OA17264A - Benzamides. - Google Patents

Abstract

The present application relates to compounds of formula (I), wherein R1 to R5 are as defined in claim 1, a pharmaceutical composition thereof and said compounds for use in the treatment of diseases related with the activity of P2X7 receptor.

Description

FIELD OF THE INVENTION

The présent invention is directed to novel compounds which inliibit 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 is a ligand-gated ion channel which is activated by extracellular ATP and is présent on a variety of cell types, including microglia in the central nervous system and other cells involved in inflammation and immune system fonction. The P2X? 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 ILl β) from these cells (Ferrari, et al. Neurophannacol, 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, astlima, clironic 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 P2X₇ receptor antagonîsts 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, indicating a potential therapeutic intervention for said antagonîsts in nervous system injury or degeneration (Sperlagli, et al., Progress in Neurobiology, 7, 327-346, 2006). Vianna, et al. (Epîlepsia, 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 useful 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 présent invention fulfills this need, and provides further related advantages.

SUMMARY QF THE INVENTION

An objective of the présent invention is to provide compounds that inhibit P2X7 receptors.

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

O R⁴

JCk

I — (^RS)„

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, Ci^hydroxyalkyl, Cm fluoroalkyl, Cm cycloalkyl, Cm alkoxy, Cm fluoroalkoxy, cyano or -SOjR⁸;

wherein R² is Cm cycloalkyl, C₃^ cy cl ohet alkyl, Cm fluoroalkyl, Cm fluoroalkoxy, Cm alkoxy, Cm alkenyl, Cm alkynyl, 6 membered heteroaryl, phenyl or Cm alkyl optionally substituted with one or more R⁹;

wherein R³ is hydrogen, fluorine, Cm alkyl or Cm fluoroalkyl; or wherein R and R combine with the carbon to which they are attached to form cyclohexyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, homomorpholinyl, homopiperidinyl or homopiperazinyl each of which îs optionally substituted

7 with one or more Cm alkyl, Cm alkenyl, C₃^-cycloalkyl, Cm alkoxy, oxo, -NR R or fluorine;

wherein R⁴ is halogen, Cm fluoroalkyl, cyano, cyclopropyl, CMalkyloxy, CMfluoroalkyloxy, SO2R⁸, -NR⁶R⁷ or CMalkyl;

wherein R⁵ is halogen, Cm alkyl, Cm fluoroalkyl, cyano, -SO2R⁸, -NR⁶R⁷, Cm alkoxy, Ci. jfluoroalkoxy or CM-cycloalkyl;

wherein R⁶ and R⁷ independently of each other are hydrogen or Cm alkyl;

wherein R⁸ is Cm alkyl, Cm cycloalkyl or Cm fluoroalkyl;

wherein R⁹ is Cm alkyl, C3^cycloalkyl, -NR^l0R^u, Cm fluoroalkyl or 3 to 7 membered heterocyclyl which is optionally substituted with one or more Cm alkyl, halogen, hydroxy, Cm fluoroalkyl, C3^ cycloalkyl, Cm alkoxy, C m fluoroalkoxy or cyano;

wherein R¹⁰ and R*¹ independently of each other are hydrogen or Cm alkyl; or wherein R¹⁰ and R¹¹ combine with the nitrogen to which they are attached to form piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, homomorpholinyl, homopiperidinyl or homopiperazinyl each of which is optionally substituted with one or more Cm alkyl, Cmalkoxy, oxo or fluorine; 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 1 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 présent 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 présent 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 présent 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 présent 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 présent 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 Alzhcimcr's disease, which involves administering a compound of Formula I.

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

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

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

DETAILED DESCRIPTION OF THE INVENTION

As previously indicated, the présent invention is based on the discovery of the compounds of Formula I, which are inhibitors of the Ρ2Χγ 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 intendcd to be a detailed catalog of ail the different ways in which the invention may be implemented, or ail tire features tirât may be added to the instant invention. Hence, the following spécification is întended to illustrate some embodiments of the invention, and not to exhaustîvely specify ail permutations, combinations and variations thereof.

In one embodiment, R^l is optionally substituted phenyl.

In one embodiment, R¹ is optionally substituted pyridyl.

In another embodiment, R¹ is optionally substituted pyrazinyl.

In one embodiment, R¹ is optionally substituted pyrimidyl.

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

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

Λ 1

In yet embodiment, R and R combine with tire nitrogen to which they are attached to form optionally substituted piperidinyl.

In one embodiment, R² and R³ combine with the nitrogen to which they are attached to form optionally substîtuted morpholinyl.

In one embodiment, R² and R³ combine with the nitrogen to which they are attached to form optionally substîtuted pyrrolidinyl.

In one embodiment, R and R combine with the nitrogen to which they are attached to form optionally substîtuted pyrrolo.

In one embodiment, R² and R³ combine with the nitrogen to which they are attached to form optionally substîtuted imidazo.

1

In one embodiment, R and R combine with the nitrogen to which they are attached to form optionally substîtuted homomoipholinyl

In one embodiment, R² and R³ combine with the nitrogen to which they are attached to form optionally substîtuted homopiperidinyl

In one embodiment, R² and R³ combine with the nitrogen to which they are attached to form optionally substîtuted homopiperazinyl

In one embodiment, R² and R³ combine with the nitrogen to which they are attached to form optionally substîtuted azetidinyl.

In one embodiment, R⁴ is chlorine, methyl or trifluorormethyl.

In one embodiment, n is 0.

In one embodiment, n is 1.

In one embodiment, n is 2.

As used herein, the term “Ci-Cg alkyl” refers to a straight chained or branched saturated hydrocarbon having from one to six carbon atoms inclusive. Examples of such substituents inciude, 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 C)-C₃ alkyl” refers to a saturated hydrocarbon having from one to three carbon atoms inclusive. Examples of such substituents inciude, but are not limited to, methyl, ethyl and n-propyl.

Likewise, the terni “Cj-Ce 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 inciude, 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 substîtuted with one or more fluorine atoms. Examples of such substituents inciude, but are not limited to, trifluoromethyl, pentafluoroethyl,

1-fluoroethyl, monofluoromethyl, difluoromethyl and 1,2-difluoroethyl.

Likewise, the term “Ci/, hydroxyalkyl” refers to a straight chained or branched saturated hydrocarbon group substituted with one hydroxyl group. Examples of such substituents include, but are not limited to, hydroxymethyl, l -hydroxy- l-methyl-ethyl and l-hydroxyethyl.

Likewise, the term “Ci/ alkenyl” refers to a straight chained or branched hydrocarbon containing 1-6 carbon atoms and having one or more double bonds. Examples of such substituents include, but are not limited to, allyl, butenyl and 2-hexenyl.

Likewise, the term “Cj/ alkynyl” refers to a straight chained or branched hydrocarbon containing 1-6 carbon atoms and having one or more triple bonds. Examples of such substituents include, but are not limited to, ethynyl, propargyl and 3-hexynyl.

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 aromatîc 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 membered heteroaryl” refers to a fully unsaturated aromatîc monocyclic ring system having 1-3 heteroatoms. Examples of such Systems include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl . Likewise the term “3 to 7 membered heterocycle” refers to fully saturated monocyclic ring system having 1-3 heteroatoms. Examples of such Systems include, but are not limited to, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, homomorpholinyl, homopiperidînyl and homopiperazinyl

The term “haiogen” 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 tire présent 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 biological 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, stabîlized (i.e., not worsenîng) 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

Tire présent invention also comprises salts of the présent compounds, typicaliy, 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 suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Représentative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartane, 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 pharmaceuticaily acceptable inorganic or organic acid addition salts include the pliannaceutically 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 pharmaceuticaily 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 suîtable 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 présent 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 présent invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceuticaily acceptable carrier. The présent invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the spécifie compounds disclosed in the Experimental Section and a pharmaceuticaily acceptable carrier.

Tlie compounds of tlie 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 in Remington: Tlie Science and Practice of Pharmacy, I9^ül Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specîfically formulated for administration by an oral route. Pharmaceutical compositions for oral administration include solid dosage foims 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 P2X₂ receptor activity”. “Inhibiting Ρ2Χγ receptor activity” or “inhibiting Ρ2Χγ activity” as used herein means, e.g. reducing or even eliminating the ability of a Ρ2Χγ receptor to exhibit a cellular response, such as inhibiting the response to stimuli or agonist ligands, or inhibiting the production or accumulation of IL I β.

Tlie présent 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 présent 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 présent 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 présent 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, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, 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 Iimited 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 ncurons, 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 Maniial of Mental Disorders (4th ed., text rev.) doi:l0.l !76/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 dimïnishment 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 Iimited to, dépressive disorders, anxiety disorders, bipolar disorders, dysthymia and schizoaffective disorders. Anxiety disorders include, but are not Iimited to, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder (PTSD). Dépressive disorders include, but are not Iimited to, major dépressive disorder (MDD), catatonie dépression, melancholîc dépression, atypical dépression, psychotic dépréssion, postpartum dépression, treatment-resistant dépression, bipolar dépression, including bipolar I and bipolar II, and mild, moderate or severe dépréssion. Personality disorders include, but are not Iimited to, paranoïa, antisocial and borderline personality disorders.

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

The présent 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 présent 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 présent invention also provides a method of inhibiting production or accumulation of ILlp, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of Formula L

In an embodiment, the présent invention provides the use of a compound of Formula I for the manufacture of a médicament for the treatment of affective disorders. The présent invention also provides the use of a compound of Formula l for the manufacture of a médicament for the inhibition of P2X₇ activity. The présent 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 présent invention provides at least one compound of Formula I for use in treating an affective disorder in a subject. In an embodiment, the présent invention provides at least one compound of Formula I for use in inhibiting P2X₇ activity in a subject. In an embodiment, the présent invention provides at least one compound of Formula I for use in inhibiting production or accumulation of ILl 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 R, R , R , R , R , R , R ,

R⁸, R⁹, R¹⁰, R¹¹ 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 readiiy apparent to tire 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 tire art, and may be found in T. Green, et al., Protective Groups in Organic Synthesis, 1991,2¹*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 Coip.) mass spectrometer (ail from Waters Corp., Milford, MA, USA), an Agilent 1100 LC pump (Agilent Technologies, Inc., Santa Clara, CA), and Agilent 1100 autosampler, with a 200 μΐ/min split to the ES! source with inline Agilent 1100 diode array detector (DAB) and variable wavelength detector (VWD) at 254 nm, and an 800 uL/min 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: 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 pump (Agilent Technologies, Inc., Santa Clara, CA), and Agilent 1100 autosampler, with a 200 μΐ/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 uL/min split to a Waters evaporative light scattering detector (ELSD). Séparation was performed on a Inertsil C8 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 30% B to 90% B. Then stepped to 100% B at 1.85 minutes and maintained at 100% B until 1.99 minutes.

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 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/minutes.

Method D: A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH Cl 8 1.7pm; 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/minutes.

Method E: 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/minutes.

Method F: 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 mUminutes.

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/minutes.

Préparative LC-MS-purification was performed on a PE Sciex API 150EX instrument with atmospheric pressure chemical ionizatîon. 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 mUminute. 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 CO₂/ EtOH(0.2%NH₃H₂O) =45/55.

’H NMR spectra were recorded at 300,400,500 or 600 MHz on Broker Avance instruments. TMS was used as internai reference standard. Chemical sliift values are expressed in ppm. The following abbreviations are used for multiplicity of NMR signais: s = singlet, d = doublet, t - triplet, q = quartet, qui = quîntet, h = heptet, dd = double doublet, dt = double triplet, 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

-Bromomethyl-1 -trifluoromethyl-cyclopropane

G·» cf₃

Step 1: To a solution of compound 1-trifluoromethyl-cyclopropanecarboxylic acid (2 g, 13 mmol) in dry THF (80 mL) was added LAH (592 mg, 16 mmol) in portions at 0°C and the resulting mixture was heated at 40°C ovemight. H₂O (592 mg, 16 mmol) was added to quench the reaction at 0°C and followed by 2N NaOH (0.6 mL). After filtration, the filtrate was distilled to remove the most solvent to give crude (l-trifluoromethyl-cyclopropyl)-methanol (1.2 g crude), which was used in the next step without further purification.

MsCI, Et₃N, DMF

NaBr

To a solution of (l-trifluoromethyl-cyclopropyl)-methanol (1.2 g, 8.57 mmol) and Et₃N (1.04 g, 10.28 mmol) in dry DMF (10 mL) at -10°C was added methanesulfonyl chloride (981 mg, 8.57 mmol) over 20 minutes, while retaining the inner température at 0°C. After the addition was complété, the resulting solution was stirred at 0°C for 30 minutes, the resulting mixture was filtered and washed with DMF (3 mL). To the combined filtrâtes was added sodium bromide (3.7 g, 36 mmol) and the resulting mixture was stirred at room température ovemight. The mixture was cooled in ice, followed by addition of pentane (20 mL) and water (15 mL) while retaining the mixture at 0°C, prior to liquid séparation. The organic phase was dried over NaiSOq and fîltered. The filtrate was distilled to remove the most of pentane to give lbromomethyl-l-trifluoromethyl-cyclopropane (0.9 g crude), which was used without further purification.

I -Bromomethyl-l -difluoromethyl-cyclopropane

K₂CO₃ (n-Bu)₄NBr DMF

Step 1: A suspension of cyano-acetic acid ethyl ester (11.3 g, 0.1 mol), 1,2-Dibromo-ethane, NH4(n-Bu)4Br and K2CO3 in DMF (100 mL) was heated to 80^ûC ovemight. The mixture was poured into water (600 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SÛ4, concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether: EtOAc = 10:1-5:1) to give 1-cyano-cyclopropanecarboxylic acid ethyl ester (10 g, yield: 72%). 'H NMR (CDCI3 400MHz): <54.21 (q, J = 7.2 Hz, 2H), 1.65-1.61 (m, 2H), 1.58-1.55 (m, 2H), 1.28 (t, J =1.2 Hz, 3H).

Step 2: To concentrated sulfuric acid (102 mL) was added 1-cyano-cyclopropanecarboxylic acid ethyl ester (60 g, 0.43 mol) dropwise followed by 2-methylpentan-2,4-diol (52 g, 0.44 mmol) dropwise at 0 °C. The mixture was stirred for an additional 1 h at 0 °C then poured onto icewater. The aqueous phase was washed with AcOEt (3* 200 mL) and then basified to pH 12 with 10 M NaOH. The resulting mixture was extracted with EtOAc (3x 500 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel to give l-(4,4,6-trimethyl-5,6-dihydro-4H[l,3]oxazîn-2-yl)-cyclopropanecarboxylic acid ethyl ester (65 g, yield: 63.2%). *H NMR (CDCI3 400MHz): M21-4.06 (m,3H), 1.73-1.69 (m, IH), 1.40-1.10 (m, 17H).

NaBH₄,THF,EtOH

-

Step 3: NaBI-L» (3.18 g, 13.3 mmol) was dissolved in H₂O (10 mL) and a drop of 10 M NaOH was added. To a solution of l-(4,4,6-trimethyl-5,6-dihydro-4H-[l,3]oxazin-2-yl)cyclopropanecarboxylic acid ethyl ester (10 g, 0.04 mol) in THF (33 mL) and éthanol (33 mL) was added the above alkaline solution of NaBHq dropwise at -40°C followed by 12M HCl (about 0.1 mL, the pH of the reaction mixture was adjusted to 6 ~ 8). The resulting mixture was stirred at -40°C for 1.5 hour. The reaction mixture was poured into water (100 mL) and basified with 10M NaOH to pH =10. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic ex tracts were washed with brine, dried over NajSOq and concentrated to give crude 1(4,4,6-trimethyl-[l,3]oxazinan-2-yl)-cycIopropanecarboxylic acid ethyl ester (9.0 g), which was used in the next step without purification.

(COOH)₂

Step 4: Oxalic acid (11.2 g, 0.124 mol) was dissolved in water (40 mL) and I-(4,4,6-trimethyl[l,3]oxazinan-2-yI)-cyclopropanecarboxylic acid ethyl ester (15 g, 0.062 mol) was added. Steam distillation of this mixture was carried out until 500 mL of distillate had been collected. The distillate was saturated with NaCl and extracted with EtOAc (2 x 100 mL). The organic extracts were dried over Na^SOq and concentrated under reduced pressure to give 1-formylcyclopropanecarboxylic acid ethyl ester (4.5 g, 51%), ^lH NMR (CDCI3 400MHz): *510.39 (s, IH), 4.26(q, J =7.2 Hz, 2H), 1.67-1.64 (m, 2H), 1.61-1.58 (m, 2H), 1.31 (t,J=7.2 Hz, 3H).

DAST

-----► ch_zci₂

Step 5: To a solution of 1-formyl-cyclopropanecarboxylic acid ethyl ester (4.0 g, 28.1 mmol) in

DCM (40 mL) was added DAST (18.6 mL, 0.14 mol) at 0°C dropwise and the resulting mixture was stirred at room température ovemight. NaHCO₃ solution (lOmL) was added to quench the reaction and extracted with DCM (100 x 3 mL). The organic extracts were dried over Na₂SO4 and concentrated under reduced pressure to give 1 -difluoromethyl-cyclopropanecarboxylic acid ethyl ester (3 g, 65%). ^lH NMR (CDCI3 400MHz): J6.42 (t, J= 57.2 Hz, IH), 4.18(q, J = 7.2

Hz, 2H), 1.28-1.21 (m, 7H).

l-Bromomethyl-l-difluoromethyl-cyclopropane was prepared as described above for the synthesis of l-Bromomethyl-l-trifluoromethyl-cyclopropane starting from l-difluoromethyicyclopropanecarboxylîc acid ethyl ester

3-Acetyl-3-chlorodihydrofuran-2(3H)-one:

SO2CI2 (68 g, 0.504 mol) was added to 3-acetyldihydrofuran-2(3H)-one (64 g, 0.499 mol) dropwise at room température under stirring for a period of l~l.5h. Then the mixture was stirred at room température for 2h. The resulting mixture was diluted with water, stirred for 30 minutes, the organic layer was separated and dried over MgSOj, filtered and distilled with oil pump at 80 °C to give 3-acetyl-3-chlorodihydrofuran-2(3H)-one as colorless oil (54 g, 66.8 % yield). ^lH NMR (CDCh 400 MHz): Ô4.45-4.36 (m, 2H), 3.19-3.15 (m, IH), 2.54 (s, 3H), 2.53-2.44 (m, IH).

3-Acetyl-3-fluorodihydrofuran-2(3H)-one:

Et₃N-3HF

Et₃N. CH₃CN

Et3N-3HF (112.2 g, 0.66 mol) and EtsN (66.7 g, 0.66 mol) was added to solution of 3-acetyl-3chlorodihydrofuran-2(3H)-one (54 g, 0.33 mol) in CH3CN (165 mL). The mixture was heated to 80°C for 3 h under stirring. Subsequently, approximately 140 mL of CH3CN are distilled off, and the residue was poured into water. The mixture was extracted with DCM, washed with aq.NaHCÛ3, dried over MgSOq, concentrated to give the crude product, which was purified by distillation with oil pump at 70 °C to give 3-acetyl-3-fluorodihydrofuran-2(3H)-one as colorless oil (28.8 g, yield: 60 %). ’H NMR (CDCh 400 MHz): Ô4.48-4.40 (m, 2H), 2.83-2.57 (m, IH), 2.55-2.41 (m, 4H).

-( 1 -Fluorocyclopropyl)ethanone:

3-acetyl-3-fluorodihydrofuran-2(3H)-one (26 g, 0.178 mol) was added to the solution of Kl (12 g, 0.07 mol) in NMP(50 ml) dropwise at 190 °C under a pressure of 0.5 bar. By distilling off continuously, 8 g of crude product was obtained and the crude product was purified by distillation again at 100⁰ C under a pressure of 0.5 bar to give l-(l-fluorocyclopropyl)ethanone as light yellow oil (3.3 g, yield: 18 %)?H NMR (CDCI₃ 400 MHz): 62.40 (s, 3 H), 1.38-1.33 (m, 4H).

-Fluorocyclopropanecarboxylîc acid:

O

NaOH

Bromïne (14.8 g, 93 mmol) was added slowly to NaOH (12.36 g, 300 mmol) in water (50 mL) below 10 °C. Afterwards, l-(l-fluorocyclopropyl)ethanone (3.3 g, 30 mmol) was added slowly below 0 °C and the reaction mixture was then stirred for one hour at room température. Na₂ S₂O₅ was added until a colorless solution was formed. 50 mL of AcOEt was added. The aqueous phase was separated and acidified to pH 2 with aq. HCl (2M) and extracted with AcOEt (3 x 50 mL). This organic phase was dried over Na₂SO4 and concentrated to give 1fluorocyclopropanecarboxylic acid as a white solid (2.2 g, 66 % yield). ^]H NMR (CDCl₃ 400 MHz): 61.49-1.45 (m, 4H).

1-Bromomethyl-l-fluoromethyl-cyclopropane was prepared as described above for the synthesis of 1 -Bromomethyl-1 -trifluoromethyl-cyclopropane fluorocyclopropanecarboxylîc acid.

(6-TrifluoromethyI-pyridin-3-yl)-acetonitrile:

O

starting

1Step 1: (6-Trifluoromethyl-pyridin-3-yl)-methanol BH₃*THF (1 M solution in THF, 393 mL, 393 mmol) was added to a solution of 6-trifluoromethyl-nicotinic acid (25.0 g, 131 mmol) in dry

THF (300 mL) at 0°C under nitrogen with vigorous stirring. The mixture was gradually warmed to room température and stirred for 16 hours. The mixture was concentrated under reduced pressure and the residue was then dissolved in DCM and cooled to 0°C. Methanol was carefully added until gas évolution ceased and the solution was concentrated again under reduced pressure. The residue was purified by silica gel chromatography (5% methanol in DCM). The fractions containing product were collected and concentrated under reduced pressure. The residue was dissolved in DCM, washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (6trifluoromethylpyridin-3-yl)-rnethanol as a yellow oil (19.7 g, 85%). IH NMR (400 MHz, CDCl₃) Ô ppm 8.63 (s, l H), 7.91 (d, >8.0 Hz, l H), 7.67 (d, >8.0 Hz IH), 4.80 (s, 2 H), 3.84 (br. s., I H). 19F NMR (400 MHz, CDCl₃) :l68cm-l . MS m/z 178.12

Step 2: 5-Chloromethyl-2-trifluoromethylpyridine

Thionyl chloride (40.3 mL, 554 mmol) was slowly added to a solution of (6trifluoromethylpyridin-3-yl)-methanol (19.6 g, 111 mmol) in DCM (195 mL) at room température under nitrogen. The reaction mixture was stirred at reflux for 16 hours then concentrated under reduced pressure. The residue was dissolved in AcOEt (200 mL), washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude 5-chloromethyl-2-trifluoromethylpyridine as a brown oil which was used in the following step without further purification (19.5 g, 90%). *H NMR (400 MHz, CDCI3) δ ppm 8.74 (s, 1 H), 7.94 (d, >8.4 Hz, 1 H), 7.72 (d, >8.4 Hz IH), 4.66 (s, 2 H). 19F NMR (400 MHz, CDClj) : 168cm-1. MS m/z 196.15; 198.09

Step 3: (6-Trifluoromethylpyridin-3-yl)-acetonitrile

5-ChIoromethyl-2-trifluoromethylpyridine (19.5 g, 99.7 mmol) in éthanol (160 mL) was added to a solution of potassium cyanide (9.74 g, 150 mmol) in water (80 mL) at 90°C over 30 minutes. The mixture was stirred at 90°C for 3 hours. Most of the éthanol was removed under reduced pressure and the aqueous layer was extracted with AcOEt (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% AcOEt in hexanes) to afford (6-trifluoromethylpyridin-3-yl)-acetonitrile as a brown oil (9.79 g, 75%). ’H NMR (400 MHz, CDCI3) δ ppm 8.63 (s, 1 H), 7.90 (d, >8.0 Hz, 1 H), 7.70 (d, >8.0 Hz 1 H), 3.88 (s, 2 H). 19F NMR(400 MHz, CDCI3) :168cm-1 .MS m/z 187.14 (2-Methyl-pyrimidin-5-yl)-methanoI

i POCI_3éDMF

-----------------1 ii. NaBF₄

Step 1: A three-neck 2-L round bottomed flask with an immersion thermometer and an addition tunnel was charged with DMF (400 mL) and cooled to 0°C. POCI3 (178 g, 1.16 mol) was carefully added to the reaction via an addition funnel maintaining an internai température of 510°C. After 2h, the yellow solution was treated with bromoacetic acid (50 g, 0.36 mol) and heated to 90°C ovemight. The mixture was cooled and a short-path distillation head was attached. DMF was distilled from the red-orange oil at 120°C under high vacuum. The tarry residue was cooled to room température and treated with ice (about 10 g). Aqueous NaBF₄ (80 g in 160 mL H₂O) was added at 0°C. As the solid residue slowly dissolved, a vîgorous exothenn occurred. The yellow-orange precipitate that formed at 0°C was collected by filtration and redissolved in hot CHjCN (2 L). After hot-filtration, excess NaBF₄ was removed and the filtrate was cooled to -30°C. The crystalline precipitate was collected and dried in vacuum to give the intermediate sait (60 g, yield: 47%).

NH

Anh, HCI

------►

EtONa, EtOH

Step 2: To 500 mL of EtOH was added sodium (12 g, 0.50 mol) in portions at room température and the resultîng mixture was stirred until the sodium was dissolved completely. To a suspension of the previously prepared sait (60 g, 0.17 mol) and acetamidine hydrochloride (17.4 g, 0.19 mol) in EtOH (2.5 L) was added the above solution at room température and the resultîng mixture was heated to reflux for 5h. After filtration, the solvent was removed under reduced pressure to give the remains, which was suspended in H₂O (200 mL) and extracted with DCM (3 mL x 100). The organic layer was washed with brine, dried over Na₂SO₄ and concentrated, The crude product was purified by column chromatography on silica gel (petroleum ether: EtOAc = 5:1 to 2:1) to afford 2-methyl-pyrimidine-5-carbaldehyde (10 g, yield: 50%). ’H NMR (CDCI3 400MHz): <510.10 (s, IH), 9.07 (s, 2H), 2.84 (s, 3H).

MeOH

A solution of 2-methyl-pyrimidine-5-carbaldehyde (5 g, 41 mmol) in MeOH (100 mL) was added NaBH₄ (2.3 g, 61.5 mmol) at 0°C in portions and the resultîng mixture was stirred at room température for lh. The solvent was removed under reduced pressure to give the remains, which was suspended in H₂O (20 mL) and extracted with EtOAc (5 x 50 ml). The organic layer was dried over Na₂SO4 and concentrated to afford the title compound (2 g, yield: 39%). ^]H NMR (CDClj 400MHz): <58.64 (s, 2H), 4.72 (s, 2H), 2.73 (s, 3H).

(2-Methyl-pyrimidin-5-yl)-acetonitrile was prepared as described above for the synthesis of (6trifluoromethyl-pyridin-3-yl)-acetonitrile starting from (2-methyl-pyrimidin-5-yl)-methanol (5-Chloro-pyridin-3-yl)-acetonitrile

O O

Step l : 5-Chloro-nicotinic acid methyl ester

To a solution of 5-chloro-nicotinic acid (20.0 g, 127 mmol, purchased from Matrix Scientific, Columbia, SC, USA) in methanol (200 mL) at 0°C was added thionyl chloride (18.6 mL, 255 mmol). The reaction mixture was refluxed for 4 hours. After cooling to room température the mixture was diluted with saturated aqueous sodium bicarbonate, extracted with AcOEt (3 x 300 mL), dried over sodium sulfate, fîltered and concentrated under reduced pressure to afford crude 5-chloro-nicotinic acid methyl ester (17.2 g, 79%). ‘H NMR (400 MHz, CDClj) Ô ppm 9.10 (d, J=1.4 Hz, l H), 8.75 (d, >2.3 Hz, l H), 8.29 (d, J=2.0 Hz, IH), 3.98 (s, 3 H). MS m/z 171.8

Step 2: (5-Chloro-pyridin-3-yl)-methanol

To a solution of 5-chloro-nicotinic acid methyl ester (17.2 g, ΙΟΙ mmol) in methanol (230 mL) and DCM (230 mL) at 0°C was added sodium borohydride (16.4 g, 434 mmol). The reaction mixture was stirred at room température for 18 hours. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water (300 mL) and extracted with AcOEt (3 x 300 mL). The combined organic layer was dried over sodium sulfate, fîltered, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography to afford (5chloro-pyridin-3-yl)-methanol (7.8 g, 54%). *H NMR (400 MHz, DMSO-d6) 5 ppm 8.45 - 8.52 (m, 2 H), 7.83 (s, 1 H), 5.45 (t, >5.8 Hz, 1 H), 4.55 (t, J=5.7 Hz, 2 H). MS m/z 144.1

Step 3 and 4: (5-Chloro-pyridin-3-yl)-acetonitriIe

Conversion of the hydroxyl group to the chloride using thionyl chloride, followed by the displacement of the chloride by potassium cyanide was performed using the same procedures described for (6-trifluoromethyl-pyridin-3-yl)-acetonitrile. *H NMR (400 MHz, CDCB) δ ppm

8.55 (d, >2.0 Hz, 1 H), 8.50 (d, >1.1 Hz, 1 H), 7.73 (s, 1 H), 4.58 (s, 2 H). MS m/z 153.0

The following intermediates were prepared in a similar way (5-Fluoro-pyridin-3-yl)-acetonitrile, from 5-fluoro-nicotinic acid;

(2,6-Dimethyl-pyridin-3-yl)-acetonitrile, from (2,6-dimethylpyridin-3-yl)-methanol;

(2-Methyl-pyrimidin-5-yl)-acetonitrile, from (2-methyl-pyrimidin-5-yl)-methanol;

3-Cyclopropyl-2-(2-trifluoromethyl-pyrimidin-5-yl)-propionitrile

DMF

KF. Cul. TMSCF₃

Br

Step l: A mixture of 5-bromo-2-iodo-pyrimidine (30 g, O.l l mol), TMSCF3 (30 g, 0.21 mol), KF (9.2 g, O.l6 mol) and Cul (30 g, O.l6 mol) in DMF (300 mL) was stirred at room température ovemight. The reaction mixture was quenched by ΝΗ3Ή2Ο (600 mL) and extracted with EtOAc (500 mL x 3). The organic layer was washed with brine, dried over Na₂SO4 and concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether) to give 5bromo-2-trifluoromethyl-pyrimidine (4 g, yield: 16,7%). ’H NMR (CDCI3 400Hz): δ8.90 (s, 2H).

KOtBu,Pd(OAc)₂. dppf dioxane

Step 2: A mixture of 5-bromo-2-trifluoromethyl-pyrimidine (1,0 g, 4.41 mmol) and cyano-acetic acid ethyl ester ( 1.0 g, 4.41 mmol) was added into a suspension of t-BuOK ( 17.64 mL, 17.64 mmol, 1M in THF) in 1,4-dioxane (10 mL) under Ar atmosphère. To the resulting mixture was added a solution of Pd(OAc)₂ (10 mg, 44.1 pmol) and dppf (48.9 mg, 88.2pmol) in 1,4-dioxane (1 mL). The resulting mixture was heated to 70°C for lh. The reaction mixture was adjusted pH to 7~8 with IN AcOH and extracted with EtOAc (3 x 20 ml). The organic layer was dried over Na₂SOj and concentrated. The residue was purified by column chromatography on silica gel (EtOAc: petroleum ether = 1:10) to give cyano-(2-trifluoromethyl-pyrimidin-5-yl)-acetic acid ethyl ester (140 mg, yield: 12.3%). 'H NMR (CDCI3 400Hz): 69.03 (s, 2H), 4.88 (s, IH), 4.34 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).

Step 3: A mixture of cyano-(2-trifluoromethyI-pyrimidin-5-yl)-acetic acid ethyl ester (240 mg, 0.93 mmol), bromomethyl cyclopropane (375 mg, 2.78 mmol) and Nal (139 mg, 0.93 mmol) in dry dioxane (2 mL) was degassed and ButOK in THF (l.l l mL, l.l 1 mmol) was added at room température. The resulting mixture was heated to 100-110°C for 24h. Saturated NH₄C1 solution was added to quench the reaction at 0°C and extracted with EtOAc (5 mL x 3). The organic layer was washed with brine, dried over NaîSO4 and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/EtOAc = 20:1—5:1 ) to give the title compound (100 mg, yield: 44.6%). ’H NMR (CDCh 400MHz): 68.94 (s, 2H), 4.09-4.01 (m, IH), 2.05-1.95 (m, IH), 1.93-1.80 (m, IH), 0.91-0.79 (m, IH), 0.69-0.60 (m, 2H), 0.25-0.14 (m, 2H).

