The present invention is directed to heteroaryl compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. § 371 of PCT Application No. PCT/US2015/065444, filed Dec. 14, 2015, which claims priority from PCT Application No. PCT/CN2014/094370, filed Dec. 19, 2014.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: orexin A (OX-A) (a 33 amino acid peptide) and the orexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999, 98, 437-451). Orexins have also been indicated as playing a role in arousal, reward, learning and memory (Harris, et al., Trends Neurosci., 2006, 29 (10), 571-577). Two orexin receptors have been cloned and characterized in mammals. They belong to the super family of G-protein coupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): the orexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2 receptor (OX2 or OX2R) is capable of binding OX-A as well as OX-B. The physiological actions in which orexins are presumed to participate are thought to be expressed via one or both of OX1 receptor and OX2 receptor as the two subtypes of orexin receptors.

SUMMARY OF THE INVENTION

The present invention is directed to heteroaryl compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:
A is selected from the group consisting of phenyl, naphthyl and heteroaryl;
X is N or CH;
Y is N or CH;
each of R1a, R1band R1cis independently selected from the group consisting of:(1) hydrogen,(2) halogen,(3) hydroxyl,(4) —(C═O)m—On—C1-6alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one to three substituents independently selected from R4,(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from R4,(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one to three substituents independently selected from R4,(7) —(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one to three substituents independently selected from R4,(8) —(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one to three substituents independently selected from R4,(9) —(C═O)m—On-heterocycle, where the heterocycle is unsubstituted or substituted with one to three substituents independently selected from R4,(10) —(C═O)m—NR10R11, wherein R10and R11are independently selected from the group consisting of:(a) hydrogen,(b) C1-6alkyl, which is unsubstituted or substituted with R4,(c) C3-6alkenyl, which is unsubstituted or substituted with R4,(d) C3-6alkynyl, which is unsubstituted or substituted with R4,(e) C3-6cycloalkyl which is unsubstituted or substituted with R4,(f) phenyl, which is unsubstituted or substituted with R4, and(g) heterocycle, which is unsubstituted or substituted with R4,(11) —S(O)2—NR10R11,(12) —S(O)q—R12, where q is 0, 1 or 2 and where R12is selected from the definitions of R10and R11,(13) —CO2H,(14) —CN, and(15) —NO2;
R3is selected from hydrogen and C1-6alkyl;
R4is selected from the group consisting of:(1) hydroxyl,(2) halogen,(3) C1-6alkyl,(4) —C3-6cycloalkyl,(5) —O—C1-6alkyl,(6) —O(C═O)—C1-6alkyl,(7) —NH2,(8) —NH—C1-6alkyl,(9) —NO2,(10) phenyl,(11) heterocycle,(12) —CO2H, and(13) —CN;
R5is selected from the group consisting of:(1) hydrogen,(2) halogen,(3) C1-6alkyl, which is unsubstituted or substituted with halogen or hydroxyl,(4) —O—C1-6alkyl, which is unsubstituted or substituted with halogen, and(5) —(C═O)—O—C1-6alkyl;
R6is selected from the group consisting of:(1) hydrogen, and(2) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl;
or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formula Ia:

An embodiment of the present invention includes compounds of the formula Ia′:

An embodiment of the present invention includes compounds of the formula Ia″:

An embodiment of the present invention includes compounds wherein A is selected from phenyl, pyridyl, thiophenyl, thiazolyl, isothiazolyl, and pyrazolyl. An embodiment of the present invention includes compounds wherein A is phenyl. An embodiment of the present invention includes compounds wherein A is pyridyl. An embodiment of the present invention includes compounds wherein A is thiophenyl. An embodiment of the present invention includes compounds wherein A is thiazolyl. An embodiment of the present invention includes compounds wherein A is isothiazolyl. An embodiment of the present invention includes compounds wherein A is pyrazolyl.

An embodiment of the present invention includes compounds wherein X is N. An embodiment of the present invention includes compounds wherein X is CH.

An embodiment of the present invention includes compounds wherein Y is N. An embodiment of the present invention includes compounds wherein Y is CH. An embodiment of the present invention includes compounds wherein X is CH and Y is CH. An embodiment of the present invention includes compounds wherein X is N and Y is CH. An embodiment of the present invention includes compounds wherein X is N and Y is N.

An embodiment of the present invention includes compounds wherein R1a, R1band R1care independently selected from the group consisting of:(1) hydrogen,(2) halogen,(3) hydroxyl,(4) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,(5) —O—C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,(6) heteroaryl, wherein heteroaryl is selected from imidazolyl, indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl, and triazolyl, which is unsubstituted or substituted with halogen, hydroxyl, C1-6alkyl, —O—C1-6alkyl or —NO2,(7) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, C1-6alkyl, —O—C1-6alkyl or —NO2,(8) —O-phenyl, which is unsubstituted or substituted with halogen, hydroxyl, C1-6alkyl, —O—C1-6alkyl or —NO2,(9) —CN, and(10) —NH—C1-6alkyl, or —N(C1-6alkyl)(C1-6alkyl), which is unsubstituted or substituted with halogen, hydroxyl, C1-6alkyl, and —O—C1-6alkyl.

An embodiment of the present invention includes compounds wherein R1a, R1band R1care independently selected from the group consisting of:(1) hydrogen,(2) halogen,(3) hydroxyl,(4) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,(5) —O—C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,(6) —CN, and(7) heteroaryl, wherein heteroaryl is selected from imidazolyl, indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl, and triazolyl, which is unsubstituted or substituted with halogen, hydroxyl, C1-6alkyl, —O—C1-6alkyl or —NO2.

An embodiment of the present invention includes compounds wherein R1a, R1band R1care independently selected from the group consisting of:(1) hydrogen,(2) halogen,(3) C1-6alkyl, which is unsubstituted or substituted with halogen,(4) —O—C1-6alkyl, which is unsubstituted or substituted with halogen,(5) —CN, and(6) heteroaryl, wherein heteroaryl is selected from imidazolyl, indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl, and triazolyl.

An embodiment of the present invention includes compounds wherein R1cis hydrogen, and R1aand R1bare independently selected from the group consisting of:(1) hydrogen,(2) fluoro,(3) chloro,(4) methyl,(5) methoxy,(6) tetrazolyl, and(7) triazolyl.

An embodiment of the present invention includes compounds wherein R3is selected from hydrogen, methyl and ethyl. An embodiment of the present invention includes compounds wherein R3is ethyl.

An embodiment of the present invention includes compounds wherein R5is selected from the group consisting of:(1) hydrogen,(2) methyl,(3) —C(CH3)2OH,(4) —CH(OH)CF3,(5) —CH(OH)CH3,(6) —C(OH)(CH3)CH2CH3,(7) —C(OH)(CF3)CH3, and(8) —C(═O)OCH3.

An embodiment of the present invention includes compounds wherein R5is selected from the group consisting of: methyl and —C(CH3)2OH.

An embodiment of the present invention includes compounds wherein R6is selected from the group consisting of:(1) hydrogen, and(2) C1-6alkyl.

An embodiment of the present invention includes compounds wherein R6is selected from the group consisting of: hydrogen and methyl.

An embodiment of the present invention includes compounds wherein R5is —C(CH3)2OH and R6is hydrogen or methyl. An embodiment of the present invention includes compounds wherein R5is —C(CH3)2OH and R6is hydrogen. An embodiment of the present invention includes compounds wherein R5is —C(CH3)2OH and R6is methyl.

