title: Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4.
abstract: Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Jongwon
authors.initials: J
authors.lastname: Lim
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Altman
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: James
authors.initials: J
authors.lastname: Baker
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Brubaker
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Thierry
authors.initials: T
authors.lastname: Fischmann
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Gibeau
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Kleinschek
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Erica
authors.initials: E
authors.lastname: Leccese
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Lesburg
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: John K F
authors.initials: JK
authors.lastname: Maclean
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Moy
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Erin F
authors.initials: EF
authors.lastname: Mulrooney
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Presland
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Larissa
authors.initials: L
authors.lastname: Rakhilina
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Graham F
authors.initials: GF
authors.lastname: Smith
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Dietrich
authors.initials: D
authors.lastname: Steinhuebel
authors.affiliation: Departments of Chemistry, Immunology, Chemistry Modeling and Informatics, Drug Metabolism and Pharmacokinetics, In Vitro Pharmacology, In Vivo Pharmacology, and Structural Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Ruojing
authors.initials: R
authors.lastname: Yang
keywords: 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; IRAK4; SAR; inflammatory disease; kinase inhibitor; serine-threonine kinase