Therapeutics for the treatment of non-tubercular mycobacterial or tuberculosis infections

Abstract

The disclosure relates to compounds of the formulae (l)-(V) and Vl-A-I and methods of using those compounds to treat, among other things, a non-tubercular mycobacterial or tuberculosis infection.

Description

THERAPEUTICS FOR THE TREATMENT OF NON-TUBERCULAR MYCOBACTERIAL OR TUBERCULOSIS INFECTIONSCROSS-REFERENCE TO RELATED APPLICAITONS

[0001] This application claims the benefit of priority from U.S. Appl. No. 63 / 635,435, filed April 17, 2024, which is incorporated by reference as if fully set forth herein.GOVERNMENT SUPPORT CLAUSE

[0002] This invention was made with government support under R01 AH 73285 awarded by National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Mycobacterium tuberculosis (Mtb) is the bacterium that causes tuberculosis (TB) in humans. In 2020, the World Health Organization (WHO) estimated that 10 million people became sick with TB and 1 .5 million people died from the disease.1 Currently, no vaccine protects against pulmonary TB. In the absence of an effective vaccine, antibiotic therapy requires patients to take a daily combination of four drugs, including rifampin (RIF), isoniazid (INH), ethambutol (EMB), and pyrazinamide, for 6months. However, the long course of treatment and incomplete therapy have led to the selection and evolution of multidrug resistant (MDR) and extensively drug-resistant (XDR) Mtb strains, which are currently spreading person to person. Therefore, additional therapeutic targets and strategies need to be identified. In addition, other pathogenic non-tuberculous mycobacteria (NTM), such as Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB), are emerging as common causes of infections, particularly in the immunocompromised, the elderly, and those with predisposing conditions, such as cystic fibrosis. These NTMs are resistant to most Mtb drugs and therefore new drugs are also needed to control NTM-mediated diseases.SUMMARY

[0004] The disclosure addresses the need for new drugs to control NTM-mediated diseases.

[0005] The disclosure relates, for example, to A compound of the formula:or R4(V) or a pharmaceutically acceptable salt thereof;wherein:R1is halo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylakyl, arylalkyloxy or heteroaryl;R1Ais H or alkyl;R2and R3are alkyl or, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocycloalkyl group;R4is H or alkyl;X1is absent, O, alkyl, haloalkyl, cycloalkyl, cycloalkyloxy, alkylcycloalkyl or heterocycloalkyl;X2and X3are each, independently, cycloalkyl; andR5is cycloalkyl, aryl, arylalkyl, aryloxy, arylalkyloxycarbonyl or heteroaryl: provided that the compound of formula (I) is not:

[0006] The disclosure also relates to a pharmaceutical composition comprising one or more compounds of, e.g., of the formulae (l)-(V) and Vl-A-I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] The disclosure also relates to a method of treating a mycobacterial infection, the method comprising administering a therapeutically effective amount of, e.g., one or more compounds of the formulae (l)-(V) and Vl-A-I or a pharmaceutical composition comprising, e.g., one or more compounds of the formulae (l)-(V) and Vl-A-I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient to a subject in need thereof. The mycobacterial infection can be non-tubercular mycobacterial or tuberculosis infection. Examples of non-tubercular mycobacterial infection comprises a M. abscessus, M. avium, M. gordonae, M. smegmatis, or M. marinum infection. Examples of tuberculosis infection comprises a M. tuberculosis, M. bovis, M. africanum, M. microti, M. cannetti, M. caprae and M. pinnipedi.DESCRIPTION

[0008] Reference will now be made in detail to certain embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0009] The disclosure generally relates to compounds of the formula:or a pharmaceutically acceptable salt thereof; wherein:R1is halo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylakyl, arylalkyloxy or heteroaryl;R1Ais H or alkyl;R2and R3are alkyl or, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocycloalkyl group;R4is H or alkyl;X1is absent, O, alkyl, haloalkyl, cycloalkyl, cycloalkyloxy, alkylcycloalkyl or heterocycloalkyl;X2and X3are each, independently, cycloalkyl; andR5is cycloalkyl, aryl, arylalkyl, aryloxy, arylalkyloxycarbonyl or heteroaryl; provided that the compound of formula (I) is not:

[0010] In any of compounds of the formulae (l)-(V), R1, when present, can be C6- C -aryl or C3-Ci2-cycloalkyl. Alternatively, R1, when present, can be Ci-C6-alkyl or Ci-C6-haloalkyl. Alternatively, R1, when present, can be C3-C6-alkenyl. Alternatively, R1, when present, can be C3-C6-heterocycloalkenyl.

[0011] Alternatively, or in combination of any of the foregoing options for R1, when present, R5, when present, can be C6-Cio-aryl. Alternatively, R5, when present, can be a C2-C5-heteroaryl group. Alternatively, R5, when present, can be a C6-Cio-aryl- Ci-Ce-alkyl group.

[0012] Alternatively, or in combination with any of the foregoing options for R1, when present, and / or R5, when present, R2and R3, when present, together with the carbon atom to which they are attached form a C2-C4-heterocycloalkyl group or a C3-Cs-cycloalkyl group.

[0013] Alternatively, or in combination with any of the foregoing options for R1, when present, R5, when present, R2, when present, R3, when present, X1, when present, can be a CrCe-alkyl group. Alternatively, X1, when present, can be O and R5is Ce-Cio-aryl. Alternatively, X1, when present, can be a Cs-Ce-heterocycloalkyl. Alternatively, X1, when present, can be a Ci-Ce-alkyloxy group.

[0014] Alternatively, or in combination with any of the foregoing options for R1, when present,, R5, when present, R2, when present, R3, when present, X1, when present, X2, when present, and X3, when present, can each, independently, be a Ci-Ce-alkyl group.

[0015] The compound of formula (I) can be:wherein:R1is halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl or aryl;R2and R3are alkyl or, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocycloalkyl group;R4is H or alkyl;X1is absent, O, alkyl or cycloalkyl; andR5is aryl, arylalkyl, arylalkyloxycarbonyl or heteroaryl.

[0016] The compound of formula (II) can be:wherein:R1is alkyl, aryl or cycloalkyl;R2and R3are alkyl or, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocycloalkyl group;R4is H or alkyl;X1is absent, O or alkyl; andR5is aryl.

[0017] The compound of formula (III) can be:R4is H or alkyl;X1is alkyl; andR5is aryl or heteroaryl.

[0018] The compound of formula (IV) can be:wherein:X2and X3are each, independently, cycloalkyl;R4is H or alkyl;X1is alkyl; andR5is aryl or heteroaryl.

[0019] The compound of formula (V) can be:wherein:R1is cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl or arylalkyloxy;R4is H or alkyl;X1is cycloalkyl or heterocycloalkyl; andR5is aryl or heteroaryl.

[0020] The disclosure relates to compounds of the formula (l)-(V) selected from:5or a pharmaceutically acceptable salt thereof.

[0021] The disclosure relates to compounds of the formula (l)-(V) selected from:pharmaceutically acceptable salt thereof.

[0022] The disclosure also relates to compounds of the formula Vl-A:or a pharmaceutically acceptable salt thereof, wherein:Ar1is aryl or heteroaryl;Ar2is aryl;X1is alkyl;R5is H or alkyl; andA represents cycloalkyl or heterocyclyl.

[0023] In examples, Ar1is optionally substituted phenyl, pyrrolyl, imidazolyl or pyrazolyl (e.g., 1 H-pyrazol-1 -yl). Alternatively or in addition, Ar2is optionally substituted phenyl. In one example, Ar2is optionally substituted phenyl (e.g., haloor haloalkyl substituted phenyl, such as chloro or trichloromethyl substituted phenyl). Alternatively or in addition, A is optionally substituted Ca-Cs cycloalkyl, such as optionally substituted Ca-Ce or C4-C6 cycloalkyl, optionally substituted tetrahydropyranyl (e.g., 4-tetrahydropyranyl), optionally substituted piperidinyl or optionally substituted morpholinyl. In one example, A is optionally substituted cyclohexyl or optionally substituted cyclopentyl. In another example, A is optionally substituted tetrahydropyranyl (e.g., 4-tetrahydropyranyl). Alternatively or in addition, X1is optionally substituted Ca-Cs alkyl (e.g., ethyl or propyl), such as C2- Cs or C2-C4 alkyl. Alternatively or in addition, R6is optionally substituted Ci-Ce alkyl (e.g., methyl), such as C1-C3 or C2-C4 alkyl. Examples of compounds of formula Vl-A include:or a pharmaceutically acceptable salt thereof.

[0024] The disclosure also relates to compounds of the formula Vl-B:or a pharmaceutically acceptable salt thereof, wherein:Ar1is aryl or heteroaryl;X4is alkyl or O;X3is halo, alkyl, cycloalkyl, alkenyl or alkynyl;R6is H or alkyl; andA represents cycloalkyl or heterocyclyl.

[0025] In examples, Ar1is optionally substituted phenyl, including napthyl (e.g., substituted with one or more halo, alkyl, haloalkyl, alkoxy, haloalkyloxy, nitro,aklyloxycarbonyl or carboxylate, such as chloro, fluoro, methyl, trifluoromethyl, trifluoroethyl, methoxy, trihalomethoxy, or two adjacent groups on the phenyl can form a dioxolyl group), optionally substituted pyridyl (e.g., 4-pyridyl), optionally substituted benzimidazole or optionally substituted pyrazolyl (e.g., 1 H-pyrazol-1 - yl; e.g., substituted with one or more alkyl, nitro or trihaloalkyl, such as methyl and trihalomethyl). Alternatively or in addition, A is optionally substituted C3-C8 cycloalkyl, such as optionally substituted C3-C6 or C4-C6 cycloalkyl, optionally substituted tetrahydropyranyl (e.g., 2-tetrahydropyranyl or 4-tetrahydropyranyl), optionally substituted piperidinyl or optionally substituted morpholinyl. In one example, A is optionally substituted cyclooctyl, optionally substituted cycloheptyl, optionally substituted cyclohexyl (e.g., substituted with one or more halo, such as fluoro), optionally substituted cyclopentyl (e.g., substituted with halo, such as fluoro) or optionally substituted cyclobutyl (e.g., substituted with halo, such as fluoro). In another example, A is optionally substituted tetrahydropyranyl (e.g., 4- tetrahydropyranyl). Alternatively or in addition, X4is O or optionally substituted C2- C8alkyl (e.g., ethyl or propyl), such as C2-C6or C2-C4alkyl. Alternatively or in addition, R6is optionally substituted Ci-Ce alkyl (e.g., methyl), such as C1-C3 or C2- C4alkyl. Alternatively or in addition, X3is halo, such as fluoro or bromo; optionally substituted Ci-C8alkyl (e.g., methyl, ethyl or propyl), such as Ci-C6or C1-C4 alkyl (e.g., substituted with alkyl or haloalkyl, such as methyl, ethyl, trifluoromethyl, and difluoromethyl); optionally substituted C2-C8alkenyl (e.g., ethylenyl, CH=CH2), such as C2-C6or C2-C4 alkenyl; or optionally substituted C2-C8alkynyl (e.g., ethynyl, C=CH), such as C2-C6or C2-C4 alkynyl. In one example, X3and A together can form an optionally substituted adamantly group (e.g. substituted with methyl). In another example, A can be cycloalkyl and X3can be cycloalkyl so as to form a spirocycle (e.g., a spiro[2.3]hexyl group). Examples of compounds of formula Vl-B include:10 or a pharmaceutically acceptable salt thereof.

[0026] The disclosure also relates to compounds of the formula Vl-C:or a pharmaceutically acceptable salt thereof, wherein:Ar1is aryl or heteroaryl;X1is alkyl;R6is H or alkyl; andB represents cycloalkyl, cycloalkenyl or aryl.

[0027] In examples, Ar1is optionally substituted phenyl, including napthyl (e.g., substituted with one or more halo, alkyl, haloalkyl, alkoxy, haloalkyloxy, nitro, aklyloxycarbonyl or carboxylate, such as chloro, fluoro, methyl, trifluoromethyl, trifluoroethyl, methoxy, trihalomethoxy, or two adjacent groups on the phenyl can form a dioxolyl group), optionally substituted pyridyl (e.g., 4-pyridyl), optionally substituted benzimidazole or optionally substituted pyrazolyl (e.g., 1 H-pyrazol-1 - yl; e.g., substituted with one or more alkyl, nitro or trihaloalkyl, such as methyl and trihalomethyl). Alternatively or in addition, B is optionally substituted C3-C8cycloalkyl, such as optionally substituted C3-C6or C4-C6cycloalkyl (e.g., substituted with methyl or haloalkyl, such as trihaloalkyl, including trifluoromethyl; the cycloalkyl can be a fused cycloalkyl, such as a bicyclo[4.1.0]heptyl group); optionally substituted C3-C8cycloalkenyl, such as optionally substituted C3-Ce or C4-C6 cycloalkenyl (e.g., substituted with one or more methyl and halo, such as chloro); or optionally substituted phenyl, including napthyl (e.g., substituted with one or more halo, alkyl, haloalkyl, alkoxy, haloalkyloxy, nitro, aklyloxycarbonyl or carboxylate, such as chloro, fluoro, methyl, trifluoromethyl, trifluoroethyl, methoxy, trihalomethoxy, or two adjacent groups on the phenyl can form a dioxolyl group). Alternatively or in addition, X1is optionally substituted C2-C8 alkyl (e.g., ethyl or propyl), such as C2-C6or C2-C4 alkyl. Alternatively or in addition, R6is optionally substituted Ci-C6alkyl (e.g., methyl), such as CrC3or C2-C4alkyl. Examples of compounds of formula Vl-C include:or a pharmaceutically acceptable salt thereof.

[0028] The disclosure also relates to compounds of the formula Vl-Dvi-D or a pharmaceutically acceptable salt thereof, wherein:Ar2is aryl;X2is alkyl;X3is halo, alkyl, cycloalkyl, alkenyl or alkynyl;R6is H or alkyl; andC represents cycloalkyl.

[0029] In examples, Ar2is optionally substituted phenyl (e.g., halo or haloalkyl substituted phenyl, such as chloro or trichloromethyl substituted phenyl). Alternatively or in addition, C is optionally substituted C3-C8cycloalkyl, such as optionally substituted C3-C6or C4-C6cycloalkyl. In one example, C is optionally substituted cyclooctyl, optionally substituted cycloheptyl, optionally substituted cyclohexyl, optionally substituted cyclopentyl or optionally substituted cyclobutyl. Alternatively or in addition, X2is optionally substituted C2-C8alkyl (e.g., ethyl orpropyl), such as C2-C6or C2-C4alkyl. Alternatively or in addition, R6is optionally substituted Ci-Cg alkyl (e.g., methyl), such as C1-C3 or C2-C4alkyl. Alternatively or in addition, X3is optionally substituted CrCs alkyl (e.g., methyl, ethyl or propyl), such as CrCe or CrC4alkyl (e.g., substituted with alkyl or haloalkyl, such as methyl, ethyl, trifluoromethyl, and difluoromethyl). Examples of compounds of formula Vl-D include:or a pharmaceutically acceptable salt thereof.

[0030] The disclosure also relates to compounds of the formula Vl-E:or a pharmaceutically acceptable salt thereof, wherein:Ar2is aryl;X2is alkyl;Y is O or NR6;Rsis H or alkyl; andC represents cycloalkyl.

[0031] In examples, Ar2is optionally substituted phenyl (e.g., halo or haloalkyl substituted phenyl, such as chloro or trichloromethyl substituted phenyl). Alternatively or in addition, C is optionally substituted C3-C8cycloalkyl, such as optionally substituted Cs-Ce or C4-Ce cycloalkyl. In one example, C is optionally substituted cyclooctyl, optionally substituted cycloheptyl, optionally substitutedcyclohexyl, optionally substituted cyclopentyl or optionally substituted cyclobutyl. Alternatively or in addition, X2is optionally substituted C2-C8 alkyl (e.g., ethyl or propyl), such as C2-C6 or C2-C4 alkyl. Alternatively or in addition, R6is optionally substituted Ci-C8alkyl (e.g., methyl), such as C1-C3 or C2-C4 alkyl. An example of a compound of formula Vl-E include:or a pharmaceutically acceptable salt thereof.

[0032] The disclosure also relates to compounds of the formula Vl-F:or a pharmaceutically acceptable salt thereof, wherein:Ar2is aryl;X1is alkyl;X2is alkyl;X7is alkyl or aryl; andR5is H or alkyl.

[0033] In examples, Ar2is optionally substituted phenyl (e.g., halo or haloalkyl substituted phenyl, such as chloro or trichloromethyl substituted phenyl). Alternatively or in addition, X1is optionally substituted C2-C8alkyl (e.g., ethyl or propyl), such as C2-C6or C2-C4alkyl. Alternatively or in addition, X2is optionally substituted C2-C8alkyl (e.g., ethyl or propyl), such as C2-C6or C2-C4alkyl. Alternatively or in addition, R6is optionally substituted Ci-C6alkyl (e.g., methyl), such as C1-C3 or C2-C4 alkyl. An example of compounds of formula Vl-F include:or a pharmaceutically acceptable salt thereof.

[0034] The disclosure also relates to compounds of the formula Vl-G:or a pharmaceutically acceptable salt thereof,wherein:X8is absent, aryl or arylalkyloxycarbonyl;X5is cycloalkyl or heterocyclyl;X3is halo, alkyl, cycloalkyl, alkenyl or alkynyl;R6is H or alkyl; andD represents cycloalkyl or cycloalkenyl; with the proviso that X8can be absent only when it is attached to a nitrogen and is absent if it would be attached to an oxygen or sulfur atom.

[0035] In examples, X8is optionally substituted phenyl (e.g., halo or haloalkyl substituted phenyl, such as chloro or trichloromethyl substituted phenyl). Alternatively, X8is arylalkyloxycarbonyl, wherein the aryl in arylalkyloxycarbonyl is phenyl, such as optionally substituted phenyl (e.g., halo or haloalkyl substituted phenyl, such as chloro or trichloromethyl substituted phenyl). Alternatively or in addition, X5is optionally substituted C3-C8cycloalkyl, such as optionally substituted C3-C6or C4-C6 cycloalkyl. In one example, X5is optionally substituted cyclooctyl, optionally substituted cycloheptyl, optionally substituted cyclohexyl, optionally substituted cyclopentyl or optionally substituted cyclobutyl. Alternatively X5is heterocyclyl such as optionally substituted C3-C8heterocyclyl, such as optionally substituted C3-C6or C4-C6heterocyclyl. In one example, X5is optionally substituted azetidinyl. Alternatively or in addition, R6is optionally substituted Ci-C6alkyl (e.g., methyl), such as Ci-C3or C2-C4 alkyl. Alternatively or in addition, X3is optionally substituted Ci-C8alkyl (e.g., methyl, ethyl or propyl), such as Ci-C6or C1-C4 alkyl (e.g., substituted with alkyl or haloalkyl, such as methyl, ethyl, trifluoromethyl, and difluoromethyl). Examples of compounds of formula Vl-G include:or a pharmaceutically acceptable salt thereof.

[0036] The disclosure also relates to compounds of the formula Vl-H:or a pharmaceutically acceptable salt thereof, wherein:Ar2is aryl;X5is cycloalkyl or heterocyclyl; g is 0, 1 , 2, 3, 4 or 5; andR6is H or alkyl.

[0037] In examples, Ar2is optionally substituted phenyl (e.g., halo or haloalkyl substituted phenyl, such as chloro or trichloromethyl substituted phenyl). Alternatively or in addition, X5is optionally substituted C3-C8cycloalkyl, such as optionally substituted C3-C6or C4-C6cycloalkyl. In one example, X5is optionally substituted cyclooctyl, optionally substituted cycloheptyl, optionally substituted cyclohexyl, optionally substituted cyclopentyl or optionally substituted cyclobutyl. Alternatively X5is heterocyclyl such as optionally substituted C3-C8heterocyclyl, such as optionally substituted C3-C6or C4-C6heterocyclyl. In one example, X5is optionally substituted azetidinyl. Alternatively or in addition, Rsis optionally substituted Ci-Ce alkyl (e.g., methyl), such as Ci-C3or C3-C4alkyl. Alternatively or in addition, g is 1 , 2 or 3. An example of a compound of formula Vl-H include:or a pharmaceutically acceptable salt thereof.

[0038] The disclosure also relates to compounds of the formula VI I :or a pharmaceutically acceptable salt thereof, wherein: Ar2is aryl;X5is cycloalkyl or heterocyclyl;X9is alkyl, aryl or arylalkyloxy;R6is H or alkyl; andD represents cycloalkyl or cycloalkenyl.

[0039] In examples, Ar2is optionally substituted phenyl (e.g., halo or haloalkyl substituted phenyl, such as chloro or trichloromethyl substituted phenyl). Alternatively or in addition, X5is optionally substituted C3-C8cycloalkyl, such as optionally substituted C3-C6or C4-C6cycloalkyl. In one example, X5is optionally substituted cyclooctyl, optionally substituted cycloheptyl, optionally substituted cyclohexyl, optionally substituted cyclopentyl or optionally substituted cyclobutyl. Alternatively X5is heterocyclyl such as optionally substituted C3-C8heterocyclyl, such as optionally substituted C3-C6or C4-C6 heterocyclyl. In one example, X5is optionally substituted azetidinyl. Alternatively or in addition, R6is optionally substituted Ci-C6alkyl (e.g., methyl), such as Ci-C3or C2-C4 alkyl. Alternatively or in addition, X9is optionally substituted C2-C8alkyl (e.g., ethyl or propyl), such as C2-C6 or C2-C4 alkyl. Alternatively, R9is optionally substituted phenyl (e.g., halo or haloalkyl substituted phenyl, such as chloro or trichloromethyl substituted phenyl). Alternatively, R9is arylalkyoxy, wherein the aryl in arylalkyoxy is optionally substituted phenyl (e.g., halo or haloalkyl substituted phenyl, such as chloro or trichloromethyl substituted phenyl). Alternatively or in addition, D is optionally substituted C3-C8cycloalkyl, such as optionally substituted C3-C6or C4-C6cycloalkyl (e.g., substituted with methyl or haloalkyl, such as trihaloalkyl, including trifluoromethyl; the cycloalkyl can be a fused cycloalkyl, such as a bicyclo[4.1 ,0]heptyl group) or optionally substituted C3-C8cycloalkenyl, such as optionally substituted C3-C8or C4-C6 cycloalkenyl (e.g., substituted with one ormore methyl and halo, such as chloro). An example of a compound of formula VI-I include:or a pharmaceutically acceptable salt thereof.

[0040] The above compounds can be synthesized in accordance with methods presented herein and / or methods known in the art.

[0041] Further provided is a pharmaceutical composition comprising one or more of the compounds of formulae (l)-(V) and Vl-A-I and a pharmaceutically acceptable carrier. Pharmaceutical compositions can be prepared in accordance with methods known in the art.

[0042] The disclosure also relates to a method of treating a non-tubercular mycobacterial or tuberculosis infection, the method comprising administering a therapeutically effective amount of one or more of the foregoing compounds or a pharmaceutical composition comprising one or more of the foregoing compounds to a subject in need thereof.

[0043] The terms “substituted,” “substituent,” and “functional group” refer to a group that can be or is substituted onto a molecule or onto another group (e.g., on an aryl or an alkyl group). Examples of substituents include, but are not limited to, a halogen (e.g., F, Cl, Br, and I), OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (OXO), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, -(CH2)0-2P(O)(OR)2, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)O-2N(R)C(0)R, (CH2)O-2N(R)C(0)OR, (CH2)O-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, or C(=NOR)R wherein each R can be, independently, hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl or two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl, which can be mono- or independently multi-substituted.

[0044] The term “alkyl” as used herein refers to substituted or unsubstituted straight chain and branched mono- or divalent alkyl groups and cycloalkyl groupshaving from 1 to 40 carbon atoms (C1-C40), 1 to about 20 carbon atoms (C1-C20), 1 to 12 carbons (C1-C12), 1 to 8 carbon atoms (C Cs), or, in some embodiments, from 1 to 6 carbon atoms (Ci-Ce). Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and ante-isoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0045] The term “alkenyl” as used herein refers to substituted or unsubstituted straight chain and branched mono- or divalent alkenyl groups and cycloalkenyl groups having at least one double bond and having from 1 to 40 carbon atoms (Cr C40), 1 to about 20 carbon atoms (C1-C20), 1 to 12 carbons (C1-C12), 1 to 8 carbon atoms (Ci-Cs), or, in some embodiments, from 1 to 6 carbon atoms (Ci-C6). Examples of straight chain alkenyl groups include those with from 1 to 8 carbon atoms such as -CH=CH-, -CH=CHCH3, and -CH2CH=CHCH2- groups, wherein the double bonds can have an E- or Z-configuration. And when there are multiple bonds, each double bond can, independently, have an E- or a Z-configuration. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH3)- and CH2C=CH(CH3) groups. Representative substituted alkenyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0046] The term “cycloalkyl” as used herein refers to substituted or unsubstituted cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups can have any number of carbon atoms, e.g., 3 to 8 carbon atoms (C3-Cs), 3 to 6 carbon atoms (C3-Ce), and 4 to 8 carbon atoms (C4-Cs). Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.

[0047] The term “cycloalkyloxy” refer to cycloalkyl groups as defined herein in which a hydrogen bond of a cycloalkyl group is replaced with a bond to an oxygen.

[0048] The term “alkylcycloalkyl” refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined herein.

[0049] The term “cycloalkenyl” as used herein refers to substituted or unsubstituted cyclic alkenyl groups comprising one, two or more double bonds such as, but not limited to, cyclopropenyl, cyclobutyenyl, cyclopentenyl, cyclohexyenyl, cycloheptenyl, and cyclooctenyl groups. In some embodiments, the cycloalkenyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkenyl groups can have any number of carbon atoms, e.g., 3 to 8 carbon atoms (C3-C8), 3 to 6 carbon atoms (C3-C6), and 4 to 8 carbon atoms (C Cs). Cycloalkenyl groups further include polycyclic cycloalkenyl groups and fused rings

[0050] The term “cycloalkylalkyl” as used herein refers to substituted or unsubstituted alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a cycloalkyl group as defined herein. Representative cycloalkylalkyl groups include, but are not limited to, cyclopentylalkyl.

