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
Assignees
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Publication Number
US-11325938-B2
Publication Date
2022-05-10
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 invention relates to compounds of Formula (IV), or pharmaceutically acceptable salts thereof, defined by Ring A, Q2, Q3, Q4, W, A, X, and multiple substituent groups R1 through R22. The compounds include extensive allowed substitutions such as hydrogen, halogen, CN, ORb, NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, and broader alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl options, with optional substitution patterns and taken together rules that permit heterocycloalkyl formation with the nitrogen atom.
The disclosure further describes CD73 inhibitor compounds of Formula (IV) and phosphonic-acid-containing nucleoside-like compounds with chlorinated pyrazolo[3,4-d]pyrimidine core or related fused heterocycles, including triazolo[4,5-d]pyrimidine, [1,2,3]triazolo/pyrazolo variants, tetrazole, imidazole, oxazole, and pyridine-containing analogs. The compounds include a tetrahydrofuran or tetrahydrofuranyl diol scaffold with multiple stereocenters, a phosphonic acid or phosphonate moiety, and pendant amino substituents such as cyclopentylamino, cyclobutylamino, cyclopropylmethylamino, and indanyl/indenyl-amino groups.
The examples presented include racemic, stereoisomeric, solvate, salt, and isotopic variants, together with specific phosphonic acid derivatives and related Table 1 structures. The described structures emphasize variable side-chain substitution, phosphonate or phosphate-containing motifs, stereochemical assignments, and excluded compound structures with a stated proviso that the compound is not among the provided excluded structures.
Claims Coverage
The consolidated claim coverage centers on one independent claim, clm-00001, directed to compounds of Formula (IV) and pharmaceutically acceptable salts. Across the provided items, the inventive features are the defined Ring A/Q2/Q3/Q4/W/A/X scaffold and the extensive R1R22 substitution framework, with one item also describing a cancer-treatment use.
Formula (IV) compound with defined ring and linker scaffold
A compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein Ring A is defined by Q2 and Q3/Q4 relationships, each W is independently hydrogen, halogen, CN, ORb, NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl, A is O or CH2, and X is O, S, S(=O)2, NR17, or C(R18)2.
Extensive R1R22 substitution framework
R1 through R22 are independently defined by broad sets of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and functional-group options, with optional substitutions and cases where paired groups are taken together with nitrogen atoms to form heterocycloalkyl or cycloalkyl groups.
Pharmaceutically acceptable salts
The claimed scope includes pharmaceutically acceptable salts of the Formula (IV) compounds.
Cancer treatment by administration
A dependent claim family member covers treating cancer in a subject by administering a compound of claim 1 or a pharmaceutically acceptable salt thereof.
Overall, the claims cover a broad Formula (IV) chemical-structure family defined by Ring A, W, A, X, and R1R22, with pharmaceutically acceptable salts included. The provided material also includes narrower structural selections and one therapeutic use statement for cancer treatment.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating cancer in a subject by administering a compound of claim 1 or a pharmaceutically acceptable salt thereof.
Biological evaluation via a CD73 biochemical assay, with biochemical IC50 categorization reported for examples.
Inhibiting CD73 by contacting CD73 with the compounds.
Treating infections by administering the compounds or pharmaceutical compositions.
Treating neurodegenerative diseases by administering the compounds or pharmaceutical compositions.
Combination therapy with one or more second therapeutic agents for diseases or disorders mediated by CD73.
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