OA18535A - Heteroramatic Compounds and their use as Dopamine D1 Ligands. - Google Patents

Heteroramatic Compounds and their use as Dopamine D1 Ligands. Download PDF

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OA18535A
OA18535A OA1201600388 OA18535A OA 18535 A OA18535 A OA 18535A OA 1201600388 OA1201600388 OA 1201600388 OA 18535 A OA18535 A OA 18535A
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alkyl
cycloalkyl
haloalkyl
group
compound
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OA1201600388
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Inc. Pfizer
Chakrapani Subramanyam
Michael Eric GREEN
Michael Aaron Brodney
Lei Zhang
David Lawrence Firman Gray
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Inc. Pfizer
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Publication of OA18535A publication Critical patent/OA18535A/en

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Abstract

The present invention provides, in part, compounds of Formula I

Description

FIELD OF THE INVENTION
The présent invention generally relates to heteroaromatic compounds, which are dopamine D1 ligands, for example dopamine D1 agonists or partial agonists.
BACKGROUND OF THE INVENTION
Dopamine acts upon neurons through two families of dopamine receptors, D1like receptors (D1Rs) and D2-like receptors (D2Rs). The D1 -like receptor family consists of D1 and D5 receptors which are expressed in many régions of the brain. D1 mRNA has been found, for example, in the striatum and nucléus accumbens. See e.g., Missale C, Nash SR, Robinson SW, Jaber M, Caron MG “Dopamine receptors: from structure to function, Physiologlcal Reviews 78:189-225 (1998). Pharmacological studies hâve reported that D1 and D5 receptors (D1/D5), namely D1 -like receptors, are linked to stimulation of adenylyl cyclase, whereas D2, D3, and D4 receptors, namely D2-like receptors, are linked to inhibition of cAMP production.
Dopamine D1 receptors are implicated in numerous neuropharmacological and neurobiological functions. For example, D1 receptors are involved in different types of memory function and synaptic plasticity. See e.g., Goldman-Rakic PS et al., “Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfonction,
Psychopharmacology 174(1):3-16 (2004). Moreover, D1 receptors hâve been implicated in a variety of psychiatrie, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, rénal, ophthalmic, endocrine, and/or other disorders described herein including schizophrenia (e.g., cognitive and négative symptoms in schizophrenia), schizotypal personality disorder, cognitive impaîrment associated with D2 antagonîst therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impaîrment (MCI), age-related cognitive décliné, Alzheimer’s dementia, Parkinson's disease (PD), Huntington's chorea, dépréssion, anxiety, treatment-resistant dépréssion (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum dépréssion, serotonin syndrome, substance abuse and drug dependence, Tourette’s syndrome, tardive dyskinesia, drowsiness, sexual dysfonction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dislipidemia, obesity, diabètes, sepsis, post-ischemic tubular necrosis, rénal failure, résistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, pain, and other disorders in a mammal. See e.g.,
Goulet M, Madras BK “D(1) dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated monkeys, Journal of Pharmacology and Experimental Therapy 292(2):714-24 (2000); Surmeier DJ étal., “The rôle of dopamine in modulating the structure and function of striatal circuits”, Prog. Brain Res. 183:149-67 (2010).
New or improved agents that modulate (such as agonize or partially agonize) D1R are needed for developing new and more effective pharmaceuticals to treat diseases or conditions associated with dysregulated activation of D1R, such as those described herein.
US20040167336 or W02002024695 reports octahydroindolizine, octahydroquinolizine and hexahydro-pyrrolizine dérivatives of the following formula:
their synthesis and their use as histaminic H1 and H3 antagonists, for example, for the treatment of disorders and conditions mediated by the histamine receptor.
US20120245172 or WO2012126922 reports heterocyclic amine dérivatives ofthe following formula:
as TAAR ligands useful in the treatment of TAAR related disease.
CN102558147 reports pyridinecarboxamide dérivatives ofthe following formula:
as inhibitors of tyrosine kinase and/or serine-threonine kinase for treating cancer.
US20130123284 or WO2011119894 reports compounds of the following formula:
(R2)p or N-oxide, Ν,Ν'-dioxide, Ν,Ν',Ν’’-trioxide, or pharmaceutically acceptable salts thereof as kinase inhibitors useful for treating, for example, lymphangiogenesis, angiogenesis and/or growth of a tumor.
W02007009524 reports 2-arylbenzothiazoles of the following formula
Rs
V M-v X
R?
useful as protein kinase inhibitors for treating diseases such as those associated with abnormal and hyperproliferation of cells.
Kim, Eun-sook et. al, “Design, synthèses and biological évaluations of nonpeptidic caspase 3 inhibitors,” Bulletin ofthe Korean Chemical Society (2002), 23(7), 1003-1010, reports design of certain scaffold for nonpeptidic caspase 3 Inhibitors, for example, compounds ofthe following formulas:
In addition, certain compounds of the following formula of x
(wherein X is H, OCH3, Cl, CN, NO2, or Ph) were prepared. But they didn't show inhibitory activities on caspase 3.
ln a first aspect, the présent invention provides a method for treating a D1SUMMARY OF THE INVENTION mediated (or D1-associated) disorder m a mammal, which method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable sait 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 12membered 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 Cm alkyl, optionally substituted cycloalkyl, and optionally substituted cyclopropylmethyl, and optionally substituted Cm alkoxy;
T6 is H, -OH, halogen, -CN, or optionally substituted C1-2 alkyl;
RN is H, Cm alkyl, Cm cycloalkyl, or - C1-2 alkyl-Ca^ cycloalkyl;
each of R1 and R2 is independently selected from the group consisting of H, halogen, -CN, Ci-β alkyl, C1-6 haloalkyl, Ci-e 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, Cm alkyl, Cm haloalkyl, Cm alkoxy, and Cm haloalkoxy;
each of R3 and R4 is independently selected from the group consisting of H, halogen, -OH, -NO2, -CN, -SFs, Cve alkyl, Ci-e haloalkyl, Ci-e 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(=0)-R8, -C(=O)-OR8, -OC(=O)R8, N(R7)(S(=O)2R8), -S(=O)2-N(Rs)(R6), -SR8, and -OR8, wherein each of said Ci-e 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, Cm alkyl, C1-4 alkoxy, C1-4 haloalkyl, Cm haloalkoxy, C3-e cycloalkyl, -N(R5)(R6), -N(R7)(C(=O)R8), -C(=O)-OR8, -C(=O)H, -C(=O)R8, -C(=O)N(R5)(R8), -N(R7)(S(=O)2R8), -S(=O)2N(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 6membered 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, -NH2, -NH(CH3), -N(CH3)2, C1-3 alkyl, Ci-3 alkoxy, Ci-3 haloalkyl, and C1-3 haloalkoxy;
R5is H, C1-4 alkyl, C1-4 haloalkyl, or C3-7 cycloalkyl;
R® is H or selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, Ce-io aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-CiM alkyl-, (4- to 10-membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-io aryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-CiM alkyl-, wherein each of the sélections 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, Cm hydroxylalkyl, -S-C1-4 alkyl, -C(=O)H, -C(=O)-Ci-4 alkyl, -C(=0)-0-Cim alkyl, -C(=O)-NH2, -C(=O)-N(Ci-4 alkyl)2, Cm haloalkyl, Cim alkoxy, and Cim haloalkoxy;
or R5 and R6 together with the N atom to which they are attached form a 4- to 10membered 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)-Cim alkyl, -C(=O)-NH2, -C(=O)-N(Ci-4 alkylfc -CN, Cm alkyl, Cm alkoxy, Cm hydroxylalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy;
R7 is selected from the group consisting of H, Cm alkyl, and C3-7 cycloalkyl;
R8 is selected from the group consisting of Cve alkyl, C3-7 cycloalkyl, a 4- to 14membered heterocycloalkyl, Ce-ioaryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)18535
Cm alkyl-, (4- to 10-membered heterocycloalkyl)-CM alkyl-, (Ce-io aryl)-CM alkyl-, and (5- to 10-membered heteroaryl)-Ci-4 alkyl-, wherein each ofthe sélections 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, Cm alkyl, Cm haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, Cm alkoxy, and Cm haloalkoxy;
each of R9 and R10 is independently selected from the group consisting of halogen, -OH, -CN, -SFs, -NO2, oxo, thiono, Ci-e alkyl, C1.6 haloalkyl, Ci-β hydroxylalkyl, Ci-6 alkoxy, Cm haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, a 4- to 10-membered heterocycloalkyl, a 5-to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 10-membered heterocycloalkyl)-CM alkyl-, (Ce-io aryl)-Ci-4 alkyl-, (5- to 10membered heteroaryl)-CM alkyl-, -N(R5)(R6), -N(R7)(C(=O)R8), -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, Ce-ίο aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 10-membered heterocycloalkyl)-CM alkyl-, (Ce-io aryl)-CiM alkyl-, and (5- to 10-membered heteroaryl)-CM alkyl- is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, OH, -CN, -NO2, Cm alkyl, Cm hydroxylalkyl, Cm alkoxy, N(R5)(R6), -S-(Cm alkyl), -S(=0)2-(Cm alkyl), Ce-io aryloxy, [(Ce-io aryl)-CM alkyloxyoptionally substituted with 1 or 2 Cm alkyl], oxo, -C(=O)H, -C(=0)-Cm alkyl, -C(=O)OCm alkyl, -C(=O)NH2, -NHC(=O)H, -NHC(=O)-(Cm alkyl), C3-7 cycloalkyl, a 5- or 6membered heteroaryl, Cm haloalkyl, and Cm 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 selectedR103; and each R10a is independently selected from the group consisting of halogen, -OH, -N(R5)(R6), -C(=O)OH, -C(=O)-Cm alkyl, -C(=O)-NH21 -C(=0)-N(Cm alkyl)2. -CN, -SFs, Cm alkyl, Cm alkoxy, Cm hydroxylalkyl, Cm haloalkyl, and Cm haloalkoxy. In some embodiments, each of T1, T2, T3, T4, and T5 is independently selected from the group consisting of H, halogen, -CN, Cim alkyl, Cm haloalkyl, C3-4 cycloalkyl, Cm halocycloalkyl, cyclopropylmethyl, Cm alkoxy, and Cm haloalkoxy; and T6 is H, F, Cl, methyl, or Ci fluoroalkyl. In some embodiments, when L1 is NRN and X1 is N, then Q1 is not unsubstituted pyrrolidînyl, unsubstituted piperidinyl, or unsubstituted morpholinyl.
In some embodiments, when L1 is NRN, then Q1 is not unsubstituted pyrrolidînyl, unsubstituted piperidinyl, or unsubstituted morpholinyl.
In some embodiments, when L1 is NRN, then Q1 is not an optionally substituted pyrrolidinyI, an optionally substituted piperidinyl, or an optionally substituted morpholinyl ring.
In some embodiments, when X1 is N, then Q1 is not unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl.
In some embodiments, when X1 is N, then Q1 is not an optionally substituted pyrrolidinyl, an optionally substituted piperidinyl, or an optionally substituted morpholinyl ring.
In some embodiments, Q1 is not an optionally substituted bicyclic heterocycloalkyl selected from octahydroquinolizinyl, octahydroindolizinyl, and hexahydropyrrolizinyl. In some embodiments, when X1 is N, then Q1 is not an optionally substituted bicyclic heterocycloalkyl selected from octahydroquinolizinyl, octahydroindolizinyl, and hexahydropyrrolizinyl.
In some embodiments, when X1 is N, then L1 is not NRN.
In some embodiments, each of the ring-forming atoms of Q1 is a nitrogen or carbon atom (i.e., Q1 ring does not hâve O or S heteroatom as a ring-forming atom).
In some embodiments, Q1 is not an optionally substituted bicyclic heterocycloalkyl selected from octahydroquinolizinyl, octahydroindolizinyl, and hexahydropyrrolizinyl; and when X1 is N or L1 is NRN, then Q1 is not an optionally substituted pyrrolidinyl, an optionally substituted piperidinyl, or an optionally substituted morpholinyl ring.
In some embodiments, when X1 is N, then Q1 is not an optionally substituted bicyclic heterocycloalkyl selected from octahydroquinolizinyl, octahydroindolizinyl, and hexahydropyrrolizinyl; and when X1 is N or L1 is NRN, then Q1 is not an optionally substituted pyrrolidinyl, an optionally substituted piperidinyl, or an optionally substituted morpholinyl ring.
In some embodiments, R9 is Cm alkyl, C1-4 haloalkyl, -CN, -SFs, -N(R5)(R6), C-i-s alkoxy, Ci-s 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), Cm alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, Cim alkoxy, and Cm haloalkoxy; and each R10 is independently selected from the group consisting of halogen, -OH, CN, -SFs, -NO2, oxo, thiono, C1-6 alkyl, C1-6 haloalkyl, Ci-e hydroxylalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cô-io aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 10membered heterocycloalkyl)-CiM alkyl-, (Ce-ίο aryl)-CiM alkyl-, (5- to 10-membered heteroaryl)-Ci^ alkyl-, -N(R5)(R6), -N(R7)(C(=O)RS), -S(=O)zN(R5)(R6), -C(=O)-N(RS)(R6), -C(=O)-R8, -C(=O)-OR8, -SR8, and -OR8, wherein each of said Ci-β alkyl, C3-7 cycloalkyl,
Ce-ίο aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C3.7 cycloalkyl)-Ci-4 alkyl-, (4- to 10-membered heterocycloalkyl)-Ci^ alkyl-, (C6-10 aryl)-Ci-4 alkyl-, and (5-to 10-membered heteroaryl)-Ci^ alkyl- is optionally substituted with 1, 2, 3, or 4 substîtuents 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-(Ci-4 alkyl), S(=O)2-(Ci-4 alkyl), C&.10 aryloxy, [(Cs-10 aryl)-Ci-4 alkyloxy- optionally substituted with 1 or 2 C1-4 alkyl], oxo, -C(=O)H, -C(=0)-Cw alkyl, -C(=O)O-Cm alkyl, -C(=O)NHz, NHC(=O)H, -NHC(=O)-(Ci-4 alkyl), C3-7 cycloalkyl, a 5- or 6-membered heteroaryl, C1-4 haloalkyl, and Ci-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.
In some embodiments, the disorder to be treated is selected from schizophrenia (e.g., cognitive and négative symptoms in schizophrenia), schizotypal personalîty disorder, cognitive impairment [e.g., cognitive impairment associated with schizophrenia, cognitive impairment associated with AD, cognitive impairment associated with PD, cognitive impairment associated with pharmacotherapy therapy (e.g., D2 antagonist therapy)], attention déficit hyperactivity disorder (ADHD), impulsivity, compulsive gambling, overeating, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive décliné, dementia (e.g., senile dementia, HIVassociated dementia, Alzheimer's dementia, Lewy body dementia, vascular dementia, or frontotemporal dementia), restless leg syndrome (RLS), Parkinson’s disease, Huntington's chorea, anxiety, dépréssion (e.g., age-related dépréssion), major dépressive disorder (MDD), treatment-resistant dépréssion (TRD), bipolar disorder, chronic apathy, anhedonîa, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum dépréssion, serotonin syndrome, substance abuse and drug dependence, drug abuse relapse, Tourette's syndrome, tardive dyskinesia, drowsiness, excessive daytime sleepiness, cachexia, inattention, sexual dysfunction (e.g., erectile dysfunction or post-SSRI sexual dysfunction), migraine, systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis, dislipidemia, obesity, diabètes, sepsis, post-ischemic tubular necrosis, rénal failure, hyponatremia, résistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, and pain.
ln some embodiments, L1 is O or S. In some further embodiments, L1 is O.
In some embodiments, L1 is S.
ln some embodiments, L1 is NH.
ln some embodiments, L1 is C(=O), CH(OH), or CH(OCH3). In some further embodiments, C(=O) or CH(OH).
ln some embodiments, each of T1, T2, T3, T4, and T5 is independently selected from the group consisting of H, halogen, -CN, methoxy, Ci fluoroalkoxy, methyl, and Ci fluoroalkyl. In some further embodiments, each of T1, T2, T3, T4, and T5 is independently selected from the group consisting of H, F, Cl, Br, -CN, methoxy, Ci fluoroalkoxy, methyl, and Ci fluoroalkyl,
In some embodiments, T6 is H.
ln some embodiments, X1 is CT1.
In some embodiments, none of X2, X2, X4, and X5 is N.
ln some embodiments, one and only one of X2, X2, X4, and X5 is N.
ln some embodiments, two of X2, X2, X4, andX5 are N.
ln some embodiments, X1 is CT1; and none of X2, X2, X4, and X5 is N.
In some embodiments, X1 is CT1; and one and only one of X2, X2, X4, and X5 is N.
In some embodiments, X1 is CT1; and two of X2, X2, X4, and X5 are N.
In some embodiments, X1 is CT1; T1 is H; and T6 is H.
ln some embodiments, X1 is CT1; and L1 is O or S. In some further embodiments, L1 is O.
In some embodiments, the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-a:
T1 l-a or a pharmaceutically acceptable sait thereof.
ln some embodiments, the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-b:
or a pharmaceutically acceptable sait thereof.
ln some embodiments, the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-c:
or a pharmaceutically acceptable sait thereof.
ln some embodiments, the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-d:
or a pharmaceutically acceptable sait thereof.
ln some embodiments, the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-e:
or a pharmaceutically acceptable sait thereof.
The embodiments described herein in the first aspect of the invention, unless specified otherwisely, include the methods for use ofa compound of Formula I, l-a, l-b, l-c, l-d, or l-e.
ln some embodiments, each of R1 and R2 is independently H or halogen.
ln some further embodiments, each of R1 and R2 is H.
ln some embodiments, each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy.
ln some embodiments, R3 is H and R4 is H, halogen, -CN, methyl, or Ci haloalkyl. ln some embodiments, R3 is H and R4 is methyl.
In some embodiments, Q1 is an N-containing 5- to 6-membered heteroaryl or an N-containing 5- to 6-membered heterocycloalkyl, each substituted with one R9 and further optionally substituted with 1, 2, 3, or 4 R10.
ln some embodiments:
(R10)m (“Moiety M1”);
ring Q1a is an N-containing 5- to 6-membered heteroaryl or an N-containing 5- to
6-membered heterocycloalkyl;
------represents a single bond or double bond;
each of Z1 and Z2 is independently C or N;
R9 is Cm alkyl, Cim 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), Cim alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, Cm alkoxy, and C-m 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, Ci-β alkoxy, C1-6 haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-io aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-CM alkyl-, (4- to 105 membered heterocycloalkyl)-CM alkyl-, (Ce-io aryl)-CM alkyl-, (5- to 10-membered heteroaryl)-Ci-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)(Re), -C(=O)-R8, -C(=O)-OR8, and OR8, wherein each of said C1-6 alkyl, C3-7 cycloalkyl, Ce-io aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 1010 membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-io aryl)-CM alkyl-, (5- to 10-membered heteroaryl)-Ci-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, Cm alkyl, Cu hydroxylalkyl, Cm alkoxy, N(R5)(R8), -S-(Cm alkyl), -S(=0)2-(Cm alkyl), Ce-io aryloxy, (Ce-io aryl)-Ciu alkyloxy15 optionally substituted with 1 or 2 Cm alkyl, oxo, -C(=O)H, -C(=0)-Cm alkyl, -C(=O)O-Ci4 alkyl, -C(=O)NH2, -NHC(=O)H, -NHC(=O)-(Cm alkyl), C3.7 cycloalkyl, a 5- or 6membered heteroaryl, Cm haloalkyl, and Cm 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)-Cm alkyl, -C(=O)-NHZ, -C(=O)-N(Cm alkyl)2, -CN, Cm alkyl, Cm alkoxy, Cm hydroxylalkyl, (C1-2 alkoxy)-CM alkyl-, Cm haloalkyl, and Cm haloalkoxy; and m is 0, 1,2, 3, or 4.
In some embodiments, Q1 is a moiety of Moiety M1 and Z1 is C.
In some embodiments, Q1 or ring Q1a is an optionally substituted N-containing 6membered heteroaryl.
In some embodiments, Q1 or ring Q1a is an optionally substituted pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. In some further embodiments, Q1 or ring Q1a is an optionally substituted pyrimidinyl, pyridazinyl, or pyrazinyl.
In some embodiments, Q1 or ring Q1a is pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of OH, Cm alkyl, Cm haloalkyl, (C1-2 alkoxy)-CM 35 alkyl-, and C3-7 cycloalkyl. ln some further embodiments, Q1 or ring Q1a is pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of C1-4 alkyl, Cia haloalkyl, (C1-2 alkoxy)-Ci-4 alkyl-, and C3-7 cycloalkyl. In still further embodiments, Q1 or ring Q1a is pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of C1-4 alkyl and C1-4 haloalkyl.
In some embodiments, Moiety M1 is selected from the group consisting of quinolinyl, isoquinolinyl, 1/7-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, 1/7pyrrolo[3,2-c]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-c][1,2,4]triazinyI, imidazo[1,5-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 1/7-indazolyl, 9/7-purinyl, imidazo[1,2-
a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, isoxazolo[5,4-c]pyridazinyl, isoxazolo[3,4c]pyridazinyl, and [1,2,4]triazolo[4,3-b]pyridazinyl, each optionally substituted with 1, 2, or 3 R10 and further optionally substituted with 1 or 2 R10a; or wherein Moiety M1 is selected from the group consisting of pyrimidinyl, pyrazinyl, pyridinyl, pyridazinyl, 1Hpyrazolyl, 1/7-pyrrolyl, 4/7-pyrazolyl, 1/7-imidazolyl, 1/7-imidazolyl, 3-oxo-2/7-pyridazinyl, 1/7-2-oxo-pyrimidinyl, 1/7-2-oxo-pyridinyl, 2,4(1 /7,3/7)-dioxo-pyrimidinyl, and 1/7-2-oxopyrazinyl, each substituted with R9 and further optionally substituted with 1, 2, or 3 R10.
ln some embodiments:
(R10)m
Moiety M1 is
-N
(“M1-a”), (R10)ti (R10)m (uM1-bn),
R10a is Cm alkyl, Cm haloalkyl, (C1-2 alkoxy)-CM alkyl-, or C3-7 cycloalkyl; t1 is 0 or 1; and tisOorl.
In some embodiments, Moiety Moiety M1 is R10 (M1-f”)
(“M1-e”), ln some embodiments, Moiety M1 is
C‘M1-j). ln some further embodiments, Moiety M1 is
membered heterocycloalkyl, wherein two of the ring-forming atoms of the 6-membered heterocycloalkyl are N atoms; four ofthe ring-forming atoms ofthe 6-membered heterocycloalkyl are C atoms; and the N-containing 6-membered heterocycloalkyl is the group consisting of oxo, -CN, Cm alkyl, Cm haloalkyl, (C1.2 alkoxy)-CM alkyl-, and optionally substituted with 1,2,3, 4, or 5 substituents each independently selected from
C3-7 cycloalkyl. ln some further embodiments, the N-containing 6-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of oxo, Cm alkyl, Cu haloalkyl, (C1-2 alkoxy)-Cm alkyl-, and C3-7 cycloalkyl.
In some embodiments:
R11 is H, Cm alkyl, Cu haloalkyl, (C1.2 alkoxy)-Ciu alkyl-, or C3-7 cycloalkyl. ln some further embodiments, R11 is Cm alkyl (e.g., methyl).
In some embodiments, R9 is Cu alkyl or -CN. ln some further embodiments, R9 is Cm alkyl. In some yet further embodiments, R9 is methyl.
In some embodiments, each R10 is independently selected from the group consisting of Cu alkyl, Cu haloalkyl, (C1-2 alkoxy)-Ci~4 alkyl-, -CN, and -N(R5)(R6), wherein each of R5 and R6 independently is H or selected from the group consisting of Cm 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, Cu alkyl, Cu alkoxy, C3-6 cycloalkyl, Cm haloalkyl, and Cm haloalkoxy. In some further embodiments, each R10 is independently Cm alkyl. ln some yet further embodiments, each R10 is methyl.
In some embodiments, none of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is as described in one ofthe embodiments provided herein (e.g., M1-g, M1-k, M1-m, or M1n). ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, none of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is
M1-g. ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O, ln still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 is independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, none of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-k. ln some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 is independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, none of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-m. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 is independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, none of X2, X2, X4, andX5 is N; Q1 is Moiety M1; and M1 is M1-n. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 is independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is as described in one ofthe embodiments provided herein (e.g., M1-g, M1-k, M1-m, or M1-n). ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 is independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-g. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 is independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
ln some embodiments, one and only one of X2, X2, X4, andX5 is N; Q1 is Moiety
M1; and M1 is M1-k. ln some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
ln some embodiments, one and only one of X2, X2, X4, andX5 is N; Q1 is Moiety M1; and M1 is M1-m. In some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-n. ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, two of X2, X2, X4, and X5 are N; Q1 is Moiety M1; and M1 is as described in one ofthe embodiments provided herein (e.g., M1-g, M1-k, M1-m, or M1n). ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, two of X2, X2, X4, andX5 are N; Q1 is Moiety M1; and M1 is M1-g. ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, two of X2, X2, X4, andX5 are N; Q1 is Moiety M1; and M1 is
M1-k. ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O.
ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, two of X2, X2, X4, andX5 are N; Q1 is Moiety M1; and M1 is M1-m. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 îs H; R3 is H; and R4 is methyl.
In some embodiments, two of X2, X2, X4, andX5 are N; Q1 is Moiety M1; and M1 is M1-n. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; none of X2, X2, X4, andX5 is N; and M1 is as described in one ofthe embodiments provided herein (e.g., M1-g, M1-k, M1-m, or M1-n). In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; none of X2, X2, X4, and X5 is N; and M1 is M1-g. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 andR4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; none of X2, X2, X4, and X5 is N; and M1 is M1-k. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; none of X2, X2, X4, andX5 is N; and M1 is M1-m.
In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, X1 is CT1; none of X2, X2, X4, andX5 is N; and M1 is M1-n. ln some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; one and only one of X2, X2, X4, andX5 is N; Q1 is Moiety M1; and M1 is as described in one ofthe embodiments provided herein (e.g., M1-g, M1-k, M1-m, or M1-n). In some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, X1 is CT1; one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-g. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
In some embodiments, X1 is CT1; one and only one of X2, X2, X4, and X5 îs N; Q1 is Moiety M1; and M1 is M1-k. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
ln some embodiments, X1 is CT1; one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-m. ln some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 îs H; R3 is H; and R4 is methyl.
ln some embodiments, X1 is CT1; one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-n. ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
ln some embodiments, X1 is CT1; two of X2, X2, X4, andX5 are N; Q1 is Moiety M1; and M1 is as described in one ofthe embodiments provided herein (e.g., M1-g, M1-k, M1m, or M1-n). ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 10 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, X1 is CT1; two of X2, X2, X4, andX5 are N; Q1 is Moiety M1;
and M1 is M1-g. ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 îs O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, X1 îs CT1; two of X2, X2, X4, and X5 are N; Q1 is Moiety M1;
and M1 is M1-k. ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and
R4 is methyl.
In some embodiments, X1 is CT1; two of X2, X2, X4, andX5 are N; Q1 is Moiety M1; and M1 is M1-m. In some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, X1 is CT1; two of X2, X2, X4, andX5 are N; Q1 is Moiety M1; and M1 is M1-n. ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen;
and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
The first aspect of the invention includes any subset of any embodiment described herein.
The first aspect of the invention includes combinations of two or more embodiments described herein, or any subset thereof.
The first aspect of the invention further provides the compound of Formula I or a pharmaceutically acceptable sait thereof for use (including ail embodiments and combinations of two or more embodiments described herein or any subset thereof) în treating a D1-mediated (or D1-associated) disorder described herein.
The first aspect of the invention further provides use of the compound of Formula I or a pharmaceutically acceptable sait thereof (including ail embodiments and combinations of two or more embodiments described herein or any subset thereof) for treating a D1-mediated (or D1-associated) disorder described herein.
The first aspect of the invention further provides use of the compound of Formula I or a pharmaceutically acceptable sait thereof (including ail embodiments and combinations of two or more embodiments described herein or any subset thereof) in manufacturing a médicament for use in treating a D1-mediated (or D1-associated) disorder described herein.
The term therapeutically effective amount as used herein refers to that amount of the compound (including a pharmaceutically acceptable sait thereof) being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. ln reference to the treatment of a D1-mediated disorder (e.g., schizophrenia), a therapeutically effective amount refers to that amount which has the effect of relieving to some extent (or, for example, eliminating) one or more symptoms associated with a D1-mediated disorder (e.g., schizophrenia, or cognitive and négative symptoms in schizophrenia, or cognitive impairment associated with schizophrenia).
The term treating, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term treatment, as used herein, unless otherwise indicated, refers to the act of treating as treating is defined herein. The term “treating also includes adjuvant and neo-adjuvant treatment of a subject
The compound of Formula I or its sait used in the method for treating a D1 mediated (or D1-associated) disorder of present invention is a D1R modulator (e.g., a
D1 agoninst for example, a D1 partial agonist). The amount ofthe compound of Formula I or a pharmaceutically acceptable amount used in the method of the présent invention is effective in modulating (e.g., agomzmg or partially agomztng) D1R.
The présent invention further provides a method for modulating (such as agonizing or partially agonizing) an activity of D1R (either in vitro or in vivo), comprising contacting (including incubating) the D1R with a compound of Formula I or a pharmaceutically acceptable sait thereof (such as one selected from Examples 1-14 herein) described herein.
In a second aspect, the présent invention provides a compound of Formula I:
or a pharmaceutically acceptable sait thereof, wherein:
L1 is O or S;
Q1 is an N-containing 5- to 6-membered heteroaryl or an N-contaîning 5- to 6membered heterocycloalkyl, each 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, X3, X4, and X5 are N;
each of T1, T2, T3, T4, and T5 is independently selected from the group consisting of H, halogen, -CN, Cm alkyl, Cu haloalkyl, C3-4 cycloalkyl, Csm halocycloalkyl, cyclopropylmethyl, Cm alkoxy, Cm haloalkoxy;
T6 is H, F, Cl, methyl, or Ci fluoroalkyl;
RN is H, Cm alkyl, C3-4 cycloalkyl, or - C1-2 alkyl-C3-4 cycloalkyl, 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, Cm haloalkoxy, C3-6 cycloalkyl, C(=O)OH, and C(=0)-0-(Cm alkyl), wherein each of said C1-6 alkyl and Ca-e cycloalkyl is
I optionally substituted with 1,2,3, 4, or 5 substituents each independently selected from halo, -OH, -CN, Cm alkyl, Cm haloalkyl, Cm alkoxy, and Cm haloalkoxy;
each of R3 and R4 is independently selected from the group consisting of H, halogen, -OH, -NO2, -CN, -SFs, Ci-e alkyl, C1-6 haloalkyl, C1.6 haloalkoxy, C2-e 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(Rs)(R6), -SR8, and -OR8, wherein each of said C1-6 alkyl, C37 cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, -OH, Cm alkyl,
Cm alkoxy, Cm haloalkyl, Cm 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)2N(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 615 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 Ci-3 haloalkoxy;
R5 is H, Cm alkyl, Cm haloalkyl, or C3-7 cycloalkyl;
R6 is H or selected from the group consisting of Cm alkyl, Cm haloalkyl, C3-7 cycloalkyl, a 4-to 10-membered heterocycloalkyl, Ce-io aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-CM alkyl-, (4-to 10-membered heterocycloalkyl)-CM alkyl-, (C6-io aryl)-CM alkyl-, and (5- to 10-membered heteroaryl)-CM alkyl-, wherein each of the sélections from the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of -OH, -CN, Cm alkyl, C3-7 cycloalkyl, Cm hydroxylalkyl, -S-Cm alkyl, -C(=O)H, -C(=O)-Cm alkyl, -C(=O)-O-Cm alkyl, -C(=O)NH2, -C(=0)-N(Cm alkyl)2, Cm haloalkyl, Cm alkoxy, and Cm haloalkoxy;
or R5 and R6 together with the N atom to which they are attached form a 4- to 10membered 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(=0)-Cm alkyl, -C(=O)-NH2, C(=O)-N(Cm alkyl)2, -CN, Cm alkyl, Cm alkoxy, Cm hydroxylalkyl, Cm haloalkyl, and Cm haloalkoxy;
R7 îs selected from the group consisting of H, Cm alkyl, and C3-7 cycloalkyl;
R8 is selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, a 4- to 14membered heterocycloalkyl, Ce-ioaryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-Ci-4 alkyl-, (C6-10 aryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-Ciu alkyl-, wherein each ofthe sélections 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-Cm alkyl, Cm alkyl, Cu haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Cu alkoxy, and Cu 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 Cu 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), Cu alkyl, Cu haloalkyl, C3-7 cycloalkyl, Cu alkoxy, and Cu 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, Ci-β alkoxy, C1-6 15 haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 10membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-io aryl)-Ci-4 alkyl-, (5- to 10-membered heteroaryl)-Ciu alkyl-, -N(R5)(R6), -N(R7)(C(=O)R8), -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, 20 Cs-io aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 10-membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-io aryl)-Ciu alkyl-, and (5- to 10-membered heteroaryl)-Ci-4 alkyl- is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, OH, -CN, -NO2, Cm alkyl, Cu hydroxylalkyl, Cu alkoxy, -N(R5)(R6), -S-(Cu alkyl),
-S(=O)2-(Ci-4 alkyl), Ce-io aryloxy, [(Cs-io aryl)-Ci-4 alkyloxy- optionally substituted with 1 or 2 Cu alkyl], oxo, -C(=O)H, -C(=0)-Cu alkyl, -C(=O)O-Cu alkyl, -C(=O)NH2, NHC(=O)H, -NHC(=O)-(Cm alkyl), C3-7 cycloalkyl, a 5- or 6-membered heteroaryl, Cu haloalkyl, and Cu 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)-Cu alkyl, -C(=O)-NH2, -C(=O)-N(Cu alkyl)2, -CN, -SFs, Cu alkyl, Cu alkoxy, Cu hydroxylalkyl, Cu haloalkyl, and Cu haloalkoxy.
ln some embodiments, when X1 is N, then Q1 is not an optionally substituted monocyclic 5-memered ring.
In some embodiments, when X1 is N, then Q1 is not an optionally substituted octahydroindolizinyl.
ln some embodiments, when X1 is N, then Q1 is not an optionally substituted bicyclic heterocycloalkyl selected from octahydroquinolizinyl, octahydroindolizinyl, and hexahydropyrrolizinyl.
In some embodiments, when X1 is N, then each of the ring-forming atoms of Q1 is a nitrogen or carbon atom.
In some embodiments, when X1 is N and Q1 is an optionally substituted 2-oxo1 /-/-pyridrn-1 -yl, then Q1 is not substituted by -C(=O)-N(R5)(R6), -C(=O)-RS, or -C(=O)OR8.
ln some embodiments, when Q1 is an optionally substituted 4/7-1,2,4-triazol-3-yl, then Q1 is not substituted by -N(R5)(R6).
ln some embodiments, Q1 is not an optionally substituted monocyclic 5-memered ring.
In some embodiments, Q1 is not an optionally substituted bicyclic heterocycloalkyl selected from octahydroquinolizinyl, octahydroindolizinyl, and hexahydropyrrolizinyl.
In some embodiments, each ofthe ring-forming atoms of Q1 is a nitrogen or carbon atom (i.e., Q1 ring does not hâve O or S heteroatom as a ring-forming atom).
ln some embodiments, a ring-forming carbon atom of Q1 is linked to the phenyl ring substituted with R1, R2, R3, and R4 of Formula I.
ln some embodiments, Q1 is not an optionally substituted monocyclic 5-memered ring; Q1 is not an optionally substituted bicyclic heterocycloalkyl selected from octahydroquinolizinyl, octahydroindolizinyl, and hexahydropyrrolizinyl; each ofthe ringforming atoms of Q1 is a nitrogen or carbon atom; and a ring-forming carbon atom of Q1 is linked to the phenyl ring substituted with R1, R2, R3, and R4 of Formula I.
ln some embodiments, L1 is O.
In some embodiments, L1 is S.
In some embodiments, each of T1, T2, T3, T4, and T5 is independently selected from the group consisting of H, halogen, -CN, methoxy, Ci fluoroalkoxy, methyl, and Ci fluoroalkyl.
In some embodiments, each of T1, T2, T3, T4, and T5 is independently selected from the group consisting of H, F, Cl, Br, -CN, methoxy, Ci fluoroalkoxy, methyl, and Ci fluoroalkyl.
ln some embodiments, T6 is H.
In some embodiments, X1 is CT1.
ln some embodiments, none of X2, X2, X4, and X5 is N.
In some embodiments, one and only one of X2, X2, X4, andX5 is N.
In some embodiments, two of X2, X2, X4, andX5 are N.
In some embodiments, X1 is CT1; and none of X2, X2, X4, andX5 is N.
In some embodiments, X1 is CT1; and only one of X2, X2, X4, and X5 is N.
In some embodiments, X1 is CT1; and two of X2, X2, X4, and X5 are N.
In some embodiments, X1 is CT1; and Q1 is not an optîonally substituted monocyclic 5-memered ring.
In some embodiments, X1 is CT1; Q1 is not an optîonally substituted monocyclic 5-memered ring; each of the ring-forming atoms of Q1 is a nitrogen or carbon atom; and a ring-forming carbon atom of Q1 is linked to the phenyl ring substituted with R1, R2, R3, and R4 of Formula I.
ln some embodiments, X1 is CT1; T1 is H; and T6 is H.
ln some embodiments, the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-a:
or a pharmaceutically acceptable sait thereof.
ln some embodiments, the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-b:
or a pharmaceutically acceptable sait thereof.
ln some embodiments, the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-c:
or a pharmaceutically acceptable sait thereof.
In some embodiments, the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-d:
or a pharmaceutically acceptable sait thereof.
In some embodiments, the compound of Formula l or a pharmaceutically acceptable sait thereof is a compound of Formula l-e:
or a pharmaceutically acceptable sait thereof.
The embodiments described herein in the second aspect, unless specified otherwisely, include a compound of Formula I, l-a, l-b, l-c, l-d, or l-e.
In some embodiments, each of R1 and R2 is independently H or halogen.
ln some further embodiments, each of R1 and R2 is H.
In some embodiments, each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy.
In some embodiments, R3is H and R4 is H, halogen, -CN, methyl, or Ci haloalkyl. In some further embodiments, R3 is H and R4 is methyl.
In some embodiments, Q1 is an N-containing 5- to 6-membered heteroaryl or an N-containing 5- to 6-membered heterocycloalkyl, each substituted with one R9 and further optionally substituted with 1, 2, 3, or 4 R10.
In some embodiments:
(R10)m (Moiety M1);
ring Q1a is an N-containing 5- to 6-membered heteroaryl or an N-containing 5- to
6-membered heterocycloalkyl;
------represents a single bond or double bond;
each of Z1 and Z2 is independently C or N;
R9 is Cm alkyl, Cm haloalkyl, C3-7 cycloalkyl, -CN, -N(R5)(R6), C1.6 alkoxy, Ci-e haloalkoxy, or C3-7 cycloalkoxy, wherein each of the Cm 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), Cm alkyl, Cim haloalkyl, C3-7 cycloalkyl, Cim alkoxy, and Cm 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, Ci-β alkoxy, C1-6 haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ίο aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-CiM alkyl-, (4- to 10membered heterocycloalkyl)-CiM alkyl-, (Ce-io aryl)-Ci-4 alkyl-, (5-to 10-membered heteroaryl)-Ci-4 alkyl-, (5- to 10-membered heteroaryl)-C2M 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)-Ci-4 alkyl-, (4- to 10membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-io aryl)-Ci-4 alkyl-, (5- to 10-membered heteroaryl)-Ci-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, Cm alkyl, C1-4 hydroxylalkyl, Cim alkoxy, N(R5)(R6), -S-(Ci-4 alkyl), -S(=O)2-(Ci-4 alkyl), Ce-io aryloxy, (C6-10 aryl)-Ci-4 alkyloxy optionally substituted with 1 or 2 Ch alkyl, oxo, -C(=O)H, -C(=O)-Ci-4 alkyl, -C(=O)O-Ci4 alkyl, -C(=O)NH2, -NHC(=O)H, -NHC(=O)-(Cm alkyl), C3-7 cycloalkyl, a 5- or 6 membered heteroaryl, Ch haloalkyl, and Ch 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(=0)-Ch alkyl, -C(=O)-NH2, -C(=O)-N(Cm alkylja, -CN, Ch alkyl, Ch alkoxy, Ch hydroxylalkyl, (Ci-2 alkoxy)-Cin alkyl-, Ch haloalkyl, and Ch haloalkoxy; and m is 0, 1, 2, 3, or 4.
ln some embodiments, Q1 is a moiety of Moiety M1 and Z1 is C.
ln some embodiments, Q1 or ring Q1a is an optionally substituted N-containing 6membered heteroaryl.
ln some embodiments, Q1 or ring Q1a is an optionally substituted pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. ln some further embodiments, Q1 or ring Q1a is an optionally substituted pyrimidinyl, pyridazinyl, or pyrazinyl.
ln some embodiments, Q1 or ring Q1a is pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with 1,2, 3, or 4 substituents each independently selected from the group consisting of OH, -CN, Ch alkyl, C1-4 haloalkyl, (Cv2 alkoxy)-Ci4 alkyl-, and C3-7 cycloalkyl. ln some further embodiments, Q1 or ring Q1a is pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of -CN, Ch alkyl, Ch haloalkyl, (C1-2 aikoxy)-Cin alkyl-, and C3-7 cycloalkyl. ln still further embodiments, Q1 or ring Q1a is pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of -CN, C1-4 alkyl and Cn haloalkyl, in yet still further embodiments, selected from the group consisting of Ch alkyl and Ch haloalkyl (e.g. methyl and Ci fluoroalkyl).
ln some embodiments, Moiety M1 is selected from the group consisting of quinolinyl, isoquinolinyl, 1H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, 1Hpy rrol o[3,2-c]py rid in y I, imidazo[1,2-a]py razinyl, imidazo[2,1 -c] [ 1,2,4]triazînyl, imidazo[1,5-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 1 H-indazolyl, 9H-purinyl, imidazo[1,2ajpyrimidinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, isoxazolo[5,4-c]pyridazinyl, isoxazolo[3,4cjpyridazinyl, and [1,2,4]triazolo[4,3-b]pyridazinyl, each optionally substituted with 1,2, or 3 R10 and further optionally substituted with 1 or 2 R10a; or wherein Moiety M1 is selected from the group consisting of pyrimidinyl, pyrazinyl, pyridinyl, pyridazinyl, 1 /-/pyrazolyl, 1H-pyrrolyl, 4H-pyrazolyl, 1/-/-imidazolyl, IH-îmidazoiyl, 3-oxo-2/-/-pyridazinyl, 1/-/-2-oxo-pyrimidinyl, 1/7-2-oxo-pyridinyl, 2,4(1/-/,3H)-dioxo-pyrimidinyl, and 1/-/-2-oxopyrazinyl, each substituted with R9 and further optionally substituted with 1, 2, or 3 R10.
In some embodiments:
{R1°)m
Moiety M1 îs
R10 (M1-h”),
R10a is Cn alkyl, Ci-* haloalkyl, (C1-2 alkoxy)-Ci-4 alkyl-, or C3-7 cycloalkyl;
t1 is 0 or 1; and t is 0 or 1.
In some embodiments, Moiety M1 is R10
In some embodiments, Moiety M1 is
I
C‘M1-j). In some further embodiments, Moiety M1 is
In some embodiments, Q1 or ring Q1a is an optionally substituted N-containing 6 membered heterocycloalkyl, wherein two of the ring-forming atoms of the 6-membered heterocycloalkyl are N atoms; four of the ring-forming atoms of the 6-membered heterocycloalkyl are C atoms; and the N-containing 6-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of oxo, -CN, Ch alkyl, Cu haloalkyl, (C1-2 alkoxy)-Ci-4 alkyl-, and
C3-7 cycloalkyl. In some further embodiments, the N-containing 6-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of oxo, Cu alkyl, Cu haloalkyl, (C1-2 alkoxy)-Cm alkyl-, and C3-7 cycloalkyl.
In some embodiments:
is Cu alkyl. In some yet further embodiments, R9 is methyl.
(M1-n); and
R11 is H, Cm alkyl, C1-4 haloalkyl, (C1-2 alkoxy)-Ci-4 alkyl-, or C3-7 cycloalkyl. In some further embodiments, R11 is Cu alkyl (e.g., methyl).
In some embodiments, R9 is Cu alkyl or -CN. In some further embodiments, R9
ln some embodiments, each R10 is independently selected from the group consisting of Cu alkyl, Cu haloalkyl, (C1-2 alkoxy)-Ci-4 alkyl-, -CN, and -N(R5)(R6), wherein each of R5 and R6 independently is H or selected from the group consisting of
Cu alkyl, Cu 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, Cm alkoxy, C3.6 cycloalkyl, Cu haloalkyl, and Cu haloalkoxy.. ln some further embodiments, each R10 is independently Cu alkyl. ln some yet further embodiments, each R10 is methyl.
ln some embodiments, none of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is as described in one ofthe embodiments provided herein (e.g., M1-g, M1-k, M1-m, or M1n). ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, none of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-g. ln some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, none of X2, X2, X4, andX5 is N; Q1 is Moiety M1; and M1 is M1-k. ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O.
ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln someembodiments, none of X2, X2, X4, andX5 is N; Q1 is Moiety M1; and M1 is
M1-m. ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O.
ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, none of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-n. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, one and only one of X2, X2, X4, andX5 is N; Q1 is Moiety M1; and M1 is as described in one ofthe embodiments provided herein (e.g., M1-g, M1-k, M1-m, or M1-n). In some further embodiments, L1 is O or S. In yet further embodiments,
L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety
M1; and M1 is M1-g. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
In some embodiments, one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety
M1; and M1 is M1-k. In some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, one and only one of X2, X2, X4, andX5 is N; Q1 is Moiety M1; and M1 is M1-m. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
In some embodiments, one and only one of X2, X2, X4, andX5 is N; Q1 is Moiety M1; and M1 is M1-n. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently
H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
ln some embodiments, two of X2, X2, X4, andX5 are N; Q1 is Moiety M1; and M1 is as described in one ofthe embodiments provided herein (e.g., M1-g, M1-k, M1-m, or M1n). In some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 îs methyl.