[0051] The term “alkylcycloalkyl” as used herein refers to substituted or unsubstituted cycloalkyl groups as defined herein in which a hydrogen of a cycloalkyl group as defined herein is replaced with a bond to an alkyl group as defined herein. Representative alkylcycloalkyl groups include, but are not limited to, alkylcyclopropyl.

[0052] The term “acyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of a substituted or unsubstituted alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a “formyl” group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-40, 6-10, 1 -5 or 2-5 additional carbon atoms bonded to the carbonyl group. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyl- 3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a “haloacyl” group. An example is a trifluoroacetyl group.

[0053] The term “heterocyclylcarbonyl” is an example of an acyl group that is bonded to a substituted or unsubstituted heterocyclyl group, as the term “heterocyclyl” is defined herein. An example of a heterocyclylcarbonyl group is a prolyl group, wherein the prolyl group can be a D- or an L-prolyl group.

[0054] The term “aryl” as used herein refers to substituted or unsubstituted cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons (Ce-Cu) or from 6 to 10 carbon atoms (C6-Cio) in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. “Aryl” and the phrase “aryl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. Accordingly, “aryl” and the phrase “aryl group” include groups of the formula:substituted or unsubstituted, such as hydroxy substituted.

[0055] Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6- substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed herein.

[0056] The terms “aralkyl” and “arylalkyl” refer to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

[0057] The terms “aralkyloxy” and “arylalkyloxy” refer to arylalkyl groups as defined herein in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an oxygen.

[0058] The term “heterocyclyl” or “heterocyclo” refers to substituted or unsubstituted aromatic and non-aromatic ring compounds containing 3 or more ring members, of which one or more (e.g., 1 , 2 or 3) is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl or aheteroaryl or, if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. In some embodiments, heterocyclyl groups include heterocyclyl groups that include 3 to 8 carbon atoms (Ca-Cs), 3 to 6 carbon atoms (Ca-Ce), 3 to 5 carbon atoms (C3-C5) or 6 to 8 carbon atoms (Ce- Cs). A heterocyclyl group designated as a Ca-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and fthe heteroatoms and so forth. Likewise, a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds, such as in the group 3,6-dihydro-2H-pyran and 3,4-dihydro-2H-pyran, having the formula:K ji and , respectively, each of which can be substituted.

[0059] The term “heterocycloalkyl” refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclo group as defined herein..

[0060] A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, but are not limited to tetrahydro-2H-thiopyran-1 ,1 -dioxide, having the formula:which can be substituted, 4a,5,6,7-tetrahydro-4H-pyrrolo[1 ,2- d][1 ,3,4]oxadiazinyl, having the formula:, which can be substituted, pyrrolidinyl, pyrrolidinone (e.g., pyrrolidin-2-one), azetidinyl, piperidynyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinonyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, imidazo[1 ,2-a]pyridinyl, having the formula:which can be substituted, triazyolyl, tetrazolyl, benzoxazolinyl, thiazolyl, benzthiazolinyl, and benzimidazolinyl groups. Examples of indolinonyl groups include groups having the general formula:

[0061] Examples of isoindolinonyl groups include groups having the general formula:, wherein R is as defined herein.

[0062] Examples of benzoxazolinyl groups include groups having the general formula:wherein R is as defined herein.

[0063] Examples of benzthiazolinyl groups include groups having the general formula:wherein R is as defined herein.

[0064] In some embodiments, the group R in benzoxazolinyl and benzthiazolinyl groups is an N(R’)2group. In some embodiments, each R’ is hydrogen or alkyl, wherein the alkyl group is substituted or unsubstituted. In some embodiments, the alkyl group is substituted with a heterocyclyl group (e.g., with a pyrrolidinyl group).

[0065] The term “heterocyclylalkyl” refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-yl methyl, furan-3- yl methyl, pyridine-3-yl methyl, tetrahydrofuran -2-yl methyl, and indol-2-yl propyl.

[0066] The term “heterocyclylalkoxy” refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein and the alkyl group is attached to an oxygen. Representative heterocyclylalkoxy groups include, but are not limited to, -O-(CH2)qheterocyclyl, wherein q is an integer from 1 to 5. In some embodiments, heterocyclylalkoxy groups include -O-(CH2)qmorpholinyl such as - O-CH2CH2-morpholine.

[0067] The term “heteroarylalkyl” refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.

[0068] The term “alkoxy” refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 or about 12-40 carbon atoms bonded to the oxygen atom, can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.

[0069] The terms “amine,” “amine group,” “amino,” and “amino group” refer to a substituent of the form -NH2, -NHR, -NR2, or -NR3+, wherein each R is defined herein, and protonated forms of each, except for -NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group.

[0070] An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group. An example of a “alkylamino” is -NH-alkyl and -N(alkyl)2.

[0071] An example of a “cycloalkylamino” group is -NH-cycloalkyl and -N(cycloalkyl)2.

[0072] An example of a “cycloalkyl heterocycloamino” group is -NH-(heterocyclo cycloalkyl), wherein the heterocyclo group is attached to the nitrogen and the cycloalkyl group is attached to the heterocyclo group.

[0073] An example of a “heterocyclo cycloamino” group is -NH-(cycloalkyl heterocycle), wherein the cycloalkyl group is attached to the nitrogen and the heterocyclo group is attached to the cycloalkyl group.

[0074] The term “amido” refers to a group of the formula -C(O)NR2, wherein R is defined herein.

[0075] The terms “halo,” “halogen,” and “halide” group, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0076] The term “haloalkyl” group includes mono-halo alkyl groups, poly-halo alkyl groups, wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1 ,1 -dichloroethyl, 1 ,2- dichloroethyl, 1 ,3-dibromo-3,3-difluoropropyl, perfluorobutyl, -CF(CH3)2and the like.

[0077] The terms “treat,” “treating,” “treated,” or “treatment” (with respect to a disease or condition) is an approach for obtaining beneficial or desired results including and preferably clinical results and includes, but is not limited to, one or more of the following: improving a condition associated with a disease, curing a disease, lessening severity of a disease, delaying progression of a disease, alleviating one or more symptoms associated with a disease, increasing the quality of life of one suffering from a disease, prolonging survival and / or prophylactic or preventative treatment.

[0078] As used herein, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active conjugates or compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound and / or other therapeutic agent without necessitating undue experimentation. A maximum dose can be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day can be used to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein.

[0079] Generally, daily oral doses of a compound are, for human subjects, from about 0.01 milligrams / kg per day to 1 ,000 milligrams / kg per day. Oral doses in the range of 0.5 to 50 milligrams / kg, in one or more administrations per day, can yield therapeutic results. Dosage can be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example,intravenous administration can vary from one order to several orders of magnitude lower dose per day. If the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) can be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound.

[0080] The term “therapeutically effective amount” as used herein, refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In one aspect, the therapeutically effective amount is that which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit / risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the compounds and compositions described herein may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician of ordinary skill.

[0081] For any compound therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.

[0082] For clinical use, any compound can be administered in an amount equal or equivalent to 0.2-2,000 milligram (mg) of compound per kilogram (kg) of body weight of the subject per day. The compounds can be administered in a dose equal or equivalent to 2-2,000 mg of compound per kg body weight of the subject perday. The compounds can be administered in a dose equal or equivalent to 20- 2,000 mg of compound per kg body weight of the subject per day. The compounds can be administered in a dose equal or equivalent to 50-2,000 mg of compound per kg body weight of the subject per day. The compounds can be administered in a dose equal or equivalent to 100-2,000 mg of compound per kg body weight of the subject per day. The compounds can be administered in a dose equal or equivalent to 200-2,000 mg of compound per kg body weight of the subject per day. Where a precursor or prodrug of a compound is to be administered, it is administered in an amount that is equivalent to, i.e. , sufficient to deliver, the abovestated amounts of the compound.

[0083] The formulations of the compounds can be administered to human subjects in therapeutically effective amounts. Typical dose ranges are from about 0.01 microgram / kg to about 2 mg / kg of body weight per day. The dosage of drug to be administered is likely to depend on such variables as the type and extent of the disorder, the overall health status of the particular subject, the specific compound being administered, the excipients used to formulate the compound, and its route of administration. Routine experiments can be used to optimize the dose and dosing frequency for any particular compound.

[0084] The compounds can be administered at a concentration in the range from about 0.001 microgram / kg to greater than about 500 mg / kg. For example, the concentration can be 0.001 microgram / kg, 0.01 microgram / kg, 0.05 microgram / kg, 0.1 microgram / kg, 0.5 microgram / kg, 1 .0 microgram / kg, 10.0 microgram / kg, 50.0 microgram / kg, 100.0 microgram / kg, 500 microgram / kg, 1 .0 mg / kg, 5.0 mg / kg, 10.0 mg / kg, 15.0 mg / kg, 20.0 mg / kg, 25.0 mg / kg, 30.0 mg / kg, 35.0 mg / kg, 40.0 mg / kg, 45.0 mg / kg, 50.0 mg / kg, 60.0 mg / kg, 70.0 mg / kg, 80.0 mg / kg, 90.0 mg / kg, 100.0 mg / kg, 150.0 mg / kg, 200.0 mg / kg, 250.0 mg / kg, 300.0 mg / kg, 350.0 mg / kg, 400.0 mg / kg, 450.0 mg / kg, to greater than about 500.0 mg / kg or any incremental value thereof. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed.

[0085] The compounds can be administered at a dosage in the range from about 0.2 milligram / kg / day to greater than about 100 mg / kg / day. For example, the dosage can be 0.2 mg / kg / day to 100 mg / kg / day, 0.2 mg / kg / day to 50 mg / kg / day, 0.2 mg / kg / day to 25 mg / kg / day, 0.2 mg / kg / day to 10 mg / kg / day, 0.2 mg / kg / day to 7.5 mg / kg / day, 0.2 mg / kg / day to 5 mg / kg / day, 0.25 mg / kg / day to 100 mg / kg / day, 0.25 mg / kg / day to 50 mg / kg / day, 0.25 mg / kg / day to 25 mg / kg / day, 0.25 mg / kg / day to 10 mg / kg / day, 0.25 mg / kg / day to 7.5 mg / kg / day, 0.25 mg / kg / day to 5 mg / kg / day, 0.5 mg / kg / day to 50 mg / kg / day, 0.5 mg / kg / day to 25 mg / kg / day, 0.5 mg / kg / day to20 mg / kg / day, 0.5 mg / kg / day to 15 mg / kg / day, 0.5 mg / kg / day to 10 mg / kg / day, 0.5 mg / kg / day to 7.5 mg / kg / day, 0.5 mg / kg / day to 5 mg / kg / day, 0.75 mg / kg / day to 50 mg / kg / day, 0.75 mg / kg / day to 25 mg / kg / day, 0.75 mg / kg / day to 20 mg / kg / day, 0.75 mg / kg / day to 15 mg / kg / day, 0.75 mg / kg / day to 10 mg / kg / day, 0.75 mg / kg / day to 7.5 mg / kg / day, 0.75 mg / kg / day to 5 mg / kg / day, 1 .0 mg / kg / day to 50 mg / kg / day,1 .0 mg / kg / day to 25 mg / kg / day, 1 .0 mg / kg / day to 20 mg / kg / day, 1 .0 mg / kg / day to 15 mg / kg / day, 1 .0 mg / kg / day to 10 mg / kg / day, 1 .0 mg / kg / day to 7.5 mg / kg / day, 1 .0 mg / kg / day to 5 mg / kg / day, 2 mg / kg / day to 50 mg / kg / day, 2 mg / kg / day to 25 mg / kg / day, 2 mg / kg / day to 20 mg / kg / day, 2 mg / kg / day to 15 mg / kg / day, 2 mg / kg / day to 10 mg / kg / day, 2 mg / kg / day to 7.5 mg / kg / day, or 2 mg / kg / day to 5 mg / kg / day.

[0086] The compounds can be administered at a dosage in the range from about0.25 milligram / kg / day to about 25 mg / kg / day. For example, the dosage can be 0.25 mg / kg / day, 0.5 mg / kg / day, 0.75 mg / kg / day, 1 .0 mg / kg / day, 1 .25 mg / kg / day, 1 .5 mg / kg / day, 1.75 mg / kg / day, 2.0 mg / kg / day, 2.25 mg / kg / day, 2.5 mg / kg / day, 2.75 mg / kg / day, 3.0 mg / kg / day, 3.25 mg / kg / day, 3.5 mg / kg / day, 3.75 mg / kg / day, 4.0 mg / kg / day, 4.2! mg / kg / day, 4.E mg / kg / day, 4.75 mg / kg / day, 5 mg / kg / day, 5.5 mg / kg / day, 6.0 mg / kg / day, 6.5 mg / kg / day, 7.0 mg / kg / day, 7.5 mg / kg / day, 8.0 mg / kg / day, 8.5 mg / kg / day, 9.0 mg / kg / day, 9.5 mg / kg / day, 10 mg / kg / day, 1 1 mg / kg / day, 12 mg / kg / day, 13 mg / kg / day, 14 mg / kg / day, 15 mg / kg / day, 16 mg / kg / day, 17 mg / kg / day, 18 mg / kg / day, 19 mg / kg / day, 20 mg / kg / day, 21 mg / kg / day, 22 mg / kg / day, 23 mg / kg / day, 24 mg / kg / day, 25 mg / kg / day, 26 mg / kg / day, 27 mg / kg / day, 28 mg / kg / day, 29 mg / kg / day, 30 mg / kg / day, 31 mg / kg / day, 32 mg / kg / day, 33 mg / kg / day, 34 mg / kg / day, 35 mg / kg / day, 36 mg / kg / day, 37 mg / kg / day, 38 mg / kg / day, 39 mg / kg / day, 40 mg / kg / day, 41 mg / kg / day, 42 mg / kg / day, 43 mg / kg / day, 44 mg / kg / day, 45 mg / kg / day, 46 mg / kg / day, 47 mg / kg / day, 48 mg / kg / day, 49 mg / kg / day, or 50 mg / kg / day.

[0087] The compound or precursor thereof can be administered in concentrations that range from 0.01 micromolar to greater than or equal to 500 micromolar. For example, the dose can be 0.01 micromolar, 0.02 micromolar, 0.05 micromolar, 0.1 micromolar, 0.15 micromolar, 0.2 micromolar, 0.5 micromolar, 0.7 micromolar, 1 .0 micromolar, 3.0 micromolar, 5.0 micromolar, 7.0 micromolar, 10.0 micromolar,15.0 micromolar, 20.0 micromolar, 25.0 micromolar, 30.0 micromolar, 35.0 micromolar, 40.0 micromolar, 45.0 micromolar, 50.0 micromolar, 60.0 micromolar, 70.0 micromolar, 80.0 micromolar, 90.0 micromolar, 100.0 micromolar, 150.0 micromolar, 200.0 micromolar, 250.0 micromolar, 300.0 micromolar, 350.0 micromolar, 400.0 micromolar, 450.0 micromolar, to greater than about 500.0micromolar or any incremental value thereof. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed.

[0088] The compound or precursor thereof can be administered at concentrations that range from 0.10 microgram / mL to 500.0 microgram / mL. For example, the concentration can be 0.10 microgram / mL, 0.50 microgram / mL, 1 microgram / mL, 2.0 microgram / mL, 5.0 microgram / mL, 10.0 microgram / mL, 20 microgram / mL, 25 microgram / mL. 30 microgram / mL, 35 microgram / mL, 40 microgram / mL, 45 microgram / mL, 50 microgram / mL, 60.0 microgram / mL, 70.0 microgram / mL, 80.0 microgram / mL, 90.0 microgram / mL, 100.0 microgram / mL, 150.0 microgram / mL, 200.0 microgram / mL, 250.0 g / mL, 250.0 micro gram / mL, 300.0 microgram / mL, 350.0 microgram / mL, 400.0 microgram / mL, 450.0 microgram / mL, to greater than about 500.0 microgram / mL or any incremental value thereof. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed.

[0089] The formulations can be administered in pharmaceutically acceptable solutions, which can routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition can be accomplished by any means known to the skilled artisan. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical.

[0090] For intravenous and other parenteral routes of administration, a compound can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.

[0091] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well- known in the art. Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, andprocessing the mixture of granules, after aciding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone (PVP). If desired, disintegrating agents can be added, such as the cross-linked PVP, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations can also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions, or can be administered without any carriers.

[0092] Also contemplated are oral dosage forms of the compounds. The compounds can be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the compound itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the compounds and increase in circulation time in the body. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, PVP and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts,” In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-lnterscience, New York, N.Y., pp. 367- 383 (1981 ); Newmark et al., J Appl Biochem 4:185-189 (1982). Other polymers that could be used are poly-1 ,3-dioxolane and poly-1 ,3, 6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable.

[0093] The location of release of a compound hereof can be the stomach, the small intestine (e.g., the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations, which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. The release can avoid the deleterious effects of the stomach environment, either by protection of the compound or by release of the compound beyond the stomach environment, such as in the intestine.

[0094] To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetatephthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings can be used as mixed films.

[0095] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules can consist of a hard shell (such as gelatin) fordelivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell can be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.

[0096] The compound can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. Therapeutic agent could be prepared by compression.

[0097] Colorants and flavoring agents may all be included. For example, the compound can be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.

[0098] One may dilute or increase the volume of the compound with an inert material. These diluents can include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts also can be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

[0099] Disintegrants can be included in the formulation of therapeutic agent into a solid dosage form. Materials used as disintegrates include, but are not limited to, starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrant is the insoluble cationic exchange resin. Powdered gums can be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0100] Binders can be used to hold the compound together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) andcarboxymethyl cellulose (CMC). PVP and hydroxypropylmethyl cellulose (HPMC) can both be used in alcoholic solutions to granulate therapeutic agent.

[0101] An anti-frictional agent can be included in the formulation of therapeutic to prevent sticking during the formulation process. Lubricants can be used as a layer between therapeutic agent and the die wall, and these can include, but are not limited to, stearic acid, including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants can also be used, such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.

[0102] Glidants, which can improve the flow properties of the drug during formulation and aid rearrangement during compression, can be added. The glidants can include starch, talc, pyrogenic silica and hydrated silicoaluminate.

[0103] To aid dissolution of therapeutic agent into the aqueous environment a surfactant can be added as a wetting agent. Surfactants can include anionic detergents, such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that can be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound or derivative thereof either alone or as a mixture in different ratios.

[0104] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. Microspheres formulated for oral administration can also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

[0105] For buccal administration, the compositions can take the form of tablets or lozenges formulated in conventional manner.

[0106] For topical administration, the compound can be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.

[0107] For administration by inhalation, compounds can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0108] Also contemplated is pulmonary delivery of the compounds (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) (endothelin-1 ); Hubbard et al., Annal Int Med 3:206-212 (1989) (a1 -antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1 -proteinase); Oswein et al., 1990, "Aerosolization of Proteins," Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant hepatocyte growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Pat. No. 5,284,656 (granulocyte colony stimulating factor; incorporated herein by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451 ,569 (specifically incorporated herein by reference for its disclosure regarding same), issued Sep. 19, 1995, to Wong et al.

[0109] Contemplated for use are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0110] Nasal delivery of a pharmaceutical composition is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition to the blood stream directly after administering therapeutic product to the nose,without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran.

[0111] The compounds, when it is desirable to deliver them systemically, can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0112] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0113] Alternatively, the active compounds can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0114] The compounds can also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0115] In addition to the formulations described above, a compound can also be formulated as a depot preparation. Such long-acting formulations can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0116] The pharmaceutical compositions also can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0117] Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharpobject to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro jcapsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-1533 (1990).

[0118] The compound and optionally one or more other therapeutic agents can be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.

[0119] Suitable buffering agents include acetic acid and a salt (1 -2% w / v); citric acid and a salt (1 -3% w / v); boric acid and a salt (0.5-2.5% w / v); and phosphoric acid and a salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01 -0.25% w / v) and thimerosal (0.004-0.02% w / v).

[0120] Pharmaceutical compositions contain an effective amount of a compound as described herein and optionally one or more other therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also can be commingled with the compounds, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0121] Therapeutic agent(s), including specifically, but not limited to, a compound, can be provided in particles. “Particles” as used herein means nanoparticles or microparticles (or in some instances larger particles) that can consist in whole or in part of the compound or the other therapeutic agent(s) as described herein. The particles can contain therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. Therapeutic agent(s) also can be dispersed throughout the particles. Therapeutic agent(s) also can be adsorbed into the particles. The particles can be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle can include, in addition to therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles can be microcapsules which contain the compound in a solution or in a semi-solid state. The particles can be of virtually any shape.

[0122] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering therapeutic agent(s). Such polymers can be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney et al., Macromolecules 26:5823-2787 (1993), the teachings of which are specifically incorporated by reference herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[0123] Therapeutic agent(s) can be contained in controlled-release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including, but not limited to, sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that can result in substantially constant blood levels of a drugover an extended time period. The term “delayed release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”

[0124] Use of a long-term sustained release implant can be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and up to 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.

[0125] As used herein, the term “salts” and “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

[0126] Pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In some instances, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, the disclosure of which is hereby incorporated by reference.

[0127] The term “solvate” means a compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non- covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0128] The term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound of the invention that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Specific prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods, such as those described by Burger’s Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001 , Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0129] Further, in each of the foregoing and following embodiments, it is to be understood that the formulae include and represent not only all pharmaceutically acceptable salts of the compounds, but also include any and all hydrates and / or solvates of the compound formulae or salts thereof. It is to be appreciated that certain functional groups, such as the hydroxy, amino, and like groups form complexes and / or coordination compounds with water and / or various solvents, in the various physical forms of the compounds. Accordingly, the above formulae are to be understood to include and represent those various hydrates and / or solvates. In each of the foregoing and following embodiments, it is also to be understood that the formulae include and represent each possible isomer, such as stereoisomers and geometric isomers, both individually and in any and all possible mixtures. In each of the foregoing and following embodiments, it is also to be understood that the formulae include and represent any and all crystalline forms, partially crystalline forms, and non-crystalline and / or amorphous forms of the compounds.

[0130] The term "pharmaceutically acceptable carrier" is art-recognized and refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof. Each carrier must be "acceptable" in the sense of being compatible with the subjectcomposition and its components and not injurious to the patient. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11 ) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21 ) other non-toxic compatible substances employed in pharmaceutical formulations.

[0131] As used herein, the term “administering” includes all means of introducing the compounds and compositions described herein to the patient, including, but are not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like. The compounds and compositions described herein may be administered in unit dosage forms and / or formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles.

[0132] Illustrative formats for oral administration include tablets, capsules, elixirs, syrups, and the like. Illustrative routes for parenteral administration include intravenous, intraarterial, intraperitoneal, epidural, intraurethral, intrasternal, intramuscular and subcutaneous, as well as any other art recognized route of parenteral administration.

[0133] Illustrative means of parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques, as well as any other means of parenteral administration recognized in the art. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH in the range from about 3 to about 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. Parenteral administration of acompound is illustratively performed in the form of saline solutions or with the compound incorporated into liposomes. In cases where the compound in itself is not sufficiently soluble to be dissolved, a solubilizer such as ethanol can be applied.

[0134] The dosage of each compound of the claimed combinations depends on several factors, including: the administration method, the condition to be treated, the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the person to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect the dosage regimen used.

[0135] It is to be understood that in the methods described herein, the individual components of a co-administration, or combination can be administered by any suitable means, contemporaneously, simultaneously, sequentially, separately or in a single pharmaceutical formulation. Where the co-administered compounds or compositions are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same or different. The compounds or compositions may be administered via the same or different routes of administration. The compounds or compositions may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.

[0136] Depending upon the route of administration, a wide range of permissible dosages are contemplated herein, including doses falling in the range from about 1 pg / kg to about 1 g / kg. The dosages may be single or divided, and may administered according to a wide variety of protocols, including q.d. (once a day), b.i.d. (twice a day), t.i.d. (three times a day), or even every other day, once a week, once a month, once a quarter, and the like. In each of these cases it is understood that the therapeutically effective amounts described herein correspond to the instance of administration, or alternatively to the total daily, weekly, month, or quarterly dose, as determined by the dosing protocol.

[0137] In addition to the illustrative dosages and dosing protocols described herein, it is to be understood that an effective amount of any one or a mixture of the compounds described herein can be determined by the attending diagnostician or physician by the use of known techniques and / or by observing results obtained under analogous circumstances. In determining the effective amount or dose, a number of factors are considered by the attending diagnosticianor physician, including, but not limited to the species of mammal, including human, its size, age, and general health, the specific disease or disorder involved, the degree of or involvement or the severity of the disease or disorder, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, the use of concomitant medication, and other relevant circumstances.

[0138] The term “patient” includes human and non-human animals such as companion animals (dogs and cats and the like) and livestock animals. Livestock animals are animals raised for food production. The patient to be treated is preferably a mammal, in particular a human being.

[0139] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

[0140] In the present disclosure the term “about” can allow for a degree of variability in a value or range, for example, within 20%, within 10%, within 5%, or within 1 % of a stated value or of a stated limit of a range.

[0141] In the present disclosure the term “substantially” can allow for a degree of variability in a value or range, for example, within 80%, within 90%, within 95%, or within 99% of a stated value or of a stated limit of a range.

[0142] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading may occur within or outside of that particular section. Furthermore, all publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

[0143] The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.

[0144] The term “substantially no” as used herein refers to less than about 30%, 25%, 20%, 15%, 10%, 5%, 3%, 2%, 1%, 0.5%, 0.1 %, 0.05%, 0.001 %, or at less than about 0.0005% or less or about 0% or 0%.

