Heteroaromatic compounds and their use as dopamine D1 ligands
The present invention provides, in part, compounds of Formula I: and pharmaceutically acceptable salts thereof and N-oxides of the foregoing; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds, salts or N-oxides, and their uses for treating D1-mediated (or D1-associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), ADHD, impulsivity, compulsive gambling, overeating, autism spectrum disorder, MCI, age-related cognitive decline, dementia, RLS, Parkinson's disease, Huntington's chorea, anxiety, depression, MDD, TRD, and bipolar disorder.
1. A method for treating a disorder in a mammal which method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I:
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, 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);
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 ;
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;
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;
Q 1 is a moiety of
(“Moiety M 1 ”);
Q 1 or ring Q 1a is an optionally substituted pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl;
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-, (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 —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-, 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, —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,
and wherein said disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, cognitive impairment, and Parkinson's disease.
2. A method for treating a disorder in a mammal which method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I:
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, 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);
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 ;
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;
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;
Q 1 is a moiety of
(“Moiety M 1 ”);
represents a single bond or double bond;
Z 1 is C;
Z 2 is C or N;
Moiety M 1 is selected from the group consisting of 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, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, isoxazolo[5,4-c]pyridazinyl, isoxazolo[3,4-c]pyridazinyl, and [1,2,4]triazolo[4,3-b]pyridazinyl, each optionally substituted with 1, 2, or 3 R 10 and further optionally substituted with 1 or 2 R 10a ; or wherein Moiety M 1 is selected from the group consisting of pyrimidinyl, pyrazinyl, pyridinyl, pyridazinyl, 1H-pyrazolyl, 1H-pyrrolyl, 4H-pyrazolyl, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl, 2,4(1H,3H)-dioxo-pyrimidinyl, and 1H-2-oxo-pyrazinyl, each substituted with R 9 and further optionally substituted with 1, 2, or 3 R 10 ;
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-, (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 —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-, 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, —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,
and wherein said disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, cognitive impairment, and Parkinson's disease.
3. A method for treating a disorder in a mammal which method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I:
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, 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);
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 ;
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;
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;
Q 1 is a moiety of
(“Moiety M 1 ”);
Moiety M 1 is
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-, (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 —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-, 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, —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;
m is 0, 1, or 2;
R 10a is C 1-4 alkyl, C 1-4 haloalkyl, or C 3-7 cycloalkyl; and
t is 0 or 1,
and wherein said disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, cognitive impairment, and Parkinson's disease.
4. A method for treating a disorder in a mammal which method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I:
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, 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);
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 ;
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;
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;
Q 1 is a moiety of
(“Moiety M 1 ”);
Moiety M 1 is
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-, (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 —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-, 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, —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; and
R 11 is H, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-7 cycloalkyl,
and wherein said disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, cognitive impairment, and Parkinson's disease.
5. The method of claim 3 wherein R 9 is C 1-4 alkyl or —CN; and each R 10 is independently C 1-4 alkyl.
6. A method for treating a disorder in a human which method comprises administering to said human a therapeutically effective amount of a compound selected from:
4-[4-(4,6-dimethylpyrimidin-5-yl)-3-fluorophenoxy]-1H-pyrrolo[3,2-c]pyridine;
(+)-4,6-dimethyl-5-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one;
(−)-4,6-dimethyl-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;
4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1H-pyrazolo[4,3-c]pyridine;
4,6-dimethyl-5-[4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one;
(−)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione;
4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-1;
4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-2;
4-[4-(4,6-dimethyl-1-oxidopyrimidin-5-yl)-3-methylphenoxy]-1H-pyrazolo[4,3-c]pyridine;
6-methyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]imidazo[1,2-a]pyrazine;
4-[4-(4,6-dimethylpyrimidin-5-yl)phenoxy]-1H-pyrrolo[3,2-c]pyridine;
2-(4,6-dimethylpyrimidin-5-yl)-5-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)benzonitrile;
4-[3-chloro-4-(4,6-dimethylpyrimidin-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-[4-(4,6-dimethylpyrimidin-5-yl)-3-fluorophenoxy]-1H-pyrazolo[4,3-c]pyridine;
4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methoxyphenoxy]-1H-pyrazolo[4,3-c]pyridine;
4-[3-chloro-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;
4,6-dimethyl-5-[4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one; and
1,5-dimethyl-6-[4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione,
or a pharmaceutically acceptable salt thereof,
and wherein said disorder is selected from the group consisting of schizophrenia, schizoaffective disorder, cognitive impairment, and Parkinson's disease.