Certain embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. Formula I shows the structure of the class of compounds without specific stereochemistry.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

The present invention also includes all pharmaceutically acceptable isotopic variations of a compound of the Formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as2H and3H, carbon such as11C,13C and14C, nitrogen such as13N and15N, oxygen such as15O,17O and18O, phosphorus such as32P, sulfur such as35S, fluorine such as18F, iodine such as123I and125I, and chlorine such as36Cl. Certain isotopically-labelled compounds of Formula I, for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labelled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.

The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

Exemplifying the invention is the use of the compounds disclosed in the Examples and herein. Specific compounds within the present invention include a compound which is selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual enantiomers or diastereomers thereof.

The present invention is also directed to the use of the compounds disclosed herein as antagonists of orexin receptor activity. The subject compounds and pharmaceutically acceptable salts thereof are useful in a method of antagonizing orexin receptor activity in a subject such as a mammal comprising the administration of an amount of the compound. In addition to primates, especially humans, a variety of other mammals may be administered with a compound of the present invention. The present invention is directed to a compound of the present invention or a pharmaceutically acceptable salt thereof that could be useful in therapy. The present invention may further be directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for antagonizing orexin receptor activity or treating the disorders and diseases noted herein in humans and animals.

A subject administered with a compound of the present invention, or a pharmaceutically acceptable salt thereof, is generally a mammal, such as a human being, male or female. The amount of compound administered to the subject is an amount sufficient to antagonize the orexin receptor in the subject. In an embodiment, the amount of compound can be an “effective amount”, wherein the subject compound is administered in an amount that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. An effective amount does not necessarily include considerations of toxicity and safety related to the administration of the compound. It is recognized that one skilled in the art may affect neurological and psychiatric disorders associated with orexin receptor activation by treating a subject presently afflicted with the disorders, or by prophylactically treating a subject likely to be afflicted with the disorders, with an effective amount of a compound of the present invention. As used herein, the terms “treatment” and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a subject that is predisposed to such disease or disorder. The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the subject.

The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The utility of the compounds in accordance with the present invention as orexin receptor OX1R and/or OX2R antagonists may be readily determined without undue experimentation by methodology well known in the art, including the “FLIPR Ca2+Flux Assay” (Okumura et al., Biochem. Biophys. Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2 receptor antagonistic activity of the compounds of the present invention was determined in accordance with the following experimental method. For intracellular calcium measurements, Chinese hamster ovary (CHO) cells expressing the rat orexin-1 receptor or the human orexin-2 receptor, are grown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/ml G418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100 μg/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into Becton-Dickinson black 384-well clear bottom sterile plates coated with poly-D-lysine. All reagents were from GIBCO-Invitrogen Corp. The seeded plates are incubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as the agonist is prepared as a 1 mM stock solution in 1% bovine serum albumin (BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSA and 2.5 mM probenecid, pH7.4) for use in the assay at a final concentration of 70 pM. Test compounds are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates, first in DMSO, then assay buffer. On the day of the assay, cells are washed 3 times with 100 μl assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 μl assay buffer containing 1 μM Fluo-4 AM ester, 0.02% pluronic acid, and 1% BSA. The dye loading solution is then aspirated and cells are washed 3 times with 100 μl assay buffer. 30 μl of that same buffer is left in each well. Within the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices), test compounds are added to the plate in a volume of 25 μl, incubated for 5 min and finally 25 μl of agonist is added. Fluorescence is measured for each well at 1 second intervals for 5 minutes and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer in place of antagonist. For each antagonist, IC50 value (the concentration of compound needed to inhibit 50% of the agonist response) is determined. Alternatively, compound potency can be assessed by a radioligand binding assay (described in Bergman et. al. Bioorg. Med. Chem. Lett. 2008, 18, 1425-1430) in which the inhibition constant (Ki) is determined in membranes prepared from CHO cells expressing either the OX1 or OX2 receptor. The intrinsic orexin receptor antagonist activity of a compound which may be used in the present invention may be determined by these assays.

All of the final compounds of the following examples had activity in antagonizing the human orexin-2 receptor in the aforementioned assays with an IC50of about 0.1 nM to 1500 nM. All of the final compounds of the following examples had activity in the FLIPR assay with an IC50 of about 5 nM to 500 nM against the orexin-2 receptor. Additional data is provided in the following Examples. Such a result is indicative of the intrinsic activity of the compounds in use as antagonists of orexin-1 receptor and/or the orexin-2 receptor. In general, one of ordinary skill in the art would appreciate that a substance is considered to effectively antagonize the orexin receptor if it has an IC50 of less than about 50 μM, or more specifically less than about 1000 nM.

The orexin receptors have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species. The compounds of the present invention could therefore potentially have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with orexin receptors, including one or more of the following conditions or diseases: sleep disorders, sleep disturbances, including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, augmenting sleep maintenance; increasing the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; improving sleep initiation; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing intermittent wakings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasing the amount and percentage of stage 2 sleep; promoting slow wave sleep; enhancing EEG-delta activity during sleep; decreasing nocturnal arousals, especially early morning awakenings; increasing daytime alertness; reducing daytime drowsiness; treating or reducing excessive daytime sleepiness; increasing satisfaction with the intensity of sleep; increasing sleep maintenance; idiopathic insomnia; sleep problems; insomnia, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleep apnea, wakefulness, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dyssomnias, night terror, insomnias associated with depression, emotional/mood disorders, Alzheimer's disease or cognitive impairment, as well as sleep walking and enuresis, and sleep disorders which accompany aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, conditions due to drugs which cause reductions in REM sleep as a side effect; fibromyalgia; syndromes which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep; conditions which result from a diminished quality of sleep; increasing learning; augmenting memory; increasing retention of memory; eating disorders associated with excessive food intake and complications associated therewith, compulsive eating disorders, obesity (due to any cause, whether genetic or environmental), obesity-related disorders overeating, anorexia, bulimia, cachexia, dysregulated appetite control, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, lung disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; sudden death, polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia, metabolic syndrome, also known as syndrome X, insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunction, such as impaired fertility, infertility, hypogonadism in males and hirsutism in females, fetal defects associated with maternal obesity, gastrointestinal motility disorders, intestinal motility dyskinesias, obesity-related gastro-esophageal reflux, hypothalmic diseases, hypophysis diseases, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), breathlessness, cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, kidney cancer, increased anesthetic risk, reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy; diseases or disorders where abnormal oscillatory activity occurs in the brain, including depression, migraine, neuropathic pain, Parkinson's disease, psychosis and schizophrenia, as well as diseases or disorders where there is abnormal coupling of activity, particularly through the thalamus; enhancing cognitive function, including cognitive dysfunctions that comprise deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders; enhancing memory; increasing memory retention; increasing immune response; increasing immune function; hot flashes; night sweats; extending life span; schizophrenia; muscle-related disorders that are controlled by the excitation/relaxation rhythms imposed by the neural system such as cardiac rhythm and other disorders of the cardiovascular system; conditions related to proliferation of cells such as vasodilation or vasorestriction and blood pressure; cancer; cardiac arrhythmia; hypertension; congestive heart failure; conditions of the genital/urinary system; disorders of sexual function and fertility; adequacy of renal function; responsivity to anesthetics; mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder, mood disorders due to a general medical condition, and substance-induced mood disorders; affective neurosis; depressive neurosis; anxiety neurosis; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition; acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington's Chorea; Huntington's disease and Tourette syndrome; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia; hypophysis tumor/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcers; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; amyotrophic lateral sclerosis; multiple sclerosis; ocular damage; retinopathy; cognitive disorders; idiopathic and drug-induced Parkinson's disease; muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, seizure disorders, absence seisures, complex partial and generalized seizures; Lennox-Gastaut syndrome; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age related cognitive decline; schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced psychotic disorder; dissociative disorders including multiple personality syndromes and psychogenic amnesias; substance-related disorders, substance use, substance abuse, substance seeking, substance reinstatement, all types of psychological and physical addictions and addictive behaviors, reward-related behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, addictive feeding, addictive feeding behaviors, binge/purge feeding behaviors, dependence, withdrawal or relapse from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, morphine, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); appetite, taste, eating or drinking disorders; movement disorders, including akinesias and akinetic-rigid syndromes (including Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), chronic fatigue syndrome, fatigue, including Parkinson's fatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorder or a circadian rhythm disorder, medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias [including tremor (such as rest tremor, essential tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), restless leg syndrome and dystonia (including generalised dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia); neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure disorders; attention deficit/hyperactivity disorder (ADHD); conduct disorder; migraine (including migraine headache); headache; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers; Kallman's syndrome (anosmia); asthma; cancer; conditions associated with visceral pain such as irritable bowel syndrome, and angina; eating disorders; urinary incontinence; substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.); psychosis; schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder); mood disorders (including depression, mania, bipolar disorders); trigeminal neuralgia; hearing loss; tinnitus; neuronal damage including ocular damage; retinopathy; macular degeneration of the eye; emesis; brain edema; pain, including acute and chronic pain states, severe pain, intractable pain, inflammatory pain, neuropathic pain, post-traumatic pain, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headache and other diseases related to general orexin system dysfunction.

