BR112015030101B1 - HETEROAROMATIC COMPOUNDS, PHARMACEUTICAL COMPOSITION AND USE OF SAID COMPOUNDS IN THE TREATMENT OF DISORDERS MEDIATED BY OR ASSOCIATED WITH DOPAMINE D1 - Google Patents

Abstract

HETEROAROMATIC COMPOUNDS, PHARMACEUTICAL COMPOSITION AND USE OF SAID COMPOUNDS IN THE TREATMENT OF DISORDERS MEDIATED BY OR ASSOCIATED WITH DOPAMINE D1. The present invention provides, in part, compounds of formula I: I and pharmaceutically acceptable salts thereof; processes for preparing such compounds or salts; intermediates used in their preparation; and compositions containing the same, and their uses for treating D1-mediated (or D1-associated) disorders including, for example, schizophrenia (e.g., its cognitive and negative symptoms), cognitive impairment (e.g., cognitive impairment associated with schizophrenia , AD, PD, or pharmacotherapy therapy), age-related cognitive decline, dementia, and Parkinson's disease.

Description

Field of Invention

[0001] The present invention generally relates to heteroaromatic compounds, which are dopamine D1 ligands, for example dopamine D1 agonists or partial agonists.

Background of the Invention

[0002] Dopamine acts on neurons through two families of dopamine receptors, D1-like receptors (D1Rs) and D2-like receptors (D2Rs). The D1-like receptor family consists of D1 and D5 receptors that are expressed in many regions of the brain. D1 mRNA has already been found, for example, in the striatum and nucleus accumbens. See, for example, Missale C, Nash SR, Robinson SW, Jaber M, Caron MG "Dopamine receptors: from structure to function," Physiological Reviews 78:189-225 (1998). Pharmacological studies have already reported that D1 and D5 (D1/D5) receptors, namely D1-like receptors, are linked to the stimulation of adenylyl cyclase, while D2, D3, and D4 receptors, namely D2-like receptors, are linked to the inhibition of cAMP production.

[0003] 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, for example, Goldman-Rakic PS et al., "Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction," Psychopharmacology 174(1):3-16. (2004). Additionally, D1 receptors have been implicated in a variety of psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine, and/or other disorders described in this report including schizophrenia (e.g., cognitive and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's dementia , Parkinson's disease (PD), Huntington's chorea, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder , postpartum depression, serotonin syndrome, substance abuse and drug dependence, Tourette syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dyslipidemia, obesity, diabetes, sepsis , post-ischemic tubular necrosis, renal failure, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotony, sleep disturbances, pain, and other disorders in a mammal. See, for example, 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 et al., "The role of dopamine in modulating the structure and function of striatal circuits," Prog. Brain Res. 183:149-67 (2010).

[0004] New or improved agents that modulate (such as agonize or partially agonize) D1 are necessary for the development of new and more effective drugs to treat diseases or conditions associated with dysregulated activation of D1, such as those described in this invention.

Summary of the Invention

[0005] The present invention relates, in part, to a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: each of T1, T2, T3, and T4 is independently selected from the group consisting of H, halogen, -CN, -SF5, -OH, -N(Ra)(Rb) , -C(=O)-N(Ra)(Rb), -C(=O)-ORc, -C(=O)-Rd, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2 -6 alkynyl, C1-6 alkoxy, C1-6 haloalkoxy, -S- (C1-6 alkyl), C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C37 cycloalkoxy, 5- or 6-membered heteroaryl, cyclopropylmethyl, and cyclo -butyl-methyl, where each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -S-(C1-6 alkyl), and C1-6 alkoxy is optionally substituted with one or more substituents each one of them independently selected from the group consisting of halogen, -OH, -CN, -N(Ra)(Rb), C1-4 alkoxy, C1-4 haloalkoxy, and -S-(C1-4 alkyl); and wherein each of C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C3-7 cycloalkoxy, 5- or 6-membered heteroaryl, cyclopropylmethyl, and cyclobutylmethyl of T1, T2, and T3 is optionally substituted with one or more substituents each of them independently selected from the group consisting of halogen, -OH, -CN, oxo, -N(Ra)(Rb), -C(=O)OH, -C(=O)-C1-4 alkyl , -C(=O)-O- C1-4 alkyl, -C(=O)-N(Ra)(Rb), C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxylalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -S-(C1-4 alkyl); L1 is selected from the group consisting of O, S, NH, N(C1-4 alkyl), N(-C1-2 alkyl-C3-4 cycloalkyl), and N(C3-6 cycloalkyl); each of Ra and Rb is independently selected from the group consisting of H, C1-4 alkyl, C3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentan-1-yl, or bicyclo[1.1 .1]pentan-2-yl), and cyclopropylmethyl; or Ra and Rb together with the N atom to which they are attached form 4- to 7-membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl or 7-azabicyclo[2.2.1]heptan-7-yl) optionally substituted with a or more substituents each independently selected from the group consisting of halogen, -OH, -CN, oxo, -NH2, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, -C(=O )OH, -C(=O)-C1-4 alkyl, -C(=O)-O-C1-4 alkyl, -C(=O)-NH2, -C(=O)-NH(C1-4 alkyl), -C(=O)-N(C1-4 alkyl)2, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, -S-(C1- 4 alkyl), and C1-4 haloalkoxy; each of Rc and Rd is independently C1-4 alkyl, C3-4 cycloalkyl-C1-2 alkyl- or C3-4 cycloalkyl; Q1 is selected from the group consisting of Q1a, Q1b, Q1c, Q1d, and Q1e: provided (a) that one ring carbon atom of the Q1 ring is bonded to the benzene ring of formula I and (b) that when L1 is NH, then the Q1 ring is replaced with at least one non-H R9, R10, R11, R12, R13, R9A, R10A, R10B, R11A, R12A or R13A; each of X1 and X2 is independently O or S; each of R1, R2, R3, and R4 is independently selected from the group consisting of H, halogen, -OH, -NO2, -CN, -SF5, C16 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, -N(R7)(S(=O)2R8), -S(=O)2-N (R5)(R6), -SR8, and -OR8, wherein each of C1-6 alkyl, C3-7 cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, oxo, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, -N(R5)(R6), -N(R7 )(C(=O)R8), -C(=O)-OR8, -C(=O)H, -C(=O)R8, -C(=O)N(R5)(R6), - N(R7)(S(=O)2R8), -S(=O)2-N(R5)(R6), -SR8, and -OR8; or R2 and R4 together with the two carbon atoms to which they are attached form a 5- or 6-membered fused heteroaryl, a 5- or 6-membered fused heterocycloalkyl ring, a 5- or 6-membered fused cycloalkyl ring, or a fused benzene ring , wherein each of the fused rings is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 ha- loalkyl, and C1-4 haloalkoxy, and wherein the fused heterocycloalkyl ring or the fused cycloalkyl ring is further optionally substituted with 1, 2 or 3 oxo; R5 is H, C1-4 alkyl, C1-4 haloalkyl or C3-7 cycloalkyl; R6 is H or selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C6-10 aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5-10 membered heteroaryl)-C1 -4 alkyl-, where each of the group selections is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of -OH, -CN, C1-4 alkyl, C3-7 cycloal- kyl, C1-4 hydroxyalkyl, -S-C1-4 alkyl, -C(=O)H, -C(=O)-C1-4 alkyl, -C(=O)-O-C1-4 alkyl, - C(=O)-NH2, -C(=O)-N(C1-4 alkyl)2, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or R5 and R6 together with the N atom to which they are attached form a 4 to 10 membered heterocycloalkyl or a 5 to 10 membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents each of them independently selected from the group consisting of halogen, -OH, oxo, -C(=O)H, -C(=O)-C1-4 alkyl, -C(=O)OH, -C(=O )-O-C1-4 alkyl, -C(=O)-NH2, -C(=O)-N(C1-4 alkyl)2, -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy; R7 is selected from the group consisting of H, C1-4 alkyl, and C3-7 cycloalkyl; R8 is selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C6-10 aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl -, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl-, wherein each of the group selections is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -CF3, -CN, -OH, oxo, -S-C1-4 alkyl, C1- 4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each R9 and R12 is independently selected from the group consisting of halogen, -OH, -CN, -SF5, -NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1- 6 haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, ( 4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, (5 to 10 membered heteroaryl)-C1-4 alkyl-, -N(R5)( R6), -N(R7)(C(=O)R8), -S(=O)2N(R5)(R6), -C(=O)-N(R5)(R6), -C(= O)-R8, -C(=O)-OR8, -SR8, and -OR8, where each of C1-6 alkyl, C3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl , (C3-7 cycloalkyl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5-10 membered heteroaryl )-C1-4 alkyl- is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, -NO2, C1-4 alkyl, C1-4 hydroxy- lalkyl, C1-4 alkoxy, -N(R5)(R6), -S-(C1-4 alkyl), -S(=O)2-(C1-4 alkyl), C6-10 aryloxy, [(C6- 10 aryl)-C1-4 alkyloxy- optionally substituted with 1 or 2 C1-4 alkyl], oxo, -C(=O)H, -C(=O)-C1-4 alkyl, -C(=O)O -C1-4 alkyl, -C(=O)NH2, -NHC(=O)H, -NHC(=O)-(C1-4 alkyl), C3-7 cycloalkyl, the 5- or 6-membered heteroaryl, C1 -4 haloalkyl, and C1-4 haloalkoxy; each of R10, R11 and R13 is independently selected from the group consisting of halogen, -OH, -CN, -SF5, -NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxylalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl )-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 al- quil-, - 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, where each of C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, heterocycloalkyl 4-10 membered, 5-10 membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl )-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl- is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, - OH, -CN, -NO2, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, -N(R5)(R6), -S-(C1-4 alkyl), -S(=O)2- (C1-4 alkyl), C6-10 aryloxy, [(C6-10 aryl)-C1-4 alkyloxy- optionally substituted with 1 or 2 C1-4 alkyl], oxo, -C(=O)H, -C( =O)-C1-4 alkyl, -C(=O)O-C1-4 alkyl, -C(=O)NH2, -NHC(=O)H, -NHC(=O)-(C1-4 alkyl ), C3-7 cycloalkyl, the 5- or 6-membered heteroaryl, C1-4 haloalkyl, and C1-4 haloalkoxy; each of R9A and R10A is independently selected from the group consisting of H, C1-6 alkyl, C1-6 hydroxyalkyl, C2-6 alkenyl, -S(=O)2N(R5)(R6), -C( =O)-N(R5)(R6), -C(=O)-R8, -C(=O)-OR8, -SR15, -C(R14)2-OH, -C(R14)2-OS (=O)2H, -C(R14)2-OP(=O)(OH)2, - C(R14)2-OR15, -C(R14)2-OC(=O)-R15, -C( R14)2-N(R5)(R6), each of R10B, R11A, R12A, and R13A is independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxylalkyl, C3- 7 cycloalkyl, C3-6 alkenyl, C3-6 alkynyl, C6-10 aryl, a 4 to 10 membered heterocycloalkyl, a 5 to 10 membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (heterocycloalkyl of 4 to 10 members)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, (5 to 10 member heteroaryl)-C1-4 alkyl-, -S(=O)2N(R5) (R6), -C(=O)-N(R5)(R6), -C(=O)-R8, and -C(=O)-OR8, where each of C1-6 alkyls, C3-7 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, ( C6-10 aryl)-C1-4 alkyl-, and (5 to 10 membered heteroaryl)-C1-4 alkyl-, is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, -NO2, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, -N(R5)(R6), -S-(C1-4 alkyl), -S( =O)2-(C1-4 alkyl), C6-10 aryloxy, [(C6-10 aryl)-C1-4 alkyloxy- optionally substituted with 1 or 2 C1-4 alkyl], oxo, -C(=O) H, -C(=O)-C1-4 alkyl, -C(=O)O-C1-4 alkyl, -C(=O)NH2, -NHC(=O)H, -NHC(=O )-(C1-4 alkyl), -OC(=O)-C1-4 alkyl, C3-7 cycloalkyl, the 5- or 6-membered heteroaryl, C1-4 haloalkyl, and C1-4 haloalkoxy; each R14 is independently H or selected from the group consisting of C1-10 alkyl, C3-14 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl , (C3-14 cycloalkyl)-C1-10 alkyl-, (4- to 14-membered heterocycloalkyl)-C1-10 alkyl-, (C6-10 aryl)-C1-10 alkyl-, (5- to 10-membered heteroaryl) -C1-10 alkyl-, where each of the group selections is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, -NO2, C1 -4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, -N(R5)(R6), -N(R7)C(=O)R8, -N(R7)C(=O)OR8, -N( R7)S(=O)2R8, - S(=O)2N(R5)(R6), -C(=O)-N(R5)(R6), -C(=O)-R8, -C( =O)-OR8, -SR8, -OR8, -S(=O)2-R8, C6-10 aryloxy, [(C6-10 aryl)-C1-4 alkyloxy- optionally substituted with 1 or 2 C1-4 alkyl ], oxo, -C(=O)H, -NHC(=O)H, C3-7 cycloalkyl, 5- or 6-membered heteroaryl, C1-4 haloalkyl, and C1-4 haloalkoxy; R15 is selected from the group consisting of C1-20 alkyl, C3-14 cycloalkyl, C2-20 alkenyl, C2-20 alkynyl, C6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, ( C3-14 cycloalkyl)-C1-20 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-20 alkyl-, (C6-10 aryl)-C1-20 alkyl-, (5- to 10-membered heteroaryl members)-C1-20 alkyl-, where each of the group selections is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, -NO2 , C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, -N(R5)(R6), -N(R7)C(=O)R8, -N(R7)C(=O)OR8, - N(R7)S(=O)2R8, -S(=O)2N(R5)(R6), -C(=O)-N(R5)(R6), -C(=O)-R8, - C(=O)-OR8, -SR8, -OR8, -S(=O)2-R8, C6-10 aryloxy, [(C6-10 aryl)-C1-4 alkyloxy- optionally substituted with 1 or 2 C1- 4 alkyl], oxo, -C(=O)H, -NHC(=O)H, C3-7 cycloalkyl, 5- or 6-membered heteroaryl, C1-4 haloalkyl, and C1-4 haloalkoxy; t1 is 0, 1 or 2; t2 is 0 or 1; and t3 is 0, 1 or 2.

[0006] The present invention also provides a composition (for example, a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

[0007] The compounds of formula I and pharmaceutically acceptable salts thereof are D1 modulators (for example, D1 agonists or partial agonists). Therefore, the present invention further provides a method for treating a D1-mediated (or D1-associated) disorder (e.g., cognitive impairment such as cognitive impairment associated with schizophrenia or cognitive impairment associated with Alzheimer's disease; schizophrenia; Alzheimer's; or Parkinson's disease), comprising administering to a mammal (e.g., a human being) in need thereof an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective in modulating (e.g., agonizing or partial agonization) of D1.

[0008] As used in this report, the term "n-membered" where n is an integer typically describes the number of ring-forming atoms in a portion in which the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl group.

[0009] In several places in this specification, substituents for the compounds of the invention are disclosed in groups or bands. The invention is specifically intended to include any and all individual subcombinations of the members of such groups and bands. For example, the term "C1-6 alkyl" is specifically intended to include C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. As 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.

[00010] As used in this report, the term "alkyl" is defined as including 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 "C1-20 alkyl" refers to linear or branched aliphatic hydrocarbon chains of 1 to 20 carbon atoms; The term "C1-10 alkyl" refers to linear or branched aliphatic hydrocarbon chains of 1 to 10 carbon atoms. As another example, as used in this report, the term "C1-6 alkyl," as well as the alkyl moieties of the other groups mentioned in this report (e.g., C1-6 alkoxy) refers to linear or branched radicals from 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl). As yet another example, the term "C1-4 alkyl" refers to linear or branched aliphatic hydrocarbon chains of 1 to 4 carbon atoms; the term "C13 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 "C1 alkyl" refers to methyl. An alkyl group may be optionally substituted with one or more (e.g. 1 to 5) suitable substituents.

[00011] As used in this report, 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 in this report, the term "C2-20 alkenyl" refers to straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 2 to 20 carbon atoms; the term "C2-10 alkenyl" refers to straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 2 to 10 carbon atoms; the term "C3-6 alkenyl" refers to straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 3 to 4 carbon atoms; and the term "C2-4 alkenyl" refers to straight or branched chain unsaturated radicals (having at least one carbon-carbon double bond) of 2 to 4 carbon atoms. As another example, 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, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, among others. An alkenyl group may be optionally substituted with one or more (e.g. 1 to 5) suitable substituents. When 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.

[00012] As used in this report, 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 in this report, the term "C2-6 alkynyl" refers to straight or branched hydrocarbon chain alkynyl radicals already defined above, having 2 to 6 carbon atoms. As another example, the term "C2-20 alkynyl" is used in this report to indicate straight or branched hydrocarbon chain alkynyl radicals already defined above, having 2 to 20 carbon atoms; the term "C2-10 alkynyl" refers to straight or branched hydrocarbon chain alkynyl radicals already defined above, having 2 to 10 carbon atoms; and the term "C3-6 alkynyl" refers to straight or branched hydrocarbon chain alkynyl radicals already defined above, having 3 to 6 carbon atoms. An alkynyl group may be optionally substituted with one or more (e.g. 1 to 5) suitable substituents.

[00013] As used in this report, the term "cycloalkyl" refers to saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or bicyclics including coiled, 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-aromatic non-cumulative double or triple bonds and/ or one to three oxo groups. In some embodiments, the bicycloalkyl group has 6 to 14 carbon atoms. For example, the term "C3-14 cycloalkyl" refers to non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon rings saturated or unsaturated ring-forming carbon atoms of 3 to 14 (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl or cyclodecanyl); and the term "C3-7 cycloalkyl" refers to saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3 to 7 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentan-1-yl or bicyclo[1.1.1]pentan-2-yl). As another example, the term "C3-6 cycloalkyl" refers to saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3 to 6 ring-forming carbon atoms. As yet another example, the term "C3-4 cycloalkyl" refers to cyclopropyl or cyclobutyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (including aryl and heteroaryl) fused to the cycloalkyl group, e.g., benzo or thienyl derivatives of cyclopentane, cyclopentene, cyclohexane, among others (e.g., 2, 3-dihydro-1H-indene-1-yl or 1H-inden-2(3H)-one-1-yl). The cycloalkyl group may be optionally substituted with 1 or more (e.g., 1 to 5) suitable substituents.

[00014] As used in this report, the term "aryl" refers to carbon-only monocyclic aromatic groups or fused ring polycyclic aromatic groups having a conjugated pi electron system. The aryl group has 6 or 10 carbon atoms in the rings. Most commonly, the aryl group has 6 carbon atoms in the ring. For example, as used in this report, the term "C6-10 aryl" means aromatic radicals containing 6 to 10 carbon atoms such as phenyl or naphthyl. The aryl group may be optionally substituted with 1 or more (e.g., 1 to 5) suitable substituents.

[00015] As used in this report, the term "heteroaryl" refers to monocyclic or polycyclic fused ring aromatic heterocyclic groups with one or more heteroatoms as ring members (ring-forming atoms) each independently 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. ring including one to four heteroatoms. The heteroaryl group may also contain one to three oxo or thiono groups (i.e., =S). In 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 already defined above with 5 ring-forming atoms in the monocyclic heteroaryl ring; the term "6-membered heteroaryl" refers to a monocyclic heteroaryl group already 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 already defined above with 5 or 6 ring-forming atoms in the monocyclic heteroaryl ring. As another example, the term "5- or 10-membered heteroaryl" refers to a monocyclic or bicyclic heteroaryl group already defined above with 5, 6, 7, 8, 9 or 10 ring-forming atoms in the monocyclic or bicyclic heteroaryl ring. . A heteroaryl group may be optionally substituted with 1 or more (e.g., 1 to 5) suitable substituents. Examples of monocyclic heteroaryl 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 fused 5- and/or 6-membered monocyclic rings including one to four heteroatoms.

[00016] 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. 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g. 1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, 1H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, 1H- pyrrolo[3,2-c]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-c][1,2,4]triazinyl, imidazo[1,5-a]pyrazinyl, imidazo[1,2-a]pyrimidinyl, 1H-indazolyl, 9H-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, isoxazolo[3,4-c]pyridazinyl, pyridone, pyrimidone, pyrazinone, pyrimidinone, 1H-imidazol-2(3H)-one , 1H-pyrrole-2,5-dione, 3-oxo-2H-pyridazinyl, 1H-2- oxo-pyrimidinyl, 1H-2-oxo-pyridinyl, 2,4(1H,3H)-dioxo-pyrimidinyl, 1H- 2- oxo-pyrazinyl, among others. The heteroaryl group may be optionally substituted with 1 or more (e.g., 1 to 5) suitable substituents.

[00017] As used in this report, the term "heterocycloalkyl" refers to a 4 to 15 membered monocyclic or polycyclic ring system [including 2 or more rings that are fused together, including spiral, fused or bridged, e.g., a bicyclic ring system], saturated or unsaturated, non-aromatic (such as a 4- to 14-membered ring system, a 4- to 10-membered ring system, a 5- to 10-membered ring system , a 4- to 7-membered ring system, a 4 to 6-membered ring system, or a 5 to 6-membered ring system), including 1 to 14 ring-forming carbon atoms and 1 to 10 ring-forming heteroatoms each independently selected from O, S and N. For example, the term "4- to 14-membered heterocycloalkyl" refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 14-membered ring system comprising 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 comprising one or more ring-forming heteroatoms each independently selected from among O, S and N. As another example, the term "4 to 6 membered heterocycloalkyl" refers to a 4 to 6 membered monocyclic or polycyclic, saturated or unsaturated, non-aromatic ring system comprising one or more heteroatoms. - ring-forming hands each independently selected from O, S and N; and the term "5 to 6 membered heterocycloalkyl" refers to a 5 to 6 membered monocyclic or polycyclic, saturated or unsaturated, non-aromatic ring system comprising one or more ring-forming heteroatoms each independently selected from O , S and N. The heterocycloalkyl group may be optionally substituted with 1 or more (e.g., 1 to 5) suitable substituents. The heterocycloalkyl group may also optionally include one to three oxo or thiono groups.

[00018] Examples of such heterocycloalkyl rings include azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl , oxathiazinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, 7-azabicyclo[2.2.1]heptan-1-yl, 7-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan -7-yl, 2-azabicyclo[2.2.1]heptan-3-on-2-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, among others. Other examples of heterocycloalkyl rings include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2- yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-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-pyrazolidin-2-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl, oxazolidinonyl, 2-oxo- piperidinyl (e.g. 2-oxo-piperidin-1-yl), among others. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings (including aryl and heteroaryl) fused to the non-aromatic heterocycloalkyl ring, for example pyridinyl, pyrimidinyl, thiophenyl, pyrazolyl, phthalimidyl, naphthalimidyl, and benzo derivatives of non-aromatic heterocycloalkyl rings. aromatics. Examples of such 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-5H-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, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5-yl, and 3 ,4-dihydroisoquinolin-1(2H)-one-3-yl. The heterocycloalkyl group is optionally substituted with 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.

[00019] As used in this report, the term "halo" or "halogen" group is defined as including fluorine, chlorine, bromine or iodine.

[00020] As used in this report, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, that is, every hydrogen atom of the alkyl group has been replaced by a halogen atom) . For example, the term "C1-6 haloalkyl" refers to a C1-6 alkyl group having one or more halogen substituents (up to perhaloalkyl, that is, every hydrogen atom in the alkyl group has been replaced by a halogen). As another example, the term "C1-4 haloalkyl" refers to a C1-4 alkyl group having one or more halogen substituents (up to perhaloalkyl, that is, every hydrogen atom in the alkyl group has been replaced by a halogen); the term "C1-3 haloalkyl" refers to a C1-3 alkyl group having one or more halogen substituents (up to perhaloalkyl, that is, 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 of the alkyl group outside replaced by a halogen atom). As yet another example, the term "C1 haloalkyl" refers to a methyl group having one, two or three halogen substituents. Examples of haloalkyl groups include CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl among others.

[00021] As used in this report, the term "halocycloalkyl" refers to a cycloalkyl group having one or more halogen substituents (up to perhalocycloalkyl, that is, every hydrogen atom of the cycloalkyl group has been replaced by a halogen atom) . For example, the term "C3-4 halocycloalkyl" refers to a cyclopropyl or cyclobutyl group having one or more halogen substituents. An example of a halocycloalkyl is 2-fluorocyclopropan-1-yl.

[00022] As used in this report, the term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. For example, the term "C1-6 alkoxy" or "C1-6 alkyloxy" refers to a -O-(C1-6 alkyl) group; and the term "C1-4 alkoxy" or "C1-4 alkyloxy" refers to a -O-(C1-4 alkyl) group; As another example, the term "C1-2 alkoxy" or "C1-2 alkyloxy" refers to a -O-(C1-2 alkyl) group. Examples of alkoxy include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, among others. The alkoxy or alkyloxy group may be optionally substituted with 1 or more (e.g., 1 to 5) suitable substituents.

[00023] As used in this report, the term "haloalkoxy" refers to a -O-haloalkyl group. For example, the term "C1-6 haloalkoxy" refers to a -O-(C1-6 haloalkyl) group. As another example, the term "C1-4 haloalkoxy" refers to a -O-(C1-4 haloalkyl) group; and the term "C1-2 haloalkoxy" refers to an -O-(C1-2 haloalkyl) group. As yet another example, the term "C1 haloalkoxy" refers to a methoxy group having one, two or three halogen substituents. An example of haloalkoxy is -OCF3 or -OCHF2.

[00024] As used in this report, the term "cycloalkoxy" or "cycloalkyloxy" refers to an -O-cycloalkyl group. For example, the term "C3-7 cycloalkoxy" or "C3-7 cycloalkyloxy" refers to a -O-(C3-7 cycloalkyl) group. As another example, the term "C3-6 cycloalkoxy" or "C3-6 cycloalkyloxy" refers to a -O-(C3-6 cycloalkyl) group. Examples of cycloalkoxy include C3-6 cycloalkoxy (e.g., cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexanoxy, among others). The cycloalkoxy or cycloalkyloxy group may be optionally substituted with 1 or more (e.g., 1 to 5) suitable substituents.

[00025] As used in this report, the term "C6-10 aryloxy" refers to a -O-(C6-io aryl) group. An example of a C6-10 aryloxy group is -O-phenyl [i.e., phenoxy]. The C6-10 aryloxy group may be optionally substituted with 1 or more (e.g., 1 to 5) suitable substituents.

[00026] As used in this report, the term "fluoroalkyl" refers to an alkyl group having one or more fluorine substituents (up to perfluoroalkyl, that is, every hydrogen atom of the 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 ). As another example, the term "C1 fluoroalkyl" refers to a C1 alkyl (i.e., methyl) group having 1, 2 or 3 fluorine substituents). Examples of fluoroalkyl groups include CF3, C2F5, CH2CF3, CHF2, CH2F, among others.

[00027] As used in this report, the term "fluoroalkoxy" refers to an -O-fluoroalkyl group. For example, the term "C1-2 fluoroalkoxy" refers to a -O-C1-2 fluoroalkyl group. As another example, the term "C1 fluoroalkoxy" refers to a methoxy group having one, two or three fluorine substituents. An example of C1 fluoroalkoxy is -OCF3 or -OCHF2.

[00028] As used in this report, the term "hydroxylalkyl" or "hydroxyalkyl" refers to an alkyl group having one or more (e.g., 1, 2 or 3) OH substituents. The term "C1-6 hydroxyalkyl" 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 "C1-4 hydroxyalkyl" or "C1-4 hydroxyalkyl" refers to a C1-4 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents; the term "C1-3 hydroxyalkyl" 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 hydroxyalkyl" 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.

[00029] As used in this report, the term "cyanoalkyl" refers to an alkyl group having one or more (e.g., 1, 2, or 3) -CN (i.e., -C=N or cyano) substituents. For example, the term "C1-4 cyanoalkyl" refers to a C1-4 alkyl group having one or more (e.g., 1, 2 or 3) -CN substituents. An example of cyanoalkyl is -CH2-CN or -CH2CH2-CN.

[00030] As used in this report, the term "oxo" refers to =O. When an oxo is substituted on a carbon atom, together they form a carbonyl moiety [-C(=O)-]. When an oxo is substituted on a sulfur atom, together they form a sulfinyl moiety [-S(=O)-]; When two oxo groups are substituted on a sulfur atom, together they form a sulfonyl moiety [-S(=O)2-].

[00031] As used in this report, the term "optionally substituted" means that the substitution is optional and therefore includes unsubstituted and substituted atoms and moieties. A "substituted" atom or portion indicates that any hydrogen in the designated atom or portion can be replaced with a selection of the indicated substituent group (until every hydrogen atom in the designated atom or portion is replaced with a selection of the indicated substituent group). ced), provided that the normal valence 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. CH3) is optionally substituted, then up to 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.

[00032] As used in this report, unless specified, the attachment point of a substituent may be at any suitable position on the substituent. For example, piperidinyl can be piperidin-1-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 in position 3 of piperidinyl) or piperidin-4-yl (linked through the C atom in position 4 of piperidinyl). As another example, pyridinyl (or pyridyl) can be 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl) or 4-pyridinyl (or pyridin-4-yl).

[00033] When shown that a bond to a substituent spans a bond connecting two atoms in a ring, then such a substituent may be bonded to any of the ring-forming atoms in that ring that are substitutable (i.e., bonded to one or more atoms of hydrogen), unless otherwise specified or otherwise implied from the context. For example, as shown in formula a-101 below, R9 can be bonded to either of two ring carbon atoms each containing a hydrogen atom (but not shown), but not to the N to which R9A is bonded ( even where R9A is H). As another example, as shown in formula a-102 below, R9 can be bonded to either of two ring carbon atoms each containing a hydrogen atom (but not shown), but not to the N that is shown bonded to an H atom. As yet another example, as shown in formula a-103 below, R12 can be bonded to either of two ring carbon atoms each containing a hydrogen atom (but not shown), but not to the ring carbon atom that is shown bonded to an H atom.

[00034] When a substituted or optionally substituted moiety is described without indicating the atom through which such moiety is attached to a substituent, then the substituent may be attached through any appropriate atom in such moiety. For example, in a substituted arylalkyl, a substituent on the arylalkyl [e.g., (C6-10 aryl)-C1-4 alkyl-] can be attached to any carbon atom on the alkyl part or the aryl part of the arylalkyl. Combinations of substituents and/or variables are only permissible if such combinations result in stable compounds.

[00035] As noted above, compounds of formula I may exist in the form of pharmaceutically acceptable salts such as acid addition salts and/or base addition salts of compounds of formula I. The expression "pharmaceutically acceptable salts", as used in this report, unless otherwise indicated, includes acid addition salts or base salts that may be present in the compounds of formula I.