7. The method of claim 1 , wherein said disorder is cognitive impairment.
8. The method of claim 1 , wherein said disorder is Parkinson's disease.
9. The method of claim 2 , wherein said disorder is cognitive impairment.
10. The method of claim 2 , wherein said disorder is Parkinson's disease.
11. The method of claim 3 , wherein said disorder is cognitive impairment.
12. The method of claim 3 , wherein said disorder is Parkinson's disease.
13. The method of claim 4 , wherein said disorder is cognitive impairment.
14. The method of claim 4 , wherein said disorder is Parkinson's disease.
15. The method of claim 5 , wherein said disorder is cognitive impairment.
16. The method of claim 5 , wherein said disorder is Parkinson's disease.
17. The method of claim 6 , wherein said disorder is cognitive impairment.
18. The method of claim 6 , wherein said disorder is Parkinson's disease.
19. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-fluorophenoxy]-1H-pyrrolo[3,2-c]pyridine or a pharmaceutically acceptable salt thereof.
20. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-fluorophenoxy]-1H-pyrrolo[3,2-c]pyridine.
21. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-fluorophenoxy]-1H-pyrrolo[3,2-c]pyridine.
22. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-fluorophenoxy]-1H-pyrrolo[3,2-c]pyridine or a pharmaceutically acceptable salt thereof.
23. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-fluorophenoxy]-1H-pyrrolo[3,2-c]pyridine.
24. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-fluorophenoxy]-1H-pyrrolo[3,2-c]pyridine.
25. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1H-pyrazolo[4,3-c]pyridine or a pharmaceutically acceptable salt thereof.
26. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1H-pyrazolo[4,3-c]pyridine.
27. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1H-pyrazolo[4,3-c]pyridine.
28. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1H-pyrazolo[4,3-c]pyridine or a pharmaceutically acceptable salt thereof.
29. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1H-pyrazolo[4,3-c]pyridine.
30. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1H-pyrazolo[4,3-c]pyridine.
31. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is (−)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof.
32. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is (−)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione.
33. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of (−)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione.
34. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is (−)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione or a pharmaceutically acceptable salt thereof.
35. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is (−)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione.
36. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of (−)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione.
37. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-1 or a pharmaceutically acceptable salt thereof.
38. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-1.
39. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-1.
40. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-1 or a pharmaceutically acceptable salt thereof.
41. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-1.
42. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-1.
43. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-2 or a pharmaceutically acceptable salt thereof.
44. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-2.
45. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-2.
46. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-2 or a pharmaceutically acceptable salt thereof.
47. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-2.
48. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of 4,6-dimethyl-5-[2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)phenyl]pyridazin-3(2H)-one, ENT-2.
49. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 2-(4,6-dimethylpyrimidin-5-yl)-5-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)benzonitrile or a pharmaceutically acceptable salt thereof.
50. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 2-(4,6-dimethylpyrimidin-5-yl)-5-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)benzonitrile.
51. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of 2-(4,6-dimethylpyrimidin-5-yl)-5-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)benzonitrile.
52. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 2-(4,6-dimethylpyrimidin-5-yl)-5-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)benzonitrile or a pharmaceutically acceptable salt thereof.
53. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is 2-(4,6-dimethylpyrimidin-5-yl)-5-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)benzonitrile.
54. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of 2-(4,6-dimethylpyrimidin-5-yl)-5-(1H-pyrrolo[3,2-c]pyridin-4-yloxy)benzonitrile.
55. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is (+)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrazin-2(1H)-one or a pharmaceutically acceptable salt thereof.
56. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is (+)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrazin-2(1H)-one.
57. The method of claim 17 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of (+)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrazin-2(1H)-one.
58. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is (+)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrazin-2(1H)-one or a pharmaceutically acceptable salt thereof.
59. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is (+)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrazin-2(1H)-one.
60. The method of claim 18 wherein the compound or pharmaceutically acceptable salt thereof to be administered is a pharmaceutically acceptable salt of (+)-1,5-dimethyl-6-[2-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yloxy)phenyl]pyrazin-2(1H)-one.