Claims for Patent: 8,809,378

Summary for Patent: 8,809,378

Title:	Metalloenzyme inhibitor compounds
Abstract:	The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
Inventor(s):	Hoekstra; William J. (Durham, NC), Rafferty; Stephen W. (Durham, NC), Yates; Christopher M. (Raleigh, NC), Schotzinger; Robert J. (Raleigh, NC), Loso; Michael R. (Carmel, IN), Sullenberger; Michael T. (Westfield, IN), Gustafson; Gary D. (Zionsville, IN)
Assignee:	Viamet Pharmaceuticals, Inc. (Durham, NC)
Application Number:	13/527,387
Patent Claims:	1. A method of treating or preventing a metalloenzyme-mediated disease or disorder in or on a plant comprising contacting a compound of Formula I with the plant or seeds: ##STR00172## wherein MBG is optionally substituted tetrazolyl, optionally substituted oxazolyl, optionally substituted pyrimidinyl, optionally substituted thiazolyl, or optionally substituted pyrazolyl; R.sub.1 is halo or haloalkyl; R.sub.2 is H, halo, alkyl, or haloalkyl; R.sub.3 is independently H, alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, cyano, haloalkyl, halo, --C(O)phenyl, --CH(OH)(aryl), --CH.sub.2(aryl), --CH.sub.2(heteroaryl), --CF.sub.2(aryl), --CF.sub.2(heteroaryl), --CH.sub.2O(aryl), --CH.sub.2O(heteroaryl), --CH.sub.2S(O).sub.x(aryl), and cyclic amino, wherein each of the alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, haloalkyl, --C(O)phenyl, --CH(OH)(aryl), --CH.sub.2(aryl), --CH.sub.2(heteroaryl), --CF.sub.2(aryl), CF.sub.2(heteroaryl), --CH.sub.2O(aryl), --CH.sub.2O(heteroaryl), --CH.sub.2S(O).sub.x(aryl), and cyclic amino may be optionally substituted with 1, 2 or 3 independent R.sub.7; R.sub.4 is aryl, heteroaryl, or cycloalkyl, each optionally substituted with 0, 1, 2 or 3 independent R.sub.8; R.sub.5 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF.sub.3, SF.sub.6, SCN, SO.sub.2R.sub.11, cycloalkyl, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; R.sub.6 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF.sub.3, SF.sub.6, SCN, SO.sub.2R.sub.11, cycloalkyl, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; each R.sub.7 is independently cyano, cycloalkyl, haloalkyl, hydroxy, alkoxy, aryl, aryloxy, heteroaryloxy, halo, haloalkoxy, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; each R.sub.8 is independently cyano, haloalkyl, hydroxy, alkoxy, halo, or haloalkoxy; R.sub.9 is H, halo, or haloalkyl; R.sub.10 is H, alkyl, --Si(R.sub.12).sub.3, --P(O)(OH).sub.2, --CH.sub.2--O--P(O)(OH).sub.2, or --C(O)alkyl optionally substituted with amino; R.sub.11 is independently alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R.sub.12 is independently alkyl or aryl; and x is independently 0, 1, or 2. 2. A method of inhibiting metalloenzyme activity in a microorganism on a plant comprising contacting a compound of Formula I with the plant or seeds: ##STR00173## wherein MBG is optionally substituted tetrazolyl, optionally substituted oxazolyl, optionally substituted pyrimidinyl, optionally substituted thiazolyl, or optionally substituted pyrazolyl; R.sub.1 is halo or haloalkyl; R.sub.2 is H, halo, alkyl, or haloalkyl; R.sub.3 is independently H, alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, cyano, haloalkyl, halo, --C(O)phenyl, --CH(OH)(aryl), --CH.sub.2(aryl), --CH.sub.2(heteroaryl), --CF.sub.2(aryl), --CF.sub.2(heteroaryl), --CH.sub.2O(aryl), --CH.sub.2O(heteroaryl), --CH.sub.2S(O).sub.x(aryl), and cyclic amino, wherein each of the alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, haloalkyl, --C(O)phenyl, --CH(OH)(aryl), --CH.sub.2(aryl), --CH.sub.2(heteroaryl), --CF.sub.2(aryl), CF.sub.2(heteroaryl), --CH.sub.2O(aryl), --CH.sub.2O(heteroaryl), --CH.sub.2S(O).sub.x(aryl), and