PROCESS FOR THE PREPARATION OF CHIRAL ISOXAZOLINE AZETIDINE DERIVATIVES AS ANTIPARASITIC AGENTS

1 . A process for the preparation of a compound having the Formula (1)

wherein

R 1a , R 1b , and R 1c are each independently hydrogen, halo, or C 1 -C 6 haloalkyl;

R 2 is hydroxyl, or fluoro;

R 3 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle;

wherein R 3 C 1 -C 6 alkyl or C 0 -C 6 alkylC 3 -C 6 cycloalkyl moiety can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, —S(O) n R c , —SH, —S(O) n NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R, —SCN, or —C(O)NR a R b , and the C 0 -C 6 alkylC 3 -C 6 cycloalkyl moiety can be further substituted with C 1 -C 6 alkyl or hydroxyC 1 -C 6 alkyl-; and

wherein R 3 C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle moiety can be further optionally substituted with at least one substituent selected from cyano, halo, oxo, ═S, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —SH, —S(O) n R, and C 1 -C 6 haloalkoxy;

R is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl optionally substituted with at least one halo substituent;

R a is hydrogen, C 1 -C 6 alkyl, or C 0 -C 3 alkylC 3 -C 6 cycloalkyl; wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent;

R b is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 0 -C 3 alkylphenyl, C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocycle, each optionally substituted, where chemically possible, with at least one substituent selected from hydroxyl, cyano, halo, or —S(O) n R;

R c is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylC 3 -C 6 cycloalkyl, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, C 0 -C 3 alkylphenyl, C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocycle each optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, —S(O) n R, —SH, —S(O) n NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R, —SCN, or —C(O)NR a R b ;

n is the integer 0, 1, or 2; and

* depicts a chiral center;

stereoisomers thereof, and veterinarily acceptable salts thereof;

said process comprising, optionally in a solvent:

a) metallating 1-bromo-4-iodobenzene with a Grignard reagent or halogen-metal exchange with an alkyllithium and reacting metallated species with a protected azetidinone in a one-pot process or in a step-wise process to provide a protected 3-(4-bromophenyl)azetidin-3-ol, wherein PG is an amine protecting group;

b) optionally fluorinating the resulting protected hydroxyazetidine by treatment with a fluorinating agent to provide a protected fluoroazetidine;

c) palladium catalyzed condensation of the bromophenylazetidine from steps a or b, above, with a vinyl ether to provide a protected 1-(4-(azetidin-3-yl)phenyl)ethanone derivative, wherein R 2 is hydroxyl or fluoro and R 4 is a C 1 -C 6 alkyl;

d) condensation of the 1-(4-(azetidin-3-yl)phenyl)ethanone derivative with a substituted trifluorophenylethanone to provide a 1-(4-(azetidin-3-yl)phenyl)-4,4,4-trifluoro-3-phenylbut-2-en-1-one analog;

e) addition of hydroxylamine to the 1-(4-(azetidin-3-yl)phenyl)-4,4,4-trifluoro-3-phenylbut-2-en-1-one analog and cyclization in the presence of a quinine based chiral catalyst to provide a protected 3-(4-(azetidin-3-yl)phenyl)-5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole analog, wherein * denotes a chiral center;

f) removal of the azetidine protecting group to provide a 3-(4-(azetidin-3-yl)phenyl)-5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole analog; and

g) Coupling the 3-(4-(azetidin-3-yl)phenyl)-5-phenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole analog with an acid or acid chloride under standard amide formation conditions.

2 . The process of claim 1 wherein

R 2 is fluoro;

stereoisomers thereof, and veterinarily acceptable salts thereof.

3 . The process of claim 2 wherein

R 1a , R 1b , and R 1c are each independently hydrogen, chloro, fluoro, bromo, or trifluoromethyl;

R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, or cyclobutyl, wherein each substituent can be optionally and independently substituted by at least one substituent selected from halo, hydroxyl, C 1 -C 6 haloalkyl, or —S(O) n R c ; and wherein the cyclopropyl and cyclobutyl can further be optionally substituted with C 1 -C 6 alkyl or hydroxyC 1 -C 6 alkyl-;

or R 3 is thietanyl, thietanyl-1-oxide, thietanyl-1,1-dioxide, pyrazolyl, —CH 2 -pyridyl or —CH 2 pyrazolyl, wherein each substituent can be further optionally substituted with at least one substituent selected from halo, or C 1 -C 6 alkyl; and

R c is C 1 -C 4 alkyl;

stereoisomers thereof, and veterinarily acceptable salts thereof.

