OA18987A

OA18987A - N-(2-(cyclic amine) ethyl) benzamide derivatives as P2X7 inhibitors

Info

Publication number: OA18987A
Application number: OA1201500127
Authority: OA
Inventors: John Paul Kilburn; Eman Mohammed ELDEMENKY; Bin Chen; Lars Kyhn Rasmussen; Yu Jiang; Mikkel JESSING
Original assignee: H. Lundbeck A/S
Priority date: 2012-10-12
Filing date: 2013-10-11
Publication date: 2019-11-22

Abstract

The present invention is directed to N-(2-(cyclic amine)ethyl)benzamide derivatives of formula (I) as P2X7 inhibitors, pharmaceutical compositions comprising said compounds and uses of the compounds to treat pain, inflammation, neurological disorders, or neuropsychiatric disorders.

Description

CYCLIC AMINES

FELD OF THE INVENTION

The present invention is directed to novel compounds which inhibit the P2X₇ receptor. Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat pain, inflammation, neurological disorders, or neuropsychiatrie disorders.

BACKGROUND ART

The purinergic 2X₇ (P2X₇) receptor îs a ligand-gated ion channel which is activated by extracellular ATP and is present on a variety of cell types, including microglia in the central nervous system and other cells involved in inflammation and immune system fonction. The P2X₇ receptor has been shown to hâve a rôle in cytolysis in the immune system (Surprenant, et al. Science, 272, 735-41,1996), and is involved in activation of lymphocytes and monocyte/macrophages leading to the increased release of pro-inflammatory cytokines (e.g., TNFa and Εΐβ) from these cells (Ferrari, et al. Neuropharmacol, 36,1295-301,1997).

Studies hâve shown that inhibiting P2X₇ receptor activation in situations of inflammation (e.g., rheumatoid arthritis and other autoimmune diseases, osteoarthritis, asthma, chronic obstructive pulmonary disease and inflammatory bowel disease) or interstitial fibrosis results in a therapeutic effect (DiVirgilio, et al. Drug Dev Res, 45, 207-13,1998). These and other studies indicate that P2X₇receptor antagonists may find use in the treatment and prophylaxis of pain, including acute, chronic and neuropathie pain (Chessel, et al, Pain, 114,386-96,2005).

Inhibiting P2X₇ activation may also diminish or reduce cell death caused by prolongation of activated P2X₇ receptors, indîcating a potential therapeutic intervention for said antagonists in nervous system injury or degeneration (Sperlagh, et al., Progress in Neurobiology, 7, 327-346, 2006). Vianna, et al. (Epilepsia, 43, 27-229, 2002) also revealed a potential rôle for P2X₇ receptors in the pathogenesis of epilepsy. Interestingly, because of the P2X₇ receptor’s rôle in microglia activation and prolifération in the central nervous system (CNS), a self-propagating cycle of neuroinflammation and neurodegeneration results from P2X₇ receptor activation in areas of the brain (Monif, et al, J Neurosci, 29, 3781-91,2009).

Thus, P2X₇ receptor antagonists, particularly small molécules with sufficient brain-penetrable properties, are désirable as useflil agents for therapeutic intervention in the central nervous system for treating pain, inflammation, neurological and neurodegenerative disorders, neuropsychiatrie disorders, or other disorders for which the réduction or otherwise stabilization of pro-inflammatory cytokines is bénéficiai. The present invention fulfills this need, and provides further related advantages.

SUMMARY OF THE INVENTION

An objective of the present invention is to provide compounds that inhibit P2X? receptors.

Accordingly, the present invention relates to compounds of Formula I.

Formula I wherein R¹ is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl or 5 membered heteroaryl, each of which is optionally substituted with one or more Cm alkyl, halogen, hydroxy, Cm fluoroalkyl, Ί cycloalkyl, Cm alkoxy, Ci^fluoroalkoxy, cyano or-SChR ;

wherein R²³ and R^2b combine with the nitrogen to which they are attached to form piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrrolo, îmidazo, azetidinyl, 6 to 10 membered .spirofheterocyclyl), homomorpholinyl, homopiperidinyl or homopiperazinyl each of which is optionally substituted with one or more Cm alkyl, Cj^alkenyl, Cj^-cycloalkyl, Ci^alkoxy, oxo, NR⁵R⁶ or fluorine;

wherein R³ is halogen, Cm fluoroalkyl, cyano, cyclopropyl, Cualkyloxy, CiMÎluoroalkyloxy, SO2R⁷, -NR⁵R⁶orC,^alkyl;

wherein R⁴ is halogen, Ci^alkyl, Cmfluoroalkyl, cyano, -SO2R⁸, -NR⁵R⁶, Ci^alkoxy, Cm fluoroalkoxy or Cj^-cycloalkyl;

wherein R⁵ and R⁶ independently of each other are hydrogen or Cm alkyl;

wherein R⁷ is Cm alkyl, cycloalkyl, Cm fluoroalkyl; and wherein n is 0-3; or a pharmaceutically acceptable sait thereof.

The invention also provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable sait thereof, and optionally a pharmaceutically acceptable carrier, excipient or diluent.

The compounds of Formula I may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. The compounds of Formula I may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers can be separated in a manner known to a person skilled in the art.

The present invention further provides methods for treating pain or inflammation in a subject, comprising administering to a subject suffering from pain or inflammation a therapeutically effective amount of a compound of Formula I.

The present invention further provides methods for treating an affective disorder in a subject comprising administering to a subject suffering from an affective disorder a therapeutically effective amount of at least one compound of Formula I.

The present invention further provides methods for treating a neurological disorder or neurodegenerative disorder in a subject comprising administering to a subject suffering from a neurological disorder or neurodegenerative disorder a therapeutically effective amount of at least one compound of Formula I.

The present invention further provides methods for treating dépréssion, major dépressive disorder, treatment résistant dépréssion, anxiety, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), neuropathie pain, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, multiple sclerosis, epilepsy, Parkinson’s Disease, Huntington’s Disease and Alzheimefs disease, which involves administering a compound of Formula I.

The present invention also provides the use a compound of Formula I for the manufacture of a médicament for the treatment of affective disorders.

The present invention also provides a compound of Formula 1 for use in treating an affective disorder in a subject.

These and other aspects of the invention will become apparent upon reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

As previously indicated, the present invention is based on the dîscovery of the compounds of Formula I, which are inhibitors of the P2X₇ receptor, and as such, are useful for the treatment of related disorders. Additionally, certain aspects of the invention are explained in greater detail below but this description is not intended to be a detailed catalog of ail the different ways in which the invention may be implemented, or ail the features that may be added to the instant invention. Hence, the following spécification is intended to illustrate some embodiments of the invention, and not to exhaustively specify ail permutations, combinations and variations thereof.

In one embodiment, R¹ is optionally substituted phenyl.

In one embodiment, R¹ is optionally substituted pyridyl.

In another embodiment, R¹ is optionally substituted pyrazînyl.

In one embodiment, R¹ is optionally substituted pyrimidyl.

In one embodiment, R¹ is optionally substituted 5 membered heteroaryl.

In one embodiment, R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted piperazinyl.

In yet embodiment, R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted pîperidinyl.

In one embodiment, R²³ and R“^b combine with the nitrogen to which they are attached to form optionally substituted morpholinyl.

In one embodiment, R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted pyrrolidinyl.

In one embodiment, R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted pyrrolo.

In one embodiment, R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted imidazo.

In one embodiment, R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted 6 to 10 membered spiro(hetcrocyclyl).

In one embodiment, R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted homomorpholinyl

In one embodiment, R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted homopiperidinyl

In one embodiment, R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted homopiperazinyl

In one embodiment, R²¹¹ and R^2b combine with the nitrogen to which they are attached to form optionally substituted azetidinyl.

In one embodiment, R³ is chlorine, methyl or trifluorormethyl.

In one embodiment, n is 0.

In one embodiment, n is 1.

In one embodiment, n is 2.

In one embodiment,R⁴ is fluorine, chlorine, C1.3 alkyl, Cm fluoroalkyl, cyano, Cj.j alkoxy or

CMfluoroalkoxy.

As used herein, the term “Ci-C₆ alkyl” refers to a straight chained or branched saturated hydrocarbon having from one to six carbon atoms inclusive. Examples of such substituents include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-l-propyl, npentyl and n-hexyl. Similarly, the term “straight chained or branched C1-C3 alkyl” refers to a saturated hydrocarbon having from one to three carbon atoms inclusive. Examples of such substituents include, but are not limited to, methyl, ethyl and n-propyl.

Likewise, the term “Ci-C₆ alkoxy” refers to a straight chained or branched saturated alkoxy group having from one to six carbon atoms inclusive with the open valency on the oxygen. Examples of such substituents include, but are not limited to, methoxy, ethoxy, n-butoxy, t-butoxy and n-hexyloxy.

As used herein, the term “C1-C4 fluoroalkyl” refers to a straight chained or branched saturated hydrocarbon having from one to four carbon atoms inclusive substituted with one or more fluorine atoms. Examples of such substituents include, but are not limited to, trifluoromethyl, pentafluoroethyl, 1 -fluoroethyl, monofluoromethyl, difluoromethyl and 1,2-difluoroethyl.

Likewise, the term “C1-C4 fluoroalkoxy” refers to a straight chained or branched saturated alkoxy group having from one to four carbon atoms inclusive with the open valency on the oxygen and in which one or more carbon atoms are substituted with one or more fluorine atoms.. Examples of such substituents include, but are not limited to, monofluoromethoxy, 1,1-difluoroethoxy and 1-monofluoron-butoxy.

Likewise the term “C₃^ cycloalkyl” refers to saturated monocyclic hydrocarbon groups. Examples of such Systems include, but are not limited to, cyclopropyl, cyclobutyl or cyclohexyl

Likewise the term “5 membered heteroaryl” refers to a fully unsaturated aromatic monocyclic ring system having 1-4 heteroatoms. Examples of such Systems include, but are not limited to, thienyl, furyl, imidazolyl and pyrrolyl.

Likewise the term “6 to 10 membered spiro(heterocyclyl)” refers to a heterocyclic ring which is a fused bicyclic system. Examples of such Systems include, but are not limited to, 2-oxa-6-azaspiro[3.3]heptane, 2-aza-spiro[3.3]heptane and 2,6-diaza-spîro[3.3]heptane.

The term “halogen” refers to fluorine, chlorine, bromine and iodine.

As used herein, the phrase “effective amount” when applied to a compound of the invention, is intended to dénoté an amount sufficient to cause an intended biological effect. The phrase “therapeutically effective amount” when applied to a compound of the invention is intended to dénoté an amount of the compound that is sufficient to ameliorate, palliate, stabilize, reverse, slow or delay the progression of a disorder or disease State, or of a symptom of the disorder or disease. In an embodiment, the method of the present invention provides for administration of combinations of compounds. In such instances, the “effective amount” is the amount of the combination sufficient to cause the intended biologicai effect.

The term “treatment” or “treating” as used herein means ameliorating or reversing the progress or severity of a disease or disorder, or ameliorating or reversing one or more symptoms or side effects of such disease or disorder. “Treatment” or “treating”, as used herein, also means to inhibit or block, as in retard, arrest, restrain, impede or obstruct, the progress of a System, condition or State of a disease or disorder. For purposes of this invention, “treatment” or “treating” further means an approach for obtaining bénéficiai or desired clinical results, where “bénéficiai or desired clinical results” include, without limitation, alleviation of a symptom, diminishment of the extent of a disorder or disease, stabilized (i.e., not worsening) disease or disorder State, delay or slowing of a disease or disorder State, amelioration or palliation of a disease or disorder State, and remission of a disease or disorder, whether partial or total, détectable or undetectable.

Pharmaceutically Acceptable Salts

The present invention also comprises salts of the present compounds, typically, pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable acid addition salts. Acid addition salts include salts of inorganic acids as well as organic acids.

Représentative examples of suitabie inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfùric, sulfamic, nitric acids and the like. Représentative examples of suitabie organic acids include formic, acetic, trichloroacetic, trifluoroacetîc, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, paminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines (for example, 8-bromotheophylline and the like). Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in S. M. Berge, et al., J. Pharm. Sci., 1977,66,2.

Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, éthanol and the like.

Racemic forms may be resolved into the optical antipodes by known methods, for example, by séparation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Séparation of such diastereomeric salts can be achieved, e.g. by fractional crystallization. The optically active acids suitable for this purpose may include, but are not limited to d- or l- tartaric, mandelic or camphorsulfonic acids. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. The compounds of the present invention may also be resolved by the formation and chromatographie séparation of diastereomeric dérivatives from chiral derivatizing reagents, such as, chiral alkylating or acylating reagents, followed by cleavage of the chiral auxiliary. Any of the above methods may be applied either to résolve the optical antipodes of the compounds of the invention per se or to résolve the optical antipodes of synthetic intermediates, which can then be converted by methods described herein into the optically resolved final products which are the compounds of the invention.

Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in Enantiomers, Racemates, and Resolutions, John Wiley and Sons, New York, 1981. Optically active compounds can also be prepared from optically active starting materials.

Pharmaceutical compositions

The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier. The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the spécifie compounds disclosed in the Experimental Section and a pharmaceutically acceptable carrier.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed tn Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed.,

Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for administration by an oral route, Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingrédient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, émulsions, suspensions, syrups and élixirs.

The term “inhibit” or “inhibiting” as used herein means to reduce, diminish, block or even eliminate, such as in e.g. “inhibiting P2X₇ receptor activity . Inhibiting P2X? receptor activity or “inhibiting P2X₇ activity” as used herein means, e.g. reducing or even eliminating the ability of a P2X₇ receptor to exhibit a cellular response, such as inhibiting the response to stimuh or agonist ligands, or inhibiting the production or accumulation of IL 1 β.

The present invention also provides a method of treating a disease or disorder, the method comprising administering a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable sait thereof to a mammal suffering from (or at risk for) the disease or disorder, or otherwise in need of the treatment. The present invention also provides a method of treating pain or inflammation, the method comprising administering a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable sait thereof to a mammal in need thereof. In an embodiment, the pain that may be treated using the compounds described herein, including acute, chronic or inflammatory pain, is caused by neuropathie pain, post-operative pain, morphine tolérance, fibromyalgia, neuralgias, headache, osteoarthntis, rheumatoid arthntis, psoriatic arthntis, irritable bowel syndrome or inflammatory bowel disease.

In other embodiments, the disease or disorder that may be treated using the compounds described herein is a neurological disorder or neurodegenerative disorder, such as epilepsy, multiple sclerosis, Parkinson’s disease, Huntington’s disease or Alzheimer s disease. As used herein, the term “neurological disorder” means a disorder of the nervous system, and includes, but is not limited to, the disorders as described hereinabove. Based on the well-known meaning of disorders of the nervous system, neurological disorders resuit from structural, biochemical, electrical, or cellular (neuronal or microglial) signaling abnormalities that may occur in the brain or spinal cord of the afflicted mammal. As used herein, the term “neurodegenerative disorder ’ means a disorder characterized by symmetrical and progressive loss of structure or function of neurons, such as death of neurons or reduced growth of neurons. Such loss of neurons may affect motor, sensory, or cognitive neuronal Systems. As such, treating a neurological or neurodegenerative disorder using the compounds described herein may resuit in the amelioration or relief of symptoms of the neurological or neurodegenerative disorder, such symptoms as paralysis, muscle weakness, poor coordination, uncontrolled movements, seizures, confusion, altered levels of consciousness, memory loss, emotional instability, loss of sensation, pain, and similar symptoms.

In an embodiment, the disease or disorder is a neuropsychiatrie disorder, such as an affective disorder. As used herein, “affective disorder” means a mental disorder characterized by a consistent, pervasive alteration of mood, and affecting thoughts, émotions and behaviors. Affective disorders include mood disorders as described in DSM-IV-TR.® (American Psychiatrie Association, 2000, Diagnostic and Statistical Mamtal of Mental Disorders (4th ed., text rev.) doi:l0.l l76/appi.books.9780890423349; which is incorporated by reference herein). As such, treating an affective disorder using the compounds described herein may resuit in the amelioration, stabilization or otherwise diminishment or relief of symptoms of the affective disorder, such symptoms as mood instability, manie épisodes, feelings of guilt or worthlessness, sleep disturbances, agitation, or the like. Examples of affective disorders include, but are not limited to, dépressive disorders, anxiety disorders, bipolar disorders, dysthymia and schizoaffective disorders. Anxiety disorders include, but are not limited to, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder (PTSD). Dépressive disorders include, but are not limited to, major dépressive disorder (MDD), catatonie dépréssion, melancholic dépréssion, atypical dépréssion, psychotic dépréssion, postpartum dépréssion, treatment-résistant dépréssion, bipolar dépréssion, including bipolar I and bipolar II, and mild, moderate or severe dépréssion. Personality disorders include, but are not limited to, paranoïa, antisocial and borderline personality disorders.

In an embodiment ofthe invention, the affective disorder treated using the compounds described herein is dépréssion, major dépressive disorder (MDD), treatment-resistant dépréssion, bipolar disorder, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, or posttraumatic stress disorder (PTSD), or a combination thereof.

The present invention provides a method of treating an affective disorder in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of Formula I.

The present invention provides a method of inhibiting P2X₇ activity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula I.

The present invention also provides a method of inhibiting production or accumulation of ILl β, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of Formula I.

In an embodiment, the present invention provides the use of a compound of Formula I for the manufacture of a médicament for the treatment of affective disorders. The present invention also provides the use of a compound of Formula I for the manufacture of a médicament for the inhibition of P2X₇ activity. The present invention further provides the use of a compound of Formula I for the manufacture of a médicament for the inhibition of production or accumulation ofILIp.

In an embodiment, the present invention provides at least one compound of Formula I for use in treating an affective disorder in a subject. In an embodiment, the present invention provides at least one compound of Formula I for use in inhibiting P2X₇ activity in a subject. In an embodiment, the present invention provides at least one compound of Formula I for use in inhibiting production or accumulation of IL 1 β in a subject.

The invention also provides a compound of Formula I for use in therapy of a subject, for example, in the treatment of affective disorders.

EXPERIMENTAL SECTION

The compounds of the présent invention of the general formula I, wherein R¹, R³, R“^b, R³, R⁴ and n are as defined above can be prepared by the methods outlined in the following reaction scheme 1 and in the examples. In the described methods, it is possible to make use of variants or modifications, which are themselves known to chemists skilled in the art or could be apparent to the person of ordinary skill in this art. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person skilled in the art in light of the following reaction schemes and examples.

The schemes may involve the use of sélective protecting groups during the synthesis of the compounds of the invention. One skilled in the art would be able to select the appropriate protecting group for a particular reaction. It may be necessary to incorporate protection and de-protection strategies for substituents such as amino, amido, carboxylic acid and hydroxyl groups in the synthetic methods described below to synthesize the compounds of Formula I. Methods for protection and de-protection of such groups are well known in the art, and may be found in T. Green, et al., Protective Groups in Organic Synthesis, 1991, 2™¹ Edition, John Wiley & Sons, New York.

General Methods

Analytical LC-MS data were obtained using one of the methods identified below.

Method A: Performed using electrospray ionization (ESI) operating in positive mode via a Waters ZQ (Waters Corp.) mass spectrometer (ail from Waters Corp., Milford, MA, USA), an Agilent 1100 LC purnp (Agilent Technologies, Inc., Santa Clara, CA), and Agilent 1100 autosampler, with a 200 pl/min split to the ESI source with inline Agilent 1100 diode array detector (DAD) and variable wavelength detector (VWD) at 254 nm, and an 800 uUmin split to a Waters evaporative light scattering detector (ELSD). Séparation was performed on a Inertsil ODS-3 3 pm 50 x 4.6 mm column using a mobile phase of A) water 1 % acetonitrile and 0.2% ammonium formate; and B) Acetonitrile, which was delivered in a gradient fashion over 1.70 minutes going from 20% B to 85% B. Then stepped to 100% B at 1.85 minutes and maintained at 100% B until 1.99 minutes.

Method B: A PE Sciex API 150EX instrument equipped with atmospheric pressure photo ionisation and a Shimadzu LC-8A/SLC-10A LC system was used. Column: 3.0 x 30 mm Waters Symmetry C18 column with 2.2 pm particle size; Column température: 50 °C; Solvent system: A = water/trifluoroacetic acid (99.965:0.035) and B = acetonitrile /trifluoroacetic acid (99.965:0.035); Method: Linear gradient elution with A:B = 90:10 to 20:80 in 1.5 minutes and with a flow rate of 1.2 mL/min.

Method C: A PE Sciex API 150EX instrument equipped with atmospheric pressure photo ionisation and a Shimadzu LC-8A/SLC-10A LC System was used. Column: 3.0 x 30 mm Waters Symmetry Cl8 column with 2.2 μιτι particle size; Column température: 50 °C; Solvent system: A — water/trifluoroacetic acid (99.965:0.035) and B = acetonitrile /trifluoroacetic acid (99.965:0.035); Method: Linear gradient elution with A:B = 100:0 to 70:30 in 1.5 minutes and with a flow rate of 1.2 mL/min.

Method D: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH Cl8 L7pm; 2.1x50mm; Column température: 60 °C; Solvent system: A = water/trifluoroacetic acid (99.965:0.035) and B = acetonitrile /water/trifluoroacetic acid (94.965:5:0.035); Method: Linear gradient elution with A:B = 90:10 to 0:100 in 1.0 minutes and with a flow rate of 1.2 mL/min.

Method E: An Agilent 1200 LCMS system with ELS detector was used. Column: Agilent TC-C18 5 pm; 2.1x50mm; Column température: 50 °C; Solvent system: A = water/trifluoroacetic acid (99.9:0.1) and B = acetonitrile /trifluoroacetic acid (99.95:0.05); Method: Linear gradient elution with A:B = 99:1 to 0:100 in 4.0 minutes and with a flow rate of 0.8 mL/min.

Method F: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH Cl8 L7pm; 2.1x50mm; Column température: 60 °C; Solvent system: A = water/trifluoroacetic acid (99.965:0.035) and B = acetonitrile /water/trifluoroacetic acid (94.965:5:0.035); Method: Linear gradient elution with A:B = 98:2 to 0; 100 in 1.0 minutes and with a flow rate of 1.2 mL/min.