[00036] Pharmaceutically acceptable salts include acid addition salts and base salts thereof.

[00037] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the salts of acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate , hybenzate, hydrochloride/chloride, hydrobromide/bromide, iodihydrate/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsilate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate /hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate.

[00038] Suitable base salts are formed from bases that form non-toxic salts. Examples include the salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc.

[00039] Hemissals of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.

[00040] For a recap on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of formula I are known to the person skilled in the art.

[00041] As used in this report the terms "formula I", "formula I or pharmaceutically acceptable salts thereof", "pharmaceutically acceptable salts of the compound or salt [of formula I]" are defined as including all forms of the compound of formula I, including hydrates, solvates, isomers (including for example rotational stereoisomers), crystalline and non-crystalline forms, isomorphs, polymorphs, metabolites, and prodrugs thereof.

[00042] As one skilled in the art knows, amine-type compounds (i.e., those comprising one or more nitrogen atoms), for example tertiary amines, can form N-oxides (also known as amine oxides or N-oxides). amine). An N- oxide has the formula of (R100R200R300)N+-O- where the parent amine (R100R200R300)N may be, for example, a tertiary amine (e.g., each of R100, R200, R300 is independently alkyl, arylalkyl, aryl, heteroaryl or similar), a heterocyclic or heteroaromatic amine [for example, (R100R200R300)N together form 1-alkylpiperidine, 1-alkylpyrrolidine, 1-benzylpyrrolidine or pyridine]. For example, an imine nitrogen, especially a heterocyclic or heteroaromatic imine nitrogen or a pyridine-type nitrogen atom (4=N~I-) [such as a nitrogen atom in pyridine, pyridazine or pyrazine] , can be N-oxidized to form the N-oxide comprising the group (^“5- Therefore, a compound according to the present invention comprising one or more nitrogen atoms (for example, an imine nitrogen atom) must be capable of forming an N-oxide thereof (e.g. mono-N-oxides, bis-N-oxides or multi-N-oxides or mixtures thereof depending on the number of nitrogen atoms suitable to form stable N-oxides ).

[00043] As used in this report, the term "N-oxides" refers to all possible forms, and in particular to all stable forms, of N-oxide of amine-type compounds (e.g., compounds comprising one or plus imine nitrogen atoms) described in this report, such as mono-N-oxides (including different isomers when more than one nitrogen atom of an amine-type compound can form a mono-N-oxide) or multi-N-oxides (e.g. bis-N-oxides) or mixtures thereof in any proportion.

[00044] The compounds of formula I and their salts described in this invention also include N-oxides thereof.

[00045] Compounds of formula I (including salts thereof) can exist in a continuum of solid states ranging from completely amorphous to completely crystalline. The term 'amorphous' refers to a state in which the material has no long-range order at the molecular level and, depending on temperature, can exhibit the physical properties of a solid or a liquid. Typically such materials do not provide distinct X-ray diffraction patterns and, although they exhibit the properties of a solid, they are more formally described as a liquid. When heated, there is a change from an apparent solid to a material with liquid properties, which is characterized 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 internal structure at the molecular level and provides a distinct X-ray diffraction pattern with defined peaks. Such materials when sufficiently heated 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 point').

[00046] Compounds of formula I (including salts thereof) can exist in non-unsolved and solvated forms. When the solvent or water is firmly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will constitute the norm.

[00047] Compounds of formula I (including salts thereof) may exist as clathrates or other complexes (for example, cocrystals). Included within the scope of the present invention are complexes such as clathrates, drug-host inclusion complexes where the drug and host are present in non-stoichiometric or stoichiometric amounts. Also included are complexes of compounds of formula I containing two or more organic and/or inorganic components, which may be in stoichiometric or non-stoichiometric quantities. The resulting complexes can be ionized, partially ionized or non-ionized. Cocrystals are typically defined as crystalline complexes of neutral molecular constituents that are bonded to each other through noncovalent interactions, but could also be a complex of a neutral molecule with a salt. Cocrystals can be prepared by crystallization from flux, by recrystallization from solvents, or by physically grinding the components together; see O. Almarsson and M. J. Zaworotko, Chem. Commun. 2004, 17, 1889-1896. For a general recap of multicomponent complexes, see J. K. Haleblian, J. Pharm. Sci. 1975, 64, 1269-1288.

[00048] The compounds of the invention (including salts thereof) can 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 (whether flux or solution). Mesomorphism that arises as the result of a change in temperature 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 have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules that have an ionic (such as -COO-Na+, -COO-K+ or -SO3-Na+) or non-ionic (such as as -N-N+(CH3)3). For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4th Edition (Edward Arnold, 1970).

[00049] The invention also relates to prodrugs of compounds of formula I. Therefore, certain derivatives of compounds of formula I that have little or no pharmacological activity on their own can, when administered in or on the body, be converted in compounds of formula I having the desired activity, for example, by hydrolytic cleavage. Such derivatives are called "prodrugs". More information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed . E. B. Roche, American Pharmaceutical Association).

[00050] The prodrugs according to the invention can, for example, be produced by replacing the appropriate functionalities present 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 edition, edited by Valentino Stella, Ronald Borchardt, Michael Hageman, Reza Oliyai, Hans Maag, Jefferson Tilley, pages 134-175 (Springer , 2007).

[00051] Furthermore, certain compounds of formula I can by themselves act as prodrugs of other compounds of formula I.

[00052] Also included in the scope of the invention are metabolites of compounds of formula I, that is, compounds formed in vivo upon administration of the drug.

[00053] Compounds of formula I (including salts thereof) include all stereoisomers and tautomers. Stereoisomers of formula I include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, atropisomers, and conformational isomers of 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 salts or base addition salts where the counterion is optically active, for example D-lactate or L-lysine or racemic, for example DL-tartrate or DL-arginine.

[00054] In some embodiments, compounds of formula I (including salts thereof) may have asymmetric carbon atoms. The carbon-carbon bonds of compounds of formula I can be represented here using a solid line , a full cuneiform stroke , a dashed cuneiform stroke The use of a solid line to represent bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of a solid or dashed wedge to represent bonds to asymmetric carbon atoms is intended to indicate that only the stereoisomer shown is included. It is possible that compounds of formula I may contain more than one asymmetric carbon atom. In these compounds, the use of a solid line to represent bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers are included. For example, unless otherwise indicated, it is anticipated that compounds of formula I may exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to represent bonds to one or more asymmetric carbon atoms in a compound of formula I and the use of a solid or dashed wedge line to represent bonds to the other asymmetric carbon atoms in it is intended to indicate that a mixture of diastereomers is present.

[00055] In some embodiments, compounds of formula I (including salts thereof) may exist in and/or be isolated as atropisomers (for example, one or more atropenantiomers). Those skilled in the art will recognize that atropisomerism can exist in a compound that has two or more aromatic rings (e.g., two aromatic rings linked through a single bond). See, for example, Freedman, T. B. et al., Absolute Configuration Determination of Chiral Molecules 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.

[00056] When any racemate crystallizes, crystals of different types are possible. One type is the racemic compound (true racemate) where a homogeneous crystal form containing both enantiomers in equimolar amounts is produced. Another type is a racemic mixture or conglomerate where two crystal forms are produced in equal or different molar quantities, each comprising a single enantiomer.

[00057] Compounds of formula I (including salts thereof) can exhibit the phenomenon of tautomerism and structural isomerism. For example, compounds of formula I can exist in various tautomeric forms, including the enol and imine form, the amide and imidic acid form, the keto and enamine form, and geometric isomers and mixtures thereof. All of these tautomeric forms are included within the scope of compounds of formula I. Tautomers can exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Although a tautomer may be described, the present invention includes all tautomers of the compounds of formula I. For example, when one of the two tautomers of the following invention is described in the experimental section of this report, those skilled in the art will easily realize that the invention also includes the other.

[00058] As another example, when one of the three tautomers of the following invention is described in the experimental section of this report, those skilled in the art will readily realize that the invention also includes each of the others.

[00059] The present invention includes all compounds of formula I (including salts thereof) isotopically labeled and pharmaceutically acceptable where 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 that predominates in nature.

[00060] 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 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S.

[00061] Certain isotopically labeled 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 detection.

[00062] Substitution with heavier isotopes such as deuterium, i.e., 2H, may present certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[00063] Replacement with positron-emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies to verify substrate receptor occupancy.

[00064] Isotopically labeled compounds of formula I (including salts thereof) generally can be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples and Preparations presented here using an appropriate isotopically labeled reagent in the place of the unmarked reagent previously used.

[00065] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, where L1 is O.

[00066] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, where L1 is S.

[00067] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, where L1 is NH, N(C1-4 alkyl), N(-C1-2 alkyl-C3-4 cycloalkyl) or N (C3-6 cycloalkyl). In a further embodiment, L1 is NH.

[00068] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, where Q1 is Q1a. In a further embodiment, X1 is O.

[00069] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula IA-1, IA-2, IA-3, IA-4, IA -5, IA-6, IA-7, IA-8, IA-9 or IA-10:

[00070] In one embodiment of a compound of formula I or a pharmaceutically acceptable salt thereof where Q1 is Q1a or in one embodiment of a compound of formula IA-1, IA-2, IA-3, IA-4, IA- 5, IA-6, IA-7, IA-8, IA-9 or IA-10 or a pharmaceutically acceptable salt thereof, each R9 is independently selected from the group consisting of -CN, C1-4 alkyl, C1 -4 haloalkyl, C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C1-4 alkyl of R9 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, - CN, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein each of the C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R9 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl , C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; and R9A is selected from the group consisting of H, C1-3 alkyl, C1-3 hydroxyalkyl, allyl, -S(=O)2N(R5)(R6), -C(=O)-N(R5)(R6 ), -C(=O)-R8, -C(=O)-OR8, -C(R14)2-OH, -C(R14)2-OS(=O)2H, -C(R14)2- OP(=O)(OH)2, -C(R14)2-OR15, and -C(R14)2-OC(=O)-R15. In a further embodiment, each R9 is independently selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl. In yet another embodiment, each R9 is independently selected from the group consisting of C1-3 alkyl and cyclopropyl. In yet another additional embodiment, each R9 is independently methyl or ethyl. In yet another additional embodiment, each R9 is methyl.

[00071] In one embodiment of a compound of formula IA-1 or IA-6 or a pharmaceutically acceptable salt thereof, R9A is selected from the group consisting of H, C1-3 alkyl, C1-3 hydroxylalkyl, and allyl. In a further embodiment, R9A is not H.

[00072] In one embodiment of a compound of formula IA-1 or IA-6 or a pharmaceutically acceptable salt thereof, R9A is selected from the group consisting of H, -S(=O)2N(R5)(R6), -C(=O)- N(R5)(R6), -C(=O)-R8, -C(=O)-OR8, -C(R14)2-OH, -C(R14)2-OS (=O)2H, -C(R14)2- OP(=O)(OH)2, -C(R14)2-OR15, and -C(R14)2-OC(=O)-R15. In a further embodiment, R9A is selected from the group consisting of H, -S(=O)2N(R5)(R6), -C(=O)-N(R5)(R6), -C(= O)-R8, -C(=O)-OR8, -CH2-OH, -CH2-OS(=O)2H, -CH2-OP(=O)(OH)2, -CH2-OR15, and -CH2 -OC(=O)-R15. In yet another embodiment, R9A is not H.

[00073] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, where Q1 is Q1b. In a further embodiment, X1 is O. In another further embodiment, X2 is O. In yet another embodiment, each of X1 and X2 is O.

[00074] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula IB-1, IB-2, IB-3, IB-4 or IB -5, IB-6, IB-7, IB-8, IB-9 or IB-10:

[00075] In an embodiment of a compound of formula I or a pharmaceutically acceptable salt thereof of the present invention where Q1 is Q1b or in an embodiment of a compound of formula IB-1, IB-2, IB-3, IB-4 , IB-5, IB-6, IB-7, IB-8, IB-9 or IB-10 or a pharmaceutically acceptable salt thereof, of the present invention: R10 is selected from the group consisting of -CN, C1 -4 alkyl, C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C1-4 alkyl of R10 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1- 4 alkoxy, and C1-4 haloalkoxy; and wherein each of the C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R10 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl, C1 -4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; R10A is selected from the group consisting of H, C1-3 alkyl, C1-3 hydroxyalkyl, C2-4 alkenyl, -S(=O)2N(R5)(R6), -C(=O)- N(R5) (R6), -C(=O)-R8, -C(=O)-OR8, -C(R14)2-OH, -C(R14)2-OS(=O)2H, - C(R14) 2-OP(=O)(OH)2, -C(R14)2-OR15, and -C(R14)2-OC(=O)-R15; and R10B is selected from the group consisting of C1-4 alkyl, C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C1-4 alkyl of R10B is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein each of the C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R10B is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl , C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, and C1-4 haloalkoxy.

[00076] In a further embodiment of the compound of formula I above or a pharmaceutically acceptable salt thereof where Q1 is Q1b or in a further embodiment of the compound of formula IB-1, IB-2, IB-3, IB-4, IB -5, IB-6, IB-7, IB-8, IB-9 or IB-10 above or a pharmaceutically acceptable salt thereof, each of R10 and R10B is independently selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl. In yet another embodiment, each of R10 and R10B is independently selected from the group consisting of C1-3 alkyl and cyclopropyl. In yet another further embodiment, each of R10 and R10B is independently methyl or ethyl. In yet another additional embodiment, each of R10 and R10B is methyl.

[00077] In one embodiment of a compound of formula IB-1 or IB-6 or a pharmaceutically acceptable salt thereof, R10A is selected from the group consisting of H, C1-3 alkyl, C1-3 hydroxylalkyl, and C2 -4 alkenyl (e.g. allyl). In a further embodiment, R10A is not H.

[00078] In one embodiment of a compound of formula IB-1 or IB-6 or a pharmaceutically acceptable salt thereof, R10A is selected from the group consisting of H, -S(=O)2N(R5)(R6), -C(=O)- N(R5)(R6), -C(=O)-R8, -C(=O)-OR8, -C(R14)2-OH, -C(R14)2-OS (=O)2H, -C(R14)2- OP(=O)(OH)2, -C(R14)2-OR15, and -C(R14)2-OC(=O)-R15. In a further embodiment, R10A is selected from the group consisting of H, -S(=O)2N(R5)(R6), -C(=O)-N(R5)(R6), -C(= O)-R8, -C(=O)-OR8, -CH2-OH, -CH2-OS(=O)2H, -CH2-OP(=O)(OH)2, -CH2-OR15, and -CH2 -OC(=O)-R15. In yet another embodiment, R10A is not H.

[00079] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, where Q1 is Q1c. In a further embodiment, X1 is O.

[00080] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula IC-1, IC-2, IC-3, IC-

[00081] In an embodiment of a compound of formula I or a pharmaceutically acceptable salt thereof of the present invention where Q1 is Q1c or in an embodiment of a compound of formula IC-1, IC2, IC-3, IC-4, IC -5 or IC-6 or a pharmaceutically acceptable salt thereof, of the present invention: each R11 is independently selected from the group consisting of -CN, C1-4 alkyl, C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, where the C1-4 alkyl of R11 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein each of the C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R11 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl, C1 -4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; and R11A is selected from the group consisting of C1-4 alkyl, C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C1-4 alkyl of R11A is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein each of the C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R11A is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl , C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, and C1-4 haloalkoxy.

[00082] In an additional embodiment of the compound of formula I above or a pharmaceutically acceptable salt thereof where Q1 is Q1c or in an additional embodiment of the compound of formula IC-1, IC2, IC-3, IC-4, IC-5 or IC-6 above or a pharmaceutically acceptable salt thereof, each of R11 and R11A is independently selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl. In yet another embodiment, each of R11 and R11A is independently selected from the group consisting of C1-3 alkyl and cyclopropyl. In yet another further embodiment, each of R11 and R11A is independently methyl or ethyl. In yet another additional embodiment, each of R11 and R11A is methyl.

[00083] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, where Q1 is Q1d. In a further embodiment, X1 is O.

[00084] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula ID-1, ID-2, ID-3, ID-4, ID -5, ID-6, ID-7, ID-8, ID-9 or ID-10:

[00085] In one embodiment of a compound of formula I or a pharmaceutically acceptable salt thereof where Q1 is Q1d or in one embodiment of a compound of formula ID-1, ID-2, ID-3, ID-4, ID- 5, ID-6, ID-7, ID-8, ID-9 or ID-10 or a pharmaceutically acceptable salt thereof, each R12 is independently selected from the group consisting of -CN, C1-4 alkyl, C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C1-4 alkyl of R12 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein each of the C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R12 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl, C1 -4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; and R12A is selected from the group consisting of C1-4 alkyl, C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C1-4 alkyl of R12A is optionally substituted with one or more substituents each independently selected from the group that consists of halogen, -OH, -CN, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein each of the C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R12A is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl, C1 -4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. In a further embodiment, each of R12 and R12A is independently selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl. In yet another embodiment, each of R12 and R12A is independently selected from the group consisting of C1-3 alkyl and cyclopropyl. In yet another further embodiment, each of R12 and R12A is independently methyl or ethyl. In yet another additional embodiment, each of R12 and R12A is methyl.

[00086] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, where Q1 is Q1e. In a further embodiment, X1 is O.

[00087] One embodiment of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula IE-1, IE-2, IE-3, IE-4 or IE -5, IE-6, IE-7, IE-8, IE-9 or IE-10:

[00088] In one embodiment of a compound of formula I or a pharmaceutically acceptable salt thereof where Q1 is Q1e or in one embodiment of a compound of formula IE-1, IE-2, IE-3, IE-4, IE- 5, IE-6, IE-7, IE-8, IE-9 or IE-10 or a pharmaceutically acceptable salt thereof, each R13 is independently selected from the group consisting of -CN, C1-4 alkyl, C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C1-4 alkyl of R13 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein each of the C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R13 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl, C1 -4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; and R13A is selected from the group consisting of C1-4 alkyl, C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C1-4 alkyl of R13A is optionally substituted with one or more substituents each independently selected from the group that consists of halogen, -OH, -CN, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein each of the C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R13A is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl , C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. In a further embodiment, each of R13 and R13A is independently selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl. In yet another embodiment, each of R13 and R13A is independently selected from the group consisting of C1-3 alkyl and cyclopropyl. In yet another further embodiment, each of R13 and R13A is independently methyl or ethyl. In yet another additional embodiment, each of R13 and R13A is methyl.

[00089] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10, i.e., a compound of formula IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8 , IA-9, IA-10, IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7, IB-8, IB-9, IB-10, IC -1, IC-2, IC-3, IC-4, IC-5, IC-6, ID-1, ID-2, ID-3, ID-4, ID-5, ID-6, ID-7 , ID-8, ID-9, ID-10, IE-1, IE-2, IE-3, IE-4, IE-5, IE-6, IE-7, IE-8, IE-9 or IE -10) or a pharmaceutically acceptable salt thereof, each of R1 and R2 is independently selected from the group consisting of H, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1 -6 haloalkoxy, C3-6 cycloalkyl, -C(=O)-(C1-4 alkyl), -C(=O)OH, and C(=O)-O-(C1-4 alkyl), where each of C1-6 alkyl and C3-6 cycloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1- 4 alkoxy, and C1-4 haloalkoxy. In a further embodiment, each of R1 and R2 is independently selected from the group consisting of H, halogen, -C1-4 alkyl, C1-4 alkoxy, and C3-4 cycloalkyl, where each of C1-4 alkyl and C1 -4 alkoxy of R1 and R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, -OH, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein the C3-4 cycloalkyl of R1 and R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy , and C1-4 haloalkoxy. In yet another embodiment, each of R1 and R2 is independently H, methyl or halogen (e.g., F). In yet another further embodiment, each of R1 and R2 is independently H or halogen (e.g., F). In yet another embodiment, each of R1 and R2 is H.

[00090] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, each of R3 and R4 is independently selected from the group consisting of H, halogen, -CN, -C1-4 alkyl, C1-4 alkoxy, and C3-4 cycloalkyl, wherein each of the C1-4 alkyl and C1-4 alkoxy of R3 and R4 is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from among halogen, -OH, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein the C3-4 cycloalkyl of R3 and R4 is optionally substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy , and C1-4 haloalkoxy. In a further embodiment, each of R3 and R4 is independently H, F, Cl, CN or methyl wherein the methyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, and C1-4 alkoxy. In yet another embodiment, R3 is H; and R4 is H, halogen or methyl, where the methyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, and C1-4 alkoxy. In yet another additional embodiment, R3 is H and R4 is methyl.

[00091] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, each of R1 and R2 is independently H, methyl or halogen (e.g., F or Cl); and each of R3 and R4 is independently H, halogen (e.g. F or Cl), CN or methyl wherein the methyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, - OH, and C1-4 alkoxy. In a further embodiment, each of R1, R2, and R3 is H, and R4 is H, halogen or methyl. In yet another embodiment, R4 is H or methyl. In yet another additional embodiment, R4 is methyl.

[00092] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, each of R1 and R3 is independently H, halogen, -CN, methyl or methoxy, where each of o methyl and me - toxi is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, and C1-4 alkoxy; and R2 and R4 together with the two carbon atoms to which they are attached form a 5- or 6-membered fused heteroaryl, a 5- or 6-membered fused heterocycloalkyl ring, a 5- or 6-membered fused cycloalkyl ring, or a fused benzene ring , wherein each of the fused rings is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy, and where the fused heterocycloalkyl ring or the fused cycloalkyl ring is further optionally substituted with 1, 2 or 3 oxo. In a further embodiment, each of R1 and R3 is independently H, halogen, -CN, methyl, C1-4 fluoroalkyl, methoxy or C1 fluoroalkoxy. In yet another embodiment, R2 and R4 together with the two carbon atoms to which they are attached form an optionally substituted 5- or 6-membered fused heteroaryl. In yet another further embodiment, each of R1 and R3 is H.

[00093] In one embodiment of a compound of formula I (for example, a compound of one of the formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, each of T1, T2, T3, and T4 is independently selected from the group consisting of H, halogen, -CN, C1 -4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C1-4 alkoxy, C1-4 haloalkoxy, and C34 cycloalkyl, where each of C1-4 alkyl, C2-4 alkenyl, and C1-4 alkoxy T1, T2, T3, and T4 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein the C3-4 cycloalkyl of T1, T2, T3, and T4 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. In a further embodiment, each of T1, T2, T3, and T4 is independently selected from the group consisting of H, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C1-4 alkoxy, C1- 4 haloalkoxy, C3-4 cycloalkyl, and C3-4 halocycloalkyl. In a further embodiment, at least one of T1, T2, T3, and T4 is other than H.

[00094] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, T1 is other than H. In a further embodiment, T1 is selected from the group consisting of halogen, C3-4 cycloalkyl, C1 -4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy, wherein each of C3-4 cycloalkyl and C1-4 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting in halogen and -OH. In yet another embodiment, T1 is selected from the group consisting of halogen, C3-4 cycloalkyl, C3-4 halocycloalkyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxylalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. In yet another additional embodiment, T1 is selected from the group consisting of halogen, cyclopropyl, halocyclopropyl, methyl, ethyl, C1-2 haloalkyl, C1-2 hydroxylalkyl, methoxy, ethoxy, and C1-2 haloalkoxy. In a further embodiment, T1 is selected from the group consisting of halogen, cyclopropyl, halocyclopropyl, methyl, C1 haloalkyl, methoxy, and C1 haloalkoxy. In a further embodiment, T1 is selected from the group consisting of C3-4 cycloalkyl, C3-4 halocycloalkyl, C1-4 alkyl, and C1-4 haloalkyl.

[00095] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, T1 is selected from the group consisting of C1-4 alkyl and C1-4 haloalkyl. In a further embodiment, T1 is selected from the group consisting of methyl, ethyl, and C1-2 haloalkyl. In a further embodiment, T1 is C1-2 haloalkyl (e.g., C1-2 fluoroalkyl).

[00096] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, T1 is selected from the group consisting of C1-4 alkoxy, and C1-4 haloalkoxy. In a further embodiment, T1 is selected from the group consisting of methoxy, ethoxy, and C1-2 haloalkoxy. In a further embodiment, T1 is C1-2 haloalkoxy (e.g., C1-2 fluoroalkoxy).

[00097] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, T1 is halogen.

[00098] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, T1 is selected from the group consisting of C3-4 cycloalkyl and C3-4 halocycloalkyl. In a further embodiment, T1 is C3-4 cycloalkyl.

[00099] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, T2 is selected from the group consisting of H, halogen, -CN, C3-4 cycloalkyl, C3-4 halocycloalkyl, C1- 4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy, wherein each of C34 cycloalkyl and C1-4 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen and -OH. In a further embodiment, T2 is selected from the group consisting of H, halogen, -CN, C3-4 cycloalkyl, C3-4 halocycloalkyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxylalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. In yet another embodiment, T2 is selected from the group consisting of H, halogen, methyl, ethyl, C1-2 haloalkyl, C1-2 hydroxylalkyl, C1-2 alkoxy, and C1-2 haloalkoxy. In yet another additional embodiment, T2 is selected from the group consisting of H, halogen, methyl, -CH2OH, and C1 haloalkyl. In yet another additional embodiment, T2 is H.

[000100] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, T3 is selected from the group consisting of H, halogen, -CN, C3-4 cycloalkyl, C3-4 halocycloalkyl, C1- 4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. In a further embodiment, T3 is selected from the group consisting of H, halogen, methyl, -CH2OH, and C1 haloalkyl (e.g., C1 fluoroalkyl). In yet another embodiment, T3 is H.

[000101] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, T4 is H, halogen, methyl, -CH2OH or C1 haloalkyl. In a further embodiment, T4 is H or F. In yet another embodiment, T4 is H.

[000102] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, each of T1, T2, and T3 is independently selected from the group consisting of H, halogen, C1-2 alkyl, C1 -2 haloalkyl, C1-2 hydroxyalkyl, C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; and T4 is H. In a further embodiment, each of T1, T2, and T3 is independently selected from the group consisting of H, halogen, methyl, C1 haloalkyl, -CH2OH, cyclopropyl, methoxy, and C1 haloalkoxy; and T4 is H. In yet another embodiment, each of T1, T2, and T3 is independently selected from the group consisting of H, halogen (F, Cl, Br or I), methyl, C1 fluoroalkyl ( e.g., CF3 or CHF2), -CH2OH, cyclopropyl, methoxy, and C1 fluoroalkoxy (e.g., -OCF3 or -OCHF2); and T4 is H. In yet another further embodiment, T1 is other than H and at least one of T2 and T3 is H. In a further embodiment, each of T2 and T3 is H.

[000103] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, T1 is selected from the group consisting of halogen (F, Cl, Br or I), methyl, -CH2OH, C1 fluoroalkyl ( e.g., CF3 or CHF2), methoxy, C1 fluoroalkoxy (e.g., -OCF3 or -OCHF2), cyclopropyl, and fluorocyclopropyl; and each of T2, T3, and T4 is H.

[000104] In one embodiment of a compound of formula I (for example, a compound of one of formulas IA-1 to IA-10, IB-1 to IB-10, IC-1 to IC-6, ID-1 to ID-10, and IE-1 to IE-10) or a pharmaceutically acceptable salt thereof, T1 is selected from the group consisting of halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxyalkyl, C1- 2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; each of T2 and T3 is independently selected from the group consisting of H, halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxylalkyl, C1-2 alkoxy, C12 haloalkoxy, cyclopropyl, and halocyclopropyl; and T4 is H. In a further embodiment, one of T2 and T3 is H and the other is not H. In another further embodiment, T2 is H and T3 is not H. In yet another further embodiment, T2 is not H and T3 is H.

[000105] In one embodiment, the compound of formula I or a salt thereof is a compound of formula IA-1 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IA-2 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IA-3 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IA-4 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IA-5 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IA-6 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IA-7 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IA-8 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IA-9 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IA-10 or a salt thereof.

[000106] In one embodiment, the compound of formula I or a salt thereof is a compound of formula IB-1 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IB-2 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IB-3 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IB-4 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IB-5 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IB-6 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IB-7 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IB-8 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IB-9 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IB-10 or a salt thereof.

[000107] In one embodiment, the compound of formula I or a salt thereof is a compound of formula IC-1 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IC-2 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IC-3 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IC-4 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IC-5 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IC-6 or a salt thereof.

[000108] In one embodiment, the compound of formula I or a salt thereof is a compound of formula ID-1 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula ID-2 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula ID-3 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula ID-4 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula ID-5 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula ID-6 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula ID-7 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula ID-8 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula ID-9 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula ID-10 or a salt thereof.

[000109] In one embodiment, the compound of formula I or a salt thereof is a compound of formula IE-1 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IE-2 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IE-3 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IE-4 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IE-5 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IE-6 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IE-7 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IE-8 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IE-9 or a salt thereof. In one embodiment, the compound of formula I or a salt thereof is a compound of formula IE-10 or a salt thereof.

[000110] In one embodiment of a compound of formula IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9 or IA-10 or a pharmaceutically acceptable salt thereof, each R9 is independently selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl; each of R1 and R2 is independently H, methyl or halogen (e.g. F); each of R3 and R4 is independently H, F, Cl, CN or methyl where the methyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, and C1-4 alkoxy ; T1 is selected from the group consisting of halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxylalkyl, C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; each of T2 and T3 is independently selected from the group consisting of H, halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxylalkyl, C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; and T4 is H. In a further embodiment, each R9 is independently selected from the group consisting of C1-3 alkyl and cyclopropyl; each of R1 and R2 is H; R3 is H; and R4 is methyl. In yet another embodiment, the compound or a salt thereof is a compound of formula IA-1 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IA-2 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IA-3 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IA-4 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IA-5 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IA-6 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IA-7 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IA-8 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IA-9 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IA-10 or a salt thereof.

[000111] In one embodiment of a compound of formula IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7, IB-8, IB-9 or IB-10 or a pharmaceutically acceptable salt thereof, each of R10 and R10B is independently selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl; each of R1 and R2 is independently H, methyl or halogen (e.g., F); each of R3 and R4 is independently H, F, Cl, CN or methyl where the methyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, and C1-4 alkoxy ; T1 is selected from the group consisting of halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxyalkyl, C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; each of T2 and T3 is independently selected from the group consisting of H, halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxylalkyl, C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; and T4 is H. In a further embodiment, each of R10 and R10B is independently selected from the group consisting of C1-3 alkyl and cyclopropyl; each of R1 and R2 is H; R3 is H; and R4 is methyl. In yet another embodiment, the compound or a salt thereof is a compound of formula IB-1 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IB-2 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IB-3 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IB-4 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IB-5 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IB-6 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IB-7 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IB-8 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IB-9 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IB-10 or a salt thereof.

