filtered to give 1-(6-bromopyridin-2-yl)-3-(2,5-dimethylphenyl)urea AD1, 552 mg, yield: 60%, as a white solid. Melting point: 212° C.

[1001] [ka]

[1002] 1 H NMR (300MHz, DMSO-d 6, 20℃), δ (ppm): 10.02 (s, 1H), 9.26 (s, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.55 (dd, J = 8.0, 0.8 Hz, 1H), 7.23 (dd, J = 8.0, 0.8 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.80 (dd, J = 7.7, 1.8 Hz, 1H), 2.26 (s, 6H). 13 C NMR (75MHz, DMSO-d 6 , 20℃), δ (ppm): 153.3, 151.6, 141.4, 137.9, 136.6, 135.2, 130.0, 124.2, 123.8, 121.2, 120.8, 110.7, 21.0, 17.8.

[1003] Process 2 1-(2,5-Dimethylphenyl)-3-(6-(4-hydroxyphenyl)pyridin-2-yl)urea (43) - Dioxane:H 2 In a mixture of 2,5-dimethylphenyl-1-(6-bromopyridin-2-yl)-3-(2,5-dimethylphenyl)urea AD1 (0.156 mmol, 1.0 equiv, 50 mg), (4-hydroxyphenyl)boronic acid (0.156 mmol, 1.0 equiv, 22 mg) and Na 2 CO 3 (0.625 mmol, 4.0 equiv, 66 mg) was added stepwise. The mixture was degassed with argon and Pd(PPh 3 ) 4 (5 mol%, 9 mg) was added and the mixture was heated at 70° C. for 18 h. The cooled reaction solution was diluted with EtOAc (3 mL) and H 2 The organic layer was separated and washed with brine and MgSO. 4Drying at 40° C. and concentration in vacuo afforded 1-(2,5-dimethylphenyl)-3-(6-(4-hydroxyphenyl)pyridin-2-yl)urea 43, 37 mg. A fraction of the crude mixture (10–20 mg) was purified by semi-preparative HPLC to give sufficient pure compound as a white solid for identification and biological assays.

[1004] [ka]

[1005] 1 H NMR (300MHz, acetone-d 6 , 20℃), δ (ppm): 10.66 (s, 1H, OH 21), 8.87 (s, 1H, NH 9 / 11), 8.77 (s, 1H, NH 9 / 11), 7.86 - 7.73 (m, 2H, CH 19), 7.77 (t, J = 7.7, 0.8 Hz, 1H, CH 14), 7.75 (d, J = 2.1 Hz, 1H, CH 8), 7.37 (dd, J = 7.7, 0.8 Hz, 1H, CH 15), 7.25 (dd, J = 7.7, 0.8 Hz, 1H, CH 13), 7.03 (d, J = 7.7 Hz, 1H, CH 4), 7.00 - 6.89 (m, 2H, CH 18), 6.82 (dd, J = 8.0, 2.1 Hz, 1H, CH 3), 2.29 (s, 3H, CH 3 1), 2.12 (s, 3H, CH 3 6). 13 C NMR (75 MHz, acetone-d 6, 20℃), δ (ppm): 158.7 (COH 20), 155.3 (C 16), 153.5 (C 12), 152.5 (CO 10), 139.2 (CH 14), 137.0 (C 5), 135.4 (C 2), 130.5 (C 17), 129.9 (CH 4), 128.5 (CH 19), 125.7 (C 7), 124.3 (CH 3), 123.5 (CH 8), 115.5 (CH 18), 113.5 (CH 15), 109.6 (CH 13), 20.4 (CH 3 1), 17.2 (CH 3 6). HRMS (ESI+): m / z C 20 H 19 N 3 O 2 Na + (M+Na) + Calculated value 356.13695; measured value 356.13660. Purity at HPLC λ = 254 nm: 98% (general conditions, R t = 20.94 minutes). MS (ESI+): m / z (%) 333.2 (100) [M+H + ].

[1006] (Example 44) 1-(2,5-dimethylphenyl)-3-(3-(4-hydroxyphenyl)cyclohexyl)urea Process 1 3-(4-Methoxyphenyl)cyclohexan-1-one (AE1) - degassed [Rh(cod)Cl] 2 (2 mol%, 15 mg) at room temperature. 2 O (6 mL), (4-methoxyphenyl)boronic acid (3.77 mmol, 2.5 equiv, 573 mg), Na 2 CO 3(3.02 mmol, 2.0 equiv, 320 mg) and cyclohex-2-en-1-one (1.51 mmol, 1.0 equiv, 145 mg, 147 μL) were added successively. The heterogeneous mixture was heated at 80° C. until completion, then cooled to room temperature and extracted with EtOAc (2×4 mL) and DCM (2×4 mL). The combined organic layers were filtered over a short pad of silica gel and the solvent was evaporated under reduced pressure. Purification was carried out using SCC (PE / EtOAc-10:1) to give 3-(4-methoxyphenyl)cyclohexan-1-one AE1, 177 mg, yield: 57%, as an off-white solid. Melting point: 84° C.

[1007] [ka]

[1008] 1 H NMR (300MHz, chloroform-d 1 , 20℃), δ (ppm): 7.19 - 7.08 (m, 2H), 6.90 - 6.83 (m, 2H), 3.79 (s, 3H), 2.96 (tt, J = 11.4, 4.2 Hz, 1H), 2.64 - 2.25 (m, 4H), 2.19 - 1.99 (m, 2H), 1.90 - 1.71 (m, 2H).

[1009] Process 2 3-(4-Methoxyphenyl)cyclohexane-1-amine (AE2) - Typical procedure 2 was followed using 3-(4-methoxyphenyl)cyclohexan-1-one AE1 (0.734 mmol, 1.0 equiv, 150 mg). After 36 h reaction and work-up, 3-(4-methoxyphenyl)cyclohexane-1-amine AE2, 86 mg, yield: 57%, was obtained as a colorless oil. The amine derivative was used without purification.

[1010] [ka]

[1011] Process 3 1-(2,5-Dimethylphenyl)-3-(3-(4-methoxyphenyl)cyclohexyl)urea (AE3) - Typical procedure 5 was followed using 2-isocyanato-1,4-dimethylbenzene (0.244 mmol, 1.0 equiv, 36 mg) and 3-(4-methoxyphenyl)cyclohexan-1-amine AE2 (0.244 mmol, 1.0 equiv, 50 mg) in dry DCM (2 mL). The solvent was evaporated and the residue was triturated with cold DCM and filtered to give 1-(2,5-dimethylphenyl)-3-(3-(4-methoxyphenyl)cyclohexyl)urea AE3 as a putative mixture of cis / trans diastereoisomers (30 / 70) (27 mg, yield: 31%) as a white solid.

[1012] [ka]

[1013] HRMS(ESI+):m / z C 22 H 28 N 2 O 2 Na + (M+Na) + Calculated value 375.2043; measured value 375.2045. HPLC purity @λ=254nm:81%+18% (general conditions, R t1 =23.68 minutes, R t2 =23.84 minutes). MS(ESI+): m / z(%) 353.3(100) [M+H + ].

[1014] Process 4 1-(2,5-Dimethylphenyl)-3-(3-(4-hydroxyphenyl)cyclohexyl)urea 44 - 1-(2,5-Dimethylphenyl)-3-(3-(4-methoxyphenyl)cyclohexyl)urea AE3 (57 μmol, 1.0 equiv, 20 mg) as the methoxy-protected urea in DCM (2 mL) with BBr 3(1M in DCM, 0.228 mmol, 4.0 equiv, 0.228 mL) and typical procedure 6 was followed. The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give pure compound 44 as a white solid in sufficient quantity for characterization and biological assays.

[1015] [ka]

[1016] HRMS(ESI+):m / z C 21 H 26 N 2 O 2 Na + (M+Na) + Calculated value 361.18865; measured value 361.18850. HPLC purity @λ=254nm:75%+25% (general conditions, R t1 =20.54 minutes, R t2 =20.75 minutes). MS(ESI+): m / z(%) 339.3(100) [M+H + ].

[1017] (Example 45) 1-(2,5-dimethylphenyl)-3-(1-(3-hydroxyphenyl)piperidin-4-yl)urea Process 1 tert-Butyl (1-(3-methoxyphenyl)piperidin-4-yl)carbamate (AF1) - Typical procedure 9 was followed using 1-iodo-3-methoxybenzene (1.07 mmol, 1.0 equiv, 250 mg) as iodine derivative and tert-butyl piperidin-4-ylcarbamate (1.28 mmol, 1.2 equiv, 257 mg) as piperidine derivative. The crude was purified using SCC (cyclohexane / EtOAc-100:0 to 80:20) to give tert-butyl (1-(3-methoxyphenyl)piperidin-4-yl)carbamate AF1, 135 mg, yield: 34% as a yellow solid. Melting point: 120 °C. Rf (cyclohexane / EtOAc-80:20): 0.2.

[1018] [ka]

[1019] 1 H NMR (400MHz, methanol-d 1 , 20℃), δ (ppm): 7.11 (t, J = 8.2 Hz, 1H), 6.56 (dd, J = 8.2, 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.41 (dd, J = 8.2, 2.4 Hz, 1H), 3.75 (s, 3H), 3.61 (dt, J = 12.5, 4.0 Hz, 2H), 3.47 (tt, J = 10.9, 4.0 Hz, 1H), 2.78 (td, J = 12.5, 2.6 Hz, 2H), 1.94 (dt, J = 11.7, 2.6 Hz, 2H), 1.56 (qd, J = 11.7, 4.0 Hz, 2H), 1.45 (s, 9H). 13 C NMR (101MHz, methanol-d 1 , 20℃), δ (ppm): 162.1, 157.8, 154.2, 130.7, 110.8, 106.0, 104.3, 80.0, 55.6, 50.2, 33.0, 28.8. One carbon was not observed.

