Dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
A compound according to Formula I: wherein R 1 , L A , Cy A , R A , R 2 , R 3 , and R 4 are as described herein. The present invention relates to novel compounds according to Formula I that antagonize GPR84, a G-protein-coupled receptor that is involved in inflammatory conditions, and methods for the production of these novel compounds, pharmaceutical compositions comprising these compounds, and methods for the prevention and/or treatment of inflammatory conditions, pain, neuroinflammatory conditions, neurodegenerative conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, cardiovascular diseases, leukemia, and/or diseases involving impairment of immune cell functions by administering a compound of the invention.
1. A compound according to Formula Va:
wherein
G 1 is
C 3-6 cycloalkyl optionally substituted with one or more independently selected halo, or
C 1-4 alkyl optionally substituted with one or more independently selected halo, —NR 7a R 7b , or C 1-4 alkoxy, which alkoxy is optionally substituted with one or more independently selected halo; and
each R 7a and R 7b is independently H or C 1-4 alkyl;
or a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof.
2. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein G 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one or more F.
3. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein G 1 is —CF 3 , —CHF 2 , —CH 2 —CHF 2 , —CH 2 —CF 3 , —CH 2 —CH 2 —N(CH 3 ) 2 , or —CH 2 —CH 2 —OCF 3 .
4. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable carrier.
5. A compound, or pharmaceutically acceptable salt thereof, wherein the compound is according to Formula Vb:
wherein
G 1 is
C 3-6 cycloalkyl optionally substituted with one or more independently selected halo, or
C 1-4 alkyl optionally substituted with one or more independently selected halo, —NR 7a R 7b , or C 1-4 alkoxy, which alkoxy is optionally substituted with one or more independently selected halo; and
each R 7a and R 7b is independently H or C 1-4 alkyl;
or a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof.
6. A compound or pharmaceutically acceptable salt thereof according to claim 5 , wherein G 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is substituted with one or more F.
7. A compound or pharmaceutically acceptable salt thereof according to claim 5 , wherein G 1 is —CF 3 , —CHF 2 , —CH 2 —CHF 2 , —CH 2 —CF 3 , —CH 2 —CH 2 —N(CH 3 ) 2 , or —CH 2 —CH 2 —OCF 3 .
8. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 5 , and a pharmaceutically acceptable carrier.
9. A compound, or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2,2,2-trifluoroethoxy)-6,7-dihydrobenzo[a]quinolizin-2-one;
9-(2-dimethylaminoethyloxy)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one;
9-(2,2-difluoroethoxy)-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-6,7-dihydrobenzo[a]quinolizin-2-one;
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-[2-(trifluoromethoxy)ethoxy]-6,7-dihydrobenzo[a]quinolizin-2-one;
4-(1,4-dioxan-2-ylmethoxy)-1-methyl-9-(2,2,2-trifluoro ethoxy)-6,7-dihydrobenzo[a]quinolizin-2-one;
3-deuterio-4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(1,1,2,2-tetradeuterio-2-fluoro-ethoxy)-6,7-dihydrobenzo[a]quinolizin-2-one; or
4-[[(2S)-1,4-dioxan-2-yl]methoxy]-1-methyl-9-(2,2,3,3,3-pentafluoropropoxy)-6,7-dihydrobenzo[a]quinolizin-2-one.
10. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 9 , and a pharmaceutically acceptable carrier.