cyclic amino may be optionally substituted with 1, 2 or 3 independent R.sub.7; R.sub.4 is aryl, heteroaryl, or cycloalkyl, each optionally substituted with 0, 1, 2 or 3 independent R.sub.8; R.sub.5 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF.sub.3, SF.sub.6, SCN, SO.sub.2R.sub.11, cycloalkyl, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; R.sub.6 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF.sub.3, SF.sub.6, SCN, SO.sub.2R.sub.11, cycloalkyl, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; each R.sub.7 is independently cyano, cycloalkyl, haloalkyl, hydroxy, alkoxy, aryl, aryloxy, heteroaryloxy, halo, haloalkoxy, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; each R.sub.8 is independently cyano, haloalkyl, hydroxy, alkoxy, halo, or haloalkoxy; R.sub.9 is H, halo, or haloalkyl; R.sub.10 is H, alkyl, --Si(R.sub.12).sub.3, --P(O)(OH).sub.2, --CH.sub.2--O--P(O)(OH).sub.2, or --C(O)alkyl optionally substituted with amino; R.sub.11 is independently alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R.sub.12 is independently alkyl or aryl; and x is independently 0, 1, or 2. 3. A method of treating or preventing a fungal disease or disorder in or on a plant comprising contacting a compound of Formula I with the plant or seeds: ##STR00174## wherein MBG is optionally substituted tetrazolyl, optionally substituted oxazolyl, optionally substituted pyrimidinyl, optionally substituted thiazolyl, or optionally substituted pyrazolyl; R.sub.1 is halo or haloalkyl; R.sub.2 is H, halo, alkyl, or haloalkyl; R.sub.3 is independently H, alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, cyano, haloalkyl, halo, --C(O)phenyl, --CH(OH)(aryl), --CH.sub.2(aryl), --CH.sub.2(heteroaryl), --CF.sub.2(aryl), --CF.sub.2(heteroaryl), --CH.sub.2O(aryl), --CH.sub.2O(heteroaryl), --CH.sub.2S(O).sub.x(aryl), and cyclic amino, wherein each of the alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, haloalkyl, --C(O)phenyl, --CH(OH)(aryl), --CH.sub.2(aryl), --CH.sub.2(heteroaryl), --CF.sub.2(aryl), CF.sub.2(heteroaryl), --CH.sub.2O(aryl), --CH.sub.2O(heteroaryl), --CH.sub.2S(O).sub.x(aryl), and cyclic amino may be optionally substituted with 1, 2 or 3 independent R.sub.7; R.sub.4 is aryl, heteroaryl, or cycloalkyl, each optionally substituted with 0, 1, 2 or 3 independent R.sub.8; R.sub.5 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF.sub.3, SF.sub.6, SCN, SO.sub.2R.sub.11, cycloalkyl, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; R.sub.6 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF.sub.3, SF.sub.6, SCN, SO.sub.2R.sub.11, cycloalkyl, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; each R.sub.7 is independently cyano, cycloalkyl, haloalkyl, hydroxy, alkoxy, aryl, aryloxy, heteroaryloxy, halo, haloalkoxy, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; each R.sub.8 is independently cyano, haloalkyl, hydroxy, alkoxy, halo, or haloalkoxy; R.sub.9 is H, halo, or haloalkyl; R.sub.10 is H, alkyl, --Si(R.sub.12).sub.3, --P(O)(OH).sub.2, --CH.sub.2--O--P(O)(OH).sub.2, or --C(O)alkyl optionally substituted with amino; R.sub.11 is independently alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R.sub.12 is independently alkyl or aryl; and x is independently 0, 1, or 2. 