AU2014246609A1 - Compounds and methods - Google Patents

Abstract

H:\rec\tevven\NRPo,,H]\DCC\REC\6865810_1docx:-9/]{/20ll Disclosed are compounds having the formula: A Z 4 L-R4 wherein X 1, X2 , X3, R', R2, R , R4 , Y, A, Z, L and n are as defined herein, and methods of making and using the same.

Description

H:\rec\Itevven\NRPo,1,]\DCC\REC\6H85810Loc,-9/]{/20]1 COMPOUNDS AND METHODS BACKGROUND OF THE INVENTION This application is a divisional of Australian Patent Application No. 2011205283, the entire content of which is incorporated herein by reference. Field of the Invention The present invention relates to compounds that inhibit histone deacetylase (HIDAC) enzymes, the preparation of these compounds, the use of these compounds in the treatment of diseases or conditions ameliorated by inhibition of HDAC activity and pharmaceutical compositions comprising these compounds. Background of the Invention Chromatin organization involves DNA wound around histone octamers that form nucleosomes. Core histones with N-terminal tails extending from compact nucleosomal core particles can be acetylated or deacetylated at epsilon lysine residues affecting histone DNA and histone-non-histone protein interactions. Histone deacetylases (HDACs) catalyze the deacetylation of histone and non-histone proteins and play an important role in epigenetic regulation. There are currently 18 known HDACs that are organized into three classes: class I HDACs (HIDAC1, HDAC2, -HDAC3, HDAC8 and HDAC 1l) are mainly localized to the nucleus; class II HDACs (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC 10), which shuttle between the nucleus and the cytoplasm; and class III HDACs (S[RTI-7), whose cellular localization includes various organelles. Class II HDACs are further characterized as class Ila HDACs and class IIb HDACs. HDAC9 is class Ila histone deacetylase highly expressed in human Tregs. HIDAC9 deficiency: 1) increases Foxp3 expression (and other Treg inarkers), 2) increases Foxp3 and histone 3 acetylation, 3) increases Foxp3 DNA binding, 4) increases Treg numbers, 5) increases suppressive activity in vitro and in vivo, and 6) ameliorates murine colitis. Tregs which are deficient in HDAC9 induce permanent tolerance of fully mismatched cardiac allografts. In addition, HDAC9 inhibitors maybe useful for treatment H:\rec\jtevven\NRPo1b]\DCC\REC\6H8580_]docx:-9/]{/20]1 - 1A of diseases and disorders associated with abnormal cell proliferation, differentiation and survival, e.g. breast and prostate tumors. Preliminary data shows that targeting HDAC7, a class Ia histone deacetylase, enhances Treg suppression in vitro and in vivo. HDAC7 enhances FOXP3+ Treg function and induces long-term allograft survival. Inhibition of HDAC6, a class lb HDAC, has been shown to increase Treg suppressive function in vitro along with increased expression of FOXP3 protein and Treg associated genes including CTLA, IL-10, TNRI8. HDAC6 inhibition in vivo decreased WO 2011/088181 PCT/US20111021089 severity of colitis in the dextran sodium sulphate-induced colitis model and the CD4.CD62Lx adoptive transfer model of colitis. In addition, inhibition of HDAC6 with a subtherapeutic dose of rapamycin led to prolonged cardiac allograft survival. Based on the above evidence, an orally available small molecule selective inhibitor 5 of Class II HDAC activity (more specifically HDAC9 or HDAC7 or HDAC6) is expected to modulate autoimmune diseases through expansion and enhancement of Treg activity. Inhibition of other Class || HDAC's for example HDAC4 and 5 impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes and maybe potentially useful for the treatment of muscle and heart diseases including cardiac hypertrophy and 10 heart failure. Also, inhibition of Class II HDAC activity, represents a novel approach for disrupting or intervening in cell cycle regulation. Class !! HDAC inhibitors have therapeutic potential in the study and/or treatment of diseases or conditions ameliorated by modulating HDAC activity (in particular, cell proliferative diseases (such as cancer), diabetes (type I and/or type il diabetes), 15 inflammation, cardiac disease, obesity, stroke, epilepsy, depression, imrriunological disease or viral or fungal infection. Many HDAC inhibitors, however, inhibit all HDAC isoforms. It would be advantageous to identify HDAC inhibitors that inhibited one or more but not all HDAC isoforns. 20 SUMMARY OF THE INVENTION The invention is directed to a compound according to Formula 1. R- R" <-7A Z>L--R 4 R X A 25 wherein: R is halo(C -C4)aikyl, wherein said haIo(CC--4)alky contains at least 2 halo groups; Y is a bond and X1 is Q, N or NH, X2 is N or CH and X 3 is N or NH, or Y is --C(O)- and X1 and X 2 are CH or N, X, is O or S, 30 or Y is -- C(O)- and X1 is 0, X 2 is CH or N, and X3 is CH or N; A is optionally substituted (C 3 -Ce)cycIoalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl, wherein any optionally substituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroary! is optionally substituted by 1-3 groups independently selected from 2 WO 2011/088181 PCT/US20111021089

(C,-C

4 )aikyl, halogen, cyano, halo(C-C 4 )alkyi, (C-C4)alkoxy, halo(Cj-C 4 )alkoxy, -NRA RA and -((CrC 4 )alkyi)NRAR^, Z is -C(=O)NRX-. -NRxC(=O)NRx, -NRxC(=O)-, -SO 2 -, -SO2NRx-. -NRXSO 2 -,

-NHCH(CF

3 )-, -CH(CF 3 )NH-, -CH(CF 3 )-, -(C-C4)alkyl-, -NRx-, or -(Cr-C3)alkyl-NRX-; 5 n is 0-4: when n is 0, R" and R 3 are independently selected from H and optionally substituted (C-C 4 )alkyi, aryl(Cr-C 4 )aIkyl-, and (C 3

-C

7 )cycloalkyl(Cr-C 4 )aikyl-, when n is 1-4. R 2 and R' are independently selected from H, fluoro, and optionally substituted (C-C 4 )alkyi, aryl(C-C4)aIkyl-, and (C 3

-C

7 )cycloalkyl(C,-C 4 )aikyl-, wherein, 10 when n is 1, R 2 is F and R3 is H, then Z is -C(=0)NR-, -NRxC(=0)NRx, -SO 2 NR-,

-NHCH(CF

3 )-, -CH(CF 3 )NH-, -CH(CF 3 )-, -(CrC4)ikyl-, -NRx-, or - and when n is 1-4. R 2 is selected from -NRAR", -(CIrC 4 )aIkyl-NRAR, -CONR^Rr.

-(C

1

-C

4 )alkyl-CONRAR 5 , -C0 2 H, -(C-C 4 )alkyl-CO 2 H, hydroxyl, hydroxy(C-C 4 )alkyl-,

(CC

2 )alkoxy, and (C 1 -C,)alkoxy(C-C4)alkyl-, and R' is selected from H and optionally 15 substituted (C-C 4 )alkyi, ary(Cr-C 4 )aIkyl-, and (C 3 -Cr)cycloalkyl(C'.C4)aikyl-, wherein the aryl, cycloalkyl and each of the (C-C4I)alkyl moieties of said optionally substituted (C-C 4 )alkyi, ary(C-C 4 )aikyl-, and (C3-C,)cycloalkyl(C, C4)aikyl- of any R2 and

R

3 are optionally substituted by 1, 2 or 3 groups independently selected from halogen, cyano, (C<C4)alkyl, halo(C-C4)alkyl, (CI-C 4 )alkoxy, halo(Ce-C 4 )alkoxy, -NR^R, 20 -((C 1

-C

4 )aikyl)NRA^, and hydroxyl; or R2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, 6, or 7 membered cycloalkyl or heterocycloalkyl group, wherein said heterocycloalky! group contains 1 or 2 heteroatoms independently selected from N, 0 and S and said optionally substituted cycloalkyl or heterocycloalky group is optionally 25 substituted by 1, 2 or 3 substituents independently selected from (C!-C4)alkyl, halo(C-C4)alkyl, halogen, cyano, aryl(C-C4)Elkyl-, (C 3 -C)cycloalkyl(C-C4)alkyl-, -ORY, -NRYR>, -C(=O)OR , -C(=0)NR R, -NRYC(=O)R , -SO 2 NRYR, -NR SO 2 R , -OC(=O)NR RY -NRYC(=0)ORl, and -NR"C(=O)NR R ; and Lis 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally 30 further substituted, wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and (C-C4)alkyl; R4 is H, (CI-C 4 )aikyl, halo, halo(C-C 4 )alkyi, (C-C4)alkoxy, ((C-C4)alkyl)((C-C4)alkyl)N(C-C 4 )alkoxy, ((C-C 4 )akyl)((C-C4)aiky)N(Cl-C 4 )alkyl-, 35 (Cj-C 4 )haloalkoxy-, (CI-C 4 )alkylamino, optionally substituted (C 3 -Cc)cycloalkyl, optionally 3 WO 2011/088181 PCT/US20111021089 substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 membered heteroaryl, wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1, 2 or 3 groups independently selected from 5 (C,-C 4 )aikyl, halogen, cyano, halo(C-C 4 )alkyi, (C-C4)alkoxy, (C-C 4 )alkylthio-. halo(C-C4)alkoxy, hydroxyl. -NRARe and -((C,-C 4 )alkyl)N RARU; or L-R 4 , taken together, form a 1,3-benzodioxolyl, 23-dihydro-1,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinoly or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionally substituted by 1, 2 or 3 groups 10 independently selected from (C-C )alkyl, halogen, cyano, halo(C-C 4 )aikyl, (CI-C 4 )aikoxy, (C-C4)aikylthio-, haIo(C,-C 4 )alkoxy, hydroxyl, -NRARc and -((CrC 4 )alkyl)NRARc wherein each RA is independently selected from H and (C-C4)alkyi; Re is H, (C-C 4 )alky, halo(CC4;)alkyl, -C(=O)(C 1 -C4)akyl, -C(=O)O(C'-C 4 )alkyl, -C(=O)NH2, --C(=0)NHI(Cr-C4)ai!kyi, -- C(=O)N((Cl-C4)alkyi)((Cr-C4)alkyl), 15 -SO2(C,-C 4 )alkyl, or R^ and RB taken together with the atom to which they are attached form a 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, 0 and S and optionally substituted by (C-C 4 )alkyl; Rc is H, (C-C 4 )aiky, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or RA and RG taken together with the atom to which they are attached form a 20 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, 0 and S and optionally substituted by (CrC 4 )~aky; each Rx is independently selected from H, (CrCe)alkyl, and optionally substituted (C-Ce)aikyl, where said optionally substituted (C-Cs)alkyl is optionally substituted by hydroxyl, cyano, amino, (C -,C 4 )alkoxy, (C-C 4 )alkyi)NH-, or ((CrC 4 )aikyl)((CrC)aikyi)N 25 and each Ry is independently selected from H, (C-C4)alkyl, pheny, and

-(C

1 -C4)alkylpheny!; or a salt thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof, and is further directed to a pharmaceutical composition comprising the compound of 30 Formula i, or a salt thereof, a method of inhibiting HDAC by contacting a HDAC with the compound of Formula I or a salt thereof, and a method of treating a subject having a disease or disorder mediated by inhibition of a HDAC comprising administering the compound of Formula 1, or a salt thereof, or a pharmaceutical composition comprising the compound of Formula I, or a salt thereof, to the subject. 35 4 WO 2011/088181 PCT/US20111021089 in one embodiment, a compound of Formula I excludes the following compounds: N-[(4-fluorophenyl)methyl]-4-[5-(2,2,2-trifluoroacetvi)-2-thienyl]-benzamide N-[(4-fluoroohenyl)methyi]-3-[5-(2,2,2-trifluoroacety!)-2-thienyl]-benzamide, 4-methoxy-N-[2-[3-(trifiuoromethyl)-1 H-1,2,4-triazoi-5-y]-3-thienyl] 5 benzeneacetamide, N-[(4-methoxyphenyi)methyl-4-[5-(trichloromethyl)-1,2,4-oxadiazo-3-yl]-1, 2,5 oxadiazol-3-amine, 4-(trifluoromethyl)-N-3-(trifiuoromethyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazo-3 yijpheny]-benzenepropanamide, 10 3-[4-(trifluorormethyl)phenyl]-N-(3-(trifluorornethyl)-4-[5-(trifiuoromethyl)-1, 2,4 oxadiazol-3-yl]phenyl}propanamide, 3-{7-methyl-2-[4-(3-methvl-5-isoxazolyl)butyl]-1-benzofuran-5-yl}-5 (trifiuoromethyl)-1,2,4-oxadiazole, 1-[3-(3-methy-5-isoxazolyi)propyl]-5-[5-(trifluorormethy!)-1,2,4-oxadiazol-3-y--1 H 15 indole, 7-methyl-1-[4-(3-methyl-5-isoxazolyl)butyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazoi-3 y:J-1H-indole, 7-methyl-1 -[5-(3-methyl-5-isoxazolyl)penty]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol 3-yl]-1H--indole, 20 7-methyl-1 -[3-(3-methyl-5-isoxazolyl)propyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol 3-yl]-2,3-dihydro-1H-indole, or N-(phenylmethy)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazo!-3 amine; or a salt thereof. 25 The invention is father directed to a pharmaceutical composition comprising a compound of the invention. The invention is still further directed to methods of inhibiting HDAC enzymes and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention. 30 DETAILED DESCRIPTION OF THE INVENTION The alternative definitions for the various groups and substituent groups of Formula I provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this invention includes any combination of these group 35 and substituent group definitions 5 WO 2011/088181 PCT/US20111021089 in one embodiment of this invention, R1 is a fluoro- alkyl group containing at least 2 fluoro groups (atoms). In another embodiment, R1 is a (C1-C 2 )aikyI group containing at least 2 fluoro groups. in a specific embodiment, R' is "CHF 2 or CF3; more specifically, R! is CF 3 5 in selected embodiments, when Y is a bond. X 1

X

2 . and X 3 , taken together with the atoms to which they are attached, form an oxadiazoly (X is 0, X 2 and X 3 are N). oxazoV (XI is 0, X 2 is CH, X 3 is N), imidazolyl (X 1 is N or NH, X 2 is CH, X 3 is N or NH); or a triazolyl (X 1 is N or NH, X 2 is N, X 3 is N or NH) ring moiety. In specific embodiments, when Y is a bond, X1, X2, and X3, taken together with the atoms to which they are 10 attached form an oxadiazolyl ring moiety. in selected embodiments, when Y is -C()-, X 1 2 X 2 , and X 3 , taken together with the atoms to which they are attached, form an thiazolyl (X 3 is S, X, is CH and X 2 is N or X 3 is S, X 1 is N and X 2 is CH), oxazoly (X 3 is0, X 1 is CH and X 2 is N or X 3 is 0 X 1 is N and X2 is CH), thienyl (X 1 and X 2 are CH, X is S) or furanyl (X, and X 2 are CH, X3 is O) ring 15 moiety. In specific embodiments, when Y is -- C(O-, X 1 , X 2 , and XK, taken together with the atoms to which they are attached form a thienyl, thiazolyl or oxazolyl ring moiety, more specifically a thieny moiety. In selected embodiments, when Y is -C0()-, X 1 , X 2 , and X 3 , taken together with the atoms to which they are attached, form a furanyl or furyl (XI is 0, X 2 and X 3 are CH), 20 oxazolyl (X 1 is 0, X 2 is CH, and X 3 is N): isoxazolyl (X 1 is O, X, is N, and X 3 is CH), or oxadiazolyl (X 1 is O, X 2 and X 3 are N) ring moiety. In specific embodiments, when Y is X()-, X X2, and X 3 , taken together with the atoms to which they are attached form a furanyl (furyl) ring moiety. The invention is further directed to a compound of Formula (I-a): R' R"

-N

\- A Z L---R // N - i 25 R' wherein R', R", R 3

,R

4 , A, Z, n and L are as defined herein. The invention is still further directed to a compound of Formula (I-b): R2 r wherein R', R2, R 3

,R

4 , A, Z, n and L are as defined herein. 30 6 WO 20111088181 PCT/US201l11021089 The invention is iUrther directed to a compound of FormUla (1-c), (1-d) or (I-e): R N RR N wherein R', R", R3,R 4 A, Z, n and L are as defire hc erein. The invention is still further directed toea compound of Formula (I-f), (1-g), (1-h), (H-) or (1j-): 10 / k ,' +A Z-'- -L R, R! C. k - A - ' Z4 LA 7 WO 2011/088181 PCT/US20111021089 R' R 3 y - A - R wherein R', R 2 , R',R 4 , A, Z n and L are as defined herein The invention is still further directed to a compound of Formula (I-k), (1-1), (I-m), or (I-n): 5 R2 3 o -- A n- . -R R R S --- A - L-R N (I-I), o o-N -A - - L-R R' (I-m, o O-N R" '1,- 1(1-n), 10 wherein R'. R 2 , R 3

,R

4 , A, n and L are as defined herein. In another embodiment, A is a phenyl group optionally substituted by 1-2 groups independently selected from (CrC4alkyl, halogen, oyano halo(C-C 4 )akyl, (Cj-C 4 )aikoxy, haIo(Cj-C 4 )alkoxy, -NRARA and -((CC4)alky)NR^R. In further embodiments, A is a phenyl group optionally substituted by 1 group selected from methyl, ethy, fluoro, chloro, 15 trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARA and -((CrC 4 )aky)NRAR^, where each RA is independently H or methyl. In specific embodiments, A is an unsubstituted phenyl group or a phenyl group substituted by an ethyl, flucro, cyano or methoxy group. In yet another embodiment, A is a cyclopropyl, cyclopenty! or cyclohexyl group, 20 optionally substituted by 1-2 groups independently selected from (C,-C 4 )akyl,

(C,-C

4 )aikoxy, -N PARA and -((CC4)aky)NR^RA. In further embodiments, A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -N RARA and 8 WO 2011/088181 PCT/US20111021089 -((Ci-C 4 )alkyl)NA RA, where each RA i independently IH or methyl. In selected embodiments of this invention, A is a cyclopropyl, cyclopentyl or cyclohexyl group. in another embodiment of this invention, A is naphthyl, optionally substituted by 1-2 groups independently selected from (CI-C4)alky, halogen, cyano, halo(C,-C 4 )alkyl, 5 (C,-C 4 )aikoxy, halo(C-C4)alkoxy, -NRARA and -((C-C4)alky)NWRA. In another embodiment of this invention, A is a 4-7 membered heterocycloalky group optionally substituted by 1-3 groups independently selected from (C 1 -C4)alkvl, halogen, cyano, halo(C-C 4 )alkyi, (Cr-C4)alkoxy, halo(Cj-C 4 )alkoxy, oxo, -NRAR^ and -((CI-C4)aikyl)NPR^RA. 10 in another embodiment of this invention, A is a 9-10 membered heteroary optionally substituted by 1-2 groups independently selected from (CI-C 4 )alkyl, halogen, cyano, halo(C-C4)alkyl, (C-C 4 )alkoxy, halo(Cr-C4)alkoxy, oxo, -NR^RA and

-((C

1

-C

4 )aikyl)N RR^. In selected embodiments, A is isoquinolyl, indazolyl, tetrahydroisoquinolinony, isoindolinonyl, and indolinyl. 15 In further embodiments, A is a 5-6 mernbered heteroaryl optionally substituted by 1-2 groups independently selected from (C-C4)alkyl, halogen, cyano, halo(C-C 4 )alkyl, (C-C4)alkoxy, halo(Cj-C 4 )alkoxy, -- NRARA and -((Cj-C 4 )alky)NR^RA. In still further embodiments, A is a 5-6 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethy, -NIRR^ and 20 -((C,.-C 4 )aikyl)N RAR^, where each R^ is independently i- or methyl and the 5-6 membered heteroaryl contains 1 ring heteroatom selected form N, 0 and S and optionally contains 1 additional ring nitrogen atom. In selected embodiments, A is oxazolyl, pyrazolyl, or thienyl optionally substituted by a methyl group. In other selected embodiments, A is pyrazoly or thienyl, optionally substituted by a methyl group. In specific embodiments, A is thienyl. In 25 other specific embodiments, A is oxazolyl. in yet other embodiments, A is a pyridyl or pyridyi-N-oxide group optionally substituted by 1-2 groups independently selected from (C,-C 4 )alkyl, halogen, cyano, halo(C 1 -C4)alkyl, (C-C 4 )alkoxy, halo(C-C 4 )alkoxy, -NRARA and -((C0-C 4 )alky)NRRA. in further embodiments, A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1 30 group selected from methyl, ethyl, fluoro, chloro, triflucromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARA and -((C-C4)alkyl)NRARA, where each RA is independently H or methy In selected embodiments, A is pyridyl or pyridyl-N-oxide In specific embodiments, A is pyridyl. in another embodiment of this invention, Z is -C(=O)NR-, -NRxC(=0)NR, or 35 -NRC(=O)-; particularly -C(=0)NRx- or -NRxC(=0)-. In another embodiment of this invention, Z is -SO 2 NRx- or -NRxS0 2 -. In another embodiment of this invention, Z is 9 WO 2011/088181 PCT/US20111021089 -NHCH(CF3)- or -CH(CF 3 )NH-. In another embodiment of this invention, Z is -CH(CF3) or -(C 1

-C

4 )alkyl- In another embodiment of this invention, Z is -N R - or -(CrlC3)alkyl-N Rx-. For each of the above embodiments of Z, R". or for -NRxC(=O)NRx, each R, may 5 be independently selected from H, (C-C4)alkvi, and optionally substituted (C 2

-C

4 )alkyi, where said optionally substituted (C 2 -C4)aikyl is ootionally substituted by hydroxyl, cyano, amino. (C -C 4 )alkoxy, (C,-C 4 )alkyl)N H-, or ((C-C 4 )alkyl)((C,-C4)alkyl)N-. For each of the above embodiments of Z, Rx, or for -NRxC(=O)NRx, each RX, may be independently selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N 10 methylarninoethyl- and dimethylarninoethyl-. In specific embodiments, each RX is independently H, methyl or cyanoethyl, more specifically, RX is H or methyl. in particular embodiments, Z is -C(=O)NR-, -SO 2 -, -SO 2 NRx-, -CH(CF 3 )NH-, methyl (methylenyl), ethyl (ethylenyl), -NR-, or -(CIrC 3 )alkyl-NRx-, where each Rx is independently H, methyl or ethyl. In specific embodiments, each Rx is iHI. In selected 15 embodiments, Z is -- C(=O)NH-, -SO 2 NH-, -. CH(CF 3 )Nl- ethyl (ethylenyl), -CH 2 NH-,

-CHN(CH

2 CH3)-, CH(CH3)N(CH 2 CH3), or -CH(CH)NH. In specific embodiments, Z is -C(=0)NI- or -- CIH2N I In another embodiment of this invention, n is 0-4, particularly 0-3. In specific embodiments, n is 1 or n is 0. 20 in another embodiment, one of R 2 and R' is other than hydrogen. In yet another embodiment, both R 2 and R3 are C1 alkyl (e.g., methyl). In a still further embodiment, one of R2 and R 3 is H and the other of R 2 and R3 is C_ alkyl (e.g, methyl). in a further embodiment, R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalky or heterocycloalkyl group, wherein 25 said heterocycloalkyl group contains 1 heteroatom selected from N. O and S and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by a substituent selected from (C-C 4 )alkyl, halo(C- 4 )alkyl, halogen, cyano, aryl(C-C 2 )akyl-,

(C

2 -Ce)cyclOalkyl(C-C 2 )alkyl-, -OR ", -NR*aR , -C(=O)OR*a, -C(=C)NRY'Ryb -NR*bC(=O)Rya, -SO 2 NR'Ry, and -NR"bSO2R"' where R is selected from H, 30 (C-C 4 )aikyl, pheny(C-C 2 )alky- and (C 3 -Cs)cycloalkyl(GC-C 2 )alkyl-, and each Ryb is independently selected from H and (C-C4)alky!, specifically H and methyl in another embodiment of this invention, when n is 0, R 2 and R 3 are independently selected from H and optionally substituted (C-C 4 )alkyl, phenyl(C-C 2 )akyl-, and

(C

2 -Ce)cycloalkyl(C 1

-C

2 )alkyl-. 10 WO 2011/088181 PCT/US20111021089 in another embodiment, when n is 1, R 2 and R' are independently selected from H and optionally substituted (CI-C 4 )alkyl, phenyi(C1-C 2 )alkyl-, and (Cr-Ce)cycloalkyl(Cr-C2)alkyl-. in another embodiment, when n is 1, R2 is F and R3 is H, then Z is -C(=O)NH-, 5 -NHC(=O)NH, -S0 2 NH-. -NHCH(CF 3 )-, -CH(CF3)NH-, -CH(CF 3 )-, -(C-C 4 )alkyl-, -NH-, or

-CH

2 NH-; more specifically, Z is -C(=0)NH- or -CH 2 NH-. In another embodiment, when n is 2-4, R 2 and R3 are independently selected from H. fluoro, and optionally substituted (C-C 4 )alky, pheny(C, C 4 )alkyl-, and

(C

3 -Ce)cycloalkyl(Cr-C 4 )alkyl-. 10 in another embodiment of this invention, when n is 1-4, R2 is selected from amino,

(C,-C

4 )aikylamino, ((C.-C 3 )alkyl)((C,-C 3 )aikyl)amino, amino(CrC4)a'lkyl, (CI-C3)aikylamino(C,-C 4 )alkyl, ((C,-C 3 )aikyl)((Cr-C 3 )aikyl)amino(C-C4)alky, (substituted(C-C3)aky!)((C-C 3 )alky)amino(C-C 4 )akyi (whe.r said (substituted (CCs)aikyl moiety is substituted by -- C(=0)OH, -C(=O)O(C.C4)aiky, or 1-6 fluoro 15 groups), aminocarbonyl(C-C 4 )alkyl, (Cl-C 3 )aikylaminocarbony(C-C 4 )alkyi, ((Cr-C 3 )alkyl)((C-C 3 )alkyflarninocarbonyi(CrC 4 )alkyihydroxyl, hydroxy(C-C4)alky-, (C,-C4)aikoxy, and (C,-C4)akoxy(C-C 4 )alkyl- and R 3 is selected from H and optionally substituted (CrC 4 )alkyi, aryl(C 1

-C

4 )aikyl-, and (Cn-C7)cycloalkyl(C-C 4 )akyl-. in another embodiment of this invention, when n is 1-4, R 2 is selected from amino, 20 hydroxyl, and (C 1

C

4 )aikoxy, and R 3 is selected from H and optionally substituted (C--C4)akyl, phenyl(C-0 2 )alkyl-, and (C 2 -Ce)cycloalkyl(C-C 2 )alkyl. In another embodiment, n is 1-3, R 2 s hydroxy! and R' is H or methy; more specifically, n is1, R 2 is hydroxyl and R 3 is H or methyl. In another embodiment of this invention, (for any value of n) R 2 and R 3 are independently selected from H and optionally substituted (C-C 4 )alkyl, 25 phenyl(C-C2)alkyl-, and (Cr-Cj)cycloalkyi(C-C 2 )alkyl-. in another embodiment of this invention, (for any value of n) R 2 is selected from H and optionally substituted (C,-C 4 )alkyl, phenyi(C-C 2 )aky-, and (CCe)cycloalkyl(C-C 2 )akyl- and R 3 is selected from H and methyl in specific embodiments of this invention (for any value of n), R 2 and R3 are 30 independently selected from H and methyl. In more specific embodiments, both R 2 and

R

2 are H or both R 2 and R 3 are methy in another embodiment of this invention, the aryi, phenyl, cycloalkyi and each of the (C 1 C4)alkyl or (C 1

-C

2 )alkyl moileties of said optionally substituted (Cj-C 4 )alkyl, aryl(CC4)alky-, phenyl (CC4)aikyl-, (C-C 7 )cycloalkyi(C-C4)alkyl- and 35 (C-C 6 )cycloalkyl(C-C 2 )akyl- of any R 2 and R 3 are optionally substituted by 1, 2 or 3 halogen (specifically fluorine) groups and/or I or 2 groups independently selected from 11 WO 2011/088181 PCT/US20111021089 cyano, (CrC 4 )alkyl, halo(C-C4)alkyl, (C-C 4 )alkOxy, halo(C,-C 4 )alkoxy, NRR',

-((C,,C

4 )alkyl)NRAR^, and hydroxyl. in another embodiment of this invention, R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyl or 5 heterocycloalkyi group, wherein said heterocycloalkyl group contains 1 hetercatom selected from N, 0 and S and said optionally substituted cycloalkyl or heterocycloalky group is optionally substituted by a substituent selected from (C-C4)alkyl, halo(C-C4)alkyl, halogen, cyano, aryl(C-C 2 )alkyl-, (C 3 -Ce)cycloalkyl(C-C 2 )alkyl-, -OR% -NR"Ry", -C(=0)OR, -C(=0)NR'RY", -NRC(=0)R", -SO 2 NR'R*, and 10 -NRY'SO2Ry", where R' is selected from H, (Cr-C 4 )aikyl phenyl(Cj-C 2 )alkyl- and

(C

3 -Ce)cycloalkyl(C,-C 2 )alkyl-, and each R" is independently selected from H and

(CI-C

4 )aikyl, specifically H and methyl. in specific embodiments of this invention, R 2 and R taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyl 15 or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N and 0 and said optionally substituted cycloalkyl or heterocycloalkyi group is optionally substituted by a substituent selected from (C. -C 4 )alkyl, aryi(C-C 2 )alkyl-, and (CrC)cycloalkyl(C 1

-C

2 )alkyl. in selected embodiments of this invention, R 2 and R'taken together with the atom 20 to which they are connected form a tetrahydropyrany, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-pipendinyl, cyclopropyl, cyclohexyl, I-ethyl-piperidinyyl, tetrahydrofurany, piperidiny!, 1-methyl-pyrrolidinyl, 1-benzyl-pyrrolidiny, 1 cyclopropylmethyl-pyrrolidiny, oxetanyl, azetidinyl, 1 -methy!-azetidiny, 1-benzyl azetidinyl, or 1-cyclopropylmethyl-azetidinyl group. 25 in specific embodiments of this invention, R 2 and R 3 taken together with the atom to which they are connected form 3 tetrahydropyrany, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl group. In another embodiment of this invention, L is 5-6 membered heteroaryl or pheny! which is substituted by R4 and is optionally further substituted, wherein when L. is further 30 substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and methyl. In another embodiment of this invention, L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L. is further substituted, L is substituted by 1 substituent selected from chloro, fluoro, cyano 35 and methyl. 12 WO 2011/088181 PCT/US20111021089 in selected embodiments, L is pyrazolyl, oxadiazoly, 1-methyl-imidazoly, thiazolyl, thienyl, triazolyl, pyridyl, phenyl, oxazoly! or isoxazolyl, any of which is substituted by a methyl group. In specific embodiments, L is thiazolyl, thienyl, triazolyi, pyridyl, phenyl, or 5 oxazoliyl, any of which is substituted by a methyl group. In another embodiment of this invention, R 4 is H, halogen, (CI-C4)alkyl, halo(CI-C 2 )alkyl, (CI-C 2 )alkoxy, ((CI-C 2 )alkyl)((C-C2)aikyl)N(C-C 3 )alkoxy-,

((C-C

2 )alkyl)((C-C 2 )alkyl)N(CI-C 3 )alkyl-, (CrC 2 )haioalkyl, (CI-C 3 )aikylamino, optionally substituted (C-C6)cycloalky, optionally substituted phenyl, optionally substituted 5-6 10 membered heterocycloalky, or optionally substituted 5-6 rnembered heteroaryl, where said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1 or 2 groups independently selected from (C-C4)alkyl, halogen, cyano, haIlo(CI-C 2 )alkyl, (CC 2 )alkoxy, halo(Cl-C 2 )alkoxy, hydroxyl, -NRARC and -((C,-C4)aikyl)N RARc. 15 in a selected embodiments, R' is H, methyl, bromo, trifluorornethyl, dimethylaminoethoxy-, dimethylaminopropyl-, and optionally substituted pyridyl, cyclohexyl, piperidinyl, piperazinyl, imidazolyl, thienyi, or phenyl, where the pyridyl, cyclohexyl, piperidinyl, piperiziny, imidazolyl, thienyl, or phenyl are optionally substituted by 1-2 substituents independently selected from methyl, chloro, bromo, fluoro, 20 trifluoromethyl, methoxy, and cyano. in a selected embodiments, Rt 4 is -1, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-, phenyl, 4-chlorophenyl, 2-bromophenyl-,4-fluorophenyl, 4 cyanophenyl, 3-trifluoromethylphenyl, 4-methoxypheny, cyclohexyl, imidazolyl, thienyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl. 25 in other embodirents of this invention, L-R 4 , taken together, form a 1,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazoly, 2,3-dihydro-1,4-benzodioxiny!, benzofuranyl, benzirnidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl group, optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, phenyl, and morpholinylpropyl-. 30 in selected embodiments of this invention, L-R 4 , taken together, form a 1,3-benzodioxolyl, tetrahydroisoquinolyl or isoindolinyl group. in another embodiment of this invention, each RA and Re is independently selected from H and (C-C4)alkyl; specifically each RA and Rc is independently selected from H, methyl and ethyl. 13 WO 2011/088181 PCT/US20111021089 in another embodiment of this invention, each RY is independently selected from H, (Cr- 4 )alkyi, phenyl, and -(Cj-C 4 )alkylpheny!; specifically each RY is independently selected from H, methyl, ethyl, phenyl, benzyl and -ethylphenyl. As used herein, the term "alky" represents a saturated, straight or branched 5 hydrocarbon moiety, which may be unsubstituted or substituted by one, or more of the substituents defined herein. Exemplary alkyls include, but are not limited to methyl (Me), ethyl (Et), n-propyi, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyi, n-pentyl, iso-pentyl (3 rmethyl-butyl), neo-pentyi (2,2-dimrethylpropyl), etc. The term "Cl-C 4 " refers to an alky containing from 1 to 4 carbon atoms. 10 When the term alkyll" is used in combination with other substituent groups, such as "haloalkyl" or "cycloalkyl-alkyl" or "arylalkyl", the term "alkyl" is intended to encompass a divalent straight or branched-chain hydrocarbon radical. For example, "arylalkyl" is intended to mean the radical -alkylaryl, wherein the alkyl moiety thereof is a divalent straight or branched-chain carbon radical and the ary! moiety thereof is as defined herein, 15 and is represented by the bonding arrangement present in a benzyl group (-CH 2 -Phenyl). In addition, the term "alkyl" may be used to define a divalent substituent, such as a group bonded to two other groups. In this instance, the term "alky!" is intended to encompass a divalent straight or branched-chain hydrocarbon radical. For example, "pentyl" is intended to represent a pentylene diradical --wherein the pentyl moiety is any 20 one of a divalent straight (-CH2CH!2CH 2

CH

2 CHr 2 -) or branched (-CH 2 CH(CHi 3 )Cl-i 2

H

2 -CH 2

CH

2

CH(CJ

2

H

2 -- , -Cl2CIH 2 C(CH3) 2 -) chain 5--carbon radical. As used herein, the term "cycloalkylr refers to a non-aromatic, saturated, cyclic hydrocarbon ring. The term "(C 3 -0C)cycloalkyr refers to a non-aromatic cyclic hydrocarbon ring having from three to eight ring carbon atoms. Exemplary 25 "(C-Ca)cycloalkyr groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. "Alkoxy" refers to a group containing an alky radical attached through an oxygen linking atom. The term (C-C 4 )akoxy" refers to a straight- or branched-chain hydrocarbon radical having at least I and up to 4 carbon atoms attached through an 30 oxygen linking atom. Exemplary "(C-C 4 )alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and t-butoxy. "Arvi" represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, 35 which may be unsubstituted or substituted by one or more of the substituents defined 14 WO 2011/088181 PCT/US20111021089 herein, and to which may be fused one or more cycioalkyl rings, which may be unsubstituted or substituted by one or more substituents defined herein. Generally, in the compounds of this invention, aryl is phenyl. Heterocyclic groups may be heteroaryl or heterocycloalkyl groups. 5 "Heterocycloalkyl" represents a group or moiety comprising a stable, non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes I to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein. The heterocycloalkyl may be attached by any atom of the 10 rnonocyclic or bicyclic radical which results in the creation of a stable structure. This term encompasses bicyclic heterocycloalkyl moieties where the rings are joined at two atoms per ring, as exemplified by the bonding arrangement in 2,5-diazabicyclo[2.2.I]hepty. 2 azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 7-oxa-2-azabicyclo[2.2.1]heptyi, 2-thia-5-azabicyclo[2.2.1] heptyl,7-azabicyclo[2.2.llheptyi, 2,6 15 diazatricyclo[3.3.1.13,7]decyl, 2-azatricyclo[3.3.1.13,7]decy. 2,4,9 triazatricyclo[3.3.1 13,7]decy, 8-azabicyclo[3.2. 1jocty, 2,5-diazabicyclo[2.2.2]octyi, 2 azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclc[3.2.1]octyl, octahydro-1f pyrrolo[3,2-b]pyridyl group. This term specifically excludes bicyclic heterocycloalkyl moieties where the rings are joined at a single atom per ring (spiro), as exemplified by the 20 bonding arrangement in a I -oxa-2-azaspiro[4.5]dec-2-en-3-y group. Illustrative examples of heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidyl (or pyrrolidiny), piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl), dihydrofuryl, oxazoliny!, thiazolinyl, pyrazolinyi, tetra hydropyranyl, dihydropyranyl, 1,3-dioxolanyi, 1,3-dioxanyl, 1,4-dioxanyi, 1,3-oxathiolanyl, 1,3-oxathiany, 25 1,3-dithianyl, azabicylo[3.2.1]octy, azabicylo[3.3.1]ronyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl and 1,5,9-triazacyclododecyl. Generally, in the compounds of this invention, heterocycloalkyl groups are 5-membered and/or 6-membered heterocycloalkyl groups, such as pyrrolidyl (or pyrrolidinyl) tetrahydrofuryl (or tetrahydrofuranyl), tetrahydrothienyl, dihydrofuryl, 30 oxazolinyl, thiazolinyl or pyrazolinyl, piperidyl (or piperidiny), piperazinyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, tetrahydro-2H-1,4-thiazinyl, 1,4-dioxanyl, 1,3-oxathianyl, and 1,3-dithianyl. "Heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including I to 4 heteroatoms 35 selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. This term also encompasses bicyclic 15 WO 2011/088181 PCT/US20111021089 heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalky ring moiety, containing 5 to 10 ring atoms, including i to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein. This term is also intended to encompass heterocyclic 5 groups containing nitrogen and/or sulfur where the nitrogen or sulfur heteroatoms are optionally oxidized. Illustrative examples of heteroaryls include, but are not limited to, thieny, pyrrolyl, imidazolyi, pyrazolyi, furyl (or furanyl), isothiazolyi, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyridyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetraziny, triazolyi, tetrazoly, benzo[b]thieny, isobenzofuryl, 2,3 10 dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindoly!, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthridinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isolndollnyl, indolinyl, cinnolinyl, pteridinyl, isothiazolyl. Some of the heteroaryl groups present in the compounds of this invention are 5-6 15 membered monocyclic heteroaryl groups. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1, 2 or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, 3 or 4 nitrogen ring heteroatoms. Selected 5- or 6-membered heteroaryl groups include thienyi, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, oxazolyl, 20 oxadiazolyl, thiazolyl, triazolyl, and tetrazoly! or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triaziny and thiadiazolyl Some of the heteroaryl groups present in the compounds of this invention are 9-10 membered bicyclic heteroaryl groups. Selected 9-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1, 2 or 3 additional 25 nitrogen ring atoms. Selected 10-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatorn, and optionally contain 1, 2, 3 or 4 additional nitrogen ring atoms. Selected 9-10 membered heteroaryl groups include benzo[bthienyl, isobenzofuryl, 2,3-dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthridinyl, quinzolinyl, 30 benzothiazolyl, benzimidazolyi, tetrahydroquinolinyl, cinnolinyl, pteridinyi. The terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo substituents. "Hydroxy" or "hydroxyl" is intended to mean the radical -OH. The term "oxo" is intended to mean a keto diradical (=O), such as present on a pyrrolidin-2-one ring. The compounds of the invention are only those which are contemplated to be 35 "chemically stable" as will be appreciated by those skilled in the art. Specifically, the invention is directed to a compound according to Formula (I-a): 16 WO 2011/088181 PCT/US20111021089 R\ R3 1 j Z--- -L-R' wherein: RI is -CF3; A is optionally substituted (C 3 -C6)cycloakyl, Phenyl, naphthyl, 4-7 membered 5 heterocycloalky, 5-6 membered heteroaryl, or 9-10 membered heteroaryl, wherein any optionally substituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or hetercary is optionally substituted by 1-3 groups independently selected from (C-C4)akyl, halogen, cyano, halo(C-C4)alkyl, (C-C 4 )alkoxy, halo(CI-C 4 )alkoxy, -NRAR^ and -((CrjC4)alky!)NRARA 10 Z is -C(=O)NRK, -NRxC(=ONRx -NXC(=)-, -SO'-, -SO 2 NR- -NRxSOr, -NHCH(CF3)-, -CH(CF3)NH-, -CH(CF 3 )-, -(CI-C 4 )aikyl-, -NRx-, or -(Cr-C 3 )alky-NR-; n s 0-4; when n is 0, R 2 and RF are independently selected from H and optionally substituted (CrC4)alkyl, aryi(CI-C 4 )alkyl-, and (C 3 -C)cycloalkyl(C-C 4 )akyl 15 when n is 1-4, R2 and R' are independently selected from H, fluoro, and optionally substituted (C-C4)alkyl, aryl(C-C 4 )alkyl-, and (C 3

-C

7 )cycloalkyl(C-C 4 )akyl-, wherein, when n is 1, R 2 is F and R' is H, then Z is -C(=O)NRx-, -NRxC(=O)NR, -SO2NRk,

-NHCH(CF

3 )-, -CH(CF 2 )NH-, -CH(CF 3 )-, -(CI- 4 )aikyl-, -NR-, or -(C-C 3 )alkyl-NR", and when n is 1-4, 2 is selected from amino, hydroxyl, and (C-C 4 )alkoxy, and R: is 20 selected from H and optionally substituted (C!-C 4 )alkyl, aryl(C-C 4 )alkyl-, and

(C

3 -C,)cycloalkyl(C-C4)akyl-, wherein the aryl, cycloalkyl and each of the (C-C 4 )alkyl moieties of said optionally substituted (C-C 4 )alkyi, aryI!(C-C 4 )aIky-, and (C 3

-C

7 )Cycloalkyl(C-C 4 )akyl- of any R' and R2 are optionally substituted by 1, 2 or 3 groups independently selected from halogen, 25 cyano, (C-C 4 )alkyl, halo(C-C4)alkyi, (C-C 4 )alkoxy, halo(C-C4)alkoxy, halogen, -NRAR^, -((C-C4)aikyl)NR^R^, (C-C 4 )alkoxy, hydroxyl, cyano, halo(C-C4)alkvI, and halo(CI-C4)alkoxy; or R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, 6, or 7 membered cycloalkyl or heterocycloalkyl group, wherein 30 said heterocycloalky group contains I or 2 heteroatoms independently selected from N, 0 and S and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from (CI-C 4 )alkyl, halo(C,-C 4 )alKyl, halogen, cyano, aryl(C 1

-C

4 )alkyl-, (C 3 -C)cycloalkyl(C 1

-C

4 )alkyl-, -- ORY, 17 WO 2011/088181 PCT/US20111021089 -NRYRY, -C(=0)OR , -C(=O)NR -R, -NRYC(=0)R , -SO) 2 NRYR , -NRnSO2R , -CC(=O)NRYRY, -NR C(=0)OR , and -NR C(=O)NRR; and L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted, 5 wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and (C-C4)alkyl;

R

4 is H, (C-C4)aikyl, halo, halo(C-C 4 )aIkyl, (C-C 4 )alkoxy, ((C-C4)alkyl)((C-C4)alkyl)N(C,-C4)alkoxy, ((C,-C 4 )aikyl)((C-C 4 )aiky!)N(C-C 4 )alkyl-,

(C

1

-C

4 )haloalkoxy-, (C 1

-C

4 )alkylamino, optionally substituted (C 3 Ce)ycloalkyl, optionally 10 substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 membered heteroaryl, wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1, 2 or 3 groups independently selected from (C-C4)aikyl, halogen, cyano, halo(CC4)alkyi, (Cl-C 4 )alkoxy, (C-C4alkylthio-, 15 halo(C 1

-C

4 )alkoxy, hydroxyl, -NR^Rc and -((C 1

,C

4 )alkyl)NR^R; or L-R 4 , taken together, form a 1,3-benzodioxolyl, 2,3-dihydro- 1,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinoly; or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionally substituted by 1, 2 or 3 groups independently selected from (C-C 4 )alkyl, halogen, cyano, halo(CC 4 )aikyl, (C, -C 4 )alkoxy, 20 (CI-C4)aikylthio-, halo(C 1 -C4)aikoxy, hydroxyl, -NRARo and -((CrC 4 )alkyl)NRAR; wherein each R^ is independently selected from H and (C -C 4 )alky!; Re is H, (Cr-C 4 )aikyi, phenyl, 5-6 membered heterocyloalkyl, or 5-6 membered heteroary!, or RA and Re taken together with the atom to which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional 25 heteroatom selected from N, O arnd S; each Rx is independently selected from H, (C-C 6 )alkyl, and optionally substituted

(C-C

6 )aikyl, where said optionally substituted (C-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (C 1

-C

4 )alk~oxy, (Cr-C 4 )alkyi)NH-, or ((C 1 -C4)aikyl)((Cr-C 4 )aikyi)N-; and 30 each RY is independently selected from H, (CrC4alkyl, phenyl, and -(Cr-C4)alkylphenyi; provided that the compound is not: 3-[4-(trifluoromethyl)phenyl]-N-(3-(trifluoromethyi)-4-[5-(trifiuoromethyl)-1,2,4 oxadiazol-3-yliphenyl}propanamido, 35 3-{7-methyl-2-[4-(3-methyl-5-isoxazolyl)buty]-1-benzofuran-5-yl}-5 (trifiuoromethyl)-1,2,4-oxadiazole, 18 WO 2011/088181 PCT/US20111021089 1-[3-(3-methyi-5-isoxaolyl)prooyl]-5-[5-(trifluoromnethy)-1 ,2,4-oxadlazo-3-y]-1 H indole, 7-methyi-1-[4-(3-methyl-5-isoxazolyl)butl]-5-[5-(trifluoromethl)-1,.2,4-oxadiazoi-3 yP]-1Hi--indole, 5 7-methyl-1-r5-(3-methyl-5-isoxazolyl)penty]-5-[5-(trifluoromethyi)-1,2,4-oxadiazo 3-yl]-1H-indole, 7-methyl-1-[3-(3-methyl-5-isoxazolyl)propyl]-5-[5-(trifluoromethyl)-1,2,4-oxadiazol 3-yl]-2,3-dihydro-1H-indole, or N-(phenylrnethyi)-4-[5-(trifluoromethyl)-I,2,4-cxadiazol-3-yl]-1,2,5-oxadiazol-3 10 amine; or a salt, particularly a pharmaceutically acceptable sait, thereof. Accordingly, the invention is further directed to a compound according to Formula 1, wherein: 15 R is CHF 2 or CF,; Y is a bond, X 1 is 0, and X 2 and X 3 are N, or Y is --C(O)-, X, and X 2 are CH, and X 3 is S, or Y is -C(O)-, X, is 0, and X and X, are CH; A is a phenyl group optionally substituted by I group selected from methyl, ethyl, 20 fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NR^R^ and -((CrC 4 )aikyl)NRAFA or A is a cyclopropyi, cyclopentyl or cyclohexy! group, optionally substituted by 1-2 groups independently selected from methyl, ethyl, tert-buty!, methoxy, ethoxy, -NRARA and -((C,.C4)aikyl)NRAR, or 25 A is a 5-6 mernbered heteroaryl or a 9-10 mernbered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethy, -NRARA and -((C-C4)akyl)N RAR^, where the 5-6 membered heteroaryl or 9-10 membered heteroaryl contains I ring heteroatomrn selected form N, 0 and S and optionally contains I additional ring nitrogen atom, 30 where each RA is independently H or methyl: Z is -C(=O)NRx-, -NRxC(=O)NRA, -NRxC(=O)-, -NHCH(CF3)-, -CH(CF3)NH

-CH(CF

3 )-, -(C-C4)alkyl-, or -(CIrC 4 )alkylNRx-, where Rx is H, (C-C4)alkyl, or optionally substituted (C 2 -C4)alkyl, where said optionally substituted (C 2 -C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (C-C4)aikoxy, (C-C 4 )alkyl)NH-, or 35 ((C-C 4 )alkyl)((C-C 4 )alkyl)N-; 19 WO 2011/088181 PCT/US20111021089 n s 0-3 and R 2 and R3 are independently selected from H and optionally substituted

(C

1

C-

4 )aikyl, phenyl(C(-C 2 )alkyl-, and (C 3 Ce)cycloalky(CrC2)alkl-, or n is 1-3 and R is hydroxyl and R3 is H or methyl, or n is 0-3 and R 2 and R' taken together with the atom to which they are connected 5 form an optionally substituted 4, 5, or 6 membered cycloalkyl or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N, 0 and S and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by a substituent selected from (Cj-C 4 )alkyl, halo(C-C 4 )alkyl, halogen, cyano, aryl(C-C 2 )alkyl-, (C 3 -CS)cycloalkyl(Cr-C 2 )alky-, -ORY', -NRY'Ry', -C(=O)OR", 10 -C(=0)NRR'b. -NROC(=0)R3, -SO 2 NRR'b, and -NR""SO 2 RY', whereR'is selected from H, (C-C 4 )aikyl pheny(C-C 2 )aIkyl- and (C 3 -Cs)cycloalkyl(C 1

-C

2 )alkyl-, and each R* is independently selected from H and (CI-C 4 )aikyl; L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 or 2 15 substituents independently selected from halogen, cyano and methyl, and

R

4 is H, halogen, (C-C4)alkyl, halo(C-C 2 )alkyl, (CrC 2 )alkoxy, ((Cr C- 2 )alkyl)((C -C2)alkyl)N(C-C 3 )alkoxy. ((C.-C 2 )alkyl)((C 1

-C

2 )alkyl)N(C-C 3 )alkyl-,

(C-C

2 )haloalkyl, (C-C 3 )alkylarnino, optionally substituted (C 3 -C6)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally 20 substituted 5-6 membered heteroaryl, where said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by I or 2 groups independently selected from (C<C 4 )alkyl, halogen, cyanc, halo(Cr-C2)aIkyl, (C-C 2 )alkoxy, halo(C,-C 2 )alKoxy, hydroxyl, -NR^Rc and -((C-C 4 )alkyl)N R^Ro; or a salt, particularly a pharmaceutically acceptable salt, thereof. 25 The invention is yet further directed to 3 compound as defined herein wherein: n is 0-3 and R 2 and R' are independently selected from H and optionally substituted

(C

1 -C04)aikyl, phenyl(C-C 2 )alkyl-, and (C3-Ce)cycloalkyi(C-C 2 )alkyl-, or n is 1-3 and R 2 is hydroxyl and R 3 is H or methyl, or 30 n is 0-3 and R 2 and R' taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyl or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N and 0 and said optionally substituted cycloalky or heterocycloalkyl group is optionally substituted by a substituent selected from (CI-C 4 )alkyl, aryl(Cj-C 2 )alkyl-, and 35 (C-C 6 )cycloalkyl(C-C 2 )alkyl Rx is H, methyl or cyanoethyl; 20 WO 2011/088181 PCT/US20111021089 L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by I substituent selected from chloro, fluoro, cyano and methyl; and R4 is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-, 5 dimethylaminopropyl-, and optionally substituted pyridyl, cyclohexyl, piperidinyl, piperazinyl, imidazolyl, thienyl, or phenyl, where the pyridyl, cyclohexyl, piperidinyl, piperizinyl, imidazolyl, thienyl, or phenyl are optionally substituted by 1-2 substituents independently selected from methyl, chloro, brorno, fluoro, trifluoromethyl, methoxy, and cyano; 10 or a salt, particularly a pharmaceutically acceptable salt, thereof. The invention is specifically directed to a compound according to Formula 1, wherein: RI is CHIF 2 or CF 3 ; 15 Y is a bond, X 1 is O, and X2 and X 3 are N, or Y is --C(O)-, X, and X 2 are CH, and X 3 is S, or Y is -- C(O)-. X, is O, and X2 and X3 are CH.; A is an unsubstituted phenyl group or a phenyl group substituted by an ethyl, fluoro, cyano or rmethoxy group, or a thienyl, pyridyl, cyclopropyl, cyclopentyl or cyclohexyl group; 20 Z is -C(=D)N H- or --C-2N i-I-; n is 0 or 1 and both R 2 and R' are H or both R 2 and R 3 are methyl, or n ;s 1 and R 2 is hydroxyl and R 3 is H or methyl, or n isO or 1 and R 2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl 25 group; L is thiazolyl, thieny, triazolyl, pyridyl, phenyl, or oxazolyl, any of which is optionally substituted by a methyl group; R4 is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-, phenyl, 4-chlorophenyl, 2-bromophenyl-,4-fluorophenyl, 4-cyanophenyl, 3-trifluoromethylphenyl, 4-methoxyphenyl, 30 cyclohexyl, midazolyl, thienyl, pyrid-2-yl, pyrid-3-y, or pyrid-4-y; or

L-R

4 , taken together, form a 1,3-benzodioxoly, tetrahydroisoquinoly! or isoindolinyl group; or a salt, particularly a pharmaceutically acceptable salt, thereof. The invention is more specifically directed to a compound according to Formula I, 35 wherein: RI is CHF 2 or CF 3 ; 21 WO 2011/088181 PCT/US20111021089 Y is a bond, X 1 is 0, and X 2 and X 3 are N; A is an unsubstituted phenyl or pyridyl group; Z is -C(=O)NH- or -CH 2 NH-; n is 1; 5 R2 and R' are both methyl, or R2 is hydroxyl and R3 is methyl, or

R

2 and R 3 are both hydrogen, or RI is methyl and R' is hydrogen, or

R

2 is hydroxyl and R 3 is hydrogen, or 10 R2 is dimethylamino and R 3 is H, or

R

2 is N,N-dimethylaminoethyl and R3 is H, or

R

2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, or a 1 -methyl-piperidinyl group; L is thiazolyl, thieny, triazolyl, pyridyl, phenyl, or oxazolyl, any of which is 15 optionally substituted by a methyl group;

R

4 is phenyl, optionally substituted by halo (chloro or fluoro), cyano, halo(C-C2.)alkyl, or (C.-C 2 )alkoxy; or a salt, particularly a pharmaceutically acceptable salt, thereof. As used herein, the term compounds() of the invention" means a compound of 20 formula (I) (as defined above) in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms. 25 As used herein, the term "optionally substituted" means unsubstituted groups or rings (e.g., cycloalkyl, heterocycle, and heteroaryl rings) and groups or rings substituted with one or more specified substituents. The compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual 30 enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in Formula i, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof Thus, compounds 35 according to Formula I containing one or more chiral centers may be used as racernic mixtures, scalemic mixtures, or as diasetermerically or enantiomerically pure materials 22 WO 2011/088181 PCT/US20111021089 individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer 5 specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to 10 liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. When a disclosed compound or its salt is named or depicted by structure, it is to be understood that the compound or salt, including solvates (particularly, hydrates) 15 thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs." It is to be understood that when named or depicted by structure, the disclosed compound, or solvates (particularly, 20 hydrates) thereof, also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, 25 and X-ray powder diffraction patterns, which rnay be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound. Because of their potential use in medicine, the sats of the compounds of 30 Formula i are preferably pharmaceutically acceptable saits. Suitable pharmaceutically acceptable salts include those described by Berge, Bighiey and Monkhouse, J Pharm.Sci (1977) 66, pp 1-19. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Typically, a salt may be readily prepared by using a desired acid or base as 35 appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. 23 WO 2011/088181 PCT/US20111021089 When a cornpound of the invention is a base (contain a basic molety), a desired salt form may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, 5 trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid. malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, and the like, or with a pyranosidyl acid, such as glucuronic acid or galacturonic acid, or with an alpha-hydroxy acid, such as citric acid or tartaric acid, or with an amino acid, such as aspartic acid or glutarnic acid, or with an arornatic acid, such as benzoic acid or cinnamic acid, or with a sulfonic acid, such 10 as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like. Suitable addition salts are formed from acids which form non-toxic salts and examples include acetate, p-aminobenzoate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, cyclohexylsulfamate, edetate, 15 edisylate, estolate, esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, hexyliresorcinate, hydrabamine, hydrobromide, hydrochloride, dihydrochloride, hydrofumarate, hydrogen phosphate, hydroiodide, hydromaleate, hydrosuccinate, hydroxynaphthoate, isethionate, itaconate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, 20 methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, oxaloacetate, pamoate (embonate), palmate, palmitate, pantothenate, phosphate/diphosphate, pyruvate, polygalacturonate, propionate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetate and valerate. 25 Other exemplary acid addition salts include pyrosulfate, sulfite, bisulfite, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, suberate, sebacate, butyne-1,4-dioate, hexyne-1,6-dicate, chlorobenzoate, methylbenzoate, din itrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate, phenylpropionate, phenylbutrate, lactate, y-hydroxybutyrate, mandelate, 30 and sulfonates, such as xylenesulfonate, propanesulfonate, naphthalene-1-sulmonate and naphthalene-2-sulfonate. ;4 an inventive basic compound is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or 35 organic base having a higher pK, than the free base form of the compound. 24 WO 2011/088181 PCT/US20111021089 When a cornocund of the invention is an acid (contains an acidic moiety), a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like. 5 Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as N-methyl-D-glucamine, diethylamine, isopropylamine, , trimethylamine, ethylene diamine, dicyclohexylarnine, ethanolamine, piperidine, morpholine, and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, 10 magnesium, manganese, iron, copper, zinc, aluminum, and lithium. Certain of the compounds of this invention may form salts with one or more equivalents of an acid (if the compound contains a basic moiety) or a base (if the compound contains an acidic moiety). The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms. 15 Compounds of the invention having both a basic and acidic moiety may be in the form of zwitterions, acid-addition salt of the basic moiety or base salts of the acidic moiety. This invention also provides for the conversion of one pharmaceutically acceptable salt of a compound of this invention, e.g., a hydrochloride salt, into another pharmaceutically acceptable salt of a compound of this invention, e.g., a sodium salt. 20 For solvates of the compounds of Formula 1, or salts thereof that are in crystalline form, the skilled artisan will appreciate that pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the 25 solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates. The subject invention also includes isotopically-labeled compounds which are 30 identical to those recited in formula (I) but for the tact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 3 H. "C, 14C, 1 8F, 1 2 3 or 1 35 Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms 25 WO 2011/088181 PCT/US20111021089 are within the scope of the present invention Isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H or "C have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, ie. 3H, and carbon-14, ie. 1 4C. isotopes are particularly preferred for their ease of 5 preparation and delectability. 1C and 1 8F isotopes are particularly useful in PET (positron emission tomography). Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure 10 and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis), Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions. The compounds of Formula I may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic 15 chemist. The synthesis provided in these Schemes are applicable for producing compounds of the invention having a variety of different R' and R 2 groups employing appropriate precursors, which are suitably protected if needed, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. While the Schemes are shown with 20 compounds only of Formula 1, they are illustrative of processes that may be used to make the compounds of the invention. Intermediates (compounds used in the preparation of the compounds of the invention) may also be present as salts. Thus, in reference to intermediates, the phrase "compound(s) of formula (number)" means a compound having that structural formula or a 25 pharmaceutically acceptable salt thereof. Specific compounds of this invention include the compounds of Examples 1-141. Representative compounds of this invention include: N-((4-(4-phenylthiazo-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl) 1,2,4-oxadiazol-3-yl)benzamide, 30 N-(4-(2-(dimethylamino)ethoxy)benzyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)benzamide, N-(2-(2-(dimethylamino)ethoxy)benzyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)benzamide, N-(4-(1 H-imidazol-1-yl)benzyl)-3-(5-(trifiuoromethyl)-1,2,4-oxadiazol-3 35 yl)benzamide, 26 WO 20111088181 PCT/US201l11021089 .N-(2-cyanoetly)-N-(pyrdi-3-yimiethyl)-3-(5-(trifl~uoronethI)-I .2A-oxadazoL-3 yl)benzarnide, (trifiuororethyl)phenyiltetrahydro-2H-pyran-4-yI)rnethyl)benzamlide 5 1 -(4'-(4-plheniylthiazoI-2-yl)tetraydo-2H-pyra-4-yI)-N-(3-(5-'rifluroethy)-1 2,4 oxadiazol-3-yi)benzyl)rnethanaminne, NV-((4-(4-pheniylthiazai-2-y~tetrahvdo-2H-pyran-4yl)met.yi)-5-(5-(trifuoromethyA) 1 ,2,4-oxadliaztI,-3-yl)rnicatinarmide, NV-((4-(4-phlenyiiic.phe-2-yi)etahydro-2-I-pyrari-4-yI)rngethiyl)-3-(5 10 (trif'ui'methiyl)-1 ,2.4-oxadiazdl-3-yilbenzarmide, oxadiazol-3-vI~benzande, N[-((4-(3-pheniyl-lH-1 .2,4-triazol-5-y!)tetrahlydro-2H-pyrani-4-yI)metly)-3-(5 (~tr'!f!uornoethy)-1 ,2.4-oxadiazcI-3-yl!)benzarnide, 15 N- ((4- (2 -phenythi azol-4 -yltetra'vd o -2H-pran- 4 -I)nehy1 3 -(5- (tri fuoromeh yA) 1 ,2,4-oxadiazcI-3-yI)bernzamide, N-(4(-4.ntlxp n')hao--y~erhdo2iprn--v~tehl-3( (~tr4!f!uorornethy)-1 ,2.-oxadiazoI-3-yF!Ibenzarnide, N-((4-(4-(4-chiopheniy)thiazoI.2-y)tetrahydro-2H-pyran.4-I)nethy)-3-(5 20 ,,tr'!f'!~romthy)-1,2.-xadiazoI-3-y'!Ibenzamnide, N-(2-,methy-2-(4-phenythazo.2-y)pr py).3-(5(trifluoronethy)-1 ,24-oxadiazol-3 yl)benzarnlde, N- ((1 -methyl 4-.(4--p hen y~th iazo -2-y I)pi perid in -4-yl)nethy) -3-(5-trf!u .ronethy) 1 ,2,4-oxadiiazoI-3-yI)bernzamnide, 25 N-(4(-4-~o pinltizl2y~erayr-f-ya.4y)nty)3(. (trif!uorornethyl)-1 2,4-oxadiazcl1-3-y!)benzanidE!, N-((4-(5-rnethyl-4-phenvI-ytliazo-2-yI)tetrahydo-2-pyra--4-y)m.etvIy)--5 (tr-if!Liorornethyl)-1 2,4-eoxadiazcl1-3-y)lbenzanide, N-((4-(4-c~yciohexylthiazoI-2-yI)tE,,tra.hydro-2H-pyra-4-y)nethy)-3-(5 30 (ltrif!Liorornethyl)-1,2,4-oxadiazo-3-yi.)benzarnide, N4-((4-(4-(pyridini-2-yI)thiazok-2-y)tetrahyidr-2H-pyrn-4-v)nethy4)-3-(5 (trifiLuororne.thyl)-1,2,4-oxadiazo-3-yl)benzarnide, N4-((4-(4-(pyridirn-4-yI)thiazok-2-y)tetrah~idro-2H-pyran-4-v)nethy4)-3-(5 (trifiLuoronethy)-1 ,2,4-oxadiazcI1-3-yl)benzarnide, 35 N4-((4-(4-phenylth~azol-2-yI)tetrahydro-2H-pyran-4-y)m-rethyl)-5-(5-(t-fluoromethI) I ,2,4-oxadiazol-3-yI)tlcphene-2-ccarboxarnide, 27 WO 20111088181 PCT/US201l11021089 .N-((4-(4-(tliio phen-2-A)th iazo -2-yl)tetra hydro-2 H-pran-4-yl)nethy)3-l ftrifiuor-orethyl)-1 2,4-o-xadi~zcI-3-yi)benzarnide, N-(2-(4-(4-flu orophenylIVthiazo 1-2-yl)-2-rnethyl pro pyl)-3-(5-(trfl uorometilyl)-1,2,4 oxadiazol-3-vI~benzande, 5 N-(2-(4-(4-chllor-Opheny)thiazoI-2-yI)-2-metlhylpmpy)--(5-(trifILoromthI)-1 .2,4 oxadiazol-3-yl)benzarnide, 3-fIuoro-N-(2-(4-(4-fIulorphenyi)thiiazoI-2-yi)2-!iethypropyl)-5-(5-(tr fiuoromety) 1 ,2,4-oxaLdiaztI,-3-yl)bernzazmide, 3-cya no-N-((4-(4 -ph erlyth iazol -2-y!)tetra hyd r-2.-pyrar-4-y)rneth y)-5-,5 10 (tr'fu.i'Omethyl)-1 ,2.4-oxadiazdl-3-yilbenzarmide, 3-rnet.hoxy-N-((4-(4-phenvthiazol-2-y ),tetrahydro,-2H-pryran-4-yl)methvI)-5-(5 (trifiuororethyl)-1,2,4-oxadiazclI3-yi)benzarnide, N-(2-(4-(4-fIucoroprhenyi)t'iazo'!-2-yI)ethy)-3-(5-(trifluoromethy'!)-'i 2,4-oxadiazo'!-3 yl)benzarnide, 15 N-(-4(-yn~hry~t'ao--lttaido2lprr--lrit v!--5 (~tr4!f'uororethyI)-1 ,2.-oxadiazoI-3-y'!)benzarnide, N-((4-(4-(4--f~uarophienyl)thiazcl-2-yI)-2,2-.drriethlyltetrahydro-2H-pyran-.4 y!)mrethvyl)-3..(5-(trifluorormethyl)--1,2,4-cxadiazoI-.3-yI)bernzarnkide, N-(4(-hn'''ao!2.lttavr.2iprn4y~nty!,3(-tiloo ehl) 20 1,24 aizl3y~bneeufra~e 3.-ethyl-N -((4-(4--phenylthiazo.2-y)etrhydr-2H-/-pyra1-4-y)rethy)-5-(5 (,trlf!Luorornethyl)-1 ,2,4-oxadiazco-3-y)benzarnide, N-((4-(3-br mophenyI)tetrahdr-2H-pyra1-4-y)methy)-3-(5-(trifuoromet.,Iy) 1 ,2,4-oxadia~zoI-3-yI)bernzamnide, 25 3-(5-(trifluaormethy)-1 ,2,4-oxadiazo!.3-yi)-N-((4-(4.(4 (trif!uorornethyl)pheniy!)th.iazolk2-yi)tetra3hydro-2H-pyranr-4-vI)rnethyl)benzamide, N-(2-.methyl-2-(4-(4-(trfluoronmehy)phenyl'ithazo-2-yI)propylW)3-(5 (tr-if!Liorornethyl)-1 2,4-oxadiazcl-3-y!)lbenzanide, N-((4-(4-phenylthiazo!-2-yI)tetrahydro-2H-pyan-4-y)m~ethyJ-2-(-(trifluoomethy) 30 1 ,2,4-oxadiazoI-3-yI)cyclopropEnecarboxarnide, N4-((1 -methyi-4-("2-pheiythiao-4-y)piperdn-4-yl)netyI)-5-(-trifiLuorom.ethy) I ,2,4-oxadiazo-3-y)nicotinamide, N4-(2-(2-(4-chloropheny)th z%4-yI)-2-metylprop'i)-5-(5-(trifIjoronethy)-1,2,4 oxad iazol-3-yl )nicotina mid e, 35 P4-((4-(2-(4-ch orcphenylth iazc-4-vl)-l -rnethvipi perid;in-4-yl)methyl)-5-(5 (trifiLuOrorethly)-1 ,2,4--xadicazcI1-3-yl)nicotiriarrnide, 28 WO 20111088181 PCT/US201l11021089 N-(24(2-(4-01IorophePnyl)th iazol-4-y)-2-Metlylpm-jpyl-3-(5-(trifl uoCromethl)- 1 .2,4 oxadiqzol-3-vl)benzarndP, N-(2-(2-(4-eh oroph eny)th a.zo-4-y)ethyl)-5-(15-(trifIulorornethy)-l ,4-oxad'azo -3 yflniotnaride, 5 N-(2-(4-(4-ech orolph eny)th iazol-2-yI)-2-methylpropy)-2-(5-(trif iuOromethI)- 1 .2,4 oxadiazol-3-yi)isonicotinami!de, N-(2-(2-(4-flu oropheny)th iazo 1-l-2-rnethyl pro py!)-3-(5-(triflu orometl yl)- ,2,4 axadiazol-3-yi)benzarnide, N-(2-(2-(4.-flu orophe ryl)th iazo-4 -yY)2-inethyl pro py)-5-(5-(trfl uorometh y)-1 2,4 10 oxadiazol-3-yi)niicotinr~nide, N-(2-(4-(4-ch lor-o.peyl)thazol-2-y )-2-metlhylpmpyl)-6-(5-(trifIuooehI- .2,4 oxad iazol-3-vi)pi colinamide, N-(2-(d imeth ylarn no)-2-(4-phenylth iazol -2-yl)eth l)-3-(5-(tri! uo romethyl- 1, 2,4 oxadiazol -3-yl)benzarnide, y;)b~rnzarr-Iide, N-.((l -(4-pheny!"hiaol-2- yI~cycop~opyl)-nL thyI)-3-.45-(trifluoromethy).1 2,4 oxadiazo -3-yl)benzarnide, 20 y;)phernvl)proparlarnide, N(2-(12-(4-Ch Ioropheny)thiazol%4- y)ethy) -3-(,5-(trifluoronethy)- 1,2,4-oxadizo!-3 y;)benzar-,ide, N- ((4-phenlythiazo- 2-y)methy)-3-(5- (tr~fluoromethy)-1 ,2,4- oxadiazol -3 yl)benzarnide, 25 N-(-4-4f~co)l~y~hao!2.l)ty)5(-tiloore!l' , 1:2,4-oxadia.'ol-3. y;)nicotinarnide, N-(2-(4-(4-ch loro phe ny)th izdzo-2-y)ethy)-3-(5-(trifluromethy)-, ,2;4-oxad iazo -3 yl)benzamide, N-(2-(4-(4-ch loro phenyI)thi d2yjehi--(-ti~oronethy)-, ,2,4-Oxad iazo 1-3 30 yl)nicotinaride, N-((4-(3,4-d 1 yd roisoqu ino i n-2 ( 1H)-ylJtetrahyd ro-2 H-pyran-4-yl)neth yI-3-f 5 (trifiLuororne.thyl)-1 ,2,4-oxadiazoI-3-yl)benzarnide, N-rnethyl-N-((4-(4-phe nvithi azol-2-yl)tetrah yd ro-2H-pyran -4-y!)methy)-3-(5 (trifLuoronethyl)-1 ,2,4-oxadiazcI1-3-yl)benzarnide, 35 N-(2-(2-(4-fhj orop htnyl)th iazo 1-4-yl)efhy;)-5-(5-(trif u oromthy )-1, ,2,4-oxad iazol-3 yl)-nicotin-amide, 29 WO 20111088181 PCT/US201l11021089 N(-24-ucroPhenvl)f iazoi-4-yI)ethyl)-3-(5-(tr'iflIororrnethyi)-i.2,4-oxadiazo-3 yl)benzarnide, N-(2-(4-(4-flu orophenylIVthiazo 1-2-yi)-2-rnethyl pro pyl)-5-(5-(trfl uorometl yl)-1,2,4 oxadiazol-3-vI~nicotinarnide, 5 2,2,2-trifl Uoro-fV-((4-(4-p henylth iazol -2-yl)tetrahydro-2H-pyra n-4-y)rnethy)--3-5 (trif'uo!ornethyl)-i 2,4-oxadiazcl-3I-yi)phenyl)ethanamline. N-(2-(3-(4-flucororphenyl)-l H-I 2,4-tlriazoI-5-yl)ethy)-3-(5-(ltrifI uoromethyI)-1,2,4 axadiazol-3-yi)benzarnide, N-(2(3-4-ck~r~henI)-H-1.24t~azi-5yI~thy)-3-5-(ifloroneiyl)-I .2,4 10 oxadiazol-3-yi)benzarnide, N-(2-me-thyI-2-(3-phenyA- H-i 2,4-triaZH-5-Vi)Pm'pyl)-3-(15-trifIuor)tome-thI)-1 .2,4 oxadiazol-3-vI~benzande, N-(2-methyl-2-(3-phenyl-1 H-i ,2,4-triazo!-51-v')prOpy!)-5-(5-(tLrifluor~omethvI)-I .2,4 oxadiazol-3-yi)nlootinamide, 15 N-(2-(3 -(4-flucrophenyl)-1.i-1- 1 2,4-*riazol-5-y!)-2-methylpropyl)-3-"5 (~tr'!'uorornethyl)-i ,2.-oxadiazoI-3-y'!)benzarnide, (~tr'!fLorornethyl)-i ,2.-oxadiazoI-3-y'!)nicotirvirnide, 20 ,,tr'!f'!~romthy)-1,2.-xadiazol-3-y'!Ibenzamnide, N-(2-(4.(4- Ch oro phe ny)thi azol-2-y y.2 -methy pro pyl) -6- meth yI5 -(5. (,trlf!Luorornethyl)-1 ,2,4.-oxadiazol-3-y!)nicotinarnide, N-(3-(4-phenylthi azol-2-y!,,pro py)-3- (5 -(trfluorometh ylI-I 12,4-.3xadiazo-3yl)benzarnide, 25 N-(2-(2.-4-fIuicroc)hey)oxao-4y)ehy)-5-(5-(trfluorrretLy) - 1:2,4-oxadia.'ol-3 y;)nicoiinarnide, N-(2-(5-phenltlhiazl-2-yJlethyl-3-(5-(trifluoronetlyl)-1 2.4-o-xadiazcl1-3 yl)benzamide, N-(22-4-fl;i crop henyl)xzo -4-y)pro y)-3-,, -(trif uronethy)- ,2 ,4-oxadiazol-3 30 y;)benzarmide, P4-(2-(2-(3-fliucrop henyl)xazo 14-y)eth y)-5-(5-trf uoro etyl)- 1 ,4-oxad iazol-3 y;)nicotin~aride, N4-(2-(4-(4-chlorophenyI)thiazo-2-yl)y2-metyiprop'I)-2-methvI-5-(5 (trifLuoronethyl)-i ,2,4-oxadiazH,-3-yll)nicotinarnide, 35 N4-(2-rnethyI-2-(5-pheniti.azo-2-yl)propy)-3-(5-(trifiujoronetly)- ,2,4-oxadiazol1-3 yl)benzamie, 30 WO 20111088181 PCT/US201l11021089 T-(-r -biph en '-3-y)tetra hdro-2-pyra n-4-y)mef y)-3-(5-(trif uo rorethy) I ,2,4-oxadiazoI-3-yI)benzanmide., 1, ,4-oxad iazo1-3-yl)n icoti nami de, 5N-((2-(4-4luor phenyl)cxazcl-4-ylirnethy)-3-(5-(triflucriornethy)-I ,2.4-oxadiazol-3 yl)benzamide, N-((4-(2-(4 -flu orop henyl)oxazo1-4-yi)- 1-met y iperid in-4-y)rnethy)-3-(5 (trifiuororniethyl)-1 2,4-oxadiazoI-31-yil~benzarmide, N-(2-rmetlhyI-2-(2-pheiyoxazo4-y)popyY)3-(5(trfluoorietly)- 2.4-r.xardiazok-3 10 yl)benrn~iae., 2-(2-(4-fiuorophenyl)oxazol-4-yi )-2-r-nethyi-N-(3-(5-(trf1iuorom)~nethyl)-1,2,4 oxad iazol-3-vl)benzyl)pro par -1 -mine, 3-(3-(4-(4-ph .envIthiazo-2-y'!)bu-tyI)pherny)-5-(trhfluoromethy)-1 ,2,4-oxadiazole, N-(2-m.ethylv-2-(5-phieny'!oxazo-2-y)propyl)-3-(5-(trifluorormethyl)-1 ,2,4-oxadiiazoI-3 15 y')benziarnide, N-(2(.,2-phenylthiazcl-5-y!)e-thyl)-3(5,'-(trif~uoromnethyl).1 ,2,4-cxadiazcI-.3 yl)benzarnide, N-(2m..ethyIv-2-('2-phieny'!th'!azoI-5-.yI)propvI)-3(.5-(trifluoromethyI)-1 ,2,4-oxadiazol-3 y')benzarnide, 20 N-((4-(2-(4-&iho-phey)thiazoI-4-y!-1 -n-ethy!piperid'!n4y!)methyI)-3-(5 (trifuororethyl)-1 ,2,4-oxadiazcI-3-yi)benzanide, N-(2.(2- (4 -flu crop henyl)oxazo 4-yl)- 2--mth ylproryl)y3 -(5-(2,2,2. trifluoroacetyI)th.Ioph ,n-2-y)benzarnide, N-(2-(2- (4 -flu crop henyl)oxazo 4-vl)- 2-eth ylpropyl).5 -(5-(2,2, 2 25 trifluoroacetyI)thiophen-2-y)rl'cotinarm.ide, N-((4-(2-(4-chlorc.pheny)thiazl-4-y)-1 -methylpipE-ridin-4-vi)methyl)-3-(5-(2,2,2 trifluoroacetyl)th-iophen-2-yI',benzarnide, 2-fluoro-N-(2-(2 -(4-fluorc -phenyl)oxazo-4-y!)-2-nmethylpi-cpyl)-5-(5'-(tifluoromethi) 1,2,4-oxadiazo-3-yl)benzarnide, 30 A4(-2(-lr~~nloxzl4y)2mtypori 2(-tiloo e-y)12,4 oxadiazoI-3-vI)oxazole-4-carboxarnide, N'-(2-(1 -methyl-2-pheny-I H-imidazo-5-yi)propDyl)-5-(5-(trifluoromehy)- .2,4 oxad iazol-3-yl)nicotina mid e, N-(2-(12-(4-flucro~rhenv)oxazo-4-yi)-2-hydroxyethyl-3-(15-(trifluoromethy)-1 .2,4 35 oxadiazol-3-yI~benzarnde, 31 WO 20111088181 PCTUS201 11021089 5-(5- (d 1fl tjo ro ethy1)-1, 2,4-oxadclia zo -3-yl)- I-(2- (2 -(4-fl u oro phe n yl)xazo-4 -yl)-2 rnethylvipropyl)n iciti nam.ide, N-(2-(d imethyirn n o)-2-(2-(4-fl uoro phenyl)oxazo-4-yl)etry)-3-(5-(trifluoro rnethy) 1 ,2,4-oxadiazol-3-yl)benzamnide hydrochloride, 5 N-(2-(3-(4-fluoroorhenyl)-1 H-I 2,4-tlriazol-5-yi)-2-methylpropyl)-5-(5"-(2,2,2 trifluoroacety)thiophen-2-yl',nicotinarnide. N-(2-(2-(4-fuoroheny)oazol-4yl)-2-nethylprooy)-2-netho-(5 (trifiuororniethyl)-1 2,4-oxadiazoI-31-yil~benzar.mide, N-(2-(2-(4-flu crop henyl)oxazo -5-yl)-2-meth yl prop yi)-3-(5-(ti-fl uoroneth yi)- 12+4 10 oxadiazol-3-yl)benzarnide, N-(4-(d m'nethylarnino)-2-(2-(4-fl ucrophienyl )oxCzo-4-vI )buityi)-3-(5-(triflujorornethy) 1 ,2,4-oxadiazol-3-yl)benzamiide, N-(4-(dimiethylarnino)-2 -(2-(4-fluoroplhenyl)oxazo-4-vI)buty)-5-(5-(trifluoronethy) 1 ,2,4-oxadiiazoI-3-yl)rnicotinartnide, 15 N-(2-(2-(4-fIuicroopheriyl)oxazo-4-yl)-2-hydoxyethyl-5-(5-(tiflurorretyIv)- 1,24 oxadiazol-3-yl)nicotinamide, N-((4-(2-(4-chloropheny!)cxazcl-4y)-1 -methyipiperidin -4-y'I~methyl)-3-(5 (~tr!fiuLorornethyl)-I ,2.-oxadiazol-3-y'I~benzarniide, 2-(2-(4-c-hioropheny!)oxazol-4-yi!)-2--mrehyi-N-(3(-5-(trifluoromethyl)-1,2,4 20 o xad iazol -3-yl)benzyl)pro pan.-I -ami ne, N.(2-(2.(4-flu rop henyl)oxazo- 5yl')eth y)-3- (5 -(trfl uorometily)- 1 2,4-oxadazol-3 yl)benzamride, N-((4-([1 ,1'-bipheny]-3-y)-1 -rethylpiperidin-4-yI)m.-ethyl)-3-(5-trifluorornethyl) 1 ,2,4-oxadiazol-3-yl)bernzemide 25 N-(2-(2.(4-methoxyphenyl)oxzol-4-y)ethy)-5-5-(tifluoretlv)-1 2:4-oxadazol) 3-yI)nicotinamide, 2-chl oro-N-(2-(2-(4-f uorophe ny)oxazo!-4-y)-2-mnethy pro pyI)-5-(5-(trifl ucro methyl) I ,2,4-oxadiazol-3-yl)benz-ernide, N-(244-fl; crop henyl)oxazo 1-4-yi)-2-rneth yl propy")-3(5-trilu oronmeth yl)-1,2,4 30 oxadiazol-3-yl)benzarnide, N-(3-(2-(4-fl~uorop henyl)oxazo 14-yi)-3-h yd roxypro py)-3-(5-( tifluoronetyl)- 1, 2,4 oxadiazol-3-yl)ben~zarnide, N4-(2-(2-(4-cyanophenv)oxazo-4-yl)ethy)-5-(5-(trif!ioromnethy)-1 2,4-oxadiazol-3 yl)nicctinamide, 35 N4-(2-(2-(2-flIucrophtnyl)oxazo-4-y)ethy)-5-(5-(trfluormiiethyl )-1 ,2,4-oxadiazol-3 yl)nicotinamide, 32 WO 20111088181 PCT/US201l11021089 3-5(-if Iuoaceyth iophen -2-y)-N-(2-(2-(4-fi Jorophen ylxzo-4-v)-2 N-(2-(2-(4-flu ,roP henyl)oxazo -4-yl)-2-rneth ylpropy!)-3-(5-(2.2,2 trifluoroacetyi)thiazoI-2-yl)benzamiide, 5 N-(2-(1-methyl-2-pheny!-1 H-imidazol-4-y!)proy)-5-(5-(tifloromehy)-1 24 oxadiazol-3-yI)nicotinarnicle. N-(2-(2-(4-flu orop, heny)azo '-4-yl)-2-rneth ylpropy!)-3-(5-(2,2,2 tin flu oroacety I)fu rarl-2-yI)beniza mide, N-(2-(2-(4-fIucroolhenryi)cixazo-4-y)-2-methoxyethy)--(5-(I iflIuOrehIl)-1 .2,4 10 oxadiaizol-3-yi)[benzarnide, N-(2-(4-(4-flucoroP henyl)th iazo 1-2-ylro pyI)-3-(5-(tifhj ffrethy)- ,2,4-oxad Pol-3 yflbenzamide, N-((4-(4-pheniy'!th'!zo'!-2-yI)tetrahvdro0-2H-pyran-4-y)met yl!)-3-(5-(2,2,2 tri fluoroacetylIth icphe n -2- y)benzam ide, 15 N- (2-(2 -(4-flucrophenyl)oxazo-4- y)ethy)-3-(5-(rfluororret!hy) -1 12,4-oxadiazo'-3 yi)b~rizarriide, N-(2-(2-(4-fI crop heny)oxazoW-4y') -2-neth yprop y-5Y5-(tiluorojrnethy!)- 1,2,4 oxadiazol -3-yl)nicotinamicle, N.(,I 1.Ibipheny] -3-y 12 -methy'!propyfl)3-(5(tifi~uronethy)- 1;2;4-oxadiazol-3 20 yi)benzarmide, N-(2-(14-fluoro--I -- -biphenylj.3-vI)-2rnethylproy)- 3-(5- (tnfluoromethy)-1 .2,4 O~adiazol -3-yl)benzamride, N- ((4- (4 -(3,5 -diil UorcoPheny)thiazol- 2-yI)tetrahydro-2H-pyran -4-y!)rnethy!) 3-(5 (~tr'!l'uororethyl)-1 2. oxadiazoI -3-y'! benzarnide, 25 N.(2-(4.-3,5-dfl uorophenyl)thiazol-2-y) -2-rnethylpropy)-3- (5-trifluoronethy') 1 ,2,4-oxadiazol-3-yI)benzarnide-, N-(2-(2-phenl xazo-4-y! jethy-3-(15-(tifI uorormethyl)- 1,2 4-oxad iazol-3 yl)benzamide, N-2(2pfnl~ao--ilty -- 1-.rfkooetil-,2,4-<adiazI-3 30 yl)nicotinaride, P4-(2-(2-(,4-ch loro phe.ny)oxazo-4-y)ethyl)-3-(,5-(tifIuoromiethyl)-, ,2,4-oxad iazo -3 yl)benzamide, P4(-1-,-hlr h nlxao-yleh)--,(tiloriLty)I, 2,4-oxad iazo -3 yl)nicoiinarnide, 35 N4-(2-rnethyl-2-(2-phe-nyoxazol-4-y)propyl)-5-(5-(tifiujoronetlyl-,2,4-oxadiazol1-3 yi)-nicoirnamicle, 33 WO 20111088181 PCTUS201 11021089 N-(24(2-(4-01lorophe nyl)oxazol-4-yl )-2-methylpru YI-3-(5-(tifl uoCromthv)- 1 .2,4 oxadiqzol-.3-yl)benzarndP, N-(2-(3-phenyl -1, ,24-oxad iazcl -5-y)ethyl -3(5-(trifiluoronethyl)-1, ,2,4-oxadi azo l-3 yilbenzamide, 5 N-(2-methyl-2-(3-pheny!-1 H-pyrazoi-5-yl)oropyl)-3-(5-(trifluoromiethyl)-l 2,4 oxadiazol-3-yl)benzanide, N-(2-(2-(4-fluorocheny)oazol-4yl)oropl)-5-(5-(triflurom!iethyl)- ,2,4-oxad' azol-3 yi)nicotinarriide, N-(2-(4 -(4-ch lor opheryl)ti'azol-2-yl)-2-rmetlyp opy)-5-(5-(tI ifl U0orrnethVl)-1 .2,4 10 oxadiazol-3-yl)nicotinr~inide, I..4-F 1'-bipheni--3-y)-l-.,iethylpipe-ridi-4-yl).,iethyl)-5-(5-(trifiuo.,rnethyl) 1 ,2,4-oxadiazol-3-yl)nicotinamide, N-(2-(2-(4-fiLucrorphenyl)oxazo!-4-y)-2-miethylpropy )-,3-(4-(2 2,2 tri fluoroacetyl Ith icphe n -2- y)benzarnide, 15 N-(2-(2-(4-fiLucroopheryl)oxazo--yl)-2-hyd-oxypropl)-3-(5-trifiuor ethy)-1 2,4 oxadiazol-3-yhlbenzarnide, N-(2-(2--4-fI crop henyl)oxao '-4yl)-2-meth yprop y! -345 -(2:2:2 tri flu oroacetylI fu rarl-3-.yI)benza rnide, N- (2 -(2.(4-f! uorop hen yl)oxazol -4- y)--2-meth yl propyl) -3- (5 -(2,2;2 20 trifluoroacetyl,,thicphen-3-yl)benzamide, N-((,4-(,4-phenylthiazol-2-yl)tetrahyo-.2H--pyran-4-y)methyl)-..(15-(2,2,2 trifluoroacetyl)-.1,2,4-oxadiazcl-3-yi)benzamlde,, and salts, particularly pharmnaceutically acceptable salts, thereof. Particular compounds of this invention include: 25 N(" 1 ,2,4-oxadiazol-3-yl)benzamnide-, N-(2-me2thyl-2-(2-phenyoxazol-4-yl)propyl)-3-(5-(tifluoromethyl)-1 ,2,4-oxadiazol-3 yl)benzarnide, N-(2-(3-(4-flucrophEniIy)- H-I,2,4-trie.,zol-5-y)-2-rneth.yIpropyl)-5-(5-(trfluornethy) 30 1 ,2,4-oxadiazol-3-yl)nicotinamide, N-(2-(2-(4-flujorophenyil)oxazoi-4-yl)i-2-meth.ypropy)-3-(5-(triflujorrniethyl)-1 2,4 oxadiazol-3-yl)benzarnide, N-(2-(dimnethvlaro)-2-(2-(4-fiuoropfenyl'ioxazol-4-yl)eiiy)-3-(5-(trifluoromethyl) I ,2,4-oxa3dia3zol-3-'!l)be-nzamide, 35 N-(2-(2-(4-flujorophienyl)oxa.zoi-4-y)-2-hydroxyethyl)-3-(5-(trifioromeiLthyl)-1 2,4 oxadiazol-3-yl)benzarnide, 34 WO 20111088181 PCTUS201 11021089 N-(2-(3-(4-FlUorophenyl)-I H-I ,2,4-tr-i.ol,-5-yl)-2-mietypropy)-5-(5-(2,2,2 trifl joroacetl)th io phe n-2-yl ' nc,,ti namide, N-(4-(d inethylarni no)-2-(2-4-fluoroph enyl )oxazol-4-yI)butyi)-3-(5-(triflIuo ro rnethylt 1 ,2,4-oxadiazol-3-yl)benzamiide, 5 N-(2-(2-(4-f u oroophen yl)oxazo -- yI)-2-rnethyl proopyI)-3-(5-(2.2.2 trifluoroacetyl)thiazol-2-yi)benzamiide, N-(2-(2-(4-fluor~oohenyl)oxazo-4l-yl,-2-hydroxypropy)-3-(5-(trnfluorome'hy)-I 2,4 oxadiazol-3-yi)benzamide, 10 oxadiazol-3-yl)phienyl)mrethenone.le and salts, Particulariy pharmaceutically acceptable salts, thereof. Compound names were generated uIsing the software naming program ChaiDrew 11.0 available from CambridgeSoft Corporation., 100 CamidgePark Drive, Cambridge, MA 02140. USA (http://wv Aw.cambridgesoFtccorm). 15 The compounds of Formula I can be prepared according to the methods outlined below. Sch1eMe I 0 CNx - ,N N@H, TH ofloy, 4h <A \HT 0 LAPH, NH-I or 20 35 WO 20111088181 PCT/US201l11021089 Scheme-? 2 NC ~ C0 2 H Nt" 2 Oi Na~CO' O N I -hydroxymuimniAn (cat.) R Et()h ''f'ux 4 I(CF30C)) 2 C) pyr'dw.o ' -N S Scheme 3 j'HATUI MPA 'R~ N HN' PK 10 Scheme 4 ''\ 0 FJOu HF j: 1 vi + - -- - - -- - - -- - -- - - -- - -- - - --- R-X j A4m 4 orDIBAL orBHKIVe -~ N NPH DMSOX NC~ 36 WO 2011/088181 PCT/US20111021089 Scheme 5 H F, TMASOF3 DOM h" , . ii 9 -- ~~oe --

