Pyridone A2R antagonists
Inventors
Leleti, Manmohan Reddy • MANDAL, Debashis • MILES, Dillon Harding • Powers, Jay Patrick • Rosen, Brandon Reid • Sharif, Ehesan U I
Assignees
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Publication Number
US-12064433-B2
Publication Date
2024-08-20
Expiration Date
Abstract
Compound that inhibit at least one of the A2A and A2B adenosine receptors, and compositions containing the compound and methods for synthesizing the compound, are described herein. Also described are the use of such compounds and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer- and immune-related disorders that are mediated, at least in part, by the adenosine A2A receptor and/or the adenosine A2B receptor.
Core Innovation
The invention relates to a compound represented by Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, with defined structural variables including G1 and G2, R3a and R3b, and extensive substituent definitions for R1a, R1b, Y, R2, R4, X1, R5, R6, R7, R8, R9, X2, Z, R10a-R10d, R11, R12, Ra, Rb, Rc, Rd, and Re. The structure allows R1a and R1b together with the attached nitrogen to form a 5-6 membered heterocycloalkyl ring optionally containing additional ring vertices selected from O, N, and S, and specifies further constraints on ring substitution patterns and allowed heterocycloalkyl groups.
Within the Formula (I) framework, the disclosure includes sub-formulas such as (Ia) through (Ii) and additional variants with particular methoxy and R9/R10 patterns. The structural scope covers pyridone-based adenosine A2A and/or A2B receptor antagonists and specifies ring types including C3-8 cycloalkyl and heterocycloalkyl systems with 1-3 heteroatom ring vertices selected from O, N, and S, together with further constraints for substituent groups.
The invention also encompasses pharmaceutical compositions including the compound of Formula (I) together with a pharmaceutically acceptable excipient. It further provides methods for treating a disease, disorder, or condition mediated by adenosine A2A receptor and/or adenosine A2B receptor by administering a therapeutically acceptable amount of a compound of Formula (I) to a subject in need, including combination therapy with an immune checkpoint inhibitor that blocks PD1, PDL1, BTLA, LAG3, TIM-3, TIGIT, a B7 family member, or CTLA4.
Claims Coverage
The claim coverage centers on one independent Formula (I) compound claim with extensive structural constraints, plus dependent coverage for sub-formulas, methoxy-containing substituent patterns, pharmaceutical compositions, and therapeutic methods. Across the inputs, the coverage is organized around the compound family and receptor-mediated treatment contexts.
Formula (I) compound with defined substituent and heterocycle constraints
A compound represented by Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein G1 and G2 are N or CR3a and CR3b, R3a and R3b are each independently H or C1-3 alkyl, R1a and R1b are each independently selected from H, C1-8 alkyl optionally substituted with from 1-3 R5 substituents, —X1—O—C1-8 alkyl optionally substituted with from 1-3 R5 substituents, —C(O)—R6, Y optionally substituted with 1-3 R7 substituents, and —X1—Y optionally substituted with 1-3 R7 substituents, and R1a and R1b together with the nitrogen form a 5-6 membered heterocycloalkyl ring optionally substituted with from 1-3 R8 substituents and having 0-2 additional heteroatom ring vertices selected from O, N, and S, with further constraints for Y, R2, R4, X1, R5, R6, R7, R8, n, R9, X2, Z, R10a-R10d, R11, and R12.
Sub-formula variants within the Formula (I) family
A compound of the Formula (I) family as further specified by alternative sub-formulas (Ia through Ii) while maintaining pharmaceutically acceptable salt, hydrate, or solvate forms.
Methoxy-containing R10 pattern
The compound of the Formula (I) family wherein at least one of substituents R10a, R10b, and R10c is methoxy.
Pharmaceutical composition with a pharmaceutically acceptable excipient
A pharmaceutical composition comprising the compound of the Formula (I) family together with a pharmaceutically acceptable excipient.
Treating a disease mediated by adenosine A2A and/or adenosine A2B receptors
A method for treating a disease, disorder, or condition mediated by adenosine A2A receptor and/or adenosine A2B receptor by administering a therapeutically acceptable amount of a compound of the Formula (I) family to a subject in need.
Combination therapy with an immune checkpoint inhibitor
The method further includes an additional therapeutic agent that is an immune checkpoint inhibitor that blocks PD1, PDL1, BTLA, LAG3, TIM-3, TIGIT, a B7 family member, or CTLA4.
Overall, the claim coverage is concentrated on the structurally constrained Formula (I) compound family, with dependent refinements covering sub-formulas, methoxy-containing substituent patterns, pharmaceutical compositions, and therapeutic methods, including combination therapy with immune checkpoint inhibitors.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a disease, disorder, or condition mediated by adenosine A2A receptor and/or adenosine A2B receptor by administering a therapeutically acceptable amount of a compound represented by Formula (I) to a subject in need.
Combination therapy for treating a disease, disorder, or condition mediated by adenosine A2A receptor and/or adenosine A2B receptor with an additional therapeutic agent that is an immune checkpoint inhibitor blocking PD1, PDL1, BTLA, LAG3, TIM-3, TIGIT, a B7 family member, or CTLA4.
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