4 . The process of claim 3 wherein

R 1a and R 1c are each chloro, R 1b is fluoro, chloro or hydrogen;

R 3 is —CH 2 S(O) 2 CH 3 or thietan-3-yl-1,1-dioxide;

stereoisomers thereof, and veterinarily acceptable salts thereof

5 . The process of claim 1 wherein

R 2 is hydroxy;

stereoisomers thereof, and veterinarily acceptable salts thereof.

6 . The process of claim 5 wherein

R 1a , R 1b , and R 1c are each independently hydrogen, chloro, fluoro, bromo, or trifluoromethyl;

R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, or cyclobutyl, wherein each substituent can be optionally and independently substituted by at least one substituent selected from halo, hydroxyl, C 1 -C 6 haloalkyl, or —S(O) n R c ; and wherein the cyclopropyl and cyclobutyl can further be optionally substituted with C 1 -C 6 alkyl or hydroxyC 1 -C 6 alkyl-;

or R 3 is thietanyl, thietanyl-1-oxide, thietanyl-1,1-dioxide, pyrazolyl, —CH 2 — pyridyl or —CH 2 pyrazolyl, wherein each substituent can be further optionally substituted with at least one substituent selected from halo, or C 1 -C 6 alkyl; and

R c is C 1 -C 4 alkyl;

stereoisomers thereof, and veterinarily acceptable salts thereof.

7 . The process of claim 6 wherein

R 1a and R 1c are each chloro, R 1b is fluoro, chloro or hydrogen;

R 3 is —CH 2 S(O) 2 CH 3 or thietan-3-yl-1,1-dioxide;

stereoisomers thereof, and veterinarily acceptable salts thereof.

8 . The process of claim 1 wherein the chiral quinine-based catalyst is selected from:

(2S)-1-(acridin-9-ylmethyl)-2-((R)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide;

(2S)-1-(acridin-9-ylmethyl)-2-((R)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium chloride;

(2S)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide; and

(2S)-1-(anthracen-9-ylmethyl)-2-((R)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium chloride.

9 . The process of claim 8 wherein the chiral quinine-based catalyst is selected from :

(2S)-1-(acridin-9-ylmethyl)-2-((R)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide; or

(2S)-1-(acridin-9-ylmethyl)-2-((R)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium chloride.

10 . The process of claim 9 wherein the chiral quinine-based catalyst is (2S)-1-(acridin-9-ylmethyl)-2-((R)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin-1-ium bromide.

11 . A compound selected from the group consisting of:

tert-butyl 3-(4-bromophenyl)-3-hydroxyazetidine-1-carboxylate;

benzyl 3-(4-bromophenyl)-3-hydroxyazetidine-1-carboxylate;

1-benzhydryl-3-(4-bromophenyl)azetidin-3-ol;

tert-butyl 3-(4-bromophenyl)-3-fluoroazetidine-1-carboxylate;

benzyl 3-(4-bromophenyl)-3-fluoroazetidine-1-carboxylate;

1-benzhydryl-3-(4-bromophenyl)-3-fluoroazetidine;

tert-butyl 3-(4-acetylphenyl)-3-hydroxyazetidine-1-carboxylate;

benzyl 3-(4-acetylphenyl)-3-hydroxyazetidine-1-carboxylate;

1-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)ethanone;

tert-butyl 3-(4-acetylphenyl)-3-fluoroazetidine-1-carboxylate;

benzyl 3-(4-acetylphenyl)-3-fluoroazetidine-1-carboxylate;

1-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)ethanone;

(E/Z)-tert-butyl 3-(4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(E/Z)-tert-butyl 3-hydroxy-3-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)phenyl)azetidine-1-carboxylate;