Method G: An Agilent 1200 LCMS system with ELS detector was used. Column: Agilent TC-C18 5 pm; 2.1x50mm; Column température: 50 °C; Solvent system: A = water/trifluoroacetic acid (99.9:0.1) and B = acetonitrile /trifluoroacetic acid (99.95:0.05); Method: Linear gradient elution with A:B = 90:10 to 0:100 in 4.0 minutes and with a flow rate of 0.8 mL/min.

Method H: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH Cl8 1.7pm; 2.1x50mm; Column température: 60 °C; Solvent system: A = water/formic acid (99.9:0.1) and B = acetonitrile /water/formic acid (94.9:5:0.1); Method: Linear gradient elution with A:B = 90:10 to 0:100 in 1.0 minutes and with a flow rate of 1.2 mL/min.

Method I: An Agilent 1200 LCMS system with ELS detector was used. Column: Waters XBridge

Sheild RP18 5 pm; 2.1x50mm; Column température: 40 °C; Solvent system: A = water/ammonia (99.95:0.05) and B = acetonitrile; Method: Linear gradient elution with A:B = 95:5 to 0:100 in 4.0 minutes and with a flow rate of 0.8 mL/min.

Préparative LC-M S-purification was performed on a PE Sciex API 150EX instrument with atmospheric pressure Chemical ionîzation. Column: 50 X 20 mm YMC ODS-A with 5 pm particle size; Solvent system: A = water/trifluoroacetic acid (99.965:0.035) and B = acetonitrile /water/trifluoroacetic acid (94.965:5:0.035); Method: Linear gradient elution with A:B = 80:20 to 0:100 in 7 minutes and with a flow rate of 22.7 mL/minute. Fraction collection was performed by split-flow MS détection.

Préparative SFC was performed on a Thar 80 instrument. Exemplified conditions can be, but not limited to: Column AD 250 X 30mm with 20 pm particle size; Column température: 38 °C, Mobile phase: Supercritical CCh/ EtOH(0.2%NH3H2O) =45/55.

'H NMR spectra were recorded at 300,400,500 or 600 MHz on Bruker Avance instruments. TMS was used as internai reference standard. Chemical shift values are expressed in ppm. The following abbreviations are used for multiplicity of NMR signais: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, dt = double tripleL dq = double quartet, tt = triplet of triplets, m = multiplet, br s = broad singlet and br = broad signal.

Benzoic acids of formula II are commercially available or available by methods described in the literature (see for example Shaikh, Tanveer Mahammad Ali, J.Org. Chem (2006), 71, 5043-5046 and Mongin, Florence; Tetrahedron Lett. (1996), 37, 6551-6554).

Abbreviations are in accordance with to the ACS Style Guide: The ACS Style guide - A manual for authors and editors Janet S. Dodd, Ed. 1997, ISBN: 0841234620

Préparation of intermediates

2-Trifluoromethyl-pyrimidine-5-carbaldehyde

DIBA-H

DCM

To a solution of ethyl 2-trifluoromethyl-pyrimidine-5-carboxylate (1 g, 5 mmol) in DCM (23 mL) at -78°C was added DIBAL-H (6 ml, 6 mmol, 1.0 M solution in toluene) slowly and stirred at the same température for 3h. The mixture was quenched with slow addition of 2M hydrochloric acid and warmed to room température. The mixture was extracted with EtOAc (3 x mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound (572 mg, yield: 71.5%). 'H NMR (CDCI3 400MHz):

Ôppm 10.27 (s, 1 H), 9.35 (s, 2H).

Morpholin-4-yl-(2-trifluoromethyl-pyrimidin-5-yl)-acetonitrile

To a mixture of 2-trifluoromethyl-pyrimidine-5-carbaldehyde (572 mg, 3.25 mmol) and TMSCN (645 mg, 6.49 mmol) in HOAc (10ml) was added dropwise morpholine (311 mg, 3.57 mmol), followed by NaOAc (320 mg, 3.90 mmol). The mixture was stirred at room température ovemight. The solvent was removed in vacuum. The residue was basified by addition of sat. aq. NaHCOj solution to pH 8; then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound (591 mg, yield: 67%). 'H NMR (CDCI3 400MHz): Ôppm 9.10 (s, 2H), 4.96 (s, IH), 3.88-3.71 (m, 4H), 2.79-2.55 (m, 4H).

2-Morpholin-4-yl-2-(2-trifluoromethyl-pyrimidin-5-yl)-ethylamine

A mixture of morpholin-4-yl-(2-trifluoromethyl-pyrimidin-5-yl)-acetonitrile (200 mg, 0.735 mmol), Raney-Ni (200 mg), NH₃ (aq) (1.5 mL) in MeOH (20 mL) was degassed and purged with Ar and H2 each 3 times. The mixture was stirred at room température under Hj (30 psi) for 25 minutes. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to yield the title compound (175 mg, yield: 86%). ’H NMR (CDCI3 400MHz): Ôppm 8.83 (s, 2H), 3.80-3.61 (m, 4H), 3.44 (t, J = 5.2 Hz, IH), 3.19-2.99 (m, 2H), 2.52-2.35 (m, 4H).

The following intermediates were prepared in a similar way: 2-Morpholin-4-yl-2-pyridin-2-yI-ethylamine;

2-Morpholin-4-yl-2-pyridin-3-yl-ethylamine;

2-Morpholin-4-yl-2-pyridin4-yl-ethylamine;

2-(4-Fluoro-phenyl)-2-rnorpholin-4-yl-ethylamine;

2-(4-Chl oro-phenyl)-2 -mo rpholin-4-yl-ethyl amine;

2-(4-Methoxy-phenyl)-2-morpholin-4-yl-ethyIamine;

2-(4-Methyl-phenyl)-2-morpholin-4-yl-ethylamine;

2-(4-Methoxy-phenyl)-2-piperidin-1 -yl-ethylamine;

2-Azetidin-l-yl-2-(4-chloro-phenyl)-ethylamine;

2-(6-Cyclopropyl-pyridin-3-yl)-2-morpholin-4-yl-ethylamine;

2-Morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine;

2-(6-Chloro-pyridin-3-yl)-2-morpholin-4-yl-ethylamine;

2-M orpholin-4-yl-2-p yri midi n-5-yl-ethyl amine;

2-(2-Methyl-pyrimidin-5-yl)-2-morpholin-4-yI-ethylamine;

2-(6-Methyl-pyridin-3-yl)-2-morpholin-4-yl-ethylamine;

2-(4-Chloro-phenyl )-2-(4,4-difluoro-piperidin-l-yl)-ethylamine;

2-(4-Fluoro-phenyl)-2-(4,4-difluoro-piperidin-l-yl)-ethylamine;

2-(4,4-Difluoro-piperidin-1 -yl)-2-(4-methoxy-phenyl)-ethylamine;

2-(4,4-Difluoro-piperidin-l-yl)-2-(6-fluoro-pyridin-3-yl)-ethylamine;

2-(4,4-Difluoro-piperidin-l-yl)-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine;

2-(4,4-<ii fl uoropiperidin-1 -yl)-2-(2-methylpyrimidin-5-yl)ethanamine;

2-(4₎4-difluoropiperidin-l-yl)-2-(2-(trifluorometliyl)pyrimidin-5-yl)ethanamine;

2-(4,4-dimethylpiperidin-1 -yl ) -2-(2-(tri fluoromethyl)pyrimidin-5 -yl )ethanamine;

2-morpholino-2-(2-(trifluoromethyl)pyrirnidin-5-yl)ethanamîne;

2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;

2-(4-fluoropîperidin-1 -yl)-2-(2-methylpyrimidin-5-yl)ethanamine;

2-(4-fluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;

2-(4,4-difluoropiperidin-1 -yl)-2-( 1 -methyl-1 H-pyrazol-4-yl)ethanamine;

2-(2-methylpyrimidin-5-yl)-2-(piperidin-1 -yl)ethanamine;

2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimidin-5-yl)ethanamine;

2-(4-methoxypiperidin-1 -yl)-2-(2-methylpyrimidin-5-yl)ethanamîne;

2-(4-chloropiperidin-1 -yl)-2-(2-methylpyrimidin-5-yl)ethanamine;

2-(4-chlorophenyl)-2-(l,4-oxazepan-4-yl)ethanamine;

2-(3-methylpiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;

2-(2-methylpyrimidin-5-yl)-2-( 1,4-oxazepan-4-yl)ethanamine;

2-(2-methylpyrimidin-5-yl)-2-(3-methylpyiTolidin-1 -yl)ethanamine;

2-(2-methylpyrimidin-5-yl )-2-(3,3,4,4-tetrafluoropyrrolidin-1 -yl)ethanamine;

2-(4,4-difluoropiperidin-1 -yl)-2-(2-methylpyrimidin-5-yl)ethanamine;

2-(2-isopropylpiperidin-1 -yl)-2-(2-methylpyrimidin-5-yl)ethanamine;

2-(2-azabicyclo[2.2.1 ]heptan-2-yl)-2-(2-methylpyrimidin-5-yl)ethanamine;

2-(2-methyIpiperidin-l-yl)-2-(2-rnethylpyrimidin-5-yl)ethanamine;

5-(2-amino-1 -(4,4-difluoropiperidin-1 -yl)ethyl)-N,N-dimethylpyrimidin-2-amine;

5-(2-amino-1 -(4,4-difluoropiperidin-1 -y l)ethyl)-1 -methylpyridin-2( 1 H)-one;

-(2-Amino-1 -(2-methylpyrimidin-5-yl)ethyl)piperidin-4-ol;

2-(4-chloropiperidin-l-yl)-2-(2-methyIpyrimidin-5-yl)ethanamine;

2-Cyclopropylpyrimîdine-5-carbaldehyde

HO i POCIj DMF ^0H ii. NaCIO₄

N—

I 2CIO4 a1

To a three-neck flask (1000 mL) was added dry DMF (85 mL) and POCI3 (103 g, 0.67 mol) was added drop-wise at room température. After the addition was completed, the mixture was stirred for 30 minutes and malonic acid (20 g, 0.19 mol) was added in portions over 40 minutes, keeping the inner température below 25°C. The resulting mixture was heated to 90 C for ovemight. The réaction mixture was cooled to room température and added into stirring icewater (80 mL) containing NaClO₄ (53 g, 0.38 mol) in portions, keeping the inner température at 0°C. The suspension was filtered; the solid was dried in air to give intermediate al, which was used in the next step without further purification.

I NH ^N— - D>“4. HCI

I Ij I 2CIO4 NH₂ * Ql-i/vQx NaOH, CH₃CN a1

To a mixture of al (ca. 0.095 mol) in CH3CN (300 mL) was added cyclopropanecarboximidamide hydrochloride (12.5 g, 0.105 mol), then sodium hydroxide (7.6 g, 0.19 mol) in water (7.6 mL) was added drop-wise at 0°C. After addition was complété, the resulting mixture was stirred at room température ovemight. After filtration, the filtrate was concentrated to remove CH3CN under reduced pressure and the residue water phase was extracted with DCM (3 x 300 mL). The organic layer was dried over Na₂SC>4, filtered and concentrated in vacuum to give a red oil, which was purified by column chromatography on silica gel (petroleum ether: EtOAc = 2: 1) to afford 2-cyclopropylpyrimidine-5-carbaldehyde (7.6 g, yield: 53.5%). ‘H NMR (CDC13 400 MHz): ό 10.06 (s, IH), 8.99 (s, 2H), 2.41-2.35 (m,

IH), 1.32-1.21 (m, 4H).

2-(2-Cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yi)acetonitrile

F F

To a solution of 2-cyclopropylpyrimidine-5-carbaldehyde (2 g, 13.5 mmol) and TMSCN (2.68 g, 27 mmol) in AcOH (30 mL) was added 4,4-difluoropiperidine hydrochloride (3.1 g, 13.5 mmol), followed by AcONa (2.66 g, 32.4 mg). The mixture was stirred at 30°C for ovemight .The solvent was removed under reduced pressure and saturated NaHCO₃ (aq) was added to the mixture to pH = 8. The resulting mixture was extracted with EtOAc (3 x 100 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated in vacuum to give the 2-(2cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropîperidin-l-yl)acetonitrile as a light red solid (3.5 g, 93%), which was used directly for next step without further purification. ‘H NMR (CDC13 400 MHz): â 8.69 (s, 2H), 4.88 (s, IH), 2.73-2.70 (t, J = 5.5 Hz, 4H), 2.34-2.27 (m, IH), 2.11-2.00 (m,4H), 1.19-1.13 (m, 4H).

2-(2-Cyclopropylpyrimîdin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethanamine

A mixture of 2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)acetonitrile (3.50 g, 126 mmol), Raney Ni (3.50 g) and NH₃.H₂O (10 mL) in MeOH (150 mL) was degassed and purged with argon and H₂, then stirred at room température under H? (50 Psi) for 4 hours. The reaction mixture was filtered and concentrated in vacuum to give 2-(2-cyclopropylpyrimidin-5yl)-2-(4,4-difluoropiperidin-l-yl)ethanamine as a yellow oil (3.10 g), which was used directly for next step without further purification.

(4-Chloro-phenyl)-pyrrolidin-1 -yl-acetonitrile

To a solution of 4-Chlorobenzaldehyde (2.50 g, 17.8 mmol) in tetrahydrofuran (15 mL) was added TMSCN (2.4 mL, 18.0 mmol) and Zinc diiodide (30.0 mg, 0.094 mmol) at 0 °C. The mixture was stirred at 0 °C for 15 min. To the mixture was added pyrrolidine (1.50 mL, 18.0 mmol) at room température. The résultant mixture was stirred at room température overnight.

Ail of the volatiles were removed by rotary evaporator. The residue was dissolved in dichloromethane (100 mL) and was washed with saturated sodium bicarbonate (aq). The organic solution was dried over MgSCXj and concentrated in vacuo.

The crude product was purified by column chromatography on silica gel (petroleum ether: EtOAc = 1:0 to 1:1) to afford (4-Chloro-phenyl)-pyrrolidin-l-yl-acetonitrile (3.52 g, yield: 85%). ^lH NMR (CDCh 400MHz): J 7.48 (d, 2H), 7.39 (d, 2H), 5.02 (s, 2H), 2.67 (m, 2 H), 2.61 (m, 2H), 1.84 (m, 4H).

2-(4-chlorophenyl)-2-(pyrrolidin-1 -yl)ethanamine

To a solution of (4-ChlorO’phenyl)-pyrrolidin-l-yl-acetonitrile (3.52 g, 15.2 mmol; in Tetrahydrofuran (96 mL) was added Lithium tetrahydroaluminate (1225 mg, 32.28 mmol) and the reaction was refluxed over night. The reaction was quenched with H₂O (1.22 ml), 2M NaOH (aq) (1.22 ml) and H₂O (2.44 ml). The solid was filtered off and the reaction was concentrated, to yield 2-(4-chlorophenyl)-2-(pyrrolidin-l-yl)ethanamine (1.14 g, 30% yield).

The following întermediates were prepared in a similar way: 2-(3-methylpiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethanamine

Bis(((di fluoromethyl)sulfinyl )oxy)zinc (DFMS)

F | O Zn, H2O A. i< .C

F S ------► Zn(SO₂CF₂H)₂

O

To a vessel equipped with a stir bar, Zn dust (1.8 g, 27.8 mmol) was added H₂O (20 mL). The reaction vessel was then capped, wrapped in aluminum foil and cooled in an ice bath to 0 C.

Difluoromethanesulfonyl chloride (5 g, 33.3 mmol) was then added via syringe open to air.

The reaction vessel was sealed with cap and the reaction mixture was removed from the ice bath and allowed to warm to room température over 2h. The excess Zn was removed via filtration, washed with EtOAc (3 x 10 mL), the filtrate was concentrated under reduced

O pressure. Residual water was removed azeotropically with toluene (3x10 mL) at 45 C, and the resulting pearly yellow powder was further dried under vacuum for an additional 3h to give bis(((difiuoromethyl)sulfinyl)oxy)zinc (DFMS) (4 g, yield:81.6%), which was used in the next step without purification. ⁽H NMR (DMSO-c/ô 400MHz): <5 5.24 (t, J= 56.0 Hz, IH).

2-MorphoIino-2-(pyrimidin-5-yl)acetonitrile n

A Q TMSCN CN

NaOAc. HOAc S

NX

To a mixture of pyrimidine-5-carbaldehyde (2 g, 18.52 mmol) and TMSCN (3.67 g, 37.0 mmol) in HOAc (50 mL) was added morpholine (2.42 g, 27.8 mmol) at room température and NaOAc (3.34 g, 40.7 mmol) was followed. The resulting mixture was stirred at room température 15 ovemight. Saturated aqueous Na₂CO₃ solution was added to quench the reaction mixture, the pH was adjusted to about 7 and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated to give crude 2-morpholino-2(pyrimidin-5-yl)acetonitrile (2.5 g, yield: 66%). 'H NMR (CDC1₃ 400MHz): <59.25 (s, IH), 8.92 (d, J= 10.0 Hz, 2H), 4.87 (s, IH), 3.79-3.70 (m, 4H), 2.67-2.56 (m, 4H).

2-(2-(Difluoromethyl)pyrimidin-5-yl)-2-morpholinoacetonitrile

F

To a solution of 2-morpholino-2-(pyrimidin-5-yl)acetonitrile (1.03 g, 5.04 mmol) and DFMS (4 g, 13.61 mmol) in DCM (40 mL) and H₂O (16 mL) at room température was added CF₃COOH 25 (575 mg, 5.04 mmol) followed by slow addition of 2-hydroperoxy-2-methylpropane (3.24 g,

70% solution in H₂O) with vigorous stirring. The reaction mixture was stirred at room température ovemight. The reaction mixture was portioned between DCM (50 mL) and saturated NaHCO₃ solution (50 mL), the organic layer was separated and the aqueous layer was extracted with DCM (5 mL><3). The organic layer was washed with brine, dried over Na₂SO₄30 and concentrated. The crude product was purified by Prep-TLC (Petroleum ether:EtOAc=l 0:1-2:1) to give 2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoacetonitrile (150 mg, yield: 11.7%). 'H NMR (CDC1₃ 400MHz): d'9.01 (d, .7= 10.0 Hz, 2H), 6.67 (t, 54.4

Hz, IH), 4.91 (s, IH), 3.95-3.62 (m, 4H), 2.81-2.46 (m, 4H).

2-(2-(Difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine

H₂.Raney Ni aq NH₃ MeOH

A mixture of 2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoacetonitrile (150 mg, 0.59 mmol), Raney-Ni (75 mg), NH₃H₂O (2 mL) in MeOH (20 mL) was degassed and purged with Ar and H₂ each 3 times. The mixture was stirred at room température under H₂ (50 psi) for 3h. The resulting mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give crude 2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine, which was used in the next step without further purification.

The following intermediates were prepared in a similar way:

2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethanamine;

2-(6-(difluoromethyl)pyridin-5-yl)-2-morpholinoethanamine;

2-(6-(difluoromethyl)pyridin-3-yl)-2-(4,4-difluoropiperidin-l-yl)ethanamine;

5-Bromopyrimidine-2-carbonitrile

NaCN

DMSO

To a solution ofNaCN (0.849 g, 17.32 mmol) and DABCO (0.390 g, 3.48 mmol) in a mixture of DMSO (4 ml) and H₂O (9 ml) was added a solution of 5-bromo-2-chloropyrimidine (3.05 g, 15.75 mmol) in DMSO (9 ml). The solution was stirred at room température ovemight, and then diluted with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated to give 5-bromopyrimidine-2-carbonitrile (2,327 g, 12,01 mmol, 76 % yield, IH NMR (CDCh 500MHz): δ 8.94 (s, 2H)).

l-(5-Bromopyrimidin-2-yl)ethanone

To a solution of 5-bromopyrimidine-2-carbonitrile (221 mg, 1.2 mmol) in THF (10 ml) was added méthylmagnésium bromide (3.0 ml, 4.20 mmol, 1.4 molar, THF) at -78 °C under nitrogen. The solution was stirred at -78 °C for 3.5 hours, and then quenched with satd aq NH₄Cl, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na^SO-j and concentrated. The reaction was purified by column chromatography on siiica gel (petroleum ether: EtOAc = l:0 to 0:l) to afford l-(5-bromopyrimidin-2-yl)ethanone (155 mg, 61% yield). ‘H NMR (CDCh 500MHz): Ô 9.00 (s, 2H), 2.80 (s, 3H).

5-Bromo-2-( l, l -difluoroethyl)pyrimidine

DAST

Br^T

l-(5-bromopyrimidin-2-yl)ethanone (304 mg, 1,514 mmol) in anhydrous DCM (50 ml), under nitrogen, was treated w Diethylaminosulfur trifluoride (1220 mg, 1 ml, 7,57 mmol). After 12 hours of stirring additional Diethylaminosulfur trifluoride (610 mg, 0,5 ml, 3,75 mmol) was added. This was repeated again after 24 hours, Diethylaminosulfur trifluoride (610 mg, 0.5 ml, 3.75 mmol). After 36 hours the reaction was quenched with sat. NaHCC»3 and extracted with

AcOEt, washed with Brine and dried over Na2SC>4, filtered and concentrated. The reaction was purified by column chromatography on siiica gel (petroleum ether: EtOAc = 1:0 to 0:1) to afford 5-bromo-2-(l,l-difluoroethyl)pyrimidine (298 mg, 88% yield). ^lH NMR (CDCfi 500MHz): Ô 8.92 (s, 2H), 2.08 (t, 2H).

2-(1,1 -Difluoroethyl)-5-vinylpyrimidine

PdOAcj (22 mg, 0.1 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (53 mg, 0,13 mmol) (DavePhos), césium carbonate (880 mg, 2.70 mmol) and potassium trifluoro(vinyl)borate (145 mg, 1.1 mmol) were mixed. THF (10 ml), water (3 ml) and 5-bromo2-(l,l-difluoroethyl)pyrimidine (200 mg, 0,897 mmol) was added. Degassed for 20 minutes, with argon. The resulting mixture was capped and heated to 100°C, for 30 min in microwave oven. The reaction mixture was partitioned between EtOAc (20 mL) and FtyO (10 mL). The aq. layer extracted with EtOAc (2x10 mL) and the combined organic layers washed with brine (10 mL), dried (Na2SÜ4) and concentrated. The reaction was purified by column chromatography on sîlica gel (petroleum ether: EtOAc = 1:0 to 0:1) to afford 2-(l,l-difluoroethyl)-5vinylpyrimidine (114 mg, 75% yield). 'H NMR (CDCI3 500MHz): δ 8.88 (s, 2H), 6,73 (m, IH), 6,02 (d, IH), 5.61 (d, IH), 2.10 (t, 2H).

