HK40000923B - Compounds as dopamine d3 ligands - Google Patents

Description

A dopamine D3 ligand compound

Technical Field

The present invention generally relates to 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine compounds that are dopamine D3 ligands, such as dopamine D3 antagonists or partial agonists, and to pharmaceutical compositions containing the compounds and methods of treatment using the compounds.

Background Art

Dopamine acts on neurons through two dopamine receptor families: D1-like receptors (D1R) and D2-like receptors (D2R). The D2-like receptor family consists of D2, D3, and D4 receptors. The D2 and D3 receptors are the most homologous pair and have a high degree of sequence identity in terms of transmembrane domains and putative ligand binding sites. See Chien, E.Y.T., et al. "Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist", Science 330: 1091-1095 (2010). Pharmacological studies have reported that D1 and D5 receptors (D1/D5) (i.e., D1-like receptors) are coupled to stimulatory Gs proteins, stimulating adenylate cyclase (AC) activity and increasing cytosolic cyclic adenosine monophosphate (cAMP) levels, whereas D2, D3, and D4 receptors (i.e., D2-like receptors) are coupled to inhibitory Gi/o proteins that inhibit AC activity and reduce cAMP production.

D3 receptor mRNA has been found in specific regions of the rodent and human brains associated with addiction. See, for example, Micheli, F.; Heidbreder, C. "Selective dopamine D3 receptor antagonists. A decade of progress: 1997-2007", Expert Opin. Ther. Patents 18(8): 821-840 (2008). In the human brain, D3 receptors are primarily expressed in midbrain limbic regions, such as the ventral striatum, ventral pallidum, internal pallidum, nucleus accumbens, insula of Calleja, olfactory tubercle, lateral septum, amygdala, and ventral tegmental area (VTA). See, for example, Cho, D.I. et al. "Current perspectives on the selective regulation of dopamine D(2) and D(3) receptors", Archives of Pharmacol. Research, 33: 1521-1538 (2010); Gurevich, E.V., Joyce, J.N. "Distribution of dopamine D3 receptor expressing neurons in the human forebrain: Comparison with D2 receptor expressing neurons." Neuropsychopharmacology, 20: 60-80 (1999); and Searle, G. et al. "Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C] PHNO, and a selective D3 receptor antagonist." Biological Psychiatry, 68: 392-399 (2010). These brain regions have been found to control certain motivated behaviors and the rewarding properties of addictive drugs. See Heidbreder, C.A.; Newman, A.H. “Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disorders” Ann. N.Y. Acad. Sci. Addiction Reviews 2, 1187: 4-34 (2010). In addition, certain D3 receptor gene polymorphisms are associated with neuropsychiatric disorders. For example, the rs6280 polymorphism, which encodes the functional missense mutation Ser9Gly, may enhance reward-related dopamine release. This polymorphism is associated with nicotine dependence, alcohol dependence, and early heroin dependence. See Keck, T.M. et al. “Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis” J. Med. Chem. 58: 5361-5380 (2015). Based on the efficacy observed in various animal models of reinstatement of drug-seeking behavior, D3 receptor antagonism may reduce relapse after drug-induced, environmental-induced, and stress-induced withdrawal and provide cognitive benefits. See, for example, Heidbreder, C. “Rationale in support of the use of selective dopamine D3 receptor antagonists for the pharmacotherapeutic management of substance use disorders” Naunyn-Schmiedeberg’s Arch. Pharmacol. 386:167-176 (2013); Hachimine, P. et al. rats" Neuroscience Letters 569:137-141 (2014); and Galaj, E. et al. "The selective dopamine D3receptor antagonist, SR21502, reduces cue-induced reinstatement of heroin seeking and heroinconditioned place preference in rats" Drug and Alcohol Dependence 156:228-233 (2015). For example, D3 antagonist compounds can be used to treat addiction, such as recurrent addiction to: drug substances such as the psychostimulants cocaine, amphetamine, methamphetamine, etc.; opioids such as heroin, morphine, oxycodone, hydrocodone, hydromorphone, etc.; nicotine; cannabinoids such as marijuana; and alcohol.

Dopamine D3 receptors are also involved in many other neuropharmacological and neurobiological functions. For example, D3 receptors have been implicated in various types of memory functions, such as cognition. Antagonism of D3 receptors has been shown to improve cognitive deficits in certain animal models. See, for example, Watson, D.J.G., et al. "Selective Blockade of Dopamine D3 Receptors Enhances while D2 Antagonism Impairs Social Novelty Discrimination and Novel Object Recognition in Rats: A Key Role for the Prefrontal Cortex", Neuropsychopharmacology 37:770-786 (2012). D3 receptors are also associated with many other diseases and conditions. D3 antagonists can be used to treat the following diseases or conditions: impulse control disorders, such as pathological gambling, hypersexuality, compulsive shopping [see Moore, T. et al. “Reports of Pathological Gambling, Hypersexuality, and Compulsive Shopping Associated with Dopamine Receptor Agonist Drugs”, JAMA Internal Medicine 2014, 174(12), 1930-1933], obsessive-compulsive control disorder; eating disorders, such as anorexia nervosa, activity-based anorexia [see, e.g., Klenotich, S.J. et al. “Dopamine D2/3 receptor antagonism reduces activity-based anorexia” Transl. Psychiatry 5:e613(2015)] or binge eating and obesity [see, e.g., Nathan, P.J. et al. “The effects of the dopamine D3 receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects", International Journal of Neuropsychopharmacology 15:149-161 (2012)]; aggression; tremor; schizophrenia and other psychotic disorders [see, e.g., Gross, G. et al. "Dopamine D3 receptor antagonism-still a therapeutic option for the treatment of schizophrenia", Naunyn-Schmiedeberg's Arch. Pharmacol. 386:155-166 (2013)]; unipolar and bipolar depression; stress-induced conditions such as anxiety and drug addiction; autism spectrum disorders; attention deficit hyperactivity disorder (ADHD); restless legs syndrome; pain; nausea (e.g., nausea caused by cytotoxic or dopaminergic agents); Parkinson's disease; premature ejaculation; levodopa-induced dyskinesia and tardive dyskinesia [see, e.g., Solis, O. et al. "Dopamine D3 receptor modulates L-DOPA-Induced Dyskinesia by Targeting D1 Receptor Mediated Striatal Signaling”, Cerebral Cortex October 18, 2015, 1-12; Payer, D. et al. “D3dopamine receptor preferring [11C] PHNO PET imaging in Parkinson patients with dyskinesia” Neurology, published ahead of print, December 30, 2015; and Mahmoudi, S. et al. “Upregulation of Dopamine D3, Not D2, Receptors Correlates With Tardive Dyskinesia in a Primate Model”, Movement Disorders 2014, 29(9), 1125]. Antagonism of D3 receptors may provide effective treatment for these diseases and conditions. In addition, antagonism of peripheral D3 receptors in the kidney may provide renal protection, for example in patients with diabetes or patients already treated with metabolically disruptive antipsychotics. See, eg, Micheli, F.; Heidbreder, C. “Dopamine D3 receptor antagonists: A patent review (2007-2012)”, Expert Opin. Ther. Patents 23(3): 363-381 (2013).

In order to provide improved therapeutic options for treating diseases or conditions associated with dysregulated D3 receptor activation, such as those described herein, new or improved agents that modulate (e.g., antagonize or partially agonize) the D3 receptor are needed. It may also be desirable to design novel agents that exhibit selectivity for the D3 receptor over the closely related D2 receptor. See Keck, T.M. et al. "Beyond Small-Molecule SAR: Using the Dopamine D3 Receptor Crystal Structure to Guide Drug Design" Advances in Pharmacology, 69: 267-300 (2014).

SUMMARY OF THE INVENTION

The first embodiment of the first aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof:

wherein R ¹ is selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and C ₃ -C ₇ cycloalkylC ₁ -C ₃ alkyl; wherein said C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl and C ₃ -C ₇ cycloalkylC ₁ -C ₃ alkyl are each optionally substituted with 1 to 3 independently selected halogen, hydroxy or C ₁ -C ₃ alkoxy groups; R ² is independently selected from halogen, hydroxy and C ₁ -C ₃ alkyl at each occurrence; a is 0, 1, 2, 3 or 4; R ³ is selected from hydrogen, hydroxy, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy, wherein said C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy are each optionally substituted with 1 to 3 fluorine groups; R ⁴ is hydrogen or C ₁ -C ₆ alkyl optionally substituted with 1 to 3 substituents independently selected from fluorine, C ₁ -C ₃ alkoxy and hydroxy; A is selected from C ₆ -C ₁₀ aryl and 5- to 10-membered heteroaryl; wherein the C ₆ -C ₁₀ aryl and 5- to 10-membered heteroaryl are optionally substituted by 1 to 3 R ⁶ ; R ⁵ is selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxyC ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkylC 1 -C 6 alkyl, C ₃ -C ₇ cycloalkylC 1 -C ₆ alkyl, C ₃ -C 7 cycloalkyloxy, phenoxy, 4- to 10-membered heterocycloalkyl and 4- to 10-membered heterocycloalkoxy; wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkoxyC ₁ -C ₆ alkyl are optionally substituted by 1 to 4 independently selected halogen or hydroxy; and wherein the C ₃ -C ₇ cycloalkyl, C ₃ -C wherein R ⁴ and R ⁵ are taken together _to be C ₁ -C ₃ alkylene; R ⁶ is selected from halogen, cyano, C ₁ -C ₆ alkyl optionally substituted by 1 to 3 fluorines, C ₁ -C ₆ alkoxy optionally substituted by 1 to 3 fluorines, and C ₁ -C ₆ alkoxy C ₁ -C 6 alkyl; or, R ^{4 and} R _{6 are taken together to be C 1 -C 3 alkylene ; or} , R ₅ and R ⁶ , when attached to adjacent carbons and taken together with the adjacent carbons to which they are attached, form a fused 5- to _{7 -} membered cycloalkyl ring or 5- to ⁷ -membered heterocycloalkyl ring each optionally substituted by ¹ to 4 R ⁸ ; R ^{R 7} is independently selected at each occurrence from halogen, hydroxy, C ₁ -C ₃ alkyl optionally substituted with 1 to 3 fluorine or C ₁ -C ₃ alkoxy, and C ₁ -C ₃ alkoxy optionally substituted with 1 to 3 fluorine; and R ⁸ is independently selected at each occurrence from halogen, hydroxy, C ₁ -C ₃ alkyl optionally substituted with 1 to 3 fluorine, and C ₁ -C ₃ alkoxy optionally substituted with 1 to 3 fluorine.

Another embodiment of the present invention is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle, diluent, or carrier. The pharmaceutical compositions described herein can be used to modulate a patient's D3 receptor (e.g., antagonize a D3 receptor); and to treat a disease or condition associated with a D3 receptor, such as addiction, impulse control disorders, or schizophrenia.

The present invention also relates to methods of treatment using the compounds of formula I, for example:

(1) A method of modulating a D3 receptor (e.g., antagonizing a D3 receptor) by administering to a patient in need thereof a therapeutically effective amount of a compound of any embodiment of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle, diluent, or carrier.

(2) Methods for treating conditions or diseases of the central nervous system and neurological disorders that may involve D3 receptors, such as Parkinson's disease in mammals (preferably humans); cognitive disorders (including amnesia, senile dementia, HIV-related dementia, Alzheimer's disease, Huntington's disease, Lewy body dementia, vascular dementia, drug-related dementia, tardive dyskinesia, myoclonus, dystonia, delirium, Pick's disease, Creutzfeldt-Jakob disease, HIV-related dementia); Tourette syndrome, epilepsy, muscle spasms and disorders associated with muscle spasms or weakness including tremors, and mild cognitive impairment ("MCI")); sleep disorders (including hypersomnia, circadian rhythm sleep disorders, insomnia, parasomnias, and sleep deprivation) and psychiatric disorders, such as anxiety (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, agoraphobia, and impulse control disorders such as obsessive-compulsive disorder); factitious disorder (including acute hallucinatory mania); impulse control disorders (including compulsive gambling and intermittent explosive disorder); mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective states, major depressive disorder, chronic major depressive disorder, seasonal depression, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PDD), and postpartum depression); psychomotor disorders Disorders; mental disorders (including schizophrenia, schizoaffective disorder, schizophrenia-like and delusional disorders); drug dependence/addiction (i.e., addiction, including relapse), such as narcotic dependence (including opioids (e.g., heroin, oxycodone, morphine, hydrocodone, hydromorphone, etc.) addiction), alcoholism, amphetamine dependence, methamphetamine dependence, cocaine dependence, nicotine dependence, cannabinoid dependence (e.g., marijuana (THC) dependence) and drug withdrawal syndrome; eating disorders (including anorexia, bulimia, binge eating disorder, excessive eating, obesity, compulsive eating disorder and pagophagia); sexual dysfunction, such as premature ejaculation; and pediatric psychiatric disorders (including attention deficit disorder, attention deficit hyperactivity disorder (ADHD), conduct disorder and autism spectrum disorder), the method comprising administering to the mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. The compound of Formula I can also be used to improve cognitive deficits and memory (short-term memory and long-term memory) and learning ability. The fourth revised edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington, D.C.) provides diagnostic tools for identifying many of the conditions described herein. Those skilled in the art will recognize that there are alternative nomenclatures, pathologies, and classification systems for the conditions described herein, including those described in the DSM-IV-TR, and that terminology and classification systems evolve as medical science advances;

(3) a method for treating a neurological disorder (e.g., Parkinson's disease; cognitive disorder; or sleep disorder) or a psychiatric disorder (e.g., anxiety; factitious disorder; impulse control disorder; mood disorder; psychomotor disorder; psychiatric disorder; drug dependence; eating disorder; and pediatric psychiatric disorder) in a mammal (preferably a human), the method comprising administering to the mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof;

(4) Methods for treating (e.g., delaying progression or onset of) kidney-related disorders associated with diabetes (including type 1 and type 2 diabetes);

(5) Methods for treating eating disorders or obesity; and

(6) Methods for treating substance addiction (e.g., relapse), wherein the substance addiction includes but is not limited to alcohol, cocaine, amphetamine, methamphetamine, opioids, cannabinoids (marijuana), or nicotine addiction.

The present invention also relates to combination therapies, wherein the compounds of the present invention may also be used in combination with other agents for treating the diseases, conditions and/or disorders described herein. Thus, methods of treatment comprising administering a compound of the present invention in combination with other agents are also provided.

All patents, patent applications, and references mentioned herein are incorporated by reference in their entirety.

Other features and advantages of the present invention will be apparent from this specification and the appended claims which describe the invention.It is to be understood that both the foregoing and the following detailed description are exemplary only and are not restrictive of the invention as claimed.

DETAILED DESCRIPTION

The present invention can be more readily understood by reference to the detailed description of the following exemplary embodiments of the present invention and the examples included therein. It should be understood that the present invention is not limited to specific synthetic methods and can certainly vary. It should also be understood that the terms used herein are intended to describe specific embodiments and are not intended to be limiting.

In this specification and the claims that follow, reference will be made to a number of terms which shall be defined to have the following meanings:

As used herein, "eating disorder" refers to a disorder in which a patient is disturbed in their eating behavior and related thoughts and emotions. Representative examples of obesity-related eating disorders include overeating, bulimia, binge eating disorder, compulsive eating, nocturnal sleep-related eating disorder, pica, Prader-Willi syndrome, and night eating syndrome.

"Patient" refers to warm-blooded animals such as guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, cows, goats, sheep, horses, monkeys, chimpanzees, and humans.

The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal to be treated therewith.

The term "therapeutically effective amount" refers to an amount of a compound of the invention that (i) treats or prevents a specific disease, condition, or disorder described herein; (ii) alleviates, alleviates, or eliminates one or more symptoms of the specific disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of the specific disease, condition, or disorder. With respect to the treatment of a D3-mediated disease or condition (e.g., addiction, impulse control disorders, or schizophrenia), a therapeutically effective amount refers to an amount that has some degree of relief from (or, for example, eliminates) one or more symptoms associated with the D3-mediated disease or condition (e.g., addiction, impulse control disorders, or schizophrenia, cognitive and negative symptoms in schizophrenia, or cognitive impairment associated with schizophrenia).

As used herein, unless otherwise indicated, the terms "treating" and "treating" refer to reversing, alleviating, preventing, inhibiting progression, delaying progression, or delaying the onset of the disorder or condition to which such terms apply, or one or more symptoms of such disorder or condition. As used herein, unless otherwise indicated, the terms "treatment" and "treating" refer to the act of treating, as "treating" is defined immediately above. The term "treating" also includes adjuvant and neoadjuvant treatment of a subject. For the avoidance of doubt, references to "treating" herein include references to therapeutic, palliative, and prophylactic treatments and the administration of drugs for such treatments.

The term "alkyl" refers to a straight or branched chain saturated hydrocarbon substituent {i.e., a substituent derived from a hydrocarbon by removing a hydrogen); in one embodiment, it contains 1 to 6 carbon atoms ( _C1 - _C6 alkyl). Non-limiting examples of these substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl, isopentyl, hexyl, and the like. Another embodiment is an alkyl group containing 1 to 3 carbon atoms ( _C1 - _C3 alkyl), which includes methyl, ethyl, propyl, and isopropyl.

The term "alkoxy" refers to a straight or branched chain saturated hydrocarbon substituent (i.e., a substituent derived from a hydrocarbon alcohol by removing a hydrogen from an OH group) attached to an oxy group; in one embodiment, it contains 1 to 6 carbon atoms ( _C1 - _C6 alkoxy). Non-limiting examples of these substituents include methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy), pentoxy, hexoxy, and the like. Another embodiment is an alkoxy group containing 1 to 3 carbon atoms ( _C1 - _C3 alkoxy), which includes methoxy, ethoxy, propoxy, and isopropoxy.

The term "alkylene" refers to an alkanediyl group (i.e., a substituent derived from a hydrocarbon by removing two hydrogens); in one embodiment, it contains from 1 to 3 carbons ( _C1 - _C3 alkylene). Alkylene groups can be straight-chain or branched. Non-limiting examples of these groups include methylene (i.e., _-CH2- ), ethylene ( _{i.e., -CH2CH2- or} -CH( _{CH3 ) -} ), and propylene ( _i.e. , _-CH2CH2CH2- , -CH( _CH2CH3 )-, or -CH( _CH3 ) _CH2- ).

In some cases, the number of carbon atoms in a hydrocarbyl substituent (i.e., alkyl, cycloalkyl, etc.) is indicated by the prefix " _Cx - _Cy " or " _Cxy ," where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms in the substituent. Thus, for example, " _C1 - _C6 alkyl" or " _C1-6 alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Further illustrating, _C3 - _C7 cycloalkyl or _C3-7 cycloalkyl refers to a saturated cycloalkyl group containing from 3 to 7 carbon ring atoms.

The term "cycloalkyl" refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molecule, for example, a cycloalkyl having 3 to 6 carbon atoms or having 3 to 7 carbon atoms. The term "cycloalkyl" includes monocyclic, bicyclic, and tricyclic saturated carbocyclic rings, as well as bridged and fused carbocyclic rings and spiro-fused carbocyclic ring systems. The term " _C3-7 cycloalkyl" refers to a radical of a 3- to 7-membered ring system, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, spiropentyl, spirohexyl, and spirohexyl. The term " _C3-6 cycloalkyl" refers to a radical of a 3- to 6-membered ring system, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclopentyl, bicyclohexyl, spiropentyl, and spirohexyl. The term " _C3-7 cycloalkoxy" refers to a 3- to 7-membered cycloalkyl radical attached to an oxy group. Examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.

In some cases, the number of atoms in a cyclic substituent (i.e., a heteroaryl or heterocycloalkyl) containing one or more heteroatoms is indicated by the prefix "x- to y-membered," where x is the minimum number of atoms forming the cyclic portion of the substituent and y is the maximum number of atoms forming the cyclic portion of the substituent. Thus, for example, "4- to 10-membered heterocycloalkyl" refers to a heterocycloalkyl group containing from 4 to 10 atoms, including 1 to 3 heteroatoms, in the cyclic portion of the heterocycloalkyl group, and "5- to 7-membered heterocycloalkyl" refers to a heterocycloalkyl group containing from 5 to 7 atoms, including 1 to 3 heteroatoms, in the cyclic portion of the heterocycloalkyl group. Similarly, the phrase "5- to 6-membered heteroaryl" refers to a heteroaryl group containing from 5 to 6 atoms, and "5- to 10-membered heteroaryl" refers to a heteroaryl group containing from 5 to 10 atoms, each heteroaryl group including one or more heteroatoms in the cyclic portion of the heteroaryl group. Furthermore, the phrases "5-membered heteroaryl" and "6-membered heteroaryl" refer to 5-membered heteroaromatic ring systems and 6-membered heteroaromatic ring systems, respectively. The heteroatoms present in these ring systems are selected from N, O and S.

The term "hydroxy" or "hydroxyl" refers to -OH. When used in combination with one or more other terms, the prefix "hydroxy" indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds having a carbon to which one or more hydroxy substituents are attached include, for example, alcohols, enols, and phenols.

The term "halo" or "halogen" refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -Cl), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I).

The term "heterocycloalkyl" refers to a substituent obtained by removing a hydrogen from a saturated or partially saturated ring structure containing a specified total number of atoms, e.g., 4 to 10 ring atoms or 5 to 7 ring atoms, at least one of which is a heteroatom (i.e., oxygen, nitrogen, or sulfur), the remaining ring atoms being independently selected from carbon, oxygen, nitrogen, and sulfur. In a group having a heterocycloalkyl substituent, the ring atom to which the group is bound in the heterocycloalkyl substituent may be a nitrogen heteroatom, or it may be a ring carbon atom. Similarly, if the heterocycloalkyl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to a ring nitrogen atom, or it may be bound to a ring carbon atom.

The term "heteroaryl" refers to an aromatic ring structure containing a specified number of ring atoms, wherein at least one ring atom is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur. Examples of heteroaryl substituents include 6-membered heteroaryl substituents such as pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and 5-membered heteroaryl substituents such as triazolyl, imidazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or 1,3,4-oxadiazolyl and isothiazolyl. Heteroaryl can also be a bicyclic heteroaromatic group, such as indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, oxazolopyridyl, imidazopyridyl, imidazopyrimidinyl etc. In the group with heteroaryl substituent, the ring atom combined with the group in the heteroaryl substituent can be a ring nitrogen atom, or can be a ring carbon atom. Similarly, if the heterocycloalkyl substituent is replaced by a group or substituent in turn, the group or substituent can be combined with the ring nitrogen atom, or can be combined with the ring carbon atom. The term "heteroaryl" also includes pyridyl N-oxide and the group containing pyridine N-oxide ring. In addition, heteroaryl can contain an oxo group, such as the oxo group present in the pyridone group. Further examples include furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-onyl, pyridazin-2(1H)-onyl, pyrimidin-2(1H)-onyl, pyrazin-2(1H)-onyl, imidazo[1,2-a]pyridinyl and pyrazolo[1,5-a]pyridinyl. Heteroaryl may be further substituted as defined herein.

Examples of monocyclic heteroaryl and heterocycloalkyl groups include furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, dihydrothienyl, tetrahydrothienyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiadiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1, 2H-1,2-oxazinyl, 6H-1,3-oxazinyl or 2H-1,4-oxazinyl), isoxazinyl (o-oxazinyl or p-oxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 2H-1,2,4-oxadiazinyl, 1,2,5-oxadiazinyl or 1,3,4-oxadiazinyl), oxadiazinyl (including 2H-1,2,4-oxadiazinyl or 2H-1,4-oxadiazinyl), oxadiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 2H-1,2,4-oxadiazinyl or 2H-1,2,5-oxadiazinyl) and morpholinyl.

The term "heteroaryl" when so designated may also include ring systems having two rings wherein the rings may be fused and wherein one ring is aromatic and the other ring is not a complete part of a conjugated aromatic system (i.e., a heteroaryl ring may be fused to a cycloalkyl or heterocycloalkyl ring). Non-limiting examples of such ring systems include 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8-tetra ...1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7,8-tetrahydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6,7,8-tetrahydro- Tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl and 4,5,6,7-tetrahydro-2H-indazolyl. It should be understood that if a carbocyclyl or heterocyclyl group can be bonded or attached to a specified substrate via different ring atoms but no specific attachment site is indicated, all possible attachment sites are contemplated, whether via a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" refers to a 2-, 3-, or 4-pyridinyl group, the term "thienyl" refers to a 2- or 3-thienyl group, and so on.

If a substituent is described as "independently" having more than one variable, each instance of the substituent is selected from the available list of variables independently of the other instances. Thus, each substituent may be the same as or different from the other substituents.

If a substituent is described as being "independently selected" from a group, each instance of the substituent is selected independently of the other substituents. Thus, each substituent may be the same as or different from the other substituents.

As used herein, the term "Formula I" may hereinafter be referred to as "compounds of the invention," "the present invention," and "compounds of Formula I." Such terms are also defined to include all forms of the compounds of Formula I, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof. For example, a compound of the invention or a pharmaceutically acceptable salt thereof may exist in both unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, such as with channel solvates and hygroscopic compounds, the water/solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometric amounts will be the norm.

The compounds of the present invention may exist in the form of inclusion compounds or other complexes, including cocrystals. Included within the scope of the present invention are complexes such as inclusion compounds, drug-host inclusion complexes, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the compounds of the present invention containing two or more organic and/or inorganic components, which may be stoichiometric or non-stoichiometric. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of these complexes, see J. Pharm. Sci., 64(8), 1269-1288 by Haleblian (August 1975). Cocrystals are generally defined as crystalline complexes of neutral molecular components bound together by non-covalent interactions, but may also be complexes of neutral molecules with salts. Cocrystals may be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together; see O. Almarsson and M. J. Zaworotko, Chem. Commun. 2004, 17, 1889-1896. For a general review of multicomponent complexes, see J. K. Haleblian, J. Pharm. Sci. 1975, 64, 1269-1288.

The compounds of the present invention (including their salts) can also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is an intermediate state between a true crystalline state and a true liquid state (melt or solution). Mesomorphism that arises due to changes in temperature is described as "thermotropic," while mesomorphism that arises due to the addition of another 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 are composed of molecules with ionic polar head groups (such as -COO ^- Na ⁺ , -COO ^- K ⁺ , or _-SO3 ^- Na ⁺ ) or nonionic polar head groups (such as -N ^- N ⁺ ( _CH3 ) ₃ ). For more information, see N.H. Hartshorne and A. Stuart, Crystals and the Polarizing Microscope, 4th edition (Edward Arnold, 1970).

Also included within the scope of the present invention are metabolites of the compounds of formula I, ie, compounds formed in vivo upon administration of the drug.

The compounds of the present invention may have asymmetric carbon atoms. The compounds of the present invention have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention may be represented using solid lines, solid wedges, or dotted wedges. Unless otherwise specified, the use of a solid line to represent bonding to an asymmetric carbon atom is intended to include all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.). The use of a solid wedge or dotted wedge to represent bonding to an asymmetric carbon atom is intended to include only the stereoisomers shown. It is possible that the compounds of Formula I may contain more than one asymmetric carbon atom. Unless otherwise specified, in those compounds, the use of a solid line to represent bonding to an asymmetric carbon atom is intended to include all possible stereoisomers. For example, unless otherwise specified, the compounds of Formula I may exist as enantiomers and diastereomers, or as racemates and mixtures thereof. The use of a solid line to represent bonding to one or more asymmetric carbon atoms in a compound of Formula I and the use of a solid wedge or dotted wedge to represent bonding to other asymmetric carbon atoms in the same compound is intended to represent the presence of a mixture of diastereomers.

Stereoisomers of Formula I include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of the invention, including compounds exhibiting more than one isomerism; and mixtures thereof (such as racemates and pairs of diastereoisomers). Also included are acid addition salts or base addition salts where the counterion is optically active, such as D-lactate or L-lysine, or racemic, such as DL-tartrate or DL-arginine.

Certain compounds of Formula I may exhibit tautomerism; it is understood that such tautomers are also considered compounds of the present invention.

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. Depending on the specific compound, a salt of the compound may be advantageous due to one or more physical properties of the salt, such as enhanced pharmaceutical stability at varying temperatures and humidities or satisfactory solubility in water or oil. In certain instances, salts of the compound may also be used as an aid in the isolation, purification, and/or resolution of the compound.

When considering the administration of a salt to a patient (as opposed to, for example, use in vitro), the salt is preferably pharmaceutically acceptable. A "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of Formula I with an acid or base, the anion of the acid or the cation of the base being generally considered suitable for human use. Pharmaceutically acceptable salts are particularly suitable for use as products of the methods of the present invention because they are more water soluble than the parent compound. For use in medicine, the salts of the compounds of the present invention are non-toxic "pharmaceutically acceptable salts." Salts encompassed by the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention, which are generally prepared by reacting a free base with an appropriate organic or inorganic acid.

Where possible, suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention include salts derived from inorganic acids (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, boric acid, fluoroboric acid, phosphoric acid, metaphosphoric acid, nitric acid, carbonic acid, sulfonic acid and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid and trifluoroacetic acid). Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic organic acids.