[0145] In the methods described herein, the steps can be carried out in any order without departing from the principles of the invention, except when a temporal or operational sequence is explicitly recited. Furthermore, specified steps can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed step of doing X and a claimed step of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0146] Those skilled in the art will appreciate that many modifications to the embodiments described herein are possible without departing from the spirit and scope of the present disclosure. Thus, the description is not intended and should not be construed to be limited to the examples given but should be granted the full breadth of protection afforded by the appended claims and equivalents thereto. In addition, it is possible to use some of the features of the present disclosure without the corresponding use of other features. Accordingly, the foregoing description of or illustrative embodiments is provided for the purpose of illustrating the principles of the present disclosure and not in limitation thereof and can include modification thereto and permutations thereof.

[0147] The disclosure also relates to the following number Clauses, which are listed in no particular order of importance:1 . A compound of the formula:OR1^N'X'R5or R4(V) or a pharmaceutically acceptable salt thereof; wherein:R1is halo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylakyl, arylalkyloxy or heteroaryl;R1Ais H or alkyl;R2and R3are alkyl or, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocycloalkyl group;R4is H or alkyl;X1is absent, O, alkyl, haloalkyl, cycloalkyl, cycloalkyloxy, alkylcycloalkyl or heterocycloalkyl;X2and X3are each, independently, cycloalkyl; andR5is cycloalkyl, aryl, arylalkyl, aryloxy, arylalkyloxycarbonyl or heteroaryl: provided that the compound of formula (I) is not:2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1is C6-Ci0-aryl or C3-Ci2-cycloalkyl.3. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein R1is Ci-C6-alkyl or Ci-C6-haloalkyl.4. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein R1is Cs-Ce-alkenyl.5. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein R1is Cs-Ce-heterocycloalkenyl.6. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein R5is Ce-C -aryl.7. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein R5is a C2-C5-heteroaryl group.8. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein R5is a C6-Cio-aryl-Ci-C6-alkyl group.9. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein R2and R3together with the carbon atom to which they are attached form a C2-C -heterocycloalkyl group or a Cs-Cs-cycloalkyl group.10. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein X1is a Ci-C6-alkyl group.11 . The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein X1is O and R5is Ce-C -aryl.12. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein X1is a Cs-Ce-heterocycloalkyl.13. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein X1is a Ci-Cg-alkyloxy group.14. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein X2and X3are each, independently, a Ci-Ce-alkyl group.15. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:wherein:R1is halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl or aryl;R2and R3are alkyl or, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocycloalkyl group;R4is H or alkyl;X1is absent, O, alkyl or cycloalkyl; andR5is aryl, arylalkyl, arylalkyloxycarbonyl or heteroaryl.16. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:wherein:R1is alkyl, aryl or cycloalkyl;R2and R3are alkyl or, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocycloalkyl group;R4is H or alkyl;X1is absent, O or alkyl; andR5is aryl.17. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:R1Ais H or alkyl;R4is H or alkyl;X1is alkyl; andR5is aryl or heteroaryl.18. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:wherein:X2and X3are each, independently, cycloalkyl;R4is H or alkyl;X1is alkyl; andR5is aryl or heteroaryl.19. The compound of Clause 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:wherein:R1is cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl or arylalkyloxy;R4is H or alkyl;X1is cycloalkyl or heterocycloalkyl; andR5is aryl or heteroaryl.20. A compound of the formula:or a pharmaceutically acceptable salt thereof.ula:22. A pharmaceutical composition comprising a compound of any preceding10 Clause, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.23. A method of treating a mycobacterial infection, the method comprising administering a therapeutically effective amount of a compound of Clauses 1 -21 or a pharmaceutical composition of Clause 22 to a subject in need thereof.24. The method of Clause 23, wherein the mycobacterial infection comprises non-tubercular mycobacterial or tuberculosis infection.25. The method of Clause 24, wherein the non-tubercular mycobacterial infection comprises a M. abscessus, M. avium, M. gordonae, M. smegmatis, or M. marinum infection.26. The method of Clause 24, herein the tuberculosis infection comprises a M. tuberculosis, M. bovis, M. africanum, M. microti, M. cannetti, M. caprae and M. pinnipedi.Examples

[0148] The disclosure can be better understood by reference to the following examples which are offered by way of illustration. The disclosure is not limited to the examples given herein.Examples 1-143

[0149] / V-[2-(4-chlorophenyl)ethyl]-1 -phenylcyclopentane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -phenyl-1 -cyclopentyl carboxylic acid (0.190 g, 1.00 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.131 g, 1.31 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.456 g, 1.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Chlorophenyl)ethylamine (0.220 g, 1.42 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 100 % ethyl acetate in hexanes and fractions containing product were combined and concentrated in vacuo to yield the final product (0.148 g, 45 %). 1 H NMR (500 MHz, Chloroform-d) 57.34 - 7.29 (m, 2H), 7.29 - 7.23 (m,3H), 7.17 - 7.12 (m, 2H), 6.86 - 6.80 (m, 2H), 5.12 (s, 1 H), 3.41 - 3.31 (m, 2H), 2.61 (t, J = 6.7 Hz, 2H), 2.47 - 2.36 (m, 2H), 1 .97 (dddd, J = 12.9, 7.7, 4.4, 2.0 Hz, 2H), 1 .87 - 1 .73 (m, 2H), 1 .72 - 1 .59 (m, 2H). HRMS ESI (+) Calc’d for [M+H] = 328.1464, found = 328.1478.

[0150] N-[2-(4-chlorophenyl)ethyl]-1 -phenylcyclopropane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -phenyl-1 -cyclopropyl carboxylic acid (0.162 g, 1.00 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.131 g, 1.31 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- bjpyridinium 3-oxid hexafluorophosphate (0.456 g, 1.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Chlorophenyl)ethylamine (0.222 g, 1.42 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 100 % ethyl acetate in hexanes and fractions containing product were combined and concentrated in vacuo. This material was further purified by reverse phase Medium Pressure Liquid Chromatography with 0 -100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield the final product (0.120 g, 40 %).1H NMR (500 MHz, Chloroform-d) 5 7.35 - 7.24 (m, 5H), 7.20 - 7.15 (m, 2H), 6.95 - 6.91 (m, 2H), 5.25 (s, 1 H), 3.37 (td, J = 6.9, 5.8 Hz, 2H), 2.65 (t, J = 6.9 Hz, 2H), 1 .57 (q, J = 3.7 Hz, 2H), 1 .02 (q, J = 3.7 Hz, 2H). HRMS ESI (+) Calc’d for [M+H] = 300.1151 , 300.1176.

[0151] N-[2-(4-chlorophenyl)ethyl]-4-phenyloxane-4-carboxamide. T o a 100 mL 24 / 40 round bottom flask containing a stir bar was added 4-phenyl- tetrahydro-2H-pyran-4-carboxylic acid (0.274 g, 1.33 mmol), N,N- dimethylformamide (4.00 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.551 g, 1.45 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Chlorophenyl)ethylamine (0.233 g, 1.50 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This material was triturated from ethyl acetate and hexanes to yield the final product (0.311 g, 68 %).1H NMR (500 MHz, DMSO-d6) 5 7.64 (t, J = 5.7 Hz, 1 H), 7.35 - 7.28 (m, 4H), 7.28 - 7.17 (m, 3H), 7.03 - 6.96 (m, 2H), 3.66 (dt, J = 11.7, 3.7 Hz, 2H), 3.32 (m, 2H), 3.24 (q, J = 6.6 Hz, 2H), 2.62 (t, J = 6.8 Hz, 2H), 2.38 (d, J = 13.1 Hz, 2H), 1.76 (ddd, J = 14.3, 10.9, 4.1 Hz, 2H). HRMS ESI (+) Calc’d for [M+H] = 344.1413, found = 344.1426.

[0152] N-[(4-chlorophenyl)methyl]-4-phenyloxane-4-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 4-phenyl- tetrahydro-2H-pyran-4-carboxylic acid (0.142 g, 0.680 mmol), N,N- dimethylformamide (0.500 mL), and triethylamine (0.101 g, 1.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.304 g, 0.80 mmol) was added as a solid and the vessel was resealed and flushed with argon. (4- chlorophenyl)methanamine (0.141 g, 1.00 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This material was triturated from ethyl acetate and hexanes to yield the final product yield the final product (0.123 g, 55 %).1H NMR (500 MHz, Chloroform-d) 5 7.42 - 7.33 (m, 4H), 7.33 - 7.28 (m, 1 H), 7.22 - 7.17 (m, 2H), 6.97 - 6.89 (m, 2H), 5.49 (s, 1 H), 4.32 (d, J = 5.9 Hz, 2H), 3.79 (dd, J = 6.6, 3.9 Hz, 4H), 2.47 - 2.36 (m, 2H), 2.17 - 2.07 (m, 2H). HRMS ESI (+) Calc’d for [M+H] = 330.1257, found = 330.1265.

[0153] N-[3-(4-chlorophenyl)propyl]-4-phenyloxane-4-carboxamide.To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 4-phenyl- tetrahydro-2H-pyran-4-carboxylic acid (0.206 g, 1 .00 mmol), N,N- dimethylformamide (1 .00 mL), and triethylamine (0.151 g, 1.50 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- bjpyridinium 3-oxid hexafluorophosphate (0.456 g, 1 .20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 3-(4- Chlorophenyl)propan-1 -amine (0.220 g, 1.30 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo. This material was further purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.143 g, 40 %).1H NMR (500 MHz, Chloroform-d) 5 7.42 - 7.33 (m, 4H), 7.32 - 7.28 (m, 1 H), 7.23 - 7.18 (m, 2H), 6.98 - 6.92 (m, 2H), 5.14 (s, 1 H), 3.83 - 3.71 (m, 4H), 3.17 (td, J = 6.9, 5.9 Hz, 2H), 2.44 - 2.31 (m, 4H), 2.07 (ddd, J = 13.3, 7.6, 4.9 Hz, 2H), 1 .65 (dtd, J = 9.0, 7.4, 6.5 Hz, 2H). HRMS ESI (+) Calc’d for [M+H] = 358.1570, found = 358.1575.

[0154] N-[3-(4-chlorophenyl)propyl]-4-phenyloxane-4-carboxamide.To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 4-phenyl- tetrahydro-2H-pyran-4-carboxylic acid (0.274 g, 1 .33 mmol), N,N- dimethylformamide (4.00 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.551 g, 1 .45 mmol) was added as a solid and the vessel was resealed and flushed with argon. 3,4- Dichlorophenyl)ethylamine (0.233 g, 1.50 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This material was triturated from ethyl acetate and hexanes to yield the final product (0.126 g, 33 %).1H NMR (500 MHz, Chloroform-d) 5 7.40 - 7.33 (m, 2H), 7.33 - 7.25 (m, 4H), 7.22 (d, J = 8.1 Hz, 1 H), 7.04 (d, J = 2.1 Hz, 1 H), 6.66 (dd, J = 8.2, 2.1 Hz, 1 H), 5.1 1 (s, 1 H), 3.79 - 3.68 (m, 4H), 3.40 (q, J = 6.4 Hz, 2H), 2.61 (t, J = 6.6 Hz, 2H), 2.40 - 2.29 (m, 2H), 2.05 (ddd, J = 13.1 , 7.8, 4.3 Hz, 2H). HRMS ESI (+) Calc’d for [M+H] = 378.1023, found = 378.1028.

[0155] N-[2-(4-chlorophenyl)ethyl]-1 -phenylcyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -phenylcyclohexane-1 -carboxylic acid (0.408 g, 2.00 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.836 g, 2.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Chlorophenyl)ethanamine (0.373 g, 2.40 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This material was further purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.413 g, 40 %).1H NMR (500 MHz, Chloroform-d) 6 7.38 - 7.31 (m, 4H), 7.30 - 7.24 (m, 1 H), 7.16 - 7.11 (m, 2H), 6.83 - 6.77 (m, 2H), 5.16 (t, J = 5.9 Hz, 1 H), 3.37 (q, J = 6.4 Hz, 2H), 2.60 (t, J = 6.6 Hz, 2H), 2.20 (ddd, J = 12.4, 8.3, 3.4 Hz, 2H), 1 .95 (ddd, J = 12.5, 8.4, 3.1 Hz, 2H), 1 .63 - 1 .33 (m, 6H). HRMS ESI (+) Calc’d for [M+H] = 342.1620, found = 342.1631 .

[0156] N-[2-(4-chlorophenyl)ethyl]-N-methyl-4-phenyloxane-4- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 4-phenyltetrahydro-2H-pyran-4-carboxylic acid (0.206 g, 1.00 mmol), N,N-dimethylformamide (2.00 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)-methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.456 g, 1 .20 mmol) was added as a solid and the vessel was resealed and flushed with argon. A / -Methyl-4- Chlorophenyl)ethanamine (0.273 g, 1 .40 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This material was further purified by silica gel chromatography with 0 - 100 % ethyl acetate in hexanes and fractions containing product were combined and concentrated in vacuo to yield the final product (0.090 g, 25 %).1H NMR (500 MHz, DMSO-d6) 6 7.42 - 7.12 (m, 8H), 6.74 (s, 1 H), 3.68 (dt, J = 12.0, 3.6 Hz, 2H), 3.49 (br s, 3H), 2.79 (d, J = 58.5 Hz, 2H), 2.38 (s, 2H), 2.14 - 2.05 (m, 2H), 1 .90 - 1 .79 (m, 2H). HRMS ESI (+) Calc’d for [M+H] =358.1570, found = 358.1581 .

[0157] N-[2-(3,4-dichlorophenyl)ethyl]-1 -phenylcyclohexane-1 - carboxamide.. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -phenylcyclohexane-1 -carboxylic acid (0.204 g, 1.00 mmol), N,N- dimethylformamide (1 .00 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1 .10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 3,4- Dichlorophenylethanamine (0.247 g, 1 .30 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed withbrine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This material was further purified by silica gel chromatography with 0 - 100 % ethyl acetate in hexanes and fractions containing product were combined and concentrated in vacuo to yield the final product (0.210 g, 56 %).1H NMR (500 MHz, Chloroform-d) 5 7.37 - 7.31 (m, 3H), 7.30 - 7.25 (m, 2H), 7.23 (d, J = 8.2 Hz, 1 H), 7.06 (d, J = 2.1 Hz, 1 H), 6.70 (dd, J = 8.2, 2.1 Hz, 1 H), 5.13 (s, 1 H), 3.41 - 3.32 (m, 2H), 2.61 (t, J = 6.6 Hz, 2H), 2.20 (ddd, J = 12.5, 8.4, 3.4 Hz, 2H), 1 .97 (t, J = 10.6 Hz, 2H), 1.63 - 1.35 (m, 6H). HRMS ESI (+) Calc’d for [M+H] = 376.1231 , found = 376.1241 .

[0158] N-[2-(4-chlorophenyl)ethyl]-1 -methylcyclohexane-1 - carboxamide.. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methylcyclohexyl-1 -carboxylic acid (0.284 g, 2.00 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.836 g, 2.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Chlorophenyl)ethylamine (0.373 g, 2.40 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.145 g, 26 %).1H NMR (500 MHz, Chloroform-d) 5 7.32 - 7.25 (m, 2H), 7.16 - 7.1 1 (m, 2H), 5.62 (s, 1 H), 3.50 (td, J = 6.9, 5.8 Hz, 2H), 2.80 (t, J = 6.9 Hz,2H), 1 .86 - 1.77 (m, 2H), 1 .55 - 1 .42 (m, 3H), 1.31 (dtd, J = 32.1 , 10.9, 9.2, 3.2 Hz, 5H), 1 .08 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 280.1464, found = 280.1474.

[0159] 1-methyl-N-(2-phenylethyl)cyclohexane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 - methylcyclohexyl-1 -carboxylic acid (0.426 g, 3.00 mmol), N,N-dimethylformamide (4.00 mL), and triethylamine (0.606 g, 6.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1 .21 g, 3.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-Phenylethylamine (0.412 g, 3.40 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.569 g, 72 %).1H NMR (500 MHz, Chloroform-d) 0 7.36 - 7.11 (m, 5H), 5.63 (s, 1 H), 3.53 (td, J = 6.8, 5.7 Hz, 2H), 2.83 (t, J = 6.9 Hz, 2H), 1 .88 - 1 .77 (m, 2H), 1 .57 - 1 .22 (m, 8H), 1 .08 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 264.1854, found = 246.1825.

[0160] N-(2,3-dihydro-1 H-inden-2-yl)-1 -methylcyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methylcyclohexyl-1 -carboxylic acid (0.255 g, 1 .80 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.722 g, 1 .90 mmol) was added as asolid and the vessel was resealed and flushed with argon. 2-Aminoindan (0.266 g, 2.00 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the final product (0.215 g, 47 %).1H NMR (500 MHz, DMSO-d6) 6 7.59 (d, J = 7.2 Hz, 1 H), 7.18 (dd, J = 5.4, 3.3 Hz, 2H), 7.16 - 7.10 (m, 2H), 4.58 - 4.46 (m, 1 H), 3.12 (dd, J = 15.8, 8.0 Hz, 2H), 2.81 (dd, J = 15.9, 7.1 Hz, 2H), 1.94 (dd, J = 13.2, 5.9 Hz, 2H), 1 .51 - 1 .37 (m, 3H), 1 .36 - 1 .10 (m, 5H), 1 .03 (s, 3H). HRMS ESI (-) Calc’d for [M-H] = 256.1706, found = 256.1698.

[0161] 3-(4-chlorophenyl)-N-(1 -methylcyclohexyl)propenamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 3-(4- chlorophenyl)propanoic acid (0.184 g, 1.00 mmol), N,N-dimethylformamide (3.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.437 g, 1 .15 mmol) was added as a solid and the vessel was resealed and flushed with argon. The septum was removed and 1 - methylcyclohexan-1 -amine hydrochloric acid salt (0.194 g, 1 .30 mmol) was added as a solid. The reaction vessel was sealed, flushed with argon, stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate,washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo.This material was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane to yield the final product (0.110 g, 39 %).1H NMR (500 MHz, dmso) 5 7.34 - 7.27 (m, 2H), 7.21 (d, J = 8.3 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 2.34 (t, J = 7.6 Hz, 2H), 2.00 - 1 .90 (m, 2H), 1 .48 - 1 .06 (m, 1 1 H). HRMS ESI (+) Calc’d for [M+H] = 280.1464, found = 280.1469.

[0162] 3-(3,4-dichlorophenyl)-N-(1 -methylcyclohexyl)propenamide.To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 3-(3,4- dichlorophenyl)propanoic acid (0.219 g, 1 .00 mmol), N,N-dimethylformamide (3.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.437 g, 1 .15 mmol) was added as a solid and the vessel was resealed and flushed with argon. The septum was removed and 1 - methylcyclohexan-1 -amine hydrochloric acid salt (0.194 g, 1 .30 mmol) was added as a solid. The reaction vessel was sealed, flushed with argon, stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo o yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. This material was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane to yield the final product (0.1 10 g, 39 %).1H NMR (500 MHz, dmso) 0 7.54 - 7.43 (m, 2H), 7.19 (dd, J = 8.3, 2.1 Hz, 1 H), 2.77 (t, J = 7.4 Hz, 2H), 2.36 (t, J = 7.4 Hz, 2H), 1 .94 (d, J = 12.5 Hz, 2H), 1 .44 - 1 .04 (m, 1 1 H). HRMS d = 314.1074.

[0163] 2-Chloro- / V-cyclohexylacetamide To a 250 mL round bottom flask with a stir bar was added 2-Chloroacetyl chloride (1 .69 g, 15.0 mmol), dichloromethane (90.0 mL), the reaction vessel sealed with a septum, flushed with argon, cooled to 0 °C in an ice bath and cyclohexylamine (3.17 g, 32.0 mmol) was added via syringe as a solution dissolved in dichloromethane (10.0 mL). The reaction was stirred for 20 hours, warming to room temperature, at which time it was transferred to a separatory funnel and washed with 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. This material was further purified by filtering it through a plug of silica (eluting with dichloromethane) and the filtrate was concentrated in vacuo io yield the final product (2.00 g, 76 %)1H NMR (500 MHz, dmso) 5 8.05 (d, J = 7.8 Hz, 1 H), 3.98 (s, 2H), 3.50 (tdt, J= 1 1 .1 , 7.7, 3.9 Hz, 1 H), 1 .76 - 1 .60 (m, 4H), 1.59 - 1 .49 (m, 1 H), 1 .30 - 1 .03 (m, 5H).

[0164] 2-(4-Chlorophenoxy)-N-cyclohexylacetamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was 4-chlorophenol (0.514 g, 4.00 mmol). The reaction vessel was sealed, flushed with argon, tetrahydrofuran (10.0 mL) was added and the reaction mixture was cooled to 0 °C in an ice bath. The septum was removed and sodium hydride (0.151 g, 4.50 mmol) was added as a solid. The septum was replaced and the reaction vessel was flushed with argon. Once hydrogen gas stopped evolving 2-chloro- / \ / -cyclohexylacetamide (0.526, 3.00 mmol) was added as a solution in tetrahydrofuran (2.00 mL), and the reaction vessel was heated to 45 °C for 20 hours. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane to yield the final product (0.331 g, 42 %).1H NMR (500 MHz, DMSO-d6) 5 7.88 (d, J = 8.1 Hz, 1 H), 7.36 - 7.29 (m, 2H), 7.01 - 6.90 (m, 2H), 4.43 (s, 2H), 3.58 (d, J = 8.1 Hz, 1 H), 1 .73 - 1 .62 (m, 4H), 1.54 (d, J = 12.7 Hz, 1 H), 1 .31 - 1 .17 (m, 4H), 1 .08 (t, J = 6.1 Hz, 1 H). HRMS ESI (+) Calc’d for [M+H] = 268.1100, found = 268.1124.

[0165] 3-(2,4-difluorophenyl)-N-(1 -methylcyclohexyl)propenamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 3-(2,4- difluorophenyl)propanoic acid (0.204 g, 1.10 mmol), N,N-dimethylformamide (3.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.456 g, 1 .20 mmol) was added as a solid and the vessel was resealed and flushed with argon. The septum was removed and 1 - Methylcyclohexan-1 -amine hydrochloric acid salt (0.200 g, 1 .31 mmol) was added as a solid. The reaction vessel was sealed, flushed with argon, stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo o yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane to yield the final product (0.060 g, 19 %).1H NMR (500 MHz, DMSO-de) 5 7.30 (td, J = 8.7, 6.7 Hz, 1 H), 7.21 - 7.08 (m, 2H), 6.98 (tdd, J = 8.6, 2.6, 1 .0 Hz, 1 H), 2.75 (t, J = 7.6 Hz, 2H), 2.34 (dd, J = 8.2, 6.9 Hz, 2H), 2.02 - 1 .88 (m, 2H), 1 .37 (dq, J = 8.7, 4.4 Hz, 1 H), 1 .29 (tt, J = 9.2, 3.8 Hz, 4H), 1 .16 (s, 6H).19F NMR (470 MHz, DMSO-d6) 5 -1 13.64 (p, J = 7.5 Hz), - 1 14.33 (q, J = 8.7 Hz). HRMS ESI (+) Calc’d for [M+H] = 282.1665, found = 282.1672.

[0166] 3-(3,5-dichlorophenyl)-N-(1 -methylcyclohexyl)propenamide.To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 3-(3,5- dichlorophenyl)propanoic acid (0.241 g, 1 .10 mmol), N,N-dimethylformamide (3.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.456 g, 1 .20 mmol) was added as a solid and the vessel was resealed and flushed with argon. The septum was removed and 1 - Methylcyclohexan-1 -amine hydrochloric acid salt (0.200 g, 1 .31 mmol) was added as a solid. The reaction vessel was sealed, flushed with argon, stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueoushydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane to yield the final product (0.210 g, 61 %).1H NMR (500 MHz, dmso) 5 7.38 (t, J = 1 .9 Hz, 1 H), 7.27 (d, J = 2.0 Hz, 2H), 7.12 (s, 1 H), 2.79 (t, J = 7.2 Hz, 2H), 2.37 (t, J = 7.3 Hz, 2H), 1 .94 (dd, J = 11 .1 , 6.4 Hz, 2H), 1 .43 - 1 .20 (m, 5H), 1 .15 (s, 6H). HRMS ESI (+) Calc’d for [M+H] = 314.1074, found = 314.1088.

[0167] 3-(2,4-dichlorophenyl)-N-(1 -methylcyclohexyl)propanamideTo a 100 mL 24 / 40 round bottom flask containing a stir bar was added 3-(2,4- dichlorophenyl)propanoic acid (0.241 g, 1 .10 mmol), N,N-dimethylformamide (3.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.456 g, 1 .20 mmol) was added as a solid and the vessel was resealed and flushed with argon. The septum was removed, and 1 - methylcyclohexan-1 -amine hydrochloric acid salt (0.200 g, 1 .31 mmol) was added as a solid. The reaction vessel was sealed, flushed with argon, stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane to yield the final product (0.075 g, 22 %).1H NMR (500 MHz, DMSO-d6) 5 7.55 (t, J = 1.3 Hz, 1 H), 7.33 (d, J = 1 .3 Hz, 2H), 7.16 (s, 1 H), 2.85 (dd, J = 8.3, 6.9 Hz, 2H), 2.36 (dd, J = 8.3, 6.9 Hz, 2H), 1 .96 (d, J = 12.7 Hz, 2H), 1.46 - 1 .37 (m, 1 H), 1 .31 (dhept, J = 13.3, 3.8, 3.2 Hz, 4H), 1.17 (s, 6H). HRMS ESI (+) Calc’d for [M+H] = 314.1074, found = 314.1086.

