1153949-98-4

Upstream product

• 15760-35-7 3-methylenecyclobutanecarbonitrile 
• 2537-48-6 diethyl 1-cyanomethylphosphonate 
• 20249-16-5 3-oxo-cyclobutanecarbonitrile 

Relevant academic research and scientific papers

Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases

Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 (22).

PYRAZOLO[1,5-A]PYRAZIN-4-YL DERIVATIVES

A compound compound having the structure: or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein A, A′ and A″ are independently O, C═O, C—R′ or N—R″, where R′ and R″ may independently be H, amino, —NR7COR6, COR6, —CONR7R8, C1-C6 alkyl, or hydroxy(C1-C6 alkyl), and R″ may be present or absent, and is present where the rules of valency permit, and where not more than one of A, A′ and A″ is O or C═O; R0 and R are independently H, Br, Cl, F, or C1-C6 alkyl; R1 is H, C1-C6 alkyl, or hydroxy(C1-C6 alkyl); R2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, hydroxy(C1-C6 alkyl), phenyl(C1-C6 alkyl), formyl, heteroaryl, heterocyclic, —COR6, —OCOR6, —COOR6, —NR7COR6, —CONR7R8, and —(CH2)n—W, where W is cyano, hydroxy, C3-C8 cycloalkyl, —SO2NR7R8, and —SO2—R9, where R9 is C1-C6 alkyl, C3-C8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl; X is C—R3 or N, where R3 may be H or C1-C6 alkyl; R4 and R5 are independently H, amino, C1-C6 alkyl, or hydroxy(C1-C6 alkyl); R6, R7 and R8 are each independently H, C1-C6 alkyl, C1-C4 alkoxy(C1-C6 alkyl), or C3-C8 cycloalkyl, said C1-C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl; and, n is 0, 1, 2 or 3. Also provided are methods of treatment as Janus Kinase inhibitors and pharmaceutical compositions containing the compounds of the invention and combinations thereof with other therapeutic agents.

HETEROCYCLIC COMPOUNDS AS JANUS KINASE INHIBITORS

The invention provides compounds of formula (I) or a salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of formula (I), processes for preparing compounds of formula (I), intermediates useful for preparing compounds of formula I and therapeutic methods for suppressing an immune response or treating cancer or a hematologic malignancy using compounds of formula (I).

AZETIDINE AND CYCLOBUTANE DERIVATIVES AS JAK INHIBITORS

The present invention relates to azetidine and cyclobutane derivatives, as well as their compositions, methods of use, and processes for preparation, which are JAK inhibitors useful in the treatment of JAK-associated diseases including, for example, inflammatory and autoimmune disorders, as well as cancer.

4-PYRAZOLYL-N-ARYLPYRIMIDIN-2-AMINES AND 4-PYRAZOLYL-N-HETEROARYLPYRIMIDIN-2-AMINES AS JANUS KINASE INHIBITORS

The present invention provides substituted bicyclic heteroaryl compounds, 5 including, for example, 4-pyrazoIyI-N-arylpyrirnidin-2-arnines and 4-pyrazolyl-N-heteroarylpyτimidin-2-amines that modulate the activity of kinases and are useful in the treatment of diseases related to activity of kinases including, for example, immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.formule :(1)