Heteroaromatic compounds and their use as dopamine D1 ligands

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is N or CT 4 ;

Q 1 is an N-containing 5- to 6-membered heteroaryl or an N-containing 5- to 6-membered heterocycloalkyl, each optionally substituted with one R 9 and further optionally substituted with 1, 2, 3, or 4 R 10 ;

each of T 1 , T 2 , T 3 , and T 4 is independently selected from the group consisting of H, halogen, —CN, C 1-4 alkyl, C 1-4 haloalkyl, cyclopropyl, fluorocyclopropyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and —C(═O)—O—(C 1-4 alkyl);

each of R 1 and R 2 is independently selected from the group consisting of H, halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, —C(═O)OH, and C(═O)—O—(C 1-4 alkyl), 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;

each of R 3 and R 4 is independently selected from the group consisting of H, halogen, —OH, —NO 2 , —CN, —SF 5 , 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 5 )(R 6 ), —N(R 7 )(C(═O)R 8 ), —C(═O)—N(R 5 )(R 6 ), —C(═O)—R 8 , —C(═O)—OR 8 , —N(R 7 )(S(═O) 2 R 8 ), —S(═O) 2 —N(R 5 )(R 6 ), —SR 8 , and —OR 8 , 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 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, —N(R 5 )(R 6 ), —N(R 7 )(C(═O)R 8 ), —C(═O)—OR 8 , —C(═O)H, —C(═O)R 8 , —C(═O)N(R 5 )(R 6 ), —N(R 7 )(S(═O) 2 R 8 ), —S(═O) 2 —N(R 5 )(R 6 ), —SR 8 , and —OR 8 ;

R 5 is H, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-7 cycloalkyl;

R 6 is H or selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of —OH, —CN, C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 hydroxylalkyl, —S—C 1-4 alkyl, —C(═O)H, —C(═O)—C 1-4 alkyl, —C(═O)—O—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-4 alkyl) 2 , C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

or R 5 and R 6 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen, —OH, oxo, —C(═O)H, —C(═O)OH, —C(═O)—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-4 alkyl) 2 , —CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxylalkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy;

R 7 is selected from the group consisting of H, C 1-4 alkyl, and C 3-7 cycloalkyl;

R 8 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, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CF 3 , —CN, —OH, oxo, —S—C 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R 9 is C 1-4 alkyl, C 1-4 haloalkyl, —CN, —SF 5 , —N(R 5 )(R 6 ), C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkoxy, or C 3-7 cycloalkyl, wherein each of the C 1-4 alkyl and C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen, —N(R 5 )(R 6 ), C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

each R 10 is independently selected from the group consisting of halogen, —OH, —CN, —SF 5 , —NO 2 , oxo, thiono, 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, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, (5- to 10-membered heteroaryl)-C 1-4 alkyl-, —N(R 5 )(R 6 ), —N(R 7 )(C(═O)R 8 ), —S(═O) 2 N(R 5 )(R 6 ), —C(═O)—N(R 5 )(R 6 ), —C(═O)—R 8 , —C(═O)—OR 8 , —SR 8 , and —OR 8 , wherein each of said C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 14 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- 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 5 )(R 6 ), —S—(C 1-4 alkyl), —S(═O) 2 —(C 1-4 alkyl), C 6-10 aryloxy, [(C 6-10 aryl)-C 1-4 alkyloxy- 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 R 9 and an adjacent R 10 together with the two ring atoms on Q 1 to which they are attached form a fused benzene ring or a fused 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 independently selected R 10a ; and

each R 10a is independently selected from the group consisting of halogen, —OH, —N(R 5 )(R 6 ), —C(═O)OH, —C(═O)—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-4 alkyl) 2 , —CN, —SF 5 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxylalkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy;

provided that the compound of Formula I is not 4-(4-imidazol-1-yl-phenoxy)-3-methyl-1H-pyrazolo[4,3-c]pyridine.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of T 1 , T 2 , T 3 , and T 4 is independently selected from the group consisting of H, F, —CN, methoxy, C 1 fluoroalkoxy, methyl, and C 1 fluoroalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein T 2 is H and T 3 is H.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula Ia:

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula Ib:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X 1 is N or CH;

each of R 1 and R 2 is independently selected from the group consisting of H, halogen, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and C 3-4 cycloalkyl;

each of R 3 and R 4 is independently selected from the group consisting of H, halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-4 cycloalkyl, a 4- to 7-membered heterocycloalkyl, —N(R 5 )(R 6 ), and —OR 8 ;

R 5 is H, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-7 cycloalkyl;

R 6 is H or selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and C 3-7 cycloalkyl;

or R 5 and R 6 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl or a 5-membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy; and

R 8 is selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl, a 4- to 7-membered heterocycloalkyl, phenyl, and a 5- to 6-membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein each of R 1 and R 2 is H.

