- Efficient, Protecting Group Free Kilogram-Scale Synthesis of the JAK1 Inhibitor GDC-4379
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The development of an improved kilogram-scale synthesis of the JAK1 inhibitorGDC-4379for the treatment of asthma is described. The new process is highlighted by a step-economical construction of a 3-substituted-4-aminopyrazole employing a telescoped oximation and hydrazine condensation of a 1,3-dielectrophile to generate nitrosopyrazole and a novel copper-catalyzed NaBH4reduction of the nitroso group. The endgame process features an amidation of aminopyrazole with acid chloride under Schotten-Baumann conditions to provide access to the penultimate intermediate. A selective N-1 alkylation of the pyrazole moiety was accomplished under phase-transfer conditions, which deliveredGDC-4379with a defined particle-size distribution suitable for micronization after recrystallization and wet milling.
- Angelaud, Remy,Burkhard, Johannes,Gosselin, Francis,Lao, David,Marx, Andreas,Ochsenbein, Miriam,Ranjan, Rohit,Stumpf, Andreas,Xu, Di
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p. 2537 - 2550
(2021/11/24)
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- Substituted heteroaryl compounds and compositions and uses thereof
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The invention discloses a substituted ceteroary compound as well as a composition and an application thereof. The compound is a compound shown in a formula (I) or a stereisomer, a tautomer, a nitric oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or prodrug of the compound shown in the formula (I). The invention further discloses a pharmaceutical composition including the compound. The compound and the pharmaceutical composition are capable of adjusting the activity of the AK kinase and can be used for preventing, processing, treating and relieving the JAK-mediated disease or disorder.
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- SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE
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The present invention provides novel heterocyclic compounds, pharmaceutical acceptable salts and formulations thereof useful in preventing, treating or lessening the severity of a JAK-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of JAK-mediated disease.
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- PREPARATION AND CHARACTERIZATION OF PYRAZOLOPYRIMIDINES
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1-Phenyl-1,3-butadione readily reacts with 3(5)-amino-1H-pyrazoles to yield mixtures of pyrazolopyrimidines which are identified by 1H nmr.Selective preparation of 5-methyl-7-phenylpyrazolopyrimidines can be achieved when 3-amino-1-phenyl-2-
- Maquestiau, A.,Taghret, H.,Eynde, J.-J. vanden
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p. 131 - 136
(2007/10/02)
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- 4,5-dihydro and 4,5,6,7-tetrahydropyrazolo(1,5-A)-pyrimidines
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Novel compounds having the following structural formula: STR1 wherein - - - may represent the presence of a double bond between the C6 and C7 position, Ia, or the absence of a double bond between the C6 and C7 position, Ib; R1 is selected from the group consisting essentially of hydrogen, bromo, chloro, carbamoyl, carboxyl, carboxyalkoxyl where alkoxyl is (C1 -C3), cyano, --CO--CF3, COONa, STR2 --CO--C(CH3)3, and STR3 where X is hydrogen, cyano, halogen and nitro; R2, R4 and R5 may be hydrogen and lower alkyl (C1 -C3); R3 is hydrogen, alkyl (C1 -C3), STR4 where R7 and R8 may be the same or different and are selected from the group consisting essentially of hydrogen, halogen, alkyl (C1 -C3), nitro, alkoxy (C1 -C3), trifluoro-methyl, acetylamino or N-alkylacetylamino where alkyl is (C1 -C3), and R3 may also be selected from a monovalent radical selected from the class consisting essentially of 3-thienyl, 2-pyridinyl, 3-pyridinyl and 4-pyridinyl, either of said pyridinyl radicals being optionally substituted with an alkyl radical R9, where alkyl is (C1 -C4), and the structures of the monovalent 2-pyridinyl, 3-pyridinyl and 4-pyridinyl moieties are depicted respectively as: STR5 R6 is hydrogen or alkyl-(C1 -C3); pharmaceutical compositions of matter containing the above-defined compounds; methods for using the compounds as anxiolytic agents, antihypertensive agents or antidepressant agents in mammals; processes for the preparation of the compounds.
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