Thus, in certain embodiments the present invention may provide methods for: enhancing the quality of sleep; augmenting sleep maintenance; increasing REM sleep; increasing stage 2 sleep; decreasing fragmentation of sleep patterns; treating insomnia and all types of sleep disorders; treating or controlling sleep disturbances associated with diseases such as neurological disorders including neuropathic pain and restless leg syndrome; treating or controlling addiction disorders; treating or controlling psychoactive substance use and abuse; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling diabetes and appetite, taste, eating, or drinking disorders; treating or controlling hypothalamic diseases; treating or controlling depression; treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis; treating or controlling dysthymic, mood, psychotic and anxiety disorders; treating or controlling depression, including major depression and major depression disorder; treating or controlling bipolar disorder; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a mammalian subject which comprises administering to the subject a compound of the present invention.

The subject compounds could further be of potential use in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to subjects (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from subject to subject depending upon the nature and severity of disease, the subject's weight, special diets then being followed by a subject, concurrent medication, and other factors which those skilled in the art will recognize. Generally, dosage levels of between 0.0001 to 10 mg/kg. of body weight daily are administered to the subject, e.g., humans and elderly humans, to obtain effective antagonism of orexin receptors. The dosage range will generally be about 0.5 mg to 1.0 g. per subject per day which may be administered in single or multiple doses. In one embodiment, the dosage range will be about 0.5 mg to 500 mg per subject per day; in another embodiment about 0.5 mg to 200 mg per subject per day; and in yet another embodiment about 5 mg to 50 mg per subject per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day. The compounds may be administered before bedtime. For example, the compounds may be administered about 1 Hour prior to bedtime, about 30 minutes prior to bedtime or immediately before bedtime.

The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is contemplated. However, the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.

Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is contemplated. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, such as about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

In another embodiment, the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.

In another embodiment, the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone.

In another embodiment, the subject compound may be employed in combination with an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the subject compound may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention may be effective for use in humans.

Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Oily suspensions may be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions may also be employed. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oleagenous suspension. The compounds of the present invention may also be administered in the form of suppositories for rectal administration. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed. The compounds of the present invention may also be formulated for administered by inhalation. The compounds of the present invention may also be administered by a transdermal patch by methods known in the art.

In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

INTERMEDIATES

Intermediate A

To a solution of NaH (1.1 g, 26.2 mmol) in DMSO (20 mL) was added compound A1 (2 g, 11.4 mmol); after stirring at RT under nitrogen for 1 h, 1-bromo-2-chloroethane (1.8 g, 12.6 mmol) was added and the mixture stirred at RT for 2 h. The mixture was quenched with ice water (10 mL) and extracted with EtOAc (10 mL×3). The organic layers were combined, dried, and concentrated in vacuo to give the crude compound, which was purified by silica gel column chromatography (4.8% EtOAc in petroleum ether) to give the title compound as a solid. MS (ESI) m/e (M+H+) was detected.

A solution of compound A2 in THF/MeOH/H2O (3:1:1, 16 mL) was treated with lithium hydroxide in water (3 mL). The mixture was stirred overnight at RT. The THF and MeOH were removed in vacuo and the resulting solution acidified to pH ˜1 with 1 N HCl to give a white crystalline precipitate. The crystals were isolated by filtration, washed with water, and dried in vacuo affording intermediate A as a solid. MS (ESI) m/e (M+H+): 187.9.

Intermediate C

Intermediate G

To a mixture of 2-bromo-4-fluorobenzoic acid (30 g, 137 mmol), cesium carbonate (89.26 g, 274 mmol), and copper(I) iodide (5.27 g, 27.4 mmol) in DMF (200 mL) were added N,N′-dimethylcyclohexane-1,2-diamine (3.7 mL, 23.3 mmol) and 1H-1,2,3-triazole (18.92 g, 274 mmol). The resulting mixture was stirred at 110° C. overnight, cooled, concentrated in vacuo, and diluted with water (150 mL). The aqueous layer was extracted with EtOAc (300 mL×3). The aqueous layer was acidified with 2 N HCl and extracted with EtOAc (300 mL×4). The combined organic layers were washed with brine (150 mL×3), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography gel (petroleum ether:EtOAc=100:1˜5:1) to provide the title compound as a solid. LRMS m/z (M+H) 208.0 found, 208.0 required.

Intermediate M

To a solution of 2-bromonicotinic acid (1.4 g, 6.93 mmol) in DMSO (14 mL) was added 1H-pyrazole (0.707 g, 10.40 mmol), cesium carbonate (4.74 g, 14.55 mmol), copper(I) iodide (0.132 g, 0.693 mmol), and N1,N2-dimethylcyclohexane-1,2-diamine (0.099 g, 0.693 mmol). The mixture was sparged with nitrogen and heated at 120° C. overnight. The cooled reaction mixture was diluted with 1 N NaOH (15 mL) and washed with EtOAc (15 mL). The aqueous layer was acidified with 12 N HCl and extracted with EtOAc (4×20 mL). The combined organic layers were washed with brine, dried over NaSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography [0-100% (5% AcOH in EtOAc)/hexanes]. The purified fractions were combined and azetroped with toluene (3×100 mL) to give 2-(1H-pyrazol-1-yl)nicotinic acid as a solid. LRMS m/z (M+H) found, required.

Intermediate P

To a suspension of sodium hydride (60 wt % in mineral oil, 278 mg, 6.95 mmol) in DMF (10 mL) was added 1H-pyrazole (279 mg, 4.11 mmol) at RT and the resulting mixture was stirred at RT for 30 mins. 3-Chloropyrazine-2-carboxylic acid (500 mg, 3.16 mmol) was added and the mixture was heated at 60° C. for 2 h. After cooling to RT, water (20 mL) was added and the mixture was extracted with 5% MeOH in DCM (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound as a solid. LRMS m/z (M+H) 191.0 found, 191.0 required.