[000112] In one embodiment of a compound of formula IC-1, IC-2, IC-3, IC-4, IC-5 or IC-6 or a pharmaceutically acceptable salt thereof, each of R11 and R11A is independently selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl; each of R1 and R2 is independently H, methyl or halogen (e.g. F); each of R3 and R4 is independently H, F, Cl, CN or methyl where the methyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, and C1- 4 alkoxy; T1 is selected from the group consisting of halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxylalkyl, C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; each of T2 and T3 is independently selected from the group consisting of H, halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxylalkyl, C12 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; and T4 is H. In a further embodiment, each of R11 and R11A is independently selected from the group consisting of C1-3 alkyl and cyclopropyl; each of R1 and R2 is H; R3 is H; and R4 is methyl. In yet another embodiment, the compound or a salt thereof is a compound of formula IC-1 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IC-2 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IC-3 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IC-4 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IC-5 or a salt thereof.

[000113] In one embodiment of a compound of formula ID-1, ID-2, ID-3, ID-4, ID-5, ID-6, ID-7, ID-8, ID-9 or ID-10 or a pharmaceutically acceptable salt thereof, each of R12 and R12A is independently selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl; each of R1 and R2 is independently H, methyl or halogen (e.g., F); each of R3 and R4 is independently H, F, Cl, CN or methyl where the methyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, and C1-4 alkoxy ; T1 is selected from the group consisting of halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxyalkyl, C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; each of T2 and T3 is independently selected from the group consisting of H, halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxylalkyl, C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; and T4 is H. In a further embodiment, each of R12 and R12A is independently selected from the group consisting of C1-3 alkyl and cyclopropyl; each of R1 and R2 is H; R3 is H; and R4 is methyl. In yet another embodiment, the compound or a salt thereof is a compound of formula ID-1 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula ID-2 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula ID3 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula ID-4 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula ID-5 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula ID-6 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula ID-7 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula ID-8 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula ID9 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula ID-10 or a salt thereof.

[000114] In one embodiment of a compound of formula IE-1, IE-2, IE-3, IE-4, IE-5, IE-6, IE-7, IE-8, IE-9 or IE-10 or a pharmaceutically acceptable salt thereof, each of R13 and R13A is independently selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl; each of R1 and R2 is independently H, methyl or halogen (e.g., F); each of R3 and R4 is independently H, F, Cl, CN or methyl where the methyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, and C1-4 alkoxy ; T1 is selected from the group consisting of halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxyalkyl, C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; each of T2 and T3 is independently selected from the group consisting of H, halogen, C1-2 alkyl, C1-2 haloalkyl, C1-2 hydroxylalkyl, C1-2 alkoxy, C1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; and T4 is H. In a further embodiment, each of R13 and R13A is independently selected from the group consisting of C1-3 alkyl and cyclopropyl; each of R1 and R2 is H; R3 is H; and R4 is methyl. In yet another embodiment, the compound or a salt thereof is a compound of formula IE-1 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IE-2 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IE-3 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IE-4 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IE-5 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IE-6 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IE-7 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IE-8 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IE-9 or a salt thereof. In yet another embodiment, the compound or a salt thereof is a compound of formula IE-10 or a salt thereof.

[000115] In one embodiment, the invention also offers one or more of the compounds described in Examples 1-81 in the Examples section of the application in question, and pharmaceutically acceptable salts of the compounds or N-oxides.

[000116] An embodiment of the present invention offers a compound selected from: (-)-6-{4-[(3-cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethyl- -pyrimidine- 2,4(1H,3H)-dione; (-)-6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-5-ethyl-1-methylpyrimidine-2,4(1H,3H)-dione; (-)-1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}- -phenyl)pyrimidine-2,4(1H,3H)-dione ; (-)-6-{4-[(3-chloro-5-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 6-{4-[(3-chloro-4-methylpyridin-2-yl)oxy]phenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; (-)-6-(4-{[3-(difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; (+)-5-(4-{[3-(difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-4,6-dimethylpyridazin-3(2H)-one; 6-{4-[(3-chloropyridin-2-yl)sulfanyl]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 5-{4-[(3-chloro-4-methylpyridin-2-yl)oxy]-2-methylphenyl}-4,6-dimethyl-pyridazin-3(2H)-one; 5-{4-[(3-cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-4,6-dimethylpyridin-3(2H)-one; 5-{4-[(3-iodopyridin-2-yl)oxy]-2-methylphenyl}-4,6-dimethylpyridazin-3(2H)-one; (-)-6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 5-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-4,6-dimethylpyridazin-3(2H)-one; 5-(4-{[3-(difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)-4,6-dimethylpyridazin-3(2H)-one; 5-(4-{[4-methoxy-3-(trifluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-4,6-dimethylpyridazin-3(2H)-one; (+)-4,6-dimethyl-5-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-phenyl)pyridazin-3(2H)-one; 6-{4-[(3-cyclopropylpyridin-2-yl)oxy]phenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 6-{4-[(3-chloro-4-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethyl-pyrazin-2(1H)-one; 6-{4-[(3-chloro-4-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethyl-pyrimidin-2(1H)-one; and 1-cyclopropyl-6-(4-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylphenyl)-5-methylpyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof.

[000117] The present invention also provides compositions (e.g., pharmaceutical compositions) comprising a compound of formula I (including a pharmaceutically acceptable salt thereof). Therefore, in one embodiment, the invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) a compound of formula I (or a pharmaceutically acceptable salt thereof) and optionally comprising a pharmaceutically acceptable carrier. In a further embodiment, the invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) a compound of formula I (or a pharmaceutically acceptable salt thereof), optionally comprising a pharmaceutically acceptable carrier and, optionally, at least one active agent. additional medicinal or pharmaceutical agent (such as an antipsychotic agent or an anti-schizophrenia agent described below). In one embodiment, the additional medicinal or pharmaceutical agent is an anti-schizophrenia agent as described below.

[000118] The pharmaceutically acceptable carrier can comprise any conventional pharmaceutical carrier or excipient. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional ingredients such as flavors, binders, and excipients among others. Therefore, for oral administration, tablets containing various excipients, such as citric acid, can be used 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 magnesium stearate, 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 elixirs are desired for oral administration, the active compound contained therein may be combined with various sweetening or flavoring agents, coloring substances or pigments and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof.

[000119] The pharmaceutical composition may be, for example, in a form suitable for oral administration as a tablet, capsule, pill, powder, systemic release formulation, solution or suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

[000120] Exemplary forms of parenteral administration include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous solutions of propylene glycol or dextrose. Such dosage forms may be suitably buffered if desired.

[000121] The pharmaceutical composition can be in unit dosage forms for a single administration of precise dosages. The person skilled in the art will appreciate that the composition can be formulated in subtherapeutic dosage such that multiple doses are anticipated.

[000122] In one embodiment the composition comprises a therapeutically effective amount of a compound of formula I (or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier.

[000123] The compounds of formula I (including pharmaceutically acceptable salts thereof) are D1 modulators. In some embodiments, a compound of formula I is a D1 agonist [i.e., binding (having affinity for) and activating D1 receptors]. In some embodiments, using dopamine as a reference total D1 agonist, a compound of formula I is a superagonist (that is, a compound that is capable of producing a greater maximal response than the endogenous D1 agonist, dopamine, to a D1 receptor). D1, and therefore 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 D1 agonist (that is, having an efficacy of about 100%, e.g., 90%-100%, compared to that of dopamine). In some embodiments, using dopamine as a reference D1 full agonist, a compound of formula I is a partial agonist [i.e., a compound having only partial efficacy (i.e., less than 100%, e.g., 10%-80% or 50%-70%) on a D1 receptor relative to the full agonist, dopamine, although it binds to and activates a D1 receptor]. A D1 agonist (including superagonist, full agonist, and partial agonist) can agonize or partially agonize a D1 activity. In some embodiments, the EC50 of a compound of formula I relative to D1 is less than about 10 μM, 5 μM, 2 μM, 1 μM, 500 nM, 200 nM, 100 nM, 50, 40, 30, 20, 10, 5, 2 or 1 nM.

[000124] The present invention further provides a method for modulating (such as agonizing or partially agonizing) a D1 receptor activity (whether in vitro or in vivo), comprising contacting (including incubating) the D1 receptor with a compound of formula I (such as a compound selected from Examples 1-81) or a pharmaceutically acceptable salt thereof.

[000125] Another embodiment of the invention includes a method for treating a D1-mediated (or D1-associated) disorder, comprising administering to a mammal (e.g., a human being) in need thereof an amount of a compound of formula I (including) effective in modulating (e.g. agonizing or partial agonizing) D1.

[000126] Compounds of formula I used for treating a D1-mediated disorder also include pharmaceutically acceptable salts of the compounds.

[000127] Disorders mediated by D1 (or associated with D1) include neurological disorders [such as Tourette syndrome; tardive dyskinesia; Parkinson's disease (including, for example, cognitive impairment associated with PD); cognitive disorders {including amnesia, age-related cognitive decline, dementia [e.g., senile dementia, dementia associated with Alzheimer's disease, dementia associated with HIV, dementia associated with Huntington's disease, dementia with Lewy dementia, vascular dementia, frontotemporal dementia, drug-related dementia (e.g., dementia associated with pharmacotherapy therapy such as D2 antagonist therapy)], delirium, and cognitive impairment (e.g., cognitive impairment associated with AD or cognitive impairment associated with PD), and mild cognitive impairment}; chorea/Huntington's disease; and restless legs syndrome (RLS)]; psychiatric disorders [such as cognitive impairment (e.g., cognitive impairment associated with schizophrenia or cognitive impairment associated with pharmacotherapy therapy (e.g., D2 antagonist therapy)); anxiety (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, and obsessive-compulsive disorder); factitious disorder (including acute hallucinatory symptoms); impulse control/impulsivity disorders (including compulsive gambling and intermittent explosive disorder); mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective state, depression {e.g., age-related depression, major depression, chronic depression, seasonal depression, psychotic depression, postpartum depression, and treatment-resistant depression (TRD)}; psychomotor disorders; psychotic disorders [including schizophrenia (including, for example, cognitive and negative symptoms in schizophrenia), schizoaffective disorder, schizophreniform disorder, and delusional disorder]; substance abuse and dependence medication (including narcotic dependence, alcoholism, amphetamine dependence, cocaine dependence, nicotine dependence, and drug withdrawal syndrome); relapse into drug substance abuse, eating disorders (including anorexia, bulimia, compulsion disorder eating, overeating, hyperphagia, and pagophagia); autism spectrum disorder (e.g., autism); chronic apathy, anhedonia, chronic fatigue, seasonal affective disorder, and pediatric psychiatric disorders (including attention deficiency disorder, attention deficiency hyperactivity disorder (ADHD), conduct disorder, and autism)], endocrine disorders (such as hi - perprolactinemia) or other disorders including drowsiness, excessive daytime sleepiness, cachexia, inattention, sexual dysfunction (e.g., erectile dysfunction, post-SSRI sexual dysfunction), pain, migraine, systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, hyponatremia, resistant edema, narcolepsy, cardiovascular diseases (e.g., hypertension), congestive heart failure, postoperative ocular hypotonia, sleep disorders , and serotonin syndrome.

[000128] Another embodiment of the invention provides a method for treating neurological disorders [such as Tourette's syndrome; tardive dyskinesia; Parkinson's disease; cognitive disorders {including amnesia, senile dementia, HIV-associated dementia, Alzheimer's disease-associated dementia, Huntington's disease-associated dementia, dementia with Lewy bodies, vascular dementia, drug-related dementia (e.g., wasting cognitive impairment associated with D2 antagonist therapy), delirium, and mild cognitive impairment)}; RLS; and chorea/Huntington's disease], psychiatric disorders [such as anxiety (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive-compulsive disorder); factitious disorder (including acute hallucinatory symptoms); impulse control/impulsivity disorders (including compulsive gambling and intermittent explosive disorder); mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective state, major depression, chronic depression, seasonal depression, psychotic depression, and postpartum depression); psychomotor disorders; psychotic disorders (including schizophrenia, schizoaffective disorder, schizophreniform disorder, and delusional disorder); drug dependence (including narcotics dependence, alcoholism, amphetamine dependence, cocaine dependence, nicotine dependence, and drug withdrawal syndrome); eating disorders (including anorexia, bulimia, binge eating disorder, hyperphagia, and pagophagia); and pediatric psychiatric disorders (including attention deficiency disorder, attention deficiency hyperactivity disorder, conduct disorder, and autism)] or endocrine disorders (such as hyperprolactinemia) in a mammal, e.g. a human, comprising administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[000129] Another embodiment of the invention includes a method for treating a disorder in a mammal (for example, a human being), which method comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a salt pharmaceutically acceptable thereof, where the disorder is selected from schizophrenia (e.g., cognitive and negative symptoms in schizophrenia), 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), and mild cognitive impairment], attention deficiency hyperactivity disorder (ADHD), impulsivity, compulsive gambling, an eating disorder (e.g., anorexia, bulimia, binge eating disorder, overeating, hyperphagia, and pagophagia), autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, dementia (e.g., senile dementia, HIV-associated dementia, dementia associated with Alzheimer's disease, dementia with Lewy bodies, vascular dementia, or frontotemporal dementia), restless legs syndrome (RLS), Parkinson's disease, Huntington's chorea, anxiety, depression (e.g., age-related depression), major depressive disorder (MDD), treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, substance abuse and drug dependence, relapse into drug substance abuse, Tourette syndrome, tardive dyskinesia, somnolence, excessive daytime sleepiness, cachexia, inattentiveness, sexual dysfunction (e.g., erectile dysfunction or post-SSRI sexual dysfunction), migraine, systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis, dyslipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, hyponatremia, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotony, disorders of sleep, and pain.

[000130] Another embodiment of the invention includes a method for treating schizophrenia (e.g., cognitive and negative symptoms in schizophrenia or cognitive impairment associated with schizophrenia) or psychosis in a mammal, for example a human being, comprising administering to said mammal (e.g., a human) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[000131] Another embodiment of the invention includes a method for treating schizophrenia (e.g., cognitive and negative symptoms in schizophrenia or cognitive impairment associated with schizophrenia) in a mammal, for example a human being, comprising administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[000132] Another embodiment of the invention includes a method for treating cognitive impairment [e.g., cognitive impairment associated with schizophrenia, cognitive impairment associated with AD, or cognitive impairment associated with PD] in a mammal, for example a human being, comprising administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[000133] Another embodiment of the invention includes a method for the treatment of AD (e.g., for the treatment of cognitive impairment associated with AD), PD (e.g., for the treatment of cognitive impairment associated with PD), RLS, depression or MDD in a mammal, for example a human being, comprising administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[000134] The term "therapeutically effective amount" as used in this report refers to that amount of the compound (including) being administered that alleviates to some extent one or more of the symptoms of the disorder being treated. In relation to the treatment of a D1-mediated disorder (e.g., schizophrenia), a therapeutically effective amount refers to that amount that has the effect of alleviating to some extent (or, e.g., eliminating) one or more symptoms associated with a D1-mediated disorder (e.g., schizophrenia or cognitive and negative symptoms in schizophrenia or cognitive impairment associated with schizophrenia).

[000135] The term "treat", as used in this report, unless otherwise indicated, means to reverse, alleviate, inhibit the progression of or prevent the disorder or condition to which the term applies or one or more symptoms of such disorder or condition. The term "treatment" as used in this report, unless otherwise indicated, refers to the act of treating as "treating" is defined. The term "treat" also includes adjuvant and neoadjuvant treatment of an individual.

[000136] The administration of compounds of formula I can be carried out by any method that allows the distribution of the compounds to the site of action. These methods include oral routes, intranasal routes, inhaled routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

[000137] In one embodiment of the present invention, compounds of formula I can be administered/taken orally.

[000138] Dosage regimens can be adjusted to give the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionately reduced or increased as indicated by the demands of the therapeutic situation. It may be advantageous to formulate parenteral compositions in a unit dosage form for ease of administration and for uniformity of dosage. Dosage unit form, as used in this report, refers to physically distinct units suitable as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications 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 obtained. In one embodiment of the present invention, compounds of formula I can be used to treat humans.

[000139] It should be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include a single dose or multiple doses. It should further be understood that for any particular individual, specific dosage regimens should be adjusted from time to time in accordance with the individual need and professional discretion of those administering or supervising the administration of the compositions, and that the dosage ranges stipulated herein are only intended. are exemplary and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Therefore, the present invention encompasses intrapatient dose escalation as determined by one skilled in the art. The determination of appropriate dosages and regimens for administration of the chemotherapeutic agent is well known in the relevant literature and should be considered within the knowledge of those skilled in the art once the teachings disclosed in this invention have been given.

[000140] The amount of the compound of formula I or a pharmaceutically acceptable salt thereof administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the availability of the compound and the discretion of the attending physician. Generally, an effective dosage ranges from about 0.0001 to about 50 mg per kg of body weight per day, for example about 0.01 to about 10 mg/kg/day, in a single dose or in 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. In some cases, dosage levels lower than the lower limit of the range mentioned above may be more appropriate, while in other cases even higher doses can be employed without causing any harmful side effects, given that such higher doses are first fractionated into several small doses to be administered throughout the day.

[000141] As used in this report, the term "combination therapy" refers to the administration of a compound of formula I or a pharmaceutically acceptable salt thereof together with at least one additional pharmaceutical or medicinal agent (for example, an agent against schizophrenia ), either sequentially or simultaneously.

[000142] The present invention includes the use of a combination of a compound of formula I (or a pharmaceutically acceptable salt thereof) and one or more additional pharmaceutically active agents. If a combination of active agents is administered, then they can be administered sequentially or simultaneously, in separate dosage forms or combined into a single dosage form. Accordingly, the present invention also includes pharmaceutical compositions comprising an amount of: (a) a first agent comprising a compound of formula I (including an N-oxide thereof or a pharmaceutically acceptable salt of the compound or the N-oxide); (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle or diluent.

[000143] Various pharmaceutically active agents can be selected for use in conjunction with compounds of formula I (including pharmaceutically acceptable salts thereof), depending on the disease, disorder or condition to be treated. Pharmaceutically active agents that can be used in combination with the compositions of the present invention include, without limitation: a. acetylcholinesterase inhibitors such as donepezil hydrochloride (ARICEPT, MEMAC); or A2A adenosine receptor antagonists such as Preladenant (SCH 420814) or SCH 412348; B. amyloid-β (or fragments thereof), such as Aβi-15 conjugated to the pan HLA DR binding epitope (PADRE) and ACC-001 (Elan/Wyeth); w. antibodies to amyloid-β (or fragments thereof), such as bapineuzumab (also known as AAB-001) and AAB-002 (Wyeth/Elan); d. amyloid-lowering or inhibitory agents (including those that reduce amyloid production, accumulation and fibrillization) such as colostrinin and bisnorcymserine (also known as BNC); It is. alpha-adrenergic receptor agonists such as clonidine (CATAPRES); f. beta-adrenergic receptor blocking agents (beta blockers) such as carteolol; g. anticholinergics such as amitriptyline (ELAVIL, ENDEP); H. anticonvulsants such as carbamazepine (TEGRETOL, CARBATROL); i. antipsychotics, such as lurasidone (also known as SM-13496; Dainippon Sumitomo); j. calcium channel blockers such as nilvadipine (ESCOR, NIVADIL); k. catechol O-methyltransferase (COMT) inhibitors such as tolcapone (TASMAR); l. central nervous system stimulants such as caffeine; m. corticosteroids such as prednisone (STERAPRED, DELTASONE); n. dopamine receptor agonists such as apomorphine (APOKYN); O. dopamine receptor antagonists such as tetrabenazine (NITOMAN, XENAZINE, dopamine D2 antagonists such as Quetiapine); P. dopamine reuptake inhibitors such as nomifensine maleate (MERITAL); q. gamma-aminobutyric acid (GABA) receptor agonists such as baclofen (LIORESAL, KEMSTRO); r. histamine 3 (H3) antagonists such as ciproxifan; s. immunomodulators such as glatiramer acetate (also known as copolymer-1; COPAXONE); t. immunosuppressants such as methotrexate (TREXALL, RHEUMATREX); u. interferons, including interferon beta-1a (AVONEX, REBIF) and interferon beta-1b (BETASERON, BETAFERON); v. levodopa (or its methyl or ethyl ester), alone or in combination with a DOPA decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA)); w. N-methyl-D-aspartate (NMDA) receptor antagonists such as memantine (NAMENDA, AXURA, EBIXA); x. monoamine oxidase (MAO) inhibitors such as selegiline (EMSAM); y. muscarinic receptor agonists (particularly the M1 subtype) such as betanochol chloride (DUVOID, URECHOLINE); z. neuroprotective drugs such as 2,3,4,9-tetrahydro-1H-carbazol-3-one oxime; aa. nicotinic receptor agonists such as epibatidine; bb. norepinephrine (noradrenaline) reabsorption inhibitors such as atomoxetine (STRATTERA); cc. phosphodiesterase (PDE) inhibitors, for example, PDE9 inhibitors such as BAY 73-6691 (Bayer AG) and PDE 10 inhibitors (for example PDE10A) such as papaverine; dd. 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)); and is. quinolines such as quinine (including its hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate salts); ff. β-secretase inhibitors such as WY-25105; gg. γ-secretase inhibitors such as LY-411575 (Lilly); hh. serotonin (5-hydroxytryptamine) 1A (5-HT1A) receptor antagonists such as spiperone; ii. serotonin (5-hydroxytryptamine)4 (5-HT4) receptor agonists such as PRX-03140 (Epix); jj. serotonin (5-hydroxytryptamine) 6 (5-HT6) receptor antagonists such as mianserin (TORVOL, BOLVIDON, NORVAL); kk. serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram (CELEXA, CIPRAMIL); ll. trophic factors, such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3), cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin , meteorin, and glial cell-derived neurotrophic factor (GDNF), and agents that stimulate the production of trophic factors, such as propentofylline; between others.

[000144] The compound of formula I (including a pharmaceutically acceptable salt thereof) is optionally used in combination with another active agent. Such an active agent may be, for example, an atypical antipsychotype agent or an agent against Parkinson's disease or an agent against Alzheimer's disease. Accordingly, another embodiment of the invention provides methods for treating a D1-mediated disorder (e.g., a D1-associated psychiatric neurological disorder), comprising administering to a mammal an effective amount of a compound of formula I (including an N -oxide thereof or a pharmaceutically acceptable salt of the compound or N-oxide) and further comprising administering another active agent.

[000145] As used in this report, the term "another active agent" refers to any therapeutic agent, other than the compound of formula I (including or a pharmaceutically acceptable salt thereof) that is useful for treating a disorder in an individual. Examples of additional therapeutic agents include antidepressants, antipsychotics (such as agents against schizophrenia), agents against pain, agents against Parkinson's disease, agents against LID (levodopa-induced dyskinesia), agents against Alzheimer's disease, and agents against anxiety. Examples of particular classes of antidepressants that can be used in combination with the compounds of the invention include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs). ), reversible monoamine oxidase inhibitors (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, a-adrenoceptor 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, buttriptyline, iprindole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Examples of suitable selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine, and sertraline. Examples of suitable monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcyclopramine. Examples of suitable reversible monoamine oxidase inhibitors include moclobemide. Examples of serotonin and norepinephrine reuptake inhibitors suitable for use in the present invention include venlafaxine. Examples of suitable atypical antidepressants include bupropion, lithium, nefazodone, Trazodone and viloxazine. Examples of agents against Alzheimer's disease include Dimebon, NMDA receptor antagonists such as memantine; and cholinesterase inhibitors such as donepezil and galantamine. Examples of suitable classes of anxiolytic agents that can be used in combination with the compounds of the invention include benzodiazepines and serotonin 1A (5-HT1A) agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. ). Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam. Suitable 5-HT1A receptor agonists or antagonists include buspirone, flesinoxan, gepirone, and ipsapirone. Suitable atypical antipsychotics include paliperidone, bifeprunox, ziprasidone, risperidone, aripiprazole, olanzapine, and quetiapine. Suitable nicotine acetylcholine agonists include ispronicline, varenicline and MEM 3454. Anti-pain agents include pregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam, ketamine and ziconotide. Examples of suitable 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 420814) or SCH 412348], benserazide (MADOPAR), α-methyldopa, monofluoromethyldopa, difluoromethyldopa, brocresine or m-hydroxybenzylhydrazine), a dopamine agonist [such as apomorphine (APOKYN), bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydroxyxidine, dihydroergocriptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN), pergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, ropinirole ( REQUIP), rotigotine (NEUPRO), SKF-82958 (GlaxoSmithKline), 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, desoxypeganine, harmine (also known as telepatin 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 N-methyl-D-aspartate (NMDA) receptor antagonist [such as amantadine (SYMMETREL)], anticholinergics [such as amitriptyline (ELAVIL, ENDEP), buttriptyline, 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, OXITROL), penthienate bromide, propantheline (PRO- BANTHINE), cyclizine, imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), trimipramine (SURMONTIL), and glycopyrrolate (ROBINUL)] or a combination thereof. Examples of agents against schizophrenia include ziprasidone, risperidone, olanzapine, quetiapine, aripiprazole, asenapine, blonanserin, or iloperidone.

[000146] As noted above, the compounds of formula I (including pharmaceutically acceptable salts thereof) can be used in combination with one or more additional anti-schizophrenia agents that are described in this report. When a combination therapy is used, the one or more additional anti-schizophrenia agents can 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 of the invention. In another embodiment, the additional anti-schizophrenia agent is administered to the mammal (e.g., a human) simultaneously with administration of the compound of the invention (or an N-oxide thereof or a pharmaceutically acceptable salt thereof).

[000147] The invention also provides a pharmaceutical composition for the treatment of schizophrenia in a mammal, including a human being, which comprises an amount of a compound of formula I (or a pharmaceutically acceptable salt thereof), already defined above (including hydrates , solvates and polymorphs of said compound or pharmaceutically acceptable salts thereof), in combination with one or more (e.g. one to three) agents against schizophrenia such as ziprasidone, risperidone, olanzapine, quetiapine, aripiprazole, asenapine, blonanserin or iloperidone , where the amounts of the active agent and the combination when taken as a whole are therapeutically effective for treating schizophrenia.

[000148] The invention also provides a pharmaceutical composition for the treatment of Parkinson's disease in a mammal (including cognitive impairment associated with PD), including a human being, comprising an amount of a compound of formula I (or a salt pharmaceutically acceptable thereof), already defined above (including hydrates, solvates and polymorphs of said compound or pharmaceutically acceptable salts thereof), in combination with one or more (for example one to three) agents against Parkinson's disease such as L-DOPA, where the amounts of the active agent and the combination when taken as a whole are therapeutically effective for treating Parkinson's disease.

[000149] It will be understood that the compounds of formula I represented above are not limited to a particular stereoisomer (e.g. enantiomer or atropisomer) shown, but also include all stereoisomers and mixtures thereof.

Detailed Description of the Invention

[000150] The compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of the numerous possible synthesis routes.

[000151] The reactions to prepare the compounds of the invention can be carried out in suitable solvents, which can be easily selected by the person skilled in the art of organic synthesis. Suitable solvents may be substantially non-reactive with the starting materials (reagents), intermediates or products at the temperatures at which the reactions are carried out, for example, temperatures ranging from the freezing temperature of the solvent to the temperature of boiling of the solvent. A given reaction can be carried out in one solvent or in a mixture of more than one solvent. Depending on the particular reaction step, solvents suitable for a particular reaction step can be selected by the person skilled in the art.

[000152] The preparation of the compounds of the invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the choice of appropriate protecting groups, can be easily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein in its entirety in reference title.

