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CN-122010846-A - 1-Phenyl-1H-benzo [ d ] imidazole compound serving as FLT3 kinase inhibitor, preparation method, pharmaceutical composition and application

CN122010846ACN 122010846 ACN122010846 ACN 122010846ACN-122010846-A

Abstract

The invention discloses a 1-phenyl-1H-benzo [ d ] imidazole compound serving as an FLT3 kinase inhibitor, a preparation method, a pharmaceutical composition and application thereof, wherein the 1-phenyl-1H-benzo [ d ] imidazole compound shown in a structural formula (I) or pharmaceutically acceptable salt thereof has obvious proliferation inhibition effect on leukemia cells, especially human acute myeloid leukemia cells MOLM-13 and MV4-11, blocks cell cycle in G0/G1 phase, induces apoptosis, has better safety and obviously inhibits tumor growth in a MOLM-13 nude mice transplantation tumor model, has the potential of being prepared into novel antitumor drugs, and has better market prospect.

Inventors

  • KONG DEXIN
  • Khalid Abdelhamid Abou Zeid
  • YANG ZIQI
  • JIA WENQING
  • ZHANG ZHE
  • PENG XIN
  • ZHAO WENNAN

Assignees

  • 天津医科大学

Dates

Publication Date
20260512
Application Date
20260414

Claims (10)