4. A method of treating or preventing fungal growth in or on a plant comprising contacting a compound of Formula I with the plant or seeds: ##STR00175## wherein MBG is optionally substituted tetrazolyl, optionally substituted oxazolyl, optionally substituted pyrimidinyl, optionally substituted thiazolyl, or optionally substituted pyrazolyl; R.sub.1 is halo or haloalkyl; R.sub.2 is H, halo, alkyl, or haloalkyl; R.sub.3 is independently H, alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, cyano, haloalkyl, halo, --C(O)phenyl, --CH(OH)(aryl), --CH.sub.2(aryl), --CH.sub.2(heteroaryl), --CF.sub.2(aryl), --CF.sub.2(heteroaryl), --CH.sub.2O(aryl), --CH.sub.2O(heteroaryl), --CH.sub.2S(O).sub.x(aryl), and cyclic amino, wherein each of the alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, haloalkyl, --C(O)phenyl, --CH(OH)(aryl), --CH.sub.2(aryl), --CH.sub.2(heteroaryl), --CF.sub.2(aryl), CF.sub.2(heteroaryl), --CH.sub.2O(aryl), --CH.sub.2O(heteroaryl), --CH.sub.2S(O).sub.x(aryl), and cyclic amino may be optionally substituted with 1, 2 or 3 independent R.sub.7; R.sub.4 is aryl, heteroaryl, or cycloalkyl, each optionally substituted with 0, 1, 2 or 3 independent R.sub.8; R.sub.5 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF.sub.3, SF.sub.6, SCN, SO.sub.2R.sub.11, cycloalkyl, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; R.sub.6 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF.sub.3, SF.sub.6, SCN, SO.sub.2R.sub.11, cycloalkyl, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; each R.sub.7 is independently cyano, cycloalkyl, haloalkyl, hydroxy, alkoxy, aryl, aryloxy, heteroaryloxy, halo, haloalkoxy, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; each R.sub.8 is independently cyano, haloalkyl, hydroxy, alkoxy, halo, or haloalkoxy; R.sub.9 is H, halo, or haloalkyl; R.sub.10 is H, alkyl, --Si(R.sub.12).sub.3, --P(O)(OH).sub.2, --CH.sub.2--O--P(O)(OH).sub.2, or --C(O)alkyl optionally substituted with amino; R.sub.11 is independently alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R.sub.12 is independently alkyl or aryl; and x is independently 0, 1, or 2. 5. A method of inhibiting microorganisms in or on a plant comprising contacting a compound of Formula I with the plant or seeds: ##STR00176## wherein MBG is optionally substituted tetrazolyl, optionally substituted oxazolyl, optionally substituted pyrimidinyl, optionally substituted thiazolyl, or optionally substituted pyrazolyl; R.sub.1 is halo or haloalkyl; R.sub.2 is H, halo, alkyl, or haloalkyl; R.sub.3 is independently H, alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, cyano, haloalkyl, halo, --C(O)phenyl, --CH(OH)(aryl), --CH.sub.2(aryl), --CH.sub.2(heteroaryl), --CF.sub.2(aryl), --CF.sub.2(heteroaryl), --CH.sub.2O(aryl), --CH.sub.2O(heteroaryl), --CH.sub.2S(O).sub.x(aryl), and cyclic amino, wherein each of the alkyl, alkenyl, cycloalkyl, heteroaryl, hydroxyalkyl, haloalkyl, --C(O)phenyl, --CH(OH)(aryl), --CH.sub.2(aryl), --CH.sub.2(heteroaryl), --CF.sub.2(aryl), CF.sub.2(heteroaryl), --CH.sub.2O(aryl), --CH.sub.2O(heteroaryl), --CH.sub.2S(O).sub.x(aryl), and cyclic amino may be optionally substituted with 1, 2 or 3 independent R.sub.7; R.sub.4 is aryl, heteroaryl, or cycloalkyl, each optionally substituted with 0, 1, 2 or 3 independent R.sub.8; R.sub.5 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF.sub.3, SF.sub.6, SCN, SO.sub.2R.sub.11, cycloalkyl, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; R.sub.6 is independently H, halo, alkyl, alkoxy, cyano, haloalkyl, haloalkoxy, halothioalkyl, thioalkyl, SF.sub.3, SF.sub.6, SCN, SO.sub.2R.sub.11, cycloalkyl, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; each R.sub.7 is independently cyano, cycloalkyl, haloalkyl, hydroxy, alkoxy, aryl, aryloxy, heteroaryloxy, halo, haloalkoxy, --C(O)alkyl, --C(O)OH, --C(O)Oalkyl; each R.sub.8 is independently cyano, haloalkyl, hydroxy, alkoxy, halo, or haloalkoxy; R.sub.9 is H, halo, or haloalkyl; R.sub.10 is H, alkyl, --Si(R.sub.12).sub.3, --P(O)(OH).sub.2, --CH.sub.2--O--P(O)(OH).sub.2, or --C(O)alkyl optionally substituted with amino; R.sub.11 is independently alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R.sub.12 is independently alkyl or aryl; and x is independently 0, 1, or 2. 