- PYRIMIDO[4,5-D]PYRIMIDIN-2-ONE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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Disclosed are a compound selected from novel pyrimido[4,5-d]pyrimidin-2-one derivative compounds having excellent anti-proliferative activity against cancer cells, pharmaceutically acceptable salts thereof, hydrates thereof and stereoisomers thereof, a method for preparing the compound, a pharmaceutical composition for preventing, alleviating or treating cancer metastasis and proliferative diseases containing the compound as an active ingredient, and an anticancer composition against cancer cells, containing the compound as an active ingredient. The compounds of this invention exhibit most excellent selective inhibitory activity agaist LCK and anti-proliferative activity against cancer cells, thus being useful for inhibiting cancer cells, and for preventing or treating cancer metastasis and proliferative diseases.
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Paragraph 0269; 0287-0289
(2021/03/05)
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- FGFR4 Inhibitor. Compositions and their use in pharmaceutical preparations
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The invention provides 3 inhibitor which takes 4 - 4 dihydropyrimidine [5 - d,2] pyrimidine - (1H) FGFR4 ketone as a mother nucleus and has a covalent structure. The examples give 9 specific compounds and kinase inhibitory activity testing of these 9 compounds, wherein LX08 for FGFR4 kinase inhibitory activity is only 7 nm, lower than FIIN - 2 of the active control, and potential application prospects. In addition, by subjecting the synthesized compound to MALDI-TOF mass spectrometry, we found that compounds of LX01, LX05, LX06, LX07, LX08 are covalently bound to FGFR4 of Cys552, cannot covalently bind FGFR4 of Cys477, and LX09 are FGFR4 inhibitors which can be covalently bound to the two cysteines Cys552 and Cys477 in FGFR4.
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Paragraph 0057; 0061-0064
(2021/10/27)
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- NOVEL PYRIMIDO[4,5-d]PYRIMIDIN-2-ONE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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The present invention is a pyrimido [4, 5-d] pyrimid -2 -one derivative compound showing an excellent anti-proliferative effect on cancer cells. The present invention relates to a pharmaceutically acceptable salt, a hydrate thereof, a stereoisomer thereof, a pharmaceutical composition for preventing, alleviating or treating cancer metastasis and proliferative diseases containing the same as an active ingredient, and an anticancer composition comprising the same as an active ingredient.
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Paragraph 0362; 0363; 0389-0394
(2021/03/30)
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- FUSED PYRIMIDINE COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOF
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The present disclosure relates to a class of fused pyrimidine compounds of Formula I, their stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, and hydrates thereof. The present disclosure also relates to a process of preparation of these fused pyrimidine compounds, and to pharmaceutical compositions containing them.
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Paragraph 0184; 0285
(2021/04/02)
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- BICYCLIC NITROGEN CONTAINING HETEROCYCLES AS INHIBITORS OF SALT-INUCED KINASE SIK2
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Provided are compounds of the Formula (I), and salts and solvates thereof: (Formula (I)) wherein R2, R3, X1, L, A, R6, R7 and Z are defined in the specification. The compounds are inhibitors of salt-inducible kinase (SIK), particular SIK2, and are useful in therapy, particularly in the treatment of a proliferative disorder, a benign neoplasm, pathological angiogenesis, an inflammatory disease or condition, a musculoskeletal disease or condition, an autoimmune disease, a haematological disease or condition, a neurological disease or condition, a psychiatric disorder, or a metabolic disorder.
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Paragraph 00137; 00208-00209
(2021/05/07)
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- BICYCLIC KINASE INHIBITORS AND USES THEREOF
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The invention relates to kinase inhibitors, in particular inhibitors of protein kinases including the SIK-family, CSF1R, HCK, TEK-family, BRK, ABL, KIT and/or their mutants. Although structurally similar to other bicyclic kinase inhibitors, the kinase inhibitors of the invention are distinctive; possessing a particular class of heterocyclic moiety. Such kinase inhibitors can display one or more certain properties distinct to their structurally similar kinase inhibitors. The kinase inhibitors of the invention or pharmaceutical compositions comprising them may be used in the treatment of a disorder or condition, such as a proliferative disorder, for example, a leukaemia or solid tumour. In particular, these and other structurally related kinase inhibitors may be used in the treatment of a proliferative disorder - such as a mixed phenotype acute leukaemia (MPAL) - characterised by (inter-alia) the presence of MEF2C protein, a human chromosomal translocation at 11q23, and/or a KMT2A fusion oncoprotein. The kinase inhibitors or pharmaceutical compositions of the invention may be used topically to modulate skin pigmentation in a subject, for example to impart UV protection and reduce skin cancer risk.
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Paragraph 613; 618; 619
(2021/11/06)
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- First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia
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GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound 11i is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML.
