Heteroaromatic compounds and their use as dopamine D1 ligands

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

L 1 is O;

Q 1 is a moiety of

R 9 is halogen, 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-, (5- to 10-membered heteroaryl)-C 2-4 alkenyl-, —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 —OW, 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-, and (5- to 10-membered heteroaryl)-C 2-4 alkenyl- is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, OH, —CN, —NC 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, —O(═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;

R 11 is H, C 1-4 alkyl, C 1-4 haloalkyl, (C 1-2 alkoxy)-C 1-4 alkyl-, or C 3-7 cycloalkyl;

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

X 1 is O, S, NH, N(C 1-4 alkyl), N(cyclopropyl), or N(—CH 2 -cyclopropyl);

X 2 is N or C-T 2 ;

X 3 is N or C-T 3 ;

provided that when X 1 is O or S, then at least one of X 2 and X 3 is not N;

X 4 is N or C-T 4 ;

T 1 is H, F, Cl, methyl, or C 1 fluoroalkyl;

each of T 2 , T 3 , and T 4 is independently selected from the group consisting of H, halogen, —CN, methoxy, C 1 fluoroalkoxy, methyl, and C 1 fluoroalkyl;

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, and C 1-6 haloalkoxy, and C 3-6 , cycloalkyl;

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

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; and

R 8 is selected from the group consisting of C 1-6 alkyl and C 3-7 cycloalkyl, 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;

with the proviso that when X 1 is NH, N(C 1-4 alkyl), N(cyclopropyl), or N(—CH 2 -cyclopropyl), then X 4 is C-T 4 .

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein T 1 is H; T 4 is H; and each of T 2 and T 3 is independently H, CN, F, Cl, Br, methoxy, C 1 fluoroalkoxy, methyl, or C 1 fluoroalkyl.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is a compound of Formula I-a, I-b, I-c, I-d, I-e, If, I-g, or I-h:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is a compound of Formula I-a or a pharmaceutically acceptable salt thereof.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein each of R 1 and R 2 is independently H or halogen; and each of R 3 and R 4 is independently H, halogen, —CN, methyl, C 1 haloalkyl, methoxy, or C 1 haloalkoxy.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein each of R 1 and R 2 is H; R 3 is H; and R 4 is H, halogen, —CN, methyl, or C 1 haloalkyl.

7. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein:

Moiety M 1 is

8. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Moiety M 1 is

9. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein:

Moiety M 1 is

and R 11 is H, C 1-4 alkyl, C 1-4 haloalkyl, (C 1-2 alkoxy)-C 1-4 alkyl-, or C 3-7 cycloalkyl.

10. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 9 is halogen, C 3-6 cycloalkyl, C 1-4 alkyl, or CN; and each R 19 is independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, (C 1-2 alkoxy)-C 1-4 alkyl-, —CN, and —N(R 5 )(R 6 ), wherein each of R 5 and R 6 independently 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.

11. A compound selected from the group consisting of:

(+)-1,5-dimethyl-6-[2-methyl-4-(thieno[3,2-d]pyri midi n-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione;

(−)-1,5-dimethyl-6-[2-methyl-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione;

4,6-dimethyl-5-[2-methyl-4-([1,2]thiazolo[5,4-c]pyridin-7-yloxy)phenyl]pyridazin-3(2H)-one;

1,5-dimethyl-6-[2-methyl-4-(thieno[2,3-c]pyridin-7-yloxy)phenyl]pyrazin-2(1H)-one;

7-[4-(4,6-dimethylpyrimidin-5-yI)-3-methylphenoxy]thieno[2,3-c]pyridine;

7-[4-(4,6-dimethylpyrimidin-5-yI)-3-methylphenoxy]furo[2,3-c]pyridine;

1,5-dimethyl-6-[2-methyl-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]pyrazin-2(1H)-one;

4-[3-chloro-4-(4,6-dimethylpyrimidin-5-yl)phenoxy]thieno[3,2-d]pyrimidine;

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

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

7-[3-chloro-4-(4,6-dimethylpyrimidin-5-yl)phenoxy]thieno[2,3-c]pyridine;

6-methyl-5-[2-methyl-4-(thieno[2,3-c]pyridin-7-yloxy)phenyl]pyrimidine-4-carbonitrile, ENT-1;

6-methyl-5-[2-methyl-4-(thieno[2,3-c]pyridin-7-yloxy)phenyl]pyrimidine-4-carbonitrile, ENT-2;

2-(4,6-dimethylpyrimidin-5-yl)-5-(thieno[2,3-c]pyridin-7-yloxy)benzonitrile;

4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy][1,3]thiazolo[5,4-c]pyridine;

4,6-dimethyl-5-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]pyridazin-3(2H)-one; and

1,5-dimethyl-6-[4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione,

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 that is (+)-1,5-dimethyl-6-[2-methyl-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 11 that is (+1,5-dimethyl-6-[2-methyl-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 11 that is 4-[3-chloro-4-(4,6-dimethylpyrimidin-5-yl)phenoxy]thieno[3,2-d]pyrimidine, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 11 that is 6-methyl-5-[2-methyl-4-(thieno[2,3-c]pyridin-7-yloxy)phenyl]pyrimidine-4-carbonitrile, ENT-1; or a pharmaceutically acceptable salt thereof.

16. The compound of claim 11 that is 6-methyl-5-[2-methyl-4-(thieno[2,3-c]pyridin-7-yloxy)phenyl]pyrimidine-4-carbonitrile, ENT-2; or a pharmaceutically acceptable salt thereof.

17. The compound of claim 11 that is 2-(4,6-dimethylpyrimidin-5-yl)-5-(thieno[2,3-c]pyridin-7-yloxy)benzonitrile; or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

T 1 is H, methyl, or C 1 fluoroalkyl;

each of T 2 , T 3 , and T 4 is independently selected from the group consisting of H, methyl, and C 1 fluoroalkyl;

each of R 1 and R 2 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy; and

each of R 3 and R 4 is independently selected from the group consisting of H, halogen, —CN, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy.

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

T 1 is H or methyl;

each of T 2 , T 3 , and T 4 is independently selected from the group consisting of H and methyl;

each of R 1 and R 2 is independently selected from the group consisting of H, halogen, C 1-6 alkyl, and C 1-6 alkoxy; and

each of R 3 and R 4 is independently selected from the group consisting of H, halogen, —CN, C 1-6 alkyl, and C 1-6 alkoxy.