Alkoxy-carbonyl-amino-alkynyl-adenosine compounds and derivatives thereof as A2AR agonists

A compound of formula Ib:

• wherein:
• R1′ and R2′ independently are selected from:
• H, C1-8 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C4-10 heterocycle, (C4-10 heterocycle)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• R3′ is —C1-8 alkyl-;
• R4′ and R4″ are independently selected from:
• H, —C2-6 alkyl-ORa′, —C2-6 alkyl-NRa′Rb′, C1-10 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• R5′ is selected from:
• C1-8 alkyl, —C2-6 alkyl-NRa′Rb′, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C4-10 heterocycle, (C4-10 heterocycle)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, —C2-6 alkyl-ORa′ and (C5-10 heteroaryl)C1-8 alkyl-;
• X′ is selected from:
• —CH2ORc′, —OCO2Rc′, —OCH2OC(O)Rc′, —C(O)NRc′Rd′, —CH2SRc′, —C(S)ORc′, —CH2OC(S)Rc′, C(S)NRc′Rd′ and —CH2NRc′Rd′;
• or X′ is a C5-6 heteroaryl;
• Ra′ and Rb′ are each independently selected from H, C1-8 alkyl, (C1-8 alkoxy)1-3C1-8 alkyl-, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• or Ra′ and Rb′, together with the nitrogen to which they are attached, form a ring selected from pyrrolidino, piperidino, morpholino, and thiomorpholino ring;
• Rc′ is selected from:
• H, C1-8 alkyl, C3-6 cycloalkyl, and (C3-6 cycloalkyl)C1-8 alkyl-;
• and
• Rd′ is selected from:
• H, C1-8 alkyl, (C1-8 alkoxy)1-3C1-8 alkyl-, C3-8 cycloalkyl, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• and stereoisomers or pharmaceutically acceptable salts thereof.

A method for achieving an effect in a subject comprising administering to the subject an effective amount of a compound of formula Ia:

• wherein:
• R1 and R2 independently are selected from:
• H, C1-8 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C4-10 heterocycle, (C4-10 heterocycle)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• R3 is —C1-8 alkyl-;
• R4 is independently selected from:
• H, —C2-6 alkyl-ORa, —C2-6 alkyl-NRaRb, C1-10 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• R5 is selected from:
• C1-8 alkyl, —C2-6 alkyl-NRaRb, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C4-10 heterocycle, (C4-10 heterocycle)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, —C2-6 alkyl-ORa and (C5-10 heteroaryl)C1-8 alkyl-;
• X is selected from:
• —CH2ORc, —OCO2Rc, —OCH2OC(O)Rc, —C(O)NRcRd, —CH2SRc, —C(S)ORc, —CH2OC(S)Rc, C(S)NRcRd and —CH2NRcRd;
• or X is a C5-6 heteroaryl;
• Ra and Rb are each independently selected from H, C1-8 alkyl, (C1-8 alkoxy)1-3C1-8 alkyl-, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• or Ra and Rb, together with the nitrogen to which they are attached, form a ring selected from pyrrolidino, piperidino, morpholino, and thiomorpholino ring;
• Rc is selected from:
• H, C1-8 alkyl, C3-6 cycloalkyl, and (C3-6 cycloalkyl)C1-8 alkyl-;
• and
• Rd is selected from:
• H, C1-8 alkyl, (C1-8 alkoxy)1-3C1-8 alkyl-, C3-8 cycloalkyl, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• and
• stereoisomers or pharmaceutically acceptable salts thereof, wherein the effect is A2A receptor agonism.

A method for achieving an effect in a subject comprising administering to the subject an effective amount of a compound of formula Ib

• wherein:
• R1′ and R2′ independently are selected from:
• H, C1-8 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C4-10 heterocycle, (C4-10 heterocycle)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• R3′ is —C1-8 alkyl-;
• R4′ and R4″ are independently selected from:
• H, —C2-6-alkyl-ORa″, C2-6 alkyl-NRa′Rb′, C1-10 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• R5′ is selected from:
• C1-8 alkyl, —C2-6 alkyl-NRa′Rb′, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C4-10 heterocycle, (C4-10 heterocycle)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, —C2-6 alkyl-ORa′ and (C5-10 heteroaryl)C1-8 alkyl-;
• X′ is selected from:
• —CH2ORc′, —OCO2Rc′, —OCH2OC(O)Rc′, —C(O)NRc′Rd′, —CH2SRc′, —C(S)ORc′, —CH2OC(S)Rc′, C(S)NRc′Rd′ and —CH2NRc′Rd′;
• or X′ is a C5-6 heteroaryl;
• Ra′ and Rb′ are each independently selected from H, C1-8 alkyl, (C1-8 alkoxy)1-3C1-8 alkyl-, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• or Ra′ and R″, together with the nitrogen to which they are attached, form a ring selected from pyrrolidino, piperidino, morpholino, and thiomorpholino ring;
• Rc′ is selected from:
• H, C1-8 alkyl, C3-6 cycloalkyl, and (C3-6 cycloalkyl)C1-8 alkyl-;
• and Rd′ is selected from:
• H, C1-8 alkyl, (C1-8 alkoxy)1-3C1-8 alkyl-, C3-8 cycloalkyl, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• and stereoisomers or pharmaceutically acceptable salts thereof, wherein the effect is A2A receptor agonism.

