- NEW COMPOUND HAVING FGFR INHIBITORY ACTIVITY AND PREPARATION AND APPLICATION THEREOF
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The present invention relates to a new compound having an FGFR inhibitory activity and preparation and application thereof. In particular, the compound according to the present invention has a structure as shown in formula I, wherein each group and substituent are as defined in the description. Also disclosed in the present invention are a preparation method for the compound and a use thereof in preparation of a drug for treating and/or preventing a tumor-related disease and/or an FGFR-related disease.
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Paragraph 0388; 0389
(2019/05/30)
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- 6-methyl 7-position-denitrified purine nucleoside compounds and application thereof
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The invention discloses6-methyl 7-position-denitrified purine nucleoside compounds and an application thereof and belongs to the field of medicinal chemistry. The 6-methyl 7-position-denitrified purine nucleoside compounds or pharmaceutically acceptable salts of the compounds having characteristics of a structure shown as formula I are a kind of novel-structured compounds designed and synthesized according to protein structure characteristics of RNA virus polymerase, and the compounds can inhibit RNA viruses, thereby being capable of serving as potential drugs for preventing and treating infection of RNA viruses such as HCV (hepatitis c virus), influenza virus, HRV (rhinovirus), RSV, Ebola virus, DENV (Dengue virus), enterovirus and the like.
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- Pre-steady state kinetic analysis of cyclobutyl derivatives of 2′-deoxyadenosine 5′-triphosphate as inhibitors of HIV-1 reverse transcriptase
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Pre-steady state kinetic analysis was utilized for biochemical evaluation of a series of cyclobutyl adenosine nucleotide analogs with HIV-1 RT WT. The phosphonyl-diphosphate form of the cyclobutyl nucleotide, 5, was the most efficiently incorporated of the series. Nucleotide 5 was fourfold more efficiently incorporated than the FDA approved TFV-DP by RTWT. The kinetics of incorporation for 5 using the drug resistant mutant enzyme K65R was also determined. Compound 5 was threefold more efficiently incorporated compared to TFV-DP with RTK65R. These results demonstrate cyclobutyl adenosine analogs can act as substrates for incorporation by HIV-1 RT and be a potential scaffold for HIV inhibitors.
- Kim, Jiae,Wang, Ligong,Li, Yongfeng,Becnel, Kimberlynne D.,Frey, Kathleen M.,Garforth, Scott J.,Prasad, Vinayaka R.,Schinazi, Raymond F.,Liotta, Dennis C.,Anderson, Karen S.
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p. 4064 - 4067
(2012/07/14)
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- Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d] pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization
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Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d] pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.
- Davies, Nicholas G.M.,Browne, Helen,Davis, Ben,Drysdale, Martin J.,Foloppe, Nicolas,Geoffrey, Stephanie,Gibbons, Ben,Hart, Terance,Hubbard, Roderick,Jensen, Michael Rugaard,Mansell, Howard,Massey, Andrew,Matassova, Natalia,Moore, Jonathan D.,Murray, James,Pratt, Robert,Ray, Stuart,Robertson, Alan,Roughley, Stephen D.,Schoepfer, Joseph,Scriven, Kirsten,Simmonite, Heather,Stokes, Stephen,Surgenor, Allan,Webb, Paul,Wood, Mike,Wright, Lisa,Brough, Paul
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p. 6770 - 6789
(2013/01/15)
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- THERAPEUTIC AGENTS
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The invention provides a compound of formula (I): wherein R1, and W have any of the values defined in the application; or a salt thereof. The compounds and salts thereof have beneficial therapeutic properties (e.g. immunosuppressant properties).
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Page/Page column 60
(2010/04/03)
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- NOVEL CYCLOBUTYL COMPOUNDS AS KINASE INHIBITORS
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The invention relates to compounds of the formula I, to the preparation and use thereof for the preparation of a medicament for the treatment of diseases, in particular tumours and/or diseases in the formation or course of which protein kinases are involved.
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Page/Page column 33
(2010/07/04)
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- Xanthine oxidase-activated prodrugs of thymidine phosphorylase inhibitors
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Thymidine phosphorylase (TP) is over-expressed in various tumour types and plays an important role in tumour angiogenesis, growth, invasion and metastasis. The enzymatic activity of TP is required for the angiogenic effect of TP, therefore, inhibitors of TP are of significant interest in cancer chemotherapy. A series of xanthine oxidase (XO) activated prodrugs of known inhibitors of TP have been designed and synthesized with the ultimate intent of improving tumour selectivity and pharmacokinetic characteristics. These prodrugs were not inhibitors of TP, but were selectively oxidized by XO at C-2 and/or C-4 of the uracil ring moiety to generate the desired TP inhibitor. Molecular modelling of both the TP inhibitors and XO-activated prodrugs rationalized their binding in the active site of the human TP crystal structure.