[1020] Process 2 1-(3-Methoxyphenyl)piperidin-4-amine dihydrochloride (AF2) - Typical procedure 10 was followed using tert-butyl (1-(3-methoxyphenyl)piperidin-4-yl)carbamate AF1 (0.212 mmol, 1.0 equiv, 65 mg). Evaporation of the solvent afforded 1-(3-methoxyphenyl)piperidin-4-amine dihydrochloride AF2 in quantitative yield.

[1021] [ka]

[1022] 1 H NMR (400MHz, methanol-d 1 , 20℃), δ (ppm): 7.48 (t, J = 8.2 Hz, 1H), 7.30 (t, J = 2.5 Hz, 1H), 7.26 (dd, J = 8.2, 2.5 Hz, 1H), 7.07 (dd, J = 8.2, 2.5 Hz, 1H), 3.87 (s, 3H), 3.86 - 3.71 (m, 4H), 3.65 (tt, J = 11.2, 5.3 Hz, 1H), 2.42 - 2.22 (m, 4H).

[1023] Process 3 1-(2,5-Dimethylphenyl)-3-(1-(3-methoxyphenyl)piperidin-4-yl)urea (AF3) - Typical procedure 5 was followed using 2-isocyanato-1,4-dimethylbenzene (0.197 mmol, 1.0 equiv, 29 mg) and 1-(3-methoxyphenyl)piperidin-3-amine dihydrochloride AF2 (0.197 mmol, 1.0 equiv, 55 mg) in dry DCM (2 mL), followed by triethylamine (0.394 mmol, 2.0 equiv, 55 μL). The mixture was stirred overnight at room temperature. The precipitate was filtered and washed with cold DCM to give 1-(2,5-dimethylphenyl)-3-(1-(3-methoxyphenyl)piperidin-4-yl)urea AF3, 53 mg, yield: 76%, as a white solid.

[1024] [ka]

[1025] 1 H NMR (300MHz, DMSO-d 6 , 20℃), δ (ppm): 7.87 (s, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.51 (s, 1H), 7.10 (td, J = 8.2, 2.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.67 (dd, J = 7.6, 1.8 Hz, 1H), 6.54 (ddd, J = 8.2, 2.6, 2.2 Hz, 1H), 6.46 (t, J = 2.6 Hz, 1H), 6.35 (dt, J = 8.2, 2.6 Hz, 1H), 3.71 (s, 3H), 3.68 - 3.62 (m, 1H), 3.60 - 3.53 (m, 1H), 2.91 - 2.81 (m, 2H), 2.21 (s, 3H), 2.12 (s, 3H), 1.97 - 1.86 (m, 2H), 1.65 - 1.37 (m, 2+1H). 13 C NMR (75MHz, DMSO-d 6, 20℃), δ (ppm): 160.2, 154.7, 152.4, 138.0, 134.9, 129.8, 129.6, 123.2, 122.3, 120.6, 108.5, 103.9, 101.8, 47.3, 46.1, 31.7, 29.0, 21.0, 17.5.

[1026] Process 4 1-(2,5-Dimethylphenyl)-3-(1-(3-hydroxyphenyl)piperidin-4-yl)urea (45) - 1-(2,5-Dimethylphenyl)-3-(1-(3-methoxyphenyl)piperidin-3-yl)urea AF3 (71 μmol, 1.0 equiv, 25 mg) as the methoxy-protected urea in DCM (2 mL) with BBr 3 (1M in DCM, 0.284 mmol, 4.0 equiv, 0.284 mL) and typical procedure 6 was followed. The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give pure compound 45 as an off-white solid in sufficient quantity for identification and biological assays.

[1027] [ka]

[1028] 1 H NMR (300MHz, acetone-d 6, 20℃), δ (ppm): 8.06 (s, 1H, OH 21), 7.82 (d, J = 2.0 Hz, 1H, CH 8), 7.12 (s, 1H, NH 9), 7.00 (td, J = 8.0; 1.1 Hz, 1H, CH 17), 6.97 (d, J = 7.5 Hz, 1H, CH 4), 6.70 (dd, J = 7.5, 2.0 Hz, 1H, CH 3), 6.44 (ddd, J = 8.0, 2.0, 1.1 Hz, 1H, CH 16 / 18), 6.43 (td, J = 2.0, 1.1 Hz, 1H, CH 20), 6.27 (ddd, J = 8.0, 2.0, 1.1 Hz, 1H, CH 16 / 18), 6.05 (d, J = 7.6 Hz, 1H, NH 11), 3.79 - 3.75 (m, 1H, CH 12), 3.63 - 3.53 (m, CH 2 14), 2.89 - 2.79 (m, CH 2 14), 2.25 (s, 3H, CH 3 1), 2.15 (s, 3H, CH 3 6), 2.01 - 1.95 (m, 2H, CH 2 13), 1.56 - 1.50 (m, 2H, CH 2 13). 13 C NMR (75MHz, アセトン-d 6 , 20℃), δ (ppm): 159.1 (COH 19), 155.6 (CO 10), 153.9 (C 15), 139.1 (C 5), 136.3 (C 2), 130.7 (CH 17), 130.4 (CH 4), 124.7 (C 7), 123.7 (CH 3), 122.4 (CH 8), 108.6 (CH 16 / 18), 106.9 (CH 16 / 18), 104.1 (CH 20), 48.9 (CH 2 14), 47.8 (CH 12), 33.1 (CH 2 13), 21.4 (CH 3 1), 17.7 (CH 3 6). HRMS (ESI+): m / z C 20 H 25 N 3 O 2 Na + (M+Na) + Calculated value 362.1839; measured value 362.1841. Purity at HPLC λ = 254 nm: 97% (general conditions, R t = 14.82 minutes). MS (ESI+): m / z (%) 340.3 (100) [M+H + ].

[1029] (Example 46) 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)piperidin-4-yl)urea Process 1 tert-Butyl (1-(4-methoxyphenyl)piperidin-4-yl)carbamate (AG1) - Typical procedure 9 was followed using 1-iodo-4-methoxybenzene (1.67 mmol, 1.0 equiv, 390 mg) as the iodine derivative and tert-butyl piperidin-4-ylcarbamate (2.0 mmol, 1.2 equiv, 400 mg) as the piperidine derivative. The crude was purified using SCC (cyclohexane / EtOAc - 100:0 to 80:20) to give tert-butyl (1-(4-methoxyphenyl)piperidin-4-yl)carbamate AG1, 312 mg, yield: 51%, as a white solid. Melting point: 110 °C. R f (Cyclohexane / EtOAc-80:20): 0.18.

[1030] [ka]

[1031] 1 H NMR (400MHz, methanol-d 1, 20℃), δ (ppm): 7.00 - 6.92 (m, 2H), 6.87 - 6.78 (m, 2H), 3.73 (s, 3H), 3.47 - 3.40 (m, 2+1H), 2.71 (td, J = 12.0, 2.6 Hz, 2H), 1.95 (dd, J = 13.7, 3.9 Hz, 2H), 1.60 (qd, J = 12.0, 3.9 Hz, 2H), 1.45 (s, 9H). 13 C NMR (101MHz, methanol-d 1 , 20℃), δ (ppm): 157.8, 155.9, 147.1, 120.5, 115.4, 80.0, 55.9, 52.0, 49.7, 33.2, 28.8.

[1032] Process 2 4-(4-Aminopiperidin-1-yl)phenol dihydrobromide (AG2) - tert-Butyl (1-(4-methoxyphenyl)piperidin-4-yl)carbamate AG1 (0.134 mmol, 1.0 equiv, 41 mg) was used according to typical procedure 10. After 2 h, the solution was quenched with ice and H 2 Extraction with 2×2 mL of O and evaporation of the solvent in vacuo was performed. A small amount of MeOH was added and the mixture was concentrated in vacuo to give 4-(4-aminopiperidin-1-yl)phenol dihydrobromide AG2, 47 mg, (yield: quantitative) as a light yellow solid.

[1033] [ka]

[1034] 1 H NMR (300MHz, methanol-d 1 , 20℃), δ (ppm): 7.65 - 7.54 (m, 2H), 7.00 - 6.88 (m, 2H), 3.91 - 3.69 (m, 4+1H), 2.44 - 2.20 (m, 4H). 13C NMR (75MHz, methanol-d 1 , 20℃), δ (ppm): 160.4, 156.7, 123.5, 117.7, 55.7, 46.4, 29.1.

[1035] Process 3 1-(2,5-Dimethylphenyl)-3-(1-(4-hydroxyphenyl)piperidin-4-yl)urea (46) - Typical procedure 5 was followed using 2-isocyanato-1,4-dimethylbenzene (0.127 mmol, 1.0 equiv, 19 mg) and 4-(4-aminopiperidin-1-yl)phenol dihydrobromide AG2 (0.127 mmol, 1.0 equiv, 45 mg) in dry DCM (4 mL), followed by triethylamine (0.254 mmol, 2.0 equiv, 35 μL). The mixture was stirred overnight at room temperature. Workup afforded 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)piperidin-4-yl)urea 46, 16 mg, yield: 37%. Trituration of the crude mixture with acetone afforded the product as a white solid, pure for identification and biological assay.

