MODULATORS

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 61/780,302, filed March 13, 2013, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The present invention is directed to substituted piperidine compounds, pharmaceutical compositions comprising them, methods of making them, and methods of using them for the modulation of the orexin receptor for the treatment of disease states, disorders, and conditions mediated by orexin receptor activity.

BACKGROUND

Orexin/hypocretin signaling is mediated by two receptors and two peptide agonists. The peptides (orexin-A and orexin-B) are cleavage products of the same gene, pre-pro orexin. In the central nervous system, neurons producing pre-pro orexin are found solely in the perifornical nucleus, the dorsal hypothalamus, and the lateral hypothalamus (Peyron et al, 1998, J. Neurosci. 18: 9996-10015). Orexigenic cells in these regions project to many areas of the brain, extending rostrally to the olfactory bulbs and caudally to the spinal cord (Van den Pol, 1999, J. Neurosci. 19: 3171-3182).

The orexins bind to two high affinity receptors, referred to as orexin-1 and orexin-2 receptors. Orexin-1 and orexin-2 receptors are G-protein-coupled, seven transmembrane receptors that share over 64% amino acid sequence identity with one another. Both receptors are generally excitatory, the common cellular response to orexin-induced receptor activation being increases in intracellular calcium. Homology between the species orthologs is high and there are no known pharmacological differences. Orexin-A and -B are usually considered equal ligands for orexin-2 receptor but orexin-B is reported to be 5- to 100-fold weaker ligand than orexin-A at the orexin-1 receptor (Sakurai et al, 1998, Cell 92: 573-585; Ammoun et al, 2003, J.

Pharmacol. Exp. Ther. 305: 507-514).

Many regions of the brain have fairly selective expression of the orexin-1 or orexin-2 receptors (Marcus et al, 2001, J. Comp Neurology 435, 6-25; Trivedi et al, 1998, FEBS Letters, 438, 71-75). Orexin-1 receptors are relatively selective for the limbic system (bed nucleus of the stria terminalis and amygdala), cingulate cortex and noradrenergic neurons in the locus coeruleus. Conversely, the orexin-2 receptor is almost the exclusive orexin receptor in the histaminergic neurons in the tuberomammilary nucleus which play a critical role in wake promotion; in paraventricular neurons and the parabrachial nucleus. In other brain regions like the dorsal raphe, the ventral tegmental area or the prefontal cortex both receptors are coexpressed.

The broad CNS distribution of cells producing orexin, as well as cells expressing the orexin receptors, suggests involvement of orexin in a number of physiological functions, including feeding and metabolism, regulation of wakefulness and sleep, sympathetic activation and stress response (de Lecea, 2012, Progress in Brain Research, 198, 15-24; Kukkonen, 2013, Am J. Physiol. Cell Physiol, 304, C2-C32). Orexin also plays a key role regulating motivation and reward associated with food intake and with drugs of abuse (Mahler et al., 2012, Progress in Brain Research, 198, 79-121).

Several lines of evidence indicate that the orexin system is an important modulator of arousal. Rodents administered orexin intracerebroventricularly spend more time awake (Piper et al, 2000, J. Neurosci. 12: 726-730. Orexin-mediated effects on arousal have been linked to orexin neuronal projections to histaminergic neurons in the tuberomammillary nucleus

(Yamanaka et al, 2002, Biochem. Biophys. Res. Comm. 290: 1237-1245). Rodents whose pre- pro orexin gene has been knocked out, or whose orexigenic neurons have been killed, display altered sleep/wake cycles similar to narcolepsy (Chemelli et al, 1999, Cell 98: 437-451; Hara et al, 2001, Neuron 30: 345-354). Dog models of narcolepsy have been shown to have mutant or non-functional orexin-2 receptors (Lin et al, 1999, Cell 98: 365-376). Orexin signaling as a target for sleep-promoting therapies was further validated clinically by findings of attenuated orexin levels and loss of orexinergic neurons in human narcoleptic patients (Mignot et al, 2001, Am. J. Hum. Genet. 68: 686-699; Minot & Thorsby, 2001, New England J. Med. 344: 692) (Peyron et al, 2000, Nature Med. 6: 991-997). Disorders of the sleep-wake cycle are therefore likely targets for orexin-2 receptor modulator activity. Examples of sleep-wake disorders that may be treated by agonists or other modulators that up-regulate orexin-2 receptor-mediated processes include narcolepsy, jet lag (sleepiness) and sleep disorders secondary to neurological disorders such as depression. Examples of disorders that may be treated by antagonists or other modulators that down-regulate orexin-2 receptor-mediated processes include insomnia, restless leg syndrome, jet lag (wakefulness) and sleep disorders secondary to neurological disorders such as mania, schizophrenia, pain syndromes and the like.

Evidence has accumulated to demonstrate a clear involvement of orexin signaling in reward pathways associated with drug dependence (Mahler et al, 2012, Progress in Brain Research, 198, 79-121). Orexinergic neurons send projections to the ventral tegmental area and other brain regions involved in reward processing. Orexin ligands mediate reward behavior, and antagonizing these effects with a selective orexin- 1 receptor antagonist in various preclinical model of addiction has suggested that these actions are mediated through orexin- 1 receptor. Specifically, a selective orexin- 1 antagonist attenuates morphine conditioned place preference and reinstatement (Harris et al, 2005, Nature, 437, 556-5599; Narita et al, 2006, J Neurosci..26. 398-405; Harris et al, 2007, Behav Brain Res, 183. 43-51), stress-induced cocaine reinstatement, cocaine-induced behavioral and synaptic plasticity (Borgland et al, 2006, Neuron, 49, 589-601), and intake and cue and stress-induced reinstatement of ethanol (Lawrence et al, 2006, Br J Pharmacol, 148, 752-759), in addition to attenuating precipitated morphine withdrawal (Sharf et al, 2008, Biol Psychiatry, 64, 175-183) and nicotine self-administration (Hollander et al, 2008, Proc Natl Acad Sci USA., 105, 19480-19485). Another recent study has also suggested a role for the orexin-2 receptor (Shoblock et al, 2011, Psychopharmacology, 215, 191-203).

Orexin's role in more complex emotional behavior is also emerging (Johnson et al, 2012, Progress in Brain Research, 198. 133-161). Changes in orexin levels in patients with panic and posttraumatic stress disorders have been noted (Johnson et al, 2010, Nature Medicine, 16, 111- 115; Fortuyn et al, 2010, General Hospital Psychiatry, 32, 49-56; Strawn et al, 2010,

Psychoneuroendocrinology, 35, 1001-1007). Lactate infusion or acute hypercapnia , which causes panic in humans, and are used as an animal model of panic, activates orexin neurons in the perifornical hypothalamus. This activation correlates with anxiety in the social interaction test or open field test. Blocking orexin signaling with either siRNA or selective orexin- 1 receptor antagonists attenuates panic-like responses to lactate (Johnson et al, 2010, Nature Medicine, 16, 111-115; Johnson et al, 2012, Neuropsychopharmacology, 37, 1911, 1922).

Cerebral spinal fluid (CSF) levels of orexin are lower in depressed or suicidal patients, and the level of orexin inversely correlates with illness severity (Brundin et al, 2007, European Neuropsychopharmacology, 17, 573-579; Salomon et al, 2003, Biol Psychiatry, 54. 96-104). A positive correlation between orexin- 1 receptor mRNA in the amygdala and depressive behavior in the forced swim test in mice has been reported (Arendt, 2013, Behavioral Neuroscience, 127, 86-94).

The orexin system also interacts with brain dopamine systems. Intracerebroventricular injections of orexin in mice increase locomotor activity, grooming and stereotypy; these behavioral effects are reversed by administration of D2 dopamine receptor antagonists

(Nakamura et al, 2000, Brain Res. 873: 181-187). Therefore, orexin receptor modulators may be useful to treat various neurological disorders; e.g., agonists or up-regulators to treat catatonia, antagonists or down-regulators to treat Parkinson's disease, Tourette's syndrome, anxiety, delerium and dementias.

Orexins and their receptors have been found in both the myenteric and submucosal plexus of the enteric nervous system, where orexins have been shown to increase motility in vitro (Kirchgessner & Liu, 1999, Neuron 24: 941-951) and to stimulate gastric acid secretion in vitro (Takahashi et al, 1999, Biochem. Biophys. Res. Comm. 254: 623-627). Orexin effects on the gut may be driven by a projection via the vagus nerve (van den Pol, 1999, supra), as vagotomy or atropine prevent the effect of an intracerebroventricular injection of orexin on gastric acid secretion (Takahashi et al, 1999, supra). Orexin receptor antagonists or other down-regulators of orexin receptor-mediated systems are therefore potential treatments for ulcers, irritable bowel syndrome, diarrhea and gastroesophageal reflux.

Body weight may also be affected by orexin-mediated regulation of appetite and metabolism. Some effects of orexin on metabolism and appetite may be mediated in the gut, where, as mentioned, orexins alter gastric motility and gastric acid secretion. Orexin antagonists therefore are likely to be useful in treatment of overweight or obesity and conditions related to overweight or obesity, such as insulin resistance/type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins and osteoarthritis. Conversely, orexin agonists are likely to be useful in treatment of underweight and related conditions such as hypotension, bradycardia, ammenorrhea and related infertility, and eating disorders such as anorexia and bulimia.

Intracerebroventricularly administered orexins have been shown to increase mean arterial pressure and heart rate in freely moving (awake) animals (Samson et al, 1999, Brain Res. 831 : 248-253; Shirasaka et al, 1999, Am. J. Physiol. 277: R1780-R1785) and in urethane-anesthetized animals (Chen et al, 2000, Am. J. Physiol. 278: R692-R697), with similar results. Orexin receptor agonists may therefore be candidates for treatment of hypotension, bradycardia and heart failure related thereto, while orexin receptor antagonists may be useful for treatment of hypertension, tachycardia and other arrhythmias, angina pectoris and acute heart failure.

From the foregoing discussion, it can be seen that the identification of orexin receptor modulators, will be of great advantage in the development of therapeutic agents for the treatment of a wide variety of disorders that are mediated through these receptor systems..

SUMMARY

The present invention is directed to compounds of Formula I:

wherein X is CRi or N; Y is CR ₂ or N; Z is NH, N-CH ₃ , or O; Ri is H, alkoxy, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or pyrimidinyl, wherein triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or pyrimidinyl is optionally substituted with up to two substituents selected from halo and alkyl; R2 is H, alkyl, or halo; R3 is H, alkyl, alkoxy, halo, triazolyl, oxazolyl, or pyrimidinyl, wherein triazolyl, oxazolyl, or pyrimidinyl are optionally substituted with up to two substituents selected from halo and alkyl; R4 is alkyl; R ₅ is pyridyl; benzoxazolyl; pyrimidinyl; pyridazinyl; quinoxalinyl; pyrazinyl; thiadiazolyl; or quinazolinyl; wherein the pyridyl;

benzoxazolyl; pyrimidinyl; pyridazinyl; thiadiazolyl, quinoxalinyl; pyrazinyl; or quinazolinyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, and phenyl; and R6 is H or alkyl. Enantiomers and diastereomers of the compounds of Formula I are also described, as well as the pharmaceutically acceptable salts.

Methods of making the compounds of Formula I are also described. The invention also relates to pharmaceutical compositions comprising therapeutically effective amounts of compounds of Formula I. Methods of using the compounds of the invention are also within the scope of the invention.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 depicts a Powder X-Ray Diffraction (PXRD) pattern for for one embodiment of the invention, Example 108.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The invention may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples.

The term "alkyl" refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. In some embodiments, an alkyl group is a Ci-Ce alkyl group. In some embodiments, an alkyl group is a C1-C4 alkyl group. Examples of alkyl groups include methyl (Me) ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec -butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Alkyl groups of the invention can be substituted with, for example, halogen atoms. One exemplary substitutent is fluoro. Preferred substituted alkyl groups of the invention include trihalogenated alkyl groups such as trifluoromethyl groups.

Alkyl groups of the invention can also refer to "cycloalkyl" moieties. Cycloalkyl refers to monocyclic, non-aromatic hydrocarbon groups having from 3 to 7 carbon atoms. Examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1- methylcyclopropyl, 2-methylcyclopentyl, and the like.

The term "alkoxy" includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. In some embodiments, an alkoxy group is a Ci-Ce alkoxy group. In some embodiments, an alkoxy group is a C ₁ -C ₄ alkoxy group. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.

oxazolyl" represents the following moiety:

The benoxazolyl moiety can be attached through any one of the 2-, 4-, 5-, 6-, or 7-position carbon atoms.

The term "halogen" represents chlorine, fluorine, bromine, or iodine. The term "halo" represents chloro, fluoro, bromo, or iodo.

The term "isoxazolyl" represents the following moiety:

The isoxazolyl moiety can be attached through any one of the 3-, 4-, or 5-position carbon atoms. Isoxazolyl groups of the invention can be optionally substituted with, for example, one or two alkyl groups, for example, one or two methyl groups.

"oxazolyl" represents the following moiety:

The oxazolyl moiety can be attached through any one of the carbon atoms.

The term "oxadiazolyl" represents a 1 ,2,3-oxadiazole, 1 ,2,4-oxadiazole, 1 ,2,5-oxadiazole, or 1,3,4-oxadiazole moiety: The oxadiazolyl moieties can be attached through any one of the carbon or nitrogen atoms. Within the scope of the invention, "oxadiazolyl" groups can be substituted with an alkyl group, preferably a methyl group.

m "phenyl" represents the following moiety: and may be substituted with for example, alkyl or halo groups.

The term "pyridyl" represents the following moiety:

The pyridyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, or 6-position carbon atoms and may be substituted with for example, alkyl or halo groups, for example methyl or trifluoromethyl or fluorine.

"pyrimidinyl" represents the following moiety:

The pyrimidinyl moiety can be attached through any one of the 2-, 4-, 5-, or 6-position carbon atoms. Within the scope of the invention, "pyrimidinyl" groups of the invention can be substituted with halogen, for example fluoro.

The term "pyrazinyl" represents the following moiety:

The pyrazinyl moiety can be attached through any one of the 2-, 3-, 5-, or 6-position carbon atoms and may be substituted with for example, alkyl or halo groups, for example methyl or trifluoromethyl or fluorine.

The term "pyridazinyl" represents the following moiety:

4 The pyridazinyl moiety can be attached through any one of the 3-, 4-, 5-, or 6-position carbon atoms and may be substituted with for example, alkyl or halo groups, for example methyl or trifluoromethyl or fluorine.

The term "pyrazolyl" represents the following moiety:

The pyrazolyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, or 5-position carbon atoms. Pyrazolyl groups of the invention can be optionally substituted with, for example, one or two alkyl groups, for example, one or two methyl groups.

The term "quinoxalinyl" represents the following moiety:

The quinoxalinyl moiety can be attached through any one of the 2-, 3-, 5-, 6-, 7-, or 8-position carbon atoms and may be substituted with for example, alkyl or halo groups, for example methyl or trifluoromethyl or fluorine.

olinyl" represents the following moiety:

3

The quinoxalinyl moiety can be attached through any one of the 2-, 4-, 5-, 6-, 7-, or 8-position carbon atoms and may be substituted with for example, alkyl or halo groups, for example methyl or trifluoromethyl or fluorine.

The term "triazolyl" represents a 1,2,3-triazole or a 1,2,4-triazole moiety:

The triazolyl moieties can be attached through any one of their atoms.

The term "thiadiazolyl" represents a 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5- thiadiazole, or 1,3,4-thiadiazole moiety: The thiadiazolyl moieties can be attached through any one of the carbon or nitrogen atoms. Within the scope of the invention, "thiadiazolyl" groups can be substituted with an alkyl group, preferably a methyl group.

"Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,

ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2 -hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as

hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

"Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

"Subject" includes humans. The terms "human," "patient," and "subject" are used interchangeably herein.

"Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

In treatment methods according to the invention, a therapeutically effective amountof a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. A "therapeutically effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.

"Compounds of the present invention," and equivalent expressions, are meant to embrace compounds of the Formula (I) as described herein, which expression includes the

pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits.

Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound can be radiolabeled, that is, contain one or more nonradioactive isotopes, such as for example, deuterium ( ² H or D), carbon- 13 ( ¹³ C), nitrogen- 15 ( ¹⁵ N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be ² H/D, any carbon may be ¹³ C, or any nitrogen may be ¹⁵ N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.

Radiolabeled compounds of the invention can be used in diagnostic methods such as Single- photon emission computed tomography (SPECT). The radioactive isotopes tritium, i.e. ³ H, and carbon- 14, i.e. ¹⁴ C, are particularly useful for their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting

11 18 15 13

isotopes, such as C, F, O and N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds of the invention, radioactive or not, are intended to be encompassed within the scope of the invention.

It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture."

"Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci-and nitro-forms of phenyl nitromethane, that are likewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)-or (^-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

The present invention is directed to compounds of Formula I:

wherein

X is CRi or ;

Y is CR ₂ or ;

Z is NH, N-CH ₃ , or O;

Ri is H, alkoxy, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or pyrimidinyl, wherein triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or pyrimidinyl is optionally substituted with up to two substituents selected from halo and alkyl;

R2 is H, alkyl, or halo;

R3 is H, alkyl, alkoxy, halo, triazolyl, oxazolyl, or pyrimidinyl, wherein triazolyl, oxazolyl, or pyrimidinyl is optionally substituted with up to two substituents selected from halo and alkyl;

R4 is alkyl;

R5 is pyridyl; benzoxazolyl; pyrimidinyl; pyridazinyl; quinoxalinyl; pyrazinyl;

thiadiazolyl; or quinazolinyl;

wherein the pyridyl; benzoxazolyl; pyrimidinyl; pyridazinyl; quinoxalinyl; pyrazinyl; or quinazolinyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, or phenyl; and

¾ is H or alkyl.

In one aspect, the invention is directed to compounds of Formula I:

wherein

X is CRi or ;

Y is CR ₂ or ;

Z is NH or O;

Ri is alkoxy, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or pyrimidinyl;

R2 is H, alkyl, or halo;

R3 is H, alkyl, alkoxy, halo, triazolyl, oxazolyl, or pyrimidinyl;

R4 is alkyl;

R5 is pyridyl; benzoxazolyl; pyrimidinyl; pyridazinyl; quinoxalinyl; pyrazinyl; or

quinazolinyl;

wherein the pyridyl; benzoxazolyl; pyrimidinyl; pyridazinyl; quinoxalinyl; pyrazinyl; or quinazolinyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, or phenyl; and

R6 is H or alkyl.

Enantiomers and diastereomers of the compounds of Formula I are also within the scope of the invention. Also within the scope of the invention are the pharmaceutically acceptable salts of the compounds of Formula I, as well as the pharmaceutically acceptable salts of the enantiomers and diastereomers of the compounds of Formula I. Also within the scope of the invention are isotopic variants of compounds of Formula I, such as, for example, deuterated compounds of Formula I.

In preferred embodiments of the invention, Z is NH. In other preferred embodiments of the invention, Z is O. In some embodiments, Z is N-CH ₃ . Preferably, in the compounds of the invention, R4 is an alkyl group containing from 1 to 6 carbon atoms (Ci_ ₆ alkyl). Examples of preferred alkyl groups for R4 include methyl, ethyl, and propyl. In exemplary embodiments of the invention, R4 is methyl.

In some embodiments of the invention, X is CRi and Y is CR2.

In other embodiments of the invention, X is N and Y is CR2.

In still other embodiments, X is CRi and Y is N.

In yet other embodiments, X and Y are each N.

In those embodiments of the invention wherein X is CRi, for example, those

embodiments wherein X is CRi and Y is CR2 or X is CRi and Y is N, Ri is alkoxy, preferably methoxy, ethoxy, or propoxy.

In those embodiments of the invention wherein X is CRi, for example, those

embodiments wherein X is CRi and Y is CR2 or X is CRi and Y is N, Ri is triazolyl, with 1,2,3- triazolyl being preferred. In preferred embodiments, the 1,2,3-triazolyl is attached through the 2- position nitrogen atom. In other embodiments, the 1,2,3-triazolyl is attached through the 1- position nitrogen atom. In some embodiments, Ri is triazolyl optionally substituted with up to two substituents selected from halo and alkyl.

In those embodiments of the invention wherein X is CRi, for example, those

embodiments wherein X is CRi and Y is CR2 or X is CRi and Y is N, Ri is oxazolyl, which can be attached through any available atom, preferably attached through the 2-position carbon. In some embodiments, Ri is oxazolyl optionally substituted with up to two substituents selected from halo and alkyl.

In those embodiments of the invention wherein X is CRi, for example, those

embodiments wherein X is CRi and Y is CR2 or X is CRi and Y is N, Ri is isoxazolyl, which can be attached through any available atom. In some embodiments, Ri is isoxazolyl optionally substituted with up to two substituents selected from halo and alkyl.

In those embodiments of the invention wherein X is CRi, for example, those

embodiments wherein X is CRi and Y is CR2 or X is CRi and Y is N, Ri is oxadiazolyl, preferably 1,2,4-oxadiazolyl attached through the 5-position carbon, although any oxadiazolyl, attached through any available carbon, is within the scope of the invention. In some

embodiments, Ri is oxadiazolyl optionally substituted with up to two substituents selected from halo and alkyl.The oxadiazolyl group can optionally be substituted with Ci- ₆ alkyl, for example methyl. In exemplary embodiments, the substituted oxadiazolyl moiety is 1,2,4-oxadiazolyl substituted with methyl. In those embodiments of the invention wherein X is CRi, for example, those

embodiments wherein X is CRi and Y is CR2 or X is CRi and Y is N, Ri is pyrimidinyl, which can be attached through any available atom. In some embodiments, Ri is pyrimidinyl optionally substituted with up to two substituents selected from halo and alkyl. The pyrimidinyl can be optionally substituted with, for example, halogen such as fluoro. Preferably, the pyrimidinyl moiety is attached through the 2-position carbon.

In preferred embodiments of the invention wherein Y is CR2, for example, those embodiments wherein X is CRi and Y is CR2 or X is N and Y is CR2, R2 is H.

In some embodiments of the invention wherein Y is CR2, for example, those

embodiments wherein X is CRi and Y is CR2 or X is N and Y is CR2, R2 is halo, preferably F, CI, or Br, with F being more preferred.

In those embodiments of the invention wherein Y is CR2, for example, those

embodiments wherein X is CRi and Y is CR2 or X is N and Y is CR2, R2 is alkyl. Preferably, the alkyl group has from one to six carbon atoms (Ci_ ₆ alkyl). In exemplary embodiments, R2 is methyl.

In some embodiments of the invention, R ₃ is H. In other embodiments, R ₃ is alkyl, preferably methyl. In some embodiments, the alkyl group can be substituted with, for example, one or more halogen atoms. One exemplary substituted alkyl group is trifluoromethyl.

In yet other embodiments, R ₃ is alkoxy, preferably methoxy or ethoxy. In still other embodiments, R ₃ is halo, preferably F, Br, or CI, with F and Br being more preferred.

In other exemplary embodiments of the invention, R3 is triazolyl, with 1,2,3-triazolyl being preferred. In some embodiments, the 1,2,3-triazolyl is attached through the 2-position nitrogen atom. In other embodiments, the 1,2,3-triazolyl is attached through the 1 -position nitrogen atom.

In still other embodiments of the invention, R ₃ is oxazolyl, which can be attached through any available atom, preferably attached through the 2-position carbon.

In yet other embodiments, R ₃ is pyrimidinyl, which can be attached through any available atom. The pyrimidinyl can be optionally substituted with, for example, halogen such as fluoro. Preferably, the pyrimidinyl moiety is attached through the 2-position carbon.

In some embodiments of the invention, R ₅ is pyridyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, or phenyl. The pyridyl can be attached through any one of the 2-, 3-, or 4-position carbon atoms. In those embodiments where the pyridyl is substituted, the subsitutents are independently selected from alkyl, for example methyl, substituted alkyl, for example, trihaloalkyl such as trifluoromethyl, and halo such as F, Br, and CI.

In some embodiments of the invention, R5 is benzoxazolyl, which can be attached through any available atom, and which can be optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, or phenyl. In those

embodiments where the benzoxazolyl is substituted, the subsitutents are independently selected from alkyl, for example methyl, substituted alkyl, for example, trihaloalkyl such as

trifluoromethyl, and halo such as F, Br, and CI.

In some embodiments of the invention, R5 is pyrimidinyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, or phenyl.

The pyrimidinyl can be attached through any one of the 2-, 4-, or 5-position carbon atoms. In those embodiments where the pyrimidinyl is substituted, the subsitutents are independently selected from alkyl, for example methyl, substituted alkyl, for example trihaloalkyl such as trifluoromethyl, and halo such as F, Br, and CI.

In some embodiments of the invention, R5 is pyridazinyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, or phenyl.

The pyridazinyl can be attached through any one of the 3- or 4-position carbon atoms. In those embodiments where the pyridazinyl is substituted, the subsitutents are independently selected from alkyl, for example methyl, substituted alkyl, for example trihaloalkyl such as

trifluoromethyl, and halo such as F, Br, and CI.

In some embodiments of the invention, R ₅ is quinoxalinyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, or phenyl.

The quinoxalinyl can be attached through any one of the 2-, 3-, 5-, or 6-position carbon atoms.

In those embodiments where the quinoxalinyl is substituted, the subsitutents are independently selected from alkyl, for example methyl, substituted alkyl, for example trihaloalkyl such as trifluoromethyl, and halo such as F, Br, and CI.

In some embodiments of the invention, R5 is pyrazinyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, or phenyl. The pyrazinyl can be attached through any one of the 2- or 3 -position carbon atoms. In those embodiments where the pyrazinyl is substituted, the subsitutents are independently selected from alkyl, for example methyl, substituted alkyl, for example trihaloalkyl such as trifluoromethyl, and halo such as F, Br, and CI.

In some embodiments of the invention, R5 is quinazolinyl, optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, or phenyl. The quinazolinyl can be attached through any one of the 2-, 4-, 5-, 6-, 7-, or 8-position carbon atoms. In those embodiments where the quinazolinyl is substituted, the subsitutents are independently selected from alkyl, for example methyl, substituted alkyl, for example trihaloalkyl such as trifluoromethyl, and halo such as F, Br, and CI.

In preferred embodiments of the invention, Re is H. In other embodiments of the invention, Re is alkyl, preferably methyl.

In some embodiments of Formula I, Ri is H and R3 is as defined above for Formula I, preferably R3 is triazolyl, oxazolyl, pyridyl or pyrimidinyl. In other embodiments of Formula I, R3 is H and Ri is as defined above for Formula I, preferably Ri is triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, or pyrimidinyl.

In some embodiments of Formula I, the group is a pyridyl group, preferably X is N, R3 is a ring selected from triazolyl, oxazolyl, or pyrimidinyl; preferably triazolyl, preferably at the ortho position; Re is H or alkyl, preferably methyl; Z is NH or O, preferably O; R5 is a heteroaryl, preferably pyridyl or pyrazinyl. In some of such embodiments, R3 is a ring at the ortho position relative to the carbonyl group in Formula I, and R6 is at the ortho, meta or para position on the relative to the carbonyl group in Formula I, preferably R6 is at the meta position adjacent to R3. In some other such embodiments, R3 is a ring at the ortho position relative to the carbonyl group in Formula I, and R6 is at the ortho, meta or para position relative to the carbonyl group in Formula I, preferably R6 is at the meta position not adjacent to R3. R3 and R5 may be optionally substituted as described above.

In some embodiments of Formula I, the group is a pyridyl group, preferably Y is

N, R3 is H, Ri is a ring selected from triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or pyrimidinyl; preferably triazolyl; R6 is H or alkyl, preferably methyl; Z is NH or O, preferably O; R5 is a heteroaryl, preferably pyridyl or pyrazinyl. In some of such embodiments, R3 is a ring at the ortho position relative to the carbonyl group in Formula I, and R6 is at the ortho, meta or para position on the relative to the carbonyl group in Formula I, preferably Re is at the meta position adjacent to Ri. In some other such embodiments, Ri is a ring at the ortho position relative to the carbonyl group in Formula I, and R6 is at the ortho, meta or para position relative to the carbonyl group in Formula I, preferably R6 is at the meta position not adjacent to Ri. R _1; R3 and R5 may be optionally substituted as described above In some embodiments of Formula I, the group is a phenyl group, Ri is H,

R ₃ is a ring selected from triazolyl, oxazolyl, or pyrimidinyl; preferably triazolyl; R6 is H or alkyl, preferably methyl; Z is NH or O, preferably O; R5 is a heteroaryl, preferably pyridyl or pyrazinyl. In some of such embodiments, R ₃ is a ring at the ortho position relative to the carbonyl group in Formula I, and R6 is at the ortho, meta or para position on the relative to the carbonyl group in Formula I, preferably R6 is at the meta position adjacent to R ₃ . In some other such embodiments, R ₃ is a ring at the ortho position relative to the carbonyl group in Formula I, and R6 is at the ortho, meta or para position relative to the carbonyl group in Formula I, preferably R6 is at the meta position not adjacent to R ₃ . R ₃ and R5 may be optionally substituted as described above.

In another aspect provided herein is a compound of Formula IA:

I

wherein

ring A is a heteroaryl ring;

Z is NH, N-CH ₃ , or O;

Ri is H, alkoxy, phenyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or pyrimidinyl, wherein triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or pyrimidinyl is optionally substituted with up to two substituents selected from halo and alkyl; R ₂ is H, alkyl, or halo;

R3 is H, alkyl, alkoxy, halo, triazolyl, oxazolyl, or pyrimidinyl, wherein triazolyl, oxazolyl, or pyrimidinyl is optionally substituted with up to two substituents selected from halo and alkyl;

R4 is alkyl;

R5 is pyridyl; benzoxazolyl; pyrimidinyl; pyridazinyl; quinoxalinyl; pyrazinyl;

thiadiazolyl; or quinazolinyl;

wherein the pyridyl; benzoxazolyl; pyrimidinyl; pyridazinyl; quinoxalinyl; pyrazinyl; or quinazolinyl is optionally substituted with one or two substituents independently selected from the group consisting of alkyl, halo, or phenyl; and

¾ is H or alkyl.

In some embodiments of Formula IA, ring A is a 5-membered heteroaryl ring. In other embodiments of Formula IA, ring A is a pyrazinyl ring. All the embodiments described above for Formula I with respect to the variables Ri, R ₂ , R3, R4, R5, R6, and Z are also applicable to compounds of Formula IA and are expressly contemplated herein.

The invention relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by orexin receptor activity. These methods are accomplished by administering to the subject a compound of the invention. In some embodiments, the compounds described herein are selective for orexin-1 receptor activity. In some embodiments, the compounds described herein are selective for orexin- 1 receptor activity over orexin-2 receptor activity.

Diseases, disorders, and conditions mediated by orexin receptor activity include disorders of the sleep-wake cycle, insomnia, restless legs syndrome, jet-lag, disturbed sleep, sleep disorders secondary to neurological disorders, mania, depression, manic depression,

schizophrenia, pain syndromes, fibromyalgia, neuropathic pain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight, obesity, or conditions related to overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, hypertension, tachycardia, arrhythmias, angina pectoris, acute heart failure, ulcers, irritable bowel syndrome, diarrhea gastroesophageal reflux, mood disorders, posttraumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse.

In one aspect, compounds of the invention are particularly suited for the treatment of mood disorders. Non-limiting examples of mood disorders include anxiety-related mood disorders, depression, panic -related mood disorders, stress related mood disorders and the like. In another aspect, compounds of the invention are suitable for the treatment of post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse (e.g., morphine abuse, cocaine abuse, alcohol abuse and the like). It will be understood that certain disorders such as, for example, depression and/or schizophrenia and/or substance abuse and/or cognitive impairments also have elements of anxiety and/or panic and/or stress associated with them and the treatment of such conditions and/or combinations of conditions are also contemplated within the scope of embodiments presented herein. In some embodiments, advantageously, compounds of the invention treat a mood disorder (e.g., anxiety) with reduced concomitant sedation and/or with reduced effect on sleep (e.g. attenuated arousal effects). In one embodiment, compounds of the invention are particularly suited for the treatment of anxious depression. In another embodiment, compounds of the invention are particularly suited for the treatment of panic, schizophrenia, and substance abuse.

Sleep disorders include, but are not limited to, sleep-wake transition disorders, insomnia, restless legs syndrome, jet-lag, disturbed sleep, and sleep disorders secondary to neurological disorders (e.g., manias, depressions, manic depression, schizophrenia, and pain syndromes (e.g., fibromyalgia, neuropathic).

Metabolic disorders include, but are not limited to, overweight or obesity and conditions related to overweight or obesity, such as insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins and osteoarthritis.

Neurological disorders include, but are not limited to, Parkinson's disease, Alzheimer's disease, Tourette's Syndrome, catatonia, anxiety, delirium and dementias.

In treatment methods according to the invention, a therapeutically effective amount of a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. A "therapeutically effective amount" means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g.,

BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.

Once improvement of the patient's disease, disorder, or condition has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

In addition, the compounds of the invention may be used in combination with additional active ingredients in the treatment of the above conditions. The additional active ingredients may be coadministered separately with a compound of the invention or included with such an agent in a pharmaceutical composition according to the invention. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by orexin activity, such as another orexin modulator or a compound active against another target associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.

The compounds of the invention are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the invention. A pharmaceutical composition of the invention comprises: (a) an effective amount of at least one compound in accordance with the invention; and (b) a pharmaceutically acceptable excipient.

Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration.

For oral administration, the compounds of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. For example, a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day. Oral tablets may include a compound according to the invention mixed with

pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the invention may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the compound of the invention with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain:

pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

The active agents of this invention may also be administered by non-oral routes. For example, the compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses may range from about 1 to 1000 .mu.g/kg/minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the compounds of the invention may utilize a patch formulation to affect transdermal delivery.

Compounds of the invention may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (I). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0 °C and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent.

Schemes 1-6 below and the Examples section below (Intermediates Al - A-39) provide synthesis of certain exemplary intermediates having the structure where LG is CI, OH or OC(0)Alk.

Scheme 1

(A) (lla) (Mb)

(Ilia) (1Mb)

Intermediate compounds of formulas (Ilia) and (Illb) are prepared, as outlined in Scheme 1 , from commercially available or synthetically accessible compounds of formula (A). X and Y are as defined in Formula I above. Compounds of formulas (Ha) and (lib), are obtained by reacting a compound of formula (A), where I¾A is -H, -alkyl,or -alkoxy, with commercially available 1 ,2,3-triazole, in the presence of, for example, K2CO ₃ in DMF or dioxane, at temperatures ranging from about 60 °C to about 100 °C. Compounds of formulas (Ilia) and (Illb) are obtained by reacting compounds of formula (II) in the presence of a base such as NaOH in a solvent such as EtOH at temperatures ranging from about 80 °C to about 100 °C. One skilled in the art will recognize that 1,2,3-triazole can exist in two tautomeric forms defined as 2H-[ l ,2,3]triazole and lH-[ l,2,3]triazole thus accounting for the formation of (Ilia) and (Illb).

Scheme 2

(IVa) W is CN (Va) W is CN

(IVb) W is C0 ₂ Alkyl (Vb) W is C0 ₂ Alkyl 0")

(IVc) W is C0 ₂ H (lll) W is C0 ₂ H

Intermediate compounds of formula (III) can be prepared, as outlined in Scheme 2, from commercially available or synthetically accessible compounds of formula (IV _a - _c ). Compounds of formulas (Va), (Vb) and (III) are obtained by reacting compounds of formula (IVa), (IVb) and (IVc) where Hal is -Br, or -I; W is C0 ₂ H, C0 ₂ Alkyl, or CN and R _3A and R4A are -H, halo, -Ci_ ₄ alkyl, -Ci_ ₄ alkoxy or R ₃ A and R4A, together with the atoms to which they are attached, form a 6- membered aryl or 6-membered heteroaryl ring, with commercially available 1,2,3-triazole, in the presence of, for example, copper(I)iodide, CS2CO ₃ and trans-Ν,Ν' -dimethyl- 1,2- cyclohexanediamine in for example, DMF or 1,4-dioxane, at temperatures ranging from about 60 °C to about 120 °C. Compounds of formula (IVc) can be converted to the corresponding esters (Vb) by treatment with, for example, alkyl iodide in the presence of a base such as K2CO ₃ in a solvent such as DMF. Compounds of formula (III) are also obtained by reacting compounds of formula (Va) and (Vb) in the presence of a base such as NaOH in a solvent such as EtOH at temperatures ranging from about 80°C to about 100°C. It will be understood that the heterocycle in (Va) and (Vb) is not limited to triazole and may be any other suitable heterocycle.

Scheme 3

(VI) (VIII) (IX)

Intermediate compounds of formula (IX) are prepared, as outlined in Scheme 3, from commercially available or synthetically accessible compounds of formula (VI) where X is CRi or N, Y is CR2 or N, Ri and R2 are H, alkyl, halo or alkoxy, R ₃ A is -H, halo, -alkyl, -alkoxy and R6 is H or alkyl, G is SnB¾ or 4,4,5,5 tetramethyl-l,dioxaboralane and Hal is CI, or Br, preferably Br in this case. Compounds of formula (VIII) are obtained by reacting a compound of formula (VI) with commercially available (VII) in the presence of a catalyst such as l, l'-Bis(di- tert-butylphosphino)ferrocene palladium dichloride and a base such as a ₂ C03 in a solvent such as 2-MeTHF or THF at temperatures ranging from about 60 °C to about 90 °C. Compounds of formula (IX) are obtained by reacting a compound of formula (VIII) in the presence of a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 80 °C to about 100 °C or acids such as H ₂ S0 ₄ in solvents such as H ₂ 0 at temparatures ranging from 80 °C to 100 °C. It will be understood that the heterocycle in (VII) is not limited to pyrimidine and may be any other suitable heterocycle. Scheme 4

(XII) (XIII) (XIV)

Intermediate compound (XIV) is prepared, as outlined in Scheme 4, from commercially available compound (X). Compound (XI) is obtained by reacting compound (X) with commercially available acrolein in a solvent such as 1,4-dioxane at temperatures of about 200°C in, for example, a microwave reactor. Compound (XII) can be prepared from compound (XI) by treatment with an acid such as HBr in a solvent such as toluene at a temperature of about 90°C. Compound (XIII) can be obtained by treatment of compound (XII) with, for example, commercially available iodoethane and a base such as K2CO ₃ in a solvent such as DMF at temperatures ranging from about 45°C to about 65°C. Compound (XIV) is obtained by treating compound (XIII) with a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 80°C to about 100°C.