- Reigan, Philip,Gbaj, Abdul,Stratford, Ian J.,Bryce, Richard A.,Freeman, Sally
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p. 1248 - 1260
(2008/09/21)
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- SUBSTITUTED PIPERIDINES HAVING PROTEIN KINASE INHIBITING ACTIVITY
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The invention provides PKA and PKB kinase-inhibiting compounds of the formula (I); or salts, solvates, tautomers or N-oxides thereof, wherein E is a five membered heteroaryl ring containing 1, 2, 3 or 4 heteroatoms selected from O, N and S provided that no more than 1 heteroatom may be other than N; q and r are each is 0 or 1; provided that q+r is 1 or 2; T is N or a group CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N- C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); Q3 is a bond or a saturated C1-3 hydrocarbon linker group optionally substituted by fluorine and hydroxy; G is NR2R3, CN or OH; m and n are each 0 or 1, provided that m+n is 1 or 2, and provided also that m or n are each 0 when the adjacent ring member of ring E is S or O; R1a and R1b are the same or different and each is hydrogen or a substituent R10; or R1a and R1b together with the carbon atoms or heteroatoms to which they are attached form a 5 or 6-membered aryl or heteroaryl ring, wherein the aryl or heteroaryl rings are optionally substituted by one or more substituents R10; and R2, R3, R4, R5, R7, R6, R8, and R10 are as defined in the claims.
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Page/Page column 112
(2008/12/06)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides a compound of the formula (I) or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N-C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members, the heterocyclic group containing up to 3 heteroatoms selected from O, N and S; Q1 is a bond or a saturated C1-3 hydrocarbon linker group, one of the carbon atoms in the linker group being optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONRq or NRqCO where Rq is hydrogen or methyl, or Rq is a C1-4 alkylene chain linked to R1 or a carbon atom of Q1 to form a cyclic moiety; and wherein the carbon atoms of the linker group Q1 may optionally bear one or more substituents selected from fluorine and hydroxy; Q2 is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the G group; and provided that when E is aryl or heteroaryl, then Q2 is other than a bond; G is hydrogen, NR2R3, OH or SH provided that when E is aryl or heteroaryl and Q2 is a bond, then G is hydrogen; R1 is hydrogen or an aryl or heteroaryl group, with the proviso that when R1 is hydrogen and G is NR2R3, then Q2 is a bond; and R2, R3, R4, R6 and R8 are as defined in the claims, wherein the compound is for use in: (a) the treatment or prophylaxis of a disease or condition in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated; and/or (b) the treatment of a subject or patient population in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase P70S6K is indicated.
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Page/Page column 116
(2008/06/13)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides a compound having the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N-C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); A is an optionally substituted saturated C1-7 hydrocarbon linker group having a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3, one of the carbon atoms in the linker group being optionally replaced by oxygen or nitrogen; E is a monocyclic or bicyclic carbocyclic or heterocyclic group or an acyclic group X-G wherein X is CH2, O, S or NH and G is a C1-4 alkylene chain wherein one of the carbon atoms is optionally replaced by O, S or NH; R1 is hydrogen or an aryl or heteroaryl group; R2 and R3 are each hydrogen, optionally substituted C1-4 hydrocarbyl or optionally substituted C1-4 acyl; or NR2R3 forms an imidazole group or a saturated monocyclic heterocyclic group having 4-7 ring members; or NR2R3 and A together form a saturated monocyclic heterocyclic group having 4-7 ring members which is optionally substituted by C1-4 alkyl; or NR2R3 and the adjacent carbon atom of linker group A together form a cyano group; or R1, A and NR2R3 together form a cyano group; and R4, R5, R6, R7 and R8 are each independently selected from hydrogen and various substituents as defined in the claims, wherein the compound is for use in: (a) the treatment or prophylaxis of a disease or condition in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase p70S6K is indicated; and/or (b) the treatment of a subject or patient population in which the modulation (e.g. inhibition) of ROCK kinase or protein kinase p70S6K is indicated.