The following intermediates were prepared in a similar way:

3-(l-fluorocyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile;

3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile;

-(4-Tri fl uorom ethyl -phenyl )- tetrahyd ro -p yran-4-carboni tri 1 e :

NaH

DMF

A solution of 4-trifluoromethylbenzyl cyanide (0.92 g, 5.0 mmol) and bis(2-bromoethyl)ether (2.3 mL, 18 mmol) in DMF (10 mL) at room température was treated portion wise with sodium hydride (60% in minerai oil, 0.6 g, 15 mmol) over a period of 10 mins followed by stirring at the same température for lh. The mixture was then stirred at 70°C for 16 h. Then cooled to room température and the reaction mixture was quenched with slow addition of methanol. Water (100 mL) was added and the mixture was extracted with EtOAc (3><50 mL). The combined organic extracts were washed with water and brine and dried over sodium sulfate, filtered and concentrated. The concentrate was purified by column chromatography using a gradient of 5% EtOAc in hexanes to 30% EtOAc in hexanes to give the title compound (1.11 g, yield: 87%). ’H NMR (CDCh 300MHz): ôppm 7.75 (d, 2H), 7.65 (d, 2H), 4.20-4.09 (m, 2H), 4.00-3.85 (m, 2H), 2.27-2.05 (m, 4H).

The following intermediates were prepared in a similar way:

4-(4-Chloro-phenyl)-tetrahydro-pyran-4-carbonitrile;

4-(6-Methylpyridin-3-yl)-tetrahydropyran-4-carbonitrile;

4-(6-Trifluoromethylpyridin-3-yI)-tetrahydropyran-4-carbonitrile;

4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carbonitrile;

4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-carbonîtrile;

3- (2-methylpyrimidin-5-yl)tetrahydrofuran-3-carbonitrile;

l-(pyridin-3-yl)cyclopentanecarbonitrile;

l-(4-methoxyphenyl)cyclopentanecarbonitrile;

1- methyl-4-pbenylpiperidine-4-carbonitrile;

4- (4-chlorophenyl)-l-methylpiperidine-4-carbonitrile;

2- (4-chlorophenyl)-4-(dimethylamino)butanenitrile;

4-(4-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4'Carbonitrile;

4-Methyl-2-(6-methylpyridin-3-yl)-pentanenitrile

To a cooled (0 °C) slurry of NaH (60% dispersion in oil, 2.74 g, 68.5 mmol) in THF (120 mL) was added a solution of (6-methylpyridin-3-yl)-acetonitrile (8.23 g, 62.3 mmol) in THF (60 mL). The mixture was stirred at room température for 3 h and then warmed to 40°C for l h. The resulting reddish brown slurry was cooled to -20°C and a solution of l -bromo-2-methylpropane (8.53 g, 62.3 mmol) in THF (30 mL) was added dropwise and then stirred for 18 h at room température. The reaction was quenched with water and extracted with AcOEt. The organic extracts were combined and washed with brine, dried over Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15 % EtOAc in hexane) to give 7.52 g (64% yield) of 4-methyl-2-(6-methylpyridin-3-yl)pentanenitrile as an oil. ’H NMR (400 MHz, CDC13) δ ppm l.OO (dd, J=6.64, 4.30 Hz, 6 H), 1.53- l.70(m, I H), 1.71 - 1.99 (m, 2 H), 2.57 (s, 3 H), 3.81 (dd, J=9.57, 6.45 Hz, 1 H), 7.19 (d, J=7.82 Hz, 1 H), 7.59 (dd, J=7.82, 2.34 Hz, 1 H), 8.43 (d, J=2.34 Hz, 1 H).

The following intermediates were prepared in a simiiar way: 1 -(4-Methoxyphenyl)-1 -cyclopentanecarbonitrile; 4-(4-Chloro-phenyl)-l-methyl-piperidine-4-carbonitrile;

2- (4-Chloro-phenyl)-4*dimethylamino-butyronitrile;

3- cyclopropyl-2-(pyridin-5-yl)propanenitrile;

Cyclopropyl-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile;

3-Cyclopropyl-2-(6-trifluoromethyl-pyridîn-3-yl)-propionitrile;

2-(5-Chloro-pyridin-3-yl)-3-cyclopropyl-propionitrile;

2- (6-Chloropyridin-3-yl)-3-cyclopropylpropanenitrile;

3- cyclopropyl-2-(6-fluoropyridin-5-yl)propanenitrile;

3-Cyclopropyl-2-(2,6-dimethyl-pyridin-3'yl)-propionîtrile;

2- (2-Methyl-pyrimidin-5-yl)-3-(l-trifluoromethyl-cyclopropyl)-propionitrile;

3- (l-Trifluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propionitrile;

3-(l-Difluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propionitrile;

2-(6-CyclopropyI-pyridin-3-yl)-3-(l-trifluoromethyl-cyclopropyl)-propionitrile;

2- (6-Cyclopropyl-pyridin-3-yl)-3-(l-difluoromethyl-cyclopropyl)-propionitriIe;

3- Cyclopropyl-2-(2-methyl-pyrimidin-5-yl)-propionitrile;

2- (2-methylpyrimidin-5-yl)-3-(l-(trifluoromethyl)cyclopropyl)propanenitrile;

3- (l-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyridin-3-yl)propanenitrile;

3-Cyclopropyl-2-(5-methyl-pyrazin-2-yl)-propionitrile;

5-Cyano-5-(6-fluoro-pyridin-3-yl)-2-hydroxy-cyclohex-l-enecarboxylic acid methyl ester

KOtBu.THF

To a solution of (6-fluoro-pyridin-3-y!)-acetonitrile (15 g, O.ll mol) and methyl acrylate (19 g, 0.22 mol) in dry THF (150 mL) cooled to -70°C in dry ice-EtOH bath was added t-BuOK-THF solution (IM, 330 mL, 0.33 mol) in portions. The reaction mixture was stirred at *70°C for 4h. After completion (LCMS) IN HCl (aq) was added slowly at -70°C (the température of reaction mixture don’t rise above -50°C) to adjust the pH to 5-6. The THF layer was separated and the aqueous phase was extracted with EtOAc (2 * 150 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to provide the crude title compound (32 g), which was used directly for the next step.

The following intermediates were prepared in a similar way:

5-Cyano-5-(6-trifluoromethyl-pyridin-3-yl)-2-hydroxy-cyclohex-l-enecarboxylic acid methyl ester;

5-Cyano-5-(6-methoxy-pyridin-3-yl)-2-hydroxy-cyclohex-l-enecarboxylic acid methyl ester; 5-Cyano-2-hydroxy-5-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohex-l -enecarboxylic acid methyl ester;

Methyl 5-cyano-2-hydroxy-5-(2-methylpyrimidin-5-yl)cyclohex-l-enecarboxylate;

Methyl 5-cyano-2-hydroxy-5-(pyrimidin-5-yl)cycIohex-l-enecarboxylate;

l-(6-Fluoro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile

NaCI -----_> dmso,h₂o

To a solution of 5-Cyano-5-(6-fluoro-pyridin-3-yl)-2-hydroxy-cyclohex-l-enecarboxylic acîd methyl ester (32 g crude, O.l l mmol) in DMSO (110 mL) was added NaCI (7.78 g, 0.133 mol) and water (6.5 mL). The reaction mixture was heated at 160 °C for 3h. It was cooled to room température and poured into water (300 mL). The aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (300 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with a gradient elution of between 10-25% EtOAc in petroleum ether) to give the title compound (12 g, 50% over two steps). ’H NMR (CDCl₃ 400MHz): d'ppm 8.34 (d, J = 2.4 Hz, IH), 7.95-7.82 (m, IH), 7.00-6.92 (m, IH), 2.95-2.87 (m, 2H), 2.60-2.2. (m, 2H), 2.50-2.40 (m, 2H), 2.28-2.20 (m, 2H).

The following intermediates were prepared in a similar way: l-(6-Trifluoromethyl-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile; l-(6-Methoxy-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile;

4-Oxo-l-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexanecarbonitrile;

4-Oxo-l-(2-methylpyrimidin-5-yl)cyclohexanecarbonitrile;

4-Oxo-l-(pyrimidin-5-yl)cyclohexanecarbonitrile;

4,4-Difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexanecarbonitrile

N

CH₂CI₂

XtaIFluor-E, NEt₃ 3HF

To a stirred suspension of diethylamino difluorosulfiinium tetrafluoroborate sait (23.8 g, 0.104 mol) in dry DCM (100 mL) at room température was added l-(6-fluoro-pyridin-3-yl)-4-oxocyclohexanecarbonitrile (12 g, 0.052 mol) followed by triethylamine trihydrofluoride (25.12 g, 0.156 mol) under a nitrogen atmosphère. The reaction mixture was stirred ovemight at room température. The resulting mixture was then quenched with saturated aq. NaHCOj solution (300 mL), stirred for 10 minutes, and the resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluting with a gradient elution of between 2-10% EtOAc in petroleum ether) to afford the title compound (8 g, yield: 64%). *H NMR (CDClj 400MHz): 6ppm 8.40-8.35 (m, IH), 7.95-7.84 (m, IH), 7.05-6.96 (m, IH), 2.40-2.10 (m, 8H).

The following intermediates were prepared in a similar way:

4.4- Difluoro-l-(6-trifluoromethyl-pyridin-3-yl)-cyclohexanecarbonitrile;

4.4- Difluoro-1 -(6-methoxy-pyridin-3-yl)-cyclohexanecarbonitrile;

4.4- Difluoro-1 -(2-methyl-pyrimidin-5-yl)-cyclohexanecarbonitrile;

4.4- Difluoro-l-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexanecarbonitrile;

4.4- Difluoro-1 -(pyrimidïn-5-yl)-cyclohexanecarbonitrile;

4.4- difluoro-1-(5-fluoropyridin-3-yl)cyclohexanecarbonitrile;

To a solution of compound 4,4-difluoro-l-(pyrimidin-5-yl)-cyclohexanecarbonitrile (1.5 g, 6.72 mmol) and DFMS (6.0 g, 0.02 mol) in trifluoromethylbenzene (53 mL) and H₂O (21 mL) at room température was added TFA (766 mg, 6.72 mmol) followed by slow addition of tBuOOH (5.2 g, 70% solution in H₂O) with vigorous stirring. The reaction mixture was stirred at room température ovemight. TLC indicates about 50% starting material remained, a second addition of DFMS (6.0 g, 0.02 mol) and t-BuOOH(5.2 g, 70% solution in H2O) were added to the reaction mixture. Upon consumption of starting material, the réaction mixture was portioned between DCM (20 mL) and saturated NaHCOj solution (20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (3 x 20 ml). The organic layer was washed with brine, dried over NaiSOj and concentrated. The crude product was purified by flash chromatography (Petroleum ether:EtOAc=3:l) to give l-(2-(difluoromethyl)pyrimidin-5-yl)-4,4difluorocyclohexanecarbonitrile (800 mg, Yield: 44.4%). ^]H NMR (CDClj 400MHz): <59.03 (s, 2H), 6.71 (t, J=54.4Hz, IH), 2.40-2.27 (m, 6H).

Step l: 5-(6-Chloro-pyridin-3-yl)-5-cyano-2-hydroxy-cyclohex-l-enecarboxylic acid methyi ester

To a solution of 2-(6-chloro-3-pyridinyl)acetonitrile (4.3g, 28 mmol, purchased from Matrix Scientific, Columbia, SC, USA) and methyi acrylate (4.8 g, 56 mmol) in dry THF (150 mL) cooled to -65 °C was added solid potassium tert-butoxide (7.9 g, 70 mmol) under nitrogen atmosphère. The reaction mixture was stirred at -65 °C for 45 minutes. The réaction mixture was then acidified with 3 N HCl and extracted with DCM (3 x 150 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude 5(6-chloro-pyridin-3-yl)-5-cyano-2-hydroxy-cyclohex-l-enecarboxylic acid methyi ester which was used in the next step without purification (6.0 g, 75%).

Step 2: l-(6-Chloro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile

To a solution of 5-(6-chloro-pyridin-3-yl)-5-cyano-2-hydroxy-cyclohex-l-enecarboxylic acid methyl ester (4.2 g, 14 mmol) in DMSO (15 mL) was added sodium chloride (0.90 g, 16 mmol) and water (0.77 mL). The reaction mixture was heated at 160 °C for 6 hours. The reaction mixture was then cooled to room température and poured into water (50 mL). The aqueous layer was extracted with diethyl ether (3 x 250 mL). The combined organic layer was dried over sodium sulfate, fîltered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel to afford l-(6-chloro-pyridin-3-yl)-4-oxocyclohexanecarbonitrile (1.7 g, 52%). ‘H NMR (400 MHz, CDCl₃) δ ppm 8.59 (s, l H), 7.83 (dd, J=8.4, 2.2 Hz, l H), 7.44 (d, J=8.5 Hz, 1 H), 2.89 - 2.98 (m, 2 H), 2.60 - 2.66 (m, 2 H), 2.48 2.54 (m, 2 H), 2.25 - 2.33 (m, 2 H).

Step 3: l-(6-Chloro-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

To a stirred suspension of (diethylamino)difluorosulfonium tetrafluoroborate (16.5g, 72.1 mmol) in DCM (150 mL) at room température under nitrogen atmosphère was added l-(6-chloropyridin-3-yl)-4-oxo-cyclohexanecarbonitrile (4.2 g , 18 mmol) followed by triethylamine trihydrofluoride (8.68 g, 53.8 mmol). The reaction mixture was stirred for 6 hours at room température. The resulting mixture was then quenched by adding a saturated aqueous solution of sodium bicarbonate, stirred for 10 minutes, and the resulting mixture was extracted with DCM (3 x 25 mL). The combined organic layer was dried over sodium sulfate, fîltered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (1:10 to 1:5 AcOEt/ hexanes) to afford l-(6-chloro-pyridin-3-yl)-4,4-difluorocyclohexanecarbonitrile (2.5 g, 54%). LC-MS (m/z) 257.0 (MH+). *H NMR (400 MHz, CDCI3) δ ppm 8.56 (d, J=2.2 Hz, 1 H), 7.79 (dd, J=8,4, 2.6 Hz, 1 H), 7.42 (d, J=8.4 Hz, 1 H), 2.09 - 2.41 (m, 8 H).

Step 4: l-(6-Bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

To a stirred solution of l-(6-chloro-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (1.3 g, 5.1 mmol) in butyronitrile (100 mL) at room température under nitrogen atmosphère was added bromotrimethylsilane (1.55 g, 10.2 mmol). The reaction mixture was heated at 120 °C for 24 hours. The reaction mixture was then cooled to room température and poured into water (25 mL) and 10% aqueous NaOH solution (25 mL). The aqueous layer was extracted with diethyl ether (3 x 250 mL). The combined organic layer was dried over sodium sulfate, fîltered and concentrated under reduced pressure. The crude residue was then purified by column chromatography on silica gel to afford l-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile as a white solid (l.O g, 65%). LC-MS (m/z) 301.0 (MH+). 'H NMR (400 MHz, CDCIj) S ppm 8.55 (d,

J=2.7 Hz, l H), 7.69 (dd, J=8.4, 2.8 Hz, l H), 7.57 (d, >8.4 Hz, l H), 2.09 - 2.41 (m, 8 H).

l-(6-Cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

A suspension of cyclopropylboronic acid (0.94 g, Il mmol), l-(6-bromo-pyridîn-3-yl)-4,4difluoro-cyclohexanecarbonitrile (1.10 g, 3.67 mmol) and potassium phosphate tribasic (2.30 g, 10.8 mmol) in a mixture of toluene (16 mL) and water (4 mL) at room température was purged with nitrogen gas for 1 hour. Then palladium acetate (31 mg, 0.14 mmol) and tricyclohexylphosphine (51 mg, 0.18 mmol) were added and the mixture was heated at 110 °C for 18 hours. After cooling to room température a saturated aqueous solution of ammonium chloride was added, followed by water. The organic layer was separated and the aqueous layer was extracted again three times with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography to afford l-(6-cyclopropyl-pyridin-3-yl)-

4,4-difluoro-cyclohexanecarbonitrile (400 mg, 27%). LC-MS (m/z) 263.0 (MH+). ’H NMR (400 MHz, CDC1₃) Ô ppm 8.59 (d, J=2.5 Hz, 1 H), 7.64 (dd, J=8.3, 2.5 Hz, 1 H), 7.19 (d, J=8.3 Hz, 1 H), 2,00 - 2.39 (m, 9 H), 0.99 - 1.06 (m, 4 H).

l-(6-Ethoxy-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile

Sodium métal (229 mg, 9.96 mmol) was added to éthanol (5 mL) at room température. To this solution was added l-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (300 mg, 1.00 mmol) and the reaction was heated at 70 °C for 6 hours. After cooling to room température the volatiles were removed under reduced pressure. The residue was diluted with water and extracted with AcOEt (2 x 50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford l-(6-ethoxy-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitriie (130 mg, 49%). LC-MS (m/z) 241.4 (MH⁺). 'H NMR (400 MHz, CDC1₃) δ ppm 8.30 (d, 7=2.7 Hz, 1 H), 7.66 (dd, 7=8.8, 2.7 Hz, 1 H), 6.78 (d, 7=8.8, Hz, 1 H), 4.38 (q, 7=7.1, Hz, 2 H), 2.07 - 2.42 (m, 8H), 1.41 (t, 7=7.1, Hz, 3 H).

l-(6-Methoxy-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile was prepared analogously to 1(6-Ethoxy-pyridin-3-yl)-4,4-d i fl uoro-cyclohex anecarbon i tri le l-[5-(l-Aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-ethanol

1. NaBH« THF. rt

2. Raney-Ni, H₂ NH₃ MeOH. rt

Step 1 : l-(6-Acetyl-pyridin-3-yl)-4,4-difiuoro-cyclohexanecarbonitrile

To a microwave vial was added l-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (276 mg, 0.918 mmol), tributyl( 1 -ethoxyvinyl)tin (663 mg, 1.84 mmol), copper iodide (26.2 mg, 0.138 mmol), PdChtPPltjh (32.2 mg, 0.0459 mmol) and acetonitrile (7.3 mL). The vial was purged under nitrogen, capped then heated in an oil bath at 80 ‘C for 16 hours. After cooling to room température the crude reaction mixture was filtered through celite with acetonitrile and the volatiles were then removed under reduced pressure. The residue obtained was dissolved in 1,4dioxane (20 mL), treated with 1.5 N aqueous HCl (20 mL) and stirred vigorously at room température for 1.5 hours. The mixture was then made basic by adding solid potassium carbonate and transferred to a 250-mL separatory funnel with water (50 mL). The aqueous layer was extracted with AcOEt (3 x 50 mL), The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was treated with a saturated solution of potassium fluoride in methanol (6 mL), stined for a few minutes, diluted with DCM, adsorbed onto silica gel and purified by silica gel chromatography to afford l-(6-acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile as a white solid (178 mg, 73%). LC-MS (m/z) 265.0 (MH⁺); t_R = 1.21. 'H NMR (300 MHz, CDC1₃) δ ppm 8.86 (d, 7=2.0 Hz, 1 H), 8.09 (dd, 7=8.3, 0.5 Hz, 1 H), 7.95 (dd, 7=8.3, 2.5 Hz, 1 H), 2.73 (s, 3 H), 2.46

2.14 (m, 8 H).

Step 2 and 3: l-[5-(l-Aminornethyl-4,4-difluoro-cyclohexyI)-pyridin-2-yl]-ethanol

To a solution of l-(6-acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (80 mg, 0,30 mmol) in THF (4.0 mL) at room température was added sodium borohydride (23 mg, 0.60 mmol) and the reaction was stirred at room température for 2.5 hours. The reaction was quenched with methanol and the volatiles were then removed under reduced pressure. The residue was taken up in AcOEt (about 10 mL) and washed with saturated aqueous sodium bicarbonate (about 10 mL). The layers were separated and the aqueous layer was extracted again with AcOEt (2x5 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then dissolved in a 7 N ammonia solution in methanol (6,7 mL) and treated with the tip of a spatula of Raneynickel, The flask was purged three fîmes then left to stir under one atmosphère of hydrogen for 15 hours, The catalyst was removed by filtration through celite and washed with methanol. The solvent was then removed under reduced pressure to afford 1 -(5-(1 -aminomethyl-4,4-difluorocyclohexyl)-pyridin-2-yl]-ethanol as a white solid (64 mg, 78%). LC-MS (m/z) 271.1 (MH⁺); tR = 0.55.

2-(5-( l-Aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2-ol

Step 1: 4,4-Difluoro-1-(6-( 1 -hydroxy-1 -methyl-ethyl)-pyridin-3-yl]-cyclohexanecarbonitrile A solution of l-(6-acetyl-pyridin-3-yi)-4,4-difluoro-cyclohexanecarbonitrile (17 mg, 0.064 mmol) in THF (1.2 mL) was cooled at -50 °C and treated with a 3.0 M solution of méthylmagnésium bromide in ether (110 pL, 0.32 mmol). After stirrîng at -50 °C for 3 hours, the reaction was quenched by adding saturated aqueous ammonium chloride (5 mL) and stirred at room température for a few minutes. AcOEt (5 mL) was added and the biphasic mixture was stirred vigorously for a few seconds. The layers were separated and the aqueous layer was extracted again with AcOEt (5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by preparative TLC, eluting with 60% AcOEt in hexanes to afford 4,4-difluoro-1-(6-(1-hydroxy-1methyl-ethyl)-pyridin-3-yl]-cyclohexanecarbonitrile as a colorless oil (8.7 mg, 48%). LC-MS (m/z) 280.0 (MH⁺); t_R= 1.11.

Step 2: 2-(5-( 1 -Aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2-ol

Réduction of the cyano group was performed following the same procedure used in the préparation of 1-(5-( l-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-ethanol. The solvent was removed under reduced pressure to afford 2-(5-( l-aminomethyl-4,4-di fl uoro-cyclohexyl)pyridin-2-yl]-propan-2-ol as a colorless oil (8.8 mg, 100%). LC-MS (m/z) 285.1 (MH⁺); tR = 0.61.

3-cycIopropyl-2-(6-(l-ethoxyvinyl)pyridin-3-yl)propanenitrile:

A solution of 2-(6-chloropyridin-3-yl)-3-cyclopropylpropanenitrile (1.0 g, 4.86 mmol), tributyl(l-ethoxyvinyl)stannane (3.4 g, 9.72 mmol), LiCl (0.612 g, 14.58 mmol) and Pd(PPhj).| (0.282 mg, 0.243 mmol) in 1,4-dioxane (20 mL) was degassed and heated to 120°C under N₂ ovemight. The reaction mixture was diluted with water and extracted with EtOAc (3^X 30 mL). The combined organic layers were dried over Na₂SO4 and concentrated to give 3-cyclopropyl-2(6-(l-ethoxyvinyl)pyridin-3-yl)propanenitrile (2 g), which was used for the next step without further purification.

A solution of 3-cyclopropyl-2-(6-(l-ethoxyvinyl)pyridin-3-yl)propanenitrile (2 g, crude) in THF (10 mL) was added 4N HCl (10 mL) and stirred at room température for 2h. The reaction mixture was adjusted pH to 6-7 by 4M aq.NaOH and extracted with EtOAc (3* 20 mL). The combined organic layers were dried over Na₂SO4 and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc: Petroleum ether = 1: 10) to give 2-(6acetylpyridin-3-yl)-3-cyclopropylpropanenitrile (600 mg, yield: 60%) ^lH NMR (CDCI3 varian 400): <58.58-8.51 (m, IH), 7.95 (d, 7= 8.0 Hz, IH), 7.75 (dd, J= 8.0 Hz, 2.4 Hz, IH), 3.92-3.85 (m, IH), 2.61 (s, 3H), 1.88-1.79 (m, 1 H), 1.71-1.65 (m, IH), 0.75-0.67 (m, IH), 0.49-0.45 (m, 2H), 0.10-0.03 (m, 2H).

3-cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propanenitrile:

A solution of 2-(6-acetylpyridin-3-yl)-3-cyclopropylpropanenitrile (520 mg, 2.43 mmol) in THF (6 mL) was added MeMgBr (0.89 mL, 2.67 mmol, 3M in Et₂O) at 0°C under N₂ and stirred at room température for 2h. The solution was quenched with water and extracted with EtOAc (3 ^χ20 mL). The organic layer was dried over NajSCL and concentrated, The crude product was purified by coiumn chromatography on silica gel (EtOAc: Petroleum ether =1: 10) to give 3cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propanenitrile (200 mg, yield: 35.6%).

NMR (CDCIj varian 400): <58.41 (d, 2.4 Hz, IH), 7.67 (dd, J= 8.0 Hz, 2.4 Hz, IH), 7.36 (dd,

J= 8.4 Hz, 0.8 Hz, IH), 4.62 (s, IH), 3.90-3.82 (m, IH), 1.90-1.83 (m, IH), 1.75-1.68 (m, IH), 1.48 (s, 6H), 0.81-0.73 (m, IH), 0.55-0.50 (m, 2H), 0.15-0.09 (m, 2H).

[4-(4-Trifluoromethyl-phenyl)-tetrahydro-pyran-4-yl]-methylamine

H₂ Raney Nickel

MeOH/NH₃

NH₂

To a solution of 4-(4-trifluoromethyl-phenyl)-tetrahydro-pyran-4-carbonitrile (Lll g, 4.35 mmol) in methanol (54 mL) and 7N ammonia in methanol (6 mL) was added Raney-Nickel (300 mg). The mixture was purged 3 times with hydrogen gas then left to stir under 1 atmosphère of hydrogen at room température overnight. The crude reaction mixture was filtered through celite, washed with methanol and the filtrate concentrated under reduced pressure to yield the title compound (1.07 g, yield: 95%) as a white solid. *H NMR (CDCIj 300MHz): 6ppm 7.67 (d, 2H), 7.45 (d, 2H), 3.90-3.79 (m, 2H), 3.61-3.50 (m, 2H), 2.90 (s, 2H), 2.24-2.12 (m, 2H), 2.00-1.88 (m, 2H), 0.87 (bs, 2H).

The following intermediates were prepared in a similar way: [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine;

( 1 -(pyridin-3-yl)cyclopentyl)methanamine; (4-(4-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-yl)methanamine;

4-Methyl-2-(6-rnethylpyridin-3-yl)-pentylamine (hydrogénation at 50 psi ovemight);

C-[4-(6-Methylpyridin-3-yl)-tetrahydropyran-4-yl]methylamine;

3-Cyclopropyl-2-(2,6-dimethyl-pyridin-3-yl)-propylamine;

C-[4,4-DifluorO' l -(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine;

3-Cyclopropyl-2-(6-fluoro-pyridin-3-yl)-propylamine;

C-[l-(6-Methoxy-pyridin-3-yl)-4,4-difluoro-cyclohexyl]-methylamine; C-[l-(6-Ethoxy-pyridin-3-yl)-4,4-difluoro-cyclohexyl]-methylamine;

C-[l'(6-Cyclopropyl-pyridin-3-yl)-4_t4-difluoro-cyclohexyl]-methylamine;

2-(6-Cyclopropyl-pyridin-3-yl)-3-(l-difluoromethyl-cyclopropyl)-propylamine (hydrogénation at 30 psi ovemight);

2- (6-Cyclopropyl-pyridin-3-yl)-3-(l-trifluoromethyl-cyclopropyl)-propylamine (hydrogénation at 50 psi for 12 h);

3- Cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine; C-[4-(6-trifluoromethylpyridin-3-yl)-tetrahydropyran-4-yl]-methylamine (hydrogénation at 45 psi for 3h);

C-[4,4-Difluoro-1 -(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine (hydrogénation at 50 psi ovemight);

3-(l-Difluoromethyl-cyclopropyl)-2-(6-trifluoroinethyl-pyridin-3-yl)-propylamine (hydrogénation at 50 psi ovemight);

3-(l-Trifluoromcthyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine (hydrogénation at 50 psi ovemight);

C-[4,4-Difluoro-l-(2-methyl-pyrimidin-5-yl)-cyclohexyl]-methylamine (hydrogénation at 30 psi for 2 h);

3-Cyclopropyi-2-(2-methyl-pyrimidin-5-yl)-propylamine (hydrogénation at 30 psi for 30 min);

2- (2-Methyl-pyrimidin-5-yl)-3-(l-trifluoromethyl-cyclopropyl)-propylamine (hydrogénation at 50 psi for 30 min);

3- Cyclopropyl'2-(2-trifluoromethyl-pyrimidin-5-yl)-propylamine (hydrogénation at 50 psi for 30 min);

2-(2-(Trifiuoromethyi)pyrimidin-5-yl)-3-(l-trifluoromethyl-cyclopropyl)-propylamine;

2- (2-(Trifluoromethyl)pyrimidin-5-yl)-3-(l-difluoromethyl-cyclopropyl)-propylamine; [4_t4-Difluoro-l-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl]methanamine;

3- Cyclopropyl-2-(5-methyl-pyrazin-2-yl)-propylamine;

[ l -(4-Methoxyphenyl)-cyclopentyl]-methylamine

lîaih₄

THF

NH₂

To a stirred solution of l-(4-Methoxyphenyl)-l-cyclopentanecarbonitrile (4.02 g, 20 mmol) in THF (50 mL) cooled to 0°C was added lithium aluminium hydride (1.52 g, 40 mmol) and the reaction was allowed to warm to room température and stirred for 16h. To the reaction mixture was added cautiously water (2.0 mL) then 2N NaOH (aq) (2 mL). The mixture was filtered and concentrated in vacuo to yield the title compound which was used without further purification (1.07 g, yield: 95%). ‘H NMR (CDC1₃ 300MHz): Ôppm 7.12 (d, 2H), 6.80 (d, 2H), 3.71 (s, 2H), 2.62 (s, 3H), 1.88-1.58 (m, 8H).

The following intermediates were prepared in a similar way:

[4-(4-Chloro-phenyl)-1 -methyl-pïperidine-4-yl]-methylamine;

( 1 -methyl-4-phenylpiperidin-4-yl)methanamine; 3-(4-Chloro-phenyl)-N 1 ,N 1 -dimethyl-butane-1,4-dîamine;

2-Cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine

BH₃-DMS

THF

NH₂

A solution of Cyclopropyl-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile (93 mg, 0.41 mmol) in THF (2.8 mL) in a 5 mL microwave vial was treated with borane-methyl sulfide complex (0.51 mL, 5.4 mmol). The reaction vessel was capped and the mixture was heated in the microwave reactor for 20 mins at 100°C. The reaction mixture was concentrated in vacuo to yield the crude title compound which was used without further purification (95 mg, purity: 73%, yield: 73%). LCMS (MH+): m/z = 231.1, t_R (minutes, Method D) = 0.40

The following intermediates were prepared in a similar way: 2-(5-Chloro-pyridin-3-yl)-3-cyclopropyl-propylamine;

4.4- difluoro-1 -(4-methyl- l H-îmidazol-1 -yl)cyclohexanecarboxylic acid:

4-methylimidazole (1.67 g, 20.3 mmol) was dissolved in THF (200 mL, 2000 mmol). Powdered sodium hydroxide (4.19 g, 104.8 mmol) was added together with 4,4-difluorocyclohexanone (2.90 g, 22 mmol). Chloroform (7.9 mL, 99 mmol) was added dropwise and the reaction was stirred ovemight at room température.

The reaction was acidified with 2M HCl and filtered. The solid was treated with MeOH, to dissolve the product and leave back NaCl. The reaction was filtered again and the residue was concentrated to give the title compound as the hydrochloride sait (3.498 g, 58%).

ethyl 4,4-difluoro-1 -(4-methyl-1 H-imidazol-1 -yl)cyclohexanecarboxylate:

4.4- Difluoro-l-(4-methyl-imidazol-l-yl)-cyclohexanecarboxylic acid; hydrochloride (662 mg,

1.18 mmol) was dissolved in THF (20 mL, 200 mmol) and cooled in ice. N,NDiisopropylethylamine (0.850 mL, 4.88 mmol) was added dropwise over 5 minutes at 5-10 °C. The mixture was stirred for 15 minutes. Ethyl chloroformate (0.150 mL, 1.57 mmol) was added dropwise over 5 minutes at 5-7 °C. The mixture was stirred 50 minutes at 5 °C. Then warmed to room température. After 1 hour the reaction was concentrated down and the residue was purified by flash column chromatography on silica gel (eluding w a gradient elution from heptane to AcOEt) to give the title compound (199 mg, 59%) ’H NMR (CDCI3 500 MHz): ôppm 7.59 (s, IH), 6.76 (s, IH), 4.20 (m, 2H), 2.61 (m, 2H), 2.43 (m, 2H), 2.24 (s, 3H), 2.03 (m, 4H), 1.22 (m, 3H).

