Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Covalent Inhibitors of the TEC Family of Kinases and Their Methods of Use Benjamin E. Blass* Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, United States Important Compound Classes.
L is selected from
wherein n is an integer from 1 to 3; and n′ is an integer from 1 to 3; E is selected from the group:
Title. Spirocyclic containing compounds and pharmaceutical uses thereof Patent Application Number. WO 2018/032104A1 Publication Date. February, 22nd, 2018 Priority Application. CA2,939,286 CA2,959,055 CA2,965,813 Priority Date. August 17th, 2016 February 27th, 2017 May 2nd, 2017 Inventors. Laurent, A.; Morris, S. J. Assignee Company. Pharmascience, Inc. Disease Area. Autoimmune diseases, cancers, and neurodegenerative diseases Biological Target. Interleukin-2 inducible T-cell kinase (ITK), resting lymphocyte kinase (RLK and TXK), Bruton’s tyrosine kinase (BTK), and tyrosine kinase expressed in hepatocellular carcinoma (TEC) Summary. The TEC family of kinase is a group of nonreceptor tyrosine kinases that are typified by the presence of a pleckstrin homology (PH) domain. This region of the protein binds phosphoinositides, and it has been hypothesized that TEC family of kinase may act as juncture points between the phosphotyrosine-mediated and phospholipid-mediated signaling systems. Members of this family include tyrosine kinase expressed in hepatocellular carcinoma (TEC), interleukin-2 inducible T-cell kinase (lTK, also known as Tsk and Emt), resting lymphocyte kinase (RLK, also known as TXK for tyrosine protein kinase), Bruton’s tyrosine kinase (BTK), and bone marrow kinase on the X-chromosome (BMX, also known as Etk). Each of the aforementioned TEC kinases has been identified as playing a role in a variety of disease states, and as such, they are potential targets for the development of novel therapeutic agents. These disease states include T-cell related diseases such as multiple sclerosis, asthma, atopic dermatitis, psoriasis, and inflammatory bowel diseases, as well as viral infections, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and cancer. The present application describes a series of functionalized benzimidazoles that inhibit members of the TEC family of kinases and may be useful for the treatment of diseases and conditions associated with improper activity of these enzymes. Definitions. R is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; © XXXX American Chemical Society
wherein Ra, Rb, and Rc are independently selected from hydrogen, halogen, −CN, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; or Ra and Rb taken together with the carbon atoms to which they are attached form a 3- to 8-membered substituted or unsubstituted cycloalkyl ring or form a 3- to 8-membered substituted or unsubstituted heterocyclic ring, and Rc is selected as above; or Rb and Rc taken together with the carbon atom to which they are attached form a 3- to 8-membered substituted or unsubstituted cycloalkyl ring or form a 3- to 8-membered heterocyclic ring, and Ra is selected as above; or Ra and Rb taken together with the carbon atoms to which they are attached form a triple bond, and Rc is selected as above; provided L-E is
R′ and R″ are independently selected from −X−Y wherein X is selected from alkylene, −(alkylene)-NR1−, −(alkylene)NR2−, −(alkylene)-O−, −O−, −S−, −S(O)m−, −NR1−, −NR2−, −C(O)−, −C(O)O−, −C(O)NR1−, −C(O)ONR1−, or −S(O)mNR1−; R1 is selected from hydrogen, lower alkyl, or lower cycloalkyl; R2 is selected from −C(O)R3, −C(O)OR3, or −S(O)mR3; R3 is selected from lower alkyl or lower cycloalkyl; m is an integer from 1 to 2; or X is a bond; and Y is selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl; or Received: April 15, 2018
A
DOI: 10.1021/acsmedchemlett.8b00178 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
R′ and R″ taken together with the carbon atoms to which they are attached form a 3- to 8-membered substituted or unsubstituted cycloalkyl ring, or a 3- to 8-membered substituted or unsubstituted heterocyclyl ring. Key Structures.
Biological Assay. Inhibition of ITK, TXK, BTK, and TEC where determined by Nanosyn (Santa Clara, CA) utilizing microfluidic detection technology and fluorescently labeled peptide substrates. Biological Data.
Claims. 41 Total claims 16 Composition of matter claims 25 Method of use claims Recent Review Articles. 1. Boucheron, N.; Ellmeier, W. The Role of Tec Family Kinases in the Regulation of T-helper-cell Differentiation. Int. Rev. Immunol. 2012, 31 (2), 133−154. 2. Horwood, N. J.; Urbaniak, A. M.; Danks, L. Tec Family Kinases in Inflammation and Disease. Int. Rev. Immunol. 2012, 31, (2), 87−103. B
DOI: 10.1021/acsmedchemlett.8b00178 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
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Patent Highlight
3. Ortutay, C.; Nore, B. F.; Vihinen, M.; Smith, C. I. E. Phylogeny of Tec family kinases: identification of a premetazoan origin of Btk, Bmx, Itk, Tec, Txk, and the Btk regulator SH3BP5. Adv. Genet. 2008, 64, 51−80.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The author declares no competing financial interest.
C
DOI: 10.1021/acsmedchemlett.8b00178 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