6. The method of claim 5, wherein R.sub.1 is fluoro. 7. The method of claim 5, wherein R.sub.2 is fluoro. 8. The method of claim 5, wherein R.sub.1 and R.sub.2 are fluoro. 9. The method of claim 5, wherein R.sub.4 is phenyl optionally substituted with 0, 1, 2 or 3 independent R.sub.8. 10. The method of claim 5, wherein R.sub.4 is phenyl optionally substituted with 0, 1, 2 or 3 independent halo. 11. The method of claim 5, wherein R.sub.4 is phenyl optionally substituted with 0, 1, 2 or 3 independent fluoro. 12. The method of claim 5, wherein R.sub.4 is 2,4-difluorophenyl. 13. The method of claim 5, wherein R.sub.5 is halo. 14. The method of claim 5, wherein R.sub.3 is heteroaryl optionally substituted with 1, 2 or 3 independent R.sub.7. 15. The method of claim 5, wherein: R.sub.1 is fluoro; R.sub.2 is fluoro; R.sub.4 is 2,4-difluorophenyl; and R.sub.3 is alkyl substituted with 1, 2 or 3 independent R.sub.7. 16. The method of claim 5, wherein: R.sub.1 is fluoro; R.sub.2 is fluoro; R.sub.4 is 2,4-difluorophenyl; and R.sub.3 is alkenyl substituted with 1, 2 or 3 independent R.sub.7. 17. The method of claim 5, wherein: R.sub.3 is halo. 18. The method of claim 5, wherein the compound is one of: 1-(5-Bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazo- l-1-yl)propan-2-ol (1); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(pyridin-2-yl)-3-(1H-tetrazol-1-yl)- propan-2-ol (2); (E)-3-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-- yl)propyl)pyridin-3-yl)acrylonitrile (3); (E)-Ethyl 3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)p- ropyl)pyridin-3-yl)acrylate (4); Ethyl 3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)p- ropyl)pyridin-3-yl)propanoate (5); (E)-2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(3-(2,2- ,2-trifluoroethoxy)prop-1-enyl)pyridin-2-yl)propan-2-ol (6); (E)-4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(H-tetrazol-1-y- l)propyl)pyridin-3-yl)but-3-en-2-one (7); 4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)p- ropyl)pyridin-3-yl)butan-2-one (8); 1-(5-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difl- uoro-3-(1H-tetrazol-1-yl)propan-2-ol (9); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-fluoropyridin-2-yl)-3-(1H-tetraz- ol-1-yl)propan-2-ol (10); 2-(4-Chloro-2-fluorophenyl)-1,1-difluoro-1-(pyridin-2-yl)-3-(1H-tetrazol-- 1-yl)propan-2-ol (11); 1-(5-Chloropyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetraz- ol-1-yl)propan-2-ol (12); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(4-fluoropyridin-2-yl)-3-(1H-tetraz- ol-1-yl)propan-2-ol (13); 1-(4-Chloropyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetraz- ol-1-yl)propan-2-ol (14); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(5-fluoropyrimidin-4-yl)pyridin-- 2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (15); 2-(2,5-Difluorophenyl)-1,1-difluoro-1-(4-fluoropyridin-2-yl)-3-(1H-tetraz- ol-1-yl)propan-2-ol (16); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(2,2,2-trif- luoroethyl)pyridin-2-yl)propan-2-ol (17); 1-(5-Cyclopropylpyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-t- etrazol-1-yl)propan-2-ol (18); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(trifluorom- ethyl)pyridin-2-yl)propan-2-ol (19); 1-(6-Bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazo- l-1-yl)propan-2-ol (20); 1-(5-Bromopyridin-2-yl)-2-(2,5-difluorophenyl)-1,1-difluoro-3-(1H-tetrazo- l-1-yl)propan-2-ol (21); 