4.4- difluoro-1 -(4-methyl-1 H-imidazol-1 -yl)cyclohexanecarboxamide:

4.4- Difluoro-l-(4-methyl-imidazol-l-yl)-cyclohexanecarboxylic acid ethyl ester (199 mg, 0.731 mmol was dissolved in 7 M ammonia in methanol (5 mL) and stirred for 72 hours. The sample was concentrated and the residue was purified by flash column chromatography on silica gel (eluding w a gradient elution from heptane to AcOEt to 5% EtjN/10 % MeOH/85% AcOEt) to give the title compound (84 mg, 45%) ^lH NMR (CDCI3 500 MHz): ôppm 7.64 (s, IH), 6.82 (s, IH), 5.17 (m, 2H), 2.68 (m, 2H), 2.41 (m, 2H), 2.30 (s, 3H), 2.23 (m, 2H), 1.85 (m, 2H). (4,4-difluoro-l -(4-methyl-1 H-imidazol-1 -yl)cyclohexyl)methanamine:

Into a round bottom flask was added 4,4-Difluoro-l-(4-methyl-imidazol-l-yl)cyclohexanecarboxylic acid amide (99 mg, 0.39 mmol) and THF (10 mL, 100 mmol) at room température, to the reaction mixture was added lithium tetrahydroaluminate (365 mg, 9.62 mmol). The reaction was refluxed for 6 hours, before being quenched with water (0.4 ml), 2M NaOH (0.4 ml) and water (0.8 ml). The reaction mixture was filtered and conc. The residue was purified by flash column chromatography on silica gel (eluding w a mixture of 5% EtjN/lO % MeOH/85% AcOEt) to give the title compound (44 mg, 47%). ‘H NMR (CDCl₃ 500 MHz):

ôppm 7.55 (s, IH), 6.71 (s, IH), 2.70 (s, 2H), 2.4-1.7 (m, 8H), 2.21 (s, 3H).

3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile:

To a solution of 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile (310 mg, I0 1.29 mmol) and Mel (0.27 g, 1.9 mmol) in dioxane (10 ml) was added t-BuOK (1.39 mL, 1.39 mmol, IM in THF) dropwise at room température under N₂. The mixture was stirred for l h, then quenched by sat.aq. NHqCl (10 mL), and extracted with EtOAc(3 χ 10 ml). The organic layer was concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (EtOAc/Petroleum ether = l:4) to give compound the title compound (120 mg, yield: 36%). 'H NMR (CDCI3 varian 400): 69.02 (s, 2H), 1.92 (d, J = 6.8

Hz, 2H), 1.87 (s, 3H), 0.80-0.67 (m, IH), 0.65-0.56 (m, IH), 0.55-0.45 (m, IH), 0.30-0.20 (m, IH), 0.05-0.04 (m, IH).

3-Cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropan-l-amine:

A solution of 2-(pyrimidin-5-yl)acetonitrile (1.8 g, 15.1 mmol) in DMF (20 mL) was degassed and (bromomethyl)cyclopropane was added (2.04 g, 15.1 mmol). The reaction mixture was cooled to -10°C, NaH was added (720 mg, 18.1 mmol, 60% in minerai oil) in portions under N₂ and stirred at the same température for 45 mins. The reaction mixture was quenched with sat.

NH4CI and extracted with EtOAc (30 ml x 3). The organic layer was washed with brine, dried over Na₂SO4 and concentrated. The crude product was purification by column chromatography on silica gel (petroleum ether: EtOAc =3:1) to give 3-cyclopropyl-2-(pyrimidin-5yl)propanenitrile (2.25 g, yield: 85%).'H NMR (CDC1₃ 400 MHz): 69.22 (s, IH), 68.78 (s, 2H),

3.80 (t, J=8Hz, 2H), 1.98-1.92 (m, 1 H), 1.83-1.79 (m, IH), 0.87-0.83 (m, IH), 0.61-0.59 (m,

2H), 0.21-0.13 (m, 2H).

The following intermediate was prepared in a similar way: 2-(Pyrimidin-5-yl)-3-(l-(trifluoromethyl)cyclopropyl)propanenitrile;

2- (5-chloropyridin-3-yl)-3-cyclopropylpropanenitrile;

3- cyclopropyl-2-(pyrimidin-5-yl)propanenitrile;

3-( 1 -fluorocyclopropyl)-2-(pyrimidin-5-yl)propanenitrile;

To a solution of 3-cyclopropyl-2-(pyrimidin-5-yl)propanenitrile (1.5 g, 8.67 mmol) and Mel (1.45 g, 13.0 mmol) in 1,4-dioxane (20 ml) was added t-BuOK (9.57 ml, 9.57 mmol) dropwise at room température under N₂. The mixture was stirred for 1 h at room température then quenched by sat.aq NH4CI (20 ml) and extracted with EtOAc (3 x 30 ml). The organic layer was dried over Na₂SO4 and concentrated under reduced pressure to give 3-cyclopropyl-2-methyl-2(pyrimidin-5-yl)propanenitrile (1.5 g), which was used directly for next step.

The following intermediate was prepared in a similar way: 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile;

3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropanenitrile

To a solution of 3-cyclopropyl-2-methyl-2-(pyrimidin-5-yl)propanenitrile (2.5 g, 13.4 mmol) and DMFS (7.8 g, 26.7 mmol) in DCM (40 ml) and H₂O (12 ml) at room température was added TFA (1.5 g, 13.4 mmol) followed by slow addition of t-BuOOH (8.6 g, 67 mmol) with vigorous stirring. The reaction mixture was stirred at room température ovemight. To the reaction mixture was added additional DMFS (7.8 g, 26.7 mmol) and t-BuOOH (8.6 g, 67 mmol). The reaction mixture was stirred at room température ovemight. The réaction mixture was added aq. NaHCCh and extracted with EtOAc (3 x 50 ml). The organic layer was dried over Na₂SO4 and concentrated. The crude product was purification by coiumn chromatography on silica gel (petroleum ether: EtOAc =4:1) to give 3-cyclopropyl-2-(2(difluoromethyl)pyrimidin-5-yl)-2-methylpropanenitrile (1.1 g, yield: 35%). ^lH NMR (CDCI3 400 MHz): Ô8.97 (s, 2H), 6.82-6.55 (m, IH), 1.92-1.90 (m, 2H), 1.85 (s, 3H), 0.71-0.65 (m, IH), 0.60-0.57 (m, IH), 0.51-0.47 (m, IH), 0.26-0.20 (m, IH), 0.03-0.00 (m, IH).

The following intermediate was prepared in a similar way:

2-(2-(Difluoromethyl)pyrimidin-5-yl)-3-(l-(trifluoromethyI)cyclopropyl)propanenitrile;

2- (2-(Difluoromethyl)pyrimidin-5-yl)-3-(l-(fluoro)cyclopropyl)propanenitrile;

3- cyclopropyl-2-methyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propanenitrile;

3-cyclopropyl-2-(2-(dîfluoromethyl)pyridin-5-yl)propanenitrile; 3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propanenitrile;

3-(l-fluorocyclopropyl)-2-(2-(difluoromethyl)pyrimidin-5-yl)propanenitrile; 3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(difluoromethyl)pyrimidin-5-yl)propanenitrile;

A mixture of 3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropanenitrile (1 g, 4.2 mmol) and NH3.H₂O (3 mL) in MeOH (20 mL) was hydrogenated with Raney Ni (1.5 g) under 50Psi for 3 h. The reaction mixture was filtered and concentrated to give 3-cyclopropyl2-(2-(difluoromethyl)pyrimidin-5-yl)-2-methylpropan-l -amine (1 g), which was used directly for next step.

The following intermediates were prepared in a similar way: 2-(2-(Difluoromethyl)pyrîmidin-5-yl)-3-(l-fluorocyclopropyl)propan-l-amine;

2- (2-(DÎfluoromethyl)pyrimidin-5-yl)-3-(l-(trifluoromethyl)cyclopropyl)propan-l-amine; (4,4-difluoro-l-(5-fluoropyridin-3-yl)cyclohexyl)methanamine;

3- (l-fluorocyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-l-amine; 3-(l-fluorocyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-l-amine;

3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propan-l -amine;

3-(l-fluorocyclopropyl)-2-(2-(difluoromethyl)pyrimidin-5-yl)propan-l-amine;

2- (2-(difluoromethyl)pyrimidin-5-yl)-3-(l-(trifluoromethyl)cyclopropyl)propan-l-amine;

3- cyclopropyl-2-methyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propan-l-amine;

3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-l-amine;

3-( l -fluorocyclopropyI)-2-(2-methylpyrimidin-5-yl)propan-1 -amine;

2-(4-Chlorophenyl)-2-(dihydro-2H-pyran-4(3H)-ylidene)acetonitrile:

Sodium (152 mg, 6.6 mmol) was added into EtOH (10 ml) and stirred at room température for 20 minutes. 2-(4-Chlorophenyl)acetonitrile (500 mg, 3.3 mmol) was added to the solution, after ail the sodium had dissolved, and the reaction was stirred at room température for 0.5 h. To the resulting mixture was added dihydro-2H-pyran-4(3H)-one (330 mg, 3.3 mmol) and stirred at room température for 1.5 h. The solvent was removed. To the residue was added water and extracted with EtOAc (3 x 20 mL). The combined organic solution were dried over NajSOj and concentrated to give crude product, which was purified by flash column chromatography (petroleum ether: EtOAc = 10:1) to give compound 2-(4-chlorophenyl)-2-(dihydro-2H-pyran4(3H)-ylidene)acetonitrile (300 mg) which was used for the next step without further

2-(4-chlorophenyI)-2-(tetrahydro-2H-pyran-4-yl)ethanamine:

A mixture of 2-(4-chlorophenyl)-2-(dihydro-2H-pyran-4(3H)-ylidene)acetonitrile (200 mg, 0.85 mmol) and NH3.H2O (2 mL) in MeOH (30 mL) was hydrogenated with Raney Ni (500 mg) under H2 (50 Psi) ovemight. The reaction mixture was filtered and concentrated to give 2-(4chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine (190 mg, 93%). ^]H NMR (CDCI3 400 MHz): J7.39-7.29 (m, 2H), 7.19-7.09 (m, 2H), 4.03-3.95 (m, IH), 3.89-3.80 (m, IH), 3.51-3.45 (m, 2H), 3.40-3.32 (m, IH), 3.30-3.20 (m, IH), 2.61-2.49 (m, 2H), 1.82-1.69 (m, 2H), 1.49-1.31 (m, IH), 1.29-1.10 (m, 2H).

The follwoing intermediates were prepared in a similar way:

2-(2-Methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine;

2-(Tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;

2-(4-Hydroxytetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile:

2-(6 (Trifluoromethyl)pyridin-3-yl)acetonitrile (260 mg, 1.4 mmol) was dissolved in THF (3 mL, 30 mmol) under Ar and cooled at -78 °C. A solution of 0.6 M sodium bis(trimethylsilyl)amide in toluene (3.49 mL) was added dropwise. After stirring at -78 °C for 4hours the reaction was allowed to reach -50 °C for 30 minutes. Then tetrahydro-4H-pyran-4-one (0.189 mL, 2.10 mmol) was added dropwise at -60 °C and the reaction was kept at this température for 45 minutes. To the reaction was added sat. aq. NHjCI (10 mL) and it was extracted AcOEt (3 x 20 mL). The combined organic phases were washed with brine, dried over MgSO.| and concentrated in vacuo.

The crude product was purified by flash chromatography to yield 2-(4-Hydroxytetrahydro-2Hpyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (189 mg, 0.660 mmol, 47%).

^lH NMR (600 MHz, DMSO) δ 8,72 (d, J = 1.9 Hz, IH), 8.08 (dd, J = 8.1, 2.0 Hz, IH), 8.00 (d, J = 8.0 Hz, IH), 4.56 (s, IH), 3.78-3.68 (m, IH), 3.67-3.61 (m, IH), 3.59 - 3.52 (m, IH), 3.44 (td, J = 11.7, 2.3 Hz, 1 H), 1.81 - 1.72 (m, IH), 1.73 - 1.60 (m, 2H), 1.04 (dd, J = 13.4, 2.3 Hz,

IH).

2-(Dihydro-2H-pyran-4(3H)-ylidene)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile: (4-Hydroxy-tetrahydro-pyran-4-yl)-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile (1.15 g, 4.02 mmol) was dissolved in thionyl chloride (50 mL, 600 mmol). One drop of DMF was added and the mixture was heated at reflux for lhour and then cooled to room température and concentrated in vacuo. The resulting crude product was purified by flash chromatography to yield 2-(dihydro2H-pyran-4(3H)-yHdene)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (1.04 g, 3.9 mmol, 95 %).

'H NMR (600 MHz, CDClj) δ 8.68 (d, J = 2.1 Hz, IH), 7.89 (ddd, J = 8.1, 2.2, 0.5 Hz, IH), 7.80 (dd, J = 8.1, 0.7 Hz, IH), 3.93 (t, J = 5.5 Hz, 2H), 3.74 (t, J = 5.5 Hz, 2H), 2.94 - 2.86 (m, 2H), 2.52 (t, J = 5.5 Hz, 2H).

2-(Tetrahydro-2H-pyran'4-yl)'2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine: 2-(Dihydro-2H-pyran-4(3H)-yHdene)-2-(6'(trifluoromethyl)pyridin-3-yl)acetonitrile ( l .04 g,

3.88 mmol) was dissolved in methanol (50 mL) and 7 Μ NH3 in methanol (20 mL) was added. The solution was flushed with Ar. Raney nickel (0.033 g, 0.39 mmol) was added and mixture hydrogenated on a Parr Apparatus at room température for 4hours. Then filtered through a plug of celite and concentrated in vacuo. The crude product was used for the next step without further purification.

LC-MS (m/z) 275.2 (MH⁺), t_R(minutes, Method E) = 0.33.

2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)acetonitrile:

A solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (l.O g, 7.51 mmol) and 4-chloropyridine hydrochloride (1.13 g, 7.51) in dioxane (20 mL) in a dried flask was degassed and filled with nitrogen. t-BuOK (18.8mL, 1M in THF) was added. The mixture was stirred at 100°C for 4h and cooled to room température, quenched by cooled sat. aq. NH4CI (20 mL). The resulting mixture was extracted with EtOAc (3^X 10 mL). The combined organic layers were washed with brine (3* 10 mL), dried over Na₂SO4, concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (MEOH: EtOAc = 1:10) to give 2(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)acetonitrile (700 mg, crude).

Br

2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile:

A dried flask was charged with 2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (l.O g, 5.38 mmol) in DME (20 ml). The mixture was degassed and filled with N₂, then t-BuOK (30 ml, 30 mmol, IM in THF), 4-bromopyridine hydrochloride (2.1 g, 10.7 mmol) and Pd(dppf)Cl₂ (39.6 mg, 0.538 mmol) was added. Tlie mixture was stirred at 60°C for 3h. After cooling to room température, sat.aq NHjCl (15 ml) was added and the solution was extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine and dried over NaiSO^ concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc: Petroleum ether=4:l) to give 2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (360 mg, yield: 25.7%). 'H NMR (CDClj 400MH_z): <58.75 (d, J = 1.6 H_z, IH), 8.71 (d, J= 6.0 H_z, 2H), 7.90 (dd, J= 8.0 Hz, 2.0 H_z, IH), 7.77 (d, J = 8.4 H_z, IH), 7.31 (d, J =6.0 H_z, 2H), 5.26 (s, IH).

2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine:

A mixture of 2-(pyridin-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (360 mg, 1.36 mmol) and ΝΗ₃.Η₂Ο (2 mL) in MeOH (30 mL) was hydrogenated with Raney Ni (700 mg) under H₂ (50 Psi) for 5h. The reaction mixture was filtered and concentrated to give 2-(pyridin-

4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (300 mg), which was used in the next step without further purification.

The follwoing intermediates were prepared in a similar way: 2-(Pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine; 2-Phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine; 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamîne;

2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine; 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyrimidin-3-yl)ethanamine;

2-phenyl-2-(6-(tri fluoromethyl)pyridin-3-yl Jethanam i ne;

2-(4,4-difluorocyclohexylidene)-2-(2-methylpyrimidin-5-yl)acetonitrile:

To a solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (l g, 7.52 mmol) and 4,4difluorocyclohexanone (l.l g, 8.27 mmol) in 1,4-dioxane (40 mL) was added t-BuOK. (0.8 g, 8.27 mmol) in two portions. After the addition was completed, the reaction was heated to 60°C and stirred ovemight. The reaction solution was cooled to 0°C, quenched by saturated NH4CI aq. solution and extracted with EtOAC (50 m x 3). The combined organic layer was washed with brine, dried over NaiSC^ and concentrated to get the crude product, which was purified by column chromatography on silica gel (Petroleum ether : EtOAc=4:l~2:l) to afford 2-(4,4difluorocyclohexylidene)-2-(2-methyIpyrimidin-5-yl)acetonitrile (440 mg, yield: 23.5%). 'H NMR (CDC13 varian 400 MHz): Ô8.61 (s, 2H), 2.97 (t, >8.0 Hz, 2H), 2.80 (s, 3H), 2.55 (t, >8.0 Hz, 2H), 2.27-2.17 (m, 2H), 2.09-1.98 (m,2H).

2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine:

A mixture of 2-(4,4-difluorocyclohexylidene)-2-(2-methylpyrimidin-5-yl)acetonitrile (290 mg, 0.57 mmol), Raney-Ni (1.5 g), ΝΗ3Ή2Ο (2 mL) in MeOH (30 mL) was degassed and purged with nitrogen and H2 each 3 times. The mixture was stirred at room température under H2 (50 psi) for 4h. The resulting mixture was filtered through the celite. The filtrate was concentrated under reduced pressure to give 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5yl)ethanamine (280 mg, crude), which was used in the next step without further purification.

The folhvoing intermediates were prepared in a simiiar way: 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;

KOtBu, DME Pd(dppf)CI₂,60 °C

2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile:

A solution of 2-(4-fluorophenyl)acetonitrile (2 g, 14.8 mmol) În DME (50 mL) was degassed. KOtBu (6.63 g, 59.2 mmol) was added in portions. After addition was completed, the mixture was stirred for 5 min at room température and a brown suspension was formed. Then 5bromo-2-(trifluoromethyl)pyridine (6,69 g, 29.6 mmol) was added followed by Pf(dppf)Cl2 (1.35 g, 1.48 mmol). The resulting mixture was heated to 60 °C for 4 h.. The reaction mixture was cooled to room température and quenched by aq. NH4C1 to pH=5~6. The mixture was extracted with EtOAc(50 mLx3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash combi (Petroleum ether/EtOAc=15:l) to give 2-(4-fiuorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (18 g, -70% purity +350 mg, pure, yield: 51.8%). ^lH NMR (CDC13 400MHz) <58.98 (s, IH), 7.89 (dd, J= 8.4, 2.4 Hz, IH), 7.73 (d, J= 8.4 Hz, IH), 7.40-7.30 (m, 2H), 7.20-7.10 (m, 2H), 5.26 (s, IH).

The follwoing intermediates were prepared in a similar way: 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)acetonitrile; 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile;

OH O

OMe ^N t-BuOK.THF Jl A methyl 5-cyano-2-hydroxy-5-(2-methylpyrimidin-5-yl)cyclohex-1 -enecarboxylate:

A solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (4 g, 0.03 amol) and methyl acrylate (5.69 g, 0.066 mol) in THF (60 mL) was added t-BuOK (93 mL, 0.093 mol, IM in THF) and stirred at room température for 4h. The reaction mixture was quenched by sat. NH4CI and extracted with EtOAc (3x150 mL). The organic layer was dried over Na₂SÜ4 and concentracted to give methyl

5-cyano-2-hydroxy-5-(2-methylpyrimidin-5-yl)cyclohex-l-enecarboxylate (5.5 g), which was used for the next step directiy.

CN l-(2-methylpyrimidin-5-yl)-4-oxocyclohexanecarbonitrile:

A solution of methyl 5-cyano-2-hydroxy-5-(2-methylpyrimidin-5-yl)cyclohex-l-enecarboxylate (6.2 g, 0.023 mol), NaCI (1.46 g, 0,025 mol) and H₂O (1.24 mL, 0.069 mol) in DMSO (50 mL) was heated to l60°C for 3h. After cooling to room température, the reaction was added water and extracted with EtOAc (6x100 mL). The organic layer was washed with brine, dried over Na₂SO₄ and concentracted. The crude product was purified by flash chromatography(EtOAc: Petroluem ether = 1:3-3:2) to give l-(2-methylpyrimidin-5-yl)-4-oxocycIohexanecarbonitrile (2 g, yield: 41%). *H NMR (CDClj 400 MHz): <58.80 (s, 2H), 3.00-2.90 (m, 2H), 2.77 (s, 3H),

4,4-difluoro-l-(2-methylpyrimidin-5-yl)cyclohexanecarbonitrile:

A solution of l-(2-methylpyrimidin-5-yl)-4-oxocyclohexanecarbonitrile (2.0 g, 9.3 mmol), XtalFlour-E (4.69 g, 20.47 mmol) and Et₃N3HF (4.79 g, 29.76 mmol) in DCM (40 mL) was stirred at room température ovemight. The reaction mixture was quenched by sat. NaHCO₃ and extracted with DCM (3x50 mL). The organic layer was dried over NajSOq and concentrated. The crude product was purified by flash column chromatography to give 4,4-difluoro-l-(2methylpyrimidin-5-yl)cyclohexanecarbonitrile (1.2 g, yield: 54%),which was not pure and used

4,4-difluoro-l-(2-methylpyrimidin-5-yl)cycIohexanecarboxylic acid:

To a mixture of 4,4-difluoro-l-(2-methylpyrimidin-5-yl)cyclohexanecarbonitrile (1.2 g, 5.1 mmol) in MeOH/H₂O (20 mL, 1:1) was added NaOH (612 mg, 15.3 mmol) and heated to 100°C ovemight. The MeOH was removed in vacuo. The aqueous layer was extracted with EtOAc (3^x30 mL) and the organic layers was discarded. The aqueous layer was adjusted pH to 3-4 with 3N HCl and extracted with EtOAc (3x30 mL). The organic layer was dried over Na₂SO₄ and concentracted to give 4,4-difluoro-l-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid (1.2 g, yield: 92%). ‘H NMR (CDC1₃ 400 MHz): <58.81 (s, 2H), 2.80-2.60 (m, 5H), 2.20-2.00 (m, 6H).

4.4- difluoro-N-methoxy-N-methyl-l-(2-methylpyrimidin-5-yl)cyclohexanecarboxamide:

A solution of 4,4-difluoro-l-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid (1.2 g, 4.68 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (456 mg, 4.68 mmol), HOBt (759,33 mg, 5.62 mmol), EDCl.HCl (1,08 g, 5.62 mmol) and DIPEA (3.23 mL, 18.73 mmol) in DMF (20 mL) was stirred at room température. The reaction mixture was added water and extracted with EtOAc (3x50 mL). The organic layer was washed with brine, dried over NaiSO.) and concentrated to give 4,4-difluoro-N-methoxy-N-methyl-l-(2-methylpyrimidin-5yl)cyclohexanecarboxamide (380 mg), which was used for the next step directly. About 0.9 g of

4.4- difluoro-l-(2-methylpyrimidin-5-yl)cyclohexanecarboxylic acid was recycled.

-(4,4-difluoro-1 -(2-methylpyrimidin-5-yl)cyclohexyl)ethanone:

A solution of 4,4-difluoro-N-methoxy-N-methyl-l-(2-methylpyrimidin-5yl)cyclohexanecarboxamide (700 mg, 2,34 mmol) in THF (20 mL) was added MeMgBr (11.7 mL, 35.12 mmol, 3M in Et₂O) at 0°C and stirred at room température for 4h. The reaction mixture was quenched by saturated NHjCl at 0°C and extracted with EtOAc (2*50 mL). The organic layer was washed with brine, dried over Na₂SO4 and concentrated to give crude product, which was purified by flash chromatography (EtOAc: petroluem ether = 1:3-3:2) to give 1-(4,4difluoro-l-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone (350 mg, yield: 59%). *H NMR (CDClj 400 MHz): <58.58 (s, 2H), 2.73 (s, 3H), 2.55-2.45 (m, 2H), 2.20-1.85 (m, 9H).

A	NHjOH.HCI	F F
	HjO.EtOH.etrC	AÎJ

(Z)-l-(4,4-difluoro-l-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone oxime:

A mixture of 1 -(4,4-difluoro- l-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone (350 mg, 1.38 mmol), NH₂OH.HC1 (143.7 mg, 2.07 mmol) and NaOH (165.6 mg, 4.14 mmol) in EtOH/H₂O (16 mL, 1:1) was heated to 80 °C ovemight. The EtOH was removed. The residue was extracted with EtOAc (2x20 mL). The organic layer was dried over Na2SÜ4 and concentrated to give (Z)l-(4,4-di fluoro-l-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone oxime (320 mg), which was used for the next step directly.

l-(4,4-difluoro-l-(2-methylpyrimidin-5-yl)cyclohexyl)ethanamine:

A mixture of (Z)-l-(4,4-difluoro-l-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone oxime (320 mg, 1.19 mmol) and aq.NHj (2 mL) was hydrogenated with Raney Ni (300 mg) under FL (50 Psi) for 3h. The reaction mixture was fîltered and concentrated. The residue was dissolved in EtOAc (15 mL), dried over Na2SO4 and concentrated to give l-(4,4-difluoro-l-(2methylpyrimidin-5-yl)cyclohexyl)ethanamine (300 mg), which was used for the next step directly.

4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carbonitrile:

A solution of 2-(2-methylpyrimidin-5-yl)acetonitrile (4 g, 0.03 amol) and l-bromo-2-(2bromoethoxy)ethane (7.66 g, 0.033 mol) in 1,4-dioxane (60 mL) was added t-BuOK. (66 mL, 0,066 mol, IM in THF) and heated to 80 °C for 4h. The reaction mixture was cooled to room température, quenched by satNHqCl. The 1,4-dioxane was removed under reduced pressure. The residue aqueous layer was extracted with EtOAc (3x150 mL). The organic layer was dried over Na2SÛ4 and concentracted to give 4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4carbonitrile (5.5 g, yield: 90.5%). 'H NMR (CDCh 400 MHz): <5'8.75 (s, 2H), 4.15-4.05 (m, 2H), 3.95-3.85 (m, 2H), 2.75 (s, 3H), 2.15-2.00 (m, 4H).

4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxylic acid:

A mixture of 4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carbonitrile(5.5 g, 0.027 mol) in MeOH/H₂O (60 mL, 1:1) was added NaOH (3.25 g, 0.081 mol) and heated to 100°C ovemight. The MeOH was removed in vacuo. The aqueous layer was extracted with EtOAc (2><30 mL) and the organic layers was discarded. The aqueous layer was adjusted pH to 2~3 with 3N HCl and extracted with EtOAc (6x50 mL). The organic layer was dried over Na₂SO4 and concentracted to give 4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxylic acid (4.0 g, yield: 67%). 'H NMR (DMSO-dû 400 MHz): <513.04 (br, IH), 8.71 (s, 2H), 3.80-3.70 (m, 2H), 3.60-3.40 (m, 2H), 2.61 (s, 3H), 2.40-2.30 (m, 2H), 2.00-1.85 (m, 2H).

ΌΗ

HOBT, EDCI. DIPEA.DMF

N-methoxy-N-methyl-4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxamide:

A solution of 4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxylic acid (4.0 g, 18.02 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (2.1 g, 21.6 mmol), HOBt (2.92 g, 21.6 mmol), EDCI.HCl (4.15 g, 21.62 mmol) and DIPEA (15.6 mL, 90.1 mmol) in DMF (50 mL) was stirred at room température ovemight. To the reaction mixture was added water and extracted with EtOAc (3x200 mL). The organic layer was washed with brine, dried over Na₂SO4 and concentrated to give crude product, which was purified by flash column chromatography (EtOAc: petroleum ether = 1: 1) to give N-methoxy-N-methyl-4-(2-methylpyrimidin-5yl)tetraliydro-2H-pyran-4-carboxamide (3.0 g, yield: 63%). 'H NMR (CDCI3 400 MHz): <58.55 (s, 2H), 3.90-3.75 (m, 4H), 3.14 (s, 3H), 2.95 (s, 3H), 2.72 (s, 3H), 2.55-2.45 (m, 2H), 2.06-1.95 (m, 2H).

l-(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)ethanone:

To a solution of N-methoxy-N-methyl-4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4carboxamide (1.0 g, 3.0 mmol, 80% purity in LC-MS) in THF (10 mL) was added MeMgBr (7.05 mL, 21.1 mmol, 3M in Et₂O) at 0°C and stirred at room température for 3h. The reaction mixture was quenched by saturated NH4CI at 0°C and extracted with EtOAc (3x50 mL). The organic layer was washed with brine, dried over Na₂SO4 and concentrated to give crude product, which was purified by flash column chromatography (EtOAc: petroleum ether = 1: 1) to give 1(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)ethanone (0.3 g, yield: 69.3%). *H NMR

(CDCl₃ 400 MHz): <58.58 (s, 2H), 3.90-3.80 (m, 2H), 3.65-3.55 (m, 2H), 2.75 (s, 3H), 2.50-2.40 (m, 2H), 2.15-2.05 (m, 2H), 2.02 (s, 3H).

NaBH₃CN,EtOH l-(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)ethanamine:

A mixture of l-(4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)ethanone (300 mg, 1.35 mmol), saturated NH4OAC in EtOH (15 mL) and aq.NH₃ (5 mL) was added NaCNBH₃ (255 mg, 4.05 mmol) and heated to reflux overnight. The EtOH was removed. The residue was extracted with EtOAc (5><10 mL) and the organic layer was discarded. The précipitation of solid was collected by filtration from the aqueous layer after 16 hours to give l-(4-(2-methylpyrimidin-5yl)tetrahydro-2H-pyran-4-yl)ethanamine (100 mg, yield: 33.3%). 'H NMR (DMSO-dô 400

MHz): <58.67 (s, 2H), 3.80-3.65 (m, 2H), 3.20-3.05 (m, 2H), 2.63 (s, 3H), 2.45-2.35 (m, IH),

2.35-2.25 (m, 2H), 1.81-1.70 (m, 2H), 0.87 (d, J= 6.4 Hz, 3H).

4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butanenitrile:

A solution of 2-(2-(trifluoromethyl)pyrimidin-5-yl)acetonitrile (500 mg, 2.67 mmol) and 1bromo-2-methoxycthane (419 mg, 2.81 mmol) in 1,4-dioxane (5 mL) was degassed and added tBuOK (2.81 mL, 2.81 mmol, IM in THF) at 0°C. The resulting mixture was stirred at room température overnight. The reaction mixture was quenched by sat.NI-LCl and extracted with EtOAc (3x10 mL). The organic layer was dried over Na₂SO4 and concentrated. The crude product was purified by flash coiumn chromatography (EtOAc: petroleum ether = 1:10) to give 4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butanenitrile (100 mg, yield: 15%, 85% purity in LCMS, [M+H] =246).

A solution of pyridazine (2.2 g, 27.5 mmol) and 2-phenylacetic acid (18.7 g, 137.5 mmol) , AgNO₃ (1.4 g, 8.25 mmol) in 2N H₂SO4 (27.7 ml) was heated to 60-70°C under stirring , then, a solution of (NH4)₂S₂0g (18.6 g, 82.5 mmol) in 80 ml of water was added within 20 minutes, After heating to 70-90°C for 1.5 hour, the reaction solution was cooled to room température and extracted with DCM (2 x 100 ml), the combined organic layers were washed with 2N H₂SO4 (3 x 70 ml), then, the combined aqueous layer was made alkaline with 50% NaOH and extracted with DCM (3 x 80 ml), dried over Na₂SC>4 and concentrated to get the crude product, which was purified by column chromatography on silica gel (petroleum Ether: EtOAc = 2:1) to afford 4benzylpyridazine (1.0 g, yield: 22%). ‘H NMR (CDC1₃ 400 MHz): 69.09 (s, IH), 9.06 (d, 5.2

Hz, 1 H), 7.40-7.28 (m, 3H), 7.25-7.20 (m, 1 H), 7.18 (d, J = 7.2 Hz, 2H), 4.0 (s, 2H).

SeO₂

---------*AcOH

Phenyl(pyridazin-4-yl)methanone:

A solution of 4-benzylpyridazine (1.0 g, 5.9 mmol) in AcOH (28 mL) was added dropwise to a stirring suspension of SeO₂ (3.2 g, 29.5 mmol) in AcOH (28 mL), the resulting mixture was heated to 100°C for lh. TLC showed the starting material had disappeared, then the reaction solution was filtrated, the filtration was concentrated under reduced pressure, and Sat.aq Na₂CO3 was added to adjust PH = 9-10, then, extracted with DCM (50 mL x 3), washed by brine, dried over Na₂SOq and concentrated to get the phenyl(pyridazin-4-yl)methanone (1,0 g, yield: 91%). 'H NMR (CDCh 400 MHz): 69.50-9.45 (m, 2H), 7.83 (d, J= 7.6 Hz, 2H), 7.78-7.74 (dd, J= 5.2,

2.4 Hz, IH), 7.74-7.68 (m, IH), 7.57 (t, J= 7.2 Hz, 2H).

(E)-Ethyl 3-phenyl-3-(pyridazin-4-yl)acrylate;

To a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.46 g, 7.93 mmol) in THF (40 mL) was added NaH (476 mg, 11.9 mmol) in portions at 0°C, the resulting mixture was stirred at 0°C for 20 minutes, then, the phenyl(pyridazin-4-yl)methanone was added in portions, the resulting mixture was stirred at 0°C for 4 hour. The LC-MS showed the MS signal of desired product was detected, then, the reaction solution was added sat. aq. NH4CI at 0°C, then, extracted with AcOEt (3 x 50 ml), the combined organic layers were washed with brine, dried over NajSOq and concentrated to get the crude product, which was purified by column chromatography on silica gel (petroleum Ether: EtOAc = 2:1) to afford (E)-ethyl 3-phenyl-3-(pyridazin-4-yl)acrylate (1.68 g, yield: 83.2%). ^lH NMR (CDClj 400 MHz): 59.25 (d, J= 5.2 Hz, IH), 9.06 (s, IH), 7.47-7.32 (m, 4H), 7.30-7.20 (m, 2H), 6.55 (s, l H), 4.95 (q, J = 7.2 Hz, 2H), l. 16 (t, J = 7.2 Hz, 3H).