[1036] [ka]

[1037] 1 H NMR (300MHz, DMSO-d 6, 20 °C), δ (ppm): 8.82 (s, 1H, OH 19), 7.70 (d, J = 1.8 Hz, 1H, CH 8), 7.50 (s, 1H, NH 9), 6.97 (d, J = 7.6 Hz, 1H, CH 4), 6.86 - 6.75 (m, 2H, CH 17), 6.66 (dd, J = 7.6, 1.8 Hz, 1H, CH 3), 6.68 - 6.58 (m, 1H, CH 16), 6.60 (d, J = 8.5 Hz, 1H, NH 11), 3.63 - 3.51 (m, 1H, CH 12), 3.36 - 3.25 (m, 1H, CH 2 14), 2.76 - 2.65 (m, 2H, CH 2 14), 2.21 (s, 3H, CH 3 1), 2.12 (s, 3H, CH 3 6), 1.97 - 1.86 (m, 2H, CH 2 13), 1.56 - 1.45 (m, 2H, CH 2 13). 13 C NMR (75 MHz, DMSO-d 6 , 20 °C), δ (ppm): 154.7 (CO 10), 150.9 (COH 18), 144.5 (C 15), 138.1 (C 7), 134.9 (C 2), 129.7 (CH 4), 123.1 (C 5), 122.3 (CH 3), 120.6 (CH 8), 118.5 (CH 17), 115.4 (CH 16), 49.4 (CH 2 14), 45.9 (CH 12), 32.2 (CH 2 13), 21.0 (CH 3 1), 17.5 (CH 3 6). HRMS (ESI+): m / z C 20 H 25 N 3 O 2 Na + (M + Na) + calculated value 362.1839; measured value 362.1841. Purity at HPLC λ = 254 nm: 94% (general conditions, R t = 15.78 minutes). MS (ESI+): m / z (%) 340.2 (100) [M+H + ].

[1038] (Example 47) 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)piperidin-3-yl)urea Process 1 tert-Butyl (1-(4-methoxyphenyl)piperidin-3-yl)carbamate (AH1) - Typical procedure 9 was followed using 1-iodo-4-methoxybenzene (1.752 mmol, 1.0 equiv, 410 mg) as the iodine derivative and tert-butyl piperidin-3-ylcarbamate (2.102 mmol, 1.2 equiv, 421 mg) as the piperidine derivative. The crude was purified using SCC (cyclohexane / EtOAc - 100:0 to 80:20) to give tert-butyl (1-(4-methoxyphenyl)piperidin-3-yl)carbamate AH1, 354 mg, yield: 55% as a beige solid. Melt point: 122 °C. Rf (cyclohexane / EtOAc - 80:20): 0.2.

[1039] [ka]

[1040] 1 H NMR (400MHz, methanol-d 1, 20℃), δ (ppm): 6.98 - 6.90 (m, 2H), 6.87 - 6.78 (m, 2H), 3.73 (s, 3H), 3.65 (t, J = Hz, 1H), 3.43 (dd, J = 11.5, 4.0 Hz, 1H), 3.24 (dt, J = 11.5, 4.0 Hz, 1H), 2.67 (td, J = 11.5, 4.0 Hz, 1H), 2.50 (dd, J = 11.3, 9.1 Hz, 1H), 1.90 - 1.80 (m, 2H), 1.76 - 1.65 (m, 1H), 1.45 (s, 9H), 1.35 (qd, J = 11.5, 4.0 Hz, 1H). 13 C NMR (101MHz, methanol-d 1 , 20℃), δ (ppm): 157.8, 155.7, 147.3, 120.5, 115.4, 80.1, 58.4, 55.9, 52.8, 31.2, 28.8, 28.0, 24.9.

[1041] Process 2 4-(3-aminopiperidin-1-yl)phenol dihydrobromide (AH2) - tert-butyl (1-(4-methoxyphenyl)piperidin-4-yl)carbamate AH1 (0.163 mmol, 1.0 equiv, 50 mg) was used following typical procedure 10. After 2 h, the solution was quenched with ice and H 2 Extraction with 2×2 mL of O and evaporation of the solvent in vacuo was performed. A small amount of MeOH was added and the mixture was concentrated in vacuo to give 4-(3-aminopiperidin-1-yl)phenol dihydrobromide AI2, 57 mg (yield: quantitative).

[1042] [ka]

[1043] 1 H NMR (300MHz, methanol-d 1, 20℃), δ (ppm): 7.70 - 7.59 (m, 2H), 7.01 - 6.90 (m, 2H), 4.00 (tt, J = 11.5, 4.0 Hz, 1H), 3.82 (dd, J = 11.5, 4.0 Hz, 1H), 3.73 - 3.61 (m, 3H), 2.33 - 2.21 (m, 3H), 1.96 - 1.90 (m, 1H). 13 C NMR (75MHz, methanol-d 1 , 20℃), δ (ppm): 160.4, 134.7, 123.5, 117.8, 57.4, 57.3, 46.9, 26.9, 22.4.

[1044] Process 3 1-(2,5-Dimethylphenyl)-3-(1-(4-hydroxyphenyl)piperidin-3-yl)urea (47) - Typical procedure 5 was followed using 2-isocyanato-1,4-dimethylbenzene (0.113 mmol, 1.0 equiv, 17 mg) and 4-(3-aminopiperidin-1-yl)phenol dihydrobromide AH2 (0.113 mmol, 1.0 equiv, 40 mg) in dry DCM (4 mL), followed by triethylamine (0.339 mmol, 3.0 equiv, 47 μL). The mixture was stirred overnight at room temperature. Workup afforded 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)piperidin-3-yl)urea 47, 29 mg, yield: 76%. Trituration of the crude mixture with acetone afforded the pure product as a white solid in sufficient quantity for identification and biological assays.

[1045] [ka]

[1046] 1 H NMR (300MHz, acetone-d 6, 20℃), δ (ppm): 7.85 (s, 1H, OH 21), 7.84 (d, J = Hz, 1H, CH 8), 7.27 (s, 1H, NH 9), 6.97 (d, J = 7.6 Hz, 1H, CH 4), 6.87 - 6.80 (m, 2H, CH 19), 6.75 - 6.69 (m, 2H, CH 18), 6.69 (dd, J = 7.6, 2.0 Hz, 1H, CH 3), 6.22 (d, J = 7.9 Hz, 1H, NH 11), 4.01 - 3.95 (m, 1H, CH 12), 3.33 - 3.24 (m, 1H, CH 2 16), 3.07 - 2.88 (m, 1H, CH 2 14), 2.86 - 2.73 (m, 1H, CH 2 16), 2.25 (s, 3H, CH 3 1), 2.15 (s, 3H, CH 3 6), 1.84 - 1.79 (m, 1H, CH 2 14), 1.83 - 1.78 (m, 1H, CH 2 13), 1.84 - 1.76 (m, 1H, CH 2 15), 1.70 - 1.64 (m, 1H, CH 2 15), 1.58 - 1.51 (m, 1H, CH 2 13). 13 C NMR (75MHz, アセトン-d 6 , 20℃), δ (ppm): 155.6 (CO 10), 152.3 (COH 20), 146.8 (C 7), 146.5 (C 17), 139.2 (C 5), 136.4 (C 2), 130.7 (CH 4), 123.7 (CH 3), 122.4 (CH 8), 120.1 (CH 19), 116.4 (CH 18), 58.4 (CH 2 16), 52.4 (CH 2 14), 46.9 (CH 12), 30.7 (CH 2 13), 24.0 (CH 215), 21.4 (CH 3 1), 17.7 (CH 3 6). HRMS (ESI+): m / z C 20 H 25 N 3 O 2 Na + (M+Na) + Calculated value 362.1839; measured value 362.1841. Purity at HPLC λ = 254 nm: 89% (general conditions, R t = 15.12 minutes). MS (ESI+): m / z (%) 340.2 (100) [M+H + ].

[1047] (Example 48) 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)-1-methylurea Process 1 1-(2,5-Dimethylphenyl)-3-(4-(4-Methoxyphenyl)butan-2-yl)-1-methylurea (AI1) - 1-(2,5-Dimethylphenyl)-3-(4-(4-Methoxyphenyl)butan-2-yl)urea 2 (0.613 mmol, 1.0 equiv, 200 mg) was dissolved in dry THF (5 mL) and cooled to 0 °C. NaH (2.452 mmol, 4.0 equiv) was added and the resulting mixture was stirred for 45 min. The ice bath was then removed and iodomethane (2.452 mmol, 4.0 equiv, 0.8 mL) was added slowly and the solution was stirred at room temperature overnight. The reaction was analyzed by NH 4 The mixture was quenched with a saturated aqueous solution of Cl (5 mL) and extracted with EtOAc (12 mL). The organic phase was washed with brine (8 mL), dried and concentrated in vacuo. The crude product was purified by SCC (PE / EtOAc-90:10 to 60:40) to give 1-(2,5-dimethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)-1-methylurea AI1, 53 mg, yield: 25% as a colorless oil.

[1048] [ka]

[1049] 1 H NMR (300MHz, acetone-d 6 , 20℃), δ (ppm): 7.19 (d, J = 7.7 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 7.10 - 7.02 (m, 2H), 7.05 (dd, J = 7.7, 1.9 Hz 1H), 6.85 - 6.78 (m, 2H), 4.56 (d, J = 8.5 Hz, 1H), 3.87 - 3.83 (m, 1H), 3.75 (s, 3H), 3.09 (s, 3H), 2.52 - 2.47 (m, 2H), 2.29 (s, 3H), 2.19 (s, 3H), 1.60 - 1.52 (m, 2H), 1.04 (d, J = 6.6 Hz, 3H). 13 C NMR (75MHz, acetone-d 6 , 20℃), δ (ppm): 158.7, 157.2, 142.9, 138.1, 135.2, 134.3, 132.2, 130.1, 130.1, 129.5, 114.5, 55.4, 46.7, 40.1, 36.4, 32.5, 23.0, 21.9, 20.9, 17.2, 14.4.

[1050] Process 2 1-(2,5-Dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)-1-methylurea (48) - 1-(2,5-Dimethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)-1-methylurea AI1 (0.156 mmol, 1.0 equiv, 53 mg) as the methoxy-protected urea in DCM (4 mL) and BBr 3(1M in DCM, 0.624 mmol, 4.0 equiv, 0.624 mL) and typical procedure 6 was followed. The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and the crude product was purified using SCC (DCM / MeOH-100:0 to 95:5) to give pure 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)-1-methylurea 48, 43 mg, yield: 85%, as a colorless oil.