B------

o dry glyme, rt, 3h Hj 2 7" 2 oP(P12 ct 11 125I m2M NaCos, DMAF, 9 002 13 Scheme 6 Rb R NH F CN HC; (g .I, aqueous NaIH

MOH-CH

2 Cl 2 j;) -_HCNCdNN 14 CN H O 15 MeOH, reflux R6 DIBAL or BH 3 .Me 2 S ____________N H2N' N' 16 5 The invention also includes various deuterated forms of the compounds of Formula . Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will 10 know how to synthesize deuterated forms of the compounds of Formula I. For example, deuterated alkyl groups (e.g., N-(deutero-methyl) amines) may be prepared by conventional techniques (see for example: methyl-dramine available from Aldrich Chemical Co., Milwaukee, WI, Cat. No.489,689-2). Employing such compounds will allow for the preparation of compounds of Formula I in which various hydrogen atoms of the N 15 methyl groups are replaced with a deuterium atom. The present invention is directed to a method of inhibiting an HDAC which comprises contacting the acetylase with a compound of Formula I or a salt thereof, 37 WO 2011/088181 PCT/US20111021089 padiIcularly a pharmaceutically acceptable salt thereof. This invention is also directed to a method of treatment of an HDAC-mediated disease or disorder comprising administering a therapeutically effective amount of the compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to a patient, specifically a human, 5 in need thereof. As used herein, "patient" refers to a mammal, specifically, a human. A therapeutically "effective amount" is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, e.g., a therapeutically effective amount of a compound of Formula i, or a pharmaceutically acceptable salt thereof, is a quantity of an inventive 10 agent that, when administered to a human in need thereof, is sufficient to inhibit the activity of HDAC such that a disease condition which is mediated by that activity is reduced, alleviated or prevented. The amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pXC,), efficacy (ECs), and the biological half-life of the particular 15 compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of 20 treatment (e.g, weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art. 'Treating" or "treatment" is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is caused or mediated by HDAC. The 25 methods of treatment for mitigation of a disease condition include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease. in one embodiment, this invention is directed to a method of treating, ameliorating, or preventing an autoimmune disorder, an immunological disease, an inflammatory 30 disorder, transplant/graft rejection (e.g., allograft), lymphopenia, or graft-versus-host disease (GvHD) in a patient, specifically in a human, comprising administering to the patient a compound of this invention, in an amount sufficient to increase the level and/or activity of a Treg cell or a population of Treg cells in the patient, thereby treating, ameliorating, or preventing the autoimmune disorder, inflammatory disorder, 35 transplant/graft rejection, lymphopenia, or GvHD in the patient 38 WO 2011/088181 PCT/US20111021089 Additional examples of diseases and conditions that may be treated by the compounds of this invention include but not limited to type || diabetes mellitus, coronary artery disease, allergies and allergic reactions, and sepsistoxic shock. Exemplary autoimmune disorders include, but are not limited to, multiple sclerosis, 5 juvenile idiopathic arthritis, psoriatic arthritis, hepatitis C virus-associated mixed cryoglobulinemia, polymyositis, dermatomyositis, polygiandular syndrome type Ili, autoimmune liver disease, Kawasaki disease, myasthenia gravis, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX (syndrome)), type i diabetes, psoriasis, hypothyroidism, hemolytic anemia, autoimmune polyendocrinopathy 10 candidiasis-ectodermal dystrophy (APECED), thrombocytopenia, spondyloarthritis, Siogren's syndrome, rheumatoid arthritis, inflammatory bowel disease (lBD), Crohn's disease, ulcerative colitis, eczema, gastritis, or thyroiditis. As part of a nonlimiting list, the inflammatory disorder can be contact hypersensitivity, atopic dermatitis or Still disease. Additional examples of autoimmune diseases include but are not limited to 15 autoimmune diseases include osteoarthritis, systemic sclerosis, sarcoidosis, insulin dependent diabetes rnellitus (MIDM, type I diabetes), reactive arthritis, scleroderma, vasculitis, Wegener's granulomatosis, Hashimoto's disease, scleroderma, oophoritis, Lupus (SLE), Grave's disease, asthma, cryoglobulinemia, primary biliary sclerosis, pemphigus vulgaris, hemolytic anemia and pernicious anemia. 20 Examples of transplant/graft rejection (e.g., allograft), iymphopenia, or graft versus-host disease (GvHD) are those arising from cell, tissue and organ transplantation procedures, such as therapeutic cell transplants such as stem cells, muscle cells such as cardiac cells, islet cells, liver cells, bone marrow transplants, skin grafts, bone grafts, lung transplants, kidney transplants, liver transplants, and heart transplants. 25 Other examples of diseases and conditions that may be treated by the compounds of this invention include but are not limited to cystic fibrosis, osteoporosis, obesity, epilepsy, depression, thalassemia, sickle cell anemia, amyotrophic lateral sclerosis (ALS) and hyperalgesia, cardiac disease (e.g., stroke, hypertension, atherothrombotic diseases, artherosclerosis or limitation of infarct size in acute coronary syndrome), diseases or 30 disorders involving muscular atrophy, gentamicin-induced hearing loss, drug resistance (e g., drug resistance in osteosarcoma and colon cancer cells), infectious diseases, and immune deficiency/immunocompromised patients. Examples of infectious diseases relate to various pathogen infections such as viral, fungal, bacterial, mycoplasm, and infections by unicellular and multicellular eukaryotic organisms. Common human pathogens include 35 but are not limited to HIV, HSV, HPV, Hepatitis A, B and C viruses, influenza, denge, zostrella, rubella, RSV, rotavirus, gram positive, gram negative, streptococcus, tetanus, 39 WO 2011/088181 PCT/US20111021089 staphalococcus, tuberculosis, listeria, and malaria. In another embodiment, this invention is directed to inhibitors of HDAC and their use to stop or reduce the growth of neoplastic cells, e.g., cancer cells and tumor cells. The growth of cancer cells and/or tumor cells that are found in the following cancer 5 types may be reduced by treatment with a compound of this invention: carcinoma (e.g., adenocarcinoma), heptaccellular carcinoma, sarcoma, myeloma (e.g., multiple myeloma), treating bone disease in multiple myeloma, leukemia, childhood acute lymphoblastic leukemia and lymphoma (e.g., cutaneous cell lymphoma), and mixed types of cancers, such as adenosquamous carcinoma, rnixed resodermal turmor, carcinosarcoma, and 10 teratocarcinoma. in one aspect of the invention, breast or prostate cancers or tumors are treated using the HDAC inhibitors of this invention. Other cancers that may be treated using the compounds of this invention include, but are not limited to, bladder cancer, breast cancer, prostate cancer, stomach cancer, 15 lung cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, endometrial cancer, pancreatic cancer, cervical cancer, ovarian cancer; head and neck cancer, and melanoma. The inhibitors of the invention may be employed alone or in combination with standard anti-cancer regimens for neoplastic cell, e.g., tumor and cancer, treatments. 20 The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, 25 transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous infection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin 30 The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing 35 regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by 40 WO 2011/088181 PCT/US20111021089 the sklled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of 5 concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Treatment of HDAC-mediated disease conditions may be achieved using the 10 compounds of this invention as a monotherapy, or in dual or multiple combination therapy, such as in combination with other agents, for example, in combination with one or more of the following agents: DNA methyltransferase inhibitors, acetyl transferase enhancers, proteasome or HSP90 inhibitors, and one or more immunosuppressants that do not activate the T suppressor cells including but are not limited to corticosteroids, rapamycin, 15 Azathioprine, Mycophenolate, Cyclosporine, Miercaptopurine (6-IMP), basiliximab, daclizumab, sirolimus, tacrolimus, Muromonab-CD3, cyclophosphamide, and methotrexate, which are administered in effective amounts as is known in the art. The compounds of the invention will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in 20 another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically- acceptable excipient The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection. 25 Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form. For oral application, for example, one or more tablets or capsules may be administered. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula I or a salt, particularly a pharmaceutically acceptable salt, thereof). When 30 prepared in unit dosage form, the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this invention. The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the 35 pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds. 41 WO 2011/088181 PCT/US20111021089 As used herein, "pharmaceuically-acceptable excipient" means a material, composition or vehicle involved in giving form or consistency to the composition Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of 5 the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceuticaliy-acceptable are avoided. in addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable. The compounds of the invention and the pharmaceutically-acceptable excipient or 10 excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. Conventional dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches. powders, syrups, elixirs, suspensions, solutions. emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for 15 reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels. Suitable pharmaceutically-acceptable excipients will vary depending upon the 20 particular dosage form chosen. in addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable 25 dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptabe excipients may be chosen for their ability to enhance patient compliance. 30 Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, 35 preservatives, stabilizers, surfactants, and buffering agents The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one 42 WO 2011/088181 PCT/US20111021089 function and may serve alternative functions depending on how much of the excipient is present in the formulation end what other ingredients are present in the formulation. Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the 5 invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceuticaliy-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Reminoton's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients 10 (the American Pharmaceutical Association arid the Pharmaceutical Press). The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company). 15 in one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium 20 phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povicone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch 25 glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc. EXAMPLES 30 The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without 35 departing from the spirit and scope of the invention. In the following experimental descriptions, the following abbreviations may be used: 43 WO 2011/088181 PCT/US20 11021089 Abbreviation Meaning AOHt acetic acid ac aqueous brne saturated aqueous NaCI

CH

2 Cia methylene chkshde CH3ON or MeCN aceton rilo

CH

3 N H methylamine d day DMF N.N-dimethyformamde [DM~SO dimethyisulfoxice equiv equivalents Et ethy EtzN triethylamine Et 2 O diethyl eter EiOAc ethyl acetate h hr hour HCI hydrochloric acid i-PrN lN'Ndiisopropyiet hyamne KOt-Bu potassium tert-butoxide LCMS l-quid chromatography-mass specroscopy Meo methyl M0eCH or C-1 3 0H methanol MgSO 4 magnesium sulfate mrin mine MS mass spectrum pw microwave N aBGt sodium borUhyuride Na 2

C)

3 sodium carbonate NaHO sodium bicarbonate NaOH sodium hiydroxide Na2SO4 sodium SUlfate

NH

4 i arnmonium chloride NiO-!.6Ht 2 o nickel (ii) choride hexahydrate NMP N-methyl-2-pyrrolidone Ph phonyl rI Ore temperature said saturated SCX strong cation exchange SP'E |solid phase extraction TFA influoroacetc acid 44 WO 2011/088181 PCT/US20111021089 -HE tetrahydrofuran rR retention timne EXAMPLE I Step 1 2-(4-Phenylthiazol-2-yl)acetonitriile CN Et-OH + H , CN ---- N H5N reflux 4h ', A mixture of 2-bromoacetophenone (2 g, 10 mmo!) and 2-cyanothioacetamide (1 g, 10 rnmol) in EtCH (25 mL) was heated to 80 'C for 4 h. The reaction mixture was cooled to room temperature and poured into an aqueous ammonia solution (final pH was >7). The mixture was then extracted with EtOAc and the organic layer was washed with 10 H0 and brine Solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (silica gel 230-400 mesh, eluent 8% EtOAc in petroleum ether) to afford 2-(4-phenylthiazol-2-yl)acetonitrile (1.5 g, yield 75%) as a yellow solid: 1 H NMR (300MHz, CDCi,) 6 7.88-7 91 (m, 2H), 7.49 (s, 1H), 7.27-7 48 (m, 3H), 4.19 (s, 2H) MS (ESI) m/z: Calculated for Cn H 0

N

2 : 200.04: found: 201.2 (M+H)*. 15 Step 2: 4-(4-Phenythiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile SCN N ----------------- N NaH, A solution of 2-(4-phenyithiazol-2-yl)acetontrile (0.84 g, 4.19 mrnol) in THF (25 20 mL) was cooled to 0 *C. NaH was added (0.5 g, 60% dispersion in oil) portionwise over 10 min. The resulting mixture was allowed to warm up to room temperature and stirred for 20 min. 2-Bromoethyl ether (1.58 mL, 12.5 mmol) was added dropwise. The reaction mixture was further stirred at room temperature for I h and then quenched with saturated

NH

4 CI solution The reaction mixture was diluted with EtOtAc and the organic layer was 25 washed with HO and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica ge! 60-120 mesh, eiuent 4-8% EtOAc in petroleum ether) to afford 4-.(4-phenylthiazol-2-yi)tetrahydro-2H-pyran-4-carbonitrile (0.97 g, yield 85%) as a yellow 45 WO 2011/088181 PCT/US20111021089 soli& H NMR (300 MHz, CDCl 3 ) 6 7.91-7 94 (m, 2H), 7.51 (s, 1H), 7.37-7.48 (im, 3H), 4.07-4.14 (in 2H), 3.87-3.96 (m, 2H), 2 32-2.43 (m, 4H). MS (ESI) m/z: Calculated for Ca 5

H,

4

N

2 OS: 270.08; found: 271.2 (M+ H). 5 Step 3: (4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran4-yl)methanamine NC: LiAIH4 THF, 0 C-rt.1h H2 To a suspension of LIAIH 4 (220 mg, 5.9 mmol) in dry THF (10 mL) was added a solution of 4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile (400 mg, 1.47 mmol) in dry THF (10 nL) at 0 "C. The reaction rnixture was stirred at room temperature for 1 h 10 and then quenched carefully with water and diluted with EtOAc. The organic iayer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (neutral alumina, eluent 5% MeOH in CHCl 3 ) to afford (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4 y)methananine (150 mg, yield 37%): 'H NMR (400 MHz, CDC13) 5 7.89-7.91 (n, 2H1-), 15 7.48 (s. 1H), 7.33-7.46 (m, 3H), 3.89-3.93 (irn, 2H), 3.63-3.69 (m, 2H), 3.03 (s, 2H), 2.30 2.33 (n, 2H), 1.90-1.97 (n, 2H). MS (ESI) rn/z: Calculated for CH,sN 2 0S: 274.11. found: 275.2 (M+H). Step 4: 3-(N-HydroxycarbamimidoyI)benzoic acid HO.

NH

2 OH.HCI, NaCO, H N NCs .Ci2 --- ------------- 1" CO2H 8-hydroxyquinoline (cat.) HN 20 EtOH, reflux, 4h 8-Hydroxyquincline (5 mg, 0.03 mmol) was added to a solution of 3-cyanobenzoic acid (1 g, 6.8 mmol) in 50 mL ethanol. To this reaction mixture were added first hydroxylamine hydrochloric acid (950 mg, 13.6 rnmol) n water (8 mL) followed by sodium carbonate (1.2 g, 10.9 mmol) in water (12 mL). The mixture was heated to reflux for 4 h. 25 After removal of ethanol under reduced pressure, the residue was diluted with water, and the aqueous solution was acidified with '10% HCI to pH ~3. The white precipitate was filtrated, washed with water and acetone and then dried under reduced pressure to afford compound 3-(NV-hydroxycarbaninidoyl)benzoic acid (1 g, yield 82%): 'H NMR (400 MHz, CDCla) 5 13.03 (br s, 1H), 9.76 (s, 1H), 8.27-8.26 (n, 1H), 7 95-7.89 (m, 2H), 7.53 (t, J = 46 WO 2011/088181 PCT/US20111021089 7.8 Hz, 1H), 5.94 (br s, 2H). MS (ESI) m/z: Calculated for C 2

H

2

N

2

O

3 : 180.05; found: 180.9 W i-H\Y Step 5: 3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid HO'N (CF 3

CO)

2 0 ' H2N~ ~ ~ ~( Y- CO2 ___ 0___, F2N CO1 pyridne. 50 *C, 3h A solution of compound 3-(A-hydroxycarbamimidoyl)benzoic acid (1 g, 5.6 mmol) in anhydrous pyridine (15 mL) was cooled to 0 IC and trifluoroacetic anhydride (2.3 mL, 16.7 mmol) was added dropwise. The reaction mixture was slowly warmed to room 10 temperature and further heated to 50 "C for 3 h. The reaction mixture was poured into ice water and adjusted to PH -4 by addition of 1.5N HlCI. The product was extracted with EtOAc and the solvent removed under reduced pressure. The crude product was purified by column chromatography [silica gel 60-120 mesh, eluent: 10% EtOAc in petroleum ether] to afford 3-(5-(trifluoromethyi)-1,2,4-oxadiazol-3-yl)benzoic acid (400mg, yield 15 28%): H NMR (400 MHz, CDCl3) 6 13.44 (br s, 1H). 8.56 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 8.21 (d, J = 7 9 Hz., H), 7 78 (t, J = 7.8 Hz, 1H). MS (ESI) m/z: Calculated for

C

10

H

5

F

3

N

2 01: 258 03; found: 257 (M-H). Step 6: N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran -4-yl)methyl)-3-(5 20 (trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide IN O A H A mixture of 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid (52mg, 0.202mmole), (4-(4-phenylthiazol-2-yl)tetrahydro-21H-pyran-4-yi)methanamine (50mg, 0.184mmole), and EDCI (38.5mg, 0.202mmole) in CH2C1 2 (2ml) was stirred at room temperature for 8 h. The reaction mixture was then diluted with methylene chloride (10 25 ml), washed with water (5 mi), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by ISCO (silica gel, elute: 2% methanol in CH 2 Cl2) to give N-((4-(4-phenylthiazol-2-yi)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifiuoromethyl) 1,2,4-oxadiazol-3-yl)benzamide as a white solid product (59mg, 62% yield): 'H NMR 47 WO 20111088181 PCT/US201l11021089 (CDC13 SO0M Hz ): 8.419(s, IIH), 8.22 (d, J=7 5Hz, I H), 7.98 kd, J=.SHz. I H)? 7,8 (d, JHz2H), 7.56-7,53(r'n, 2H), 7.52 sa. 11H), 7.369-7,31 (mn, 31H), 3.97-3.93 (mn, 2H), 3-91 (d, J=5.5Hz, 2H), 3.77-3.74 (in. 2H), 2.36-2.28 (in. 2H), 2.06-2.04 (in. 2H). MIS (ESI) rn/lz: CaIlculated for C 2 5F! 2 1 1F 3

N

4 3 S: 514.13; found: 515.1 (M+.H)+. Exarn.les 2-6 wvere synthesized from 3-(5-(trifluororinethyl)-1,24j-oxadiazo-3 y')benzoic acid and readily available marines in a similar manner as part of a screening collection and characterized by LCIMS and 'H NMR. Example Comrpound Strujcture Compounnd Name No. N N (Dimethyiamino)athioxy)bnzyl)-3 1oxadiazo-3-yI~bernzar-ide i (.Dimethyiame!o)ethoxv)be-nzyl)-3 o (5-(trifluoromethyl)-1,2,4 4 oxa-diazo-3-yI)beonzamide N- F ~N-(2-!-Cyanoethy!)o-N-pyridinz-3 F i 4 0 2xs4iaoa L.3-ybe.ylabenzamet F F 3-f5-(Trifluoromothyi)-1,2,4 i 1 ~cxadiazo-3-l}-N-iL(4-(4 (t.rifluoromeithyI~phernyl~tetrahydro F P !~~ / ~2H-pyran..4--yl)methyi)benzammide 46 WO 2011/088181 PCT/US20111021089 EXAMPLE 7 (3-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)methanoi 'NN THF, 50 IC, 4h Borne dimethyl sulfide complex (0.3 mL, 2.9 mmol) was added to a stirred 5 solution of 3-(5-(trifluoromethyi)-1,2,4-oxadiazol-3-yl)benzoic acid (0.5g, 1.9 mmol) in dry THF (10 mL) at 0 4C. The reaction mixture was slowly warmec to room temperature and further heated to 50 0 C for 41 h. Reaction mixture was then carefully quenched with dry MeOH and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) to 10 get pure alcohol compound (3-(5-(trifluoromethyl)-1,2,4-cxadiazol-3--yi)phenyl)methanol (190 mg, yield 41%): IH NMR (400 MHz, CDC1 3 ) 8 8.14 (in, IH), 8.06 (d, J= 7.5 Hz, IH), 7.61 -7.51 (m, 2H), 4.81 (s, 2H) 3-(6-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde ON H N % Dess-Marin periodinane FC N > N OH I N 15

CH

2

C

2 , 0 "C-rt, 5h A solution of compound 3-(5-(trifluoromethy)-1,2,4-oxadiazol-3-yi)phenyl)methanol (150mg, 0.6 mmol) in dry CH 2

C

2 (10 mL) was purged with argon for 10 min and Dess Martin periodinane (0.39g, 0.9 mmol) was added to the solution at 0 "C . The reaction mixture was allowed to come to room temperature and stirred for 5 h. The reaction 20 mixture was then quenched with saturated sodium thiosulfate solution and extracted with

CH

2 Ci 2 . The organic laver was washed with brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to yield 3-1(5 (trifiuoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (140 mg, crude) which was carried through without further purification. 'H NMR (400 MHz, CDC6i) 6 10. 13 (s, 1 H), 8.64 (s, 25 11H), 8.41-8.39 (dt, J= 7.8 Hz, 1.5 Hz, 11H), 8,13-8.11 (dt, J = 7.8 Hz, 1.5 lz, 1-1), 7.76 (t, J = 7.7 Hz, 1H). 49 WO 2011/088181 PCT/US20111021089 I -(4-(4-Phenylthiazol-2-yl)tetrahydro2-pyran-4-y)-N-(3-(S-(trifluoromethyl)-1,2,4 oxadiazol-3-yl)benzyl)methanamine O -N FsC- 9 NaBH(OAc)-, DCE,0 * h Sodium triacetoxy borohydride (200 mg 0.9 mmol) was added to a solution of 3 5 (5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzaldehyde (140 mg, 0.6 mmol) and (4-(4 phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (170 mg, 0.6 mmol) in dry dichioroethane (20 mL) at 0 'C under nitrogen atmosphere and stirred at room temperature for 8 h. The reaction mixture was carefully quenched with 10% NaHCO 3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over 10 anhydrous Na 2

SO

4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to get 1-(4-(4-phenylthiazol-2-yi)tetrahydro-2H-pyran-4-y)-N-(3-(5 (trifiuoromthyl)-1,2,4-oxadiazol-3-yl)benzyl)methanamine (65 mg, yield 22%): 1H NMR (400 MHz, CDCi 3 ) 6 7.98 (m, 2H), 7 89 (d, J = 7.6 Hz, 2H), 7.48 (s, IH), 7.46-7.27 (m, 15 5H), 3.86-3.81 (m, 4H), 3.69-3.64 (m, 2H), 2.91 (s, 2H), 2 36 (m, 2H), 2.03-1 97 (ddd, J = 13.7 Hz, 9.7 Hz, 4 Hz, 2H). MS (ESI) m/& Calculated for C2mH 2 TF3N40 2 S: 500 15; found: 501.0 (M-H) EXAMPLE 8 20 Methyl-5-bromonicotinate MeOH Br~ ,CO 2 H 1-2304 (cat.) B CO2Me '~ reflux, 12h ' A solution of 5-bromonicotinic acid (10 g, 49.5 mmol) in MCeIH (200mL) was cooled to 0 2C and conc. -1 2 SO4 (5 mL) was added dropwise. The reaction mixture was heated to reflux for 12 h. After completion, the reaction mixture was concentrated under 25 reduced pressure, diluted with water and the aqueous layer was washed with EtOAc. The resulting mixture was poured over an aqueous saturated NaHCO 3 solution to adjust the pH 7-8, it was then extracted with EtOAc and the organic layer was dried over anhydrous 50 WO 2011/088181 PCT/US20111021089 Na 2

SO

4 Solvent was evaporated under reduced pressure to get the solid product methyl 5-brornonicotinate as an off-white solid (7g, yield 66%): H NMR (400 MHz, CDCia) 6 914 (s, 1H). 8.86 (s, 1H), 8.45 (s, 1 H), 3.98 (s, 3H) 5 Methyl 5-cyanonicotinate Br COMe CuCN, DMF NC. CO 2 Me No 160 "C, 12h N' CuCN (5.22 g, 58.3 mmcl) was added to a solution of methyl 5-bromonicotinate (6 g, 27.8 mmol) in dry DMF (150 mL). The solution was purged with argon and heated to 160 "C for 12 h under argon atmosphere. The reaction mixture was cooled to room 10 temperature and then quenched with saturated NH 4 Ci solution. Further EtOAc was added and the reaction mixture was stirred for 10 mn., The reaction mixture was filtered through a Celite plug, the organic layer was separated, washed with water and brine, and dried over anhydrous Na 2

SO

4 Solvent was evaporated under reduced pressure to get methyl 5-cyano-nicotinate as greenish-white solid (2 7g, yield 60%): IH NMR (300 MHz, DMSO 15 de) 6 9,29-9.27 (n, 2H), 8.77 (s, IH), 3.91 (s, 3H) 3-Cyanonicotinic acid NC -CO-Me LiOH.H, NC - CO2H N THF-H 2 0 7:3 v/v 'N 0 IC-rt, 1h LiOH (150 mg, 6.2 mmol) was added to solution of methyl 5-cyanonicotinate (1 g, 20 6.17 mmol) in THF-H 2 O (7:3 viv, 50 mL) at 0 *C . The reaction mixture was stirred at room temperature for I h. THF was then removed under reduced pressure and the reaction mixture was diluted with water and washed with EtOAc. The resulting reaction mixture was acidified with 1.5N HCI to pH 3-4. The mixture was extracted with EtOAc and the organic layer was dried over anhydrous Na 2 SO. Solvent was evaporated under 25 reduced pressure to get 3-cyanonicotinic acid as an off-white solid (0.7 g, yield 78%). 1 H NMR (300 MvHz, DMSO-ds) 5 13.9 (br s, IH), 9.27 (s, 1H), 9.23 (s, 2H), 8.71 (S, 1H). MS (ESI) m/z: Calculated for CrH 4 NO2: 148.03; found: 147.0 (M-H). 51 WO 2011/088181 PCT/US20111021089 5-(N'-HydroxycarbaminiJoyl)nicotinic acid N H 2 OH.HCI, Na.

2 CO HO N N CO-H H N _ _CO2H 8-hydroxyquinoline (cat.) N EtOH, reflux, 3h N This compound was synthesized from 5-cyanonicotinic acid as described in example I step 4 (330 mg, yield 54%): 1 H NMR (400 MHz, DMSO-dc) 5 13.54 (br s, 1H), 5 9.98 (s, 1H), 9 16 (m, 2H), 8.49 (s, IH), 6.11 (br s, 2H). MS (ESI) m/z: Calculated for

C

7

H

7 N0 3 : 181 05; found: 182.2 (M+H)*. 5-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid HO' ~ C (CF 3

CO)

2 C / H2N r OHeFC N -CO2.H || pyridine, 65 1C. 3h N 10 This compound was synthesized from 5-(N-hydroxycarbamimidoyl)nicotinic acid as described in example 1 step 5 (260mg, yield 63%). 'H NMR (400 MHz, DMSO-de) 6 13.93 (brs, 1H), 9.43 (d, J= 2.1 Hz, 1H), 9.31 (d, j= 2.1 Hz, 1H), 8.77 (t, J= 2.1 Hz. 1-). MS (ESI) m/z: Calculated for C 9 i- 4 FANaO3. 259.02; found: 258.0 (M-H). 15 Step 6: N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran4-yl)methyi)-5-(5 (trifluoronethyl)-1,2,4-oxadiazol-3-yl)nicotinamide NN yi)nicatic acid (100 mg, 0.4 mmol) in dry DMF (5 mL) were added HATU (180 mg, 0.46 20 mrnol) followed by hydrochloride salt of (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4 yi)methanamine (120 mg, 0.4 mrnol) and NMM (0.12 rnL, 1.1 rnaol) at 0 "C. The reaction mixture was slowly warmed to roorn temperature and stirred for further 10 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 25 The crude product was purified by column chromatography (silica 60-120 mesh, eluent 50-60% EtOAc in petroleum ether) to get pure product N-((4-(4-phenylthiazol-2 yi)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethy)-1,2,4-oxadiazol-3 52 WO 2011/088181 PCT/US20111021089 yl)nicofinamide (70 mg, yield 37%): 'H NMR (400 MHz, CDCI 3 ) 5 9.43 (d, J= 2 Hz, IH), 9.21 (br s, IH), 8.76 (br s, IH), 7.87 (d, J = 7 Hz, 2H), 7.75 (br s, 1H), 7.53 (s, IH), 7.41 7.32 (m, 3H), 3.99-3.95 (m, 2H), 3.79-3.74 (m, 2H), 2.35-2.32 (m, 2H), 2.07-2.03 (m, 2H). MS (ESI) m/z: Calculated for C 2 4

H

2

[F

3 N5O 3 S: 515.12; found: 516.0 (M+H)-. 5 EXAMPLE 9 5-((4-Phenylthiophen-2-yi)methylene)-2-thioxothiazolidin-4-one K _NHS Ph Ph /ONH AcOH, NaOAc S 0 reflux, 2h A solution oi 4-phenyl thiophene-2-carboxaldehyde (1 g, 5.3 mmol) and rhodanine 10 (700 mg, 5.3 mmol) in 10 mL of glacial acetic acid was heated with anhydrous sodium acetate (1.22 g, 14.8 mmol) for 2 h. The reaction mixture was then poured into cold water The precipitate was filtered, washed with water and dried under reduced pressure to get 5-((4-phenvithiophen-2-yl)methylene)-2-thioxothiazolidin-4-one (1.4 g, yield 87%). MS (ESI) m/z: Calculated for C, 4

HCNOS

3 : 302.98; found: 302.0 (M-H) The crude product 15 was carried through without further purification. 3-(4-Phenylthiophen-2-yl)-2-thioxopropanoic acid S Ph NH 10% NaOH P\ S OH N \\ retlux h A suspension of product 5-((4-phenylthiophen-2-y!)methylene)-2-thoxothazolidin 20 4-one (1.4 g, 4.6 mmol) in 12 mL of 10% aqueous NaO-i was heated to 95 *C for 1 h. The solution was cooled to room temperature and diluted with water. The aqueous phase was washed with EtOAc. and acidified with 10% HCI. The precipitate that was formed was filtered, washed with water and dried under reduced pressure to get the product 3-(4-. phenylthiophen- 2 -yl)-2- thioxopropanoic acid (0.9 g, yield 74%). MS (ESi) m/z: Calculated 25 for C131-302S2: 262.01; found: 261.0 (M-H). The crude product was carried through without further purification 53 WO 2011/088181 PCT/US20111021089 2-(Hydroxyiniino)-3-(4-phenylthiophen-2-yl)propanoic acid Ph psOH -- OH NH 2 OH.HCI, NaOEt " OH EtOH, 1.5h, reluix 06 0 3-(4-Phenylthiophen-2-vl)-2-thioxopropanoic acid (0.9 g, 3.4 mmol), hydroxylamine hydrochilorlde (740 mg, 10.6 mmol), and an ethanolic solution sodium ethoxide [prepared 5 from 0.4 g of sodium and 30 mL of absolute ethanol] was refluxed for 1.5 h. Solvent was removed under reduced pressure and the residue was diluted with water and acidified with 1.5N HCI to adjust the pH of the solution -3. The solid product was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO 4 , then removal of the solvent under reduced pressure yielded 2 -(hydroxyimino) -3-(4--phenylthiophen--2-yl)propanoi acid 10 (0.8 g, yield 89%) as an off-white solid. lH NMR (400 MHz, MeOD) 6 7.59-7.57 (m, 2H), 7.37-7.33 (m, 3H), 7.24-7.23 (m, 2H), 3.31 (s, 2H). MS (ESI) rn/z: Calculated for

O

13 HiNO 3 8: 262.05; found: 262 0 (M+H)'. 2-(4-Phenylthiophen-2-yl)acetonitrile Ph ,OH NOrH Ac2 reflux, 1.5h ' Z 15 S O S 2-(Hydroxyimino)-3-(4-phenylthiophen-2-yl)propanoic acid (0.8 g, 3.1 nmol) was heated in acetic anhydride (5mL) for 1.5 h. The reaction mixture was cooled to room temperature and treated with water. The product was extracted with EtOAc and the organic layer was washed with H 2 0 and brine, dried over anhydrous Na 2 SO4 and 20 concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60-120 mesh, eluent 10 -15% EtOAc in petroleum ether) to afford 2-(4-phenylthiophen-2-y!)acetonitrle (0.45 g, yield 73%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl) 5 7.57-7.53 (.m, 21-), 7.43--7.39 (m, 2H), 7.37-7.36 (in, 2H), 7.34 7.30 (m, 1H), 3.96 (s, 2H) 25 4-(4-Phenylthiophen-2-yl)tetrahydro-2H-pyran-4-carbonitrile Ph Br' Br NaH, THF 0 C-.rt 3h 54 WO 2011/088181 PCT/US20111021089 This compound was synthesized from 2-(4-phenvlthiophen-2-yl)acetonitrile as described in example I step 2 (0.32 g, yield 68%) as a yellow solid. H NMR (400 MHz,

CDC

3 ) 5 7.59-7.57 (dd, J = 8.2 Hz, 1.1 Hz, 2H). 7.45-7.40 (in, 4H), 7.35-7.31 (in, 1H), 4.11-4.07 (m, 2H), 3.93-3.86 (td, J = 12 Hz, 2.4 Hz, 2H), 2.29-2.15 (in, 4H). 5 (4-(4-Phenylthiophen-2-yl)tetrahydro-2H-pyran-4-yl)methananine LiAIH 4 NC --------------- H- N S THF, 0 "C-rt. 1h This compound was synthesized from 4-(4-phenylthiophen-2-yi)tetrahydro-2H pyran-4-carbonitrile as described in example 1 step 3 (210 mg, yield 65%). 'H NMR (400 10 MHz, CDCl 3 ) 5 7 61-7.59 (d. J = 7.3 Hz, 2H), 7.43-7.30 (m, 4H), 7.19-7.18 (d, J = 1 Hz, 1H), 3.86-3.82 (in, 2H), 3.62-3.57 (m, 2H), 2.69 (br s, 2H), 2.11-1.96 (m, 2H), 1.81-1 74 (m, 2H). MS (ESI) mi: Calculated for C,,HINOS: 273.12; found: 274.2 (M+H)*. N-((4-(4-Phenylthiophen-2-yl)tetrahydro-2H-pyran4-yl)nethyl)-3-(5-(trifluoromethyl) 15 1,2,4-oxadiazol-3-yI)benzamide {/~ N a, N OH

H

2 N , ------------- FI'> HATU, NVMM ' DF,C VC-rt 8h This compound was synthesized from (4-(4-phenylthiophen-2-yl)tetrahydro-2H pyran-4-yl)methanamine and 3-(5-(trifluoroinethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (80 mg, yield 20%). 1 H NMR (400 MHz, CDCl) 5 8.43 (m, 20 1H), 8.25 (d, J1 = 7.8 Hz, 1H), 7.96 (d, J = 7.B Hz, 1H), 7.62-7.58 (m, 3H), 7.45 (d, J = 1.2 Hz, 1H), 7.40 (t, J= 7.7 Hz, 2H), 7.31 (m, 1H), 7.23 (d, J= 1.5 Hz, 1H), 6.15 (t, j= 6.5 Hz, 1H), 3.96-3.91 (dt, J = 11. 9 Hz, 4.2 Hz, 2H), 3.74 (d, J = 6.4 Hz, 2H), 3.71-3.66 (in, 2H), 2.18-2.14 (m, 2H), 2.08-2.03 (in, 2H). MS (ESI) m/z: Calculated for CH1 2

F

3

N

3 3 S: 513.13; found: 514.2 (M+H). 25 55 WO 20111088181 PCT/US201l11021089 EXAMPLE 10 1 .(4-Phenlhzol-2-yl)cyclopentanrbonitri le NOr" ,--.-NS NaH, 7H.- ( Thcneisncompond was synthesized from 2-(4-phenyltlhiazol-2-yl)acetontriie as 5 decried n examle stp using 1,4-dibromobutane (580 mng, yield 91%). '1. NMR (300 MHz, C~D1 3 ) 6 7.93-7.92 (mn, 2H), 7.90-7 33 (in, 4H41), 2.58-2 49 (m, 4H), 2.06-2.C0 (rn, 4H). M'VS (ESI) rnz: Calculated for C 1 5Hj,,N2-S 254.09; found: 255.2 (M+HY (1 -(4-Phenylthiazol-2-yi)cyclopentyl)methanamine

N

TlHF0 OC.rt 05h( This compcound was synthesized from 1-(4-phenylthiazoi-2 yi)cyclopentanecarbonitrile as described in example 1 step 3 (20mg, yield 42%). 'H NPAR (400O MHz, DMASO-d,) 6 7.96-7.93 (in, 3H), 7.44-7.40 (in, 2H), 7.33-7.29 (mn, 1H). 2.85 is, 2H), 2Z06-3.01 (in. 2H), 1.94-1,87 (mn, 2H), 1.73-1.66 (-In, 6H). MS (ESI) rn/z: 15 Calculated for CHj6N2S: 258.12. found: 5. (#) oxadiazo-3-yI)benzamide O-N 0I -S H.ATu, NMM 10~4 lh 20 This compound as synthesized frnm (1I-(4-pheny!thiazol-2 yi)cycloperitylhrethanamnine and 3-(5-(trifluioroie-thyl)-1,2,4-oxeadiazo-3-yl)benzoic acid as described in example 8 step 6 (65 mng, yield 34%). I-l NMVIR (400 MHz. DMSO-d 6 ) 6 8.78 (in. 18H), 8.44 (s, 18H), 8.19 (d, J= 7.6 Hz, 18H), 8.06 (d,1J--7.9 Hz, 18H), 7.96 (S, 18H), 56 WO 20111088181 PCT/US201l11021089 7.93 (d, J= 7 3 Hz, 2H), 7.71 it? J =7.9 Hz, I H), 73N (in, 2H), 7.30 (in. H), 3,69 (d, J 6 2 Hz, 2H), 2 19 (in. 2H), 2.07 (in. 2H), 1.76 (in, 2H). 1.64 (in, 2H). MS (ESI) / Calculated for C 2 5H~ 1

F

2

N

4 0 2 S: 498.13: found: 499.2 MH. 5 EXAMPLE 11 4-(3-PhenyilH-I 2,4-triazol-5-yl)tetrahydro-2H-pyran.-4-carbonitriie BrA Br~ \\. N N ONr NaH"NH NH H 0 lc-rt'1 dqy " This compound was synthesized from (5-phenyl-21--[1 .2,4]bltrazoi!-3-yl)i-aceton'!rii!e as described in example 'I step 2 (0.22 g, yield 16%). 1 1H NMR (300 MHz, CDO!?) 6 7.96 '10 7.92 (dd, J = 6.6 Hz, 3.1 Hz, 2H), 7.54-7.49 (in, 3H), 4,094.03 (CA, J= 12.1 Hz, 3.7 HZ, 2H), 3.95-3.87 (mn, 2H), 2.44-2.38 (mn, 2H), 2.29-2.25 (mn, 2H). MS (ESI) miz; Calculated for ClH iNO: 254.12, found: 255.2 PAM-'-H. (4-(3-Phenyl-1 H-I ,2,4-triazol-5-yI)tetrahydro-2H-pyran-4-yl)rnethanamine NN 'N'N H THF 0 -- rt,0.91 '15 0) This compound was synthesized from 4-(3-phenyl-IHN-1,2,4-triazol-5-yi~tetrahydro 2H-pyran-4-carbonitrile as described in example 1 step 3 (170 ig. crude). 'H NIvR (300 MHz DMSO-d,) 6 8,05-8.02 (dd. J .0 Hz, 1.4 Hz, 2H), 7.51-7.40 (in, 3H). 3.76-3.72 (in, 2H), 3.42-3,38 (mn, 2H), 2.97 (br s, 2H), 2,23-2.18 (d, J 11.8 Hz, 2H), 176-1.68 (mn, 2H). 20 MS (ESl)m: Calculatad for C,/H 1

CN

4 0; 258.15; found: 259.2 (M+H) . 57 WO 2011/088181 PCT/US20111021089 N-((4-(3-Phenyl-1 H-1,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-y)methyl)-3-(5 (trifluoromethyl)-1,2,4-oxadiazol-3-yI)benzamide N 0 F FC-< J N O N- \ N O- N

H

2 N NF N H HATU, NMM [J DMF, U C-rt, 8n This compound was synthesized from (4-(3-phenyl-I H-1,2,4-triazol-5 5 yi)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazo-3 y!)benzoic acid as described in example 8 step 6 (80 mg, yield 24%). '-1 NMR (400MHz, CDCl3) 5 8.56 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.02 (dd, J = 7.3 Hz, 1.8 lz, 21-1), 7.89 (br s, 11-), 7.62 (t, J = 7.8 Hz, I H), 7.46 (m, 3H), 3 97-3.92 (dt, J = 11.9 Hz, 4 5 Hz, 2H), 3.83 (d, J = 5 8 Hz, 2H), 3.71-3.66 (n, 2H), 2.44-2.42 (d, J = 13.6 10 Hz, 2H), 1.96-1.89 (ddd, J = 13.4 Hz, 9.2Hz 3.5 Hz, 2H), MS (ESI) mn/z: Calculated for

C,

4

H,,F

3 Nf-0.: 498.16: found: 499.2 (M+H)*. EXAMPLE 12 4-(2-Phenylthiazol4-yI)tetrahydro-2H-pyran-4-carbonitrile N B 0 r --- NC, NaH, THF 15 \pl rt-reflux, lh 0 This compound was synthesized from (2-phenyl-thiazol-4-yl)-acetonitrle as described in example 1 step 2 (0.53 g, yield 79%) as a yellow solid. 'H NMR (300 MHz, CDCI) 5 7.98-7.94 (dd, J =6.5 Hz, 3.2 Hz, 2H), 7.47-7.43 (rn, 3H), 7.33 (s, 1H),4.12-4.08 (ddd, J 12.3 Hz, 3.9 Hz, 1.5 Hz, 2H), 3.93-3.85 (td, J = 12.3 Hz, 2.1 Hz, 2H), 2.49-2.38 20 (ddd, J= 13.7 Hz, 12.3 Hz, 4.5 Hz 2H), 2.18-2.13 (dd, .J = 13.6 Hz, 2.0 Hz, 2H). MS (ESI) m/z: Calculated for C1-sHN2OS. 270.08; found: 271.2 (M+H)*. 58 WO 20111088181 PCTUS201 11021089 (4-(2-Phenylthiazol4-y)t.etra hydro-2H-pyran -4-yl)m etha nam ine N~ N-

H

2

N><

0T. ., 0 C-Ft,1 h This compound was synthesized from 4-(2-phenylthiazo-4-l)tetrahydr-2H--pyran 4-carbonitrile as described in example 1 step 3 (380 mg, yield 72%) 'H4 NNMR (400 MlHz, 53 CDC11) 6 679 ,J= 7 -H, 2 H, 2., 7.477.1 (in. 3H), 6.99 (s, 1H), 3.89-3.84 (dt, J = 11.7 HM. 4 0 Hz, 2H), 3 58-3.52 (m,. 2H), 2.91 (s, 2H), 2 31-2.28 (A, . = 1358 Hz, 21-), 1 87-1.80 (ddd. J = 13 9 Hz. 10.2 H~z, 4.3 Hz, 2H). IMS (ESI) n*z: Calculated for C15nH 1 sN 2 OS- 274.11: found: 275.2 (MHT 10 N-((4-(2-PheiiylttiezoI-4-yI)tetw-ahydro-2l1-pyran-4yi)rethyl)3(54trifluorormethy) I ,2.4-oxadiazol.3-yl)benzamiide I( -N 0 / -- -- -- ----- ----- --- F C -- -( j HATLJ, NMM K .2 [AMP; 0 IC-rt, 2h ~H This compound was synthesized from (4-(2-pheLnylthiazol1-4-yltetrahydro-2 pyran-4-yi)inethanamine and 3-(5 -ktrifiujoro.inethyl)-1 ,2,4-o-xadiazcl-3-yi)benzoic acid as 15 described in example 8 step 6 (85 mg, yield 45%). 1H NMR (400 MlHz, DMSO-d,) 5 8.56 (t. i = 6.2 Hz. IH), 8.41 (in, I-11): 8.15 (d, J' = 7.8 Hz, I H), 8.05 (d: J = 7.6 Hz.2 1l1-1), 7.91 7.89 (in, 21-), 7.69-7.65 (t, j=7.13Hz, IH), 7.53 (s, 1H) 7,46-7.43 (dd; 3=4.8 Hz, 1.9 HZ, 3HF), 3.79-3.76 im, 2 H), 3.54 -3.52 (d, J3 6.2 Hz, 2 H), 3.37 (mn, 2 F), 2.26 -2.22 (d, J = 13,.5 Hz: 214), 1.89-1.84 (in, 2H ). NIS (ESI) rr/z: Calculated for 0C 42 ,1 FN.CI 3 S: 514.13; found: 20 515.0 W(1 -HY. EXAMPLE 13 2-(4-(4-MethioxyphenyI)thiazoI-2-yI)acetornitrile 0 C CN Fir S O + ~reflx. 3h 0'. 6; 59 WO 2011/088181 PCT/US20111021089 This compound was synthesized from 2-bromo-l-(4-methoxvphenyl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (1 5 g, yield 75%) IH NMR (300MHz. CDCl 3 ) 5 7.83 (d, J = 8.9 Hz, 2H), 7.35 (s, 1H), 6.98 (d, J = 8.9 Hz, 2H), 4.17 (S. 2H), 3.86 (S5 3H). MS (ESI) m/z: Calculated for C1 2

H

10

N

2 OS: 230.05; found: 231.2 5 (M+HY 4-(4-(4-Methoxyphenyl)thiazol-2-yI)tetrahydro-2H-pyran-4-carbonitrile _-S ,CN Br' Os Br N N__xSNC NaH, THF 0 *C-rt, 2h 0 This compound was synthesized from 2-(4-(4-methoxypheny)thiazo-2 10 yl)acetonitrile as described in example 1 step 2 (1.6 g, yield 82%). 'H NMR (400MHz, CDC13) 5 7.86 (d, J = 8.8 Hz, 2H), 7.36 (s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 4.11-4.07 (m, 2H), 3.96-3.87 (dd, J = 11.3 Hz, 2.5 Hz. 2H), 3.86 (s, 3H), 2.41-2.31 (m, 4H). MS (ESI) rn/z: Calculated for C,,H,,N20 2 S: 300.09; found: 301.2 (M+;H)*. 15 (4-(4-(4-Methoxyphenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)mnethanamine N N LiAlH 4 M . -------------------------- 2 x ' THF, 0 *C-rt, 0.511 This compound was synthesized from 4-(4-(4-methoxyphenyl)thiazo-2 y!)tetrahydro-2H-pyran-4-carbonitr!e as described in example 1 step 3 (200 mg, yield 40%). 1 H NMR (300M Hz, CDC1 3 ) 6 7.86 (d, J= 8.8 Hz, 2H), 7.33 (s, 1H), 6.97 (d, J =8.8 20 Hz, 2H), 3.93-3.88 (im, 5H), 3.68-3.59 (n, 2H), 2.97 (s, 2H), 2.33 (m, 2H), 1.94-1.86 (m, 2H). MS (ESI) M/z: Calculated for C 1

,HMN

2 023: 304.12; found: 305.2 (M+H)*. 60 WO 20111088181 PCTUS201 11021089 N-((4-(4-(4-MethoxyphenyI)thiiazol-2-yI)tetrahiydro-2H-pyran-4-yl)miehy)-3(S (trifl uoromethyl).1 ,2,4-oxad iazol-3-yl)benizamnide H N HAFU, MAUI 0 () MF. 0 C-rit, 8h .0 This compound~ was synthesized fromn (4-(4-(4-rnethoxyphenyfl.tiiazol-2 5 vi)tetrahydro-2H-pyrar -4 yl)rnethan-amine and 3-(5-(tri fluoromethvl)-1.2,4-oxadiazo-3 yloenzoic acid as described in example 8 step 6 (80 mg, yield 38%). ILH NMR (400MHz, DPASO-d)68.78It: J6.31Hz, 1H), 8,13 (s: I H), 8.20 (d J= 7. Hz, 1H),8.07 (d, J= 7.9 Hz, 1 H): 7.91 (s, 1I ) 7.86 (d, J '8.9 Hz. 2H), 7.71 (t: J' 78,Hz, 11-H), 6,95 (d, J 8.5 Hz, 2H), 3.86 (in, 2H): 3.77 (s, 3H): 3.518 (d: J ' 6.4 Hz, 2H), 3.43 (t, J ' 10.5 Hz, 2H), 3.33 (s: 10 2H), 2.25 (d, J. 14 Hz, 2H), 2.02 (rn, 2H). MS (ESI) in/'z- Calculated for- C 2 6H 23

F

3 1N 4 0) S: 544.14; found: 545.2 (Mi-H)r. EXAMPLE 14 2-(4-(4-Chlorophenyl)thiazol-2-yl)acetoniitrile -reflUX, 40 mm r, 15 This compound was synthesized from 2- brorno-1 .- (4-cn lorop hen yl )etna none and 2 cyanothioacetamide as described in example 1 step 1 (1.51 g: yield 75%). 'H NMIR (300MHz, Cfjd;) 6' 7 84 (d, J n 8.8 Hz, 2H), 7.49 (s, 1H), 7.43 (d, .J = 8.8 Hz, 2H), 4.18 (S, 2H). MS (ESI) rn,1z: Calculated for C,H 7 ClN-Z: 234.00: found: 235.0 (M H)'. 20 4-(4-44-Chlorophienyl)thiazol-2-yl)tetrahydro.2Hpyrai4-carbonitrile C IN Cl ~ NaH, THF 61 WO 2011/088181 PCT/US20111021089 This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)acetonitrile as described in example I step 2 (1 15 g, yield 86%). 'H NMR (300MHz, CDCi 3 ) 5 7.88 (d, J = 8.6 Hz, 2H), 7.50 (s, IH), 7.43 (d, J = 8.6 Hz, 2H), 4.14-4.07 (dt, J = 12.3 Hz, 3.4 Hz, 2H), 3.95-3.86 (i, 2H), 2.45-2.30 (m, 4H). MS (ESI) n/z: Calculated for 5 CH' 3

CIN

2 OS: 304.04; found: 305.0 (M+H)*. (4-(4-(4-Chlorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yflmethanamine CI N-\,. NC LiAIH 4 \ HS THF, O*C-rt, 1h 0 This compound was synthesized 4-(4-(4-chlorophenyi)thiazol-2-y!)tetrahydro-2H.

10 pyran-4-carbonitrile as described in example 1 step 3 (250 mg, yield 50%). 1H NMR (400MHz DMSO-d6) 5 8.14 (s, 1H), 7,99 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8,5 Hz, 2H), 3.79-3.75 (m, 2H), 3.47-3.42 (m, 2H), 2.81 (s, 2H), 2.13 (d, J = 13.7 Iz, 2H), 1.91-1.83 (in, 2H). MS (ESI) rm/z: Calculated for CI 5

HI-CIN

2 OS: 308.08; found: 309.2 (M+H)*. 15 N4-((4-(4-(4-ChlorophenyI)thiazol-2-yI)tetrahydro-2H-pyran-4-yl)methyl)-3-(5 (trifluoromethyl)-1,2,4-oxadiazol-3-yI)benzamide C;l Ci F3C CO2H 0-N 0 N-, NN HNN F3C H2N -IXHATU. NMM p< DMF, 0 'C-rt, 8h 0 This compound was synthesized (4-(4-(4-chlorophenyi)thiazol-2-y!)tetrahydro-2-i. pyran-4--yi)methanamine and 3-(5-.(trifiuoromethyl)-1,2,4.-o:adiazol-3-yl)benzoic acid as 20 described in example 8 step 6 (75 mg, yield 42%). 1 H NMR (400MHz, CDCi 3 ) 5 8.47 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 9 lz, 1H), 7. 83 (m, 2H), 7.59 (t, J = 7.8 Hz, I H), 7.52 (s, 1H), 7.42 (t, J= 5.4 Hz, 1H), 7.35 (d, J 8.5 Hz, 21), 3.99-3.94 (n, 2H), 3.58 (d, J = 5.8 Hz, 2H), 3.77-3.71 (m, 2H), 2.35-2.29 (m, 2H), 2.08-2.05 (rn, 21-). MS (ESI) m/z: Calculated for C 25

H

20

CIF

3

N

4 0 3 S: 548.09; found: 549.0 (M+H). 25 62 WO 2011/088181 PCT/US20111021089 EXAMPLE 15 2-Methyl-2-(4-phenylthiazol-2-yl)propanenitrile Mel N N / CN NaH, DMSO P s ' 0 C-rt, 3h X This compound was synthesized from 2-(4-phenylthiazol-2-yl)acetontrile as 5 described in example I step 2 using iodorethane (250 mrg, crude). 1 H NMR (300 MHz CDCl 3 ) 5 7.94-7 91 (in, 2H), 7.47 (s, 1 H), 7 46-7.36 (in, 3H), 1.93 (s, 6H). 2-Methyl-2-(4-phenylthiazol-2-yl)propan-1 -amine ) LiAIH 4 / N -\ i 2 THF, C "C-rt 1h Ih H2N "SK 10 This compound was synthesized from 2-methvl-2-(4-phenyithiazol-2 yl)propanenitrile as described in example 1 step 3 (100 mg, yield 45%). IH NMR (400 MHz, DMSO-da) 6 7.95-.7.93 (im, 3H), 7.44-7.40 (t, J = 7.3 Hz, 2H), 7.33-7.31 (m, 1H), 2.81 (s, 2H), 1.35 (s, 6H). MS (ESI) m/z: Calculated for C,3Hi1N 2 S: 232.10; found: 233.2 (M+H)*. *15 N-(2-Methyl-2-(4-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)benzamide

O

FC N N ' x S a ">HATU, NMM I H DMF, 0 "C-r.t 8h This compound was synthesized from 2-methyi-2-(4-phenylthiazol-2-yl)propan-1 20 amine and 3-(5-(trifiuoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (75 mg, yield 38%). 1 H NMR (400 MHz, MeOD) 5 8.52 (t, J = 1 8 Hz, IH), 8.27 (d, J =7.8 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.92-7.90 (m, 2H), 7.69 (s, 1H), 7.67-7.63 (t, J = 7.8 Hz, I H), 7 36-7.29 (m, 2H), 7.28-7.26 (m, 1 H), 3.79 (d, J = .3 Hz, 2H), 1.58 (s, 6H). MS (ESI) rniz: Calculated for C 23

H,

9

F

3

N

4 0 2 S: 472.12; found: 473.0 25 (Mi-H). 63 WO 2011/088181 PCT/US20111021089 EXAMPLE 16 1 -Methyl4-(4-phenylthiazol-2-yi)piperidine-4-carbonitrile HCI sy^ ____CN( s C NaH ___N !\aN 5 This compound was synthesized from 2-(4-phenylthiazol-2-y)ac.etonitrile as described in example I step 2 using 2-chloro-Pj-(2-chlorcethyl)-N-methylethanamine hydrochloride and heating the reaction mixture at 60 0C overnight (200 mg, 40% yield). MS (ESI) m/z: Calculated for CH, 7

N

3 S: 283.11: found 284.1 (M+H)*. 10 Step 1b: Alternate synthesis of 1-methyl-4-(4-phenylthiazol-2-yl)piperidine4 carbonitrile C N UCHCI

SNH

4 0H- / S .CN O \-/ NC NaNHtoluenc. 110 iC, 3h N' Sodium aide (878 mg, 22.4 mrnol) was suspended in toluene (15 mL) and cooled to 0 *C, To this suspension was added dropwise a solution of (4-phenyl-thiazoi-2 15 yl)-acetonitrile (1.5 g, 7.4 mmol) in toluene (10 mL) while maintaining the temperature at 0 0C. The reaction mixture was stirred for 20 min Separately the bis-(2 chloroethyl)methylamine hydrochloride (1.45 g, 7.4 mmol) was taken in water (8 mL), cooled to 0 C, and basified with aqueous ammonia solution (adjusted to pH of the solution to -8). The oily layer was separated out from the aqueous layer and the organic 20 product was extracted with toluene. The toluene layer was dried over sodium hydroxide pellets. The dry toluene solution of bis-(2-chloroethyl)methylamine was added to the reaction mixture at 0 *C. The reaction mixture was allowed to warm up to room temperature and further heated to 110 OC for 3 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and extracted with EtOAc. The combined extracts 25 were washed with water and brine, dried over anhydrous sodium sulfate and concentrated 64 WO 20111088181 PCTUS201 11021089 under reduced PI-eSSUre. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5% MeOH in. CH 2 Ci1 2 ) to afford I-rnethyl-4-(4 phenylthiazol-2-yl)piperidine-4-carbonitile (350 mg, yield 17%). ' 1 NMVR ( 400MHI-z. DNASO-de) 5 8.22 (s. 1 H), 7,99 - 7.97 (mn, 2H). 7.49 - 7.44 (in, 2H), 7.40 - 7.36 (in, 1 H), 5 2.92 - 2.90 (rn, 2H ), 2.40 - 2.37 (in, 2P!',. 2.31 - 2.16 (in. 7H). MIS (ESI) nn/z: Calculated for C,,H,,N 3 S: 283.11; found: 284.2 (M+H)7. (I -MethiyI-4(4-penylthiiazol-2-yIl)piperidin-4-,yI)rethanparmine H N 10 This compound was synthesized from 1-mnethyI-4-(,4-phenlyithiazo-2-y)piperidine 4-carbonitrile as described in example 1 step 3 (200 mg, crude). MS (ESI) in/z: Calculated for CI,H 21 N3S: 287.15, found: 266.1 (KP.-H)', M-((1 -Methyh-4-(4-phenylthiazol-2-yh)piperidiri-4-yI)rnethyl)-3-f5-(trifluoromethyl) 15 1 ,2,4-oxadie~zol-3-yl)benzaemide P-N )-N 0 I'' 3' .02 H, x

N

This compound was synthesized from (1-methyl-4-(4-phenylthiazo.-2-yl)piperidin. 4-vl)methanamine and 3..(5-(trifluoromethyl)-1 ,2,4-oxadszol.3-yl)benzcic: acid as described in example 8 step 6 (9 mg, 23% yield): 1 H NIOR (300 MHz, CDC 3 ) 6 8.51 (S; 20 1H), 8.21 (d, j=7.5 Hz, IfI), 7.98 (d, 1=7.5 Hz, 1IH), 7.86 (d, J=6,3 Hz, 1H), 7.76 (mn, 1H), 7.54 (t, J-6.2 Hlz, 214), 7.46 (s, lI-H); 7.34-7.25 in. 2H), 3.86 (s, 21H), 2.69 (mn, 21Hi), 2.57 in, 4[4), 2.34 (s, 31-1, 2.13 (m; 2H-), MS (ESII rn&z Calculated for C26l- 24

F

3

N

5 0-)S: 527.16; found: 528.1 (M+l-l)7 25 65 WO 2011/088181 PCT/US20111021089 EXAMPLE 17 2-(4-(4-Fljorophenyl)thiazol-2-yi)acetonitrile F B, NO S EtOH r ,J NC , fij N ~ NH2 reflux N F -NCJ(S2 fIL S This compound was synthesized from 2-bromo-1-(4-fluorophenyl)ethanone and 2 5 cyanothicacetamide as described in example 1 step 1 (3.2 g, yield 72%). MS (ESI) m/z: Calculated for CjlHFNS: 218.03; found: 219.0 (M+H) 4-(4-(4-Fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile I Xi NCBr' ' Br N NC NaH. THF 10 This compound was synthesized from 2-(4-(4-fLuorophenyl)thiazol-2-yl)acetonitrile as described in example 1 step 2 (3.0 g, yield 66%). MS (ESI) m/z: Calculated for C,,HI3FN 2 OS: 288.07; found: 289.0 (M+H)> (4-(4-(4-Fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine F F LiAIH 4 N -, N THF, 0 *C-rt This compound was synthesized from 4-(4-(4-f;uorophenyl)thiazcl-2-yl)tetrahydro 2H-pyran-4-carbonitrile as described in example I step 3 (600 mg, crude) and it was carried through without further purification. MS (ESI) nVz: Calculated for CisH1 7 FNOS: 292.10; found: 293 1 (M+H)*. 20 66 WO 20111088181 PCTUS201 11021089 N-((4-(4-(4-Fhj orophenyl~thiazol -2 y)tetahyd ro-2H-pyran 4-y)m ethyl)-3-( (trifi uoromethyl).1 ,2,4-oxad iazol-3-yl)benzam ide H This compound was synthesized from (4-(4-(4-41 uoroph enyl)thao-2-yM)tetra hyd ro 5 2H-Pyra n-4-y!)methana min e and 3-(5-(trifluoromethyl)-1.2,4-oxadiao-3-yllnenzoic acid as described in example 8 step 6 (11 mg, 27% yield): I H NMR (300 MHz, CDC13) 68.45 (s, 1H), 8.23 (d, 11= 6.4 Hz, 1H), 7.98 (d, 1=6.4 Hiz, ILI), 7.85 (t, J=5.1 Hz, 2H), 7 55 (t, J 7.7 Hz, 1 H), 7.25 (s, I H), 7,04 (t, J=7.7 Hz, 2H) 3.94 (in, 2H), 3.87 (in, 21H), 3.21 (in, 2H), 2.28 (mn, 2H), 2.04 (in. 2H). MS (ESI) PVT: Calcuisteid fOr C 25

H

20 ' 4

N.