[0168] 3-(3,5-difluorophenyl)-N-(1-methylcyclohexyl)propenamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 3-(3,5- difluorophenyl)propanoic acid (0.186 g, 1 .00 mmol), N,N-dimethylformamide (3.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1 .10 mmol) was added as a solid and the vessel was resealed and flushed with argon. The septum was removed and 1 - methylcyclohexan-1 -amine hydrochloric acid salt (0.179 g, 1 .20 mmol) was added as a solid. The reaction vessel was sealed, flushed with argon, stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo o yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane to yield the final product (0.127 g, 46 %).1H NMR (500 MHz, DMSO-d6) 5 7.11 (s, 1 H), 7.00 (tt, J = 9.4, 2.4 Hz, 1 H), 6.93 (qd, J = 6.2, 3.1 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 2.37 (t, J = 7.4 Hz, 2H), 1 .95 (d, J = 13.0 Hz, 2H), 1.43 - 1.35 (m, 1 H), 1.35 - 1.21 (m, 4H), 1.21 - 1.11 (m, 6H). 19F NMR (470 MHz, DMSO-d6) 5 -110.93 (t, J = 8.8 Hz). HRMS ESI (+) Calc’d for [M+H] = 282.1665, found = 282.1684. c

[0169] N-[2-(3,5-difluorophenyl)ethyl]-1 -methylcyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1-methylcyclohexyl-1 -carboxylic acid (0.113 g, 0.800 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.252 g, 2.50 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.342 g, 0.900 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(3,5- Difluorophenyl)ethylamine (0.180 g, 1.10 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined,concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo. This material was further purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.157 g, 70%).1H NMR (500 MHz, cdcl3) 5 6.77 - 6.62 (m, 3H), 5.66 (s, 1 H), 3.51 (td, J = 6.7, 5.7 Hz, 2H), 2.82 (t, J = 6.9 Hz, 2H), 1 .87 - 1 .78 (m, 2H), 1 .58 - 1 .40 (m, 3H), 1 .40 - 1 .22 (m, 5H), 1 .09 (s, 3H). 19F NMR (470 MHz, cdcl3) 0 -110.09 (t, J = 8.2 Hz). HRMS ESI (+) Calc’d for [M+H] = 282.1665, found = 282.1674.

[0170] N-[2-(3,5-dichlorophenyl)ethyl]-1 -methylcyclohexane-1 - carboxamide.. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1-methylcyclohexyl-1 -carboxylic acid (0.227 g, 1.60 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.684 g, 1.80 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(3,5- Dichlorophenyl)ethylamine (0.380 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo. This material was further purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.362 g, 73 %).1H NMR (500 MHz, cdcl3) 5 7.21 (t, J = 1 .9 Hz, 1 H), 7.07 (d, J = 1 .9 Hz, 2H), 5.72 (t, J = 6.1 Hz, 1 H), 3.47 (td, J = 6.8, 5.9 Hz, 2H), 2.79 (t, J = 6.9 Hz, 2H), 1 .88 - 1 .78(m, 2H), 1 .59 - 1 .41 (m, 3H), 1.41 - 1 .23 (m, 5H), 1 .09 (s, 3H). HRMS ESI (+) 336.0898, found = 336.0899.

[0171] N,N-di(propan-2-yl)-3-(1 ,3,5-trimethyl-1 H-pyrazol-4- yl)propenamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 3-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)propanoic acid (0.182 g, 1 .00 mmol), N,N-dimethylformamide (2.50 mL), and triethylamine (0.120 g, 1 .20 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1 .10 mmol) was added as a solid and the vessel was resealed and flushed with argon. Diisopropylamine (0.202 g, 2.00 mmol) was added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield the final product (0.098 g, 37 %).1H NMR (500 MHz, cdcl3) 5 3.88 (p, J = 6.8 Hz, 1 H), 3.71 (s, 3H), 3.57 (s, 1 H), 2.73 - 2.62 (m, 2H), 2.41 - 2.35 (m, 2H), 2.20 (s, 3H), 2.18 (s, 3H), 1 .38 (d, J = 6.8 Hz, 6H), 1 .13 (d, J = 6.7 Hz, 6H). HRMS ESI (+) Calc’d for [M+H] = 266.2228, found = 266.2236.

[0172] 3-(1 ,3,5-Trimethyl-1 H-pyrazol-4-yl)propanoic acid. To a 100 mL24 / 40 round bottom flask was added a stir bar, ethanol (15.0 mL) and (2E)-3- (1 ,3,5-trimethyl-1 H-pyrazol-4-yl)prop-2-enoic acid (0.410 g, 2.20 mmol) and 10 %palladium on carbon (0.1 13 g). The reaction vessel was sealed with a septum, evacuated and backfilled 3 times with hydrogen gas. The reaction mixture was stirred for 1 hour, filtered through celite and concentrated in vacuo to yield the product (0.395 g, 99 %).1H NMR (500 MHz, dmso) 5 12.06 (s, 1 H), 3.56 (s, 3H), 2.52 - 2.46 (m, 2H), 2.26 (dd, J = 8.1 , 7.1 Hz, 2H), 2.09 (s, 3H), 2.00 (s, 3H).

[0173] (2E)-3-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)prop-2-enoic acid. To a 100 mL 24 / 40 round bottom flask was added a stir bar and ethyl (2E)-3-(1 ,3,5- trimethyl-1 H-pyrazol-4-yl)prop-2-enoate (1 .13 g, 5.42 mmol), water (5.00 mL), ethanol (25.0 mL), and sodium hydroxide (0.278 g, 7.00 mmol). The reaction mixture was heated to 60 °C for 22 hours, cooled to 0 °C and hydrochloric acid (8.00 mmol as 2.00 mL of a 4.00 M solution of hydrochloric acid in 1 ,4-dioxane) was added. The reaction mixture was concentrated to a minimum volume and purified by reverse phase Medium Pressure Chromoatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined and lyophilized to yield the pure product (0.410 g, 42 %).1H NMR (500 MHz, dmso-de) 5 7.43 (d, J= 16.1 Hz, 1 H), 5.90 (d, J = 16.1 Hz, 1 H), 3.65 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H).

[0174] Ethyl (2E)-3-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)prop-2-enoate. To a 250 mL round bottom flask containing a stir bar was added triethyl phosphonoacetate (2.01 g, 9.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, tetrahydrofuran (20.0 mL) was added and the reaction vessel was cooled to 0 °C in an ice bath. The septum was removed and sodium hydride (0.319 g, 9.50 mmol) was added as a solid. The septum was replaced, the reaction vessel was flushed with argon and once gas had stopped evolving, 1 ,3,5- trimethyl-1 H-pyrazole-4-carbaldehyde (1 .10 g, 7.50 mmol) was added as a solution dissolved in tetrahydrofuran (5.00 mL). The reaction was stirred for 48hours, warming to room temperature, at which time it was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by silica gel chromatography with 0 - 100 % ethyl acetate in hexanes. Fractions containing product were combined concentrated in vacuo to yield the final product (1.13 g, 72 %).1H NMR (500 MHz, cdcl3) 6 7.59 (d, J = 16.1 Hz, 1 H), 6.04 (d, J = 16.1 Hz, 1 H), 4.24 (q, J= 7.1 Hz, 2H), 3.73 (s, 4H), 2.34 (d, J= 7.3 Hz, 6H), 1 .32 (t, J= 7.1

[0175] N-[2-(3,4-dimethylphenyl)ethyl]-1-methylcyclohexane-1- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cyclohexane carboxylic acid (0.227 g, 1.60 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.684 g, 1.80 mmol) was added as a solid and the vessel was resealed and flushed with argon. 3,4- Dimethylphenylethylamine (0.298 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to yield the final product (0.333 g, 76 %)1H NMR (500 MHz, cdcl3) 57.07 (d, J = 7.6 Hz, 1 H), 6.97 (d, J = 1 .8 Hz, 1 H), 6.93 (dd, J = 7.6, 1 .9 Hz, 1 H), 5.65 (s, 1 H), 3.50 (td, J = 6.9, 5.7 Hz, 2H), 2.75 (t, J = 6.9 Hz, 2H), 2.24 (d, J = 1 .2 Hz, 6H), 1 .89 - 1 .80 (m, 2H), 1 .53 - 1 .23 (m, 8H), 1 .09 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 274.2167, found = 274.2177.

[0176] N-[2-(3,4-dichlorophenyl)ethyl]-1 -methylcyclohexane-1 - carboxamide.. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cyclohexane carboxylic acid (0.380 g, 2.00 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.684 g, 1.80 mmol) was added as a solid and the vessel was resealed and flushed with argon. 3,4- Dichlorophenylethylamine (0.298 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to yield the final product (0.41 5, 76 %)1H NMR (500 MHz, CDCI3) 0 7.37 (d, J = 8.2 Hz, 1 H), 7.29 (d, J = 2.1 Hz, 1 H), 7.04 (dd, J = 8.2, 2.1 Hz, 1 H), 5.66 (s, 1 H), 3.50 (td, J = 6.9, 5.9 Hz, 2H), 2.80 (t, J = 6.9 Hz, 2H), 1 .90 - 1 .78 (m, 2H), 1 .58 - 1 .41 (m, 3H), 1.41 - 1.23 (m, 5H), 1.10 (s, 3H). HRMS ESI (+) Calc’d for [M+Na] = 336.0898, found = 336.0860.

[0177] N-[2-(2,4-Difluorophenyl)ethyl]-1 -methylcyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cyclohexane carboxylic acid (0.247 g, 1.70 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.684 g, 1 .80 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2,4- Difluorophenylethylamine (0.314 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.138 g, 29 %).1H NMR (500 MHz, cdcl3) 6 7.16 (td, J = 8.4, 6.4 Hz, 1 H), 6.87 - 6.76 (m, 2H), 5.70 (s, 1 H), 3.50 (td, J = 6.8, 5.8 Hz, 2H), 2.89 - 2.80 (m, 2H), 1 .87 - 1 .78 (m, 2H), 1 .56 - 1 .47 (m, 2H), 1 .47 - 1 .40 (m, 1 H), 1 .40 - 1 .23 (m, 5H), 1 .08 (s, 3H). 19F NMR (470 MHz, cdch) 5 -1 12.54 (p, J = 7.7 Hz), -1 14.23 (q, J = 8.5 Hz). HRMS ESI (+) Calc’d for [M+H] = 282.1665. found = 282.1676.

[0178] N-[2-(2,4-Dichlorophenyl)ethyl]-1-methylcyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cyclohexane carboxylic acid (0.247 g, 1 .70 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.684 g, 1 .80 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2,4- Dichlorophenylethylamine (0.380 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.100 g, 19 %).1H NMR (500 MHz, cdch) 6 7.38 (d, J = 1 .9 Hz, 1 H), 7.22 - 7.14 (m, 2H), 5.71 (s, 1 H), 3.53 (td, J = 6.9, 5.8 Hz, 2H), 2.95 (t, J = 6.9 Hz, 2H),1.88 - 1 .78 (m, 2H), 1 .57 - 1 .48 (m, 2H), 1 .48 - 1 .41 (m, 1 H), 1.41 - 1 .27 (m, 5H), 1 .10 (s, 3H). HRMS ESI (+) Calc’d for [M+Na] = 336.0898, found = 336.0905.

[0179] N-[2-(3-Fluorophenyl)ethyl]-1-methylcyclohexane-1- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cyclohexane carboxylic acid (0.247 g, 1.70 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.684 g, 1.80 mmol) was added as a solid and the vessel was resealed and flushed with argon. 3- Fluorophenylethylamine (0.278 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.100 g, 19 %).1H NMR (500 MHz, cdch) 6 7.27 (td, J = 7.7, 6.1 Hz, 1 H), 6.98 (dt, J = 7.8, 1.1 Hz, 1 H), 6.92 (ddt, J = 13.7, 7.7, 2.4 Hz, 2H), 5.64 (s, 1 H), 3.53 (td, J = 6.8, 5.8 Hz, 2H), 2.83 (t, J = 6.8 Hz, 2H), 1 .88 - 1 .77 (m, 2H), 1 .56 - 1 .47 (m, 2H), 1 .44 (q, J = 5.4 Hz, 1 H), 1.41 - 1 .23 (m, 5H), 1 .09 (s, 3H). 19F NMR (470 MHz, cdcl3) 5 -112.54 (p, J = 7.3 Hz), -113.29 - -113.36 (m), -114.23 (q, J = 8.7 Hz). HRMS ESI (+) Calc’d for [M+H] = 264.1759, found = 264.1768.

[0180] 1 -methyl-N-{2-[3-(trifluoromethyl)phenyl]ethyl]cyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cyclohexane carboxylic acid (0.247 g, 1.70 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). Thereaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.684 g, 1 .80 mmol) was added as a solid and the vessel was resealed and flushed with argon. 3- (Trifluoromethyl)phenylethylamine (0.378 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.245 g, 46 %).1H NMR (500 MHz, cdcb) 6 7.50 (dt, J = 7.4, 1 .9 Hz, 1 H), 7.47 - 7.36 (m, 3H), 5.65 (s, 1 H), 3.55 (td, J = 6.9, 5.9 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H), 1 .88 - 1 .78 (m, 2H), 1 .57 - 1 .47 (m, 2H), 1 .44 (d, J = 6.6 Hz, 1 H), 1 .39 - 1 .22 (m, 5H), 1 .09 (s, 3H).19F NMR (470 MHz, cdcl3) 5 -62.64. HRMS ESI (+) Calc’d for [M+H] = 314.1727, found = 314.1748.

[0181] N-[2-(3-Chlorophenyl)ethyl]-1-methylcyclohexane-1- carboxamide, To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cyclohexane carboxylic acid (0.247 g, 1 .70 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.684 g, 1 .80 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(3- Chlorophenyl)ethylamine (0.311 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractionscontaining product were combined and concentrated in vacuo to yield the final product (0.069 g, 15 %).1H NMR (500 MHz, cdch) 6 7.25 - 7.17 (m, 3H), 7.08 (dt, J = 7.1 , 1 .6 Hz, 1 H), 5.63 (s, 1 H), 3.51 (td, J = 6.8, 5.9 Hz, 2H), 2.81 (t, J = 6.9 Hz, 2H), 1 .86 - 1 .78 (m, 2H), 1 .51 (dt, J = 12.8, 4.9 Hz, 2H), 1 .45 (q, J = 5.6 Hz, 1 H), 1 .41 - 1.24 (m, 5H), 1.09 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 280.1461 . found =280.1472.

[0182] 1 -Methyl-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cyclohexane carboxylic acid (0.247 g, 1 .70 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.684 g, 1 .80 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylpheny)lethylamine (0.378 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.035 g, 6 %).1H NMR (500 MHz, cdcl3) 5 7.61 - 7.53 (m, 2H), 7.36 - 7.29 (m, 2H), 5.66 (s, 1 H), 3.55 (td, J = 7.0, 5.9 Hz, 2H), 2.90 (t, J = 7.0 Hz, 2H), 1 .88 - 1 .76 (m, 2H), 1 .56 - 1 .45 (m, 2H), 1 .45 - 1 .39 (m, 1 H), 1 .39 - 1 .23 (m, 5H), 1 .09 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 314.1727, found = 314.1736.

[0183] 4-Methyl-N-{2-[4-(trifluoromethyl)phenyl]ethyl}oxane-4- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 4-methyltetrahydro-2H-pyran-4-carboxylic acid (0.378 g, 1 .50 mmol), N,N-dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)-methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.646 g, 1 .70 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylpheny)lethylamine (0.378 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.353 g, 75 %).1H NMR (500 MHz, cdc ) 6 7.50 (d, J = 7.7 Hz, 1 H), 7.47 - 7.42 (m, 2H), 7.39 (d, J = 7.6 Hz, 1 H), 5.55 (s, 1 H), 3.70 (ddd, J = 1 1 .7, 6.1 , 3.7 Hz, 2H), 3.62 - 3.50 (m, 4H), 2.91 (t, J = 6.9 Hz, 2H), 1 .90 (dt, J = 15.2, 4.6 Hz, 2H), 1.48 (ddd, J = 13.1 , 8.4, 3.7 Hz, 2H), 1 .17 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 316.1520, observed = 316.1535.

[0184] N-[2-(4-Methoxyphenyl)ethyl]-1 -methylcyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methylcyclohexyl-1 -carboxylic acid (0.213 g, 1 .50 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.646 g, 1 .70 mmol) was added as a solid and the vessel was resealed and flushed with argon. 4- (Methoxyphenyl)ethylamine (0.302 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractionscontaining product were combined and concentrated in vacuo to yield the final product (0.217 g, 53 %).1H NMR (500 MHz, cdch) 5 7.18 - 7.06 (m, 2H), 6.91 - 6.80 (m, 2H), 5.62 (s, 1 H), 3.79 (s, 3H), 3.49 (td, J = 6.9, 5.7 Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H), 1 .86 - 1 .76 (m, 2H), 1 .54 - 1 .46 (m, 2H), 1 .42 (dt, J = 10.5, 6.8 Hz, 1 H), 1 .40 - 1 .24 (m, 5H), 1 .08 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 276.1959, observed = 276.1969.

[0185] 1 -Methyl-N-{2-[4-(trifluoromethoxy)phenyl]ethyl]cyclohexane-1 -carboxamide. To a 100 ml_ 24 / 40 round bottom flask containing a stir bar was added 1-Methylcyclohexyl-1 -carboxylic acid (0.213 g, 1.50 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.646 g, 1.70 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-[4- (Trifluoromethoxy)phenyl]ethylamine (0.410 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.241 g, 49 %).1H NMR (500 MHz, cdch) 6 7.24 - 7.19 (m, 2H), 7.17 - 7.13 (m, 2H), 5.63 (s, 1 H), 3.53 (td, J = 7.0, 5.9 Hz, 2H), 2.84 (t, J = 6.9 Hz, 2H), 1.85 - 1 .77 (m, 2H), 1 .54 - 1 .46 (m, 2H), 1 .43 (q, J = 6.8 Hz, 1 H), 1 .37 - 1 .24 (m, 5H), 1.08 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 330.1677, observed = 330.1685.

[0186] 1 -Methyl-N-[2-(4-methylphenyl)ethyl]cyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar wasadded 1-methylcyclohexyl-1 -carboxylic acid (0.255 g, 1.80 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.505 g, 5.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.760 g, 2.00 mmol) was added as a solid and the vessel was resealed and flushed with argon. 4- (Methylphenyl)ethylamine (0.279 g, 2.20 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.282 g, 60 %).1H NMR (500 MHz, cdc ) 5 7.10 (q, J = 8.1 Hz, 4H), 5.65 (s, 1 H), 3.50 (td, J = 6.9, 5.7 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), 2.32 (s, 3H), 1 .89 - 1 .74 (m, 2H), 1 .54 - 1 .40 (m, 3H), 1 .40 - 1 .20 (m, 5H), 1 .08 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 260.2010, observed = 260.2018.

[0187] N-[2-(4-Bromophenyl)ethyl]-1-methylcyclohexane-1- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1-methylcyclohexyl-1 -carboxylic acid (0.255 g, 1.80 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.505 g, 5.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.760 g, 2.00 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Bromophenyl)ethylamine (0.440 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractionscontaining product were combined and concentrated in vacuo to yield the material which was recrystallized from dichlorohexane and hexanes to yield the final product (0.149 g, 31 %).1H NMR (500 MHz, cdcl3) 5 7.46 - 7.40 (m, 2H), 7.13 - 7.03 (m, 2H), 5.63 (s, 1 H), 3.50 (td, J = 6.9, 5.8 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), 1.87 - 1 .76 (m, 2H), 1 .51 (ddd, J = 12.2, 6.8, 3.4 Hz, 2H), 1 .43 (d, J = 7.4 Hz, 1 H), 1.39 - 1.22 (m, 5H), 1.08 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 324.0959, observed = 324.0976.

[0188] N-[2-(4-tert-butylphenyl)ethyl]-1 -methylcyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1-methylcyclohexyl-1 -carboxylic acid (0.284 g, 2.00 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.505 g, 5.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.836 g, 2.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-tert- butylphenyl)ethylamine (0.410 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.404 g, 67 %).1H NMR (500 MHz, cdcl3) 5 7.37 - 7.31 (m, 2H), 7.16 - 7.11 (m, 2H), 5.64 (s, 1 H), 3.53 (td, J = 6.9, 5.7 Hz, 2H), 2.80 (t, J = 6.9 Hz, 2H), 1 .82 (dd, J = 12.7, 6.9 Hz, 2H), 1 .54 - 1 .39 (m, 3H), 1 .31 (s, 14H), 1 .08 (s, 3H). 0, observed = 302.2493.

[0189] N-[2-(4-brornophenyl)ethyl]-1-methylcyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methylcyclohexyl-1 -carboxylic acid (0.298 g, 2.10 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.760 g, 2.00 mmol) was added as a solid and the vessel was resealed and flushed with argon. 4-(2- Aminoethyl)pyridine (0.268 g, 2.20 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo io yield the final product (0.345 g, 70 %).1H NMR (500 MHz, cdch) 5 8.59 - 8.49 (m, 2H), 7.20 - 7.09 (m, 2H), 5.68 (s, 1 H), 3.56 (td, J = 6.9, 5.9 Hz, 2H), 2.86 (t, J = 6.9 Hz, 2H), 1 .86 - 1 .77 (m, 2H), 1 .55 - 1 .47 (m, 2H), 1 .44 (t, J = 6.3 Hz, 1 H), 1 .40 - 1 .24 (m, 5H), 1 .09 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 247.1806, observed = 247.1817.

[0190] 1-Methyl-N-[2-(pyridin-4-yl)ethyl]cyclohexane-1 -carboxamide.To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 - methylcyclohexyl-1 -carboxylic acid (0.298 g, 2.10 mmol), N,N-dimethylformamide (3.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.760 g, 2.00 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(2-Pyridyl)ethanamine (0.268 g, 2.20 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gelchromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.366 g, 73 %).1H NMR (500 MHz, cdcl3) 0 8.53 (ddd, J = 5.0, 1 .9, 0.9 Hz, 1 H), 7.63 (td, J = 7.6, 1 .8 Hz, 1 H), 7.22 - 7.14 (m, 2H), 6.83 (s, 1 H), 3.71 - 3.63 (m, 2H), 3.05 - 2.97 (m, 2H), 1 .88 (td, J = 7.8, 3.7 Hz, 2H), 1 .53 - 1 .45 (m, 2H), 1 .42 (q, J = 5.7 Hz, 1 H), 1 .38 - 1 .20 (m, 5H), 1 .08 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 247.1806, observed = 247.1808.

[0191] N-[2-(4-Chlorophenyl)ethyl]-4-methyloxane-4-carboxamide. To a 100 ml_ 24 / 40 round bottom flask containing a stir bar was added 4- methyltetrahydro-2H-pyran-4-carboxylic acid (0.259 g, 1.80 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)-methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.722 g, 1 .90 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Chlorophenyl)ethylamine (0.268 g, 2.20 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.380 g, 75 %).1H NMR (500 MHz, cdcl3) 6 7.31 - 7.25 (m, 2H), 7.16 - 7.07 (m, 2H), 5.54 (s, 1 H), 3.70 (ddd, J = 11 .7, 6.2, 3.7 Hz, 2H), 3.59 - 3.49 (m, 4H), 2.81 (t, J = 6.9 Hz, 2H), 1 .89 (dddd, J = 13.7, 5.8, 3.3, 1 .3 Hz, 2H), 1 .48 (ddd, J = 13.2, 8.4, 3.7 Hz, 2H), 1.17 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 282.1257, observed = 282.1262.

[0192] N-[2-(4-h lorophenyl)ethyl]-1 -(trif luoromethyl)cyclopentane-1 - carboxamide.. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentane carboxylic acid (0.200 g, 1 .09 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)-methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.475 g, 1 .25 mmol) was added as a solid and the vessel was resealed and flushed with argon. (4- Chlorophenyl)ethylamine (0.233 g, 1 .50 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.247 g, 71 %).1H NMR (500 MHz, cdch) 6 7.32 - 7.25 (m, 2H), 7.16 - 7.09 (m, 2H), 5.84 (s, 1 H), 3.54 (td, J = 6.9, 5.8 Hz, 2H), 2.81 (t, J = 6.9 Hz, 2H), 2.27 - 2.17 (m, 2H), 2.00 - 1 .91 (m, 2H), 1 .77 - 1 .61 (m, 4H). 19F NMR (470 MHz, cdcl3) 5 -70.28. 320.1025, observed = 320.1028.

[0193] N-[2-(4-Chlorophenyl)ethyl]-1-methylcyclobutane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cyclobutyl carboxylic acid (0.200 g, 1 .75 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.760 g, 2.00 mmol) was added as a solid and the vessel was resealed and flushed with argon. (4- Chlorophenyl)ethylamine (0.342 g, 2.20 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, andconcentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. This material was further purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to yield the final product (0.289 g, 66 %).1H NMR (500 MHz, cdch) 0 7.33 - 7.25 (m, 2H), 7.17 - 7.10 (m, 2H), 5.40 (s, 1 H), 3.49 (td, J = 6.9, 5.9 Hz, 2H), 2.80 (t, J = 6.9 Hz, 2H), 2.40 - 2.29 (m, 2H), 2.03 - 1 .89 (m, 1 H), 1 .83 - 1 .73 (m, 3H), 1.35 (s, 3H). HRMS ESI (+) Calc’d for [M+H] = 252.1151 , observed = 252.1157.

[0194] N-[2-(4-Chlorophenyl)ethyl]-1-methylcycloheptane-1- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cycloheptyl carboxylic acid (0.200 g, 1.28 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.532 g, 1.40 mmol) was added as a solid and the vessel was resealed and flushed with argon. (4- Chlorophenyl)ethylamine (0.249 g, 1.60 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. This material was further purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to yield the final product (0.147 g, 39 %).1H NMR (500 MHz, cdch) 5 7.30 - 7.24 (m, 3H), 7.14 - 7.09 (m, 2H), 5.57 (s, 1 H), 3.49 (td, J = 6.9, 5.8 Hz,2H), 2.79 (t, J = 6.9 Hz, 2H), 2.01 - 1 .88 (m, 2H), 1 .57 - 1 .44 (m, 8H), 1 .44 - 1 .35 (m, 2H), 1 .07 (s, 3H). HRMS ESI (+) Calc’d for [M+H] =294.1620, observed = 294.1632.

