METALLOENZYME INHIBITOR COMPOUNDS, COMPOSITIONS INCLUDING SUCH COMPOUNDS, THERAPEUTIC USE OF THE SAM

专利摘要:
metalloenzyme inhibitor compounds. the present invention describes compounds endowed with metalloenzyme modulating activity, and their uses in methods of treating diseases, disorders or symptoms mediated by such metalloenzymes.
公开号:BR112014013963B1
申请号:R112014013963-6
申请日:2012-12-10
公开日:2021-06-22
发明作者:William J. Hoekstra；Christopher M. Yates
申请人:Nqp 1598, Ltd；
IPC主号:

专利说明:

Background
[001] Living organisms have developed tightly regulated processes that specifically import metals, transport these metals to sites of intracellular deposit and finally to sites of use. One of the most important functions of metals, such as zinc and iron, in biological systems is to enable the activity of metalloenzymes. Metalloenzymes are enzymes that incorporate metal ions into the enzyme's active site and use the metal as part of the catalytic process. More than a third of all characterized enzymes are metalloenzymes.
[002]The function of metalloenzymes is highly dependent on the presence of the metal ion in the active site of the enzyme. Agents that bind to the metal and inactivate the metal ion of the active site substantially increase the activity of the enzyme. Nature applies this same strategy in order to reduce the activity of some metalloenzymes during periods of undesirable enzymatic activity. For example, protein TIMP (metalloprotease inhibitor tissue) binds to zinc ion at the active site of several matrix metalloproteinase enzymes and thereby dampens enzyme activity. The pharmaceutical industry uses the same strategy when designing therapeutic agents. For example, the antifungal agents azole, fluconazole and voriconazole contain a 1-(1,2,4-triazole) group that binds to heme iron present in the active site of the enzyme lanosterol demethylase, inactivating the desired enzyme. Another example includes the zinc-binding hydroxamic acid group that has been incorporated into the most published inhibitors of matrix metalloproteinases and histone deacetylases. Another example is the zinc-binding carboxylic acid group that has been incorporated into the most published angiotensin-converting enzyme inhibitors.
[003] In designing effective and clinically safe metalloenzyme inhibitors, it is essential to use the most appropriate metal-binding group for the specific targeted clinical indication. If a metal binding group with weak binding action is used, the potency may be less than ideal. On the other hand, if a metal-binding group with strong binding action is used, the selectivity for the desired enzyme in relation to related metalloenzymes may be less than ideal. The lack of ideal selectivity can be one of the causes of clinical toxicity due to the involuntary inhibition of untargeted metalloenzymes. An example of clinical toxicity is the involuntary inhibition of human drug metabolizing enzymes such as CYP2C9, CYP2C19 and CYP3A4 by currently available azole-type antifungal agents such as fluconazole and voriconazole. This involuntary inhibition is believed to be primarily caused by the indiscriminate binding of currently used 1-(1,2,4-triazole) to iron at the active site of CYP2C9, CYP2C19, and CYP3A4. Another example is the joint pain observed in several clinical trials of matrix metalloproteinase inhibitors. This toxicity is considered to be related to the inhibition of unwanted metalloenzymes due to the indiscriminate binding of the hydroxamic acid group to zinc at the unwanted active sites.
[004] Therefore, the search for metal-binding groups that can achieve a more satisfactory balance between potency and selectivity remains an important goal and would be relevant in the production of therapeutic agents and methods to address current gaps in disease treatment and prevention , disorders and their symptoms. Brief Summary of the Invention
[005] The invention is directed to compounds (for example, any of those presented herein), methods of modulating the activity of metalloenzymes, and methods for the treatment of diseases, disorders or their symptoms. The methods can comprise the compounds indicated herein.
[006] It is understood that the embodiments of the invention discussed below with reference to the preferred variable selections may be adopted alone or in combination with one or more embodiments or preferred variable selections of the invention, as if each combination were explicitly listed.
[007] A compound of the formula (I), or the salt, solvate, hydrate or prodrug thereof, wherein: R5-ORbR2
R1 is halo; R2 is halo; each R3 is independently cyano, haloalkyl, alkoxy, halo, haloalkoxy, hydroxy, amino, -NR6R9, -SR10, -C(O)R10, optionally substituted haloalkyl, optionally substituted arylalkoxy, -C(O)NR6R7, -CH(OH )-haloalkyl, optionally substituted alkyl, hydroxyalkyl, optionally substituted alkoxyalkyl, isocyano, cycloalkylaminocarbonyl, optionally substituted aryloxyalkyl, optionally substituted arylalkylthio, haloalkylthio, optionally substituted arylalkylsulfinyl, optionally substituted arylalkylsulfinyl, optionally substituted heteroarylalkoxy, or haloalkylcarbonyl; n is 0, 1, 2 or 3; R4 is aryl optionally substituted by 0, 1, 2 or 3 independently R8; R5 is H, alkyl, phosphate, phosphite, alkoxyphosphate, or -C(O)alkyl optionally substituted by amino; R6 is independently H or alkyl; R7 is independently H, optionally substituted alkyl, optionally substituted haloalkyl, or optionally substituted arylalkyl; each R8 is independently cyano, haloalkyl, alkoxy, halo, or haloalkoxy; each R9 is independently H, alkyl, -C(O)alkyl, -C(O)H, -C(O)haloalkyl, or optionally substituted haloalkyl; each R10 is independently H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl; Ar2 is
R11 is optionally substituted phenyl, optionally substituted alkyl, optionally substituted thienyl, pyrrolyl, furanyl, optionally substituted pyridyl, -CH(OH)-alkyl, -CH(OH)-haloalkyl, optionally substituted arylalkyl, optionally substituted aryloxyalkyl, haloalkyl, haloalkoxyalkyl, optionally substituted indolyl, optionally substituted benzofuranyl, heterocycloalkyl, or
R12 is R4, -C(O)R4, -C(O)R7, -SO2R4;
[008] MBG is optionally substituted tetrazolyl, optionally substituted triazolyl, optionally substituted oxazolyl, optionally substituted pyrimidinyl, optionally substituted thiazolyl, or optionally substituted pyrazolyl.
[009] Another aspect is a compound of formula (I), or salt, solvate, hydrate or
R1 is halo; R2 is halo; each R3 is independently cyano, haloalkyl, alkoxy, halo, haloalkoxy, hydroxy, amino, -NR6R9, -SR10, -C(O)R10, optionally substituted haloalkyl, optionally substituted arylalkoxy, -C(O)NR6R7, -CH(OH )-haloalkyl, optionally substituted alkyl, hydroxyalkyl, optionally substituted alkoxyalkyl, isocyano, cycloalkylaminocarbonyl, optionally substituted aryloxyalkyl, optionally substituted arylalkylthio, haloalkylthio, optionally substituted arylalkylsulfonyl, optionally substituted arylalkylsulfinyl, optionally substituted heteroarylalkoxy, optionally substituted arylthioalkyl, or haloalkylcarbonyl; n is 0, 1, 2 or 3; R4 is aryl optionally substituted by 0, 1, 2 or 3 independently R8; R5 is H, alkyl, phosphate, phosphite, alkoxyphosphate, or -C(O)alkyl optionally substituted by 1 or 2 amino; R6 is independently H or alkyl; R7 is independently H, optionally substituted alkyl, optionally substituted haloalkyl, or optionally substituted arylalkyl; each R8 is independently cyano, haloalkyl, alkoxy, halo, or haloalkoxy; each R9 is independently H, alkyl, -C(O)alkyl, -C(O)H, -C(O)haloalkyl, optionally substituted arylalkyl, or optionally substituted haloalkyl; each R10 is independently H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted arylalkyl; air2 is
R11 is optionally substituted phenyl, optionally substituted alkyl, optionally substituted thienyl, pyrrolyl, furanyl, optionally substituted pyridyl, -CH(OH)-alkyl, -CH(OH)-haloalkyl, optionally substituted arylalkyl, optionally substituted aryloxyalkyl, haloalkyl, haloalkoxyalkyl, optionally substituted indolyl, optionally substituted benzofuranyl, heterocycloalkyl, or
R12 is R4, -C(O)R4, -C(O)R7, -SO2R4;
[010] MBG is optionally substituted tetrazolyl, optionally substituted triazolyl, optionally substituted oxazolyl, optionally substituted pyrimidinyl, optionally substituted thiazolyl, or optionally substituted pyrazolyl.
[011] Another aspect is a compound of the present formula, wherein R1 is fluorine.
[012] Another aspect is a compound of the present formula, wherein R2 is fluorine.
[013] Another aspect is a compound of the present formula, wherein R1 and R2 represent fluorine.
[014] Another aspect is a compound of the present formula, wherein R4 is phenyl optionally substituted by 0, 1, 2 or 3 independently R8.
[015] Another aspect is a compound of the present formula, wherein R4 is phenyl optionally substituted by 0, 1, 2 or 3 independently halo.
[016] Another aspect is a compound of the present formula, wherein R4 is phenyl optionally substituted by 0, 1, 2 or 3 independently fluorine.
[017] Another aspect is a compound of the present formula, wherein R4 is 2,4-difluorophenyl.
[018] Another aspect is a compound of the present formula, wherein R5 is H.
[019] Another aspect is a compound of the present formula, wherein R5 is acyl substituted amino.
[020] Another aspect is a compound of the present formula, wherein R5 is -C(O)alkyl optionally substituted by 1 or 2 amino.
[021] Another aspect is a compound of the present formula, wherein R5 is phosphate.
[022] Another aspect is a compound of the present formula, wherein: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; R5 is H;
Ar2 is MBG is 1-tetrazolyl.
[023] Another aspect is a compound of the present formula, wherein: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; R5 is H;
Ar2 is MBG is 1-tetrazolyl; R11 is phenyl, thienyl, arylalkyl, aryloxyalkyl, each optionally substituted by 0, 1, 2, or 3 independently R3; each R3 is independently cyano, haloalkyl, halo, haloalkoxy, optionally substituted arylalkoxy, haloalkylaminocarbonyl, optionally substituted arylalkylaminocarbonyl; and n is 1 or 2.
[024] Another aspect is a compound of the present formula, wherein: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; R5 is H;
Ar2 is MBG is 1-tetrazolyl; R11 is phenyl, thienyl, arylalkyl, aryloxyalkyl, each optionally substituted by 0, 1, 2, or 3 independently R3; each R3 is independently cyano, haloalkyl, halo, haloalkoxy, arylalkoxy optionally substituted by halo, cyano, haloalkyl, or haloalkoxy, haloalkylaminocarbonyl, arylalkylaminocarbonyl optionally substituted by halo, cyano, or haloalkyl; and n is 1 or 2. Another aspect is a compound of the present formula, wherein: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; R5 is H;
Ar2 is MBG is 1-tetrazolyl; R11 is phenyl, thienyl, arylalkyl, aryloxyalkyl, each optionally substituted by 0, 1, 2, or 3 independently R3; each R3 is independently -NR6R9, haloalkylcarbonyl, alkoxyalkyl, hydroxyalkyl, acyl, haloalkylthio, -CH(OH)-haloalkyl, alkyl, alkoxy, cyano, haloalkyl, halo, haloalkoxy, arylalkoxy optionally substituted by halo, cyano, haloalkyl, or haloalkoxy, haloalkylaminocarbonyl, arylalkylaminocarbonyl optionally substituted by halo, cyano, haloalkoxy, or haloalkyl; and n is 1 or 2.
[025] Another aspect is a compound of the present formula, wherein: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; R5 is H; Ar2 is
MBG is 1-tetrazolyl; R11 is phenyl, thienyl, arylalkyl, aryloxyalkyl, each optionally substituted by 0, 1, 2, or 3 independently R3; each R3 is independently cyano, haloalkyl, halo, haloalkoxy, optionally substituted arylalkoxy, haloalkylaminocarbonyl, optionally substituted arylalkylaminocarbonyl; and is 1.
[026] Another aspect is a compound of the present formula, wherein: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; R5 is H;
Ar2 is MBG is 1-tetrazolyl; R11 is phenyl optionally substituted by 0, 1, 2, or 3 independently R3; each R3 is independently cyano, haloalkyl, halo; and n is 1 or 2.
[027] Another aspect is a compound of the present formula, wherein: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; R5 is H;
Ar2 is MBG is 1-tetrazolyl; R11 is phenyl optionally substituted by 0, 1, 2, or 3 independently R3; each R3 is independently -NR6R9, haloalkylcarbonyl, alkoxyalkyl, hydroxyalkyl, acyl, haloalkylthio, -CH(OH)-haloalkyl, alkyl, alkoxy, cyano, haloalkyl, halo, haloalkoxy, arylalkoxy optionally substituted by halo, cyano, haloalkyl, or haloalkoxy, haloalkylaminocarbonyl, arylalkylaminocarbonyl optionally substituted by halo, cyano, haloalkoxy, or haloalkyl; and n is 1 or 2.
[028] Another aspect is a compound of the present formula, wherein: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; R5 is H;
Ar2 is MBG is 1-tetrazolyl; R11 is thienyl optionally substituted by 0, 1, 2, or 3 independently R3; each R3 is independently haloalkylaminocarbonyl, optionally substituted arylalkylaminocarbonyl; and n is 1 or 2.
[029] Another aspect is a compound of the present formula, wherein: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; R5 is H;
Ar2 is MBG is 1-tetrazolyl; R11 is thienyl optionally substituted by 0, 1, 2, or 3 independently R3; each R3 is independently haloalkylaminocarbonyl or arylalkylaminocarbonyl optionally substituted by halo, cyano, or haloalkyl; and n is 1 or 2.
[030] Another aspect is a compound of the present formula, wherein: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; R5 is H;
Ar2 is MBG is 1-tetrazolyl; R11 is thienyl optionally substituted by 0, 1, 2, or 3 independently R3; each R3 is independently -NR6R9, haloalkylcarbonyl, alkoxyalkyl, hydroxyalkyl, acyl, haloalkylthio, -CH(OH)-haloalkyl, alkyl, alkoxy, cyano, haloalkyl, halo, haloalkoxy, arylalkoxy optionally substituted by halo, cyano, haloalkyl, or haloalkoxy, haloalkylaminocarbonyl, arylalkylaminocarbonyl optionally substituted by halo, cyano, haloalkoxy, or haloalkyl; and n is 1 or 2.
[031] Another aspect is a compound of the present formula, wherein: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; and R5 is H.
[032] Another aspect is a compound of the present formula, wherein: each R3 is independently cyano, haloalkyl, halo, haloalkoxy, optionally substituted arylalkoxy, haloalkylaminocarbonyl, optionally substituted arylalkylaminocarbonyl; and n is 1 or 2.
[033] Another aspect is a compound of the present formula, wherein: each R3 is independently -NR6R9, haloalkylcarbonyl, alkoxyalkyl, hydroxyalkyl, acyl, haloalkylthio, -CH(OH)-haloalkyl, alkyl, alkoxy, cyano, haloalkyl, halo, haloalkoxy, arylalkoxy optionally substituted by halo, cyano, haloalkyl, or haloalkoxy, haloalkylaminocarbonyl, arylalkylaminocarbonyl optionally substituted by halo, cyano, haloalkoxy, or haloalkyl; and n is 1 or 2.
[034] Another aspect is a compound of the present formula, wherein: each R3 is independently cyano, haloalkyl, halo, haloalkoxy, optionally substituted arylalkoxy, haloalkylaminocarbonyl, optionally substituted arylalkylaminocarbonyl; and n is 1.
[035] Another aspect is a compound of the present formula, wherein: i. each R3 is independently cyano, haloalkyl, halo, haloalkoxy, optionally substituted arylalkoxy, haloalkylaminocarbonyl, optionally substituted arylalkylaminocarbonyl; and n is 2.
[036] Another aspect is a compound of the present formula, wherein: each R3 is independently hydroxy, amino, -NR6R9, -SR10, -C(O)R10, C(O)NR6R7, -CH(OH)-haloalkyl, optionally substituted alkyl, hydroxyalkyl, alkoxyalkyl, isocyano, cycloalkylaminocarbonyl, aryloxyalkyl, arylalkylthio, haloalkylthio, arylalkylsulfonyl, arylalkylsulfinyl, optionally substituted heteroarylalkoxy, or haloalkylcarbonyl; and n is 1 or 2.
[037] Another aspect is a compound of the present formula, wherein: each R3 may be optionally substituted with halo, cyano, haloalkyl, haloalkoxy, alkylaminocarbonyl, heteroaryl, or aryl.
[038] Another aspect is a compound of the present formula, wherein: each arylalkoxy may be optionally substituted with halo, cyano, haloalkyl, haloalkoxy, alkylaminocarbonyl, heteroaryl, or aryl.
[039] Another aspect is a compound of the present formula, wherein: each aryloxyalkyl may be optionally substituted with halo, cyano, haloalkyl, haloalkoxy, or aryl.
[040] Another aspect is a compound of the present formula, wherein: each arylalkylthio may be optionally substituted with halo, haloalkyl, haloalkoxy or cyano.
[041] Another aspect is a compound of the present formula, wherein: each arylalkylsulfonyl may be optionally substituted with halo, haloalkyl, haloalkoxy, or cyano.
[042] Another aspect is a compound of the present formula, wherein: each arylalkylsulfinyl may be optionally substituted with halo, haloalkyl, haloalkoxy, or cyano.
[043] Another aspect is a compound of the present formula, wherein: each heteroarylalkoxy may be optionally substituted with halo, haloalkyl, haloalkoxy, or cyano.
[044] Another aspect is a compound of the present formula, wherein: each arylthioalkyl may be optionally substituted with halo, haloalkyl, haloalkoxy, or cyano.
[045] Another aspect is a compound of the present formula, wherein: each thienyl may be optionally substituted with halo, haloalkyl, alkyl, haloalkylcarbonyl, haloalkylaminocarbonyl, haloarylalkylaminocarbonyl, cyanoarylalkylaminocarbonyl, haloalkylarylalkylaminocarbonyl, heterocycloalkylcarbonyl, methylsulfonyl-phenylalkylaminocarbonyl, or cyano.
[046] Another aspect is a compound of the present formula, wherein: each pyridyl within the definition of R11 may be optionally substituted with halo, cyano, haloalkoxy, or haloalkyl.
[047] Another aspect is a compound of the present formula, wherein: each indolyl may be optionally substituted with halo, cyano, haloalkoxy, or haloalkyl.
[048] Another aspect is a compound of the present formula, wherein: each benzofuranyl may be optionally substituted with halo, cyano, haloalkoxy, or haloalkyl.
[049] Another aspect is a compound of the present formula, wherein: each MBG may be optionally substituted with halo, cyano, haloalkoxy, or haloalkyl.
[050] Another aspect is a compound of the present formula, wherein: each R11 may be optionally substituted with halo, cyano, alkyl, haloalkoxy, or haloalkyl.
[051] Another aspect is a compound of the present formula, wherein: each R3 is independently 4-cyano, 4-trifluoromethyl, 3-cyano, 4-isopropoxy, 4-fluoro, 3-trifluoromethoxy, 4-trifluoromethoxy, 3-chloro , 4-chloro, 2-fluoro, 5-fluoro, 4-(2,2,2-trifluoroethoxy), 4-(3,3,3-trifluoro, 2,2-difluoropropoxy), 4-cyano-3-fluorophenylmethoxy , 4-cyanophenylmethoxy, 1-hydroxy-2,2,2-trifluoroethyl, or (4-fluorophenylmethyl)NHC(O)-, 2,4-di-fluoro, 1-methyl, 3,4-di-fluoro, 2 -fluoro-4-trifluoromethyl, 3-fluoro, 4-difluoromethyl, 2-fluoro-4-methyl, 5-chloro, 5-trifluoromethyl, 3,5-di-fluoro, 2-fluoro-5-methoxy, 2,6 -di-fluoro, 5-methyl, 4-(1,1,-difluoroethane), 4-difluoromethoxy, 4-trifluoromethylthio, 3-fluoro-4-chloro, 4-acetyl, 4-hydroxymethyl, 4-methoxymethyl, 5- bromine, 5-difluoromethyl, 5-trifluoroacetyl, 1-(2,2,2-trifluoroethyl), 2-fluoro-4-(methylamino), 4-dimethylamino, 3-fluoro-4-difluoromethyl, 1-difluoromethyl, 2, 5-difluoro, 4-formylamino, 4-isocyano, 2-fluoro-4-cyano, 3-fluoro-4-cyano, 2-fluoro-5-cyano, 5-( 2,2,2-trifluoroethyl), 4-trifluoroacetylamino, 4-(2,2,2-trifluoroethyl)amino, 4-aminocarbonyl, 2-fluoro-4-amino, 4-acetylamino, 4-(fluorophenyl)methylamino, 4 -(2,2,2-trifluoroethyl), (2,2,2-trifluoroethyl)aminocarbonyl, pyrrolidinylcarbonyl, 4-(fluorophenyl)methyloxy, 4-(fluorophenyl)carbonyl, 1-trifluoroacetyl, 3-(2,2,2 -trifluoroethyl)oxy, 3-(cyanophenyl)methyloxy, 4-(trifluoromethoxyphenyl)methyloxy, [(2-fluoro-4-cyano)phenyl]methyloxy, [(2-fluoro-5-cyano)phenyl]methyloxy, 3-( trifluoromethoxy)methyloxy, 2,4-(di-fluorophenyl)methyloxy, 3,4-(di-fluorophenyl)methyloxy, 4-(chlorophenyl)methyloxy, (2-fluoro-4-chlorophenyl)methyloxy, [4-(methylaminocarbonyl) phenyl]methyloxy, (5-cyano-2-pyridyl)methyloxy, (2-thiazol)methyloxy, (3-cyano-4-fluorophenyl)methyloxy, (2,3-di-fluorophenyl)methyloxy, 2-fluoro-4- chloro, (3-cyanophenyl)methylaminocarbonyl, (4-cyanophenyl)methylaminocarbonyl, (4-trifluoromethylphenyl)methylaminocarbonyl, (1-morpholino)carbonyl, [4-(methanesulfonyl)phenyl]methylaminocarbonyl, (2-fluoro-4-cyanophenyl)meth yloxy, (3-fluoro-5-cyanophenyl)methyloxy, (4-fluorophenyl)sulfonyl, 1-hydroxy-(2,2,3,3,3-pentafluoro)propyl, (3-cyanophenyl)methylsulfonyl, (2-cyano -5-pyridyl)methyloxy, (3-fluoro-4-cyanophenyl)methyloxy, 1-hydroxyethyl, 2-fluoro-4-methoxy, 4-methylamino, 4-hydroxy, (4-fluorophenyl)methylamino, (3-fluorophenyl) methylaminocarbonyl, (4-fluorophenyl)methylaminocarbonyl, (2-fluoro-3-cyanophenyl)methyloxy, (4-cyanophenyl)methylthio, (3-fluoro-4-chlorophenyl)methyloxy, (4-biphenyl)methyloxy, (4-methylphenyl) methyloxy, (4-ethylphenyl)methyloxy, (4-difluoromethylphenyl)methyloxy, (4-trifluoromethylphenyl)methyloxy, 3-cyano-4-fluoro, (4-(1-pyrrolyl)phenyl)methyloxy, 4-phenyl, (4- (2-oxazolyl)phenyl)methyloxy, 4-(5-cyanothienyl)methyloxy.
[052] Another aspect is a compound of formula (II), or salt, solvate, hydrate or prodrug thereof, wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are defined as described in the above embodiments; Ar is aryl or heteroaryl; n is 0, 1, 2 or 3.
[053] In one aspect, the compound of any of the present formulas (eg, formula I or formula II) is one wherein the compound inhibits (or is identified to inhibit) lanosterol demethylase (CYP51).
[054] In one aspect, the compound of any of the present formulas (for example, formula I or formula II) is one in which the compound is identified as having a range of activity against a desired enzyme (for example, MIC of C. albicans <1.0 μg/mL and A. fumigatus MIC <64 μg/mL).
[055] The present compounds include those in which the compound is identified as having affinity, at least in part, for a metalloenzyme through the formation of one or more of the following types of interactions or chemical bonds with a metal: sigma bonds, covalent bonds , coordinate covalent bonds, ionic bonds, pi bonds, delta bonds, or feedback interactions. Compounds can also obtain affinity through weaker metal interactions, such as van der Waals interactions, cation-pi interactions, pi-anion interactions, dipole-dipole interactions, ion-dipole interactions. In one aspect, the compound is identified as having a binding interaction with the metal via the 1-tetrazolyl moiety; in another aspect, the compound is identified as having a binding interaction with the metal through N2 of the 1-tetrazolyl moiety; in another aspect, the compound is identified as having a binding interaction with the metal through N3 of the 1-tetrazolyl moiety; in another aspect, the compound is identified as having a binding interaction with the metal through N4 of the 1-tetrazolyl moiety. In one aspect, the compound is identified as having a binding interaction with the metal via the 2-tetrazolyl moiety; in another aspect, the compound is identified as having a binding interaction with the metal through N1 of the 2-tetrazolyl moiety; in another aspect, the compound is identified as having a binding interaction with the metal through N3 of the 2-tetrazolyl moiety; in another aspect, the compound is identified as having a binding interaction with the metal through N4 of the 2-tetrazolyl moiety.
[056] Methods of evaluating metal-ligand bond interactions are known in the art as exemplified in references which include, for example, "Principles of Bioinorganic Chemistry" by Lippard and Berg, University Science Books, (1994); “Mechanisms of Inorganic Reactions” by Basolo and Pearson John Wiley & Sons Inc; 2- edition (September 1967); “Biological Inorganic Chemistry” by Ivano Bertini, Harry Gray, Ed Stiefel, Joan Valentine, University Science Books (2007); Xue et al. "Nature Chemical Biology", vol. 4, No. 2, 107-109 (2008).
[057] In some cases, compounds of the invention are selected from any of the following formulas (eg, formula I or formula II) (and pharmaceutically acceptable salts, solvates, or hydrates thereof) 2-(2,4-Difluorophenyl )-1,1-difluoro-1-(5-(phenylethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2-ol (1); 1-(5-((4-Chlorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane-2 -ol(2); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (3); 2-(2,4-Difluorophenyl)-1-(5-((2,4-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (4); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethyl)phenyl)ethynyl)pyridin-2-yl) propane-2-ol (5); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(4-fluorobenzyl)thiophene-2-carboxamide (6); 4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl) propyl) pyridin-3-yl)) ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (7); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)benzonitrile (8); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoro-1-hydroxyethyl)) phenyl)ethynyl)pyridin-2-yl)propane-2-ol (9); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-methyl-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazole -1-yl)propane-2-ol (10); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)thiophen-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (11); 2-(2,4-Difluorophenyl)-1-(6-((3,4-difluorophenyl)ethynyl)pyridazin-3-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (12); 4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)but-3-yn -2-ol (13); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-hydroxyethyl)) thiophene-2-yl)ethynyl)pyridin-2-yl)propane-2-ol (14); 2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)pyrazin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (15); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-hydroxy ethyl) )furan-2-yl)ethynyl)pyridin-2-yl)propane-2-ol (16); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(3-fluorophenyl)prop-1-yn-1-yl)pyridin-2-yl)-3-(1H -tetrazol-1-yl)propane-2-ol (17); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)pyridin-2-yl)-3-(1H -tetrazol-1-yl)propane-2-ol (18); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-(4-fluorophenyl)piperidin-4-yl)ethynyl)pyridin-2-yl)-3-(1H- tetrazol-1-yl)propane-2-ol (19); 1-(5-((4-((4-Cyanobenzyl)oxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(dihydrogen phosphate 1H-tetrazol-1-yl)propane-2-yl (20); 1-(5-((3-chlorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane-2 -ol(21); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-(trifluoromethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol- 1-yl)propane-2-ol (22); 2-(2,4-difluorophenyl)-1-(5-(3,3-difluoroprop-1-ynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl) propane-2-ol (23); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (24); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (25); 1-(5-((4-(difluoromethyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl) propane-2-ol (26); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-methylphenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (27); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((3-fluoropyridin-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (28); 1-(5-((5-chlorothiophen-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (29); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(trifluoromethyl)thiophen-2-yl)ethynyl)pyridine- 2-yl)propane-2-ol (30); 2-(2,4-difluorophenyl)-1-(5-((3,5-difluoropyridin-2-yl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1 -yl)propane-2-ol (31); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((5-fluoropyridin-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (32); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((6-fluoropyridin-3-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (33); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethoxy)phenyl)ethynyl)pyridin-2-yl) propane-2-ol (34); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-methoxyphenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (35); 2-(2,4-difluorophenyl)-1-(5-((2,6-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (36); 2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (37); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((5-methylthiophen-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (38); 1-(5-((4-(1,1-difluoroethyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (39); 1-(5-((4-(difluoromethoxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl) propane-2-ol (40); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethylthio)phenyl)ethynyl)pyridin-2-yl) propane-2-ol (41); 1-(5-((4-chloro-3-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (42); 2-(4-chloro-2-fluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane -2-ol (43); 1,1-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1- yl)propane-2-ol (44); 2-(2,5-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (45); 2-(3,4-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (46); 1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )phenyl)ethanone (47); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (48); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-((4-fluorophenyl)ethynyl)pyridazin-3-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (49); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(hydroxymethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl) propane-2-ol (50); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(methoxymethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl) propane-2-ol (51); 4-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)-1,1, 1-trifluorobut-3-yn-2-ol (52); 1-(5-((5-bromothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (53); 1-(5-((5-(difluoromethyl)thiophen-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (54); 1-(5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )thiophene-2-yl)-2,2,2-trifluoroethanone (55); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((1-(2,2,2-trifluoroethyl)-1H-pyrrole) -3-yl)ethynyl)pyridin-2-yl)propane-2-ol (56); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(3-(2,2,2-trifluoroethoxy)prop-1-inyl )pyridin-2-yl)propane-2-ol (57); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(thiophene-2-ylethynyl)pyridin-2-yl)propane-2- ol (58); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-(methylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol- 1-yl)propane-2-ol (59); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(methylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl) propane-2-ol (60); 2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)thiophen-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (61); 2-(2,4-difluorophenyl)-1-(5-((4-(dimethylamino)phenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl) propane-2-ol (62); 1-(5-((1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (63); 1-(5-((4-(difluoromethyl)-3-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1 -yl)propane-2-ol (64); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(3-(3-fluorophenyl)prop-1-ynyl)pyridin-2-yl)-3-(1H-tetrazol-1 -yl)propane-2-ol (65); 1-(5-((1-(difluoromethyl)-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H -tetrazol-1-yl)propane-2-ol (66); 2-(2,4-difluorophenyl)-1-(5-((2,5-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (67); N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )phenyl)formamide (68); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzonitrile ( 69); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-isocyanophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (70); 3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzonitrile ( 71); 1-(5-((5-bromofuran-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (72); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-3 -fluorobenzonitrile (73); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-2 -fluorobenzonitrile (74); 3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-4 -fluorobenzonitrile (75); 1-(5-((5-(difluoromethyl)furan-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (76); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoroethyl)thiophene-2- yl)ethynyl)pyridin-2-yl)propane-2-ol (77); 1-(5-((4-aminophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane-2 -ol (78); N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )phenyl)-2,2,2-trifluoroacetamide (79); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoroethylamino)phenyl)ethynyl) pyridin-2-yl)propane-2-ol (80); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenol ( 81); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzamide ( 82); 1-(5-((4-amino-2-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (83); N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )phenyl)acetamide (84); 1-(5-(3-(2,4-difluorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazole -1-yl)propane-2-ol (85); 4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop- 2-ynyloxy)benzonitrile (86); 1-(5-((1H-indol-5-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (87); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-fluorobenzylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1- yl)propane-2-ol (88); 1-(5-(benzofuran-5-ylethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane-2- ol (89); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoroethyl)phenyl)ethynyl) pyridin-2-yl)propane-2-ol (90); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(2,2,2-trifluoroethyl)benzamide (91); (4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl )(pyrrolidin-1-yl)methanone (92); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1- yl)propane-2-ol (93); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(2,2,2-trifluoroethyl)thiophene-2-carboxamide (94); (4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)piperidine -1-yl)(4-fluorophenyl)methanone (95); 1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )piperidine-1-yl)-2,2,2-trifluoroethanone (96); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((3-(2,2,2-trifluoroethoxy)phenyl)ethynyl) pyridin-2-yl)propane-2-ol (97); 3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(2,2,2-trifluoroethyl)benzamide (98); 1,1-difluoro-2-(4-fluorophenyl)-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2-ol (99); 3-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)benzonitrile (100); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(4-(trifluoromethoxy)benzyloxy)phenyl)ethynyl)pyridine -2-yl)propane-2-ol (101); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-3-fluorobenzonitrile (102); 3-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-4-fluorobenzonitrile (103); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(3-(trifluoromethoxy)benzyloxy)phenyl)ethynyl)pyridine -2-yl)propane-2-ol (104); 1-(5-((4-(2,4-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (105); 1-(5-((4-(3,4-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (106); 1-(5-((4-(4-chlorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1- yl)propane-2-ol (107); 1-(5-((4-(4-chloro-2-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H- tetrazol-1-yl)propane-2-ol (108); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-N-methylbenzamide (109); 6-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)nicotinonitrile (110); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(thiazol-2-ylmethoxy)phenyl)ethynyl)pyridine- 2-yl)propane-2-ol (111); 5-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (112); 1-(5-((4-(2,3-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (113); 1-(5-(3-(4-chlorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1 -yl)propane-2-ol (114); 4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop- 2-ynyloxy)-3-fluorobenzonitrile (115); 4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop- 2-ynyloxy)-2-fluorobenzonitrile (116); 1-(5-(3-(4-chloro-2-fluorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H -tetrazol-1-yl)propane-2-ol (117); 1-(5-(3-(4-(difluoromethyl)phenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H- tetrazol-1-yl)propane-2-ol (118); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(3-fluorobenzyl)thiophene-2-carboxamide (119); N-(3-cyanobenzyl)-5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridine- 3-yl)ethynyl)thiophene-2-carboxamide (120); N-(4-cyanobenzyl)-5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridine- 3-yl)ethynyl)thiophene-2-carboxamide (121); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (122); (5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophene -2-yl)(morpholino)methanone (123); (5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophene -2-yl)(pyrrolidin-1-yl)methanone (124); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(4-(methylsulfonyl)benzyl)thiophene-2-carboxamide (125); 3-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (126); 3-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-5-fluorobenzonitrile (127); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(piperidin-4-ylethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2- ol (128); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((1-(4-fluorophenylsulfonyl)piperidin-4-yl)ethynyl)pyridin-2-yl)-3-(1H- tetrazol-1-yl)propane-2-ol (129); 1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )phenyl)-2,2,3,3,3-pentafluoropropane-1-ol (130); 4-((4-((6-(2-(2,5-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (131); 4-((4-((6-(2-(4-chloro-2-fluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridine-3- yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (132); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenylthio)methyl)-2-fluorobenzonitrile (133); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenylsulfinyl)methyl)-2-fluorobenzonitrile (134); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenylsulfonyl)methyl)-2-fluorobenzonitrile (135); 4-((4-((6-(2-(2,5-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)benzonitrile (136); 4-((4-((6-(2-(4-chloro-2-fluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridine-3- yl)ethynyl)phenoxy)methyl)benzonitrile (137); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenylthio)methyl)benzonitrile (138); 5-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)picolinonitrile (139); 1-(5-((4-(4-cyanobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazole) dihydrogen phosphate -1-yl)propane-2-yl (140); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)ethynyl)-N -(4-fluorobenzyl)thiophene-2-carboxamide (141); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)benzonitrile (142); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (143); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane hydrochloride -2-yl 2-aminoacetate (144); (2S)-2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1) dihydrochloride -yl)propane-2-yl 2,6-diaminohexanoate (145); 1-(5-((4-(4-chloro-3-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H- tetrazol-1-yl)propane-2-ol (146); 1-(5-((4-(biphenyl-4-ylmethoxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (147); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-methylbenzyloxy)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1- yl)propane-2-ol (148); 2-(2,4-difluorophenyl)-1-(5-((4-(4-ethylbenzyloxy)phenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1- yl)propane-2-ol (149); 1-(5-((4-(4-(difluoromethyl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazole -1-yl)propane-2-ol (150); (+)-1-(5-((4-(4-(difluoromethyl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3- (1H-tetrazol-1-yl)propane-2-ol ((+)-150); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(4-(trifluoromethyl)benzyloxy)phenyl)ethynyl)pyridine -2-yl)propane-2-ol (151); 4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )benzyloxy)-3-fluorobenzonitrile (152); 5-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )benzyloxy)-2-fluorobenzonitrile (153); 1-(5-((4-(4-(1H-pyrazol-1-yl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro- 3-(1H-tetrazol-1-yl)propane-2-ol (154); 4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )benzyloxy)benzonitrile (155); 1-(5-((4-((4-chlorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazole -1-yl)propane-2-ol (156); 1-(5-((4-((biphenyl-4-yloxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H -tetrazol-1-yl)propane-2-ol (157); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-(oxazol-2-yl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-3- (1H-tetrazol-1-yl)propane-2-ol (158); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-((4-fluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazole -1-yl)propane-2-ol (159); 1-(5-((4-((3,4-difluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H -tetrazol-1-yl)propane-2-ol (160); 1-(5-((4-((4-(difluoromethyl)phenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-( 1H-tetrazol-1-yl)propane-2-ol (161); 4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )benzylthio)benzonitrile (162); 5-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)thiophene-2-carbonitrile (163); 4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )benzyloxy)-2-fluorobenzonitrile (164); 1-(5-((4-((4-chloro-3-fluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3- (1H-tetrazol-1-yl)propane-2-ol (165); 4-((3-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)benzonitrile (166).
[058] In another aspect, the invention provides a pharmaceutical composition comprising the compound of any of the present formulas (eg formula I or formula II) and a pharmaceutically acceptable carrier.
[059] In other aspects, the invention provides a method for modulating metalloenzyme activity in an individual, which comprises contacting the individual with a compound of any of the present formulas (eg, formula I or formula II), in sufficient quantity and conditions to modulate metalloenzyme activity.
[060] In another aspect, the invention provides a method of treating an individual carrying or susceptible to a disorder or disease, wherein the individual has been identified as in need of treatment for the disorder or disease, which comprises administering to said individual in need thereof , an effective amount of a compound or pharmaceutical composition of any of the present formulas (for example, formula I or formula II), such that said individual is treated for said disorder.
[061] In another aspect, the individual is an animal other than man.
[062] The present methods include those in which the disorder or disease is associated with one or more of the following pathogenic fungi: Absidia corymbifera, Ajellornyces dermatitidis, Arthroderma benhamiae, Arthroderma fulvum, Arthroderma gypseum, Arthroderma incurvaturne, Arthroderma oderma Aspergillus flavus, Aspergillus fumigates, Aspergillus niger, Blastomyces dermatitidis, Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa, Cladophialophora carrionii, Coccidioides imnningham neophytes, Ex. dermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusarium solani, Geotrichum candidum, Histoplasma capsulaturn, Hortaea werneckii, Issatschenkia orientalis, Madurella grisae, Malassezia fur fur, Malassezia globosa, Malassezia patussezia, Malassezia obtussezia, Malassezia restrictia, Malassezia restrictia, Malassezia restrictia, Malassezia restricta sympodialis, Microsporum canis, Microsporum fulvum, Microsporum gypseum, Mucor circinelloides, Nectria haematococca, Paecilomyces variotii, Paracoccidioides brasiliensis, Penicillium marneffei, Pichia anomala, Pichia boypusmondallii, Pichia guilliermondallii, Pichia boypusumallii, Pneumocystinitis caru Sporothrix schenckii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichosporon asahii, Trichosporon cutaneum, Trichosporon inkin, Trichosporon mucoides.
[063] The present methods include those in which the disorder or disease is aspergillosis, blastomycosis, candidiasis, chromomycosis, coccidioidomycosis, cryptococcosis, dermatophytosis, histoplasmosis, keratomicosis, Lobomycosis, Malassezia infection, mucormycosis, paracoccidioidomycosis, pheenicophilic infection , Pneumocyctis pneumonia, or rhinosporidiosis.
[064] The present methods include one in which the disorder or disease is Chagas disease (Trypanosoma genus), African trypanosomiasis (Trypanosoma genus), leishmaniasis (Leishmania genus), tuberculosis (Mycobacterium genus), leprosis (Mycobacterium genus), malaria (Genus Plasmodium), or tinea (capitis, corporis, pedis, tonsurans, versicolor).
[065] In one aspect, the invention provides a method of treating a subject carrying or susceptible to a metalloenzyme-related disorder or disease, which comprises administering to the subject an effective amount of a compound or pharmaceutical composition of any of the present formulas (eg formula I or formula II).
[066] In another aspect, the invention provides a method of treating an individual carrying or susceptible to a metalloenzyme-related disorder or disease, wherein the individual has been identified as in need of treatment for a metalloenzyme-related disorder or disease, which comprises administering to said individual in need thereof, an effective amount of a compound or pharmaceutical composition of any of the present formulas (for example, formula I or formula II), such that said individual is treated for said disorder.
[067] In another aspect, the invention provides a method of treating an individual having or susceptible to a metalloenzyme-mediated disorder or disease, wherein the individual has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, which comprises administering to said individual in need thereof, an effective amount of a compound or pharmaceutical composition of any of the present formulas (e.g., formula I or formula II), so as to modulate metalloenzyme activity in said individual (e.g., down-regulated , inhibited).
[068] The present methods include those in which the disease or disorder is mediated by any of the following: 4-hydroxyphenyl pyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase N, angiotensin converting enzyme, aromatase (CYP19 ), calcineurin, carbamoyl phosphate synthetase, carbonic anhydrase family, catechol-methyl transferase, cyclooxygenase family, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA aminotransferase, HIF-prolyl , histone deacetylase family, HIV integrase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51), matrix metalloproteinase family, methionine aminopeptidase, neutral endopeptidase, nitric oxide synthase family, phosphodiesterase III, phosphodiesterase IV , phosphodiesterase V, ferredoxin oxidoreductase pyruvate, renal peptidase, ribonucleoside diphosphate reductase, thromboxa in synthase (CYP5a), thyroid peroxidase, tyrosinase, urease, or xanthine oxidase.
[069] The present methods include those in which the disease or disorder is mediated by any of the following: 1-deoxy-d-xylulose-5-phosphate reductisomerase (DXR), 17-alpha hydroxylase (CYP17), aldosterone synthase (CYP11B2 ), aminopeptidase P, anthrax lethal factor, arginase, beta-lactamase, cytochrome P450 2A6, d-ala d-ala ligase, dopamine beta-hydroxylase, endothelin-1 converting enzyme, glutamate carboxypeptidase II, glutaminyl cyclase, glyoxalase, heme oxygenase, HPV/HSV E1 helicase, indoleamine 2,3-dioxygenase, leukotriene A4 hydrolase, methionine aminopeptidase 2, peptide deformylase, phosphodiesterase VII, relaxase, retinoic acid hydroxylase (CYP26), TNF-alpha converting enzyme (TACE) , UDP-(3-O-(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase (LpxC), vascular adhesion protein-1 (VAP-1), or vitamin D hydroxylase (CYP24).
[070] The present methods include those in which the disease or disorder is represented by cancer, cardiovascular disease, inflammatory disease, infectious disease, metabolic disease, eye disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease.
[071] The present methods include those in which the disease or disorder is represented by prostate cancer, breast cancer, inflammatory bowel disease, psoriasis, systemic fungal infection, fungal infection of the dermal structure, fungal infection of the mucosa, or onychomycosis.
[072] The methods presented here include those in which the individual is identified as in need of a particular informed treatment. The identification of the individual in need of treatment would be subject to the judgment of an individual or health professional, and could be subjective (eg, report) or objective (eg, measured by a test or diagnostic method).
[073] Another aspect of the invention is a composition comprising a compound of one of the present formulas (e.g. formula (I) or formula (II)) and an agriculturally acceptable carrier.
[074] Another aspect of the invention is a method of treating or preventing a metalloenzyme-mediated disorder or disease in a plant which comprises contacting one of these compounds with the plant.
[075] Another aspect of the invention is a method of inhibiting the metalloenzyme activity in or in a plant which comprises contacting a compound described herein with the plant. Detailed Description Definitions a. In order for the invention to be more readily understood, some terms are first defined for the sake of convenience. b. As used herein, the term "treating" a disorder encompasses preventing, ameliorating, alleviating and/or controlling the disorder and/or the conditions that would cause the disorder. The terms "treat" and "treatment" refer to a method of alleviating or reducing an illness and/or its accompanying symptoms. According to the present invention "treating" includes preventing, blocking, inhibiting, attenuating, protecting against, modulating, reversing the effects of and reducing the occurrence of, for example, the harmful effects of a disorder. c.As used herein, "inhibit" encompasses preventing, reducing, and halting evolution. Note that “enzyme inhibition” (eg metalloenzyme inhibition) is distinguished and described below. d.The term "modulate" refers to increases or decreases in the activity of an enzyme in response to exposure to a compound of the invention. e.The terms "isolated", "purified", or "biologically pure" refer to material free substantially or essentially from components that normally accompany them as found in their native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. Particularly, in the embodiments, the compound has a minimum purity of 85%, more preferably a minimum purity of 90%, more preferably a minimum purity of 95%, and most preferably a minimum purity of 99%. f.The term "administration" or "administering" includes routes of introduction of the compound(s) into an individual to perform the intended function. Examples of useable routes of administration include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal and transdermal. g.The term "effective amount" includes an amount effective, in dosages and for periods of time necessary, to achieve the desired result. The effective amount of the compound would depend on factors such as the stage of the disease, age and weight of the individual, and the ability of the compound to elicit the desired response in the individual. Dosing regimens can be adjusted to provide the optimal therapeutic response. An effective amount is also one in which any toxic or harmful effects (e.g., side effects) of the inhibiting compound are outweighed by the beneficial effects from a pharmaceutical standpoint. h. The terms "systemic administration", "systemically administered", "peripheral administration" and "peripherally administered" as used herein mean the administration of a compound(s), drug or other material in order to penetrate the patient's system and, therefore, subjected to metabolism and other similar processes.
[076] The term "therapeutically effective amount" refers to that sufficient amount of the compound that is administered to prevent the development or alleviate to some degree one or more of the symptoms of the condition or disorder being treated. aThe therapeutically effective amount of the compound (i.e., the effective dosage) can range from about 0.005 µg/kg to about 200 mg/kg, preferably about 0.01 mg/kg to about 200 mg/kg, more preferably about 0.015 mg/kg to about 30 mg/kg of body weight. In other embodiments, the therapeutically effective amount can range from about 1.0 pM to about 10 µM. The skilled practitioner will find it interesting that some factors may influence the dosage required to effectively treat an individual, including, but not limited to, the severity of the disease or disorder, previous treatments, general health and/or age of the individual, and other present diseases. In addition, treating an individual using a therapeutically effective amount of a compound can include a single treatment or, preferably, a series of treatments. In one example, the subject is treated with a compound in the range maintained between about 0.005 µg/kg to about 200 mg/kg of body weight, once daily for about 1 to 10 weeks, preferably between 2 to 8 weeks. , more preferably between about 3 to 7 weeks, and even more preferably for about 4, 5, or 6 weeks. In another example, the individual may be treated daily for several years when the illness or condition is chronic. It would further be interesting if the effective dosage of a compound used in the treatment could be increased or decreased over the course of a particular treatment.
[077]The term "chiral" refers to the property of certain molecules of not being superimposable on their mirror image, while the term "achiral" refers to molecules superimposable on their mirror image.
[078]The term "diastereomers" refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another. a.The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. An equimolar mixture of two enantiomers is called a “racemic mixture” or “racemate.” b.The terms “isomers” or “stereoisomers” refer to compounds of identical chemical constitution but distinct in the organization of atoms or groups in space. cThe term "prodrug" includes compounds with fractions that can be metabolized in vivo. Generally speaking, prodrugs are metabolized in vivo by esterases or other mechanisms forming active drugs. Examples of prodrugs and their use are well established in the art (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-9. Prodrugs can be prepared in situ during the final isolation and purification of the compounds , or by separately reacting the purified compound in the form of its free acid or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted to esters by treatment with carboxylic acid. Examples of prodrug moieties include moieties of substituted and unsubstituted lower alkyl ester, branched or unbranched (eg propionic acid esters), lower alkenyl esters, lower dialkylamino lower alkyl esters (eg dimethylaminoethyl ester), acylamino lower alkyl esters (eg acetyloxymethyl ester), acyloxy lower alkyl esters (eg pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl lower alkyl esters (eg benzyl ester), substituted aryl (eg , by the substituents methyl, halo, or methoxy) and aryl lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Preferred prodrug fractions are propionic acid esters and acyl esters. Prodrugs that are converted to active forms using other in vivo mechanisms are also included. In some aspects, compounds of the invention are prodrugs of any of the present formulas.
[079] The term "individual" refers to animals such as mammals, including but not limited to primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and other similar animals. . In some modalities, the individual is the man.
[080] The terms "a", "an", "o" and "a" refer to "one or more" when used in this order, including in the claims. Thus, for example, the reference to “a sample” includes a plurality of samples, unless the context clearly expresses otherwise (for example, a plurality of samples), and so on.
[081] Throughout this descriptive report and in the claims, the words “understand”, “understand”, and “understand” are used in a non-excludable sense, except when the context implies otherwise.
[082] As used herein, the term "about" in reference to a value encompasses variations, in some modalities of ± 20%, in some modalities ± 10%, in some modalities ± 5%, in some modalities ± 1%, in some embodiments ± 0.5%, and in some embodiments ± 0.1% relative to the specified amount, as appropriate variations to accomplish the disclosed methods or to employ the disclosed compositions.
[083] The use of the word "inhibitor" in this document means a molecule that inhibits the inhibiting activity of a metalloenzyme. By “inhibit” is meant the reduction of metalloenzyme activity in relation to metalloenzyme activity in the absence of the inhibitor. In some embodiments, the term "inhibit" means reducing the metalloenzyme activity by at least about 5%, at least by about 10%, at least by about 20%, at least about 25%, at least by about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibiting means reducing metalloenzyme activity from about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100 %. In some embodiments, inhibit means a reduction in metalloenzyme activity of about 95% to 100%, for example, a reduction in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such reductions can be measured using multiple techniques that would be recognized by the person skilled in the art. Particular tests for measuring individual activity are described below.
[084] Furthermore, the compounds of the invention include olefins endowed with one of the geometries: "Z" refers to the so-called "cis" configuration (on the same side) while "E" refers to the so-called "trans" configuration (opposite side). Regarding the nomenclature of a chiral center, the terms configuration "d" and "l" are defined by the IUPAC Recommendations. As for the use of the terms, diastereomer, racemate, epimer and enantiomer, these will be used in their normal context to describe the stereochemistry of the preparations.
[085]As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon group containing 1 to 12 carbon atoms. The term "lower alkyl" refers to a C1-C6 alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. Alkyl groups can be optionally substituted by one or more substituents.
[086]The term "haloalkyl" refers to an alkyl group that is substituted by one or more halo substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl, and 2,2,2-trifluoroethyl.
[087]The term "alkenyl" refers to an unsaturated hydrocarbon chain, which may be a straight or branched chain, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Alkenyl groups can be optionally substituted by one or more substituents.
[088] The term "arylalkenyl" refers to an unsaturated hydrocarbon chain, which may be a straight or branched chain, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond in which one or more of the sp2 hybridized carbons of the alkenyl unit attaches to an aryl fraction. Alkenyl groups can be optionally substituted by one or more substituents.
[089]The term "alkynyl" refers to an unsaturated hydrocarbon chain, which may be a straight or branched chain, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups can be optionally substituted by one or more substituents.
[090] The term "arylalkynyl" refers to an unsaturated hydrocarbon chain, which may be a straight or branched chain, containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond in which one or more hybridized carbons sp da alkynyl unit binds to an aryl moiety. Alkynyl groups can be optionally substituted by one or more substituents.
[091] The sp2 or sp carbons of an alkenyl group and an alkynyl group, respectively, can optionally be the attachment point of the alkenyl or alkynyl groups.
[092] The term "alkoxy" refers to an -O-alkyl substituent.
[093] As used herein, the term "halogen", "hal" or "halo" means -F, -Cl, -Br or -I.
[094]The term "alkylthio" refers to an -S-alkyl substituent.
[095]The term "alkoxyalkyl" refers to an -alkyl-O-alkyl substituent.
[096]The term "haloalkoxy" refers to an -O-alkyl that is substituted by one or more halo substituents. Examples of haloalkoxy groups include trifluoromethoxy, and 2,2,2-trifluoroethoxy.
[097]The term "haloalkoxyalkyl" refers to an -alkyl-O-alkyl' where the alkyl' is substituted by one or more halo substituents.
[098] The term "haloalkylaminocarbonyl" refers to a -C(O)-amino-alkyl where the alkyl is substituted by one or more halo substituents.
[099]The term "haloalkylthio" refers to an -S-alkyl that is substituted by one or more halo substituents. Examples of haloalkylthio groups include trifluoromethylthio, and 2,2,2-trifluoroethylthio.
[0100]The term "haloalkylcarbonyl" refers to a -C(O)-alkyl that is substituted by one or more halo substituents. An example of a haloalkylcarbonyl group includes trifluoroacetyl.
[0101] The term "cycloalkyl" refers to a 3-8 membered monocyclic or 7-14 membered bicyclic hydrocarbon ring system having at least one saturated ring or at least one non-aromatic ring, wherein the ring non-aromatic may exhibit some degree of unsaturation. Cycloalkyl groups can be optionally substituted by one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be replaced by a substituent. Representative examples of the cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.
[0102]The term "cycloalkoxy" refers to an -O-cycloalkyl substituent.
[0103]The term "cycloalkoxyalkyl" refers to an -alkyl-O-cycloalkyl substituent.
[0104]The term "cycloalkylalkoxy" refers to an -O-alkyl-cycloalkyl substituent.
[0105]The term "cycloalkylaminocarbonyl" refers to a -C(O)-NH-cycloalkyl substituent.
[0106]The term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system. Aryl groups can be optionally substituted by one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be replaced by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.
[0107]The term "aryloxy" refers to an -O-aryl substituent.
[0108]The term "arylalkoxy" refers to an -O-alkyl-aryl substituent.
[0109] The term "arylalkylthio" refers to an -S-alkyl-aryl substituent.
[0110]The term "arylthioalkyl" refers to an -alkyl-S-aryl substituent.
[0111]The term "arylalkylaminocarbonyl" refers to a -C(O)-amino-alkyl-aryl substituent.
[0112]The term "arylalkylsulfonyl" refers to an -S(O)2-alkyl-aryl substituent.
[0113]The term "arylalkylsulfinyl" refers to an -S(O)-alkyl-aryl substituent.
[0114]The term "aryloxyalkyl" refers to an -alkyl-O-aryl substituent.
[0115]The term "alkylaryl" refers to an -aryl-alkyl substituent.
[0116]The term "arylalkyl" refers to an -alkyl-aryl substituent.
[0117] The term "heteroaryl" refers to a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic aromatic ring system having 1-4 heteroatoms, if monocyclic, 1- 6 heteroatoms, if bicyclic, or 1-9 heteroatoms, if tricyclic, said heteroatoms selected from O, N, or S, and the remainder of the ring atoms being carbon (with appropriate hydrogen atoms, unless otherwise indicated). Heteroaryl groups can optionally be substituted by one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be replaced by a substituent. Examples of heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indnerazolyl, and congeners.
[0118]The term "heteroaryloxy" refers to an -O-heteroaryl substituent.
[0119] The term "heteroarylalkoxy" refers to an -O-alkyl-heteroaryl substituent.
[0120]The term "heteroaryloxyalkyl" refers to an -alkyl-O-heteroaryl substituent.
[0121] The term "nitrogen-containing heteroaryl" refers to a heteroaryl group having 1-4 ring nitrogen heteroatoms if monocyclic, 1-6 ring nitrogen heteroatoms if bicyclic, or 1-9 ring nitrogen heteroatoms , if tricyclic.
[0122] The term "heterocycloalkyl" refers to a non-aromatic 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system comprising 1-3 heteroatoms, if monocyclic, 1- 6 heteroatoms, if bicyclic, or 1-9 heteroatoms, if tricyclic, said heteroatoms selected from O, N, S, B, P or Si, wherein the non-aromatic ring system is fully saturated. by one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may be substituted with a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1 ,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thirenyl, and the like.
[0123]The term "alkylamino" refers to an amino substituent which is further substituted by one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent that is further substituted by one or more amino groups. The term "hydroxyalkyl" or "hydroxylalkyl" refers to an alkyl substituent which is further substituted by one or more hydroxyl groups. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may optionally be substituted with one or more substituents.
[0124] Acids and bases useful in these methods are known in the art. Acid catalysts are any acidic chemical substance, which can be inorganic (eg, hydrochloric, sulfuric, nitric, aluminum trichloride) or organic (eg, camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, aluminum triflate) in nature. ytterbium). Acids are useful in catalytic or stoichiometric volumes to facilitate chemical reactions. Bases are any basic chemical substance and can be inorganic (eg sodium bicarbonate, potassium hydroxide) or organic (eg triethylamine, pyridine) in nature. Bases are useful in catalytic or stoichiometric volumes to facilitate chemical reactions.
[0125]Alkylating agents are any reagent capable of effecting the alkylation of the functional group in question (eg, oxygen atom of an alcohol, nitrogen atom of an amino group). Alkylating agents are known in the art, including references cited in this specification, and include alkyl halides (eg, methyl iodide, benzyl chloride or bromide), alkyl sulfates (eg, methyl sulfate), or other combinations of the alkyl group-labile group known in the art. Labile groups are stable species capable of detaching from a molecule during the reaction (eg, elimination reaction, substitution reaction) and are known in the art, including references cited in this specification, and include halides (eg, I- , Cl-, Br-, F-), hydroxy, alkoxy (eg -OMe, -Ot-Bu), acyloxy anions (eg -OAc, -OC(O)CF3), sulfonates (eg mesyl , tosyl), acetamides (eg -NHC(O)Me), carbamates (eg N(Me)C(O)Ot-Bu), phosphonates (eg -OP(O)(OEt)2) , water or alcohols (protic conditions), and the like.
[0126] In some embodiments, the substituents on any group (such as, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be on any atom in that group, any group that can be substituted (such as, for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be optionally substituted by one or more substituents (which may be the same or different), each substituting one hydrogen atom. Examples of suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl) , carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminoylcarbonyl or alkylaminoylcarbonyl substituted aryl; arylalkylamino, aralkylaminocarbonyl, starch, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, carboxamido, carbamido, carbamyl, thioureido, thiocyanate, sulfoamido, sulfonylalkyl, sulfonyl-alkyl, N'-mercaptoyl, or N'-mercaptoyl hydroxyamidinyl.
[0127] The compounds of the invention can be produced using means known in the art of organic synthesis. Methods for optimizing reaction conditions, if necessary minimizing competing by-products, are known in the art. Extrapolation and reaction optimization can advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (eg, Design and Optimization in Organic Synthesis, 2nd edition, Carlson R, Ed, 2005; Elsevier Science Ltd.; Jãhnisch , K et al, Angew. Chem. Int. Ed. Engl. 2004 43: 406; and references contained in those documents). Additional reaction schemes and protocols can be determined by the experienced practitioner using commercially available structure query database software, eg, SciFinder® (CAS division of the Ameripode Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by correctly searching the keyword using an internet search engine, namely Google® or keyword databases such as the US Patent and Trademark Office text database.
[0128] As the skilled practitioner will appreciate, the methods of synthesizing the compounds of the present formulas will be recognized by the person skilled in the basic art, including the schemes and examples given herein. Additionally, the various synthetic steps can be carried out in order or in staggered sequence to produce the desired compounds. Also, solvents, temperatures, reaction times, etc. presented herein are merely illustrative and one skilled in the basic art will recognize that varying reaction conditions can produce the desired compounds of the present invention.
[0129] The present compounds may also contain bonds (eg, carbon-carbon bonds) where the rotation of the bond is restricted around that particular bond, for example, the restriction resulting from the presence of a ring or double bond. Consequently, all cis/trans and E/Z isomers are expressly included in the present invention. The present compounds may also be represented in multiple tautomeric forms, in which case the invention expressly includes all tautomeric forms of the compounds described herein, although only a single tautomeric form may be represented. All of these isomeric forms of the present compounds are expressly included in the present invention. All polymorphs and crystalline forms of the compounds described herein are expressly included in the present invention. Extracts and fractions comprising the compounds of the invention are further incorporated. The term isomers includes diastereoisomers, enantiomers, regioisomers, structural isomers, rotating isomers, tautomers, and the like. For compounds which contain one or more stereogenic centers, e.g. chiral compounds, the methods of the invention can be carried out with a compound enriched as an enantiomer, a racemate, or a mixture of diastereomers.
[0130] Preferred enriched compounds in the enantiomeric aspect have an enantiomeric excess equal to or above 50%, more preferably the compound has an enantiomeric excess equal to or above 60%, 70%, 80%, 90%, 95%, 98%, or 99%. In preferred embodiments, only one enantiomer or diastereomer of a chiral compound of the invention is administered to the cells or an individual. Treatment Methods
[0131] In one aspect, the invention provides a method of treating an individual carrying or susceptible to a disorder or disease, which comprises administering to the individual an effective amount of a compound or pharmaceutical composition of any of the present formulas (e.g. , formula I or formula II).
[0132] In other aspects, the invention provides a method of treating an individual having or susceptible to a disorder or disease, the individual having been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, which comprises administering to said subject in need thereof, an effective amount of a compound or pharmaceutical composition of any of the present formulas (for example, formula I or formula II), such that said subject is treated for said disorder.
[0133] In one aspect, the invention provides a method of modulating the metalloenzyme activity of a cell in an individual, which comprises contacting the individual with a compound of any of the present formulas (e.g., formula I or formula II ), in sufficient quantity and conditions to modulate the metalloenzyme activity.
[0134]In one modality, modulation consists of inhibition.
[0135] In another aspect, the invention provides a method of treating an individual carrying or susceptible to a metalloenzyme-mediated disorder or disease, which comprises administering to the individual an effective amount of a compound or pharmaceutical composition of any of the present formulas ( for example formula I or formula II).