Specific examples of suitable organic acid salts include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, pamoate (pamoate), , methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, p-aminobenzenesulfonate, cyclohexylsulfamate, alginic acid, beta-hydroxybutyric acid, mucate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecyl sulfate, glucoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.

Furthermore, when the compounds of the present invention carry an acidic group, suitable pharmaceutically acceptable salts thereof may include lighter alkali metal salts (i.e., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with appropriate organic ligands (e.g., quaternary ammonium salts). In another embodiment, base salts are formed from bases that form non-toxic salts, including aluminum salts, arginine salts, benzathine salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, meglumine salts, choline salts, tromethamine salts, and zinc salts.

Organic salts can be prepared from secondary, tertiary, or quaternary amines such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quaternized by reagents such as lower alkyl ( _Ci - _C6 ) halides (e.g., methyl, ethyl, propyl, butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate), long-chain halides (e.g., decyl, lauryl, myristyl, stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like.

In one embodiment, hemisalts of acids and bases may also be formed, such as hemisulphate and hemicalcium salts.

Also within the scope of the present invention are so-called "prodrugs" of the compounds of the present invention. Thus, certain derivatives of the compounds of the present invention that themselves have little or no pharmacological activity can, when administered to or on the human body, be converted into the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Such derivatives are referred to as "prodrugs." Further information on the use of prodrugs can be found in the literature "Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series (T. Higuchi and V. Stella)" and "Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E.B. Roche, American Pharmaceutical Association)." Prodrugs according to the present invention can be prepared, for example, by using certain groups known to those skilled in the art as "progroups" to replace appropriate functional groups present in any of the compounds of formula I, such as those described in the literature "Design of Prodrugs, H. Bundgaard (Elsevier, 1985)."

The present invention also includes isotopically labeled compounds, which are identical to those shown in Formula I, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively. Compounds of the present invention, prodrugs thereof, or pharmaceutically acceptable salts of the compounds or prodrugs containing the above-mentioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, those incorporating radioactive isotopes (such as ³ H and ¹⁴ C), are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium (i.e., ² H), may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in certain circumstances. Substitution with positron-emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N, may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy.

Isotopically labeled compounds of Formula I and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the following reaction schemes and/or Examples and Preparations by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

The compounds of Formula I (including salts thereof) can exist in a continuous solid state form ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a substance lacks long-range order at the molecular level and, depending on the temperature, can exhibit the physical properties of a solid or a liquid. Such substances generally do not produce a unique X-ray diffraction pattern and, although exhibiting solid properties, are more formally described as liquids. Upon heating, a change occurs from an apparent solid to a substance having liquid properties, characterized by a change in state, typically a second-order change ("glass transition"). The term "crystalline" refers to a solid phase in which a substance has a regular, ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with definite peaks. Such substances, when fully heated, will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase transition, typically a first-order phase transition ("melting point").

A second embodiment of the first aspect of the present invention is a compound of the first embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein ^R1 is hydrogen or _C1 - _C3 alkyl optionally substituted by _C1 - _C3 alkoxy or fluorine; ^R2 is _C1 - _C3 alkyl; a is 0 or 1; ^R3 is _C1 - _C3 alkoxy optionally substituted by 1 to 3 fluorines; and ^R4 is hydrogen.

A third embodiment of the first aspect of the present invention is a compound according to the second embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, methyl, ethyl, propyl, 3-fluoropropyl or 2-methoxyethyl; a is 0; and R ³ is methoxy, difluoromethoxy or isopropoxy.

The fourth embodiment of the first aspect of the present invention is a compound according to any one of the first to third embodiments of the first aspect, or a pharmaceutically acceptable salt thereof, wherein A is phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted with R ⁶ .

The fifth embodiment of the first aspect of the present invention is a compound of the fourth embodiment of the first aspect or a pharmaceutically acceptable salt thereof, wherein A is

^R5 is selected from halogen, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, C1- _C4 alkoxyC1 _{-C4 alkyl} , _C3 - _C6 cycloalkyl, _C3 -C6 cycloalkyloxy, 4- to _{6 -} membered heterocycloalkyl and 4- to 6-membered heterocycloalkoxy; wherein said _C1 - _C4 alkyl, _C1 - _C4 alkoxy and _C1 - _C4 alkoxyC1- _C4 alkyl are optionally substituted with 1 to 3 independently selected halogen or hydroxy; and wherein said _C3 - _C6 cyclocycloalkyl, _C3 -C6 cycloalkoxy, 4- to ₆ -membered heterocycloalkyl and 4- to 6-membered heterocycloalkoxy are optionally substituted _with 1 to 3 ^R7 ; ^R6 is halogen or _C1 - _C3 alkyl; or, ^R5 and ^R6 , when attached to adjacent carbons and taken together at the adjacent carbons to which they are attached, form a radical optionally substituted with 1 to 3 R ⁸ -substituted fused 5- to 6-membered heterocycloalkyl ring.

A sixth embodiment of the first aspect of the present invention is a compound of the fifth embodiment of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, wherein ^R is selected from chloro, methyl, propyl, isopropyl, difluoromethoxy, ethoxy, 1-(methoxy)ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopentyloxy, tetrahydrofuranyloxy, and tetrahydropyranyloxy, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopentyloxy, tetrahydrofuranyloxy, and tetrahydropyranyloxy are ^each optionally substituted with 1 to 2 R; ^R is fluoro or methyl; or, ^R and ^R , when attached to adjacent carbons and taken together with the adjacent carbons to which they are attached, form a fused tetrahydrofuran or a fused tetrahydropyran, each optionally substituted with one to ^two R; R ⁷ is independently selected at each occurrence from fluoro, hydroxy, methyl, trifluoromethyl, methoxy, ethoxy, and 2-fluoroethoxy; and R ⁸ is fluoro or methyl at each occurrence.

The seventh embodiment of the first aspect of the present invention is a compound of the sixth embodiment of the first aspect or a pharmaceutically acceptable salt thereof, wherein A is

The eighth embodiment of the first aspect of the present invention is a compound of the sixth embodiment of the first aspect or a pharmaceutically acceptable salt thereof, wherein A is

The ninth embodiment of the first aspect of the present invention is a compound of the sixth embodiment of the first aspect or a pharmaceutically acceptable salt thereof, wherein A is

The tenth embodiment of the first aspect of the present invention is a compound of the seventh embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from methyl, cyclobutyl, cyclopentyl, tetrahydropyran-4-yl and tetrahydropyran-2-yl, wherein said cyclobutyl, cyclopentyl, tetrahydropyran-4-yl and tetrahydropyran-2-yl are each optionally substituted with 1 to 2 R ⁷ .

The eleventh embodiment of the first aspect of the present invention is the compound of the fourth embodiment of the first aspect or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heteroaryl optionally substituted by R ⁶ .

The twelfth embodiment of the first aspect of the present invention is the compound of the eleventh embodiment of the first aspect or a pharmaceutically acceptable salt thereof, wherein A is pyridinyl or pyrimidinyl, each optionally substituted with R ⁶ .

The thirteenth embodiment of the first aspect of the present invention is the compound of the twelfth embodiment of the first aspect or a pharmaceutically acceptable salt thereof, wherein A is

^R5 is selected _{from C1-C4 alkyl} , _C1 - _C4 alkoxy, C1- _C4 alkoxyC1- _C4 alkyl, _C3 - _C6 cycloalkyl, _C3 - _C6 cycloalkylC1- _C3 alkyl, _C3 - _C6 cycloalkyloxy, phenoxy, _4- to _{6 -} membered heterocycloalkyl, and 4- to 6-membered heterocycloalkoxy; wherein said _C1 - _C4 alkyl, _C1 - _C4 alkoxy, and _C1 - _C4 alkoxyC1- _C4 alkyl are optionally substituted with 1 to ₃ independently selected halogen or hydroxyl groups; and wherein said C3- _C6 cycloalkyl, C3- _C6 cycloalkylC1 _{- C3} alkyl, _C3 - _C6 cycloalkoxy, phenoxy, 4- to _6- membered heterocycloalkyl, and 4- to 6-membered heterocycloalkoxy groups are optionally substituted with 1 to 3 ^R7 _; and

R ⁶ is halogen or C ₁ -C ₃ alkyl.

The fourteenth embodiment of the first aspect of the present invention is a compound of the thirteenth embodiment of the first aspect, or a pharmaceutically acceptable salt thereof, wherein ^R is selected from the group consisting of tert-butoxy, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyloxy, cyclopentyloxy, phenoxy, cyclopentylmethyl, and tetrahydropyranyl, wherein the cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyloxy, cyclopentyloxy, phenoxy, cyclopentylmethyl, and tetrahydropyranyl are optionally substituted with 1 to 2 R; ^{R is} fluoro or methyl; and ^R is independently selected at each occurrence from the group consisting of fluoro, hydroxy, methyl, trifluoromethyl, methoxy, ethoxy, and 2-fluoroethoxy.

The fifteenth embodiment of the first aspect of the present invention is a compound of the fourteenth embodiment of the first aspect or a pharmaceutically acceptable salt thereof, wherein A is

The sixteenth embodiment of the first aspect of the present invention is a compound of the fourteenth embodiment of the first aspect or a pharmaceutically acceptable salt thereof, wherein A is

The seventeenth embodiment of the first aspect of the present invention is a compound of the first embodiment of the first aspect or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

6-cyclohexyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

6-(Cyclopentyloxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide

4-[trans-3-(2-fluoroethoxy)cyclobutyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-methylbenzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydro-2H-pyran-2-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2S)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide;

N-(2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide;

4-(trans-1-fluoro-3-methoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

6-(1-fluorocyclopentyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

N-[2-(Difluoromethoxy)-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]-4-(propan-2-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-methylbenzenesulfonamide;

4-Ethoxy-N-[7-ethyl-2-(propan-2-yloxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]benzenesulfonamide;

6-(Cyclopentyloxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

6-cyclopentyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

6-(cyclobutyloxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

2-(Cyclopentyloxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyrimidine-5-sulfonamide;

6-(1-fluorocyclohexyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[trans-3-(2-fluoroethoxy)cyclobutyl]benzenesulfonamide;

4-(cis-3-ethoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-(trans-3-ethoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-6-(cis-1-hydroxy-3-methoxycyclobutyl)pyridine-3-sulfonamide;

6-cyclobutyl-5-fluoro-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

6-(cis-1-fluoro-3-methylcyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

N-(2-methoxy-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-methylbenzenesulfonamide;

4-Chloro-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-Ethoxy-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-Ethoxy-N-[2-methoxy-7-(2-methoxyethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]benzenesulfonamide;

4-cyclopropyl-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-3,4-dihydro-2H-chromene-6-sulfonamide;

4-(1-methoxyethyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(oxetan-3-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-3-fluoro-4-methylbenzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydrofuran-3-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(3R)-tetrahydrofuran-3-yloxy]benzenesulfonamide;

4-(trans-4-methoxycyclohexyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-(cis-1-fluoro-4-methoxycyclohexyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-(4,4-difluorotetrahydro-2H-pyran-2-yl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-[(2R)-4,4-difluorotetrahydro-2H-pyran-2-yl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-[(2S)-4,4-difluorotetrahydro-2H-pyran-2-yl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-3-fluoro-4-[(2S)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide;

N-[7-(3-Fluoropropyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]-4-(propan-2-yl)benzenesulfonamide;

4-cyclohexyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-(Cyclopentyloxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

6-[Cyclopentyl(difluoro)methyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

4-(trans-3-ethoxy-1-fluorocyclobutyl)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(2-methoxy-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(propan-2-yl)benzenesulfonamide;

4-Ethoxy-N-(2-methoxy-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(propan-2-yl)benzenesulfonamide;

4-Ethoxy-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-methylbenzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(propan-2-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[1-(trifluoromethyl)cyclopropyl]benzenesulfonamide;

N-(7-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(propan-2-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-3,4-dihydro-2H-chromene-6-sulfonamide;

4-(Difluoromethoxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-6-phenoxypyridine-3-sulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-3,4-dimethylbenzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-propylbenzenesulfonamide;

4-(Cyclopentyloxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-2,2-dimethyl-3,4-dihydro-2H-chromene-6-sulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-2,4-dimethylbenzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-2,4-dimethylbenzenesulfonamide;

N-[7-ethyl-2-(propan-2-yloxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]-3,4-dihydro-2H-chromene-6-sulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-2-methyl-2,3-dihydro-1-benzofuran-5-sulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(trans-3-methoxycyclobutyl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydro-2H-pyran-2-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydrofuran-3-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(cis-3-methoxycyclobutyl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2S)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(4-fluorotetrahydro-2H-pyran-4-yl)benzenesulfonamide;

4-(trans-3-methoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydro-2H-pyran-3-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydro-2H-pyran-4-yloxy)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide;

4-(4-fluorotetrahydro-2H-pyran-4-yl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-(cis-3-methoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydrofuran-3-yloxy)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(3R)-tetrahydro-2H-pyran-3-yl]benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(3S)-tetrahydro-2H-pyran-3-yl]benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide;

4-[(4R)-2,2-Dimethyltetrahydro-2H-pyran-4-yl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-[(4S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R,4S)-2-methyltetrahydro-2H-pyran-4-yl]benzenesulfonamide;

4-[(1S)-1-methoxyethyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-[(1R)-1-methoxyethyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(3S)-tetrahydrofuran-3-yloxy]benzenesulfonamide;

4-(cis-4-methoxycyclohexyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-(trans-1-fluoro-4-methoxycyclohexyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(1-fluoro-4-methoxycyclohexyl)benzenesulfonamide;

4-(1-methoxycyclopentyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(trans-1-fluoro-3-methoxycyclobutyl)benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2S)-tetrahydrofuran-2-yl]benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydrofuran-2-yl]benzenesulfonamide;

6-(1-methoxycyclopentyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-6-(1-fluorocyclopentyl)pyridine-3-sulfonamide;

6-cyclopentyl-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

6-tert-Butoxy-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-3-methyl-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-3-methyl-4-[(2S)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide;

4-(4-fluorotetrahydro-2H-pyran-2-yl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-3-methyl-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide;

4-(4-Fluorotetrahydro-2H-pyran-2-yl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-benzenesulfonamide, diastereomer-1;

4-(4-Fluorotetrahydro-2H-pyran-2-yl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-benzenesulfonamide, diastereomer-2;

3-Fluoro-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide;

3-Fluoro-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2S)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-6-(1-fluorocyclohexyl)pyridine-3-sulfonamide;

6-cyclobutyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

6-cyclohexyl-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

N-[7-(3-Fluoropropyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]-4-methylbenzenesulfonamide;

2-(Cyclobutyloxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyrimidine-5-sulfonamide;

2-tert-Butoxy-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyrimidine-5-sulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-propylbenzenesulfonamide;

N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[cis-3-(2-fluoroethoxy)cyclobutyl]benzenesulfonamide;

4-(cis-3-ethoxycyclobutyl)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-(trans-3-ethoxycyclobutyl)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

6-(Cyclopentyloxy)-N-[7-(3-fluoropropyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]pyridine-3-sulfonamide;

2-cyclopentyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyrimidine-5-sulfonamide;

6-(Cyclopentyloxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-5-methylpyridine-3-sulfonamide;

6-(Cyclopentyloxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-5-methylpyridine-3-sulfonamide;

6-(cyclobutyloxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-5-methylpyridine-3-sulfonamide;

2-cyclohexyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyrimidine-5-sulfonamide;

6-(Cyclopentyloxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-2-methylpyridine-3-sulfonamide;

N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-6-[(2R)-tetrahydro-2H-pyran-2-yl]pyridine-3-sulfonamide;

6-(cyclopentylmethyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

4-(trans-3-ethoxy-1-fluorocyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-[trans-1-fluoro-3-(2-fluoroethoxy)cyclobutyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

6-(trans-3-ethoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

6-(cis-3-ethoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

6-(trans-1-fluoro-3-methylcyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

6-(cyclopentyloxy)-5-fluoro-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide;

4-Ethoxy-N-(7-ethyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-Chloro-N-(7-ethyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide;

4-methyl-N-[7-methyl-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]benzenesulfonamide; and

N-(2-ethyl-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide.

The eighteenth embodiment of the first aspect of the present invention is the compound 6-(cyclopentyloxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide or a pharmaceutically acceptable salt thereof.

The nineteenth embodiment of the first aspect of the present invention is the compound 4-[trans-3-(2-fluoroethoxy)cyclobutyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.

The twentieth embodiment of the first aspect of the present invention is the compound N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.

The twenty-first embodiment of the first aspect of the present invention is the compound N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-methylbenzenesulfonamide or a pharmaceutically acceptable salt thereof.

The twenty-second embodiment of the first aspect of the present invention is the compound N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide or a pharmaceutically acceptable salt thereof.

The twenty-third embodiment of the first aspect of the present invention is the compound 4-(trans-1-fluoro-3-methoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro)-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.

The twenty-fourth embodiment of the first aspect of the present invention is the compound 6-(1-fluorocyclopentyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide or a pharmaceutically acceptable salt thereof.

The first embodiment of the second aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the first to twenty-fourth embodiments of the first aspect or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle, diluent or carrier.

A first embodiment of the third aspect of the present invention is a method for treating a disease or condition selected from Parkinson's disease, schizophrenia, dementia, psychosis, depression, mania, anxiety, movement disorders, substance abuse, substance addiction, sexual dysfunction, restless legs syndrome, cardiovascular disease, metabolic disorders, hormonal disorders, renal insufficiency and diabetes, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of the first to twenty-fourth embodiments of the first aspect, or a pharmaceutically acceptable salt thereof.

A second embodiment of the third aspect of the present invention is the method of the first embodiment of the third aspect, wherein the disease or disorder is substance addiction.

A third embodiment of the third aspect of the present invention is the method of the second embodiment of the third aspect, wherein the substance addiction is recurrent substance addiction.

A fourth embodiment of the third aspect of the present invention is the method of the second embodiment of the third aspect, wherein the substance addiction is alcohol, cocaine, amphetamine, methamphetamine, opioid, marijuana or nicotine addiction.

A first embodiment of the fourth aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt of said compound in the preparation of a medicament for treating a disease or condition selected from Parkinson's disease, schizophrenia, dementia, psychosis, depression, mania, anxiety, movement disorders, drug abuse, substance addiction, sexual dysfunction, restless legs syndrome, cardiovascular disease, metabolic disorders, hormonal disorders, renal insufficiency and diabetes.

A second embodiment of the fourth aspect of the present invention is the use of the first embodiment of the fourth aspect, wherein the disease or disorder is substance addiction.

A third embodiment of the fourth aspect of the present invention is the use of the second embodiment of the fourth aspect, wherein the substance addiction is recurrent substance addiction.

A fourth embodiment of the fourth aspect of the present invention is the use of the second embodiment of the fourth aspect, wherein the substance addiction is alcohol, cocaine, amphetamine, methamphetamine, opioid, cannabis or nicotine addiction.

A first embodiment of the fifth aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt of said compound for treating a disease or condition, wherein said compound is as defined in any one of the first to twenty-fourth embodiments of said first aspect, said disease or condition being selected from Parkinson's disease, schizophrenia, dementia, psychosis, depression, mania, anxiety, movement disorders, drug abuse, substance addiction, sexual dysfunction, restless legs syndrome, cardiovascular disease, metabolic disorders, hormonal disorders, renal insufficiency and diabetes.

A second embodiment of the fifth aspect of the present invention is the use of the first embodiment of the fifth aspect, wherein the disease or disorder is substance addiction.

A third embodiment of the fifth aspect of the present invention is the use of the second embodiment of the fifth aspect, wherein the substance addiction is recurrent substance addiction.

A fourth embodiment of the fifth aspect of the present invention is the use of the second embodiment of the fifth aspect, wherein the substance addiction is alcohol, cocaine, amphetamine, methamphetamine, opioid, cannabis or nicotine addiction.

The present invention also provides a composition (e.g., a pharmaceutical composition) according to the second aspect of the present invention, comprising a novel compound of Formula I (including a pharmaceutically acceptable salt thereof). Thus, in one embodiment, the present invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) a novel compound of Formula I (or a pharmaceutically acceptable salt thereof) and optionally a pharmaceutically acceptable carrier. In another embodiment, the present invention provides a pharmaceutical composition comprising (a therapeutically effective amount of) a compound of Formula I (or a pharmaceutically acceptable salt thereof), optionally a pharmaceutically acceptable carrier, and optionally at least one other drug or agent (e.g., a drug for treating addiction, a drug for treating impulse control disorders, or an antipsychotic or anti-schizophrenia agent as described herein). In one embodiment, the other drug or agent is a drug for treating addiction. In one embodiment, the other drug or agent is a drug for treating impulse control disorders. In yet another embodiment, the other drug or agent is an anti-schizophrenia agent as described herein.

Pharmaceutically acceptable carriers can contain any conventional pharmaceutical carrier or excipient. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). If necessary, the pharmaceutical composition can contain other ingredients, such as flavorings, adhesives, excipients, etc. 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 some composite silicates) and adhesives (such as sucrose, gelatin and gum arabic). In addition, lubricants (such as magnesium stearate, sodium lauryl sulfate and talc) are often used for tableting purposes. Similar types of solid compositions can also be used in the form of soft-filled and hard-filled gelatin capsules. Therefore, the non-limiting examples of materials include lactose or lactose and high molecular weight polyethylene glycol. When aqueous suspensions or elixirs are required for oral administration, the active compound may be combined with various sweetening or flavoring agents, colorants or dyes and, if desired, emulsifying or suspending agents and with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

The pharmaceutical composition may, for example, be in a form suitable for oral administration (such as tablets, capsules, pills, powders, sustained-release formulations, solutions or suspensions), a form suitable for parenteral injection (such as sterile solutions, suspensions or emulsions), a form suitable for topical administration (such as ointments or creams) or a form suitable for rectal administration (such as suppositories).

Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, such as aqueous propylene glycol or dextrose. Such dosage forms can be suitably buffered, if necessary.

The pharmaceutical composition may be in unit dosage form suitable for single administration of a precise dosage. One of ordinary skill in the art will appreciate that the composition may be formulated at sub-therapeutic doses, thereby contemplating multiple administrations.

In one embodiment, the composition contains a therapeutically effective amount of a compound of Formula I (or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier.

The compounds of Formula I (including pharmaceutically acceptable salts thereof) are D3R modulators. In some embodiments, the compounds of Formula I are D3R antagonists [i.e., they bind to (have affinity for) and deactivate D3R receptors]. As used herein, when referring to a compound, the term "D3R modulator" or "D3R antagonist" refers to a compound that is a D3 receptor modulator or D3 receptor antagonist, respectively (i.e., not necessarily completely selective between/among subtypes of D2-like receptors; for example, the compound may be selective for the D3 receptor, but may not be completely so, particularly with respect to the closely related D2 receptor).

Administration of the compound of Formula I can be achieved by any method that enables the compound to be delivered to the site of action. These methods include, for example, enteral routes (e.g., oral routes, buccal routes, sublabial routes, sublingual routes), intranasal routes, inhalation routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intramuscular, intravascular or infusion), intrathecal routes, epidural routes, intracerebral routes, intracerebroventricular routes, topical routes and rectal administration.

In one embodiment of the present invention, the compounds of formula I can be administered by oral route.

The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is advantageous to formulate parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, a unit dosage form refers to a physically discrete unit suitable for use in a bulk dose in a mammalian subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in combination with a desired pharmaceutical carrier. The specifications of the unit dosage forms of the present invention are governed by a variety of factors, such as the unique characteristics of the therapeutic agent and the specific therapeutic or preventive effect to be achieved. In one embodiment of the invention, the compound of Formula I can be used to treat humans.

It should be noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, a specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition, and the dosage ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition. For example, the dosage may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects, such as toxic effects and/or experimental values. Therefore, the present invention encompasses intra-patient dose escalation as determined by those skilled in the art. Determining the appropriate dosage and regimen for administering a chemotherapeutic agent is well known in the relevant art, and once the teachings disclosed herein are provided, those skilled in the art will understand that the appropriate dosage and regimen are encompassed therein.

The amount of the compound of Formulas I administered depends on the severity of the individual, disease or the patient's condition, the administration rate of the compound, disposal and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50 mg/kg body weight/day, for example, about 0.01 to about 10mg/kg/day (single or divided administration). For 70kg people, this amounts to about 0.007mg/day to about 3500mg/day, for example, about 0.7mg/day to about 700mg/day. In some cases, it may be enough to be less than the dosage level of the lower limit of the aforementioned scope, and in other cases, it is still possible to adopt a larger dose in the case of not causing any harmful side effects, condition being that first the larger dose is divided into several smaller doses to be administered throughout the day.

As used herein, the term "combination therapy" refers to the sequential or simultaneous administration of a compound of Formula I and at least one other drug or agent (eg, an anti-schizophrenia agent).

The present invention includes the use of a compound of Formula I (or a pharmaceutically acceptable salt thereof) in combination with one or more other pharmaceutically active agents. If a combination of active agents is administered, the active agents can be administered sequentially or simultaneously in separate dosage forms or combined in a single dosage form. Accordingly, the present invention also includes a pharmaceutical composition comprising an amount of: (a) a first agent comprising a compound of Formula I or a pharmaceutically acceptable salt thereof; (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle, or diluent.

Depending on the disease, disorder or condition to be treated, a variety of pharmaceutically active agents may be selected for use in combination with the compounds of Formula I (including pharmaceutically acceptable salts thereof). Pharmaceutically active agents that may be used in combination with the compositions of the present invention include, but are not limited to:

(i) acetylcholinesterase inhibitors, such as donepezil hydrochloride (ARICEPT, MEMAC); or adenosine _A2A receptor antagonists, such as prednisone (SCH 420814) or SCH 412348;

(ii) amyloid-β (or fragments thereof), such as Aβ _1-15 conjugated to an epitope that binds pan HLA DR (PADRE), and ACC-001 (Elan/Wyeth);

(iii) antibodies to amyloid-β (or fragments thereof), such as bapineuzumab (also known as AAB-001) and AAB-002 (Wyeth/Elan);

(iv) amyloid reducers or inhibitors (including those that reduce amyloid production, accumulation, and fibrillation), such as colostrinin and bisnorcymserine (also known as BNC);

(v) α-adrenergic receptor agonists, such as clonidine (CATAPRES);

(vi) β-adrenergic receptor blockers (β-blockers), such as carteolol;

(vii) anticholinergics, such as amitriptyline (ELAVIL, ENDEP);

(viii) anticonvulsants, such as carbamazepine (TEGRETOL, CARBATROL);

(ix) antipsychotics, such as lurasidone (also known as SM-13496; Dainippon Sumitomo);

(x) calcium channel blockers, such as nilvadipine (ESCOR, NIVADIL);

(xi) catechol O-methyltransferase (COMT) inhibitors, such as tolcapone (TASMAR);

(xii) central nervous system stimulants, such as caffeine;

(xiii) corticosteroids, such as prednisone (STERAPRED, DELTASONE);

(xiv) dopamine receptor agonists, such as apomorphine (APOKYN);

(xv) dopamine receptor antagonists, for example tetrabenazine (NITOMAN, XENAZINE, dopamine D2 antagonists such as quetiapine); dopamine D3 antagonists or partial agonists, for example BP 897, PG 619, YQA14, RGH 188 (cariprazine), [3H]LS-3-134, SB277011A, GSK598809, buspirone NGB 2904, CJB 090, PG01037, PG 622, R-PG 648, BAK 2-66, S33138, BP1.4979, SR 21502;

(xvi) dopamine reuptake inhibitors, such as nomifensine maleate (MERITAL);

(xvii) gamma-aminobutyric acid (GABA) receptor agonists, such as baclofen (LIORESAL, KEMSTRO);

(xviii) histamine 3 (H3) antagonists, such as ciproxifan;

(xix) immunomodulators, such as glatiramer acetate (also known as copolymer-1; COPAXONE);

(xx) immunosuppressants, such as methotrexate (TREXALL, RHEUMATREX);

(xxi) interferons, including interferon beta-1a (AVONEX, REBIF) and interferon beta-1b (BETASERON, BETAFERON);

(xxii) levodopa (or its methyl or ethyl ester), alone or in combination with a DOPA decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA));

(xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine (NAMENDA, AXURA, EBIXA);

(xxiv) monoamine oxidase (MAO) inhibitors, such as selegiline (EMSAM);

(xxv) Muscarinic receptor (particularly M1 subtype) agonists, such as bethanechol (DUVOID, URECHOLINE);

(xxvi) neuroprotective drugs such as 2,3,4,9-tetrahydro-1H-carbazol-3-one oxime;

(xxvii) nicotinic receptor agonists, such as epibatidine;

(xxviii) norepinephrine reuptake inhibitors, such as atomoxetine (STRATTERA);

(xxix) phosphodiesterase (PDE) inhibitors, for example PDE9 inhibitors such as BAY 73-6691 (Bayer AG) and PDE 10 (for example PDE10A) inhibitors, for example papaverine;

(xxx) other PDE inhibitors, including (a) PDE1 inhibitors (e.g., vinpocetine), (b) PDE2 inhibitors (e.g., erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA)), (c) PDE4 inhibitors (e.g., rolipram), and (d) PDE5 inhibitors (e.g., sildenafil (VIAGRA, REVATIO));

(xxxi) Quinolines, for example quinine (including its hydrochloride, dihydrochloride, sulfate, hydrogensulfate and gluconate);

(xxxii) β-secretase inhibitors, such as WY-25105;

(xxxiii) γ-secretase inhibitors, such as LY-411575 (Lilly);

(xxxiv) serotonin (5-hydroxytryptamine) 1A (5-HT1A) receptor antagonists, such as spiperone;

(xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT4) receptor agonists, such as PRX-03140 (Epix);

(xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT6) receptor antagonists, such as mianserin (TORVOL, BOLVIDON, NORVAL);

(xxxvii) serotonin (5-HT) reuptake inhibitors, such as alapropamide, citalopram (CELEXA, CIPRAMIL);

(xxxviii) 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), neuroblastoids, Meteorin, and glial cell-derived neurotrophic factor (GDNF), and agents that stimulate the production of trophic factors, such as propentofylline; etc.

