# US 10,766,889 B2 · Aryl-2,2′-tandem bisthiazole compound and preparation method and use thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,766,889 B2 - Document ID: US10766889B2 - Status: Granted - Kind: B2 - Application number: 16/329,336 - Filed: 2017-08-24 - Published: 2019-07-11 - Granted: 2020-09-08 - Earliest claimed: 2016-08-31 - Assignees: Shanghai Institute of Materia Medica, Chinese Academy of Sciences - Applicants: Shanghai Institute of Materia Medica, Chinese Academy of Sciences - Inventors: Fajun Nan; Jia Li; Jian Ding; Meiyu Geng; Yangming Zhang; Yi Chen; Yubo Zhou; Chaojun Gong; Mingbo Su; Anhui Gao - Web page: https://patentgrep.com/patent/US10766889B2 ## CPC - C07D 417/04: directly linked by a ring-member-to-ring-member bond - A61K 31/427: not condensed and containing further heterocyclic rings - A61P 35/00: Antineoplastic agents - A61P 35/02: specific for leukemia - C07D 277/56: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen - C07D 277/60: condensed with carbocyclic rings or ring systems - Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS ## Abstract The invention describes an aryl-2,2′-tandem bisthiazole compound and a preparation method and the use thereof. In particular, disclosed in the present invention are an aryl-2,2′-tandem bisthiazole compound with the structure as shown in general formula I and the preparation method thereof and use thereof as a histone deacetylase inhibitor in the preparation of antitumor drugs. ## Claims ### Claim 1 A compound of formula I or an optical isomer thereof, or a pharmaceutically acceptable salt thereof: wherein, R1 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C5-C10 aryl; and R2 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C5-C10 aryl; or R1 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C5-C10 aryl; and R2 is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C5-C10 aryl; or R1 and R2 together with the carbon atom to which they are attached form a 5-7 membered saturated or partially saturated ring; R3 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C5-C10 aryl; and R4 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl and C2-C6 alkynyl; wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C5-C10 aryl is unsubstituted or substituted with one or more groups selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, and C5-C10 aryl. ### Claim 2 (depends on 1) The compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 1, wherein, R1 is H, C1-C6 alkyl, or C6-C10 aryl, and R2 is C1-C6 alkyl or C6-C10 aryl; or R1 is C1-C6 alkyl or C6-C10 aryl, and R2 is H, C1-C6 alkyl, or C6-C10 aryl; or R1 and R2 together with the carbon atom to which they are attached form a 5, 6 or 7 membered partially saturated ring. ### Claim 3 (depends on 1) The compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 1, wherein, R3 is C1-C4 alkyl, C6-C10 aryl substituted C1-C4 alkyl or C3-C6 cycloalkyl. ### Claim 4 (depends on 1) The compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 1, wherein, R4 is C1-C6 alkyl. ### Claim 5 A compound selected from the group consisting of: or an optical isomer thereof, or a pharmaceutically acceptable salt thereof. ### Claim 6 (depends on 1) A method for preparing the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 1, wherein the compound is of formula II-1, R1, R2, and R3 are defined as in claim 1, and R4 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl and C2-C6 alkynyl, the method comprising: (1) condensing methyl 4-acetylbenzoate with tert-butyl sulfenamide to form tert-butyl sulfoximine 1; (2) reacting tert-butyl sulfinimide 1 with a Grignard reagent to form tert-butyl sulfenamide 2; (3) deprotecting tert-butyl sulfinamide 2 to form amine 3; (4) condensing amine 3 with acid 4 to form methyl ester 5; and (5) reacting methyl ester 5 with alkali to form a hydrolysis product, reacting the hydrolysis product with a hydroxylamine protected by a protecting group to form a condensation product protected by the protecting group, and removing the protecting group to form the compound of formula II-1; or wherein the compound is of formula II-2, R1, R2, and R3 are defined as in claim 1, or the method comprising: (i) reacting acid 4 with methyl 4-aminomethylbenzoate to form methyl ester 8; (ii) reacting methyl ester 8 with alkali to form a hydrolysis product, reacting the hydrolysis product with a hydroxylamine protected by a protecting group to form a condensation product, and removing the protecting group to form the compound of formula II-2. ### Claim 7 (depends on 1) A pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 1, and pharmaceutically acceptable carriers. ### Claim 8 (depends on 1) A method of inhibiting a histone deacetylase in a subject in need thereof comprising administering to the subject an effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1. ### Claim 9 (depends on 1) A method of inhibiting tumor cells or a tumor in a subject in need thereof comprising administering to the subject an effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1. ### Claim 10 (depends on 9) A method of claim 9, wherein the tumor cells are multiple myeloma cells, colon cancer cells, lung cancer cells, embryo lung cells, liver cancer cells, breast cancer cells, ovarian cancer cells, pancreatic cancer cells, rectal cancer cells, gastric cancer cells, lymphoma cells or leukemia cells; and the tumor is multiple myeloma, colon cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, pancreatic cancer, rectal cancer, gastric cancer, lymphoma, or leukemia. ### Claim 11 (depends on 5) A pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof of claim 5, and pharmaceutically acceptable carriers. ### Claim 12 (depends on 5) A method of inhibiting a histone deacetylase in a subject in need thereof comprising administering to the subject an effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 5. ### Claim 13 (depends on 5) A method of inhibiting tumor cells or a tumor in a subject in need thereof comprising administering to the subject an effective amount of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 5. ### Claim 14 (depends on 13) A method of claim 13, wherein the tumor cells are multiple myeloma cells, colon cancer cells, lung cancer cells, embryo lung cells, liver cancer cells, breast cancer cells, ovarian cancer cells, pancreatic cancer cells, rectal cancer cells, gastric cancer cells, lymphoma cells or leukemia cells; and the tumor is multiple myeloma, colon cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, pancreatic cancer, rectal cancer, gastric cancer, lymphoma, or leukemia. ### Claim 15 A compound selected from the group consisting of: and an optical isomer thereof, or a pharmaceutically acceptable salt thereof. ### Claim 16 (depends on 15) A pharmaceutical composition comprising an effective amount of the compound, the optical isomer, or the pharmaceutically acceptable salt thereof of claim 15, and a pharmaceutically acceptable carrier. ### Claim 17 (depends on 15) A method of inhibiting a histone deacetylase in a subject in need thereof comprising administering to the subject an effective amount of the compound, the optical isomer, or the pharmaceutically acceptable salt thereof according to claim 15. ### Claim 18 (depends on 15) A method of inhibiting tumor cells or a tumor in a subject in need thereof comprising administering to the subject an effective amount of the compound, the optical isomer, or the pharmaceutically acceptable salt thereof according to claim 15. ### Claim 19 (depends on 18) A method of claim 18, wherein the tumor cells are multiple myeloma cells, colon cancer cells, lung cancer cells, embryo lung cells, liver cancer cells, breast cancer cells, ovarian cancer cells, pancreatic cancer cells, rectal cancer cells, gastric cancer cells, lymphoma cells or leukemia cells; and the tumor is multiple myeloma, colon cancer, lung cancer, liver cancer, breast cancer, ovarian cancer, pancreatic cancer, rectal cancer, gastric cancer, lymphoma, or leukemia.