- Cho, Hanna,Shin, Injae,Ju, Eunhye,Choi, Seunghye,Hur, Wooyoung,Kim, Haelee,Hong, Eunmi,Kim, Nam Doo,Choi, Hwan Geun,Gray, Nathanael S.,Sim, Taebo
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supporting information
p. 8353 - 8383
(2018/09/27)
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- UREA COMPOUNDS CONTAINING 3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-2(1H)-ONE SKELETON AS PROTEIN KINASE INHIBITORS
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The present invention provides a pharmaceutical composition, as an effective ingredient, a urea compound having a protein kinase inhibitory activity and containing a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one skeleton, and a pharmaceutically acceptable salt thereof.
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Paragraph 0089-0090
(2018/03/25)
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- 6-MEMBERED HETEROCYCLIC DERIVATIVE AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
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A compound represented by Formula (I): wherein or the like Y1 is O or the like; Z1 is C(R4) or N; Z2a is C(R5a) or the like; Z3a is C(R6) or the like; R4, R5a and R6 are each independently a hydrogen atom or the like; R1 is substituted or unsubstituted aromatic carbocyclyl or the like; R2a, R2b, R2c and R2d are each independently a hydrogen atom or the like; X is N(R7a) or the like; R7a is a hydrogen atom or the like; R3 is or the like Ring B is a 6-membered aromatic carbocycle or the like; R9a and R10a are each independently halogen or the like; n is an integer from 1 to 5; m is an integer from 0 to 4; and p1 is an integer from 0 to 3, or a pharmaceutically acceptable salt thereof.
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Paragraph 0677; 0678
(2018/03/25)
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- PYRIMIDINE DERIVATIVES AND THEIR USE IN TREATING OR PREVENTING A RESPIRATORY SYNCYTIAL VIRUS INFECTION
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Pyrimidine derivatives of formula (I) wherein: Z is a direct bond or -(CH2)n- wherein n is 1 or 2; one of X and Y is N, CH or CF, and the other of X and Y is CH; one of R1 and R2 is selected from -NHR, -NR2, -OR, -SR, -S(O)R, -S(O)2R and a group of the following formula (A) and the other of R1 and R2 is selected from -NHR', -OH, -OR' and a group of the above formula (A); R is unsubstituted C1-C6 alkyl; R' is a group selected from C1-C6 alkyl, 5- to 12-membered aryl and C3-C6 cycloalkyl, which group is unsubstituted or substituted; W is -(CH2)m-, -CH2-O-CH2-, -CH2-S-CH2- or -CH2-S(O)2-CH2-; p is 1, q is an integer of 1 - 6 and V is N; or p is 1, q is 0 and V is CH; or p is 0, q is 0 and V is N; r is 0 or 1; and R3 is -(CH2)s-NH2 or -(CH2)s-OH wherein s is 0 or an integer of 1 to 4; and the pharmaceutically acceptable salts thereof are inhibitors of RSV and can therefore be used to treat or prevent an RSV infection.
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Page/Page column 24
(2018/03/28)
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- BICYCLIC UREA KINASE INHIBITORS AND USES THEREOF
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The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.
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Paragraph 00262; 00263
(2018/09/25)
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- MK2 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 0322
(2016/04/09)
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- BICYCLIC HETEROCYCLES AS FGFR4 INHIBITORS
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The present invention relates to bicyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of the FGFR4 enzyme and are useful in the treatment of FGFR4-associated diseases such as cancer.
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Paragraph 0358
(2016/05/19)
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- BICYCLIC HETEROCYCLES AS FGFR4 INHIBITORS
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The present disclosure relates to bicyclic heterocycles of formula (I), and pharmaceutical compositions of the same, that are inhibitors of the FGFR4 enzyme and are useful in the treatment of FGFR4-associated diseases such as cancer.
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Paragraph 0228
(2016/09/15)
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- BICYCLIC HETEROCYCLES AS FGFR4 INHIBITORS
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The present invention relates to bicyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of the FGFR4 enzyme and are useful in the treatment of FGFR4-associated diseases such as cancer.
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Page/Page column 59
(2016/09/15)
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- MONOCYCLIC PYRIMIDINE/PYRIDINE COMPOUNDS AS INHIBITORS OF P97 COMPLEX
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Monocyclic pyrimidine and pyridine compounds having a benzyl amine substituent at the 4 position and a 5:6 bicyclic heteroaryl substituent at the 2 position of the pyrimidine or pyridine ring as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the ring are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.
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Page/Page column 131
(2015/06/25)
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- HETEROARYL COMPOUNDS AND USES THEREOF
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The present invention relates to compounds useful as inhibitors of protein kinases, containing a cysteine residue in the ATP binding site. The invention further provides for pharmaceutically acceptable compositions comprising therapeutically effective amounts of one or more of the protein kinase inhibitor compounds and methods of using said compositions in the treatment of cancers and carcinomas.
