Adenosine receptor ligands

A compound of formula I

• 12
• wherein
• R1 is selected from (RS)-[1,4]dioxan-2-yl-, (R)-[1,4]dioxan-2-yl-, and (S)-[1,4]dioxan-2-yl-;
• R2 is
• a) —(CH2)n-pyridin-2, 3 or 4-yl, or
• —(CH2)n-pyridin-2, 3 or 4-yl substituted by
• -lower alkyl,
• —(CH2)m—O-lower alkyl,
• —(CH2)mNR′R″,
• —(CH2)mmorpholinyl,
• —(CH2)m-pyrrolidin-1-yl,
• —(CH2)m-piperidine-1-yl,
• —(CH2)m-piperidine-1-yl substituted by hydroxy,
• —(CH2)m—O—(CH2)o—CF3,
• —(CH2)n—O—(CH2)m-cycloalkyl,
• —(CH2)m—O—(CH2)n—O-lower alkyl,
• —(CH2)m—O—(CH2)m—O-2-oxo-pyrrolidin-1-yl,
• —(CH2)m—O-tetrahydropyran-4-yl,
• —(CH2)m—O—(CH2)o-morpholinyl,
• -di-hydropyran-4-yl,
• -tetra-hydropyran-4-yl,
• -azetidin-1-yl, or
• -azetidin-1-yl substituted by halogen, lower alkoxy or hydroxy;
• or
• b) —(CH2)n-piperidine-1-yl, or
• —(CH2)n-piperidine-1-yl substituted by one or two substituents selected from
• -hydroxy, -hydroxy-lower alkyl, -lower alkyl and —(CH2)m—O-lower alkyl;
• or
• c) —(CH2)n-phenyl, or
• —(CH2)n-phenyl substituted by one or two substituents selected from
• -halogen, -lower allyl, -lower alkoxy and —(CH2)n—NR′R″;
• or
• d) -benzo[1.3]dioxol-5-yl;
• —(CH2)n-morpholinyl;
• —(CH2)n-tetrahydropyran-4-yl;
• —(CH2)n—O-lower alkyl;
• —(CH2)n-cycloalkyl;
• —(CH2)n—C(O)—NR′R″;
• —(CH2)n-2-oxo-pyrrolidin-1-yl;
• —(CH2)nNR′R″;
• -2-oxa-5-aza-bicyclo[2.2.1]heptane-5-yl;
• or
• -1-oxa-8-aza-spiro[4.5]decane-8-yl;
• R′ and R″ are each independently selected from lower alkyl;
• —(CH2)o—O-lower alkyl;
• cycloalkyl;
• lower alkyl substituted by hydroxy, —(CH2)o—O-lower alkyl substituted by hydroxy;
• and cycloalkyl substituted by hydroxy,
• n is 0, 1, 2 or 3;
• m is 0 or 1;
• and
• o is 1 or 2;
• or a pharmaceutically acceptable salt thereof.

A process for preparing a compound of formula I

• 13
• wherein
• R1 is selected from (RS)-[1,4]dioxan-2-yl-, (R)-[1,4]dioxan-2-yl-, and (S)-[1,4]dioxan-2-yl-;
• R2 is
• a) —(CH2)n-pyridin-2,3 or 4-yl, or
• —(CH2)m-pyridin-2, 3 or 4-yl substituted by
• -lower alkyl,
• —(CH2)m—O-lower alkyl,
• —(CH2)mNR′R″,
• —(CH2)mmorpholinyl,
• —(CH2)m-pyrrolidin-1-yl,
• —(CH2)m-piperidine-1-yl,
• —(CH2)m-piperidine-1-yl substituted by hydroxy,
• —(CH2)m—O—(CH2)o—CF3,
• —(CH2)n—O—(CH2)m-cycloalkyl,
• —(CH2)n—O—(CH2)o—O-lower alkyl,
• —(CH2)n—O—(CH2)o-2-oxo-pyrrolidin-1-yl,
• —(CH2)m—O-tetrahydropyran-4-yl,
• —(CH2)n—O—(CH2)o-morpholinyl,
• -di-hydropyran-4-yl,
• -tetra-hydropyran-4-yl
• -azetidin-1-yl, or
• -azetidin-1-yl substituted by halogen, lower alkoxy or hydroxy;
• or
• b) —(CH2)n-piperidine-1-yl, or
• —(CH2)n-piperidine-1-yl substituted by one or two substituents selected from
• -hydroxy, -hydroxy-lower alkyl, -lower alkyl and —(CH2)m—O-lower alkyl;
• or
• c) —(CH2)n-phenyl, or
• —(CH2)n-phenyl substituted by one or two substituents selected from
• -halogen, -lower alkyl, -lower alkoxy and —(CH2)n—NR′R″;
• or
• d) -benzo[1.3]dioxol-5-yl;
• —(CH2)n-morpholinyl;
• —(CH2)n-tetrahydropyran-4-yl;
• —(CH2)n—O-lower alkyl;
• —(CH2)n-cycloalkyl;
• —(CH2)n—C(O)—NR′R″;
• —(CH2)n-2-oxo-pyrrolidin-1-yl;
• —(CH2)nNR′R″;
• -2-oxa-5-aza-bicyclo[2.2.1]heptane-5-yl;
• or
• -1-oxa-8-aza-spiro [4.5]decane-8-yl;
• R′ and R″ are each independently selected from lower alkyl;
• —(CH2)o—O-lower alkyl;
• cycloalkyl;
• lower alkyl substituted by one or more substituents selected from hydroxy and lower alkyl;
• —(CH2)o—O-lower alkyl substituted by one or more substituents selected from hydroxy and lower alkyl;
• and cycloalkyl substituted by one or more substituents selected from hydroxy and lower alkyl;
• n is 0, 1, 2 or 3;
• m is o or 1;
• and
• o is 1 or 2;
• or a pharmaceutically acceptable salt thereof,
• which process comprises
• a) reacting a compound of formula 5
• 14
• with a compound of formula
• ClC(O)R2/base (6)
• or with a compound of formula
• HOC(O)R2/HATU/base (7)
• to produce a compound of formula I
• 15
• wherein R1 is as defined above,