[000153] Reactions can be monitored according to any suitable method known in the literature. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV visible), mass spectrometry, or by chromatographic methods. such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[000154] The compounds of formula I and intermediates thereof can be prepared according to the following reaction schemes and the discussion that accompanies them. Unless otherwise indicated, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R10B, R11, R11A, T1, T2, T3, T4, Q1, and X1, and the structural formula I in the reaction schemes and discussion that follow have the definitions given above. In general, the compounds of this invention can be made by processes that include processes analogous to those known in the chemical arts, particularly in light of the description given in this report. Certain processes for producing the compounds of this invention and intermediates thereof are given as additional aspects of the invention and are illustrated by the following reaction schemes. Other processes are described in the experimental section. The schemes and examples given in this report (including the corresponding description) are given for illustrative purposes only, and are not intended to limit the scope of the present invention. Scheme 1

[000155] Scheme 1 relates to the preparation of compounds of formula 1-5 (that is, compounds of formula I where L1 is O). With reference to Scheme 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 [where Z1 may be, e.g., halogen (e.g., Br or I) or trifluoromethanesulfonate (triflate)] are commercially available or can be made by methods described in this report or by 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. Coupling can be effected, for example, by heating a mixture of a compound of formula 1-1 with a compound of formula 1-2 in the presence of a base, such as Cs2CO3, in a suitable solvent, such as dimethyl sulfoxide ( DMSO). Alternatively, a catalyst-metal coupling (such as using a palladium or copper-based catalyst) can be employed to effect the aforementioned coupling. In this variant of coupling, a mixture of a compound of formula 1-1 and a compound of formula 1-2 may be heated in the presence of a base (such as Cs2CO3), a metal-based catalyst [such as a -palladium-based lyser, e.g., Pd(OAc)2], and a ligand [such as 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphane) (BINAP)] in an appropriate solvent, such as 1,4-dioxane. A compound of formula 1-3 can be subsequently reacted with a compound of formula Q1-Z2 [where Z2 can be Br; B(OH)2; B(OR)2 where each R is independently H or C1-6 alkyl or where 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 plus C1-6 alkyl; a trialkyltin portion; or similar] by a metal-catalyzed coupling reaction (such as using a palladium-based catalyst) to obtain a compound of formula I. Compounds of formula Q1-Z2 are commercially available or can be made by methods described in this report or by methods analogous to those described in the chemical literature. Alternatively, a compound of formula 1-3 can be converted to a compound of formula 1-4 (where Z2 is as already defined above). For example, a compound of formula 1-3 (where Z1 is halogen such as Br or I) can be converted to a compound of formula 1-4 [where Z2 is B(OH)2; B(OR)2 where each R is independently H or C1-6 alkyl or where the two groups (OR), 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 in this report or other methods known to those skilled in the art. In this example, this reaction can be carried out, for example, by reacting a compound of formula 1-3 (where Z1 is halogen such as Br) with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane, a suitable base (such as potassium acetate), and a palladium-based catalyst {such as [1,1'-bis( diphenylphosphine)ferrocene]dichloropalladium (II)} in a suitable solvent such as 1,4-dioxane. In another example, a compound of formula 1-3 (where Z1 is a halogen such as Br) can be converted to a compound of formula 1-4 (where Z2 is a trialkyltin moiety) by alternative methods described in this report or other known methods. by experts in the art. In this example, this reaction can be carried out, for example, by reacting a compound of formula 1-3 (where Z1 is halogen such as Br) with a hexaalkyldiestane (such as hexamethyldiestane) in the presence of a palladium-based 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 (where Z1 is as already defined above) by a metal-catalyzed coupling reaction (such as using a palladium-based catalyst) to obtain a compound of formula l. Compounds of formula Q1-Z1 are commercially available or can be made by methods described in this report or by methods analogous to those described in the chemical literature. The type of reaction used depends on the choice of Z1 and Z2. For example, when Z1 is halogen or triflate and the reactant Q1-Z2 is a boronic acid or boronic ester, a Suzuki reaction can be used [A. Suzuki, J. Organomet. Chem. 1999, 576, 147-168; N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457-2483; AF Littke et al., J. Am. Chem. Soc. 2000, 122, 40204028]. In some specific 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-based catalyst is added, such as the precatalyst S-Phos {also known as chloro(2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl)[2- (2 -aminoethylphenyl)] palladium (II) - tert-butyl methyl ether adduct }, and the reaction mixture is heated. Alternatively, when Z1 is halogen or triflate and Z2 is trialkyltin, a Stille coupling can be employed [V. Farina et al., Organic Reactions 1997, 50, 1-652]. More specifically, a compound of formula 1-3 (where Z1 is Br, I or triflate) can be combined with a compound of formula Q1-Z2 (where compound Q1-Z2 is a compound of the Q1-stannan type) in the presence of a palladium-based catalyst, such as dichloro-bis(triphenylphosphine) palladium (II), in a suitable organic solvent such as toluene, and the reaction can be heated. Where Z1 is Br, I or triflate and Z2 is Br or I, a Negishi coupling can be used [E. Erdik, Tetrahedron 1992, 48, 9577-9648]. More specifically, a compound of formula 1-3 (where Z1 is Br, I or triflate) can be transmetallated by treatment with 1 to 1.1 equivalents of an alkyl lithium-based reagent followed by a solution of 1.2 to 1.4 equivalents of lithium chloride. zinc in a suitable solvent such as THF at a temperature ranging from -80°C to -65°C. After heating to a temperature between 10°C and 30°C, the reaction mixture was treated with a compound of formula Q1-Z2 (where Z2 is Br or I), and heated to a temperature of 50°C to 70°C with addition of catalyst such as tetrakis(triphenylphosphine)palladium (0). The reaction can be carried out for periods ranging from 1 to 24 hours to give the compound of formula 1-5. Scheme 1'

[000156] Similar to the chemical transformations described in Scheme 1, compounds of formula I can be prepared starting from compounds of formula 1'-3 according to Scheme 1' Scheme 2

[000157] Scheme 2 also refers to the preparation of compounds of formula 1-5. With reference to Scheme 2, compounds of formula 1-5 can be prepared using chemical transformations analogous to those described in Scheme 1, but with a different order of steps. Compounds of formula 2-1 [where Pg1 is a suitable protecting group such as methyl, benzyl, tetrahydropyranyl (THP) or tert-butyldimethyl (TBS)] are commercially available or can be made by methods described in this report or other methods 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 can be then deprotected, using appropriate conditions depending on the choice of 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 give a compound of formula 1-5 . The coupling conditions employed may be analogous to those described for the preparation of a compound of formula 1-3 in Scheme 1. Scheme 3

[000158] Scheme 3 refers to the preparation of a compound of formula 3-5 where A1 is a moiety of formula A1a or or a suitable protecting group Pg2. (e.g. methyl, benzyl, THP or TBS). Referring to Scheme 3, compounds of formula 3-1 are commercially available or can be made by methods described herein or other methods known to those skilled in the art. A compound of formula 3-2 can be prepared by reacting an aryl ketone 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 by treatment with formaldehyde (or its equivalent such as metaformaldehyde or polyformaldehyde) in the presence of an acid (such as an aqueous solution of hydrochloric acid). Those of formula 3-3 can be reacted with glycinamide or a salt thereof (such as an acetic acid salt) 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 treating a compound of formula 3-4 with a base [such as lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LHMDS ), among others] and a compound of formula R11A-Z3 [where Z3 is an acceptable leaving group such as Cl, Br, I, methanesulfonate (mesylate), among others and where R11A is for example C1-3 alkyl (e.g. methyl)]. Suitable solvents for the reaction can be selected from polar aprotic solvents such as N,N-dimethylformamide (DMF), 1,4-dioxane or THF. Scheme 4

[000159] Alternatively, a compound of formula 3-5 can be prepared as described in Scheme 4 where L1 is O, NH, N(C1-4 alkyl) and N(C3-6 cycloalkyl). Referring to Scheme 4, compounds of formula 4-1 and 4-2 are commercially available or can be made by methods described herein or other methods known to those skilled in the art. A compound of formula 43 can be prepared by coupling a compound of formula 41 with a compound of formula 4-2. The aforementioned coupling may be effected 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 ethanol). A compound of formula 4-3 can be reacted with maleic anhydrous and hydrogen peroxide in a solvent (such as dichloromethane) to give a compound of formula 4-4, which may contain a mixture of N-oxide regioisomers. A compound of formula 4-5 can be prepared from a compound of formula 4-4 by heating with acetic anhydride; The starting product can be saponified 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 among others), lithium bromide, and a compound of formula R11A-Z3 (where Z3 is an acceptable leaving group such as Cl, Br, I, mesylate, among others). Suitable solvents for the reaction can typically be selected from polar aprotic solvents (such as DMF, 1,4-dioxane or THF). Scheme 5

[000160] Scheme 5 refers to the preparation of a compound of formula 5-5 where L1 is O, NH, N(C1-4 alkyl) and N(C3-6 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 5-2 are commercially available or can be made by methods described in this report or other methods 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 aforementioned coupling may be effected 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 acetate palladium (II)], optionally a suitable ligand (such as tricyclohexylphosphine), and optionally a suitable phase transfer catalyst such as tetrabutylammonium chloride. Suitable solvents for the reaction can typically 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 equivalents of a suitable base [such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)] in an oxygen atmosphere to obtain a compound of formula 5-4. Suitable solvents for the reaction can typically 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

[000161] Scheme 6 refers to the preparation of a compound of formula 6-5. Referring to Scheme 6, a compound of formula 6-1 can be prepared in the manner described in Scheme 5, where Pg2 is a suitable protecting group (such as benzyl). A compound of formula 6-1 can be converted to a suitably protected compound of formula 6-2 using methods described in this report or other methods known to those skilled in the art, wherein Pg3 is a suitable protecting group (such as THP) that can be removed. under orthogonal reaction conditions to Pg2. A compound of formula 6-3 can be prepared by selective removal of Pg2 under suitable deprotection conditions depending on the choice of Pg2. For example, when Pg2 is a benzyl group, it can be removed by treatment with palladium (10% on carbon) under hydrogenation conditions in a suitable solvent, such as methanol and ethyl acetate. Using the above-mentioned reaction conditions described in Scheme 1, a compound of formula 6-3 can be coupled with a reagent of formula 1-1 to give 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 choice 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

[000162] Scheme 7 refers to the preparation of a compound of formula 7-5 [where R10 is, for example, C1-3 alkyl (for example, methyl); R10B is, for example, H or C1-3 alkyl (e.g. methyl); and Pg4 is a suitable protecting group [e.g., 2-(trimethylsilyl)ethoxymethyl (SEM), tert-butoxycarbonyl (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 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(diphenylphosphine)ferrocene]dichloropalladium (II)}. A compound of formula 7-3 can be prepared by selective removal of Pg2 under suitable deprotection conditions depending on the choice of Pg2. For example, when Pg2 is a benzyl group, it can be removed by treatment with palladium (10% on carbon) under hydrogenation conditions in a suitable solvent, such as methanol and ethyl acetate. Using the above-mentioned reaction conditions described in Scheme 1, a compound of formula 7-3 can be coupled with a reagent of formula 1-1 to give a compound of formula 7-4. Alternatively, a compound of formula 7-4 can be prepared from intermediate 1-4 by 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

[000163] Scheme 8 refers to the preparation of a compound of formula 8-1 [where R10 is, for example, C1-3 alkyl (for example, methyl); R10B is, for example, H or C1-3 alkyl (e.g. methyl)]. Referring to Scheme 8, compounds of formula 8-1 can be prepared by treating a compound of formula 7-5 with a suitable thiannating reagent, such as Lawesson's reagent [2,4-bis(4). -methoxyphenyl)-1,3,2,4-dithiadiphosphetan-2,4-dithion] or phosphorus pentasulfide, in a suitable solvent such as toluene. Scheme 9

[000164] Scheme 9 refers to the preparation of compounds of formula 9-5 and 9-6. Referring to Scheme 9, compounds of formula 9-1 are commercially available or can be made by methods described herein or other methods known to those skilled in the art. A compound of formula 9-1 can be converted to a compound of formula 9-2 either directly or after conversion to a compound of formula 9-3 using methods analogous to those described in Scheme 1. The nitro group of a compound of formula 9 -2 can then be converted to an amine via hydrogenation in the presence of a suitable catalyst, such as palladium (10% on carbon), to give a compound of formula 9-4. A compound of formula 9-4 can then be coupled with a compound of formula 1-1 in Scheme 1 to give a compound of formula 9-5. The coupling conditions employed may be analogous to those described for the preparation of a compound of formula 1-3 in Scheme 1. A compound of formula 9-6 may be prepared via N-alkylation of a compound of formula 9-5 using a reagent of Y-Z3, where Y is C1-4 alkyl or C3-6 cycloalkyl, and Z3 is an acceptable leaving group such as Cl, Br, I, mesylate, among others. Scheme 10

[000165] Scheme 10 refers to the preparation of compounds of formula 10-4. Referring to Scheme 10, a compound of formula 10-1 can be prepared via triflation of a compound of formula 24 (Scheme 2) using a suitable reagent such as trifluoromethanesulfonic anhydride in the presence of a suitable base such as triethylamine. A compound of formula 10-1 can be converted to a compound of formula 10-2 by coupling with potassium thioacetate, in the presence of a suitable metal-based catalyst, such as tris(dibenzylideneacetone)dipalladium(0), and a ligand suitable, such as (R)-(-)-1-[(SP)-2-(dicyclohexylphosphine)ferrocenyl]ethyldi-tert-butylphosphine, in a suitable solvent, such as toluene. A compound of formula 10-2 can then be hydrolyzed to obtain a compound of formula 10-3, which in turn can be coupled with a compound of formula 1-1 in Scheme 1 to give a compound of formula 104. The conditions of Coupling employed may be analogous to those described for the preparation of a compound of formula 1-3 in Scheme 1. A compound of formula 10-4 may then be deprotected, using appropriate conditions depending on the choice of the Pg1 group, to obtain a compound of formula I.

[000166] Additional starting materials and intermediates useful for making the compounds of the present invention can be purchased from chemical sellers such as Sigma-Aldrich or can be made according to methods described in the chemical literature.

[000167] Those skilled in the art will recognize that all schemes described in this report, if there are functional (reactive) groups present in a part of the structure of the compound such as a substituent group, for example R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R10B, R11, R11A, T1, T2, T3, T4, Q1, and X1 etc. other modifications may be made if appropriate and/or desired, using methods well known to those skilled in the art. For example, a -CN group can be hydrolyzed to give 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. As another example, an OH group can be converted into a better displacing group such as methanesulfonate, which in turn is suitable for nucleophilic substitution, such as by cyanide ion (CN-). As another example, an -S- can be oxidized to -S(=O)- and/or -S(=O)2-. As yet another example, an unsaturated bond such as C=C or C=C can be reduced to a saturated bond by hydrogenation. In some embodiments, a primary amine moiety or a secondary amine moiety (present in a substituent group such as R3, R4, R9, R10, etc.) can be converted into an amide, sulfonamide, urea or thiourea moiety by reacting the same with a suitable reagent such as an acid chloride, a sulfonyl chloride, an isocyanate or an isocyanate-type compound. One skilled in the art will recognize other such modifications. Therefore, a compound of formula I having a substituent containing a functional group can be converted into another compound of formula I having a different substituent group.

[000168] Similarly, those skilled in the art can also recognize that in all schemes described in this report, if there are functional (reactive) groups present on a substituent group such as R3, R4, R9, R10, etc., these groups Functionals may be protected/deprotected in the course of the synthetic scheme described herein, 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 at a later stage in the synthesis process. As another example, an NH2 group can be protected by a benzyloxycarbonyl (Cbz) or Boc group; the conversion back to the NH2 group can be carried out at a later stage of the synthesis process via deprotection.

[000169] As used in this report, the term "react" (or "reaction" or "reacted") refers to bringing together designated chemical reagents so that a chemical transformation occurs generating a compound different from any of those initially introduced into the system. Reactions can occur in the presence or absence of solvent.

[000170] Compounds of formula I can 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 solution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, 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 tartaric acid or 1- phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization and one or both diastereomers converted to the corresponding pure enantiomers by means well known to the person skilled in the art. Chiral compounds of formula I (and chiral precursors thereof) can be obtained in an 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 2% to 20%, and 0% to 5% an alkylamine, typically 0.1% diethylamine. Concentration of the eluate gives the enriched mixture. Stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994), the description of which is incorporated herein in its entirety by reference. Suitable stereoselective techniques are well known to those skilled in the art.

[000171] Where a compound of formula I contains an alkenyl or alkenylene (alkylidene) group, geometric cis/trans (or Z/E) isomers are possible. cis/trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. The salts of the present invention can be prepared according to methods well known to those skilled in the art.

[000172] 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 animals, it is generally desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert it back to the free base-type compound by treatment. with an alkaline reagent and subsequently converting this latter free base into a pharmaceutically acceptable acid addition salt. Acid addition salts of the basic compounds of this invention can be prepared by treating the basic compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic to the solution.

[000173] If the inventive compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the literature, for example, treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid , sulfuric acid, nitric acid, and phosphoric acid among others 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, salicyclic, isonicotinic acid, lactic acid, pantothenic acid, bitartharic acid, ascorbic acid, 2,5-dihydroxybenzoic acid, gluconic acid, saccharic acid, formic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, and pamoic acid [i.e., 4,4'-methanediylbis(3-hydroxynaphthalene-2-carboxylic acid)], a pyranosidylic acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, a sulfonic acid such as ethanesulfonic acid or the like.

[000174] 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 metal or alkaline earth metal salts, and particularly the sodium and potassium salts. All these salts are prepared by conventional techniques. The chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those that form non-toxic base salts with the acidic compounds of formula I. These salts may be prepared by any suitable method, for example, treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide or similar. These salts can also be prepared by treating the corresponding acid compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, for example under reduced pressure. Alternatively, they can also be prepared by mixing lower alkanolic solutions of the acid compounds and the desired alkali metal alkoxide with each other, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reactants are, for example, employed to ensure completion of the reaction and maximum yields of the desired final product.

[000175] Pharmaceutically acceptable salts of compounds of formula I (including compounds of formula Ia or Ib) can be prepared by one or more of three methods: a. by reacting the compound of formula I with the desired acid or base; B. by removing the labile acid or base protecting group from a suitable precursor of the compound of formula I or by ring opening a suitable cyclic precursor, for example, the lactone or lactam, using the desired acid or base; or c. by converting one salt of the compound of formula I into another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[000176] All three reactions are typically carried out in solution. The resulting salt may precipitate and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to practically non-ionized.

[000177] Polymorphs can be prepared according to techniques well known to those skilled in the art, for example, by crystallization.

[000178] When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemic) mentioned above where a homogeneous crystal form containing both enantiomers in equimolar amounts is produced. The second type is the racemic mixture or conglomerate where two crystal forms are produced in equimolar quantities, each comprising a single enantiomer.

[000179] Although the two crystal forms present in a racemic mixture may have almost identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eli-el and S. H. Wilen (Wiley, New York, 1994).

[000180] The invention also includes isotopically labeled compounds of formula I where one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass 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 N-oxides thereof) generally can be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in this report, using an appropriate isotopically labeled reagent in place of the unmarked reagent otherwise used.

[000181] The prodrugs according to the invention can be produced, for example, by replacing the appropriate functionalities present 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).

[000182] Compounds of formula I must be evaluated for their biopharmaceutical properties, such as solubility and stability in solution (through pH), permeability, etc., to select the most appropriate dosage form and route of administration for treatment of the proposed indication.

[000183] The compounds of the invention intended for pharmaceutical use can be administered as crystalline or amorphous products. They can be obtained, for example, as solid buffers, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying. Microwave or radio frequency drying can be used for this purpose.

[000184] They can 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 in this report to describe any principle other than the compounds of the invention. The choice of excipient will depend largely 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.

[000185] Pharmaceutical compositions suitable for delivering compounds of the present 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 can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

[000186] The compounds of the invention (including pharmaceutically acceptable salts thereof and N-oxides thereof) can be administered orally. Oral administration may involve swallowing, whereby the compound enters the gastrointestinal tract, and/or buccal, lingual or sublingual administration whereby the compound enters the bloodstream directly from the mouth.

[000187] Formulations suitable for oral administration include solid, semisolid and liquid systems such as tablets; soft or hard capsules containing multiparticulates or nanoparticulates, liquids or powders; tablets (including liquid-filled); ways of chewing; gels; fast dispersion dosage forms; films; eggs; sprays; and mouth/mucoadhesive plasters.

[000188] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, of gelatin or hydroxypropyl methyl cellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose. or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, from a sachet.

[000189] The compounds of the invention can also be used in fast-dissolving and fast-disintegrating dosage forms such as those described by Liang and Chen, Expert Opinion in Therapeutic Patents 2001, 11, 981-986.

[000190] For tablet dosage forms, depending on the dose, the drug may constitute from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form. In addition to the drug, tablets usually 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% by weight to 25% by weight, for example, from 5% by weight to 20% by weight of the dosage form.

[000191] Binders are generally used to impart cohesive qualities 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, among others), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[000192] The tablets may also optionally contain surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surfactants may comprise from 0.2% by weight to 5% by weight of the tablet, and glidants may comprise from 0.2% by weight to 1% by weight of the tablet.

[000193] The tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25% by weight to 10% by weight, for example, from 0.5% by weight to 3% by weight of the tablet.

[000194] Other possible ingredients include antioxidants, coloring, flavoring agents, preservatives and flavor masking agents.

[000195] Exemplary tablets contain up to about 80% drug, from about 10% by weight to about 90% by weight binder, from about 0% by weight to about 85% by weight diluent, from about from 2% by weight to about 10% by weight disintegrant, and from about 0.25% by weight to about 10% by weight lubricant.

[000196] Tablet mixtures can be pressed directly or by a cylinder to form tablets. Tablet mixtures or portions of mixtures may alternatively be wet granulated, dry granulated or melt granulated, melt solidified or extruded before tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it can even be encapsulated.

[000197] The tablet formulation is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[000198] Consumable oral films for human or veterinary use are typically water-soluble or water-swellable malleable thin film dosage forms that can be rapidly dissolved or mucoadhesive and typically comprise a compound of formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifying agent and a solvent. Some components of the formulation may perform more than one function.

[000199] The compound of formula I (or pharmaceutically acceptable salts thereof or N-oxides thereof) may be soluble or insoluble in water. A water-soluble compound typically comprises from 1% by weight to 80% by weight, more typically from 20% by weight to 50% by weight, of the solutes. Less soluble compounds may comprise a smaller proportion of the composition, typically up to 30% by weight of the solutes. Alternatively, the compound of formula I may be in the form of multiparticulate globules.

[000200] The film-forming polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is typically present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight.

[000201] Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, salivary flow stimulating agents, cooling agents, cosolvents (including oils), emollients, bulking agents, antifoaming agents, surfactants and chewing agents of flavor.

[000202] The films according to the invention are typically prepared by evaporative drying of thin aqueous films applied to a detachable secondary support or paper. This can be done in an oven or drying tunnel, typically a combined coater and dryer, or by freeze or vacuum drying.

[000203] Solid formulations for oral administration can be formulated for immediate and/or modified release. Modified-release formulations include delayed, systematic, pulsed, controlled, vectored, and programmed release.

[000204] Modified release formulations suitable 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 can be found in Verma et al., Pharmaceutical Technology Online, 25(2), 1-14 (2001). The use of chewing gum to obtain controlled release is described in document WO 00/35298.

[000205] The compounds of the invention (including pharmaceutically acceptable salts thereof) can also be administered directly into the bloodstream, muscle or an internal organ. Suitable media for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous media. Devices suitable for parenteral administration include needle injectors (including microneedle), needleless injectors and infusion techniques.

[000206] Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (for example to obtain a pH of 3 to 9), but, for some applications, they can be formulated more appropriately as a sterile non-aqueous solution or as a dry form to be used in conjunction with a suitable vehicle such as sterile pyrogen-free water.

[000207] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be easily carried out using traditional pharmaceutical techniques well known to those skilled in the art.

[000208] The solubility of compounds of formula I (including pharmaceutically acceptable salts thereof) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

[000209] Formulations for parenteral administration can be formulated for immediate and/or modified release. Modified-release formulations include delayed, systematic, pulsed, controlled, vectored, and programmed release. Accordingly, the compounds of the invention can be formulated as a suspension or as a solid, semisolid or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of formulations include drug-coated and semisolid stents and suspensions comprising drug-loaded poly(DL-lactic-coglycolic acid) (PLGA) microspheres.

[000210] The compounds of the invention (including pharmaceutically acceptable salts thereof) can also be administered topically, (intra)dermally or transdermally to the skin or mucosa. Typical formulations for this include gels, hydrogels, lotions, solutions, creams, ointments, powders, bandages, foams, films, skin plasters, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated. See, for example, Finnin and Morgan, J. Pharm. Sci. 1999, 88, 955-958.

[000211] Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needleless injection (e.g., Powderject™, Bioject™, etc.).

[000212] Formulations for topical administration can be formulated for immediate and/or modified release. Modified-release formulations include delayed, systematic, pulsed, controlled, vectored, and programmed release.

[000213] The compounds of the invention (including pharmaceutically acceptable salts thereof) can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone; as a mixture, for example, in a dry mixture with lactose; or as a particle of mixed components, e.g. mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurized container, pump, spray bottle, atomizer (e.g. an atomizer using electro-hydrodynamics 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.

[000214] The pressurized container, pump, sprayer, atomizer or nebulizer contains a solution or suspension of the compounds of the invention comprising, for example, ethanol, aqueous ethanol or an alternative agent suitable for dispersing, solubilizing or prolonging the release of the active, a propellant such as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid or an oligolactic acid.

[000215] Before being used in a dry powder or suspension formulation, the drug product is micronized to a size suitable for distribution by inhalation (typically less than 5 microns). This can be achieved by any appropriate comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

[000216] Capsules (made, for example, of gelatin or hydroxypropyl methyl cellulose), blisters and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, a powder base suitable such as lactose or starch and a performance modifier such as L-leucine, mannitol or magnesium stearate. Lactose can be anhydrous or can be in monohydrate form. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[000217] A solution formulation suitable for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 μL to 100 μL. A typical formulation may comprise a compound of formula I or a pharmaceutically acceptable salt thereof, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

[000218] Suitable flavors, such as menthol and levomenthol or sweeteners, such as saccharin or sodium saccharin, can be added to the formulations of the invention intended for inhalation/intranasal administration.

[000219] Formulations for inhalation/intranasal administration can be formulated for immediate release and/or modified using, for example, PGLA. Modified-release formulations include delayed, systematic, pulsed, controlled, vectored, and programmed release.

[000220] In the case of dry powder and aerosol inhalers, the dosage unit is determined by means of a valve that distributes a regulated amount. Units according to the invention are typically arranged to deliver a regulated dose or "puff" containing from 0.01 to 100 mg of the compound of formula I. The total daily dose will typically vary in the range of 1 μg to 200 mg, which it can be administered in a single dose or, more usually, as divided doses during the day.

[000221] The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema. Cocoa butter is a traditional suppository base, but several alternatives can be used as appropriate.

[000222] Formulations for rectal/vaginal administration can be formulated for immediate and/or modified release. Modified-release formulations include delayed, systematic, pulsed, controlled, vectored, and programmed release.

[000223] The compounds of the invention (including pharmaceutically acceptable salts thereof) can also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted sterile saline. Other formulations for ocular and aural administration include ointments, gels, biodegradable (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 cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropyl methyl cellulose, hydroxyethyl cellulose or methyl cellulose or a heteropolysaccharide polymer, for example, gellan gum, can be incorporated together with a preservative, such as such as benzalkonium chloride. Such formulations can also be distributed by iontophoresis.

[000224] Formulations for ocular/aural administration can be formulated for immediate and/or modified release. Modified-release formulations include delayed, systematic, pulsed, controlled, vectored, and programmed release.

[000225] The compounds of the invention (including pharmaceutically acceptable salts thereof) can be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol, to improve their solubility, dissolution rate, flavor masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

[000226] Drug-cyclodextrin complexes, for example, generally prove useful for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct drug complexation, cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. The most commonly used for this purpose are the alpha-, beta- and gamma-cyclodextrins, examples of which can be found in International Patent Application Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

[000227] As the present invention has an aspect that refers to the treatment of the diseases/conditions described in this report with a combination of active ingredients that can be administered separately, the invention also refers to combining separate pharmaceutical compositions in the form of a kit. The kit comprises two separate pharmaceutical compositions: a compound of formula I, a prodrug thereof or a salt of such a compound or prodrug and a second compound already described above. The kit comprises means for containing the separate compositions such as a container, a divided bottle or a divided aluminum package. Typically the kit comprises instructions for administering 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 parenteral), are administered at different dosage intervals or when titration of the individual components of the combination is desired by the physician. assistant.

[000228] An example of such a kit is the so-called honeycomb packaging. Honeycomb packaging is well known in the packaging industry and is being widely used to package pharmaceutical unit dosage forms (tablets, capsules, among others). Honeycomb packaging generally consists of a sheet of relatively rigid material covered with a sheet of a transparent plastic material. During the packaging process recesses are formed in the plastic sheet. The recesses are the size and shape of the tablets or capsules to be packaged. Then, the tablets or capsules are placed in the recesses and the sheet of relatively rigid material is sealed against the plastic sheet on the side of the sheet that is opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic sheet and the sheet of relatively rigid material. In some embodiments, the strength of the sheet of relatively rigid material is such that tablets or capsules can be removed from the blister packaging by manually applying pressure to the recesses thereby forming an opening in the sheet of relatively rigid material in place of the recess. The tablet or capsule can then be removed through said opening.

[000229] It may be desirable to present a reminder about the kit, for example, in the form of numbers next to the tablets or capsules with the numbers corresponding to the days of the regimen on which the specified tablets or capsules are to be taken. Another example of such a reminder is a calendar printed on the card, for example, as follows: "First Week, Monday, Tuesday, etc. Second Week, Monday, Tuesday,..." etc. Other variations of reminders will be readily apparent. A "daily dose" can be a single pill or capsule or multiple pills or capsules that must be taken on a given day. Also, a daily dose of a compound of formula I may consist of one tablet or capsule while a daily dose of the second compound may consist of several tablets or capsules and vice versa. The reminder should reflect this information.

[000230] In another specific embodiment of the invention, a dispenser designed to dispense daily doses, one of each in the order desired, is provided. For example, the dispenser is equipped with a reminder to make sticking to the regimen even easier. An example of such a reminder is a mechanical counter that indicates the number of daily doses that must be dispensed. Another example of such a reminder is a battery-operated microchip memory coupled to a liquid crystal reader, an audible warning signal that, for example, reads the date when the last daily dose should be taken and/or reminds the patient when the next dose should be taken.

[000231] The invention will be described in more detail by means of specific examples. The following examples are offered by way of illustration, and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be altered or modified to produce essentially the same results. Additional compounds within the scope of this invention can be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the literature. In the following Examples and Preparations, "DMSO" means dimethyl sulfoxide, "N" when referring to concentration means Normal, "M" means molar, "mL" means milliliter, "mmol" means millimole, "μmol" means micromoles, "eq." means equivalent, "°C" means degrees Celsius, "MHz" means megahertz, "HPLC" means high performance liquid chromatography.

EXAMPLES

[000232] The experiments were generally carried out in an inert atmosphere (nitrogen or argon), particularly in cases where reagents or intermediates sensitive to oxygen or humidity were used. Commercial solvents and reagents were generally used without further purification. Anhydrous solvents were employed where appropriate, typically AcroSeal® products from Acros Organics or DriSolv® products from EMD Chemicals. In other cases, commercial solvents were passed through columns packed with 4Å molecular sieves, until the following QC standards for water were reached: a) <100 ppm for dichloromethane, toluene, N,N-dimethylformamide and tetrahydrofuran; b) <180 ppm for methanol, ethanol, 1,4-dioxane and diisopropylamine. For very sensitive reactions, the solvents were further treated with sodium metal, calcium hydride or molecular sieves, and distilled immediately before use. The products were generally vacuum dried before being transported to other reactions or subjected to biological tests. Mass spectrometry data is presented whether from liquid chromatography coupled to mass spectrometry (LCMS), atomospheric pressure chemical ionization (APCI) or gas chromatography coupled to mass spectrometry (GCMS) instrumentation. Chemical shifts for nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, δ) in relation to residual peaks of the deuterated solvents used. In some examples, chiral separations have been made to separate atropisomers (or atropenantiomers) of certain compounds of the invention. In some examples, the optical rotation of an atropisomer was measured using a polarimeter. According to its observed rotation data (or its specific rotation data), an atropisomer (or atropenantiomer) with a clockwise rotation was designated as the (+)-atropisomer [or the (+)-atropenantiomer] and an atropisomer (or atropenantiomer) with a counterclockwise rotation was designated as the (-)-atropisomer [or the (-)-atropenantiomer].

[000233] Reactions proceeding through detectable intermediates were generally monitored by LCMS, and allowed to proceed until complete conversion before adding subsequent reagents. For syntheses referring to procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. In general, reactions were monitored by thin-layer chromatography or mass spectrometry, and subjected to processing when appropriate. Purifications may vary between experiments: in general, the solvents and solvent ratios used for eluents/gradients were chosen to give appropriate Rfs or retention times. Examples 1 and 2 (+)-6-{4-[(3-Cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (1) and (-)-6-{4-[(3-Cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (2) Step 1. Synthesis of 6-amino-1,5-dimethylpyrimidine-2,4(1H,3H)-dione, hydrochloride salt (C1).