2-(1,1 -Difluoroethyi)pyrimidine-5-carbaldehyde

NalO₄ OsO₄tBuOH/H₂O

2-(l,l-difluoroethyl)-5-vinylpyrimidine (110 mg, 0.646 mmol) was dissolved in THF (5ml) and water (2 ml). NaIO₄ (571 mg, 2.67 mmol), 2,6-lutidine (143 mg, 0,155 ml, 1.3 mmol) and osmium tetraoxide (138 mg, 0.17 ml, 0.013 mmol, 0.078 molar in tBuOH) was added. The reaction mixture was stirred at room température for 2 hours. Water was added and the mixture was extracted with diethyl ether. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. ^lH NMR showed a mixture of aldéhyde and lutidine, which was used directly in the next reaction, (166 mg, 42% yield, 28% pure). 'H NMR (CDCI3 500MHz): δ 10.24 (s, IH), 9.30 (s, 2H), 2.12 (t, 2H).

2-(2-( 1,1 -Difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-1 -yl)acetonitrile

To a solution of 2-(1,1 -difluoroethyl)pyrimidine-5-carbaldehyde (166 mg, 0.270 mmol, 28 %) in THF (4 ml) was added TMS cyanide (79 mg, 0.1 ml, 0.8 mmol) and zinc iodide (2.2 mg, 6.89 pmol). The mixture was stirred for 15 min. To the mixture was added 4,4-difluoropiperidine hydrochloride (62 mg, 0.393 mmol) and DIPEA (37 mg, 0.05 ml, 0.286 mmol). The résultant mixture was stirred at room température ovemight. The volatiles were removed by rotary evaporator and the reaction was purified by column chromatography on sîlica gel (petroleum ether: EtOAc = 1:0 to 0:1) to afford 2-(2-( 1,1 -difluoroethyl)pyrimidin-5-yl)-2-(4,4difluoropiperidin-l-yl)acetonitrile (as a 1:1 mixture of nitrile and aldéhyde) (39 mg, 24% yield). ‘H NMR (CDCI3 500MHz): δ 9.03 (s, 2H), 5.02 (s, IH), 2,76 (m, 4H), 2.10 (m, 6H).

2-(2-(1,1 -Difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethanamine

2-(2-(1,l-difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)acetonitrile (39 mg, 0.065 mmol, 50 %) was dissolved in ammonia (2034 μΐ, 4.07 mmol, 2 molar in MeOH) and hydrogenated on H-Cube, by passing the solution over the Ra-Ni catcart 3 times at 60°C and 60 bar. The solution was concentrated to afford 2-(2-( 1,1 -difluoroethyl)pyrimidin-5-yl)-2-(4,4difluoropiperidin-I-yl)ethanamine, which was used crude in the next reaction.

Compounds of formula I can be prepared by employing standard amîde bond forming coupling procedures by the reaction of a carboxylic acid of formula II with an amine of formula m.

II ni

This reaction is typically carried out in a solvent such as THF or DMF, employing peptide coupling reagents exemplifîed by, but not limited to EDC and HOBt in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine (DIPEA), at a température ranging from about 10° C to about 30° C. Other non-limiting examples of coupling reagents include carbonyldiimidazole, Ν,Ν’-dicyclohexylcarbodiimide or benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate as reported by Coste et al. Tetrahedron Lett. (1990) 31 (2): 205. Or Compounds of formula I can be prepared by employing standard amide bond forming coupling procedures by the reaction of a carboxylic acid chloride of formula IV with an amine of formula III.

O R³

IV

III

This reaction is typically carried out in a solvent such as THF, DCM or DMF in the presence of a tertiary amine base such as triethylamine or diisopropylethylamine (DIPEA), at a température ranging from about 10° C to about 30° C.

Préparation of the compounds of the invention

Exampie la

2-Chloro-5-methyl-N-(2-morpholkM-yl-2-pyridin-2-yl-ethyl)-benzamide

PyBOP D1PEA.DCM

A mixture of (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine (62.2 mg, 0.3 mmol), 2-chloro-5methylbenzoic acid (54 mg, 0.315 mmol), PyBOP (187 mg, 0.36 mmol) and DIPEA (78 mg, 0.60 mmol) in DCM (1.5 mL) was stirred at room température ovemight. The mixture was purified by préparative HPLC to yield the title compound (100 mg, yield: 90%). LCMS (MH'): m/z = 360.0, t_R(minutes, Method A) = 0.89

The following compounds were synthesised in a similar way as to example 1 a:

Example 1b

2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-benzamide

Example le

From 2-chloro-5-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyl)amîne. LCMS (MH):

m/z = 360.0, t_R (minutes, Method A) = 0.77

2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-pyridin-4-yl-ethyl)-benzamide

From 2-chloro-5-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)amine. LCMS (MH*): m/z = 360.0, îr (minutes, Method A) = 0.77

Example Id

2-Methyl-N-(2-morpholin-4-yl-2-pyridin-2-yl-ethyl)-benzamide

From 2-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-2-ylcthyl)amine.

LCMS (MH*): m/z = 326.1, tR (minutes, Method A) = 0.76

Example le

2-Methyl-N-(2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-benzamide

From 2-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyl)amine.

LCMS (MH*): m/z = 326.0, t_R (minutes, Method A) = 0.62

Example If

2-Methyl-N-(2-morpholin-4-yl-2-pyridin-4-yl-ethyl)-benzamide

From 2-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)arnine.

LCMS (MH*): m/z - 326.1, îr (minutes, Method A) = 0.62

Example 1g

2,3-Dichloro-N-(2-morpholin-4-yl-2-pyridin-2-yl-ethyl)-benzamide

From 2,3-dichlorobenzoic acid and (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine.

LCMS (MH⁺): m/z = 380.1, t_R (minutes, Method A) =0.83

Example Ih

2,3-Dichloro-N-(2-morpholin^l-yl-2-pyridm-3-yl-ethyl)-benzamide

From 2,3-dichlorobenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyl)amine.

LCMS (MH⁺): m/z = 379.9, t_R (minutes, Method A) - 0.79

Example li

2,3-Dichloro-N-(2-morpholin-4-yl-2-pyridin-4-yl-ethyl)-benzamide

From 2,3-dichlorobenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)amine.

LCMS (MH⁺): m/z = 379.9, t_R (minutes, Method A) = 0.79

Example Ij

2,3-Dimethyl-N-(2-morpholin-4-yl-2-pyridin-2-yl-ethyl)-benzamide

From 2,3-dimethylbenzoic acid and (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine.

LCMS (MH'): m/z = 340.1, t_R (minutes, Method A) = 0.83

Example 1k

2,3-Dimethyl-N-(2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-benzamide

From 2,3-dimethylbenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyI)amine.

LCMS (MIT): m/z = 340.1, îr (minutes, Method A) = 0.73

Example ll

2,3-Dimethyl-N-(2-morpholin-4-yl-2-pyridin-4-yl-ethyl)-benzamide

From 2,3-dimethylbenzoic acid and (2-morpholin-4-yl-2-pyridin-4-ylethyl)amine.

LCMS (MH⁺): m/z = 340.0, t_R (minutes, Method A) - 0.73

Example 1m

2,3-Dichloro-N-[2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and 2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyiamine.

LCMS (MH⁺): m/z = 396.9, îr (minutes, Method A) 1.22

Example In

2,3-Dichloro-N-[2-(4-methoxy-phenyl)-2-piperidin-l-yl-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and 2-(4-methoxy-phenyl)-2-piperidin-l -yl-ethylamine.

LCMS (MIT): m/z = 407.0, tR (minutes, Method A) “ 1.28

Example lo

2,3-Dichloro-N-[2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethyI]-benzamide

From 2,3-dichlorobenzoic acid and 2-(4-methoxy-phenyl)-2-morpholin-4-yI-ethylamine.

LCMS (MH’): m/z = 408.9, îr (minutes, Method A) = 1.17

Example Ip

N-[2-(4-Fluoro-phenyl)-2-morpholin-4-yl-ethyl]-2,3-dimethyl-benzamide

From 2,3-dimethylbenzoic acid and 2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamîne.

LCMS (MH^-): m/z = 357.0, t_R (minutes, Method A) = L16

Example Iq

N-[2-(4-Methoxy-phenyl)-2-piperidin-l-yl-ethyl]-2,3-dimethyl-benzamide

From 2,3-dimethylbenzoic acid and 2-(4-methoxy-phenyl)-2-piperidin-l-yl-ethylamine.

LCMS (MH~): m/z = 367.1, t_R (minutes, Method A) = 1.09

Example Ir

N-[2-(4-Methoxy-phenyl)-2-morpholin-4-yl-ethyl]-2,3-dimethyl-benzamide

From 2,3-dimethylbenzoic acid and 2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine.

LCMS (MPT): m/z = 369.0, t_R (minutes, Method A) = L10

Example 1s

2-Chloro-N-[2-f4-iluoro-phenyl)-2-morpholin-4-yl-ethyl]-5-methyl-benzamide

From 2-chlorobenzoic acid and 2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine.

LCMS (MET): m/z = 376.9, t_R (minutes, Method A) = 1.21

Example It

2-Chloro-N-[2-(4-methoxy-phenyl)-2-piperidin-l-yl-ethyl]-5-methyl-benzamide

From 2-chlorobenzoic acid and 2-(4-methoxy-phenyl)-2-piperidin-l-yl-ethylamine.

LCMS (MFT): m/z = 387.0, t_R (minutes, Method A) = 1.19

Example lu

2-Chloro-N-[2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethyl]-5-methyl-benzamide

From 2-chlorobenzoic acid and 2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine.

LCMS (MH⁺): m/z = 388.9, t_R (minutes, Method A) -1.16

Example Iv

N-[2-(4-Fluoro-phenyl)-2-morpholin-4-yl-ethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and 2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine.

LCMS (MPT): m/z = 343.0, t_R (minutes, Method A) = 1.07

Example Iw

N-[2-(4-Methoxy-phenyl)-2-piperidin-l-yl-ethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and 2-(4-methoxy-phenyl)-2-piperidin-l-yl-ethylamine.

LCMS (MH*): m/z = 353.0, tR (minutes, Method A) = 0.96

Example Ix

N-[2-(4-Methoxy-phenyl)-2-morpholin-4-yl-ethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and 2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethylamine.

LCMS (MET); m/z = 355.0, îr (minutes, Method A) = 1.01

Example ly

2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-p-tolyl-ethyl)-benzamide

From 2-chloro-5-methylbenzoic acid and 2-(4-methyl-phenyl)-2-morpholin-4-yI-ethylamine.

LCMS (MH⁺): m/z - 373.0, tR (minutes, Method A) = 1.18

Example Iz

N-[2-(4-Chloro-phenyl)-2-(4,4-difluoro-piperidin-l-yl)-ethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and 2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-l-yl)-ethylamine.

LCMS (MH⁺): m/z = 392.9, t_R (minutes, Method A) = l .62

Example lal

N-[2-(4-Chloro-phenyl)-2-(4,4-difluoro-piperidin-l-yl)-ethyl]-2,3-dimethyl-benzamide

From 2,3-dimethylbenzoic acid and 2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidm-l-yl)ethylamine.

LCMS (MH⁺): m/z = 407.0, t_R (minutes, Method A) = l .68

Example Ibl

N-[2-(4-Chloro-phenyl)-2-(4,4-difluoro-piperidin-l-yl)-ethyl]-2,3-dichloro-benzamide

From 2,3-dichlorobenzoic acid and 2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-l-yl)-ethylamine.

LCMS (MH⁺): m/z = 446.8, t_R (minutes, Method A) = 1.73

Example 2a

2,3-Dichloro-N-[2-(4,4-difiuoro-l-piperidyl)-2-(6-fluoro-3-pyridyl)ethyl]benzamide

HO8t.EDCI.HCI

DIPEA.DMF

A mixture of2-(4,4-difluoro-piperidin-l-yl)-2-(6-fluoro-pyridin-3-yl)-ethylamine (100 mg, 0.38 mmol), 2,3-dichlorobenzoic acid (51 mg, 0.28 mmol), HOBT (57 mg, 0.42 mmol), EDC.HC1 (81 mg, 0.42 mmol) and DIPEA (108 mg, 0.84 mmol) in DMF (4mL) was stirred at room température ovemight. The mixture was purified by préparative HPLC directly to yield the title compound (43 mg, yield: 30%)

LCMS (Μ1Γ): m/z = 432.0, t_R (minutes, Method E) = 2.33

The following compounds were synthesised in a similar way:

Example 2 b

2,3-Dichloro-N-[2-(4-chloro-phenyl)-2-morpholin-4-yl-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and 2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine.

LCMS (MH⁴): m/z = 412.8, t_R (minutes, Method D) = 0.54

Example 2c

2,3-Dichloro-N-[2-(6-cyclopropyl-pyridin-3-yl)-2-morpholin-4-yl-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-2-morpholin-4-yl-ethylamine.

LCMS (MH⁺): m/z = 412.8, t_R (minutes, Method D) = 0.54

Example 2d

N-[2-(4-Chloro-phenyl)-2-morpholinri-yl-ethyl]-2-methyl-bcnzamide

From 2-methylbenzoic acid and 2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine.

LCMS (MH⁴): m/z = 359.2, t_R (minutes, Method F) = 0.55

Example 2e

2,3-Dichloro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)ethylamine.

LCMS (MH*): m/z = 448.1, îr (minutes, Method B) = 0.91

Example 2f

2-Chloro-N-[2-(4-chloro-phenyl)-2-morpholin-4-yl-ethyl]-3-methyl-benzamide

From 2-chloro-3-methylbenzoic acid and 2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine.

LCMS (MH*): m/z = 393.2, îr (minutes, Method F) = 0.58

Example 2g

2,3-Dichloro-N-[2-(6-chloro-3-pyridyl)-2-morpholino-ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(6-chloro-3-pyridyl)-2-morpholin-4-yl-ethylamine.

LCMS (MH*): m/z = 415.8, t_R (minutes, Method C) = L15

Example 2h

2,3-DichIoro-N-(2-morpholino-2-pyrimidin-5-yl-ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-morpholin-4-yl-2-pyrimidin-5-yl-ethylamine.

LCMS (MH*): m/z = 381.1, tR (minutes, Method C) = 0.92

Example 2i

2,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-2-morpholino-ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl-ethylamine.

LCMS (MH⁴): m/z = 395.0, îr (minutes, Method C) = 0.94

Example 2j

2,3-Dichloro-N-[2-morpholino-2-[2-(trifIuoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(2-(trifluoromethyl)pyrimidin-5-yl)-2-morpholin-4-ylethylamîne.

LCMS (MH⁴): m/z = 449.0, îr (minutes, Method B) = 0.95

Example 2k

2,3-Dichloro-N-[2-(4,4-difluoro-piperidin-l-yl)-2-(4-fluoro-phenyl)-ethyl]-benzamide

From 2,3-dichlorobenzoic acid and 2-(4-fluoro-phenyl)-2-(4,4-difluoro-piperidin-l-yl)-ethylamine.

LCMS (MH⁴): m/z = 431.2, t_R (minutes, Method D) = 0.57

Example 21

2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(4-methoxyphenyl)ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(4-methoxy-phenyl)-2-(4,4-difluoro-piperidin-l-yl)ethylamine.

LCMS (MET): m/z = 443.1, t_R (minutes, Method E) = 1.81

Example 2m

2,3-Dichloro-N-[2-(4,4-difluoro-l-piperidyI)-2-(6-fluoro-3-pyridyl)ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(6-fluoro-3-pyridyl)-2-(4,4-difluoro-piperidin-l-yl)ethylamine.

LCMS (MET): m/z - 432.0, t_R (minutes, Method E) “ 2.33

Example 2n

2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(6-fluoro-3-pyridyl)ethyl]benzamide

From 2-chlorobenzoic acid and 2-(6-fluoro-3-pyridyl)-2-(4,4-difluoro-piperidin-l -yl)-ethylamine.

LCMS (MET): m/z = 398.1, t_R (minutes, Method E) - 2.10

Example 2o

2,3-Dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[6-(trifluoromethyl)-3- pyridyl] ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(6-(trifluoromethyl)-3-pyridyl)-2-(4,4-difluoro-piperidin-l-yl)ethylamine.

LCMS (MH⁺): m/z = 482.0, t_R (minutes, Method E) = 2.62

Example 2p

2-Chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[6-(trifluoromethyl)-3-pyridyi]ethyl]benzamide

From 2-chlorobenzoic acid and 2-(6-(trifluoromethyl)-3-pyridyl)-2-(4,4-difluoro-piperidin-l-yl)ethylamine.

LCMS (MH⁺): m/z = 448.1, t_R (minutes, Method E) = 2.30

Example 2q

2,3-dichloro-N-(2-(4-chlorophenyl)-2-(l,4-oxazepan-4-yl)ethyl)benzamide

From 2,3-dichIorobenzoic acid and 2-(4-chlorophenyl)-2-(l,4-oxazepan-4-yl)ethanamine.

LCMS (MH+): m/z = 429.0, t_R (minutes, Method H) = 0.51

Example 2r

2,3-dichloro-N-(2-(4-chlorophenyl)-2-(pyrrolidin-l-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4-chlorophenyl)-2-(pyrrolidin-l-yl)ethanamine.

LCMS (MH+): m/z = 397.2, t_R (minutes, Method D) = 0.54

Example 2s

2-chloro-3-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine.

LCMS (MH+): m/z - 379.2, îr (minutes, Method D) - 0.36

Example 2t

2,6-difluoro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2,6-difluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholinoe±anamine.

LCMS (MH+): m/z = 363.2, tR (minutes, Method D) = 0.40

Example 2u

2,6-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2,6-dichlorobenzoic acid and 2-(2-methylpyrirnidin-5-yl)-2-morpholinoethanamine.

LCMS (MH+): m/z = 395.2, tR (minutes, Method D) = 0.45

Example 2v

2-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholinoethanarnine.

LCMS (MH+): m/z = 379.2, îr (minutes, Method D) = 0.43

Example 2x

2,3-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4,4-difluOTOpiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine.

LCMS (MH+): m/z = 483.1, t_R (minutes, Method F) = 2.56

Example 2y

2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(4,4-diiluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine.

LCMS (MH+): m/z = 449.1, t_R (minutes, Method F) = 2.38

Example 2z

2,3-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine.

LCMS (MH+): m/z = 429.1, t_R (minutes, Method F) = 1.83

Example 2al

2,3-dichloro-N-(2-(4,4-dimethylpiperidîn-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5- yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4,4-dimethylpiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine.

LCMS (MH+): m/z = 475.1, t_R (minutes, Method G) = 2.23

Example 2b 1

2,3-dichloro-N-(2-(4-methoxypiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethy1)benzamide

From 2,3-dichlorobenzoic acid and 2-(4-methoxypiperidin-l-yi)-2-(2-methylpyrimidin-510 yl)ethanamine.

LCMS (MH+): m/z = 423.1, t_R (minutes, Method F) = 2.04

Example 2c 1

2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethanamine.

LCMS (MH+): m/z = 409.1, t_R (minutes, Method D) = 0.40

Example 2dl

2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethanamine.

LCMS (MH+): m/z = 375.1, îr (minutes, Method D) = 0.33

Example 2e 1

2-chloro-3-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethanamine.

LCMS (MH+): m/z = 393.1, îr (minutes, Method D) = 0.35

Example 2fl

2,6-dichloro-N-(2-(2-methylpyrimidin-5-yI)-2-(l,4-oxazepan-4-yl)ethyl)benzamide

From 2,6-dichlorobenzoîc acid and 2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethanamine.

LCMS (MH+): m/z = 409.1, t_R (minutes, Method D) = 0.35

Example 2gl

2-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethyl)benzamide

From 2-chloro-6-fluorobcnzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan4-yl)ethanamine.

LCMS (MH+): m/z = 393.1, t_R (minutes, Method D) = 0.32

Example 2hl

2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(3-methylpyrrolidin-l-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(3-methylpyrrolidin-lyl)ethanamine.

LCMS (MH+): m/z = 393.1, t_R (minutes, Method D) = 0.44

Example 2 il

2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(3,3,4,4-tetrafluoropyrrolidin-lyl )ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(3,3,4,4-tetrafluoropyrrolidin-lyl)ethanamîne.

LCMS (MH+): m/z = 451.1, t_R (minutes, Method D) = 0.64

Example 2jl

2,4-dichloro-N-(2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and 2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.

LCMS (MH+): m/z = 449.1, t_R (minutes, Method D) - 0.63

Example 2kl

2,4-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

yl)ethanamine.

LCMS (MH+): m/z = 429.2, t_R (minutes, Method D) = 0.61

From 2,4-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-541

Example 211

2,3-dichloro-N-(2-(3-methylpiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(3-methylpiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethanamme.

LCMS (MH+): m/z = 407.2, t_R (minutes, Method D) = 0.49

Example 2ml

2,3-dichloro-N-(2-(2-isopropylpiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamîde

From 2,3-dichlorobenzoic acid and 2-(2-isopropylpiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine.

LCMS (MH+): m/z = 435.2, t_R (minutes, Method D) = 0.51

Example 2nl

2,3-dichloro-N-(2-(2-methylpiperidin-1 -yl)-2-(2-methyIpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(2-methylpîperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.

LCMS (MH+): m/z = 407.1, t_R (minutes, Method E) = 0.49

Example 2ol

N-(2-(2-azabicyclo[2.2.1]heptan-2-yl)-2-(2-methylpyrimidin-5-yl)ethyi)-2,3-dichlorobenzamide

From 2,3-dichlorobenzoic acid and 2-(2-azabicyclo[2.2.1]heptan-2-yl)-2-(2-methylpyrimidin-5yl)ethanamine.

LCMS (MH+): m/z - 405.2, t_R (minutes, Method D) = 0.46

Example 2pl

2,3-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(dimethylamino)pyrimidm-5- yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 5-(2-amino-l-(4,4-difluoropipendin-I-yI)ethyl)-N,Ndimethylpyrimidin-2-amine.

LCMS (MH+): m/z = 458.2, t_R (minutes, Method D) = 0.57

Example 2ql

2-chloro-3-fluoro-N-(2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5yi)ethanamine.