[0136] In other aspects, the invention provides a method of treating an individual having or susceptible to a metalloenzyme-mediated disorder or disease, the individual having been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, which comprises administering to said individual in need thereof an effective amount of a compound or pharmaceutical composition of any of the present formulas (for example, formula I or formula II), such that said individual is treated for said disorder.
[0137] In some embodiments, the invention provides a method of treating a disease, disorder or symptom of this disease, in which the disorder is cancer, cardiovascular disease, inflammatory disease or infectious disease. In other embodiments the disease, disorder, or disease symptom is a metabolic disease, eye disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease. In some modalities, the disease is prostate cancer, breast cancer, inflammatory bowel disease, psoriasis, systemic fungal infection, dermal structure fungal infection, mucosal fungal infection, and onychomycosis.
[0138] In some embodiments, the individual is a mammal, preferably a primate or human.
[0139] In another embodiment, the invention provides a method as described above, in which the effective amount of the compound of any of the present formulas (for example, formula I or formula II) is described above.
[0140] In another embodiment, the invention provides a method as described above, in which the compound of any of the present formulas (for example, formula I or formula II) is administered intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally or topically .
[0141] In another embodiment, the invention provides a method as described herein wherein the compound of any of the present formulas (for example, formula I or formula II) demonstrates selectivity for a range of activity against a desired enzyme (for example, MIC of C. albicans <1.0 μg/mL and MIC of A. fumigatus <64 μg/mL).
[0142] In other embodiments, the invention provides a method as described above, wherein the compound of any of the present formulas (for example, formula I or formula II) is administered alone or in combination with one or more other therapeutic substances. In a further embodiment, the additional therapeutic agent is an anticancer agent, antifungal agent, cardiovascular agent, anti-inflammatory agent, chemotherapeutic agent, an antiangiogenesis agent, cytotoxic agent, an antiproliferative agent, metabolic disease agent, ophthalmic disease agent, agent of central nervous system disease (CNS), urological disease agent, or gastrointestinal disease agent.
[0143] Another object of the present invention is the use of a compound as described herein (for example, of any of the formulas described herein) in the manufacture of a medicament for use in the treatment of a disorder or disease mediated by the metalloenzyme. Another object of the present invention is the use of a compound as described herein (for example, of any of the formulas described herein) for use in the treatment of a metalloenzyme-mediated disorder or disease. Another object of the present invention is the use of a compound as described herein (e.g. any of the formulas described herein) in the manufacture of an agricultural composition for use in treating or preventing a metalloenzyme-mediated disorder or disease in agricultural or agrarians. Pharmaceutical Compositions
[0144] In one aspect, the invention provides a pharmaceutical composition comprising the compound of any of the present formulas (eg formula I or formula II) and a pharmaceutically acceptable carrier.
[0145] In another embodiment, the invention provides a pharmaceutical composition that further comprises an additional therapeutic agent. In a further embodiment, the additional therapeutic agent is an anticancer agent, antifungal agent, cardiovascular agent, anti-inflammatory agent, chemotherapeutic agent, antiangiogenesis agent, cytotoxic agent, antiproliferative agent, metabolic disease agent, ophthalmic disease agent, disease agent central nervous system (CNS), urological disease agent, or gastrointestinal disease agent.
[0146] In one aspect, the invention provides a kit comprising an effective amount of a compound of any of the present formulas (eg, formula I or formula II), in unit dosage form, together with instructions for administering the compound to an individual having or susceptible to a metalloenzyme-mediated disorder or disease, including cancer, solid tumor, cardiovascular disease, inflammatory disease, infectious disease. In other embodiments the disease, disorder, or disease symptom is a metabolic disease, eye disease, central nervous system (CNS) disease, urological disease, or gastrointestinal disease.
[0147] The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable carrier" includes salts of the active compounds which are prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salt. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired acid, neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, namely, hydrochloric, hydrobromic, nitric, carbonic, monohydrogen-carbonic, phosphoric, monohydrogen-phosphoric, dihydrogen-phosphoric, sulfuric, monohydrogen-sulfuric, hydroiodic, acids, or phosphorous and the like, as well as salts derived from relatively non-toxic organic acids, such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric acids , tartaric, methanesulfonic, and the like. Amino acid salts such as arginate and the like, and organic acid salts such as glucuronic or galactunonic acids and the like are also included (see, for example, Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)).
[0148] Some specific compounds of the present invention contain both basic and acidic functionalities, which makes it possible to convert the compounds into base or acid addition salts. Other pharmaceutically acceptable carriers familiar to those of skill in the art are suitable for the present invention.
[0149]The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the original compound in the conventional manner. The original form of the compound differs from the various salt forms in some physical properties, such as solubility in polar solvents, otherwise the salts are equivalent to the original form of the compound for purposes of the present invention.
[0150] In addition to salt forms, the present invention provides compounds that are in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention using chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir along with a suitable chemical reagent or enzyme.
[0151] Some compounds of the present invention may exist in solvated and unsolvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are within the scope of the present invention. Some compounds of the present invention can exist in multiple amorphous or crystalline forms. Generally speaking, all physical forms are equivalent for the uses contemplated by the present invention and are within the scope of the present invention.
[0152] The invention further provides a pharmaceutical composition, which comprises an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In one embodiment, the compound is administered to the individual using a pharmaceutically acceptable formulation, for example, a pharmaceutically acceptable formulation that provides for sustained delivery of the compound to an individual for at least 12 hours, 24 hours, 36 hours, 48 hours, one week , two weeks, three weeks, or four weeks after the pharmaceutically acceptable formulation is administered to the subject.
[0153] Effective dosage levels and time of administration of the active ingredients in the pharmaceutical compositions of this invention may vary in order to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a specific patient, composition and mode of administration , without exhibiting toxicity (or unacceptable toxicity) to the patient.
[0154] In use, at least one compound according to the present invention is administered in pharmaceutically effective amount to a subject in need thereof in a pharmaceutical carrier with intravenous, intramuscular, subcutaneous, or intracerebroventricular injection or oral administration or topical application. In accordance with the present invention, a compound of the invention may be administered alone or together with a second, distinct therapeutic agent. By "along with" is meant substantially simultaneous or sequentially. In one embodiment, a compound of the invention is administered acutely. The compound of the invention, therefore, can be administered for a short period of treatment, for example, for about 1 day to about 1 week. In another embodiment, the compound of the invention may be administered for a longer period to alleviate chronic disorders, for example, from approximately one week to several months, depending on the condition being treated.
[0155] By "pharmaceutically effective amount" as used herein is meant an amount of a compound of the invention, high enough to positively and significantly modify the condition being treated, yet low enough to avoid serious side effects (in a reasonable benefit/risk ratio) within the scope of the physician's judgment. There will be variations in the pharmaceutically effective amount of a compound of the invention according to the particular objective to be achieved, the age and physical condition of the patient being treated, severity of the underlying disease, duration of treatment, nature of the coincident therapy and the specific compound employee. For example, a therapeutically effective amount of a compound of the invention administered to a child or newborn will be scaled down at the discretion of the physician. The effective amount of a compound of the invention, then, will be the minimum amount that will provide the desired effect.
[0156] The undeniable practical advantage of the present invention is that the compound can be administered in a convenient manner, namely, by intravenous, intramuscular, subcutaneous, oral or intracerebroventricular injection routes or by topical application, such as, in cream or gel. Depending on the route of administration, active ingredients comprising a compound of the invention may require coating with a material that protects the compound from the action of enzymes, acids and other natural conditions that may inactivate the compound. To administer a compound of the invention by a route other than parenteral administration, the compound may be coated or administered together with a material to prevent inactivation.
[0157] The compound can be administered parenterally or intraperitoneally. Dispersions can also be prepared, for example, in glycerol, liquid polyethylene glycol, and mixtures thereof, and in oils.
[0158]Some examples of substances that can act as pharmaceutical carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethycellulose, ethylcellulose and cellulose acetates; powdered tragacanth; malt; gelatin; baby powder; stearic acids; magnesium stearate; calcium sulfate; vegetable oils such as peanut oils, cottonseed oil, sesame oil, olive oil, corn oil, cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acids; pyrogen-free water; isotonic saline solution; and phosphate buffer solution; skim powdered milk; as well as other non-toxic compatible substances used in pharmaceutical formulations, such as Vitamin C, estrogen and echinacea, for example. Wetting and lubricating agents, such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tabletting agents, stabilizers, antioxidants and preservatives, may also be present. Solubilizing agents, including, for example, cremaphore and beta-cyclodextrins are also used in these pharmaceutical compositions.
[0159] Pharmaceutical compositions comprising the active compounds of the presently disclosed object (or its prodrugs) can be manufactured by means of conventional mixing, dissolving, granulating, polishing processes for the manufacture of dragée, emulsification, encapsulation, trapping or lyophilization . The compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
[0160] The pharmaceutical compositions of the presently disclosed matter can be in a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, and so on. type, or a form suitable for administration by inhalation or insufflation.
[0161]For topical administration, the active compound(s) or prodrug(s) can be formulated as solutions, gels, ointments, creams, suspensions, and the like.
[0162] Systemic formulations include those intended for administration via injection, eg, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those intended for transdermal, transmucosal, oral, or pulmonary administration.
[0163] Advantageous injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles. The compositions may also contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Formulations for injection may be presented in unit dosage form (for example, in ampoules or in multi-dose containers) and may include preservatives.
[0164] Alternatively, the injectable formulation may be provided as a powder for reconstitution with a suitable vehicle, including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, and the like, before use. For this, the active compound(s) can be dried using any procedure known in the art, such as lyophilization, and reconstituted before use.
[0165]For transmucosal administration, penetrants suitable for the barrier to be permeated are used in the formulation. Penetrants are known in the art.
[0166] For oral administration, pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared using conventional means together with pharmaceutically acceptable excipients such as binding agents (for example, pregelatinized corn starch , polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (eg lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrators (for example potato starch or sodium starch glycolate); or wetting agents (eg, sodium lauryl sulfate). Tablets can be coated by methods well known in the art together with sugars or enteric coatings, for example.
[0167] Liquid preparations for oral administration may take the form, for example, of elixirs, solutions, syrups or suspensions, or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can be prepared using conventional media with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehicles (eg almond oil, oleyl esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffering, preservative, flavoring, coloring and sweetening agents as needed.
[0168]Preparations for oral administration can be formulated correctly to produce controlled release of the active compound or prodrug, as already determined.
[0169] For oral administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner.
[0170]For rectal and vaginal routes of administration, the active compound(s) may be formulated as solutions (for retention enemas), suppositories, or ointments containing conventional suppository bases such as butter cocoa or other glycerides.
[0171] For nasal administration or administration by inhalation or insufflation, the active compound(s) or prodrug(s) can be conveniently delivered in the form of an aerosol spray from pressurized packs or nebulizer with the use of the suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by a valve that would deliver the metered amount. Capsules and cartridges for use in an inhaler or insufflator (for example, capsules and cartridges formed from gelatin) may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[0172] A specific example of an aqueous suspension formulation suitable for nasal administration using commercially available nasal spray devices includes the following ingredients: active compound or prodrug (0.5-20 mg/ml); benzalkonium chloride (0.1-0.2 mg/ml); polysorbate 80 (TWEEN® 80; 0.5-5 mg/ml); carboxymethylcellulose sodium or microcrystalline cellulose (1-15 mg/ml); phenylethanol (1-4 mg/ml); and dextrose (20-50 mg/ml). The pH of the final suspension can be adjusted to range from approximately pH5 to pH7, with an approximate pH of 5.5 being typical.
[0173]For ocular administration, the active compound(s) or prodrug(s) may be formulated as a solution, emulsion, suspension, and the like, suitable for administration to the eye. A variety of vehicles suitable for administering the ocular compounds are known in the art. Specific non-limiting examples are described in U.S. Patent No. 6,261,547; United States Patent No. 6,197,934; United States Patent No. 6,056,950; United States Patent No. 5,800,807; United States Patent No. 5,776,445; United States Patent No. 5,698,219; United States Patent No. 5,521,222; United States Patent No. 5,403,841; United States Patent No. 5,077,033; United States Patent No. 4,882,150; and United States Patent No. 4,738,851, each of which is incorporated herein by this reference in its entirety.
[0174]For prolonged delivery, the active compound(s) or prodrug(s) may be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient may be formulated with suitable polymeric or hydrophobic materials (eg as an emulsion in an acceptable oil) or ion exchange resins, or as partially soluble derivatives, for example as a partially soluble salt. Alternatively, transdermal delivery systems manufactured as an adhesive or adhesive disc that slowly release the active compound(s) for percutaneous absorption can be used. For this purpose, permeation enhancers can be used to facilitate transdermal penetration of the active compound(s). Suitable transdermal patches are described, for example, in U.S. Patent No. 5,407,713; United States Patent No. 5,352,456; United States Patent No. 5,332,213; United States Patent No. 5,336,168; United States Patent No. 5,290,561; United States Patent No. 5,254,346; United States Patent No. 5,164,189; United States Patent No. 5,163,899; United States Patent No. 5,088,977; United States Patent No. 5,087,240; United States Patent No. 5,008,110; and United States Patent No. 4,921,475, each of which is incorporated herein by this reference in its entirety.
[0175]Alternatively, other pharmaceutical delivery systems can be employed. Liposomes and emulsions are well-established examples of delivery vehicles that can be used to deliver the active compound(s) or prodrug(s). Some organic solvents such as dimethylsulfoxide (DMSO) can also be used.
[0176] If desired, the pharmaceutical compositions may be presented in a package or dispensing device that would contain one or more unit dosage forms containing the active compound(s). The package, for example, can comprise a metallic or plastic sheet, such as a blister pack. The pack or dispensing device may contain instructions for administration.
[0177] The active compound(s) or prodrug(s) of the presently disclosed matter, or compositions thereof, will generally be used in an effective amount to achieve the intended result, for example, in an effective amount to treat or prevent the specific disease that is being treated. The compound(s) can be administered therapeutically to achieve therapeutic benefit or prophylactically to achieve prophylactic benefit. By therapeutic benefit is meant the eradication or amelioration of the underlying disorder being treated and/or the eradication or amelioration of one or more of the symptoms associated with the underlying disorder so that the patient reports an improvement in the sensation or condition, regardless of the patient may still feel affected by the underlying disorder. For example, administering a compound to a patient suffering from an allergy confers therapeutic benefit not only when the underlying allergic response is eradicated or alleviated, but also when the patient reports a reduction in the severity or duration of symptoms associated with the allergy after exposure. to the allergen. As a further example, therapeutic benefit in the context of asthma includes improving breathing after the onset of an asthma attack, or reducing the frequency or severity of asthmatic episodes. The therapeutic benefit also includes stopping or decreasing the progression of the disease, regardless of whether there has been improvement.
[0178]For prophylactic administration, the compound can be administered to a patient at risk of developing one of the diseases described above. A patient at risk for developing a disease may be a patient with characteristics that include him or her in a designated group of patients at risk, as defined by an appropriate medical team or physician. The patient at risk may also be a patient in a frequent or normal state which would give rise to the development of the underlying disease subject to treatment by the administration of a metalloenzyme inhibitor in accordance with the invention. In other words, the patient at risk is one who is usually or frequently exposed to conditions causing the disease or illness or may remain acutely exposed for a limited period of time. Alternatively, prophylactic administration can be applied to prevent the onset of symptoms in a patient diagnosed with the underlying disorder.
[0179] The amount of compound administered will depend on a number of factors, including, for example, the particular indication being treated, the mode of administration, whether prophylactic or therapeutic, the benefit desired, the severity of the indication being treated, and the age and patient weight, the bioavailability of the specific active compound, and other such factors. Determining an effective dosage is perfectly within the skills of individuals versed in the technique.
[0180]Effective dosages can be initially estimated with in vitro assays. For example, an initial dosage for use in animals can be formulated to achieve a circulating serum or blood concentration of the active compound that is at or above the IC50 of the particular compound as measured in the in vitro assay, e.g., the MFC or Fungus MIC in vitro and other in vitro assays described in the Examples section. The calculation of dosages to achieve these concentrations in the serum or blood in circulation taking into account the bioavailability of the particular compound is perfectly within the skills of knowledgeable professionals. For guidance, see Fingl & Woodbury, “General Principles,” In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pagamonon Press, and references cited in this literature, which are hereby incorporated by this citation.
[0181] Initial dosages can also be estimated from in vivo data, for example, from animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described above are well known in the art.
[0182] The dosage amount will typically be in the range of about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, which may be higher or lower, depending, among others. factors, the activity of the compound, its bioavailability, the mode of administration, and the various factors already discussed. The dosage amount and interval can be adjusted individually to provide plasma levels of the compound(s) that are sufficient to maintain the therapeutic or prophylactic effect. In cases of local administration or selective absorption, such as local topical administration, the effective local concentration of active compound(s) cannot be related to the plasma concentration. Knowledgeable professionals will be able to improve effective local dosages without undue experimentation.
[0183] The compound(s) can be administered once a day, a few or several times a day, or even multiple times a day, depending, among other things, on the indication that is treated and the judgment of the physician .
[0184] Preferably, the compound(s) will provide therapeutic or prophylactic benefit without causing substantial toxicity. Toxicity of the compound(s) can be determined using conventional pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effect is the therapeutic index. Compound(s) with high therapeutic indices are preferred. a.The recitation of a list of chemical groups in any definition of a variable includes definitions of that variable as any single group or combination of the groups listed. The recitation of a modality to a variable includes that modality as any single modality or in combination with any other modality or parts thereof. The recitation of a modality includes that modality as any single modality or in combination with any other modalities or parts thereof. Applications in Agriculture
[0185] The compounds and compositions described can be used in methods of modulating the metalloenzyme activity in a microorganism in a plant, which comprise contacting a compound with the plant (for example, seed, seedling, grass, grass, grain ). The present compounds and compositions can be used to treat a plant, field or other agricultural area (eg as herbicides, pesticides, growth regulators, etc.) by administering the compound or composition (eg contacting, applying, spraying , atomize, sprinkle, etc.) to the plant, field or other relevant agricultural area. Administration can be pre- or post-emergence. Administration can consist of treatment or prevention.
[0186] An aspect is a method of treating or preventing a disease or disorder of a fungal nature in or in a plant which comprises contacting a compound of any of the present formulas with the plant. Another aspect is a method of treating or preventing fungal growth in or on a plant which comprises contacting a compound of any of the present formulas with the plant. Another aspect is a method of inhibiting microorganisms in or on a plant which comprises contacting a compound of any of the present formulas with the plant.
[0187] Compositions comprising these compounds can be used, for example, in the form of directly sprayable aqueous solutions, powders, suspensions, suspensions or aqueous, oily or other highly concentrated dispersions, emulsions, oily dispersions, pastes, dusts, materials for spreading or granules, by spraying, atomizing, dusting, spreading or pouring.
[0188] Aqueous use forms can be prepared from emulsion concentrates, suspensions, pastes, wettable powders or water dispersible granules by the addition of water. For the preparation of emulsions, pastes or oily dispersions, the substances, in the state or dissolved in oil or solvent, can be homogenized in water with a wetting agent, tackifier, dispersant or emulsifier. However, it is also possible to prepare concentrates consisting of active substance, wetting agent, tackifier, dispersant or emulsifier and, if appropriate, solvent or oil, and these concentrates are suitable for dilution with water.
[0189] Granules, eg coated granules, impregnated granules and homogeneous granules, can be prepared by binding the active ingredients (eg the compounds described) to solid carriers. Solid carriers are mineral earths such as silicas, silica gel, silicates, talc, kaolin, limestone, lime, chalk, bole clay, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate, magnesium oxide, material synthetic soil, fertilizers such as ammonium sulfate, ammonium phosphate, ammonium nitrate, ureas and plant products, namely, cereal bran, tree bark bran, wood bran and bark bran, powders of cellulose or other solid carriers.
[0190] The compounds described herein can be formulated as tablets, capsules, solids, liquids, emulsions, slurries, oils, granules or common fine powders, which are suitable for administration to plants, fields or other agricultural areas. In preferred embodiments, the preparation includes between 1 and 95% (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 25%, 75%, 80%, 90%, 95% ) of the compost in a carrier or thinner. The compositions provided herein include the compounds of the formulas shown, as well as additional agricultural agents if present, in amounts effective to control (e.g., modulate, inhibit) a metalloenzyme-mediated disorder or disease.
[0191] In one approach, the compound is provided in an encapsulated formulation (liquid or powder). Specific materials suitable for use in the capsule materials include, among others, porous substrates or particulates such as silica, perlite, talc, clay, pyrophyllite, diatomaceous earth, gelatin and gel, polymers (e.g., polyurea, polyurethane, polyamide, polyester, etc.), polymeric particles, or cellulose. These include, for example, hollow fibers, hollow tubes or tubes that release a compound specified herein through the walls, capillary tubes that release the compound through an opening in the tubes, polymeric blocks of different shapes, eg strips, blocks, tablets , disks, which release the compound through the polymer matrix, membrane systems that contain the compound in an impermeable container and release it through a measured permeable membrane, and combinations of the foregoing. Examples of such dispensing compositions are polymer laminates, polyvinyl chloride pellets, and microcapillaries.
[0192]Encapsulation processes are typically classified as chemical or mechanical. Examples of chemical processes for encapsulation include, but are not limited to, complex coacervation, polymer-polymer incompatibility, interfacial polymerization in a liquid medium, in situ polymerization, drying in liquid, thermal and ionic gelling in a liquid medium, desolvation in a liquid medium, chemical processes based on starch, entrapment in cyclodextrins, and liposome formation. Examples of mechanical processes for encapsulation include, but are not limited to, spray drying, spray freezing, fluidized bed, electrostatic deposition, centrifugal extrusion, rotating suspension or rotating disk separation, annular jet encapsulation, polymerization at the liquid-gas or solid interface -gas, solvent evaporation, pressure extrusion or bath spraying in solvent spray.
[0193]Microcapsules are also convenient for prolonged release of the active compound. Microcapsules are small particles that contain a nuclear material or active ingredient surrounded by a coating or shell. Microcapsule size typically ranges from 1 to 1000 microns with capsules smaller than 1 micron classified as nanocapsules and capsules larger than 1000 microns as macrocapsules. Core loading typically ranges from 0.1 to 98 weight percent. Microcapsules can exhibit diverse structures (continuous, multinuclear, or monolithic core/shell) and take on irregular or geometric shapes.
[0194]In another approach, the compound is supplied in an oil-based delivery system. Oil release substrates include vegetable and/or mineral oils. In one embodiment, the substrate further contains a surface active agent that makes the composition readily dispersible in water; such agents include wetting agents, emulsifying agents, dispersing agents, and the like.
[0195] The compounds of the invention can also be provided as emulsions. Emulsion formulations can be found as water in oil (w/o) or oil in water (o/w). Droplet size can range from the nanometer scale (colloidal dispersion) to several hundred microns. A variety of surfactants and thickeners are normally incorporated into the formulation to modify droplet size, stabilize the emulsion, and modify release.
[0196] Alternatively, the compounds of the invention may also be formulated into a solid tablet and comprise (and preferably consist essentially of) an oil, a protein/carbohydrate material (preferably of vegetable origin), a sweetener and a useful active ingredient in the prevention or treatment of a metalloenzyme-mediated agricultural disorder or disease. In one embodiment, the invention provides a solid tablet and comprises (and preferably consists essentially of) an oil, a protein/carbohydrate material (preferably of vegetable origin), a sweetener and an active ingredient (eg, the compound described herein or combinations or derivatives thereof) useful in preventing or treating a metalloenzyme mediated agricultural disorder or disease. Tablets typically contain about 4-40% (eg 5%, 10%, 20%, 30%, 40%) by weight of an oil (eg vegetable oil such as corn, sunflower, peanut, olive oils, grape seed, tung, turnip, soybean, cottonseed, walnut, palm, castor, sedge, hazelnut, avocado, sesame, Croton tiglium, cocoa, flaxseed, rapeseed, and canola and their hydrogenated derivatives; (eg paraffins and petroleum jelly), and other water immiscible hydrocarbons (eg paraffins) The tablets additionally contain about 5-40% (eg 5%, 10%, 20%, 30% , 40%) by weight of a protein/carbohydrate material of vegetable origin. The material contains a carbohydrate fraction (eg cereal grain derivatives such as wheat, rye, barley, oats, corn, rice, millet , sorghum, canary seed, buckwheat, alfalfa, myelga, corn bran, soybean bran, grain flour, wheat semolina, wheat bran, millet gluten bran ho, seaweed bran, dry yeast, beans, rice) and a protein fraction.
[0197] Optionally, various excipients and binders can be used to assist in the delivery of the active ingredient or to provide the proper structure to the tablet. Preferred excipients and binders include anhydrous lactose, microcrystalline cellulose, corn starch, magnesium stearate, calcium stearate, zinc stearate, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and mixtures thereof.
[0198] The invention provides kits for the treatment or prevention of disease or plant disorders or in the agricultural sector. In one embodiment, the kit includes a composition containing an effective amount of the described compound in a form suitable for delivery to the plant. In some embodiments, the kit comprises a container that contains a compound of any of the present formulas (for example, formula I or formula II); such containers may be boxes, ampoules, bottles, jars, tubes, pouches, sachets, carton packs, or other suitable forms of container known in the art. Such containers can be made of plastic, glass, laminated paper, foil, or other materials suitable for containing compounds.
[0199] If desired, the compound(s) of the invention are provided along with instructions for their administration to a plant, field, or other agricultural area. Instructions in general will include information on the use of the composition for the treatment or prevention of a metalloenzyme-mediated agricultural disorder or disease. In other embodiments, instructions include at least one of the following: description of the compound; dosing and administration schedule for treating or preventing a metalloenzyme-mediated agricultural disorder or disease; precautions; warnings; description of research studies; and/or references. Instructions may be printed directly on the container (where present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder provided on or with the container. Examples
[0200] The present invention will then be demonstrated using specific examples that should not be interpreted as limiting.
[0201] General Description of Experimental Procedures i. The definitions of variables in the structures in the indicated schemes are compatible with those of the corresponding positions in the formulas presented here. Synthesis of Azoles
(I)
[0202]The syntheses of alkyne targets (I) can be performed using the exemplary synthesis below (Scheme 1). A wide range of arenes and heterocyclics (R11 = aryl or heteroaryl) can be prepared starting with aryl bromides starting materials (eg 1). For the purposes of this example, R4 is a halogenated benzene moiety. An example synthesis of targets (I) starts with the condensation of 2,5-dibromo-pyridine with copper activated α-bromo ethyl acetate followed by the condensation of the incipient ethyl ester product with lithium treated bromodifluorobenzene to produce ketone B (Scheme 1). The ketone is epoxidized with diazomethane to provide C. The product 1-tetrazol D (and the 2-tetrazol isomer) is obtained by opening the epoxide C with tetrazole in the presence of potassium carbonate. The resulting pyridyl bromide D is treated with phenylacetylenes to produce the coupled products (eg 1). Scheme 1

