Heteroaromatic Compounds and their Use as Dopamine D1 Ligands

Abstract

The present invention provides, in part, compounds of Formula I: and pharmaceutically acceptable salts thereof and N-oxides thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds (N-oxides thereof or or pharmaceutically acceptable salts of the compound or the N-oxides) and the uses of such compounds (N-oxides thereof or or pharmaceutically acceptable salts of the compound or the N-oxides) for the treatment of D1-mediated (or D1-associated) disorders including cognitive and motivational impairments and negative symptoms associated with illnesses such as schizophrenia, depression, bipolar disorder, Parkinson's disease, Mild cognitive impairment (MCI), Alzheimer's disease, lupus, Huntington's disease, Parkinson's, dyskinesia, ADHD, post-traumatic stress disorder, autism spectrum disorder, treatment-resistant depression, major depressive disorder (MDD), drug dependence, Tourette's syndrome, tardive dyskinesias as well as impairments associated with age, chronic stress, sleep deprivation, combat, chronic fatigue; endocrine or metabolic diseases such as hyperglycemia, dislipidemia, diabetes, obesity, and sepsis; and cardiovascular disorder such as hypertension. The present invention further provides a D1 agonist with reduced D1R desensitization, a D1 agonist with a reduced β-arrestin recruitment activity relative to Dopamine, a D1 agonist interacting significantly with the Ser188 but not significantly with the Ser202 of a D1R when binding to the D1R, a D1 agonist interacting less strongly the Asp103 and interacting less strongly with the Ser198 of a D1R when binding to the D1R, and their uses.

What is claimed is: 
     
         1 . A method for treating Parkinson's disease in a human, which method comprises administering to said human a therapeutically effective amount of a D1 agonist with reduced D1R desensitization, wherein:
 the D1 agonist has an EC 50  value of less than about 2 μM with respect to human D1 receptor;   the D1 agonist desensitizes rat D1R cAMP signaling less than about 25% relative to Control, wherein Control is 0.1% DMSO in serum free neurobasal media; the percentage reduced D1R desensitization is measured by an assay using rat primary striatal neurons endogenously expressing rat D1Rs; and the assay comprises: a) pretreating rat D1Rs expressed in rat primary striatal neurons with Control for 30 minutes and then measuring the pretreated rat D1Rs′ ability in cAMP accumulation in the presence of SKF-81297 (1 μM) for 30 minutes, (b) pretreating rat D1Rs expressed in rat primary striatal neurons with 10 μM of the D1 agonist in serum free neurobasal media then measuring the pretreated rat D1Rs' ability in cAMP accumulation in the presence of SKF-81297 (1 μM) for 30 minutes, and (c) calculating percentage reduced desensitization by calculating percentage decrease in cAMP accumulation by the D1 agonist as measured in (b) relative to Control as measured in (a);   the D1 agonist with reduced D1R desensitization is not a catechol derivative; and   the D1 agonist interacts significantly with the Ser188 but not significantly with the Ser202 residue of a human D1R when binding to the human D1R, wherein the interactions are measured by an assay substantially the same as the one in Example CC.   
     
     
         2 . The method of  claim 1  wherein the D1 agonist desensitizes rat D1R cAMP signaling less than about 20% relative to Control according to the assay as in  claim 1 . 
     
     
         3 . The method of  claim 1  wherein the D1 agonist interacts less strongly with the Asp103 residue or the Ser198 residue of the human D1R when binding to the human D1R wherein the interactions are measured by an assay substantially as the one in Example CC. 
     
     
         4 . The method of  claim 2  wherein the D1 agonist interacts less strongly with the Asp103 residue or the Ser198 residue of the human D1R when binding to the human D1R wherein the interactions are measured by an assay substantially as the one in Example CC. 
     
     
         5 . The method of  claim 1  wherein the D1 agonist is a partial D1 agonist, and wherein the percentage intrinsic activity of the D1 agonist is about 10% to about 80% with respect to Dopamine. 
     
     
         6 . The method of  claim 2  wherein the D1 agonist is a partial D1 agonist, and wherein the percentage intrinsic activity of the D1 agonist is about 10% to about 80% with respect to Dopamine. 
     