LCMS (MH+): m/z = 433.3, tR (minutes, Method D) ‘ 0.57

Example 2rl

2,3-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(l-methyl-6-oxo-l,6-dihydropyridin-3yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 5-(2-amino-l-(4,4-difluoropiperidin-l-yl)ethyl)-l-methylpyridin2(lH)-one.

LCMS (MH+): m/z = 323.0, t_R (minutes, Method E) = 0.43

Example 2sl

2,3-dichloro-N-(2-(4-chloropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4-chloropiperidin -l-yl)-2-(2-methylpyrimidin-5yl)ethanamine.

LCMS (MH+): m/z = 427.0, t_R (minutes, Method F) = 1.95

Example 2t 1

2,4-dichloro-N-(2-(4-chloropîperidin -l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,4-dichlorobenzoîc acid and 2-(4-chloropiperidin yl)ethanamine.

LCMS (MH+): m/z = 427.0, t_R (minutes, Method F) = 1.99

-1 -yl)-2-(2-methylpyrimidin-5Example 3a (-)2,3-Dichloro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

A mixture of 2-Morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (200 mg, 0.72 mmol),

2,3-dichlorobenzoic acid (138 mg, 0.726 mmol), HOBT (147 mg, 1.09 mmol), EDCl.HCl (207 mg,

1.09 mmol) and DIPEA (281 mg, 2.18 mmol) in DMF (2mL) was stirred at room température overnight. The mixture was purified by preparative HPLC directly to yield the racemic compound (150 mg, yield: 46.3%).

The racemic mixture was separated into the two enantiomers by preparative SFC to yield the title compound LCMS (MHQ: m/z = 448.0, t_R (minutes, Method E) - 2.31. [a]^?= -5.7 (c = 2.28 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 3b (+)2,3-Dichloro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

LCMS (MET): m/z = 448.0, t_R (minutes, Method E) = 2.31. [a]T?= 5.4 (c = 5.2mg/mL,CHCl₃)

The following compounds were synthesîsed in a similar way:

Example 3c (-)2-Chloro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]-3(trifluoromethyl)benzamide

From 2-chloro-3-(trifluoromethyl)benzoic acid and 2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-

3-yl)-ethylamine.

LCMS (MIT): m/z = 482.1, t_R (minutes, Method E) = 2.43. [<±]t9⁼ -6.67 (c = 1.2mg/mL,CHCl₃)

Example 3d (+)2-Chloro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]-3(tri fluoromethyl)benzamide

LCMS (ΜίΓ): m/z = 482.1, t_R (minutes, Method E) - 2.42. [α]Τ?= 5.83 (c = 1.2mg/mL,CHCl₃)

Example 3e (-)2,3-Dichloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(2-(trifluoromethyl)pyrimidin-5-yl)-2-morpholin-4-ylethyiamine.

LCMS (MH*): m/z = 449.0, t_R (minutes, Method E) = 2.49. [α]$= -17.14 (c = L4mg/mL,CHCl₃)

Example 3f (+)2,3-Dichloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

LCMS (MH⁺): m/z = 449.0, t_R (minutes, Method E) = 2.49. [tx]î9= 17.47 (c = 1,66mg/mL,CHCl₃)

Example 3g (-)2-Chloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-310 (trifluoromethyl)benzamide

From 2-chloro-3-(trifluoromethyl)benzoic acid and 2-(2-(trifluoromethyl)pyrimidin-5-yl)-2morpholin-4-yl-ethylamine.

LCMS (MH⁺): m/z = 483.1, t_R (minutes, Method E) = 2.62. [«]$= -15.09 (c = 1.06mg/mL,CHCl₃)

Example 3h (+)2-Chloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3(trifluoromethyl)benzamide

LCMS (MH’): m/z = 483.1, t_R (minutes, Method E) = 2.62. [a]ÿ*= 15.04 (c = 1.33mg/mL,CHCl₃)

Example 3i (-)2-Chloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2-chlorobenzoîc acid and 2-(2-(trifluoromethyl)pyrimidin-5-yl)-2-morpholin-4-yl25 ethyiamine.

LCMS (MH⁺): m/z = 415.1, t_R (minutes, Method E) = 2.30. [α]τ?= -16.0 (c = 2.00mg/mL,CHCl₃)

Example 3j (-)2-Chloro-N-[2-morpholino-2-[2-(tnfluoromethyl)pyrimidin-5-yl]ethyl]benzamide

LCMS (MH⁺): m/z = 415.1, tR (minutes, Method E) = 2.30. [a]l?⁼ 16.5 (c = 2.00mg/mL,CHCl3)

Example 3k (-)2-Fluoro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2-fluorobenzoic acid and 2-(2-(trifluoromethyl)pyrimidin-5-yl)-2-morpholin-4-ylethylamine.

LCMS (MH⁺): m/z = 399.1, t_R (minutes, Method E) = 2.27. [α]Ϊ9= -16.9 (c = 1.6mg/mL,CHCl₃)

Example 31 (+)2,3-Dichloro-N-[2-(6-methyl-3-pyridyl)-2-morpholino-ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(6-methyl-pyridin-3-yl)-2-morpholin-4-yl-ethylamine. LCMS (Ml Γ): m/z = 394.0, t_R (minutes, Method E) = 1.79. [α]χ9= 8.3 (c = 4.7mg/mL,CHCl₃)

Example 3m (+)2-Chloro-3-methoxy-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

From 2-chloro-3-methoxybenzoic acid and 2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)ethylamine

LCMS (MET): m/z = 444.2, t_R (minutes, Method E) = 2.08. [cî]t9= 7.5 (c = 2.0mg/mL,CHCl₃)

Example 3n (-)2,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-2-morpholmo-ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholin-4-yl-ethylamine.

LCMS (MH*): m/z = 395.1, t_R (minutes, Method E) = 1.56. [a]ÿ= -6.67 (c = 0.9mg/mL,CHCl₃)

Example 3o (+)2,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-2-morpholino-ethyl]benzamide

LCMS (MH⁺): m/z = 395.1, t_R (minutes, Method E) = 1.58. [a]î?= 6.9 (c = 0.87mg/mL,CHCl₃)

Example 3p (+)2,6-Difluoro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

From 2,6-difluorobenzoic acid and 2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)ethylamine

LCMS (MH⁺): m/z = 416.2, t_R (minutes, Method E) = 1.75. [a]î?= 7.9 (c = 2.8mg/mL,CHCl₃)

Example 3q (+)2-Methoxy-N-[2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-benzamide

From 2-methoxybenzoic acid and 2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)-ethy!amine LCMS (MH*): m/z = 410.2, t_R (minutes, Method E) = 1.96. [a]îÿ= 24.8 (c = 7.0 mg'mL^HCh).

Example 3r (-)2-Methoxy-N-[2-morpholin^-yl-2-(6-tnfluoromethyl-pyridin-3-yl)-ethyl]-benzamide

LCMS (MH⁺): m/z = 410.2, t_R (minutes, Method E) = 1.96. [α]χ9= -20.7 (c = 7.0 mg/mL,CHC1₃).

Ex ample 3s (-)2-chloro-3-methoxy-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH*): m/z = 442.2, t_R (minutes, Method F) = 2.10. [cx]î9= -8.0 (c = 1.5 mg/mL,CHCl₃).

Example 3t (-)2,6-difluoro-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH*): m/z = 416.2, t_R (minutes, Method F) = 1.73. [a]l?= -7.5 (c = 2.4 mg6nL,CHC13).

Example 3u (+)2-chloro-6-fluoro-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and 2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin-3-yl)ethy lamine

LCMS (MH*): m/z = 432.2, t_R (minutes, Method F) = 2.09. [a]^?= 12.1 (c = 1.9 mg/mL,CHC13).

Example 3v (-)2-chloro-6-fluoro-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH⁴): m/z = 432.2, t_R (minutes, Method F) = 2.38. [a]ÎJ= -12.5 (c = 2.0 mg/mL,CHCl₃).

Example 3x (+)2-chloro-5-(methylsulfonyl)-N-(2-morpholino-2-(6-(trifiuorornethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-5-(methylsulfonyl)benzoic acid and 2-morpholin-4-yl-2-(6-trifluoromethyl-pyridin3-yl)-ethyl amine

LCMS (MH⁴): m/z = 492.1, t_R (minutes, Method F) = 1.73. [a]î9= 5.8 (c = 3.6 mg/mL,CHCl₃).

Example 3y (-)2-chloro-5-(methylsulfonyl)-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide LCMS (MH⁴): m/z = 492.1, t_R (minutes, Method F) = 1.74. [ü]Î?= -5.8 (c = 3.8 mg/mL,CHCl₃).

Example 3z (+)2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2-chlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine

LCMS (MH⁴): m/z= 361.1, t_R (minutes, Method I) = 1.48. [a]?Ç= 12.86 (c = 2.8 mg'mLCHCh).

Example 3a 1 (-)2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide

LCMS (MH⁴): m/z = 361.1, t_R (minutes, Method I) = 1.48. [a]ÿ= -13.23 (c = 3.4 mg/mL,CHCl₃).

Example 3bl (+)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-5-(methylsulfonyl)benzamide

From 2-chloro-5-(methylsulfonyl)benzoic acid and 2-(4-chlorophenyl)-2-morpholinoethanamine LCMS (MH⁴): m/z = 457.1, t_R (minutes, Method F) = 1.96. [α]γ?= 18.3 (c = 1.2 mg/mL,CHCI3).

Example 3cl (-)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-5-(methylsulfonyl)benzamide

LCMS (MH⁴): m/z = 457.1, t_R (minutes, Method F) = 1.95. [α]τ9= -17.6 (c = 2.6 mg/mL,CHCI3).

Example 3dl (+)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl )-5 -cyanobenzamide

From 2-chloro-5-cyanobenzoic acid and 2-(4-chlorophenyl)-2-morpholinoethanamine LCMS (MH⁴): m/z = 404.1, t_R (minutes, Method F) = 1.78. [a]^?= 5.7 (c = 2.3 mg/mL,CHCI3).

Example 3e 1 (-)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-5-cyanobenzamide

LCMS (MH⁴): m/z = 404.1, t_R (minutes, Method F) = 1.77. [a]l9= -4.6 (c = 1.3 mg/mL,CHCI3).

Example 3fl (-)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-5-(isopropylsulfonyl)benzamide

From 2-chloro-5-(isopropylsulfonyl)benzoic acid and 2-(4-chlorophenyl)-2-morpholinoethanamine

LCMS (MH⁴): m/z = 485.1, t_R (minutes, Method F) = 1.90. [a]^?= -5.6 (c = 3.56 mg/mL,CHCI3).

Example 3g 1 (+)2-chloro-3-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

N

N H

O Cl

X -F

From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamîne

LCMS (MH⁺): m/z = 413.2, t_R (minutes, Method F) = 1.75. [a]?Ç= 9.06 (c = 3.2 mg^mL,CHC13).

Example 3hl (-)2-chloro-3-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide LCMS (MH⁺): m/z = 413.2, t_R (minutes, Method F) = 1.75. [a]?9= -7.74 (c = 3.1 mg/mL,CHCI3).

Example 3il (+)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

N

N H

From 2-chloro-6-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpynmidin-5yl)ethanamine

LCMS (MJ-Γ): m/z = 413.2, t_R (minutes, Method F)= 1.67. [u]l9= 13.56 (c = 4.5 mg/mL,CHCI3).

Example 3jl (-)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-rnethylpyrimidin-5-yl)ethyl)benzamide LCMS (MH*): m/z = 413.2, t_R (minutes, Method F) = 1.67. [a]^?= -10.21 (c = 4.8 mg/mL,CHCI3).

Example 3kl (+)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3fluorobenzamide

From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(trifluoromethyl)pyrimidin -5 -yl )ethanamine

LCMS (Μ1Γ): m/z = 467.1, t_R (minutes, Method F) = 2.52. [a]î9= 9.33 (c = 1.5 mg/mL,CHCl₃).

Example 311 (-)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimïdin-5-yl)ethyl)-3fluorobenzamide

LCMS (MFT): m/z = 467.2, t_R (minutes, Method F) = 2.52. [a]$= -8.57 (c = 1.4 m^mL,CHCl₃).

Example 3ml (+)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)b enzamide

From 2-chloro-6-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(trifluoromethyl)pyrimidin-5-yl)ethanamine

LCMS (MH⁺): m/z = 467.1, t_R (minutes, Method F) = 2.5. [a]î?= 19.32 (c = 2.07 mg/mL,CHCl₃).

Example 3nl (-)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MFT): m/z = 467.1, t_R (minutes, Method F) = 2.5. [α]τ?= -18.87 (c = 1.59 mg/mL,CHCl₃).

Example 3ol (+)2-chloro-3-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyridin-5-yl)ethyI)benzamide

From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyridin-5yl)ethanamine

LCMS (MH*): m/z = 412.2, t_R(minutes, Method F) = 1.69. [α]τ?= 13.24 (c = 3.4 mg/mL,CHCI3).

Example 3pl (-)2-chloro-3-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyridin-5-yl)ethyl)benzamide LCMS (MH*): m/z = 412.2, t_R (minutes, Method F) = 1.70. [a]$= -13.71 (c = 3.5 mg/mL,CHCi₃).

Example 3ql (+)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(6-methylpyridin-3-yl)ethyl)-6-fluorobenzamide

From 2-chloro-6-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyridin-5yl)ethanamine

LCMS (MH*): m/z = 412.2, t_R (minutes, Method F) = 1.64. [cl]t9= 15.79 (c = 3.8 mg/mL,CHCI3).

Example 3rl (-)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(6-methylpyridin-3-yl)ethyl)-6-fluorobenzamide LCMS (MH*): m/z = 412.2, t_R (minutes, Method F) = 1.64. [a]S*= -15.14 (c = 3.5 mg/mL,CHCI3).

Example 3sl (+)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)-3fluorobenzamide

From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yi)-2-(2-(trifluoromethyl)pyridin

-5-yl)ethan amine

LCMS (MH⁺): m/z = 466.1, t_R (minutes, Method F) = 2.29. [a]ï?= 10.97 (c = 3.1 mg/mL,CHCl₃).

Example 3t 1 (-)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)-3fluorobenzamide

LCMS (MFT): m/z = 466.1, t_R (minutes, Method F) = 2.30. [cl]t9= -9.69 (c = 3.2 mg/mL,CHCl₃).

Example 3ul (+)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyridin-5yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyridin5-yl)ethanamine

LCMS (MH⁺): m/z = 466.1, tR (minutes, Method F) = 2.27. [α]??⁼ 12.14 (c = 2.8 mg/mL,CHCl3).

Example 3vl (-)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-l-yI)-2-(trifluoromethyl)pyridin-5yl)ethyl )benzamide

LCMS (MH⁺): m/z = 466.1, t_R (minutes, Method F) = 2.27. [a]îS= -12.96 (c = 2.7 mg/mL,CHCl₃).

Example 3x1 (+)2-chloro-3-methoxy-N-(2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-methoxybenzoic acid and 2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine

LCMS (MH*): m/z = 445.1, t_R (minutes, Method F) = 1.91. [α]ΐ?= 6.4 (c = 4.2 mg/mL,CHCI3).

Example 3zl (-)2-chloro-3-methoxy-N-(2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide LCMS (MH*): m/z = 445.1, t_R (minutes, Method F) = 1.91. [a]î9= -8.25 (c = 4.0 mg/mL,CHCI3).

Example 3a2 (+)2-chloro-3-methoxy-N-(2-morpholino-2-(2-(trifluoromethyi)pyridin-5-yl)ethyl)benzamide

From 2-chloro-3-methoxybenzoic acid and 2-morpholino-2-(2-(trifluoromethyl)pyridin-5yl)ethanamine

LCMS (MH*): m/z = 424.2, t_R (minutes, Method F) - 1.84. [a]î?= 5.3 (c = 8.6 mg/mL,CHCI3).

Example 3b2 (-)2-chloro-3-methoxy-N-(2-morpholino-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)benzamide

LCMS (MH*): m/z = 424.2, t_R (minutes, Method F) = 1.85. [a]î?= -4.3 (c = 7.9 mg/mL,CHCI3).

Example 3c2 (+)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-3-methoxybenzamide

From 2-chloro-3-methoxybenzoic acid and 2-(4-chlorophenyl)-2-morpholinoethanamine LCMS (MH*): m/z = 409.1, t_R (minutes, Method F) = 1.79. [α]?9= 11.5 (c = 7.2 mg/mL,CHCI3).

Example 3d2 (-)2-chloro-N-(2-(4-chlorophenyl)-2-morpholinoethyl)-3-methoxybenzamide

LCMS (MH*): m/z = 409.1, t_R (minutes, Method F) = 1.78. [α]Ϊ9= -12.2 (c = 6.6 mg/mL,CHCI3).

Example 3e2 (+)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(4-fluorophenyl)ethyl)-3-methoxybenzamide

From 2-chloro-3-methoxybenzoic acid and 2-(4,4-difluoropiperidin-l-yI)-2-(4fluorophenyl) ethanamine

LCMS (MH⁴): m/z = 427.1, t_R (minutes, Method F) = 1.55. [ct]îÿ= 9.1 (c = 8.1 mg'mUCHCh).

Example 3f2 (-)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(4-fluorophenyl)ethyl)-3-methoxybenzamide LCMS (MH⁴): m/z = 427.2, t_R (minutes, Method F) = 1.58. [¢^=-10.8 (c = 7.9 mg/mL,CHCfi).

Exampie 3g2 (+)2,3-dichloro-N-(2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine

LCMS (MH⁴): m/z = 429.0, t_R (minutes, Method F) - 2.52. 7.0 (c = 4.8 mg/mL,CHCI3).

Example 3h2 (-)2,3-dichloro-N-(2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide LCMS (MH⁴): m/z = 429.0, t_R (minutes, Method F) = 2.52. [a]î?= -7-6 (c = 6.0 mg/mL,CHCI3).

Example 3g2 (+)2-chloro-N-(2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine 57

LCMS (MIT): m/z = 395.1, t_R (minutes, Method F) = 2.32. [a]T?= 7.8 (c = 5.0 mg/mL,CHC1₃).

Example 3h2 (-)2-chloro-N-(2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide LCMS (MH*): m/z = 395.1, t_R (minutes, Method F) = 2.32. [a]ÿ= -7.0 (c = 5.1 mg/mL,CHC1₃).

Example 3g2 (+)2-chloro-3-fIuoro-N-(2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine

LCMS (MH*): m/z = 413.1, t_R (minutes, Method F) = 2.41. [ot]?9= 8.4 (c - 5.0 mg/mL,CHC1₃).

Example 3h2 (-)2-chloro-3-fluoro-N-(2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide LCMS (MH*): m/z = 413.1, t_R (minutes, Method F) = 2.42. [a]î9= -7.8 (c = 4.6 mg/mL,CHC1₃).

Example 3g2 (+)2-chloro-6-fluoro-N-(2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and 2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine

LCMS (MH*): m/z = 413.1, t_R (minutes, Method F) = 2.33. [a]î9= 10.5 (c = 5.4 mg/mL,CHC1₃).

Example 3î2

Example 3h2 (-)2-chloro-6-fluoro-N-(2-(3,3-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH*): m/z = 413.1, t_R (minutes, Method F) = 2.33. [a]ÿ= -9.5 (c = 4.3 mg/mL,CHC1₃).

(+)2-chloro-N-(2-(4-fluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

F

From 2-chlorobenzoic acid and 2-(4-fluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS (MH⁴): m/z = 377.1, t_R (minutes, Method F) = 1.64. [a]î?= 3.0 (c = 6.0 mg/mL,CHCl₃).

Example 3j2 (-)2-chloro-N-(2-(4-fluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁴): m/z = 377.1, t_R (minutes, Method F) - 1.63. [a]?9= -3.06 (c = 6.2 mg/mL,CHCl₃).

Example 3k2 (+)2,3-dichloro-N-(2-(4-fluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4-fluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine

LCMS (MH⁴): m/z = 411.1, t_R (minutes, Method F) = 1.85. [a]î9= 3.14 (c = 5.73 mg/mL,CHCl₃).

Example 312 (-)2,3-dichloro-N-(2-(4-fluoropiperidin-l-yl)-2-(2-rnethylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁴): m/z = 411.1, t_R (minutes, Method F) = 1.85. [a]î9= -3.32 (c = 6.03 mg/mL,CHCl₃).

Example 3m2 (+)2,6-dichloro-N-(2-(4-fluoropiperidin-l-yI)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

F

From 2,6-dichlorobenzoic acid and 2-(4-fluoropiperidm-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine

LCMS (MH⁴): m/z = 411.1, t_R (minutes, Method F) * 1.70. [α]ΐί?⁼9.83 (c = 6.0 mg/mL,CHC13).

Example 3n2 (-)2,6-dichloro-N-(2-(4-fluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide LCMS (MFT): m/z = 411.1, t_R (minutes, Method F) = 1.69. [a]?9=-10.0 (c = 5.1 mgùnLjCHCb).

Example 3o2 (+)2-chloro-N-(2-(4-fluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(4-fluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine

LCMS (MH⁺): m/z = 431.1, t_R (minutes, Method F)= 1.90. [α]χ9= 13.1 (c = 2.6mg/mL,CHC13).

Ex ample 3p2 (-)2-chloro-N-(2-(4-fluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide LCMS (MH⁴): m/z = 431.1, t_R (minutes, Method F) = 1.91. [a]??=-l 1.5 (c = 2.7 mg/mL,CHC13).

Example 3q2 (+)2,3 -dichloro-N-(2-(4-fluoropiperidin-1 -yl)-2-(2-(trifl uoromethyl)pyrimid î n-5 -yl)ethyl )benzamide

From 2,3-dichlorobenzoic acid and 2-(4-fluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine

LCMS (MH⁴): m/z = 465.0, t_R (minutes, Method F) = 2.39. [α]τ9= 6.4 (c = 2.8 mg/mL,CHC13).

Example 3r2 (-)2,3 -dichloro-N-(2-(4-fluoropiperidin-1 -yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁴): m/z = 465.1, t_R (minutes, Method F) = 2.10. [a]?ÿ= -6.6 (c = 3.8 mg/mL,CHCl₃).

Example 3s2 (+)2,6-dichloro-N-(2-(4-fluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

F

From 2,6-dichlorobenzoic acid and 2-(4-fluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine

LCMS (MH⁴): m/z = 465.1, t_R (minutes, Method F) = 2.00. [a]i9= 12.2 (c = 2.3 mg/mL,CHCh).

