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-12018043-B2
Publication Date
2024-06-25
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 relates to treating cancer in a subject by administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The method targets lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, renal cancer, lymphoma, leukemia, and multiple myeloma. The chemical definition in Formula (I) includes Q1, Q2, Q3, W, X, Ring A, n, and substituent classes such as R1, R2, R3, R4, R5, R6, R7-R10, R13, R21, and R22, with optional substitution-count constraints.
The disclosure also describes CD73-inhibiting compounds and pharmaceutical compositions comprising compounds defined by Formula (I), including Formulas (Ia) through (Ic). The compounds are provided as CD73-inhibiting agents, including pharmaceutically acceptable salts, solvates, stereoisomers, and isotopic variants. The biological rationale is described in terms of CD73 5′-nucleotidase activity, where CD73 hydrolyzes AMP to adenosine and adenosine signaling is linked to immunosuppression, tumor immune escape, and therapy resistance.
The disclosure further describes therapeutic approaches in which CD73 inhibition is achieved through contact with CD73 and administration of the CD73-inhibiting compounds. Pharmaceutical compositions are described with pharmaceutically acceptable excipients, and combination is described with a second therapeutic agent, including a chemotherapeutic agent or an immunotherapy agent. The disclosure also describes combination therapy embodiments with anti-emetic agents, epoetin-α, G-CSF/filgrastim, NSAIDs, and radiation therapy for localized tumors and for leukemia/lymphoma.
Claims Coverage
The consolidated claim coverage includes one independent method claim directed to treating cancer in a subject by administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The inventive features combine the selected cancer indication with extensive structural limitations across Formula (I), including the defined substituent scope and optional substitution-count rules.
Treating selected cancers by administering Formula (I) or a pharmaceutically acceptable salt
A method of treating cancer in a subject by administering a compound of Formula (I), or a pharmaceutically acceptable salt thereof, where the cancer is selected from lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, renal cancer, lymphoma, leukemia, and multiple myeloma.
Formula (I) core definitions and heteroatom selection
In Formula (I), Q1 is CW, Q2 is N, Q3 is N, W is hydrogen, X is —O—, Ring A is heterocycloalkyl or heteroaryl, and n is 0, 1, 2, 3, or 4.
Substituent scope for R1, R2, and optional R1a substitution
R1 and R2 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkyl(aryl), C1-C6 alkyl(heteroaryl), C1-C6 alkyl(cycloalkyl), or C1-C6 alkyl(heterocycloalkyl), wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one, two, or three R1a; and each R1a is independently halogen, —CN, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 hydroxyalkyl.
Substituent scope for R3 with optional R3a substitution and alkynyl/alkyl limits
R3 is hydrogen, halogen, —CN, ORb, SRb, C1-C6 alkyl, C2-C6 alkynyl, or C1-C6 hydroxyalkyl; wherein the alkyl and alkynyl is independently optionally substituted with one, two, or three R3a; and each R3a is halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 hydroxyalkyl, or cycloalkyl.
Linkage variables R4, R5, R6, and Rb constrained to specified groups
R4 and R5 are —ORb; R6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, or heterocycloalkyl, wherein the alkyl is independently optionally substituted with one, two, or three R6a; each R6a is —OR13, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, or heteroaryl; and Rb is independently hydrogen or C1-C6 alkyl.
Terminal variables R7, R8, R9, and R10 constrained
R7, R8, R9, and R10 are independently hydrogen, deuterium, or C1-C6 alkyl.
The claim coverage centers on the method of treating the specified cancers by administering a compound of Formula (I), or a pharmaceutically acceptable salt, with the compound structure constrained by the defined Q1/Q2/Q3, X, Ring A, n, and R-group substituent scope.
Stated Advantages
CD73 inhibition is positioned as enabling immune re-sensitization and as potentially beneficial for infection and CNS disorders.
Adenosine signaling is described as driving immunosuppression and tumor immune escape and is linked to therapy resistance.
Documented Applications
Treating cancer in a subject, including lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, gallbladder cancer, prostate cancer, renal cancer, lymphoma, leukemia, and multiple myeloma.
Combination therapy with a second therapeutic agent, including a chemotherapeutic agent or an immunotherapy agent.
Administration with anti-emetic agents, epoetin-α, G-CSF/filgrastim, NSAIDs, and radiation therapy for localized tumors and for leukemia/lymphoma.
Treating infections, including viral or parasitic infections, and neurodegenerative diseases.
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