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 and intermediates for preparation of; and compositions and uses thereof. The present invention further provides D1 agonists with reduced D1R desensitization, D1 agonists with a reduced β-arrestin recruitment activity relative to Dopamine, D1 agonists interacting significantly with the Ser188 but not significantly with the Ser202 of a D1R when binding to the D1R, D1 agonists interacting less strongly with the Asp103 and interacting less strongly with the Ser198 of a D1R when binding to the D1R, and their uses.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or an N-oxide thereof, or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein: 
         X 1  is O or S; 
         Y 1  is O, S, or NR N ; 
         Q 1  is an N-containing 5- to 10-membered heterocycloalkyl, an N-containing 5- to 10-membered heteroaryl, or phenyl, wherein the heterocycloalkyl or heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 7 ; and the phenyl is optionally substituted with 1, 2, 3, 4, or 5 independently selected R 7a ; 
         R T1  and R T2  are each independently selected from the group consisting of H, C 1-3  alkyl, C 1-3  fluoroalkyl, cyclopropyl, fluorocyclopropyl, C 1-3  alkoxy, C 1-3  haloalkoxy, —C(═O)—O—(C 1-3  alkyl), and —C(═O)OH; 
         R 1  is selected from the group consisting of H, F, —C(═O)OH, —C(═O)—O—(C 1-3  alkyl), C 1-3  alkyl, C 1-3  fluoroalkyl, C 3-6  cycloalkyl, and C 3-6  fluorocycloalkyl, wherein said C 3-6  cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halo, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, and C 1-4  haloalkoxy; 
         R 2  is selected from the group consisting of H, halogen, —CN, —OH, C(═O)OH, C(═O)—O—(C 1-3  alkyl), C 1-3  alkoxy, C 1-3  haloalkoxy, —N(R 8 )(R 9 ), C 1-3  alkyl, C 1-3  fluoroalkyl, C 3-6  cycloalkyl, C 3-6  fluorocycloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl, wherein said C 3-6  cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halo, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, and C 1-4  haloalkoxy; 
         R 3  and R 4  are each independently selected from the group consisting of H, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, —CN, C 3-6  cycloalkyl, —C(═O)OH, C(═O)—O—(C 1-4  alkyl), and halogen, wherein each of said C 1-6  alkyl and C 3-6  cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halo, —OH, —CN, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, and C 1-4  haloalkoxy; 
         R 5  and R 6  are each independently selected from the group consisting of H, halogen, —OH, —NO 2 , —CN, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, a 4- to 10-membered heterocycloalkyl, —N(R 8 )(R 9 ), —N(R 10 )(C(═O)R 11 ), —C(═O)—N(R 8 )(R 9 ), —C(═O)—R 12 , —C(═O)—OR 12 , and —OR 13 , wherein each of said C 1-6  alkyl, C 3-7  cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, —OH, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  haloalkoxy, C 3-6  cycloalkyl, —N(R 14 )(R 15 ), —N(R 16 )(C(═O)R 17 ), —C(═O)—OR 18 , —O(═O)H, —O(═O)R 18 , —O(═O)N(R 14 )(R 15 ), and —OR 19 ; 
         or R 5  and R 3  together with the two carbon atoms to which they are attached form a fused N-containing 5- or 6-membered heteroaryl, a fused N-containing 5- or 6-membered heterocycloalkyl, a fused 5- or 6-membered cycloalkyl, or a fused benzene ring, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, —CN, —OH, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, and C 1-3  haloalkoxy; 
         R 7  and R 7a  are each independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , oxo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxylalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, —CH═N—O—(C 1-3  alkyl), —N(R 14 )(R 15 ), —N(R 16 )(C(═O)R 17 ), —S(═O) 2 N(R 14 )(R 15 ), —O(═O)N(R 14 )(R 15 ), —C(═O)—R 12 , —O(═O)—OR 18 , and —OR 19 , wherein each of said C 1-6  alkyl, C 3-7  cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, C 6-10  aryl, heterocycloalkyl and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, OH, —CN, —NO 2 , C 1-4  alkyl, C 1-4  hydroxylalkyl, C 1-4  alkoxy, —N(R 14 )(R 15 ), —S—(C 1-3  alkyl), —S(═O) 2 —(C 1-4  alkyl), aryloxy, arylalkyloxy optionally substituted with 1 or 2 C 1-4  alkyl, oxo, —C(═O)H, —C(═O)—C 1-4  alkyl, —C(═O)O—C 1-4  alkyl, —C(═O)NH 2 , —NHC(═O)H, —NHC(═O)—(C 1-4  alkyl), C 3-7  cycloalkyl, a 5- or 6-membered heteroaryl, C 1-4  haloalkyl, and C 1-4  haloalkoxy; 
         or two adjacent R 7a  together with the two carbon atoms to which they are attached form a fused 5- or 6-membered cycloalkyl, a fused 5- or 6-membered heterocycloalkyl, or a fused benzene ring, each optionally substituted with 1, 2, 3, or 4 R 7b , wherein each R 7b  is independently selected from the group consisting of halo, —CN, —NO 2 , —NH 2 , —NH(C 1-4  alkyl), —N(C 1-4  alkyl) 2 , azetidin-1-yl, pyrrolidin-1-yl, pyridin-1-yl, OH, oxo, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  hydroxylalkyl, C 1-4  haloalkyl, and C 1-4  haloalkoxy; 
