CD73 inhibitors
Inventors
Du, Xiaohui • Eksterowicz, John • Fantin, Valeria R. • Sun, Daqing • YE, Qiuping • Moore, Jared • Zavorotinskaya, Tatiana • BLANK, Brian R. • Rew, Yosup • Wu, Kejia • Zhu, Liusheng • Pham, Johnny • Kawai, Hiroyuki • Yeh, Chien-Hung
Assignees
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Publication Number
US-11530236-B2
Publication Date
2022-12-20
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 concerns phosphonic-acid-containing pyrazolo[3,4-d]pyrimidine derivatives of Formula (I), including a pharmaceutically acceptable salt thereof, together with stereoisomers, isotopically labeled compounds, and deuterated variants. The compounds are defined by structural variables and substituent options across multiple positions, including Q1, Q2, Q3, R1 and R2, R3, R4 and R5, R6, R7-R10, X, Ring A, n, RA, R13, and R21/R22.
The compound family includes a chlorinated pyrazolo[3,4-d]pyrimidine linked to a stereodefined tetrahydrofuran diol scaffold and a phosphonic acid or phosphonate-containing side chain. The examples show varied amino substituents and terminal heterocycles such as tetrazolyl, triazolyl, and oxadiazolyl, as well as cyclopentylamino, cyclobutylamino, cyclopropylmethylamino, isopropylamino, and isobutylamino variants.
The disclosure further provides specific embodiments and characterization for phosphonic acid products and related intermediates, including separated diastereomer pairs, enantiomeric and diastereomeric forms, and methylsulfonyl/d3 variants. Examples and intermediates are reported with characterization and identity information, including LC/ESI m/z values, ESI-MS, and 1H NMR data, and the examples are linked to CD73 inhibitory assessment context.
Claims Coverage
The claim coverage centers on compounds of Formula (I) or pharmaceutically acceptable salts thereof, with extensive structural constraints across multiple variables, and includes a method claim to inhibit CD73 by contacting CD73 with a Formula (I) compound. The independent structural claim framework defines the compound by one clearly identified set of inventive structural features, with dependent claims refining substituent identity, linker identity, Ring A, and variable values.
Formula (I) phosphonic-acid-containing pyrazolo[3,4-d]pyrimidine derivatives
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, with constrained values for Q1, Q2, Q3, W, X, Ring A, n, R13, R21, R22, and rb, together with defined substituent options for R1, R2, R3, R4, R5, R6, and R7-R10.
Stereochemically defined and isotopically labeled forms
The scope includes stereoisomers, isotopically labeled compounds, and deuterium and deuteroalkyl options in the defined substituent set.
CD73 inhibition by contacting with a Formula (I) compound
A method to inhibit CD73 by contacting CD73 with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Dependent claim refinements for substituent and scaffold variables
Dependent claims refine specific options such as R2 being hydrogen or C1-C6 alkyl, X being O, Ring A being heteroaryl, and n being 0.
The claim coverage is centered on a Formula (I) structural definition with extensive substituent and scaffold constraints, including linker X, Ring A, n, and other defined variables, together with a CD73 inhibition method claim.
Stated Advantages
Inhibits CD73.
Documented Applications
Methods of inhibiting CD73.
Biochemical CD73 inhibitory assay evaluation context for Examples 1-60.
Treatment of diseases including cancer, infections, neurodegenerative disorders, and psychiatric disorders, where CD73 is described as overexpressed or upregulated in cancers.
Treating cancer.
Treating infections, including viral and parasitic infections.
Treating neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.
Treating specified psychiatric disorders, including schizophrenia and autism.
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