     
         7 . The method of  claim 3  wherein the D1 agonist is a partial D1 agonist, and wherein the percentage intrinsic activity of the D1 agonist is about 10% to about 80% with respect to Dopamine. 
     
     
         8 . The method of  claim 4  wherein the D1 agonist is a partial D1 agonist, and wherein the percentage intrinsic activity of the D1 agonist is about 10% to about 80% with respect to Dopamine. 
     
     
         9 . The method of  claim 1  wherein the D1 agonist is a full D1 agonist. 
     
     
         10 . The method of  claim 3  wherein the D1 agonist is a full D1 agonist. 
     
     
         11 . A method for treating Parkinson's disease in a human, which method comprises administering to said human a therapeutically effective amount of a D1 agonist with a reduced β-arrestin recruitment activity relative to Dopamine, wherein:
 the D1 agonist has an EC 50  value of less than about 2 μM with respect to human D1 receptor; 
 a human D1R, after binding to the D1 agonist with a reduced β-arrestin recruitment activity, recruits less than about 70% of β-arrestin relative to the human D1R binding to Dopamine, wherein the percentage of reduced β-arrestin recruitment activity is measured by an assay comprising: (a) incubating U2OS cells co-expressing human Dopamine D1 receptor and human β-arrestin2-green fluorescent fusion protein (GFP) for 1 hour in serum free media (SFM); subsequently treating the cells for 10 minutes at 37° C. with 1 μM of Dopamine in SFM; and subsequently determining β-arrestin2-GFP located at the plasma membrane of the cells by using Total Internal Reflection Fluorescence Microscopy (TIRFM) to assess total intensity/cell and/or total area/cell; (b) incubating U2OS cells co-expressing human Dopamine D1 receptor and human β-arrestin2-GFP for 1 hour in SFM; subsequently treating the cells for 10 minutes at 37° C. with 1μM of the D1 agonist in SFM; and subsequently determining β-arrestin2-GFP located at the plasma membrane of the cells by using TIRFM to assess total intensity/cell and/or total puncta area/cell; (c) normalizing the total intensity/cell and/or total area/cell in step (a) as 100%; and (d) calculating percentage β-arrestin2 recruitment activity by comparing the total intensity/cell and/or total puncta area/cell in step (b) to that in (a); 
 the D1 agonist with a reduced β-arrestin recruitment activity is not a catechol derivative; and 
 the D1 agonist interacts significantly with the Ser188 residue but not significantly with the Ser202 residue of a human D1R when binding to the human D1R wherein the interactions are measured by an assay substantially as the one in Example CC. 
 
     
     
         12 . The method of  claim 1  wherein a human D1R, after binding to the D1 agonist with a reduced β-arrestin recruitment activity, recruits less than about 50% of β-arrestin relative to the human D1R binding to Dopamine according to the assay as in  claim 11 . 
     
     
         13 . The method of  claim 11  wherein the D1 agonist interacts less strongly with the Asp103 residue or the Ser198 residue of the human D1R when binding to the human D1R wherein the interactions are measured by an assay substantially as the one in Example CC. 
     
     
         14 . The method of  claim 12  wherein the D1 agonist interacts less strongly with the Asp103 residue or the Ser198 residue of the human D1R when binding to the human D1R wherein the interactions are measured by an assay substantially as the one in Example CC. 
     
     
         15 . The method of  claim 11  wherein the D1 agonist is a partial D1 agonist, and wherein the percentage intrinsic activity of the D1 agonist is about 10% to about 80% with respect to Dopamine. 
     
     
         16 . The method of  claim 12  wherein the D1 agonist is a partial D1 agonist, and wherein the percentage intrinsic activity of the D1 agonist is about 10% to about 80% with respect to Dopamine. 
     
     
         17 . The method of  claim 13  wherein the D1 agonist is a partial D1 agonist, and wherein the percentage intrinsic activity of the D1 agonist is about 10% to about 80% with respect to Dopamine. 
     
     
         18 . The method of  claim 14  wherein the D1 agonist is a partial D1 agonist, and wherein the percentage intrinsic activity of the D1 agonist is about 10% to about 80% with respect to Dopamine. 
     
     
         19 . The method of  claim 11  wherein the D1 agonist is a full D1 agonist. 
     
     
         20 . The method of  claim 13  wherein the D1 agonist is a full D1 agonist.