1353637-44-1Relevant articles and documents
Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability
Wang, Xiaojing,Kolesnikov, Aleksandr,Tay, Suzanne,Chan, Grace,Chao, Qi,Do, Steven,Drummond, Jason,Ebens, Allen J.,Liu, Ning,Ly, Justin,Harstad, Eric,Hu, Huiyong,Moffat, John,Munugalavadla, Veerendra,Murray, Jeremy,Slaga, Dionysos,Tsui, Vickie,Volgraf, Matthew,Wallweber, Heidi,Chang, Jae H.
, p. 4458 - 4473 (2017/06/05)
Pim kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three Pim kinase isoforms. The discovery of extensive intestinal metabolism and major metabolites helped refine our design strategy, and we observed that optimizing the pharmacokinetic properties first and potency second was a more successful approach than the reverse. In the resulting work, novel analogs such as 20 (GNE-955) were discovered bearing 5-azaindazole core with noncanonical hydrogen bonding to the hinge.
PYRAZOLOPYRIDINES AND PYRAZOLOPYRIMIDINES
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Paragraph 0684, (2015/12/26)
A compound having the structure: or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein A and A′ are independently C or N, where C may be unsubstituted or substituted by halo or C1-C6 alkyl; R and R0 are independently selected from the group consisting of H, C1-C6 alkyl, hydroxy(C1-C6 alkyl), phenyl(C1-C6 alkyl), and —(CH2)n—W, where W is C3-C8 cycloalkyl, phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic containing 1-3 N, S and/or O atoms, —SO2—R′, —NHSO2—R′, —NR″SO2—R′ and SR′, where R′ and R″ are independently C1-C6 alkyl or C3-C8 cycloalkyl, etc.; wherein each of said alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl may be unsubstituted or substituted by phenyl, heteroaryl, etc.; or, R and R0 and the N atom to which they are bonded together form a monocyclic or bicyclic heterocyclic ring which may be unsubstituted or substituted by (a) halo, hydroxy, heteroaryl, C1-C6 alkyl, C1-C6 alkoxy, etc., or (b) —(CH2)n—W, where W is C3-C8 cycloalkyl, phenyl, etc.; R1 is H, halo or cyano; R2 and R2′ are independently H, C1-C6 alkyl, cyano, C1-C6 alkoxy, C1-C6 alkylthio, or C3-C8 cycloalkyl where alkyl, alkoxy, or cycloalkyl is optionally substituted by one or more fluorine atoms; X is a bond, —CO—, —CONH—, —SO2—, —SONH—, or —(CH2)m—; R3 is H, C1-C4 alkyl, phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic containing 1-3 N atoms, a 5-membered heteroaryl or heterocyclic, etc., or (c) 2 O or S atoms and 0-2 N atoms; wherein each of said phenyl, naphthyl, heteroaryl or heterocyclic is optionally substituted by alkyl, 1 substituent —Y—R4 and/or 1-4 substituents each independently selected from R5; with the proviso that when X is —CO— or —SO2—, R3 is not H; Y is a bond, —(CH2)m— or —O—; R4 is (a) H, C1-C6 alkyl, C3-C8 cycloalkyl, halo, oxo, —OR6, —NR7R8, —SR6, —SOR9, —SO2R9, —COR6, —OCOR6, —OCOR6, —NR6COR6, —CONR7R8, etc.; (b) phenyl or naphthyl, said phenyl and naphthyl being optionally substituted with 1-5 substituents selected from C1-C6 alkyl, C3-C8 cycloalkyl, halo, cyano, —OR6, —NR7R8, etc.; or (c) a 3 to 8-membered saturated or partially unsaturated monocyclic heteroaryl, etc.; R6 is H, C1-C6 alkyl or C3-C8 cycloalkyl, etc.; R7 and R8 are each independently H, C1-C6 alkyl or C3-C8 cycloalkyl or are taken together with the nitrogen atom to which they are attached to form a 4-, 5- or 6-membered saturated heterocyclic ring containing 1-2 nitrogen atoms or 1 nitrogen and 1 oxygen atom, said C1-C6 alkyl is optionally substituted by C3-C8 cycloalkyl, halo, etc., and said heterocyclic ring being optionally substituted by one or more C1-C6 alkyl or C3-C8 cycloalkyl groups; R9 is C1-C6 alkyl or C3-C8 cycloalkyl; and, m and n are independently 0, 1, 2 or 3. The invention also relates to pharmaceutically acceptable salts of these compounds and to pharmaceutically acceptable solvates thereof; to compositions containing such compounds; and to the uses of such compounds in the treatment of various diseases, particularly asthma and COPD.
5-AZAINDAZOLE COMPOUNDS AND METHODS OF USE
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Page/Page column 121; 122, (2014/01/17)
5-Azaindazole compounds of Formula (I), including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. 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.
Fused Pyrazoles as FGFR Inhibitors
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Paragraph 0294, (2014/06/25)
The present invention relates to fused pyrazole derivatives, and pharmaceutical compositions including the same, that are inhibitors of one or more FGFR enzymes and are useful in the treatment of FGFR-associated diseases such as cancer.