8. The compound of any one of claim 7 , or a pharmaceutically acceptable salt thereof, wherein each of R 3 and R 4 is independently H, halogen, —CN, methyl, C 1 haloalkyl, —O-methyl, or C 1 haloalkoxy.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 3 is H and R 4 is methyl.

10. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein:

Q 1 is a moiety of

(“Moiety M 1 ”);

ring Q 1a is an N-containing 5- to 6-membered heteroaryl or an N-containing 5- to 6-membered heterocycloalkyl;

represents a single bond or double bond;

Z 1 is C;

Z 2 is C or N;

R 9 is C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, —CN, —N(R 5 )(R 6 ), C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-7 cycloalkoxy, wherein each of the C 1-4 alkyl and C 3-7 cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen, —N(R 5 )(R 6 ), C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

each R 10 is independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , oxo, thiono, 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, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, (5- to 10-membered heteroaryl)-C 1-4 alkyl-, —N(R 5 )(R 6 ), —N(R 7 )(C(═O)R 8 ), —S(═O) 2 N(R 5 )(R 6 ), —C(═O)—N(R 5 )(R 6 ), —C(═O)—R 8 , —C(═O)—OR 8 , and —OR 8 , wherein each of said C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, (5- to 10-membered heteroaryl)-C 1-4 alkyl- 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 5 )(R 6 ), —S—(C 1-4 alkyl), —S(═O) 2 —(C 1-4 alkyl), C 6-10 aryloxy, (C 6-10 aryl)-C 1-4 alkyloxy- 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 R 9 and the adjacent R 10 together with the two ring atoms on ring Q 1a to which they are attached form a fused benzene ring or a fused 5- or 6-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 independently selected R 10a ;

each R 10a is independently selected from the group consisting of halogen, —OH, —C(═O)OH, —C(═O)—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-4 alkyl) 2 , —CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxylalkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy; and

m is 0, 1, 2, 3, or 4.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 9 is C 1-4 alkyl or —CN; and each R 19 is independently C 1-4 alkyl.

12. A compound selected from the group consisting of:

4-[4-(1,4-dimethyl-1H-pyrazol-5-yl)-3-methylphenoxy]-1H-pyrrolo[3,2-c]pyridine;

4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]-1H-pyrrolo[3,2-c]pyridine, ENT-1;

4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]-1H-pyrrolo[3,2-c]pyridine, ENT-2;

5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]imidazo[1,2-a]pyrazine;

5-[2-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]-6-methylpyrimidine-4-carbonitrile;

6-methyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyrimidine-4-carbonitrile;

5-[2-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]-6-methylimidazo[1,2-a]pyrazine;

6-methyl-5-[4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]imidazo[1,2-a]pyrazine;

4-[4-(4,6-dimethylpyrimidin-5-yl)-2,5-difluorophenoxy]-1H-pyrrolo[3,2-c]pyridine;

4-[4-(4,6-dimethylpyrimidin-5-yl)-2,3-difluorophenoxy]-1H-pyrrolo[3,2-c]pyridine;

4-{3-fluoro-4-[4-(3-fluoroazetidin-1-yl)-6-methylpyrimidin-5-yl]phenoxy}-1H-pyrrolo[3,2-c]pyridine;

(+)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyrazin-2(1H)-one;

4-methyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one;

6-methyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one;

4-[3-methyl-4-(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenoxy]-1H-pyrazolo[4,3-c]pyridine;

6-methyl-5-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one;

2-(4,6-dimethylpyrimidin-5-yl)-5-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)benzonitrile;

5-[2-fluoro-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]-6-methylpyrimidine-4-carbonitrile;

4-[4-(4,6-dimethylpyrimidin-5-yl)-2-fluoro-5-methylphenoxy]-1H-pyrazolo[4,3-c]pyridine;

4-[4-(4,6-dimethylpyrimidin-5-yl)phenoxy]-1H-pyrazolo[4,3-c]pyridine;

(−)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrazin-2(1H)-one;

4-methyl-5-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one;

4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1H-pyrrolo[3,2-c]pyridine-3-carbonitrile;

4,6-dimethyl-5-{4-[(3-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)oxy]phenyl}pyridazin-3(2H)-one;

4,6-dimethyl-5-{4-[(6-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)oxy]phenyl}pyridazin-3(2H)-one; and

5-{4-[(7-methoxy-1H-pyrazolo[4,3-c]pyridin-4-yl)oxy]phenyl}-4,6-dimethylpyridazin-3(2H)-one,

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. 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 a pharmaceutically acceptable salt thereof, wherein the disorder is selected from the group consisting of schizophrenia, cognitive impairment, and Parkinson's disease.