BENZENESULFONAMIDE THIAZOLE COMPOUNDS AND THEIR USE FOR THE TREATMENT OF CANCER - Patent application

Abstract

The present inventors have demonstrated that certain benzenesulfonamide thiazole compounds (I) have the ability to induce early endoplasmic reticulum stress, which also leads to the inhibition of proliferation and death of cancerous cells.

Description

Detailed Description of the Invention

[0001] FIELD OF THEINVENTION The present invention relates to novel benzenesulfonamide thiazole compounds and their use for the treatment of cancer.

[0002] BACKGROUND OF THEINVENTION Multiple diseases, such as cancer, are attributed to uncontrolled metabolism and protein synthesis that overwhelms the protein folding capacity of the endoplasmic reticulum (ER), resulting in the pathological accumulation of misfolded proteins, known as ER stress (Song et al. Trends in Immunology, 2019). As a result, the unfolded protein response (UPR) complex is overactivated to cope with the high flux of proteins being processed through the ER and to maintain ER homeostasis. Alterations in ER homeostasis cause the accumulation of misfolded / unfolded proteins in the ER, activating signaling pathways that orchestrate adaptive cellular responses. One of the key proteins involved in the UPR is HSPA5 / GRP78 / BiP.

[0003] GRP78 regulates the balance between cancer cell viability and apoptosis by maintaining ER protein folding competence and maintaining ER stress sensors and ER-associated pro-apoptotic machinery in an inactive state.

[0004] When misfolded proteins accumulate in the ER, GRP78 binds to them, thereby releasing the UPR sensor and leading to activation of the UPR pathway. Conversely, depletion or inactivation of GRP78 can trigger the UPR spontaneously, leading to diverse physiological outcomes (Lee, A. Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer 14, 263-276 (2014). https: / / doi.org / 10.1038 / nrc3701).

[0005] Therefore, HSPA5 is not only thought to function as a protein chaperone, but also to be a master regulator of the UPR. Thus, HSPA5 is positively correlated with poor prognosis, especially in cancer. Indeed, HSPA5 is positively correlated with tumor progression, increased tumor size, and poor prognosis in melanoma patients (Michael Cerezoa and Stephane Rocchi, New anti-cancer molecules targeting HSPA5 / BIP toduce endoplasmic reticulum stress, autophagy and apoptosis, Autophagy.2017; 13(1):216-217).

[0006] Therefore, the identification of new candidate molecules that act on ER stress by targeting HSPA5 is a promising therapeutic strategy for cancer treatment and is widely supported by the scientific community.

[0007] WO2014072486 discloses the first series of benzenesulfonamide thiazole compounds invented by the present inventors, which show activity in the treatment of cancer, especially melanoma models, in a mechanism mediated by HSPA5 selective binding. Among these compounds, the lead compound HA15 shows anti-melanoma effects by targeting the ER stress axis, which induces specific cancer cell death by simultaneous induction of autophagy and apoptosis. These results highlight the important role of this specific pathway in melanoma malignancy and cancer, and strengthen the idea that ER stress inducers will be useful in the treatment of various areas of cancer in the future (Michael Cerezoa and Stephane Rocchi, New anti-cancer molecules targeting HSPA5 / BIP toduce endoplasmic reticulum stress, autophagy and apoptosis, Autophagy.2017; 13(1):216-217).

[0008] The inventors have optimized the series described in WO2014 / 072486 to generate novel hydrophobic derivatives that are also involved in the induction of ER stress and show substantially higher potency in melanoma models (WO2017 / 017004). The phenyl groups of these compounds are (C6-C 12 ) alkyl group. We have demonstrated the advantage of introducing apolar substituents into this ring. A clear correlation between the size of the apolar group and activity has been found. Indeed, highly active compounds are substituted in the para position with octyne, hexyl, and octyl chains.

[0009] We have now improved these compounds in terms of pharmacological properties (potency and drug-like properties). These novel derivatives highly reduce ER stress markers in several in vitro and in vivo cancer models via a GRP78(BiP)-mediated mechanism, supporting their ability to treat cancer, especially those overexpressing HSPA5.

[0010] Summary of the Invention The invention is defined by the claims.

[0011] In a first aspect, the present invention relates to benzenesulfonamide thiazole compounds of formula (I): [ka] During the ceremony, R1 is a 5-(dimethylamino)naphthalene group or a 4-pentylphenyl group; R2 is selected from H, halogen, and OR6; R3 is selected from C1-C8 alkyl, NR4R5; R4 is selected from H, alkyl optionally substituted with a nitrogen-containing heterocycle; R5 is selected from H, alkyl optionally substituted with a nitrogen-containing heterocycle, and COR7; R4 and R5 can alternatively together form an optionally substituted nitrogen-containing heterocycle; R6 is selected from C1-C8 alkyl, C1-C8 alkyl-O-C1-C8 alkyl; R7 is, Optionally substituted nitrogen-containing heterocycles ·O-alkyl, NHCO-alkyl, NHCOO-alkyl, COO-alkyl, NH-alkyl, NH-alkyl-OH, NHP(O)(O-alkyl)2, NH-alkyl-SO3H, NH-alkyl-N(alkyl)2 Alkenyl is selected from C1-C8 alkyl optionally substituted with

[0012] The present inventors have demonstrated that certain benzenesulfonamide thiazole compounds have the ability to induce early endoplasmic reticulum stress, which also leads to the inhibition of cancer cell proliferation and death.

[0013] Therefore, in a second aspect, the present invention relates to a benzenesulfonamide thiazole compound of formula (I) for use in the treatment of cancer.

[0014] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1: Incucyte® IC50 determinations of PB628 and HA15 in A375 melanoma cells.

[0015] Figure 2: Toxicity of fibroblasts and melanoma cells after treatment with PB628 or HA15.

[0016] Detailed Description The present inventors demonstrated the efficacy of novel benzenesulfonamide thiazole compounds in reducing CHOP, a known endoplasmic reticulum (ER) stress marker, in a human melanoma cell line (A375), human gastric cancer-derived cell lines (SH-10-TC, KatoIII), and esophageal squamous cell carcinoma (Kyse70), all of which overexpress HSPA5.

[0017] CHOP, also known as DNA damage-induced transcript 3 and C / EBP homologous protein, is a proapoptotic transcription factor encoded by the DDIT3 gene CHOP is believed to be a key player in ER stress and an initiator of ER stress-associated cell death, and has also shown that these compounds lead to cancer cell proliferation inhibition and death.

[0018] Thus, in a first aspect, the present invention relates to a benzenesulfonamide thiazole of formula (I): [ka] During the ceremony R1 is a 5-(dimethylamino)naphthalene group or a 4-pentylphenyl group; R2 is selected from H, halogen, and OR6; R3 is selected from C1-C8 alkyl, NR4R5; R4 is selected from H, alkyl optionally substituted with a nitrogen-containing heterocycle; R5 is selected from H, alkyl optionally substituted with a nitrogen-containing heterocycle, and COR7; R4 and R5 can alternatively together form an optionally substituted nitrogen-containing heterocycle; R6 is selected from C1-C8 alkyl, C1-C8 alkyl-O-C1-C8 alkyl; R7 is, Optionally substituted nitrogen-containing heterocycles O-alkyl, NHCO-alkyl, NHCOO-alkyl, COO-alkyl, NH-alkyl, NH-alkyl-OH, NHP(O)(O-alkyl)2, NH-alkyl-SO3H, NH-alkyl-N(alkyl)2 Alkenyl is selected from C1-C8 alkyl optionally substituted with

[0019] (Compound of formula (I)) In the above general formula (I), unless otherwise specified: Alkyl denotes a straight or branched chain group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of suitable alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl etc. C1-C8 alkyl corresponds to an alkyl group containing from 1 to 8 carbon atoms.

[0020] Alkenyl denotes a straight or branched chain group containing 2, 3, 4, 5 or 6 carbon atoms and one or more double bonds. Examples of suitable alkenyl radicals are ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, isopentenyl, n-hexenyl, etc.

[0021] Heterocycles contain 3 to 8 atoms and at least one heteroatom different from a carbon atom. Examples of suitable heterocycles include piperidine, piperazine, methylpiperazine, morpholine, 4-membered β-lactams, 5-membered 1,2,3-triazoles, imidazoles, benzimidazoles, pyrazoles, oxadiazoles, oxazoles, isoxazoles and thiazoles, 6-membered quinolines, quinazolines, pyrimidines and pyrimidinones. Such heterocycles may be substituted, for example, with C1-C8 alkyl or C1-C8 alkyl-OH, CONH2.

[0022] The halogen atoms are selected from the group consisting of fluorine, chlorine, bromine and iodine.

[0023] In the above general formula (I), a preferred group of compounds includes compounds of formula (II) in which R1 is a 5-(dimethylamino)naphthalene group: [ka] In the formula, R2 and R3 are as defined above.

[0024] Another preferred group of compounds includes compounds of formula (III) in which R1 is a 4-pentylphenyl group: [ka] In the formula, R2 and R3 are as defined above.

[0025] Another preferred group of compounds comprises compounds of formula (IV): [ka] Compound of formula (V) [ka] Compound of formula (VI) [ka] In the formula, R1, R2R4 and R5 are as defined above.

[0026] Preferred compounds according to the invention are: [Table 1] JPEG2025500428000010.jpg255166 JPEG2025500428000011.jpg241169 JPEG2025500428000012.jpg238169 JPEG2025500428000013.jpg235169

[0027] Thus, in one embodiment, the benzenesulfonamide thiazole compound of formula (I) is selected from among: N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-fluorophenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide 2-(2,3-dihydroxypropoxy)-N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)acetamide tert-Butyl (6-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-6-oxohexyl)carbamate Ethyl 5-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-5-oxopentanoate 6-Acetamido-N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)hexanamide tert-Butyl (4-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-4-oxobutyl)carbamate 4-((4-(3-((5-(dimethylamino(napthalene)-1-sulfonamido)phenyl)thiazol-2-yl)butanamide 5-(Dimethylamino)-N-(3-(2-methylthiazol-4-yl)phenyl)naphthalene-1-sulfonamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-morpholinoacetamide. N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide 1-(2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)piperidine-4-carboxamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-((2-hydroxyethyl)amino)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-((3-morpholinopropyl)amino)acetamide Diethyl-(2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)phosphoramidate N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-fluorophenyl)thiazol-2-yl)acetamide 2-((2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)amino)ethane-1-sulfone 2-(4-Methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide N-(5-(2-aminothiazol-4-yl)-2-methoxyphenyl)-4-pentylbenzenesulfonamide N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 6-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide 2-(4-methylpiperazin-1-yl)-N-(4-(4-(4-methylpiperazin-1-yl)-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-6-(4-methylpiperazin-1-yl)hexanamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(prop-2-yn-1-yloxy)phenyl)thiazol-2-yl)acrylamide 5-(Dimethylamino)-N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)naphthalene-1-sulfonamide N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acrylamido)phenyl)thiazol-2-yl)acrylamide N-(3-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide, N-(3-(2-(4-(2-hydroxyethyl)piperazin-1-yl)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide.

[0028] In one embodiment, the benzenesulfonamide thiazole compound of formula (I) is selected from among: N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-fluorophenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide 2-(2,3-dihydroxypropoxy)-N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)acetamide tert-Butyl (6-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-6-oxohexyl)carbamate Ethyl 5-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-5-oxopentanoate 6-Acetamido-N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)hexanamide tert-Butyl (4-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-4-oxobutyl)carbamate 4-((4-(3-((5-(dimethylamino(napthalene)-1-sulfonamido)phenyl)thiazol-2-yl)butanamide 5-(Dimethylamino)-N-(3-(2-methylthiazol-4-yl)phenyl)naphthalene-1-sulfonamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-morpholinoacetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide 1-(2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)piperidine-4-carboxamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-((2-hydroxyethyl)amino)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-((3-morpholinopropyl)amino)acetamide Diethyl-(2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)phosphoramidate N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-fluorophenyl)thiazol-2-yl)acetamide 2-((2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)amino)ethane-1-sulfone N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-6-(4-methylpiperazin-1-yl)hexanamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(prop-2-yn-1-yloxy)phenyl)thiazol-2-yl)acrylamide 5-(Dimethylamino)-N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)naphthalene-1-sulfonamide

[0029] In a further embodiment, the benzenesulfonamide thiazole compound of formula (I) is selected from the following: 2-(4-Methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide N-(5-(2-aminothiazol-4-yl)-2-methoxyphenyl)-4-pentylbenzenesulfonamide N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 6-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide 2-(4-methylpiperazin-1-yl)-N-(4-(4-(4-methylpiperazin-1-yl)-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide. N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acrylamido)phenyl)thiazol-2-yl)acrylamide N-(3-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide N-(3-(2-(4-(2-hydroxyethyl)piperazin-1-yl)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide.

[0030] In a preferred embodiment, the benzenesulfonamide thiazole compound of formula (I) is selected from among: 2-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 6-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 2-(4-methylpiperazin-1-yl)-N-(4-(4-(4-methylpiperazin-1-yl)-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide.

[0031] The benzenesulfonamide thiazole compound according to the present invention may be in the form of a pharma- ceutically acceptable salt, including its acid addition salts and base salts.

[0032] Suitable acid addition salts are formed from acids which form non-toxic salts, such as acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate and xinafoate salts.

[0033] Suitable base salts are formed from bases that form non-toxic salts.For example, aluminum salt, arginine salt, benzathine salt, calcium salt, choline salt, diethylamine salt, diolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, olamine salt, potassium salt, sodium salt, tromethamine salt and zinc salt.Hemi-salts of acids and bases can also be formed, such as hemisulfate salt and hemicalcium salt.For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 2002).

[0034] The benzenesulfonamide thiazole compounds used in the context of the present invention may exist in both unsolvated and solvated forms. The term "solvate" refers to a molecular complex containing a benzenesulfonamide thiazole compound and a stoichiometric amount of one or more pharma- ceutical acceptable solvent molecules, e.g., ethanol. The term "hydrate" is used when the solvent is water. Also included are complexes such as clathrates, drug-host inclusion complexes, in which, in contrast to the aforementioned solvates, the inclusion of the drug and the host is present in stoichiometric or nonstoichiometric amounts. Also included are complexes of the drug containing two or more organic and / or inorganic components, which may be in stoichiometric or nonstoichiometric amounts. The resulting complexes may be ionized, partially ionized or non-ionized. For a review of such complexes, see Haleblian, J Pharm Sci, 64 (8), 1269-1288 (August 1975).

[0035] Thus, references to the benzenesulfonamide thiazole compounds of formula (I) include references to salts, solvates and complexes thereof, and solvates and complexes of salts thereof. References to the benzenesulfonamide thiazole compounds of formula (I) include all polymorphs and crystal habits thereof, prodrugs thereof, and isomers (including optical isomers, geometric isomers and tautomers) and isotopically labeled compounds of formula (I).

[0036] [Synthetic Route] The compounds of the present invention can be prepared using conventional procedures, such as the exemplary methods described below.

[0037] [Synthetic pathways for PB600, PB601, PB602, PB603, PB604, PB651, PB690, PB691, PB692 and PB696] This route requires the synthesis of intermediate thiazoleanilines 3a, 3b, 3c according to the following methods, each of which is described below in relation to each step: [ka]

[0038] [2a] 4-(4-Fluoro-3-nitrophenyl)thiazol-2-amine (2a). To a solution of α-bromoacetophenone 1a (7.20 g, 27.5 mmol, 1 eq) in ethanol was added the corresponding thiourea (2.09 g, 27.5 mmol, 1 eq). The reaction mixture was then heated to 80° C. for 3 h and cooled to room temperature. The precipitate was filtered and washed with ethanol and diethyl ether to give the corresponding thiazole as a yellow solid in 74% yield (6.52 g). 1 H NMR (DMSO-d6, 200MHz): δ 7.45(s,1H),7.72(dd,J=11.2,8.8Hz,1H),8.19(ddd,J=8.8,4.2,2.4Hz,1H),8.50(dd,J=7.1,2.4Hz,1H).

[0039] [2b] 4-(4-Methoxy-3-nitrophenyl)thiazol-2-amine (2b). To a suspension of fluoroaryl 2a (2.40 g, 10.00 mmol) in THF (15 mL) was slowly added sodium methoxide (1.08 g, 20.00 mmol). The reaction intermediate was stirred at room temperature until the starting material was completely consumed (TLC monitoring CHx:EtOAc 60:40). THF was removed under reduced pressure and the crude residue was diluted with 100 mL of water and extracted three times with EtOAc (50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4 and concentrated under reduced pressure. The crude was subjected to silica gel column chromatography (DCM:EtOAc 100:0 to 50:50) to give 2b (2.31 g, 91%). 1 H NMR(400MHz,DMSO-d6) δ 8.28(d,J=2.3Hz,1H),8.05(dd,J=8.8,2.3Hz,1H),7.48(d,J=8.9Hz,1H),7.28(s,1H),3.98(s,3H).MS-ESI(m / z):[M+H] + =252.5.

[0040] [2c] 4-(4-(2-Methoxyethoxy)-3-nitrophenyl)thiazol-2-amine (2c). To a suspension of sodium hydride (60% in oil) (240.0 g, 10.08 mmol) in dry THF (33 mL) at 0° C., 2-methoxyethanol (760.0 μL, 9.66 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 20 min and a suspension of fluoroaryl 2a (1.00 g, 4.20 mmol) in dry THF (15 mL) was added very slowly. The reaction intermediate was stirred at 0° C. for 15 min and left at room temperature overnight until the starting material was completely consumed (TLC monitoring CHx:EtOAc 60:40). THF was removed under reduced pressure and the crude residue was diluted with 100 mL of water and extracted three times with EtOAc (50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4 and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (DCM:EtOAc 100:0 to 50:50) to give 2-ethoxymethanoyl 2c (1.22 g, 98%). 1 H NMR(Acetone-d6,200MHz):δ 3.36(s,3H),3.81-3.69(m,2H),4.39-4.23(m,2H),6.54(s,2H),7.02(s,1H ),7.33(d,J=8.8Hz,1H),8.05(dd,J=8.8,2.3Hz,1H),8.28(d,J=2.2Hz,1H).