Example 3t2 (-)2,6-dichloro-N-(2-(4-fluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yI)ethyl)benzamide

LCMS (MH⁴): m/z = 465.1, t_R (minutes, Method F) = 1.99. [<ί]Τ?= -12.7 (c = 1.5 mg'mL^HCh).

Example 3u2 (+)2-chloro-N-(2-(4,4-difluoropiperidin-l -yl)-2-( 1 -methyl-1 H-pyrazol-4-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(l -methyl-1 H-pyrazol-4yl)ethanamine

LCMS (MH⁴): m/z = 383.1, t_R (minutes, Method F) = 1.70. [a]l9= 8.6 (c = 1.8 mg/mL,CHC13).

Example 3v2 (-)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-( 1 -methyl- lH-pyrazol~4-yl)ethyl)benzamide

LCMS (MH⁴): m/z = 383.1, t_R (minutes, Method F) = 1.70. [α]γ{?= -7.1 (c = 1.8 mg/mL,CHCh).

Example 3u2 (+)2,3-dichloro-N-(2-(4,4-difluoropiperidin-1 -yl)-2-( 1 -methyl-1 H-pyrazol-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(l-methyl-lH-pyrazol-4yl)ethanamine

LCMS (MFT): m/z = 417.0, t_R (minutes, Method F)= 1.91. [a]19= 11.1 (c = 2.4 mg/mL,CHCl₃).

Example 3v2 (-)2,3 -dichloro-N-(2-(4,4-difluoropiperidin-1 -yl)-2-( 1 -methyl-1 H-pyrazol-4-yl)ethyl)benzamide LCMS (MH⁴): m/z = 417.0, t_R (minutes, Method F) =1.91. [α]^?= -11.5 (c = 2.3 mg/mL,CHCl₃).

Example 3u2 (+)2,6-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(l-methyl-lH-pyrazol-4-yl)ethyl)benzamide

From 2,6-dîchlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(l-methyl-IH-pyrazol-4yl)ethanamine

LCMS (MH⁴): m/z = 417.0, t_R (minutes, Method F) = 1.75. [α]τ9= 7.9 (c = 4.9 mg/mL,CHCl₃).

Example 3v2 (-)2,6-dichloro-N-(2-(4,4-difluoropiperidin-1 -yl)-2-( 1 -methyl-1 H-pyrazol-4-yl)ethyl)benzamide LCMS (MFT): m/z = 417.0, t_R (minutes, Method F) = 1.76. [a]^?= -8.7 (c = 4.0 mg/mL,CHCl₃).

Example 3u2 (+)2,3-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(l-methyl-lH-pyrazol-4yl)ethyl)benzamide

From 2,3-dichloro-5-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(l-methyl-lHpyrazo l-4-yl )ethanamine

LCMS (MH⁴): m/z = 435.0, t_R (minutes, Method F) = L97. [a]^?= 12.7 (c = 3.7 mg/mL,CHCI3).

Example 3v2 (-)2,3-dichloro-5-fluoro-N-(2-(4,4-difluorOpiperidin-1 -yl)-2-( 1 -methyl-1 H-pyrazol-4yl )ethyl)benzamide

LCMS (MH⁴): m/z = 435.0, t_R (minutes, Method F) = 1.97. [α]^?= -11.3 (c = 3.7 mg/mL,CHCI3).

Example 3x2 (+)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyI)pyrimidin-5-yl)ethyl)-3methoxybenzamide

From 2-chloro-3-methoxybenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(trifluoromethyl)pyrimidin-5-yl)ethanamine

LCMS (MH⁴): m/z = 479.1, t_R (minutes, Method F) = 2.73. [α]γ9= 4.22 (c = 3.0 mg/mL,CHCI3).

Example 3y2 (-)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-3methoxybenzamide

LCMS (MH⁴): m/z = 479.1, t_R (minutes, Method F) = 2.73. [a]^?= -3.95 (c = 3.8 mg/mL,CHCI3).

Example 3z2 (+)2,6-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin5-yl)ethanamine

LCMS (MH*): m/z = 483.0, t_R (minutes, Method F) = 2.88. 4.85 (c = 2.2 mg/mL,CHCl3).

Example 3a3 (-)2,6-dichloro-N-(2-(4,4-difluoropiperÎdin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH*): m/z = 483.0, t_R (minutes, Method F) = 2.85. [a]i9= -5.76 (c = 2.2 mg/mL,CHCl₃).

Example 3b3 (+)2,6-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

From 2,6-dichloro-5-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(trifluoromethyl)pyrimidin-5-yl)ethanamine

LCMS (MH*): m/z — 501.0, t_R (minutes, Method F) = 2.95. [a]j9= 6.33 (¢= 2.0 mg/mL,CHClî).

Example 3c3 (-)2,6-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH*): m/z = 501.0, t_R (minutes, Method F) = 2.95. [a]^?= -8.0 (c = 2.0 mg/mL,CHClj).

Example 3d3 (+)2,3-dichloro-5-fluoiO-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamîde

From 2,3-dichloro-5-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(trifluoromethyl)pyrimidin-5-yl)ethanamine

LCMS (MH⁺): m/z = 501.1, t_R (minutes, Method F) = 2.75. [α]τ9= 2.94 (c = 4.2 mg/mL,CHCl₃).

Example 3e3 (-)2,3-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH⁺): m/z = 501.1, tR (minutes, Method F) = 2.75. [cl]Î?⁼ -3.33 (c - 3.8 mg/mL,CHCl3).

Example 3β (+)2-chloro-N-(2-(2-rnethylpyrimidin-5-yl)-2-(piperidin-l-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(piperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethanamine

LCMS (MH⁺): m/z = 359.2, t_R (minutes, Method F) = 1.47. [α]χ?= 6.67 (c = 2.8 mgônL,CHCl₃).

Example 3g3 (-)2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(piperidin-l-yl)ethyl)benzamide

LCMS (MH⁺): m/z = 359.2, t_R (minutes, Method F) = 1.47. [α]χ9= -5.04 (c = 2.38 mg/mL,CHCl₃).

Example 3h3 (+)2,3-dichloro-N-(2-(2-rnethylpyrimidin-5-yl)-2-(piperidin-l-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(piperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethanamine LCMS (MH⁺): m/z = 393.2, t_R (minutes, Method F) = 1.68. [a]^?= 5.70 (c = 4.21 mg/mL,CHCl₃).

Example 3i3 (-)2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(piperidin-l-yl)ethyl)benzamide

LCMS (MET): m/z = 393.1, t_R (minutes, Method F) = 1.69. [α]χ9= -2.48 (c = 4.56 mg/mL,CHCl₃).

Example 3j3 (+)2,3-dîchloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine

LCMS (MH⁴): m/z = 429.1, t_R (minutes, Method F) - 2.19. [a]19= 7.18 (c = 4,32 mg/mL,CHC13).

Example 3k3 (-)2,3-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide LCMS (MH⁺): m/z = 429.1, t_R (minutes, Method F) = 2.20. [α] T?- -8.18 (c = 4.89 mg/mL,CHC13).

Example 313 (+)2,6-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine

LCMS (MH⁴): m/z = 429.1, t_R (minutes, Method F) ~ 2.30. [a]19= 10.73 (c = 8.0 mg/mL,CHCb).

Example 3m3 (-)2,6-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyriinidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z = 429.1, t_R (minutes, Method F) = 2.31. [a]i9= -7.1 (c = 5.5 mg/mL,CHCh).

Example 3n3 (+)2,3-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-niethylpyrimidin-5yl)ethyl)benzamide

From 2,3-dichloro-5-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine

LCMS (MH*): m/z = 447.1, t_R (minutes, Method F) = 2.54. [a]^f?= 6.7 (c = 3.2 mg/mL,CHCl₃).

Exaniple 3o3 (-)2,3-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide LCMS (MH⁴): m/z = 447.1, t_R (minutes, Method F) = 2.53. [a]ÏÏ*= -5.5 (c = 3.4 mg/mL,CHCl₃).

Example 3p3 (+)2,6-dichloro-5-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethyl)benzamide

N H

Cl

From 2,6-dichloro-5-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine

LCMS (MH⁺): m/z = 447.0, t_R (minutes, Method F) = 2.18. [ct]^9= 5.63 (c = 3.2 mg/mL,CHCl₃).

Example 3q3 (-)2,6-dichloro-5-fluoro-N-(2-(4,4-difluoiOpiperidin-l-yl)-2-(2-rnethylpyrimidin-5-yl)ethyl)benzamide LCMS (MET)· m/z = 447.0, t_R (minutes, Method F) = 2.17. [a]^?= -3.96 (c = 3.2 mg/mL,CHCl₃).

Example 3r3 (+)2-chloro-3-methoxy-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

O Cl JL X .0

F F

From 2-chloro-3-methoxybenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethanamine

LCMS (MH⁴): m/z = 425.1, t_R (minutes, Method F) = 1.99. [<x]T?= 8.56 (c = 4.4 mg/mL,CHCl₃).

Example 3s3 (-)2-chloro-3-methoxy-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-rnethylpyrirnidin-5-yl)ethyl)benzamide

LCMS (MH⁴]): m/z ~ 425.1, t_R (minutes, Method F) = l .83. [a]l{?= -7.8 (c - 4.4 mg/mL,CHCl₃).

Example 3t3 (+)2-chloro-3-(difluoromethoxy)-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethyl)benzamide

From 2-chloro-3-(difluoromethoxy)benzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2methylpyrimidin-5-yl)ethanamine

LCMS (MH⁴): m/z = 461.2, t_R (minutes, Method F) = 2.44. [α]γ9= 25.19 (c = 2.62 mg/mL,CHCI3).

Example 3u3 (-)2-chloro-3-(difluorornethoxy)-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-rnethylpyrimidin-5yl)ethyl)benzamide

LCMS (MH⁴): m/z = 461.1, t_R (minutes, Method F) = 2.44. [a] 19= -23.23 (c = 1.65 mg/mL,CHCI3).

Example 3v3 (+)2,3-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine LCMS (MH^4-): m/z = 431.1, t_R (minutes, Method F) = 2.36. [a]^9= 14.88 (c = 2.71 mg/mL,CHCI3).

Example 3x3 (-)2,3-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

LCMS (MH⁴): m/z = 431.1, t_R (minutes, Method F) = 2.37. [α]χ9= -11.93 (c = 2.85 mg/mL,CHCI3).

Example 3y3 (+)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2-chlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine LCMS (MH*): m/z = 397.1, t_R (minutes, Method F) = 1.90. [a]l?= 12.72 (c = 1.73 mg/mL,CHCl₃).

Example 3z3 (-)2-chloro-N-(2-(2-(difluoromethyI)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

LCMS (MH*): m/z = 397.1, t_R (minutes, Method F) = 1.90. [a]ÿ= -11.70 (c = 1.68 mg/mL,CHCl₃).

Example 3a4 (+)2-chloro-3-fluoro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-rnorpholinoethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-2morpholinoethanamine

LCMS (MH*): m/z = 415.1, t_R (minutes, Method F) = 2.24. [a]î?= 16.38 (c= 3.54 mg/mL,CHCl₃).

Example 3b4 (-)2-chloro-3-fluoro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide LCMS (MH*): m/z = 415.1, t_R (minutes, Method F) = 2.23. [a]?9= -13.82 (c = 4.56 mg/mL,CHCl₃).

Example 3c4 (+)2-chloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethanamine

LCMS (MH⁴): m/z = 421.2, t_R (minutes, Method F) = 2.36. [α]$= 26.88 (c = 6.2 mg/mL,CHC1₃).

Example 3d4 (-)2-chloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide LCMS (MH J: m/z = 421.2, t_R (minutes, Method F) = 2.35. [a]î?= -28.02 (c = 4.7 mg/mL,CHCI3).

Example 3e4 (+)2,3-dichloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethanamîne

LCMS (MET): m/z = 455.1, t_R (minutes, Method F) = 2.41. [α]ΐ9= 27.06 (c = 11.0 mg/mL,CHCI3).

Example 3f4 (-)2,3-dichloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide LCMS (MH⁴): m/z = 455.1, t_R (minutes, Method F) = 2.42. [α]τ9= -28.03 (c = 10.0 mg/mL,CHC1₃).

Example 3g4 (+)2,6-dichloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and 2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethanamine

LCMS (MH⁺): m/z = 455.0, t_R (minutes, Method F) = 2.3 L [a]S*⁼ 25.50 (c = 6.6 mg/mL,CHCI3).

Example 3h4 (-)2,6-dichloro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide

LCMS (MH): m/z = 455.1, t_R (minutes, Method F) = 2.30. [a]T?- -27.65 (c - 5.8 mg/mL,CHCI3).

Example 3i4 (+)2-chloro-6-fluoro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and 2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidinl-yl)ethanamine

LCMS (MH*): m/z = 439.2, t_R (minutes, Method F) = 2.40. [a]^?= 27.66 (c = 7.1 mg/mL,CHCI3).

Example 3j4 (-)2-chloro-6-fluoro-N-(2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl )ethyl)benzamide

LCMS (MH*): m/z - 439.1, t_R (minutes, Method F) - 2.40. [a]î9= -26.27 (c = 7.0 mg/mL,CHCI3).

Example 3k4 (+)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimidin-5yl)ethanamine

LCMS (MH*): m/z = 409.2, t_R (minutes, Method F) = 2.34. [a]^?= 20.94 (c = 7.21 mg/mL,CHCI3).

Example 314 (-)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH*): m/z = 409.2, t_R (minutes, Method F) = 2.34. [a]^?= -19.15 (c = 7.99 mg/mL,CHCI3).

Example 3m4 (+)2,3-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimidin-5yl)ethanamîne

LCMS (MFT): m/z = 443.1, t_R (minutes, Method F) = 2.56. [α]τ9= 23.67 (c = 7.73 mg/mL,CHCl₃).

Example 3n4 (-)2,3-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH*): m/z = 443.1, t_R (minutes, Method F) = 2.55. -23.24 (c = 7.4 mg/mL,CHCl₃).

Example 3o4 (+)2,6-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimîdin-5yl)ethanamine

LCMS (MFT): m/z = 443.1, t_R (minutes, Method F) = 2.44. [a]?J?= 17.52 (c = 6.45 mg/mL,CHCl₃).

Example 3p4 (-)2,6-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH⁺): m/z = 443.1, t_R (minutes, Method F) = 2.44. [α]τ9= -18.95 (c= 6.28 mg/mL,CHCl₃).

Example 3q4 (+)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimidîn-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-ethylpyrimidin-5yl)ethanamine

LCMS (MH*): m/z = 427.2, t_R (minutes, Method F) = 2.37. [a]?ÿ= 21.82 (c = 7.15 mg/mL,CHC1₃).

Example 3r4 (-)2-chloro-6-fluoro-N-(2-(4,4-difluoropiperidin-l~yl)-2-(2-ethylpyrimidin-5-yl)ethyl)benzamide LCMS (MH*): m/z = 427.2, t_R (minutes, Method F) = 2.38. [a]?9= -21.79 (c = 7.02 mg/mL,CHCI3).

Example 3s4 (+)2,4-dich]oro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

From 2,4-dichIorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin5-yl)ethanamine

LCMS (MH*): m/z = 483.1, t_R (minutes, Method F) = 2.95. [α]1?= 11.6 (c = 3.7 mg/mL,CHCI3).

Example 3t4 (-)2,4-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH*): m/z = 483.1, t_R (minutes, Method F) = 2.95. [a]ÿ= -14.4 (c = 4.0 mg/mL,CHCI3).

Example 3u4 (+)2-chIoro-4-methoxy-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

From 2-chloro-4-methoxybenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(trifluoromethyl)pyrimidin-5-yl)ethanamine

LCMS (MH⁴): m/z = 479.2, t_R(minutes, Method F) = 3.03. [a]S*= 1 Ll (c = 3.0 mg/mL,CHCl₃).

Example 3v4 (-)2-chloro-4-methoxy-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH⁴): m/z = 479.1, tR (minutes, Method F) = 3.04. [α]γ9= -13.6 (c - 3.0 mg^/mL,CHCl3).

Example 3x4 (+)2,4-dichloro-6-fluoro-N-(2-(4,4-difIuoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

From 2,4-dichloro-6-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(trifluoromethyl)pyrimidin-5-yl)ethanamine

LCMS (MH⁴): m/z = 501.0, t_R (minutes, Method F) = 3.01. [α]γ9= 22.8 (c = 3.2 m^mL^HCh).

Example 3y4 (-)2,4-dichloro-6-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl )ethyl)benzamide

LCMS (MH⁴): m/z = 501.0, t_R (minutes, Method F) = 3.01. [a]t9= -23.4 (c = 3.0 mgrinL^HCh).

Example 3z4 (+)2-chloro-3,4-dimethoxy-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrirnidin-5yl)ethyl)benzamide

From 2-chloro-3,4-dimethoxybenzoic acid (trifluoromethyl)pyrimidin-5-yl)ethanamine and 2-(4,4-difluoropiperidin-1 -yl)-2-(274

LCMS (MH*): m/z - 509.1, t_R (minutes, Method F) = 2.77. [a]^?= 23.3 (c = 3.6 mg/mL,CHCI3).

Example 3a5 (-)2-chloro-3,4-dimethoxy-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyi)pyrimidin-5yl)ethyl)benzamide

LCMS (MH*): m/z = 509.1, t_R (minutes, Method F) = 2.78. [a]?9= -19.2 (c = 3.5 mg/mL,CHCI3).

Example 3b5 (+)2,6-dichloro-4-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pynmidin-5yl)ethyl)benzamide

N H

Cl

From 2,6-dichloro-4-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(trifluoromethyl)pyrimidin-5-yl)ethanamine

LCMS (MH*): m/z = 501.1, t_R (minutes, Method F) = 3.17. [a]^?= 19.64 (c = 2.24 mg/mL,CHCI3).

Example 3c5 (-)2,6-dichloro-4-fluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimîdin-5yl)ethyl)benzamide

LCMS (MH*): m/z = 501.1, t_R (minutes, Method F) = 3.17. [a]^?=-19.73 (c = 2.23 mg/mL,CHCI3).

Example 3d5 (+)2-chloro-4,6-difluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

N

H

F

From 2-chloro-4,6-difluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(tri fluoromethyl)pyri midi n-5 - yl )ethanamine

LCMS (MH*): m/z = 485.1, t_R (minutes, Method F) = 3.12. [α]$= 14.40 (c= 2.43 mg/mL,CHC1₃).

Example 3e5 (-)2-chloroA6-difluoro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH*): m/z = 485.1, t_R (minutes, Method F) = 3.12. [a]?9=-12.21 (c = 2.13 mg/mL,CHCI3).

Example 315 (+)2-chloro-N-(2-(4,4-difluoropiperidin-l-yi)-2-(2-(trifluorornethyl)pyrimidin-5-yl)ethyI)-6-fluoro-3methoxybenzamide

From 2-chloro-3-methoxy-6-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(trifluoromethyl)pyrimidin-5-yl)ethanamine

LCMS (MH*): m/z = 497.1, t_R (minutes, Method F) = 3.05. [α]χ9= 18.30 (c = 4.48 mg/mL,CHC1₃).

Ex ample 3g5 (-)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)-6-fluoro-3methoxybenzamide

LCMS (MH*): m/z = 497.1, t_R (minutes, Method F) = 3.05. [a]?9= -16.07 (c = 4.48 mg/mL,CHCI3).

Example 3h5 (+)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)-3(trifluoromethoxy)benzamide

From 2-chloro-3-(trifluoromethoxy)benzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2methylpyrimidin-5-yl)ethanamine

LCMS (MH*): m/z = 479.1, t_R (minutes, Method F) = 2.63. [α]τ?= 16.0 (c = 6.0 m^mHCHCh).

Example 3i5 (-)2-chloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-rnethylpyriniidin-5-yl)ethyl)-3(trifluoromethoxy)benzamide

LCMS (MET): m/z = 479.1, t_R (minutes, Method F) - 2.63. [a]iÇ= -13.3 (c = 4.9 mg/mL,CHCI3).

Example 3j5 (+)2-chloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-(difluoromethyl)pyridin-5yl)ethanamine

LCMS (MH): m/z = 430.1, t_R (minutes, Method F) = 2.45. [a]^?= 4.10 (c = 1.95 mg/mL,CHCI3).

Exampie 3k5 (-)2-chloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoiOpipendin-l-yl)ethyl)benzamide LCMS (MH⁴): m/z = 430.1, t_R (minutes, Method F) = 2.45. [α]ΐ9= -6.06 (c = 1.98 mg/mL,CHCI3).

Example 315 (+)2,3-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-(difluoromethyl)pyridin-5yl)ethanamine

LCMS (MH⁴): m/z = 464.1, t_R (minutes, Method F) = 2.65. [a]^?= 3.06 (c = 3.27 mg/mL,CHCI3).

Example 3m5 (-)2,3-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide LCMS (MH⁺): m/z = 464.1, t_R (minutes, Method F) = 2.65. [a]i9= -4.71 (c = 2.76 mg/mL,CHCI3).

Example 3n5 (+)2,6-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-(difluoramethyl)pyridin-5yl)ethan amine

LCMS (MET): m/z = 464.1, t_R (minutes, Method F) = 2.57. [a]l?= 12.02 (c = 2.08 mg/mL,CHCl·}).

Example 3o5 (-)2,6-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide

LCMS (MH): m/z = 464.1, t_R (minutes, Method F) = 2.57. [α]ΐ9= -11.47 (c = 2.18 mg/mL,CHC13).

Example 3p5 (+)2,4-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-(difluoromethyl)pyridin-5yl)ethanamine

LCMS (Ml-Γ): m/z = 464.1, t_R (minutes, Method F) = 2.69. [ct]T?= 11.56 (c = 1.47 mg/mL,CHC13).

Example 3q5 (-)2,4-dichloro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide LCMS (MH ' ): m/z = 464.1, t_R (minutes, Method F) = 2.70. [α]^?= -11.90 (c = 2.52 mg/mL,CHCl₃).

Example 3r5 (+)2-chloro-3-methoxy-N-(2-(2-(difluoromethyl)pyridin-5-yl )-2-(4,4-difluoropiperidin-1 yl)ethyl)benzamide

From 2-chloro-3-methoxybenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(difluoromethyl)pyridin-5-yl)ethanamine

LCMS (MH⁺): m/z = 460.1, t_R (minutes, Method F) = 2.45. [a]T?= 4.07 (c = 2.95 mg/mL,CHCl₃).