In some embodiments, two of X2, X2, X4, andX5 are N; Q1 is Moiety M1; and M1 is M1-g. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, two of X2, X2, X4, andX5 are N; Q1 is Moiety M1; and M1 is M1-k. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 îs H; and R4 is methyl.
ln some embodiments, two of X2, X2, X4, and X5 are N; Q1 is Moiety M1; and M1 is M1-m. In some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, two of X2, X2, X4, andX5 are N; Q1 is Moiety M1; and M1 is M1-n. ln some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; none of X2, X2, X4, and X5 is N; and M1 is as described in one of the embodiments provided herein (e.g., M1-g, M1-k, M1-m, or M1-n).
ln some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 is independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; none of X2, X2, X4, and X5 is N; and M1 is M1-g. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 is independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, X1 is CT1; none of X2, X2, X4, andX5 is N; and M1 is M1-k. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 is independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; none of X2, X2, X4, andX5 is N; and M1 is M1-m. ln some further embodiments, L1 îs O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 is independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; none of X2, X2, X4, and X5 is N; and M1 is M1-n. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 is independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl, ln some embodiments, X1 is CT1; one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is as described in one ofthe embodiments provided herein (e.g., M1-g, M1-k, M1-m, or M1-n). ln some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independentiy H or halogen; and each of R3 and R4 îs independentiy H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-g. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
In some embodiments, X1 is CT1; one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-k. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
In some embodiments, X1 is CT1; one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-m. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
In some embodiments, X1 is CT1; one and only one of X2, X2, X4, and X5 is N; Q1 is Moiety M1; and M1 is M1-n. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
In some embodiments, X1 is CT1; two of X2, X2, X4, and X5 are N; Q1 is Moiety M1; and M1 is as described in one of the embodiments provided herein (e.g., M1-g, M1-k, M1m, or M1-n). In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; two of X2, X2, X4, and Xs are N; Q1 is Moiety M1;
and M1 is M1-g. In some further embodiments, L1 is O or S. In yet further embodiments,
L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; two of X2, X2, X4, and X5 are N; Q1 is Moiety M1; and M1 is M1-k. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; two of X2, X2, X4, and X5 are N; Q1 is Moiety M1; and M1 is M1-m. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, X1 is CT1; two of X2, X2, X4, and X5 are N; Q1 is Moiety M1; and M1 is M1-n. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-a or a sait thereof; and Q1 is M1; and M1 is M1-g. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-a or a sait thereof; and Q1 is M1; and M1 is M1-k. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-a or a sait thereof; and Q1 is M1; and M1 is M1-m. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-a or a sait thereof; and Q1 is M1; and M1 is M1-n. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further 10 embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-b or a sait thereof; and Q1 is M1; and M1 îs M1-g. In some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-b or a sait thereof; and Q1 is M1; and M1 is M1-k. In some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-b or a sait thereof; and Q1 is M1; and M1 is M1-m. In some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-b or a sait thereof; and Q1 is M1; and M1 is M1-n. In some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-c or a sait thereof; and Q1 is M1; and M1 is M1-g. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-c or a sait thereof; and Q1 is M1; and M1 is M1-k. In some further embodiments, L1 is O or S, In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-c or a sait thereof; and Q1 is M1; and M1 is M1-m. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-c or a sait thereof; and Q1 is M1; and M1 is M1-n. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-d or a sait thereof; and Q1 is M1; and M1 is M1-g. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-d or a sait thereof; and Q1 is M1; and M1 is M1-k. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-d or a sait thereof; and Q1 is M1; and M1 is M1-m. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-d or a sait thereof; and Q1 is M1; and M1 is M1-n. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-e or a sait thereof; and Q1 is M1; and M1 is M1-g. In some further embodiments, L1 is O or S. ln yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3is H; and R4 is methyl.
ln some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-e or a sait thereof; and Q1 is M1; and M1 is M1-k. ln some further embodiments, L1 is O or S, In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-e or a sait thereof; and Q1 is M1; and M1 is M1-m. ln some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. In still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. In yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
In some embodiments, the compound of Formula I or a sait thereof is a compound of Formula l-e or a sait thereof; and Q1 is M1; and M1 is M1-n. In some further embodiments, L1 is O or S. In yet further embodiments, L1 is O. ln still further embodiments, each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, or Ci haloalkoxy. ln yet still further embodiments, each of R1 and R2 is H; R3 is H; and R4 is methyl.
ln some embodiments, the invention also provides one or more of the compounds described in Examples 1-14 in the Examples section ofthe subject application, pharmaceutically acceptable salts of the compounds or the N-oxides of the compound or sait.
ln some embodiments, the prevent invention provides a compound selected from:
1.5- dimethyl-6-[2-methyl-4-(1,7-naphthyridin-8-yloxy)phenyl]pyrimidine2,4(1H,3H)-dione;
4.6- dimethyl-5-[2-methyl-4-(1,7-naphthyridin-8-yloxy)phenyl]pyridazin-3(2/7)-one; (+)-4]6-dimethyl-5-[2-methyl-4-(1,7-naphthyridin-8-yloxy)phenyl]pyridazin-3(2/-/)- one;
(-)-4,6-dimethyl-5-[2-methyl-4-(1,7-naphthyridin-8-yloxy)phenyl]pyridazin-3(2H)one;
4.6- dimethyl-5-[4-(1,7-naphthyridin-8-yloxy)phenyl]pyridazin-3(2/7)-one; 6-[4-(isoquinolin-1-yloxy)-2-methylphenyl]-1,5-dimethylpyrimidine-2,4(1H,3H)- dione;
8-[4-(4l6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1,7-naphthyridine;
1.5- dimethyl-6-[4-(1,7-naphthyridin-8-yloxy)phenyl]pyrimidine-2,4(1/-/,3/-/)-dione;
4.6- dimethyl-5-[2-methyl-4-(2,7-naphthyridin-1-yloxy)phenyl]pyridazin-3(2/-/)-one;
4.6- dimethyl-5-[2-methyl-4-(pyrido[3,4-b]pyrazin-5-yloxy)phenyl]pyridazin-3(2/7)one;
4.6- dimethyl-5-[2-methyl-4-(1,6-naphthyridin-5-yloxy)phenyl]pyridazin-3(2/-/)-one; 5-[4-(isoquinolin-1-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2/7)-one;
5-{4-[(7-methoxyisoquinolin-1-yl)oxy]-2-methylphenyl}-4,6-dimethylpyrïdazin3(2H)-one;
-[4-(3,5-dimethyl-6-oxo-1,6-d i hyd ropy rida zi n -4-y I )-3methylphenoxy]isoquinoline-7-carbonitrile; and
-[4-(3,5-dimethyl-6-oxo-1,6-dihydropy rid a zi n -4-y I )-3methylphenoxy]isoquinoline-8-carbonitrile, or a pharmaceutically acceptable sait thereof.
The second aspect of the invention includes any subset of any embodiment described herein.
The second aspect of the invention includes combinations of two or more embodiments described hereinabove, or any subset thereof.
The second aspect of the invention further provides the compound of Formula I or a pharmaceutically acceptable sait thereof (including ail embodiments and combinations of two or more embodiments described herein or any subcombination thereof) for use in treating a D1-mediated (or D1-associated) disorder described herein.
The second aspect of the invention further provides use of the compound of Formula I or a pharmaceutically acceptable sait thereof (including ail embodiments and combinations of two or more embodiments described herein or any subcombination 10 thereof) for treating a D1 -mediated (or D1 -associated) disorder described herein.
The second aspect of the invention further provides use of the compound of Formula I or a pharmaceutically acceptable sait thereof (including ail embodiments and combinations of two or more embodiments described herein or any subcombination thereof) in manufacturing a médicament for use in treating a D1-mediated (or D115 associated) disorder described herein.
The compound of Formula I or its sait of the second aspect of présent invention is a D1R modulator (e.g., a D1R agoninst for example, a D1R partial agonist). Thus, the second aspect of présent invention further provides a method for modulating (such as agonizing or partially agonizing) an activity of D1R (either in vitro or in vivo), comprising 20 contacting (including incubating) the D1R with a compound of Formula I or a pharmaceutically acceptable sait thereof (such as one selected from Examples 1-14 herein) described herein.
As used herein, the term “n-membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is 25 n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl group.
At various places in the présent spécification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such 30 groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to include Ci alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, C4 alkyl, Cs alkyl, and Ce alkyl. For another example, the term “a 5- to 10-membered heteroaryl group is specifically intended to include any 5-, 6-, 7-, 8-, 9- or 10-membered heteroaryl group.
As used herein, the term alkyl is defîned to include saturated aliphatic hydrocarbons including straight chains and branched chains. In some embodiments, the alkyl group has 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. For example, the term O-e alkyl,” as well as the alkyl moieties of other groups referred to herein (e.g., Ci-e alkoxy) refers to linear or branched radicals of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, îsobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl). For yet another example, the term Cu alkyl” refers to linear or branched aliphatic hydrocarbon chains of 1 to 4 carbon atoms; the term C1-3 alkyl refers to linear or branched aliphatic hydrocarbon chains of 1 to 3 carbon atoms; the term C1-2 alkyl” refers to linear or branched aliphatic hydrocarbon chains of 1 to 2 carbon atoms; and the term Ci alkyl refers to methyl. An alkyl group optionally can be substituted by one or more (e.g. 1 to 5) suitable substituents.
As used herein, the term alkenyl refers to aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight chains and branched chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, as used herein, the term C2-6 alkenyl means straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 2 to 6 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.. An alkenyl group optionally can be substituted by one or more (e.g. 1 to 5) suitable substituents. When the compounds of Formula I contain an alkenyl group, the alkenyl group may exist as the pure E form, the pure Z form, or any mixture thereof.
As used herein, the term alkynyl refers to aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight chains and branched chains having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group has 2 to 20, 2 to 10, 2 to 6, or 3 to 6 carbon atoms. For example, as used herein, the term C2-6 alkynyl refers to straight or branched hydrocarbon chain alkynyl radicals as defined above, having 2 to 6 carbon atoms. An alkynyl group optionally can be substituted by one or more (e.g. 1 to 5) suitable substituents.
As used herein, the term cycloalkyl” refers to saturated or unsaturated, nonaromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclics such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclics including spiro, fused, or bridged Systems (such as bicyclo[1.1.1 ]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl or bicyclo[5.2.0]nonanyl, decahydronaphthalenyl, etc.). The cycloalkyl group has 3 to 15 carbon atoms. In some embodiments the cycloalkyl may optionally contain one, two or more non-cumulative non-aromatic double or triple bonds and/or one to three oxo groups.
ln some embodiments, the bicycloalkyl group has 6 to 14 carbon atoms. For example, the term C3-14 cycloalkyl refers to saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3 to 14 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, or cyclodecanyl); and the term C3-7 cycloalkyl” refers to saturated or unsaturated, nonaromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3 to 7 ringforming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentan-1-yl, or bicyclo[1.1.1]pentan-2-yl). For another example, the term Ca-e cycloalkyl refers to saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3 to 6 ring-forming carbon atoms. For yet another example, the term C3-4 cycloalkyl” refers to cyclopropyl or cyclobutyl. Also included in the définition of cycloalkyl are moieties that hâve one or more aromatic rings (including aryl and heteroaryl) fused to the cycloalkyl ring, for example, benzo or thienyl dérivatives of cyclopentane, cyclopentene, cyclohexane, and the like (e.g., 2,3-dihydro1H-indene-1-yl, or 1H-inden-2(3H)-one-1-yl). The cycloalkyl group optîonally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.
As used herein, the term aryl refers to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated pi-electron system. The aryl group has 6 or 10 carbon atoms in the ring(s). Most commonly, the aryl group has 6 carbon atoms in the ring. For example, as used herein, the term “Ce-io aryl means aromatic radicals containing from 6 to 10 carbon atoms such as phenylor naphthyl. The aryl group optîonally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.
As used herein, the term heteroaryl refers to monocyclic or fused-ring polycyclic aromatic heterocyclic groups with one or more heteroatom ring members (ring-forming atoms) each independentiy selected from O, S and N in at least one ring. The heteroaryl group has 5 to 14 ring-forming atoms, including 1 to 13 carbon atoms, and 1 to 8 heteroatoms selected from O, S, and N. In some embodiments, the heteroaryl group has 5 to 10 ring-forming atoms including one to four heteroatoms. The heteroaryl group can also contain one to three oxo or thiono (i.e. =S) groups. ln some embodiments, the heteroaryl group has 5 to 8 ring-forming atoms including one, two or three heteroatoms. For example, the term 5-membered heteroaryl refers to a monocyclic heteroaryl group as defined above with 5 ring-forming atoms in the monocyclic heteroaryl ring; the term 6-membered heteroaryl” refers to a monocyclic heteroaryl group as defined above with 6 ring-forming atoms in the monocyclic heteroaryl ring; and the term 5- or 6-membered heteroaryl” refers to a monocyclic heteroaryl group as defined above with 5 or 6 ring-forming atoms in the monocyclic heteroaryl ring. For another example, term 5- or 10-membered heteroaryl refers to a monocyclic or bicyclic heteroaryl group as defined above with 5, 6, 7, 8, 9 or 10 ringforming atoms in the monocyclic or bicyclic heteroaryl ring. A heteroaryl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents. Examples of monocyclic heteroaryls include those with 5 ring-forming atoms including one to three heteroatoms or those with 6 ring-forming atoms including one, two or three nitrogen heteroatoms. Examples of fused bicyclic heteroaryls include two fused 5- and/or 6membered monocyclic rings including one to four heteroatoms.
Examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, 1/7-imtdazo[4,5c]pyridinyl, imidazo[1,2-a]pyridinyl, 1/7-pyrrolo[3,2-c]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-c][1,2,4]triazinyl, imidazo[1,5-a]pyrazinyl, imidazotl^-ajpyrimidinyl, 1/7indazolyl, 9/7-purinyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, isoxazolo[5,4-c]pyridazinyl, isoxazolotSAcjpyridazinyl, pyridone, pyrimidone, pyrazinone, pyrimidinone, //7-imidazol-2(3/7)-one, f/7-pyrrole-2,5dione, 3-oxo-2/7-pyridazinyl, 1/7-2-oxo-pyrimidinyî, 1/7-2-oxo-pyridinyl, 2,4(1/7,3/7)-dioxopyrimidinyl, 1 H-2-oxo-pyrazinyl, and the like. The heteroaryl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.
As used herein, the term “heterocycloalkyl” refers to a monocyclic or polycyclic [including 2 or more rings that are fused together, including spiro, fused, or bridged Systems, for example, a bicyclic ring system], saturated or unsaturated, non-aromatic 4to 15-membered ring system (such as a 4- to 14-membered ring system, 4- to 12membered ring system, 5- to 10-membered ring system, 4- to 7-membered ring system,
4- to 6-membered ring system, or 5- to 6-membered ring system), including 1 to 14 ringforming carbon atoms and 1 to 10 ring-forming heteroatoms each independently selected from O, S and N. The heterocycloalkyl group can also optionally contain one or more oxo or thiono (i.e. =S) groups. For example, ; the term 4- to 12-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, nonaromatic 4- to 12-membered ring system that comprises one or more ring-forming heteroatoms each independently selected from O, S and N; and the term 4- to 10 membered heterocycloalkyl refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 10-membered ring system that comprises one or more ring-fomning heteroatoms each independently selected from O, S and N. For another example, the term 4- to 6-membered heterocycloalkyr refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 6-membered ring system that comprises one or more ring-forming heteroatoms each independently selected from O, S and N; and the term 5- to 6-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 5- to 6-membered ring system that comprises one or more ring-forming heteroatoms each independently selected from O, S and N. Also included in the définition of heterocycloalkyl are moieties that hâve one or more aromatic rings (including aryl and heteroaryl) fused to the nonaromatic heterocycloalkyl ring, for example pyridinyl, pyrimidinyl, thiophenyl, pyrazolyl, phthalimidyl, naphthalimidyl, and benzo dérivatives of the nonaromatic heterocycloalkyl rings. The heterocycloalkyl group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substîtuents.
Examples of such heterocycloalkyl rings include azetidînyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, quinuclidinyI, chromanyl, isochromanyl, benzoxazinyl, 7-azabîcyclo[2.2.1]heptan-1-yl, 7-azabicyclo[2.2.1]heptan2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, 2-azabicyclo[2.2.1]heptan-3-on-2-yl, 3azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl and the like. Further examples of heterocycloalkyl rings include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1yl, imidazolidîn-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidîn-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1 -yl, piperazin-2-yl,
1,3-oxazolidin-3-yl, 1,4-oxazepan-1-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidîn-2-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl, 1,2-tetrahydrodiazin-2yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl, oxazolidinonyl, 2-oxo-piperidinyl (e.g., 2oxo-piperidin-1 -yl), and the like. Some examples of aromatic-fused heterocycloalkyl groups include indolinyl, isoindolinyl, isoindolin-1-one-3-yl, 5,7-dihydro-6H-pyrrolo[3,4-
b] pyridin-6-yl, 6,7-dihydro-5/-/-pyrrolo[3,4-d]pyrimidin-6-yl, 4,5,6,7-tetrahydrothieno[2,3-
c] pyridine-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, 1,4,5,6tetrahydropyrrolo[3,4-c]pyrazol-5-yl, and 3,4-dihydroisoquinolin-1(2/-/)-one-3-yl groups. The heterocycloalkyl group is optionally substituted by 1 or more (e.g., 1 to 5) suitable substituents. Examples of heterocycloalkyl groups include 5- or 6-membered monocyclic rings and 9- or 10-membered fused bicyclic rings.
As used herein, the term halo or halogen group is defined to include fluorine, chlorine, bromine or iodine.
As used herein, the term haloalkyl refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom). For example, the term “Ci-e haloalkyl” refers to a C1-6 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom). For another example, the term “Cu haloalkyl” refers to a Ci-4 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom); the term C1-3 haloalkyl refers to a C1-3 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom); and the term “C1-2 haloalkyl refers to a C1-2 alkyl group (i.e. methyl or ethyl) having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom ofthe alkyl group has been replaced by a halogen atom). For yet another example, the term Ci haloalkyl refers to a methyl group having one, two, or three halogen substituents. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CH2CF3, CH2CI and the like.
As used herein, the term “halocycloalkyl” refers to a cycloalkyl group having one or more halogen substituents (up to perhalocycloalkyl, i.e., every hydrogen atom ofthe cycloalkyl group has been replaced by a halogen atom). For example, the terni C3-4 halocycloalkyl refers to a cyclopropyl or cyclobutyl group having one or more halogen substituents. An example of halocycloalkyl is 2-fluorocyclopropan-1-yl.
As used herein, the term alkoxy or “alkytoxy refers to an -O-alkyl group. For example, the term “C1-6 alkoxy” or C1-6 alkyloxy refers to an -O-(Ci-e alkyl) group; and the term “Cin alkoxy” or “C1-4 alkyloxy refers to an -O-(Ch alkyl) group; For another example, the term “C1-2 alkoxy” or “C1-2 alkyloxy refers to an -O-(Ci-2 alkyl) group. Examples of alkoxy include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), fert-butoxy, and the like. The alkoxy or alkyloxy group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.
As used here, the term “haloalkoxy refers to an -O-haloalkyl group. For example, the term “C1-6 haloalkoxy refers to an -O-(Ci-6 haloalkyl) group. For another example, the term “Ch haloalkoxy refers to an -O-(Ci-4 haloalkyl) group; and the term “Ci-2 haloalkoxy” refers to an -O-(Ci-2 haloalkyl) group. For yet another example, the term Ci haloalkoxy” refers to a methoxy group having one, two, or three halogen substituents. An example of haloalkoxy is -OCF3 or -OCHF2.
As used herein, the term “cycloalkoxy” or “cycloalkyloxy refers to an -Ocycloalkyl group. For example,, the term “C3-7 cycloalkoxy” or C3-7 cycloalkyloxy” refers to an -O-(C3-7 cycloalkyl) group. For another example,, the term “C3-6 cycloalkoxy or “C3-6 cycloalkyloxy” refers to an -O-(Û3O cycloalkyl) group. Examples of cycloalkoxy include Cm cycloalkoxy (e.g., cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexanoxy, and the like). The cycloalkoxy or cycloalkyloxy group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.
As used here, the term “Ce-io aryloxy” refers to an -0-(C6-ioaryl) group. An example of a Ce-io aryloxy group is -O-phenyl [i.e., phenoxy]. The Ce-ίο aryloxy y group optionally can be substituted by 1 or more (e.g., 1 to 5) suitable substituents.
As used herein, the term fluoroalkyl” refers to an alkyl group having one or more fluorine substituents (up to perfluoroalkyl, i.e., every hydrogen atom ofthe alkyl group has been replaced by fluorine). For example, the term “C1-2 fluoroalkyl refers to a C1-2 alkyl group having one or more fluorine substituents (up to perfluoroalkyl, i.e., every hydrogen atom of the C1-2 alkyl group has been replaced by fluorine). For another example, the term “Ci fluoroalkyl” refers to a Ci alkyl group (i.e., methyl) having 1, 2, or 3 fluorine substituents). Examples of fluoroalkyl groups include CF3, C2F5, CH2CF3, CHF2, CH2F, and the like.
As used here, the term “fluoroalkoxy refers to an -O-fluoroalkyl group. For example, the term C1-2 fluoroalkoxy refers to an -O-C1-2 fluoroalkyl group. For another example, the term “Ci fluoroalkoxy refers to a methoxy group having one, two, or three fluorine substituents. An example of Ci fluoroalkoxy is -OCF3 or -OCHF2.
As used herein, the term “hydroxylalkyl or “hydroxyalkyl” refers to an alkyl group having one or more (e.g., 1,2, or 3) OH substituents. The term “Ci-e hydroxylalkyl or “C1-6 hydroxyalkyl” refers to a C1-6 alkyl group having one or more (e.g., 1,2, or 3) OH substituents. The term “Cm hydroxylalkyl or “Cm hydroxyalkyl” refers to a Cm alkyl group having one or more (e.g., 1, 2, or 3) OH substituents; the term “C1-3 hydroxylalkyl” or C1-3 hydroxyalkyl refers to a C1-3 alkyl group having one or more (e.g., 1,2, or 3) OH substituents; and the term “C1-2 hydroxylalkyl” or C1-2 hydroxyalkyl” refers to a C1-2 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents. An example of hydroxylalkyl is -CH2OH or -CH2CH2OH.
As used herein, the term “oxo refers to =O. When an oxo is substituted on a carbon atom, they together form a carbonyl moiety [-C(=O)-j. When an oxo is substituted on a sulfur atom, they together form a sulfinyI moiety [-S(=O)-J; when two oxo groups are substituted on a sulfur atom, they together form a sulfonyl moiety [S(=O)2-J.
As used herein, the term thiono” refers to =S. When an thiono is substituted on a carbon atom, they together form moiety of [-C(=S)-J.
As used herein, the term optionally substituted means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A substituted atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a sélection from the indicated substituent group (up to that every hydrogen atom on the designated atom or moiety is replaced with a sélection from the indicated substituent group), provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group (i.e., CHa) is optionally substituted, then up to 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.
As used herein, the term optionally substituted Cm alkyl refers to Cm alkyl optionally substituted by one or more (e.g. 1 to 5) substituents each independently selected from the group consisting of-OH, halogen, -CN, -NH2, -NH(Cm alkyl), -N(Cm alkyl)2, Cm alkoxy, and Cm haloalkoxy.
As used herein, the term optionally substituted C1.2 alkyl refers to C1-2 alkyl optionally substituted by one or more (e.g. 1 to 5) substituents each independently selected from the group consisting of-OH, halogen, -CN, -NH2, -NH(Cm alkyl), -N(Cm alkyl)2, Cm alkoxy, and Cm haloalkoxy.
As used herein, the term optionally substituted C3-4 cycloalkyl refers to Cm cycloalkyl optionally substituted by one or more (e.g. 1 to 5) substituents each independently selected from the group consisting of -OH, halogen, -CN, -ΝΗ2, -NH(Cm alkyl), -N(Cm alkyl)2, Cm alkyl, Cm haloalkyl, Cm hydroxylalkyl, Cm alkoxy, and Cm haloalkoxy.
As used herein, the term optionally substituted cyclopropylmethyr' refers to cyclopropylmethyl optionally substituted by one or more (e.g. 1 to 5) substituents each independently selected from the group consisting of-OH, halogen, -CN, -NH2, -NH(Cm alkyl), -N(Cm alkyl)2, Cm alkyl, Cm haloalkyl, Cm hydroxylalkyl, Cm alkoxy, and Cm haloalkoxy.
As used herein, the term optionally substituted Cm alkoxy refers to Cm alkoxy optionally substituted by one or more (e.g. 1 to 5) substituents each independently selected from the group consisting of-OH, halogen, -CN, -NH2, -NH(Cm alkyl), -N(Ci-4 alkyl)2, Cm alkoxy, and Cm haloalkoxy.
As used herein, unless specified, the point of attachment of a substituent can be from any suitable position of the substituent. For example, piperidinyl can be piperidin1 -yl (attached through the N atom of the piperidinyl), piperidin-2-yl (attached through the C atom at the 2-position of the piperidinyl), piperidin-3-yl (attached through the C atom at the 3-position of the piperidinyl), or piperidin-4-yl (attached through the C atom at the 4-position of the piperidinyl). For another example, pyridinyl (or pyridyl) can be 2pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any of the ring-forming atoms in that ring that are substitutable (i.e., bonded to one or more hydrogen atoms), unless otherwise specifized or otherwise implicit from the context. For example, as shown in Formula a-
101 below, R10 may be bonded to either of the two ring carbon atoms each of which bears a hydrogen atom (but not shown). For another example, as shown in Formula a-
102 below, R10 may be bonded to either of the two ring carbon atoms on the pyrazine ring each of which bears a hydrogen atom (but not shown); and R10a may be bonded to either of the two ring carbon atoms on the imidazole ring each of which bears a hydrogen atom (but not shown).
When a substituted or optionally substituted moiety is described without indicating the atom via which such moiety is bonded to a substituent, then the substituent may be bonded via any appropriate atom in such moiety. For example in a substituted arylalkyl, a substituent on the arylalkyl [e.g., (Ce-io aryl)-Ci-4 alkyl-] can be bonded to any carbon atom on the alkyl part or on the aryl part of the arylalkyl. Combinations of substituents and/or variables are permissible only if such combinations resuit in stable compounds.
As noted above, the compounds of Formula I may exist in the form of pharmaceutically acceptable salts such as acid addition salts and/or base addition salts ofthe compounds of Formula I. The phrase pharmaceutically acceptable salt(s), as used herein, unless otherwise indicated, includes acid addition or base salts which may be présent in the compounds of Formula L
Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stéarate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts,
Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnésium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Sélection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of Formula I are known to one of skill in the art.
As used herein the terms “Formula I”, “Formula I or pharmaceutically acceptable salts thereof, “pharmaceutically acceptable salts of the compound or the sait [of Formula I] are definedto include ail forms ofthe compound of Formula I, including hydrates, solvatés, isomers (including for example rotational stereoisomers), crystalline and non-crystalline forms, isomorphs, polymorphs, métabolites, and prodrugs thereof.
As it is known to the person skilied in the art, amine compounds (i.e., those comprising one or more nitrogen atoms), for example tertiary amines, can form N-oxides (also known as amine oxides or amine /V-oxides). An /V-oxide has the formula of (R100R200R300)N+-O- whereîn the parent amine (R100R200R300)N can be for example, a tertiary amine (for example, each of R100, R200, R300 is independently alkyl, arylalkyl, aryl, heteroaryl, or the like), a heterocyclic or heteroaromatic amine [for example, (R100R200R300)N together forms 1 -alkylpiperidine, 1-alkylpyrrolidine, 1-benzylpyrrolidine, or pyridine]. For instance, an imine nitrogen, especially heterocyclic or heteroaromatic imine nitrogen, or pyridine-type nitrogen (=1=N-atom [such as a nitrogen atom in pyridine, pyridazine, or pyrazine], can be N-oxidized to form the N-oxide comprising the p* group ( :I=N-^'). Thus, a compound according to the présent invention comprising one or more nitrogen atoms (e.g., an imine nitrogen atom) may be capable of forming an Noxide thereof (e.g., mono-/V-oxides, bis-W-oxides or multi-A/-oxides, or mixtures thereof depending on the number of nitrogen atoms suitable to form stable AAoxides).