Scheme 5

(XIV) (VII) (XV) (XVI)

Intermediate compounds of formula (XVI) are prepared, as outlined in Scheme 5, from a commercially available or synthetically accessible compounds of formula (XIV) where R3 is -H, -alkyl,or -alkoxy and Hal is CI or Br. Compounds of formula (XV) are obtained by reacting a compound of formula (XIV) with commercially available (VII) in the presence of a catalyst such as Pd(dppf)Cl ₂ and a base such as a ₂ C03 in a solvent such as 2-MeTHF at temperatures ranging from about 75 °C to about 150 °C. Compounds of formula (XVI) are obtained by reacting a compound of formula (XV) in the presence of a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 80 °C to about 100 °C.

Scheme 6

(XVII) (XVIII)

XVIII _a W is COOH

XVIII W is C0 ₂ Alkyl

(XX) ( ^χχι )

Intermediate compounds of formula (XXI) can be prepared, as outlined in Scheme 6, from a commercially available or synthetically accessible compounds of formula (XVII) where Hal is Br or I; and where I¾A is -H, halo, -alkyl, -alkoxy and R-6 is H or alkyl. Compounds of formula (XVIIIa) can be converted to the corresponding ester (XVIIIb) by treatment with, for example, thionyl chloride in a solvent such as MeOH. Compounds of the formula (XX) are obtained by reacting compounds of formula (XVIIIb) with commercially available compounds of the formula XIX where L is a heterocyle such as pyrazole, pyridyl, or oxazole; G is SnBu ₃ or 4,4,5,5 tetramethyl-l,dioxaboralane and RIA and I¾A are -H, -alkyl,or -alkoxy; or Ri _A and R2A are -H, halo, -alkyl,or -alkoxy; in the presence of a catalyst such as Pd(Ph ₃ P) ₄ and a base such as a ₂ C0 ₃ in a mixture of solvents such as DME and ¾0 at temperatures ranging from about 100 °C to about 150 °C. Compounds of formula (XXI) are obtained by reacting a compound of formula (XX) in the presence of a base such as NaOH in a solvent such as MeOH at

temperatures ranging from about 80 °C to about 100 °C. Scheme 7

(+)-XXXVIa (-)-XXXVIb

Referring to Scheme 7, compounds of formula (+)-(XXXVIa) and (-)-(XXXVIb) were synthesized from compounds of formula (XXII) where PGi is, for example, a Boc protecting group, R4 is alkyl and Bn represents a benzyl group, -CH ₂ Ph. Treatment of compounds of formula (XXII) with hydrogen in the presence of, for example, a metal catalyst such as Pt0 ₂ , Pd/C, or Pd(OH) ₂ in solvents such as AcOH provide compounds of formula (±)-(XXIII) as a mixture of diastereomers favoring the cis diastereomer of formula (±)-(XXIII). Compounds of formula (±)-(XXXIV) were synthesized from compounds of formula (±)-(XXIII) upon treatment with a base such as sodium methoxide in solvents such as methanol at reflux temperature. The amine in these compounds was protected as PGl using reagents such as Boc ₂ 0 in the presence of bases such as a ₂ C0 ₃ in solvents such as THF and water. Compounds of formula (±)-(XXXV) were synthesized from compounds of formula (±)-(XXXIV) by treatment with bases such as sodium hydroxide, lithum hydroxide or potassium hydroxide in solvents such as water, THF or methanol. Compounds of formula (±)-(XXXVI) were synthesized from compounds of formula (±)-(XXXV) by treatment with , for example, DPPA in solvents such as toluene in the presence of bases such as TEA at temperatures ranging from about 70-1 10 °C followed by, for example, benzyl alcohol followed by continued heating to temperatures ranging from about 70-110 °C. Compounds of formula (±)-(XXXVI) were resolved into individual enantiomers using SFC chromatography on a chiral SFC (CHIRALPAK AD-H 5 mM 250 X 30mm) column to provide compounds of formula (+)-(XXXVIa) and (-)-(XXXVIb).

Scheme 8

(±)-XXIII (±)-XXXVII (±)-XXXVIII

Referring to Scheme 8, compounds of formula (±)-(XXXVIII) were synthesized from compounds of formula (±)-(XXIII) where PGi is, for example, a Boc protecting group, R ₄ is alkyl and Bn represents a benzyl group, -CH ₂ PI1. The amine in compounds of formula (±)- (XXIII) was protected as PGi using reagents such as B0C ₂ O in the presence of bases such as a ₂ C0 ₃ in solvents such as THF and water. Compounds of formula (±)-(XXXVII) were synthesized from compounds of formula (±)-(XXIII) by treatment with bases such as sodium hydroxide, lithum hydroxide, or potassium hydroxide in solvents such as water, THF, or methanol after protection with PGi as described. Compounds of formula (±)-(XXXVIII) were synthesized from compounds of formula (±)-(XXXVII) by treatment with, for example, DPPA in solvents such as toluene in the presence of bases such as TEA at temperatures ranging from about 70- 1 10 °C followed by benzyl alcohol followed by continued heating to temperatures ranging from about 70- 1 10 °C.

Scheme 9

XLI (±)-XLII

Referring to Scheme 9 , compounds of formula XLII were synthesized from compounds of formula (±)-(XXXVIa) where PGi is, for example, a Boc protecting group, R4 is alkyl, LG is CI, OH or OC(0)Alk, W is CI, Br, F or I and Bn represents a benzyl group, -CH ₂ Ph.

Compounds of formula (XXXIX) were obtained from compounds of formula (±)-(XXXVIa) by treatment with, for example, Pd catalysts such as 10 wt% Pd/C wet Degussa under an atmosphere of ¾ in a solvent such as EtOH to give compound of formula (XXXIX).

Compounds of formula (XL) were obtained from compounds of formula (XXXIX) using compounds R5-W in a suitable solvent such as DMSO or DMF in the presence of a base such as K2CO ₃ at a temperature of about 70 °C. Compounds of formula (XL) were also obtained when compounds of formula (XXXIX) and R5-W were treated with, for example, Pd catalysts such as Pd(OAc)2 or Pd(dba) ₂ , ligands such as racemic ΒΓΝΑΡ or Q-PHOS, a base such as sodium tert- butoxide in a solvent such as toluene at a temperature of about 70 °C. Compounds of formula

(XLI) were obtained from compounds of formula (XL) when treated with an acid such as HCl or TFA in a suitable solvent such as EtOAc or DCM at room temperature. Compounds of formula (XLII) were obtained from compounds of formula (XLI) using compounds of formula (XLIII) in a suitable solvent such as DMF or DCM in the presence of a peptide coupling reagent such as HATU, HBTU or T3P, a base such as DIPEA, a solvent such as DMF, ACN, THF or DCM at a temperature ranging from rt to about 45 °C. One skilled in the art will recognize similar chemistry can be done with compounds of formula (±)-XXXVI to give compounds of formula (±)-XLII. Scheme 10

(±)-XXXVIII (±)-XLIV

Referring to Scheme 10 compounds of formula (±)-XLIV were synthesized from compounds of formula (±)-XXXVIII using similar chemistry as described for the compounds in Scheme 9.

Scheme 1 1

(+)-XLV (+)-XLVI

Referring to Scheme 1 1 compounds of formula (±)-XLV were synthesized from compounds of formula (±)-XLVI (J. Org. Chem. 2008, 73, 2898) using similar chemistry as described for the compounds in Scheme 9.

In one group of embodiments, provided herein is a compound of Formula I of Examples 1-172, 174-177, 179-273 with structures and names as set forth in the Examples section below. In another group of embodiments, provided herein is a compound of Formula I of Examples 1- 146 with structures and names as set forth in the Examples section below. In yet another embodiment, provided herein is a compound of Formula I of Examples 147-172, 174-177, 179- 273 with structures and names as set forth in the Examples section below. In one group of embodiments, provided herein is a compound of Formula I or Formula IA having structures and names as set forth in Table 2 below. In a further group of embodiments, provided herein is a compound of Formula IA of Examples 173 and 178 with structures and names as set forth in the Examples section below. EXAMPLES

Abbreviations Term Acronym

Diisopropyl azodicarboxylate DIAD

Diphenylphosphoryl azide DPPA

Toluene PhCH ₃

N-Methy 1-2 -pyrrolidone ΝΜΡ

4,5-Bis(diphenylphosphino)-9,9-

Xantphos

dimethylxanthene

l,2,3,4,5-Pentaphenyl-l'-(di-t-

CTC-Q-Phos or QPHos

butylphosphino)ferrocene

Bis(dibenzylideneacetone)palladium(0) Pd(dba) ₂

Tris(dibenzylideneacetone)dipalladium(0) Pd ₂ (dba) ₃

1 , 1 '-Bis(di-tert-butylphosphino)ferrocene

PdCl ₂ (dtbpf)

palladium dichloride

1 -Propanephosphonic anhydride or

T3P

2,4,6-Tripropyl- 1 ,3,5,2,4,6- trioxatriphosphorinane-2 ,4, 6-trioxide

Supercritical fluid chromatography SFC

Room temperature rt

Chemistry:

In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were "dried," they were generally dried over a drying agent such as Na S0 ₄ or MgS0 _4; filtered and concentrated. Where mixtures, solutions, and extracts were "concentrated", they were typically concentrated on a rotary evaporator under reduced pressure. Reactions under microwave irradiation conditions were carried out in a Biotage Initiator or CEM Discover instrument.

Melting point determinations were performed in open capillary tubes on a FP62 or MP50 apparatus (Mettler-Toledo). Melting points were measured with a temperature gradient of 10 °C/minute. Maximum temperature was 300 °C. The melting point was read from a digital display.

Normal-phase flash column chromatography (FCC) was performed on silica gel (Si0 ₂ ) using prepackaged cartridges, eluting with the indicated solvents. Where compounds were purified by "Prep HPLC" the method employed was either: Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Gilson HPLC with an Xterra Prep RPis (5 μιη, 30 x 100 mm, or 50 X 150 mm) column, and a gradient of 10 to 99% acetonitrile/water (20 mM NH ₄ OH) over 12 to 18 min, and a flow rate of 30 mL/min.

or

Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Agilent 1 100 Series HPLC with an XBridge C18 column (5 μιη, 30 x 100mm), mobile phase of 5%ACN in 20mM NH40H (hold for 2min) then ramp 5-99%ACN over 15 min, hold at 99% ACN for 5 min. and a flow rate of 40 mL/min.

or

Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Agilent 1 100 Series HPLC with an XBridge CI 8 column (5 μιη, 50 x 100mm), mobile phase of 5%ACN in 20mM NH40H (hold for 2min) then ramp 5-99%ACN over 15 min, hold at 99% ACN for 5 min. and a flow rate of 80 mL/min.

or

Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Gilson HPLC with an Xterra Prep RPis (5 μιη, 30 x 100 mm, or 50 X 150 mm) column, and a gradient of 10 to 99% acetonitrile/water (20 mM NH ₄ OH) over 12 to 18 min, and a flow rate of 30 mL/min.

Analytical chromatography data was acquired using an Agilent 1 100 HPLC, with an Inertsil ODS-3 3mm 4.6 x 50mm column, purchased from GL Sciences (Part # 1010L050W046). Samples were run using a gradient profile of 10 - 99% acetonitrile (ACN) in water, each containing 0.05% trifluoroacetic acid (TFA) over 1.6 minutes, then holding at 99% acetonitrile for 0.3 minutes. Flow rate was 5 mL/min and column temperature was set to 50 °C (Method A).

Mass spectra (MS) were obtained on an Agilent series 1 100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers. The format of the 1H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration). Definitions for multiplicity are as follows: s = singlet, d = doublet, t= triplet, q = quartet, m = multiplet, br = broad. For compounds that are present as a mixture of rotamers the ratio is represented so that the total is 1, e.g. 0.80:0.20. Alternatively, 1H NMR data may be reported for only the major rotamer as indicated, or the data may be reported for one or more rotamers such that the total is less than 1. It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution.

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoft Corp.,

Cambridge, MA) or ACD/Name Version 10.01 (Advanced Chemistry).

Where compounds were purified by "SFC Chromatography" the method employed was either:

on a preparative APS 1010 system with autoprep motion from Berger instrument, consisted of two varian SD-1 pumps (walnut creek, CA, USA), one of which was extensively modified to pump CO _2, a special pump head heat exchanger, a julabo FT 401 chiller

(labortechnik GmbH, Sellback, Germany), a model SCM 2500 phase separator (berger instruments) with selection valve and set of collection vessels in a Bodan robot. A model Knauer 2500 UV detector with high pressure flow cell (berlin, germany). Samples were applied using a six-port injection valve (Valco, Houston, TX, USA)) with a 5 mL sample loop and a model YP-300 syringue pump (cavro, san Jose, CA).

or

On a SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). Modifier was pump with a model K1800 Knauer (Berlin, germany), with 100 mL Pump Head. The CO ₂ was pump with 2 lewa pumps (Leonberg Germany). Cooling of the pump head and the CO ₂ line was achieved by a coil alimented by a Huber chiller (Offenburg / Germany). Sample injections were made using 6 switching valves (Valco, Houston, TX, USA) and a 5 mL sample loop. The system is managed by a PLC automation system.

Examples 114-1 15, 1 17-123, 126-127, 140, 141, 144-146, 225-264, 266-273 are suitable for preparation using methods analogous to the methods described in the synthetic schemes and in the Examples section.

All stereochemistries depicted above and in Table 1 and Table 2 and in the Examples section are relative. A notation of (±) or R/S indicates that the product is a racemic mixture of diastereomers. A notation of, for example, (2S, 3R) indicates that the starting material was optically pure and the product stereochemistry depicted is based on the known stereochemistry of the starting material. A notation of, for example, (2S*, 3R*) indicates that the product is a pure and single diastereomer but the absolute stereochemistry is not established and relative stereochemistry is shown. INTERMEDIATES

Intermediate Name Structure Reference

A-19 6-methyl-3- WO 2010/063663

(pyrimidin-2- Description 69

yl)picolinic acid

0

A-20 5-methyl-3- Prepared analogous

(pyrimidin-2- to intermediate A-19 yl)picolinic acid using 3-bromo-5- methylpicolinonitrile

0

Intermediate A-18: 6-methyl-3-(oxazol-2-yl)picolinic acid.

Step A: 3-bromo-6-methylpicolinic acid. To 3-bromo-6-methylpicolinonitrile (4g, 20.3 mmol) in EtOH (40 mL) in a sealed tube was added aqueous 4M NaOH (15 mL). The reaction was heated at 90 °C for 24h. Additional aqueous 4M NaOH was added and heating continued at 90 °C for 24h. The reaction was cooled to rt, acidified to pH=3 with IN HCl (aq), concentrated and used without further purification in subsequent steps. MS (ESI) mass calcd. for C ₇ H ₆ BrN0 ₂ , 216.0; m/z found 218 [M+H] ⁺ _.

Step B: Methyl 3-bromo-6-methylpicolinate. To the title compound of step A (10.3 g, 20 mmol) in MeOH (50 mL) was added thionyl chloride (4.4 mL, 60 mmol). The reaction was heated at reflux overnight, cooled to rt and concentrated. Purification via silica gel

chromatography (0-15% EtOAc in heptane) gave the title compound (1.9g, 40%). MS (ESI) mass calcd. for C ₈ H ₈ BrN0 ₂ , 230.1; m/z found 232 [M+H] ⁺ .

Step C: Methyl 6-methyl-3-(oxazol-2-yl)picolinate. In a microwave vial was dissolved the title compound of step B (185 mg, 0.8 mmol) and 2-(tributylstannyl)oxazole (0.22 mL, 1 mmol) in PhCH ₃ (2.4 mL). The solution was degassed with N ₂ and Pd(PPh ₃ ) ₄ (92 mg, 0.1 mmol) were added. The reaction was purged with N ₂ and heated at 120 °C for 20 min using microwave irradiation. The reaction was cooled to rt, filtered through a pad of celite and purified via silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound of step A (333 mg, 67%). The mixture was diluted with ¾0 and extracted with EtOAc. The combined organics were dried (MgS0 ₄ ) and purified via silica gel chromatography (0-50% EtOAc in heptane) to give the title compound (56 mg, 32%). MS (ESI) mass calcd. for C11H1 ₀ 2O ₃ , 218.2; m/z found 219.1 [M+H] ⁺ _.

Step D: 6-methyl-3-(oxazol-2-yl)picolinic acid. To the title compound of step C (56 mg, 0.3 mmol) was added MeOH (0.6 mL) and 2M NaOH _(aq) (0.6 mL). After lh at rt, 1M HCl _(aq) was added. The reaction mixture was concentrated to give the title compound (52 mg) that was used without further purification in subsequent steps. MS (ESI) mass calcd. for C1 ₀ H ₈ 2O ₃ , 204.2; m/z found 205.1 [M+H] ⁺ .

Inter l-3-(2H-l,2,3-triazol-2-yl)picolinic acid.

Step A: 5-methyl-3-(2H-l,2,3-triazol-2-yl)picolinonitrile. To 2-bromo-5-methyl-3-(2H- l,2,3-triazol-2-yl)pyridine (1.5 g, 7.6 mmol) in DMF (19 mL) was added K ₂ C0 ₃ (1.2 g, 8.4 mmol) and 2H-l,2,3-triazole (440 μί, 7.6 mmol). The mixture was heated to 100 °C for 16 h, cooled to rt and extracted with EtOAc (2X). The combined organics were dried ( a2S04) and concentrated. Purification via silica gel chromatography (5-60% EtOAc in hexanes) gave the title compound (490 mg, 35%) and 5-methyl-3-(lH-l,2,3-triazol-l-yl)picolinonitrile (387 mg, 27%).

Step B: (sodium 5-methyl-3-(2H-l,2,3-triazol-2-yl)picolinate). To a solution of the the title compound of Step A (489 mg, 2.6 mmol) in EtOH (7 mL) was added 4 N NaOH (660 μί, 2.6 mmol). The mixture was heated at 100°C for 24 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps.

Inter ethyl-3-(2H-l,2,3-triazol-2-yl)picolinic acid.

Step A: 6-methyl-3-(2H-l,2,3-triazol-2-yl)picolinonitrile. To 3-bromo-6- methylpicolinonitrile (2.2 g, 11 mmol) in DMF (28 mL) was added K2CO ₃ (1.7 g, 12 mmol) and 2H-l,2,3-triazole (650 μί, 11 mmol). The mixture was heated to 100 °C for 36 h, cooled to rt and extracted with EtOAc. The combined organics were dried ( a2S04) and concentrated. Purification via silica gel chromatography (10-100% EtOAc in hexanes) gave the title compound (lg, 48%).

Step B: 6-methyl-3-(2H-l,2,3-triazol-2-yl)picolinic acid. To a solution of the the title compound of Step A (730 mg, 4 mmol) in EtOH (10 mL) was added 4 N NaOH (1 mL, 4 mmol). The mixture was heated at 100°C for 24 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps.

Intermediate A-25: 2-(5-fluoropyrimidin-2-yl)benzoic acid.

Step A: 5-fluoro-2-iodopyrimidine. To a solution of 2-chloro-5-fluoropyrimidine (4 mL, 32 mmol) in propionitrile (33 mL) was added chlorotrimethylsilane (12 mL, 97 mmol) and sodium iodide (15 g, 97 mmol), and the reaction mixture was heated to 150 °C for 1 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature and the solvent removed. The residue was taken up in EtOAc and a solution of saturated aHC03. The organic layer was dried over MgS0 ₄ , filtered and evaporated. Purification via silica gel chromatography (0-20% EtOAc in hexanes) gave the title compound (2.82 g, 39%).

Step B: 2-(5-fluoropyrimidin-2-yl)benzonitrile. In a microwave vial was dissolved cyanophenylboronic acid (500 mg, 3.40 mmol) in THF (15 mL), and the reaction mixture was degassed with N ₂ . Then, the title compound of step A (915 mg, 4.08 mmol), a ₂ C03 (1.08 g, 10.2 mmol), water (5 mL), and PdCl ₂ (dtbpf) (CAS 95408-45-0) (89 mg, 0.14 mmol) were added, and the reaction mixture was stirred at room temperature for 1 h and then heated via microwave heating to 75 °C for 2 h. The mixture was cooled to room temperature and water and EtOAc added. The reaction mixture was extracted with EtOAc. The combined organic layers were dried over MgS0 ₄ , filtered and concentrated. The crude was purified via silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound (280 mg, 41%). MS (ESI) mass calcd. for CnH ₆ FN ₃ , 199.1; m/z found 200.0 [M+H] ⁺ .

Step C: 2-(5-fluoropyrimidin-2-yl)benzoic acid. A solution of the title compound of step

B (1.24 g, 6.22 mmol) in H ₂ S0 ₄ (6 mL) and water (6 mL) was stirred at 80 °C for 1 h. Then, the reaction mixture was cooled to 0 °C and the aqueous phase extracted with DCM (2X). A solution of 20 M NaOH (11 mL) was added to the aqueous layer until pH -3-4. The aqueous layer was extracted again with EtOAc and DCM. The combined organic layers were dried over MgS0 ₄ , filtered and concentrated to afford the title compound (672 mg, 50%). MS (ESI) mass calcd. for C11H7FN2O2, 218.1; m/z found 219.1 [M+H] ⁺ .

Intermediate A-26: 3-fluoro-2-(5-fluoropyrimidin-2-yl)benzoic acid.

Prepared analogous to Intermediate A-25, substituting cyanophenylboronic acid with (2- cyano-6-fluorophenyl)boronic acid (CAS 656235-44-8). MS (ESI) mass calcd. for CnH ₆ F _{2 2} 0 ₂ 236.0; m/z found 237.1 [M+H] ⁺ . -27: 3-methyl-2-(pyrimidin-2-yl)benzoic acid.

Step A: methyl 3-methyl-2-(pyrimidin-2-yl)benzoate. In a microwave vial was dissolved methyl 3-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benz oate (619 mg, 2.24 mmol) and 2-chloropyrimidine (314 mg, 2.69 mmol) in 2-MeTHF (10 mL). a ₂ C0 ₃ (713 mg, 6.73 mmol) was then added followed by water (3.4 mL) and the reaction mixture was degassed with 2 for 45 minutes. Pd(dppf)Cl ₂ (66 mg, 0.09 mmol) and the reaction mixture was heated at 75 °C for 28h. More Pd(dppf)Cl ₂ (33 mg, 0.045 mmol) was added and the reaction mixture was heated at 150 °C for 3.5h. The mixture was filtered through a pad of celite and the fileter cake rinsed with EtOAc and water. The layers were separated and the aqueous was extracted once with EtOAc. The combined organic layers were dried over MgS0 ₄ , filtered and evaporated. The crude was purified via silica gel chromatography (0-50% EtOAc in hexanes) to afford the title compound (116 mg, 23%). MS (ESI) mass calcd. for Ci ₃ H _{12 2} 02, 228.1; m/z found 229.1

[M+H] ⁺ _. ^X H NMR (500 MHz, CDC13) 8.95 - 8.76 (m, 2H), 7.99 - 7.75 (m, 1H), 7.50 - 7.44 (m, 1H), 7.43 - 7.37 (m, 1H), 7.32 - 7.24 (m, 1H), 3.64 (s, 3H), 2.15 (s, 3H).

Step B: 3-methyl-2-(pyrimidin-2-yl)benzoic acid. To a solution of the title compound of step A (980 mg, 4.29 mmol) in MeOH (21 mL) was added 10 M NaOH (2 mL), and the reaction mixture was stirred at 50 °C for 48 h. The solvent was removed and the crude was diluted with water and acidified with 6 M HCl _(aq) until pH = 3. The aqueous layer was saturated with solid NaCl and extracted with 20% PrOH in CHCI ₃ (3X). The combined organic layers were dried over MgS0 ₄ , filtered and concentrated to afford the title compound (892 mg, 96%). MS (ESI) mass calcd. for Ci2H _{10 2} O2, 214.1 ; m/z found 215.1 [M+H] ⁺ _.

Synthesis of 3-fluoro-2-(pyrimidin-2-yl)benzonitrile (Intermediate in the synthesis of interme

To a solution of 3-fluoro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benz onitrile

(4.98 g, 19.1 mmol) and 2-bromopyrimidine (3.85 g, 23 mmol) in THF (96 mL) was added a ₂ C0 ₃ (6 g, 57.4 mmol) followed by water (43 mL). The reaction mixture was degassed with 2 for 10 minutes. PdCi ₂ (dtbpf) (374 mg, 0.57 mmol) was added and the reaction mixture was stirred at 80 °C for 5h. The solution was cooled to room temperature and a mixture of EtOAc and water was added. The aqueous was extracted twice with EtOAc and the combined organic layers were dried over MgS04, filtered and evaporated. The title compound was precipitated by dissolving the residue in a minimum amount of EtOAc and then adding hexanes. The solid was filtered, washed with hexanes and dried to afford the title compound (2.46 g, 64%). MS (ESI) mass calcd. for CnH ₆ FN ₃ , 199.1; m/z found 200.1 [M+H] ⁺ _. ^X H NMR (400 MHz, Chloroform-d) 5 9.02 - 8.91 (m, 2H), 7.65 (dt, J= 7.7, 1.0 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.51 - 7.43 (m, 1H), 7.41 (t, J= 4.9 Hz, 1H). 4: 4-fluoro-2-(oxazol-2-yl)benzoic acid.

Step A: 2-bromo-N-(2,2-dimethoxyethyl)-6-fluorobenzamide. To a solution of 2-bromo- 6-fluorobenzoic acid (2 g, 9.1 mmol) in DMF (27 niL) was added HBTU (5.20 g, 13.7 mmol) and DIPEA (4.7 niL, 27 mmol), and the reaction mixture was stirred for 10 min. Then, 2,2- dimethoxyethylamine (1.3 mL, 11.9 mmol) was added and the reaction mixture stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous aHC03. The combined organic layers were dried over MgS0 ₄ , filtered and concentrated. Purification via silica gel chromatography (0-25% EtOAc in hexanes) gave the title compound (2.3 g, 82%).

Step B: 2-(2-bromo-6-fluorophenyl)oxazole. To P2O5 (6.4 g, 22.6 mmol) was added methanesulfonic acid (52 mL, 801 mmol), and the reaction mixture was stirred at room temperature for 1 h. Then, the title compound of step A (2.3 g, 7.54 mmol) was added to the reaction mixture, and the mixture heated to 140 °C for 2 h. DCM was added and the mixture was slowly poured into a saturated solution of aqueous NaHC0 ₃ on ice. The mixture was extracted with DCM. The combined organic layers were dried over MgS0 ₄ , filtered and concentrated. Purification via silica gel chromatography (0-10% EtOAc in hexanes) gave the title compound (1.5 g, 82%). MS (ESI) mass calcd. for C ₉ H ₅ BrFNO, 240.95; m/z found 242.0 [M+H] ⁺ .

Step C: Methyl 3-fluoro-2-(oxazol-2-yl)benzoate. A solution of the title compound of step B (2.18 g, 8.99 mmol), Pd(OAc) ₂ (40 mg, 0.18 mmol), 1,1'- bis(diphenylphosphino)ferrocene (199 mg, 0.36 mmol), and Et ₃ N (3.7 mL, 27 mmol) in 1 : 1 MeOH/l,4-dioxane (36 mL) was degassed with 2 for 15 min. Then, the mixture was stirred at 95 °C under an atmosphere of carbon monoxide overnight. The reaction mixture was diluted with EtOAc and washed with a solution of aHC03. The organic layer was separated, dried over MgS0 ₄ , filtered, and concentrated. Purification via silica gel chromatography (0-12% EtOAc in hexanes) gave the title compound (1.7 g, 83%). MS (ESI) mass calcd. for CnH ₈ FN0 ₃ , 221.1; m/z found 222.0 [M+H] ⁺ .

Step D: 3-fluoro-2-(oxazol-2-yl)benzoic acid. To a solution of the title compound of step C (1.65 g, 7.46 mmol) in MeOH (22 mL) was added 2 M NaOH (7.5 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 1 M HCl _(aq ) and the solvents evaporated in vacuo. The mixture was diluted with water and extracted with DCM. The combined organic were dried over MgS0 ₄ , filtered and concentrated to afford the title compound (905 mg, 58%). MS (ESI) mass calcd. for Ci ₀ H ₆ FNO ₃ , 207.0; m/z found 208.0 [M+H] ⁺ _. MP = 182 °C.

Intermediate A-35: 5-fluoro-2-(oxazol-2-yl)benzoic acid.

Step A: Methyl 5-fluoro-2-(oxazol-2-yl)benzoate. To a solution of methyl 2-bromo-5- fluorobenzoate (1.1 g, 4.8 mmol) and 2-(tri-n-butylstannyl)oxazole (1.3 mL, 6.2 mmol) in toluene (14 mL) was added Pd(PPh ₃ ) ₄ (550 mg, 0.476 mmol), and the reaction mixture was heated via microwave heating to 150 °C for 30 min. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgS0 ₄ , filtered and concentrated. Purification via silica gel chromatography (0-40% EtOAc in hexanes, followed by a second column 0-10% EtOAc in hexanes) gave the title compound (553 mg, 52%). MS (ESI) mass calcd. for CnH ₆ FN0 ₃ , 221.1; m/z found 222.1 [M+H] ⁺ .

Step B: 5-fluoro-2-(oxazol-2-yl)benzoic acid. Prepared analogous to intermediate 34, step

D, to give the title compound (858 mg, 99%). MS (ESI) mass calcd. for Ci ₀ H ₆ FNO ₃ , 207.0; m/z found 208.1 [M+H] ⁺ . 6: 4-fluoro-2-(3 -methyl- l,2,4-oxadiazol-5-yl)benzoic acid

Step A: 5-(2-bromo-5-fluorophenyl)-3-methyl-l,2,4-oxadiazole. To a solution of 2- bromo-5-fluorobenzoyl chloride (2.17 g, 9.13 mmol) in THF (18 mL) was added DIPEA (1.7 mL, 10 mmol). Then, acetamide oxime (676 mg, 9.13 mmol) was added portionwise, and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with EtOAc and washed with a saturated solution of aHC0 ₃ . The combined organic layers were dried over

MgS0 ₄ , filtered and concentrated. Purification via silica gel chromatography (0-20% EtOAc in hexanes) gave the title compound (2.35 g, 57%). MS (ESI) mass calcd. for C ₉ H ₆ BrFN ₂ 0, 255.96; m/z found 257.0 [M+H] ⁺ .

Step B: 4-fluoro-2-(3 -methyl- l,2,4-oxadiazol-5-yl)benzoic acid. Prepared analogous to intermediate 34, steps C and D, to give the title compound. MS (ESI) mass calcd. for

C10H7FN2O3, 222.0; m/z found 223.0 [M+H] ⁺ . -39: 5-methyl-2-(pyrimidin-2-yl)nicotinic acid.

Step A: Methyl 5-methyl-2-(pyrimidin-2-yl)nicotinate. To a sealed tube containing methyl 2-chloro-5-methylnicotinate (CAS 65169-43-9) (745 mg, 4.01 mmol), Cul (38 mg, 0.2 mmol), LiCl (169 mg, 4.01 mmol), and Pd(PPh ₃ ) ₄ (231 mg, 0.2 mmol) in toluene (15 mL) was added 2-(tributylstannyl)pyrimidine (1.5 mL, 4.4 mmol), and the reaction mixture was heated at 120 °C overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over MgS0 ₄ , filtered and evaporated. Purification via silica gel chromatography (0-50% EtOAc in hexanes) gave the title compound (494 mg, 52%). MS (ESI) mass calcd. for C HnNsOz, 229.1 ; m/z found 229.99.

Step B: 5-methyl-2-(pyrimidin-2-yl)nicotinic acid. To a solution of the title compound of step A (466 mg, 2.03 mmol) in MeOH (10 mL) was added 10 M NaOH (1 mL), and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed and the crude was diluted with water and acidified with 6 M HCl _(aq) until pH = 3. The aqueous layer was saturated with solid NaCl and extracted with 20% /PrOH in CHCI ₃ (3X). The combined organic layers were dried over MgS0 ₄ , filtered and concentrated to afford the title compound (432 mg, 99%). MS (ESI) mass calcd. for C11H ₉ N ₃ O2, 215.1; m/z found 216.1 [M+H] ⁺ _. ^X H NMR (500 MHz, Methanol-d ₄ ) δ 8.90 (br. s, 2H), 8.64 (br. s, 1H), 8.17 (s, 1H), 7.55 (br. s, 1H), 2.51 (s, 3H).

Intermediate B-l : trans-(±)-tert-butyl-3-(((benzyloxy)carbonyl)amino)-2-methy lpiperidine-l- carboxylate.

Step A: trans-(±)-l-(tert-butoxycarbonyl)-2-methylpiperidine-3-carb oxylic acid. Methyl

2-methylnicotinate (28.6 g, 190 mmol) and Pt0 ₂ (430 mg) in AcOH (500 mL) was stirred under an atmosphere of ¾ for 48h. Additional Pt0 ₂ was added and the reaction continued for an additional 24h. Then the reaction mixture was filtered through a pad of celite and the filtrate concentrated. The resulting residue was partitioned between 2M NaOH (aq) and DCM. The organic layer was extracted with DCM (2X). The combined organic layers were dried (MgS0 ₄ ) and concentrated to give 27.2 g of a residue.

To this residue in MeOH (450 mL) was added sodium methoxide (4.5 M in MeOH, 56 mL, 260 mmol). The reaction was heated at reflux for 15h, then cooled to rt, concentrated, ¾0 was added and the mixture extracted with DCM. The combined organics were dried (MgS04) and concentrated to give 23.9 g of product that was dissolved in THF (300 mL) and H20 (60 mL). Then, a ₂ C0 ₃ (38.3g, 456 mmol) was added followed by B0C2O (33.2 g, 152 mmol). After stirring overnight, the mixture was diluted with ¾0 and extracted with DCM. The combined organics were dried (MgS0 ₄ ) and concentrated to give 39.2g of material (9: 1 trans:cis isomers).

To this material in THF (300 mL) and H ₂ 0 (100 mL) was added LiOH (7.3 g, 305 mmol). After stirring overnight, the mixture was diluted with FLO and extracted with DCM. The organic extract was discarded. The aqueous layer was acidified with HCl and extracted with DCM. The combined organics were dried (MgS0 ₄ ) and concentrated. Purification via silica gel chromatography (0-100% EtOAc in heptane) gave the title compound (30.2 g) as a -86: 13 mixture of trans:cis diastereomers. MS (ESI) mass calcd. for C12H21 O4, 243.2; m/z found 188.1 [M-55] ⁺ .

Step B: trans-(±)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-2-methylpiperidine-l- carboxylate. To the title compound of step A (10 g, 41 mmol) in PI1CH ₃ (60 mL) was added DIPEA (7.4 mL, 43 mmol) and the mixture heated at 50 °C for lh. Then DPPA (8.9 mL, 41 mmol) in PI1CH ₃ was added dropwise and the mixture heated at 75 °C for 2h and BnOH (4.5 mL, 43 mmol) and the mixture stirred at 80 °C for 20h. The reaction was allowed to cool to rt, diluted with saturated aHC03 (aq) and extracted with PhCH3. The combined organics were dried (MgS0 ₄ ). Purification via silica gel chromatography (0-20% EtOAc in hexanes) gave the title compound (2.6 g, 18%). MS (ESI) mass calcd. for Ci ₉ H ₂ 8 ₂ 0 ₄ , 348.2; m/z found 249.2 [M- 100] ⁺ , 293.2 [M-55] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 7.39 - 7.30 (m, 5H), 5.24 - 5.00 (m, 3H), 4.35 - 4.22 (m, 1H), 4.01 - 3.85 (m, 1H), 3.74 - 3.51 (m, 1H), 2.89 - 2.71 (m, 1H), 1.87 - 1.30 (m, 13H), 1.19 (d, J = 7.0 Hz, 3H). Example B-2: (2R*,3S*)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-2-methylpiperidine-l- carboxylate. and (2S*,3R*)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-2-methylpiperidine-l-carboxyl ate.

The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 μΜ 250 X 30mm) resolution of Intermediate B-l (38.2 g) using 93% C0 ₂ /7% MeOH as the mobile phase to give enantiomer A (18.8 g, 1st eluting enantiomer) and enantiomer B (19.3 g, 2 ^nd eluting enantiomer).

Enantiomer A: [a] _D -31.9° (c 0.7, DMF). MS (ESI) mass calcd. for Ci ₉ H ₂ 8 ₂ 0 ₄ , 348.2; m/z found 349.2 [M+H] ⁺ _. 1H NMR consistent with intermediate B-l.

Enantiomer B: [a] _D ² ° +28.0° (c 0.96, DMF). MS (ESI) mass calcd. for Ci ₉ H ₂ 8 ₂ 0 ₄ , 348.2; m/z found 349.2 [M+H] ⁺ _. 1H NMR consistent with intermediate B-l.

Intermediate B-3 : ?ra«s-(±)-ter?-butyl-3-amino-2-methylpiperidine- 1 -carboxylate

Intermediate B-l (8.9 g, 25.4 mmol) and wet 10 wt% Pd/C (880 mg) in MeOH (200 mL) was stirred under an atmosphere of ¾ overnight. The reaction mixture was filtered through a pad of celite and the filtrate concentrated to give the title compound (5.7 g) that was used without further purification. MS (ESI) mass calcd. for CnH _{22 2} 02, 214.3; m/z found 159.1 [M-55] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) 4.19 - 4.08 (m, 1H), 4.00 - 3.88 (m, 1H), 2.91 - 2.72 (m, 2H), 1.86 - 1.61 (m, 1H), 1.61 - 1.33 (m, 12H), 1.15 (d, J= 7.0 Hz, 3H). B-4: (2S*,3R*)-tert-butyl 3-amino-2-methylpiperidine-l-carboxylate.