Example 3s5 (-)2-chloro-3-methoxy-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)benzamide

LCMS (MH⁺): m/z = 460.1, t_R (minutes, Method F) = 2.45. [a]î9= -5.07 (c = 2.96 mg/mL,CHCl₃).

Example 3t5 (+)2-chloro-3-fluoro-N-(2-(2-(dîfluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2(difluoromethyl)pyri d i n-5-yl )ethanam ine

LCMS (MH⁺): m/z = 448.1, t_R (minutes, Method F) = 2.54. [a]î?= 10.75 (c = 1.86 mg/mL,CHCl₃).

Example 3u5 (-)2-chloro-3-fluoro-N-(2-(2-(difluoromethyl)pyridin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)benzamide

LCMS (MH⁴): m/z = 448.1, t_R (minutes, Method F) = 2.54. [a]t9= -13.72 (c= 2.55 mg/mL,CHCl₃).

Example 3v5 (+)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide

From 2-chlorobenzoîc acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-(difluoromethyl)pyrimidin-5 yl)ethanamine

LCMS (MH⁴): m/z = 43 Ll, t_R (minutes, Method F) = 2.53. [α]τ9= 17.6 (c = 3.5 mg/mL,CHCI3).

Example 3x5 (-)2-chloro-N-(2-(2-(difluoromethyi)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethyl)benzamide LCMS (MH⁴): m/z = 431.1, t_R (minutes, Method I) = 2.23. [α]ΐ9= -17.0 (c = 3.7 mg/mL,CHCI3).

Example 3y5 (+)2,3-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-(difluoromethyl)pyrimidin5-yl)ethanamine

LCMS (MH⁴): m/z = 465.1, t_R (minutes, Method F) = 2.74. [α]χ9= 17.7 (c = 3.7 mg/mL,CHCI3).

Example 3z5 (-)2,3-dichlono-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)benzamide

LCMS (MH⁴): m/z = 465.1, t_R (minutes, Method F) = 2.74. [a]^Ç= -17.9 (c = 4.5 mg/mL,CHCI3).

Example 3a6 (+)2,6-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)benzamide

From 2,6-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-(difluoromethyl)pyrimidin5-yl)ethanamine

LCMS (MH*): m/z = 465.1, t_R (minutes, Method I) = 2.36. 19.5 (c = 3.6 mg/mL,CHCl3).

Example 3b6 (-)2,6-dichloro-N-(2-(2-(difluoromethyI)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)benzamide

LCMS (MH*): m/z = 465.1, t_R (minutes, Method I) = 2.36. [α]^9= -l8.3 (c = 3.8 mg/mL,CHCl₃).

Example 3c6 (+)2,4-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl )benzamide

From 2,4-dichlorobenzoic acid and 2-(4,4-difluoropiperidin-l-yl)-2-(2-(difluoromethyl)pyrimidin5-yl)ethanamine

LCMS (MH*): m/z = 465.1, t_R (minutes, Method G) = 2.16. [α]χ9= 18.9 (c = 3.6 mg/mL,CHCl₃).

Example 3d6 (-)2,4-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)b enzamide

LCMS (MH*): m/z = 465.1, t_R (minutes, Method G) = 2.16. [a]*$= -16.5 (c = 4.0 mg/mL,CHCl₃).

Example 3e6 (+)2-chloro-3-methoxy-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-ly 1) ethyl )benzamide

From 2-chloro-3-methoxybenzoic acid and 2-(4,4-difluoropiperidin- l-yl)-2-(2(difluoromethyl)p yrimidi n-5 -yl)ethanam ine

LCMS (MH⁴): m/z = 461.1, t_R (minutes, Method I) = 2.26. [a]l9= 19.6 (c = 3.7 mg/mL,CHC13).

Example 3f6 (-)2-chloro-3-methoxy-N-(2-(2-(difluorornethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)benzamide

LCMS (MH⁴): m/z = 461.1, t_R (minutes, Method I) = 2.26. [a]l9= -20.2 (c = 4.0 mg/mL,CHC13).

Example 3g6 (+)2-chloro-3-fluoro-N-(2-(2-(difluorornethyl)pyrimidm-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluoropiperidin- l-yl)-2-(2(difluoromethyl)pyrimidin-5-yl)ethanamine

LCMS (MH⁴): m/z = 449.1, t_R (minutes, Method E) = 2.62. [α]τ9= 16.4 (c = 3.8 mgïnL,CHC13).

Example 3h6 (-)2-chloro-3-fluoro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-lyl)ethyl)benzamide

LCMS (MH⁴): m/z = 449.1, t_R (minutes, Method E) = 2.63. [a]î9= -14.1 (c = 3.8 mg/mL,CHCl3).

Example 3i6 (+)2-chloro-N-(2-(2-(difluoromethyl )pyrimidin- 5-yl)-2-morpholinoethyl )-3 -methoxybenzamide

From 2-chIoro-3-methoxybenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-2morpholi noethanami ne

LCMS (MH⁴): m/z = 427.1, t_R (minutes, Method E) = 2.06. 11.11 (c = 1.8 m^mL,CHC13).

Example 3j 6 (-)2-chloro-N-(2-(2-(di fluoromethyl )pyrimidin-5-yl)-2-morphoI inoethyl)-3 -methoxybenzamide

LCMS (MH⁴): m/z = 427.1, t_R (minutes, Method E) = 2.05. [α]$= -10.78 (c = 1.67 mg/mL,CHCl₃).

Example 3k6 (+)2,4-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

From 2,4-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethanamine LCMS (MH⁴): m/z = 431.1, t_R (minutes, Method F) - 2.32. [a]iJ?= 15.0 (c = 1.0 mg'rnLjCHCh).

Example 316 (-)2,4-dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)benzamide

LCMS (MH⁴): m/z = 431.1, t_R (minutes, Method E) = 2.31. [α]^?= -15.74 (c - 1.08 mg/mL,CHC13).

Example 3m6 (+)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)-3(trifluoromethyl)benzamide

From 2-chloro-3-(trifluoromethyl)benzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-2morpholinoethanamine

LCMS (MH*): m/z = 465.1, t_R (minutes, Method E) = 2.42. [α]19= 17.0 (c = 1.0 mg/mL,CHCl₃).

Example 3n6 (-)2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-2-morpholinoethyl)-3(trifluoromethyl)benzamide

LCMS (MH*): m/z = 465.1, t_R (minutes, Method E) = 2.42. [a]ÿ= -19.42 (c = 1.03 mg/mL,CHCl₃).

2-(2-(l,l-Difluoroethyl)pyrimidin-5-yl)-2-(4,4-difluoropiperidin-l-yl)ethanamine (34 mg, 0.044 mmol, 40% pure) and 2,3-dichlorobenzoyl chloride (65 mg, 0.31 mmol), was dissolved in anhydrous THF (4400 mg, 5 ml, 61,0 mmol), DIPEA (111 mg, 0,15 ml, 0,859 mmol) was added 15 and stirred over night. The solution was concentrated and purified by column chromatography on silica gel (petroleum ether: EtOAc ⁼ 1:0 to 0:1) followed by HPLC, to afford 2,3-dichloro-N-(2(2-(l ,l-difluoroethyl)pyrimidin-5-yl )-2-(4,4-difluoropiperidin-l -yl)ethyl)benzamide (10 mg,

47% yield).

LCMS (MH*): m/z = 479.3, t_R (minutes, Method D) = 0.71.

Example 5

2,3-Dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(4-oxopiperidin-l-yl)ethyl)benzamide

O

To a solution of 2,3-dichloro-N-(2-(4-hydroxypiperidin-l-yl)-2-(2-methylpyrimidin-5yl)ethyl)benzamide (130 mg, 0.32 mmol) in DCM (5 mL) was added 4A molecular sieves (1.3 g), NMO (205 mg, 1.75 mmol) and TPAP (2.2 mg). The mixture was stirred at room température overnight. The resulting mixture was filtered. The filtrate was washed with water, dried over Na2SO4 and concentrated. The residue was purified by préparative TLC (EtOAc:MeOH=100:3) to give 2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(4-oxopiperidin-l-yl)ethyl)benzamide (31 mg, yield: 24%) as a white solid. 'HNMR (CDC1₃ 400MHz): 68.59 (s, 2H), 7.56 (dd, J= 8.0 Hz, 1.6 Hz, 1 H), 7.49 (dd, J = 7.6 Hz, 1.6 Hz, 1 H), 7.34-7.27 (m, 1 H), 6.63 (br, 1 H), 4.08-3.82 (m, 3H), 2.95-2.82 (m, 2H), 2.79-2.65 (m, 5H), 2.55-2.40 (m, 4H). LCMS (MH+): m/z = 425.0, t_R(minutes, Method F) = 1.75

The following compounds were synthesisied ina similar way;

Example 51

2,4-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-( -l-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and 2-(4-oxopiperidin -l-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.

LCMS (MH+): m/z = 425.1, t_R (minutes, Method F) = 2.01

Example 6 Ρ2Χγ binding assay

This example illustrâtes représentative assays for use in evaluating the test compounds for antagonist activity. Compounds of the present invention were tested in vitro for their ability to act as antagonists to the P2X? receptor.

Screening assays to détermine P2X₇ receptor antagonism are well known to the person skiiled in the art. Functional assays, such as second messenger assays, and cytokine measurement assays done in vitro are also well known in the art and may be used to assess the spécifie binding and cellular activity of P2X₇ receptor compounds.

In vitro assay example

Cell culture: 293 HEK cells, stably transfected with plasmids capable of expressing human P2X₇receptor, were cultured by standard methods. Cells were plated to cell density of approximately 15,000 cells/well in 384-well assay plates (50 μΐ/well) with 1.5% low sérum media (DMEM, 1.5% BCS, 1% L-glut (2 mM), 1% P/S).

293 HEK cells, stably transfected with plasmids capable of expressing rat or mouse P2X₇ receptor, were cultured by standard methods. Cells were plated to cell density of approximately 15,000 cells/well in 384-well assay plates (50 μΐ/well) with 1.5% low sérum media (DMEM, 1.5% FBS, 1% L-glut (2 mM), 10 mM HEPES, 1% P/S). Cells were plated 24 hours prior to assay. Cells expressing human, rat or mouse P2X₇ receptor were assayed in the following manner.

Fluorescent Imaging Plate Reader (FLIPR) assay: Briefly, 293-human or mouse P2X₇ stable cells were incubated in sucrose buffer, pH 7.4 [KC1 (5 mM), NaHiPO^HzO (9.6 mM), HEPES (25 mM), sucrose (280 mM), glucose (5 mM), CaCl₂ (0.5 mM), and probenecid (0.1425 g in 3 mL IN NaOH was added for 500 mL solution)] in 384-well plates.

293-rat P2X₇ stable cells were incubated in HHPB (pH 7.4) [consisting of Hank’s BSS (IX); HEPES (pH 7.4) (20 mM) (Sigma); probenecid (0.710 g/5 mL IN NaOH) (Sigma); and BSA (0.05%) (Roche) which was added after the pH had been adjusted] in 384-well plates. Fluo-4 NW dye mix (Molecular Probes, Inc., Eugene, OR, USA) was prepared in buffer (see manufacturées instructions). Cell plates were removed from the 37 °C incubator, the media discarded and then 30 pL of dye was added to each well. Plates were placed in the 37 °C, non-CCL incubator for 30 minutes and then room température for 30 minutes.

Two sets of drug plates were prepared: A) Mixtures of compound plus agonist were prepared as follows, in order to déterminé dose response: BzATP: 11 point 1/2 log, diluted in buffer, starting from 1 mM. Testing compounds: 11 point 1/2 log, diluted in 2% DMSO buffer starting from 10 μΜ.

B) Agonist only mixture was prepared with BzATP at a single concentration in buffer (concentration determined by dose response).

Compound mixtures (A) were added to assay plates containing cells and placed at room température for 30 minutes, then BzATP (B) was added. Fluorescence was read using the Tetra FLIPR® (Molecular Devices, Inc., Sunnyvale, CA, USA) and IC50 values were calculated by standard methods to détermine antagonist activity.

Assay for stimulating ILl β release from THP-1 cells: THP-1 cells (The Global Bioresource Center, ATCC #: TIB-202™) were differentiated by incubation with 10 ng/mL IFN-gamma (Sigma, Cat#: 13265) in Tl 50 plates, at a cell density of 0.5 E⁶cells/mL, in RPMI 1640 media (ATCC, Cat# 30-2001) with 10% FBS and 1% P/S for 48 hours. The cells then were stimulated with 100 ng/mL LPS (Sigma, 10 Cat#: L4516) in sérum free CTL Test media (Sigma Cat#: CTLT-005), without L-glutamine and antibiotics, for 3 hours. Test compounds (antagoniste) were added and incubated for 30 minutes. BzATP (at final concentration of 1 mM) was added and incubated for 30 minutes.

Cell plates were centrifuged at 3000 rpm for 5 minutes and the supematants were immediately 15 collected for AlphaLISA® immunoassay (PerkinElmer Inc., Waltham, MA, USA; Catalog No.

AL220C) or aliquoted and stored at < -20C. The AlphaLISA® immunoassay was performed according to the manufacturer’s instructions.

Table 1 : Exemplified IC50 values of compounds of the invention:

Chemical name	P2X7 ICso (nM)
2-Chloro-5 -methyl-N-(2-morpholin-4-yl-2- pyridin-3-yl-ethyl)-benzamide	3000
2-Chloro-5-methyl-N-(2-morphol in-4-yl-2pyridin-4-yl-ethyl)-benzamide	2700
2,3-Dichloro-N-(2-morpholin-4-yl-2-pyridin3-yl-ethyl )-benzamide	1100
2,3-Dichloro-N-(2-morpholin-4-yl-2-pyridin- 4-yl-ethyl)-benzamide	750
2,3-Dimethyl-N-(2-morpholin-4-yl-2-pyridin- 3-yl-ethyl)-benzamide	2700
2,3-Dimethyl-N-(2-morpholin-4-yl-2-pyridin- 4-yl-ethyl)-benzamide	1400
2,3-Dichloro-N-[2-(4-fluoro-phenyl)-2morpholin-4-yl-ethyl] -benzamide	11
2,3-Dichloro-N-[2-(4-methoxy-phenyl)-2piperidin-1 -yl-ethyl]-benzamide	350
2,3-Dichloro-N-[2-(4-methoxy-phenyl)-2morpholin-4-yl-ethyl] -benzami de	13
N-[2-(4-Fluoro-phenyl)-2-morpholin-4-yl- ethyl]-2,3-dimethyl-benzamide	20
N-[2-(4-Methoxy-phenyl)-2-piperidm-1 -ylethyl] -2,3 -dimethyl-benzamîde	420
N-[2-(4-Methoxy-phenyl)-2-morpholin-4-yl-	___________________47__________________

ethyl]-2,3-dimethyl-benzamide
2-Chloro-N-[2-(4-fluoro-phenyl)-2- morpholin-4-yl-ethyl]-5-mctliyl-benzamide	21
2-Chloro-N-[2-(4-methoxy-phenyl)-2piperidin-1 -yl-ethyl] -5-methyl-benzamîde	650
2-Chloro-N-[2-(4-methoxy-phenyl)-2jmorpholin-4-yl-ethyl]-5-methyl-bcnzamide	59
N-[2-(4-Fluoro-phenyl)-2-morpholin-4-ylethyl]-2-methyl-benzamide	110
N-[2-(4-Methoxy-phenyl)-2-piperidin-1 -ylethyl]-2-methyl-benzaniide	3900
N-[2-(4-Methoxy-phenyl)-2-moipholin-4-ylethyl] -2-methyl-benzamide	500
2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-ptolyl-ethyl)-benzamide	38
N-[2-(4-Chloro-phenyl)-2-(4,4-difluoropiperidin-1 -yl)-ethyl]-2-methyl-benzamide	2
N-[2-(4-Chloro-phenyl)-2-(4,4-difluoropiperidin-1 -yl)-ethyl]-2,3-dimethylbenzamide	3.6
2,3-Dichloro-N-[2-(4-chloro-phenyl)-2-(4,4difluoro-piperidin-1 -yl)-ethyl]-benzamide	46
2,3-Dichloro-N-[(S)-2-(4-chloro-phenyl)-2- morpholin-4-yl-ethyl]-benzamide	0.62
2,3-Dichloro-N-[2-(6-cyciopropyl-pyridin-3- yl)-2-morpholin-4-yl-ethyl]-benzamide	8.2
N-[(S)-2-(4-Chloro-phenyl)-2-morpholin-4yl-ethyl]-2-methyl-benzamide	9.3
2,3-dichloro-N-[2-morpholino-2-[6- (tri fl uoromethyl)-3-pyridyl] ethyl]benzami de	4.6
2-Chloro-N-[(S)-2-(4-chloro-phenyl)-2- morpholin-4-yl-ethyl]-3-methyl-benzamide	0.53
2,3-dichloro-N-[2-(6-chloro-3-pyridyl)-2- morpholino-ethyl]benzamide	3.9
2,3-dichloro-N-(2-morpholino-2-pyrimidin-5yl-ethyl)benzamîde	28
2,3-dichloro-N-[2-(2-methylpyrimidin-5 -yl)- 2-morpholino-efhyl]benzamide	21
2,3-dichloro-N-[2-morpholino-2-[2- (trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide	8.2
2,3-Dichloro-N-[2-(4,4-difluoro-piperidin-1 yl)-2-(4-fluoro-phenyl)-ethyl]-benzarnide	0.33
(-)2-chloro-N-[2-morpholino-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]-3- (tri fluoromethyl)benzamide	12
(+)2-chloro-N-[2-morpholino-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]-3- (trifluoromethyl)benzamide	24
(-)2,3-dichloro-N-[2-morpholino-2-[2- (tri fluoromethyl)pyrimidin-5-	3.2

yl]ethyl]benzamide
(+)2,3-dichloro-N-[2-morpholino-2-[2- (trifluoromethyl)pyrimidin-5yl]ethyl]benzamide	4.8
(-)2-chloro-N-[2-morpholino-2-[2- (trifluoromethyl)pyrimidin-5-yl]ethyl]-3- (trifluoromethyl)benzamide	9.9
(+)2-chloro-N-[2-morpholino-2-[2- (trifluoromethyl)pyrimidin-5-yl]ethyl]-3- (trifluoromethyl)benzamide	17
(-)2,3-dichloro-N-[2-morpholino-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]benzamide	2
(+)2,3-dichloro-N-[2-morpholino-2-[6- (trifluoromethyl)-3-pyridyl]ethyI]benzamîde	5.5
2,3-dichloro-N-[2-(4,4-difhioro-l-piperidyl)- 2-(4-methoxyphenyl)ethyl]benzamide	0.6
2,3 -dichloro-N-[2-(4,4-difluoro-1 -piperidyl)2-(6-fluoro-3-pyridy!)ethyl]benzamide	0.89
2-chloro-N-[2-(4,4-di fluoro-1 -piperidyl )-2-(6fluoro-3-pyridyl)ethyl]b enzamide	4
2,3-dichloro-N-[2-(4,4-difluoro-1 -piperidyl)- 2-[6-(trifluoromethyl)-3- pyridyl] ethyl] b enzamide	1.3
2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2-[6(trifluoromethyl)-3-pyridyl ] ethyl]benzamide	1.8
(-)2-chloro-N-[2-morpholino-2-[2- (tri fluoromethyl)pyrimidin-5- yl]ethyl]benzamide	15
(+)2-chloro-N-[2-morpholino-2-[2- (trifluoromethyl)pyrimidin-5yl ] ethyl ]benzamide	30
(-)2-fluoro-N-[2-morpholino-2- [2- (trifluoromethyl)pyrimidin-5 yl]ethyl]benzamide	44
(+)2,3 -dichloro-N-[2-(6-rnethyl-3 -pyridyl)-2morpholino-ethyl]benzamide	44
2,3-Dichloro-N-[2-(4-chloro-phenyl)-2- [ 1,4]oxazepan-4-yl-ethyl]-benzamide	17
(-)2-chloro-3-methoxy-N-(2-morpholino-2-(6- (trifluoromethyl)pyridin-3-yl)ethyl)benzamide	3.5
(+)2-chloro-3-methoxy-N-[2-morpholino-2- [6-(trifluoromethyl)-3- pyridyl]ethyl]benzamide	14
(-)2-chloro-6-fluoro-N-(2-morpholino-2-(6- (trifluoromethyl)pyridin-3-yl)ethyl)benzamide	6.1
(+)2-chloro-6-fluoro-N-[2-moipholino-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]benzamide	32
(-)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2- morpholino-ethyl]benzamide	110
(+)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2- morpholino-ethyl]benzamide	630

(-)2,3-dichloro-N-[2-(2-methylpyrimidin-5- yl)-2-morpholino-ethyl]benzamide	27
(+)2,3-dichloro-N-[2-(2-methylpyrimidin-5- yl)-2-morpholino-ethyl]benzamide	69
(-)2,6-difluoro-N-[2-morphol ino-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]benzamîde	480
(+)2,6-difluoro-N-[2-morpholino-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]benzamide	29
(-)2-chloro-5-methylsulfonyl-N-[2morpholino-2-[6-(trifluoromethyl)-3pyridyl] ethyl]benzamide	51
(+)2-chloro-5-methylsulfonyl-N-[2morpholmo-2-[6-(trifluoromethyl)-3 pyridyl]ethyl]benzamide	71
(+)2-chloro-N-[2-(4-chlorophenyl)-2- morpholino-ethyl]-5-methylsulfonylbenzamide	180
(-)2-chloro-N-[2-(4-chlorophenyl)-2- morphoIino-ethyl]-5-methylsulfonylbenzamide	65
2,3 -D ichloro-N-[2-(4-chloro-phenyl)-2pyrrolidÎn-1 -yl-ethyl]-benzamide	1800
(-)2-methoxy-N-[2-morpholino-2-[6- (tri fluoromethyl)-3 -pyridyl ] ethyl]benzamîde	21
(+)-2-methoxy-N-(2-rnorpholino-2-(6- (trifluoromethyl)pyridîn-3 -y l ) ethyl )benzamide	98
(+)2-chloro-N-[2-(4-chlorophenyl)-2- rnorpholino-ethyl] -5-cyano-benzamide	23
(-)2-chIoro-N-[2-(4-chlorophenyl)-2- morpholino-ethyl]-5-cyano-benzamide	110
2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)- 2-[2-(trifluorornethyl)pyrimidin-5- yl]ethyl]benzamide	0.65
2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2-[2(tri fluorornethyl)pyrimidin-5 yl]ethyl]benzamide	2.8
2,3-dichloro-N-[2-(4,4-difluoro-1 -piperidyl)- 2-(2-methylpyrnnidin-5-yl)ethyl]benzamide	4.3
(-)2-chloro-N-[2-(4-chlorophenyl)-2- morpholino-ethyl]-5-isopropylsulfonylbenzamide	47
2-Chloro-3 -fluoro-N -[2-(2-methyl-pyrimidin5-yl)-2-morpholin^-yl-ethyl]-benzamide	1200
2,6-dichloro-N-(2-(2-methylpyrimidin-5-yl)- 2-morpholinoethyl)benzamide	120
2-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5- yl)-2-morpholinoethyl)benzamide	590
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- (2-methylpyriniidm-5-yl)ethyl]benzamide	13
(-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2- (2-methylpyrimidin-5-yl)ethyl]benzamide	___