(E/Z)-tert-butyl 3-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(E/Z)-tert-butyl 3-(4-(3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(E/Z)-benzyl 3-(4-(3-(3, 5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(E/Z)-benzyl 3-hydroxy-3-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)phenyl)azetidine-1-carboxylate;

(E/Z)-benzyl 3-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(E/Z)-benzyl 3-(4-(3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(E/Z)-1-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-en-1-one;

(E/Z)-1-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-1-one;

(E/Z)-1-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-en-1-one;

(E/Z)-1-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-en-1-one;

(E/Z)-tert-butyl 3-(4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;

(E/Z)-tert-butyl 3-fluoro-3-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)phenyl)azetidine-1-carboxylate;

(E/Z)-tert-butyl 3-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;

(E/Z)-tert-butyl 3-(4-(3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;

(E/Z)-benzyl 3-(4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;

(E/Z)-benzyl 3-fluoro-3-(4-(4,4,4-trifluoro-3-(3,4, 5-trich lorophenyl)but-2-enoyl)phenyl)azetidine-1-carboxylate;

(E/Z)-benzyl 3-(4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;

(E/Z)-benzyl 3-(4-(3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;

(E/Z)-1-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-en-1-one;

(E/Z)-1-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-1-one;

(E/Z)-1-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-en-1-one;

(E/Z)-1-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-3-(3,4-dichloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluorobut-2-en-1-one;

(S)-tert-butyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(S)-tert-butyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(S)-tert-butyl 3-hydroxy-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;

(S)-tert-butyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(R)-tert-butyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(R)-tert-butyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(R)-tert-butyl 3-hydroxy-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;

(R)-tert-butyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(S)-tert-butyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(S)-tert-butyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(S)-tert-butyl 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;

(S)-tert-butyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(R)-tert-butyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(R)-tert-butyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(R)-tert-butyl 3-fluoro-3-(4-(5-(3,4, 5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;

(R)-tert-butyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(S)-benzyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(S)-benzyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(S)-benzyl 3-hydroxy-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;

(S)-benzyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(R)-benzyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(R)-benzyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(R)-benzyl 3-hydroxy-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;

(R)-benzyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate;

(S)-benzyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(S)-benzyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(S)-benzyl 3-fluoro-3-(4-(5-(3,4, 5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;

(S)-benzyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(R)-benzyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(R)-benzyl 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(R)-benzyl 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidine-1-carboxylate;

(R)-benzyl 3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate;

(S)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(S)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(S)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(S)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(R)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(R)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(R)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(R)-3-(4-(1-benzhydryl-3-hydroxyazetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(S)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(S)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(S)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(S)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(R)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(R)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(R)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(R)-3-(4-(1-benzhydryl-3-fluoroazetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(S)-3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;

(S)-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;

(S)-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;

(S)-3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;

(R)-3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;

(R)-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;

(R)-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;

(R)-3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)azetidin-3-ol;

(S)-5-(3,5-dichloro-4-fluorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(S)-5-(3,5-dichlorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(S)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(S)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(R)-5-(3,5-dichloro-4-fluorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(R)-5-(3,5-dichlorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(R)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole; and

(R)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole.

12 . A compound selected from the group consisting of 3-(4-acetyl-phenyl)-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester;

(Z)-tert-butyl 3-(4-(3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;

(Z)-tert-butyl 3-(4-(3-(3, 5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl)-phenyl)-3-fluoro-azetidine-1-carboxylate;

(Z)-tert-butyl 3-(4-(3-(3,4,5-trichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl)-phenyl)-3-fluoro-azetidine-1-carboxylate; and

(R)-tert-butyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate.

13 . A compound of claim 12 selected from the group consisting of

(Z)-tert-butyl 3-(4-(3-(3, 5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl)phenyl)-3-fluoroazetidine-1-carboxylate;

(Z)-tert-butyl 3-(4-(3-(3, 5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl)-phenyl)-3-fluoro-azetidine-1-carboxylate; and

(Z)-tert-butyl 3-(4-(3-(3,4, 5-trichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl)-phenyl)-3-fluoro-azetidine-1-carboxylate.

14 . A compound of claim 12 which is (R)-tert-butyl 3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidine-1-carboxylate.