(xxxix) Medications used to treat various drug addictions, such as methadone, buprenorphine (and), naloxone, naltrexone, levo-alpha acetylcarbinol (LAAM), bupropion, varenicline, nicotine patches or chewing gum, acamprosate, disulfiram, and topiramate

The compound of Formula I (including its pharmaceutically acceptable salt) is optionally used in combination with another active agent. Such an active agent can be, for example, an atypical antipsychotic agent, an anti-Parkinson's disease agent, or an anti-Alzheimer's disease agent. Accordingly, another embodiment of the present invention provides a method for treating a D3-mediated disorder (e.g., a neurological and psychiatric disorder associated with D3) comprising administering to a mammal an effective amount of a compound of Formula I (including its pharmaceutically acceptable salt) and further comprising administering another active agent.

As used herein, the term "another active agent" refers to any therapeutic agent other than a compound of Formula I (including a pharmaceutically acceptable salt thereof) that can be used to treat an individual's condition. Examples of the other therapeutic agent include drugs for treating addiction, drugs for treating impulse control disorders, antidepressants, antipsychotics (e.g., anti-schizophrenia) drugs, anti-pain agents, anti-Parkinson's disease agents, anti-LID (levodopa-induced dyskinesia) agents, anti-Alzheimer's disease agents, and antianxiety agents. Examples of specific classes of antidepressants that can be used in combination with the compounds of the present invention include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, α-adrenergic receptor antagonists, and atypical antidepressants. Suitable norepinephrine reuptake inhibitors include tertiary and secondary amine tricyclics. Examples of suitable tertiary and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dosulpirine, butriptyline, iprapindole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine, and maprotiline. Examples of suitable selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine, and sertraline. Examples of 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 anti-Alzheimer's disease agents include dimebon, NMDA receptor antagonists (e.g., memantine); and cholinesterase inhibitors (e.g., donepezil and galantamine). Examples of suitable classes of antianxiety agents that can be used in combination with the compounds of the present invention include benzodiazepines and serotonin 1A (5-HT1A) agonists or antagonists (particularly 5-HT1A partial agonists), and corticotropin-releasing factor (CRF) antagonists. Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chloramine butate, diazepam, halazepam, lorazepam, oxazepam, and prazepam. Suitable 5-HT1A receptor agonists or antagonists include buspirone, flusinoxan, gepirone, and izspirone. Suitable atypical antipsychotics include paliperidone, bifenazol, ziprasidone, risperidone, aripiprazole, olanzapine, and quetiapine. Suitable nicotinic acetylcholine agonists include iprocyclidine, varenicline, and MEM 3454. Anti-pain agents include pregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam, ketamine, and ziconotide. Examples of suitable anti-Parkinson's disease agents include L-DOPA (or its methyl or ethyl ester), DOPA decarboxylase inhibitors (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA), adenosine _A2A receptor antagonists [e.g., pregabalin (SCH 420814) or SCH 412348], benserazide (MADOPAR), alpha-methyldopa, monofluoromethyldopa, difluoromethyldopa, bromocriptine or meta-hydroxyprocarbazine), dopamine agonists [such as apomorphine (APOKYN), bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydroergocriptine, dihydroergocriptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN), pergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine (NEUPRO), SKF-82958 (GlaxoSmithKline), and sarizotan], monoamine oxidase (MAO) inhibitors [e.g., selegiline (EMSAM), selegiline hydrochloride (L-selegiline (L-deprenyl), ELDEPRYL, ZELAPAR), dimethylselegiline, brofaromine, phenelzine (NARDIL), tranylcypromine (PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide, isocarboxazid (MARPLAN), niamide (NIAMID), rasagiline (AZILECT), iproniazid (MARSILID, IPROZID, IPRONID), CHF-3381 (Chiesi Farmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), difemelane, deoxydapramine, harmine (also known as harmaline or banasterine), harmaline, linezolid (ZYVOX, ZYVOXID) and pargyline (EUDATIN, SUPIRDYL)], catechol O-methyltransferase (COMT) inhibitors [such as tolcapone (TASMAR), entacapone (COMTAN), and tropolone], N-methyl-D-aspartate (NMDA) receptor antagonists [such as amantadine (SYMMETREL)], anticholinergics [such as amitriptyline (ELAVIL, ENDEP), butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN), scopolamine (TRANSDERM-SCOP), methylscopolamine bromide (PARMINE), dicyclomine (BENTYL, BYCLOMINE, DIBENT, DILOMINE, tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL, OXYTROL), pentothiabendium, 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 anti-schizophrenia agents include ziprasidone, risperidone, olanzapine, quetiapine, aripiprazole, asenapine, blonanserin, or iloperone. Some other examples of "another active agent" include rivastigmine (Exelon), clozapine, levodopa, rotigotine, Aricept, methylphenidate, memantine, milnacipran, guanfacine, bupropion, and atomoxetine.

As described above, the compound of Formula I (including its pharmaceutically acceptable salt) can be used in combination with one or more other agents described herein. When using combination therapy, one or more other agents can be administered sequentially or simultaneously with the compound of the present invention. In one embodiment, before administering the compound of the present invention, the compound of the present invention is administered to a mammal (e.g., a human). In another embodiment, after administering the compound of the present invention, the compound of the present invention is administered to a mammal. In another embodiment, other agents are administered to a mammal (e.g., a human) while administering the compound of the present invention or its pharmaceutically acceptable salt.

The present invention also provides a pharmaceutical composition for treating addiction in mammals (including humans), comprising an amount of a compound of Formula I as defined above (or a pharmaceutically acceptable salt thereof) (including hydrates, solvates, and polymorphs thereof) in combination with one or more (e.g., one to three) drugs used to treat addiction (e.g., methadone, buprenorphine, naloxone, naltrexone, levo-α-acetylmethadol (LAAM), bupropion, varenicline, nicotine patches or chewing gums, acamprosate, disulfiram, and topiramate), wherein the amount of the active agent and the combination (when taken as a whole) is therapeutically effective for treating the addiction. The choice of other agents used in the pharmaceutical composition can be tailored to the specific addiction being treated.

The present invention also provides a pharmaceutical composition for treating impulse control disorders (including intermittent explosive disorder, kleptomania, pathological gambling, mania, trichotillomania and dermatillomania) in mammals (including humans), which contains a certain amount of a compound of Formula I as defined above (or a pharmaceutically acceptable salt thereof) (including hydrates, solvates and polymorphs of the compound or its pharmaceutically acceptable salt) in combination with one or more (e.g., one to three) agents for treating impulse control disorders (e.g., clomipramine, selective serotonin reuptake inhibitors (SSRIs), pimozide, anticonvulsants (e.g., topiramate), antipsychotics and anxiolytics (e.g., benzodiazepines)), wherein the amount of the active agents and the combination (when taken as a whole) is therapeutically effective for treating impulse control disorders.

It should be understood that the compounds of Formula I described above are not limited to the specific stereoisomers shown (eg, enantiomers or atropisomers), but also encompass all stereoisomers and mixtures thereof.

The compounds of the present invention or their pharmaceutically acceptable salts can be prepared by various methods known in the art. The reaction schemes described below, along with synthetic methods known in the art of organic chemistry or modifications and derivatizations familiar to those skilled in the art, illustrate methods for preparing the compounds. Other methods, including modifications thereof, will be readily apparent to those skilled in the art.

The starting materials used herein are commercially available or can be prepared by conventional methods known in the art (such as those disclosed in standard reference books, such as COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-XIII (published by Wiley-Interscience)). Preferred methods include, but are not limited to, those described below.

The reaction of preparing the compounds of this invention can be carried out in a suitable solvent, and the solvent can be easily selected by the technical staff of organic synthesis field. Suitable solvent can be substantially unreactive with raw material (reactant), intermediate or product at the temperature being reacted, for example, and the temperature range can be from the freezing temperature of solvent to the boiling temperature of solvent. The specified reaction can be carried out in a solvent or in a mixture of more than one solvent. By considering specific reactions steps, those skilled in the art can select the suitable solvent for the specific reactions step.

During any of the following synthetic procedures, it may be necessary and/or desirable to protect sensitive or reactive groups in any of the molecules concerned. This can be achieved by conventional protecting groups, for example, those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1981; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 2007, which are incorporated herein by reference.

The compounds of the present invention or pharmaceutically acceptable salts or tautomers and radioisotopes of the compounds can be prepared according to the reaction routes discussed below. Unless otherwise indicated, the substituents in the routes are as defined above. Isolation and purification of the products are accomplished by standard procedures known to those of ordinary skill in the art.

Those skilled in the art will recognize that in some cases the compounds in Schemes 1 to 5 will be produced as mixtures of diastereomers and/or enantiomers; these can be separated at various stages of the synthetic route using conventional techniques, or combinations of such techniques, such as, but not limited to, crystallization, normal phase chromatography, reverse phase chromatography, and chiral chromatography, to provide the single enantiomers of the invention.

Those skilled in the art will understand that the various symbols, superscripts, and subscripts used in the schemes, methods, and examples are for convenience of presentation and/or to reflect the order in which they are introduced into the schemes and are not intended to necessarily correspond to the symbols, superscripts, or subscripts in the appended claims. The schemes represent methods that can be used to synthesize the compounds of the present invention. It should be understood that they do not limit the scope of the present invention in any way.

It will be appreciated by those skilled in the art that some blocking groups (-Z) cannot withstand some reaction conditions described in the reaction scheme hereinafter. Therefore, some blocking group operations may be required to fully complete the synthesis. Due to multiple protection-deprotection possibilities, these operations will not be clearly described.

Scheme 1 below illustrates two methods for obtaining the intermediate nitro-pyridylaza F from commercially available starting materials A or B. Dibromopyridone A (wherein R ³ is OH) is commercially available. Treatment of A with an appropriate alkylating agent (e.g., an alkyl halide) in the presence of a base and possible additives (e.g., silver carbonate) (Synthesis 2009, 16, 2725-2728; Journal of Medicinal Chemistry 2003, 46(6), 921-924) can provide the desired dibromoalkoxypyridine B. Alternatively, some dibromopyridines are commercially available and can be used directly as starting points for the preparation of aza F. Dibromopyridine B can then be subjected to palladium-mediated coupling with a tetrahydropyran-protected trifluoroborate C as described in JOC 2012, 77(22), 10399-10408. Removal of the tetrahydropyran protecting group under acidic aqueous conditions provides intermediate D. Intermediate D is treated with a sulfonyl chloride (e.g., methanesulfonyl chloride or p-toluenesulfonyl chloride) and a base to activate the hydroxyl group for final displacement with a nucleophile. Disulfonates are treated with an amine source under mild alkaline conditions to displace the sulfonate and provide a cyclized nitrogen heterocycle, which provides compounds of formula E. Examples of similar conversions from diols to azacycles have been described in references such as WO2008051547, CN 101712675, WO 2008038051, WO 2007028132, and WO 2005058328. The amine source (as shown, _NH2Z ) can range from simple ammonia, alkylamines with the desired ^R1 group (i.e., Z is ^R1alkyl ) to various protected amines, depending on the type of chemistry to be subsequently performed. Compounds of formula E can then be nitrated under standard nitration conditions (HNO ₃ , H ₂ SO ₄ , neat or with solvent, usually starting at < room temperature) to give nitro intermediates of formula F.

Alternatively, compounds of formula F can be synthesized starting from an azacyclic ketone of formula G, the synthesis of which has been previously described in the literature (JACS 2012, 134(42), 17440-17443). Compounds of formula G are treated with nitroacetamide under alkaline conditions from room temperature to 150°C to provide pyridone azacyclic ketones of formula H. When a compound wherein R ³ is a suitable alkoxy group (e.g., C ₁ -C ₆ alkoxy) is desired, pyridone H can be alkylated by treatment with an alkyl halide and a base to provide compounds of formula F. Compound H can also be treated with phosphorus oxychloride, phosphorus oxybromide, or phosphorus pentoxide and tetrabutylammonium bromide at temperatures from 20°C to ~100°C, either neat or in a suitable solvent, to provide compound J, wherein X is Cl or Br. When R ³ is a suitable alkoxy group, intermediate J can be treated with an appropriate alcohol under conventional nucleophilic aromatic substitution reaction (S _N Ar examples: Australian Journal of Chemistry 2003, 56 (9), 913-916; European Journal of Organic Chemistry 2004, 16, 3477-3483; Journal of Organic Chemistry 2003, 68 (18), 7119-7122) conditions to provide compound F. Intermediate J can also be used for Suzuki-Miyaura type reaction (Chemical Society Reviews 2014, 43, 412-443; Accounts of Chemical Research 2013, 46, 2626-2634), where a palladium source, a suitable phosphine ligand, a base and a suitable boronate ester [B (OR) ₂ R ₃ ] can be used to attach a suitable R ³ alkyl group.

Route 1

Scheme 2 describes a synthetic procedure for converting intermediate F to intermediate T. When the substituent ^R is a methoxy group instead of the desired final substituent, the methyl portion of the methoxy group can be removed using a number of known methods, such as by treatment with hydrobromic acid and acetic acid at elevated temperature (WO 2013025733) or by treatment with p-toluenesulfonic acid and lithium chloride at elevated temperature (Synthetic Communications 2011, 41(12), 1852-1857), to afford a nitropyridone aza intermediate of formula H. Compound H can then be converted to the desired intermediate F by treatment of H with an appropriate alkylating agent (e.g., an alkyl halide) in the presence of a base and possibly an additive (e.g., silver carbonate) (Synthesis 2009, 16, 2725-2728; Journal of Medicinal Chemistry 2003, 46(6), 921-924). The nitro group of intermediate F can then be reduced to the desired amine of formula Y by treatment with palladium on carbon or Raney nickel in the presence of hydrogen (Tetrahedron 1997, 53(37), 12505-12524; Journal of Medicinal Chemistry 2005, 48(6), 1948-1964), or by treatment with a metal such as iron, tin or zinc, typically in the presence of an acid source (Organic Letters 2009, 11(22) 5142-5145; ACS Medicinal Chemistry Letters 2010, 1(1), 39-43; WO 2008038051). If intermediate Y contains Z, wherein group Z is a protecting group, the protecting group can be removed and the desired R1 substituent can then be incorporated to provide intermediate T by introduction of the desired alkyl halide (WO 2014188173, Journal of Medicinal Chemistry 2014, 57(24), 10424-10442; ACS Medicinal Chemistry Letters 2014, 5(4), 304-308), or by condensation with an appropriate ^aldehyde followed by treatment with an appropriate reducing agent (Journal of Medicinal Chemistry 2015, 58(20), 8236-8256; European Journal of Medicinal Chemistry 2014, 85, 16-26; Chemical Biology & Drug Design 2014, 83(2), 149-153).

Route 2

Route 3 describes the synthetic route of the compound of formula I ', and the compound is a compound of formula I, wherein R ³ is a suitable C 1 -C ₆ alkoxy group represented as OR ³ ' in the route. The synthesis of the compound of formula P has been previously described (WO 2007/140213). The sulfonamide of formula Q is a very common reactant, and a large amount of these are commercially available. If the compound of desired formula Q is not commercially available, it can be synthesized by the sulfonyl chloride of formula J, which is from commercial sources or from conversion (see, for example, WO 2015007668, WO 2014082379, WO 2014106800) of the sulfonyl chloride of corresponding formula J when treated with a chlorinating agent (such as phosphorus oxychloride, phosphorus pentachloride or thionyl chloride). The intermediate of formula P is treated with an appropriate sulfonamide of formula Q in the presence of a palladium catalyst, an appropriate ligand and a base in a Hartwig-Buchwald type coupling reaction to attach the desired sulfonamide to the pyridyl aza core (see, for example, Organic Letters 2011, 13(10), 2564-2567; WO 2010106436; Tetrahedron Letters 2008, 49(31), 4585-4587). Similar couplings between sulfonamides and aryl bromides have been described, typically using copper, an appropriate ligand and a base at elevated temperature (Tetrahedron 2005, 46(43), 7295-7298; Journal of Chemical Sciences 2010, 122(2), 143-148; Tetrahedron Letters 2003, 44(16), 3385-3386). If necessary, the protecting group is removed to give a compound of formula S. The compound of formula S can then be converted to a compound of formula I' having the desired R1 substituent by treating the amine S with the desired alkyl halide (WO 2014188173, Journal of Medicinal Chemistry 2014, 57(24), 10424-10442; ACS Medicinal Chemistry Letters 2014, 5(4), 304-308) or by condensation with an appropriate aldehyde followed by treatment with a reducing agent (Journal of Medicinal Chemistry 2015, 58(20), 8236-8256; European Journal of Medicinal Chemistry 2014, 85, 16-26; Chemical Biology & Drug Design 2014, ⁸³ (2), 149-153).

Route 3

Scheme 4 describes an alternative synthetic route to commercially unavailable sulfonyl chlorides that can be used to provide certain compounds of Formula I. Appropriately substituted aryl halides (e.g., chlorides, bromides, or iodides) can be coupled with thiols (e.g., benzyl mercaptan, as shown, or p-methoxybenzyl mercaptan), typically at elevated temperatures using a catalyst (e.g., various palladium or copper catalysts), a suitable ligand, a base, and a solvent (Journal of Organic Chemistry 2011, 76(11), 4371-4378; Tetrahedron Letters 2007 48(40), 7199-7202; Tetrahedron 2005, 61(22), 5253-5259) to provide intermediate U. Intermediate U can be treated with an oxidant and a chloride source to provide the desired sulfonyl chloride J. Representative literature examples of this transformation include: Tetrahedron 2010 51(2), 418-421; Tetrahedron 1998 54(45), 13737-13750; Journal of Organic Chemistry 1996, 61(26), 9289-9292.

Route 4

Scheme 5 describes another method for synthesizing compounds of formula I. The protected intermediate Y is reacted with the desired sulfonyl chloride J in a suitable solvent (with or without a base) at a temperature of 0°C to 100°C to obtain the intermediate W. Examples of similar condensations are known in the art and have been described in references such as Bioorganic & Medicinal Chemistry Letters 2009 19(22), 6452-6458; WO 2008038051; Bioorganic & Medicinal Chemistry Letters 2007, 17(2), 400-405. If a compound of formula I in which R ⁴ is hydrogen is desired, the intermediate W can be deprotected and the desired R 1 substituent can be introduced by treating the resulting amine with the desired alkyl halide (WO 2014188173; Journal of Medicinal Chemistry 2014, 57(24), 10424-10442; ACS Medicinal Chemistry Letters 2014, 5(4), 304-308), or condensing with an appropriate aldehyde followed by treatment with an appropriate reducing agent (similar reductive aminations are described in references such as: Journal of Medicinal Chemistry 2015, 58(20), 8236-8256; ^{European Journal of Medicinal Chemistry 2014, 85, 16-26; Chemical Biology & Drug Design 2014, 83(2), 149-153) to give a compound of formula I in which R 4 is} hydrogen. If ^R4 is desired to be alkyl, intermediate W can be treated with a base (e.g., sodium hydride) in the presence of the desired alkyl halide (see, e.g., US 20050137186; WO 2005118549) or under Mitsunobu conditions (see, e.g., WO 2003068732; WO 2003068732), wherein the desired ^R4 alkyl group is obtained by treating W with an appropriate alcohol to provide intermediate AA. AA is deprotected and the desired R 1 substituent is added by treating the resulting amine with the desired alkyl halide (WO 2014188173, Journal of Medicinal Chemistry 2014, 57(24), 10424-10442; ACS Medicinal Chemistry Letters 2014, 5(4), 304-308) or condensing with an appropriate aldehyde followed by treatment with a reducing agent such as sodium triacetoxyborohydride (similar reductive aminations have been described: Journal of Medicinal Chemistry 2015, 58(20), 8236-8256; European Journal of Medicinal Chemistry 2014, 85, 16-26; Chemical Biology & Drug Design 2014, 83(2), 149-153) to afford compounds of formula ^I wherein R ⁴ is alkyl.

When the desired ^R1 group is already present on the aza group (i.e., intermediate T), treatment with the desired sulfonyl chloride J (with or without base) in an appropriate solvent at a temperature between 0°C and 100°C provides compounds of formula I wherein ^R4 is hydrogen (Bioorganic & Medicinal Chemistry Letters 2009 19(22), 6452-6458; WO2008038051; Bioorganic & Medicinal Chemistry Letters 2007, 17(2), 400-405). When a compound of formula I wherein ^R is a suitable alkyl group is desired, the compound of formula I wherein R is hydrogen can be treated with a base (e.g., sodium hydride) in the presence of the desired alkyl halide (see, e.g., US20050137186; WO 2005118549) or under Mitsunobu conditions (see, e.g., WO 2003068732; WO2003068732), wherein the desired ^{R alkyl} group is derived from treatment of the compound of formula I wherein R ^is hydrogen with the desired alcohol to provide the desired compound of formula I wherein ^R is alkyl.

Route 5

As used herein, the term "reacting" refers to the mixing of specified chemical reactants to produce a chemical transformation that is different from any compound initially introduced into the system. The reaction can be carried out in the presence or absence of a solvent.

The compound of formula I can exist in the form of stereoisomers (e.g., atropisomers, racemates, enantiomers, or diastereomers). Conventional techniques for preparing/isolating single enantiomers include chiral synthesis by suitable optically pure precursors, or using, for example, chiral high performance liquid chromatography (HPLC) or chiral supercritical fluid chromatography to split the racemate. Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound (e.g., ethanol), or with an acid or base (such as tartaric acid or 1-phenylethylamine) in the case where the compound contains an acidic or basic group. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers can be converted into the corresponding pure enantiomers by means well known to those skilled in the art. The chiral compound of Formula I (and its chiral precursor) can be obtained in enantiomerically enriched form using chromatography (typically HPLC) on an asymmetric resin, wherein the mobile phase consists of a hydrocarbon (typically heptane or hexane) and contains 0% to 50% (typically 2% to 20%) 2-propanol and 0% to 5% alkylamine (typically 0.1% diethylamine). The eluate is concentrated to obtain an enriched mixture. Stereoisomeric aggregates can be separated by conventional techniques known to those skilled in the art. See, for example, E.L. Eliel and S.H. Wilen, Stereochemistry of Organic Compounds (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety. Suitable stereoselective techniques are well known to those of ordinary skill in the art.

When the compound of Formula I contains an alkenyl or alkenylene (alkylene) group, geometric cis/trans (or Z/E) isomers may exist. Cis/trans isomers can be separated by conventional techniques well known to those skilled in the art (e.g., chromatography and fractional crystallization). The salts of the present invention can be prepared according to methods known to those skilled in the art.

In nature, the compound of formula I that is alkaline can form multiple salts with multiple mineral acids and organic acids. Although such salt must be pharmaceutically acceptable when administered to animals, in practice, it is often necessary to first separate the compound of the present invention in the form of a pharmaceutically unacceptable salt by reaction mixture, then simply convert the latter (described pharmaceutically unacceptable salt) back into a free base compound by treating with an alkaline reagent, then convert the latter's free base into a pharmaceutically acceptable acid-addition salt. The acid-addition salt of the basic compound of the present invention can be prepared by treating the basic compound with substantially equal amounts of the selected mineral acid or organic acid in an aqueous solvent medium or in a suitable organic solvent (such as methanol or ethanol). After evaporating the solvent, desired solid salt is obtained. Required acid salt can also be precipitated from the solution by adding appropriate mineral acid or organic acid to the solution of the free base in an organic solvent.

If the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, isonicotinic acid, lactic acid, pantothenic acid, ascorbic acid, or the like. , 2,5-dihydroxybenzoic acid, gluconic acid, glucaric 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)], pyranosidic acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid) aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as ethanesulfonic acid), etc.

Compounds of Formula I that are acidic in nature can form alkali salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, particularly sodium salts and potassium salts. These salts are all prepared by conventional techniques. The chemical base used as the reagent for preparing the pharmaceutically acceptable alkali salts of the present invention is those that form non-toxic alkali salts with the acidic compound of Formula I. These salts can be prepared by any suitable method, for example, by treating the free acid with an inorganic base or an organic base, such as an amine (primary amine, umbilical amine or tertiary amine), an alkali metal hydroxide or an alkaline earth metal hydroxide. These salts can also be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation, and then (for example, under reduced pressure) evaporating the resulting solution to dryness. Alternatively, it can also be prepared by mixing a lower alkanol solution of the acidic compound with the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as before. In either case, a stoichiometric amount of reagent is used to ensure that the reaction is complete and the yield of the desired final product is the highest.

Pharmaceutically acceptable salts of compounds of Formula I can be prepared by one or more of three methods:

(i) by reacting a compound of formula I with a desired acid or base;

(ii) by removing an acid-labile or base-labile protecting group of a suitable precursor of a compound of formula I using the desired acid or base, or by ring-opening a suitable cyclic precursor (e.g., a lactone or lactam) using the desired acid or base; or

(iii) converting one salt of a compound of formula I into another salt by reaction with an appropriate acid or base or by passing through a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration or can be recovered by evaporating the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost non-ionized.

Polymorphs may be prepared according to techniques well known to those skilled in the art, for example by crystallization.

When any racemate is crystallized, two different types of crystals are possible. The first type is the racemic compound (true racemate) mentioned above, in which one homogeneous form of crystal is produced containing equimolar amounts of two enantiomers. The second type is a racemic mixture or agglomerate, in which two forms of crystal are produced in equimolar amounts, each containing a single enantiomer.

The two crystalline forms present in a racemic mixture may have nearly identical physical properties, but 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, E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds (Wiley, New York, 1994).

The present invention also includes isotopically labeled compounds of formula I, wherein one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Isotopically labeled compounds of formula I (or pharmaceutically acceptable salts thereof or N-oxides thereof) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriately isotopically labeled reagents in place of the unlabeled reagents otherwise used.

The biopharmaceutical properties of the compound of Formula I (e.g., solubility and solution stability (across pH), permeability, etc.) should be evaluated to select the most appropriate dosage form and route of administration for the treatment of the proposed indication. The compound of the present invention intended for pharmaceutical use can be administered in the form of a crystalline or amorphous product. It can be obtained in the form of, for example, a solid plug, powder, or film by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radiofrequency drying can be used for this purpose.

It can be administered alone, or in combination with one or more other compounds of the present invention, or in combination with one or more other drugs (or in any combination thereof). Generally speaking, it will be administered in combination with one or more pharmaceutically acceptable excipients in the form of a formulation. The term "excipient" is used herein to describe any ingredient other than the compound of the present invention. The choice of excipient will depend to a large extent on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the properties of the dosage form. Pharmaceutical compositions suitable for delivering the compounds of the present invention (or their pharmaceutically acceptable salts) and methods for their preparation will be apparent to those skilled in the art. The compositions and methods for their preparation can be found in, for example, Remington's Pharmaceutical Sciences, 19th edition (Mack Publishing Company, 1995).

The compounds of the present invention (including pharmaceutically acceptable salts thereof and N-oxides thereof) can be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract; and/or buccal, lingual or sublingual administration, thereby allowing the compound to enter the bloodstream directly from the mouth.

Formulations suitable for oral administration include solid, semisolid, and liquid systems, such as tablets; soft or hard capsules containing multi- or nanoparticulates, liquids, or powders; lozenges (including liquid-filled ones); chewable tablets; gels; rapidly dispersing dosage forms; films; ovoids; sprays; and buccal/mucoadhesive patches.

Liquid preparations include suspensions, solutions, syrups, and elixirs. Such preparations can be used as fillers in soft or hard capsules (e.g., made from gelatin or hydroxypropyl methylcellulose) and typically contain a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifiers and/or suspending agents. Liquid preparations can also be prepared by reconstituting a solid (e.g., from a sachet). The compounds of the present invention can also be used in fast-dissolving, fast-disintegrating dosage forms, such as those described by Liang and Chen in Expert Opinion in Therapeutic Patents 2001, 11, 981-986.

For tablet dosage forms, the drug may comprise 1 to 80 weight percent of the dosage form, more typically 5 to 60 weight percent, depending on the dosage. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise 1 to 25 weight percent, e.g., 5 to 20 weight percent, of the dosage form.