1-(5-Bromopyridin-2-yl)-2-(4-chloro-2-fluorophenyl)-1,1-difluoro-3-(1H-te- trazol-1-yl)propan-2-ol (22); 1-(5-Bromopyridin-2-yl)-1,1-difluoro-2-(2-fluoro-4-(trifluoromethyl)pheny- l)-3-(1H-tetrazol-1-yl)propan-2-ol (23); 1-(4-Bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazo- l-1-yl)propan-2-ol (24); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-methylpyridin-2-yl)-3-(1H-tetraz- ol-1-yl)propan-2-ol (25); 2-(4-Chloro-2-fluorophenyl)-1-(5-chloropyridin-2-yl)-1,1-difluoro-3-(1H-t- etrazol-1-yl)propan-2-ol (26); 2-(4-Chloro-2-fluorophenyl)-1,1-difluoro-1-(5-fluoropyridin-2-yl)-3-(1H-t- etrazol-1-yl)propan-2-ol (27); 1-(5-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl)-2-(4-chloro-2-fluorophenyl)-1,1- -difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (28); 1-(6'-Chloro-[3,3'-bipyridin]-6-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3- -(1H-tetrazol-1-yl)propan-2-ol (30); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(6'-fluoro-[3,3'-bipyridin]-6-yl)-3- -(1H-tetrazol-1-yl)propan-2-ol (31); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(5-methoxythiophen-2-yl)pyridin-- 2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (32); 1-(5-(5-(Difluoromethyl)thiophen-2-yl)pyridin-2-yl)-2-(2,4-difluorophenyl- )-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (33); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(5-(trifluo- romethyl)thiophen-2-yl)pyridin-2-yl)propan-2-ol (34); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(6'-(trifluoro- methyl)-[3,3'-bipyridin]-6-yl)propan-2-ol (35); 1-(5-(5-Bromothiazol-2-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluo- ro-3-(1H-tetrazol-1-yl)propan-2-ol (36); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(2-methoxypyrimidin-5-yl)pyridin- -2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (37); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(thiazol-2-- yl)pyridin-2-yl)propan-2-ol (38); 2-(4-Chloro-2-fluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(2,2,2- -trifluoroethyl)pyridin-2-yl)propan-2-ol (39); 2-(4-Chloro-2-fluorophenyl)-1-(5-cyclopropylpyridin-2-yl)-1,1-difluoro-3-- (1H-tetrazol-1-yl)propan-2-ol (40); Methyl 2-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)- propyl)pyridin-3-yl)thio)acetate (41); (E)-1-(5-(3-(1H-Tetrazol-1-yl)prop-1-en-1-yl)pyridin-2-yl)-2-(2,4-difluor- ophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (42); (E)-3-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-- yl)propyl)pyridin-3-yl)prop-2-en-1-ol (43); 3-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)p- ropyl)pyridin-3-yl)propan-1-ol (44); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(3-(2,2,2-t- rifluoroethoxy)propyl)pyridin-2-yl)propan-2-ol (45); (E)-4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-- yl)propyl)pyridin-3-yl)but-3-en-2-ol (46); 4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)p- ropyl)pyridin-3-yl)butan-2-ol (47); (E)-2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-methoxyprop-1-en-1-yl)pyr- idin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (48); (Z)-2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-methoxyprop-1-en-1-yl)pyr- idin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (49); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-methoxypropyl)pyridin-2-yl)-3- -(1H-tetrazol-1-yl)propan-2-ol (50); (E)-2-(2,4-Difluorophenyl)-1-(5-(3-ethoxyprop-1-en-1-yl)pyridin-2-yl)-1,1- -difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (51); (Z)-2-(2,4-Difluorophenyl)-1-(5-(3-ethoxyprop-1-en-1-yl)pyridin-2-yl)-1,1- -difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (52); 2-(2,4-Difluorophenyl)-1-(5-(3-ethoxypropyl)pyridin-2-yl)-1,1-difluoro-3-- (1H-tetrazol-1-yl)propan-2-ol (53); (E)-2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-isopropoxyprop-1-en-1-yl)- pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (54); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-isopropoxypropyl)pyridin-2-yl- )-3-(1H-tetrazol-1-yl)propan-2-ol (55); 1-(5-(2-Chloropyrimidin-5-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-dif- luoro-3-(1H-tetrazol-1-yl)propan-2-ol (56); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(2,2,2-trif- luoro-1-hydroxyethyl)pyridin-2-yl)propan-2-ol (57); 2-(5-Bromopyridin-2-yl)-1-(2,4-difluorophenyl)-2,2-difluoro-1-(pyrimidin-- 5-yl)ethanol (58); 1-(5-(Cyclopropylmethyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro- -3-(1H-tetrazol-1-yl)propan-2-ol (59); 2-(4-Chloro-2-fluorophenyl)-1-(5-(cyclopropylmethyl)pyridin-2-yl)-1,1-dif- luoro-3-(1H-tetrazol-1-yl)propan-2-ol (60); 1-(5-Allylpyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazo- l-1-yl)propan-2-ol (61); 1-(5-Bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-pyrazol- -3-yl)propan-2-ol (62); 1-(5-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difl- uoro-3-(1H-pyrazol-3-yl)propan-2-ol (63); 1-(5-(1H-1,2,3-Triazol-1-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difl- uoro-3-(1H-pyrazol-3-yl)propan-2-ol (64); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-pyrazol-4-yl)-1-(pyridin-2-yl)p- ropan-2-ol (65); (6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)pro- pyl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)methanone (66); (4-Chlorophenyl)(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-t- etrazol-1-yl)propyl)pyridin-3-yl)methanone (67); (6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)pro- pyl)pyridin-3-yl)(4-(2,2,2-trifluoroethoxy)phenyl)methanone (68); (6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)pro- pyl)pyridin-3-yl)(4-fluorophenyl)methanone (69); (3,4-Difluorophenyl)(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(- 1H-tetrazol-1-yl)propyl)pyridin-3-yl)methanone (70); (4-Chloro-3-fluorophenyl)(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydrox- y-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)methanone (71); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(hydroxy(4-(trifluoromethyl)phen- yl)methyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (72); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(trifluo- romethyl)benzyl)pyridin-2-yl)propan-2-ol (73); 1-(5-((4-Chlorophenyl)difluoromethyl)pyridin-2-yl)-2-(2,4-difluorophenyl)- -1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (74); 1-(5-Benzylpyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetraz- ol-1-yl)propan-2-ol (75); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(trifluo- romethoxy)benzyl)pyridin-2-yl)propan-2-ol (76); 1-(5-(4-Chlorobenzyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-- (1H-tetrazol-1-yl)propan-2-ol (77); 1-(5-(5-Bromothiophen-2-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-diflu- oro-3-(1H-tetrazol-1-yl)propan-2-ol (78); 4-((6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)- propyl)pyridin-3-yl)methoxy)benzonitrile (79); 4-((6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)- propyl)pyridin-3-yl)methoxy)benzonitrile (80); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-morpholinopyridin-2-yl)-3-(1H-te- trazol-1-yl)propan-2-ol (81); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(piperidin-1-yl)pyridin-2-yl)-3-- (1H-tetrazol-1-yl)propan-2-ol (82); 1-(5-Bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(oxazol-5-y- l)propan-2-ol (83); 3-(5-Bromopyridin-2-yl)-2-(2,4-difluorophenyl)-3-fluoro-1-(1H-tetrazol-1-- yl)butan-2-ol (84); 