Anaplastic lymphoma kinase (ALK), a family of tyrosine kinases has been recently elucidated as a potential target for various cancers due to its implications of tumorigenesis by ALK gene mutations, overexpressions, and amplifications. ALK was first identified in 1994 as a part of nucleophosmin NPM-ALK fusion gene in 60% of anaplastic large-cell lymphoma (ALCL), in late 2007 EML4-ALK fusion gene was found in 3-7% of non-small cell lung cancer, and a kind of ALK fusion genes are found one by one in various cancers such as DLBCL, inflammatory myofibroblastic tumor (IMT), plasmacytoma, esophageal cancer, renal cell carcinoma, breast cancer, colon cancer, and ovarian cancer. Moreover mutated ALK is much implicated in neuroblastoma and thyroid carcinoma. Crizotinib (Xalkori) was the first small molecule inhibitor which was approved as a treatment of NSCLC including ALK fusion gene by FDA in 2011. Crizotinib, a potent inhibitor of both c-Met and ALK tyrosine kinases is a 3-benzyloxy-2-aminopyridine derivative derived from c-Met inhibitors and surprisingly its overall clinical benefit was 87%. Many pharmaceutical companies have been looking forward to finding better ALK inhibitors and among them, CH-5424802 by Chugai Pharm., LDK378 by Novartis/GNF, and AZD-3463 by Astrazeneca are showing excellent progress. 2-Aminopyrimidine derivatives have been massively studied as various kinase inhibitors such as for ALK, EGFR, Aurora kinase, JAK, CK1, LRR2, etc. Especially, imatinib and nilotinib for BCR-ABL, dasatinib for BCR-ABL/Src/c-Kit/etc., fostamatinib for Syk, and pazopanib for VEGFR2/PDGFR/c-Kit had approved as new chemical entities by US FDA. We designed a new series of pyrimidine derivatives to discover a new ALK inhibitor, and among them 4-{4-(piperazin-1-)yl-2-methoxy-phenyl}amino-2-(methoxy-substitutedphenyl)aminopyrimidines were well-matched with crizotinib and LDK378 in docking study. We synthesized those pyrimidine derivatives and evaluated ALK inhibitory activities. 5-Substituted-2,4-dichloropyrimidine 1 (X=F, Cl) was reacted with 4-(N-acetylpiperazin-1-yl)-2-methoxyaniline 2 in DMF at 80 C overnight to predominantly afford 4-substituted-pyrimidine 3 in good yield and it was reacted with various methoxyanilines in 0.08 M HCl solution of ethoxyethanol at 110 C overnight to afford 5 in moderate to good yields (Scheme 1). In case of 2,4-dichloro-5-trifluoromethylpyrimidine, reaction of 6 with aniline (2) in the presence of base in DMF gave a mixture of 2-substituted and 4-substituted pyrimidines with a trace of 2,4-disubstituted pyrimidine, and the regioisomers could hardly been separated by TLC. Fortunately, 6 reacted with 4-(N-Boc-piperazin-1-yl)-2-methoxyaniline 7 in the presence of diisopropylethylamine as a base at room