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Paragraph 00354
(2014/09/29)
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- Flow synthesis of annulated 5-aryl-substituted pyridines by tandem intramolecular inverse-electron-demand hetero-/retro-Diels-Alder reaction
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5-Aryl-substituted annulated pyridines can be accessed directly from the corresponding acetylene substituted pyrimidines through an intramolecular inverse-electron-demand hetero-/retro-Diels-Alder (ihDA/rDA) reaction cascade carried out in continuous flow. Exploiting this new process, a series of cycloalka[c]pyridines that represent useful building blocks for medicinal chemistry were prepared in good to excellent yields with short processing times (45 min). Importantly, utilizing the ability to superheat solvents in flow permits the replacement of typically employed high boiling solvents (e.g.; nitrobenzene or chlorobenzene) with toluene.
- Martin, Rainer E.,Lenz, Mario,Alzieu, Thibaut,Aebi, Johannes D.,Forzy, Liliane
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supporting information
p. 6703 - 6707
(2013/11/19)
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- Falcipain inhibitors: Optimization studies of the 2-pyrimidinecarbonitrile lead series
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Falcipain-2 and falcipain-3 are papain-family cysteine proteases of the malaria parasite Plasmodium falciparum that are responsible for host hemoglobin hydrolysis to provide amino acids for parasite protein synthesis. Different heteroarylnitrile derivatives were studied as potential falcipain inhibitors and therefore potential antiparasitic lead compounds, with the 5-substituted-2- cyanopyrimidine chemical class emerging as the most potent and promising lead series. Through a sequential lead optimization process considering the different positions present in the initial scaffold, nanomolar and subnanomolar inhibitors at falcipains 2 and 3 were identified, with activity against cultured parasites in the micromolar range. Introduction of protonable amines within lead molecules led to marked improvements of up to 1000 times in activity against cultured parasites without noteworthy alterations in other SAR tendencies. Optimized compounds presented enzymatic activities in the picomolar to low nanomolar range and antiparasitic activities in the low nanomolar range.
- Coterón, Jose M.,Catterick, David,Castro, Julia,Chaparro, María J.,Díaz, Beatriz,Fernández, Esther,Ferrer, Santiago,Gamo, Francisco J.,Gordo, Mariola,Gut, Jiri,De Las Heras, Laura,Legac, Jennifer,Marco, Maria,Miguel, Juan,Mu?oz, Vicente,Porras, Esther,De La Rosa, Juan C.,Ruiz, Jose R.,Sandoval, Elena,Ventosa, Pilar,Rosenthal, Philip J.,Fiandor, Jose M.
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experimental part
p. 6129 - 6152
(2010/10/21)
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- COMPOSITIONS AND METHODS FOR FGF RECEPTOR KINASES INHIBITORS
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Described are compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat or prevent disease or disordered associated with abnormal or deregulated kinase activity, particularly diseases or disorders that
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Page/Page column 43-44
(2008/06/13)
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- Fused heterotricyclic compounds as inhibitors of 17beta-hydroxysteroid dehydrogenase 3
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Fused heterotricyclic compounds, methods of using such compounds in the treatment of hormone sensitive diseases such as prostate cancer, and pharmaceutical compositions containing such compounds.
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Page/Page column 39
(2008/06/13)
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- Pyrimido compounds having antiproliferative activity
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Disclosed are novel pyrimido compounds that are selective inhibitors of both KDR and FGFR kinases. These compounds and their pharmaceutically acceptable salts are anti-proliferative agents useful in the treatment or control of solid tumors, in particular breast, colon, lung and prostate tumors. Also disclosed are pharmaceutical compositions containing these compounds and methods of treating cancer.
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Page/Page column 6; 10
(2010/02/08)
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- Novel dihydropyridinone compounds
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Disclosed are novel dihydropridinone compounds that are selective inhibitors of both KDR and FGFR kinases. These compounds and their pharmaceutically acceptable salts are anti-proliferative agents useful in the treatment or control of solid tumors, in particular breast, colon lung and prostate tumors. Also, disclosed are pharmaceutical compositions containing these compounds and methods of treating cancer.
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Page/Page column 10-11
(2010/02/07)
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- 5-Ethylthiomethyl- and 5-Ethylsulfonylmethylpyrimidines
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In 2,4-dichloro-5-ethylthiomethylpyrimidines 3a,b and in (2,4-dichloro-5-pyrimidinylmethyl)ethyl sulfones 5a,b, resp., by reaction with ammonia, diethylamine, isopropylamine, sodium methanolate and sodium ethylthiolate, resp., the halogen atoms have been substituted by amino, methoxy or ethylthio groups, resp., and thus the compounds 4a-4r and 5c-5f have been obtained.Keywords: Halogen exchange, in pyrimidines; Pyrimidines, 5-ethylsulfonyl-methyl-; Pyrimidines, 5-ethylthiomethyl-
- Eichberger, Guenter,Hayden, Walter,Schwarz, Wolfgang,Griengl, Herfried
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p. 385 - 392
(2007/10/02)
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