Prepared analogous to Intermediate B-3 substituting intermediate B- 1 with intermediate (+)-B-2 (enantiomer B). B-5: (2R*,3S*)-tert-butyl 3-amino-2-methylpiperidine-l-carboxylate.

Prepared analogous to Intermediate B-3 substituting intermediate B- 1 with intermediate (-)-B-2 (enantiomer A). B-6: c«-(±)-tert-butyl-3-amino-2-methylpiperidine-l -carboxylate

Step A: cw-(±)-l-(tert-butoxycarbonyl)-2-methylpiperidine-3-carboxy lic acid. Methyl 2- methylnicotinate (100 g, 662 mmol) and Ρί(¾ (1.5 g) in AcOH (300 mL) was stirred under an atmosphere of ¾ for 7 days. The reaction mixture was filtered and the filtrate concentrated. The resulting residue was partitioned between saturated NaHCCh (aq) and DCM. The organic layer was extracted with DCM (4X200 mL). The combined organic layers were dried ( a ₂ S0 ₄ ) and concentrated to give 80 g of a residue.

To this residue in THF (200 mL) was added DIPEA (37 mL, 200 mmol) and Boc ₂ 0 (32g, 150 mmol). After stirring overnight, the mixture was concentrated, diluted with H20 and extracted with EtOAc. The combined organics were dried (NaS0 ₄ ) and concentrated.

Purification via silica gel chromatography (10% EtOAc in petroleum ethers) gave cz ^' s-(±)-l-tert- butyl 3-methyl 2-methylpiperidine-l,3-dicarboxylate.

To the crude mixture of cz ^' s-(±)-l-tert-butyl 3-methyl-2-methylpiperidine-l,3- dicarboxylate from above in MeOH (150 mL) was added 2M NaOH (aq.). The reaction was heated at 70 °C for 2h, cooled to rt, concentrated, treated with H20 (400 mL) and extracted with MTBE (100 mL). The aqueous layer was then acidified to pH=6 with IN HC1 (aq) and concentrated. To this was added MeOH (400 mL) and concentrated to give the title compound (5g) as a white solid.

Step B: cis-(±)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-2-methylpiperidine-l- carboxylate. To the title compound of step A (5.3 g, 21 mmol) in PhCH ₃ was added DIPEA (4.3 mL, 26 mmol) and DPPA (7.2 g, 26 mmol). The mixture was heated at reflux overnight, cooled to rt, concentrated and treated with 20% KOH (aq). The mixture was heated at 100 °C for 2h, cooled to rt and extracted with DCM (2X). The combined organics were dried (Na2S04), concentrated and purified via silica gel chromatography (10% MeOH in DCM) to give the title compound (1.5g). Example 1 : (±)-?ra«s-(3-((4,6-dimethylpyrimidin-2-yl)amino)-2-methylp iperidin-l-yl)(4-fluoro- 2- -l,2,3-triazol-2-yl)phenyl)methanone.

Step A: (±)-ter?-butyl-3-((4,6-dimethylpyrimidin-2-yl)amino)-2-meth ylpiperidine-l- carboxylate. To a microwave vial was weighed intermediate B-3 (260 mg, 1.2 mmol), 2-chloro- 4,6-dimethylpyrimidine (208 mg, 1.5 mmol), Pd(dba) ₂ (17 mg, 0.03 mmol), CTC-Q-Phos (27 mg, 0.06 mmol) and sodium tert-butoxide (175 mg, 1.8 mmol). The vial was capped, evacuated, refilled with 2 (2X) and PI1CH ₃ was added. The reaction was then heated in the microwave at 150 °C for 120 min. The mixture was then cooled to rt, directly applied to and purified via silica gel chromatography (1-7% 2M NH ₃ /MeOH in CH ₂ C1 ₂ ) to give the title compound (205 mg, 53%) as a brown oil. MS (ESI) mass calcd. for Ci ₇ H _{28 4} 02, 320.2; m/z found 321.2 [M+H] ⁺ . 1H (CDC13): 6.30 (s, 1H), 5.39 - 5.25 (m, 1H), 4.46 - 4.31 (m, 1H), 4.10 - 3.85 (m, 2H), 2.94 - 2.71 (m, 1H), 2.34 - 2.20 (m, 6H), 1.87 - 1.62 (m, 3H), 1.52 - 1.33 (m, 10H), 1.22 (d, J= 7.0 Hz, 2.5H), 1.09 - 1.01 (m, 0.5H).

Step B: (±)-/ra«s-4,6-dimethyl-N-(2-methylpiperidin-3-yl)pyrimidin -2-amine. To the title compound from Step A (75 mg, 0.23 mmol) in DCM (4 mL) was added TFA (4 mL). Upon completion (~3h), the reaction was concentrated, neutralized with 5% a ₂ C0 ₃ (aq) and extracted with DCM (3X). The combined organics were dried ( a ₂ S0 ₄ ) to give the title compound (52 mg) which was used without further purification. MS (ESI) mass calcd. for Ci ₂ H ₂₀ N ₄ ,220.2; m/z found 221.1 [M+H] ⁺ _.

Step C: (±)-?ra«s-(3-((4,6-dimethylpyrimidin-2-yl)amino)-2-methylp iperidin-l-yl)(4- fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone. To the title compound from Step B (29 mg, 0.13 mmol) in DMF (1.3 mL) was added TEA (0.022 mL, 0.16 mmol), intermediate A-l (30 mg, 0.14 mmol) and HATU (55 mg, 0.14 mmol). Upon completion of the reaction, purification was performed using Agilent prep method A to give the title compound (29 mg, 55% yield). MS (ESI) mass calcd. for C ₂ iH ₂₄ FN ₇ O,409.2; m/z found 410.0 [M+H] ⁺ _. HPLC R _t =0.85 (Analytical Method A). Example 2: (±)-?ra«s-(3-((4,6-dimethylpyrimidin-2-yl)amino)-2-methylp iperidin-l-yl)(2-fluoro- -(pyrimidin-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 1 substituting intermediate A- 1 with intermediate A-2. MS (ESI) mass calcd. for C ₂ 3H ₂ 5FN ₆ O,420.2; m/z found 421.2 [M+H] ⁺ .

Example 3: (±)-?ra«s-(3-((4,6-dimethylpyrimidin-2-yl)amino)-2-methylp iperidin-l-yl)(2-fluoro- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.

The title compound was prepared analogous to example 1 substituting intermediate A- 1 with intermediate A-23. MS (ESI) mass calcd. for C ₂ iH ₂₂ FN ₇ O,407.5; m/z found 408.2 [M+H] HPLC R _t =0.85 (Analytical Method A).

Example 4: (±)-/ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(3-((4,6-dimeth ylpyrimidin-2-yl)amino)- 2-methylpiperidin- 1 -yl)methanone.

The title compound was prepared analogous to example 1 substituting intermediate A- 1 with intermediate A-4. MS (ESI) mass calcd. for C ₂ iH ₂ 5N ₇ 0,391.2; m/z found 392.2 [M+H] ⁺ _.

Example 5: (±)-?ra«s-(3-((4,6-dimethylpyrimidin-2-yl)amino)-2-methylp iperidin-l-yl)(5-fluoro- -(2H-l,2,3-triazol-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 1 substituting intermediate A- 1 with intermediate A-24. MS (ESI) mass calcd. for C ₂ iH ₂₄ FN ₇ O,409.2; m/z found 410.2 [M+H] ⁺ Example 6: (±)-?ra«s-(3-((4,6-dimethylpyrimidin-2-yl)amino)-2-methylp iperidin-l-yl)(5- methyl-2-(pyrimidin-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 1 substituting intermediate A- 1 with intermediate A-5. MS (ESI) mass calcd. for C ₂₄ H ₂₈ N ₆ 0,416.2; m/z found 417.2 [M+H] ⁺ .

Example 7: (±)-?ra«s-(5-methyl-2-(pyrimidin-2-yl)phenyl)(2-methyl-3-( (6-methyl-2- (trifluoromethyl)pyrimidin-4-yl)amino)piperidin-l-yl)methano ne.

Step A: (±)-ter?-butyl-2-methyl-3-((6-methyl-2-(trifluoromethyl)pyr imidin-4- yl)amino)piperidine-l-carboxylate. To intermediate B-3 (135 mg, 0.63 mmol) in DMF (1.5 mL) was added CS2CO ₃ (308 mg, 0.95 mmol) and 4-chloro-6-methyl-2-(trifluoromethyl)pyrimidine (149 mg, 0.76 mmol). The flask was then heated with an oil bath at 70 °C for 18h. The reaction was allowed to cool to rt, diluted with H ₂ O and extracted with EtOAc (2X). The combined organics were washed with brine and dried (Na ₂ S0 ₄ ). Silica gel chromatography (EtOAc in hexanes) gave the title compound (11 1 mg, 47%). MS (ESI) mass calcd. for Ci ₇ H ₂ 5F _{3 4} 02, 374.2; m/z found 275.2 [M+H-100J+. 1H NMR (CDC13): 6.24 (s, 1H), 5.44 (s, 1H), 4.48 - 4.31 (m, 1H), 4.15 - 3.60 (m, 2H), 2.97 - 2.78 (m, 1H), 2.42 (s, 3H), 1.85 (s, 2H), 1.74 - 1.32 (m, 10H), 1.26 (d, J= 7.0 Hz, 3H).

Step B: (±)-?ra«s-6-methyl-N-(2-methylpiperidin-3-yl)-2-(trifluoro methyl)pyrimidin-4- amine. The title compound was prepared analogous to example 1, Step B substituting (±)-tert- butyl-3-((4,6-dimethylpyrimidin-2-yl)amino)-2-methylpiperidi ne-l-carboxylate with the title compound from Step A.

Step C: (±)-?ra«s-(5-methyl-2-(pyrimidin-2-yl)phenyl)(2-methyl-3-( (6-methyl-2- (trifluoromethyl)pyrimidin-4-yl)amino)piperidin- 1 -yl)methanone. The title compound was prepared analogous to example 1, Step C substituting intermediate A-l with intermediate A-5 and (±)-4,6-dimethyl-N-(2-methylpiperidin-3-yl)pyrimidin-2-amin e with the title compound of Step B. MS (ESI) mass calcd. for C ₂₄ H ₂ 5F ₃ N ₆ O,470.2; m/z found 471.2 [M+H] ⁺ _.

Example 8: (±)-/ra«s-(5-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)(2-met hyl-3-((6-methyl-2- (trifluoromethyl)pyrimidin-4-yl)amino)piperidin-l-yl)methano ne.

The title compound was prepared analogous to Example 7 substituting intermediate A-5 with intermediate A-6. MS (ESI) mass calcd. for C ₂ 2H ₂ 4F ₃ 70, 459.2; m/z found 460.2 [M+H]"

Example 9: (±)-?ra«s-(5-fluoro-2-(pyrimidin-2-yl)phenyl)(2-methyl-3-( (6-methyl-2- (trifluoromethyl)pyrimidin-4-yl)amino)piperidin-l-yl)methano ne.

The title compound was prepared analogous to Example 7 substituting intermediate A-5 with intermediate A-7. MS (ESI) mass calcd. for C ₂ 3H ₂₂ F ₄ 60, 474.2; m/z found 475.2 [M+H]"

Example 10: (±)-?ra«s-(2-fluoro-6-(2H-l,2,3-triazol-2-yl)phenyl)(2-met hyl-3-((4- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)methano ne.

The title compound was prepared analogous to Example 7 substituting 4-chloro-6- methyl-2-(trifluoromethyl)pyrimidine with 2-chloro-4-(trifluoromethyl)pyrimidine and intermediate A-5 with intermediate A-23. MS (ESI) mass calcd. for C2oHi ₉ F _{4 7} 0,449.2; m/z found 450.2 [M+H] ⁺ _.

Example 11: (±)-/ra«s-(6-methyl-2-(lH-l,2,3-triazol-l-yl)pyridin-3-yl) (2-methyl-3-((4- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 10 substituting intermediate A- 23 with intermediate A-9. MS (ESI) mass calcd. for C ₂ oH ₂₁ F ₃ N ₈ 0,446.2; m/z found 447.2

[M+H] ⁺ .

Example 12: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-methyl-3-((5 - (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

?ra«s-(±)-tert-butyl-2-methyl-3-((5-(trifluoromethyl)pyrid in-2- yl)amino)piperidine-l-carboxylate. To intermediate B-3 (3 g, 14 mmol) in DMSO (100 mL) was added 2-fluoro-5-(trifluoromethyl)pyridine (3.4 g, 21 mmol) and DIPEA (4.8 mL, 28 mmol). The reaction was then heated at 100 °C for 4h. The reaction was allowed to cool to rt, diluted with saturated aHC03 (aq) and extracted with DCM. The combined organics were washed with brine and dried (MgS0 ₄ ). Silica gel chromatography (EtOAc in heptane) gave the title compound (2.7 g, 54%). MS (ESI) mass calcd. for Ci ₇ H24F ₃ 302,359.2; m/z found 360.2

[M+H] ⁺ _. Step B. ?ra«s-(±)-2-methylpiperidin-3-yl)-5-(trifluoromethyl)pyrid in-2-amine. Prepared analogous to Example 1 substituting (±)-ter?-butyl-3-((4,6-dimethylpyrimidin-2-yl)amino)-2- methylpiperidine- 1 -carboxylate with the title compound from Step A. MS (ESI) mass calcd. for Ci2H ₁₆ F ₃ N ₃ , 259.1; m/z found 260.2 [M+H] ⁺ .

Step C. (±)-?ra«s-tert-butyl-2-methyl-3-((5-(trifluoromethyl)pyrid in-2- yl)amino)piperidine- 1 -carboxylate. Prepared analogous to Example 1 substituting (±)-?ra«s-(3- ((4,6-dimethylpyrimidin-2-yl)amino)-2-methylpiperidin-l-yl)( 4-fluoro-2-(2H- 1,2,3 -triazol-2- yl)phenyl)methanone with the title compound from Step B, intermediate A- 1 with intermediate A-4 and HATU with HBTU. MS (ESI) mass calcd. for C ₂ iH ₂₁ F ₃ N ₆ O,430.2; m/z found 431.2 [M+H] ⁺ . MP=154.7 °C. (Mixture of 4 isomers, undefined ratio). ^X H NMR (300 MHz, DMSO) δ 8.36 (d, J= 21.8 Hz, 0.44H), 8.24 (d, J= 12.9 Hz, 0.36H), 8.08 (d, J= 1.3 Hz, 1.62H), 7.97 (s, 0.47H), 7.91 (d, J= 8.2 Hz, 0.41H), 7.83 - 7.32 (m, 4.20H), 7.32 - 7.21 (m, 0.48H), 7.06 - 6.96 (m, 0.47H), 6.82 (d, J= 8.9 Hz, 0.76H), 6.71 (dd, J= 13.9, 7.0 Hz, 0.59H), 6.60 (s, 0.10H), 6.15 (d, J= 8.8 Hz, 0.10H), 4.93 (d, J= 6.0 Hz, 0.12H), 4.68 (q, J= 6.8 Hz, 0.39H), 4.41 (t, J= 13.4 Hz, 0.65H), 4.17 - 3.83 (m, 0.78H), 3.81 - 3.61 (m, 0.73H), 3.20 (d, J= 14.4 Hz, 0.35H), 2.94 (t, J= 11.7 Hz, 0.52H), 2.85 - 2.66 (m, 0.46H), 2.19 - 1.49 (m, 3.53H), 1.49 - 1.22 (m, 2.07H), 0.74 (d, J= 6.9 Hz, 1.40H).

Example 13: (±)-/ra«s-(4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)(2-met hyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogously to Example 12 substituting intermediate A-4 with intermediate A- 11. MS (ESI) mass calcd. for C ₂ 2H ₂ 3F ₃ N ₆ 0,444.2; m/z found 445.2 [M+H]+. MP=136.4 °C. (Mixture of 4 isomers, undefined ratio). 1H NMR (300 MHz, DMSO) δ 8.41 (d, J = 20.3 Hz, 0.34H), 8.28 (d, J = 13.4 Hz, 0.34H), 8.21 - 7.94 (m, 2.16H), 7.88 - 7.67 (m, 1.27H), 7.60 (dd, J = 12.3, 7.4 Hz, 0.92H), 7.53 - 7.21 (m, 1.81H), 6.96 - 6.72 (m, 1.41H), 6.60 (s, 0.11H), 6.51 (d, J = 7.4 Hz, 0.53H), 6.17 (s, 0.11H), 4.96 (s, 0.11H), 4.72 (d, J = 7.3 Hz, 0.34H), 4.42 (d, J = 14.1 Hz, 0.68H), 4.11 (s, 0.45H), 3.98 (s, 0.20H), 3.77 (d, J = 6.8 Hz, 0.56H), 3.67 (dd, J = 12.1, 6.0 Hz, 0.68H), 3.26 (d, J = 13.4 Hz, 0.34H), 2.96 (t, J = 11.7 Hz, 0.50H), 2.86 - 2.71 (m, 0.50H), 2.49 (s, 1.07H), 2.43 (s, 0.33H), 2.26 (s, 1.24H), 2.18 - 1.52 (m, 3.57H), 1.53 - 1.33 (m, 0.90H), 1.30 (d, J = 7.0 Hz, 0.94H), 0.76 (d, J = 6.9 Hz, 1.57H).

Example 14: (4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogously to Example 13 substituting intermediate B-3 with intermediate B-4. MS (ESI) mass calcd. for C ₂ 2H ₂ 3F ₃ N ₆ 0,444.2; m/z found 445.2 [M+H] ⁺ _. MP= 119.4 °C.

Example 15 : (4-methyl-2-(2H- 1 ,2,3-triazol-2-yl)phenyl)((2R,3 S)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogously to Example 13 substituting intermediate B-3 with intermediate B-5.

MS (ESI) mass calcd. for C ₂ 2H ₂ 3F ₃ N ₆ 0,444.2; m/z found 445.2 [M+H] ⁺ _. MP=130.4 °C.

(Mixture of 4 isomers, undefined ratio). 'H NMR (300 MHz, CDC1 ₃ ) δ 8.38 (s, 0.2H), 8.33 (s, 0.10H), 8.21 (s, 0.35H), 8.09 (s, 0.45H), 7.96 (s, 0.70H), 7.92 (s, 0.30H), 7.86 - 7.68 (m, 0.70H), 7.70 - 7.43 (m, 0.50H), 7.44 - 7.09 (m, 3.40H), 6.84 (d, J= 7.7 Hz, 0.10H), 6.52 (d, J= 7.7 Hz, 0.10H), 6.47 - 6.33 (m, 0.30H), 6.24 (d, J= 9.0 Hz, 0.10H), 6.08 (d, J= 8.8 Hz, 0.70H), 5.31 - 5.08 (m, 0.35H), 5.08 - 4.82 (m, 0.20H), 4.70 (br d, J= 13.7 Hz, 0.50H), 4.26 - 4.05 (m, 0.90H), 3.99 (br s, 0.40H), 3.93 - 3.80 (m, 0.20H), 3.60 (br s, 0.10H), 3.49 (br d, J= 9.6 Hz, 0.30H), 3.34 - 3.12 (m, 0.35H), 3.02 - 2.70 (m, 0.70H), 2.45 (d, J= 7.4 Hz, 2.00H), 2.14 - 1.73 (m, 2.00H), 1.73 - 1.01 (m, 3.80H), 1.01 - 0.76 (m, 2.00H), 0.71 (d, J= 7.0 Hz, 0.20H). The signal corresponding to the NH group was not observed.

Example 16: (±)-?ra«s-(3-ethoxy-6-methylpyridin-2-yl)(2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogously to Example 12 substituting intermediate A-4 with intermediate A-

12. MS (ESI) mass calcd. for C ₂ iH25F _{3 4} 0 ₂ ,422.2; m/z found 423.2 [M+H] ⁺ . MP=153.6 °C. The product is present as a mixture of conformers (ratio ca. 70:30) ^X H MR (300 MHz, DMSO) δ 8.34 (s, 0.3H), 7.97 (s, 0.7H), 7.65 (dd, J= 8.9, 2.4 Hz, 0.3H), 7.59 (dd, J= 8.9, 2.5 Hz, 0.7H), 7.39 (d, J= 8.6 Hz, 0.3H), 7.27 - 7.12 (m, 2H), 6.96 (d, J= 8.6 Hz, 0.7H), 6.75 (d, J= 8.9 Hz, 0.3H), 6.69 (d, J= 8.9 Hz, 0.7H), 4.85 (q, J= 6.9 Hz, 0.3H), 4.48 - 4.33 (m, 0.7H), 4.11 - 3.72 (m, 3H), 3.59 (d, J= 2.4 Hz, 0.7H), 3.22 - 3.08 (m, 0.3H), 3.07 - 2.96 (m, 0.3H), 2.96 - 2.82 (m, 0.7H), 2.38 (s, 0.9H), 2.10 - 1.54 (m, 6.1H), 1.32- 1.22 (m, 6H).

Example 17: (±)-?ra«s-(5-chloro-2-(2H-l,2,3-triazol-2-yl)phenyl)(2-met hyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 12 substituting intermediate A-4 with intermediate A- 13. MS (ESI) mass calcd. for C ₂ iH ₂ oClF ₃ N ₆ 0,464.2; m/z found 465.1 [M+H] ⁺ _. MP=224.4 °C.

(Mixture of 4 isomers, undefined ratio). ^X H NMR (300 MHz, DMSO) δ 8.42 - 8.24 (m, 0.64H), 8.20 (s, 0.12H), 8.11 (d, J= 3.7 Hz, 1.64H), 8.04 (s, 0.48H), 7.96 (dd, J= 8.7, 5.0 Hz, 0.41H), 7.85 - 7.53 (m, 2.49H), 7.53 - 7.27 (m, 1.57H), 7.24 (s, 0.08H), 7.13 (d, J= 2.4 Hz, 0.50H), 6.89 - 6.69 (m, 0.91H), 6.63 (s, 0.08H), 6.12 (s, 0.08H), 4.91 (d, J= 6.7 Hz, 0.08H), 4.64 (d, J= 12 Hz, 0.41H), 4.37 (d, J= 13.0 Hz, 0.63H), 4.11 (s, 0.38H), 4.01 (s, 0.08H), 3.90 (d, J= 18.5 Hz, 0.24H), 3.68 (dd, J= 23.6, 6.5 Hz, 0.76H), 3.21 (d, J= 16.3 Hz, 0.41H), 3.05 - 2.91 (m, 0.41H), 2.78 (t, J= 11.7 Hz, 0.6H), 2.15 - 1.46 (m, 3.56H), 1.45 - 1.15 (m, 1.92H), 0.70 (d, J= 6.9 Hz, 1.52H). Example 18: (±)-/ra«s-(2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)am ino)piperidin-l-yl)(6- triazol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to Example 12 substituting intermediate A-4 with intermediate A-22. MS (ESI) mass calcd. for C ₂₁ H ₂₂ F ₃ N ₇ 0,445.2; m/z found 446.0 [M+H] ⁺ . MP=105.7 °C.

(Mixture of 4 isomers, undefined ratio). 'H NMR (300 MHz, CDC1 ₃ ) δ 8.39 - 8.22 (m, 1.15H), 8.17 (d, J= 8.4 Hz, 0.74H), 8.05 (s, 0.33H), 7.92 (s, 1.23H), 7.64 - 7.51 (m, 0.23H), 7.45 (d, J= 8.7 Hz, 0.74H), 7.38 - 7.29 (m, 1.15H), 6.96 (br s, 0.74H), 6.44 (d, J= 8.8 Hz, 0.23H), 6.33 (br s, 0.23H), 6.17 (br s, 0.23H), 5.11 (q, J= 7.2 Hz, 0.23H), 4.65 (br d, J= 13.3 Hz, 0.74H), 4.13 - 3.85 (m, 1.35H), 3.49 (br s, 0.47H), 3.42 - 3.17 (m, 0.47H), 3.11 - 2.92 (m, 0.74H), 2.82 (s, 0.47H), 2.72 - 2.53 (m, 2.53H), 2.14 - 1.74 (m, 2.30H), 1.54 - 1.03 (m, 2.53H), 1.00 - 0.75 (m, 2.17H). The signal corresponding to the NH group was not observed.

Example 19: (±)-?ra«s-(5-methoxy-2-(2H-l,2,3-triazol-2-yl)phenyl)(2-me thyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 12 substituting intermediate A-4 with intermediate A- 14.

MS (ESI) mass calcd. for C ₂ 2H ₂ 3F _{3 6} O2,460.2; m/z found 461.0 [M+H] . MP=170.8 °C.

(Mixture of 4 isomers, undefined ratio). 'H NMR (300 MHz, CDC1 ₃ ) δ 8.41 - 8.29 (m, 0.33H), 8.28 - 8.11 (m, 0.55H), 8.05 (s, 0.45H), 7.99 (d, J= 9.0 Hz, 0.27H), 7.93 (s, 0.90H), 7.90 - 7.65 (m, 1.00H), 7.59 (dd, J= 8.7, 2.2 Hz, 0.33H), 7.54 - 7.38 (m, 0.59H), 7.35 (dd, J= 8.8, 2.3 Hz, 0.5H), 7.11 - 6.94 (m, 1.00H), 6.83 (d, J= 2.7 Hz, 0.45H), 6.77 (d, J= 2.8 Hz, 0.33H), 6.61 (d, J = 2.7 Hz, 0.10H), 6.41 (t, J= 9.1 Hz, 0.33H), 6.23 (d, J= 8.7 Hz, 0.10H), 6.13 (d, J= 8.8 Hz, 0.50H), 5.99 (br s, 0.27H), 5.26 - 5.09 (m, 0.37H), 5.07 - 4.90 (m, 0.20H), 4.68 (br d, J= 13.5 Hz, 0.60H), 4.25 - 4.04 (m, 1.06H), 3.98 (s, 0.41H), 3.93 - 3.78 (m, 2.48H), 3.57 (s, 0.25H), 3.54 - 3.39 (m, 0.72H), 3.22 (td, J= 13.4, 3.2 Hz, 0.39H), 2.93 (td, J= 13.1, 3.0 Hz, 0.52H),

2.13 - 1.59 (m, 3.30H), 1.52 (d, J= 6.9 Hz, 1.51H), 1.42 (d, J= 7.1 Hz, 0.78H), 1.37 - 1.19 (m, 0.78H), 1.00 - 0.62 (m, 0.63H). The signal corresponding to the NH group was not observed..

Example 20: (±)-/ra«s-(3-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)(2-met hyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 12 substituting intermediate A-4 with intermediate A- 15. MS (ESI) mass calcd. for C ₂ 2H ₂ 3F ₃ N ₆ 0,444.2; m/z found 445.2 [M+H] ⁺ . MP=153.0. (Mixture of 4 isomers, undefined ratio). 'H NMR (300 MHz, CDC1 ₃ ) δ 8.41 - 8.31 (m, 0.19H), 8.26 (s, 0.56H), 8.07 (s, 0.19H), 7.98 (s, 1.09H), 7.90 - 7.70 (m, 0.76H), 7.64 - 7.52 (m, 0.19H), 7.52 - 7.33 (m, 2.15H), 7.25 - 7.09 (m, 0.75H), 6.76 (br d, J= 26.3 Hz, 0.19H), 6.49 (d, J= 8.8 Hz, 0.56H), 6.43 (d, J= 9.0 Hz, 0.19H), 6.30 (d, J= 8.8 Hz, 0.19H), 5.17 (br d, J= 6.9 Hz, 0.19H), 5.00 - 4.76 (m, 0.19H), 4.53 (br d, J= 13.4 Hz, 0.56H), 4.20 - 4.00 (m, 1.09H), 3.94 (br s, 0.19H), 3.64 - 3.55 (m, 0.19H), 3.51 (d, J= 5.3 Hz, 0.35H), 3.40 (br d, J= 14.7 Hz, 0.19H), 3.22 (s, 0.19H), 2.96 (s, 0.19H), 2.86 (td, J= 13.2, 3.4 Hz, 0.66H), 2.32 (s, 1.75H), 2.28 (s, 0.35H), 2.22 (s, 0.19H), 2.13 (br s, 0.19H), 2.09 - 1.77 (m, 2.15H), 1.77 - 1.63 (m, 1.74H), 1.51 (d, J = 7.0 Hz, 2.15H), 1.38 (d, J= 7.1 Hz, 0.56H), 1.33 - 1.21 (m, 0.19H), 1.15 (d, J= 6.1 Hz, 0.19H), 1.07 (d, J= 6.9 Hz, 0.19H), 1.02 - 0.82 (m, 0.35H). The signal corresponding to the NH group was not observed.

Example 21: (±)-?ra«s-(3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)(2-methyl -3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 12 substituting intermediate A-4 with intermediate A- 16. (ESI) mass calcd. for C ₂ oH2oF ₃ 70,431.2; m/z found 432.2 [M+H] ⁺ . MP=79.6 °C. (Mixture of 4 isomers, undefined ratio). ¾ NMR (300 MHz, CDC1 ₃ ) δ 8.64 (dd, J= 4.7, 1.3 Hz, 0.3H), 8.57 (d, J= 3.6 Hz, 0.7H), 8.45 (d, J= 8.4 Hz, 0.3H), 8.38 (s, 0.3H), 8.31 (d, J= 8.2 Hz, 0.7H), 8.24 (s, 0.3H), 8.12 (s, 0.7H), 7.95 (s, 1.0H), 7.59 (d, J= 8.4 Hz, 0.3H), 7.55 - 7.34 (m, 1.4H), 6.99 (br d, J= 6.9 Hz, 0.7H), 6.43 (d, J= 8.9 Hz, 0.3H), 6.32 (br s, 0.7H), 6.10 (br s, 0.3H), 5.15 (br d, J= 7.2 Hz, 0.3H), 4.66 (br d, J= 13.4 Hz, 0.7H), 4.20 - 3.83 (m, 0.9H), 3.49 (d, J= 5.0 Hz, 0.7H), 3.44 - 3.26 (m, 0.7H), 3.14 - 2.94 (m, 0.7H), 2.13 - 1.76 (m, 2.7H), 1.75 - 1.61 (m, 1.20H), 1.48 (dd, J= 6.9, 4.2 Hz, 2.5H), 0.99 - 0.93 (m, 0.3H), 0.82 - 0.76 (m, 0.3H). The signal corresponding to the NH group was not observed.. Example 22: (±)-?ra«s-(2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)am ino)piperidin-l-yl)(6- methyl-3-(oxazol-2-yl)pyridin-2-yl)methanone hydrochloride.

Prepared analogous to Example 12 substituting intermediate A-4 with intermediate A- 18. MS (ESI) mass calcd. for C ₂ 2H ₂₂ F _{3 5} 02,445.2; m/z found 446.2 [M+H] ⁺ _. (Mixture of 4 isomers, undefined ratio). ¾ NMR (300 MHz, DMSO) δ 8.46 (s, 0.31H), 8.37 (d, J= 6.2 Hz, 0.58H),

8.31 (s, 0.58H), 8.24 - 8.02 (m, 0.47H), 7.82 (d, J= 7.4 Hz, 0.76H), 7.73 - 7.44 (m, 3.35H), 7.37 (d, J= 8.2 Hz, 0.76H), 6.89 (d, J= 9.0 Hz, 0.47H), 6.59 (br s, 0.72H), 4.94 (d, J= 6.7 Hz, 0.58H), 4.51 (d, J= 12.1 Hz, 0.76H), 3.86 (d, J= 6.8 Hz, 0.66H), 3.76 (br s, 0.58H), 3.30 - 3.08 (m, 0.66H), 3.00 (t, J= 11.7 Hz, 0.76H), 2.63 (s, 1.27H), 2.36 (s, 1.73H), 2.19 - 1.89 (m, 1.73H), 1.88 - 1.56 (m, 2.27H), 1.41 (d, J= 6.6 Hz, 1.27H), 1.21 (d, J= 6.5 Hz, 1.73H)..

Example 23: (±)-?ra«s-(2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)am ino)piperidin-l-yl)(6- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone hydrochloride.

Prepared analogous to Example 12 substituting intermediate A-4 with intermediate A- 19. MS (ESI) mass calcd. for C ₂ 3H ₂ 3F ₃ N ₆ 0,456.2; m/z found 457.2 [M+H] ⁺ _. (Mixture of 4 isomers, undefined ratio). ¾ NMR (300 MHz, DMSO) δ 9.00 (d, J= 4.9 Hz, 1.90H), 8.86 (d, J= 8.2 Hz, 0.45H), 8.45 - 8.36 (m, 1.00H), 8.53 - 8.08 (m, 0.67H), 8.21 (s, 0.55H), 7.85 (dd, J= 27.3, 8.5 Hz, 1.33H), 7.69 (d, J= 8.4 Hz, 0.55H), 7.60 (dt, J= 11.9, 4.9 Hz, 1.00H), 7.44 (d, J= 8.2 Hz, 0.55H), 7.22 (d, J= 9.0 Hz, 0.45H), 6.62 (br s, 0.55H), 4.77 (br d, J= 7.2 Hz, 0.67H), 4.46 (br d, J= 13.3 Hz, 0.67H), 4.00 - 3.80 (m, 1.15H), 3.29 (br s, 0.78H), 2.99 (t, J= 12.3 Hz, 0.78H), 2.81 (s, 1.40H), 2.44 (s, 1.60H), 2.17 - 1.73 (m, 3.18H), 1.66 (br d, J= 12.3 Hz, 0.67H), 1.59 - 1.25 (m, 3.15H).

Example 24: (±)-/ra«s-(5-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)(2-met hyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone

Prepared analogous to Example 14 substituting intermediate A-11 with intermediate A-

24. MS (ESI) mass calcd. for C ₂ iH ₂ oF ₄ N ₆ 0, 448.2; m/z found 449.2 [M+H] ⁺ . MP=168.1 °C. The product is present as a mixture of conformers (ratio ca. 60:40) ^X H NMR (300 MHz, DMSO) δ 8.32 (s, 0.4H), 8.08 (s, 1.2H), 8.07 (s, 0.8H), 8.00 (s, 0.6H), 7.94 (dd, J= 9.0, 4.9 Hz, 0.4H), 7.77 - 7.56 (m, 2H), 7.54 - 7.28 (m, 1.6H), 7.10 (td, J= 8.5, 2.9 Hz, 0.6H), 6.87 - 6.76 (m, 1.4H), 4.62 (q, J= 7.0 Hz, 0.4H), 4.43 - 4.23 (m, 0.6H), 3.79 - 3.56 (m, 1.6H), 3.23 (d, J= 15.9 Hz, 0.4H), 3.08 - 2.93 (m, 0.4H), 2.85 - 2.68 (m, 0.6H), 2.13 - 1.29 (m, 4H), 1.25 (d, J= 7.0 Hz, 1.2H), 0.67 (d, J= 6.9 Hz, 1.8H).

Example 25: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)amino) piperidin-l-yl)(6- methyl-3-(oxazol-2-yl)pyridin-2-yl)methanone hydrochloride.

Prepared analogous to Example 14 substituting intermediate A- 11 with intermediate A- 18. MS (ESI) mass calcd. for C ₂ 2H ₂₂ F _{3 5} 0 ₂ ,445.2; m/z found 446.2 [M+H] ⁺ _. The product is present as a mixture of conformers (ratio ca. 70:30) ^X H NMR (300 MHz, CDC1 ₃ ) δ 8.36 (s, 0.3H), 8.29 - 8.20 (m, 1H), 8.14 (d, J = 8.2 Hz, 0.7H), 7.81 (s, 1H), 7.65 - 7.49 (m, 0.6H), 7.41 (d, J = 7.0 Hz, 0.7H), 7.36 (s, 0.7H), 7.32 - 7.22 (m, 1H), 7.12 ( br s, 0.7H), 6.84 (br s, 0.3H), 6.46 (d, J= 8.8 Hz, 0.3H), 6.24 (d, J= 8.4 Hz, 0.7H), 5.20 (q, J= 7.8 Hz, 0.3H), 4.82 - 4.64 (m, 0.7H), 4.12 (d, J = 6.3 Hz, 0.3H), 4.02 (d, J = 5.6 Hz, 0.7H), 3.76 (q, J = 6.7 Hz, 0.7H), 3.36 - 3.14 (m, 0.6H), 3.11 - 2.94 (m, 0.7H), 2.63 (s, 0.9H), 2.60 (s, 2.1H), 2.09 - 1.52 (m, 4H), 1.49 (d, J= 7.1 Hz, 0.9H), 1.43 (d, J= 6.9 Hz, 2.1H).

Example 26: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)amino) piperidin-l-yl)(5- -triazol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to Example 14 substituting intermediate A-l 1 with intermediate A- 21. MS (ESI) mass calcd. for C ₂ iH ₂₂ F ₃ N ₇ 0,445.2; m/z found 446.2 [M+H] ⁺ _. MP=116.2 °C. The product is present as a mixture of conformers (ratio ca. 70:30) ^l H NMR (300 MHz, CDCI ₃ ) δ 8.45 (s, 0.3H), 8.38 (s, 1.1H), 8.24 (s, 1.1H), 8.15 - 8.04 (m, 1.1H), 7.93 (s, 1.1H), 7.58 (dd, J= 8.8, 2.1 Hz, 1.4H), 7.45 (d, J= 7.1 Hz, 0.3H), 6.99 (d, J= 7.2 Hz, 0.7H), 6.43 (d, J= 8.8 Hz, 0.3H), 6.31 (d, J= 8.4 Hz, 0.7H), 6.15 (d, J = 7.7 Hz, 0.3H), 5.13 (q, J = 6.7 Hz, 0.3H), 4.64 (d, J= 12.6 Hz, 0.7H), 4.09 - 3.85 (m, 1.7H), 3.45 - 3.21 (m, 0.6H), 3.11 - 2.92 (m, 0.7H), 2.48 (s, 0.9H), 2.44 (s, 2.1H), 2.10 - 1.72 (m, 3.3H), 1.65 - 1.58 (m, 0.7H), 1.52 - 1.41 (m, 3H). Example 27: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)amino) piperidin-l-yl)(5- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Prepared analogous to Example 14 substituting intermediate A-l 1 with intermediate A- 20. MS (ESI) mass calcd. for C ₂ iH ₂₂ F ₃ N ₇ 0,445.2; m/z found 446.2 [M+H] ⁺ _. MP=11 1.4 °C. The product is present as a mixture of conformers (ratio ca. 80:20) ^X H NMR (300 MHz, CDCI ₃ ) δ 8.93 - 8.74 (m, 2H), 8.59 (d, J= 8.2 Hz, 0.2H), 8.38 (d, J= 8.1 Hz, 0.8H), 8.28 (s, 0.2H), 8.20 (s, 0.8H), 7.52 - 7.13 (m, 2.8H), 6.48 (d, J= 8.8 Hz, 0.4H), 6.17 (d, J= 5.9 Hz, 0.8H), 5.06 - 4.88 (m, 0.2H), 4.62 (d, J= 13.3 Hz, 0.8H), 4.12 (d, J= 7.0 Hz, 0.2H), 4.04 - 3.79 (m, 1.8H), 3.32 - 3.1 1 (m, 0.2H), 3.08 - 2.86 (m, 0.8H), 2.60 (s, 0.6H), 2.57 (s, 2.4H), 2.10 - 1.54 (m, 4H), 1.50 - 1.41 (m, 3H).