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Page/Page column 121
(2008/06/13)
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- ORTHO- CONDENSED PYRIDINE AND PYRIMIDINE DERIVATIVES (E. G. PURINES) AS PROTEIN KINASES INHIBITORS
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The invention provides a compound for use in the prophylaxis or treatment of a disease state or condition mediated by protein kinase B, the compound having the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N-C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); A is an optionally substituted saturated C1-7 hydrocarbon linker group having a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3, one of the carbon atoms in the linker group being optionally replaced by oxygen or nitrogen; E is a monocyclic or bicyclic carbocyclic or heterocyclic group or an acyclic group X-G wherein X is CH2, O, S or NH and G is a C1-4 alkylene chain wherein one of the carbon atoms is optionally replaced by O, S or NH; R1 is hydrogen or an aryl or heteroaryl group; R2 and R3 are each hydrogen, optionally substituted C1-4 hydrocarbyl or optionally substituted C1-4 acyl; or NR2R3 forms an imidazole group or a saturated monocyclic heterocyclic group having 4-7 ring members; or NR2R3 and A together form a saturated monocyclic heterocyclic group having 4-7 ring members which is optionally substituted by C1-4alkyl; or NR2R3 and the adjacent carbon atom of linker group A together form a cyano group; or R1, A and NR2R3 together form a cyano group; and R4, R5, R6, R7 and R8 are each independently selected from hydrogen and various substituents as defined in the claims.
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Page/Page column 122-123
(2008/06/13)
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- Synthesis and enzymatic evaluation of xanthine oxidase-activated prodrugs based on inhibitors of thymidine phosphorylase
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A series of xanthine oxidase-activated prodrugs of known inhibitors of thymidine phosphorylase are described. These prodrugs were oxidised by xanthine oxidase at C-2 and/or C-4 of the uracil ring to generate the desired TP inhibitor. The scheme shows the prodrug of TPI. A series of xanthine oxidase-activated prodrugs of known inhibitors of thymidine phosphorylase has been designed and synthesised to introduce tumour selectivity. These prodrugs were oxidised by xanthine oxidase at C-2 and/or C-4 of the uracil ring to generate the desired TP inhibitor.
- Reigan, Philip,Gbaj, Abdul,Chinje, Edwin,Stratford, Ian J.,Douglas, Kenneth T.,Freeman, Sally
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p. 5247 - 5250
(2007/10/03)
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- β-Homoalanyl-PNA: A Special Case of β-Peptides with β-Sheet-Like Backbone Conformation; Organization in Higher Ordered Structures
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Although β-homoalanyl peptide nucleic acid oligomers possess a β-peptide backbone, they contain nucleobases in their side chains and are thus an interesting special case of β-peptides. These nucleobases are mainly responsible for the formation of secondary structures through base pairing and stacking. We have investigated the pairing properties of β-homoalanyl-PNA oligomers using adenine and 7-carbaadenine. Simple model studies indicate the existence of Watson-Crick and Hoogsteen pairing planes as an intrinsic structural feature of purinyl β-PNA. As a consequence, the adeninyl-β-PNA hexamer and pentamer form higher ordered structures and the 7-carbaadenine-β-PNA hexamer, which lacks a Hoogsteen pairing site, pairs as a double strand. The synthesis of adeninyl and carbaadeninyl β-nucleoamino acids and their oligomerization is described. Pairing mode and strand orientation were investigated through experiment and simple model studies. In the context of β-peptides the β-PNA oligomers for the most part tend to exist as double strands and prefer the extended β-sheet-like backbone conformation which provides an interesting structure motif in addition to the 31-helix observed for β-peptides.
- Diederichsen, Ulf,Schmitt, Harald W.
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p. 827 - 835
(2007/10/03)
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- Acyclic Nucleoside Analogs. II. Acyclic Analogs of Guanosine, 7-Deazaguanosine, and 7-Deazaadenosine with a cis-Hydroxypentene Fragment
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Condensations of 5-acetoxy-1-bromo-2-pentene with 2-amino-6-chloropurine, 4-chloropyrrolopyrimidine, and 2-amino-4-chloropyrrolopyrimidine sodium salts gave acyclic analogs of guanosine, 7-deazaguanosine, and 7-deazaadenosine.The subsequent deprotection with 0.1 N NaOH or methanol saturated with ammonium yielded the desired nucleoside analogs containing a cis-hydroxypentene fragment and either natural or modified heterocycle. - Keywords: nucleosides; acyclic analogs; pyrrolopyrimidines.
- Tsytovich, A. V.,Shamshin, D. V.,Burkovskii, V. B.,Shvets, V. I.
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p. 756 - 761
(2007/10/03)
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