Claims for Patent: 8,754,227

Summary for Patent: 8,754,227

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), Schotzinger; Robert J. (Raleigh, NC), Rafferty; Stephen W. (Durham, NC)
Assignee:	Viamet Pharmaceuticals, Inc. (Durham, NC)
Application Number:	13/561,586
Patent Claims:	1. A method of inhibiting metalloenzyme activity comprising contacting a compound of formula (I), or salt thereof, with a metalloenzyme, wherein: ##STR00032## MBG is optionally substituted tetrazolyl, optionally substituted triazolyl, or optionally substituted pyrazolyl; R.sub.1 is halo; R.sub.2 is halo; each R.sub.3 is independently alkyl, cyano, haloalkyl, alkoxy, halo, haloalkoxy; R.sub.4 is aryl optionally substituted with 0, 1, 2 or 3 independent R.sub.3; R.sub.5 is H, or --C(O)alkyl optionally substituted with amino; n is 0, 1, 2 or 3; and the metalloenzyme is lanosterol demethylase (CYP51). 2. A method of treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, comprising administering to the subject an effective amount of a compound of formula (I), or salt, thereof, wherein: ##STR00033## MBG is optionally substituted tetrazolyl, optionally substituted triazolyl, or optionally substituted pyrazolyl; R.sub.1 is halo; R.sub.2 is halo; each R.sub.3 is independently alkyl, cyano, haloalkyl, alkoxy, halo, haloalkoxy; R.sub.4 is aryl optionally substituted with 0, 1, 2 or 3 independent R.sub.3; R.sub.5 is H, or --C(O)alkyl optionally substituted with amino; n is 0, 1, 2 or 3; and the metalloenzyme-related disorder or disease is mediated by lanosterol demethylase (CYP51). 3. The method of claim 1, wherein the disease or disorder is superficial fungal infection, mucosal fungal infection, systemic fungal infection, or onychomycosis. 4. A method of treating a subject suffering from or susceptible to a disorder or disease, wherein the subject has been identified as in need of treatment for the disorder or disease, comprising administering to said subject in need thereof, an effective amount of a compound of formula (I), or salt, thereof, wherein: ##STR00034## MBG is optionally substituted tetrazolyl, optionally substituted triazolyl, or optionally substituted pyrazolyl; R.sub.1 is halo; R.sub.2 is halo; each R.sub.3 is independently alkyl, cyano, haloalkyl, alkoxy, halo, haloalkoxy; R.sub.4 is aryl optionally substituted with 0, 1, 2 or 3 independent R.sub.3; R.sub.5 is H, or --C(O)alkyl optionally substituted with amino; n is 0, 1, 2 or 3; wherein the disorder or disease is selected from one or more of the group consisting of superficial fungal infection, mucosal fungal infection, systemic fungal infection, Aspergillosis, Blastomycosis, Candidiasis, Chromomycosis, Coccidioidomycosis, Cryptococcosis, Dermatophytosis, Histoplasmosis, Keratomycosis, Lobomycosis, Malassezia infection, Mucormycosis, Onychomycosis, Paracoccidioidomvcosis, Penicillium marneffei infection, Phaeohyphomycosis, Pneumocyctis pneumonia, and tinea (unguium, capitis, corporis, pedis, tonsurans, versicolor). 5. The method of claim 4, wherein the disorder or disease is tinea (unguium). 6. The method of claim 4, wherein R.sub.1 is fluoro. 7. The method of claim 4, wherein R.sub.2 is fluoro. 8. The method of claim 4, wherein R.sub.1 and R.sub.2 are fluoro. 9. The method of claim 4, wherein R.sub.4 is phenyl optionally substituted with 0, 1, 2 or 3 independent halo. 10. The method of claim 4, wherein R.sub.4 is phenyl optionally substituted with 0, 1, 2 or 3 independent fluoro. 11. The method of claim 4, wherein R.sub.4 is 2,4-difluorophenyl. 12. The method of claim 4, wherein R.sub.5 is H. 13. The method of claim 4, wherein R.sub.5 is amino substituted acyl. 14. The method of claim 4, wherein: R.sub.1 is fluoro; R.sub.2 is fluoro; R.sub.4 is 2,4-difluorophenyl; and R.sub.5 is H. 15. The method of claim 4, wherein: each R.sub.3 is independently cyano, haloalkyl, alkoxy, halo, haloalkoxy, and n is 1 or 2. 