[1051] [ka]

[1052] 1 H NMR (300MHz, acetone-d 6 , 20℃), δ (ppm): 8.08 (s, 1H, OH 20), 7.17 (d, J = 7.7 Hz, 1H, CH 4), 7.06 (dd, J = 7.7, 1.9 Hz, 1H, CH 3), 7.02 (d, J = 1.9 Hz, 1H, CH 8), 7.00 - 6.93 (m, 2H, CH 18), 6.75 - 6.65 (m, 2H, CH 17), 4.52 (d, J = 8.5 Hz, 1H, NH 11), 3.82 (dq, J = 8.5, 6.6 Hz, 1H, CH 12), 3.07 (s, 3H, CH 3 11), 2.52 - 2.38 (m, 2H, CH 2 15), 2.31 - 2.25 (m, 3H, CH 3 1), 2.17 (s, 3H, CH 3 6), 1.63 - 1.44 (m, 2H, CH 2 14), 1.01 (d, J = 6.6 Hz, 3H, CH 3 13). 13 C NMR (75MHz, acetone-d 6, 20℃), δ = 157.2 (COH 19), 156.3 (CO 10), 142.8 (C 7), 138.0 (C 2), 134.2 (C 5), 133.9 (C 16), 132.0 (CH 4), 130.1 (CH 8), 130.0 (CH 17), 129.4 (CH 3), 115.9 (CH 18), 46.7 (CH 12), 40.1 (CH 2 14), 36.3 (CH 3 11), 32.5 (CH 2 15), 21.8 (CH 3 13), 20.8 (CH 3 1), 17.1 (CH 3 6). HRMS (ESI+): m / z C 20 H 26 N 2 O 2 Na + (M+Na) + Calculated value 349.18865; measured value 349.18870. Purity at HPLC λ = 254 nm: 95% (general conditions, R t = 20.77 minutes). MS (ESI+): m / z (%) 327.3 (100) [M+H + ].

[1053] (Example 49) 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)-1,3-dimethylurea Process 1 4-(4-Methoxyphenyl)-N-methylbutan-2-amine (AJ1) - Analogously to typical procedure 12, 4-(4-methoxyphenyl)butan-2-one (2.244 mmol, 1.0 equiv, 400 mg) and MeNH 2 (40% aqueous, 8.977 mmol, 4.0 equiv, 0.777 mL) was dissolved in MeOH (4 mL) and stirred for 45 min. Then, NaBH 3CN (3.366 mmol, 1.5 equiv, 212 mg) was added in portions at 0° C. and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with a solution of 1 M HCl (15 mL). MeOH was evaporated and the aqueous phase was washed with Et 2 2H 2 O (2×10 mL) and basified with 1M NaOH (16 mL). The solution was extracted with DCM (2×15 mL) and the combined organic layers were dried and concentrated in vacuo to give 4-(4-methoxyphenyl)-N-methylbutan-2-amine AJ1, 140 mg, yield: 32% as a clear oil.

[1054] [ka]

[1055] 1 H NMR (300MHz, acetone-d 6 , 20℃), δ (ppm): 7.15 - 7.08 (m, 2H), 6.85 - 6.79 (m, 2H), 3.75 (s, 3H), 2.61 - 2.55 (m, 2H), 2.53 - 2.44 (m, 1H), 2.32 (s, 3H), 1.87 - 1.83 (m, 1H), 1.73 - 1.46 (m, 2H), 1.04 - 1.00 (d, J = 6.3 Hz, 3H).

[1056] Process 2 3-(2,5-dimethylphenyl)-1-(4-(4-methoxyphenyl)butan-2-yl)-1-methylurea (AJ2) - Following typical procedure 5 using 4-(4-methoxyphenyl)-N-methylbutan-2-amine AJ1 (0.724 mmol, 1.0 equiv, 140 mg) and 2-isocyanato-1,4-dimethylbenzene (0.724 mmol, 1.0 equiv, 0.103 mL) dissolved in dry DCM (4 mL) and stirred overnight at room temperature. Evaporation of the solvent in vacuum afforded pure 3-(2,5-dimethylphenyl)-1-(4-(4-methoxyphenyl)butan-2-yl)-1-methylurea AJ2, 253 mg (yield: quantitative) as a clear oil.

[1057] [ka]

[1058] 1 H NMR (300MHz, acetone-d 6 , 20℃), δ (ppm): 7.57 (d, J = 1.9 Hz, 1H), 7.10 - 7.05 (m, 2H), 7.00 (d, J = 7.7 Hz 1H), 6.80 - 6.76 (m, 2H), 6.05 (s, 1H), 4.45 - 4.38 (m, 1H), 3.72 (s, 3H), 2.77 (s, 3H), 2.66 - 2.45 (m, 2H), 2.28 (s, 3H), 2.12 (s, 3H), 1.85 - 1.62 (m, 2H), 1.13 (d, J = 6.8 Hz, 3H).

[1059] Process 3 1-(2,5-Dimethylphenyl)-3-(4-(4-Methoxyphenyl)butan-2-yl)-1,3-Dimethylurea (AJ3) - Under an inert atmosphere, 3-(2,5-Dimethylphenyl)-1-(4-(4-Methoxyphenyl)butan-2-yl)-1-methylurea AJ2 (0.743 mmol, 1.0 equiv, 253 mg) was dissolved in dry THF (5 mL) and cooled to 0 °C. NaH (7.431 mmol, 10.0 equiv) was then added and the resulting mixture was stirred for 45 min. The ice bath was removed and iodomethane (7.431 mmol, 10.0 equiv, 0.46 mL) was slowly added and the reaction was stirred overnight. The solution was diluted with NH 4 The mixture was quenched with a saturated aqueous solution of Cl (5 mL) and extracted with EtOAc (15 mL), and the organic layer was washed with brine (8 mL), dried and concentrated in vacuo. The crude product was purified by SCC (PE / EtOAc-100:0 to 90:10) to give pure 1-(2,5-dimethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)-1,3-dimethylurea AJ3, 221 mg, yield: 84% as a colorless oil.

[1060] [ka]

[1061] 1 H NMR (300MHz, acetone-d 6 , 20℃), δ (ppm): 7.07 (d, J = 7.7 Hz, 1H), 7.04 - 6.99 (m, 2H), 6.92 (dd, J = 7.7, 1.9 Hz 1H), 6.84 - 6.76 (m, 2H), 6.77 (d, J = 1.9 Hz, 1H), 4.06 - 3.94 (m, 1H), 3.75 (s, 3H), 2.99 (s, 3H), 2.42 - 2.16 (m, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H), 1.64 - 1.46 (m, 2H), 0.83 (d, J = 6.7 Hz, 3H). 13 C NMR (75MHz, acetone-d 6 , 20℃), δ (ppm): 163.3, 157.7, 145.4, 136.7, 134.0, 131.2, 130.9, 129.1, 127.3, 127.1, 113.7, 55.2, 51.5, 38.9, 36.3, 31.9, 28.4, 20.7, 17.3, 17.2.

[1062] Process 4 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)-1,3-dimethylurea (49) - 1-(2,5-dimethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)-1,3-dimethylurea AJ3 (0.623 mmol, 1.0 equiv, 221 mg) as the methoxy-protected urea in DCM (14 mL) with BBr 3 (1M in DCM, 2.492 mmol, 4.0 equiv, 2.492 mL) and typical procedure 6 was followed. The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give pure compound 49 as an off-white oil in sufficient quantity for identification and biological assays.

[1063] [ka]

[1064] 1 H NMR (300MHz, acetone-d 6, 20℃), δ(ppm): 8.13 (s, 1H, OH 20), 7.14 (d, J = 7.7 Hz, 1H, CH 4), 6.96 (dd, J = 7.7, 1.9 Hz, 1H, CH 3), 7.00 - 6.92 (m, 2H, CH 18), 6.78 (d, J = 1.9 Hz, 1H, CH 8), 6.78 - 6.70 (m, 2H, CH 17), 4.02 - 3.90 (m, 1H, CH 12), 2.92 (s, 3H, CH 3 9), 2.37 (s, 3H, CH 3 11), 2.37 - 2.30 (m, 2H, CH 2 15), 2.23 (s, 3H, CH 3 1), 2.17 (s, 3H, CH 3 6), 1.68 - 1.45 (m, 2H, CH 2 14), 0.81 (d, J = 6.7 Hz, 3H, CH 3 13). 13 C NMR (75MHz, アセトン-d 6 , 20℃), δ (ppm): 163.7 (CO 10), 156.4 (C 19), 146.8 (C 7), 137.5 (C 2), 133.7 (C 5), 132.1 (CH 4), 132.0 (C 16), 130.0 (CH 17), 128.0 (CH 8), 127.8 (CH 3), 116.0 (CH 18), 52.2 (CH 12), 39.3 (C 9), 37.2 (CH 2 14), 32.7 (CH 2 15), 28.7 (CH 3 11), 20.8 (CH 3 1), 17.6 (CH 3 13), 17.4 (CH 3 6). HRMS (ESI+): m / z C 21 H 28 N 2 O 2 Na + (M+Na)+ Calculated value 363.2043; measured value 363.2045. Purity at HPLC λ = 254 nm: 98% (general conditions, R t = 22.13 minutes). MS (ESI+): m / z (%) 341.3 (100) [M+H + ].

[1065] (Example 50) 4-(4-hydroxyphenyl)butan-2-yl(2,5-dimethylphenyl)carbamate Process 1 4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)butan-2-one (AK1) - In a round bottom flask, 4-(4-hydroxyphenyl)butan-2-one (18.26 mmol, 1.0 equiv, 3.0 g) and imidazole (73.07 mmol, 4.0 equiv, 4.97 g) were dissolved in dry DCM (73 mL, 0.25 M). tBDMSCl (36.54 mmol, 2.0 equiv, 6.31 mL, 5.51 g) was added slowly and the resulting mixture was stirred at room temperature overnight. NH 4 An aqueous solution of Cl (20 mL) was added and the solution was extracted with DCM (20 mL). The combined organic layers were washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. Purification was carried out by SCC (cyclohexane / EtOAc-100:0 to 60:40) to give 4-(4-((tert-butyldimethylsilyl)oxy)phenyl)butan-2-ol AK1, 5.37 g, yield: 107%, as a colorless oil. f (Cyclohexane / EtOAc-60:40): 0.65.