[0203] In embodiments, the invention provides the intermediate compounds of the formulas given herein and methods of converting such compounds to compounds of the present formulas (for example, in Scheme 1, A in B; B in D; C in 1; or D in 1) which comprises reacting a compound with one or more reactants in one or more chemical transformations (including those provided herein) to produce the compound of any of the present formulas or an intermediate compound.
[0204] The synthetic methods described herein may further include steps, before or after any of the steps described in any scheme, to add or remove suitable protecting groups to ultimately enable the synthesis of the compound of formulas described herein. The methods presented herein contemplate converting compounds of one formula to compounds of another formula (for example, in Scheme 1, A in B; B in D; C in 1; or D in 1). The conversion process refers to one or more chemical transformations, which can be carried out in situ, or with the isolation of intermediate compounds. Transformations may include reacting starting compounds or intermediates with additional reagents using techniques and protocols known in the art, including those cited in references herein. Intermediates can be used with or without purification (eg, filtration, distillation, sublimation, crystallization, trituration, solid phase extraction, and chromatography). EXAMPLE 1 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(phenylethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2-ol ( 1)
[0205] To a suspension of copper powder (2.68 g, 42.2 mmol) in DMSO (35 mL) was added ethyl bromodifluoro acetate (2.70 mL, 21.10 mmol), and the mixture was stirred for 1 h at room temperature. 2,5-Dibromopyridine (2.50 g, 10.55 mmol) was then added and continued to stir for 15 h at room temperature. The reaction was quenched with aqueous NH4Cl and extracted with DCM (3 x 25 mL). The combined organic layers were washed with water, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to provide the crude product mixture, and column purification using EtOAc/hexane provided the intermediate ethyl ester (2, 40 g, 8.57 mmol, 81%) as pale yellow oil, 1H NMR (500 MHz, CDCl3): δ 8.71 (s, 1H), 8.00 (d, J = 9.0 Hz, 1 H), 7.64 (d, J = 9.0Hz, 1H), 4.42-4.35 (m, 2H), 1.39-1.31 (m, 3H).
[0206] To a stirred solution of 2,4-difluoro-bromobenzene (1.65 g, 8.57 mmol) in diethyl ether (10 mL) was added n-BuLi (3.70 mL, 8.57 mmol) at -70 °C followed by addition of ester (2.40 g, 8.57 mmol) in diethyl ether (5 mL) after 15 minutes. The reaction mixture was stirred for 1 hour at -70°C and warmed to room temperature at which point it was stirred for a further 2 hours. The reaction was cooled with aqueous NH4Cl solution and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography to provide ketone B (1.30 g, 3.73 mmol, 43%) as a yellow liquid. 1H NMR (500 MHz, CDCl3): δ 8.62 (s, 1H), 8.08-8.04 (m, 2H), 7.74-7.70 (m, 1H), 7. 05-6.95 (m, 1H), 6.88-6.78 (m, 1H), MS (ESI): 347, 349 [(M++1)+2].
[0207] To a stirred solution of ketone B (1.30 g, 3.73 mmol) in diethyl ether (300 mL) was added freshly prepared diazomethane at 0°C followed by warming to room temperature. The reaction mixture was stirred for 2 h. Volatile substances were removed under reduced pressure to give a mixture of the crude product which, with column chromatography using EtOAc/hexane as eluent, provided oxirane C (800 mg, 2.20 mmol, 59%) as a pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 7.89 (d, J = 9.0Hz, 1H), 7.39-7.35 (m, 2H) , 6.86-6.83 (m, 1H), 6.77-6.74 (m, 1H), 3.44 (s, 1H), 2.98 (s, 1H). MS (ESI): 362, 364 [(M++1)+2].
[0208] To a stirred solution of epoxide C (5 g, 13.8 mmol) in DMF (15 mL) was added K2CO3 (1.9 g, 13.87 mmol) followed by 1H-tetrazol (1.55 g , 20.72 mmol) at room temperature. The resulting reaction mixture was heated to 70 °C and mixed for 16 h. The evolution of the reaction was monitored by TLC. The reaction was cooled with cold water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with water (30 mL), brine (30 mL) and dried over anhydrous Na 2 SO 4 to obtain a crude product which was purified by silica gel column chromatography eluting with 40% EtOAc/hexane to provide the product D 1-Tetrazol (2.7 g, 6.24 mmol, 45.3%) as white solid. 1H NMR (500 MHz, CDCl3): 8.73 (s, 1H), 8.62 (s, 1H), 7.95 (dd, J = 2.0 Hz, 8.0 Hz, 1H), 7. 46 (d, J = 8.5Hz, 1H), 7.31-7.28 (m, 1H), 6.86 (s, 1H), 6.77-6.73 (m, 1H), 6 .70-6.66 (m, 1H), 5.60 (d, J = 14.5 Hz, 1H), 5.11 (d, J = 14.5 Hz, 1H).
[0209] Mass: m/z 433.3 [M++2]
[0210] To a stirred solution of compound D (100 mg, 0.23 mmol) in DMF (2 mL) was added phenyl acetylene (35 mg, 0.34 mmol) followed by TPP (6 mg, 0.023 mmol), Pd( PPh3)2Cl2 (16 mg, 0.023 mmol), CuI (4 mg, 0.023 mmol) and Et3N (5 mL) at room temperature and purged with argon for a period of 30 min, keeping the mixture for 16 h at room temperature . The reaction mixture was cooled to room temperature, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was washed with water (15 ml), brine (15 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to provide the crude product. The crude product was purified by column chromatography on silica gel eluting with EtOAc/hexane gradients to provide 1 (30mg, 0.06mmol, 28%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.65 (s, 1H), 7.88 (dd, J =2.0Hz, 8.5Hz, 1H), 7 .55-7.53 (m, 3H), 7.41-7.37 (m, 3H), 7.31-7.26 (m, 2H), 6.766.75 (m, 1H), 6.66 -6.64 (m, 1H), 5.61 (d, J = 14.0 Hz, 1H), 5.12 (d, J = 14.0 Hz, 1H). HPLC: 96.4%. MS (ESI): m/z 453 [M++1].
1-(5-((4-Chlorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane-2 -ol (2)
[0211] To a stirred solution of compound D (100 mg, 0.231 mmol) in THF (5 mL) was added 4-chloro phenyl acetylene (47 mg, 0.345 mmol) followed by Pd(PPh3)2Cl2 (16 mg, 0.023 mmol), CuI (4.4 mg, 0.023 mmol) and diisopropyl ethylamine (0.08 mL, 0.462 mmol) at room temperature under an argon atmosphere. The resulting reaction mixture was mixed for 16 h at reflux temperature under an argon atmosphere. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was cooled to room temperature, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water (15 ml) and extracted with ethyl acetate (4 x 30 ml). The combined organic layer was washed with water (10 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to provide the crude product. The crude product was purified by prep. (mobile phase: CH3CN: 0.1% TFA in H2O, gradient; flow rate: 15.0 mL/min) to provide 2 (14 mg, 0.028 mmol, 12.5%) as pale yellow solid form. 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.64 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 9.0 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.33-7.28 ( m, 1H), 6.78-6.74 (m, 1H), 6.68-6.65 (m, 1H), 5.60 (d, J = 14.5 Hz, 1H), 5.13 (d, J = 14.5 Hz, 1H). HPLC: 99.5%. MS (ESI): m/z 488 [M++1]. EXAMPLE 3
2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (3)
[0212] To a stirred solution of compound D (250 mg, 0.578 mmol) in DMF (5 mL) was added 4-fluoro phenyl acetylene (104 mg, 0.868 mmol) followed by TPP (15 mg, 0.0578 mmol) , CuI (11 mg, 0.0578 mmol) and Et3N (16 mL) at room temperature and purged with argon for a period of 20 min. To the resulting reaction mixture was added Pd(PPh3)2Cl2 (40 mg, 0.0578 mmol), again purged with argon for 20 min and stirred at room temperature. After 16 h, only 0.87% conversion was observed by LC-MS; the reaction mixture was then slowly heated to 60 °C and mixed for 6 h. After 6 h, the reaction mixture was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water (50 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic layer was washed with water (2 x 15 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to provide the crude product. The crude product was purified by silica gel column chromatography eluting with 35% EtOAc/hexane to provide 3 (25 mg, 0.053 mmol, 9.2%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.63 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.55-7, 51 (m, 2H), 7.33-7.27 (m, 2H), 7.09 (t, J = 8.0 Hz, 2H), 6.78-6.74 (m, 1H), 6 .68-6.65 (m, 1H), 5.61 (d, J = 14.5 Hz, 1H), 5.13 (d, J = 14.5 Hz, 1H). HPLC: 92.97%. MS (ESI): m/z 472.4 [M++1]. EXAMPLE 4
2-(2,4-Difluorophenyl)-1-(5-((2,4-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (4)
[0213] To a stirred solution of compound D (100 mg, 0.232 mmol) in DMF (3 mL) was added 2,4-difluoro phenyl acetylene (47.9 mg, 0.347 mmol) followed by TPP (6 mg, 0.023 mmol), CuI (4.39 mg, 0.023 mmol) at room temperature and purged with argon for a period of 20 min. To the resulting reaction mixture was added Pd(PPh3)2Cl2 (16.24 mg, 0.023 mmol), again purged with argon for 15 min and mixed for 16 h at room temperature. The reaction mixture was cooled to room temperature, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water (20 ml) and extracted with ethyl acetate (4 x 20 ml). The combined organic layer was washed with water (2 x 10 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to provide the crude product. The crude product was purified by prep HPLC (mobile phase: (A) CH3CN (B) 0.1% TFA in H2O, isocratic: A:B =70:30; flow rate: 15.0 mL/min) to provide 4 (18 mg, 0.036 mmol, 15.9%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.66 (s, 1H), 7.91 (dd, J = 1.5 Hz, 8.0 Hz, 1H), 7 .56 (d, J = 8.0 Hz, 1H), 7.53-7.49 (m, 1H), 7.32-7.27 (m, 1H), 6.94-6.88 (m , 2H), 6.78-6.74 (m, 1H), 6.69-6.65 (m, 1H), 5.61 (d, J = 14.0 Hz, 1H), 5.13 ( d, J = 14.0 Hz, 1H). HPLC: 99.7%. MS (ESI): m/z 490 [M++1]. EXAMPLE 5
2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethyl)phenyl)ethynyl)pyridin-2-yl) propane-2-ol (5)
[0214] To a stirred solution of compound D (300 mg, 0.69 mmol) in DMF (5 mL) was added 4-(trifluoromethyl)phenyl acetylene (177 mg, 1.0 mmol) followed by TPP (18 mg) , 0.069 mmol), CuI (13 mg, 0.069 mmol), Pd(PPh3)2Cl2 (48 mg, 0.069 mmol) and Et3N (10 mL) at room temperature and purged with argon for a period of 30 min. The resulting reaction mixture was mixed for 16 h at room temperature. The reaction mixture was cooled to room temperature, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water (50 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic layer was washed with water (2 x 20 mL), brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to provide the crude product. The crude product was purified by prep HPLC (mobile phase: CH3CN: 0.1% TFA rm H2O, gradient; flow rate: 15.0 mL/min) to provide 5 (18 mg, 0.034 mmol, 5%) in the form pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.66 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.65 (s, 3H), 7.53 (d, J = 8.5Hz, 1H), 7.34-7.29 (m, 1H), 6.78-6.74 (m, 1H), 6.69-6 .66 (m, 1H), 5.61 (d, J = 14.5 Hz, 1H), 5.15 (d, J = 14.5 Hz, 1H). HPLC: 99.3%. MS (ESI): m/z 522.3 [M++1]. Scheme 2
Preparation of intermediate G Tributyltin
[0215] To a stirred solution of compound C (20.0 g, 55.24 mmol) in THF (300 mL) was added TMS-acetylene (10.3 mL, 82.87 mmol) followed by CuI (525 mg , 2.76 mmol), Pd(PPh3)2Cl2 (1.93 g, 2.76 mmol) and Et3N (20 mL) at room temperature under inert atmosphere and mixed for 16 h; the evolution of the reaction was monitored by TLC. The reaction mixture was filtered through a pad of celite and washed with EtOAc (3 x 100 mL). The filtrate was washed with water (150 ml), brine (150 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 7% EtOAc/hexanes) to provide compound E (18.0 g, 47.5 mmol, 85%) as pale yellow solid form. 1H NMR (400 MHz, CDCl3): δ 8.69 (s, 1H), 7.78 (d, J = 10.0 Hz, 1H), 7.76 (d, J = 10.0 Hz, 1H) , 7.37-7.31 (m, 1H), 6.85-6.80 (m, 1H), 6.76-6.71 (m, 1H), 3.45 (d, J = 5. 0 Hz, 1H), 2.96 (d, J = 5.0 Hz, 1H), 0.26 (s, 9H).
[0216] To a stirred solution of E (18.0 g, 47.5 mmol) in THF (200 mL) was added TBAF (52.2 mL, 52.25 mmol; 1M solution in THF) at 0°C under inert atmosphere and mixed for 1 h; the evolution of the reaction was monitored by TLC. Volatile substances were then evaporated under reduced pressure; the residue obtained was diluted with EtOAc (500 ml), washed with water (250 ml), brine (250 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 8-10% EtOAc/hexanes) to provide compound F (9.0 g, 29.31 mmol, 61.7%) as pale yellow solid form. 1H NMR (400 MHz, CDCl3): δ 8.73 (d, J = 1.5 Hz, 1H), 7.82 (dd, J = 8.0, 1.5 Hz, 1H), 7.44 ( d, J = 8.0Hz, 1H), 7.38-7.34 (m, 1H), 6.85-6.81 (m, 1H), 6.76-6.72 (m, 1H) , 3.44 (d, J = 5.0 Hz, 1H), 3.31 (s, 1H), 2.97 (d, J = 5.0 Hz, 1H).
[0217] To a stirred solution of compound F (9.0 g, 29.31 mmol) in Et2O (200 mL) was added n-BuLi (22.0 mL, 35.18 mmol; 1.6M in hexane) at -78°C under an inert atmosphere. After stirring at -78°C for 30 min, n-Bu3SnCl (11.9 mL, 43.97 mmol) was added. The reaction mixture reached room temperature and was stirred for 16 h. The evolution of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NH 4 Cl solution, extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with water (150 ml), brine (150 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude product-G (20.0 g). The crude product was used for the next reaction without further purification. Scheme 3
EXAMPLE 6 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl) -N-(4-fluorobenzyl)thiophene-2-carboxamide (6)
[0218] To a stirred solution of acid-H (1.50 g, 7.24 mmol) in DMF (20 mL) was added 4-fluoro benzyl amine (1.35 g, 10.84 mmol) followed by HOBt (1.08 g, 7.95 mmol) and DIPEA (3 mL, 18.07 mmol) under inert atmosphere at room temperature and mixed for 5 min. Then, EDCI (1.52 g, 7.96 mmol) was added to the reaction mixture and mixing continued for 16 h; the evolution of the reaction was monitored by TLC. The reaction mixture was then diluted with EtOAc (100 mL) and washed with 0.1N HCl (100 mL). The separated organic layer was washed with saturated NaHCO 3 solution (100 ml), brine (100 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc/hexane) to give amide-I (1.5 g, 4.77 mmol, 66%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.31-7.28 (m, 2H), 7.23 (d, J = 4.0 Hz, 1H), 7.05-6.99 (m, 3H) ), 6.21 (bs, 1H), 4.55 (d, J = 5.6 Hz, 2H).
[0219] To a stirred solution of compound G (4.0 g, crude) in 1,4-dioxane (20 mL) was added compound I (600 mg, 1.91 mmol) followed by purging with argon for 20 min. Pd(PPh3)4 (434 mg, 0.37 mmol) was then added to the mixture at room temperature and purged with argon for a further 20 min. The reaction mixture was gradually heated to 80 °C and mixed for 3 h; the evolution of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and volatile substances were evaporated under reduced pressure to provide compound J (1.0 g, crude). The crude compound was used for the next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 7.85 (dd, J = 8.0, 2.0 Hz, 1H), 7.47 (d, J = 8.0 , Hz, 1H), 7.40-7.31 (m, 4H), 7.27 (d, J = 4.0 Hz, 1H), 7.06-7.02 (m, 2H), 6. 86-6.81 (m, 1H), 6.77-6.71 (m, 1H), 6.25 (t, J = 5.6 Hz, 1H), 4.59 (d, J = 5. 6 Hz, 2H), 3.47 (d, J = 5.0 Hz, 1H), 2.98 (d, J = 5.0 Hz, 1H). LC-MS (ESI): m/z 540.0 [M]+ at 4.28 RT (86% purity).
[0220] To a stirred solution of epoxide J (1.0 g, crude) in dry DMF (10 mL) was added 1H-tetrazol (194 mg, 2.77 mmol) followed by K2CO3 (255 mg, 1.85 mmol) at room temperature under an inert atmosphere. The resulting reaction mixture was heated gradually to 65 °C and mixed for 16 h; the evolution of the reaction was monitored by TLC. The reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluted with 45-50% EtOAc/hexanes) to provide 6 (500 mg, 0.82 mmol) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 8.64 (s, 1H), 7.89 (dd, J = 8.4, 2.0 Hz, 1H), 7 .56 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 4.0 Hz, 1H), 7.35-7.27 (m, 4H), 7.14 (bs, OH), 7.05 (t, J = 8.4 Hz, 2H), 6.79-6.73 (m, 1H), 6.69-6.64 (m, 1H), 6.22 (t , J = 5.6 Hz, 1H), 5.59 (d, J = 14.0 Hz, 1H), 5.14 (d, J = 14.0 Hz, 1H), 4.60 (d, J =5.6Hz, 2H). Chiral preparative HPLC method for the separation of 6-enantiomers:
[0221]Racemate-6 (303 mg, 0.49 mmol) was separated by preparative high-performance liquid chromatography (QUIRALPAK IA, 250 x 20 mm, 5μ; using (A) n-Hexane, (B) EtOH (A :B, 75:25) as mobile phase; Flow rate: 15 mL/min) to obtain 6-(+) (100 mg) as an off-white solid. Analytical data for 6-(+):
[0222] Chiral HPLC purity: 98.5% ee Rt = 20.22 min (QUIRALPAK IA, 250 x 4.6mm, 5μ; mobile phase (A) n-Hexane, (B) EtOH (A:B :: 75:25); flow rate: 1.00 mL/min). Optical rotation [α]D20: + 19.76° (c = 0.1% in MeOH). 1H-NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 8.64 (s, 1H), 7.89 (dd, J = 8.4, 2.0 Hz, 1H), 7 .56 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 4.0 Hz, 1H), 7.35-7.27 (m, 4H), 7.14 (bs, OH), 7.05 (t, J = 8.4 Hz, 2H), 6.79-6.73 (m, 1H), 6.69-6.64 (m, 1H), 6.22 (t , J = 5.6 Hz, 1H), 5.59 (d, J = 14.0 Hz, 1H), 5.14 (d, J = 14.0 Hz, 1H), 4.60 (d, J =5.6Hz, 2H). Mass: m/z 611 [M+H]+. HPLC: 98.5%. Scheme 4
EXAMPLE 7 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridine-3- il) ethynyl) phenoxy) methyl)-2-fluorobenzonitrile (7)
[0223] To a stirred solution of 4-bromophenol (K) (1.0 g, 5.78 mmol) in DMF (10 mL) was added K2CO3 (1.6 g, 11.56 mmol) followed by bromide. 4-cyano-3-fluorobenzyl (1.36 g, 6.36 mmol) at room temperature under inert atmosphere. The resulting reaction mixture was heated gradually to 70 °C and mixed for 3 h; the evolution of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (2 x 50 ml), brine (100 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel column chromatography (eluent: 15% EtOAc/Hexanes) to give L (1.2 g, 3.93 mmol, 68%) as brown solid. 1H NMR (400 MHz, CDCl3): δ 7.66-7.62 (m, 1H), 7.41 (d, J = 6.8 Hz, 2H), 7.32-7.29 (m, 2H) ), 6.82 (d, J = 6.8 Hz, 2H), 5.09 (s, 2H). LC-MS: m/z 304.7 [M-H]-at 4.80 RT (75.9%) purity.
[0224] To a stirred solution of compound G (3.0 g, crude) in 1,4-dioxane (15 mL) was added L (1.2 g, 3.93 mmol) and purged with inert gas for 15 min. To the resulting reaction mixture was added Pd(PPh3)4 (291 mg, 0.25 mmol) and was purged for an additional 10 min. The reaction mixture was then heated gradually to 90 °C and stirred for 3 h; the evolution of the reaction was monitored by TLC. The reaction mixture was then cooled to room temperature; volatile substances were evaporated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 18% EtOAc/hexanes) to give M (0.7 g, crude) as yellow solid form.1H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 8.4, 1.6 Hz, 1H), 7.53 (d, J = 6.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.41-7.33 (m, 3H), 6.97 (d, J = 6.8 Hz, 2H), 6.88-6.83 (m, 1H), 6.77-6.71 (m, 1H), 5.17 (s, 2H), 3.48 (d, J = 5.2 Hz , 1H), 3.00 (d, J = 5.2 Hz, 1H). LCMS: m/z 533.9 [M+H]+ at 5.29 RT (89.0%) purity.
[0225] To a stirred solution of M (0.7 g, crude) in DMF (7 mL) was added 1H-tetrazol (138 mg, 1.97 mmol) followed by K 2 CO 3 (181 mg, 1.31 mmol) at room temperature under an inert atmosphere. The resulting reaction mixture was gradually heated to 65 °C and mixed for 7 h; the evolution of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature; diluted with cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 50 ml), brine (50 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel column chromatography (eluent: 40% EtOAc/hexanes) to give 7 (350 mg, 0.58 mmol) as yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.62 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.34-7.32 ( m, 4H), 6.95 (d, J = 9.0 Hz, 2H), 6.77-6.75 (m, 1H), 6.67-6.65 (m, 1H), 5.59 (d, J = 14.0 Hz, 1H), 5.15 (s, 2H), 5.12 (d, J = 14.0 Hz, 1H). Chiral preparative HPLC method for separation of 7 enantiomers:
[0226] The enantiomers of 7 (35 mg) were separated by normal phase preparative high-performance liquid chromatography (QUIRALPAK IC, 250 x 20 mm, 5μ; using (A) 0.1% TEA in n-hexane, (B ) Ethanol (A:B :: 70:30) as mobile phase; Flow rate: 15 mL/min) to obtain 7-(+) (15 mg) in off-white solid form. Analytical data for 7-(+): Chiral HPLC: 100% ee Rt = 27.72 min (Chiralpak IC, 250 x 4.6mm, 5μ; mobile phase (A) 0.1% TEA in n-Hexane, (B ) Ethanol (A: B :: 70:30); flow rate: 1.00 mL/min) Optical rotation [α]D20: + 29.80° (c = 0.1% in MeOH). 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.62 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.347.32 (m, 4H) , 6.95 (d, J = 9.0 Hz, 2H), 6.77-6.75 (m, 1H), 6.67-6.65 (m, 1H), 5.59 (d, J = 14.0 Hz, 1H), 5.15 (s, 2H), 5.12 (d, J = 14.0 Hz, 1H). MS (ESI): 603 [M+H]+. HPLC: 99.0%. Scheme 5
EXAMPLE 8 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridine-3- yl)ethynyl)phenoxy)methyl)benzonitrile (8)
[0227] To a stirred solution of 4-bromophenol (K) (2.9 g, 14.45 mmol) in DMF (20 mL) was added K2CO3 (4.0 g, 28.90 mmol) followed by bromide 4 -benzylic cyano (3.4 g, 17.34 mmol) under inert atmosphere at room temperature. The mixture was gradually heated to 80 °C and mixed for 1 h; the evolution of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, quenched with cold water (100 mL), extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc/hexane) to provide compound N (2.9 g, 10.06 mmol, 71%) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 9.2 Hz, 2H), 6.83 (d, J = 9.2 Hz, 2H), 5.09 (s, 2H).
[0228] To a stirred solution of compound G (3.5 g, crude) in 1,4-dioxane (20 mL) was added compound N (2.7 g, 9.39 mmol) and was purged with argon for 20 min. Pd(PPh3)4 (678 mg, 0.58 mmol) was added to the mixture at room temperature and purged with argon for a further 20 min. The reaction mixture was gradually heated to 80 °C and mixed for 3 h; the evolution of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and volatile substances were evaporated under reduced pressure to provide compound O (800 mg, crude). The crude product was used for the next reaction without further purification. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H) , 7.55 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7 .39-7.35 (m, 1H), 6.96 (d, J = 9.0 Hz, 2H), 6.85-6.82 (m, 1H), 6.76-6.72 (m , 1H), 5.16 (s, 2H), 3.47 (d, J = 5.0 Hz, 1H), 2.98 (d, J = 5.0 Hz, 1H). Mass (ESI): m/z 515 [M+H]+.
[0229] To a stirred solution of epoxide O (800 mg, crude) in dry DMF (10 mL) was added 1H-tetrazol (163 mg, 2.33 mmol) followed by K2CO3 (215 mg, 1.55 mmol) at room temperature under an inert atmosphere. The resulting reaction mixture was heated gradually to 65 °C and mixed for 16 h; the evolution of the reaction was monitored by TLC. The reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluted with 40-45% EtOAc/hexanes) to provide 8 (360 mg, 0.61 mmol, 39.5%) as yellow solid. 1H-NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.62 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.70 (d , J = 8.0 Hz, 2H), 7.69-7.51 (m, 3H), 7.47 (d, J = 7.5 Hz, 2H), 7.33-7.27 (m, 2H), 6.96 (d, J = 7.5Hz, 2H), 6.78-6.73 (m, 1H), 6.69-6.64 (m, 1H), 5.60 (d , J = 14.0 Hz, 1H), 5.16 (s, 2H), 5.12 (d, J = 14.0 Hz, 1H). Chiral preparative HPLC method for the separation of enantiomers 8 (preparation of 8 (+)):
[0230] The enantiomers of 8 (300 mg, 0.51 mmol) were separated by preparative high-performance liquid chromatography (QUIRALPAK IC®, 250 x 20 mm, 5μ; using (A) 0.1% DEA in n-Hexane , (B) EtOH (A:B :: 60:40) as mobile phase; Flow rate: 15 mL/min) to obtain 8-(+) (115 mg) in off-white solid form. Analytical data for 8-(+): 1H-NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.62 (s, 1H), 7.84 (d, J = 8.0 Hz , 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.69-7.51 (m, 3H), 7.47 (d, J = 7.5 Hz, 2H), 7 .33-7.27 (m, 2H), 6.96 (d, J = 7.5Hz, 2H), 6.78-6.73 (m, 1H), 6.69-6.64 (m , 1H), 5.60 (d, J = 14.0 Hz, 1H), 5.16 (s, 2H), 5.12 (d, J = 14.0 Hz, 1H). Chiral HPLC purity: 99.74% ee Rt = 18.11 min (QUIRALPAK IC®, 250 x 4.6mm, 5μ; mobile phase (A) 0.1% DEA in n-Hexane, (B) EtOH (A :B :: 60:40); flow rate: 1.00 mL/min). Optical rotation [α]D20: + 27.00° (c = 0.1% in MeOH). Mass: m/z 585 [M+H]+. HPLC: 98.7%. Scheme 6
EXAMPLE 9 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoro-1-) hydroxyethyl)phenyl)ethynyl)pyridin-2-yl)propane-2-ol (9)
[0231] To a stirred solution of 4-bromobenzaldehyde (P) (2.0 g, 10.81 mmol) in DME (20 mL) were added CF3TMS (1.4 mL, 16.2 mmol) and CsF (1 .64 g, 10.81 mmol) at 0°C under inert atmosphere. The resulting reaction mixture was mixed for 16 h at room temperature; the evolution of the reaction was monitored by TLC. The reaction mixture was then cooled with aq. 1N (8 ml) and the mixture was kept for another 1 h at room temperature. Volatile substances were evaporated under reduced pressure; the residue was diluted with water (100 ml) and extracted with DCM (2 x 100 ml). The combined organic layer was washed with water (100 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel column chromatography (eluent: 5-6% EtOAc/hexanes) to provide Q (0.65 g, 2.54 mmol, 23.5%) as yellow syrup. 1H NMR (500 MHz, CDCl3): δ 7.54 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.0 Hz, 2H), 5.01-4.98 ( m, 1H), 2.87 (bs, OH).
