- PYRIMIDOPYRIMIDINONES USEFUL AS WEE-1 KINASE INHIBITORS
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The present invention relates to compounds that are useful as inhibitors of the activity of Wee-1 kinase. The present invention also relates to pharmaceutical compositions comprising these compounds and to methods of using these compounds in the treatment of cancer and methods of treating cancer.
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Page/Page column 90; 91
(2015/07/07)
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- 2-AMINOPYRIDO[4,3-D]PYRIMIDIN-5-ONE DERIVATIVES AND THEIR USE AS WEE-1 INHIBITORS
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The present invention relates to compounds of formula (I) that are useful as inhibitors of the activity of Wee-1 kinase. The present invention also relates to pharmaceutical compositions comprising these compounds and to methods of using these compounds i
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Page/Page column 76
(2014/10/29)
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- Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5, 7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27) ,9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer
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Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26h as a preferred compound with target IC50 of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively. Pharmacokinetic (PK) studies of 26h in preclinical species showed good oral exposures. Oral efficacy was observed in colon (HCT-116) and lymphoma (Ramos) xenograft studies, in line with the observed PK/PD correlation. 26h (SB1317/TG02) was progressed into development in 2010 and is currently undergoing phase 1 clinical trials in advanced leukemias and multiple myeloma.
- William, Anthony D.,Lee, Angeline C.-H.,Goh, Kee Chuan,Blanchard, Stéphanie,Poulsen, Anders,Teo, Ee Ling,Nagaraj, Harish,Lee, Chai Ping,Wang, Haishan,Williams, Meredith,Sun, Eric T.,Hu, Changyong,Jayaraman, Ramesh,Pasha, Mohammed Khalid,Ethirajulu, Kantharaj,Wood, Jeanette M.,Dymock, Brian W.
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experimental part
p. 169 - 196
(2012/03/12)
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- Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7, 26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27) ,16,21,23-decaene (SB1518), a potent Janus Kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma
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Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2 V617F), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2 WT and JAK2V617F, respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.
- William, Anthony D.,Lee, Angeline C.-H.,Blanchard, Stéphanie,Poulsen, Anders,Teo, Ee Ling,Nagaraj, Harish,Tan, Evelyn,Chen, Dizhong,Williams, Meredith,Sun, Eric T.,Goh, Kee Chuan,Ong, Wai Chung,Goh, Siok Kun,Hart, Stefan,Jayaraman, Ramesh,Pasha, Mohammed Khalid,Ethirajulu, Kantharaj,Wood, Jeanette M.,Dymock, Brian W.
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experimental part
p. 4638 - 4658
(2011/09/14)
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- Protecting-group-free amination of halogenated nitrobenzaldehyde with palladium catalyst
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"One-step" method for the synthesis of secondary aliphatic amine substituted nitrobenzaldehyde was developed. In the presence of Pd catalyst, halogenated nitrobenzaldehyde could be smoothly coupled with secondary aliphatic amine to give the target product
- Cao, Jing,Feng, Jun Xiang,Wu, Yong Xiang,Tuo, Ya Ya
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experimental part
p. 935 - 938
(2011/11/13)
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- Synthesis of spiroheterocyclic systems from barbituric acids and N,N-disubstituted o-aminobenzaldehydes
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Reactions of barbituric, 1,3-dimethylbarbituric, and 2-thiobarbituric acids with 2-(1-pyrrolidinyl)benzaldehyde, its 6- and 7-membered homologs, and 4-phenylpiperazine and morpholine analogs lead to formation of fused systems with a spirocyclic 2,4,6-trio
- Krasnov,Kartsev
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p. 901 - 906
(2007/10/03)
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- TRICYCLIC TETRAHYDROQUINOLINE ANTIBACTERIAL AGENTS
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The invention includes tetrahydroquinoline and related compounds of formula (I), and pharmaceutical compositions thereof, that exhibit useful antibacterial activity against a wide range of human and veterinary pathogens.
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