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US 9,850,232 B2Granted
Heteroaromatic compounds and their use as dopamine D1 ligands
AssigneePfizer Inc.
InventorsDavid Lawrence Firman Gray, Lei Zhang, Michael Aaron Brodney, Michael Eric Green, Chakrapani Subramanyam
Life of this patent
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Abstract
The present invention provides, in part, compounds of Formula I: and pharmaceutically acceptable salts thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating D1-mediated (or D1-associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), schizotypal personality disorder, cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), ADHD, Parkinson's disease, anxiety, and depression.
Claims25
A compound of Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- the compound of Formula I is a compound of Formula I-c, I-d, or I-e:
- Q1 is an N-containing 5- to 6-membered heteroaryl or an N-containing 5- to 6-membered heterocycloalkyl, each optionally substituted with one R9 and further optionally substituted with 1, 2, 3, or 4 R10;
- each of T1, T2, T3, T4, and T5 is independently selected from the group consisting of H, halogen, —CN, C1-4 alkyl, C1-4 haloalkyl, C3-4 cycloalkyl, C3-4 halocycloalkyl, cyclopropylmethyl, C1-4 alkoxy, C1-4 haloalkoxy;
- T6 is H, F, Cl, methyl, or C1 fluoroalkyl;
- each of R1 and R2 is independently selected from the group consisting of H, halogen, —CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, —C(═O)OH, and C(═O)—O—(C1-4 alkyl), wherein each of said C1-6 alkyl and C3-6 cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halo, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
- each of R3 and R4 is independently selected from the group consisting of H, halogen, —OH, —NO2, —CN, —SF5, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, —N(R5)(R6), —N(R7)(C(═O)R8), —C(═O)—N(R5)(R6), —C(═O)—R8, —C(═O)—OR8, —OC(═O)R8, —N(R7)(S(═O)2R8), —S(═O)2—N(R5)(R6), —SR8, and —OR5, wherein each of said C1-6 alkyl, C3-7 cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, —OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, —N(R5)(R6), —N(R7)(C(═O)R8), —C(═O)—OR8, —C(═O)H, —C(═O)R8, —C(═O)N(R5)(R6), —N(R7)(S(═O)2R8), —S(═O)2—N(R5)(R6), —SR8, and —OR8;
- or R1 and R3 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, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;
- R5 is H, C1-4 alkyl, C1-4 haloalkyl, or C3-7 cycloalkyl;
- R6 is H or selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)—C1-4 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, C1-4 alkyl, C3-7 cycloalkyl, C1-4 hydroxylalkyl, —S—C1-4 alkyl, —C(═O)H, —C(═O)—C1-4 alkyl, —C(═O)—O—C1-4 alkyl, —C(═O)—NH2, —C(═O)—N(C1-4 alkyl)2, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
- or R5 and R6 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)—C1-4 alkyl, —C(═O)—NH2, —C(═O)—N(C1-4 alkyl)2, —CN, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxylalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy;
- R7 is selected from the group consisting of H, C1-4 alkyl, and C3-7 cycloalkyl;
- R8 is selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, a 4- to 14-membered heterocycloalkyl, C6-10 aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)—C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)—C1-4 alkyl-, (C6-10 aryl)C1-4 alkyl-, and (5- to 10-membered heteroaryl)—C14 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, —CF3, —CN, —OH, oxo, —S—C1-4 alkyl, C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
- R9 is C1-4 alkyl, C1-4 haloalkyl, —CN, —SFS, —N(R5)(R6), C1-6 alkoxy, C1-6 haloalkoxy, C3-7 cycloalkoxy, or C3-7 cycloalkyl, wherein each of the C1-4 alkyl and C3-7 cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen, —N(R5)(R6), C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
- each R10 is independently selected from the group consisting of halogen, —OH, —CN, —SFS, —NO2, oxo, thiono, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxylalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, (C3-7 cycloalkyl)—C1-4 alkyl-, —N(R5)(R6), —N(R7)(C(═O)R8), —S(═O)2N(R5)(R6), —SR8, and —OR8, wherein each of said C1-6 alkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)—C1-4 alkyl-, is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, OH, —CN, —NO2, C1-4 alkyl, C1-4 hydroxylalkyl, C1-4 alkoxy, —N(R5)(R6), —S—(C1-4 alkyl), —S(═O)2—(C1-4 alkyl), C6-10 aryloxy, [(C6-10 aryl)—C1-4 alkyloxy-optionally substituted with 1 or 2 C1-4 alkyl], oxo, —C(═O)H, —C(═O)—C1-4 alkyl, —C(═O)O-C1-4 alkyl, —C(═O)NH2, —NHC(═O)H, —NHC(═O)—(C1-4 alkyl), C3-7 cycloalkyl, a 5- or 6-membered heteroaryl, C1-4 haloalkyl, and C1-4 haloalkoxy;
- or R9 and an adjacent R10 together with the two ring atoms on Q1 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 selectedR10a;
- and
- each R10a is independently selected from the group consisting of halogen, —OH, —N(R5)(R6), —C(═O)OH, —C(═O)—C1-4 alkyl, —C(═O)—NH2, —C(═O )—N(C1-4 alkyl)2, —CN, —SF5, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxylalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy, with the proviso that
- when Q1 is an optionally substituted 4H-1,2,3,4-triazol-3-yl, then Q1 is not substituted by —N(R5)(R6).