[0232] To a stirred solution of Q (0.45 g, 1.76 mmol) in Et3N (5 mL) was added TMS-acetylene (0.33 mL, 2.65 mmol), Pd(PPh3)2Cl2 ( 41 mg, 0.035 mmol) and CuI (11 mg, 0.053 mmol) at room temperature under inert atmosphere. The resulting reaction mixture was gradually heated to 75 °C and mixed for 16 h; the evolution of the reaction was monitored by TLC. The reaction mixture was then cooled to room temperature, diluted with water (50 mL) and extracted with Et2O (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc/hexane) to give R (0.4 g, 1.47 mmol, 83%) as a brown syrup. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 5.04-5.01 ( m, 1H), 2.68 (bs, OH), 0.26 (s, 9H).
[0233] To a stirred solution of compound R (0.4 g, 1.47 mmol) in THF (3 mL) was added TBAF (1.5 mL, 1.47 mmol, 1M in THF) dropwise. 0°C and blended for 1 h; the evolution of the reaction was monitored by TLC. Volatile substances were evaporated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc/Hexane) to provide S (0.25 g, 1.25 mmol, 85%) as a brown syrup. 1H NMR (500 MHz, CDCl3): δ 7.53 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 5.04-5.02 ( m, 1H), 3.11 (s, 1H), 2.62 (bs, OH).
[0234] To a stirred solution of S (0.1 g, 0.5 mmol) in Et2O (6 mL) was added n-BuLi (0.7 mL, 1.1 mmol; 1.6 M in hexane) at -78°C under an inert atmosphere. After being mixed for 45 min, n-Bu3SnCl (0.27 mL, 1.0 mmol) was added dropwise and mixed for a further 10 min at -78 °C. The resulting reaction mixture reached room temperature and mixing continued for a further 2 h; the evolution of the reaction was monitored by TLC. The reaction was then quenched with aqueous NH4Cl (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to provide T (0.3 g, crude) as a yellow syrup. This was used for the next step without further purification.
[0235] To a stirred solution of compound C (10.0 g, 27.62 mmol) in DMF (20 mL) was added 1H-tetrazol (2.85 g, 41.43 mmol) followed by K2CO3 (3, 81 g, 27.62 mmol) at room temperature. The resulting reaction mixture was heated gradually to 65 °C and mixed for 16 h; the evolution of the reaction was monitored by TLC. The reaction was diluted with cold water (250 mL) and extracted with EtOAc (2 x 250 mL). The combined organic layer was washed with water (200 ml), brine (200 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain a crude product. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc/hexanes) to provide U (5.20 g, 12.03 mmol, 43.5%) as pale yellow solid form. 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.62 (s, 1H), 7.95 (dd, J = 8.0, 2.0 Hz, 1H), 7. 46 (d, J = 8.0Hz, 1H), 7.31-7.27 (m, 1H), 6.86 (s, OH), 6.77-6.73 (m, 1H), 6 .70-6.66 (m, 1H), 5.60 (d, J = 14.5 Hz, 1H), 5.11 (d, J = 14.5 Hz, 1H). Chiral preparative HPLC method for separating the U enantiomers (preparation of U(-)):
[0236]The U enantiomers (5.20 g, 12.03 mmol) were separated by normal phase preparative high-performance liquid chromatography (QUIRALPAK IA, 250 x 20 mm, 5μ; using (A) n -Hexane, ( B) EtOH (A:B :: 90:10) as mobile phase; Flow rate: 15 mL/min) to obtain U-(-) (2.5 g) in off-white solid form. Analytical data for U-(-): Chiral HPLC: 99.46% ee Rt= 20.05 min (Chiralpak IA, 250 x 4.6mm, 5μ; mobile phase (A) n-hexane- (B) Ethanol (A) : B : 90:10); flow rate: 1.00 mL/min). Optical rotation [α]D25: - 16.48° (c = 0.1% in MeOH). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.62 (s, 1H), 7.95 (dd, J = 8.0, 2.0 Hz, 1H), 7. 46 (d, J = 8.0Hz, 1H), 7.31-7.27 (m, 1H), 6.86 (s, OH), 6.77-6.73 (m, 1H), 6 .70-6.66 (m, 1H), 5.60 (d, J = 14.5 Hz, 1H), 5.11 (d, J = 14.5 Hz, 1H). Mass: m/z 430 [M-2]-. HPLC: 99.7%.
[0237] To a stirred solution of T (0.43 g, crude) in 1,4-dioxane (5 mL) was added U-(-) (0.18 g, 0.42 mmol) at room temperature and purged. if with argon for 5 min. To the resulting reaction mixture was added Pd(PPh3)4 (24 mg, 0.03 mmol) and purged with argon for a further 10 min at room temperature. The resulting reaction mixture was gradually heated to 90°C and mixed for 2 h; the evolution of the reaction was monitored by TLC. The reaction mixture was then cooled to room temperature; volatile substances were evaporated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc/hexane) to give 9 (90 mg, crude) as brown solid. Chiral preparative HPLC method for the separation of U enantiomers (preparation of 9(-)):
[0238] The enantiomers of 9 (35 mg) were separated by normal phase preparative high-performance liquid chromatography (QUIRALPAK IA, 250 x 20 mm, 5μ; using (A) 0.1% DEA in n-Hexane, (B ) EtOH:MeOH (80:20) (A:B: 80:20) as mobile phase; Flow rate: 15 mL/min) to obtain 9(-) (15 mg) in off-white solid form. Analytical data for 9-(-): Chiral HPLC: 100% ee Rt = 19.56 min (Chiralpak IA, 250 x 4.6mm, 5μ; mobile phase (A) 0.1% DEA in n-Hexane- (B ) EtOH: MeOH (80:20) (A: B :: 80:20); flow rate: 1.00 mL/min) Optical rotation [α]D20: + 2.16° (c = 0.1% in MeOH). 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.66 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.60-7, 51 (m, 5H), 7.34-7.28 (m, 1H), 6.79-6.73 (m, 1H), 6.67-6.65 (m, 1H), 5.61 ( d, J = 14.4 Hz, 1H), 5.13 (d, J = 14.4 Hz, 1H), 5.09-5.06 (m, 1H), 2.98 (bs, OH). Mass: m/z 552.1 [M+H]+. HPLC: 99.5%. Scheme 7
EXAMPLE 10 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-methyl-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-3-(1H -tetrazol-1-yl)propane-2-ol (10)
[0239] To a stirred solution of 1H-pyrrole (V) (3.0 g, 44.7 mmol) in THF (100 mL) was added n-BuLi (30.7 mL, 49.1 mmol; 1.6M solution) in hexane) at -78°C and which was kept for 30 min at the same temperature under an argon atmosphere. To the reaction mixture was added triisopropylsilyl chloride (9.56 mL, 44.7 mmol) at -78°C and the resulting reaction mixture reached room temperature which was then mixed for a further 30 min. After fully consumed starting material (monitored by TLC), the reaction mixture was cooled with sat. NH 4 Cl and then extracted with EtOAc (2x100 mL). The combined organic extracts were washed with water (100 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain W (6.5 g, 29.14 mmol, 65%) as a colorless syrup. 1H NMR (500 MHz, CDCl3): δ 6.79 (s, 2H), 6.31 (s, 2H), 1.52-1.42 (m, 3H), 1.09 (d, J = 7 .5Hz, 18H).
[0240] To a stirred solution of compound W (3.0 g, 13.45 mmol) and Hg(OAc)2 (4.7 g, 14.84 mmol) in DCM (200 mL) was added a solution of iodine (3.41 g, 13.45 mmol) in DCM (300 mL) dropwise over a period of 45 min at -25 °C and which was then kept for 5 h at the same temperature under an argon atmosphere. After the starting material was completely consumed (monitored by TLC), the reaction mixture was concentrated under reduced pressure to obtain crude X. The crude material was triturated with hexane (15 mL) and the material obtained (2.1 g) was directly carried on to the next reaction without further purification. 1H NMR (500 MHz, CDCl3): δ 6.64 (s, 1H), 6.36 (s, 1H), 6.31 (s, 1H), 1.53-1.25 (m, 3H), 1.09 (d, J = 7.5 Hz, 18H).
[0241] To a stirred solution of the epoxidized tin compound G (1.0 g, crude) in 1,4-dioxane (20 mL) was added compound X (936 mg, crude) followed by Pd(PPh3)4 ( 193 mg, 0.167 mmol) at room temperature under an inert atmosphere. The resulting solution was purged with argon gas for 15 min. The reaction mixture was slowly heated to 90°C and then held for 3 h. After fully consumed starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc/hexane) to give Y (90 mg) as a colorless semi-solid. This compound contained a certain volume of tin impurities, which were carried directly to the next step without further purification. LC-MS(ESI): m/z 529 [M+H]+ at RT 6.06 min with 67.2% purity.
[0242] To a stirred solution of compound Y (600 mg, mixture) in THF (20 ml) was added TBAF (1.1 ml, 1.13 mmol) at 0°C under inert atmosphere. The reaction mixture reached room temperature and was held for 30 min. After completely consumed starting material (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2x30 mL). The combined organic extracts were washed with water (40 ml), brine (40 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (15-20% EtOAc in hexane gradient) to provide compound Z (200 mg, 0.53 mmol) as a pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 8.38 (s, NH), 7.78 (dd, J = 8.5, 1.5 Hz, 1H), 7. 40 (d, J = 8.5Hz, 1H), 7.38-7.33 (m, 1H), 7.13 (s, 1H), 6.84-6.71 (m, 3H), 6 .43 (s, 1H), 3.46 (d, J = 5.0 Hz, 1H), 2.97 (d, J = 5.0 Hz, 1H). MS (EI): m/z 373 [M+H]+.
[0243] To a stirred solution of compound Z (100 mg, 0.26 mmol) in ACN (10 mL) was added K2CO3 (111 mg, 0.80 mmol) at room temperature under inert atmosphere. After being mixed for 30 min, iodomethane (0.1 mL, 1.3 mmol) was added slowly to the reaction mixture at room temperature and the resulting reaction mixture was heated to 80°C and then mixed for 6 h. After fully consumed starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in EtOAc (25 ml), washed with water (20 ml), brine (20 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (10-15% EtOAc in hexane gradient) to provide compound AA (50 mg, 0.12 mmol, 48%) as a brown syrup. 1H NMR (500 MHz, CDCl3): δ 8.70 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H) 7.367.33 (m, 1H), 6.93 (s, 1H), 6.84-6.81 (m, 1H), 6.75-6.71 (m, 1H), 6.56 (s , 1H), 6.33 (s, 1H), 3.67 (s, 3H), 3.46 (d, J = 5.0 Hz, 1H), 2.97 (d, J = 5.0 Hz , 1H).
[0244] To a stirred solution of compound AA (100 mg, 0.25 mmol) in DMF (5 mL) was added K2CO3 (35 mg, 0.25 mmol) followed by 1H-tetrazol (27 mg, 0.38 mmol) at room temperature under an inert atmosphere. The reaction mixture was then heated to 65 °C and then mixed for 16 h. After fully consumed starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in EtOAc (30 ml), washed with water (20 ml), brine (20 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 30-35% EtOAc in hexane gradient) to give 10 (23 mg, 0.05 mmol, 20%) as a colorless solid. 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.57 (s, 1H), 7.79 (dd, J = 8.5, 1.5 Hz, 1H), 7. 49 (s, OH), 7.48 (d, J = 8.5Hz, 1H), 7.30-7.27 (m, 1H), 6.92 (s, 1H), 6.76-6 6.72 (m, 1H), 6.66-6.63 (m, 1H), 6.56 (s, 1H), 6.31 (s, 1H), 5.63 (d, J = 14.0 Hz, 1H), 5.08 (d, J = 14.0 Hz, 1H), 3.67 (s, 3H). MS (EI): m/z 457 [M+H]+. HPLC: 97.17%. Scheme 8
EXAMPLE 11 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)thiophen-2-yl)-3-(1H-tetrazol-1-yl)propane -2-ol (11)
[0245] To a stirred suspension of copper powder (2.07 g, 33.0 mmol) in DMSO (5 mL) was added ethyl bromodifluoro acetate (2.0 mL, 16.52 mmol) at room temperature and then the mixture was kept for 1 h under an inert atmosphere. Compound AB (2.0 g, 8.26 mmol) was then mixed and the mixture stirred at room temperature for 10 h. After completion of the reaction (monitored by TLC), the reaction was cooled with saturated aqueous NH4Cl solution (30 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (0-2% EtOAc in hexane gradient) to provide compound AC (0.56 g, 1.96 mmol, 23.7%) as a brown syrup. 1H NMR (500 MHz, CDCl3): δ 7.17 (d, J = 4.0 Hz, 1H), 7.02 (d, J = 4.0 Hz, 1H), 4.39 (q, J = 7.0 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H).
[0246] To a stirred solution of 1-bromo-2,4-difluorobenzene AC (0.25 ml, 1.96 mmol) in Et2O (10 ml) was added n-BuLi (1.3 ml, 1.96 mmol;1.6M in hexane) at -78°C and which was mixed for 30 min under an inert atmosphere. A solution of AC ester (560 mg, 1.96 mmol) in Et2O (2 mL) was added to the reaction mixture at -78 °C and the mixture was kept for a further 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled with saturated NH 4 Cl solution (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (30 ml), brine (30 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. The crude material was purified by silica gel column chromatography (15-20% EtOAc in hexane gradient) to provide ketone AD (400 mg, 1.13 mmol, 57.6%) as a brown syrup. 1H NMR (500 MHz, CDCl3): δ 7.86-7.81 (m, 1H), 7.10 (d, J = 4.0 Hz, 1H), 7.04 (d, J = 4.0 Hz, 1H), 7.01-6.98 (m, 1H), 6.91-6.84 (m, 1H). MS(EI): m/z 354 [M+H]+.
[0247] To a stirred solution of ketone AD (430 mg, 1.218 mmol) in Et2O (10 mL) was added freshly prepared diazomethane [repared by dissolving NMU (627 mg, 6.09 mmol) in mixture 1: 1 of 10% aqueous KOH solution (40 mL) and Et2O (40 mL) at 0°C followed by separation and drying of the organic layer using KOH] pellets at -5°C and mixing for 2 h. The resulting reaction mixture reached room temperature and was stirred for an additional 3 h. The evolution of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and the crude material obtained was purified by silica gel column chromatography (20-25% EtOAc in hexane gradient) to provide the epoxide EA (320 mg, 0.87 mmol, 71, 5%) as a brown syrup. 1H NMR (500 MHz, CDCl3): δ 7.36-7.29 (m, 1H), 6.98 (d, J = 4.0 Hz, 1H), 6.94 (d, J = 4.0 Hz, 1H), 6.876.76 (m, 2H), 3.36 (d, J = 5.0 Hz, 1H), 2.98 (d, J = 5.0 Hz, 1H). MS(EI): m/z 368 [M]+.
[0248] To a stirred solution of epoxide EA (320 mg, 0.87 mmol) in DMF (5 mL) was added 1H-tetrazol (92 mg, 1.3 mmol) followed by K2CO3 (120 mg, 0.87 mmol) at room temperature under an inert atmosphere. The reaction mixture was gradually heated to 65 °C and held for 8 h. The evolution of the reaction was monitored by TLC. After consumption of starting material was complete, the reaction mixture was diluted with cold water (20 mL) and then extracted with EtOAc (3x30 mL). The combined organic extracts were washed with water (30 ml), brine (30 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (40-45% EtOAc in hexane gradient) to provide AF (120 mg, 0.27 mmol, 31.5%) as a brown solid. 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H), 7.39-7.35 (m, 1H), 6.93 (d, J = 4.0 Hz, 1H), 6. 83 (d, J = 4.0 Hz, 1H), 6.79-6.75 (m, 2H), 5.60 (d, J = 14.0 Hz, 1H), 5.00 (d, J = 15.0 Hz, 1H), 4.39 (s, OH). MS(EI): m/z 435 [M-H]- . HPLC: 91.2%. 1-Ethynyl-4-fluorobenzene (22mg, 0.18mmol), CuI (2mg, 0.01mmol), PPh3 (3mg, 0.01mmol) were added successively to a stirred solution of AF (50mg, 0.114 mmol) in Et3N-DMF (2:1; 6 mL) at room temperature under an inert atmosphere. The resulting mixture was degassed by purging with argon for 15 min. Pd(PPh3)2Cl2 (8 mg, 0.01 mmol) was then added and the mixture was again purged with argon for 15 min. The resulting mixture was then heated to 90°C and kept for 16 h at the same temperature. After consumption of starting material (monitored by TLC) was complete, the reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with water (30 ml), brine (30 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (40-45% EtOAc in hexane gradient) to provide 11 (35 mg) in 79% HPLC purity.
[0249]Note: The above reaction was conducted in two batches (50 mg x 2) and then purified. The product obtained (70 mg) as a mixture was further purified by preparative HPLC to give 11 (35 mg, 0.073 mmol, 32%). 1H NMR (500 MHz, CDCl3): δ 8.64 (s, 1H), 7.50-7.47 (m, 2H), 7.36-7.29 (m, 1H), 7.097.03 (m , 3H), 6.97 (d, J = 5.0 Hz, 1H), 6.80-6.74 (m, 2H), 5.63 (d, J = 15.0 Hz, 1H), 5 .03 (d, J = 15.0 Hz, 1H), 4.41 (s, OH). MS(EI): m/z 475 [MH]-. HPLC: 98.43%. Scheme 9
EXAMPLE 12 2-(2,4-Difluorophenyl)-1-(6-((3,4-difluorophenyl)ethynyl)pyridazin-3-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (12)
[0250] To a stirred solution of compound AG (6.0 g, 31.08 mmol) in THF (20 mL), was added trimethylsilyl acetylene (6 mL, 42.4 mmol), Et3N (6.0 mL, 43.2 mmol) followed by CuI (344 mg, 1.81 mmol) at room temperature and purged with argon for 10 min. To this mixture, Pd(PPh3)2Cl2 (1.3 g, 1.85 mmol) was added at room temperature and the mixture was kept for 16 h under inert atmosphere. After completely consumed starting material (monitored by TLC), the reaction mixture was filtered through a pad of celite and the celite cake was washed with EtOAc (3 x 75 mL). The filtrate was washed with water (75 ml), brine (75 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: hexanes) to provide compound AH (5.8 g, 27.61 mmol, 88.8%) as a dark brown liquid. 1H NMR (500 MHz, CDCl3): δ 7.28-7.20 (m, 1H), 7.20-7.17 (m, 1H), 7.107.05 (m, 1H), 0.22 (s , 9 AM)
[0251] To a stirred solution of compound AH (5.8 g, 27.61 mmol) in THF (50 mL) was added TBAF (27 mL, 27.61 mmol; 1M solution in THF) at 0°C under inert atmosphere and which was stirred at the same temperature for 1 h. After fully consumed starting material (by TLC), volatile substances were concentrated under reduced pressure; the residue obtained was diluted with Et2O (100 ml), washed with water (100 ml), brine (100 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude product AI (3.4 g) as a brown liquid. The crude product was used in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 7.31-7.21 (m, 2H), 7.13-7.08 (m, 1H), 3.06 (s, 1H)
[0252] To a stirred solution of compound AJ (3.0 g, 12.61 mmol) in THF (30 mL) was added compound AI (2.78 g, crude) followed by CuI (0.12 g, 0.63 mmol), Pd(PPh3)2Cl2 (0.44 g, 0.63 mmol) and Et3N (3 mL) at room temperature under inert atmosphere and mixed for 16 h. After all starting material was consumed (by TLC), the reaction mixture was filtered through a pad of celite and the celite cake was washed with EtOAc (3 x 75 mL). The filtrate was washed with water (75 ml), brine (75 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel column chromatography (eluent: 5% EtOAc/Hexanes) to give compound AK (1.3 g, 4.40 mmol, 35%) as brown solid. 1H NMR (500 MHz, CDCl3): δ 7.67 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.467.42 (m, 1H) , 7.39-7.37 (m, 1H), 7.22-7.17 (m, 1H).
[0253] To a stirred suspension of copper-brass (3.23 g, 17.62 mmol) in DMSO (20 mL) was added ethyl bromodifluoro acetate (1.13 mL, 8.81 mmol) at room temperature and which was mixed for 1 h under an inert atmosphere. A solution of compound AK (1.3 g, 4.40 mmol) in DMSO (5 mL) was added to the reaction mixture and the mixture was kept for a further 16 h at room temperature. After the starting material was consumed (monitored by TLC), the reaction was diluted with aqueous NH 4 Cl solution (20 mL), filtered through a pad of celite and the celite cake washed with DCM (3 x 55 mL). The collected filtrate was washed with water (30 ml), brine (30 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by column chromatography (eluent: 20% EtOAc/Hexanes) to provide the ester AL (550 mg, 1.62 mmol, 37%) as a brown solid. 1H NMR (500 MHz, CDCl3): δ 7.88 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.42-7.39 ( m, 2H), 7.24-7.20 (m, 1H), 4.43 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H)
[0254] To a stirred solution of 1-bromo-2,4-difluorobenzene (0.19 mL, 1.62 mmol) in Et2O (20 mL) was added n-BuLi (1.6 mL, 2.43 mmol) ;1.6M in hexane) dropwise at -78°C and which was mixed for 30 min. A solution of compound AL (550 mg, 1.62 mmol) in Et2O (10 mL) was added to the reaction mixture at -78°C and the mixture was kept for a further 5 min. After starting material was consumed (monitored by TLC), the reaction mixture was quenched with saturated aqueous NH 4 Cl solution (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by column chromatography (eluent: 10% EtOAc/Hexanes) to afford ketone AM (420 mg, 1.03 mmol, 64%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.18-8.14 (m, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.46-7.39 (m, 2H), 7.24-7.18 (m, 1H), 7.05-7.02 (m, 1H), 6.83-6, 79 (m, 1H).
[0255] To a stirred solution of compound AM (420 mg, 1.03 mmol) in Et2O (10 mL) was added freshly prepared diazomethane [repared by dissolving NMU (527 mg, 5.17 mmol) in aqueous solution. 10% KOH (100 mL) and Et2O (100 mL) at 0°C followed by separation and drying of the organic layer using KOH] pellets at 0°C and the mixture was kept for 30 min at 0°C. The resulting reaction mixture reached room temperature and was mixed for 16 h. The evolution of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc/Hexanes) to provide compound AN (350 mg) as an off-white solid. 1H-NMR showed all characteristic peaks along with other irrelevant impurities. This material was taken directly to the next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.45-7.40 ( m, 3H), 7.24-7.19 (m, 1H), 6.88-6.85 (m, 1H), 6.79-6.76 (m, 1H), 3.51 (d, J = 5.0 Hz, 1H), 3.04 (d, J = 5.0 Hz, 1H).
[0256] To a stirred solution of compound one (300 mg, mixture) in DMF (5 mL) was added 1H-tetrazol (75 mg, 1.07 mmol) followed by K2CO3 (99 mg, 0.71 mmol) at room temperature under inert atmosphere. The resulting reaction mixture was heated gradually to 65 °C and mixed for 16 h; the evolution of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature; diluted with cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 50 ml), brine (50 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by prep HPLC to provide 12 (25 mg, 0.05 mmol) as brown solid. 1H NMR (500 MHz, CD3OD): δ 8.98 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H) , 7.64-7.60 (m, 1H), 7.51-7.49 (m, 1H), 7.40-7.35 (m, 1H), 7.17-7.12 (m, 1H), 1H), 6.98-6.95 (m, 1H), 6.76-6.73 (m, 1H), 5.82 (d, J = 14.5 Hz, 1H), 5.25 (d , J = 14.5 Hz, 1H). MS (ESI): 491 [M+H] +. HPLC: 97.19% Scheme 10
EXAMPLE 13 4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)but-3 -in-2-ol (13)
[0257] To a stirred solution of alkyne F (800 mg, 2.6 mmol) in Et2O (50 mL) was added n-BuLi (1.63 mL, 2.6 mmol; 1.6M solution in hexane) to -78°C and kept for 30 min at the same temperature. To a resulting reaction mixture, freshly distilled acetaldehyde (0.14 mL, 3.1 mmol) was added at -78°C. After being mixed for 2 h at -78°C, the reaction mixture reached room temperature and was mixed for a further 2 h. The evolution of the reaction was monitored by TLC. After all starting material was consumed, the reaction mixture was quenched with saturated NH 4 Cl solution (10 mL) and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (10-15% EtOAc in hexane gradient) to provide compound AO (600 mg, 1.7 mmol, 65%) as a colorless semi-solid. 1H NMR (500 MHz, CDCl3): δ 8.68 (s, 1H), 7.75 (dd, J = 8.5, 1.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.37-7.33 (m, 1H), 6.84-6.81 (m, 1H), 6.75-6.71 (m, 1H), 4.81-4, 76 (m, 1H), 3.45 (d, J = 5.0 Hz, 1H), 2.97 (d, J = 5.0 Hz, 1H), 2.04 (s, OH), 1, 58 (d, J = 7.0 Hz, 3H). MS(EI): m/z 353 [M+2]+ .
[0258] To a stirred solution of compound AO (500 mg, 1.4 mmol) in DMF (25 mL) was added K2CO3 (196 mg, 1.4 mmol) followed by 1H-tetrazol (150 mg, 2.1 mmol) at room temperature under an inert atmosphere. The reaction mixture was then heated to 65°C and mixed for 16 h. After fully consumed starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in EtOAc (40 ml), washed with water (20 ml), brine (20 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (30-35% EtOAc in hexane gradient) to provide 13 (250 mg, 0.59 mmol, 41%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.54 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.30-7.27 (m, 1H), 7.22 (s, OH), 6.77-6.73 (m, 1H), 6.67-6 .64 (m, 1H), 5.58 (d, J = 14.5 Hz, 1H), 5.12 (d, J = 14.5 Hz, 1H), 4.794.76 (m, 1H), 1 .93 (s, OH), 1.56 (d, J = 7.0 Hz, 3H). MS(EI): m/z 421 [M]+. HPLC: 98.02%. Scheme 11
EXAMPLE 14 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-) hydroxyethyl)thiophene-2-yl)ethynyl)pyridin-2-yl)propane-2-ol (14)
[0259] To a stirred solution of 5-bromothiophene-2-carboxaldehyde AP (5.0 g, 26.1 mmol) in DME (30 mL) was added CsF (3.9 g, 26.1 mmol) at 0°C kept at stirring for 10 min under inert atmosphere. CF3TMS (6.2 mL, 39 mmol) was added to the reaction mixture at 0°C and the mixture was kept for a further 18 h at room temperature. The evolution of the reaction was monitored by TLC. The reaction mixture was cooled with 1N HCl solution (20 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with water (100 ml), brine (100 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 4-5% EtOAc/Hexanes) to give compound AQ (5.0 g, 19.15 mmol, 73.3%) as brown oil. 1H NMR (500 MHz, CDCl3): δ 6.99 (d, J = 4.0 Hz, 1H), 6.93 (d, J = 4.0 Hz, 1H), 5.21-5.16 ( m, 1H), 3.16 (d, J = 4.5 Hz, OH)