  1. 1. A1-phenyl-1H-benzo [ d ] imidazole compound serving as an FLT3 kinase inhibitor is characterized in that the 1-phenyl-1H-benzo [ d ] imidazole compound shown in a structural formula (I) or pharmaceutically acceptable salt thereof: (I); Wherein, the R 1 is selected from one of-C (O) NH-, SO 2 , C (O) and-C (S) NH-; R 2 、R 3 and R 4 are independently selected from one of hydrogen atom, C1-6 alkyl, halogen and CF 3 、-OCH 3 ; R 5 is selected from one of halogen, phenol and m-tolyl carbamate.
  2. 2. The 1-phenyl-1H-benzo [ d ] imidazole compound used as an FLT3 kinase inhibitor according to claim 1, wherein R 1 is-C (O) NH-, R 2 、R 3 and R 4 are selected from one of hydrogen atom, methyl group, -OCH 3 、CF 3 and chlorine atom, R 2 、R 3 and R 4 are the same or different, R 5 is selected from one of phenol, bromine atom and phenyl m-toluylcarbamate; Or R 1 is SO 2 ,R 2 ,R 3 and R 4 is selected from one of hydrogen atom, -OCH 3 and chlorine atom, R 2 、R 3 and R 4 are the same or different, R 5 is selected from one of phenol and bromine atom; Or R 1 is C (O), R 2 ,R 3 and R 4 are selected from one of hydrogen atom, -OCH 3 and chlorine atom, R 2 、R 3 and R 4 are the same or different, R 5 is selected from one of phenol and bromine atom; Or R 1 is-C (S) NH-, R 2 ,R 3 and R 4 are selected from one of hydrogen atom, -OCH 3 and chlorine atom, R 2 、R 3 and R 4 are the same or different, and R 5 is bromine atom.
  3. 3. The 1-phenyl-1H-benzo [ d ] imidazole compound according to claim 1, which is an inhibitor of FLT3 kinase, wherein the compound is any one of the following compounds: compound 1, n- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3-chlorobenzenesulfonamide; Compound 2 n- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -4-methoxybenzenesulfonamide; Compound 3:N- (4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3-chlorobenzenesulfonamide; Compound 4 n- (4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -4-methoxybenzenesulfonamide; compound 5:1- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (3-chlorophenyl) thiourea; Compound 6:1- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-methoxyphenyl) thiourea; Compound 7:1- (4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3- (3-chlorophenyl) thiourea; compound 8:1- [4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-methoxyphenyl) thiourea; Compound 9- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (3-chlorophenyl) urea; Compound 10:1- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (m-tolyl) urea; Compound 11- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-chloro-3-trifluoromethylphenyl) urea; Compound 12:1- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-chloro-2-methylphenyl) urea; Compound 13:1- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3- (4-methoxyphenyl) urea; Compound 14:1- [4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (3-chlorophenyl) urea; compound 15:1- [4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (m-tolyl) urea; compound 16- [4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-chloro-3- (trifluoromethyl) phenyl) urea; Compound 17:1- [4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-chloro-2-methylphenyl) urea; Compound 18 n- (3- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -4-methoxybenzamide; Compound 19 n- (4- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -4-methoxybenzamide; compound 20-chloro-N- (3- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) benzenesulfonamide; compound 21 n- (3- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -4-methoxybenzenesulfonamide; Compound 22-chloro-N- (4- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) benzenesulfonamide; Compound 23 n- (4- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -4-methoxybenzenesulfonamide; compound 24:1- (3-chlorophenyl) -3- (3- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) urea; Compound 25:1- (3- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -3- (m-tolyl) urea; Compound 26:1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (3- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) urea; compound 27:1- (4-chloro-2-methylphenyl) -3- (3- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) urea; Compound 28:1- (3- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -3- (4-methoxyphenyl) urea; compound 29:1- (3-chlorophenyl) -3- (4- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) urea; compound 30:1- (4- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -3- (m-tolyl) urea; Compound 31:1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (4- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) urea; Compound 32:1- (4-chloro-2-methylphenyl) -3- (4- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) urea; Compound 33:1- (4- (5- (4-hydroxyphenyl) -1H-benzo [ d ] imidazol-1-yl) phenyl) -3- (4-methoxyphenyl) urea; Compound 34- (1- (3- (3- (m-tolyl) ureido) phenyl) -1H-benzo [ d ] imidazol-5-yl) phenyl m-tolyl carbamate.
  4. 4. A process for preparing a 1-phenyl-1H-benzo [ d ] imidazole compound as an inhibitor of FLT3 kinase according to claim 3, wherein compound 1, compound 2, compound 3, and compound 4 are the first compounds; The preparation method of the first compound comprises the following steps of dissolving benzenesulfonamide compounds in pyridine, cooling in an ice bath, adding benzenesulfonyl chloride derivatives, heating the reaction mixture to room temperature, stirring, concentrating the reaction solution under reduced pressure, pouring into ice water, filtering, washing filter cakes, and drying to obtain the first compound; The benzenesulfonamide compound is selected from one of 3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) aniline and 4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) aniline; the benzenesulfonyl chloride derivative is selected from one of 4-methoxybenzenesulfonyl chloride or 3-chlorobenzenesulfonyl chloride; Compound 20, compound 21, compound 22, compound 23 are second compounds; the preparation method of the second compound comprises the following steps: Dissolving benzenesulfonamide derivatives and 4-hydrogen phenylboronic acid pinacol ester in dioxane aqueous solution, introducing nitrogen, then adding Pd (PPh 3 ) 4 and potassium carbonate, heating and refluxing for reaction for 3 hours, concentrating the reaction solution under reduced pressure, pouring into ice water, filtering, washing a filter cake, and drying to obtain a second compound; The benzenesulfonamide derivative is selected from one of N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3-chlorobenzenesulfonamide, N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -4-methoxybenzenesulfonamide and N- (4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3-chlorobenzenesulfonamide.