Example 28: (±)-?ra«s-(3-fluoro-2-methoxyphenyl)(2-methyl-3-((5-(trifl uoromethyl)pyridin-2- yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 42 substituting intermediate A-4 with 3-fluoro-2- methoxybenzoic acid and 5-bromo-2-fluoropyridine with 2-chloro-5-(trifluoromethyl)pyridine. MS (ESI) mass calcd. for C ₂ oH ₂₁ F _{4 3} 0 ₂ ,411.2; m/z found 412.2 [M+H] ⁺ _. 1H NMR (CDC13): 8.35-8.05 (m, 1H), 7.76-7.39 (m, 1H), 7.17-5.95 (m, 4H), 5.26-4.63 (m, 1H), 4.29-2.75 (m, 6H), 2.17-1.56 (m, 4H), 1.48-1.23 (m, 3H).

Example 29: (±)-?ra«s-(2-ethoxyphenyl)(2-methyl-3-((5-(trifluoromethyl )pyridin-2- yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 42 substituting intermediate A-4 with 2-ethoxybenzoic acid and 5-bromo-2-fluoropyridine with 2-chloro-5-(trifluoromethyl)pyridine. MS (ESI) mass calcd. for C ₂ iH ₂₄ F _{3 3} O2,407.2; m/z found 408.2 [M+H] ⁺ _. 1H NMR (CDC13): 8.32-8.04 (m, 1H), 7.85-7.27 (m, 2H), 7.21-6.23 (m, 4H), 5.25-2.83 (m, 5H), 2.07-1.24 (m, 11H).

Example 30: (±)-/ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(3-((5-chloropy rimidin-2-yl)amino)-2- methylpiperidin- 1 -yl)methanone.

Step A: (±)-?ra«s-tert-butyl-3-((5-chloropyrimidin-2-yl)amino)-2-m ethylpiperidine-l- carboxylate. To intermediate B-3 (300 mg, 1.4 mmol) in w-BuOH (5 mL) was added 2,5- dichloropyrimidine (210 mg, 1.4 mmol) and DIPEA (480 μί, 2.8 mmol). The reaction was then heated at 120 °C overnight. The reaction was allowed to cool to rt, diluted with ¾0 and extracted with EtOAc. The combined organics were dried (MgS0 ₄ ). Silica gel chromatography (EtOAc in heptane) gave the title compound (237 mg, 43%). MS (ESI) mass calcd. for

Ci ₅ H ₂₃ Cl ₄ 02, 326.2, m/z found 327.0 [M+H] ⁺ .

Step B. ?ra«s-(±)-5-chloro-N-(2-methylpiperidin-3-yl)pyrimidin-2-a mine. Prepared analogous to Example 1 substituting (±)-ter?-butyl-3-((4,6-dimethylpyrimidin-2-yl)amino)-2- methylpiperidine- 1 -carboxylate with the title compound from Step A.

Step C. (±)-?ra«s-tert-butyl-3-((5-chloropyrimidin-2-yl)amino)-2-m ethylpiperidine-l- carboxylate. Prepared analogous to Example 12 substituting /raws-(±)-2-methylpiperidin-3-yl)-5- (trifluoromethyl)pyridin-2 -amine with the title compound from Step B. MS (ESI) mass calcd. for Ci ₉ H ₂ oClN ₇ 0,397.2; m/z found 398.2 [M+H] ⁺ . MP=200.5 °C. The product is present as a mixture of conformers (ratio ca. 60:40) ^X H NMR (300 MHz, CDC1 ₃ ) δ 8.31 - 7.77 (m, 5H), 7.62 - 7.24 (m, 3.4H), 6.60 (d, J= 8.4 Hz, 0.6H), 5.25 (q, J= 6.9 Hz, 0.6H), 4.80 - 4.68 (m, 0.4H), 4.26 - 4.03 (m, 1H), 3.93 (d, J= 7.4 Hz, 0.4H), 3.51 (dd, J= 13.7, 3.9 Hz, 0.6H), 3.25 (td, J= 13.4, 3.3 Hz, 0.6H), 3.08 - 2.84 (m, 0.4H), 1.96 - 1.59 (m, 4H), 1.50 (d, J= 6.9 Hz, 1.2H), 1.44 (d, J= 7.1 Hz, 1.8H).

Example 31: (±)-/ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-methyl-3-((5 -methylpyrimidin-2- yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 30 substituting 2,5-dichloropyrimidine with 2-chloro-5- methylpyrimidine and «-BuOH with DMSO. MS (ESI) mass calcd. for C2 ₀ H2 ₃ N7O, 377.2; m/z found 378.2 [M+H] ⁺ _. MP=153.0 °C.

Example 32: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(3-((5-chloropy ridin-2-yl)amino)-2- methylpiperidin- 1 -yl)methanone.

Step A: trans-(±)-tert-butyl-3-((5-chloropyridin-2-yl)amino)-2-meth ylpiperidine-l- carboxylate. To 5-chloro-2-iodopyridine (246 mg, 1 mmol) in THF 10 mL) was added Pd2(dba)3 (30 mg, 0.03 mmol), Xantphos (38 mg, 0.07 mmol) and sodium tert-butoxide (180 mg, 1.9 mmol). Then 2 was bubbled through the solution for 10 min and intermediate B-3 (200 mg, 0.9 mmol) was added. The reaction was then heated at 90 °C overnight, cooled to rt and saturated aHC03 (aq) was added followed by extraction with EtOAc. The combined organics were dried and purified via silica gel chromatography (EtOAc in heptane) to give the title compound (98 mg, 32%). MS (ESI) mass calcd. for 325.2; m/z found 326.0 [M+H] ⁺ _.

Step B: trans-(±)-5-chloro-N-(2-methylpiperidin-3-yl)pyridin-2-amin e.

Prepared analogous to Example 1 substituting (±)-ter/-butyl-3-((4,6-dimethylpyrimidin-2- yl)amino)-2-methylpiperidine-l -carboxylate with the title compound from Step A. Step C: (±)-tra«5-(2-(2H- 1,2,3 -triazol-2-yl)phenyl)(3-((5-chloropyridin-2-yl)amino)-2- methylpiperidin-l-yl)methanone. Prepared analogous to Example 30 substituting trans-(±)-2- methylpiperidin-3-yl)-5-(trifluoromethyl)pyridin-2-amine with the title compound from Step B.

MS (ESI) mass calcd. for C ₂ oH ₂₁ ClN ₆ 0, 396.2; m/z found 397.0 [M+H] _. MP=128.0 °C. The product is present as a mixture of conformers (12: 13 :35:40). ^X H NMR (300 MHz, DMSO) 8.25 (d, J = 12.3 Hz, 0.37H), 8.07 (s, 1.48H), 7.98 (d, J = 2.6 Hz, 0.25H), 7.97 - 7.86 (m, 0.48H), 7.86 - 7.77 (m, 0.25H), 7.73 (d, J = 8.1 Hz, 0.48H), 7.70 - 7.40 (m, 2.76H), 7.34 (t, J = 7.1 Hz, 0.75H), 7.26 (d, J = 1 1.5 Hz, 0.13H), 7.07 (d, J = 6.5 Hz, 0.40H), 6.93 (d, J = 6.8 Hz, 0.53H), 6.87 (d, J = 7.7 Hz, 0.40H), 6.78 (t, J = 7.1 Hz, 0.48H), 6.72 (d, J = 9.0 Hz, 0.88H), 6.62 (d, J = 9.1 Hz, 0.12H), 6.08 (d, J = 9.0 Hz, 0.12H), 6.03 (d, J = 7.9 Hz, 0.12H), 4.95 - 4.82 (m, 0.13H), 4.66 (q, J = 7.5 Hz, 0.37H), 4.38 (br d, J = 13.9 Hz, 0.41H), 4.01 - 3.89 (m, 0.25H), 3.89 - 3.77 (m, 0.40H), 3.70 (d, J = 7.4 Hz, 0.48H), 3.19 (br d, J = 14.4 Hz, 0.48H), 2.92 (br t, J = 11.7 Hz, 0.48H), 2.84 - 2.65 (m, 1H), 2.13 - 1.47 (m, 4H), 1.43 (d, J = 6.9 Hz, 0.36H), 1.31 (d, J = 7.0 Hz, 0.39H), 1.24 (d, J = 7.0 Hz, 1.05H), 0.77 (d, J = 7.0 Hz, 1.20H).

Example 33: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-methyl-3-((6 - (trifluoromethyl)pyridazin-3-yl)amino)piperidin- 1 -yl)methanone hydrochloride.

Prepared analogous to Example 31 substituting 2-chloro-5-methylpyrimidine with 3- chloro-6-(trifluoromethyl)pyridazine. MS (ESI) mass calcd. for C2 ₀ H2 ₀ F ₃ N7O, 431.2; m/z found 432.0 [M+H]+. MP=167.0 °C. (Mixture of 4 isomers, undefined ratio). ^X H NMR (300 MHz, DMSO) δ 8.33 - 7.98 (m, J= 25.2, 1.88H), 7.91 (d, J= 8.0 Hz, 0.43H), 7.85 - 7.31 (m, 4.06H), 7.31 - 7.03 (m, 1.49H), 6.97 (d, J= 6.5 Hz, 0.50H), 6.72 (t, J= 7.2 Hz, 0.50H), 6.50 (s, 0.14H), 5.14 - 4.93 (m, 0.14H), 4.77 (q, J= 7.0 Hz, 0.43H), 4.52 - 4.30 (m, 0.70H), 4.26 - 4.05 (m, 0.58H), 3.38 - 3.10 (m, 0.83H), 3.06 - 2.87 (m, 0.63H), 2.79 (t, J= 1 1.8 Hz, 0.69H), 2.20 - 1.50 (m, 3.64H), 1.50 - 1.17 (m, 2.07H), 0.73 (d, J= 6.9 Hz, 1.29H). Example 34: (2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-((5-fluoropyridi n-2-yl)amino)-2- methylpiperidin- 1 -yl)methanone.

Prepared analogous to Example 32 substituting 5-chloro-2-iodopyridine with 5-fluoro-2- iodopyridine. MS (ESI) mass calcd. for C ₂ oH ₂₁ FN ₆ 0, 380.2; m/z found 381.2 [M+H] ⁺ _. MP= 189.4 °C. (Mixture of 4 isomers, undefined ratio). ¾ NMR (300 MHz, DMSO) δ 8.25 (d, J= 11.1 Hz, 0.44H), 8.15 - 7.99 (m, 1.77H), 7.90 (d, J= 8.1 Hz, 0.52H), 7.84 - 7.42 (m, 4.24H), 7.35 (t, J= 7.8 Hz, 0.65H), 7.12 (d, J= 7.7 Hz, 0.71H), 7.06 - 6.91 (m, 0.51H), 6.91 - 6.77 (m, 0.78H), 6.76 - 6.67 (m, 0.16H), 6.21 - 6.07 (m, 0.22H), 4.93 - 4.76 (m, 0.35H), 4.66 (q, J= 6.9 Hz, 0.61H), 4.38 (d, J= 12.7 Hz, 0.83H), 3.30 - 3.11 (m, 0.85H), 3.03 - 2.85 (m, 0.86H), 2.84 - 2.71 (m, 0.5H), 2.12 - 1.47 (m, 3.52H), 1.48 - 1.14 (m, 2.50H), 0.79 (d, J= 6.9 Hz, 0.98H).

Example 35: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-methyl-3-((5 - (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)methano ne.

Prepared analogous to Example 30 substituting 2,5-dichloropyrimidine with 2-chloro-5- (trifluoromethyl)pyrimidine. MS (ESI) mass calcd. for C2 ₀ H2 ₀ F ₃ N7O, 431.2; m/z found 432.2 [M+H _]+. MP=204.4 °C. (Mixture of 4 isomers, undefined ratio). ^X H NMR (300 MHz, CDC1 ₃ ) δ 8.60 - 8.45 (m, 1.37H), 8.45 - 8.23 (m, 1.95H), 8.23 - 8.11 (m, 0.63H), 8.12 - 8.00 (m, 0.58H), 7.96 (d, J= 7.3 Hz, 0.27H), 7.88 (d, J= 8.3 Hz, 0.09H), 7.82 (d, J= 6.5 Hz, 0.27H), 7.56 (td, J= 7.9, 1.5 Hz, 0.89H), 7.51 - 7.33 (m, 1.45H), 7.30 (d, J= 1.4 Hz, 0.78H), 7.07 (dd, J= 7.7, 1.3 Hz, 0.08H), 6.97 (t, J= 10.4 Hz, 0.56H), 6.81 (t, J= 7.5 Hz, 0.08H), 5.88 (d, J= 7.3 Hz, 0.08H), 5.72 (d, J= 6.2 Hz, 0.08H), 5.28 (q, J= 6.9 Hz, 0.48H), 5.05 (d, J= 7.1 Hz, 0.08H), 4.76 (d, J= 13.6 Hz, 0.38H), 4.40 - 4.24 (m, 0.48H), 4.14 (q, J= 7.1 Hz, 0.38H), 4.04 (d, J= 7.5 Hz, 0.22H), 3.97 - 3.83 (m, 0.08H), 3.68 (s, 0.08H), 3.53 (dd, J= 15.5, 4.7 Hz, 0.7H), 3.27 (td, J = 13.4, 3.3 Hz, 0.58H), 3.14 - 2.76 (m, 0.38H), 2.16 - 1.21 (m, 6.56H), 1.15 (d, J= 6.1 Hz, 0.08H), 1.05 - 0.93 (m, 0.08H), 0.93 - 0.82 (m, 0.12H), 0.73 (d, J= 7.0 Hz, 0.16H).

Example 36: (±)-trans -(2-(2H- 1,2,3 -triazol-2-yl)phenyl)(2-methyl-3-(pyridin-2- ylamino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 32 substituting 5-chloro-2-iodopyridine with 2- iodopyridine. MS (ESI) mass calcd. for C ₂ oH ₂₂ N ₆ 0, 362.2; m/z found 363.2 [M+H] ⁺ _. MP=277.1 °C. (Mixture of 4 isomers, undefined ratio). ^X H NMR (300 MHz, DMSO) δ 8.99 - 8.49 (m, 0.83H), 8.40 (d, J = 5.3 Hz, 0.15H), 8.22 (br s, 0.32H), 8.18 - 7.73 (m, 4.79H), 7.70 - 7.43 (m, 1.78H), 7.42 - 7.03 (m, 1.68H), 7.03 - 6.77 (m, 1.25H), 6.77 - 6.67 (m, 0.10H), 6.67 - 6.51 (m, 0.10H), 4.92 - 4.77 (m, 0.15H), 4.68 (q, J= 6.8 Hz, 0.60H), 4.43 (br d, J= 13.9 Hz, 0.42H), 4.06 (br s, 0.60H), 3.92 (br s, 0.32H), 3.86 - 3.67 (m, 0.60H), 3.24 (br s, 0.29H), 2.99 (t, J = 11.9 Hz, 0.60H), 2.83 (t, J= 1 1.5 Hz, 0.42H), 2.24 - 1.54 (m, 3.04H), 1.54 - 1.12 (m, 3.13H), 0.88 (d, J = 6.6 Hz, 0.83H).

Example 37: (±)-/ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-methyl-3-((5 -methylpyridin-2- yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 32 substituting 5-chloro-2-iodopyridine with 2-chloro-5- methylpyridine. MS (ESI) mass calcd. for C ₂ iH ₂₄ N ₆ 0, 376.2; m/z found 377.2 [M+H] ⁺ .

MP=148.0 °C. (Mixture of 4 isomers, undefined ratio). ^X H NMR (300 MHz, DMSO) δ 8.66 (d, J = 8.0 Hz, 0.64H), 8.57 (br s, 0.34H), 8.25 (d, J= 8.1 Hz, 0.41H), 8.14 (d, J= 9.9 Hz, 1.66H), 8.05 - 7.76 (m, 3.39H), 7.76 - 7.52 (m, 1.66H), 7.45 (t, J= 8.2 Hz, 0.34H), 7.35 (d, J= 9.7 Hz, 0.64H), 7.28 (d, J= 7.1 Hz, 0.34H), 7.23 - 7.13 (m, 0.16H), 6.99 (t, J= 7.5 Hz, 0.34H), 6.60 (br s, 0.08H), 4.86 (br s, 0.16H), 4.72 (q, J= 6.9 Hz, 0.64H), 4.47 (br d, J= 12.9 Hz, 0.41H), 4.07 (br s, 0.64H), 3.95 (br s, 0.34H), 3.76 (br s, 0.64H), 3.27 (br s, 0.11H), 3.01 (dd, J= 21.0, 8.4 Hz, 0.64H), 2.92 - 2.81 (m, 0.34H), 2.74 (s, 0.41H), 2.72 - 2.67 (m, 0.08H), 2.25 (s, 2.59H), 2.19 - 1.57 (m, 3.30H), 1.56 - 1.40 (m, 1.14H), 1.37 (d, J= 7.0 Hz, 1.57H), 1.29 (s, 0.16H), 0.90 (d, J = 6.8 Hz, 0.83H).

Example 38: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-methyl-3-((5 - (trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 31 substituting 2-chloro-5-methylpyrimidine with 2- chloro-5-(trifluoromethyl)pyrazine and DIPEA with K2CO ₃ . MS (ESI) mass calcd. for C ₂ oH ₂ oF _{3 7} 0, 431.2; m/z found 432.2 [M+H] ⁺ _. ¾ NMR (300 MHz, DMSO) δ 8.42 (br s, 0.5H), 8.27 - 8.17 (m, 1.09H), 8.15 (s, 0.26H), 8.10 (s, 1.31H), 8.08 (s, 0.62H), 8.06 - 7.99 (m, 0.62H), 7.99 - 7.91 (m, 0.62H), 7.90 (s, 0.26H), 7.80 - 7.39 (m, 2.14H), 7.27 (t, J= 7.1 Hz, 0.50H), 7.11 (s, 0.09H), 7.07 (d, J = 7.7 Hz, 0.45H), 6.94 (s, 0.09H), 6.66 (t, J = 7.6 Hz, 0.45H), 4.72 (q, J = 6.6 Hz, 0.50H), 4.41 (br d, J = 12.7 Hz, 0.70H), 4.04 (br s, 0.50H), 3.98 - 3.90 (m, 0.45H), 3.31 - 3.27 (m, 0.28H), 3.18 (br s, 0.62H), 3.03 - 2.91 (m, 0.50H), 2.84 - 2.76 (m, 0.45H), 2.31 - 2.25 (m, 0.26H), 2.15 - 1.84 (m, 1.81H), 1.84 - 1.67 (m, 1.09H), 1.67 - 1.49 (m, 1.09H), 1.39 (d, J= 7.2 Hz, 0.62H), 1.32 (s, 0.09H), 1.27 (d, J= 7.0 Hz, 0.95H), 0.66 (d, J= 6.9 Hz, 1.09H).

Example 39: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-methyl-3-(qu inazolin-2- ylamino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 30 substituting 2,5-dichloropyrimidine with 2- chloroquinazoline. MS (ESI) mass calcd. for Ο^Η^ τΟ, 413.2; m/z found 414.2 [M+H] ⁺ _.

(Mixture of 4 isomers, undefined ratio). 'H NMR (300 MHz, CDC1 ₃ ) δ 9.02 (s, 0.44H), 8.83 (s, 0.15H), 8.35 (s, 0.61H), 8.14 (d, J= 8.1 Hz, 0.44H), 8.08 (s, 0.28H), 8.00 (d, J= 7.6 Hz, 0.33H), 7.91 (d, J= 7.9 Hz, 0.33H), 7.86 - 7.10 (m, 7.45H), 7.10 - 6.94 (m, 0.23H), 6.82 (br s, 0.15H), 6.64 (d, J= 8.0 Hz, 0.44H), 6.30 (br s, 0.15H), 5.77 (br s, 0.15H), 5.54 (br s, 0.15H), 5.29 (br d, J= 5.5 Hz, 0.61H), 5.18 - 5.03 (m, 0.15H), 4.84 - 4.61 (m, 0.33H), 4.41 (d, J= 7.9 Hz, 0.44H), 4.30 (br s, 0.15H), 4.25 - 3.97 (m, 0.61H), 3.91 - 3.68 (m, 0.15H), 3.50 (d, J= 10.1 Hz, 0.44H), 3.25 (t, J= 11.9 Hz, 0.49H), 3.09 - 2.69 (m, 0.39H), 2.39 - 1.81 (m, 1.13H), 1.81 - 1.56 (m, 1.30H), 1.52 (d, J= 6.8 Hz, 0.80H), 1.44 (dd, J= 13.1, 6.7 Hz, 1.94H), 1.02 - 0.62 (m, 1.83H). The signal corresponding to the NH group was not observed.

Example 40: (±)-/ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(3-((5-fluoropy rimidin-2-yl)amino)-2- methylpiperidin- 1 -yl)methanone.

Prepared analogous to Example 31 substituting 2-chloro-5-methylpyrimidine with 2- chloro-5-fluoropyrimidine. MS (ESI) mass calcd. for C ₉ H2 ₀ FN7O, 381.2; m/z found 382.1

[M+H] ⁺ . (Mixture of 4 isomers, undefined ratio). ¾ NMR (300 MHz, DMSO) δ 8.48 (s, 0.47H), 8.39 (d, J= 7.6 Hz, 1.01H), 8.24 (s, 0.61H), 8.17 (s, 0.47H), 8.07 (d, J= 3.7 Hz, 1.01H), 8.02 (d, J= 8.4 Hz, 0.37H), 7.88 (d, J= 7.0 Hz, 0.47H), 7.73 (d, J= 7.8 Hz, 0.58H), 7.69 - 7.28 (m, 2.90H), 7.00 (d, J= 6.4 Hz, 0.37H), 6.83 (t, J= 7.1 Hz, 0.37H), 6.42 (d, J= 8.5 Hz, 0.37H), 4.94 (dd, J= 13.8, 7.1 Hz, 0.37H), 4.68 (dd, J= 13.4, 6.2 Hz, 0.37H), 4.44 (d, J= 12.4 Hz, 0.20H), 4.34 (d, J= 11.9 Hz, 0.37H), 4.04 (d, J= 8.5 Hz, 0.37H), 3.94 (t, J= 10.0 Hz, 0.37H), 3.77 (dd, J = 14.2, 7.0 Hz, 0.37H), 3.47 - 3.38 (m, 0.47H), 3.20 (d, J= 13.7 Hz, 0.37H), 3.01 - 2.82 (m,

0.37H), 2.82 - 2.67 (m, 0.37H), 2.12 - 1.79 (m, 1.74H), 1.76 - 1.47 (m, 1.55H), 1.44 (d, J= 6.9 Hz, 0.52H), 1.35 (d, J= 7.2 Hz, 0.86H), 1.33 - 1.26 (m, 0.61H), 1.23 (d, J= 7.0 Hz, 0.86H), 0.77 (d, J= 7.0 Hz, 0.86H). Example 41: (±)-/ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(3-(benzo[d]oxa zol-2-ylamino)-2- methylpiperidin- 1 -yl)methanone.

Step A: (±)-tert-butyl 3-(benzo[d]oxazol-2-ylamino)-2-methylpiperidine-l-carboxylat e. To intermediate B-3 (1.4 g, 6.6 mmol) in 1,4-dioxane (20 mL) was added DIPEA (2.3 mL, 13.2 mmol) and 2-(methylsulfinyl)benzo[d]oxazole (2.4 g, 13.2 mmol). After heating at 80 °C for 4h, the mixture was cooled to rt and saturated NaHC03 (aq) was added. The aqueous layer was extracted with EtOAc (3X). The combined organics were dried (MgS0 ₄ ). Purification via silica gel chromatography (0-50% EtOAc in hexanes) gave the title compound (1.7 g, 77%).

Step B: (±)-N-(-2-methylpiperidin-3-yl)benzo[d]oxazol-2-amine. Prepared analogous to Example 1 substituting (±)-tert-butyl-3-((4,6-dimethylpyrimidin-2-yl)amino)-2- methylpiperidine- 1 -carboxylate with the title compound from step A.

Step C: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(3-(benzo[d]oxa zol-2-ylamino)-2- methylpiperidin-l-yl)methanone. Prepared analogous to Example 30 substituting trans-(±)-5- chloro-N-(2-methylpiperidin-3-yl)pyrimidin-2-amine with the title compound from step B. MS (ESI) mass calcd. for C ₂ 2H ₂₂ N ₆ O2,402.2; m/z found 403.2 [M+H] ⁺ . (Mixture of 4 isomers, undefined ratio). ¾ NMR (300 MHz, DMSO) δ 8.03 (dd, J= 12.9, 10.4 Hz, 0.82H), 7.91 (d, J = 6.3 Hz, 0.36H), 7.84 (d, J= 2.8 Hz, 1.27H), 7.81 - 7.70 (m, 0.36H), 7.66 (d, J= 7.8 Hz, 0.46H), 7.59 - 7.47 (m, 0.82H), 7.47 - 7.23 (m, 1.79H), 7.24 - 7.08 (m, 1.27H), 7.08 - 6.95 (m, 0.61H), 6.95 - 6.65 (m, 2.88H), 6.16 (t, J= 7.8 Hz, 0.36H), 4.90 - 4.76 (m, 0.36H), 4.57 (q, J= 7.1 Hz, 0.46H), 4.25 - 4.06 (m, 0.46H), 3.91 - 3.78 (m, 0.36H), 3.75 - 3.56 (m, 0.82H), 3.56 - 3.44 (m, 0.36H), 3.32 - 3.19 (m, 0.36H), 2.97 (br d, J= 14.4 Hz, 0.36H), 2.82 - 2.63 (m, 0.46H), 2.06 - 2.00 (m, 0.18H), 1.91 - 1.18 (m, 4.56H), 1.18 - 1.08 (m, 0.82H), 0.80 (d, J= 6.1 Hz, 0.36H), 0.58 (d, J = 6.9 Hz, 1.08H).

Example 42: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(3-((5-bromopyr idin-2-yl)amino)-2- methylpiperidin- 1 -yl)methanone.

Step A: (±)-trans-tert-butyl 3-((5-bromopyridin-2-yl)amino)-2-methylpiperidine-l- carboxylate. Intermediate B-3 (1.6 g, 7.5 mmol), 5-bromo-2-fluoropyridine (2.9 g, 15 mmol) and K ₂ C0 ₃ (4.1 g, 30 mmol) were heated in NMP (50 mL) at 100 °C for 8h. The reaction was allowed to cool to rt then concentrated and purified via silica gel chromatography (50% EtOAc in petroleum ethers). Step B: (±)-trans-5-bromo-N-(2-methylpiperidin-3-yl)pyridin-2-amine .

To the title compound from step A in DCM (10 mL) was added TFA (1 mL). After lh, the reaction was concentrated to give the title compound that was used without further purification.

Step C: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(3-((5-bromopyr idin-2-yl)amino)-2- methylpiperidin-l-yl)methanone. The title compound from Step B (50 mg), DIPEA (1 mL), intermediate A-4 (100 mg) and HATU (200 mg) were stirred in THF at rt for 3h. Upon completion of the reaction, purification was performed using preparative HPLC to give the title compound (20 mg, 55% yield). MS (ESI) mass calcd. for C ₂ oH ₂₁ BrN ₆ 0,440.2; m/z found 441.1 [M+H] ⁺ . 1H NMR (CDC13): 8.11-7.26 (m, 8H), 7.11-5.91 (m, 1H), 5.19-4.55 (m, 1H), 4.26-2.68 (m, 3H), 2.11-0.71 (m, 7H).

Example 43: (±)-/ra«s-(3-((5-bromopyridin-2-yl)amino)-2-methylpiperidi n-l-yl)(3-fluoro-2- methoxyphenyl)methanone.

Prepared analogous to Example 42 substituting intermediate A-4 with 3-fluoro-2- methoxybenzoic acid. MS (ESI) mass calcd. for C ₁₉ H ₂₁ BrFN ₃ 0 ₂ ,421.2; m/z found 422.1

[M+H] ⁺ . 1H MR (CDC1 ₃ ): 8.03-7.50 (m, 2H), 7.33-6.09 (m, 4H), 5.24-4.61 (m, 1H), 4.02-3.33 (m, 5H), 3.30-2.84 (m, 1H), 2.24-1.16 (m, 7H). Example 44: (±)-?ra«s-(3-(5-bromopyridin-2-yl)amino)-2-methylpiperidin -l-yl)(2- ethoxyphenyl)methanone.

Prepared analogous to Example 42 substituting intermediate A-4 with 2-ethoxybenzoic acid. MS (ESI) mass calcd. for C ₂ oH ₂₄ BrN ₃ 0 ₂ ,417.2; m/z found 418.1 [M+H] ⁺ _. IH NMR (CDC13): 7.93-6.19 (m, 7H), 5.20-4.52 (m, IH), 4.32-3.87 (m, 2H), 3.81-2.83 (m, 3H), 2.22-1.76 (m, 3H), 1.52-1.21 (m, 7H).

Example 45: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(3-((5-chlorobe nzo[d]oxazol-2- yl)amino)-2-methylpiperidin- 1 -yl)methanone.

Prepared analogous to Example 42 substituting 5-bromo-2-fluoropyridine with 2,5- dichlorobenzo[d]oxazole. MS (ESI) mass calcd. for C ₂₂ H ₂ iCl ₆ 0 ₂ ,436.2; m/z found 437.2

[M+H] ⁺ _. IH NMR (CDC13): 11.55 (s, IH), 8.14-7.71 (m, 4H), 7.60-7.28 (m, 4H), 7.23-6.98 (m, IH), 5.42-4.67 (m, IH), 4.27-3.94 (m, IH), 3.50-3.45 (m, IH), 3.07-2.94 (m, IH), 2.18-1.80 (m, 3H), 1.7-1.39 (m, 4H).

Example 46: (±)-?ra«s-(3-((5-chlorobenzo[d]oxazol-2-yl)amino)-2-methyl piperidin-l-yl)(2- ethoxyphenyl)methanone.

Prepared analogous to Example 45 substituting intermediate A-4 with 2-ethoxybenzoic acid. MS (ESI) mass calcd. for C ₂ 2H ₂ 4C1 ₃ 0 ₃ ,413.2; m/z found 414.2 [M+H] ⁺ _. 1H NMR (CDC13): 7.47-6.19 (m, 7H), 5.85-4.57 (m, 1H), 4.57-2.68 (m, 5H), 2.25-0.99 (m, 10H).

Example 47: (±)-?ra«s-(3-((5-chlorobenzo[d]oxazol-2-yl)amino)-2-methyl piperidin-l-yl)(3- fluoro-2-methoxyphenyl)methanone.

Prepared analogous to Example 45 substituting intermediate A-4 with 3-fluoro-2- methoxybenzoic acid. MS (ESI) mass calcd. for C ₂₁ H ₂₁ C1FN ₃ 0 ₃ ,417.2; m/z found 418.1

[M+H] ⁺ _. 1H NMR (CDC13): 7.37-7.25 (m, 1H), 7.23-6.52 (m, 5H), 5.26-4.62 (m, 1H), 4.24-3.85 (m, 3H), 3.83-3.60 (m, 1H), 3.41-3.09 (m, 1H), 2.97-2.88 (m, 1H), 2.32-1.57 (m, 4H), 1.56-1.05 (m, 3H). Example 48: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-methyl-3-(qu inoxalin-2- ylamino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 42 substituting 5-bromo-2-fluoropyridine with 2- chloroquinoxaline. MS (ESI) mass calcd. for C ₂₃ H ₂ 3 ₇ 0, 413.2; m/z found 414.2 [M+H] ⁺ . IH NMR (CDC13): 8.40-7.95 (m, 2H), 7.95-7.70 (m, 3H), 7.70-7.26 (m, 6H), 5.36-4.56 (m, IH), 4.42-2.77 (m, 3H), 2.16-0.68 (m, 7H).

Example 49: (±)-?ra«s-(2-ethoxyphenyl)(2-methyl-3-(quinoxalin-2-ylamin o)piperidin-l- yl)methanone.

Prepared analogous to Example 48 substituting intermediate A-4 with 2-ethoxybenzoic acid. MS (ESI) mass calcd. for C ₂₃ H ₂₆ N ₄ O2,390.2; m/z found 391.2 [M+H] ⁺ _. IH NMR (CDC13): 8.72-8.36 (m, IH), 7.98-7.29 (m, 5H), 7.24-6.57 (m, 3H), 5.27-2.90 (m, 6H), 2.13-1.76 (m, 3H), 1.62-1.30 (m, 7H).

Example 50: (±)-?ra«s-(3-fluoro-2-methoxyphenyl)(2-methyl-3-(quinoxali n-2- ylamino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 48 substituting intermediate A-4 with 3-fluoro-2- methoxybenzoic acid. MS (ESI) mass calcd. for C ₂ 2H ₂₃ F ₄ 02, 394.2; m/z found 395.2 [M+H] ⁺ . 1H NMR (CDC13): 8.75-8.26 (m, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.84 (t, J = 9.2 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.37-6.08 (m, 3H), 5.32-4.60 (m, 1H), 4.31-3.80 (m, 4H), 3.77-2.91 (m, 2H), 2.29-1.51 (m, 4H), 1.51-1.29 (m, 3H).

Example 51: (±)-?ra«s-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-methyl-3-((4 -phenylpyrimidin-2- yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 42 substituting 5-bromo-2-fluoropyridine with 2-chloro- 4-phenylpyrimidine. MS (ESI) mass calcd. for C ₂ 5H ₂ 5 ₇ 0, 439.2; m/z found 440.2 [M+H] ⁺ .

Example 52: (±)-?ra«s-(3-fluoro-2-methoxyphenyl)(2-methyl-3-((4-phenyl pyrimidin-2- yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 51 substituting intermediate A-4 with 3-fluoro-2- methoxybenzoic acid. MS (ESI) mass calcd. for C24H25F 4O2, 420.2; m/z found 421.2 [M+H] 1H MR (CDC13): 10.31-9.49 (m, 1H), 8.18-8.09 (m, 2H), 7.81-6.43 (m, 8H), 5.57-4.67 (m, 1H), 4.60-4.13 (m, 1H), 4.13-2.77 (m, 5H), 2.38-1.88 (m, 3H), 1.88-1.09 (m, 4H).

Example 53: (±)-?ra«s-(2-ethoxyphenyl)(2-methyl-3-((4-phenylpyrimidin- 2-yl)amino)piperidin- -yl)methanone.

Prepared analogous to Example 51 substituting intermediate A-4 with 2-ethoxybenzoic acid. MS (ESI) mass calcd. for C25H2 ₈ 4O2, 416.2; m/z found 417.2 [M+H] ⁺ . 1H NMR (CDC13): 10.37-9.49 (m, 1H), 8.29-6.29 (m, 11H), 5.58-4.61 (m, 1H), 4.61-4.25 (m, 1H), 4.25-2.84 (m, 4H), 2.22-1.89 (m, 3H), 1.80-1.07 (m, 7H). Example 54: (±)-c«-(3-fluoro-2-methoxyphenyl)(2-methyl-3-((5-(trifluor omethyl)pyridin-2- yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 28 substituting intermediate B-3 for intermediate B-6. MS (ESI) mass calcd. for C ₂ oH ₂₁ F _{4 3} 0 ₂ , 41 1.2; m/z found 412.1 [M+H] ⁺ _. IH NMR (CDC13): 8.38-7.38 (m, 2H), 7.23-5.71 (m, 4H), 5.68-3.74 (m, 6H), 3.35-2.78 (m, IH), 2.03-1.39 (m, 4H), 1.36-1.02 (m, 3H).

Example 55: (±)-c s-(2-ethoxyphenyl)(2-methyl-3-((5-(trifluoromethyl)pyridin-2 - yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 54 substituting 3-fluoro-2-methoxybenzoic acid with 2- ethoxybenzoic acid. MS (ESI) mass calcd. for C ₂ iH ₂₄ F ₃ N ₃ O2,407.2; m/z found 408.1 [M+H] ⁺ _. IH NMR (CDC13): 8.37-7.27 (m, 3H), 7.25-6.18 (m, 4H), 6.01-3.98 (m, 4H), 3.97-2.68 (m, 2H), 1.95-1.65 (m, 3H), 1.59-1.32 (m, 4H), 1.29-0.98 (m, 3H).

Example 56: (±)-c«-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-methyl-3-((5-(t rifluoromethyl)pyridin- 2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 54 substituting 3-fluoro-2-methoxybenzoic acid with intermediate A-4. MS (ESI) mass calcd. for C ₂ iH ₂₁ F ₃ N ₆ O,430.2; m/z found 431.2 [M+H] ⁺ _. 1H NMR (CDC13): 8.14-7.72 (m, 4H), 7.64-7.30 (m, 3H), 7.24-6.41 (m, 2H), 5.32-2.70 (m, 4H), 2.06-1.35 (m, 4H), 1.33-1.16 (m, 3H).

Example 57: (±)-c«-(2-(2H-l,2,3-triazol-2-yl)phenyl)(3-((5-bromopyridi n-2-yl)amino)-2- methylpiperidin- 1 -yl)methanone.

Prepared analogous to Example 42 substituting Intermediate B-3 with Intermediate B-6.