Intermediate T

To a suspension of 2,2-difluoroethanol (492 mg, 6.0 mmol) in DMF (10 mL) at 0° C. was added NaH (180 mg, 4.5 mmol) and the mixture was stirred at 0° C. for 0.5 h. A suspension of 2-fluoronicotinic acid (423 mg, 3.0 mmol) and NaH (180 mg, 4.5 mmol) in DMF (5 mL) was added dropwise at 0° C. and the resulting mixture was stirred at RT overnight. The mixture was diluted with water, acidified to pH˜3 with 1 N HCl and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude product which was used without further purification. LRMS m/z (M+H) 204.1 found, 204.0 required.

The following intermediates were made as described above, replacing 2,2-difluoroethanol with the appropriate alcohol.

To a mixture of 2-chloroisonicotinonitrile (1.6 g, 11.55 mmol) in dioxane (4 mL)/water (1 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.67 g, 17.32 mmol), tetrakis (triphenylphosphoranyl) palladium (0.667 g, 0.577 mmol), and Na2CO3(1.469 g, 13.86 mmol). The resulting mixture was stirred at 90° C. for 7 h. After cooling to RT, the mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (15% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 131.1 found, 131.1 required.

To a solution of the product from Step 1 (600 mg, 4.61 mmol) in EtOH (3 mL) was added Et3N (2 mL) and ethanamine hydrochloride (414 mg, 5.07 mmol). The mixture was stirred in a sealed tube at 90° C. for 3 h. After cooling to RT, the mixture was concentrated in vacuo to give the crude product as a oil, which was used without further purification. LRMS m/z (M+H) 176.1 found, 176.1 required.

To a solution of the product from Step 2 (360 mg, 2.05 mmol) in DCM (5 mL) was added Et3N (3 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 mins, then a solution of 2-(2H-1,2,3-triazol-2-yl)-benzoyl chloride (466 mg, 2.46 mmol) in DCM (2 mL) was added dropwise at 0° C. The resulting mixture was stirred at RT overnight. The mixture was diluted with DCM (10 mL) and washed with saturated, aqueous NaHCO3(20 mL×3) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 347.1 found, 347.1 required.

A solution of the product from Step 3 (270 mg, 0.78 mmol) in HCl (4 M in MeOH, 5 mL) was stirred at RT for 4 h. The mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (10 mL×3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a oil. LRMS m/z (M+H) 380.1 found, 380.2 required.

To a solution of the product from Step 4 (50 mg, 0.132 mmol) in THF (1.5 mL) was added MeMgBr solution (3 M in ether, 6 mmol, 2 mL) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 4 h, then quenched with saturated, aqueous NH4Cl. The resulting mixture was filtered and the filtrate was purified by prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 380.3 found, 380.2 required.

To a mixture of 6-bromopicolinonitrile (1.0 g, 5.46 mmol) in 1,4-dixoane (4 mL)/water (1 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.01 g, 6.56 mmol), tetrakis (triphenylphosphoranyl) palladium (0.317 g, 0.273 mmol), and Na2CO3(0.869 g, 8.20 mmol) under N2. The resulting mixture was stirred at 90° C. for 7 hours. After cooling to RT, the mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (15% EtOAc in petroleum) to give the title compound as a oil. LRMS m/z (M+H) 131.1 found, 131.1 required.

To a solution of the product from Step 1 (600 mg, 4.61 mmol) in EtOH (5 mL) was added Et3N (2 mL) and ethanamine hydrochloride (414 mg, 5.07 mmol). The resulting mixture was stirred at 90° C. in a sealed tube for 3 h. After cooling to RT, the mixture was concentrated in vacuo to give the title compound as a yellow oil, which was used without further purification. LRMS m/z (M+H) 176.1 found, 176.1 required.

To a solution of the product from Step 2 (400 mg, 2.28 mmol) in DCM (5 mL) was added Et3N (3 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 mins, then a solution of 2-(2H-1,2,3-triazol-2-yl) benzoyl chloride (518 mg, 2.74 mmol) in DCM (2 mL) was added dropwise at 0° C. The resulting mixture was stirred at RT overnight, then diluted with DCM (10 mL) and washed with saturated, aqueous NaHCO3(20 mL×3) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 347.3 found, 347.2 required.

A solution of the product from Step 3 (100 mg, 0.289 mmol) in HCl (3 M in MeOH, 5 mL) was stirred at RT for 4 h. The mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (10 mL×3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a yellow solid, which was used without further purification. LRMS m/z (M+H) 380.2 found, 380.2 required.

To a solution of the product from Step 4 (80 mg, 0.211 mmol) in THF (1.5 mL) was added MeMgBr solution (3 M in ether, 6 mmol, 2 mL) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 4 h, then quenched with saturated, aqueous NH4Cl. The resulting mixture was filtered and the filtrate was purified by prep-HPLC, providing the title compound as a solid. LRMS m/z (M+H) 380.4 found, 380.2 required.

To a solution of 2,6-dibromopyridine (10 g, 42.2 mmol) in dioxane (100 mL) and water (20 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (6.47 g, 42.2 mmol), Na2CO3(8.95 g, 84.4 mmol), and Pd(dppf)Cl2(0.5 g, 0.6 mmol). The resulting mixture was stirred at 70° C. for 5 h under N2. After cooling to RT, the mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 184.0, 186.0 found, 184.0, 186.0 required.

To a solution of the product from Step 1 (4.0 g, 21.7 mmol) in EtOH (40 mL) was added Et3N (8.7 g, 86.8 mmol) and ethanamine hydrochloride (5.3 g, 65.2 mmol). The resulting mixture was stirred in a sealed tube at 90° C. overnight. After cooling to RT, the mixture was concentrated in vacuo. The residue was purified by silica gel gradient chromatography (5%-10% MeOH in DCM) to give the title compound as a oil. LRMS m/z (M+H) 229.0, 231.0 found, 229.0, 231.0 required.

To a solution of the product from Step 2 (2.9 g, 12.7 mmol) in THF (20 mL) and water (20 mL) was added Na2CO3(4.0 g, 38.1 mmol). CbzCl (4.3 g, 25.4 mmol) was added dropwise at 0° C. The resulting mixture was stirred for 1 h at RT, then quenched with water and extracted with DCM (100 mL×4). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (9.1% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 363.1, 365.1 found, 363.1, 365.1 required.

To a solution of the product from Step 3 (4.8 g, 13.2 mmol) in MeOH (50 mL) was added Et3N (3.99 g, 39.6 mmol) and Pd(dppf)Cl2(0.97 g, 1.3 mmol). The resulting mixture was stirred under 3 MPa of CO at 80° C. overnight. After cooling to RT, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel gradient chromatography (10%-30% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 343.1 found, 343.2 required.

To a solution of the product from Step 4 (1.3 g, 3.8 mmol) in THF (15 mL) was added MeMgBr solution (3 M in ether, 6.4 mL, 19.2 mmol) at −20° C. dropwise. After addition, the resulting mixture was stirred at 0° C. for 5 h, then quenched with saturated, aqueous NH4Cl (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (9.1%-33% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 343.2 found, 343.2 required.

