Abstract
Provided herein are novel lactams as Cbl-b inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.
Important Compound Classes
Title
Lactams as Cbl-b Inhibitors
Patent Publication Number
WO 2022/169997 A1
Publication Date
August 11, 2022
Priority Application
US 63/145,401
Priority Date
February 3, 2021
Inventors
Liang, J.; Jakalian, A.; Lambrecht, M. J.; Larouche-Gauthier, R.; Huestis, M.; Ung, M. U.; Wang, X.; Yadav, A.; Zbieg, J. R.; Broccatelli, F.
Assignee Company
Genentech Inc., USA
Disease Area
Cancer
Biological Target
Cbl-b
Summary
Casitas B-lineage lymphoma-b (Cbl-b) is a member of the Cbl family of RING E3 ubiquitin ligases. A common function of Cbl family proteins is the negative regulation of receptor tyrosine kinase signaling. Since Cbl-b inhibition leads to immune activation, it has been expected that Cbl-b could be broadly active in multiple oncology indications.
Cbl proteins comprise three principal domains: a conserved N-terminal tyrosine kinase binding (TKB) domain, a short linker region, and a RING finger (RF) domain. The TKB domain is, in turn, composed of three subdomains: a 4-helix bundle (4H), a calcium binding domain with an EF-hand fold, and a variant Src homology region 2 (SH2) domain, all three of which are involved in phosphotyrosine binding.
Mouse models have surprisingly demonstrated that the loss of Cbl-b leads to increased adaptive and innate anti-tumor immunity, mediated by enhanced T cell effector function as well as increased natural killer cell activity.
The present application describes a series of novel lactams as Cbl-b inhibitors for the treatment of cancer. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
Q = 5-membered heteroaryl, optionally substituted by one or more alkyl, cycloalkyl, aryl, or haloalkyl groups;
Y1 and Y2 = CH, CF, or N;
R3 and R4 = selected from H, halogen, alkyl, CN, OH, alkoxy, and haloalkyl, wherein at least one of R3 and R4 is halogen;
R5 = H, halo, CN, or L1a-R10, wherein L1a is -C(L1bR11)(R12)-, -N(L1bR11)-, -C(=O)N(L1bR11)-, O, S, carbonyl, or a bond;
X = halo, haloalkyl, or cycloalkyl; and
Z = -L2NR7R8 or -C(H)(NR7R8)R6a.
Key Structures
Biological Assay
The Cbl-b LCK Ub TR-FRET assay was performed. The compounds described in this application were tested for their ability to inhibit Cbl-b. The Cbl-b IC50 (μM) are shown in the following table.
Biological Data
The table below shows representative compounds tested for Cbl-b
inhibition and the biological data obtained from testing
representative examples.−
Claims
Total claims: 10
Compound claims: 8
Pharmaceutical composition claims: 1
Method of treatment claims: 1
The author declares no competing financial interest.
Recent Review Articles. References
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