MS (ESI) mass calcd. for C ₂ oH ₂₁ BrN ₆ 0,440.2; m/z found 441.1 [M+H] ⁺ _. IH MR (CDC13): 9.69 (brs, 1H), 8.10-7.67 (m, 4H), 7.65-7.38 (m, 3H), 7.36-6.01 (m, 2H), 5.35-4.43 (m, 1H), 4.03-2.60 (m, 3H), 2.03-1.77 (m, 2H), 1.76-0.76 (m, 5H). Example 58: (±)-c«-(3-(5-bromopyridin-2-yl)amino)-2-methylpiperidin-l- yl)(3-fluoro-2- methoxyphenyl)methanone.

Prepared analogous to Example 57 substituting intermediate A-4 with 3-fluoro-2- methoxybenzoic acid. MS (ESI) mass calcd. for C ₁₉ H ₂₁ BrFN ₃ 0 ₂ ,421.2; m/z found 421.9

[M+H] ⁺ _. 1H NMR (CDC13): 8.10-7.27 (m, 2H), 7.23-6.72 (m, 3H), 6.71-5.94 (m, 1H), 5.41-4.52 (m, 1H), 4.19-3.53 (m, 4H), 3.35-2.77 (m, 3H), 2.08-0.99 (m, 7H).

Example 59: (±)-c«-(3-(5-bromopyridin-2-yl)amino)-2-methylpiperidin-l- yl)(2- ethoxyphenyl)methanone.

Prepared analogous to Example 57 substituting intermediate A-4 with 2-ethoxybenzoic acid. MS (ESI) mass calcd. for C ₂ oH ₂₄ BrN ₃ 02,417.2; m/z found 418.0 [M+H] ⁺ _. 1H NMR (CDC13): 8.01-7.29 (m, 3H), 7.24-6.81 (m, 3H), 6.51-5.76 (m, 1H), 5.36-4.64 (m, 1H), 4.35-3.78 (m, 3H), 3.77-2.76 (m, 2H), 2.11-0.83 (m, 10H).

Example 60: (±)-cis-( (2-(2H-l,2,3-triazol-2-yl)phenyl)(3-((5-chlorobenzo[d]oxazol -2- yl)amino)-2-methylpiperidin- 1 -yl)methanone.

Prepared analogous to Example 45 substituting intermediate B-3 with intermediate B-6. MS (ESI) mass calcd. for C ₂ 2H ₂₁ C1N ₆ 0 ₂ ,436.2; m/z found 437.1 [M+H] ⁺ _. IH MR (CDC13): 11.37-10.92 (m, 1H), 8.21-7.97 (m, 1H), 7.90-7.88 (m, 1H), 7.81-7.80 (m, 1H), 7.61-7.27 (m, 5H), 7.24-7.10 (m, 1H), 5.47-4.04 (m, 1H), 4.01-3.46 (m, 1H), 3.41-2.74 (m, 2H), 2.06-0.96 (m, 7H).

Example 61: (±)-c s-(3-((5-chlorobenzo[d]oxazol-2-yl)amino)-2-methylpiperidin- l-yl)(2- ethoxyphenyl)methanone.

Prepared analogous to Example 60 substituting intermediate A-4 with 2-ethoxybenzoic acid. MS (ESI) mass calcd. for C ₂ 2H ₂ 4C1N ₃ 0 ₃ ,413.2; m/z found 414.0 [M+H] ⁺ _. IH NMR (CDC13): 7.42-7.27 (m, 3H), 7.21-6.84 (m, 4H), 5.39-4.70 (m, 1H), 4.27-3.68 (m, 4H), 3.41-2.74 (m, 1H), 2.07-1.61 (m, 3H), 1.60-1.04 (m, 7H).

Example 62: (±)-c«-(3-((5-chlorobenzo[d]oxazol-2-yl)amino)-2-methylpip eridin-l-yl)(3-fluoro- 2-methoxyphenyl)methanone.

Prepared analogous to Example 60 substituting intermediate A-4 with 3-fluoro-2- methoxybenzoic acid. MS (ESI) mass calcd. for C ₂ iH ₂₁ ClFN ₃ 0 ₃ ,417.2; m/z found 417.9 [M+H] ⁺ 1H NMR (CDC13): 7.35-6.88 (m, 6H), 5.54-3.57 (m, 5H), 3.39-2.72 (m, 3H), 2.12-1.37 (m, 4H), 1.33-1.00 (m, 3H).

Example 63: (±)-c«-(2-(2H-l,2,3-triazol-2-yl)phenyl)(2-methyl-3-(quino xalin-2- ylamino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 48 substituting intermediate B-3 with intermediate B-6.

MS (ESI) mass calcd. for C ₂ 3H ₂ 3 ₇ 0, 413.2; m/z found 414.2 [M+H] ⁺ _. 1H NMR (CDC13): 11.03 (s, 1H), 8.97-8.37 (m, 1H), 8.14-7.28 (m, 10H), 5.41-3.90 (m, 2H), 3.74-2.57 (m, 2H), 2.20-1.82 (m, 2H), 1.80-0.85 (m, 5H). Example 64: (±)-cis-(3 -fluoro-2-methoxyphenyl)(2-methyl-3 -(quinoxalin-2-ylamino)piperidin- 1 - yl)methanone.

Prepared analogous to Example 63 substituting intermediate A-4 with 3-fluoro-2- methoxybenzoic acid. MS (ESI) mass calcd. for C ₂₂ H ₂₃ F ₄ 0 ₂ , 394.2; m/z found 395.2 [M+H] ⁺ _. 1H MR (CDC13): 8.96-8.1 1 (m, 1H), 8.08-7.64 (m, 3H), 7.55 (s, 1H), 7.22-6.85 (m, 3H), 5.45- 4.59 (m, 1H), 4.41-2.79 (m, 6H), 2.30-1.06 (m, 7H).

Example 65: (±)-c s-(2-ethoxyphenyl)(2-methyl-3-(quinoxalin-2-ylamino)piperidi n-l- yl)methanone.

Prepared analogous to Example 63 substituting intermediate A-4 with 2-ethoxybenzoic acid. MS (ESI) mass calcd. for C ₂ 3H ₂₆ N ₄ O ₂ ,390.2; m/z found 391.2 [M+H] ⁺ _. 1H NMR (CDC13): 8.96-8.35 (m, 1H), 8.01-7.29 (m, 5H), 7.25-6.59 (m, 3H), 5.43-5.16 (m, 1H), 4.81-2.64 (m, 5H), 2.26-1.71 (m, 3H), 1.71-1.12 (m, 7H). Example 66: (±)-cz ^' s-(2-(2H- 1,2,3 -triazol-2-yl)phenyl)(2-methyl-3-((4-phenylpyrimidin-2- yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 51 substituting intermediate B-3 with intermediate B-6. MS (ESI) mass calcd. for C25H25N7O, 439.2; m/z found 440.2 [M+H] ⁺ . 1H NMR (CDC13): 9.88- 9.51 (m, 1H), 8.35-7.93 (m, 3H), 7.92-7.27 (m, 8H), 7.24-5.46 (m, 2H), 4.98-3.88 (m, 2H), 3.49- 2.73 (m, 2H), 2.09-0.84 (m, 7H).

Example 67: (±)-c«-(3-fluoro-2-methoxyphenyl)(2-methyl-3-((4-phenylpyr imidin-2- yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 66 substituting intermediate A-4 with 3-fluoro-2- methoxybenzoic acid. MS (ESI) mass calcd. for C24H25F 4O2, 420.2; m/z found 421.2 [M+H] 1H MR (CDC13): 10.18-9.91 (m, 1H), 8.42-7.48 (m, 6H), 7.24-5.53 (m, 4H), 4.76-3.81 (m, 5H), 3.79-2.77 (m, 2H), 2.13-1.41 (m, 4H), 1.38-0.97 (m, 3H). Example 68: (±)-c«-(2-ethoxyphenyl)(2-methyl-3-((4-phenylpyrimidin-2-y l)amino)piperidin-l- yl)methanone.

Prepared analogous to Example 66 substituting intermediate A-4 with 2-ethoxybenzoic acid. MS (ESI) mass calcd. for C ₂ 5H _{28 4} 02, 416.2; m/z found 417.2 [M+H] ⁺ . 1H NMR (CDC13): 9.34 (s, 1H), 8.32-7.89 (m, 3H), 7.74-7.46 (m, 3H), 7.37-7.31 (m, 1H), 7.23-6.73 (m, 3H), 6.29- 5.49 (m, 1H), 4.82-3.76 (m, 4H), 3.41-2.76 (m, 2H), 1.99-1.63 (m, 3H), 1.61-1.10 (m, 7H).

Example 69: (6-methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S,3R)-2-m ethyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)methano ne.

Step A: (2S,3R)-tert-butyl 2-methyl-3-((5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-l-carboxylate. A solution of intermediate B-4 (lg), 2-chloro-5- (trifluoromethyl)pyrimidine (850 mg) and DIPEA (1.6 mL) in n-BuOH (15 mL) was heated to 100 °C for lh. The mixture was diluted with Ι¾0 and extracted with EtOAc. The combined organics were dried (MgS0 ₄ ). Purification via silica gel chromatography (0-30% EtOAc in heptane) gave the title compound (1.5 g, 89%). MS (ESI) mass calcd. for C1 ₆ H2 ₃ F ₃ 4O2, 360.24; m/z found 305.1 [M-55] ⁺ .

Step B: N-((2S,3R)-2-methylpiperidin-3-yl)-5-(trifluoromethyl)pyrimi din-2-amine. To the title compound of step A (1.5 g) in DCM (12 mL) was added TFA (4 mL). After lh, the reaction was diluted with saturated a ₂ C0 ₃ (aq) and extracted with DCM. The organic layers were dried (MgS04) and concentrated to give the title compound (1.03 g) that was used without further purification.

Step C: (6-methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S,3R)-2-m ethyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)methano ne. To a solution of the title compound from Step B (100 mg), intermediate A-8 (118 mg) and DIPEA (0.2 mL) in DMF (5 mL) was added HBTU (218 mg). After lh, H ₂ 0 and EtOAc were added. The organic layer was separated and dried (MgS04). Purification via silica gel chromatography (0-30% EtOAc in heptane) gave the title compound (86 mg, 47%). MS (ESI) mass calcd. for C2 ₀ H21F _{3 8} O, 446.2; m/z found 447.2 [M+H] ⁺ . MP=245.2 °C. (Mixture of 4 isomers, undefined ratio). ¾ NMR (300 MHz, CDCI ₃ ) δ 8.52 (br d, J= 1 1.5 Hz, 1.51H), 8.35 (s, 1.27H), 8.18 (br s, 0.10H), 8.09 (s,

0.46H), 7.87 (d, J= 5.3 Hz, 0.46H), 7.80 (d, J= 7.7 Hz, 0.10H), 7.74 - 7.49 (m, 0.87H), 7.43 - 7.14 (m, 1.73H), 6.87 (d, J= 8.3 Hz, 0.46H), 6.61 (d, J= 7.7 Hz, 0.10H), 5.85 (d, J= 7.0 Hz, 0.10H), 5.69 (d, J= 5.5 Hz, 0.10H), 5.34 - 5.16 (m, 0.46H), 5.01 (q, J= 6.6 Hz, 0.10H), 4.73 (br d, J= 14.3 Hz, 0.30H), 4.29 (br d, J= 6.5 Hz, 0.46H), 4.19 - 3.95 (m, 0.46H), 3.83 (br d, J= 7.0 Hz, 0.15H), 3.65 (br s, 0.15H), 3.47 (dd, J= 13.7, 4.2 Hz, 0.46H), 3.26 (td, J= 13.4, 3.1 Hz,

0.60H), 3.05 - 2.83 (m, 0.46H), 2.80 (s, 0.26H), 2.78 - 2.64 (m, 2.16H), 2.61 (s, 0.52H), 2.52 (s, 0.26H), 1.95 - 1.81 (m, 1.73H), 1.80 - 1.70 (m, 0.26H), 1.71 - 1.54 (m, 1.13H), 1.53 - 1.19 (m, 3.37H), 1.08 (dd, J= 14.4, 6.7 Hz, 0.10H), 1.00 - 0.84 (m, 0.15H), 0.74 (d, J= 6.9 Hz, 0.26H).

Example 70: (6-methyl-2-( 1 H- 1 ,2,3 -triazol- 1 -yl)pyridin-3 -yl)((2S,3 R)-2-methyl-3 -((5

(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)meth anone.

Prepared analogous to Example 69 substituting intermediate A-8 with intermediate A-9. MS (ESI) mass calcd. for C ₂ oH ₂₁ F ₃ 80, 446.2; m/z found 447.2 [M+H] ⁺ . MP=181.6 °C.

(Mixture of 4 isomers, undefined ratio). 'H NMR (300 MHz, CDC1 ₃ ) δ 8.66 - 8.15 (m, 2.14H), 7.90 (d, J= 10.8 Hz, 0.45H), 7.83 - 7.67 (m, 0.68H), 7.60 (dd, J= 7.7, 2.6 Hz, 0.45H), 7.41 - 7.14 (m, 1.53H), 6.79 (d, J= 8.6 Hz, 0.26H), 6.61 (d, J= 7.8 Hz, 0.16H), 5.82 (dd, J= 26.8, 6.6 Hz, 0.33H), 5.17 (q, J= 6.8 Hz, 0.33H), 5.05 - 4.86 (m, 0.26H), 4.71 (t, J= 15.1 Hz, 0.33H), 4.35 (br d, J= 7.7 Hz, 0.45H), 4.25 - 4.00 (m, 0.78H), 3.87 (q, J= 6.9 Hz, 0.26H), 3.73 (br s, 0.26H), 3.54 - 3.37 (m, 0.33H), 3.36 - 3.05 (m, 0.62H), 3.03 - 2.75 (m, 0.45H), 2.62 (s, 1.14H), 2.59 (s, 0.76H), 2.46 (s, 0.50H), 2.18 - 1.83 (m, 1.62H), 1.81 - 1.55 (m, 1.41H), 1.53 - 0.79 (m, 4.57H). The signal corresponding to the NH group was not observed.

Example 71 : (4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)methano ne.

Prepared analogous to Example 69 substituting intermediate A-8 with intermediate A- 1 1. MS (ESI) mass calcd. for C ₂ iH ₂₂ F ₃ 70, 445.2; m/z found 446.2 [M+H] ⁺ . The product is present as a mixture of conformers (ratio ca. 60:40) ^X H NMR (300 MHz, CDC1 ₃ ) δ 8.51 (d, J = 10.7 Hz, 1.4H), 8.40 - 8.28 (m, 0.9H), 8.25 (s, 1.2H), 8.00 (s, 0.6H), 7.96 (s, 0.6H), 7.86 - 7.71 (m, 0.9H), 7.24 - 7.1 1 (m, 1.8H), 7.02 - 6.88 (m, 0.6H), 5.24 (q, J = 7.1 Hz, 0.6H), 4.73 (d, J = 13.1 Hz, 0.4H), 4.33 - 4.23 (m, 0.6H), 4.14 (q, J = 6.6 Hz, 0.4H), 4.00 (d, J = 6.6 Hz, 0.4H), 3.59 - 3.48 (m, 0.6H), 3.31 - 3.13 (m, 0.6H), 3.01 - 2.88 (m, 0.4H), 2.46 (s, 1.8H), 2.43 (s, 1.2H), 2.07 - 1.53 (m, 4H), 1.48 (d, J= 6.9 Hz, 1.2H), 1.42 (d, J= 7.1 Hz, 1.8H).

Example 72: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrazin-2-yl)amino) piperidin

methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

Step A: (2S,3R)-tert-butyl 2-methyl-3-((5-(trifluoromethyl)pyrazin-2- yl)amino)piperidine-l-carboxylate. To 2-chloro-5-(trifluoromethyl)pyrazine (326 μΚ) in DMSO (8 mL) was added intermediate B-4 (600 mg) and K2CO ₃ (658 mg). The reaction was heated in a microwave reactor at 120 °C for 5 min. The mixture was diluted with saturated aHC0 ₃ (aq) and extracted with DCM. The combined organics were washed with brine and dried (MgSC^). Purification via silica gel chromatography (0-16% EtOAc in heptane) gave the title compound (459 mg, 46%). MS (ESI) mass calcd. for Ci ₆ H ₂₃ F _{3 4} 0 ₂ , 360.24; m/z found 305.1 [M-55] ⁺ _.

Step B: N-((2S,3R)-2-methylpiperidin-3-yl)-5-(trifluoromethyl)pyrazi n-2-amine.

Prepared analogous to example 69 Step B substituting the title compound of Step A example 69 with the title compound of Step A. MS (ESI) mass calcd. for C11H15F ₃ N4, 260.2; m/z found 261 [M+H] ⁺ _.

Step C: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrazin-2-yl)amino) piperidin-l-yl)(5- methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone. Prepared analogous to example 69 substituting intermediate A-8 with intermediate A-21. MS (ESI) mass calcd. for C2 ₀ H21F _{3 8} O, 446.2; m/z found 447 [M+H] ⁺ . The product is present as a mixture of conformers (ratio ca. 70:30) 'H NMR (300 MHz, CDC1 ₃ ) 8.46 (s, 0.3H), 8.39 (s, 0.7H), 8.34 (s, 0.3H), 8.25 (s, 0.3H), 8.22 (s, 0.7H), 8.13 (s, 0.7H), 8.03 - 7.76 (m, 3H), 7.48 (d, J= 6.6 Hz, 0.7H), 6.47 (d, J= 7.9 Hz, 0.3H), 5.20 - 5.05 (m, 0.3H), 4.72 - 4.58 (m, 0.7H), 4.16 (br s, 0.3H), 4.08 - 3.87 (m, 1.7H), 3.43 - 3.25 (m, 0.3H), 3.12 - 2.95 (m, 0.7H), 2.49 (s, 0.9H), 2.46 (s, 2.1H), 2.08 - 1.63 (m, 4H), 1.50 - 1.47 (m, 3H).

Example 73: ((2S,3R)-3-(benzo[d]oxazol-2-ylamino)-2-methylpiperidin-l-yl )(5-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to example 41 substituting intermediate B-3 with intermediate B-4 and intermediate A-4 with intermediate A-21. MS (ESI) mass calcd. for C22H23N7O2, 417.2; m/z found 418.2 [M+H] ⁺ . MP=112.9 °C. The product is present as a mixture of conformers (ratio ca. 60:40) ^X H NMR (300 MHz, CDC1 ₃ ) δ 8.46 (s, 0.4H), 8.42 (s, 0.6H), 8.29 (s, 0.4H), 8.18 (s, 0.6H), 8.09 (s, 0.8H), 7.99 (s, 1.2H), 7.72 (d, J= 7.1 Hz, 0.6H), 7.38 (d, J= 7.8 Hz, 0.4H), 7.33 - 7.27 (m, 1H), 7.23 - 6.95 (m, 2.6H), 6.64 (d, J= 8.8 Hz, 0.4H), 5.34 - 5.16 (m, 0.4H), 4.66 (d, J = 12.2 Hz, 0.6H), 4.26 - 4.2 (m, 0.4H), 4.03 (q, J = 6.8 Hz, 0.6H), 3.92 (d, J = 6.7 Hz, 0.6H), 3.50 - 3.34 (m, 0.8H), 3.12 - 2.94 (m, 0.6H), 2.49 (s, 1.2H), 2.43 (s, 1.8H), 2.30 - 1.62 (m, 4H), 1.54 - 1.45 (m, 3H).

Example 74: (6-methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S,3R)-2-m ethyl-3-((5- (trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to example 72 substituting intermediate A-21 with intermediate A-8. MS (ESI) mass calcd. for C2 ₀ H21F _{3 8} O, 446.2; m/z found 447 [M+H] ⁺ . MP=172.8 °C. (Mixture of 4 isomers, undefined ratio). ¾ NMR (300 MHz, CDC1 ₃ ) δ 8.37 (br s, 0.21H), 8.32 (s, 0.11H), 8.21 (s, 0.40H), 8.15 - 7.97 (m, 1.26H), 7.97 - 7.84 (m, 0.66H), 7.78 (d, J= 7.7 Hz, 0.14H), 7.74 - 7.53 (m, 1.46H), 7.40 - 7.14 (m, 1.35H), 6.54 (d, J= 7.8 Hz, 0.11H), 6.18 (br s, 0.30H), 5.47 (s, 0.14H), 5.28 - 5.09 (m, 0.39H), 5.08 - 4.90 (m, 0.18H), 4.70 (br d, J= 13.3 Hz, 0.66H), 4.22 - 3.94 (m, 1.59H), 3.80 (br s, 0.21H), 3.64 (br s, 0.21H), 3.55 - 3.39 (m, 0.30H), 3.38 - 3.17 (m, 0.40H), 3.05 - 2.90 (m, 0.66H), 2.89 - 2.79 (m, 0.18H), 2.71 (s, J= 3.7 Hz, 0.92H), 2.70 (s, 1.04H), 2.26 - 1.12 (m, 6.39H), 0.88 (t, J= 6.8 Hz, 0.40H), 0.69 (d, J= 6.9 Hz, 0.21H). The signal corresponding to the NH group was not observed.

Example 75: ((2S,3R)-3-(benzo[d]oxazol-2-ylamino)-2-methylpiperidin-l-yl )(6-methyl-2-(2H- -triazol-2-yl)pyridin-3-yl)methanone.

Prepared analogous to example 73 substituting intermediate A-21 with intermediate A-8.

MS (ESI) mass calcd. for C22H23N7O2, 417.2; m/z found 418.2 [M+H] ⁺ . MP=136.3 °C. The product is present as a mixture of conformers (ratio ca. 50:50) ^X H NMR (300 MHz, CDCI ₃ ) δ 8.25 (s, 1H), 8.09 (s, 1H), 7.69 - 7.52 (m, 1H), 7.42 - 6.91 (m, 5.5H), 6.44 (d, J= 8.6 Hz, 0.5H), 5.39 - 5.22 (m, 0.5H), 4.81 - 4.63 (m, 0.5H), 4.27 - 3.91 (m, 1.5H), 3.54 - 3.40 (m, 0.5H), 3.39 - 3.22 (m, 0.5H), 3.06 - 2.83 (m, 0.5H), 2.72 (s, 1.5H), 2.67 (s, 1.5H), 2.24 - 1.64 (m, 4H), 1.51 (d, J= 7.0 Hz, 1.5H), 1.45 (d, J= 7.2 Hz, 1.5H).

Example 76: ((2S,3R)-3-(benzo[d]oxazol-2-ylamino)-2-methylpiperidin-l-yl )(6-methyl-2-(lH- 1 ,2,3 -triazol- 1 -yl)pyridin-3 -yl)methanone.

Prepared analogous to example 73 substituting intermediate A-21 with intermediate A-9. MS (ESI) mass calcd. for C ₂ 2H ₂ 3 ₇ 02, 417.2; m/z found 418.2 [M+H] ⁺ . MP=206.3 °C. The product is present as a mixture of conformers (ratio ca. 50:50) ^X H NMR (300 MHz, CDCI ₃ ) δ 8.60 (s, 0.5H), 8.41 (s, 0.5H), 7.94 (s, 1H), 7.66 - 7.50 (m, 1H), 7.40 - 6.87 (m, 5.5H), 6.55 (d, J = 9.5 Hz, 0.5H), 5.28 - 5.17 (m, 0.5H), 4.79 - 4.68 (m, 0.5H), 4.34 - 4.22 (m, 0.5H), 4.22 - 4.11 (m, 0.5H), 4.10 - 3.94 (m, 0.5H), 3.73 - 3.39 (m, 0.5H), 3.37 - 3.23 (m, 0.5H), 3.04 - 2.89 (m, 0.5H), 2.63 (s, 1.5H), 2.56 (s, 1.5H), 2.15 - 1.70 (m, 4H), 1.50 (d, J= 7.0 Hz, 1.5H), 1.44 (d, J = 7.0 Hz, 1.5H). Example 77: ((2S,3R)-3-((5-chloropyridin-2-yl)amino)-2-methylpiperidin-l -yl)(5-methyl-3- (oxazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to example 32 substituting intermediate B-3 with intermediate B-4 and intermediate A-4 with intermediate A-17. MS (ESI) mass calcd. for C21H22CIN5O2, 411.1 ; m/z found 412.1 [M+H] . MP=206.3 °C. The product is present as a mixture of conformers (ratio ca. 70:30) ^X H NMR (300 MHz, CDC1 ₃ ) δ 8.46 (s, 0.3H), 8.38 (s, 0.7H), 8.24 (s, 0.3H), 8.13 - 8.02 (m, 1.7H), 7.96 - 7.89 (m, 2H), 7.36 (dd, J = 8.9, 2.6 Hz, 0.3H), 7.23 (dd, J = 8.9, 2.5 Hz, 0.7H), 6.56 (d, J= 7.2 Hz, 0.7H), 6.36 (d, J = 8.9 Hz, 0.3H), 6.22 (d, J = 8.8 Hz, 0.7H), 5.72 (d, J= 7.2 Hz, 0.3H), 5.17 - 5.03 (m, 0.3H), 4.69 - 4.56 (m, 0.7H), 3.99 - 3.81 (m, 1.6H), 3.32 (q, J = 13.8 Hz, 0.7H), 3.11 - 2.87 (m, 0.7H), 2.48 (s, 0.9H), 2.45 (s, 2.1H), 2.08 - 1.73 (m, 3H), 1.69 - 1.61 (m, 1H), 1.51 - 1.39 (m, 3H).

Example 78: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrimidin-2-yl)amin o)piperidin-l-yl)(6- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Prepared analogous to Example 69 substituting intermediate A-8 with intermediate A- 19. MS (ESI) mass calcd. for C22H22F3N7O, 457.2; m/z found 458.2 [M+H] ⁺ . MP=116.9 °C.

Example 79: (4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to example 72 substituting intermediate A-21 with intermediate A- 1 1. MS (ESI) mass calcd. for C21H22F ₃ N7O, 445.2; m/z found 446.2 [M+H] ⁺ . MP=116.2 °C.

Example 80: ((2S,3R)-3-((5-bromopyridin-2-yl)amino)-2-methylpiperidin-l- yl)(5-methyl-3- (oxazol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to example 42 substituting intermediate B-3 with intermediate B-4 and intermediate A-4 with intermediate A-17. MS (ESI) mass calcd. for C2iH22Br ₅ 0 ₂ , 455.1 ; m/z found 457 [M+H] ⁺ . MP=135.6 °C.

Example 81 : ((2S,3R)-3-(benzo[d]oxazol-2-ylamino)-2-methylpiperidin-l-yl )(6-methyl-3- (pyrimidin-2 -y l)pyridin-2 -y l)methanone

Prepared analogous to example 73 substituting intermediate A-21 with intermediate A- 19. MS (ESI) mass calcd. for C ₂ 4H24 ₆ 0 ₂ , 428.2; m/z found 429.2 [M+H] ⁺ . MP=143.9 °C.

Example 82: (4-methoxy-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl -3-((5- (trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to example 72 substituting intermediate A-21 with intermediate A- 10. MS (ESI) mass calcd. for C ₂ iH ₂₂ F _{3 7} 0 ₂ , 461.2; m/z found 462.2 [M+H] ⁺ . MP=1 12.7 °C.

Example 83: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrazin-2-yl)amino) piperidin-l-yl)(5- methyl-3-(oxazol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to example 72 substituting intermediate A-21 with intermediate A- 17. MS (ESI) mass calcd. for C ₂ iH ₂₁ F ₃ N ₆ 0 ₂ , 446.2; m/z found 447.2 [M+H] ⁺ . MP=122.9 °C.

Example 84: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrazin-2-yl)amino) piperidin-l-yl)(6- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Prepared analogous to example 72 substituting intermediate A-21 with intermediate A- 19. MS (ESI) mass calcd. for C ₂ 2H ₂₂ F ₃ 70, 457.2; m/z found 458.2 [M+H] ⁺ . MP=120.6 °C.

Example 85: (2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl-3-((5-(tr ifluoromethyl)pyrazin- -yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to example 72 substituting intermediate A-21 with intermediate A-4. MS (ESI) mass calcd. for C ₂ oH ₂ oF ₃ 70, 431.2; m/z found 432 [M+H] ⁺ . MP=202.4 °C.

Example 86: ((2S,3R)-3-((5-chloropyrazin-2-yl)amino)-2-methylpiperidin-l -yl)(5-methyl-3- (oxazol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to example 77 substituting 5-chloro-2-iodopyridine with 2-chloro-5- iodopyrazine. MS (ESI) mass calcd. for C ₂ oH ₂₁ ClN ₆ 0 ₂ , 412.1; m/z found 413.1 [M+H] ⁺ . Example 87: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)amino) piperidin-l-yl)(6- -triazol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to example 12 substituting intermediate B-3 with intermediate B-4 and intermediate A-4 with intermediate A-22. MS (ESI) mass calcd. for C21H22F ₃ N7O, 445.2; m/z found 446 [M+H] ⁺ .

Example 88: ((2S,3R)-3-(benzo[d]oxazol-2-ylamino)-2-methylpiperidin-l-yl )(5-methyl-3- (oxazol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to example 73 substituting intermediate A-21 with intermediate A- 17. MS (ESI) mass calcd. for C23H23N5O3, 417.2; m/z found 418.2 [M+H] ⁺ . MP=196.8 °C.

Example 89 (5-methoxy-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl -3-((5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)methano ne.

analogous to Example 69 substituting intermediate A-8 with intermediate A- 14. MS (ESI) mass calcd. for C21H22F ₃ N7O2, 461.2; m/z found 462.2 [M+H] ⁺

Example 90 (5-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2

(trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 72 substituting intermediate A-21 with intermediate A- 24. MS (ESI) mass calcd. for C20H19F4N7O, 449.2; m/z found 450 [M+H] ⁺ . MP=106.2 °C. Example 91 ((2S,3R)-3-((5-chloropyrimidin-2-yl)amino)-2-methylpiperidin -l-yl)(4-methyl-2-

(2H-l,2,3-triazol-2-yl)phenyl)methanone.

Prepared analogous to Example 30 substituting intermediate B-3 with intermediate B-4 and intermediate A-4 with intermediate A-11. MS (ESI) mass calcd. for C2 ₀ H22CIN7O, 41 1.2; m/z found 412.2 [M+H] ⁺ . MP=166.3 °C.

Example 92 ((2S,3R)-3-((5-bromopyridin-2-yl)amino)-2-methylpiperidin-l- yl)(5-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to example 42 substituting intermediate B-3 with intermediate B-4 and intermediate A-4 with intermediate A-21. MS (ESI) mass calcd. for 02ΟΙ½ΒΓ 70, 455.2; m/z found 457 [M+H] ⁺ .

Example 93 (6-methyl-2-(lH-l,2,3-triazol-l-yl)pyridin-3-yl)((2S,3R)-2-m ethyl-3-((5-

(trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 87 substituting intermediate A-22 with intermediate A-9. MS (ESI) mass calcd. for C ₂ iH ₂₂ F ₃ 70, 445.2; m/z found 446.2[M+H] ⁺ . MP=159.8 °C.

Example 94 ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrimidin-2-yl)amin o)piperidin-l-yl)(5- methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 69 substituting intermediate A-8 with intermediate A-21. MS (ESI) mass calcd. for C ₂ oH ₂₁ F ₃ 80, 446.2; m/z found 447 [M+H] ⁺ . MP=101.2 °C.

Example 95 (4-methoxy-2-(2H- l ,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin- l -yl)methanone.

Prepared analogous to Example 69 substituting intermediate A-8 with intermediate A- 10. MS (ESI) mass calcd. for C ₂ iH ₂₂ F _{3 7} 0 ₂ , 461.2; m/z found 462.2 [M+H] ⁺ . The product is present as a mixture of conformers (ratio ca. 60:40) Η NMR (300 MHz, CDC1 ₃ ) δ 8.51 (d, J = 10.0 Hz, 1.4H), 8.37 (d, J= 10.3 Hz, 0.6H), 8.25 (s, 1.4H), 8.00 (s, 0.4H), 7.78 (d, J= 4.4 Hz, 0.4H), 7.67 (d, J= 2.3 Hz, 0.6H), 7.46 (d, J= 2.3 Hz, 0.4H), 7.24 (d, J= 9.3 Hz, 0.6H), 7.17 (d, J= 8.5 Hz, 0.6H), 7.03 - 6.85 (m, 1.6H), 5.24 (q, J= 6.7 Hz, 0.6H), 4.72 (d, J= 13.2 Hz, 0.4H), 4.27 (d, J= 6.7 Hz, 0.6H), 4.22 - 4.08 (m, 0.4H), 4.01 (d, J= 6.4 Hz, 0.4H), 3.91 (s, 1.8H), 3.87 (s, 1.2H), 3.55 (dd, J= 13.6, 3.7 Hz, 0.6H), 3.23 (td, J= 13.4, 3.0 Hz, 0.6H), 2.99 - 2.90 (m, 0.4H), 2.09 - 1.52 (m, 4H), 1.48 (d, J= 6.9 Hz, 1.2H), 1.42 (d, J= 7.1 Hz, 1.8H).

Example 96 (6-methyl-2-(lH-l ,2,3-triazol- l -yl)pyridin-3-yl)((2S,3R)-2-methyl-3-((5-

(trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 72 substituting intermediate A-21 with intermediate A-9. MP=149.6 °C.

Example 97 (4-methoxy-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl -3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 87 substituting intermediate A-22 with intermediate A- 10. MS (ESI) mass calcd. for C ₂ 2H ₂ 3F _{3 6} 02, 460.2; m/z found [M+H] ⁺ .

Example 98 (6-methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S,3R)-2-m ethyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Prepared analogous to Example 87 substituting intermediate A-22 with intermediate A-8. MS (ESI) mass calcd. for C ₂₁ H ₂₂ F _{3 7} 0, 445.2; m/z found 446 [M+H] ⁺ . Example 99 ((2S,3R)-3-((5-chloropyridin-2-yl)amino)-2-methylpiperidin-l -yl)(4-methyl-2-(2H-

1 ,2,3 -triazol-2-yl)phenyl)methanone

Prepared analogous to Example 32 substituting intermediate B-3 with intermediate B-4 and intermediate A-4 with intermediate A-11. MS (ESI) mass calcd. for C ₂ iH ₂₃ Cl ₆ 0, 410.2; m/z found 41 1.2 [M+H] ⁺ .

Example 100 (2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-((5-chloropyridi n-2-yl)amino)-2- methylpiperidin- 1 -yl)methanone.

Prepared analogous to Example 32 substituting intermediate B-3 with intermediate B-4. MS (ESI) mass calcd. for C ₂ oH ₂₁ ClN ₆ 0, 396.1; m/z found 397 [M+H] ⁺ . MP=140.1 °C.

Example 101 ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrimidin-2-yl)oxy) piperidin-l-yl)(5- methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

Step A: (2S,3R)-tert-butyl 2-methyl-3-((5-(trifluoromethyl)pyrimidin-2- yl)oxy)piperidine-l-carboxylate. To (2S,3R)-tert-butyl 3-hydroxy-2-methylpiperidine-l- carboxylate (670 mg, prepared according to J. Org. Chem. 2008, 73, 2898) in THF (15 mL) at 0 °C was added NaH (60 wt%, 188 mg). After 15 min, 2-chloro-5-(trifluoromethyl)pyrimidine (570 mg) was added and the reaction allowed to proceed at rt overnight. The reaction was diluted with FLO and extracted with DCM. The organic layers were dried (MgS0 ₄ ).

Purification via silica gel chromatography (0-40% EtOAc in heptane) gave the title compound (813 mg, 72%).

Step B: 2-(((2S,3R)-2-methylpiperidin-3-yl)oxy)-5-(trifluoromethyl)p yrimidine. To the title compound of step A (813 mg) in DCM (6 mL) was added TFA (2 mL). After lh, the reaction was diluted with saturated a ₂ C03 (aq) and extracted with DCM. The organic layers were dried (MgSC^) and concentrated to give the title compound (452 mg) that was used without further purification.

Step C: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrimidin-2-yl)oxy) piperidin-l-yl)(5- methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone. To a solution of the title compound from Step B (100 mg), intermediate A-21 (118 mg) and DIPEA (0.2 mL) in DMF (5 mL) was added HBTU (218 mg). After lh, H ₂ 0 and EtOAc were added. The organic layer was separated and dried (MgSC^). Purification via prep HPLC gave the title compound (62 mg, 36%). MS (ESI) mass calcd. for C ₂ oH ₂ oF ₃ 702, 447.2; m/z found 448.2 [M+H] ⁺ . MP=214.9 °C.

Example 102 (4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

Prepared analogous to Example 101 substituting intermediate A-21 with intermediate A- 11. MS (ESI) mass calcd. for C ₂ iH ₂₁ F ₃ N ₆ 02, 446.2; m/z found 447.2 [M+H] ⁺ . MP=163.7 °C.

Example 103 (2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

Prepared analogous to Example 101 substituting intermediate A-21 with intermediate A- 4. MS (ESI) mass calcd. for C ₂ oH ₁₉ F _{3 6} 02, 432.2; m/z found 433 [M+H] ⁺ .

Example 104 ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrimidin-2-yl)oxy) piperidin-l-yl)(6- methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 101 substituting intermediate A-21 with intermediate A 22. MS (ESI) mass calcd. for C ₂ oH ₂ oF _{3 7} 0 ₂ , 447.2; m/z found 448 [M+H] ⁺ . MP=161.5 °C.

Example 105 ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrazin-2-yl)oxy)pi peridin-l-yl)(5- -triazol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to Example 101 substituting 2-chloro-5-(trifluoromethyl)pyrimidine with 2-chloro-5-(trifluoromethyl)pyrazine. MS (ESI) mass calcd. for C2 ₀ H2 ₀ F ₃ 7O2, 447.2; m z found 448 [M+H] ⁺ . MP=149.7 °C.

Example 106 (2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

Prepared analogous to Example 105 substituting intermediate A-21 with intermediate A- 4. MS (ESI) mass calcd. for C20H19F3N6O2, 432.2; m/z found 433.2 [M+H] ⁺ . MP=11 1.2 °C.

Example 107 ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrazin-2-yl)oxy)pi peridin-l-yl)(6- azol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to Example 105 substituting intermediate A-21 with intermediate A . MS (ESI) mass calcd. for C20H20F3N7O2, 447.2; m/z found 448 [M+H] ⁺ . MP=161.5 °C.