[0195] 1-Methyl-1 -cycloheptyl carboxylic acid. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cycloheptyl carboxylic acid methyl ester (1 .00 g, 5.88 mmol), methanol (25.0 mL), water (5.00 mL) and potassium hydroxide (0.690 g, 12.3 mmol). The reaction mixture was heated to 55 °C for 23 hours, cooled to room temperature diluted with ethyl acetate, transferred to a separatory funnel and washed with 1 .0 N aqueous hydrochloric acid, brine, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the product which was purified by filtration through a plug of silica using 2 % methanol in dichloromethane as an eluent. The filtrate was concentrated in vacuoto yield the product (0.594 g, 65 %).1H NMR (500 MHz, cdch) 5 2.15 - 2.03 (m, 2H), 1.62 - 1 .40 (m, 10H), 1 .20 (s, 3H).

[0196] 1-Methyl-1 -cycloheptyl carboxylic acid methyl ester. A 250 mL24 / 40 round bottom flask containing a stir bar was sealed with a septum, flushed with argon, tetrahydrofuran (40.0 mL) was added and the reaction vessel was cooled to - 78 °C in a dry ice / acetone bath. Diisopropylamine (5.05 g, 50.0 mmol) was added by syringe, followed by n-butyllithium (19.5 mL of 2.5 M solution in hexanes, 48.75 mmol). The reaction mixture was stirred for 10 minutes and cycloheptane carboxylate methyl ester (1 .56 g, 10.0 mmol) was added as a solution dissolved in tetrahydrofuran (2.00 mL). The reaction mixture was stirred for 1 hour at - 78 °C and methyl iodide (8.51 g, 60.0 mmol) was added by syringe. The reaction mixture was stirred for 22 hours, warming to room temperature, quenched with methanol (5.00 mL), concentrated in vacuo, partitioned between ethyl acetate and brine, washed with 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine and concentrated in vacuo to yield a product that was purified by silica gel chromatography with 0 - 100 % ethyl acetate inhexanes (1.124 g, 100 %).1H NMR (500 MHz, cdcl3) 6 3.66 (s, 3H), 2.10 - 2.02 1.51 (p, J= 3.6 Hz, 8H), 1.47 - 1.41 (m, 2H), 1.15 (s, 3H).

[0197] Cycloheptane carboxylic acid methyl ester. To a 100 mL 24 / 40 round bottom flask was added cycloheltane carboxylic acid (1 .56 g, 10.0 mmol), methanol (50.0 mL) and sulfuric acid (1 drop from a pipet). The reaction mixture was heated to 60 °C for 24 hours, cooled to room temperature and concentrated in vacuo to ~ 5.00 mL volume, partitioned between ethyl acetate and saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the product (1 .60 g. 96 % yield) which was used in the next step with no further purification.1H NMR (500 MHz, cdch) 5 3.66 (s, 3H), 2.49 (td, J= 9.6, 4.7 Hz, 1 H), 1 .92 (ddd, J= 14.5, 7.2, 3.7 Hz, 2H), 1 .77 - 1 .61 (m, 4H), 1.55 (tt, J = 11.4, 4.9 Hz, 5H), 1.48 (ddd, J= 16.2, 8.4, 3.8 Hz, 2H).

[0198] N-[2-(4-Chlorophenyl)ethyl]-4,4-difluoro-1- methylcyclohexane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 4, 4-difluoro-l -methylcyclohexanecarboxylic acid (0.267 g, 1 .50 mmol), N,N-dimethylformamide (3.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.646 g, 1.70 mmol) was added as a solid and the vessel was resealed and flushed with argon. (4- Chlorophenyl)ethylamine (0.295 g, 1.90 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined, concentrated, and triturated from dichloromethane and hexanes. This material was further purified by reverse phase Medium PressureLiquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to yield the final product (0.130 g, 28 %).1H NMR (500 MHz, cdcl3) 5 7.34 - 7.24 (m, 3H), 7.17 - 7.10 (m, 2H), 5.58 (s, 1 H), 3.54 (q, J = 6.6 Hz, 2H), 2.82 (t, J = 6.9 Hz, 2H), 2.03 - 1 .77 (m, 6H), 1 .55 (ddd, J = 17.5, 9.4, 3.9 Hz, 3H), 1 .14 (s, 3H). -94.63 (d, J = 231 .4 Hz), -100.15 (d, J = 238.3 Hz). HRMS ESI (+) Calc’d for [M+H] = 316.1275, observed = 316.1282.

[0199] 4,4-Difluoro-1-methylcyclohexanecarboxylic acid. To a 250 mL 24 / 40 round bottom flask containing a stir bar was added 4,4-difluoro-1 - methylcyclohexanecarboxylic acid ethyl ester (2.20 g, 10.6 mmol), ethanol (20.0 mL), water (30.0 mL) and solid potassium hydroxide (1.40 g, 25.0 mmol). The reaction mixture was stirred at room temperature for 46 hours, 1.0 N aqueous hydrochloric acid (30.0 mL, 30.0 mmol). The reaction mixture was extracted with ethyl acetate, the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield a solid that was filtered through a plug of silica eluting with a 2 % methanol in dichloromethane mobile phase. The filtrate was concentrated in vacuo to yield the product (1 .46 g, 77 %).1H NMR (500 MHz, cdcl3) 5 2.25 - 2.14 (m, 2H), 2.06 - 1 .81 (m, 4H), 1 .62 - 1 .51 (m, 2H), 1 .29 (s, 3H).19F NMR (470 MHz, cdcl3) 5 -93.80 (d, J= 236.0 Hz), -101 .27 (d, J = 237.0 Hz).

[0200] 1-Methyl-ethyl 4,4-difluorocyclohexane carboxylate. A 250 mL 24 / 40 round bottom flask containing a stir bar was sealed with a septum, flushed with argon, tetrahydrofuran (40.0 mL) was added, and the reaction vessel was cooled to - 78 °C in a dry ice / acetone bath. Diisopropylamine (5.05 g, 50.0 mmol) was added by syringe, followed by n-butyllithium (19.5 mL of 2.5 M solution in hexanes, 48.75 mmol). The reaction mixture was stirred for 10 minutes and ethyl 4,4-difluorocyclohexane carboxylate (1 .92 g, 10..0 mmol) was added as a solutiondissolved in tetrahydrofuran (2.00 ml_). The reaction mixture was stirred for 1 hour at - 78 °C and methyl iodide (8.51 g, 60.0 mmol) was added by syringe. The reaction mixture was stirred for 22 hours, warming to room temperature, quenched with methanol (5.00 mL), concentrated in vacuo, partitioned between ethyl acetate and brine, washed with 1 .0 N aqurous hydrochloric acid, saturated aqueous sodium bicarbonate, brine and concentrated in vacuo to yield a product that was carried on without purification (2.20 g, 100 %).1H NMR (500 MHz, cdcl3) 5 4.17 (qd, J= 7.2, 0.7 Hz, 2H), 2.22 - 2.15 (m, 2H), 1 .97 (ddddd, J= 11 .5, 10.0, 8.0, 5.6, 1 .3 Hz, 2H), 1 .88 - 1 .72 (m, 2H), 1 .60 - 1 .47 (m, 3H), 1 .26 (td, J = 7.1 , 0.7 Hz, 3H), 1 .21 (d, J= 0.6 Hz, 3H).19F NMR (470 MHz, cdch) 6 -93.49 (d, J= 234.7 Hz), -101 .23 (d, J = 235.6 Hz).

[0201] N-[2-(4-Chlorophenyl)ethyl]-1-methylcyclopentane-1- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methyl-1 -cyclopentyl carboxylic acid (0.256 g, 2.00 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.454 g, 4.50 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.836 g, 2.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. (4- Chlorophenyl)ethylamine (0.373 g, 2.40 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. This material was further purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. This material was triturated from ethyl acetate and hexanes to yield the final product (0.265 g, 50 %).1H NMR (500 MHz, cdcl3) 5 7.34 - 7.24 (m, 2H), 7.17 - 7.09 (m, 2H), 5.58 (s, 1 H), 3.49 (td, J = 6.9, 5.9 Hz, 2H), 2.80 (t, J = 6.9 Hz,2H), 1 .96 (ddt, J = 12.5, 7.6, 4.5 Hz, 2H), 1 .76 - 1 .65 (m, 4H), 1 .49 - 1 .39 (m, 2H), 1 .17 (s, 3H). HRMS ESI (+) calc’d for [M + H] = 266.1307, observed = 266.1333.

[0202] N-[2-(4-chlorophenyl)ethyl]-3,5-dimethyladamantane-1- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 3, 5-dimethyladamantane-1 -carboxylic acid (0.300 g, 1 .44 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.608 g, 1 .60 mmol) was added as a solid and the vessel was resealed and flushed with argon. (4- Chlorophenyl)ethylamine (0.280 g, 1 .80 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane to yield the final product (0.239 g, 50 %).1H NMR (500 MHz, cdch) 5 3.46 (q, J = 6.7 Hz, 2H), 2.77 (t, J = 7.0 Hz, 2H), 2.11 (h, J = 3.3 Hz, 1 H), 1 .61 (d, J = 3.2 Hz, 2H), 1 .46 - 1 .35 (m, 4H), 1 .34 (dd, J = 3.2, 1 .9 Hz, 4H), 1 .19 - 1 .09 (m, 2H), 0.84 (s, 6H). HRMS ESI (+) calc’d [M + H] = 346.1933, observed = 346.1938.

[0203] N-[2-(4-Chlorophenyl)ethyl]adamantane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added adamantane-1 - carboxylic acid (0.360 g, 2.00 mmol), N,N-dimethylformamide (2.00 mL), and triethylamine (0.505 g, 5.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.836 g, 2.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. (4-Chlorophenyl)ethylamine (0.373 g, 2.40 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe.The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane to yield the final product (0.391 g, 62 %).1H NMR (500 MHz, cdcl3) 5 7.32 - 7.23 (m, 3H), 7.19 - 7.06 (m, 2H), 5.57 (s, 1 H), 3.46 (td, J = 6.9, 5.8 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), 2.02 (p, J = 3.1 Hz, 3H), 1.78 (d, J = 2.9 Hz, 6H), 1.76 - 1.71 (m, 3H), 1 .71 - 1.65 (m, 3H). HRMS ESI (+) calc’d [M + H] = 318.1620, observed = 318.1630.

[0204] N-[2-(4-Chlorophenyl)ethyl]-2-methyloxane-2-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added tetrahydro-2- methyl-2H-pyran-2-carboxylic acid (0.293 g, 2.00 mmol), N,N-dimethylformamide (3.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.836 g, 2.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. (4-Chlorophenyl)ethylamine (0.373 g, 2.40 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined, concentrated in vacuo and purified by recrystallization from ethyl acetate and hexanes. The supernatant was filtered away from the solid and concentrated in vacuo to yield the final product (0.197 g, 35 %).1H NMR (500 MHz, cdcl3) 5 7.29 - 7.24 (m, 3H), 7.16 - 7.12 (m, 2H), 6.64 (s, 1 H), 3.69 (dtd, J = 11 .8, 4.0, 2.0 Hz, 1 H), 3.52 (td, J = 7.1 , 6.0 Hz, 2H), 3.49 - 3.43 (m, 1 H), 2.82 (t, J = 7.1 Hz, 2H), 2.06 - 1 .98 (m, 1 H), 1 .70 - 1 .60 (m, 3H), 1 .53 - 1 .40 (m, 3H), 1 .30 (s, 3H). HRMS ESI (+) calc’d for [M+H] = 282.1257, observed = 282.1257.

[0205] 2-Methyl-N-{2-[4-(trifluoromethyl)phenyl]ethyl]oxane-2- carboxamide To a 100 mL 24 / 40 round bottom flask containing a stir bar was added tetrahydro-2-methyl-2H-pyran-2-carboxylic acid (0.288 g, 2.00 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.505 g, 5.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.836 g, 2.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl) ethylamine (0.454 g, 2.40 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane followed by silica gel chromatography with 0 - 100 % ethyl acetate in hexanes. The supernatant was filtered away from the solid and concentrated in vacuo to yield the final product (0.178 g, 28 %).1H NMR (500 MHz, cdcl3) 0 7.57 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.67 (s, 1 H), 3.74 - 3.64 (m, 1 H), 3.57 (q, J = 6.9 Hz, 2H), 3.46 (ddd, J = 11 .4, 7.8, 3.7 Hz, 1 H), 2.92 (t, J = 7.1 Hz, 2H), 2.01 (ddd, J = 11 .0, 5.5, 3.2 Hz, 1 H), 1 .66 (ddt, J = 10.5, 7.8, 4.3 Hz, 2H), 1 .56 - 1 .37 (m, 3H), 1 .31 (s, 3H). 19F NMR (470 MHz, cdcl3) 5 -62.43. HRMS ESI (+) calc’d for [M+H] = 316.1520, observed = 316.1545.

[0206] 1 -Fluoro-N-{2-[4-(trifluoromethyl)phenyl]ethyl]cyclohexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -fluorocyclohexanecarboxylic acid (0.292 g, 2.00 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.606 g, 6.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.836 g, 2.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl) ethylamine (0.454 g, 2.40 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane (0.178 g, 28 %).1H NMR (500 MHz, cd3od) 6 7.58 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 3.47 (t, J = 7.2 Hz, 2H), 2.90 (t, J = 7.2 Hz, 2H), 1 .92 - 1 .51 (m, 9H), 1 .38 - 1 .23 (m, 1 H). 19F NMR (470 MHz, cdcl3) 0 -62.45, -167.50. HRMS ESI (+) calc’d for [M+H] = 318.1477, found = 318.1498.

[0207] 1 -(Trifluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 - cyclopentyl carboxylic ac d (0.193 g, 1 .05 mmol), N,N-dimethylformamide (2.00 mL), and triethylamine (0.252 g, 2.50 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1 .10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl) ethylamine (0.227 g, 1 .20 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane (0.123 g, 33 %).1H NMR (500 MHz, cdch) 5 7.61 - 7.54 (m, 2H), 7.36 - 7.27 (m, 2H), 5.85 (s, 1 H), 3.57 (td, J = 6.9, 5.8 Hz, 2H), 2.90 (t, J = 6.9 Hz, 2H), 2.25 - 2.15 (m, 2H), 1 .98 - 1 .87 (m, 2H), 1 .75 - 1 .61 (m, 4H).19F NMR (470 MHz, cdcl3) 5 -62.47, -70.28. HRMS ESI (+) Calc’d for [M + H] = 354.1 128, found = 354.1318.

[0208] 1-Brorno-N-{2-[4-(trifluoromethyl)phenyl]ethyl]cyclohexane-1- carboxamide . To a 100 ml_ 24 / 40 round bottom flask containing a stir bar was added 1 -bromocyclohexanecarboxylic acid (0.210 g, 1.01 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1 .10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl) ethylamine (0.227 g, 1 .20 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane (0.173 g, 44 %).1H NMR (500 MHz, cdcl3) 0 7.57 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 6.67 (s, 1 H), 3.57 (td, J = 7.0, 5.9 Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H), 2.08 (ddd, J = 14.8, 1 1 .0, 3.8 Hz, 2H), 2.02 - 1 .93 (m, 2H), 1.80 - 1 .61 (m, 5H), 1 .31 (dtd , J = 16.3, 7.0, 4.1 Hz, 1 H).19F NMR (470 MHz, cdcl3) 0 -62.43. HRMS ESI(+) calc’d for [M+H] = 378.0674, observed = 378.0706.

[0209] N-[2-(4-Chlorophenyl)ethyl]-2-methyloxane-2-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 2-methyl tetrahydropyran-2-carboxylic acid (0.293 g, 2.00 mmol), A / ,A / -dimethylformamide (3.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 0.836 g, 2.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 4-Chlorophenylethylamine (0.373 g, 2.40 mmol) was dissolved in A / , / V-dimethylformamide (1 .00 mL), and added to thereaction mixture by syringe which was stirred for 20 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography (0 - 10 % methanol in dichloromethane) and fractions containing product were combined and concentrated in vacuo. The final product was obtained as a white solid by triturating the material with ethyl acetate which was filtered, washed with hexanes, and dried in vacuo (0.197 g, 35 % yield).1H NMR (500 MHz, cdc ) 5 7.29 - 7.24 (m, 3H), 7.16 - 7.12 (m, 2H), 6.64 (s, 1 H), 3.69 (dtd, J = 1 1 .8, 4.0, 2.0 Hz, 1 H), 3.52 (td, J = 7.1 , 6.0 Hz, 2H), 3.49 - 3.43 (m, 1 H), 2.82 (t, J = 7.1 Hz, 2H), 2.06 - 1 .98 (m, 1 H), 1.70 - 1 .60 (m, 3H), 1 .53 - 1 .40 (m, 3H), 1 .30 (s, 3H). HRMS ESI (+) calc’d for [M+H] = 282.1257, observed = 282.1257.

[0210] 2-Methyl tetrahydropyran-2-carboxylic acid. To a 250 mL 24 / 40 round bottom flask containing a stir bar was added tetrahydrofuran (20.0 mL) which was sealed with a septum, flushed with argon, and diisopropylethylamine (5.05 g, 50.0 mmol). The reaction mixture was stirred and cooled to - 78 °C in a dry ice / acetone bath. After 5 minutes n-butyl lithium was added (55.0 mmol, 22.0 mL of a 2.5 M solution in hexanes) by syringe. The reaction mixture was stirred for 30 minutes at - 78 oC and tetrahydropyran-2-carboxylic acid methyl ester was added (1 .44 g, 10.0 mmol, as a solution dissolved in 5.00 mL of tetrahydrofuran). The reaction mixture was stirred for 1 hour at - 78 oC and methyl iodide was added (9.93 g, 70.0 mmol) by syringe after which the reaction was stirred for 19 hours, warming to room temperature. The crude reaction was concentrated in vacuo and partitioned between ethyl acetate and dilute aqueous hydrochloric acid. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine. This material was purified by filtration through silica gel (eluting with a 1 :9 ethyl acetate: hexanes solution) to produce tetrahydro-2-methyl-2H-pyran-2- carboxylic acid methyl ester which was used without additional purification (1 .46 g, 92 %). To a 100 mL 24 / 40 round bottom flask containing a stir bar was added tetrahydro-2-methyl-2H-pyran-2-carboxylic acid methyl ester (1.46 g, 9.22 mmol), methanol (30.0 mL), water (20.0 mL) and potassium hydroxide (2.80 g, 50.0 mmol). A reflux condenser was attached to the reaction vessel which was heatedin a sand bath to 55 °C for 22 hours, at which time it was cooled to 0 °C in an ice bath and dilute hydrochloric acid was added (60.0 mmol, 10.0 mL of 6.0 M aqueous hydrochloric acid). The reaction mixture was warmed to room temperature and extracted with ethyl acetate three times. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield the product, which was filtered through a plug of silica (eluting with 10 % methanol in dichloromethane) and concentrated in vacuo to yield the final product as a yellow solid (1 .10 g, 83 % yield).1H NMR (500 MHz, cdcl3) 6 3.92 - 3.83 (m, 1 H), 3.79 - 3.68 (m, 1 H), 2.12 - 2.05 (m, 1 H), 1 .80 - 1 .71 (m, 1 H), 1 .63 - 1 .51 (m, 4H), 1 .46 (s, 3H).

[0211] Tetrahydropyran-2-carboxylic acid methyl ester. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added tetrahydropyran-2- carboxylic acid (2.48 g, 19.0 mmol), methanol (25.0 mL), and p-toluenesulfonic acid monohydrate (0.019 g, 1.00 mmol). The reaction vessel was heated to 55 °C for 22 hours, cooled to room temperature, and concentrated in vacuo. The crude material was purified by filtration through a plug of silica (eluting with 1 % methanol in dichloromethane) and concentrated in vacuo to yield the product (2.73 g, 100 % yield).1H NMR (500 MHz, cdcl3) 5 4.13 - 4.06 (m, 1 H), 4.01 (dd, J = 10.6, 2.7 Hz, 1 H), 3.77 (s, 3H), 3.51 (td, J = 1 1 .4, 2.3 Hz, 1 H), 2.02 - 1.93 (m, 1 H), 1 .93 - 1 .85 (m, 1 H), 1 .73 - 1.48 (m, 3H).

[0212] 2-Methyl-N-{2-[4-(trifluoromethyl)phenyl]ethyl}oxane-2- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 2-methyl tetrahydropyran-2-carboxylic acid (0.288 g, 2.00 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- bjpyridinium 3-oxid hexafluorophosphate, 0.836 g, 2.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl)ethylamine (0.454 g, 2.40 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 20 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by reverse-phase medium pressure liquid chromatography (0 to 100 % methanol in 25.0 mM aqueous ammonium formate). Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered, and purified by silica gel chromatography (0 - 10 % methanol in dichloromethane). The material was purified by silica gel chromatography again (0 to 100 % ethyl acetate in hexanes, switching to 1 :9 methanol: ethyl acetate) and fractions containing product were combined and concentrated in vacuo. The pure product was obtained as a clear oil (0.178 g, 28 % yield).1H NMR (500 MHz, cdc ) 5 7.57 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.67 (s, 1 H), 3.74 - 3.64 (m, 1 H), 3.57 (q, J = 6.9 Hz, 2H), 3.46 (ddd, J = 1 1 .4, 7.8, 3.7 Hz, 1 H), 2.92 (t, J = 7.1 Hz, 2H), 2.01 (ddd, J = 1 1 .0, 5.5, 3.2 Hz, 1 H), 1 .66 (ddt, J = 10.5, 7.8, 4.3 Hz, 2H), 1.56 - 1 .37 (m, 3H), 1 .31 (s, 3H). 19F NMR (470 MHz, cdcl3) 5 -62.43. HRMS ESI (+) calc’d for [M+H] = 316.1520, observed = 316.1545.

[0213] 1-Fluoro-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclohexane-1- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -fluorocyclohexane carboxylic acid (0.292 g, 2.00 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.606 g, 6.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 0.836 g, 2.20 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl)ethylamine (0.373 g, 2.40 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 20 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried oversodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography (0 - 10 % methanol in dichloromethane) and fractions containing product were combined and concentrated in vacuo. The final product was obtained as a white solid by triturating the material with hexanes, filtration, and drying (0.240 g, 38 % yield).1H NMR (500 MHz, cd3od) 6 7.58 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 3.47 (t, J = 7.2 Hz, 2H), 2.90 (t, J= 7.2 Hz, 2H), 1 .92 - 1 .51 (m, 9H), 1 .38 - 1 .23 (m, 1 H).19F NMR (470 MHz, cdcl3) 5 -62.45, -167.50. HRMS ESI (+) calc'd for [M+H] = 318.1477, found = 318.1498.

[0214] 1-(Trifluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclopentane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trif luoromethyl-1 - cyclopentane carboxylic acid (0.193 g, 1 .05 mmol), W,W-dimethylformamide (2.00 mL), and triethylamine (0.252 g, 2.50 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]py rid in ium 3-oxid hexafluorophosphate, 0.418 g, 1 .10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl)ethylamine (0.229 g, 1 .20 mmol) was dissolved in A / , / V-dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 20 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography (0 - 10 % methanol in dichloromethane) and fractions containing product were combined and concentrated in vacuo. The final product was obtained as a white solid by triturating the material with dichloromethane / hexanes, filtration, and drying (0.123 g, 34 %).1H NMR (500 MHz, cdcl3) 6 7.61 - 7.54 (m, 2H), 7.36 - 7.27 (m, 2H), 5.85 (s, 1 H), 3.57 (td, J= 6.9, 5.8 Hz, 2H), 2.90 (t, J = 6.9 Hz, 2H), 2.25 - 2.15 (m, 2H), 1 .98 - 1 .87 (m, 2H), 1 .75 - 1 .61 (m, 4H).19F NMR (470 MHz, cdcl3) 5 -62.47, -70.28. HRMS ESI (+) Calc’d for [M + H] = 354.1 128, found = 354.1318.

[0215] 1-Brorno-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclohexane-1- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -bromocyclohexane carboxylic acid (0.210 g, 1 .01 mmol), A / ,A / - dimethylformamide (2.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, 0.418 g, 1.10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl)ethylamine (0.229 g, 1 .20 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 22 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography (0 - 10 % methanol in dichloromethane) and fractions containing product were combined and concentrated in vacuo. The final product was obtained as a white solid by triturating the material with dichloromethane / hexanes, filtration, and drying (0.173 g, 23 %).1H NMR (500 MHz, cdcl3) 0 7.57 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 6.67 (s, 1 H), 3.57 (td, J = 7.0, 5.9 Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H), 2.08 (ddd, J= 14.8, 1 1 .0, 3.8 Hz, 2H), 2.02 - 1 .93 (m, 2H), 1.80 - 1 .61 (m, 5H), 1 .31 (dtd , J = 16.3, 7.0, 4.1 Hz, 1 H).19F NMR (470 MHz, cdch) 5 -62.43. HRMS ESI(+) calc’d for [M+H] = 378.0674, observed = 378.0706.

[0216] 1-Phenyl-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclobutane-1- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -phenylcyclobutane carboxylic acid (0.352 g, 2.00 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 0.798 g, 2.10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl)ethylamine (0.416 g, 2.20 mmol) was dissolved in N,N- dimethylformamide (2.00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography (first using 0 - 10 % methanol in dichloromethane as the mobile phase and a second time using 0 to 100 % ethyl acetate in hexanes) and fractions containing product were combined and concentrated in vacuo (0.221 g, 32 % yield).1H NMR (500 MHz, dmso-de) 5 7.59 (t, J = 5.7 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 2H), 7.31 - 7.22 (m, 4H), 7.22 - 7.15 (m, 3H), 3.24 (q, J = 6.5 Hz, 2H), 2.71 (t, J = 6.8 Hz, 2H), 2.66 - 2.56 (m, 2H), 2.32 - 2.24 (m, 2H), 1 .69 (dddt, J= 17.6, 9.0, 5.6, 2.9 Hz, 2H).19F NMR (470 MHz, dmso- de) 5 -60.77. HRMS ESI (+) calc’d for [M+H] = 348.1571 , found = 348.1593.