Binders are generally used to impart adhesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally contain surfactants (e.g., sodium lauryl sulfate and polysorbate 80) and glidants (e.g., silicon dioxide and talc). When present, surfactants may comprise 0.2% to 5% by weight of the tablet and glidants may comprise 0.2% to 1% by weight of the tablet.

Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants typically comprise 0.25% to 10% by weight of the tablet, for example 0.5% to 3% by weight.

Other possible ingredients include antioxidants, colorings, flavorings, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and about 0.25% to about 10% lubricant.

Tablet blends can be compressed directly or by roller compression to form tablets. Alternatively, tablet blends or portions of a blend can be wet-, dry-, or melt-granulated, melt-agglomerated, or extruded prior to tableting. The final formulation can contain one or more layers and can be coated or uncoated; it can even be encapsulated.

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

Oral thin films for human or veterinary use are typically flexible, water-soluble or water-swellable film dosage forms that are rapidly dissolving or mucoadhesive and typically contain a compound of Formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifier, and a solvent. Some components of the formulation may perform more than one function.

The compound of formula I (or its pharmaceutically acceptable salt) can be soluble in water or insoluble in water. Water-soluble compounds generally account for 1% to 80% by weight of the solute, more generally 20% to 50% by weight. The less soluble compound can account for a smaller proportion of the composition, generally accounting for up to 30% by weight of the solute. Alternatively, the compound of formula I can be in the form of multi-particulate beads.

The film-forming polymer may be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is typically present in an amount of 0.01 to 99% by weight, more typically 30 to 80% by weight.

Other possible ingredients include antioxidants, colorants, flavorings and flavor enhancers, preservatives, saliva stimulants, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants, and taste masking agents.

The film of the present invention is usually prepared by evaporating an aqueous film coated on a peelable backing or paper. This can be done in a drying oven or drying tunnel (usually a combined coating dryer) or by freeze drying or vacuuming.

Solid dosage forms for oral administration can be formulated as immediate release and/or modified release formulations. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release formulations.

Suitable modified release formulations for the purposes of the present invention are described in U.S. 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 chewable tablets to achieve controlled release is described in WO 00/35298.

The compounds of the present invention (including pharmaceutically acceptable salts and N-oxides thereof) can also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes, and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and buffers (e.g., buffered to a pH of 3 to 9), but for some applications, parenteral formulations may be more suitably formulated as sterile non-aqueous solutions or in dry form for use with a suitable vehicle (e.g., sterile, pyrogen-free water).

The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

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

Preparations for parenteral administration can be formulated as immediate release and/or modified release formulations. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release formulations. Therefore, the compounds of the present invention can be formulated as suspensions or solids, semisolids, or thixotropic liquids to provide an implantable reservoir for modified release of the active compound. Examples of such preparations include drug-coated stents and semisolids and suspensions containing drug-loaded poly (DL-lactic-co-glycolic acid) (PLGA) microspheres.

The compounds of the present invention (including pharmaceutically acceptable salts thereof and N-oxides thereof) can also be administered topically, intradermally, or transdermally to the skin or mucous membranes. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, medicated glutinous rice paper, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerol, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated. See, for example, Finnin and Morgan, J. Pharm. Sci. 1999, 88, 955-958.

Other means of local administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (eg, Powderject ^™ , Bioject ^™ , etc.) injection.

Preparations for topical administration can be formulated for immediate and/or modified release. Modified release preparations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release preparations.

The compounds of the present invention (including pharmaceutically acceptable salts thereof and N-oxides thereof) can also be administered intranasally or by inhalation, usually in the form of a dry powder from a dry powder inhaler (alone; in a mixture, for example, a dry blend with lactose; or in the form of mixed component particles, for example, mixed with a phospholipid (such as phosphatidylcholine)), in the form of an aerosol spray from a pressurized container, a pump, a nebulizer, an atomizer (for example, an atomizer using electrohydrodynamics to produce a fine mist) or a nebulizer with or without a suitable propellant (such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane), or in the form of nasal drops. For intranasal use, the powder may contain a bioadhesive, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer or nebulizer contains a solution or suspension of the compound of the invention containing, for example, ethanol, aqueous ethanol or other alternative substances suitable for dispersing, solubilizing or prolonging the release of the active substance, a propellant as a solvent and optionally a surfactant (for example, sorbitan trioleate, oleic acid or oligolactic acid).

Prior to use in dry powder or suspension formulations, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (e.g., made from gelatin or hydroxypropylmethylcellulose), blister packs, and cartridges for use in an inhaler or insufflator can be formulated as a powder mix containing a compound of the invention, a suitable powder base (e.g., lactose or starch), and a potency modifier (e.g., L-leucine, mannitol, or magnesium stearate). Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

Solution formulations suitable for use in atomizers using electrohydrodynamics to generate a fine mist may contain 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 contain a compound of Formula I or a pharmaceutically acceptable salt thereof, propylene glycol, sterile water, ethanol, and sodium chloride. Other alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavorings (such as menthol and levomenthol) or sweeteners (such as saccharin or saccharin sodium) may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration can be formulated as immediate and/or modified release formulations using, for example, PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release formulations.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered dose. The units of the present invention are typically configured to administer a metered dose or "puff" containing 0.01-100 mg of a compound of Formula I. The total daily dose will typically be 1 μg to 200 mg, which can be administered in a single dose or, more typically, in divided doses throughout the day.

The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema. Cocoa butter is a traditional suppository base, but a variety of alternatives may be used where appropriate.

Formulations for rectal/vaginal administration can be formulated for immediate and/or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release formulations.

The compounds of the present invention 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 suitable for ophthalmic and otic administration include ointments, gels, biodegradable implants (e.g., absorbable gel sponges, collagen) and non-biodegradable implants (e.g., silicones), drug-coated wafers, lenses, and granules or vesicle systems (e.g., vesicles or liposomes). Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methylcellulose), or heteropolysaccharide polymers (e.g., agarose gel) can be blended with preservatives (e.g., benzalkonium chloride). Such formulations can also be delivered by iontophoresis.

Formulations for ocular/aural administration can be formulated for immediate and/or modified release, including delayed, sustained, pulsed, controlled, targeted, or programmed release.

The compounds of the present invention may be combined with soluble polymeric entities (e.g., cyclodextrins and suitable derivatives thereof, or polymers containing polyethylene glycol) to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability when used in any of the aforementioned modes of administration.

For example, drug-cyclodextrin complexes are generally found to be useful in a wide variety of dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, i.e., as carriers, diluents, or solubilizers. The most commonly used for these purposes are α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, examples of which can be found in International Patent Applications Nos. WO 91/11172, WO 94/02518, and WO 98/55148.

Since one aspect of the present invention relates to treating the disease/condition described herein with a combination of active ingredients that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in the form of a kit. The kit contains 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 as described above. The kit contains a device for accommodating the separated compositions, such as a container, a separate bottle, or a separate foil package. The kit typically contains instructions for administering the separated components. When the separated components are administered, for example, in different dosage forms (e.g., oral and parenteral), at different dosing intervals, or when the prescribing physician needs to titrate the individual components of the combination, the kit form is particularly beneficial.

The example of such medicine box is so-called blister pack. Blister pack is well known in the packaging industry and is widely used in packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister pack is usually composed of a thin sheet of relatively rigid material covered with a transparent plastic material foil. During the packaging process, a groove is formed in the plastic foil. The groove has the size and shape of the tablet or capsule to be packaged. Then, the tablet or capsule is placed in the groove, and with respect to the plastic foil, the thin sheet of relatively rigid material is sealed on the side opposite to the direction in which the groove is formed on the foil front. Therefore, the tablet or capsule is sealed in the groove between the plastic foil and the thin sheet. In some embodiments, the strength of the thin sheet makes the tablet or capsule can be removed from the blister pack, and it forms an opening in the thin sheet at the groove position by manually applying pressure on the groove. Then, the tablet or capsule can be removed through the opening.

It may be necessary to provide a memory aid on the kit, for example in the form of numbers next to the tablets or capsules, where the numbers correspond to the days of the treatment regimen on which the specified tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, for example as follows "Week 1, Monday, Tuesday, etc. ... Week 2, Monday, Tuesday..." etc. Other variations of memory aids will be apparent. A "daily dose" can be a single tablet or capsule, or several pills or capsules, to be taken on a specified day. In addition, a daily dose of a compound of Formula I can consist of one tablet or capsule, while a daily dose of a second compound can consist of several tablets or capsules, or vice versa. The memory aid should reflect this.

In another specific embodiment of the present invention, a dispenser is provided that is designed to dispense one or more daily doses one at a time in the desired order of use. For example, the dispenser is equipped with a memory aid to further promote compliance with the treatment regimen. An example of such a memory aid is a mechanical counter that indicates the number of daily doses dispensed. Another example of such a memory aid is a battery-powered microchip memory combined with a liquid crystal reader or an audio reminder signal that, for example, reads out the date of taking the previous daily dose and/or reminds when to take the next dose.

Experimental process

The following illustrates the synthesis of various compounds of the present invention. Other compounds within the scope of the present invention can be prepared using the methods illustrated in these examples, alone or in combination with techniques known in the art.

Experiments were typically performed under an inert atmosphere (nitrogen or argon), particularly when oxygen- or moisture-sensitive reagents or intermediates were employed. Commercial solvents and reagents were typically used without further purification. Anhydrous solvents were included where appropriate (typically products from Acros Organics or EMD Chemicals). Otherwise, commercial solvents were passed through a column filled with molecular sieves until the following QC water standards 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, solvents were further treated with sodium metal, calcium hydride, or molecular sieves and distilled before use. Products were typically dried under vacuum before proceeding to further reactions or submitting for biological testing. Mass spectral data were reported by liquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI), or gas chromatography-mass spectrometry (GCMS). The chemical shifts of nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm) with reference to the residual peaks from the deuterated solvent employed. In some embodiments, chiral separations are performed to separate the enantiomers of certain compounds of the present invention (in some embodiments, the separated enantiomers are designated as ENT-1 and ENT-2, according to their elution order). In some embodiments, the optical rotation of the enantiomers is measured using a polarimeter. According to the rotation data observed (or its specific rotation data), the enantiomer with clockwise optical rotation is designated as (+)-enantiomer, and the enantiomer with counterclockwise optical rotation is designated as (-)-enantiomer. In some cases, racemic compounds are represented by the presence of (+/-) adjacent to the structure; in these cases, the indicated stereochemical structure represents the relative (rather than absolute) configuration of the compound substituents.

The reaction carried out by detectable intermediate is usually subsequently carried out LCMS, and before adding subsequent reagents, is converted completely.For the synthetic reference process in other embodiments or methods, reaction conditions (reaction time and temperature) can change.Usually, carry out thin layer chromatography or mass spectral analysis after the reaction, and carry out aftertreatment when appropriate.Purification can change between experiments: usually, select solvent and the solvent ratio for eluent/gradient to provide suitable Rfs or retention time.

The following abbreviations may be used in the description of the experimental section:

br = broad; CDCl ₃ = deuterated chloroform; CD ₃ OD = deuterated methanol; d = doublet, dd = doublet of doublets; EDC or EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; g = gram; GCMS = gas chromatography-mass spectrometry; h = hour; HATU = O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HCl = hydrochloric acid; HPLC = high performance liquid chromatography; Hz = hertz; L = liter; LCMS = liquid chromatography-mass spectrometry; m = multiplet; M = mole; mg = milligram; MHz = megahertz; min = minute; μL = microliter; mL = milliliter; μmol = micromolar; mmol = millimole; mol = mole; n-BuLi = n-butyllithium; NEt ₃ = triethylamine; NH ₄ Cl = ammonium chloride; NaHCO ₃ = sodium bicarbonate; NaOAc = sodium acetate; NaOCl = sodium hypochlorite; NaOH = sodium hydroxide; NaOMe = sodium methoxide; t-BuONa = sodium tert-butoxide; NH ₂ OH.HCl = hydroxylamine hydrochloride; NMR = nuclear magnetic resonance; NOE = nuclear polarization effect; Pd ₂ (dba) ₃ = tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl ₂ = [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; PPh ₃ = triphenylphosphine; psi = pounds per square inch; q = quartet; rt = room temperature; s = singlet; t = triplet; t-butylXPhos = di-tert-butyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphine; TFA or CF ₃ CO ₂ H = trifluoroacetic acid; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

Preparation of P1

2,2'-(6-methoxypyridine-2,3-diyl)diethanol (P1)

Step 1. Synthesis of 2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethoxy]tetrahydro-2H-pyran (C1).

A mixture of 2-(2-bromoethoxy)tetrahydro-2H-pyran (84.0 g, 402 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (153 g, 602 mmol), lithium methoxide (30.5 g, 803 mmol), copper(I) iodide (7.65 g, 40.2 mmol), and polymer-bound triphenylphosphine (equivalent to 10.5 g, 40.0 mmol) in N,N-dimethylformamide (2.0 L) was stirred at room temperature for 20 hours. The mixture was then diluted with dichloromethane (2 L) and filtered through a pad of Celite; the filter pad was rinsed with dichloromethane (2 x 500 mL), and the combined filtrates were concentrated under vacuum. The residue was poured into saturated aqueous ammonium chloride (1.0 L), and the resulting mixture was extracted with diethyl ether (4 x 500 mL). After washing the combined organic layers with water (2 x 500 mL) and saturated aqueous sodium chloride solution (500 mL), they were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product as a colorless oil. Yield: 85 g, 330 mmol, 82%. ¹ H NMR (400 MHz, CDCl ₃ ) 4.60 (dd, J = 4.1, 2.8 Hz, 1H), 3.92-3.84 (m, 2H), 3.56-3.44 (m, 2H), 1.87-1.76 (m, 1H), 1.73-1.64 (m, 1H), 1.62-1.44 (m, 4H), 1.23 (s, 12H), 1.17 (t, J = 7.9 Hz, 2H).

Step 2. Synthesis of trifluoro[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]borate potassium salt (C2).

Saturated aqueous potassium bifluoride solution (56 g, 720 mmol) was added to a solution of C1 (60 g, 230 mmol) in tetrahydrofuran (900 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum; the resulting viscous gum was washed with acetone (4 x 200 mL) and the acetone washings were filtered. The combined filtrate was concentrated under reduced pressure to a volume of approximately 150 mL. Diethyl ether was added until a small precipitate formed, and the mixture was stirred at 0 ° C for 30 minutes and then filtered. The filter cake was washed with a small amount of diethyl ether to obtain a white solid product. Yield: 40 g, 170 mmol, 74%. ¹ H NMR (400 MHz, DMSO-d6), characteristic peaks: 4.46-4.41 (m, 1H), 3.76-3.68 (m, 1H), 3.57 (ddd, J = 13, 10, 5 Hz, 1H), 3.22 (ddd, J = 13, 10, 5 Hz, 1H), 1.76-1.65 (m, 1H), 1.59-1.50 (m, 1H), 1.49-1.31 (m, 4H), 0.44-0.19 (m, 2H).

Step 3. Synthesis of 6-methoxy-2,3-bis[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyridine (C3).

1,4-Dioxane (450 mL) and water (150 mL) were added to a mixture of 2,3-dibromo-6-methoxypyridine (12 g, 45 mmol), C2 (31.8 g, 135 mmol), di(1-adamantyl)-n-butylphosphine (A; 3.22 g, 8.98 mmol), palladium(II) acetate (3.03 g, 13.5 mmol), and cesium carbonate (87.9 g, 270 mmol). The reaction vessel was evacuated and filled with nitrogen. This evacuation cycle was repeated twice, and the reaction mixture was stirred at reflux for 20 hours. The reaction mixture was partitioned between ethyl acetate (300 mL) and saturated aqueous sodium chloride solution (200 mL), and the aqueous layer was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was treated with triethylamine (3 mL), dissolved in dichloromethane, and treated with silica gel. The mixture was concentrated to dryness and chromatographed on silica gel (gradient: 0% to 6% ethyl acetate in petroleum ether) to afford the product as a brown oil. Yield: 10 g, 27 mmol, 60%. LCMS m/z 388.0 [M+Na] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.39 (d, J = 8.3 Hz, 1H), 6.52 (d, J = 8.3 Hz, 1H), 4.63 (dd, J = 4.0, 2.8 Hz, 1H), 4.58 (dd, J = 4.0, 2.8 Hz, 1H), 4.19-4.11 (m, 1H), 3.94-3.71(m,4H),3.89(s,3H),3.58-3.42(m,3H),3.05(t,J＝7.2Hz,2H),2.89(t,J＝7.2 Hz,2H),1.86-1.74(m,2H),1.74-1.64(m,2H),1.62-1.44(m,8H).

Step 4. Synthesis of 2,2'-(6-methoxypyridine-2,3-diyl)diethanol (P1).

A mixture of C3 (29.7 g, 81.3 mmol) and p-toluenesulfonic acid monohydrate (16.2 g, 85.2 mmol) in methanol (400 mL) was stirred at 15 ° C overnight. After the reaction mixture was concentrated under vacuum, the residue was distributed between dichloromethane (300 mL) and saturated aqueous sodium bicarbonate solution (200 mL), and the aqueous layer was extracted with dichloromethane (5 x 200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown gummy product. Yield: 15.6 g, 79.1 mmol, 97%. LCMS m/z 198.2 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.43 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 4.06(t,J＝5.3Hz,2H),3.90(s,3H),3.81(t,J＝6.7Hz,2H),2.98(t,J＝5.3Hz,2H),2.81(t,J＝6.6Hz,2H).

Preparation of P2

1-(3-Amino-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl)-2,2,2-trifluoroethanone (P2)

Step 1. Synthesis of (6-methoxypyridine-2,3-diyl)diethane-2,1-diyl dimethanesulfonate (C4).

Methanesulfonyl chloride (31.6 g, 276 mmol) was added to a 0°C solution of P1 (15.6 g, 79.1 mmol) and triethylamine (40 g, 400 mmol) in dichloromethane (400 mL). The reaction mixture was stirred at room temperature for 20 minutes and then quenched with saturated aqueous sodium bicarbonate solution (200 mL). The organic layer was washed with saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give a brown gummy product that solidified upon standing. Yield: 28 g, 79 mmol, 100%. ¹ HNMR (400MHz, CDCl ₃ )7.42(d,J＝8.4Hz,1H),6.62(d,J＝8.4Hz,1H),4.75(t,J＝6.5Hz,2H),4.35(t,J＝7.0Hz,2H),3.91(s,3H),3.17(t,J＝6.4Hz, 2H), 3.04 (t, J = 6.9Hz, 2H), 2.96 (s, 3H), 2.95 (s, 3H).

Step 2. Synthesis of 7-benzyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C5).

A solution of C4 (12.5 g, 35.4 mmol) and benzylamine (40 mL, 370 mmol) in 1,2-dichloroethane (40 mL) was heated at 40 ° C overnight. The reaction mixture was then diluted with dichloromethane (300 mL), washed sequentially with saturated aqueous sodium bicarbonate solution (300 mL) and saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (gradient: 0%-30% ethyl acetate in petroleum ether) gave the product as a yellow gummy product. Yield: 5.5 g, 20 mmol, 56%. LCMS m/z 269.0 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.4-7.2(m,6H),6.47(d,J＝8Hz,1H),3.89(s,3H),3.64(s,2H),3.1-3.0(m,2H), 2.8-2.7(m,2H),2.7-2.6(m,4H).

Step 3. Synthesis of 2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C6).

Wet palladium on carbon (10%, 3 g) was added to a solution of C5 (6.0 g, 22 mmol) in methanol (150 mL). The reaction mixture was degassed under vacuum and then purged with hydrogen; this evacuation cycle was repeated several times. The reaction mixture was then stirred under hydrogen (50 psi) at 50 ° C for 72 hours and then filtered through a pad of celite. The filter pad was washed with methanol (2×100 mL) and the combined filtrate was concentrated under vacuum to give the product as a light yellow gummy substance. Yield: 3.85 g, 21.6 mmol, 98%. ¹ H NMR (400MHz, CDCl ₃ )7.28(d,J＝8Hz,1H),6.47(d,J＝8.0Hz,1H),3.90(s,3H),3.08-3.03(m,2H),3.02-2.96(m,2H),2.96-2.91(m,2H), 2.83-2.77(m,2H).

Step 4. Synthesis of 2,2,2-trifluoro-1-(2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl)ethanone (C7).

Trifluoroacetic anhydride (5.44 g, 25.9 mmol) was added to a 0°C solution of C6 (3.85 g, 21.6 mmol) and triethylamine (6.56 g, 64.8 mmol) in dichloromethane (60 mL). The reaction mixture was stirred at 0°C for 20 minutes, then diluted with dichloromethane (50 mL), washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to afford the product as a yellow gum. Yield: 5.8 g, 21 mmol, 97%. ¹ H NMR analysis suggested that the material existed as a ~1:1 mixture of two rotamers at the trifluoroacetamide group. This was true for many subsequent intermediates bearing this functional group. LCMS m/z 274.9 [M+H] ⁺ . ¹ HNMR (400 MHz, CDCl ₃ ) δ [7.35 (d, J=8.3 Hz) and 7.33 (d, J=8.3 Hz), total 1H], [6.56 (d, J=8.2 Hz) and 6.55 (d, J=8.2 Hz), total 1H], [3.92 (s) and 3.91 (s), total 3H], 3.85-3.68 (m, 4H), 3.18-3.10 (m, 2H), 2.94-2.86 (m, 2H).

Step 5. Synthesis of 2,2,2-trifluoro-1-(2-methoxy-3-nitro-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl)ethanone (C8).

Nitric acid (70%, 19 g, 211 mmol) was added to a solution of C7 (5.8 g, 21 mmol) in sulfuric acid (40 mL), and the reaction mixture was stirred at 45 ° C for 16 hours. It was then poured into ice water (500 mL) and extracted with ethyl acetate (2 x 100 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (gradient: 0%-30% ethyl acetate in petroleum ether) gave the product as a yellow gum. Yield: 4.2 g, 13 mmol, 62%. LCMS m/z 319.8 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ [8.13 (s) and 8.11 (s), total 1H], [4.11 (s) and 4.09 (s), total 3H], 3.89-3.73 (m, 4H), 3.27-3.18 (m, 2H), 3.04-2.96 (m, 2H).

Step 6. Synthesis of 1-(3-amino-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl)-2,2,2-trifluoroethanone (P2).

Wet palladium on carbon (10%, 1.00 g) was added to a solution of C8 (6.40 g, 20.0 mmol) in methanol (200 mL). The reaction mixture was degassed under vacuum and then purged with hydrogen; this evacuation cycle was repeated several times. The reaction mixture was then stirred under hydrogen (30 psi) at 30°C for 3 hours and then filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was dissolved in acetonitrile (100 mL). The solvent was removed under reduced pressure to give the product as a light brown solid. Yield: 5.61 g, 19.4 mmol, 97%. LCMS m/z 289.8 [M+H]+. ¹ H NMR (400MHz, CDCl ₃ ) δ7.22-7.08(m,1H), 4.01(s,3H), 3.85-3.65(m,4H), 3.19-3.05(m,2H), 2.92-2.80(m,2H).

Preparation of P3 and P4

2-Methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-3-amine (P3) and 2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-3-amine hydrochloride (P4)

Step 1. Synthesis of 2-methoxy-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C9).

A mixture of C8 (12.0 g, 37.6 mmol) and potassium carbonate (7.79 g, 56.4 mmol) in methanol (100 mL) was stirred at 50° C. for 3 hours, and the reaction mixture was then partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was concentrated under vacuum to remove the methanol, and then extracted with ethyl acetate (2 x 240 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product as a brown solid. Yield: 8.03 g, 36.0 mmol, 96%. ¹ H NMR (400 MHz, CDCl ₃ ) 8.04 (s, 1H), 4.08 (s, 3H), 3.16-3.10 (m, 2H), 3.04-2.96 (m, 4H), 2.91-2.86 (m, 2H).

Step 2. Synthesis of 2-methoxy-7-methyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C10).

The experiment was carried out in duplicate. To C9 (4.0 g, 18 mmol) was added formic acid (8.25 g, 179 mmol) and formaldehyde (37% aqueous solution, 11.6 g, 143 mmol). After the reaction mixture was stirred at 70 ° C for 2.5 hours, they were combined and basified to a pH greater than 10 by adding aqueous sodium hydroxide solution. The resulting suspension was extracted with ethyl acetate (3 x 90 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (gradient: 0%-10% methanol in dichloromethane) gave the product as a yellow solid. Yield: 6.88 g, 29.0 mmol, 81%. ¹ H NMR (400MHz, CDCl ₃ ) 8.04 (s, 1H), 4.09 (s, 3H), 3.18-3.10 (m, 2H), 2.94-2.87 (m, 2H), 2.66-2.55 (m, 4H), 2.40 (s, 3H).

Step 3. Synthesis of 2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-3-amine (P3).

A suspension of C10 (6.80 g, 28.7 mmol) and palladium on carbon (10%, 800 mg) in methanol (250 mL) was stirred under hydrogen (30 psi) at 22°C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate and concentrated under reduced pressure to give the product as a yellow gum. Yield: 5.7 g, 27 mmol, 94%. LCMS m/z 208.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.67 (s, 1H), 3.95 (s, 3H), 3.7-3.5 (br s, 2H), 3.02-2.95 (m, 2H), 2.78-2.71 (m, 2H), 2.61-2.49 (m, 4H), 2.37 (s, 3H).

Step 4. Synthesis of 2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-3-amine hydrochloride (P4).

A mixture of P3 (85.7% purity for this batch by quantitative NMR; 6.19 g, 25.6 mmol) and methoxybenzene (40 mL) was stirred at room temperature for 10 minutes, then cooled in a cold tap water bath and treated dropwise with hydrogen chloride (1.25 M in ethanol; 25 mL, 31.2 mmol). The reaction mixture was stirred at room temperature overnight, the precipitate was collected by filtration, and the filter cake was washed with methoxybenzene (2 x 5 mL) to give the product as an off-white solid. Yield: 4.96 g, 20.3 mmol, 79%. ¹ H NMR (400 MHz, DMSO-d ₆ ) 11.11 (br s, 1H), 6.72 (s, 1H), 4.85 (br s, 2H), 3.82 (s, 3H), 3.59-3.43 (m, 2H), 3.40-3.26 (m, 1H, assumed; partially obscured by water peak), 3.23-3.09 (m, 1H), 3.06-2.89 (m, 2H), 2.89-2.68 (m, 2H), 2.76 (s, 3H).

Alternative synthesis of C9

2-Methoxy-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine(C9)

Step 1. Synthesis of tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate (C11).

A hexane solution of n-butyllithium (2.5 M, 50.5 mL, 126 mmol) was added dropwise to a solution of ethynyl(trimethyl)silane (12.4 g, 126 mmol) in tetrahydrofuran (250 mL) at -75°C over 30 minutes. The reaction mixture was stirred at -75°C for 30 minutes, and then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (21.0 g, 105 mmol) in tetrahydrofuran (100 mL) was added dropwise over 40 minutes. Stirring was continued at this temperature for an additional 30 minutes, after which the reaction mixture was warmed to room temperature and stirred for 3 hours. Methanol (120 mL) was added to the solution, followed by potassium carbonate (16.0 g, 116 mmol), and the reaction mixture was stirred at room temperature for 5 hours. The solvent was then removed in vacuo, and the residue was suspended in diethyl ether (200 mL), washed sequentially with water (50 mL) and saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from heptane to give the product as a white solid. Yield: 22 g, 97 mmol, 92%. GCMS m/z 225.2 [M+]. ^1H NMR (400 MHz, CDCl ₃ ) 3.87-3.70 (m, 2H), 3.28 (ddd, J=13.4, 9.5, 3.1 Hz, 2H), 2.55 (s, 1H), 2.10 (s, 1H), 1.96-1.84 (m, 2H), 1.78-1.66 (m, 2H), 1.47 (s, 9H).

Step 2. Synthesis of tert-butyl 4-hydroxy-4-{1-[(4-methylphenyl)sulfonyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate (C12).

4-Methylbenzenesulfonyl azide (3.24 g, 16.4 mmol, 15% solution in toluene) and copper(I) thiophene-2-carboxylate (94.5 mg, 0.496 mmol) were added to a 0°C solution of C11 (3.7 g, 16 mmol) in toluene (30 mL). After 1 hour, the ice bath was removed and the reaction mixture was stirred for 10 hours. It was then cooled in an ice bath for 30 minutes and filtered; the collected solid was washed with cold toluene (5 mL) to afford the product as a pale white powder. Yield: 6.4 g, 15 mmol, 94%. ¹ H NMR (400MHz, CDCl ₃ )8.03-7.99(m,2H),8.02(s,1H),7.43-7.39(m,2H), 4.00-3.79(m,2H),3.38-3.22(m,2H),2.47(s,3H),2.39-2.35(m,1H),2.07-1.97(m,2H), 1.90-1.82(m,2H),1.47(s,9H).