- I l l - Example 108 ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pi peridin-l-yl)(6- -triazol-2-yl)pyridin-2-yl)methanone.

Step A: (2S,3R)-tert-butyl 2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidine- l- carboxylate. To (2S,3R)-tert-butyl 3-hydroxy-2-methylpiperidine-l-carboxylate (1.5 g, 6.97 mmol, prepared according to J. Org. Chem. 2008, 73, 2898) in THF (20 mL) at 0 °C was added NaH (60 wt%, 418 mg, 10.5 mmol). After 15 min, 2-chloro-5-(trifluoromethyl)pyridine (1.33 g, 7.32 mmol) was added and the reaction allowed to proceed at rt overnight. The reaction was diluted with H ₂ 0 and extracted with EtOAc. The combined organic layers were dried (MgS0 ₄ ), filtered and concentrated. Purification via silica gel chromatography (0-25% EtOAc in heptane) gave the title compound (2.37 g, 94%, 97% purity). MS (ESI) mass calcd. for CnH^Fs^Os, 360.2; m/z found 361.0 [M+H] ⁺ .

Step B: 2-(((2S,3R)-2-methylpiperidin-3-yl)oxy)-5-(trifluoromethyl)p yridine. To the title compound of step A (3.45 g, 9.57 mmol) in DCM (37 mL) was added TFA (12 mL), and the reaction mixture was stirred at rt for 1 h. Then, the crude reaction was diluted with saturated a ₂ C03 (aq) and extracted with DCM. The organic layers were dried (MgS0 ₄ ) and concentrated to give the title compound (2.34 g) that was used without further purification. MS (ESI) mass calcd. for CnHisFs^O, 260.1; m/z found 261 [M+H] ⁺ .

Step C: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pi peridin-l-yl)(6- methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone. To a solution of the title compound from Step B (2.34 g), intermediate A-22 (4.58 g, 10.8 mmol) and DIPEA (4.6 mL, 27 mmol) in DMF (27 mL) was added HBTU (5.10 g, 13.5 mmol). After lh, a solution of saturated NaHC0 ₃ (aq) and EtOAc were added. The reaction mixture was extracted with EtOAc (3X). The combined organic layer was dried (MgS0 ₄ ), filtered and concentrated. Purification via prep silica gel chromatography (0-50% EtOAc in heptane) gave the title compound as crystalline material (3.43 g, 70%, 98% purity). MS (ESI) mass calcd. for C ₂ iH ₂₁ F ₃ N ₆ 0 ₂ , 446.2; m/z found 447 [M+H] ⁺ . ¾ NMR (500 MHz, Chloroform-d) δ 8.45 - 8.36 (m, 0.45H), 8.16 (d, J= 8.4 Hz, 0.45H), 8.15 - 8.13 (m, 0.55H), 8.07 (d, J= 8.4 Hz, 0.55H), 7.81 (s, 1.1H), 7.80 (s, 0.9H), 7.77 (dd, J= 8.7, 2.6 Hz, 0.45H), 7.68 (dd, J= 8.7, 2.6 Hz, 0.55H), 7.30 (d, J= 8.4 Hz, 0.45H), 7.11 (d, J= 8.5 Hz, 0.55H), 6.96 - 6.88 (m, 0.45H), 6.68 (d, J= 8.7 Hz, 0.55H), 5.31 - 5.25 (m, 0.45H), 5.15 - 5.08 (m, 0.45H), 4.89 - 4.82 (m, 0.55H), 4.79 - 4.72 (m, 0.55H), 4.08 - 3.99 (m, 0.55H), 3.38 - 3.29 (m, 0.45H), 3.13 - 3.03 (m, 0.45H), 2.94 (td, J= 13.4, 3.2 Hz, 0.55H), 2.65 (s, 1.3H), 2.25 (s, 1.7H), 2.19 - 1.86 (m, 3H), 1.67 - 1.61 (m, 0.55H), 1.47 - 1.32 (m, 1.8H), 1.06 (d, J= 7.0 Hz, 1.65H).

Example 109 (±)-/raws-(2-methyl-3 -((5-(trifluoromethyl)pyridin-2-yl)oxy)piperidin- -triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 108 using (±)-trans-tert-butyl 3-hydroxy-2- methylpiperidine-l-carboxylate. MS (ESI) mass calcd. for C21H21F3 6O2, 446.2; m/z found 447.2 [M+H] ⁺ . MP=161.3 °C.

Example 110 (2-(2H ,2,3 riazol-2-yl)phenyl)((2S,3R)-2-methyl-3-((5-(trifluoromethyl) pyridin- 2-yl)oxy)piperidin- 1 -yl)methanone.

Prepared analogous to Example 108 substituting intermediate A-22 with intermediate A- 4. MS (ESI) mass calcd. for 431.2; m/z found 432.2 [M+H] ⁺ . MP=159.7 °C.

Example 1 1 1 ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pi peridin-l-yl)(5- methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

Prepared analogous to Example 108 substituting intermediate A-22 with intermediate A- 21. MP=281.7 °C. Example 1 12 (4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

Prepared analogous to example 108 substituting intermediate A-22 with intermediate A- 1 1. MS (ESI) mass calcd. for C ₂ iH ₂₁ F ₃ N ₆ 02, 446.2; m/z found 447 [M+H] ⁺ . MP=167.1 °C.

Example 1 13 (4-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

Prepared analogous to Example 105 substituting intermediate A-21 with intermediate A- 1 l.MS (ESI) mass calcd. for C ₂₁ H ₂₁ F _{3 6} 0 ₂ , 446.2; m/z found 447 [M+H] ⁺ . MP=167.1 °C

The following compounds are also within the scope of the invention. They can be prepared using methods known in the art, in combination with the experimental details and schemes provided herein.

Example 1 14. (3-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-((5-fluoropyri din-2-yl)oxy)-2- methylpiperidin- 1 -yl)methanone.

Example 1 15. (3-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-((5-fluoropyri midin-2-yl)oxy)-2- methylpiperidin- 1 -yl)methanone.

Example 116 (3-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 147 substituting intermediate A- 1 with intermediate A-28. MS (ESI): mass calcd. for C ₂ 3H ₂ oF _{4 4} 0 ₂ , 460.2; m/z found, 460.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.82 (d, J= 5.0 Hz, 2H), 8.39 (s, 0.6H), 8.21 (s, 0.4H), 7.90 - 7.70 (m, 1H), 7.55 - 7.40 (m, 0.6H), 7.25 - 7.17 (m, 2H), 7.07 - 6.98 (m, 0.4H), 6.95 - 6.74 (m, 2H), 5.22 (s, 0.6H), 5.05 - 4.87 (m, 1H), 4.63 - 4.47 (m, 0.4H), 4.25 - 4.08 (m, 0.4H), 3.62 - 3.44 (m, 0.6H), 3.10 (td, J= 13.2, 3.3 Hz, 0.6H), 2.75 (t, J= 13.1 Hz, 0.4H), 2.14 - 1.78 (m, 3H), 1.62 - 1.54 (m, 0.6H), 1.49 - 1.36 (m, 0.4H), 1.25 - 1.12 (m, 1.6H), 1.06 - 0.94 (m, 1.4H).

Example 117. (3-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 1 18. (3-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 1 19. ((2S,3R)-3-(benzo[d]oxazol-2-yloxy)-2-methylpiperidin-l-yl)( 3-fluoro-2 (pyrimidin-2-yl)phenyl)methanone.

Example 120. ((2S,3R)-3-(benzo[d]oxazol-2-yloxy)-2-methylpiperidin-l-yl)( 3-fluoro-2-(2H- -triazol-2-yl)phenyl)methanone.

Example 121. (3-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-((5-flu oropyridin-2-yl)oxy)- 2-methylpiperidin- 1 -yl)methanone.

Example 122. (3-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-((5-flu oropyrimidin-2- yl)oxy)-2-methylpiperidin- 1 -yl)methanone.

Example 123. (3-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 124: (3-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 147 substituting intermediate A- 1 with intermediate A-3. MS (ESI): mass calcd. for C ₂ iH ₁₉ F _{4 5} 0 ₂ , 449.1; m/z found, 449.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.42 - 8.36 (m, 0.55H), 8.23 - 8.18 (m, 0.45H), 7.96 - 7.72 (m, 3H), 7.57 - 7.46 (m, 0.55H), 7.40 - 7.27 (m, 1H), 7.18 - 7.08 (m, 0.45H), 6.96 - 6.76 (m, 2H), 5.26 - 5.19 (m, 0.55H), 5.05 - 4.88 (m, 1H), 4.61 - 4.52 (m, 0.45H), 4.15 - 4.01 (m, 0.55H), 3.49 - 3.36 (m, 0.45H), 3.03 - 2.90 (m, 0.55H), 2.82 - 2.68 (m, 0.45H), 2.08 - 1.76 (m, 3H), 1.46 - 1.21 (m, 1H), 1.15 (d, J= 7.1 Hz, 1.45H), 0.98 (d, J= 7.0 Hz, 1.55H). Example 125: (3-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 147 substituting 2-chloro-5- (trifluoromethyl)pyridine with 2-chloro-5-(trifluoromethyl)pyrazine, and intermediate A-1 with intermediate A-3. MS (ESI): mass calcd. for C ₂ oH ₁₈ F ₄ N ₆ 0 ₂ , 450.1; m/z found, 450.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.44 - 8.38 (m, 0.6H), 8.30 (s, 0.4H), 8.26 (s, 0.6H), 8.21 (s, 0.4H), 7.87 (s, 1H), 7.85 (s, 1H), 7.58 - 7.47 (m, 0.6H), 7.38 - 7.26 (m, 1.4H), 7.17 - 7.07 (m, 0.4H), 6.97 - 6.85 (m, 0.6H), 5.24 - 5.14 (m, 0.6H), 5.07 - 4.97 (m, 0.6H), 4.95 - 4.82 (m, 0.4H), 4.65 - 4.51 (m, 0.4H), 4.04 - 3.87 (m, 0.6H), 3.47 - 3.37 (m, 0.6H), 3.05 - 2.89 (m, 0.4H), 2.82 - 2.64 (m, 0.4H), 2.15 - 1.78 (m, 3H), 1.65 - 1.56 (m, 0.4H), 1.51 - 1.40 (m, 0.6H), 1.14 (d, J= 7.1 Hz, 2H), 0.90 (d, J= 7.0 Hz, 1H).

Example 126. ((2S,3R)-3-(benzo[d]oxazol-2-yloxy)-2-methylpiperidin-l-yl)( 3-fluoro-2-(2H- l,2,3-triazol-2-yl)phenyl)methanone.

Example 127. ((2S,3R)-3-(benzo[d]oxazol-2-yloxy)-2-methylpiperidin-l-yl)( 2-fluoro-6-(2H- l,2,3-triazol-2-yl)phenyl)methanone.

Example 128. (2-fluoro-6-(2H- 1,2,3 -triazol-2-yl)phenyl)((2S,3R)-3-((5-fluoropyridin-2-yl)oxy)- 2-methylpiperidin- 1 -yl)methanone.

Example 129. (2-fluoro-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-((5-flu oropyrimidin-2- yl)oxy)-2-methylpiperidin- 1 -yl)methanone.

Example 130. (2-fluoro-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 131. (2-fluoro-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 132. (2-fluoro-6-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 133. (2-fluoro-6-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 134. (2-fluoro-6-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 135. (2-fluoro-6-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 136. (2-fluoro-6-(pyrimidin-2-yl)phenyl)((2S,3R)-3-((5-fluoropyri midin-2-yl)oxy)-2- methylpiperidin- 1 -yl)methanone.

Example 137. (2-fluoro-6-(pyrimidin-2-yl)phenyl)((2S,3R)-3-((5-fluoropyri din-2-yl)oxy)-2- methylpiperidin- 1 -yl)methanone.

Example 138: (5-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 143 substituting intermediate A- 29 with intermediate A-7. MS (ESI): mass calcd. for C2 ₃ H2 ₀ F4 4O2, 460.2; m/z found, 461.2 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.76 (d, J= 4.8 Hz, 1H), 8.72 (d, J= 4.9 Hz, 1H), 8.50 - 8.35 (m, 1H), 8.23 (dd, J= 8.8, 5.6 Hz, 0.5H), 8.17 (s, 0.5H), 7.84 (dd, J= 8.7, 2.5 Hz, 0.5H), 7.79 (dd, J= 8.8, 2.5 Hz, 0.5H), 7.24 - 7.15 (m, 1.5H), 7.10 (dd, J= 8.5, 2.7 Hz, 0.5H), 6.96 (td, J= 8.4, 2.7 Hz, 0.5H), 6.90 - 6.84 (m, 1H), 6.81 (dd, J= 8.5, 2.7 Hz, 0.5H), 5.34 - 5.30 (m, 0.5H), 5.15 - 5.05 (m, 0.5H), 4.93 - 4.85 (m, 0.5H), 4.79 - 4.71 (m, 0.5H), 4.11 - 4.00 (m, 0.5H), 3.44 - 3.33 (m, 0.5H), 3.18 - 3.04 (m, 0.6H), 2.95 - 2.89 (m, 0.4H), 2.16 - 1.84 (m, 3H), 1.70 - 1.60 (m, 0.5H), 1.48 - 1.33 (m, 2H), 0.90 (d, J= 7.0 Hz, 1.5H).

Example 139: (4-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 143 substituting intermediate A- 29 with intermediate A-37. MS (ESI): mass calcd. for C ₂ 3H ₂ oF _{4 4} 0 ₂ , 460.2; m/z found, 461.2 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.78 (d, J= 4.8 Hz, 0.9H), 8.75 (d, J= 4.8 Hz, 1.1H), 8.42 (s, 0.6H), 8.19 (s, 0.4H), 8.11 (dd, J= 10.2, 2.7 Hz, 0.4H), 7.95 (d, J= 10.1 Hz, 0.6H), 7.84 (d, J= 8.7 Hz, 0.4H), 7.78 (dd, J= 8.8, 2.6 Hz, 0.6H), 7.38 (dd, J= 8.4, 5.5 Hz, 0.6H), 7.25 - 7.17 (m, 1.6H), 7.09 - 7.01 (m, 0.4H), 6.86 (d, J= 8.7 Hz, 1H), 6.64 - 6.55 (m, 0.4H), 5.35 - 5.28 (m, 0.6H), 5.17 - 5.07 (m, 0.6H), 4.89 (s, 0.4H), 4.82 - 4.67 (m, 0.4H), 4.10 - 4.01 (m, 0.4H), 3.44 - 3.31 (m, 0.6H), 3.15 - 3.00 (m, 0.6H), 2.94 - 2.89 (m, 0.4H), 2.13 - 1.81 (m, 3H), 1.70 - 1.61 (m, 0.4H), 1.47 - 1.32 (m, 2.2H), 0.91 (d, J= 7.0 Hz, 1.4H).

Example 140. (4-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 141 : (2-(5-fluoropyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 143 substituting intermediate A- 29 with intermediate A-25. MS (ESI): mass calcd. for C2 ₃ H2 ₀ F4 4O2, 460.2; m/z found, 461.2 [M+H] ⁺ . ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.72 - 8.56 (m, 2H), 8.45 - 8.40 (m, 0.4H), 8.34 - 8.28 (m, 0.4H), 8.22 - 8.10 (m, 1.2H), 7.88 - 7.81 (m, 0.4H), 7.80 - 7.74 (m, 0.4H), 7.55 - 7.45 (m, 1.2H), 7.45 - 7.36 (m, 0.4H), 7.33 - 7.26 (m, 0.6H), 7.11 - 7.00 (m, 0.4H), 6.92 - 6.82 (m, 1.6H), 5.38 - 5.28 (m, 0.6H), 5.17 - 5.07 (m, 0.4H), 4.89 (s, 0.4H), 4.81 - 4.71 (m, 0.4H), 4.15 - 4.03 (m, 0.6H), 3.50 - 3.37 (m, 0.6H), 3.16 - 3.03 (m, 0.6H), 2.98 - 2.84 (m, 0.4H), 2.18 - 1.83 (m, 3H), 1.78 - 1.60 (m, 0.6H), 1.47 - 1.31 (m, 2.2H), 0.94 (d, J= 7.0 Hz, 1.2H). Exmaple 142. (3-fluoro-2-(5-fluoropyrimidin-2-yl)phenyl)((2S,3R)-2-methyl -3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 143: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pi peridin-l-yl)(2-

(pyrimidin-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 101 steps A and B, substituting 2-chloro-5-(trifluoromethyl)pyrimidine with 2-chloro-5-(trifluoromethyl)pyridine. Step C: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pi peridin-l-yl)(2-( yrimidin-2- yl)phenyl)methanone. To 2-(((2S,3R)-2-methylpiperidin-3-yl)oxy)-5-(trifluoromethyl)p yridine (48 mg, 0.181 mmol) and intermediate A-29 (43 mg, 0.217 mmol) was added DCM (1 mL) and DIPEA (0.04 mL, 0.235 mmol). T ₃ P (0.325 mL, 0.542 mmol, 50% solution in DMF) was then added dropwise and the mixture heated to 45 °C. Upon completion the reaction was quenched with saturated aHC03 solution and the aqueous layer extracted with EtOAc (3X). The combined organics were washed saturated aHC03 solution, brine, dried with MgS0 ₄ , filtered, and concentrated. Purification via silica gel chromatography (0-100 % EtOAc in hexanes) gave the title compound (67.2 mg, 84 %). MS (ESI): mass calcd. for C ₂ 3H ₂₁ F ₃ 402, 442.2; m/z found 443.2 [M+H] ⁺ . 'H NMR (400 MHz, CDC1 ₃ ) δ 8.78 (d, J= 4.8 Hz, 1.1H), 8.74 (d, J= 4.9 Hz, 0.9H), 8.42 (s, 0.5H), 8.39 - 8.33 (m, 0.5H), 8.20 (d, J= 8.0 Hz, 0.5H), 8.13 (s, 0.5H), 7.86 - 7.81 (m, 0.5H), 7.78 (dd, J= 8.8, 2.6 Hz, 0.5H), 7.54 - 7.47 (m, 1H), 7.44 - 7.38 (m, 0.5H), 7.31 - 7.27 (m, 0.5H), 7.18 (t, J= 4.8 Hz, 1H), 7.05 (d, J= 7.5 Hz, 0.5H), 6.91 - 6.83 (m, 1.5H), 5.35 - 5.28 (m, 0.5H), 5.18 - 5.08 (m, 0.5H), 4.94 - 4.83 (m, 0.5H), 4.82 - 4.72 (m, 0.5H), 4.13 - 4.01 (m, 0.5H), 3.49 - 3.34 (m, 0.5H), 3.17 - 3.02 (m, 0.5H), 2.94 - 2.8 (m, 0.5H), 2.17 - 1.81 (m, 3H), 1.68 - 1.61 (m, 0.5H), 1.45 - 1.32 (m, 2H), 0.88 (d, J= 7.0 Hz, 1.5H).

Example 144. (2-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl)((2S,3R)-2-methyl-3 -((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Example 145. (4-fluoro-2-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl)((2S,3R)-2 -methyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Example 146. (3-fluoro-2-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl)((2S,3R)-2 -methyl-3-((5- (trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1 -yl)methanone.

Example 147: (4-fluoro-2-(2H- l ,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 101 steps A and B, substituting 2-chloro-5-(trifluoromethyl)pyrimidine with 2-chloro-5-(trifluoromethyl)pyridine. Step C: (4- fluoro-2-(2H- l,2,3 riazol-2-yl)phenyl)((2S,3R)-2-methyl-3-((5-(trifluoromethyl) pyridin-2- yl)oxy)piperidin- l-yl)methanone. To 2-(((2S,3R)-2-methylpiperidin-3-yl)oxy)-5- (trifluoromethyl)pyridine (50 mg, 0.169 mmol) in DCM (5 mL) was intermediate A-l (38 mg, 0.185 mmol), HOBt (38 mg, 0.279 mmol), EDCI (53 mg, 0.279 mmol) and DIPEA (72 μΕ, 0.418 mmol). After stirring at room temperature for 2 h, saturated aHC03 (aq.) was added and the mixture was extracted with DCM (3X). The combined organics were dried (Na ₂ S0 ₄ ), filtered and concentrated. Purification via silica gel chromatography (0-100 % EtOAc in hexanes) gave the title compound (66.6 mg, 88 %). MS (ESI): mass calcd. for C21H1 ₉ F4N5O2,

449.1 ; m/z found, 449.9 [M+H] ⁺ . 'H NMR (400 MHz, CDC1 ₃ ) δ 8.42 - 8.41 (m, 0.5H), 8.23 -

8.16 (m, 0.5H), 7.89 - 7.75 (m, 3.6H), 7.65 (dd, J= 9.5, 2.5 Hz, 0.5H), 7.44 (dd, J= 8.5, 5.8 Hz,

0.4H), 7.15 (td, J= 8.2, 2.5 Hz, 0.5H), 7.05 (dd, J= 8.5, 5.8 Hz, 0.5H), 6.84 (d, J= 8.7 Hz, 1H),

6.56 - 6.48 (m, 0.5H), 5.32 - 5.24 (m, 0.5H), 5.16 - 5.09 (m, 0.5H), 4.91 - 4.84 (m, 0.5H), 4.77 - 4.68 (m, 0.5H), 4.05 - 3.94 (m, 0.5H), 3.37 - 3.28 (m, 0.5H), 2.99 - 2.81 (m, 1H), 2.18 - 1.80 (m, 3H), 1.68 - 1.61 (m, 0.6H), 1.42 - 1.34 (m, 1.9H), 0.83 (d, J= 7.0 Hz, 1.5H).

Example 148: (2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S,3R)-2-methyl-3-( (5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 125 substituting intermediate A- 3 with intermediate A-31. MS (ESI): mass calcd. for C19H18F3 7O2, 433.1; m/z found, 433.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.66 (dd, J= 4.8, 1.8 Hz, 0.5H), 8.48 - 8.44 (m, 0.5H), 8.42 (dd, J= 4.8, 1.8 Hz, 0.5H), 8.31 - 8.26 (m, 1H), 8.20 - 8.14 (m, 0.5H), 7.95 - 7.83 (m, 2.5H), 7.50 (dd, J= 7.6, 1.8 Hz, 0.5H), 7.45 (dd, J= 7.7, 4.8 Hz, 0.5H), 6.82 (dd, J= 7.6, 4.7 Hz, 0.5H), 5.31 - 5.24 (m, 0.5H), 5.20 - 5.09 (m, 0.5H), 4.86 - 4.80 (m, 0.5H), 4.80 - 4.69 (m, 0.5H), 3.90 - 3.79 (m, 0.5H), 3.33 - 3.24 (m, 0.5H), 3.03 - 2.86 (m, 1H), 2.11 - 1.65 (m, 3.5H), 1.48 - 1.34 (m, 2.5H), 0.82 (d, J= 7.0 Hz, 1H).

Example 149: (5-methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S,3R)-2-m ethyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 147 substituting intermediate A- 1 with intermediate A-30. MS (ESI): mass calcd. for C ₂ iH ₂₁ F _{3 6} 0 ₂ , 446.2; m/z found, 446.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.49 - 8.44 (m, 0.4H), 8.43 - 8.41 (m, 0.4H), 8.27 - 8.22 (m, 0.6H), 8.21 - 8.19 (m, 0.6H), 7.87 (s, 1.2H), 7.86 - 7.81 (m, 1.4H), 7.78 (dd, J= 8.8, 2.6 Hz, 0.4H), 7.67 - 7.63 (m, 0.4H), 7.31 (dd, J= 2.3, 0.8 Hz, 0.6H), 6.87 - 6.80 (m, 1H), 5.30 - 5.26 (m, 0.4H), 5.17 - 5.07 (m, 0.4H), 4.88 - 4.82 (m, 0.6H), 4.78 - 4.69 (m, 0.6H), 4.05 - 3.95 (m, 0.6H), 3.30 - 3.21 (m, 0.4H), 2.97 - 2.85 (m, 1H), 2.46 (s, 1.2H), 2.11 - 1.83 (m, 4.8H), 1.73 - 1.62 (m, 0.6H), 1.38 (d, J= 7.3 Hz, 1.6H), 0.83 (d, J= 7.0 Hz, 1.8H). Example 150: (6-methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S,3R)-2-m ethyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 147 substituting intermediate A- 1 with intermediate A-8. MS (ESI): mass calcd. for C21H21F _{3 6} O2, 446.2; m/z found, 446.9

[M+H] ⁺ . ^X H NMR (400 MHz, CDCI3) δ 8.43 - 8.39 (m, 0.4H), 8.15 - 8.10 (m, 0.6H), 7.87 (s, 1H), 7.86 - 7.81 (m, 1.4H), 7.80 - 7.73 (m, 1H), 7.32 - 7.27 (m, 1H), 6.86 - 6.79 (m, 1H), 6.58 (d, J= 7.8 Hz, 0.6H), 5.30 - 5.25 (m, 0.4H), 5.16 - 5.06 (m, 0.4H), 4.85 - 4.77 (m, 0.6H), 4.77 - 4.67 (m, 0.6H), 4.03 - 3.89 (m, 0.6H), 3.33 - 3.25 (m, 0.4H), 2.97 - 2.83 (m, 1H), 2.70 (s, 1.2H), 2.52 (s, 1.8H), 2.13 - 1.70 (m, 3.6H), 1.42 - 1.34 (m, 1.6H), 0.79 (d, J= 7.0 Hz, 1.8H).

Example 151: (3-methyl-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 143 substituting intermediate A- 29 with intermediate A-27. MS (ESI): mass calcd. for C24H2 ₃ F ₃ 4O2, 456.2; m/z found, 457.2 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.91 - 8.71 (m, 2H), 8.37 (s, 0.6H), 8.24 (s, 0.4H), 7.89 - 7.80 (m, 0.4H), 7.75 (d, J= 8.8 Hz, 0.6H), 7.41 - 7.09 (m, 3.4H), 6.94 (dd, J= 38.0, 8.2 Hz, 0.6H), 6.88 - 6.72 (m, 1H), 5.19 (s, 0.6H), 5.00 (s, 0.4H), 4.98 - 4.87 (m, 0.6H), 4.55 - 4.43 (m, 0.4H), 4.35 - 4.23 (m, 0.4H), 3.67 - 3.53 (m, 0.6H), 3.13 - 3.01 (m, 0.6H), 2.95 (s, 1.8H), 2.88 (s, 1.2H), 2.79 - 2.66 (m, 0.4H), 2.27 (s, 1H), 2.04 - 1.79 (m, 2.4H), 1.51 - 1.35 (m, 0.6H), 1.22 - 1.00 (m, 3H).

Example 152: (3-methyl-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl- 3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 147 substituting intermediate A-

1 with intermediate A-25. MS (ESI): mass calcd. for C22H22F ₃ N5O2, 445.2; m/z found, 446.2

[M+H] ⁺ . ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.38 (s, 0.6H), 8.24 (s, 0.4H), 7.95 - 7.78 (m, 3.4H), 7.75

(dd, J= 8.8, 2.4 Hz, 0.6H), 7.58 - 7.30 (m, 1H), 7.20 - 7.16 (m, 0.5H), 6.97 (d, J= 7.6 Hz, 0.5H),

6.88 (d, J= 8.7 Hz, 0.4H), 6.84 - 6.78 (m, 0.6H), 5.21 - 5.16 (m, 0.6H), 5.01 - 4.98 (m, 0.4H),

4.97 - 4.89 (m, 0.6H), 4.56 - 4.46 (m, 0.4H), 4.17 - 4.10 (m, 0.4H), 3.49 - 3.41 (m, 0.6H), 3.03 - 2.95 (m, 0.6H), 2.79 - 2.65 (m, 0.4H), 2.20 (s, 1.6H), 2.12 (s, 1.4H), 2.03 - 1.76 (m, 3H), 1.44 1.23 (m, 1H), 1.14 (d, J= 7.0 Hz, 1.2H), 1.04 (d, J= 7.1 Hz, 1.8H).

Example 153: (2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S,3R)-2-methyl-3-( (5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 147 substituting intermediate A- 1 with intermediate A-31. MS (ESI): mass calcd. for C ₂ oH ₁₉ F _{3 6} 0 ₂ , 432.2; m/z found, 433.2 [M+H] ⁺ . ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.66 (dd, J= 4.7, 1.8 Hz, 0.4H), 8.47 - 8.38 (m, 1.1H), 8.19 - 8.11 (m, 0.5H), 7.89 (s, 1H), 7.89 - 7.86 (m, 1.6H), 7.84 (dd, J= 8.8, 2.7 Hz, 0.4H), 7.78 (dd, J= 8.8, 2.5 Hz, 0.4H), 7.49 - 7.42 (m, 1.2H), 6.85 - 6.82 (m, 0.9H), 6.77 (dd, J= 7.6, 4.8 Hz, 0.5H), 5.36 - 5.28 (m, 0.4H), 5.16 - 5.06 (m, 0.4H), 4.87 - 4.81 (m, 0.6H), 4.77 - 4.70 (m, 0.6H), 4.01 - 3.90 (m, 0.6H), 3.30 - 3.24 (m, 0.4H), 3.05 - 2.87 (m, 1H), 2.14 - 1.79 (m, 3H), 1.70 - 1.62 (m, 0.6H), 1.41 - 1.33 (m, 1.9H), 0.86 (d, J= 7.0 Hz, 1.5H).

Example 154: ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- yl)(2-(pyrimidin-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 143 substituting 2-chloro-5- (trifluoromethyl)pyridine with 2-chloro-3-fluoro-5-(trifluoromethyl)pyridine. MS (ESI): mass calcd. for CzsH^^Oz, 460.2; m/z found, 460.9 [M+H] ⁺ . 'H NMR (400 MHz, CDC1 ₃ ) δ 8.78 (d, J= 4.8 Hz, 0.8H), 8.74 (d, J= 4.9 Hz, 1.2H), 8.39 - 8.32 (m, 0.6H), 8.27 - 8.17 (m, 1H), 7.95 (s, 0.4H), 7.62 - 7.45 (m, 2H), 7.45 - 7.38 (m, 0.5H), 7.33 - 7.25 (m, 1H), 7.22 - 7.15 (m, 1H), 7.05 - 6.98 (m, 0.5H), 5.41 - 5.36 (m, 0.6H), 5.22 - 5.11 (m, 0.6H), 4.97 - 4.93 (m, 0.4H), 4.85 - 4.75 (m, 0.4H), 4.09 - 3.99 (m, 0.4H), 3.48 - 3.36 (m, 0.6H), 3.17 - 3.04 (m, 0.6H), 2.95 - 2.90 (m, 0.4H), 2.14 - 1.91 (m, 3H), 1.72 - 1.59 (m, 0.5H), 1.46 - 1.35 (m, 2.3H), 0.93 (d, J= 7.0 Hz, 1.2H).

Example 155: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)oxy)-2-methylpiperidin-l-yl)me thanone.

The title compound was prepared analogous to Example 154 substituting intermediate A-

29 with intermediate A-28. MS (ESI): mass calcd. for C ₂ 3H ₁₉ F _{5 4} 0 ₂ , 478.1; m/z found, 478.9 [M+H] . Analytical HPLC was obtained on a Agilent 1100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 6.32 min at 254 nm.

Example 156: ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- yl)(2-(5-fluoropyrimidin-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 154 substituting intermediate A- 29 with intermediate A-25. MS (ESI): mass calcd. for C23H19F5N4O2, 478.1; m/z found, 478.9 [M+H] ⁺ . Analytical HPLC was obtained on a Agilent 1100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 6.85 min at 254 nm.

Example 157: ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- l,2,3-triazol-2-yl)pyridin-3-yl)methanone.

The title compound was prepared analogous to Example 147 substituting 2-chloro-5-

(trifluoromethyl)pyridine with 2-chloro-3-fluoro-5-(trifluoromethyl)pyridine, and substituting intermediate A-1 with intermediate A-30. MS (ESI): mass calcd. for C21H2 ₀ F4 ₆ O2, 464.2; m z found, 465.0 [M+H] ⁺ . 1H NMR (400 MHz, CDC1 ₃ ) δ 8.51 - 8.40 (m, 0.5H), 8.34 - 8.26 (m,

0.5H), 8.25 - 8.18 (m, 0.5H), 8.11 - 8.03 (m, 0.5H), 7.87 (s, 1.2H), 7.84 (s, 0.8H), 7.69 - 7.65 (m,

1H), 7.63 - 7.53 (m, 1H), 5.43 - 5.36 (m, 0.4H), 5.21 - 5.11 (m, 0.4H), 5.06 - 4.96 (m, 0.6H), 4.84 - 4.68 (m, 0.6H), 4.01 - 3.89 (m, 0.6H), 3.34 - 3.24 (m, 0.4H), 3.05 - 2.88 (m, 1H), 2.46 (s, 1.2H), 2.19 (s, 1.8H), 2.14 - 1.92 (m, 3H), 1.69 - 1.61 (m, 0.5H), 1.50 - 1.33 (m, 1.7H), 0.91 (d, J = 7.0 Hz, 1.8H).

Example 158: ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -methyl-2-(2H- 1,2,3 -triazol-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 157 substituting intermediate A- 30 with intermediate A-15. MS (ESI): mass calcd. for C ₂ 2H ₂₁ F _{4 5} 0 ₂ , 463.2; m/z found, 463.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.18 - 8.15 (m, 0.6H), 8.09 - 8.05 (m, 0.4H), 7.82 (s, 0.8H), 7.79 (s, 1.2H), 7.65 - 7.59 (m, 0.4H), 7.51 (dd, J= 9.4, 2.1 Hz, 0.6H), 7.45 - 7.31 (m, 2H), 7.27 - 7.18 (m, 0.6H), 7.02 - 6.95 (m, 0.4H), 5.28 - 5.23 (m, 0.6H), 5.09 - 5.05 (m, 0.4H), 5.04 - 4.91 (m, 0.6H), 4.57 - 4.49 (m, 0.4H), 4.26 - 4.07 (m, 0.4H), 3.52 - 3.40 (m, 0.6H), 3.11 - 2.94 (m, 0.6H), 2.79 - 2.68 (m, 0.4H), 2.20 (s, 1.8H), 2.13 (s, 1.2H), 2.04 - 1.85 (m, 3H), 1.48 - 1.25 (m, 1H), 1.16 (d, J= 7.0 Hz, 1.2H), 1.07 (d, J= 7.2 Hz, 1.8H).

Example 159: (3 -fluoro-2-(2H- 1 ,2,3 -triazol-2-yl)phenyl)((2S,3 R)-3 -((3 -fluoro-5 - (trifluoromethyl)pyridin-2-yl)oxy)-2-methylpiperidin-l-yl)me thanone.

The title compound was prepared analogous to Example 157 substituting intermediate A- 30 with intermediate A-3. MS (ESI): mass calcd. for C ₂ iH ₁₈ F _{5 5} 0 ₂ , 467.1; m/z found, 467.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.18 (s, 0.6H), 8.05 (s, 0.4H), 7.87 (s, 0.8H), 7.84 (s, 1.2H), 7.64 - 7.43 (m, 2H), 7.37 - 7.28 (m, 1H), 7.25 - 7.04 (m, 1H), 5.35 - 5.27 (m, 0.6H), 5.09 - 4.97 (m, 1H), 4.64 - 4.56 (m, 0.4H), 4.12 - 3.98 (m, 0.4H), 3.47 - 3.38 (m, 0.6H), 3.07 - 2.96 (m, 0.6H), 2.86 - 2.71 (m, 0.4H), 2.10 - 1.90 (m, 3H), 1.16 (d, J= 7.1 Hz, 1.8H), 1.02 (d, J= 7.0 Hz, 1.2H). * 1H buried under water peak.

Example 160: ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- yl)(6-methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone .

The title compound was prepared analogous to Example 157 substituting intermediate A-

30 with intermediate A-22. MS (ESI): mass calcd. for C21H2 ₀ F4 ₆ O2, 464.2; m/z found, 465.0 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.24 - 8.19 (m, 0.5H), 8.16 (d, J= 8.4 Hz, 0.5H), 8.05 (d, J= 8.4 Hz, 0.5H), 7.91 - 7.87 (m, 0.5H), 7.81 (s, 1H), 7.77 (s, 1H), 7.53 (dd, J= 9.7, 2.2 Hz, 0.5H), 7.39 (dd, J= 9.6, 2.1 Hz, 0.5H), 7.28 (d, J= 8.5 Hz, 0.5H), 7.13 (d, J= 8.5 Hz, 0.5H), 5.36 - 5.31 (m, 0.5H), 5.24 - 5.15 (m, 0.5H), 4.92 - 4.84 (m, 0.5H), 4.80 - 4.71 (m, 0.5H), 4.23 - 4.13 (m, 0.5H), 3.39 - 3.30 (m, 0.5H), 3.20 - 3.09 (m, 0.5H), 2.98 (td, J= 13.4, 3.2 Hz, 0.5H), 2.63 (s, 1.6H), 2.30 (s, 1.4H), 2.12 - 1.98 (m, 3H), 1.76 - 1.66 (m, 0.5H), 1.46 - 1.37 (m, 2H), 1.17 (d, J= 7.0 Hz, 1.5H). Example 161 : ((2S,3R)-3-((5-chloropyrimidin-2-yl)oxy)-2-methylpiperidin-l -yl)(3-fluoro-2- (2H-l,2,3-triazol-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 147 substituting 2-chloro-5- (trifluoromethyl)pyridine with 2,5-dichloropyrimidine, and substituting intermediate A-1 with intermediate A-3. MS (ESI): mass calcd. for Ci ₉ Hi ₈ ClFN ₆ 02, 416.1 ; m/z found, 417.0 [M+H] ⁺ . ¹ HNMR contains a mixture of more than two rotamers. Analytical HPLC was obtained on a Agilent 1 100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5- 99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 6.44 min at 254 nm.

Example 162: ((2S,3R)-3-((5-chloropyrimidin-2-yl)oxy)-2-methylpiperidin-l -yl)(5-methyl-2- (2H-l,2,3-triazol-2-yl)pyridin-3-yl)methanone.