As used herein, the term 'W-oxide(s)” refer to all possible, and in particular all stable, N-oxide forms ofthe amine compounds (e.g., compounds comprising one or more imine nitrogen atoms) described herein, such as mono-/V-oxides (including different isomers when more than one nitrogen atom of an amine compound can form a mono-/V-oxide) or multi-W-oxides (e.g., bis-/V-oxides), or mixtures thereof in any ratio.
Compounds of Formula I and their salts described herein further include W-oxides thereof.
Compounds of Formula I (including salts thereof) may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long-range order at the molecular level and, depending upon température, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from apparent solid to a material with liquid properties occurs, which is characterised by a change of state, typically second order (‘glass transition'). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internai structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point1).
Compounds of Formula I (including salts thereof) may exist in unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will hâve a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvatés and hygroscopic compounds, the water/solvent content will be dépendent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
The compounds of Formula I (including salts thereof) may exist as clathrates or other complexes (e.g., co-crystals). Included within the scope ofthe invention are complexes such as clathrates, drug-host inclusion complexes wherein the drug and host are présent in stoichiometric or non-stoichiometric amounts. Also included are complexes of the compounds of Formula I containîng two or more organic and/or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. Co-crystals are typically defîned as crystalline complexes of neutral molecular constituents that are bound together through non-covalent interactions, but could also be a complex of a neutral molécule with a sait. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together; see O. Almarsson and M. J. Zaworotko, Chem. Commun. 2004, 17, 1889-1896. Fora general review of multi-component complexes, see J. K. Haleblian, J. Pharm. Soi. 1975, 64, 1269-1288.
The compounds of the invention (including salts thereof) may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the resuit of a change in température is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that hâve the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molécules which possess an ionic (such as -COO Na+, COO K+, or -SO3’Na+) or non-ionic (such as -N'N*(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4lh Edition (Edward Arnold, 1970).
The invention also relates to prodrugs of the compounds of Formula I. Thus certain dérivatives of compounds of Formula I which may hâve little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage. Such dérivatives are referred to as prodrugs. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Sériés (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug
Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical
Association).
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities présent in the compounds of Formula I with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985), or in Prodrugs: Challenges and Reward, 2007 édition, edited by Valentino Stella, Ronald Borchardt, Michael Hageman, Reza Oliyai, Hans Maag, Jefferson Tilley, pages 134-175 (Springer, 2007).
Moreover, certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.
Also included within the scope ofthe invention are métabolites of compounds of Formula I, that is, compounds formed in vivo upon administration ofthe drug.
The compounds of Formula I (including salts thereof) include ail stereoisomers and tautomers. Stereoisomers of Formula I include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, géométrie isomers, rotational isomers, atropisomers, and conformational isomers ofthe compounds of Formula I, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or Llysine, or racemic, for example, DL-tartrate or DL-arginine.
ln some embodiments, the compounds of Formula I (including salts thereof) may hâve asymmetric carbon atoms. The carbon-carbon bonds of the compounds of Formula I may be depicted herein using a solid line (-----), a solid wedge ( ), or a dotted wedge ( .......... ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that ail possible stereoisomers (e.g., spécifie enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of Formula I may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that ail possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of Formula I can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of Formula I and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is présent.
ln some embodiments, the compounds of Formula I (including salts thereof) may exist in and/or be isolated as atropisomers (e.g., one or more atropenantiomers). Those skilled in the art would recognize that atropisomerism may exist in a compound that has two or more aromatic rings (for example, two aromatic rings linked through a single bond). See e.g., Freedman, T. B. et al., Absolute Configuration Détermination of Chiral Molécules in the Solution State Using Vibrational Circular Dichroism. Chirality 2003, 15, 743-758; and Bringmann, G. et al., Atroposelective Synthesis of Axially Chiral Biaryl Compounds. Angew. Chem., Int. Ed. 2005, 44, 5384-5427.
When any racemate crystallizes, crystals of different types are possible. One type is the racemic compound (true racemate) wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. Another type is a racemic mixture or conglomerate wherein two forms of crystal are produced in equal or different molar amounts each comprising a single enantiomer.
The compounds of Formula I (including salts thereof) may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds of Formula I may exist in several tautomerîc forms, including the enol and imine form, the amide and imidic acid form, and the keto and enamine form and géométrie isomers and mixtures thereof. Ali such tautomeric forms are included within the scope of the compounds of Formula I. Tautomers may exist as mixtures of a tautomeric set in solution, ln solid form, usually one tautomer prédominâtes. Even though one tautomer may be described, the présent invention includes ail tautomers ofthe compounds of Formula I. For example, when one of the following two tautomers of the invention is disclosed in the experimental section herein, those skilled in the art would readily recognize that the invention also includes the other.
O OH
For another example, when one of the following three tautomers of the invention is disclosed in the experimental section herein, those skilled in the art would readily recognize that the invention also includes other tautomers such as the other two shown below.
The présent invention includes ail pharmaceutically acceptable isotopicallylabelled compounds of Formula I (including salts thereof) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which prédominâtes in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention (including salts thereof) include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150,17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S.
Certain isotopically-labelled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of détection.
Substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron-emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of Formula I (including salts thereof) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Préparations using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.
The présent invention also provides compositions (e.g., pharmaceutical compositions) comprising a novel compound of Formula I (including a pharmaceutically acceptable sait thereof) in the second aspect of the invention. Accordingly, in one embodiment, the invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) a novel compound of Formula I (or a pharmaceutically acceptable sait thereof) and optîonally comprising a pharmaceutically acceptable carrier. In one further embodiment, the invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) a compound of Formula I (or a pharmaceutically acceptable sait thereof), optîonally comprising a pharmaceutically w acceptable carrier and, optîonally, at least one additional médicinal or pharmaceutical agent (such as an antipsychotic agent or anti-schizophrenia agent described below). In one embodiment, the additional médicinal or pharmaceutical agent is an antischizophrenia agent as described below.
The pharmaceutically acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. Suitable pharmaceutical carrière include inert diluents or fïllers, water and various organic solvents (such as hydrates and solvatés). The pharmaceutical compositions may, if desired, contain additional ingrédients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid, may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnésium stéarate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or élixirs are desired for oral administration, the active compound therein may be combined with various sweetening orflavoring agents, coloring matters or dyes and, if desired, emulsifÿing agents or suspending agents, together with diluents such as water, éthanol, propylene glycol, glycerin, or combinations thereof.
The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution or suspension, for parentéral injection as a stérile solution, suspension or émulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
Exemplary parentéral administration forms include solutions or suspensions of active compounds in stérile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.
The pharmaceutical composition may be in unit dosage forms suitable for single administration of précisé dosages. One of ordinary skill in the art would appreciate that the composition may be formulated in sub-therapeutic dosage such that multiple doses are envisioned.
In one embodiment the composition comprises a therapeutically effective amount of a compound of Formula I (or a pharmaceutically acceptable sait thereof) and a pharmaceutically acceptable carrier.
Compounds of Formula I (including pharmaceutically acceptable salts thereof) are D1R modulators. In some embodiments, a compound of Formula I is a D1R agonist [i.e., binding (having affinity for) and activating D1R receptors]. In some embodiments, using dopamine as a reference full D1R agonist, a compound of Formula I is a super agonist (i.e., a compound that is capable of producing a greater maximal response than the endogenous D1R agonist, dopamine, for a D1R receptor, and thus exhibiting an efficacy of more than about 100%, for example 120%). In some embodiments, using dopamine as a reference full agonist, a compound of Formula I is a full D1R agonist (i.e., having an efficacy of about 100%, for example, 90%-100%, compared to that of dopamine). In some embodiments, using dopamine as a reference full D1R agonist, a compound of Formula I is a partial agonist [i.e., a compound having only partial efficacy (i.e., less than 100%, for example 10%-80% or 50%-70%) at a D1 receptor relative to the full agonist, dopamine, although it binds and activâtes a D1 receptor], A D1R agonist (including superagonist, full agonist, and partial agonist) can agonize or partially agonize an activity of D1 R. In some embodiments, the ECso of a compound of Formula
I with respect to D1R is less than about 10 pM, 5 pM, 2 pM, 1 pM, 500 nM, 200 nM, 100 nM, 50, 40, 30, 20, 10, 5, 2, or 1 nM.
As used herein, when referencing to a compound, the term “D1R modulator or “D1R agonist (including a super D1R agonist, a full D1R agonist, or a partial D1R agonist) refers to a compound that is a D1 -like receptor modulator or a D1 -like receptor agonist respectively (i.e., not necessarily sélective between/among subtypes of D1 -like receptors). See Lewis, JPET 286:345-353, 1998. D1Rs include, for example, D1 and D5 in humans and D1A and D1B in rodents.
Administration ofthe compounds of Formula I may be effected by any method that enables delivery of the compounds to the site of action. These methods include, for example, enterai routes (e.g., oral routes, buccal routes, sublabial routes, sublingual routes), oral routes, intranasal routes, inhaled routes, intraduodenal routes, parentéral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion),intrathecal routes, épidural routes, intracérébral routes, intracerbroventricular routes, topical, and rectal administration.
In one embodiment ofthe present invention, the compounds of Formula I may be administered/effected by oral routes.
Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be advantageous to formulate parentéral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrète units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The spécifications for the dosage unit forms of the invention are dictated by a variety of factors such as the unique characteristics of the therapeutic agent and the particular therapeutic or prophylactic effect to be achieved. In one embodiment of the present invention, the compounds of Formula I may be used to treat humans.
It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, spécifie dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamie parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration ofthe chemotherapeutic agent is well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.
The amount of the compound of Formula I or a pharmaceutically acceptable sait thereof administered will be dépendent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition ofthe compound and the discrétion of the prescribing physician. Generaliy, an effective dosage is in the range of about 0.0001 to about 50 mg per kg body weight per day, for example about 0.01 to about 10 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.007 mg to about 3500 mg/day, for example about 0.7 mg to about 700 mg/day. ln some instances, dosage levels below the lower limit of the aforesaid range may be more than adéquate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
As used herein, the term “combination therapy refers to the administration of a compound of Formula I or a pharmaceutically acceptable sait thereof together with an at least one additional pharmaceutical or médicinal agent (e.g., an anti-schizophrenia agent), either sequentially or simultaneously.
The présent invention includes the use of a combination of a compound of Formula I (or a pharmaceutically acceptable sait thereof) and one or more additional pharmaceutically active agent(s). If a combination of active agents is administered, then they may be administered sequentially or simultaneously, in separate dosage forms or combined in a single dosage form. Accordingly, the présent invention also includes pharmaceutical compositions comprising an amount of: (a) a first agent comprising a compound of Formula I (including an /V-oxide thereof or a pharmaceutically acceptable sait of the compound or the /V-oxide); (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle or diluent.
Various pharmaceutically active agents may be selected for use in conjunction with the compounds of Formula I (including or pharmaceutically acceptable salts thereof), depending on the disease, disorder, or condition to be treated. Pharmaceutically active agents that may be used in combination with the compositions of the présent invention include, without limitation:
(i) acetylcholinesterase inhibitors such as donepezil hydrochloride (ARICEPT, MEMAC); or Adenosine A2a receptor antagonists such as Preladenant (SCH 420814) or SCH 412348;
(îi) amyloid-β (or fragments thereof), such as Αβι-15 conjugated to pan HLA DRbinding epitope (PADRE) and ACC-001 (Elan/Wyeth);
(iii) antibodies to amyloid-β (or fragments thereof), such as bapineuzumab (also known as AAB-001) and AAB-002 (Wyeth/Elan);
(iv) amyloid-lowering or -inhibiting agents (including those that reduce amyioid production, accumulation and fibrillization) such as colostrinin and bisnorcymserine (also known as BNC);
(v) alpha-adrenergic receptor agonists such as clonidine (CATAPRES);
(vi) beta-adrenergic receptor blocking agents (beta blockers) such as carteolol;
(vii) anticholinergics such as amitrîptyline (ELAVIL, ENDEP);
(viii) anticonvulsants such as carbamazepine (TEGRETOL, CARBATROL);
(ix) antipsychotics, such as lurasidone (also known as SM-13496; Dainippon Sumitomo);
(x) calcium channel blockers such as nilvadipine (ESCOR, NIVADIL);
(xi) catechol O-methyltransferase (COMT) inhibitors such as tolcapone (TASMAR);
(xii) central nervous system stimulants such as caffeine;
(xiii) corticosteroids such as prednisone (STERAPRED, DELTASONE);
(xiv) dopamine receptor agonists such as apomorphine (APOKYN);
(xv) dopamine receptor antagonists such as tetrabenazine (NITOMAN, XENAZINE, dopamine D2 antagonist such as Quetiapine);
(xvi) dopamine reuptake inhibitors such as nomifensine maleate (MERITAL);
(xvii) gamma-aminobutyric acid (GABA) receptor agonists such as baclofen (LIORESAL, KEMSTRO);
(xviii) histamine 3 (H3) antagonists such as ciproxifan;
(xix) immunomodulators such as glatiramer acetate (also known as copolymer-1 ; COPAXONE);
(xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX);
(xxi) interferons, including interferon beta-1a (AVONEX, REBIF) and interferon beta-1b (BETASERON, BETAFERON);
(xxii) levodopa (or its methyl or ethyl ester), alone or in combination with a DOPA decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA));
(xxiii) /V-methyl-D-aspartate (NMDA) receptor antagonists such as memantine (NAMENDA, AXURA, EBIXA);
(xxiv) monoamine oxidase (MAO) inhibitors such as selegiline (EMSAM);
(xxv) muscarinîc receptor (particularly M1 subtype) agonists such as bethanechol chloride (DUVOID, URECHOLINE);
(xxvi) neuroprotective drugs such as 2,3,4,9-tetrahydro-1/-/-carbazol-3-one oxime;
(xxvii) nicotinic receptor agonists such as epibatidine;
(xxviii) norepinephrine (noradrenaline) reuptake inhibitors such as atomoxetine (STRATTERA);
(xxix) phosphodiesterase (PDE) inhibitors, for example,PDE9 inhibitors such as BAY 73-6691 (Bayer AG) and PDE 10 (e.g. PDE10A) inhibitors such as papaverine;
(xxx) other PDE inhibitors including (a) PDE1 inhibitors (e.g., vinpocetine), (b) PDE2 inhibitors (e.g., erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA)), (c) PDE4 inhibitors (e.g., rolipram), and (d) PDE5 inhibitors (e.g., sildenafil (VIAGRA, REVATIO));
(xxxi) quinolines such as quinine (including its hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate salts);
(xxxii) β-secretase inhibitors such as WY-25105;
(xxxiii) γ-secretase inhibitors such as LY-411575 (Lilly);
(xxxiv) serotonin (5-hydroxytryptamine) 1A (5-HTia) receptor antagonists such as spiperone;
(xxxv) serotonin (5-hydroxytryptamine) 4 (S-HTî) receptor agonists such as PRX03140 (Epix);
(xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HTe) receptor antagonists such as mianserin (TORVOL, BOLVIDON, NORVAL);
(xxxvîi) serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram (CELEXA, CIPRAMIL);
(xxxviii) trophic factors, such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3), cardiotrophin-1, brainderived neurotrophic factor (BDNF), neublastin, meteorin, and glial-derived neurotrophic factor (GDNF), and agents that stimulate production of trophic factors, such as propentofylline;
and the like.
The compound of Formula I (including a pharmaceutically acceptable sait thereof) is optionally used in combination with another active agent Such an active agent may be, for example, an atypical antipsychotic or an anti-Parkinson’s disease agent or an anti-Alzheimer's agent. Accordingly, another embodiment of the invention provides methods of treating a D1-mediated disorder (e.g., a neurological and psychiatrie disorder associated with D1), comprising administering to a mammal an effective amount of a compound of Formula I (including an A/-oxide thereof or a pharmaceutically acceptable sait of the compound or the N-oxide) and further comprising administering another active agent.
As used herein, the term “another active agent refers to any therapeutîc agent, other than the compound of Formula I (including or a pharmaceutically acceptable sait thereof) that is useful for the treatment of a subject disorder. Examples of additional therapeutîc agents include antidepressants, antipsychotics (such as anti-schizophrenia), anti-pain, anti-Parkinson’s disease agents, anti-LID (levodopa-induced dyskinesia), antiAlzheimer’s and anti-anxiety agents. Examples of particular classes of antidepressants that can be used in combination with the compounds ofthe invention include norepinephrine reuptake inhibitors, sélective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs), réversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, and atypical antidepressants. Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Examples of suitable tertiary amine tricyclics and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butriptyline, iprindole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Examples of suitable sélective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine, and sertraline. Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcyclopramine. Examples of suitable réversible inhibitors of monoamine oxidase include moclobemide. Examples of suitable serotonin and noradrenaline reuptake inhibitors of use in the présent invention include venlafaxine. Examples of suitable atypical anti-depressants include bupropion, lithium, nefazodone, trazodone and viloxazine. Examples of anti-Alzheimer’s agents include Dimebon, NMDA receptor antagonists such as memantine; and cholinestérase inhibitors such as donepezil and galantamine. Examples of suitable classes of anti-anxiety agents that can be used in combination with the compounds of the invention include benzodiazépines and serotonin 1A (5-HT1A) agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Suitable benzodiazépines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazépam, oxazepam, and prazepam. Suitable 5-HT1A receptor agonists or antagonists include buspirone, flesinoxan, gepirone, and ipsapirone. Suitable atypical antipsychotics include paliperidone, bifeprunox, ziprasidone, rispéridone, aripiprazole, olanzapine, and quetiapine. Suitable nicotine acétylcholine agonists include ispronicline, varenicline and MEM 3454. Anti-pain agents include pregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam, ketamine and ziconotide.
Examples of suitable anti-Parkinson’s disease agents include L-DOPA (or its methyl or ethyl ester), a DOPA decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA), an Adenosine A2A receptor antagonist [e.g., Preladenant (SCH 420Θ14) or SCH 412348], benserazide (MADOPAR), α-methyldopa, monofluoromethyldopa, difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine), a dopamine agonist [such as apomorphine (APOKYN), bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydrexidine, dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN), pergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine (NEUPRO), SKF-82958 (GlaxoSmithKIine), and sarizotan], a monoamine oxidase (MAO) inhibitor [such as selegiline (EMSAM), selegiline hydrochloride (L-deprenyl, ELDEPRYL, ZELAPAR), dimethylselegilene, brofaromine, phenelzine (NARDIL), tranylcypromine (PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide, isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT), iproniazide (MARSILID,
IPROZID, IPRONID), CHF-3381 (Chiesi Farmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), bifemelane, desoxypeganîne, harmine (also known as telepathine or banasterine), harmaline, linezolid (ZYVOX, ZYVOXID), and pargyline (EUDATIN, SUPIRDYL)], a catechol O-methyltransferase (COMT) inhibitor [such as tolcapone (TASMAR), entacapone (COMTAN), and tropolone], an A/-methyl-D-aspartate (NMDA) receptor antagonist [such as amantadine (SYMMETREL)], anticholinergics [such as amitriptyline (ELAVIL, ENDEP), butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN), scopolamine (TRANSDERM-SCOP), scopolamine methylbromide (PARMINE), dicycloverine (BENTYL, BYCLOMINE, DIBENT, DILOMINE, tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL, OXYTROL), penthienate bromide, propantheline (PROBANTHINE), cyclizine, imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepîn (SINEQUAN, ZONALON), trîmipramine (SURMONTIL), and glycopyrrolate (ROBINUL)J, or a combination thereof. Exemples ofanti-schizophrenia agents include ziprasidone, rispéridone, olanzapine, quetiapine, aripiprazole, asenapine, blonanserin, or iloperidone. Some additional another active agent examples include rivastigmine (Exelon), Clozapine, Levodopa, Rotigotine, Aricept, Methylphenidate, memantine. milnacipran, guanfacine, bupropion, and atomoxetine.
As noted above, the compounds of Formula I (including pharmaceutically acceptable salts thereof) may be used in combination with one or more additional antischizophrenia agents which are described herein. When a combination therapy is used, the one or more additional anti-schizophrenia agents may be administered sequentially or simultaneously with the compound of the invention. In one embodiment, the additional anti-schizophrenia agent is administered to a mammal (e.g., a human) prior to administration of the compound of the invention. In another embodiment, the additional anti-schizophrenia agent is administered to the mammal after administration of the compound ofthe invention, ln anotherembodiment, the additional anti-schizophrenia agent is administered to the mammal (e.g., a human) simultaneously with the administration of the compound of the invention (or an N-oxide thereof or a pharmaceutically acceptable sait of the foregoing).
The invention also provides a pharmaceutical composition for the treatment of schizophrenia in a mammal, including a human, which comprises an amount of a compound of Formula I (or a pharmaceutically acceptable sait thereof), as defined above (including hydrates, solvatés and polymorphs of said compound or pharmaceutically acceptable salts thereof), in combination with one or more (for example one to three) anti-schizophrenia agents such as ziprasidone, rispéridone, olanzapine, quetiapine, aripiprazole, asenapine, blonanserin, or iloperidone, wherein the amounts ofthe active agent and the combination when taken as a whole are therapeutically effective for treating schizophrenia.
The invention also provides a pharmaceutical composition for the treatment of Parkinson’s disease in a mammal (including cognition impairment associated with PD), including a human, which comprises an amount of a compound of Formula I (or a pharmaceutically acceptable sait thereof), as defined above (including hydrates, solvatés and polymorphs of said compound or pharmaceutically acceptable salts thereof), in combination with one or more (for example one to three) anti-Parkinson’s disease agents such as L-DOPA, wherein the amounts of the active agent and the combination when taken as a whole are therapeutically effective for treating Parkinson’s disease.
It will be understood that the compounds of Formula I depicted above are not limited to a particular stereoisomer (e.g. enantiomer or atropisomer) shown, but also include ail stereoisomers and mixtures thereof.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the invention, including /V-oxides and salts of the compounds or M-oxides, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.
The reactions for preparing compounds of the invention can be carried out in suitable solvents, which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the températures at which the reactions are carried out, e.g., températures that can range from the solvent's freezing température to the solvent’s boiling température. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.
Préparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the sélection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.
Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic résonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographie methods such as high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
Compounds of Formula I and intermediates thereof may be prepared according to the following reaction schemes and accompanying discussion. Unless otherwise indicated, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, L1, X1, X2, X3, X4, X5, T6, Q1, and structural Formula I in the reaction schemes and discussion that follow are as defined above. In general, the compounds of this invention may be made by processes which include processes analogous to those known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of this invention and intermediates thereof are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes are described in the experimental section. The schemes and examples provided herein
(including the corresponding description) are for illustration only, and not intended to limit the scope of the présent invention.
