Cyclic amide-containing pyridyl xanthines as A2B antagonists

A method for treating an adenosine A2B receptor associated state in a subject, comprising:

• administering to the subject an effective amount of a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof:
• wherein:
• n is selected from 1-10, wherein the (CH2)n group is substituted with 0-1 groups selected from:
• C1-6 alkyl, C3-6 cycloalkyl, and —C1-3 alkylene-C3-6 cycloalkyl;
• Ring A is selected from phenyl, naphthyl, and a 5-10 membered heteroaryl;
• R1 is selected from:
• C1-6 alkyl, C3-6 cycloalkyl, —(CH2)2—OCH3, —(CH2)3—OCH3, —(CH2)4—OCH3, —(CH2)2—NH(C(O)CH3, and —C1-6 alkylene-4-10 membered cyclic amide;
• R2 is selected from:
• C1-6 alkyl, C3-6 cycloalkyl, —(CH2)2—OCH3, —(CH2)3—OCH3,
• —(CH2)4—OCH3, —(CH2)2—NH(C(O)CH3, and —C1-6 alkylene-4-10 membered cyclic amide;
• R3 is a 4-10 membered cyclic amide;
• R4 is selected from:
• H, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, —C1-3 alkylene-C3-6 cycloalkyl, OR6, SR6, —CN, NR6R7, CF3, OCF3, CO2R6, OC(O)R6, O2R6, C(O)NR6R7, OC(O)NR6R7, NR7COR6, NR7CO2R6, NR7C(O)NR6R7, and S(O)pNR6R7;
• R5 is selected from:
• H, F, Cl, Br, I, C1-6 alkyl, C3-6 cycloalkyl, —C1-3 alkylene-C3-6 cycloalkyl, OR6, SR6, —CN, NR6R7, CF3, OCF3, CO2R6, OC(O)R6, O2R6, C(O)NR6R7, OC(O)NR6R7, NR7COR6, NR7CO2R6, NR7C(O)NR6R7, and S(O)pNR6R7;
• R6 is independently selected from:
• H, C1-6 alkyl, C3-6 cycloalkyl, and,
• —C1-3 alkylene-C3-6 cycloalkyl;
• R7 is independently selected from:
• H, C1-6 alkyl, C3-6 cycloalkyl, and,
• —C1-3 alkylene-C3-6 cycloalkyl;
• and,
• p is independently selected from:
• 0, 1, and 2;
• alternatively, R4 and R5 are absent, and Ring A is replicated by a group selected from:
• C1-6 alkyl, CF3, C3-6 cycloalkyl, —CH2—OCH3, —(CH2)2—OCH3, —CH2—O-phenyl, and
• —CH2—O-pyridyl;
• alternatively, —(CH2)n—R3 is selected from:
• C1-6 alkyl, —C1-3 alkylene-C3-6 cycloalkyl,
• (CH2)2—OCH3, —(CH2)3—OCH3, and —(CH2)4—OCH3, provided that at least one of R1 and R2 is an amide-containing group independently selected from:
• —(CH2)2—NH(C(O)CH3 and —C1-6 alkylene-4-10 membered cyclic amide wherein the adenosine A2B receptor associated state is asthma, bronchoconstriction, pain, diabetic retinopathy, bladder cancer and breast cancer, and wherein treatment is inhibiting the adenosine A2B receptor associated state and/or relieving the adenosine A2B receptor associated state and/or ameliorating a symptom of the adenosine A2B receptor associated state.