Step 3. Synthesis of tert-butyl (4E)-4-({[(4-methylphenyl)sulfonyl]amino}methylene)-5-oxoazepane-1-carboxylate (C13).

A solution of C12 (6.1 g, 14 mmol) in toluene (50 mL) was degassed and purged with nitrogen. Rhodium(II) octanoate dimer (112 mg, 0.144 mmol) was added, and the reaction mixture was heated at 50°C for 3 hours. After the solvent was removed in vacuo, the residue was purified by silica gel chromatography (gradient: 25% to 33% ethyl acetate in heptane) to give the product as a pale white solid. Yield: 4.9 g, 12 mmol, 86%. ¹ H NMR (400MHz, CDCl ₃ ) 11.49 (br d, J = 10 Hz, 1H), 7.75 ( br d, J = 8.4Hz, 2H), 7.33 ( br d, J = 8.2Hz, 2H), 6.92 ( d, J = 10.5Hz, 1H), 3.57-3.47(m,4H),2.69-2.61(m,2H),2.47-2.39(m,2H),2.44(s,3H),1.46(s,9H).

Step 4. Synthesis of tert-butyl 3-nitro-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (C14).

To a solution of 2-nitroacetamide triethylamine salt (838 mg, 4.08 mmol) in a mixture of water (0.9 mL) and 2-propanol (9 mL) was added C13 (1.24 g, 3.14 mmol). The reaction mixture was stirred at 50 ° C for 15 hours, and then diethyl ether (10 mL) was added. The resulting mixture was stirred for 30 minutes and filtered; the collected solid (869 mg) was suspended in ethyl acetate (10 mL) and then heated to reflux for 10 minutes. Methanol (2 mL) was added until the mixture became a solution and it was cooled overnight. The resulting solid was collected by filtration to give a bright yellow solid product. Yield: 779 mg, 2.52 mmol, 80%. ¹ H NMR (400MHz, CDCl ₃ )13.71-13.54(br s,1H),8.33(s,1H), 3.73-3.65(m,2H),3.64-3.56(m,2H),3.14-3.05(m,2H),2.87-2.79(m,2H),1.50(s,9H).

Step 5. Synthesis of tert-butyl 2-methoxy-3-nitro-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (C15).

A mixture of C14 (73.7 mg, 0.238 mmol), iodomethane (69 mg, 0.49 mmol), and silver carbonate (133 mg, 0.482 mmol) in dichloromethane was stirred at room temperature for 48 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the product. Yield: 69 mg, 0.21 mmol, 88%. LCMS m/z 268.3 [(M- 2-methylprop-1-ene) + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 4.09 (s, 3H), 3.68-3.55 (m, 4H), 3.17-3.09 (m, 2H), 2.93-2.85 (m, 2H), 1.50 (s, 9H).

Step 6. Synthesis of 2-methoxy-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C9).

Trifluoroacetic acid (3 mL) was added to a solution of C15 (620 mg, 1.92 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 3 hours, after which the solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (40 mL). The aqueous layer was extracted with ethyl acetate (2 x 40 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the product as a yellow oil. Yield: 417 mg, 1.87 mmol, 97%. ^H NMR (400 MHz, CDCl ₃ ) 8.16 (s, 1H), 4.12 (s, 3H), 3.49-3.40 (m, 6H), 3.26-3.20 (m, 2H).

Preparation of P5

7-Ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-3-amine (P5)

Step 1. Synthesis of 7-ethyl-2-methoxy-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C16).

Ethyl iodide (8.87 g, 56.9 mmol) was added to a 5°C mixture of C9 (6.35 g, 28.4 mmol) and potassium carbonate (11.8 g, 85.4 mmol) in acetonitrile (100 mL). The reaction mixture was stirred at 25°C for 5 hours, then treated with water (350 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum; purification by silica gel chromatography (gradient: 0% to 6% methanol in dichloromethane) afforded the product as an orange gum. Yield: 5.68 g, 22.6 mmol, 80%. ¹ H NMR (400MHz, CDCl ₃ )8.05(s,1H), 4.09(s,3H),3.19-3.11(m,2H),2.96-2.88(m,2H),2.74-2.65(m,4H),2.61(q,J＝7.2Hz, 2H), 1.12 (t, J = 7.2Hz, 3H).

Step 2. Synthesis of 7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-3-amine (P5).

A suspension of C16 (5.28 g, 21.0 mmol) and wet palladium on carbon (10%, 1.35 g) in methanol (200 mL) was stirred at 27°C under hydrogen (30 psi) for 4 hours, then allowed to stand at 27°C under hydrogen for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum; the residue was combined with the product of a similar reaction performed on C16 (1.39 g, 5.53 mmol) and dissolved in dichloromethane (150 mL). The solvent was removed under reduced pressure to give the product as an orange oil (5.92 g, containing some dichloromethane by ¹ H NMR analysis). Yield corrected for dichloromethane: 5.74 g, 25.9 mmol, 98%. LCMS m/z 221.9 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ6.67(s,1H),3.95(s,3H),3.59(br s,2H),3.03-2.95(m,2H),2.78-2.71(m,2H), 2.67-2.58(m,4H),2.58(q,J＝7.2Hz,2H),1.10(t,J＝7.2Hz,3H).

Example 1

6-Cyclohexyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide (1)

Step 1. Synthesis of 1-(5-bromopyridin-2-yl)cyclohexanol (C17).

To a slurry of 2,5-dibromopyridine (10.0 g, 42.2 mmol) in toluene (150 mL) at -78°C was added n-butyllithium (2.5 M in hexane, 18.6 mL, 46.4 mmol). A solution of cyclohexanone (6.21 g, 63.3 mmol) in toluene (10 mL) was then added dropwise, and the reaction mixture was stirred at -78°C for 2 hours before being quenched by the addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (150 mL), and the organic layer was washed sequentially with water (50 mL) and saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Silica gel chromatography (gradient: 0%-20% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 8.0 g, 31 mmol, 73%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.58 (dd, J=2.3, 0.7 Hz, 1H), 7.81 (dd, J=8.5, 2.3 Hz, 1H), 7.34 (dd, J=8.5, 0.7 Hz, 1H), 4.23 (br s, 1H), 1.92-1.27 (m, 10H, assumed; integrated into ∼1.5× 10H).

Step 2. Synthesis of 5-bromo-2-(cyclohex-1-en-1-yl)pyridine (C18).

Concentrated sulfuric acid (2 mL) was added dropwise to C17 (2.0 g, 7.8 mmol) at 15°C. After the addition was complete, the reaction mixture was stirred at 20°C for 1 hour, then poured into ice water (50 mL) and basified to pH <8 by adding 20% aqueous sodium hydroxide solution. The resulting mixture was extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to afford the product as a yellow oil. Yield: 1.7 g, 7.1 mmol, 91%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.58 (br d, J＝2.3Hz, 1H), 7.73 (dd, J＝8.5, 2.4Hz, 1H), 7.27 (br d,J＝8.5Hz,1H),6.73-6.68(m,1H),2.51-2.44(m,2H),2.29-2.22(m,2H),1.83-1.75(m,2H),1.72-1.64(m,2H).

Step 3. Synthesis of 2-(cyclohex-1-en-1-yl)-5-[(4-methoxybenzyl)sulfanyl]pyridine (C19).

A mixture of C18 (1.7 g, 7.1 mmol), (4-methoxyphenyl)methanethiol (1.43 g, 9.27 mmol), N,N-diisopropylethylamine (2.77 g, 21.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (131 mg, 0.143 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 207 mg, 0.358 mmol) in 1,4-dioxane (20 mL) was purged with nitrogen at 22°C for 2 minutes and then stirred at 110°C for 16 hours. The reaction mixture was combined with a similar reaction mixture using C18 (400 mg, 1.7 mmol), concentrated under vacuum, and purified by silica gel chromatography (gradient: 0% to 20% ethyl acetate in petroleum ether) to give the product as a yellow solid. Yield: 2.3 g, 7.4 mmol, 84%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.47(d,J＝2.1Hz,1H),7.49(dd,J＝8.3,2.3Hz,1H), 7.24(d,J＝8.4Hz,1H),7.16(br d,J＝8.5Hz,2H),6.81(br d,J＝8.5Hz,2H),6.73-6.68 (m,1H),4.03(s,2H),3.79(s,3H),2.51-2.43(m,2H),2.30-2.23(m,2H),1.83-1.75(m,2H),1.72-1.63(m,2H).

Step 4. Synthesis of 2-cyclohexyl-5-[(4-methoxybenzyl)sulfanyl]pyridine (C20).

Palladium hydroxide on carbon (10%, 1 g) was added to a solution of C19 (1.8 g, 5.78 mmol) in methanol (100 mL). The mixture was degassed under vacuum and then purged with hydrogen; this vacuum-purge cycle was performed three times. The reaction mixture was then stirred under hydrogen (50 psi) at 40°C for 18 hours, after which it was filtered and concentrated under vacuum to yield the product as an off-white solid. Analysis by ¹ H NMR indicated that the material contained some impurities. Yield: 1.1 g, <3.5 mmol, <61%. LCMS m/z 313.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ), characteristic product peaks: δ 8.45 (br d, J = 2.3 Hz, 1H), 7.49 (dd, J = 8.2, 2.4 Hz, 1H), 7.15 (br d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.2 Hz, 1H), 6.81 (br d, J = 8.7 Hz, 2H), 4.02 (s, 2H), 3.79 (s, 3H), 2.70-2.61 (m, 1H).

Step 5. Synthesis of 6-cyclohexylpyridine-3-sulfonyl chloride (C21).

N-Chlorosuccinimide (1.87 g, 14.0 mmol) was added to a suspension of C20 (1.1 g, 3.5 mmol) in acetic acid (20 mL) and water (5 mL), and the reaction mixture was stirred at 25 ° C for 1 hour. It was then diluted with ethyl acetate (50 mL), washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and saturated aqueous sodium chloride solution (50 mL), and concentrated under vacuum. Silica gel chromatography (gradient: 0%-5% ethyl acetate in petroleum ether) gave the product as an off-white oil. Yield: 500 mg, 1.9 mmol, 54%. ¹ H NMR (400MHz, CDCl ₃ ) δ9.14(d,J＝2.4Hz,1H),8.20(dd,J＝8.4,2.5Hz,1H),7.41(d,J＝8.4Hz,1H),2.86(tt, J=11.8, 3.4Hz, 1H), 2.02-1.86 (m, 4H), 1.84-1.75 (m, 1H), 1.64-1.51 (m, 2H), 1.51-1.37 (m, 2H), 1.37-1.24 (m, 1H).

Step 6. Synthesis of 6-cyclohexyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide (1).

A solution of P3 (30 mg, 0.14 mmol) and C21 (45.1 mg, 0.174 mmol) in pyridine (2 mL) was stirred at 20°C for 1 hour and then allowed to stand at 20°C for 18 hours. The reaction mixture was concentrated to dryness under vacuum; the residue was dissolved in dichloromethane (20 mL), washed sequentially with saturated aqueous sodium bicarbonate solution (10 mL) and saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (gradient: 0% to 10% methanol in dichloromethane) gave the product as a white solid. Yield: 19.8 mg, 46.0 μmol, 33%. LCMS m/z 431.0[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.68-8.63(m,1H),7.96(br d, J＝8Hz,1H),7.51(s,1H),7.39(d,J＝8.0Hz,1H),3.53(s,3H),3.04-2.94(m,2H), 2.91-2.82(m,2H),2.82-2.71(m,1H),2.68-2.55(m,4H),2.39(s,3H),1.94-1.81(m,4H), 1.81-1.72(m,1H),1.62-1.23(m,5H).

Example 2

6-(Cyclopentyloxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide (2)

Step 1. Synthesis of 2-(cyclopentyloxy)-5-[(4-methoxybenzyl)sulfanyl]pyridine (C22).

A mixture of 5-bromo-2-(cyclopentyloxy)pyridine (2.90 g, 12.0 mmol), (4-methoxyphenyl)methanethiol (2.5 mL, 18 mmol), N,N-diisopropylethylamine (3.10 g, 24.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (275 mg, 0.300 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (348 mg, 0.601 mmol) in 1,4-dioxane (20 mL) was purged with nitrogen for 1 minute. The reaction mixture was stirred at 105° C. for 16 hours, then concentrated under vacuum and purified by silica gel chromatography (gradient: 0% to 8% ethyl acetate in petroleum ether) to afford the product as a light yellow oil. Yield: 3.41 g, 10.8 mmol, 90%. ¹ H NMR (400 MHz, CDCl ₃ ) 8.08 (dd, J=2.4, 0.6 Hz, 1H), 7.43 (dd, J=8.5, 2.5 Hz, 1H), 7.08 (br d, J=8.8 Hz, 2H), 6.80 (br d, J=8.7 Hz, 2H), 6.56 (dd, J=8.6, 0.7 Hz, 1H), 5.38-5.31 (m, 1H), 3.90 (s, 2H), 3.79 (s, 3H), 2.01-1.89 (m, 2H), 1.84-1.73 (m, 4H), 1.68-1.57 (m, 2H, assumed; partially obscured by water peak).

Step 2. Synthesis of 6-(cyclopentyloxy)pyridine-3-sulfonyl chloride (C23).

N-Chlorosuccinimide (5.76 g, 43.1 mmol) was added to a 0°C suspension of C22 (3.40 g, 10.8 mmol) in acetic acid (30 mL) and water (8 mL). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at 26°C for 2 hours. It was then poured into water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The combined organic layers were combined with the crude product obtained from a similar reaction using C22 (1.51 g, 4.79 mmol). Purification by silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether) twice afforded the product as a colorless oil. Yield: 3.4 g, 13 mmol, 83%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.81 (dd, J＝2.6, 0.5Hz, 1H), 8.09 (dd, J＝8.9, 2.8Hz, 1H), 6.83 (dd, J＝9.0, 0.6Hz, 1H), 5.58-5.52(m,1H),2.07-1.95(m,2H),1.89-1.75(m,4H),1.73-1.61(m,2H).

Step 3. Synthesis of 6-(cyclopentyloxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide (2).

To a solution of P5 (25.4 mg, 0.115 mmol) in pyridine (2 mL) was added C23 (30.0 mg, 0.115 mmol), and the reaction mixture was stirred at 28 ° C for 16 hours. After the reaction mixture was concentrated under vacuum, the residue was distributed between ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was extracted with ethyl acetate (2 x 30 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative silica gel thin layer chromatography (eluent: 10: 1 dichloromethane / methanol) gave a yellow gummy product. Yield: 36.4 mg, 81.5 μmol, 71%. LCMS m / z 447.1 [M + H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 (d, J = 2.5 Hz, 1H), 7.93 (dd, J = 8.8, 2.6 Hz, 1H), 7.62 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.45-5.39 (m, 1H), 3.68 (s, 3H), 3.34-3.28 (m, 4H, assumed; obscured by solvent peak), 3.23-3.15 (m, 4H), 3.12-3.06 (m, 2H), 2.02-1.91 (m, 2H), 1.83-1.71 (m, 4H), 1.70-1.61 (m, 2H), 1.35 (t, J = 7.3 Hz, 3H).

Example 3

4-[trans-3-(2-fluoroethoxy)cyclobutyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide (3)

Step 1. Synthesis of 1-bromo-4-[trans-3-(2-fluoroethoxy)cyclobutyl]benzene (C24).

To a 0°C solution of trans-3-(4-bromophenyl)cyclobutanol (300 mg, 1.32 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 79.3 mg, 1.98 mmol), and the reaction mixture was stirred at 15°C for 30 minutes. 2-Fluoroethyl 4-methylbenzenesulfonate (346 mg, 1.59 mmol) was added, and stirring was continued at 15°C for 1 hour. The reaction mixture was then heated at 50°C for 18 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with saturated aqueous sodium chloride (3 x 30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) afforded the product as a light yellow oil. Yield: 260 mg, 0.952 mmol, 72%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.43 (br d, J = 8.3Hz, 2H), 7.12 (br d, J = 8.5Hz, 2H), 4.59 (ddd, J = 47.4, 4.1, 4.1Hz, 2H), 4.26-4.18 (m, 1H), 3.64 (ddd, J = 29.5, 4.1, 4.1Hz, 2H), 3.6-3.54 (m, 1H), 2.57-2.47 (m, 2H), 2.43-2.34 (m, 2H).

Step 2. Synthesis of 1-[trans-3-(2-fluoroethoxy)cyclobutyl]-4-[(4-methoxybenzyl)sulfanyl]benzene (C25).

To a solution of C24 (260 mg, 0.952 mmol) in 1,4-dioxane (10 mL) was added (4-methoxyphenyl)methanethiol (161 mg, 1.04 mmol) and N,N-diisopropylethylamine (369 mg, 2.85 mmol). The mixture was degassed with nitrogen for 2 minutes, then tris(dibenzylideneacetone)dipalladium(0) (21.8 mg, 23.8 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27.5 mg, 47.5 μmol) were added. The reaction mixture was stirred at 100°C for 18 hours, then concentrated under vacuum; purification by silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 265 mg, 0.765 mmol, 80%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27 (br d, J = 7.9 Hz, 2H, assumed; partially obscured by solvent peak), 7.21 (br d, J = 8.4 Hz, 2H), 7.14 (br d, J = 8.2 Hz, 2H), 6.83 (br d, J = 8.4 Hz, 2H), 4.59 (ddd, J = 47.6, 4.5, 3.8 Hz, 2H), 4.26-4.19 (m, 1H), 4.06 (s, 2H), 3.80 (s, 3H), 3.64 (ddd, J = 29.5, 4.3, 3.9 Hz, 2H), 3.6-3.54 (m, 1H), 2.55-2.45 (m, 2H), 2.44-2.34 (m, 2H).

Step 3. Synthesis of 4-[trans-3-(2-fluoroethoxy)cyclobutyl]benzenesulfonyl chloride (C26).

N-Chlorosuccinimide (231 mg, 1.73 mmol) was added to a 10°C solution of C25 (150 mg, 0.433 mmol) in acetic acid (5 mL) and water (1 mL), and the reaction mixture was stirred at 10°C for 30 minutes. It was then diluted with ethyl acetate (30 mL), washed sequentially with saturated aqueous sodium bicarbonate solution (50 mL) and saturated aqueous sodium chloride solution (2 x 30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give the product as a pale yellow oil. Yield: 127 mg, assumed amount.

Step 4. Synthesis of 4-[trans-3-(2-fluoroethoxy)cyclobutyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide (3).

To a solution of P3 (40.0 mg, 0.193 mmol) in pyridine (3 mL) was added C26 (63.5 mg, 0.217 mmol), and the reaction mixture was stirred at 8 to 10 ° C for 18 hours. After removing the solvent under vacuum, the residue was dissolved in dichloromethane (30 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated aqueous sodium chloride solution (20 mL) in sequence, and concentrated under reduced pressure. Purification by preparative silica gel thin layer chromatography (eluent: 10:1 dichloromethane/methanol) gave a solid, which was dissolved in acetonitrile (3 mL), treated with water (~40 mL) and lyophilized to give a white solid product. Yield: 29.7 mg, 64.1 μmol, 33%. LCMS m/z 464.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ7.69(br d,J＝8.4Hz,2H),7.53(s,1H),7.29(br d,J＝8.2Hz,2H),4.58 (ddd,J＝47.7,4.1,4.1Hz,2H),4.24-4.17(m,1H),3.73(s,3H),3.70-3.62(m,1H),3.63 (ddd,J＝29.7,4.1,4.1Hz,2H),3.09-3.00(m,2H),2.93-2.84(m,2H),2.70-2.57(m,4H), 2.58-2.49(m,2H),2.45-2.34(m,2H),2.44(s,3H).

Example 4

N-(2-Methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (4)

Step 1. Synthesis of 4-[4-(benzylsulfanyl)phenyl]tetrahydro-2H-pyran (C27).

The reaction of 4-(4-bromophenyl)tetrahydro-2H-pyran with phenylmethylmercaptan was carried out using the method described in Example 1 for the synthesis of C19 from C18. The product was obtained as a yellow solid. Yield: 6.9 g, 24 mmol, 86%. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.33-7.22 (m, 7H), 7.13 (br d, J=8.2 Hz, 2H), 4.14-4.05 (m, 2H), 4.11 (s, 2H), 3.57-3.48 (m, 2H), 2.77-2.67 (m, 1H), 1.85-1.70 (m, 4H).

Step 2. Synthesis of 4-(tetrahydro-2H-pyran-4-yl)benzenesulfonyl chloride (C28).

N-Chlorosuccinimide (14.8 g, 111 mmol) was added to a slurry of C27 (10.0 g, 35.2 mmol) in acetic acid (60 mL) and water (20 mL) at 0°C. The reaction mixture was warmed to 25°C and stirred for 2 hours, then diluted with ethyl acetate (200 mL), washed sequentially with water (100 mL) and saturated aqueous sodium chloride solution (2 x 100 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (gradient: 0%-60% ethyl acetate in petroleum ether) gave the product as a solid; the material was washed with tert-butyl methyl ether (30 mL) and petroleum ether (20 mL). The product was isolated by filtration to give a white solid. Yield: 6.70 g, 25.7 mmol, 73%. ¹ H NMR (400 MHz, CDCl ₃ ) δ8.00 (br d, J＝8.5Hz, 2H), 7.48 (br d, J＝8.3Hz, 2H), 4.16-4.08 (m, 2H), 3.60-3.51(m,2H),2.96-2.86(m,1H),1.92-1.76(m,4H).

Step 3. Synthesis of N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-benzenesulfonamide (4).

A solution of P3 (1.50 g, 7.24 mmol) in pyridine (20 mL) was cooled in an ice bath, divided into five portions, and treated with C28 (1.98 g, 7.59 mmol). The reaction mixture was then stirred at 26°C for 16 hours before being concentrated under vacuum. The residue was dissolved in dichloromethane (200 mL), washed sequentially with saturated aqueous sodium bicarbonate solution (200 mL) and saturated aqueous sodium chloride solution (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting material was dissolved in dichloromethane (10 mL) and slowly added to petroleum ether (40 mL) over 10 minutes, stirring at 24-26°C. The mixture was then cooled to 5-10°C and stirred for 10 minutes; the resulting precipitate was collected by filtration to yield the product as a yellow solid. Yield: 2.75 g, 6.37 mmol, 88%. LCMS m/z 432.1 [M+H]+. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.61(br d,J＝8.3Hz,2H),7.41(br d,J＝8.3Hz,2H),7.32(s, 1H),3.98-3.90(m,2H),3.47(s,3H),3.47-3.38(m,2H),2.90-2.80(m,3H),2.76-2.69(m, 2H),2.47-2.39(m,4H),2.25(s,3H),1.72-1.61(m,4H).

Example 5

N-(2-Methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-methylbenzenesulfonamide (5)

4-Methylbenzenesulfonyl chloride (404 mg, 2.12 mmol) was added to a solution of P3 (418 mg, 2.02 mmol) in pyridine (10 mL). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The residue was azeotroped with heptane and then distributed between saturated aqueous sodium bicarbonate solution (25 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Silica gel chromatography (eluent: 0.15% ammonium hydroxide in a 4:1 mixture of ethyl acetate and methanol) gave a light yellow solid product. Yield: 500 mg, 1.38 mmol, 68%. LCMS m/z 362.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ7.63 (br d, J = 8.3 Hz, 2H), 7.50 (s, 1H), 7.24-7.19 (m, 2H), 3.72 (s, 3H), 3.00-2.95(m,2H),2.84-2.79(m,2H),2.58-2.50(m,4H),2.37(s,6H).

Example 6

N-(2-Methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydro-2H-pyran-2-yl)benzenesulfonamide (6)

Step 1. Synthesis of 1-(4-bromophenyl)-5-chloropentan-1-ol (C29).

Sodium borohydride (412 mg, 10.9 mmol) was added to a solution of 1-(4-bromophenyl)-5-chloropentan-1-one (2.00 g, 7.26 mmol) in tetrahydrofuran (50 mL) and water (5 mL), and the reaction mixture was stirred at room temperature overnight. Methanol (10 mL) was added, and the mixture was concentrated to dryness under reduced pressure; the residue was dissolved in ethyl acetate (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to give the product as a colorless gum. Yield: 1.95 g, 7.02 mmol, 97%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (br d, J = 8.4 Hz, 2H), 7.23 (br d, J = 8.3 Hz, 2H), 4.70-4.63 (m, 1H), 3.53 (t, J = 6.6 Hz, 2H), 1.88 (d, J = 3.4 Hz, 1H), 1.85-1.65 (m, 4H), 1.64-1.51 (m, 1H, assumed; partially obscured by water peak), 1.50-1.38 (m, 1H).

Step 2. Synthesis of 2-(4-bromophenyl)tetrahydro-2H-pyran (C30).

Potassium tert-butoxide (1.18 g, 10.5 mmol) was added to a 0°C solution of C29 (1.95 g, 7.02 mmol) in tetrahydrofuran (50 mL). The reaction mixture was warmed to ambient temperature (approximately 15°C) and stirred overnight, then partitioned between water (50 mL) and ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give a yellow liquid product that solidified upon standing overnight. Yield: 1.62 g, 6.72 mmol, 96%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.46 (br d, J = 8.4Hz, 2H), 7.23 (br d, J = 8.3Hz, 2H), 4.29 (dd, J = 11, 2Hz, 1H), 4.17-4.11 (m, 1H), 3.65-3.57 (m, 1H), 2.00-1.90(m,1H),1.85-1.77(m,1H),1.74-1.48(m,4H).

Step 3. Synthesis of 2-{4-[(4-methoxybenzyl)sulfanyl]phenyl}tetrahydro-2H-pyran (C31).

Using the method described in Example 3 for synthesizing C25 from C24, C30 (1.62 g, 6.72 mmol) was reacted with (4-methoxyphenyl)methanethiol. In this case, silica gel chromatography was performed using a 0% to 30% dichloromethane in petroleum ether gradient. The product was obtained as a white solid. Yield: 2.0 g, 6.4 mmol, 95%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26 (brAB quartet, J _AB =8.5 Hz, Δν _AB =12 Hz, 4H), 7.20 (br d, J=8.7 Hz, 2H), 6.81 (br d, J=8.7 Hz, 2H), 4.32-4.26 (m, 1H), 4.17-4.10 (m, 1H), 4.06 (s, 2H), 3.79 (s, 3H), 3.65-3.57 (m, 1H), 1.98-1.91 (m, 1H), 1.84-1.77 (m, 1H), 1.73-1.62 (m, 2H), 1.62-1.53 (m, 2H, assumed; partially obscured by water peak).

Step 4. Synthesis of 4-(tetrahydro-2H-pyran-2-yl)benzenesulfonyl chloride (C32).

The conversion of C31 to C32 was carried out using the method described in Example 1 for synthesizing C21 from C20. A white solid product was obtained, which contained some impurities as determined by ¹ H NMR. Yield: 1.55 g, <5.94 mmol, <93%. ¹ H NMR (400 MHz, CDCl ₃ ), product peak only: δ 8.01 (br d, J = 8.5 Hz, 2H), 7.60 (br d, J = 8.7 Hz, 2H), 4.44 (br dd, J = 11.2, 1.9 Hz, 1H), 4.21-4.15 (m, 1H), 3.68-3.59 (m, 1H), 2.02-1.96 (m, 1H), 1.93-1.86 (m, 1H), 1.76-1.60 (m, 3H), 1.57-1.45 (m, 1H).

Step 5. Synthesis of N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(tetrahydro-2H-pyran-2-yl)benzenesulfonamide (6).

The reaction of C32 with P3 was carried out according to the method for synthesizing 1 from C21 and P3 described in Example 1. Chromatographic purification in this case was performed using preparative silica gel thin-layer chromatography (eluent: 10:1 dichloromethane/methanol) to afford the product as a white solid. Yield: 54.1 mg, 0.125 mmol, 66%. LCMS m/z 431.9 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.69 (br d, J＝8.5Hz, 2H), 7.60 (s, 1H), 7.44 (br d, J＝8.3 Hz, 2H), 4.40 (br dd,J＝11.2,1.9Hz,1H),4.12-4.06(m,1H),3.66-3.58(m,1H),3.64(s, 3H),3.31-3.20(m,4H),3.20-3.12(m,2H),3.09-3.01(m,2H),2.86(s,3H),1.97-1.89(m, 1H),1.88-1.80(m,1H),1.79-1.55(m,3H),1.50-1.39(m,1H).

Example 7

N-(2-Methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide (7)

Step 1. Synthesis of (1R)-1-(4-bromophenyl)-5-chloropentan-1-ol (C33).