To a solution of the product from Step 5 (950 mg, 2.78 mmol) in THF (20 mL) was added Pd/C (10 wt %, 100 mg) at RT. The resulting mixture was stirred under a balloon of H2for 16 h. The mixture was filtered and concentrated in vacuo to give the title compound as a oil, which was used directly without further purification. LRMS m/z (M+H) 209.1 found, 209.2 required.

To a solution of 2-isopropoxynicotinic acid (41 mg, 0.23 mmol) in DMF (2 mL) was added DIEA (89.1 mg, 0.69 mmol), HATU (95 mg, 0.25 mmol), and the product from Step 6 (43.7 mg, 0.21 mmol). The resulting mixture was stirred at RT overnight, then filtered. The filtrate was purified by prep-HPLC to give the title compound as a oil. LRMS m/z (M+H) 372.3 found, 372.2 required.

The following compounds were prepared according to the general procedure provided in Example 5 and procedures herein. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

To a solution of 2-(6-(2-(ethylamino)ethyl)pyridin-2-yl)propan-2-ol (14, Example 5, Step 6, 30 mg, 0.144 mmol) in DCM (3 mL) was added 2-(pyrimidin-2-yl)benzoic acid (144 mg, 0.720 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (367 mg, 1.152 mmol). The resulting mixture was stirred at 50° C. for 12 h. After cooling to RT, the mixture was quenched with water (20 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over MgSO4and filtered. The filtrate was concentrated in vacuo and the residue was purified by prep-TLC (50% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 391.2 found, 391.2 required.

To a mixture of 6-chloronicotinonitrile (3 g, 21.65 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.00 g, 26.0 mmol) in dioxane (22 mL) and water (5 mL) was added Na2CO3(5.74 g, 54.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.500 g, 0.433 mmol) under N2. The resulting mixture was stirred at 80° C. overnight. After cooling to RT, the mixture was filtered and concentrated in vacuo. The residue was diluted with water and extracted with DCM (100 mL×4). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (9% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 131.1 found, 131.1 required.

To a solution of the product from Step 1 (900 mg, 6.92 mmol) in EtOH (9 mL) was added ethanamine hydrochloride (620 mg, 7.61 mmol) and Et3N (3.86 ml, 27.7 mmol). The resulting mixture was stirred at 90° C. for 4 h. The residue was concentrated in vacuo to give the title compound as a oil which was used without further purification. LRMS m/z (M+H) 176.1 found, 176.1 required.

A solution of 2-(2H-1,2,3-triazol-2-yl)benzoic acid (300 mg, 1.586 mmol) in SOCl2(0.347 mL, 4.76 mmol) was stirred at 80° C. for 1 h. After cooling to RT, the mixture was concentrated in vacuo. To a solution of the product from Step 2 (417 mg, 2.379 mmol) and Et3N (0.884 mL, 6.34 mmol) in DCM (2 mL) was dropwise added a solution of the above residue in DCM (2 mL) at 0° C. The resulting mixture was stirred at RT for 12 h, then poured into water and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (50% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 347.1 found, 347.2 required.

A solution of the product from Step 3 (200 mg, 0.577 mmol) in HCl (4 M in MeOH, 5 mL) was stirred at RT for 3 h. The mixture was concentrated in vacuo. The residue was purified by prep-TLC (50% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 380.1 found, 380.2 required.

To a solution of the product from Step 4 (100 mg, 0.264 mmol) in dry THF (2 mL) at 0° C. was added MeMgBr solution (3 M in ether, 0.26 mL, 0.78 mmol) dropwise. The resulting mixture was stirred at 0° C. for 2.5 h, then quenched with water (20 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over MgSO4and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-TLC (50% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M-18+H) 380.3 found, 380.2 required.

To a mixture of 4-chloropicolinonitrile (1.0 g, 7.2 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.79 g, 11 mmol), and Na2CO3(1.9 g, 18 mmol) in dioxane (10 mL) and water (2 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol). The resulting mixture was stirred at 80° C. under N2overnight. After cooling to RT, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with DCM (20 mL×4). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 131.1 found, 131.1 required.

To a solution of the product from Step 1 (220 mg, 1.7 mmol) and Et3N (343 mg, 3.4 mmol) in EtOH (6 mL) was added ethanamine hydrochloride (150 mg, 1.9 mmol). The resulting mixture was stirred at 90° C. overnight. After cooling to RT, the mixture was concentrated in vacuo to give the crude product as a oil which was used without further purification. LRMS m/z (M+H) 176.1 found, 176.1 required.

To a solution of 2-(2H-1,2,3-triazol-2-yl)benzoic acid (324 mg, 1.7 mmol) in DCM (2 mL) was added SOCl2(601 mg, 5.1 mmol) at RT. The resulting mixture was stirred at 50° C. for 2 h. After cooling to RT, the mixture was concentrated in vacuo. To a solution of the product from Step 2 (300 mg, 1.7 mmol) and the above residue in DCM (6 mL) at 0° C. was added Et3N (515 mg, 5.1 mmol) slowly. The resulting mixture was stirred at 0° C. for 20 mins, then quenched with water (10 mL) and extracted with DCM (20 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (EtOAc) to give the title compound as a oil. LRMS m/z (M+H) 347.1 found, 347.2 required.

To a solution of the product from Step 3 (100 mg, 0.3 mmol) in MeOH (1.0 mL) was added HCl (4 M in MeOH, 2 mL) at 0° C. The resulting mixture was stirred at RT for 4 h. The mixture was concentrated in vacuo and the residue was purified by prep-TLC (EtOAc) to give the title compound as a oil. LRMS m/z (M+H) 380.1 found, 380.2 required.

To a solution of MeMgBr (3 M in ether, 0.5 mL, 1.5 mmol) in dry THF (1 mL) was added a solution of the product from Step 4 (50 mg, 0.13 mmol) in THF (2 mL) dropwise at 0° C. under N2. The resulting mixture was stirred at 0° C. for 1 h, then quenched with saturated, aqueous NH4Cl and extracted with EtOAc (3 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound as a oil. LRMS m/z (M+H) 380.2 found, 380.2 required.

To a solution of 2-(5-bromopyridin-3-yl)acetic acid (0.6 g, 2.31 mmol) in THF (6 mL) was added BH3THF (11.1 mL, 9.26 mmol) dropwise at 0° C. The resulting mixture was stirred at 50° C. overnight. After cooling to RT, the mixture was slowly quenched with water (10 mL) at 0° C. and then extracted with EtOAc (15 mL×3). The combined organic layers were washed with saturated, aqueous NaHCO3(10 mL×3), then with brine (10 mL×3), then dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product as a oil. LRMS m/z (M+H) 202.0, 204.1 found, 202.2, 204.0 required.

To a solution of the product from Step 1 (100 mg, 0.49 mmol) and Et3N (60.1 mg, 0.59 mmol) in THF (1 mL) was added MsCl (62.3 mg, 0.54 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 1 h to afford a solution of the title compound in THF (1 mL), which was used directly in the next step. LRMS m/z (M+H) 280.0, 282.1 found, 280.0, 282.0 required.

A mixture of the product solution from Step 2 and aqueous EtNH2(70%, 3 mL) was stirred at 50° C. in sealed tube overnight. After cooling to RT, the mixture was diluted with water and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (5 mL×3), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound as a oil. LRMS m/z (M+H) 229.0, 231.0 found, 229.0, 231.0 required.