[0260] To a stirred solution of compound G (1.5g, crude) in 1,4-dioxane (10 mL) was added compound AQ (985 mg, 3.77 mmol) at room temperature and purged with argon through 20 min. To the resulting reaction mixture was added Pd(PPh3)4 (288 mg, 0.25 mmol) and further degassed for 15 min at room temperature. The resulting reaction mixture was heated gradually to 90 °C and mixed for 5 h; the evolution of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, filtered through a pad of celite and the celite cake washed with EtOAc (3 x 30 mL); the filtrate was concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 12% EtOAc/Hexanes) to provide compound AR (800 mg) as a colorless liquid. This compound contained a certain volume of tin impurities, which were carried directly to the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H) , 7.39-7.34 (m, 1H), 7.27 (d, J = 3.5 Hz, 1H), 7.12 (d, J = 3.5 Hz, 1H), 6.85- 6.82 (m, 1H), 6.76-6.73 (m, 1H), 5.28 (d, J = 6.0 Hz, 1H), 3.47 (d, J = 5.0 Hz , 1H), 2.98 (d, J = 5.0 Hz, 1H), 2.91 (s, OH).
[0261] To a stirred solution of compound AR (800 mg, crude) in DMF (8 mL) was added K2CO3 (224 mg, 1.63 mmol) followed by 1H-tetrazol (172 mg, 2.45 mmol) to the room temperature under an inert atmosphere. The reaction mixture was then heated to 65°C and then mixed for 16 h. After fully consumed starting material (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in EtOAc (50 ml), washed with water (50 ml), brine (50 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 35% EtOAc/Hexanes) to give 14 (280 mg, 0.50 mmol) as pale yellow solid form. 1H NMR (500 MHz, CDCl3): δ 8.76 (s, 1H), 8.63 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.32-7.27 (m, 2H), 7.21 (s, OH), 7.13 (d, J = 4.0 Hz, 1H), 6, 78-6.74 (m, 1H), 6.68-6.65 (m, 1H), 5.61 (d, J = 14.0 Hz, 1H), 5.30-5.28 (m, 1H), 5.13 (d, J = 14.0 Hz, 1H), 3.08 (s, OH). MS(EI): m/z 558 [M+H]+ . HPLC: 97.43%. Scheme 12
EXAMPLE 15 2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)pyrazin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (15)
[0262] To a stirred suspension of copper powder (1.48 g, 23.30 mmol) in DMSO (20 mL) was added ethyl bromodifluoro acetate (1.6 mL, 11.65 mmol) at room temperature and which stirred at room temperature for 1 h under an inert atmosphere. A solution of 2-bromo-5-chloropyrazine AS (1.5 g, 7.77 mmol) in DMSO (5 mL) was added to the reaction mixture and the mixture was kept for a further 16 h at room temperature. After the starting material was completely consumed (by TLC), the reaction was diluted with saturated aqueous NH4Cl solution (100 mL), filtered through a pad of celite and the celite cake was washed with DCM (3 x 75 mL) . The collected filtrate was washed with water (100 ml), brine (50 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc/Hexane) to provide the AT ester (1.0 g, 4.23 mmol, 54.5%) as a pale yellow syrup. 1H NMR (500 MHz, CDCl3): δ 8.78 (s, 1H), 8.62 (s, 1H), 4.38 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H).
[0263] To a stirred solution of 1-bromo-2,4-difluorobenzene (0.816 g, 4.23 mmol) in Et2O (20 mL) was added n-BuLi (2.64 mL, 4.23 mmol; 1 1.6M in hexane) dropwise at -78°C and was mixed for 30 min. A solution of compound AT (1.0 g, 4.23 mmol) in Et2O (10 mL) was added to the reaction mixture at -78°C and the mixture was kept for a further 2 h. After completely consumed starting material (by TLC), the reaction mixture was cooled with saturated aqueous NH 4 Cl solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (50 ml) and brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc/Hexanes) to give ketone AU (1.0 g, 3.28 mmol, 77.6%) as pale yellow syrup. 1H NMR (500 MHz, CDCl3): δ 8.86 (s, 1H), 8.56 (s, 1H), 8.06-8.02 (m, 1H), 7.05-7.01 (m , 1H), 6.88-6.84 (m, 1H).
[0264] To a stirred solution of compound AU (1.0 g, 3.28 mmol) in Et2O (10 mL) was added freshly prepared diazomethane [repared by dissolving NMU (1.7 g, 16.49 mmol) in 10% aqueous KOH solution (30 mL) and Et2O (30 mL) at 0°C followed by separation and drying of the organic layer using KOH pellets] at 0°C and mixing was maintained for 30 min at the same temperature. The resulting reaction mixture reached room temperature and mixed for 16 h; the evolution of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc/Hexanes) to provide the epoxide AV (0.8 g, 2.51 mmol, 76.5%) as a brown solid. 1H NMR (500 MHz, CDCl3): δ 8.62 (s, 1H), 8.51 (s, 1H), 7.427.37 (m, 1H), 6.90-6.86 (m, 1H), 6.79-6.75 (m, 1H), 3.43 (d, J = 5.0 Hz, 1H), 3.00 (d, J = 5.0 Hz, 1H).
[0265] To a stirred solution of compound AI (400 mg, 1.25 mmol), compound AV (277 mg, 2.0 mmol), Et3N (0.4 mL, 3.12 mmol) in DMF (10 mL) ) CuI (12 mg, 0.08 mmol) was added at room temperature and then purged with argon for 10 min. To this was added Pd(PPh3)2Cl2 (44 mg, 0.08 mmol) and the resulting mixture was gradually heated to 80 °C and mixed for 4 h. After fully consumed starting material (monitored by TLC); the reaction mixture was cooled to room temperature; filtered through a pad of celite and the celite cake was washed with EtOAc (4 x 50 mL). The filtrate was washed with water (50 ml), brine (50 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc/Hexanes) to give compound AW (180 mg, 0.42 mmol, 34%) as brown solid. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.70 (s, 1H), 7.47-7.39 (m, 3H), 7.23-7.18 (m , 1H) 6.89-6.86 (m, 1H), 6.79-6.74 (m, 1H), 3.46 (d, J = 5.0 Hz, 1H), 3.01 (d , J = 5.0 Hz, 1H). MS (EI): m/z 421 [M+H]+.
[0266] To a stirred solution of compound AW (180 mg, 0.42 mmol) in DMF (5 mL) was added K2CO3 (59 mg, 0.42 mmol) followed by 1H-tetrazol (45 mg, 0.64 mmol) at room temperature under an inert atmosphere. The reaction mixture was gradually heated to 65 oC and then held for 16 h. The evolution of the reaction was monitored by TLC. After completely consumed starting material, the reaction mixture was cooled to room temperature, diluted with cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 35% EtOAc/hexanes) to provide 15 (25 mg, 0.05 mmol, 12%) as a brown solid. 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.71 (s, 1H), 8.62 (s, 1H), 7.46-7.38 (m, 2H), 7.387.18 (m, 2H), 6.81-6.77 (m, 1H), 6.74-6.71 (m, 1H), 5.64 (d, J = 15.0 Hz, 1H) , 5.56 (s, OH), 5.17 (d, J = 15.0 Hz, 1H). MS (EI): 491[M+H]+. HPLC: 92.9%. Scheme 13
EXAMPLE 16 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-) hydroxy ethyl)furan-2-yl)ethynyl)pyridin-2-yl)propane-2-ol (16)
[0267] To a stirred solution of 5-bromofuran-2-carbaldehyde AX (250 mg, 1.43 mmol) in DME (10 mL) was added CsF (108 mg, 0.71 mmol) at 0°C and that was mixed for 10 min under inert atmosphere. CF3TMS (0.27 mL, 1.71 mmol) was added to the reaction mixture at 0°C and the mixture was kept at 0°C-RT for 18 h. The evolution of the reaction was monitored by TLC. The reaction mixture was cooled with 1N HCl (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude product AY (200 mg), which was directly carried on to the next reaction without being purified. 1H NMR (500 MHz, CDCl3): δ 6.51 (d, J = 3.0 Hz, 1H), 6.35 (d, J = 3.0 Hz, 1H), 5.03-4.99 ( m, 1H), 2.78 (bs, OH).
[0268] To a stirred solution of compound G (500 mg, crude) in 1,4-dioxane (20 mL) was added compound AY (309 mg, crude) at room temperature and purged with argon for 15 min. To this was added Pd(PPh3)4 (97 mg, 0.08 mmol) which was further degassed for 15 min. The resulting reaction mixture was heated gradually to 80 °C and mixed for 3 h; the evolution of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, filtered through a pad of celite and the celite cake was washed with EtOAc (2 x 50 mL) and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 10-12% EtOAc/Hexanes) to give epoxide AZ (200 mg, mixture) as colorless oil. 1H-NMR showed all characteristic peaks along with few tin impurity peaks. The product was taken directly to the next reaction without further purification. 1H-NMR (500 MHz, CDCl3): δ 8.77 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H ), 7.37-7.32 (m, 1H), 6.79-6.75 (m, 3H), 6.60 (d, J = 3.5Hz, 1H), 4.90-5, 10 (m, 1H), 3.46 (d, J = 5.0 Hz, 1H), 2.98 (d, J = 5.0 Hz, 1H), 2.75 (d, J = 7.0 Hz, OH).
[0269] To a stirred solution of epoxide AZ (200 mg, crude) in DMF (10 mL) was added 1H-tetrazol (44.5 mg, 0.63 mmol) followed by K2CO3 (58.6 mg, 0, 42 mmol) at room temperature under an inert atmosphere. The resulting reaction mixture was heated gradually to 65 °C and mixed for 16 h; the evolution of the reaction was monitored by TLC. The reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc/hexanes) to provide 16 (20 mg, 0.037 mmol) as an off-white solid. 1H-NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.64 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.56 (d , J = 8.5Hz, 1H), 7.32-7.29 (m, 1H), 7.10 (s, OH), 6.78-6.65 (m, 3H), 6.60 ( d, J = 3.5 Hz, 1H), 5.59 (d, J = 14.5 Hz, 1H), 5.13 (d, J = 14.5 Hz, 1H), 5.10-5, 07 (m, 1H), 2.78 (d, J = 7.0 Hz, OH) Mass: m/z 542 [M+H]+. HPLC: 95.59%. Scheme 14
EXAMPLE 17 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(3-fluorophenyl)prop-1-yn-1-yl)pyridin-2-yl)-3- (1H-tetrazol-1-yl)propane-2-ol (17)
[0270] To a stirred solution of trimethylsilylacetylene (1.49 mL, 10.47 mmol) in THF (20 mL) was added n-BuLi (6 mL, 9.67 mmol, 1.6M in Hexane) at 0° C under inert atmosphere. After mixing for 1 h, 3-fluorobenzaldehyde BA (1.0 g, 8.06 mmol) was added at 0 °C and mixing continued for a further 2 h. The evolution of the reaction was monitored by TLC. The reaction was cooled with saturated aqueous NH4Cl solution and extracted with DCM (2 x 50 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (5-10% EtOAc in hexane gradient) to provide compound BB (1.1 g, 4.95 mmol, 61.5%) as a yellow syrup. 1H NMR (400 MHz, CDCl3): δ 7.37-7.28 (m, 3H), 7.04-6.99 (m, 1H), 5.44 (d, J = 6.4Hz, 1H ), 2.23 (d, J = 6.4 Hz, 1H), 0.21 (s, 9H).
[0271] To a stirred solution of compound BB (1.1 g, 4.95 mmol) in MeOH (12 mL) was added K 2 CO 3 (1.02 g, 7.43 mmol) at 0°C under inert atmosphere. After being mixed for 1 h, the reaction progress was monitored by TLC. The reaction was cooled with water (10 mL) and extracted with Et2O (2x50 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude BC product (600 mg). The crude material was used for the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 7.38-7.26 (m, 3H), 7.05-7.02 (m, 1H), 5.47 (dd, J = 4.5, 2, 0 Hz, 1H), 2.69 (d, J = 2.0 Hz, 1H), 2.33 (d, J = 4.5 Hz, 1H).
[0272] To a stirred solution of compound U (250 mg, 0.578 mmol) in DMF (5 mL) was added compound BC (140 mg, 1.5 eq), purged with argon gas for 20 min. CuI (11mg, 0.05mmol), Pd(PPh3)4 (34mg, 0.03mmol) was added followed by Et3N (0.1ml, 0.69mmol) at room temperature and then purged. if again with argon gas for 15 min. The resulting mixture was heated gradually to 90 °C and held for 5 h. After completely consumed starting material (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (3 x 40 mL). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude. The crude product was purified by silica gel column chromatography (40-45% EtOAc in hexane gradient) to provide compound BD (180 mg, 0.35 mmol, 62%) as a pale yellow syrup. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.58 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.67-7, 64 (m, 1H), 7.54-7.28 (m, 4H) 7.16 (s, OH), 7.08-7.04 (m, 1H), 6.78-6.72 (m , 1H), 6.68-6.63 (m, 1H), 5.71 (d, J = 5.2 Hz, 1H), 5.59 (d, J = 14.5 Hz, 1H), 5 .12 (d, J = 14.5 Hz, 1H), 2.74 (d, J = 5.2 Hz, 1H). MS(EI): m/z 502 [M+H]+.
[0273] To a stirred solution of compound BD (110 mg, 0.22 mmol) in ACN (10 mL) was added Et3SiH (0.052 mL, 0.33 mmol) followed by BF3.Et2O (0.04 mL, 0 .33 mmol) at 0°C under an inert atmosphere and kept for 5 h at the same temperature. The evolution of the reaction was monitored by TLC. The reaction was quenched with cold water (10 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (40 ml), brine (40 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent with 40-45% EtOAc/hexanes 25-30% EtOAc in hexane gradient) to afford 17 (8.0 mg) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 8.48 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.38-7.24 (m, 2H), 7.14-7.09 (m, 1H), 7.02-6.92 (m, 2H), 6 .78-6.72 (m, 1H), 6.67-6.62 (m, 1H), 6.41 (s, OH), 5.60 (d, J = 14.5 Hz, 1H), 5.09 (d, J = 14.5 Hz, 1H), 3.53 (s, 2H). HPLC: 79.36%. LC-MS (ESI): m/z 488 at RT 4.01 min with 88% purity. Scheme 15
EXAMPLE 18 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)pyridin-2-yl)-3- (1H-tetrazol-1-yl)propane-2-ol (18)
[0274] To a stirred solution of 4-fluorophenol (1.0 g, 8.9 mmol) in DMF (25 mL) was added K2CO3 (1.84 g, 13.3 mmol) followed by the dropwise addition of propargyl bromide (1.1 mL, 9.8 mmol; 80% by weight toluene) at 0°C under inert atmosphere. The resulting reaction mixture reached room temperature and was then mixed for 8 h; the evolution of the reaction was monitored by TLC. The reaction mixture was cooled with cold water (40 mL) and extracted with EtOAc (2x40 mL). The combined organic extracts were washed with water (40 ml), brine (40 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (0-5% EtOAc in hexane gradient) to provide compound BE (0.6 g, 4.0 mmol, 45%) as a colorless syrup. 1H NMR (500 MHz, CDCl3): δ 7.00-6.91 (m, 4H), 4.65 (d, J = 2.5 Hz, 2H), 2.51 (t, J = 2.5 Hz, 1H). MS(EI): m/z 151 [M+H]+.
[0275] A stirred mixture of compound U (50 mg, 0.11 mmol), compound BE (28 mg, 0.18 mmol), Pd(dppf)Cl2.CH2Cl2 complex (8.1 mg, 0.011 mmol), triphenylphosphine (3.0 mg, 0.011 mmol) and CuI (2.2 mg, 0.011 mmol) in Et3N-DMF (2:1; 6 mL) was degassed by purging with argon for 15 min. The resulting reaction mixture was heated slowly to 900°C and the mixture was kept for 8 h. After all starting material was consumed (by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of celite and the celite cake was washed with EtOAc (3 x 20 mL). The filtrate was diluted with water (40ml) and extracted with EtOAc (2x30ml). The combined organic extracts were washed with water (30 ml), brine (30 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (25-30% EtOAc in hexane gradient) to provide 18 (25 mg, 0.049 mmol, 45%) as a brown semi-solid. 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.54 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.30-7.28 (m, 1H), 7.14 (s, OH), 7.03-6.99 (m, 2H), 6.96-6 6.93 (m, 2H), 6.76-6.73 (m, 1H), 6.67-6.64 (m, 1H), 5.58 (d, J = 14.0 Hz, 1H), 5.11 (d, J = 14.0 Hz, 1H), 4.89 (s, 2H). MS(EI): m/z 502 [M+H]+. HPLC: 97.55%. Scheme 16
EXAMPLE 19 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-(4-fluorophenyl)piperidin-4-yl)ethynyl)pyridin-2-yl)-3-( 1H-tetrazol-1-yl)propane-2-ol (19)
[0276] To a suspension of piperidine-4-ylmethanol (750 mg, 6.51 mmol) in DCM (20 mL) was added 4-fluorophenylboronic acid BF (794 mg, 6.51 mmol), Cu(OAc) 2 (1.18 g, 6.51 mmol), pyridine (2.6 mL, 32.55 mmol), powdered 4A molecular sieves and the reaction was stirred at room temperature for 16 h under oxygen atmosphere. After the starting material was consumed (monitored by TLC), the reaction mixture was filtered through a pad of celite and the celite cake was washed with DCM (2 x 100 mL). The filtrate was washed with water (50 ml), brine (50 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc/hexanes) to give compound BG (500 mg, mixture) as a thick colorless syrup. This material was carried on to the next reaction without further purification.
[0277] To a stirred solution of oxalyl chloride (0.42 mL, 4.78 mmol) in DCM (50 mL) was cooled to -78°C by adding DMSO (0.74 mL, 9.47 mmol) ) dropwise in a nitrogen atmosphere. After mixing for 15 min, a solution of compound BG (500 mg, crude) in DCM (10 ml) was slowly added at -78°C and then kept at the same temperature for 15 min. Et3N (1.25 mL, 9.47 mmol) was then added and the mixture was kept at -78°C for a further 30 min. The resulting mixture reached room temperature; the evolution of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 ml) and extracted with DCM (2 x 50 ml). The combined organic extracts were washed with saturated aqueous Na2CO3 solution (50 mL), water (50 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude BH product (500 mg). The crude material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 9.71 (s, 1H), 6.98-6.91 (m, 4H), 3.50-3.45 (m, 2H), 2.842.78 (m , 2H), 2.39-2.36 (m, 1H), 2.07-2.04 (m, 2H), 1.87-1.77 (m, 2H).
[0278] To a stirred solution of compound BH (500 mg, crude) in MeOH (15 mL) was added K2CO3 (833 mg, 6.03 mmol) followed by Bestmann reagent (695 mg, 3.62 mmol) at temperature environment under inert atmosphere. The reaction mixture was stirred at room temperature for 30 min. After completion of the reaction (by TLC), volatile substances were removed under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc/Hexanes) to provide compound BI (320 mg, 1.58 mmol) as a white solid. 1H NMR (400 MHz, CDCl3): δ 6.94-6.87 (m, 4H), 3.38-3.33 (m, 2H), 2.92-2.86 (m, 2H), 2 .57-2.53 (m, 1H), 2.10 (s, 1H), 2.00-1.96 (m, 2H), 1.85-1.79 (m, 2H). MS (EI): m/z 204 [M+H]+
[0279] To a stirred solution of compound BJ (300 mg, crude) in DCM (20 mL) was added Et3N (0.28 mL, 1.20 mmol) followed by Tf2O (0.24 mL, 1.46 mmol) ) at 0°C and mixed for 20 min; the evolution of the reaction was monitored by TLC. The reaction mixture was cooled with cold water (20 ml) and extracted with DCM (2 x 50 ml). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain crude product BK (360 mg, crude). The crude material was used in the next step without further purification.
[0280] To a stirred solution of compound BK (150 mg, crude), compound BI (84.3 mg, 0.417 mmol), Et3N (0.15 mL, 0.62 mmol) in DMF (10 mL) was added CuI (3.3 mg, 0.017 mmol), and Pd(PPh3)2Cl2 (24.4 mg, 0.034 mmol) under inert atmosphere. The reaction mixture was heated gradually to 120 °C in microwave for 20 min. After fully consumed starting material (by TLC), the reaction mixture cooled to room temperature; was filtered through celite pad and the celite cake was washed with EtOAc (4 x 25 mL). The filtrate was washed with water (40 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc/Hexanes) to give compound BL (200 mg, crude) as a pale yellow solid.
[0281] To a stirred solution of compound BL (200 mg, crude) in DMF (10 mL) was added 1H-tetrazol (43.4 mg, 0.619 mmol) followed by K2CO3 (57 mg, 0.413 mmol) at room temperature under inert atmosphere. The resulting reaction mixture was gradually heated to 65°C and mixed for 16 h. The evolution of the reaction was monitored by TLC. The reaction mixture was diluted with cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (40 ml), brine (40 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (eluent: 40% EtOAc/hexanes) to give 19 (60 mg, 0.108 mmol) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.52 (s, 1H), 7.77 (dd, J = 8.4, 2.0 Hz, 1H), 7. 49 (d, J = 8.4Hz, 1H), 7.49 (s, OH), 7.32-7.27 (m, 1H), 6.99-6.85 (m, 4H), 6.816 .72 (m, 1H), 6.70-6.60 (m, 1H), 5.59 (d, J = 14.4 Hz, 1H), 5.10 (d, J = 14.4 Hz, 1H), 3.423.36 (m, 2H), 2.97-2.91 (m, 2H), 2.81-2.76 (m, 1H), 2.06-2.04 (m, 2H) , 1.93-1.87 (m, 2H). MS (ESI): m/z 555 [M+H]+. HPLC: 97.52%. Scheme 17
EXAMPLE 20 1-(5-((4-((4-Cyanobenzyl)oxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3 dihydrogen phosphate -(1H-tetrazol-1-yl) propane-2-yl (20)
[0282] To a stirred suspension of 8(+) (400 mg, 0.686 mmol) and 1H-tetrazol (236 mg, 3.43 mmol) in DCM (25 mL) was added a solution of diallyl-N,N- device-isopropylphosphoramidite (0.72 mL, 2.74 mmol) in DCM (5 mL) at room temperature and mixed for 2 h. A solution of mCPBA (472 mg, 2.74 mmol) in DCM (5 mL) was slowly added at -5°C and mixed for 1h. After the starting material was fully consumed, the reaction mixture was diluted with DCM (50 mL), washed with 5% aqueous Na2S2O5 (2 x 40 mL), 10% aqueous NaHCO3 (2 x 40 mL), brine ( 50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The residue was purified by mass-based preparative HPLC to provide compound BM (250 mg, 0.336 mmol, 49%) as a colorless semi-solid. 1H NMR (500 MHz, CDCl3): δ 9.10 (s, 1H), 8.75 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.56-7.50 (m, 4H), 7.46-7.42 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H ), 6.96 (d, J = 8.0 Hz, 2H), 6.83-6.80 (m, 1H), 6.66-6.62 (m, 1H), 6.19 (d, J = 16.0 Hz, 1H), 6.02-5.97 (m, 1H), 5.91 (d, J = 16.0 Hz, 1H), 5.85-5.79 (m, 1H) ), 5.44 (d, J = 17.0 Hz, 1H), 5.33-5.22 (m, 3H), 5.16 (s, 2H), 4.74 (d, J = 4. 0 Hz, 2H), 4.49-4.39 (m, 2H). HPLC: 98.46%.
[0283] To a stirred solution of compound BM (220 mg, 0.295 mmol) in THF (10 mL) was added TPP (58 mg, 0.221 mmol) followed by Pd(PPh3)4 (27 mg, 0.023 mmol), Et3N (0.08 mL, 0.59 mmol) and 1M acetic acid solution (1.47 mL, 1.47 mmol) at 0°C. The resulting mixture was stirred at room temperature for 16 h; the evolution of the reaction was monitored by TLC. The reaction mixture was filtered through a pad of celite and the celite cake was washed with DCM (3 x 30 mL) and EtOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude material was purified by mass-based preparative HPLC to provide 20 (70 mg, 0.105 mmol, 35.60%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 9.33 (s, 1H), 8.70 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.45-7.39 ( m, 1H), 7.34-7.27 (m, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.95-6.89 (m, 1H), 6.83 -6.78 (m, 1H), 6.21 (d, J = 15.2 Hz, 1H), 5.94 (d, J = 15.2 Hz, 1H), 5.21(s, 2H) . 31P NMR (500 MHz, CD3OD): δ -6.98 (s). MS (ESI): m/z 665 [M]+. HPLC: 97.83%. Scheme 18
EXAMPLE 144 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl) hydrochloride )propane-2-yl 2-aminoacetate (144)
[0284] To a stirred solution of 3(+) (25mg, 0.053mmol) in dry THF (3ml) was added NaH (5mg, 0.21mmol) at 0°C which was stirred at 0°C for 2 h under an inert atmosphere. A solution of N-Boc-Gly-OSu (28.8 mg, 0.10 mmol) in dry THF (2 mL) was added to the reaction mixture at 0°C and the mixture was kept at the same temperature for a further 10 H. The evolution of the reaction was monitored by TLC. The reaction was quenched with cold water (10 mL) and then extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with water (10 ml), brine (10 ml), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain the crude product.
[0285] Note: The reaction was conducted in 2 x batches of 25 mg and the obtained crude product was combined and purified by preparative TLC to provide BN (12 mg, 0.019 mmol, 18%) as a pale yellow semi-solid. 1H NMR (500 MHz, CDCl3): δ 9.27 (s, 1H), 8.82 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.57-7, 54 (m, 2H), 7.407.39 (m, 1H), 7.11-7.08 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.93-6 .91 (m, 1H), 6.676.63 (m, 1H), 6.05 (d, J = 15.0 Hz, 1H), 5.68 (d, J = 15.0 Hz, 1H), 5 .09 (bs, 1H), 4.194.14 (m, 1H), 3.97-3.93 (m, 1H), 1.45 (s, 9H). MS (ESI): m/z 629 [M+H] +.
[0286] To a stirred solution of compound BN (18 mg, 0.028 mmol) in 1,4-dioxane (1 mL) was added dropwise a solution of 4M HCl in 1,4-dioxane (0.5 mL) at room temperature which was kept for 2 h. The evolution of the reaction was monitored by TLC. Volatile substances were evaporated under reduced pressure. The obtained crude product was triturated with diethyl ether (3 x 3 mL) to provide 144 (10 mg, 0.017 mmol, 62%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.82 (s, 1H), 8.59 (bs, 3H), 8.03 (d, J = 7.6 Hz, 1H), 7.69-7.67 (m, 2H), 7.44-7.42 (m, 1H), 7.34-7.30 (m, 4H), 7.12-7, 10 (m, 1H), 6.15 (d, J = 15.6 Hz, 1H), 5.56 (d, J = 15.6 Hz, 1H), 4.13 (d, J = 17.6 Hz, 1H), 3.90 (d, J = 17.6 Hz, 1H). MS (ESI): m/z 529 [(M-HCl)+H] +. HPLC: 97.9%. Scheme 19
EXAMPLE 145 (2S)-2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4 of (2S)-2-(2,4-Difluorophenyl)-1,1) dihydrochloride -difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2-yl 2,6-diaminohexanoate (145) 1H NMR ( 400 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.86 (s, 1H), 8.73 (bs, 3H), 8.07 (d, J = 8.0 Hz, 1H ), 7.97 (bs, 3H), 7.71-7.69 (m, 3H), 7.33-7.21 (m, 4H), 7.187.12 (m, 1H), 6.15 ( d, J = 15.6 Hz, 1H), 5.63 (d, J = 15.6 Hz, 1H), 4.25-4.20 (m, 1H), 2.76-2.72 (m , 2H), 1.90-1.83 (m, 2H), 1.61-1.22 (m, 4H) MS (ESI): m/z 600 [(M-2HCl)+H]+. HPLC: 96.5%.
[0287]Examples 21-166 were prepared essentially according to the procedures synthesized below. The table below contains compound information and analytical data for examples 1-166.

































































