[000234] A solution of sodium methoxide in methanol (4.4 M, 27 mL, 119 mmols) was added to a solution of ethyl 2-cyanopropanoate (95%, 13.2 mL, 99.6 mmols) and 1-methylurea (98%, 8.26 g, 109 mmols) in methanol (75 mL), and the reaction mixture was heated at reflux for 18 hours, and then cooled to room temperature. After removal of the solvent in vacuum, the residue was repeatedly evaporated under reduced pressure with acetonitrile (3 x 50 mL), and then partitioned between acetonitrile (100 mL) and water (100 mL). Aqueous 6 M hydrochloric acid was slowly added until the pH reached approximately 2; and the resulting mixture was stirred for one hour. The precipitate was collected via filtration and washed with tert-butyl methyl ether, giving the product as a white solid. Yield: 15.2 g, 79.3 mmols, 80%. LCMS m/z 156.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (br s, 1H), 6.39 (s, 2H), 3.22 (s, 3H), 1.67 (s, 3H). Step 2. Synthesis of 6-bromo-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C2).

[000235] A 1:1 mixture of acetonitrile and water (120 mL) was added to a mixture of C1 (9.50 g, 49.6 mmols), sodium nitrite (5.24 g, 76 mmols), and bromide of copper (II) (22.4 g, 100 mmols) {Caution: bubbling and mild exothermal}, and the reaction mixture was allowed to stir at room temperature for 66 hours. Addition of aqueous sulfuric acid (1N, 200 mL) and ethyl acetate (100 mL) produced a precipitate, which was collected via filtration and washed with water and ethyl acetate to give the product as a pale yellow solid (7.70 g). . The organic layer of the filtrate was concentrated to a smaller volume, during which more precipitate formed; this was isolated via filtration and washed with 1:1 ethyl acetate/heptane to give more product (0.4 g). Total yield: 8.1 g, 37 mmols, 75%. GCMS m/z 218, 220 [M+]. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (br s, 1H), 3.45 (s, 3H), 1.93 (s, 3H). Step 3. Synthesis of 6-bromo-1,5-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H)-dione (C3).

[000236] To a mixture of C2 (21.9 g, 99.8 mmols) and 2-(trimethylsilyl)ethoxymethyl chloride (20 g, 120 mmols) in acetonitrile (400 mL) was added 1,8-diazabicyclo[5.4.0 ]undec-7-ene (DBU, 18.3 g, 120 mmols), and the reaction mixture was stirred at 60 ° C for 18 hours. More 2-(trimethylsilyl)ethoxymethyl chloride (5 g, 30 mmols) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g, 30 mmols) were added, and stirring continued at 60°C. for 18 hours. After the mixture was concentrated in vacuo, the residue was diluted with water (500 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were concentrated; and purification using silica gel chromatography (Gradient: 20% to 50% ethyl acetate in petroleum ether) gave the product as a colorless oil. Yield: 22.5 g, 64.4 mmols, 64%. 1H NMR (400 MHz, CDCl3) δ 5.41 (s, 2H), 3.61-3.72 (m, 5H), 2.13 (s, 3H), 0.93-1.02 (m , 2H), 0.00 (s, 9H). Step 4. Synthesis of 6-[4-(benzyloxy)-2-methylphenyl]-1,5-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H)-dione (C4).

[000237] A mixture of C3 (10 g, 29 mmols), [4-(benzyloxy)-2-methylphenyl]boronic acid (10.4 g, 43.0 mmols) and cesium carbonate (28 g, 86 mmols) in 1,4-dioxane (400 mL) was added [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (II) (2.2 g, 3.0 mmols). The reaction mixture was heated at reflux for 4 hours, and then filtered. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (Gradient: 10% to 20% ethyl acetate in petroleum ether) to give the product as a light yellow solid. Yield: 10 g, 21 mmols, 72%. 1H NMR (400 MHz, CDCh) δ 7.34-7.49 (m, 5H), 7.00 (d, half of the AB quartet, J=8.3 Hz, 1H), 6.91-6, 97 (m, 2H), 5.50 (AB quartet, JAB=9.2 Hz, ΔVAB=4.1 Hz, 2H), 5.10 (s, 2H), 3.73-3.79 (m , 2H), 3.03 (s, 3H), 2.15 (s, 3H), 1.65 (s, 3H), 1.001.06 (m, 2H), 0.03 (s, 9H). Step 5. Synthesis of 6-(4-hydroxy-2-methylphenyl)-1,5-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H)-dione (C5 ).

[000238] A mixture of C4 (10 g, 21 mmols) and palladium hydroxide (2 g, dry) in methanol (300 mL) was stirred at room temperature for 24 hours at a pressure of 0.28 bar (40 psi) of hydrogen. After filtration of the reaction mixture, the filtrate was concentrated to give the product as a light yellow solid. Yield: 8.0 g, 21 mmols, 100%. 1H NMR (400 MHz, CDCl3) δ 6.92 (d, half of AB quartet, J=8.2 Hz, 1H), 6.81-6.87 (m, 2H), 5.52 (quartet of AB, JAB=9.5 Hz, ΔvAB=2.7 Hz, 2H), 3.73-3.80 (m, 2H), 3.03 (s, 3H), 2.11 (s, 3H), 1.65 (s, 3H), 0.99-1.05 (m, 2H), 0.01 (s, 9H). Step 6. Synthesis of 2-chloro-3-cyclopropylpyridine (C6).

[000239] A mixture of 2-chloro-3-iodopyridine (2.39 g, 9.98 mmols), cyclopropylboronic acid (860 mg, 10 mmols) and potassium carbonate (4.14 g, 30.0 mmols) in 1,4-dioxane (50 mL) tetrakis(triphenylphosphine)palladium (0) (1.16 g, 1.00 mmols) was added. The reaction mixture was stirred at 120°C for 4 hours, and then diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (Gradient: 10% to 30% ethyl acetate in petroleum ether) to give the product as a colorless oil. Yield: 1 g, 6 mmols, 60%. 1H NMR (400 MHz, CDCh) δ 8.20 (dd, J=4.7, 1.8 Hz, 1H), 7.24-7.28 (m, 1H), 7.14 (br dd, J =7.6, 4.8 Hz, 1H), 2.12-2.21 (m, 1H), 1.04-1.11 (m, 2H), 0.67-0.72 (m, 2H ). Step 7. Synthesis of 6-{4-[(3-cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2 ,4(1H,3H)-dione (C7).

[000240] Palladium (II) acetate (61 mg, 0.27 mmol) and di-tert-butyl[3,4,5,6-tetramethyl-2',4',6'-tri(propan-2- yl)biphenyl-2-yl]phosphane (130 mg, 0.27 mmol) were added to a mixture of C6 (615 mg, 4.00 mmol), C5 (1.0 g, 2.6 mmol) and cesium carbonate ( 2.6 g, 8.0 mmols) in 1,4-dioxane (25 mL). The reaction mixture was stirred at 120°C under microwave radiation for 5 hours, and then diluted with ethyl acetate (50 mL) and filtered. After removing the solvents in vacuum, the residue was purified via chromatography on silica gel (Gradient: 0% to 25% ethyl acetate in petroleum ether) to give the product as a yellow gum. Yield: 900 mg, 1.8 mmol, 69%. LCMS m/z 494.1 [M+H]+, 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J=4.8, 1.8 Hz, 1H), 7.30 (dd, J =7.4, 1.8 Hz, 1H), 7.11-7.14 (m, 1H), 7.08-7.10 (m, 2H), 7.01 (dd, J=7.5 , 4.8 Hz, 1H), 5.51 (AB quartet, JAB=9.3 Hz, ΔVAB=3.8 Hz, 2H), 3.74-3.80 (m, 2H), 3.08 (s, 3H), 2.18 (s, 3H), 2,162.24 (m, 1H), 1.70 (s, 3H), 1.00-1.06 (m, 4H), 0.74- 0.79 (m, 2H), 0.03 (s, 9H). Step 8. Synthesis of (+)-6-{4-[(3-cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (1 ) and (-)-6-{4-[(3-cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (2).

[000241] Trifluoroacetic acid (1.5 mL) was added to a solution of C7 (875 mg, 1.77 mmol) in dichloromethane (8 mL). The reaction mixture was stirred at room temperature for two hours and concentrated in vacuo; the residue was dissolved in methanol (10 mL), treated with potassium carbonate (1.22 g, 8.83 mmols) and stirred at room temperature for 18 hours. After removing the solids via filtration, the filtrate was concentrated under reduced pressure and distributed between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed sequentially with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) gave a mixture of 1 and 2, which was separated via reversed-phase chiral chromatography (Column: Chiral Technologies, Chiralpak IA; Gradient: heptane to ethanol). The first atropenantiomer to elute, obtained as a solid that exhibited a positive (+) rotation, was designated as Example 1. Yield: 210 mg, 0.578 mmol, 33%. The second atropenantiomer to elute, also obtained as a solid but with a negative rotation (-), was designated as Example 2. Yield: 190 mg, 0.523 mmol, 30%. 1: LCMS m/z 364.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.94 (br d, J=5 Hz, 1H), 7.48 (br d, J=7.6 Hz, 1H), 7.22 (d, J=8.2 Hz, 1H) , 7.03-7.14 (m, 3H), 3.04 (s, 3H), 2.20 (s, 3H), 2.15-2.23 (m, 1H), 1.63 (s , 3H), 0.99-1.06 (m, 2H), 0.75-0.82 (m, 2H), 2: LCMS m/z 364.2 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 7.94 (dd, J=4.8, 1.7 Hz, 1H), 7.48 (dd, J=7.5, 1.8 Hz, 1H), 7.22 (d , J=8.3 Hz, 1H), 7.09-7.14 (m, 2H), 7.06 (dd, J=8.4, 2.3 Hz, 1H), 3.04 (s, 3H), 2.20 (s, 3H), 2.15-2.23 (m, 1H), 1.63 (s, 3H), 0.99-1.06 (m, 2H), 0.75 -0.82 (m, 2H). Examples 3 and 4 (-)-6-{4-[(3-Chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)- dione (3) and (+)-6-{4-[(3-Chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H) -dione (4) Step 1. Synthesis of 6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methyl }pyrimidine-2,4(1H,3H)-dione (C8).

[000242] Cesium carbonate (476 mg, 1.46 mmol) was added to a mixture of 3-chloro-2,5-difluoropyridine (97%, 150 mg, 0.97 mmol) and C5 (366 mg, 0.972 mmol ) in dimethyl sulfoxide (5 mL), and the reaction mixture was stirred at 80 ° C for 6 hours. Water was added, and the mixture was extracted three times with ethyl acetate; The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 10% to 40% ethyl acetate in heptane) gave the product as a sticky solid. Yield: 414 mg, 0.818 mmol, 84%. 1H NMR (400 MHz, CDCh) δ 7.96 (d, J=2.7 Hz, 1H), 7.64 (dd, J=7.1, 2.7 Hz, 1H), 7.09-7 .15 (m, 3H), 5.51 (AB quartet, JAB=9.3 Hz, ΔVAB=3.4 Hz, 2H), 3.74-3.80 (m, 2H), 3.07 ( s, 3H), 2.19 (s, 3H), 1.69 (s, 3H), 1.00-1.06 (m, 2H), 0.03 (s, 9H). Step 2. Synthesis of (-)-6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H) -dione (3) and (+)-6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H )-dione (4).

[000243] Trifluoroacetic acid (812 μL, 10.9 mmols) was added to a solution of C8 (187 mg, 0.370 mmol) in dichloromethane (3.0 mL), and the reaction mixture was stirred at room temperature for one hour. The solvents were removed in vacuo, and the residue was taken up in tetrahydrofuran (4.5 mL) and treated with concentrated aqueous ammonium hydroxide (9 mL). After 4 hours, the reaction mixture was concentrated at reduced pressure, combined with the crude product from an identical reaction carried out in C8 (200 mg, 0.395 mmol), and purified via silica gel chromatography (Gradient: 20% to 40% ethyl acetate in heptane), to give the racemic product as a white solid. Yield: 219 mg, 0.583 mmol, 76%. This was separated into its atropenantiomers via chiral chromatography (Column: Phenomenex Lux Cellulose-1; Gradient: 50% to 100% ethanol in heptane). The first atropenantiomer to elute, which was obtained as a white solid, exhibited a negative rotation (-) and was designated as Example 3. Yield: 25 mg, 66 μmol, 9%. The second atropenantiomer to elute was also a white solid, but exhibited a positive (+) rotation; this was designated as Example 4. Yield: 62 mg, 160 μmol, 21%. 3: LCMS m/z 376.1, 378.0 [M+H]+, 1H NMR (400 MHz, CDCh) δ 8.35 (br s, 1H), 7.97 (d, J=2.7 Hz, 1H), 7.64 (dd, J=7.1, 2.8 Hz, 1H), 7.117.16 (m, 3H), 3.04 (s, 3H), 2.20 (s, 3H ), 1.67 (s, 3H), 4: LCMS m/z 376.2, 378.2 [M+H]+, 1H NMR (400 MHz, CDCl3) δ 8.46 (br s, 1H), 7.97 (d, J=2.7 Hz, 1H), 7.64 (dd, J=7.1, 2.7 Hz, 1H), 7.12-7.16 (m, 3H), 3 .04 (s, 3H), 2.20 (br s, 3H), 1.67 (s, 3H). Example 5 6-{4-[(3-Chloropyridin-2-yl)oxy]-2-methylphenyl}-1-ethyl-5-methylpyrimidine-2,4(1H,3H)-dione (5) Step 1. Synthesis of 6-amino-1-ethyl-5-methylpyrimidine-2,4(1H,3H)-dione (C9).

[000244] Sodium hydride (1.84 g, 76.7 mmols) was added little by little to a solution of 1-ethylurea (5.7 g, 65 mmols) and ethyl 2-cyanopropanoate (7.5 g, 59 mmols) in methanol (60 mL) that had been cooled to 0 to 5°C. The reaction mixture was stirred for 18 hours and then concentrated in vacuo. Acetonitrile (200 mL) was added, and the mixture was again concentrated to dryness. The residue was diluted with a mixture of acetonitrile (100 ml) and water (30 ml); and 12 M aqueous hydrochloric acid was added dropwise until the pH was approximately 1 - 2. After the mixture was stirred for one hour, the precipitate was collected via filtration and washed with tert-butyl methyl ether, giving the product as a white solid. Yield: 8.15 g, 48.2 mmols, 82%. 1H NMR (400 MHz, DMSO-d6) δ 3.84 (q, J=6.9 Hz, 2H), 1.66 (s, 3H), 1.07 (t, J=7.0 Hz, 3H ). Step 2. Synthesis of 6-bromo-1-ethyl-5-methylpyrimidine-2,4(1H,3H)-dione (C10).

[000245] To a solution of C9 (6.2 g, 36.6 mmols) in a 1:1 mixture of acetonitrile and water (70 mL) were added sodium nitrite (3.8 g, 55 mmols) and copper bromide ( II) (16.4 g, 73.4 mmols), and the reaction mixture was stirred for 18 hours at room temperature. A mixture of 1N aqueous sulfuric acid (100 mL) and ethyl acetate (50 mL) was added, and stirring continued for one hour, at which time the organic layer was separated, and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were concentrated in vacuo; and chromatography on silica gel (Gradient: 0% to 50% ethyl acetate in petroleum ether) gave the product as a green solid. Yield: 5.0 g, 21 mmols, 57%. 1H NMR (400 MHz, CDCl3) δ 8.87 (br s, 1H), 4.21 (q, J=7.0 Hz, 2H), 2.11 (s, 3H), 1.32 (t, J=7.0Hz, 3H). Step 3. Synthesis of 6-bromo-1-ethyl-5-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H)-dione (C11).

[000246] Compound C10 was converted into the product using the method described for the synthesis of C3 in Examples 1 and 2. The product was obtained as a yellow gum. Yield: 1.28 g, 3.52 mmols, 17%, 1H NMR (400 MHz, CDCl3) δ 5.41 (s, 2H), 4.24 (q, J=7.1 Hz, 2H), 3.65 -3.72 (m, 2H), 2.13 (s, 3H), 1.31 (t, J=7.1 Hz, 3H), 0.94-1.01 (m, 2H), 0, 00 (s, 9H). Step 4. Synthesis of 6-[4-(benzyloxy)-2-methylphenyl]-1-ethyl-5-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H) -dione (C12).

[000247] Compound C11 was converted into the product using the method described for the synthesis of C4 in Examples 1 and 2. The product was obtained as a yellow gum. Yield: 1.09 g, 2.27 mmols, 78%. 1H NMR (400 MHz, CDCI3) δ 7.34-7.49 (m, 5H), 7.05 (d, J=8.2 Hz, 1H), 6.91-6.97 (m, 2H) , 5.50 (s, 2H), 5.10 (s, 2H), 3.79-3.89 (m, 1H), 3.74-3.80 (m, 2H), 3.23-3 .34 (m, 1H), 2.15 (s, 3H), 1.62 (s, 3H), 1.00-1.07 (m, 5H), 0.03 (s, 9H). Step 5. Synthesis of 1-ethyl-6-(4-hydroxy-2-methylphenyl)-5-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H)-dione (C13).

[000248] The product, obtained as a gray solid, was synthesized from C12 using the method described for the synthesis of C5 in Examples 1 and 2. Yield: 800 mg, 2.05 mmols, 90%. 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J=8.2 Hz, 1H), 6.79-6.85 (m, 2H), 5.51 (s, 2H), 3.79 -3.89 (m, 1H), 3.73-3.80 (m, 2H), 3.24-3.34 (m, 1H), 2.12 (s, 3H), 1.62 (s , 3H), 0.99-1.06 (m, 5H), 0.02 (s, 9H). Step 6. Synthesis of 6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1-ethyl-5-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine -2,4(1H,3H)-dione (C14).

[000249] Cesium carbonate (127 mg, 0.390 mmol) and C13 (50 mg, 0.13 mmol) were added to a solution of 2,3-dichloropyridine (38 mg, 0.26 mmol) in dimethyl sulfoxide (3 mL ), and the reaction mixture was heated at 80°C for 18 hours. After removing the solids via filtration, the filtrate was distributed between ethyl acetate (20 mL) and water (20 mL), and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparatory thin layer silica gel chromatography (Eluent: 3:1 petroleum ether/ethyl acetate) to give the product as a yellow gum. Yield: 31 mg, 62 μmol, 48%. 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J=4.7, 1.4 Hz, 1H), 7.81 (dd, J=7.7, 1.4 Hz, 1H), 7 .11-7.19 (m, 3H), 7.05 (dd, J=7.6, 4.9 Hz, 1H), 5.50 (s, 2H), 3.81-3.93 (m , 1H), 3.72-3.80 (m, 2H), 3.25-3.37 (m, 1H), 2.19 (s, 3H), 1.65 (s, 3H), 0, 98-1.10 (m, 5H), 0.02 (s, 9H). Step 7. Synthesis of 6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1-ethyl-3-(hydroxymethyl)-5-methylpyrimidine-2,4(1H,3H) -dione (C15).

[000250] Compound C14 (31 mg, 62 μmol) was treated with trifluoroacetic acid (3 mL), and the reaction mixture was stirred at room temperature for one hour. Removal of the solvent in vacuum gave the product (24.8 mg), which was used in the next step without further purification. Step 8. Synthesis of 6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1-ethyl-5-methylpyrimidine-2,4(1H,3H)-dione (5).

[000251] To a solution of C15 (from the previous step, 24.8 mg, <62 μmol) in methanol (5 mL) was added potassium carbonate (83 mg, 0.60 mmol), and the reaction mixture was stirred at room temperature for an hour. After removal of the solids via filtration, the filtrate was concentrated and the residue was purified by preparatory thin layer silica gel chromatography (Eluent: 20:1 dichloromethane/methanol) to give the product as a white solid. Yield: 7.7 mg, 21 μmol, 34% in two steps. LCMS m/z 372.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.07 (dd, J=4.8, 1.5 Hz, 1H), 7.98 (dd, J=7.8, 1.6 Hz, 1H), 7 .32 (d, J=8.2 Hz, 1H), 7.12-7.21 (m, 3H), 3,783.89 (m, 1H), 3.27-3.38 (m, 1H, assumed ; partially obscured by solvent peak), 2.21 (s, 3H), 1.60 (s, 3H), 1.07 (t, J=7.1 Hz, 3H). Example 6 6-{4-[(3-Chloropyridin-2-yl)oxy]-2-methylphenyl}-5-ethyl-1-methylpyrimidine-2,4(1H,3H)-dione (6) Step 1. Synthesis of 6-amino-5-ethyl-1-methylpyrimidine-2,4(1H,3H)-dione (C16).

[000252] Ethyl 2-cyanobutanoate was reacted with 1-methylurea according to the method for the synthesis of C9 in Example 5. The product was obtained as a white solid. Yield: 5.95 g, 35.2 mmols, 66%. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 6.41 (s, 2H), 3.22 (s, 3H), 2.22 (q, J=7.3 Hz , 2H), 0.87 (t, J=7.3 Hz, 3H). Step 2. Synthesis of 6-bromo-5-ethyl-1-methylpyrimidine-2,4(1H,3H)-dione (C17).

[000253] To a solution of C16 (5.95 g, 35.2 mmols) in a 1:1 mixture of acetonitrile and water (80 mL) were added sodium nitrite (3.6 g, 52 mmols) and copper bromide ( II) (15.7 g, 70.3 mmols), and the reaction mixture was stirred for 18 hours at room temperature. A mixture of 1N aqueous sulfuric acid (100 mL) and ethyl acetate (50 mL) was added, and stirring continued for one hour. The resulting solid was collected via filtration and the filtrate cake washed with aqueous ethyl acetate, giving the product as a white solid (4 g). The organic layer of the filtrate was separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL); and the combined organic layers were concentrated in vacuo to give further product as a green solid (3 g). Yield: 7 g, 30 mmols, 85%. 1H NMR (400 MHz, CDCI3) δ 8.92 (br s, 1H), 3.62 (s, 3H), 2.58 (q, J=7.4 Hz, 2H), 1.09 (t, J=7.4Hz, 3H). Step 3. Synthesis of 6-bromo-5-ethyl-1-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H)-dione (C18).

[000254] Compound C17 was converted into the product using the method described for the synthesis of C3 in Examples 1 and 2. The product was obtained as a yellow gum. Yield: 3.1 g, 8.5 mmols, 28%. 1H NMR (400 MHz, CDCl3) δ 5.41 (s, 2H), 3.66 (s, 3H), 3.64-3.72 (m, 2H), 2.61 (q, J=7, 4 Hz, 2H), 1.09 (t, J=7.4 Hz, 3H), 0.95-1.01 (m, 2H), 0.00 (s, 9H). Step 4. Synthesis of 6-[4-(benzyloxy)-2-methylphenyl]-5-ethyl-1-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H) -dione (C19).

[000255] The compound C18 was converted into the product using the method used for the synthesis of C4 in Examples 1 and 2. The product was obtained as a yellow gum. Yield: 1.26 g, 2.62 mmols, 59%. 1H NMR (400 MHz, CDCl3) δ 7.34-7.49 (m, 5H), 7.03 (d, J=8.0 Hz, 1H), 6.91-6.97 (m, 2H) , 5.47-5.54 (m, 2H), 5.10 (s, 2H), 3.73-3.80 (m, 2H), 3.00 (s, 3H), 2.18-2 .29 (m, 1H), 2.16 (s, 3H), 1.86-1.97 (m, 1H), 0.99-1.07 (m, 2H), 0.91 (t, J =7.3Hz, 3H), 0.03 (s, 9H). Step 5. Synthesis of 5-ethyl-6-(4-hydroxy-2-methylphenyl)-1-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H)-dione (C20).

[000256] The product, obtained as a gray solid, was synthesized from C19 using the method described for the synthesis of C5 in Examples 1 and 2. Yield: 850 mg, 2.18 mmols, 83%. LCMS m/z 413.2 [M+Na+], 1H NMR (400 MHz, CDCl3) δ 6.97 (d, J=7.9 Hz, 1H), 6.79-6.86 (m, 2H) , 5.48-5.54 (m, 2H), 3.73-3.80 (m, 2H), 3.01 (s, 3H), 2.18-2.30 (m, 1H), 2 .13 (s, 3H), 1.86-1.97 (m, 1H), 0.99-1.06 (m, 2H), 0.90 (t, J=7.3 Hz, 3H), 0.02 (s, 9H). Step 6. Synthesis of 6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-5-ethyl-1-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine -2,4(1H,3H)-dione (C21).

[000257] A mixture of C20 (80 mg, 0.20 mmol), 2,3-dichloropyridine (45 mg, 0.30 mmol) and cesium carbonate (199 mg, 0.611 mmol) in dimethyl sulfoxide (8 mL) was heated at 120°C for 18 hours. After addition of water and ethyl acetate, the mixture was extracted with ethyl acetate. The combined organic layers were dried, filtered, and concentrated under reduced pressure. Preparatory thin-layer silica gel chromatography (Eluent: 1:1 petroleum ether/ethyl acetate) gave the product as a colorless oil. Yield: 82 mg, 0.16 mmol, 80%. Step 7. Synthesis of 6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-5-ethyl-1-methylpyrimidine-2,4(1H,3H)-dione (6).

[000258] A solution of C21 (82 mg, 0.16 mmol) in trifluoroacetic acid (3 mL) was heated at 80°C for one hour. After removal of the solvent under vacuum, the residue was dissolved in methanol (5 mL), treated with potassium carbonate (68 mg, 0.49 mmol), and stirred at room temperature for one hour. The reaction mixture was filtered, and the filtrate was concentrated; Purification via preparatory thin layer chromatography (Eluent: ethyl acetate) gave the product as a white solid. Yield: 28 mg, 75 μmol, 47%. LCMS m/z 372.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.07 (br d, J=4 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.29 (d, J=8, 3Hz, 1H), 7.11-7.21 (m, 3H), 3.01 (s, 3H), 2.22 (s, 3H), 2.17-2.27 (m, 1H), 1.87-1.98 (m, 1H), 0.93 (t, J=7.3 Hz, 3H). Examples 7 and 8 (-)-1,5-Dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H,3H) -dione (7) and (+)-1,5-Dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H, 3H)-dione (8) Step 1. Synthesis of tert-butyl 4-bromo-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)-carboxylate (C22).

[000259] Compound C2 (800 mg, 3.65 mmols), di-tert-butyl dicarbonate (99%, 966 mg, 4.38 mmols), triethylamine (0.62 mL, 4.4 mmols) and 4- (dimethylamino)pyridine (45 mg, 0.36 mmol) were combined in tetrahydrofuran (15 mL) and the mixture was heated to 70 ° C for one hour, and then allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was purified via silica gel chromatography (Gradient: 10% to 25% ethyl acetate in heptane) to give the product as a white solid. Yield: 1.10 g, 3.45 mmols, 94%. 1H NMR (400 MHz, CDCh) δ 3.64 (s, 3H), 2.12 (s, 3H), 1.61 (s, 9H). Step 2. Synthesis of tert-butyl 4-[4-(benzyloxy)-2-methylphenyl]-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)-carboxylate (C23 ).

[000260] A mixture of C22 (1.00 g, 3.13 mmols), [4-(benzyloxy)-2-methylphenyl]boronic acid (98%, 1.16 g, 4.68 mmols), chlorine adduct (2 -dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium (II) - tert-butyl methyl ether (S-based precatalyst -Phos) (119 mg, 0.156 mmol), and cesium carbonate (3.06 g, 9.39 mmols) in 2-methyltetrahydrofuran (10 mL) and water (3 mL) was heated to 50°C for 66 hours. The reaction mixture was diluted with water and ethyl acetate, and then filtered to remove suspended solids. The filtrate was extracted several times with ethyl acetate, and the combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in a 1:3 mixture of ethyl acetate and heptane, stirred for several minutes, and filtered, giving the product as a white solid. Yield: 970 mg, 2.22 mmols, 71%. LCMS m/z 337.2 [(M-Boc)+H]+. 1H NMR (400 MHz, CDCl3) δ 7.34-7.48 (m, 5H), 6.91-7.01 (m, 3H), 5.10 (s, 2H), 3.01 (s, 3H), 2.16 (br s, 3H), 1.66 (s, 9H), 1.64 (s, 3H). Step 3. Synthesis of 6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C24).

[000261] Compound C23 (250 mg, 0.573 mmol) was mixed with a 30% solution of hydrogen bromide in acetic acid (1 mL, 5 mmols) and allowed to stir for 18 hours at room temperature. After removing the acetic acid under reduced pressure, the residue was dissolved in a minimal amount of ethanol and diluted with 4 M aqueous hydrochloric acid to give a slightly cloudy mixture; this was evaporated to dryness, and the resulting solid was suspended in 4N aqueous hydrochloric acid, stirred for several minutes, and filtered, giving the product as a yellow solid. Yield: 125 mg, 0.508 mmol, 89%. LCMS m/z 247.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.36 (br s, 1H), 9.71 (v br s, 1H), 6.99 (d, J=8.2 Hz, 1H), 6, 76 (d, J=2.3 Hz, 1H), 6.72 (d, J=8.1, 2.3 Hz, 1H), 2.82 (s, 3H), 2.03 (s, 3H ), 1.44 (s, 3H). Step 4. Synthesis of 1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H,3H)-dione ( C25).

[000262] 2-Chloro-3-(trifluoromethyl)pyridine (98%, 269 mg, 1.45 mmol), C24 (325 mg, 1.32 mmol) and cesium carbonate (521 mg, 1.60 mmol) were combined in N,N-dimethylformamide (6 mL) and the resulting suspension was heated at 100°C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with 1 M aqueous hydrochloric acid and extracted several times with ethyl acetate. The combined organic layers were washed twice with water and once with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in a 1:1 mixture of ethyl acetate and heptane, stirred for several minutes and collected by filtration, giving the product as a white solid. Yield: 440 mg, 1.12 mmol, 85%. LCMS m/z 392.2 [M+H]+, 1H NMR (400 MHz, CDCl3) δ 8.31-8.36 (m, 2H), 8.05 (br d, J=7.5 Hz, 1H), 7.13-7.22 (m, 4H), 3.06 (s, 3H), 2.21 (s, 3H), 1.69 (s, 3H). Step 5. Isolation of (-)-1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4( 1H,3H)-dione (7) and (+)-1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine -2,4(1H,3H)-dione (8).