3-(5-Bromopyridin-2-yl)-2-(2,4-difluorophenyl)-3-fluoro-1-(1H-tetrazol-1-- yl)butan-2-ol (85); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(pyridin-2-yl)-3-(thiazol-5-yl)prop- an-2-ol (86); 1-(5-(5-Chlorothiophen-2-yl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difl- uoro-3-(1H-tetrazol-1-yl)propan-2-ol (87); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)- propyl)pyridin-3-yl)methoxy)-3-fluorobenzonitrile (88); 3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)- propyl)pyridin-3-yl)methoxy)-2-fluorobenzonitrile (89); 4-(((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl- )propyl)pyridin-3-yl)methyl)thio)-3-fluorobenzonitrile (90); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(isopropoxymethyl)pyridin-2-yl)-- 3-(1H-tetrazol-1-yl)propan-2-ol (91); 1-(5-((difluoromethoxy)methyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-di- fluoro-3-(1H-tetrazol-1-yl)propan-2-ol (92); 1-(5-chloro-[2,3'-bipyridin]-6'-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3- -(1H-tetrazol-1-yl)propan-2-ol (93); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(trifluorom- ethyl)-[2,3'-bipyridin]-6'-yl)propan-2-ol (94); 6'-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)pro- pyl)-[2,3'-bipyridine]-5-carbonitrile (95); 1-([3,4'-bipyridin]-6-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetra- zol-1-yl)propan-2-ol (96); 1-(5-((6-chloropyridin-3-yl)methyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1- ,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (97); 6-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)- propyl)pyridin-3-yl)methoxy)nicotinonitrile (98); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(((5-(trifl- uoromethyl)pyridin-2-yl)oxy)methyl)pyridin-2-yl)propan-2-ol (99); 1-(5-(((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)pyridin-2-yl)- -2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (100); 1-(5-(difluoro(4-fluorophenyl)methyl)pyridin-2-yl)-2-(2,4-difluoro- phenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (101); 1-(5-(difluoro(4-(trifluoromethyl)phenyl)methyl)pyridin-2-yl)-2-(2,4-difl- uorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (102); or 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)- propyl)pyridin-3-yl)difluoromethyl)benzonitrile (103). 19. The method of claim 3, wherein the fungal disease or disorder is selected from the group consisting of apple scab, speckled leaf blotch of wheat, leaf spot of sugarbeets, leaf spot of peanut, cucumber anthracnose, wheat leaf rust, grape powdery mildew, wheat powdery mildew, and black sigatoka. 20. The method of claim 5, wherein the microorganism belongs to at least one genera selected from Blumeria, Podosphaera, Sphaerotheca, Uncinula, Erysiphe, Puccinia, Phakopsora, Gymnosporangium, Hemileia, Uromyces, Alternaria, Cercospora, Cladosporium, Cochliobolus, Colletotrichum, Magnaporthe, Mycosphaerella, Phaeosphaeria, Pyrenophora, Ramularia, Rhyncosporium, Septoria, Venturia, Ustilago, Aspergillus, Penicillium, Drechslera, Fusarium, Botrytis, Gibberella, Rhizoctonia, Pseudocercosporella, Sclerotinia, Helminthosporium, Stagonospora, Exserohilum, and Pyricularia. 21. The method of claim 5, wherein the microorganism is selected from the group consisting of Venturia inaequalis, Septoria tritici, Cercospora beticola, Cercospora arachidicola, Colletotrichum lagenarium, Puccinia graminis f. sp. tritici, Puccinia recondita tritici, Uncinula necator, Blumeria graminis, and Mycosphaerella fijiensis.

Details for Patent 8,809,378

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Aimmune Therapeutics, Inc.	PALFORZIA	peanut (arachis hypogaea) allergen powder-dnfp	Powder	125696	January 31, 2020	8,809,378	2032-06-19