16. The method of claim 4, wherein: each R.sub.3 is independently cyano, haloalkyl, alkoxy, halo, haloalkoxy, and n is 1. 17. The method of claim 4, wherein the compound of formula (I) is one of: 4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)p- ropyl)pyridin-3-yl)benzonitrile (1); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(trifluo- romethyl)phenyl)pyridin-2-yl)propan-2-ol (2); 3-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)p- ropyl)pyridin-3-yl)benzonitrile (3); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(4-isopropoxyphenyl)pyridin-2-yl- )-3-(1H-tetrazol-1-yl)propan-2-ol (4); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(4-fluorophenyl)pyridin-2-yl)-3-- (1H-tetrazol-1-yl)propan-2-ol (5); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(3-(trifluo- romethoxy)phenyl)pyridin-2-yl)propan-2-ol (6); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(trifluo- romethoxy)phenyl)pyridin-2-yl)propan-2-ol (7); 1-(5-(3-Chlorophenyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-- (1H-tetrazol-1-yl)propan-2-ol (8); 1-(5-(4-Chlorophenyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-- (1H-tetrazol-1-yl)propan-2-ol (9); 2-(2,4-Difluorophenyl)-1-(5-(2,5-difluorophenyl)pyridin-2-yl)-1,1-difluor- o-3-(1H-tetrazol-1-yl)propan-2-ol (10); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-t- rifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (11); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(4-(2,2,3,3,3-pentafluoropropoxy- )phenyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (12); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-t- rifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl 3-aminopropanoate (13); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-t- rifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl 2-aminoacetate hydrochloride (14); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-pyrazol-3-yl)-1-(5-(4-(trifluor- o methoxy)phenyl)pyridin-2-yl)propan-2-ol (15); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(4-fluorophenyl)pyridin-2-yl)-3-- (1H-1,2,4-triazol-1-yl)propan-2-ol (16); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-1-(5-(4-(2,- 2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (17); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-1-(5-(4-(tr- ifluoromethoxy)phenyl)pyridin-2-yl)propan-2-ol (18); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-1,2,3-triazol-1-yl)-1-(5-(4-(tr- ifluoromethoxy)phenyl)pyridin-2-yl)propan-2-ol (19); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(2H-tetrazol-1-yl)-1-(5-(4-(2,2,2-t- rifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (20); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(2H-tetrazol-1-yl)-1-(5-(3-(fluorop- henyl)pyridin-2-yl)propan-2-ol (21); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(2H-tetrazol-1-yl)-1-(5-(4-(trifluo- romethylphenyl)pyridin-2-yl)propan-2-ol (22); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-1,2,3-triazol-1-yl)-1-(5-(4-(tr- ifluoromethylphenyl)pyridin-2-yl) propan-2-ol (23); 4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)p- ropyl)pyridin-3-yl)phenol (24); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-isopropylphenyl)pyridin-2-yl)- -3-(1H-tetrazol-1-yl)propan-2-ol (25); 2-(2,4-Difluorophenyl)-1-(5-(3,4-difluorophenyl)pyridin-2-yl)-1,1-difluor- o-3-(1H-tetrazol-1-yl)propan-2-ol (26); 1-(5-(3-(Difluoromethoxy)phenyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-- difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (27); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-((triflu- oromethyl)thio)phenyl)pyridin-2-yl)propan-2-ol (28). 18. The method of claim 4, wherein the disease or disorder is superficial fungal infection, mucosal fungal infection, systemic fungal infection, or onychomycosis. 19. The method of claim 18, wherein the said superficial fungal infection comprises a skin or a nail infection. 20. The method of claim 18, wherein the said systemic fungal infection comprises an invasive fungal infection.