4 0 3 S; 532 12; found 10 533.2 (M+Hy). EXAMPLE 1S 2-(8-Methyl-4-phenyithiazol-2-yl~acetoniitriie S ['O'ON '15 This compound was synthesized from 2- broino-1 -phenylpropan-l-one and 2 cyanothiccetamide as described in example 1 step 1 (1.7 g, 56% yied %.MS (ESI) 0hilz: Calculated for C 1 2 -H~iN 2 .S: 214.06; found: 215.0 (M+H)Y. 4-(8-Methyl-4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile -S ('N N NaH, H. 20 r '0 This compound was synthesized from 2-(5-.inethyl-4-phenvlthiszol-2-yl' acetontrile. as described in example 1 step 2 (3.0 g, yieid 66%). MS (ESl) t,/z Calculated for

C

16 H,,,N2S: 284.10; found: 258.1 (M+H. 67 WO 2011/088181 PCT/US20111021089 (4-(5-Methyl..4-phenylthiazol-2-yl)tetrahyd ro-2H-pyran.-4-yl)methanamine N I NC_ LIA!H 4 THF, 0 IC-rt H2N This compound was synthesized from 4-(5-methyl-4-phenylthiazol-2-yl)tetrahydro 2H-pyran-4-carbonitrile as described in example 1 step 3 (600 mg, crude) and it was 5 carried through without further purification. MS (ESI) m/z: Calculated for ClBHN 2 OS: 288.13; found: 289.1 (M+-H). N-((4-(5-Methyl-4-phenylthiazol-.2-yl)tetrahydro-2H-pyran4yl~methy)-3-(5 (trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide F"c-- ,k COHHN-HTNAM A1, F3C 10 NL H< This compound was synthesized from (4-(5-methyl-4-phenylthiazol-2-yl)tetrahydro 2H-pyran-4-y!)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-vl)benzoic acid as described in example 8 step 6 (55 mg, 89% yield): 1 H NMR (300 MHz, CDCi3) 5 8.48 (t. J = 1.1 Hz, 1H), 8.23 (dt, J= 6.2 Hz, 1.1, 1H), 7.98 (dt, J=7.9 Hz, 1.1 Hz, 1-I), 7.74 (bs, 15 1 H), 7.64 (m, 2H), 7.49 (t, J= 7.7 Hz, 1 H), 7.39-7.29 (n, 2H), 3.92 (m, 2H), 3.85 (d, J= 5.7 Hz, 2H), 3.74 (m, 2H), 2.59 (s, 3H), 2.24 (m, 2H) 1.95 (m, 2H). MS (ESI) m/z: Calculated for C 2 eH 2 3FnN40 3 S: 528.14; found. 529.1 (M+H)* EXAMPLE 19 20 2-(4-Cyclohexylthiazol-2-yl)acetontrile CN +2 N H2N- reflux, 3h Lj This compound was synthesized from 2-broro-1-cyclohexylethanone and 2 cyanothicacetamide as described in example 1 step 1 (0.4 g, yield 80%). ' 1 H NMR (300MHz, CDC1 3 ) 5 6.88 (s, 1-h) 4.11 (s, 2H), 2.74 (m, IH), 2.06-2.04 (m, 2H), 1.84-1.72 68 WO 20111088181 PCTUS201 11021089 (rn, 4H), 1 44-1.31 (in, 4H). MS (FSI) n V CalCuJlated for- C. H 1 4

N

2 S 206.09: found- 207.2 IM i- H\ 4-(4-CyclohexylthiazoI-2-yI)tetrahydro-2l1-pyran-4-carbonitrile (1 B, N' N NC-.-. K> NaHTHF ( This compound was synthesized frorn 2-(4-cyciohexylthiazol-2-yl)acetoritriie. as described in example I step 2 (0.3 g, yield 60%) as a yellow solid. 'H INMR (400MIz. GODh) 66.87 (a, 1l-I) 4.07-4.03 (dt, J =12.2 Hz, 3.3 Hz, 2H), 3.90-3.83 (in, 2H), 2.77 (in1, 111), 2.3-5-2.25 (in, 4H), 2.08-2.06 (d; i = 6.0 Hz, 2H), 1.83-1.72 (in. 41-), 1.43-1.33 (mn, '10 4H). MS (ESI) rn/z: Calculated for C.,,HN2CS: 276.13; found: 277.2 (M+HY., (4-(4-Cclohexylthiazol-2-yl)tetrahydro-2H-pyran-4-yI)methanamine TH F, 0 C-r, 1 h,~ ( This compound was synthesized from 4-(4-cvclohexylthiazol-2-yi)tetr.ahydro-2H 15 Pyran-4-carbonitrile as described in example 1 step 3 (120 ing, yield 40%). 'H NNMR (400 MHz, DMSO0-d 6 ) 8 7.14 (s, IHj). 3.75-3.69 (m:. 2H), 3,39-3.34 (6m, 4H), 2.69 (in. IH), 2.03 (m, 4H), 1..83-1.67 (in, 6H), 1.43 (mn, 4H\, MS (ESI) Mlzi: Calculated for C 5 ,Nj 2,80.16; found: 281.2 (+Y 69 WO 20111088181 PCT/US201l11021089 N-((4-(4-Cyclohexylthiazol-2.yI)tetrahydro-21-pyran4-y)mnethyl)-3-(S (trifl uoromethyl).1 ,2,4-oxad iazol 3 yl)benza mide 0 N K HI.~ INH HATLJ, NJVIV DMF, Q0- 8h This compound was synthesized from (4 -(4- cyclo hexyth iazol -2- y!tetra hdro- 2K. 5 Pyran-4-yi)rneffhnamine and 3-(5-.(trifl!uo~ornethly)-1 ,2,4.-oxadiazcl.-3-yl!Ibenzoic acid as described in example 8 step 6 (70 rmg, yield 32%). 'H NMIR (400 rMHz, NMeCDI 5 8.50 (t: J = 1.5 Hz, 1H), 8.29 (dt, J = 7.8 Hz: 1.4 Hz, IH)I, 7.98 (in, 1H), 7.67 (t: J = 7.8 Hz, 1H), 7.05 (s, 1IH), 3.90 -3.86 (dt, J = 11 .8 Hz, 3.9 Hz, 2 H), 3.65 (s, 2H), 3.55 -3.49 (in, 2"), 2.69 (in, I1H, 2 35 (d, J = 13.8 Hz, 2H), 2.04-1 96 (m,4H), 1.76-1.73 (rn. 2H), 1,39 (irn, )HY. PAS 10 (ESI) rplz' Calculated for C 25

H)

7

F

3

N

4 03S 520.18; found: 521.2 (M+Hr EXAMPLE 20 2-(4-(Pyridin-2-ylthiazol-2-yl)acetonitrile SrEtCOH N' + H 2 N' ' N -------- K' reflax. 31 N. '15 T-his compound was synthesized from 2-bromo-1-(Ipyricon-2--yl)ethEanone and 2 cvanothicacetamide as described in example 1 step '1 (0.37 g, yield 73% f: 1 H NMR (400MHz, CDCl3) 6 8.65 (d. J = 5.5 Hz, IH), 8.15 (mn, 2HI), 7.84 (t, J = 8.4 Hz, 'IH), 7.30 (in, 1H), 4.21 (s, 2H). IMS (ESI) rnflz: Calculated for CIOHTN 3 S: 201.04: found: 202.2 (M+ H) 20 4-(4-(Pyridin-2-yl)thiazol-2-yl)tetrehydra.2H-pyran.-4-carbonitrile S C N BN - NeH. TI-IF 0'Crt3h This compound was synthesized from 2-(4-(poyridin-2-yl)thiazol-2-yl)acetonitriie as described in example 1 step 2 (0.37 g, yield 74%): IH NMR (300 MHz, CDCi,,) 6, 6.64 (d, 25 J =3.9 Hz, 1H): 8.18 (mn, 2H), 7.83 (td, i '-7.8 Hz, 1.8 Hz, 11I) 7.29 (rn, 1I), 4.14-4.08 70 WO 20111088181 PCTUS201 11021089 (rn, 2H), 3,,6-3.87 (in. 2H), 2 46-2.32 (m?. 4H).. MS (ESI) m/z: CaICUlated for (Ci 4 Hia3N! 3 ()S: 271.08; found: 272 2 (M+H) (4-(4-(Pyridin-2-yl)thiazol-2-yl)tetrahiydro-2If-pyran-4-yI)r~nethanaminie fl3N THF, 0 c-Irt, 0.51',N«< K) This comnpounld was synthesized from 4--,4-(:)yridin-2-yiflhiazcl-2.-yI)tetrahydro-2H pyran-4-carbontrile as described in example I step 3 (1501 mng, crude), and it was carried through without any further purification. MS (ES1) rn/z: Calculated for Cl 4

HI

7

N

3 0S: 275, 11;ftound: 276.2 AM±H)4. N-((4-(4-(Pyridin-2-yljthiazol-2-yl)tc-trahydro-2--pyran-4-y)methyl)-3-( (trifhuoromethyl)-1 Z,4-oxadiazol-3-yI)benzamide P-N0NI N S loll~ HAT , N MI NIJV' > DUR 0 -r-t, 1lh This compound was synthesized from (4-(4-(riyridin-2-yl)thiezol1-2-yiltetrahydro 15 2H-py-ran-4-yI)mnethanainne and 3-(5-(trifluoromnethyI ' -1 ,24-oxadiazo-3-vl)benizoic acid as described in example 8 step 6 (35 mg, yield 13%). 1 HI NMR (400 MHz, MeODI, 6 8.54 (d: J = 5.5 Hz, 11-1, 8.44 (in, 1H), 8.25 (d: J 8.0 Hiz, 1 H), 8.17 (a. i H), 8.11 (d, J = 8.0 H-z: 1 H). 7.97 (d, J 7.8 Hiz. 1 -I), 7.79 (td: J =7.7 Hz, 1.6 Hz, 1 H), 7.62 Qt, J 7.8 Hz, 1 H-), 7.32 (in. 1H), 3.97-3.93 'dt. J 11.8 Hz, 3.8 Hz. 2H), 3.75 (in, 2iH). 3.62 -3.56 (mn, 2iH1) 20 2.47-2.44 (in, 2H1), 2.12-2.08 (ddd, J =14.1 Hz, 10.5 Hz, 4.3 Hz, 21). IMS (ESI r/z Calculated fo! C 24 H F3N 5 CS: 5115.12; found: 516.0 (M, H)'. 71 WO 2011/088181 PCT/US2011/021089 EXAMPLE 21 2-(4-(Pyridin-4-yl)thiazol-2-yl)acetonitrile O 0S CN EtOH +i ------------- N reflux, 3h N This compound was synthesized from 2-brormo-1-(pvridin-4-yl)ethanone and 2 5 cvanothicacetamide as described in example I step 1 (0.23 g, yield 46%): 1 H NMR (300MHz, MeCOD) 6 8.59 (n, 2H), 8.24 (s, I H), 7.98 (m, 2H), 4.44 (s, 2H). MS (ESi) m/z: Calculated for CICH 7

N

3 OS: 201.01; found: 202.2 (M+H)*. 4-(4-(Pyridin-4-yl)thiazol-2-yl)tetrahydro-21-pyran4-carbonitrile rS CN -/ Br Br 1;) SO -- N NC, -,_' e 'N _ ______ ______ N C N NaH, THF 10 0 C-rt, 2h This compound was synthesized from 2-(4-(pyridin-4-yl)thiazol-2-yl)acetonitrile as described in example I step 2 (0.18 g, yield 58%): H NMR (300 MHz, MeOD) 6 8.60 (m, 2H), 8.29 (s, IH), 7.99 (m, 2H), 4.10-4.04 (dt, J = 12.2 Hz, 3.1 Hz, 2H), 3.88-3.79 (Im, 2H), 2.37-2.33 (m, 41-). MS (ESI) m/z: Calculated for C.

4

H

1

,N

3 OS: 271.08; found: 272.2 15 (M+HY. (4-(4-(Pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine ,--N ---N LiAlHN NC ------------------- S T HF, 0 OC-rt 1h H 2 N This compound was synthesized from 4-(4-(pyridin-4-yi)thiazol-2-yl)tetrahydro-2H 20 pyran-4-carbonitrile as described in example I step 3 (90 mg, crude), and it was carried through without any further purification. IH NMR (300 M-lz, DMSO-ds) 6 8.63 (m, 2H), 8.42 (s, 1H), 7.90 (n, 2H), 3.79-3.74 (m, 2H), 3.51-3.42 (m, 21-), 2.79 (s, 2H), 2.14-2.10 (rn, 2H), 1.89-1.82 (m, 2H). MS (ESI) m/z: Calculated for C,,H, 7 NOS: 275.11; found: 276.2 (+ H)*. 72 WO 2011/088181 PCT/US20111021089 N-((4-(4-(Pyridin4-yl)thizo-2-yl)tetrahydro-2H-pyran-4-yl)methyl)--(5 (trifluoroniethyl)-1,2,4-oxadiazol-3-yl)benzamide r-N/ /1P-N J- F 3 C-CO2H N O/N O ( HATU, NMM - DMF, 0 C-rt, 2h 0 5 This compound was synthesized frorn (4-(4-(pyridin-4-yl)thiazol-.2-yl)tetrahydro 2H-pyran-4-yl)methanamine and 3-(5-.(trifluoromethyl)-1,2,4-oxadiazo.-3-vl)benzoic acid as described in example 8 step 6 (60 mg, yield 38%): IH NMR (400 MHz, DMSO-de) 6 8.82 (t, J= 6.3 Hz, I H), 8.57 (d, J = 5.8 Hz, 2H), 8.45 (s, IH), 8.40 (s, 1H), 8.19 (d, J = 7.9 10 Hz, IH), 8.05 (d, J = 7.9 Hz, 1H), 7 87 (d, J = 5.8 Hz, 2H), 7.70 (t, J = 7.8 Hz, 1H), 3.87 3,84 (dt, J = 12.1 Hz, 3.4 Hz, 2H), 3.59-3.58 (d, J = 6.1 Hz, 2H) 3.42 (m, 2H), 2.28-2.24 (d, J = 13.4Hz, 2H), 2.04-1.96 (m, 2H). MS (ESI) nz: Calculated for C 2

H

2 oF 2 NO08: 515.12; found: 516 0 (M+H) 15 EXAMPLE 22 Methyl 5-((hydroxyimino)methyl)thiophene-2-carboxylate NH2OH.HCI, pyridine M C MeO2' s CHOMeO2C g/ WCl EtOH, 3h, reflux

N-

0 8 Hydroxylarnine hydrochloride (420 mg, 6.1 mmol) and pyridine (0.5 mL) were added to a solution of methyl 5-formylthiophene-2-carboxylate (690 mg, 4.1 mmol) in 20 EtOH (25 mL). The reaction mixture was refluxed for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether, the organic laver was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get product methyl 5 ((hydroxyimino)rnethyl)thiophene-2-carboxylate (440 ig, yield 60%), which was carried 25 through without any further purification. 'H NMR (400 MHz, DMSO-d.) 5 12.5 (s, 1H) 7.98 (s, 1H), 7.78 (d, J=4.1 Hz, 1H), 7.51 (d, J=4.1Hz, IH), 3.82 (s, 3H). MS (ESI) m/z: Calculated for C 7 -1 7 N0 3 S: 185.01; found: 186.0 (M+H) 73 WO 2011/088181 PCT/US20111021089 Methyl 5-cyanothiophene-2-carboxylate AcfO/ MeO 2 C'- - MeO2C' - CN O eflux, 16h N'OH A solution of methyl 5-((hydroxyimino)methyl)thiophene-2-carbcxylate (440 mg, 2.4 mmol) in acetic anhydride (10 mL) was refluxed for 16 h. After completion, the 5 reaction mixture was cooled to room temperature, concentrated under reduced pressure and the residue was dissolved in diethyl ether. The organic layer was washed with 10% aqueous NaOH solution, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield methyl 5-cyancthiophene-2 carboxylate (5-cyano-thiophene-2-carboxylic acid methyl ester) (400 mg, yield 90%) which 10 was carried through without any further purification. 'H NMR (400 MHz, DMSO-d6) 6 7.77 (d, J = 4.2 Hz, IH), 7.60 (d, J = 4.1 Hz, 1H), 3.95 (s, 3H). Methyl and ethyl 5-(N'-hydroxycarbamimidoyl)thiophene-2-carboxylate \\ NH20H.HCi, Na2CO3 -\- N MeO2 s ------------- " Me- s H + tO. s O 8 -hydrcxyquiroliIne (Cat) NH2 N Et,0H. reflIux, h 15 This mixture of compounds was synthesized from methyl 5-cyanothiophene-2 carboxylate as described in example 1 step 4 and it was isolated as a mixture of methyl and ethyl esters (2:3 ratio), and it was carried through without any further purification. MS (ESI) mz: Calculated for C 7 1-1N 2 0 3 S. 200.03; found: 201.2 (M+H) (methyl ester), Calculated for CsHION 2 03S: 214.04; found. 215.0 (V+H1). (ethyl ester) 20 Methyl and ethyl 5-(5-(trifluoronethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxylate ON - F3 N S O NN'I (CFNCO) 2 O M Et02C - 'Y ------- +

NH

2 NH7 pyricine 21 IC, 3h F 3 " N -E This mixture of compounds was synthesized from a mixture of methyl and ethyl 5 (N-hydroxycarbamimidoyl)thiophene-2-carboxylate as described in example 1 step 5 and 25 it was isolated as a mixture of methyl and ethyl esters (2:3 ratio), and it was carried through without any further purification. MS (ESI) m/Z: Calculated for C 2

H

5

F

3

N

2

O

3 S: 278.00; found: 278.0 (M)-. (methyl ester); Calculated for C 0

H

7

FN

2 0 3 S: 292.01; found: 292.0 (M)-. (ethyl ester) 74 WO 2011/088181 PCT/US20111021089 5-(6-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)th iophene-2-carboxylic acid F3-N S O2 Me~t LIOHN THF-H20 7:3 v/v N CC 2 H N3 . S CO2Et rt, 2 days LIOH (37 mg) was added to a solution of a mixture of compounds methyl and ethyl 5 5-.(5-(trifiuoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2-carboxylate (300mg) in THF: H 2 0 (10 mL, 7:3 v/v) and the mixture was stirred at room temperature for 2 days. The reaction mixture was then diluted with water and the aqueous layer was washed with EtOAc. The aqueous layer was acidified to pH -4, extracted with EtOAc. The combined extracts were concentrated under reduced pressure to yield 5-(5-(trifluoromethyl)- 1,2,4-oxadiazol-3 10 yi)thiophene-2--carboxylic acid (60 mg), which was carried through without any further purification. l1H NMR (400 MHz, DMSO-da) 5 13.78 (br s, 1-), 8.01-7.94 (m, IH); 7.84 7.79 (dd, J = 18.2 Hz, 3.8 Hz, IH). MS (ESI) m/z: Calculated for CsH3FN 2

O

3 S: 263.98; found: 263.0 (M-H) 15 N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyrar-4-yl)methyl)--(5-(trifluoromethyl) 1,2,4-oxadiazol-3-yl)thiophene-2-carboxamide H2NN 0N 0-N N i HATU. NMM -3 \C H DMIF, 0 IC -rt, 8h This compound was synthesized from (4-(4-phenylthiazol-2-yi)tetrahydro-2H pyran-4-yi)methanamnine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)thiophene-2 20 carboxylic acid as described in example 8 step 6 (25 mg, yield 22%): H NMR (400 MHz, CDC1 3 ) 5 7.96 (d, J 7.3 Hz, 2H), 7.78 (m, J = 4.0 Hz, IH), 7.62 (br s, 11H), 7.53-.7.48 (m, 4H), 7.42 -7.36 (in, 1HI), 3.97-3.91 (rn, 2H), 3.86 (d, J = 5.5 Hz, 2H), 3.78-3.73 (ddd, J = 11.6 Hz, 7.5 Hz, 3.5 Hz, 2H), 2.33-2.27 (ddd, J = 13.6 Hz, 7.0 Hz, 3.5 Hz, 2H), 2.06-1.99 (ddd, J = 13.8 Hz, 7.3 Hz 3.3 Hz, 2H). MS (ESI) i/z: Calculated for C 23

H

19

F

3

N

4 0 3 S2: 25 520.09; tound: 521.0 (M+H)*. 75 WO 2011/088181 PCT/US20111021089 EXAMPLE 23 2-(4-(Thiophen-2-yl)thiazol-2-yl)acetonitrile C C EtOH ) >- + CN N reflux. 3h -h 5 This compound was synthesized from 2-bromo-1-(thiophen-2-yI)ethanone and 2 cyanothicacetarnide as described in example 1 step 1 (0.25 g, yield 49%): 1 H NMR (400MHz, CDCl 3 ) 5 7.47 (d, J = 3.4 Hz, 1II), 7.36 (s, 1H1), 7.33 (d, J = 5.1 Hz, 1H), 7.09 (t, J = 4.2 Hz, 1H), 4.17 (s, 2H). MS (ESI) m/z: Calculated for C.HcN 2

S

2 : 206.00; found. 207.0 (M4-H). 10 4-(4.-(Thiophen-2-.yl)thiazol-2-.yl)tetrahydro-2H-pyrari-4.carbonitrile ~.-S -S S CN Br B NaH, THF 0 "C-rt, 2h This compound was synthesized from 2-(4-(thiophen-2-yl)thiazol-2-yl)acetonitr~ie as described in example 1 step 2 (0.2 g, yield 60%): 1H NMR (300MHz, CDC 3 ) 6 7.49 15 7.47 (dd, J= 3.6 Hz, 1.2 Hz, 1H), 7.36 (s, 1-4), 7.32 (dd, J= 5.2 Hz, 1.2 Hz, 1H), 7.09-7.07 (dd, J = 5.0 Hz, 3.5 Hz, 1H), 4.13-4.07 (m, 2H), 3.94-3.85 (td, J = 11.8 Hz. 2.5 Hz, 2Hil), 2.46-2.33 (in, 4H). MS (ESI) m/-: Calculated for C 1 3

H,

2

N

2 0S 2 : 276.04; found: 277.0 (M+H). 20 (4-(4-(Thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)mnethanamine LiAlH4

NC

THF.O "-rt, 1h) 1 -1 This compound was synthesized from 4-(4-(thiophen-2-yl)thiazol-2-yl)tetrahydro 2H.-pyran-4--carbonitrile as described in example 1 step 3 (80 mg, yield 40%): 'H NMR (400 MHz, DMSO-de) 6 7.88 (s, 1H), 7.54-7.47 (in, 2H), 7.10-7.08 (m, 1-1), 3.76-3.72 (m, 25 2H), 3.49-3.39 (m, 2H), 2.79 (s, 2H), 2.08-1.96 (in, 2H), 1.87-1.81 (m, 2H). MS (ESi) m/z: Calculated for C1-1 6

N

2 5 2 . 280.07; found: 281,2 (M+H)*. 76 WO 2011/088181 PCT/US20111021089 N-((4-(4-(Thiophen-2-y)thiazol-2-y)tetrahydro-2H-pyran 4-yl)methyl)-3-(5 (trifluoromethyl)-1,2,4-oxadiazol-3-yi)benzamide O N -S F3N 3. >a CO9 N ON 0 N ---- --- --- -- -- -- -- -- - N -N X

H~

2 N N>' , F C N s~ HATU, NMM O DMVF, V C-rt, Sh '5 This compound was synthesized from (4-(4-(thiophen-2-yl)thiazol-2-yl)tetrahydro 2H-pyran-4-yi)rnethanamine and 3-(5-(trifluorocethyl)-1,2,4-oxadiazoi-3-yl)benzoic acid as described in example 8 step 6 (70 mg, yield 46%): IH NMR (400 MHz, MeOD) 5 8.47 (t, J = 1.5 Hz, 1H), 8.26 (m, 1H), 8.00 (dt, J = 7.8 Hz, 1.4 Hz, IH), 7.63-7.61 (m, 2H), 7.46 10 (dd, J = 3.8 Hz, 1.0 Hz, IH), 7.29 (dd, J = 5.0 Hz, 1.0 Hz 1H), 7.01 (dd, J 5.0 Hz, 3.8 Hz, 1H), 3,95-3.92 (dt, J= 11.9 Hz, 4.0 Hz, 2H), 3.71 (s, 2H), 3.62-3.56 (m, 2H), 2.42-2.38 (d, J = 13.8 Hz, 2H), 2.08-2.02 (ddd J = 143 Hz, 10.4 Hz, 4.4 Hz, 2H), MS (ESI) 1/z: Calculated for C 23 HF3N 4 03S 2 : 520.09; found: 521.0 (M+H)*. 15 EXAMPLE 24 2-(4.-(4-Fluorophenyl)thiazol-2-yl)-.2-nethylpropanienitrile F ,!. />' Mel N F' if NaH, THF NC A rt, This compound was synthesized from 2-(4-(4-fluorophenyl)thiazol-2-yl)acetonitriie using iodomethane as described in example 1 step 2, and it was used directly without any 20 purification in the next step. 'H NMR (CDCI 3 ) 67.88 (2H, n), 7.39 (1H, s), 7 10 (2H, m), 1.90 (6H, s). MS (ESI) m/z: Calculated for C, 3

H

11

FN

2 S: 246.06; found: 247.0 (M+H). 77 WO 2011/088181 PCT/US20111021089 2-(4-(4-Fluorophenyl)thiazol-2-y)-2-methylpropan-1 -amine N- LiAI-4 N NCTIHF. 0 *C-i H 2 N PS This compound was synthesized from 2-(4-(4 -Fluorophenyl)thiazol-2-yl)-2 methylpropanenitrile as described in example I step 3 (29 mg, 6% yield). 'H NMR 5 (DMSO-de) 67.98-- 7.94 (2H, m), 7.92 (1h, s), 7.26-7.22 (2H, in), 2.77 (2H, s), 1.33 (6H, s); MS (ESI) m/z: Calculated for C13H 1 5

FN

2 S: 250 09; found: 251.1 (M+H). Step 6: N-(2-(4-(4-Fluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifl uoromethyl) 1,2,4-oxadiazol-3-yI)benzamide N CH F '-N O \- -- - - 10C EDl HOMi, DCM, rN O s 2-(4-(4-Fluorophenyl)thiazol-2-y-2-methylpropan-1-amine (140 mg, 0.56 mmol), 3-(5-(trifiuorommethyl)-1,2,4-oxadiazol-3-yi)benzoic acid (144.37 mg, 0.56 mrnol), N-(3 dimethylaminopropyl)-N-ethycarbodiinide hydrochloride (EDCI) (214.42 mg, 1.12 mmol), and 1-hydroxybenzotriazole (HOB) (120.91 mg, 0.89 mmol) were dissolved in 15 dichloromethane (3 mL) at room temperature. Dilsopropylethylamine (DIEA) (0.39 mL, 2.24 mmol) was then introduced at room temperature and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was diluted with dichloromnethane (60 mL) and washed with water (1 X 20 mL) and brine (1 X 20 mL). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to 20 give the crude product. The crude product was then purified on Combiflash ISCO (0-30 % Ethyl Acetate : Hexanes) to give the desired product (164 mg, 60% yield). lH NMR (CoDCl) 6 8.52 (1H, t), 8.22 (1H dt), 8 12 (1H, t), 8.03 (1H, dt), 7.85-7 81 (2H, m), 7.57 (1 H, d), 7.35 (1H, s), 7.05-7.00 (2H, m), 3.80 (2H, d: J = 4 Hz), 1.55 (6H, s); MS (ESI) m/n: Calculated for C 23 H-aF 4

N

4 02S: 490. 11 found: 491.1 (M+H)' 25 78 WO 20111088181 PCTUS201 11021089 EXAMPLE 26 2 -(4-(4-(h Ioaphenyl)th iazol-2 -yfl 2-m ethylp ropane.nitri le CAl -Mel Nal-l, DIVISO P-, NC. This compound was synthesized from 2-(4-,4-onlorophenl)thiazol-2-yl)acetontrii.e 5 using iodomethane as described in example I step 2 (470 mng, yield 94%): 'H WAR (400 MHz, ODC1 3 ) 6 7,86-7.85 (d, J =8.5 Hz, 2H-1, 7.46 (s, 1H), 7.41-7.39 (d, J 8.5 Hz, 2H); 1.92 (s, 6H), IMS (ESI) P12: Calculated for C 13

H

1 ,CINS: 262.03; found; 263.0 (uM+HV'. 2 -(4-(4-C hloro pheny)th iazol -2 -yi)-2-m ethyl propan -1 -am ine

N-

VHF. 0 'C-r. I III 10 XIHN This compound was synthesized from -4(-horneynhezl2y)2 methyipropanlenitile ascdescribed in example 1 step 3 (120 mg, yield 47%): '1-1 MR (400 MHz. DMSO-d 6 ) 6 6.04 (d, J =1.2 Hz: 1H), 7.98 (d. i 8.4 Hz, J = 1.7 Hiz, 2H), 7.51 7.48 (dd, J =6.5 Hz, J =1.5 Hz, 2H), 2.81 (s, 21-), 1.37 (s: 61H). MAS (ESI) m'z. Calculated 15 for 0, 1 ,,-CiN 2 S: 266.06; Found: 267.2 (NM±H11. N'-(2-(4-(4-C hlorophe nyl)th iazol -2-yl) -2-m ethyl propyl) -3-(B-(trifluorom ethyl) -1 ,24 oxadiazol-3-yl)benzamide INI -2 y .DMF, 0 IC-rt, 2h 20 This -compound was synthesized from 2-(4-( ,4-chlorophenyl)thdiezol-2-y)-2 methvlpropan-i-amine and 3-(5-(tr!fluiorcrnethyl)-1,2,4-oxadiazol-3-yi)benzoic acid as described in example 8 step 6 (80 mg, yield 35%): 1 1H NMR (400 MAHz. CDC1 3 ) 5 8.54 (in. 1 H), 8 27 (d, =7.8 Hz, IH)? 8.10 -8.04 (mn, 2H), 7.82-7.80 (d, J 6 .5 HY. 2H-1), -7 .62-7.58 79 WO 2011/088181 PCT/US20111021089 (t, J = 7 8 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = .5 Hz, 2H) 3.82 (d, J = 5.8 Hz, 2H), 1 58 (s, 6H). MS (ESI) m/z: Calculated for C 23

H

1 sCiF 3 N40S: 506 08; found: 507 0 (M-H), EXAMPLE 26 5 3-Fluoro-5-(N'-hydroxycarbanimidoyl)benzoic acid HOs Nh lNH2CH.HCi, Na 2 COs OH ~H2N-O2 8-hydroxyguincline (cat.) EtOH, reflx 3h 7 This compound was synthesized from 3-cyano-5-fluorobenzoic acid as described i example 1 step 4 (442 mg, yieid 37%) and it was carried through without further purification. MS (ESI) m/z: Calculated for CsHrFN 2

O

3 198.04; found: 199.1 (M+H)*. 10 3-Fluoro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yi)benzoic acid O'N (CF3CO) 2

H

2 N )> CO2H ,yii'e6 0 .l F 3 C---O2 FFF This compound was synthesized from 3-fluoro-5-(N hydroxycarbamimidoyl)benzoic acid as described in example 1 step 5 (351mg, yield 51%) 15 and it was carried through without further purification. MS (ESI) m/z: Calculated for

CO

1

H

4

F

4

N

2 O2: 276.02; found: 277.1 (M+H) 3-Fiuoro-N-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifiuoromethyl) 1,2,4-oxadiazol-3-yl)benzamide ,o-N N N O 20 F This compound was synthesized from 2-(4-(4-flucoophenyl)th'i!azo!-21-yl)-2 mnethylpropanl-1-amnine anid 3-fluoro-5-(5-(tifluoromethlyl)-1,2,4-oxadiiazai'-3-yl)benizoic acid as described in example 8 step 6 (23 mng, yield 32%): 'H NMvR (40-1 011z, CDCi3) 5 25 8.32 (br s, 1H), 8.23 (br. t, J = 5 Hz, 1H-), 7 94 (br, d, J = 8 Hz, 1H), 7.86-7.75 (mn, 3H), 7.06 80 WO 2011/088181 PCT/US2011/021089 7.00 (n, 2H), 3.78 (d, J = 4 Hz, 2H), 1,55, (s, 6H). MS (ESI) n/z: Calculated for

C

23

H!

1

F

5

N

4

O

2 S: 508.10; found: 509.1 (M+H)*. EXAMPLE 27 5 Methyl 3,5-dicyanobenzoate Br Br CuCN NC CN DMF. 160 IC, 26h

CO

2 Me CO 2 Me 3,5-Dibromornethylbenzoate (1 g, 3.4 mmol) was dissolved in dry DMF (35 mL) and copper cyanide (1 2g, 13 6 mmoi) was added. The reaction mixture was heated to 160 "C under argon atmosphere for 26 h, allowed to cool down to room temperature and 10 then quenched with saturated ammonium chloride solution. The reaction mixture was diluted with EtOAc and filtered through a Celite plug. The filtrate was diluted with EtOAc and the organic layer was washed with water and brine. The solvent was evaporated under reduced pressure to get the crude rnethyl 3,5-dicyanobenzoate (400 mg, crude, confirmed by GC-MS), which was carried through without further purification. 15 3,5-Dicyanobenzoic acid NCsX 7 CN Li1H NC CN THF-H0 7:3 v/v

CO

2 Me rt, 1h cO2H Methyl 3,5-dicyanobenzoate (400 mg, 2.1 rnmol) was dissolved in THF-H 2 0 (7:3 v/v, 30 mL), the solution was cooled to 0 'C and LiOH (51 mg, 2.1 mmol) was added. The 20 reaction mixture was allowed to warm up to room temperature and stirred for 1 h. THF was removed under reduced pressure and the aqueous layer was washed with EtOAc, acidified to pH - 2-3 using 1.5N ICI, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, 25 eluent 20% MeOH in CHCl 3 ) to get pure product 3,5-dicyanobenzoic acid (100 mg, yield 28%): 'H NMR (400 MHz, DMSO-de) 5 8.53 (s, IH), 8.50 (s, 2H). MS (ESI) m/z: Calculated for CqH4N2O2: 172.03; found: 171.2 (M-H). 81 WO 2011/088181 PCT/US20111021089 3-Cyano-S-(N'-hydroxycarbaminidoyl)benzoic acid SN-1 2 0H.Hl-CI HO, N ' 2 C0 3

C

2 - -------------------------- H CCO2H 8-hydroxyquincline (cat.) '2 | 0 2 H EtDH, reflx, 3h CN This compound was synthesized from 3,5-dicyanobenzoic acid as described in example 1 step 4 (120 g, crude), and it was carried through without any further 5 purification. MS (ESi) m/z: Calculated for CgH 7

N

3

O

3 : 205.05; found. 204.0 (M-H). 3-Cyano-5-(5-(trifluorormethyl)-1,2,4-oxadiazol-3-yI)benzoic acid HO, 0'N O.N (CF3CO) 2 O F3 - As- a CO 2 H N F 3 C-4' K H2N- CO2HN pyridine reflux, 3h ON ON This compound was synthesized from 3-cyano-5-(N' 10 hydroxycarbamimidcyl)benzoic acid as described in example 1 step 5 (45 mg, yield 27%): 'H NMR (400 MHz, DMSO-d6) 6 8.79 (s, 1H), 8.39 (s, 2H). MS (ESI) m/z: Calculated for CgH 4

N

2

O

2 : 283.02; found: 282.0 (M-H-. 3-Cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5 15 (trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide H-N N' X O-N 0 N F ,C--A H 2 -> F0-2H I i F N COHOFC-N S HATU, NMM N CN DMF, G *C-rt, 12h This compound was synthesized from (4-(4.-.phenylthiazol-2-y!)tetrahydro-21-i. pyran-4--yi)methanamine and 3-cyano-.5-(5-.(trifluoromethy)-1,2,4-oxadiazoi-3-yl)benzoic acid as described in example 8 step 6 (25 mg, yield 30%): 1H NMR (400 MHz, MeOD) 6 20 8.63 (t, J = 1.6 Hz, 1H), 8.52 (t, J = 1.5 Hz, IH), 8.25 (t, J 1.6 Hz, 1H), 7.87-7.85 (im, 2H), 7.81 (s, 1H), 7.32-7.28 (m, 21-), 7.25-7.21 (m, IH), 3.97-3.92 (m, 2H), 3.71 (s, 21-), 3.62-3.58 (td, J= 11.4 Hz, 2.1 Hz, 2H), 2.48-2,44 (d, J = 13.3 Hz, 2H), 2.11-2.04 (ddd, J= 82 WO 20111088181 PCTUS201 11021089 14.3 Hz, i0M5 Hz, 4,3 Hz, 2H). MS (ESI) n7/z: Calculated for C 26 H2 0

FN

5

O,

3 S 53P.12: found- 540.0 (M+iH)f. EXAMPLE 28 5 3-(N -Hydroxycarbarnimidoy1)-5-methioxybenzoic acid 11 N 8. Shydroxyquinoline (cat-) EtOH, reflux. 2hi This compound was synthesized from 3-cyano-5-methoxybenzoic acid as described in example 1 step 4 (500 mg, yield 84%): 1H NMR (4100 MHz, DIMISO-d! 6 ) 6 11.27 (Ibis, lH)l, 9.07 (br s, 2FA). 7.83 (s, 1I, 7.68 (s, 1H), 7.55 (in, IFA), 3.69 (S' 3H). MS 10 (ESI) miz: Calculated for C9HlGNN O,: 2*10.06; found: 211,2 (+Y 3-Methoxy-S-(5-(trifluoro-nethy)-1 ,2,4-oxadiazal-3-yI)benizoic acid HuhN C~C 2 .~ .0 2 H Pyridinie reflux, 3h Ome 6Mle This compound was synthesized from 3-(N -hydr-oxyca ,rbamimidoyl)-5 15 mnethoxybenzoic acid as described in example 1 step 5 (170 mng. yield 40%), and it was carried through without any furher pulrifcation. 'H NMR (400 MHz, ODMSG-d6) 66816 (It, J = 1 3 Piz, I H), 7.74 (dd, J =2.6 Hz. 1. 5 Hz, IHI), 7 69 (dd, J =2.6 Hz, 1.5 Hz, I H), 3.91 (s, 31-). MS (ESI) rn,1z: CalcOated for C,,.H 1

F

3

N

2 0 4 : 266 04; found: 267.0 (rvl-H). 20 3 -Methoxy-N-((4-(4 -phenylth iazo I-2-yl)tetrahydro-2-pyra n4 -y) methyl) -5-(5 (Lrifluoronethyd)-1 ,2,4-oxadiazo-3-yI)benarride 0 Fu.. .CC) 2 H FuK.J.' HA'T J, -M Ome DIM F, 0 OC-rr. IlD Ob This compound was synthesized from (4'-(4-phenylthiazol-2-y!)tetrahydro-2H pyran-4-yiymethanarnine and 3-methioxy-5-(5-(tifluoromrethiyl)- 1 .2,4-oxadiazol-3 83 WO 2011/088181 PCT/US2011/021089 yl)benzoic acid as described in example 8 step 6 (70 mg, yield 46%): IH NMR (400 MHz, CDCl 3 ) 8 8.75 (t, J = 6.3 Hz, IH), 8.08 (s, IH), 8.02 (s, IH), 7 91 (d, J = 7.0 Hz, 2H), 7.63 (m, 1H), 7.57 (m,. 1 H), 7.38 -7.35 (n, 2H), 7.30-7.26 (m, 1H), 3.85 (S, 3H), 3.83 (im, 2H), 3.56 (d, J = 6.5 Hz, 2H), 3.41-3.36 (m, 2H), 2.23 (d, J = 13.5 Hz, 2H), 2.01-1.94 (m, 2H). 5 MS (ESI) m/z: Calculated for C?,H 23

F

3

N

4 4S: 544.14; found: 545.2 (M-H). EXAMPLE 29 2-(4-(4-Fluorophenyl)thiazol-2-yi)etharnamine CN BH 3 .THF N4 ------------------- + 'N \NH 10 2-(4-(4-fluorophenyllthiazol-2-yl)acetonitrile (400 mg, 1.83 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature. Borane tetrahydrofuran complex solution (1M in tetrahydrofuran, 9.16 rnL, 9.16 mmol) was added and the reaction mixture was stirred for 1h at room temperature. The reaction mixture was cooled to 0 *C and quenched with methanol (5 eq., 0.4 mL). The reaction was allowed to warm to room 15 temperature and 2N HCI was added until the reaction mixture was confirmed acidic by a pH paper. The reaction mixture was then refluxed at 65 "C for 30 min. The reaction mixture was then allowed to cool to room temperature and was concentrated under reduced pressure. The solid obtained was triturated with ether (2 X 20 mL) and dichlorornethane (2 X 20 mL). The remaining solid was dissolved in water (50 mL) and 20 basified to pH - 111 with NaOH pellets. The aqueous mixture was then extracted with ether (2 X 100 mL). The organic layer was dried over anhdrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was used directly without any purification in the next step (100 mg, 25% yield). MS (ESI) rm/z: Calculated for C 1

,HI

1

FN

2 S: 222.06; tound: 223.1 (M+H)V 25 N-(2-(4-(4-Fluorophenyl)thiazol-2-yl)ethyl)-3-(5-(trifluoronethyl)-1,2,4-oxadiazol-3 yl)benzamide N r F H ------------ -------------- ---- N N F S DCI HOBt DcM., F ,yN s This compound was synthesized from 2-(4-(4-fluorophenyl)thiazol-2-yl)ethanamine 30 and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 26 step 6 (180 mg, 86% yield). 'H NMR (CDCI,) j 8.51 (1H, t), 8.22 (IH, dt), 8.04 (1H1, dt), 84 WO 2011/088181 PCT/US20111021089 7.85-781 (2H, n), 7 64 (1H, m), 7 59 (i H t), 7,31 (i H s), 7 06-7.02 (2H, m), 3.97 (2H, q), 3.35 (2H, t); MS (ESI) m/z Calculated for C 21

H

14

F

4

N

4 0 2 S: 462 08; found: 463.1 (M+H)*. EXAMPLE 30 5 2-(4-(4-Bronophenyl)thiazol-2-yl)acetonitrile 0 - ,CN OEtH +CN --------- N Br' H 2 N '' flux This compound was synthesized from 2-bromo-1-(4-bromophenyl)ethanone and 2 cyanothioacetamide as described in example I step 1 (2.4 g, 48% yield), and it was carried through without further purification. MS (ESI) m/z: Calculated for Cj 1

H

7 BrN 2 S: 10 277.95; found: 279.0 (M+H)*. 4-(4-(4-Bronophenyi)thiazo-2-yl)tetrahydro.-2H-pyran-4-carbonirile Br 0-NN 8 ' N B1 1 Br , '11 N -------------- N C NaH, THF t rf, This compound was synthesized from 2-(4-(4-bromophenyl)thiazol-2-yl)acetonitrile 15 as described in example 1 step 2 (1 9 g, yield 80%). MS (ESI) m/z: Calculated for Cj5HL BrN2OS: 347.99, found: 349.0 (M+H). (4-(4-(4-Bronopheny)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)metianamine Br Br NC 9 LiAiH 4 N S ------- THFc, (ri H2N < S 20 This compound was synthesized ron 4-(4-(4-bromophenyl)thiazol-2-yl)tetrahydro 2H-pyran-4-carbontrile as described in example I step 3 (1.7 g), and it was carried through without any further purification. MS (ESI) m/z: Calculated for CH 7 BrN 2 CS: 352.02; found: 353.0 (M+H)*. 85 WO 2011/088181 PCT/US20111021089 4-(2-(4-(Aninomethyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)benzonitrile O S NH2S NH- 2 N N Br NC (4-(4-(4-Bromophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (200 mg, 5 0.56 mmol), zinc cyanide (53mg, 0.45 mmol). and DMF (2 mL) were placed in microwave tube and degassed. 1 ,1-Bis(diphenylphosphino)ferrocene-pa||adium(II)dichloride (41 mg, 0.05 mmol) was added. Reaction was microwaved at 200 'C for 10 min intervals until complete. The reaction was quenched with ammonium hydroxide/water (1:4) and washed with ethyl acetate. Organic layer was dried over sodium sulfate. Crude was purified using 10 silica chromatography with an ethyl acetate wash followed by 10%Methanoi in dichloromethane with 1% triethylamine to yield 4-(2-(4.-(aminomethyl)tetrahydro-2H-pyran- 4-yl)thiazol-4-yl)benzonitrile (20 mg, 10% yield). MS (ES') m/z: Calculated for

C

1 0-11 7 NOS: 299.11; found: 300.1 (M+H)*. 15 N-((4-(4-(4-Cyanophenyl)thiazol-2-yl)tetrahydro-2H-pyran4-yl)methyl)-3-(5 (trifluoromethyl)-1,2,4-oxadiazol-3-.yI)benzarmide ON CN ONN H _ -N 0 Ng> 3--------------- --N H2N" ---- , This compound was synthesized from 4-(2-(4-(raminomethyl)tetrahydro-2H-pyran 4-yl)thiazoi-4-yl)benzonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as 20 described in example 8 step 6 (3 mg, 7% yield) IH NMR (300 MHz, CD3OD) 5 8.40 (d, J=1.8 Hz, 1H), 8.23 (d, J= 7.2 Hz, 1H), 8.10-8.07 (in, 2H), 7.94 (m, 1H), 7.81 (in 1H), 7.69-7.53(m, 3H)) 3.94 (m, 2H), 3.87 (s, 2H), 3.55 (m, 2H), 2.45 (m., 2H), 2.08 (m, 2H). MS (ESI) m/z: Calculated for CwHDFNgOS: 539.12; found: 540.1 (M+H). 86 WO 2011/088181 PCT/US20111021089 EXAMPLE 31 4-(4-(4-Fluorophenyl)thiazol-2-yi)-2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile CN INC FF F 2-(4-(4-Fluorophenyl)thiazol-2-yl)acetonitrile (325 mg, 1.5 mmol), potassium 5 carbonate (617 mg, 4.47 mmol), and i-chloro-2-(2-chloroethoxy)-2-methylpropane (254mg, 1.5 mmol) in DMF (5 mL) were microwaved at 160 'C for 5 min then 20 min. A second addition of potassium carbonate and 1-chloro-2-(2-chloroethoxy)-2-methylpropane was made and then the reaction was microwaved acain for 30 min two times. The reaction was diluted with ethyl acetate and washed with water. The organic layer was 10 dried over sodium sulfate and purified on silica using a gradient of 0-30% ethyl acetatelhexanes to afford 4-(4-(4-Fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-21pyran-4-carbonitrile (228 mg, 48% yield). MS (ESI) m/z: Calculated for C1H1FN 2 (S: 316.10; found: 317.1 (M+H)*. 15 (4-(4-(4-Fluorophenyl)thiazol-2-yi)-2,2-dimethyltetrahydro-2H-pyran-4 yl)methanarmine r-0 ------- N NH 2 F F This compound was synthesized from 4-(4-(4-fluorophenyl)thiazol-2-y)-2,2 dimethyltetrahydro-2H-pyran-4-carbonitrile as described in example 1 step 3 (100 mg), 20 and it was carried through without any further purification. MS (ESI) m/z: Calculated for

C

17

H

1

FN

2 OS: 320.14; found: 321.1 (M+H). 87 WO 2011/088181 PCT/US20111021089 N-((4-(4-(4-Fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl) 3-(S-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide F ,'N O N'-T NH N This compound was synthesized from (4-(4-(4-fluorophenyl)thiazol-2-yl)-2,2 5 dimethyltetrahydro-2H-pyran-4-yI)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol 3-yl)benzoic acid as described in example 8 step 6 (7 mg, yield 17%): 1 H NMR (500 MHz, CDaOD)5 8.41 (t, J=1IHz,1H), 8.23 (d, J= 4Hz, 1H), 7.96-7.90 (m, 3H), 7.76 (s, 1H), 7.61 (t, J= 7.7 Hz, IH), 7.69-7.04 (t, J=8 8 Hz, 2H), 3,88 (n, 2H), 3.60 (s, 2H), 2 52 (m, 2H), 1.95 (m, 2H), 1.29 (s, 3H), 0.81 (s, 3H). MS (ESI) m/z: Calculated for 10 C,,H-F 4

N

4 OS: 560.15 found: 561.1 (M+H) . EXAMPLE 32 3-Cyanobenzene-1-sulfonyl chloride i) NaNO, conc HCI 0 *C, 30min NC, 1-1 NI- ii) S0 2 (g) in AcOH 2I' _ , NC_.Y: SO 2 CI iii) CuCl 0 "C-rt. 1h 15 3-Aninobenzonitrile (2.5g, 21 mmol) was dissolved in conc. HCi (20 mL) and water (20 mL), cooled to 0 'C and a solution of sodium nitrite (1.5 g, 22 mmol) in water (5 mL) was added dropwise. The reaction mixture was stirred for 10 min to complete the diazonium salt formation. In a separate flask was added copper(l) chloride (0.2g) over a saturated solution of sulfur dioxide in AcOH (25 miL) and stirred at 0 'C for 10 min. The 20 resulting solution was added dropwise to the diazonium salt and stirred at 0 'C for 1 h, The reaction mixture poured into ice water and the product was extracted with tert butylmethylether. The combined organic layer was washed with water and brine. The crude product was purified by column chromatography (silica gel 60-120 mesh using 5% EtOAc in petroleum ether) to get the pure 3-cyanobenzene-1-sulfonyl chloride (1.9 g, yield 25 45%) as an off-white solid. 'H NM.R (300MHz, CDC13) 5 8.35 (t, J = 1.5 Hz, 1 H), 8.31-8.27 (m, I H), 8.06-8 02 (m, 1H), 7.82 (t, J = 7 9 Hz, 1 H) 88 WO 2011/088181 PCT/US20111021089 3-Cyano-N-((4-(4-phenylthiazol-2-yI)tetrahydro-2Hq-pyran4 yl)methyl)benzenesulfonamide \/ NIN NC ~ ~NCNSI-,I S ----------- --- H N.CH!-2Cl2 O C-rt, ih 0 Et 3 N (0.15 mL, 1.43 mmol) was added dropwise to an ice cold solution of (4-(4 5 phenylthiazol-2-yl)tetrahydro-2H-pyran-4-vl)methanarmine (130 mg, 0.48 mrnmol) in dry

CH

2 Ci 2 (3 mL) The resulting reaction mixture was stirred at 0 'C for 5 min, then a solution of 3-cyanobenzene-1-sulfonyl chloride (105 mg, 0.52 mrnmol) in dry CH 2 Cl2 (2 mL) was added dropwise. The reaction mixture was further stirred at room temperature for 1 h. The reaction mixture was diluted with CH 2 CL and the organic layer was washed with H20 and 10 brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60-120 mesh, eluent 35% EtOAc in petroleum ether) to afford compound 3-cyano-N-((4-(4-phenylthiazoi-2 yi)tetrahydro-2H--pyran-4-yl)methyl)benzenesulfonamide (0.13 g, yield 61%) as an off white solid. IH NMR (300 MHz, CDCl 3 ) 5 8.03-7.98 (n, 2H), 7.85-7.76 (n, 3H), 7.59-7.54 15 (m, 1H), 7.50-7.38 (in, 4H), 3.87-3.79 (m, 21-), 3.74-3.66 (m, 2H), 3.36 (s, 2H); 2.27-2.19 (ddd, J = 13.5 Hz, 6.7 Hz, 3.5 Hz, 2H), 2.01- 1.93 (ddd, J = 13.8 Hz, 7.5 Hz, 3.7 Hz, 2H). MS (ESI) m/z. Calculated for C 2

H

2

N

3

O

3 S?: 439.10, found: 440.0 (M+H). N'-Hydroxy-3-(N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4 20 yl)methyl)sulfamoyl)benzimidamide O HO

NNH

2 OH.HCL, Na 2

CO

3 N N 8-hydroxytuinrcine (cat) 2 I cm on -- -------------------------- t EtDH, reflux, Oh This compound was synthesized from 3-cyan -N-((4-(4-phenylthiazoi-2 yi)tetrahydro-2H-pyran-4-yl)nethyl)benzenesulfonamid e as described in example 1 step 4 (125 ng, yield 89%) and it was carried through without furthe puriication H NMR (400 25 MHz, DMSO-de) 6 9.83 (s, 1H), 8.08 (m, 2H), 7.95 (d, J 7.0 Hz, 2H), 7.86 (d, J= 7.9 Hz, 89 WO 2011/088181 PCT/US20111021089 1H), 7.79 (t, J = 6.7 Hz, 1H), 7.74 (d, J = 7.9 Hz, iH), 7.55 (m ,1H), 7.44 (m, 2H), 7.34 (m ,1H), 5.96 (s, 2H), 3.78 (m, 2H), 3.41 (t, J= 10.2 Hz, 2H), 3 01 (d, J = 6.7 Hz, 2H), 2.15 2.12 (m, 2H), 1.94- 1.87 (m, 2H). MS (ESI) r/z: Calculated for C 22

H

24

N

4 O2S 2 : 472.12 found: 473.2 (M+H)*. 5 N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-y)methyl)-3-(5-(trifluoronethyl) 1,2,4-oxadiazol-3-yl)benzenesulfonamide HO, (CF3CO)2 O N HN F3C HI1 -~ pyridiwr, 1 i~~-.-* h ~

'O

This compound was synthesized from N'-hydroxy-3-(N-((4-(4-phenylthiazo-2 10 y!)tetrahydro-2H-pyran-4-yl)methyl)sulfanoyl)benzimidamide as described in example 1 step 5 (80mg, yield 57%). IH NMR (400 MHz, DMSO-de) 6 8.32 (s, 1 H), 8.22 (d, J = 7.6 Hz, 1H), 8.05 (t, J = 6.9 Hz, 1H), 7.999 (n, 2H), 7.89 (d, J = 7.3 Hz, 2H), 7.76 (t, J = 7.8 Hz ,1H), 7.40 (i, 2H), 7.30 (m ,1H), 3.79-3.76 (m, 2H), 3.39 (t, i = 10.8 Hz, 2H), 3.11 (d, J = 6.7 Hz, 2H), 2.16-2.13 (n, 2H), 1.93- 1.86 (n, 2H). MS (ESI) m/z. Calculated for 15 C 2 4H 2 1F 3

N

4 0 2

S

2 : 550.10; found: 551.0 (M+H)1. EXAMPLE 33 3-Bromo-5-(methoxycarbonyl)benzoic acid MeO 2 C CO2Me NOH Meo:Cs - CO2H acetone-MeOH 2:1 v/v Br rt, h 20 Liimethyl-5-bromoisophthalate (3 g, 11.0 mmol) was dissolved in acetone-H2O (2:1 v/v, 60 mL) and NaOH (0.40 g, 11.0 mmol) was added. The reaction mixture was allowed to stir for 4 h. Acetone was removed under reduced pressure and the aqueous layer was washed with EtOAc, acidified to pH ~ 2-3 using 1.5N HC!, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed 25 under reduced pressure to yield 3-bromo-5-(methoxycarbonyl)benzoic acid (2.55 g, yield 89%): 1H NMR (300 MHz, IDMSO-d 6 ) 6 13 75 (br s, 1H), 8.40 (d, J = 1.0 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 8.23 (d, J = 1.0 Hz, 1H), 3.89 (s, 3H). MS (ESI) rm/z: Calculated for CHBrO,: 257.95: found: 258.0 (M+H) . 30 Methyl 3-bromo-5-(methoxy(methyl)carbamoyl)benzoate 90 WO 2011/088181 PCT/US20111021089 MeO 2 C C0 2 H MeONHMe,HCI Me02C OMe EDC.HCI, HOBt J Me Br EtIN, CH 2 01 2 Br 0 'C-rt, 4.5h NO-Dimethylhydroxylamine hydrochloride (1.15 g, 11.8 mmol) was dissolved in

CH

2 C1 2 (50 mL) and Et 3 N (4.8 mL, 34.4 mrnmol) was added. The solution was stirred for 30 min. The resultant solution was cooled to 0 "C and compound 3-bromo-5 5 (methoxycarbonyi)benzoic acid (2.55 g, 9.84 mmol) was added followed by EDC.HCI (3 77 g, 19.6 mmol) and HOBt (0 26 g, 1.96 mmoi). The reaction mixture was allowed to come to room temperature and stirred for another 4 h. After completion, the reaction mixture was diluted with CH 2

CI

2 . The organic layer was washed with water and brine solution and dried over anhydrous sodium sulfate. Solvent was removed under reduced 10 pressure and the crude product was purified by column chromatography (silica 60-120 mesh. eluent 20% EtOAc in petroleum ether) to get methyl 3-bromo-5 (rnethoxy(methyl)carbamoyl)benzoate (2.3 g, yield 77%) as colorless liquid. 1 H NMR (400 MHz, CDCI,) 6 8.29 (m, 1H), 8.27 (t, J= 1.8 Hz, 1H), 8.02 (t, J= 1.6 Hz, 1H), 3.95 (s, 3iHl), 3.57 (s, 3H), 3.39 (s, 3H). MS (ESI) m/z: Calculated for Cn 1 H1 2 BrNO4: 300.99; found: 15 302.0 (M-H). Methyl 3-acetyl-5-bromobenzoate 0 NC.i 0 MeMgCI (3M in THF) Me2 e THF, O *Ct, 6h Br Br The compound methyl 3-bromo-5-(methoxy(methyi)carbamoyl)benzoate (2 3 g, 20 7.6 mnmol) was dissolved in dry THF (50 mL), solution was cooled to 0 *C and methylmagnesium chloride (3M in THF, 2.5 mL, 7.6 mmol)) was added dropwise. The reaction mixture was slowly allowed to come to room temperature and stirred further for 6 h. The reaction mixture was cooled to 0 'C and quenched with saturated NH 4 CI solution. The product was extracted with EtOAc. The organic layer was washed with water and 25 brine and dried over anhydrous sodium sulfate The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 5% EtOAc in petroleum ether) to get methyl 3-acetyl-5-bromobenzoate (0.95 g, yield 49%) as a white solid. 'H NMR (400 MHz, CDC13) 5 8.51 (t, J = 1 3 Hz, IH), 8.37 (t, J = 1.7 Hz, 1H), 8.28 (t, J = 1.6 Hz, 11H), 3.97 (s, 3H), 2.65 (s, 3H). 91 WO 2011/088181 PCT/US20111021089 3-Bromo-5-ethylbenzoic acid Me2 NH 4

.H

2 0, KOH HO 2 C ethylene glycol, { 200 C, 1h Br Br The compound methyl 3-acetyl-5-bromobenzoate (1.2 g, 4.8 mmol) was dissolved 5 in ethylene glycol (10 mL) and KOH (0.41 g, 7.3 mmo!) followed by hydrazine hydrate (0.44 mL, 7.3 mmol) were added. The reaction mixture was heated to 200 *G for I h The reaction mixture was cooled to room temperature and diluted with water. The pH of the aqueous layer was adjusted to 2-3 using 1.5N HCI. The product was extracted with EtOAc. The organic layer was washed with water and brine and dried over anhydrous 10 sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 50% EtOAc in petroleum ether) to yield 3-bromo-5-ethylbenzoic acid (0.95 g, yield 89%) as a yellow solid. IH NMR (300 MHz, CDCi 3 ) 5 8.07 (m, 1H), 7 88 (m, IH), 7.59 (m, IH), 2.73 (q, J = 7.6 Hz, 2H), 1 28 (t, J = T6 Hz, 3H). MS (ESI) m/z: Calculated for CqHCBrO 2 : 227.98; 15 found: 229.0 (M+H). Methyl 3-bromo-5-ethylbenzoate HO2s S~l, MOHMeO2C', - ~ rt, 10h Br Br The compound 3-bromo-5-ethylbenzoic acid (0.95 g, 4.14 mmol) was dissolved in 20 MeOH (50 mL), reaction mixture was cooled to 0 "C and SOCi 2 (0 5 mL) was added. The reaction mixture was allowed to stir at room temperature for 10 h. The reaction mixture was concentrated under reduced pressure and diluted with CH 2

C

2 . The organic layer was washed with 10% NaICO 3 solution, water and brine. The organic phase was dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. Methyl 3 25 bromo-5-ethylbenzoate (0.92 g, yield 92%) was isolated as colorless liquid and carried through without further purification. 'H NMR (300 MHz, CDCI 3 ) 6 7.99 (t, J = 1.6 Hz, 1H), 7.81 (d, J = 1.4 Hz, 1H), 7.54 (t, J = 1.6 Hz, 1H). 3.92 (s, 3H), 2.69 (q, J = 7.6 iHlz, 2iHL), 1.26 (t: J = 7.6 Hz, 3H). 30 Methyl 3-cyano-5-ethylbenzoate 92 WO 2011/088181 PCT/US20111021089 MeO 2 , ^' cuCN MeO C DMF 150 *C, 12h ON The product methyl 3-bromo-5-ethylbenzoate (0.9 g, 3.7 mmol) was dissolved in dry DMF (50 mL) and copper cyanide (0 84 g, 9.43 mmol) was added. The reaction mixture was heated to 150 'C under argon atmosphere for 12 h (monitored by TLC: 5 petroleum ether/EtOAc 9:1). The reaction mixture was allowed to come to room temperature and then quenched with saturated ammonium chloride solution. The reaction mixture was diluted with EtOAc and filtered through a Celite bed. The filtrate was diluted with EtOAc and the organic layer was washed with water and brine. The solvent was evaporated under reduced pressure. The crude product was purified by column 10 chromatography (silica 60-120 mesh. eluent 5% EtOAc in petroleum ether) to get methyl 3-cyano-5-ethylbenzoate (0.27 g, yield 39%) as colorless liquid, which was carried through without further purification. 3-Cyano -5-ethylbenzoic acid MeO 2 C' LiOH HOC THF-H,0 3:1 viv 15 CN rt, 31h The compound methyl 3-cyano-5-ethylbenzoate (270 mg, 1.42 mmol) was dissolved in THF-H 2 0 (7:3 v/v. 10 mL), solution was cooled to 0 'C and LiOH (59 mg, 1.42 mmo) was added. The reaction mixture was allowed to come to room temperature and stirred for 3 h (monitored by TLC; petroleum ether/EtOAc 1:1). Solvent THF was removed 20 under reduced pressure and the aqueous layer was washed with EtOAc to remove the non-polar impurities. The pH of the aqueous layer was adjusted to 2-3 using 1.5N HCI. The product was extracted with EtCAc. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 3-cyano-5 ethylbenzoic acid (200 mg, yield 80%), which was carried through without father 25 purification. 'H NMR (400 MHz, CDC 3 ) 6 8.23 (n, 1H), 8.17 (i, IH), 7.74 (i, iH), 2.81 (q, J= 7.6 Hz, 2H), 1.32 (t, J= 7.6 Hz, 3H). 93 WO 2011/088181 PCT/US20111021089 3.-Ethyl -5.(N-hydroxycarbamimidoyl)benzoic acid HON HO2C I NH2OH.ICI, Na2CO , H2N CO2H 8-hydroxyquinoline (cat.) I" EtOH, reflux, 8h CN This compound was synthesized from 3-cyano-5-ethylbenzoic acid as described in example 1 step 4 (200 mg, crude), and it was carried through without further purification. 5 3.-Ethyl-6- (5-(trifluorom ethyl)- 1 2,4-oxadiazo-3-yl)benzoic acid HO, N O H2N_'___CO2H (C',CO)-O FC CO 2 H pyridine, reflux, 8h This compound was synthesized from 3-ethyl-5-(Nehydroxycarbamimidoyl)benzoic acid as described in example I step 5 (130 mg, yield 52%). 'H NMR (300 MHz, CDCla) 6 10 8.69 (im, IH), 8.21 (n, 1H), 8.17 (m, 1 H), 2.85 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H). MS (ESI) m/z: Calculated for C.HqF 3 N20 3 : 286.06; found: 285.0 (M-H) 3 -Ethyl-N-((4-(4-phenylthiazoI-2-yl)tetrahydro-2H-pyran -4-yl)methyl)-5-(5 (trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide N

H

2 N I [ PN O F3<cNN ,COH N NH S N' 2~N, - ._ __ __ __ __ __ .H r HATU, NMM DMF, 0C-rt, 16h This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H pyran-4-yi)methanarnine and 3-ethyl-5-(5-(trifluorormethy!)-1,2,4-oxadiazoi-3-yl)benzoic acid as described in example 8 step 6 (85 mg, yield 45%). 'H NMR (400 MHz, CDC13) 6 8.29 (s, 1H), 8.05 (s, 1H), 7.89 (m, 21-h, 7.80 (s, 1H), 7.52 (m, 2H), 7.37-.7.29 (m, 31-), 20 4.00-3.94 (m, 2H), 3.89 (d, J = 5.5 Hz, 2H), 3.78-3.72 (ddd, J 11.7 Hz, 7.8 Hz, 3.3 Hz, 2H), 2.69 (J = 7.7 Hz, 21-), 2.36-2.30 (ddd, J = 13.6 Hz, 6.5 Hz, 3.3 Hz, 2H), 2.08-2.02 94 WO 20111088181 PCTUS201 11021089 (ddd, J = 13.6 Hz. 7.7 Hz. 3.3 Hz, 2H), 1.23 (t, J = 7.7 Hz? 3H). MS (P;I) mlz: CaICUlated for C 27

H

2 5F: 3 N4C 3 S: 542.16: found: 543.2 (M+HY) EXAMPLE 34 5 4-(3-BromophenyI)tetrahydro-2H-pyran-4-carbonitrile H Br' ' -- NC)<W, ' Br ~ ------------------------ NaH, THF This compound was synthesized From 2-(3-bromophenyi)acetoni'tril!e as described iir example 1 step 2 (1.3 g, 65% yield). MS (ES1) rrlz. Calculated for CjH 2 EBrNO(. 265.01; found: 266.0 (M+H)'. (4-(3-Bromophenyl)tetrahydro-2H-pyran-4-yl)methanamine NC,>.i N A TE. 0'C-c' This compound was synthesized from 4-('3-bromoi(phernyi)tetrahiydro-2H-pyran-4 carbonjirile as described in example I step 3 (11.3g, crude), arid it was carried through 15 without further. purification. MS (ESI) rnlz: CalCUlated for C 12 H-,eBrNO: 269.04; Found 2170.0 (IM H). N-((4-(3-BromophenyI)tetrahydro-2H-pyran-4-yIjm ethyl)]-3-(5-(trifl uoromnethy)-1,2,4 oxadiazol-3-yI)benzarnide N

P

HAT-N 0& N -C0<~ 2 r H N KjX 'B --- u u N' .. 20 N" o 0 This compound was synthesized frcom(4-(3-bromoi(phenyi)tetrahlydio 2H-pyran-4 yl)methariarine arid 3-5(rfurmty)1,,-xdac--lbnocacid as desi. ibed in example 8 step 6 (40 mgs, 34% yield). IH NMR (300 MHz, CDC 3 ) 5 8.30-8.22 (in, 2H) 7.86 (d, J = 3.7 H-mz, 1H). 760 (t, J = 3.7 Hz. 1H), 7.52-7.44 (mh 21-1), 7.38-7.30 im, 21-I), 25 3.90 (in. 21-1), 3.71 (d, J =3.3 Hz, 2H), 3.64 (n, 2H), 2.13 (m, 2H); 2.02 (in, 2H-). MJS (ESI) rn/c Calculated for C 22 HjBrF 3

NC

3 : 509.06; found: 509.9 (M+HYI. 95 WO 2011/088181 PCT/US20111021089 EXAMPLE 35 2-(4-(4-(Trifluoromethyi)phenyl)thiazol-2-yl)acetonitrile S K ,~8 CN M

F

3 C'-d reflux This compound was synthesized from 2-bromo-1-(4 5 (trifiuoromethyl)phenyi)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (2.4 g, 48% yield), and it was carried through without further purification. MS (ESI) n/z: Calculated for C 1 2

H-,N

2 S: 268.03: found: 269.0 (M+H)*. 4-(4-(4-(Trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile CFN I/ CN Br' '' Br N - - - - - NC NaH THF

F

1 ~ 10 This compound was synthesized from 2-(4-(4-(trifluoromethyl)phenvl)thiazo-2 yl)acetonitrile as described in example 1 step 2 (690 mg, yield 98%), and it was carried through without further purification. MS (ESI) rrz. Calculated for C,,HI 3

F

3

N

2 OS. 338.07; found: 339.1 (M+H). 15 (4-(4-(4-(Trifluoromethyl)phienyl)thiazol-2-yl)tetrahydro-2H-pyrani-4-yl)methanamfine _F3 N> NC, LiAH 4 TH F, 0 1 C-rt H2N S This compound was synthesized from 4-(4-(4-(trifluoromethyl)phenyl)thiazoi-2 20 yl)tetrahydro-2H-pyran-4-carbonitrle as described in example 1 step 3. The material was carried through without further purification. MS (ESI) m/z: Calculated for CH 7 F3N 2 0S: 342.10: found: 343.1 (M+H)'. 96 WO 20111088181 PCTUS201 11021089 3.(5-(Trifluoromethiyl)1 ,2,4-oxadiazol-3-y)N-((4-(4-(4 (tri'l u oronethyl)phenyl)th iazoI-2-yl)tetrahydro-2H-pyra n-4-yi) methyll)benzaiide Cl, /G H 1- 2 N x I F ] HATU, NMM DMF, 0 OC-11 5 This compouro was synthesized from (,4-.(4-a(trfluoromethyi)phenvl)thexzo-2. yi)tetrahydro-2/i pyrr4-yI)methanamrine and 3-(5-ftr'fluoromethyl}i-1,'2,4-oxadazo-3 y'!)benzoic acid as described in example 8 step 6 (9 mgs, 19% yield). 'H NMR (300 MHz;

