Heteroaromatic compounds and their use as dopamine D1 ligands

Patent metadata

Field	Value
Publication number	US-9856263-B2
Application number	US-201515305390-A
Country	US
Kind code	B2
Filing date	Apr 15, 2015
Priority date	Apr 28, 2014
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

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.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
L 1 is O, S, NR N , C(═O), or CH(OH);
Q 1 is an N-containing 5- to 10-membered heteroaryl, an N-containing 4- to 12-membered heterocycloalkyl, or phenyl, wherein each of the heteroaryl, heterocycloalkyl, or phenyl is optionally substituted with one R 9 and further optionally substituted with 1, 2, 3, or 4 R 10 ;
X 1 is N or C-T 1 ;
X 2 is N or C-T 2 ;
X 3 is N or C-T 3 ;
X 4 is N or C-T 4 ;
provided that at most two of X 1 , X 2 , X 3 , and X 4 are N;
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, C 3-4 cycloalkyl, C 3-4 halocycloalkyl, cyclopropylmethyl, C 1-4 alkoxy, C 1-4 haloalkoxy;
T 5 is H, F, Cl, methyl, or C 1 fluoroalkyl;
R N is H, C 1-4 alkyl, C 3-4 cycloalkyl, or —C 1-2 alkyl-C 3-4 cycloalkyl,
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, C 1-6 haloalkoxy, C 3-6 cycloalkyl, —C(═O)OH, and C(═O)—O—(C 1-4 alkyl), wherein each of said C 1-6 alkyl and C 3-6 cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halo, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
each of R 3 and R 4 is independently selected from the group consisting of H, halogen, —OH, —NO 2 , —CN, —SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, —N(R 5 )(R 6 ), —N(R 7 )(C(═O)R 8 ), —C(═O)—N(R 5 )(R 6 ), —C(═O)—R 8 , —C(═O)—OR 8 , —OC(═O)R 8 , —N(R 7 )(S(═O) 2 R 8 ), —S(═O) 2 —N(R 5 )(R 6 ), —SR 8 , and —OR 8 , wherein each of said C 1-6 alkyl, C 3-7 cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, —OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, —N(R 5 )(R 6 ), —N(R 7 )(C(═O)R 8 ), —C(═O)—OR 8 , —C(═O)H, —C(═O)R 8 , —C(═O)N(R 5 )(R 6 ), —N(R 7 )(S(═O) 2 R 8 ), —S(═O) 2 —N(R 5 )(R 6 ), —SR 8 , and —OR 8 ;
or R 1 and R 3 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, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, and C 1-3 haloalkoxy;
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;
R 8 is selected from the group consisting of C 1-6 alkyl, C 3-7 cycloalkyl, a 4- to 14-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, 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;
R 9 is halogen, C 1-4 alkyl, C 1-4 haloalkyl, —CN, —SF 5 , —N(R 5 )(R 6 ), C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkoxy, or C 3-7 cycloalkyl, 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, —SF 5 , —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-, —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 , —SR 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-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- 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 an adjacent R 10 together with the two ring atoms on Q 1 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 ; and
each R 10a is independently selected from the group consisting of halogen, —OH, —N(R 5 )(R 6 ), —C(═O)OH, —C(═O)—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-4 alkyl) 2 , —CN, —SF 5 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxylalkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy,

with the proviso that
(1) when L 1 is NR N , then X 2 is CT 2 ; and
(2) when L 1 is O, X 2 is N, then Q 1 is not an optionally substituted tetrazolyl group.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is O or S.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L 1 is O.

4. The compound of claim 1 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, F, Cl, Br, —CN, methoxy, C 1 fluoroalkoxy, methyl

Assignees

• Pfizer

Inventors

• Gray David Lawrence Firman
• Davoren Jennifer Elizabeth
• Dounay Amy Beth
• Efremov Ivan Viktorovich
• Mente Scot Richard
• Subramanyam Chakrapani

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title