[000263] The C25 racemate (1.30 g, 3.32 mmols) was separated into its atropenantiomers via chiral chromatography (Column: Phenomenex Lux Cellulose-2; Gradient: heptane/ethanol). The first atropenantiomer to elute, obtained as a brown solid that exhibited a negative rotation (-), was designated as Example 7. Yield: 536 mg, 1.37 mmol, 41%. The second atropenantiomer to elute, also obtained as a brown solid but with a positive rotation (+), was designated as Example 8. Yield: 553 mg, 1.41 mmol, 42%. 7: LCMS m/z 392.2 [M+H]+, 1H NMR (400 MHz, CDCb) δ 8.34 (ddq, J=4.9, 1.9, 0.6 Hz, 1H), 8 .30 (br s, 1H), 8.05 (ddq, J=7.6, 1.9, 0.7 Hz, 1H), 7.13-7.21 (m, 4H), 3.06 ( s, 3H), 2.21 (br s, 3H), 1.69 (s, 3H), 8: LCMS m/z 392.2 [M+H]+, 1H NMR (400 MHz, CDCl3) δ 8 .34 (br d, J=4.9 Hz, 1H), 8.30 (br s, 1H), 8.05 (br d, J=7.5 Hz, 1H), 7.13-7.22 (m, 4H), 3.06 (s, 3H), 2.21 (br s, 3H), 1.69 (s, 3H). Examples 9 and 10 (+)-6-{4-[(3-Chloro-5-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyri-midine-2,4(1H, 3H)-dione (9) and (-)-6-{4-[(3-Chloro-5-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H ,3H)-dione (10) Step 1. Synthesis of 6-bromo-3-(3,4-dimethoxybenzyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C26).

[000264] 1,8-Diazabicyclo[5.4.0]undec-7-ene (98%, 5.57 mL, 36.5 mmols) was added to a suspension of C2 (4.00 g, 18.3 mmols) and 4 -(chloromethyl)-1,2-dimethoxybenzene (5.16 g, 27.6 mmols) in acetonitrile (80 mL), and the reaction mixture was heated at 60 ° C for 18 hours. After removing the solvent in vacuo, the residue was purified via silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) to give the product as a white solid. Yield: 5.70 g, 15.4 mmols, 84%. 1H NMR (400 MHz, CDCh) δ 7.08-7.12 (m, 2H), 6.80 (d, J=8.0 Hz, 1H), 5.07 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H), 2.14 (s, 3H). Step 2. Synthesis of 3-(3,4-dimethoxybenzyl)-6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C27).

[000265] An aqueous solution of potassium carbonate (3.0 M, 14 mL, 42 mmols) was added to a mixture of C26 (5.00 g, 13.5 mmols), (4-hydroxy-2-methylphenyl)boronic acid (4.12 g, 27.1 mmols), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (II), complex in dichloromethane (98%, 1.13 g, 1.36 mmol) and 1.4 -dioxane (120 mL). After the reaction mixture was heated at 100°C for 18 hours, it was cooled to room temperature, diluted with ethyl acetate and water, and filtered through diatomaceous earth. The organic layer from the filtrate was washed sequentially with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 25% to 75% ethyl acetate in heptane) gave the product as a white foam. Yield: 2.71 g, 6.84 mmols, 51%. LCMS m/z 397.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J=2.0 Hz, 1H), 7.19 (dd, J=8.1, 2.0 Hz, 1H), 6.93 (d , J=8.2 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 6.80-6.82 (m, 1H), 6.76-6.80 (m, 1H), 5.16 (AB quartet, JAB=13.3 Hz, ΔVAB=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 3. Synthesis of 6-{4-[(3-chloro-5-methylpyridin-2-yl)oxy]-2-methylphenyl}-3-(3,4-dimethoxybenzyl)-1,5-dimethylpyrimidine-2, 4(1H,3H)- dione (C28).

[000266] A mixture of 2,3-dichloro-5-methylpyridine (735 mg, 4.54 mmols), C27 (1.5 g, 3.8 mmols) and cesium carbonate (2.46 g, 7.55 mmols) in dimethyl sulfoxide (36 mL) was stirred at 100°C for 40 hours, and at 120°C for another 48 hours. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 x 200 mL); the combined organic layers were dried, filtered, and concentrated in vacuo. Chromatography on silica gel (Gradient: 10% to 60% ethyl acetate in petroleum ether) gave the product as a yellow solid. Yield: 1.7 g, 3.2 mmols, 84%. 1H NMR (400 MHz, CDCh) δ 7.89-7.92 (m, 1H), 7.64-7.66 (m, 1H), 7.23 (br d, J=1.9 Hz, 1H ), 7.20 (br dd, J=8.2, 1.9 Hz, 1H), 7.10-7.12 (br s, 1H), 7.06-7.09 (m, 2H), 6.83 (d, J=8.2 Hz, 1H), 5.16 (AB quartet, JAB=13.4 Hz, ΔvAB=20.4 Hz, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.06 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.68 (s, 3H). Step 4. Synthesis of 6-{4-[(3-chloro-5-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C29 ).

[000267] This experiment was carried out in three batches. A mixture of C28 (600 mg, 1.15 mmol) and methoxybenzene (622 mg, 5.75 mmol) in trifluoroacetic acid (20 mL) was stirred at 120°C for 48 hours, and then at 125°C for more 48 hours. The three batches were combined, concentrated at reduced pressure, and purified via chromatography on silica gel (Gradient: 10% to 70% ethyl acetate in petroleum ether). The product was obtained as a light brown solid. Yield: 690 mg, 1.86 mmol, 54%. LCMS m/z 371.8, 373.9 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.90-7.92 (m, 1H), 7.82-7.84 (m, 1H), 7.23 (d, J=8.4 Hz, 1H) , 7.14 (br d, J=2.2 Hz, 1H), 7.08 (br dd, J=8.2, 2.2 Hz, 1H), 3.03 (s, 3H), 2, 33 (br s, 3H), 2.20 (br s, 3H), 1.62 (s, 3H). Step 5. Isolation of (+)-6-{4-[(3-chloro-5-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H) -dione (9) and (-)-6-{4-[(3-chloro-5-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine- 2,4(1H,3H )-dione (10).

[000268] Compound C29 (690 mg, 1.86 mmol) was separated into its atropenantiomers via supercritical fluid chromatography (Column: Chiral Technologies, Chiralcel OJ-H, 5 μm; Eluent: 7:3 carbon dioxide/methanol) . The first atropenantiomer to elute, obtained as a solid that exhibited a positive rotation (+), was designated as Example 9. Yield: 240 mg, 0.645 mmol, 35%. The second atropenantiomer to elute, also obtained as a solid but with a negative rotation (-), was designated as Example 10. Yield: 250 mg, 0.672 mmol, 36%. 9: LCMS m/z 372.1, 374.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.36 (br s, 1H), 7.91-7.93 (m, 1H), 7.65-7.66 (m, 1H), 7.13-7 .14 (m, 1H), 7.10-7.11 (m, 2H), 3.04 (s, 3H), 2.32-2.34 (m, 3H), 2.18-2.19 (m, 3H), 1.67 (s, 3H), 10: LCMS m/z 372.1, 374.1 [M+H]+, 1H NMR (400 MHz, CDCl3) δ 8.35 (br s , 1H), 7.91-7.93 (m, 1H), 7.65-7.66 (m, 1H), 7.13-7.14 (m, 1H), 7.10-7.11 (m, 2H), 3.04 (s, 3H), 2.33 (dd, J=0.7, 0.7 Hz, 3H), 2.19 (d, J=0.6 Hz, 3H) , 1.67 (s, 3H). Example 11 6-{4-[(3-Chloro-4-methylpyridin-2-yl)oxy]phenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (11) Step 1. Synthesis of tert-butyl 4-[4-(benzyloxy)phenyl]-3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)-carboxylate (C30).

[000269] A solution of C22 (23.3 g, 73.0 mmols), [4-(benzyloxy)phenyl]boronic acid (25 g, 110 mmols), [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (II) (2.68 g, 3.66 mmols), and cesium carbonate (95.2 g, 292 mmols) in 2-methyltetrahydrofuran (360 mL) and water (120 mL) was purged with nitrogen and heated up to 50°C for 5 hours. After cooling to room temperature, the reaction mixture was stirred at room temperature for 18 hours, and then diluted with water and ethyl acetate. The mixture was filtered, and the filtrate was extracted several times with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was combined with that collected from the initial filtration, and extracted several times with hot ethyl acetate; the combined ethyl acetate extracts were concentrated under reduced pressure. The residue was suspended in a 1:3 mixture of ethyl acetate and heptane, stirred for several minutes, and filtered, giving the product as a gray solid, which was used without further purification. Yield: 21.8 g, 51.6 mmols, 71%. LCMS m/z 323.1 [(M-Boc)+H]+. 1H NMR (400 MHz, DMSO-d6), characteristic peaks: δ 7.46-7.51 (m, 2H), 7.42 (br dd, J=7.5, 7.4 Hz, 2H), 7 .32-7.38 (m, 3H), 7.18 (br d, J=8.8 Hz, 2H), 5.16 (s, 2H), 2.92 (s, 3H), 1.54 (s, 9H). Step 2. Synthesis of 6-(4-hydroxyphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C31).

[000270] Compound C30 (21.8 g, 51.6 mmols) was mixed with a 30% solution of hydrogen bromide in acetic acid (100 mL, 520 mmols) and the mixture was stirred at room temperature for 4 hours. Acetic acid was removed under reduced pressure, and the resulting oil was dissolved in a minimal amount of ethanol and diluted with water, giving a slightly cloudy mixture. After this was evaporated to dryness, the resulting solid was suspended in water and stirred for several minutes. Filtration gave the product as a brown solid, which was used without further purification. Yield: 11.4 g, 49.1 mmols, 95%. LCMS m/z 233.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.34 (br s, 1H), 9.85 (br s, 1H), 7.14 (br d, J=8.6 Hz, 2H), 6, 89 (br d, J=8.6 Hz, 2H), 2.88 (s, 3H), 1.50 (s, 3H). Step 3. Synthesis of 6-{4-[(3-chloro-4-methylpyridin-2-yl)oxy]phenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (11).

[000271] Cesium carbonate (32.6 g, 100 mmols) was added to a mixture of C31 (11.4 g, 49.1 mmols) and 2,3-dichloro-4-methylpyridine (11.9 g, 73 .4 mmols) in 1-methylpyrrolidin-2-one (100 mL), and the reaction mixture was heated at 140 ° C for 24 hours. More 2,3-dichloro-4-methylpyridine (4.0 g, 25 mmols) was added, and heating continued for 24 hours. The reaction mixture was cooled to approximately 50°C and poured into ice water (500 mL); the resulting suspension was stirred for 5 minutes and then filtered. The collected solid was dissolved in hot ethanol (600 mL), treated with charcoal and magnesium sulfate, and stirred with heating for 10 minutes. The hot mixture was filtered through diatomaceous earth, and the hot filtrate was diluted with heptane (400 mL) with stirring, and then cooled to 0°C. After stirring for 45 minutes at 0°C, the mixture was filtered to give the crude product as an off-white solid (11.75 g). The filtrate was concentrated under reduced pressure, suspended in diethyl ether, and filtered to give a solid, which was extracted several times with hot ethyl acetate; the combined ethyl acetate extracts were concentrated in vacuo, giving more crude product (2 g). The two batches of crude product were combined and recrystallized from ethyl acetate/heptane to give the final product as a white solid. Yield: 11.1 g, 31.0 mmols, 63%. LCMS m/z 358.2, 360.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.42 (br s, 1H), 8.00 (d, J=5.0 Hz, 1H), 7.42 (br d, J=8.8 Hz , 2H), 7.30 (br d, J=8.7 Hz, 2H), 7.21 (br d, J=5.0 Hz, 1H), 2.91 (s, 3H), 2.44 (s, 3H), 1.53 (s, 3H). Example 12 6-(4-{[3-(Difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-1-ethyl-5-methylpyri-midine-2,4(1H,3H)-dione ( 12) Step 1. Synthesis of 2-(4-bromo-3-methylphenoxy)-3-(difluoromethyl)pyridine (C32).

[000272] To a mixture of 2-chloro-3-(difluoromethyl)pyridine (15 g, 92 mmols) and cesium carbonate (90 g, 280 mmols) in dimethyl sulfoxide (300 mL) was added 4-bromo-3- methylphenol (19.8 g, 106 mmols). The reaction mixture was stirred at 100°C for 18 hours, and then diluted with water (1 L) and extracted with ethyl acetate (5 x 200 mL). The combined organic layers were dried, filtered, and concentrated in vacuo. Chromatography on silica gel (Eluent: 40:1 petroleum ether/ethyl acetate) gave the product as a white solid. Yield: 27 g, 86 mmolS, 93%. 1H NMR (400 MHz, CD3OD) δ 8.19 (br d, J=4 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H), 7.56 (d, J=8, 5 Hz, 1H), 7.19-7.25 (m, 1H), 7.10 (br d, J=2.5 Hz, 1H), 7.08 (t, JHF=54.8 Hz, 1H ), 6.90 (dd, J=8.6, 2.6 Hz, 1H), 2.39 (s, 3H). Step 2. Synthesis of 3-(difluoromethyl)-2-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyridine (C33).

[000273] To a mixture of C32 (27 g, 86 mmols), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2 -dioxaborolane (32.8 g, 129 mmols) and potassium acetate (25.8 g, 263 mmols) in 1,4-dioxane (500 mL) were added [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (II) (6.3 g, 8.6 mmols). The mixture was stirred at 100°C for 18 hours, and then filtered. After concentration of the filtrate under reduced pressure, the residue was purified via chromatography on silica gel (Eluent: petroleum ether) to give the product as a yellow oil. Yield: 16 g, 44 mmols, 51%. LCMS m/z 362.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.18-8.22 (m, 1H), 8.07 (br d, J=7 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.22 (dd, J=7.6, 5.0 Hz, 1H), 7.07 (t, JHF=55.0 Hz, 1H), 6.93 (br d, J=2 Hz , 1H), 6.90 (br dd, J=8, 2 Hz, 1H), 2.52 (s, 3H), 1.35 (s, 12H). Step 3. Synthesis of 6-bromo-3-(3,4-dimethoxybenzyl)-1-ethyl-5-methylpyrimidine-2,4(1H,3H)-dione (C34).

[000274] The compound C10 was converted into the product according to the method used for the synthesis of C26 in Examples 9 and 10. The product was obtained as a light yellow oil. Yield: 720 mg, 1.88 mmol, 84%. 1H NMR (400 MHz, CDCh) δ 7.07-7.14 (m, 2H), 6.80 (d, J=8.2 Hz, 1H), 5.06 (s, 2H), 4.23 (q, J=7.0 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.13 (s, 3H), 1.30 (t, J=7, 0Hz, 3H). Step 4. Synthesis of 6-(4-{[3-(difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-3-(3,4-dimethoxybenzyl)-1-ethyl-5-methylpyrimidine-2 ,4(1H,3H)-dione (C35).

[000275] A mixture of C34 (57.5 mg, 0.150 mmol), C33 (108 mg, 0.299 mmol), and tetrakis(triphenylphosphine)palladium (0) (17 mg, 15 μmol) in a mixture of 1,4-dioxane (3 mL) and water (20 drops) barium hydroxide (77 mg, 0.45 mmol) was added. The reaction mixture was stirred at 60°C for 20 hours, and then diluted with a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried, filtered, and concentrated in vacuo. Preparatory high-performance liquid chromatography gave the product as a white solid. Yield: 30 mg, 56 μmol, 37%. LCMS m/z 538.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.28 (br d, J=4 Hz, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.10-7.25 (m, 6H), 7.02 (t, JHF=55.1 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 5.17 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.81-3.9 (m, 1H), 3.27-3.38 (m, 1H), 2.18 (s, 3H), 1.66 (s, 3H), 1.07 (t, J=7.0 Hz, 3H). Step 5. Synthesis of 6-(4-{[3-(difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-1-ethyl-5-methylpyrimidine-2,4(1H,3H)-dione ( 12).

[000276] Compound C35 was deprotected using the method described for the synthesis of C29 in Examples 9 and 10. In this case, purification was carried out via reversed-phase high-performance liquid chromatography (Column: Waters Sunfire C18, 5 μm; phase mobile phase A: 0.05% trifluoroacetic acid in water (v/v); mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 30% to 50% B) . LCMS m/z 388.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.34 (br d, J=4.5 Hz, 1H), 8.13 (br d, J=7.2 Hz, 1H), 7.35 (d , J=8.3 Hz, 1H), 7.32 (dd, J=7.4, 5.0 Hz, 1H), 7.28 (t, JHF=54.4 Hz, 1H), 7.24 (br d, J=2.1 Hz, 1H), 7.18 (br dd, J=8.2, 2.3 Hz, 1H), 3.63-3.71 (m, 1H), 3, 08-3.15 (m, 1H), 2.15 (s, 3H), 1.45 (s, 3H), 0.95 (t, J=7.0 Hz, 3H). Example 13 (-)-6-(4-{[3-(Difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethyl--pyrimidine-2,4(1H,3H)- dione (13) Step 1. Synthesis of 2-chloro-3-(difluoromethoxy)pyridine (C36).

[000277] This reaction was carried out 3 times. A mixture of potassium carbonate (282 g, 2.04 mol) and N,N-dimethylformamide (750 mL) was heated to 100°C and treated slowly, in drops over one hour, with a solution of 2-chloropyridine- 3-ol (66.7 g, 515 mmol) and sodium chloro(difluoro)acetate (200 g, 1.31 mol) in N,N-dimethylformamide (750 mL). After completion of the addition, the reaction mixture was stirred at 100°C for one hour, and then cooled to 25°C and distributed between water (10 L) and tert-butyl methyl ether (5 L). The aqueous layer was extracted with ethyl acetate (4 x 2.5 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution (6 x 2.5 L), dried over sodium sulfate, filtered, and concentrated in vacuo. . The combined products from the three reactions were purified via distillation at reduced pressure (30-40°C, 1-5 mm Hg) to give the product as a colorless oil. Yield: 192 g, 1.07 mol, 69%. LCMS m/z 180.0 [M+H]+, 1H NMR (400 MHz, CDCl3) δ 8.26-8.30 (m, 1H), 7.60 (br d, J=8.2 Hz, 1H), 7.28 (br dd, J=8.0, 4.8 Hz, 1H), 6.60 (t, JHF=72.5 Hz, 1H). Step 2. Synthesis of 3-[(benzyloxy)methyl]-6-bromo-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C37).

[000278] 1,8-Diazabicyclo[5.4.0]undec-7-ene (6.00 mL, 40.2 mmols) was added to a suspension of C2 (8.00 g, 36.5 mmols) and benzyl chloromethyl ether (95%, 5.86 mL, 40.2 mmols) in acetonitrile (100 mL). After 90 hours at room temperature, the reaction mixture was concentrated in vacuo, diluted with water, and extracted several times with ethyl acetate. The combined organic layers were washed sequentially with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel (Gradient: 10% to 25% ethyl acetate in heptane) gave the product as a white solid. Yield: 10.1 g, 29.8 mmols, 82%. 1H NMR (400 MHz, CDCl3) δ 7.24-7.39 (m, 5H), 5.52 (s, 2H), 4.71 (s, 2H), 3.63 (s, 3H), 2.11 (s, 3H). Step 3. Synthesis of 3-[(benzyloxy)methyl]-6-[4-(methoxymethoxy)-2-methylphenyl]-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C38).

[000279] A mixture of C37 (10.5 g, 31.0 mmols), [4-(methoxymethoxy)-2-methylphenyl]boronic acid (7.58 g, 38.7 mmols) and potassium carbonate (13 g, 94 mmols) in 1,4-dioxane (170 mL) [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (II) complex in dichloromethane (1.3 g, 1.6 mmol) was added. The reaction mixture was stirred at 80°C for 18 hours and filtered; the filtrate was concentrated in vacuo. Purification via chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in petroleum ether) gave the product as a yellow oil. Yield: 10.5 g, 25.6 mmols, 83%. 1H NMR (400 MHz, CDCh) δ 7.25-7.46 (m, 5H), 6.93-7.02 (m, 3H), 5.60 (AB quartet, JAB=9.4 Hz, ΔVAB=9.7 Hz, 2H), 5.22 (s, 2H), 4.79 (s, 2H), 3.52 (s, 3H), 3.00 (s, 3H), 2.12 ( br s, 3H), 1.63 (s, 3H). Step 4. Synthesis of 3-[(benzyloxy)methyl]-6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C39).

[000280] To a solution of C38 (9.0 g, 22 mmols) in tetrahydrofuran (70 mL) aqueous hydrochloric acid (8 M, 70 mL) was added, and the reaction mixture was stirred at room temperature for one hour . After extraction with ethyl acetate (5 x 100 mL), the combined organic layers were concentrated in vacuo; Chromatography on silica gel (Gradient: 0% to 50% ethyl acetate in petroleum ether) gave the product as a white solid. Yield: 6.3 g, 17 mmols, 77%. LCMS m/z 389.0 [M+Na+]. 1H NMR (400 MHz, CDCl3) δ 7.43 (br d, J=7 Hz, 2H), 7.25-7.37 (m, 3H), 6.91 (d, J=7.9 Hz, 1H), 6.78-6.84 (m, 2H), 5.61 (AB quartet, JAB=9.4 Hz, ΔvAB=9.2 Hz, 2H), 5.47 (s, 1H), 4.79 (s, 2H), 3.01 (s, 3H), 2.09 (s, 3H), 1.64 (s, 3H). Step 5. Synthesis of 3-[(benzyloxy)methyl]-6-(4-{[3-(difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethylpyrimidine-2,4( 1H,3H)-dione (C40).

[000281] A suspension of C39 (10 g, 27 mmols), C36 (5.88 g, 32.7 mmols), and cesium carbonate (99%, 13.5 g, 41.0 mmols) in dimethyl sulfoxide (200 mL) was heated to 80°C for 18 hours. Compound C36 (2.9 g, 16 mmol) was added, and the reaction mixture was heated to 90°C for 3 hours, and then to 80°C for 66 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water (5 x 300 mL), washed with saturated aqueous sodium chloride solution (200 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) gave the product as a viscous light yellow oil. Yield: 10.8 g, 21.2 mmols, 78%. LCMS m/z 510.2 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 8.05 (dd, J=4.9, 1.7 Hz, 1H), 7.61-7.65 (m, 1H), 7.40-7.44 ( m, 2H), 7.30-7.36 (m, 2H), 7.24-7.29 (m, 1H), 7.11-7.16 (m, 2H), 7.10 (dd, J=7.9, 4.9 Hz, 1H), 7.08 (br d, J=8 Hz, 1H), 6.70 (t, JHF=73.5 Hz, 1H), 5.61 (quartet of AB, JAB=9.5 Hz, ΔVAB=9.2 Hz, 2H), 4.79 (br s, 2H), 3.04 (s, 3H), 2.16 (br s, 3H), 1 .66 (s, 3H). Step 6. Synthesis of (-)-6-(4-{[3-(difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)- dione (13).

[000282] A mixture of C40 (10.8 g, 21.2 mmols) and trifluoroacetic acid (110 mL) was heated at 80°C for one hour. The reaction mixture was concentrated in vacuo, treated with dichloromethane and concentrated again, and then treated with tetrahydrofuran, concentrated under reduced pressure, and dried in high vacuum. The residue was diluted with tetrahydrofuran (50 mL), cooled in an ice bath, and treated with concentrated ammonium hydroxide (50 mL). The flask was removed from the ice bath and the reaction mixture was stirred at room temperature for 45 minutes; After removing the solvents in vacuum, purification via chromatography on silica gel (Gradient: 25% to 100% ethyl acetate in heptane) gave a racemic mixture of 13 and its atropenantiomer. This was combined with material obtained from a similar reaction carried out in C40 (15.3 g, 30.0 mmols), and separated via supercritical fluid chromatography (Column: Phenomenex Lux Cellulose-2, 5 μm; Eluent: 3: 2 carbon dioxide/methanol). The first atropenantiomer to elute, which exhibited a negative rotation (-), was designated as atropenantiomer 13. Yield: 4.8 g, 12 mmols, 23%. This material was dissolved in hot ethyl acetate (200 mL) and slowly treated with heptane (100 mL) with the mixture being kept at reflux. After slowly cooling to room temperature, the mixture was stirred at room temperature for 18 hours, and then cooled to 0°C and stirred for 30 minutes. Filtration gave the product as a white powdery solid. Yield: 4.17 g, 10.7 mmols, 89% from recrystallization. LCMS m/z 390.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (br s, 1H), 8.06 (dd, J=4.8, 1.5 Hz, 1H), 7.81 (br d, J= 7.9 Hz, 1H), 7.32 (t, JHF=73.4 Hz, 1H), 7.12-7.31 (m, 4H), 2.87 (s, 3H), 2.14 ( s, 3H), 1.48 (s, 3H). Examples 14 and 15 (-)-6-(4-{[3-(Difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethyl-pyrimidine-2,4(1H,3H )-dione (14) and (+)-6-(4-{[3-(Difluoromethyl)py-ridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethylpyrimidine-2,4( 1H,3H)-dione (15) Step 1. Synthesis of 3-[(benzyloxy)methyl]-6-(4-{[3-(difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethylpyrimidine-2,4( 1H,3H)-dione (C41).

[000283] Compound C39 was reacted with 2-chloro-3-(difluoromethyl)pyridine using the method described for the synthesis of C40 in Example 13. The product was obtained as a white solid. Yield: 17.3 g, 35.1 mmols, 86%. LCMS m/z 494.2 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 8.27-8.31 (m, 1H), 8.02-8.07 (m, 1H), 7.41-7.46 (m, 2H), 7, 32-7.37 (m, 2H), 7.26-7.31 (m, 1H), 7.08-7.21 (m, 4H), 7.03 (t, JHF=55.1 Hz, 1H), 5.62 (AB quartet, JAB=9.5 Hz, ΔVAB=9.5 Hz, 2H), 4.80 (br s, 2H), 3.05 (s, 3H), 2.17 (br s, 3H), 1.68 (s, 3H). Step 2. Synthesis of (-)-6-(4-{[3-(difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)- dione (14) and (+)-6-(4-{[3-(difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)- dione (15).

[000284] Compound C41 was converted into a racemic mixture of the products using the method described for the synthesis of 13 in Example 13. This racemate was obtained as an off-white solid. Yield: 12.1 g, 32.4 mmols, 92%. It was separated into its component atropenantiomers via supercritical fluid chromatography (Column: Phenomenex Lux Cellulose-2.5 μm; Eluent: 55:45 carbon dioxide/methanol). The first atropenantiomer to elute exhibited a negative rotation (-), and was designated as Example 14 (5.15 g). This material was dissolved in hot ethyl acetate, concentrated to a volume of 50 mL, and allowed to crystallize at room temperature; 14 was isolated as a white solid, 3.35 g. The filtrate was concentrated and similarly recrystallized to give a white solid (450 mg). Combined yield of 14: 3.8 g, 10 mmols, 28%. The second atropanantiomer to elute, obtained as an off-white solid exhibiting a positive (+) rotation, was designated as Example 15. Yield: 4.9 g, 13.1 mmols, 37%. 14: LCMS m/z 374.2 [M+H]+. 1H NMR (400 MHz, CDCb) δ 8.47 (br s, 1H), 8.27-8.31 (m, 1H), 8.02-8.07 (m, 1H), 7.127.21 (m , 4H), 7.03 (t, JHF=55.0 Hz, 1H), 3.06 (s, 3H), 2.21 (br s, 3H), 1.68 (s, 3H), 15: LCMS m/z 374.0 [M+H]+, 1H NMR (600 MHz, CDCl3) δ 8.98 (br s, 1H), 8.29 (br d, J=4.7 Hz, 1H), 8.04 (br d, J=7.5 Hz, 1H), 7.13-7.21 (m, 4H), 7.03 (t, JHF=55.1 Hz, 1H), 3.06 ( s, 3H), 2.21 (s, 3H), 1.68 (s, 3H). Examples 16 and 17 (+)-5-(4-{[3-(Difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-4,6-dimethylpy-ridazin-3(2H)-one ( 16) and (-)-5-(4-{[3-(Difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-4,6-dimethylpyridazin-3(2H)-one (17) Step 1. Synthesis of 4-hydroxy-3,5-dimethylfuran-2(5H)-one (C42).

[000285] Methylation of ethyl 3-oxopentanoate according to the method of D. Kalaitzakis et al., Tetrahedron: Asymmetry 2007, 18, 2418-2426, gave ethyl 2-methyl-3-oxopentanoate; subsequent treatment with 1 equivalent of bromine in chloroform gave 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 internal temperature of the reaction 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 the slow addition of concentrated hydrochloric acid. After extraction with ethyl acetate, the aqueous layer was saturated with solid sodium chloride and extracted three more times with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 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 filtrates were concentrated in vacuo and treated with a 3:1 mixture of heptane and diethyl ether (300 mL). The mixture was vigorously centrifuged until some of the oil began to solidify. It was then concentrated under reduced pressure to give 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 gave the product as an off-white solid. Yield: 28.0 g, 219 mmols, 37%. 1H NMR (400 MHz, CDCh) 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 trifluoromethanesulfonate (C43).

[000286] Trifluoromethanesulfonic anhydride (23.7 mL, 140 mmols) was added little by little to a solution of C42 (15.0 g, 117 mmols) and N,N-diisopropylethylamine (99%, 24.8 mL, 140 mmols) in dichloromethane (500 mL) at -20°C, at a rate sufficient to maintain the internal temperature of the reaction below -10°C. The reaction mixture was allowed to gradually warm from -20°C to 0°C over 5 hours. It was then passed through a pad of silica gel, dried over magnesium sulfate, and concentrated in vacuum. 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) gave the product as a pale yellow oil. Yield: 21.06 g, 80.94 mmols, 69%. 1H NMR (400 MHz, CDCh) 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]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (C44).

[000287] Benzyl 4-bromo-3-methylphenyl ether was converted to the product using the method described for the synthesis of C33 in Example 12. The product was isolated as a yellow gel. Yield: 15 g, 46 mmols, 67%. 1H NMR (400 MHz, CDCl3) 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 (C45).

[000288] The compound C43 (5.0 g, 19 mmols), C44 (7.48 g, 23.1 mmols), tetrakis(triphenylphosphine) palladium (0) (2.22 g, 1.92 mmol), and carbonate sodium (4.07 g, 38.4 mmols) were combined in 1,4-dioxane (100 mL) and water (5 mL), and heated at reflux for two hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Purification using silica gel chromatography (Eluents: 10:1, then 5:1 petroleum ether/ethyl acetate) gave the product as a white solid. Yield: 5.8 g, 19 mmols, 100%. NMR (400 MHz, CDCl3) δ 7.33-7.49 (m, 5H), 6.98 (d, J=8.5 Hz, 1H), 6.94 (br d, J=2.5 Hz , 1H), 6.88 (br dd, J=8.3, 2.5 Hz, 1H), 5.20 (qq, J=6.7, 1.8 Hz, 1H), 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-3,5-dimethylfuran-2(5H)-one (C46).