Ethyl 3-phenyl-3-(pyridazin-4-yl)propanoate:

To a solution of (E)-ethyl 3-phenyl-3-(pyridazin-4-yl)acrylate (1.8 g, 7.09 mmol) in PhMe (40 mL), TsNHNH₂ (2.64 g, 14.2 mmol) and Et₃N (2.15 g, 21.3 mmol) was added, the resulting mixture was heated to 100°C ovemight. The reaction was detected by TLC, TLC showed the appearance of desired product, then, the solvent was removed under reduced pressure, H₂O was added and extracted with AcOEt (3 x 50 ml), the combined organic layers were washed by brine, dried over Na₂SÛ4 and concentrated to get the crude product, which was purified by column chromatography on silica gel (Petroleum Ether: EtOAc - 3:2) to afford ethyl 3-phenyl-3(pyridazin-4-yl)propanoate (1.20 g, yield: 66%). 'H NMR (CDC1₃ 400 MHz): 69.12 (d, J= 2.0 Hz, IH), 9.09 (d, J= 6.8 Hz, IH), 7.40-7.24 (m, 4H), 7.20 (d, J= 7.2 Hz, 2H), 4.56 (t, J= 8.0

Hz, 1 H), 4.08 (q, J = 7.2 Hz, 2H), 3.09 (d, J = 8.0 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H).

To a solution of ethyl 3-phenyl-3-(pyridazin-4-yl)propanoate (1.0 g, 3.9 mmol) in MeOH (20 mL) was added 2N NaOH (6mL, 11.7mmol), the resulting mixture was stirred at room température ovemight. MeOH was removed under reduced pressure and pH adjusted to 4-5 by aq. HCl (2N), extracted with AcOEt (6 x 100 ml), the combined organic layer was washed with brine, dried over Na₂SO4 and concentrated to get the 3-phenyl-3-(pyridazin-4-yl)propanoic acid (750 mg, yield: 84%). 'H NMR (CDC1₃ 400 MHz): 69.27 (d, J= 1.2 Hz, IH), 9.09 (dd, J= 4.0, 1.2 Hz, 1 H), 7.67 (dd, J = 5.6, 2.4 Hz, 1 H), 7.41-7.36 (m, 2H), 7.34-7.27 (m, 2H), 7.24-7.18 (m,

IH), 4.48 (t, 7=8.0 Hz, 1 H), 3.27-3.15 (m, IH), 3.10-3.00 (m, IH).

To a solution of 3-phenyl-3-(pyridazin-4-yl)propanoic acid (570 mg, 2.5 mmol) in DMF (30 mL) was added EtîN (505 mg, 5.0 mmol), followed by the DPPA (722 mg, 2.6 mmol) in portions at 0°C, the resulting mixture was stirred at room température for l .5 hour. The reaction was diluted with water, extracted with AcOEt (3 x 40 ml), the combined organic layer was washed by brine, dried over Na₂SO4 and concentrated to get the 3-phenyl-3-(pyridazin-4-yl)propanoyl azide (crude 650 mg), which was used for next step directly.

t-BuOH

----------->.

PhMe, 80°C

NHBoc tert-Butyl (2-phenyl-2-(pyridazin-4-yl)ethyl)carbamate:

A solution of 3-phenyl-3-(pyridazin-4-yl)propanoyl azide (650 mg, 2.57 mmol) in t-BuOH (3 ml) and PhMe (10 ml) was stirred at 80°C ovemight. The reaction was detected by LC-MS, LCMS indicate the desired product was formed, then, the solvent was removed under reduced pressure to get the crude product, which was purified by column chromatography on silica gel (petroleum Ether: EtOAc = 3:2-1:2) to afford tert-butyl (2-phenyl-2-(pyridazin-4yl)ethyl)carbamate (200 mg, yield: 26%). ’H NMR. (CDCI3 400 MHz): 69.12-9.07 (m, 2H), 7.427.28 (m, 4H), 7.23-7.18 (m, 2H), 4.62 (m, 1 H), 4.30-4.20 (t, J = 7.6 Hz, 1 H), 3.95-3.83 (ni, 1 H), 3.75-3.65 (m, IH), 1.40 (s, 9H).

2-Phenyl-2-(pyridazin-4-yl)ethanamine:

A solution of tert-butyl (2-phenyl-2-(pyridazin-4-yl)ethyl)carbamate (120 mg, 0.40 mmol) in DCM (2 ml) and TFA(2 ml) was stirred at room température for 4 hours. The solvent was removed under reduced pressure and the residue was diluted with sat.aq Na₂CO3 to adjust pH = 9-10, then, extracted with AcOEt (3 x 30 ml), the combined organic layer was washed with brine, dried over Na₂SO4 and concentrated to get the 2-phenyl-2-(pyridazin-4-yl)ethanamine (crude 80 mg), which was used for next step directly.

5-(Diisopropoxymethyl)-2-methylpyrimidine:

To a mixture of 2-methylpyrimidine-5-carbaldehyde (l.O g, 8.2 mmol) and triisopropoxymethane (2.3 g, 12 mmol) in isopropanol (15 ml) was added methanesulfonic acid (0.079 g, 0.053 ml, 0.819 mmol). The reaction was stirred at room température for 23hours. Potassium carbonate (1.132 g, 8.19 mmol) was added and the mixture was filtered and the solution was concentrated in vacuo. The crude mixture was purified by flash chromatography to yield 5(diisopropoxymethyl)-2-methylpyrimidine (536 mg, 29%) ^lH NMR (500 MHz, CDCh) δ 8.71 (s, 2H), 5.60 (s, IH), 3.93 (dt, J = 12.3, 6.1 Hz, 2H), 2.74 (s, 3H), 1.21 (dd, J = 14.8,6.1 Hz, 12H).

2-Isopropoxy-2-(2-methylpyrimidin-5-yl)acetonitrile:

A solution of 5-diisopropoxymethyl-2-methyl-pyrimidine (335 mg, 1.49 mmol) in DCM (5 mL, 80 mmol) was cooled at 0 °C. Zinc diiodide (47.7 mg, 0.149 mmol) TMSCN (219 uL, 1.64 mmol) were added and cooiing removed. After stirring for 24hours TLC indicated that starting materiale was présent. TMSCN (60 uL, 0.45 mmol) and zinc diiodide (48 mg, 0.15 mmol) were added and the reaction was stirred for a further 3.5hours.The reaction was poured into water (20 mL) and extracted with DCM (3x20 mL). The combined organic phases were washed with brine, dried over MgSCL and concentrated in vacuo. The crude product was purified by flash chromatography 2-Isopropoxy-2-(2-methylpyrimidin-5-yl)acetonitrile (217 mg, 76%).

*H NMR (500 MHz, CDCh) δ 8.75 (s, 2H), 5.29 (s, IH), 4.21 - 3.95 (m, IH), 2.78 (s, 3H), 1.32 (dd, J — 21.7, 6.1 Hz, 6H).

2-Isopropoxy-2-(2-methylpyrimidin-5-yl)ethanamine:

2-Isopropoxy-2-(2-methylpyrimidin-5-yl)acetonitrile (169 mg, 0.884 mmol) was dissolved in methanol (10 ml) and 7M NH₃ in methanol (4 ml). Argon was bubbled through the solution for 5 minutes. To the reaction was added Raney nickel (100 mg, 1.704 mmol) and it was fitted with a

Hî-filled balloon. After stirring at room température for 20hours LCMS shows only around 30% conversion and raney nickel (100 mg, 1.70 mmol) was added. The reaction was stirred for another 72hours, then filtered through a plug of celite and concentrated in vacuo. The crude product used for next reaction without further purification.

LC-MS (m/z) 196.2 (MH+), t_R (minutes, Method D) = 0.29.

The follwoing intermediates were prepared in a similar way: 4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butan-l-amine;

( 1 -Methyl-1 H-pyrazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanone:

A solution of 4-îodo-l-methyl-lH-pyrazole (0.80 g, 3.9 mmol) in THF (7.04 g, 8.00 ml, 98 mmol) was cooled at 0 °C. A solution of isopropylmagnesium chloride lithium chloride complex in THF (5.42 ml, 4.23 mmol, 0.78 molar) was added dropwise and the reaction was stirred for l'/ihour. A solution of N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide (0.733 g, 4.23 mmol) in THF (2 mL) was added dropwise. Cooling was removed after 15 min and réaction was then stirred for 2 hours. To the mixture was added 2 M HCl (20 mL) and it was extracted with AcOEt (3x25 mL). The combined organic phases were washed with brine, dried over MgSOq and concentrated in vacuo. The crude product was purified by flash chromatography to yield (1methyl-lH-pyrazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanone (220 mg, 1.13 mmol, 29.4 % yield).

*H NMR (600 MHz, CDC1₃) δ 7.87 (s, III), 7.87 (s, IH), 4.03 (ddd, J = 11.4, 4.1, 2.4 Hz, 2H), 3.92 (s, 3H), 3.49 (td, J = 11.7, 2.3 Hz, 2H), 3.06 (tt, J = 11.3, 3.8 Hz, IH), 1.86 (dtd, J = 13.8, 11.7, 4.4 Hz, 2H), 1.72 (ddd, J = 13.4, 3.7, 2.0 Hz, 2H).

Ethyl 3-(l-methyl-1 H-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)acrylate:

Sodium hydride (60% suspension in minerai oil) (96 mg, 2.41 mmol, 60 %) was suspended in

THF (2 ml) under argon. Triethyl phosphonoacetate (492 mg, 0.435 ml, 2.19 mmol) was added dropwise to the mixture over a period of 30 min and the reaction was then stirred for 60 minutes.

(l -Methyl-lH-pyrazol-4-yl)(tetrahydro-2H-pyran-4-yl)methanone (213 mg, l .097 mmol) in THF (2.0 mL) was added dropwise. The reaction was stirred for 3 hours at room température. Heated for 22 hours at reflux and cooled to room température. The reaction was poured into H₂O (25 mL) and extracted with AcOEt (3x25 mL), the combined organic phases were washed with brine, dried over MgSOq and concentrated in vacuo.The crude product was used for the next step without further purification.

Ethyl 3-(l-methyl-lH-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate:

Ethyl 3-(l-methyl-lH-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)acrylate (205 mg, 0.78 mmol) was dissolved in methanol (10 ml) and argon was bubbled through the solution for 5 minutes. To the solution was added 10% Pd/C (41 mg) and the flask was fitted with a balloon containing hydrogen. The reaction was stirred at room température for 16 hours. The catalyst was removed by filtration through a plug of celite. And solution was concentrated in vacuo. The crude product was used dîrectly in the next reaction.

tert-Butyl (2-( 1 -methyl-1 H-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate:

Crude ethyl-3-(l-methyl-lH-pyrazol-4-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate (207 mg, 0.777 mmol) dissolved in THF (5 ml). Trimethylsilanol, sodium sait solution in THF (0.855 ml, 0.855 mmol, 1 molar) was added at room température. The mixture stirred for 3 days and concentrated in vacuo. LCMS showed only partial conversion. Trimethylsilanol, sodium sait solution in THF (10 ml, 10,00 mmol, 1 molar) was added and mixture stirred ovemight at room température. A 2 M HCl in solution in THF (20 mL) was added to the reaction and it was stirred for 30 minutes. The mixture was now fïltered through a plug of celite and concentrated in vacuo. The crude carboxylic acid sait was suspended in tert-butanol (5 ml). Triethyl amine (0.189 g, 0.260 ml, 1.865 mmol) and diphenylphosphoryl azide (0.280 g, 0.219 ml, 1.017 mmol) were added and the mixture was heated at 80°C ovemight. The reaction was cooled to room température and poured into H₂O (15 mL) and extracted with AcOEt (3xl 5 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography.

LC-MS (m/z) 310.2 (MH+), t_R (minutes, Method D) = 0.62.

2-(l-Methyl-lH-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine:

tert-Butyl (2-(l -methyl- lH-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate (49 mg, 0.132 mmol) was dissolved in DCM (5 ml) and cooled at 0°C. TFA (740 mg, 0.5 ml, 6.49 mmol) was added and mixture stirred for 30 min after which cooling was removed and the mixture was stirred for afurther 30 minutes.

Concentrated in vacuo to yield the crude amine as the trifluoroacetic acid sait.

5-(l,3-Dioxan-2-yl)-2-methylpyrimidine:

To a solution of 2-methylpyrimidine-5-carbaldehyde (0.808 g, 6.62 mmol) and propane-1,3-diol (1.01 g, 0.868 ml, 13.2 mmol) in toluene (7.6 ml) and THF (1.9 ml) was added p-toluenesulfonic acid (11 mg, 0.066 mmol). The reaction was heated at 65 °C for 4.5 hours. The reaction mixture was then poured into H₂O (50 mL) and extracted with AcOEt (3x50 mL). The combined organic phases were washed with brine, dried over MgSOq and concentrated in vacuo to yield 5-(1,3dioxan-2-yl)-2-methylpyrimidine (620 mg, 3.44 mmol, 52%) used for next step without further purification.

2-(3-Hydroxypropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile:

To an ice-cold solution of 5-(l,3-dioxan-2-yl)-2-methylpyrimidine (140 mg, 0.78 mmol) in DCM (5.0 ml) was added zinc iodide (124 mg, 0.39 mmol). Trimethylsilyl cyanide (116 mg, 0.155 ml, 1.17 mmol) was added dropwise over a period of 10 minutes.Cooling was removed and the reaction was stirred for 40 hours at room température. The mixture was poured into H2O (20 mL) and extracted with DCM (3 x 20 mL), the combined org. phases were washed with brine, dried over MgSOq and concetrated in vacuo. The crude product was used for next step without further purification.

^lH NMR (600 MHz, CDCl₃) δ 8.78 (s, 2H), 5.32 (s, IH), 4.00 (dt, J = 8.9, 6.0 Hz, IH), 3.82 (dt, J = 8.9, 6.1 Hz, IH), 3.78 (t, J = 6.0 Hz, 2H), 2.79 (s, 3H), 1.95 (p, J = 6.0 Hz, 2H).

OH

2-(3-Bromopropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile:

A solution of 2-(3-hydroxypropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile (54 mg, 0.26 mmol) and CBr4 (259 mg, 0.782 mmol) in DCM (3 ml) was cooled at 0 °C. Triphenylphosphine (205 mg, 0.782 mmol) in DCM (l ml) was added dropwise over a period of 5 minutes. The reaction was stirred for 2 hours and then allowed to warm to room température. To the mixture was added Et2<3 (5 mL) and the cloudy solution was filtred through a plug of celite. The resulting solution was concentrated in vacuo and purified by flash chromatography to yield 2-(3-Bromopropoxy)2-(2-methylpyrimidin-5-yl)acetonitrile.

'H NMR (500 MHz, CDClj) δ 8.75 (s, 2H), 5.27 (s, IH), 3.97 (m, IH), 3.79 (m, IH), 3.47 (t, J = 6.3 Hz, 2H), 2.77 (s, 3H), 2.24 - 2.12 (m, 2H).

2-(2-Methylpyrimidin-5-yl)tetrahydrofuran-2-carbonitrile:

A solution of 2-(3-bromopropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile (24 mg, 0.089 mmol) in THF (3 mL) was cooled at -78°C. Lithium bis(trimethylsilyl)amîde in THF (141 μΐ, 0,141 mmol, l molar) was added slowly and the mixture was stirred for l hour at -78°C. To the reaction mixture was added sat. aq, NH4CI (ÎO mL) and the mixture was allowed to warm to room température. The reaction mixture was dilluted with H₂O (ÎO mL) and extracted with AcOEt (3xl 5 mL). The combined org. phases were washed with brine, dried over MgSC>4 and concentrated in vacuo. The crude product was used directly for next step without further purification.

LC-MS (m/z) 190.1 (MH+), t_R (minutes, Method D) = 0.38,

(2-(2-Methylpyrimidin-5-yl)tetrahydrofuran-2-yl)methanamine:

2-(2-Methylpyrimidin-5-yl)tetrahydrofuran-2-carbonitrile (18 mg, 0.095 mmol) was dissolved in MeOH(5 ml) and 7M NH3 in MeOH (1 ml). Argon was bubbled through the solution. Raney Nickel (6 mg, 0.1 mmol) was added and the flask was fitted with a H₂-balloon and stirred at room température for 1 ^l/i hour. Reaction was filtred through a plug of celite and concentrated in vacuo. Used for next step without further purification.

LC-MS (m/z) 194.0 (MH+), t_R (minutes, Method D) = 0.17.

( 1 -methyl-1 H-pyrazol-4-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone:

A solution of 5-bromo-2-(trifluoromethyl)pyridine (3.80 g, 16.82 mmol) in THF (24 ml) was cooled at -18 °C. A solution of isopropylmagnesium chloride lithium chloride complex in THF (17.97 ml, 14.02 mmol, 0.78 molar) was added dropwise over a period of 30 minutes. The reaction was then cooled at -78 °C kept there for 1½ hour. The reaction was allowed to reach -3 °C before being cooled to -10 °C. A solution of N-methoxy-N,l-dimethyl-lH-pyrazole-4carboxamîde (2.372 g, 14.02 mmol) in THF (8 ml) was added dropwise over a period of 5 minutes. The reaction was allowed to warm to room température and stirred over night. Cooled to 0 °C and a 2 M HCl solution (150 mL) was added slowly. The crude mixture was extracted with AcOEt (3x150 mL), the combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by comlumn chromatography to yield (l-methyl-lH-pyrazol-4-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone 1.22 g (34%) as a light yellow solid.

*H NMR (600 MHz, DMSO) δ 9.12 (d, J = 2.0 Hz, IH), 8.53 (s, IH), 8.45 (ddd, J = 8.0, 2.1, 0.4

Hz, IH), 8.10 (dd, J = 8.1, 0.7 Hz, IH), 8.06 (d, J = 0.7 Hz, IH), 3.93 (s, 3H).

LC-MS (m/z) 256.0 (MH+), t_R (minutes, Method D) = 0.54.

N-N

Ethyl 3-(l-methyl-lH-pyrazol-4-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate: Triethyl phosphonoacetate (2.1 g, 1.9 ml, 9.4 mmol) was added dropwise to a suspension of sodium hydride suspension (0,41 g, 10.3 mmol, 60 %) in THF (10 ml). The mixture was stirred for 1½ hour and then a solution of ( 1-methyl-lH-pyrazol-4-yl)(6-(trifluoromethyl)pyridin-3yl)methanone (1.2 g, 4.7 mmol) in THF (10 ml) was added dropwise. The reaction was stirred for 2 hours at room température and then heated at 65 °C ovemight. The mixture was cooled to room température and poured into H2O (25 mL), extracted with EA (3x25 mL). The combined org. phases washed were washed with brine, dried over MgSO₄ and concentrated in vacuo.

To the crude product was added MeOH (20 ml) and 10% Pd/C (0.500 g) and the mixture was flushed with argon for 5 min and then fitted with a balloon containing H2. After stirring at room température ovemight complété conversion was observed by TLC. The reaction was filtred through celite, concentrated in vacuo and purified by flash chromatography to yield 1.15 g (75%) ethyl 3-( 1 -methyl-1 H-pyrazol-4-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate.

'H NMR (600 MHz, DMSO) δ 8.75 (d, J = 2.0 Hz, IH), 8.01 (dd, J = 8.1, 2.1 Hz, IH), 7.84 (d, J = 8.1 Hz, IH), 7.57 (s, IH), 7.37 (d, J = 0.5 Hz, IH), 4.50 (t, J = 8.0 Hz, IH), 3.97 (qd, J = 7.1, 0.9 Hz, 2H), 3.75 (s, 3H), 3.11 (d, J = 8.0 Hz, 2H), 1.05 (t, J = 7.1 Hz, 3H).

LC-MS (m/z) 328.0 (MH+), t_R (minutes, Method E) = 0.60.

N-N \

tert-Butyl (2-( l-methyl-lH-pyrazol-4-yt)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)carbamate: Ethyl 3-(l-methyl-lH-pyrazol-4-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoate (1.15 g, 3.51 mmol) was mixed with trimethylsilanol, sodium sait solution in THF (30 ml, 30.0 mmol, l molar) and stirred for 24 hours at room température. Trimethylsilanol, sodium sait solution in THF (30 ml, 30.0 mmol, l molar) added and mixture stirred ovemight at room température, LCMS shows incomplète comversion and reaction heated at reflux for 3 hours. The mixture was cooled on an ice bath and HCl in Et20 (48.0 g, 40 ml, 80 mmol, 2 molar) was added and after 10 min the mixture was concentrated in vacuo. The crude reaction mixture was then suspended dry THF (150 mL) and the solid filtred off. The liquid phase was concentrated in vacuo and used for next step without purification.

3-(l-methyl-lH-pyrazol-4-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanoic acid (0.531 g, 1.774 mmol) dissolved in tert-butanol (10 ml. TEA (0.395 g, 0.544 ml, 3.90 mmol) and diphenylphosphoryl azide (0.59 g, 0.46 ml, 2.1 mmol) were added. Heated at 80°C for 29 hours. The reaction was poured into H₂O (50 mL) and extracted with EA (3x50 mL), the combined org. phases washed with brine, dried over MgSCL, concentrated in vacuo and purified by flash chromatography to yield 49 mg (7%) tert-butyl (2-(l -methyl-1 H-pyrazol-4-yl)-2-(6(trifluoromethyl)pyridin-3-yl)ethyl)carbamate.

LC-MS (m/z) 371.2 (MH+), t_R (minutes, Method E) = 0.67.

2-(l-Methyl-lH-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine

Tert-butyl (2-( l -methyl-1 H-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)carbamate (49 mg, 0.132 mmol) was dissolved in DCM (5 ml) and cooled at 0°C. TFA (740 mg, 0.5 ml, 6.49 mmol) was added and mixture stirred for 30 min after which cooling was removed and the mixture was stirred for afurther 30 minutes.

Concentrated in vacuo to yield the crude amine as the trifluoroacetic acid sait.

The following intermediates were prepared in a similar way:

2-( 1 -methyl-1 H-pyrazol-5-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;

2-( 1 -methyl-1 H-imidazol-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine;

C-( l -Methyl-4-phenyl-piperidin-4-yl)-methylamine

Prepared according to the ref: Diamond, J. et al. J. Org. Chem., 1965, 1840

C-( 1 -Pyridin-3-yl-cyclopentyl)-methylamine

Commercially available from Chengdu Chemicals

2-(4-Chloro-phenyl)-2-phenyl-ethyl amine

Commercially available from Sigma Aldrich Chemicals

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

Scheme 1.

This reaction is typically carried out in a solvent such as THF or DMF, employing peptide coupling reagents exemplified 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. Scheme 2.

This reaction is typically carried out in a solvent such as THF or DCM 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-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2,3-dimethyl-benzamide

A mixture of [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine (67.7 mg, 0.3 mmol), 2,3dimethylbenzoyl cliloride (53 mg, 0.315 mmol) and DIPEA (78 mg, 0.60 mmol) in DCM (1.5mL) was stirred at room température for 16 h. The mixture was purified by préparative HPLC to yield the title compound (70.5 mg, yield: 66%). ^]H NMR (CDClj 300MHz): δ ppm 7.40 - 6.98 (m, 7H), 5.35 (bs, IH), 3.95 - 3.87 (m, 2H), 3.70 (d, 2H), 3.70-3.60 (m, 2H), 2.31 (s, 3H), 2.23 (s, 3H), 2.18 - 1.92 (m, 4H). LCMS (MH+): m/z = 358.0, tR (minutes, Method B) = l .03

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

Example lb

N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2-methoxy-benzamide

From 2-methoxybenzoyl chloride and [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine.

LCMS (MH*): m/z = 360.0, îr (minutes, Method B) = 1.01

Example le

2,3-Dicliloro-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2,3-dichlorobenzoyl chloride and [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine.

LCMS (MH⁴): m/z = 399.9, t_R (minutes, Method B) = l .03

Exampie ld

N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2-methyl-benzamide

From 2-methylbenzoyl chloride and [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁴): m/z = 344.0, t_R (minutes, Method A) = l .26

Exampie 2a

2-ChIoro-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-5-methyl-benzamide

A mixture of [4-(4-Chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine (67.7 mg, 0.3 mmol), 2choloro-5-methylbenzoic 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 for 16 h. The mixture was purified by préparative HPLC to yield the title compound (35.5 mg, yield: 31%). LCMS (MH⁺): m/z - 378.0, r_R (minutes, Method A) = 1.38

The following compounds were synthesised in a similar way as to example 2a:

Exampie 2b

N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2-cyano-benzamide

From 2-cyanobenzoic acid and [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁴): m/z = 372.0, t_R (minutes, Method B) = 0.96

Example 2c

2,3-Dichloro-N-( 1 -pyridin-3 -yl-cyclopentylmethyl)-benzamide

From 2,3-dichlorobenzoic acid and C-(l-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH⁴): m/z = 348.9, îr (minutes, Method A) = l. 16

Example 2d

2,3-Dimethyl-N-(l-pyridin-3-yl-cyclopentylmethyl)-benzamide

From 2,3-dimethylbenzoic acid and C-(l-pyrîdin-3-yl-cyclopentyl)-methylamine. LCMS (MH⁴): m/z = 309.1, Îr (minutes, Method A) = 1.11

Example 2e

2-Chloro-5-rnethyl-N-(l-pyridin-3-yl-cyclopentylmethyl)-benzarnide

From 2-chloro-5- methylbenzoic acid and C-(l-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH⁴): m/z = 329.0, tR (minutes, Method A) = 1.14

Example 2f

N-[4-(4-ChloiO-phenyl)-tetrahydro-pyran-4-ylmethyl]-2-trifluoromethyl-benzamide

From 2-trifluoromethylbenzoic acid and [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine.

LCMS (MH⁴): m/z = 397.9, t_R (minutes, Method B) = 1.04

Example 2g

2-Methyl-N-( 1 -pyridin-3-yl-cyclopentylmethyl)-benzamide

From 2-methylbenzoic acid and C-(l-pyridin-3-yl-cyclopentyl)-methylamîne. LCMS (MH⁴): m/z = 357.0, t_R (minutes, Method B)= I.l6

Example 2h

N-[4-(4-Chloro-phenyl)4etrahydro-pyran-4-ylmethyl]-2-fluoro-3-trifluoromethyl-benzamide

From 2-fluoro-3-trifluoromethylbenzoic acid and [4-(4-chloro-phenyi)-tetrahydro-pyran-4-yl]~ methylamine. LCMS (MH⁴): m/z = 415.9, t_R (minutes, Method B) = l. 19

Example 2i

3-Chloro-N-[4-(4-chIoro-phenyl)-tetrahydro-pyran-4-ylmethyI]-2-fluoro-benzamide

From 3-chloro-2-fluorobenzoic acid and [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamîne.

LCMS (MH⁴): m/z = 381.9, t_R (minutes, Method B) = l. 10

Example 2j

N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2,5-difluoro-benzamide

From 2,5-difluorobenzoic acid and [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁴): m/z = 366.0, t_R (minutes, Method B) = l.05

Example 2 k

2-Chloro-N-[ 1 -(4-methoxy-phenyl)-cyclopentylmethylJ -5 -methyl-benzamide

From 2-chloro-5- methylbenzoic acid and [l-(4-methoxyphenyl)-cyclopentyl]-mcthylamine. LCMS (MH*): m/z = 358.0, îr (minutes, Method B) = l. 13

Example 21

2,3-Dichloro-N-[ l -(4-methoxy-phenyl)-cyclopentylmethyl]-benzamide

From 2,3-dichlorobenzoic acid and [l-(4-methoxyphenyl)-cyclopentyl]-methylamine. LCMS (MH⁺): m/z = 377.9, tR (minutes, Method B) = 1.22

Example 2m

N-[ l -(4-Methoxy-phenyl)-cyclopentylmethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and [l-(4-methoxyphenyl)-cyclopentyl]-methylamine. LCMS (MH⁴): m/z = 324.0, tR (minutes, Method B) = l. 18

Exampie 2n

N-[ l -(4-Methoxy-phenyl)-cyclopentylmethyl]-2,3-dimethyl-benzamide

From 2,3-dimethylbenzoic acid and [l-(4-methoxyphenyl)-cyclopentyl]-methylamine. LCMS (MH⁴): m/z = 338.0, îr (minutes, Method B) = 1.23

Example 2o

2,3-Dichloro-N-( l -methyl-4-phenyl-piperidin-4-ylmethyl)-benzamide

From 2,3-dichlorobenzoic acid and C-(l-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH⁴): m/z = 376.9, tR (minutes, Method A) = 0.69

Exampie 2p

2,3-Dimethyl-N-(l-methyl-4-phenyl-piperidin-4-ylmethyl)-benzamide

From 2,3-dimethylbenzoic acid and C-(l-methyl-4-phenyl-piperidin-4'yl)-methylamine. LCMS (MH⁴): m/z - 337.0, îr (minutes, Method A) = 0.65

Example 2q

2-Chloro-5-methyl-N-(l-methyl-4-phenyl-piperidin-4-ylmethyl)'benzamide

From 2-chloro-5-methylbenzoic acid and C-(l-methyl-4-phenyl-piperidin-4-yl)-methylamine.

LCMS (MH⁴): m/z = 367.0, îr (minutes, Method A) = 0.68

Exampie 2r

2-Methyl-N-( 1 -methyl-4-phenyl-piperidin-4-ylmethyl)-benzamide

From 2-methylbenzoic acid and C-(l-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH⁴):

m/z = 323.1, Ir (minutes, Method A) = 0.56

Example 2s

N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-2,3,5-trifluoro-benzamide

From 2,3,5-trifluorobenzoic acid and [4-(4-chIoro-phenyl)-tetrahydro-pyran-4-yl]-methylainine.

LCMS (MH*): m/z = 384.0, t_R (minutes, Method B) = 1.25

Example 2t

N-[2-(4-Chloro-phenyl)-4-dimethylamino-butyl]-2-methyl-benzamide

From 2-methylbenzoic acid and 3-(4-chloro-phenyl)-Nl,Nl-dimethyl-butane-l,4-diamine. LCMS (MH*): m/z = 345.1, t_R (minutes, Method A) = 0.8

Example 2u 2-Chloro-N-[4-(4-chloro-phenyl)-l-methyl-pipcridin-4-ylmethyl]-5-methyl-benzamide

From 2-chloro-5-methylbenzoic acid and [4-(4-chloro-phenyl)-l-methyl-piperidine-4-yl]methylamine. LCMS (MH*): m/z = 391.0, t_R (minutes, Method B) = 0.71

Example 2v

N-[4-(4-Chloro-phenyl)-l-methyl-piperidin-4-yltnethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and [4-(4-chloro-phenyl)-l-methyl-piperidine-4-yl]-methylamine.

LCMS (MH*): m/z = 357.1, îr (minutes, Method B) = 0.61

Example 2w

2,3-Dichloro-N-[4-methyl-2-(6-metliyl-pyridin-3-yl)-pentyl]-benzamide

From 2,3-dichlorobenzoic acid and 4-methyl-2-(6-methylpyridin-3-yl)-pentylamine. LCMS (MH⁴):

m/z = 364.9, t_R (minutes, Method A) = 1.43

Example 2x

2,3-Dimethyl-N-[4-methyl-2-(6-methyl-pyrid in-3-yl)-pentylj-benzamide

From 2,3-dimethylbenzoic acid and 4-methyl-2-(6-methyIpyridin-3-yl)-pentylamine. LCMS (MH⁴):

m/z = 325.0, t_R (minutes, Method A) = 1.38

Example 2y

2-Methyl-N-[4-methyl-2-(6-rnethyl-pyridin-3-yl)-pentyl]-benzamide

From 2-methylbenzoîc acid and 4-methyl-2-(6-methylpyridin-3-yl)-pentylamine. LCMS (MH⁴): m/z = 311.0, t_R (minutes, Method A) = 1.31

Example 2z 2-Chloro-5-methyl-N-[4-(6-methyI-pyridin-3-yl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2-chloro-5-methylbenzoic acid and C-[4-(6-methylpyridin-3-yl)-tetrahydropyran-4yl]methylamine. LCMS (MH⁴): m/z = 359.0, t_R (minutes, Method B) = 0.74

Example 2al

2-Methyl-N-[4-(6-methyl-pyridin-3-yl)-tetrahydro-pyran-4-ylmethyl]-benzarnide

From 2-methylbenzoic acid and C-[4-(6-methylpyridin-3-yI)-tetrahydropyran-4-yl]methylamine.