A process for preparing a compound of formula I

• 16
• wherein
• R1 is selected from (RS)-[1,4]dioxan-2-yl-, (R)-[1,4]dioxan-2-yl-, and (S)-[1,4]dioxan-2-yl-;
• R2 is
• a) —(CH2)n-pyridin-2,3 or 4-yl, or
• —(CH2)n-pyridin-2,3 or 4-yl substituted by
• -lower alkyl,
• —(CH2)m—O-lower alkyl,
• —(CH2)mNR′R″,
• —(CH2)mmorpholinyl,
• —(CH2)m-pyrrolidin-1-yl,
• —(CH2)m-piperidine-1-yl,
• —(CH2)m-piperidine-1-yl substituted by hydroxy,
• —(CH2)m—O—(CH2)o—CF3,
• —(CH2)n—O—(CH2)m-cycloalkyl,
• —(CH2)m—O—(CH2)n—O-lower alkyl,
• —(CH2)m—O—(CH2)o-2-oxo-pyrrolidin-1-yl,
• —(CH2)n—O-tetrahydropyran-4-yl,
• —(CH2)n—O—(CH2)o-morpholinyl,
• -di-hydropyran-4-yl,
• -tetra-hydropyran-4-yl
• -azetidin-1-yl, or
• -azetidin-1-yl substituted by halogen, lower alkoxy or hydroxy, or
• b) —(CH2)n-piperidine-1-yl, or
• —(CH2)n-piperidine-1-yl substituted by one or two substituents selected from
• -hydroxy, -hydroxy-lower alkyl, -lower alkyl and —(CH2)m—O-lower alkyl;
• or
• c) —(CH2)n-phenyl, or
• —(CH2)n-phenyl substituted by one or two substituents selected from
• -halogen, -lower alkyl, -lower alkoxy and —(CH2)n—NR′R″;
• or
• d) -benzo[1.3]dioxol-5-yl;
• —(CH2)n-morpholinyl;
• —(CH2)n-tetrahydropyran-4-yl;
• —(CH2)n—O-lower alkyl;
• —(CH2)n-cycloalkyl;
• —(CH2)n—C(O)—NR′R″;
• —(CH2)n-2-oxo-pyrrolidin-1-yl;
• —(CH2)nNR′R″;
• -2-oxa-5-aza-bicyclo[2.2.1]heptane-5-yl;
• or
• -1-oxa-8-aza-spiro [4.5]decane-8-yl;
• R′ and R″ are each independently selected from lower alkyl;
• —(CH2)o—O-lower alkyl;
• cycloalkyl;
• lower alkyl substituted by one or more substituents selected from hydroxy and lower alkyl;
• —(CH2)o—O-lower alkyl substituted by one or more substituents selected from hydroxy and lower alkyl;
• and cycloalkyl substituted by one or more substituents selected from hydroxy and lower alkyl;
• n is 0, 1, 2 or 3;
• m is 0 or 1;
• and
• o is 1 or 2;
• or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula 8
• 17
• with a compound of formula
• HR2/base (9)
• to produce a compound of formula I
• 18
• wherein R1 is as defined above.

