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CN-121991078-A - TYK2 inhibitor and application thereof

CN121991078ACN 121991078 ACN121991078 ACN 121991078ACN-121991078-A

Abstract

The present invention provides compounds, compositions thereof, and methods of use thereof for inhibiting TYK2 and treating TYK 2-mediated disorders.

Inventors

  • C.E. Maas
  • J.R. Greenwood
  • S. Montar
  • S. D. examination paper
  • T. H. McLean

Assignees

  • 武田药品工业株式会社

Dates

Publication Date
20260508
Application Date
20180726
Priority Date
20170728

Claims (20)

  1. N- (2-methoxycyclobutyl) -7- (methylamino) -5- ((2-oxo-2H- [1,2' -bipyridyl ] -3-yl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof.
  2. 2. The compound of claim 1, selected from the group consisting of: And pharmaceutically acceptable salts thereof.
  3. 3. The compound of claim 1, selected from the group consisting of: And pharmaceutically acceptable salts thereof.
  4. 4. The compound according to claim 1 or 2, which is: 。
  5. 5. a compound according to claim 1 or claim 3, which is: 。
  6. 6. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  7. 7. The pharmaceutical composition of claim 6, comprising a compound of claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  8. 8. The pharmaceutical composition of claim 6, comprising a compound of claim 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  9. 9. The pharmaceutical composition of claim 6, comprising a compound of claim 4, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  10. 10. The pharmaceutical composition of claim 6, comprising a compound of claim 5, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  11. 11. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for use as a medicament.
  12. 12. A compound, pharmaceutically acceptable salt or pharmaceutical composition for use according to claim 11, wherein the compound is a compound according to claim 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is a pharmaceutical composition according to claim 7.
  13. 13. A compound, pharmaceutically acceptable salt or pharmaceutical composition for use according to claim 11, wherein the compound is a compound according to claim 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition is a pharmaceutical composition according to claim 8.
  14. 14. The compound or pharmaceutical composition for the use according to claim 11, wherein the compound is a compound according to claim 4, or the pharmaceutical composition is a pharmaceutical composition according to claim 9.
  15. 15. The compound or pharmaceutical composition for the use according to claim 11, wherein the compound is a compound according to claim 5, or the pharmaceutical composition is a pharmaceutical composition according to claim 10.
  16. 16. A method for inhibiting TYK2 in a biological sample, the method comprising contacting the sample with a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, a compound according to any one of claims 4 or 5, or a pharmaceutical composition according to any one of claims 6-10.
  17. 17. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for use in a method of treating a TYK 2-mediated disorder, disease or condition in a patient, the method comprising administering to the patient a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6.
  18. 18. A compound or pharmaceutically acceptable salt thereof or a pharmaceutical composition for use according to claim 17, the method comprising administering to the patient a compound or pharmaceutically acceptable salt thereof according to claim 2 or a pharmaceutical composition according to claim 7.
  19. 19. A compound or pharmaceutically acceptable salt thereof or a pharmaceutical composition for use according to claim 17, the method comprising administering to the patient a compound or pharmaceutically acceptable salt thereof according to claim 3 or a pharmaceutical composition according to claim 8.
  20. 20. A compound or pharmaceutical composition for use according to claim 17, the method comprising administering to the patient a compound according to claim 4 or a pharmaceutical composition according to claim 9.

Description

TYK2 inhibitor and application thereof The application is a divisional application of patent application No. 201880057821.5, the application name is TYK2 inhibitor and application thereof, and the application date is 2018, 7, 26 (PCT application No. PCT/US 2018/043917). Technical Field The present invention relates to compounds and methods useful for inhibiting non-receptor tyrosine protein kinase 2 ("TYK 2"; also known as tyrosine kinase 2). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. Background In recent years, by better understanding the structure of enzymes and other biomolecules associated with diseases, great help has been provided to seek novel therapeutic agents. An important class of enzymes that is the subject of intensive research is the protein kinase family. Protein kinases constitute a large group of structurally related enzymes responsible for controlling a variety of signal transduction processes within cells. Protein kinases are thought to evolve from a common ancestral gene because of their conserved structure and catalytic function. Almost all kinases contain similar catalytic domains of 250-300 amino acids. Kinases can be divided into families (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.) according to the substrates they phosphorylate. In general, protein kinases mediate intracellular signaling by effecting phosphoryl transfer from nucleoside triphosphates to protein receptors involved in the signaling pathway. These phosphorylation events act as molecular on/off switches that can regulate or modulate the biological function of the target protein. These phosphorylation events are eventually triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins, and H 2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-alpha)), and growth factors (e.g., granulocyte macrophage colony-stimulating factor (GM-CSF), and Fibroblast Growth Factor (FGF)). Extracellular stimuli can affect one or more cellular responses associated with cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle. Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, alzheimer's disease and hormone-related diseases. Thus, there remains a need to find protein kinase inhibitors that can be used as therapeutic agents. Disclosure of Invention It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as TYK2 kinase inhibitors. The compounds of the invention and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders, or conditions associated with the modulation of signaling pathways involving TYK2 kinase. The disease, disorder or condition includes the disease, disorder or condition described herein. The compounds provided by the invention can also be used for researching TYK2 enzyme in biological and pathological phenomena, researching intracellular signal transduction paths appearing in body tissues, and comparatively evaluating novel TYK2 inhibitors or other regulatory factors of kinase, signal transduction paths and cytokine content in vitro or in vivo. Detailed Description 1. General description of certain embodiments of the invention: the compounds of the present invention and compositions thereof are useful as inhibitors of TYK2 protein kinase. The pseudo-kinase binding pocket of TYK2 contains multiple hydration sites, each occupied by a single water molecule. Each of these water molecules has a stability rating associated with it. As used herein, the term "stability grade" refers to a numerical calculation incorporating the enthalpy, entropy, and free energy values associated with each water molecule. This stability rating allows for a measurable determination of the relative stability of water molecules occupying the hydration sites in the binding pocket of TYK 2. Water molecules occupying the hydration sites in the binding pocket of TYK2 with a stability rating of >2.5 kcal/mol are referred to as "labile water". Without wishing to be bound by any particular theory, it is believed that the use of inhibitors replaces or destroys unstable water molecules (i.e., water molecules with a stability rating of > 2.5 kcal/mol), or displace