CDC

3 ) 8.44 (s, 1H), 8.24 (d, J= 7T7 Hz; 1H), 8.00 (m, 21-1 7.65-7.58 (m,4H), 7.36 (s, 11-1), 4.02-378 (m, 4H), 3.74 (in, 21-1, 2.30 (mn, 2H), 2.05 (m, 21-). MS (ESI) m&/z 10 Calculated 'or C,,H,FNC 3 S: 582.12; found; 583.1 (M+.H)' EXAMPLE 36 2 -Methyl -2-(4-(4-ftrifluoromnethyl)phenylI)thiazol-2-yI) propane nitrile CF, NN FC NC. 15 This compound was synthesized from 2- (4 -(4- (tri flu orornethy;)p henyl)1h iazol-2 y;)a-.etonitrile using odometnane as described in example 1 step 2 (620 mng. yield 73%) and it was carried through without further purification MS (ESI) nv'z; Calculated for

C

1

H,JFN

2 S: 296.06; round: 297.0 (IM+H)', 20 2-Methyl-2-(4-f4-(triflijoromethyl)pheniyl)thiazol-2-yI)propan-I -amine H 33 / LAIH 4 / NC j ) THF:, 0 1 0 -rt 97 WO 2011/088181 PCT/US20111021089 This compound was synthesized from 2-methyl-2-(4-(4 (trifiuoromethyl)phenyi)thiazol-2-y!)propanentrile as described in example 1 step 3. The material was carried through without further purification. MS (ESI) m/z: Calculated for

C

14

H

15

F

3 NS: 300.09; found: 301.1 (M+H)*. 5 N-(2-Methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazo-2-yl)propyl)-3-(5-(trifluoromethyl) 1,2,4-oxadiazol-3-yl)benzamide

/F

3 / CF 3 P-N N V -- - - - -- - -- - - -- - -- - - -- - -- - - -- - H1N S HATU, NMM 'N' IMF. 0 "C-rt This compound was synthesized from 2- methyl-2-(4-(4 10 (trif!uoromethyl)pheny!)thiazol-2-yi)propan- 1 -amine and 3-(5-(trifIuoromethyl)-I 24 oxadiazol-3-yi)benzoic acid as described in example 8 step 6 (10 mgs, 24% yield). 'H NMR (300 MHz, CDCI 3 ) 6 8.51 (s, IH), 8.25 (d, J = 7.4 Hz, 1H), 8.09-7.96 (m, 4H), 7,64 7.53 (m, 3H), 3.82 (bs, 2H), 1.56 (s, 6H). MS (ES!) mi/z: Calculated for C 2 4 HgF 6

N

4 0 2 S: 540.11; found: 541.1 (M+H)*. 15 EXAMPLE 37 1-(2-Ethoxy-2-oxoethyl)tetrahydro-1I-thiophenium bromide Brs ,CO2Et ' acotone, rt, 3days CO2Et Tetrahydrothiophene (10 g, 113 mmol) and ethyl bromoacetate (13 mL, 113 imol) 20 were taken in acetone (50 mL) and stirred at room temperature for 3 days. The precipitate was filtered, washed with acetone and air dried to get 1-(2-ethoxy-2-oxoethyi)tetrahydro 1H-thiophenium bromide (23 g, yield 82%), which was carried through without further purification. 25 Ethyl 2-cyanocyclopropanecarboxylate B 50% KOH, satd K2CO3 CNC2Et r12 -: i~OE CO,,Et CHCl3, o "c, ih

CO

2 Et 0 'C-rt, 48h 98 WO 2011/088181 PCT/US2011/021089 50% KOH solution (16 mL) and saturated K 2 C0 3 solution (60 nL) were added to a cooled solution of compound get 1-(2-ethoxy-2-oxoethvi)tetrahydro-1H-thiophenium bromide (23 g, 90 mmol) in CHCI 3 (70 mL). The mixture was stirred at 0 'C for 1 h. The organic layer was separated and the aqueous layer was further extracted with CHCi,. The 5 combined organic extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to get the zwitterionic intermediate (11 g, yield 76%). This crude intermediate was dissolved in CHCl 3 (100 mL) and cooled to 0 "-. Acrylonitrile (4 mL, 68.3 mirnol) was added to the reaction mixture and the mixture was further stirred at room temperature for 48 h. The solvent was evaporated under reduced pressure and 10 the crude product was purified by column chromatography (silica 60-120 mesh, eluent 30% EtOAc in petroleum ether) to get ethyl 2-cyanocyclopropanecarboxylate (5 g, yield 53%). 'H NMR (300 MHz, CDCl) 6 4,19 (q, J = 7.0 Hz, 2H), 2.29-2.23 (ddd, J = 8.8 Hz, 6.0 Hz. 4.3 Hz, 1H), 1.96-1.91 (ddd, J= 9.1 Hz, 6.4 Hz, 4.3 Hz, 1H), 1.56-1.45 (m, 2H), 1.30 (t, J= 7.0 Hz, 3H) 15 2-Cyanocyclopropanecarboxylic acid /L CD 2 p IN NaCH /\C 2 H NC '

------

,- 2 MeOH, 0 IC-rt. 2h NC. Ethyl 2-cyanocyclopropanecarboxylate (5 g, 35.9 mmol) was dissolved in MeOH (20 mL) and IN NaCH (35 mL) was added. The reaction mixture was stirred at room 20 temperature for 2 h. After completion of the reaction MeCH was evaporated under reduced pressure. The pH of the aqueous layer was adjusted to 2-3 using 1.5N HCI. The white precipitate was collected by filtration and dried under reduced pressure to get 2 cyanocyclopropanecarboxylic arid (3.3 g, yield 85%): 'H NMR (400 MHz, DMSO-da) 6 12.78 (br s, i1H), 2.26-2.21 (ddd, J = 8.3 Hz, 6.0 Hz, 4.3 Hz, 1H), 2.14-2.09 (ddd, J = 9.4 25 Hz, 6.2 Hz, 4.4 Hz, 1H), 1.53-1.48 (m, 1H), 1.36-1.32 (m, IH). MS (ESI) m/z: Calculated for C5HEN0 2 : 111 03; found: 110.2 (M-H) 99 WO 20111088181 PCTUS201 11021089 2 -Cya no-N-((4-(4-phenylthiazc;I 2-yl)tetrahyd ro-2/1pyra n4 yl) methyl)cyclop ro panecarboxam ide

H

2 N ,,,. S ACOIIH 0' 14C ,~ NC' HATU, NrMH K D 0.F. 0 C-rt, 1lh This compound was synthesized from (4'-.(4-phenylthiazol-2-y!)tetrehydro-2H 5 pyran-4-ylymethanarnine and 2- cyanocydo rp!o pa necar boxy fic acid as described in example 6 step 6 (90 mg, yield 29%): IH NIVR (400 MHz, ODd1 3 ) 6 7.92 (in, 2H), 7.52 7.46 (in, 3H), 7.41-7.37 (in, 1H), 6.72 (t, J= 5.3 Hz, 1H), 3.92-3.86 (m, 2H), 3.75-3.68 (mn, 4H-), 2.30 -2.22 (dddd, J = 11.2 Hz, 9.8 Hz, 6.5 Hz, 3 4Hz, 21H), 1.99-1.89 (in, 4H), 1.52 1.47 (ddd, J = 91 Hz, 5 8 Hz, 46 Hz, 1IH), 1.38-1.33 (ddd, J= 86 Hz, 6 1 Hz, 4 9Hz, 1 H) 10 MVS (ES1) m17: Calculated for O20H 21

IN

3 0 2 ,S: 367 14; found: 368.2 (+1 2-(N'-Hydroycarbminidoy)-N-((4-(4-phenylthiazol-2-yl~tetreihydro-2H-pyran-4 yl)rnethyl)cyclopropanecarboxamide HO,_ NC, N D 2 NC 3 / K) Etl-l, 0'x,3 15 This compound 'was synthesized from 2-cyano-N-((4-(4-.phenyithiazo-2 yl!)tetrahydro-.2H1-pyrarn-4-.y)inethly)cycloproparnecarboxamide as described in example I step 4 (90 mg, crude) and !I was used carried. through without further purification. MS (ES1) rn'z: Calculated for C 2 ,l- 24

N

4 0 3 S: 400.16: found: 401.2 ±H 20 WO 2011/088181 PCT/US2011/021089 N-((4-(4-Phenylthiazo.-2-yl)tetrahydro-2H-pyran-4-y)nethyl)-2-(S-(trifluoromethyl) 1,2,4-oxadiazol-3-yi)cyclopropanecarboxamide 'N N- CO)0 0 -N O)

H

2 N 7 > N~i~S pyrdine, C-rt, 3h ~HN This compound was synthesized from 2-(N'-hydroxycarbaninidoyl)-N-((4-(4 5 phenylthiazol-2-yl)tetrahydro-2-H-pyran-4-yl)methyl)cyclopropanecarboxamide as described in example I step 5 (45 rng, yield 45%): 'H NMR (400 MHz, MeOD) 6 7.94 (n, 2H), 7.77 (s, 1H), 7.38 (m, 2H), 7.30 (m, 1H), 3.92-3.88 (dt: J = 12.0 Hz, 3.8 Hz, 2H), 3.61-3.50 (m, 4H), 2.55 -2.48 (ddd, J = 9.2 Hz, 5.6 Hz, 4.0 Hz, 1H), 2.35 (d, J = 13.8 Hz, 2H), 2.31-2.27 (ddd, J= 8.7 Hz, 5.7 Hz, 4.1 Hz, 1H), 2.02-1.94 (m, 2H), 1.51-1.47 (m, 1-), 10 1.39-1.34 (m ,1H). MS (ESI) rm/z: Calculated for C22HI- 21

F

3 N40S: 478.13; found: 479.2 (M+H)*. EXAMPLE 38 2-Chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride 15 H HCHO, HCOOH C1- N CI .HCI ------------------ CI -HCl 100 0C, 4" then 120 *C 0.5h 1,5-Dichloroazapentane hydrochloride (1.0 g, 5.6 mmcl) was taKen in formic acid 20 (0.43 mL, 11.2 mmol). A formaldehyde solution (1.2 mL, 37% in water) was added and the reaction mixture was heated to 100 'C for 4 h and then to 120 'C for 0 5 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude mixture was washed with hexane to afford 2-chloro-N-(2-chloroethyl) N-methylethanamine hydrochloride (1.0 g, yield 92%) as a white solid. 'H NMR (300MHz, 25 DMSO-d6) 6 11.21 (br s, 1H), 4.04 - 4.00 (t, J = 6.8 Hz, 4H), 3.54 - 3.48 (m, 4H), 2.82 (s, 3H). 101 WO 2011/088181 PCT/US20111021089 I -Methyl4-(2-phenylthiazol4-yl)piperidine-4-carbonitrile C N CI .HCI 5 NH 4 0H 00C N C < 0 , N CN ________ N S NaNH 2 10 50 "C 0.5h thon, 110 *C 5h N This compound was synthesized from (2-phenyl-thiazoi-4-yl)-acetonitrile and 2 chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride as described in example 16 steP lb (135 mg, yield 25%). 'H NMR (300MHz, CDCl3) 6 7.97 - 7.94 (m, 2H), 7.45 - 15 7.43 (m, 3H), 7.30 (s: 1H), 3.00 - 2.96 (m, 2H), 2.53 - 2.40 (m, 7H), 2.25 --2.20 (m, 2H). MS (ESI) m/z: Calculated for C,6H 1 7

N

3 S: 283.11; found: 284.2 (M-H). (1 -Methiyl-4-(2-phienylthiiazol-4-yl)piperidin-4-yl)methanamnine NCN2 yS LiAIH 4 _ H2 L - THF, 0 C-r 14h N IN 20 This compound was synthesized from 1-methyl-4-(2-phenylthiazol-4-yl)piperidine 4-carbonitrile as described in example 1 step 3 (110 mg) and it was carried through without further purification. MS (ESi) m/z: Calculated for C 1 6H 2

:N

3 S: 287.15; found: 288.2 (M+H). 25 102 WO 2011/088181 PCT/US20111021089 N-((1 -Methyl4-(2-phenylthiazol4-yl)piperidin4-y)mnethyl)-5-(S-(trifluoromethyl) 1,2,4-oxadiazol-3-yl)nicotinamide o N HATU, 40MM" O N O W-,1 N Y'K OH p F,0-.< j",. D<MF, 0 "C-1, 12h LN' This compound was synthesized from (1-methyl-4-(2-phenylthiazol-4-vl)piperidin 5 4-yl)methanamine and 5-(5-(trifluoromethy)-1,2,4-oxadiazoi-3-yl)nicotinic acid as described in example 8 step 6 (15 mg, yield 8%). 'H NMR (400MHz, CDCl 3 ) 5 9.43 (d, J = 1.5 Hz, 1H), 9.22 (d, j = 1.8 Hz, 1H), 8.76 (m, 1H), 7.92 - 7.90 (in, 3H), 7.42 - 7.41 (m, 3H), 7.19 (s, 1H), 3.92 - 3.87 (m, 2H), 3.00 (m, 2H), 2.84 (m, 2H), 2.57 (m, 5H), 2.25 (m, 21H). MS (ESI) m/z: Calculated for C 25 H 3

F

3

NO

2 S: 528.55 found: 529.2 (M-H)*. 10 EXAMPLE 39 4-(Chloronethyl)-2-(4-chlorophenyl)thiazole Ci NH2 EtOI--TH F 3:1 v/v

N

2 + C .,. c; C I reflux, 10h A mixture of 4-chlorothiobenzamide (0.5 g, 2.9 mmol) and 1,3-dichloroacetone (0 4 15 g, 3.18 mmol) in EtOH-THF (20 mL-l0 mL) was heated to 85 *C for 10 h. The reaction mixture was cooled to room temperature and quenched with 10% NaHCO3 solution. The organic product was extracted with EtOAc and the organic layer was washed with H 2 0 and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica 20 gel 60-120 mesh, eluent 3-5% EtOAc in petroleum ether) to afford 4-(chIoromethyl)-2-(4 chlorophenyl)thiazole (0.55 g, yield 77%) as a white solid. 'H NMR (400MHz, CDCl 3 ) 6 7.91 - 7.88 (m, 2H), 7.44 - 7.41 (m, 2H), 7.33 (s, 1H), 4.75 (s, 2H). MS (ESI) in/z: Calculated for CcH 7 Cl 2 NS: 242.97; found: 244.0 (M+H)*. 25 103 WO 2011/088181 PCT/US20111021089 2-(2-(4-Chlorophenyl)thiazol-4-yl)acetonitrile KGN KNN) 8- (cat.) C;- M/ MeCN, reflux, 10h NC A catalytic amount of 18-crown-6-ether (20 mg) was added to a solution of 4 (chloromethyl)-2-(4-chlorophenyl)thiazole (0.55 g, 2.25 mmol) in acetonitrile (20 mL), 5 followed by potassium cyanide (0.22 g, 3.37 mmol) and the reaction mixture was refluxed for 10 h. The reaction mixture was then quenched with water and the organic product extracted with EtOAc. The combined extracts were washed with -120 and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 15% 10 EtOAc in petroleum ether) to afford 2-(2-(4-chlorophenyl)thiazol-4-yl)acetonitrile (0.43 g, yield 82%) as an off-white solid. 'H NMR (300MHz, CD)Cis) 5 7.89 - 7.86 (d, J = 8 6 Hz, 2H), 7.45 - 7.42 (d, J = 8.6 Hz, 2H), 7.32 (n, IH), 3 96 (s, 2H). MS (ESI) m/z: Calculated for CH 7 CINS: 234.00; found: 235.0 (M+H)*. 15 2-(2-(4-ChIlorophenyl)thiazol-4-yl)-2-rnethylpropanenitrile CI Mel S NaH, DM0S 0 C-rt2h NC This compound was synthesized from 2-(2-(4-chiorophenyl)thiazol-4-yl)acetonitrile using iodomethane as described in example 1 step 2 (0.15 g, yield 70%) as a pale yellow solid. IH NMR (300 MHz, CDC13) 5 7.92 - 7 88 (d, J = 8.6 Hz, 2H), 7.44 - 7.41 (d, J = 8.6 20 Hz, 2H), 7.29 (s, 1H), 1.82 (s, 6H) MS (ESI) m/z: Calculated for C 13

.HCIN

2 S 262.03; found: 263 0 (M+H,) 104 WO 20111088181 PCTUS201 11021089 2 -(2-(4-C hlo-o pheny)th iazol -4-yl) -2-m ethyl propan-1 -amine LA H 4 / N THF, 0 0 -rt. 1 h

NCJ

7

H

2 X This compound wee synthesized fror 2(-4Clrneyltizi4y)2 methylpropanlenitile as described in exarmple step 3, (60 mg, yield 40%). '- NMR (400 5 MHz. CDCl3) 6 7.90 - 7,8 (d: J = 8.6 Hz, 2H), 7.42 - 7.40 (d, j =6.6 IHz, 21-), 6.99 (s, 11-H), 2.98 (s, 2H): 1.39 (s, 6iH). MIS (ESI) rr~z. Calculated for Cj 1 5CIN 2 S: 266.06; found. 267.0 (N11+14)'. N-(2-(2-(4-chlorophenyl)thiazol-4-y)-2-methylpropy)--(6-(trifluoromethy)- 2,4 10 oxadiazol--yl)nicotinamide N F-N 0 N ~~~ ~HATU, NMM N~ h~~ D)MF' 0 4 h IN This compound was synthesized from 2-(2-(4-chloro ' henyl)th'azol--y)-2 methylpropan-1 -amine and 5-(5-(trifluoromiethyl)-1 ,2,4-oxadiazol-3-yl)nicotinic acid as described in example 6 step 6 (50 mig, yield 51%). 'H NMVR (400MHz, CDl,) c) 9.46 (d, JI 15 1.5 Hz IH), 9.24 (d, J 1.6 Hz, 11H), 8.79 (in, 11-), 8.22 (t, J =4.5 Hz, 1 H), 7.85 -7.63 ,d, J = 85Hz, 2H 7.8 7.36 (d, J --8.5 Hz, 2H4), 7.09 (s, 1 H) , 3.72 (d, J = 5.5 Hz, 2H), 1.50 is, 6H). MS (-ES!) rniz: Calculated for C 22 H-1 7

CIF

3

N

5 0 2 5. 507.07; found: 506.0 WM iH) . 20 105 WO 2011/088181 PCT/US2011/021089 EXAMPLE 40 4-(2-(4-Chiorophenyl)thiazol-4-yl)-1-methylpiperidine.4-carbonitrile CIC NaNH 2 50C 0.5h then 110 *C24h This compound was synthesized from 2-(2-(4-chloropheny)thiazol-4-yl)acetontrie 5 and 2-chloro-N-(2-chloroethyi)-N-methylethanamine hydrochloride as described in example 16 step lb (350 mg, yield 32%). 'H NMR (300MHz, CDCl) 6 7.91 - 7.88 (d, J= 8.6 Hz, 2H), 7.43 - 7.40 (d, J = 8.6 Hz, 2H), 7.32 (s, 1H), 3.03 - 2.98 (m, 2H), 2.57 - 2.38 (m, 7H), 2.26 -- 2.21 (i, 2H). MS (E' r/z: Calculated for CjH 1 CINS: 317.08; found: 318.2 (M+H1)*. 10 (4-(2-(4-Chlorophenyl)thiazol-4-yl)-i-methylpiperidin-4-yl)methanamine C1 Cl ///F TH F, 0 "C-rt, 14h H This compound was synthesized from 4-(2-(4-chlcrophenyl)hiazol-4-y)-1 methylpiperidine-4-carbonitrile as described in example I step 3 (130 mg, crude) and it 15 was carried through without further purification. MS (ESI) m/z: Calculated for CI HKCIN 3 S. 321.11; found: 322.2 (M+H)+. 106 WO 20111088181 PCTUS201 11021089 (trifl uoromethyl)-1 ,2,4-oxad iazol-3-yl)n icot inamnide Cl C;

VF

3 C--K., N >N NH H"N F 3 C- 'N'- I H.N.2< ~HATU. INKM ~ N 9

'

7 K, iDMIF. 0O C-rt, 1 Oh N N." This compound wes synthesized from (4-'2-(4-chkcrophenyl)mazc)1-4-y)-1 5 methvlpilnrirdi n-4-yi )methenamin teand 5-(5-(tr ifluororneth yl) 12 4-oxadiazo-3-yl)nico-tinlic acid as described in example 8 sten 6 (17 mg, yield 1)'.H NMR (400M.Hz, MeOD) 6 9.36 (d. J 2.0O Hz, 11H), 9,09 (d, .1 = 2.0 Hz, I H), 8.72 (t, J =2.0 Hz? 1 H)5 7.95 - 7.93 (d, J -8.5 Hz, 2H), 71.59 (bras, 1H), 7.44 - 7.42 (d, J = 8.6 Hz, 2H), 3.73 (in. 2H), 3.50 - 3.49 (in, 2H), 2.87 - 2,83 (mn, 7H), 2.21 - 2.16 (in, 2H). MS (ESI) m'/z: Calculated for 10 C 25

H

22 ClF 3

N

6 0 2 S: 562.12; found: 563.2 (Mi-Hf . EXAMPLE 41 N-(2-(2(4-chloropheriyl)thpiazol-4-yi)-2-rnethiylpropyl)-3-(5-(trifluformehy)-1,2,4 oxadiaol-3-yllbenzamide P-Nl Cl _ ,C02 P-N 0

H

2 N~~~ 7 S I-IHATU, NMM FG.\K .J. '5DMF, 0 C-rt, 4h N This compound was synthesized from 2-(2.-(4- chi crop heiyl)th iazol -4- yl).2 methylpropanl-1- amine and 3-(5-..(tri!fluoicmethyl)-1 ,2.4.-oxadiazol -3-y'I~benzoic acid as desc-ribed. in example 8 step 6 (75 mg, yield 2-5%). 1H- NIVR (4-,0M.Hz CDC1 2 ) 6 8.53 ini, 20 1IH), 6.27 -- 8.25 (in, I H), 8.10 -- 8.05 (in, 2H), 7.66 -- 7.84 (d, J =8.5 Hz, 2H), 7.62 -- 7.59 (t, J = 7.8 Hz, 1H);7.33 -- 7.31 (d, J = 8.5 Hz, 2H., 7.08 (a, I H, 3.71 -- 3.69 (8, J =5.3 Hz, 2H), 1.49 (s, 6H). MIS (ESI) rn'z; Calculated for C 2 , H 1 8CIF 3 1N 4 0 2 S: 506.08; found: 507.0 + 'H . 25 WO 2011/088181 PCT/US20111021089 EXAMPLE 42 2-(2-(4-Chiorophenyl)thiazol-4-yl)ethanamine Cl Cl B EH-Me2S THF, reflux, 0.5h NN Borane dimethyl sulfide complex (0.24 mL, 2.5 mmol) was added to a solution of 5 2-(2-(4-chlorophenyl)thiazol-4-yl)acetonitrile (150 mg, 0.63 mmol) in dry THF (15 mL) at room temperature. The reaction mixture was refluxed for 0.5 h and then quenched carefully with methanol. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-(2-(4 10 chiorophenyl)thiazol-4-yl)ethanamine (150 mg, crude) which was used as such for the next step. N-(2-(2-(4-Chlorophenyl)thiazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazo-3 yl)nicotinamide GI C'N N_ FCC CO. N D-N O N: <

N'F

3 C--4 it HATU, NMM N' 15 H2N' DMF, O 0 C-rt, 3h N This compound was synthesized from 2-(2-(4-chlorophenyl)thiazoi-4 yl)ethanamine and 5-(5-(trifluoromethy)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in e example 8 step 6 (13 mg, yield 23%). 1H NMR (400MHz, CDCla) 6 9.46 (m, 1H), 9.25 (n, I H), 8,81 - 8.80 (t, J = 2 Hz, I 1H), 7.87 - 7,84 (m, 2H), 7.40 -7.37 (m, 2H), 7.08 (s, 1 H), 20 3.93 - 3.89 (m, 2H), 3.16 - 3.13 (m, 2H). MS (ESI) m/z: Calculated for C 20 HCIF3NO 2 S: 479.04; found: 480.0 (M+H). 108 WO 2011/088181 PCT/US20111021089 EXAMPLE 43 Methyl 2-cyanoisonicotinate Me 3 SiCN \ 0 -- N --- 4/ C. NC, ,CO 2 Me - ' N 0- r { d CH2Cl2, r, 12h N Trimethylsilyl cyanide (3.8 g, 0 0386 mol) and dimethyicarbamyl chloride (5.0 g, 5 0.0483 mol) were added to a solution of methylisonicotinate N-oxide (5.0 g, 0.0322 mol) in dry CH 2

CI

2 (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h and then quenched with 10% K 2 C0 3 solution. The organic product was extracted with CH 2 Cl 2 and the organic laver was washed with H 2 0 and brine, dried over anhydrous Na 2

SO

4 and concentrated under reduced pressure. The crude product 10 was purified by flash column chromatography (silica 230-400 mesh, eluent 1-2% MeOH in

CH

2

CI

2 ) to afford methyl 2-cyanoisonicotinate (1.75 g, yield 33%) as an off-white solid. 'H NMR (400 MHz, DMSO-ds) 5 8.97 - 8.95 (d, J = 5.0 Hz, IH), 8.41 (m, IH), 8.15 - 8.13 (dd, J= 4.8 Hz, 1 .6 Hz, 1 H), 3.92 (s, 3H). 15 2-Cyanoisonicatinic acid NC .CO2Me LiOH NC C2H TH-iF4-H207:3v/v 0 C-rt, 1h Lithium hydroxide (96 mg, 4.0 mmol) was added to a solution of methyl 2 cyanoisonicotinate (0 6 g, 3.7 mmol) in THF-H 2 0 (20 mL, 7:3 vIv) at 0 'C. The reaction mixture was allowed to warm up to room temperature and further stirred for 1 h. The 20 reaction mixture was concentrated under reduced pressure and then diluted with water. The aqueous layer was washed with EtOAc. The pH of the aqueous layer was adjusted to --3 using 1.5N HCI and the organic product was extracted with EtOAc. The organic layer was dried over anhydrous Na 2

SO

4 and concentrated under reduced pressure to afford 2 cyanoisonicotinic acid (490 mg, yield 89%) as a white solid. 'H NMR (300 MHz, DMSO 25 d6) 6 14.11 (br s, 1H), 8.93 - 8.91 (dd, J = 4.9 Hz, 0.8 Hz, 1H), 8.34 (d, i = 0.9 Hz, 1H), 8.11 - 8.10 (m, 1 H). MS (ESI) im/z: Calculated for 7

H

4

N

2 0 2 148.03; found: 147.2 (M-H). 109 WO 2011/088181 PCT/US20111021089 2-(N'-Hyd roxycarbaninidoyl)isonicotinic acid HO. NC, CO2H NH 2 OH.HCI, Na2COI 1 -1 2 N '1 C 2 N B-hydroxyquinoline (cat.) tOH, reflux, 3h This compound was synthesized from 2-cyanoisonicotinic acid as described in example 1 step 4 (500 mg, crude), which was carried through without further purification. 5 IH NMIR (400 MHz, DMSO-d 6 ) 5 10.86 (br s, IH), 10 36 (br s, 2H), 10.13 (br s, IH), 8.87 8.86 (d, J = 4.9 Hz 1H), 8.44 (s, 1H), 799 - 7.98 (d, J = 4.9 Hz, 1H). MS (ESI) m/z: Calculated for C 7

H

7 N30s: 181.05; found: 182.2 (M+H), 2-(5-(rifluoromethyl)-1,2,4-oxadiazol-3-yl)isonicotinic acid HO, ,ON N (CF 3

CC)

2 0 FC- 0 " H H2N Y 'OHN 0pynie, rerlux, 3h N This compound was synthesized from 2-(N'-hydroxycarbamimidoyl)isonicotinic acid as described in example 1 step 5 (200 mg, yield 23%) as a white solid H NMR (400 MHz, DMSO-ds) 6 14.11 (br s, 1H), 9.02 - 9.00 (dd, J= 4.8 Hz, 0.7 Hz, iH), 8 45 (m, 1H), 8.09 - 8.07 (dd, J = 5 0 Hz, 1.5 Hz, 1H). MS (ESI) m/z: Calculated for CgH 4 F3N 3

O

3 : 15 259.02; found: 260 0 (M+H) N-(2-(4-(4-Chlorophenyl)thiazoI-2-yl)-2-methylpropyl)-2-(5-(trifiuoromethyl)-1,2,4 oxadiazol-3-yl)isonicotinamide F3c--\ cosH - HATU, NMM - N y~~r'~ + oDM, o ec-r,+ 4 Fc N ~ N, S2-~ m2N X. N-) 20 This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-y)-2 methylpropan-1-amine and 2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)isonicotinic acid as described in example 8 step 6 (65 mg, yield 33%). 'H NMR (400MHz, CDCI,) 6 8.94 8.92 (dd, J 5.0 Hz, 0.8 Hz, 1 H), 8.50 (m, 1H), 8.39 -- 8.36 (t, J = 5.6 Hz, 1H), 7. 88 25 7.86 (dd, J 5.0 Hz, 1.5 Hz, 1H), 7.79 -- 7.77 (d, J = 8.5 Hz. 21-), 7.44 (s, 1i), 7.35 -- 7.33 (d, = 8.5 Hz, 2H), 3.83 -- 3.82 (d, J = 5.8 Hz, 2H), 1.57 (s, 6H). MS (ESI) mr/z: Calculated for C 22

H.

7

CIF

3

N

5 2 S: 507.07, found: 508.0 (M+-)I. 110 WO 2011/088181 PCT/US20111021089 EXAMPLE 44 4-(Chloromethyl)-2-(4-fluorophenyl)thiazole F S 0 EtOH-THF 3:1 v/v

+--C---C------------+

F refljx, 10h N This compound was synthesized from 4-fluorothiobenzamide and 1,3 5 dichlioroacetone as described in example 39 step 1 (0.65 g, yield 89%) as a white solid. H NMR (400MHz, CDC 3 ) 6 7,96 - 7.93 (m, 2H), 7.30 (s, 1H), 7.16 - 7.12 (F, J = 8.7 Hz, 2H), 4.75 (s, 2H). MS (ESI) m/z: Calculated for Cl 3 i-lCIFNS: 227.00; found: 228.0 (M+HY. 10 2-(2-(4-Fluorophenyl)thiazol-4-yl)acetonitrile F F KCN N- ' 18-C -6 (ca~t.)N S MeCN, reflux, 10h NC.f-/ This compound was synthesized frn 4-(chloronethyl)-2-(4.-fluorophenyl)thiazole as described in example 39 step 2 (0.27 g, yield 80%) as an off-white solid. 1H NMR (400MHz, CDCl 3 ) 5 7.95 - 7.91 (m, 2H), 7.30 (s, 1iH) 7.17 -- 7.13 (t, J = 8.7 Hz, 2H), 3.95 15 (s, 2H). MS (ESi) m/z. Calculated for CH 7

FN

2 S: 218.03; found. 219.0 (M+H) 2-(2-(4-Fluorophenyl)thiazol4-yl)-2-methylpropanenitrile F Mel S NaH,DMSO N 0 "C-t, 2h NC, This compound was synthesized from 2-(2-(4-fluorophenyl)thiazol-4-yl)acetonitrile 20 and methyl iodide as described in example 1 step 2 (250 mg, yield 75%). 1 H NMR (400 MHz, CDCIs) 5 7.98 - 7.94 (m, 2H), 7.41 (s, 1H), 7.17 - 7.12 (t, J = 8.7 Hz, 2H), 1.82 (s, 6H). MS (ESI) m/z: Calculated for C 3

H

1

FN

2 S: 246.06; found: 247.2 (M+H)+ 111 WO 20111088181 PCTUS201 11021089 2-2.4-luroheylTHP ao--I.-ehlrpn1-mn This compound was synthesized from -- 4furohnltiz--y)2 methylproparlenitlile as described in example i step 3 (200 mg, crude) and it was carried 5 through without further purification, MS (ESI) 77/-7 Calculated for 0 1 3

H

1

FN

2 S: 250.09; found: 251.2 (M+1-1ly, N-(2-(2-(4-Fluorophenyl)thiazol-4-yi)-2-rrnethylpropyl)-3-(6-(trifluroriethyl)-1 F2.4 omadiazol-3-yi)benzamide F -.- ~. Kr'-'HATU, NMM F. C-~\ 10

[M,

0 C:-it, H9 This compound was synthesized from 2-(2-(4-fluocrop henlythiazol-4-y)-2 methylpropan-1 -amine and 3-(5-(tnifluoromethyl)-1,2,4-oxadia3zcl-3-vI)benzoic acid as described in exannple 8 step 6 (55 mg, yield 30%)I. H9 NNR (400MHz, CDC13) 6 8.53 (mn, 15 1H), 8.26 -8.24 (d, J= 7 8 Hiz, 19), 8.13I- 8.11 (in, 1%) 8,07 - 805 (d, J= 7.5 -1z, 11H), 792- 7.89 (in, 2H), 7 62-7.58M (t? J =7 8 Hz, 11-), 7.06 - 7.02 (in, 3H), 3.71 - 3.89 (d, J = 5.3 Liz, 2H), 1.49 (s, SH). MVS (IESi), r,17, Calculated for C 23

H

1 sr-4N 4 0 2 S: 490.11; found: 491.0 (NM.+H)r 20 112 WO 2011/088181 PCT/US20111021089 EXAMPLE 46 N-(2-(2-(4-Fluorophenyl)thiazol4-y)-2-nethylpropyl)-S-(5-(trifiuoromethyl)-1,2,4 oxadiazol-3-yl)nicotinamide IF F N N~ O 0O N J S --- - - - F f C S HATU, NMM N X< N H H DMF. O "C-t 4hN This compound was synthesized from 2-(2-(4-fluorophenyl)thiazo4-yl)-2 methylpropan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nictinic acid as described in example 8 step 6 (50 mg, yield 26%). IH NMR (400MHz, MeOD) 5 9.36 (d, J = 2.0 Hz, 1H), 9 11 (d, J = 2.3 Hz, 1H), 8.77 - 8.76 (t, J = 2.1 Hz, 1H), 8.00 - 7.96 (n, 10 2H), 7 30 (s, 1H), 7.18- 7 14 (t, J = 8.8 Hz, 2H), 3 75 (s, 2H), 1.50 (s, 6H) MS (ESI) m/z Calculated ;or C 22

H-F,N

5 O.S: 491 10; found: 492.0 (M+H)*. EXAMPLE 46 6-((Benzyloxy)carbonyl)picolinic acid

HO

2 Cs N CO 2 H PhCH2OH HO 2 C. N ---------------------------- +OPh cono H2SO 4 , H20 15 .reflux, 1Oh, rt, 24h A mixture of 2,6-pyridinedicarboxylic acid (10 g, 0.06 moi) and benzyl alcohol (68 mL, 0.66 mol) were taken in water (25 mL), and concentrated H 2 SO4 (3.5 mL) was added. The reaction mixture was refluxed for 10 h and further allowed to stir at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and the organic 20 product was extracted with CHCI 3 . The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gei 60-120 mesh, eluent 5% MeOl in C-1 2 Cl 2 ) to afford 6-((benzyloxv)carbonyl)picolinic acid (4.6 g, yield 30%) as a white solid. 'H NMR (400 MHz, DMSO-d,) 5 13.54 (br s, 1H), 8.29 - 8.24 (m, 2H), 8.20 - 8.16 (m, 1H), 7.52 - 7.50 (n, 2H), 7.44 - 7.36 (m, 3H), 5.43 (s, 2H). MS (ESI) m2/z: 25 Calculated for C,,HN0 4 : 257.07; found: 258.2 (M-H)*. 113 WO 2011/088181 PCT/US20111021089 6-Carbarnoylpicolinic acid saturated NH, 4 0H sealed tube, 90 C. fih A solution of 6-((benzyoxy)carbonyi)picolinic acid (3.0 g, 11.7 mrnol) in saturated NH,0H (100 mL) was heated in a sealed tube at 90 "C for 6 h and monitored by TLC 5 (CHCl3/MeOH 8.2 v/v). The reaction mixture was evaporated to dryness to get the 6 carbamoylpicolinic acid (1.8 g, yield 94%) as a white solid, which was carried through without further purification. MS (ESI) m/z: Calculated for C 7 H5N,0: 166.04; found: 167.0 (M+H)'. 10 6-Cyanopicolinic acid HO2C, N, P'H -- Cl, -i 2 C, I, CN I. 'N H 2 --------- 6-Car bamoyloicolinic acid (1.0 g, 6.0 mmol) was taken in phosphorus oxychloride (20 rmrL) and heated to eflux for 4 h. Excess POC1 was removed under reduced pressure and the residue was quenched with ice water. The organic product was extracted with 15 EtOAc and the solvent was removed under reduced pressure to afford 6-cyanopicolinic acid (500 mg, yield 56%), which was carried through without further purification. 'H NMR (300 MHz, DMSO-d 6 ) 6 8.31 --- 8.28 (m, 2H), 8,26 -8 .21 (m, 1H). MS (ESI) n/z: Calculated for C 1

H

4

N

2 0 2 : 148.03; found: 147.2 (M-H) 20 6-(N'-Hydroxycarbamimidoyl)picolinic acid H2N ~N, CN NH 2 OH.HCI, Na2CC, H --------- N CO2H 8-hydoxyquinoline (cat.) H 2 N N 2 EtOH, reflux, 4h This compound was synthesized from 6-cyanopicolinic acid as described in example I step 4 (500 mg, crude), which was carried through without further purification. 1 H NMR (400 MHz, D20) 6 8.31 - 8 29 (m, 1H), 8.18 - 8.14 (t, J = 7 8 Hz, IH), 8.07 25 8.05 (m, 1 H). 114 WO 2011/088181 PCT/US2011/021089 O-(5-(Triflusommethyi)-1 ,2,4-oxadiazol-3-yi)picolinic acid N (CrCO)2O N SN ,CO2H - F 3C N CO2H

H

2 N pyridine N j refux, -3h This compound was synthesized from 6-(N'-hydroxycarbamimidoyl)picolinic acid as described in example I step 5 (110 mg, yield 20%) as an off-white solid. 'H NMR (400 5 MHz, DMSO-de) 6 13 64 (br s, 1H), 8.36 - 8.34 (m, 1H), 8.27 - 8.25 (m, 2H). MS (ESI) m/z: Calculated for C 9

H

4 F3N 3 0 3 : 259.02; found: 260.0 (M+H)*. N-(2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropyl)-6-(5-(trifluorom ethyl)-1,2,4 oxadiazol-3-yI)picolinamide F HN)CCC HATU, NMM 10 MFP, 0C-r4 This compound was synthesized from 6-(5-(trifluoromethyl)-1,2,4-oxad azoi-3 yi)picolinic acid and 2-(4-(4-chlorophenvl)thiazoi-2-yl)-2-methylpropan-1 -amine as described in example 8 step 6 (55 mg, yield 56%). 'H NMR (400MHz, CDC.

3 ) 6 8.87 8.85 (m, IH), 8.43- 8.41 (dd, J = 7.8 Hz, 1 Hz, 1H), 8.27 - 8.24 (dd, J = 7.8 Hz, 1.3 Hz, 15 1 H), 8 10 - 8.06 (m, 1H), 7.89 - 7 87 (d, J = 8.5 Hz, 2H), 7 41 (s, 1H), 7.32 - 7.29 (d, J = 8.8 Hz, 2H), 3.91 - 3.89 (d, J = 6.5 Hz, 2H), 1.56 (s, 6H). MS (ESI) m/z: Calculated for C 2

H

17

CIF

3

N

5 0,S: 507.07; found: 508 0 (M+H)*. EXAMPLE 47 20 (4-Phenylthiazol-2-yl)methanol Ph S Ph _S OH KOH N - -------------- N EtOH, 0 *C-rt, 1 h Potassium hydroxide (1.06 g, 18.84 mmnloi) was added to an ice cooled solution of benzoic acid (4-phenylthiazol-2-yl)methyi benzoate (3.71 9 12.56 mmol) in EtOH (40 nL). The reaction mixture was slowly warmed to room temperature and allowed to stir for I h. 25 The reaction mixture was concentrated under reduced pressure and then diluted with 115 WO 2011/088181 PCT/US20111021089 water. The organic product was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10% EtOAc in petroleum ether) to get the pure (4-phenylthiazol-2-yl)methano (2.1 g, yield 87%). 1 H 5 NMR (400 MHz, CDC' 3 ) 6 7,89 - 7.87 (m, 2H), 7.46 - 7.41 (m, 3H), 7.37 - 7.33 (in, 1H), 5.01 (s, 2H). MS (ESI) m/z: Calculated for CmnHqNOS: 191.04; found: 192.2 (M+H). 4-Phenylthiazole-2-carbaldehyde 1 S OH _-S C -\ Dss-Martin 1y N 'N

CH

2

CI

2 , 0 "C-d, 3h 10 A solution of (4-phenylthiazol-2-vl)methanol (2.1 g, 10.98 mmol) in dry CH 2 Cl2 (50 mL) was purged with argon for 10 min and Dess-Martin periodinane (7.0 g, 16.5 mmol) was added to the solution at 0 IC. The reaction mixture was allowed to warm up to room temperature and further stirred for 3 h (monitored by TLC, petroleum ether/EtOAc 8:2 v/v). The reaction mixture was then quenched with saturated sodium thiosulfate solution. The 15 organic product was extracted with CH 2

C'

2 , and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield aldehyde 4-phenylthiazole-2-carbaidehyde (1.95 g, yield 94%), which was carried through without further purification. 'H NMR (300 MHz, CDC'.) 6 10.08 (m, 1H), 7.98 - 7.95 (m, 2H), 7.90 (im, 1H), 7.52 - 7.39 (m, 31-). MS (ESI) mn/z: Calculated for CJH 7 NOS: 189.02; 20 found: 190.0 (M+H) 2.-(Direthylanino)-2.-(4-phenylthiazol.-2-yl)acetonitrile -S O Me2NH.HCI, NaCN N H -------------- + MeOH-H20 1:2 viv NC rt. 4h Sodium cyanide (124 mg, 2.53 mmol) was added to a solution of dimethylamine 25 hydrochloride (280 mg, 3.43 mmol) in water (10 mL), followed by the addition of a solution of 4-phenylthiazole-2-carbaldehyde (400 mg, 2.11 mmol) in methanol (20 mL) while maintaining the temperature at -- 25 IC. The reaction mixture was further stirred for 4 h at same temperature, then it was diluted with water and the organic product was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium 30 sulfate, and concentrated under reduced pressure to get the crude product which was 116 WO 2011/088181 PCT/US20111021089 purified by column chromatography (silica 60-120 mesh, eluant 15% EtOAc in petroleum ether), to yield 2-(dimethviamino)-2-(4-phenvIthiazol-2-yl)acetonitrile (160 rng, yield 31%) 'H NMR (400 MHz, CDCi,) 6 7.97 - 7.94 (m, 2H), 7.57 (s, 1H), 7.46 - 7.42 (m, 2H), 7.38 - 7.33 (m, 1H), 5,12 (s, 1H), 2.50 (s, 6H). MS (ESI) n/z: Calculated for C 13

HIN

3 S: 5 243.08; found: 244.2 (M-HY. N,N-Dimethyl-1-(4-phenylthiazol-2-yl)ethane-1,2-diamine N LiAlH 4 NC S THF, *C..rt, 2h H 2 N S N This compound was synthesized from 2-(dimethylamino)-2-(4-phenylthiazoi.-2 10 yl)acetonitrile as described in example I step 3 (130 mg, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for CG.H, 7

N

3 S: 247.11; found: 248.2 (M+H)*. NV-(2-(Dimethylamino)-2-(4-phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1 2,4 15 oxadiazol-3-yl)benzamide 5

H

2 N' yVSF-- - N 2 H-ATU, NMM Hjj~ <~ NMF, 0 C-rt, 4h This compound was synthesized from N,N-diiethyl-1-(4-phenylthiazoi.-2 yl)ethane-1,2-diamine and 3-(5-(trifluoromethyl)- 1,2,4-oxadiazol-3-.yl)benzoic acid as described in example 8 step 6 (16 mg, yield 17%). 'H NMR (400MI-lz, CDCI 3 ) 5 8.57 - 20 8.56 (t, J = 1.5 Hz, 1-), 8.26 .-- 8.23 (ot, J = 7.8 Hz, 1.4 Hz. 1 H), 8.07 -- 8.05 (dt, J = 7.8 Hz, 1.4 Hz, 1H), 7.91 -- 7.87 (m, 3H): 7.63 - 7.59 (t, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.42 - 7.38 (m, 2H), 7.36 -- 7.31 (m, 1H), 4.35 - 4,29 (ddd, J = 13.2 Hz, 6.6 Hz, 5.5 Hz, IH), 4.15 - 4.12 (m, 1W, 3.85 -3.78 (ddd, J = 13.0 Hz, 8.3 Hz, 4.6 Hz, 1H), 2.51 (s, 6H). MS (ESI) m/z: Calculated for C 23

H

20 F N5O2S: 487.13; found: 488.2 (M+H)*, 25 117 WO 2011/088181 PCT/US20111021089 EXAMPLE 48 2-(3-Phenyl-1H-1,2.4-triazol-5-yl)ethanamine BN M S4N NG,_LAN H 2 N H THF, reflux, Ih Borne dimethyl sulfide complex (0.2 mL, 2.16 mmol) was added to a solution of 5 compound 2-(3-phenvi-1H-1,2,4-triazoi-5-yl)acetonitrile (100 mg, 0.54 mmio) in dry THF (5 mL) at room temperature. The reaction mixture was refluxed for 1 h, then quenched carefully with methanol and again heated to reflux for 0.5 h. The reaction mixture was concentrated under reduced pressure and then diluted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under 10 reduced pressure to afford 2-(3-.phenyl-1H-1,2,4-triazol-5-yljethanarnine (130 mg, crude), which was carried through without further purification. MS (ESI) m'z: Calculated for

C

10 iHLN4: 188. 11; found: 189.2 (M+H) N-(2-(3-Phenyl-1H-1,2,4-triazol-5-yI)ethyl)-3-(5-(trifluorormethyl)-1,2,4-oxadiazol-3 15 yl)benzamide O-N 0 N - -OH N N HF-- N---N- N H HATU, NMM H H DMF, 0 "C-rt. 4h This compound was synthesized from 2-(3-pheny-1 H-1,2,4-triazoi-5 yi)ethanamine and 3-.(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (17 mg, yield 21%). 'H NMR (400Mi-lz, CDCi 3 ) 6 8.53 (s, 1H), 8.21 20 8.19 (d, J = 7.8 Hz, 1 H), 8.06 - 8.04 (t, J = 7.8 Hz, 1H), 8.01 - 7.99 (m, 2H), 7.89 (m, 1H), 7.58 -- 7.54 (d, J = 7,8 Hz, 1 H), 7.40 -- 7.39 (m, 3H), 4.00 -- 3.95 (q, J = 5.9 Hz, 2H), 3.24 3.21 (d, J = 6.1 Hz, 2H). MS (ESI) m/z: Calculated for C 2 0

H,

5

F

3

NBO

2 : 428.12; found: 429.2 (M+H). 25 118 WO 2011/088181 PCT/US2011/021089 EXAMPLE 49 1 -(4-Phenylthiazol -2-y)cyclopropanecarbonitrile / r Br N 50%A N~aOH NN NC !o ) NC S BnE 3 NCI (cat) CHi2C1 2 , 0 1C-rr, 10h Benzyltriethyl ammonium chloride (34 mg, 0.15 mmo) and 50% aqueous NaOH 5 solution (0.59 g dissolved in 1 mL of water) were added to a solution of 2-(4-phenylthiazol 2-yl)acetonitrile (0.3 g, 1.5 mmol) in CH 2 Cl 2 (10 mL). The reaction mixture was cooled at 0 'C and 1,2-dibromoethane (0.15 rnL, 1.79 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 10 h. The reaction mixture was diluted with CH 2 Cl 2 and the organic layer was washed with H20 and brine, 10 dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica ge 60-120 mesh, eluent 5% EtOAc in petroleum ether) to afford 1-(4-phenvlthiazol-2-yl)cvclopropanecarbonitrile (0.14 g, yield 41%) as an off-white solid. 1 H NMR (300 MHz, CDCIs) 657.86- 7.83 (m, 2H), 7.45 - 7.34 (m, 4H), 2.02- 1.95 (m, 2H), 1.93- 1.86 (n, 2H). MS (ESI) m/z: Calculated for 15 C 1 3

H

0

N

2 ,S: 226 06; found: 227.2 (M+H). (1 -(4-Phenylthiazol-2-yl)cyclopropyl)iethanamine N- LiAIH 4 N --------- -------- NC THF, 0 C-r. 1h H 2 N" X( S This compound was synthesized frorn 1-(4-phenylthiazo-2 20 yi)cyclopropanecarbontrie as described in example 1 step 3 (59 mg, yield 42%) as a pale yellow liquid. 'H NMR (400 MHz, CDCI 3 ) 6 7.91 - 7.89 (n, 2H), 7.44 - 7.40 (in, 2H), 7.35 - 7.33 (in, 1H), 7.30 (s, 1H), 3.11 (s, 2H), 1.26 - 1.24 (m, 2H), 1.11 - 1.09 (m, 2H). MS (ESI) m/z Calculated for Cl 3 HlN 2 S: 230.09; found: 231.2 (M+H). 25 119 WO 2011/088181 PCT/US20111021089 N-((1 -(4-Phenylthiazo.-2-yl)cycloprpyi)nethyl)-3-(5-(trifluioromethyl)-1,2,4 oxadiazol-3-yl)benzamide N - C--N HN x sHATU, NIVM N N 'S 2 / DMF, 0 'C-r,1 3h H This compound was synthesized from (1-(4-phenyithiazoi-2 5 y!)yclopropy!)methanamine and 3-(5-(trifluoromethy)-1,2,4-oxadiazoi-3-vl)benzoic acid as described in example 8 step 6 (47 mg, yield 49%). 'H NMR (400 MHz, CDCI1) 1.59 (s, 1lH), 8.25 - 8.23 (m, 2H), 8.09 - 8.07 (m, 1-1), 7.90 - 7.88 (m, 2H), 7.63 - 7.59 (t, J 7.9 Hz, 1H), 7.41 - 7.38 (in, 2H), 7.35 7.33 (m, 1H1): 7.32 (s, 1H), 3.93 (d, J = 5.5 Hz, 2H), 1.42 -- 1.39 (m, 2H), 1.23 -- 1.20 (m, 2H). MS (ESI) m/z: Calculated for 10 C: 3

H

1

F

3

N

4 0S: 470.10; found: 471.0 (M+H). EXAMPLE 50 N'-Hydroxy-3-nitrobenzimidamide HOs N NO2 NH OH HCI, Na 2 CO N 6-hydroxyquinoline (ca".) EOH, reflux, 4h 15 This compound was synthesized from 3-nitrobenzonitrile as described in example I step 4 (5.5 g, crude)and it was carried through without further purification. 'H NMR (300MHz, DMSO-d6) 6 9.96 (s, 1H), 8.50 (d, J 1.3 Hz, 11-) 8.23 - 8.19 (m, 1H), 8.12 8.10 (m, 1H), 7.67 (t, J = 8.0 Hz, 1H), 6.09 (Im, 2H). MS (ESI) m/z. Calculated for

C.HIN

3 O3: 181 .05; found: 182.2 (M+H) 20 3-(3-Nitrophenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole

CFCO)

2 O - 'N H-2NA_-:_NO2__ FC 2 pyridine, 0 "C-rt, 2h This compound was synthesized from N'-hydroxy-3-nitrobenzimidamide as described in example 1 step 5 (1.6 g, yield 56%) and it was carried through without further 25 purification. 1-1 NMR (300 MHz, DMSO-d) 6 8.72 (t, J= 1.9 Hz, 1H), 8.53 -- 8.48 (m, 2H), 7.93 (t, J = 8.0 Hz, 1i1H). MS (ESI) m/z: Calculated for C.H4F 3

N

3 03: 259.02; found: 260.0 (M+HY2 120 WO 2011/088181 PCT/US2011/021089 3-(8-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)aniline O-N Na2S2 4 Q-N nBuNBr (cat.) 30 N NH2

THF-H

2 0 1:1 v/v rt, 2h Sodium dithionite (1.61 g, 9.2 mmoi) and a catalytic amount of tetra-n 5 butylammonium bromide (20 mg) were added to a solution of 3-(3-nitrophenyl)-5 (trifiuoromethyl)-1,2,4-oxadiazole (11.6 g, 6.1 mmol) in THF-H 2 0 (30 mL, 1:1 viv), and the reaction mixture was stirred at room temperature for 2 h and monitored by TLC (petroleum ether/EtOAc 1:1). Solvent was removed under reduced pressure and the product was extracted with EtOAc. The organic layer was washed with brine, dried over 10 anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica ge! 60-120 mesh, eluent 30-35% EtOAc in petroleum ether) to afford 3-(5-(trifluoromethy)-1,2,4-oxadiazol-3-yl)aniiine (0.8 g, yield 57%) H NMR (300 MHz, CDCi3) 5 7.52 - 7.49 (dt, J = 7.7 Hz, 1.2 Hz, IH), 7.42 (m, 1H), 7.30 (t. J= 8.0 Hz, 1H), 6.89 - 6.86 (ddd, J = 7.9 Hz, 2.4 Hz, 0.9 Hz, IH), 3.87 (br s, 2H). 15 MS (ESI) m/z: Calculated for CHsF 3

N

3 O: 229.05; found: 230.0 (M+H)*. Methyl 4-amino4-thioxobutanoate 0S H2N ---- --- - H2"N'O H2!'4 6 THF, irh 0 Methyl succinamate (2 g, 15.2 mmol) was dissolved in dry THF (50 mL) and P 2 Sq 20 (3 4 g, 15.2 mmol) was added and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was filtered through a sintered funnel and the clear filtrate was concentrated under reduced pressure to get the crude product, which was further purified by column chromatography (silica gel 60-120 mesh, eluent 50% EtOAc in petroleum ether) to afford methyl 4-amino-4-thioxobutanoate (1.25 g, yield 53%) as a 25 white solid. 'H NMR (300 MHz, CDC1s) , 7.27 (br s, 2H), 3.72 (s, 3H), 2.96 - 2.85 (m,. 4H). MS (ESI) m/z: Calculated for C 5

H

3

NO

2 S: 147.04; found: 148.2 (M+HY. 121 WO 2011/088181 PCT/US20111021089 Ethyl 3-(4-(4-fluorophenyl)thiazol-2-yl)propanoate 0 H42N r N r EtOH. reflux. 3h F A mixture of methyl 4-amino-4-thioxobutanoate (0.3 g, 2.03 mmol) and 2-bromo-4 fluoroacetophenone (0.440 g, 2.03 mmio) in EtOH (10 mL) was refluxed for 3 h. The 5 reaction mixture was cooled to room temperature and solvent was removed under reduced pressure. The organic product was extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 8-10% EtOAc in petroleum ether) to afford ethy 3-(4-(4 10 fluorophenyl)thiazol-2-yl)propanoate (0.45 g, crude containing 7% of methyl ester product), which was carried through without further purification. 'H NMR (300MHz, CDCla) 5 7.88 - 7.83 (m. 2H), 7.28 (s, 1H), 7.13 - 7.07 (t, J = 8.8 Hz, 2H), 4.22 - 4.15 (q, J = 7.0 Hz, 2H), 3.40 - 3.35 (t, J = 7.3 Hz, 2H), 2.93 - 2.88 (t, J = 7.3 Hz, 2H), 1.30 - 1.25 (t, J = 7.1 Hz, 3H). MS (ESi) m/z. Calculated for C1 4

H

1 4FNO 2 S. 279.07; found: 280.2 15 (M+H )7 3-(4-(4-Fluorophenyl)thiazol-2-yl)propaioic acid OH c -- ----- ~s 1N NaoH IN NaOH (5 mL) was added to an ice-cooled solution of crude ethyl 3-(4-(4 fluorophenyl)thiazol-2-yl)propanoate (450 mg 1.61 mmol) in MeOH (5 mL) and the 20 solution was allowed to stir at room temperature for I h. Solvent was evaporated and the reaction mixture was diluted with water. The aqueous lever was washed with EtOAc and the pH of the aqueous solution was adjusted to -2 using IN HI. The organic productwas extracted with EtOAc and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 3-(4-(4-fluorophenyl)thiazoi-2-yl)propanoic 25 acid (320 mg, yield 79%) as a white solid. 1H NMR (300MHz, DMSO-de) 5 12.29 (br s. 1H), 7.99 - 7 96 (m, 2H)., 7.93 (s, 1H), 7.28 - 7 22 (t, J 90 Hz, 2H), 3.25 - 3.20 (t, J = 7.1 Hz, 2H), 2.78 - 2.74 (t, J 7 1 Hz, 2H). MS (ESI) r/z: Calculated for C12HIFNO2S: 251.04; found: 252 2 (M+H)*. 122 WO 20111088181 PCTUS201 11021089 3-(4.(4-Fluoropheniyl)thiazol2-yi)N-(3-(-(triflujoroiiethyl)- ,2,4-oxadao-.13 yl)phenyl)propanamide F-NC NH OH HATLI. NMMN : DMNF, 0 Oc-t 6Oh This compound was synthesized From 3-(5-(tr-ifluororrethiyl)-1 ,2,4-oxadi!azo!-3 5 yi)aniiine and 3-(4.-(4I-fiuoophenyllthiazol-2-yi)propanoc acid as described in example 8 step 6 (80 mg, yield 43!/). 1 H NMR (400Miz, CDCI,) 5 8.80 (bra, 11-), 8.11 (S, 1H), 7.88 7.83 (in, 4H ), 7.48-- 7.44 (*, -J--- 7.9 Hz, IH): 7.33 (s, IH.I 7.14 --7.10 (t, j= 8.7 Hiz, 2H), 3.52 -- 3.48 (m,. 2H), 3.04 -- 3.01 (m,. 2H). MS (E-SI) rnfr Calculated for Cu2l-l.

4

F

4 1N402S: 482.08; found: 483.0 (M+Hi)% 10 EXAMPLE 51 N-(2-(2-(4-ChiorophenyI)thiazoI4-yl)ethyd)-3-(5-(trifuioromethy)-1,24-oxadiazo-3 yI)benzamnide N______ X-N C S~ HATUNIMM N~- N

F

2 N DIVF, 0 CC-it, 3h '15 This compound was synthesized from 2..(2-(4-chloroph.enyl)thazo..4 y!)ethanarnine and 3-(5-(trifluoroinethyl-1,24-oxadiazol-3-yl)benzoc acid as desorlbed in example 6 step 6 (40 mg, yield 22%) 1 1- NMVR (400MHz, CDCIk) 6 8.53 (t, J = 1.5 Hz, IH), 8 27 -8.25 (dt, J =7 8 Hz, 1.3 Hz, 11-), 8.09 -8.07 (dt, i= 7.8 Hz, 1.4 Hz, I H). 7.89 - 7.87 (in, 2H), 7.68 (in. 1HL), 7.62 (t, J =7.8 Hz. ILI), 7.36 - 7.34 (in. 2H), 7.09 (s, 1IH). 20 3.92 - 3.87 (in, 2H), 3.16 (t, J = 6.0 Hz, 2H). MS (.3) m1/z Calculated for C.,H,.ClF 3

N

4 rO 2 S 478.05; found: 479.0 (M+H)+. EXAMPLE 52 N-((4-Phenylthiiazol-2-yh)methyl)benzamide EtCHA Hh ---------- Ph- H2reflux, 2h L. 250 123 WO 2011/088181 PCT/US20111021089 A mixture of N-(2-amino-2-thioxoethyi)benzamide (300 mg, 1.54 minl) and 2 bromoacetophenone (305 mg, 1.54 mmol) in EtOH (10 mL) was heated to 80 C for 2 h The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The concentrated reaction mixture was diluted with EtOAc and 5 the organic layer was washed with H 2 0 and brine, and concentrated under reduced pressure to yield N-((4-phenyithiazol-2-yi)methyl)benzamide (04 g, yield 88%) as a white solid, which was carried through without further purification. 'H NMR (400MHz, CDC3l) 6 8.69 (br s, 1 H), 8.04 - 8.01 (dd, J= 7.8 Hz, 1.5 Hz, 2H), 7.99 - 7.97 (n, 2H), 7.64 (s, 1 H), 7.56 - 7.52 (m, 4H), 7.48 - 7.44 (in, 2H), 5.34 (d, i 6 Hz, 2H). MS (ESI) m/z. 10 Calculated for Cl 7

HI

4

N

2 OS: 294.08; found. 295.0 (M+H)*. (4-Phenylthiazol-2-yl)methanamnine Ph S, HN-P' i) 6N HCI s NH 2 ) f--" O dioxane, reflux,24 NN i) work up with 10% NaHCO3 6N HCI (4.5 mL) was added to a solution of N-((4-phenyithiazo-2 15 y!)methyl)benzamide (150 mg, 0.51 mmol) in dioxane (10 mL) and the reaction mixture was stirred at 100 'C for 24 h (reaction monitored by TLC, eluant CHCis/MeOH). Reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The aqueous layer was washed twice with EtOAc. The pH of the aqueous layer was then adjusted to pH -9 using 10% NaHCO 3 and the organic product was extracted 20 with EtOAc. The organic layer was washed with brine and concentrated under reduced pressure to yield (4-pheny!thiazo!-2-yl)methanamine (75 mg, yield 77%) as orange colored liquid, which was carried through without further purification, 'H NMR (300MHz, CDC13) 5 7.91 - 7.88 (m, 2H), 7.45 - 7.40 (m, 3H), 7.36 - 7.31 (m, IH), 4.25 (br s. 2H), 3.79 - 3.75 (m, 1H), 3 68 - 3 63 (m. IH). MS (ESI) m/z: Calculated for C 10

H,

0 NS: 25 190.06; found: 191 2 (M+H)*. 124 WO 20111088181 PCTUS201 11021089 N-((4-Phe nylth iazol -2-yi) rnethyl)-3-(S-(trfluorom ethyl) -1 ,2,4-oxadiazol -3 yl)benzamnide -s NH~ --- N 0 ft HATLJ, NMM N N<* DMr,0 -- it 4h "" This compound was synthesized from (4-plhenylthiazol1-2-yi)mnethaneaM.lne and 3 5 (5-(trifliuorom-ietlhyl)-i ,2,4-ojxadiazojl-3-yl)benzoic acid as described in example 8 step 6 (60 mg? yield 38%) as a white solid. 'LH NMR (400MlHz, LCCh) 5 8.59 (in, 1H ' , 8,31 - 8.29 (dd, J = 7.8 Hz, 1 0 Hz, IH), 8.12 - 8.10 (mn, IH), 7.91 - 7.89 (m, 2H), 7.67 (t. J = 7 8 Hz, 1 H), 7.47 (55 1 H), 7.44 (t, J = 7.5 HLz, 2H), 7.38 - 7.34 (mn, 1 H)2 7.23 (t, J = 4.8 Hz, 1IH). 5.04 (d, J- 1.5 Hz, 2H). NIS (ESI) m'lz: Calculated for C 20 Hj 3

F

3

N

4 0 2 S: 430.07: found: 10 A 3 1. 0(M4 HY. EXAMPLE 53 M-(2 -(4 -(4-Fu o ro ph eny l)th iazo 1-2-V I)ethyl) -5 -(S-(trifl u oro m ethyl)4 -, 2,4oxad i zo 1 3 F P-N0 HATLJ, 'AR41 NN 0 G ',C-Crt, 4h This compound was synthesized from 2-(4-(4-fiuorophenyl)thiazci 2 yl'cthanam~rine and 5-(5-(trifluo roinethvl)-1, 2,4-oxadilazo1-3-yl )ni!coif!nic acid as described in example 8 step 6 (50 mg, yield 29%). 'H NPAR (400M 1-z, COO! 3 ) 69..45 (d, J = 1.3 Hz, 11H), 9.24 (0d, J =1.5 Hz, I H). 8.80 (t, = 2.1 Hz, 1 H), 7 88- 7.82 (in. 3H), 7.35 (s, 1 L), 7.11- 7.07 (in, 20 21-), 4.05 - 400 (q, j 5.7 Hz, 2H)j, 3.41 - 3.38 (mn, 2H), MS (ESI) rn1z: Calculated for

C

20 Hj, 3

F

4

N

5 0 2 S: 463.07: found- 464.0 (M.+H)r. 125 WO 20111088181 PCT/US201l11021089 EXAMPLE 64 2-(4-(4-C'hioropheniyl)thiiazol-2-yflethianamine -A O IIN A.lT~ 75 IC, 3:bj ~ ,ji This compound was synthesized from 2-(4-.14-cnlorophenyl)thiazoI-2-yl)acetontrie 5 as described in example 42 step 1 (400mg, ::rude)and it was carried through, without further purification. MS (ESI) rriz: Calculated for C, 1

H,,C!N

2 S: 238.03; found: 239.0 (+H) N-42-f4-(4-Chloropheny)thiazol2.y)ethy)--((trifluoromethy).1 ,2,4-.oxadiazol-3 10 yl)benzamide C1 0 -N C -( F 3 C-<, f J F 4 h--N SHATLI, NIMM N DIMF, 0 OCrt 4h This compound was synthesized from 2-(4-(4-chlorophlenvl~thiazo!-2 yi)ethanamine and 3-(5-(trifIuorornethyI)- 1,2,4-oxadiazol-3-yl)benzo'!c acid as described in exampleS step 6 (30 mg.yield 16%). 1 M 40~,Od)65 s H.82 d 15 J = 7.8 Hz, I H), 8.06 (d, J - 7.8 Hz, I iIh; 7.81 id, J 6.6 H-z. 2H), 7.64 -- 7.60 'in, 2H), 7.39 (s, IH), 7.34 (d, 8.6 Hz, 2H), 4.02 - 3.97 (q, J 5.8 Hz. 2H), 3.39 - 3.36 (t, J 5.9 Hz, 29H). NIS (ESI) rnl: Calculated for C 2 ,ilI14CIF 3

N

4 0 2 S: 476.05, found: 479.0 20 126 WO 2011/088181 PCT/US20111021089 EXAMPLE 55 N-(2-(4-(4-Chlorophenyl)thiazo-2-yl)ethyl)--(5-(trifljoromethyl)-1,2,4-oxadiazol-3 yl)nicotinamide Cl , Nl I:I N,, N-NNN H HATU, NMA F 3 N IN S DMF, 0 "C-rt, 4h N 5 This compound was synthesized from 2-(4 (4-chlorophenyl)thiazoi-2 yi)ethanarnine and 5-(5-(trifluoromethya)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (65 mg, yield 35%). 1 H NMR (400MHz, CDCi,) 6 9.46 (d. .J = 1.8 Hz, 1H), 9.24 (d, J = 1.8 Hz, IH), 8.80 (t J = 2.1 Hz, IH), 7.82 - 7.80 (m, 3H), 7.41 (s, 1H). 7.38- 7.36 (m, 2H), 4.05 -4.01 (q, J = 5.8 Hz, 2H), 3.43 - 3.40 (t, J = 5.9 Hz. 2H). MS 10 (ESI) m/z: Calculated for C 23 H1 3 CIFN5O 2 S: 479.04; found: 480.0 (M+H)7 EXAMPLE 56 4-(3.4-Dihydroisoquinolin-2(1k)-yl)tetrahydror-2H-pyran-4-carboritrile conc HCI NC N 1 + 1 + KCN N H H'20 15 34,5,6-Tetrahydro-4H-pyran-4-one (0.37 g, 3.75 mmoi) was added to a solution of 1,2,3,4-tetrahydroisoquinoline (0.47 rnL, 3.75 rnmol) in conc. HCI (0.4 mL) diluted with ice water (1.5 rnL), followed by a solution of KCN (0.24 g, 3.75 mmio) dissolved in water (2 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water and the organic product was extracted with EtOAc. 20 The organic layer was washed with H 2 0 and brine, dried over anhydrous Na 2

SO

4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica 60-120 mesh, eluent 6% EtOAc in petroleum ether) to afford 4 (3,4-dihydroisoquinolin-2(1H)-yl)tetrahydro-2H-pyran-4-carbonitrile (300 mg, yield 33%). IH NIR (300 MHz, CDCi,) F 7 19 - 7.11 (m, 3H), 7.07 - 7.05 (m, I H), 4.10 - 4 04 (dt, J = 25 12.3 Hz, 3.5 Hz, 2H), 3.87 (s, 2H), 3 76 - 3 68 (m, 2H), 2.97 - 2.91 (M, 4H), 2.28 - 2.23 (dd, J = 13.3 Hz, 1.4 Hz, 2H), 1.93 - 1.84 (td, J 12 4 Hz, 4.2 Hz, 2H). MS (ESI) nVz: Calculated for C1H1 8 N-0: 242.14; found: 243.2 (M+H). 127 WO 20111088181 PCTUS201 11021089 (4-(3,4-Dihyd~roisoqujinolin.2(1 14-yl)tetrahydro.-21ipyrani-4.yI)mnethanarnine NC N LLI 4 H-, K.]TH F,0 >C-rt. I h 0 This cornpound was synthesized from 4 -(3,4-.dihydroisoquinolri-2(1 KH) yi)te trahyd ro -2H-pyra..4 -car bonitri le as described in example 1 step 3 (80 ung, yield 5 26%). 'F NMR (300 MI-z, CD01 3 ) 6 7.15 -- 7.12 (mn, 3iH). 7.06 .-- 7.03 (m,. IHF), 3.90 (s: 21H), 3.87 .- 3.84 (in, 2H), 3.65 -- 3.58 (ddd: j = 11.3 Hiz. 8.1 H~z, 3.2 Hz' 2H): 2.94 --. 2.85 (in, 6H), 1.99 -- 1.91 (m,. 21-1), 1.65 -- 1.62 (m, 2H1). IMS (ES!) m/'z: Calculated for Ci 5

H

22

N

2 0. 246.17: found: 247.2 (M+Hr' 10 N-((4-(3,4-Dnihydroisoquinolin-2(1I-M-yl)tetrahydro-21-pyran-4-yh)methyl)-3-(5 (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide N G02H 0 ~ DMF. 0 *C-rt, 4h This compound was synthesized from (4-(3.4-dihydroisoquino'in;-21 H) yi!)tetrahydro-.2H.-.pyrarn-4-.yI)methlanamine and 3-(5-(trifluorornekhyl)- 1:2,4-oxadiazol-3 15 yl)benzoic acid as described in example 8 step 6 (40 mo, yield 30%). IH NMR (400 MHz,

CDCI

3 ) 6 8.45 (s, 1 H), 8.22 (d, J -- 7.8 Hz, 1 H), 7.91 J7.89 (d; i =7.5 Ilz, 11H); 7.59 --7.55 ,t, j -.7.8 Hz, 1H1); 7.17-- 7.15 (in. 3H), 7.12 -- 7.07 (mn, 2H): 3.96 - 3.93 (mn, 4H), 3.86 - 3.65 (d, J = 4.8 Hz, 21-), 3.74 --. 3.68 (in, 2H), 2.951 (in, 4H), 2.15-- 2.07 t!in , 2H), 1.56 1.55 (in. 2H), MS (ESI).rn/z: Calculate-d for 0N 2 2F 3 N. rd 487.2 (PM±H)>. 20 EXAMPLE 87 M-Methyl-'I -(4-(4-phenylthiazoh-2-yI)tetrahydro-2H-pyran.4-yh)methenarnine HOHIO (35% aqueous solution: HN' N- --------------------------- eH N2BH(OAc)3, DCE 0 'C, 1 h K )I 128 WO 2011/088181 PCT/US20111021089 (4-(4-phenylthiazol-2-yi)tetrahydro-2H-pyran-4-yl)methanamine (300 mg, 1.1 mmol) was dissolved in 1,2-dichloroethane (30 mL) and cooled to 0 IC. Formaline solution (--0.1 mL, 35%) was added to the solution, followed by sodiumtriacetoxy borohydride (0,16g, 0.76 mmol). The reaction mixture was further stirred for 45 min maintaining the 5 same temperature. The reaction mixture was then quenched with 10% NaHCO 3 solution and diluted with CH 2 Cl 2 . The organic layer was separated, dried over anhydrous Na 2

SO

4 , and concentrated under reduced pressure. The residue was purified by column chromatography (silica 60-120 mesh, eluent 10-20% MeOH in CHC) to afford N-methyl 1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (120 mg, yield 38%). 'H 10 NMR (300 MHz, CDCi 3 ) 6 790 - 7.88 (n, 2H), 7.48 (s, 1H), 7.44 - 7.34 (m, 3H), 3.93 3.86 (n. 2H), 3.75 - 3.67 (ddd, = 12.0 Hz, 8.9 Hz, 3.0 Hz, 2H), 3.01 (s, 2H), 2.49 (s, 3H), 2.36- 2.39 (m, 2H), 2.09 - 2.01 (in, 2H). MS (ESI) n/z: Calculated for C.