This experiment was performed in triplicate. (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborolidine [(S)-2-methyl-CBS-oxazaborolidine; 1 M solution in toluene, 16 mL, 16 mmol] was added to a 0°C solution of borane (1 M solution in tetrahydrofuran; 188 mL, 188 mmol) and tetrahydrofuran (500 mL). The reaction mixture was stirred at 0°C for 45 minutes, then cooled to -5°C, and a solution of 1-(4-bromophenyl)-5-chloropentan-1-one (43.0 g, 156 mmol) in tetrahydrofuran (600 mL) was added dropwise over 4 hours while maintaining the reaction temperature below -4°C. After the addition was complete, the reaction mixture was stirred at -5 to 0°C for 10 minutes, at which point the reaction was quenched by the addition of methanol (300 mL) at 0-5°C. The resulting mixture was stirred at -5 to 5°C for 30 minutes, then aqueous hydrochloric acid solution (1M, 450mL) was added at 0°C. The mixture was warmed to room temperature and stirred at 25°C for 18 hours; it was then diluted with water (700mL) and extracted with ethyl acetate (2x 1L). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under vacuum. The three batches were combined and subjected to silica gel chromatography (gradient: 5% to 17% ethyl acetate in petroleum ether) to obtain a colorless oily product. The absolute stereochemistry shown was confirmed by X-ray crystal structure analysis performed on 7 (see below). Yield: 130g, 468mmol, 100%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.48 (br d, J = 8.4Hz, 2H), 7.23 (br d, J = 8.4Hz, 2H), 4.66 (dd, J = 7.3, 5.7Hz, 1H), 3.53 (t, J = 6.6Hz, 2H), 1.86-1.36 (m, 6H).

Step 2. Synthesis of (2R)-2-(4-bromophenyl)tetrahydro-2H-pyran (C34).

This experiment was performed in duplicate. Potassium tert-butoxide (1 M solution in tetrahydrofuran; 330 mL, 330 mmol) was slowly added to a 0°C solution of C33 (65.0 g, 234 mmol) in tetrahydrofuran (700 mL); after the addition was complete, the ice bath was removed and the reaction was stirred at 25°C for 2 hours. The reaction mixture was then cooled to 0°C and quenched by the addition of aqueous hydrochloric acid (1 M, 700 mL). The mixture was extracted with ethyl acetate (2 x 1 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under vacuum. The two batches were combined and purified by silica gel chromatography (gradient: 5% to 9% ethyl acetate in petroleum ether) to give the product as a colorless oil. Yield: 109 g, 452 mmol, 97%. LCMS m/z 241.1, 243.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (br d, J = 8.5 Hz, 2H), 7.23 (br d, J = 8.3 Hz, 2H), 4.29 (br dd, J = 11, 2 Hz, 1H), 4.17-4.11 (m, 1H), 3.65-3.57 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.78 (m, 1H), 1.73-1.48 (m, 4H, assumed; partially obscured by water peak).

Step 3. Synthesis of (2R)-2-[4-(benzylsulfanyl)phenyl]tetrahydro-2H-pyran (C35).

This experiment was performed in duplicate. To a stirred solution of C34 (53.0 g, 220 mmol) in 1,4-dioxane (700 mL) was added phenylmethanethiol (35.5 g, 286 mmol), N,N-diisopropylethylamine (85.2 g, 660 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.09 g, 8.80 mmol), and tris(dibenzylideneacetone)dipalladium(0) (4.03 g, 4.40 mmol). The vessel containing the reaction mixture was evacuated and filled with nitrogen; this cycle was repeated twice, and the reaction mixture was then stirred at 115°C for 16 hours. After cooling to room temperature, the two crude mixtures were combined and concentrated under vacuum. After silica gel chromatography (gradient: 2% to 5% ethyl acetate in petroleum ether), two recrystallizations from a mixture of dichloromethane and petroleum ether (1:12, 3.9 L) gave the product as a yellow solid. Yield: 100 g, 352 mmol, 80%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.21 (m, 9H), 4.29 (br dd, J=11, 2 Hz, 1H), 4.17-4.11 (m, 1H), 4.10 (s, 2H), 3.65-3.57 (m, 1H), 1.99-1.90 (m, 1H), 1.85-1.77 (m, 1H), 1.73-1.51 (m, 4H, assumed; partially obscured by water peak).

Step 4. Synthesis of 4-[(2R)-tetrahydro-2H-pyran-2-yl)benzenesulfonyl chloride (C36).

This experiment was performed in duplicate. N-Chlorosuccinimide (84.5 g, 633 mmol) was slowly added to a stirred suspension of C35 (45.0 g, 158 mmol) in acetic acid (500 mL) and water (140 mL) at 0°C. The reaction mixture was then warmed to room temperature, stirred at 22°C for 1 hour, and poured into tert-butyl methyl ether (1.5 L); the resulting mixture was washed with water (3 x 1.5 L), and the pH was adjusted to 7 by adding saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under vacuum. The two batches were combined and purified by silica gel chromatography (gradient: 3% to 5% ethyl acetate in petroleum ether), followed by crystallization from tert-butyl methyl ether and petroleum ether (1:10, 1.1 L) at -65°C under nitrogen to afford the product as a white solid. Yield: 63.0 g, 242 mmol, 77%. LCMS m/z 332.1 [M+H] ⁺ of N-benzyl-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide after dissolution in dichloromethane and treatment with pyridine and benzylamine.

Step 5. Synthesis of N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide (7).

A solution of C36 (2.38 g, 9.13 mmol) and P3 (1.80 g, 8.68 mmol) in pyridine (20 mL) was stirred at 28 ° C for 4 hours. The reaction mixture was then concentrated under vacuum, and the residue was distributed between saturated aqueous sodium bicarbonate solution (40 mL) and ethyl acetate (40 mL). The aqueous layer was extracted with ethyl acetate (2 x 30 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (gradient: 0% to 10% methanol in dichloromethane) gave a white solid product showing positive (+) rotation. Yield: 2.66 g, 6.16 mmol, 71%. LCMS m / z 432.1 [M + H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.72(br d,J＝8.5Hz,2H),7.51 (s,1H),7.41(br d,J＝8.2Hz,2H),4.34(br dd,J＝11,2Hz,1H),4.17-4.10(m,1H),3.73 (s,3H),3.63-3.55(m,1H),3.00-2.94(m,2H),2.84-2.78(m,2H),2.58-2.49(m,4H),2.37 (s, 3H), 1.98-1.91 (m, 1H), 1.85-1.78 (m, 1H), 1.74-1.56 (m, 3H, assumed; partially obscured by water peak), 1.53-1.41 (m, 1H).

A sample of 7 was crystallized from ethyl acetate and methanol; single crystal X-ray structure analysis (see below) confirmed the absolute stereochemistry of 7.

Single crystal X-ray structure determination of 7

Data collection was performed on a Bruker APEX diffractometer at room temperature. Data collection included omega and phi scans.

The structure was solved by a direct method using the SHELX software suite in space group P2 _1. The structure was subsequently refined using full-matrix least-squares fits. All non-hydrogen atoms were found and refined using anisotropic displacement parameters.

The hydrogen atoms located on the nitrogen are found from the Fourier difference map and refined freely. The remaining hydrogen atoms are placed in the calculated positions and centered on their carrier atoms. The final refinement includes isotropic displacement parameters for all hydrogen atoms.

The absolute structure was analyzed using PLATON (Spek, 2010) using the likelihood method (Hooft, 2008). The results indicate that the absolute structure was correctly assigned. This method calculated a probability of 100.0 that the structure was correct. The Hooft parameter was reported as 0.12, with an estimated deviation (ESD) of 0.06. The Flack parameter refinement yielded a similar value of 0.08 (0.06).

The final R index was 5.5%. The final Fourier difference display showed no disappearance or dislocation of electron density.

The relevant crystal, data collection, and refinement information are summarized in Table 1. Atomic coordinates, bond lengths, bond angles, and displacement parameters are listed in Tables 2–5.

Software and References

SHELXTL, Version 5.1, Bruker AXS, 1997.

PLATON, A. L. Spek, J. Appl. Cryst. 2003, 36, 7-13.

MERCURY, C.F. Macrae, P.R. Edington, P. McCabe, E. Pidcock, G.P. Shields, R. Taylor, M. Towler, and J. van de Streek, J. Appl. Cryst. 2006, 39, 453-457.

OLEX2, O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, and H. Puschmann, J. Appl. Cryst. 2009, 42, 339-341.

R. W. W. Hooft, L. H. Straver, and A. L. Spek, J. Appl. Cryst. 2008, 41, 96-103.

H. D. Flack, Acta Cryst. 1983, A39, 867-881.

Table 1. Crystallographic data and structure refinement of 7.

Table 2. Atomic coordinates (x 10 ⁴ ) of 7 and the equivalent isotropic displacement parameter U(eq) defined as one-third of the trace of the orthogonalized U ^ij tensor.

Table 3. Bond lengths and angles [°] of 7.

Symmetry transformations used to generate equivalent atoms.

Table 4. Anisotropic shift parameters for 7 The anisotropic shift factor exponent takes the following form: -2π ² [h ² a* ² U ¹¹ +...+2h ka*b*U ¹² ].

Table 5. Hydrogen coordinates (x 10 ⁴ ) and isotropic displacement parameters of 7

Alternative Synthesis of Example 7

N-(2-Methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide (7)

Compound C36 (3.98 g, 15.3 mmol) was added to a suspension of P4 (93%, 4.01 g, 15.2 mmol) and pyridine (1.4 mL, 17 mmol) in dichloromethane (40 mL), and the reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution (20 mL) was added, and the mixture was stirred at room temperature for 5 minutes. The organic layer was washed with water (20 mL), aqueous hydrochloric acid solution (1 M, 20 mL, 20 mmol), saturated aqueous sodium bicarbonate solution (20 mL) and saturated aqueous sodium chloride solution (20 mL), then dried over sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in ethyl acetate (130 mL) by rotating the flask with a warm bath at 80 to 85 ° C on a rotary evaporator. The water bath was cooled to 40 ° C, and the solution was concentrated to a total volume of approximately 65 mL, during which time it became turbid. The solid was granulated overnight, and the flask was then cooled in an ice bath for 30 minutes. The precipitate was collected by filtration, and the filter cake was washed with the mother liquor; then washed with cooled heptane (20 mL) to give a white solid product. Yield: 5.18 g, 12.0 mmol, 79%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.7-9.45 (v br s, 1H), 7.63 (br d, J=8.4 Hz, 2H), 7.46 (br d, J=8.3 Hz, 2H), 7.32 (s, 1H), 4.38 (br d, J=11 Hz, 1H), 4.06-3.99 (m, 1H), 3.57-3.47 (m, 1H), 3.47 (s, 3H), 2.90-2.85 (m, 2H), 2.76-2.70 (m, 2H), 2.49-2.42 (m, 4H), 2.27(s,3H),1.89-1.77(m,2H),1.70-1.58(m,1H),1.58-1.50(m,2H),1.40-1.27(m,1H).

Example 8

N-(2-Methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2S)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide (8)

Step 1. Synthesis of (1S)-1-(4-bromophenyl)-5-chloropentan-1-ol (C37).

(3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborolidine [(R)-2-methyl-CBS-oxazaborolidine; 1 M solution in toluene, 3.63 mL, 3.63 mmol], borane (1 M solution in tetrahydrofuran; 38.1 mL, 38.1 mmol), and tetrahydrofuran (100 mL) were cooled to 0°C. A solution of 1-(4-bromophenyl)-5-chloropentan-1-one (10.0 g, 36.3 mmol) in tetrahydrofuran (50 mL) was added dropwise while maintaining the internal reaction temperature below 5°C. After 30 minutes, the cooling bath was removed and the reaction mixture was stirred at 26°C for 3 hours. The reaction mixture was then cooled to 0°C and treated with methanol (50 mL). The resulting mixture was stirred at 0°C for 30 minutes, at which point aqueous hydrochloric acid (1 M, 80 mL) was added and stirring continued at 26°C for 1 hour. After standing for 18 hours, the mixture was partitioned between ethyl acetate (150 mL) and saturated aqueous ammonium chloride (100 mL). The organic layer was washed with saturated aqueous sodium chloride (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was dissolved in dichloromethane (200 mL) and filtered; the filtrate was concentrated under reduced pressure to afford the product as a light yellow oil. Yield: 10 g, 36 mmol, 99%. ¹ H NMR (400 MHz, CDCl ₃ ), characteristic peaks: δ 7.49 (br d, J = 8.4 Hz, 2H), 7.23 (br d, J = 8.3 Hz, 2H), 4.67 (dd, J = 7.0, 5.9 Hz, 1H), 3.53 (t, J = 6.6 Hz, 2H).

Step 2. Synthesis of (2S)-2-(4-bromophenyl)tetrahydro-2H-pyran (C38).

Potassium tert-butoxide (1 M solution in tetrahydrofuran; 54 mL, 54 mmol) was slowly added to a 0°C solution of C37 (10 g, 36 mmol) in tetrahydrofuran (100 mL). After the addition was complete, the ice bath was removed and the reaction was stirred at 25°C for 16 hours. The reaction mixture was then cooled to 0°C, treated with aqueous hydrochloric acid (1 M, 80 mL) while maintaining the internal reaction temperature below 10°C, and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated aqueous sodium chloride (80 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Silica gel chromatography (gradient: 0% to 20% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 7.5 g, 31 mmol, 86%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (br d, J = 8.4 Hz, 2H), 7.23 (br d, J = 8.3 Hz, 2H), 4.29 (br d, J = 11 Hz, 1H), 4.17-4.10 (m, 1H), 3.65-3.57 (m, 1H), 1.99-1.91 (m, 1H), 1.82 (br d, J = 13 Hz, 1H), 1.73-1.48 (m, 4H, assumed; partially obscured by water peak).

Step 3. Synthesis of (2S)-2-[4-(benzylsulfanyl)phenyl]tetrahydro-2H-pyran (C39).

A mixture of C38 (7.5 g, 31 mmol), phenylmethanethiol (5.02 g, 40.4 mmol), N,N-diisopropylethylamine (12.1 g, 93.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (570 mg, 0.622 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (720 mg, 0.1.24 mmol) in 1,4-dioxane (100 mL) was evacuated and filled with nitrogen; this cycle was repeated twice, and the reaction mixture was then stirred at 110° C. for 16 hours. After removing the solvent under vacuum, the residue was purified by silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether) followed by supercritical fluid chromatography [column: Chiral Technologies Chiralpak AD, 10 μm; mobile phase: 35% (ethanol containing 0.1% ammonium hydroxide) in carbon dioxide] to give the product as an off-white solid. Yield: 7.5 g, 26 mmol, 84%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.19 (m, 9H), 4.31-4.25 (m, 1H), 4.16-4.10 (m, 1H), 4.09 (s, 2H), 3.64-3.56 (m, 1H), 1.97-1.89 (m, 1H), 1.83-1.76 (m, 1H), 1.72-1.49 (m, 4H, assumed; partially obscured by water peak).

Step 4. Synthesis of 4-[(2S)-tetrahydro-2H-pyran-2-yl)benzenesulfonyl chloride (C40).

N-Chlorosuccinimide (14.1 g, 106 mmol) was added to a suspension of C39 (7.5 g, 26 mmol) in acetic acid (70 mL) and water (20 mL) at 0°C. The ice bath was removed and the reaction mixture was stirred at 25°C for 2 hours. It was then diluted with ethyl acetate (80 mL), washed sequentially with water (50 mL) and saturated aqueous sodium chloride solution (2 x 50 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. Silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether) was performed twice to obtain the product as a white solid. Yield: 5.52 g, 21.2 mmol, 82%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.03-7.99(m,2H),7.62-7.58(m,2H),4.44(br dd,J＝11.2, 2.1Hz,1H),4.21-4.15(m,1H),3.68-3.59(m,1H),2.03-1.95(m,1H),1.93-1.86(m,1H), 1.76-1.60(m,3H),1.57-1.45(m,1H).

Step 5. Synthesis of N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2S)-tetrahydro-2H-pyran-2-yl)benzenesulfonamide (8).

A solution of P3 (800 mg, 3.86 mmol) and C40 (1.00 g, 3.84 mmol) in pyridine (20 mL) was stirred at 25 ° C for 16 hours. C40 (200 mg, 0.77 mmol) was added again and stirring was continued for 5 hours. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL) and saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Silica gel chromatography (gradient: 0% to 7% methanol in dichloromethane) gave a white solid product. The material exhibited negative (-) optical rotation. Yield: 1.12 g, 2.60 mmol, 68%. LCMS m/z 432.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ7.72(br d,J＝8.4Hz,2H),7.51(s,1H),7.41(br d,J＝8.3Hz,2H),4.35 (br d,J＝11Hz,1H),4.17-4.10(m,1H),3.73(s,3H),3.63-3.55(m,1H),3.01-2.94(m, 2H),2.84-2.78(m,2H),2.58-2.50(m,4H),2.37(s,3H),1.98-1.91(m,1H),1.86-1.78(m, 1H), 1.76-1.55 (m, 3H, assumed; partially obscured by water peak), 1.53-1.41 (m, 1H).

Example 9

N-(2-Methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide (9)

Step 1. Synthesis of N-[2-methoxy-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide (C41).

To a solution of P2 (200 mg, 0.691 mmol) in pyridine (3 mL) was added C36 (198 mg, 0.759 mmol) in one portion, and the reaction mixture was stirred at 25°C for 16 hours. After removing the solvent in vacuo, the residue was chromatographed on silica gel (gradient: 0% to 30% ethyl acetate in petroleum ether, followed by 30% ethyl acetate in dichloromethane) to afford the product as a red solid. The ¹ H NMR spectrum determined that the material was a mixture of rotamers. Yield: 274 mg, 0.534 mmol, 77%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78-7.71 (m, 2H), [7.55 (s) and 7.54 (s), total 1H], 7.46-7.40 (m, 2H), [6.82 (br s) and 6.81 (br s), total 1H], 4.35 (br d, J=11 Hz, 1H), 4.17-4.10 (m, 1H), 3.78-3.73 (m, 2H), 3.77 (s, 3H), 3.72-3.66 (m, 2H), 3.64-3.55 (m, 1H), 3.07-3.00 (m, 2H), 2.91-2.83 (m, 2H), 1.99-1.92 (m, 1H), 1.86-1.79 (m, 1H), 1.72-1.6 (m, 3H, assumed; partially obscured by water peak), 1.53-1.42 (m, 1H).

Step 2. Synthesis of N-(2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide (9).

Potassium carbonate (258 mg, 1.87 mmol) was added to a solution of C41 (274 mg, 0.534 mmol) in methanol (25 mL), and the resulting suspension was stirred at 24°C for 3 hours. The reaction mixture was then concentrated under vacuum and purified by reverse-phase HPLC (column: Agela Durashell C18, 5 μm; mobile phase A: ammonia, pH 10; mobile phase B: acetonitrile; gradient: 9% to 29% B) to afford the product as a light yellow solid. Yield: 202 mg, 0.484 mmol, 91%. LCMS m/z 418.0 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ7.71(br d,J＝8.4Hz, 2H),7.40(br d,J＝8.3Hz,2H),7.31(s,1H),4.38(br dd,J＝11.2,2.2Hz,1H),4.11-4.05 (m,1H),3.66(s,3H),3.65-3.58(m,1H),2.95-2.90(m,2H),2.87-2.81(m,4H),2.76-2.71 (m,2H),1.97-1.89(m,1H),1.86-1.79(m,1H),1.75-1.55(m,3H),1.53-1.42(m,1H.

Example 10

4-(trans-1-fluoro-3-methoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide (10)

Step 1. Synthesis of cis-1-(4-bromophenyl)-3-methoxycyclobutanol (C42).

n-Butyllithium (2.5 M in hexane; 4.80 mL, 12.0 mmol) was added dropwise over 10 minutes to a -70°C solution of 1,4-dibromobenzene (2.52 g, 10.7 mmol) in tetrahydrofuran (30 mL), while maintaining the internal temperature below -65°C. After the addition was complete, the suspension was stirred at -70°C for 20 minutes, followed by the addition of 3-methoxycyclobutanone (890 mg, 8.89 mmol) dropwise over 2 minutes. The reaction mixture was warmed to 25°C over 3 hours; then treated with aqueous citric acid (2 M; ~30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated under vacuum, and the residue was purified by silica gel chromatography (gradient: 0% to 30% ethyl acetate in petroleum ether) to yield the product as a yellow oil. Two-dimensional NMR (NOE) supported the relative stereochemistry shown. Yield: 1.39 g, 5.41 mmol, 61%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.53-7.48(m,2H),7.38-7.34(m,2H),3.75-3.67(m,1H),3.30(s,3H),2.93-2.85(m,2H),2.42-2.34(m,3H).

Step 2. Synthesis of cis-3-methoxy-1-{4-[(4-methoxybenzyl)sulfanyl]phenyl}cyclobutanol (C43).

This experiment was performed in duplicate. (4-Methoxyphenyl)methanethiol (500 mg, 3.24 mmol) and N,N-diisopropylethylamine (750 mg, 5.80 mmol) were added to a solution of C42 (550 mg, 2.14 mmol) in 1,4-dioxane (20 mL), and the mixture was degassed with nitrogen for 2 minutes. Tris(dibenzylideneacetone)dipalladium(0) (50 mg, 55 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (60 mg, 0.10 mmol) were added, and the reaction mixture was stirred at 100°C for 20 hours. It was then concentrated under vacuum, and the residue was dissolved in dichloromethane (100 mL), washed sequentially with saturated aqueous sodium bicarbonate solution (50 mL) and saturated aqueous sodium chloride solution (50 mL), and concentrated under reduced pressure. Silica gel chromatography (gradient: 20% to 50% ethyl acetate in petroleum ether) and combining the two batches gave the product as a yellow solid. Yield: 1.26 g, 3.81 mmol, 89%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.35 (m, 2H), 7.33-7.29 (m, 2H), 7.26-7.21 (m, 2H), 6.86-6.81 (m, 2H), 4.09 (s, 2H), 3.80 (s, 3H), 3.72-3.64 (m, 1H), 3.29 (s, 3H), 2.94-2.86 (m, 2H), 2.41-2.33 (m, 2H), 2.33-2.27 (br s, 1H).

Step 3. Synthesis of 1-(trans-1-fluoro-3-methoxycyclobutyl)-4-[(4-methoxybenzyl)sulfanyl]benzene (C44).

To a solution of C43 (1 g, 3.03 mmol) in dichloromethane (40 mL) at -50 °C was added (diethylamino)sulfur trifluoride (732 mg, 4.54 mmol), and the reaction mixture was warmed to -30 °C over 30 min. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (30 mL) at -30 °C; the organic layer was then washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to afford the product as a yellow solid. Two-dimensional NMR (NOE) studies supported the relative stereochemistry shown. Yield: 1.00 g, 3.01 mmol, 99%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.31 (s, 4H), 7.26-7.21 (m, 2H), 6.86-6.81 (m, 2H), 4.33-4.25 (m, 1H), 4.10 (s, 2H), 3.80(s,3H),3.31(s,3H),2.98-2.84(m,2H),2.51-2.36(m,2H).

Step 4. Synthesis of 4-(trans-1-fluoro-3-methoxycyclobutyl)benzenesulfonyl chloride (C45).

The conversion of C44 to C45 was carried out according to the method for synthesizing C21 from C20 described in Example 1. The product was obtained as a yellow solid, which contained some impurities as determined by ¹ H NMR. Two-dimensional NMR (NOE) studies supported the relative stereochemistry shown. Yield: 620 mg, <2.22 mmol, <74%. ¹ H NMR (400 MHz, CDCl ₃ ), product peak only: δ 8.09-8.04 (m, 2H), 7.75-7.69 (m, 2H), 4.37-4.28 (m, 1H), 3.34 (s, 3H), 3.06-2.92 (m, 2H), 2.58-2.43 (m, 2H).

Step 5. Synthesis of 4-(trans-1-fluoro-3-methoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-benzenesulfonamide (10).

The reaction of C45 with P3 was carried out according to the method for synthesizing 2 from C23 and P5 as described in Example 2. The product was obtained as a yellow solid. Yield: 26.7 mg, 59.4 μmol, 49%. LCMS m/z 450.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 7.75 (br d, J = 8.0 Hz, 2H), 7.57 (s, 1H), 7.55 (br d, J = 8 Hz, 2H), 4.32-4.23 (m, 1H), 3.60 (s, 3H), 3.30 (s, 3H), 3.13-3.06 (m, 2H), 3.05-2.95 (m, 6H), 2.95-2.83 (m, 2H), 2.68 (s, 3H), 2.53-2.37 (m, 2H).

Example 11

6-(1-Fluorocyclopentyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide (11)

Step 1. Synthesis of 5-bromo-2-(1-fluorocyclopentyl)pyridine (C46).

(Diethylamino) sulfur trifluoride 899mg, 5.58mmol) is added dropwise to a mixture of 1-(5-bromopyridin-2-yl) cyclopentanol [which can be synthesized using the general method described by B Guo et al., J.Med.Chem.2013,56,2642-2650] (900mg, 3.72mmol) in dichloromethane (30mL) at 0°C. The reaction mixture is stirred at 0°C for 30 minutes, then quenched with water (10mL) and extracted with dichloromethane (2x 20mL). The combined organic layers are washed with saturated aqueous sodium chloride solution (10mL), dried over sodium sulfate, filtered and concentrated under vacuum. Silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether) gives a yellow oily product. Yield: 650mg, 2.66mmol, 72%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.62-8.59 (m, 1H), 7.82 (dd, J = 8.4, 2.4 Hz, 1H), 7.50 (ddd, J = 8.4, 1.5, 0.7Hz, 1H), 2.35-2.04 (m, 4H), 2.04-1.86 (m, 4H).

Step 2. Synthesis of 2-(1-fluorocyclopentyl)-5-[(4-methoxybenzyl)sulfanyl]pyridine (C47).

The conversion of C46 to C47 was carried out using the method for the synthesis of C22 described in Example 2. The product was obtained as a white solid. Yield: 640 mg, 2.02 mmol, 76%. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.47-8.44 (m, 1H), 7.58 (dd, half of the ABX pattern, J = 8.3, 2.3 Hz, 1H), 7.47 (ddd, half of the ABXY pattern, J = 8.3, 1.4, 0.8 Hz, 1H), 7.19 (brd, J = 8.8 Hz, 2H), 6.83 (br d, J = 8.8 Hz, 2H), 4.06 (s, 2H), 3.80 (s, 3H), 2.35-2.04 (m, 4H), 2.03-1.85 (m, 4H).

Step 3. Synthesis of 6-(1-fluorocyclopentyl)pyridine-3-sulfonyl chloride (C48).

The conversion of C47 to C48 was carried out according to the method for synthesizing C28 from C27 described in Example 4. In this case, the crude product was subjected to two silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether) to afford the product as a white solid. Yield: 300 mg, 1.14 mmol, 56%. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.18-9.15 (m, 1H), 8.31 (dd, J=8.5, 2.4 Hz, 1H), 7.90-7.85 (m, 1H), 2.42-2.10 (m, 4H), 2.09-1.92 (m, 4H).

Step 4. Synthesis of 6-(1-fluorocyclopentyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)pyridine-3-sulfonamide (11).

A mixture of P3 (20 mg, 96 μmol) and C48 (25.4 mg, 96.3 μmol) in pyridine (2 mL) was stirred at 25 ° C for 16 hours and then concentrated under vacuum. The residue was dissolved in dichloromethane (30 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated aqueous sodium chloride solution (20 mL), and concentrated under reduced pressure. Preparative silica gel thin layer chromatography (eluent: 10:1 dichloromethane/methanol) gave the product as a white solid. Yield: 21.2 mg, 48.8 μmol, 51%. LCMS m/z 435.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.77-8.74(m,1H),8.08(dd,J＝8.3,2.3Hz,1H),7.72-7.68(m,1H),7.62(s,1H),3.57 (s,3H),3.18-3.09(m,6H),3.07-3.00(m,2H),2.76(s,3H),2.34-2.02(m,4H),2.02-1.87(m,4H).

Example 12

N-[2-(Difluoromethoxy)-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]-4-(propan-2-yl)benzenesulfonamide (12)

Step 1. Synthesis of 2-methoxy-3-nitro-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C49).

A mixture of C9 (830 mg, 3.72 mmol), potassium carbonate (1.54 g, 11.1 mmol), and 1-bromopropane (1.35 mL, 14.9 mmol) in acetonitrile (37 mL) was heated to 50°C for 1.75 hours, at which point more 1-bromopropane (1.35 mL, 14.9 mmol) was added. After an additional 3 hours at 50°C, the reaction mixture was cooled and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum to give the product as an oil that solidified upon standing at room temperature. Yield: 930 mg, 3.50 mmol, 94%. LCMS m/z 266.3 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.04(s,1H), 4.09(s,3H),3.19-3.12(m,2H),2.95-2.88(m,2H),2.77-2.65(m,4H),2.54-2.46(m,2H), 1.61-1.50(m,2H),0.93(t,J＝7.3Hz,3H).

Step 2. Synthesis of 2-methoxy-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-3-amine (C50).

Zinc powder (2.29 g, 35.0 mmol) was added to a mixture of C49 (930 mg, 3.50 mmol) and acetic acid (35 mL). The reaction mixture was heated to 30°C for 2.5 hours, then cooled to room temperature and filtered through a pad of celite. The filter pad was rinsed with dichloromethane, and the combined filtrate was concentrated under vacuum; the residue was carefully basified by adding saturated aqueous sodium bicarbonate and solid sodium bicarbonate, then extracted with dichloromethane (2 x 110 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the product as a viscous orange gum. Yield: 830 mg, 3.5 mmol, 100%. LCMS m/z 236.3 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ6.80 (s, 1H), 3.92 (s, 3H), 3.18-3.07 (m, 6H), 2.96-2.89 (m, 4H), 1.79-1.67 (m, 2H), 0.99 (t, J = 7.4Hz, 3H).