[1066] [ka]

[1067] 1 H NMR (300MHz, acetone-d 6, 20℃), δ (ppm): 7.14 - 7.03 (m, 2H), 6.82 - 6.73 (m, 2H), 2.79 - 2.70 (m, 4H), 2.08 (s, 3H), 0.98 (s, 9H), 0.19 (s, 6H). 13 C NMR (75MHz, acetone-d 6 , 20℃), δ (ppm): 207.3, 154.6, 135.2, 130.1, 120.7, 45.5, 30.2, 29.6, 26.1, 18.7, -4.3.

[1068] Process 2 4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)butan-2-ol AK2 - In a round bottom flask, 4-(4-((tert-butyldimethylsilyl)oxy)phenyl)butan-2-one AK1 (2.16 mmol, 1.0 equiv, 600 mg) was dissolved in dry MeOH (5 mL). The stirred solution was cooled to 0 °C. NaBH 4 (2.16 mmol, 1.0 equiv, 81 mg) was added in small portions (ca. 20 mg x 4) and then allowed to warm to room temperature. After complete conversion (ca. 3 h, monitored by TLC), the solvent was evaporated and the resulting mixture was redissolved in EtOAc (20 mL) and washed with brine (20 mL). The aqueous phase was extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL) and dried with MgSO. 4 After drying at 40° C., filtration and evaporation of the solvent under vacuum, crude 4-(4-((tert-butyldimethylsilyl)oxy)phenyl)butan-2-ol AK2, 551 mg, was obtained as a colorless oil, which was used directly in the next step without purification. f (Cyclohexane / EtOAc-60:40): 0.55.

[1069] [ka]

[1070] 1 H NMR (300MHz, acetone-d6 , 20℃), δ (ppm): 7.12 - 7.06 (m, 2H), 6.80 - 6.74 (m, 2H), 3.72 (qd, J = 6.2, 4.9 Hz, 1H), 3.47 (d, J = 4.9 Hz, 1H), 2.77 - 2.50 (m, 2H), 1.76 - 1.57 (m, 2H), 1.15 (d, J = 6.2 Hz, 3H), 0.99 (s, 9H), 0.19 (s, 6H). 13 C NMR (75MHz, acetone-d 6 , 20℃), δ (ppm): 154.4, 136.4, 130.1, 120.6, 66.9, 42.3, 32.0, 26.1, 24.1, 18.7, -4.3.

[1071] Process 3 4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)butan-2-yl(2,5-dimethylphenyl)carbamate AK3 - 4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)butan-2-ol AK2 (0.178 mmol, 1.0 equiv, 50 mg), DiPEA (0.356 mmol, 2.0 equiv, 62 μL), 4-dimethylaminopyridine (DMAP) (0.073 mmol, 0.4 equiv, 9 mg) and 2-isocyanato-1,4-dimethylbenzene (0.356 mmol, 2.0 equiv, 52 mg) were added sequentially to dry DCM (1.8 mL) under argon in a round bottom flask. The reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was purified by SCC (cyclohexane / EtOAc-100:0 to 90:10) to give 4-(4-((tert-butyldimethylsilyl)oxy)phenyl)butan-2-yl(2,5-dimethylphenyl)carbamate AK3, 48 mg, yield: 63%, as a colorless oil. f (Cyclohexane / EtOAc-70:30): 0.75.

[1072] [ka]

[1073] 1 H NMR (300MHz, acetone-d 6 , 20℃), δ (ppm): 7.69 (s, 1H), 7.50 - 7.42 (m, 1H), 7.14 - 7.06 (m, 2H), 7.06 (d, J = 7.7 Hz, 1H), 6.88 - 6.80 (m, 1H), 6.83 - 7.76 (m, 2H), 4.88 - 4.82 (m, 1H), 2.78 - 2.56 (m, 1H), 2.64 - 2.58 (m, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 1.99 - 1.77 (m, 2H), 1.27 (d, J = 6.3 Hz, 3H), 0.98 (s, 3H), 0.19 (s, 6H).

[1074] Process 4 4-(4-Hydroxyphenyl)butan-2-yl(2,5-dimethylphenyl)carbamate (50) - In a round bottom flask under argon, 4-(4-((tert-butyldimethylsilyl)oxy)phenyl)butan-2-yl(2,5-dimethylphenyl)carbamate AK3 (0.09 mmol, 1.0 equiv, 42 mg) was added in THF (0.34 mL) followed by the dropwise addition of TBAF (1 M solution in THF, 0.14 mmol, 1.5 equiv, 43 μL). The reaction mixture was stirred at room temperature overnight. The solution was diluted with H 2 The mixture was diluted with O (0.5 mL) and extracted with EtOAc (3 x 1 mL). The combined organic layers were washed with MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure. The purification was confirmed by preparative TLC (cyclohexane / EtOAc-100:0 to 70:30, R f :0.35) to give pure 4-(4-hydroxyphenyl)butan-2-yl(2,5-dimethylphenyl)carbamate 50, 10 mg, yield: 32%, as a beige solid. Melting point: 115° C.

[1075] [ka]

[1076] 1 H NMR (300MHz, アセトン-d 6 , 20℃), δ (ppm): 8.10 (s, 1H, OH 18), 7.70 (s, 1H, NH 9), 7.47 (d, J = 1.8 Hz, 1H, CH 8), 7.10 - 7.05 (m, 2+1H, CH 16+4), 6.89 - 6.80 (m, 1H, CH 3), 6.80 - 6.69 (m, 2H, CH 17), 4.84 (dqd, J = 7.7, 6.2, 5.1 Hz, 1H, CH 11), 2.72 - 2.49 (m, 2H, CH 2 14), 2.27 (s, 3H, CH 3 1), 2.24 (s, 3H, CH 3 6), 1.99 - 1.69 (m, 2H, CH 2 13), 1.27 (d, J = 6.2 Hz, 3H, CH 3 12). 13 C NMR (75MHz, アセトン-d 6 , 20℃), δ (ppm): 157.5 (COH 18), 155.1 (CO 10), 138.4 (C 5), 136.7 (C 2), 133.2 (C 15), 131.2 (CH 16), 130.3 (CH 4), 126.0 (CH 3), 124.7 (CH 8), 116.3 (CH 7), 116.2 (CH 17), 71.5 (CH 11), 38.7 (CH 2 13), 32.3 (CH 2 14), 21.4 (CH 3 12), 20.8 (CH 3 1), 17.8 (CH 3 6). HRMS (ESI+): m / z C 19 H 23 N 3 O 2 Na + (M+Na)+ Calculated value 336.15701; measured value 336.15700. Purity at HPLC λ = 254 nm: 95% (general conditions, R t = 22.06 minutes). MS (ESI+): m / z (%) 314.2 (100) [M+H + ].

[1077] (Example 51) 1-(2,4-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea Process 1 1-(2,4-Dimethylphenyl)-3-(4-(4-Methoxyphenyl)butan-2-yl)urea (AL1) - Typical procedure 5 was followed using 4-(4-Methoxyphenyl)butan-2-amine W1 (0.276 mmol, 1.0 equiv, 41 mg) and isocyanato-2,4-dimethylbenzene (0.279 mmol, 1.0 equiv, 50 mg). The crude product was purified by SCC (PE / acetone - 100:0 to 80:20) to give 1-(2,4-Dimethylphenyl)-3-(4-(4-Methoxyphenyl)butan-2-yl)urea AL1, 103 mg, yield: 74%, as a white solid. Melting point: 158 °C. R f (DCM / Acetone-95:5): 0.35

[1078] [ka]

[1079] 1 H NMR (300MHz, DMSO-d 6, 20℃), δ (ppm): 7.67 (d, J = 8.1 Hz, 1H), 7.43 (s, 1H), 7.16 - 7.07 (m, 2H), 6.95 - 6.85 (m, 2H), 6.86 - 6.80 (m, 2H), 6.36 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H), 3.68 - 3.59 (m, 1H), 2.60 - 2.51 (m, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 1.74 - 1.55 (m, 1H), 1.10 (d, J = 6.5Hz, 3H). 13 C NMR (75MHz, DMSO-d 6 , 20℃), δ (ppm): 157.4, 155.0, 135.7, 133.8, 130.56, 130.5, 129.1, 126.7, 126.4, 120.6, 113.7, 54.9, 44.4, 38.8, 30.9, 21.3, 20.3, 17.8.

[1080] Process 2 1-(2,4-Dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea (51) - 1-(2,4-Dimethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea AL1 (0.153 mmol, 1.0 equiv, 50 mg) as the methoxy-protected urea in DCM (7 mL) with BBr 3 (1M in DCM, 0.613 mmol, 4.0 equiv, 0.613 mL) and typical procedure 6 was followed. The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. Removal of the solvent and purification by SCC (DCM / MeOH-100:0 to 98:2) afforded pure 1-(2,4-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea 51, 24 mg, yield: 51%, as a white solid.