  5. 5. A process for the preparation of 1-phenyl-1H-benzo [ d ] imidazoles as inhibitors of FLT3 kinase according to claim 3, wherein compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 14, compound 15, compound 16, compound 17 are third compounds; the preparation method of the third compound comprises the following steps: Dissolving aromatic amine compound in anhydrous N, N-dimethylformamide or anhydrous dichloromethane, slowly adding corresponding aryl isothiocyanate derivative, stirring the reaction mixture at room temperature, concentrating the reaction solution under reduced pressure, pouring into ice water, filtering, washing filter cake, and drying to obtain a third compound; The aromatic amine compound is selected from one of 3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) aniline and 4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) aniline; The aryl isothiocyanate derivative is 3-chloro aryl isothiocyanate or 4-methoxy aryl isothiocyanate, and the aryl isocyanate derivative is one of 3-chloro aryl isocyanate, 3-methyl aryl isocyanate, 4-chloro-3-trifluoromethyl aryl isocyanate, 4-chloro-2-methyl aryl isocyanate and 4-methoxy aryl isocyanate.
  6. 6. A process for the preparation of 1-phenyl-1H-benzo [ d ] imidazoles as inhibitors of FLT3 kinase according to claim 3, wherein compound 18, 19 is a fourth compound; The preparation method of the fourth compound comprises the following steps: Dissolving aromatic amine compounds in pyridine, adding acyl chloride derivatives, stirring the reaction mixture at room temperature, filtering, washing to obtain an intermediate, dissolving the intermediate and 4-hydroxyphenylboronic acid pinacol ester in dioxane aqueous solution, introducing nitrogen, adding Pd (PPh 3 ) 4 and potassium carbonate, heating and refluxing for 2-4h, cooling the reaction mixture, concentrating under reduced pressure, and purifying by column chromatography to obtain a fourth compound; The aromatic amine compound is selected from one of 3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) aniline and 4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) aniline; The acyl chloride derivative is 4-methoxy benzoyl chloride.
  7. 7. A process for preparing 1-phenyl-1H-benzo [ d ] imidazoles as inhibitors of FLT3 kinase according to claim 3, wherein compound 24, compound 25, compound 26, compound 27, compound 28, compound 29, compound 30, compound 31, compound 32, compound 33 are fifth compounds; the preparation of the fifth compound comprises the following steps: Dissolving urea derivatives and 4-hydrogen phenylboronic acid pinacol ester in dioxane aqueous solution, introducing nitrogen, adding Pd (PPh 3 ) 4 and potassium carbonate, and carrying out heating reflux reaction for 2-4 hours; The urea derivative is selected from 1- (4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3- (3-chlorophenyl) urea, 1- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (m-tolyl) urea, 1- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-chloro-3-trifluoromethylphenyl) urea, 1- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-chloro-2-methylphenyl) urea, 1- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3- (4-methoxyphenyl) urea, 1- [4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (3-chlorophenyl) urea, 1- [4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (m-tolyl) urea, 1- [4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-chloro-3- (trifluoromethyl) phenyl) urea, 1- [4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-chloro-2-methylphenyl) urea, 1- (4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3- (4-methoxyphenyl) urea.
  8. 8. A process for preparing 1-phenyl-1H-benzo [ d ] imidazole compound as an inhibitor of FLT3 kinase according to claim 3, wherein compound 13 is a sixth compound, Dissolving 1,1' -carbonyl diimidazole in anhydrous DCM, cooling in ice bath, adding triethylamine, dropwise adding anhydrous DCM solution of p-methoxyaniline into the cooled solution in nitrogen atmosphere, and continuing stirring in ice bath for reaction for 1-3 hours to obtain a reaction solution; Dropwise adding a solution of 3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) aniline into the reaction solution, subsequently heating the reaction system to room temperature and continuously stirring, concentrating the reaction solution under reduced pressure, filtering, washing, drying, and purifying by flash column chromatography to obtain a sixth compound; compound 34 is a seventh compound; The preparation method of the seventh compound comprises the following steps of slowly adding the corresponding aryl isocyanate derivative to a solution of 4- (1- (3-aminophenyl) -1H-benzo [ d ] imidazol-5-yl) phenol in anhydrous DCM, stirring the mixture at room temperature, filtering the reaction mixture, washing with diethyl ether, drying and purifying by column chromatography to obtain the seventh compound.
  9. 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition is in the form of an oral formulation or injection.
  10. 10. Use of a 1-phenyl-1H-benzo [ d ] imidazole compound as FLT3 kinase inhibitor according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 9 as an active ingredient for the preparation of an antitumor drug having inhibitory activity against human acute myeloid leukemia cell lines MOLM-13 and MV 4-11.