         R 8  and R 9  are each independently selected from the group consisting of H, C 1-6  alkyl, C 1-6  haloalkyl, C 3-10  cycloalkyl, a 4- to 10-membered heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each of said C 1-6  alkyl, C 3-10  cycloalkyl, 4- to 10-membered heterocycloalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of —OH, —CN, C 1-3  alkyl, C 3-7  cycloalkyl, C 1-3  hydroxylalkyl, —S—C 1-3  alkyl, —C(═O)H, —C(═O)—C 1-3  alkyl, —C(═O)—O—C 1-3  alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-3  alkyl) 2 , C 1-3  haloalkyl, C 1-3  alkoxy, and C 1-3  haloalkoxy; 
         or R 8  and R 9  together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl or heteroaryl optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, —OH, oxo, —C(═O)H, —C(═O)OH, —C(═O)—C 1-3  alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-3  alkyl) 2 , —CN, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  hydroxylalkyl, C 1-3  haloalkyl, and C 1-3  haloalkoxy; 
         R 10  is selected from the group consisting of H, C 1-3  alkyl, and C 3-7  cycloalkyl; 
         R 11  is selected from the group consisting of C 1-6  alkyl, C 3-7  cycloalkyl, a 4- to 14-membered heterocycloalkyl, C 6-10  aryl, a 5- to 10-membered heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CF 3 , —CN, —OH, oxo, —S—C 1-3  alkyl, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 1-6  alkoxy, and C 1-6  haloalkoxy; 
         R 12  is H or is selected from the group consisting of C 1-10  alkyl, C 3-7  cycloalkyl, a 4- to 14-membered heterocycloalkyl, C 6-10  aryl, a 5- to 10-membered heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CF 3 , —CN, —OH, —C(═O)OH, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 1-6  alkoxy, and C 1-6  haloalkoxy; 
         R 13  is selected from the group consisting of C 1-10  alkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, a 4- to 14-membered heterocycloalkyl, C 6-10  aryl, a 5- to 10-membered heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, —N(R 14 )(R 15 ), —C(═O)N(R 14 )(R 15 ), —N(R 16 )(C(═O)R 17 ), —C(═O)H, —C(═O)N(R 16 )(OR 18 ), —C(═O)—R 18 , —C(═O)—OR 18 , —O—C(═O)R 18 , —CF 3 , —CN, —OH, —O—(C 1-6  hydroxylalkyl), C 1-6  alkyl, oxo, C 1-6  hydroxylalkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 1-6  alkoxy, and C 1-6  haloalkoxy; 
         R 14  and R 15  are each independently selected from the group consisting of H, C 1-6  alkyl, C 2-6  alkenyl, C 3-10  cycloalkyl, a 4- to 14-membered heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each of said C 1-6  alkyl, C 3-7  cycloalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of —OH, —CN, oxo, —NHC(═O)—(C 1-3  alkyl), —C(═O)N(C 1-3  alkyl) 2 , —O—(C 1-6  hydroxylalkyl), —S(═O) 2 —C 1-3  alkyl, —S—C 1-3  alkyl, C 1-3  alkyl, C 3-7  cycloalkyl, C 1-3  hydroxylalkyl, a 5- to 10-membered heteroaryl, C 1-3  alkoxy, C 1-3  haloalkyl, and C 1-3  haloalkoxy; 
         or R 14  and R 15  together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, oxo, —OH, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  haloalkoxy, C 1-3  hydroxylalkyl, C 2-4  alkoxyalkyl, oxo, a 5- to 6-membered heteroaryl, —NH 2 , —N(C 1-3  alkyl) 2 , —S(═O) 2 —C 1-3  alkyl, —S—C 1-3  alkyl, —C(═O)H, —C(═O)OH, —C(═O)NH 2 , and —C(═O)—C 1-3  alkyl; 
         R 16  is selected from the group consisting of H, C 1-3  alkyl, and C 3-7  cycloalkyl; 
         R 17  is selected from the group consisting of C 1-6  alkyl, C 3-7  cycloalkyl, a 4- to 14-membered heterocycloalkyl, C 6-10  aryl, a 5- to 10-membered heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CF 3 , —CN, —OH, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 1-6  alkoxy, and C 1-6  haloalkoxy; 
         R 18  is H or is selected from the group consisting of C 1-6  alkyl, C 3-7  cycloalkyl, a 4- to 14-membered heterocycloalkyl, C 6-10  aryl, a 5- to 10-membered heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CF 3 , —CN, —OH, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 3-7  alkynyl, C 3-7  cycloalkyl, C 1-6  alkoxy, and C 1-6  haloalkoxy; 
         R 19  is selected from the group consisting of C 1-6  alkyl, C 1-6  haloalkyl, C 3-7  cycloalkyl, a 4- to 14-membered heterocycloalkyl, C 6-10  aryl, a 5- to 10-membered heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —N(R 14 )(R 15 ), —C(═O)N(R 14 )(R 15 ), —N(R 16 )(C(═O)R 17 ), —C(═O)—R 18 , —C(═O)—OR 18 , —CF 3 , —CN, —OH, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 1-6  alkoxy, and C 1-6  haloalkoxy; and 
         R N  is selected from the group consisting of H, C 1-6  alkyl, C 3-6  cycloalkyl, C 3-6  fluorocycloalkyl, heteroarylalkyl, and arylalkyl, wherein each of said C 3-6  cycloalkyl, heteroarylalkyl, and arylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halo, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, and C 1-4  haloalkoxy. 
       