[0041] 〔3a〕 4-(3-amino-4-fluorophenyl)thiazol-2-amine (3a). To a stirred suspension of nitro-aryl 2a (6.34 g, 19.80 mmol, 1.0 eq) in MeOH (0.01 M) were successively added ammonium chloride (2.11 g, 39.60 mmol, 2.0 eq) and zinc (9.71 g, 148.50 mmol, 7.5 eq). The reaction mixture was stirred at 70 °C until the starting material was completely consumed and the crude was filtered through a pad of Celite. The resulting filtrate was extracted three times with EtOAc and purified by silica gel flash chromatography (DCM:MeOH; 100:0 to 90:10) to give aniline 3a as a white powder (4.10 g, 99%). 1H NMR (DMSO-d6, 200MHz): δ 5.15 (s, 2H), 6.74 (s, 1H), 7.08-6.87 (m, 4H), 7.31-7.15 (m, 1H). 13 C NMR(DMSO-d6,50MHz):δ 100.3,113.7(dd,J=14.7,5.6Hz),114.9(d,J=18.7Hz),131.6(d,J=2.9Hz),136.11(d,J=13.2Hz),147.8,149.8,152.5,168.0. 19 F NMR(Acetone-d6,189MHz):δ -136.5(q,J=8.8Hz).

[0042] (3b) 4-(3-amino-4-methoxyphenyl)thiazol-2-amine (3b). To a stirred suspension of nitro-aryl 2b (2.00 g, 8.00 mmol, 1.0 eq) in MeOH (0.01 M) was added ammonium chloride (880.0 mg, 16.00 mmol, 2.0 eq) and zinc (3.92 g, 148.50 mmol, 7.5 eq) successively. The reaction mixture was stirred at 70 °C until the starting material was completely consumed and the crude was filtered through a pad of Celite. The resulting filtrate was extracted three times with EtOAc and purified by silica gel flash chromatography (DCM:MeOH; 100:0 to 90:10) to give aniline 3b as a white powder (1.68 g, 95%). 1 H NMR (DMSO-d6,400MHz)δ 3.77(s,4H),6.64(s,1H),6.78(d,J=8.4Hz,1H),6.97(s,2H),7.01(dd,J=8.3,1.9Hz,1H),7.11(d,J=2.0Hz,1H).

[0043] [3c] 4-(3-amino-4-(2-methoxyethoxy)phenyl)thiazol-2-amine (3c). To a stirred suspension of nitro-aryl 2c (1.22 g, 4.13 mmol, 1.0 eq) in MeOH (0.01 M) were successively added ammonium chloride (440.0 mg, 8.26 mmol, 2.0 eq) and zinc (2.03 g, 30.98 mmol, 7.5 eq). The reaction mixture was stirred at 70 °C until the starting material was completely consumed and the crude was filtered through a pad of Celite. The resulting filtrate was extracted three times with EtOAc and purified by silica gel flash chromatography (DCM:MeOH; 100:0 to 90:10) to give the aniline 3c as a white powder (560.0 mg, 33%). 1 H NMR(Acetone-d6,200MHz):δ 3.37(s,3H),3.80-3.61(m,2H),4.19-4.03(m,2H),6.43(s,2H),6.63(s,1H),6.8 0(d,J=8.4Hz,1H,H8),7.09(dd,J=8.3,2.1Hz,1H,H9),7.23(d,J=2.1Hz,1H,H5).

[0044] [Synthesis of compounds PB651, PB600 and PB603] These compounds are prepared by the methods described below. [ka] Each step will be described below for compounds 4a, 4b, and 4c and the resulting compounds.

[0045] [4a] N-(5-(2-aminothiazol-4-yl)-2-fluorophenyl)-5-(dimethylamino)naphthalene-1-sulfonamide (4a). To a solution of 3a (2.00 g, 9.62 mmol, 1 eq) in anhydrous DMF (0.2 M) was added anhydrous triethylamine (1.6 eq) and dansyl chloride (2.85 g, 10.58 mmol, 1.1 eq) under argon. The reaction mixture was reacted at room temperature until complete conversion of the starting material. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:EtOAc; 100:0 to 60:40) to give the title sulfonamide 4a as a yellow fluorescent powder (1.22 g, 29%). 1 H NMR(Acetone-d6,200MHz):δ 2.84(s,6H),6.50(s,2H),6.78(s,1H),6.93(dd,J=10.2,8.7Hz,1H),7.26(dd,J=7.6,0.9Hz,1H),7.66 -7.43(m,3H),7.96(dd,J=7.8,2.2Hz,1H),8.24(dd,J=7.3,1.2Hz,1H),8.63-8.45(m,2H),9.22(s,1H).

[0046] [4b] N-(5-(2-aminothiazol-4-yl)-2-methoxyphenyl)-5-(dimethylamino)naphthalene-1-sulfonamide (4b). To a solution of 3b (222.0 mg, 0.50 mmol, 1 eq) in anhydrous DMF (0.2 M) was added anhydrous triethylamine (1.6 eq) and dansyl chloride (148.0 mg, 0.55 mmol, 1.1 eq) under argon. The reaction mixture was reacted at room temperature until complete conversion of the starting material. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:EtOAc; 100:0 to 60:40) to give the title sulfonamide 4b as a pale yellow fluorescent powder (120.2 mg, 53%). 1H NMR(Acetone-d6,200MHz):δ 2.83(s,6H),3.24(s,3H),6.42(s,2H),6.70(s,2H),7.26(d,J=7.5Hz,1H),7.69-7.38(m,3H) ,7.94(d,J=2.1Hz,1H),8.13(dd,J=7.3,1.2Hz,1H),8.34(s,1H),8.50(dd,J=8.6,3.8Hz,2H).

[0047] [4c] N-(5-(2-aminothiazol-4-yl)-2-(2-methoxyethoxy)phenyl)-5-(dimethylamino)naphthalene-1-sulfonamide (4c). To a solution of 3c (415.0 mg, 1.57 mmol, 1 eq) in anhydrous DMF (0.2 M) was added anhydrous triethylamine (1.6 eq) and dansyl chloride (465.1 mg, 1.72 mmol, 1.1 eq) under argon. The reaction mixture was reacted at room temperature until complete conversion of the starting material. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:EtOAc; 100:0 to 70:30) to give the title sulfonamide 4c as a pale yellow fluorescent powder (326.3 mg, 42%). 1 H NMR(Acetone-d6,200MHz):δ 2.84(s,6H),3.40-3.25(m,5H),3.80-3.68(m,2H),6.44(s,2H),6.83-6.68(m,2H),7.27(dd,J=7.6, 0.9Hz,1H),7.66-7.38(m,3H),8.01(d,J=2.1Hz,1H),8.20(dd,J=7.3,1.3Hz,1H),8.60-8.39(m,3H).

[0048] [PB651] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-fluorophenyl)thiazol-2-yl)acetamide (PB651). Amine 4a (25.2 mg, 0.06 mmol) was placed in pure acetic anhydride (600 μL) at 40° C. for 1 h. The solvent was then removed under reduced pressure. The crude product was precipitated with Et2O and washed twice with Et2O (10 mL) to give the pure amide PB651 as a yellow fluorescent powder (24.5 mg, 89%). 1 H NMR(Acetone-d6,200MHz):δ 2.29(s,3H),2.85(s,6H),6.97(dd,J=10.2,8.6Hz,1H),7.36-7.12(m,2H),7.63-7.47(m,3H),8.07(dd, J=7.8,2.2Hz,1H),8.22(dd,J=7.4,1.3Hz,1H),8.52(dd,J=8.6,5.1Hz,2H),9.26(s,1H),11.20(s,1H). 13 C NMR(Acetone-d6,125MHz):δ 22.9,45.7,108.4,116.3,116.6(d,J=20.4Hz),120.2,122.9,124.1,124.38(d,J=7.4Hz),126.16(d,J=13.2Hz), 129.1,130.73(d,J=9.8Hz),130.9,131.6,132.47(d,J=3.2Hz),136.3,154.3,156.2,158.9,152.9,159.1,169.2. 19 F NMR(Acetone-d6,188MHz):δ -128.3.HRMS-ESI(m / z):[M+H] + calcd for C 23 H 22 O3N4FS2,485.1112;found:485.1116.

[0049] [PB600] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)acetamide (PB600). Amine 4b (45.4 mg, 0.10 mmol) was placed in pure acetic anhydride (1 mL) at 40° C. for 1 h. The solvent was then removed under reduced pressure. The crude product was precipitated with Et2O and washed twice with Et2O (10 mL) to give the pure amide PB600 as a yellow fluorescent powder (35.7 mg, 72%). 1 H NMR(Acetone-d6,200MHz):δ 2.29(s,3H),2.83(s,6H),3.27(s,3H),6.72(d,J=8.6Hz,1H),7.25(d,J=11.4Hz,2H),7.69-7.38(m,3H) ),8.04(d,J=2.1Hz,1H),8.12(dd,J=7.3,1.1Hz,1H),8.40(s,1H),8.51(t,J=7.8Hz,2H),11.15(s,1H). 13 C NMR(acetone-d6,50MHz):δ 22.9,45.7,55.9,106.8,112.0,116.1,120.6,121.5,123.9,124.0,127.2,128.7,128.8,13 0.6,130.7,130.8,131.1,136.4,149.8,151.6,152.8,158.9,169.1.HRMS-ESI(m / z):[M+H] + calcd for C 24 H 25 O4N4S2,497.1312,found:497.1312.HPLC(λ 254 ) Purity: 96.1%.

[0050] [PB603] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)acetamide (PB603). Amine 4c (115.0 mg, 0.23 mmol) was added to a solution of acetic anhydride (2 mL). The mixture was stirred at 40 °C for 8 h, and the mixture was quenched with a 4 M aqueous solution of sodium hydroxide (6 mL). The mixture was stirred for an additional 30 min and diluted with 20 mL water and 20 mL EtOAc. The aqueous layer was extracted twice with EtOAc (2 × 20 mL), and the combined organic layers were washed with water (2 × 20 mL) and 40 mL brine, and dried over MgSO4. The crude residue was subjected to silica gel chromatography DCM:EtOAc (100:0 to 60:40) to give amide PB603 as a yellow fluorescent powder (96.0 mg, 77%). 1 H NMR(Acetone-d6,200MHz):δ 2.29(s,3H),2.82(s,6H),3.33(d,J=6.4Hz,5H),3.84-3.68(m,2H),6.81(d,J=8.6Hz,1H),7.2 6(d,J=7.0Hz,2H),7.69-7.40(m,3H),8.24-8.05(m,2H),8.49(d,J=8.3Hz,2H),11.19(s,1H). 13 C NMR(Acetone-d6,50MHz):δ 22.9,45.7,59.0,69.7,71.1,107.1,114.7,116.2,120.4,120.7,123.6,124.0,128.2,128.9,129 .4,130.6,130.7,130.7,131.2,136.4,149.7,150.3,152.8,158.9,169.1.HRMS-ESI(m / z):[M+H] + calcd for C 26 H 29 O5N4S2,541.1574;found:541.1578.HPLC(λ 254 ) Purity: 95.5%;t R :7.04 minutes (method 1).

[0051] [Synthesis of compounds PB601, PB602 and PB604] These compounds are prepared by the methods described below. [ka] Each step will be described below for compounds 4a, 5b, and 5c and the resulting compounds.

[0052] 〔5a〕 To a stirred solution of amine 4a (1.00 g, 2.77 mmol) in dry THF (15 mL) was added DIEA (0.81 mL, 4.54 mmol). Chloroacetyl chloride (0.36 mL, 4.54 mmol) was then added dropwise to the mixture and allowed to react at room temperature for 30 min until the starting material was completely consumed (TLC DCM:EtOAc 70:30). The mixture was then quenched with 4 M aqueous sodium hydroxide solution (10 mL) and further stirred at room temperature for 30 min. The reaction mixture was diluted with 10 mL of water and extracted three times with EtOAc (30 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The crude residue was subjected to silica gel column chromatography (DCM:EtOAc 100:0 to 60:40) to give pure chloroacetyl 5a as a yellow fluorescent powder (0.70 g, 60%). 1 H NMR(Acetone-d6,200MHz):δ 2.84(s,6H),4.51(s,2H),6.98(dd,J=10.1,8.7Hz,1H),7.27(d,J=7.6Hz,1H),7.41(s,1H),7.66-7.45(m,3H),8 .09(dd,J=7.8,2.1Hz,1H),8.23(dd,J=7.3,1.1Hz,1H),8.52(dd,J=8.6,3.7Hz,2H),9.30(s,1H),11.54(s,1H).

[0053] 〔5b〕 To a stirred solution of amine 5a (100.0 mg, 0.22 mmol) in dry THF (1.5 mL) was added DIEA (115.0 μL, 0.44 mmol). Chloroacetyl chloride (38.0 μL, 0.44 mmol) was then added dropwise to the mixture and allowed to react at room temperature for 30 min until the starting material was completely consumed (TLC DCM:EtOAc 70:30). The mixture was then quenched with 4 M aqueous sodium hydroxide solution (10 mL) and further stirred at room temperature for 30 min. The reaction mixture was diluted with 10 mL of water and extracted three times with EtOAc (30 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The crude residue was subjected to silica gel column chromatography (DCM:EtOAc 100:0 to 60:40) to give chloroacetyl 5a (42.0 mg, 36%). 1 H NMR(Acetone-d6,200MHz):δ 2.84(s,6H),3.28(s,3H),4.50(s,2H),6.75(d,J=8.6Hz,1H),7.38-7.22(m,2H),7.67-7.41 (m,3H),8.05(d,J=2.2Hz,1H),8.12(dd,J=7.4,1.2Hz,1H),8.62-8.44(m,3H),11.48(s,1H).

[0054] [5c] To a stirred solution of amine 4c (190.0 mg, 0.38 mmol) in dry THF (2 mL) was added DIEA (132.0 μL, 0.76 mmol). Chloroacetyl chloride (61.0 μL, 0.76 mmol) was then added dropwise to the mixture and allowed to react for 30 min at room temperature until the starting material was completely consumed (TLC DCM:EtOAc 70:30). The mixture was then quenched with 4 M aqueous sodium hydroxide solution (10 mL) and further stirred for 30 min at room temperature. The reaction mixture was diluted with 10 mL of water and extracted three times with EtOAc (30 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The crude residue was subjected to silica gel column chromatography (DCM:EtOAc 100:0 to 60:40) to give chloroacetyl 5c as a yellow fluorescent powder (175.2 mg, 80%).1 H NMR(Acetone-d6,200MHz):δ 2.84(s,6H),3.34(d,J=8.4Hz,5H),3.87-3.68(m,2H),4.50(s,2H),6.84(d,J=8.6Hz,1H),7.28(d,J=7. 6Hz,1H),7.35(s,1H),7.68-7.42(m,3H),8.11(d,J=2.1Hz,1H),8.18(d,J=6.3Hz,1H),8.60-8.43(m,3H) 11.50(s,1H).

[0055] [PB601] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-fluorophenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide (PB601). To a suspension of chloroalkyl 5a (224.0 mg, 0.43 mmol, 1 eq) in acetonitrile or THF (0.2 M) was added triethylamine (1 eq) and N-hydroxyethylpiperazine (113.0 mg, 0.87 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:EtOAc 100:0 to 0:100) to give PB601 as a yellow fluorescent powder (165.0 mg, 63%). 1 H NMR(Acetone-d6,200MHz):δ 2.71-2.45(m,10H),2.83(s,6H),3.29(s,2H,),3.62(t,J=5.8Hz,2H),7.00(dd,J=10.2,8.7Hz,1H),7.26(d,J= 7.5Hz,1H),7.36(s,1H),7.67-7.48(m,3H),8.10-7.93(m,1H),8.25(dd,J=7.3,1.1Hz,1H),8.61-8.45(m,2H). 13C NMR(Acetone-d6,125MHz):δ 45.7,54.2,54.3,59.5,61.1,61.9,108.8,116.3,116.7(d,J=20.5Hz),120.2,123.0,124.1,124.5(d,J=7.4Hz),126.3(d,J=13.3Hz), 129.1,130.7(d,J=8.7Hz),130.9,131.6,132.3(d,J=3.5Hz),136.4,149.0,152.9,154.4,156.3,158.5,169.7.HRMS-ESI(m / z):[M+H] + calcd for C 29 H 34 O4N6FS2,613.2062,found:613.2065.HPLC(λ 254 ) Purity:>99%;t R :5.20 minutes (method 1).

[0056] [PB602] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide (PB602). To a suspension of chloroalkyl 5b (33.0 mg, 0.062 mmol, 1 eq) in acetonitrile or THF (0.2 M), triethylamine (1 eq) and N-hydroxyethylpiperazine (20.0 μL, 0.19 mmol, 3 eq) were added. The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 90:10) to give pure PB602 as a yellow fluorescent powder (23.1 mg, 56%). 1H NMR(Acetone-d6,200MHz):δ 2.74-2.45(m,10H),2.84(s,6H),3.29(d,J=2.0Hz,5H),3.61(t,J=5.9Hz,2H),6.76(d,J=8.5Hz,1H),7.27(d,J =7.3Hz,2H),7.70-7.43(m,3H),8.01(d,J=2.1Hz,1H),8.15(dd,J=7.3,1.3Hz,1H),8.52(dd,J=8.6,2.7Hz,2H). 13 C NMR(Acetone-d6,125MHz):δ 45.7,54.1,54.2,55.9,59.5,61.1,61.9,107.2,112.0,116.1,120.6,121.6,123.9,124.2,127.3,1 28.5,128.8,130.7,130.9,131.2,136.5,150.0,151.8,152.8,158.2,169.6.HRMS-ESI(m / z):[M+H] + Calculate for C 30 H 37 O5N6S2,625.2261;found:625.2268.HPLC(λ 254 )Purity:>99%;t R :5.27 points (Method 1).

