1609467-45-9

Upstream product

• 1609467-43-7 benzyl 3-[5-amino-4-cyano-3-(4-phenoxy-phenyl)-pyrazol-1-yl]-piperidine-1-carboxylate 
• 1609467-44-8 5-amino-3-(4-phenoxy-phenyl)-1-piperidin-3-yl-1H-pyrazole-4-carbonitrile 
• 1623-95-6 4-phenoxybenzoyl chloride 
• 2215-77-2 4-Phenoxybenzoic acid 
• 330792-68-2 2-[hydroxy-(4-phenoxy-phenyl)-methylene]-malononitrile 
• 330792-70-6 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile 
• 85275-45-2 N-tert-butoxycarbonyl-3-piperidinol 
• 85275-46-3 1,1-dimethylethyl 3-{[(4-methylphenyl)sulfonyl]oxy}-1-piperidinecarboxylate 
• 1612774-47-6 tert-butyl 3-(5-amino-4-cyano-3-(4-phenoxyphenyl)-1H-pyrazol-1-yl)-piperidine-1-carboxylate 
• 1284940-16-4 benzyl 3-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate 
• 1609467-42-6 3-(tert-butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acid benzyl ester 
• 61995-20-8 N-(benzyloxycarbonyl)-3-piperidone 
• 330792-69-3 2-[(4-phenoxy-phenyl)-methoxy-methylene]-malononitrile 

Downstream Products

• 1609468-23-6 (S)-5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1H-pyrazole-4-carboxylic acid amide 
• 1609467-02-8 1-[(3S)-1-acryloylpiperidin-3-yl]-5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 
• 1558038-42-8 (R)-5-amino-3-(4-phenoxyphenyl)-1-piperidin-3-yl-1H-pyrazole-4-carboxylic acid amide 
• 1558036-85-3 1-[(3R)-1-acryloylpiperidin-3-yl]-5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 
• 1609467-04-0 5-amino-1-{(3R)-1-[(2E)-4-hydroxybut-2-enoyl]piperidin-3-yl}-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 
• 1609465-65-7 5-amino-1-[(3R)-1-cyanopiperidin-3-yl]-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 
• 1609465-66-8 5-amino-1-[(3S)-1-cyanopiperidin-3-yl]-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 
• 1609467-03-9 5-amino-1-{1-[(2E)-but-2-enoyl]piperidin-3-yl}-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 
• 1609465-64-6 5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole carboxamide 
• 1609465-67-9 5-amino-1-[1-(cyanomethyl)piperidin-3-yl]-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 
• 1612774-17-0 1-(1-acryloylpiperidin-3-yl)-5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 
• 1612774-23-8 (E)-5-amino-1-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide 
• 1612774-21-6 5-amino-3-(4-phenoxyphenyl)-1-(1-(vinylsulfonyl)piperidin-3-yl)-1H-pyrazole-4-carboxamide 

Relevant academic research and scientific papers

Aminopyrazole Carboxamide Bruton's Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning

Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.

Therapeutic Combinations of a Proteasome Inhibitor and a BTK Inhibitor

Therapeutic combinations of a proteasome inhibitor and a Bruton's tyrosine kinase (BTK) inhibitor are described. In some embodiments, the invention provides pharmaceutical compositions comprising combinations of a proteasome inhibitor and a BTK inhibitor and methods of using the pharmaceutical compositions for treating a disease, in particular a cancer.

Methods of Using BTK Inhibitors to Treat Dermatoses

In certain embodiments, the invention includes therapeutic methods of using a BTK inhibitor to treat dermatoses, such as psoriasis, atopic dermatitis, contact dermatitis, scleroderma, and cutaneous lupus erythematosus. In other embodiments, the methods of the invention further comprise the step of administering a therapeutically effective dose of an anti-inflammatory agent.