[0217] 2-Methyl-2-phenyl-N-{2-[4-(trifluoromethyl)phenyl]ethyl}propanamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 2-Methyl-2-phenylpropionic carboxylic acid (0.328 g, 2.00 mmol), A / , / V-dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H- 1 ,2,3-solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl)ethylamine (0.416 g, 2.20 mmol) was dissolved in N,N- dimethylformamide (2.00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography (first using 0 - 10 % methanol in dichloromethane as the mobile phase and a second time using 0 to 100 % ethyl acetate in hexanes) and fractions containing product were combined and concentrated in vacuo (0.798 g, 97%).1H NMR (500 MHz, cdch) 6 7.56 - 7.41 (m, 2H), 7.35 - 7.23 (m, 5H), 7.13 - 7.06 (m, 2H), 5.09 (s, 1 H), 3.43 (td, J = 6.8, 5.9Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H), 1 .53 (s, 6H).19F NMR (470 MHz, cdcl3) 6 -62.45.HRMS ESI (+) calc’d for [M+H] = 336.1571 , found = 336.1599.

[0218] 1-(Trifluoromethyl)-N-{2-[3-(trifluoromethyl)phenyl]ethyl]cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trif luoromethyl-1 - cyclopentyl carboxylic acid (0.266 g, 1 .46 mmol), A / ,W-dimethylformamide (2.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, (0.570 g, 1.50 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(3-Trifluoromethylphenyl)ethylamine (0.302 g, 1 .60 mmol) was dissolved in A / ,A / -dimethylformamide (2.00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography using 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.376 g, 69 %).1H NMR (500 MHz, cdcl3) 5 7.51 (d, J = 8.0 Hz, 1 H), 7.47 - 7.42 (m, 2H), 7.41 - 7.36 (m, 1 H), 5.86 (s, 1 H), 3.58 (q, J = 6.6 Hz, 2H), 2.91 (t, J= 6.9 Hz, 2H), 2.21 (dq, J= 9.7, 5.1 Hz, 2H), 2.00 - 1 .88 (m, 2H), 1 .70 (q, J= 6.1 Hz, 4H).19F NMR (470 MHz, cdcl3) 5 -62.71 , -70.35. HRMS calc’d for [M+Na] = 376.1150, observed = 376.1 112.

[0219] N-{2-[4-(Trifluoromethoxy)phenyl]ethyl}-1-(trifluoromethyl)cyclopentane-l -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 2-methyl-2-phenylpropionic carboxylic acid (0.282 g, 1 .54 mmol), A / , / V-dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed withargon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, (0.608 g, 1.60 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethoxyphenyl) ethylamine (0.384 g, 2.20 mmol) was dissolved in A / ,A / -dimethylformamide (2.00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography using 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo (0.360 g, 63 %).1H NMR (500 MHz, cdcl3) 6 7.21 (d, J = 8.7 Hz, 2H), 7.17 (d, J= 8.4 Hz, 2H), 5.84 (s, 1 H), 3.56 (q, J = 6.6 Hz, 2H), 2.85 (t, J = 6.9 Hz, 2H), 2.21 (dt, J = 11 .7, 5.5 Hz, 2H), 1 .99 - 1 .89 (m, 2H), 1 .69 (h, J = 7.2 Hz, 4H).19F NMR (470 MHz, cdcl3) 6 - 57.97, -70.30. HRMS calc’d for [M+H] = 370.1237, observed = 370.1275.

[0220] 1 -(1 H-Pyrazol-1 -yl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclohexane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -(1 H-pyrazol-1 - yl)cyclohexane-1 -carboxylic acid (0.113 g, 0.580 mmol), A / ,A / -dimethylformamide (1 .00 mL), and triethylamine (0.101 g, 1 .00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, (0.235 g, 0.620 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl)ethylamine (0.132 g, 0.700 mmol) was dissolved in A / ,A / -dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography using 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo. This material was further purified by reverse phase MediumPressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate, fractions containing product were combined concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield the final product (0.360 g, 63 %).1H NMR (500 MHz, dmso-d6) 6 7.78 (d, J = 2.4 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 1 .8 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 2H), 6.98 (s, 1 H), 6.29 (t, J = 2.1 Hz, 1 H), 3.25 (q, J = 6.6 Hz, 2H), 2.70 (t, J = 6.8 Hz, 2H), 2.27 (d, J = 13.8 Hz, 2H), 2.17 - 2.06 (m, 2H), 1 .50 - 1 .39 (m, 2H), 1 .39 - 1 .26 (m, 2H), 1 .21 (dd, J = 9.7, 3.7 Hz, 2H).19F NMR (470 MHz, dmso-d6) 6 -60.73 (d, J = 9.2 Hz), -60.77. HRMS calc’d for [M+Na] = 388.1613, observed = 388.1613.

[0221] 1-(1 H-Pyrazol-1 -yl)cyclohexane-1 -carboxylic acid. This material was prepared according to the procedure described in Tett. Lett., 2009, 50, 2497. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added pyrazole (0.408 g, 6.00 mmol) after which the reaction vessel was sealed with a septum and flushed with argon. Anhydrous tetrahydrofuran (40.0 mL) was added by syringe, the reaction vessel was cooled to 0 °C in an ice bath, the septum was removed and sodium hydroxide (1 .16 g, 30.0 mmol, freshly powdered) was added as a solid. The septum was replaced and the reaction vessel was flushed with argon, after which cyclohexanone (1 .76 g, 18.0 mmol) was added by syringe, followed by chloroform (3.57 g, 30.0 mmol). The reaction mixture was stirred for 22 hours, warming to room temperature, at which time the crude reaction mixture was filtered. The solid was dissolved in water and extracted with diethyl ether, after which the pH was lowered to ~3.0 by adding acetic acid. The aqueous solution was extracted with ethyl acetate, the organic layers were concentrated in vacuo and coevaporated with chlorobenzene. The resulting solid was recrystallized from dichloromethane and hexanes, filtered, washed with hexanes and dried in vacuo to yield the final product (0.357 g, 36 %).1H NMR (500 MHz, cdcl3) 6 10.01 (s, 1 H), 7.64 (dd, J = 5.2, 2.2 Hz, 2H), 6.35 (t, J = 2.2 Hz, 1 H), 2.54 - 2.21 (m, 4H), 1 .70 (dq, J = 13.3, 6.1 Hz, 2H), 1 .62 - 1 .36 (m, 4H).

[0222] 1 -(Trifluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]cyclopropyl}cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trit luoromethyl-1 - cyclopentyl carboxylic acid (0.173 g, 0.95 mmol), A / , / \ / -dimethylformamide (1.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, (0.368 g, 0.970 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl)cyclopropanamine hydrochloric acid salt (0.252 g, 1.06 mmol) was dissolved in A / ,A / -dimethylformamide (2.00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography using 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo. This material was further purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate, fractions containing product were combined concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This material was purified by silica gel chromatography with 0 - 100 % ethyl acetate in hexanes and fractions containing product were combined and concentrated in vacuo to to yield the final product (0.101 g, 29 %).1H NMR (500 MHz, dmso-d6) 5 8.29 (d, J = 3.9 Hz, 1 H), 7.59 (d, J= 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 2.91 (tt, = 8.0, 3.8 Hz, 1 H), 2.28 (dq, J = 12.5, 6.0 Hz, 2H), 2.04 (ddd, J = 9.6, 6.2, 3.4 Hz, 1 H), 1 .88 - 1 .77 (m, 2H), 1 .62 (d, J = 8.1 Hz, 2H), 1 .54 (d, J = 8.4 Hz, 2H), 1.38 - 1 .32 (m, 1 H), 1 .24 (dt, J = 7.9, 6.0 Hz, 1 H).19F NMR (470 MHz, dmso-d6) 5 -60.65, -70.02. HRMS calc’d for [M+Na] = 388.1112, observed = 388.1129.

[0223] 4,4-Dif luoro-1 -methyl-N-{[4-(trifluoromethyl)phenyl]methyl}cyclohexane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 4,4-difluoro-1 -methyl-1 - cyclohexyl carboxylic acid (0.178 g, 1 .00 mmol), A / ,A / -dimethylformamide (1 .00 mL), and triethylamine (0.250 g, 2.50 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, (0.399 g, 1.05 mmol) was added as a solid and the vessel was resealed and flushed with argon. 4-Trifluoromethyl benzylamine (0.192 g, 1 .10 mmol) was dissolved in A / ,A / -dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo o yield the crude material which was purified by silica gel chromatography using 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo. This material was further purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate, fractions containing product were combined concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield the final product (0.210 g, 59 %).1H NMR (500 MHz, cdcl3) 5 7.60 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H), 5.98 (s, 1 H), 4.52 (d, J =5.8 Hz, 2H), 2.14 - 2.04 (m, 2H), 2.04 - 1 .85 (m, 4H), 1 .63 (ddd, = 14.5, 10.1 ,4.9 Hz, 2H), 1.25 (s, 3H).19F19F NMR (470 MHz, cdcl3) 5 -62.57, -94.95 (d, J = 237.1 Hz), -99.89 (d, J = 233.2 Hz). HRMS calc’d for [M+H] = 358.1207, observed = 358.1234.

[0224] 1 -(Trifluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclohexane-1 -carboxamide. To a 100 mL 24 / 40round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclohexyl carboxylic acid (0.196 g, 1.00 mmol), A / ,A / -dimethylformamide (1 .00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, (0.418 g, 1.10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl)ethanamine (0.227 g, 1 .20 mmol) was dissolved in A / , / V-dimethylformamide (2.00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography using 0 - 10 % methanol in dichloromethane and fractions containing product were combined and concentrated in vacuo to yield the final product (0.105 g, 27 %).1H NMR (500 MHz, cdc ) 5 7.63 - 7.49 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 5.89 (s, 1 H), 3.62 (td, J = 7.0, 5.9 Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H), 2.11 (dq, J = 13.6, 2.1 Hz, 2H), 1.70 - 1 .59 (m, 3H), 1 .54 (td, J = 13.3, 3.7 Hz, 2H), 1 .31 - 1 .10 (m, 3H).19F NMR (470 MHz, cdcl3) 5 -62.48, -74.76. HRMS calc’d for [M+H] = 390.1269, observed = 390.1286.

[0225] M3,3-Difluoro-1 -methyl-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclobutane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 3,3-difluoro-1 - methylcyclobutane carboxylic acid (0.378 g, 2.00 mmol), N,A / -dimethylformamide (2.00 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]py rid in ium 3-oxid hexafluorophosphate (0.798 g, 2.10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl)-ethylamine (0.378 g, 2.00 mmol) was dissolved in / V, / V-dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed withbrine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography (0 - 10 % methanol in dichloromethane) and fractions containing product were combined and concentrated in vacuo (0.147 g, 28 %).1H NMR (500 MHz, dmso-d6) 5 7.90 (t, J = 5.5 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 3.31 (d, J = 6.5 Hz, 2H), 2.90 - 2.76 (m, 4H), 2.39 - 2.28 (m, 2H), 1 .30 (s, 3H).19F NMR (470 MHz, dmso-d6) 5 -60.77, -85.55 (tt, J= 13.5, 9.0 Hz), -85.96 (tt, J = 13.9, 9.2 Hz), -88.59 (p, J = 14.2 Hz), -89.00 (p, J = 14.2 Hz). HRMS ESI (+) calc’d for [M+H] = 322.1226, found = 322.1265.

[0226] N-{2-[4-(T rifluoromethyl)phenyl]ethyl}spiro[2.3]hexane-1 - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added spiro[2.3]hexane-1 -carboxylic acid (0.252 g, 2.00 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.505 g, 5.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.779 g, 2.05 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl)ethylamine (0.416 g, 2.20 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography (0 - 10 % methanol in dichloromethane) and fractions containing product were combined and concentrated in vacuo (0.082 g, 13 %).1H NMR (500 MHz, cdch) 6 7.56 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 5.42 (s, 1 H), 3.51 (td, J = 7.1 , 6.0 Hz, 2H), 2.87 (t, J = 7.0 Hz, 2H), 1 .24 (s, 6H), 1 .13 (s, 6H), 0.76 (s, 1 H).19F NMR (470 MHz, cdcl3) 5 -62.41 . HRMS ESI (+) calc’d for [M+H] = 314.1727, found = 314.1761 .

[0227] N-[2-(Naphthalen-2-yl)ethyl]-1-(trifluoromethyl)cyclopentane-1 -carboxamide. To a 100 ml_ 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.299 g, 1.64 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.505 g, 5.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.646 g, 1.70 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-Naphthalen-2-yl- ethylamine (0.308 g, 1.80 mmol) was dissolved in A / , / V-dimethylformamide (1.00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography (0 - 10 % methanol in dichloromethane) and then by reverse phase medium pressure liquid chromatography (0 - 100 % methanol in 25 mM aqueous ammonium formate). Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate and concentrated in vacuo io yield the final product (0.123 g, 22 %).1H NMR (500 MHz, dmso-de) 5 8.08 (t, J = 5.6 Hz, 1 H), 7.90 - 7.75 (m, 3H), 7.64 (d, J = 1 .7 Hz, 1 H), 7.44 (dddd, J = 14.4, 8.2, 6.9, 1.5 Hz, 2H), 7.35 (dd, J = 8.3, 1.7 Hz, 1 H), 3.50 - 3.40 (m, 2H), 2.89 (t, J = 7.1 Hz, 2H), 2.23 (dt, J = 12.9, 5.5 Hz, 2H), 1.83 - 1.73 (m, 2H), 1 .63 - 1 .51 (m, 2H), 1 .51 - 1 .33 (m, 2H).19F NMR (470 MHz, dmso-d6) 5 -69.94. HRMS ESI (+) calc’d for [M+Na] = 358.1395, found = 358.1423.

[0228] 1-Ethyl-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclohexane-1- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1-ethyl-1 -cyclohexyl carboxylic acid (0.119 g, 0.760 mmol), N,N- dimethylformamide (1 .00 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.304 g, 0.800 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl)ethylamine (0.189 g, 1.00 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography first with 0 - 10 % methanol in dichloromethane as a solvent system then further with a second column using 0 - 100 % ethyl acetate in hexanes. Fractions containing product were concentrated in vacuo to yield the final product (0.037 g, 15%).1H NMR (500 MHz, cdcb) 57.59 - 7.54 (m, 2H), 7.33 (d, J = 7.9 Hz, 2H), 5.63 (s, 1 H), 3.58 (td, J = 7.0, 5.9 Hz, 2H), 2.90 (t, J = 7.0 Hz, 2H), 1 .89 - 1 .79 (m, 2H), 1 .44 (q, J = 7.6 Hz, 5H), 1 .27 (q, J = 10.9 Hz, 5H), 0.74 (t, J = 7.5 Hz, 3H).19F NMR (470 MHz, cdcb) 6 -62.44. HRMS ESI (+) calc’d for [M+Na] = 350.1708, found = 350.1745.

[0229] 1 -(Difluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -dif luoromethyl-1 - cyclopentyl carboxylic acid (0.223 g, 1.36 mmol), A / , / \ / -dimethylformamide (2.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.532 g, 1 .40 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl)-ethylamine (0.283 g, 1.50 mmol) was dissolved in A / ,A / -dimethylformamide (1.00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane as a solvent system. Fractions containing product were concentrated in vacuo and subsequently triturated from dichloromethane and hexanes, filtered, and dried to yield the final product (0.117 g, 10%).1H NMR (500 MHz, cdcb) 5 7.57 (d, J = 8.0 Hz, 2H), 7.31(d, J = 8.0 Hz, 2H), 6.00 - 5.68 (m, 2H), 3.56 (q, J = 6.7 Hz, 2H), 2.89 (t, J = 6.9 Hz, 2H), 2.05 - 1 .96 (m, 2H), 1 .89 - 1 .78 (m, 2H), 1 .65 (s, 4H).19F NMR (470 MHz, cdcl3) 5 -62.45, -122.40, -122.52. HRMS ESI (+) calc’d for [M+H] = 336.1383, found = 336.1421 .

[0230] 1 -(T rifluoromethyl)-N-{2-[4-(trifluoromethyl)-1 H-pyrazol-1 - yl]ethyl}cyclopentane-1 -carboxamide To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.200 g, 1 .10 mmol), A / , / V-dimethylformamide (2.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.437 g, 1 .15 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-[4- (trifluoromethyl)-l H-pyrazol-1 -yl]ethanamine (0.231 g, 1 .20 mmol) was dissolved in A / ,A / -dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane as a solvent system. Fractions containing product were concentrated in vacuo and subsequently triturated from dichloromethane and hexanes. The supernatant was concentrated and further purified by silica gel chromatography using ethyl acetate / hexanes to give the final product (0.030 g, 8 %).1H NMR (500 MHz, dmso- d6) 5 8.16 - 8.02 (m, 1 H), 7.84 (d, J = 2.3 Hz, 1 H), 6.67 (d, J = 2.4 Hz, 1 H), 4.33 - 4.20 (m, 2H), 3.54 - 3.39 (m, 2H), 2.20 (dt, J = 12.8, 6.0 Hz, 2H), 1 .82 - 1 .73 (m, 2H), 1 .57 (d, J = 7.8 Hz, 2H), 1 .47 (d, J = 7.8 Hz, 2H).19F NMR (470 MHz, dmso- de) 5 -60.22, -70.05. HRMS ESI (+) calc’d for [M+H] = 344.1 193, found = 344.1222.

[0231] 1 -(trifluoromethyl)-N-{1 -[4-(trifluoromethyl)phenyl]propan-2- yl]cyclopentane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid(0.200 g, 1 .10 mmol), A / , / V-dimethylformamide (2.00 ml_), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.380 g, 1 .00 mmol) was added as a solid and the vessel was resealed and flushed with argon. 1 -[4- (trifluoromethylphenyl)]propan-2-amine (0.216 g, 1 .06 mmol) was dissolved in A / ,A / -dimethylformamide (1.00 ml_), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane as a solvent system. Fractions containing product were combined and concentrated in vacuo io yield the final product (0.181 g, 52 %).1H NMR (500 MHz, cdcl3) 5 7.55 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 5.59 (d, J = 7.5 Hz, 1 H), 4.31 (hept, J = 6.9 Hz, 1 H), 2.88 (dd, J = 13.6, 6.5 Hz, 1 H), 2.81 (dd, J = 13.6, 6.9 Hz, 1 H), 2.20 (td, J = 11 .7, 5.3 Hz, 1 H), 2.10 (dt, J = 12.2, 6.3 Hz, 1 H), 1.99 - 1 .85 (m, 2H), 1 .76 - 1 .55 (m, 4H), 1 .16 (d, J = 6.7 Hz, 3H).19F NMR (470 MHz, cdcl3) 5 -62.46, -70.23. HRMS ESI (+) calc’d for [M+H] = 368.1445, found = 368.1480.

[0232] 1 -(Trifluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]propyl}cyclopentane-1 -carboxamide. To a 100 ml_ 24 / 40 round bottom flask containing a stir bar was added 1 -trif luoromethyl-1 - cyclopentyl carboxylic acid (0.182 g, 1 .00 mmol), A / ,A / -dimethylformamide (2.00 ml_), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.391 g, 1 .03 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-[4-(trifluoromethylphenyl)]propan-2-amine (0.261 g, 1 .08 mmol) was dissolved in A / ,A / -dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate,water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane as a solvent system. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.160 g, 43 %).1H NMR (500 MHz, cdcl3) 0 7.58 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 5.72 (s, 1 H), 3.57 (dt, J = 13.6, 6.2 Hz, 1 H), 3.39 (ddd, J = 13.8, 8.5, 5.7 Hz, 1 H), 3.08 (dt, J = 8.3, 6.6 Hz, 1 H), 2.17 (dt, J = 12.8, 6.2 Hz, 1 H), 2.10 (dt, J = 12.5, 6.1 Hz, 1 H), 1.89 (dddd, J = 13.7, 6.8, 3.0, 1.8 Hz, 2H), 1 .76 - 1 .57 (m, 4H), 1 .29 (d, J = 7.0 Hz, 3H).19F NMR (470 MHz, cdcl3) 0 - 62.48, -70.33. HRMS ESI (+) calc’d for [M+H] = 368.1445, found = 368.1477.

[0233] 1 -(Trifluoromethyl)-N-{[4-(trifluoromethyl)phenyl]methoxy}cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trif luoromethyl-1 - cyclopentyl carboxylic acid (0.338 g, 1.85 mmol), / V,A / -dimethylformamide (2.00 mL), and triethylamine (0.505 g, 5.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.741 g, 1.95 mmol) was added as a solid and the vessel was resealed and flushed with argon. 0-[4-(Trifluoromethylbenzyl)-

[0234] hydroxylamine] (0.466 g, 2.05 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane as a solvent system. Fractions containing product were combined and concentrated in vacuo o yield the final product (0.122 g, 18 %).1H NMR (500 MHz, cdcl3) 58.39 (s, 1 H), 7.66 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 4.98 (s, 2H), 2.26 (dq, J = 13.5, 4.3 Hz, 2H), 2.05 - 1 .89 (m, 2H), 1 .74 (td, J = 8.4, 4.7 Hz, 4H).19F NMR (470 MHz, cdcl3) 5 -62.70, -70.07. HRMS ESI (+) calc’d for [M+H] = 356.1081 , found = 356.1115.

[0235] 1 -(Tr if I u oromethyl)-N-{3-[4-(trifluoromethyl)phenyl]cyclobutyl}cyclopentane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trif luoromethyl-1 - cyclopentyl carboxylic acid (0.169 g, 0.930 mmol), A / , / V-dimethylformamide (1.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.365 g, 0.950 mmol) was added as a solid and the vessel was resealed and flushed with argon. (1 R, 3R)-3-[4-(Trifluoromethyl)phenyl]cyclobutan-1 -amine hydrochloric acid salt (0.248 g, 0.980 mmol) was dissolved in A / ,A / -dimethylformamide (1.00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and repurified by silica gel chromatography with 0 - 100 % ethyl acetate in hexanes. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.191 g, 54 %).1H NMR (500 MHz, cdcl3) 6 7.59 (d, J= 8.1 Hz, 2H), 7.38 (d, J= 8.1 Hz, 2H), 6.11 (s, 1 H), 4.57 - 4.45 (m, 1 H), 3.67 (tt, J= 10.1 , 5.8 Hz, 1 H), 2.61 (dddd, J = 13.1 , 8.0, 5.4, 2.5 Hz, 2H), 2.43 (dtd, J = 12.8, 6.2, 2.7 Hz, 2H), 2.31 (dq, J = 13.3, 4.2 Hz, 2H), 2.08 - 1.96 (m, 2H), 1.82 - 1.68 (m, J = 5.8 Hz, 4H).19F NMR (470 MHz, cdcl3) 5 -62.35, -70.22. HRMS ESI (+) calc’d for [M+H] = 380.1445, found = 380.1475.

[0236] 1 -(Trifluoromethyl)-N-{3-[4-(trifluoromethyl)phenyl]cyclobutyl]cyclopentane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trif luoromethyl-1 - cyclopentyl carboxylic acid (0.163 g, 0.900 mmol), A / ,A / -dimethylformamide (1.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.361 g, 0.950 mmol) was added as a solid and the vessel was resealed and flushed with argon. C / s-3-[4-(Trifluoromethyl)- phenyl]cyclobutan-1 -amine (0.248 g, 0.980 mmol, CAS 1812174-93-8) was dissolved in A / , / V-dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo io yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo lo yield the final product (0.194 g, 55 %).1H NMR (500 MHz, cdch) 5 7.56 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.92 (s, 1 H), 4.41 (ddt, J = 16.5, 9.2, 7.3 Hz, 1 H), 3.37 - 3.25 (m, 1 H), 2.88 (dtd, J = 8.6, 7.5, 2.8 Hz, 2H), 2.27 (dt, J = 13.5, 5.7 Hz, 2H), 2.05 - 1 .93 (m, 4H), 1.73 (td, J = 8.5, 4.6 Hz, 4H).19F NMR (470 MHz, cdcl3) 5 -62.37, -70.29. HRMS ESI (+) calc’d for [M+H] = 380.1445, found = 380.1474.

[0237] N-[2-(2,2-Difluoro-2H-1 ,3-benzodioxol-5-yl)ethyl]-1 -(trifluoromethyl)cyclopentane-l -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.182 g, 1.00 mmol), A / ,A / -dimethylformamide (1 .00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.399 g, 1.05 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(2,2-Difluorobenzo[d][1 ,3]-dioxol-5- yl)ethan-1 -amine (0.223 g, 1 .11 mmol) was dissolved in A / ,A / -dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractionscontaining product were combined and concentrated in vacuo to yield the final product (0.147 g, 40 %).1H NMR (500 MHz, cdch) 6 6.99 (d, J = 8.1 Hz, 1 H), 6.96 - 6.82 (m, 2H), 5.86 (s, 1 H), 3.53 (q, J = 6.6 Hz, 2H), 2.83 (t, J = 6.9 Hz, 2H), 2.22 (dq, J = 12.8, 6.7 Hz, 2H), 2.02 - 1 .91 (m, 2H), 1 .80 - 1 .65 (m, 4H).19F NMR (470 MHz, cdcl3) 5 -50.03, -70.26. HRMS calc’d for [M+H] = 366.1 124, found = 366.1150.

[0238] 1 , 2,2,3, 3-Pentamethyl-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclopropane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added pentamethylcyclopropane carboxylic acid (0.200 g, 1 .28 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.505 g, 1 .33 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl)-ethylamine (0.264 g, 1.40 mmol) was dissolved in N,N- dimethyl-formamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.350 g, 84 %).1H NMR (500 MHz, cdcl3) 5 7.55 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 5.26 (t, J = 6.1 Hz, 1 H), 3.53 (td, J = 7.1 , 6.0 Hz, 2H), 2.89 (t, J = 7.1 Hz, 2H), 1 .18 (s, 3H), 1.02 (s, 6H), 0.97 (s, 6H).19F NMR (470 MHz, cdcl3) 5 -62.43, -62.47. HRMS calc’d for [M+H] = 328.1884, found = 328.1918.

