- PHOSPHOINOSITIDE 3-KINASE INHIBITORS WITH ZINC BINDING MOIETY
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PROBLEM TO BE SOLVED: To provide phosphoinositide 3-kinase inhibitors with a zinc binding moiety. SOLUTION: There is provided a compound represented by formula (I) in the figure. (X is S, O or the like; Y is CH, N or the like; G1 is optionally substituted N or the like; R1 and R2 are each independently H or the like; C is a substituted heterocycle or the like; B is a linear alkyl or the like; Ra and Rb together with the nitrogen atom coupled to them are morpholino or the like; G2 is an indazole ring or the like; q, r and s are independently from 0 to 1, provided that at least one of them is 1; t is from 0 to 1; n is from 0 to 4; and p is from 0 to 2.) COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0171
(2016/10/07)
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- Linear propargylic alcohol functionality attached to the indazole-7-carboxamide as a JAK1-specific linear probe group
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Selective inhibition of JAK1 has recently been proposed as an appropriate therapeutic rationale for the treatment of inflammatory diseases such as rheumatoid arthritis (RA) In this study, through pairwise comparison and 3D alignment of the JAK isozyme structures bound to the same inhibitor molecule, we reasoned that an alkynol functionality would serve as an isozyme-specific probe group, which would enable the resulting inhibitor to differentiate the ATP-binding site of JAK1 from those of other isozymes The 3-alkynolyl-5- (4′-indazolyl)indazole-7-carboxamide derivatives were thus prepared, and in vitro evaluation of their inhibitory activity against the JAK isozymes revealed that the propargyl alcohol functionality endowed the 5-(4′-indazolyl)indazole-7-carboxamide scaffold with JAK1 selectivity over other JAK isozymes, particularly JAK2
- Kim, Mi Kyoung,Shin, Heerim,Cho, Seo Young,Chong, Youhoon
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p. 1156 - 1162
(2014/02/14)
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- DIOXINO-AND OXAZIN-[2,3-D]PYRIMIDINE PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
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Dioxino-and oxazin-[2,3-d]pyrimidine PI3K inhibitor compounds of Formula I with anti-cancer activity, anti-in-flammatory activity, or immunoregulatory properties, and more specifically with PI3 kinase modulating or inhibitory activity are de-scribed. Methods are described for using the tricyclic PI3K inhibitor compounds of Formula I for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions.
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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K-ras mutation in a subject in need thereof. The method comprises the steps of: (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) administering to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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Paragraph 0173
(2013/05/08)
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- TRICYCLIC PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
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Tricyclic PI3k inhibitor compounds of Formula I with anti-cancer activity, anti- inflammatory activity, or immunoregulatory properties, and more specifically with PI3 kinase modulating or inhibitory activity are described. Methods are described for using the tricyclic PI3K inhibitor compounds of Formula I for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions. Formula I compounds include stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof. The dashed lines indicate an optional double bond, and at least one dashed line is a double bond. The substituents are as described.
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- TREATMENT OF CANCERS HAVING K-RAS MUTATIONS
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The present invention provides a method of treating a cancer associated with a K- ras mutation in a subject in need thereof. The method comprises the steps of (1) identifying a subject with a cancer associated with a K-ras mutation; and (2) adminsiterign to the subject (i) an inhibitor of PI3 kinase and (ii) an HDAC inhibitor, wherein the PI3 kinase inhibitor and the HDAC inhibitor are administered in amounts which together are therapeutically effective.