1 H2aN 2 OS: 288.13; found: 289.2 (M-H)*. 15 N-Methyl-N-((4-(4-phenylthiazol-2-.y)tetrahydro-2H-pyran-4-yi)methyl)-3-(5 (trifluoromethyl)-1,2,4-oxadiazol-3-y)benzamide N O NC 'OH < F0 ' ' HATU, NMMI11 DMVF, 0 IC-rt, 4h ' This Compound was synthesized from N-methyl-1-(4-(4-phenylthiazoi-2 yi)tetrahydro-2H-pyran!-4-yl)metha~nmine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazo'-3 20 y!)benzoic acid as described in example 8 step 6 (30 mng, yield 14%). 1H NMIR (400 MHz, CDr-i,) 5 8.13 - 8.09 (m, 21H), 71.96 - 7.94 (m, 2H), 7.57 -- 7.55 (m, 21H), 7.48 -- 7.41 (m, 31H), 7.36 -- 7.32 (m, 11H), 3.99 - 3.96 (m, 2H), 3.92 (s, 2H1), 3.66 - 3.60 (m, 2H), 2.53 (6, 3H-), 2.48-- 2.44 (m, 2H), 2.23 -- 2.16 (m, 2H). MS (E-S;) mr/z: Calculated for C26tH23-F3N40-3S: 528.14; found: 529.2(MH. 25 129 WO 20111088181 PCTUS201 11021089 EXAMPLE 68 2-(2-(4-Flljoropheny)thiazol-4-yi)ethaniamine SH~lMe 2 S N TH. 75 "G. 30minHm 11his compound was syntheszed from 2-(2-(4-Iiuorophenyl)thiazol-4-yl"-acetonitrie. 5 as described in example 42 step 1 (150 mg, crude)and it was carried through without further purification. MS (ESI) i'.,: Calculated 'or C1,H,1FN S: 222.06: found 223.0 (M+ H Y. jV( ( ( FIuor heFi ~hiao1-- ~ty)- (-tif fiehl -, 2,4-oxad iazo 1 3 10 yI)nicofinsrnide I FC--X\ " ) 0 i INN D MF, 0 0 C-,t, 3hH This compound was synthesized from 2-(2-(4-fiuoro~phenyl)thiazcl-.4-yl)ethianramine arid 5-.(5-(triflucrorrnethy)-1, 2,4-oxadiazol-3-.yhn)icotnic acid as described in example 8 step 6 (30, mg, yield 17%). 1 1H NIVR (400MHz, DMSO-d6) 6 9.45 (br s, IH-), 9.26 (br s, 15 11-H), 8.82 (t, = 2.0 Hz, 1H), 7.96-7.92 (ri, 3H), 7.14- 7.08 (in, 3H), 3.94- 3.69 (mn, 2H), -3.19 - 3.16 (in, 21-). MS (ES1) rr~z. Calculated for C 2

H

3 1

~

2 :463.07: found. 464.0 EXAMPLE 59 20 N-(2-(2-(4-Fluorophenyl)thiazohA4-yI)ethyl)-3-(6-(trifluoromethyl)-1 ,2,4-oxadiazol-3 yl)benzarnide 0 -W 0 j D IM-F,00 C- n, 3h

H~

130 WO 2011/088181 PCT/US20111021089 This compound was synthesized from 2-(2-(4-fluorophenyl)thiazol-4-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiiazol-3-yl)benzic acid as described in example 8 step 6 (60 mg, yield 45%). H NMR (400MHz, CDCi 3 ) 6 8.53 (t, J = 1.4 Hz, 1H), 8.27 8.24 (dt, J = 7.9 Hz, 1.3 Hz, 1H), 8.09 - 8.06 (dt, .J = 7.6 Hz, 1.6 Hz, 1H), 7.94 - 7.90 (m, 5 2H), 7.70 (m, IH), 7.63 - 7.59 (t, J = 7.8 Hz, 1H), 7.09 - 7.05 (m, 3H), 3.91 - 3.86 (M,. 2H), 3.16 -3.13 (t, J =6.0 Hz, 2H). MS (ESI) m/z: Calculated for C ,H, 4 F4N40 2 S: 462 08; found: 463.0 (M+H). EXAMPLE 60 10 N-(2-(4-(4-Fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4 oxadiazol-3-yl)nicatinamide F C N

(F

3 C -CO2H \7 N IN 0-'N O F C H i -S- HATL, NMM N N > ' DMF, *C-rt, 4 h This compound was synthesized from 2-(4-(4-fluorophenyl)thiazo-2-y)-2 methylpropan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as 15 described in example 8 step 6 (55 mg, yield 42%). 'H NMR (400MHz, CDC1l) 5 9.45 (5, 1H), 9.24 (a, 1H), 8.79 (m, 1H). 8.25 (n, 11-), 7.85 -- 7.81 (dd, J = 8.6 Hz, 5.4 Hz, 21-) 7.37 (s, 1H), 7.10 -- 7.06 (t, J = 8.6 Hz, 2H), 3.84 (d, J = 5.6 -z, 2H), 1.57 (s, 6H). MS (ESI) m/z: Calculated for C 22 1-H 7

IF

4

N

5 0S. 491.10; found: 492.0 (M+H)*. 20 EXAMPLE 61 3-(2,2,2-Trifluoro-1-(((4-(4-phenylthiazol-2-yI)tetrahydro-2H-pyran-4 yl)niethyl)imino)ethyl)benzonitrile CF3NMCF 3 N3 NC H2N TICl 4 (ca NC Et<N, CH2Cl2 cri 0 *C-r, Sh 25 Triethylamine (1.0 mL, 2.7 nmol) was added to a solution of 3-cyano-2 2,2 trifluoroacetophenone (0.48 g, 2.4 mmol) and (4-(4.-phenylthiazol-2-yl)tetrahydro-.2H pyran-4--yi)methanamine (0.66 g, 2.4 mmol) in dry CH2Cl 2 (25 mL), followed by a solution 131 WO 2011/088181 PCT/US20111021089 of titanium tetrachloride in CH 2 C2 (1.2 mL, 1.2 rmol, I M solution in CH 2 Cl2) at 0 *C and the reaction mixture was warmed to room temperature and further stirred for 8 h. The reaction was concentrated under reduced pressure and the organic product was extracted with EtOAc. The organic layer was washed with water and brine solution, dried over 5 anhydrous sodium sulfate and the solvent was removed under reduced pressure to get 3 (2,2,2-trifluoro-1-(((4-(4-phenylthiazoi-2-yl)tetrahydro-2H-pyran-4 yi)methyl)imino)ethyi)benzonitrile (0.6 g, crude), which was carried through without further purification. 1 H NMR (400MHz, CDCl 3 ) 6 7.88 - 7.85 (rn, 2H), 7.70 - 7.67 (rn, iH), 7.50 (s, IH), 7.46 - 7.41 (m, 3H). 7.39 - 7.36 (n, .1H), 7.23 (s, IH), 7.07 (d, J = 8.0 Hz, 1H), 10 3.93 - 3.88 (dt, i = 11.9 Hz, 4.0 Hz, 2H), 3.66 - 3.62 (m, 4H), 2.43 - 2.40 (m, 2H), 2.15 2.00 (ddd, J = 141 Hz, 10.3 Hz, 4.3 Hz, 2H). MS (ESI) m/z Calculated for

C

24 HcF 3

N

3 0: 455.13; found: 456.2 (M+H). 3-(2,2,2-Trifluoro-1-(((4-(4-phenylthiazol-2-yi)tetrahydro-2H-pyran-4 15 yl)rmethyl)amino)ethyl)benzonitrile CF3 NeBH\ CF N NCC NaBSH4 N IN - ,,-----------------Nx' MeOH -120 8:2 v/v H 0 0 C-r, 2h 3-(2,2,2-trifluoro-1-(((4- (4-phenylthiazol-2-yi)tetrahydro-2H-pyran -4 yl)methyl)irmino)ethyl)benzonitrile (600 mg, 1.3 mmol) was dissolved in MeOH-H 2 0 (20 mL, 8.2 v/v) and cooled to 0 "C. Sodium borohydride (250 ig, 6.6 imol) was added to 20 this solution portionwise. The reaction mixture was allowed to warm uo to room temperature, stirred for 2 h, and then quenched with water and concentrated under reduced pressure to remove the MAeOH. The aqueous mixture was diluted with EtOAc and the organic layer was washed with H-1 2 O and brine, dried over anhydrous sodium sulfate and concentrate under reduced pressure. The crude product was purified by column 25 chromatography (silica gel 60-120 mesh, eluant 15-20% EtOAc in petroleum ether) to afford 3-(2,2,2-trifluoro- 1 -(((4-(4-phenylthiazol-2-yltetrahydro-2H-pyran-4 yi)methyl)anino)ethyi)benzonitrile (300 mg, yield 50%). 'H NMR (300MHz, CDCIs) 6 7.89 - 7.86 (m, 2H), 7.63 - 7,60 (dt, J = 7.6 Hz, 1.4 Hz, 1H), 7.55 - 7.51 (m, 2H), 7.50 (s, 1H), 7.47 - 7.41 (m, 3H), 7.39 - 7.36 (m, .1 H), 4.16 - 4.03 (m, 1 H), 3.84 - 3.74 (m, 2H) 3.71 30 3.61 (m, 2H), 2.95 (d, J = 11.4 Hz, 1H), 2.76 (d, J = 11.4 Hz, IH), 2.36 - 2.24 (in, 2H), 132 WO 20111088181 PCTUS201 11021089 2.01 - 1.M (ddd. of 13.5 Hz, 9.0 Hz, 4.1 Piz, 2H) MS (1=81) rnlc: Calculated for

C

2 4H7 2

F

3

N

3 CS': 457 14; found: 458.2 (M-FH N'-Hydroxy-3-(2,2,2-trifluoro-I -(((4-(4-phenylthiazol-2-yI)tetrahydro-2H-pyran-4 5 yI)rnethyl)arntino)ethyI)benzimidarnide CF~ N--\ ) iM- 2 0H.H(' , Na.O 3 N (F N, H 8-hy rox 'unoThe (catr.) HN y ~ N 2 -D H, ref.ljx, 4h H> This compound was synthesized from 3-(2,2,2-trifluo ,ro-1-(((4-(4-pnerythiazo-2 yi)tetrahydro-2i-f-pyranl-4-yI)methlyll~am-'io)ethyl)benizonitrl& acid as described ir example 10 1 step 4 (300 mg, crude), which was carried through without further purficatior. MS (ESI) rn/c Calculated for C, 4

H

25

F

3

HI

4 0 2 S: 490.17. found: 491.2 1,N44H)'. 2,2.2-Trifluoro-N-((4-.(4-phernylthiazoI-.2.-y)tetrahydro-2I1-pyran.4-y)methy)- -. (3-(8.

(trifluoromethyl)-1,2,4-oxadiazoI-3.-yI)pheriyl)ethianarniine HOH This compound was synthesized from NI'h ydroxy-3-(2,2,2-trifljocro- 1 -((4-(4 p her.ylthiazol -2-yl)tetra3hyd ro-2H-pyran.-4-yl)methyl)am noehl)enzmida3mid acid as described in example 1 ste p 5 (TOmg, yield 20%), 'H NMR (400 Ml-z DMSO d 6 ) 68. 11 - 809 (dt, Jz= 7.2 Hz, 1. 7 Hz, I H), 8.05 (s, IH), 7.85 - 783 (m, 2H, T53 -749 (m, 2H), 20 7.7 (s, 1lH), 7.42 - 7.38 (m,. 2H), 7.35 -7.31 (in, IH), 4 15 4.10 (q, J = 7. Hz 1H), 3.81 - 3.74 (in, 2H), 3.70 -3.62 (mn, 2H), 2.99 -2.96 (m I1H ) 2.86 -283 (m, I .) 2.33 2.27 (mn, 21H), 2.04 - 1.93 (ddd. 3 = 13.4 Hz. 9.0 Hz, 4.0 Hz, 21H). MS (ES1) rn/z: Calculated for C, 26

F

22 F6N 4 0 2 S: 568.14; found: 569.2 (M+H) 25 133 WO 2011/088181 PCT/US20111021089 EXAMPLE 62 Methyl 4-fluorobenzimidate hydrochloride NH NHCI (g) F nMeCH-CH2Cl 2 F A-' . HCI Dry HCI (g) was bubbled through a solution of 4-fluorobenzonitrile (5.0 g, 0.041 5 mol) in dry MeOH-CH 2 CIt (20 mL, 1 1 v/v) until saturation. The clear solution was kept at 0 *C for 2 days to crystallize methyl 4-fluorobenzimidate as hydrochloride salt, which was isolated by filtration (2.8 g, yield 36%). 'H NMR (400 MHz, DMSO-ds) 5 7.95 - 7.92 (m,. 2H), 7.38 (br s, 1H), 7.29 - 7.25 (m, 2H), 3.06 (s, 3H). MS (ESI) m/z: Calculated for C HFNO: 153.06; found: 154.2 (M+H) 10 2-(3-(4-Fluorophenyl)-1H-1,2,4-triazol-5-yl)acetonitrile F NH i) aqueous NaOH ----------------------- - N d FHCi H NC -NN H l ) . N,, . * H2N' C MeOl-, reflux. 1h 2-Cyancacetohydrazide (172 mg, 1.74 mmol) and NaOH (66 mg, 1.66 mnol) were added to a solution of methyl 4-fluorobenzimidate hydrochloride (300 mg, 1.58 15 minrol) in dry MeOH (5 mL) and the mixture was heated to reflux for 1 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 20-25% EtOAc in 20 petroleum ether) to yield 2-(3-(4-fluoropheny)-1H-1,2,4-triazcl-5-yl)acetonitrile (150 mg, yield 47%). 'H NMR (400 MHz, DMSO-d,) 5 8,04 -- 7.99 (n, 2H), 7.39 -- 7.33 (m, 2H), 4.11 (s, 2H). MS (ESI) m/z: Calculated for ClOH 7

FN

4 : 202.07; found: 203.2 (M+H)-' 134 WO 2011/088181 PCT/US2011/021089 2-(3-(4-Fluorophenyl)-1 H-1,2,4-triazol-S-yl)ethananine F F N BM EIn.Me2S N H THF, reflux, lh HIN H This compound was synthesized from 2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5 yl)acetonitrile as described in example 42 step 1 (40 mg, crude)and it was carried through 5 without further purification MS (ESI) m/z: Calculated for CjGH 11 FN4: 206.10; found: 207 2 (M+H). N-(2-(3-(4-Fluorophenyl)-1H-1.2,4-triazol-6-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4 oxadiazol-3-yl)benzamide

.\F

3 C- -N C /0N OH NN N O~ > H N ' N . N -- __________________----F----N-N ' N'N H HATU, NMM H H 10 DN1, 0 "-I 4h This compound was synthesized from 2-(3-(4-fluorophenyl)-IH-1,24-triazol-5 yi)ethanamine and 3-.(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (11 mg, yield 13%). 1 H NMR (400MHz, CDCi 3 ) 6 8.52 (s, 1H), 8.26 8.24 (d, J = 7.8 Hz, 1H), 8.07 -- 8.03 (m, 3H), 7.67 -- 7.59 (rn, 2H), 7.13 -- 7.09 (t, J = 8.7 15 Hz, 2H), 4,01 -- 3,96 (q, J = 5.9 Hz, 2H), 3,24 -- 3.21 (d, J = 6.1 Hz, 2H). MS (ESI) m/z: Calculated for C 2

PH

4 1F 4

N

6 O2: 446.11; found: 447.2 (M+H) EXAMPLE 63 Methyl 4-chlorobenzimidate hydrochloride NH CN HCI (g) 20 Cl MeOH r. - . HCI This compound was synthesized from 4-chlorobenzonitrile as described in example 62 step 1 (3.5 g, 47%). IH NMR (400 MHz, DMSO-d6) 6 7.95 - 7 92 (m, 2H), 7.38 (br s, 1H), 7.29 - 7.25 (m, 2H), 3.06 (s, 3H). MS (ESI) m/z: Calculated for C8HECINO: 169.02; found: 170 0 (M+H) 25 135 WO 2011/088181 PCT/US20111021089 2-(3-(4-Chlorophenyl)-1 H-1,2,4-triazol-6-yl)acetonitrile CI NH i) aqueous NaOH CI* HCI ii) NC,. ".N

H

2 N' CN H 0 MeOH, reflux, 3h1 This compound was synthesized from methyl 4-chlorobenzimidate hydrochloride as described in example 62 step 2 (200 mg, yield 38%). 'H NMR (300 MHz, CDCli) 6 5 7.87 - 7.84 (in, 1 H), 7.63 - 7.60 (m, I H). 7.51 - 7.47 (m, 2H), 3.96 (s, 2H). MS (ESI) m/z. Calculated for C 1

H

7 CIN4: 218.04; found: 219.0 (M+H) 2-(3-(4-Chlorophenyl)-1H-1,2,4-triazol-5-y)ethanamine C1 Cl N-' BH>. Me2 N N N N. N H THF, reflux, 1h H 10 This compound was synthesized from 2-(3-(4-chlorophenyl)-1H-1,2,4-triazoi-5 yl)acetonitrile as described in example 42 step 1 (90 mg, crude) and it was carried through without further purification. MS (ESI) m?/z: Calculated for C 10

H

1 ,CiN 4 : 222.07 found: 223.2 (M+H)*. oxadiazol-3-yl)benzamide C1) N OH .0--N 0 H N N T NF 3 C N N 2 L HATU, NMM H H DMF, 0 oC-rt, 4h This compound was synthesized from 2-(3-(4-chlorophenyl)-1H-1 2.4-triazoi-5 yl)ethanamine and 3-.(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in 20 example 8 step 6 (15 ng, yield 13%). 1 H NMR (400MHz, CDCi3) 6 8.53 (s, 1H), 8.28 8.26 (d, J= 7.8 Hz, I1H), 8.09 -- 8.06 (m, 1 H), 8.02 .- 8.00 (d, J = 8.5 Hz, 2H), 7.65 - 7.61 136 WO 2011/088181 PCT/US20111021089 (tJ7HzH),756-753 (m, 1H), 7 42 - 7.40 (d, j= 8.5 Hz, 2H), 4 03 -3.6 (qJ = 6.0 Hz, 2H), 325 - 3.22 (d, J = 6.0 Hz. 2H). MS (ESI) m/z: Calculated for

C

2 oH, 4

CIF

3

N

6

O

2 : 462.08; found: 463.0 (M+H) , 5 EXAMPLE 64 Methyl 2-cyano-2-methylpropanoate -Mel, NaH CN CN S DM.F-THF (7:1 v/v) o O*C-rt, 12h NaH (15.5 g, 60% dispersion in oil) was added pottionwise over 10 min to the solution of ethyl cyanoacetate (20 g, 0.177 mol) in dry DMF (300 rnL) at 0 'C. The 10 resulting reaction mixture was stirred at room temperature for 30 min and cooled again to 0 'C. Methyl iodide (28 mnL, 0.44 mol) in THF (50 mL) was added dropwise and the reaction mixture was stirred at room temperature for 12 h, and then quenched with saturated NH 4 CI solution. The mixture was then diluted with EtOAc; the organic layer was washed with H 2 0 and brine, dried over anhydrous Na 2 SO, and concentrated under 15 reduced pressure to afford crude product that was purified by column chromatography (silica gel 60-120 mesh, eluent 5% EtOAc in petroleum ether) to afford methyl 2-cyano-2 methylpropanoate (12 g, yield 48%) as a pale yellow solid. 2-Cyano-2-methylpropanehydrazide

N

2

H

4 .H20 (99%) H N-------------------- H 2 N' CN 20 0 EtOH, t, Ih O Hydrazine hydrate (1.8 mL, 35 mmol) was added to a solution of methyl 2-cyano 2-methylpropanoate (5.0 g, 35.0 mmol) in EtOH (5 mL), and the reaction mixture was stirred at room temperature for 1 h (monitored by TLC, eluant petroleum ether:EtOAc 7:3 vWv). The reaction mixture was diluted with dietnyl ether and the precipitate formed was 25 filtered. The clear filtrate was concentrated under reduced pressure to get 2-cyano-2 methylpropanehydrazide (1.75 g, yield 38%), which was carried through without further purification. MS (ESI) m/z: Calculated for CsHqN 3 0O 127.07; found: 128.2 (M+H)*. 137 WO 2011/088181 PCT/US20111021089 2-Methyl-2-(3-phenyl-1 H-1,2,4-triazol-5-yl)propanenitrile NH S + H2N ( ~CN jMerreu t NC~ N -- . HCI C) i eH rfu,1 2-Cyano-2-methyipropanehydrazde (100 mg, 0.78 mmo) and Et 3 N (0.1 mL, 0.86 mmol) were added to a solution of methyl benzmidate hydrochloride (100 mg, 0.58 mmol) 5 in dry MleOH (10 mL), and the mixture was heated to reflux for 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product was purified by column chromatography (silica 60-120 mesh, eluant 15% EtOAc in petroleum ether) to get 2-methyl-2-(3-phenyi-1H-1,2,4-triazoi-5-yl)propanenitrle (80 mg, yield 51%). IH NMR (300 MHz, MeOD) 5 7.98 - 7,95 (n, 2H), 7,52 - 7.50 (in. 3H), 1.82 (s, 6H). MS (ESI) 7/z 10 Calculated for C1 2 H1 2

N

4 212.11; found. 213.2 (M+-1)'. 2-Methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yI)propan-1-amine N DIAL (IM in TFI N lN THF, 0 "C-rt, 2h H 2 N N DIBAL-H (0.75 mL., 0.75 mmoi, IM in THF) was added to a solution of 2-methyl-2 15 (3-phenyl-1H-1,2,4-triazoi-5-yl)propanenitrile (80 ng, 0.37 minmol) in dry THF (5 mL) at 0 IC. The reaction mixture was allowed to warm up to room temperature and further stirred for 2 h. The reaction mixture was then quenched carefully with water and diluted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-methyl-2-(3-phenyl-iH-1,2,4-triazol-5-yl)propan-1 20 amine (70 mg, crude), which was carried through without further purification. MS (ESI) n/z: Calculated for C, 2 HjNs. 216.14; found: 217.2 (M+H4) N-(2-Methyl-2-(3-phenyl-1H-1, 2,4-triazol-5-yl)propy)-3-(5-(trifluoromethyl)-1 ,2,4 oxadiazol-3-yI)benzamide O-N 17-\ FC--' 'i -IC2 'N C' N j ,N--------------+ N N H-12N' NHATU, NMMH H 25 DMF, 0 "C-rt, 6h 138 WO 20111088181 PCT/US201l11021089 This compound was synthesged frm2-m-ethylk2-(3-phenvi-l H-I .2,4-triazoi-5 yl~propan-l-amine and 3-(5-(triflujoror)nethy0)-1,2,4-oxacdiazo-3-vI)benzoic acid as described in example 8 step 6 (35 ing, yield 251,1.. 'H NMR (400MHz, MeOD) 5 8&55 (s5 H), 8,29 - 8.27 (d, J = 7.8 Hz, 1 H), 8.06 -7.97 (m, 3H), 7,71 - 7.67 (t, .J=8.7 Hz,1) 5 7.50 - 7.41 (i, 1,H), 3.75 (s, 2H), 1.54 - 1,51 (in. 6H), NIS (ESI) ,7/z: Calculated for

G

2 HjF 3 1N60; 456.15: fOUnd: 457.2 (M+H)., EXAMPLE 65 10 oxadiazol-3-yI)nicotinamide ON 0~~kh I, r P--N 0 ,

'

2 1N JrN N__ _ _ FC-~ ' jJ N ! 1-1 HAT U, N4M1 H DM;, ') IC-rt. 5~h This coipound was synthesized from 2-inethyl-2-(3-phenlvi-IH-1.2,4-trazo-5 yi)propan-1 arnilne and5(-tiloonty)1,4oaizl3y~ioii acid as descrlibedl in exarnple 8 ste 'p 68(20 mg, yield 23%). 1 H NMR (40OMHz, MeOD) 8 9.37 (m,. 15 1 H), 9.16 I'n IH), 8.84 -8.13 (in, IH): 8.02 - 7.99 (in. 2H), 7.48 - 7.42, (in, 3H), 3.77 (s, 1,H), 1.54 (in 6H). MS (ESi, rn/z: Calculated for C 2 1

H

1

F

3

N

7 0 2 . 457.15; found:. 458.2 WM i-) 139 WO 20111088181 PCTUS201 11021089 EXAMPLE 6 2.(3-(4-FIijorophenyl)-1 A1l ,4-riazo-5-y)-2-methylpropanenitrie NH HN N- >JC 0E~ H2 ' 'N ------------- -- IN N 0 i. MeOI1-1, reflux, 1lh CK This comoound was svinthesized from 2 -cyano-2-methylpropanehlydreazide and 5 methyl 4-filuorobenzimidate hydrochloride as described in example 64 step 3 (300 Ing5 yied 70%). 'H WAR (300 MHz MeOD) 5 8.03 - 71.98 (in, 2H), 7.29 - 7.23 (in, 2H), 1. 81 (5. 6H). PAS (ESI) m/z: Calculated for C 12

H

11 FNa: 230.10; found: 231.2 (M+Hy>. 2-(3.4(4-Fluorophieny))1 H-I 2.4-4riazo-8-yI)-2-rniethylpropan-1 -amirne 77 DIi3AL(1MVin THF) NC Ni~ N ----- 10 HF, 0 0 0qt,2h N- , 'This compound was syntliesized from 2-(3..(4-fluoroph.eny!)-IH..1,2,4-triazol-5-y) 2-methylpropanienitrile as described in example 64 step 4 (200 mg, crude)and it was carried through without further purification. MS (ESI) miz Calculated for C- 2 Hj 5

FN

4 : 234.13; found: 235.2 (M-tH)*. N-(2-(3-(4-Fluorophenyl)-l H-I ,2,4-triasol-8-yI)-2-r-nethylpropyl)-3-(5-(trifluoromethyl) I 2,4-oxadiazol-3-yl)be-nzamnide IF P-N -- -- IN N -F, -N yl C HN" HATL]NMIM N' N IN, DMF, 0 "GC-rt, 5h This compound was synthesized From 2-(3..(4-fluorophieny!)- 1 Hi ,2,4-triazol-5-yl) 20 2-mrethylpropan.1 -am.inle and 3 -(5- (tri Flu oromethyl)- 1 ,2,4- oxad iazol- 3 -yl)berlzoic acid as described in example 8 step 6 (12 ing, yield 7%). 'FA NMVR (400MV.I-z, IMeOD) 6 8.54 (a, 11-H), 8.29 -- 8.27 (d: J =7.8 Hz, 1 H)l, 8.05 .- 8.03 (nn, 3H), 7.71 -- 7.67 (t, J 7.8 ilz, 1i-1). 140 WO 20111088181 PCT/US201l11021089 7.27 - 7 13 (in, 2H), 3.74 (s, 2H), 1.53 - 1,50 (rn2 6H), MS (ES"i r/ Calculated for

C

22 HLj,F 4

N(

2 : 474.14: found: 475 2 (M+H. EXAMPLE 67 5 N-(2-(3-(4-Fiuoroplhenyl)-1 H-I 2,4-triazol-&-yi)-2-methylpropyfl-6-(5-(trifiuoromethyl) 1,2,4-oxadiazoi-3-yi)nicotinaniide F P-N 0 N O ~H 'N j PN 0 N" N. -3~KN1 -\' 17-1N- ,L " N DMF, S 'C-rt, 6h Nf This compound was synthesized from 2-(3-(4-fluoropheny)-1 H-I 2'1-triazol-5-y), 2-methylpropari-I-amine and 5-(5-(trifluoroinethyl)-1 2,4-oxadiazo-3-vl)ni;cotirlic acid as 10 described in example 8 step 6 (20 mng, yield 11%). 'H NMNR (400MHz, MeCD) 5 9.38 9.37 (d: J = 1.5 Hz, I H), 9.15 (d, i 1.5 Hz. I1H), 8.82 (in, IH), 8.06 -8.02 (mn, 2H), 7.21 - 7.17 (t: J = 8.5 Hz, 21-), 3.76 (s, 2H), 1.53 (s, 6H). MS (ESI) rn/.z: Calculated for

C

21

,H

17

F

4

N

7 02i 475.14; found. 476.2 (M+l-4i -. 15 EXAMPLE 68 2-(3-(4.-Chlorophenyl)-1H-1 ,2,4-triazoI.-5-y).2-nmethypropanenitrile C1 NH H \ )EbN 0C H 2 ' ) M CH, reflux, ii- NC, ' This compound was synthesized from 2-cyan~o-2-rnethylprcpanehydrezide- and methyl 4-c hlo robenzi m;date hydrochloride aS described in example 564 step 3 (220 ing, 20 yield 55%). 'H NMVR (400 MHz, CDC13) 6 7.93 -7.91 (mn, 2H), 7,47 -7.45 (in. 2H), 1.86 (s, 6H). NIS (E SI!) nilz- Calcu lated for C, 2 H11CItk,: 246.07: found- 245.2 (M-H) 141 WO 2011/088181 PCT/US2011/021089 2-(3-(4-Chlorophenyl)-1I-1,2,4-triazol-6-yl)-2-methylpropan-1 -amine CI N- DIBAL (1M in THF)PN NC," ,! N U N H THF, 0 *C- 2h H This compound was synthesized from 2-(3-(4-chloropheny!)-1H-1,2,4-triazol-5-yl) 2-methylpropanenitrile as described in example 64 step 4 (140 mg, crude)and it was 5 carried through without further purification. MS (ESI) m/z. Calculated for CH 5

CIN

4 : 250.10; found: 251.2 (M+H)*. NV-(2-(3-(4-Chlorophenyl)-1H-1,2,4-triazol-5-yl)-2-methyipropyl)-3-(5-(trifluoromethyl) 1,2,4-oxadiazol-3-yl)benzamide O N lQl I., Cl)2

F

3 C% - 2

CO

2 H / O-N 0 N 1 'N N N N N HN -ATU, NMM H H 10 DMF, 0 C-rt. 6h This compound was synthesized from 2-(3-(4-chlorophenvi)-1H-1,2,4-tiazol-5-yl) 2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (15 mg, yield 8%). 'H NMAR (400MHz, CDCl 3 ) 6 8.59 (s, 1H), 8.30 - 8.28 (d, J = 8.0 Hz, 1H), 8.14 - 8.12 (n, IH), 8.06 - 8.04 (d, J = 8.3 Hz, 2H), 15 7.93 (br s, 1H), 7.67 - 7.63 (t, J = 7.7 Hz, 1H), 7.43 - 7.41 (d. J = 8.5 Hz, 2H), 3.83 - 3.82 (in, 2H), 1.56 (s, 6H). MS (ESI) r/z: Calculated for C1-IrqCIF 3 NrO2: 490.11: found: 491.2 (M+-H). EXAMPLE 69 20 Ethyl 5-cyano-6-methylnicotinate NC CO 2 Et Zn powder, NH 4 CI NC, CO 2 Et rt, 3h Ammonium chloride (3.58 g, 66.7 mmo in 10 mL water) was added to a solution of ethyl 2-chlorC-5-cyano-6-methylnicotinate (1.0 g, 4.4 mmol) in dioxane-THF-DMF (50 mL, 3:11), followed by zinc powder (2.3 g, 35.6 mmol) portionwise at room temperature. The 142 WO 2011/088181 PCT/US20111021089 reaction mixture was allowed to stir at room temperature for 3 h, diluted with EtOAc, and filtered through a pad of Celite. The clear filtrate of organic layer was washed with HO and brine, dried over anhydrous Na 2 SO. and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 10 5 15% EtOAc in petroleum ether) to afford ethyl 5-cyano-6-methylnicotinate (230 mg, yield 27%) as a white solid. 'H NMR (400 MHz. CDCla) 6 9.25 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.0 Hz, IH), 7.27 (s, 1H), 4.47 - 4.42 (q, J = 7.2 Hz, 2H), 2.86 (s, 3H), 1.45- 1.41 (t, J = 7.0 Hz, 3H). MS (ESI) n/z: Calculated for C.

1

HI

0

N

2

O

2 : 190.07; found: 191.2 (M+H)*. 10 5-Cyano-6-methyinicotinic acid NCI CO.,Et LiOH.H 2 0 NC CO 2 H

-------------

- N THF-H 2 0 7:3 vv N 0 'C-rt, ' This compound was synthesized from ethyl 5-cyano-6-methylnicotinate as described in example 43 step 2 (150 mg, yield 76%) as a white solid. 'H NMR (300 MHz, DMSO-d ) 6 13.77 (br s, 1H), 9.13 - 9.12 (d, J = 2.0 Hz, 1H). 8.61 - 8.60 (d, J = 2.0 Hz, 15 1 H), 2.74 (s, 3H). MS (ESI) m/z: Calculated for C 8

HON

2 02: 162.04, found: 161.2 (M+H)*. 5-(N'-Hydroxycarbamimidoyl)-6-methyinicotinic acid HO, NC, CO2H NH 2 OH.HCI, Na2CO H N H2N a:CO2Hi N. 8-hydroxyquinolire (cat.) H 2 N C EtOH, reflux, 4h AN This compound was synthesized from 5-cyano-6-methylnicatinic acid as described 20 in example I step 4 (130 mg, crude)and it was carried through without further purification. MS (ESI) m/: Calculated for C3HqNO 3 : 195.06; found: 196.2 (M+H)*. 6-Methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid HO..N N (CFsCO)2 F il C2 H,;N ,-'CO 2 H ) 2 0 N C"02 pyridia, reflux, 3h N N 25 This compound was synthesized from 5-(N'-hydroxycarbarmirmidayl)-6 methylnicotinic acid as described in example 1 step 5 (25 mg, yield 15%) as a white solid. 'H NMR (300 MHz, DMSO-d,) 5 13.71 (brs, 1H), 9.14 - 9.13 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1 H), 2.66 (s, 3H). MS (ESI) m/z: Calculated for CmHiF 3

N

3 0 3 : 273.04; found: 274.0 (M-H). 143 WO 2011/088181 PCT/US20111021089 N-(2-(4-(4-Chlorophenyl)thiazo-2-yl)-2-methylpropyl)-8-methyl- -(5-(trifluorornethyl) 1,2,4-oxadiazol-3-yl)nicotinamide Cl C N .,.,CO 2 H N 4 0 -N O N N -K - - - - - - - - --- - F H2N S HATLU, NMM NS DMF, 0 *C-it, 5h N' 5 This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-y)-2 methylpropan-1-amine and 8-methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (28 mg, yield 59%). 'H NMR (400MHz, CDCi 3 ) 6 9.11 (br s, IH), 8.80 (br s, 1H), 8.07 (br s. 1H), 7.79 - 7.77 (d, J = 8.8 Hz, 2H), 7.43 (5. 1 H), 7.35 - 7.33 (d, J = 8.8 Hz, 2H), 3.86 - 3.84 (d, J =5 .5 Hz, 2H), 3.02 (s, 3H), 1.57 (s, 10 6H). MS (ESI) m/z: Calculated for C 23 HlCIFN5O 2 S: 521.09; found: 522.0 (M+H)7 EXAMPLE 70 Methyl 4-anino.-4-thioxobutanoate 0 S H2N' ------------ - HN , OCt, Sh 15 A solution of methyl succinamate (2.5 g, 0.019 mol) in THF (60 mL) was cooled to 0 'C and P 2

S

5 (4.2 g, 0.019 mol) was added. The reaction mixture was warmed to room temperature and stirred for 6 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gei 60-120 mesh, eluent 35-40% EtOAc in petroleum ether) to afford methyl 4-amino-4-thioxobutanoate (1.6 g, 20 yield 57%). %H NMR (300 MHz, CDCJ) 6 7.49 (br s, 21-1), 3.72 (s, 31-), 2.95 - 2.86 (m, 4H). MS (ESI) r/z: Calculated for C 5 1-1 9 N0 2 S: 147.04; found 248.2 (M+H-t Ethyl 3-(4-phenylthiazol-2-yl)propanoate 0 6 / B r O HN --- ------ N 0 EtOH, reflux, 3h 60% 144 WO 2011/088181 PCT/US20111021089 A mixture of 2-bromo acetophenone (2.1 g, 10 55 mmol) and methyl 4-amino-4 thioxobutanoate (1.6 g, 1086 mmol) in EtiH (15 mL) was heated to 80 *C for 3 h. Reaction mixture was cooled to room temperature and solvent was evaporated under reduced pressure. The product was extracted with EtOAc and the organic layer was 5 washed with H2O and brine, dried over anhydrous Na 2 SOs. and concentrated under reduced Pressure to afford ethyl 3-(4-phenyithiazol-2-yl)propanoate (1.1 g, yield 40%) as a white solid, which was carried through without further purification. IH NMR (300MHz, CDCl3) 5 7.90 - 7.87 (m, 2H), 7.44 - 7.39 (m, 2H), 7.35 - 7.30 (in, 2H), 4.22- 4.15 (q, J = 7.2 Hz, 2H), 3.41 - 3.36 (t, i = 7.5 Hz, 2H), 2.94 - 2.89 (t, J = 7.3 Hz, 2H), 1.30 - 1.25 (t, 10 J= 7.1 Hz, 3H). MS (ESi) m'z: Calculated for Cl 4

H

1 sNO 2 S: 261.08; found: 262.2 (M+H)7 3-(4-Phenylthiazol-2-yl)propan-1-ol \ /f-,( NaBlH4 -m _ W -~ N MeCH-H20 9:1 v/v 0 'C-rt, 8h A solution of ethyl 3-(4-phenylthiazol-2-yi)propanoate (0.5 g, 1.91 mmol) in MeoH 15 H 2 0 (10 mL, 9:1 v/v) was cooled to 0 *C and sodium borohydride (0.29 g, 7.65 mmol) was added. The reaction mixture was warmed to room temperature and further stirred for 8 h. The mixture was quenched with ice water and the organic product was extracted with EtOAc. The combined extracts were washed with H 2 0 and brine, dried over anhydrous Na 2 SOI, and concentrated under reduced pressure to afford 3-(4-phenylthiazo-2 20 yi)propan-1-ol (0.4 g, yield 95%) as colorless liquid, which was carried through without further purification. H NMR (400 MHz, CDCI) 5 7.87 -- 7.85 (m, 2H), 7.44-- 7.40 (m, 2H), 7.35 - 7.32 (m, 2H), 3.83 -- 3.81 (t, J = 5.8 Hz, 2H), 3.24 -- 3.21 (m, 3H), 2.14 -- 2.08 (m, 2H). MS (ESI) m/7: Calculated for C,?H 1 NOS: 219 07; found: 220.2 (M+H). 25 3-(4-Phenylthiazol-2-yl)propyl methanesulfonate C OH O--S MAsCI. pyridino 0 N. 0 0 C-rn 1h A solution of 3-(4-phenyithiazoi-2-yl)propan-1-oi (0.4 g, 1.82 mmol) in dry pyridine (8 mL) was cooled to 0 "C and methanesulfonyl chloride (0.43 mL, 5.47 ninol) was added dropwise. The reaction mixture was allowed to warm up to room temperature, stirred for 1 30 h, and quenched with ice water. The organic product was extracted with EtOAc and 145 WO 2011/088181 PCT/US2011/021089 organic layer was washed with brine, dried over anhydrous Na 2

SO

4 and concentrated under reduced pressure to afford 3-(4-phenylthiazol-2-yl)propy methanesulfonate (0.4 g, yield 74%) as a pale yellow liquid, which was carried through without further purification. IH NMR (300 MHz, CDCl 3 ) 6 7.90 - 7.87 (m, 2H), 7.46- 7.40 (n, 2H), 7.37 - 7.31 (m, 5 2H), 4.42 - 4.38 (, J = 6.1 Hz, 2H), 3.24 - 3.19 (t, j = 7.2 Hz, 2H), 3.04 (s, 3H). 2.39 2.30 (m, 2H). MS (ESI) m/z Calculated for C,,H 5

NO

3

S

2 : 297.05; found: 298.0 (M+H). 2-(3-Azidopropyl)-4-phenyithiazole

NON

3 -N N DMF, 100 C, 2h N 10 Sodium azide (263 mg, 4.05 mmol) was added to a solution of 3-(4-phenyithiazol 2-yl)propyl methanesultonate (0.4 g, 1.35 mmol) in dry DMF (8 mL), and the reaction mixture was heated to 100 'C for 2 h. The mixture was allowed to cool down to room temperature and diluted with EtOAc The organic product was extracted with EtOAc and the organic layer was washed with H 2 0 and brine, dried over anhydrous Na 3 SO4, and 15 concentrated under reduced pressure to afford 2-(3-azidopropyl)-4.-phenylthiazole (0.3 g, yield 91%) as a pale orange liquid, which was carried through without further purification. H NMR (300 MHz, CDCI 3 ) 5 7.91 - 7.89 (m, 2H), 7.46- 7.41 (in, 2H), 7.36 - 7.31 (in, 2H), 3,49 - 3,44 (t, J = 6.7 Hz, 2H), 3.20 - 3.15 (t, i = 7.5 Hz, 2H), 2.21 - 2.12 (m, 2H). MS (ESI) m/z- Calculated for C.H 12 N4S: 244.08; found: 245.2 (M+H) 20 3-(4-Phenylthiazol-2-yi)propan-1-amine N, NH2 78, e- ~ PPh, '-S, e N THF-H20 8:2 v/v 'N 0 "C-rt, 3h Triphenylphosphine (485 Mg, 1.85 mnol) was added to a solution of 2-(3 azidopropyl)-4-phenylthlazole (0.3 g, 1.23 mmol) in THF-H20 (10 Ml, 82 v/v) at 0 'C. The 25 reaction mixture was allowed to warm up to room temperature, stirred for 8 h and then concentrated under reduced pressure. The residue was diluted with 1.5N HCI and the aqueous layer was washed with CH 2

CI

2 . The pH of the aqueous layer was adjusted to -8 9 using 10% NaOH solution and the organic product was extracted with CH 2

CI

2 . The combined extracts were washed with brine, dried over anhydrous Na 2 SG4, and 30 concentrated under reduced pressure to afford 3-(4-phenylthiazol-2-yl)propan-1-amine 146 WO 2011/088181 PCT/US20111021089 (240 mg, yield 89%) as a pale yellow liquid, which was carried through without further purification. MS (ESI) m/z: Calculated for C N 12

H

1

S

2 F' 1- 8.09; found: 219.2 (M+H)* N-(3-(4-Phenylthiazol-2-yl)propyl)-3-(5-(trifluorom ethyl)-1,2,4-oxadiazol-3 5 yl)benzarnide _________ FNC-. 0 .' NN FC DMF, 0 'C-rO, 4h This compound was synthesized from 3-(4-phenylthiazol-2-yl)propan-1-amine and acid as decie example 8 ste6 3-5(rfurmethyl)-1,2,4-oxadiazcl-3-yi)benzoic aiasdescribed in eape8sep 6 (100 mg, yield 70%). 1 H NMR (400MHz, CDCl,) 6 8.40 (m, 11H), 8.17 -- 8.14 (m, 1H), 7.96 10 -- 7.94 (m, 1 -), 7.80-- 7.78 (m, 2H), 7.45 - 7.41 (m, 1 H), 7.34 -- 7.29 (m, 4H), 3.70 -- 3,66 (q, J 6.3 Hz, 2H), 3.27 -- 3.23 (t, J = 6.7 Hz, 2H), 2.29 -- 2.23 (m, 2H). MS (ESI) mr/z: Calculated for C 2 2 H - 7

F

3

N

4 0 2 S: 458. 10; found: 459.2 (M+H), EXAMPLE 71 15 4-(ChlIoromethyl)-2-(4-fluorophenyl)oxazole 0 EtOH-THP 3:1 viv CI N NH2 + CF CI F F- N reflux. 24h A mixture of 4-fluorobenzarnide (2.5 g, 17.9 nnol) and 1,3-dichloroacetone (2.7 9, 21.6 mrnoi) in EtOH-THF (20 mL-10 mL) was heated to 85 'C for 24 h. The reaction mixture was cooled to room temperature and quenched with 10% NaHCO, solution. The 20 organic product was extracted with EtCAc and the organic layer was washed with H 2 0 and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 6-10% EtOAc in petroleum ether) to afford 4-(chloromethyl)-2-(4 fluorophenyl)oxazole (1 2 g, yield 32%) as a white solid 'H NMR (300MHz, CDCIl) 6 25 8.07 - 8.02 (m, 2H), 7.70 (m, IH), 7.19 - 7.13 (t, J = 8 8 Hz, 2H), 4.58 (m, 2H). MS (ESI) m/z: Calculated for C 13

H

7 FCINO: 211 02; found: 212.0 (M+H). 147 WO 2011/088181 PCT/US20111021089 2-(2-(4-Fluorophenyl)oxazo[l4-yl)acetonitrile c NN /-- I /-'.N /-,\ NaC N N '^ NI /- DMF rt 30 min. DIMF IrGh K (3.14 g, 18.9 mmol) was added to a solution of 4-(chloromethyl)-2-(4 fluorophenyl)oxazole (1.0 g, 4.7mmol) in dry DMF (20 mL) at room temperature. The 5 reaction mixture was stirred for 30 min, diluted with EtCAc, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 2-(4-fluorophenyl)-4-(iodomethyl)oxazoie. The crude product was dissolved in DMF (20 mL) and sodium cyanide (0.46 g, 9.4 mrnol) was added to the solution. The reaction mixture was stirred at room temperature for 6 h and 10 quenched with water. The organic product was extracted with EtOAc and the organic layer was washed with H 2 0 and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) to afford 2-(2-(4-iuorophenyl)oxazol-4-y)acetonitrile (0.75 g, yield 78%) as an off-white 15 solid. 'H NMR (300MHz, CDC13) 5 8.05 - 8.00 (m, 2H), 7.73 (in, 1H), 7 20 - 7 14 (t, J = 8.6 Hz, 2H) 3.73 (s, 2H). MS (ESI) r/z: Calculated for C 1

,H

7

FN

2 0: 202.05; found: 203 0 (M+H) 2-(2-(4-Fluorophenyl)oxazo[-4-yl)ethanamine DIBAL ( M in toluene) H -N /=\ H ~ ~ ~ ~ ~ / -- F---------. 20 THF5(, C-rt, 1h C / This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitriie as described in example 64 step 4 (120 mg, crude)and it was carried through without further purification. 25 N-(2-(2-(4-Fluorophenyl)oxazol4-yl)ethyl)-5-(5-(trifluoromethyi)-1,2,4-oxadiazol-3 yl)nicotinamide /ON F H-F FC o HATU, NMM N- N DMF, 0 C-r, 4h N This compound was synthesized from 2-(2-(4-fiuorophenyl)cxazol-4-yi)ethanamine and 5-(5-(triflucromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 148 WO 2011/088181 PCT/US20111021089 step 6 (55 mg, yield 46%). 1 H NMR (400MHz, MeOD) 5939 (d, J= 2.0 Hz, IH), 9.19 (d, J = 2.0 Hz, IH), 8.89 (t, J = 2.0 Hz, IH), 8 07 - 8.03 (m, 2H), 7.81 (s, IH) 7.26- 7.22 (m, 2H), 3.78 - 3.75 (t, J = 6.9 Hz, 2H), 2.97 - 2.94 (t, J = 6.9 Hz, 2H). MS (ESI) n/z: Calculated for C 2 0H, 3 F4NO 3 : 447.10; found: 448.2 (M+H)*. 5 EXAMPLE 72 Ethyl 2-oxo-2-((2-oxo-2-phenylethyl)amino)acetate C C NI-12 -I S~L NH 2 EN N .HCI + CI - CH2Cl201C-r,16h Triethylamine (36 mL, 262.1 mmol) was added to a solution of 2 10 arninoacetophenone hydrochloride (15.0 g, 87.39 mmol) in dry CH 2 Cl 2 (300 mL), followed by ethyl chlorooxoacetate (10 mL, 87.39 mmol) at 0 "C. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h. The mixture was then diluted with water and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. 15 The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20-30% EtOAc in petroleum ether) to afford ethyl 2-oxo-2-((2-oxo-2 piheyrvlethyl)amino)acetate (13.5 g, yield 66%). 'H NMR (400 MHz, CDCi 2 ) 5 8.09 (br S, I H), 8.02 - 8.00 (m, 2H), 7.68 - 7.64 (Im, I H), 7.55 - 7.51 (m, 2H), 4.85 - 4.84 (d, J = 4.9 -z, 2H), 4.44 - 4.39 (q, J = 7.0 Hz, 2H), 1.44 - 1.41 (t, J = 7.2 Hz, 3H). MS (ESI) m/z: 20 Calculated for C, 2 HI1NO 4 : 235.08; found 236.2 (M+H). Ethyl 5-phenylthiazole-2--carboxylate C ., C O -N 2 -F~ --------- ~ A CHCl 3 reflux, 5h \>

P

2

S

2 (255 g, 114.7 mmol) was added to a solution of ethyl 2-oxo-2-((2-oxo-2 25 phenylethyl)arnino)acetate (13.5 g, 57.39 mmol) in dry CHCi 3 (150 mL), and the resulting reaction mixture was heated to reflux for 5 h. The reaction mixture was quenched with water and the organic product was extracted with CHC. The combined extracts were washed with H 2 0 and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 30 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) to afford ethyl 5-phenylthiazole-2 carboxylate (10 g, yield 75%) as a white solid. 'H NMR (400 MHz, CDC1 3 ) 5 8.16 (S, 1H), 149 WO 2011/088181 PCT/US2011/021089 7.64 - 7 62 (m, 2H), 7.48 - 7 39 (m, 3H), 4.53 - 4.47 (q J = 7.0 Hz, 2H), 1 49 - 1.45 (t, J = 7 2 Hz, 3H) MS (ESI) M/z: Calculated for C0 2 1

.

1

N

2 S: 233.05; found: 234.0 (M+H)' (5-Phenylthiazol-2-yl)methanol -N -N DIBAL (IMN in foluane) C ~~(H -------- --- 5 THF, 0 C-rt, 2h This compound was synthesized from ethyl 5-phenvithiazole-2-carboxylate as described in example 64 step 4 (3.5 g, yield 71%)and it was carried through without further purification. H NMR (300 MHz, CDCI ) 6 7.89 (s, 1H), 7.57 - 7.54 (m, 2H), 7.44 7.35 (m, 3H), 4.97 (s, 2H). MS (ESI) rn/z: Calculated for CioH 4 NCS: 191 04; found: 192.2 10 (M+H)*. 2-(Bromomethyl)-5-phenylthiazole -N r-N H CB 4 , PP/ Br

CH

2 CIH 0 IC rt, 1 h CBr4 (8.65 g, 26.1 mmol) and Ph3P (5.1 9, 19.6 mmol) were added to a solution of 15 (5-phenvlthiazol-2-yl)methanol (2.5 g, 13.07 mmol) in dry CH 2 Cl 2 (30 mL.) at 0 "C. The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced Pressure. The residue was diluted with diethyl ether and filtered. The clear filtrate was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5-10% EtOAc in petroleum ether) 20 to aiFord 2-(bromromethyl)-5-phenylthiazoie (2 g, yield 60%). IH NMR (300 MHz, CDCIs) 6 7.89 (s, IH), 7 57 - 7 55 (m, 2H), 7.45 - 7 36 (m, 3H), 4.76 (s, 2H). MS (ESI) r/z: Calculated for CjcHnBrNS: 254.95; found: 256.0 (M+H) 2-(5-Phenylthiazol-2-yl)acetonitrile -N N r Br NaCN '- CN 25 toH, reflux, 2h NaCN (0.46 g, 9.4 mmol) was added to a solution of 2-(bromomethyl)-5 phenylthiazole (2.0 g, 7.87 mmol) in dry ETOH (10 mL). The resulting reaction mixture was stirred at 70 "C for 2 h and then concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with H 2 0 and brine, dried over anhydrous 30 sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10% EtOAc in 150 WO 2011/088181 PCT/US20111021089 petroleum ether) to afford 2-(5-phenylthiazol-2-y)acetonitrile (350 mg, yield 22%) as a white solid. H NMR (400 MHz, CDCl 3 ) 8 791 (s, I H), 7.56 - 7.54 (in, 2H), 7.46 - 740 (m, 3H), 4.15 (s, 2H). MS (ESI) n/z: Calculated for CI 1 HaN 2 S: 200.04; found: 201.2 2-(5-Phenylthiazol-2-yl)ethanamnine /-N \ BH 3 .MeS , '7 ct----------- ------ , S-~, V S THF, r-60*C, 3h ' This compound was synthesized from 2-(5-phenylthiazol-2-yl)acetontrile as described in example 42 step 1 (100 ig, crude)and it was carried through without further 10 purification. MS (ESI) r/z: Calculated for C 11 Hl 2 NS: 204.07; found: 205.2 (M+H)*. N-(2-(5-Phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)benzarnide P-N FK CO,.H -N H2H -HATU, CN CI T DMF, 0C-r.4h 15 This compound was synthesized from 2-(5-phenylthiazoi-2-yl)ethanamine and 3 (5-(trifliuoromethyl)-1,2,4-oxadiazol-3-yl)benzoc acid as described in example 8 step 6 (7 ng, yield 5%). 1 H NMR (400 MHz, MeOD) 5 8.60 -- 8.59 (*, J = 1.4 Hz, 1H), 8.31 -- 8.28 (dt, J = 7.8 Hz, 1.4 Hz, 1H), 8.08 -- 8.05 (dt, J = 7.9 Hz, 1.3 Hz, 1H), 7.96 (s, 11-), 7.72 7.68 (t, J = 7.9 Hz, 1H), 7.61 -- 7.59 (m, 2H), 7.43 - 7.39 (m, 2H), 7.36 -- 7.32 (m, 1H), 20 3.85 - 3.82 (t, J = 6.9 Hz, 2H), 3.40 - 3.36 (t, J = 6.8 Hz, 2H). MS (ESI) m/z: Calculated for C 2 ,H,5F 3 N4 1 0 2 S: 444.09; found: 445.0 (M+H)*. EXAMPLE 73 2-(2-(4-Fluoropheny)oxazol-4-yl)propanenitrile NC-' N - Mel, NaH NC'N = C-F -C 25 * -~ \*~I HF,0 C rt, 3h ~ 25 NaH (360 mg, 60% dispersion in oil) was added portionwise over 5 min to a solution of 2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile (1.5 g, 7.42 mmol) in dry THF (60 mL) at 0 IC. The resulting reaction mixture was slowly allowed to warm up to room 151 WO 2011/088181 PCT/US20111021089 temperature and stirred for 1 h The reaction mixture was again cooled to 0 *C and a solution of methyl iodide (0.5 mL, 7.4 mmol) in dry THF (10 mL) was added dropwise at 0 "C over 30 min. The reaction mixture was stinred at 0 "C for 1 h and then at room temperature for another 1 h. The reaction mixture was quenched with saturated NH4Cl 5 solution, diluted with EtOAc and further extracted with EtOAc. The combined extracts were washed with H 2 0 and brine, dried over anhydrous Na 2

SO

4 , and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60 120 rmesh, eluant 10% EtOAc in petroleum ether) to get 2-(2-(4-fluorophenyl)oxazo-4 yi)propanenitrile (360 mg, yield 23%). "H NMR (400 MHz, CDC',) F 8.05 - 8.02 (m, 2H), 10 7.71 - 7.70 (d, J = 1.1 Hz, 1H), 7.19 - 7.14 (t, J = 8.7 Hz, 2H), 3.97 - 3.92 (m, 1H), 1.73 1.72 (d, J = 7.2 Hz, 3H). MS (ESI) m/z: Calculated for CUH.,FN 2 C: 216 07; found: 216.9 (M+ HV 2-(2.-(4-Fluorophenyl)oxazol-4-yl)propan-1-amine N LAlH 4 H2N N A --- ii1r--K 15 THF, C UC--r, ih \----'\/--r 15 () 0 This compound was synthesized from 2-(2-(4-fluorophenyl)oxazoi-4 yi)propanenitrile as described in example 1 step 3 (320 mg, crude)and it was carried through without further purification. MS (ESI) m/z: Calculated for C, 2 HlFN 2 0: 220.10; found: 220.8 (M+H)f 20 N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)propyl)-3-(-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)benzamide F 00-N HATU, NMM N DMF, 0 -C-rt, 4h This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-y)propan-1 25 amine and 3-(5-(trifLuoromethyl)-1,2,4-oxadiazol-3-yl)benzoc acid as described in example 8 step 6 (95 mg, yield 36%) as a yellow solid. IH NMR (400MHz, CDCIs) 6 8.59 - 8 58 (t, J = 1.5 Hz, 1H), 8.28 - 8.26 (dt, J = 7 8 Hz, 1.3 Hz, 1H), 8.17 - 8.14 (dt, J = 7 8 Hz, 14 Hz, 1H), 8.09 - 8.05 (m, 2H), 7.90 (m, 1H), 7.67 -7.63 (t, J= 7.6 Hz, IH), 7.53 (d, J = 0.8 Hz, IH), 7,14 - 7.10 (in, 2H), 3.99 - 3.93 (ddd, J = 13.2 Hz, 6.4 Hz, 4.3 Hz, 1H), 152 WO 2011/088181 PCT/US20111021089 3.53 - 3.46 (ddd, J= 13,2 Hz, 8.8 Hz, 4.3 Hz, 1H), 3.19 - 3 12 (m, iH), 141 - 1.39 (d, J= 7.0 Hz, 3H). MS (ESI) m/z: Calculated for C 2 ,H1 6

F

4

N

4 0 3 : 460.12: found: 461 1 (M+H)' EXAMPLE 74 5 4-(Chloroniethyl)-2-(3-fluorophenyl)oxazole + C 1L.C 1 F F 1,3-Dichloroacetone (3.65 g, 28 75 mmol) was added to a solution of 3 fluorobenzamide (2 g, 14.37 mmol) in dry toluene (20 mL) The resulting reaction mixture was stirred at 100 'C for 5 h. The reaction mixture was concentrated under reduced 10 pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eiuent 10% EtOAc in petroleum ether) to afford 4-(chioromethyl)-2-(3 fluorophenyl)oxazole (1.2 g, yield 39%) as a yellow liquid. 'H NMR (300 MHz, CDCi 3 ) 6 7.85 - 7.83 (m, 1H), 7.77 - 7.73 (in, 2H), 7.48 - 7.41 (m, 1H), 7 20 - 7.14 (, 1 H), 4.58 (d, J = 0.9 Hz, 2H). 15 2-(2-(3-Fluorophenyl)oxazol4-yl)acetonitrile Cl , N, -- =- i) Ki, DMF, rt, 1. NC'- N O -( li) NaCN, 'C F DMF, rt, 2h F This compound was synthesized from 4--(chloromethyl)-2-(3-fluorophenyl)oxazole as described in example 71 step 2 (0.15 g, yield 35%). 'H NMR (300 MHz, CDCla) 6 7.83 20 - 7.81 (n, 1H1), 7.76 - 7.70 (m, 2H), 7.49 - 7.42 (n, 1H1) 7.22 - 7.15 (m,I 1H), 3.74 (s, 2H). MS (ESI) rm/z: Calculated for C,,HrFN 2 0: 202.06 found: 203.2 (M+H)*. 2-(2-(3-Fluorophenyl)oxazol-4-yl)ethanamine NC-N....N -N BH 3 .Me 2 S H 2 N. N 0 - THF, reflux, 0 5hL F 25 This compound was synthesized from 2-(2-(3-f!Luorophenyl)oxazol-4-yl)acetonitrile as described in example 42 step 1 (120 ing, crude)and it was carried through without further purification. MS (ESI) m/z: Calculated for Cl 1 H,,FN0: 206.09: found: 206.9 (M+H) + 153 WO 2011/088181 PCT/US20111021089 yl)nicatinamide FC-K)~ CO2H Fi NN N 0 N 0 F' HIATU, NMM H DMF, 0 C-it, 4h This compound was synthesized from 2-(2-(3-fluorophenyl)oxazol-4-yijethanamine 5 and 5-(5-(trifluoromethy)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (15 mg, yield 9%) 'H NMR (400MHz, MeOD) 5 9.39 (d, J= 2.0 Hz, 1H), 9.19 (d, J = 2.3 Hz, 1H), 8.90 - 8.88 (t, J = 2.1 Hz, 1 H), 7.84 - 7.82 (m, 2H), 7.72 - 7.69 (m, 1 H), 7.54 - 7.49 (in. 1 H), 7.26 - 7.21 (m, I H), 3.79 - 3 76 (t, J = 6 9 Hz, 2H), 2.98 - 2.95 (t, J = 6.9 Hz, 2H). MS (ESI) m/z: Calculated for C 2 oH.

3

F

4 N:0 3 . 447.10; found: 448.0 (M+H) . 10 EXAMPLE 75 Methyl 6-chloro-5-cyano-2-methylnicotinate NC. - CO 2 Me POCI PC6 NC, .CO 2 Me HO' N 'Me 120 "C, 24h C1 N 'Me 15 A mixture of methyl-5-cyano-.6-hydroxy-2.-methylnicatinate (2.0 g, 10.41 mmol), POCl (40 mL) and PCI 5 (1.08 g, 5.2 mmol) was heated to 110 "C for 24 h. The reaction mixture was concentrated under reduced pressure and querched with ice-water. The organic product was extracted with EtOAc and the organic layer was washed with H 2 0 and brine, dried over anhydrous sodium sulfate and concentrated under reduced 20 pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) to afford methyl 6-chloro-5-cyano-2 methylnicotinate (1.5 g, yield 68%). IH NMR (300 MHz, CDCi!) 5 8.48 (s, 1H), 3.96 (s, 3H), 2.90 (s, 3H). 25 154 WO 2011/088181 PCT/US20111021089 Methyl 5-cyano-2-methylnicotinate NC CO 2 Me Zn powder, NH 4 C! NC, .CO 2 Me C N N Me dioxane-THF-DMF-H20 2:1:1:0.5 H IN 'Me r, 4h This compound was synthesized from methyl 6-chloro-5-cyano-2-mnethyinicotinate as described in example 69 step 1 (230 mg, yield 23%). 'H NMR (300 MHz, DMSO-ds) 6 5 9.07 - 9.06 (d, J = 2 2 Hz, IH), 8.62 - 8.61 (d, J = 2.2 Hz, 1H), 3.87 (n 3H), 2.78 (s, 3H). MS (ESI) m/z: Calculated for CHsN 2 O2: 176.06; found: 176.7 (MiH). 5-Cyano-2-methyinicotinic acid NC .,CO 2 Me LI-.H 2 O N C H 3N Me THF-H 2 0 7:3 v/v N Me 0 C-rt 45 min 10 This compound was synthesized from methyl 5-cyano-2-methylnicotinate as described in example 69 step 2 (175 mg, yield 83%) as a white solid. 1 H NMR (300 MHz, DMSO-dr) 6 13.78 (br s, 1H), 9.02 - 9.01 (d, J = 1.8 Hz, 1 H), 8.56 - 8.55 (d, J = 1.5 Hz, I H), 2.78 (s, 3H) MS (ESI) nz: Calculated for CH 6

N

2 0 2 : 162.04 found: 160 6 (M-H)-. 15 N-(2-(4-(4-Chlorophenyl)thiazol-2-yl)-2-methylpropyl)-5-cyano-2 -methylnicotinamide Cl NNCO SS 'N Me HATU, NMM D I fN Me DMF, 0 "C-rt, 51h This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)-2 nethylpropan-1-amine and 5-cyano-2-methyinicotinic acid as described in example 8 step 6 (200 mg, yield 46%). 1 H NMR (300 MHz, CDCi,) 5 8.81 (n, 1H). 8.00 - 7.99 (n, 1H), 20 7.70 - 7.67 (n, 2H), 7.50 - 7.46 (mI 1H), 741 - 7.37 (m, 3H), 3.81 - 3.79 (d, J = 5.7 Hz, 2H), 2.81 (s, 3H), 1.57 (s, 6H). MS (ESI) m/z: Calculated for C 21

H,

9

CIN

4 08: 410.10; found: 411.1 (M+H)7 155 WO 20111088181 PCT/US201l11021089 5-((2-(4-(4-Chloroplhenyl)thiazol-2-yl)-2-methylpropyl)carbaoy)O m ethyl nicoti nohyd razonic acid C1 0) N-- INH 2 OriHA. N8 2 CQO H2.N 0 - S -hdrxqunoie ca) HO PA . K. .1 me [:tOl , reflux, 3h .14 MC This compound was synthesized from mnethyl 5-cyano-2-methylnicotinate as 5 described in example I step 4 (200 mg, crude)and it was carried through without further o~rification. IH NMR (400 MHz, MeOD) 6 8,71 - 870 (d, J = 2.3 Hz, 1H), 8 04 -8.03 (d. J-- 23 Hz? 1IH), 7,P3- 791~ (d, J = 8 5Hz, 2H), 7.73 (s? 1.)% 7,40- 7,38 (d, J = 8 5 Hz, 2H-), 3.76 (s, 2H). 2 50 (br s, 3H), 1.58 (s, FH). MS (ESI) m/2z Calclae for

C

2 1H1 2 CIN5O 2 S: 443.12. found: 444.1 (IMH)'. N-(2-(4-(4 -C h orophenyl)th iazol -2 -yl) -2-m ethyl propyl) -2-nethy---(5-(tfifI uororn ethy) I ,2,4-oxadiazol-3-yl)niicotiniamide N ) N~ (CF:COO O-N 0 HO' . N" N pyrioine, reflux, 3h N 'N'><~ This cor.npound was synthesized from 5- ((t2-'4--4-chi croonenyl)th izol -2- yl)-2 15 methylpropyl)carbamoyl: -. methylnicot'!nohydrazonic acid as descrhbed in example I step 5 '20 mng, yield 91c). IH NUIR (400 MHz, MePOD) 6 9.14 -9.13 (d, J 2.0 Hz, 11-), 8.34 (d, J = 2,10Hz, 114) 793 - 791 (d, J'=8.8 Hz, 2W.., 7,74 (s, 1H) 7.35- 7,33 (d, J = 8 8 Hz, 2H). 3.80 (s, 2H), 2.58 (hbr s, 3H), 1 60 (s, 6H). MS (ESI) rniz: Calculated for C~H~CiN)NQ 2 S:521.09; found: 522 1 (M-'-H)>. 20 EXAMPLE 76 2-Methyl-2-(5-phenylthiazol-2-ypiropanernitrile THF, 0 C-ft.21- / This compound was synthesized from 2-(5--pher..ylth iazol-2-yI)acetontrile as 25 described in example 1 step 2 using iodornethane (200 mng, yield 58%), II NIMR (400 156 WO 2011/088181 PCT/US20111021089 MHz, CDCI 3 ) 5 7.90 (s, I H), 7.56 - 7.54 (in, 2H), 7.45 - 7.37 (i, 3H), 1,90 (s, 6H). MS (ESI) m/z: Calculated for C13HN 1

N

2 S: 228.07.10; found: 2288 (M+H) 2-Methyl-2-(5-phenylthiazol-2-yl)propan-1-amine C-- LiAl-4N 5 g / THF, O ~C-rt, 1h This compound was synthesized from 2-..methyl-2-(5-phenylthiazol-2 y!)propanenitrile as described in example 1 step 3 (70 mg, yield 34%) and it was carried through without further purification. MS (ESI) m/z: Calculated for C 3HwN2S: 232.10; found: 233.2 (M+H)*. 10 N-(2-Methyl-2-(5-.phenyIthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)benzamide 0 N N' prN l H \/ r__NH2____ N ,_ ,.A N S HATU, NMM O-N O N-/ MF, 0 "C-rt, 4h 15 This compound was synthesized from 2-inethyl-2-(5-phenylthiazol-2-y)propan-1 amine and 3-(5-(trifiuoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (20 ng, yield 17%). 'H NMR (400 MHz, MeOD) 5 8.55 (i, 1H), 8.29 8.27 (m, IH), 8.03 - 8.01 (im, 1H), 7 96 (s, IH), 7.98 (s, 1H), 7.71 - 7.67 (t, J = 7 8 Hz, I H), 7.63 - 7.61 (m, 2H), 7.43 - 7.39 (m, 2H), 7.35 - 7.32 (m, 1H), 3.75 (s, 2H), 1.56 (a, 20 6H). MS (ESI) r/z: Calculated for C 23 H F 3

N

4 0 2 S: 472.12; found: 473.1 (M+H)*. EXAMPLE 77 2-(1[1,1'-Bipheniyl]-3-yl)acetonitrile r--Br ,--CN __ NaCN ,= r= ----- ,. / \ / \ DMF, rt, 3h 25 NaCN (1.1 g, 22.26 mmol) was added to a solution of 3-phenylbenzyl bromide (5.0 g, 20.23 mmol) in dry DMF (100 mL). The resulting reaction mixture was stirred at room temperature for 3 h and then quenched with water. The organic product was extracted with EtOAc and the combined extracts were washed with H 2 O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product 157 WO 2011/088181 PCT/US20111021089 was purified by column chromatography (silica gel 60-120 mesh, eluent 5% EtOAc in petroleum ether) to afford 2-([1,1'-bipheny']-3-yl)acetonitrle (3.8 g, yield 97%) 'H NMR (300 MHz, CDCla) 6 761 - 7.56 (m, 4H), 7.50 - 7.45 (m, 3H), 7.42 - 7.36 (m, 1H), 7 34 7.31 (m, 1H), 3.83 (s, 2H) 5 4-([1,1'-Biphenyll-3-yl)tetrahydro-2H-pyran-4-carbonitrile /-NBr' Br N NaH -, THF p 0 "C-rt then reflux, 8h This compound was synthesized from 2-([1,1'-biphenyl]-3-yl)acetonitrile as described in example 1 step 2 using 2-bromoethyl ether (0.5 g, 73%). 'H NMR (300 MHz, 10 COCla) 6 7.72 - 7.71 (m, 1H), 7 62 - 7.57 (m, 3H), 7 51 - 7.45 (m, 4H), 7 42 - 7 37 (m, 1 H), 4.15 - 4 10 (m, 2H), 3 99 - 3.91 (in, 2H). 2.28 - 2.20 (m, 4H) (4-([1 1'-Biphenyl]-3-yI)tetrahydro-2H-pyran4-yl)methanamine NC H-A - HN X> THF, 0 "C-rt, 1h 0 15 This compound was synthesized from 4-([1 1'-biphenyl]-3-yI)tetrahydro-2-1-pyran-4 carbonitrile as described in example 1 step 3 (230 mg, yield 46%) as a pale yellow oil. 1 H NMR (300 MHz, DMSO-d,) 6 7.66 - 7.63 (m, 2H), 753 - 7.41 (m1, 5H), 7.37 - 7.31 (m, 2H), 3.70 - 3.65 (in, 2H), 3.43 - 3.37 (m, 2H), 2.68 (s, 2H), 2.11 - 2.05 (in 2H), 1.87 1.79 (im, 2H). MS (ESI) m/z: Calculated for C,sH 2 ,N0: 267.16; found: 267.9 (M+H)*. 20 NV-((4-([,1'-Bi phenl]-3-yl)tetrahyd ro-2H-pyran -4-yl) me thyl) -3-(5-(trifluo romnethyl) 1,2,4-oxadiazol-3-yI)benzamide N <dx F NWC O0 2 H PN N HATU, NMMN i H DMF, G *C-rt, Sh This compound was synthesized from (4-([1,1'-biphenyl]-3-yl)tetrahydro-2H-pyran 25 4-yl)methanainne and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (110 mg, yield 56%) as a white solid. IH NMR (400 MHz, 158 WO 2011/088181 PCT/US20111021089 CDCIs)8 28 (s. IH), 8.23 - 8.21 (d, J = 7.7 Hz, IH), 7.86 - 7.84 (d, J = 8,0 Hz, 1H), 7.58 - 7.55 (in, 6H), 7.45 - 7.37 (m, 4H), 5.85 - 5.82 (t, J = 6 1 Hz, IH): 3.96 - 3.91 (im, 2H), 3.79 - 3.78 (d, J = 6.4 Hz, 2H), 3.74 - 3.69 (m, 2H), 2.27 - 2.22 (m, 2H), 2.10 - 2.04 (m, 2H). MS (ESI) m/z: Calculated for C 2 3H,1F 3 N30 3 : 507.18; found: 508.1 (M+H)* 5 EXAMPLE 78 N-((4-([1,1'-Bipheniyl]-3-yl)tetrahydro-2H-pyr~an-4-yl)miethiyl)-5-(5-(tr-ifluoromethiyl) 1 ,2,4-oxadiazol-3-yl)nicotinamaide F NC C07H HN X HATU NNM. X H DMF, 0 C-I, Sh N 10 This compound was synthesized from (4-([1,1'-biphenyl]-3-yl)tetrahydro-2H-pyran 4-yl)methanamine and 5-(5-(trifluoromethy)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (95 mg, yield 48%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) C 9 40 (br s, IH), 8.97 (br s, 1H), 8.61 - 8.60 (t, J = 1.9 Hz, IH), 7 58 - 7.55 (m, 15 5H), 7.46 - 7.43 (t. J = 7.5 Hz, 2H), 7.39 - 7.35 (n. 2H), 5.89 - 5.86 (t, J = 6.1 Hz, 1H), 3.96 - 3.92 (in, 2H), 3 82 - 3.81 (d, J = 6.1 Hz, 2H), 3 74 - 3 68 (m, 2H), 2.29 - 2.23 (m, 2H), 2.09 - 2.03 (m, 2H). MS (ESI) m/r Calculated for C 2 7

H

23

F

3

N

4 0 3 : 508.17; found: 507.2 (M-H). 20 EXAMPLE 79 2.-(4-Fluorophenyl)-4-(iodonethyl)oxazole 2 ~ ~K\ 1---- ,,N

-

0 DMF, r, 30 mir C -- KI (3.14 g, 18.9 mrnol) was added to a solution of 4-chlorornethyl-2-(4 fluorophenyl)-oxazole (1 g, 4 7 mmol) in dry DMF (10 mL) at room temperature. The 25 resulting reaction mixture was stirred for 30 min and then diluted with EtOAc The mixture was extracted with EtOAc and the combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to get 2 (4-fluorophenyl)-4-(iodonethyl)oxazole (1.2 g, crude), which was carried through without further purification. 'H NMR (300 MHz, CIDCI) 6 8.05- 8.00 (m, 2H), 7.68 (S, 1H), 7.17 30 7.11 (m, 2H), 4.33 (s, 2H). MS (ESI) rnz: Calculated for COH,FINO: 302.96: found: 304.0 (M+H)*. 159 WO 2011/088181 PCT/US2011/021089 4-(Azidomethyl)-2-(4-fluorophenyl)oxazole I--''N /= NaNa N N /-=N r-F ----------- ' DMF, 70 *C, 8h /-F A solution of 2-(4-fluorophenyl)-4-(iodomethyl)oxazole (1.2 g, 3.96 mmol) in dry 5 DMF (10 mL) was added sodium azide (515 mg, 7.9 mmol) and the reaction mixture was heated to 70 'C for 8 h. The reaction mixture was allowed to cool down to room temperature and diluted with EtOAc. The mixture was extracted with EtOAc and the combined extracts were washed with water and brine, dried over anhydrous Na2SO. and concentrated under reduced pressure to afford 4-(azidomethyl)-2-(4-fluorophenyl)oxazole 10 (0.73 g, yield 85%) as a pale orange liquid, which was carried through without further purification. 'H NMR (400 MHz, CDC 3 ) 6 8.04 - 8.01 (m, 2H), 7.67 (s, 1H), 7.16 - 7,12 (m, 2H), 4.34 (s, 2H) MS (ESi) m/z: Calculated for C 1