[1081] [ka]

[1082] 1 H NMR (300MHz, アセトン-d 6 , 20℃), δ (ppm): 8.09 (s, 1H, OH 20), 7.76 (d, J = 8.9 Hz, 1H, CH 6), 7.05 (s, 1H, NH 9), 7.08 - 6.98 (m, 2H, CH 18), 6.92 (s, 1H, CH 3), 6.91 (d, J = 8.9 Hz, 1H, CH 7), 6.78 - 6.68 (m, 2H, CH 17), 5.81 (d, J = 8.2 Hz, 1H, NH 11), 3.85 (dtq, J = 8.2, 7.3, 6.5 Hz, 1H, CH 12), 2.70 - 2.48 (m, 2H, CH 2 15), 2.22 (s, 3H, CH 3 5), 2.17 (s, 3H, CH 3 1), 1.79 - 1.60 (m, 2H, CH 2 14), 1.15 (d, J = 6.6 Hz, 3H, CH 3 13). 13 C NMR (75MHz, アセトン-d 6 , 20℃), δ (ppm): 156.3 (COH 19), 156.0 (CO 10), 136.8 (C 8), 133.8 (C 16), 132.3 (C 4), 132.0 (C 2), 131.5 (CH 3), 130.1 (CH 18), 127.5 (CH 7), 122.5 (CH 6), 115.9 (CH 17), 46.0 (CH 12), 40.4 (CH 2 14), 32.3 (CH 2 15), 21.9 (CH 3 13), 20.7 (CH 3 5), 18.1 (CH 3 1). HRMS (ESI+): m / z C 19 H 24 N2 O 2 Na + (M+Na) + Calculated value 335.1730; measured value 335.1732. Purity at HPLC λ = 254 nm: 96% (general conditions, R t = 18.69 minutes). MS (ESI+): m / z (%) 313.2 (100) [M+H + ].

[1083] (Example 52) 1-(3-cyclopropylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea Process 1 1-(3-cyclopropylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea (AM1) - Following typical procedure 5Bis part 2 using 1-(3-isocyanatobutyl)-4-methoxybenzene (0.558 mmol, 1.0 equiv, 114 mg), 3-cyclopropylaniline hydrochloride (0.558 mmol, 1.0 equiv, 95 mg) and triethylamine (1.116 mmol, 2.0 equiv, 152 μl). The crude product was purified by SCC (PE / acetone-100:0 to 80:20) to give 11-(3-cyclopropylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea AM1, 93 mg, yield: 49%, as a colorless mixture.

[1084] [ka]

[1085] 1 H NMR (300MHz, acetone-d 6, 20℃), δ (ppm): 7.86 (s, 1H), 7.28 - 7.18 (m, 2H), 7.09 (m, 2H), 6.84 - 6.76 (m, 3H), 6.67 - 6.60 (m, 1H), 5.76 (d, J = 8.2 Hz, 1H), 3.97 - 3.78 (m, 1H), 3.73 (s, 3H), 2.73 - 2.50 (m, 2H), 1.90 - 1.77 (m, 1H), 1.76 - 1.64 (m, 2H), 1.15 (d, J = 6.6 Hz, 3H), 0.94 - 0.80 (m, 2H), 0.67 - 0.56 (m, 3H).

[1086] Process 2 1-(3-cyclopropylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea (52) - 1-(3-cyclopropylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea AM1 (0.266 mmol, 1 equiv, 90 mg) as the methoxy-protected urea in DCM (4 mL) with BBr 3 (1M in DCM, 1.064 mmol, 4.0 equiv, 1.064 mL) and typical procedure 6 was followed. The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give pure compound 52 as a white solid in sufficient quantity for characterization and biological assays.

[1087] [ka]

[1088] 1 H NMR (300MHz, acetone-d 6, 20 °C), δ (ppm): 8.10 (s, 1H, OH 20), 7.71 (s, 1H, NH 9), 7.25 - 7.22 (m, 2H, CH 6 - 7), 7.10 - 7.07 (m, 1H, CH 4), 7.06 - 7.00 (m, 2H, CH 18), 6.77 - 6.70 (m, 2H, CH 17), 6.65 - 6.62 (m, 1H, CH 5), 5.63 (d, J = 8.2 Hz, 1H, NH 11), 3.92 - 3.79 (m, 1H, CH 12), 2.67 - 2.50 (m, 2H, CH 2 15), 1.89 - 1.80 (m, 1H, CH 2), 1.75 - 1.67 (m, 2H, CH 2 14), 1.15 (d, J = 6.5 Hz, 3H, CH 3 13), 0.93 - 0.87 (m, 2H, CH 2 6), 0.65 - 0.60 (m, 2H, CH 2 1). 13 C NMR (75 MHz, acetone - d 6 , 20 °C), δ (ppm): 156.3 (COH 19), 155.7 (CO 10), 145.3 (C 3), 141.8 (C 5), 133.7 (CH 17), 130.1 (CH 18), 129.3 (C 7), 119.4 (C 8), 116.0 (C 6), 116.0 (C 4), 115.9 (C 16), 45.9 (CH 12), 40.3 (CH 2 14), 32.3 (CH 2 15), 21.8 (CH 3 13), 16.0 (CH 2), 9.4 (CH 2 1). HRMS (ESI+): m / z C 20 H 24 N 2 O 2 Na + (M + Na) + calculated value for 347.1730; measured value 347.1733. Purity at HPLC λ = 254 nm: 99% (general conditions, R t = 20.16 minutes). MS (ESI+): m / z (%) 325.3 (100) [M+H + ].

[1089] (Example 53) 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(5-isopropyl-2-methylphenyl)urea Process 1 1-(5-isopropyl-2-methylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea (AN1) - Part 2 of typical procedure 5Bis was followed using 1-(3-isocyanatobutyl)-4-methoxybenzene (0.244 mmol, 1.0 equiv, 50 mg) and 5-isopropyl-2-methylaniline (0.244 mmol, 1.0 equiv, 29 mg). The crude product was purified by SCC (PE / acetone-100:0 to 80:20) to give 1-(5-isopropyl-2-methylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea AN1, 56 mg, yield: 66% as a white solid. R f (DCM / MeOH-98:2): 0.65.

[1090] [ka]

[1091] 1 H NMR (300MHz, acetone-d 6, 20℃), δ (ppm): 7.89 (d, J = 1.9 Hz, 1H), 7.17 - 7.10 (m, 2H), 7.08 (s, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.86 - 6.80 (m, 2H), 6.78 (dd, J = 7.7, 1.9 Hz, 1H), 5.89 (d, J = 8.2 Hz, 1H), 3.93 - 3.82 (m, 1H), 3.75 (s, 3H), 2.83 - 2.79 (m, 1H), 2.72 - 2.55 (m, 2H), 2.16 (s, 3H), 1.82 - 1.63 (m, 2H), 1.21 (d, J = 6.9 Hz, 6H), 1.16 (d, J = 6.6 Hz, 3H).

[1092] Process 2 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(5-isopropyl-2-methylphenyl)urea (53) - 1-(5-isopropyl-2-methylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea AN1 (0.158 mmol, 1.0 equiv, 56 mg) as the methoxy-protected urea in DCM (3 mL) with BBr 3 (1M in DCM, 0.632 mmol, 4.0 equiv, 0.632 mL) and typical procedure 6 was followed. The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give pure compound 53 as a white solid in sufficient quantity for characterization and biological assays.

[1093] [ka]

[1094] 1 H NMR (500MHz, acetone-d 6, 20 °C), δ (ppm): 8.04 (s, 1H, OH 21), 7.88 (d, J = 1.9 Hz, 1H, CH 9), 7.15 (s, 1H, NH 10), 7.09 - 6.99 (m, 2H, CH 18), 7.01 (d, J = 7.7 Hz, 1H, CH 5), 6.77 (dd, J = 7.7, 1.9 Hz, 1H, CH 4), 6.79 - 6.69 (m, 2H, CH 19), 5.98 (d, J = 8.1 Hz, 1H, NH 12), 3.88 - 3.84 (m, 1H, CH 13), 2.83 (septet, J = 6.9 Hz, 1H, CH 2), 2.69 - 2.54 (m, 2H, CH 2 16), 2.18 (s, 3H, CH 3 7), 1.80 - 1.62 (m, 2H, CH 2 15), 1.21 (d, J = 6.9 Hz, 6H, CH 3 1), 1.16 (d, J = 6.6 Hz, 3H, CH 3 14). 13 C NMR (125 MHz, acetone-d 6 , 20 °C), δ (ppm): 156.5 (COH 20), 156.1 (CO 11), 147.8 (C 3), 139.5 (C 8), 134.0 (C 17), 130.9 (CH 5), 130.2 (CH 18), 125.5 (C 6), 121.0 (CH 4), 120.3 (CH 9), 116.1 (CH 19), 46.2 (CH 13), 40.5 (CH 2 15), 34.8 (CH 2), 32.5 (CH 2 16), 24.6 (CH 3 1), 22.0 (CH 3 14), 17.9 (CH 3 7). HRMS (ESI+): m / z C 21 H 28 N 2 O 2 Na +(M+Na) + Calculated value 363.2048; measured value 363.2051. Purity at HPLC λ = 254 nm: 93% (general conditions, R t = 21.60 minutes). MS (ESI+): m / z (%) 341.3 (100) [M+H + ].

[1095] (Example 54) 1-(2-ethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea Process 1 1-(3-Cyclopropylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea (AO1) - Typical procedure 5Bis part 2 was followed using 1-(3-isocyanatobutyl)-4-methoxybenzene (0.487 mmol, 1.0 equiv, 100 mg) and 2-ethylaniline (0.487 mmol, 1.0 equiv, 59 mg). The reaction flask was sealed and heated at 35° C. overnight. The solution was evaporated, triturated with DiPE and filtered to give 1-(2-ethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea AO1, 121 mg, 76% yield as an off-white solid. Melting point: 115° C.

[1096] [ka]

[1097] 1 H NMR (300MHz, chloroform-d 1 , ,20℃), δ (ppm): 7.33 - 7.27 (m, 2H), 7.24 - 7.19 (m, 2H), 7.11 - 7.02 (m, 2H), 6.84 - 6.77 (m, 2H), 5.89 (s, 1H), 4.31 (s, 1H), 3.98 - 3.88 (m, 1H), 3.77 (s, 3H), 2.70 - 2.53 (m, 4H), 1.73 - 1.60 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H), 1.14 (d, J = 6.5 Hz, 3H). 13 C NMR (75MHz, chloroform-d 1 , 20℃), δ (ppm): 158.0, 156.3, 139.8, 135.4, 134.0, 129.7, 129.3, 127.3, 127.0, 126.9, 114.0, 55.4, 46.2, 39.5, 31.7, 24.6, 21.7, 14.7.