16 more elements
A compound that is selected from the group consisting of:
- 6-[4-(isoquinolin-1-yloxy)-2-methylphenyI]-1,5-dimethylpyrimidine-2,4(1H,3H)-dione;
- 5-[4-(isoquinolin-1-yloxy)-2-methylphenyI]-4,6-dimethylpyridazin-3(2H)-one;
- 5-{4-[(7-methoxyisoquinolin-1-yl)oxy]-2-methylphenyl}-4,6-dimethylpyridazin-3(2H)-one;
- 1-[4-(3,5-dimethyl-6-oxo-1,6-dihydropyridazin-4-yl)-3-methylphenoxy]isoquinoline-7-carbonitrile;
- and
- 1-[4-(3,5-dimethyl-6-oxo-1,6-dihydropyridazin-4-yl)-3-methylphenoxy]isoquinoline-8-carbonitrile,
- or a pharmaceutically acceptable salt thereof.
4 more elements
A compound of Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- L1 is O or S;
- Q1 is
- R10a is C1-4 alkyl or C1-4 haloalkyl;
- t1 is 0 or 1;
- t is 0 or 1;
- or Q1 is
- or Q1 is R11 is H, C1-4 alkyl, C1-4 haloalkyl, (C1-2 alkoxy)—C1-4 alkyl-, or C3-7 cycloalkyl;
- X1 is C-T1;
- X2 is C-T2;
- X3 is C-T3;
- X4 is C-T4;
- X5 is C-T6;
- each of T1, T2, T3, T4, and 5 is independently selected from the group consisting of H, halogen, —CN, C1-4 alkyl, C1-4 haloalkyl, C3-4 cycloalkyl, C3-4 halocycloalkyl, cyclopropylmethyl, C1-4 alkoxy, C1-4 haloalkoxy;
- T6 is H, F, Cl, methyl, or C1 fluoroalkyl;
- each of R1 and R2 is independently selected from the group consisting of H, halogen, —CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, —C(═O)OH, and C(═O)—O—(C1-4 alkyl), wherein each of said C1-6 alkyl and C3-6 cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halo, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
- each of R3 and R4 is independently selected from the group consisting of H, halogen, —OH, —NO2, —CN, —SF5, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, —N(R5)(R6), —N(R7)(C(═O)R8), —C(═O)—N(R5)(R6), —C(═O)—R8, —C(═O)—OR8, —OC(═O)R8, —N(R7)(S(═O)2R8), —S(═O)2—N(R5)(R6), —SR8, and —OR8, wherein each of said C1-6 alkyl, C3-7 cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, —OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, —N(R5)(R6), —N(R7)(C(═O)R8), —C(═O)—OR8, —C(═O)H, —C(═O)R8, —C(═O)N(R5)(R6), —N(R7)(S(═O)2R8), —S(═O)2—N(R5)(R6), —SR8 and —OR8;
- or R1 and R3 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, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;
- R5 is H, C1-4 alkyl, C1-4 haloalkyl, or C3-7 cycloalkyl;
- R6 is H or selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)—C1-4 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, C1-4 alkyl, C3-7 cycloalkyl, C1-4 hydroxylalkyl, —S—C1-4 alkyl, —C(═O)H, —C(═O)—C1-4 alkyl, —C(═O)—O—C1-4 alkyl, —C(═O)—NH2, —C(═O)—N(C1-4 alkyl)2, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
- or R5 and R6 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)—C1-4 alkyl, —C(═O)—NH2, —C(═O)—N(C1-4 alkyl)2, —CN, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxylalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy;
- R7 is selected from the group consisting of H, C1-4 alkyl, and C3-7 cycloalkyl;
- R8 is selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, a 4- to 14-membered heterocycloalkyl, C6-10 aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)—C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)—C1-4 alkyl-, (C6-10 aryl)—C1-4 alkyl-, and (5- to 10-membered heteroaryl)—C1-4 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, —CF3, —CN, —OH, oxo, —S—C1-4 alkyl, C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
- R9 is C1-4 alkyl, C1-4 haloalkyl, —CN, —SF5, —N(R5)(R6), C1-6 alkoxy, C1-6 haloalkoxy, C3-7 cycloalkoxy, or C3-7 cycloalkyl, wherein each of the C1-4 alkyl and C3-7 cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen, —N(R5)(R6), C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;
- each R10 is independently selected from the group consisting of halogen, —OH, —CN, —SF5, —NO2, oxo, thiono, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxylalkyl,C1-6 alkoxy, C1-6 haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, (C3-7 cycloalkyl)—C1-4 alkyl—, —N(R5)(R6), —N(R7)(C(═O)R8), —S(═O)2N(R5)(R6), —SR8, and —OR8, wherein each of said C1-6 alkyl, C3-7 cycloalkyl, and (C3-7 cycloalkyl)—C1-4 alkyl- is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, OH, —CN, —NO2, C1-4 alkyl, C1-4 hydroxylalkyl, C1-4 alkoxy, —N(R5)(R6), —S—(C1-4 alkyl), —S(═C)2-(C1-4 alkyl), C6-10 aryloxy, [(C6-10 aryl)—C1-4 alkyloxy- optionally substituted with 1 or 2 C1-4 alkyl], oxo, —C(═O)H, —C(═O)—C1-4 alkyl, —C(═O)O—C1-4 alkyl, —C(═O)NH2, —NHC(═O)H, —NHC(═O)-(C1-4 alkyl), C3-7, cycloalkyl, a 5- or 6-membered heteroaryl, C1-4 haloalkyl, and C1-4 haloalkoxy;
- or R9 and an adjacent R10 together with the two ring atoms on Q1 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 R10a;
- and
- each R10a is independently selected from the group consisting of halogen, —OH, —N(R5)(R6), —C(═O)OH, —C(═C)—C1-4 alkyl, —C(═O)—NH2, —C(═O)—N(C1-4 alkyl)2, —CN, —SF5, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxylalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy, with the proviso that when Q1 is an optionally substituted 4H-1,2,4-triazol-3-yl, then Q1 is not substituted by —N(R5)(R6).
25 more elements
Dependencies are inferred from the claim text.