LCMS (MH⁴): m/z = 325.0, îr (minutes, Method B) = 0.60

Exampie 2bl

5-Bromo-2-chloro-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-benz amide

From 5-bromo-2-chlorobenzoic acid and [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]methylamine. LCMS (MH⁺): m/z = 443.7, (r (minutes, Method A) = 1.52

Exampie 2cl

2-Chloro-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2-clilorobenzoic acid and [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine. LCMS (MH⁴): m/z = 363.9, tR (minutes, Method A) = l .34

Exampie 3a

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

A solution of C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine (38 mg, 0.157 mmol), 2,3-dichlorobenzoic acid (30 mg, 0.157 mmol), HOBt (25 mg, 0.185 mmol), EDCI.HCI (36 mg, 0.185 mmol) and DIPEA (48 mg, 0.345 mmol) in DMF (2 mL) was stirred at room température ovemight. Water was added to the solution followed by extraction with EtOAc (3 x 10 ml). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude product was purified by Prep. HPLC to give the title compound (25 mg, yield: 38%). *H NMR (CDCI3 300MHz): J ppm 8.18 (d, J = 2.8 Hz, IH), 7.89-7.80 (m, IH), 7.50 (dd, J = 8.0 Hz, 2.0 Hz, IH), 7.33 (dd, J = 7.6 Hz, 1.6 Hz, IH), 7.28-7.18 (m, IH), 6.98 (dd, J = 8.8 Hz, 3.2 Hz, IH), 5.85 (t, J = 6.8 Hz, IH), 3.64 (d, J = 6.8 Hz, 2H), 2.36-2.00 (m, 6H), 1.87-1.65 (m, 2H). LCMS (MH*): m/z = 417.1, t_R (minutes, Method C)= 1.11

The following compounds were synthesised in a similar way as to example 3a, purification of the compounds was performed by prep. HPLC or Combiflash:

Example 3b 2-Chloro-N-[[4,4-difluoro-l-(6-fluoro-3-pyridyl)cyclohexyl]methyl]-6-fluoro-benzamide

F F

From 2-chloro-6-fluorobenzoic acid and C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH*): m/z = 401.1, t_R (minutes, Method C) = 1.07

Example 3c

2-Chloro-N-[[4,4-difluoro-l-(6-fluoro-3-pyridyl)cyclohexyl]methyl]-5-methyl-benzamide

From 2-chIoro-5-methylbenzoic acid and C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH*): m/z = 397.2, t_R (minutes, Method C) = 1.11

Exampie 3d

2-Chloro-N-[[4,4-difluoro-l-(6-fluoro-3-pyridyl)cyclohexyl]methyl]-5-(trifluoromethyl)benzamide

From 2-chloro-5-trifluorornethylbenzoic acid and C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)cyclohexyl]-methylamine. LCMS (MH*): m/z = 451.1, t_R (minutes, Method C) = 1.15

Exampie 3e

N-[4,4-Difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2-fluoro-benzamide

From 2-fluorobenzoic acid and C-[4,4-difluorO'l-(6-fluoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH⁴): m/z = 367.1, îr (minutes, Method D) = 0.69

Exampie 3f

4-Cyano-N-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2-fluoro-benzamide

From 2-fluoro-4-cyanobenzoic acid and C-[4,4-difiuoro-l-(6-fluoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH⁴): m/z = 392.1, îr (minutes, Method D) = 0.68

Exampie 3g

N-[4,4-DifluorOl-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2-fluoro-3-methoxy-benzamide

From 2-fluoro-3-methoxybenzoic acid and C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH⁴): m/z = 397.2, îr (minutes, Method D) = 0.69

Exampie 3h

2-Chloro-N-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-5-methanesulfonyl-benzamide

From 2-chloro-5-methanesulfonylbenzoic acid and C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)cyclohexyl]-methylamine. LCMS (MH⁴): m/z = 46l.l, îr (minutes, Method D) = 0.64

Example 3i

2-Chloro-N-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-benzamide

From 2-chlorobenzoic acid and C-[4,4-difluoro-l-(6-fiuoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH⁴): m/z = 383.1, îr (minutes, Method D) = 0.69

Example 3j

N-[4,4-Difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2-fluoro-5-methoxy-benzamide

From 2-fluoro-5-methoxybenzoic acid and C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH⁺): m/z = 397.1, tR(minutes, Method D) = 0.71

Example 3k

N-[4,4-Difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2-fluoro-3-methyl-benzamide

From 2-fluoro-3-methylbenzoic acid and C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH⁴): m/z = 381.1, îr (minutes, Method D) = 0.74

Example 3I

N-[4,4-Difluoro-1 -(6-fluoro-pyri din-3 -yl )-cyclohexyl methyl] -2,5-d i fluoro-benzamide

From 2,5-difluorobenzoic acid and C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH⁴): m/z = 385.2, îr (minutes, Method D) = 0.71

Example 3m

2,5-Dichloro-N-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-benzamide

F F

From 2,5-dichlorobenzoic acid and C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH*): m/z = 4l7.l, ta (minutes, Method D) = 0.76

Example 3n

2-Chloro-N-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-5-methoxy-benzamide

From 2-chloro-5-methoxybenzoic acid and C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH*): m/z = 413.1, îr (minutes, Method D) = 0.72

Example 3o

N-[4,4-Difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexylmethyl]-2,3-difluoro-benzamide

From 2,3-difluorobenzoic acid and C-[4,4-difluoro-l-(6-fluoro-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH*): m/z = 385.0, Ir (minutes, Method D) = 0.71

Example 3p

2,3-Dichloro-N-[4-(4-chloro-phenyl)-tetrahydro-pyran-4-ylmethyl]-benzamide ci •Cl

From 2,3-dichlorobenzoic acid and [4-(4-chloro-phenyl)-tetrahydro-pyran-4-yl]-methylamine.

LCMS (MH*): m/z = 398.1, tR (minutes, Method D) = 0.79

Example 3q

2,3-Dichloro-N-[4-(4-trifluoromethyl-phenyl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2,3-dichlorobenzoic acid and [4-(4-trifluoromethyl-phenyl)-tetrahydro-pyran-4-yl]methylamine. LCMS (MH⁴): in/z = 432.0, t_R (minutes, Method E) = 0.83

Example 3r

2,3-Dichloro-N-[4,4-difluoro-l-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-benzamide

From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-l-(6-trifluoromethyI-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH⁺): m/z = 467.0, t_R (minutes, Method E) = 0.83

Example 3s

2,3-Dicli!oro-N-[4-(6-trifluoromethyl-pyridin-3-yl)-tetrahydro-pyran-4-ylmethyl]-benzamide

From 2,3-dichlorobenzoic acid and [4-(6-trifluoromethyl-pyridin-3-yl)-tetrahydro-pyran-4-yl]methylamine. LCMS (MH⁺): m/z = 433.3, t_R (minutes, Method E) = 0.72

Example 3t

2,3-Dichloro-N-[l-(6-cyclopropyl-pyridin-3-yl)-4,4-difluoro-cyclohexylmethyl]-benzamide

From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-l-(6-cyclopropyl-pyridin-3-yl)-cyclohexyl] methylamine. LCMS (MH+): m/z = 439.0, îr (minutes, Method E) = 0.55

Example 3u

2,3-Dichloro-N-[4,4-difluoro-l-(6-methoxy-pyridin-3-yl)-cyclohexylmethyl]-benzamide

From 2,3-dichlorobenzoic acid and C-[4,4-difluoiO-l-(6-methoxy-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH+): m/z = 429.1, îr (minutes, Method D) = 0.67

Example 3v

2-Cyano-N-[4,4-difIuoro-l-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-benzamide

From 2-cyanobenzoic acid and C-[4,4-difluoro-l-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH+): m/z = 424.2, t_R (minutes, Method D) = 0.66

Example 3w

2-Chloro-N-[4,4-difluoro-I-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-4-methanesulfbnylbenzamide

From 2-chloro-4-methanesulfonylbenzoic acid and C-[4,4-difluoro-l-(6-trifluoromethyi-pyridin-3-yl)cyclohexyl]-methylamine. LCMS (MH+):m/z = 51 l.l, îr (minutes,MethodD) = 0.68

Ex ample 3x

N-[4,4-Difluoro-l-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-2-methyl-benzamide

From 2-methylbenzoic acid and C-(4,4-difluoro-l-(6-trifluorometliyl-pyridin-3-yl)-cyclohexyl]methylamine. LCMS (MH+): m/z = 413.2, t_R (minutes, Method D) = 0.74

Example 3y

2,3-Dichloro-N-[2-cyclopropyl-2-(6-tri fluoromethyl-pyrid in-3-yl)-ethyl] -benzamide

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

LCMS (MH+): m/z = 403.1, t_R (minutes, Method D) = 0.79

Example 3z

N-[4,4-Difluoro-l-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-2-methanesulfonyl-benzamide

From 2-methaneulfonylbenzoic acid and C-[4,4-difluoro-l-(6-trifluoromethyl-pyridin-3-yl)cyclohexyl]-methylamine. LCMS (MH+): m/z = 413.2, t_R (minutes, Method D) = 0.74

Example 3al

2,3-Dichloro-N-[4,4-difluoro-l-(5-fluoro-pyridin-3-yl)-cyclohexylmethyl]-benzamide

F

From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-l-(5-fluoro-pyridîn-3-yl)-cyclohexyl]methylamine. LCMS (MH+): m/z = 417.2, t_R (minutes, Method D) = 0.68

Example 3bl

2,3-Dichloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

F rF

From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine.

LCMS (MH+): m/z = 416.9, îr (minutes, Method C) = 1.29

Example 3cl

2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)’3-pyridyl]propyl]benzamide

From 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine. LCMS (MH+): m/z = 382.9, tR (minutes, Method C) = 1.24

Example 3dl

N-[4,4-Difluoro-l-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-3-fluoro-2-methyl-benzamide

From 3-fluoro-2-methylbenzoic acid and C-[4,4-difluoro-l-(6-trifluoromethyl-pyridin-3-yl)cyclohexylj-methylamine. LCMS (MH+): m/z = 431.2, îr (minutes, Method D) = 0.79

Example 3el bI-[4,4-Difluoro-l-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-3-methoxy-2-methylbenzamide

From 3-methoxy-2-methylbenzoic acid and C-[4,4-difluoro-l-(6-trifluoromethyl-pyridin-3-yl)cyclohexyl]-methylamine. LCMS (MH+): m/z = 443.2, t_R (minutes, Method D) = 0.78

Example 3f 1

N-[4,4-Dîfluoro-l-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-5-fluoro-2-methyl-benzamide

From 5-fluoro-2-methylbenzoic acid and C-[4,4-difluoro-l-(6-trifluoromethyl-pyridin-3-yl)cyclohexylj-methylamine. LCMS (MH+): m/z = 431.2, t_R (minutes, Method D) = 0.79

Example 3gl

N-[4,4-Difluoro-l-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-2-methyl-5-trifluoromethylbenzamide

From 54rifluoromethyl-2-methylbenzoic acid and C-[4,4-difluoro-l-(6-trifluoromethyl-pyridin-3-yI)cyclohexyl]-methylamine. LCMS (MH+): m/z = 481.1, t_R (minutes, Method D) = 0.86

Example 3hl

3-Bromo-N-[4,4-difluoro-l-(6-trifluoroinethyl-pyridin-3-yl)-cyclohexylmethyl]-2-methyl-benzamide

Br

From 3-bromo-2-methylbenzoic acid and C-[4,4-difluoro-l-(6-trifluoromethyl-pyridin-3-yl)cyclohexyl]-methylamine. LCMS (MH+): m/z = 491.1, t_R (minutes, Method D) = 0.84

Example 3i 1

2-Chloro-N-[4,4-difiuoro-l-(6-trifluoroinethyl-pyridin'3-yl)-cyclohexylmethyl]-3-methyl-benzamide

From 2-chloro-3-methylbenzoic acîd and C-[4,4-difluoro-l-(6-trifluoromethyl-pyridin-3-yl)cyclohexyl]-methylamine, LCMS (MH+): m/z = 447.1, Ir (minutes, Method D) = 0.80

Exampie 3j 1

3-Cyano-N-[4,4-difluoro-l-(6-trifluoromethyl-pyridin-3-yl)-cyclohexylmethyl]-2-methyl-benzamide

From 3-cyano-2-methylbenzoic acid and C-[4,4-difluoro-l-(6-trifluoromethyl-pyridin-3-yl)cyclohexyl]-methylamine. LCMS (MH+): m/z = 438.2, t_R (minutes, Method D) = 0,75

Example 3k 1

2,3-Dichloro-N-[2-(5-chloro-pyridin-3-yl)-3-cyclopropyl-propyl]-benzamide

From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(5-chloro-pyridin-3-yl)-propylamine. LCMS (MH+): m/z = 383.0, îr (minutes, Method D) = 0.74

Example 311

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

From 2,3-dichlorobenzoic acid and 2-(4-chloro-phenyl)-2-phenyl-ethylamine. LCMS (MH+): m/z =

404.0, îr (minutes, Method D) = 0.91

Example 3ml

2,3-Dichloro-N-[3-cyclopropyl-2-(2,6-dimethyl-3-pyridyl)propyl]benzamide

From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(2,6-dimethyl-pyridîn-3-yl)-propylamine. LCMS (MH+): m/z = 377.1, t_R (minutes, Method G) = 1.68

Ex'ample 3nl

2,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-3-[l-(trifluoromethyl)cyclopropyl]propyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(2-methyi-pyrimidin-5-yl)-3-(l-trifluoromethylcyclopropyl)-propylamine. LCMS (MH+): m/z = 377.1, t_R (minutes, Method F) = 1.68

Example 3ol

2,3-Dichloro-N-[3-[l-(trifluoromethyl)cyclopropyl]-2-[6-(trifluoroinethyl)-3pyridyl]propyl]benzamide

From 2,3-dichlorobenzoic acid and 3-(l-trifluoromethyl-cyclopropyl)-2-(6-trifluoromethylpyridin-3-yl)-propylamine. LCMS (MH+): m/z = 485,1, t_R (minutes, Method G) = 2.74

Example 3pl

2,3-Dichloro-N-[2-(6-cyclopropyl-3-pyridyl)-3-[l-(trifluoromethyl)cyclopropyl]propyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-3-(l-trifluoromethylcyclopropylj-propylamine. LCMS (MH+): m/z = 457, l, t_R (minutes, Method G) = l ,96

Example 3ql

2,3-Dichloro-N-[2-(6-cyclopropyl-3-pyridyl)-3-[l-(difluoromethyl)cyclopropyl]propyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-3-(l-difluoromethylcyclopropyl)-propylamine, LCMS (MH+): m/z = 439, l, t_R (minutes, Method G) = 2.09

Exampie 3rl

2,3-DicMoro-N-[3-[l-(difluorometliyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

F

From 2,3-dichlorobenzoic acid and 2-(6-trifluoromethyl-pyridin-3-yl)-3-(l-difluoromethylcyclopropyl)-propylamine. LCMS (MH+): m/z = 467.1, t_R (minutes, Method G) = 2.62

Example 3s 1

2-Chloro-N-[2-(6-cyclopropyl-3-pyridyl)-3-[l-(trifluoromethyl)cyclopropyl]propyl]benzamide

From 2-chlorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-3-(l-trifluoromethyl-cyclopropyl) propylamine. LCMS (MH+): m/z = 423.1, t_R (minutes, Method G) = 2.04

Example 3tl

N-^-tô-Cyclopropyl^-pyridyO'S-tl-itrifluoromethyOcyclopropylJpropylJ^-fluoro-benzamide

From 2-fluorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-3-(l-trifluoromethyl-cyclopropyl)propylamine. LCMS (MH+): m/z = 407.1, t_R (minutes, Method G) = 2.01

Example 3ul

2-Chloro-N-[3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl]benzamide

From 2-chlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-3-cyclopropyl-propylamine. LCMS (MH+): m/z = 330.1, t_R (minutes, Method F) = 2.32

Example 3vl

2,3 -Dichloro-N-[3 -cyclopropyl-2-(2-methylpyrimidi n-5-yl)propyl ] benzamide

From 2,3-dichlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-3-cyclopropyl-propyIamine. LCMS (MH+): m/z = 364.1, t_R (minutes, Method F) = 2.52

Example 3wl

2-Chloro-N-[3-[l-(trifluorometl'iyl)cyclopropyl]-2-[6-(trifluorometliyl)-3-pyridyl]propyl]benzamide

From 2-chlorobenzoic acid and 3-(l-trifluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3yl)-propylamine. LCMS (MH+): m/z = 451.1, t_R (minutes, Method G) = 2.58

Example 3x1

2-FIuoro-N-[3-[l-(trifluoromethyl)cyclopropyl]-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

From 2-fluorobenzoic acid and 3-(l-trifluoromethyl-cyclopropyl)-2-(6-trifluoromethyl-pyridin-3yl)-propylamine. LCMS (MH+): m/z = 435.1, t_R (minutes, Method G) = 2.58

Example 3yl

2-Chloro-N-[[4,4-difluoro-l-(2-methylpyrimidin-5-yl)cyclohexyl]methyl]benzamide

From 2-chlorobenzoic acid and C-[4,4-difluoro-l-(2-methyl-pyrimidin-5-yl)-cyclohexyl]10 methylamine. LCMS (MH+): m/z = 380.1, t_R (minutes, Method F) = 2.37

Example 3zl

2,3-Dichloro-N-[[4,4-difluoro-l-(2-methylpyrimidin-5-yl)cyclohexyl]niethyl]benzamide

From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-l-(2-methyl-pyrimidin-5-yl)-cyclohexyl]methylamine. LCMS (MH+): m/z = 414.1, t_R (minutes, Method F) = 2.57

Example 3a2

2,3-Dichloro-N-[3-cyclopropyl-2-[2-(trifluoromethyl)pyrimidin-5-yl]propyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(2-trifluoromethyl-pyrimidin-5-yl)-3-cyclopropylpropylamine. LCMS (MH+): m/z = 418.1, îr (minutes, Method G) = 2.55

Exampie 3b2

2,3-Dichloro-N-[[4,4-difluoro-1 -[6-( 1 -hydroxy-1 -methyl-ethyl)-3pyridyl]cyclohexyl]methyl]benzamide

From 2,3-dichlorobenzoic acid and 2-[5-(l-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]propan-2-ol. LCMS (MH+): m/z = 457.1, tR (minutes, Method F) = 1.97

Example 3c2

2-Chloro-N-[[4,4-difluoro-1 -[6-( 1 -hydroxy-1 -methyl-ethyl)-3-pyridyl]cyclohexyl]methyl]benzamide

From 2-chlorobenzoic acid and 2-(5-(1 -aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2ol. LCMS (MH+): m/z = 423.2, t_R (minutes, Method F) = 1.78

Example 3d2

2-chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]-3-methoxy-benzamide

From 2-chloro-3-methoxybenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-lamine. LCMS (MH+): m/z = 413.1, îr (minutes, Method G) = 2.84

Example 3c2

2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-6-fluorobenzamide

From 2-chloro-6-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-lamine. LCMS (MH+): m/z = 401.1, îr (minutes, Method G) = 2.88

Example 312

N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-methoxybenzamide

From 2-methoxybenzoic acid and 3-cyclopropyl-2-(6-(triiluoromethyl)pyridin-3-yl)propan-l-amine.

LCMS (MH+): m/z = 379.1, tR (minutes, Method G) = 2.91

Example 3g2

N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2,6-difluorobenzamide

From 2,6-difluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-l-amine.

LCMS (MH+): m/z = 385.1, tR (minutes, Method G) = 2.82

Example 3h2

2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-5(methylsulfonyl)benzamide

From 2-chloro-5-(methylsulfonyl)benzoic acid and 3-cyclopropyl’2-(6-(trifluoromethyl)pyridin-3yl)propan-l-amine. LCMS (MH+): m/z = 461.1, t_R (minutes, Method G) = 2.88

Exampie 3i2

2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-3-fluorobenzamide

From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-lamine. LCMS (MH+): m/z = 401.1, t_R (minutes, Method G) = 2.51

Example 3j2

2-chloro-N-(3-cyclopropyl-2-(6-fluoropyridin-3-yl)propyl)benzamide

From 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-fluoropyridin-3-yl)propan-l -amine.

LCMS (MH+): m/z = 333.1, t_R (minutes, Method F) = 2.43

Example 3k2

2,3-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-l-amine. LCMS (MH+): m/z = 364.1, t_R (minutes, Method F) = 2.52

Example 312

2-chloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chlorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-

1- amine.

LCMS (MH+): m/z = 398.1, t_R (minutes, Method F) = 2.64

Example 3 ni 2

2- chloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3fluorobenzamide

From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimtdin-5yl)propan-1 -amine.

LCMS (MH+): m/z = 416.1, t_R (minutes, Method G) = 2.49

Exampie 3n2

2,3-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-lamine. LCMS (MH+): m/z = 418.l,t_R (minutes, Method G) = 2.48

Example 3o2

2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-l-amine.

LCMS (MH+): m/z = 384.1, îr (minutes, Method F) = 2.55

Exampie 3p2

2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-fluorobenzamide

From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-lamine. LCMS (MH+): m/z = 402.1, tR (minutes, Method F) = 2.61

Exampie 3q2

2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-6-fluorobenzamide

From 2-chIoro-6-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluorometliyl)pyrimidin-3-yl)propan-lamine. LCMS (MH+): m/z = 402.1, îr (minutes, Method F) = 2.59

Example 3h2

2,3-dichloro-N-(2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z = 412.1, îr (minutes, Method G) = 2.49

Example 3 ΐ2

2-chIoro-N-(2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

Ό

From 2-chlorobenzoic acid and 2-(4-ch!orophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z = 378.1, tR (minutes, Method G) = 2.34

Example 3i2

2-chloro-6-fluoro-N-(2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

Cl

0'

From 2-chloro-6-fluorobenzoic acid and 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran'4-yl)ethanamine. LCMS (MH+): m/z = 396.1, tR (minutes, Method G) = 2.36

Example 312 2-chloro-3-fluoro-N-(2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

Cl

O

From 2-chloro-3-fluorobenzoic acid and 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z = 396.1, tp> (minutes, Method G) = 2.36

Example 3j2

2,3-dichloro-N-((4-(2“methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide .Cl

Ό'

From 2,3-dichlorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4yl)methanamine. LCMS (MH+): m/z = 380,1, t_R (minutes, Method F) = 1.80

Example 3k2

2-chloro-N-((4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

From 2-chlorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z = 346.1, t_R (minutes, Method F) = 1.55

Example 312

2-chloro-6-fluoro-N-((4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamîde

From 2-chloro-6-fluorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4yl)methanamine. LCMS (MH+): m/z = 364.1, t_R (minutes, Method F) = 1.57

Example 3ni2

2-chloro-3-fluoro-N-((4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

From 2-chloro-3-fluorobenzoic acid and (4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-420 yl)methanamine. LCMS (MH+): m/z = 364.1, t_R (minutes, Method F) = 1.95

Example 3n2

2,3-dichloro-N-((4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4- yl)methyl)benzamide

From 2,3-dichlorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin -5-yl)tetrahydro-2H-pyran-4yl)methanamine. LCMS (MH+): m/z - 434.1, ta (minutes, Method F) = 2.34

Example 3o2

2-chloro-N-((4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide

From 2-chlorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin -5-yl)tetrahydro-2H-pyran-4yl)methanamine. LCMS (MH+): m/z = 400.1, t_R (minutes, Method F) = 2.15

Example 3p2

2-chloro-6-fluoro-N-((4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4yl)methyl)benzamide

O Cl

From 2-chloro-6-fluorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin -5-yl)tetrahydro-2H-pyran4-yl)methanamine. LCMS (MH+): m/z = 418.1, t_R (minutes, Method F) = 2.17

Example 3q2

2-chloro-3-fiuoro-N-((4-(2-(trifluoromethyl)pyrimÎdin-5-yl)tetrahydro-2H-pyran-4yl)methyl)benzamide

From 2-chloro-3-fluorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin -5-yl)tetrahydro-2H-pyran4-yl)methanamine. LCMS (MH+): m/z = 418.1, t_R (minutes, Method F) = 2.24

Example 3q2

2,3-dichloro-N-(3-cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(5-( l-amino-3-cyclopropylpropan-2-yl)pyridin-2-yl)propan-2-ol.

LCMS (MH+): m/z = 407.1, t_R (minutes, Method F) = 1.98

Example 3r2

2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-methoxybenzamide

From 2-cliloro-3-methoxybenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyriinidin-5yl)propan-l-amine. LCMS (MH+): m/z = 414.0, t_R (minutes, Method F) = 2.53

Example 3s2

2-methyl-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3-methoxybenzamide

From 2-methyl-3-methoxybenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5yl)propan-l-amine. LCMS (MH+): m/z = 394.0, t_R (minutes, Method F) = 2.59

Example 3t2

2,3-dichloro-N-(3-(l-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and 3-(l-fluorocycIopropyl)-2-(6-(trifluoromethyI)pyridin-3-yl)propan1 -amine. LCMS (MH+): m/z = 435.1, t_R (minutes, Method G) = 2.46

Example 3u2

2,6-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

O Cl

From 2,6-dichlorobenzoic acid and 3-cyclopropyi-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-l“ amine. LCMS (MH+): m/z = 418.1, t_R (minutes, Method G) = 2.62

Example 3v2

2,6-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyridin-5-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyridin-5-yl)propan-l-amine.

LCMS (MH+): m/z = 417.1, t_R (minutes, Method F) = 2.50

Ex ample 3x2

2,6-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl)benzamide

From 2,6-diclilorobenzoic acid and 3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-l-amine. LCMS (MH+): m/z = 364.1, t_R (minutes, Method G) = 2.43

Exampie 3y2

2,3-dichloro-N-(3-(l-fluorocycIopropyl)-2-(6-(trifluoromethyl)pyrimidin-3-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and 3-(l-fluorocyclopropyl)-2-(6-(trifluoromethyl)pyrimidin-3yl)propan-l-amine. LCMS (MH+): m/z = 436.1, îr (minutes, Method G) = 2.61

Exampie 3z2

2,3-dichloro-N-((4,4-difluoro-l-(2-(trifluoromethyl)pyrimidin-5yl )cyclohexyl)methyl)b enzam ide

From 2,3-dichlorobenzoic acid and (4,4-difluoro-l-(2-(trifluoromethyl)pyrimidin-5yl)cyclohexyl)methanamine. LCMS (MH+): m/z = 468.1, tR (minutes, Method G) = 2.48

Example 3a3

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

From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+): m/z = 3 87.1, îr (minutes, Method F) = 1,56

Exampie 3b3

2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+): m/z = 353.1, îr (minutes, Method F) = 1.62

Example 3c3

2-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine.

LCMS (MH+): m/z = 371,1, t_R (minutes, Method F) = 1.65

Example 3d3

2-chloro-3-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethyl)benzamide

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

LCMS (MH+): m/z = 371.1, îr (minutes, Method F) = 1.73

Example 3e3

2-chloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamÎde

From 2-chlorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan1 -amine. LCMS (MH+): m/z = 398.1, îr (minutes, Method F) = 2.62

Example 3f3

2-chloro-3-fluoro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5yl)propyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5yl)propan-l-amine. LCMS (MH+): m/z = 416.1, t_R (minutes, Method G) = 2.48

Example 3g3

2,3-dichloro-N-(3~cyclopropyl-2-methyl-2-(2-(trifluoroniethyl)pyrimidin-5-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5yl)propan-1-amine. LCMS (MH+): m/z = 432.1, t_R (minutes, Method G) = 2.58

Example 3h3

2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z = 360.1, t_R (minutes, Method F) = l .97

Example 3i3

2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4yl)ethanamine. LCMS (MH+): m/z = 394.1, tR (minutes, Method F) = 1.88

Example 3J3

2-chloro-3-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4yl)ethanamine. LCMS (MH+): m/z = 378.1, îr (minutes, Method F) = 2.00

Example 3k3

2-chloro-6-fluoro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyi)benzamide

From 2-chloro-6-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4yl)ethanamine. LCMS (MH+): m/z = 378.1, îr (minutes, Method F) = 2.06

Example 313

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

From 2,3-dichlorobenzoic acid and 2-(4,4-dif]uorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z = 428, l, îr (minutes, Method G) = 2.04

100

Example 3ηι3

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

From 2-chlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z = 394.1, îr (minutes, Method F) = 2.1

Example 3n3 2-chloro-6-fluoroN-(2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5yl)ethanamine. LCMS (MH+): m/z = 412.1, tR (minutes, Method F) = 2.14

Example 3o3

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

From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluoiOcycIohexyl)-2-(2-methylpyrimidin-5yl)ethanamine. LCMS (MH+): m/z = 412.1, îr (minutes, Method F) = 2.18

Example 3p3

2-chloro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)propyl)benzamide

101

From 2-chlorobenzoic acid and 3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)propan-l-amine. LCMS (MH+): m/z = 452.0, t_R (minutes, Method F) = 3.03

Example 3q3

2,3-dichloro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5- yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and

3-( l -(trifluoromethyl)cyclopropyl)-2-(2(trifluoromethyl)pyrimidin-5-yl)propan-l -amine, LCMS (MH+): m/z = 486.1, t_R (minutes, Method F) = 2.77

Example 3r3

2-chloro-3-fluoro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)propyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 3-(l-(trifluoromethyl)cyclopropyl)-2-(2(trifluoromethyl)pyrimidin-5-yl)propan-l -amine. LCMS (MH+): m/z = 470.0, t_R (minutes, Method F) = 3.07

Example 3s3

102

2-chloro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5yl)propyl)benzamide

From 2-chlorobenzoîc acid and 3-(l-(trifIuoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5yl)propan-l -amine. LCMS (MH+): m/z = 45l.l, t_R (minutes, Method G) = 2.50

Example 3t3

2,3-dichloro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5- yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and 3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5yl)propan-l -amine. LCMS (MH+): m/z = 485.1, t_R (minutes, Method G) = 2.63

Example 3u3

2-chloro-3-fluoro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5yl)propyl)benzamide

Example 3v3

From 2-chloro-3-fluorobenzoic acid and 3-(l -(tri fluoromethyl)cyclopropy 1)-2-(2(trifluoromethyl)pyridin-5-yl)propan-l-amine. LCMS (MH+); m/z = 469.1, t_R (minutes, Method G) =

2.54

103

2,3-dichloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-y 1)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine. LCMS (MH+): m/z = 448.0, ta (minutes, Method F) = 2.72

Example 3x3

2-chloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimïdin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5 yl)ethanamine. LCMS (MH+): m/z = 414.1, tR (minutes, Method F) = 2.54

Example 3y3

2-chloro-3-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z = 432.1, îr (minutes, Method F) =

2.48

Example 3z3

2-chloro-6-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

104

From 2-chloro-6-fluorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z = 432.1, îr (minutes, Method F) = 2.6

Example 3a4

2,3-dichloro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

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

LCMS (MH+): m/z = 457.0, t_R (minutes, Method G) = 3.02

Example 3b4

2-chloro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine.

LCMS (MH+): m/z = 423.1, t_R (minutes, Method G) = 2.58

Example 3c4

2-chloro-3-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

105

From 2-chloro-3-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3yl)ethanamine. LCMS (MH+): m/z = 441.1, t_R (minutes, Method G) = 2.63

Exampie 3d4

2-chloro-6-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3yl)ethanamine. LCMS (MH+): m/z = 441.0, t_R (minutes, Method G) = 2.86

Example 3c4

2-chloro-N-(2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.

LCMS (MH+): m/z = 407.1, t_R (minutes, Method F) = 2.25

Exampie 3f4

2,3-dichloro-N-(2-(pyridin-4-yI)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

106

From 2,3-dichlorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluorometliyl)pyrimidÎn-5-yl)ethanamine.

LCMS (MH+): m/z = 441.1, tR (minutes, Method F) = 2.43

Example 3g4

2-chloro-N-(2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethanamine. LCMS (MH+): m/z = 406.1, tR (minutes, Method F) = 2.27

Example 3h4

2,3-dichloro-N-(2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethyl)benzamide

From 2,3-diclilorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyridin-5-yl)ethanamine.

LCMS (MH+): m/z = 440.0, t_R (minutes, Method F) = 2.43

Example 3i4

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

107

From 2,3-dichlorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine. LCMS (MH+): m/z = 458.0, t_R (minutes, Method G) = 2.91

Example 3j4

2-chloro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine.

LCMS (MH+): m/z = 424,1, t_R (minutes, Method F) = 3.19

Exampie 3k4

2-chloro-3-fluoro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyI)benzaniide

From 2-chloro-3-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-515 yl)ethanamine. LCMS (MH+): m/z = 442.1, t_R (minutes, Method F) = 3.24

Exampie 314

2-chloro-6-fluoro-N-(2-(4-fluorophenyl)-2“(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

108

O Cl

From 2-chloro-6-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine. LCMS (MH+): m/z = 442.0, t_R (minutes, Method F) = 2.99

Exampie 3m4

2-chloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cthyl)benzamide

O Cl

From 2-chlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine. LCMS (MH+): m/z = 448.1, t_R (minutes, Method F) = 2.95

Example 3n4

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

From 2,3-dichlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethanamine. LCMS (MH+): m/z = 482.1, t_R (minutes, Method G) = 2.76

Exampie 3o4

2-chloro-6-fluoro-N-(2-(4_]4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

109

From 2“Chloro-6-fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyI)pyrimidin-5yl)ethanamine. LCMS (MH+): m/z = 466.1, t_R (minutes, Method F) = 2.97

Example 3p4

2-chloro-3-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl ) ethyl )b enzamide

From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-510 yl)ethanamine. LCMS (MH+): m/z = 466.1, t_R (minutes, Method F) = 2.67

Example 3q4

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

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

LCMS (MH+): m/z = 448.1, t_R (minutes, Method F) = 2.95

Example 3r4

2,3“dichloro-N-(4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butyl)benzamide

OMe

110

From 2,3-dichlorobenzoic acid and 4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butan-l-amine.