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Page/Page column 128
(2011/11/01)
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- PURINE PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
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Purine compounds of Formula I, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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- THIAZOLOPYRIMIDINE PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
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Compounds of Formulas (Ia and Ib), and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of formula Ia and Ib for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed
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Page/Page column 70
(2009/05/29)
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- PYRAZOLOPYRIMIDINE PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
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Compounds of Formula I, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. [Fomula I]
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Page/Page column 67; 68
(2009/09/05)
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- 4' SUBSTITUTED COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
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The present disclosure provides compounds having affinity for the 5-HT6 receptor which are of the formula (I): wherein R1, R2, R5, R6, B, D, E, G, Q, x and n are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 21
(2009/01/24)
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- Pharmaceutical compounds
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A thienopyrimidine of formula (I): and the pharmaceutically acceptable salts thereof have activity as inhibitors of PI3K with selectivity for the P110α subtype, and may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour, particularly those associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Processes for synthesizing the compounds are also described.
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Page/Page column 8-9
(2008/06/13)
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- Pharmaceutical compounds
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Compounds of Formulae Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia and Ib for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 75
(2008/06/13)
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- The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1- ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer
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Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110α. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.
- Folkes, Adrian J.,Ahmadi, Khatereh,Alderton, Wendy K.,Alix, Sonia,Baker, Stewart J.,Box, Gary,Chuckowree, Irina S.,Clarke, Paul A.,Depledge, Paul,Eccles, Suzanne A.,Friedman, Lori S.,Hayes, Angela,Hancox, Timothy C.,Kugendradas, Arumugam,Lensun, Letitia,Moore, Pauline,Olivero, Alan G.,Pang, Jodie,Patel, Sonal,Pergl-Wilson, Giles H.,Raynaud, Florence I.,Robson, Anthony,Saghir, Nahid,Salphati, Laurent,Sohal, Sukhjit,Ultsch, Mark H.,Valenti, Melanie,Wallweber, Heidi J. A.,Nan, Chi Wan,Wiesmann, Christian,Workman, Paul,Zhyvoloup, Alexander,Zvelebil, Marketa J.,Shuttleworth, Stephen J.
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experimental part
p. 5522 - 5532
(2009/09/06)
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- PHARMACEUTICAL COMPOUNDS
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Fused pyrimidines of formula (I): wherein A represents a thiophene or furan ring; n is 0, 1 or 2; R1 is a group of formula: wherein m is 0 or 1; R30 is H or C1-C6 alkyl; R4 and R5 form, together with the N atom to which they are attached, a 5- or 6- membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatoms selected from N, S and O, which may be fused to a benzene ring and which is unsubstituted or substituted; or one of R4 and R5 is alkyl and the other is a 5- or 6-membered saturated N-containing heterocyclic group as defined above or an alkyl group which is substituted by a 5- or 6-membered saturated N-containing heterocyclic group as defined above; R2 is a heteroaryl group which contains I5 2, 3 or 4 ring nitrogen atoms and 0,1 or 2 additional heteroatoms selected from O, N and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted; and R3 is selected from: (a) a group of the following formula: wherein B is a phenyl ring which is unsubstituted or substituted and Z is selected from H, -OR, -SR, CH2OR, -CO2R, CF2OH, CH(CF3)OH, C(CF3)2OH, -(CH2)qOR, - (CH2)qNR2, -C(O)N(R)2, -NR2, -NRC(O)R, -S(O)mN(R)2, -OC(O)R, OC(O)N(R)2, - NRS(O) mR, -RC(O)N(R)2, CN, halogen and -NO2, wherein each R is independently selected from H, C1-C6 alkyl, C3 - C10 cycloalkyl and a 5- to 12-membered aryl or heteroaryl group, the group being unsubstituted or substituted, m is 1 or 2 and q is 0, 1 or 2; (b) a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from O and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted; and (c) a group comprising a benzene ring which is unsubstituted or substituted and which is fused to a heteroaryl group as defined above; and the pharmaceutically acceptable salt thereof have activity as inhibitors of PBK and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Processes for synthesizing the compounds are also described.
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Page/Page column 42-43
(2008/06/13)
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- PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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Compounds of Formulas (Ia) and (Ib), and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula (Ia) and (Ib) for in vitro, in situ, and in vivodiagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 138
(2008/06/13)
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