[000289] A solution of C45 (5.4 g, 18 mmols) and 1,8-diazabicyclo[5.4.0]undec-7-ene (13.3 g, 87.4 mmols) in acetonitrile (100 mL) was cooled to -60°C. Oxygen was bubbled into the reaction mixture for 20 minutes at -60°C; and the solution was then stirred at 50°C for 18 hours. The reaction mixture was concentrated in vacuo and purified via silica gel chromatography (Eluent: 5:1 petroleum ether/ethyl acetate) to give the product as a colorless oil. Yield: 3.5 g, 11 mmols, 61%. 1H NMR (400 MHz, CDCh), characteristic peaks: δ 7.33-7.49 (m, 5H), 6.92-6.96 (m, 1H), 6.88 (dd, J=8.5 , 2.5 Hz, 1H), 5.09 (s, 2H), 2.20 (s, 3H), 1.73 (s, 3H). Step 6. Synthesis of 5-[4-(benzyloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3(2H)-one (C47).

[000290] A mixture of C46 (3.5 g, 11 mmols) and hydrated hydrazine (85% in water, 1.9 g, 32 mmols) in n-butanol (60 mL) was heated at reflux for 18 hours. After removing the volatiles under reduced pressure, the residue was stirred with ethyl acetate (20 mL) for 30 minutes, and after filtration gave the product as a white solid. Yield: 2.0 g, 6.2 mmols, 56%. 1H NMR (400 MHz, CDCl3) δ 10.93 (br s, 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-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (C48 ).

[000291] A mixture of C47 (17.8 g, 55.6 mmols), 3,4-dihydro-2H-pyran (233 g, 2.77 mols) and p-toluenesulfonic acid monohydrate (2. 1 g, 11 mmols) 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. Chromatography on silica gel (Gradient: 0% to 25% ethyl acetate in petroleum ether) gave the product as a solid, presumably a mixture of diastereomeric atropisomers from its 1H NMR spectrum. Yield: 20 g, 49 mmol, 88%. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 7.32-7.50 (m, 5H), 6.82-6.96 (m, 3H), 6.15 (br d, J=10, 3Hz, 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-2H-pyran-2-yl)pyridazin-3(2H)-one (C49).

[000292] Palladium (10% on charcoal, 1.16 g, 1.09 mmol) was added to a solution of C48 (1.47 g, 3.63 mmol) in methanol (30 mL) and ethyl acetate (10 mL ), and the mixture was hydrogenated (3.45 bar (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 acetate; the combined filtrates were concentrated in vacuo and triturated with heptane, giving the product as a white solid, which was presumed to be a mixture of diastereomeric atropisomers from its 1H NMR spectrum. Yield: 1.01 g, 3.21 mmols, 88%. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 6.74-6.85 (m, 3H), 6.12-6.17 (m, 1H), 4.15-4.23 (m, 1H ), 3,763.84 (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). Step 9. Synthesis of 5-(4-{[3-(difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-4,6-dimethyl-2-(tetrahydro-2H-pyran-2- il)pyridazin-3(2H)-one (C50).

[000293] Compound C49 was reacted with 2-chloro-3-(difluoromethyl)pyridine using the method described for the synthesis of C8 in Examples 3 and 4. The product was obtained as a white solid, presumably a mixture of atropisomers diastereomeric values from their 1H NMR spectrum. Yield: 17.5 g, 39.6 mmols, 82%. LCMS m/z 358.2 [(M - tetrahydropyran)+1]. 1H NMR (400 MHz, DMSO-d6) δ 8.31-8.35 (m, 1H), 8.11-8.15 (m, 1H), 7.29 (t, JHF=54.5 Hz, 1H), 7.28-7.33 (m, 1H), 7.20-7.22 (m, 1H), 7.11-7.19 (m, 2H), 5.92-5.98 ( m, 1H), 3.94-4.01 (m, 1H), 3.57-3.65 (m, 1H), 2.13-2.26 (m, 1H), 2.02 and 2, 03 (2 br s, total 3H), 1.93-2.0 (m, 1H), 1.92 (s, 3H), 1.78 (s, 3H), 1.61-1.74 (m , 2H), 1.48-1.58 (m, 2H). Step 10. Synthesis of (+)-5-(4-{[3-(difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-4,6-dimethylpyridazin-3(2H)-one (16) and (-)-5-(4-{[3-(difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-4,6-dimethylpyridazin-3(2H)-one (17).

[000294] Hydrogen chloride in 1,4-dioxane (4 M, 198 mL, 792 mmols) was added to a solution of C50 (17.5 g, 39.6 mmols) in dichloromethane (200 mL) and 1.4 -dioxane (200 mL), and the reaction mixture was stirred at room temperature for 18 hours. After the solvents were removed in vacuo, the residue was suspended in diethyl ether (200 ml) and slowly treated with a semi-saturated aqueous solution of sodium bicarbonate. The suspension was vigorously stirred for 15 minutes, and then filtered; the collected solid was washed twice with water and twice with diethyl ether. The solid was then suspended in ethanol (200 mL), concentrated to dryness, resuspended in ethanol (200 mL) and concentrated once again. The residue was similarly treated with diethyl ether and heptane to give the racemic product as a white solid. Yield: 12.0 g, 33.6 mmols, 85%. LCMS m/z 358.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.82 (br s, 1H), 8.32-8.36 (m, 1H), 8.10-8.15 (m, 1H), 7.29 (t, JHF=54.2 Hz, 1H), 7.28-7.33 (m, 1H), 7.19-7.22 (m, 1H), 7.10-7.17 (m, 2H ), 2.02 (s, 3H), 1.87 (s, 3H), 1.74 (s, 3H). Separation of the racemate into its component atropenantiomers was done via supercritical fluid chromatography (Column: Chiral Technologies, Chiralpak AS-H, 5 μm; Eluent: 85:15 carbon dioxide/methanol). The first atropenantiomer to elute, obtained as a white solid that exhibited a positive (+) rotation, was designated as Example 16. Yield: 5.22 g, 14.6 mmols, 37%. The second atropenantiomer to elute, also obtained as a white solid but with a negative rotation (-), was designated as Example 17. Yield: 5.31 g, 14.8 mmols, 37%. 16: LCMS m/z 358.2 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 8.23-8.27 (m, 1H), 8,088.12 (m, 1H), 7.26 (dd, J=7.5, 4.9 Hz, 1H), 7.18-7.20 (m, 1H), 7.12-7.14 (m, 2H), 7.12 (t, JHF =55 Hz, 1H), 2.09 (br d, J=0.4 Hz, 3H), 2.00 (s, 3H), 1.90 (s, 3H), 17: LCMS m/z 358, 2 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 8.23-8.27 (m, 1H), 8.08-8.12 (m, 1H), 7.26 (dd, J =7.6, 5.0 Hz, 1H), 7.18-7.20 (m, 1H), 7.12-7.14 (m, 2H), 7.12 (t, JHF=55 Hz, 1H), 2.09 (br d, J=0.5 Hz, 3H), 2.00 (s, 3H), 1.90 (s, 3H). Example 18 6-{4-[(3-Chloropyridin-2-yl)sulfanyl]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (18) Step 1. Synthesis of 4-(3,5-dimethyl-2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,3,6-tetrahydropyrimidin-4-yl) -3-methylphenyl trifluoromethanesulfonate (C51).

[000295] Trifluoromethanesulfonic anhydride (1.3 g, 4.6 mmols) was slowly added to a 0°C solution of C5 (600 mg, 1.6 mmol) in pyridine (15 mL), and the reaction mixture was stirred at room temperature for 3 hours. After the solvent was removed under reduced pressure, the residue was purified by silica gel chromatography (Gradient: 5% to 17% ethyl acetate in petroleum ether) to give the product as a yellow oil. Yield: 790 mg, 1.55 mmol, 97%. 1H NMR (400 MHz, CDCl3) δ 7.27-7.33 (m, 2H), 7.21-7.25 (m, 1H), 5.50 (AB quartet, JAB=9.2 Hz, ΔVAB=4.1 Hz, 2H), 3.73-3.79 (m, 2H), 3.02 (s, 3H), 2.26 (br s, 3H), 1.63 (s, 3H) , 1.00-1.06 (m, 2H), 0.03 (s, 9H). Step 2. Synthesis of S-[4-(3,5-dimethyl-2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,2,3,6-tetrahydropyrimidin-4 -yl)-3-methylphenyl] ethanethioate (C52).

[000296] Tris(dibenzylideneacetone)dipalladium (0) (27 mg, 29 μmol) and (R)-(-)-1-[(SP)-2-(dicyclohexylphosphine)ferrocenyl]ethyldi-tert-butylphosphine (ligand of Josiphos, 33 mg, 60 μmol) was added to a solution of C51 (305 mg, 0.600 mmol) in degassed toluene (7 mL), and the mixture was stirred for 5 minutes at room temperature. Potassium thioacetate (274 mg, 2.40 mmols) was added and the reaction mixture was heated at 120 ° C for 24 hours. It was then filtered through a pad of diatomaceous earth, and the pad was washed with ethyl acetate; the combined filtrates were concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in petroleum ether) gave the product as a brown gum. Yield: 172 mg, 0.396 mmol, 66%. 1H NMR (400 MHz, CDCb) δ 7.38-7.44 (m, 2H), 7.15 (d, J=7.8 Hz, 1H), 5.48-5.53 (m, 2H) , 3.73-3.79 (m, 2H), 3.03 (s, 3H), 2.47 (s, 3H), 2.20 (s, 3H), 1.65 (s, 3H), 1.00-1.06 (m, 2H), 0.03 (s, 9H). Step 3. Synthesis of 1,5-dimethyl-6-(2-methyl-4-sulfanylphenyl)-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H)-dione (C53 ).

[000297] A solution of C52 (300 mg, 0.69 mmol) and potassium hydroxide (168 mg, 2.99 mmols) in a mixture of methanol (10 mL) and water (3 drops) was stirred at room temperature for 3 hours. After neutralization with 1M aqueous hydrochloric acid, the mixture was concentrated in vacuo. Chromatography on preparatory thin-layer silica gel (Eluent: 3:1 petroleum ether/ethyl acetate) gave the product as a yellow syrup. Yield: 170 mg, 0.433 mmol, 63% yield. Step 4. Synthesis of 6-{4-[(3-chloropyridin-2-yl)sulfanyl]-2-methylphenyl}-1,5-dimethyl-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2 ,4(1H,3H)-dione (C54).

[000298] Compound C53 was reacted with 3-chloro-2-fluoropyridine using the method described for the synthesis of C8 in Examples 3 and 4. The product was obtained as a white solid. Yield: 20 mg, 40 μmol, 40%. Step 5. Synthesis of 6-{4-[(3-chloropyridin-2-yl)sulfanyl]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (18).

[000299] A solution of C54 (20 mg, 40 μmol) in trifluoroacetic acid (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in methanol (5 mL). Potassium carbonate (69 mg, 0.50 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours and filtered; The filtrate was concentrated in vacuo and purified via preparatory thin-layer silica gel chromatography (Eluent: 1:2 petroleum ether/ethyl acetate) to give the product as a white solid. Yield: 7.5 mg, 20 μmol, 50%. LCMS m/z 374.0 [M+H]+, 1H NMR (400 MHz, CDCl3) δ 8.25 (dd, J=4.7, 1.6 Hz, 1H), 8.19 (br s, 1H), 7.64 (dd, J=7.9, 1.6 Hz, 1H), 7.55-7.57 (m, 1H), 7.51-7.55 (m, 1H), 7 .15 (d, J=7.8 Hz, 1H), 7.06 (dd, J=7.9, 4.6 Hz, 1H), 3.05 (s, 3H), 2.21 (br s , 3H), 1.68 (s, 3H). Example 19 1,5-Dimethyl-6-(7-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1H-indol-4-yl)pyrimidine-2,4(1H,3H)-dione ( 19) Step 1. Synthesis of tert-butyl 7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (C55).

[000300] To a solution of tert-butyl 4-bromo-7-methoxy-1H-indole-1-carboxylate (which can be prepared via tert-butoxycarbonyl protection of 4-bromo-7-methoxy-1H-indole) ( 1.0 g, 3.1 mmols) in 1,4-dioxane (20 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi -1,3,2-dioxaborolane (1.46 g, 5.75 mmols), potassium acetate (902 mg, 9.19 mmols) and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (II), complex in dichloromethane (498 mg, 0.610 mmol). The reaction mixture was stirred for 5 hours at 120°C, and then cooled and filtered; The filtrate was concentrated under reduced pressure and purified via silica gel chromatography (Gradient: 0% to 6% ethyl acetate in petroleum ether) to give the product as a yellow solid. Yield: 520 mg, 1.4 mmol, 45%. 1H NMR (400 MHz, CDCh) δ 7.69 (d, J=8.0 Hz, 1H), 7.55 (d, J=3.5 Hz, 1H), 7.10 (d, J=3 .6 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 3.96 (s, 3H), 1.62 (s, 9H), 1.37 (s, 12H). Step 2. Synthesis of tert-butyl 4-{1-[(benzyloxy)methyl]-3,5-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl}-7 -methoxy-1H-indole-1-carboxylate (C56).

[000301] To a solution of C55 (600 mg, 1.6 mmol) in 1,4-dioxane (20 mL) were added C37 (600 mg, 1.8 mmol), tetrakis (triphenylphosphine) palladium (0) (186 mg, 0.161 mmol) and barium hydroxide (830 mg, 4.8 mmols). The reaction mixture was stirred for 18 hours at 60°C, and then cooled and filtered; the filtrate was concentrated in vacuum and subjected to chromatography on silica gel (Gradient: 0% to 35% ethyl acetate in petroleum ether), giving the product as a yellow gum. Yield: 310 mg, 0.61 mmol, 38%. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=3.6 Hz, 1H), 7.45 (br d, J=7 Hz, 2H), 7,277.39 (m, 3H, assumed; partially obscured by the solvent peak), 6.94 (AB quartet, JAB=8.2 Hz, ΔVAB=35.2 Hz, 2H), 6.24 (d, J=3.6 Hz, 1H), 5.63 (AB quartet, JAB=9.4 Hz, ΔVAB=6.7 Hz, 2H), 4.81 (s, 2H), 4.01 (s, 3H), 3.00 (s, 3H), 1.66 (s, 9H), 1.64 (s, 3H). Step 3. Synthesis of 6-(7-hydroxy-1H-indol-4-yl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C57).

[000302] Boron tribromide (1.5 g, 6.0 mmols) was added dropwise to a -78°C solution of C56 (310 mg, 0.61 mmol) in dichloromethane (10 mL), and the mixture reaction was stirred for 18 hours at room temperature. After addition of methanol (10 ml) and sodium bicarbonate (1 g), the mixture was filtered and the filtrate was concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 4% methanol in dichloromethane) gave the product as a yellow gum. Yield: 40 mg, 0.15 mmol, 24%. 1H NMR (400 MHz, CD3OD) δ 7.29 (d, J=3.0 Hz, 1H), 6.70 (AB quartet, JAB=7.7 Hz, ΔvAB=41.9 Hz, 2H), 6.18 (d, J=3.1 Hz, 1H), 3.00 (s, 3H), 1.61 (s, 3H). Step 4. Synthesis of 1,5-dimethyl-6-(7-{[3-(trifluoromethyl)pyridin-2-yl]oxy}-1H-indol-4-yl)pyrimidine-2,4(1H,3H) -dione (19).

[000303] 2-Chloro-3-(trifluoromethyl)pyridine (133 mg, 0.733 mmol) and cesium fluoride (12 mg, 79 μmol) were added to a solution of C57 (20 mg, 74 μmol) in N, N-dimethylformamide (5 mL). The reaction mixture was stirred for 18 hours at 100°C, and then cooled and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparatory thin-layer silica gel chromatography (Eluent: 10:1 dichloromethane/methanol) to give the product as a white solid. Yield: 9.2 mg, 22 μmol, 30%. LCMS m/z 417.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.20-8.27 (m, 2H), 7.34 (d, J=3.1 Hz, 1H), 7.28 (br dd, J=7.5 Hz, 1H), 7.01 (AB quartet, JAB=7.9 Hz, ΔVAB=4.4 Hz, 2H), 6.35 (d, J=3.1 Hz, 1H), 3.05 ( s, 3H), 1.65 (s, 3H). Preparations

[000304] Preparations P1 and P2 describe the preparation of some starting materials or intermediates used for the preparation of certain exemplary compounds of the invention. Preparation P1 6-(4-Hydroxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one (P1) Step 1. Synthesis of 1-(4-methoxy-2-methylphenyl)propan-2-one (C58).

[000305] This experiment was carried out four times. Tributyl(methoxy)stannan (400 g, 1.24 mol), 1-bromo-4-methoxy-2-methylbenzene (250 g, 1.24 mol), prop-1-en-2-yl acetate (187 g, 1.87 mol), palladium(II) acetate (7.5 g, 33 mmols) and tri-o-tolylphosphine (10 g, 33 mmols) were together stirred in toluene (2 L) at 100°C for 18 hours . After cooling to room temperature, the reaction mixture was treated with an aqueous solution of potassium fluoride (4 M, 400 mL) and stirred for two hours at 40°C. The resulting mixture was diluted with toluene (500 mL) and filtered through diatomaceous earth; the filter pad was vigorously washed with ethyl acetate (2 x 1.5 L). The organic phase from the combined filtrates was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via chromatography on silica gel (Gradient: 0% to 5% ethyl acetate in petroleum ether) gave the product as a yellow oil. Combined yield: 602 g, 3.38 mol, 68%. LCMS m/z 179.0 [M+H]+, 1H NMR (400 MHz, CDCl3) δ 7.05 (d, J=8.3 Hz, 1H), 6.70-6.77 (m, 2H ), 3.79 (s, 3H), 3.65 (s, 2H), 2.22 (s, 3H), 2.14 (s, 3H). Step 2. Synthesis of 1-(4-methoxy-2-methylphenyl)propane-1,2-dione (C59).

[000306] Compound C58 (6.00 g, 33.7 mmols) and selenium dioxide (7.47 g, 67.3 mmols) were suspended in 1,4-dioxane (50 mL) and heated to 100°C for 18 hours. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth; the filtrate was concentrated in vacuo. Chromatography on silica gel (Eluent: 10% ethyl acetate in heptane) gave the product as a bright yellow oil. Yield: 2.55 g, 13.3 mmols, 39%. LCMS m/z 193.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.6 Hz, 1H), 6.81 (br d, half of AB quartet, J=2.5 Hz, 1H), 6, 78 (br dd, half standard of ABX, J=8.7, 2.6 Hz, 1H), 3.87 (s, 3H), 2.60 (br s, 3H), 2.51 (s, 3H). Step 3. Synthesis of 6-(4-methoxy-2-methylphenyl)-5-methylpyrazin-2(1H)-one (C60).

[000307] Compound C59 (4.0 g, 21 mmols) and glycinamide acetate (2.79 g, 20.8 mmols) were dissolved in methanol (40 mL) and cooled to -10°C. An aqueous sodium hydroxide solution (12 N, 3.5 mL, 42 mmols) was added, and the resulting mixture was slowly warmed to room temperature. After stirring for 3 days, the reaction mixture was concentrated in vacuo. The residue was diluted with water, and 1 M aqueous hydrochloric acid was added until the pH reached approximately 7. The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated at reduced pressure. The resulting residue was suspended with 3:1 ethyl acetate/heptane, stirred for 5 minutes, filtered, and concentrated in vacuo. Chromatography on silica gel (Eluent: ethyl acetate) gave the product as a brown solid that contained 15% of an unwanted regioisomer; this material was used without further purification. Yield: 2.0 g. LCMS m/z 231.1 [M+H]+. 1H NMR (400 MHz, CDCh) δ 8.09 (s, 1H), 7.14 (d, J=8.2 Hz, 1H), 6.82-6.87 (m, 2H), 3.86 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H). Step 4. Synthesis of 6-(4-methoxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one (C61)

[000308] Compound C60 (from the previous step, 1.9 g) was dissolved in N,N-dimethylformamide (40 mL). Lithium bromide (0.86 g, 9.9 mmols) and sodium bis(trimethylsilyl)amide (95%, 1.91 g, 9.89 mmols) were added, and the resulting solution was stirred for 30 minutes . Methyl iodide (0.635 mL, 10.2 mmols) was added and stirring continued at room temperature for 18 hours. The reaction mixture was then diluted with water and brought to a pH of approximately 7 by the slow and gradual addition of 1 M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed several times with water, dried. over magnesium sulfate, filtered, and concentrated. Chromatography on silica gel (Gradient: 75% to 100% ethyl acetate in heptane) gave the product as a viscous orange oil. Yield: 1.67 g, 6.84 mmol, 33% in two steps. LCMS m/z 245.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.03 (br d, J=8 Hz, 1H), 6.85-6.90 (m, 2H), 3.86 ( s, 3H), 3.18 (s, 3H), 2.08 (br s, 3H), 2.00 (s, 3H). Step 5. Synthesis of 6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one (P1).

[000309] To a solution at -78°C of C61 (1.8 g, 7.4 mmols) in dichloromethane (40 mL) was added a solution of boron tribromide in dichloromethane (1 M, 22 mL, 22 mmols). The cooling bath was removed after 30 minutes, and the reaction mixture was allowed to warm to room temperature and stir for 18 hours. The reaction was cooled to -78°C, and methanol (10 mL) was added slowly; the resulting mixture gradually warmed to room temperature. After the solvent was removed in vacuo, methanol (20 mL) was added, and the mixture was again concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 mL) and water (200 mL), the aqueous layer was brought to pH 7 via the gradual addition of a saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to give the product as a light brown oil. Yield: 1.4 g, 6.0 mmols, 81%. LCMS m/z 231.1 [M+H]+. 1H NMR (400 MHz, CDCI3) δ 8.21 (s, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.876.89 (m, 1H), 6.85 (br dd, J=8.2, 2.5 Hz, 1H), 3.22 (s, 3H), 2.06 (br s, 3H), 2.03 (s, 3H). Preparation P2 6-(4-Hydroxy-2-methylphenyl)-1,5-dimethylpyrimidin-2(1H)-one (P2) Step 1. Synthesis of 1-(4-hydroxy-2-methylphenyl)propan-1-one (C62).

[000310] 3-Methylphenol (9.0 g, 83 mmols) was combined with trifluoromethanesulfonic acid (90 mL), cooled to -10 ° C, and treated dropwise with propanoyl chloride (7.7 g, 83 mmols). The reaction mixture was stirred at -10°C for 3 hours and then at room temperature for 18 hours, after which it was poured into ice water (600 mL). The resulting solid was collected via filtration and purified by chromatography on silica gel (Gradient: 5% to 70% ethyl acetate in petroleum ether) to give the product as an off-white solid. Yield: 6.7 g, 41 mmols, 49%. 1H NMR (400 MHz, CD3OD) δ 7.75 (d, J=8.5 Hz, 1H), 6.64-6.69 (m, 2H), 2.92 (q, J=7.3 Hz , 2H), 2.45 (s, 3H), 1.13 (t, J=7.3 Hz, 3H). Step 2. Synthesis of 3-(dimethylamino)-1-(4-methoxy-2-methylphenyl)-2-methylprop-2-en-1-one (C63).

[000311] This experiment was carried out in four batches. A mixture of C62 (1.0 g, 6.1 mmols) and N,N-dimethylformamide dimethyl acetal (15 mL) was stirred at 130°C for 30 hours. The four reaction mixtures were combined and concentrated to dryness, giving the product as a dark oil. This was used in the next step without further purification. Yield: 5.0 g, 21 mmols, 86%. Step 3. Synthesis of 6-(4-methoxy-2-methylphenyl)-1,5-dimethylpyrimidin-2(1H)-one (C64).

[000312] This experiment was carried out in two batches. A mixture of C63 (from the previous step, 2.5 g, 11 mmols), 1-methylurea (1.35 g, 18.2 mmols) and p-toluenesulfonic acid (3.13 g, 18.2 mmols) in 1 ,4-dioxane (100 mL) was heated at reflux for 40 hours, and then concentrated under reduced pressure. The residue was mixed with toluene (100 mL), treated with p-toluenesulfonic acid (3.13 g, 18.2 mmols) and heated at reflux for a further 20 hours. The two crude products were combined and concentrated in vacuum. Purification via silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) gave the product as a brown solid. Yield: 2.5 g, 10 mmols, 45%. 1H NMR (400 MHz, CDCh) δ 8.52 (s, 1H), 6.98 (br d, half of AB quartet, J=9 Hz, 1H), 6.86-6.92 (m, 2H ), 3.87 (s, 3H), 3.24 (s, 3H), 2.08 (s, 3H), 1.78 (s, 3H). Step 4. Synthesis of 6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrimidin-2(1H)-one (P2).

[000313] To a -70°C solution of C64 (2.5 g, 10 mmols) in dichloromethane (100 mL) was added boron tribromide (17.9 g, 71.4 mmols) in drops. The reaction mixture was stirred at a temperature of -60°C to -70°C for one hour and then at room temperature for 18 hours, after which it was cooled to -60°C and quenched with methanol. Water (100 mL) was added, and the mixture was adjusted to a pH of 6 via the slow addition of solid sodium bicarbonate. The mixture was extracted with dichloromethane (100 ml) and ethyl acetate (5 x 100 ml); the combined organic layers were dried, filtered, and concentrated in vacuo. The residue was washed with a mixture of petroleum ether and ethyl acetate (4:1, 40 mL) and the solid was collected by filtration to give the product as a yellow solid. Yield: 2.2 g, 9.5 mmols, 95%. LCMS m/z 231.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 7.05 (d, J=8.3 Hz, 1H), 6.88-6.91 (br s, 1H), 6, 87 (br dd, J=8.3, 2.2 Hz, 1H), 3.38 (s, 3H), 2.11 (s, 3H), 1.89 (s, 3H). Method A

[000314] Method A describes a specific method for preparing certain exemplary compounds of the invention. Preparation of 1,5-dimethyl-6-[2-methyl-4-(substituted pyridin-2-yloxy)phenyl]pyrimidine-2,4(1H,3H)-diones Step 1. Synthesis of 1,5-dimethyl-6-[2-methyl-4-(substituted pyridin-2-yloxy)phenyl]-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4( 1H,3H)- diones (C65).

[000315] A solution of C5 in N,N-dimethylformamide (0.33 M, 300 μL, 100 μmol) was combined in a reaction flask with the appropriately substituted 2-chloropyridine or 2-fluoropyridine (100 μmol). Potassium carbonate (300 μmol), copper(I) iodide (10 μmol), and tetrabutylammonium bromide (20 μmol) were added in a nitrogen atmosphere, and the flask was capped and shaken at 130°C for 16 hours. The solvent was removed using a Speed-Vac® concentrator, and the residue was partitioned between ethyl acetate (1 mL) and water (1 mL); the aqueous layer was extracted with ethyl acetate (2 x 1 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the crude product, which was used directly in the next step. Step 2. Synthesis of 1,5-dimethyl-6-[2-methyl-4-(substituted pyridin-2-yloxy)phenyl]pyrimidine-2,4(1H,3H)-diones.

[000316] A 1,5-dimethyl-6-[2-methyl-4-(substituted pyridin-2-yloxy)phenyl]-3-{[2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H ,3H)-dione (C65) from the previous step was dissolved in a mixture of dichloromethane and trifluoroacetic acid (4:1, 1 mL), and the reaction vial was capped and stirred at 30°C for 16 hours. After removing the solvents, the product was purified by high-performance liquid chromatography using one of the following systems: a) DIKMA Diamonsil(2) C18, 5 μm; mobile phase A: water containing 0.225% formic acid; B: acetonitrile containing 0.225% formic acid; Gradient: 35% to 70% B; b) Phenomenex Gemini C18, 8 μm; mobile phase A: aqueous ammonium hydroxide, pH 10; mobile phase B: acetonitrile; Gradient: 35% to 75% B.