Scheme 1
Scheme 1 refers to préparation of compounds of Formula I. Referring to Scheme 10 1, compounds of Formula 1-1 [where Lg1 is a suitable leaving group such as halo (e.g.,
F, Cl or Br)] and 1-2 [wherein Z1 can be, e.g., halogen (e.g., Br or I) or trifluoromethanesulfonate (triflate)] are commercially available or can be made by methods described herein or other methods well known to those skilled in the art. A compound of Formula 1-3 can be prepared by coupling a compound of Formula 1-1 with a compound of Formula 1-2 under suitable conditions. The coupling can be accomplished, for example, by heating a mixture ofa compound of Formula 1-1 with a compound of Formula 1-2 in the presence ofa base, such as CS2CO3, in an appropriate solvent, such as dimethyl sulfoxide (DMSO). Altematively, a metal-catalyzed (such as using a palladium or copper catalyst) coupling may be employed to accomplish the aforesaid coupling. ln this variant of the coupling, a mixture of a compound of Formula 1-1 and a compound of Formula 1-2 can be heated in the presence of a base (such as CS2CO3), a métal catalyst [such as a palladium catalyst, e.g., Pd(OAc)2], and a ligand [such as 1 ,T-bînaphthalene-2,2'-diylbis(diphenylphosphane) (BINAP)Jin an appropriate solvent, such as 1,4-dioxane. A compound of Formula 1-3 can subsequently be reacted with a compound of Formula Q1-Z2 [wherein Z2 can be Br; B(OH)2; B(OR)2 wherein each R is independently H or Ci-e alkyl, or wherein the two (OR) groups, together with the B atom to which they are attached, form a 5- to 10-membered heterocycloalkyl optionally substituted with one or more Ci-e alkyl; a trialkyltin moiety; or the like] by a metalcatalyzed (such as using a palladium catalyst) coupling reaction to obtain a compound of Formula I. Compounds of Formula Q1-Z2 are commercially available or can be made by methods described herein or by methods analogous to those described in the chemical art. Altematively, a compound of Formula 1-3 can be converted to a compound of Formula 1-4 (wherein Z2 is defîned as above). For example, a compound of Formula 1-3 (wherein Z1 is halogen such as Br or I) can be converted to a compound of Formula 1-4 [wherein Z2 îs B(0H)2j B(OR)2 wherein each R is independently H or Ci-e alkyl, or wherein the two (OR) groups, together with the B atom to which they are attached, form a 5- to 10-membered heterocycloalkyl or heteroaryl optionally substituted with one or more C1-6 alkyl] by methods described herein or other methods weil known to those skilled in the art. In this example, this reaction can be accomplished, for example, by reacting a compound of Formula 1-3 (wherein Z1 is halogen such as Br) with 4,4,4'l4',5,5,5',5'-octamethyl-2,2’-bi-1,3,2-dioxaborolane, a suitable base (such as potassium acetate), and a palladium catalyst {such as [1,1’bis(diphenylphosphino)ferrocene]dichloropalladium(ll)} in a suitable solvent such as 1,4dioxane. In another example, a compound of Formula 1-3 (wherein Z1 is halogen such as Br) can be converted to a compound of Formula 1-4 (wherein Z2 is a trialkyltin moiety) by alternate methods described herein or other methods weil known to those skilled in the art. In this example, this reaction can be accomplished, for example, by reacting a compound of Formula 1-3 (wherein Z1 is halogen such as Br) with a hexaalkyldîstannane (such as hexamethyldistannane) in the presence of a palladium catalyst [such as tetrakis(triphenylphosphine)palladium(0)] in a suitable solvent such as
1,4-dioxane. A compound of Formula 1-4 can then be reacted with a compound of Formula Q1-Z1 (wherein Z1 is defîned as above) by a metal-catalyzed (such as using a palladium catalyst) coupling reaction to obtain a compound of Formula I, Compounds of Formula Q1-Z1 are commercîally available or can be made by methods described herein or by methods analogous to those described in the chemical art. The type of reaction employed dépends on the sélection of Z1 and Z2. For example, when Z1 is halogen or triflate and the Q1-Z2 reagent is a boronic acid or boronic ester, a Suzuki reaction may be used [A. Suzuki, J. Organomet. Chem. 1999, 576, 147-168; N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457-2483; A. F. Littkeétal., J. Am. Chem. Soc. 2000, 122, 4020-4028], In some spécifie embodiments, an aromatic iodide, bromide, or triflate of Formula 1-3 is combined with an aryl or heteroaryl boronic acid or boronic ester of Formula Q1-Z2 and a suitable base, such as potassium phosphate, in a suitable organic solvent such as tetrahydrofuran (THF). A palladium catalyst is added, such as S-Phos precatalyst {also known as chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,rbiphenyl)[2-(2-aminoethylphenyl)]palladium(ll) - tert-butyl methyl ether adduct}, and the reaction mixture is heated. Altematively, when Z1 is halogen or triflate and Z2 is trialkyitin, a Stille coupling may be employed [V. Farina et al., Organic Reactions 1997, 50, 1-652], More specifically, a compound of Formula 1-3 (wherein Z1 is Br, I, or triflate ) may be combined with a compound of Formula Q1-Z2 (wherein the Q1-Z2 compound is a Q1-stannane compound) in the presence of a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(ll), in a suitable organic solvent such as toluene, and the reaction may be heated. Where Z1 is Br, I, or triflate and Z2 is Br or I, a Negishi coupling may be used [E. Erdik, Tetrahedron 1992, 48, 9577-9648]. More specifically, a compound of Formula 1-3 (wherein Z1 is Br, I, or triflate) may be transmetallated by treatment with 1 to 1.1 équivalents of an alkyllithium reagent followed by a solution of 1.2 to 1.4 équivalents of zinc chloride in an appropriate solvent such as THF at a température ranging from -80 °C to -65 °C. After warming to a température between 10 °C and 30 °C, the reaction mixture may be treated with a compound of Formula Q1-Z2 (wherein Z2 is Br or I), and heated at 50 °C to 70 °C with addition of a catalyst such as tetrakis(triphenylphosphine)pailadium(0). The reaction may be carried out for times ranging from 1 to 24 hours to yield the compound of Formula I.
Scheme 2
Scheme 2 also refers to préparation of compounds of Formula I. Referring to Scheme 2, compounds of Formula I may be prepared utilîzing analogous chemical transformations to those described in Scheme 1, but with a different ordering of steps. Compounds of Formula 2-1 [wherein Pg1 is a suitable protecting group such as Boc or Cbz when L1 is NH or methyl, benzyl, tetrahydropyranyl (THP), or tert-butyldimethyl (TBS) when L1 is O] are commercially available or can be made by methods described herein or other methods well known to those skilled in the art. A compound of Formula 2-1 can be converted to a compound of Formula 2-2 either directly or after conversion to a compound of Formula 2-3 using methods analogous to those described in Scheme 1. A compound of Formula 2-2 may then be deprotected, using appropriate conditions depending on the sélection ofthe Pg1 group, to obtain a compound of Formula 2-4, which in turn can be coupled with a compound of Formula 1-1 in Scheme 1 to afford a compound of Formula I. The coupling conditions employed may be analogous to those described for the préparation of a compound of Formula 1-3 in Scheme 1.
Scheme 3
A1 is Pg1 or a moiety of A1a: 1
X3' > fl A1“
J X5
Scheme 3 refers to a préparation of a compound of Formula 3-5 wherein A1 is a moiety of Formula A1a or a Pg1. Referring to Scheme 3, compounds of Formula 3-1 are commercially available or can be made by methods described herein or other methods well known to those skilled in the art. A compound of Formula 3-2 can be prepared by reacting an arylketone of Formula 3-1 with an alkyl nitrite (e.g., isoamyl nitrite) in the presence of an acid (such as hydrochloric acid). The resulting oxime of Formula 3-2 can be converted to the diketone of Formula 3-3 upon treatment with formaldéhyde (or its équivalent such as métaformaldéhyde or polyformaldéhyde) in the presence of an acid (such as an aqueous hydrochloric acid solution). Diketones of Formula 3-3 can be reacted with glycinamide or a sait thereof (such as an acetic acid sait) in the presence of a base such as sodium hydroxide to obtain pyrazinones of Formula 3-4. Alkylation of the pyrazinone nitrogen to obtain a compound of Formula 3-5 can be achieved by treatment of a compound of Formula 3-4 with a base [such as lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LHMDS), and the like] and a compound ofthe formula R11-Z3 [wherein Z3 is an acceptable leaving group such as Cl, Br, I, methanesulfonate (mesylate), and the like and wherein R11 is for example C1-3 alkyl (e.g., methyl)]. Suitable reaction solvents typically can be selected from polar aprotic solvents such as /V,A/-dimethylformamide (DMF), 1,4-dioxane, or THF.
Scheme 4
ΛΛΛΛΛ
A1 is Pg1 or a moiety of A1a: x=-A r<^N A1a
X5 ^x1>^T6
Altematively, a compound of Formula 3-5 may be prepared as in Scheme 4 wherein L1 is O, NH, N(Ci-4 alkyl) and N(C3-e cycloalkyl). Referring to Scheme 4, compounds of Formula 4-1 and 4-2 are commerciaily available or can be made by methods described herein or other methods well known to those skilled in the art. A compound of Formula 4-3 can be prepared by coupling a compound of Formula 4-1 with 10 a compound of Formula 4-2. The aforesaid coupling may be accomplished by reacting a compound of Formula 4-1 with a compound of Formula 4-2 in the presence of a suitable base (such as potassium carbonate), a suitable catalyst [such as tetrakis(triphenylphosphine)palladium(0)], and a suitable solvent (such as éthanol). A compound of Formula 4-3 can be reacted with maleic anhydride and hydrogen peroxide in a solvent (such as dichloromethane) to provide a compound of Formula 4-4, which may contain a mixture of /V-oxide regioisomers. A compound of Formula 4-5 can be prepared from a compound of Formula 4-4 by heating with acetic anydride; the initial product can be saponîfied using a base (such as NaOH) in a suitable polar solvent (such as water or methanol). A compound of Formula 3-5 can be prepared from a compound of Formula 4-5 by reaction with a suitable base (such as LDA, LHMDS and the like), lithium bromide, and a compound oftheformula R11-Z3 (wherein Z3 is an acceptable leaving group such as Cl, Br, I, mesylate, and the like). Suitable reaction solvents typically can be selected from polar aprotic solvents (such as DMF, 1,4dioxane, or THF).
h2n—nh2 o R® A. R3 Y NH A1 is Pg2 or a moiety of A1a:
ΑΛη
RL. «ΑΛΑΛ I
L1> s *7 rS *’
I A1 R2
5-5
Scheme 5 refers to a préparation of a compound of Formula 5-5 wherein L1 is O, NH, carbonyl, N(Cm alkyl) and N(C^ cycloalkyl) and A1 is a moiety of Formula A1a, or a Pg2 (such as a benzyl group). Referring to Scheme 5, compounds of Formula 5-1 and 52 are commercially available or can be made by methods described herein or other methods well known to those skilled in the art. A compound of Formula 5-3 can be prepared by coupling a compound of Formula 5-1 with an enol trifluoromethanesulfonate of Formula 5-2. The aforesaid coupling may be accomplished by reacting a compound of Formula 5-1 with a trifluoromethanesulfonate of Formula 5-2 in the presence of a suitable base (such as potassium carbonate or sodium carbonate), a suitable catalyst [such as palladium(ll) acetate], optionally a suitable ligand (such as tricyclohexylphosphine), and optionally a suitable phase-transfer catalyst such as tetrabutylammonium chloride. Suitable reaction solvents typically can be selected from polar aprotic solvents such as 1,4-dioxane or THF. A compound of Formula 5-3 can be ) reacted with 1 to 5 équivalents of a suitable base [such as 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU)] under an oxygen atmosphère to obtain a compound of Formula 5-4. Suitable reaction solvents typically can be selected from polar aprotic solvents such as DMF, 1,4-dioxane, or THF. A compound of Formula 5-5 can be obtained by reacting a compound of Formula 5-4 with hydrazine in a suitable solvent such as 1-butanol.
Scheme 6
Scheme 6 refers to a préparation of a compound of Formula 6-5. Referring to
Scheme 6, a compound of Formula 6-1 can be prepared as described in Scheme 5, wherein Pg2 is a suitable protecting group (such as benzyl). A compound of Formula 61 can be converted to a suitably protected compound of Formula 6-2 using methods described herein or other methods well known to those skilled in the art, wherein Pg3 is a suitable protecting group (such as ΤΗΡ) that can be removed under orthogonal reaction conditions to Pg2. A compound of Formula 6-3 can be prepared by sélective removal of Pg2 under suitable deprotection conditions depending on the sélection of Pg2. For example, when Pg2 is a benzyl group, it can be removed by treatment with palladium (10% on carbon) under hydrogénation condition in a suitable solvent, such as methanol and ethyl acetate. Using the aforementioned reaction conditions described in Scheme 1, a compound of Formula 6-3 can be coupled with a reagent of Formula 1-1 to yield a compound of Formula 6-4. A compound of Formula 6-5 can be obtained by removing Pg3 under suitable deprotection conditions depending on the sélection of Pg3. For example, when Pg3 is THP, it can be removed under acidic conditions, such as hydrogen chloride in a suitable solvent, such as dichloromethane. Scheme 7
7-4
7-5
Scheme 7 refers to a préparation of a compound of Formula 7-5 [wherein R10 is, for example, C1-3 alkyl (e.g., methyl ); R10B is, for example, H or C1-3alkyl (e.g., methyl );
and Pg4 is a suitable protecting group [e.g., 2-(trimethylsilyl)ethoxymethyl (SEM), tertbutoxycarbonyl (Boc), or benzyloxymethyl acetal (BOM)]. Referring to Scheme 7, compounds of Formula 2-3 and 7-1 are commercially available or can be prepared by methods described herein or other methods well known to those skilled in the art. A compound of Formula 7-2 can be prepared by coupling a compound of Formula 2-3 with a compound of Formula 7-1, in the presence of a suitable base (such as potassium carbonate) and a suitable catalyst {such as [1,1 ’bis(diphenylphosphino)ferrocene]dichloropalladium(ll)}. A compound of Formula 7-3 can be prepared by sélective removal of Pg2 under suitable de-protection conditions depending on the sélection of Pg2. For example, when Pg2 is a benzyl group, it can be removed by treatment with palladium (10% on carbon) under hydrogénation condition in a suitable solvent, such as methanol and ethyl acetate. Using the aforementioned reaction conditions described in Scheme 1, a compound of Formula 7-3 can be coupled with a reagent of Formula 1-1 to yield a compound of Formula 7-4. Alternatively, a compound of Formula 7-4 can be prepared from intermediate 1-4, following the coupling conditions described in Scheme 1. A compound of Formula 7-5 can then be obtained from a compound of Formula 7-4 by removing Pg4 under suitable deprotection conditions that are known to those skilled in the art.
Scheme 8
8-4
8-6
Scheme 8 refers to préparation of compounds of Formula 8-5 and 8-6. Referring to Scheme 8, compounds of Formula 8-1 are commercially available or can be made by methods described herein or other methods well known to those skilled in the art. A compound of Formula 8-1 can be converted to a compound of Formula 8-2 either directly or after conversion to a compound of Formula 8-3 using methods analogous to those described in Scheme 1. The nitro group of a compound of Formula 8-2 can then be converted to an amine via hydrogénation in the presence of a suitable catalyst, such as palladium (10% on carbon), to yield a compound of Formula 8-4. A compound of Formula 8-4 can then be coupled with a compound of Formula 1-1 in Scheme 1 to afford a compound of Formula 8-5. The coupling conditions employed may be analogous to those described for the préparation of a compound of Formula 1-3 in Scheme 1. A compound of Formula 8-6 can be prepared via A/-alkylation of a compound of formula 85 using a reagent of Y-Z3, wherein Y is Cm alkyl, or C3-6 cycloalkyl, and Z3 is an acceptable leaving group such as Cl, Br, I, mesylate, and the like.
Scheme 9
Scheme 9 refers to préparation of compounds of Formula 9-4. Referring to Scheme 9, a compound of Formula 9-1 can be prepared via inflation of a compound of Formula 2-4 (Scheme 2) using a suitable reagent such as trifluoromethanesulfonic anhydride in the presence of a suitable base such as triethylamine. A compound of Formula 9-1 can be converted to a compound of Formula 9-2 by coupling with potassium thioacetate, in the presence of a suitable métal catalyst, such as tris(dibenzylideneacetone)dîpalladium(0), and a suitable ligand, such as (R)-(-)-1-[(Sp)18535
2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine, in a suitable solvent, such as toluene. A compound of Formula 9-2 can then be hydrolyzed to obtain a compound of Formula 9-3, which in turn can be coupled with a compound of Formula 11 in Scheme 1 to afford a compound of Formula 9-4. The coupling conditions employed may be analogous to those described for the préparation of a compound of Formula 1-3 in Scheme 1. A compound of Formula 9-4 may then be deprotected, using appropriate conditions depending on the sélection ofthe Pg1 group, to obtain a compound of Formula I.
A1 is Pg1 or a moiety of A1B:
Scheme 10 refers to a préparation of a compound of Formula 10-3 [wherein A1 is either Pg2 as defined above or a moiety of Formula A1a], which can be used in Scheme as intermediate/starting material for the préparation of compounds of Formula I.
Referring to Scheme 3, compounds of Formula 10-1 are commercially available or can be made by methods described herein or other methods well known to those skilled in the art. A compound of Formula 10-1 can be reacted with 4-chloro-3-nitropyridine and the initial product can be subsequently reduced to obtain a compound of Formula 10-2.
Examples of suitable reaction conditions for the coupling of a compound of Formula 10 1 with 4-chloro-3-nitropyridine include mixing the two reactants with a suitable base, such as triethylamine, in a suitable reaction solvent such as éthanol. The subséquent réduction ofthe nitro group to afford a compound of Formula 10-2 can be achieved by, for example, hydrogénation in the presence of a catalyst such as palladium on carbon in a suitable solvent such as methanol. Suitable hydrogen pressures for the aforesaid reaction are typically between 1 atm and 4 atm. A compound of Formula 10-2 can then be heated with acetic anhydride and triethyl orthoformate to obtain a compound of
Formula 10-3.
11-2
Scheme 11 refers to a préparation of a compound of Formula 11-1 [wherein R10 can be H or C1-3 alkyl, for example methyl], which is an example of a compound of Formula I. Referring to Scheme 11, a compound of Formula 11-1 can be prepared by methods described in Scheme 1. A compound of Formula 11-1 can be reacted with chloroacetaldehyde to obtain a compound of Formula 11-2 typically at an elevated température for about 1 hour to 24 hours.
Additional starting materials and intermediates useful for making the compounds ofthe présent invention can be obtained from chemical vendors such as Sigma-Aldrich or can be made according to methods described in the chemical art.
Those skilied in the art can recognize that in ail of the Schemes described herein, if there are functional (reactive) groups présent on a part of the compound structure such as a substituent group, for example R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, L1, X1, X2, X3, X4, X5, T6, and Q1, etc., further modification can be made if appropriate and/or desired, using methods well known to those skilied in the art. For example, a CN group can be hydrolyzed to afford an amide group; a carboxylic acid can be converted to an amide; a carboxylic acid can be converted to an ester, which in turn can be reduced to an alcohol, which in turn can be further modified. For another example, an OH group can be converted into a better leaving group such as a methanesulfonate, which in turn is suitable for nucleophilic substitution, such as by a cyanîde ion (CN'). For another example, an -S- can be oxidized to -S(=O)- and/or -S(=O)2-. For yet another example, an unsaturated bond such as C=C or ΟξΟ can be reduced to a saturated bond by hydrogénation. In some embodiments, a primary amine or a secondary amine moiety (présent on a substituent group such as R3, R4, R9, R10, etc.) can be converted to an amide, sulfonamide, urea, or thiourea moiety by reacting it with an appropriate reagent such as an acid chloride, a sulfonyl chloride, an isocyanate, or a thioisocyanate compound. One skilled in the art will recognize further such modifications. Thus, a compound of Formula I having a substituent that contains a functional group can be converted to another compound of Formula I having a different substituent group.
Similarly, those skilled in the art can also recognize that in ail of the schemes described herein, if there are functional (reactive) groups présent on a substituent group such as R3, R4, R9, R10, etc., these functional groups can be protected/deprotected in the course of the synthetic scheme described here, if appropriate and/or desired. For example, an OH group can be protected by a benzyl, methyl, or acetyl group, which can be deprotected and converted back to the OH group in a later stage of the synthetic process. For another example, an NH2 group can be protected by a benzyloxycarbonyl (Cbz) or Boc group; conversion back to the NH2 group can be carried out at a later stage of the synthetic process via deprotection.
As used herein, the term “reacting” (or “reaction” or “reacted”) refers to the bringing together of designated chemical reactants such that a chemical transformation takes place generating a compound different from any initially introduced into the system. Reactions can take place in the presence or absence of solvent.
Compounds of Formula I may exist as stereoisomers, such as atropisomers, racemates, enantiomers, or diastereomers. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral highperformance liquid chromatography (HPLC). Altemativeïy, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartane acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of Formula I (and chiral precursors thereof) may be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0% to 50% 2-propanol, typically from 2% to 20%, and from 0% to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Stéréoisomeric conglomérâtes may be separated by conventional techniques known to those skilled in the art. See, e.g., Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety. Suitable stereoselective techniques are well known to those of ordinary skill in the art.
Where a compound of Formula I contains an alkenyl or alkenylene (alkylidene) group, géométrie cis/trans (or ZÆ) isomers are possible. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Salts of the present invention can be prepared according to methods known to those of skill in the art.
The compounds of Formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animais, it is often désirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable sait and then simply convert the latter back to the free base compound by treatment with an aIkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition sait. The acid addition salts of the basic compounds of this invention can be prepared by treating the basic compound with a substantially équivalent amount ofthe selected minerai or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or éthanol. Upon évaporation of the solvent, the desired solid sait is obtained. The desired acid sait can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate minerai or organic acid to the solution.
If the inventive compound is a base, the desired pharmaceutically acceptable sait may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, isonicotinic acid, lactic acid, pantothenic acid, bitartric acid, ascorbic acid, 2,5-dihydroxybenzoîc acid, gluconic acid, saccharic acid, formic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, and pamoic [i.e., 4,4'-methanediylbis(3-hydroxynaphthalene-2carboxylic acid)] acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartane acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cînnamic acid, a sulfomc acid, such as ethanesulfonic acid, or the like.
Those compounds of Formula I that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali métal or alkaline earth métal salts, and particularly the sodium and potassium salts. These salts are ail prepared by conventional techniques. The chemical bases which are used as reagents to préparé the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of Formula I. These salts may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali métal hydroxide or alkaline earth métal hydroxide, or the like. These salts can also be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, for example under reduced pressure. Altematively, they may also be prepared by mixing lower alkanolic solutions ofthe acidic compounds and the desired alkali métal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are, for example, employed in order to ensure completeness of reaction and maximum yields of the desired final product.
Pharmaceutically acceptable salts of compounds of Formula I (including compounds of Formula la or Ib) may be prepared by one or more of three methods:
(i) by reacting the compound of Formula I with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one sait of the compound of Formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
Ail three reactions are typically carried out in solution. The resulting sait may precipitate out and be collected by filtration or may be recovered by évaporation of the solvent. The degree of ionization in the resulting sait may vary from completely ionized to almost non-ionized.
Polymorphs can be prepared according to techniques well-known to those skilled in the art, for example, by crystallization.
When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantîomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
While both of the crystal forms présent in a racemic mixture may hâve almost identical physical properties, they may hâve different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemîstry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).
The invention also includes isotopically labeled compounds of Formula I wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or hnass number different from the atomic mass or mass number usually found in nature. Isotopically labeled compounds of Formula I (or pharmaceutically acceptable salts thereof or /V-oxides thereof) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the nonlabeled reagent otherwise employed.
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities présent in the compounds of Formula I with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
The compounds of Formula I should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication.
Compounds ofthe invention intended forpharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as précipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingrédient other than the compound(s) of the invention. The choice of excipient will to a large extent dépend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
Pharmaceutical compositions suitable for the delivery of compounds of the présent invention (or pharmaceutically acceptable salts thereof) and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
The compounds ofthe invention (including pharmaceutically acceptable salts thereof and /V-oxides thereof) may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid, semi-solid and liquid Systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
Liquid formulations include suspensions, solutions, syrups and élixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropyl methyl cellulose) and typically comprise a carrier, for example, water, éthanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fastdisintegrating dosage forms such as those described by Liang and Chen, Expert Opinion in Therapeutic Patents 2001, 11, 981-986.
For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, for example, from 5 weight % to 20 weight % of the dosage form.
Binders are generally used to impart cohesive qualifies to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dîbasic calcium phosphate dihydrate.
Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When présent, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % ofthe tablet.
Tablets also generally contain lubricants such as magnésium stéarate, calcium stéarate, zinc stéarate, sodium stearyl fumarate, and mixtures of magnésium stéarate with sodium lauryl sulfate. Lubricants generally comprise from 0.25 weight % to 10 weight %, for example, from 0.5 weight % to 3 weight % of the tablet.
Other possible ingrédients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.
Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
Tablet blends may be compressed directly or by rollerto form tablets. Tablet blends or portions of blends may altematively be wet-, dry-, or melt-granulated, meltcongealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
The formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
Consumable oral films for human or veterinary use are typically pliable watersoluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of Formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer oremulsifier, a viscositymodifying agent and a solvent. Some components of the formulation may perform more than one function.
The compound of Formula I (or pharmaceutically acceptable salts thereof or Noxides thereof) may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutés, Less soluble compounds may comprise a smaller proportion of the composition, typically up to 30 weight % ofthe solutés. Altematively, the compound of Formula I may be in the form of multiparticulate beads,
The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically présent in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
Other possible ingrédients include anti-oxidants, colorants, flavorings and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), émollients, bulking agents, anti-foaming agents, surfactants and tastemasking agents.
Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freezedrying orvacuuming,
Solid formulations for oral administration may be formulated to be immédiate and/or modifïed release. Modifïed release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
Suitable modifïed release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001), The use of chewing gum to achieve controlled release is described in WO 00/35298.
The compounds of the invention (including pharmaceutically acceptable salts thereof) may also be administered directly into the blood stream, into muscle, or into an internai organ. Suitable means for parentéral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intrauréthral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parentéral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
Parentéral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (for example to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a stérile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as stérile, pyrogen-free water.
The préparation of parentera! formulations under stérile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of Formula I (including pharmaceutically acceptable salts thereof) used in the préparation of parentera! solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubilityenhancing agents.
Formulations for parentera! administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds ofthe invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(DL-lactic-coglycolic acid) (PLGA) microspheres.
The compounds ofthe invention (including pharmaceutically acceptable salts thereof) may also be administered topically, (intra)dermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, minerai oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Pénétration enhancers may be incorporated. See e.g., Finnin and Morgan, J. Pharm. Sci. 1999, 88, 955-958.
Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g., Powderject™, Bioject™, etc.) injection.
Formulations for topical administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention (including pharmaceutically acceptable salts thereof) can also be administered intranasally or by inhalation, typically in the fomn of a dry powder (either alone; as a mixture, for example, in a dry blend with lactose; or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aérosol spray from a pressurized container, pump, spray, atomizer (for example an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, éthanol, aqueous éthanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an olîgolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
Capsules (made, for example, from gelatin or hydroxypropyl methyl cellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as L-leucine, mannitol, or magnésium stéarate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 pg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 pL to 100 pL. A typical formulation may comprise a compound of Formula I or a pharmaceutically acceptable sait thereof, propylene glycol, stérile water, éthanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin orsaccharin sodium, may be added to those formulations ofthe invention intended for înhaled/intranasal administration.
Formulations for inhaled/intranasal administration may be formulated to be immédiate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
In the case of dry powder inhalers and aérosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or puff” containing from 0.01 to 100 mg ofthe compound of Formula I. The overall daily dose will typically be în the range 1 pg to 200 mg, which may be administered in a single dose or, more usually, as divided doses throughout the day.
The compounds ofthe invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
Formulations for rectal/vaginal administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds ofthe invention (including pharmaceutically acceptable salts thereof) may also be administered directly to the eye or ear, typically in the form of drops ofa micronized suspension or solution in isotonie, pH-adjusted, stérile saline. Other formulations suitable for ocular and aurai administration include ointments, gels, biodégradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses and particulate or vesicular Systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
Formulations for ocular/aural administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
The compounds of the invention (including pharmaceutically acceptable salts thereof) may be combined with soluble macromolecular entities, such as cyclodextrin and suitable dérivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
Since the présent invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingrédients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula I a prodrug thereof or a sait of such compound or prodrug and a second compound as described above. The kit comprises means for containîng the separate compositions such as a container, a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are for example administered in different dosage forms (e.g., oral and parenterai), are administered at different dosage intervals, or when titration of the individual components of the combination îs desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are weil known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses hâve the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a resuit, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. In some embodiments, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be désirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows First Week, Monday, Tuesday, etc.... Second Week, Monday, Tuesday,...’’ etc. Other variations of memory aids will be readily apparent. A daily dose can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula I compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
In another spécifie embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. For example, the dispenser is equipped with a memory aid, so as to further facilitate compliance with the regimen. An example of such a memory aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
The invention will be described in greater detail by way of spécifie examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention în any manner. Those of skill in the art will readily recognize a variety of noncritical parameters that can be changed or modified to yield essentially the same results. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art. In the following Examples and Préparations, “DMSO means dimethyl sulfoxide, “N“ where referring to concentration means Normal, “M” means molar, “mL means milliliter, “mmol means millimoles, “pmol” means micromoles, eq. means équivalent, “°C means degrees Celsius, “MHz means mégahertz, “HPLC means high-performance liquid chromatography.
EXAMPLES
Experiments were generally carried out under inert atmosphère (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were employed. Commercial solvents and reagents were generally used without further purification. Anhydrous solvents were employed where appropriate, generally AcroSeal® products from Acros Organics or DriSolv® products from EMD
Chemicals. In other cases, commercial solvents were passed through columns packed with 4Â molecular sieves, until the following QC standards for water were attained: a) <100 ppm for dichloromethane, toluene, A/,A/-dimethylformamîde and tetrahydrofuran; b) <180 ppm for methanol, éthanol, 1,4-dioxane and diisopropylamine. For very sensitive reactions, solvents were further treated with metallic sodium, calcium hydride or molecular sieves, and distilled just prior to use. Products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing. Mass spectrometry data is reported from either liquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI) or gas chromatography-mass spectrometry (GCMS) instrumentation. Chemical shifts for nuclear magnetic résonance (NMR) data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvents employed. ln some examples, chiral séparations were carried out to separate enantiomers or atropisomers (or atropenantiomers) of certain compounds of the invention (in some examples, the separated atropisomers are designated as ENT-1 and ENT-2, according to their order of elution). In some examples, the optical rotation of an enantiomer or atropisomer was measured using a polarimeter. According to its observed rotation data (or its spécifie rotation data), an enantiomer or atropisomer (or atropenantiomer) with a clockwise rotation was designated as the (+)-enantiomer or (+)-atropisomer [or the (+) atropenantiomer] and an enantiomer or atropisomer (or atropenantiomer) with a counter-clockwise rotation was designated as the (-)-enantiomer or (-)-atropisomer [or the (-) atropenantiomer].
Reactions proceeding through détectable intermediates were generally followed by LCMS, and allowed to proceed to full conversion prior to addition of subséquent reagents. For synthèses referencing procedures in other Examples or Methods, reaction conditions (reaction time and température) may vary. ln general, reactions were followed by thin-layer chromatography or mass spectrometry, and subjected to work-up when appropriate. Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents/gradients were chosen to provide appropriate Rts or rétention times.
Example 1
1,5-Dimethyl-6-[2-methyl-4-( 1,7-naphthyridin-8-yloxy)phenyl]pyrimidine2,4(1H,3H)-dione (1)
nh2
•HCl
θ
o o
Step 1. Synthesis of 6-amino-1,5-dimethylpyrimidine-2,4(1H,3H)-dione, hydrochloride sait (C1).
A solution of sodium methoxide in methanol (4.4 M, 27 mL, 119 mmol) was added to a solution of ethyl 2-cyanopropanoate (95%, 13.2 mL, 99.6 mmol) and 1methylurea (98%, 8.26 g, 109 mmol) in methanol (75 mL), and the reaction mixture was heated at reflux for 18 hours, then cooled to room température. After removal of solvent in vacuo, the residue was repeatedly evaporated under reduced pressure with acetonitrile (3 x 50 mL), then partitioned between acetonitrile (100 mL) and water (100 mL). Aqueous 6 M hydrochloric acid was slowly added until the pH had reached approximately 2; the resulting mixture was stirred for 1 hour. The precipitate was collected via filtration and washed with tert-butyI methyl ether, affording the product as a white solid. Yield: 15.2 g, 79.3 mmol, 80%. LCMS m/z 156.1 [M+H]+. 1H NMR (400 MHz,
DMSO-de) δ 10.38 (br s, 1H), 6.39 (s, 2H), 3.22 (s, 3H), 1.67 (s, 3H).
Step 2. Synthesis of 6-bromo-1 .S-dimethylpyrimidine^^fliï.Sty-dione (C2).
A 1:1 mixture of acetonitrile and water (120 mL) was added to a mixture of C1 (9.50 g, 49.6 mmol), sodium nitrite (5.24 g, 76 mmol), and copper(ll) bromide (22.4 g, 100 mmol) {Caution: bubbling and siight exotherm!}, and the reaction mixture was allowed to stir at room température for 66 hours. Addition of aqueous sulfuric acid (1 N, 200 mL) and ethyl acetate (100 mL) provided a precipitate, which was collected via filtration and washed with water and ethyl acetate to afford the product as a light yellow solid (7.70 g). The organic layer of the filtrate was concentrated to a smaller volume, during which additional precipitate formed; this was isolated via filtration and washed with 1:1 ethyl acetate / heptane to provide additional product (0.4 g). Total yield: Θ.1 g, 37 mmol, 75%. GCMS m/z 218, 220 [M+], 1H NMR (400 MHz, DMSO-cfe) δ 11.58 (br s, 1H), 3.45 (s, 3H), 1.93 (s, 3H).
Step 3. Synthesis of6-bromo-3-(3,4-dimethoxybenzyl)-1,5-dimethylpyrimidine2,4(1H,3H)-dione (C3).
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 98%, 5.57 mL, 36.5 mmol) was added to a suspension of C2 (4.00 g, 18.3 mmol) and 4-(chloromethyl)-1,2-dimethoxybenzene (5.16 g, 27.6 mmol) in acetonitrile (80 mL), and the reaction mixture was heated at 60 °C for 18 hours. After removal of solvent in vacuo, the residue was purified via silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) to afford the product as a white solid. Yield: 5.70 g, 15.4 mmol, 84%. 1H NMR (400 MHz, CDCh) δ 7.08-7.12 (m, 2H), 6.80 (d, J=8.0 Hz, 1 H), 5.07 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H),
2.14 (s, 3H).
Step 4. Synthesis of 3-(3,4-dimethoxybenzyl)-6-(4-hydroxy-2-methylphenyl)-1,5dimethylpyrimidine-2,4(1H, 3ï-\)-dione (C4).
An aqueous solution of potassium carbonate (3.0 M, 14 mL, 42 mmol) was added to a mixture of C3 (5.00 g, 13.5 mmol), (4-hydroxy-2-methylphenyl)boronic acid (4.12 g, 27.1 mmol), (1,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), dichloromethane complex (98%, 1.13 g, 1.36 mmol) and 1,4-dioxane (120 mL). After the reaction mixture had been heated at 100 °C for 18 hours, it was cooled to room température, diluted with ethyl acetate and water, and filtered through diatomaceous earth. The organic layer from the filtrate was washed sequentially with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over magnésium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 25% to 75% ethyl acetate in heptane) afforded the product as a white foam. Yield: 2.71 g, 6.84 mmol, 51%. LCMS m/z 397.2 [M+H]+. 1H NMR (400 MHz, CDCh) δ 7.22 (d, J=2.0 Hz, 1H), 7.19 (dd, J=8.1, 2.0 Hz, φ 1 Η), 6.93 (d, J=8.2 Hz, 1 H), 6.83 (d, J=8.3 Hz, 1 H), 6.80-6.82 (m, 1 H), 6.76-6.80 (m, 1H), 5.16 (ABquartet, Jab=13.3 Hz, ΔΟαβ=19.2 Hz, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.02 (s, 3H), 2.11 (br s, 3H), 1.66 (s, 3H).
Step 5. Synthesis of 3-(3,4-dimethoxybenzyl)-1,5-dimethyl-6-[2-methyl-4-(1,75 naphthyridin-8-yloxy)phenyl]pyrimidine-2,4(1H, 3H)-dione (C5).
Compound C4 (518 mg, 1.31 mmol) was added to a mixture of 8-chloro-1,7naphthyridine (280 mg. 1.70 mmol), césium carbonate (1.28 g, 3.92 mmol), palladium(ll) acetate (58.6 mg, 0.261 mmol), and di-tert-butyl[3,4,5,6-tetramethyl-2',4',6’-tri(propan-2yl)biphenyl-2-yl]phosphane (126 mg, 0.262 mmol) in 1,4-dioxane (20 mL). After the reaction had been heated at 110 °C for 20 hours, it was cooled to room température and filtered through diatomaceous earth. The filter pad was rinsed with ethyl acetate, and the combined organic filtrâtes were washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 50% to 100% ethyl acetate in heptane) afforded the product as an orange solid. Yield: 380 mg, 0.73 mmol, 55%. LCMS m/z 525.0 [M+H]* 1H NMR (400 MHz, CDCh) δ 9.17 (m, 1H), 8.32-8.30 (m, 1H),
8.15 (d, J=5.7 Hz, 1H), 7.81-7.78 (m, 1H), 7.45 (d, J-5.7 Hz, 1H), 7.38-7.34 (m, 2H), 7.24 (d, J=2.0 Hz, 1H), 7.21 (dd, J=2.0, 8.0 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 5.18 (AB quartet, Jab=13.5 Hz, ΔΠαβ=23.5 Hz, 2H), 3.92 (s, 3H), 3.88 (s,
3H), 3.10 (s, 3H), 2.21 (s, 3H), 1.72 (s, 3H).
Step 6. Synthesis of 1,5-dimethyl-6-[2-methyl-4-(1,7-naphthyridin-8yloxy)phenyl]pyrimidine-2,4(1l·), 3iï)-dione (1).
Trifluoroacetic acid (8 mL) was added to a mixture of C5 (380 mg, 0.73 mmol) and anisole 0.39 mL, 3.6 mmol). After the reaction mixture had been heated at 120 °C for 12 hours, it was cooled to room température, and trifluoroacetic acid (6 mL) and anisole (0.50 mL, 4.62 mmol) were added to the reaction mixture. After the reaction mixture had been heated at 125 °C for 12 hours, it was cooled to room température and concentrated in vacuo. The crude residue was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution, dried over magnésium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 50% to 100% ethyl acetate in heptane) followed by additional purification using supercritical fluid chromatography (Column: IC 250mm x 21.2mm 5u; Eluent: 45% methanol / 55% carbon dioxide, flow: 15 mL/ min) provided the product as a solid. Yield: 35 mg, 93 pmol,
13%. LCMS m/z 375.2 [M+H]*. 1H NMR (400 MHz, CDCh) δ 9.11 (dd, J=4.3, 1.8 Hz, φ 1 Η), Θ.35 (br s, 1 Η), 8.21 (dd, J=8.4, 1.8 Hz, 1 H), 8.11 (d, J=5.7 Hz, 1 H), 7.71 (dd, J=8.2, 4.1 Hz, 1H), 7.41 (d, J=5.9 Hz, 1H), 7.35-7.31 (m, 2H), 7.18 (d, J=8.0 Hz, 1H), 3.08 (S, 3H), 2.22 (s, 3H), 1.70 (s, 3H).
Examples 2 and 3 (+)-4,6-Dimethyl-5-[2-methyl-4-(1,7-naphthyridin-8-yloxy)phenyl]pyridazin-3(2H)one (2) and (-)-4,6-Dîmethyl-5-[2-methyl-4-(1,7-naphthyridin-8-yloxy)phenyl]pyridazin-
Step 1. Synthesis of 4-hydroxy-3,5-dimethylfuran-2(5H)-one (C6).
Méthylation of ethyl 3-oxopentanoate according to the method of D. Kalaitzakis et al., Tetrahedron: Asymmetry 2007, 18, 2418-2426, afforded ethyl 2-methyl-35 oxopentanoate; subséquent treatment with 1 équivalent of bromine in chloroform provided ethyl 4-bromo-2-methyl-3-oxopentanoate. This crude material (139 g, 586 mmol) was slowly added to a 0 °C solution of potassium hydroxide (98.7 g, 1.76 mol) in water (700 mL). The internai reaction température rose to 30 °C during the addition. The reaction mixture was then subjected to vigorous stirring for 4 hours in an ice bath, at which point it was acidified via slow addition of concentrated hydrochloric acid. After extraction with ethyl acetate, the aqueous layer was saturated with solid sodium chloride and extracted three additional times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnésium sulfate, filtered, and concentrated under reduced pressure to afford a mixture of oil and solid (81.3 g). This material was suspended in chloroform (200 mL); the solids were removed via filtration and washed with chloroform (2 x 50 mL). The combined filtrâtes were concentrated in vacuo and treated with a 3:1 mixture of heptane and diethyl ether (300 mL). The mixture was vigorously swirled until some of the oil began to solidify, whereupon it was concentrated under reduced pressure to afford an oily solid (60.2 g).
After addition of a 3:1 mixture of heptane and diethyl ether (300 mL) and vigorous stirring for 10 minutes, filtration afforded the product as an off-white solid. Yield: 28.0 g, 219 mmol, 37%. 1H NMR (400 MHz, CDCIs) δ 4.84 (br q, J=6.8 Hz, 1H), 1.74 (br s, 3H), 1.50 (d, J=6.8 Hz, 3H).
Step 2. Synthesis of 2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl 25 trifluoromethanesulfonate (C7).
Trifluoromethanesulfonic anhydride (23.7 mL, 140 mmol) was added portion-wise to a solution of C6 (15.0 g, 117 mmol) and N./V-diisopropylethylamine (99%, 24.8 mL, 140 mmol) in dichloromethane (500 mL) at -20 °C, at a rate sufficient to maintain the internai reaction température below -10 °C. The reaction mixture was allowed to warm 30 gradually from -20 °C to 0 °C over 5 hours. It was then passed through a plug of silica gel, dried over magnésium sulfate, and concentrated in vacuo. The residue was suspended in diethyl ether and filtered; the filtrate was concentrated under reduced pressure. Purification using silica gel chromatography (Gradient: 0% to 17% ethyl acetate in heptane) afforded the product as a pale yellow oil, Yield: 21.06 g, 60.94 mmol, 69%. 1H NMR (400 MHz, CDCIs) δ 5.09-5.16 (m, 1H), 1.94-1.96 (m, 3H), 1.56 (d, J=6.6 Hz, 3H).
Step 3. Synthesis of 2-[4-(benzyloxy)-2-methylphenyl]-4,4l5,5-tetramethyl-1,3,2dioxaborolane (C8).
A mixture of benzyl 4-bromo-3-methylphenyl ether (19.0 g, 66.6 mmol), [1,1bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (7.5 g, 10 mmol), potassium acetate (26.9 g, 274 mmol) and 4,4,4',4,,5,5l5'l5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (20 g, 79 mmol) in 1,4-dioxane (500 mL) was heated at reflux for 2 hours. The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 1% ethyl acetate in petroleum ether) provided the product as a yellow gel. Yield: 15 g, 46 mmol, 67%. 1H NMR (400 MHz, CDCIa) δ 7.73 (d, J=8.0 Hz, 1H), 7.30-7.46 (m, 5H), 6.76-6.82 (m, 2H), 5.08 (s, 2H), 2.53 (s, 3H), 1.34 (s, 12H).
Step 4. Synthesis of 4-[4-(benzyloxy)-2-methylphenyl]-3,5-dimethylfuran-2(5H)one (C9).
Compound C7 (5.0 g, 19 mmol), C8 (7.48 g, 23.1 mmol), tetrakis(triphenylphosphine)palladium(0) (2.22 g, 1.92 mmol), and sodium carbonate (4.07 g, 38.4 mmol) were combined in 1,4-dioxane (100 mL) and water (5 mL), and heated at reflux for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Silica gel chromatography (Eluents: 10:1, then 5:1 petroleum ether / ethyl acetate) provided the product as a white solid. Yield: 5.8 g, 19 mmol, 100%. NMR (400 MHz, CDCIa) δ 7.33-7.49 (m, 5H), 6.98 (d, J=8.5 Hz, 1 H), 6.94 (br d, J=2.5 Hz, 1 H), 6.88 (br dd, J=8.3, 2.5 Hz, 1 H), 5.20 (qq, J=6.7, 1.8 Hz, 1 H), 5.09 (s, 2H), 2.21 (s, 3H), 1.78 (d, J=1.8 Hz, 3H), 1.31 (d, J=6.8 Hz, 3H).
Step 5. Synthesis of 4-[4-(benzyloxy)-2-methylphenyl]-5-hydroxy-3,5dimethylfuran-2(5H)-one (C10).
A solution of C9 (5.4 g, 18 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (13.3 g, 87.4 mmol) in acetonitrile (100 mL) was cooled to -60 °C. Oxygen was bubbled into the reaction mixture for 20 minutes at -60 °C; the solution was then stirred at 50 °C for 18 hours. The réaction mixture was concentrated in vacuo and purified via silica gel chromatography (Eluent: 5:1 petroleum ether / ethyl acetate) to provide the product as a φ colorless oil. Yield: 3.5 g, 11 mmol, 61%. 1H NMR (400 MHz, CDCh), characteristic peaks: δ 7.33-7.49 (m, 5H), 6.92-6.96 (m, 1H), 6.88 (dd, 3=8.5, 2.5 Hz, 1 H), 5.09 (s, 2H), 2.20 (s, 3H), 1.73 (s, 3H).
Step 6. Synthesis of 5-[4-(benzyloxy)-2-methylphenyl]-4,6-dimethylpyridazin5 3f2H)-one (C11).
A mixture of C10 (3.5 g, 11 mmol) and hydrazine hydrate (85% in water, 1.9 g, 32 mmol) in n-butanol (60 mL) was heated at reflux for 18 hours. After removal of volatiles under reduced pressure, the residue was stirred with ethyl acetate (20 mL) for 30 minutes, whereupon filtration provided the product as a white solid. Yield: 2.0 g, 6.2 mmol, 56%. 1H NMR (400 MHz, CDCh) δ 10.93 (brs, 1H), 7,33-7.51 (m, 5H), 6.96 (s, 1H), 6.88-6.94 (m, 2H), 5.10 (s, 2H), 2.04 (s, 3H), 1.95 (s, 3H), 1.91 (s, 3H).
Step 7. Synthesis of 5-[4-(benzyloxy)-2-methylphenyl]-4,6-dimethyl-2-(tetrahydro2H-pyran-2-yl)pyridazin-3(2H)-one (C12).
A mixture of C11 (17.8 g, 55.6 mmol), 3,4-dihydro-2/-/-pyran (233 g, 2.77 mol) and p-toluenesulfonic acid monohydrate (2.1 g, 11 mmol) in tetrahydrofuran (800 mL) was heated at reflux for 18 hours. Triethylamine (10 mL, 72 mmol) was added, and the mixture was concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 25% ethyl acetate in petroleum ether) afforded the product as a solid, presumed to be a mixture of diastereomeric atropisomers from its 1H NMR spectrum. Yield: 20 g, 49 mmol,
88%. 1H NMR (400 MHz, CDCh), characteristic peaks: δ 7.32-7.50 (m, 5H), 6.82-6.96 (m, 3H), 6.15 (brd, J=10.3 Hz, 1H), 5.08 (s, 2H), 4.14-4.23 (m, 1H), 3.76-3.85 (m, 1H), 2.28-2.41 (m, 1H), 2.01 and 2.04 (2 s, total 3H), 1.97 and 1.98 (2 s, total 3H), 1.89 and 1.89 (2 s, total 3H).
Step 8. Synthesis of 5-(4-hydroxy-2-methylphenyl)-4,6-dimethyl-2-(tetrahydro-2}-l25 pyran-2-yl)pyridazin-3(2H)-one (C13).
Palladium (10% on carbon, 1.16 g, 1.09 mmol) was added to a solution of C12 (1.47 g, 3.63 mmol) in methanol (30 mL) and ethyl acetate (10 mL), and the mixture was hydrogenated (50 psi) on a Parr shaker for 18 hours at room temperature. The reaction mixture was filtered through diatomaceous earth, and the filter pad was rinsed with ethyl 30 acetate; the combined filtrâtes were concentrated in vacuo and triturated with heptane, affording the product as a white solid, judged to be a mixture of diastereomeric atropisomers from its 1H NMR spectrum. Yield: 1.01 g, 3.21 mmol, 88%. 1H NMR (400 MHz, CDCh), characteristic peaks: δ 6.74-6.85 (m, 3H), 6.12-6.17 (m, 1 H), 4.15-4.23 (m, 1H), 3.76-3.84 (m, 1H), 2.28-2.41 (m, 1H), 1.99 and 2.01 (2 s, total 3H), 1.97 and
1.98 (2 s, total 3H), 1.89 and 1.89 (2 s, total 3H).
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Step 9. Synthesis of 4,6-dimethy!-5-[2-methyl-4-(1,7-naphthyridin-8-yloxy)phenylJ2-(tetrahydro-2iï-pyran-2-yl)pyridazin-3(2iï)-one (C14).
Césium carbonate (1.74 g, 5.33 mmol) was added to a solution of 8-chloro-1,7naphthyridine (220 mg, 1.3 mmol) and C13 (400 mg, 1.33 mmol) in dimethyl sulfoxide (12 mL). After the reaction had been heated at 120 °C for 4.5 hours, the reaction mixture was cooled to room température and filtered through diatomaceous earth. The filter pad was rinsed with ethyl acetate, and the combined organic filtrâtes were washed with water and with saturated aqueous sodium chloride solution, dried over magnésium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 50% to 100% ethyl acetate in heptane) afforded the product as a yellow oil. Yield: 394 mg, 0.890 mmol, 67%. LCMS m/z 443.3 [M+H]+. 1H NMR (400 MHz, CDCb), characteristic peaks: δ 9.11 (dd, J=4.3,1.8 Hz, 1 H), 8.20 (dd, J=8.2, 1.6 Hz, 1 H), 8.11 (d, J=5.7 Hz, 1H), 7.11 (dd, J=8.4, 4.3 Hz, 1 H), 7.39 (d, J=5.7 Hz, 1H), 7.30-7.24 (m, 3H), 7.06-7.01 (m, 1H), 6.16-6.14 (m, 1H), 4.23-4.18 (m, 1H), 3.84-3.79 (m, 1H), 2.392.34 (m, 1 H), 2.11 and 2.08 (2 s, total 3H), 2.04 and 2.03 (2 s, total 3H), 1.96 and 1.95 (2 s, total 3H).
Step 10. Synthesis of (+)-4,6-dimethyl-5-[2-methyl-4-(1,7-naphthyridin-8yloxy)phenyl]pyridazin-3(2iï)-one (2) and (-)-4,6-dimethyl-5-[2-methyl-4-(1,7naphthyridin-S-yloxylphenyllpyridazin-Sféty-one (3).