THERAPEUTIC COMBINATIONS OF A CD19 INHIBITOR AND A BTK INHIBITOR

Therapeutic combinations of a CD 19 inhibitor and a Bruton's tyrosine kinase (BTK) inhibitor are described. In some embodiments, the invention provides pharmaceutical compositions comprising combinations of a CD 19 inhibitor and a BTK inhibitor and methods of using the pharmaceutical compositions for treating a disease, in particular a cancer, such as a hematological malignancy. A combination of a BTK inhibitor and a CD 19 inhibitor, such as a CD19-targeted antibody or a CD19-targeted chimeric antigen receptor expressing T cell or NK cell, and compositions and uses thereof are disclosed. Combinations of a BTK inhibitor and a CD 19 inhibitor with a programmed death- 1 (PD-1) or PD-1 ligand (PD-L1) inhibitor and compositions and uses thereof are also disclosed.

Therapeutic Combinations of an IRAK4 Inhibitor and a BTK Inhibitor

Therapeutic combinations of an interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor and a Bruton's tyrosine kinase (BTK) inhibitor are described. In some embodiments, the invention provides pharmaceutical compositions comprising combinations of an IRAK4 inhibitor and a BTK inhibitor, and methods of using the pharmaceutical compositions for treating a disease, in particular a cancer.

BTK INHIBITORS TO TREAT SOLID TUMORS THROUGH MODULATION OF THE TUMOR MICROENVIRONMENT

In certain embodiments, the invention includes therapeutic methods of using a BTK inhibitor to treat solid tumor cancers by modulation of the tumor microenvironment, including macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.

THERAPEUTIC COMBINATIONS OF A BTK INHIBITOR, A PI3K INHIBITOR, A JAK-2 INHIBITOR AND/OR A CDK 4/6 INHIBITOR

Therapeutic combinations of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms (PI3K-γ,δ, PI3K-γ, and PI3K-δ, a Janus kinase-2 (JAK-2) inhibitor, a cyclin-dependent kinase- 4/6 (CDK4/6) inhibitor, and/or a Bruton's tyrosine kinase (BTK) inhibitor are described. In certain embodiments, the invention includes therapeutic combinations of a cyclin-dependent kinase-4/6 (CDK4/6) inhibitor and a BTK inhibitor, a PI3K-δ inhibitor and a BTK inhibitor, a JAK-2 and a BTK inhibitor, and a JAK-2, PI3K-δ, and BTK inhibitor.

THERAPEUTIC COMBINATIONS OF A BTK INHIBITOR, A PI3K INHIBITOR, A JAK-2 INHIBITOR, AND/OR A BCL-2 INHIBITOR

Therapeutic combinations of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms (PI3K-γ,δ, PI3K-γ, and PI3K-δ), a Janus kinase-2 (JAK-2) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, and/or a B-cell lymphoma-2 (BCL-2) inhibitor are described. In some embodiments, the invention provides therapeutic combinations of a PI3K-δ inhibitor and a BTK inhibitor, a JAK-2 and a BTK inhibitor, and a BCL-2 and BTK inhibitor.

METHODS OF TREATING CANCERS, IMMUNE AND AUTOIMMUNE DISEASES, AND INFLAMMATORY DISEASES BASED ON BTK OCCUPANCY AND BTK RESYNTHESIS RATE

In an embodiment, therapeutic methods and use of a Bruton's Tyrosine Kinase (BTK) inhibitor for treatment of cancer, inflammation, immune disorders, and autoimmune disorders, and for transplantation prophylaxis, based on BTK occupancies and/or BTK resynthesis rates for B cells in various diseases, tissue compartments, including bone marrow and lymph nodes, are described. In an embodiment, dosing regimens for a BTK inhibitor for treatment of cancer, inflammation, immune disorders, and autoimmune disorders, and for transplantation prophylaxis, based on BTK occupancies and/or BTK resynthesis rates for B cells in various diseases, tissue compartments, including bone marrow and lymph nodes, are described.

Protein Kinase Inhibitors and Uses Thereof

The invention is compounds of formula (I), and salts thereof, compositions thereof, and methods of use therefor. In particular, disclosed herein are certain compounds that can be useful for inhibiting protein kinase, including Bruton's tyrosine kinase (Btk), and for treating disorders mediated thereby.