[0239] N-{2-Methyl-1 -[4-(trifluoromethyl)phenyl]propan-2-yl}-1 - (trifluoromethyl)cyclopentane-l -carboxamide To a 100 mL 24 / 40 roundbottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.172 g, 0.940 mmol), N,N-dimethylformamide (2.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.380 g, 1 .00 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-Methyl-1 -(4-Trifluoromethylphenyl)- propan-2-amine (0.266 g, 1 .05 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.221 g, 62 %).1H NMR (500 MHz, cdch) 6 7.53 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.39 (s, 1 H), 3.16 (s, 2H), 2.21 (dt, J = 12.3, 5.7 Hz, 2H), 1 .97 - 1.89 (m, 2H), 1.72 (q, J = 6.1 Hz, 4H), 1.34 (s, 6H).19F NMR (470 MHz, cdcl3) 6 -62.38, -70.27. HRMS calc’d for [M+H] = 382.1601 , found = 382.1624.

[0240] 1-(Trifluoromethyl)-N-(1-{[4- (trifluoromethyl)phenyl]methyl}cyclopropyl)cyclopentane-1 -carboxamide.To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 - trifluoromethyl-1 -cyclopentyl carboxylic acid (0.172 g, 0.940 mmol), N,N- dimethylformamide (1 .00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.380 g, 1 .00 mmol) was added as a solid and the vessel was resealed and flushed with argon. 1 -(4- Trifluoromethylphenyl)methyl)-cyclopropan-1 -amine hydrochloric acid salt (0.264 g, 1.05 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water andbrine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.218 g, 61 %).1H NMR (500 MHz, cdcl3) 5 7.56 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 5.87 (s, 1 H), 2.99 (s, 2H), 2.13 (dt, J = 12.8, 6.2 Hz, 2H), 1.89 (dddd, J = 13.7, 8.0, 5.2, 2.3 Hz, 2H), 1 .68 (dq, J = 12.3, 6.7 Hz, 4H), 0.95 - 0.85 (m, 2H), 0.85 - 0.75 (m, 2H).19F NMR (470 MHz, cdcl3) 0 -62.41 , -70.30. HRMS calc’d for [M+H] = 380.1445.

[0241] 1 -(T rifluoromethyl)-N-{1 -[4-(trifluoromethyl)phenyl]propan-2- yl}cyclohexane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclohexyl carboxylic acid (0.235 g, 1 .15 mmol), N,N-dimethylformamide (1 .00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1 .10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 1 -(4- Trifluoromethylphenyl)propan-2-amine (0.264 g, 1 .05 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo io yield the final product (0.259 g, 65 %).1H NMR (500 MHz, cdcl3) 5 7.56 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 5.63 (d, J = 8.2 Hz, 1 H), 4.47 - 4.35 (m, 1 H), 2.91 (dd, J = 13.7, 7.0 Hz, 1 H), 2.84 (dd, J = 13.7, 6.9 Hz, 1 H), 2.14 (dq, J = 13.7, 3.5 Hz, 1 H), 2.07 (dd, J = 13.3, 3.3 Hz, 1 H), 1 .67 (d, J = 13.5 Hz, 1 H), 1 .60 (d, J = 11 .6 Hz, 1 H), 1 .57 - 1 .55 (m, 1 H), 1 .52 (dt, J = 13.3, 4.2 Hz, 2H), 1 .33 - 1 .20 (m, 1 H), 1 .19 (d, J = 6.6 Hz, 3H), 1 .17 - 1 .03 (m, 2H).19F NMR (470 MHz, cdcl3) 5 -62.47, -74.85. HRMS calc’d for [M+H] = 382.1601 , found = 3821 .1627.

[0242] 1 -(T rifluoromethyl)-N-{2-[3-(trifluoromethyl)-1 H-pyrazol-1 - yl]ethyl}cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.191 g, 1 .05 mmol), N,N-dimethylformamide (1 .00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.399 g, 1 .10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-[3- Trifluoromethyl)-1 H-pyrazol-1 -yl]ethanamine (0.21 1 g, 1 .17 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.173 g, 48%)1H NMR (500 MHz, cdcl3) 5 7.41 (dd, J = 2.4, 1 .1 Hz, 1 H), 6.54 (d, J = 2.3 Hz, 1 H), 6.41 (s, 1 H), 4.38 - 4.31 (m, 2H), 3.82 - 3.72 (m, 2H), 2.23 (dt, J = 12.8, 5.8 Hz, 2H), 1.98 (dddd, J = 13.9, 8.1 , 5.0, 2.1 Hz, 2H), 1.79 - 1 .64 (m, 4H).19F NMR (470 MHz, cdcl3) 5 -62.11 , -70.65. HRMS ESI (+) calc’d for [M+H] = 344.1 193, found = 344.1217.

[0243] 1-Methoxy-N-{2-[4-(trifluoromethyl)phenyl]ethyl]cyclohexane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -methoxycyclohexane-1 -carboxylic acid (0.183 g, 0.960 mmol), N,N- dimethylformamide (1 .00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.399 g, 1 .05 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-trifluoromethylphenyl)ethylamine (0.208 g, 1.10 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.267 g, 84 %).1H NMR (500 MHz, cdch) 0 7.56 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 6.47 (s, 1 H), 3.56 (td, J = 7.0, 6.0 Hz, 2H), 3.07 (s, 3H), 2.90 (t, J = 7.0 Hz, 2H), 1.81 - 1 .53 (m, 7H), 1 .44 (qt, J = 12.9, 3.6 Hz, 2H), 1 .25 (qt, J = 12.0, 3.6 Hz, 1 H).19F NMR (470 MHz, cdcl3) 0 -62.45. HRMS calc’d for [M+H] =330.1677, found = 330.1704.

[0244] 1-Bromo-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclobutane-1- carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -Bromocyclobutane-1 -carboxylic acid (0.510 g, 2.80 mmol), N,N- dimethylformamide (3.00 mL), and triethylamine (0.606 g, 6.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (1 .10 g, 2.90 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- trifluoromethylphenyl)ethanamine (0.586 g, 3.10 mmol) was dissolved in N,N- dimethylformamide (2.00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.267 g, 84 %).1H NMR (500 MHz, cdcl3) 5 7.58 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 6.37 (s, 1 H), 3.57 (q, J = 6.8 Hz, 2H), 3.03 - 2.88 (m, 4H), 2.57 (dddd, J = 12.8, 9.5, 6.0, 1 .2 Hz, 2H), 2.28 (dtt, J = 1 1 .1 , 9.6, 6.7 Hz, 1 H), 1 .99(dddd, J = 14.8, 11.1 , 8.8, 6.0 Hz, 1 H).19F NMR (470 MHz, cdcl3) 5 -62.43. HRMS calc’d for [M+H] = 350.0363, found = 350.0395.

[0245] N-{[4-(2,2,2-Trifluoroethyl)phenyl]methyl}-1 -(trifluoromethyl)cyclopentane-l -carboxamide. To a 100 ml_ 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.182 g, 1 .00 mmol), N,N-dimethylformamide (0.500 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.399 g, 1 .05 mmol) was added as a solid and the vessel was resealed and flushed with argon. 1 -[4-(2,2,2- trifluoromethylphenyl)]methanamine (0.249 g, 1 .10 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL), and added to the reaction mixture by syringe which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.242 g, 69%).1H NMR (500 MHz, cdcl3) 5 7.33 - 7.20 (m, 4H), 6.16 (s, 1 H), 4.51 (d, J = 5.6 Hz, 2H), 3.37 (q, J = 10.8 Hz, 2H), 2.33 (dt, J = 13.4, 6.5 Hz, 2H), 2.09 - 1 .97 (m, 2H), 1 .75 (dd, J = 1 1 .2, 3.3 Hz, 4H).19F NMR (470 MHz, cdcl3) 5 -65.94, -65.96 (t, J = 11 .0 Hz), -70.16. HRMS calc’d for [M+H] = 354.1288, found = 354.1326.

[0246] 1 -(T rifluoromethyl)-N-[2-(3,4,5-trimethyl-1 H-pyrazol-1 - yl)ethyl]cyclopentane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.250 g, 1 .37 mmol), N,N-dimethylformamide (2.50 mL), and triethylamine (0.505 g, 5.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.551 g, 1 .45 mmol) was added as a solid and the vessel was resealed, flushed with argon, and stirred for 5 minutes at room temperature. At this time, the septum was removed and 2- (Trimethyl-1 H-pyrazol-1 -yl)ethanamine bis hydrochloric acid salt (0.339 g, 1.50 mmol) was added as a solid. The reaction vessel was resealed, flushed with argon, and stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo o yield the final product (0.1 17 g, 33%).1H NMR (500 MHz, cdcl3) 5 6.99 (s, 1 H), 4.12 - 4.03 (m, 2H), 3.66 - 3.56 (m, 2H), 2.24 (dt, J = 12.8, 6.2 Hz, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1 .97 (dtt, J = 13.8, 6.1 , 2.1 Hz, 2H), 1 .89 (s, 3H), 1 .70 (dd, J = 11 .4, 5.0 Hz, 4H).19F NMR (470 MHz, cdcb) 6 -70.80. HRMS calc’d for [M+H] = 318.1789, found = 318.1828.

[0247] N-[2-(3,5-Dimethyl-1 H-pyrazol-1 -y l)et hyl ]-1 -(trifluoromethyl)cyclopentane-l -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.273 g, 1.50 mmol), N,N-dimethylformamide (1 .50 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)

[0248] methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.589 g, 1 .55 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-[3,5-dimethyl-1 H-pyrazol-1 -yl)ethanamine (0.229 g, 1 .64 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction vessel was resealed, flushed with argon, and stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.221g, 48%).1H NMR (500 MHz, cdcl3) 6 6.94 (s, 1 H), 5.79 (s, 1 H), 4.10 - 4.04 (m, 2H), 3.71 - 3.59 (m, 2H), 2.80 (s, 1 H), 2.29 - 2.22 (m, 2H), 2.22 - 2.17 (m, 6H), 1.97 (dddd, J = 13.9, 8.2, 5.8, 2.0 Hz, 2H), 1.77 - 1.64 (m, 4H).19F NMR (470 MHz, cdcl3) 5 -70.78. HRMS calc’d for [M+H] = 304.1632, found = 304.1667.

[0249] N-[2-(1 H-Pyrazol-1 -y l)ethy I ]-1 -(trifluoromethyl)cyclopentane-l - carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.364 g, 2.00 mmol), N,N- dimethylformamide (2.00 mL), and triethylamine (0.505 g, 5.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- bjpyridinium 3-oxid hexafluorophosphate (0.789 g, 2.10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-1 H-pyrazol-1 -yl ethanamine (0.246 g, 2.21 mmol was dissolved in N,N-dimethylformamide (1.00 mL) and added by syringe. The reaction vessel was resealed, flushed with argon, stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.277 g, 50%).1H NMR (500 MHz, cdcl3) 5 7.55 (d, J = 1 .9 Hz, 1 H), 7.46 - 7.34 (m, 1 H), 6.55 (s, 1 H), 6.26 (t, J = 2.1 Hz, 1 H), 4.32 - 4.24 (m, 2H), 3.79 - 3.67 (m, 2H), 2.81 (s, 1 H), 2.23 (dt, J = 12.7, 5.9 Hz, 2H), 1 .96 (dddd, J = 13.8, 8.2, 5.7, 2.2 Hz, 2H), 1 .77 - 1.62 (m, 4H).19F NMR (470 MHz, cdcl3) 6 -70.66. HRMS calc’d for [M+H] = 276.1319, found = 276.1352.

[0250] 1 -Fluoro-2,2,3,3-tetramethyl-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclopropane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -fluoro-2, 2,3,3- tetramethylcyclopentyl carboxylic acid (0.159 g, 1.00 mmol), N,N- dimethylformamide (1 .00 mL), and triethylamine (0.202 g, 2.00 mmol). Thereaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1 .10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluorophenyl)ethylamine (0.227 g, 1.20 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.144 g, 44%).1H NMR (500 MHz, cdc ) 6 7.57 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 6.44 (s, 1 H), 3.57 (tdd, J = 7.4, 6.2, 0.9 Hz, 2H), 2.91 (t, J = 7.2 Hz, 2H), 1 .26 (d, J = 2.2 Hz, 6H), 1 .14 (d, J = 2.2 Hz, 6H).19F NMR (470 MHz, cdch) 5 -62.43, -197.22 (d, J = 5.5 Hz). HRMS ESI (+) calc’d for 322.1633, found = 322.1665.

[0251] 1-(Trifluoromethyl)-N-{2-[6-(trifluoromethyl)pyridin-3- yl]ethyl}cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -Trifluoromethyl-1 -cyclopentyl carboxylic acid (0.182 g, 1 .00 mmol), N,N-dimethylformamide (1 .00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.399 g, 1 .10 mmol) was added as a solid, followed by dimethylaminopyridine (0.00780 g, 0.0600 mmol), and the vessel was resealed and flushed with argon. 2-[6- trifluoromethyl)pyridine-3-yl]ethylamine hydrochloric acid salt (0.227 g, 1 .20 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at 55 °C, at which time it was cooled to room temperature, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. This material was additionally purified by reverse phase MediumPressure Liquid Chromatography (0 - 100 % methanol in 25 mM aqueous ammonium formate). Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the final product (0.060 g, 17 %).1H NMR (500 MHz, cdcl3) 5 8.65 - 8.53 (m, 1 H), 7.72 (dd, J = 8.0, 2.1 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 5.93 (s, 1 H), 3.60 (q, J = 6.7 Hz, 2H), 2.96 (t, J = 7.0 Hz, 2H), 2.29 - 2.16 (m, 2H), 2.03 - 1 .89 (m, 2H), 1 .70 (q, J = 7.8 Hz, 4H).19F NMR (470 MHz, cdcl3) 5 - 67.83, -70.22. HRMS ESI (+) calc’d for [M+H] = 355.1241 , found = 355.1269.

[0252] 1 -(T rifluoromethyl)-N-{1 -[3-(trifluoromethyl)-1 H-pyrazol-1 - yl]propan-2-yl}cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.209 g, 1 .15 mmol), N,N-dimethylformamide (0.500 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.456 g, 1 .20 mmol) was added as a solid, and the vessel was resealed and flushed with argon. 1 -[3-trifluoromethyl)-1 H-pyrazol-1 -yl]propan- 2-amine (0.244 g, 1 .26 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at 55 °C, at which time it was cooled to room temperature, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. This material was additionally purified by reverse phase Medium Pressure Liquid Chromatography (0 - 100 % methanol in 25 mM aqueous ammonium formate). Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the final product (0.040 g, 10 %).1H NMR (500 MHz, cdcl3) 5 7.44 (dd, J = 2.3, 1 .1 Hz, 1 H), 6.55 (d, J = 2.4 Hz, 2H), 4.48 - 4.33 (m, 2H), 4.28 - 4.13 (m, 1 H), 2.27 (dt, J = 12.6, 6.1 Hz, 1 H), 2.24 - 2.18 (m, 1 H), 2.08 - 1 .90 (m, 2H), 1 .80 - 1 .59 (m, 4H), 1 .15 (d, J = 6.7 Hz, 3H).19F NMR (470 MHz,cdcl3) 5 -62.16, -70.70. HRMS ESI (+) calc’d for [M+H] = 358.1350, found = 358.1373.

[0253] 1-(Trifluoromethyl)-N-{2-[5-(trifluoromethyl)pyridin-2- yl]ethyl}cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.406 g, 2.20 mmol), N,N-dimethylformamide (1 .50 mL), and triethylamine (0.404 g, 4.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.874 g, 2.30 mmol) was added as a solid, and the vessel was resealed and flushed with argon. 2-[5- Trifluoromethyl)pyridine-3-yl]ethylamine (0.631 g, 2.40 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, at which time it was cooled to room temperature, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. This material was additionally purified by reverse phase Medium Pressure Liquid Chromatography (0 - 100 % methanol in 25 mM aqueous ammonium formate). Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the final product (0.180 g, 23 %).1H NMR (500 MHz, cdcl3) 6 8.80 (dt, J = 2.0, 0.9 Hz, 1 H), 7.86 (ddd, J = 8.2, 2.4, 0.8 Hz, 1 H), 7.30 (d, J = 8.1 Hz, 1 H), 6.92 (s, 1 H), 3.78 - 3.71 (m, 2H), 3.10 (t, J = 6.2 Hz, 2H), 2.29 - 2.19 (m, 2H), 1 .96 (dddt, J = 13.8, 8.2, 6.2, 2.0 Hz, 2H), 1 .76 - 1 .61 (m, 4H).19F NMR (470 MHz, cdcl3) 5 -62.36, -70.66. HRMS ESI (+) calc’d for [M+H] = 355.1241 , found = 355.1266.

[0254] N-{2-[5-Methyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]ethy I }-1 -(trifluoromethyl)cyclopentane-l -carboxamide To a 100 mL 24 / 40 roundbottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.218 g, 1.20 mmol), N,N-dimethylformamide (1.00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.475 g, 1 .25 mmol) was added as a solid, and the vessel was resealed and flushed with argon. 2-[5-methyl-3-trifluoromethyl)-1 H-pyrazol-1 - yl]ethan-1 -amine (0.250 g, 1.29 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, at which time it was cooled to room temperature, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. This material was additionally purified by reverse phase Medium Pressure Liquid Chromatography (0 - 100 % methanol in 25 mM aqueous ammonium formate). Fractions containing product were combined and concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the final product (0.105 g, 25 %).1H NMR (500 MHz, cdcl3) 56.59 (s, 1 H), 6.27 (s, 1 H), 4.19 (dd, J = 6.5, 4.9 Hz, 2H), 3.77 - 3.69 (m, 2H), 2.28 (s, 3H), 2.20 (dt, J = 12.9, 6.5 Hz, 2H), 1.95 (dddd, J = 15.6, 7.9, 4.9, 1 .8 Hz, 2H), 1 .76 - 1 .58 (m, 4H).19F NMR (470 MHz, cdcl3) 5 -62.37, -70.87. HRMS ESI (+) calc’d for [M+H] = 358.1350, found = 358.1383.

[0255] 1 -(T rifluoromethyl)-N-{3-[3-(trifluoromethyl)-1 H-pyrazol-1 - yl]propyl}cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.211 g, 1 .15 mmol), N,N-dimethylformamide (2.00 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.456 g, 1.20 mmol) was added as a solid, and the vessel was resealed and flushed with argon. 3-[3-trifluoromethyl)-1 H-pyrazol-1 -yl]propan-1 -amine (0.242 g, 1 .25 mmol) was dissolved in N,N-dimethylformamide (1 .00 ml_) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, at which time it was cooled to room temperature, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.092 g, 22 %).1H NMR (500 MHz, cdc ) 5 7.49 (dd, J = 2.3, 1 .1 Hz, 1 H), 6.53 (d, J = 2.3 Hz, 1 H), 6.26 (s, 1 H), 4.22 (t, J = 6.5 Hz, 2H), 3.31 (q, J = 6.3 Hz, 2H), 2.27 (dt, J = 12.7, 6.0 Hz, 2H), 2.11 (p, J = 6.5 Hz, 2H), 2.01 (dddd, J = 13.7, 8.1 , 5.7, 2.0 Hz, 2H), 1 .81 - 1 .65 (m, 4H).19F NMR (470 MHz, cdch) 6 -61 .95, -70.50. HRMS ESI (+) calc’d for [M+H] = 358.1350, found = 358.1383.

[0256] N-[(trans-2,2-Dimethyl-3-phenylcyclopropyl]-1 - (trifluoromethyl)cyclopentane-l -carboxamide. To a 100 ml_ 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.208 g, 1.15 mmol), N,N-dimethylformamide (1 .50 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.456 g, 1 .20 mmol) was added as a solid, and the vessel was resealed and flushed with argon. Trans-2,2-dimethyl-3-phenylcyclopropan-1 - amine (0.209 g, 1 .25 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, at which time it was cooled to room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.256 g, 68%).1H NMR (500 MHz, cdcl3) 5 7.36 - 7.14 (m, 5H), 6.04 (s, 1 H), 2.97 (dd, J = 4.6, 3.0 Hz, 1 H), 2.41 - 2.24 (m, 2H), 2.01 (dtdd, J =12.9, 7.4, 4.8, 2.2 Hz, 2H), 1 .89 (d, J = 4.6 Hz, 1 H), 1 .81 - 1.69 (m, 4H), 1 .22 (s, 3H), 0.90 (s, 3H).19F NMR (470 MHz, cdcl3) 5 -70.20. HRMS ESI (+) calc’d for [M+H] = 326.1727, found = 326.1758.

[0257] N-{2-Fluoro-2-[4-(trifluoromethyl)phenyl]ethyl}-1 - (trifluoromethyl)cyclopentane-l -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.180 g, 1 .00 mmol), N,N-dimethylformamide (0.500 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1 .10 mmol) was added as a solid, and the vessel was resealed and flushed with argon. 2-Fluoro-2-[4-(trifluoromethylphenyl)]ethan- 1 -amine (0.229 g, 1 .20 mmol) was dissolved in N,N-dimethylformamide (1 .50 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, at which time it was cooled to room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.218 g, 58%).1H NMR (500 MHz, cdch) 5 7.66 (d, J = 8.1 Hz, 2H), 7.55 - 7.44 (m, 2H), 6.23 (s, 1 H), 5.74 - 5.51 (m, 1 H), 4.00 - 3.82 (m, 1 H), 3.66 - 3.48 (m, 1 H), 2.28 (dd, J = 13.2, 6.8 Hz, 1 H), 2.25 - 2.17 (m, 1 H), 2.07 - 1 .92 (m, 2H), 1 .82 - 1 .60 (m, 4H).19F 19F NMR (470 MHz, cdcl3) 5 -62.76, -70.35, -187.35 (ddd, J = 48.8, 29.7, 19.8 Hz). HRMS ESI (+) calc’d for [M+H] = 372.1194, found = 372.1215.

[0258] N-[2-(5-Methyl-1 H-pyrazol-1 -yl)ethyl]-1 -(trifluoromethyl)cyclopentane-l -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentyl carboxylic acid (0.199 g, 1 .10 mmol), N,N-dimethylformamide (0.800 mL), andtriethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.456 g, 1 .20 mmol) was added as a solid, and the vessel was resealed and flushed with argon. 2-(5-Methyl-1 H-pyrazol-1 -yl) ethan-1 -amine (0.162 g, 1 .30 mmol) was dissolved in N,N-dimethylformamide (2.00 ml_) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, at which time it was cooled to room temperature, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo io yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.249 g, 78%).1H NMR (500 MHz, cdcl3) 5 7.42 (d, J = 1 .7 Hz, 1 H), 6.73 (s, 1 H), 6.03 (d, J = 1 .8 Hz, 1 H), 4.20 - 4.14 (m, 2H), 3.74 (q, J = 5.6 Hz, 2H), 2.33 - 2.17 (m, 5H), 1 .97 (dddd, J = 12.0, 8.1 , 5.4, 2.3 Hz, 2H), 1 .69 (q, J = 7.7 Hz, 4H).19F NMR (470 MHz, cdcl3) 6 -70.78. HRMS ESI (+) calc’d for [M+H] = 290.1476, found = 290.1510.

[0259] Trans-2-(trifluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added rac-(trans)-2- trifluoromethyl cyclopentane-1 -carboxylic acid (0.214 g, 1.17 mmol), N,N- dimethylformamide (1 .60 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.463 g, 1 .22 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluorophenyl)ethylamine (0.255 g, 1.35 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gelchromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.104 g, 25%).1H NMR (500 MHz, cdcl3) 0 7.57 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 5.52 (s, 1 H), 3.60 (dq, J = 13.5, 6.7 Hz, 1 H), 3.49 (dtd, J = 13.7, 7.0, 5.8 Hz, 1 H), 3.06 (tt, J = 9.7, 6.9 Hz, 1 H), 2.89 (hept, J = 6.8 Hz, 2H), 2.53 (q, J = 7.6 Hz, 1 H), 2.07 - 1 .86 (m, 2H), 1 .86 - 1 .73 (m, 3H), 1 .68 (ddt, J = 10.9, 7.2, 3.3 Hz, 1 H).19F NMR (470 MHz, cdcl3) 5 -62.46, -70.56 (d, J = 9.9 Hz). HRMS ESI (+) calc’d for [M+H] = 354.1288, found = 354.1313.

[0260] 2-(Trifluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclohexane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 2-trif luoromethyl cyclohexane- 1 -carboxylic acid (0.253 g, 1 .29 mmol), N,N-dimethylformamide (0.800 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.513 g, 1 .35 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluorophenyl)ethylamine (0.283 g, 1 .50 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.254 g, 53%).1H NMR (500 MHz, cdcl3) 5 7.56 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 5.50 (s, 1 H), 3.68 - 3.55 (m, 1 H), 3.47 - 3.37 (m, 1 H), 2.91 (dt, J = 13.5, 6.7 Hz, 1 H), 2.82 (dt, J = 14.1 , 7.3 Hz, 1 H), 2.49 (q, J = 4.4 Hz, 1 H), 2.38 - 2.26 (m, 1 H), 2.26 - 2.12 (m, 1 H), 2.10 - 1 .96 (m, 1 H), 1 .92 - 1 .76 (m, 2H), 1 .71 (dq, J = 12.7, 4.2 Hz, 1 H), 1 .57 - 1 .42 (m, 2H), 1 .38 - 1 .22 (m, 1 H).19F NMR (470 MHz, cdcl3) 5 -62.44, -69.18. HRMS ESI (+) calc’d for [M+H] = 368.1445, found = 368.1467.

[0261] N-[(Cis)-3-[4-(trifluoromethyl)phenyl]cyclobutyl]-1 - (trifluoromethyl)cyclohexane-l -carboxamide To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl cyclohexane-1 -carboxylic acid (0.196 g, 1 .00 mmol), N,N-dimethylformamide (1 .00 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.399 g, 1 .05 mmol) was added as a solid and the vessel was resealed and flushed with argon. C / s-3-[4- (Trifluoromethyl)phenyl]cyclobutanamine (0.236 g, 1 .10 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane then by silica gel chromatography with 0 - 100 % ethyl acetate in hexanes. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.137 g, 35%).1H NMR (500 MHz, cdch) 5 7.57 (d, J = 8.0 Hz, 2H), 7.35 - 7.29 (m, 2H), 5.94 (d, J = 6.9 Hz, 1 H), 4.47 (ddt, J = 16.6, 9.3, 7.3 Hz, 1 H), 3.32 (p, J = 8.9 Hz, 1 H), 2.96 - 2.83 (m, 2H), 2.23 - 2.14 (m, 2H), 2.07 - 1.95 (m, 2H), 1 .73 (d, J = 15.5 Hz, 3H), 1 .60 (dd, J = 13.3, 3.6 Hz, 2H), 1 .46 - 1 .29 (m, 2H), 1 .29 - 1 .16 (m, 1 H).19F NMR (470 MHz, cdcl3) 6 -62.36, -74.80. HRMS ESI (+) calc’d for [M+H] = 394.1601 . found = 394.1601.