[1098] Process 2 1-(2-Ethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea (54) - 1-(2-Ethylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea AO1 (0.077 mmol, 1.0 equiv, 25 mg) as the methoxy-protected urea in DCM (2 mL) with BBr 3 (1M in DCM, 0.308 mmol, 4.0 equiv, 0.308 mL) and typical procedure 6 was followed. The mixture was quenched by adding ice (#2 g / 0.1 mmol) and extracted with DCM and EtOAc. The solvent was removed and a fraction of the crude mixture (10-20 mg) was purified by semi-preparative HPLC to give pure compound 54 as a white solid in sufficient quantity for characterization and biological assays.

[1099] [ka]

[1100] 1 H NMR (300MHz, アセトン-d 6 , 20℃), δ (ppm): 8.14 (s, 1H, OH 20), 7.92 (dd, J = 8.1, 1.3 Hz, 1H, CH 7), 7.18 (s, 1H, NH 9), 7.13 (dd, J = 8.1, 1.3 Hz, 1H, CH 4), 7.10 (td, J = 7.5, 1.4 Hz, 1H, CH 6), 7.06 - 6.98 (m, 2H, CH 18), 6.94 (td, J = 7.5, 1.4 Hz, 1H, CH 5), 6.78 - 6.69 (m, 2H, CH 17), 5.95 (d, J = 8.2 Hz, 1H, NH 11), 3.87 (dtq, J = 8.2, 7.3, 6.6 Hz, 1H, CH 12), 2.60 (q, J = 7.6 Hz, 2H, CH 2 2), 2.64 - 2.52 (m, 2H, CH 2 15), 1.80 - 1.61 (m, 2H, CH 2 14), 1.17 (t, J = 7.6 Hz, 3H, CH 3 1), 1.15 (d, J = 6.6 Hz, 3H, CH 3 13). 13 C NMR (75MHz, アセトン-d 6 , 20℃), δ (ppm): 156.3 (COH 19), 156.1 (CO 10), 138.6 (C 8), 134.2 (C 3), 133.7 (C 16), 130.1 (CH 18), 129.1 (CH 4), 126.9 (CH 6), 123.5 (CH 5), 122.9 (CH 7), 115.9 (CH 17), 46.0 (CH 12), 40.4 (CH 2 14), 32.3 (CH 2 15), 24.9 (CH 2 2), 21.9 (CH 3 13), 14.5 (CH 3 1). HRMS (ESI+): m / z C 19 H 24 N 2 O 2 Na + (M+Na) + Calculated value 335.1730; measured value 335.1731. Purity at HPLC λ = 254 nm: 98% (general conditions, R t = 19.36 minutes). MS (ESI+): m / z (%) 313.3 (100) [M+H + ].

[1101] (Example 55) 1-(3-fluoro-5-methylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea Process 1 1-Fluoro-3-isocyanato-5-methylbenzene (AP1) - Typical procedure 5Bis part 1 was followed using 3-fluoro-5-methylaniline (0.799 mmol, 1.0 equiv, 100 mg) and triethylamine (1.6 mmol, 2.0 equiv, 216 μL) in a solution of DCM (10 mL) under argon atmosphere. The mixture was cooled to 0-5 °C, then triphosgene (0.4 mmol, 0.5 equiv, 120 mg) pre-dissolved in DCM (2 mL) was slowly added to the reaction and the mixture was allowed to warm to room temperature. The reaction was monitored by TLC and stopped upon complete consumption of the amine derivative (4 h). The reaction mixture was concentrated in vacuo, then filtered and purified by HPLC with Et 2 The organic layer was concentrated in vacuo to give crude 1-fluoro-3-isocyanato-5-methylbenzene AP1, which was directly reused in the next step.

[1102] [ka]

[1103] Process 2 1-(3-Fluoro-5-methylphenyl)-3-(4-(4-methoxyphenyl)butan-2-yl)urea (AP2) - Following typical procedure 5Bis part 2 using a solution of 4-(4-methoxyphe...

Claims

1. Formula I: 【Chemistry 1】 [In the formula, A is selected from -NH-, -N(Me)-, and -O-; L is 【Chemistry 2】 or LA is 【Chemistry 3】 and; Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH 2 - and -C(O)NH-, or a single bond; Z is O or S; R 1 and R 2 is independently selected from H and OH, with the proviso that R 1 and R 2 At least one of is H, and R 1 and R 2 provided that is not simultaneously H; Cy: 【Chemistry 4】 (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen; R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl; R 5 is H or C1-C4-alkyl; R 6 is H, C1-C4-alkyl, C3-C4-cycloalkyl, halogen, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 is selected from R 8 and R 9 are independently selected from hydrogen, C1-C4-alkyl and C3-C4-cycloalkyl; R 9 is C1-C4-alkyl; R 10 is selected from H and C1-C4-alkyl; R 7 is H or C1-C4-alkyl; However, R 3 , R 4 , R 5 , R 6 and R 7 provided that not all of are simultaneously H); 【Chemistry 5】 (In the formula, R 11 and R 12 are independently selected from hydrogen and C1-C4-alkyl; 【Chemistry 6】 Selected from; However, Cy is 【Chemistry 7】 If R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 provided that not all are simultaneously H; below: (R)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,4-dimethylbenzamide; (R)-4-Fluoro-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)benzamide; (S)-N-Ethyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (S)-N-Cyclopropyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (S)-N1-(5-carbamoyl-2-fluorophenyl)-N2-(4-(4-hydroxyphenyl)butan-2-yl)oxalamide; (R)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,4-dimethylbenzamide; (S)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)acetamide; (S)-1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(5-iodo-2-methylphenyl)urea; (S)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)propionamide; (S)-3-acetamido-N-(4-(4-hydroxyphenyl)butan-2-yl)-4-methylbenzamide; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)benzamide; (R)-N-Ethyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; Methyl (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzoate; (R)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)isobutyramide; (S)-1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,N,4-trimethylbenzamide; (S)-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; (R)-N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylphenyl)acetamide; (R)-N1-(5-carbamoyl-2-methylphenyl)-N2-(4-(4-hydroxyphenyl)butan-2-yl)oxalamide; N-Ethyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; 3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,4-dimethylbenzamide; 3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; 3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,2-dimethylbenzamide; 4-Fluoro-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)benzamide; 4-Fluoro-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N-methylbenzamide; N-cyclopropyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; N-(3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)phenyl)isobutyramide; N-(5-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-2-methylphenyl)acetamide; (S)-1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(m-tolyl)urea; 1-(2,5-dimethylphenyl)-3-(4-phenylbutan-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-hydroxyphenethyl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(2-fluorophenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(2-ethyl-6-methylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; N-(2,5-dimethylphenyl)-4-(3-hydroxyphenyl)piperazine-1-carboxamide; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-phenylurea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(m-tolyl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(p-tolyl)urea; 1-Cyclohexyl-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; and 1-(benzo[d][1,3]dioxol-5-yl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea A compound of formula I, a pharma- ceutically acceptable salt or solvate thereof, which is not any of:

2. 2. The compound of claim 1, wherein Z is O.

3. R 1 is OH and R 2 The compound according to claim 1 or 2, wherein is H.

4. Formula VII: 【Chemistry 8】 (In the formula, R 1 , R 2 , L, A, Z, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined in claim 1), or a pharma- ceutically acceptable salt or solvate thereof.

5. Formula IX: 【Chemistry 9】 (In the formula, L, A, Y, R 3 , R 4 , R 5 , R 6 and R 7 is as defined in claim 1), or a pharma- ceutically acceptable salt or solvate thereof.

6. 1-(2,5-dimethylphenyl)-3-(4-hydroxybenzyl)urea; 1-(2,5-dimethylbenzyl)-3-(4-hydroxybenzyl)urea; 1-(2,5-dimethylbenzyl)-3-(4-hydroxyphenethyl)urea; 1-(2,5-dimethylphenyl)-3-(3-(4-hydroxyphenyl)propyl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)-2-methylbutan-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)but-3-yn-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(3-(4-hydroxyphenyl)prop-2-yn-1-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)-2-methylbut-3-yn-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-indol-3-yl)urea; N-(2,5-dimethylphenyl)-4-(4-hydroxyphenyl)piperazine-1-carboxamide; 1-(2,5-dimethylphenyl)-3-(3'-hydroxy-[1,1'-biphenyl]-4-yl)urea; 1-(2,5-dimethylphenyl)-3-(4'-hydroxy-[1,1'-biphenyl]-4-yl)urea; 1-(2,5-dimethylphenyl)-3-(4'-hydroxy-[1,1'-biphenyl]-3-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)cyclohexyl)urea; 1-(2,5-dimethylphenyl)-3-(1-(3-hydroxyphenyl)piperidin-3-yl)urea; 3-(2,5-dimethylphenyl)-1-(4-(4-hydroxyphenyl)butan-2-yl)-1-methylurea; 2-(2,5-dimethylphenyl)-N-(4-(4-hydroxyphenyl)butan-2-yl)acetamide; 2,5-Dimethylphenyl(4-(4-hydroxyphenyl)butan-2-yl)carbamate; 4-(4-hydroxyphenyl)butan-2-yl 2-(2,5-dimethylphenyl)acetate; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)thiourea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(o-tolyl)urea; 1-(3,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(3-isopropylphenyl)urea; 1-(benzo[d]thiazol-6-yl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(quinolin-7-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(2-methylnaphthalen-1-yl)urea; 1-(2-(tert-butyl)phenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(2,5-dimethylbenzyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(3-(3-hydroxyphenyl)prop-2-yn-1-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(3-hydroxyphenyl)but-3-yn-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(3-hydroxyphenyl)-2-methylbut-3-yn-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(6-(4-hydroxyphenyl)pyridin-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(3-(4-hydroxyphenyl)cyclohexyl)urea; 1-(2,5-dimethylphenyl)-3-(1-(3-hydroxyphenyl)piperidin-4-yl)urea; 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)piperidin-4-yl)urea; 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)piperidin-3-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)-1-methylurea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)-1,3-dimethylurea; 4-(4-hydroxyphenyl)butan-2-yl(2,5-dimethylphenyl)carbamate; 1-(2,4-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(3-cyclopropylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(5-isopropyl-2-methylphenyl)urea; 1-(2-ethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(3-fluoro-5-methylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; and 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(1H-indol-6-yl)urea 2. The compound of claim 1, selected from the group consisting of:

7. Formula I: 【Chemistry 10】 [In the formula, A is selected from -NH-, -N(Me)-, and -O-; L is 【Chemistry 11】 or LA is 【Chemistry 12】 and; Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH 2 - and -C(O)NH-, or a single bond; Z is O or S; R 1 and R 2 is independently selected from H, OH, and OMe, with the proviso that R 1 and R 2 is H; Cy: 【Chemistry 13】 (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen; R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl; R 5 is H or C1-C4-alkyl; R 6 is H, C1-C4-alkyl, C3-C4-cycloalkyl, halogen, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 is selected from R 8 and R 9 are independently selected from hydrogen, C1-C4-alkyl and C3-C4-cycloalkyl; R 9 is C1-C4-alkyl; R 10 is selected from H and C1-C4-alkyl; R 7 is H or C1-C4-alkyl); 【Chemistry 14】 (In the formula, R 11 and R 12 are independently selected from hydrogen and C1-C4-alkyl; 【Chemistry 15】 or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable carrier, diluent, excipient and / or adjuvant.

8. For use in the treatment of cancer, Combined with anticancer drugs Formula I: 【Chemistry 16】 [In the formula, A is selected from -NH-, -N(Me)-, and -O-; L is 【Chemistry 17】 or LA is 【Chemistry 18】 and; Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH 2 - and -C(O)NH-, or a single bond; Z is O or S; R 1 and R 2 is independently selected from H, OH, and OMe, with the proviso that R 1 and R 2 is H; Cy: 【Chemistry 19】 (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen; R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl; R 5 is H or C1-C4-alkyl; R 6 is H, C1-C4-alkyl, C3-C4-cycloalkyl, halogen, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 is selected from R 8 and R 9 are independently selected from hydrogen, C1-C4-alkyl and C3-C4-cycloalkyl; R 9 is C1-C4-alkyl; R 10 is selected from H and C1-C4-alkyl; R 7 is H or C1-C4-alkyl); 【Chemistry 20】 (In the formula, R 11 and R 12 are independently selected from hydrogen and C1-C4-alkyl; 【Chemistry 21】 or a pharma- ceutically acceptable salt or solvate thereof.

9. 2. A compound of formula I: 【Chemical 22】 [In the formula, A is selected from -NH-, -N(Me)-, and -O-; L is 【Chemistry 23】 or LA is 【Chemistry 24】 and; Y is -NH-, -N(Me)-, -NH-CH 2 -, -O-, -CH 2 - and -C(O)NH-, or a single bond; Z is O or S; R 1 and R 2 is independently selected from H, OH, and OMe, with the proviso that R 1 and R 2 is H; Cy: 【Chemistry 25】 (In the formula, R 3 is selected from H, C1-C4-alkyl and halogen; R 4 is selected from H, C1-C4-alkyl and C3-C4-cycloalkyl; R 5 is H or C1-C4-alkyl; R 6 is H, C1-C4-alkyl, C3-C4-cycloalkyl, halogen, C(O)NR 8 R 9 , NHC(O)R 10 and C(O)OR 11 is selected from R 8 and R 9 are independently selected from hydrogen, C1-C4-alkyl and C3-C4-cycloalkyl; R 9 is C1-C4-alkyl; R 10 is selected from H and C1-C4-alkyl; R 7 is H or C1-C4-alkyl); 【Chemistry 26】 (In the formula, R 11 and R 12 are independently selected from hydrogen and C1-C4-alkyl; 【Chemical 27】 or a pharma- ceutically acceptable salt or solvate thereof.

10. 10. The compound for use according to claim 8 or 9, wherein Z is O.

11. R 1 is OH and R 2 10. The compound for use according to claim 8 or 9, wherein is H.

12. The compound is 1-(2,5-dimethylphenyl)-3-(4-hydroxybenzyl)urea; 1-(2,5-dimethylbenzyl)-3-(4-hydroxybenzyl)urea; 1-(2,5-dimethylbenzyl)-3-(4-hydroxyphenethyl)urea; 1-(2,5-dimethylphenyl)-3-(3-(4-hydroxyphenyl)propyl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)-2-methylbutan-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)but-3-yn-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(3-(4-hydroxyphenyl)prop-2-yn-1-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)-2-methylbut-3-yn-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-indol-3-yl)urea; N-(2,5-dimethylphenyl)-4-(4-hydroxyphenyl)piperazine-1-carboxamide; 1-(2,5-dimethylphenyl)-3-(3'-hydroxy-[1,1'-biphenyl]-4-yl)urea; 1-(2,5-dimethylphenyl)-3-(4'-hydroxy-[1,1'-biphenyl]-4-yl)urea; 1-(2,5-dimethylphenyl)-3-(4'-hydroxy-[1,1'-biphenyl]-3-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)cyclohexyl)urea; 1-(2,5-dimethylphenyl)-3-(1-(3-hydroxyphenyl)piperidin-3-yl)urea; 3-(2,5-dimethylphenyl)-1-(4-(4-hydroxyphenyl)butan-2-yl)-1-methylurea; 2-(2,5-dimethylphenyl)-N-(4-(4-hydroxyphenyl)butan-2-yl)acetamide; 2,5-Dimethylphenyl(4-(4-hydroxyphenyl)butan-2-yl)carbamate; 4-(4-hydroxyphenyl)butan-2-yl 2-(2,5-dimethylphenyl)acetate; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)thiourea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(o-tolyl)urea; 1-(3,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(3-isopropylphenyl)urea; 1-(benzo[d]thiazol-6-yl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(quinolin-7-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(2-methylnaphthalen-1-yl)urea; 1-(2-(tert-butyl)phenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; (S)-1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; (R)-1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-phenylbutan-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-hydroxyphenethyl)urea; N-(2,5-dimethylphenyl)-4-(3-hydroxyphenyl)piperazine-1-carboxamide; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(p-tolyl)urea; 3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; 3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-N,4-dimethylbenzamide; 4-Fluoro-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)benzamide; N-Ethyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; N-cyclopropyl-3-(3-(4-(4-hydroxyphenyl)butan-2-yl)ureido)-4-methylbenzamide; N 1 -(5-carbamoyl-2-fluorophenyl)-N 2 -(4-(4-hydroxyphenyl)butan-2-yl)oxalamide; 1-(2,5-dimethylbenzyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(3-(3-hydroxyphenyl)prop-2-yn-1-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(3-hydroxyphenyl)but-3-yn-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(3-hydroxyphenyl)-2-methylbut-3-yn-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(6-(4-hydroxyphenyl)pyridin-2-yl)urea; 1-(2,5-dimethylphenyl)-3-(3-(4-hydroxyphenyl)cyclohexyl)urea; 1-(2,5-dimethylphenyl)-3-(1-(3-hydroxyphenyl)piperidin-4-yl)urea; 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)piperidin-4-yl)urea; 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)piperidin-3-yl)urea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)-1-methylurea; 1-(2,5-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)-1,3-dimethylurea; 4-(4-hydroxyphenyl)butan-2-yl(2,5-dimethylphenyl)carbamate; 1-(2,4-dimethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(3-cyclopropylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(5-isopropyl-2-methylphenyl)urea; 1-(2-ethylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(3-fluoro-5-methylphenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(1H-indol-6-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-phenylurea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(m-tolyl)urea; 1-Cyclohexyl-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; and 1-(benzo[d][1,3]dioxol-5-yl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea 10. The compound for use according to claim 8 or 9, selected from the group consisting of:

13. 13. The compound for use according to any one of claims 8 to 12, wherein the anticancer agent is an alkylating agent.

14. 14. The compound for use according to claim 13, wherein the alkylating agent is temozolomide.

15. 15. The compound for use according to any one of claims 8 to 14, wherein the cancer is selected from glioblastoma, triple negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer.

16. 1-(2,5-dimethylphenyl)-3-(6-(3-hydroxyphenyl)pyridin-3-yl)urea; 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-1H-pyrrol-3-yl)urea; 1-(2,5-dimethylphenyl)-3-(1-(4-hydroxyphenyl)-2-(prop-1-en-2-yl)-1H-indol-3-yl)urea; 1-(3,5-difluorophenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; 1-(4-(4-hydroxyphenyl)butan-2-yl)-3-(3-methyl-5-(trifluoromethyl)phenyl)urea; and 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(4-hydroxyphenyl)butan-2-yl)urea; a hydroxyphenyl compound selected from the group consisting of or a pharma- ceutically acceptable salt or solvate thereof.

17. 17. A pharmaceutical composition comprising a hydroxyphenyl compound according to claim 16, or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable carrier, diluent, excipient and / or adjuvant.

18. 17. The hydroxyphenyl compound of claim 16, in combination with an anti-cancer drug, for use in the treatment of cancer.

19. 17. The hydroxyphenyl compound of claim 16 for use in increasing the sensitivity of cancer cells to anticancer drugs in the treatment of cancer.

20. 20. The hydroxyphenyl compound for use according to claim 18 or 19, wherein the anticancer agent is an alkylating agent.

21. 21. The hydroxyphenyl compound for use according to claim 20, wherein the alkylating agent is temozolomide.

22. 22. The hydroxyphenyl compound for use according to any one of claims 18 to 21, wherein the cancer is selected from glioblastoma, triple negative breast cancer, lung cancer, osteosarcoma, prostate cancer, ovarian cancer and pancreatic cancer.

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