A process for preparing a compound of formula I

• 19
• wherein
• R1 is selected from (RS)-[1,4]dioxan-2-yl-, (R)-[1,4]dioxan-2-yl-, and (S)-[1,4]dioxan-2-yl-;
• R2 is
• a) —(CH2)n-pyridin-2,3 or 4-yl, or
• —(CH2)n-pyridin-2, 3 or 4-yl substituted by
• -lower alkyl,
• —(CH2)m—O-lower allyl,
• —(CH2)mNR′R″,
• —(CH2)mmorpholinyl,
• —(CH2)m-pyrrolidin-1-yl,
• —(CH2)m-piperidine-1-yl,
• —(CH2)m-piperidine-1-yl substituted by hydroxy,
• —(CH2)m—O—(CH2)o-CF3,
• —(CH2)n—O—(CH2)m-cycloalkyl,
• —(CH2)m—O—(CH2)n—O-lower alkyl,
• —(CH2)m—O—(CH2)o-2-oxo-pyrrolidin-1-yl,
• —(CH2)m—O-tetrahydropyran-4-yl,
• —(CH2)m—O—(CH2)o-morpholinyl,
• -di-hydropyran-4-yl,
• -tetra-hydropyran-4-yl
• -azetidin-1-yl, or
• azetidin-1-yl substituted by halogen, lower alkoxy or hydroxy, or
• b) —(CH2)n-piperidine-1-yl, or
• —(CH2)n-piperidine-1-yl substituted by one or two substituents selected from
• -hydroxy, -hydroxy-lower alkyl, -lower alkyl and —(CH2)m—O-lower alkyl;
• or
• c) —(CH2)n-phenyl, or
• —(CH2)n-phenyl substituted by one or two substituents selected from
• -halogen, -lower alkyl, -lower alkoxy and —(CH2)n—NR′R″;
• or
• d) -benzo[1.3]dioxol-5-yl;
• —(CH2)n-morpholinyl;
• —(CH2)n-tetrahydropyran-4-yl;
• —(CH2)n—O-lower alkyl;
• —(CH2)n-cycloalkyl;
• —(CH2)n—C(O)—NR′R″;
• —(CH2)n-2-oxo-pyrrolidin-1-yl;
• —(CH2)nNR′R″;
• -2-oxa-5-aza-bicyclo[2.2.1]heptane-5-yl;
• or
• -1-oxa-8-aza-spiro [4.5]decane-8-yl;
• R′ and R″ are each independently selected from lower alkyl;
• —(CH2)o—O-lower alkyl;
• cycloalkyl;
• lower alkyl substituted by one or more substituents selected from hydroxy and lower alkyl;
• —(CH2)o—O-lower alkyl substituted by one or more substituents selected from hydroxy and lower alkyl;
• and cycloalkyl substituted by one or more substituents selected from hydroxy or lower alkyl;
• n is 0, 1, 2 or 3;
• m is 0 or 1;
• and
• o is 1 or 2;
• or a pharmaceutically acceptable salt thereof, which process comprises separating a racemic compound of formula I into its (R)- and (S)-enantiomers.

