Heteroaromatic compounds and their use as dopamine d1 ligands

A method for treating a D1-mediated (or D1-associated) 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:
• L1 is O, S, NRN, C(═O), CH(OH), or CH(OCH3);
• Q1 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 R9 and further optionally substituted with 1, 2, 3, or 4 R10;
• X1 is N or C-T1;
• X2 is N or C-T2;
• X3 is N or C-T3;
• X4 is N or C-T4;
• X5 is N or C-T5;
• provided that at most two of X2, X2, X4, and X5 are N;
• each of T1, T2, T3, T4, and T5 is independently selected from the group consisting of H, —OH, halogen, —CN, optionally substituted C1-4 alkyl, optionally substituted C3-4 cycloalkyl, optionally substituted cyclopropylmethyl, and optionally substituted C1-4 alkoxy;
• T6 is H, —OH, halogen, —CN, or optionally substituted C1-2 alkyl;
• RN is H, C1-4 alkyl, C3-4 cycloalkyl, or —C1-2 alkyl-C3-4 cycloalkyl;
• each of Wand R2 is independently selected from the group consisting of H, halogen, —CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and C3-6 cycloalkyl, 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, —NH2, —NH(CH3), —N(CH3)2, —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, —NH2, —NH(CH3), —N(CH3)2, —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, —NH2, —NH(CH3), —N(CH3)2, —CN, C1-4 alkyl, C3-7 cycloalkyl, C1-4 hydroxylalkyl, —S—C1-4 alkyl, —O(═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, —NH2, —NH(CH3), —N(CH3)2, 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, —NH2, —NH(CH3), —N(CH3)2, 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, 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)R9), —S(═O)2N(R5)(R6), —C(═O)—N(R5)(R6), —C(═O)—R8, —C(═O)—OR8, —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,
• with the proviso that
• (a) when L1 is NRN, then Q1 is not unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl;
• and
• (b) when X1 is N, then Q1 is not an optionally substituted bicyclic heterocycloalkyl selected from octahydroquinolizinyl, octahydroindolizinyl, and hexahydropyrrolizinyl,
• wherein the D1-mediated (or D1-associated) disorder is selected from the group consisting of schizophrenia, schizotypal personality disorder, cognitive impairment, attention deficit hyperactivity disorder (ADHD), impulsivity, compulsive gambling, overeating, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, dementia, restless leg syndrome (RLS), Parkinson's disease, Huntington's chorea, anxiety, depression, major depressive disorder (MDD), treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum depression, serotonin syndrome, substance abuse and drug dependence, drug abuse relapse, Tourette's syndrome, tardive dyskinesia, drowsiness, excessive daytime sleepiness, cachexia, inattention, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis, dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, hyponatremia, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, and pain.