A mixture of 2-(2H-1,2,3-triazol-2-yl)benzoic acid (100 mg, 0.528 mmol) in SOCl2(251.5 mg, 2.11 mmol) was stirred at RT for 0.5 h, then concentrated in vacuo. To a solution of the product from Step 3 (110 mg, 0.48 mmol) and Et3N (145.7 mg, 1.44 mmol) in DCM (1 mL) at 0° C. was added a solution of the above residue in DCM (1 mL) dropwise. The resulting mixture was stirred at 0° C. for 2 h, then quenched with water (1 mL) and extracted with DCM (2 mL×3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 400.0, 402.0 found, 400.1, 402.1 required.

A mixture of the product from Step 4 (87 mg, 0.21 mmol), Et3N (65.9 mg, 0.65 mmol), and Pd(dppf)Cl2(15.9 mg, 0.021 mmol) in MeOH (2 mL) was stirred at 100° C. under 3 Mpa of CO in a sealed tube overnight. After cooling to RT, the mixture was filtered and concentrated in vacuo. The residue was purified by prep-TLC (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 380.2 found, 380.2 required.

To a solution of MeMgBr (3 M in ether, 0.2 mL, 0.6 mmol) in THF (1 mL) at 0° C. was added a solution of the product from Step 5 (25 mg, 0.06 mmol) in THF (0.5 mL) dropwise. The resulting mixture was stirred at 0° C. for 3 h, then quenched with saturated, aqueous NH4Cl (2 mL) and extracted with EtOAc (3 mL×3). The combined organic layers were washed with brine (2 mL×3), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound as a oil. LRMS m/z (M+H) 380.2 found, 380.2 required.

To a solution of 6-chloropyrazine-2-carbonitrile (1 g, 7.17 mmol) in dioxane (15 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.21 g, 14.33 mmol), Na2CO3(1.52 g, 14.33 mmol), and Pd(dppf)Cl2(40 mg, 0.072 mmol) under N2. The resulting mixture was stirred at 100° C. overnight. After cooling to RT, the mixture was diluted with EtOAc (30 mL), washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (9% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 132.1 found, 132.1 required.

To a solution of the product from Step 1 (100 mg, 0.763 mmol) in EtOH (5 mL) was added ethanamine (33% in EtOH, 313 mg, 2.29 mmol). The resulting mixture was stirred at 80° C. for 2 h. After cooling to RT, the mixture was concentrated in vacuo to give the crude product as a red oil, which was used without further purification. LRMS m/z (M+H) 177.1 found, 177.1 required.

To a solution of 2-(2H-1,2,3-triazol-2-yl)benzoic acid (160 mg, 0.85 mmol) in DMF (3 mL) was added HATU (360 mg, 0.95 mmol) and Et3N (0.27 ml, 1.91 mmol). After the mixture was stirred at 25° C. for 20 mins, the product from Step 2 (160 mg, 0.64 mmol) was added. The resulting mixture was stirred at RT for 2 h, then quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (9%-50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 348.2 found, 348.2 required.

A solution of the product from Step 3 (150 mg, 0.43 mmol) in HCl (4 M in MeOH, 5 mL) was stirred at 25° C. for 5 h. The mixture was concentrated in vacuo. The residue was diluted with water (10 mL) and with saturated, aqueous Na2CO3, adjusting to pH ˜9. The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4and filtered. The filtrate was concentrated in vacuo and the residue was purified by prep-TLC (67% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 381.2 found, 381.2 required.

To a solution of the product from Step 4 (60 mg, 0.16 mmol) in THF (3 mL) at 0° C. was added MeMgBr solution (3 M in ether, 0.16 mL, 0.48 mmol). The resulting mixture was stirred at 0° C. for 1 h, then quenched with saturated, aqueous NH4Cl and concentrated in vacuo. The residue was purified by prep-TLC (67% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 381.2 found, 381.2 required.

To a solution of the product from Step 1 (100 mg, 0.71 mmol) in toluene was added ethylamine (33% in EtOH, 106 μL, 0.78 mmol). The resulting mixture was stirred at RT for 5 h and the mixture was used in the next step without work-up. LRMS m/z (M+H) 186.2 found, 186.1 required.

To a solution of 2-(2H-1,2,3-triazol-2-yl)benzoic acid (208 mg, 1.1 mmol) in THF (5 mL) was added HATU (418 mg, 1.1 mmol), DIEA (419 mg, 3.2 mmol), and a solution of the product from Step 2 (0.71 mmol in toluene). The resulting mixture was stirred at RT for 16 h, then diluted with EtOAc (20 mL), washed with saturated, aqueous Na2CO3(20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound as a oil. LRMS m/z (M+H) 357.1 found, 357.1 required.

To a suspension of Hg(OAc)2(160 mg, 0.5 mmol) in water was added a solution of the product from Step 4 (35 mg, 0.097 mmol) in THF (2 mL). The resulting mixture was stirred at RT for 2 h, then aqueous NaOH (0.9 mL, 0.3 mmol) was added, followed by NaBH4(11 mg, 0.3 mmol). The resulting mixture was stirred at RT for 1.5 h, diluted with water (10 mL), and extracted with EtOAc (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound as a oil. LRMS m/z (M+H) 381.2 found, 381.2 required.

To a solution of 2,5-dibromopyrimidine (2.0 g, 8.41 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.56 g, 10.09 mmol), and Pd(dppf)Cl2 (0.31 g, 0.42 mmol) in dioxane (20 mL) and water (2 mL) was added Na2CO3(1.782 g, 16.82 mmol) under N2. The resulting mixture was stirred at 90° C. for 12 h. After cooling to RT, the mixture was diluted with water and extracted with EtOAc (100 mL×3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2-30% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 185.1, 187.1 found, 185.1, 187.1 required.

To a solution of the product from Step 1 (500 mg, 2.70 mmol) in EtOH (5 mL) was added ethanamine (33% in EtOH, 738 mg, 5.40 mmol). The resulting mixture was stirred at 80° C. for 4 h. After cooling to RT, the mixture was concentrated in vacuo to give the title compound as a oil, which was used without further purification. LRMS m/z (M+H) 230.0, 232.0 found, 230.0, 232.0 required.

A solution of the product from Step 2 (711 mg, 3.09 mmol), HATU (1762 mg, 4.63 mmol), DIEA (1.619 ml, 9.27 mmol), and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (701 mg, 3.71 mmol) in DCM (10 mL) was stirred at RT for 3 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (5-50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 401.1, 403.1 found, 401.1, 403.1 required.

To a solution of the product from Step 3 (200 mg, 0.50 mmol), Pd(PPh3)4 (57.6 mg, 0.050 mmol), and potassium trifluoro(prop-1-en-2-yl)borate (111 mg, 0.75 mmol) in toluene (2.0 mL), EtOH (2.0 mL), and water (2.0 mL) was added Na2CO3(106 mg, 1.0 mmol). The resulting mixture was stirred at 80° C. for 12 h under N2. After cooling to RT, the mixture was diluted with water and extracted with EtOAc (30 mL×3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 363.1 found, 363.2 required.

To a mixture of Hg(OAc)2(677 mg, 2.13 mmol) in water (2 mL) was added a solution of the product from Step 4 (220 mg, 0.61 mmol) in THF (2 mL). The resulting mixture was stirred at RT under N2for 3 h, then 0.17 mL of 1 M aqueous NaOH solution and 0.17 mL of 0.5 M NaBH4solution in NaOH (3.0 M) were added respectively. The resulting mixture was stirred at RT for 3 h, then diluted with water and extracted with EtOAc (30 mL×3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (60% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 381.1 found, 381.2 required.