DH

7

FN

4 0: 218 06; found 219 2 (M+iH)V. 15 (2-(4-Fluorophenyl)oxazol-4-yl)methanamine N^ N PPh H -N F F O' K! THF-H2O S:2 v/v F rt. 4h A solution of 4-(azidomethyl)-2-(4-fLiuorophenyi)oxazole (0 5 g, 2.3 mmol) in THF

H

2 0 (15 i, 8:2 v/v) was cooled to 0 C and triphenylphosphine (892 mg, 3.4 mmol) was added. The reaction mixture was allowed to warm up to room temperature and then 20 stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with 1.5N HCI. The aqueous layer was washed with CH 2 Cl 2 and then the pH of the aqueous layer was adjusted to -8-9 using 10% NaOH solution. The organic product was extracted with CH 2 l0 2 and organic layer was washed with brine, dried over anhydrous Na 2 SO4, and concentrated under reduced pressure to afford (2-(4 25 fluorophenyl)oxazol-4-yl)methanamine (330mg, yield 75%) as a pale yellow liquid, which was carried through without further purification. 'H NMR (400 MHz, DMSO-d6) 5 8.01 7.98 (in, 21-), 7,94 (s, 1H), 7.38 - 7.34 (m, 2H), 3.65 (d, J = 1.1 Hz, 2H). MS (ESI) m/z Calculated for C, 0 HqFN 2 0: 192.07; found: 193.2 (M+H)*. 160 WO 2011/088181 PCT/US2011/021089 N-((2-(4-Fluorophenyl)oxazol.-.yl)methyl)-3-(5-(trifluoromnethyl)-1,.2,4-oxadiazol-3 yl)benzamide FC N2H N-N O HN__N F 3 C--< < 1 -FN rY N YO -- I HATU, NMM H DMP 0 C-rt, 4" This compound was synthesized from (2-(4-fluorophenyl)oxazol-4-y!)methanarine 5 and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-y!)benzoic acid as described in example 8 step 6 (65 mg, yield 26%) as a white solid. 1 H NMR (400MHz, DMSO-ds) 5 9.35 - 9.32 (m, 1H), 8.60 (t, J = 1.5 Hz, 1H), 8.25 - 8.19 (m, 2H), 8.12 (m, 1H), 8.04 - 8.00 (m, 2H) 7.77 - 7.73 (t, J = 7.8 Hz, 1 H), 7,41 - 7.36 (I, 2H), 4.48 - 4.47 (d, J' 5.2 Hz, 2H). MS (ESI) m/z: Calculated for C 2 0l-11 2

F

4

N

4 0 3 : 432.08, found: 433.2 (M+H). 10 EXAMPLE 80 4-(2-(4-Fluorophenyl)oxazol-4-y)-1 -methylpiperidine-4-carbonitrile

NH

4 0H N N NC >-- CI NC, C -N/ NaNH,, toluene S0 'C, 0.5h then 100 "C 31 N This compound was synthesized from 2-(2-(4-fluorophenyl)cxazl-4-yl)acetonitrile 15 and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride as described in example 16 step lb (430 mg, yield 30%). 'H NMR (300MHz, DMSO-de) 6 8.30 (s, 1), 8.05 - 8.00 (m, 21-), 7.41 - 7.35 (m, 21-i), 2.83 - 2.79 (m, 2H), 2.26 - 2.18 (n, 7H), 2.04 1.94 (m, 2H). MS (ESI) rm/z: Calculated for CasH ,FNO: 285.13; found: 286.2 (MWH)*. 161 WO 20111088181 PCTUS201 11021089 (4-(2-(4.Flujoroplhenyl)oxazl.-4-yi)-1 -metlhylpiperidin-4-yl)methanarnine FF T F, G DC-rt, 2h N' N This compound was synthesized irorn 4-(2-(4-flu,,orhenyl)oxazoi-4-y)-1 rneth-.ylpipen-din-e-4-carbonitrile as described in example 1 step 3 (170 mng, crude)tand it S was carried through without further purification. MS (ESI) m/2/p Calculated for C, 6

FH

2

FIN

3 C. 289.16; found: 290.2 (.M+H)+. Ni-((4-(2-(4-Fluorophenyl)oxazol-4-y)- -methyl piperidi n-4-yl)m ethyl) -3-(5 (trifluoromethyl)-1 ,2,4-oxadiazol-3-yI)benzamide /F N'N * r ~~+~<~C NATU, NAMMF3~Nyyi C N" DMRO) C-rt,& N 10 This compound was synthesized from (4 -(2- (4-flu crop henyl)oxazo 1-4-yl)-1 methylpiperidin-4-yl)mnethanarmine.F and 3-(5-(trifluoromeFtiyl)- 1 2,4-oxadiazo:!-3-yl)benzoi-, acid as described in example 8 step 6 (50 mg, yield 24%11, 'H MR (400MNz, CDCI 3 ) 6 8.55 (s, 1IH). 8.29 - 8.27 (in, 1 H) . .13 - 8.05 (in, 3H), 7.67 -7.62 (in, 2H), 7.17 - 7.13 (t, 15 J =8 7 Hz, 2H), 3.85 - 3 84 (m, 2H), 3.14 - 3.00 (mn, 4H), 2.67 (in, 3-H), 2.43 - 2.42 (in. 2HW, 2.24 - 2.23 (in, 2H). MAS (F,9) m/z: Caiculated for C 2 6 1H 23 4

N

5 0 3 : 529.17; foiund 530.2 (IV i-Fby+ EXAMPLE S1 20 4-(Chloromethyl)-2-phenyloxazole 0 tolueneC l~- 1 162 WO 2011/088181 PCT/US20111021089 This compound was synthesized from 1,3-dichloroacetone and benzamide as described in example 71 step 1 (65 g, yield 68%) as a white solid. 'H NMR (300MHz,

CDC

3 ) 5 8.06 - 8.04 (m, 2H), 7.72 (m, 1H), 7.49 - 7.46 (n, 3H), 4.59 (d, J = 1.1 Hz, 2H). MS (ESI) m/z: Calculated for CoH3CINO: 193.03; found: 194.2 (M+H)'. 5 2-(2-Phenyloxazol-4-yi)acetonitrile \ KI, DMF, rt, 1h NC-'- N Oi0) NOCN, DMF, rt, 2h .' \__// This compound was synthesized from 4.-(chloromethyi)-2-phenyloxazole as described in example 71 step 2 (24 g, yield 50%) as a white solid. 'H NMR (300MHz, 10 CDCI,) 5 8.04 - 8.01 (m, 2H), 7.74 (t, J = 1,2 Hz, 1H), 7.49 -- 7.46 (m, 3H), 3.74 (d, J= 1.1 Hz, 2H), MS (ESI) m/z: Calculated for C, 1 HsN 2 O: 184.06; found: 185.2 (M+H)*, 2-Methyl-2-(2-phenyloxazol-4-yl)propanenitrile N N /=- Mel, NaH ------ ------- NC' y N S \/ TIF, 0 OC-r,1.5h | 15 This compound was synthesized from 2-(2-phenyloxazo-4-yl)acetonitrle using lodomethane as described in example 1 step 2 (18 g, yield 6 5%) as a yellow solid. 1 H NMR (300 MHz, CDCl) 6 8.06 - 8.03 (m, 2H), 7.68 (s, I H), 7.48 - 7.46 (m, 3H), 1.77 (s, 6H). MS (ESI) r/z: Calculated for C 13 H1 2

N

2 0: 212.09; found: 213.2 (M+H)*. 20 2-Methyl-2-(2-phenyloxazol-4-yl)propan-1 -amine NIC -NLiANLAH 4 H THF, 0 "C-rt, 15 This compound was synthesized from 2-methyl-2-(2-phenyioxazoi-4 yi)propanenitrile as described in example 1 step 3 (16.2 g, crude)and it was carried through without further purification. MS (ESI) m/z: Calculated for C1 3 ,HN20: 216.13, 25 found: 217.2 (M+FH). 163 WO 2011/088181 PCT/US20111021089 N-(2-Methyl-2-(2-phenyloxazol-4-yl)propyl)-3-(S-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)benzamide 00 ONN DMF, ) 0 "C-rt, 4 h This compound was synthesized from 2-methyl-2-(2-p'henyloxazol-4-yi)propan-1 5 amine and 3-(5-(trifLuoromethyl)-1,2,4-oxadiazol-3-yl)benzoc acid as described in example 8 step 6 (15 g, yield 44%) as a white solid. 1 H NMR (400MHz, CDCs) 5 8.66 (t, J = 1.5 Hz, IH), 8.29 - 8.26 (m, 2H), 8.20 - 8.17 (dt, J = 8.0 Hz, 1.2 Hz, IH), 8 09 - 8.06 (m, 2H), 7.68 - 7.64 (t, J = 7.9 Hz, 1H), 7.51 (s, 1 H), 7,47- 7.40 (in, 3H), 3.66 (d, J = 5.6 Hz, 2H), 1.43 (s, 6H). MS (ESI) m/z: Calculated for C 23

H

3

F

3

N

4 03: 456.14; found: 457 2 10 (M+HY EXAMPLE 82 2-(2-(4-Fluorophenyl)oxazol-4-yi)-2-rnethylpropanenitrile S.-N Mel, HNalH > TH, '-rt, CN -- F 15 This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)acetontrie using lodomethane as described in example 1 step 2 (15 g, yield 66%) as a white solid. 'H NMR (300 MHz, CDCis) 5 8,07 - 8.02 (dd, J= 8.9 Hz, 5.4 Hz, 2H), 7.66 (s, 1H), 7.19 7.13 (t, J = 8.7 Hz, 2H), 1.76 (s, 6H). MS (ESI) m/z: Calculated for C.H 1

FN

2 0: 230.09; found: 231.2 (M+H)*. 20 2-(2-(4-Fljorophenyl)oxazol-4-yl)-2-methylpropan-1 -amine .\,<Li/H H2N -/ CN----N-----\--------- I6 N ~~ 1 LLAH- Fk - THF, 0 C-rt, 1 \\ F/ This compound was synthesized from 2-(2-(4-fluorophenyl)oxazo-4-yl)-2 methylpropanenitrile as described in example 1 step 3 (14 g, crude) and it was carried 25 through without further purification. 'H NMR (300 MHz, MeOD) 5 8.07 -- 8.03 (dd, J = 8.9 Hz, 5.4 Hz. 2H), 7.73 (s, 11-), 7.26 -- 7.20 (m, 2H), 2.85 (s, 2iHl), 1.31 (s, 6H). MS (ESI) m/iz: Calculated for C 13 i-lj 5

FN

2 0: 234.12; found: 235.2 (M+Hi)*. 164 WO 2011/088181 PCT/US20111021089 2-(2-(4-Fluorophenyl)oxazol4-yl)-2-methyl-N(3-( -(trifuoromethyl)-1,2,4-oxadiazol 3-yl)benzyl)propan-1 -amine Sodiumtriacetoxy borohydride (197 mg, 0.9 mmol) was added to a solution of 3-(5 5 (trifiuoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (150 mg, 0.62 mmol) and 2-(2-(4 fluorophenyl)oxazol-4-yI)-2-methylpropan-1-amine (150 mg, 0.64 mmol) in dry DCE (2 mL) at 0 C under nitrogen atmosphere and stirred at room temperature for 8 h (monitored by TLC, petroleum etheriEtOAc 6:4). Reaction mixture was carefully quenched with 10% NaHCO 3 solution and the organic product was extracted with EtOAc. The combined 10 extracts were washed with brine, dried over anhydrous Na2SO, and concentrated under reduced Pressure. The crude product was purified by column chromatography (silica 60 120 mesh, eiuant 10-15% EtOAc in petroleum ether) to get 2-(2-(4-fluorophenyl)oxazoi-4 yi)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine (50 mg, yield 18%). 1-1 NMR (400 MHz, MeCD) 6 8.01 (im, 2H), 7.96 -- 7.92 (m, 3H); 767 (s, 1-), 15 7.54 -- 7.52 (m,I 1H), 7.49 -- 7.45 (m, 1H), 7.20 - 7.15 (m, IH), 3.82 (s, 21-), 2.76 (s, 2H), 1.32 is, 6H). MS (ES!) m/z: Calculated for CGH 2

F

4

N

4 02: 460.15; found: 461.2 (M+H)*. EXAMPLE 83 4-Phenylthiazol-2(3H)-one B KSCN, KI q 50% H2SO4 O 20 -MF, 80 *C, 2h C m A suspension of 2-bromoacetophenone (5 g, 0.0251 moi), potassium thiocyanate (8,6 g, 0.088 mol) and potassium iodide (0.25 g, 0.0015 mol) in dry DMF (25 mL) was heated to 80 IC for 2 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in glacial acetic acid (25 nL) and 50% aqueous 25 H 2

SO

4 was added to it. The reaction mixture was heated to 100 *C for 10 min. The reaction mixture was poured in ice water and the precipitate formed was filtered and dried under reduced pressure to get 4-phenylthiazol-2(3H)-one (3.3 g, yield 75%) as a brown solid, which was carried through without further purification. 30 165 WO 2011/088181 PCT/US20111021089 2-Bromo-4-phenylthiazole JPOr 3 - ' 100 *C, 1Oh sealed tube A mixture of 4-phenylthiazol-2(3H)-one (300 mg, 1.7 mmol) and POBr, (4.85 g, 17.0 mmol) was heated to 100 *C in a sealed tube for 10 h. The reaction mixture was 5 poured in ice water and the organic product was extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 1% EtOAc in petroleum ether) to get 2-bromo-4 phenylthiazole (300 mg, yield 73%) as light brown colored liquid. 1 H NMR (300MHz, 10 00013) 6 7 88 - 7.85 (m, 2H), 7.46 - 7 35 (m, 4H). MS (ESI) m/z: Calculated for

C

0 HeBrNS: 240.94; found: 242.0 (M+H)*. 3-(4,4-Dibromobut-3-en-1 -yl)benzonitrile NC, N car'; Plh NCBr Pd(OA c)2 (cat) C26B nBuNC. NaHCO3 0 0 C-r, 2h DMF, 0 -C-rt, 26 15 Tetrabutyl ammonium chloride (6.0 g, 21.83 mmol) and sodium bicarbonate (4.5g, 54.5 mnol) were taken in dry DMF (15 mL) and cooled to 0 "C and 3-iodobenzonitrile (5.0 g, 21.83 rnmol) was added. Allyl alcohol (2.2 mL, 32.7 mrno) was added to the reaction mixture, followed by a catalytic amount of Pd(OAc) 2 (146 mg, 0.65 mrnmol) and the mixture was stirred at 0 "C for 30mn. The reaction mixture was slowly warmed up to room 20 temperature and further stirred for 2 h. The reaction mixture was diluted with water and the organic product was extracted with ether. The combined extracts were dried over anhydrous Na 2 SO4 and concentrated under reduced pressure to get the crude product aldehyde. The crude aldehyde (5 0 g, 31 4 mmol) was added to a cold solution of carbon tetrabromide (20.8 g, 62.8 mmol) and triphenyl phosphine (32 8 g, 125 mmol) in CH 2 Cl2 25 (100 mL) at 0 C The reaction mixture was further stirred for 2 h maintaining the same temperature. The mixture was then diluted with hexane and the precipitate formed was filtered. The clear filtrate was concentrated to get the crude product which was purified by column chromatography (silica 60-120 mesh, eluant 10-15% EtOAc in petroleum ether) to get 3-(4,4-dibromobut-3-en-1-yl)benzonitrile (2.25 g, overall yield 33%) as a brown oil. 1 H 30 NMR (300 MHz, CDC13) 6 7,66 - 7.63 (dt, J = 7.7 Hz, 1.3 Hz, 1H), 7.55 - 7.49 (m, 2H), 166 WO 2011/088181 PCT/US20111021089 7.44 -742 (m, 1H), 6.42 -6.37 (t,J= 7.2 Hz 1H), 281 -2.76 (m, 2H), 246- 2 39 (q, J = 7 4 Hz, 2H) 3-(But-3-yn-1 -yl)benzonitrile i) NaHMDS (1 M in THF) NC. Br THF, -60 !C, 0.5h NC, 5 Br ii) nttuLi, -70 IC, 0.5k - I Sodium bis(trimethyisilyl)amide (10.7 mL, 10 7 mmol, I M in THF) was added dropwise to a solution of 3-(4,4-dibromobut-3-en-1-vl)benzonitrle (2.25 g 7.14 mmol) in dry THF (45mL) at -60 C. The reaction mixture was stirred for another 0.5 h maintaining the same temperature. The mixture was then cooled to -70 'C and n-BuLi (8.9 mL, 14 3 10 mmnol, 1.6 M in hexane) was added dropwise. The reaction mixture was stirred for 0.5 h, quenched with saturated NH 4 CI solution, and extracted with EtOAc. The combined extracts were concentrated under reduced pressure to obtain the 3-(but-3-yn-1 yi)benzonitrile (600 mg, yield 54%). iH NMR (300 MHz, CDCl 3 ) 5 7.55 (n, 1H), 7.53 7.51 (n, 1H), 7.46 - 7.39 (m, 2H), 2.90 - 2.85 (m, 2H), 2.54 - 2.48 (*d, J 7.2 Hz, 2.6 Hz, 15 21H), 2.01 - 1.99 (t, J = 2.6 Hz, 1 H). 3-(4-(4-Phenylthiazol-2-yl)but-3-yn-1-yl)benzonitrile -SPd(PPhs,)a,(cat)N N4C, Br cua (O NC, N. DMF. rt12h 3-(But-3-yn-1-yl)benzonitrile (462 mg, 2.98 mmol) and 2-bromo-4-phenyithiazole 20 (650 mg 2.71 nmol) were taken in dry DMF (20 mL) and purged with nitrogen gas for 15 min. Et 3 N (1.9 mL, 13.5 mmol) was added to the reaction mixture, followed by a catalytic amount of copper iodide (51 mg, 0.27 mmol) and Pd(PPh 3

)

4 (115 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 12 h and then quenched with water. The organic product was extracted with EtOAc, and the combined extracts were 25 concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 15-20% EtOAc in petroleum ether) to get 3 (4-(4-phenyithiazol-2-yl)but-3-yn-1-yl)benzonitrie (430mg, yield 50%) as a pale yellow solid. IH NMR (300 MHz, CDCis) 6 7.92 - 7.90 (m, 2H), 7.59 - 7.52 (m, 3H), 7.47 - 7.33 (m, 5H), 3.04 - 2.99 (m, 2H), 2.83 - 2 78 (m, 2H). MS (ESI) m/z: Calculated for 30 C, 0

HN

2 S: 314 09; found: 315.2 (M+H). 167 WO 2011/088181 PCT/US2011/021089 3-(4-(4-Phenylthiazol-2-yl)butyl)benzonitrile Ph Ph NC H2, 10% Pd-C EtOH, rt, 48h 10% Palladium on charcoal (215mg) was added to a solution of 3-(4-(4 phenvlthiazol-2-yl)but-3-vn-1-y!)benzonitrile (430mg, 1.37 mmol) in ethanol (15 mL), the 5 reaction mixture was put under -2kg H2-pressure for 48 h. The reaction mixture was filtered through a celite bed and washed thoroughly with EtOAc. The solvent was concentrated under reduced pressure to obtain 3-(4-(4-phenylthiazol-2 y!)butyl)benzonitrile (330 mg, 76%) as colorless viscous liquid. 'H NMR (300 MHz, CDCi 3 ) 6 7.90 - 7.87 (m, 2H), 7.50 - 7.33 (m, 8H), 3 13 - 3 08 (t, J = 7.5 Hz, 2H), 2 75 10 270 (t, J = 7.5 Hz, 2H), 1.93 - 1.85 (in, 2H), 1.83 - 1.75 (m, 2H). MS (ESI) n/z Calculated for C 2

CHIN

2 S: 318.12. found: 319.2 (M+H)*. N'-Hydroxy-3-(4-(4-phenylthiazol-2-yl)butyl)benzimidanide Ph HOPh Y~( NH 2 OH.H-Ci, NaoCO~ i* NC ------- H N < 8-hydroxyquinolin (cat.) EtOH, reflux, 4h 15 This compound was synthesized from 3-(4-(4-phenylthiazoi-2-yl)buty)benzonitrile as described in example I step 4 (290 mg, crude)and it was carried through without further purification. 'H NMR (300 MHz, DMSO-d6) 5 9.55 (s, I H), 7.92 - 7.90 (In 2H), 7.51 - 7.39 (in, 5H), 7.33 - 7.18 (in, 3H), 5 74 (br s, 2H), 3.07 - 3.02 (t, J = 6.9Hz, 2H), 2.67 - 2 62 (t, J = 71 Hz, 2H), 1.80 - 1.67 (m, 4H). MS (ESI) m/2: Calculated for 20 C 20

H

2 1N 3 0S: 351. 14: found: 352 2 (M+H)*. 3-(3-(4-(4-Phenylthiazol-2-yI)butyl)phenyl)-5-(trifluoromnethyl)-1 2,4-oxadiazole N/ (CFaCOO F O-N S \ - ---- +FNN 2 s pyridine, r&iux. 3h This compound was synthesized from N'-hydroxy-3-(4-(4-phenylthiazoi-2 25 yl)butyl)benzinidamide as described in example 1 step 5 (70 mg, yield 20%) as a yellow liquid. "H NMR (400 MHz, CDC1 3 ) 5 7.96 - 7 95 (m, 2H), 7.90 - 7.88 (m, 2H), 7.47 - 7.40 (n, 4H), 7.36 - 7.31 (m, 2H), 3.15 - 3.12 (t, J = 7 5 Hz, 2H), 2.81 - 2.77 (t, J = 7.5 Hz 2H), 1.95 - 1 90 (im, 2H), 1.88 - 1.82 (in, 2H) MS (ESI) in/z: Calculated for

C

22

HF

3

N

3 OS: 429.11; found: 430.2 (M+H)*. 168 WO 2011/088181 PCT/US20111021089 EXAMPLE 84 2-Diazo-1 -phenylethanone 0 ThNHNHTs' A B r ----------- N2 Ph' I DBU, THF 0 (C, 30min 5 DBU (7 5 mL, 50.2 mmol) was added dropwise to a solution of 2-bromo-1 phenvlethanone (2.0 g, 10.05 mmol) and NN'-bis(p-toluenesulfonyl) hydrazine (6.8 g, 20.1 mmol) in dry THF (30 mL) at 0 *C. The reaction mixture was stirred at 0 C for 30 min. and quenched with aqueous saturated NaHCO 3 solution The organic product was extracted with EtOAc and the combined extracts were washed with brine, dried over 10 anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chrornatography (silica 60-120 mesh, eluant 10-15% EtCAc in petroleum ether) to get 2-diazo-1-phenylethanone (1.2 g, yield 82%) as a yellow solid. 'H NMR (300 MHz, CDCl) F, 7.78 - 7.76 (m, 2H), 7.56 - 7.53 (m, 1H), 7.48 - 7.43 (m, 2-1), 5.91 (s, 1H). 15 2-(5.-Phenyloxazol-2-yI)acetonitrile O NC ,CN

IBF

3 .Et2O DCM, 0 hC-rt, 1h

BF

3 ,Et 2 0 (1.1 mL, 8.5 mmol) was added dropwise to a solution of malononitrile (2.26 g, 34.2 mmol) in dry CH 2 Cl 2 (20 rnL) at 0 "C, followed by addition of 2-diazo-1 20 phenylethanone (0.5 g, 3.4 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for I i and then quenched with aqueous 10% NaOH solution. The organic product was extracted with EtOAc and the combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 5 25 10% EtOAc in petroleum ether) to get 2-(5-phenyloxazoi-2-yl)acetonitrile (200 mg, yield 32%) as a brown solid. H NMR (300 MHz, CDla) 5 7.66 - 7.63 (m, 2H), 7.47 - 7.38 (m, 3H), 7.32 (s, 1H), 4.02 (s, 2H). MS (ESI) m/z: Calculated for CIHsN 2 0: 184.06; found: 185.2 (M+H). 30 2-Methyl-2-(5-phenyloxazol-2-yl)propanenitrile 169 WO 2011/088181 PCT/US20111021089 Mel, NaH NC / NC-THF, *C-t 1 This compound was synthesized from 2-(5-phenyloxazoi-2-yl)acetonitrle using lodomethane as described in example 1 step 2 (150 mg, yield 65%). 'H NMR (300 MHz, CDCI) o 7.56 - 7.64 (m, 2H), 7 47 - 7.36 (m, 3H), 7 29 (s, IH), 1.88 (s, 6H). MS (ESI) 5 rn/z: Calculated for C,,HN,0: 212.10 found: 213.2 (M+H)'. 2-Methyl-2-(5-phenyloxazol-2-yl)propan-1-amine NC v4l==\H2N V THF, 0 *CI-rt, 1 O This compound was synthesized from 2-nethyl-2-(5-phenyloxazol-2 10 vi)propanenitrile as described in example I step 3 (100 mg, crude)and it was carried through without further purification MS (ESI) m/z: Calculated for C 13

H

16

N

2 0: 216.13; found: 217 2 (M+H) N-(2-Methyl-2-(5-phenyloxazol-2-yI)propyl)-3-(6-(trifluoromethyl)-I,2,4-oxadiazol-3 15 yl)benzamide NN OH Fac-\N / HN-------------------- + e HATU NMM 0 DMF, OC-rt 4h This compound was synthesized from 2-methyl-2-(5-phenyloxazol-2-yi)propan.1 amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (18 mg, yield 10%) as a yellow viscous liquid. 'H NMR (400 MHz, 20 MeOD) 6 8.50 - 8.49 (t, J = 1.8 Hz, 1H), 8.28 - 8.25 (dt, J = 7.8 Hz, 1.4 Hz, 1H), 8.00 7.98 (dt, J = 7.8 Hz, 1.5 Hz, 1H), 7.68 - 7.64 (m, 3H), 7.39 - 7.36 (m, 3H), 7.32 - 7.27 (Im, 1H), 4.58 (s, 2H), 1 54 (s, 6H). MS (ESI) m/z: Calculated for C2 3 HsF 3

N

4 0 3 : 456.14; found: 457 2 (M+H) 25 170 WO 2011/088181 PCT/US20111021089 EXAMPLE 85 Ethyl 2-phenylthiazole.-carboxylate NBs Ph P C2 EE0 0 Ph dioxane-H0 1:1 / dioxane-H 2 0 1:1 vv -1i0 oc-et, 1 h sL sr - c, ibh Ethyl-3-ethoxyacryalate (4.0 g, 27 7 mmol) was dissolved in dioxane-H 2 0 (30 ml. 5 1:1 v/v) and cooled to -10 'C. N-Bromosuccinimide (5.43 g, 30.5 mmol) was added to this solution and the reaction mixture was allowed to warm up to room temperature and further stirred for I h. Thiobenzamide (3.8 g, 27.7 mmol) was then added and the reaction mixture was further heated to 80 'C for 1 h. The reaction mixture was then cooled to room temperature and quenched with aqueous ammonia solution. The organic product was 10 extracted with EtOAc and combined extracts were washed with H 2 0 and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica ge 60-120 mesh, eluent 5-10% EtOAc in petroleum ether) to afford ethyl 2-phenylthiazole-5-carboxylate (1.1 g, yield 17%) as a yellow solid. 'l-i NMR (300 MHz, CDC 3 ) Z 8.43 (s, 1-1), 8.01 - 7.98 (m, 2H), 7.48 - 7.48 15 (m, 3H), 4.44 - 4.37 (q, J = 7.2 Hz, 2H), 1.44 - 1.39 (t: J = 7.2 Hz, 3H). MS (ESI) m/z: Calculated for C, 2

HINO

2 S: 233.05; found: 234.0 (M+H)'. (2-Phertylthiazol-5-yl)methanol LAiH 4

N

O THF, 0 *C-rt, 1h S 20 This compound was synthesized from ethyl 2-phenylthiazole-5-carboxylate as described in example 1 step 3 (390 mg. yield 95%) as a yellow solid. 'H NMR (300 MHz, CDC1s) 5 7.95 -- 7.92 (m, 2H), 7.71 (s, 1 H), 7.46 -- 7.43 (im, 3H), 4.91 (s, 2H). MS (ESI) m/z: Calculated for C, 2 i-1 9 NOS: 191.04; found: 192.2 (Mil+H)'. 25 5-(Bromomethyl)-2-phenylthiazole N--,\ Cr 4 PPh2 N-- Ph W H ___ ___ _ P Or Ph- P CH2C2 -h 6 (2-phenylthiazol-5-y!)methano (390 mg, 2.03 mmol) was dissolved in dry CH 2 C2 (10 mL) and cooled to 0 "C. Triphenyl phosphine (800 mg, 3.05 mmol) was then added, followed by carbon tetrabromide (1.35 g, 4.07 mmol). The reaction mixture was allowed to 30 warm up to room temperature and stirred for i h. The reaction mixture was then concentrated under reduced pressure and the crude product was purified by column 171 WO 2011/088181 PCT/US20111021089 chromatography (silica 60-120 mesh, eluant 5% EtOAc in petroleum ether) to get 5 (bromomethyl)-2-phenylthiazole (250 mg, yield 48%) as light yellow solid. 'H NMR (400 MHz, CDCI 3 ) 5 7.95 - 7.92 (m, 2H), 7.80 (s, IH), 7.46 - 7.45 (n, 3H), 4.77 (s, 2H). IS (ESI) m/z: Calculated for C 1 DHsBrNS: 254.95; found: 256.0 (M+H)'. 5 2-(2-Phenylthiazol-5-yl)acetonitrile N--- KON N--- N Ph- - CN S DMFrr, 10hb KCN (154 mg, 2.36 mmol) was added to a solution of 5-(bromomethyl)-2 phenylthiazole (400 ng, 1.57 mmol) in dry DMF (10 mL). The resulting reaction mixture 10 was stirred at room temperature for 10 h. The mixture was then quenched with water and the organic product was extracted with EtOAc. The combined extracts were washed with

H

2 C and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 20% EtOAc in petroleum ether) to afford 2-(2-phenylthiazol-5-yl)acetonitrile 15 (230 mg, yield 73%) as a white solid. 'FH NMR (300 MlHz, CDCl 3 ) 5 7.94 - 7.90 (m, 2H), 7.76 (s, 1H), 7.47 -- 7.45 (m, 3H), 3.98 (d, J = 1.1 Hz, 2H). MS (ESI) m/z: Calculated for

C,

1 ,H.N2S: 200.05; found: 201.2 (M+H)*. 2-(2-Phenylthiazol-5-yl)ethanamine

BH

3 .M0 2 S Ph -- CN----------- o f'NH, 20 T HF. rt. 60 *C, lh 'h '' This compound was synthesized from 2-(2-phenylthiazol-5-yl)acetonitrile as described in example 42 step 1 (150 mg, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for CH 1 2

N

2 S- 204.08; found: 205.2 (M+H)* 25 N-(2-(2-Phenylthiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)benzamide F3C''CO2H H Ph'- -F HA7rU. NMM N ' ' DMF, 0 C-rt 6h This compound was synthesized from 2-(2-phenylthiazoi-5-.yl)ethanamine and 3 (5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (35 172 WO 2011/088181 PCT/US20111021089 mg, yield 27%) as an off white solid 'H NMR (400 MHz, MeOD) 5 8.61 (t, J= 1.5 Hz, 1H), 8 32-8.29 (dt, J= 78 Hz, 1.3 Hz, I1H), 8.09-8.06 (dt, .J= 7.8 Hz, 1.5 Hz, IH), 7.90 - 7.88 (m, 2H), 7.73 - 7.69 (t, J = 7.9 Hz, 1H), 7.66 (s, 1H), 7.47 - 7.45 (im, 3H), 375 3.71 (t, j = 6.8 Hz, 2H), 3,28 - 3.25 (t, J = 6.8 Hz, 2H). MS (ESI) m/z: Calculated for 5 C2HF 3

N

4 O2S: 444.09; found: 445.0 (M+H)+, EXAMPLE 86 2-Methyl-2-(2-phenylthiazol-5-y)propanenitrile N- Mel, NaH N-, Ph N - - -- CN .___ _ _ _ PhC Ph 0 DMSO, 0 C-rt, 1.5h P 10 This compound was synthesized from 2-(2-phenylthiazol-5-yl)acetonitrile using lodomethane as described in example 1 step 2 (210 mg, yield 80%) as a yellow liquid. 1 H NMR (400 MHz, CDCl 3 ) 6 7.93 -- 7.90 (m, 2H) 7.79 (s, 1H), 7.47 - 7.45 (m, 3H), 1.86 (s, 61H). MS (ESI) m/z: Calculated for C 1 3 H,

N

2S. 228.07; found: 229.2 (M+-H)*. 15 2-Methyl-2-(2-phenylthiazol-5-yl)propan-1 -amine N--7 , LiAlH 4 N---- \ Ph N Ph> NH2 / THF. 0 "C-rt 1h , / This compound was synthesized from 2-methyl-2-(2-phenythiazo-5 yl)propanenitrile as described in example I step 3 (100 mg, crude) and it was carried through without further purification. MS (ESI) rnz: Calculated for CI3H6N 2 -S: 232.10: 20 found: 233.2 (M+H)*. N-(2-Methyl-2-(2-phenylthiazol-5-yl)propyl)-3-(5-(trifluorornethyl)-1,2,4-oxadiazol-3 yl)benzamide

PNH

2 - - - - - - - - - - - - - - - - - F C x HATU, NUM 0 -N 0 DMF. 0 "C-r. 4h 25 This compound was synthesized from 2-rnethyi-2-(2-phenylthiazol-5-y!)propan-1 amine and 3-(5-(trifiuoromethyl)-1,2,4-oxadiazol-3-yl)benzoc acid as described in example 8 step 6 (70 mg, yield 51%). 1 H NMR (400MHz, MeCOD) 5 8.55 (t, J = 1.6 Hz, I H), 8.29 - 8.26 (dt, J = 7.9 Hz, 1.3 Hz, 11H), 8 03- 8.01 (dt, J = 7.8 Hz, 1.5 Hz, I H), 7.91 173 WO 2011/088181 PCT/US20111021089 - 7.88 (n, 2H), 7.70 - 7.66 (m, 2H), 7.47 - 7 45 (m, 3H), 3.64 (s, 2H), 1.53 (s, OH). MS (ESI) m/z: Calculated for C 23

HOFN

4 0 2 S- 472.12; found: 473.2 (M+H)*. EXAMPLE 87 5 N-((4-(2-(4-Chlorophenyl)thiazol-4-yl)-1 -methylpiperidin4-yl)methyl)-3-(5 (trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide /f\0,--N O N O N N O N r HATU. NMM H IN O Cr,1hN This compound was synthesized from (4-(2-(4-chlorophenyl)thiazo!-4-y)-1 methylpiperidin-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazoi-3-vl)benzoic 10 acid as described in example 8 step 6 (50 mg, yield 23%). 'H NMR (400MHz, DMSO-d,) 6 .54 - 8.51 (m, IH), 8.39 (m, 1H), 8.18 - 8.16 (d, J = 7.6 Hz, 1H), 8.04 - 8.02 (d, J 7.6 Hz, IH), 7.91- 7.89 (d, J = 8.2 Hz, 2H), 7.69 - 7.65 (t, J = 7.8 Hz, 1H), 7.52 - 7.49 (m, 3H), 3.49 - 3.48 (m, 2H), 2.66 - 2.63 (rn, 2H), 2.31 - 2.28 (m, 2H), 2.12 - 2.04 (M, 5H), 1.90 - 1.84 (m, 2H). MS (ESI) m/z: Calculated for C23H 2 3 ClF 3 NsO 2 S: 561.12 found: 562.0 15 Mi-H). EXAMPLE 88 1 .- (-Bromnothiophei-.2-y)-2,2,2-trifluoroethano H / ~ CsF, TMSCF, FC Br --- --------- - Br dry glyme. rt. 3h HO 20 CsF (400 mg, 2.6 mmol) was added to a solution of 5-bromothiophene-2 carbaldehyde (5.0 g, 26.17 mmol) in dry 1,2-dinethoxyethane (20 mIL), followed by trifluoromethyl trimethylsilane (4.6 mL, 31.4 mmol) dropwise at 0 "C. The reaction mixture was stirred at room temperature for 3 h, quenched with 1.5N HCI, and stirred for an additional 30 min. The crude product was extracted with CH 2 Ci;. The combined extracts 25 were dried over anhydrous Na2.SO 4 , and concentrated under reduced pressure The crude product was purified by column chromatography (silica 60-120 mesh, eluant 5-10% EtOAc n petroleum ether) to get 1-(5-bromothiophen-2-yi)-2,2,2-trifluoroethano (4 g, yield 59%). H NMR (400 MHz, CDCi 3 ) 6 7.01 (m, 1H), 6.95 (m, 1H), 5.23 - 5.18 (q, J = 5.9 Hz, 1H), 3.07 (br s, IH). MS (ESI) m/z: Calculated for CfH4BrF 3 OS: 261.91; found: 260.7 (M-1)-. 174 WO 2011/088181 PCT/US20111021089 1 -(5-Brornothiophen-2-yi)-2,2,2-4rifiuoroethanone F3C Dess-Martin F 3 C Br ------------- ESBr H CH 2 CI O 0 *C-ri, 3h This compound was synthesized from 1-(5-bromothiophen-2-yi)-2,2,2 5 trifluoroethanol as described in example 47 step 2 (0.8g, yield 42%). H NMR (400 MHz,

CDC

3 ) 6 7.72 - 7.71 (m, 1H1), 7.24 - 7.23 (d, J = 4.3 Hz, 1H). 3-(5-(2,2,2-Trifluoroacetyl)thiophen-2-yl)benzoic acid HO2C B(H F3C F 3 C / -- 'Br ----------- CO2H- Pd(PPhs) 4 (cat.) 2M Na2CO3, DM, 90 "C,h 10 1-(5-Bromothiophen-2-yl)-2,2,2-trifiuoroethanone (0.8 g, 3.09 mmol) and 3 carboxyphenylboronic acid (0.5 g, 3.01 mmoi) were dissolved in DMF (10 mL) and the solution was purged with argon for 10 min. 2M aqueous solution of Na 2

CO

3 (0.65 g, 6.17 mmol) and catalytic Pd(PPh 3

)

4 (178 mg. 0.15 mmol) were added to the reaction mixture and heated to 90 'C for 10 h. The reaction mixture was cooled to room temperature, 15 diluted with water and acidified to pH -6 with 1.5 N HCI. The crude product was extracted with EtOAc. The combined extracts were dried over anhydrous Na 2 SO, and concentrated under reduced pressure The crude product was triturated with diethvl ether to get 3-(5 (2,2,2-triflucroacetyi)thiophen-2-yi)benzoic acid (700 mg, yield 79%). 'H NMR (400 MHz, DMSO-do) 6 13.35 (br s, 1H), 8.31- 8.30 (im 1H), 8.16 - 8.11 (in, 2H), 8.04 - 8.02 (d, J = 20 7.6 Hz, 1H), 7.93 -- 7.92 (d, J= 4.3 Hz, IlH), 7.67 -- 7.63 (t, J= 7.8 Hz, 1H). MS (ESI) M/z: Calculated for C,3HF 3 0 3 S: 300.01; found. 299.0 (M-1)~. 175 WO 20111088181 PCT/US201l11021089 N-(2-(2-(4.Fluioroplhenyl)oxazol-4-yi)-2-methiylpropyl)-3(5-(2,2,2 trifi ueroacetyl)th iophe n-2-yl) benza mide HXTN,\N / 'PAF 0- -- r 4 This cpun vvs snhszd fo 4-4-l Arphnloao14y)2 rneth 2 _opan-__amine and 35-222ti'Looaeyth plr--ybriic cd a mahvprpa-i-mie ns3-5-22,2-Trfurae-ltiole--lntrii actlidpe--ibzi cda desorised0'),' ineape Stp6( g ild5) H M 40M),DS-d)885 15 This,2-Tfcompondtwast snthes--y~iedni frm1acid onoho0e.2y.)22 Pd(PH 1 ) catL)1 2N Na AU. M N0I , 0 15 This compound Was syntesizd from 1-(-bft(rootinoxen--y)-,2 ~~~~~~~n -'-222trifluoroathanlone and 5-borononicotinic acid asdecidineape8 stp3(7 m, 25dsrbdMeape8se 4 yield 262). 1 H NM (300 MHz, DMSO-dI,1.4 S , H, .0 9.29 a H,91 9.10 J(in.1 Hzi .H,9 (,1H), 8.59 -85 8.60 (m .0H , 1H), 8. 52 - (i ,5 (t, 80 -2.05 (in, 1H).&2 20176 WO 2011/088181 PCT/US20111021089 - 8.20 (n i H), 8 02 - 7 98 (m, 4H), 7.36 - 7.30 (m, 2H), 3.53 - 3.52 (d, J = 0.1 Hz, 2H), 1 30 (s, 6H). EXAMPLE 90 5 N-((4-(2-(4-Chloropheny)thiazol-4-yl)-I -methylpiperidin-4-yi)methyl)-3-(5-(2.2,2 trifluoroacetyl)thiophen-2-yl)benzamide LAF, 3'2-r, 10h~ Th~ H This compound was synthesized from (4-(2-(4-chlorophenyl)thiazoi-4-yl)-1 methylpiperidin-4-yl)nethanarnine and 3-(5-(2,2,2-triluoroacetyl)thioohen-2-yl)benzoic 10 acid as described in example 8 step E (8.5 mg, yield 4%). 'H NMR (400 MHz, DMSO-d6) 6 8.54 (m, 1H), 8.14 -8.13 (im, 2H-), 8.00 -- 7.86 (n, 41-i), 7.82 - 7.77 (m, 1H), 7.70 (m, 1H), 7.60 - 7.56 (m, 1), 7.48 .- 7.46 (m, 2H), 3.50 (m, 21H), 3.39-3.17 (m, 41H), 2.57 (in, 3H), 2.43 (m, 2H), 2.08 (m, 2H). 15 EXAMPLE 91 5-Cyano-2-fluorobenzoic acid 30% H 02 NaCI02 (aqueoIus solution) NC NalH 2

PO

4 (aqueous solutori NC -' C 2 H F MeCN, *C-rt, Ih F NaH 2

PO

4 (87 mg, 0.724 mmol) in water (3.5 mL) was added to a solution of 5 cyano-2-fluorobenzaldehyde (500 mg, 3.35 mmol) in acetonitrile (7 mL), followed by 30% 20 H 2 0 2 (0.31 mL). Sodium chlorite (434 mg, 4.8 mmol) in water (3.5 mL) was added dropwise to this reaction mixture at 0 "C. The mixture was stirred at room temperature for 1 h, quenched with aqueous sodium sulfite solution at 0 'C and then acidified with 1.5N HCi solution. The aqueous solution was extracted with EtOAc and the combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 25 afford 5-cyano-2-fluorobenzoic acid (500 mg, yield 90%). 'H NMR (300 MHz, DMSO-dG) 6 13.79 (br s, 1 H), 8.30 -- 8.27 (dd, J = 6.6 Hz, 2.2 Hz, 1HI), 8.17 - 8.12 (ddd, J = 8.6 Hz, 4.4 Hz, 2.3 Hz, 1H) 760 - 7.53 (dd, J = 10.5 Hz, 8.8 Hz, 1H). MS (ESI) m/z: Calculated for CH 8 1- 4 FNO2: 165.02; found: 163.6 (M-H)~. 177 WO 2011/088181 PCT/US20111021089 2-Fluoro-5-(N'-hydroxycarbaninidoyl)benzoic acid NH2OH.HCI, Na2CO HO N NC- -CO 2 H ~----------" HNCO 2 H 8-hydroxyquinoline (cat) F EtOH, rflux, 4h This compound was synthesized from 5-cyano-2-fluorobenzoic acid as described in example I step 4 (400 mg, crude) and it was carried through without further purification. 5 1H NMNIR (400 MHz, DMSO-d 6 ) 5 13.72 (br s, IH), 11 43 (br s, IH), 10.39 (br s, 2H), 8.24 8.22 (m, 1H), 8.04 - 8.01 (m, 1H), 7.61 - 7.56 (t, J = 9.6 Hz, 1H). MS (ESI) m/z: Calculated for C3H 7

FN

2

O

3 : 198.04; found: 1988 (M+H)*. 2-Fluoro-5-(5-(trifluoromethyl)-1.2,4-oxadiazol-3-yl)benzoic acid HO, PN IIN. (CF 3

CO)

2 0) F ,C H2N A O 2 H r N CO2H pyridire, reflux, 3h F F 10N N This compound was synthesized from 2-fluoro-5-(N' hydroxycarbamimidoyl)benzoic acid as described in example 1 step 5 (130 mg, yield 23%). 'H NMR (300 MHz, DMSO-d,) 5 13.72 (br s, 1H), 8.51 -- 8.48 (dd, J = 6.9 Hz, 2.3 Hz 1H), 8.33 -- 8.29 (m, 1H), 7.62 -- 7.55 (dd, J = 10.2 Hz, 8.9 Hz, 1H). MS (ESI) m/z: 15 Calculated for C1OH 4 F4N 2 0 3 : 276.02 found: 274.8 (M-H). 2-Fluoro-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl) 1,2,4-oxadiazoI-3-yl)benzamide \F N N O FU i i ji I F/c- c1\ Fac- HATU, NMM F 20 This compound was synthesized from 2-(2-.(4-flucropheny)oxazo-4-yl)-2 methylpropan-1-amine and 2-fluoro-5-(5-(trfluoromethyl)- 1,2,4-oxadiazoi-3-yl)benzoic acid as described in example 8 step 6 (75 mg, yield 32%) as a yellow viscous liquid. 1 H NMR (400M-lz, MeOD) 6 8.46 -- 8.43 (dd, J = 6.8 Hz, 2.3 Hz, i1H), 8.29 - 8.25 (ddd, J 8.7 Hz, 4.8 Hz, 2.4 Hz, 1H) 8.09 - 8.05 (dd, J = 9.0 Hz, 5.3 Hz, 2H), 7.77 (s, IH), 7.47 25 7.42 (dd, J = 10.3 Hz, 8.8 Hz, 1H),7.25 -- 7.20 (t; J = 8.9 Hz, 2H), 3.67 (s, 2H), 1.41 (s, 6H). MS (ESI) rm/z: Calculated for C 2 3H 17 lFN 4 03: 492.12: found: 493.2 (M+H)*. EXAMPLE 92 178 WO 2011/088181 PCT/US20111021089 (E)-ethyl 2-styryloxazole4-ca rboxylate aC ) NaHCC-, THF, reiux, 23h Ph < NH 2 + r. 'COcE Phe N H) (CF 3 CO)O. THFP, 0 C-rt, 1 Oh Ethyl bromopyruvate (10 mL, 81.55 rnmol) was added dropwise to a solution of 3 phenylacrylamide (5 g, 33.97 mmol) and NaHCO 3 (11.42 g, 135.89 mmol) in anhydrous 5 THF (120 mL) at 0 "C. The reaction mixture was heated to reflux for 23 h. The mixture was then filtered through Celite and the solvent was removed under reduced pressure. The crude product was dissolved in anhydrous THF (80 mL) and trifluoroacetic anhydride (37 mL) was added dropwise at 0 OC. The reaction mixture was stirred at room temperature for 10 h, and quenched with saturated NaHCO, solution at 0 C. The organic 10 product was extracted with EtOAc, and the combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10% EtOAc in petroleum ether) to afford (E)-ethyl 2-styryloxazole4-carboxylate (4.22 g, yield 51%) as an off white solid. IH NMR (300 MHz, CDC 3 ) 6 8.21 (s, 1H), 7.66- 7.61 (d, 15 J = 16,4 Hz, 1H), 7,56 - 7.52 (m, 2H), 7,44 - 7.36 (m, 3H), 7,00 - 6.94 (d, J = 16.4 Hz, IH), 4.46 - 4.39 (q, j = 7.0 Hz, 2H), 1.44 - 1.39 (t, J = 7.0 Hz, 3H). MS (ESI) n/z: Calculated for CIH.1 3

NO

3 : 243.09; found: 243.8 (M+H) . Ethyl 24ormyloxazole-4-carboxylate i) 03%04 (4% in H20) MesN(O) acetone-iH2 10.1 v/v rt, 3h 0 -- CC Et IN -i Oz Xf'N Ph ii) Pb(OAcA veOH K2COs 20 0 C-rt 20mir Os0 4 [10 mL, 0.41 mmol, 4 % in H 2 O] was added dropwise to a solution of (E) ethyl 2-styryloxazole-4-carboxylate (4 g, 16 44 mmol) and trimethylamine N-oxide (1.84 g, 24.5 mmol) in acetone-H 2 0 (88 mL; 10:1 viv) The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. The crude product 25 was purified by column chromatography (silica gel 60-120 mesh, eluent 50% EtOAc in petroleum ether) to afford an intermediate (1.5 g, 5.41 mmo) which was dissolve in anhydrous benzene (30 mL). K 2

CO

3 (0.85 g, 6.17 mmol) was added to the reaction mixture followed by Pb(OAc) 4 (2.73 g, 6.17 mmol). The reaction mixture was stirred at room temperature for 20 min and then quenched with saturated NaHCO 3 solution. The 30 organic product was extracted with EtOAc. Solvent was removed under reduced pressure 179 WO 2011/088181 PCT/US20111021089 and the crude product was purified by column chromatography (silica gel 60-120 mesh, fluent 30% EtOAc in petroleum ether) to afford ethyl 2-formyloxazole-4-carboxylate (0.65g, overall yield 24%) as an off white solid. '4H NMR (400 MHz, CDCWl) 6 9.84 (s, 1H), 8.43 (s, 1H), 4.49 - 4.44 (q, J = 7.0 Hz, 2H), 1.45 - 1.41 (t, J = 7.0 Hz, 3H). MS (ESI) 5 mi: Calculated for CrHrNO 4 : 169.04; found: 169.8 (M+H)*. Ethyl 2-cyanooxazole-4-carboxylate i) 50% aq. NH 2 OH MeOH, rt, 3h O 7-C2Eti -- C-00Et O N i) T3P (5% irn EtOAc) N DMF, 100 "C, 2h A solution of ethyl 2-forrmyloxazole-4-carboxylate (650 mg, 3.84 mmol) in methanol 10 (25 mL) was cooled to 0 'C and 50% aqueous hydroxylamine (0.22 mL, 7.68 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. Solvent was removed under reduced pressure and the crude product (0.52 g) obtained was dissolved in DMF (20 mL). TP (3.4 mL, 5.65 mmol; 50% in EtOAc) was added to the reaction mixture and heated to 100 *C for 2 h. The reaction mixture was quenched with 15 saturated NaHCO 3 solution and the organic product was extracted with EtOAc. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10% EtOAc in petroleum ether) to afford ethyl 2- cyanooxazole -4-carboxylate (O.34g, yield 53%) as an off white solid. '-I NMR (300 MHz, CDClI) 6 8.39 (s, 11H), 4.48 -- 4.41 (q, J = 7.0 lz, 2H), 1.44 -- 1.39 (t, J = 7.0 Hz, 20 3H). Ethyl 2-(N'-hydroxycarbamimidoyl)oxazole4-carboxylate

NH

2 OH.HCI, Na 2 C>

-CO

2 Et M| 7-OEt ---------------------- N N N -- N E 8-hydroxyquincline (cat.) EtOH, reflux. 2h NI-1 2 This compound was synthesized from ethyl 2-cyanocxazole-.4-carboxylate as 25 described in example 1 step 4 (500 mg, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for CrHjN 3 0 4 : 199.06; found: 199.8 (M+H)*. 180 WO 20111088181 PCTUS201 11021089 Ethyl 2-(6-(trifluoronmethyl).1,24-oxadiazol-3-yl)oxazole.4-carboxykate N Y---(CF3CO) 2 C) HO'y , pyridine, F 2 C N

NH

2 reflx, 3h0 This -cornpound wes synthesized from ethyl 2- (N.h yd roxycarba mi mid oy)oxazole-. 4--caboxylate as described in example 1 step 5 (50 mg, yield 7%). 'H NMR (400 MHz, 5 ODd1 3 ) 6 8.49 Is, 1 H), 4.49 .-- 4.44 (q, J = 7.0 1-Iz, 2[40, 1.45 -- 1.41 (t, J = 7.0 Hz; 31-I). MS (ES1.) n/z: Calculated for CJ-H61 3 N30 4 : 277.03: found: 277.9 (M.1-H)'. 2-(8-(r'rifluoromethyl)-1 ,2,4-oxadiazol-3-yl)oxazole-4-carboxylic acid i > --- CO 2 -E+ LiOl-l --- I F2 THF-H20 7- ' F 2

C-

b~ 0 (.;- r" 1 h 10 This compound was synthesized from ethyl 2-(S5-(trifluoromethyl)-1.2.4-oxadiazol 3-yl)oxazole-4-carboxylate as described in example 43 step 2 (25 mng. 56%) as an of white -Aolid. 'H NMR (400 M Hz, DMSO-dfe) 5 13.65 (bor s, I H), 9.18S (s, I1H). MIS (Es1) m/z Calculated for C, H 2

F

3 N3(O 4 : 249 00; found: 248 0 (M.%-H)-. 15 N-(2-(2-(4-Fluioroplhenyl~oxazol-4-yl)-2-methylpropyl)-2(6-(trifluoromnetyl)-1,2,4 oxadiazol--yl)oxazole-4-carboxarnide

.~-O

2 ' PO , - I-jATLJ, NOM 0 -N N DOAF. 0 ICrt, Sh This compound was syntheized from 2-(2-(4-filucrophenyl)oxazo-4-y)-2 methvylpropan-i -amnine ano 2-(5-(ti !luormmethy)-1 ,2,4-oxadiazol-3-y)oxazole-4-carboxylic 20 acid as described in example 8 step 6 (6 mg, yield 13%). 'H NNMR (400 M,-Hz., CDC1,) 6 8.88 -8.86 (in, 1 H), 8.49 (s, 1IH), 8.25 -8.21 (m? 2H), 7.46(,? I H), 7.23 -7.19 (t, J =8 8 Hz, 2H), 3.62 - 3.60 (d, J =8.0 Hz, 2H), 1 39 (s, 6H). MS (ESI) m/,z.: CaIlulated for

C

20

-HI,F

4 1N 5 0 4 : 465.11; fOUnd: 468 1 (M+HY)' 25 WO 2011/088181 PCT/US20111021089 EXAMPLE 93 Methyl 1-methyl-2-phenyl- H-imidazole-5-carboxylate HIO OH 2M K2CO3 Br Pd 2dpf, -- :oluene-EtOH N reflux, 1 h Methyl-2-bromo-1-methyl-1H-imidazole-5-carboxylate (1 g, 4.56 mmol) and 5 phenviboronic acid (0.67 g, 5.48 mmol) were dissolved in toluene-EtOH (80 mL, 5:3 v/v) and the solution was purged with argon for 10 min. K 2

CO

3 (10 mL, 2M solution) and catalytic PdCl 2 (dppf) (82 mg, 0.12 mmol) were added and the reaction mixture was heated to 100 'C for I h. The reaction mixture was then cooled to room temperature and concentrated under reduced Pressure. The residue was diluted with water and washed 10 with EtOAc. The aqueous layer was acidified to pH ~6 using 1.5N HCI and the crude product was extracted with EtOAc. The combined extracts were dried over anhydrous Na 2

SO

4 , and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 35-45% EtOAc in petroleum ether) to get methyl 1-methyl-2-phenyl-1H-imidazole-5-carboxylate (800 mg, yield 81%) as a pale 15 yellow solid. IH NMR (400 MHz, CDCs) 6 7.86 (s, 1H), 7.63 -- 7.61 (m, 2H), 7.51 7.48 (in, 3H), 3.96 (s, 3H), 3.89 (s, 3H). MS (ESI) rn/: Calculated for C1 1 l-L 2

N

2

O

2 : 216.09; found: 2168.8 (M+H)*. (1 -Methyl-2-phenyl-1H-imidazol-5-yl)methanol o N LiAH4 H N.

r4 ' I, --- ' HO N 20 '--N THF, O"C-rt, Ih This compound was synthesized from 1-methyi-2-phenyl-1H-imidazole-5 carboxylate as described in example 1 step 3 (600 mg, yield 86%) as a white solid. 1 H NMR (300 MHz, MeOD) 6 7.60 - 7.57 (m, 2H), 7.50 - 7.48 (m, 3H), 7.00 (s, 1H), 4.64 (s. 2H), 3.72 (s, 3H). MS (ESI) m/z: Calculated for Cn H N20: 188.09; found: 188.8 (M+H) 25 5-(Ctlloromethyl)-1-methyl-2-phenyl-1H-irmidazole hydrochloride HO N ISOC\ N reflux, 1h HC A solution of (1-methyl-2-phenyl-1H-imindazo-5-yl)nethanol (0.600 g, 3.19 mmol) in dry SOCl 2(11 mL) was refluxed at 80 *C for 1 h. The reaction mixture was concentrated 30 under reduced pressure and the residue was co-evaporated with CH 2 Cl2, and then 182 WO 2011/088181 PCT/US20111021089 triturated with diethyl ether, fitered and dried under suction to afford 5-(chloronethyl)-1 nethyl-2-phenyl-1H-irnidazole hydrochloride (067 g, yield 86%) as a white solid. 'H NMR (300 MHz, MeOD) 6 7.79 - 7.79 (i, 6H). 4.98 (s, 2H), 3.93 (s, 3H). 5 2-(1-Methyl-2-phenyl-1H-inidazol-6-yl)acetonitrile N / N'CN C ----- -- ---- C --N . rt 8h N This compound was synthesized from 5-(chooromnethyl)-1-rethyl-2-phenyl-l inidazole hydrochloride as described in example 77 step 1 (400 mg, yield 90%). IH NMR (300 MHz, CDCI 2 ) 6 7.61 - 7.58 (n, 2H), 7.49 - 7.44 (m, 3H), 7.12 (s, 11-), 3.79 (s, 2H), 10 3.71 (s, 3H). MS (ESI) m/z: Calculated for C 12

HN

3 : 197.10; found: 197.9 (M+H)*. 2-(1 -Methyl-2-phenyl-1H-imidazol-5-yl)propanenitrile N Mel, NaH N NC ----------------- - NC -N THF, 0 "C, 3.hN This compound was synthesized from 2-(1-nethyl-2--phenyl-1H-imidazoi-5 15 yi)acetonitrile as described in example 1 step 2 (170 mg, yield 53%) as colorless oil. 'H NMR (400 MHz, CDClk) 6 7.61 - 7.58 (m, 2H), 7.52 - 7.46 (m, 3H), 7.10 (m, 11-), 4.00 3.95 (q, J = 7.2 Hz, 1i ), 3.74 (s, 3H), 1.83 -- 1.81 (d, J= 7.2 Hz, 3H). MS (ESI) m/z: Calculated forC3H 3 N,: 211.11; found. 211.9 (M+H-)*. 20 2-(1 -Methyl-2-phenyl-1IH-imidazol-5-yl)propan-1-amine N LiAlH (2M in THFi . > CN H 2 N N SN O *C-ft, 1h This compound was synthesized from 2-(1 -methyl-2-phenyl-1H-imidazol-5 yi)propanenitrile as described in example 1 step 3 (155 mg, crude) and it was carried through without further purification. MS (ESi) m/z: Calculatec for C1H 17 N3: 215.14; found: 25 215.9 (M+H)*. 183 WO 2011/088181 PCT/US20111021089 N-(2-(1 -Methyl-2-phenyl-1 H-imidazol-5-yl)pro~pyl)-S-(5-(trifluorom-ethyl)-1,2,4 oxadiazol-3-yl)nicotinamide C \\-!t FCN '''OH N HATU, N.M DMF 0 C-ri, 3h This compound was synthesized from 2-(1-methyl-2-phenyl-1H-iridazo-5 5 yi)propan-1 -amine and 5-.(5-(trifiuoromethyl) -1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (35 mg, yield 28%). 1 H NMR (400MHz, DMSO-d,) 6 9.36 (d, J = 2.1 lz, 11H), 9.26 -- 9.26 (m, 2H) 8.84 - 8.83 (t, J = 2.0 Hz, 1 H), 7.65 - 7.63 (in, 2H), 7.50 - 7.42 (m, 4H), 6.92 (s, 1H), 3.70 (s, 3H), 3.66 .-- 3.61 (n, IH), 3.32 - 3.28 (m, 1H), 3.22 - 3.17 (m, 1H), 1.33 - 1.32 (d, J = 6.7 Hz, 3H). MS (ESI) m/z: Calculated for 10 C 22 HqF 3

N

6 O2: 456.15; found: 457.2 (M+HY. EXAMPLE 94 Methyl 2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate

CO

2 Me NH .C / HO NH2 HCI MeC2C C- ----------------------- ~ iPr2NEt,. CHCl2 Fe 15 N, N-Disopropylethylamine (11 mL. 63.3 mmol) was added dropwise to a solution of methyl 4-fluorobenzimidate hydrochloride (10 g, 52.74 mmol) and DL-serine methyl ester HCI salt (9.9 g, 63.63 mmol) in dry CH 2

C

2 (200 mL) at 0 "C. The reaction mixture was stirred at room temperature for 24 h and then concentrated under reduced pressure. The reaction mixture was diluted with CH 2 CI1 and the organic layer was washed with HO 20 and brine, dried over anhydrous Na 2 SO, and concentrated under reduced pressure to get methyl 2-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate (95 g, yield 81%) as an orange liquid - H NMR (300 MHz, CDC13) 5 8.02 - 7 97 (m. 2H), 7 13 - 7.07 (t, J = 8.7 Hz, 2H), 4.98 - 4.92 (m, IH), 4.73 - 4.57 (m, 2H), 3.83 (s, 3H). MS (ESi) n/z Calculated for CnHFNO: 223 06; found: 223.8 (M+H)*. 25 164 WO 2011/088181 PCT/US20111021089 Methyl 2-(4-fluorophenyl)oxazole-4-carboxylate NBS, BZ202 2 henie, ret'lux, 2hi~ FF Benzoyl peroxide (0 49 g, 2.0 mmol) was added to a solution of methyl 2-(4 fluorophenyl)-4,5- diydrooxazoie-4-carboxylate (9 0 g, 40 3 mmol) in dry benzene (180 5 mL) and the mixture was refluxed for 15 min. N-bromosuccinimide (8.6 g, 48.3 mmol) was then added and the reaction mixture was refluxed for 2 h The reaction mixture was quenched with ice-cold water and the crude product was extracted with EtOAc. The combined extracts were washed with 10% aqueous NaHCC3 solution, H20 and brine, dried over anhydrous Na 2 S, and concentrated under reduced pressure. The crude 10 product was Purified by column chromatography (silica 60-120 mesh, eluant 10-15% EtOAc in petroleum ether) to get methyl 2-(4-fluoropheriyl)oxazole-4-carboxylate (6 g, yield 67%) as a white solid. 'H NMR (400 MHz, CDCL) 6 8.29 (s, 11-i), 8.14 - 8.10 (m, 2H), 7.19 - 7.15 (t, J = 8.5 Hz, 2H), 3.96 (s, 3H). MS (ESI) m/z. Calculated for

C

1 d-1FNO3: 221.05; found: 221.8 (M+Hf. 15 (2-(4-Fluorophenyl)oxazol-4-yl)methanol MeO.LC DIBAL (1M in toluene) HO - THF, 0C-rt, 3h F / F This compound was synthesized from methyl 2-(4-fluorophenyl)oxazole-4 carboxylate as described in example 64 step 4 (4.5 g, yield 86%) as a yellow solid 1 H 20 NMR (300 MHz, CDCl1) 5 8 06 - 8.01 (m, 2H), 7.65 (s, 1H), 7.18 - 7.12 (t, J = 8.7 Hz, 2H), 4.68 (s 2H). MS (ESI) m/z: Calculated for CaHBFNO2: 193.05; found: 193.8 (M+H)*. 2-(4-Fluorophenyl)oxazole4-carbaldehyde _0 HO -- ess-Martin N F 0 C-r, 3h 25 This compound was synthesized from (2-(4-fluorophenyl)oxazol-4-yl)methano as described in example 47 step 2 (2,8g, yield 63%) as a white solid. 'H NMR (300 MHz, CDC1s) 6 10.01 (s, IH), 8.32 (s, 1H), 8.14 - 8.10 (m, 2H), 7.23 - 7.17 (t, J = 8.8 Hz, 2H). MS (ESI) m/z: Calculated for C, 0

HFNO

2 : 191,04; found: 191.8 (M+H)'. 185 WO 2011/088181 PCT/US20111021089 2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-hydroxyacetonitrile F 0 / 03-KH 2

PO

4 N F DMF-H 20 4: !v N' rt, 1h 6 KH2PO4 (712 mg, 5.23 mmol) and NaCN (251 mg, 5.12 mmol) were added to a sOlution of 2-(4-fluorophenyl)oxazole-4-carbaldehyde (500 mg, 2 62 mmol) in DMF-H:0 5 (10 mL., 4:6, v!v) The resulting reaction mixture was stirred at room temperature for I h, then diluted with water and extracted with EtOAc The combined extracts were washed with H 2 0 and brine, dried over anhydrous Na 2

SO

4 and concentrated under reduced pressure to afford 2-(2-(4-fluoropheny)oxazol-4-y)-2-hydroxyacetonitrile (500 mg, yieid 87%). 1 H NMR (400 MHz, CDC13) 6 8.07 - 8.02 (n, 2H), 7.88 (s, IH), 7.20 - 7.16 (t, J= 10 8.8 Hz, 2H), 5.62 (s, IH), 4.38 (br a, 1H). MS (ES m/z Calculated for CI 1

H

7

FN

2 0 2 : 218.05; found: 218.8 (M+H). 2-Amino-I-(2-(4-fluorophenyl)oxazol-4-yI)ethanol NaBH 4 , CF-,CO 2 H N N THIF r 8h

H

2 N OH OH 15 Trifluoroacetic acid (0.35 mL, 4.60 mmol) was added dropwise to a suspension of NaBH 4 (0 174 g, 4.60 mrnmoi) in dry THF (10 mL) at 0 'C, followed by addition of 2-(2-(4 fluorophenyl)oxazol-4-yl)-2-hydroxyacetonitrie (0 20 g, 0.92 mmol) also portionwise. The reaction mixture was stirred at room temperature for 8 h, and then concentrated under reduced pressure and diluted with ice-water. The mixture was acidified to pH ~2 using 20 1.5N HCI at 0 *C and then heated to 50 'C for 20 mn. The solution was basified with aqueous NH 4 0H solution and the organic product was extracted with CHCI. The combined extracts were washed with brine and concentrated under reduced pressure to afford 2-.amino-1-(2-(4-.fluorophenyl)oxazol-.4-yl)ethanol (120 mg, crude), which was carried through without further purification. MS (ESI) imz: Calculated for CI 1

H

1 4FN 2

O

2 : 25 222.08; found: 222.8 (M+H)*. 186 WO 20111088181 PCTUS201 11021089 N-(2-(2-(4.Fluioroplhenyl)oxazol4-yi)-2-hydroxyethyl)-3-(5-(triflijqoromiethyl)-1,2,4 oxadiazol-3 yl)benzamnide 117-1 DF. 0 "C-r., 3h.H OH This compound was synthesized from 2-amino-l-(2-(4-fluorophenyl)oxazo.-4 5 y')ethano! and 3-(5-(tr.ifluoOrnethyI)-1,2A--oxadiazok-3-y',benzoic acid as described in example 8 step 6 (70 mg, 1il 39)5HNR(0Mz 8.51 (rn: 1 H), 8.28 8.26 (in, 1H): 8.08 - 8.01 (m:. 3H), 7.73 (s, 1H) 7.66 - 7,62 (rn, I1H), 7.17 - 7.08 (mn, 3H), 5.05 --. 5.03 (mn, I H, 4.12-- 4.06 (ddd, J -. 14.1 Hz, 6.3 Hz, 3.8 Hz, 1 h; .91 .- 3.65 irn, 1[4, 3.77 (br s, 1H,. MS (ESI) mix: Calculated for C 2

.