A pharmaceutical composition which comprises a compound of formula I

• 20
• wherein
• R1 is selected from (RS)-[1,4]dioxan-2-yl-, (R)-[1,4]dioxan-2-yl-, and (S)-[1,4]dioxan-2-yl-;
• R2 is
• a) —(CH2)n-pyridin-2,3 or 4-yl, or
• —(CH2)n-pyridin-2,3 or 4-yl substituted by
• -lower alkyl,
• —(CH2)m—O-lower alkyl,
• —(CH2)mNR′R″,
• —(CH2)mmorpholinyl,
• —(CH2)m-pyrrolidin-1-yl,
• —(CH2)m-piperidine-1-yl,
• —(CH2)m-piperidine-1-yl substituted by hydroxy,
• —(CH2)m—O—(CH2)n—CF3,
• —(CH2)m—O-(CH2)m-cycloalkyl,
• —(CH2)m—O—(CH2)o—O-lower alkyl,
• —(CH2)m—O—(CH2)o-2-oxo-pyrrolidin-1-yl,
• —(CH2)m—O-tetrahydropyran-4-yl,
• —(CH2)m—O—(CH2)o-morpholinyl,
• -di-hydropyran-4-yl,
• -tetra-hydropyran-4-yl
• -azetidin-1-yl, or
• -azetidin-1-yl substituted by halogen, lower alkoxy or hydroxy;
• or
• b) —(CH2)n-piperidine-1-yl, or
• —(CH2)n-piperidine-1-yl substituted by one or two substituents selected from
• -hydroxy, -hydroxy-lower alkyl, -lower alkyl and —(CH2)m—O-lower alkyl;
• or
• c) —(CH2)n-phenyl, or
• —(CH2)n-phenyl substituted by one or two substituents selected from
• -halogen, -lower alkyl, -lower alkoxy and —(CH2)n—NR′R″;
• or
• d) -benzo[1.3]dioxol-5-yl;
• —(CH2)n-morpholinyl;
• —(CH2)n-tetrahydropyran-4-yl;
• —(CH2)n—O-lower alky;
• —(CH2)n-cycloalkyl;
• —(CH2)n—C(O)—NR′R″;
• —(CH2)n-2-oxo-pyrrolidin-1-yl;
• —(CH2)nNR′R″;
• -2-oxa-5-aza-bicyclo[2.2.1]heptane-5-yl;
• or
• -1-oxa-8-aza-spiro [4.5]decane-8-yl;
• R′ and R″ are each independently selected from lower alkyl;
• —(CH2)o—O-lower alkyl;
• cycloalkyl;
• lower alkyl substituted by one or more substituents selected from hydroxy and lower alkyl;
• —(CH2)o—O-lower alkyl substituted by one or more substituents selected from hydroxy and lower alkyl, and cycloalkyl substituted by one or more substituents selected from hydroxy or lower alkyl;
• 5 n is 0, 1, 2 or 3;
• m is 0 or 1;
• and o is 1 or 2;
• or a pharmaceutically acceptable salt thereof,
• and a pharmaceutically acceptable excipient.

A method of treating a disease based on adenosine A2a receptor activity comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of formula I

• 21
• wherein
• R1 is selected from (RS)-[1,4]dioxan-2-yl-, (R)-[1,4]dioxan-2-yl-, and (S)-[1,4]dioxan-2-yl-;
• R2 is
• a) —(CH2)n-pyridin-2, 3 or 4-yl, or
• —(CH2)n-pyridin-2,3 or 4-yl substituted by
• -lower alkyl,
• —(CH2)m—O-lower alkyl,
• —(CH2)mNR′R″,
• —(CH2)mmorpholinyl,
• —(CH2)m-pyrrolidin-1-yl,
• —(CH2)m-piperidine-1-yl,
• —(CH2)m-piperidine-1-yl substituted by hydroxy,
• —(CH2)n—O—(CH2)n—CF3,
• —(CH2)n—O—(CH2)m-cycloalkyl,
• —(CH2)n—O—(CH2)o—O-lower alkyl,
• —(CH2)m—O(CH2)o-2-oxo-pyrrolidin-1-yl,
• —(CH2)m—O-tetrahydropyran-4-yl,
• —(CH2)n—O—(CH2)o-morpholinyl,
• -di-hydropyran-4-yl,
• -tetra-hydropyran-4-yl
• -azetidin-1-yl, or
• -azetidin-1-yl substituted by halogen, lower alkoxy or hydroxy, or
• b) —(CH2)n-piperidine-1-yl, or
• —(CH2)n-piperidine-1-yl substituted by one or two substituents selected from
• -hydroxy, -hydroxy-lower alkyl, -lower alkyl and —(CH2)m—O-lower alkyl;
• or
• c) (CH2)n-phenyl, or
• —(CH2)n-phenyl substituted by one or two substituents selected from
• -halogen, -lower alkyl, -lower alkoxy and —(CH2)n—NR′R″;
• or
• d) -benzo[1.3]dioxol-5-yl;
• —(CH2)n-morpholinyl;
• —(CH2)n-tetrahydropyran-4-yl;
• —(CH2)n—O-lower alkyl;
• —(CH2)n-cycloalkyl;
• —(CH2)n—C(O)—NR′R″;
• —(CH2)n-2-oxo-pyrrolidin-1-yl;
• —(CH2)n NR′R″;
• -2-oxa-5-aza-bicyclo[2.2.1]heptane-5-yl;
• or
• -1-oxa-8-aza-spiro [4.5]decane-8-yl;
• R′ and R″ are each independently selected from lower alkyl;
• —(CH2)o—O-lower alkyl;
• cycloalkyl;
• lower alkyl substituted by one or more substituents selected from hydroxy and lower alkyl;
• —(CH2)o—O-lower alkyl substituted by one or more substituents selected from hydroxy and lower allyl;
• and cycloalkyl substituted by one or more substituents selected from hydroxy or lower alkyl;
• 6 n is 0, 1, 2 or 3;
• m is 0 or 1;
• and o is 1 or 2;
• or a pharmaceutically acceptable salt thereof.