To a solution of 2-chloropyrimidine-4-carbonitrile (900 mg, 6.45 mmol) in dioxane (8 mL)/water (2 mL) was added K2CO3(2.20 g, 16.12 mmol), Pd(dppf)Cl2(1.0 g, 1.29 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.5 g, 9.67 mmol). The resulting mixture was stirred at 90° C. overnight. After cooling to RT, the mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography column (9% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 132.1 found, 132.1 required.

To a solution of the product from Step 1 (380 mg, 2.90 mmol) in EtOH (12 mL) was added ethylamine (33% in EtOH, 435 mg, 3.19 mmol). The resulting mixture was stirred at 80° C. for 2 h. After cooling to RT, the mixture was concentrated in vacuo to give the title compound as a yellow oil, which was used in the next step without further purification. LRMS m/z (M+H) 177.1 found, 177.1 required.

To a solution of the product from Step 2 (460 mg, 2.61 mmol) in DMF (6 mL) was added HATU (993 mg, 2.61 mmol), DIEA (0.456 ml, 2.61 mmol), and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (593 mg, 3.13 mmol). The resulting mixture was stirred at 30° C. for 2 h. After cooling to RT, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 ml×4). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography column (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 348.1 found, 348.2 required.

A solution of the product from Step 3 (150 mg, 0.432 mmol) in HCl (4 M in MeOH, 10 mL, 40 mmol) was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (15 ml×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (EtOAc) to give the title compound as a oil. LRMS m/z (M+H) 381.2 found, 381.2 required.

To a solution of MeMgBr (3 M in ether, 0.351 ml, 1.052 mmol) in THF (2 mL) was added a solution of the product from Step 4 (40 mg, 0.105 mmol) in THF (1 mL) dropwise at −78° C. The resulting mixture was stirred at −78° C. for 2 h, then quenched with saturated, aqueous NH4Cl dropwise at −78° C. The mixture was diluted with water and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (67% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 365.1 found, 365.2 required.

To a solution of the product from Step 5 (30 mg, 0.082 mmol) in MeOH (2 mL) was added NaBH4(9.34 mg, 0.247 mmol). The resulting mixture was stirred at RT for 30 mins, then concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 367.1 found, 367.2 required.

To a mixture of CeCl3(23 mg, 0.092 mmol) in dry THF (3 mL) was added MeMgBr (3 M in ether, 1.0 mL, 3.0 mmol). The resulting mixture was stirred at 70° C. for 1 h. The mixture was cooled at −78° C. and a solution of 2-(2-(N-ethyl-2-(2H-1,2,3-triazol-2-yl)benzamido)ethyl)pyrimidine-4-carboxylate (Example 43, Step 4, 70 mg, 0.184 mmol) in dry THF (2 mL) was added dropwise at −78° C. under N2. The resulting mixture was stirred at −78° C. for 3 h and then quenched with saturated, aqueous NH4Cl, diluted with water, and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (EtOAc) to give the title compound as a oil. LRMS m/z (M+H) 381.2 found, 381.2 required.

To a solution of 2,5-dibromopyrazine (300 mg, 1.261 mmol) in dioxane (2 mL)/water (1 mL) was added Na2CO3(267 mg, 2.52 mmol), Pd(dppf)Cl2(92 mg, 0.126 mmol), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (194 mg, 1.261 mmol) under N2. The resulting brown mixture was stirred at 90° C. overnight, becoming red. After cooling to RT, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (9% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 184.9, 186.9 found, 185.0, 187.0 required.

To a solution of the product from Step 1 (100 mg, 0.540 mmol) in EtOH (10 mL) was added ethanamine (33% in EtOH, 148 mg, 1.081 mmol). The resulting mixture became yellow and was stirred at 80° C. for 4 h. After cooling to RT, the mixture was concentrated in vacuo to give the title compound as a oil which was used in next step without further purification. LRMS m/z (M+H) 230.0, 232.0 found, 230.0, 232.0 required.

To a solution of the product from Step 2 (130 mg, 0.565 mmol) in DCM (6 mL) was added HATU (387 mg, 1.017 mmol), DIEA (0.395 ml, 2.26 mmol), and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (160 mg, 0.847 mmol). The resulting mixture was stirred at RT for 2 h and then quenched with water (15 mL) and extracted with EtOAc (20 mL×4). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 401.0, 403.0 found, 401.1, 403.1 required.

To a solution of the product from Step 3 (100 mg, 0.249 mmol) in MeOH (8 mL) was added Et3N (0.104 ml, 0.748 mmol) and Pd(dppf)Cl2(36.5 mg, 0.050 mmol). The resulting mixture was stirred under 3 MPa of CO at 80° C. overnight. After cooling to RT, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (EtOAc) to give the title compound as a yellow oil. LRMS m/z (M+H) 381.1 found, 381.2 required.

To a mixture of CeCl3(29.4 mg, 0.079 mmol) in dry THF (2 mL) was added MeMgBr (3 M in ether, 1.0 mL, 3.00 mmol). The resulting mixture was stirred at 70° C. for 1 h. The mixture was cooled to −78° C. and a solution of the product from Step 4 (50 mg, 0.131 mmol) in dry THF (2 mL) was added dropwise at −78° C. The resulting mixture was stirred at −78° C. for 3 h, then quenched with saturated, aqueous NH4Cl solution, diluted with water, and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 381.2 found, 381.2 required.

To a solution of 2,5-dibromo-4-methylpyridine (500 mg, 1.99 mmol) in dioxane (5 mL)/water (0.5 mL) was added Na2CO3(423 mg, 3.98 mmol), Pd(dppf)Cl2(77 mg, 0.10 mmol), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (307 mg, 1.99 mmol). The resulting mixture was stirred at 90° C. under N2for 2 h. After cooling to RT, the mixture was diluted with water (10 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (2% EtOAc in petroleum ether) to give the title compound as a solid. LRMS m/z (M+H) 197.9, 199.9 found, 197.9, 199.9 required.

To a solution of the product from Step 1 (250 mg, 1.262 mmol) in EtOH (4 mL) was added ethanamine (33% in EtOH, 517 mg, 3.79 mmol) and Et3N (0.704 mL, 5.05 mmol). The resulting mixture was stirred at 90° C. for 4 h. After cooling to RT, the mixture was concentrated in vacuo to give the crude compound as a oil, which was used in the next step without further purification. LRMS m/z (M+H) 243.1, 245.1 found, 243.0, 245.0 required.

To a solution of the product from Step 3 (100 mg, 0.241 mmol), Na2CO3(51.2 mg, 0.483 mmol), and Pd(PPh3)4(27.9 mg, 0.024 mmol) in toluene (2.0 mL), EtOH (2.0 mL), and water (2.0 mL) was added potassium isopropenyltrifluoroborate (35.7 mg, 0.241 mmol). The resulting mixture was stirred at 80° C. for 12 h. After cooling to RT, the mixture was diluted with water and extracted with EtOAc (30 mL×3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 376.3 found, 376.2 required.

A solution of the product from Step 4 (80 mg, 0.213 mmol) in DCM (5 mL) and MeOH (0.1 mL) was stirred at −78° C. under 03 for 5 minutes until the mixture changed from colorless to blue. The mixture changed to colorless after stirring at −78° C. under O2for 1 min. Dimethylsulfane (0.5 mL) was added to quench the reaction and the mixture was concentrated in vacuo. The residue was purified by prep-TLC (65% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 378.1 found, 378.2 required.