1 1al 4

N

4 O g 462.10g found 463.1 EXAMPLE 95 5-(6-(Difluoromethyl)-1 ,2,4-oxadiazol-3-yI)nicotinic acid 0 HO, N F - INN 15 This compound was synthesized from 5-(N-hydrcxycarbam-imi-idcyliiicotinic acid using ethyl difluoroacetete as dePscribed in example 1 step 5 (100 rng, yield 30%). 1 H NIVR (40-0 MHz, DIMS-d6) 5 13.94 (br s, It-I), 9.40 (d, J =2.1 Hlz, li-i), 9.28 (d, J = 2.1 Hz, 1 H). 8.76 -8.75 (t, J1 = 2.1 Hz, I H), 71.73 - 7.47 (rn, 1 H). NIS (ESI).rn/z: Calculated for CgH F21N,O,: 241.03; found: 241.8 (M+H). 20 5-(5-(Difluoromethyl)-1,2,4-oxadiazoi-3-yi)-N-(2-(2-(4-fluorophenyloxzo.-4-y)-2 ffiethylpropyl)riicotiriarnide N' HATU, NM/ N W~ 187 WO 2011/088181 PCT/US20111021089 This compound was synthesized from 2-(2-(4-flucrophenyl)oxazol-4-yl)-2 methylpropan-1-amine and 5-(5-(difiuoromethyl)-1,2,4-cxadiazl-3-yl)nicotinic acid as described in example 8 step 6 (45 mg, yield 24%). 'H NMR (400MHz, DMSO-d) 6 9.32 (d, j = 2.1 Hz, 1H), 9,20 (d, J = 2.1 Hz, 1H), 8.82 - 8.78 (m, 1H), 875 - 874 (t, J = 2.1 5 Hz, 1H), 8.04 - 8.00 (m, 3H), 7.74 - 7.48 (m, 1H), 7.38 - 7.33 (t, J = 8.9 Hz, 2H), 3.55 3.53 (d, J = 6.1 Hz, 2H), 1,31 (s, 6H). MS (ESI) m/z: Calculated for CH ,FN 5

O

3 : 457.14; found: 458.2 (M+H) EXAMPLE 96 10 2 -(Dimi ethy lam ino) -2 -(2-(4-flu orophenylI)oxazo 14-yl)aceto nitr ile F 0\ N NaCN, Me 2 N-l.HCI ---- N- ------- ----- N ~ MeO-l-THF 1:1 v/v 0/ W F 0 AC-r, 2h N 2-(4-Fluorophenyl)oxazoie-4-carbaldehyde (1.0 g, 5.23 mmol) was dissolved in THF-MeOH (20 mL, 1:1 v/v) This solution was added to a solution of dimethylamine hydrochloride (470 mg, 5.7 mmol) and NaCN (540 mg, 13.0 mmol) in water. The resulting 15 reaction mixture was stirred at room temperature for 2 h, and then diluted with water and extracted with EtOAc. The combined extracts were washed with H 2 0 and brine, dried over anhydrous Na 2

SO

4 , and concentrated under reduced pressure to afford 2 (dimethylaminc)-2-(2-(4-flucrophenyl)oxazol-4-yl)acetonitrile (1.0 g, crude) as a brown oil, which was used without further purification. MS (ESI) rn/z: Calculated for C 3

H

2 FN3C: 20 245.10; found: 245.9 (M+H)+. 1-(2-(4-Fluorophenyl)oxazol-4-yi)-Nl,N1-dinethylethane-1,2-diamine F F LiAlH 4 (2M in T-IF) N ------------ N K N v--. ~ THF, 0 0 C-rt,2h H2N IN -H 2 N N, This compound was synthesized from 2-(dimethylamino)-2-(2-(4 25 fluorophenyl)oxazol-4-yl)acetonitrile as described in example 1 step 3 (0.6 g) and it was 188 WO 20111088181 PCTUS201 11021089 carried through without further Purification. 1MS4 (F.8I) I'z Calculated for 0 3

,H,

6

FN

3 C: 249.13; found: 249 9 (M+H) N-(2-(D im ethyl am ino) -2-(2 -(4-fluoroph enyl)oxazol-4-yl)ethyl) -3-(5-(trffl uorom ethyl) 5 1,2.4-oxadiazol-3-yl)benzamide hydrochloride F /C-N 0 1) 0 -N 0 / HATU, NIMM N lKT 2 DMF, 0 0 C-rf. 31 ,N2) HOI in dioxane 801 0 C-~ 0.5h1 N-(2- (dimetlylamirnoy-2-(2--(,4-fluorophenl)oxazo-4- yl)ethy)-3- (5-(trifluoromethy) I 2,4-oxadIazo-3-yl)benzamide was synthesized from 1-(2-(4-f!uorophenyl)oxazol-4-yl) N. !NI-dirnethylethane,-1 2-diamine and 3-(5-(trifluoromethy)-1 ,2,4-oxadiazol-3-y;)benzoic 10 acid as described in example 8 step 6. The free base was then stirred with HCI in dioxane solution (4 ml) 'or 0.5 h at 0 'C to room temperature. The reaction m ixture vias concentrated and triturated with diethyl ether to afford Nj-(2-(dimnethyla3mino)-2-(2-(4 fl.uorophenyl)oxazol-4-yl)ethy)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)bhenzamide hydrochloride (130 mg, yield 16%) as light brown solid. Id NIMR (400MHz, DMSO-d 6 ) 6 15 10.39 (br s, 1H), 9 18- 9.15 (t. / = 56 Hz, 1H), 6.55 - 8.54 (in, 2H), 8.27- 8.25 (mn, 1H). 8.21 -8.19 (mn, 1H), 8.11 -8.07(rn, 2H), 779-7.75(t, J=7.8 Hz, 1H). 7.45-7.41 (t, J= 8.9 Hz,21-), 4.84 -4.81 (t., .J= 6.1 Hz, I H). 4.20 -4.13 (m, 1H), 3.87 - 382(n, 18H), 2.87 - 2.84 (dd, J = 6.9 Hz, 5.0 Hz, 68I) MS (ESI) mi:Calculated for C2/ 3 1H,]F4N50 3 : 489. 14', found; 490.2 (MI+H)Y 20 EXAMPLE 97 M-(2-(3-(4-Fluorophenyl)-1 H-1,2,4-triazol-8.-yl)-2-methiyipropy1)-5-(S-(2,2,2 triftucroacetyl)thiophen-2yl)nicotinanide F F h----------------- - 1/ Hl-I ATU, NNMM Hir H -H IDMF, 0 IC-rt, 5h1 189 WO 2011/088181 PCT/US20111021089 This compound was synthesized from 2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl) 2-methylpropan-1-amine and 5-(5-(2,2,2-trifLuoroacetyl)thiophen-2-l)nicotinic acid as described in example 8 step 6 (28 mg, yield 20%) as a yellow viscous liquid. 'H NMR (400MHz, DMSO-de) 6 9.20 (d, J = 2.3 Hz, 1H), 9 01 - 8.98 (m, 1H), 8,80 - 8.77 (m, 1H), 5 8.51 - 8.48 (m, 1H), 8.21 - 8.19 (m, 1H), 8.01 - 7.96 (m, 4H), 7.24 - 7.19 (m, 2H), 3.59 3.57 (d,J= 6.2 Hz, 2H), 1.42 (s, 6H). MS (ESI) m/z: Calculated for C2, 4

HF

4

NO

2 S: 517.12; found: 516.4 (M-H)-. EXAMPLE 98 10 Methyl 5-cyano-2-methoxybenzoate NC, CO 2 Me Mel, K2CC' NCN > -CO 2 Me eo,65,10h OMe A solution of acid methyl 5-cyano-2-hydroxybenzoate (2 g, 11.2 mrnmol) in dry acetone (50 mL) was cooled to 0 C and K2CO 3 (2.34 g, 16.9 mmol) followed by Mel (1.1 mL, 16.9 mmniol) were added dropwise. The reaction mixture was allowed to stir at 65 'C 15 for 10 h and then diluted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield methyl 5-cyano-2-methoxybenzoate (600 mg, crude), which was carried through without further purification. 1 H NMR (300 MHz, CDCI 3 )6 .11 (d, J = 2.2 Hz, 1H): 7.78 -- 7.74 (dd, J = 8.8 Hz, 2.2 Hz, IH), 7.08 -- 7.05 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H). MS 20 (ESI) m/z: Calculated for CgaHgNO 3 : 191,06; found: 191.8 (M+H)*. 5-Cyano-2-methoxybenzoic acid NC. CO 2 Me LiOH NC, C0 2 1

S-THF-H

2 0 7:3 v/v This compound was synthesized from 5-cyano-2-methoxybenzoic acid as 25 described in example 43 step 2 (300 mg, yield 72%) as a white solid. IH NMR (400 MHz, DMSO-de) 6 13.13 (br s, 1H), 8.02 - 8.01 (d, J = 2.1 Hz, 1H), 7.99 -- 7.96 (dd. J = 8.8 Hz, 2.1 Hz, 1H), 7.32 - 7.30 (d, J = 8,8 Hz, 1H), 3,90 (s, 3H). MS (ESI) m/z: Calculated for CGH7NO 3 : 177.04; found: 175.6 (IM-Hy. 30 190 WO 20111088181 PCTUS201 11021089 5-(N'-Hydroxycarbanirnidoyl).2-methozybenzoic acid H0, NC,-- 0? NH- OH.HCl, Nae,-0; 1~.- --------------------- - 2 N L,~Cu ,z -Om 8-hvdroxyquinnicinp (rat) MtOH, refluw, 4h We'O~ This comPound was synthesized frcarn 5-cyano-2-methaxybenzoic acid as described in example I step 4 (300 mcg end it w as carried through Without further 5 Purification. NIS (P131) mlz: Calculated for CgHICf.20, 210 06; found: 2106 8MH 2-Methoxy-5-(5-(trifluoromethyl)-1,24-oxadiazol-3-yi)benzoic acid 0,N O-NO~r pyridine, ref lux, 3h 0 M P.-,"'w Tiiis compound was synthesized from 5-(PIj'-hydroxycarbemimido'yl)-2 10 methoxybenzoic acid as described in example 1 step 5 (40 mg, yield 35%). -H NMR (300 RMHz, D MSO -d,) 6 1 30 5 (bras, IH.), 8.30 - 6.29 (d, J = 2.2 Hz, 1 H), 8.20 -68.16 (d d, J = 8.8 Hiz, 2 2 Hz, *1H), 7.36 - 7 35 (d, d = 6.8 Hz, I H), 3.92 (s, 3H). MAS (ES1) m/;z: Calculated fOr C! 1

HTF

3 N O : 266.04: found: 28667 (M-HY. 15 N-2-(2-(4-Fluorophenyl)oxazol-4-yi)-2.rneLthylpropyl)2-methioxy--(5 (trifi uomoniethyl)-1 ,2,4-oxadiazol-3-yi)benzamide P-N~ -0 ~, ~ C0 2 H J, L ~~i >< ' ............. . N r A . DOM', 0 'c*-rt 911 This compound was synthesized from 2-(2-.(4-flucro ,ohenl)oxazo-'-yl)--2 mathyprop n-imineand 2-.methoxy-5-(5-(trifluorormethyl)-1 .2,4-Oxadiazol!-3.yl)banzoic 20 acid as described in example 6 step 6 (40 mg, yield 36%). HNR(4MzeO)6 6.64 .-- 8.63 (d; J = 2.3 Hz, 1 H), 8.45 - 6.42 (t: J -. 5.6 Hz; 1 H), 8.24-.21 (dd, j 6 .6 Hiz. 2.4 Hz, 1H-), 6.11 -- 68.07 (in, 2H-), 7.63 (s, 11-i), 7.34 -- 7.32 (d, J 8. 4.6z, 1i-1), 7.27 - 7.23(t, j 6 .6 Hz, 2HA): 3.91 (s, 31-). 3.72 - 3.71 (in. 21-), 1.41 (s, 611). MS (ESI) mhz. Calculated for C,,H, 0

F

4 NO: 504.14: found: 505.2 (M+H)'. 25 191 WO 2011/088181 PCT/US20111021089 EXAMPLE 99 2-(2-(4-Flujorophenyl)oxazol-5-yl)-2-rnethylpropanenitrile NC --- ' x Mel, NaH NC' > O, $1 1 , \ ) I 'z. DMSO, 0 *CCt, i h N _/ This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-5-yl)acetonitrile 5 using iodomethane as described in example 1 step 2 (170 mg, yield 60%). 1 H NMR (300 MHz, CDCI 3 ) 5 8.06 -- 8.02 (im, 2H), 7.20 - 7.14 (t, J = 8.7 Hz, 2H), 7.06 (s, 1H), 1.81 (s, 6H). MS (ESI) rlz: Calculated for C 3

H

11

FN

2 0: 230.09; found: 230.9 (M+H)*. 2-(2-(4-Fluorophenyl)oxazol-5-yi)-2-nethylpropan-1-amine LiA 114 HN -F ----- F--------

--

10 N - TH-iF. 0 'C-rt, 1h N This compound was synthesized from 2-(2-(4-fluorophenyl)oxazo-5-y)-2 methylpropanenitrile as described in example 1 step 3 (100 mg, crude) and it was carried through without further purification MS (ESI) m/z Calculated for C 13

H

1

,FN

2 0: 234.12; found: 235.2 (M+H)*. 15 N-(2-(2-(4-Fluorophenyl)oxazol-5-yi)-2-nethylpropyl)-3-(5-(trifluoromethyl)-1,2,4 oxadiazol-3-yi)benzamide FacdN HN r= = HATU NMM 0 -N 0 N " DMF 0 *C-rt, 4h This compound was synthesized from 2-(2-(4-fluorophenyl)oxazo-5-y)-2 20 methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (30 mg, yield 15%). H NMR (400MHz, MeCD) 5 8.48 8.47 (r, 1H1), 8.28 - 8.25 (m, 1H), 8.00 - 7.97 (m, 3H), 7.68 - 7 64 (t, J = 7.8 Hz 1H), 7.21 - 7.16 (t, = 8.8 Hz, 2H), 7.00 (s, 1H), 3.66 (s, 2H), 1.46 (s, 6H). MS (ESI) m/z: Calculated for C 2 3H-?F 4

N

4 03: 474 13; found: 475.2 (M+H). 25 192 WO 2011/088181 PCT/US20111021089 EXAMPLE 100 4-(Dimethylamino)-2-(2-(4-fliorophenyl)oxazol-4-yl)butanenitrile N

--

CI.CI

NH

4 0H toluene!, reflux, Fh N This compound was synthesized from 2-(2-(4-.fluorophenyl)oxazol-.4-yl)acetonitrile 5 and 2-chLoro-N,N-dimethylethanamine hydrochloride as described in example 16 step 1b (400 mg, yield 48%). 'H NMR (400MHz, MeOD) 5 8.10-- 8.07 (m, 2H), 7.99 (m, 1H), 7.29 - 7.25 (t, J = 8.9 Hz, 2H), 4.24 - 4.20 (t, J = 7.3 Hz, 1 H), 2.59 - 2.46 (m, 2H), 2.29 (s, 6H), 2.23 - 2.17 (m, 2H). MS (ESI) rm/z: Calculated for CixHixFN 3 O: 273.13; found: 274.2 (M+H)*. 10 3-(2-(4-Fluorophenyl)oxazol4-yl)-N1,N1-dimethylbutane-1,4-diamine -N-a \ CoC 2 , NaBH, F cN - ___ __ ___ __ H2N == MeOH, 0 0-rt, ih Cobalt (ii) chloride (380 mg, 2.9 mmol) was added to a solution of 4 (direthylamino)-2-(2-(4-flucrophenyl)oxazol-4-yl)butanenitrile (400 mg, 1.46 mmol) in dry 15 methanol (10 mL) at 0 *C, followed by sodium borohydride (550 mg, 14.6 mmol) portionwise. The resulting mixture was stirred at room temperature for I h, then quenched carefully with ice water, and filtered through a Celite bed. The filtrate was concentrated under reduced pressure to afford crude 3-(2-(4-fluorophenyl)oxazol-4-yl)-Ni,Ni dimethylbutane-1,4-dianine (180 mg, crude), which was carried through without further 20 purification. MS (ESI) m/z: Calculated for C 1

,H

2

HFN

3 O: 277.16; found: 278.2 (MH.) 193 WO 20111088181 PCTUS201 11021089 1,2,4-oxadiazol-3-yl)benzamide /-N

H

2 Ny ~HA-U. NUM N -> OMF, 0 'C-rL, 4i N, 0%1 This compound was synthesized from 3-(2-Y'4-f*uo 'opnenvl)oxazo I yP ,NI NI 5 dimrefhylbutane- I 4-diamire and 3-(5.-(trifluiocrethly)-1 .2.4-oxadi!azol-3-.yI)benzoic acid as described in example 8 step 6 (17 mo. yield 10%). 'HNMR (400MH1-z. MaCI) 76 6.55 8.54 (t, J = 1.5 Hz, . H), 830 - 8.27 (in, I H); 8,08- 8.02 (mn, 3H), 7,82 (s, 1 H), 7.71 - 7.67 It, i = 7.8 Hz 1H.) 7.26 -7.21 (t, J = 8.9 Hz, 2H), 3.76 - 3.65 (mn, 2H), 3,16 - 3.10 (mn, I H), 2.533- 2.40 (m, 2H), 2.30 (in, 6H), 2.04 - 1.98 (m, 2H). NIS (S)mtCalculated for 10 C 2 41-H221 4 1N1 6 0: 518,17" found: 519 2M+1 EXAMPLE 101 IN-(4-(D i methyl am ino) -2-(2-A4-fluoropheny)oxazo-4-yI) buty) -- (6-(trffluoromethyll 15 1 ,2,4-oxadia~zol-3-yl)nicotinamide F N" HI XT U, N 1C DMIF- 0 0 C-in, 4h T-his compound was synthesized from 3-(2-(4-.fluoropnenyl)oxazol-4-yl' -N',NI dimrethylnutane-1,4-diarnine and 5-(5-(triflucrornethyl)- 1.2,4-oxadazo-3.yfl'nicotnic acid as described in example 8 step 6 ('16 mng, yield 10%), 'H NMVR (400MHz, MeG(S) 8 9.39 - 20 9.38 i = 2.0 Hz, 1 H), 9.16 (d, i 2.0 Hz, 1H1-), 8.85 -8.84 (t, i = 2.1 Hz, 1H), 8.08 8.05 (in, 2H), 7.84 (s, I H); 7.26 - 7.22 (t, J= 8,9 Hz, 2H1, 3,79 -3.66(mn, 2H-), 3.18 -3.11 (in I H), 2.63 -2.46 (m, 21H), 2.37 (in 6H), 2.00 -2.00 (mn, 2H). MS (ESI) inz: Calculated for C 2 i-l 2

FN

6

CD

3 : 518.17: found: 519.2 (~) 25 EXAMPLE 102 194 WO 2011/088181 PCT/US2011/021089 N-(2-(2-(4-Fluorophenyl)oxazol-4-y)-2-hydroxyethyl)--(5-(triflujoromethyl)-1,2,4 oxadiazol-3-yl)nicotinamide F O' P P-N 0 N bF3C--NN

H

2 N HATU. NMM H OH DMF, 0 *C-rt, 3h Ni-i This compound was synthesized from 2-amino-1-(2-(4-fluorophenyl)oxazo-4 5 yi)ethano! and 5-(5-(trifiuoromethyl)-1,2,4-oxadiazol-3-yi)nicotinic acid as described in example 8 step 6 (120 mg, yield 45%) IH NMR (400MHz, DMSO-ds) 5 9.35 (d, J = 1 8 Hz, 1H), 9.27 (d, J = 1.8 Hz, 1H), 9.13 - 9 10 (t, J = 5.6 Hz, 1H), 8.84 - 8.83 (t, J = 1.8 Hz 1H), 8.11 (s, 1H), 8.03 - 8.00 (dd, J= 8.5 Hz, 5.5 Hz, 2H), 7.39 - 7.35 (t, J = 8.9Hz, 2H), 5.74 - 5.73 (d, J = 5.2 Hz, IH), 4.85 - 4.81 (m, IH), 3.77 - 3.71 (m, 1-1), 3.56 - 3.49 (m, 10 1 H). MS (ESI) rm/z: Calculated for C 2 0H 1 3

F

4 N5O,: 463.09; found. 464.0 (M+H)*. EXAMPLE 103 4.-(Chloronethyl).-2-(4-chlorophenyl)oxazole Ce NH-toun N / Y -+---------- ---------------- I j-C C' +DMF, 3 *C, 12h -C 15 This compound was synthesized from 4-chlorobenzamide and 1,3-dichloroacetone as described in example 74 step 1 (3.4 g, yield 46%). 1 H NMR (300 MHz, CDCl 3 ) C 8.01 7.98 (d, J = 8.8 Hz, 2iH1), 7.72 (s, 1 H), 7.47 -- 7.44 (d, J = 8.8 Hz, 2H), 4.59 (d, J 0.9 Hz, 2H). 20 2-(2-(4-Chlorophenyl)oxazol-4-yl)acetonitrile Ci'- N /-\ O)KI, DMF, r' ih N . N =\ FI ------- c----------------- . >---- I / Cl 0 -- / i) NaCN, DMF, rt, 3h This compound was synthesized from 4-(chloromethy!)-2-(4-chlorophenyl)oxazole as described in example 71 step 2 (1.7 g, yield 53%). 1 H NMR (300 MHz, CDCl 3 ) 6 7.98 7.95 (d, J = 8,8 Hz, 2H), 7.75 - 7.74 (d, J = 1.3 Hz, 1H), 7.47 -7.44 (d, J = 8,8 Hz, 2H), 25 3.73 (d, j = 1.3 Hz, 2H). MS (ES) m/z: Calculated for C 11

H

7

CIN

2 0: 218.02; found: 219.0 (M+H). 4-(2-(4-Chlorophenyi)oxazo-4-y)-1 -methylpiperidine-4-carbonitrile 195 WO 2011/088181 PCT/US20111021089 Cl .N

NH

4 0H

NC--'

NCe- N r=\ C N C NC C!------ ------------------------------------ -- N 0 '~-'/ ~ ~ NNHs tuen, 110 C, 3h SN This compound was synthesized from 2-(2-(4-chlorophenyl)cxazol-4-yl)acetonitrile as described in example 16 step lb (140 mg, yield 20%). 'H NMR (400MHz, CDC;') 6 8.00 -- 7.97 (n, 2H), 7.74 (s, 1H), 7.47 - 7.45 (m, 2H), 3.67 - 3.63 (n, 2H), 3.25 - 3.18 5 (m, 2H), 2.99 - 2.95 (m, 2H), 2.89 (s, 3H), 2.49 - 2.46 (In, 2H). MS (ESI) m/z: Calculated for Cj6F-I, 6

CIN

3 C 301.10; found: 302.1 (M+-)*. (4-(2-(4-Chlorophenyl)oxazol-4-yl)-1 -methylpiperidin4-yl)methanamine C1 i N (2M in THF) THF, 0 "C-rt. 0.5h N N 10 This compound was synthesized from 4-(2-(4-chloropheny)oxazo-4-y)-1 methylpiperidine-4-carbonitrile as described in example 1 step 3 (100 mg, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for C16H 2 0CIN 3 0: 305.13; found: 306.2 (M+H)*. 15 196 WO 2011/088181 PCT/US20111021089 N-((4-(2-(4-Chlorophenyl)oxazol4-yl)-1 -nethylpiperidin-4-yl)nethyl)-3-(S (trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide hydrochloride F! Cr 10 3. 01 HATUr NMM N1 DMF, ) *C-rt, 5h N HCl 2) HCl in Dioxane 0 *C-rt, 30mwn This compound was synthesized from (4-(2-(4- chloropherlv)oxazo1-4- yl)-1 5 nethylpiperidin-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazo!-3-yl)benzoic acid as described in example 96 step 3 (12 mg, yield 5%). 'H NMR (400MHz, CDC;s) free amine] , 8.56 (s, 1H), 8.28 - 8.26 (d, J = 7.7 Hz, I H), 8.13 - 8 11 (d, J = 7 6 Hz, 1H), 8.02 - 8 00 (d, J = 8.5 Hz, 2H), 7.79 - 7 75 (m, 1H), 7.66 - 7.62 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.42 - 7.40 (d, J = 8.2 Hz, 2H), 3.77 - 3 76 (d, J = 4 7 Hz, 2H), 2 79 - 2 77 (m, 10 2H), 2.59 (m, 2H), 2 42 (m, 3H), 2.22 - 2.21 (m, 2H), 2.08 - 2.04 (m, 2H). MS (ESI) m/z: Calculated for CzeH 2 3 C1F 3 N503: 545.14; found: 546.2 (M+H) EXAMPLE 104 2-(2-(4-Chlorophenyi)oxazol4-yl)-2-methylpropanenitrile N N Mel, NaH C N 15 'O ' TI-F, 0 *C-rt, 3h 0 This compound was synthesized from 2-(2-(4.-chlorophenyl)oxazl-.4-yl)acetontrile using iodomethane as described in example 1 step 2 (300 mg yield 53%) 1H NMR (400 MHz, CDCla) 5 8.00 - 7 98 (d, J = 8.7 Hz, 2H), 7.68 (s, 1H), 7 48 - 7.44 (d, J = 8.7 Hz, 2H), 1 76 (s, 6H). MS (ESI) m/z: Calculated for CNHI CIN 2 0: 246.06; found: 2470 20 (M+H). 2-(2-(4-Chlorophenyl)oxazoI-4-yl)-2-methylpropan-1 -amrline N ,= L/EUH 4

H

2 N -- -Ci N -< N-C1 ) \ THF, 0 *C-rt, 0.5h _C' This compound was synthesized from 2--(2-(4 -chlorophenyl)oxazo4-yl)-2 25 methylpropanenitrile as described in example I step 3 (155 mg, yield 59%) and it was 197 WO 2011/088181 PCT/US2011/021089 used without further purification. MS (ESI) m/z: Calculated for CeA CN 2 : 250.09; found: 251.1 (M+H). 2-(2-(4-Chlorophenyl)oxazol4-yl)-2-nethyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol 5 3-yl)benzyl)propan-1 -amine hydrochloride FacH2DCE, 0 C-rt, Ch O-NN -------___________,--F-C o - )HCI in dioxame HI 0 C- 30wmin 2-(2-(4-Chlorophenyl'oxazo-4-yl)-2-methl-N-(3-(5-(trifluoromethyl)-1, 2,4 oxadiazol-3-yl)benzyl)propan-I-amine was synthesized from 3-(5-(trifluoromethyl)-1 2,4 10 oxadiazol-3-yl)benzaldehyde and 2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropan-1 amine as described in example 7 step 3. The free amine was then treated with HCI in dioxane (2 M) at 0 "C and stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. The crude was purified by washing with dry hexane to get 2-(2-(4-chlorophenyl)oxazol-4-y)-2-methyl-N-(3-(5-(trifluoromethv)-1,2,4 15 oxadiazol-3-yl)benzyl)propan-1-amine hydrochloride (20 mg, yield 6%). 'H *NMR (400 MHz, DMSO-ds) 5 8.87 (br s, 2H), 8.26 (s, 1H), 8.11 - 8.08 (n. 2H), 7.85 - 780 (m, 3H), 7.69 - 7.65 (+, J = 7.6 Hz, 1H), 7.55 - 7.52 (d, J = 8.5 Hz, 2H), 4.28 (brs, 2H), 3.12 (m, 2H), 1.33 (s, 6H). MS (ESI) mV: Calculated for C 23

H

2 0CIF 3

N

4 02: 476.12; found: 477.2 (M+H)* 20 EXAMPLE 105 2-(2-(4-Fluorophenyl)oxazol-5-yl)ethanamine N\CM

H

3 Me 2 S H2N F -F N - HF, 60 "C, 1h -NI \ --- 1 This compound was synthesized from 2-(2-(4-luorophenyl)oxazol-5-y)acetonitrile as 25 described in example 42 step 1 (70 mg) and it was carried through without further purification. MS (ESI) m/z: Calculated for C HI 1

FN

2 0: 206.09; found: 206.8 (M+H)*. 198 WO 20111088181 PCT/US201l11021089 yl)benzamnide / 0

F

3 C - o NN~ DM 'AF, 4h This compound was synti-esized from 2-(2-(4-fiuor'opheniyl)cxazcl-5-yi!)ethanarn.in'e 5 and 3-(5-(trifl*uorornethyl)-1,2,4-oxadiazol-3-yi!)benzcic acid as described in example 8 step 6 (28 mig, yield 20%), 'H NMR (400M0Hz, MeOD) 8 8.516- 8.55 (in: I H), 8.30 - 8.28 (dq, J 7,8 Hz, 0.9 Hz, I H), 8.06 - 8.04 (m, I1H), 8.00 - 7.96 (dd, J 9.0 Hz, 5.3 Hz, 2H): 7.71 - 7.69 (t, J . 7.8 Hz, I H), 7.21 - 7.17 (t, i 8.8 Hz, 2H); 7.03 (s, I H); 3.78 -3.75 (f, J = 6.7 Hz, 21-i), 3.15-- 3.12 (in. 21-hl. MS (ESI) m/z: Calculated for C 21

H,

4 FN,0 3 : 446.10 '10 found- 447.0 (M+Hy. EXAMPLE 106 4-([1 AV-Biphenylj-3-yI)-1 -methylpiperidine-A-carbonitrile

SNH

4 0H /X-\jCN Ii~ N '-~>i NC~~ Nal% 2r 0 IC, 4: 11 15This compound was synthesized from 2-([1I -ipi .enyl -3-yI)acetonlithile as described in example 16 step lb (500 mg, yield 35%). IH NMR '400MHz, Me) "67.75 (mn, 1 H), 7.64 - 760 (in, 3H), 7.53 - 751 (mn, 2H), 7 48 7.44 (m, 2H), 7.39 -7.35 (in. 1 H), 3.08 -3.05 (iii, 2H), 2.57 -2.50 (in, 2H), 2.42,sa, 3H), 2,2 - 2.20 'in. 4H). IMS (ESI) m/z: Calculated for CIIH 2

N

2 : 276.16; found: 277.0 (M+H' , 20 (4-([1 .V-Biphenyj-3-yI)-1 -methylpiperidin-4-yi)methanamine NC UAIIH 7 N 4 ~ 'NN 199 WO 2011/088181 PCT/US20111021089 This compound was synthesized from 4-([1,1'-biphenyl]-3-yl)-1-methylpiperidine-4 carbonitrile as described in example I step 3 (250 mg, yield 50%). "H NMR (400MHz, MeOD) 5 7.63 - 7.58 (m, 3H), 7.52 - 7.42 (m, 4H), 7.39 - 7.32 (m, 2H), 2.77 (s, 2H), 2.69 - 2.66 (m, 2H), 2.37 - 2,27 (m, 4H), 2.22 (s, 3H), 1.91 - 1.86 (m, 2H). MS (ESI) m/z: 5 Calculated for CH 2 4

N

2 : 280.19: found: 281.0 (M+H)*. N-((4-([1,1'-Bi phe nyl] -3-y!) -1-m ethyl pi perid in-4-yi)methyl)-3 -(5-(trifl uoromrethyl) -1,2,4 oxadiazol-3-yl)benzamnide N HANrU, NMM DMF, 0 oC-rtL 10n 10 This compound was synthesized from (4-([1,1'-biphenyl-3-yl)-1-nethylpiperidin-4 y!)nethanamine and 3-(5-(trifiuoroiethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (60 mg, yield 31%) as an off white solid. 'H NMR (400MHz, MeOD) 6 8.39 (m, 1H), 8.23 - 8.21 (m, 1H), 7.90 - 7.88 (m, 1H), 7.64 - 7.54 (m, 4H), 7.49 - 7.47 (m, 3H), 7.39 - 7.36 (m, 2H), 7.31 - 7.28 (m, 1 H), 3.60 (m, 2H), 2.79 - 2.76 (m, 2H), 2.42 15 - 2.30 (m, 4H), 2.23 (mr, 3H), 2.11 - 2.06 (m, 2H). MS (ESi) rm/z: Calculated for

C

2

GH

27

F

3

N

4

O

2 : 520.21; found: 521.2 (M+H). EXAMPLE 107 4-(Chlioromethyl)-2-(4-methoxypheny)oxazole 0 tot ene NH~ ~N -N r--x + CI C, --------------- + __-N ~ 20 1 ' 10 0 *C, 4h 0 -- \ This compound was synthesized from 4-methoxybenzamide and 1,3 dichioroacetone as described in example 74 step 1 (2.3 g, yield 78%) as a yellow solid. IH NMR (400MHz, CDCi 3 ) 5 7.98 - 7.96 (d, J = 8.3 Hz, 2H), 7 65 (s, IH), 6.97 - 6.95 (d, J = 8.3 Hz, 2H), 4.56 (s, 2H), 3 86 (s, 3H). MS (ESI) m/z: Calculated for C 11

HOCINO

2 : 25 223.04; found: 223.8 (M+H)*. 200 WO 2011/088181 PCT/US20111021089 2-(2-(4-Methoxyphenyl)oxazol-4-yl)acetonitrile N, 0,i Ki, DMVIF, rt, 1 h ii) NaCN.D MF, rt, 2h This compound was synthesized from 4-(chloromethyl)-2-(4 methoxyphenyl)oxazole as described in example 71 step 2 (0.65 g, yield 57%) as an off 5 white solid. H NMR (300MHz, CDCI,) 5 7.97 - 7.94 (d, J = 8,6 Hz 2H), 7.69 (s, 1H), 6.99 - 6.97 (d, J = 8.6 Hz, 2H), 3.87 (s, 3H), 3.71 (s, 2H), MS (ESI) m/z: Calculated for C 2

H

1 cN 2 0 2 : 214.07; found: 214.8 (M+H)*. 2-(2-(4-Methoxyphenyl)oxazol-4-yilethanamine NC N /--\ BH3.Me 2 S H 2 N /N \\~~~J. >-------------- 10 0 'r HF, reflux, 0.51h 0 This compound was synthesized from 2-(2-(4-methoxyphenyl)oxazoi-4 y0acetonitrle as described in example 42 step 1 (130 mg, crude) and it was carried through without further purification. MS (ESI) n/z: Calculated for C 12

HIN

2 0 2 : 218.11; found: 218.8 (M+H)*. 15 N-(2-(2-(4-Methoxyphenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)nicotinamide

K

C N Hl2NA N O -ATU, NMM H DMF, 0 C-rt 4h N This compound was synthesized from 2-(2-(4-rnethoxyphenyl)oxazoi-4 20 yl)ethanamine and 5-(5-(trifluoromethyi)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (35 mg, yield 19%) as a white solid, 1 H NMR (400MHz, CDCIs) 6 9.47 (m, 1H), 9.34 (m, IH), 8.90 -- 8.89 (t, J = 2.0 Hz, 1H), 8.08 - 8.06 (m, 1H), 8.03 -8.00 (d, J = 8.8 Hz, 2H), 7.55 (s, 1H), 6.99- 6.97 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.87 -- 3.84 (in, 2H), 2,96 - 2.93 (t, J = 5.9 Hz, 2H), MS (ESI) m/z: Calculated for C2,H, 6

F

3 N,0 4 : 459.12; 25 found: 460.1 (M+H). 201 WO 2011/088181 PCT/US20111021089 EXAMPLE 108 2-Chloro-5-cyanobenzoic acid H2,N CCO2H NaNO21 /HCI N(" .CO'2H KCN / CuSO4 -5 IC to 0 "C, 1h 'CI 50 *C, 1h A solution of NaNO 2 (2.21 g, 32 mmol) in water (10 mL) was added to a solution of 5 5-amino-2-chlorobenzoic acid (5.0 g, 29.14 mmol) in water (40 mL) at 0 *C, followed addition of by conc. HCI (10 mL) at -5 *C. The reaction mixture was stirred at -5 "C for an additional I h and then the diazonium solution was added dropwise into a solution cf potassium cuprotetracyanide [prepared by dropwise addition of a solution of KCN (10 g, 15.38 mmo!) in water (18 mL) to a solution of CuS0 4 (7 g, 43.8 mmol) in water (12 mL) at 10 70 "C] at 50 C for 1 h. The reaction mixture was acidified with 1.5 N HCI solution and the product was extracted with EtOAc. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 1 2% MeOH in CHC) to get 2-chlorc-5-cyanobenzoic acid (1.8 g, yield 34%). 1H NMR 15 (400MHz, DMSO-d 6 ) 5 13.92 (br s, IH), 8.24 (d, J = 2.1 Hz, 1H), 8.02 - 7.99 (d, J = 8 4 Hz, 2 1 Hz, 1H), 7.80 - 7.78 (d, J = 8.2 Hz, IH). MS (ESI) m/z: Calculated for CH 4 ClINO 2 : 180.99; found: 179 6 (M-H)-. 2-Chloro-5-cyano-N-(2-(2-(4-fluorophenyl)oxazol4-yl)-2-methylpropyl)benzamide N~ K, C2 - 2 (crudc) Nc > ~ ' H2NN NN= NC.I--U. N 20 DMF, ") *C-rt, 3h This compound was synthesized from 2-(2-(4-fluorophenyl)oxazo-4-y)-2 methylpropan-1 -amine and 2-chloro-5-cyanobanzoic acid as described in example 8 step 6 (300 mg, yield 44%). H NMR (400MHz, CDC13) 6 8.02 (d, J = 2 0 Hz, 1 H), 7. 98 - 7.95 (n, 2H), 7.66 - 7.63 (m, 1 H), 7 56 - 7 54 (d, J = 8 3 Hz, 1 H), 7.48 (s, 1 H), 7.39 (m, 1 H), 25 717 - 7 13 (t, J = 8.8 Hz, 2H), 3.68 - 3.68 (d, J = 5.8 Hz, 2H), 1.41 (s, 6H). MS (ESI) m/z: Calculated for C21H 7 CiFN 3

C

2 : 397 10; found: 396.4 (M-H) 202 WO 20111088181 PCTUS201 11021089 4-Ch loro-3-((2 -(2-(4-fl uorophe nyl)oxazol 4-y)-2 -methyl propyl)carha moyl) benzohydrazonic acid 0 1-0 /--z NHI,0H.HOi N~aCO, H 2 . N N - -N -- ---- -- -- --- -- -- N N This cornpound was synthesized fromn 2-.chlcro-5-cyaro-N-~(2-( -4-. 5 fl.uorophenyl)oxazol.4-yI)-2-..nethlylpropyllbenzarmide as described in example 1 step 4 30 mg, crue and it was carried through without further purificain I-i NMR (300MVIFz, MeCD) 6 8.06 - 8.02 (in, 2H), 7. 74 - 7.73 mi, 2H), 7.67 - 7.63 (mn, 1 H), 7.46 - 7.43 (d, .J 8. z H.7.24- .1t J =8.8 Hz, 21-1)3.61 (a, 2H), 1.40 (s: 6H). NIS (ESI) rrI/z. Calculated for C 21 HOC1FNO,: 430.12; found: '129.4 (M-HA). 2 -Ch loro.N-(2 -(2..(4-fl u rophenyl~oxazol-4 -yl) -2--raethyl propyl) -5- (5 -(tri f!uoroiethyl) 1,2,4-oxadiazoIk3-yI)benzarnide o rN, N ~- C0 .P4 -N This compound was synthesized from 4- ch loro -3- ((2 -(2..(4-flucrop her..vl)oxazo!-4. '15 yi)-2-methylpropyl)carbamoyl)benzohydrazonic acid as described in example I step 5 (133 rng, yield 37%). 'H~ NMR (400MHz, MVIetD) 6 8.15 - 8.12 (in. 2H), 8.07 - 8.04 (m,. 21H), 7.76 (s. 1IH), 7.68- 7.66 (rn, 1H-): 7.23 -- 7.18 in, 2H), 3.67 (s, 2111, 1.43 (s, 6H). MIS (ESI) m'z: Calculated for C 23 l-l 1 ClFN'Cl: 508.09; found: 509.1 (M+Hi)'. 20 EXAMPLE 109 oxadiazol-3-yl)[benzanicle IT \> HATu, NMM. FCM. .> DMF, 0 C-Ir, 5h This compound was synthesized from 24(2+(4-flu crop henyl)oxazo I--yl)-2 25 mnethvylpropan-i.-amnine and 3-(5-(triflu-ormIethyl)-1,2,4-oxadiazol-3-yi)benizoic acid as described in example 8 step 8 (18 m-.g, yield 12%), '!H NMR (400MIHz, MeOtD) 6 8.55 (s: 1 H), 8.29 (d, J 7.8 Hz, IH), 8.09 -8.05 (in. 3H), 778 (s: 1H), 7.71 - 7.88 (t: J =7,8 Hz, 203 WO 2011/088181 PCT/US20111021089 IH), 7.24- 7.19 (m, 2H), 3.66 (s, 2H), 1.41 (s, 6H). MS (ESI) mz: Calculated for

C

23

H

1 sF 4

N

4 C3: 474.13; found: 475 1 (M+H) EXAMPLE 110 5 1-(2-(4-Fluorophenyl)oxazol-4-yi)ethanone -NCH2N2 CHC, 0 "C-, ih FF A solution of 2-(4-fluorophenyl)oxazole-4-carbaidehyde (400 mg, 2.09 mmol) in dry chloroform (5 mL) was cooled to 0 IC and a freshly prepared solution of diazomethane in ether (20 rL) was added. The reaction mixture was stirred for 1 h and quenched with 10 10% aqueous NaHCO 3 solution. The crude product was extracted with CH 2 Cl7 and the combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chrcmatography (silica gel 60-120 mesh, eluent 5-8 % EtOAc in petroleum ether) to afford 1-(2-(4 fliuoroohenyl)oxazol-4-yl)ethanone (250 mg, yield 58%) as a white solid. 'H NMR (400 15 MHz, CDCIs) 5 8.25 (s, 1H), 8.12 -- 8.09 (m, 2H), 7.21 - 7.17 (t, J = 8.7 Hz, 2H), 2.60 (a, 3H). MS (ESI) rm/z: Calculated for C0,-1sFNO 2 : 205.05; found: 205.9 (M+HY. 3-(2-(4-Fluorophenyi)oxazol-4-yl)-3-hydroxypropanenitrile KCN NC

KH

2

PO

4 HOK N, DMF.t-H,0 4:84v F 80 'C, h 20 A solution of 1.-(2-(4-fluorophenyi)oxazol-4-y!)ethanone (250 mg, 1.22 mrnol) in DMF.-1 2 0 (7 mL: 2.5 vN) was cooled to 0 IC and KH 2

PO

4 (327 mg, 2.4 mmol) was added, followed by KCN (116 mg, 1.8 mmol). The reaction mixture was stirred at 80 'C 10 h and then diluted with water. The organic product was extracted with EtOAc and the combined extracts were washed with H 2 0 and brine, dried over anhydrous sodium sulfate, and 25 concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 8-12% EtOAc in petroleum ether) to afford 3-(2-(4-f!luorophenyl)oxazol-4-yl)-3-hydroxypropanenitrile (60 mg, yield 21%) as a light yellow solid. 1H NMR (300 Mli-z, DMSO-d,) 6 8.11 (d, J-= 0.7 Hz, 1H), 8.03 - 7.98 (dd, J= 8.9 Hz, 5.4 Hz, 2H), 7.40 -7.34 (t J= 8.9 Hz, 2 H), 6.13 -- 6.12 (d, J 5.3 Hz1 H), 30 4.93 -- 4.87 (m, 1H), 2.98 -- 2.93 (dd, J = 8.9 Hz, 5.8 Hz, 2H). MS (ESI) m/z: Calculated for C 2 H FN 2 02: 232.06; found: 233.0 (M+H)', 204 WO 2011/088181 PCT/US20111021089 3-Amino-I -(2-(4-fluorophenyl)oxazol4-yi)propan-I -ol NC.HN

-CFCO

2 H H -- - F ------------------------------ -- ) -- THF. rt. 8h This compound was synthesized from 3-(2-(4-fluorophenyl)oxazoi-4-y)-3 5 hydroxypropanenitrile as described in example 94 step 6 (110 mg, crude) and it was carried through without further purification MS (ESi) m/z: Calculated for C 1 2

H,

3

FN

2

O

2 : 236.10; found: 237.0 (M+H)*. N-(3-(2-(4-Fluorophenyl)oxazoI4-yl)-3-hydroxypropyl)-3-(5-(trifluoromethyl) -1,2,4 10 oxadiazol-3-yI)benzamide P-N 0 N OHO 2N -.0 N O OH HO N Fac e-(<k N F HATU. NMM DMIF, O0-rt, 2h This compound was synthesized from 3-amino.-1-(2.(4-fluorophervl)oxazol-4 yi)propan-1-ol and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-.yl)benzoic acid as described in example 8 step 6 (35 mg, yield 19%) as a white solid. 'H NMR (400MHz, DMSO-ds) 6 15 8.80 - 8.77 (t, J = 5.3 Hz, 1H), 8.51 (s, 11H) 8.20 - 8.18 (d, J = 7.6 Hz, 1H), 8.13 -- 8.11 (d J= 7.9 Hz, 1H), 8.00 (s, 1H), 7.99 -- 7.96 (ad, J= 8.8 Hz, 5.5 Hz, 2H), 7.72 - 7.68 (t, J = 7.8 Hz, 1 H), 7,37 -- 7.32 (t, J = 8.8 Hz, 2H), 5.44 --5.43 (d, J = 5.2 Hz, 1H), 4.69 - 4.65 (n, 1H), 3,47 - 3.42 (im, 2H), 2.17 - 2.08 (m, 1H), 1,99 - 1.90 (m, IH). MS (ESI) m/z: Calculated for C 22

H

6 F4N40 4 : 476.11; found: 477.1 (M+H)*. 20 EXAMPLE 111 2-(4-Bromophenyl)4-(chloromethyl)oxazole NH 0 toluenc C N-N /

N-

2 -Br Br ~>100"C,24h This compound was synthesized from 4-bromobenzamide and 1,3 25 dichloroacetone as described in example 74 step 1 (1.5g. yield 14%) as a white solid. 1 H NMR (400MHz, CDCl2) 6 7.92 - 7.89 (d, J = 8.8 Hz, 21-), 7.71 (s, 1H), 7.61 - 7.59 (d, J = 205 WO 2011/088181 PCT/US20111021089 8.8 Hz, 2H), 4.57 (s,. 2H). MS (ESI) r/z: Calculated for C3H 7 9rCINO: 272.94; found: 273.8 (M+ H)*. 2-(2-(4-Bromophenyl)oxazol-4-yl)acetonitrile N, i) Ki . DMF, rt 2h N 5 ' ' - ii) NaCN, DMF, r i This compound was synthesized from 2-(4-brormophenyl)-4-(chlorormerthvl)oxazole as described in example 71 step 2 (1.4 g, yield 76%) as a off-white solid. 'H NMR (300MHz, CDCl 3 ) 5 7.90 - 7.88 (d, J 8.8 Hz, 2H), 7.75 - 7.74 (t. J = 13 Hz, I H), 7.63 7.60 (d, J = 8.8 Hz, 2H), 3.73 (d, J = 1.3 Hz, 21-). MS (ESI) m/z: Calculated for 10 CIH 7 BrN 2 C: 261.97, found: 262.9 (M+H1). 2-(2-(4-Bromophenyl)oxazol-4-yl)ethanamine NC"E;e, /= MozS H2N ,,\N, r Br -- Br -'O - _ THF, reflux, 0.Sh C This compound was synthesized from 2-(2-(4-bromophenyl)cxazl-4-yl)acetontrile 15 as described in example 42 step 1 (0.4 g, yield 56%) as a yellow liquid. 'H NMR (300MHz, DMSO-ds) 6 6.02 (m, 1H), 7.89 -- 7.86 (d, J = 8.6 Hz, 2H), 7.73 -- 7.71 (d, J = 8.6 Hz, 2H), 2.96 -- 2.91 (m, 2H), 2.73 -- 2.68 (m, 2H). MS (ESI) m/z: Calculated for

C

11

H

11 BrN 2 0: 266.01; found: 267.1 (M+H). 20 N-(2-(2-(4-Bromophenyl)oxazol-4-yl)ethyl)-2,2,2-trifluoroacetamide H2N N 3

CO

2 Et F3C. N - ELN, MeH - I rt, 2h Triethylamine (0.31 mL, 2.24 mimol) was added to a solution of 9-(2-(4-. bromopheny)oxazol-4-y!)ethanarnine (0.4 g, 1.49 mrnmol) in dry methanol (20 nL), followed by ethyl trifluoro acetate (0.27 mL, 2.25 mmol) dropwise at 0 IC. The reaction 25 mixture was slowly warmed to room temperature and further stirred for 2h. The reaction mixture was then concentrated under reduced pressure. The reaction mixture was diluted with EtOAc and washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 1% MeOH in CHC1 3 ) to afford N-(2-(2-(4 30 broiopheny!)oxazol-4-yi)eathyl)-2,2,2-trifluoroacetamide (0.26 g, yield 48%) as an off white solid. "H NMR (300MHz, CDCl 3 ) , 7.98 - 7.95 (d, J = 8.6 Hz, 2H), 7.68 -- 7.65 (d, J 206 WO 2011/088181 PCT/US20111021089 8.6 Hz, 2H), 7.61 (m, 1H), 3.78 - 3.72 (m, 2H)., 2.96 - 2,92 (t, J= 6.1 Hz, 2H). MS (ESI) M/z: Calculated for C 1 3

H,

0 BrF3N 2

O

2 : 361 99; found: 362.5 (M+H)*. N-(2-(2-(4-Cyanophenyl)oxazol-4-y)ethyl)-2.2,2-trifluoroacetamnide H Zn(CN), F PdC(dppf) (oat) F3C. $ - DMF, 150 'C, 48h 6- -- \ / - N N-.(2-(2.-(4-Bromophenyl)oxazol-4-y!)ethyl)-2,2,2-trifiuoroacetamide (200 mg, 0.55 mmol) was dissolved in dry DMF (10 mL) and the solution was purged with argon for 10 min. Zn(CN) 2 (97 mg, 0.83 mnol) and PdCik(dppf) (302 mg, 0.04 mmol) were added to the reaction mixture and heated to 150 "C for 48 h. The reaction mixture was filtered 10 through Celite and the filtrate was concentrated under reduced pressure. The residue was diluted with water and the product was extracted with EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get N (2-(2-(4-cyanophenyl)oxazol-4-yl)ethl)-2,2,2-trifluoroacetamide (150 mg), which was used for the next step without further purification. MS (ESI) rm/z: Calculated for 15 Cj4HF 3

N

3 0 2 : 309.07; found 307.9 (M-H)-. 4-(4-(2-Aminoetihyl)oxazol-2-yl)benzonitrile

F:

3 C,'Pf" N t-1jN rK 2 CO3 H 2 N,_ N r==s e r-CN -- CN 7~~~ MeCH-H P 7:3 vf 1N rt, 3h

K

2

CO

3 (0.20 g, 1.45 mmol) was added portionwise to a solution of N-(2-(2-(4 20 cyanophenyl)oxazol.4-yl)ethy!)-2,2,2-trifluoroacetamide (0.15 g, 0.49 mmol) in dry methanol:water (10 mL, 7:3 v/v). The reaction mixture was stirred at room temperature for 3 h and then diluted with water. The crude product was extracted with chloroform. The organic layer was dried over anhydrous Na 2

SO

4 and concentrated under reduced pressure to get 4-(4-(2-aminoethyl)oxazol-2-yl)benzonitrile (80 mg), which was used for 25 the next step without further purification. MS (ESI) m/z: Calculated for C 1 2 H N30: 213.09; found: 214.0 (M+H)*. 207 WO 2011/088181 PCT/US20111021089 N-(2-(2-(4-Cyanophenyl)oxazol-4-yl)ethyl)-5-(S-(trifluoromethyl)-1.2,4-oxadiazol-3 yl)nicotinamide N '-, 0 HATU, NMM Dr, O 0 C-rt, 4h This compound was synthesized from 4-(4-(2-aminoethyl)oxazol-2-yi)benzonitrile 5 and 5-(5-(trifluoromethy)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (30 mg, yield 23%) as an off white solid. 'H NMR (400MHz, CDCl 3 ) 59.69 (n, 1H), 9.47 (in, 1H), 9.18 (m, 1H), 8.18 - 8.16 (d, J =.3 Hz, 2H), 7.78 - 7.76 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H), 3.92 - 3.91 (n, 2H), 3.05 - 3.02 (t, J 6.0 Hz, 2H). MS (ESI) rn/z. Calculated for CuiH, 3 F3NG 3 : 454.10; found: 453.2 (M-H) 10 EXAMPLE 112 4-(Chloromethyl)-2-(2-fluorophenyl)oxazole q

NH

2 c 130 "C, 2h C----\ sealed tube F A mixture of 2-fluorobenzamide (500 mg, 3.59 mmol) and 1,3-dichloroacetone 15 (1.82 g, 14.36 miiol) was heated to 130 *C for 2 h in a sealed tube. The reaction mixture was diluted with EtOAc and washed with water and brine. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 2-3% EtOAc in petroleum ether) to afford 4-(chloromethyl)-2-(2 fluorophenyl)oxazole (500 rng, yield 66%) as a white solid. 'H NMR (300MHz, CDC 2 ) 6 20 8.08 - 8.02 (td, J = 7.6 Hz, 1.6 Hz, 11H), 7.78 (s, 1 H), 7.50 - 7.43 (m, 11H), 7.28 - 7.18 (m, 2H), 4.61 (d, J = 0.7 Hz, 2H). MS (ESI) mlz: -Calculated for CHCIFNO: 211.02; found: 211.9 (M+H). 2-(2-2-Fluorophenyl)oxazol-4-yl)acetonitrile CI'N /-=- i ) KI, DMF, rt, I h NC - /=\ ii) NaCN, DMF, r., 2h 25 F F This compound was synthesized from 4-(chlorormethyl)-2-(2-fl uorophenyl)oxazole as described in example 71 step 2 (0.2 g, yield 29%) as a white solid. 'H NMR (300MHz, 208 WO 20111088181 PCTUS201 11021089

CDCI

3 ) 6 8.05 -8.1n (td. J =7.6 Hz, 1,8 Hz, 1IH), 7 82 - 7,81 (t, J = 13 Hz, I H). 750 745 (in, 1H), 7.30 - 720 (mn, 2H), 3.77 (d, J =1.1 Hz, 2H,. MS (ESI) m/z CaICLlated for

-

1

,H

7 FN2O: 202.05; found: 202.9 (ty 5 2 -(2-(2-F uorophe nyl)oxazol 4-yi)ethanam ine F This compound was synthesized from -2(-loopeyrxzl4-laeoiri as described in example 42 step 1 (100 Mg, Mrode) and it was carried through without further purification. MS (ESI) m17': Calculated for C 11

HFN'

2 0: 206.09; fOUnd: 2070 10 (U.+ H 'Y N-(2-(2-(2-Fuorophenyl)oxazol-4-yI)ethy)-5-(5-(trifluoronethyl)-1 ,2,4-oxadiazol-3 yl)nicotiniamide ~N N HN, -- N F, HATJ NMI DINF C-r Sh '15 T-his compound was synthesized from 2.-(2-(2-f!oropheryl)oxazol-4-yi)etha.naiine and 5 -(5- (trifluo romethyl) -1, 2,4- oxad iazoI..3-vl)n!cot; n ic acid as described in example 8 step 6 (10 mg, yield 6%) as a white solid. 'H NKPR (400MHz, MeOD) 8 9.39 (d, J =2.0 Hz, I H), 9.20 (d. J = 2.0 Hz, 1 H), 8.90 - 8.89 (t, J =2.0 Hz, IH), 8.03- 7,99 (td; J = 7.7 Hz, 1 8 Hz, 1 H), 7.89 (s, I H. 7.56 - 7.51 (mn, 1 H). 7.33 - 7.25 (in, 2H), 3.80 - 3.76 (t, J = 20 6.9 Hz, 2H), 3.00 - 2.97 t. J = 6.9 Hz, 2H). MS (PSI) m/z Calculated for C 2 0Hi- F 4 NrO.

3 447.10; found: 448.1 (MIv+H)h EXAMPLE 113 1 -(8-Brornothiioplhen-2-yi)-2,2-difluoroethanone I) LDA TH F, -78 IC p ~E 25 0) -78 1C 209 WO 2011/088181 PCT/US20111021089 A solution of 2-bromothiophene (0.5 g, 3.00 mmol) in dry THF (5 mL) was cooled to -78 IC and freshly prepared lithium diisopropylamide (prepared from diisopropyl amine (0.5 mL, 3.60 mmol) and n~uLi (2.3 mL, 3.60 mmol, 1.6M in THF) was added dropwise. The reaction mixture was stirred at -78 C for 1 h. Ethyl difluoro acetate (409 mg, 3.30 5 mmol) was added dropwise at -78 0C and the reaction mixture was stirred for 1 h, then slowly warmed up to room temperature and quenched with saturated NH 4 CI solution. The organic product was extracted with EtCAc and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to get 1-(5-bromthiophen-2-yl)-2,2 difiluoroethanone (500 mg, yield 69%). 'H NMR (400 MHz, CDCi2) 5 7.77 - 7.75 (m, 1H), 10 7.21 - 7.20 (d, J 4.1 Hz, IH), 6.27 - 6.00 (n, IH). 3-(5-(2,2-Difluoroacetyl)thiophen-2-yl)benzoic acid H0 2 Cs .BOH)2 F 7F Fr ----------- -------- COH Pd(PPh ) (cat-) 2M Na 2

CO

3 , DMF, 100 IC, 4h This compound was synthesized from 1-(5-bromothiophen-2-y!)-.2,2 15 diflucroethanone as described in example 88 step 3 (300 mg, yield 51 %) as a brown solid. H NMR (300 MIz, DMSO-d,) 6 13.24 (br s, 1H), 8.28 (s, IH), 8.15 - 8.14 (d, J = 4.2 Hz, I H), 8.09 -- 8.06 (m, 1H), 8.01 -- 7.99 (m, 1H), 7.88 -- 7.87 (d, J 4.2 lz),1) 7.65 -- 7.60 (t, J = 7.8 Hz, 1H), 7.20 - 6.85 (m1-). MS (ESI) m/z: Calculated for C F 3 1-1 8 2 0 3 S: 282.02; found: 280.6 (M-H) . 20 3.-(5-(2,2-Difluoroacetyl)thiopheni-2-yl)-.N-(2-(2.-(4-fluorophentyl)oxazol-4-yl)-2.

methylpropyl)benzamide F Fo HATU, NMM oM ,0 "C-rt, 5h This compound was synthesized from 2- (2-(4 -fluorophenyl)oxazoM-4-yl)-2 25 methylpropan-1-amine and 3-(5-(2,2-difluoroacetyl)thiophen--2-yl)benzcic acid as described in example 8 step 6 (60 mg, yield 34%). 1H NMR (400MHz, DMSO-d 6 ) 5 8.51 8.48 (t, J = 6.2 Hz, 1H), 6.19 - 8.15 (m, 2H), 8.02 - 7.97 (m, 3H), 7.90 - 7.88 (m, 1H), 7.84 -7.83 (d, J = 4.3 Hz, 1H), 7.61 -7.57 (t, J = 7.8 Hz, 1H), 7.35 -7.31 (t, J = 8.8 Hz, 210 WO 2011/088181 PCT/US20111021089 2H), 716 - 6.90 (m, 1H), 3.52 - 3.50 (d, J = 6.4 Hz, 2H), 1.29 (s, 6H). MS (ESI) m/z: Calculated for C 2

H

2 1

FN

2 O3 3 S: 498.12; found: 499.1 (M+H)* EXAMPLE 114 5 1-(2-Bromothiazol-5-yi)-2,2,2-trifluoroethanoI N -N CsF, TMSCF3 F3C / I B jr ------------------ 'B dry glyme. rt, 3h HO This compound was synthesized from 2-bromothiazole-5-carbaldehyde as described in example 88 step 1 (0.6 g, yield 44%). 1 H NMR (300 MHz, CDCl) 6 7.63 (s, IH), 5.37-529(m, IH), 354 (d, J=50 Hz, IH) 10 1-(2-Bromothiazol-5-yl)-2,2,2-trifluoroethanone FC N Dss-Martin F 3 C Br --------------- B,, Fr 0 'C-rt, 3h This compound was synthesized from 1 -(2-bromothiazol-5-yl)-2,2,2 trifluoroethanol as described in example 47 step 2 (0.35 g, yield 59%). 'H NMR (300 15 MHz, CDCl 3 ) 6 8.32 (m,I 1H). MS (ESI) m/z: Calculated for C 5 1-IBrF3NOS: 260.89; found: 261.0 (M+H)*. 3-(5-(2,2,2-Tritluoroacetyl)thiazol-2-yl)benzoic acid HO2C,- -B(OH-)2 r-N FC /;-N F------C-----Br---------- ----- -- y CO2 0 Pd(PPh3) 4 (cat.) 2 N2CO3, DIMF, 90 'C, 5h 20 This compound was synthesized from 1-(2-bromothiazol-5-yI)-2,2,2 trifluoroethanone as described in example 88 step 3 (120 mg, crude) and it was carried through without furher purification. MS (ESI) m/z: Calculated for CH.F 3 N0 3 S: 301.00 found: 299.9 (M-H). 25 211 WO 2011/088181 PCT/US20111021089 N-(2-(2-(4-Fluorophenyl)oxazol-4-yi)-2-methylpropyl)-3-(5-(2,2,2 trifl uoroacetyl)thiazol-2-yl)benzamide FH/N N --- N -- Co2H ___f HATU, NMM DMF. 0 'c-rt 4h This compound was synthesized from 2-(2-.(4-flucrophenyl)oxazol-4-yl)-2 5 methylpropan-1 -amine and 3-(5-(2,2,2-trifluoroacetyl)thiazol-2-yl)benzoic acid as described in example 8 step 6 (7 mg, yield 3%). 'H NMOR (400 MI-lz, DMSO-de) 6 8.56 - 8.53 (t, J = 5.5 Hz, 1H); 8.35 (m, 1H), 8.28 (m, 2H), 8.10 -- 8.08 (m, IH), 8.02 - 8.00 (m, 2H), 7.94 (im, 1H), 7.61 - 7.57 (t, J = 7.8 Hz, 1H), 7.35 - 7.31 (t, J = 8.7 Hz, 2H), 3.51 - 3.50 (d, J = 5.8 Hz, 2H), 1.29 (s, 6H). M (ESI) mz: Calculated for C2 IIF4N 00S: 10 517.11; found: 516.1 (M-H)-. EXAMPLE 115 4-(((tert-ButyldiphenyIsilyl)oxy)methyl)-2-pheny-1IH-imidazole NH Ph -NH HO iuPh 2 SiC \g imidazole, CH 2 Cl 2 Ph 0 C-rt, h 15 BuPh 2 SiCl (5 5 g, 19.9 mmol) was added dropwise to a suspension of 2-phenyl IH-imidazole-4-methanol (2.9 g, 16.65 mmol) and midazole (1.7 g, 24 97 mmol) in dry

CH

2 Ci 2 (60 mL.) at 0 IC. The reaction mixture was allowed to warm up to room temperature and stirred for 8 h. The reaction mixture was diluted with CH 2

CI

2 and the organic layer was washed with 10% NaHCO solution, water and brine. The organic layer 20 was dried over anhydrous Na2S0 4 and concentrated under reduced pressure to yield 4 (((tert-butyldiphenylsilyl)oxy)methyi)-2-phenyl-IH-imlidazoe (5 7 g, yield 83%), which was carried through without further purification. 'H NMR (300 MHz CDC13) 5 7.77 - 7.69 (m,. 6H), 746 - 7.37 (m, 9H), 695 (m, 1 H), 4.81 (s, 2H), 1.09 (s, 9H). MS (ESI) m/z Calculated for C 2 eH 2 8N 2 OSi: 412 20; found: 413.3 (M+H)*. 25 4-(((tert-Butyldiphenylsilyl)oxy)niethyl)-1 -nethyl-2-phenyl-1H-inidazole P -NH Ph --N 0 <.-~/~o MeNeNF- ' N-N Ph hTHF,0 C, ih Ph 212 WO 2011/088181 PCT/US20111021089 This compound was synthesized from 4-(((tedt-butyldiphenvlsilyl)oxy)rnethyl)-2 phenyl-1H-imidazole as described in example 1 step 2 (1 25 g, yield 21%) as a yellow viscous liquid. 'H NMR (400 MHz, CDCis) 6 7.82 - 7.75 (m, 3H), 7.69 - 7.67 (im, 4H), 7.61 - 7.60 (m, 2H), 7.46 - 7.41 (m, 6H), 6.95 (s, 1H), 5.14 (d, J = 1.3 Hz, 2H), 3.88 (s, 5 3H), 1.13 (s, 9H). MS (ESI) r/z: Calculated for C 2

,H

30

N

2 0SI: 426.21; found: 427.3 (M+ -H) (1-Methyl-2-phenyl-I1H-imidazol-4-yi)methanoI Ph N Ph g-- TBAF (1M in THF) r---N -- 1 -- -- - - - - -- - -_ ' Ph N' THF, 0oC-rt. 3h 10 A solution of 4-(((tedt-butyldiphenylslyi)oxy)methyl)-1-methyl-2-phenyl- 1i iidazole (1.25 g, 2.93 mmol) in dry THF (25 mL) was cooled to OC and tetrabutylammonium fluoride (5.9 mL, 5.86 mmol, 1M in THF) was added dropwise. The reaction mixture was allowed to warm up to room temperature and further stirred for 3 h. The reaction mixture was quenched with brine and extracted with EtOAc. The organic 15 layer was dried over anhydrous Na 2 -S.O4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 2-4% MeCH in CH 2 Cl 2 ) to get (1-methyl-2-phenyl-1H- imidazol- 4-yl)methano (0.26 mg, yleid 47%) as a white solid. 'H NMR (400 MHz, DMSO-d,) 6 7.68 - 7.66 (m, 2H), 7.50 - 7.41 (m, 3H), 7.11 (s, 1H), 4.92 (br s, IH), 4.37 (s, 2H), 3.71 (s, 3H). MS (ESI) m/z: Calculated 20 for C 11

H

12

N

2 0: 188.09; found: 188.9 (M+H)*. 4-(Chloromethyl)-1 -methyl-2-phenyl-1 H-imidazole i- SOCl2 HO Ch N N " reflux, ih This compound was synthesized from (1-methyl-2-phenyl-1H-imidazoi-4 25 yl)methanol as described in example 93 step 3 (0.28 g, crude) as hydrochloride salt as a brown solid. ' 1 H NMR (300 MHz, DMSO-ds) 6 7.90 (s, 11H), 7.82 -7.80 (m, 2H), 7.70 - 7.66 (m, 3H), 4.93 (s, 2H), 3.84 (s, 3H). 213 WO 2011/088181 PCT/US20111021089 2-(1-Methyl-2-phenyl-1 H-imidazol4-yl)acetonitrile fi N/ i -- N NsCN NC N N HC DMF, rt, 12h N This compound was synthesized from 4-(chloromethyl)-1-methyi-2-phenyl-lH imdazoie as described in example 77 step 1 (120 rng, yield 44%) as a brown liquid. 'H 5 NMR (300 MHz, CDCIl) 6 7.61 - 7.58 (m, 2H), 7.49 - 7.43 (m, 3H), 7 02 (s, 1H). 3.75 (d, J = 0.9 Hz, 2H), 3.73 (s, 3H). MS (ESI) m/z: Calculated for CUHIN 3 : 197.10; found: 197.9 (M-+H). 2-(1-Methyl-2-phenyl-1H-limidazol-4-yl)propanenitrile N V- NCj Mel, N;aH N C." 10 N/ THF, 0 "C-rt 3h,-J This compound was synthesize frorn 2-(1-methyl-2-phenyl-IH-irnidazo-4 yi)acetonitrile as described in example I step 2 (60 mrg, yield 47%) as light yellow oil. 'H NMR (300 MHz, CDCI,) 6 7.62 - 7.59 (m, 2H), 7.47- 7.45 (m 3H), 7.01 (s, 1H), 4.01 3.94 (i. J = 7.1 Hz, 1H), 3.72 (s, 3H), 1.71 - 1.69 (d, J = 7.2 Hz. 3H). MS (ESI) M/z: 15 Calculated for C,H, 3

N

3 : 211.11; found: 212.0 (M+H)*. 2-(1-Methyl-2-phenyl-1H-imidazol-4-yl)propan-1-amine N N LiAlH 4 (2M in THF) 0 NC, 30 min This compound was synthesized from 2-(1-methyl-2-phenyl-1H-inidazo-4 20 yl)propanenitrile as described in example 1 step 3 (60 mg, crude) and it was carried through without further purification. MS (ESI) m/z. Calculated for CjHjN: 215.14: found: 216.0 (M+H)*. 214 WO 20111088181 PCT/US201l11021089 N-(2-(l -Methyl-2-phenyl-1 H-imidazoh-4.y)propyl)-6S-(5-(trifluoror-nethyl)-1 ,2,4 oxadiazol-3-yl)nicatinamnide N 0H I I L{I -'ATU, NMN K. N DMF, Vt. Sh4 I This compound was synthnesizedl from 2-(1-rnethyl-2-phienylI-H-mdazol.-4 5 yi)pronspn-1-arnine a nd -((tiuonethly)-1 ,2.4-oxasdiazd-3-y)nicotikIic acid as described in example B step 6 (10 mng, yield 16%). 1 H1 NvMR (400M~z, C~DC 3 ) 6 9.40 (d, J -2.1 Hz, 1 H). 9.31 (d, J =2.1 !Hz, 1 H), 9.16 - 9.15 (in, IH)2 6.87- 8.86 (t, J 2.1 Hz. 1 H), 7.62 - 7.59 (in, 2H), 7.42 - 71.40 (m,. 3H), 6.81 (s. -1 H), 4.02 - 3.96 (ddd. J 12.9 Hz, 6.2 Hz, 4.3 Hz: -1-), 3.75 (s: 3H), 3.42--3.35 (ddd, J n 12.9 Hz: 9.4 Hz. 3.2 Hz, 1 H), 3.15 10 .-- 3.10 (rrl, IH)V 1.40 .-- 1.36 (d, J 6.7 Hz, 3H). MS (ES!) rnlz: Calculated For C22-I,9F 3 1\180: 456.15. found: 457.3 (NI-HY'. EXAMPLE 116 1 -(5SIBrornofurani-2-yi)-2,2,24rifluoroethanoI H 177~~ OaF, TMSCF 3 F, / *7?~~~ ~~ Br------------- y . -~ d dry 5ym e. rt8 6h This compound was synthesized frm5-bromcofu ran -2-carbalde hyde as described n example 88 step 1 (2.6 g, yield 62%). IH NMR (,300 MHz, CODCl 3 ) 6 6.52 - 651 (d, J 3.5 Hz, I H), 6.36 -635 (d, J = 3 5 Hz, I H), 5,07 - 4,98 (in, I H), 2.91 - 2.69 (d, J =7.2 Hz, 1IH). 20 1 -(6-Bromofuran-2-yI)-2,2.2-tritluoroethanone 1H2 0 0 -C-rt, 8hd This compound was synthesized from I-(5-brornofur an-2-yi)-2.2,2-tr.ifiLuoroethlanroI as described in example 47 step 2 (1.2 g, yield 47%). 1H NPAR (300 Mv-Fz, C0013) 5 7.46 25 7.44 (in, 11-1), 6.66 -6.65 (d, J = 3.7 iz, 1IH). 215 WO 2011/088181 PCT/US2011/021089 3-(5-(2,2,2-Trifluoroacetyl)furan-2-yl)benzoic acid 10 2 C Y - B(OH)2 O Br CO2H O Pd(PPh ) 4 (cat) 2M Na 2 CO, DMF. 90 "C, 3h This compound was synthesized from 1-(5-bromofuran-2-yi)-2,2,2 trifluoroethanone as described in example 88 step 3 (500 rng, crude). H NMR (300 MHz, 5 DMSO--d,) 6 13.26 (br s, IH), 8.41 (m, 1H), 8.19 -- 8.16 (m, 1H), 8.05- 8.03 (m, 1H), 7.98 - 7.97 (m, 1H), 7.70 - 7.67 (m, 1 H): 7.58 --7.57 (m, 1 H). N-(2-(2-(4-Fluorophenylloxazol4-yl)-2-methylpropyl)-3-(6-(2,2,2 trifluoroacetyl)furan-2-yi)benzam ide -FN -o1---O- FNc- -F -T3P, EN H 10 cH 2 Cb, 0 'c-4, 4 This compound was synthesized from 2-(2--(4-fluorophenyl)oxazol-4-yl)--2 methylpropan-1--amine and 3-(5.-(2,2,2-trifluoroacetyl)furan-2-yl)benzoic acid as described in example 8 step 6 (20 mg, yield 6%). 1 H NMR (400 MHz, DMSO-.dg) 6 8.52 -- 8.49 (t, J = 6.2 Hz, I H), 8.30 -- 8.29 (t, J = 1.6 Hz, 1 H), 8.09 -- 8.06 (dt, J= 8.1 Hz, 1.2 Hz, 1 H), 8.01 15 7.98 (m, 4H), 7.94 - 7,92 (dt, J = 8.1 Hz, 1.2 Hz, 1 H), 7.66 -- 7.62 (t, J = 7.8 Hz, IH), 7.51 - 7.50 (d, J = 4.0 Hz, I H), 7.35 - 7.31 (t, J = 9.0 Hz, 2H), 3.52 - 3.50 (d, J = 6.4 Hz, 2H), 1.29 (s, 6H). MS (ESI) m/z: Calculated for C2 6

H

2

F

4

N

2 0 4 : 500.14; found: 499.4 (M-H)-. EXAMPLE 117 20 4-(Dimethoxymethyl)-2-(4-fluorophenyi)oxazole N MaSiOMe, TMSOIf 0 /~--- ----------------------- ~ / \g X F CI-12C2, -78 'C to rt, 24h F Methoxytrimethyisilane (545 mg, 5.23 mmol) and trimethylsilyl trifluoromethanesulfonate (30 mg, 0.13 mmol) were added to a solution of 2-(4 fluorophenyl)oxazole -4-carbaldehyde (500 mg, 2.62 miol) n dry CH 2 Cl2 (2 mL) at -78 'C. 25 The reaction mixture was allowed to warm up to room temperature and stirred for 24 h, quenched with saturated aqueous NaHCO 3 solution, and the crude product was extracted 216 WO 2011/088181 PCT/US20111021089 with EtOAc. The organic layer was washed with 10% NaHCO 3 solution, water and brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to get 4-(dimethoxymethyl)-2-(4-fluorophenyl)oxazole (400 mg, crude), which was carried through without further purification. 'H NMR (400 MHz, CDC1 3 ) 6 8.08 - 8.05 (in 2H), 7.71 5 (d, J = 1.2 Hz, 1H), 7.16 - 7.12 (m, 2H), 5.50 (d, J = 0.9 Hz, 1H), 3.41 (s, 6H). MS (ESI) riz: Calculated for C,,H' 2

FNO

3 : 237.08; found: 259.9 (M+Na+ 2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methoxyacetonitrile ~0 0 - IMe SiCN NC- N F 10 Trimethylsilyl cyanide (4.13 g, 41.76 mmol) was added to a solution of 4 (dimethoxymethyl)-2-(4-fluorophenyl)oxazole (400 mg, 1.69 mmol) at room temperature, followed by boron trifluoride diethyl etherate (37 mg, 0.26 mnmol). The reaction mixture was stirred for 20 min, quenched with saturated aqueous NaHCO 3 solution, and extracted with EtOAc. The combined extracts were washed with H 2 0 and brine, dried over 15 anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eiuent 8-10% EtOAc in petroleum ether) to afford 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methoxyacetonitrile (100 mg, yield 16%) as a light yellow liquid. 'H NMR (400 MHz, CDCis) 6 8.08 - 8.06 (m, 2H), 7.90 (d, J = 0.9 Hz, 1H), 719 - 7.15 (in, 2H), 5.29 (d, J = 0.9 Hz, 1H), 3.62 (s, 3H). MS 20 (ESI) m/z: Calculated for Cl 2

H.FN

2

O

2 : 232.21; found: 232.9 (M+H)*. 2-(2-(4-Fluoropheriyl)oxazol4-y)-2-riethoxyethanamine NC- NaBH CFC0OH H 2 N % TF, rt,, 8 h This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2 25 methoxyacetonitrile as described in example 94 step 6 (100 mg, crude) and it was carried through without further purification. MS (ESI) rm/z: Calculated for C2 1

H

3

FN

2 O2: 236.10; found: 236.9 (M+H)*. N-(2-(2-(4-Fluorophenylloxazol-4-yl)-2-methoxyethyl)-3-(5-(trifluoromethyl)-1,2,4 30 oxadiazoI-3-yl)benzamide 217 WO 2011/088181 PCT/US20111021089 FaC N ~OH HATU, NMMv N r N \ N F DMF. 0 'C-rt, 2h 0 '. This compound was synthesized from 2-(2-.(4-fluorophenyl)oxazo-4-yl)-2 methoxyethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (44 mg, yield 22%) as an off-white solid. 'H NMR 5 (400MHz CDCi 3 ) 6 8.56 - 8.55 (t, J = 1.6 Hz, 1H), 8.29 - 8.26 (dt, J = 7.9 Hz, 1.3 Hz, 1 H), 8.11 -- 8.06 (m, 3H), 7.73 (s, 1H), 7.67 -- 7.63 (t, J 7.7 Hz, 1H), 7.22 -- 7.19 (m, 1H), 7.17 -- 7.13 (t, J= 8.7 Hz, 2H), 4.54 -- 4.51 (dd, J = 5.9 Hz, 5.1 Hz, 1Hi) 4.12 -- 4.06 (ddd, J = 13.9 Hz, 6.5 Hz, 4.9 Hz, 1H), 3.87 - 3.81 (didd, J = 13.9 Hz, 6.1 Hz, 4.8 Hz, IH), 3.45 (s, 3H). MS (ESI) nm/z: Calculated for C 2 HfF,N 4 0 4 : 476.11; found: 475.6 (M). 10 EXAMPLE 118 2-(4-(4-Fluorophenyl)thiazol-2-yl)propanenitrile N N LiHMDS, Mel N THF, -78*C F F' To a stirred solution of 2-(4-(4-fluoropheny!)thiazol-2-yl)acetonitrile (500 mg, 2.29 15 mrnol) in THF (10 mL) at -78 0C was added LiHMDS (IM in THF; 2.06 IL, 2.06 mrnol) and the reaction mixture was stirred at -78 OC for 10 min. lodomethane (0.12 mL, 2.06 mmol) in THF (2 mL) was then added dropwise and the reaction mixture was stirred at -78 "C for 30 min. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NH 4 CI solution, water, brine, and dried over anhydrous sodium sulfate. The 20 organic layer was concentrated under reduced pressure to give the crude product; which was purified on a Teledyne ISCO automated column chromatography system (0 - 30 % EtOAc / Hexanes) to give 2-(4-(4-fluorophenyl)thiazol-2-yl)propanenitrile (180 mg, yield 34%). MS (ESI) m/z: Calculated for C 2

H

9

FN

2 S: 232.05; found: 233.1 (M+H) 25 218 WO 2011/088181 PCT/US20111021089 2-(4-(4-Fiuorophenyl)thiazol-2-yl)propan-1 -amine N S N H2 F- 2F' j To a stirred solution of 2-(4-(4-fluorophenyi)thiazol-2-y!)propanenitrile (140 mg, 0.6 mmo!) in THF (3 mL) at room temperature was added borane (1 Iin THF; 3,01 mL, 3.01 5 mmol) and the reaction mixture was stirred at room temperature for 1h and then heated at 40 0C for 1h. The reaction mixture was then cooled to 0 'C and quenched with MeOH (~5eg, ~0.2 mL), and allowed to warm to room temperature where 2N HCI solution was added until the pH - 2. The reaction mixture was refluxed at 65 "C for 15 min and then cooled to room temperature and concentrated under reduced pressure. The solid 10 obtained was triturated with ether twice and dichloromethane another two times. The remaining solid was dissolved in water (-50 mL) and basified to pH -- 11 with NaOH pellets. The aqueous Mixture was then extracted with ether and dried over sodium sulfate and concentrated under reduced pressure to give 2-(4-(4-fluorophenyl)thiazoi-2-vl)propan 1-amine (75 mg, yield 52%), which was carried through without further purification; MS 15 (ESI) m/z: Calculated for CH 1 3

FN

2 S: 236.08; found: 237 1 (M+H)+. N-(2-(4-(4-Fluorophenyl)thiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)benzamide F - N H H2N-N ----- ----------- --- F N N Y F oEDC. HO, DcM, t ' y-N 0 s _ 20 2-(4-(4-Fluoropheny!)thiazol-2-yl)propan-1 -amine (50 mg, 0.21 mmol), 3-(5-. (trifiuoromethy)-1,2,4-oxadiazol-3-y)benzoic acid (54.62 mg, 0.21 mmol) N-(3 dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC) (61.12 mg, 0.42 mmol). and 1-hydroxybenzotriazole (HO13t) (45.74 mg, 0.39 mmol) were dissolved in dichloromethane (3 mL) at room temperature. Dilsopropylethylamine (DIEA) (0.147 mL, 25 0.85 mmol) was then introduced at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichlorornethane (100 rL) and washed with water (1 X 20 mL) and brine (1 X 20 mL). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified on a Teledyne ISCO automated column 30 chromatography system (0 -- 30 % EtOAc / Hexanes) to give N-(2-(4-(4-. fuorophenyl)thiazol-2-yl)prpyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (36 219 WO 2011/088181 PCT/US20111021089 mg, 36% yield). IH NMR (CDCl3) 6 8.50 (1h, s), 8.23 (1H, d, J = 8 Hz), 8.03 (1H, 1H, d, J = 8 Hz), 7.85-7.81 (3H, m), 7.58 (1H, t), 7.35 (1H, s), 7 03 (2H. m), 4 05 (1H, m), 3.65 (1H, m), 1.54 (3H, d, J = 8 Hz). MS (ESI) m/z: Calculated for C2H 1 sF 4

N

4 0 2 S 476.09 found 477.1 (M+H)Th 5 EXAMPLE 119 N-((4-(4-Phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yi)methyl)-3-(5-(2,2,2 trifluoroacetyl)thiophen-2-yl)benzamnide F N NN o OH + HN- HOSt F FA. 10 This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H pyran-4-yi)nethanamine and 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoc acid as described in example 118 step 3 (0.022g, yield 15%). 'H NMR (400 MHz, DMSO) 6 8.650-8 681 (t, I H), 6 6.132 (s, 2 H), 6 8.071 (s, 1 H), 6 7.973-7 991 (d, 1 H), 6 7 897 7,915 (d, 1H), 7.826-7.846 (d, 1 H), 7 786-7.797 (d, I H), 7.532-7 571 (t, 1 H), 7.320 15 7.357 (.t, 2 H), 7.254-7.272 (d, I H), 3.814-3.843 (d 2 H), 3.553-3.568 (d, 2 H), 3 282 3.409 (d, 2 H), 2 22-2.26 (d, 2 H), 1.936-2.006 (m, 2 H); MS (ESI+) m/z 555.1 (M - H). EXAMPLE 120 N-(2-(2-(4-Fluorophenylloxazol-4-yI)ethyl)-3-(6-(trifluoromethyl)-1 2,4-oxadiazol-3 20 yl)benzamide N- --F F> CO2H HP-9N O N.