Step 3. Synthesis of 4-ethoxy-N-(2-methoxy-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide (C51).

4-Ethoxybenzenesulfonyl chloride (778 mg, 3.53 mmol) was added to a room temperature solution of C50 (830 mg, 3.5 mmol) in pyridine (15 mL). After 5 minutes, the reaction mixture was concentrated under vacuum and then azeotroped three times with heptane. The residue was purified twice by silica gel chromatography (eluent #1: 15% methanol in ethyl acetate; eluent #2: 8% methanol in ethyl acetate). The product was isolated as a light yellow solid. Yield: 441 mg, 1.05 mmol, 30%. LCMS m/z 420.4 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ7.66(br d,J＝8.8Hz,2H), 7.49(s,1H),6.86(br d,J＝9.0Hz,2H),4.04(q,J＝7.0Hz,2H),3.73(s,3H),2.99-2.92 (m,2H),2.83-2.76(m,2H),2.64-2.56(m,4H),2.47-2.40(m,2H),1.58-1.46(m,2H), 1.41(t,J＝6.9Hz,3H),0.90(t,J＝7.4Hz,3H).

Step 4. Synthesis of 3-amino-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (C52).

A mixture of C51 (165 mg, 0.393 mmol) and aqueous hydrogen bromide (48%, 4 mL) was heated to 100°C for 15 minutes and then cooled to room temperature. The reaction mixture was slowly basified by the addition of solid sodium bicarbonate and then extracted with a mixture of chloroform and methanol (2 x 40 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the product as a gummy substance (165 mg). Analysis by ^1H NMR indicated that the material contained a significant impurity bearing a 4-ethoxybenzenesulfonyl group; it was carried on to the next step without further purification. LCMS showed a major peak with m/z 222.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD), product peak only: δ 6.69 (s, 1H), 3.29-3.15 (m, 4H), 3.10-2.96 (m, 4H), 2.93-2.86 (m, 2H), 1.82-1.69 (m, 2H), 0.98 (t, J=7.4 Hz, 3H).

Step 5. Synthesis of N-(2-hydroxy-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-(propan-2-yl)benzenesulfonamide (53).

4-(Propan-2-yl)benzenesulfonyl chloride (130 μL, 0.72 mmol) was added to a room temperature solution of C52 (from the previous step; 165 mg, ≤0.39 mmol) in pyridine (1.4 mL). After 15 minutes, the reaction mixture was concentrated under vacuum and azeotroped with heptane. The residue was partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and dichloromethane (25 mL), and the aqueous layer was extracted with dichloromethane (25 mL); the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (eluent: 80:20:0.2 ethyl acetate/methanol/0.2% ammonium hydroxide) gave a solid product (100 mg), which was impure by LCMS and ¹ H NMR analysis. The material was carried on to the next step without further purification. LCMS showed a main peak with m/z 404.2 [M+H] ⁺ .

Step 6. Synthesis of N-[2-(difluoromethoxy)-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]-4-(propan-2-yl)benzenesulfonamide (12).

Sodium hydride (60% suspension in mineral oil, 13.4 mg, 0.335 mmol; washed twice with heptane and then dried under high vacuum before use) was added to a slurry of C53 (from the previous step; 75 mg, ≤0.19 mmol) in acetonitrile (1.9 mL). The reaction mixture was stirred at room temperature for 15 minutes, then difluoro(fluorosulfonyl)acetic acid (19.2 μL, 0.186 mmol) was added. After 10 minutes, the reaction was quenched by adding a few drops of water; the mixture was then partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was combined with the organic layer from a similar reaction using C53 (from the previous step; 25 mg, ≤62 μmol) and purified by silica gel chromatography (eluent: 20% methanol in ethyl acetate) to give a solid product. Yield: 27 mg, 60 μmol, 15% over 3 steps. LCMS m/z 454.2 [M+H] ⁺ . ¹ H NMR (400MHz, benzene-d ₆ ) δ7.73 (s, 1H), 7.65 (br d, J = 8.4Hz, 2H), 7.02 (t, J _HF = 72.9Hz, 1H), 6.76 (br d,J＝8.4Hz,2H),2.78-2.71(m,2H),2.47-2.33(m,3H),2.31-2.18(m,4H),2.17-2.10(m,2H),1.37-1.26(m,2H),0.85(d,J＝6.8Hz,6H), 0.80(t,J=7.3Hz,3H).

Example 13

N-(7-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-methylbenzenesulfonamide (13)

Step 1. Synthesis of 2-(3-bromo-6-methoxypyridin-2-yl)ethanol (C54).

To a 0°C solution of 2-(6-methoxypyridin-2-yl)ethanol (2.10 g, 13.7 mmol) in ethanol (20 mL) was added bromine (3.29 g, 20.6 mmol); the reaction mixture was stirred at 0°C for 1.5 hours and then at room temperature overnight. After basification with 1 M aqueous sodium hydroxide solution, the mixture was concentrated under vacuum to remove ethanol, and the aqueous residue was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product as a yellow liquid. Yield: 2.8 g, 12 mmol, 88%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.69 (d, J = 8.7 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 4.06 (t, J = 5.5 Hz, 2H), 3.91 (s, 3H), 3.08 (t, J = 5.5 Hz, 2H).

Step 2. Synthesis of 2-(3-bromo-6-methoxypyridin-2-yl)ethyl methanesulfonate (C55).

Methanesulfonyl chloride (3.33 g, 29.1 mmol) was added to a 0°C solution of C54 (2.8 g, 12 mmol) and triethylamine (3.66 g, 36.2 mmol) in dichloromethane (50 mL). After 1 hour, saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under vacuum to give the product as a yellow oil. Yield: 3.70 g, 11.9 mmol, 99%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.66 (d, J=8.7Hz, 1H), 6.55 (d, J=8.7Hz, 1H), 4.72 (t, J=6.8Hz, 2H), 3.91 (s, 3H), 3.31 (t, J=6.7Hz, 2H), 2.99 (s, 3H).

Step 3. Synthesis of N-[2-(3-bromo-6-methoxypyridin-2-yl)ethyl]prop-2-en-1-amine (C56).

To a solution of C55 (3.70 g, 11.9 mmol) in acetonitrile (40 mL) was added prop-2-en-1-amine (9.74 g, 171 mmol), and the reaction mixture was stirred at room temperature overnight. After removing the solvent in vacuo, the residue was dissolved in ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting material (3.3 g) was used directly in the next step without further purification. LCMS m/z 270.9 (bromine isotope pattern observed) [M+H] ⁺ .

Step 4. Synthesis of N-[2-(3-bromo-6-methoxypyridin-2-yl)ethyl]-2,2,2-trifluoro-N-(prop-2-en-1-yl)acetamide (C57).

Trifluoroacetic anhydride (3.07 g, 14.6 mmol) was added to a solution of triethylamine (3.69 g, 36.5 mmol) and C56 (from the previous step; 3.3 g, ≤11.9 mmol) in dichloromethane (50 mL) at 5°C to 10°C. The reaction mixture was stirred at this temperature for 10 minutes and then partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under vacuum; silica gel chromatography (gradient: 0% to 5% ethyl acetate in petroleum ether) gave the product as a light yellow oil. Based on the detection of the ¹ H NMR spectrum, the substance was considered to be a mixture of rotamers. Yield: 2.4 g, 6.5 mmol, 55% over two steps. ¹ H NMR (400 MHz, CDCl ₃ ) δ [7.65 (d, J=8.8 Hz) and 7.64 (d, J=8.8 Hz), total 1H], [6.54 (d, J=8.5 Hz) and 6.52 (d, J=8.5 Hz), total 1H], 5.88-5.67 (m, 1H), 5.30-5.17 (m, 2H), [4.12 (d, J=5.8 Hz) and 3.92 (d, J=5.8 Hz), total 2H], 3.89 (s, 3H), 3.86-3.78 (m, 2H), 3.16 (dd, J=7.5, 7.3 Hz, 2H).

Step 5. Synthesis of 2,2,2-trifluoro-1-(2-methoxy-5-methylene-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl)ethanone (C58).

A mixture of C57 (2.4 g, 6.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (2.29 g, 3.26 mmol) and sodium acetate (1.61 g, 19.6 mmol) in N,N-dimethylacetamide (20 mL) was degassed with nitrogen for several minutes. The resulting mixture was then stirred at 140 ° C for 24 hours and then concentrated under vacuum. The residue was purified by silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether) to give a yellow oily product. Based on the detection of the ¹ H NMR spectrum, it was speculated that the substance was a mixture of rotamers. Yield: 900 mg, 3.14 mmol, 48%. LCMS m / z 286.8 [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ [7.52 (d, J=8.5 Hz) and 7.52 (d, J=8.4 Hz), total 1H], 6.62 (d, J=8.4 Hz, 1H), [5.44-5.41 (m), 5.37 (br s), 5.33 (br s), and 5.29 (br s), total 2H], [4.45 (br s) and 4.42 (br s), total 2H], 3.95-3.88 (m, 5H), 3.24-3.17 (m, 2H).

Step 6. Synthesis of 2,2,2-trifluoro-1-(2-methoxy-5-methyl-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl)ethanone (C59).

Wet palladium on carbon (10%, 35 mg) was added to a solution of C58 (350 mg, 1.22 mmol) in methanol (20 mL); the mixture was evacuated several times and then purged with hydrogen. The reaction mixture was then stirred at room temperature under hydrogen (15 psi) for 1 hour, filtered, and the filtrate concentrated under vacuum to yield the product as a colorless oil. Based on ¹ H NMR spectroscopy, the material was presumed to be a mixture of rotamers. Yield: 330 mg, 1.14 mmol, 93%. LCMS m/z 288.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ [7.39 (d, J=8.3 Hz) and 7.38 (d, J=8.4 Hz), total 1H], [6.60 (d, J=8.5 Hz) and 6.58 (d, J=8.3 Hz), total 1H], 4.14-3.79 (m, 2H), [3.92 (s) and 3.91 (s), total 3H], 3.66-3.38 (m, 2H), 3.33-3.21 (m, 1H), 3.18-3.05 (m, 2H), [1.33 (d, J=7.3 Hz) and 1.30 (d, J=7.3 Hz), total 3H].

Step 7. Synthesis of 1-(3-bromo-2-methoxy-5-methyl-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl)-2,2,2-trifluoroethanone (C60).

To a mixture of C59 (330 mg, 1.14 mmol) in methanol (20 mL) and sodium hydrogen phosphate buffer (100 mL) was added bromine (274 mg, 1.71 mmol); the reaction mixture was stirred at room temperature for 2 hours, then concentrated under vacuum to remove the methanol. The aqueous residue was extracted with ethyl acetate (2 x 30 mL), and the combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the product as a yellow solid. Based on ¹ H NMR spectroscopy, the material was presumed to be a mixture of rotamers. Yield: 370 mg, 1.01 mmol, 89%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.60 (s, 1H), 4.19-3.79 (m, 2H), [3.99 (s) and 3.98 (s), total 3H], 3.67-3.35 (m, 2H), 3.29-3.18 (m, 1H), 3.17-3.03 (m, 2H), [1.34 (d, J=7.0 Hz) and 1.30 (d, J=7.3 Hz), total 3H].

Step 8. Synthesis of N-(2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-methylbenzenesulfonamide (C61).

A mixture of C60 (50 mg, 0.14 mmol), 4-methylbenzenesulfonamide (32.6 mg, 0.190 mmol), and cesium carbonate (222 mg, 0.681 mmol) in 2-methylbutan-2-ol (5 mL) was degassed with nitrogen for several minutes. Palladium (II) acetate (1.63 mg, 7.26 μmol) and 5-(di-tert-butylphosphanyl)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole (BippyPhos; 8.28 mg, 16.3 μmol) were added, and the reaction mixture was stirred at 120°C overnight. It was then filtered and concentrated under vacuum; purification by preparative thin-layer chromatography on silica gel (eluent: 10:1 dichloromethane/methanol) gave the product as a yellow solid. Yield: 32 mg, 89 μmol, 64%. ¹ H NMR (400 MHz, CD ₃ OD), characteristic peaks: δ 7.66-7.6 (m, 3H), 7.29 (brd, J=8 Hz, 2H), 3.69 (s, 3H), 2.38 (s, 3H), 1.42 (d, J=7.3 Hz, 3H).

Step 9. Synthesis of N-(7-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)-4-methylbenzenesulfonamide (13).

Sodium cyanoborohydride (55.6 mg, 0.885 mmol) was added to a solution of C61 (32 mg, 89 μmol) and acetaldehyde (60% in ethanol; 65 mg, 0.89 mmol) in ethanol (3 mL), and the reaction mixture was stirred at room temperature overnight. After removing the solvent under vacuum, the residue was partitioned between water and ethyl acetate; the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by preparative thin-layer chromatography on silica gel (eluent: 10:1 dichloromethane/methanol) followed by reverse-phase HPLC (column: Phenomenex Gemini C18, 8 μm; mobile phase A: ammonia water, pH 10; mobile phase B: acetonitrile; gradient: 26% to 46% B). The product was isolated as a gray solid. Yield: 9.9 mg, 25 μmol, 28%. LCMS m/z 390.0 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.59(br d,J＝8.3Hz,2H),7.53(s,1H),7.28(br d,J＝8.0Hz,2H),3.64(s,3H), 3.17-2.83(m,5H),2.68-2.57(m,2H),2.38(s,3H),2.37-2.19(m,2H),1.32(d,J＝7.3Hz,3H),1.13(t,J＝7.1Hz,3H).

Example 14

4-Ethoxy-N-[7-ethyl-2-(propan-2-yloxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]benzenesulfonamide (14)

Step 1. Synthesis of 2,2,2-trifluoro-1-(2-hydroxy-3-nitro-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl)ethanone (C62).

Acetic acid (33 wt%; 12 mL) and hydrogen bromide in water (3 mL) were added to C8 (1.20 g, 3.76 mmol), and the resulting solution was stirred at room temperature for 10 minutes. The reaction mixture was neutralized by adding saturated aqueous sodium bicarbonate and solid sodium bicarbonate, then extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (gradient: 0% to 5% methanol in petroleum ether) afforded the product as a yellow solid. Based on ¹ H NMR spectroscopy, the material was presumed to be a mixture of rotamers. Yield: 485 mg, 1.59 mmol, 42%. LCMS m/z 306.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 13.75-12.70 (v br s, 1H), [8.36 (s) and 8.34 (s), total 1H], 3.96-3.72 (m, 4H), 3.25-3.15 (m, 2H), 3.00-2.90 (m, 2H).

Step 2. Synthesis of 2,2,2-trifluoro-1-[3-nitro-2(propan-2-yl)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl]ethanone (C63).

A mixture of C62 (100 mg, 0.328 mmol), silver carbonate (109 mg, 0.395 mmol) and 2-iodopropane (279 mg, 1.64 mmol) in acetone (2.6 mL) was stirred at room temperature overnight, then diluted with ethyl acetate (80 mL) and filtered through a pad of celite. The filtrate was washed with saturated aqueous sodium bicarbonate (15 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum to give a gummy product. Based on the detection of the ¹ H NMR spectrum, it was speculated that the substance was a mixture of rotamers. Yield: 110 mg, 0.317 mmol, 97%. ¹ H NMR (400 MHz, CDCl ₃ ) δ [8.04 (s) and 8.02 (s), total 1H], 5.56-5.42 (m, 1H), 3.86-3.70 (m, 4H), 3.23-3.12 (m, 2H), 3.01-2.91 (m, 2H), [1.38 (d J=6.2 Hz) and 1.37 (d, J=6.2 Hz), total 6H].

Step 3. Synthesis of 3-nitro-2-(propan-2-yloxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C64).

A mixture of C63 (110 mg, 0.317 mmol) and potassium carbonate (101 mg, 0.731 mmol) in methanol (3 mL) and water (0.6 mL) was heated to 60°C for 15 minutes. The reaction mixture was then partitioned between saturated aqueous ammonium chloride (10 mL) and dichloromethane; the aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum to afford the product as a brown gum. Yield: 61 mg, 0.24 mmol, 76%. LCMS m/z 252.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.05 (s, 1H), 5.51 (septet, J = 6.2 Hz, 1H), 3.18-3.11 (m, 2H), 3.04-2.91 (m, 6H), 1.36 (d, J = 6.2 Hz, 6H).

Step 4. Synthesis of 7-ethyl-3-nitro-2-(propan-2-yloxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C65).

To a solution of C64 (61 mg, 0.24 mmol) in acetonitrile (2.4 mL) was added potassium carbonate (101 mg, 0.731 mmol) followed by iodoethane (97.9 μL, 1.22 mmol), and the reaction mixture was stirred at room temperature overnight. It was then partitioned between saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (50 mL), and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried, filtered, and concentrated under vacuum; silica gel chromatography (eluent: 25% methanol in ethyl acetate) afforded the product as a colorless gum. Yield: 50 mg, 0.18 mmol, 75%. LCMS m/z 280.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 5.51 (septet, J=6 Hz, 1H),3.20-3.11(m,2H),2.97-2.89(m,2H),2.76-2.68(m,4H),2.65(q,J＝7.1Hz,2H), 1.39(d,J＝6.2Hz,6H),1.14(t,J＝7.1Hz,3H).

Step 5. Synthesis of 7-ethyl-2-(propan-2-yloxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-3-amine (C66).

Palladium on carbon (10%, 50 mg) was added to a hydrogenation bomb; the catalyst was moistened by dropwise addition of methanol, and a solution of C65 (50 mg, 0.18 mmol) in methanol (10 mL) was slowly added to the catalyst. The reaction vessel was then sealed, evacuated, filled with nitrogen, evacuated again, and hydrogen was added. The hydrogenation reaction was carried out at room temperature under 50 psi of hydrogen for 2 hours. After the reaction mixture was filtered through a pad of celite, the pad was rinsed with methanol, and the combined filtrates were concentrated under vacuum to give a gummy product. Yield: 36 mg, 0.14 mmol, 78%. LCMS m/z 250.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 6.78 (s, 1H), 5.27 (septet, J=6 Hz, 1H), 2.99-2.90 (m, 2H), 2.81-2.73 (m, 2H), 2.72-2.63 (m, 4H), 2.62 (q, J=7.1 Hz, 2H), 1.31 (d, J=6.1 Hz, 6H), 1.14 (t, J=7.2 Hz, 3H).

Step 6. Synthesis of 4-ethoxy-N-[7-ethyl-2-(propan-2-yloxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]benzenesulfonamide (14).

A solution of C66 (11 mg, 44 μmol) in pyridine (0.5 mL) was treated with 4-ethoxybenzenesulfonyl chloride (10.2 mg, 46.2 μmol). After stirring for 1 hour, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (3 mL) and ethyl acetate (15 mL); the organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. Purified by reverse phase HPLC (column: Waters XBridge C18, 5 μm; mobile phase A: 0.03% ammonium hydroxide in water; mobile phase B: 0.03% ammonium hydroxide in acetonitrile; gradient: 5% to 100% B). Yield: 10.9 mg, 25.1 μmol, 57%. LCMS m/z 434.3 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.25-9.13 (br s, 1H), 7.62 (br d, J=8.9 Hz, 2H), 7.34 (s, 1H), 7.01 (br d, J=8.9 Hz, 2H), 5.00 (septet, J=6.1 Hz, 1H), 4.08 (q, J=7.0 Hz, 2H), 2.90-2.81 (br s, 2H), 2.77-2.69 (br s, 2H), 2.6-2.4 (m, 6H, assumed; obscured by solvent peak), 1.32 (t, J=7.0 Hz, 3H), 1.04 (d, J=6.1 Hz, 6H), 1.04-0.98 (br m, 3H).

Example 137

4-Ethoxy-N-(7-ethyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide trifluoroacetate (137)

Step 1. Synthesis of 1-(2-bromo-3-nitro-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl)-2,2,2-trifluoroethanone (C67).

A mixture of C62 (527 mg, 1.73 mmol), phosphorus pentoxide (613 mg, 4.32 mmol) and tetrabutylammonium bromide (741 mg, 2.30 mmol) in toluene (30 mL) was heated to 110 ° C. After 30 minutes, the reaction mixture was cooled to room temperature; the yellow supernatant was decanted (the dark brown material remained in the reaction flask) and concentrated under vacuum. The resulting material was purified by silica gel chromatography (eluent: 25% ethyl acetate in heptane) to obtain a colorless gummy product. By ¹ H NMR analysis, it was composed of a mixture of rotamers. Yield: 300 mg, 0.815 mmol, 47%. LCMS m / z 368.0 (bromine isotope pattern observed) [M + H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ [7.99 (s) and 7.96 (s), total 1H], 3.89-3.82 (m, 2H), 3.82-3.76 (m, 2H), 3.36-3.28 (m, 2H), 3.11-3.01 (m, 2H).

Step 2. Synthesis of 2-bromo-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C68).

A mixture of potassium carbonate (260 mg, 1.88 mmol) and C67 (300 mg, 0.815 mmol) in methanol (9 mL) and water (1.8 mL) was heated to 60°C for 15 minutes, and the reaction mixture was then cooled to room temperature. Saturated aqueous ammonium chloride (15 mL) was added, and the resulting mixture was extracted twice with ethyl acetate; the combined organic layers (100 mL) were dried over magnesium sulfate, filtered, and concentrated under vacuum to give a brown gummy product (230 mg). This material was used directly in the next step. LCMS m/z 272.0 (bromine isotope pattern observed) [M+H] ⁺ .

Step 3. Synthesis of 2-bromo-7-ethyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C69).

A solution of C68 (from the previous step; 230 mg, ≤0.815 mmol) in acetonitrile (8.4 mL) was treated with potassium carbonate (350 mg, 2.53 mmol) and then with iodoethane (204 μL, 2.55 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organic layers were dried, filtered, concentrated under vacuum, and subjected to silica gel chromatography (eluent: 25% methanol in ethyl acetate) to give the product as a viscous orange oil. Yield: 128 mg, 0.426 mmol, 52% for 2 steps. LCMS m/z 300.0 (bromine isotope pattern observed) [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.88 (s, 1H), 3.27-3.20 (m, 2H), 3.00-2.93 (m, 2H), 2.73-2.66 (m, 4H), 2.59 (q, J=7.2Hz, 2H), 1.09 (t, J=7.0Hz, 3H).

Step 4. Synthesis of 7-ethyl-2-methyl-3-nitro-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (C70).

A mixture of C69 (128 mg, 0.426 mmol), potassium carbonate (177 mg, 1.28 mmol), tetrakis(triphenylphosphine)palladium(0) (30.3 mg, 26.2 μmol) and trimethylcyclotriboroxane (64 mg, 0.51 mmol) in 1,4-dioxane (2 mL) and water (2 mL) was degassed by bubbling nitrogen for 5 minutes. The reaction mixture was heated at reflux for 5 hours, cooled to room temperature, and diluted with ethyl acetate and water. The resulting slurry was filtered through a celite pad. The filter pad was rinsed with additional water and ethyl acetate, and the organic layer of the combined filtrate was dried over magnesium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluent: 25% methanol in ethyl acetate) gave a yellow gummy product. Yield: 40 mg, 0.17 mmol, 40%. LCMS m/z 236.1[M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.00 (s, 1H), 3.25-3.19 (m, 2H), 3.00-2.94 (m, 2H), 2.79 (s, 3H), 2.73-2.66 (m, 4H), 2.60 (q, J＝7.1Hz, 2H), 1.10 (t, J = 7.1Hz, 3H).

Step 5. Synthesis of 7-ethyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-3-amine (C71).

Methanol was added dropwise to wet palladium carbon (10%, 40 mg), and a solution of C70 (40 mg, 0.17 mmol) in methanol (10 mL) was slowly added to the catalyst. The reaction vessel was then evacuated and filled with nitrogen. Hydrogenation was performed at room temperature under 50 psi for 2 hours, and the reaction mixture was then filtered through a celite pad. The filter pad was rinsed with methanol, and the combined filtrate was concentrated under vacuum to obtain a colloidal product. Yield: 35 mg, 0.17 mmol, 100%.

LCMS m/z 206.1[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ6.89 (s, 1H), 3.11-3.04 (m, 2H), 2.94-2.86 (m, 6H), 2.82 (q, J = 7.2Hz, 2H), 2.31 (s, 3H), 1.21 (t, J = 7.2Hz, 3H).

Step 6. Synthesis of 4-ethoxy-N-(7-ethyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide trifluoroacetate (137).

4-Ethoxybenzenesulfonyl chloride (12.6 mg, 57.1 μmol) was added to a solution of C71 (11 mg, 54 μmol) in pyridine (0.5 mL). After the reaction mixture was stirred at room temperature for 1 hour, it was partitioned between saturated aqueous sodium bicarbonate solution (3 mL) and ethyl acetate (15 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum; the product was purified by reverse phase HPLC (column: Waters XBridge C18, 5 μm; mobile phase A: 0.05% trifluoroacetic acid (v/v) in water; mobile phase B: 0.05% trifluoroacetic acid (v/v) in acetonitrile; gradient: 5% to 40% B). Yield: 15.8 mg, 40.6 μmol, 75%. LCMS m/z 390.2 [M+H] ⁺ . ¹ H NMR (600MHz, DMSO-d ₆ ), characteristic peaks: δ9.62(br s,1H),9.6-9.5(v br s,1H),7.58(br d,J＝8.8Hz,2H), 7.29(s,1H),7.05(br d, J＝8.9Hz, 2H), 4.10 (q, J＝7.0Hz, 2H), 3.67-3.56 (m, 2H), 2.07 (s, 3H), 1.34 (t, J＝7.0Hz, 3H), 1.24 (t, J＝7.2Hz, 3H).

Table 6. Preparation methods, structures and physicochemical properties of Examples 15-25

1. The desired 1-(5-bromopyridin-2-yl)cyclopentanol can be synthesized using the general method described by B. Guo et al., J. Med. Chem. 2013, 56, 2642-2650.

2. The raw material 5-bromo-2-(cyclobutyloxy)pyridine was synthesized by the sodium hydride-mediated reaction of 5-bromo-2-fluoropyridine with cyclobutanol.

3. cis-3-(4-bromophenyl)cyclobutanol was deprotonated with sodium hydride and alkylated with iodoethane to give the desired 1-bromo-4-(cis-3-ethoxycyclobutyl)benzene.

4. 2,5-Dibromopyridine is reacted with n-butyllithium and then with 3-methoxycyclobutanone to give the desired cis-1-(5-bromopyridin-2-yl)-3-methoxycyclobutanol.

5. In this case, the dehydration reaction is carried out by treatment with sodium hydride and methanesulfonyl chloride rather than acid treatment.

6. The fluorinated product, 2-(1-fluoro-3-methylcyclobutyl)-5-[(4-methoxybenzyl)sulfanyl]pyridine, was obtained as a mixture of isomers; supercritical fluid chromatography (column: Chiral Technologies Chiralcel OJ, 10 μm; mobile phase: 4:1 carbon dioxide/(0.1% ammonium hydroxide in ethanol)) afforded two isomers. Based on NOE studies, the second-eluting isomer was assigned as 2-(cis-1-fluoro-3-methylcyclobutyl)-5-[(4-methoxybenzyl)sulfanyl]pyridine, and this material was used in the synthesis of Example 25.

Table 7. Preparation methods, structures and mass spectrometry data of Examples 26-136 and 138-140

1. The desired 7-substituted 2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-3-amine was synthesized from C9 using the method described in Preparation P5.

2. The methyl ether group of the desired bromoaromatic intermediate is attached by reaction of commercially available alcohols with sodium hydride and iodomethane.

3. Preparation of 3-(4-bromophenyl)oxetane by nickel-catalyzed Suzuki-Miyaura coupling reaction of (4-bromophenyl)boronic acid with 3-iodooxetane.

4. Reaction of 2-hydroxybenzaldehyde with (propan-2-yl)magnesium bromide provides 2-(1-hydroxy-2-methylpropyl)phenol; treatment with Amberlyst 15 at elevated temperature yields 2,2-dimethyl-2,3-dihydro-1-benzofuran. Subsequent reaction with chlorosulfonic acid provides the desired 2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonyl chloride.

5. The desired (3R)-3-(4-bromophenoxy)tetrahydrofuran was obtained by Mitsunobu reaction of 4-bromophenol and (3S)-tetrahydrofuran-3-ol.

6. In this case, the alcohol resulting from the addition of the lithiated aromatic reagent to the ketone is deoxygenated by treatment with triethylsilane and trifluoroacetic acid.

7. In this case, two isomers of 4-(1-fluoro-4-methoxycyclohexyl)benzenesulfonyl chloride were obtained; these materials were separated by silica gel chromatography (gradient: 0% to 10% ethyl acetate in petroleum ether). The first eluting isomer (Isomer-1) was used in Examples 93 and 94, and the second eluting isomer (Isomer-2) was used in Example 39.

