CD73 inhibitors
Inventors
Du, Xiaohui • Eksterowicz, John • Fantin, Valeria R. • Jackson, Erica L. • Sun, Daqing • YE, Qiuping • Moore, Jared • Zavorotinskaya, Tatiana
Assignees
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Publication Number
US-11377469-B2
Publication Date
2022-07-05
Expiration Date
Abstract
Described herein are CD73 inhibitors and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of cancer, infections, and neurodegenerative diseases.
Core Innovation
The disclosure provides compounds of Formula (IIa), including pharmaceutically acceptable salts and stereoisomers thereof, with A as O, Q1 and Q2 as N, and Z as NR1R2. The compounds are defined by extensive substituent variables, including R1 and R2 options or taken together with the nitrogen atom to form a heterocycloalkyl, together with R3 as halogen, R4 and R7 as OH, R5 and R6 as hydrogen, X1 as a bond, Y1 as S(=O)2, and Y2 as (CR45R46)v2 with v2 equal to 1-3.
The structural scope further includes R45 and R46 selected from hydrogen, halogen, OH, ORa, NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl, and additional variable groups R21 and R22, R23 and R24, R25 and R26, and w. The disclosed embodiments apply the same style of optional substitution limits and, in some cases, allow R21 and R22 to be taken together to form a heterocycloalkyl.
The provided content also describes Formula (I), Formula (II), Formula (III), and Formula (IV) embodiments, including CD73 inhibitor scaffolds and phosphonic acid-containing pyrazolo[3,4-d]pyrimidine derivatives. The disclosures include stereochemically defined compounds, phosphonic-acid-containing derivatives, and example structures spanning pyrazolo[3,4-d]pyrimidine, triazolo[4,5-d]pyrimidine, and related fused heterocycle scaffolds.
Claims Coverage
The consolidated claim coverage centers on one independent compound claim for Formula (IIa), with pharmaceutically acceptable salts and stereoisomers, and multiple dependent refinements. The independent claim includes broad structural definition across the main variable positions and extensive allowed substituent sets, covering a single generic compound scaffold with numerous inventive features.
Formula (IIa) compound with fixed A, Q1, and Q2
A compound of Formula (IIa), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A is O, Q1 is N, Q2 is N, and Z is NR1R2.
Defined Z substituent and heterocycloalkyl formation
Z is NR1R2, where R1 and R2 are independently selected from hydrogen and broad C1-C6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and related substituted options, or R1 and R2 are taken together with the nitrogen atom to form a heterocycloalkyl.
Defined linker and substituent pattern
R3 is halogen, R4 and R7 are OH, R5 and R6 are hydrogen, X1 is a bond, Y1 is S(=O)2, and Y2 is (CR45R46)v2 with v2 equal to 1-3.
Defined R45 and R46 substituent set
R45 and R46 are each independently selected from hydrogen, halogen, OH, ORa, NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl, with optional substitution limits across the allowed substituent positions.
Additional variable groups R21, R22, R23, R24, R25, R26, and w
R21 and R22, R23 and R24, R25 and R26, and w are defined by extensive allowed substituent sets and optional substitution rules, including cases where R21 and R22 are taken together to form a heterocycloalkyl.
The claim coverage is a broad generic definition of Formula (IIa) compounds with tightly specified variable positions, optional heterocycloalkyl formation, and extensive permitted substituent classes.
Stated Advantages
Re-sensitize tumors via CD73 blockade by reducing adenosine signaling.
Address infection and CNS disease mechanisms via reduced adenosine signaling.
Documented Applications
Treating cancer in a subject with a CD73 inhibitor compound, optionally together with one or more antitumor immunotherapy agents.
Antitumor immunotherapy combination settings, including checkpoint inhibitors, cancer vaccines, oncolytic viruses, cytokines, and CAR-T cells.
Checkpoint inhibitor combinations including anti-PD1 inhibitors and anti-PD-L1 inhibitors.
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