-( rA-F. N -V H DMF, 0 "C- r 4h This compound was synthesized from 2-(2-(4-fLuorophenyl)oxazol-4-yl)ethanamTine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-y!)benzoic acid as described in example 8 step 6 (45 mg, yield 27%). IH NMR (400MHz, DMSO-d,) 5 8.91 (t, J = 5.4 Hz, 1H), 8.51 25 (s, I H), 8.20 (d, J = 7 9 Hz, I H), 8.12 (d, J = 8.2 Hz, I H), 8.00 - 7.97 (m. 3H), 7 74- 770 (t, J = 7.8 Hz 1H), 7.37- 7 32 (t, J = 8.8 Hz, 2H), 3.61 - 3.56 (m, 2H), 2.84 - 2.80 (t, J = 7.0 Hz, 2H). MS (ES1) mr/z: Calculated for C 21 H4F4N 4 0 3 : 446.10: found: 447.2 (M+H). 220 WO 2011/088181 PCT/US20111021089 EXAMPLE 121 N-(2-(2-(4-Fluorophenyl)oxazol-4-yI)-2-methylpropyl)-5-(5-(trifluoromethyl)-1,2,4 oxadiazol-3-yl)nicotinamide FN ~~CO2H H2N -F -------- --------------------------- NN HATU NMM H DMF, OC-rt, 4h This compound was synthesized frorn 2- (2-(4-Fluorophenyl)oxazoi4+-yl)-2 methylpropan-1-amine and 5-(5-trifiuoromethyl-[1,2,4ioxadiazol-3-yI)-nicotinic acid as described in example 8 step 6 (19 mg, yield 13%). IH NMR (400MHz, MeOD) 5 9.38 (d, J 1.5 Hz, 1H), 9 17 (d, J = 1.8 Hz, IH), 8.84 (d, J = 1 8 Hz, 1 H), 8.09 - 8 05 (m, 2H), 7.78 10 (s, 1H), 7.25 - 7.20 (m, 2.H), 3.68 (s, 2H), 1 42(s, 6H). MS (ESI) m/z: Calculated for CaHl/F 4 NaO: 475.13; found: 476.2 (M+H)'. EXAMPLE 122 2-(3-Bromophenyl)-2-methylpropanenitrile NC Br' CNNG 15 This compound was synthesized from 2-(3-bromopheny!)acetonitrile as described in example I step 2 using lodomethane, (1.2 g, used crude) and it was carried through without further purification MS (ESI) m/z: Calculated for C 1 0HgBrN: 223.00; found: 224 0 (M+H). 20 2-(3-Brormophenyl)-2-methylpropan-1 -amine NC ~ LiAIH 4 NCs Br THF, 0 C-rt H 2 N Br This compound was synthesized from 2-(3-bromophenyl)-2-methylpropanenitrile as described in example 1 step 3 (1.3 g, used crude), and it was carried through without 25 further purification. MS (ESI) mn/z: Calculated for C1H.

1 4 BrN: 227.03; found: 228.0 (M+H)*. N-(2-(3-Bromophenyl)-2-methypropyl)-3-(5-(trifluoromethy)-1 2,4-oxadiazol-3 yl)benzamide 221 WO 2011/088181 PCT/US20111021089 ~K6,1,TUNMM N This compound was synthesized from 2-(3-bromophenyl)-2-methylpropan-1-amine and 3-(5-(trifauoromethyl)-1,24-oxadiazol-3-yl)benzc acid as described in example 8 step 6 (90 mg, yield 83%). MS (ESI) n/z: Calculated for CH 17 BrF3)N 3 02: 467.05; found: 5 468.0 (M-H). N-(2 -([1 '.-Bi phenyl]-3-yl)-2- methylpropyl).-3-(5-(trifluoromethyl) -1,2,4-oxadiazol -3 yl)benzarmide N-K~ ~' N''Y Br * ' || HH/\ | N N H / \ T7HF. SO "C / 10 A solution of N-I(2-(3-bromophenyl)-2-methylpropyl)-3-(5-(trifluoromethy)-1,2,4 oxadiazol-3-yl)benzarmide (30 mg, 0 064 mmol) and phenyl boronic acid (39 mgs, 0.32 mmol) in THF (1.2 mL) was degassed with nitrogen. Dichloro [1,1' bis(di-tert butylphosphinol]ferrocene palladium (II) (5 rmgs, 0.006 mmol) and 1 M potassium carbonate (1.2 mL) were added. The reaction was heated overnight at 60 *C. The 15 reaction was extracted with ethyl acetate and dried over sodium sulfate. The crude was purified by prep TLC using 30% EA/hexanes.to yield N-(2-[,1'-biphenyij-3-y)-2 methylpropyl)-3-(5-(trifluoromethyi)-1,2,4-oxadiazol-3-yl)benzarnide (6 mgs, yield 18%). H NMR (300 MHz, CDCI 3 ) 5 8.29 (s, IH) 8.18 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 7.2 Hz, I H), 7.64-7 30 (m, 10H) 5.88 (s, 1 H), 3 73 (d, J = 7.2 Hz, 2H) 1.48 (s, 6H). MS (ESI) m/z: 20 Calculated for C, 6

H

22

F

3

N

3 0 2 : 465 17; found: 466.2 (M+H)*. EXAMPLE 123 NV-(2-(4'-Fluoro-[1,1'-bipheniyl]-3-yl)-2-methiylpropyl)-3-(5-(trifluoromiethiyl)-1,2,4 oxadiazol-3-yI)benzamide FN OH Fac---- Irc c A 25 'v This compound was synthesized from N-(2-(3-bromophenyl)-2-methylpropyl)-3-(5 (trifiuoromethyl)-1,2,4-oxadiazol-3-yl)benzamide and 4-fluoroboronic acid as described in example 122 step 4 (8mg, 25 % yield). 1H NMR (300 MHz, CDCi3) 5 8.27 (s, 1H) 8.18 (dJ = 7.2 Hz, IH), 7.82 (d, J = 7.2Hz 1H), 7.60-7.38 (n, 8H) 7.11 (n, 1H), 5.71 (s, 1H), 222 WO 20111088181 PCT/US201l11021089 3.73 (d, J = 7.2 Hz, 2H)2 1.47 (s, 6H), L,1 (ESI) 'z: Ca!CLclated for C 26

H

2 1F 4

N

3

O)

2 483.16; found- 484.2 (NliH)f. EXAMPLE 124 5 2-(4-(36-Difluoropheniyi)thiiazol-2-yflacetonitrile F~ $ EtCOH N -( refliix F F This compound was synthesized from 2-brorno-1-(3,5-difiuorophen~yl)ethanone as described in example 1 step 1 (3 g, yield 94%). MS (ESI) mv~: Calculated for C 11 H F 2

N

2 S: 236.02; found: 237 1 MH 4-(4-43,-Difluom-pleriy)thiazo-2-yl)tetrahydr-o-2H-pyran4-carbonitile -F Br S~r . NsH, 7TIF This compound was synthesized from 2-(4-(3,5-difILuoroph!envl)thi!azo-2 y!)acetornitrile using 2%bromoethyl ether as described in example 1 ste 'p 2 (1.0 g: yield 15 99%). MS (ESI) rn'z. Calculated for CI 11

H

12

F

2

N

2 0S: 306.06, found: 307.1 (IV!H)'. 223 WO 20111088181 PCTUS201 11021089 (4-(4-(3, 6-Difl uorophenyl)th iazoll-2-yl)tetrahyd ro-2k1-pyra n 4-yi) metha namr ie FF (/F S --- -- - - - - -- - - T HF, 0 H2N-rt' .This compound was synthesized from 4-(4-(3.5-difluorophenyl)thiazo-2 y!)te3trahydro-2H-pyran-4-carbon-itn-ie as described in examPle I step 3 (1 9, crude), and it 5 was carried through without further purification. INAS (ESI) mfr- Calculated for Cj 5 Hj 6 rF 2

N

2 GS: 310 10; found: 311.1 (M+H)*> N-((4-(4-(35-Difluoropheniylthiazol-2-y)tetrahydro-21-pyran4-y)nethyl)-3-(5 (trifluoroniethyl)-1,2,4-oxadiazoI-3-yi)benzaniide -F / H N -IATL, NMIM ' 10 01 0 -- t This compound vvas synthesized from (4(-35diiurpel)hiz-2 yl)tetrahlydr-o-2H-pyran,-4-yl)m,.etlhanarriirne and 3-(5-(trifluoromnethyly-1 2,4-oxadazol-3 yi)benzoic acid as described in example 8 step 6 (20 mrg, 10% yield). 1lFl NMR (300 M~iz, LCh1) 6 8.45 (s: 10), 8.24 (d, J= 8.3 Hz, 10H), 7.88 (d, J=8.3 Hz, 10), 7.64-7.54 (in, 2H), 15 7.35 (d, J= 5,5 Hz, li-I; 6.73 (n, 2 1-), 3.95 (in, 2 H), 3.85 (d, J= 5.5 Iz, 21-), 3.70 (.m, 21-1); 2.28 (m,. 2H), 2.05 (in, 2H). MS (ESI) rnz Calculated for C,,H.F N 4 03S: 550.11; found: 5511A(--H~ EXAMPLE 128 20 2 -(4-(3,5-Difl uorophenyl)th iazol -2-yl) -2-methylpro pane nithle F, _-S IN Fy N 224 WO 2011/088181 PCT/US20111021089 This compound was synthesized from 2-(4-(35-difluorophenl)thiazoi-2 y!)acetonitrile using iodomethane as described in example 1 step 2 (1.0 g, yield 60%) MS (ESI) m/z: Calculated for C13HrIF 2

N

2 S: 264.05 found: 265.1 (M+H)*. 5 2-(4-(3,5-Difluorophenyl)thiazol-2-yl)-2-methylpropan-1 -amine F LiAlH4 N- -N-----------+ NC, THF0 *C-rt

H

2 N' This compound was synthesized frorn 2-(4-(3,5-difluorophenyl)thiazol-2-yl)-2 methvlpropanenitrile as described in example I step 3 (1 g, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for C 13 l-i1 4

F

2

N

2 S: 268.08; 10 found: 269.1 (M+H). N-(2-(4-(3,5-Difluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(6-(trifluoromethyl)-1,2,4 oxadiazol-3-yl)benzamide -W71J MMM r. P-'J '4 S \ Fc- co 2 H F-------- F \ H F 15 This compound was synthesized from 2-(4-(3,5-diflucroohenyl)thiazol-2-y)-2 methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yi)benzoic acid as described in example 8 step 6 (85 mg, yield 24%). 1 H NMR (300 Mi z, CDCl 3 ) 6 8.54 (s, 1H), 8.25 (d, J= 7.6 Hz, 1H). 8.04 (m, 1H) 7.62 (*, J=9.2 Hz, 1H), 7.47(s, 1H), 7.35 (d, J= 7.6 Hz, 2H), 6.72 (m, 1-), 3.79 (d, J=2.8 Hz, 21-), 1.55 (s, 6H). MS (ESI) m/z: Calculated 20 for C 2 3H 17 FfN 4 0 2 S: 508.10; found: 509.1 (M+H) EXAMPLE 126 2-(2-Phenyloxazol-4-yl)ethanamine \ N DIBAL (1M in THF) O ' NH 2 k - N ~ -- ---------------- THF, 0 C-rt 25 This compound was synthesized from 2-(2-phenyloxazol-4-yl)acetontrile as described in example 64 step 4 (400 mg, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for C 11

H

1

,N

2 O: 188.09; found: 189.1 (M+H). 225 WO 2011/088181 PCT/US20111021089 N-(2-(2-Phenyloxazol4-yl)ethyl)-3-(S-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)benzamide F ac- t 0 2 NH2 p This compound was synthesized from 2-(2-phenyloxazol-4-yl)ethanamine and 3 5 (5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (40 mgs, yield 25%). 'H NMR (CDC) 6 8.59 (s, 1H), 8.26 (d, J= 7.8 Hz, 1H), 8 13 (d, J= 8.1 Hz, 1H), 8.05 (m, 2H), 7.62-7.56 (m, 3H), 7.43 (m, 2H), 3.84 (m, 2H), 2.93 (m, 2H). MS (ESI) m/z: Calculated for C, HF 3

N

4 0 3 : 428.11; found: 429.1 (M+H)*. 10 EXAMPLE 127 N-(2-(2-Phenyloxazol-4-yl)ethyl)-5-(6-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)nicotinamide ,N, N sN - N F3 F -1 0 This compound was synthesized from 2-(2-phenyioxazoi-4-yl)ethanarine and 5 15 (5-(trifliuoroiethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (42 mgs, yield 32%). 'H NMR (CDCi 3 ) 9.46 (d, J = 2.1 Hz, 1H), 9.32 (d, J = 2.1 Hz, 1H), 8.87 (t, J = 2.7 Hz, 1H), 8.06-7.96 (mn, 3H), 7.57-7.44 (m, 31-), 3.85 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H). MS (ESI) r/z: Calculated for C 2 aH kF 3

N

5

O

3 : 429.10 found: 430.1 (M+H)*. 20 EXAMPLE 128 2-(2-(4-Chlorophenyl)oxazol-4-yljethananine CN DIBAL (1M in THF) NH2 -- ------------------------ N N N THF, 0 'C-rt This compound was synthesized from 2-(2-.(4-chlorophenyl)oxazol-4-y!)acetontrile as described in example 64 step 4 (466 mg, crude) and it was carried through without 25 further purification. MS (ESI) rtz: Calculated for Cj 1

H-,CIN

2 0: 222.06; found: 223.1 (M+H)*. 226 WO 20111088181 PCTUS201 11021089 N-(2-(2-(4-.Chlorophenyl)o)xazol-4-yl)ethyl)-3-(5-(trifluoro-nethyl)-1 ,2,4-o)xadiazoI-3 yl)benzarmide NN '<~ cIF< bN ' This compound was synthesized from 2- (2 -(4- ch lorophenyl)oxazoI-1 5 yi)ethanarnine and 3-.(5-(trifiuoromethyl).1,2,4-oxadiazol-3-yl)benizo!c acid as described in example 8 step 6 (4 mngs, 2% yield). H NMIR (CDC1 3 ) 68.55 (s, 1H), 8.25 (d, J = 7 8 Hz, I H) 8.2 (. J .8 z. H),7.9 (d J .8 Hz, 2H),7.68-7.5 (in, 2H), 7.41 (d: J 8.4 Hz, 2H), 3.86 (in: 2H), 3.94 (mn, 2H-1). MS3 (E3[) n~z: Calculated for C 21 H, C!F 3 1N 4 03: 482.07; found; 463.1 (MeAiH)'. 10 EXAMPLE 129 N-2(-4Clrpeyioao-- ehl--(-tilooehl-,2,4-oxadiazI-3 yl)niccotinamide N. 15 This compound was synthesized from 2-(2-(4-chlloroph.enyl'ioxazo.-4 yiOethanainine and 5-(5-(trifluinomethyi}-1,2,4-oxadiazo-3-l)nitotnlic acid as described in example 8 step 6 (14 mgs, 10% yield). 'H NKMR (CDC11 3 ) 69.45 (a, 1H), 9.29 (s, 1H), 8.84 (a, 1 H), 7.97 (d? J 8.4 Hz, 1 H): 7.80 (S5 1 H), 7.57 (,a, 1 H), 7.43 (d, J = 8.1 Hz, 1 H)? 726 (s. 1H), 3.85 (d, J 5.1 Hz, 2H)2 2.93 Qt, J =5.4 Hz, 2H). NIS (ESI) m'lz: Calculated for 20 C,,H,CIF 3

N

5 O,; 463.07; found: 464.1 (MCHg . EXAMPLE 130 IV(-ehl2(-hnl ao--ipoy)S(S(rfurrity)12.4-ozediazol-3 yI)nicotinamide 25 Nr ~~0 This compound was synthesized from 2-inethyl..2-(2..phenyloxazol-4-yi!)propan-1.. amnine and 5-(5-(triflu-ororneth yi)-1,2,4-oxadiazol-3-y)nicotinic acid as described in example 8 stepS6 (18 ings, 13% yield). 11H NMR (CDC1 3 ) 6 9.45 (t, J = 9.0 Hz, 1H), 9[35 (s, 30 1 H), 8.42 (s: IH)f, 8.03 (s, 2H-): 7.51-7.401 (in, 4H), 3.62 (bs, 21-I), 1.42 (s, 6H). MS (ESI) rn'z Calculated for C 2 2 i-ligF 3

N

5

O

3 : 457.14, found; 458.1 ',V!H)'. 227 WO 20111088181 PCT/US201l11021089 EXAMPLE 131 2-(2-(4-Chlorophenyl)oxazol-4-yl)-2-methylpropanenitrile O~\ C O-r' CN CrV .5 This compound was synthesized from 2-(2-(4-chlor-ophenyl)oxazol-4-yi!',acetontrile using iodomethane as described in example 1 step 2 (100 mig. crude, anid it was carried through without further purification MS (ESI) rrriz: Calculated for Cl 1

,H

11

CIN

2 0: 246.06. found- 247.1 (MI+H)7. 10 2-(2-(4-Chioropheniyl)oxazol-4-yl)-2-rnethyipropan-1 -a mine a CIN --,\ ~ ?~-K LAIH- 4 T IN ------ NC - - C I-N I . TH F,CCr This compound was synthesized From 2--(2-(4.-chlorophenyl)oxazo.4-yI)-2mnethvylpropanenitrile as described in example I step 3 (100 mng, crude) and it was carriedi through without further purification. MAS (ESI) ti/z: Calculated for C 1 3H, 5

CIN

2 0: 250.09. 15 found, 251.1 (MiHF-). N-(2-(2-(4.Chloroplhenyl)oxazol-4-.yI)-2-methylpropyl)-.3-(8..(trifluorometlyl-1 2,4oxadiazal-3-yIfbenzamide -N H~NHT,~ -. ~ NIH 4r-; WAY N - 20 T-his -compound was synthesized from 2-(2-( '4-chlcropheny)oxzo-4-yI)-2 metlhylpropan-1-arninp and 3-(5-(trifiLuorcrnethyl)-1,2,4-oxadiazol-3-yi)benzoic acid as described in example 8 step 6j (3 mg, yield 14%). 11- WAR (CDC13) 6, 8.59 (t, J =,1.7 Hz; I H), 8.25 (d, J = 7.9 Hz. 1H), 8.12 (d, J = 6 7 Hz, 1H), 7.99 (d, - =6.6 Hz, 2H), 7.64 (t, J = 7.7 Hz, 2H 7.49 (s, 1H), 7.38 (d. J =4.9 Hz, IH), 2 03 (s, 2H), 40I,61H). MS (681) rn'z 25 Calculated for C, 3 1HIC1F.;NO: 490.10; found: 491.1 ([M±H)'. 228 WO 2011/088181 PCT/US20111021089 EXAMPLE 132 Methyl 3-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzanido)propanoate F 0 N O HATU, NMM F O N '---- ---- F - N S This compound was synthesized from methyl 3-aminopropanoate and 3-(5 (trifluoromethyl)-1,2,4-oxadiazol-3-y)benzoic acid as described in example 8 step 6 (120 ngs, yield 75%). MS (ESI) m/z: Calculated for C0HF 3

N

3

O

4 : 34308: found: 3441 (MV+H). 10 3-(3-(S-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)propanoic acid F, P-N OF 0 N N' % NH F COmeCOH A sodium hydroxide solution (0.2 mL, 5 M) was added to a solution of methyl 3-1(3 (5-(trifluoromethyl)-1, 2,4-oxadiazol-3- yl)benzamido)propanoate in THFiMeIH/water (4:1:1, 15 mL). The reaction was stirred for 30 min and acidified with 2 M HCI. The 15 reaction was extracted with ethyl acetate several times, dried over sodium sulfate, and used crude. MS (ESI) m/z: Calculated for C 13 H oF 3

N

3 0 4 : 329,06; found: 3301 (M+H)'. N-(2-(3-Phenyl-1,2,4-oxadiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)benzarnide F O'N O F% A- N'H SN 0No9 20 CO2H HOBt (47 mg, 0.35 mmol), EDCi (67 mg, 0.35 mmol), and diisopropylethylamine (0 7 mL, 1.0 mmol) were added to a solution of 3-(3-(5-(trifluoromethyl)-1,2,4-oxadiazo-3 yi)benzamido)propanoic acid (115 mg, 0.35 mmol) and N'-hydroxybenzimidamide (47 mg, 0.35 mmol) in dichloromethane (3.5 mL) with a few drops of DMF. The reaction was 25 stirred I h and then toluene was added and the reaction was heated to 90 C for I h. The reaction was diluted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate and dried over sodium sulfate. The product was purified on reverse phase using water/acetonitrile to give N-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl)-3-(5 229 WO 2011/088181 PCT/US2011/021089 (trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (10 mg, yield 7%). 'H NMR (CD0i3) 68.60 (s, 1H), 8.22 (m, IH), 8.10 (m, 3H,) 7.60 (m, 1H), 7.55-7.45 (n, 3H), 4.05 (n, 2H), 3.26 (n, 2H). MS (ESI) m/z: Calculated for C 23 Hs 4

F

3

N

5

O

3 : 429.10; found: 430.1 (M+H)+ 5 EXAMPLE 133 Ethyl I -benzyl-5-phenyl-1 H-pyrazole-3-carboxylate -N O HN O N Benzyl bromide (696 mg, 4.01 mmol) was added to ethyl 5-phenyl-1H-pyrazole-3 carboxylate (880 mg, 4 1 mmol) and potassium carbonate (562 mg, 4.01) in DMF (8 mL). 10 The reaction was stirred for several h and then diluted with water. The mixture was washed several times with ethyl acetate and the combine extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified on IS10 using 0-100% ethyl acetatehexane gradient to give ethyl 1-benzyI-5-phenyl-1H pyrazole-3-carboxylate (1.3g, quantitative). MS (ESI) m/z: Calculated for CH 8

N

2 O2: 15 306.14; found: 307.1 (M+H) . (I -Benzyl-5-phenyl-1 H-pyrazol-3-yl)rnethanol NNN O 0-\ ~

"~

At 0 *C, LAH (1.8 mL, 3.7 mmol, 2M in THF) was added to ethyl 1-benzyl-5 20 phenvl-1H-pyrazole-3-carboxylate (560 mg, 1.8 mmol) in THF (18 mL). The reaction was stirred for 10 min and then warmed to room temperature for 1 h. Minimal water was slowly added to the reaction followed by 1 mL of 5 M sodium hydroxide. The reaction was stirred for 30 min, sodium sulfate was added, and the solids were removed by filtration. The filtrate was concentrated under reduced pressure to yield crude (1-benzy-5-phenyl 25 IH-pyrazol-3-yl)nethanol, which was carried through without further purification. MS (ESI) m/z: Calculated for Ci;'HwN 2 0: 264.13; found: 265.1 (M+H) 230 WO 2011/088181 PCT/US2011/021089 1 -Benzyi-3-(bromomethyl)--phenyl-1 H-pyrazole N-N OH ------ N r Carbon tetrabromide (2.5 g, 7.6 mmol) and then triphenylphosphine (2.Og ,76 5 mrnmol) was added to (1-benzyl-5-phenyl-1H-pyrazol-3-yl)rmethanoi (1.Og, 3.8 mmol) in dicholomethane (38 mL) at 0 0. Upon completion of the reaction as monitored by LCMS, the reaction was filtered through silica washing with methylene chloride and then purified on an ISCO using 0-30% ethyl acetate/hexanes to give 1-benzyl-3-(bromomethyl)-5 phenyl-1H-pyrazole (0.5 g, yield 43%). MS (ESI) m/z: Calculated for C 17 HBrN 2 : 326.04; 10 found: 327.0 (M+H)*. 2-(I-Benzyl-5-pheny -1H-pyrazol-3-y-)acetonitrile N Br ---- ~ N N C4 N 1-Benzyl-3-(bromomethyl)-5-phenvl-H-pyrazole (200 mg, 0.6 mmol) and sodium 15 cyanide (30 mc, 0.6 mmol) were stirred in DMF (6 mL). After several h, more sodium cyanide (60 mg, 1.2 mmo) was added to the reaction. A 25% ammonium hydroxide solution in water was added to the reaction and the reaction mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to yield 2-(1-benzyl-.5-phenyl-1H-pyrazoi-3-yl)acetonitrile (130 20 mg, yield 80%) MS (ESI) m/z: Calculated for CHIN: 273.13; found: 274.1 (M+H) 231 WO 2011/088181 PCT/US20111021089 2-(1 -Benzyl-S-phenyl-1 H-pyrazol-3-yl)-2-methylpropanenitrile PIN NNC \X This compound was synthesized from 2-(1-benzyl-5-pheny-1H-pyrazo-3 yl)acetonitrile using iodomethane as described in example 1 step 2 (500 mg, yield 91%). 5 MS (ESI) rn/z Calculated for CcH 1 sN 3 : 301.16; found: 302.2 (M+H)* 2-(1 -Benzyl-5-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1 -amine NH NN CN 2-(1-Benzyl-5-phenyl-1H-pyrazo!-3-yl)-2-methylpropanenitrile (50 mg, 0.16 mmol) 10 was dissolved in THF (1.6 mL). Borane-tetrahydrofuran (0.8 mL, 1 NI solution) was added and the reaction was heated to 60 "C for 3 h. Minimal water was added to quench the reaction. Ethyl acetate was added followed by sodium sulfate and the solids were rernoved by filtration. The filtrate was concentrated under reduced pressure to yield 2-(1 benzyl-5-phenyl-.1 H-.pyrazol-3-yl)-.2-methylpropan-1-amine (50 mg, crude), which was 15 carried through without further purification. MS (ESI) ,m'z: Calculated for CH 2 3N3: 305.19; found: 306.2 (M+H)*. 2-Methyl-2-(5-phenyl-1 H-pyrazol-3-yl)propan-1 -amine NH2 / ANH2 N 20 2-(1-Benzyl-5-phenyl-1H-pyrazoi-3-yl)-2-methylpropan-1 -amine (50 mg, 0.2 mmol) was stirred under an atmosphere of hydrogen in methanol/concentrated sulfuric acid (5:1, 5 mL) with 5% palladium on carbon (350 mg). After several h, more palladium on carbon 232 WO 2011/088181 PCT/US20111021089 was added (350 mg). The reaction was stopped after 3 days with starting material remaining. The solution was degassed and filtered through Celite Methanol was removed under vacuum and 1 M potassium carbonate was added until the reaction was basic. The slurry was extracted multiple times with 30% isopropanol/chloroform. The 5 combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 2-methyl-2-(5-phenyl-1H-pyrazol-3-yl)propan-1-amine, which was carried through without further purification. NV-(2-Methyl-2-(3-phenpyl-1H-pyrazol-5-yl)profpyl)-3-(5-(trifluoromethiyl)-1,2,4 10 oxadiazol-3-yl)benzamide , NVM r\ N H.- N NT00C-rt, F '-N H- This compound was synthesized from 2-methyl-2-(5-phenyL-1H-pyrazol-3 yi)propan-1-amine and 3-(5-(triflucrornethyl)-1, 2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (10 mg, yield 11 %) "H NMR (CDCs) 6 8,52 (s, 1H) 8.20 15 (d, J = 7.4, 1H), 8.05 (d, J = 7.4, 1H), 7.64-7.52 (in 3H), 7.46-7.32 (m, 3H), 6.47 (s, 1H), 3.70 (d, J = 4.5, 2H). 1 44 (s, 6H). MS (ESI) m/z: Calculated for C23H 2 0F3NsO2: 455.16 found: 456.2 (M+H). EXAMPLE 134 20 N-(2-(2-(4-Fluorophenyl)oxazol-4-yI)propyl)-5-(5-(trifliuoromethyl)-1,2,4-oxadiazol-3 yl)nicotinamide

F

3 C~ CO2H N2 _ N N N 0 N;-\ FC --- ~ S\ ,! 1X, I0 HATU, NMM H DMF, d 'C-r. 12h N This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yi)propan-1 amine and 5-(5-(trifluorormethyi)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in 25 example 8 step 6 (75 mg, yield 28%) as a yellow solid. 1H NMR (400MHz, CDCI,) 6 9.47 - 9.46 (d, J = 2.0 Hz. 1H), 9.33 (d, J = 2.0 Hz, 1H), .88 - 8.87 (t, J = 2.1 Hz, 1H), 8.11 8.04 (m, 3H), 7.54 (d. J = 1.0 Hz, 1 H). 7.18 - 7.14 (t, J = 8.8 Hz, 2H), 4.02 - 3.96 (ddd, J 13.2 Hz, 6.5 Hz, 4.1 Hz, 1H), 3.53 - 3.46 (ddd, J = 13.1 Hz, 9.0 Hz, 4.3 Hz, 1H) 3.20 233 WO 20111088181 PCTUS201 11021089 3.11 (in, 11H), 1.42-I 140 ((],,I= 7.0 Hz, 31H). MS (I in: Calculated for C 21

IH

1 5FAN3g 4F1.11; found: 462 1 (M+H) EXAMPLE 135 5 Ni-(2-(4-(4-C hlorophe nyl)th iazoll-2-yl) -2-m ethyl propl -- (5-(trifluorom ethyl) -1 ,24 oxadiazol-3-yI)nicotinami P-N Cl 2l J INI N-11T. M

H

2 N~)2 MF, 0 cCrt 4h This compound was synthesized from 2-(4-(4-chl crophenl tffzol-2-yi)-2 maethylpropan-i -amnine and W-a(rfuooahl- .24oaizl3ylnctncai as 10 described in example 8 step 6 (18 mg: yield 16%). 1 H NtM.R (400MHz, CDCI,) F5 9.46 (d: J ?.0 Hz, 11H), 9.23 (d J = 2.3 Hz, H): 8.80 (t. J =2.1 Hz, IF!): 8.21 .m 11H), 7.81 -7.78 (in, 2H), 7.43 (i,1H). 7.38 - 7.35 (m:. 2H) , 3.85 (d: J = 5.8 1z 2H), 1.56 (s: 6fH). Ms (ESI) n/z: Calculated for C 22

H

17 ClF 3 NE0 2 S: 507.07; Found: 508.0 (M±H)W. 15 EXAMPLE 136 N-((4-.([1 lV-.Bipheniy1-3-yi) -1-metlhylpiperidini4-y)metly)--(5-(trifluoroiethyl)-1 2,4 oxachzol-3-yIl)nicutinrnide P-N HA1m, NMM N 20 This compound was synthesized From (--([,1.-biphieryl'-3-.yl).-i-methylpiperidin.-4 y'Oinethanarnine and 5-.(5-(trifluorornethyl)- 1 .2,4-oxadiazoi!-3-.yiinicotnic acid as described in example 8 step 6 (60 mng, yield 30%) as an off white solid. HI- NUR (400MHz, NPMeOD) ,5 9.32 (d, J -- 2.0 Hz, I H), 9.01 (d; J = 2.0 Hz, I H), 8.68 -- 8.67 (t; J = 2.0 Hz, I v), 7.65 (in 11); 7.57 -- 7.55 (nn, 2H), 7.50 -- 7.47 (n, 3H-), 7.40 -7.36 (t, J= 7.4 Hz, 2H), 7.31 - 25 7.28 (in, IH), 3.62 (m,. 21-I), 2.79 -- 2.76 (in. 2H), 2.44 -- 2.31 (in, 41-1), 2.24 (mn, 31-), 2. 1' 2.05 (in, 21H). MS (ESI)mrnz: Calculated for C 2 3H 2 6 ,F,450,: 521.20; found: 522.2 (MI-+H)'. 234 WO 2011/088181 PCT/US2011/021089 EXAMPLE 137 5-Broniothiophene-3-carbaldehyde OHIC Br-,, AIck H - ----------------------- B s CH 2

C

2 , 0 'C-reflux, 1.h 5 Anhydrous aluminum chloride ('.9 g, 44.5 mmol) was added in small portions over a period of 2 h to a soILition of thiophene-3-carbaldehyde (2.0 g, 17.8 mmol) in CH 2 Cl2 (100 mL) maintaining the temperature at 0 C Bromine (2.56 g, 16.0 mmoi) in CH 2 Cl, (50 mL) was then added dropwise to the reaction mixture at 0 C. The reaction mixture was refluxed at 40 *C for 1 h, quenched with water and extracted with CH2Ci,. The combined 10 extracts were dried over anhydrous Na 2 SC4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10% EtOAc in petroleum ether) to give 5-bromothiophene-3-carbaldehyde (3.0 g, yield 88%) 15 1 -(5-Bromothiophen-3-yI)-2,2,2-triftluoroethanol OH OHC CsF, TMSCF 3 S dry glyme. n, 4h This compound was synthesized from 5-bromothiophene-3-carbaldehvde as described in example 88 step 1 (3.0 g, yield 73%) as a yellow liquid. 'H NMR (300 MHz, CDC13) 5 7.36 (s, 1H), 7.15 (s, 1H), 5.05 - 5.03 (m, 1H), 3.28 (br s, 1H). 20 1 -(5-Bromnothiophen-3-y)-2,2,2-trifluoroethanone OHo F3C Dess-Martin periodinane F0 FsC -A B Br CH2Cl, 0 'C-r, 2h B This compound was synthesized from 1-(5-bromothiophen-3-yi)-2,2,2 trifluoroethanol as described in example 47 step 2 (1.85 g, yield 62%). 'H NMR (400 25 MHz, CDCI ) 5 8.25 (m, 1H), 7.62 (d, J = 1.1 Hz, 1H). 235 WO 20111088181 PCTUS201 11021089 3-(4.(2,2,2-Triftuoroacetyl)thiopheni-2.yl)benzoic acid HC. . B(01H1 2 - / - fIBr--------- - ---------------- - A ,> S Pdk(PPhl) 4 (cat.)S 2Pl NSCO 3 . DMF, 90 -C, 51h This compound wa s Synthesized from 1-(5-bromothilop hen -3-vi)-2,2,2 trifluoroethanone and 3-carboxyphenyidoronic adid as described in example 86 Ste" 3 5 (150 m~g, yield 16%) as a yellow solid 1H NMR (300 MHz, DMSO0-d,) 6 13.26 (br s, 1H), 8.85 (s, 1H), 8,19 (s, 1H), 8 07 -8.05 (m,. 2H), 7.96 - 7.93 (d, J =7.9 Hz, I H). 7.62- 7.57 (t, J = 7.7 Hz, I H. N-(2-{2-(4-Fluorophenyl)oxazol-4-yi)-2-rnethylpropyl)-3-(4-(2,2.2 10 trifluoroacetyl)ttiaopten-2-yI)betnzamide o ~~H 2 \ ./ V~ r.. co1H . O F4-r, 4h, This compound was synthesized from 2-(2-<4-filuoropheanyl)oxazo-4-y)-2 rnethylpropan-I -amine and 3-(4..(2,2,2-trifuoroacetyl)thiophen-2-yi)benzoic acid as '15 descrioed in example 8 step 6 ('75 mg, yield 30%), 'H NMR (400 MHz, DMSO-d,) 6 8.21 - 8.16 (in, 1H), 8.11 - 6.10 (mn, 11H), 8.02 - 796 (in, 3H), 7.91 - 7.90 (rn, 1H), 7.88 - 73 (mn, I1H), 7.77 - 7.75 (in, I H), 7.67- 7.48 (mn, 2H), 7.31 - 7.25 (in, 21H), 3.56 - 3.54 (i, 2H), 1.33 (d, J = 2.1 Hz, 6H). MVS (ESI) rnlz: Calculated for C 2 f1 1 2 01 F1N2 3 S: 51611, found: 515S 7 (M-H)-. 20 EXAMPLE 138 N-(2-(2-(4-Fluorophenyl)oxazol-4-yi)-2-oxoethiyl)-3-(5-(trifluioromethyl)- p2.4 oxadiazol-3-y1)benzaniide -- 1 F 0Hr N 4 -1 61 25 This compound was synthesized from N..(2-(2.-(4-flucro ' henl)oxazo-4.yl)-2 hydroxyethyl)-3-(5--(triflujoromEthyl)-1 2,4-oxad~azol-3-.yl)benzamide= as described in 236 WO 2011/088181 PCT/US20111021089 example 47 step 2 (150 mg, yield 43%) as an off-white solid. 1 H NMR (300 MHz, CDCi 3 ) 6 8.62 (t, J = 1.5 Hz, 1H), 8.40 (s, 1H), 8.32 - 8 29 (dt, J = 7.8 Hz, 1 2 Hz, 1H), 8.15 8.11 (m, 3H), 7.70 - 7.65 (t, J = 7.8 Hz, 1 H), 7.25 - 7.19 (t, J = 8.7 Hz, 3H), 5.02 - 5.00 (d, J = 4.6 Hz, 2H). MS (ESI) m/z: Calculated for C 2 lHl 2

F

4

N

4 0 4 : 460.08; found: 459.4 (M 5 H) N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-hydroxypropyl)-3-(5-(trifluoromethyl)-1,2,4 oxadiazol-3-yl)benzamide /F 2-N 0 N 1 MelO 131,1 ih THF) P-N O N _ ___ __H 9-N 0 N< N Y -50 ocV3h N qN H H - OH 10 N-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-oxoethy)-3-(5-(trifluoromethyl)-1,2,4 oxadiazol-3-yl)benzamide (150 mg, 0.33 mmol) was dissolved in dry THF (10 mL) and the reaction mixture was cooled to -50 IC. Methylmagnesium chIloride (0 32 mL, 0.98 mmol, 3M in THF) was then added and the reaction mixture was stirred at -50 IC for 3h. The 15 reaction mixture was quenched with aqueous saturated NH 4 CI solution, and extracted with EtOAc. The combined extracts were washed with water and brine, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 25-30% EtOAc in petroleum ether) followed by preparative TLC (eluent 30% EtOAc in petroleum ether) to afford N-(2-(2-(4-fluorophenyi)oxazol-4-yl) 20 2-hydroxypropyi)-3-(5-(trifluoronethy)-1,2,4-oxadiazoi-3-yl)benzamide (15 ng, yield 10%) as a white solid. IH NMR (400 MHz, CDCIs) 6 8.49 (t, J = 1.5 Hz, IH), 8.28 - 8.25 (dt, J= 7.9 Hz, 1.3 Hz, 1H), 8.05 - 8.01 (m, 3H), 7.70 (s, IH), 7.64 - 7.61 (t, J = 7.8 Hz, IH), 7.16 - 7.11 (t, J = 8.7 Hz, 2H), 7.05 - 7.02 (i, 1H), 3.96 - 3.85 (Im, 2H), 3.81 (s, 1H), 1.65 (s, 3H). MS (ESI) m/z: Calculated for C 22 HF4N 4

O

4 : 476.11: found: 475.5 (M-H). 25 EXAMPLE 139 1-(4I-Bromofuran-2-yI)-2,2,2-trifluoroethanoI Br, Br- H CSF, TMSCIF, C --- FTMF--- CF -o O dry glymre, 0 0 6 C-rt, 10h OH This compound was synthesized from 4-bromofuran-2-carbaldehyde as described 30 in example 88 step 1 (1.0 g, yield 72%) as a pale yellow liquid. 'H NMR (400 MHz, 237 WO 2011/088181 PCT/US20111021089 DMSO-d6) 8 799 (d, J = 0.9 Hz, 1H), 7 10 - 7.08 (d, J= 6.4 Hz, 1H), 6.75 (s, 1H), 5 29 5.22 (m, IH). 1 -(4-Bronofuran-2-yi)-2,2,2-trifiuoroethanone Br Br,

CF

3 Dess-Martir periodinane CF 5 OH CH2Cl 2 , 0 C-rt, 3h o This compound was synthesized from 1 -(4-bromofuran -2-y!)-2,2,2-triflucroethanol as described in example 47 step 2 (0.8 g, yield 81%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCI 2 ) 6 7.82 (m, 1H), 7.52 -- 7.51 (in, 1 H). 10 3-(5-(2,2,2-Trifluoroacetyl)furan-3-yi)benzoic acid Bi HOC32C BOH) 2 -\C CF3 F / CO 2 H 0 Pd(Pr'h-)4 (ct) 2M Na2C'3, DMF, 90 1C, 5h This compound was synthesized from 1-(4-bromofuran-2-yi)-2,2,2 trifluoroethanone and 3-carboxyphenyboronic acid as described in example 88 step 3 15 (150 mg, yield 26%) as a pale yellow solid. 'H NMR (300 MHz, DMSO-d,) 5 13.14 (br s, I H), 899 (s, I H), 8.44 (s, 1 H), 8.31 (m, 1 H), 8.07 - 8.04 (m. 1 H), 7.93 - 7.90 (im, 1 H). 7.60 - 7.55 (t, J = 7.7 Hz, 1H). MS (ESI) rn/z. Calculated for C 13

H

7

F

3 0 4 : 284.03; found: 282.9 (M-H). 20 Ni-(2-(2-(4-Fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2 trifLuoroacetyl)furan -3-yi)benzamide H ------------------------------------ + F N C' - HATU. NIMM F DMF, 0oc, 2h This compound was synthesized from 2-(2-(4-fluorophenyl)oxazoi-4-y)-2 nethylpropan-1-amine and 3-(5-(2,2,2-triflucroacetylifuran-3-yl)benzoic acid as described 25 in example 8 step 6 (30 mg, yield 14%). 1H NMR (400 MHz, DMSO-de) 5 8.91 (s, 1H), 8.40 - 8.35 (rn, 2H), 816 (n, IH), 8.02 - 7.94 (in, 4H), 7.82 - 7.80 (m, 1H), 7.57 - 7.53 (t, J = 7.8 Hz, 1H), 7.36 - 7.31 (t, J = 9.0 Hz, 2H), 3.53 - 3.51 (d, J = 6.1 Hz, 2H), 1.30 (s, 6H). MS (ESI) rm/z: Calculated for O 2 6-1 2

,

3 F4N 2 0 4 : 500.14; Found: 499.5 (M-H) 238 WO 2011/088181 PCT/US20111021089 EXAMPLE 140 1-(4-Bromothiophen-2-yi)-2,2,2-trifluoroethanoI Br, Br. - CsF, TMSCF3 -CHO CF~~y~A 3 dry glyme, rt. 3h S OH 5 This compound was synthesized from 4-bromothiophene-2-carbaldehyde as described in example 88 step 1 (2.0 g, yield 74%) as a pale yellow liquid. 1H NMR (300 MHz, CDCi) 5 7.30 (d, J = 1.3 Hz, I H), 7.12 (m, 1H), 5.27 - 5.22 (m, 1H), 3.17 (br s, 1H). 1 -(4-Brornothiophen-2-yi)-2,2,2-4rifiuoroethanone Br\ Br,' Dess-Martin periodinane 10 OH CH2C1 2 . Q C-rt, 3h This compound was synthesized from 1-(4-bromothiophen-2-yl)-2,2,2 trifluoroethanol as described in example 47 step 2 (1.5 g, yield 75%) as dark brown liquid. H NMR (300 MHz, CDC13) 6 7.86 (rn 1H), 7.80 (d, J = 0.9 Hz, 1 H). 15 3-(5-(2,2.2-Trifluoroacetyl)thiophen-3-y)benzoic acid

HO

2 C B(OH)2 Br. F3C S F- CO2 ------ .- C 0 o PdC1 2 (PPhl) 2 , 0 'S 1M K 2 C0 3 , dioxane, 90 'C, 3h This compound was synthesized from 1-(4-bromothiophen-2-yi)-2,2,2 trifluoroethanone and 3-carboxyphenyiboronic acid as described in example 88 step 3 (400 m-g, yield 46%) as a pale yellow solid. 'H NMR (400 MHz, DMSO-de) 6 13.19 (br s, 20 1H), 8.85 (d, J = 1.2 Hz, 1H), 8.50 (s, IH), 8.29 (n, 1H), 8.10 - 8.08 (d, J= 7.6 Hz, 1H), 7.96 - 7.94 (d, J = 7 6 Hz IH), 7.62 - 7. 59 (t, J = 7.8 Hz, I H) MS (ESI) mi/z Calculated for CIH7FO 3 S: 300.01; found: 298 9 (M-H)-. 239 WO 2011/088181 PCT/US2011/021089 N-(2-(2-(4-Fluorophenyl)oxazol-4-y)-2-methylpropyl)-3-(5-(2,2,2 trifluoroacetyl)thiophen-3-yl)benzamide F H ---------------- - ------------ F- 7 HATU, NMM F F DMF O C-rit, This compound was synthesized from 2-(2-(4-fluorophenyl)oxazo-4-y)-2 5 methylpropan-1 -amine and 3-(5-(2,2,2-trifluoroacetvl)thiophen-3-yi)benzoic acid as described in example 8 step 6 (30 mg, yield 17%). 'H NMR (400 MHz, DMSO-de) 6 8.67 (d, J = 1.2 Hz, 1H), 8.43 (m, 1H), 8.16 -- 8.12 (m, 2H), 8.00 -- 7,97 (dd, J = 9.0 Hz, 5.3 Hz, 2H), 7.92 - 7.90 (m, 2H), 7.84 - 7.82 (m, 1H), 7.57 - 7.53 (t, J 7.8 Hz, IH), 7,30 - 7.25 (t, J = 90 Hz, 2H), 3.56 (d. J = 6.4 Hz, 2H), 1.34 (s, 6H). MS (ESI) m/z: Calculated for 10 C 2 6H 2 eCF 4 N200S: 516.11; found: 515.5 (M-H)-. EXAMPLE 141 3-Cyano-N-((4-(4-phenylthiazol-2-yi)tetrahydro-2H-pyran-4-yl)methyl)benzamide N \ ii>

H

2 N' X S 0 0 NC ~ N N' S OH HATUJ, NMM DMF, 0 "C-rt, 3h 15 This compound was synthesized from (4-(4-phenylthiazol-2-yi)tetrahydro-2H pyran-4 -yi)nethanamine and 3-cyanobenzoic acid as described in example 8 step 6 (6.6 g, yield 89%) as a white solid. 'H NMR (300 MHz, CDCIk) 5 8.11 -- 8.10 (m, 1H), 8.02 7.99 (dt, J = 7.9 Hz, 1.5 Hz, 1H), 7.91 - 7.88 (n, 2H), 7.78 - 7.74 (di, J = 7.7 Hz, 1.3 Hz, I H), 7.71 - 7.68 (m, 1 H), 7.53 -- 7.46 (m, 3H), 7.42 -- 7.36 (m, 1H), 3.97 -- 3.90 (m, 21-), 20 3.85 - 3.83(d, J= 5.7 Hz, 2H), 3.77 - 3.69 (mi, 2H), 2.35 -2.29 (m, 2H), 2.07 - 1.98 (I, 2H). MS (ESI) m/z: Calculated for C 23

H

2 1 N,0 2 S: 403.14; found: 402.2 (M-H). 240 WO 2011/088181 PCT/US20111021089 (N'-Hydroxycarbaminidoyl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran..4 yl)methyl)benzarnide 0 N NHOH.HC, HO' N N N H 8-hydraxyqin~oiin -H 2 | HC EtCH, reflux, 6hN 0 This compound was synthesized from 3-cyano-N-((4-(4-phenylthazol-2 5 yi)tetrahydro-2-f-pyran-4-yl)methyl)benzamide as described in example 1 step 4 (6.8 g, crude), which was used without further purification. 'H NMR (400 MHz, MeOD) 6 8.05 8.04 (in, 1 H), 7,93 - 7,91 (m, 2H), 7.78 - 7.75 (n, 3H), 7.43 - 7.37 (in, 3H), 7.32 - 7.28 (m, 1H), 3.94 - 3.91 (in, 2H), 3.69 (in, 2H), 3.63 - 3.56 (in, 2H), 2.43 -2.39 (d. J = 13.8 Hz, 2H), 2.10 -- 2.06 (m, 2H). MS (ESI) m/z: Calculated for C 23 l-1 24

N

4 0'S: 436.16; found: 10 437.2 (M+H)*. Ethyl 3-(3-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran4-yl)rmethy)carbanoyl) phenyl)-1,2,4-oxadiazole-5-carboxylate HO., C II -/N N 15 3-(N'-Hydroxycarbaniinidoyl)-N-((4-(4-phenylth iazol-2-yl)tetrahydro-2H-pyran-4 yl)methyl)benzamide (6.8 g, 15.57 mnol) was dissolved in anhydrous pyridine (68 mL) and the reaction mixture was cooled to 0 IC. Ethyl chlorooxoacetate (5.2 mL, 46.73 mmol) was added dropwise, and the reaction mixture was heated at 60 *C for 1 h, quenched with 1.5N HCI solution, and diluted with EtOAc. The organic layer was washed 20 with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 25-30% EtOAc in petroleum ether) to afford ethyl 3-(3-(((4-(4 phenylthiazol-2-yl)tetrahydro-2H-pyran-4-y)methyl)carbamoi)phenyl)-1,2,4-oxadiazole-5 carboxylate (6.8 g, yield 87%). 'H NMR (430 MHz, CDCla) 6 8.21 (d, J= 7.9 Hz, 1-1), 8.11 25 - 8.09 (m, 1Hi1), 7.78 - 7.76 (m, 1H), 7.61 - 7.59 (m, 2H), 7.44 (s, 11-), 7.32 - 7.27 (m, 1 H), 7.23 -- 7.21 (m, 31H), 4.62 -- 4.57 (q, J = 7.0 Hz, 2H), 3.97 - 3.94 (m, 2H), 3.81 - 3.76 (in, 2H), 3.56 -- 3.50 (n, 21-), 2.41 -2.37 (in, 2H), 2.19 --2.12 (m, 2H), 1.53 -- 1.50 (t, J= 7.2 Hz, 3H). MS (ESI) r/z: Calculated for C 27

H

2 eN40 5 S: 518.16; found. 517.1 (M-H). 241 WO 2011/088181 PCT/US20111021089 3-(5-(Hydroxymethyl)-1,2,4-oxadiazol-3-yl)-N-((4-(4-phenyithiazol-2-yl)tetrahydro-2H pyranA-yl)methyl)benzamide 0 O'N O N H ,N O N N (NLiBHe "HF 'N Ethyl 3-(3-(((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4 yl)methyl)carbamoyl)pheny)-1,2,4-oxadiazole-5-carboxylate (1.0 g, 1.93 mmol) was dissolved in anhydrous THF (20 mL) and the reaction mixture was cooled to 0 C. Lithium borohydride (1.15 mL, 2.3 mmol, 2M in THF) was added, and the reaction mixture was 10 stirred for 30 min, quenched with ice, and diluted with EtOAc. The organic layer was washed with water and brine, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluant: 70-80% EtOAc in petroleum ether) to afford 3-(5.-(hydroxymethyl)-1,2,4-oxadiazol-3-y)-N-((4-(4phenylthiazol -2-yl)tetrahydro- 2H-.pyran-4-.yl)methyl)benzarmide (300 mg, yield 32%). 1H 15 NMR (300 MHz, DMSO-d)6 8.46 (m, 11-1), 8.20 -- 8.17 (m, IH), 7.96 (m, IH), 7.91 -- 7.88 (m, 2H), 7.62 (m, IH), 7.53 -- 7.51 (m, 2H), 7.36 - 7.34 (m, 3H), 4,89 (s, 2H), 3.99 -- 3.92 (rn, 2H), 3.90 -- 3.88 (d, J= 5.7 Hz, 2H), 3,78 -- 3.70 (m, 2H), 2.35 -2.27 (m, 2H), 2.08 - 2.00 (m. 2H), MS (ESI) rn/z: Calculated for C 25

H

2 4N 4 04S: 476,15; found: 475.7 (M-.H) 20 3-(5-Forrnyl-1,2,4-oxadiazol-3-yl)-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4 yl)methyl)benzarnide 'K'' HO - 0 N10 0 -. 0 N N' 'S --------------------------------- N CHIl %0 IC-rt, 2h ~L This compound was synthesized. from 3-(5-.(hydroxyiethyl)-1,2,4-oxadiazol-3-yl) 25 N-((4-(4--phervlthiazol-2-yl)tetrahydro-.2H.-.pyran-4-.yl)iethyl)benzamide as described in example 47 step 2 (340 m yield 57%). 'H NMR (300 MHz, CDC-) 6 9.89 (s, 1H), 8.49 (m, 1H), 827 17 (, 1H), 8.04 8.01 (m, 11-), 7.90 - 7.88 (m, 2H), 7.71 -- 7.9 (m, 1 H), 7.60 - 7.52 (m, 2H), 7.37 - 7.30 (m, 2H), 4.00 - 3.92 (m, 2H), 3.91 -- 3,89 (d, J = 5.7 242 WO 20111088181 PCTUS201 11021089 Hz, 2H), 3 78 - 3.71 (,n, 2H), 2,383 -2,28 (rn. 2H), 2.09 - 2,01 (rn. 2H) MS (ESI) rn/z CalCulated for (C5 2 2

KN

4

O)

4 S: 474 14; found: 473.4 (Ml-H) N-((4-(4-Pheniylthiazol-2-yI)tetrahydro-2H-pyran-4-yi)mnethyl)-3 (5 (2,2,2-trifluoro-I 5 hydroxyethyl)-i ,2,4-oxadiazol-3-yl)benzamide J.. dygyme, r , h A N This -omnpound was synthesized from3(5fry124 izl-yI.N(.(4 p hen ylth iazol -2--yl)tetrahyd ro -2H' -pyran-4-yl)inethyl)benzanid e as descri bed in example 88 step 1 (30 mng, yield 17%). PAS (ES)) rn/a: Calculated for C 26

H

22

F

3

N,

4 0 4 S: 544.14; 10 found: 545.2 (M+H)7. NV-((4-(4-Phenylthiazol-2-yi)tetrahydro-2H -pyran-4-yI)rnethyl)-3-(5-(2,22 triyracel)nth)-3 2-5xad 2.iaol--iy, nza yl-24-xr"a ,--;)enad ads 243 WO 2011/088181 PCT/US20111021089 Pharmaceutical Compositions Example A Tablets are prepared using conventional methods and are formulated as follows: 5 ingredient Amount per tablet Compound of Example 1 5mg Microcrystalline cellulose 100mg Lactose 100mg Sodium starch glycollate 30mg 10 Maanesium stearate 2mg Total 237mg Example B Capsules are prepared using conventional methods and are formulated as follows: 1 5-_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Irgedient ____ ___ ____ ___ ___Amount pertablet___ Compound of Example 3 15mg Dried starch 178mg M-g es-m--e___________2m g____________ 20 Total 195mg Histone Deacetylase 9 (HDAC9) Inhibition Assay: Novel histone deacetylase 9 (HDAC9) inhibitors were characterized in an in vifro 25 biochemical functional assay. The assay measures the increased fluorescent signal due to deacetylation, by HDAC9, of a fluorogenic substrate. The commercial available substrate is Class |la HDAC-specific and contains an acetylated lysine residue and would releases the fluorescent signal upon trypsin cleavage after deacetylation. Specifically, test compounds diluted to various concentrations in 100% DMSO are 30 first dispensed into 384-well assay plates. Recombinant HIDAC9 isoform 4 (purchased from BPS Bioscience) in complete assay buffer (50 mM TIns-HCI, pi- 8.0 137 mM NaCI, 2.7 mM KCI, 1 mM MgCl 2 , 0.05% BSA & 0.005% Tween 20) were then added to each well (5uL'well) using Multidrop Comb; (Thermo Scientific), followed by 5 uL/well substrate (purchased from BPS Bloscience, 4.5 uM final). After 45 minutes incubation at room 35 temperature, 10uL 2x developer solution (assay buffer with 40 uM Trypsin and 20 uM Trichostatin A) was added. The plates were then incubated 1 hour at room temperature before reading in fluorescent intensity mode at 450nm in an Envision (Perkin Elmer) plate 244 WO 2011/088181 PCT/US20111021089 reader. Percent Inhibition of HDAC9 activity by compounds in each test wells was calculated by normalizing to fluorescent signal in control wells containing DMSO only. The plC50s value of test compounds were calculated from non-linear curve fitting, using ActivityBase5 data analysis tool (IDBS), from 11 point 3x dilution series starting from 100 5 uM final compound concentration. For dose response experiments, normalized data were fit by ABASE/XC50 using the equation y = a + (b-a)/(1+(10^x/10^c)^d), where a is the minimum % activity, b is the rmaxirurn % activity, c is the plC>o, d is the Hill slope. The plCoos are averaged to determine a mean value, for a minimum of 2 10 experiments. As determined using the above method, the compounds of Examples 1-141 exhibited a pICso greater than 4.8. For instance, the compounds of Examples 21, 32, 78, 110 and 132 inhibited HDAC9 in the above method with a mean plCco > 6. References: 15 US 20060269559, US Patent No. 7,521,044, W02007084775 "Deacetylase inhibition promotes the generation and function of regulatory T cells," R.Tao, E. F. de Zoeten, E. 0" zkaynak, C. Chen, L. Wang, P. M. Porrett, B. Li, L. A. Turka, E. N. Olson, M. I. Greene, A. D. Wells, W. W. Hancock, Nature Medicine, 13 (11), 2007. 20 "Expression of HDAC9 by T Regulatory Cells Prevents Colitis in Mice," E. F de Zoeten, L. Wang, H. Sai, W. H. Dillmann, W. W. Hancock, Gastroenterology. 2009 Oct 28 "Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells," L Wang, E F. de Zoeten, M. 1. Greene and W. W. Hancock, Nature Review Drug Discovery. 8(12):969-81, 2009 and references therein. 25 "HDAC7 targeting enhances FOXP3+ Treg function and induces long-term allograft survival," L. Wang, et al., Am. J. Transplant 9, S621 (2009). "Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes," A Nebbioso, F. Manzo, M. Miceli, M Conte, L Manente, A Baldi, A De Luca, D Rotili, S. Valente, A. Mai, A. Usiello, H. Gronemeyer, L. 30 Altucci, EMBO reports 10 (7), 776-782, 2009. and references therein. "Myocyte Enhancer Factor 2 and Class II Histone Deacetylases Control a Gender Specific Pathway of Cardioprotection Mediated by the Estrogen Receptor," E. van Rooij, J. Fielitz, L. B. Sutherland, V. L. Thijssen, H. J. Crijns, M. J. Dimaio, J. Shelton, L. J. De Windt, J. A. Hill, E.N. Olson, Circulation Research, Jan 2010. 35 245

Claims (21)

1. A compound according to the Formula: R2 R3 A Z ' L-R 4 R 1 wherein: RI is halo(C 1 -C 4 )alkyl, wherein said halo(C 1 -C 4 )alkyl contains at least 2 halo atoms; A is optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl, wherein any optionally substituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 groups independently selected from (CI-C 4 )alkyl, halogen, cyano, halo(C1 -C 4 )alkyl, (CI-C4)alkoxy, halo(C 1 -C 4 )aikoxy, -NR R and -((C 1 -C4)alkyl)NR RA; Zis C(=O)NRx-, -NRxC(=O)NR, -NRxC(=O)-, -SO 2 -, -SO

2 NRX-, -NRxSO 2 -, -NHCH(CF 3), -CH(CF

3 )NH-, -CH(CF 3 )-, -(C 1 -C4)alkvl-, -NRx-, or -- R" n is 1-4 and R2 and R3 are independently selected from H, fluoro, and optionally substituted (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )akyl-, and (C 3 -C 2 )cycloalkyl(C 1 -C 4 )alkyl-, wherein, when n is 1, R2 is F and R 3 is H, then Z is C(:=0)NRX-, -NRXC(:=O)NRX, -SO2NRX-, -NHCH(CF 3 )-, -CH(CF 3 )NH-, -CH(CF 3 )-, -(C 1 -C 4 ) alkyl-, -NIR-, or -(C 1 -C3)alkyl-NRx-, or n is 1-4 and R2 is selected from -NR R.B, -(C 1 -C4)alkyl-NR. AB, -CONR R -(CI-C4)alkyl-CONR RB, -CO2H, -(C 1 -C4)alkyl-CO2H, hydroxy, hydroxy(C 1 -C4kyl (CI-C 3 )alkoxy, and (C 1 -C3)alkoxy(C 1 -C 4 )alkyl-, and R3 is selected from H and optionally substituted (C 1 -C 4 )alkvl, aryl(C 1 -C 4 )alkvl-, and (C 3 -C7)Cycloalkyl(C 1 -C 4 )alkyl-, wherein the aryl, cycloalkyl and each of the (C 1 -C 4 )alkyl moieties of said optionally substituted (C 1 -C 4 )alkyl, aryvl(C 1 -C 4 )alkyl-, and (C 3 -C.)cycloalkyl(C1-C 4 )alkyl- of any R2 and R3 are optionally substituted by 1, 2 or 3 groups independently selected from halogen, cyano, (C 1 -C4)alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, -NRARA, -((C 1 -C4)alkyl)NRAR , and hydroxyl; H:\mc\Itevven\NRIoH]\DCC\REC\6865810_Ldoc:-9/]f,/20ll - 247 or n is 0-4 and R 2 and R3 taken together with the atom to which they are connected form an optionally substituted 4, 5, 6, or 7 mrembered cycloalkyl or heterocycloalkyl group, wherein said heterocycloalkyl group contains I or 2 heteroatoms independently selected from N, 0 and S and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by 1, 2 or 3 substituents independently selected from (C1-C 4 )alkyi, halo(C -C 4 )alkyl, halogen, cyano, aryl(C -C 4 )alkyl-, (C3-C-7)cycloalkyl(C1-C 4 )alkyl-, OR, -NRR -C(=O)NR R , -NRYC(=O)Rx, -S0 2 NRYR , -NR SO 2 R , -OC(=O)NRYRY, -NR C(= O)OR, and -NRYC(O)NReR ; and L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by I or 2 substituents independently selected from halogen, cyano and (CI-C 4 )alkyl; R 4 is H, (CI-C4)alkyl, halo, halo(CI-C4)alkyl, (C 1 -C 4 )alkoxy, ((C 1 -C 4 )alkyl)((CI-C 4 )alkyl)N(C1-C 4 )alkoxy, ((C1I-C 4 )alkyl)((C 1 -C 4 )alkyl)N(C1-C 4 )alkyl-, (C 1 -C4)haloalkoxy-, (C 1 -C 4)alkylamino, optionally substituted (C 3 -C) cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 membered heteroaryl, wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1, 2 or 3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C, 1 -C4)alkylthio-, A C A C ialo(C 1 -C4)alkoxy, hydroxyl, -NR R and -((C 1 -C 4 )alkyl)NR IR or L-R 4 , taken together, forni a I ,3-benzodioxolyl, 2,3 -dihydro-1,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionally substituted by 1, 2 or 3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -CI)alkylthio-, halo(C 1 -C4)alkoxy, hydroxyl, -NRARC and -((C1-C 4 )alkyl)NR ARC. wherein each R is independently selected from H and (C 1 -C 4 )alkyl; Re is H, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, -C(=O)(C 1 -C 4 )alkyl, C(=O)O(C 1 -C 4 )alkyl, -C(=O)NH 2 , -C(=O)NH(CI-C 4 )alkyl, C(=0)N ((C1i-C 4 )alkyl)((C1i-C 4 )alky), - SO2( CI-C4)alkyl, or RA and RB taken together with H:\rec\tevven\NRPo,,H]\DCC\REC\6865810_Ldoc,-9/]{/20ll - 248 the atom to which they are attached form a 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, 0 and S and optionally substituted by (C 1 -C 4 )alkyl; Rc is H4, (Ci-C4)alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or RA and RC'taken together with the atom to which they are attached form a

4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, 0 and S and optionally substituted by (IC 1 -C 4 )alkyl; each Rx is independently selected from H, (C 1 -C 6 )alkyl, and optionally substituted (C2-C)alkyl, where said optionally substituted (C 2 -C 6 )alkyl is optionallv substituted by hydroxyl, cyano, amino, (CI-C 4 )alkoxy, (CI-C 4 )alkyl)NH-, or ((C1-C 4 )alkyl)((CI-C4)alkyl)N-; and each RY is independently selected from H, (C 1 -C 4 )alkyl, phenyl, and -(C1-C 4 )alkylphenyl; or a salt thereof. 2. The compound or salt according to claim 1, wherein R, is C-IF or CF 3 . 3. The compound or salt according to claim 2, wherein R' is CF;. 4. The compound or salt according to any one of claims 1-3, wherein A is a phenyl group optionally substituted by 1-2 groups independently selected from (C 1 -C4)alkyl, halogen, cyano, hal o(C 1 -C4)alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C4)alkoxy, -NRAR- and -((C- C 4 )alkyl)NRA R

5. The compound or salt according to any one of claims 1-3, wherein A is an unsubstituted phenyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group.

6. The compound or salt according to any one of claims 1-3, wherein A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1 -2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NRARA and (N wI e c A Ais -(1-C,4)alkyl)NR R , where each Ri independently H or methyl; or H:\rec\tevven\NRPo,,H]\DCC\REC\686581_,Ldoc,-9/]{/20ll - 249 A is naphthyl, optionally substituted by 1-2 groups independently selected from (CI-C 4 )alkyl, halogen, cyano, halo(CI-C 4 )alkyl, (C 1 -C4)alkoxy, halo(C 1 -C4)alkoxy, -NR RA and -((C 1 -C 4 )alkyl)NR RA; or A is isoqui noly, indazolyl, tetrahydroisoquinolinonyl, isoindolinonyl, and indolinyl; or A is oxazolyl, pyrazolyl, or thienyl, optionally substituted by a methyl group or A is a pyridyl or pyridyl-N-oxide group optionally substituted by I group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NR A A and -((C1-C 4 )alkyi)NRAR , where each RA is independently H or methyl.

7. The compound or salt according to claim 4, wherein Z is -C(:=O)N-- or CH2,NH

8. The compound or salt according to claim 7, wherein n is 0 or 1.

9. The compound or salt according to claim 8, wherein both R 2 and R3 are C 1 . 4 alkyl

10. The compound or salt according to claim 8, wherein both R 2 and R 3 are I or both R2 and R 3 are methyl or R 2 is hydroxyl and R 3 is H or methyl.

11. The compound or salt according to claim 8, wherein R2 and R3 taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyl or heterocycloalkyl group, wherein said heterocycloalkyl group contains I heteroatom selected from N and 0 and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by a substituent selected from (C 1 -C 4 )alkyl, aryl(C 1 -C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(C 1 -C 2 )alkyl-.

12. The compound or salt according to claim 8, wherein R2 and R3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl, cyclopropyl, cyclohexyl, I-ethyl piperidinyyl, tetrahydrofuranyl, piperidinyl, 1-methyl-pyrrolidinyl, 1-benzyl-pyrrolidinyl, H:\ec\Itevven\NRPoH]\DCC\REC\6865810_Ldoc,-9/]{/20ll - 250 1-cyclopropylmethyl-pyrrolidinyl, oxetanyl, azetidinyl, 1-methyl-azetidinvl, 1-benzvl azetidinyl, or I -cyclopropylimethyl-azetidinyi group.

13. The compound or salt according to any one of claims 1-12, wherein L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by I substituent selected from chloro, fluoro, cyano and methyl.

14. The compound or salt according to any one of claims 1-12, wherein L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl which is substituted by a methyl group.

15. The compound or salt according to claim 13 or claim 14, wherein R 4 is H, methyl, bromo, trifluoromethyl, dimethylami noethoxy-, dimethylaminopropyl-, and optionally substituted pyridyl, cyclohexyl, piperidinyl, piperazinyl, imidazolyl, thienyl, or phenyl, where the pyridyl, cyclohexyl, piperidinyl, piperizinyl, imidazolyl, thienyl, or phenyl are optionally substituted by 1-2 substituents independently selected from methyl, chloro, bromo, fluoro, trifluoromethyl, methoxy, and cyano.

16. The compound or salt according to claim 15, wherein R. is H, methyl, bromo, trifluoromethyl, dim ethylaminoethoxy-, dim ethylaminopropyl-, and optionally substituted pyridyl, cyclohexyl, piperidinyl, piperazinyl, imidazolyl, thienyl, or phenyl, where the pyridyl, cyclohexyl, piperidinyl, piperizinyl, imidazolyl, thienyl, or phenyl are optionally substituted by 1-2 substituents independently selected from methyl, chloro, bromo, fluoro, trifluoromethyl, methoxy, and cyano.

17. The compound or salt according to any one of claims 1-12, wherein L-R.* taken together, form a 1,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl, 2,3-dihydro-1,4-benzodioxinyl, benzofuranyi, benzimidazolyl, benzimi dazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl group, optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, phenyl, and morpholinylpropyl-. H:\rec\tevven\NRPo,,H]\DCC\REC\6865810_Ldoc,-9/]{/20ll -251

18. The compound or salt according to claim 1, wherein each R- and RB is independently selected from H and (CI-C 4 )alkyl.

19. The compound or salt according to any one of claims 1-18, wherein said salt is a pharmaceutically acceptable salt.

20. A compound which is: N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methlvpropyl)-3-(5-(2,2,2 trifluoroacetyl)thiophen-2-yl)benzamide, N-(2-(2-(4-fl uorophenyvl)oxazol-4-yi)-2-methyipropyl)-5-(5 -(2,2,2 trifluoroacetyl)thiophen-2-yl)nicotinamide, N-((4-(2-(4-chlorophenyl)thiazol-4-yl)-I-methylpiperidin-4-yl)methyl)-3 -(5-(2,2,2 tri fl uoroacetyl )thi op hen-2-yl )benzamide, N-(2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5 -yl)-2-methylpropyl)-5-(5-(2,2,2 trifluoroacetyl)thiophen-2-yl)nicotinamide, 3-(5-(2,2 --difluoroacetyl)thiophen-2-yl)-N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2 methylpropyl)benzamide, N-((4-(4-phenylthiazol-2 -yl)tetrahydro-2H-pyran-4-vl)methyl')-3-(5-(2,2,2 trifluoroacetyl)thiiophen-2-yl)benzami de., or a pharmaceutically-acceptable salt thereof.

21. A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt thereof, according to claim 19 or claim 20 and one or more pharmaceutically-acceptable recipients.