Hydrogen chloride (4 M solution in 1,4-dîoxane, 7.5 mL) was added to a solution of C14 (394 mg, 0.890 mmol) in 1,4-dioxane (20 mL) and dichloromethane (20 mL). After 12 hours, the reaction was concentrated in vacuo and the residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using supercritical fluid chromatography (Column: Chiral Technologies Chiralcel OJ-H, 5 pm; Eluent: 1:4 methanol / carbon dioxide) afforded the products as tan solids. The firsteluting atropenantiomer exhibited a positive (+) rotation, and was designated as Example 2; accordingly, the second-eluting atropenantiomer, which gave a négative (-) rotation, was assigned as Example 3. Yield: 2, 150 mg, 0.42 mmol; 3, 150 mg, 0.42 mmol; 94%. LCMS for a mixture of 2 and 3: m/z 359.1 [M+H]+ 2:1H NMR (400 MHz, CD3OD), characteristic peaks: δ 9.02 (dd, J=4.3, 1.4 Hz, 1H), 8.44 (dd, J=8.4, 1.4 Hz, 1H), 8.05 (d, J=5.7 Hz, 1H), 7.85 (dd, J=8.4, 4.3 Hz, 1H), 7.57 (d, J=5.7 Hz, 1H), 7.35-
7.15 (m, 3H), 2.12 (s, 3H), 2.03 (s, 3H), 1.93 (s, 3H). 3: 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 9.02 (dd, J=4.3, 1.6 Hz, 1H), 8.44 (dd, J=8.4, 1.4 Hz, 1H), 8.05
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3H), 2.12 (s, 3H), 2.03 (s, 3H), 1.93 (s, 3H).
Example 4
4,6-Dimethyl-5-[4-(1,7-naphthyridin-8-yloxy)phenyl]pyridazin-3(2l·()-one (4)
Step 1. Synthesis of 4,6-dimethyl-5-[4-(1,7-naphthyridin-8-yloxy)phenyl]-2(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (C16).
8-Chloro-1,7-naphthyridine (55 mg, 0.33 mmol) was added to a solution of C15 (prepared in similar manner to C13, but beginning with benzyl 4-bromophenyl ether rather than benzyl 4-bromo-3-methylphenyl ether) (100 mg, 0.33 mmol) in dimethyl sulfoxide (3.0 mL). To this mixture was added césium carbonate (434 mg, 1.33 mmol).
After the reaction mixture had been heated at 120 °C for 4.5 hours, it was cooled to room température and filtered through diatomaceous earth. The filter pad was rinsed with ethyl acetate, and the combined organic filtrâtes were washed with water / saturated aqueous sodium chloride solution (1:1, v:v), washed with aqueous 2 N sodium hydroxide solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 50% to 100% ethyl acetate in heptane) afforded the product as a yellow solid. Yield: 126 mg, 0.294 mmol, 88%. LCMS m/z 429.2 [M+H]+. 1H NMR (400 MHz, CDCIs) Ô9.01 (dd, J=4.1, 1.6 Hz, 1H), 8.20 (dd,
J=8.4, 1.6 Hz, 1H), 8.09 (d, J=5.7 Hz, 1 H), 7.71 (dd, J=8.4, 4.3 Hz, 1H), 7.43 (m, 2H),
7.39 (d, J=5.7 Hz, 1H), 7.19 (m, 2H), 6.16 (dd, J=10.9, 2.2 Hz, 1H), 4.19 (m, 1H), 3.81 (m, 1H), 2.36 (m, 1H), 2.13 (s, 3H), 2.08-2.04 (m, 3H), 2.02 (s, 3H), 1.8-1.74 (m, 3H).
Step 2. Synthesis of 4l6-dimethyl-5-[4-(1,7-naphthyridin-8-yloxy)phenyl]pyridazin3(2H)-one (4).
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Hydrogen chloride (4 M solution in 1,4-dioxane, 2.5 mL) was added to a solution of C16 (126 mg, 0.295 mmol) in 1,4-dioxane (4 mL) and dichloromethane (4 mL). After 12 hours, the reaction mixture was concentrated in vacuo and the crude residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate to provide the product as a solid. Yield: 69 mg, 0.20 mmol, 68%. LCMS m/z 345.2 [M+H]+. 1H NMR (400 MHz, CDaOD) δ 9.05 (dd, J=4.3, 1.6 Hz, 1H), 8.48 (dd, J=8.4, 1.6 Hz, 1H), 8.07 (d, J=5.9 Hz, 1 H), 7.89 (dd, J=8.4, 4.3 Hz, 1H), 7.59 (d, J=5.9 Hz, 1H), 7.50-7.44 (m, 2H), 7.39-7.33 (m, 2H), 2.11 (s, 3H), 2.00 (s, 3H).
Example 5 e-ft-flsoquinolin-l-yloxyj-Z-methylphenylJ-I.S-dimethylpyrimidine-Z^liï.Siï)dione (5)
Step 1. Synthesis of 3-(3,4~dimethoxybenzyl)-6-[4-(isoquinolin-1-yloxy)-2methylphenyl]-1,5-dimethylpyrimidine-2,4( 1 H, 3H)-d/one (C17)
Césium carbonate (987 mg, 3.03 mmol) was added to a solution of 1chloroisoquinoline (124 mg, 0.76 mmol) and C4 (300 mg, 0.758 mmol) in dimethyl sulfoxide (3.8 mL). The reaction mixture was heated for 24 hours at 100 °C, then warmed to 120 °C. After 2.5 hours, additional 1-chloroisoquinoline was added to the reaction mixture (124 mg, 0.758 mmol); after an additional 4 hours at 120 °C, the reaction mixture was cooled to room température, water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnésium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to
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100% ethyl acetate in heptane) provided the product as a pale yellow foam. LCMS m/z
524.3 [M+H]+. 1H NMR (400 MHz, CDCh) δ 8.42 (d, J=8.2 Hz, 1H), 8.00 (d, J=5.8 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.77 (ddd, J=8.2, 6.9, 1.2 Hz, 1H), 7.86 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 7.40 (d, J=5.9 Hz, 1H), 7.28-7.20 (m, 4H), 7.14 (d, J=8.2 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 5.18 (AB quartet, Jab=13.6 Hz, ΔΟαβ=23.8 Hz, 2H) 3.92 (s, 3H), 3.88 (s, 3H), 3.11 (s, 3H), 2.20 (s, 3H), 1.73 (s, 3H).
Step 2. Synthesis of 6-[4-(isoquinolin-1-yloxy)-2-methylphenyl]-1,5dimethylpyrimidine-2,4(1H,3iï)-dione (5).
Trifluoroacetic acid (2 mL) was added to a mixture of C17 (100 mg, 0.19 mmol) and anisole 0.10 mL, 0.96 mmol). After the reaction mixture had been heated at 120 °C for 72 hours, it was cooled to room température, treated with trifluoroacetic acid (6 mL) and anisole (0.50 mL, 4.62 mmol), and heated at 125 °C for 12 hours, whereupon it was cooled to room température and concentrated in vacuo. The residue was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution, dried over magnésium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography provided the product as an off-white solid. Yield: 60 mg, 0.16 mmol, 84%. LCMS m/z 374.2 [M+H]+. 1H NMR (400 MHz, DMSO-cfe) Ô 11.46 (brs, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.02-7.99 (m, 2H), 7.87 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.75 (ddd, J=8.3, 6.9, 1.1 Hz, 1H), 7.58 (d, J=5.9 Hz, 1H), 7.35-7.27 (m, 3H), 2.90 (s, 3H), 2.17 (s, 3H), 1.51 (s, 3H).
Préparation P1
4-(4,6-Dimethylpyrimidin-5-yl)-3-methylphenol (P1)
Préparation P1 describes préparations of P1 that can be used as starting materials for préparation of certain examples of compounds ofthe invention.
Step 1. Synthesis of 5-(4-methoxy-2-methylphenyl)-4,6-dimethylpyrimidine (C18).
[1,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll)-dichloromethane complex (5 g, 6 mmol) was added to a degassed mixture of 2-(4-methoxy-2methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30 g, 120 mmol), 5-bromo-4,6dimethylpyrimidine (22.5 g, 120 mmol), and potassium phosphate (76.3 g, 359 mmol) in
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1,4-dioxane (300 mL) and water (150 mL). The reaction mixture was heated at reflux for 4 hours, whereupon it was filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: ethyl acetate in petroleum ether) provided the product as a brown solid. Yield: 25 g, 110 mmol, 92%. LCMS m/z 229.3 [M+H+j. 1H NMR (300 MHz,
CDCIa) δ 8.95 (s, 1 H), 6.94 (d, J=8.2 Hz, 1 H), 6.87-6.89 (m, 1 H), 6.84 (dd, J=8.3, 2.5 Hz, 1H), 3.86 (s, 3H), 2.21 (s, 6H), 1.99 (s, 3H).
Step 2. Synthesis of 4-(4,6-dimethylpyrimidin-5-yl)-3-methyiphenol (P1).
Boron tribromide (3.8 mL, 40 mmol) was added drop-wise to a solution of C18 (3.0 g, 13 mmol) in dichloromethane (150 mL) at -70 °C. The reaction mixture was stirred at room température for 16 hours, then adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (3 x 200 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 60% to 90% ethyl acetate in petroleum ether) afforded the product as a yellow solid. Yield: 1.2 g, 5.6 mmol, 43%. LCMS m/z 215.0 [M+H+j. 1H NMR (400 MHz, CDCh) δ 8.98 (s, 1 H), 6.89 (d, J=8.0 Hz, 1 H), 6.86 (d, J=2.3 Hz, 1 H), 6.80 (dd, J=8.3, 2.5 Hz, 1 H), 2.24 (s, 6H), 1.96 (s, 3H).
Table 1 below lists some additional examples of compounds of invention (Examples 6-14) that were made using methods, starting materials or intermediates, and préparations described herein.
Table 1. Examples 6-14 (including Method of Préparation, Non-Commercial starting materials, and Physicochemical Data).
Exampl e Number Method of Preparati on; Noncommer cial starting materials Structure 1H NMR (400 MHz, CDCh) δ (ppm); Mass spectrum, observed ion m/z [M+H+] (unless otherwise indicated)
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6 Example s 2 and 3; P11 Av C N 9.11 (dd, J=4.5, 1.5 Hz, 1 H), 8.98 (s, 1 H), 8.20 (dd, J-8.0, 1.5 Hz, 1 H), 8,11 (d, J=5.5 Hz, 1H), 7.70 (dd, J=8.0, 4.0 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H), 7.32- 7.26 (m, 2H), 7.11 (d, J=8.Q Hz, 1H), 2.26 (s, 6H), 2.05 (s, 3H); [M+H+] 343.1
7 Example 1; C3 0 Ai N H AAfAû oV ' A^AA 1H NMR (400 MHz, CDaOD) Ô 9.03 (dd, J=4.3, 1.7 Hz, 1H), 8.45 (dd, J=8.4,1.6 Hz, 1H), 8.05 (d, J=5.7 Hz, 1H), 7.87 (dd, J=8.4, 4.3 Hz, 1H) 7.59 (d, J=5.9 Hz, 1H), 7.51-7.44 (m, 4H), 3.11 (s, 3H), 1.71 (s, 3H); [M+H+] 361.2
8 Example s 2 and 3; C13 o i Ai NH A CÔ 11.59 (br s, 1 H), 9.83 (br s, 1 H), 8.82 (d, J=5.5 Hz, 1H), 8.19 (d, J=6.0 Hz, 1H), 7.66 (d, J-5.5 Hz, 1H), 7.34 (d, J=6.0 Hz, 1 H), 7.30-7.25 (m, 2H), 7.11 (d, J=8.0, 1H), 2.13 (s, 3H), 2,04 (s, 3H), 2.00 (s, 3H); [M+H+] 359.3
9 Example s 2 and 3; C13 o I Ai NH Av r> N 10.49 (brs, 1H), 9.10 (d, J=1.5 Hz, 1H), 9.03 (d, J=2.1 Hz, 1H), 8.32 (J=5.5 Hz, 1H), 7.69 (d, J=6.0 Hz, 1H), 7.31-7.27 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 2.12 (s, 3H), 2.02 (s, 3H), 1.98 (s, 3H); [M+H+] 360.2
10 Example s 2 and 3; C13 o I Ai NH A Ata 1H NMR (400 MHz, CDaOD) δ 9.12 (d, J=3.0 Hz, 1H), 8,89 (d, J=8.0 Hz, 1H), 8.18 (d, J=6.0 Hz, 1H), 7.76 (dd, J=8.5, 4.5 Hz, 1H), 7.62 (d, J=6.0 Hz, 1H), 7.33-7.18 (m, 3H), 2.12 (s, 3H), 2.03 (s, 3H), 1.93 (s, 3H); [M+H+] 359.3
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11 Example s 2 and 3; C13 O 10.56 (brs, 1H), 8.44 (d, J=8.0 Hz, 1H), 8.02 (d, J=5.5 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.78-7.75 (m, 1 H), 7.68-7.64 (m, 1 H), 7.40 (d, J=6.0 Hz, 1 H), 7.24 (d, J=8.5 Hz, 1H), 7.07 (d, J=8.0 Hz, 1 H), 2.11 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H); [M+H+] 358.3
12 Example s 2 and 3; C13 0 I NH 10.59 (br s, 1 H), 7.92 (d, J=6.0 Hz, 1 H), 7.76 (d, J=9.0 Hz, 1H), 7.68 (d, J-2.5 Hz, 1H), 7.41 (dd, J=9.0, 2.0 Hz, 1 H), 7.34 (d, J=6.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.08 (d, J=8.5 Hz, 1H), 3.99 (s, 3H), 2.11 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H); [M+H+] 388.3
13 Example s 2 and 3; C13 o I ''Tl NH /ANCOÔN 10.75 (brs, 1H), 8.84 (s, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.5, 1.5 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H), 7.25 (dd, J=8.5, 2.5 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 2.13 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H); [M+H+] 383.3
14 Example s 2 and 3; C13 o 1 ï NH Χγ CN 10.60 (brs, 1H), 8.84 (s, 1H), 8.16 (d, J=5.5 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.5, 1.5 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H), 7.25 (dd, J=8.5, 2.5 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 2.13 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H); [M+H+] 383.3
1. ln this case the reaction was carried out for 0.5 hours at 150 °C using a microwave reactor. The reaction mixture was filtered and the filtrate was purified using préparative HPLC (Column: Phenomenex Synergi C18, 4 pm; Mobile phase A: water containing
0.225% formic acid; Mobile phase B: acetonitrile containing 0.225% formic acid;
Gradient: 30% to 50% B) to provide the product.
107
Example AA: Human D1 Receptor Binding Assay and Data
The affinity of the compounds described herein was determined by compétition binding assays similar to those described in Ryman-Rasmussen et al., Differential activation of adenylate cyclase and receptor internalization by novel dopamine D1 receptor agonists”, Molecular Pharmacology 68(4):1039-1048 (2005), This radioligand binding assay used [3H]-SCH23390, a radiolabeled D1 ligand, to evaluate the ability of a test compound to compete with the radioligand when binding to a D1 receptor.
D1 binding assays were performed using over-expressing LTK human cell lines. To détermine basic assay parameters, ligand concentrations were determined from saturation binding studies where the Ka for [3H]-SCH23390 was found to be 1.3 nM. From tissue concentration curve studies, the optimal amount of tissue was determined to be 1.75 mg/mL per 96 well plate using 0.5 nM of [3H]-SCH23390. These ligand and tissue concentrations were used in time course studies to détermine linearity and equilibrium conditions for binding. Binding was at equilibrium with the specified amount of tissue in 30 minutes at 37 °C. From these parameters, Ki values were determined by homogenizing the specified amount of tissue for each species in 50 mM Tris (pH 7.4 at 4 °C) containing 2.0 mM MgCl2 using a Polytron and spun in a centrifuge at 40,000 x g for 10 minutes. The pellet was resuspended in assay buffer [50 mM Tris (pH 7.4@ RT) containing 4 mM MgSCX and 0.5 mM EDTA], Incubations were initiated by the addition of 200 pL of tissue to 96-well plates containing test drugs (2.5 μΙ_) and 0.5 nM [3H]SCH23390 (50 μΙ_) in a final volume of 250 pL. Non-specific binding was determined by radioligand binding in the presence of a saturating concentration of (+)-Butaclamol (10 μΜ), a D1 antagonist After a 30 minute incubation period at 37 °C, assay samples were rapidly filtered through Unifilter-96 GF/B PEI-coated filter plates and rinsed with 50 mM Tris buffer (pH 7.4 at 4 °C). Membrane bound [3H]-SCH23390 levels were determined by liquid scintillation counting ofthe filterplates in Ecolume. The ICso value (concentration at which 50% inhibition of spécifie binding occurs) was calculated by linear régression of the concentration-response data in Microsoft Excel. Ki values were calculated according to the Cheng-Prusoff équation:
K = ICso
1+ <[L]/Ka) where [L] = concentration of free radioligand and Kd = dissociation constant of radioligand for D1 receptor (1.3 nM for [3H]-SCH23390).
108
Example BB: D1 cAMP HTRF Assay and Data
The D1 cAMP (Cyclic Adenosine Monophosphate) HTRF (Homogeneous TimeResolved Fluorescence) Assay used and described herein is a compétitive immunoassay between native cAMP produced by cells and cAMP labeled with XL-665. This assay was used to détermine the ability of a test compound to agonize (including partially agonize) D1. A Mab anti-cAMP labeled Cryptate visualizes the tracer. The maximum signal is achieved if the samples do not contain free cAMP due to the proximity of donor (Eu-cryptate) and acceptor (XL665) entities. The signal, therefore, is inversely proportional to the concentration of cAMP în the sample. A time-resolved and ratiometric measurement (em 665 nm/em 620 nm) minimizes the interférence with medium. cAMP HTRF assays are commercially available, for example, from Cisbio Bioassays, IBA group.
Materials and Methods
Materials: The cAMP Dynamic kit was obtained from Cisbio International (Cisbio 62AM4PEJ). Multidrop Combi (Thermo Scientific) was used for assay additions. An EnVision (PerkinElmer) reader was used to read HTRF.
Cell Cuture: A HEK293T/hD1#1 stable cell line was constructed internally (Pfizer Ann Arbor). The cells were grown as adhèrent cells in NuncTsoo flasks in high glucose DMEM (Invitrogen 11995-065), 10% fêtai bovine sérum dialyzed (Invitrogen 26400-044), 1x MEM NEAA (Invitrogen 1140, 25 mM HEPES (Invitrogen 15630), 1x Pen/Strep (Invitrogen 15070-063) and 500 pg/mL Genenticin (Invitrogen 10131-035) at 37 °C and 5% CO2. At 72 or 96 hours post-growth, cells were rinsed with DPBS, and 0.25% Trypsin-EDTA was added to dislodge the cells. Media was then added and cells were centrifuged and media removed. The cell pellets were re-suspended in Cell Culture Freezing Medium (Invitrogen 12648-056) at a density of 4e7 cells/mL. One mL aliquots of the cells were made in Cryo-vials and frozen at -80 °C for future use in the D1 HTRF assay.
D1 cAMP HTRF assay procedure: Frozen cells were quickly thawed, resuspended in 50 mL warm media and allowed to sit for 5 min prior to centrifugation (1000 rpm) at room température. Media was removed and cell pellet was re-suspended in PBS/0.5 μΜ IBMX generating 2e5 cells/mL. Using a Multidrop Combi, 5 pL cells/well was added to the assay plate (Greiner 784085), which already contained 5 pL of a test compound. Compound controls [5 pM dopamine (final) and 0.5% DMSO (final)] were also included on every plate for data analysis. Cells and compounds were incubated at room température for 30 min. Working solutions of CAMP-D2 and anti-cAMP-cryptate
109
P were prepared according to Cisbio instructions. Using Multîdrop, 5 pL CAMP-D2 working solution was added to the assay plate containing the test compound and cells. Using Multidrop, 5 pL anti-cAMP-cryptate working solutions was added to assay plate containing test compound, cells and cAMP-D2. The assay plate was încubated for 1 hour at room température. The assay plate was read on an EnVision plate reader using Cisbio recommended settings. A cAMP standard curve was generated using cAMP stock solution provided in the Cisbio kit.
Data Analysis: Data analysis was done using computer software. Percent effects were calculated from the compound controls. Ratio ECso was determined using the raw 10 ratio data from the EnVision reader. The cAMP standard curve was used in an analysis program to détermine cAMP concentrations from raw ratio data. cAMP ECso was determined using the calculated cAMP data.
Table 2. Biological Data and Compound Name for Examples 1-14.
Example Number Human D1 Receptor Binding, Ki (nM); Géométrie mean of 2 - 4 déterminations (unless otherwise indicated) Compound Name
1 28.5 1,5-dimethyl-6-[2-methyl-4-(1,7-naphthyridin-8yloxy)phenyl]pyrimidine-2,4(1H,3H)-di°ne
2 115 (+)-4,6-dimethyl-5-[2-methyl-4-(1,7-naphthyridin-8yloxy)phenyl]pyridazin-3(2/-/)-one
3 102a (-)-4,6-dimethyl-5-[2-methyl-4-(1,7-naphthyridin-8yloxy)phenyl]pyridazin-3(2H)-one
4 205b 4,6-dimethyl-5-[4-(1,7-naphthyridin-8- yloxy)phenyl]pyridazin-3(2/7)-one
5 1.9 6-[4-(isoquinolin-1-yloxy)-2-methylphenyl]-1,5dimethylpyrimidine-2,4(1H,3/-/)-dione
6 105b 8-(4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1,7naphthyridine
110
7 119b 1 f5-dimethyl-6-[4-( 1,7-naphthyridin-8yloxy)phenyl]pyrimidine-2,4(1H,3H)-dione
8 141b 4,6-dimethyl-5-[2-methyl-4-(2,7-naphthyridîn-1- yloxy)phenyl]pyridazin-3(2/-/)-one
9 306b 4,6-dimethyl-5-[2-methyl-4-(pyrido[3,4-b]pyrazin-5- yloxy)phenyl]pyridazin-3(2/7)-one
10 124b 4,6-dimethyl-5-[2-methyl-4-(1,6-naphthyridin-5- yloxy)phenyl]pyridazin-3(2/-/)-one
11 7.8 5-[4-(isoquinolin-1-yloxy)-2-methylphenyl]-4,6- dimethylpyridazin-3(2H)-one
12 186 5-{4-[(7-methoxyisoquinolin-1-yl)oxy]-2-methylphenyl}- 4,6-dimethylpyridazin-3(2H)-one
13 334 1 -[4-(3,5-dîmethyl-6-oxo-1,6-dihydropyridazin-4-yl)-3methylphenoxy]isoquinoline-7-carbonitrile
14 261 1-[4-(3,5-dimethyl-6-oxo-1,6-dihydropyridazin-4-yl)-3- methylphenoxy]isoquinoline-8-carbonitrile
a. Reported Ki value is the géométrie mean of £5 déterminations.
b. Ki value is from a single détermination
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appendant claims. Each reference (including ail patents, patent applications, journal articles, books, and any other publications) cited in the présent application is hereby incorporated by reference in its entirety.

Claims (28)

φ WHAT IS CLAIMED IS:
1 -[4-(3,5-d imethy l-6-oxo-1,6-dihydropyridazin-4-yl)-3methylphenoxy]isoquinoline-8-carbonitrile, or a pharmaceutically acceptable sait thereof.