(+)2-ch!oro-N-[2-(4,4-difluoro-1 -piperidyl)-2- [6-(trifluoromethyl)-3-pyridy1]ethyl]-3-fluorobenzamide	1.7
(-)2-chloro-N-[2-(4,4-dîfluoro-l-piperidyl)-2[6-(trifluoromethyl )-3-pyridyl]ethyl] -3-fluorobenzamide	5.7
(+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2- [6-(trifluoromethyl)-3-pyridyl]ethyl]-6-fluorobenzamide	0.62
(-)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2[6-(trifluoromethyl)-3-pyridyl]ethyl]-6-fluorobenzamide	3
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2(6-methyl-3-pyridyl)ethyl]-3-fluorobenzamide	33
(-)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- (6-methyl-3 -pyridyl)ethyl]-3-fluorobenzamide	21
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2(6-methyl-3-pyridyl)ethyl]-6-fluorobenzamide	110
(-)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- (6-methyl-3-pyridyl)ethyl]-6-fluorobenzamide	22
2,6-difluoro-N-(2-(2-methylpyrimidin-5-yl)' 2-morpholinoethyl)benzamide	1100
(+)2-chloro-N-[2-(4,4-difluoro-1 -pîperidyl)-2- (2-methylpyrimidin-5-yl)ethyl]-3-fluorobenzamide	15
(-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2- (2-methylpyrimidin-5-yl)ethyl]-3-fluorobenzamide	19
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2(2-methylpyrimidin-5 -yl)ethyl]-6-fluorobenzamide	19
(-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2- (2-methylpyrimidin-5-yl)ethyl]-6-fluorobenzamide	32
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- [2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-6fluoro-benzamide	8.3
(-)2-chloro-N-[2-(4,4-difluoro-1-piperidyl)-2[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-6fluoro-benzamide	8.2
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- [2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3fluoro-benzamide	1.7
(-)2-chIoro-N-[2-(4,4-di fluoro-1 -piperidyl)-2[2-(trifluoromethyl)pyrimidin-5-yl ] ethyl]-3fluoro-benzamide	4.2
2,3-dîchloro-N-[2-(4,4-dimethyl-1 -piperidyl)-	2500

2-[2-(trifluoromethyl)pyrimîdin-5yl] ethyl]benzamide
2-chloro-N-[2-(4,4-dimethyl-1 -piperidyl)-2[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3fluoro-benzamide	3600
2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)- 2-( 1,4-oxazepan-4-yl)ethyl)benzamide	29
2,6-dichloro-N-(2-(2-methylpyrimidin-5-yl)- 2-( 1,4-oxazepan-4-yl)ethyl)benzamide	740
2-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5yl)-2-( 1,4-oxazepan-4-yl)ethyl)benzamide	820
2-chloro-N-(2-(2-meÜiylpyrimidin-5-yI)-2- ( 1,4-oxazepan-4-yl)ethyl)benzamide	680
2-chloro-3-fluoro-N-(2-(2-methylpyrimidin-5yl)-2-(l ,4-oxazepan-4-yl)ethyl)benzamide	330
(-)2-chloro-3-methoxy-N-[2-morphoIino-2-[2- (trifluoromethyl)pyrimidin-5- yl]ethyl]benzamide	8.2
(+)2-chloro-3-methoxy-N-[2-morpholino-2- [2-(tri fl uoromcthyl)pyrimidin-5- yl] ethyl]benzamide	16
(-)3-methoxy-2-methyl-N-[2-morpholino-2- [6-(trifluoromethyl)-3- pyridyl]ethyl]benzamide	16
(+)3-methoxy-2-methyl-N-[2 -morpholîno-2[ 6-(tri fluoromethyl )-3 pyridyl] ethyl ]bcnzamide	13
(-)2-chloro-N-[2-(4,4-difluoro-l-piperidyi)-2- (4-fluorophenyl)ethyl]-3-methoxy-benzamide	2.6
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- (4-fluorophenyl)ethyl]-3-methoxy-benzamide	2.6
2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)- 2-(3-methylpyrrolidin-1 -yl)ethyl)benzamide	1000
2,3 -dichloro-N-(2-(2-methylpyrimidin-5 -yl)2-(3,3,4,4-tetrafluoropyrrolidin-1 yl)ethyl)benzamide	2.6
(-)2-chloro-N-[2-(4-chlorophenyl)-2- morpholino-ethyl] -3 -methoxy-benzamide	1.5
(+)2-chloro-N-[2-(4-chlorophenyl)-2- morpholino-ethyl] -3 -methoxy-benzamide	4.2
(+)2-chloro-N-[2-(3,3-difluoro-l-piperidyl)-2- (2-methylpyrimidin-5-yl)ethyl]-6-fluorobenzamide	53
(-)2-chloro-N-[2-(3,3-difluoro-l-piperidyl)-2- (2-methylpyrimidin-5-yl)ethyl]-6-fluorobenzamide	280
(+)2-chloro-N-[2-(3,3-difluoro-1-piperidyl)-2- (2-methylpyrimidin-5-yl)ethyl]-3-fluorobenzamide	100
(-)2-chloro-N-[2-(3,3-difluoro-1 -piperidyl)-2- (2-methylpyrimidin-5-yl)ethyl] -3-fluoro-	41

benzamide
(+)2,3 -dichloro-N-[2-(3,3 -di fluoro-1 piperidyl)-2-(2-methylpyrimidin-5yl)ethyl]benzamide	14
(+)2-chloro-N-[2-(3,3-difluoiO-1 -piperidyl)-2- (2-methylpyrimidin-5-yl)ethyl]benzamide	85
(-)2-chloro-N-[2-(3,3-difluoro-1 -piperidyl)-2(2-methylpyrimidin-5-yl)ethyl]benzamide	28
(+)2-chloro-N-[2-(4-fluoro-l-piperidyl)-2-[2- (trifluoromethyl)pyrimidin-5yl]ethyl]benzamide	15
(-)2-chloro-N-[2-(4-fluoro-1 -piperidyl)-2-[2- (trifluoromethyl)pyrimîdin-5yl]ethyl]benzamide	13
(+)2,6-dîchloro-N-[2-(4-fluoro-1 -piperidyl)-2- [2-(trifluoromethyl)pyrimidin-5 yl]ethyl]benzamide	6.1
(-)2,6-dichloro-N-[2-(4-fluoro-l-piperidyl)-2[2-(tri fluoromethyl)pyrimidin- 5yl]ethyl]benzamide	15
(+)2,3-dichloro-N-[2-(4-fluoro-l-piperidyl)-2[2-(trifluoromethyl )pyrimidin-5- yl] ethyl]benzamide	3.5
(-)2,3-dichloro-N-[2-(4-fluoro-1 -piperidyl)-2- [2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide	4.7
(+)2,6-dicliloro-N-[2-(4-fluoro-1 -piperidyl)-2- (2-methyipyrimidin-5-yl)ethyl]benzamide	9.6
(-)2,6-dichloro-N-[2-(4-fluoro-1 -piperidyl)-2(2-methylpyrimidin-5-yl)ethyl]benzamide	53
(+)2,3-dichloro-N-[2-(4-fluoro-1 -piperidyl)-2(2-methylpyrimidin-5 -yl)ethyl]benzamide	6.5
(-)2,3-dichloro-N-[2-(4-fluoro-1 -piperidyl)-2- (2-methylpyrimidin-5-yl)ethyi]benzamide	14
(+)2-chloro-N-[2-(4-fluoro-1 -piperidyl)-2-(2methylpyrimidin-5-yl)ethyl]benzaniide	50
(-)2-chloro-N-[2-(4-fluoro-1 -piperidyl)-2-(2methylpyrimidin-5-yl)ethyl]benzamide	45
2,4-dîchloro-N-(2-morphol ino-2-(2(tri fluoromethyl)pyrirnidin-5yl)ethyl)benzamide	12
(-)2,3 -dichloro-N-[2-(4,4-difluoro-1piperidyl)-2-( 1 -methylpyrazol-4yl)ethyl ]benzamide	25
(+)2,3-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-( 1 -methylpyrazol-4yl)ethyl]benzamide	12
(-)2,3-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-( 1 -methylpyrazol-4-yl)ethyl]-5fluoro-benzamide	26
(+)2,3-dichloro-N-[2-(4,4-difluoro-1 -	__34__________________

piperidyl)-2-( l -methylpyrazol-4-yl)ethyl]-5fluoro-benzamide
(-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2- ( 1 -methylpyrazol-4-yl )ethyl]benzamide	230
(+)2-chloro-N-[2-(4,4-difluoro-1 -pîperidyl)-2( 1 -methylpyrazol -4-yl)ethyl]benzamide	180
(-)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- [2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3methoxy-benzamide	4.8
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2[2-(trifluoromethyl)pyrimidin-5-yl] ethyl] -3 methoxy-benzamide	3.6
(-)2,6-dichloro-N-[2-(4,4-difluoro-1 - piperidyl)-2-[2-(trifluorornethyl)pyrimidin-5yl ] ethyl]benzamide	6.9
(+)2,6-dichIoro-N-[2-(4,4-difluoro-1- piperidyl)-2-[2-(trifluoromethyI)pyrimidin-5- yl]ethyl]benzamide	4.7
(-)2,6-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl] ethyl]-3-fluoro-benzamide	4.9
(+)2,6-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethy1 ]-3-fluoro-benzamide	7.1
(-)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2- ( 1 -piperidyl)ethyl]benzamide	120
(+)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2- ( 1 -piperidyl)ethyl]benzamide	59
(-)2,3-dichloro-N-[2-(2-methylpyrimidin-5- yl)-2-( 1 -piperidyl)ethyl]benzamide	21
(+)2,3-dichloro-N-[2-(2-methylpyrimidin-5y 1)-2-( 1 -piperidyl)ethyl]benzamide	8.9
(-)2,3-dichloro-N-[2-(4,4-difluoro-1 - piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5- yl]ethyl]-5-fluoro-benzamide	2.2
(+)2,3 -dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]-5-fluoro-benzamide	4.9
(-)2,6-dichloro-N-[2-(4,4-dîfluoro-1 piperidyl)-2-( 1 -methylpyrazol-4yl)ethyl]benzamide	44
(+)2,6-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-( 1 -methylpyrazol-4yl)ethyl]benzamide	56
(-)2-chloro-N-[2-[2- (difluoromethyl)pyrimidin-5-yl]-2- morpholino-ethyl]benzamide	15
(+)2-chloro-N-[2-[2- (difluoromethyl)pyrimidin-5-yl]-2- morpholino-ethyl]benzamide	60
\| (-)2-chloro-N-[2-(4,4-difluoro-l -piperidyl)-2-	11

(2-methylpyrimidin-5-yl)ethyl]-3-methoxybenzamide
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- (2-methylpyrimidin-5-yl)ethyl]-3-methoxybenzamide	12
(-)2,6-dichloro-N-[2-(4,4-difluoro-1 - piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]- 3 -fluoro-benzamide	37
(+)2,6-dichloro-N-[2-(4,4-dîfluoro-1 piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]3-fluoro-benzamide	25
(-)2,6-dichloro-N-[2-(4,4-difluoro-l- piperidyI)-2-(2-methylpyrimidin-5- yl)ethyl]benzamide	22
(+)2,6-dichloro-N-[2-(4,4-difluoro-l- piperidyl)-2-(2-methylpyrimidin-5yl )ethyl ] benzamide	19
(-)2,3-dichloro-N-[2-(4,4-difluoro-lpipcridyl)-2-(2-mcthyl pyrimidin-5-yl) ethyl ] 5-fluoro-benzamide	14
(+)2,3-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]5-fluoro-benzamide	5.1
(-)2,3-dichloro-N-[2-(4,4-difIuoro-1 piperidyl )-2-(2-methylpyrimidi n-5 yl)ethyl]benzamide	5.8
(+)2,3-dichloro-N-[2-(4,4-difluoro-1 piperi dyl)-2-(2-methylpyrimidin-5yl)ethyl]benzamide	3.2
(-)2,3-dichloro-N-[2-[2- (difluoromethyl)pyrimidin-5-yl]-2- morpholino-ethyl]benzamide	9.6
(+)2,3-dichloro-N-[2-[2- (difluoromethyl)pyrimidin-5-yl ] -2morpholino-ethyl]benzami de	3.9
(-)2-chloro-N-[2-[2- (di fluoromethyl)pyrimidin-5 -y 1 ] -2morpholino-ethyl] -3 -fluoro-benzamide	38
(+)2-chloro-N-[2-[2- (difluoromethyl)pyrimidin-5-yl ]-2morpholino-ethyl]-3-fluoro-benzamide	4.8
(-)2-chloro-N-[2-(2-cyclopropylpyrimidin-5yl)-2-(4,4-difluoro-l pîperidyl)ethyl]benzamide	7.6
(+)2-chloro-N-[2-(2-cyclopropylpyrimidin-5yl)-2-(4,4-difluoro-1 piperidyl)ethyl]benzamide	3
(-)2,6-dichloro-N-[2-(2cyclopropylpyrimidin-5-yl)-2-(4,4-di fluoro-1 pi peridyl)ethyl]benzamide	5.8
(+)2,6-dichlorO-N-[2-(2-	5.3

cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-1 pîperidyl)ethyl]benzamide
(-)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- (2-ethylpyrimidin-5-yl)ethyl]benzamîde	17
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- (2-ethylpyrimidin-5-yl)ethyl]benzamide	12
(-)2,6-dichloro-N-[2-(4,4-difluoro-1piperidyl)-2-(2-ethylpyrimidin-5 yl)ethyl ]benzamide	27
(+)2,6-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-(2-ethylpyrimidin-5yl)ethyl]benzamide	15
(-)2-chloro-3-(difluoromethoxy)-N-[2-(4,4difluoro-1 -piperidyl)-2-(2-methylpyrirnidin-5yl)ethyl]benzamide	37
(+)2-chloro-3-(difluoromethoxy)-N-[2-(4,4difluoro-1 -piperidyl)-2-(2-methylpyrimidin-5yl)ethyl ]benzamide	7
(-)2,3-dichloro-N-[2-(4,4-difluoro-l- piperidyl)-2-(2-ethylpyrimidin-5- yl)ethyl]benzamide	4.9
(+)2,3 -dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-(2-ethylpyrimidin-5yl)ethyl]benzamide	2.6
(-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2(2 -ethylpyrimidin-5-yl)ethyl] -6-fluorobenzamide	36
(+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2- (2-ethylpyrimidin-5-yl)ethyl]-6-fluorobenzamide	14
(-)2,3-dichloro-N-[2-(2- cyclopropylpyrimidin-5-yl )-2-(4,4-difluoro-l- piperidyl)ethyl]benzamide	3.5
(+)2,3-dichloro-N-[2-(2- cyclopropylpyrimidin-5-yl)-2-(4,4-difluorO’ 1 piperidyl)ethyl]benzamîde	4.3
(-)2-chloro-N-[2-(2-cyclopropylpyrimidin-5- yl)-2-(4,4-difluoro-l-piperidyl)ethyl]-6- fluoro-benzamide	11
(+)2-chloro-N-[2-(2-cyclopropylpyrimîdin-5- yl)-2-(4,4-difluoro-1 -piperidyl)ethyl]-6fluoro-benzamide	9.9
2,4-dichloro-N-(2-(4,4-difluoropiperidin-1 - yl)-2-(2-methylpyrimidin-5- yl)ethyl)benzamide	44
2,3-dichloro-N-(2-(3-methylpiperidin-1 -y l)-2(2-methylpyrimidin-5-yl)ethyl)benzamide	170
(-)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- [2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-4,6difluoro-benzamide	31
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2-	9.4

[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-4,6difluoro-benzamide
(-)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- [2-(trifluoromethyl)pyrimîdin-5-yl]ethyl]-6- fluoro-3-methoxy-benzamide	31
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- [2-(trifluoromethyl)pyTirnidin-5-yl]ethyl]-6fluoro-3 -methoxy-benzamîde	8.9
2,3 -dichloro-N-(2-(2-isopropylpîperidin-1 -yl)2-(2-methylpyrimidin-5-yl)ethyl)benzamide	1900
2_J3-dichloro-N-(2-(4,4-difluoropiperidin-1- yl)-2-(2-(dimethylamino)pyrimidin-5yl)ethyl )benzamide	6.6
N-(2-(2-azabicyclo[2.2.1 ]heptan-2-yl)-2-(2- methylpyrimidin-5-yl)ethyI)-2,3 dichlorobenzamide	3200
2,3 -dicWoro-N-(2-(2-methyl piperidin-1 - y I )-2(2-methylpyrimidin-5-yl)ethyl)benzamide	310
(-)2,4-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide	6.4
(+)2,4-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamîde	5.6
(-)2,4-dichloro-N-[2-(4,4-difluoro-1 - piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5- yl]ethyi]-6-fluoro-benzamide	6.5
(+)2,4-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2’[2-(trifluoromethyl)pyrimidin-5yl]ethyl] -6-fluoro-benzamide	4.7
(-)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- [2-(trifluoromethyi)pyrimidin-5-yl]ethyl]-4methoxy-benzamide	2.2
(+)2-chloro-N-[2-(4,4-difluoro-1 -piperidyl)-2- [2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-4methoxy-benzamide	4.3
(-)2-chloro-N-[2-(4,4-difluoro-1 -piperidyI)-2[2-(trifluoromethyl)pyrimidin-5-yl] ethyl]-3,4dimethoxy-benzami de	7.8
(+)2-chloro-N-[2-(4,4-difluoro-1 -pîperidyl)-2[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3,4dimethoxy-benzamide	14
2,3-dichloro-N-[2-(4-rnethoxy-1 -piperidyl)-2(2-methylpyrimidin-5-yl)ethyl]benzamide	3800
(-)2,6-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2-[2-(trifluoromethyI)pyrimidin-5yl]ethyl] -4-fl uoro-benzamide	15
(+)2,6-dichloro-N-[2-(4,4-difluoro-1 piperidyl)-2- [ 2 -( tri fluoromethyl)pyrimidin-5yl]ethyl]-4-fluoro-benzamide	7.5
(-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-	40

(2-methylpyrimidin-5-yl)ethyl] -3(trifluoromethoxy)benzamide
(+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2- (2-methylpyrimidin-5-yl)ethyl]-3- (trifluoromethoxy)benzamide	21
2,3-dichloro-N-[2-(2-methylpyrimidm-5-yl)- 2-(4-oxo-1 -piperidyl)ethyl]benzamide	19
2,4-dichloro-N-[2-(2-methylpyrimidin-5-yl)- 2-(4-oxo-1 -piperidyl)ethyl]benzamide	970
2,3-dichloro-N-[2-(4-chIoro-1 -piperidyl)-2-(2methylpyrimidin-5-yl)ethyl]benzamïde	5.7
2,4-dichloro-N-[2-(4-chloro-1 -piperidyl)-2-(2methylpyrinüdin-5 -yl)ethyl]benzamide	280
2-chloro-3-fluoro-N-(2-morpholino-2-(2(tri fl uoromethyl) pyrimidin-5 yl)ethyl)benzamide	11
(+)2-chloro-N-[2-[6-(difluoromethyl)-3pyridyl]-2-(4,4-difluoro-l piperidyl)ethyl]benzamide	9
(-)2-chloro-N-[2-[6-(difluoromethyl)-3pyridyl]-2-(4,4-difluoro-1 piperidyl)ethyl]benzamide	12
(+)2,3-dichloro-N-[2-[6-(difluoromethyl)-3pyridyl]-2-(4,4-difluoro-1 piperidyl)ethyl]benzamide	2.4
(-)2,3-dichloro-N-[2-[6-(difluoromethyl)-3pyridyI]-2 -(4,4-difluoro-1 piperidyl)ethyl]benzamide	4.2
(+)2,6-dichloro-N-[2-[6-(difluoromethyl)-3 pyridyl]-2-(4,4-difluoro-1 piperidyl )ethyl]benzamide	8.7
(-)2,6-dichloro-N-(2-[6-(difluoromethyl)-3pyridyl] -2-(4,4-difluoro-1 piperidyl) ethyl]benzamide	5.5
(+)2-chloro-N-[2-[6-(difluoromethyl)-3pyridyl]-2-(4,4-difluoro-1 -piperidyl)ethyl]-3methoxy-benzamide	2.3
(-)2-chloro-N-[2-[6-(difluoromethyl)-3pyridyl]-2-(4,4-difluoro-1 -piperidyl)ethyl]-3methoxy-benzamide	1.9
2,3-Dichloro-N-[2-(4-chloro-phenyl)-2- morpholin-4-yl-ethyl]-benzamide	0.6

Units which are used in this spécification and which are not in accordance with the metric system may be converted to the metric system with the aid of the following conversion factor:

psi = 6.895 x 10³ Pa.