[0057] 〔PB604〕

change

[0058] [Synthesis of compounds PB690, PB691 and PB692] These compounds are prepared by the methods described below. [ka]

[0059] [PB690] [ka] N-(5-(2-aminothiazol-4-yl)-2-methoxyphenyl)-4-pentylbenzenesulfonamide (PB690). To 3b (1.00 g, 4.50 mmol, 1 eq) in anhydrous DMF (0.2 M) was added anhydrous triethylamine (1.6 eq) and 4-pentylbenzene-1-sulfonyl chloride (1.23 g, 5.00 mmol, 1.1 eq) under argon. The reaction mixture was allowed to react at room temperature until complete conversion of the starting material. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:MeOH, 100:0 to 95:5) to give the title sulfonamide PB690 as a white powder (410.2 mg, 21%). 1 H NMR(CD2Cl2-d2,400MHz):δ 0.86(t,J=7.0Hz,3H),1.34-1.23(m,4H),1.60-1.53(m,2H),2.60(t,J=7.9Hz,2H),3.60(s,3H),5.73(br s,2H),6.63(s,1H),6.74(d,J=8.6Hz,1H),7.04(s,1H),7.22(d,J=8.4Hz,2H ),7.47(dd,J=8.5,2.2Hz,1H),7.64(d,J=8.4Hz,2H),7.89(d,J=2.1Hz,1H). 13 C NMR(CD2Cl2-d2,101MHz):δ 14.1,22.8,31.1,31.7,36.1,56.1,101.8,111.1,119.8,123.5,126.3,127 .6,128.6,129.2,136.6,149.3,149.9,150.5,168.3,HRMS-ESI(m / z):[M+H] +calc. for C 21 H 26 N3O3S2,432.1410;Found:432.1401.HPLC(λ 254 ):Purity >99%;t R :5.92 minutes (method mauro 3).

[0060] [Compound 6 in the above reaction] To a stirred solution of PB690 (350.0 mg, 0.81 mmol, 1 eq) in dry THF (10 mL) was added DIEA (420.0 μL, 2.43 mmol, 3 eq). Chloroacetyl chloride (126.0 μL, 1.62 mmol, 2 eq) was then added dropwise to the mixture and allowed to react for 30 min at room temperature until the starting material was completely consumed (TLC DCM: EtOAc 70:30). The mixture was then quenched with 4 M aqueous sodium hydroxide solution (10 mL) and stirred for another 30 min at room temperature. The reaction mixture was diluted with 10 mL of water and extracted three times with EtOAc (30 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure to give the respective chloroacetyl intermediates as brown powders (400 mg, 98%). The crude chloroacetyl 6 was used directly in the synthesis of PB691 and PB692 without further purification.

[0061] [PB691] [ka] N-(4-(4-Methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (PB691). To a suspension of chloroalkyl 6 (100.0 mg, 0.20 mmol, 1 eq) in acetonitrile (0.2 M), triethylamine (1 eq) and N-methylpiperazine (65.0 μL, 0.60 mmol, 3 eq) were added. The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 95:5) to give the pure target PB691 as a white powder (42.0 mg, 37%). 1 H NMR(CD2Cl2-d2,400MHz):δ 0.86(t,J=6.7Hz,3H),1.28-1.22(m,4H),1.67-1.49(m,2H),2.29(s,3H),2.64-2.53(m,10H),3.24(s,2H),3.62(s,3H),6.78(d,J= 8.6Hz,1H),7.07(s,2H),7.22(d,J=8.5Hz,2H),7.57(dd,J=8.5,2.2Hz,1H),7.68-7.61(m,2H),7.99(d,J=2.1Hz,1H),10.32(s,1H). 13 C NMR(CD2Cl2-d2,101MHz):δ 14.1,22.8,31.1,31.7,36.1,46.1,54.4,55.3,56.1,61.4,107.0,111.2,119.8,123.7,12 6.6,127.6,128.2,129.2,136.7,149.3,149.5,150.2,157.5,169.1.HRMS-ESI(m / z):[M+H] + calc. for C 28 H 38 N5O4S2,572.2359;Found:572.2348.HPLC(λ 254 ):Purity >99%;t R :5.25 minutes (method mauro 3).

[0062] [PB692] [ka] 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide (PB692) To a suspension of chloroalkyl 6 (100.0 mg, 0.20 mmol, 1 eq) in acetonitrile (0.2 M), triethylamine (1 eq) and N-hydroxyethylpiperazine (78.0 mg, 0.60 mmol, 3 eq) were added. The reaction mixture was stirred at 50 °C until the starting material was completely consumed. Purification by silica gel column chromatography (DCM:MeOH 100:0 to 95:5) afforded the pure target PB692 as a white powder (48.0 mg, 40%). 1 H NMR(CD2Cl2-d2,400MHz):δ 0.86(t,J=7.0Hz,3H),1.31-1.23(m,4H),1.60-1.52(m,2H),2.13(br s,1H) 2.67-2.58(m,12H),3.26(s,2H),3.62-3.58(m,5H),6.78(d,J=8.6Hz,1H),7.07(s,2H),7.21(d,J= 8.4Hz,2H),7.56(dd,J=8.5,2.2Hz,1H),7.64(d,J=8.4Hz,2H),8.00(d,J=2.1Hz,1H),10.34(s,1H). 13 C NMR(CD2Cl2-d2,101MHz):δ 14.1.22.8,31.1,31.7,36.1,53.1,54.4,56.1,58.0,59.8,61.5,107.1,111.2,119.9,123.6, 126.6,127.6,128.2,129.1,136.7,149.29,149.5,150.3,157.6,169.0.HRMS-ESI(m / z):[M+H] + calc. for C 29 H 40 N5O5S2,602.2465;Found:602.2460.HPLC(λ 254 ):Purity >99%;t R :5.21 minutes (method mauro 3).

[0063] [Synthesis of PB696] [ka]

[0064] [Compound 7 in the above reaction] 4-(4-(4-Methylpiperazin-1-yl)-3-nitrophenyl)thiazol-2-amine (7). To a stirred suspension of nitro-aryl 2a (2.38 g, 10.0 mmol, 1.0 eq) in DMSO (0.1 M) was added N-methylpiperazine (3.00 g, 30 mmol; 3.0 eq) successively. The reaction mixture was stirred at room temperature until the starting material was completely consumed. The crude was added to ice water and the reddish solid was filtered in vacuum to give the nitro product 7 in 72% (2.29 g). 1 H NMR(400MHz,DMSO-d6)δ 2.23(s,3H),2.44(d,J=3.9Hz,4H),3.08-2.87(m,4H),7.11(d,J=21.8Hz,3H ),7.30(d,J=8.7Hz,1H),7.96(dd,J=8.7,1.9Hz,1H),8.19(d,J=1.9Hz,1H).

[0065] [Compound 8 in the above reaction] [ka] 4-(3-Amino-4-(4-methylpiperazin-1-yl)phenyl)thiazol-2-amine (8). To a stirred suspension of nitro-aryl 8 (3.0 g, 9.4 mmol, 1.0 eq) in DMSO (0.1 M) were successively added ammonium chloride (1.00 g, 18.8 mmol, 2.0 eq) and zinc (4.58 g, 141.00 mmol, 7.5 eq). The reaction mixture was stirred at 70 °C until the starting material was completely consumed and the crude was filtered through a pad of Celite. The resulting filtrate was concentrated to give the aniline 8 as a white powder (992.0 mg, 36%). 11H NMR (400 MHz, DMSO-d6) δ 2.72 (s, 3H), 3.07 (s, 4H), 3.28 (s, 4H), 4.89 (s, 2H), 6.69 (s, 1H), 6.85 (d, J = 8.2 Hz, 1H), 7.02 - 6.94 (m, 3H), 7.14 (d, J = 1.8 Hz, 1H).

[0066] 〔PB696〕

Chem.

[0067] [Compounds PB631, PB624, PB633, PB628, PB649, PB635, PB625, PB638, PB639, PB640, PB643, PB644, PB654, PB605, PB697, PB698, PB688, PB689, PB693, PB694, PB695, PB704, PB707, PB708, PB705, PB706 synthetic resin] Compounds 2a-c can be synthesized by the following method:

change

[0068] [ka] tert-Butyl (4-((4-(3-nitrophenyl)thiazol-2-yl)amino)-4-oxobutyl)carbamate. To a solution of 4-N-Boc-aminobutanoic acid (1.15 g, 5.67 mmol) in dry DMF (15 mL) at room temperature under argon was added HOBT (0.87 g, 5.67 mmol), DIC (0.89 mL, 5.67 mmol) and triethylamine (0.79 mL, 5.67 mmol) sequentially over 15 min. Then 1 (1.00 g, 4.52 mmol) was added to the mixture and stirred at room temperature for 3 h and at 80 °C for further 24 h. DMF was removed under reduced pressure, the crude residue was dissolved in technical EtOAc (30 mL) and the organic layer was washed three times with distilled water (50 mL). The aqueous layer was extracted three times with EtOAc (30 mL), and the combined organic layers were washed with brine (60 mL), dried over MgSO4, and concentrated under reduced pressure. The crude material was subjected to silica gel chromatography eluting with DCM / EtOAc (100:0 to 70:30) to give amide 2b as a yellow powder (0.32 mg, 17%). 1 H NMR(DMSO-d6,200MHz):δ 1.48-1.31(m,9H),1.71(quint.,J=6.9Hz,2H),1.71(p,J=6.9Hz,2H),2.96(q,J=6.7Hz,2H),6.84(d,J=6.0Hz,1H),7.72(t,J =8.1Hz,1H),7.92(s,1H),8.16(ddd,J=8.2,2.4,1.0Hz,1H),8.33(dt,J=7.9,1.2Hz,1H),8.72(t,J=2.0Hz,1H),12.34(s,1H).

[0069] [ka] tert-Butyl (6-((4-(3-nitrophenyl)thiazol-2-yl)amino)-6-oxohexyl)carbamate. To a solution of 6-N-Boc-aminocaproic acid (1.07 g, 4.64 mmol) in dry DMF (20 mL) at room temperature under argon was added HOBT (0.63 g, 4.64 mmol), DIC (0.729 mL, 4.64 mmol) and triethylamine (0.65 mL, 4.64 mmol) sequentially over 15 min. Then 1 (0.77 g, 3.45 mmol) was added to the mixture and stirred at room temperature for 3 h and further heated at 80 °C for 24 h. DMF was removed under reduced pressure, the crude residue was dissolved in technical EtOAc (50 mL) and the organic layer was washed three times with distilled water (50 mL). The aqueous layer was extracted three times with EtOAc (50 mL), and the combined organic layers were washed with brine (100 mL), dried over MgSO4, and concentrated under reduced pressure. The crude material was subjected to silica gel chromatography eluting with DCM / EtOAc (100:0 to 60:40) to give amide 2c (0.69 mg, 45%) as a yellow-orange powder. 1 H NMR(DMSO-d6,200MHz):δ 1.45-1.18(m,13H,H1),1.60(quint.,J=7.3,6.7Hz,2H),2.57-2.30(m,2H),2.90(q,J=6.4Hz,2H),6.79(t,J=5.7Hz,1H),7.71(t ,J=8.0Hz,1H),7.90(s,1H),8.15(ddd,J=8.2,2.4,1.0Hz,1H),8.32(dt,J=7.9,1.2Hz,1H),8.71(t,J=2.0Hz,1H),12.32(s,1H).

[0070] Next, compounds 3a-3c were synthesized according to the following method: [ka]

[0071] 〔3a〕 [ka] tert-Butyl (2-((4-(3-aminophenyl)thiazol-2-yl)amino)-2-oxoethyl)carbamate. To a suspension of nitro-aryl 2a (90.0 mg, 0.50 mmol, 1 eq) and Pd / C-10% (19.0 mg, 10 wt%) in methanol (0.01 M) was carefully added sodium borohydride (95.0 mg, 2.51 mmol, 5 eq) in portions at 0 °C under stirring. The reaction mixture was stirred at 0 °C until sodium borohydride was completely dissolved and then allowed to react at room temperature. The crude mixture was filtered through a pad of Celite, concentrated under reduced pressure and purified by silica gel column chromatography (DCM:EtOAc; 70:30 to 40:60) to give aniline 3a as a white powder (54.7 mg, 31%). 1 H NMR (CD3OD-d4, 200MHz): δ 1.47(s,9H),3.97(s,2H),6.68(ddd,J=7.7,2.3,1.3Hz,1H),7.11(t,J=7.7Hz,1H),7.33-7.17(m,3H,H7).

[0072] (3b) [ka] tert-Butyl (4-((4-(3-aminophenyl)thiazol-2-yl)amino)-4-oxobutyl)carbamate. To a suspension of nitro-aryl 2b (266.0 mg, 0.65 mmol, 1 eq) and Pd / C-10% (26.6 mg, 10 wt%) in methanol (0.01 M) was carefully added sodium borohydride (123.6 mg, 3.27 mmol, 5 eq) in portions at 0° C. under stirring. The reaction mixture was stirred at 0° C. until sodium borohydride was completely dissolved and then allowed to react at room temperature. The crude mixture was filtered through a pad of Celite, concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH; 100:0 to 90:10) to give the title compound 3b as a white powder (190.1 mg, 77%). 1H NMR(CD3OD-d4,200MHz):δ 1.42(s,9H),1.86(quint.,J=7.1Hz,2H),2.49(t,J=7.4Hz,2H),3.12(t,J=6.8 Hz,2H),6.68(dd,J=9.4,1.7Hz,1H),7.11(t,J=7.7Hz,1H),7.31-7.16(m,3H).

[0073] [3c] [ka] tert-Butyl (6-((4-(3-nitrophenyl)thiazol-2-yl)amino)-6-oxohexyl)carbamate. To a suspension of nitro-aryl 2c (346.0 mg, 0.80 mmol, 1 eq) and Pd / C-10% (34.6 mg, 10 wt%) in methanol (0.01 M) was carefully added sodium borohydride (158.8 mg, 4.18 mmol, 5 eq) in portions at 0 °C under stirring. The reaction mixture was stirred at 0 °C until sodium borohydride was completely dissolved and then allowed to react at room temperature. The crude mixture was filtered through a pad of Celite, concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH; 100:0 to 94:6) to give aniline 3c as a white powder (166.5 mg, 52%). 1 H NMR(DMSO-d6,200MHz):δ 1.42-1.22(m,13H),1.59(quint.,J=13.8,7.1Hz,2H),2.55-2.34(m,2H),2.90(q,J=6.4Hz,2H),5.12(s ,2H),6.52(dt,J=6.5,2.6Hz,1H),6.78(t,J=5.5Hz,1H),7.16-6.95(m,3H),7.35(s,1H),12.18(s,1H).

[0074] Compounds 4a, PB631 and PB624 were then synthesized according to the following methods: [ka]

[0075] [4a] [ka] tert-Butyl (2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)carbamate. To a solution of 3a (54.0 mg, 0.16 mmol, 1 eq) in anhydrous DMF (0.2 M) was added anhydrous triethylamine (1.6 eq) and dansyl chloride (49.9 mg, 0.19 mmol, 1.1 eq) under argon. The reaction mixture was reacted at room temperature until the starting material was completely converted. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:EtOAc; 100:0 to 80:20) to give 4a as a yellow fluorescent powder (40.0 mg, 44%). 1 H NMR(CD3OD-d4,200MHz):δ 1.46(s,9H),3.96(s,2H),6.88(dd,J=8.0,2.2Hz,1H),7.10-6.98(m,2H),7.17(d,J=7.6H z,1H),7.48-7.29(m,2H),7.70-7.47(m,2H),8.20(d,J=7.3Hz,1H),8.41(t,J=7.9Hz,2H).

[0076] [PB631] [ka] tert-Butyl (4-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-4-oxobutyl)carbamate. To a solution of 3b (117.0 mg, 0.31 mmol, 1 eq) in anhydrous DMF (0.2 M) was added anhydrous triethylamine (1.6 eq) and dansyl chloride (100.3 mg, 0.37 mmol, 1.1 eq) under argon. The reaction mixture was reacted at room temperature until the starting material was completely converted. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:EtOAc; 100:0 to 70:30) to give PB631 as a yellow fluorescent powder (135.7 mg, 65%). 1 H NMR(CD3OD-d4,200MHz):δ 1.41(s,9H),1.85(quint.,J=7.2Hz,2H),2.48(t,J=7.3Hz,2H),2.79(s,6H),3.18-3.05(m,2H),6.96-6.82(m,1H),7.16 -7.01(m,2H),7.22(d,J=7.6Hz,1H),7.49-7.37(m,2H),7.65-7.53(m,2H),8.20(d,J=7.3Hz,1H),8.44(d,J=8.6Hz,2H). 13 C NMR(CD3OD-d4,50MHz):δ 26.6,28.7,33.9,40.8,45.7,80.0,108.9,116.4,119.1,120.3,120.8,122.9,124.1,129.2,130.2,13 1.0,131.0,131.3,131.5,136.0,136.8,139.2,150.4,153.2,158.5,159.3,173.2.MS-ESI(m / z):[M+H] + =610.3.