8. Treatment of 4-bromobenzaldehyde with but-3-en-1-ol and sulfuric acid at elevated temperature, followed by oxidation of the resulting alcohol with pyridinium chlorochromate, affords 2-(4-bromophenyl)tetrahydro-4H-pyran-4-one. Reaction with (diethylamino)sulfur trifluoride affords the desired 2-(4-bromophenyl)-4,4-difluorotetrahydro-2H-pyran.

9. Racemic Example 40 was separated into its component enantiomers by supercritical fluid chromatography [column: Chiral Technologies Chiralpak AD, 5 μm; mobile phase: 65:35 carbon dioxide/(0.1% ammonium hydroxide in ethanol)]. Example 41 was the first eluting enantiomer and Example 42 was the second eluting enantiomer.

10. The desired bromoaryl ketone starting material is generated by a Friedel-Crafts reaction between an appropriate bromoaromatic reactant and an acid chloride reactant.

11. In this case, (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborolidine [(R)-2-methyl-CBS-oxazaborolidine] was used for the ketone reduction.

12. In this case, the alkylation of C9 was carried out with 4-methylbenzenesulfonate reagent instead of bromo or chloro derivatives.

13. 2,5-Dibromopyridine is lithiated with n-butyllithium and treated with cyclopentylcarboxaldehyde; the resulting (5-bromopyridin-2-yl)(cyclopentyl)methanol is oxidized to the ketone with iodine and potassium carbonate in tert-butanol. Subsequent reaction with (diethylamino)sulfur trifluoride affords the desired 5-bromo-2-[cyclopentyl(difluoro)methyl]pyridine.

14. The desired 4-[1-(trifluoromethyl)cyclopropyl]benzenesulfonyl chloride was synthesized by treating [1-(trifluoromethyl)cyclopropyl]benzene with chlorosulfonic acid.

15. 1-Bromo-4-iodobenzene reacts with (propan-2-yl)magnesium chloride, followed by the introduction of tetrahydro-4H-pyran-4-one to give 4-(4-bromophenyl)tetrahydro-2H-pyran-4-ol; this substance is reacted with a mixture of titanium(IV) chloride and dimethylzinc to give the desired 4-(4-bromophenyl)-4-methyltetrahydro-2H-pyran.

16. Racemic Example 70 was separated into its component enantiomers by supercritical fluid chromatography [column: Chiral Technologies Chiralcel OJ, 5 μm; mobile phase: 7:3 carbon dioxide/(0.1% ammonium hydroxide in ethanol)]. Example 73 was the first eluting enantiomer and Example 74 was the second eluting enantiomer.

17. Cesium carbonate-mediated alkylation of 4-(benzylsulfanyl)phenol with tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate affords 4-[4-(benzylsulfanyl)phenoxy]tetrahydro-2H-pyran, which is reacted with N-chlorosuccinimide in acetic acid and water to afford the desired 4-(tetrahydro-2H-pyran-4-yloxy)benzenesulfonyl chloride.

18. Racemic Example 77 was separated into its component enantiomers by supercritical fluid chromatography [column: Chiral Technologies Chiralpak AD, 5 μm; mobile phase: 3:2 carbon dioxide/(0.1% ammonium hydroxide in methanol)]. Example 83 was the first eluting enantiomer and Example 84 was the second eluting enantiomer.

19. The intermediate trans-4-{4-[(4-methoxybenzyl)sulfanyl]phenyl}-2-methyltetrahydro-2H-pyran was separated into its enantiomers by supercritical fluid chromatography [column: Chiral Technologies Chiralpak AS, 10 μm; mobile phase: 3:1 carbon dioxide/(0.1% ammonium hydroxide in ethanol)]. The second-eluting enantiomer (ENT-2) was used in Example 85, and the first-eluting enantiomer (ENT-1) was used in Example 88.

20. The racemic product was separated into its component enantiomers by supercritical fluid chromatography [column: Chiral Technologies Chiralpak AD, 5 μm; mobile phase: 7:3 carbon dioxide/(0.1% ammonium hydroxide in methanol)]. Example 86 was the first eluting enantiomer and Example 87 was the second eluting enantiomer.

21. Treatment of 1-bromo-4-(1-methoxycyclopentyl)benzene with n-butyllithium, sulfur dioxide, and sulfuryl chloride affords the desired 4-(1-methoxycyclopentyl)benzenesulfonyl chloride.

22. The desired 1-(5-bromopyridin-2-yl)cyclopentanol can be synthesized using the general method described by B. Guo et al., J. Med. Chem. 2013, 56, 2642-2650.

23. In this case, the alcohol of the intermediate 1-(5-bromopyridin-2-yl)cyclopentanol was methylated with sodium hydride and iodomethane rather than converted to the fluoride.

24. The reaction of 2,5-dibromopyridine with potassium tert-butoxide gives 5-bromo-2-tert-butoxypyridine.

25. 2-(4-Bromophenyl)-4-fluorotetrahydro-2H-pyran can be prepared by reacting 4-bromobenzaldehyde with but-3-en-1-ol and boron trifluoride diethyl etherate, followed by treatment with trifluoromethanesulfonic anhydride and cesium fluoride.

26. The isomers of 4-fluoro-2-{4-[(4-methoxybenzyl)sulfanyl]phenyl}tetrahydro-2H-pyran were separated by supercritical fluid chromatography (column: Chiral Technologies Chiralpak AD, 10 μm; mobile phase A: carbon dioxide; mobile phase: 0.1% ammonium hydroxide in ethanol; gradient: 50% to 80% B). The first eluting material proved to be a racemate and was used to synthesize Examples 108 and 109. The second eluting material was one enantiomer of the other geometric isomer and was used to prepare Example 106. The third eluting material was the enantiomer of the second eluting material by ¹ H NMR analysis.

27. The component enantiomers of racemic 4-(4-fluorotetrahydro-2H-pyran-2-yl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl)benzenesulfonamide (from the first eluting material described in footnote 26) were separated by supercritical fluid chromatography [column: Chiral Technologies Chiralcel OJ, 5 μm; mobile phase: 4:1 carbon dioxide/(0.05% ammonium hydroxide in ethanol)]. Example 108 is the first eluting enantiomer (ENT-1) and Example 109 is the second eluting enantiomer (ENT-2).

28. Reaction of cyclobutanol with sodium hydride and 5-bromo-2-chloropyrimidine affords the desired 5-bromo-2-(cyclobutyloxy)pyrimidine.

29. The reaction of 5-bromo-2-chloropyrimidine with potassium tert-butoxide gives 5-bromo-2-tert-butoxypyrimidine.

30. cis-3-(4-Bromophenyl)cyclobutanol was deprotonated with sodium hydride and alkylated with iodoethane to give the desired 1-bromo-4-(cis-3-ethoxycyclobutyl)benzene.

31. The desired 5-bromo-2-(cyclopentyloxy)-3-methylpyridine was prepared by reaction of 5-bromo-3-methylpyridin-2(1H)-one with bromocyclopentane and silver carbonate.

32. The reaction of cyclobutanol with sodium hydride and 5-bromo-2-fluoro-3-methylpyridine gave the desired 5-bromo-2-(cyclobutyloxy)-3-methylpyridine.

33. The reaction of 5-chlorovaleryl chloride with N,O-dimethylhydroxylamine yields 5-chloro-N-methoxy-N-methylvaleramide. 2,5-Dibromopyridine is treated with n-butyllithium and added to 5-chloro-N-methoxy-N-methylvaleramide to yield 1-(5-bromopyridin-2-yl)-5-chloropentan-1-one.

34. In this case, cyclopentylcarboxaldehyde was used; rather than fluorination, the intermediate cyclopentyl{5-[(4-methoxybenzyl)sulfanyl]pyridin-2-yl}methanol was deoxygenated by treatment with carbon tetrabromide and triphenylphosphine, followed by zinc in acetic acid. The product was then further processed to yield the desired 6-(cyclopentylmethyl)pyridine-3-sulfonyl chloride.

35. The intermediate 1-(trans-3-ethoxy-1-fluorocyclobutyl)-4-[(4-methoxybenzyl)sulfanyl]benzene was analyzed using NOE studies to confirm the orientation of the substituents on the cyclobutane.

36. In this case, 3-oxocyclobutyl acetate is used; the acetate group remains until trans-3-fluoro-3-{4-[(4-methoxybenzyl)sulfanyl]phenyl}cyclobutyl acetate is prepared and then removed by treatment with lithium hydroxide. The resulting alcohol is alkylated with sodium hydride and 2-fluoroethyl 4-methylbenzenesulfonate to give 1-[trans-1-fluoro-3-(2-fluoroethoxy)cyclobutyl]-4-[(4-methoxybenzyl)sulfanyl]benzene.

37. The intermediate 2-(1-fluoro-3-methylcyclobutyl)-5-[(4-methoxybenzyl)sulfanyl]pyridine was subjected to supercritical fluid chromatography (column: Chiral Technologies Chiralcel OJ, 10 μm; mobile phase: 4:1 carbon dioxide/(0.1% ammonium hydroxide in ethanol)). The first-eluting isomer was analyzed by NOE studies and assigned as 2-(trans-1-fluoro-3-methylcyclobutyl)-5-[(4-methoxybenzyl)sulfanyl]pyridine; this material was used in the synthesis of Example 136.

38. C67 is reacted with methyl difluoro(fluorosulfonyl)acetate and copper(I) iodide in the presence of N,N,N',N',N",N"-hexamethylphosphoric triamide to give 2,2,2-trifluoro-1-[3-nitro-2-(trifluoromethyl)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl]ethanone; this is converted to the desired 7-methyl-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine using the chemistry described in Preparations P3 and P4.

39. The reaction of 7-methyl-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine with 4-methylbenzenesulfonyl chloride and triethylamine in dichloromethane gave primarily the disulfonylated product, 4-methyl-N-[(4-methylphenyl)sulfonyl]-N-[7-methyl-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-yl]benzenesulfonamide; this material was treated with sodium hydroxide and methanol at 50°C to afford Example 139.

40. Reaction of C67 with tributyl(vinyl)stannane, tetrakis(triphenylphosphine)palladium(0), and triphenylphosphine affords 1-(2-vinyl-3-nitro-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepin-7-yl)-2,2,2-trifluoroethanone. This material is converted to the desired 2-ethyl-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine using the chemistry described in Preparations P3 and P4.

Human D2 receptor and human D3 receptor binding assay:

Saturation binding studies were performed using Chinese hamster ovary cells expressing either the human dopamine D2 receptor (hD2R) (with [ ³ H]-spiperone) or the human dopamine D3 receptor (hD3R) (with [ ³ H]-7-OH-DPAT) to determine _Kd values. The _Kd for hD2 was 1.61 nM, and for hD3 was 1.37 nM. The optimal cell homogenate volume per 96-well plate was determined to be ⁴ mg/mL for hD2 and 7 mg/mL for hD3 with 2 nM [ ³ H]-spiperone or 1.5 nM [ 3 H]-7-OH-DPAT. These determined ligand and tissue concentrations were used in time course studies to determine the linearity and equilibrium conditions of binding. For both receptors, binding reached equilibrium within 20 minutes at 37°C with the indicated amount of tissue. hD2R assay buffer contains 50 mM Tris (pH 7.4 at 37°C), 100 mM NaCl, and ₁ mM MgCl2. hD3R assay buffer consists of 50 mM Tris (pH 7.4 at 37°C), 120 mM NaCl, ₅ mM MgCl2, 5 mM KCl, and 2 mM _CaCl2 . Competitive binding experiments were initiated by adding 200 μL of the respective cell homogenate to a 96-well plate containing 2.5 μL of test drug (10 concentrations using a 1/2 log dilution) and 50 μL of ^3H -radioligand for a final volume of 250 μL. Nonspecific binding was determined by radioligand binding in the presence of a saturating concentration of Haldol (10 μM). After incubation at 37°C for 20 minutes, the assay samples were rapidly filtered through Unifilter-96GF/B PEI-coated filter plates and rinsed with ice-cold 50 mM Tris buffer (pH 7.4°C). Membrane-bound [ ³ H]-spiperidone or [ ³ H]-7-OH-DPAT levels were determined by liquid scintillation counting of the filter plates in 50 μL Ecolume. IC ₅₀ values (the concentration at which 50% inhibition of specific binding occurs) were calculated by linear regression of concentration-response data in ActivityBase. Ki values were then calculated according to the Cheng-Prusoff equation:

Where [L] = concentration of free radioligand, Kd = dissociation constant of radioligand for D3 receptor or D2 receptor.

Table 8. Biological activities and IUPAC names of Examples 1-140

Unless otherwise stated, reported _K values are the geometric mean of 2–5 determinations.

b. Ki values are from a single assay.

c.N.D - not determined.

In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. These modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

Claims (29)

1. A compound of formula I or a pharmaceutically acceptable salt thereof: in ^R1 is selected from hydrogen, _C1 - _C6 alkyl, _C3 - _C7 cycloalkyl, and _C3 - _C7 cycloalkyl- _C1 - _C3 alkyl; wherein each of the _C1 - _C6 alkyl, _C3 - _C7 cycloalkyl, and _C3 -C7 cycloalkyl- _C1 - _{C3 alkyl} is optionally substituted with one to three independently selected halogens, hydroxyl groups, or _C1 - _C3 alkoxy groups; ^R2 is independently selected from halogens, hydroxyl groups, and _C1 - _C3 alkyl groups each time it appears; a can be 0, 1, 2, 3, or 4; ^R3 is selected from hydroxyl, _C1 - _C6 alkyl and _C1 - _C6 alkoxy, wherein the _C1 - _C6 alkyl and C1 _{- C6} alkoxy are each optionally substituted with 1 to 3 fluorine atoms; ^R4 is hydrogen; A is selected from phenyl and 5- to 6-heteroaryl groups; wherein the phenyl and 5- to 6-heteroaryl groups are optionally substituted by one R ⁶ ; ^R5 is selected from halogens, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 alkoxy- _C1 - _C6 alkyl, _C3 - _C7 cycloalkyl, C3- _C7 cycloalkyl- _C1 - _C6 alkyl, _{C3 - C7} cycloalkoxy, phenoxy, 4- to 10-membered heterocyclic alkyl, and 4- to 10-membered heterocyclic alkoxy; wherein the _C1 - _C6 alkyl, _C1 - _C6 alkoxy, and _C1 - _C6 alkoxy- _C1 - _C6 alkyl are optionally substituted by 1 to 4 substituents independently selected from halogens and hydroxyl groups; and wherein the _C3 - _C7 cycloalkyl, _C3 - _C7 cycloalkyl- _C1 - _C6 alkyl, _C3 - _C7 cycloalkoxy, phenoxy, 4- to 10-membered heterocyclic alkyl, and 4- to 10-membered heterocyclic alkoxy are optionally substituted by 1 to 4 ^R7s ; ^R6 is selected from halogens, cyano groups, and _C1 - _C6 alkyl groups; Alternatively, ^R5 and ^R6 , when they are attached to and bonded together with adjacent carbons, form fused 5- to 7-membered cycloalkyl rings or 5- to 7-membered heteroalkyl rings, each optionally substituted with 1 to 4 ^R8s . ^R7, in each occurrence, is independently selected from halogens, hydroxyl groups, _C1 - _C3 alkyl groups optionally substituted with 1 to 3 fluorine or _C1 - _C3 alkoxy groups, and _C1 - _C3 alkoxy groups optionally substituted with 1 to 3 fluorine groups; and ^R8 is a _C1 - _C3 alkyl group each time it appears. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... ^R1 is hydrogen or a _C1 - _C3 alkyl group optionally substituted with one _C1 - _C3 alkoxy or fluorine; ^R2 is a _C1 - _C3 alkyl group; a is 0 or 1; ^R3 is a _C1 - _C3 alkoxy group optionally substituted with 1 to 3 fluorine atoms. 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen, methyl, ethyl, propyl, 3-fluoropropyl, or 2-methoxyethyl; a is 0; and R ³ is methoxy, difluoromethoxy, or isopropoxy. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein... A is a phenyl or a 6-membered heteroaryl group, wherein the phenyl or 6-membered heteroaryl group is optionally substituted with one R ⁶ . 5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein A is ^R5 is selected from halogens, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, _C1 - _C4 alkoxy- _C1 - _C4 alkyl, _C3 - _C6 cycloalkyl, _C3 -C6 cycloalkoxy, 4-to- ₆ -membered heterocyclic alkyl, and 4-to-6-membered heterocyclic alkoxy; wherein the _C1 - _C4 alkyl, _C1 - _C4 alkoxy, and _C1 - _C4 alkoxy- _C1 - _C4 alkyl are optionally substituted by 1 to 3 substituents independently selected from halogens and hydroxyl groups; and wherein the _C3 - _C6 cycloalkyl, _C3 - _C6 cycloalkoxy, 4-to-6-membered heterocyclic alkyl, and 4-to-6-membered heterocyclic alkoxy are optionally substituted by 1 to 3 ^R7s ; ^R6 is a halogen or a _C1 - _C3 alkyl group; Alternatively, ^R5 and ^R6 , when they are attached to adjacent carbons and fused together with the adjacent carbons to which they are attached, form fused 5- to 6-membered heterocyclic alkyl rings optionally substituted with 1 to 3 ^R8s . 6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein... ^R5 is selected from chloro, methyl, propyl, isopropyl, difluoromethoxy, ethoxy, 1-(methoxy)ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopentoxy, tetrahydrofuranoxy, and tetrahydropyranoxy, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopentoxy, tetrahydrofuranoxy, and tetrahydropyranoxy are each optionally substituted by one to two ^R7s ; ^R6 is fluorine or methyl; Alternatively, ^R5 and ^R6 , when they are attached to adjacent carbons and fused together with the adjacent carbons to which they are attached, form fused tetrahydrofurans or fused tetrahydropyrans, each optionally substituted with one or two ^R8s . R ⁷ is independently selected from fluorine, hydroxyl, methyl, trifluoromethyl, methoxy, ethoxy, and 2-fluoroethoxy in each occurrence; and ^R8 is a methyl group each time it appears. 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein... A is 8. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein A is 9. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein A is 10. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein ^R5 is selected from methyl, cyclobutyl, cyclopentyl, tetrahydropyran-4-yl, and tetrahydropyran-2-yl, wherein each of the cyclobutyl, cyclopentyl, tetrahydropyran-4-yl, and tetrahydropyran-2-yl is optionally substituted by one or two ^R7s . 11. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein A is a 6-membered heteroaryl group that is optionally replaced by one R ⁶ . 12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein A is either a pyridinyl or pyrimidinyl group, each optionally substituted with one R ⁶ . 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein A is ^R5 is selected from C1 _{- C4} alkyl, _C1 - _C4 alkoxy, _C1 - _C4 alkoxy- _C1 - _C4 alkyl, C3-C6 cycloalkyl, _C3 - _C6 cycloalkyl-C1- _C3 alkyl, _C3 - _C6 cycloalkyl- _C1 - _C3 alkyl _, phenoxy, 4-to-6-membered heterocyclic alkyl, and 4-to-6-membered heterocyclic alkoxy; wherein the _C1 - _C4 alkyl, _C1 - _C4 alkoxy, and _C1 - _C4 alkoxy- _C1 - _C4 alkyl are optionally substituted with 1 to 3 independently selected halogens or hydroxyl groups; and wherein the _C3 - _C6 cycloalkyl, _C3 - _C6 cycloalkyl- _C1 - _C3 alkyl, C3- _C6 cycloalkyl-C1- _C3 alkyl, phenoxy, 4-to-6-membered heterocyclic alkyl, and 4-to-6-membered heterocyclic alkoxy are optionally substituted with 1 to 3 ^R7s ; and ^R6 is a halogen or a _C1 - _C3 alkyl group. 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein ^R5 is selected from tert-butoxy, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutoxy, cyclopentoxy, phenoxy, cyclopentylmethyl and tetrahydropyranyl, wherein the cyclobutyl, cyclopentyl, cyclohexyl, cyclobutoxy, cyclopentoxy, phenoxy, cyclopentylmethyl and tetrahydropyranyl are optionally substituted by 1 to 2 ^R7s . ^R6 is fluorine or methyl; and ^R7 is selected independently from fluorine, hydroxyl, methyl, trifluoromethyl, methoxy, ethoxy, and 2-fluoroethoxy each time it appears. 15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein... A is 16. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein... A is 17. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from: 6-Cyclohexyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 6-(cyclopentoxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide 4-[trans-3-(2-fluoroethoxy)cyclobutyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-methylbenzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(tetrahydro-2H-pyran-2-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(2S)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide; N-(2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide; 4-(trans-1-fluoro-3-methoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 6-(1-Fluorocyclopentyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; N-[2-(difluoromethoxy)-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl]-4-(propyl-2-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-methylbenzenesulfonamide; 4-Ethoxy-N-[7-Ethyl-2-(propyl-2-yloxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl]benzenesulfonamide; 6-(cyclopentoxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 6-Cyclopentyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 6-(cyclobutoxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 2-(cyclopentoxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyrimidine-5-sulfonamide; 6-(1-Fluorocyclohexyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[trans-3-(2-fluoroethoxy)cyclobutyl]benzenesulfonamide; 4-(cis-3-ethoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-(trans-3-ethoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-6-(cis-1-hydroxy-3-methoxycyclobutyl)pyridine-3-sulfonamide; 6-Cyclobutyl-5-fluoro-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 6-(cis-1-fluoro-3-methylcyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; N-(2-methoxy-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-methylbenzenesulfonamide; 4-Chloro-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-Ethoxy-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-Ethoxy-N-[2-methoxy-7-(2-methoxyethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl]benzenesulfonamide; 4-Cyclopropyl-N-(7-Ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-3,4-dihydro-2H-chromene-6-sulfonamide; 4-(1-Methoxyethyl)-N-(2-Methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(oxecyclobutane-3-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-3-fluoro-4-methylbenzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(tetrahydrofuran-3-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(3R)-tetrahydrofuran-3-yloxy]benzenesulfonamide; 4-(trans-4-methoxycyclohexyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-(cis-1-fluoro-4-methoxycyclohexyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-(4,4-difluorotetrahydro-2H-pyran-2-yl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-[(2R)-4,4-difluorotetrahydro-2H-pyran-2-yl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-[(2S)-4,4-difluorotetrahydro-2H-pyran-2-yl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-3-fluoro-4-[(2S)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide; N-[7-(3-fluoropropyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl]-4-(propyl-2-yl)benzenesulfonamide; 4-Cyclohexyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-(cyclopentoxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 6-[cyclopentyl(difluoro)methyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 4-(trans-3-ethoxy-1-fluorocyclobutyl)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(2-methoxy-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(propyl-2-yl)benzenesulfonamide; 4-Ethoxy-N-(2-methoxy-7-propyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(prop-2-yl)benzenesulfonamide; 4-Ethoxy-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-methylbenzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(propyl-2-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[1-(trifluoromethyl)cyclopropyl]benzenesulfonamide; N-(7-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(prop-2-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-3,4-dihydro-2H-chromene-6-sulfonamide; 4-(difluoromethoxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-6-phenoxypyridine-3-sulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-3,4-dimethylbenzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-propylbenzenesulfonamide; 4-(cyclopentoxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-2,2-dimethyl-3,4-dihydro-2H-chromene-6-sulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-2,4-dimethylbenzenesulfonamide; N-[7-ethyl-2-(prop-2-yloxy)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl]-3,4-dihydro-2H-chromene-6-sulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-2-methyl-2,3-dihydro-1-benzofuran-5-sulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(trans-3-methoxycyclobutyl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(tetrahydro-2H-pyran-2-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(tetrahydrofuran-3-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(cis-3-methoxycyclobutyl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(2S)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(4-fluorotetrahydro-2H-pyran-4-yl)benzenesulfonamide; 4-(trans-3-methoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(tetrahydro-2H-pyran-3-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(tetrahydro-2H-pyran-4-yloxy)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide; 4-(4-fluorotetrahydro-2H-pyran-4-yl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-(cis-3-methoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(tetrahydrofuran-3-yloxy)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(3R)-tetrahydro-2H-pyran-3-yl]benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(3S)-tetrahydro-2H-pyran-3-yl]benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(trans-2-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide; 4-[(4R)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-[(4S)-2,2-dimethyltetrahydro-2H-pyran-4-yl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[trans-2-methyltetrahydro-2H-pyran-4-yl]benzenesulfonamide; 4-[(1S)-1-methoxyethyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-[(1R)-1-methoxyethyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(3S)-tetrahydrofuran-3-yloxy]benzenesulfonamide; 4-(cis-4-methoxycyclohexyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-(trans-1-fluoro-4-methoxycyclohexyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(1-fluoro-4-methoxycyclohexyl)benzenesulfonamide; 4-(1-Methoxycyclopentyl)-N-(2-Methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(trans-1-fluoro-3-methoxycyclobutyl)benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-6-(tetrahydrofuran-3-yloxy)pyridine-3-sulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(2S)-tetrahydrofuran-2-yl]benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(2R)-tetrahydrofuran-2-yl]benzenesulfonamide; 6-(1-Methoxycyclopentyl)-N-(2-Methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-6-(1-fluorocyclopentyl)pyridine-3-sulfonamide; 6-Cyclopentyl-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 6-tert-butoxy-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-3-methyl-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-3-methyl-4-[(2S)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide; 4-(4-fluorotetrahydro-2H-pyran-2-yl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-3-methyl-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide; 4-(4-fluorotetrahydro-2H-pyran-2-yl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-benzenesulfonamide, diastereomeric-1; 4-(4-fluorotetrahydro-2H-pyran-2-yl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-benzenesulfonamide, diastereomeric-2; 3-Fluoro-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide; 3-Fluoro-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(2S)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-6-(1-fluorocyclohexyl)pyridine-3-sulfonamide; 6-Cyclobutyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 6-Cyclohexyl-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; N-[7-(3-fluoropropyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl]-4-methylbenzenesulfonamide; 2-(cyclobutoxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyrimidine-5-sulfonamide; 2-tert-butoxy-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyrimidine-5-sulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-propylbenzenesulfonamide; N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[cis-3-(2-fluoroethoxy)cyclobutyl]benzenesulfonamide; 4-(cis-3-ethoxycyclobutyl)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-(trans-3-ethoxycyclobutyl)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 6-(cyclopentoxy)-N-[7-(3-fluoropropyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl]pyridine-3-sulfonamide; 2-Cyclopentyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyrimidine-5-sulfonamide; 6-(cyclopentoxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-5-methylpyridine-3-sulfonamide; 6-(cyclopentoxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-5-methylpyridine-3-sulfonamide; 6-(cyclobutoxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-5-methylpyridine-3-sulfonamide; 2-Cyclohexyl-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyrimidine-5-sulfonamide; 6-(cyclopentoxy)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-2-methylpyridine-3-sulfonamide; N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-6-[(2R)-tetrahydro-2H-pyran-2-yl]pyridine-3-sulfonamide; 6-(cyclopentylmethyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 4-(trans-3-ethoxy-1-fluorocyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-[trans-1-fluoro-3-(2-fluoroethoxy)cyclobutyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 6-(trans-3-ethoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 6-(cis-3-ethoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 6-(trans-1-fluoro-3-methylcyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 6-(cyclopentoxy)-5-fluoro-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide; 4-Ethoxy-N-(7-Ethyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-Chloro-N-(7-ethyl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide; 4-Methyl-N-[7-methyl-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl]benzenesulfonamide; and N-(2-ethyl-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide. 18. Compound 6-(cyclopentoxy)-N-(7-ethyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide or a pharmaceutically acceptable salt thereof. 19. Compound 4-[trans-3-(2-fluoroethoxy)cyclobutyl]-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof. 20. The compound N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof. 21. The compound N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-methylbenzenesulfonamide or a pharmaceutically acceptable salt thereof. 22. The compound N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)-4-[(2R)-tetrahydro-2H-pyran-2-yl]benzenesulfonamide or a pharmaceutically acceptable salt thereof. 23. Compound 4-(trans-1-fluoro-3-methoxycyclobutyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof. 24. Compound 6-(1-fluorocyclopentyl)-N-(2-methoxy-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]aza-3-yl)pyridine-3-sulfonamide or a pharmaceutically acceptable salt thereof. 25. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable medium, diluent or carrier. 26. Use of a compound or a pharmaceutically acceptable salt of said compound in the preparation of a medicament for treating a disease or condition, wherein said compound is as defined in any one of claims 1 to 24, and said disease or condition is selected from Parkinson's disease, schizophrenia, dementia, psychosis, depression, mania, anxiety disorder, movement disorder, substance abuse, substance addiction, sexual dysfunction, restless legs syndrome, cardiovascular disease, metabolic disorder, hormonal disorder, renal insufficiency, and diabetes. 27. The use of claim 26, wherein the disease or condition is substance addiction. 28. The use of claim 27, wherein the substance addiction is recurrent substance addiction. 29. The use of claim 26, wherein the substance addiction is alcohol, cocaine, amphetamine, methamphetamine, opioid substances, cannabis, or nicotine addiction.