Mobile Phase B: IPA 30% Mobile Phase C: Hexanes 55% Flow Rate: 1.0 mL/min Example 167: Metalloenzyme Activity Minimum Inhibitory Concentration (MIC)
[0288]The compounds were evaluated for their ability to inhibit the growth of common fungal strains, C. albicans using a conventional procedure (M27-A2 CLSI).
[0289] Stock solutions of standards and test compounds were prepared in DMSO at 1600 μg/mL (C. albicans). Eleven serial half-dilutions of compounds were prepared in 96-well plates in RPMI + MOPS. The assay concentration ranges were 1 - 0.001 μg/mL (C. albicans). C. albicans cell suspensions were prepared and added to each well at concentrations of approximately 3.7 X 103 colony-forming units per milliliter (cfu/ml). All tests took place in duplicates. Inoculated plates were incubated for approximately 48 h at 35±1 °C. At the end of the incubation, the wells of each plate were visually assessed for the presence of fungal growth.
[0290]For fluconazole and test compounds, the MIC was the concentration there was significant reduction in growth (reduction of about 50%). For voriconazole, the MIC was the concentration that reduced the growth of C. albicans by 50% (by CLSI, M27-A2). For QC purposes the C. krusei ATCC 6258 isolate (4.0 X 103 cfu/ml) was included in the VOR assay. This isolate did not exhibit monitoring growth against voriconazole, so the MIC was the concentration at which growth was completely inhibited.
[0291]MICs of A. fumigatus were determined at 50% and 100% growth inhibition following CLSI guidelines in a concentration range of 64 - 0.062 μg/mL (CLSI M38-A2). Results: Example Antifungal Activity. Candida MIC * Aspergillus MIC 2 0.004 8 5 0.016 8 9 <0.001 0.5 101 0.25 2 108 0.062 4 Voriconazole 0.016 0.25 • MIC50 values of Candida albicans (median inhibitory concentration) expressed in μg/mL; MIC50 values of Aspergillus fumigatus expressed in ug/ml.
[0292]The compounds of the present invention inhibit the growth of A. fumigatus in a standard 4-day mouse model. For example, oral administration of Compound (-)-9 at 20 mg/kg every 4 days reduced the renal fungus load in mice by 84% compared to control.
[0293] The compounds of the present invention inhibit the growth of Septoria and Puccinia to protect plants against fungal infection (in vitro and in planta). For example, Compounds 2, 3, and 21 exhibit a range of MIC = 0.25-1.0 ug/ml in a standard MIC assay in Septoria tritici (ATCC 26517, CLSI protocol). The compounds of the present invention, e.g. Compound 2, confer protection against fungal growth when applied at 50 ppm in planta against the pathogens Septoria and Puccinia. Incorporation through Citation
[0294] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this specification are expressly incorporated into this document in its entirety by way of reference. Equivalents
[0295] Individuals skilled in the art will recognize, or may certify using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are encompassed by the following claims.