The title compound was prepared analogous to Example 161 substituting intermediate A-

3 with intermediate A-30. MS (ESI): mass calcd. for Ci ₉ H ₂ oCl ₇ 02, 413.1 ; m/z found, 414.0 [M+H] ⁺ . 1H NMR (400 MHz, CDCI ₃ , multiple rotamers present, two major rotamers reported) δ 8.45 (s, 1H), 8.42 (d, J= 2.1 Hz, 0.5H), 8.35 (s, 1H), 8.26 (d, J= 2.1 Hz, 0.5H), 7.86 (s, 1H), 7.82 (s, 1H), 7.70 (dd, J= 2.2, 0.9 Hz, 0.5H), 7.61 (dd, J= 2.2, 0.9 Hz, 0.5H), 5.20 - 5.14 (m, 0.5H), 5.12 - 5.08 (m, 0.5H), 4.79 - 4.66 (m, 1H), 4.02 - 3.88 (m, 0.5H), 3.36 - 3.21 (m, 0.5H), 2.91 (td, J= 13.3, 3.1 Hz, 1H), 2.42 (s, 1.5H), 2.16 (s, 1.5H), 2.03 - 1.83 (m, 3H), 1.44 - 1.35 (m, 2.5H), 0.89 (d, J= 7.0 Hz, 1.5H).

Example 163 : ((2S,3R)-3-((5-chloropyrimidin-2-yl)oxy)-2-methylpiperidin-l -yl)(3-methyl-2- (2H-l,2,3-triazol-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 161 substituting intermediate A- 3 with intermediate A-15. MS (ESI): mass calcd. for C ₂ oH ₂₁ ClN ₆ 02, 412.1 ; m/z found, 412.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDCI ₃ , multiple rotamers present, two major rotamers reported) δ 8.42 - 8.36 (m, 2H), 7.84 - 7.74 (m, 2H), 7.45 - 7.33 (m, 2H), 7.22 - 7.13 (m, 0.7H), 6.90 (t, J = 7.6 Hz, 0.3H), 5.09 - 4.92 (m, 1.4H), 4.85 - 4.77 (m, 0.3H), 4.55 - 4.44 (m, 0.3H), 4.18 - 4.10 (m, 0.3H), 3.53 - 3.37 (m, 0.7H), 3.09 - 2.93 (m, 0.7H), 2.78 - 2.65 (m, 0.3H), 2.19 (s, 2.1H), 2.1 1 (s, 0.9H), 2.10 - 1.77 (m, 3H), 1.49 - 1.28 (m, 1H), 1.16 (d, J= 7.0 Hz, 0.9H), 1.05 (d, J= 7.1 Hz, 2.1H).

Example 164: ((2S,3R)-3-((5-chloropyrimidin-2-yl)oxy)-2-methylpiperidin-l -yl)(6-methyl-3- (2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

The title compound was prepared analogous to Example 161 substituting intermediate A- 3 with intermediate A-22. MS (ESI): mass calcd. for Ci ₉ H ₂ oCl ₇ 0 ₂ , 413.1 ; m/z found, 414.0 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.45 (s, 1.4H), 8.23 (s, 0.6H), 8.17 (d, J= 8.4 Hz, 0.7H), 8.08 (d, J= 8.5 Hz, 0.3H), 7.93 (s, 1.4H), 7.79 (s, 0.6H), 7.28 (d, J= 8.7 Hz, 0.7H), 7.16 (d, J= 8.5 Hz, 0.3H), 5.26 - 5.16 (m, 0.7H), 5.14 - 5.04 (m, 0.7H), 4.81 - 4.68 (m, 0.3H), 4.69 - 4.60 (m, 0.3H), 4.19 - 4.09 (m, 0.3H), 3.40 - 3.27 (m, 0.7H), 3.19 - 3.05 (m, 0.7H), 2.97 (td, J= 13.5, 3.3 Hz, 0.3H), 2.63 (s, 2.1H), 2.34 (s, 0.9H), 2.11 - 1.89 (m, 3H), 1.40 (d, J= 7.2 Hz, 2.1H), 1.37 - 1.28 (m, 1H), 1.18 (d, J= 7.0 Hz, 0.9H).

Example 165: (2-(5-fluoropyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 101, steps A and B, and

Example 143 step C, substituting intermediate A-29 with intermediate A-25. MS (ESI): mass calcd. for C ₂ 2H ₁₉ F _{4 5} 0 ₂ , 461.1; m/z found, 462.0 [M+H] ⁺ . 'H NMR (400 MHz, CDC1 ₃ ) δ 9.04 (s, 1H), 8.80 - 8.75 (m, 2H), 8.63 (s, 1H), 8.59 (s, 1H), 8.32 - 8.23 (m, 1H), 7.56 - 7.41 (m, 2H), 5.40 - 5.30 (m, 0.5H), 5.29 - 5.24 (m, 0.7H), 5.24 - 5.16 (m, 0.5H), 4.87 - 4.81 (m, 0.3H), 4.82 - 4.72 (m, 0.3H), 3.51 - 3.38 (m, 0.7H), 3.23 - 2.84 (m, 1H), 2.15 - 1.89 (m, 3H), 1.43 (d, J= 7.1 Hz, 1.5H), 1.39 (d, J= 7.3 Hz, 1.5H), 1.36 - 1.27 (m, 1H).

Example 166: (2-(5-fluoropyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 143 substituting 2-chloro-5- (trifluoromethyl)pyridine with 2-chloro-5-(trifluoromethyl)pyrazine, and intermediate A-29 with intermediate A-25. MS (ESI): mass calcd. for 461.1 ; m/z found, 461.9 [M+H] ⁺ . Analytical HPLC was obtained on a Agilent 1100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 6.34 min at 254 nm. Example 167: (3-methyl-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 165 substituting intermediate A- 25 with intermediate A-27. MS (ESI): mass calcd. for C2 ₃ H22F ₃ N5O2, 457.2; m/z found, 457.9 [M+H] . Analytical HPLC was obtained on a Agilent 1 100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 5.69 min at 254 nm. Example 168: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrazin-2-yl)oxy)pi peridin-l-yl)(2- (pyrimidin-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 166 substituting intermediate A- 25 with intermediate A-29. MS (ESI): mass calcd. for C22H2 ₀ F ₃ 5O2, 443.2; m/z found, 443.95 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.64 (s, 0.8H), 8.59 (s, 1.2H), 8.45 (s, 0.8H), 8.35 - 8.27 (m, 1.2H), 8.16 - 8.11 (m, 1H), 7.58 - 7.36 (m, 2H), 7.33 - 7.26 (m, 1.2H)*, 7.10 - 6.99 (m, 0.4H), 6.87 (t, J= 7.5 Hz, 0.4H), 5.30 (s, 0.6), 5.24 - 5.08 (m, 0.5H), 4.90 - 4.82 (m, 0.4H), 4.82 - 4.74 (m, 0.4H), 4.06 - 3.92 (m, 0.5H), 3.55 - 3.33 (m, 0.6H), 3.22 - 3.05 (m, 0.6H), 2.98 - 2.82 (m, 0.4H), 2.21 - 1.81 (m, 3H), 1.77 - 1.63 (m, 0.4H), 1.43 (d, J= 12 Hz, 2.4H), 0.89 (d, J= 6.9 Hz, 1.2H). *Peak is partially buried under CDCI ₃ peak.

Example 169: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrimidin-2-yl)oxy) piperidin- 1 -yl)(2- (pyrimidin-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 165 substituting intermediate A- 25 with intermediate A-29. MS (ESI): mass calcd. for C22H2 ₀ F ₃ N5O2, 443.2; m/z found, 444.0 [M+H] . Analytical HPLC was obtained on a Agilent 1 100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 5.63 min at 254 nm.

Example 170: (2-(5-fluoropyrimidin-2-yl)-3-methylphenyl)((2S,3R)-2-methyl -3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 165 substituting intermediate A-

25 with intermediate A-38. MS (ESI): mass calcd. for C ₂ 3H ₂₁ F ₄ N502, 475.2; m/z found, 475.9 [M+H] . Analytical HPLC was obtained on a Agilent 1 100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 6.30 min at 254 nm.

Example 171 : (3-methyl-2-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 166 substituting intermediate A- 25 with intermediate A-27. MS (ESI): mass calcd. for C ₂ 3H ₂₂ F ₃ 502, 457.2; m/z found, 458.0 [M+Hf. Analytical HPLC was obtained on a Agilent 1100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 6.04 min at 254 nm.

Example 172: (4-methoxy-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl -3-((5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 125 substituting intermediate A- 3 with intermediate A-10. MS (ESI): mass calcd. for C ₂ iH ₂₁ F ₃ N ₆ 0 ₃ , 462.2; m/z found, 463.0 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.44 (s, 0.4H), 8.29 (s, 1.2H), 8.18 (s, 0.4H), 7.80 (s, 1.2H), 7.78 (s, 0.8H), 7.52 (d, J= 2.5 Hz, 0.4H), 7.40 - 7.35 (m, 1.1H), 7.03 - 6.94 (m, 1.1H), 6.36 (dd, J= 8.5, 2.5 Hz, 0.4H), 5.27 - 5.23 (m, 0.4H), 5.22 - 5.11 (m, 0.6H), 4.86 - 4.82 (m, 0.6H), 4.79 - 4.69 (m, 0.6H), 4.01 - 3.92 (m, 0.4H), 3.91 (s, 1.8H), 3.77 (s, 1.2H), 3.45 - 3.30 (m, 0.4H), 2.93 - 2.77 (m, 1H), 2.13 - 1.85 (m, 3H), 1.70 - 1.62 (m, 0.4H), 1.44 - 1.27 (m, 2.4H), 0.76 (d, J= 7.0 Hz, 1.2H). Example 173: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrazin-2-yl)oxy)pi peridin-l-yl)(3- phenylpyrazin-2-yl)methanone.

The title compound was prepared analogous to Example 125 substituting intermediate A- 3 with intermediate A-33. MS (ESI): mass calcd. for C22H2 ₀ F ₃ N5O2, 443.2; m/z found, 443.9 [M+Hf. Analytical HPLC was obtained on a Agilent 1100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 6.07 and 6.18 min at 254 nm.

Example 174: (4-methoxy-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-2-methyl -3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 161 substituting 2,5- dichloropyrimidine with 2-chloro-5-(trifluoromethyl)pyrimidine, and substituting intermediate A-3 with intermediate A-10.MS (ESI): mass calcd. for C21H21F ₃ N ₆ O ₃ , 462.2; m/z found, 464.1 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.78 (s, 0.3H), 8.75 (s, 0.7H), 8.65 (s, 0.7H), 8.09 (s, 0.3H), 7.80 (s, 1H), 7.77 (s, 1H), 7.50 (d, J= 2.6 Hz, 0.5H), 7.40 (d, J= 8.5 Hz, 0.5H), 7.38 (d, J = 2.5 Hz, 0.5H), 7.12 (d, J= 8.5 Hz, 0.5H), 6.95 (dd, J= 8.5, 2.5 Hz, 0.5H), 6.37 (dd, J= 8.5, 2.6 Hz, 0.5H), 5.25 - 5.12 (m, 1H), 4.85 - 4.80 (m, 0.5H), 4.79 - 4.71 (m, 0.5H), 4.10 - 4.01 (m, 0.5H), 3.89 (s, 2H), 3.77 (s, 1H), 3.43 - 3.31 (m, 0.5H), 2.92 - 2.80 (m, 1H), 2.07 - 1.87 (m, 3H), 1.69 - 1.61 (m, 0.5H), 1.44 - 1.31 (m, 2H), 0.86 (d, J= 7.0 Hz, 1.5H).

Example 175: (5-fluoro-2-(oxazol-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 174 substituting intermediate A- 10 with intermediate A-35. MS (ESI): mass calcd. for C21H18F4 4O3, 450.1 ; m/z found, 452.0 [M+H] ⁺ . ¹ FTNMR contains a mixture of more than two rotamers. Analytical HPLC was obtained on a Agilent 1100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 5.73 min at 254 nm.

Example 176: (5-methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S,3R)-2-m ethyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 174 substituting intermediate A- 10 with intermediate A-30. MS (ESI): mass calcd. for C ₂ oH ₂ oF ₃ N702, 447.2; m/z found, 448.1 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.77 (s, 1H), 8.68 (s, 1H), 8.44 (d, J= 2.2 Hz, 0.7H), 8.25 (d, J= 2.2 Hz, 0.3H), 7.87 (s, 1H), 7.83 (s, 1H), 7.71 (d, J= 2.2 Hz, 0.5H), 7.66 (d, J= 2.2 Hz, 0.5H), 5.28 - 5.24 (m, 0.5H), 5.24 - 5.15 (m, 0.5H), 4.89 - 4.84 (m, 0.5H), 4.82 - 4.70 (m, 0.5H), 3.99 - 3.90 (m, 0.5H), 3.31 - 3.22 (m, 0.5H), 2.93 (td, J= 13.2, 3.1 Hz, 1H), 2.43 (s, 1.8H), 2.14 (s, 1.2H), 2.12 - 1.86 (m, 3H), 1.74 - 1.64 (m, 0.5H), 1.49 - 1.37 (m, 2H), 0.92 (d, J = 7.0 Hz, 1.5H).

Example 177: (5-methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S,3R)-2-m ethyl-3-((5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 125 substituting intermediate A-

3 with intermediate A-30. MS (ESI): mass calcd. for C ₂ oH ₂ oF ₃ 702, 447.2; m/z found, 448.0 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.49 - 8.44 (m, 1H), 8.31 (d, J= 1.4 Hz, 0.5H), 8.28 (d, J = 1.3 Hz, 0.5H), 8.25 - 8.20 (m, 1H), 7.88 (s, 1H), 7.85 (s, 1H), 7.68 - 7.64 (m, 0.5H), 7.38 - 7.34 (m, 0.5H), 5.29 - 5.25 (m, 0.5H), 5.19 - 5.10 (m, 0.5H), 4.89 - 4.80 (m, 0.5H), 4.81 - 4.70 (m, 0.5H), 3.94 - 3.82 (m, 0.5H), 3.33 - 3.23 (m, 0.5H), 2.91 (td, J= 13.2, 3.1 Hz, 1H), 2.47 (s, 1.5H), 2.05 (s, 1.5H), 2.04 - 1.77 (m, 3H), 1.49 - 1.34 (m, 2.5H), 0.81 (d, 1.5H).

Example 178: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyrimidin-2-yl)oxy) piperidin phenylpyrazin-2-yl)methanone.

The title compound was prepared analogous to Example 174 substituting intermediate A- 10 with intermediate A-33. MS (ESI): mass calcd. for C ₂ 2H ₂ oF _{3 5} 02, 443.2; m/z found, 0-521-4 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.78 (d, J= 0.9 Hz, 1.3H), 8.68 (d, J= 2.4 Hz, 0.65H), 8.61 (d, J= 0.9 Hz, 0.7H), 8.55 (d, J= 2.4 Hz, 0.65H), 8.50 (d, J= 2.4 Hz, 0.35H), 8.09 (d, J= 2.4 Hz, 0.35H), 7.94 - 7.76 (series of m, 2H), 7.62 - 7.43 (series of m, 3H), 5.30 - 5.22 (m, 0.65H), 5.19 - 5.11 (m, 0.65H), 4.89 - 4.79 (m, 0.35H), 4.81 - 4.69 (m, 0.35H), 4.01 - 3.90 (m, 0.35H), 3.32 - 3.15 (m, 0.65H), 3.09 - 2.94 (m, 0.65H), 2.88 (td, J= 13.4, 3.3 Hz, 0.35H), 2.19 - 1.82 (m, 3H), 1.39 - 1.30 (m, 1H), 1.29 - 1.21 (m, 3H).

Example 179: (5-fluoro-2-(oxazol-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyrazin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 125 substituting intermediate A-

3 with intermediate A-35. MS (ESI): mass calcd. for C ₂ iH ₁₈ F _{4 4} 0 ₃ , 450.1; m/z found, 451.0 [M+H] ⁺ . ¹ HNMR contains a mixture of more than two rotamers. Analytical HPLC was obtained on a Agilent 1100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 6.04 min at 254 nm. Example 180: ((2S*,3R*)-3-((5-chloropyrazin-2-yl)amino)-2-methylpiperidin - 1 -yl)(4-methyl-2- (2H-l,2,3-triazol-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 86 substituting intermediate A- 17 with intermediate A-l 1. MS (ESI): mass calcd. for C20H22CIN7O, 411.2; m/z found, 412.2 [M+H] ⁺ . MP=11 1.1 °C.

Example 181 : ((2S*,3R*)-3-((5-chloropyridin-2-yl)amino)-2-methylpiperidin - l-yl)(4-methoxy- 2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 77 substituting intermediate A- 17 with intermediate A-10. MS (ESI): mass calcd. for C ₂ iH ₂₃ Cl ₆ 02, 426.2; m/z found, 427.2 [M+H] ⁺ . MP=115.4 °C.

Example 182: ((2S*,3R*)-3-((5-chloropyrazin-2-yl)amino)-2-methylpiperidin -l-yl)(5-methyl-3- (2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

The title compound was prepared analogous to Example 86 substituting intermediate A- 17 with intermediate A-21. MS (ESI): mass calcd. for Ci ₉ H ₂₁ ClN ₈ 0, 412.2; m/z found, 413.1 [M+H] ⁺ . MP=84.4 °C.

Example 183: ((2S*,3R*)-3-((5-chloropyrimidin-2-yl)amino)-2-methylpiperid in-l-yl)(5-methyl- 3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

The title compound was prepared analogous to Example 30 substituting intermediate A-4 with intermediate A-21. MP=1 12.9 °C.

Example 184: (5-methoxy-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S*,3R*)-2-meth yl-3-((5- (trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 38 substituting intermediate A-4 with intermediate A-14. MP=148.5 °C.

Example 185: ((2S*,3R*)-3-((5-chloropyrimidin-2-yl)amino)-2-methylpiperid in-l-yl)(4- methoxy-2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 30 substituting intermediate A-4 with intermediate A- 10. MP=99.5 °C.

Example 186: ((2S*,3R*)-3-((5-chloropyrazin-2-yl)amino)-2-methylpiperidin - 1 -yl)(4-methoxy- 2-(2H-l,2,3-triazol-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 86 substituting intermediate A- 17 with intermediate A-10. MS (ESI): mass calcd. for C ₂ oH ₂₂ ClN ₇ 02, 427.2; m/z found, 428.1 [M+H] ⁺ . MP= 112.8 °C. Example 187: ((2S*,3R*)-3-(benzo[d]oxazol-2-yl(methyl)amino)-2-methylpipe ridin-l-yl)(5- -triazol-2-yl)pyridin-2-yl)methanone.

Step D: ((2S*,3R*)-3-(benzo[d]oxazol-2-yl(methyl)amino)-2-methylpipe ridin-l-yl)(5- methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone. To a solution of compound of Example 73 (20 mg, 0.047 mmol) in DMF (0.47 mL) was added sodium tert-butoxide (6 mg, 0.06 mmol) followed by iodomethane (3 μί, 0.049 mmol). The reaction mixture was stirred at room temperature for 16h. Solvent was evaporated and purification via prep HPLC gave the title compound (14 mg, 69%). MS (ESI): mass calcd. for C _ZS H^ _T O _Z , 431.2; m/z found, 432.0

[M+H] ⁺ . ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.47 (s, 1H), 8.18 (s, 1H), 7.90 - 7.75 (m, 2H), 7.37 (d, J = 7.7 Hz, 1H), 7.27 (d, J= 8.9 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.04 - 6.98 (m, 1H), 5.05 - 4.92 (m, 1H), 4.44 - 4.32 (m, 1H), 3.43 - 3.33 (m, 4H), 3.34 - 3.21 (m, 1H), 2.48 (s, 3H), 2.18 - 2.04 (m, 1H), 1.99 - 1.76 (m, 2H), 1.62 - 1.53 (m, 1H), 1.47 (d, J= 6.8 Hz, 3H). Example 188: (6-methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S*,3R*)-2 -methyl-3- (methyl(5-(trifluoromethyl)pyridin-2-yl)amino)piperidin-l-yl )methanone.

The title compound was prepared analogous to Example 14 substituting intermediate A- 1 1 with intermediate A-8, followed by step D of Example 187. MS (ESI): mass calcd. for C22H24F3N7O, 459.2; m/z found, 460.0 [M+H] ⁺ . 'H NMR (500 MHz, CDC1 ₃ ) δ 8.38 (s, 1H), 7.90 - 7.85 (m, 2H), 7.70 (d, J= 7.7 Hz, 1H), 7.64 (dd, J= 9.1, 2.6 Hz, 1H), 7.30 (d, J= 7.5 Hz, 1H), 6.54 (d, J= 9.0 Hz, 1H), 4.92 - 4.74 (m, 2H), 3.29 - 3.19 (m, 1H), 3.09 (s, 3H), 3.02 - 2.89 (m, 1H), 2.70 (s, 3H), 1.92 - 1.74 (m, 2H), 1.72 - 1.62 (m, 1H), 1.59 - 1.43 (m, 1H), 1.39 - 1.29 (m, 3H).

Example 189: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((2S*,3R*)-2-methyl-3-((5 - (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 14 substituting intermediate A- 1 1 with intermediate A-28. MS (ESI): mass calcd. for C2 ₃ H21F4N5O, 459.2; m/z found, 460.0 [M+H] ⁺ . ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.94 (d, J= 4.9 Hz, 2H), 8.32 - 8.15 (m, 2H), 7.53 - 7.33 (m, 3H), 7.13 (d, J= 7.2 Hz, 1H), 6.24 (d, J= 8.8 Hz, 1H), 4.56 (d, J= 13.5 Hz, 1H), 4.25 - 4.12 (m, 1H), 4.04 (s, 1H), 2.97 - 2.80 (m, 1H), 2.1 1 - 1.90 (m, 2H), 1.77 - 1.62 (m, 2H), 1.52 (d, J = 6.9 Hz, 3H). 1H buried under CDC1 ₃ peak. Example 190: (4-fluoro-2-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl)((2S*,3R*) -2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 14 substituting intermediate A- 1 1 with intermediate A-36. MS (ESI): mass calcd. for C22H21F4N5O2, 463.2; m/z found, 464.0 [M+H] . Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μιη, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C).R _t = 1.37 min (major rotamer) at 254 nm.

Example 191 : (4-fluoro-2-(pyrimidin-2-yl)phenyl)((2S*,3R*)-2-methyl-3-((5 - (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 14 substituting intermediate A- 1 1 with intermediate A-37. MS (ESI): mass calcd. for C2 ₃ H21F4N5O, 459.2; m/z found, 460.0 [M+H] ⁺ . ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.94 (d, J= 4.9 Hz, 2H), 8.21 (s, 1H), 7.89 (dd, J= 9.5, 2.7 Hz, 1H), 7.87 - 7.79 (m, 1H), 7.40 (t, J= 4.9 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.23 - 7.16 (m, 2H), 6.01 - 5.84 (m, 1H), 4.77 - 4.64 (m, 1H), 4.24 - 4.13 (m, 1H), 3.01 - 2.90 (m, 1H), 1.77 (m, 4H), 1.52 (d, J= 6.9 Hz, 3H).

Example 192: (4-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S*,3R*)-2-methy l-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 14 substituting intermediate A- 1 1 with intermediate A-1. MS (ESI): mass calcd. for C21H20F4 6O, 448.2; m/z found, 448.9 [M+H] . Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μηηη, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C).R _t = 1.34 min (major rotamer) at 254 nm.

Example 193: (2-chloro-6-methoxypyridin-3-yl)((2S*, 3R*)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 14 substituting intermediate A- 1 1 with intermediate A-32. MS (ESI): mass calcd. for C1 ₉ H2 ₀ CIF ₃ N4O2, 428.1; m/z found, 428.9 [M+Hf. Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μιη, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C).R _t = 1.34 min (major rotamer) at 254 nm.

Example 194: (3-ethoxy-6-methylpyridin-2-yl)((2S*,3R*)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 14 substituting intermediate A- 1 1 with intermediate A-12. MS (ESI): mass calcd. for C21H25F ₃ N4O2, 422.2; m/z found, 423.0 [M+H] ⁺ . ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.35 - 8.19 (m, 1H), 7.58 - 7.47 (m, 1H), 7.20 - 7.02 (m, 2H), 6.59 - 6.44 (m, 1H), 6.37 (s, 1H), 4.78 - 4.61 (m, 1H), 4.14 - 3.97 (m, 2H), 3.88 (s, 1H), 3.78 - 3.63 (m, 1H), 2.97 (td, J= 13.2, 3.3 Hz, 1H), 2.52 - 2.37 (m, 3H), 2.05 - 1.95 (m, 1H), 1.94 - 1.73 (m, 2H), 1.64 - 1.55 (m, 1H), 1.49 - 1.38 (m, 3H), 1.33 (d, J= 6.9 Hz, 3H). Example 195 : ((2S*,3R*)-2-methyl-3-((5-(trifluoromethyl)-l ,3,4-thiadiazol-2- yl)amino)piperidin- l-yl)(5-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

Step A: (2S ,3R )-tert-butyl 2-methyl-3-((5-(trifluoromethyl)-l ,3,4-thiadiazol-2- yl)amino)piperidine- l-carboxylate. In a microwave vial was dissolved intermediate B-4 (58 mg, 0.27 mmol) in ACN (0.7 mL). 2-Chloro-5-(trifluoromethyl)- l,3,4-thiadiazole (0.59 mg, 0.30 mmol) was added followed by DIPEA (0.12 mL, 0.68 mmol). The microwave vial was capped and the reaction mixture was heated at 120 °C for 30 minutes using microwave and was then diluted with EtOAc. The organic phase was washed with a saturated solution of aHC03, NaCl, dried over MgS0 ₄ , filtered and evaporated. Purification via silica gel chromatography (0-40% EtOAc in hexanes) gave the title compound (87 mg, 88%). MS (ESI): mass calcd. for

Ci ₄ H ₂₁ F _{3 4} 0 ₂ S, 366.1; m/z found, 367.0 [M+H] ⁺ . Analytical HPLC was obtained on a Agilent 1100 Series using an Inertsil ODS-3 column (3μιη, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C). R _t = 1.409 min at 254 nm.

Step B and C: ((2S*,3R*)-2-methyl-3-((5-(trifluoromethyl)-l,3,4-thiadiazol -2- yl)amino)piperidin-l-yl)(5-methyl-3-(2H-l,2,3-triazol-2-yl)p yridin-2-yl)methanone. The title compound was prepared analogous to Example 1, steps B and C, substituting intermediate A-l with intermediate A-21. MS (ESI): mass calcd. for 452.1; m/z found, 452.9 [M+H] ⁺ . 1H NMR (500 MHz, CDC1 ₃ ) δ 8.45 (s, 1H), 8.27 - 8.18 (m, 1H), 8.11 (s, 1H), 7.96 (s, 2H), 4.68 - 4.60 (m, 1H), 4.08 - 4.00 (m, 1H), 3.99 - 3.92 (m, 1H), 3.04 (td, J= 13.4, 3.3 Hz,

1H), 2.48 (s, 3H), 2.21 (d, J= 14.0 Hz, 1H), 2.09 - 1.93 (m, 2H), 1.92 - 1.79 (m, 1H), 1.56 - 1.47 (m, 3H).

Example 196: (6-methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)((2S*,3R*)-2 -methyl-3-((5- (trifluoromethyl)- 1 ,3 ,4-thiadiazol-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 195 substituting intermediate A-

21 with intermediate A-8. MS (ESI): mass calcd. for CisH^FsNsOS, 452.1; m/z found, 452.9

[M+H] ⁺ . ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.33 (d, J= 8.1 Hz, 0.6H), 8.30 (s, 0.8H), 8.04 (s, 1.2H),

7.61 (d, J= 7.8 Hz, 0.6H), 7.57 (d, J= 7.7 Hz, 0.4H), 7.33 (d, J= 7.8 Hz, 0.6H), 7.28 (d, J= 8.0

Hz, 0.4H), 7.02 (d, J= 8.5 Hz, 0.4H), 5.38 - 5.29 (m, 0.4H), 4.74 - 4.62 (m, 0.6H), 4.20 - 4.11

(m, 0.6H), 4.11 - 4.05 (m, 0.6H), 3.83 - 3.69 (m, 0.4H), 3.60 - 3.42 (m, 0.4H), 3.31 (td, J= 13.5, 3.3 Hz, 0.4H), 2.96 (td, J= 13.4, 3.3 Hz, 0.6H), 2.71 (s, 1.2H), 2.70 (s, 1.8H), 2.23 - 1.67 (series of m, 4H), 1.52 (d, J= 6.9 Hz, 1.8H), 1.45 (d, J= 7.1 Hz, 1.2H).

Example 197: (4-fluoro-2-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl)((2S*,3R*) -2-methyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)methano ne.

The title compound was prepared analogous to Example 69 substituting intermediate A- 21 with intermediate A-36. MS (ESI): mass calcd. for C21H2 ₀ F4 ₆ O2, 464.2; m/z found, 464.9 [M+H] . Analytical HPLC was obtained on a Agilent 1100 Series using an Inertsil ODS-3 column (3μιη, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C).R _t = 1.42 min (major rotamer) at 254 nm.

Example 198: (4-fluoro-2-(2H-l,2,3-triazol-2-yl)phenyl)((2S*,3R*)-2-methy l-3-((5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)methano ne.

The title compound was prepared analogous to Example 69 substituting intermediate A- 21 with intermediate A-l . MS (ESI): mass calcd. for C2oH ₁₉ F ₄ N70, 449.2; m/z found, 449.9 [M+H] . Analytical HPLC was obtained on a Agilent 1 100 Series using an Inertsil ODS-3 column (3μιη, 50 x 3 mm), mobile phase of 5-99% ACN in 0.05% TFA over 1.6 min and then hold at 99% ACN for 0.4 min, at a flow rate of 2.2 mL/min (Temperature = 50 °C).R _t = 1.43 min (major rotamer) at 254 nm.

Example 199: (3-ethoxy-6-methylpyridin-2-yl)((2S*,3R*)-2-methyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)methano ne.

The title compound was prepared analogous to Example 69 substituting intermediate A- 21 with intermediate A-12. MS (ESI): mass calcd. for C2 ₀ H24F ₃ N5O2, 423.2; m/z found, 424.0 [M+H] ⁺ . ^X H NMR (400 MHz, CDCI3) δ 8.50 - 8.42 (m, 2H), 8.39 (s, 1H), 7.20 - 7.03 (m, 2H), 4.76 - 4.62 (m, 1H), 4.18 - 4.02 (m, 2H), 3.90 - 3.81 (m, 1H), 3.79 - 3.64 (m, 1H), 2.97 (td, J = 13.2, 3.3 Hz, 1H), 2.49 (s, 3H), 2.11 - 2.01 (m, 1H), 1.99 - 1.74 (m, 3H), 1.67 - 1.56 (m, 1H), 1.46 - 1.42 (m, 2H), 1.33 (d, J= 7.0 Hz, 3H).

Example 200: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((2S*,3R*)-2-methyl-3-((5 - (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)methano ne.

The title compound was prepared analogous to Example 69 substituting intermediate A- 21 with intermediate A-28. MS (ESI): mass calcd. for C ₂ 2H ₂ oF _{4 6} 0, 460.2; m/z found, 460.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 9.21 (d, J= 7.0 Hz, 1H), 9.03 (d, J= 5.0 Hz, 2H), 8.43 (s, 1H), 8.37 (s, 1H), 7.50 - 7.41 (m, 1H), 7.37 (t, J= 5.0 Hz, 1H), 7.15 (d, J= 7.6 Hz, 1H), 4.68 - 4.54 (m, 1H), 4.25 - 4.13 (m, 1H), 4.09 - 3.94 (m, 1H), 2.90 (td, J= 13.4, 3.3 Hz, 1H), 2.16 - 2.04 (m, 1H), 1.98 - 1.86 (m, 1H), 1.81 - 1.56 (m, 2H), 1.52 (d, J= 6.9 Hz, 3H). 1H buried under CDCI3 peak.

Example 201 : (2-chloro-6-methoxypyridin-3-yl)((2S*,3R*)-2-methyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 69 substituting intermediate A- 21 with intermediate A-32. MS (ESI): mass calcd. for CisHigClFs jOz, 429.1; m/z found, 429.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDCI ₃ , multiple rotamers present, only major rotamer reported) δ 8.49 (broad s, 2H), 7.63 (d, J= 8.2 Hz, 1H), 7.07 (d, J= 8.3 Hz, 1H), 6.10 (d, J= 8.3 Hz, 1H), 5.71 (d, J= 6.3 Hz, 1H), 5.18 - 4.98 (m, 1H), 4.69 (d, J= 13.5 Hz, 1H), 3.87 (s, 3H), 3.48 - 3.26 (m, 1H), 1.99 - 1.72 (m, 4H), 1.48 - 1.39 (m, 3H).

Example 202: (4-fluoro-2-(pyrimidin-2-yl)phenyl)((2S*,3R*)-2-methyl-3-((5 - (trifluoromethyl)pyrimidin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 69 substituting intermediate A- 21 with intermediate A-37. MS (ESI): mass calcd. for C ₂₂ H ₂ oF _{4 6} 0, 460.2; m/z found, 460.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 9.18 (d, J= 4.9 Hz, 0.6H), 8.98 (d, J= 4.9 Hz, 1.4H), 8.82 (d, J= 7.4 Hz, 0.7H), 8.52 (s, 0.6H), 8.44 - 8.35 (m, 0.7H), 8.30 - 8.24 (m, 0.7H), 8.21 - 8.16 (m, 0.3H), 7.89 (dd, J= 9.6, 2.6 Hz, 0.7H), 7.37 - 7.29 (m, 1.3H), 7.21 - 7.15 (m, 1H), 5.30 - 5.21 (m, 0.3H), 4.72 (d, J= 13.5 Hz, 0.7H), 4.34 - 4.23 (m, 0.3H), 4.23 - 4.12 (m, 0.7H), 4.08 - 3.98 (m, 0.7H), 3.54 - 3.44 (m, 0.3H), 3.23 (td, J= 13.3, 3.2 Hz, 0.3H), 2.95 (td, J= 13.3, 3.1 Hz, 0.7H), 2.14 - 1.63 (m, 4H), 1.52 (d, J= 6.9 Hz, 2.1H), 1.44 (d, J= 7.1 Hz, 0.9H).

Example 203: (4-fluoro-2-(oxazol-2-yl)phenyl)((2S*,3R*)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 14 substituting intermediate A-

11 with intermediate A-34. MS (ESI): mass calcd. for C ₂₂ H ₂ oF _{4 4} 0 ₂ , 448.2; m/z found, 448.9

[M+H] ⁺ . ¾ NMR (400 MHz, CDC1 ₃ ) δ 8.36 (s, 0.5H), 8.19 (s, 0.5H), 7.89 - 7.86 (m, 0.5H), 7.85

- 7.80 (m, 0.5H), 7.79 (dd, J= 9.6, 2.5 Hz, 0.5H), 7.61 (dd, J= 9.2, 2.5 Hz, 0.5H), 7.57 (dd, J =

8.9, 2.5 Hz, 0.5H), 7.41 - 7.27 (m, 1.5H), 7.25 - 7.14 (m, 2H), 6.98 - 6.88 (m, 1H), 6.45 (d, J =

9.1 Hz, 0.5H), 5.97 (d, J= 8.8 Hz, 0.5H), 5.34 - 5.19 (m, 0.5H), 4.83 - 4.70 (m, 0.5H), 4.18 - 4.05 (m, 1H), 3.93 - 3.82 (m, 0.5H), 3.36 - 3.27 (m, 0.5H), 3.20 (td, J= 13.3, 3.2 Hz, 0.5H), 2.97 (td, J= 13.3, 12.7, 3.3 Hz, 0.5H), 1.99 - 1.65 (m, 4H), 1.46 - 1.39 (m, 3H).

Example 204: ((2S*,3R*)-3-(benzo[d]oxazol-2-ylamino)-2-methylpiperidin-l- yl)(3-fluoro-2- (pyrimidin-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 73 substituting intermediate A- 21 with intermediate A-28. MS (ESI): mass calcd. for C24H22FN5O2, 431.2; m/z found, 432.0 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 9.17 (d, J= 7.3 Hz, 1H), 9.01 (d, J= 5.0 Hz, 2H), 7.54 - 7.41 (m, 2H), 7.33 - 7.26 (m, 2H), 7.19 - 7.07 (m, 3H), 6.96 (td, J= 7.8, 1.3 Hz, 1H), 4.64 - 4.52 (m, 1H), 4.26 - 4.17 (m, 1H), 4.01 - 3.93 (m, 1H), 2.91 (td, J= 13.4, 3.2 Hz, 1H), 2.32 - 2.19 (m, 1H), 2.05 - 1.91 (m, 1H), 1.84 - 1.57 (m, 2H), 1.52 (d, J= 6.9 Hz, 3H).

Example 205: (4-fluoro-2-(oxazol-2-yl)phenyl)((2S*,3R*)-2-methyl-3-((5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)methano ne.

The title compound was prepared analogous to Example 69 substituting intermediate A- 21 with intermediate A-34. MS (ESI): mass calcd. for C ₂ iH ₁₉ F _{4 5} 0 ₂ , 449.1 ; m/z found, 449.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.55 - 8.47 (m, 2H), 8.07 (d, J= 0.8 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.84 - 7.75 (m, 2H), 7.25 - 7.13 (m, 2H), 5.37 - 5.23 (m, 1H), 4.42 - 4.28 (m, 1H), 3.45 - 3.30 (m, 1H), 3.21 (td, J= 13.4, 3.3 Hz, 1H), 2.06 - 1.64 (m, 4H), 1.43 (d, J= 7.3 Hz, 3H).