LCMS (MH+): m/z = 422.0, t_R (minutes, Method F) = 2.73

Exampie 3s4

2,3-dichloro-N-(2-phenyl-2-(pyridazin-4-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-phenyl-2-(pyridazin-4-yl)ethanamine. LCMS (MH+): m/z =

372.1, t_R (minutes, Method G) = 2.05

Exampie 314

2,4-dichloro-N-(2-phenyl-2-(pyridazin-4-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and 2-phenyl-2-(pyridazin-4-yl)ethanamîne. LCMS (MH+): m/z =

372.1, t_R (minutes, Method G) = 2.09

Example 3u4

2-chloro-N-(3-cyclopropyl-2-(6-(dîfluoromethyl)pyridin-3-yl)propyl)benzamide

F

From 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-l-amine.

LCMS (MH+): m/z = 365.1, t_R (minutes, Method F) = 2.97

Ex ample 3v4

2,3-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

111

From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-l-amine.

LCMS (MH+): m/z = 399.1, îr (minutes, Method G) = 2.57

Example 3w4

2-chloro-3-fluoro-N-(3-cyclopropyl-2-(6-(difluoromethyi)pyridin-3-yl)propyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-lamine. LCMS (MH+): m/z = 383.1, îr (minutes, Method F) = 3.02

Example 3x4

2-chloro-3-methoxy-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

From 2-chloro-3-methoxybenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-lamine. LCMS (MH+): m/z = 395.1, t_R (minutes, Method F) = 2.96

Ex ample 3y4

2,4-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

From 2,4-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-l-amine.

LCMS (MH+): m/z = 399.1, t_R (minutes, Method G) = 2.61

112

Example 3z4

2,6-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-l-amine.

LCMS (MH+): m/z = 399.1, t_R (minutes, Method F) = 3.06

Example 3a5

2-chloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoiomethyl)pyrimidin-3-yl)propan-l-amine.

LCMS (MH+): m/z = 366.1, t_R (minutes, Method F) = 2.84

Example 3b5

2,3-dÎchloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yI)propan-lamine. LCMS (MH+): m/z = 400.1, t_R (minutes, Method F) = 3.00

Example 3c5

2-chloro-3-fluoro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yi)propyl)benzamide

113

From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-lamine. LCMS (MH+): m/z = 384.1, t_R (minutes, Method F) = 2.90

Example 3d5

2-chloro-3-methoxy-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidÎn-5-yl)propyl)benzamide

From 2-chloro-3-methoxybenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propanl-amine. LCMS (MH+): m/z = 396.1, t_R(minutes, Method F) = 2.84

Example 3c5

2,4-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

From 2,4-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyrimïdin-3-yl)propan-l15 amine. LCMS (MH+): m/z = 400.1, t_R (minutes, Method F) = 3.04

Example 3f5

2,6-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyi)pyrimidin-5-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-lamine. LCMS (MH+): m/z = 400.1, t_R (minutes, Method F) = 2.93

114

Example 3g5

2,3-dichloro-N-((4,4-difluoro-l-(4-methyl-lH-imidazol-l-yl)cyclohexyl)methyl)benzamide

From 2,3-dîchlorobenzoic acid and (4,4-difluoro-l-(4-methyl-lH-imidazol-lyl)cyclohexyl)methanamine. LCMS (MH+): m/z = 402.0, t_R (minutes, Method E) = 0.45

Example 3h5

N-(l-(l-(6-bromopyridin-3-yl)-4,4-difluorocyclohexyl)ethyl)-2,3-dichlorobenzamide

From 2,3-dichlorobenzoic acid and l-(l-(6-bromopyridin-3-yl)-4,4-difluorocyclohexyl)ethanamine.

LCMS (MH+): m/z = 493.1, t_R (minutes, Method D) = 0.83

Example 3i5

2,3-dichloro-N-((4,4-difluoro-l-(6-methylpyridin-3-yl)cyclohexyl)methyl)benzamide

From 2,3-dichlorobenzoic acid and (4,4-difluoro-l-(6-methylpyridin-3-yl)cyclohexyl)methanamine.

LCMS (MH+): m/z = 413.2, t_R (minutes, Method D) = 0.51

Example 3j5

2-chloro-3-fluoro-N-((4,4-difluoro-l-(6-fluoropyridin-3-yl)cyclohexyl)methyl)benzamide

115

From 2-chloro-3-fluorobenzoic acid and (4,4-difluoro-1-(6-fluoropyridin-3yl)cyclohexyl)methanamine. LCMS (MH+): m/z = 40L2, îr (minutes, Method D) = 0.72

Example 3k5

3-chloro-N-((4,4-difluoro-l-(6-fluoropyridin-3-yl)cyclohexyl)methyl)-2-fluorobenzamide

From

3-chloro-2-fluorobenzoic acid and (4,4-difluoro-1 - (6 -fl uoropyridin-3yl)cyclohexyl)methanamine. LCMS (MH+): m/z = 401.2, îr (minutes, Method D) = 0.75

Example 315

2-chloro-N-((4,4-difluoro-l-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methyl)benzamide

From

2-chlorobenzoic acid and (4,4-difluoro-1 -(6-(trifluoromethyl)pyridin-3yl)cyclohexyl)methanamine. LCMS (MH+): m/z = 433.2, îr (minutes, Method D) = 0.78

Example 3m5

2-chloro-3-methoxy-N-((4,4-difluoro-l-(6-(trifluoromethyl)pyridin-3yl)cyclohexyl)methyl)benzamide

From 2-chloro-3-methoxybenzoic acid and (4,4-difluoro-l-(6-(trifluoromethyI)pyridin-3yl)cyclohexyl)methanamine. LCMS (MH+): m/z = 463.2, Ir (minutes, Method D) = 0.77

Example 3n5

2-chloro-3-fluoro-N-((4,4-difluoro-l-(6-(trifluoromethyl)pyridin-3yl)cyclohexyl)methyl)benzamide

116

From 2-chloro-3-fluorobenzoic acid and (4,4-difluoro-l-(6-(trifluoromethyl)pyridin-3yl)cyclohexyl)methanamine. LCMS (MH+): m/z = 451.2, t« (minutes, Method D) = 0.79

Example 3o5

3-chloro-N-((4,4-difluoro-l-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methyl)-2fluorobenzamide

From 3-chloro-2-fluorobenzoic acid and (4,4-difluoro-l-(6-(trifluoromethyl)pyridin-3yl)cyclohexyl)methanamine. LCMS (MH+): m/z = 433.2, tR (minutes, Method D) = 0.83

Exampie 3p5

3-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-fluorobenzamide

From 3-chloro-2-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-lamine. LCMS (MH+): m/z = 401.2, Ir (minutes, Method D) = 0.84

Exampie 3q5

2-chloro-4-fluoro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)benzamide

117

From 2-chloro-4-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-lamine. LCMS (MH+): m/z = 401.0, t_R (minutes, Method D) = 0.79

Example 3r5

2,6-dichloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-l -amine.

LCMS (MH+): m/z = 417.2, t_R (minutes, Method D) = 0.89

Example 3s5

2,6-dichloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propyl)benzamide

From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-lamine. LCMS (MH+): m/z = 418.1, t_R (minutes, Method D) = 0.79

Example 3t5

2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propyl)benzamide

O Cl

From 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyi)pyrimidin-3-yl)propan-l-amine.

LCMS (MH+): m/z =384.1, t_R (minutes, Method D) = 0.76

Example 3u5

2-chloro-3-fluoro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propyl)benzamide

118

From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-lamîne. LCMS (MH+): m/z = 402.1, t_R (minutes, Method D) = 0.78

Example 3v5

2-chloro-6-fluoro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propyl)benzamide

From 2-chloro-6-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-lamine. LCMS (MH+): m/z = 402.1, t_R (minutes, Method D) = 0.77

Example 3w5

2,4-dichloro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2,4-dichlorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+); m/z = 439.0, t_R (minutes, Method E) = 0.81

Example 3x5

2,3-dichloro-N-((3-(2-methylpyrimidin-5-yl)tetrahydrofuran-3-yl)methyl)benzamide

From 2,3-dichlorobenzoic acid and (3-(2-methylpyrimidin-5-yl)tetrahydrofuran-3-yl)methanamine.

LCMS (MH+); m/z = 366.0, t_R (minutes, Method E) = 0,45

119

Example 3y5

2-Chloro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)etlianamine. LCMS (MH+): m/z = 405.2, t_R (minutes, Method D) = 0.79

Example 3z5

2-chloro-6-fluoro-N-(2-phenyI-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chIoro-6-fluorobenzoic acid and 2-phenyI-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine.

LCMS (MH+): m/z = 423.1, t_R (minutes, Method D) = 0.80

Example 3a6

2-chloro-3-fluoro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chloro-3-fluorobenzoic acid and 2-phenyI-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine.

LCMS (MH+): m/z = 423.1, t_R (minutes, Method D) = 0.81

Example 3b6

2,3-dichlorO“N-(2“phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

120

From 2,3-dichlorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z = 439.2, t_R (minutes, Method D) = 0.84

Example 3c6

2-Chloro-N-(3-cyclopropyl-2-(5-methylpyrazin-2-yl)propyl)benzamide

From 2-chIorobenzoic acid and 3-cyclopropyl-2-(5-methylpyrazin-2-yl)propylamine. LCMS (MH+): m/z = 330.0, t_R (minutes, Method E) = 0.61

Example 3d6

2-Chloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3 yl)ethanamîne. LCMS (MH+): m/z = 413.0, t_R (minutes, Method E) = 0.64

Example 3e6

2-Chloro-3-fluorO“N-(2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3yl)ethyl)benzamîde

121

From 2-chloro-3-fluorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(6(trifluoromethyl)pyridin-3-yl)ethanamine, LCMS (MH+): m/z = 431.2, t_R (minutes, Method D) =

0.69

Exampie 3f6

2,3-Dichloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3- yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3yl)ethanamine. LCMS (MH+): m/z = 447.0, t_R (minutes, Method E) = 0.70

Exampie 3g6

2-Chloro-6-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3yl)ethyl)benzamide

From 2-chloro-6-fluorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(6(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z = 431.0, t_R (minutes, Method E) =

0.64

Exampie 3h6

2-Chloro-N-(2-isopropoxy-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2-chlorobenzoic acid and 2-îsopropoxy-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z = 334.0, t_R (minutes, Method E) = 0.52

122

Exampie 3i6

2,3-Dichloro-N-(2-isopropoxy-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

From 2,3-dichlorobenzoic acid and 2-isopropoxy-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z = 368.1, t_R (minutes, Method D) = 0.64

Exampie 3j6

2,3-Dîchloro-N-(2-(l-methyl-lH-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide .Cl

From 2,3-dichlorobenzoic acid and 2-(l-methyl-lH-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-4yljethanamîne. LCMS (MH+): m/z = 382.0, t_R (minutes, Method E) = 0.52

Example 3k6

2,3-DichIoro-N-((2-(2-methylpyrimidin-5-yI)tetrahydrofuran-2-yl)methyl)benzamide .ci

From 2,3-dichlorobenzoic acid and (2-(2-methylpyrimidin-5-yl)tetrahydrofuran-2-yl)methanamine. LCMS (MH+): m/z = 366.0, t_R (minutes, Method E) = 0.52

Example 316

2,3-Dichloro-N-(2-(l-methyl-lH-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyridin-3yl)ethyl)benzamide

N

N—N \

CI

123

From 2,3-dichlorobenzoic acid and 2-(l-methyl-lH-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyridin-3yl)ethanamine. LCMS (MH+): m/z = 443.2, t_R (minutes, Method D) = 0.67

Example 3m6

2,3-Dichloro-N-[2-(l-methylpyrazol-4-yl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(l-methyl-lH-pyrazol-4-yl)-2-(6-(trifluoromethyl)pyrimidin5-yl)ethanamine. LCMS (MH+): m/z = 444.1, t_R (minutes, Method F) = 2.73

Example 3n6

2,3-dichloro-N-[2-(l-methylpyrazol-3-yl)-2-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]benzamide

From 2,3-dichlorobenzoic acid and 2-(l-methyl-lH-pyrazo!-3-yl)-2-(6-(trifluoromethyl)pyrimidin5-yl)ethanamine. LCMS (MH+): m/z = 444.1, t_R (minutes, Method F) = 2.87

Example 3o6

2,3-Dichloro-N-[2-(l-methyl-lH-imidazol-4-yl)-2-(2-trifluoromethyl-pyrimidin-5-yl)-ethyl]- benzamide

acid and 2-( 1 -methyl-1 H-imidazol-4-yl)-2-(6(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z = 443.8, t_R (minutes, Method F) =

1.97

124

Example 3p6

2-Chloro-N-((4,4-difluorO’l-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3methoxybenzamide

From 2-chloro-3-methoxybenzoic acid and [4,4-Difluoro-l-(2-(trifluoromethyl)pyrimidin-5yl)cyclohexyl]methanamine. LCMS (MH+): m/z = 464.1, t_R (minutes, Method F) = 3,02

Example 3q6

2-Chloro-N-[[4_J4-difluoro-l-[2-(trifluoromethyl)pyrimidin-5-yl]cyclohexyl]methyl]benzamide

From 2-chlorobenzoic acid and [4,4-Difluoro-l-(2-(trifluoromethyl)pyrimidin-5yl)cyclohexyl]methanamine. LCMS (MH+): m/z = 434.1, t_R (minutes, Method F) = 3.04

Example 3r6

2-Chloro-N-((4,4-difluoro-l-(2-(trifiuoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3fluorobenzamide

F

From 2-chloro-3-fluorobenzoic acid and [4,4-Difluoro-l-(2-(trifluoromethyl)pyrimidin-5yl)cyclohexyl]methanamine. LCMS (MH+): m/z = 452.1, t_R (minutes, Method F) = 3.08

Example 3s6 2“Chloro-N-((4,4-difluoro-l-(2-(trifluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3(trifluoromethyl)benzamide

125

From 2-chloro-3-trifluoromethylbenzoic acid and [4,4-Difluoro-l-(2-(trifluoromethyl)pyrimidin-5yl)cyclohexyl]methanamine. LCMS (MH+): m/z = 502.1, îr (minutes, Method F) = 3.25

Example 3t6

2-Chloro-N-((4,4-difluoro-l-(2-(difiuoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3methoxyb enzam ide

From 2-chloro-3-methoxybenzoic acid and (l-(2-(difluoromethyl)pyrimidin-5-yl)-4,4difluorocyclohexyl)methanamine. LCMS (MH+): m/z = 446.1, îr (minutes, Method F) = 2.82

Example 3u6

2-Chloro-N-((4,4-difluoro-l-(2-(difluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)benzamide

From 2-chlorobenzoic acid and (l-(2-(difluoromethyl)pyrimidin-5-yl)-4,4difluorocyclohexyl)methanamine. LCMS (MH+): m/z = 416,1, îr (minutes, Method F) = 2.83

Example 3v6

2,3-dichloro-N-((4,4-difluoro-l-(2-(difluoromethyl)pyrimidin-5yl ) cyclohexyl )methyl)b enzamide

126

From 2,3-dichlorobenzoic acid and (l-(2-(difluoromethyI)pyrimidin-5-yl)-4,4-

difluorocyclohexyl)methanamine. LCMS (MH+): m/z = 450.1, t_R (minutes, Method F) = 2.98

Example 3w6

2-Chloro-N-((4,4-difluoro-l-(2-(difluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3fluorobenzamide

From 2-chloro-3-fluorobenzoic acid (l-(2-(difluoromethyl)pyrimidin-5-yl)-4,410 difluorocyclohexyl)methanamine. LCMS (MH+): m/z = 434.1, t_R (minutes, Method F) = 2.88

Example 3x6

2-Chloro-N-((4,4-difluoro-l-(2-(difluoromethyl)pyrimidin-5-yl)cyclohexyl)methyl)-3(trifluoromethyl)benzamide

From 2-cliloro-3-trifluoromethylbenzoic (l-(2-(difluoromethyl)pyrimidin-5-yl)-4,4difluorocyclohexyl)methanamine. LCMS (MH+): m/z = 484.0, t_R (minutes, Method F) = 3.07

Example 3y6

2,6-dichloro-N-((4,4-difluoro-1 -(2-(difluoromethyl)pyrimidin-5yl)cyclohexyl)methyl)benzamide

127

From 2,6-dichlorobenzoic acid and (l-(2-(difluoromethyl)pyrimidin-5-yl)-4,4difluorocyclohexyl)methanamine. LCMS (MH+): m/z = 450.1, t_R (minutes, Method F) = 2.93

Example 4a (+)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyi]benzamide

The racemic mixture which was prepared as described for example 3cl was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 383.1, t_R (minutes, Method G) = 2.5. [α]τ?= +13.66 (c = 3.0 mg/mL,CHCl₃)

And the corresponding enantiomer

Exampie 4b (-)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

LCMS (MH+): m/z = 383.1, t_R (minutes, Method G) = 2.5. [a]ÿ= -l 3.0 (c = 3.0 mg/mL,CHCl₃)

Exampie 4 c (+)-2,3-Dichloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

The racemic mixture wliich was prepared as described for example 3a was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 417.1, t_R (minutes,

Method G) = 2.64. [ot]?9= +l 5.0 (c = 3.0 mg/mL,CHCl₃)

And the corresponding enantiomer

Exampie 4d

128 (-)-2,3-Dicliloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]benzamide

LCMS (MH+): m/z = 417.1, t_R (minutes, Method G) = 2.64. [a]ÿ=-12.0 (c = 3.0 mg/mL,CHCl₃)

Example 4e (+)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]-3-(trifluoromethyl)benzamîde

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3trifluoromethylbenzoic acid and 3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 451.1, t_R (minutes, Method G) = 3.11. [a]^J?= +26.0 (c = 2.0 mg/mLjCHCb)

And the corresponding enantiomer

Example 4f (-)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]-3-(trifluoromethyl)benzaniide LCMS (MH+): m/z = 451.1, t_R (minutes, Method G) = 3.11. [a]yÇ= -25.0 (c = 2.0 mg/mL.CHClj)

Example 4g (-)-2,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-3-[l-(trifluoromethyl)cycIopropyl]propyl]benzamide ci

The racemic mixture which was prepared as described for example 3a was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 432.0, t_R (minutes, Method F) = 2.72. [a]$= -34.0 (c = 4.5 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4h (+)-2,3-Dichloro-N-[2-(2-methylpyrimidin-5-yl)-3-[l-(trifluoromethyl)cycIopropyl]propyl]benzamide LCMS (MH+): m/z = 432.0, t_R (minutes, Method F) = 2.72. [a]?9= 35.7 (c = 4.7 mg/mL,CHCI₃)

Example 4i

129 (-)-2-Chloro-N-[2-(2-methylpyrimidin-5-yl)-3-[l-(trifluoromethyl)cyclopropyl]propyl]benzamide

N.

The racemîc mixture wliich was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(2-methyl-pyrimidin-5-yl)-3-(l-trifluoromethyl-cyclopropyl)-propylamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 398.1, t_R (minutes, Method F) = 2.55. [a]?j?= -25.5 (c = 5.1 mg/mL,CHC13)

And the corresponding enantiomer

Example 4j (+)-2-Chloro-N-[2-(2-methylpyrimidin-5-yl)-3-[l-(trifluoromethyl)cyclopropyl]propyl]benzamide LCMS (MH+): m/z = 398.1, t_R (minutes, Method F) = 2.55. [a]ÿ= 27.1 (c = 5.5 mg/mL,CHCl₃)

Example 4k (+)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]-3-methoxy-benzaniide

The racemîc mixture which was prepared in a similar manner to example 3a from 2-chloro-3methoxybenzoic acid and 3-cyclopropyL2-(6-trifluoromethyl-pyridin-3-yl)-propylamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 413.1, t_R (minutes, Method G) = 2.84. [α]?9= +20.9 (c = 0.86 mg/mL,CHCl₃)

Example 41 (-)-2-Chloro-N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3-pyridyl]propyl]-3-methoxy-benzamide LCMS (MH+): m/z = 413.1, t_R(minutes, Method G) = 2.84. [a]^?=-22.09 (c = 0.86mg/mL,CHCl₃)

Example 4 m (-)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-6-fluorobenzamide

130

The racemic mixture which was prepared in a similar mariner to example 3a from 2-chloro-6fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 401.1, t_R (minutes, Method G) = 2.88. [a]îÿ= -25.9 (c = 0.81 mg/mL,CHCi₃)

And the corresponding enantiomer

Example 4n (+)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-6-fluorobenzamide LCMS (MH+): m/z = 401.1, t_R (minutes, Method G) = 2.88. [a]î?= 25.9 (c = 0.81 mg/mL,CHCl₃)

Exampie 4o (-)-bi-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-methoxybenzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-methoxybenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1 -amine was separated into the two enantiomers by préparative SFC to yield tire title compound. LCMS (MH+): m/z = 379.1, t_R (minutes, Method G) = 3.01. [a]?Ç = -6.67 (c = 3.9 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4p (+)-N-(3-cycIopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2-methoxybenzamide

LCMS (MH+): m/z = 379.1, t_R (minutes, Method G) = 3.01. [a]îJ = 6.89 (c = 4.5 mg/mL,CHCl₃)

Example 4q (-)-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2,6-difluorobenzamide

131

The racemic mixture which was prepared in a similar manner to example 3a from 2,6-difluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 385.1, t_R (minutes, Method G) = 2.92. [a]î? = -35.71 (c = 0.84 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4r (+)-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-2,6-difluorobenzamide

LCMS (MH+): m/z = 385.1, t_R (minutes, Method G) = 2.92. [α]$ = 36.9 (c = 0.84 mg/mL,CHCl₃)

Example 4s (+)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-5(methylsul fonyl)benzamide

O

The racemic mixture which was prepared in a similar manner to example 3a fiom 2-cldoro-5(methylsulfonyl)benzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 461.1, t_R (minutes, Method F) = 2.98. [a]^?=+28.75 (c = 0.8 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4t (-)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-5(methylsulfonyl)benzamide

LCMS (MH+): m/z = 461.1, t_R (minutes, Method F) = 2.98. [a]?9= -27.0 (c = 1.0 mg/mL,CHCl₃)

Example 4u (+)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-3-fluorobenzamide

132

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+):

m/z = 401.1, t_R (minutes, Method G) = 2.61. [a]?Ç=+28.13 (c= 1.6 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4v (“)-2-chloro-N-(3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propyl)-3-fluorobenzamide

LCMS (MH+): m/z = 401.1, t_R (minutes, Method G) = 2.61. [α]$= -26.25 (c = 1.6 mg/mL,CHCl₃)

Example 4w (+)-2-chloro-N-(3-cyclopropyl-2-(6-fluoropyridin-3-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-fluoropyridin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 333.1, t_R (minutes, Method F) = 2.53. [a]?ÿ= +29.0 (c = 2.0 mg/mL,CHCIj)

And the corresponding enantiomer

Example 4x (-)-2-chloro-N-(3-cyclopropyl-2-(6-fluoropyridin-3-yl)propyl)benzamide

LCMS (MH+): m/z = 333.1, t_R (minutes, Method F) = 2.53. [η]19⁼ -24.5 (c = 2.0 mgànL,CHCl₃)

Example 4y (+)-2,3-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl)benzamide

133

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-l -amine was separated into tlie two enantiomers by préparative SFC to yield the title compound LCMS (MH+): m/z = 364.1, t_R (minutes, Method F) = 2.64, [α]$= +41.3 (c = 1.5 mg/mL,CHCI₃)

And the correspondîng enantiomer

Example 4z (-)-2,3-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z = 364.1, t_R (minutes, Method F) = 2.64. [a]$= -40.7 (c= 1.5 mg/mL,CHCl₃)

Example 4al (+)-2,3-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

Cl

Tlie racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoroinethyl)pyrimidin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield tlie title compound. LCMS (MH+): m/z = 418.1, t_R (minutes, Method G) = 2.59. [ct]T?= +21.41 (c = 3.27 mg/mL,CHCl₃)

And tlie correspondîng enantiomer

Example 4bl (-)-2,3-dichloro-N-(3-cyclopropyl-2-(2-( tri fluoromethyl)pyrimidin-5-yl)propyl)benzamide LCMS (MH+): m/z = 418.1, t_R (minutes, Method G) = 2.59. [a]S*= -22.00 (c = 3.0 mg/mL,CHCl₃)

Example 4 cl (+)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-l-amine was separated into tlie two

134 enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 384.1, t_R (minutes, Method F) = 2.66. [a]?9= +23.68 (c = 5.49 mg/mL,CHCl₃)

And the corresponding enantiomer

Exampie 4dl (-)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyi)pyrimidin-5-yl)propyl)benzamide LCMS (MH+): m/z = 384.1, t_R (minutes, Method F) = 2.66. [ot]î9= -21.63 (c = 5.27 mg/mL,CHCl₃)

Example 4el (+)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyI)-3-fluorobenzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-l -amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 402.1, t_R (minutes, Method F) = 2.71. [α]$= +24.77 (c = 4.44 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4fl (-)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyi)-3-fluorobenzamide LCMS (MH+): m/z = 402.1, t_R (minutes, Method F) = 2.71. [a]?9= -21.77 (c = 4.50 mg/mL,CHCl₃)

Example 4gl (+)-2-chIoro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-6-fluorobenzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-6fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-l-amine was

135 separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 402.1, t_R (minutes, Method F) = 2.69. [a]^?= +35.56 (c = 2.25 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4hl (-)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-6-fluorobenzamide LCMS (MH+): m/z = 402.1, îr (minutes, Method F) = 2.69. [a]$= -34.27 (c = 2.48 mg/mL,CHCl₃)

Example 4il (+)-2,3-dichloro-N-(3-cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propyl)benzamide

OH

Cl

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(5-(l-amino-3-cyclopropy!propan-2-yl)pyridin-2-yl)propan-2-ol was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (ΜΉ+): m/z = 407.1, îr (minutes, Method F) = 1.98. [a]$= +23.89 (c = 3.0 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4j 1 (-)-2,3-dichloro-N-(3-cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propyl)benzamide LCMS (MH+): m/z = 407.1, t_R (minutes, Method F) = 1.98. [a]^Ç=-28.17 (c = 3.1 mg/mL,CHCl₃)

Example 4kl (+)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3methoxybenzamide .OMe

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3methoxybenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-l-amine was

136 separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 414.0, t_R (minutes, Method F) = 2.53. [a] ^=+26.3 (c = 4.0 mg/mL.CHCli)

And the corresponding enantiomer

Example 411 (-)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3methoxybenzamide

LCMS (MH+): m/z = 414.0, t_R (minutes, Method F) = 2.53. [a]$= -29.5 (c = 3.7 mg/mL,CHCl₃)

Example 4ml (+)-2-methyl-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3methoxybenzamide ,OMe

The racemic mixture which was prepared in a similar manner to example 3a from 2-methyl-3methoxybenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-l -amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 394.0, t_R (minutes, Method F) = 2.59. [ct]^Ç= +26.8 (c = 3.90 mg/mL,CHClj)

And the corresponding enantiomer

Exampie 4nl (-)-2-methyl-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)-3methoxybenzamide

LCMS (MH+): m/z = 394.0, t_R (minutes, Method F) = 2.59. [α]τ9= -26.9 (c = 3.40 mg/mL,CHClî)

Ex a ni pie 4ol (+)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-l-amine was separated into the

137 two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 418.1, îr (minutes, Method F) = 2.62. [a]î?= +21.87 (c = 3.2 mg/mL,CHCl₃)

And the corresponding enantiomer

Exampie 4pl (-)-2,6-dichIoro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z = 418.1, t_R (minutes, Method F) = 2.62. [a]î9= -21.43 (c = 2.8 mg/mL,CHCl₃)

Exampie 4ql (+)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(trifIuoromethyl)pyridin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyridin-5-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound LCMS (MH+): m/z = 417.1, îr (minutes, Method G) = 2.50. [α]$= +20.64 (c = 4.7 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4rl (-)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(trifluorometliyl)pyridin-5-yl)propyl)benzamide

LCMS (MH+): m/z = 417.1, îr (minutes, Method G) = 2.50. [a]??= -20.3 (c = 3.5 mg/mL,CHCl₃)

Exampie 4s 1 (+)-2,6-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyI)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 364.1, tR (minutes,

Method F) = 2.43. [a]$=+15.42 (c = 2.4 mg/mL,CHCl₃)

And the corresponding enantiomer

138

Example 4tl (-)-2,6-dichloro-N-(3-cyclopropyl-2-(2-methylpyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z = 364.1, t_R (minutes, Method F) = 2.43. [α]?9= -11.51 (c = 1.87 mg/mL,CHCl₃)

Example 4ul (+)-2-chloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propyl)benzamide

Tlie racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-l -amine was separated into tlie two enantiomers by préparative SFC to yield tlie title compound. LCMS (MH+): m/z = 398.1, t_R (minutes, Method F) = 2.62. [ci]^?= +13.77 (c = 5.30 mg/mL,CHClj)

And the corresponding enantiomer

Example 4vl (-)-2-chloro-N-(3-cyclopropyl-2-nictliyl-2-(2-(trifluoiOniethyl)pyrimidiii-5-yl)propyl)benzamide LCMS (MH+): m/z = 398.1, t_R (minutes, Method F) = 2.62. [ct]l9= -14.16 (c = 5.86 mg/mL,CHCl₃)

Example 4x1 (+)-2-chIoro-3-fluoro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3fluorobenzoîc acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-l -amine was separated into the two enantiomers by préparative SFC to yield tlie title compound. LCMS (MH+): m/z = 416.1, t_R (minutes, Method G) = 2.48. [α]?9= +13.80 (c = 5.87 mg/mL,CHC13)

And tlie corresponding enantiomer

Example 4yl

139 (-)-2-chloro-3-fluoro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5yl )prop yl )b enzam i de

LCMS (MH+): m/z = 416.1, t_R (minutes, Method G) = 2.48. [a]?9= -13.85 (c = 5.63 mg/mL,CHClj)

Example 4zl (+)-2,3-dichloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-l -amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 432.1, t_R (minutes, Method G) = 2.58. [α]^?= +17.42 (c = 6.6 mgftnL,CHCl₃)

And tlie corresponding enantiomer

Example 4a2 (-)-2,3-dichloro-N-(3-cyclopropyl-2-methyl-2-(2-(trifluoromethyl)pyrimidin-5y l )propyl)benzamide

LCMS (MH+): m/z = 432.1, t_R (minutes, Method G) = 2.58. [a]^?=-l7.32 (c = 6.6 mg/mL.CHCh)

Example 4b2 (+)-2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

Tlie racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(2-methyIpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 360.1, t_R (minutes,

Method F) = 1.97/1.65. [α]$= +43.43 (c = l .75 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4c2

140 (-)-2-chloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

LCMS (MH+): m/z = 360.1, t_R (minutes, Method F) = 1.97. [a]$= -38.00 (c= 1.5 mg/mL,CHCl₃)

Example 4d2 (+)-2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound LCMS (MH+): m/z = 394.1, t_R (minutes, Method F) = 1.88. [a]^9= +57.50 (c = 2.0 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4e2 (-)-2,3-dichloro-N-(2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide LCMS (MH+): m/z = 394.1, t_R (minutes, Method F) = 1.88. [cl]t9= -57.89 (c= 1.9 mgfrnL,CHCl₃)

Example 4f2 (+)-2-chloro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 3-( 1 -(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1 -amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 452.0, t_R (minutes, Method F) = 3.03. [α]γ9= +27.50 (c = 4.80 mg/mL,CHCI₃)

And the corresponding enantiomer

Example 4g2

141 (-)-2-chloro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)propyl)benzamide

LCMS (MH+): m/z = 452.0, t_R (minutes, Method F) = 3.03. [α]χ?= -27.32 (c = 3.88 mg/mLCHCb)

Example 4h2 (+)-2,3-dichloro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)propyl)benzamide

CI

The racemic mixture which was prepared in a simiiar manner to example 3a from 2,3-dichlorobenzoic acid and 3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-l-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z = 486.1, t_R (minutes, Method F) = 2.77. [a]î?= +31.03 (c = 5.80 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4i2 (-)-2,3-dichloro-N-(3-(l-(tri fIuoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)propyl)benzamide

LCMS (MH+): m/z = 486.1, t_R (minutes, Method F) = 2.77. [ci]Î9= -31.87 (c = 5.02 mg/mL,CHCl₃)

Example 4j2 (+)-2-chloro-3-fluoro-N-(3-(l-(trifluorornethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5yl )propy l )b enzamide

The racemic mixture which was prepared in a simiiar manner to example 3a from 2-chloro-3fluorobenzoic acid and 3-(l-(trifluorornethyl)cyclopropyl)-2-(2-(trifluorornethyl)pyrimidin-5yl)propan-l-amine was separated into the two enantiomers by preparative SFC to yield the title