[000317] Table 1 below lists some additional exemplary compounds of the invention (Examples 20-81) that were made using methods, intermediates, and preparations described in this report. Table 1. Examples 20 - 81 (including Synthesis Method and Data 1. In this case, the reaction with chloropyridine was carried out using tris(dibenzylideneacetone)dipalladium (0), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) and potassium tert-butoxide in toluene at elevated temperature . 2. Compound C11 was reacted with (4-hydroxyphenyl)boronic acid, under the conditions described for the synthesis of C12 in Example 5, to give 1-ethyl-6-(4-hydroxyphenyl)-5-methyl-3-{[ 2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H)-dione. 3. Compound C18 was reacted with (4-hydroxyphenyl)boronic acid, under the conditions described for the synthesis of C19 in Example 6, to give 5-ethyl-6-(4-hydroxyphenyl)-1-methyl-3-{[ 2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H)-dione. 4. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1 x 50 mm, 5 μm. Mobile phase A: 0.05% ammonium hydroxide in water; Mobile phase B: acetonitrile. Gradient: 0 to 0.5 minutes, 5% B; 0.5 to 3.4 minutes, linear from 5% to 100% B. Flow rate: 0.8 mL/minute. 5. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1 x 50 mm, 5 μm. Mobile phase A: 0.0375% trifluoroacetic acid in water; Mobile phase B: 0.01875% trifluoroacetic acid in acetonitrile. Gradient: 0 to 0.5 minutes, 25% B; 0.5 to 3.5 minutes, linear from 25% to 100% B. Flow rate: 0.8 mL/minute. 6. Identical to footnote 5, except the gradient used was: 0 to 0.6 minutes, linear from 1% to 5% B; 0.6 to 4.0 minutes, linear from 5% to 100% B. 7. The requisite 2-chloropyridine was prepared via reaction of 2-chloro-3-iodopyridine with a salt of the appropriate azetidine, using palladium acetate (II ), 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphane) (BINAP) and cesium carbonate in toluene at elevated temperature. 8. Reaction of 2-chloropyridin-3-ol with bromocyclopropane, in the presence of cesium carbonate in N,N-dimethylacetamide at 150°C, gave 2-chloro-3-(cyclopropyloxy)pyridine. 9. Reaction of 2-chloro-5-fluoropyridin-4-ol with iodomethane and silver carbonate gave 2-chloro-5-fluoro-4-methoxypyridine. 10. The reaction between phenol C5 and chloropyridine was carried out via reaction with copper (I) iodide and cesium carbonate in pyridine at 120°C. 11. Deprotection was carried out according to Example 5. 12. Reaction of ethyl 2-chloropyridine-3-carboxylate with methylmagnesium iodide gave 2-(2-chloropyridin-3-yl)propan-2-ol. 13. Olefin reduction was carried out via hydrogenation using palladium on carbon and N,N-diisopropylethylamine in methanol. 14. In this case, the reaction with chloropyridine was carried out using 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) in place of di-tert-butyl[3,4,5,6-tetramethyl-2 ',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane. 15. 1-(2-Chloropyridin-3-yl)ethanone was converted to 2-chloro-3-(1,1-difluoroethoxy)pyridine using the method of DB Horne et al., Te-trahedron Lett. 2009, 50, 5452-5455. With deprotection, the difluoroethoxy group was also cleaved. 16. In this case, cesium fluoride was used instead of cesium carbonate in the reaction of chloropyridine with phenol C49. 17. Compound C3 was reacted with (4-hydroxyphenyl)boronic acid, under the conditions described for the preparation of C4 in Examples 1 and 2, to give 6-(4-hydroxyphenyl)-1,5-dimethyl-3-{[ 2-(trimethylsilyl)ethoxy]methyl}pyrimidine-2,4(1H,3H)-dione. 18. In this case, deprotection was carried out in trifluoroacetic acid at 100°C. 19. The racemic product was separated into its atropenantiomers via high-performance liquid chromatography (Column: Chiral Technologies, Chiralpak AD-H, 5 μm; Gradient: ethanol in heptane). This Example was the first atropenantiomer to elute, and it exhibited a positive (+) rotation. 20. Compound C49 was reacted with 2-chloro-3-iodopyridine to give 5-{4-[(3-iodopyridin-2-yl)oxy]-2-methylphenyl}-4,6-dimethyl-2-(tetra - hydro-2H-pyran-2-yl)pyridazin-3(2H)-one; subsequent Suzuki reaction with cyclopropylboronic acid gave 5-{4-[(3-cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-4,6-dimethyl-2-(tetrahydro-2H-pyran-2- il)pyridazin-3(2H)-one. Deprotection in this case was carried out with trifluoroacetic acid and not hydrochloric acid. 21. The requisite 2-chloro-3-(oxetan-3-yl)pyridine was prepared from (2-chloropyridin-3-yl)boronic acid using the method described by MAJ Duncton et al., Org. Lett. 2008, 10, 3259-3262. 22. 2-Chloro-3-(difluoromethoxy)-4-methylpyridine was prepared from 2-chloro-4-methylpyridin-3-ol using the conditions described by LF Frey et al., Tetrahedron 2003, 59, 6363-6373 . 23. The racemic product was separated into its component atropenantiomers using chiral separation. Conditions for analytical HPLC. Column: Chiralpak AD-H, 20 x 250 mm; Mobile phase A: Heptane; Mobile phase B: Ethanol; Gradient: 5.0% to 95% B, linear for 12 minutes; Flow rate: 28 mL/minute. The first atropenantiomer to elute, which exhibited a positive rotation (+), was designated as Example 55; the second atropenantiomer to elute, which gave a negative rotation (-), was designated as Example 54. 24. A 2-[1-(3,4-dimethoxybenzyl)-3,5-dimethyl-2,6-dioxo-1 ,2,3,6-tetrahydropyrimidin-4-yl]-5-hydroxybenzonitrile requirement was prepared via reaction of C26 with 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan- 2-yl)benzonitrile, mediated by chloro(2-dicyclohexylphosphino-2',6'-dimethoxy- 1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium (II) and potassium phosphate. 25. Conditions for analytical HPLC. Column: Waters Atlantis dC18, 4.6 x 50 mm, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95% B, linear over 4.0 minutes; Flow rate: 2 mL/minute. 26. Reaction of C49 with methyl 2-chloropyridine-3-carboxylate gave methyl 2-{4-[3,5-dimethyl-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1, 6-dihydropyridazin-4-yl]-3-methylphenoxy}pyridine-3-carboxylate; the ester group was converted to an amide via subjection to ammonium hydroxide in methanol at elevated temperature, to give 2-{4-[3,5-dimethyl-6-oxo-1-(tetrahydro-2H-pyran-2 -yl)-1,6-dihydropyridazin-4-yl]-3-methylphenoxy}pyridine-3-carboxamide. 27. Methyl 2-{4-[3,5-dimethyl-6-oxo-1-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridazin-4-yl]-3 -methylphenoxy}pyridine-3-carboxylate (see footnote 26) was deprotected to give this Example. 28. 2,4-Dichloro-3-methylpyridine was converted to 2-chloro-4-methoxy-3-methylpyridine via reaction with sodium hydride/methanol. 29. In this case, deprotection was carried out with trifluoroacetic acid in dichloromethane at room temperature. 30. The requisite 2-chloro-4-methyl-3-(trifluoromethyl)pyridine was prepared via reaction of 2-chloro-3-iodo-4-methylpyridine with methyl difluoro(fluorosulfonyl)acetate and copper(I) iodide in N,N-dimethylformamide at 90°C. 31. Reaction of 2-chloro-4-methoxypyridine-3-carbaldehyde with (diethylamino)sulfur trifluoride gave 2-chloro-3-(difluoromethyl)-4-methoxypyridine. 32. Reaction of 2,4-dichloro-3-iodopyridine with sodium methoxide in methanol gave 2-chloro-3-iodo-4-methoxypyridine; this material was converted to 2-chloro-4-methoxy-3-(trifluoromethyl)pyridine as described in footnote 30. 33. Final deprotection was carried out using hydrogen chloride in methanol at room temperature. 34. Deprotection was performed using the method described in Examples 16 and 17. 35. Separation of atropenantiomers was performed via supercritical fluid chromatography (Column: Chiral Technologies, Chiralpak AS-H, 5 μm; Eluent: 85:15 carbon dioxide/methanol). The first atropenantiomer to elute exhibited a positive spin (+), and was designated as Example 66. The second atropenantiomer to elute exhibited a negative spin (-), and was designated as Example 65. 36. In this case, the spectrometry data of mass were obtained in the racemate, before the separation of the atropenantiomers. 37. Compound C37 was reacted with (4-hydroxyphenyl)boronic acid, using the method described for the preparation of C4 in Examples 1 and 2, to give 3-[(benzyloxy)methyl]-6-(4-hydroxyphenyl)- 1,5-dimethylpyrimidine-2,4(1H,3H)-dione. 38. The conditions for the reaction of phenol with chloropyridine were similar to those used for the synthesis of C7 in Examples 1 and 2. 39. After the coupling reaction, the reaction mixture was distributed between water and ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo; this material was deprotected with hydrogen chloride in 1,4-dioxane. 40. Purification was carried out via reversed-phase high-performance liquid chromatography. Column: Waters Sunfire C18, 5 μm; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v); Gradient: 30% to 50% B. 41. Purification was carried out via reversed-phase high-performance liquid chromatography using an appropriate gradient in one of the following systems: a) Column: Agela Durashell C18, 5 μm; Mobile phase A: ammonium hydroxide in water, pH 10; Mobile phase B: acetonitrile; b) Column: Phenomenex Gemini, 10 μm; Mobile phase A: ammonium hydroxide in water, pH 10; Mobile phase B: acetonitrile; c) Column: Phenomenex Gemini, 8 μm; Mobile phase A: 0.225% formic acid in water; Mobile phase B: acetonitrile; d) Column: YMS C18, 5 μm; Mobile phase A: ammonium hydroxide in water, pH 10; Mobile phase B: acetonitrile. 42. Conditions for analytical HPLC. Column: Waters XBridge C18, 2.1 x 50 mm, 5 μm. Mobile phase A: 0.0375% trifluoroacetic acid in water; Mobile phase B: 0.01875% trifluoroacetic acid in acetonitrile. Gradient: 0 to 0.5 minutes, 10% B; 0.5 to 4.0 minutes, linear from 10% to 100% B. Flow rate: 0.8 mL/minute. 43. Compound C33 was reacted with 6-bromo-3-(3,4-dimethoxybenzyl)-1-cyclopropyl-5-methylpyrimidine-2,4(1H,3H)-dione, using the method described for example 12, to give Example 81. The intermediate, 6-bromo-3-(3,4-dimethoxybenzyl)-1-cyclopropyl-5-methylpyrimidine-2,4(1H,3H)-dione, was prepared from 1-cyclopropyl urea commercially available following the methods described for the preparation of C10 and C34.

Example AA: D1 and Data Receptor Binding Assay

[000318] The affinity of the compounds described in this invention was determined by competitive binding assays similar to those described by 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 in binding to a D1 receptor.

[000319] D1 binding assays were performed using human LTK overexpressing cell lines. To determine the basic parameters of the assay, ligand concentrations were determined from saturated binding studies where it was found that the Kd for [3H]-SCH23390 was equal to 1.3 nM. From tissue concentration curve studies, it was determined that the optimal amount of tissue is 1.75 mg/mL per 96-well plate using 0.5 nM [3H]-SCH23390. These ligand and tissue concentrations were used in time course studies to determine linearity and equilibrium conditions for binding. Binding occurred in 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 MgCh using a Polytron and centrifugation in a centrifuge at 40,000 xg for 10 minutes. The pellet was resuspended in assay buffer [50 mM Tris (pH 7.4 at room temperature) containing 4 mM MgSO4 and 0.5 mM EDTA]. Incubations were initiated by adding 200 μL of tissue to 96-well plates containing test drugs (2.5 μL) and 0.5 nM [3H]-SCH23390 (50 μL) in a final volume of 250 μL. Nonspecific binding was determined by radioligand binding in the presence of a saturating concentration of (+)-Butaclamol (10 μM), a D1 antagonist. After a 30-minute incubation period at 37°C, assay samples were quickly filtered through Unifilter-96 GF/B PEI-coated filter plates and rinsed with 50 mM Tris buffer (pH 7.4 to 4 °C). Levels of membrane-bound [3H]-SCH23390 were determined by liquid scintillation counting of filter plates in Ecolume. The IC50 value (concentration at which 50% inhibition of specific binding occurs) was calculated by linear regression of concentration-response data in Microsoft Excel. Ki values were calculated according to the Cheng-Prusoff equation: where [L] = concentration of free radioligand and Kd = radioligand dissociation constant for the D1 receptor (1.3 nM for [3H]-SCH23390). Example BB: HTRF D1 cAMP Assay and Data

[000320] The HTRF (homogeneous time-resolved fluorescence) assay of D1 cAMP (cyclic adenosine monophosphate) used and described in this report is a competitive immunoassay between native cAMP produced by cells and cAMP labeled with XL-665. This assay was used to determine the ability of a test compound to agonize (including partially agonize) D1. A cryptate labeled with Mab anti-cAMP labeled Cryptate visualizes the tracer. The maximum signal was obtained when the samples did not contain free cAMP due to the proximity of the donor (Eu cryptate) and acceptor (XL665) entities. The signal was therefore inversely proportional to the concentration of cAMP in the sample. A time-resolved and ratiometric measurement (at 665 nm/at 620 nm) minimizes interference with the medium. cAMP HTRF assays are commercially available, for example, from Cisbio Bioassays, IBA group.

Materials and methods

[000321] Materials: The "cAMP Dynamic" kit was purchased from Cisbio International (Cisbio 62AM4PEJ). Multidrop Combi (Thermo Scientific) was used for assay additions. An EnVision reader (PerkinElmer) was used to read the HTRF.

[000322] Cell culture: A stable cell line HEK293T/hD1#1 was constructed in-house (Pfizer Ann Arbor). Cells were grown as adherent cells in NuncT500 flasks in high glucose DMEM (Invitrogen 11995-065), 10% dialyzed fetal bovine serum (Invitrogen 26400-044), 1x MEM NEAA (In-vitrogen 1140, 25 mM HEPES 72 or 96 hours after growth, the cells were rinsed with DPBS, and 0.25% Trypsin-EDTA was added to dislodge the cells. Medium was then added and the cells were centrifuged and the medium was removed. The cell pellets were resuspended in cell culture freezing medium (Invitrogen 12648-056) at a density of 4e7 cells/mL One mL aliquots of the cells were made into cryovials and frozen at -80°C for future use in the D1 HTRF assay.

[000323] Procedure for the D1 cAMP HTRF assay: Frozen cells were quickly thawed, resuspended in 50 mL of warm medium and allowed to settle for 5 minutes before centrifugation (1000 rpm) at room temperature. The medium was removed and the cell pellet was resuspended in PBS/0.5 μM IBMX generating 2e5 cells/mL. Using a Multidrop Combi, 5 μL cells/well were added to the assay plate (Greiner 784085), which already contained 5 μL of a test compound. Control compounds [5 μM dopamine (final) and 0.5% DMSO (final)] were also included in all plates for data analysis. Cells and compounds were incubated at room temperature for 30 minutes. Working solutions of cAMP-D2 and anti-cAMP-cryptate were prepared according to Cisbio instructions. Using Multidrop, 5 μL of cAMP-D2 working solution was added to the assay plate containing the test compound and cells. Using Multidrop, 5 μL of anti-cAMP-cryptate working solutions were added to the assay plate containing the test compound, cells, and cAMP-D2. The assay plate was incubated for one hour at room temperature. The breadboard was read on an EnVision plate reader using Cisbio recommended settings. A cAMP standard curve was generated using the cAMP stock solution offered in the Cisbio kit.

[000324] Data Analysis: Data analysis was done using computer software. Percentage effects were calculated from control compounds. The EC50 ratio was determined using raw ratio data from the EnVision reader. The cAMP standard curve was used in an analysis program to determine cAMP concentrations from the raw ratio data. The EC50 of cAMP was determined using the calculated cAMP data. Table 2. Biological Data and Compound Name for Examples 1 - 81. The. Value represents a single determination.

[000325] Various modifications of the invention, in addition to those described in this report, will become apparent to those skilled in the art from the preceding description. Such modifications are also considered to fall within the scope of the appended claims. Each reference (including all patents, patent applications, newspaper articles, books, and any other publications) cited in this application is incorporated herein in its entirety by reference.

Claims (30)

1. Compound, characterized by the fact that it has formula I: or a pharmaceutically acceptable salt thereof, wherein: each of T1, T2, T3, and T4 is independently selected from the group consisting of H, halogen, -CN, -SF5, -OH, -N(Ra)(Rb ), -C(=O)-N(Ra)(Rb), -C(=O)-ORc, -C(=O)-Rd, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkoxy, -S- (C1-6 alkyl), C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C37 cycloalkoxy, 5- or 6-membered heteroaryl, cyclopropylmethyl, and cyclobutylmethyl, where each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -S-(C1-6 alkyl), and C1-6 alkoxy is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, -N(Ra)(Rb), C1-4 alkoxy, C14 haloalkoxy, and -S-(C1-4 alkyl); and wherein each of C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C3-7 cycloalkoxy, 5- or 6-membered heteroaryl, cyclopropylmethyl, and cyclobutylmethyl of T1, T2, and T3 is optionally substituted with one or more substituents each of them independently selected from the group consisting of halogen, -OH, -CN, oxo, -N(Ra)(Rb), -C(=O)OH, -C(=O)-C1-4 alkyl, - C(=O)- O-C1-4 alkyl, -C(=O)-N(Ra)(Rb), C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyl-alkyl, C1-4 cyanoalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and -S-(C1-4 alkyl); L1 is selected from the group consisting of O and S; each of Ra and Rb is independently selected from the group consisting of H, C1-4 alkyl, C3-7 cycloalkyl, and cyclopropylmethyl; or Ra and Rb together with the N atom to which they are attached form 4 to 7 membered heterocycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, oxo, - NH2, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, -C(=O)OH, -C(=O)-C1-4 alkyl, -C(=O)-O- C1-4 alkyl, -C(=O)-NH2, -C(=O)-NH(C1-4 alkyl), -C(=O)- N(C1-4 alkyl)2, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, -S-(C1-4 alkyl), and C1-4 haloalkoxy; each of Rc and Rd is independently C1-4 alkyl, C3-4 cycloalkyl-C1-2 alkyl- or C3-4 cycloalkyl; Q1 is Q1b: provided that a ring carbon atom of the Q1 ring is bonded to the benzene ring of formula I; each of X1 and X2 is independently O or S; each of R1, R2, R3, and R4 is independently selected from the group consisting of H, halogen, -OH, -NO2, -CN, -SF5, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, a 4 to 10 membered heterocycloalkyl, - N(R5)(R6), -N(R7)(C(=O)R8), -C (=O)-N(R5)(R6), -C(=O)-R8, -C(=O)-OR8, - N(R7)(S(=O)2R8), -S(=O )2-N(R5)(R6), -SR8, and -OR8, wherein each of C1-6 alkyl, C3-7 cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, -CN, oxo, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6 cycloalkyl, -N(R5)(R6), -N(R7)(C(=O)R8), -C(=O)-OR8, -C(=O)H, -C(=O)R8, -C(=O)N(R5)( R6), -N(R7)(S(=O)2R8), -S(=O)2-N(R5)(R6), -SR8, and -OR8; or R2 and R4 together with the two carbon atoms to which they are attached form a 5- or 6-membered fused heteroaryl, a 5- or 6-membered fused heterocycloalkyl ring, a 5- or 6-membered fused cycloalkyl ring, or a fused benzene ring , wherein each of the fused rings is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, -CN, -OH, C1-4 alkyl, C1-4 alkoxy, C1-4 ha- loalkyl, and C1-4 haloalkoxy, and wherein the fused heterocycloalkyl ring or the fused cycloalkyl ring is further optionally substituted with 1, 2 or 3 oxo; R5 is H, C1-4 alkyl, C1-4 haloalkyl or C3-7 cycloalkyl; R6 is H or selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C6-10 aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5-10 membered heteroaryl)-C1 -4 alkyl-, where each of the group selections is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of -OH, -CN, C1-4 alkyl, C3-7 cycloal- kyl, C1-4 hydroxyalkyl, -S-C1-4 alkyl, -C(=O)H, -C(=O)-C1-4 alkyl, -C(=O)-O-C1-4 alkyl, - C(=O)-NH2, -C(=O)-N(C1-4 alkyl)2, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or R5 and R6 together with the N atom to which they are attached form a 4 to 10 membered heterocycloalkyl or a 5 to 10 membered heteroaryl, each optionally substituted with 1, 2, 3, 4 or 5 substituents each of them independently selected from the group consisting of halogen, -OH, oxo, -C(=O)H, -C(=O)-C1-4 alkyl, -C(=O)OH, -C(=O )-O-C1-4 alkyl, -C(=O)-NH2, - C(=O)-N(C1-4 alkyl)2, -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, C1-4 haloalkyl, and C1-4 haloalkoxy; R7 is selected from the group consisting of H, C1-4 alkyl, and C3-7 cycloalkyl; R8 is selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C6-10 aryl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl -, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl-, wherein each of the group selections is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -CF3, -CN, -OH, oxo, -S-C1-4 alkyl, C1- 4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; R10 is selected from the group consisting of halogen, -OH, -CN, -SF5, -NO2, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (heterocycloalkyl 4 to 10 membered)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, (5 to 10 membered heteroaryl)-C1-4 alkyl-, -N(R5)(R6), -N(R7)(C(=O)R8), - S(=O)2N(R5)(R6), -C(=O)-N(R5)(R6), -C(=O)- R8, -C(=O)-OR8, -SR8, and - OR8, where each of C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10 membered, (C3-7 cycloalkyl)-C1-4 alkyl-, (4 to 10 membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (C1-4 alkyl) 5 to 10 members)-C1-4 alkyl- is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, -NO2, C1-4 alkyl , C1-4 hydroxyalkyl, C1-4 alkoxy, -N(R5)(R6), -S-(C1-4 alkyl), -S(=O)2-(C1-4 alkyl), C6-10 aryloxy, [(C6-10 aryl)-C1-4 alkyloxy- optionally substituted with 1 or 2 C1-4 alkyl], oxo, -C(=O)H, -C(=O)-C1-4 alkyl, -C( =O)O-C1-4 alkyl, -C(=O)NH2, - NHC(=O)H, -NHC(=O)-(C1-4 alkyl), C3-7 cycloalkyl, the heteroaryl of 5 or 6 members, C1-4 haloalkyl, and C1-4 haloalkoxy; R10A is selected from the group consisting of H, C1-6 alkyl, C1-6 hydroxyalkyl, C2-6 alkenyl, -S(=O)2N(R5)(R6), -C(=O)-N(R5) (R6), -C(=O)-R8, -C(=O)-OR8, -SR15, -C(R14)2-OH, -C(R14)2-OS(=O)2H, - C (R14)2-OP(=O)(OH)2, -C(R14)2-OR15, -C(R14)2-OC(=O)-R15, and -C(R14)2- N(R5 )(R6); R10B is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C3-7 cycloalkyl, C3-6 alkenyl, C3-6 alkynyl, C6-10 aryl, a 4 to 10 members, a 5- to 10-membered heteroaryl, (C3-7 cycloalkyl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)- C1-4 alkyl-, (5- to 10-membered heteroaryl)-C1-4 alkyl-, -S(=O)2N(R5)(R6), -C(=O)- N(R5)(R6 ), -C(=O)-R8, and -C(=O)-OR8, where each of C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, 4- to 10-membered heterocycloalkyl, heteroaryl 5- to 10-membered, (C3-7 cycloalkyl)-C1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl-, (C6-10 aryl)-C1-4 alkyl-, and (5- to 10-membered heteroaryl)-C1-4 alkyl-, is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, -NO2, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, -N(R5)(R6), -S-(C1-4 alkyl), -S(=O)2- (C1-4 alkyl), C6 -10 aryloxy, [(C6-10 aryl)-C1-4 alkyloxy- optionally substituted with 1 or 2 C1-4 alkyl], oxo, -C(=O)H, -C(=O)-C1-4 alkyl , - C(=O)O-C1-4 alkyl, -C(=O)NH2, -NHC(=O)H, -NHC(=O)-(C1-4 alkyl), -OC(=O) -C1-4 alkyl, C3-7 cycloalkyl, 5- or 6-membered heteroaryl, C1-4 haloalkyl, and C1-4 haloalkoxy; each R14 is independently H or selected from the group consisting of C1-10 alkyl, C3-14 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl, C6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl , (C3-14 cycloalkyl)-C1-10 alkyl-, (4- to 14-membered heterocycloalkyl)-C1-10 alkyl-, (C6-10 aryl)-C1-10 alkyl-, (5- to 10-membered heteroaryl) -C1-10 alkyl-, where each of the group selections is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, -NO2, C1 -4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, - N(R5)(R6), -N(R7)C(=O)R8, -N(R7)C(=O)OR8, -N( R7)S(=O)2R8, - S(=O)2N(R5)(R6), -C(=O)-N(R5)(R6), -C(=O)-R8, -C( =O)-OR8, -SR8, -OR8, -S(=O)2-R8, C6-10 aryloxy, [(C6-10 aryl)-C1-4 alkyloxy- optionally substituted with 1 or 2 C1-4 alkyl ], oxo, -C(=O)H, -NHC(=O)H, C3-7 cycloalkyl, 5- or 6-membered heteroaryl, C1-4 haloalkyl, and C1-4 haloalkoxy; R15 is selected from the group consisting of C1-20 alkyl, C3-14 cycloalkyl, C2-20 alkenyl, C2-20 alkynyl, C6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, ( C3-14 cycloalkyl)-C1-20 alkyl-, (4- to 10-membered heterocycloalkyl)-C1-20 alkyl-, (C6-10 aryl)-C1-20 alkyl-, (5- to 10-membered heteroaryl members)-C1-20 alkyl-, where each of the group selections is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, -NO2 , C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, -N(R5)(R6), -N(R7)C(=O)R8, -N(R7)C(=O)OR8, - N(R7)S(=O)2R8, -S(=O)2N(R5)(R6), -C(=O)-N(R5)(R6), -C(=O)-R8, - C(=O)-OR8, -SR8, -OR8, -S(=O)2-R8, C6-10 aryloxy, [(C6-10 aryl)-C1-4 alkyloxy- optionally substituted with 1 or 2 C1- 4 alkyl], oxo, -C(=O)H, -NHC(=O)H, C3-7 cycloalkyl, 5- or 6-membered heteroaryl, C1-4 haloalkyl, and C1-4 haloalkoxy; and t2 is 0 or 1. 2. Compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is a compound of formula IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB- 7, IB-8, IB-9 or IB-10: 3. Compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: R10 is selected from the group consisting of -CN, C1-4 alkyl, C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl , wherein the C1-4 alkyl of R10 is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein each of the C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R10 is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, C1- 4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; R10A is selected from the group consisting of H, C1-3 alkyl, C1-3 hydroxyalkyl, C2-4 alkenyl, -S(=O)2N(R5)(R6), -C(=O)-N(R5) (R6), -C(=O)-R8, -C(=O)-OR8, -C(R14)2-OH, -C(R14)2-OS(=O)2H, -C(R14) 2- OP(=O)(OH)2, -C(R14)2-OR15, and -C(R14)2-OC(=O)-R15; and R10B is selected from the group consisting of C1-4 alkyl, C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C1-4 alkyl of R10B is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein each of the C3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R10B is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. 4. Compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that: each of R10 and R10B is independently selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, and cyclopropyl. 5. Compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized by the fact that: each of R10 and R10B is independently methyl or ethyl. 6. Compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, characterized in that each of R1 and R2 is independently selected from the group consisting of H, halogen, -CN, C1- 6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, -C(=O)- (C1-4 alkyl), -C(=O)OH, and C(=O )-O-(C1-4 alkyl), wherein each of C1-6 alkyl and C3-6 cycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1 -4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. 7. Compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, characterized in that each of R1 and R2 is independently H, methyl or halogen. 8. Compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, characterized in that each of R1 and R2 is H. 9. Compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, characterized in that each of R3 and R4 is independently selected from the group consisting of H, halogen, - CN, - C1-4 alkyl, C1-4 alkoxy, and C3-4 cycloalkyl, where each of the C1-4 alkyl and C1-4 alkoxy of R3 and R4 is optionally substituted with 1, 2, or 3 substituents each one of them independently selected from halogen, - OH, C1-4 alkoxy, and C1-4 haloalkoxy; and wherein the C3-4 cycloalkyl of R3 and R4 is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1- 4 haloalkoxy. 10. Compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, characterized by the fact that R3 is H; and R4 is H, halogen or methyl, where the methyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, -OH, and C1-4 alkoxy. 11. Compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, characterized by the fact that R3 is H and R4 is methyl. 12. Compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, characterized by the fact that each of T1, T2, T3, and T4 is independently selected from the group that consists of H, halogen, -CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C1-4 alkoxy, C1-4 haloalkoxy, and C3-4 cycloalkyl, where each of the C1-4 alkyls , C2-4 alkenyl, and C1-4 alkoxy of T1, T2, T3, and T4 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkoxy , and C1-4 haloalkoxy; and wherein the C3-4 cycloalkyl of T1, T2, T3, and T4 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, -OH, -CN, C1-4 alkyl, C1 -4 haloalkyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, and C1-4 haloalkoxy. 13. Compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, characterized by the fact that each of T1, T2, T3, and T4 is independently selected from the group that consists of H, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, and C3-4 halocycloalkyl. 14. Compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, characterized in that T1 is selected from the group consisting of halogen, cyclopropyl, halocyclopropyl, methyl, C1 haloalkyl, methoxy , and C1 haloalkoxy; and T4 is H. 15. Compound according to claim 1, characterized in that it is selected from: (-)-6-{4-[(3-cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethyl- - pyrimidine-2,4(1H,3H)-dione; (-)-6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-5-ethyl-1-methylpyrimidine-2,4(1H,3H)-dione; (-)-1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}- -phenyl)pyrimidine-2,4(1H,3H)-dione ; (-)-6-{4-[(3-chloro-5-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 6-{4-[(3-chloro-4-methylpyridin-2-yl)oxy]phenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; (-)-6-(4-{[3-(difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 6-{4-[(3-chloropyridin-2-yl)sulfanyl]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; (-)-6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 6-{4-[(3-cyclopropylpyridin-2-yl)oxy]phenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione; 6-{4-[(3-chloro-4-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethyl-pyrimidin-2(1H)-one; and 1-cyclopropyl-6-(4-((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylphenyl)-5-methylpyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 16. Compound according to claim 1, characterized in that it is (+)-6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine- 2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 17. Compound according to claim 1, characterized in that it is (-)-6-{4-[(3-chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine- 2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 18. Compound according to claim 1, characterized in that it is (+)-1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine -2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 19. Compound according to claim 1, characterized in that it is (-)-1,5-dimethyl-6-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine -2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 20. Compound according to claim 1, characterized in that it is (+)-6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethyl-pyrimidine-2 ,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 21. Compound according to claim 1, characterized in that it is (-)-6-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethyl-pyrimidine-2 ,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 22. Compound according to claim 1, characterized in that it is (+)-6-{4-[(3-cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethyl-pyrimidine-2 ,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 23. Compound according to claim 1, characterized in that it is (-)-6-{4-[(3-cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethyl-pyrimidine-2 ,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 24. Compound according to claim 1, characterized in that it is (+)-6-{4-[(3-chloro-5-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine- 2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 25. Compound according to claim 1, characterized in that it is (-)-6-{4-[(3-chloro-5-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine- 2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 26. Compound according to claim 1, characterized in that it is (+)-6-(4-{[3-(difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethylpyrimidine-2 ,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 27. Compound according to claim 1, characterized in that it is (-)-6-(4-{[3-(difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethylpyrimidine-2 ,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof. 28. Pharmaceutical composition, characterized in that it comprises a compound as defined in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 29. Use of a compound as defined in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, or of a composition as defined in claim 28, characterized in that it is in the preparation of a pharmaceutical composition for the treatment of a disorder that is selected from schizophrenia, cognitive impairment, attention deficiency hyperactivity disorder (ADHD), impulsivity, compulsive gambling, overeating, autism spectrum disorder, mild cognitive impairment (MCI), related cognitive decline with age, dementia, restless legs syndrome (RLS), Parkinson's disease, Alzheimer's disease, Huntington's chorea, anxiety, depression, major depressive disorder (MDD), treatment-resistant depression (TRD), bipolar disorder, chronic apathy , anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, postpartum depression, serotonin syndrome, chemical substance abuse and drug dependence, relapse into drug substance abuse, Tourette's syndrome, tardive dyskinesia, drowsiness, excessive daytime sleepiness, cachexia, lack of attention, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis, dyslipidemia, obesity, diabetes, sepsis, necrosis post-ischemic tubular, renal failure, hyponatremia, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, and pain. 30. Use according to claim 29, characterized in that the disorder is selected from schizophrenia, cognitive impairment, mild cognitive impairment (MCI), age-related cognitive decline, dementia, Parkinson's disease, chronic apathy, and Alzheimer's disease.