A method of reducing intraocular pressure in a subject comprising administering to the subject an effective amount of a compound of formula Ia

• wherein:
• R1 and R2 independently are selected from:
• H, C1-8 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C4-10 heterocycle, (C4-10 heterocycle)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• R3 is —C1-8 alkyl-;
• R4 is independently selected from:
• H, —C2-6 alkyl-ORa, —C2-6 alkyl-NRaRb, C1-10 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• R5 is selected from:
• C1-8 alkyl, —C2-6 alkyl-NRaRb, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C4-10 heterocycle, (C4-10 heterocycle)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, —C2-6 alkyl-ORa and (C5-10 heteroaryl)C1-8 alkyl-;
• X is selected from:
• —CH2ORc, —OCO2Rc, —OCH2OC(O)Rc, —C(O)NRcRd, —CH2SRc, —C(S)ORc, —CH2OC(S)Rc, C(S)NRcRd and —CH2NRcRd;
• or X is a C5-6 heteroaryl;
• Ra and Rb are each independently selected from H, C1-8 alkyl, (C1-8 alkoxy)1-3C1-8 alkyl-, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• or Ra and Rb, together with the nitrogen to which they are attached, form a ring selected from pyrrolidino, piperidino, morpholino, and thiomorpholino ring;
• Rc is selected from:
• H, C1-8 alkyl, C3-6 cycloalkyl, and (C3-6 cycloalkyl)C1-8 alkyl-;
• and
• Rd is selected from:
• H, C1-8 alkyl, (C1-8 alkoxy)1-3C1-8 alkyl-, C3-8 cycloalkyl, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• or stereoisomers or pharmaceutically acceptable salts thereof,
• formula Ib
• wherein:
• R1′ and R2′ independently are selected from:
• H, C1-8 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C4-10 heterocycle, (C4-10 heterocycle)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• R3′ is —C1-8 alkyl-;
• R4′ and R4″ are independently selected from:
• H, —C2-6-alkyl-ORa′, —C2-6 alkyl-NRa′Rb′, C1-10 alkyl, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• R5′ is selected from:
• C1-8 alkyl, —C2-6 alkyl-NRa′Rb′, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C4-10 heterocycle, (C4-10 heterocycle)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, —C2-6 alkyl-ORa′ and (C5-10 heteroaryl)C1-8 alkyl-;
• X′ is selected from:
• —CH2ORc′, —OCO2Rc′, —OCH2OC(O)Rc′, —C(O)NRc′Rd′, —CH2SRc′, —C(S)ORc′, —CH2OC(S)Rc′, C(S)NRc′Rd′ and —CH2NRc′Rd′;
• or X′ is a C5-6 heteroaryl;
• Ra′ and Rb′ are each independently selected from H, C1-8 alkyl, (C1-8 alkoxy)1-3C1-8 alkyl-, C3-8 cycloalkyl, (C3-8 cycloalkyl)C1-8 alkyl-, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• or Ra′ and Rb′, together with the nitrogen to which they are attached, form a ring selected from pyrrolidino, piperidino, morpholino, and thiomorpholino ring;
• Rc′ is selected from:
• H, C1-8 alkyl, C3-6 cycloalkyl, and (C3-6 cycloalkyl)C1-8 alkyl-;
• and Rd′ is selected from:
• H, C1-8 alkyl, (C1-8 alkoxy)1-3C1-8 alkyl-, C3-8 cycloalkyl, C6-10 aryl, (C6-10 aryl)C1-8 alkyl-, C5-10 heteroaryl, and (C5-10 heteroaryl)C1-8 alkyl-;
• or stereoisomers or pharmaceutically acceptable salts thereof,
• or formula I
• wherein
• R6 is hydrogen, C1-8 alkyl, or C3-6 cycloalkyl,
• R7 is hydrogen atom or C1-10 alkyl;
• R8 is C1-8 alkyl, C3-8 cycloalkyl, unsubstituted phenyl, or a phenyl substituted with at least a halogen atom or -G-O—R9;
• R9 is alkyl, cycloalkyl, phenyl, (cycloalkyl)alkyl, or (phenyl)alkyl;
• and G is alkylene;
• or stereoisomers or pharmaceutically acceptable salts thereof,
• such that the intraocular pressure is reduced.