     
     
         2 . The compound of  claim 1 , or an N-oxide thereof or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein Y 1  is O. 
     
     
         3 . The compound of  claim 1 , or an N-oxide thereof or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein X 1  is O. 
     
     
         4 . The compound of  claim 1 , or an N-oxide thereof or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein Q 1  is selected from quinolinyl, isoquinolinyl, 1H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-c][1,2,4]triazinyl, imidazo[1,5-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 1H-indazolyl, 9H-purinyl, pyrimidinyl, pyrazinyl, pyridinyl, pyridazinyl, 1H-pyrazolyl, 1H-pyrrolyl, 4H-pyrazolyl, 4H-imidazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, 1H-imidazolyl, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl, 2,4(1H,3H)-dioxo-pyrimidinyl, and 1H-2-oxo-pyrazinyl, each optionally substituted with 1, 2, 3, or 4 independently selected R 7 . 
     
     
         5 . The compound of  claim 1 , or an N-oxide thereof or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein Q 1  is selected from: 
       
         
           
           
               
               
           
         
       
       and
 each m is independently 0, 1, 2, or 3. 
 
     
     
         6 . The compound of  claim 1 , or an N-oxide thereof or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein R T1  and R T2  are both H; R 1  is H; and R 2  is H, —CN, Br, C 1-3  alkyl, or cyclopropyl. 
     
     
         7 . The compound of  claim 1 , or an N-oxide thereof or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein R 3  and R 4  are each independently selected from the group consisting of H, F, Cl, and C 1-3  alkyl. 
     
     
         8 . The compound of  claim 1 , or an N-oxide thereof or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein one of R 5  and R 6  is H; and the other of R 5  and R 6  is selected from the group consisting of H, —OH, —CN, Cl, F, methyl, ethyl, CF 3 , CH 2 F, and —OCH 3 . 
     
     
         9 . The compound of  claim 1 , or an N-oxide thereof or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein each of R 7  and R 7a  is independently selected from the group consisting of C 1-4  alkyl, C 1-4  fluoroalkyl, oxo, —OH, C 1-4  alkoxy, and C 1-4  haloalkoxy; wherein the C 1-4  alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, OH, C 1-4  alkoxy, —NH 2 , —NH(C 1-4  alkyl), —N(C 1-4  alkyl) 2 , azetidin-1-yl, pyrrolidin-1-yl, and pyridin-1-yl. 
     