[0262] 3-Fluoro-N-[(cis)-3-[4-(trifluoromethyl)phenyl]cyclobutyl]-1- (trifluoromethyl)cyclopentane-l -carboxamide To a 100 mL 24 / 40 round bottom flask containing a stir bar was added c / s-3-Fluoro-1 -(trifluoromethyl) cyclopentane-1 -carboxylic acid (0.235 g, 1 .18 mmol), N,N-dimethylformamide (0.800 mL), and triethylamine (0.151 g, 1 .50 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate (0.456 g, 1 .20 mmol) was added as a solid and the vessel was resealed and flushed with argon. C / s-3-[4- (Trifluoromethyl)phenyl]cyclobutanamine (0.269 g, 1 .25 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane then by silica gel chromatography with 0 - 100 % ethyl acetate in hexanes. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.139 g, 21 %).1H NMR (500 MHz, cdcl3) 5 7.58 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 6.02 (s, 1 H), 5.36 - 5.14 (m, 1 H), 4.40 (ddt, J = 16.6, 9.4, 7.3 Hz, 1 H), 3.38 - 3.25 (m, 1 H), 2.96 - 2.78 (m, 3H), 2.36 - 2.20 (m, 3H), 2.19 - 2.06 (m, 1 H), 2.01 (qd, J = 9.6, 2.7 Hz, 2H), 1 .95 - 1 .76 (m, 1 H).19F NMR (470 MHz, cdcl3) 5 -62.37, -69.62 (d, J = 4.2 Hz), -171.77 - -172.19 (m). HRMS ESI (+) calc’d for [M+H] = 398.1351 , found = 398.1345.

[0263] Benzyl 3-{[1-(trifluoromethyl)cyclopentane-1 - carbonyl]amino}azetidine-1 -carboxylate. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -Trifluoromethyl cyclopentane-1 -carboxylic acid (0.933 g, 5.10 mmol), N,N-dimethylformamide (2.00 mL), and triethylamine (0.606 g, 6.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (2.01 g, 5.30 mmol) was added as a solid and the vessel was resealed and flushed with argon. 1 - Carbamoylbenzyloxy-3-aminoazetidine (1.56 g, 6.00 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gelchromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (1 .13 g, 60%).1H NMR (500 MHz, cdcl3) 0 7.42 - 7.20 (m, 5H), 6.19 (s, 1 H), 5.10 (s, 2H), 4.70 - 4.59 (m, 1 H), 4.35 (ddd, J = 9.5, 7.7, 0.8 Hz, 2H), 3.81 (ddd, J = 9.4, 5.2, 0.8 Hz, 2H), 2.25 (dd, J = 13.2, 6.3 Hz, 2H), 2.05 - 1.97 (m, 2H), 1.81 - 1 .65 (m, 4H).19F NMR (470 MHz, cdcl3) 0 -70.18. HRMS ESI (+) calc’d for [M+H] = 371.1578, found = 371.1577.

[0264] 3,3-Dif luoro-1 -(trifluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclobutane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 3, 3-difluoro-1 -trifluoromethyl cyclobutane-1 -carboxylic acid (0.276 g, 1 .35 mmol), N,N-dimethylformamide (1 .00 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.532 g, 1 .40 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluorophenyl)ethylamine (0.283 g, 1 .50 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.191 g, 37%).1H NMR (500 MHz, cd3od) 0 7.60 (s, 2H), 3.38 (q, J = 13.4 Hz, 2H), 3.25 - 3.05 (m, 2H).19F NMR (470 MHz, cd3od) 5 -71 .52, -87.14 (d, J = 192.0 Hz), -89.73 (d, J = 193.3 Hz), -91 .36. HRMS ESI (+) calc’d for [M+H] = 388.0039, found = 388.0048.

[0265] Trans-3-[(tert-butoxycarbonyl)amino]cyclobutyl methanesulfonate. To a 250 mL 24 / 40 round bottom flask with a stir bar was added dichloromethane (100 mL), tert-butyl(trans-3-hydroxycycyclobutane) carbamate (2.54 g, 13.5 mmol) and triethylamine (3.00 g, 30.0 mmol). The reaction vessel was sealed, flushed with argon, and cooled to - 30 oC in a dry ice / acetonitrile bath. Methanesulfonyl chloride (2.29 g, 20.0 mmol) was added by syringe over a 20 minute period. The reaction mixture was warmed to room temperature, washed with 1.0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate and concentrated in vacuo to yield a product (2.85 g, 80 %) that was used in the next step without purification.1H NMR (500 MHz, cdcl3) 6 5.16 (td, J = 7.0, 3.5 Hz, 1 H), 4.73 (s, 1 H), 4.27 (s, 1 H), 3.27 - 3.09 (m, 1 H), 3.00 (s, 3H), 2.67 (ddd, J = 13.1 , 8.2, 4.3 Hz, 2H), 2.49 - 2.36 (m, 2H), 1.44 (s, 9H).

[0266] C / s-3-[(tert-butoxycarbonyl)amino]cyclobutyl methanesulfonate. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 4-trifluoromethyl-1 H-pyrazole (1.60 g, 6.03 mmol) and N,N- dimethylacetamide (12.0 mL). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The reaction vessel was cooled to 0 °C in an ice bath and the septum was removed briefly to add sodium hydride (0.504 g, 15.0 mmol) before it was replaced and vented with argon until bubbles ceased to evolve. After hydrogen gas ceased to evolve Trans-3- [(tert- butoxycarbonyl)amino]cyclobutyl methanesulfonate (1.22 g, 9.00 mmol) was dissolved in dimethylacetamide (3.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at 70 °C, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 100 % ethyl acetate in hexanes. This material was further purified by reverse phase Medium Pressure Liquid Chromatography with 0 - 100 % methanol in 25 mM aqueous ammonium formate. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.191 g, 37%).1H NMR (500 MHz, cdcl3) 5 7.72 (d, J = 15.6 Hz, 2H), 4.91 (s, 1 H), 4.46 (p, J = 8.1 Hz, 1 H), 4.16 - 3.96 (m, 1 H), 3.05 - 2.89 (m, 2H), 2.50 (p, J = 9.1 Hz, 2H), 1 .45 (s, 9H).19F NMR (470MHz, cdcl3) 6 -56.39. HRMS ESI(+) calc’d for [M+H-Boc] = 206.0900, found = 206.0901 .

[0267] Benzyl {1 -[4-(trifluoromethyl)phenyl]azetidin-3-yl}carbamate.To a 100 mL 24 / 40 round bottom flask containing a stir bar was added benzyl azetidinyl-3-carbamate hydrochloric acid salt (1.21 g, 5.00 mmol), anhydrous potassium carbonate (2.07 g, 15.0 mmol) and N,N-dimethylformamide (10.0 mL). The reaction vessel was sealed with a septum, flushed with argon, and heated to 60 °C. 4-Fluorobenzotrifluoride (0.984 g, 6.00 mmol) was added via syringe. The reaction mixture was stirred at 60 °C for 20 hours, partitioned between ethyl acetate and brine, washed with water, saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 - 100 % ethyl acetate in hexanes) to yield the product (0.040 g, 2 %).1H NMR (500 MHz, cdcl3) 5 7.44 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 5.8 Hz, 5H), 6.44 (d, J = 8.3 Hz, 2H), 5.19 (s, 1 H), 5.13 (s, 2H), 4.71 (s, 1 H), 4.28 (t, J = 7.7 Hz, 2H), 3.71 (dd, J = 7.9, 5.4 Hz, 2H).19F NMR (470 MHz, cdcl3) 6 -61 .08. HRMS ESI(+) calc’d for [M+H] = 351 .1316, found = 351 .1309.

[0268] 1 -(trifluoromethyl)-N-[trans-2-[4-(trifluoromethyl)phenyl]cyclopentyl]cyclopentane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl cyclopentane-1 -carboxylic acid (0.163 g, 0.900 mmol), N,N-dimethylformamide (1 .00 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.361 g, 0.950 mmol) was added as a solid and the vessel was resealed and flushed with argon. Trans-2-[4-(trifluoromethyl)-1 -cyclopentan- 1 -amine (0.243 g, 1 .06 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at roomtemperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.188 g, 53%).1H NMR (500 MHz, cdcl3) 0 7.55 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.34 (d, J = 8.0 Hz, 1 H), 4.63 (p, J = 7.4 Hz, 1 H), 3.48 (q, J = 7.8 Hz, 1 H), 2.29 - 2.10 (m, 3H), 2.03 - 1 .88 (m, 2H), 1.85 - 1 .72 (m, 2H), 1 .68 (dt, J = 12.7, 7.1 Hz, 1 H), 1 .64 - 1 .56 (m, 2H), 1 .52 (ddd, J = 14.4, 1 1.5, 6.1 Hz, 2H), 1 .47 - 1.28 (m, 2H).19F NMR (470 MHz, cdcl3) 0 -62.53, -70.56. HRMS ESI(+) calc’d for [M+H] = 394.1600, found = 394.1587.

[0269] 7,7-Difluoro-N-{2-[4-(trifluoromethyl)phenyl]ethyl}bicyclo[4.1.0]heptane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 7,7- difluorobicyclo[4.1 ,0]heptane-1 -carboxylic acid (0.192 g, 1 .08 mmol), N,N- dimethylformamide (1 .00 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.361 g, 0.950 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl)ethylamine (0.227 g, 1 .20 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.246 g, 66%).1H NMR (500 MHz, cdcl3) 0 7.58 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.63 (s, 1 H), 3.65 - 3.47 (m, 2H), 2.90 (t, J = 7.0 Hz, 2H), 2.20 (dddd, J = 15.5, 8.8, 4.1 , 2.5 Hz, 1 H), 2.01 - 1 .92 (m, 1 H), 1 .88 (h, J = 7.2 Hz, 2H), 1 .72 (q, J = 8.1 Hz, 1 H), 1 .43 - 1.22 (m, 4H).19F NMR (470 MHz, cdcl3) 6 -62.44, -131.16(dd, J = 154.4, 15.6 Hz), -141 .11 (d, J = 154.6 Hz). HRMS ESI(+) calc’d for [M+H] = 348.1381 , found = 348.1380.

[0270] N-{2-[3,5-Bis(trifluoromethyl)phenyl]ethyl}-1 -(trifluoromethyl)cyclopentane-l -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentane carboxylic acid (0.278 g, 1.52 mmol), N,N-dimethylformamide (1.50 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.608 g, 1 .60 mmol) was added as a solid and the vessel was resealed and flushed with argon. The reaction mixture was stirred at room temperature for 5 minutes and 3,5-bis(trifluoromethyl)benzeneethanamine (0.437 g, 1.700 mmol) was added as a solid. The reaction vessel was sealed with a septum, flushed with argon and stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined, concentrated in vacuo and further purified by reverse-phase Medium Pressure Liquid Chromatography (using 0 - 100 % methanol in a 25 mM aqueous ammonium formate buffer). Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate and concentrated in vacuo. This material was further purified by silica gel chromatography using 0 - 100 % ethyl acetate in hexanes to yield the final product (0.402 g, 63%).1H NMR (500 MHz, cdch) 67.77 (s, 1 H), 7.64 (d, J= 1.7 Hz, 2H), 5.89 (s, 1 H), 3.59 (td, J = 6.8, 5.8 Hz, 2H), 3.00 (t, J = 6.8 Hz, 2H), 2.21 (dq, J = 12.7, 6.8 Hz, 2H), 2.01 - 1 .90 (m, 2H), 1 .79 - 1 .62 (m, 4H).19F NMR (470 MHz, cdch) 6 -62.92, -62.94, -62.99 (d, J = 8.9 Hz), -70.35. HRMS ESI(+) calc’d for [M+H] = 422.1162, found = 422.1187.

[0271] 1 -(Prop-2-en-1 -yl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclohexane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -(prop-2-en-1 -yl) cyclohexane- 1 -carboxylic acid (0.297 g, 1.76 mmol), N,N-dimethylformamide (1 .00 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.703 g, 1 .85 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl) ethylamine (0.380 g, 2.00 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and added by syringe. The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.149 g, 25%).1H NMR (500 MHz, cdcl3) 0 7.57 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 5.73 - 5.47 (m, 2H), 5.08 - 4.91 (m, 2H), 3.57 (q, J = 6.7 Hz, 2H), 2.91 (t, J = 7.1 Hz, 2H), 2.18 (d, J = 7.4 Hz, 2H), 1 .84 (d, J = 12.4 Hz, 2H), 1 .55 - 1 .43 (m, 3H), 1 .29 (dq, J = 16.4, 8.5 Hz, 5H).19F NMR (470 MHz, cdcb) 6 -62.43. HRMS ESI(+) calc’d for [M+H] = 340.1884, found = 340.1905.

[0272] 1 -(T rifluoromethyl)-N-{3-[4-(trifluoromethyl)-1 H-pyrazol-1 - yl]propyl}cyclopentane-1-carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 1 -trifluoromethyl-1 -cyclopentane carboxylic acid (0.163 g, 0.900 mmol), N,N-dimethylformamide (2.50 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate (0.505 g, 1.33 mmol) was added as a solid and the vessel was resealed and flushed with argon. The reaction mixture was stirred at room temperature for 5 minutes and 3-[4-(trifluoromethyl)-1 / - / -pyrazol-1 -yl]propan-1 - amine (0.230 g, 1 .00 mMol) was added as a solid. The reaction vessel was sealed with a septum, flushed with argon and stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined, concentrated in vacuo and further purified by reverse-phase Medium Pressure Liquid Chromatography (using 0 - 100 % methanol in a 25 mM aqueous ammonium formate buffer). Fractions containing product were combined, concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate and concentrated in vacuo. This material was further purified by silica gel chromatography using 0 - 100 % ethyl acetate in hexanes to yield the final product (0.119 g, 37 %).1H NMR (500 MHz, cdcl3) 5 7.72 (d, J = 4.3 Hz, 2H), 6.32 (s, 1 H), 4.19 (t, J = 6.5 Hz, 2H), 3.32 (q, J = 6.2 Hz, 2H), 2.27 (dt, J = 12.7, 6.2 Hz, 2H), 2.09 (p, J = 6.4 Hz, 2H), 2.00 (dddd, J = 12.3, 8.0, 5.8, 1.8 Hz, 2H), 1.72 (hept, J = 5.9 Hz, 4H).19F NMR (470 MHz, cdch) 6 -56.36, -70.44. HRMS ESI(+) calc’d for [M+H] = 358.1350, found = 258.1375.

[0273] 1 -[C / s-2-(trifluoromethyl)cyclohexyl]-4-[4-(trifluoromethyl)phenyl]butan-1-one. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added rac-(cis)-2-trifluoromethyl cyclohexane-1 - carboxylic acid (0.196 g 1.00 mmol), N,N-dimethylformamide (0.700 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1.10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl)ethylamine (0.227 g, 1.20 mMol) was dissolved in N,N-dimethylformamide (1.00 mL) and added to the reaction mixture by syringe, which was stirred for 18 hours at roomtemperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.092 g, 25 %).1H NMR (500 MHz, cdcl3) 5 7.62 - 7.52 (m, 2H), 7.39 - 7.30 (m, 2H), 5.50 (s, 1 H), 3.60 (ddt, J = 13.7, 7.4, 6.4 Hz, 1 H), 3.42 (dtd, J = 12.9, 7.2, 5.6 Hz, 1 H), 2.92 (dt, J = 13.6, 6.8 Hz, 1 H), 2.82 (dt, J = 14.1 , 7.3 Hz, 1 H), 2.49 (q, J = 4.2 Hz, 1 H), 2.36 - 2.25 (m, 1 H), 2.25 - 2.14 (m, 1 H), 2.12 - 1 .95 (m, 1 H), 1 .95 - 1 .79 (m, 2H), 1 .71 (dq, J = 12.8, 4.1 Hz, 1 H), 1 .56 - 1 .44 (m, 2H), 1 .39 - 1 .22 (m, 1 H).19F NMR (470 MHz, cdcl3) 0 -62.43, -69.18. HRMS ESI(+) calc’d for [M+H] = 368.1445, found = 368.1470.

[0274] 7rans-2-(trifluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclohexane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added rac-(trans)-2-Trifluoromethyl cyclohexane-1 -carboxylic acid (0.210 g 1 .07 mmol), N,N-dimethylformamide (0.500 mL), and triethylamine (0.252 g, 2.50 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1 .10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl)ethylamine (0.235 g, 1 .25 mMol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added to the reaction mixture by syringe, which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane and subsequently in another silica gel column using 0 - 100 % ethyl acetate in hexanes. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.068 g, 17 %).1H NMR (500 MHz, cdcl3) 6 7.57 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 5.45 (s, 1 H), 3.65 (dq, J = 13.6, 6.7 Hz, 1 H), 3.46 - 3.37 (m,1 H), 2.93 (dt, J = 13.5, 6.6 Hz, 1 H), 2.82 (dt, J = 14.1 , 7.3 Hz, 1 H), 2.57 (dtd, J = 1 1 .5, 7.9, 3.8 Hz, 1 H), 2.08 - 1 .94 (m, 2H), 1 .86 - 1 .72 (m, 3H), 1 .62 (td, J = 12.7, 3.5 Hz, 1 H), 1 .43 - 1 .11 (m, 3H).19F NMR (470 MHz, cdcl3) 5 -62.44, -71 .1 1 (d, J = 8.1 Hz). HRMS ESI(+) calc’d for [M+H] = 368.1445, found = 368.1465.

[0275] 2-(Trifluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}piperidine-1 -carboxamide To a 100 mL 24 / 40 round bottom flask containing a stir bar was 2-(4-Trifluoromethylphenyl)ethylamine (0.302 g, 1.60 mmol), triethylamine (0.202 g, 2.00 mmol) and dichloromethane (3.00 mL). The reaction vessel was sealed with a septum, cooled to 0 °C in an ice bath, and flushed with argon. In a separate vessel 2-(trifluoromethyl)piperidine carbonyl chloride (0.323 g, 1 .49 mmol) was added, followed by dichloromethane (2.00 mL). The 2-(trifluoromethyl)piperidine carbonyl chloride / dichloromethane solution was added to the solution at 0 °C by syringe. The reaction mixture was stirred for 20 hours, warming to room temperature. The reaction mixture was concentrated to a minimal volume and purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo io yield the final product (0.441 g, 80 %).1H NMR (500 MHz, cdcl3) 5 7.57 (d, J = 8.0 Hz, 2H), 7.31 (d, J= 8.0 Hz, 2H), 4.92 (d, J = 1 1 .5 Hz, 1 H), 4.50 (s, 1 H), 3.59 - 3.44 (m, 3H), 3.14 - 3.01 (m, 1 H), 2.91 (td, J = 6.9, 3.7 Hz, 2H), 2.09 - 1 .96 (m, 1 H), 1.78 - 1 .62 (m, 5H), 1 .44 (dd, J = 13.8, 7.8 Hz, 1 H).19F NMR (470 MHz, cdcl3) 6 -62.41 , -69.70 (d, J = 9.7 Hz). HRMS ESI(+) calc’d for [M+H] = 369.1397, found = 369.1423.

[0276] 2-(Trifluoromethyl)-N-{2-[4-(trifluoromethyl)phenyl]ethyl}benzamide To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 2-trifluoromethyl benzoic acid (0.354 g, 1 .86 mmol), N,N-dimethylformamide (1 .50 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.741 g, 1 .95 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl)ethylamine (0.387 g, 2.05 mmol) was dissolved in N,N- dimethylformamide (1 .00 mL) and added to the reaction mixture by syringe, which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.445 g, 65 %).1H NMR (500 MHz, dmso-de) 5 7.42 (dt, J = 9.3, 1 .0 Hz, 1 H), 7.17 (s, 1 H), 7.05 - 6.82 (m, 1 H), 4.94 (s, 1 H), 3.59 (s, 1 H), 3.18 (d, J = 13.0 Hz, 1 H), 2.01 (d, J = 15.1 Hz, 2H), 1.83 - 1 .48 (m, 4H).19F NMR (470 MHz, dmso-d6) 5 -67.86, -68.72 (d, J = 9.9 Hz). HRMS ESI(+) calc’d for [M+H] = 362.0974, found = 362.0996.

[0277] 2,2-Difluoro-N-{2-[4-(trifluoromethyl)phenyl]ethyl}cyclohexane-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 2,2-difluorocyclohexane-1 - carboxylic acid (0.174 g, 1 .06 mmol), N,N-dimethylformamide (0.800 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 - [bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1 .15 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4-Trifluoromethylphenyl) ethylamine (0.217 g, 1 .15 mmol) was dissolved in N,N-dimethylformamide (1 .00 mL) and added to the reaction mixture by syringe, which was stirred for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with brine, 1 .0 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude material which was purified by silica gel chromatography with 0 - 10 % methanol in dichloromethane. Fractions containing product were combined and concentrated in vacuo to yield the final product (0.090 g, 25 %).1H NMR (500 MHz, cdcl3) 5 7.56 (d, J = 7.9 Hz, 2H), 7.32 (t, J = 7.8 Hz, 2H), 6.52 - 5.90 (m, 1 H), 3.67 - 3.46 (m, 2H), 2.91 (dt, J = 10.7, 7.0 Hz, 2H), 2.62 - 2.50 (m, 1 H), 2.39 - 2.22 (m, 1 H), 2.16 (d, J = 11 .2 Hz, 1 H), 2.09 - 1 .96 (m, 1 H),1.84 - 1 .57 (m, 5H), 1 .30 (q, J = 12.9 Hz, 1 H).19F NMR (470 MHz, cdcl3) 6 -62.41 (d, J = 8.4 Hz), -91.03 (d, J = 42.8 Hz), -91.57 HRMS ESI(+) calc’d for [M+H] = 336.1381 , found = 336.1410.

[0278] 2-Chloro-N-{2-[4-(trifluoromethyl)phenyl]ethyl]cyclohex-1- ene-1 -carboxamide. To a 100 mL 24 / 40 round bottom flask containing a stir bar was added 2-chlorocyclohex-1-ene-1 -carboxylic acid (0.164 g, 1.01 mmol), N,N- dimethylformamide (0.800 mL), and triethylamine (0.202 g, 2.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred. The septum was removed and 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.418 g, 1.10 mmol) was added as a solid and the vessel was resealed and flushed with argon. 2-(4- Trifluoromethylphenyl) ethylamine (0.227 ...

Claims

What is claimed is:

1. A compound of the formula:or R4(V) or a pharmaceutically acceptable salt thereof; wherein:R1is halo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylakyl, arylalkyloxy or heteroaryl;R1Ais H or alkyl;R2and R3are alkyl or, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocycloalkyl group;R4is H or alkyl;X1is absent, O, alkyl, haloalkyl, cycloalkyl, cycloalkyloxy, alkylcycloalkyl or heterocycloalkyl;X2and X3are each, independently, cycloalkyl; andR5is cycloalkyl, aryl, arylalkyl, aryloxy, arylalkyloxycarbonyl or heteroaryl: provided that the compound of formula (I) is not:

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1is C6-Cio-aryl or C3-Ci2-cycloalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1is Ci-Ce-alkyl or Ci-Ce-haloalkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1is Cs-Ce-alkenyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1is C3-C6-heterocycloalkenyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R5is C6-Cio-aryl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R5is a C2-Cs-heteroaryl group.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R5is a C6-Cio-aryl-Ci-C6-alkyl group.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R2and R3together with the carbon atom to which they are attached form a C2-C4- heterocycloalkyl group or a Cs-Cs-cycloalkyl group.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X1is a Ci-C6-alkyl group.1 1 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X1is O and R5is C6-Cio-aryl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X1is a Cs-Ce-heterocycloalkyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X1is a Ci-Ce-alkyloxy group.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X2and X3are each, independently, a Ci-Ce-alkyl group.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:wherein:R1is halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl or aryl;R2and R3are alkyl or, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocycloalkyl group;R4is H or alkyl;X1is absent, O, alkyl or cycloalkyl; andR5is aryl, arylalkyl, arylalkyloxycarbonyl or heteroaryl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:wherein:R1is alkyl, aryl or cycloalkyl;R2and R3are alkyl or, together with the carbon atom to which they are attached, form a cycloalkyl or a heterocycloalkyl group;R4is H or alkyl;X1is absent, O or alkyl; andR5is aryl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:R1Ais H or alkyl;R4is H or alkyl;X1is alkyl; andR5is aryl or heteroaryl.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:wherein:X2and X3are each, independently, cycloalkyl;R4is H or alkyl;X1is alkyl; andR5is aryl or heteroaryl.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:wherein:R1is cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl or arylalkyloxy;R4is H or alkyl; X1is cycloalkyl or heterocycloalkyl; andR5is aryl or heteroaryl.

20. A compound of the formula:or a pharmaceutically acceptable salt thereof.21 . A compound of the formula:

22. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. A method of treating a mycobacterial infection, the method comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 22 to a subject in need thereof.

24. The method of claim 23, wherein the mycobacterial infection comprises non- tubercular mycobacterial or tuberculosis infection.

25. The method of claim 24, wherein the non-tubercular mycobacterial infection comprises a M. abscessus, M. avium, M. gordonae, M. smegmatis, or M. marinum infection.

26. The method of claim 24, herein the tuberculosis infection comprises a M. tuberculosis, M. bovis, M. africanum, M. microti, M. cannetti, M. caprae and M. pinnipedi.

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