Dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
A compound according to Formula Ia: wherein L 1 , G, and R 1 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 (for example inflammatory bowel diseases (IBD), rheumatoid arthritis, vasculitis, lung diseases (e.g. chronic obstructive pulmonary disease (COPD) and lung interstitial diseases (e.g. idiopathic pulmonary fibrosis (IPF))), neuroinflammatory conditions, infectious diseases, autoimmune diseases, endocrine and/or metabolic diseases, and/or diseases involving impairment of immune cell functions by administering a compound of the invention.
1. A compound according to Formula IIIa:
wherein
L 1 is absent;
W is C 1-4 alkylene, C 2-4 alkenylene having one double bond, or C 2-4 alkynylene having one triple bond;
L 2 is absent or is —O—;
R 2 is C 3-7 cycloalkyl optionally substituted with one R 5 group,
R 5 is oxo or R 6 ; and
R 6 is selected from OH and C 1-6 alkyl,
or a pharmaceutically acceptable salt, or a solvate, or a solvate of the pharmaceutically acceptable salt thereof.
2. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein W is C 2-4 alkynylene having one triple bond.
3. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 2 is C 3-7 cycloalkyl.
4. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is selected from:
9-Cyclopentylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2([1,4]Dioxan-2-ylmethoxy)-9-(1-hydroxy-cyclopentylethynyl)- 6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopentyloxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopentyloxymethyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-([1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9(2-Cyclopropyl-ethynyl) -2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopentyloxymethyl-2-((R)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9(2-Cyclopropyl-ethyl)-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
9-Cyclopentyloxymethyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one,
2-((S)-1-[1,4]Dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one, and
2-((R)-1-[1,4]Dioxan-2-ylmethoxy)-9-[2-(1-hydroxy-cyclopentyl)-ethyl]-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one.
5. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof, according to claim 1 , and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition according to claim 5 comprising a further therapeutic agent.
7. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
8. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is according to Formula Va:
wherein R 2 is C 3-7 cycloalkyl optionall substituted with one R 5 group,
R 5 is oxo or R 6 ; and
R 6 is selected from —OH and C 1-6 alkyl.
9. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is according to Formula Vb:
wherein R 2 is C 3-7 cycloalkyl optionally substituted with one R 5 group;
R 5 is oxo or R 6 ; and
R 6 is selected from —OH and C 1-6 alkyl.