1 -[4-(3,5-dimethyl-6-oxo-1,6-dihydropyridazin-4-yl)-3methylphenoxy]isoquinoline-7-carbonitrile; and
125
1.5- dimethyl-6-[4-(1,7-naphthyridin-8-yloxy)phenyl]pyrimidine-2,4(1 H,3H)-dione;
1.5- dimethyl-6-[2-methyl-4-(1,7-naphthyridin-8-yloxy)phenyl]pyrimidine2,4(1/-/,3/7)-dione;
1. Use of a compound of Formula I:
or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for treating a D1-mediated (or D1-associated) disorder in a mammal, wherein:
L1 is O, S, NRN, C(=O), CH(OH), orCH(OCH3);
Q1 is an N-containing 5- to 10-membered heteroaryl, an N-containing 4- to 12membered 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 Cm alkyl, optionally substituted C3-4 cycloalkyl, optionally substituted cyclopropylmethyl, and optionally substituted Cm alkoxy;
T6 is H, -OH, halogen, -CN, or optionally substituted C1-2 alkyl;
RN is H, Cm alkyl, C3.4 cycloalkyl, or - C1-2 alkyl-C3-4 cycloalkyl;
each of R1 and R2 is independently selected from the group consisting of H, halogen, -CN, Cm alkyl, Cm haloalkyl, Cm alkoxy, Cm haloalkoxy, and Cm cycloalkyl, wherein each of said Cm alkyl and C3-6 cycloalkyl is optionally substituted with 1,2,3, 4, or 5 substîtuents each independently selected from halo, -OH, -NH2, -NH(CH3), N(CH3)2,-CN, Cm alkyl, Cm haloalkyl, Cm alkoxy, and Cm haloalkoxy;
each of R3 and R4 is independently selected from the group consisting of H, halogen, -OH, -NO2, -CN, -SFs, Cm alkyl, Cm haloalkyl, Cm haloalkoxy, C2-6 alkenyl,
112 φ C2-e 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 Cm alkyl, C37 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, Cm alkoxy, Ch haloalkyl, Cm 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)2N(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 6membered 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, Cm alkyl, Cm haloalkyl, or C3-7 cycloalkyl;
R6 is H or selected from the group consisting of Cm alkyl, Cm haloalkyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C6-10 aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-CM alkyl-, (4-to 10-membered heterocycloalkyl)-CM alkyl-, (Ce-io aryl)-CM alkyl-, and (5- to 10-membered heteroaryl)-CM alkyl-, wherein each of the sélections 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, Cm alkyl, C3-7 cycloalkyl, Cm hydroxylalkyl, -S-Cm alkyl, -C(=O)H, -C(=O)-Cm alkyl, -C(=O)-O-Cm alkyl, -C(=O)-NH2, -C(=O)-N(Cm alkyl)2, Cm haloalkyl, Cm alkoxy, and Cm haloalkoxy;
or R5 and R6 together with the N atom to which they are attached form a 4- to 10membered 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, -0(=Ο)ΟΗ, C(=O)-Cm alkyl, -C(=O)-NH2, -C(=O)-N(Cm alkyl)2, -CN, Cm alkyl, Cm alkoxy, Cm hydroxylalkyl, Cm haloalkyl, and Cm haloalkoxy;
R7 is selected from the group consisting of H, Cm alkyl, and C3-7 cycloalkyl;
R8 is selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, a 4- to 14membered heterocycloalkyl, Ce-ίο aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)Cm alkyl-, (4- to 10-membered heterocycloalkyl)-CM alkyl-, (Ce-io aryl)-CM alkyl-, and (5- to 10-membered heteroaryl)-CM alkyl-, wherein each ofthe sélections from the
113 group is optionally substituted with 1,2, or 3 substituents each independently selected from the group consisting of halogen, -CFs, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, oxo, S-C1-4 alkyl, Cm alkyl, Cm haloalkyl, C2-8 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Cm alkoxy, and Cm haloalkoxy;
R9 is Cm alkyl, Cm haloalkyl, -CN, -SFs, -N(R5)(R6), C1-6 alkoxy, Cm haloalkoxy, C3-7 cycloalkoxy, or C3-7 cycloalkyl, wherein each of the Cm 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), Cm alkyl, Cm haloalkyl, C3-7 cycloalkyl, Cm alkoxy, and Cm haloalkoxy;
each R10 is independently selected from the group consisting of halogen, -OH, CN, -SFs, -NO2, oxo, thiono, C1-6 alkyl, Cve haloalkyl, C1-6 hydroxylalkyl, Cm alkoxy, Cm haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-e alkynyl, Ce-io aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-CM alkyl-, (4- to 10membered heterocycloalkyl)-CM alkyl-, (Ce-ίο aryl)-CM alkyl-, (5- to 10-membered heteroaryl)-CM alkyl-, -N(R5)(R6), -N(R7)(C(=O)R8), -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, Ce-10 aryl, 4-to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-CM alkyl-, (4- to 10-membered heterocycloalkyl)-CM alkyl-, (Ce-io aryl)-CM alkyl-, and (5- to 10-membered heteroaryl)-CM alkyl- is optionally substituted with 1,2, 3, or 4 substituents each independently selected from the group consisting of halogen, OH, -CN, -NO2, Cm alkyl, Cm hydroxylalkyl, Cm alkoxy, -N(R5)(R6), -S-(Cm alkyl), -S(=0)2-(Cm alkyl), Cs-io aryloxy, [(Cs-io aryl)-CM alkyloxy- optionally substituted with 1 or 2 Cm alkyl], oxo, -C(=O)H, -C(=O)-Cm alkyl, -C(=O)O-Cm alkyl, -C(=O)NH2, NHC(=O)H, -NHC(=O)-(Cm alkyl), C3-7 cycloalkyl, a 5- or 6-membered heteroaryl, Cm haloalkyl, and Cm 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 selectedR103; and each R10a is independently selected from the group consisting of halogen, -OH, -N(R5)(R6), -C(=O)OH, -C(=O)-Cm alkyl, -C(=O)-NH2, -C(=O)-N(Cm alkyl)2, -CN, -SFs, Cm alkyl, Cm alkoxy, Cm hydroxylalkyl, Cm haloalkyl, and Cm haloalkoxy, with the proviso that (a) when L1 is NRN, then Q1 is not unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; and
114 φ (b) when X1 is N, then Q1 is not an optionally substituted bicyclic heterocycloalkyl selected from octahydroquinolizinyl, octahydroindolizinyl, and hexahydropyrrolizïnyl.
(2) when X1 is N, then Q1 is not an optionally substituted bicyclic heterocycloalkyl selected from octahydroquinolizinyl, octahydroindolizinyl, and hexahydropyrrolizinyl;
2. The use of Claim 1 wherein the disorder is selected from schizophrenîa (e.g., cognitive and négative symptoms in schizophrenîa), schizotypal personality disorder, cognitive impairment [e.g., cognitive impairment associated with schizophrenîa, cognitive impairment associated with AD, cognitive impairment associated with PD, cognitive impairment associated with pharmacotherapy therapy (e.g., D2 antagonist therapy)], attention déficit hyperactivity disorder (ADHD), impulsivîty, compulsive gambling, overeating, autism spectrum disorder, mild cognitive impairment (MCI), agerelated cognitive décliné, dementia (e.g., senile dementia, HIV-associated dementia, Alzheimer’s dementia, Lewy body dementia, vascular dementia, or frontotemporal dementia), restless leg syndrome (RLS), Parkinson’s disease, Huntington’s chorea, anxiety, dépréssion (e.g., age-related dépréssion), major dépressive disorder (MDD), treatment-resistant dépréssion (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum dépréssion, serotonin syndrome, substance abuse and drug dependence, drug abuse relapse, Tourette's syndrome, tardive dyskinesia, drowsiness, excessive daytime sleepiness, cachexia, inattention, sexual dysfunction (e.g., erectile dysfunction or post-SSRI sexual dysfunction), migraine, systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis, dislipidemia, obesity, diabètes, sepsis, post-ischemic tubular necrosis, rénal failure, hyponatremia, résistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, and pain.
(3) when X1 îs N, then each of the ring-forming atoms of Q1 is a nitrogen or carbon atom;
3. The use of Claim 1 or 2, wherein the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-a, l-b, l-c, l-d, or l-e:
115 or a pharmaceutically acceptable sait thereof.
4.6- dimethyl-5-[2-methyl-4-(1l6-naphthyridin-5-yloxy)phenyl]pyridazin-3(2H)-one; 5-[4-(isoquinolin-1-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2/-/)-one;
4.6- dimethyl-5-[2-methyl-4-(pyrido[3,4-b]pyrazin-5-yloxy)phenyl]pyridazin-3(2H)one;
4.6- dimethyl-5-[2-methyl-4-(2,7-naphthyridin-1 -yloxy)phenyl]pyridazin-3(2H)-one;
4.6- dimethyl-5-[4-(1,7-naphthyndin-8-yloxy)phenyl]pyridazin-3(2H)-one;
(-)-4,6-dimethyl-5-[2-methyl-4-(1,7-naphthyridin-8-yloxy)phenyl]pyridazin-3(2/-/)one;
4.6- dimethyl-5-[2-methyl-4-(1,7-naphthyridin-8-yloxy)phenyl]pyridazin-3(2/-/)-one; (+)-4,6-dimethyl-5-[2-methyl-4-(1,7-naphthyridin-8-yloxy)phenyl]pyridazin-3(2H)- one;
(4) when X1 is N and Q1 is an optionally substituted 2-oxo-1 /-/-pyridin-1 -yl, then Q1 is not substituted by -C(=O)-N(R5)(R6), -C(=O)-R8, or -C(=O)-OR8; and (5) when Q1 is an optionally substituted 4H-1,2,4-triazol-3-yI, then Q1 is not substituted by -N(R5)(R6).
4. The use of any one of Claims 1 to 3, wherein:
ring Q1a îs an N-containing 5- to 6-membered heteroaryl or an N-containing 5- to 6-membered heterocycloalkyl;
———- represents a single bond or double bond;
each of Z1 and Z2 is independently C or N;
R9 is Cm alkyl, Cm haloalkyl, C3-7 cycloalkyl, -CN, -N(R5)(R6), C1-6 alkoxy, C1-6 haloalkoxy, or C3-7 cycloalkoxy, wherein each of the Cm 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), Cm alkyl, Cm haloalkyl, C3.7 cycloalkyl, Cm alkoxy, and Cm haloalkoxy;
each R10 is independently selected from the group consisting of halogen, -OH, CN, -NO2, oxo, thiono, C1-6 alkyl, C1-6 haloalkyl, Ci-e hydroxylalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, a 4- to 10-membered heterocycloalkyl, a 5-to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 10membered heterocycloalkyl)-CiM alkyl-, (Ce-io aryl)-CiM alkyl-, (5- to 10-membered
116 φ heteroaryl)-CM 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)-Ra, -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)-CM alkyl-, (4- to 10membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-io aryl)-CM alkyl-, (5- to 10-membered heteroaryl)-Ci-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, Cm hydroxylalkyl, Cm alkoxy, N(R5)(R6), -S-(Cm alkyl), -S(=O)2-(Cm alkyl), Ce-io aryloxy, (Ce-io aryl)-CM alkyloxyoptionally substituted with 1 or 2 Cm alkyl, oxo, -C(=O)H, -C(=O)-Cm alkyl, -C(=O)O-Ci4 alkyl, -C(=O)NH2, -NHC(=O)H, -NHC(=O)-(Cm alkyl), C3-7 cycloalkyl, a 5- or 6membered heteroaryl, Cm haloalkyl, and Cm 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)-Cm alkyl, -C(=O)-NH2, -C(=O)-N(Cm alkyl)2, -CN, Cm alkyl, Cm alkoxy, Cm hydroxylalkyl, (C1-2 alkoxy)-CM alkyl-, Cm haloalkyl, and Cm haloalkoxy; and m is 0, 1,2, 3, or 4.
5-{4-[(7-methoxyisoquinolin-1-yl)oxy]-2-methylphenyl}-4,6-dimethylpyridazin3(2H)-one;
5. A compound of Formula I:
or a pharmaceutically acceptable sait thereof, wherein:
L1 is O or S;
Q1 is an N-containing 5- to 6-membered heteroaryl or an N-containing 5- to 6membered heterocycloalkyl, each optionally substituted with one R9 and further optionally substituted with 1, 2, 3, or 4 R10;
X1 isNorC-T1;
117
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, X3, X4, and X5 are N;
each of T1, T2, T3, T4, and T5 is independently selected from the group consisting of H, halogen, -CN, Ch alkyl, C1-4 haloalkyl, C3-4 cycloalkyl, C3-4 halocycloalkyl, cyclopropylmethyl, C-m alkoxy, Ch haloalkoxy;
T6 is H, F, Cl, methyl, orCi fluoroalkyl;
RN is H, Ch alkyl, C3-4 cycloalkyl, or -C1-2 alkyl-C3-4 cycloalkyl, each of R1 and R2 is independently selected from the group consisting of H, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, Ci-e alkoxy, C1-6 haloalkoxy, C^ cycloalkyl, C(=O)OH, and C(=O)-O-(Ci-4 alkyl), wherein each of said Cne alkyl and C3-6 cycloalkyl is optionally substituted with 1,2,3, 4, or 5 substituents each independently selected from halo, -OH, -CN, Cn alkyl, C1-4 haloalkyl, Ch alkoxy, and C1-4 haloalkoxy;
each of R3and R4 is independently selected from the group consisting of H, halogen, -OH, -NO2, -CN, -SFs, 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 Ci-e alkyl, C37 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, Ch alkoxy, Ci-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, -N(R5)(R6), -N(R7)(C(=O)R8), -C(=O)-ORa, -C(=O)H, -C(=O)R8, -C(=O)N(R5)(R6), -N(R7)(S(=O)2R8), -S(=O)2N(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 6membered 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;
R5is H, Ch alkyl, C1-4 haloalkyl, or C3-7 cycloalkyl;
R6 is H or selected from the group consisting of C-m 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)-Ci-4 alkyl-, (4- to 10-membered heterocycloalkyl)-Cin alkyl-,
118 (Ce-ιο aryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-Ciu alkyl-, wherein each of the sélections from the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of -OH, -CN, Cm alkyl, C3-7 cycloalkyl, Cm hydroxylalkyl, -S-Cm alkyl, -C(=O)H, -C(=O)-Cm alkyl, -C(=O)-O-Cu alkyl, -C(=O)NH2, -C(=O)-N(Ci-4 alkyl)2, Cm haloalkyl, Cm alkoxy, and Cm haloalkoxy;
or R5 and R6 together with the N atom to which they are attached form a 4- to 10membered 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)-Cm alkyl, -C(=O)-NH2, C(=0)-N(Ci-4 alky 1)2, -CN, Cm alkyl, Cm alkoxy, Cu hydroxylalkyl, Cm haloalkyl, and Cm haloalkoxy;
R7 is selected from the group consisting of H, Cm alkyl, and C3-7 cycloalkyl;
Re is selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, a 4- to 14membered heterocycloalkyl, Ce-ioaryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)Cm alkyl-, (4- to 10-membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-ιο aryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-Ci-4 alkyl-, wherein each ofthe sélections 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-Cm alkyl, Cm alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkoxy, and Cm haloalkoxy;
R9 is Cu alkyl, Cm haloalkyl, -CN, -SFs, -N(R5)(R6), C1-6 alkoxy, Ci-β haloalkoxy, C3-7 cycloalkoxy, or C3-7 cycloalkyl, wherein each of the Cm 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), Cu alkyl, Cm haloalkyl, C3-7 cycloalkyl, C1-4 alkoxy, and Cu 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, Ci-β alkoxy, C1-6 haloalkoxy, C3.7 cycloalkyl, C2-6 alkenyl, C2-e alkynyl, Ce-ιο aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 10membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-ιο aryl)-Ci-4 alkyl-, (5- to 10-membered heteroaryl)-Ciu alkyl-, -N(R5)(R6), -N(R7)(C(=O)R8), -S(=O)2N(R5)(R6), -C(=O)-N(R5)(R6), -C(=O)-R8, -C(=O)-OR8, -SR8, and -OR8, wherein each of said Ci-e alkyl, C3-7 cycloalkyl, Ce-ιο aryl, 4-to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-CiM alkyl-, (4- to 10-membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-ιο aryl)-Ciu alkyl-, and (5- to 10-membered heteroaryl)-Ci-4 alkyl- is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen,
119
OH, -CN, -NO2, Cm alkyl, Cm hydroxylalkyl, Cm alkoxy, -N{R5)(R6), -S-(Ci-4 alkyl), -S(=O)2-(Cim alkyl), Ce-io aryloxy, [(C6-10 aryl)-Ci-4 alkyloxy- optionally substituted with 1 or 2 Cm alkyl], oxo, -C(=O)H, -C(=O)-Cm alkyl, -C(=O)O-Cm alkyl, -C(=O)NH2, NHC(=O)H, -NHC(=O)-(Cm alkyl), C3.7 cycloalkyl, a 5- or 6-membered heteroaryl, Cm haloalkyl, and Cm 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 selectedR103; and each R10a is independently selected from the group consisting of halogen, -OH, -N(R5)(R6), -C(=O)OH, -C(=O)-Cm alkyl, -C(=O)-NH2, -C(=O)-N(Cm alkyl)2, -CN, -SFs, Cm alkyl, Cm alkoxy, Cm hydroxylalkyl, Cm haloalkyl, and Cm haloalkoxy, with the proviso that (1) when X1 is N, then Q1 is not an optionally substituted monocyclic 5-memered ring;
6-[4-(isoquinolin-1-yloxy)-2-methylphenyl]-1,5-dimethylpyrimidine-2,4(1/4,3H)- dione;
6-membered heterocycloalkyl;
------ represents a single bond or double bond;
each of Z1 and Z2 is independentiy C or N;
R9 is Cu alkyl, Cm 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 optîonally substituted with 1, 2, 3, 4, or 5 substituents each independentiy selected from the group consisting of halogen, -N(R5)(R6), Cm alkyl, Cm haloalkyl, C3-7 cycloalkyl, C1-4 alkoxy, and Cu haloalkoxy;
each R10 is independentiy selected from the group consisting of haiogen, -OH, CN, -NO2, oxo, thiono, C1-6 alkyl, Cve haloalkyl, C1-6 hydroxylalkyl, C1-6 alkoxy, Cu haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-CM alkyl-, (4- to 10membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-io aryl)-Cw alkyl-, (5- to 10-membered heteroaryl)-Ci-4 alkyl-, (5- to 10-membered heteroaryl)-C2u alkenyl-, -N(R5)(R6), N(R7)(C(=O)Ra), -S(=O)2N(R5)(R6), -C(=O)-N(R5)(R6), -C(=O)-Re, -C(=O)-ORe, and OR8, wherein each of said C1-6 alkyl, C3-7 cycloalkyl, Ce-io aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-Ci-4 alkyl-, (4- to 10membered heterocycloalkyl)-Ci-4 alkyl-, (Ce-io aryl)-Ci-4 alkyl-, (5- to 10-membered heteroaryl)-Ci-4 alkyl-, and (5- to 10-membered heteroaryl)-C2u alkenyl- is optîonally substituted with 1, 2, 3, or 4 substituents each independentiy selected from the group consisting of halogen, OH, -CN, -NO2, C1-4 alkyl, Cu hydroxylalkyl, C1-4 alkoxy, N(R5)(R6), -S-(Cu alkyl), -S(=0)2-(Cu alkyl), Ce-io aryloxy, (C6-10 aryl)-Ciu alkyloxyoptionally substituted with 1 or 2 Cu alkyl, oxo, -C(=O)H, -C(=0)-Ci-4 alkyl, -C(=O)O-Ci
122
Λ alkyl, -C(=0)NH2, -NHC(=O)H, -NHC(=O)-(Cm alkyl), C3.7 cycloalkyl, a 5- or 6membered heteroaryl, Cm haloalkyl, and Cm 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)-Cm alkyl, -C(=O)-NH2, -C(=O)-N(Cm alkylja, -CN, Cm alkyl, Cm alkoxy, Cm hydroxylalkyl, (Ci-2 alkoxy)-CM alkyl-, Cm haloalkyl, and Cm haloalkoxy;
and m is 0, 1, 2, 3, or 4.
6. The compound of Claim 5 or a pharmaceutically acceptable sait thereof, wherein L1 îs O.
7. The compound of Claim 5 or 6, or a pharmaceutically acceptable sait thereof, wherein each of T1, T2, T3, T4, and T5 is independently selected from the group consisting of H, F, Cl, Br, -CN, methoxy, Ci fluoroalkoxy, methyl, and Ci fluoroalkyl,
8-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1,7-naphthyridine;
8. The compound of any one of Claims 5 to 7 or a pharmaceutically acceptable sait thereof, wherein:
X1 is CT1;
T1 is H; and
T6 is H.
120
9. The compound of any one of Claims 5 to 8 or a pharmaceutically acceptable sait thereof, wherein the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-a, l-b, l-c, l-d, or l-e:
l-e or a pharmaceutically acceptable sait thereof.
10. The compound of any one of Claims 5 to 9 or a pharmaceutically acceptable sait thereof, wherein the compound of Formula I or a pharmaceutically acceptable sait thereof is a compound of Formula l-a or a pharmaceutically acceptable sait thereof.
11. The compound of any one of Claims 5 to 10 or a pharmaceutically acceptable sait thereof, wherein each of R1 and R2 is independently H or halogen; and each of R3 and R4 is independently H, halogen, -CN, methyl, Ci haloalkyl, methoxy, orCi haloalkoxy.
121
12. The compound of any one of Claims 5 to 11 or a pharmaceutically acceptable sait thereof, wherein each of R1 and R2 is H; R3is H; and R4 is H, halogen, -CN, methyl, or Ci haloalkyl.
13. The compound of any one of Claims 5 to 12 or a pharmaceutically acceptable (R10)m (Moiety M1”);
ring Q1a is an N-containing 5- to 6-membered heteroaryl or an N-containing 5- to
14. The compound of Claim 13 or a pharmaceutically acceptable sait thereof, wherein Moiety M1 is selected from the group consisting of quinolinyl, isoquinolinyl, 1Himidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, 1 H-pyrrolo[3,2-c]pyridinyl, imidazo[1,2ajpyrazinyl, imidazo[2,1-c][1,2,4]triazinyl, imidazo[1,5-a]pyrazinyl, imidazo[1,2ajpyrimidinyl, 1 /-/-indazolyl, 9/-/-purinyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[1,5a]pyrimidinyl, isoxazolo[5,4-c]pyridazinyl, isoxazolo[3,4-c]pyridazinyl, and [1,2,4]triazolo[4,3-b]pyridazinyI, each optionally substituted with 1, 2, or 3 R10 and further optionally substituted with 1 or 2 R10a; or wherein Moiety M1 is selected from the group consisting of pyrîmidinyl, pyrazinyl, pyridinyl, pyridazinyl, 1 H-pyrazolyl, 1 H-pyrrolyl, 4Hpyrazolyl, 1H-imidazolyl, 1 H-imidazolyl, 3-oxo-2/7-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1/-/2-oxo-pyridinyl, 2,4(1 /-/,3H)-dioxo-pyrimidinyl, and 1/-/-2-oxo-pyrazinyl, each substituted with R9 and further optionally substituted with 1,2, or 3 R10.
15. The compound of Claim 13 or a pharmaceutically acceptable sait thereof, wherein:
123
Moiety M1 is
I
R10a is Cm alkyl, Cm haloalkyl, (C1-2 alkoxy)-CM alkyl-, or C3-7 cycloalkyl; t1 is 0 or 1; and t is 0 or 1.
16. The compound of Claim 13 or a pharmaceutically acceptable sait thereof,
17. The compound of Claim 13 or a pharmaceutically acceptable sait thereof, wherein:
; and
R11 is H, Cm alkyl, Cm haloalkyl, (C1-2 alkoxy)-CM alkyl-, or C3-7 cycloalkyl.
124 φ
18. The compound of any one of Claims 5 to 17 or a pharmaceutically acceptable sait thereof, wherein:
R9 is Cm alkyl or-CN; and each R10 is independently selected from the group consisting of Cm alkyl, Cm haloalkyl, (C1-2 alkoxy)-CM alkyl-, -CN, and -N(R5)(R6), wherein each of R5 and R6 independently is H or selected from the group consisting of Cm alkyl, Cm 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 substîtuents each independently selected from the group consisting of halogen, -CN, Cm alkyl, Cm alkoxy, C3-6 cycloalkyl, Cm haloalkyl, and Cm haloalkoxy.
19. A compound of Claim 5 that is selected from the group consisting of:
20. The compound of Claim 19 that is 1,5-dimethyl-6-[2-methyl-4-(1,7-naphthyridin-8yloxy)phenyl]pyrimidine-2,4(1/-/,3H)-dione, or a pharmaceutically acceptable sait thereof.
21. The compound of Claim 19 that is (+)-4,6-dimethyl-5-[2-methyl-4-(1,7naphthyridin-8-yloxy)phenyl]pyridazin-3(2/-/)-one, or a pharmaceutically acceptable sait thereof.
22. The compound of Claim 19 that is (-)-4,6-dimethyl-5-[2-methyl-4-(1,7naphthyridin-8-yloxy)phenyl]pyridazin-3(2H)-one, or a pharmaceutically acceptable sait thereof.
23. The compound of Claim 19 that is 4,6-dimethy 1-5-(4-( 1,7-naphthyridin-8yloxy)phenyl]pyridazin-3(2H)-one, or a pharmaceutically acceptable sait thereof.
24. The compound of Claim 19 that is 8-(4-(4,6-d imethylpyrim idin-5-yl)-3methylphenoxy]-1,7-naphthyridine, or a pharmaceutically acceptable sait thereof.
25. The compound of Claim 19 that is 1,5-dimethy 1-6-(4-( 1,7-naphthyridin-8yloxy)phenyl]pyrimidine-2,4(1/-/,3/-/)-dione, or a pharmaceutically acceptable sait thereof.
26. A pharmaceutical composition comprising a compound of any one of Claims 5-25 or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.
27. Use of a compound of any one of Claims 5-25 or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for treating a D1-mediated (or D1associated) disorder.
28. The compound of any one of Claims 5-25 or a pharmaceutically acceptable sait thereof for use in a method for treating a D1-mediated (or D1-associated) disorder.
OA1201600388 2014-04-25 2015-04-09 Heteroramatic Compounds and their use as Dopamine D1 Ligands. OA18535A (en)

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