     
         10 . A compound of  claim 1  selected from:
 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyridine; 
 2-(4,6-dimethylpyrimidin-5-yl)-5-(furo[3,2-c]pyridin-4-yloxy)benzonitrile; 
 5-[2-fluoro-4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-4,6-dimethylpyridazin-3(2H)-one; 
 5-[4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-4,6-dimethylpyridazin-3(2H)-one; 
 (+)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one; 
 (−)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one; 
 5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one; 
 (+)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-a]pyrazine; 
 (−)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-a]pyrazine; 
 5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-a]pyrazine; 
 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-fluorophenoxy]furo[3,2-c]pyridine; 
 4-[4-(4,6-dimethylpyrimidin-5-yl)phenoxy]furo[3,2-c]pyridine; 
 (−)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one; 
 (+)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one; 
 6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1H)-one; 
 6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrimidin-2(1H)-one; 
 4-[4-(4,6-dimethylpyrimidin-5-yl)-2-fluorophenoxy]furo[3,2-c]pyridine; 
 5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-2,4,6-trimethylpyridazin-3(2H)-one; 
 5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4-methylpyridazin-3(2H)-one; 
 (+)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyridine; 
 (−)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyridine; 
 4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyridine; 
 4-[4-(3,5-dimethyl-6-oxo-1,6-dihydropyridazin-4-yl)phenoxy]furo[3,2-c]pyridine-3-carbonitrile; 
 (−)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methoxyphenoxy]furo[3,2-c]pyridine; 
 (+)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methoxyphenoxy]furo[3,2-c]pyridine; 
 4-[4-(3,5-dimethylpyridazin-4-yl)-3-methoxyphenoxy]furo[3,2-c]pyridine; 
 6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 
 (−)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 
 (+)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; and 
 6-[4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-1,5-dimethylpyrimidine-2,4(1H,3H)-dione, 
 or an N-oxide thereof or a pharmaceutically acceptable salt of said compound or said N-oxide. 
 
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 1  or an N-oxide thereof or a pharmaceutically acceptable salt of said compound or said N-oxide, and a pharmaceutically acceptable carrier. 
     
     
         12 . A method for treating a disorder in a human, which method comprises administering to said human a therapeutically effective amount of a compound according to  claim 1  or an N-oxide thereof or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein the disorder is selected from schizophrenia, cognitive impairment, attention deficit hyperactivity disorder (ADHD), impulsivity, compulsive gambling, overeating, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, dementia, restless leg syndrome (RLS), Parkinson's disease, Huntington's chorea, anxiety, depression, major depressive disorder (MDD), treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum depression, serotonin syndrome, substance abuse and drug dependence, drug abuse relapse, Tourette's syndrome, tardive dyskinesia, drowsiness, excessive daytime sleepiness, cachexia, inattention, a movement disorder, a therapy-induced movement disorder, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis, dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, hyponatremia, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, and pain. 
     
     
         13 . A D1 agonist with reduced D1R desensitization, wherein the D1 agonist desensitizes D1R cAMP signaling less than about 25% relative to Control; and wherein the D1 agonist with reduced D1R desensitization is not a catechol derivative. 
     
     
         14 . A D1 agonist with a reduced β-arrestin recruitment activity relative to Dopamine, wherein a 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 D1R binding to Dopamine; and wherein the D1 agonist with a reduced β-arrestin recruitment activity is not a catechol derivative. 
     
     
         15 . The D1 agonist of  claim 14  wherein the D1 agonist interacts significantly with the Ser188 but not significantly with the Ser202 of a D1R when binding to the D1R. 
     
     
         16 . The D1 agonist of  claim 15  wherein the D1 agonist interacts less strongly with the Asp103 or the Ser198 of the D1R when binding to the D1R. 
     
     
         17 . The D1 agonist of  claim 14  wherein the D1 agonist is a partial D1 agonist. 
     
     
         18 . The D1 agonist of  claim 14  wherein the D1 agonist is a full D1 agonist. 
     
     
         19 . A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt thereof and a pharmaceutically acceptable carrier, wherein the compound or salt thereof is a D1 agonist of  claim 14 . 
     
     
         20 . A method for treating a disorder in a human, which method comprises administering to said human a therapeutically effective amount of a compound or salt thereof wherein the compound or salt thereof is a D1 agonist of  claim 14 , and wherein the disorder is selected from schizophrenia, cognitive impairment, attention deficit hyperactivity disorder (ADHD), impulsivity, compulsive gambling, overeating, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, dementia, restless leg syndrome (RLS), Parkinson's disease, Huntington's chorea, anxiety, depression, major depressive disorder (MDD), treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum depression, serotonin syndrome, substance abuse and drug dependence, drug abuse relapse, Tourette's syndrome, tardive dyskinesia, drowsiness, excessive daytime sleepiness, cachexia, inattention, a movement disorder, a therapy-induced movement disorder sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis, dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, hyponatremia, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, and pain.