142 compound. LCMS (MH+): m/z = 470.0, t_R (minutes, Method F) = 3.07. [α]τ9= +28.85 (c = 3.05 mg/mL,CHCl3)

And the corresponding enantiomer

Ex a mple 4k2 (-)-2-chloro-3-fluoro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)propyl)benzamide

LCMS (MH+): m/z = 470.0, t_R (minutes, Method F) = 3.07. [a]T?= -28.97 (c = 3.21 mg/mL.CHCh)

Example 412 (+)-2-chIoro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 451.1, t_R (minutes, Method G) = 2.50. [a]ï?= +33.55 (c = 3.07 mg/mL,CHClj)

And the corresponding enantiomer

Example 4m2 (-)-2-chloro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5yl)propyl)benzamide

LCMS (MH+): m/z = 451.1, t_R (minutes, Method G) = 2.50. [a]î?= -32.98 (c = 3.20 mg/mL.CHClj)

Example 4n2 (+)-2,3-dichloro-N-(3-(l-(trifluoromethyl)cyclopropyI)-2-(2-(trifluoromethyl)pyridin-5yl)propyl)benzamide

143

The racemic mixture which was prepared în a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-(l-(trifluoromethyl)cyclopropyI)-2-(2-(trifluorornethyl)pyridin-5-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield tlie title compound. LCMS (MH+): m/z = 485.1, t_R (minutes, Method G) = 2.63. [a]^?= +27.63 (c = 1.52 mg/mL.CHCb)

And the corresponding enantiomer

Exampie 4o2 (-)-2,3-dichloro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5yl)propyl)benzamide

LCMS (MH+): m/z = 485.1, t_R (minutes, Method G) = 2.63. [a] ?9= -26.67 (c = 1.50 mg/mL,CHCh)

Exampie 4p2 (+)-2-chloro-3-fluoro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5yl)propyl)benzamide

Tlie racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3fluorobenzoic acid and 3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-lamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 469.1, t_R (minutes, Method G) = 2.54. [a]?9= +27.60 (c = 3.20 mg/mL.CHCh) And the corresponding enantiomer

Example 4q2 (-)-2-chloro-3-fluoro-N-(3-(l-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5yl)propyl)benzamide

LCMS (MH+): m/z = 469.1, t_R (minutes, Method G) = 2.54. [α]ΐ?= -27.55 (c = 3.40 mg/mL,CHCl₃)

144

Example 4r2 (+)-2,3-dichloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)bcnzamide

O

The racemic mixture which was prepared in a simiiar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 448.0, t_R (minutes, Method F) = 2.72. [a]ÿ= +42.52 (c = 3.8 mg/mL,CHClj)

And the corresponding enantiomer

Example 4s2 (-)-2,3-dicliloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH+): m/z = 448.0, t_R (minutes, Method F) = 2.72. [a]ÿ= -42.62 (c = 3.66 mg/mL,CHCl₃)

Example 4t2 (+)-2-chloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide '0'

The racemic mixture which was prepared in a simiiar manner to example 3a from 2-chlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 414.1, t_R (minutes, Method F) = 2.54. [α]?9= +38.57 (c = 2.80 mg/mL,CHCl₃)

And tlie corresponding enantiomer

Example 4u2 (-)-2-chloro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

145

LCMS (MH+): m/z = 414.1, t_R (minutes, Method F) = 2.54. [a]?9= -38.13 (c = 3.20 mg/mL,CHCl₃)

Exampie 4v2 (+)-2-chloro-3-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3fluorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 432.1, t_R (minutes, Method F) = 2.48. [a]?9= +32.38 (c = 3,27 mg/mL,CHCl₃) And the corresponding enantiomer

Example 4x2 (-)-2-chloro-3-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH+): m/z = 432.1, t_R (minutes, Method F) = 2.48. [«]$= -35.64 (c = 3.18 mg/mL,CHCl₃)

Exampie 4y2 (+)-2-chloro-6-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide '0'

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-6fluorobenzoic acid and 2-(tetrahydro-2H-pyran-4-y!)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 432.1, t_R (minutes, Method F) = 2.6. [a]^?= +37.86 (c = 4.20 mg/mL,CHCl₃)

And the corresponding enantiomer

Ex ample 4z2

146 (-)-2-chloro-6-fluoro-N-(2-(tetrahydro-2H-pyran-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH+): m/z = 432.1, t_R (minutes, Method F) = 2.6. [a]T?= -37.86 (c = 3.83 mg/mL,CHCl₃)

Exampie 4a3 (+)-2,6-dichloro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2,6-dichlorobenzoic acid and 2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 439.1, t_R (minutes, Meüiod G) = 2.76. [a]$= +3.18 (c = 6.38 mg/mL,CHCl₃)

And tlie corresponding enantiomer

Exampie 4b3 (-)-2,6-dichloro-N-(2-phenyl-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH+): m/z = 439.1, t_R (minutes, Method G) = 2.76. [a]?9= -4.19 (c = 7.8 mg/mL,CHCl₃)

Exampie 4c3 (+)-2,3-dichloro-N-(2-(4-fluorophenyl)-2-(6-( tri fluoromethyl)pyridin-3-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 457.0, t_R (minutes,

Method G) = 3.02. [a]îJ= +4.17 (c = 3.04 mg/mL,CHCl₃)

And the corresponding enantiomer

Exampie 4d3

147 (-)-2,3-dichloro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH+): m/z = 457.0, t_R (minutes, Method G) = 3.02. [a]?9⁼ -4.31 (^{c =} 3.64 mg/mL.CHCh)

Exampie 4c3 (+)-2-chloro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

The racemic mixture which was prepared in a si mil ar manner to example 3 a from 2-chlorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yi)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z - 423.1, t_R (minutes, Method G) = 2.58. [α]$=+18.1 (c = 5.22 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 413 (-)-2-chloro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH+): m/z = 423.1, t_R (minutes, Method G) = 2.58. [a]î?= -16.1 (c = 5.26 mg/mL,CHCl₃)

Exampie 4g3 (+)-2-chloro-3-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3fluorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+):

m/z = 441.1, t_R (minutes, Method G) = 2.63. [α]^?=+10.60 (c = 5.6 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4113

148 (-)-2-chloro-3-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

LCMS (MH+): m/z = 44l.l,t_R(minutes, Method G) = 2.63. [a]$=-10.96 (c = 5.2 mg/mL,CHCl₃)

Exampie 4i3 (+)-2-chloro-6-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-6fluorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound LCMS (MH+): m/z = 441.0, t_R (minutes, Method G) = 2.86. [α]^9= +17.1 (c = 4.44 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4j3 (-)-2-chloro-6-fluoro-N-(2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)benzamide LCMS (MH+): m/z = 441.0, t_R (minutes, Method G) = 2.86. [a]$= -15.7 (c = 4.58 mg/mL,CHCl₃)

Example 4k3 (+)-2,3-dichloro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 458.0, t_R (minutes, Method G) = 2.91. [α]$=+14.2 (c = 8.50 mg/mL,CHCI₃)

And the corresponding enantiomer

Example 413

149 (-)-2,3-dichloro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z = 458.0, t_R (minutes, Method G) = 2.91. [a]?9= -14.3 (c = 7.90 mg/mL,CHCl₃)

Example 4m3 (+)-2-chloro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

F

The racemîc mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 424.1, t_R (minutes, 10 Method F) = 3.19. [a]?9= +16.4 (c = 6.80 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4n3 (-)-2-chloro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z = 424.1, t_R (minutes, Method F) = 3.19. [a]ÿ*= -14.3 (c = 6.40 mg/mL,CHCl₃)

Example 4o3 (+)-2-ch)oro-3-fluoro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

F

The racemîc mixture which was prepared in a similar manner to example 3a from 2-chloro-3fluorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 442.1, t_R (minutes, Method F) = 3.24. [«]T?= +12.8 (c = 6.8 mg/mL,CHCl₃)

And the corresponding enantiomer

150

Example 4p3 (-)-2-chloro-3-fluoro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH+): m/z = 442.1, t_R (minutes, Method F) = 3.24. [a]îÿ= -12.3 (c = 7.0 mg/mL,CHCl₃)

Example 4q3 (+)-2-chloro-6-fluoro-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5yl )ethyl)b enzamide

F

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-6fluorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 442.0, t_R (minutes, Method F) = 2.99. [a]l9=+18.1 (c = 4.0 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4r3 (-)-2-chloro-6-fluoTO-N-(2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5yl )ethyl )b enzam i d e

LCMS (MH+): m/z = 442.0, t_R (minutes, Method F) = 2.99. [a]$= -16.1 (c = 4.0 mg/mL,CHCI₃)

Example 4s3 (+)-2-chloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(4,4-difluorocycIohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the

151 two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 448.1, t_R (minutes, Method F) = 2.95. [a]^?= +28,00 (c = 1.5 mg/mL,CHCi₃)

And the corresponding enantiomer

Example 4t3 (-)-2-chloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH+): m/z = 448.1, t_R (minutes, Method F) = 2.95. [a]?Ç= -28.83 (c = 1.63 mg/mL,CHCl₃)

Example 4u3 (+)-2,3-dichloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl ) ethyl)b enzam i de

CI

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 482.1, t_R (minutes, Method G) = 2.76. [a]î9= +24.29 (c = 0.70 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4v3 (-)-2,3-dichloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH+): m/z = 482.1, t_R (minutes, Method G) = 2.76. [α]$= -23.46 (c = 0.81 mg/mL,CHCl₃)

Ex ample 4x3 (+)-2-chloro-6-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

152

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-6-

fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyriniÎdin-5-yl)ethanamine was separated into die two enantiomers by préparative SFC to yield die title compound. LCMS (MH+): m/z = 466.1, t_R (minutes, Method F) = 2.97. [a]?9= +36.00 (c = 1.50 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4y3 (-)-2-chloro-6-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

LCMS (MH+): m/z = 466.1, t_R (minutes, Method F) = 2.97. [a]l9= -34.89 (c = 1.50 mg/mL,CHC13)

Example 4z3 (+)-2-chloro-3-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 466.1, t_R (minutes, Method F) = 2.67. [a]$= +28.57 (c = 0.56 mg/mL.CHCh)

And tiie corresponding enantiomer

Example 4a4 (-)-2-chloro-3-fluoro-N-(2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5yl) ethyl)b enzam id e

LCMS (MH+): m/z = 466.1, t_R (minutes, Metiiod F) = 2.67. [a]T?= -28.83 (c = 0.61 mg/mL.CHCh)

153

Example 4b4 (+)-2,3-dichloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 448.1, t_R (minutes, Method F) = 2.95. [a]î?= +49.6 (c = 4.8 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4c4 (-)-2,3-dichloro-N-(2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethyl)benzamide

LCMS (MH+): m/z = 448.1, t_R (minutes, Method F) = 2.95. [«]$= -47.0 (c = 5.20 mg/mL,CHCl₃)

Example 4d4 (+)-2-chloro-N-(3-cyclopropyl-2-(6-(dîfluoromethyl)pyridin-3-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-clilorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z - 365.1, t_R (minutes, Method F) = 2.97. [a]$= +21.00 (c = 3.00 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4c4 (-)-2-chloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyi)benzamide

LCMS (MH+): m/z = 365.1, t_R (minutes, Method F) = 2.97. [a]ÿ= -20.00 (c = 2.90 mg/mL,CHCl₃)

Example 4f4 (+)-2,3-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

154

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 399.1, t_R (minutes, Method G) = 2.57. [«]$= +20.45 (c = 2.20 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4g4 (-)-2,3-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

LCMS (MH+): m/z = 399.1, t_R (minutes, Method G) = 2.57. [ci] t9= -19.43 (c = 2.11 mg/mL,CHCI₃)

Example 4h4 (+)-2-chloro-3-fluoro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3fluorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-l -amine was separated into the two enantiomers by prcparative SFC to yield the title compound. LCMS (MH+): m/z = 383.1, t_R (minutes, Method F) - 3.02. [α]^?= +21.03 (c = 2.90 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4Î4 (-)-2-chloro-N-(3-cyclopropyl-2-(2-(trifluoromethyl)pyridtn-5-yl)propyl)-6-fluorobenzamide

LCMS (MH+): m/z = 383.1, t_R (minutes, Method F) = 3.02. [a]î?= -20.40 (c = 2.50 mg/mL,CHCl₃)

Example 4j4 (+)-2-chloro-3-methoxy-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

155

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3methoxybenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 395.1, t_R (minutes, Method F) = 2.96. [a)î9= +28.21 (c = 2.80 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4k4 (-)-2-cliloro-3-methoxy-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide LCMS (MH+): m/z = 395.1, t_R (minutes, Method F) = 2.96. [a]ÿ= -28.21 (c = 2.80 mg/mL,CHCl₃)

Example 4!4 (+)-2,4-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

Tlie racemic mixture which was prepared in a similar manner to example 3a from 2,4-diclilorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-l -amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 399.1, t_R (minutes, Method G) = 2.61. [a]ÿ= +29.58 (c = 2.40 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4m4 (-)-2,4-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

LCMS (MH+): m/z = 399.1, t_R (minutes, MeÜiod G) = 2.61. [a]?ÿ= -30.22 (c = 2.78 mg/mL,CHCl₃)

Example 4n4 (+)-2,6-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

1S6

The racemic mixture which was prepared in a similar manner to example 3a from 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 399.1, ta (minutes, Method F) = 3.06. [a]$= +31.97 (c = l .22 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4o4 (-)-2,6-dichloro-N-(3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propyl)benzamide

LCMS (MH+): m/z = 399.1, (r (minutes, Method F) = 3.06. [a]l9= -30.25 (c = l .62 mg/mL,CHCl₃)

Example 4p4 (+)-2-chloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyriinidin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 366.1, îr (minutes, Method F) = 2.84. [ajî9= +26.75 (c = 2.43 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4q4 (-)-2-chloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z = 366.1, t_R (minutes, Method F) = 2.84 [a]?ÿ= -24.52 (c = 2.08 mg/mL,CHCl₃)

Example 4r4 (+)-2,3-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

157

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-l -amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 400.1, t_R (minutes, Method F) = 3.00. [a]?9= +24.20 (c = 2.81 mg/mL,CHC13)

And the correspondîng enantiomer

Example 4s4 (-)-2,3-dichloro-hI-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide • LCMS (MH+): m/z = 400.1, t_R (minutes, Method F) = 3.00. [a]î9= -27.31 (c = 2.38 mg/mL.CHCb)

Example 4t4 (+)-2-chloro-3-fluoro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

Tlie racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-315 fluorobenzoic acid and 3-cyclopropyl-2-(6-(ditluoromethyl)pyrimidin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 384.1, t_R (minutes, Method F) = 2.90. [a]?V= +20.59 (c = 4.08 mg/mL,CHC13)

And tlie correspondîng enantiomer

Example 4u4 (-)-2-chloro-3-fluoro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z = 384.1, t_R (minutes, Method F) = 2.90. [a]?ÿ= -20.87 (c = 4.12 mg/mL.CHCh)

Example 4v4 (+)-2-chloro-3-methoxy-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-525 yl)propyl)benzamide

158

The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-

methoxybenzoic acid and 3-cyclopropyl-2-(6-(difluoiOmethyl)pyrimidin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+):

m/z = 396.1, t_R (minutes, Method F) = 2.84. [α]τ9— +24.50 (c = 4.98 mg/mL.CHCh)

And tlie corresponding enantiomer

Exampie 4x4 (-)-2-chIoro-3-methoxy-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5yl)propyl)benzamide

LCMS (MH+): m/z = 396.1, t_R (minutes, Method F) = 2.84. [a]?9= -25.19 (c = 5.16 mg/mL,CHCl₃)

Ex ample 4y4 (+)-2,4-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2,4-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-l-amine was separated into tlie two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 400.1, t_R (minutes, Method F) = 3.04. [a]?9= +28.45 (c - 4.64 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4z4 (-)-2,4-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z = 400.1, t_R (minutes, Method F) = 3.04. [α]τ9= -28.60 (c = 4.79 mg/mL,CHCl₃)

Example 4a5 (+)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyl)pyrimidin-5-yl)propyl)benzamide

159

The racemic mixture wliich was prepared in a similar manner to example 3a from 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 400.1, t_R (minutes, Method F) = 2.93. [a]î?=+18.43 (c = 3.58 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4b5 (-)-2,6-dichloro-N-(3-cyclopropyl-2-(2-(difluoromethyI)pyrimidin-5-yl)propyl)benzamide

LCMS (MH+): m/z = 400.1, t_R (minutes, Method F) = 2.93. [a]^Ç= -18.51 (c = 4.16 mg/mL,CHCl₃)

Example 4c5 (+)-2-chloro-N-[(3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]-2-methyl-

The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoîc acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)-2-methyl-propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 380.1, t_R (minutes, Method F) = 2.82. [a]^?= +11.73 (c = 5.20 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4d5 (-)-2-chloro-N-[(3-cyclopropyl-2-[2-(difluoroinethyl)pyrimidin-5-yl]-2-methylpropyl]benzamide. LCMS (MH+): m/z = 380.1, t_R (minutes, Method F) = 2.82. [a]?9= -13.47 (c = 5.27 mg/mL,CHCl₃)

Example 4e5 (+)-2,4-Dichloro-N-[(3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]-2-methylpropyl]benzamide

160

F

The racemic mixture which was prepared in a similar manner to example 3a from 2,4-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)-2-methyl-propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 414.1, t_R (minutes, Method F) = 2.99. [«]!?= +l 7.16 (c = 5.07 mg/mLjCHCh)

And the corresponding enantiomer

Example 4Γ5 (-)-2,4-Dichloro-N-[(3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]-2-methylpropyljbenzamide. LCMS (MH+): m/z = 4l4.l, t_R (minutes, Method F) = 2.99. [a]?9=-17.55 (c = 5.30 mgànL.CHCh)

Example 4g5 (+)-2,3-Dichloro-N-[(3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]-2-methylpropyljbenzamide

F

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyrimidin-3-yl)-2-methyl-propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 414.1, t_R (minutes, Method F) = 2.96. [a]^?= +18,40 (c = 6.63 mg/mL.CHCL)

And the corresponding enantiomer

Example 4h5 (-)-2,3-Dichloro-N-[(3-cyclopropyl-2-[2-(difluoromethyl)pyrimidin-5-yl]-2-methylpropyljbenzamîde. LCMS (MH+): m/z = 414.1, t_R (minutes, Method F) = 2.96. [a]^9= -20.13 (c = 5.91 mg/mL,CHCl₃)

Example 4i5 (+)-2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(l-fluorocyclopropyl)propyl)benzamide

161

The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(l-fluorocyclopropyl)propan-l -amine was separated into the two enantiomers by préparative SFC to yield tlie title compound. LCMS (MH+): m/z = 384.1, t_R (minutes, Method F) = 2.72. [α]Έ?= +21.30 (c = 2.39 mg/mL,CHCI₃)

And the corresponding enantiomer

Example 4j5 (-)-2-chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(l-fluorocyclopropyl)propyl)benzamide.

LCMS (MH+): m/z = 384.1, t_R (minutes, Method F) = 2.72. [α]τ9= -20.80 (c = 2.02 mg/mL,CHCl₃)

Example 4k5 (+)-2,4-Dichloro-N-(2-(2-(difluorornethyl)pyrimidin-5-yl)-3-( lfluorocyclopropyl)propyl)benzamide

Tlie racemic mixture which was prepared in a similar manner to example 3a from 2,4-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(l-fluorocyclopropyl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 418.l, t_R (minutes, Method F) = 2.93. [«]??= +25.40 (c = 3.42 mg/mL,CHCl₃)

And the corresponding enantiomer

Example 4I5 (-)-2,4-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(lfluorocyclopropyl)propyl)benzamide. LCMS (MH+): m/z = 418.1, t_R (minutes, Method F) = 2.93.

[a]T$*= -29.5 (c = 2.71 mg/mL,CHCl₃)

Example 4m5

162 (+)-2,3-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(lfluorocyclopropyl)propyl)benzamide

F

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(l-fluorocyclopropyl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 418.1,Îr(minutes, Method F) = 2.89. [a]î?=+21.70(c = 3.00mg/mLjCHCh)

And the corresponding enantiomer

Example 4n5 (-)-2,3-Dichloro-N-(2-(2-(dîfluoromethyl)pyrimidin-5-yl )-3-( 1 fluorocyclopropyl)propyl)benzamide. LCMS (MH+): m/z = 418.1, t_R (minutes, Method F) = 2.89. [α]Τ?= -23.7 (c = 3.20 mg/mL.CHCIj)

Example 4o5 (+)-2-Chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(l(trifluoromethyl)cyclopropyl)propyl)benzamide

The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(l-(trifluoromethyl)cyclopropyl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 434.0, t_R (minutes, Method F) = 2.42. [«]t9= +25.30 (c = 3.75 mg/mL,CHClj)

And the corresponding enantiomer

Example 4p5 (-)-2-Chloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(l(trifluoromethyl)cyclopropyl)propyl)benzamide. LCMS (MH+): m/z = 434.0, t_R (minutes, Method

F) = 2.72. [α]χ9= -28.50 (c = 3.86 mg/mL,CHClj)

163

Exampie 4q5 (+)-2,4-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-( l (trifluoromethyl)cyclopropyl)propyl)benzamide

F

F

The racemic mixture which was prepared in a similar manner to example 3a from 2,4-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(l-(trifluoromethyl)cyclopropyl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 468.0, t_R (minutes, Method F) = 3.14. [a]$=+32.40 (c = 3.15 mg/mL,CHCl₃) And the corresponding enantiomer

Exampie 4r5 (-)-2,4-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-( l (trifluoromethyl)cyclopropyl)propyl)benzamide. LCMS (MH+): m/z = 468.0, t_R (minutes, Method F) = 3.14. [«]$= -45.3 (c = 2.76 mg/mL,CHCl₃)

Example 4s5 (+)-2,3-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-( 1 (trifluoromethyl)cyclopropyl)propyl)benzamide

CI

The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dîchlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(l-(trifluoromethyl)cyclopropyl)propan-l-amine was separated into the two enantiomers by préparative SFC to yield the title compound. LCMS (MH+): m/z = 468.0, t_R (minutes, Method F) = 2.84. [α]$= +27.80 (c = 3.41 mg/mL,CHCl₃) And the corresponding enantiomer

Example 4t5

164 (-)-2,3-Dichloro-N-(2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(l(trifluoromethyl)cyclopropyl)propyl)benzamîde. LCMS (MH+): m/z = 468.0, t_R (minutes, Method F) = 2.57. [a]îJ= -35.8 (c = 2.37 mg/mL,CHCl₃)

Example 5 P2 X₇ binding ass ay

This example illustrâtes représentative assays for use in evaluating the test compounds for antagonist activity. Compounds of tlie présent invention were tested in vitro for their ability to act as antagonists to tlie P2X₇ receptor.

Screening assays to détermine P2X₇ receptor antagonism are well known to the person skilled in tlie art. Functional assays, such as second messenger assays, and cytokine measurement assays done in vitro are also well known În tlie art and may be used to assess tlie 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 P2X₇ receptor, were cultured by standard methods. Cells were plated to cell density of approximately 15,000 cells/well in 384-xvell assay plates (50 μΙ/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 μΙ/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 buifer, pH 7.4 [KC1 (5 mM), NaH₂PO₄.2H₂O (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 manufacturer^ instructions). Cell plates were removed from the 37 °C incubator, tlie media discarded and then 30 pL of dye was added to each

165 well. Plates were placed in the 37 °C, non-CÛ2 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 rend 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 IL!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 RPMI1640 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, Cat#: L4516) in sérum free CTL Test media (Sigma Cat#: CTLT-005), without L-glutamine and antibiotics, for 3 hours. Test compounds (antagonists) 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 collected for AlphaLISA® immunoassay (PerkinElmer Inc., Waltham, MA, USA; Catalog No. AL220C) or aliquoted and stored at < -20°C. The AlphaLISA® immunoassay was performed according to the manufacturées instructions.

Table 1: Exemplified IC50 values ofcompounds ofthe invention:

Chemical nanie	IC50(nM)
2-Chloro-N-[4-(4-cliloro-phenyl)-tetrahydropyran-4-ylmethyl ]-5-methyl-benzamide	62
2-Chloro-N-[4-(4-chloro-phenyl)-tetrahydropyran-4-ylmethyl]-5-methyl-benzamide	62
N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4yImethyl]-2,3-dimethyl-benzamide	170
N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4ylmethyl]-2-methoxy-benzamide	620
2,6-Dichloro-N-[4-(4-chloro-phenyl)-	360

166

tetrahydro-pyran-4-ylmethyl]-benzamide
N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4ylmethyl]-2-inethyl-benzamidc	2100
2,3-Dichloro-N-(l-pyridin-3-ylcyclopentylmethyl)-benzamide	2200
2-Chloro-5-methyl-N-( 1 -pyridin-3-ylcyclopentylmethyl)-benzamide	2900
N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4ylmethyl]-2-trifluorornethyl-benzamide	1200
2-Methyl-N-(l -pyridin-3-ylcyclopentylmethyl)-benzamide	3600
N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4ylmethyl]-2-fluoro-3-trifluoromethylbenzamide	4300
3-CHoro-N-[4-(4-clüoro-phenyl)-tetrahydropyran-4-ylmethyl]-2-fluoro-benzamide	890
N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4ylmethyl]-2,5-difluoro-benzamide	3000
2-Chloro-N-[ 1 -(4-methoxy-phenyl)cyclopentylmethyl]-5-methyl-benzamide	190
2,3-Dichloro-N-[ 1 -(4-methoxy-phenyl)cyclopentylmethyl]-benzamide	260
N-[ 1 -(4-Methoxy-phenyl)-cyclopentylmethyl]2-methyl-benzamide	1400
N-[l-(4-Methoxy-phenyl)-cyclopentylmethyl]- 2,3-dimethyl-bcnzamide	600
2-Chloro-5-methyl-N-( 1 -methyI-4-phenylpiperidin-4-ylmethyl)-benzamide	2.4
2-Methyl-N-( 1 -methyl -4-phenyl-pipcridin-4ylmethylj-benzamide	64
N-[4-(4-Chloro-phenyl)-tetrahydro-pyran-4ylmethyl]-2,3,5-trifluoro-benzamide	3600
N-[4-(4-Chloro-phenyl)-1 -methyl-piperidin-4ylmethyl]-2-methyl-benzamide	60
2,3-Dichloro-N-[4-methyl-2-(6-methyl-pyridin- 3-yl)-pentyl]-benzamide	1
2,3-Dimethyl-N-[4-methyl-2-(6-methylpyridin-3-yl)-pentyl]-benzamide	4.4
2-Methyl-N-[4-methyl-2-(6-methyl -pyridin-3yl)-pentyl]-benzamide	29
2-Chloro-5-methyl-N-[4-(6-methyl-pyridin-3yl)-tetrahydro-pyran-4-ylmethyl]-benzamide	3400
5-Bromo-2-chloro-N-[4-(4-chloro-phenyl)tetrahydro-pyran-4-ylmethyl]-benzaniîde	130
2-Chloro-N-[4-(4-chloro-phenyl)-tetrahydro- pyian-4-ylmethyI]-benzamide	800
2,3-dichloro-N-[[4,4-difluoro-1 -(6-fluoro-3pyridyl)cyclohexyl]methyl]benzamide	0.28
2,3-dichloro-N-[ [4,4-difluoro-1 -(6-fl uoro-3 pyridyl)cyclohexyl]methyl]benzamide	0.28
2-chloro-N-[[4,4-difluoro-l-(6-fluoro-3-	14

167

pyridyl)cyclohexyl]methyl]-6-fluorobenzamide
2-chIoro-N-[[4,4-difluoro-1 -(6-fluoro-3pyridyl)cyclohexyl]methyl]-5-methylbenzamide	0.76
2-chloro-N-[[4,4-difluoro-1 -(6-fluoro-3pyridyl)cyclohexyl]methyl]-5(tri fluoromethyl)b enzamide	1.2
N-((4,4-difluoro-1 -(6-fluoropyridin-3yl)cyclohexyl)methyl)-2-fluorobenzamide	190
N-((4,4-difluoro-1 -(6-fluoropyridin-3yl)cyclohexyl)methyl)-2-fluoro-3methoxybenzamîde	100
2-chloro-N-((4,4-d i fluoro-1 -(6-fluoropyridin-3yl)cyclohexyl)methyl)-5- (methylsul fonyl)benzamide	8.7
2-chloro-N-((4,4-dî fluoro-1 -(6-fluoropyridin-3yl)cyclohexyl)metliyl)benzamide	25
N-((4,4-difluoro-1 -(6-fluoropyridin-3yl)cyclohexyl)methyl)-2-fluoro-5methoxybenzamide	65
N-((4,4-difluoro-1 -(6-fluoropyridin-3yl)cyclohexyl)methyl)-2-fluoro-3methylbenzamide	78
N-((4,4-difluoro-1 -(6-fluoropyridin-3- yl)cyclohexyl)methyl)-2,5-difluorobenzamide	1500
2,5-dichloro-N-((4,4-difluoro-l-(6fluoropyridin-3yl)cyclohexyl)methyl)benzamide	2.3
2-chloro-N-((4,4-difluoro-l-(6-fluoropyridin-3- yl)cyclohexyl)methyl)-5-methoxybenzamide	0.83
N-((4,4-difl uoro-1 -(6 -fluoropyridi n-3 yl)cyclohexyl)methyl)-2,3-difluorobenzamide	290
2,3-dichloro-N-((4-(4-chlorophenyl)tetrahydro- 2H-pyran-4-yl)methyl)benzamide	43
2,3-dichIoro-N-((4-(4- (trifluoromethyl)phenyl)tetrahydro-2H-pyran- 4-yl)methyl)benzamîde	41
2,3-dichloro-N-((4,4-difluoro-l-(6- (trifluoromethyl)pyridin-3yl)cyclohexyl)methyl)benzamide	1.2
2,3-dichloro-N-((4-(6-(trifluoromethyl)pyridin- 3-yl)tetrahydro-2H-pyran-4yl)methyl)benzamide	52
2,3-dtchloro-N-((l-(6-cyclopropylpyridin-3- yl)-4,4-difluorocyclohexyl)methyl)benzamide	1.3
2,3-dichloro-N-((4,4-difluoro-l-(6methoxypyridin-3 yl)cyclohexyl)methyl)benzamide	0.96
2-cyano-N-((4,4-difluoro-1 -(6- (trifluoromethyl)pyridin-3-	150

168

yl)cyclohexyl)methyl)benzamide
2-chloro-N-((4,4-difluoro-l -(6(trifluoromethyl)pyri din-3 yl)cycl ohexyl)methyl)-4(methylsulfonyl)benzamide	1800
N -((4,4-d i fluoro-1 -(6-(trifluoromethyl)pyridin3-yl)cyclohexyl)methyl)-2-methylbenzamide	2.6
2,3-dichloro-N-(2-cyclopropyl-2-(6- (trifluoromethyl)pyridin-3-yl)ethyl Jbenzamide	120
N-((4,4-di fluoro-1 - (6-(tri fluoromethyljpyridin3-yl)cyclohexyl)methyl)-2- (methylsul fonyl Jbenzamide	480
2,3-dichIoro-N-((4,4-difluoro-l-(5fluoropyridin-3yl)cyclohexyl)methyl)benzamide	1.2
2,3-dichloro-N-[3-cyclopropyl-2-[6- (trifl uoromethyl)-3-pyridyl ] propyl Jbenzamide	0.55
2-chloro-N-[3-cyclopropyi-2-[6- (trifl uoromethyl)-3-pyridyl]propyl]benzamide	3.4
N-((4,4-difluoro-1 -(6-(trifluoromethyl)pyridin- 3-yl)cyclohexyl)methyl)-3-fluoro-2methylbenzamide	4
N-((4,4-difluoro-1 -(6-(trifluoromethyI)pyridin- 3-yl)cyclohexyl)methyl)-3-methoxy-2- methylbenzamide	1.6
N-((4,4-difluoro-1 -(6-(trifluoromethyl)pyridin- 3-yl)cyclohexyl)methyl)-5-fluoro-2methylbenzamîde	9.1
N-((4,4-difluoro-1 -(6-(trifluoromethyl)pyridin3-yl)cyclohexyl)methyl)-2-methyl-5(trifluoromethyl)benzamide	39
3-bromo-N-((4,4-difluoro-1 -(6- (trifluoromethyl)pyridin-3- yl)cyclohexyl)methyl)-2-methylbenzamide	0.71
2-chloro-N-((4,4-difluoro-1 -(6- (tri fl uoromethyl)pyridin-3 yl)cyclohexyl)methyl)-3-methylbenzamide	0.54
3-cyano-N-((4,4-difluoro-l -(6- (trifluoromethyl)pyridin-3- yl)cyclohexyl)methyl)-2-methylbenzamide	45
2,3-dichloro-N-(2-(5-chloropyridin-3-yl)-3cyclopropylpropyl)benzamide	5.5
2,3-dichloro-N-(2-(4-clilorophenyl)-2phenylethyl )benzamide	120
2,3-dichloro-N-[3-cyclopropyl-2-(2,6dimethyl-3-pyridyl)propyl]benzamide	1300
2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)-3[i- (trifluoromethyl)cyclopropyl]propyl]benzamide	7.1
(+)2-chloro-N-[3-cyclopropyl-2-[6- (trifluoromethyl)-3-pyridyl]propyl]benzamide	63