Claims

What is Claimed:

1. A compound of formula I

wherein R¹ is pyrazinyl or pyrimidyl, each of which is optionally substituted with one or more Ci^ alkyl, halogen, hydroxy, C_M fluoroalkyl, C₃^cycloalkyl, Ci^ alkoxy, C^fluoroalkoxy, cyano or schR⁷;

wherein R²³ and R^2b combine with the nitrogen to which they are attached to form piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrrolo, imidazo, azetidinyl, 6 to 10 membered spiro(heterocyclyl), homomorpholinyl, homopiperidinyl or homopiperazinyl each of which is optionally substituted with one or more Ci^ alkyl, C,^ alkenyl, Ca^-cycloalkyL Calkoxy, oxo, NR⁵R⁶ or fluorines;

wherein R³ is halogen, C_Mfluoroalkyl, cyano, cyclopropyl, Cwalkyloxy, Cufluoroalkyloxy, SO₂R⁷, -NR⁵R⁶ or C^alkyl;

wherein R⁴ is halogen, Cj^ alkyl, Ci^fluoroalkyl, cyano, -SCbR⁸, -NR⁵R⁶, Ci-6 alkoxy, Cm fluoroalkoxy or Cj^-cycloalkyl;

wherein R⁵ and R⁶ independently of each other are hydrogen or C_w alkyl;

wherein R⁷ is C^ alkyl, C^ cycloalkyl, C_M fluoroalkyl and wherein n is 0-3; or a pharmaceutically acceptable sait thereof.
2. The compound ofclaim 1, wherein R¹ is optionally substituted pyrazinyl.
3. The compound of claim 1, wherein R¹ is optionally substituted pyrimidyl.
4. The compound ofanyone ofdaims 1 -3, wherein R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted piperazinyL
5. The compound of anyone of daims 1 -3, wherein R and R combine with the nitrogen to which they are attached to form optionally substituted piperidinyl.
6. The compound of anyone of daims 1 -3, wherein R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted morpholinyl.
7. The compound of anyone of claims 1 -3, wherein R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted pyrrolidinyl.
8. The compound of anyone of claims 1-3, wherein R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted pyrrolo.
9. The compound of anyone of claims 1 -3, wherein R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted imidazo.
10. The compound of anyone of claims 1-3, wherein R²³ and R~^b combine with the nitrogen to which they are attached to form optionally substituted 6 to 10 membered spiro(heterocyclyl).
11. The compound of anyone of claims 1-3, wherein R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted homomorpholinyl
12. The compound of anyone of claims 1 -3, wherein R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted homopiperidinyl
13. The compound of anyone of claims 1 -3, wherein R²³ and R^2b combine with the nitrogen to which they are attached to form optionally substituted homopiperazinyl
14. The compound of anyone of claims 1 -3, wherein R²³ and R^b combine with the nitrogen to which they are attached to form optionally substituted azetidinyl.
15. The compound of anyone of claims 1-14, wherein R³ is chlorine, methyl or trifluorormethyl.
16. The compound of anyone of claims 1-15, wherein n is 0.
17. The compound of anyone of claims 1-15, wherein n is 1.
18. The compound of anyone of claims 1-15, wherein n is 2.
19. The compound of anyone of claims 1-18, wherein R⁴ is fluorine, chlorine, C1.3alkyl, fluoroalkyl, cyano, C].3 alkoxy or Cm fluoroalkoxy.
20. A compound selected from the group consisting of:

2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-benzamide 2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-pyridin-4-yl-ethyl)-benzamide

2.3- Dichloro-N-(2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-benzamide

2,3 - Di chloro-N-(2-morpholin-4-yl-2 -pyrid in-4-yl-ethyl)-benzam ide

2.3- Dimethyl-N-(2-morpholin-4-yl-2-pyridin-3-yl-ethyl)-benzamide

2.3- Dimethyl-N-(2-morpholin-4-yl-2-pyridin-4-yl-ethyl)-benzamide

2.3- Dichloro-N-[2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-benzamide

2.3- Dichloro-N-[2-(4-methoxy-phenyl)-2-piperidin-l-yl-ethyl]-benzamide

2.3- Dichloro-N-[2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethyl]-benzamide N.[2-(4-Fluoro-phenyl)-2-morpholin-4-yl-ethyl]-2,3-dimethyl-benzamide N-[2-(4-Methoxy-phenyl)-2-piperidin-l-yl-ethyl]-2,3-dimethyl-benzamide N-[2-(4-Methoxy-phenyl)-2-morpholin-4-yl-ethyl]-2,3-dimethyI-benzamide 2-Chloro-N-[2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethyl]-5-methyl-benzamide 2-Chloro-N-[2-(4-methoxy-phenyl)-2-piperidin-l-yl-ethyl]-5-methyl-benzamide 2-Chloro-N-[2-(4-methoxy-phenyl)-2-morpholin-4-yl-ethyl]-5-methyl-benzamide N-[2-(4-Fluoro-phenyl)-2-morpholin-4-yl-ethyl]-2-methyl-benzamide N-[2-(4-Methoxy-phenyl)-2-piperidin-l-yl-ethyl]-2-methyl-benzamide N-[2-(4-Methoxy-phenyl)-2-morpholin-4-yl-ethyl]-2-methyl-benzamide

100

2-Chloro-5-methyl-N-(2-morpholin-4-yl-2-p-tolyl-ethyl)-benzamide N-[2-(4-Chloro-phenyl)-2-(4,4-difluoro-piperidin-l-yl)-ethyl]-2-methyl-benzamide N-[2-(4-Chloro-phenyl)-2-(4,4-difluoro-piperidin-l-yl)-ethyl]-2,3-dimethyl-benzamide

2.3- Dichloro-N-[2-(4-chloro-phenyl)-2-(4,4-difluoro-piperidin-l-yl)-ethyl]-benzamide

2.3- Dichloro-N-[(S)-2-(4-chloro-phenyl)-2-morpholin-4-yl-ethyl]-benzamide

2.3- Dichloro-N-[2-(6-cyclopropyl-pyridin-3-yl)-2-morphoIin-4-yl-ethyl]-benzamîde N-[(S)-2-(4-Chloro-phenyl)-2-morpholin-4-yl-ethyl]-2-methyl-benzamide

2.3- dichloro-N-[2-moipholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide 2-Chloro-N-[(S)-2-(4-chloro-phenyl)-2-morpholin-4-yl-ethyI]-3-methyl-benzamide

2.3- dichloro-N-[2-(6-chloro-3-pyridyl)-2-morpholino-ethyl]benzamide

2.3- dichloro-N-(2-morphoIino-2-pyrimidin-5-yl-ethyl)benzamide

2.3- dichloro-N-[2-(2-methylpyrimidin-5-yl)-2-morphoIino-ethyl]benzamide

2.3- dichloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

2.3- Dichloro-N-[2-(4,4-difluoro-piperidin-l-yl)-2-(4-fluoro-phenyl)-ethyl]-benzamide (-)2-chloro-N-[2-morpholino-2-[6-(trifluoromcthyl)-3-pyridyl]ethyl]-3(trifluoromethyl)benzamide (+)2-chloro-N-[2-morphoIino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]-3(trifluoromethyl)benzamide (-)2,3-dichloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide (+)2,3-dichloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide (-)2-chloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3(trifluoromethyl)benzamide (+)2-chloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3(trifluoromethyl)benzamide (-)2,3-dichloro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide (+)2,3-dichloro-N-[2-morpholino-2-[6-(trifluorornethyl)-3-pyridyl]ethyl]benzamide

2.3- dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(4-methoxyphenyl)ethyl]benzamide

2.3- dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(6-fluoro-3-pyridyl)ethyl]benzamide 2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(6-fluoro-3-pyridyl)ethyl]benzamide

2.3- dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[6-(trifluoromethyl)-3pyridyl]ethyl]benzamide 2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[6-(trifluoromethyl)-3pyridyl]ethyl]benzamide (-)2-chloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide (+)2-chloro-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide (-)2-fluoro-N-[2-morpholino-2-[2-(trifluorornethyl)pyrimidin-5-yl]ethyl]benzamide (+)2,3-dichloro-N-[2-(6-methyl-3-pyridyl)-2-morpholino-ethyl]benzamide

2.3- Dichloro-N-[2-(4-chloro-phenyl)-2-[I_>4]oxazepan-4-yl-ethyl]-benzamide (-)2-chIoro-3-methoxy-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3yl)ethyl)benzamide (+)2-chloro-3-methoxy-N-[2-morpholino-2-[6-(trifluoromethyl)-3pyridyl] ethyl]benzamide (-)2-chloro-6-fluoro-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3- yl ) ethyl )b enzamide (+)2-chloro-6-fluoro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide (-)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2-morpholino-ethyl]benzamide (+)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2-morpholino-ethyl]benzamide (-)2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)-2-morpholino-ethyl]benzamide (+)2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)-2-morpholino-ethyl]benzamide (-)2,6-difluoro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide (+)2,6-difluoro-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide

101 (-)2-chloro-5-methylsulfonyl-N-[2-morpholino-2-[6-(trifluoromethyl)-3pyridyl]ethyl]benzamîde (+)2-chloro-5-methylsulfonyl-N-[2-morpholino-2-[6-(trifluoromethyl)-3pyridyl]ethyl]benzamide (+)2-chloro-N-[2-(4-chlorophenyl)-2-morpholino-ethyl]-5-methylsulfonyl-benzamide (-)2-chloro-N-[2-(4-chlorophenyl)-2-morpholino-ethyl]-5-methylsulfonyl-benzamide

2.3- Dichloro-N-[2-(4-chloro-phenyl)-2-pyrrolidin-l-yl-ethyl]-benzamide (-)2-methoxy-N-[2-morpholino-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide (+)-2-methoxy-N-(2-morpholino-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide (+)2-chloro-N-[2-(4-chlorophenyl)-2-morpholino-ethyl]-5-cyano-benzamide (-)2-chloro -N-[2-(4-chlorophenyl)-2 -morpholi no-ethyl ]-5 - cyano -b enzami de

2.3- dichloro-N-[2-(4₎4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide 2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide

2.3- dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide (-)2-chloro-N-[2-(4-chlorophenyl)-2-morpholino-ethyl]-5-isopropylsulfonyl-benzamide 2-Chloro-3-fluoro-N-[2-(2-methyl-pyrimidin-5-yl)-2-morpholin-4-yl-ethyl]-benzamide

2.6- dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide 2-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]-3fluoro-benzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]-3fluoro-benzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]-6fluoro-benzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[6-(trifluoromethyI)-3-pyridyl]ethyl]-6fluoro-benzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(6-methyl-3-pyridyl)ethyl]-3-fluorobenzamide (-)2-chloro-N-[2-(4,4-difluoro-l“piperidyl)-2-(6-methyl-3-pyridyl)ethyl]-3-fluorobenzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(6-methyl-3-pyridyl)ethyl]-6-fluorobenzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(6-methyl-3-pyridyl)ethyl]-6-fluorobenzamide

2.6- difluoro-N-(2-(2-methylpyrimidin-5-yl)-2-morpholinoethyl)benzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-3-fluorobenzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-3-fluorobenzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-6-fluorobenzamide (’)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-6-fluorobenzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]6-fluoro-benzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifiuoromethyl)pyrimidin-5-yl]ethyl]-6fl uoro -b enzami de

102 (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]3 - fluoro -b enzami de (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-(trifluoromethyI)pyrimidin-5-yl]ethyl]-3fluorobenzamide

2.3- dichloro-N-[2-(4_J4-dimethyl-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5- yl ] ethyl] benzami de

2-chloro-N-[2-(4,4-dimethyl-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3fluoro-benzamide

2.3- dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethyl)benzamide

2,6-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethyl)benzamide 2-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethyl)benzamide 2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethyl)benzamide 2-chloro-3-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(l,4-oxazepan-4-yl)ethyl)benzamide (-)2-chloro-3-methoxy-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimidin-5- yl] ethyl ] b enzami de (+)2-chloro-3-methoxy-N-[2-morpholino-2-[2-(trifluoromethyl)pyrimîdin-5yl]ethyi]benzamide (-)3-methoxy-2-methyl-N-[2-morpholino-2-[6-(trifluoromethyl)-3pyridyl]ethyl]benzamide (+)3-methoxy-2-methyl-N-[2-morpholino~2-[6-(trifluoromethyl)-3pyrid yl ] ethyl] benz amide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(4-fluorophenyl)ethyl]-3-methoxybenzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(4-fluorophenyl)ethyl]-3-methoxybenzamide

2.3- dichloro-N-(2-(2-methylpyrimidin-5-yI)-2-(3-methylpyrrolidin-l-yl)ethyl)benzamide

2.3- dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(3,3,4,4-tetrafluoiOpyiTolidin-lyl )ethyl)b enzamide (-)2-chloro-N-[2-(4-chloiOphenyl)-2-rnorpholino-ethyl]-3-methoxy-benzamide (+)2-chloro-N - [2-(4-chl orophenyl )-2-morphol ino-ethyl ]-3-m ethoxy-b enzami de (+)2-chloro-N-[2-(3,3-difluoro-l-pipcridyl)-2-(2-metliyIpyrimidin-5-yl)ethyl]-6-fluorobenzamide (-)2-chloro-N-[2-(3,3-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-6-fluorobenzamide (+)2-chloro-N-[2-(3,3-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-3-fluorobenzamide (-)2-chloro-N-[2-(3,3-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-3-fluorob enzamide (+)2,3-dichloro-N-[2-(3,3-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5yl)ethyl]benzamide (+)2-chloro-N-[2-(3,3-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide (-)2-chloro-N-[2-(3,3-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide (+)2-chloro-N-[2-(4-fluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrirnidin-5yl ] ethyl ]benzamide (-)2-chloro-N-[2-(4-fluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide (+)2,6-dichloro-N-[2-(4-fluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide (-)2,6-dichloro-N-[2-(4-fluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl] ethyl ]benzamide (+)2,3-dichloro-N-[2-(4-fluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide

103 (-)2,3-dichloro-N-[2-(4-fluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl] ethyl] b enzamide (+)2,6-dichloro-N-[2-(4-fluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide (-)2,6-dichloro-N-[2-(4-fluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide (+)2,3-dichloro-N-[2-(4-fluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide (-)2,3-dichloro-N-[2-(4-fluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide (+)2-chloro-N-[2-(4-fluoro-l-piperidyl)-2-(2-methylpyrirmdin-5-yl)ethyl]benzamide (-)2-chloro-N-[2-(4-fluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide

2,4-dichloro-N-(2-morpholino-2-(2-(trifluorornethyl)pyrimidm-5-yl)ethyl)benzamide (-)2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(l-methylpyrazol-4-yl)ethyl]benzamide (+)2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(l-methylpyrazoI-4-yl)ethyl]benzamide (-)2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(l-methylpyrazol-4-yl)ethyl]-5-fluorobenzamide (+)2,3-dichloro-N-[2-(4,4-difluoro-1 -piperidyl)-2-(l -methylpyrazol-4-yl)ethyl]-5-fluorobenzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(l-methylpyrazol-4-yl)ethyl]benzamide (+)2-chloro-N-[2-(4,4-difIuoro-l -piperidyI)-2-( 1 -methylpyrazol-4-yl)ethyl]benzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-3methoxy-benzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]3 -methoxy-benzam i de (-)2,6-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide (+)2,6-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl] ethyl ] b enzam ide (-)2,6-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]-3-fluoro-benzamide (+)2,6-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl] ethyl] -3 -fluoro-benzamide (-)2-chloro-N-[2-(2-methylpyrimîdin-5-yl)-2-(l-piperidyl)ethyl]benzamide (+)2-chIoro-N-[2-(2-methylpyrimîdin-5-yl)-2-(l-piperidyl)ethyl]benzamide (-)2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)-2-(l-piperidyl)ethyl]benzamide (+)2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)-2-(l-piperidyl)ethyl]benzamide (-)2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyï)pyrimidin-5yl]ethyl]-5-fluoro-benzamide (+)2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]-5-fluoro-benzamide (-)2,6-dichloro-N-[2-(4,4-difluoro-1 -piperidyl)-2-( 1 -methylpyrazol-4-yl)ethyl]benzamide (+)2,6-dichloro-N-[2-(4,4-difluoro- 1 -piperidyl)-2-(l -methylpyrazol-4-yl)ethyl]benzamide (-)2-chloro-N-[2-[2-(difluoromethyl)pyrimidin-5-yl]-2-morpholino-ethyl]benzamide (+)2-chloro-N-[2-[2-(difluoromethyl)pyrimidin-5-yl]-2-morpholino-ethyl]benzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-3-methoxybenzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-3methoxy-benzamide (-)2,6-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidm-5-yl)ethyl]-3fluoro-benzamide (+)2,6-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethy1]-3fluoro-benzamide (-)2,6-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5yl)ethyl]benzamide

104 (+)2,6-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5yi)ethyl]benzamide (-)2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-5fluoro-benzamide (+)2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-5fl uoro -b enzami de (-)2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5yl)ethyl]benzamide (+)2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5yl)ethyl]benzamide (-)2,3-dichloro-N-[2-[2-(difluoromethyl)pyrimidin-5-yl]-2-morpholino-ethyl]benzamide (+)2,3-dichloro-N-[2-[2-(difluoromethyI)pyrimidin-5-yl]-2-morpholino-ethyl]benzamide (-)2-chloro-N-[2-[2-(difluoromethyl)pyrimidin-5-yl]-2-morpholino-ethyl]-3-fluorobenzamide (+)2-chloro-N-[2-[2-(difluoromethyl)pyrimidîn-5-yl]-2-morpholino-ethyl]-3-fluorobenzamide (-)2-chloro-N-[2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide (+)2-chloro-N-[2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide (-)2,6-dichloro-N-[2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide (+)2,6-dichloro-N-[2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide (-)2-chloro-N-[2-(4,4“difluoro~l-piperidyl)-2-(2-ethylpyrimidin-5-yl)ethyl]benzaniide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-ethylpyrimidin-5-yl)ethyl]benzamide (-)2,6-dichIoro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-ethylpyrimidin-5-yl)ethyl]benzamide (+)2,6-dichloro-N-[2-(4_J4-difluoro-l-piperidyl)-2-(2-ethylpyrimidin-5yl)ethyl]benzamide (-)2-chloro-3-(difluoromethoxy)-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5yl)ethyl]benzamide (+)2-chloro-3-(difluoromethoxy)-N-[2-(4,4-difluorO’l-piperidyl)-2-(2-methylpyrimidin5-yl)ethyl]benzamide (-)2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)'2-(2-ethylpyrimidin-5-yl)ethyl]benzamide (+)2,3-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-ethylpyrimidin-5yl)ethyl]benzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-ethylpyrimîdin-5-yl)ethyl]-6-fluorobenzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-ethylpyrimidin-5-yl)ethyl]-6-fluorobenzamide (-)2,3-dichloro-N-[2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide (+)2,3-dichloro-N-[2-(2-cyclopropyIpyrimidin-5-yl)-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide (-)2-chloro-N-[2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-l-piperidyl)ethyl]-6fluoro-benzamide (+)2-chloro-N-[2-(2-cyclopropylpyrimidin-5-yl)-2-(4,4-difluoro-l-piperidyl)ethyl]-6fluoro-benzamide

2,4-dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-methylpyrimidin-5yl) ethyl)b enzamide

2,3-dichloro-N-(2-(3-methylpiperidin-I-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

105 (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-

4,6-difluoro-benzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-

4,6-difluoro-benzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-6fluoro-3-methoxy-benzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]6-fluoro-3-methoxy-benzamide

2.3- dichloro-N-(2-(2-isopropylpiperidin-l-yl)-2-(2-methylpyrimidin-5- yl) ethyl)benzami de

2.3- dichloro-N-(2-(4,4-difluoropiperidin-l-yl)-2-(2-(dimethylamino)pyrimidin-5- yl ) ethyl)benzami de

N-(2-(2-azabicyclo[2.2.l]heptan-2-yl)-2-(2-methylpyrimidin-5-yl)ethyl)-2,3dichlorobenzamide

2.3- dichloro-N-(2-(2-methylpiperidin-l-yl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide (-)2,4-dichIoro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide (+)2,4-dichIoro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide (-)2,4-dÎchIoro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl] ethyl]-6-fluoro-benzamide (+)2,4-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl] ethyl] -6-fluoro-benzamide (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-4methoxy-benzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-

4-methoxy-benzamide (-)2-chloro-N-[2-(4_J4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-

3.4- dimethoxy-benzamide (+)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]-

3.4- dimethoxy-b enzamide

2.3- dichloro-N-[2-(4-methoxy-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide (-)2,6-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5yl]ethyl]-4-fluoro-benzamide (+)2,6-dichloro-N-[2-(4,4-difluoro-l-piperidyl)-2-[2-(trifluoromethyl)pyrimidin-5y l] ethyl]-4-fl uoro-b enzami de (-)2-chloro-N-[2-(4,4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-3(trifluorometho xy)b enzami de (+)2-chloro-N-[2-(4₎4-difluoro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]-3(tri fl uoromethoxy)b enzamide

2.3- dichloro-N-[2-(2-methyIpyrimidin-5-yl)-2-(4-oxo-l-piperidyl)ethyl]benzamide

2.4- dichloro-N-[2-(2-methylpyrimidin-5-yI)-2-(4-oxo-l-piperidyl)ethyl]benzamide

2.3- dichloro-N-[2-(4-chloro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide

2.4- dichloro-N-[2-(4-chloro-l-piperidyl)-2-(2-methylpyrimidin-5-yl)ethyl]benzamide

2-chloro-3-fluoro-N-(2-morpholino-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide (+)2-chloro-N-[2-[6-(difluoromethyl)-3-pyridyl]-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide (-)2-chloro-N-[2-[6-(difluoromethyl)-3-pyridyl]-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide (+)2,3-dichloro-N-[2-[6-(difluoromethyl)-3-pyridyl]-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide

106 (-)2,3-dichloro-N-[2-[6-(difluoromethyl)-3-pyridyl]-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide (+)2,6-dichloro-N-[2-[6-(difluoromethyl)-3-pyridyl]-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide

5 (-)2,6-dichloro-N-[2-[6-(difluoromethyl)-3-pyridyl]-2-(4,4-difluoro-lpiperidyl)ethyl]benzamide (+)2-chloro-N-[2-[6-(difluoromethyl)-3-pyridyl]-2-(4,4-difluoro-l-piperidyl)ethyl]-3methoxy-benzamide (-)2-chloro-N-[2-[6-(difluoromethyl)-3-pyridyl]-2-(4,4-difluoro-l-piperidyl)ethyl]-310 methoxy-benzamide

2,3-Dichloro-N-[2-(4-chloro-phenyl)-2-morpholin-4-yl-ethyl]-benzamide.
21. A pharmaceutical composition comprising a compound of anyone of daims 1-20.