US Patent No. 9,133,190

HETEROAROMATIC COMPOUNDS AND THEIR USE AS DOPAMINE D1 LIGANDS


Patent No. 9,133,190
Issue Date September 15, 2015
Title Heteroaromatic Compounds And Their Use As Dopamine D1 Ligands
Inventorship Jennifer Elizabeth Davoren, Cambridge, MA (US)
Amy Beth Dounay, Colorado Springs, CO (US)
Ivan Viktorovich Efremov, Chestnut Hill, MA (US)
David Lawrence Firman Gray, Groton, MA (US)
Scot Richard Mente, Arlington, MA (US)
Bruce Nelsen Rogers, Belmont, MA (US)
Chakrapani Subramanyam, South Glastonbury, CT (US)
Lei Zhang, Auburndale, MA (US)
Assignee PFIZER INC., New York, NY (US)

Claim of US Patent No. 9,133,190

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 T1, T2, T3, and T4 is independently selected from the group consisting of H, halogen, —CN, C1-4 alkyl, C1-4 haloalkyl, cyclopropyl, fluorocyclopropyl, C1-4 alkoxy, C1-4 haloalkoxy, and —C(?O)—O—(C1-4 alkyl);

X1 is N or CH;

each of R1 and R2 is independently selected from the group consisting of H, halogen, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C3-4 cycloalkyl;

each of R3 and R4 is independently selected from the group consisting of H, halogen, —OH, —CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C3-4 cycloalkyl, a 4- to 7-membered heterocycloalkyl, —N(R5)(R6), and —OR8;

each of R5 and R6 independently is H or selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, and C3-7 cycloalkyl;

or R5 and R6 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,
C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy;

R8 is selected from the group consisting of C1-4 alkyl, C3-6 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, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy;

Q1 is a moiety of

(“Moiety M1”);
Q1 or ring Q1a is an optionally substituted pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl;

represents a single bond or double bond;
Z1 is C;

Z2 is C or N;

R9 is C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, —CN, —N(R5)(R6), C1-6 alkoxy, C1-6 haloalkoxy, or C3-7 cycloalkoxy, 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, —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, C6-10 aryl, a 4- to 10-membered heterocycloalkyl, 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-, (5- to 10-membered heteroaryl)-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C2-4 alkenyl-, —N(R5)(R6), —N(R7)(C(?O)R8), —S(?O)2N(R5)(R6), —C(?O)—N(R5)(R6), —C(?O)—R8, —C(?O)—OR8, and —OR8, wherein each of said C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, 4- to 10-membered heterocycloalkyl, 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-, (5- to 10-membered heteroaryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C2-4 alkenyl- 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 the adjacent R10 together with the two ring atoms on ring Q1a 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;

each R10a is independently selected from the group consisting of halogen, —OH, —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; 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.