权利要求:
Claims (29)
[0001]
1. Compound CHARACTERIZED by the fact that it is represented by formula (I): in which:
[0002]
2. Compound according to claim 1, CHARACTERIZED by the fact that R1 is fluorine.
[0003]
3. Compound according to claim 1, CHARACTERIZED by the fact that R2 is fluorine.
[0004]
4. Compound according to claim 1, CHARACTERIZED by the fact that R1 and R2 are fluorine.
[0005]
5. Compound according to claim 1, CHARACTERIZED by the fact that R4 is phenyl substituted with 0, 1, 2 or 3 independent R8.
[0006]
6. Compound according to claim 1, CHARACTERIZED by the fact that R4 is phenyl substituted with 0, 1, 2 or 3 independent halo.
[0007]
7. Compound according to claim 1, CHARACTERIZED by the fact that R4 is phenyl substituted with 0, 1, 2 or 3 independent fluorines.
[0008]
8. Compound according to claim 1, CHARACTERIZED by the fact that R4 is 2,4-difluorophenyl.
[0009]
9. Compound according to claim 1, CHARACTERIZED by the fact that R5 is H.
[0010]
10. Compound according to claim 1, CHARACTERIZED by the fact that R5 is acyl with amino.
[0011]
11. Compound according to claim 1, CHARACTERIZED by the fact that R5 is phosphate.
[0012]
12. Compound, according to claim 1, CHARACTERIZED by the fact that: R1 is fluorine; R2 is fluorine; R4 is 2,4-difluorophenyl; R5 is H; Ar2 is
[0013]
13. Compound according to claim 12, CHARACTERIZED by the fact that: R11 is phenyl, thienyl, arylalkyl, aryloxyalkyl, each substituted with an independent R3; each R3 is independently cyano, haloalkyl, haloalkoxy, substituted arylalkoxy, haloalkylaminocarbonyl, substituted arylalkylaminocarbonyl; and n is 1 or 2.
[0014]
14. Compound according to claim 12, CHARACTERIZED by the fact that: R11 is phenyl, thienyl, arylalkyl, aryloxyalkyl, each substituted with an independent R3; each R3 is independently cyano, haloalkyl, haloalkoxy, substituted arylalkoxy, haloalkylaminocarbonyl, substituted arylalkylaminocarbonyl; and n is 1.
[0015]
15. Compound according to claim 12, CHARACTERIZED by the fact that: R11 is phenyl substituted with R3 independently; each R3 is independently cyano or haloalkyl; and n is 1 or 2.
[0016]
16. Compound according to claim 12, CHARACTERIZED by the fact that: R11 is thienyl substituted with R3 independently; each R3 is independently haloalkylaminocarbonyl, substituted arylalkylaminocarbonyl; and n is 1 or 2.
[0017]
17. A compound, according to claim 1, CHARACTERIZED by the fact that it is one of the following compounds: 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(phenylethynyl)pyridine-2 -yl)-3-(1H-tetrazol-1-yl)propane-2-ol (1); 1-(5-((4-Chlorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane-2 -ol(2); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (3); 2-(2,4-Difluorophenyl)-1-(5-((2,4-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (4); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethyl)phenyl)ethynyl)pyridin-2-yl) propane-2-ol (5); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(4-fluorobenzyl)thiophene-2-carboxamide (6); 4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl) propyl) pyridin-3-yl)) ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (7); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)benzonitrile (8); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoro-1-hydroxyethyl)) phenyl)ethynyl)pyridin-2-yl)propane-2-ol (9); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-methyl-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazole -1-yl)propane-2-ol (10); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)thiophen-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (11); 2-(2,4-Difluorophenyl)-1-(6-((3,4-difluorophenyl)ethynyl)pyridazin-3-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (12); 4-(6-(2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)but-3-yn -2-ol (13); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-hydroxyethyl)) thiophene-2-yl)ethynyl)pyridin-2-yl)propane-2-ol (14); 2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)pyrazin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (15); 2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoro-1-hydroxy ethyl) )furan-2-yl)ethynyl)pyridin-2-yl)propane-2-ol (16); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(3-fluorophenyl)prop-1-yn-1-yl)pyridin-2-yl)-3-(1H -tetrazol-1-yl)propane-2-ol (17); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-(3-(4-fluorophenoxy)prop-1-yn-1-yl)pyridin-2-yl)-3-(1H -tetrazol-1-yl)propane-2-ol (18); 2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((1-(4-fluorophenyl)piperidin-4-yl)ethynyl)pyridin-2-yl)-3-(1H- tetrazol-1-yl)propane-2-ol (19); 1-(5-((4-((4-Cyanobenzyl)oxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(dihydrogen phosphate 1H-tetrazol-1-yl)propane-2-yl (20); 1-(5-((3-chlorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane-2 -ol(21); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-(trifluoromethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol- 1-yl)propane-2-ol (22); 2-(2,4-difluorophenyl)-1-(5-(3,3-difluoroprop-1-ynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl) propane-2-ol (23); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (24); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (25); 1-(5-((4-(difluoromethyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl) propane-2-ol (26); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-methylphenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (27); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((3-fluoropyridin-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (28); 1-(5-((5-chlorothiophen-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (29); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(trifluoromethyl)thiophen-2-yl)ethynyl)pyridine- 2-yl)propane-2-ol (30); 2-(2,4-difluorophenyl)-1-(5-((3,5-difluoropyridin-2-yl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1 -yl)propane-2-ol (31); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((5-fluoropyridin-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (32); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((6-fluoropyridin-3-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (33); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethoxy)phenyl)ethynyl)pyridin-2-yl) propane-2-ol (34); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-methoxyphenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (35); 2-(2,4-difluorophenyl)-1-(5-((2,6-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (36); 2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (37); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((5-methylthiophen-2-yl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-ol (38); 1-(5-((4-(1,1-difluoroethyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (39); 1-(5-((4-(difluoromethoxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl) propane-2-ol (40); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(trifluoromethylthio)phenyl)ethynyl)pyridin-2-yl) propane-2-ol (41); 1-(5-((4-chloro-3-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (42); 2-(4-chloro-2-fluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane -2-ol (43); 1,1-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1- yl)propane-2-ol (44); 2-(2,5-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (45); 2-(3,4-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (46); 1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )phenyl)ethanone (47); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (48); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-((4-fluorophenyl)ethynyl)pyridazin-3-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (49); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(hydroxymethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl) propane-2-ol (50); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(methoxymethyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl) propane-2-ol (51); 4-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)-1,1, 1-trifluorobut-3-yn-2-ol (52); 1-(5-((5-bromothiophene-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (53); 1-(5-((5-(difluoromethyl)thiophen-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (54); 1-(5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )thiophene-2-yl)-2,2,2-trifluoroethanone (55); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((1-(2,2,2-trifluoroethyl)-1H-pyrrole) -3-yl)ethynyl)pyridin-2-yl)propane-2-ol (56); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(3-(2,2,2-trifluoroethoxy)prop-1-inyl )pyridin-2-yl)propane-2-ol (57); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(thiophene-2-ylethynyl)pyridin-2-yl)propane-2- ol (58); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((2-fluoro-4-(methylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol- 1-yl)propane-2-ol (59); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(methylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl) propane-2-ol (60); 2-(2,4-difluorophenyl)-1-(5-((3,4-difluorophenyl)ethynyl)thiophen-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (61); 2-(2,4-difluorophenyl)-1-(5-((4-(dimethylamino)phenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl) propane-2-ol (62); 1-(5-((1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (63); 1-(5-((4-(difluoromethyl)-3-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1 -yl)propane-2-ol (64); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(3-(3-fluorophenyl)prop-1-ynyl)pyridin-2-yl)-3-(1H-tetrazol-1 -yl)propane-2-ol (65); 1-(5-((1-(difluoromethyl)-1H-pyrrol-3-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H -tetrazol-1-yl)propane-2-ol (66); 2-(2,4-difluorophenyl)-1-(5-((2,5-difluorophenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane -2-ol (67); N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )phenyl)formamide (68); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzonitrile ( 69); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-isocyanophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -ol (70); 3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzonitrile ( 71); 1-(5-((5-bromofuran-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (72); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-3 -fluorobenzonitrile (73); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-2 -fluorobenzonitrile (74); 3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-4 -fluorobenzonitrile (75); 1-(5-((5-(difluoromethyl)furan-2-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (76); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((5-(2,2,2-trifluoroethyl)thiophene-2- yl)ethynyl)pyridin-2-yl)propane-2-ol (77); 1-(5-((4-aminophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane-2 -ol (78); N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )phenyl)-2,2,2-trifluoroacetamide (79); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoroethylamino)phenyl)ethynyl) pyridin-2-yl)propane-2-ol (80); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenol ( 81); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)benzamide ( 82); 1-(5-((4-amino-2-fluorophenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (83); N-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )phenyl)acetamide (84); 1-(5-(3-(2,4-difluorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazole -1-yl)propane-2-ol (85); 4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop- 2-ynyloxy)benzonitrile (86); 1-(5-((1H-indol-5-yl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl )propane-2-ol (87); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-fluorobenzylamino)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1- yl)propane-2-ol (88); 1-(5-(benzofuran-5-ylethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propane-2- ol (89); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(2,2,2-trifluoroethyl)phenyl)ethynyl) pyridin-2-yl)propane-2-ol (90); 4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(2,2,2-trifluoroethyl)benzamide (91); (4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenyl )(pyrrolidin-1-yl)methanone (92); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1- yl)propane-2-ol (93); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(2,2,2-trifluoroethyl)thiophene-2-carboxamide (94); (4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)piperidine -1-yl)(4-fluorophenyl)methanone (95); 1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )piperidine-1-yl)-2,2,2-trifluoroethanone (96); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((3-(2,2,2-trifluoroethoxy)phenyl)ethynyl) pyridin-2-yl)propane-2-ol (97); 3-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(2,2,2-trifluoroethyl)benzamide (98); 1,1-difluoro-2-(4-fluorophenyl)-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2-ol (99); 3-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)benzonitrile (100); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(4-(trifluoromethoxy)benzyloxy)phenyl)ethynyl)pyridine -2-yl)propane-2-ol (101); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-3-fluorobenzonitrile (102); 3-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-4-fluorobenzonitrile (103); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(3-(trifluoromethoxy)benzyloxy)phenyl)ethynyl)pyridine -2-yl)propane-2-ol (104); 1-(5-((4-(2,4-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (105); 1-(5-((4-(3,4-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (106); 1-(5-((4-(4-chlorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1- yl)propane-2-ol (107); 1-(5-((4-(4-chloro-2-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H- tetrazol-1-yl)propane-2-ol (108); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-N-methylbenzamide (109); 6-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)nicotinonitrile (110); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(thiazol-2-ylmethoxy)phenyl)ethynyl)pyridine- 2-yl)propane-2-ol (111); 5-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (112); 1-(5-((4-(2,3-difluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (113); 1-(5-(3-(4-chlorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1 -yl)propane-2-ol (114); 4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop- 2-ynyloxy)-3-fluorobenzonitrile (115); 4-(3-(6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)prop- 2-ynyloxy)-2-fluorobenzonitrile (116); 1-(5-(3-(4-chloro-2-fluorophenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H -tetrazol-1-yl)propane-2-ol (117); 1-(5-(3-(4-(difluoromethyl)phenoxy)prop-1-ynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H- tetrazol-1-yl)propane-2-ol (118); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(3-fluorobenzyl)thiophene-2-carboxamide (119); N-(3-cyanobenzyl)-5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridine- 3-yl)ethynyl)thiophene-2-carboxamide (120); N-(4-cyanobenzyl)-5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridine- 3-yl)ethynyl)thiophene-2-carboxamide (121); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(4-(trifluoromethyl)benzyl)thiophene-2-carboxamide (122); (5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophene -2-yl)(morpholino)methanone (123); (5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)thiophene -2-yl)(pyrrolidin-1-yl)methanone (124); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)-N -(4-(methylsulfonyl)benzyl)thiophene-2-carboxamide (125); 3-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (126); 3-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-5-fluorobenzonitrile (127); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(piperidin-4-ylethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2- ol (128); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((1-(4-fluorophenylsulfonyl)piperidin-4-yl)ethynyl)pyridin-2-yl)-3-(1H- tetrazol-1-yl)propane-2-ol (129); 1-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )phenyl)-2,2,3,3,3-pentafluoropropane-1-ol (130); 4-((4-((6-(2-(2,5-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (131); 4-((4-((6-(2-(4-chloro-2-fluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridine-3- yl)ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (132); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenylthio)methyl)-2-fluorobenzonitrile (133); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenylsulfinyl)methyl)-2-fluorobenzonitrile (134); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenylsulfonyl)methyl)-2-fluorobenzonitrile (135); 4-((4-((6-(2-(2,5-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)benzonitrile (136); 4-((4-((6-(2-(4-chloro-2-fluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridine-3- yl)ethynyl)phenoxy)methyl)benzonitrile (137); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenylthio)methyl)benzonitrile (138); 5-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)picolinonitrile (139); 1-(5-((4-(4-cyanobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1- yl)propane-2-yl dihydrogen phosphate (140); 5-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)ethynyl)-N -(4-fluorobenzyl)thiophene-2-carboxamide (141); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)benzonitrile (142); 4-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)-2-fluorobenzonitrile (143); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propane-2 -yl 2-aminoacetate hydrochloride (144); (2S)-2-(2,4-Difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1-yl )propane-2-yl 2,6-diaminohexanoate dihydrochloride (145); 1-(5-((4-(4-chloro-3-fluorobenzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H- tetrazol-1-yl)propane-2-ol (146); 1-(5-((4-(biphenyl-4-ylmethoxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol- 1-yl)propane-2-ol (147); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-methylbenzyloxy)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazol-1- yl)propane-2-ol (148); 2-(2,4-difluorophenyl)-1-(5-((4-(4-ethylbenzyloxy)phenyl)ethynyl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1- yl)propane-2-ol (149); 1-(5-((4-(4-(difluoromethyl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazole -1-yl)propane-2-ol (150); (+)-1-(5-((4-(4-(difluoromethyl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3- (1H-tetrazol-1-yl)propane-2-ol ((+)-150); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-((4-(4-(trifluoromethyl)benzyloxy)phenyl)ethynyl)pyridine -2-yl)propane-2-ol (151); 4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )benzyloxy)-3-fluorobenzonitrile (152); 5-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )benzyloxy)-2-fluorobenzonitrile (153); 1-(5-((4-(4-(1H-pyrazol-1-yl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro- 3-(1H-tetrazol-1-yl)propane-2-ol (154); 4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )benzyloxy)benzonitrile (155); 1-(5-((4-((4-chlorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazole -1-yl)propane-2-ol (156); 1-(5-((4-((biphenyl-4-yloxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H -tetrazol-1-yl)propane-2-ol (157); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-(4-(oxazol-2-yl)benzyloxy)phenyl)ethynyl)pyridin-2-yl)-3- (1H-tetrazol-1-yl)propane-2-ol (158); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-((4-fluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-3-(1H-tetrazole -1-yl)propane-2-ol (159); 1-(5-((4-((3,4-difluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H -tetrazol-1-yl)propane-2-ol (160); 1-(5-((4-((4-(difluoromethyl)phenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-( 1H-tetrazol-1-yl)propane-2-ol (161); 4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )benzylthio)benzonitrile (162); 5-((4-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)thiophene-2-carbonitrile (163); 4-(4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl )benzyloxy)-2-fluorobenzonitrile (164); 1-(5-((4-((4-chloro-3-fluorophenoxy)methyl)phenyl)ethynyl)pyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3- (1H-tetrazol-1-yl)propane-2-ol (165); 4-((3-((6-(2-(2,4-difluorophenyl))-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl) ethynyl)phenoxy)methyl)benzonitrile (166).
[0018]
18. In vitro method of inhibiting metalloenzyme activity, CHARACTERIZED by the fact that it comprises contacting a compound, as defined in any one of claims 1 to 17, with a metalloenzyme.
[0019]
19. Method for treating or preventing fungal growth on or on a plant CHARACTERIZED by the fact that it comprises contacting a compound, as defined in any one of claims 1 to 17, with the plant or seeds.
[0020]
20. Composition CHARACTERIZED by the fact that it comprises a compound, as defined in claim 1, and an agriculturally acceptable vehicle.
[0021]
21. Composition CHARACTERIZED by the fact that it comprises a compound, as defined in claim 1, and a pharmaceutically acceptable vehicle.
[0022]
22. Use of a compound as defined in claim 1, CHARACTERIZED in that it is for the manufacture of a medicine to treat an individual carrying or susceptible to a metalloenzyme-related disorder or disease.
[0023]
23. Use, according to claim 22, CHARACTERIZED by the fact that the disease or disorder is cancer, cardiovascular disease, endocrinological disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, eye disease, central nervous system disease (CNS ), urological disease, or gastrointestinal disease.
[0024]
24. Use, according to claim 22, CHARACTERIZED by the fact that the disease or disorder is a systemic fungal infection or onychomycosis.
[0025]
25. Use of a compound as defined in claim 1, CHARACTERIZED by the fact that it is for the manufacture of a medicine to treat an individual having or susceptible to a disorder or disease.
[0026]
26. Use, according to claim 25, CHARACTERIZED by the fact that the disorder or disease is associated with one or more of the following pathogenic fungi: Absidia corymbifera, Ajellornyces dermatitidis, Arthroderma benhamiae, Arthroderma fulvum, Arthroderma gypseum, Arthroderma in otae, Arthroderma vanbreuseghemii, Aspergillus flavus, Aspergillus fumigates, Aspergillus niger, Blastomyces dermatitidis, Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida pelliculosa, Candida pelliculosa, Cladophialophora. , Epidermophyton floccosum, Exophiala dermatitidis, Filobasidiella neoformans, Fonsecaea pedrosoi, Fusarium solani, Geotrichum candidum, Histoplasma capsulaturn, Hortaea werneckii, Issatschenkia orientalis, Madurella grisae, Malassezia pamphlet, Malassezia pamphlet, Malassezia pas, restricta fur, ezia slooffiae, Malassezia sympodialis, Microsporum canis, Microsporum fulvum, Microsporum gypseum, Mucor circinelloides, Nectria haematococca, Paecilomyces variotii, Paracoccidioides brasiliensis, Penicillium marneffei, Rhhosporum gypseum, Pichia anomala, Pichia anomala , Schizophyllum commune, Sporothrix schenckii, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum, Trichophyton violaceum, Trichosporon asahii, Trichosporon cutaneum, Trichosporon inkin, Trichosporon mucoides.
[0027]
27. Use, according to claim 25, CHARACTERIZED by the fact that the disorder or disease is Aspergillosis, Blastomycosis, Candidiasis, Chromomycosis, Coccidioidomycosis, Cryptococcosis, Dermatophytoses, Histoplasmosis, Keratomicosis, Lobomycosis, Malassezia infection, Mucormycosis, Paracosis by Penicillium marneffei, Pheohyphomycosis, Pneumocyctis pneumonia, or Rhinosporidiosis.
[0028]
28. Use, according to claim 25, CHARACTERIZED by the fact that the disorder or disease is Chagas disease (Genus Trypanosoma), African trypanosomiasis (Genus Trypanosoma), leishmaniasis (Genus Leishmania), tuberculosis (Genus Mycobacterium), leprosy ( Mycobacterium genus), malaria (Plasmodium genus), or tinea (capitis, corporis, pedis, tonsurans, versicolor).
[0029]
29. Use, according to claim 25, CHARACTERIZED by the fact that the individual is an animal other than a human.

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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-05-02| B25D| Requested change of name of applicant approved|Owner name: VIAMET PHARMACEUTICALS (NC), INC. (US) |

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2019-04-24| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-06-04| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2019-10-01| B25A| Requested transfer of rights approved|Owner name: VPS-3, INC. (US) |

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2019-10-22| B25D| Requested change of name of applicant approved|Owner name: VPS-3, LLC. (US) |

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2019-11-12| B25A| Requested transfer of rights approved|Owner name: NQP 1598, LTD. (KY) |

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2020-11-17| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2021-03-30| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-06-01| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2021-06-22| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 10/12/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161569279P| true| 2011-12-11|2011-12-11|

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US61/569,279|2011-12-11|

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US201261701370P| true| 2012-09-14|2012-09-14|

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US61/701,370|2012-09-14|

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PCT/US2012/068818|WO2013090210A1|2011-12-11|2012-12-10|Metalloenzyme inhibitor compounds|

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