169

(-)2-chloro-N-[3-cyclopropyl-2-[6- (tri fluoromethyl )-3 -pyridyl ] propyl ] benzamide	2.3
(+)2,3-dichloro-N-[3-cyclopropyl-2-[6(tri fl uoromethyl)-3 -pyridyl] propyl ]benzamide	2.6
(-)2,3 -dichîoro-N- [ 3-cyclopropyl-2-[6- (trifluoromethyl)-3-pyridyl]propyl]benzamide	0.31
2,3-dichloro-N-[3-[l- (trifluoromethyl)cyclopropyl]-2- [6- (tri fluoromethyl)-3-pyridyl ] propyljbenzamide	19
2,3-dichloro-N-[2-(6-cyclopropyl-3-pyridyl)-3[i- (trifluoromethyl)cyclopropyl]propyl]benzamide	15
2,3-dichloro-N-[2-(6-cyclopropyl-3-pyridyl)-3[1- (difluoromethyl)cyclopropyl]propyl]benzamide	0.76
(+)2-chloro-N-[3-cyclopropyl-2-[6- (trifluoromethyl)-3-pyridyl]propyl]-3(trifluoromethyl)benzamide	1100
(-)2-chloro-N-[3-cyclopropyl-2-[6- (trifluoromethyl)-3-pyridyl]propyl]-3(trifluoromethyl)benzamide	110
2,3-dichloro-N-[3-[l- (di fluoromethyl )cyclopropyl]-2- [6- (trifluoromethyl)-3-pyridyl]propyl]benzamide	1.6
(-)2,3-dichl oro-N-[2-(2-methyl pyrimidi n-5-y 1 ) 3-[l- (trifluoromethyl)cyclopropyl]propyl]benzamide	64
(+)2,3-di chloro-N-[2-(2-methylpyrirnidin-5 yl)-3-[l- (tri fluoromethyl)cyclopropyl] propyl]benzamîde	1.5
(-)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-3[l- (tri fl uoromethyl)cycl opropyl]propyi]benzamide	650
(+)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-3[1- (trifluoromethyl)cyclopropyl]propyl]benzamide	130
2-chloro-N-[2-(6-cyclopropyl-3-pyridyl)-3-[ 1 - (trifluoromethyl)cyclopropyl]propyl]benzamide	94
N-[2-(6-cyclopropyl-3 -pyridyl)-3 -[ 1 - (trifiuoromethyl)cyclopropyl]propyl]-2-fluorobenzamide	1700
2-chloro-N-[3-cyclopropyl-2-(2methylpyrimidin-5-yl)propyl]benzamide	1200
2,3-dichloro-N-[3-cyclopropyl-2-(2methylpyrimidin-5-yl)propyl]benzamide	60
2-chloro-N-[3-[l- (trifluoromethyl)cyclopropyl ]-2-[6- (trifluoromethyl)-3-pyridyl]propyl]benzamide	2.1
2-fluoro-N-[3-[l- (tri fluoromethyl)cyclopropyl]-2-[6- (trifluoromethyl)-3-pyridyl]propyl]benzamide	430

170

2-chloro-N-[[4,4-difluoro-1 -(2methylpyrimidin-5yl)cyclohexyl]methyl]benzamide	120
2,3-dichloro-N-[[4,4-difluoro-1 -(2methylpyrimidin-5yl)cyclohexyl ] methyljbenzamide	8.6
2,3-dichloro-N-[3-cyclopropyl-2-[2- (trifluoromethyl)pyrimidin-5y 1] propyl ] benzamîde	0.88
2,3-dichloro-N-[[4,4-difluoro-l -(6-(1 -hydroxy- 1 -methy!-ethyl)-3- pyridyl] cyclohexyl]methyl]benzami de	23
2-chloro-N-[[4,4-difluoro-l-[6-(l-hydroxy-lmethyl-ethyl)-3pyridyl]cyclohexyl]methyl]benzamide	380
(+)2-chloro-N-[3-cyclopropyl-2-[6- (trifluoromethyl)-3-pyridyl]propyl]-3-methoxybenzamide	12
(-)2-chloro-N-[3-cyclopropyl-2-[6- (trifluoromethyl)-3-pyridyl]propyl]-3-methoxybenzamide	4.2
(+)2-chIoro-N-[3-cyclopropyl-2-[6- (trifluoromethyl)-3-pyridyl]propyl]-6-fluorobenzamide	50
(-)2-chloro-N-[3-cyclopropyl-2-[6- (trifluoromethyl)-3-pyridyl]propyl]-6-fluorobenzamide	2.1
(+)N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3- pyridyl]propyl]-2-methoxy-benzamide	990
(-)N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3pyridyl]propyl]-2-methoxy-benzamidc	53
(+)N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3pyridyl]propyl]-2,6-difluoro-benzamide	740
(-)N-[3-cyclopropyl-2-[6-(trifluoromethyl)-3pyridyl]propyl]-2,6-difluoro-benzamîde	130
(+)2-chloro-N-[3-cycIopropyl-2-[6(trifluoromethyl)-3-pyridyl]propyl]-5methylsul fonyl-benzamide	560
(-)2-chloro-N-[3-cyclopropyl-2-[6(trifluoromethyl)-3 -pyridyl] propyl]-5 methylsulfonyl-benzamide	8.1
2,3*dichloro-N-((4,4-difluoro-1 -(4-methyl-1Himidazol-1 -yl)cyclohexyl)methyl)benzamide	90
(+)2-chloro-N-[3 -cyclopropyl-2-[6- (tri fluoromethyl)-3-pyridyl ] propyl] -3 -fl uorobenzamide	11
2(-)-chloro-N-[3-cyclopropyl-2-[6- (tri fluoromethyl)-3-pyridyl ] propyl] -3 -fl uorobenzamide	2.9
(-)2-chloro-N-[3-cyclopropyl-2-(6-fluoro-3pyridyl)propyl]benzamide	16

171

(+)2-chloro-N-[3-cyclopropyl-2-(6-fluoro-3- pyridyljpropyljbenzamide	510
N-( 1 -(l-(6-bromopyridin-3-yl)-4,4difluorocyclohexyl)ethyl)-2,3dichlorobenzamide	43
(-)2,3-dichloro-N-[3-cyclopropyl-2-(2methylpyrimidin-5-yl)propyl]benzamide	39
(+)2,3-dichloro-N-[3-cyclopropyl-2-(2methylpyrimidin-5-yl)propyl]benzamide	260
2-chloro-N-((4,4-difluoro-l -(6- (trifluoromethyl)pyridin-3yl)cyclohexyl)methyl)benzamide	2
2,3-dichloro-N-((4,4-difluoro-l-(6methylpyridin-3yl)cyclohexyl)methyl)benzamide	7.3
2-cHoro-N-((4,4-difluoro-l-(6- (tri fl uoromethyl)pyrid in-3- yl)cyclohexyl)methyl)-3-methoxybenzamide	7.1
2-chloro-N-((4,4-difluoro-1 -(6- (trifluoromethyl)pyridin-3- yl)cyclohexyl )methyl)-3-fl uorob enzamide	1.4
2-chloro-N -((4,4-d i fluoro-1 -(6-fluoropyri din-3yl)cyclohexyl)methyl)-3-fluorobenzamide	5.3
3-chloro-N-((4,4-d i fluoro-1 -(6- (tri fl uoromethyl)pyridin-3 - yl)cyclohexyl)methyl)-2-fluorobenzamide	3.2
3-chloro-N-((4,4-difluoro-1 -(6-fluoropyridin-3- yl)cyclohexyl)methyl)-2-fluorobenzamide	11
3-chloro-N-(3-cyclopropyl-2-(6- (trifluoromethyl)pyridin-3-yl)propyl)-2fluorobenzamide	660
2-chloro-N-(3-cyclopropyl-2-(6(trifluoromethyl)pyridin-3-yl)propyl)-4fluorobenzamide	310
2,6-dichloro-N-(3-cyclopropyl-2-(6- (trifluoromethyl)pyridin-3- yl)propyl)benzamide	0.71
2-chloro-N-[3-cyclopropyl-2-methyl-2-[2(tri fl uoromethyl)pyrimidin-5 yljpropyljbenzamide	21
2-cliloro-N-[3-cyclopropyl-2-mcthyl-2-[2(trifluoromethyl)pyrimidin-5-yl]propylJ-3fluoro-benzamide	16
(-)2,3-dÎchloro-N-[3-cyclopropyl-2-[2(tri fluoromethyl)pyrimidin-5 yljpropyljbenzamide	0.86
(+)2,3-dichloro-N-[3-cyclopropyl-2-[2- (trifluoromethyl)pyrimidin-5- yl] propyljbenzamide	3.9
(+)2-chloro-N-[3-cyclopropyl-2-[2- (trifluoromethyl)pyrimidin-5-	38

172

yljpropyljbenzamide
(-)2-chloro-N-[3-cyclopropyl-2-[2- (trifluoromethyl)pyrimidin-5' yl]propyl]benzamide	3.2
(+)2-chIoro-N-[3-cyclopropyl-2-[2(tri fluoromethyl)pyrimidin-5 -yljpropyl] -3 fluoro-benzamide	50
(-)2-chloro-N-[3-cyclopropyl-2-[2- (trifluoromethyl)pyrimidin-5-yl]propyl]-3fluoro-benzamide	4.7
(+)2-chloro-N-[3-cyclopropyl-2-[2(tri fl uoromethyl)pyrimidin-5 -yl]propyl]-6fluoro-benzamide	41
2,3-dichloro-N- [2-(4-chlorophenyl )-2tetrahydropyran-4-yl-ethyl]benzamide	1.6
2-chloro-N-[2-(4-chlorophenyl)-2tetrahydropyran-4-yl-ethyl]benzamide	14
2-cliloro-N-[2-(4-chlorophenyl)-2tetraliydropyran-4-yl-ethyl]-6-fluorobenzamide	30
2-chloro-N-[2-(4-chlorophenyl)-2tetraliydropyraiM-yl-ctliyl]-3-fluorobenzamîde	15
2,6-dichloro-N-(3-cyclopropyl-2-(2(tri fl uoromethyl)pyrimidin-5 yl)propyl)benzamide	5.1
2-chloro-N-(3-cyclopropyl-2-(2(tri fluorornethyl)pyrimidin-5yl)propyl)benzamide	13
2-chloro-N-(3-cyclopropyl-2-(2- (trifluoromethyl)pyrimidin-5-yl)propyl)-3fluorobenzamide	14
2-chloro-N-(3-cyclopropyl-2-(2- (trifluoromethyl)pyrimidin-5-yl)propyl)-6fluorobenzamide	22
2,3-dichloro-N-[[4-[2- (trifluoromethyl)pyrimidin-5- yl]tetrahydropyran-4-yl]rnethyl]bcnzarnide	250
2-chloro-N-[[4-[2-(trifluoromethyl)pyrimidin- 5-yl]tetrahydropyran-4-yl]methyl]benzamide	4400
2-chloro-6-fluoro-N-[[4-[2- (trifluoromethyl)pyrimidin-5- yl] tetrahydropyran-4-yl] methyl Jbenzamidc	1600
(-)2-chloro-N-[3-cyclopropyl-2-[2(trifluoromethyl)pyrimidin-5 - yl ]propy 1] -3 methoxy-benzamide	3.4
(+)2-chloro-N-[3-cyclopropyl-2-[2- (trifluoromethyl)pyrimîdin-5-yl]propyl]-3methoxy-benzamide	14
(-)N-[3-cyclopropyl-2-[2- (tri fluoromethyI)pyrimidin-5-yl]propyl ] -3 -	1.4

173

methoxy-2-methyl-benzamide
(+)N-[3-cyclopropyl-2-[2- (trifluoromethyl)pyrimidin-5-yl]propylJ-3methoxy-2-methyl-benzamide	9
2,3-dichloro-N-[3-( 1 -fluorocyclopropyl)-2-[6- (trifluorometliyl)-3-pyridyl]propyl]benzamide	3.7
(-)2,6-dichloro-N-[3-cyclopropyl-2-[6- (trifluoromethyl)-3 -pyridyl ] propyljbenzamîde	1.2
(+)2,6-dichloro-N-[3-cyclopropyl-2-[6- (trifluoromethyl)-3-pyridyl J propyljbenzamîde	0.89
(-)2,6-dîchloro-N-[3-cyclopropyl-2-[2- (trifluoromethyl)pyrimidin-5yljpropyljbenzamide	0.82
(+)2,6-dichloro-N-[3-cyclopropyl-2-[2- (trifluoromethyl)pyrimidin-5- yl] propyljbenzamîde	3.8
2,3-dicHoro-N-[3-(l-fluorocyclopropyl)-2-[2- (trifluoromethyl)pyrirnidin-5- yl J propyljbenzamîde	9.3
2,3-dichloro-N-[2-(2-methylpyrimidin-5-yl)-2- (4-pyridyl ) ethyl ]benzamide	50
2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2-(4- pyridyl)ethyl]benzamîde	1300
2-chloro-6-fluoro-N-[2-(2-methylpyriinidin-5- yl)-2-(4-pyridyl)ethylJbenzamide	640
2-chloro-3-fluoro-N-[2-(2-methylpyrimidin-5- yl)-2-(4-pyridyl)ethyl] benzamide	860
(-)2,6-dichloro-N-[3-cyclopropyl-2-(2methylpyrimidîn-5-yl)propylJbenzamide	9.9
(+)2,6-dichloro-N-[3-cyclopropyl-2-(2methylpyrimidin-5-yl)propyl]benzamide	220
(+)2-cliloiO-N-[3-cycIopropyl-2-methyl-2-[2- (tri fl uoromethyl)pyrimidi n-5yl J propyljbenzamîde	460
(-)2-chloro-N-[3-cyclopropyl-2-methyl-2-[2- (trifluoromethyl)pyrimidin-5- yl] propyljbenzamîde	17
2,3-dicldoro-N-[[4,4-difluoro-l-[2- (trifluoromethyl)pyrimidin-5yljcyclohexyljmethyljbenzamide	0.95
(+)2-chloro-N-[3-cyclopropyl-2-methyl-2-[2- (trifluoromethyl)pyrimidin-5-yl]propyl]-3fluoro-benzamide	360
(-)2-chloro-N-[3-cyclopropyl-2-methyl-2-[2- (trifluoromethyl)pyrimidin-5-yl]propyl]-3fluoro-benzamîde	34
(+)2,3-dîchloro-N-[3-cyclopropyl-2-methyl-2- [2-(trifluoromethyl)pyrimi di n-5yljpropyljbenzamide	74
(-)2,3-dichloro-N-[2-(2-methylpyrimidîn-5-yl)- 2-tetrahydropyran^4-yl-ethyl]benz amide	58

174

(+)2,3-dich]oro-N-[2-(2-methylpyrimidin-5yl)-2-tetrahydropyran-4-yl -ethyl Jbenzamide	28
(-)2-chloro-N-[2-(2-rncthylpyrimidin-5-yl)-2- tetrahydropyran-4-yl-ethyl]benzamide	570
(+)2-chloro-N-[2-(2-methylpyrimidin-5-yl)-2tetrahydropyran-4-yl-ethyl ] benzamide	970
2,3-dichloro-N-[2-(4,4-difluorocyclohexyi)-2(2-methylpyrimidin-5-yl)ethyl]benzamide	6.2
2-chloro-N-[2-(4,4-difluorocyclohexyl)-2-(2methyIpyrimidin-5-yl)ethyl]benzamide	90
(+)2-chloro-N-[3-[l- (tri fluoromethyl)cyclopropyl] -2-[2(trifl uoromethyl)pyrimidin-5- yl] propyljbenzamide	2.4
2-chloro-6-fluoro-N-[2-(2-methylpyrimidin-5yl)-2-tetrahydropyran-4-yl-ethyl]benzamide	1900
2-chloro-3-fluoro-N-[2-(2-methylpyrimidin-5yl)-2-tetrahydropyran-4-yl-ethyl]benz amide	210
2-chloro-N-[2-(4,4-difluorocyclohexyl)-2-(2methylpyrimi di n-5-yl)ethyl]-6-fl uorobenzamide	150
2-chloro-N-[2-(4,4-difluorocyclohexyl)-2-(2methylpyrimidin-5-yI)ethyl]-3-fluorobenzamide	83
(+)2-chloro-N-[3-[l- (trifluoromethyl)cyclopropyl]-2-[6- (trifluoromethyl )-3-pyridyl ] propyl] benzamide	0.09
(-)2-chloro-N-[3-[l- (tri fl uoromethyl)cyclopropyl ] -2-[6- (trifluoromethyl)-3-pyridyl]propyl]benzamide	32
(+)2,3-dichloro-N-[3-[l- (tri fluoromethyl)cyclopropyl ] -2-[6- ( tri fluoromethyl)-3 -pyridyl ]propyl]benzamide	12
(-)2,3-dichloro-N-[3-[l- (trifluoromethyl)cyclopropyl]-2-[6- (trifluoromethyl)-3-pyridyl]propyl]benzamide	25
(+)2-chloro-3-fluoro-N-[3-[l(trifluoromethyl)cyclopropyl]-2-[2(trifluoromethyl)pyrimidin-5yl]propyl] benzamide	4.5
(-)2-chloro-3-fluoro-N-[3-[ l(trifluoΓomethyl)cycloproρylj-2-[2(trifluoromethyl)pyrimidin-5yl]propyl]benzamide	29
(+)2,3-dichloro-N-[3-[l(trifluoromethyl)cyclopropyl ] -2-[2(trifluoromethyl)pyrimid i n-5 yl]propyl]benzamide	1.6
(-)2,3-dichloro-N-[3-[l- (trifluoromethyl)cyclopropyl]-2-[2- (trifluoromethyI)pyrimidin-5 -	21

175

yljpropyljbenzamide
(+)2-chloro-3-fluoro-N-[3-[ 1 - (trifluoromethyl)cyclopropyl]-2-[6- (trifluoromethyl)-3-pyridyl]propyl]benzamide	7.2
(-)2-chloro-3-fluoro-N-[3'[ 1- (trifluoromethyl)cyclopropyl]-2-[6(trifluoromethyl)-3-pyridyl]propyl]benzamide	16
(+)2,3-dichloro-N-[3-cyclopropyl-2-[6-( 1 hydroxy-1 -methyl-ethyl)-3pyridyljpropyljbenzamide	740
(-)2,3-dichloro-N-[3-cycIopropyl-2-[6-( 1 hydroxy-1 -methyl-ethyl)-3pyridyl]propyl]benzamide	30
(+)2,3-dichloro-N-[2-tetrahydropyran-4-yl-2[2-(trifluorometliyl)pyrimidin-5yl]ethyl]benzamide	4.1
(-)2,3-dicliloro-N-[2-tetrahydropyran-4-yl-2-[2- (tri fluoromethyl)pyrimidin-5 - yl] ethyl ] benzamide	11
(+)2-chloro-N-[2-tetrahydropyran-4-yl-2-[2(tri fluorom ethyl )pyri midin-5 - yl] ethyl ] benzamide	51
(-)2-chloro-N-[2-tetrahydropyran-4-yl-2-[2(tri fluoromethyl)pyrimidin-5 yl]ethyl]benzamide	56
(+)2-chloro-6-fluoro-N-[2-tetrahydropyran-4yl-2-[2-(trifluorometliyl)pyrimidin-5yl]ethyl]benzamide	56
(-)2-chloro-6-fluoro-N-[2-tetrahydropyran-4yl-2-[2-(trifluoromethyl)pyrimidin-5yl] ethyljbenzamide	68
(+)2-chloro-3-fl uoro -N - [2-tetrahydropyran -4yl-2-[2-(trifluoromethyl)pyrimidin-5yl] ethyljbenzamide	32
(-)2-chloro-3-fluoro-N-[2-tetrahydropyran-4yl-2-[2-(trifluoromethyI)pyrimidin-5yljethyljbenzamide	64
(+)2,6-dichloro-N-[2-phenyl-2-[6- (trifl uoromethyl)-3-pyridyl] etliyl Jbenzamide	12
(-)2,6-dichloro-N-[2-phenyl-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]benzamide	18
2,4-dichloro-N-(2-phenyl-2-(6- (trifluoromethyl)pyridin-3-yl)ethyl)benzamide	25
2-chloro-6-fluoro-N-[l-[4-(2-methylpyrimidin- 5-yl)tetrahydropyran-4-yl]ethyl]benzamide	55
2-chloro-3-fluoro-N-[ 1 -[4-(2-methylpyrimidin- 5-yl)tetrahydropyran-4-yl]ethyl]benzamide	15
2,3-dichloro-N-((3-(2-methylpyrimidin-5yl)tetrahydrofuran-3 -yl)methyl)benzamide	15
(+)2,3-dichloro-N-[2-(4-fluorophenyl)-2-[6- (trifluorornethyl)-3-pyridyl]ethyl]benzamide	12

176

(-)2,3-dichloro-N-[2-(4-fluorophenyl)-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]benzamide	9.4
(+)2-chloro-6-fluoro-N-[2-(4-fluorophenyl)-2- [6-(trifluoromethyl)-3-pyridyl] ethyl] benzamide	15
(-)2-chloro-6-fluoro-N-[2-(4-fluorophenyl)-2[6-(trifluoromethyl)-3-pyridyl] ethyl] benzam ide	8.5
(+)2-chloro-3-fluoro-N-[2-(4-fluorophenyl)-2- [6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide	4.6
(-)2-chloro-3-fluoro-N-[2-(4-fluorophenyl)-2[6-(trifluoromethyl)-3-pyridyl]ethyl]benzamide	7
(+)2-chloro-N-[2-(4-fluorophenyl)-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]benzamide	2.2
(-)2-chloro-N-[2-(4-fluorophenyl)-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]benzamide	3.1
2-chloro-N-[2-(4-pyridyl)-2-[2(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide	30
2,3-dichioro-N-[2-(4-pyridyl)-2-[2- (trifluoromethyl)pyrimidin-5yl] ethyl] benzamide	6.2
2-chloro-N-[2-(4-pyridyl)-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]benzamide	11
2,3-dichloro-N-[2-(4-pyridyl)-2-[6- (trifluoromethyl)-3-pyridyl]ethyl]benzamide	200
(+)2,3-dichloro-N-[2-(4-fluorophenyl)-2-[2- (trifluoromethyl)pyrimidin-5- yl] ethyl] benzamide	1.1
(-)2,3-dichloro-N-[2-(4-fluorophenyl)-2-[2- (trifluoromethyl)pyrimidin-5- yl] ethyl]benzamide	1.2
(+)2-chloro-N-[2-(4-fluorophenyl )-2-(2- (trifluoromethyl)pyrimidin-5- yl ] ethyl] benzamide	4.4
(-)2-chloro-N-[2-(4-fluorophenyl)-2-[2- (trifluoromethyl)pyrimidin-5yl]ethyl]benzamide	2
2,3-dichloro-N-[l -[4,4-dî fluoro-1 -(2methylpyrimidin-5yl)cyclohexyl]ethyl]benzamide	960
2-chloro-N-[l-[4,4-difluoro-l-(2methylpyrimidin-5yl)cyclohexyl]ethyl]benzamide	1600
(+)2-chloro-6-fluoro-N-[2-(4-fluorophenyl)-2[2-(trifluoromethyl)pyrimidîn-5yl]ethyl]benzamide	6.7
(-)2-chloro-6-fluoro-N-[2-(4-fluorophenyl)-2[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide	2.6
(+)2-chloro-3-fluoro-N-[2-(4-fluorophenyl )-2[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide	4.8

177

(-)2-chloro-3 - fl uoro-N-[2-(4- fluorophenyl)-2[2-(trifluoromethyl)pyrimidin-5yl]ethyl]benzamide	1.8
2-chloro-N -[ 1 -[4,4-di fluoro-1 -(2methylpyrimid i n-5-yl)cyclohexyl] ethyl]-6fluoro-benzamide	1400
2-chloro-N-[ 1 -[4,4-di fluoro-1 -(2methylpyrimidin-5-yl)cyclohexyl]ethyl]-3fluoro-benzamide	2000
(-)2,3-dichloro-N-[2-(4,4-difluorocyclohexyl)- 2-(2-methylpyrimidin-5-yl)ethyl]benzamide	16
(+)2,3-d ichloro-N-[2-(4,4-d i fluorocyclohexyl)- 2-(2-methylpyrimidin-5-yl)ethyl]benzamide	8.4
(+)2-chloro-N-[2-(4,4-difluorocyclohexyl)-2[2-(trifl uoromethyl)pyrimidin-5-yl] ethyl]-3fluoro-benzamide	45
(-)2-cbloro-N-[2-(4,4-difluorocyclohexyl)-2-[2- (trifluoromethyl)pyrimidin-5-yl]cthyl]-3fluoro-benzamide	44
(+)2-chloro-N-[2-(4,4-difluorocyclohexyl)-2[2-(tri fluoromethyl)pyrimidin-5yl]ethyl]benzamide	32
(-)2-chloro-N-[2-(4,4-difluorocyclohexyl)-2-[2- (trifluoromethyl)pyrimidin-5yl]ethyl]benzamide	6.4
(+)2,3-dichloro-N-[2-(4,4-difluorocyclohexyl)- 2-[2- (tri fluoromethyljpyri mid in-5 yl]ethyi]benzamide	5.7
(-)2,3-dichloro-N-[2-(4,4-difluorocyc!ohexyl)- 2-[2-(tri fluoromethyl)pyri m id i n-5yl ] ethyljb enzamide	4.3
(+)2-chloro-N-[2-(4,4-difluorocyclohexyl)-2[2-(tri fluoromethyl)pyrirnidin-5 -yl ] ethyl]-6fluoro-benzamide	75
(-)2-chloro-N-[2-(4,4-difluorocyclohexyl)-2-[2- (trifluoromethyi)pyrimidin-5-yl]ethyl]-6fluono-benzamide	61
2,3-dichloro-N-[4-methoxy-2- [ 2(trifluoromethyl)pyrimidin-5yl]butyl]benzamide	2200
2,3-dichloro-N-(2-phenyl-2-pyridazin-4-ylethyl)benzamide	94
2,4-dichloro-N-(2-phenyl-2-pyrid azin-4-yl ethyl)benzamide	720
(~)2,3-dichloro-N-[3-cyclopropyl-2-[2- (difluoromethyl)pyrimidi n-5 yl]propyl]benzamide	23
(-)2,3-dichloro-N-[3-cyclopropyl-2-[2- (difluoromethyl)pyrimidin-5yl]propyi]benzamide	1.9
(+)2-chloro-N-[3-cyclopropyl-2-[6-	640

178

(difluoromethyl)-3-pyridyl]propyl]benzamide
(-)2-chloro-N-[3-cyclopropyl-2-[6- (difluoromethyl)-3-pyridyl]propyl]benzamîde	17
(+)2,3-dichloro-N-[3-cyclopropyl-2-[6- (difluorometliyl)-3-pyridyl]propyl]benzamide	24
(-)2,3-dichloro-N-[3-cyclopropyl-2-[6- (difluoromethyl)-3-pyridyl]propyl]benzamide	1.9
(+)2-chloro -N-[3 -cyclopropyl-2-[6(difluoromethyl)-3-pyridyl]propyl]-3-fluorobenzamide	800
(-)2-chloro-N-[3-cyclopropyl-2-[6(difluoromethyl)-3-pyridyl]propyl]-3-fluorobenzamide	19
(+)2-chloro-N-[3-cyclopropyl-2-[6(difluoromethyl)-3-pyridyl]propyl]-3-methoxybenzamide	4.4
N-[4,4-Difluoro-1 -(6-fluoro-pyridin-3-yl)cyclohexylmethyl]-2-fluorObenzamide	14

179

Claims (23)

1. What is Claimed:

   l. A compound of formula I

   O R⁴ wherein R¹ is phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl or 5 membered heteroaryl, each of which is optionaily substituted with one or more Cm alkyl, halogen, hydroxy, Cm hydroxyalkyl,

   Q

   Cm fluoroalkyl, Cm cycloalkyl, Cm alkoxy, Cm fluoroalkoxy, cyano or-SOjR ;

   wherein R is Cm cycloalkyl, C₃^cyclohetalkyl, Cm fluoroalkyl, Cm fluoroalkoxy, Cm alkoxy, CMalkenyl, Ci^alkynyl, 6 membered heteroaryl, phenyl or Cm alkyl optionaily substituted with one or more R⁹;

   wherein R³ is hydrogen, fluorine, Cm alkyl or C] 4 fluoroalkyl; or wherein R² and R³ combine with the carbon to which they are attached to form cyclohexyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, homomorpholinyl, homopiperidinyl or homopiperazinyl each of which is optionaily substituted with one or more Cm alkyl, Cm alkenyl, C₃^-cycloalkyl, Cm alkoxy, oxo, -NR⁶R⁷ or fluorine;

   wherein R⁴ is halogen, Cm fluoroalkyl, cyano, cyclopropyl, CMalkyloxy, CMÎluoroalkyloxy, SO₂R⁸, -NR⁶R⁷ or Cj^alkyl;

   wherein R⁵ is halogen, Cm alkyl, Cm fluoroalkyl, cyano, -SO2R⁸, -NR⁶R⁷, Cm alkoxy, C>. 4fluoroalkoxy or C₃_6-cycloalkyl;

   wherein R⁶ and R⁷ independently of each other are hydrogen or Cm alkyl;

   wherein R⁸ is ÜMaikyl, Cm cycloalkyl or Cm fluoroalkyl;

   wherein R⁹ is Cm alkyl, Cm cycloalkyl, -NR¹⁰R^H, Cm fluoroalkyl or 3 to 7 membered heterocyclyl which is optionaily substituted with one or more Cmalkyl, halogen, hydroxy, Cm fluoroalkyl, Cm cycloalkyl, Cm alkoxy, Cm fluoroalkoxy or cyano;

   wherein R¹⁰ and R¹¹ independently of each other are hydrogen or Cm alkyl; or

   180 wherein R¹⁰ and R¹¹ combine with the nitrogen to which they are attached to form piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, homomorpholinyl, homopiperidinyl or homopiperazinyl each of which is optionally substituted with one or more C)^ alkyl, C|^ alkoxy, oxo or fluorine; and wherein n is 0-3; or a pharmaceutically acceptable sait thereof.
2. 2. Tlie compound of claim 1, wherein R¹ is optionally substituted phenyl.
3. 3. Tlie compound ofclaim 1, wherein R¹ is optionally substituted pyridyl.
4. 4. Tlie compound ofclaim 1, wherein R¹ is optionally substituted pyrazinyl.
5. 5. The compound of claim 1, wherein R¹ is optionally substituted pyrimidyl.
6. 6. The compound of claim 1, wherein R¹ is optionally substituted 5 membered heteroaryi.
7. 7. Tlie compound ofanyone ofdaims 1 -6, wherein R² and R³ combine with tlie nitrogen to which they are attached to form optionally substituted piperazinyl.

   A A
8. 8. The compound of anyone ofdaims 1-6, wherein R and R combine with the nitrogen to which they are attached to form optionally substituted piperidinyl.
9. 9. Tlie compound of anyone of daims 1-6, wherein R² and R³ combine with the nitrogen to which they are attached to form optionally substituted morpholinyl.

   A *
10. 10. Tlie compound of anyone of daims 1-6, wherein R and R combine with tlie nitrogen to which they are attached to form optionally substituted pyrrolidinyl.
11. 11. The compound of anyone of daims 1 -6, wherein R² and R³ combine with tlie nitrogen to which they are attached to form optionally substituted pyrrolo.

    A 1
12. 12. The compound of anyone of daims 1-6, wherein R and R combine with the nitrogen to which they are attached to form optionally substituted imidazo.
13. 13. The compound of anyone of daims 1-6, wherein R² and R³ combine with the nitrogen to which they are attached to form optionally substituted homomorpholinyl
14. 14. The compound of anyone of daims 1-6, wherein R² and R³ combine with the nitrogen to which they are attached to form optionally substituted homopiperidinyl
15. 15. The compound of anyone of daims 1 -6, wherein R² and R³ combine with tlie nitrogen to which they are attached to form optionally substituted homopiperazinyl
16. 16. The compound of anyone of daims 1 -6, wherein R² and R³ combine with tlie nitrogen to which they are attached to form optionally substituted azetidinyl.
17. 17. The compound of anyone of daims 1-16, wherein R⁴ is chlorine, methyl or trifluorormethyl.
18. 18. The compound of anyone of daims 1-17, wherein n is 0.

    181
19. 19. The compound of anyone of claims l -17, wherein n is l.
20. 20. The compound of anyone of claims l -17, wherein n is 2.
21. 21. The compound of anyone of claims l -20, wherein R⁵ is fluorine, chlorine, C1.3 alkyl, C14 fluoroalkyl, cyano, C j .3 alkoxy or Cu fluoroalkoxy.

    5
22. 22. Any of the compounds of Table l
23. 23. A pharmaceutical composition comprising a compound of anyone ofclaims l-22.