title: Design and synthesis of novel 3-sulfonylpyrazol-4-amino pyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors.
abstract: Anaplastic lymphoma kinase (ALK) is a highly attractive therapeutic target for the treatment of some non-small cell lung cancer patients. This Letter describes the further SAR exploration on the novel 3-sulfonylpyrazol-4-amino pyrimidine scaffold. This work identified a compound 53 with very good in vitro/in vivo efficacies, good DMPK properties together with better hERG tolerability and it is currently being profiled for the evaluation as a potential pre-clinical candidate.
authors.affiliation: Department of Applied Chemistry, Beijing Institute of Technology, Zhongguancun South Street, Beijing 100081, China; Beijing Pearl Biotech Ltd, No. 203, Section 2, Wangjing Lize Zhongyuan, Chaoyang District, Beijing 100102, China.
authors.forename: Peilong
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China. Electronic address: djiaqiang@163.com.
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Dong
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Boyu
authors.initials: B
authors.lastname: Zhong
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Deyi
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Can
authors.initials: C
authors.lastname: Jin
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Xiangyuan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Li
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Ji
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Guowei
authors.initials: G
authors.lastname: Song
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Meng
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Sun
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Joe
authors.initials: J
authors.lastname: Shih
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Ruihao
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Hou
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Crown Bioscience Inc. (Taicang), 6 Beijing West Road, Taicang Economic Development Area, Taicang 215400, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000612184:3-sulfonylpyrazol-4-amino pyrimidine; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; Anti-tumor; Kinase; NSCLC; Pyrimidine