Compounds and methods for modulating adenosine A2B receptor and adenosine A2A receptor
Inventors
Li, Zhihong • Filonova, Lubov Konstantinovna • Bradley, Erin Kathleen • Verner, Erik
Assignees
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Publication Number
US-11254686-B1
Publication Date
2022-02-22
Expiration Date
Abstract
Disclosed herein, inter alia, are certain substituted thieno[3,2-b]pyrimidine compositions and methods for modulating Adenosine Receptors, for example, having the formula:
Core Innovation
The invention relates to a compound having a formula in which Ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, and Ring B is heterocycloalkyl. The formula further includes L1 as substituted or unsubstituted C1-C3 alkylene, together with variable substituent groups R1, R4, R5, and R6, and integer parameters z1 from 0 to 5 and z6 from 1 to 10.
The substituent space is broadly defined by enumerated halogen, fluorinated, oxygen-containing, nitrogen-containing, sulfur-containing, carbonyl-containing, cyano, hydroxy, amino, carboxylic acid, and related alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl options. The definitions also allow optional bonding of substituents on the same nitrogen atom to form substituted or unsubstituted heterocycloalkyl.
The document further provides thieno[3,2-d]pyrimidine derivatives and analogs, including carboxamide, carboxylate, and methanone derivatives, stereochemical variations at amine substituents, and variations in pyrrolidinyl, piperidinyl, azetidinyl, imidazolidine, piperazine, and related cyclic amine motifs. The examples include fluoropyridyl and pyridinyl side-chain variations, Boc-carbamates, acetamides, and other substituted core compounds, with reported characterization data and example labels across multiple compound series.
Claims Coverage
The claims cover a broad formula-defined compound class with Ring A selected from five aromatic or heteroaromatic options, Ring B as heterocycloalkyl, L1 as substituted or unsubstituted C1-C3 alkylene, broad variable substituent definitions for R1, R4, R5, and R6, and integer constraints on z1 and z6. Dependent claims further narrow Ring B, constrain z1 and z6, and include a pharmaceutical composition embodiment.
Structural formula with Ring A and Ring B selection
A compound having the formula wherein Ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, and Ring B is heterocycloalkyl.
L1 and integer parameter constraints
L1 is substituted or unsubstituted C1-C3 alkylene; z1 is an integer from 0 to 5; and z6 is an integer from 1 to 10.
Broad R1 substituent set
R1 is independently halogen, fluorinated and halogenated groups, cyano, hydroxyl, amino-related groups, carboxy and amide-related groups, nitro, thiol, sulfonyl/sulfonic-acid-like groups, or substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
R4 and R5 substituent definitions
R4 is hydrogen, —CX4X3, —NR4AR4B, or substituted or unsubstituted C1-C6 alkyl; and R5 is hydrogen or substituted or unsubstituted C1-C6 alkyl.
R6 substituent class
R6 is independently halogen, —CX6X3, —CHX6X2, —CH2X6, —OCX6X3, —OCH2X6, —OCHX6X2, —CN, —SR6D, —SO2R6D, —NR6AR6B, —C(O)R6C, —C(O)OR6C, —C(O)NR6AR6B, —C(O)NR6AOR6B, —OR6D, —NR6AC(O)R6C, —NR6AC(O)OR6C, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
Optional nitrogen-linked heterocycloalkyl formation
R1A and R1B, R4A and R4B, and R6A and R6B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl.
Halogen definition for X1, X4, and X6
Each X1, X4, and X6 is independently F, Cl, Br, or I.
Dependent narrowing to specific Ring B options
Ring B is substituted as either pyrrolidinyl or piperidinyl.
Discrete z1 and fixed z6 values
z1 takes a value of 0, 1, or 2, and z6 equals 2.
Pharmaceutical composition including pharmaceutically acceptable excipient
A pharmaceutical composition that includes the compound together with a pharmaceutically acceptable excipient.
Overall, the claim coverage centers on a structural formula with Ring A selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, Ring B as heterocycloalkyl, and multiple variable substituent positions governed by defined group lists and the integer parameters z1 and z6. Dependent claims further narrow Ring B, restrict R1 options, constrain z1 and z6, and extend coverage to a pharmaceutical composition including a pharmaceutically acceptable excipient.
Stated Advantages
Inhibits adenosine A2A receptor activity and adenosine A2B receptor activity.
Provides ratio-based inhibition relationships involving A2B:A2A and comparisons with A2B:A3 and A2B:A1.
The series is described as being prepared and characterized, including 1H NMR and LCMS characterization, with reported yields for the labeled compounds.
The document includes metabolic and drug-interaction metrics, including CYP3A and CYP2D inhibition indices, and at least one IC50 value for CYP3A inhibition.
Documented Applications
Treating cancer.
Treating fibrotic disease, including pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF).
Treating neurodegenerative disease, including Alzheimer's disease and Parkinson's disease.
Methods treating cancer, fibrotic disease, and neurodegenerative disease by contacting adenosine A2A and/or adenosine A2B receptor proteins with the described compounds.
Embodiment examples are provided that define specific Ring A/R1 substituent combinations and Ring B/R6 heterocycloalkyl examples, illustrating concrete instantiations of the claimed scaffold substituents and linkage positions.
The disclosure includes preparation and characterization of thieno[3,2-d]pyrimidine derivatives and key intermediates supporting the compound series.
Metabolic and drug-interaction evaluation is reported using CYP3A and CYP2D inhibition indices, with species-dependent exposure values including rat and human, and in one case dog and monkey.
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