To a solution of MeMgBr (3 M in ether, 0.265 ml, 0.795 mmol) in dry THF (1 mL) was added a solution of the product from Step 5 (60 mg, 0.159 mmol) in dry THF (1 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 1 h, quenched with saturated, aqueous NH4Cl (1 mL), diluted with water (10 mL), and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 394.2 found, 394.2 required.

To a solution of 3-methylpicolinonitrile (2.5 g, 21.16 mmol) in DCM (100 mL) at 25° C. was added 3-chlorobenzoperoxoic acid (4.20 g, 24.34 mmol). The resulting mixture was stirred at RT overnight. The mixture was washed with 10% aqueous NaHSO3 (75 mL) and brine (75 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo and the residue was washed with petroleum ether (50 mL) to give the title compound as a solid. LRMS m/z (M+H) 135.2 found, 135.1 required.

A mixture of the product from Step 1 (1.2 g, 8.95 mmol) in POCl3(29.7 g, 194 mmol) was stirred at reflux for 1 h. The mixture was cooled to RT, poured into 50 mL of water, and basified with saturated, aqueous NaHCO3to pH 7-8, and extracted with EtOAc (100 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound as a solid, which was used in the next step without further purification. LRMS m/z (M+H) 153.1 found, 153.0 required.

To a stirred mixture of the product from Step 2 (200 mg, 1.31 mmol), Pd(Ph3P)4(76 mg, 0.066 mmol), and Na2CO3(278 mg, 2.62 mmol) in toluene (4 mL), EtOH (2 mL), and water (1 mL) was added potassium vinyltrifluoroborate (263 mg, 1.97 mmol) under N2. The resulting mixture was stirred at 90° C. overnight. The mixture was cooled to RT, and then the organic layer was separated. The organic phase was washed with water (5 mL×2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 145.1 found, 145.1 required.

To a solution of the product from Step 3 (100 mg, 0.694 mmol) in EtOH (5 mL) was added ethanamine (33% in EtOH, 0.52 mL, 3.47 mmol). The resulting mixture was stirred in a sealed tube at 80° C. for 4 h. After cooling to RT, the mixture was concentrated in vacuo. The residue was purified by prep-TLC to give the title compound as a oil. LRMS m/z (M+H) 190.2 found, 190.1 required.

A mixture of 2-(2H-1,2,3-triazol-2-yl)benzoic acid (84 mg, 0.446 mmol), HATU (196 mg, 0.515 mmol), and DIEA (0.240 ml, 1.374 mmol) in DMF (2 mL) was stirred at RT for 15 mins. The product from Step 4 (65 mg, 0.343 mmol) was added and the resulting mixture was stirred at RT for 16 h, then quenched with water (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (67% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 361.2 found, 361.1 required.

To a solution of MeMgBr (3 M in ether, 0.842 mL, 2.53 mmol) in dry THF (2 mL) at 0° C. was added a solution of the product from Step 5 (130 mg, 0.361 mmol) in 3 mL of THF dropwise. The resulting mixture was stirred at 0° C. for 3 h, then quenched with 5 mL of water and extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine (2×15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (67% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 378.2 found, 378.2 required.

To a solution of MeMgBr (3 M in diethyl ether, 0.464 mL, 1.391 mmol,) in 2 mL of dry THF at 0° C. was added a solution of the product from Step 6 (70 mg, 0.185 mmol) in 3 mL of dry THF. The resulting mixture was stirred at 0° C. for 2 h, diluted with EtOAc (25 mL), then quenched with water (15 mL). The separated organic phase was washed with brine (15 mL), dried over Na2SO4, filtered, concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound as oil. LRMS m/z (M+H) 394.2 found, 394.2 required.

To a solution of 6-bromonicotinonitrile (4.0 g, 21.8 mmol) in dioxane (40 mL) and water (8 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.04 g, 26.2 mmol), Na2CO3(4.63 g, 43.7 mmol), and Pd(dppf)Cl2(0.80 g, 1.093 mmol) under N2. The resulting mixture was stirred at 80° C. overnight. After cooling to RT, the mixture was filtered and concentrated in vacuo. The residue was diluted with water and extracted with DCM (100 mL×4). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography column (10% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 131.1 found, 131.1 required.

To a solution of the product from Step 1 (1.6 g, 12.3 mmol) in EtOH (30 mL) was added ethylamine (33% in ethanol, 0.665 g, 14.75 mmol) and Et3N (1.714 mL, 12.29 mmol). The resulting mixture was stirred in a sealed tube at 80° C. for 4 h. After cooling to RT, the mixture was concentrated in vacuo to give the crude product as a oil. LRMS m/z (M+H) 176.1 found, 176.1 required.

To a solution of the product from Step 2 (2.8 g, 16.0 mmol) in THF (20 mL) and water (8 mL) was added Na2CO3(3.39 g, 32.0 mmol) and Cbz-Cl (2.74 mL, 19.17 mmol) at 0° C. dropwise. The resulting mixture was stirred at RT overnight. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (30% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 310.1 found, 310.2 required.

To a solution of MeMgBr (3 M in ether, 20.47 mL, 61.4 mmol) in THF (40 mL) was added a solution of the product from Step 3 (3.8 g, 12.28 mmol) at 0° C. dropwise. The resulting mixture was stirred at RT for 1 h, then quenched with saturated, aqueous NH4Cl and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 327.1 found, 327.2 required.

To a solution of MeMgBr (3 M in ether, 2.04 mL, 6.13 mmol) in THF (6 mL) was added a solution of the product from Step 4 (400 mg, 1.226 mmol) at 0° C. dropwise. The resulting mixture was stirred at RT for 2 h. The mixture was quenched with saturated, aqueous NH4Cl and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to give the title compound as a oil. LRMS m/z (M+H) 343.1 found, 343.2 required.

To a solution of the product from Step 5 (1.4 g, 4.09 mmol) in MeOH (30 mL) was added Pd/C (10 wt %, 0.87 g). The resulting mixture was stirred at RT for 1 h under an H2atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a oil. LRMS m/z (M+H) 209.1 found, 209.2 required.

To a solution of 2-(1H-pyrazol-1-yl)nicotinic acid (25.5 mg, 0.135 mmol) in DMF (2 mL) was added HATU (61.6 mg, 0.162 mmol), DIEA (0.094 mL, 0.540 mmol), and the product from Step 6 (30 mg, 0.135 mmol). The resulting mixture was stirred at RT overnight. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound as a solid. LRMS m/z (M+H) 380.2 found, 380.2 required.

The following compounds were prepared according to the general procedure provided in Example 4 and procedures herein. The starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.

The following table shows representative data for the compounds of the Examples as orexin receptor antagonists as determined by the assays described herein.

As indicated by the data herein, the compounds of the present examples provide greater functional selectivity for the orexin-2 receptor over the orexin-1 receptor. The distinction in potency between the orexin-2 receptor and the orexin-1 receptor in the whole cell FLIPR functional assay provides enhanced predictive value for determining in vivo efficacy. Increasing the functional selectivity for the orexin-2 receptor reduces the potential for dual receptor antagonism in vivo. Such greater functional selectivity may provide benefits over other orexin receptor antagonists that are known in the art.

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention.