US Patent No. 9,868,744

HETEROAROMATIC COMPOUNDS AND THEIR USE AS DOPAMINE D1 LIGANDS


Patent No. 9,868,744
Issue Date January 16,2018
Title Heteroaromatic Compounds And Their Use As Dopamine D1 Ligands
Inventorship David Lawrence Firman Gray, Groton, MA (US)
Lei Zhang, Auburndale, MA (US)
Jennifer Elizabeth Davoren, Cambridge, MA (US)
Amy Beth Dounay, Colorado Springs, CO (US)
Ivan Viktorovich Efremov, Brookline, MA (US)
Chewah Lee, Wallingford, CT (US)
Scot Richard Mente, Arlington, MA (US)
Bruce Nelsen Rogers, Belmont, MA (US)
Chakrapani Subramanyam, South Glastonbury, CT (US)
Assignee Pfizer Inc., New York, NY (US)

Claim of US Patent No. 9,868,744

1. A compound of Formula I-a:
or a pharmaceutically acceptable salt thereof, wherein:
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;

T1 is H, F, Cl, methyl, or C1 fluoroalkyl;

each of T2 and T3 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;

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, a 4- to 10-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, 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 halogen, 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, 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-, —N(R5)(R6), —N(R7)(C(?O)R8), —S(?O)2N(R5)(R6), —C(?O)—N(R5)(R6), —C(?O)—R8, —C(?O)—R8, —SR8, 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-, and (5- to 10-membered heteroaryl)-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 selected R10a; 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.