[0077] [PB624] [ka] tert-Butyl (6-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-6-oxohexyl)carbamate. To a solution of 3c (250.0 mg, 0.62 mmol, 1 eq) in anhydrous DMF (0.2 M) was added anhydrous triethylamine (1.6 eq) and dansyl chloride (199.6 mg, 0.74 mmol, 1.1 eq) under argon. The reaction mixture was reacted at room temperature until the starting material was completely converted. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:EtOAc; 100:0 to 80:20) to give PB624 as a yellow fluorescent powder (319.5 mg, 81%). 1 H NMR(Acetone-d6,200MHz):δ 1.28-1.56(m,13H),1.74(quint,J=7.4Hz,2H),2.58(t,J=7.4Hz,2H),2.8 2(s,6H),3.08(q,J=6.5Hz,2H),5.95(s,1H),7.01(ddd,J=8.0,2.3,1.1Hz, 1H),7.31-7.08(m,3H),7.67-7.40(m,3H),7.78(t,J=1.9Hz,1H),8.28(dd, J=7.3,1.2Hz,1H),8.50(dt,J=8.8,1.0Hz,2H),9.40(s,1H),11.10(s,1H). 13 C NMR(Acetone-d6,50MHz):δ 25.7,27.1,28.7,36.3,41.0,45.6,78.4,108.7,116.2,118.4,120.1,122.5,124.1,129.1,130.2,130 .6,130.7,131.1,131.3,136.1,136.6,139.2,149.7,152.9,156.7,159.0,172.2.MS-ESI(m / z):[M+H] + =638.4.

[0078] Intermediate compounds 5a, 5b and 5c were synthesized according to the following method: [ka]

[0079] 〔5a〕 [ka] 2-Ammonium-N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)acetamide trifluoroacetate. To a stirred solution of BOC-protected 4a (40.0 mg, 0.07 mmol) in DCM (1 mL) was added TFA (1 mL, excess). The mixture was reacted at room temperature for 30 min and the TFA:DCM mixture was removed under reduced pressure. The crude residue was suspended in a minimum amount of DCM, precipitated with diethyl ether, and washed three times with diethyl ether (10 mL) to give ammonium 5a as a yellow fluorescent powder (30.5 mg, 73%). 1 H NMR(CD3OD-d4,200MHz):δ 2.89(s,6H),3.98(s,2H),6.97-6.79(m,1H),7.09(t,J=7.9Hz,1H),7.24(s,1H),7. 35(d,J=7.6Hz,1H),7.70-7.41(m,4H),8.24(d,J=7.3Hz,1H),8.48(t,J=13.9,2H). 13 C NMR(CD3OD-d4,50MHz):δ 41.9,46.0,109.6,116.9,119.2,121.1,123.0,124.5,129.4,130.4,130.9,131.41,1 31.3,131.5,136.3,136.7,139.4,150.8,152.4,158.6,165.9.HRMS-ESI(m / z):[M+H] + calcd for C 23 H 24 O3N5S2,482.1315;found:482.1315.HPLC(λ 254 ) Purity: 98.4%;t R :5.78 minutes (method 3).

[0080] 〔5b〕 [ka] 4-((4-(3-((5-(dimethylamino(naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-oxobutan-1-aminium trifluoroacetate. To a stirring solution of BOC-protected PB631 (108.0 mg, 0.18 mmol) in DCM (1 mL) was added TFA (1 mL, excess). The mixture was reacted at room temperature for 30 min and the TFA:DCM mixture was removed under reduced pressure. The crude residue was suspended in a minimum amount of DCM, precipitated with diethyl ether, and washed three times with diethyl ether (15 mL) to give ammonium 5b as a yellow fluorescent powder (106.5 mg, 96%). 1 H NMR(CD3OD-d4,200MHz):δ 2.03(p,J=7.1Hz,2H),2.64(t,J=7.0Hz,2H),3.07-2.97(m,8H),6.86(ddd,J=8.0,2.3,1.0Hz,1H),7.28 -7.01(m,2H),7.75-7.37(m,5H),8.26(dd,J=7.4,1.2Hz,1H),8.45(d,J=8.6,1H),8.59(d,J=8.7Hz,1H). 13 C NMR(CD3OD-d4,50MHz):δ 23.9,33.2,40.4,46.4,109.2,117.6,119.2,121.0,122.4,123.1,125.1,129.3,130.3,130.4 ,130.5,131.1,131.7,136.6,136.9,139.3,150.3,150.6,159.3,172.3.HRMS-ESI(m / z):[M+H] + calcd for C 25 H 28 O3N5S2,510.1628;found:510.1623.HPLC(λ 254 ) Purity: 97.2%;t R :2.78 minutes (method 3).

[0081] [5c] [ka] 6-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-6-oxohexane-1-aminium trifluoroacetate. To a stirred solution of BOC-protected PB624 (1.25 g, 1.95 mmol) in DCM (4 mL) was added TFA (4.24 mL, 57.10 mmol). The mixture was reacted at room temperature for 30 min and the TFA:DCM mixture was removed under reduced pressure. The crude residue was suspended in a minimum amount of DCM, precipitated with diethyl ether, and washed three times with diethyl ether (20 mL) to give pure ammonium 5c as a yellow fluorescent powder (1.10 g, 87%). 1 H NMR(DMSO-d6,200MHz):δ 1.45-1.18(m,2H),1.77-1.43(m,4H),2.56-2.39(m,2H),2.92-2.67(m,8H),6.97(d,J=8.2Hz,1H),7.25-7.15(m,2H),7 .49-7.37(m,2H),7.72-7.51(m,3H),7.85(s,3H),8.33-8.16(m,1H),8.40(d,J=8.4Hz,2H),10.82(s,1H),12.25(s,1H). 13 C NMR(DMSO-d6,50MHz):δ 24.2,25.4,26.8,34.7,45.0,108.4,115.3,116.1,118.2,118.7,120.9,123.5,128.2,129.0, 129.5,129.8,130.1,134.8,135.2,138.2,148.1,151.5,158.0,171.5.HRMS-ESI(m / z):[M+H] + calcd for C 27 H 33 O3N5S2,538.1941;found:538.1937.HPLC(λ 254 ) Purity: 97.5%;t R :7.17 minutes (method 2).

[0082] [Compounds PB633 and PB628 were synthesized from 5b and 5c according to the following method.] [ka]

[0083] [PB633] [ka] 4-((4-(3-((5-(dimethylamino(napthalene)-1-sulfonamido)phenyl)thiazol-2-yl)butanamide. The corresponding ammonium 5b (93.0 mg, 0.15 mmol) was dissolved in acetic anhydride (1 mL, excess), then DMAP (22.0 mg, 0.18 mmol) was added to the mixture. The reaction intermediate was reacted at room temperature for 1 h until the starting material was completely consumed, and the product was precipitated using diethyl ether. The yellow fluorescent residue was filtered, washed three times with EtO, and dried to give the corresponding amide PB633 as a yellow fluorescent powder (71.5 mg, 84%). 1 H NMR(DMSO-d6,200MHz):δ 1.89-1.59(m,5H),2.56-2.37(m,2H),2.76(s,6H),3.10-2.96(m,2H),6.95(d,J=7.8Hz,1H),7.26-7.09(m,2H),7.47- 7.41(m,2H),7.68-7.51(m,3H),7.86(s,1H),8.22(d,J=7.3Hz,1H),8.39(d,J=8.5Hz,2H),10.76(s,1H),12.19(s,1H). 13 C NMR(CD3OD-d4,50MHz):δ 22.6,24.7,32.4,38.0,45.0,108.4,115.3,116.1,118.2,118.6,120.9,123.5,128.2,129.0,129.0, 129.4,129.7,130.1,134.8,135.2,138.1,148.1,151.5,157.9,169.1,171.3.HRMS-ESI(m / z):[M+H] + calcd for C 27 H 30 O4N5S2,552.1734;found:552.1733.HPLC(λ 254 ) Purity:>99%;t R :7.42 minutes (method 4).

[0084] [PB628] [ka] 6-Acetamido-N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)hexanamide. The corresponding ammonium 5c (50.0 mg, 0.08 mmol) was dissolved in acetic anhydride (1 mL, excess) and DMAP (12.3 mg, 0.10 mmol) was added to the mixture. The reaction intermediate was reacted at room temperature for 1 h until the starting material was completely consumed, and the product was precipitated with diethyl ether. The yellow fluorescent residue was filtered, washed three times with Et2O, and dried to give the corresponding amide PB628 as a yellow fluorescent powder (43.6 mg, 94%). 1 H NMR (DMSO-d6, 200MHz): δ 1.51-1.17(m,4H),1.59(m,J=7.4Hz,2H),1.77(s,3H),2.55-2.36(m,2H),2 .78(s,6H),3.01(q,J=6.4Hz,2H),7.3-6.91(m,1H),7.30-7.13(m,2H),7.43 (d,J=8.6Hz,2H),7.60(ddd,J=8.6,7.4,5.8Hz,3H),7.82(s,1H),8.24(dd, J=7.4,1.2Hz,1H),8.40(dd,J=8.5,6.0Hz,2H),10.79(s,1H),12.21(s,1H). 13 C NMR(DMSO-d6,50MHz):δ 22.6,24.4,26.0,28.9,34.8,38.4,45.0,108.3,115.2,116.2,118.2,118.7,120.9,123.5,128.2,129.0,129. 0,129.4,129.4,129.7,130.1,134.8,135.2,138.1,148.1,151.4,157.9,168.9,171.6.HRMS-ESI(m / z):[M+H] + calcd for C 29 H 34 O4N5S2,580.2047;found:580.2048.HPLC(λ 254) Purity:>99%;t R :8.03 minutes (method 2).

[0085] Compound PB649 was synthesized based on compound 5a: [ka]

[0086] [PB649] [ka] Diethyl-(2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)phosphoramidate. To a stirred solution of amine 5a (75.0 mg, 0.16 mmol) in dry THF (1 mL) was added DIEA (41.0 mg, 0.32 mmol) and diethyl chlorophosphate (23.0 μL, 0.16 mmol) sequentially. The mixture was reacted at room temperature for 15 min until the starting material was completely consumed (TLC DCM:EtOAc 40:60). The reaction mixture was diluted with 10 mL of water and extracted three times with EtOAc (5 mL). The combined organic layers were washed twice with brine, dried over MgSO4, and concentrated under reduced pressure. Purification by silica gel column chromatography (DCM:EtOAc 100:0 to 0:100) afforded PB649 as a yellow fluorescent powder in 64% yield (63.1 mg). 1H NMR(Acetone-d6,500MHz)δ 1.28(td,J=7.1,0.8Hz,6H),2.82(s,6H),3.95(dd,J=13.1,7.1Hz,2H),4.06-4.14(m,4H),4. 69(dt,J=11.3,7.1Hz,1H),7.05(ddd,J=8.1,2.3,1.0Hz,1H),7.16(q,J=7.9Hz,1H),7.25(d, J=7.6Hz,1H),7.31(s,1H),7.49(d,J=8.2Hz,1H),7.58(ddd,J=13.0,8.6,7.5Hz,2H),7.77(t ,J=1.9Hz,1H),8.30(dd,J=7.3,1.2Hz,1H),8.50(d,J=8.2Hz,2H),9.52(s,1H),11.19(s,1H). 13 C NMR(Acetone-d6,126MHz)δ 16.6,16.6,45.4,45.6,63.2,63.2,109.0,116.2,118.2,119.9,120.1,122.3,124.2,129.1,130.2,130 .6,130.7,131.1,131.3,136.2,136.4,139.3,149.9,152.9,158.5,170.2,206.2,206.4,206.5,206.7; 31 P NMR(81MHz,Acetone)δ 8.61.HRMS-ESI(m / z):[M+H] + calc. for C 27 H 33 N5O6PS2,618.1604;Found:618.1606.HPLC(λ 254 ):Purity 95.2%;t R :6.35 points (Method 1).

[0087] [Compound PB635] Compounds 6 and 7 were synthesized by the following method, and compound PB635 was obtained.

change

[0088] [Compound 7] 2-Methyl-4-(3-nitrophenyl)thiazole. To a solution of α-bromo-3-nitroacetophenone 6 (1.00 g, 6.06 mmol 1 eq) in ethanol was added thioacetamide (460.0 mg, 6.06 mmol 1 eq). The reaction mixture was heated to 80° C. for 3 h and cooled to room temperature. The precipitate was filtered and washed with ethanol and diethyl ether to give thiazole 7 as a yellow solid in 96% yield (1.28 g). 1 H NMR(DMSO-d6,200MHz):δ 2.72(s,3H),7.68(t,J=8.0Hz,1H),8.13(ddd,J=8.2,2.3,1.0Hz,1H),8.21(s,1H),8.33(ddd,J=7.8,1.7,1.0Hz,1H),8.72-8.65(m,1H).

[0089] [Compound 8] [ka] 2-Methyl-4-(3-aminophenyl)thiazole. To a suspension of nitro-aryl 7 (1.20 g, 5.50 mmol, 1 eq) and Pd / C-10% (120.0 mg, 10 wt%) in methanol (0.01 M) was carefully added sodium borohydride (2.07 g, 27.50 mmol, 5 eq) in portions under stirring at 0 °C. The reaction mixture was stirred at 0 °C until sodium borohydride was completely dissolved and then allowed to react at room temperature. The crude mixture was filtered through a pad of Celite, concentrated under reduced pressure and purified by silica gel column chromatography (CHx:EtOAc; 100:0 to 50:50) to give aniline 8 as a white powder (760.0 mg, 73%). 1 H NMR (CD3OD-d4, 200MHz): δ 2.70(s,3H),6.70(dt,J=6.5,2.3Hz,1H),7.29-7.05(m,3H),7.45(s,1H). [ka]

[0090] [PB635] [ka] 5-(Dimethylamino)-N-(3-(2-methylthiazol-4-yl)phenyl)naphthalene-1-sulfonamide. To a solution of 8 (100.0 mg, 0.53 mmol, 1 eq) in anhydrous DMF (0.2 M) was added anhydrous triethylamine (1.6 eq) and dansyl chloride (169.9 mg, 0.63 mmol, 1.1 eq) under argon. The reaction mixture was reacted at room temperature until the starting material was completely converted. DMF was removed under reduced pressure. The pure compound was precipitated from DCM with Et2O and washed three times with diethyl ether (20 mL) to give PB635 as a yellow fluorescent powder (107.5 mg, 48%). 1 H NMR(Acetone-d6,200MHz):δ 2.68(s,3H),2.82(s,6H),7.30-7.05(m,3H),7.69-7.49(m,4H),7.85-7.74( m,1H),8.32(dd,J=7.4,1.2Hz,1H),8.51(dd,J=8.3,1.1Hz,2H),9.44(s,1H). 13 C NMR(Acetone-d6,50MHz):δ 19.2,45.6,114.2,116.3,118.6,119.9,120.1,122.6,124.2,129.1,130.3,130.7,1 30.7,131.2,131.4,136.2,136.5,139.3,153.0,154.9,166.5.HRMS-ESI(m / z):[M+H] + calcd for C 22 H 22 O2N3S2,424.1148;found:424.1146.HPLC(λ 254 ) Purity: >99%; tR: 4.81 min (Method 4).

[0091] [Compound PB625] Compounds 9 and 10 were synthesized according to the following methods to give PB625. [ka] N-(3-(2-aminothiazol-4-yl)phenyl)-5-(dimethylamino)naphthalene-1-sulfonamide. To a solution of 9 (0.88 g, 4.60 mmol, 1 eq) in anhydrous DMF (0.2 M) was added anhydrous triethylamine (1.6 eq) and dansyl chloride (1.37 g, 5.10 mmol, 1.1 eq) under argon. The reaction mixture was reacted at room temperature until complete conversion of the starting material. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:EtOAc; 100:0 to 70:30) to give 10 as a pale yellow fluorescent powder (1.74 g, 89%). 1 H NMR(DMSO-d6,200MHz):δ 2.74(s,6H),6.82(s,1H),7.26-6.89(m,4H),7.35(d,J=7.7Hz,1H),7.69 -7.51(m,3H),8.25(d,J=7.3Hz,1H),8.41(d,J=8.6Hz,2H),10.71(s,1H). 13 C NMR(DMSO-d6,50MHz):δ 45.0,102.0,115.3,116.3,117.5,118.7,120.6,123.5,128.2,129.0,129.0,129. 1,129.7,130.1,134.8,135.7,137.9,149.3,151.4,168.1.HRMS-ESI(m / z):[M+H] + calcd for C 21 H 21 N4O2S2,425.1100; found:425.1103.HPLC(λ 254 ) Purity: 99.2%;t R :3.34 minutes (method 3). [ka]

[0092] [PB625] [ka] Ethyl 5-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-5-oxopentanoate. To a stirred solution of amine 10 (101.5 mg, 0.24 mmol) in dry THF (1.2 mL) under argon, DIPEA (50.0 μL, 0.29 mmol) and glutaric acid monomethyl ester chloride (40.0 μL, 0.29 mmol) were added sequentially. The mixture was stirred at room temperature for 1 h until the starting material was completely consumed (monitored by TLC using DCM:EtOAC (70:30) as eluent). All volatiles were removed under reduced pressure and the crude residue was subjected to silica gel flash chromatography purification (DCM:EtOAc; 100:0 to 70:30) to give the corresponding amide PB625 as a pale yellow fluorescent powder (83.1 mg, 92%). 1 H NMR(Acetone-d6,200MHz):δ 1.20(t,J=7.1Hz,3H),2.13-1.91(m,2H),2.41(t,J=7.3Hz,2H),2.65(t,J=7.3Hz,2H),2.81(s,6H) 4.08(q,J=7.1Hz,2H),7.00(ddd,J=8.0,2.2,1.1Hz,1H),7.14(t,J=7.9Hz,1H),7.33-7.20(m,2H),7.69-7.4 0(m,3H),7.77(t,J=1.9Hz,1H),8.27(dd,J=7.3,1.2Hz,1H),8.49(d,J=8.8,2H),9.46(s,1H),11.15(s,1H). 13 C NMR(Acetone-d6,50MHz):δ 14.6,21.1,33.9,35.2,45.6,60.7,108.7,116.2,118.3,120.1,122.4,124.1,129.1,130.2,130.6, 130.7,131.1,131.3,136.1,136.6,139.2,149.8,152.9,158.9,171.7,173.3.HRMS-ESI(m / z):[M+H] + calcd for C 28 H 31 O5N4S2,567.1730;found:527.1740.HPLC(λ 254 ) Purity: 96.0%;tR :4.88 minutes (method 1).

[0093] [Compounds PB638, 639, 640, 643 and 644] Compounds 10 and 11 were first synthesized according to the following method: [ka]

[0094]

[11] [ka] 2-Chloro-N-(3-(2-(2-chloroacetamido)thiazol-4-yl)phenyl)-N-((5-(dimethylamino)naphthalen-1-yl)sulfonyl)acetamide. To a stirred solution of amine 10 (1.08 g, 2.55 mmol) in dry THF (17 mL) was added DIEA (1.33 mL, 7.65 mmol). Chloroacetyl chloride (0.41 mL, 5.10 mmol) was then added dropwise to the mixture and allowed to react for 30 min at room temperature until the starting material was completely consumed (TLC DCM:EtOAc 70:30). The mixture was then quenched with 4 M aqueous sodium hydroxide solution (10 mL) and stirred for an additional 30 min at room temperature. The reaction mixture was diluted with 10 mL of water and extracted three times with EtOAc (30 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure to give chloroacetyl 11 as a brown-yellow fluorescent powder (1.36 g, quantitative). 1 H NMR(Acetone-d6,200MHz):δ 2.80(s,6H),4.49(s,2H),7.04(d,J=9.0Hz,1H),7.28-7.09(m,2H),7.36(s,1H),7.64- 7.41(m,1H),7.81(t,J=1.7Hz,1H),8.29(dd,J=7.3,1.2Hz,1H),8.49(d,J=11.7Hz,2H).

[0095] Compounds PB638, 639, 640, 643 and 644 are obtained according to the following method: [ka]

[0096] [PB638] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide. To a suspension of chloroalkyl 11 (75.0 mg, 0.13 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and N-methylpiperazine (39.0 mg, 0.39 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 90:10) to give PB638 as a yellow fluorescent powder (38.4 mg, 70%). 1 H NMR(Acetone-d6,200MHz):δ 2.27(s,3H),2.71-2.41(m,8H),2.81(s,6H),3.26(s,2H),7.28-7.02(m,3H),7.33(s,1H), 7.65-7.45(m,3H),7.75(t,J=2.0Hz,1H),8.31(dd,J=7.3,1.3Hz,1H),8.50(d,J=8.8,1H). 13 C NMR(Acetone-d6,50MHz):δ 45.6,46.1,53.8,55.7,61.7,109.0,116.3,118.3,120.0,120.1,122.4,124.1,129.1,130.2,130 .7,130.7,131.1,131.3,136.2,136.4,139.2,149.9,152.9,158.3,169.6.HRMS-ESI(m / z):[M+H] + calcd for C 28 H 33 O3N6S2,565.2050;found:565.2060.HPLC(λ 280) Purity: 96.9%;t R :5.80 minutes (method 4).

[0097] [PB639] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-morpholinoacetamide. To a suspension of chloroalkyl 11 (75.0 mg, 0.13 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and morpholine (33.5 mg, 0.39 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 90:10) to give morpholine PB639 as a yellow fluorescent powder (52.1 mg, 69%). 1 H NMR(Acetone-d6,200MHz):δ 2.70-2.56(m,4H),2.82(s,6H),3.31(s,2H),3.72(dd,J=5.7,3.6Hz,4H),7.38-6.99(m,4H),7.68-7.43(m ,3H),7.75(t,J=1.9Hz),8.39-8.21(m,1H),8.51(ddt,J=8.8,3.8,1.0Hz,2H),9.43(s,1H),10.76(s,1H). 13 C NMR(CD3OD-d4,125MHz):δ 45.9,54.9,62.2,67.9,109.6,116.6,119.3,120.5,121.2,123.1,124.3,129.4,130.5,131.1, 131.2,131.5,131.7,136.2,136.7,139.5,150.5,153.36,159.2,170.6.HRMS-ESI(m / z):[M+H] + calcd for C 27 H 30 O4N5S2,552.1734;found:552.1741.HPLC(λ 280 ) Purity: 96.1%;t R:3.18 minutes (method 3).

[0098] [PB640] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide. To a suspension of chloroalkyl 11 (75.0 mg, 0.13 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and morpholine (101.4 mg, 0.78 mmol, 6 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 90:10) to give morpholine PB640 as a yellow fluorescent powder (45.2 mg, 58%). 1 H NMR(CD3OD-d4,200MHz):δ 2.69-2.54(m,10H),2.81(s,6H),3.29(s,2H),3.70(t,J=6.0Hz,2H) 6.91(ddd,J=8.0,2.3,1.0Hz,1H),7.11(t,J=7.9Hz,1H),7.18(s,1H),7.23(d,J=7.3Hz,1 H),7.49-7.35(m,2H),7.63-7.53(m,2H),8.20(dd,J=7.4,1.3Hz,1H),8.51-8.39(m,2H). 13 C NMR(CD3OD-d4,125MHz):δ 45.9,54.1,54.4,59.9,61.3,61.7,109.5,116.6,119.3,120.5,121.2,123.1,124.3,129.4,130.5, 131.1,131.2,131.5,131.7,136.2,136.7,139.5,150.5,153.3,159.3,170.7.HRMS-ESI(m / z):[M+H] + calcd for C 29 H 35 O4N6S2,595.2158;found:595.2162.HPLC(λ280 ) Purity: 95.7%;t R :5.76 minutes (method 4).

[0099] [PB643] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-((2-hydroxyethyl)amino)acetamide. To a suspension of chloroalkyl 11 (150.0 mg, 0.26 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and morpholine (47.6 mg, 0.78 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to a silica gel column (DCM:MeOH 100:0 to 90:10) to give hydroxyl PB643 as a yellow fluorescent powder (84.1 mg, 62%). 1 H NMR(CD3OD-d4,200MHz):δ 2.85-2.61(m,8H),3.54(s,2H),3.67(t,J=5.4Hz,2H),6.94-6.83(m,1H),7.08-6.96(m,2H),7.13(dd,J =7.6,0.9Hz,1H),7.43-7.25(m,2H),7.62-7.48(m,2H),8.19(dd,J=7.4,1.2Hz,1H),8.50-8.32(m,2H). 13 C NMR(CD3OD-d4,50MHz):δ 45.8,52.5,52.6,62.0,109.3,116.5,119.1,120.4,120.8,123.0,124.2,129.4,130.4,131.1 ,131.1,131.5,131.7,136.2,136.7,139.4,150.4,153.2,159.2,172.1.HRMS-ESI(m / z):[M+H] + calcd for C 25 H 28 O4N5S2,526.1577;found:526.1584.HPLC(λ 254 ) Purity:>99%;t R:5.09 minutes (method 1).

[0100] [PB644] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-((3-morpholinopropyl)amino)acetamide. To a suspension of chloroalkyl 11 (150.0 mg, 0.26 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and morpholine (112.3 mg, 0.78 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 90:10) to give morpholine PB644 as a yellow fluorescent powder (81.2 mg, 51%). 1 H NMR(CD3OD-d4,200MHz):δ 1.77(m,2H),2.71-2.52(m,6H),2.88-2.70(m,8H),3.35(s,2H) 3.74-3.69(m,4H),7.26-6.86(m,4H),7.46-7.33(m,2H),7.66-7.49(m,2H),8.20(d,J=7.3Hz,1H),8.41(t,J=7.7Hz,2H),. 13 C NMR(CD3OD-d4,50MHz):δ 25.09.25.3,45.9,51.8,54.5,58.6,67.1,109.5,116.6,119.1,120.1,120.9,131.1,131.1, 131.2,131.4,131.7,136.2,136.7,139.5,150.6,153.3,159.1,170.7.HRMS-ESI(m / z):[M+H] + calcd for C 30 H 37 O4N6S2,609.2312;found:609.2321.HPLC(λ 280 ) Purity: 95.4%;t R :4.75 minutes (method 1).

[0101] [Compounds PB654 and 605] First, compounds 10 and 12 were synthesized according to the following method: [ka]

[0102] [Compound 12] [ka] To a stirred solution of amine 10 (560.0 g, 1.32 mmol) in dry THF (7 mL) was added DIEA (274 μL, 1.58 mmol). Bromoacetyl bromide (138 μL, 1.58 mmol) was then added dropwise to the mixture and allowed to react for 60 min at room temperature until the starting material was completely consumed (TLC DCM:EtOAc 70:30). The mixture was then quenched with water (10 mL) and stirred at room temperature for an additional 30 min. The reaction mixture was diluted with water (10 mL) and extracted three times with EtOAc (30 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride, dried over MgSO4, concentrated under reduced pressure, and purified using flash column chromatography eluting with CHCl:EtOAc (100:0 to 70:30) to give bromoacetyl 12 as a brown-yellow fluorescent powder (648.0 mg, 90%). 1 H NMR(Acetone-d6,200MHz):δ 2.75(s,6H),4.23(s,2H),7.25-6.95(m,4H),7.31(s,1H),7.65-7.37(m,3H),7.7 8(s,1H),8.26(d,J=7.3Hz,1H),8.46(t,J=8.0Hz,2H),9.45(s,1H),11.57(s,1H).

[0103] Compound PB654 was synthesized based on compound 12: [ka]

[0104] [PB654] [ka] 2-((2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)amino)ethane-1-sulfone. To a mixture of HO and AcN (1:2 4 mL), bromoacetyl 12 (110.0 mg, 0.2 mmol), DIPEA (69.5 μL, 0.4 mmol) and taurine (50.2 mg, 0.4 mmol) were added. The mixture was reacted at room temperature for 2 h and then placed at 50 °C for another 5 h until the starting material was completely consumed. The solvent was removed under reduced pressure and the crude was subjected to silica gel column chromatography (DCM:MeOH 95:5 to 85:15) to give the pure sulfonic acid PB654 as a brown-yellow fluorescent product (89.6 mg, 76%). 1 H NMR(DMSO-d6,500MHz):δ 2.66(t,J=6.7Hz,2H),2.78(s,6H),2.88(t,J=6.7Hz,2H),3.52(s,2H),6.98(ddd,J=8.1,2.3,1.0Hz,1H),7.19(t,J=7.9Hz, 1H),7.24(d,J=7.2Hz,1H),7.52-7.37(m,2H),7.66-7.54(m,3H),8.25(dd,J=7.4,1.2Hz,1H),8.41(dd,J=15.5,8.6Hz,2H). 13 C NMR(DMSO-d6,125MHz):δ 45.0,45.3,50.5,51.2,108.6,115.3,116.1,118.1,118.7,120.8,123.5,128.2,129.0,129.0 ,129.4,129.8,130.1,134.8,135.0,138.2,148.2,151.4,157.6,170.0.HRMS-ESI(m / z):[M+H] + calcd for C 25 H 28 O6N5S3,590.1196;found:590.1199.HPLC(λ 254 ) Purity: 96.4%;t R :5.33 minutes (method 1). [ka]

[0105] [PB605] [ka] 2-(2,3-Dihydroxypropoxy)-N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)acetamide. To a flask containing dry THF (1 mL) under argon at 0° C. was added sodium hydride (17.6 mg, 0.44 mmol) followed by a solution of glycerol isopropylidene (53.2 mg, 0.40 mmol) dropwise. The resulting mixture was allowed to react at 0° C. for 30 min before a solution of chloroacetyl 11 (100.0 mg, 0.20 mmol) in THF (0.5 mL, 0.4 M) was added dropwise. The mixture was allowed to react at 0° C. for 5 min and further at room temperature for 1 h. The mixture was quenched with water (2 mL) and the volatiles were removed under reduced pressure. The resulting aqueous solution was extracted three times with EtOAc (5 mL) and the combined organic layers were washed with brine and dried over MgSO4. The crude residue was subjected to flash chromatography on silica gel eluting with DCM:EtOAc (100:0 to 60:40) to give dioxolane intermediate 13 (54.1 mg, 45%). 1H NMR (Acetone-d6, 200MHz): δ 1.37(s,3H), 1.45(s,3H), 2.81(s,6H), 4.17-3.63(m,4H), 4.48-4.28(m,3H), 7.11-6.95(m,1H), 7.30-7.11(m,2H), 7.33(s,1H), 7.70-7.47(m,3H), 7.79(t,J=1.9Hz,1H), 8.31(d,J=7.2Hz,1H), 8.50(d,J=8.5Hz,2H), 9.43(s,1H), 10.82(s,1H).Dioxolane intermediate 13 (45.0mg, 0.075mmol) was dissolved in THF (6mL) and concentrated hydrochloric acid (37%, 2mL) was added to the reaction intermediate. The mixture was stirred at room temperature for 2 h and diluted with 10 mL of water. The crude was extracted twice with EtOAc (10 mL) and the combined organic layers were washed with 20 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The crude residue was subjected to silica gel chromatography (DCM:MeOH 100:0 to 90:10) to give dihydroxyl PB605 in 82% yield (34.0 mg). 1 H NMR(Acetone-d6,200MHz):δ 2.82(s,6H),4.05-3.55(m,6H),4.30(s,2H),4.58(s,1H),7.09-6.99(m,2H),7.29-7.11(m,2H),7.32(s,1H),7.6 6-7.46(m,3H),7.75(t,J=1.9Hz,1H),8.32(dd,J=7.4,1.3Hz,1H),8.55-8.44(m,2H),9.47(s,1H),11.18(s,1H). 13 C NMR(Acetone-d6,50MHz):δ 45.6,64.1,70.8,71.7,74.8,109.1,116.2,118.3,119.9,120.1,122.5,124.2,129.1,130.2,130 .6,130.7,131.2,131.4,136.1,136.5,139.2,150.0,152.9,158.2,169.9.HRMS-ESI(m / z):[M+H] + Calcd for. HRMS-ESI(m / z):[M+H] + calcd for C 26 H 29O6N4S2,557.1523;found:557.1526.HPLC(λ 254 ) Purity: 97.5%;t R :6.22 minutes (method 1).

[0106] [Compounds PB697 and PB698] Compounds 10 and 14 were used to obtain compounds PB697 and PB698 as follows: [ka]

[0107]

[14] [ka] To a stirred solution of amine 10 (450 mg, 1.06 mmol) in dry THF (10 mL) was added DIEA (0.54 mL, 3.13 mmol). 6-Bromohexanoyl chloride (0.33 mL, 2.15 mmol) was then added dropwise to the mixture and allowed to react at room temperature for 30 min until the starting material was completely consumed (TLC DCM:EtOAc 80:20). The mixture was then quenched with 4 M aqueous sodium hydroxide solution (5 mL) and stirred for another 30 min at room temperature. The reaction mixture was diluted with 10 mL of water and extracted three times with EtOAc (30 mL). The combined organic layers were washed twice with brine, dried over MgSO4, and concentrated under reduced pressure to give bromoalkyl 14 as a brown-yellow powder (230 mg, 36% yield). This crude bromoalkyl was used as is without further purification.

[0108] [PB697] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-6-(4-methylpiperazin-1-yl)hexanamide. To a suspension of bromoalkyl 14 (100.0 mg, 0.17 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and N-methylpiperazine (51.0 mg, 0.51 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 90:10) to give PB697 as a yellow fluorescent powder in 30% yield (29.2 mg). 1 H NMR (CDCl 2- d2,400MHz):δ 1.10-1.02(m,2H),1.53-1.34(m,4H),2.08(t,J=7.6Hz,2H),2.49(s,3H),2.66(t,J=7.1Hz,2H),2.80(s,6H),3.00(br s,8H),7.00(s,1H),7.16-7.11(m,3H),7.44-7.40(m,2H),7.58(t,J=7.8 Hz,1H),7.68(s,1H),8.25(dd,J=7.3,0.9Hz,1H),8.46(t,J=6.2Hz,2H). 13 C NMR (CDCl 2- d2,101MHz,):δ 24.6,24.7,26.5,35.9,44.8,45.5,51.2,52.7,57.3,108.8,115.7,118.1,119.2,119.9,122.4,123.4,129.1 ,129.9,129.9,130.1,130.6,131.3,134.6,135.7,138.2,149.0,152.4,159.5,171.6.HRMS-ESI(m / z):[M+H] + calc. for C 32 H 41 N6O3S2,621.2676;Found:621.2664.HPLC(λ 254 ):purity 94.1%;t R :4.42 minutes (method mauro 7).

[0109] [PB698] [ka] N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanamide. To a suspension of bromoalkyl 14 (100.0 mg, 0.17 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and N-hydroxyethylpiperazine (66.0 mg, 0.51 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 90:10) to give PB698 (19.5 mg) as a yellow fluorescent powder in 18% yield. 1 H NMR (CDCl 2- d2,400MHz):δ 1.32-1.25(m,2H),1.72-1.60(m,4H),2.37(t,J=7.5Hz,2H),2.85-2.73(m,11H),3.02(br s,4H),3.12(br s,4H),3.73-3.70(m,2H),7.03-6.99(m,2H),7.14(dd,J=15.6,7.7Hz,2H),7.39(d,J=7.8Hz,1H),7.44(dd,J= 8.4,7.5Hz,1H),7.60-7.56(m,2H),8.24(dd,J=7.4,1.1Hz,1H),8.40(d,J=8.7Hz,1H),8.46(d,J=8.5Hz,1H). 13 C NMR (CDCl 2- d2,101MHz):δ 24.3,24.6,26.3,35.7,45.5,50.8,51.7,57.2,57.8,59.2,108.6,115.7,118.0,119.0,119.5,122.1,123.5,12 8.9,129.9,129.9,130.2,130.5,131.2,134.8,135.7,138.2,149.1,152.4,158.8,172.0.HRMS-ESI(m / z):[M+H] + calc. for C33 H 43 N6O4S2,651.2769;Found:651.2781.HPLC(λ 254 ):purity 95.1%;t R :4.36 minutes (method mauro 7).

[0110] [Compounds PB688, PB689 and PB693] [ka] N-(3-(2-aminothiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide. To a solution of 9 (1.06 g, 5.50 mmol, 1 eq) in anhydrous DMF (0.2 M) was added anhydrous triethylamine (1.6 eq) and 4-pentylbenzene-1-sulfonyl chloride (1.50 g, 6.10 mmol, 1.1 eq) under argon. The reaction mixture was reacted at room temperature until complete conversion of the starting material. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:MeOH, 100:0 to 95:5) to give the title sulfonamide 15 as a white powder (1.16 g, 53%). 1 H NMR(CD2Cl2-d2,400MHz)δ 0.86(t,J=7.0Hz,3H),1.34-1.25(m,4H),1.61-1.53(m,2H),2.61(t,J=7.6Hz,2H),5.29(br s,2H),6.70(s,1H),6.88(s,1H),6.97-6.95(m,1H),7.21(t,J=8.1Hz,1H),7.25(d,J=8.3Hz,2H),7.50-7.48(m,2H),7.67(d,J=8.3Hz,2H). 13 C NMR(CD2Cl2-d2,101MHz)δ 14.1,22.8,31.2,31.7,36.1,104.0,119.4,120.7,123.0,127.6,129.4,129.8 136.3,136.6,137.4,149.5,150.4,167.9.HRMS-ESI(m / z):[M+H] + calcd for C 20 H 24N3O2S2,402.1304;found:402.1298.HPLC(λ 254 ) Purity:>96.6%;t R :6.12 minutes (method mauro 3) [ka]

[0111]

[15] [ka] 2-Chloro-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide. To a stirred solution of amine 15 (900.0 mg, 2.25 mmol, 1 eq) in dry THF (12 mL) was added DIEA (1.17 mL, 6.75 mmol, 3 eq). Chloroacetyl chloride (0.35 mL, 4.50 mmol, 2 eq) was then added dropwise and the mixture was allowed to react for 30 min at room temperature until the starting material was completely consumed (TLC DCM:EtOAc 70:30). The mixture was then quenched with 4 M aqueous sodium hydroxide solution (10 mL) and stirred for an additional 30 min at room temperature. The reaction mixture was diluted with 10 mL of water and extracted three times with EtOAc (30 mL). The combined organic layers were washed twice with saturated brine solution, dried over MgSO4, and concentrated under reduced pressure to give the respective α-chloroacetyl 16 as a brown powder (976.0 mg, 91%). The crude chloroacetyls were used as such without further purification.

[0112] [PB688] [ka] 2-(4-Methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2 yl)acetamide. To a suspension of chloroalkyl 16 (120.0 mg, 0.25 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and N-methylpiperazine (83.0 μL, 0.75 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 95:5) to give the pure target PB688 as a white powder (70.0 mg, 52%). 1 H NMR(CD2Cl2-d2,400MHz):δ 0.85(t,J=7.0Hz,3H),1.31-1.2(m,4H),1.60-1.53(m,2H),2.39(s,3H),2.61(t,J=7.9Hz,2H),2.73-2.69(m,8H),3.27(s,2H), 7.02(ddd,J=8.0,2.2,0.9Hz,1H),7.27-7.24(m,3H),7.13(s,1H),7.58-7.55(m,1H),7.60-7.59(m,1H),7.68(d,J=8.4Hz,2H). 13 C NMR(CD2Cl2-d2,101MHz):δ 14.1,22.8,31.0,31.7,36.1,45.6,53.2,55.0,61.2,108.9,119.3,120.8,123.0,127.6,129 .4(2C),130.0(2C),135.9,136.6,137.7,149.2,149.5,157.7,168.9.HRMS-ESI(m / z):[M+H] + calc. for C 27 H 36 N5O3S2,542.2254;Found:542.2241.HPLC(λ 254 ):purity 95.7%;t R :5.11 minutes (method mauro 3).

[0113] [PB689] [ka] 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide. To a suspension of chloroalkyl 16 (120.0 mg, 0.25 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and N-hydroxyethylpiperazine (100.0 mg, 0.75 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 95:5) to give the pure target PB689 as a white powder (51.0 mg, 36%). 1 H NMR(CD2Cl2-d2,400MHz):δ 0.85(t,J=7.0Hz,3H),1.31-1.24(m,4H),1.60-1.53(m,2H),2.61(t,J=7.9Hz,2H),2.69(t,J=5.2Hz,2H),2.74(br s,8H),3.27(s,2H),3.66(t,J=5.3Hz,2H),7.00(dd,J=8.0,1.3Hz,1H),7.14(s,1H) ,7.28-7.24(m,3H),7.57(d,J=7.8Hz,1H),7.61-7.60(m,1H),7.68(d,J=8.4Hz,2H). 13 C NMR(CD2Cl2-d2,101MHz):δ 14.1.22.8,31.0,31.72,36.1,53.1,57.8(2C),59.7,61.3,108.9,119.4,120.9,123.1,12 7.6,129.4,130.0,135.9,136.6,137.6,149.2,149.5,157.7,168.9.HRMS-ESI(m / z):[M+H] + calc. for C 28 H 38 N5O4S2,572.2359;Found:572.2347.HPLC(λ 254 ):purity 95.2%;t R :5.19 minutes (method mauro 3).

[0114] [PB693] [ka] 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide. To a suspension of chloroalkyl 16 (120.0 mg, 0.25 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and N,N-dimethylethane-1,2-diamine (83 μL, 0.75 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 95:5) to give the pure target PB693 as a light yellow powder (15.0 mg, 12%). 1 H NMR(CD2Cl2-d2,400MHz):δ 0.82(t,J=7.0Hz,3H),1.28-1.19(m,4H),1.52-1.44(m,2H),2.51(t,J=7.9Hz,2H),2.83(s,6H),2.97(t,J=5.4Hz,2H),3 .13(t,J=5.4Hz,2H),3.56(s,3H),7.03(s,1H),7.17-7.15(m,3H),7.41-7.39(m,1H),7.73(s,1H),7.76(d,J=8.3Hz,2H), 13 C NMR(CD2Cl2-d2,101MHz):δ 14.1,22.8,30.9,31.7,36.0,44.4,45.0,52.4,57.9,108.8,118.9,119.9,122.3,127.7 ,129.4,129.9,135.7,136.6,138.2,148.9,149.3,158.2,170.9,HRMS-ESI(m / z):[M+H] + calc. for C 26 H 36 N5O3S2,530.2254;Found:530.2245.HPLC(λ 254 ):purity 97.3%;t R :4.83 minutes (method mauro 3).

[0115] [Compound PB624, PB625] Compounds PB624 and PB625 were synthesized based on compounds 15 and 17 according to the following method: [ka]

[0116]

[17] [ka] 6-Bromo-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide. To a stirred solution of amine 15 (200 mg, 0.5 mmol, 1 eq) in dry THF (5 mL) was added DIEA (260.0 μL, 1.50 mmol, 3 eq). Then, 6-bromohexanoyl chloride (152.0 μL, 1.00 mmol, 2 eq) was added dropwise to the mixture and allowed to react for 30 min at room temperature until the starting material was completely consumed (TLC DCM:EtOAc 70:30). Then, the mixture was quenched with 4 M aqueous sodium hydroxide solution (10 mL) and stirred for an additional 30 min at room temperature. The reaction mixture was diluted with 10 mL of water and extracted three times with EtOAc (30 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride, dried over MgSO4, and concentrated under reduced pressure to give the respective bromoalkyl 17 as a brown powder (193.2 mg, 64%). The crude bromoalkyl was used directly in the synthesis of PB694 and PB695 without further purification.

[0117] [PB694] [ka] 6-(4-Methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide. To a suspension of bromoalkyl 17 (60.0 mg, 0.10 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and N-methylpiperazine (33 μL, 0.30 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 95:5) to give the pure target PB694 as a white powder (30.0 mg, 51%). 1 H NMR (CD3OD - d4,400MHz):δ 0.85(t,J=7.1Hz,3H),1.33-1.21(m,4H),1.48-1.40(m,2H),1.60-1.52(m,2H),1.68-1.61(m,2 H),1.80-1.73(m,2H),2.51(t,J=7.3Hz,2H),2.63-2.59(m,5H),2.70(t,J=6.7Hz,2H),2.95(br s,8H),6.96(ddd,J=8.0,2.2,0.9Hz,1H),7.21(t,J=7.9Hz,1H),7.28-7.2 6(m,3H),7.59-7.56(m,1H),7.67(d,J=8.4Hz,2H),7.72(t,J=1.8Hz,1H). 13 C NMR (CD3OD - d4,101MHz):δ 14.3,23.4,25.9,26.3,27.4,31.9,32.4,36.3,36.6,44.6,52.2,54.3,58.1,109.0,119.9,121.6,1 23.3,128.3,129.9,130.3,136.9,138.2,139.50,149.9,150.5,159.3,173.6,HRMS-ESI(m / z):[M+H] + calc. for C 31 H 44 N5O3S2,598.2880;Found:598.2870.HPLC(λ 254 ):purity 97.8%;t R :4.97 minutes (method mauro 3).

[0118] [PB695] [ka] 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide. To a suspension of bromoalkyl 17 (60.0 mg, 0.10 mmol, 1 eq) in acetonitrile (0.2 M) was added triethylamine (1 eq) and N-hydroxyethylpiperazine (40.0 mg, 0.30 mmol, 3 eq). The reaction mixture was stirred at 50 °C until the starting material was completely consumed. The volatiles were removed under reduced pressure and the crude residue was subjected to silica gel column chromatography (DCM:MeOH 100:0 to 95:5) to give the pure target PB695 as a white powder (39.0 mg, 63%). 1 H NMR (CD3OD - d4,400MHz):δ 0.85(t,J=7.1Hz,3H),1.33-1.21(m,4H),1.48-1.40(m,2H),1.60-1.52(m,2H),1.70-1.6 3(m,2H),1.81-1.73(m,2H),2.51(t,J=7.3Hz,2H),2.61(t,J=7.6Hz,2H),2.76-2.74(m,4 H),2.91(s,8H),3.71(t,J=5.6Hz,2H),6.97(ddd,J=8.0,2.2,0.9Hz,1H),7.21(t,J=7.9H z,1H),7.28-7.26(m,3H),7.59-7.57(m,1H),7.67(d,J=8.4Hz,2H),7.71(t,J=1.8Hz,1H). 13 C NMR (CD3OD -d4,101MHz):δ 14.3,23.4,25.9,26.1,27.5,31.9,32.4,36.3,36.6,52.7,52.7,58.4,58.9,60.3,109.0,119.9,121.6 ,123.3,128.3,129.9,130.3,136.9,138.21,139.5,149.9,150.5,159.4,173.6.HRMS-ESI(m / z):[M+H] + calc. for C 32 H 46 N5O4S2,628.2986;Found:628.2976.HPLC(λ 254 ):Purity >99%;t R :4.95 minutes (method mauro 3).

[0119] [Compounds PB703, PB704, PB707, PB705 and PB706] These compounds were synthesized according to the following method: [ka]

[0120]

[18] [ka] 2-Bromo-4-(3-nitrophenyl)thiazole. To a solution of α-bromoacetophenone 6 (4.88 g, 20.0 mmol, 1 eq) in ethanol was added potassium isothiocyanate (3.88 g, 40.0 mmol, 2 eq). The reaction mixture was then heated to 80° C. for 3 h and cooled to room temperature. The precipitate was filtered and washed with cold ethanol and diethyl ether. The resulting solid (18) was suspended in glacial acetic acid (10 mL) and HBr / AcOH (10 mL, 33% HBr) was added dropwise over 30 min. After addition, the mixture was allowed to react overnight. The reaction was diluted with AcOH (20 mL) and the solid was filtered and washed with AcOH (10 mL) and diethyl ether (40 mL). Finally, the resulting white powder was dissolved in EtOAc (50 mL) and washed three times with saturated NaHCO3 solution (20 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure to give 2-bromothiazole 19 as a white powder in 72% yield (4.10 g). 1 H NMR (CDCl 2- d2,400MHz):δ 7.75(t,J=8.0Hz,1H),8.21(ddd,J=8.2,2.2,0.8Hz,1H),8.37-8.35(m,1H),8.49(s,1H),8.68(t,J=1.9Hz,1H). [ka]

[0121] 〔twenty one〕 [ka] 4-(3-aminophenyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)thiazol-2-amine. To a solution of 2-bromo-4-(3-nitrophenyl)thiazole 19 (1.15 g, 4.00 mmol, 1 eq) in anhydrous dioxane (0.2 M) was added 2-(4-methylpiperazin-1-yl)ethan-1-amine (2.30 g, 16.00 mmol, 4.0 eq). The reaction mixture was heated to reflux for 48 h. The solvent was removed under reduced pressure and the crude material (20) was redissolved in methanol (20 mL) and treated with Zn powder (1.56 g, 24.00 mmol, 6 eq) and ammonium chloride (1.07 g, 20.00 mmol, 5 eq) for a further hour. The reaction was diluted with methanol (30 mL) and filtered through a pad of celite. The volatiles were removed in vacuo and the crude product was subjected to silica gel chromatography (DCM:MeOH 100:0 to 90:10) to afford aniline 21 in 65% yield as a yellow solid (824.0 mg). 1 H NMR (DMSO - d6,400MHz):δ,2.15(s,3H).2.33(br s,4H),2.44(br s,4H),2.53-2.50(m,2H),3.37(q,J=5.9Hz,2H),5.04(s,2H),6.47(d,J=7.5 Hz,1H),6.80(s,1H),7.01-6.94(m,2H),7.05(s,1H),7.41(t,J=5.3Hz,1H).

[0122] [PB703] [ka] 5-(Dimethylamino)-N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)naphthalene-1-sulfonamide. To a solution of aniline 21 (85.0 mg, 0.22 mmol, 1 eq) in anhydrous DMF (0.2 M) was added anhydrous triethylamine (1.6 eq) and dansyl chloride (74.0 mg, 0.27 mmol, 1.1 eq) under argon. The reaction mixture was reacted at room temperature until complete conversion of the starting material. DMF was removed under reduced pressure and the crude material was purified on a silica gel column. Chromatography (DCM:MeOH, 100:0 to 95:5) afforded the title sulfonamide PB703 as a yellow fluorescent powder (26.1 mg, 20%). 1 H NMR (CDCl 2- d2,400MHz):δ 2.68(s,3H),2.93-2.72(m,12H),3.06(s,4H),3.53(t,J=6.2Hz,2H),6.64(s,1H), 6.84(dd,J=8.0,1.4Hz,1H),7.07(t,J=7.9Hz,1H),7.24(d,J=7.4Hz,1H),7.35(d,J =7.9Hz,1H),7.47(dd,J=8.4,7.5Hz,1H),7.54(t,J=1.7Hz,1H),7.60(dd,J=8.5,7. 7Hz,1H),8.22(dd,J=7.3,1.1Hz,1H),8.44(d,J=8.7Hz,1H),8.48(d,J=8.5Hz,1H). 13 C NMR (CDCl 2- d2,101MHz):δ 42.6,44.2,45.8,51.8,54.9,57.5,102.4,116.4,119.3,120.3,120.5,122.8,124.1,129.3,130 .1,131.0,131.1,131.4,131.6,136.1,137.2,139.1,151.4,153.2,170.9.HRMS-ESI(m / z):[M+H] + calc. for C 28 H 35 N6O2S2,551.2257;Found:551.2225.HPLC(λ 254 ):purity 99.1%;t R:4.32 minutes (method mauro 7). [ka]

[0123] 〔23a〕 [ka] 3-(2-(4-Methylpiperazin-1-yl)thiazol-4-yl)aniline. To a solution of 2-bromo-4-(3-nitrophenyl)thiazole 19 (800.0 mg, 2.80 mmol, 1 eq) in anhydrous dioxane (0.2 M) was added N-methylpiperazine (1.12 g, 16.00 mmol, 4.0 eq). The reaction mixture was heated to reflux for 48 h. The solvent was removed under reduced pressure and the crude material (22a) was redissolved in methanol (20 mL) and treated with Zn powder (1.56 g, 24.00 mmol, 6 eq) and ammonium chloride (1.07 g, 20.00 mmol, 5 eq) for an additional 1 h. The reaction was diluted with methanol (30 mL) and filtered through a pad of Celite. The volatiles were removed in vacuo and the crude product was subjected to silica gel chromatography (DCM:MeOH 100:0 to 90:10) to give aniline 23a in 41% yield as a yellow solid (314.0 mg). 1 H NMR (DMSO - d6,400MHz):δ 2.23(s,3H).2.44(br s,4H),3.43(br s,4H),5.06(s,2H),6.48(d,J=6.2Hz,1H),7.09-6.96(m,4H).

[0124] 〔23b〕 [ka] 2-(4-(4-(3-aminophenyl)thiazol-2-yl)piperazin-1-yl)ethan-1-ol. To a solution of 2-bromo-4-(3-nitrophenyl)thiazole 19 (1.15 g, 4.00 mmol, 1 eq) in anhydrous dioxane (0.2 M) was added N-hydroxyethylpiperazine (2.08 g, 16.00 mmol, 4.0 eq). The reaction mixture was heated to reflux for 48 h. The solvent was removed under reduced pressure and the crude material (22b) was redissolved in methanol (20 mL) and treated with Zn powder (1.56 g, 24.00 mmol, 6 eq) and ammonium chloride (1.07 g, 20.00 mmol, 5 eq) for 1 h. The reaction was then diluted with methanol and filtered through a pad of Celite. The solvent was removed in vacuo, and the crude product was purified by silica gel column chromatography (DCM:MeOH, 100:0 to 95:5) to give the aniline product 23b as a yellowish oil (250 mg, 20% yield). 1 H NMR (DMSO - d6,400MHz)δ 2.45(t,J=6.2Hz,3H).2.57-2.54(m,4H),3.44-3.42(m,4H),3.54(q,J=6.0Hz,2H),4.45(t ,J=5.4Hz,1H),6.49-6.46(m,1H),5.06(s,2H),7.02-6.96(m,2H),7.03(s,1H),7.08(s,1H) [ka]

[0125] [PB704] [ka] N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide. To a solution of aniline 21 (85.0 mg, 0.22 mmol, 1 eq) in anhydrous DMF (0.2 M) under argon was added anhydrous triethylamine (1.6 eq) and 4-pentylbenzene-1-sulfonyl chloride (66.0 mg, 0.27 mmol, 1.1 eq). The reaction mixture was reacted at room temperature until complete conversion of the starting material. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:MeOH, 100:0 to 95:5) to give the title sulfonamide PB704 as a white powder (58.1 mg, 41%). 1 H NMR (CD3OD - d4,400MHz):δ 0.86(t,J=7.1Hz,3H),1.35-1.22(m,4H),1.62-1.54(m,2H),2.28(s,3H),2. 53(s,8H),2.64-2.60(m,2H),2.67(t,J=6.6Hz,2H),3.49(t,J=6.6Hz,2H),6 .71(s,1H),6.98(dd,J=8.0,1.3Hz,1H),7.17(t,J=7.9Hz,1H),7.27(d,J=8. 3Hz,2H),7.44(d,J=7.8Hz,1H),7.51(t,J=1.8Hz,1H),7.68(d,J=8.3Hz,2H). 13 C NMR (CD3OD - d4,101MHz):δ 14.3,23.5,31.9,32.5,36.6,43.0,46.0,53.7,55.7,57.9,102.1,119.9,121.3,122.8 ,128.3,129.9,130.0,137.3,138.8,140.3,149.5,151.7,171.0.HRMS-ESI(m / z):[M+H] + calc. for C 27 H 38 N5O2S2,528.2461;Found:528.2430.HPLC(λ 280 ):purity 98.2%;t R :5.26 minutes (method mauro 3).

[0126] [PB707] [ka] N-(3-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide. To a solution of aniline 23a (60.0 mg, 0.22 mmol, 1 eq) in anhydrous DMF (0.2 M) under argon was added anhydrous triethylamine (1.6 eq) and 4-pentylbenzene-1-sulfonyl chloride (66.0 mg, 0.27 mmol, 1.1 eq). The reaction mixture was reacted at room temperature until complete conversion of the starting material. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:MeOH, 100:0 to 95:5) to give the title sulfonamide PB707 as a white powder (75.2 mg, 71%). 1 H NMR (CD2Cl2-d2 / CD3OD - d4,400MHz)δ 0.85(t,J=7.0Hz,3H),1.31-1.24(m,4H),1.61-1.53(m,2H),2.35(s,3H),2.63-2.56(m,6H),3.55-3.53(m,4H),6.83(s,1H),7.02(d dd,J=8.0,2.1,0.9Hz,1H),7.20(t,J=7.9Hz,1H),7.25(d,J=8.4Hz,2H),7.51-7.49(m,1H),7.54-7.53(m,1H),7.68(d,J=8.4Hz,2H). 13 C NMR (CD2Cl2-d2 / CD3OD - d4,101MHz)δ 14.2,23.2,31.5,32.1,36.4,46.2,48.7,54.8,103.3,119.5,120.9,122.9,127. 9,129.7,129.9,136.9,137.8,138.8,149.5,151.9,172.1.HRMS-ESI(m / z):[M+H] + calc. for C 25 H 33 N4O2S2,485.2039;Found:485.2008.HPLC(λ 280 ):Purity >99.9%;tR : 5.36 minutes (method mauro 3).

[0127] [PB708] [ka] N-(3-(2-(4-(2-hydroxyethyl)piperazin-1-yl)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide. To a solution of aniline 23b (85.0 mg, 0.20 mmol, 1 eq) in anhydrous DMF (0.2 M) under argon was added anhydrous triethylamine (1.6 eq) and 4-pentylbenzene-1-sulfonyl chloride (53.0 mg, 0.22 mmol, 1.1 eq). The reaction mixture was reacted at room temperature until complete conversion of the starting material. DMF was removed under reduced pressure and the crude material was purified by silica gel column chromatography (DCM:MeOH, 100:0 to 95:5) to give the title sulfonamide PB708 as a white powder (19.1 mg, 20%). 1 H 1H NMR (CD3OD - d4,400MHz)δ 0.86(t,J=7.1Hz,3H),1.30-1.26(m,4H),1.61-1.54(m,2H),2.64-2.60(m,4H),2.70-2.68 (m,4H),3.56-3.53(m,4H),3.73(t,J=5.8Hz,2H),6.88(s,1H),7.01(ddd,J=8.0,2.1,0.8Hz 1H),7.19(t,J=7.9Hz,1H),7.28(d,J=8.3Hz,2H),7.50(d,J=7.9Hz,1H),7.54(t,J=1.8Hz,1H),7.68(d,J=8.4Hz,2H). 13 C NMR (CD3OD - d4,101MHz)δ 14.3,23.5,31.9,32.5,36.6,53.7,59.8,61.2,103.5,119.9,121.3,123.2,128. 4,129.9,130.2,137.4,138.3,139.3,149.8,152.3,172.5.HRMS-ESI(m / z):[M+H] + calc. for C 26H 35 N4O3S2 + ,515.2145;Found:515.2113.HPLC(λ 280 ):Purity >99.9%;t R :5.30 minutes (method mauro 3). [ka]

[0128] [PB705] [ka] N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide. To a stirred solution of PB704 (105 mg, 0.2 mmol, 1 eq) in dry THF (5 mL) was added TEA (104.0 μL, 0.60 mmol, 3 eq). Then, acetyl chloride (28.0 μL, 0.4 mmol, 2 eq) was added dropwise to the mixture and allowed to react for 30 min at room temperature until the starting material was completely consumed. The reaction mixture was then diluted with 10 mL of water and extracted three times with EtOAc (30 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH, 100:0 to 95:5) to give the title sulfonamide PB705 as a white powder (11.2 mg, 9%). 1 H NMR (400MHz, CD3OD - d4)δ 8.06(d,J=8.2Hz,1H),7.93(d,J=8.4Hz,3H),7.55(t,J=7.9Hz,2H),7.45(d,J=8.4Hz,2H),7.26(dd,J=7.8,1.2Hz,1H),4.44 (t,J=6.8Hz,2H),2.80-2.48(m,15H),2.28(s,3H),1.92(s,3H),1.72-1.64(m,2H),1.41-1.32(m,4H),0.92(t,J=6.9Hz,3H). 13C NMR (101MHz, CD3OD - d4)δ 172.48,171.99,160.57,151.50,148.55,138.78,137.96,137.74,131.19,130.32,130.18,130.00,128.83, 128.14,111.76,56.59,55.79,54.11,46.79,45.93,36.86,32.62,32.02,25.15,23.54,22.71,14.34.HPLC(λ 280 ):Purity >99.9%;t R :5.57 minutes (method mauro 3).

[0129] [PB706] [ka] N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acrylamido)phenyl)thiazol-2-yl)acrylamide. To a stirred solution of PB704 (105 mg, 0.2 mmol, 1 eq) in dry THF (5 mL) was added TEA (104.0 μL, 0.60 mmol, 3 eq). Then, acryloyl chloride (35.0 μL, 0.4 mmol, 2 eq) was added dropwise to the mixture and allowed to react for 30 min at room temperature until the starting material was completely consumed. The reaction mixture was then diluted with 10 mL of water and extracted three times with EtOAc (30 mL). The combined organic layers were washed twice with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH, 100:0 to 95:5) to give the title sulfonamide PB706 as a white powder (8.0 mg, 6.3%). 1 H NMR (400MHz, CD3OD -d4)δ 8.07(d,J=8.1Hz,1H),7.93(d,J=8.4Hz,2H),7.87(t,J=1.7Hz,1H),7.60(s,1H),7.56(t,J=7.9Hz,1H), 7.45(d,J=8.4Hz,2H),7.20(dd,J=7.8,1.2Hz,1H),7.02(dd,J=16.6,10.5Hz,1H),6.54(dd,J=16.6,1.6 Hz,1H),6.33(dd,J=16.8,1.5Hz,1H),5.98(ddd,J=23.6,12.7,6.0Hz,2H),4.54(t,J=7.1Hz,2H),2.65( ddd,J=140.1,52.2,13.6Hz,11H),1.80-1.60(m,2H),1.37(dd,J=7.2,3.7Hz,4H),0.92(t,J=6.9Hz,3H). 13 C NMR (101 MHz, CD3OD - d4)δ 167.19,166.39,160.85,151.62,148.68,137.87,137.64,137.45,132.07,131.85,131.22,130.59,130.43,130.0 1,129.78,129.15,128.52,128.20,112.43,57.06,55.76,54.01,45.95,45.85,36.88,32.64,31.98,23.53,14.35. HPLC(λ 280 ):Purity = 98.8%; t R :5.80 points (Method Mauro 3).

[0130] 〔PB700〕

change

[0131] Therapeutic Use The endoplasmic reticulum (ER) is a major organelle responsible for multiple cellular functions, including protein folding and maturation, and maintaining cellular homeostasis. ER stress is activated by various factors and triggers the unfolded protein response (UPR) to restore homeostasis or activate cell death. Several studies have revealed the link between ER stress and cancer, particularly the involvement of the UPR. The UPR orchestrates the paradoxical cancer microenvironment and, as such, may be one of the resistance mechanisms to cancer therapy.

[0132] [Unfolded protein response regulator GRP78 / BiP / HSPA5] Endoplasmic reticulum (ER) luminal glucose-regulated protein 78 (GRP78) functions as an unfolded protein response (UPR) signal regulator by binding to ER stress sensors (PRKR-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1)) and maintaining them in an inactive form. It also binds to ER-associated caspase-7 and caspase-12 and inhibits their activation. Upon ER stress, GRP78 is titrated by binding to misfolded proteins. This triggers the UPR, represented by the dimerization of PERK and IRE1, leading to the activation of their downstream signaling pathways, leading to translation arrest and ER-associated protein degradation (ERAD). The UPR also generates active nuclear ATF6 (ATF6(N)), as well as ATF4 and spliced ​​X-box binding protein 1 (XBP1s), which function with other transcription factors such as YY1, nuclear transcription factor Y (NFY), TFII-I, and chromatin modifiers to activate ER stress response elements (ERSEs) present in the promoters of ER stress-responsive genes. The main UPR response is to induce the transcription of ER folding proteins such as GRP to increase the folding capacity of ER proteins and to induce the transcription of the mitochondrial chaperone GRP75. Stressed cells actively promote the relocalization of GRP78 and GRP94 to the plasma membrane and in some cases their secretion; these cells also generate a cytoplasmic isoform of GRP78 (GRP78va) by alternative splicing. Nevertheless, the UPR can also induce transcription of the proapoptotic transcription factor CHOP; and, following release from GRP78, activates caspase-7 and caspase-12, thereby triggering apoptosis. Thus, the UPR regulates the balance between survival and cell death in stressed cells, and upregulation of GRPs represents a major adaptive protective effect that occurs throughout cellular homeostasis.eIF2α, eukaryotic translation initiation factor 2α;P, phosphorylated (Lee, A. Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer 14, 263-276 (2014). https: / / doi.org / 10.1038 / nrc3701).

[0133] [CHOP (C / -EBP homologous protein)] CHOP, DNA damage-induced transcript 3, also known as C / EBP homologous protein, is a pro-apoptotic transcription factor encoded by the DDIT3 gene.

[0134] CHOP is a key player in endoplasmic reticulum stress and an initiator of ER stress-related cell death. Therefore, CHOP is commonly used as a marker of endoplasmic reticulum (ER) stress (Cerezo et al., Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance, Cancer Cell (2016), http: / / dx.doi.org / 10.1016 / j.ccell.2016.04.013).

[0135] Advantageously, the inventors have demonstrated that the compounds of the present invention induce specific cancer cell death by targeting the ER stress axis and simultaneously inducing autophagy and apoptosis.

[0136] Thus, in one embodiment, the present invention relates to a benzenesulfonamide thiazole compound of formula (I) for inducing early endoplasmic reticulum stress: [ka] During the ceremony, R1 is a 5-(dimethylamino)naphthalene group or a 4-pentylphenyl group; R2 is selected from H, halogen, and OR6; R3 is selected from C1-C8 alkyl, NR4R5; R4 is selected from H, alkyl optionally substituted with a nitrogen-containing heterocycle; R5 is selected from H, alkyl optionally substituted with a nitrogen-containing heterocycle, and COR7; R4 and R5 can alternatively together form an optionally substituted nitrogen-containing heterocycle; R6 is selected from C1-C8 alkyl, C1-C8 alkyl-O-C1-C8 alkyl; R7 is, Optionally substituted nitrogen-containing heterocycles ·O-alkyl, NHCO-alkyl, NHCOO-alkyl, COO-alkyl, NH-alkyl, NH-alkyl-OH, NHP(O)(O-alkyl)2, NH-alkyl-SO3H, NH-alkyl-N(alkyl)2 Alkenyl and C1-C8 alkyl optionally substituted with

[0137] These compounds also show strong efficacy in melanoma cells and the NCI-60 human tumor cell line.

[0138] Thus, the benzenesulfonamide thiazole compounds of the present invention are used to treat cancer in a patient.

[0139] Thus, the present disclosure provides a method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a benzenesulfonamide thiazole as defined above.

[0140] The present disclosure also relates to the use of a benzenesulfonamide thiazole as defined above for the treatment of cancer.

[0141] The present disclosure also relates to the use of a benzenesulfonamide thiazole as defined above in the manufacture of a medicament for the treatment of cancer.

[0142] The present disclosure also relates to a pharmaceutical composition for the treatment of cancer, comprising a benzenesulfonamide thiazole as defined above.

[0143] The terms "subject" and "patient" refer to a human or animal suffering from cancer. Preferably, the patient is a human.

[0144] For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment. "Treatment" is intended to ameliorate, alleviate, inhibit the progression or prevent the disorder or condition to which such term applies, or to ameliorate, alleviate, inhibit the progression or prevent one or more symptoms of the disorder or condition to which such term applies.

[0145] The term "cancer" as used herein refers to a physiological condition in a subject characterized by unregulated or dysregulated cell proliferation or cell death. The term "cancer" includes solid tumors and liquid cancers.

[0146] In one embodiment, the present invention relates to a benzenesulfonamide thiazole compound of formula (I) for use for the treatment of cancer: [ka] During the ceremony R1 is a 5-(dimethylamino)naphthalene group or a 4-pentylphenyl group; R2 is selected from H, halogen, and OR6; R3 is selected from C1-C8 alkyl, NR4R5; R4 is selected from H, alkyl optionally substituted with a nitrogen-containing heterocycle; R5 is selected from H, alkyl optionally substituted with a nitrogen-containing heterocycle, and COR7; R4 and R5 can alternatively together form an optionally substituted nitrogen-containing heterocycle; R6 is selected from C1-C8 alkyl, C1-C8 alkyl-O-C1-C8 alkyl; R7 is, Optionally substituted nitrogen-containing heterocycles O-alkyl, NHCO-alkyl, NHCOO-alkyl, COO-alkyl, NH-alkyl, NH-alkyl-OH, NHP(O)(O-alkyl)2, NH-alkyl-SO3H, NH-alkyl-N(alkyl)2 Alkenyl is selected from C1-C8 alkyl optionally substituted with

[0147] All of the previously described substituents are encompassed in this embodiment.

[0148] In one embodiment, the benzenesulfonamide thiazole compound for use in the treatment of cancer is selected from the following: N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-fluorophenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-morpholinoacetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-((3-morpholinopropyl)amino)acetamide Diethyl-(2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)phosphoramidate 2-((2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)amino)ethane-1-sulfone N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-6-(4-methylpiperazin-1-yl)hexanamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(prop-2-yn-1-yloxy)phenyl)thiazol-2-yl)acrylamide 5-(Dimethylamino)-N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)naphthalene-1-sulfonamide.

[0149] In another embodiment, the benzenesulfonamide thiazole compound for use in the treatment of cancer is selected from the following: 2-(4-Methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide. 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide. N-(5-(2-aminothiazol-4-yl)-2-methoxyphenyl)-4-pentylbenzenesulfonamide N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide. 6-(4-Methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide. 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide. 2-(4-methylpiperazin-1-yl)-N-(4-(4-(4-methylpiperazin-1-yl)-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide. N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide. N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acrylamido)phenyl)thiazol-2-yl)acrylamide. N-(3-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide. N-(3-(2-(4-(2-hydroxyethyl)piperazin-1-yl)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide.

[0150] In a preferred embodiment, the benzenesulfonamide thiazole compound for use in the treatment of cancer is selected from the following: N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 6-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide 2-(4-methylpiperazin-1-yl)-N-(4-(4-(4-methylpiperazin-1-yl)-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(prop-2-yn-1-yloxy)phenyl)thiazol-2-yl)acrylamide.

[0151] In one embodiment, the patient is afflicted with a solid or liquid cancer.

[0152] In one embodiment, the patient is afflicted with a liquid cancer, such as lymphoma, leukemia, or hematopoietic cancer.

[0153] In one embodiment, the patient is afflicted with a solid cancer selected from the group consisting of skin cancer (e.g., melanoma, non-melanoma skin cancer), gastrointestinal carcinoid tumor (e.g., choriocarcinoma, destructive villous adenoma), prostate cancer, colorectal cancer, breast cancer (e.g., ductal carcinoma in situ, invasive ductal carcinoma, invasive lobular carcinoma, lobular carcinoma in situ), kidney cancer, autonomic ganglion cancer, esophageal cancer, stomach and gastric cancer, endometrial cancer, upper aerodigestive cancer, ovarian cancer, colon cancer, liver cancer, central nervous system cancer, pancreatic cancer, lung cancer, urinary tract cancer, soft tissue cancer, biliary tract cancer, thyroid cancer, pleural cancer (including mesothelioma cancer), bone cancer, and salivary gland cancer.

[0154] The present inventors have demonstrated that expression of HSPA5 in melanoma cell lines correlates with sensitivity to HA15. Without wishing to be bound by any theory, the present inventors believe that the efficacy of the compound correlates with the expression of HSPA5 in cancer tissues.

[0155] Several types of cancer have HSPA5 expression levels that exceed those in the A375 cell line (as exemplified in Example 9). Since the efficacy of the compounds correlates with HSPA5 expression in cancer tissues, the applicability and efficacy of the compounds of the present invention can be reasonably extrapolated to cancer cell lines with high HSPA5 expression levels, such as autonomic ganglion cancer, esophageal cancer, stomach / gastric cancer, endometrial cancer, upper respiratory tract / digestive tract cancer, ovarian cancer, colon cancer, liver cancer, central nervous system cancer, pancreatic cancer, lung cancer, urinary tract cancer, soft tissue cancer, biliary tract cancer, thyroid cancer, pleural cancer (including mesothelioma cancer), bone cancer, and salivary gland cancer.

[0156] Thus, in one embodiment, the cancer is a cancer that overexpresses HSPA5.

[0157] In one embodiment, the patient is afflicted with a solid cancer selected from the group consisting of skin cancer (e.g., melanoma, non-melanoma skin cancer), esophageal cancer, gastric cancer, gastrointestinal carcinoid tumor (e.g., choriocarcinoma, destructive villous adenoma), stomach cancer, prostate cancer, colon cancer, and breast cancer (e.g., ductal carcinoma in situ, invasive ductal carcinoma, invasive lobular carcinoma, lobular carcinoma in situ).

[0158] According to a preferred embodiment, the cancer to be treated according to the present invention is stomach and gastric cancer, esophageal cancer or skin cancer, preferably cutaneous melanoma.

[0159] In one embodiment, the benzenesulfonamide thiazole compound for use in the treatment of skin cancer, preferably melanoma, is selected from the following: N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-fluorophenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide 2-(2,3-dihydroxypropoxy)-N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)acetamide tert-Butyl (6-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-6-oxohexyl)carbamate. Ethyl 5-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-5-oxopentanoate 6-Acetamido-N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)hexanamide tert-Butyl (4-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-4-oxobutyl)carbamate 4-((4-(3-((5-(dimethylamino(napthalene)-1-sulfonamido)phenyl)thiazol-2-yl)butanamide 5-(Dimethylamino)-N-(3-(2-methylthiazol-4-yl)phenyl)naphthalene-1-sulfonamide. N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-morpholinoacetamide. N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide 1-(2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)piperidine-4-carboxamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-((2-hydroxyethyl)amino)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-((3-morpholinopropyl)amino)acetamide. Diethyl-(2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)phosphoramidate N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-fluorophenyl)thiazol-2-yl)acetamide 2-((2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)amino)ethane-1-sulfone.

[0160] In a further preferred embodiment, 2-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 6 -(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 2-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide )thiazol-2-yl)acetamide, N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide or N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide is used for the treatment of skin cancer, preferably melanoma.

[0161] In a further preferred embodiment, 2-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide, Setoamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 6-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide or N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide is used to treat skin cancer, preferably melanoma.

[0162] In another preferred embodiment, 2-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide Setoamide, 6-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 2-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide or N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide is used to treat stomach and gastric cancer and / or esophageal cancer.

[0163] In a further preferred embodiment, 2-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-(( 4-Pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 6-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide or N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide are used for the treatment of stomach cancer. It is used to treat esophageal and / or gastric cancer.

[0164] The compound used in the context of the present invention can be administered by any suitable route.Those skilled in the art know which administration route should be used as well as the corresponding dosage.The compound useful in the context of the present invention is typically administered by parenteral (for example, intravenous, intramuscular or subcutaneous) administration.

[0165] The present invention is further illustrated by the following figures and examples, which should not, however, be construed in any way as limiting the scope of the present invention.

[0166] [Example] [Example 1: Improvement of stability against HA15] The compounds of the present invention show higher chemical stability than HA15. As a representative example, compound PB704 shows complete stability under the following conditions: PBS (pH 7.4), 20% DMSO, 24 hours; aqueous HCl (0.1M), 24 hours; PBS (pH 7.4), 20% DMSO, 24 hours, 80° C. Meanwhile, HA15 shows partial decomposition under the latter conditions.

[0167] [Example 2: Improvement of solubility for HA15] The compounds of the present invention exhibit higher water solubility than HA 15. The following table shows examples of the water solubility of HA 15 and some compounds of the present invention. [Table 2]

[0168] Example 3: Improved exposure to HA15 Compounds of the invention demonstrate increased exposure in mice over HA15. The following table shows examples of the AUC of several compounds of the invention compared to HA15. [Table 3]

[0169] Example 4: Improvement of half-life for HA15 The compounds of the invention exhibit a longer half-life in mice than HA15. The following table shows examples of the AUC of some compounds of the invention compared to HA15. [Table 4] [Table 5]

[0170] Example 5: Effect of the compounds of the present invention on cell viability of A375 melanoma cells Cell viability was assessed by measuring the number of viable cells in different cell samples. Measurement of cell viability was performed by cell counting using the trypan blue exclusion method. Results were expressed as a percentage of the relative number of viable cells compared to the number of viable cells in the presence of DMSO, which corresponds to the negative control, associated with a value of 100%.

[0171] Viability was measured at 48 hours. Different doses of these compounds were tested (10 μM; 5 μM and 1 μM). [Table 6]

[0172] The compounds of the present invention affect the viability of melanoma cells.

[0173] Example 6: NCI-60 Human Tumor Cell Line Screening The National Cancer Institute's Developmental Therapeutics Program, DTP-NCI-60 human tumor cell line screen, is used to screen PB compounds for potential anticancer activity. The screening procedure uses 60 different human tumor cell lines representing leukemia, melanoma, and lung, colon, brain, ovarian, breast, prostate, and renal cancers.

[0174] Compounds were evaluated at one dose against a panel of 60 cells and then at five concentration levels for the most active compound.

[0175] The single dose data is reported as an average graph of percent proliferation of treated cells and will look similar to the average graph from the 5 dose assay. The numbers reported for the 1 dose assay are proliferation relative to the no drug control and proliferation relative to the cell count at time zero. This allows for detection of both growth inhibition (values ​​between 0 and 100) and lethality (values ​​below 0). This is the same as for the 5 dose assay.

[0176] For example, a value of 100 means no growth inhibition; a value of 40 means 60% growth inhibition; a value of 0 means no net growth over the experimental period; a value of -40 means 40% death; a value of -100 means all cells have been killed. [Table 7]

[0177] The compounds of the present invention show greater potency than HA15 against the NCI-60 human tumor cell line.

[0178] Example 7: Effect of the compound according to the present invention on ER stress marker (CHOP) Starved A375 melanoma cells, Kyse 70, SH10TC and KATO III were treated with the compounds for 24 or 48 hours, after which the cells were lysed and the lysates were analyzed by Western blot using CHOP as an ER stress marker antibody. [Table 8] [Table 9]

[0179] The compounds according to the present invention kill cancer cells by increasing ER stress by targeting the ER stress marker CHOP.

[0180] Example 8: IC in A375 cells at 24 hours / 48 hours (10% SVF) 50 Decision of IC of the compounds of the present invention in A375 melanoma cells 50 was compared to HA15:Starved A375 melanoma cells were treated with the title compound for 24 hours. Cells were then counted using the blue trypan exclusion method. The results are shown in the table below. [Table 10]

[0181] These results show that the compounds of the present invention have an advantageous IC50 superior to HA15, a benzenesulfonamide thiazole compound described in WO2014072486, which is active in the treatment of cancer, particularly against melanoma cells.

[0182] Example 9: Toxicity of compounds according to the present invention in FHN compared to HA15 in normal fibroblasts at 24 hours Normal human fibroblasts (FHN) were treated with the title compounds at IC50 or 10x IC50 concentrations determined in A375 cells (Example 4) for 24 hours. Then, cells were counted using blue trypan exclusion method. "OK" means that the compound is not toxic. [Table 11]

[0183] These results indicate that the new HA15-derivatives according to the present invention are not toxic to normal human fibroblasts, which is surprising considering the significantly improved anti-proliferative effect over HA15.

[0184] Example 10: Correlation between HSPA5 expression levels and compound efficacy The present inventors have demonstrated that expression of HSPA5 in melanoma cell lines correlates with sensitivity to HA15. Without wishing to be bound by any theory, the present inventors believe that the efficacy of the compound correlates with the expression of HSPA5 in cancer tissues.

[0185] As shown in the table below, several types of cancer have HSPA5 expression levels equal to or greater than A375. Because compound efficacy correlates with HSPA5 expression in cancer tissue, the applicability and efficacy of the compounds of the present invention can be reasonably extrapolated to all indications cited in the table. [Table 12]

[0186] Therefore, the compounds according to the present invention can target HSPA5 to induce specific cancer cell death and are useful for the future treatment of a wide spectrum of cancers.

[0187] Example 11: Toxicity of the compounds according to the present invention against HA15 Incucyte® Cell Number Proliferation Assay Briefly, A375 melanoma cells transformed with Nuclight Green Lentivirus (puro) (ref. 4624) were seeded in 24-well plates at a density of 26,000 cells / well in DMEM 10% SVF medium. Cells were starved for 16 h and then treated with the indicated concentrations of different compounds and 1 mg / mL propidium iodide diluted 1 / 300. Cells were incubated for 72 h, with expression monitored using the IncuCyte® S3 Live-Cell Analysis System. The assay parameters were: objective lens used 20x; channel selection: phase+fluorescence (red 800 ms and green 400 ms), scans were performed at 2-h intervals. Cell viability was calculated in comparison to the control condition by the following formula: total green object area (μm 2 / Image) / Total area of ​​red objects (μm 2 / image).

[0188] The results are shown in Figure 1. This figure shows that PB628, a compound according to the invention, has a lower IC50 against HA15, and therefore PB628 is effective at lower concentrations than HA15.

[0189] [In vitro toxicity test using normal human cells] Normal human melanoma cells and normal human fibroblasts were prepared and maintained as described above. Fresh, sterilized tissues were obtained from surgical waste from patients diagnosed with metastatic melanoma at the Nice CHU Hospital and processed as previously described (Cerezo et al., 2016). Briefly, the tissues were dissected and digested with collagenase A (0.33 U / mL), dispase (0.85 U / mL), and DNase I (144 U / mL) for 1–2 h at 37 °C with rapid shaking. Large debris was removed by filtration through a 70 mm cell strainer. Written informed consent was obtained from each patient who participated in the study, and the study was approved by the hospital ethics committee (Nice Hospital Center and University of Nice Sophia Antipolis, Nice, France, no. 210-2998).

[0190] Normal human fibroblasts (FHN) and normal human melanoma cells (MHN) were plated in 12-well plates at 35,000 cells / well in DMEM 10% SVF medium or 100,000 cells / well in Cascade medium, respectively. The next day, cells were treated with the indicated concentrations of drugs. After 48 hours, cells were harvested and counted by trypan blue method.

[0191] The results are shown in Figure 2. As demonstrated in this figure, PB628 shows no toxicity at concentrations 10-fold higher than its IC50, especially in fibroblasts.

[0192] Thus, the compounds of the present invention are effective at lower doses and are less toxic than HA15. [Brief description of the drawings]

[0193] [Figure 1] Incucyte® IC50 determinations of PB628 and HA15 in A375 melanoma cells. [Diagram 2] Toxicity of fibroblasts and melanoma cells after treatment with PB628 or HA15.

Claims

1. The benzenesulfonamide thiazole compound of formula (I): 【Chemistry 1】 During the ceremony, R １ is a 5-(dimethylamino)naphthalene group or a 4-pentylphenyl group, R ２ is H, halogen, OR ６ is selected from R ３ is C １ -C ８ Alkyl, NR ４ R ５ is selected from R ４ is selected from H, alkyl optionally substituted with a nitrogen-containing heterocycle; R ５ is H, alkyl optionally substituted with a nitrogen-containing heterocycle, COR ７ is selected from R ４ and R ５ can alternatively together form an optionally substituted nitrogen-containing heterocycle; R ６ is C １ -C ８ Alkyl, C １ -C ８ Alkyl-O-C １ -C ８ alkyl, R ７ teeth, optionally substituted nitrogen-containing heterocycles O-alkyl, NHCO-alkyl, NHCOO-alkyl, COO-alkyl, NH-alkyl, NH-alkyl-OH, NHP(O)(O-alkyl) ２ , NH-alkyl-SO ３ H, NH-alkyl-N(alkyl) ２ Alkenyl C optionally substituted with １ -C ８ alkyl.

2. 2. The benzenesulfonamide thiazole compound of claim 1, wherein the benzenesulfonamide thiazole compound is a compound of formula (II): 【Chemistry 2】

3. The benzenesulfonamide thiazole compound according to claim 1 , wherein the benzenesulfonamide thiazole compound is a compound of the following formula: 【Transformation 3】

4. 2. The benzenesulfonamide thiazole compound of claim 1, wherein the compound is selected from the group consisting of: N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-fluorophenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-methoxyphenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide 2-(2,3-dihydroxypropoxy)-N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)acetamide tert-butyl(6-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-6-oxohexyl)carbamate 5-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-5-oxopentanoic acid ethyl ester 6-acetamido-N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)hexanamide tert-butyl(4-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-4-oxobutyl)carbamate 4-((4-(3-((5-(dimethylamino(napthalene)-1-sulfonamido)phenyl)thiazol-2-yl)butanamide 5-(dimethylamino)-N-(3-(2-methylthiazol-4-yl)phenyl)naphthalene-1-sulfonamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-morpholinoacetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)acetamide 1-(2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)piperidine-4-carboxamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-((2-hydroxyethyl)amino)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-2-((3-morpholinopropyl)amino)acetamide Diethyl-(2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)phosphoramidate N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-fluorophenyl)thiazol-2-yl)acetamide 2-((2-((4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)amino)-2-oxoethyl)amino)ethane-1-sulfone 2-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide N-(5-(2-aminothiazol-4-yl)-2-methoxyphenyl)-4-pentylbenzenesulfonamide N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 6-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide 2-(4-methylpiperazin-1-yl)-N-(4-(4-(4-methylpiperazin-1-yl)-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-6-(4-methylpiperazin-1-yl)hexanamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)phenyl)thiazol-2-yl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)hexanamide N-(4-(3-((5-(dimethylamino)naphthalene)-1-sulfonamido)-4-(prop-2-yn-1-yloxy)phenyl)thiazol-2-yl)acrylamide 5-(dimethylamino)-N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)naphthalene-1-sulfonamide N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acrylamido)phenyl)thiazol-2-yl)acrylamide N-(3-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide N-(3-(2-(4-(2-hydroxyethyl)piperazin-1-yl)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide.

5. 2. The benzenesulfonamide thiazole compound of claim 1, wherein the compound is selected from the group consisting of: 2-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide 6-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide 2-(4-methylpiperazin-1-yl)-N-(4-(4-(4-methylpiperazin-1-yl)-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide, and N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide.

6. A pharmaceutical composition comprising the benzenesulfonamide compound of claim 1 for the treatment of cancer.

7. The pharmaceutical composition according to claim 6 , wherein the cancer is selected from the group consisting of solid cancers and liquid cancers.

8. The pharmaceutical composition according to claim 7, wherein the liquid cancer is lymphoma, leukemia, or hematopoietic cancer.

9. 8. The pharmaceutical composition of claim 7, wherein the solid cancer is selected from the group consisting of skin cancer, gastrointestinal carcinoid tumor, prostate cancer, colorectal cancer, breast cancer, kidney cancer, autonomic ganglion cancer, esophageal cancer, stomach and gastric cancer, endometrial cancer, upper respiratory tract and digestive tract cancer, ovarian cancer, colon cancer, liver cancer, central nervous system cancer, pancreatic cancer, lung cancer, urinary tract cancer, soft tissue cancer, biliary tract cancer, thyroid cancer, pleural cancer, bone cancer, and salivary gland cancer.

10. 10. The pharmaceutical composition according to claim 7 or 9, wherein the cancer is selected from the group consisting of stomach and gastric cancer, esophageal cancer and skin cancer.

11. The pharmaceutical composition of claim 7 or 9, wherein the cancer is a skin cancer, preferably melanoma.

12. The compounds include 2-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, and N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide. 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 6-(4-methylpiperazin-1-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 2-(4-methylpiperazin-1-yl)-N-(4-(4-(4-methylpiperazin-1-yl)-3-((4-pentylphenyl)sulfonamido)phenyl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 2-(4-methylpiperazin-1-yl)-N-(4-(4-(4-methylpiperazin-1-yl)-3-((4-pentylphenyl)sulfonamido)phenyl) 12. The pharmaceutical composition of claim 11, wherein the compound is selected from the group consisting of N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide, and N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide.

13. The pharmaceutical composition according to claim 7 or 9, wherein the cancer is stomach and gastric cancer or esophageal cancer.

14. The compounds include 22-(4-methylpiperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 6-(4-methylpiperazin-1-yl)acetamide, 2-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(4-methoxy-3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 2-((2-(dimethylamino)ethyl)amino)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)acetamide, 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 6-(4-(2-hydroxyethyl)piperazin-1-yl)-N-(4-(3-((4-pentylphenyl)sulfonamido)phenyl)thiazol-2-yl)hexanamide, 2-(4-methylpiperazin-1-yl)-N-(4-(4-(4-methylpiperazin-1-yl)-3-((4-pentylphenyl)sulfonamido)phenyl) 14. The pharmaceutical composition of claim 13, wherein the compound is selected from the group consisting of N-(3-(2-((2-(4-methylpiperazin-1-yl)ethyl)amino)thiazol-4-yl)phenyl)-4-pentylbenzenesulfonamide, and N-(2-(4-methylpiperazin-1-yl)ethyl)-N-(4-(3-(N-((4-pentylphenyl)sulfonyl)acetamido)phenyl)thiazol-2-yl)acetamide.

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