Description

1-Phenyl-1H-benzo [ d ] imidazole compound serving as FLT3 kinase inhibitor, preparation method, pharmaceutical composition and application Technical Field The invention belongs to the technical field of medicines, and particularly relates to a 1-phenyl-1H-benzo [ d ] imidazole compound serving as an FLT3 kinase inhibitor, a preparation method, a pharmaceutical composition and application. Background Acute Myeloid Leukemia (AML), the most common acute leukemia in adults, is a serious challenge to the global health system with high lethality, high economic burden and cross-age killing. AML progresses rapidly with a median survival of only 8 weeks in untreated subjects. Even with intensive chemotherapy, the overall survival rate is still less than 30% for 5 years (older <10%, young about 40% -50%). The new cases of 2024 worldwide are over 12 ten thousand, 11 ten thousand deaths (WHO data), and cancer death causes in young and strong years between 15 and 39 are three in front. Among AML patients, FLT3 gene mutations occur at rates up to 25% -30%, and a number of clinical studies indicate that AML patients harboring FLT3-ITD mutations often exhibit leukocytosis, high recurrence rates, significant cardiotoxicity, and significantly shortened overall survival. Whereas normal cells have no FLT3 mutation. Thus, FLT3 mutations have been considered as poor prognostic factors and become an important break for targeted therapies. Currently, a variety of FLT3 inhibitors (e.g., first generation midostaurin, second generation gelitinib) have been approved for clinical use, significantly improving survival in some patients. Abnormal activation of signal pathway caused by FLT3 mutation causes disorder of cell cycle and/or apoptosis, and further causes disordered growth and proliferation of tumor cells, so that the cell cycle of tumor cells can be inhibited, apoptosis can be induced, growth and proliferation of AML cells can be inhibited by targeted inhibition of FLT3, and an efficient low-toxicity anti-tumor effect can be realized. Disclosure of Invention In view of the above, the present invention aims to provide a 1-phenyl-1H-benzo [ d ] imidazole compound as an FLT3 kinase inhibitor, a preparation method, a pharmaceutical composition and an application thereof, so as to solve at least one technical problem in the background art. In order to achieve the above purpose, the technical scheme of the invention is realized as follows: 1-phenyl-1H-benzo [ d ] imidazoles as FLT3 kinase inhibitors, 1-phenyl-1H-benzo [ d ] imidazoles of formula (I) or pharmaceutically acceptable salts thereof: (I); Wherein, the R 1 is selected from one of-C (O) NH-, SO 2, C (O) and-C (S) NH-; R 2、R3 and R 4 are independently selected from one of hydrogen atom, C1-6 alkyl, halogen and CF 3、-OCH3; R 5 is selected from one of halogen, phenol and m-tolyl carbamate. Further, wherein R 1 is-C (O) NH-, R 2、R3 and R 4 are selected from one of hydrogen atom, methyl, -OCH 3、CF3 and chlorine atom, R 2、R3 and R 4 are the same or different, R 5 is selected from one of phenol, bromine atom and m-tolylcarbamate; Or R 1 is SO 2,R2,R3 and R 4 is selected from one of hydrogen atom, -OCH 3 and chlorine atom, R 2、R3 and R 4 are the same or different, R 5 is selected from one of phenol and bromine atom; Or R 1 is C (O), R 2,R3 and R 4 are selected from one of hydrogen atom, -OCH 3 and chlorine atom, R 2、R3 and R 4 are the same or different, R 5 is selected from one of phenol and bromine atom; Or R 1 is-C (S) NH-, R 2,R3 and R 4 are selected from one of hydrogen atom, -OCH 3 and chlorine atom, R 2、R3 and R 4 are the same or different, and R 5 is bromine atom. Further, it is any one of the following compounds: The structural formula of the compound 1 is shown in (1) and N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3-chlorobenzenesulfonamide: (1); The structural formula of the compound 2 is shown in (2) N- (3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -4-methoxybenzene sulfonamide; (2); compound 3:N- (4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3-chlorobenzenesulfonamide, the structural formula of which is shown in (3); (3); the structural formula of the compound 4 is shown as (4) N- (4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -4-methoxybenzene sulfonamide; (4); the structural formula of the compound 5:1- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (3-chlorophenyl) thiourea is shown in (5); (5); 1- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-methoxyphenyl) thiourea of the compound 6, the structural formula is shown in (6); (6); The structural formula of the compound 7 is shown in (7) and 1- (4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl) -3- (3-chlorophenyl) thiourea; (7); 1- [4- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (4-methoxyphenyl) thiourea, wherein the structural formula of the compound is shown in (8); (8); 1- [3- (5-bromo-1H-benzo [ d ] imidazol-1-yl) phenyl ] -3- (3-chlorophenyl) urea, the stru