Example 206: ((2S*,3R*)-3-(benzo[d]oxazol-2-ylamino)-2-methylpiperidin-l- yl)(4-fluoro-2- (pyrimidin-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 73 substituting intermediate A- 21 with intermediate A-37. MS (ESI): mass calcd. for C24H22FN5O2, 431.2; m/z found, 432.0 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.99 (d, J= 4.9 Hz, 2H), 8.80 (d, J= 7.6 Hz, 1H), 7.88 (dd, J= 9.5, 2.7 Hz, 1H), 7.44 (t, J= 4.9 Hz, 1H), 7.33 - 7.27 (m, 2H), 7.24 - 7.16 (m, 1H), 7.14 7.02 (m, 2H), 6.97 - 6.91 (m, 1H), 4.79 - 4.63 (m, 1H), 4.31 - 4.19 (m, 1H), 4.03 - 3.90 (m, 1H), 2.97 (td, J= 13.4, 3.1 Hz, 1H), 2.22 (d, J= 14.0 Hz, 1H), 2.06 - 1.95 (m, 1H), 1.94 - 1.78 (m, 1H), 1.74 - 1.66 (m, 1H), 1.53 (d, J= 6.9 Hz, 3H). Example 207: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((2S*,3R*)-2-methyl-3-((5 - (trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 38 substituting intermediate A-4 with intermediate A-28. MS (ESI): mass calcd. for C22H2 ₀ F4 ₆ O, 460.2; m/z found, 460.9

[M+H] ⁺ . ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.92 (d, J= 5.0 Hz, 2H), 8.69 (d, J= 7.6 Hz, 1H), 8.22 (s, 1H), 7.73 (s, 1H), 7.52 - 7.44 (m, 1H), 7.42 (t, J= 5.0 Hz, 1H), 7.29 (d, J= 9.4 Hz, 1H), 7.13 (d, J= 7.6 Hz, 1H), 4.63 - 4.52 (m, 1H), 4.23 - 4.14 (m, 1H), 4.13 - 4.00 (m, 1H), 2.99 - 2.81 (m, 1H), 2.10 - 1.88 (m, 2H), 1.76 - 1.63 (m, 2H), 1.53 (d, J= 6.9 Hz, 3H).

Example 208: (4-fluoro-2-(oxazol-2-yl)phenyl)((2S*,3R*)-2-methyl-3-((5- (trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 38 substituting intermediate A-4 with intermediate A-34. MS (ESI): mass calcd. for C21H19F4N5O2, 449.1; m/z found, 449.9

[M+H] ⁺ . ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.34 (s, 0.4H), 8.18 (s, 0.6H), 8.04 - 7.95 (m, 1H), 7.87 (s, 0.6H), 7.83 - 7.76 (m, 0.8H), 7.62 (dd, J= 9.0, 2.6 Hz, 0.6H), 7.54 - 7.47 (m, 0.4H), 7.41 (s, 0.6H), 7.33 - 7.28 (m, 0.6H), 7.25 - 7.17 (m, 1.4H), 5.33 - 5.18 (m, 0.4H), 4.84 - 4.68 (m, 0.6H), 4.37 - 4.21 (m, 0.4H), 4.16 - 4.04 (m, 0.6H), 3.96 - 3.83 (m, 0.6H), 3.43 - 3.30 (m, 0.4H), 3.24 (td, J= 13.4, 3.2 Hz, 0.4H), 2.98 (td, J= 13.2, 3.1 Hz, 0.6H), 2.05 - 1.67 (m, 4H), 1.51-1.41 m, 3H). Example 209: (4-fluoro-2-(pyrimidin-2-yl)phenyl)((2S*,3R*)-2-methyl-3-((5 - (trifluoromethyl)pyrazin-2-yl)amino)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 38 substituting intermediate A-4 with intermediate A-37. MS (ESI): mass calcd. for C ₂ 2H ₂ oF _{4 6} 0, 460.2; m/z found, 460.9

[M+H] ⁺ . ^X H NMR (500 MHz, CDC1 ₃ ) δ 8.91 (d, J= 4.9 Hz, 2H), 8.31 (d, J= 7.9 Hz, 1H), 8.20 (s, 1H), 7.90 (dd, J= 9.4, 2.6 Hz, 1H), 7.40 (t, J= 4.9 Hz, 1H), 7.37 (s, 1H), 7.30 (dd, J= 8.5, 5.3 Hz, 1H), 7.20 (td, J= 8.1, 2.7 Hz, 1H), 4.79 - 4.66 (m, 1H), 4.25 - 4.16 (m, 1H), 4.15 - 4.01 (m, 1H), 2.97 (td, J= 13.3, 3.2 Hz, 1H), 2.09 - 1.92 (m, 2H), 1.88 - 1.63 (m, 2H), 1.54 (d, J= 6.9 Hz, 3H).

Example 210 : ((2 S * , 3 R* )-2 -methy 1-3 -((5 -(trifluoromethy l)pyridin-2 -y l)oxy)piperidin- 1 -y 1)(3 - (pyrimidin-2-yl)pyridin-2-yl)methanone.

The title compound was prepared analogous to Example 143 substituting intermediate A- 29 with intermediate A-38. MS (ESI): mass calcd. for C22H20F3N5O2, 443.2; m/z found, 444.1 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.82 - 8.75 (m, 2H), 8.72 (dd, J= 4.8, 1.7 Hz, 0.5H), 8.64 (dd, J= 8.0, 1.7 Hz, 0.5H), 8.50 (dd, J= 8.0, 1.7 Hz, 0.4H), 8.44 - 8.40 (m, 0.6H), 8.09 - 8.03 (m, 0.4H), 8.00 (dd, J= 4.8, 1.7 Hz, 0.6H), 7.76 (dd, J= 8.8, 2.6 Hz, 0.6H), 7.69 (dd, J= 8.8, 2.6 Hz, 0.4H), 7.44 (dd, J= 8.0, 4.7 Hz, 0.5H), 7.29 - 7.14 (m, 1.5H), 6.92 (d, J= 8.8 Hz, 0.6H), 6.69 (d, J= 8.7 Hz, 0.4H), 5.35 - 5.30 (m, 0.6H), 5.17 - 5.08 (m, 0.6H), 4.88 - 4.80 (m, 0.4H), 4.80 - 4.70 (m, 0.4H), 4.10 - 3.97 (m, 0.4H), 3.47 - 3.34 (m, 0.6H), 3.21 (td, J= 12.9, 3.0 Hz, 0.6H), 2.98 (td, J= 13.3, 3.2 Hz, 0.4H), 2.25 - 1.91 (m, 3H), 1.76 - 1.48 (m, 1H), 1.44 (d, J = 7.2 Hz, 1.8H), 1.14 (d, J= 7.0 Hz, 1.2H).

Example 211 : (5-methyl-2-(pyrimidin-2-yl)pyridin-3-yl)((2S,3R)-2-methyl-3 -((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 143 substituting intermediate A- 29 with intermediate A-39. MS (ESI): mass calcd. for 457.2; m/z found, 458.2 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.87 (d, J= 4.8 Hz, 1H), 8.84 (d, J= 4.8 Hz, 1H), 8.71 - 8.67 (m, 0.5H), 8.50 - 8.46 (m, 0.5H), 8.45 - 8.41 (m, 0.5H), 8.24 - 8.15 (m, 0.5H), 7.87 - 7.81 (m, 0.5H), 7.79 (dd, J= 8.6, 2.6 Hz, 0.5H), 7.59 - 7.53 (m, 0.5H), 7.32 - 7.24 (m, 1.5H), 6.89 - 6.82 (m, 1H), 5.36 - 5.31 (m, 0.5H), 5.17 - 5.08 (m, 0.5H), 4.92 - 4.85 (m, 0.5H), 4.81 - 4.74 (m, 0.5H), 4.08 - 4.01 (m, 0.5H), 3.45 - 3.26 (m, 0.5H), 3.16 - 3.01 (m, 0.5H), 2.97 - 2.85 (m, 0.5H), 2.47 (s, 1.5H), 2.15 - 1.80 (m, 4.5H), 1.76 - 1.60 (m, 0.5H), 1.52 - 1.35 (m, 2H), 0.88 (d, J= 7.0 Hz, 1.5H).

Example 212: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 143 substituting intermediate A- 29 with intermediate A-40. MS (ESI): mass calcd. for C ₂ 3H ₂ oF _{4 4} 0 ₂ , 460.2; m/z found, 461.0 [M+H] ⁺ . ¹ HNMR contains a mixture of more than two rotamers. Analytical HPLC was obtained on a Agilent 1100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 6.79 min at 254 nm.

Example 213: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pi peridin-l-yl)(6- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

The title compound was prepared analogous to Example 143 substituting intermediate A- 29 with intermediate A-19. MS (ESI): mass calcd. for C ₂ 3H ₂₂ F ₃ N ₅ 0 ₂ , 457.2; m/z found, 457.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.76 (d, J= 3.4 Hz, 1H), 8.75 (d, J= 3.5 Hz, 1H), 8.53 (d, J= 8.1 Hz, 0.5H), 8.45 - 8.38 (m, 1H), 8.16 - 8.09 (m, 0.5H), 7.78 (dd, J= 8.8, 2.6 Hz, 0.5H), 7.62 (dd, J= 8.7, 2.5 Hz, 0.5H), 7.30 - 7.27 (m, 0.5H), 7.23 - 7.16 (m, 1H), 7.10 (d, J= 8.2 Hz, 0.5H), 6.94 (d, J= 8.7 Hz, 0.5H), 6.54 (d, J= 8.7 Hz, 0.5H), 5.33 - 5.28 (m, 0.5H), 5.19 - 5.08 (m, 0.5H), 4.87 - 4.83 (m, 0.5H), 4.82 - 4.76 (m, 0.5H), 4.09 - 4.00 (m, 0.5H), 3.41 - 3.31 (m, 0.5H), 3.14 (td, J= 13.0, 3.0 Hz, 0.5H), 2.96 (td, J= 13.3, 3.2 Hz, 0.5H), 2.65 (s, 1.5H), 2.27 (s, 1.5H), 2.21 - 1.90 (m, 3H), 1.71 - 1.62 (m, 0.5H), 1.44 (d, J= 7.1 Hz, 1.5H), 1.41 - 1.32 (m, 0.5H), 1.11 (d, J = 7.0 Hz, 1.5H). Example 214: ((2S,3R)-3-((5-chloropyridin-2-yl)oxy)-2-methylpiperidin-l-y l)(5-methyl-2-(2H- l,2,3-triazol-2-yl)pyridin-3-yl)methanone.

The title compound was prepared analogous to Example 147 substituting 2-chloro-5- (trifluoromethyl)pyridine with 2-bromo-5-chloropyridine and substituting A-1 with A-41. MS (ESI): mass calcd. for C ₂ oH ₂₁ ClN ₆ 0 ₂ , 412.1; m/z found, 412.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.45 (d, J= 2.3 Hz, 0.4H), 8.28 (d, J= 2.2 Hz, 0.6H), 8.07 (d, J= 2.8 Hz, 0.4H), 7.86 (s, 1.2H), 7.85 - 7.82 (m, 1.4H), 7.66 - 7.63 (m, 0.4H), 7.57 (dd, J= 8.8, 2.7 Hz, 0.6H), 7.53 (dd, J= 8.8, 2.6 Hz, 0.4H), 7.32 - 7.29 (m, 0.6H), 6.76 - 6.68 (m, 1H), 5.19 - 5.14 (m, 0.4H), 5.13 - 5.04 (m, 0.4H), 4.77 - 4.67 (m, 1.2H), 4.05 - 3.93 (m, 0.6H), 3.30 - 3.19 (m, 0.4H), 2.96 - 2.83 (m, 1H), 2.44 (s, 1.2H), 2.13 - 1.77 (m, 4.8H), 1.67 - 1.60 (m, 0.6H), 1.36 (d, J= 7.1 Hz, 1.2H), 1.33 - 1.18 (m, 0.4H), 0.82 (d, J= 7.0 Hz, 1.8H).

Example 215: ((2S,3R)-3-((5-chloropyridin-2-yl)oxy)-2-methylpiperidin-l-y l)(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

The title compound was prepared analogous to Example 214 substituting intermediate A- 41 with intermediate A-22. MS (ESI): mass calcd. for C ₂ oH ₂ iCl ₆ 0 ₂ , 412.1; m/z found, 412.9 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.15 (d, J= 8.3 Hz, 0.5H), 8.08 (d, J= 8.4 Hz, 0.5H), 8.05 (d, J= 2.7 Hz, 0.5H), 7.80 (s, 1H), 7.79 (s, 1H), 7.78 (d, J= 2.7 Hz, 0.5H), 7.51 (dd, J = 8.8, 2.7 Hz, 0.5H), 7.42 (dd, J= 8.8, 2.7 Hz, 0.5H), 7.29 (d, J= 8.4 Hz, 0.5H), 7.14 (d, J= 8.5 Hz, 0.5H), 6.79 (d, J= 8.8 Hz, 0.5H), 6.54 (d, J= 8.8 Hz, 0.5H), 5.17 - 5.13 (m, 0.5H), 5.11 - 5.03 (m, 0.5H), 4.80 - 4.68 (m, 1H), 4.03 - 3.93 (m, 0.5H), 3.34 - 3.27 (m, 0.5H), 3.06 (td, J= 13.0, 3.1 Hz, 0.5H), 2.92 (td, J= 13.4, 3.3 Hz, 0.5H), 2.64 (s, 1.5H), 2.31 (s, 1.5H), 2.24 - 1.77 (m, 3H), 1.68 - 1.54 (m, 0.5H), 1.42 - 1.28 (m, 2H), 1.02 (d, J= 6.9 Hz, 1.5H).

Example 216: ((2S,3R)-3-((5-chloropyridin-2-yl)oxy)-2-methylpiperidin-l-y l)(5-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone.

The title compound was prepared analogous to Example 143 substituting 2 -chloro-5- (trifluoromethyl)pyridine with 2-bromo-5-chloropyridine, and substituting A-29 with A-20. MS (ESI): mass calcd. for 0 ₂₂ Η ₂₂ ΟΓΝ ₅ 0 ₂ , 423.1; m/z found, 424.1 [M+H] ⁺ . ^X H NMR (400 MHz, CDCI3) δ 8.81 - 8.74 (m, 2H), 8.57 - 8.51 (m, 0.6H), 8.46 - 8.39 (m, 0.6H), 8.33 - 8.28 (m, 0.4H), 8.10 - 8.04 (m, 0.6H), 7.94 - 7.88 (m, 0.4H), 7.75 - 7.68 (m, 0.4H), 7.51 (dd, J= 8.8, 2.7 Hz, 0.6H), 7.45 (dd, J= 8.8, 2.7 Hz, 0.4H), 7.24 - 7.18 (m, 1H), 6.79 (d, J= 8.8 Hz, 0.6H), 6.55 (d, J = 8.8 Hz, 0.4H), 5.23 - 5.14 (m, 0.6H), 5.12 - 5.03 (m, 0.6H), 4.79 - 4.71 (m, 0.4H), 4.69 - 4.66 (m, 0.4H), 4.01 - 3.90 (m, 0.4H), 3.43 - 3.34 (m, 0.6H), 3.17 (td, J= 12.9, 3.0 Hz, 0.6H), 2.93 (td, J= 13.3, 3.2 Hz, 0.4H), 2.44 (s, 1.8H), 2.32 (s, 1.2H), 2.18 - 1.81 (m, 3H), 1.68 - 1.57 (m, 0.6H), 1.41 (d, J= 7.1 Hz, 1.8H), 1.39 - 1.32 (m, 0.4H), 1.07 (d, J= 7.0 Hz, 1.2H). Example 217: ((2S,3R)-3-((5-chloropyridin-2-yl)oxy)-2-methylpiperidin-l-y l)(5-methyl-2- (pyrimidin-2-yl)pyridin-3-yl)methanone.

The title compound was prepared analogous to Example 216 substituting A-20 with A- 19. MS (ESI): mass calcd. for C ₂₂ H ₂₂ C1N ₅ 0 ₂ , 423.1; m/z found, 424.2 [M+H] ⁺ . Analytical HPLC was obtained on a Agilent 1100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 4.90 min at 254 nm.

Example 218: ((2S,3R)-3-((5-chloropyridin-2-yl)oxy)-2-methylpiperidin-l-y l)(3-(pyrimidin-2- yl)pyridin-2-yl)methanone.

The title compound was prepared analogous to Example 216 substituting A-20 with A- 38. MS (ESI): mass calcd. for C ₂ iH ₂ oClN ₅ 0 ₂ , 409.1; m/z found, 410.1 [M+H] ⁺ . 'H NMR (400 MHz, CDC1 ₃ ) δ 8.81 - 8.76 (m, 2.4H), 8.73 (dd, J= 4.8, 1.7 Hz, 0.6H), 8.64 (dd, J= 8.0, 1.7 Hz, 0.6H), 8.53 (dd, J= 8.0, 1.7 Hz, 0.4H), 8.14 (dd, J= 4.7, 1.7 Hz, 0.4H), 8.07 (d, J= 2.7 Hz, 0.6H), 7.73 (d, J= 2.8 Hz, 0.4H), 7.52 (dd, J= 8.8, 2.7 Hz, 0.6H), 7.49 - 7.39 (m, 1H), 7.25 -

7.19 (m, 1H), 6.80 (d, J= 8.7 Hz, 0.6H), 6.52 (d, J= 8.9 Hz, 0.4H), 5.24 - 5.17 (m, 0.6H), 5.15 - 5.03 (m, 0.6H), 4.80 - 4.70 (m, 0.8H), 4.02 - 3.92 (m, 0.4H), 3.44 - 3.31 (m, 0.6H), 3.20 (td, J= 13.0, 3.1 Hz, 0.6H), 2.97 (td, J= 13.3, 3.2 Hz, 0.4H), 2.25 - 1.57 (m, 3.4H), 1.47 - 1.34 (m, 2.4H), 1.13 (d, J= 7.1 Hz, 1.2H). Example 219: (3-ethoxy-6-methylpyridin-2-yl)((2S,3R)-2-methyl-3-((5-(trif luoromethyl)pyridin- -yl)oxy)piperidin- 1 -yl)methanone.

The title compound was prepared analogous to Example 143 substituting intermediate A- 29 with intermediate A-12. MS (ESI): mass calcd. for C ₂ iH ₂ 4F _{3 3} 0 ₃ , 423.2; m/z found, 424.0 [M+H] ⁺ . ^X H NMR (400 MHz, CDC1 ₃ ) δ 8.45 - 8.40 (m, 0.4H), 8.16 - 8.04 (m, 0.6H), 7.85 - 7.67 (m, 1H), 7.16 - 7.03 (m, 1H), 6.97 - 6.83 (m, 2H), 5.32 - 5.25 (m, 0.4H), 5.23 - 5.12 (m, 0.4H), 4.90 - 4.83 (m, 0.6H), 4.81 - 4.69 (m, 0.6H), 4.02 - 3.80 (m, 2.6H), 3.34 - 3.17 (m, 0.8H), 2.97 (td, J= 13.4, 12.9, 3.0 Hz, 0.6H), 2.51 (s, 1.2H), 2.16 (s, 1.8H), 2.14 - 1.89 (m, 3H), 1.69 - 1.61 (m, 0.4H), 1.43 - 1.32 (m, 6H). *0.6H buried under solvent peak.

Example 220: ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -methyl-2-(pyrimidin-2-yl)phenyl)methanone.

The title compound was prepared analogous to Example 143 substituting 2-chloro-5- (trifluoromethyl)pyridine with 2-chloro-3-fluoro-5-(trifluoromethyl)pyridine, and substituting intermediate A-29 with intermediate A-27. MS (ESI): mass calcd. for C24H22F4N4O2, 474.2; m/z found, 475.1 [M+Hf. Analytical HPLC was obtained on a Agilent 1100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature

= 6.60 min at 254 nm.

Example 221 : (5-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)oxy)-2-methylpiperidin- l -yl)methanone.

Prepared analogous to Example 220 substituting intermediate A-27 with intermediate A- 7. MS (ESI): mass calcd. for C23H19F5N4O2, 478.1 ; m/z found, 479.1 [M+H] ⁺ . 'H NMR (400 MHz, CDC1 ₃ ) δ 8.76 (d, J= 4.8 Hz, 1H), 8.72 (d, J= 4.8 Hz, 1H), 8.40 (dd, J= 8.8, 5.6 Hz, 0.5H), 8.26 - 8.20 (m, 1H), 7.99 - 7.95 (m, 0.5H), 7.65 - 7.57 (m, 0.5H), 7.56 (dd, J= 9.5, 2.1 Hz, 0.5H), 7.23 - 7.15 (m, 1.5H), 7.12 (dd, J= 8.5, 2.7 Hz, 0.5H), 7.04 - 6.94 (m, 1H), 5.42 - 5.37 (m, 0.5H), 5.19 - 5.09 (m, 0.5H), 5.04 - 4.94 (m, 0.5H), 4.82 - 4.72 (m, 0.5H), 4.07 - 3.96 (m, 0.5H), 3.41 - 3.33 (m, 0.5H), 3.18 - 3.06 (m, 0.5H), 2.99 - 2.84 (m, 0.5H), 2.15 - 1.89 (m, 3H), 1.70 - 1.63 (m, 0.5H), 1.47 - 1.37 (m, 2H), 0.93 (d, J= 7.0 Hz, 1.5H).

Example 222: (4-fluoro-2-(pyrimidin-2-yl)phenyl)((2S,3R)-3-((3-fluoro-5- (trifluoromethyl)pyridin-2-yl)oxy)-2-methylpiperidin- l -yl)methanone.

Prepared analogous to Example 220 substituting intermediate A-27 with intermediate A- 37. MS (ESI): mass calcd. C23H19F5N4O2, 478.1; m/z found, 479.1 [M+H] ⁺ . Analytical HPLC was obtained on a Agilent 1100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 6.72 min at 254 nm.

Example 223: ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Prepared analogous to Example 220 substituting intermediate A-27 with intermediate A-

19. MS (ESI): mass calcd. for 475.2; m/z found, 476.1 [M+H] ⁺ . 'H NMR (400 MHz, CDC1 ₃ ) δ 8.77 (d, J= 4.8 Hz, 1H), 8.72 (d, J= 4.9 Hz, 1H), 8.49 (d, J= 8.1 Hz, 0.5H), 8.39 (d, J= 8.1 Hz, 0.5H), 8.25 - 8.16 (m, 0.5H), 7.90 - 7.81 (m, 0.5H), 7.53 (dd, J= 9.7, 2.1 Hz, 0.5H), 7.32 - 7.22 (m, 1H), 7.21 - 7.17 (m, 0.5H), 7.16 - 7.10 (m, 1H), 5.39 - 5.32 (m, 0.5H), 5.25 - 5.16 (m, 0.5H), 4.87 - 4.76 (m, 1H), 4.23 - 4.15 (m, 0.5H), 3.43 - 3.31 (m, 0.5H), 3.25 - 3.10 (m, 0.5H), 2.99 (td, J= 13.3, 3.2 Hz, 0.5H), 2.62 (s, 1.7H), 2.35 (s, 1.3H), 2.13 - 1.96 (m, 3H), 1.76 - 1.66 (m, 0.5H), 1.45 (d, J= 7.2 Hz, 1.7H), 1.43 - 1.37 (m, 0.5H), 1.24 (d, J= 7.0 Hz, 1.3H). Example 224: (2-(2H-l,2,3-triazol-2-yl)phenyl)((2S,3R)-3-((3-fluoro-5-(tr ifluoromethyl)pyridin- 2-yl)oxy)-2-methylpiperidin- 1 -yl)methanone.

Prepared analogous to Example 220 substituting intermediate A-27 with intermediate A- 4. MS (ESI): mass calcd. for C ₂ iH ₁₉ F _{4 5} 0 ₂ , 449.2 m/z found, 450.1 [M+H] ⁺ . Analytical HPLC was obtained on a Agilent 1 100 Series using a Zorbax SB-C18 column (3.5 μιη, 150 x 4.6 mm), mobile phase of 5-99% ACN in 0.05% TFA over 7 min and then hold at 99% ACN for 3 min, at a flow rate of 2 mL/min (Temperature = 50 °C). R _t = 6.61 min at 254 nm.

Example 225: (3-fluoro-2-(5-fluoropyrimidin-2-yl)phenyl)((2S,3R)-2-methyl -3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 226: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pi peridin-l-yl)(5- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 227: (3-fluoro-2-(oxazol-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)oxy)piperidin- 1 -yl)methanone.

Example 228: ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -methyl-2-(2H- 1,2,3 -triazol-2-yl)pyridin-3 -yl)methanone.

Example 229: ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- yl)(5-methyl-2-(pyrimidin-2-yl)pyridin-3-yl)methanone.

Example 230: (3-fluoro-2-(5-fluoropyrimidin-2-yl)phenyl)((2S,3R)-3-((3-fl uoro-5- (trifluoromethyl)pyridin-2-yl)oxy)-2-methylpiperidin-l-yl)me thanone.

Example 231 : ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 232: (3 -fluoro-2-(oxazol-2-yl)phenyl)((2 S,3 R)-3 -((3 -fluoro-5 -(trifluoromethyl)pyridin- 2-yl)oxy)-2-methylpiperidin- 1 -yl)methanone.

Example 233: ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -(pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 234: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pi peridin-l-yl)(4- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 235: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- yl)(6-methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)methanone .

Example 236: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -methyl-2-(2H-l,2,3-triazol-2-yl)pyridin-3-yl)methanone.

Example 237: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -methyl-3-(2H-l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

Example 238: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- yl)(2-(pyrimidin-2-yl)phenyl)methanone.

Example 239: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -methyl-2-(pyrimidin-2-yl)phenyl)methanone.

Example 240: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -(5-fluoropyrimidin-2-yl)phenyl)methanone.

Example 241: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- yl)(3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 242: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 243: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -methyl-2-(pyrimidin-2-yl)pyridin-3-yl)methanone.

Example 244: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- yl)(3-fluoro-2-(5-fluoropyrimidin-2-yl)phenyl)methanone.

Example 245: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- yl)(5-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 246: ((2S,3R)-3-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)-2 -methylpiperidin-l- -fluoro-2-(oxazol-2-yl)phenyl)methanone.

Example 247: ((2S,3R)-3-((5-chloropyridin-2-yl)oxy)-2-methylpiperidin-l-y l)(3-fluoro-2- (oxazol-2-yl)phenyl)methanone.

Example 248: ((2S,3R)-3-((5-chloropyridin-2-yl)oxy)-2-methylpiperidin-l-y l)(3-fluoro-2-(5- fluoropyrimidin-2-yl)phenyl)methanone.

Example 249: ((2S,3R)-3-((5-chloropyridin-2-yl)oxy)-2-methylpiperidin-l-y l)(6-methyl-2-(2H- l,2,3-triazol-2-yl)pyridin-3-yl)methanone.

Example 250: ((2S,3R)-3-((5-chloropyridin-2-yl)oxy)-2-methylpiperidin-l-y l)(2-(pyrimidin-2- yl)phenyl)methanone.

Example 251: ((2S,3R)-3-((5-chloropyridin-2-yl)oxy)-2-methylpiperidin-l-y l)(3-methyl-2- (pyrimidin-2-yl)phenyl)methanone.

Example 252: ((2S,3R)-3-((5-chloropyridin-2-yl)oxy)-2-methylpiperidin-l-y l)(2-(5- fluoropyrimidin-2-yl)phenyl)methanone.

Example 253: ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(6-methyl-2-(2H- l,2,3-triazol-2-yl)pyridin-3-yl)methanone.

Example 254: ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(5-methyl-2-(2H- l,2,3-triazol-2-yl)pyridin-3-yl)methanone.

Example 255: ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(6-methyl-3-(2H- l,2,3-triazol-2-yl)pyridin-2-yl)methanone.

Example 256: ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(2-(pyrimidin-2- yl)phenyl)methanone.

Example 257: ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(3-methyl-2- (pyrimidin-2-yl)phenyl)methanone.

Example 258: ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(2-(5- fluoropyrimidin-2-yl)phenyl)methanone.

Example 259: ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(3-(pyrimidin-2- yl)pyridin-2-yl)methanone.

Example 260: ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(6-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 261 : ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(5-methyl-2-

(pyrimidin-2-yl)pyridin-3-yl)methanone.

Example 262: ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(3-fluoro-2-(5- fluoropyrimidin-2-yl)phenyl)methanone.

Example 263: ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(5-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 264: ((2S,3R)-3-((5-bromopyridin-2-yl)oxy)-2-methylpiperidin-l-yl )(3-fluoro-2- (oxazol-2-yl)phenyl)methanone.

Example 265: ((2S*,3R*)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)amin o)piperidin-l-yl)(3- (pyrimidin-2-yl)pyridin-2-yl)methanone.

The title compound was prepared analogous to Example 14 substituting intermediate A- 1 1 with intermediate A-38. MS (ESI): mass calcd. for C ₂ 2H ₂₁ F ₃ 60, 442.2; m/z found, 443.2 [M+H] . Analytical HPLC was obtained on a Agilent 1 100 Series using a XBridge CI 8 column (5μπι, 100 x 4.6mm), mobile phase of 10-100% ACN in 20 mM NH ₄ OH over 8 min and then hold at 100% ACN for 3 min, at a flow rate of 1 mL/min (Temperature = 30 °C). R _t = 6.71 min at 280 nm.

Example 266: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)amino) piperidin-l-yl)(5- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 267: ((2S,3R)-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)amino) piperidin-l-yl)(4- methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 268: ((2S,3R)-3-((5-chloropyridin-2-yl)amino)-2-methylpiperidin-l -yl)(3-(pyrimidin-2- yl)pyridin-2-yl)methanone.

Example 269: ((2S,3R)-3-((5-chloropyridin-2-yl)amino)-2-methylpiperidin-l -yl)(5-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 270: ((2S,3R)-3-((5-chloropyridin-2-yl)amino)-2-methylpiperidin-l -yl)(4-methyl-3- (pyrimidin-2-yl)pyridin-2-yl)methanone.

Example 271 : ((2S,3R)-3-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino) -2-methylpiperidin- -yl)(2-fluoro-6-(pyrimidin-2-yl)phenyl)methanone.

Example 272: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((2S,3R)-2-methyl-3-((5- (trifluoromethyl)pyridin-2-yl)amino)piperidin- 1 -yl)methanone.

Example 273: ((2S,3R)-3-((5-chloropyridin-2-yl)amino)-2-methylpiperidin-l -yl)(2-fluoro-6- (pyrimidin-2-yl)phenyl)methanone.

Assays:

The in vitro affinity of the compounds of the invention for the rat/human orexin 1 and human orexin 2 receptors was determined by competitive radioligand binding using [ ³ H] (l-(5- (2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-l-((S)-2-(5-phenyl- (l,3,4)oxadiazol-2-ylmethyl)- pyrrolidin-l-yl)-methanone)(Langmead et al, 2004) and [ ³ H]EMPA (n-ethyl-2[96-methoxy- pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmeth yl acetamide), respectively

(Langmead et al, 2004, British Journal of Pharmacology 141:340-346; Malherbe et al, 2004, British Journal of Pharmacology 156:1326-41).

The in vitro functional antagonism of the compounds on the human orexin 1 and orexin 2 receptors was determined using fluorometric imaging plate reader (FLIPR) based calcium assays.

Data are analyzed using pc-Sandy macro and graphed on Graphpad Prism 5. For analysis, each concentration point is averaged from triplicate values and the averaged values are plotted on Graphpad Prism. The IC50 was determined by applying the following equation (GraphPad Prism 5.0, SanDiego) for one site competition where X=log (concentration) and

Y=specific binding. Top denotes the total [¾]- (l-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)- l-((S)-2-(5-phenyl-(l,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-l -yl)-methanone) binding, bottom denotes the nonspecific [¾]- (l-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-l-((S)-2-(5-p henyl- (1,3 ,4)oxadiazol-2-ylmethyl)-pyrrolidin- 1 -yl)-methanone) binding. Graphpad Prism calculates

Ki value from IC50 and the pre-determined Kd values for [¾]- (l-(5-(2-fluoro-phenyl)-2- methyl-thiazol-4-yl)-l-((S)-2-(5-phenyl-(l,3,4)oxadiazol-2-y lmethyl)-pyrrolidin-l-yl)- methanone) and [3HJ-EMPA. The Ki for each compound is then uploaded into 3DX. Each run comprises individual compounds in triplicate. The data in Table 1 and Table 2 represent averages from between 2-20 runs.

Rat and human orexin 1 receptor radioligand binding studies

Human Embryonic Kidney 293 cells (HEK293) stably expressing rat orexin 1 receptor

(Genebank accession number NM_001525) or Chinese ovary cells (CHO) stably expressing human orexin 1 receptor (Genebank accession number NM_001526) were grown to confluency in DMEM (Hyclone, cat # SH30022), 10% FBS, IX Pen/Strep, IX sodium pyruvate, 10 mM HEPES, 600 μg/mL G418 and DMEM/F12 (Gibco, Cat #1 1039), 10%FBS, IX Pen/Strep, 600 μg/mL G418 media, respectively on 150 cm ² tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phoshpate Buffered Saline IX with Calcium and Magnesium, Cat # SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2K xG, 5 min at 4 °C), the supernatant was aspirated and the pellets frozen and stored at -80°C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #1 1836145001) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and homogenized for 45 sec prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using [ ³ H]- (l-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-l-((S)-2-(5-p henyl-(l,3,4)oxadiazol- 2-ylmethyl)-pyrrolidin-l-yl)-methanone) (Moraveck Corporation, specific activity = 35.3 Ci/mmol), diluted to a 10 nM concentration in PBS (4 nM final). Compounds were solubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentrations (from 0.1 nM to 10 μΜ). The final concentration of DMSO in the reactions is equal to or less than 0.1%. Total and nonspecific binding was determined in the absence and presence of 10 μΜ almorexant. The total volume of each reaction is 200 μΐ _^ (20 μΐ _^ of diluted compounds, 80 μΐ _^ of [ ³ H]- (l-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-l-((S)-2-(5-p henyl-(l,3,4)oxadiazol-2- ylmethyl)-pyrrolidin-l-yl)-methanone) diluted in PBS and 100 μϊ _^ of the cell suspension).

Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55 °C oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).

IC5 ₀ values (i.e. concentration of unlabelled compound required to compete for 50% of specific binding to the radioligand) was calculated using the GraphPad Prism software

(GraphPad Prism Software Inc., San Diego, CA) with a fit to a sigmoidal dose-response curve. Apparent Ki values were calculated as ¾ = ICso/(l+C/K _d ), where C is concentration of radioligand and ¾ = 4 nM for rat orexin 1 receptor and 6 nM for human orexin 1 receptor.

Human orexin 2 receptor radioligand binding studies

HEK293 stably expressing human orexin 2 receptor (Genebank accession number

NM_001526) were grown to confluency in DMEM (Hyclone, cat # SH30022) , 10%FBS, IX Pen/Strep, IX NaPyruvate, 10 mM HEPES, 600 ug/ml G418 media on 150 cm ² tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phoshpate Buffered Saline IX with Calcium and Magnesium, Cat # SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2K xG, 5 min at 4°C), the supernatant was aspirated and the pellets frozen and stored at -80°C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and homogenized for 45 sec just prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using [ ³ H]-EMPA (Moraveck Corporation, specific activity = 29.6 Ci/mmol), diluted to a 5 nM concentration in PBS (2 nM final concentration). Compounds were solubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentration (from 0.1 nM to 10 μΜ). The final concentration of DMSO in the reactions is equal to or less than 0.1%. Total and nonspecific binding was determined in the absence and presence of 10 μΜ almorexant. The total volume of each reaction is 200 μϊ _^ (20 μϊ _^ of diluted compounds, 80 of [ ³ H]-EMPA diluted in PBS and 100 μΐ _^ of the cell suspension). Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55°C oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).

IC5 ₀ values (i.e. concentration of unlabelled compound required to compete for 50% of specific binding to the radioligand) was calculated using the GraphPad Prism software

(GraphPad Prism Software Inc., San Diego, CA) with a fit to a sigmoidal dose-response curve. Apparent Ki values were calculated as ¾ = ICso/(l+C/K _d ), where C is concentration of radioligand and ¾ = 2 nM.

Human orexin 1 receptor Ca ²⁺ mobilization assay CHO cells stably transfected with the human orexin 1 receptor (Genebank accession number NM_001526) were grown to confluency in DMEM/F12, 10% FBS, IX pen-strep, 400 μg/ml G418. Cells were seeded on to 384-well Packard viewplates at a density of 10,000 cells/well and incubated overni ght at 37°C, 5% C02. The cells were dye-loaded with BD Calcium Assay kit (BD, cat # 640178) in HBSS (Gibco, cat# 14025-092) with 2.5 mM probenecid and incubated at 37°C, 5% CO2 for 45 min. Cells were pre-incubated with compounds (diluted in DMEM/F-12) for 15-30 minutes before agonist (orexin A, 10 nM) stimulation. Ligand-induced Ca ²⁺ release was measured using a Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, CA). Functional responses were measured as peak fluorescence intensity minus basal. The concentration of agonist that produced a half- maximal response is represented by the EC5 ₀ value. Antagonistic potency values were converted to apparent ρ¾ values using a modified Cheng-Prusoff correction. Apparent ρΚβ = - log ICso/l+tconc agonist/ECso]. Human orexin 2 receptor Ca ²⁺ mobilization assay

PFSK-1 cells endogenously expressing the human orexin 2 receptor were grown to confluency in RPMI1640 (Hyclone, cat# 30027.02), 10% FBS, IX pen-strep. Cells were seeded on to 384-well Packard viewplates at a density of 5,000 cells/well and incubated overnight at 37°C, 5% C02. The cells were dye-loaded with BD Calcium Assay kit (BD, cat # 640178) in HBSS (Gibco, cat# 14025-092) with 2.5 mM probenecid and incubated at 37°C, 5% C0 ₂ for 45 min. Cells were pre-incubated with compounds (diluted in DMEM/F-12) for 15-30 minutes before agonist (orexin B, 100 nM) stimulation. Ligand-induced Ca ²⁺ release was measured using a Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, CA).

Functional responses were measured as peak fluorescence intensity minus basal. The concentration of agonist that produced a half-maximal response is represented by the EC5 ₀ value. Antagonistic potency values were converted to apparent pK _B values using a modified Cheng- Prusoff correction. Apparent pK _B = - log ICso/l+tconc agonist/ECso].

Preferred compounds of the invention are set forth in Table 1 below. Orexin receptor activity of certain compounds of the invention is also set forth in the below table. Table 1

Preferred compounds of the invention are set forth in Table 2 below. Data for Orexin receptor activity additional testing of certain compounds of the invention is also set forth in Table 2.

Table 2