HK1228376A1

HK1228376A1 - Metalloenzyme inhibitor compounds

Info

Publication number: HK1228376A1
Application number: HK17101822.3A
Authority: HK
Inventors: W.J.胡克斯特拉; C．M．耶茨; R.J.肖茨英格尔; M．洛索; Z．A．巴肯; M．萨伦伯杰
Original assignee: 威尔金制药有限公司
Priority date: 2011-06-19
Filing date: 2017-02-20
Publication date: 2017-11-03

Description

Metalloenzyme inhibitor compounds

The application is a divisional application of an invention patent application with the title of "metalloenzyme inhibitor compound" and the application number of "201280040415.0" filed on 6/19/2012.

Background

Living organisms have developed a tightly regulated process that specifically imports metals, transports them to intracellular storage sites, and finally transports them to sites of use. One of the most important functions of metals such as zinc and iron in biological systems is to achieve metalloenzyme activity. Metalloenzymes are enzymes that bind metal ions to the active site of an enzyme and utilize the metal as part of the catalytic process. More than one third of all characterized enzymes are metalloenzymes.

The function of metalloenzymes is highly dependent on the presence of metal ions in the active site of the enzyme. It is well recognized that agents that bind to and inactivate the active site metal ions greatly reduce the activity of the enzyme. Nature employs this same strategy to reduce the activity of certain metalloenzymes during periods when enzyme activity is not required. For example, the protein TIMP (tissue inhibitor of metalloproteinases) binds zinc ions in the active site of various matrix metalloproteinases, thereby inhibiting enzymatic activity. The pharmaceutical industry has used the same strategy in the design of therapeutics. For example, the azole antifungal agents fluconazole (fluconazole) and voriconazole (voriconazole) contain a 1- (1,2, 4-triazole) group that binds to heme iron present in the active site of the target enzyme lanosterol demethylase, thereby inactivating the enzyme. Another example includes a zinc-binding hydroxamate group that has been incorporated into most of the disclosed inhibitors of matrix metalloproteinases and histone deacetylases. Another example is a carboxylic acid group that binds zinc, which has been incorporated into most of the disclosed angiotensin converting enzyme inhibitors.

The use of the most suitable metal binding group for a particular target and clinical indication is crucial in the design of clinically safe and effective metalloenzyme inhibitors. If a weakly binding metal binding group is used, the efficacy may not be optimal. On the other hand, if very tightly bound metal binding groups are used, the selectivity for the target enzyme may not be optimal relative to the relevant metalloenzyme. The lack of optimal selectivity may be the cause of clinical toxicity due to unintended inhibition of these off-target metalloenzymes. An example of such clinical toxicity is the unintended inhibition of human drug metabolizing enzymes such as cytochrome P4502C 9(CYP2C9), CYP2C19, and CYP3a4 by currently available azole antifungal agents such as fluconazole and voriconazole. It is believed that this off-target inhibition is primarily caused by indiscriminate binding of the currently employed 1- (1,2, 4-triazole) to iron in the active sites of CYP2C9, CYP2C19 and CYP3a 4. Another example of this is the joint pain observed in many clinical trials of matrix metalloproteinase inhibitors. This toxicity is thought to be related to the inhibition of off-target metalloenzymes due to indiscriminate binding of hydroxamate groups to zinc in the off-target active site.

Thus, the search for metal binding groups that can achieve a better balance of potency and selectivity remains an important goal and is of great interest in achieving therapeutic agents and methods that address the unmet need in the treatment and prevention of diseases, disorders, and symptoms thereof.

Fungicides are compounds of natural or synthetic origin which act to protect and cure plants from damage caused by agriculturally relevant fungi. Typically, there is no single fungicide available in all cases. Thus, research is being conducted to produce fungicides that can have better performance, are easier to use, and are less costly.

The present disclosure relates to compounds of formula I shown below and derivatives thereof, and their use as fungicides. The compounds of the present disclosure may provide protection against ascomycetes (ascomycetes), basidiomycetes (basidiomycetes), deuteromycetes (deuteromycetes) and oomycetes (oomycetes).

Disclosure of Invention

The present invention relates to compounds (e.g., any of the compounds described herein), methods of modulating metalloenzyme activity, and methods of treating diseases, disorders, or symptoms thereof. The above methods may include the compounds herein.

One aspect is a compound of formula I or a salt, solvate, hydrate or prodrug thereof, wherein:

MBG is optionally substituted tetrazolyl, optionally substituted triazolyl, optionally substituted oxazolyl, optionally substituted pyrimidinyl, optionally substituted thiazolyl, or optionally substituted pyrazolyl;

R₁is H, halogen, alkyl or haloalkyl;

R₂is H, halogen, alkyl or haloalkyl;

R₃independently H, alkyl, nitro, cyano, haloalkyl, alkoxy, halogen, haloalkoxy, alkenyl, haloalkenyl, cycloalkyl, halocycloalkyl, alkynyl, haloalkynyl, thioalkyl, SF₃、SF₆、SCN、SO₂R₆-c (O) -alkyl, -c (O) OH, -c (O) O-alkyl, c (O) H, CH ═ N-O-alkyl, -CH ═ N-O-arylalkyl;

R₄is aryl, heteroaryl, or cycloalkyl, optionally substituted with 0,1, 2, or 3 independent R₃Substitution;

R₅is alkyl, haloalkyl, cycloalkyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, each of which is optionally substituted with 0,1, 2 or 3 independent R₃Substitution;

R₆is alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

R₇is H, alkyl, -Si (R)₈)₃、-P(O)(OH)₂、-CH₂-O-P(O)(OH)₂or-C (O) -alkyl optionally substituted with amino;

R₈independently is an alkyl or aryl group;

R₉independently is H, alkyl, halogen or haloalkyl; and is

X is O or S.

Another aspect is a method of controlling a pathogen-induced disease in a plant at risk of developing a disease due to a pathogen, comprising contacting one of the plant and an area adjacent to the plant with a composition of formula I or a salt, solvate, hydrate or prodrug thereof, wherein:

R₁is H, halogen, alkyl or haloalkyl;

R₂is H, halogen, alkyl or haloalkyl;

R₄is aryl, heteroaryl, alkyl or cycloalkyl, optionally substituted with 0,1, 2 or 3 independent R₃Substitution;

R₆is alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

R₈independently is an alkyl or aryl group;

R₉independently is H, alkyl, halogen or haloalkyl; and is

X is O or S.

Other aspects are compounds of any of the formulae herein, wherein:

MBG is optionally substituted tetrazolyl or optionally substituted triazolyl;

R₁is fluorine;

R₂is fluorine;

R₁and R₂Is fluorine;

R₄is optionally substituted by 0,1, 2 or 3 independent R₃Substituted phenyl;

R₄is phenyl optionally substituted with 0,1, 2 or 3 independent halogens;

R₄is phenyl optionally substituted with 0,1, 2 or 3 independent fluoro;

R₄is 2, 4-difluorophenyl;

R₅is optionally substituted by 0,1, 2 or 3 independent R₃A substituted aryl group;

R₅is optionally substituted by 0,1, 2 or 3 independent R₃Substituted arylalkyl;

R₅is optionally substituted by 0,1, 2 or 3 independent R₃Substituted heteroarylalkyl;

R₅is optionally substituted by 0,1, 2 or 3 independent R₃Substituted heteroaryl;

R₅is pyridyl, pyridazinyl, pyrimidinyl, triazinyl, imidazolyl, triazolyl, tetrazolyl or pyrazolyl, each of which is optionally substituted with 0,1, 2 or 3 independent R₃Substitution;

R₉is H;

R₉is halogen;

MBG is 1H-tetrazol-1-yl, 2H-tetrazol-2-yl, 4H-1,2, 4-triazol-4-yl or 1H-1,2, 4-triazol-1-yl;

MBG is 1H-tetrazol-1-yl or 2H-tetrazol-2-yl;

MBG is 4H-1,2, 4-triazol-4-yl or 1H-1,2, 4-triazol-1-yl;

wherein:

R₁is fluorine;

R₂is fluorine;

R₄is 2, 4-difluorophenyl; and is

wherein:

R₁is fluorine;

R₂is fluorine;

R₄is 2, 4-difluorophenyl; and is

wherein:

R₁is fluorine;

R₂is fluorine;

R₄is 2, 4-difluorophenyl; and is

wherein:

R₅is optionally substituted by 0,1, 2 or 3 independent R₃A substituted benzyl group.

Wherein:

R₅is optionally substituted by 0,1, 2 or 3 independent R₃substituted-CH₂-a heteroaryl group. Wherein:

R₅is optionally substituted by 0,1, 2 or 3 independent R₃substituted-CH₂CF₂-an aryl group. Wherein:

x is O;

R₁is fluorine;

R₂is fluorine; and is

R₄Is 2, 4-difluorophenyl;

wherein:

x is O;

R₁is fluorine;

R₂is fluorine;

R₄is 2, 4-difluorophenyl; and is

wherein:

x is O;

R₁is fluorine;

R₂is fluorine; and is

R₄Is 2, 4-difluorophenyl; and is

compounds herein include those compounds wherein the compounds are identified as achieving affinity for metalloenzymes, at least in part, by forming one or more of the following types of chemical interactions or bonds with metals: sigma bonds, covalent bonds, coordinate-covalent bonds, ionic bonds, pi bonds, or feedback bonds (backspinning) interactions. These compounds can also achieve affinity by weaker interactions with metals, such as van der waals interactions, pi-cation interactions, pi-anion interactions, dipole-dipole interactions, ion-dipole interactions. In one aspect, the compound is identified as having a binding interaction with a metal via a 1-tetrazole moiety; in another aspect, the compound is identified as having a binding interaction with a metal via N2 of the 1-tetrazolyl moiety; in another aspect, the compound is identified as having a binding interaction with a metal via N3 of the 1-tetrazolyl moiety; in another aspect, the compound is identified as having a binding interaction with a metal via N4 of the 1-tetrazolyl moiety. In one aspect, the compound is identified as having a binding interaction with the metal via the 4-triazole moiety; in another aspect, the compounds are identified as having a binding interaction with a metal via N1 of the 4-triazolyl moiety; in another aspect, the compounds are identified as having binding interactions with metals via N2 of the 4-triazolyl moiety.

Methods of evaluating metal-ligand binding interactions are known in the art, as exemplified in the literature, including, for example, "Principles of bioinformatic Chemistry", lipprard and Berg, university science Books, (1994); "Mechanisms of organic Reactions", Basolo and Pearson, John Wiley & Sons Inc; second edition (9 months 1967); "Biological organic Chemistry", IvanoBertini, Harry Gray, Ed Stiefel, Joan Valentine, University Science Books (2007); xue et al, "Nature Chemical Biology", vol.4, No.2, 107-.

In some cases, the compounds of the present invention are selected from compounds of formula I (and pharmaceutically and agriculturally acceptable salts, solvates, or hydrates thereof) below:

1- (5- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (1);

1- (5- (2, 4-difluorobenzyloxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (2);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (3-fluorobenzyloxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (3);

1- (5- (4-chlorobenzyloxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (4);

4- (6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yloxy) benzonitrile (5);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (4-fluorophenoxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (6);

1- (5- (4-chlorophenoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (7);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5-methoxypyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (8);

4- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) methyl) benzonitrile (9);

4- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) methyl) -2-fluorobenzonitrile (10);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5-phenoxypyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (11);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- (2,2, 2-trifluoroethoxy) pyridin-2-yl) propan-2-ol (12);

1- (4- ((2, 4-difluorobenzyl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (13);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- (vinyloxy) pyridin-2-yl) propan-2-ol (14);

4- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) thio) methyl) -3-fluorobenzonitrile (15);

4- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) thio) methyl) -3-fluorobenzonitrile (16);

4- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) -2-fluorobenzonitrile (17);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((2,2, 2-trifluoroethyl) thio) pyridin-2-yl) propan-2-ol (18);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- ((4-fluorobenzyl) oxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (19);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((4- (2,2, 2-trifluoroethoxy) benzyl) oxy) pyridin-2-yl) propan-2-ol (20);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((4- (trifluoromethoxy) benzyl) oxy) pyridin-2-yl) propan-2-ol (21);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((4- (trifluoromethyl) benzyl) oxy) pyridin-2-yl) propan-2-ol (22);

1- (5- ((2, 3-difluorobenzyl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (23);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- ((2-fluoro-4- (trifluoromethyl) benzyl) oxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (24);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((3- (2,2, 2-trifluoroethoxy) benzyl) oxy) pyridin-2-yl) propan-2-ol (25);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((3- (trifluoromethyl) benzyl) oxy) pyridin-2-yl) propan-2-ol (26);

1- (5- ((4-chloro-3-fluorobenzyl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (27);

1- (5- ((3, 4-difluorobenzyl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (28);

2- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) acetonitrile (29);

1- (5- (benzyloxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (30);

1- (5- (benzyloxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (2H-tetrazol-2-yl) propan-2-ol (31);

1- (5- (but-2-yn-1-yloxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (32);

1- (5- (but-2-yn-1-yloxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (2H-tetrazol-2-yl) propan-2-ol (33);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- ((3-methoxybenzyl) oxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (34);

1- (5- ((3, 5-difluorobenzyl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (35);

1- (5- ((3, 5-difluorobenzyl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (2H-tetrazol-2-yl) propan-2-ol (36);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (pyridin-2-ylmethoxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (37);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (pyridin-2-ylmethoxy) pyridin-2-yl) -3- (2H-tetrazol-2-yl) propan-2-ol (38);

1- (5- (cyclopropylmethoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (39);

1- (5- (cyclopropylmethoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (2H-tetrazol-2-yl) propan-2-ol (40);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- ((4-methoxybenzyl) oxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (41);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5-isopropoxypyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (42);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5-isobutoxypyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (43);

1- (5- ((2, 3-difluorobenzyl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-1,2, 3-triazol-1-yl) propan-2-ol (44);

1- (5- ((2, 3-difluorobenzyl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-1,2, 4-triazol-1-yl) propan-2-ol (45)

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- ((2-fluorobenzyl) oxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (46);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((1,1, 1-trifluoropropan-2-yl) oxy) pyridin-2-yl) propan-2-ol (47);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (2H-tetrazol-2-yl) -1- (5- ((1,1, 1-trifluoropropan-2-yl) oxy) pyridin-2-yl) propan-2-ol (48);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- (thiophen-2-ylmethoxy) pyridin-2-yl) propan-2-ol (49);

6- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) methyl) nicotinonitrile (50);

6- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) methyl) nicotinonitrile (51);

3- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) methyl) benzonitrile (52);

3- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) methyl) benzonitrile (53);

2- (4-chloro-2-fluorophenyl) -1- (5- (cyclopropylmethoxy) pyridin-2-yl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (54);

4- (((6- (2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) methyl) benzonitrile (55);

4- (((6- (2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) methyl) benzonitrile (56);

4- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) methyl) -3-fluorobenzonitrile (57);

4- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) methyl) -3-fluorobenzonitrile (58);

3- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) methyl) -4-fluorobenzonitrile (59);

2- (2, 4-difluorophenyl) -1- (5- ((3, 5-difluoropyridin-2-yl) methoxy) pyridin-2-yl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (60);

6- (((6- (2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) methyl) nicotinonitrile (61);

6- (((6- (2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) methyl) nicotinonitrile (62);

1- (5- (but-2-yn-1-yloxy) pyridin-2-yl) -2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (63);

1- (5- (but-2-yn-1-yloxy) pyridin-2-yl) -2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-3- (2H-tetrazol-2-yl) propan-2-ol (64);

5- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) methyl) -2-fluorobenzonitrile (65);

5- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) methyl) -2-fluorobenzonitrile (66);

3- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) methyl) -2-fluorobenzonitrile (67);

3- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) methyl) -2-fluorobenzonitrile (68);

2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-1- (5-isobutoxypyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (69);

2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-1- (5-isobutoxypyridin-2-yl) -3- (2H-tetrazol-2-yl) propan-2-ol (70);

2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- (2,2, 2-trifluoroethoxy) pyridin-2-yl) propan-2-ol (71);

2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-3- (2H-tetrazol-2-yl) -1- (5- (2,2, 2-trifluoroethoxy) pyridin-2-yl) propan-2-ol (72);

5- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) methyl) thiophene-2-carbonitrile (73);

5- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) methyl) thiophene-2-carbonitrile (74);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- (4- (trifluoromethyl) phenoxy) pyridin-2-yl) propan-2-ol (75);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- (4- (trifluoromethoxy) phenoxy) pyridin-2-yl) propan-2-ol (76);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (3-fluorophenoxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (77);

3- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) benzonitrile (78);

4- ((6- (2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) benzonitrile (79);

4- ((6- (2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) benzonitrile (80);

4- ((6- (2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) -2-fluorobenzonitrile (81);

4- ((6- (2- (4-chloro-2-fluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) -2-fluorobenzonitrile (82);

4- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) methyl) benzonitrile (83);

1- (5- (3-chlorophenoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (84);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (3-methoxyphenoxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (85);

1- (5- (3, 4-difluorophenoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (86);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (4-methoxyphenoxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (87);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (2-fluorophenoxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (88);

4- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) -3-fluorobenzonitrile (89);

4- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H-tetrazol-2-yl) propyl) pyridin-3-yl) oxy) -3-fluorobenzonitrile (90);

methyl 2- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) thio) acetate (91);

1- (5- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (92);

6- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) nicotinonitrile (93);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((5- (trifluoromethyl) pyridin-2-yl) oxy) pyridin-2-yl) propan-2-ol (94);

1- (5- ((5-chloropyridin-2-yl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (95);

4- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) cyanopyridine (96);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (pyrimidin-2-yloxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (97);

1- (5- ((5-chloropyrimidin-2-yl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (98);

1- (5- ((5-bromopyrimidin-2-yl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (99);

5- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) pyrimidine-2-carbonitrile (100);

6- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) nicotinaldehyde (101);

(E) -6- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) nicotinaldehyde O-methyloxime (102);

(E) -6- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) nicotinaldehyde O-benzyl oxime (103);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- ((3-fluoro-5- (trifluoromethyl) pyridin-2-yl) oxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (104);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((5- (trifluoromethyl) pyrimidin-2-yl) oxy) pyridin-2-yl) propan-2-ol (105);

1- (5- ((5-bromopyridin-2-yl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (106);

2- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) thiazole-5-carbonitrile (107);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (quinolin-2-yloxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (108);

1- (5- ((5-chlorobenzo [ d ] thiazol-2-yl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (109);

1- (5- ((6-chlorobenzo [ d ] thiazol-2-yl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (110);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((6- (trifluoromethyl) pyridin-3-yl) oxy) pyridin-2-yl) propan-2-ol (111);

5- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) cyanopyridine (112);

1- (5- ((5-chloropyridin-2-yl) methoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (113);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((5- (trifluoromethyl) pyridin-2-yl) methoxy) pyridin-2-yl) propan-2-ol (114);

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((6- (trifluoromethyl) pyridin-3-yl) methoxy) pyridin-2-yl) propan-2-ol (115);

1- (5- ((6-chloropyridin-3-yl) methoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (116);

1- (5- ((2-chloropyridin-4-yl) methoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (117);

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (pyridin-4-ylmethoxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (118);

1- (5- (2, 2-difluoro-2-phenylethoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (119);

1- (5- (2- (4- (difluoromethoxy) phenyl) -2, 2-difluoroethoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (120);

1- (5- (2- (4-chlorophenyl) -2, 2-difluoroethoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (121);

4- (2- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) -1, 1-difluoroethyl) benzonitrile (122);

1- (5- (2- (4- (difluoromethoxy) phenyl) -2-fluoroethoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (123); or

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (2-fluoro-2-phenylethoxy) pyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (124).

In another aspect, the present invention provides an agricultural composition comprising a compound of formula I and an agriculturally acceptable carrier.

In other aspects, the invention provides a compound of any of the formulae herein, wherein the compound inhibits (or is identified to inhibit) lanosterol demethylase (CYP 51).

In other aspects, the invention provides a compound of any of the formulae herein, wherein the compound is identified as having a range of activity against a target organism (e.g., candida albicans (c.albicans) Minimum Inhibitory Concentration (MIC) <0.25 micrograms/mL (μ g/mL); septoria tritici (s.tritici) Minimum Inhibitory Concentration (MIC) <0.5 micrograms/mL (μ g/mL); e.g., puccinia tritici (p.triticina) Minimum Inhibitory Concentration (MIC) <0.5 micrograms/mL (μ g/mL)).

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.

In other aspects, the invention provides methods of modulating metalloenzyme activity in a subject comprising contacting the subject with a compound of any of the general formulae herein (e.g., formula I) in an amount and under conditions sufficient to modulate metalloenzyme activity.

In one aspect, the invention provides a method of treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, comprising administering to the subject an effective amount of a compound of any of the general formulae herein (e.g., formula I) or a pharmaceutical composition thereof.

In another aspect, the present invention provides a method of treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, wherein the subject has been identified as in need of treatment for the metalloenzyme-related disorder or disease, comprising administering to said subject in need thereof an effective amount of a compound of any of the general formulae herein (e.g. formula I) or a pharmaceutical composition thereof, such that said subject is treated for said disorder.

In another aspect, the present invention provides a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, wherein the subject has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, comprising administering to said subject in need thereof an effective amount of a compound of any of the general formulae herein (e.g., formula I) or a pharmaceutical composition thereof, such that metalloenzyme activity in said subject is modulated (e.g., down-regulated, inhibited).

The methods herein include wherein the disease or disorder is caused by 4-hydroxyphenylpyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase N, angiotensin converting enzyme, aromatase (CYP19), calcineurin, carbamyl phosphate synthase, family of carbonic anhydrases, catechol-O-methyltransferase, family of cyclooxygenases, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA aminotransferase, HIF-prolyl hydroxylase, family of histone deacetylases, HIV integrase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51), family of matrix metalloproteinases, methionine aminopeptidase, neutral endopeptidase, family of nitric oxide synthases, Those mediated by any of phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, pyruvate ferredoxin oxidoreductase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease, or xanthine oxidase.

The methods herein include wherein the disease or disorder is caused by 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), 17-alpha hydroxylase (CYP17), aldosterone synthase (CYP11B2), aminopeptidase P, anthrax lethal factor, arginase, beta-lactamase, cytochrome P4502A 6, D-Ala D-Ala ligase, dopamine beta-hydroxylase, endothelin-converting enzyme-1, glutamate carboxypeptidase II, glutaminyl cyclase, glyoxalase, heme oxygenase, HPV/HSV E1 helicase, indoleamine 2, 3-bis, leukotriene A4 hydrolase, methionine aminopeptidase 2, peptide demethylase, phosphodiesterase VII, releasease, retinoic acid hydroxylase (CYP26), TNF-alpha converting enzyme (TACE), UDP- (3-O- (R-3-hydroxytetradecanoyl)) -N-phosphate oxygenase -acetylglucosamine deacetylase (LpxC), vascular adhesion protein-1 (VAP-1), or vitamin D hydroxylase (CYP 24).

The methods herein include those wherein the disease or disorder is cancer, cardiovascular disease, inflammatory disease, infectious disease, metabolic disease, ophthalmic disease, Central Nervous System (CNS) disease, urological disease, or gastrointestinal disease.

The methods herein include those wherein the disease or condition is prostate cancer, breast cancer, inflammatory bowel disease, psoriasis, systemic fungal infection, fungal infection of skin structures, fungal infection of mucous membranes, or onychomycosis.

The methods described herein include those in which the subject is identified as being in need of a particular prescribed treatment. Identifying a subject in need of such treatment can be at the discretion of the subject or health care professional, and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

Another aspect of the invention is a composition comprising a compound of the general formula herein (e.g., formula I) and an agriculturally acceptable carrier.

Another aspect of the invention is a method of treating or preventing a metalloenzyme-mediated disease or condition in or on a plant comprising contacting a compound herein with the plant.

Another aspect of the invention is a method of inhibiting metalloenzyme activity in or on a plant comprising contacting a compound herein with the plant.

Detailed Description

Definition of

In order that the present invention may be more readily understood, certain terms are first defined herein for convenience.

As used herein, the term "treating" a disorder includes preventing, ameliorating, alleviating and/or controlling the disorder and/or the condition that causes the disorder. The term "treating" refers to a method of alleviating or alleviating a disease and/or its attendant symptoms. According to the present invention, "treating" includes preventing, blocking, inhibiting, alleviating, protecting, modulating, reversing the effects of and reducing the occurrence of adverse effects such as disorders.

As used herein, "inhibit" includes preventing, reducing and halting progression. Note that "enzyme inhibition" (e.g., metalloenzyme inhibition) is distinguished therefrom and described below.

The term "modulate" refers to an increase or decrease in the activity of an enzyme in response to exposure to a compound of the invention.

The terms "isolated," "purified," or "biologically pure" refer to a substance that is substantially or essentially free of components that normally accompany it as found in its natural state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. Specifically, in embodiments the compound is at least 85% pure, more preferably at least 90% pure, more preferably at least 95% pure, and most preferably at least 99% pure.

The term "administering" or "administering" includes the route by which the compounds are introduced into a subject to perform their intended function. Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal and transdermal.

The term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. The effective amount of the compound may vary depending on factors such as: the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimal therapeutic response. An effective amount is also an amount at which the therapeutically beneficial effect of the inhibitor compound outweighs any toxic or detrimental effects (e.g., side effects).

The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" as used herein refer to the administration of a compound, drug, or other material to enter a patient's system and thereby undergo metabolism and other like processes.

The term "therapeutically or agriculturally effective amount" means an amount of a compound administered sufficient to prevent development of, or alleviate to some extent, one or more symptoms of the condition or disorder being treated.

A therapeutically effective amount (i.e., effective dose) of the compound may range from about 0.005 micrograms/kilogram (μ g/kg) to about 200 milligrams/kilogram (mg/kg) of body weight, preferably from about 0.01mg/kg to about 200mg/kg of body weight, and more preferably from about 0.015mg/kg to about 30mg/kg of body weight. In other embodiments, the therapeutically effective amount may range from about 1.0 picomolar (pM) to about 10 μ Μ. The skilled artisan will appreciate that certain factors may affect the dosage required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, prior treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a compound may comprise a monotherapy, or preferably may comprise a series of therapies. In one embodiment, a subject is treated with a compound in a range of about 0.005 μ g/kg to about 200mg/kg body weight 1 time per day for about 1 to 10 weeks, preferably for about 2 to 8 weeks, more preferably for about 3 to 7 weeks, and even more preferably for about 4,5, or 6 weeks. In another embodiment, the subject may be treated daily for years in the case of a chronic condition or disease. It is also understood that the effective dose of the compound for treatment may be increased or decreased over the course of a particular treatment.

The term "chiral" refers to a molecule having the property of not coinciding with a mirror partner, while the term "achiral" refers to a molecule coinciding with its mirror partner.

The term "diastereomer" refers to a stereoisomer that has two or more asymmetric centers and whose molecules are not mirror images of each other.

The term "enantiomer" refers to two stereoisomers of a compound that are non-coincident mirror images of each other. An equimolar mixture of two corresponding isomers is called a "racemic mixture" or "racemate".

The term "isomer" or "stereoisomer" refers to compounds that are identical in chemical composition but differ in the arrangement of atoms or groups in space.

The term "prodrug" includes compounds having moieties that can be metabolized in vivo. Typically, prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (see, e.g., Berge et al (1977) "Pharmaceutical Salts", J.pharm.Sci.66: 1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compounds, in their free acid form or hydroxy group, with a suitable esterifying agent. The hydroxyl group can be converted to an ester by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionates), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetoxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl esters), aryl lower alkyl esters (e.g., benzyl esters), substituted (e.g., substituted with methyl, halogen, or methoxy substituents) aryl and aryl lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Preferred prodrug moieties are propionates and acyl esters. Prodrugs that are converted to the active form in vivo by other mechanisms are also included. In some aspects, the compounds of the invention are prodrugs of any of the formulae herein.

The term "subject" refers to an animal, e.g., a mammal, including, but not limited to, a primate (e.g., human), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, and the like. In certain embodiments, the subject is a human.

The terms "a" and "the" when used in this application, including the claims, mean "one or more". Thus, for example, reference to "a sample" includes a plurality of samples, and so forth, unless the context clearly dictates otherwise (e.g., a plurality of samples).

Throughout the specification and claims, the words "comprise", "comprising" and "contain" are used in a non-exclusive sense, unless the context requires otherwise.

As used herein when referring to numerical values, the term "about" is intended to include variations of ± 20% of the specified amount, in some embodiments ± 10% of the specified amount, in some embodiments ± 5% of the specified amount, in some embodiments ± 1% of the specified amount, in some embodiments ± 0.5% of the specified amount, and in some embodiments ± 0.1% of the specified amount, as such variations are suitable for practicing the disclosed methods or using the disclosed compositions.

The word "inhibitor" is used herein to mean a molecule that exhibits activity to inhibit metalloenzymes. By "inhibiting" herein is meant that the activity of the metalloenzyme is reduced compared to the activity of the metalloenzyme in the absence of the inhibitor. In some embodiments, the term "inhibit" refers to a decrease in metalloenzyme activity of at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least 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, inhibition refers to a decrease in metalloenzyme activity of about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibition refers to a decrease in metalloenzyme activity of about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such a reduction can be measured using a variety of techniques known to those skilled in the art. Specific assays for measuring the respective activities are described below.

Further, the compounds of the present invention include olefins having any of the following geometries: "Z" refers to a geometry referred to as the "cis" (same side) configuration and "E" refers to a geometry referred to as the "trans" (opposite side) configuration. For nomenclature of chiral centers, the terms "d" and "l" configurations are defined by IUPAC nomenclature (IUPAC Recommendation). For the use of the terms below, diastereomers, racemates, epimers and enantiomers will be used in their ordinary sense to describe the stereochemistry of the formulation.

As used throughout this specification, unless otherwise indicated, the term "R" means a group consisting of C_1-8Alkyl radical, C_2-8Alkenyl or C_2-8Alkynyl groups.

The term "alkyl" as used herein refers to a straight or branched chain hydrocarbon group containing from 1 to 12 carbon atoms. The term "lower alkyl" refers to C₁-C₆An alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl. Alkyl groups may be optionally substituted with one or more substituents.

The term "haloalkyl" refers to an alkyl group substituted with one or more halo substituents. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl and 2,2, 2-trifluoroethyl.

The term "alkenyl" refers to an unsaturated hydrocarbon chain that may be straight or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. The alkenyl group may be optionally substituted with one or more substituents.

The term "alkynyl" refers to an unsaturated hydrocarbon chain that may be straight or branched, containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.

Sp of alkenyl and alkynyl²Or the sp carbon may each optionally be the point of attachment of an alkenyl or alkynyl group.

The term "alkoxy" refers to the-OR substituent.

The term "halogen", "halo" or "halo" as used herein refers to-F, -Cl, -Br or-I.

The term "haloalkoxy" refers to a-OR substituent wherein R is substituted, fully OR partially, with Cl, F, I, OR Br, OR any combination thereof. Examples of haloalkoxy groups include trifluoromethoxy and 2,2, 2-trifluoroethoxy.

The term "cycloalkyl" refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one saturated ring or having at least one non-aromatic ring, wherein the non-aromatic ring may have some unsaturation. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0,1, 2,3, or 4 atoms in each ring of the cycloalkyl group may be substituted with a substituent. Representative examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

The term "aryl" refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. The aryl group may be optionally substituted with one or more substituents. In one embodiment, 0,1, 2,3, 4,5, or 6 atoms in each ring of the aryl group may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and the remaining ring atoms being carbon (with appropriate hydrogen atoms, unless otherwise specified). Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0,1, 2,3, or 4 atoms in each ring of the heteroaryl group may be substituted with a substituent. Examples of heteroaryl groups include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, isoquinolinyl, indazolyl, and the like.

The term "nitrogen-containing heteroaryl" refers to heteroaryl groups having 1-4 ring nitrogen heteroatoms if monocyclic, 1-6 ring nitrogen heteroatoms if bicyclic, or 1-9 ring nitrogen heteroatoms if tricyclic.

The term "heterocycloalkyl" refers to a non-aromatic 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system that includes 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. The heterocycloalkyl group may be optionally substituted with one or more substituents. In one embodiment, 0,1, 2,3, or 4 atoms in each ring of the heterocycloalkyl group can be substituted with a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1, 3-dioxolanyl, tetrahydrofuranyl, tetrahydrothienyl, thiapropenyl (thirenyl), and the like.

The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups. The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups. The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxyl groups. The alkyl or aryl moiety in alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.

Acids and bases useful in the methods herein are known in the art. The acid catalyst is any acidic chemical, which may be inorganic (e.g., hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or organic in nature (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate). The acid is used in catalytic or stoichiometric amounts to promote the chemical reaction. The base is any basic chemical, which may be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic in nature (e.g., triethylamine, pyridine). The base is used in catalytic or stoichiometric amounts to promote the chemical reaction.

An alkylating agent is any agent capable of alkylating the functional group in question (e.g. an oxygen atom of an alcohol, a nitrogen atom of an amino group). Alkylating agents are known in the art, including in the references cited herein, and include alkyl halides (e.g., methyl iodide, benzyl bromide, or chloride), alkyl sulfates (e.g., methyl sulfate), or other art-recognized combinations of alkyl leaving groups. Leaving groups are any stable species capable of being detached from a molecule during a reaction (e.g., elimination, substitution) and are known in the art, including in the references cited herein, and include halides (e.g., I-, C1-, Br-, F-), hydroxy, alkoxy (e.g., -OMe, -O-t-Bu), acyloxy anions (e.g., -OAc, -OC (O) CF)₃) Sulfonates (e.g., methylsulfonyl, tosyl), acetamides (e.g., -NHC (O) Me), carbamates (e.g., N (Me) C (O) Ot-Bu), phosphonates (e.g., -OP (O) (OEt)₂) Water or alcohol (proton state), etc.

In certain embodiments, substituents on any group (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be on any atom of the group, wherein any group that can be substituted (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, heterocycloalkyl) can be optionally substituted with one or more substituents (which can be the same or different), each substituted for a hydrogen atom. Examples of suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, oxy (i.e., carbonyl), carboxy, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamino, alkylcarbonyl, or arylamino substituted aryl; arylalkylamino, aralkylaminocarbonyl, acylamino, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imino, ureido, carbamoyl, thioureido, thiocyanato, sulfonamido, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, N-hydroxyamidino, or N' -aryl, N "-hydroxyamidino.

The compounds of the invention may be prepared by means known in the art of organic synthesis. Methods for optimizing reaction conditions, and if necessary, minimizing competing by-products, are known in the art. Reaction Optimization And amplification may advantageously utilize high-speed parallel synthesis apparatus And computer-controlled microreactors (e.g., Design And Optimization in organic synthesis, second edition, Carlson R, Ed, 2005; Elsevier Science Ltd.;k et al, angelw.chem.int.ed.engl.2004, 43,406; and references therein). The technician can search the database software by utilizing commercially available structures, e.g.(of the American chemical societyChemical Abstracts ServiceSection) and CrossFire(Elsevier MDL), or by using a web search engine, e.g. asOr a keyword database, such as the U.S. patent and trademark office text database, to perform a suitable keyword search to determine other reaction schemes and procedures.

The compounds herein may also contain linkages (e.g., carbon-carbon bonds) in which the rotation of the bond is restricted around that particular linkage, such as by the presence of a ring or double bond. Thus, all cis/trans and E/Z isomers are expressly included in the present invention. The compounds herein may also be represented in various tautomeric forms; in such cases, the invention expressly includes all tautomeric forms of the compounds described herein, even though only one tautomeric form may be represented. All such isomeric forms of these compounds herein are expressly included in the present invention. All crystal forms and polymorphs of the compounds described herein are expressly included in the present invention. Extracts and fractions comprising the compounds of the invention are also practiced. The term "isomers" is intended to include diastereomers, enantiomers, regioisomers (regioisomers), structural isomers, rotamers, tautomers, and the like. For compounds containing one or more stereogenic centers, such as chiral compounds, the methods of the invention can be practiced using enantiomerically enriched compounds, racemates, or diastereomeric mixtures.

Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or more, more preferably the compounds have an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more. In a preferred embodiment, only one enantiomer or diastereomer of a chiral compound of the invention is administered to a cell or subject.

In another aspect, the present invention provides a method of synthesizing a compound of formula I (or any of the general formulae herein) as described herein. Another embodiment is a method of using any one or a combination of the reactions described herein to prepare a compound of any of the formulae herein. The method may comprise the use of one or more intermediates or chemical reagents as described herein.

Method of treatment

In one aspect, the invention provides a method of modulating metalloenzyme activity in a cell in a subject, comprising contacting the subject with a compound described herein (e.g., of any of the formulae herein) in an amount and under conditions sufficient to modulate metalloenzyme activity.

In one embodiment, the modulation is inhibition.

In another aspect, the invention provides a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, comprising administering to the subject an effective amount of a compound described herein (e.g., of any formula herein) or a pharmaceutical or agricultural composition thereof.

In other aspects, the invention provides a method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, wherein the subject has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, comprising administering to said subject in need thereof an effective amount of a compound described herein (e.g., of any formula herein) or a pharmaceutical or agricultural composition thereof, such that said subject is treated for said disorder.

In certain embodiments, the invention provides methods of treating a disease, disorder, or symptom thereof, wherein the disorder is cancer, a cardiovascular disease, an inflammatory disease, or an infectious disease. In other embodiments, the disease, disorder, or symptom thereof is a metabolic disease, an ophthalmic disease, a Central Nervous System (CNS) disease, a urological disease, or a gastrointestinal disease. In certain embodiments, the disease is prostate cancer, breast cancer, inflammatory bowel disease, psoriasis, systemic fungal infection, fungal infection of skin structures, fungal infection of mucous membranes, and onychomycosis.

In certain embodiments, the subject is a mammal, preferably a primate or a human.

In another embodiment, the present invention provides a method as described above, wherein the effective amount of a compound described herein (e.g., of any formula herein) is as described above.

In another embodiment, the present invention provides a method as described above, wherein the compound described herein (e.g., of any of the formulae herein) is administered intravenously, intramuscularly, subcutaneously, intracerebroventricularly, orally or topically.

In other embodiments, the present invention provides methods as described above, wherein a compound described herein (e.g., of any of the formulae herein) is administered alone or in combination with one or more other therapeutic agents. In another embodiment, the additional therapeutic agent is an anti-cancer agent, an anti-fungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, a metabolic disease agent, an ophthalmic disease agent, a Central Nervous System (CNS) disease agent, a urological disease agent, or a gastrointestinal disease agent.

Another object of the invention is the use of a compound described herein (e.g., of any of the formulae herein) in the manufacture of a medicament for the treatment of a metalloenzyme-mediated disorder or disease. Another object of the invention is the use of a compound described herein (e.g., of any of the formulae herein) for the treatment of a metalloenzyme-mediated disorder or disease. Another object of the invention is the use of a compound described herein (e.g., of any of the formulae herein) in the manufacture of an agricultural composition for the treatment or prevention of a metalloenzyme-mediated disease or disorder in an agricultural or land environment.

Pharmaceutical composition

In one aspect, the invention provides a pharmaceutical composition comprising a compound described herein (e.g., of any of the formulae herein) and a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides a pharmaceutical composition further comprising an additional therapeutic agent. In a further embodiment, the additional therapeutic agent is an anti-cancer agent, an antifungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, a metabolic disease agent, an ophthalmic disease agent, a Central Nervous System (CNS) disease agent, a urological disease agent, or a gastrointestinal disease agent.

In one aspect, the invention provides a kit comprising an effective amount of a compound described herein (e.g., of any formula herein) in unit dosage form, and instructions for administering the compound to a subject suffering from or susceptible to a metalloenzyme-mediated disease or condition, including cancer, solid tumor, cardiovascular disease, inflammatory disease, infectious disease. In other embodiments, the disease, disorder, or symptom thereof is a metabolic disease, an ophthalmic disease, a Central Nervous System (CNS) disease, a urological disease, or a gastrointestinal disease.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable carrier" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either 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 salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge et al, j.pharm.sci.1977,66, 1-19). Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into base addition salts or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for use in the present invention.

The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are the same as the parent form of the compound for the purposes of the present invention.

In addition to salt forms, the present invention also provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical means in an ex vivo environment. For example, prodrugs can be slowly converted to compounds of the present invention when placed in a transdermal patch reservoir (reservoir) with a suitable enzyme or chemical agent.

Certain compounds of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

The invention also provides pharmaceutical compositions comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In one embodiment, the compound is administered to the subject using a pharmaceutically acceptable formulation, e.g., the pharmaceutically acceptable formulation provides sustained delivery of the compound to the subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after administration of the pharmaceutically acceptable formulation to the subject.

The actual dosage level and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic (or unacceptably toxic) to the patient.

In use, at least one compound according to the invention is administered to a subject in need thereof in a pharmaceutically effective amount in a pharmaceutical carrier by intravenous injection, intramuscular injection, subcutaneous injection, or intracerebroventricular injection, or by oral or topical administration. According to the present invention, the compounds of the present invention may be administered alone or in combination with a second, different therapeutic agent. "in combination with … …" means substantially simultaneously or sequentially co-administered. In one embodiment, the compounds of the invention are administered acutely. Thus, for short term treatment, e.g., from about 1 day to about 1 week, the compounds of the invention may be administered. In another embodiment, the compounds of the invention may be administered over a longer period of time to ameliorate a chronic condition, for example for about 1 week to several months depending on the condition to be treated.

As used herein, a "pharmaceutically effective amount" refers to an amount of a compound of the present invention that is high enough to significantly positively modify the condition to be treated, but low enough to avoid serious side effects (reasonable benefit/risk ratio), within the scope of sound medical judgment. The pharmaceutically effective amount of a compound of the invention will vary depending upon the particular objective to be achieved, the age and physical condition of the patient to be treated, the severity of the underlying disease, the duration of the treatment, the nature of concurrent therapy, and the particular compound employed. For example, a therapeutically effective amount of a compound of the invention administered to a child or infant will be proportionally reduced according to sound medical judgment. An effective amount of a compound of the invention will therefore be the lowest amount that provides the desired effect.

A definite practical advantage of the present invention is that the compounds can be administered in a convenient manner, for example by intravenous, intramuscular, subcutaneous, oral or intracerebroventricular injection routes, or by topical administration, for example as an ointment or gel. Depending on the route of administration, the active ingredient comprising the compounds of the present invention may need to be encapsulated within a material to protect the compound from the action of enzymes, acids and other natural conditions that may inactivate the compound. To administer the compounds of the present invention by means other than parenteral administration, the compounds may be coated with or administered with a material to prevent inactivation.

The compounds may be administered parenterally or intraperitoneally. Dispersants can also be prepared, for example, in glycerol, liquid polyethylene glycols, and mixtures thereof, as well as oils.

Some examples of substances that can act as drug carriers are: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline; and a phosphate buffer solution; skimmed milk powder; and other non-toxic compatible substances used in pharmaceutical preparations, such as vitamin C, estrogens and Echinacea (Echinacea). Wetting and lubricating agents such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives may also be present. Solubilizers including, for example, cremaphore and beta-cyclodextrin may also be used in the pharmaceutical compositions herein.

Pharmaceutical compositions comprising the active compounds (or prodrugs thereof) of the presently disclosed subject matter can be prepared by conventional mixing, dissolving, granulating, dragee-making, milling, emulsifying, encapsulating, entrapping or lyophilizing processes. The compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.

The pharmaceutical compositions of the presently disclosed subject matter can take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal administration, and the like, or a form suitable for administration by inhalation or insufflation.

For topical administration, the active compound or prodrug may be formulated as a solution, gel, ointment, cream, suspension, or the like.

Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.

Useful injectable formulations include sterile suspensions, solutions or emulsions of the active compounds in aqueous or oily vehicles. The composition may also contain formulating agents (formulating agents), such as suspending, stabilizing and/or dispersing agents. Formulations for injection may be presented in unit dosage form (e.g., in ampoules or in multi-dose containers), and may contain an added preservative.

Alternatively, the injectable formulations can be provided in powder form for reconstitution with a suitable vehicle, including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, and the like, prior to use. To this end, the active compounds may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets, or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated, for example with sugar or an enteric coating, by methods well known in the art.

Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl parabens or sorbic acid). The formulations may also optionally contain buffer salts, preservatives, flavouring agents, colouring agents and sweetening agents.

It is well known that formulations for oral administration may be suitably formulated to provide controlled release of the active compound or prodrug.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For rectal and vaginal administration, the active compounds may be formulated as solutions (for retention enemas), suppositories, or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

For nasal administration or administration by inhalation or insufflation, the active compound or prodrug may conveniently be delivered in the form of an aerosol spray from a pressurised container or nebuliser, using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbon, carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by setting a valve to deliver a metered amount. Capsules and cartridges (e.g., of gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

Specific examples of aqueous suspension formulations suitable for nasal administration using commercially available nasal spray devices include the following: active compound or prodrug (0.5-20 mg/mL); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (C)80; 0.5-5 mg/mL); sodium carboxymethylcellulose or microcrystalline cellulose (1-15 mg/mL); phenyl ethanol (1-4 mg/mL); and dextrose (20-50 mg/mL). The pH of the final suspension may be adjusted to range from about pH 5 to pH 7, typically about pH 5.5.

For ophthalmic administration, the active compounds or prodrugs can be formulated as solutions, emulsions, suspensions, and the like, suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. patent nos. 6,261,547; U.S. patent No. 6,197,934; U.S. patent No. 6,056,950; U.S. patent No. 5,800,807; U.S. Pat. nos. 5,776,445; U.S. patent No. 5,698,219; U.S. patent No. 5,521,222; U.S. patent No. 5,403,841; U.S. patent No. 5,077,033; U.S. patent No. 4,882,150; and U.S. patent No. 4,738,851, each of which is incorporated herein by reference in its entirety.

For delayed delivery, the active compound or prodrug may be formulated as a depot (depot) formulation for administration by implantation or intramuscular injection. The active ingredient may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt. Alternatively, transdermal delivery systems may be used which are manufactured as a suction cup or patch for the slow release of the active compound for transdermal absorption. To this end, penetration enhancers may be used to facilitate transdermal penetration of the active compound. Suitable transdermal patches are described, for example, in U.S. patent nos. 5,407,713; U.S. patent No. 5,352,456; U.S. patent No. 5,332,213; U.S. Pat. nos. 5,336,168; U.S. patent No. 5,290,561; U.S. patent No. 5,254,346; U.S. patent No. 5,164,189; U.S. patent No. 5,163,899; U.S. patent No. 5,088,977; U.S. patent No. 5,087,240; U.S. patent No. 5,008,110; and U.S. patent No. 4,921,475, each of which is incorporated herein by reference in its entirety.

Alternatively, other drug delivery systems may be employed. Liposomes and emulsions are examples of known delivery vehicles that can be used to deliver the active compounds or prodrugs. Certain organic solvents such as Dimethylsulfoxide (DMSO) may also be employed.

If desired, the pharmaceutical composition may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound. The package may, for example, comprise a metal or plastic foil, such as a blister pack. The packaging or dispensing device may be accompanied by instructions for administration.

The active compounds or prodrugs of the presently disclosed subject matter, or compositions thereof, will generally be used in an amount effective to achieve the desired result, e.g., in an amount effective to treat or prevent the particular disease being treated. The compound may be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a prophylactic benefit. A therapeutic benefit refers to the elimination or amelioration of the underlying disorder being treated and/or the elimination or amelioration of one or more symptoms associated with the underlying disorder such that the patient reports a sensory or pathological improvement, although the patient may still be afflicted with the underlying disorder. For example, administration of a compound to a patient suffering from an allergy provides a therapeutically beneficial effect not only when the underlying allergic reaction is eliminated or ameliorated, but also when the patient reports a decrease in the severity or duration of symptoms associated with the allergy following exposure to the allergen. As another example, therapeutic benefits in the context of asthma include improved breathing or reduced frequency or severity of asthma attacks following an asthma attack. Therapeutic benefits also include halting or slowing the progression of the disease, whether or not improvement is achieved.

For prophylactic administration, the compound may be administered to a patient at risk of developing one of the previously described diseases. As determined by an appropriate medical professional or panel, a patient at risk of developing a disease may be a patient having characteristics that cause the patient to be assigned to a designated population of at-risk patients. The patient at risk may also be a patient who is generally or often in a situation where progression may occur for a potential disease that may be treated by administration of a metalloenzyme inhibitor of the invention. In other words, a patient at risk is a person who is generally or commonly exposed to a disease or condition causing condition or who may be severely exposed for a limited time. Alternatively, prophylactic administration may be employed to avoid the onset of symptoms in patients diagnosed with an underlying condition.

The amount of the compound administered will depend on a variety of factors including, for example, the particular indication being treated, the mode of administration, whether the benefit desired is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular active compound, and the like. Determination of an effective dose is within the ability of those skilled in the art.

Effective doses may be estimated initially by in vitro assays. For example, the initial dose for use in an animal may be formulated to achieve a circulating blood or serum concentration of the active compound at or above the IC of the particular compound measured in an in vitro assay₅₀In vitro assays are, for example, in vitro fungal MIC or Minimum Fungicidal Concentration (MFC) and other in vitro assays described in the examples section. It is within the ability of one skilled in the art to calculate the dose to achieve this circulating blood or serum concentration taking into account the bioavailability of the particular compound. For guidance, see Fingl&Woodbury, "General Principles," In: Goodmanand Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp.1-46, 12 th edition, McGraw-Hill Professional, and references cited therein, which are incorporated herein by reference.

Initial doses can also be estimated from in vivo data, such as animal models. Animal models for testing the efficacy of compounds to treat or prevent the various diseases described above are well known in the art.

The dosage will generally be in the range of about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower depending on, among other factors, the activity of the compound, its bioavailability, mode of administration, and the various factors discussed above. The dosage amounts and intervals can be adjusted individually to provide plasma levels of the compound sufficient to maintain a therapeutic or prophylactic effect. In the case of topical administration or selective uptake, such as topical administration, the effective local concentration of the active compound cannot be correlated with the plasma concentration. The skilled artisan is able to optimize effective topical dosages without undue experimentation.

The compound may be administered once daily, several times or several times daily, or even multiple times daily, depending on, among other factors, the indication being treated and the judgment of the prescribing physician.

Preferably, the compounds will provide therapeutic or prophylactic benefit without causing substantial toxicity. Standard pharmaceutical procedures can be used to determine the toxicity of the compounds. The dose ratio of toxic to therapeutic (or prophylactic) effect is the therapeutic index. Compounds that exhibit high therapeutic indices are preferred.

Recitation of a list of chemical groups in the definition of any variable herein includes definitions of the variable as any single group or combination of groups listed. Recitation of embodiments of variables herein includes embodiments that are presented as any single embodiment or in combination with any other embodiment or portions thereof. The recitation of embodiments herein includes embodiments that are a single embodiment or in combination with any other embodiment or portion thereof.

Agricultural applications

The compounds of formula I may be formulated as agriculturally acceptable acid addition salts. By way of non-limiting example, amine functions can form salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic, hydroxymethanesulfonic, and hydroxyethanesulfonic acids. Further, by way of non-limiting example, the acid function may form salts, including salts derived from alkali or alkaline earth metals, as well as salts derived from ammonia and amines. Examples of preferred cations include sodium, potassium and magnesium.

The compounds of formula I may be formulated as salt derivatives. By way of non-limiting example, salt derivatives may be prepared by contacting the free base with a sufficient amount of the desired acid to form a salt. The free base can be regenerated by treating the salt with an appropriate dilute aqueous base solution, such as dilute aqueous solutions of sodium hydroxide (NaOH), potassium carbonate, ammonia, and sodium bicarbonate. By way of example, in many cases, pesticides such as 2,4-D are made more water soluble by converting them to their dimethylamine salt.

Suitable salts include those derived from alkali or alkaline earth metals, as well as those derived from ammonia and amines. Preferred cations include sodium, potassium, magnesium and ammonium cations of the formula:

R¹⁰R¹¹R¹²R¹³N⁺

wherein R is¹⁰、R¹¹、R¹²And R¹³Each is independentStands for hydrogen or C₁～C₁₂Alkyl radical, C₃～C₁₂Alkenyl or C₃～C₁₂Alkynyl, each of which is optionally substituted by one or more hydroxy, C₁～C₄Alkoxy radical, C₁～C₄Alkylthio or phenyl substituted with the proviso that R¹⁰、R¹¹、R¹²And R¹³Are spatially compatible. Furthermore, R¹⁰、R¹¹、R¹²And R¹³Any two of which may together represent an aliphatic difunctional moiety containing from 1 to 12 carbon atoms and up to two oxygen or sulfur atoms. Salts of the compounds of formula I may be prepared by: the compounds of formula I are prepared by treatment with a metal hydroxide, such as sodium hydroxide, with an amine, such as ammonia, trimethylamine, diethanolamine, 2-methylthiopropylamine, diallylamine, 2-butoxyethylamine, morpholine, cyclododecylamine or benzylamine, or with a tetraalkylammonium hydroxide, such as tetramethylammonium hydroxide or choline hydroxide. Amine salts are generally the preferred form of the compounds of formula I because they are water soluble and participate in the preparation of desirable water-based herbicidal compositions.

The compounds and compositions herein can be used in a method of modulating metalloenzyme activity in a microorganism on a plant, the method comprising contacting the compounds herein with a plant (e.g., seed, seedling, grass, weed, grain). The compounds and compositions herein can be used to treat plants, fields, or other agricultural areas (e.g., as herbicides, insecticides, growth regulators, etc.) by applying the compounds or compositions to the target plants, fields, or other agricultural areas (e.g., contacting, applying, spraying, misting, dusting, etc.). Application can be carried out before or after unearthing. Administration may be a therapeutic or prophylactic regimen.

One aspect is a method of treating or preventing a fungal disease or disorder in or on a plant comprising contacting a compound (or composition) of any of the formulae herein with the plant. Another aspect is a method of treating or preventing fungal growth in or on a plant comprising contacting a compound (or composition) of any of the formulae herein with the plant. Another aspect is a method of inhibiting a microorganism in or on a plant comprising contacting a compound (or composition) of any of the formulae herein with the plant.

The compounds and compositions herein can be used in a method of preventing or controlling a pathogen-induced disease on a plant, the method comprising contacting the compounds herein with the plant (e.g., seed, seedling, grass, weed, grain) or an area adjacent to the plant. The compounds and compositions herein can be used to treat plants, fields, or other agricultural areas by applying the compounds or compositions to the target plants, fields, or other agricultural areas (e.g., contacting, applying, spraying, misting, dusting, etc.). Application can be carried out before or after unearthing. Administration may be a therapeutic or prophylactic regimen. As such, the compounds, compositions and agricultural uses herein include lawn, turf, ornamental, home and horticultural, agricultural, pasture grass applications. The pathogen may be any pathogen on a plant, including those described herein.

One embodiment of the present disclosure is the use of a compound of formula I for protecting a plant from attack by a phytopathogenic organism or for treating a plant infested by a phytopathogenic organism, which comprises applying the compound of formula I or a composition comprising the compound to the soil, the plant, a part of the plant, the leaves and/or the seeds.

Furthermore, another embodiment of the present disclosure is a composition useful for protecting plants from attack by phytopathogenic organisms and/or for treating plants infested by phytopathogenic organisms, comprising a compound of formula I and a phytologically acceptable carrier material.

The compounds of the present disclosure may be applied as compounds or as formulations comprising the compounds by any of a variety of known techniques. For example, the compounds may be applied to the roots, seeds or leaves of plants for controlling various fungi without compromising the commercial value of the plants.

The compounds herein may be used alone or in combination with other agriculturally active agents. The use of a compound or composition (and compositions) herein may further comprise an additional active agent, for example an azole fungicide selected from the group consisting of epoxiconazole (epoxyconazole), tebuconazole (tebuconazole), fluquinconazole (fluquinconazole), flutriafol (flutriafol), metconazole (metconazole), myclobutanil (myclobutanil), cyproconazole (cyproconazole), prothioconazole (prothioconazole) and propiconazole (propiconazole).

The use of a compound or composition (and compositions) herein may further comprise an additional active agent, for example an azole fungicide selected from trifloxystrobin (trifloxystrobin), pyraclostrobin (pyraclostrobin), orysastrobin (orysastrobin), fluoxastrobin (fluoxastrobin) and azoxystrobin (azoxystrobin).

Preferably, the compounds of the present disclosure are used in the form of a formulation comprising one or more compounds of formula I together with an agriculturally or phytologically acceptable carrier. For example, compositions comprising the compounds herein may be used in the form of directly sprayable aqueous solutions, powders, suspensions, and highly aqueous, oily or other suspensions or dispersions, emulsions, oil dispersions, pastes, dusts, materials for dispersion, or granules by spraying, atomizing, sprinkling, scattering, or pouring.

The present disclosure contemplates all vehicles by which one or more compounds can be formulated for delivery and use as fungicides. Typically, the formulations are used as aqueous suspensions or emulsions. Aqueous use forms can be prepared from emulsion concentrates, suspensions, pastes, wettable powders or water-dispersible granules by adding water. For the preparation of emulsions, pastes or oil dispersions, the substances themselves or dissolved in oils or solvents can be homogenized in water by wetting, viscosity-increasing, dispersing or emulsifying agents. However, it is also possible to prepare concentrates composed of active substance, wetting agent, tackifier, dispersant or emulsifier and, if appropriate, solvent or oil, which are suitable for dilution with water.

Wettable powders can be compacted to form water-dispersible granules comprising a homogeneous mixture of one or more compounds of formula I, an inert carrier and a surfactant. The concentration of the compound in the wettable powder can be from about 10 wt% to about 90 wt%, more preferably from about 25 wt% to about 75 wt%, based on the total weight of the wettable powder. In the preparation of wettable powder formulations, the compounds may be mixed with any finely divided solid such as pyrophyllite, talc, chalk, gypsum, fuller's earth, bentonite, attapulgite, starch, casein, gluten, montmorillonite clay, diatomaceous earth, purified silicates and the like. In such operations, finely divided carrier and surfactant are typically mixed with the compound and milled.

Particles may be prepared by combining the active ingredient (e.g., a compound herein) with a solid carrier, such as coated particles, impregnated particles, and homogeneous particles. The solid carrier is a mineral earth such as silica, silica gel, silicate, talc, kaolin, limestone, lime, chalk, bole, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium oxide, ground synthetic material; fertilizers such as ammonium sulfate, ammonium phosphate, ammonium nitrate, urea; and products of vegetable origin, such as cereal flours, bark flours, wood and nutshell flours, cellulose flours; or other solid support.

The compounds herein may be formulated as tablets, capsules, solids, liquids, emulsions, slurries, oils, fine particles or powders of ordinary skill suitable for application to plants, fields or other agricultural areas. In a preferred embodiment, the formulation includes between 1 and 95% (e.g., 1,2,3, 4,5, 6, 7, 8,9, 10, 25%, 75%, 80%, 90%, 95%) of the compound herein in a carrier or diluent. The compositions described herein include a compound of the general formula described herein, and additional agricultural agents (if present), in an amount effective to control (e.g., modulate, inhibit) a metalloenzyme-mediated agricultural disease or disorder.

In one approach, the compounds herein are provided in an encapsulated formulation (liquid or powder). Specific materials suitable for use in the capsule material include, but are not limited to, porous particulates or matrices, such as silica, perlite, talc, clay, pyrophyllite, diatomaceous earth, gelatin and gels, polymers (e.g., polyureas, polyurethanes, polyamides, polyesters, etc.), polymeric particles, or cellulose. These include, for example, hollow fibers; a hollow tube or conduit through the wall to release the compounds identified herein; a capillary tube for releasing the compound from the opening of the conduit; polymeric blocks of different shapes such as strips, blocks, sheets, discs releasing the compound from the polymer matrix; a membrane system that holds the compound within an impermeable container and releases the compound through a permeable membrane that is measured; and combinations of the foregoing. Examples of such dispensing compositions are polymer laminates, polyvinyl chloride pellets, and microcapillaries.

The encapsulation process is generally divided into chemical or mechanical processes. Examples of chemical process encapsulation include, but are not limited to, complex coacervation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in situ polymerization, drying in liquid, thermionic gelation in liquid media, desolvation in liquid media, starch-based chemical processes, entrapment in cyclodextrins, and liposome formation. Examples of mechanical process encapsulation include, but are not limited to, spray drying, spray freezing, fluidized bed, electrostatic deposition, centrifugal extrusion, spinning disk or rotating suspension separation, annular jet encapsulation, polymerization at the liquid-gas or solid-gas interface, solvent evaporation, pressurized extrusion, or spraying into a solvent extraction bath.

Microcapsules are also suitable for the long-term release of the active compounds herein. Microcapsules are small particles containing a core material or active ingredient surrounded by a coating or shell. The size of the microcapsules typically varies between 1 and 1000 microns, with capsules smaller than 1 micron being classified as nanocapsules and capsules larger than 1000 microns being classified as macrocapsules. The core payload typically varies between 0.1 to 98 weight percent. The microcapsules may have a variety of structures (continuous core/shell structure, multi-core structure, or monolithic structure) and have irregular or geometric shapes.

In another aspect, the compounds herein are provided as an oil delivery system. The oil-releasing substance comprises vegetable oil and/or mineral oil. In one embodiment, the matrix also contains a surfactant, which makes the composition readily dispersible in water; these surfactants include wetting agents, emulsifying agents, dispersing agents and the like.

The compounds of the present invention may also be provided as emulsions. Water-in-oil (w/o) or oil-in-water (o/w) emulsion formulations can be found. Droplet sizes can vary from nano-sized (colloidal dispersions) to hundreds of microns. Various surfactants and thickeners are commonly incorporated into the formulation to alter the droplet size, stabilize the emulsion, and modify the release.

Emulsifiable concentrates of the compounds of formula I may include a convenient concentration of the compound, for example, from about 10 wt% to about 50 wt% of the compound in a suitable liquid, based on the total weight of the concentrate. The compound may be dissolved in an inert carrier which is a water-miscible solvent or a mixture of a water-immiscible organic solvent and an emulsifier. The concentrate may be diluted with water and oil to form a spray mixture in the form of an oil-in-water emulsion. Useful organic solvents include aromatic solvents, particularly the high boiling naphthalene and alkene portions of petroleum, such as heavy aromatic naphtha. Other organic solvents may also be used, such as terpene solvents, including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol.

The emulsifying agent which may be advantageously used herein may be readily determined by one skilled in the art and includes various nonionic, anionic, cationic and amphoteric emulsifying agents, or a mixture of two or more emulsifying agents. Examples of nonionic emulsifiers that can be used to prepare the emulsifiable concentrates include polyalkylene glycol ethers, and condensation products of alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, propylene oxide, for example ethoxylated alkyl phenols, and carboxylic acid esters dissolved with polyhydric alcohols or polyoxyalkylenes. The cationic emulsifier includes quaternary ammonium salt compound and fatty amine salt. Anionic emulsifiers include oil-soluble salts (e.g., calcium salts) of alkylaryl sulfonic acids, oil-soluble salts of sulfated polyglycol ethers, and suitable salts of phosphated polyglycol ethers.

Representative organic liquids that can be used to prepare emulsifiable concentrates of the compounds of the present invention are aromatic liquids, such as xylene, propylbenzene fractions; or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids, such as dioctyl phthalate; kerosene; dialkylamides of various fatty acids, in particular dimethylamides of aliphatic glycols and glycol derivatives (e.g. n-butyl, ethyl or methyl ether of diethylene glycol, methyl ether of triethylene glycol), petroleum distillates or hydrocarbons, such as mineral oils, aromatic solvents, paraffin oils, etc.; vegetable oils such as soybean oil, rapeseed oil, olive oil, castor oil, sunflower oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, tung oil and the like; esters of the above vegetable oils; and so on. Mixtures of two or more organic liquids may also be used in the preparation of emulsifiable concentrates. The organic liquid includes xylene and propylbenzene fractions, with xylene being most preferred in some cases. The surface active dispersants are generally used in the liquid formulation in an amount of 0.1 to 20 wt% based on the total weight of the dispersant and one or more compounds. The formulations may also contain other compatible additives, for example, plant growth regulators and other biologically active compounds used in agriculture.

Aqueous suspensions include suspensions of one or more water-insoluble compounds of formula I dispersed in an aqueous vehicle at a concentration of about 5 wt% to about 50 wt%, based on the total weight of the aqueous suspension. The suspension was prepared by: one or more compounds are finely ground and the ground material is vigorously mixed into a medium consisting of water and a surfactant selected from the same types described above. Other ingredients, such as inorganic salts and synthetic or natural gums, may also be added to increase the density and viscosity of the aqueous medium. By preparing the aqueous mixture and homogenizing it in equipment such as a sand mill, ball mill or piston homogenizer, simultaneous grinding and mixing is often most effective.

Aqueous emulsions comprise an emulsion of one or more water-insoluble pesticidally active ingredients, typically emulsified in an aqueous vehicle at a concentration of about 5 wt% to about 50 wt%, based on the total weight of the aqueous emulsion. If the pesticidally active ingredient is a solid, it must be dissolved in a suitable water-immiscible solvent prior to preparing the aqueous emulsion. The emulsion is prepared by emulsifying the liquid insecticidal active ingredient or a water-immiscible solution thereof into an aqueous medium typically containing a surfactant which, as noted above, aids in the formation and stabilization of the emulsion. This is often achieved by means of intensive mixing provided by a high shear mixer or homogenizer.

The compounds of formula I may also be applied as granular formulations, which are particularly useful for application to soil. Granular formulations typically contain from about 0.5% to about 10% by weight of the compound, based on the total weight of the granular formulation, dispersed in an inert carrier which consists entirely or to a large extent of coarsely divided inert material such as attapulgite, bentonite, diatomaceous earth, clay or similar inexpensive materials. Such formulations are generally prepared by the following method: the compound is dissolved in a suitable solvent and applied to a particulate support which has been preformed to an appropriate particle size of from about 0.5 to about 3 mm. Suitable solvents are those in which the compound is substantially or completely soluble. Such formulations may also be prepared by the following method: a dough or paste of the carrier and the compound and solvent is made, and comminuted and dried to give the desired particulate particles.

Alternatively, the compounds of the invention may also be formulated as solid tablets and comprise (preferably consist essentially of) an oil, a protein/carbohydrate material (preferably a plant species), a sweetener, and an active ingredient for the prevention or treatment of a metalloenzyme-mediated agricultural disease or condition. In one embodiment, the present invention provides a solid tablet and comprises (and preferably consists essentially of) an oil, a protein/carbohydrate material (preferably a plant), a sweetener, and an active ingredient (e.g., a compound herein or a combination or derivative thereof) for preventing or treating a metalloenzyme-mediated agricultural disease or condition. Tablets typically contain about 4-40% by weight (e.g., 5%, 10%, 20%, 30%, 40%) of an oil (e.g., vegetable oils such as corn oil, sunflower oil, peanut oil, olive oil, grape seed oil, tung oil, radish oil, soybean oil, cottonseed oil, walnut oil, palm oil, castor oil, sweet chestnut oil (earth almond oil), hazelnut oil, avocado oil, sesame oil, croton oil, cocoa butter, linseed oil, rapeseed oil, and canola oil and hydrogenated derivatives thereof; petroleum derived oils (e.g., paraffin and petrolatum), and other water immiscible hydrocarbons (e.g., paraffin). The tablet further comprises about 5-40% (e.g., 5%, 10%, 20%, 30%, 40%) by weight of a vegetable based protein/carbohydrate material. The material contains a carbohydrate fraction (e.g., derived from a cereal such as wheat, rye, barley, oats, corn, rice, millet, sorghum, bird feed (birdsed), buckwheat, alfalfa (alfalfa), mielga, corn flour, soybean flour, cereal flour, wheat middling (wheat midling), wheat bran, corn gluten meal, seaweed meal, dried yeast, beans, rice) and a protein fraction.

Optionally, a variety of excipients and binders may be used in order to aid in the delivery of the active ingredient or to provide a suitable structure for the tablet. Preferred excipients and binders include anhydrous lactose, microcrystalline cellulose, corn starch, magnesium stearate, calcium stearate, zinc stearate, sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose, and mixtures thereof.

Powders containing a compound of formula I may be prepared by: one or more compounds in powder form are homogeneously mixed with a suitable dusty agricultural carrier (e.g., such as kaolin, ground volcanic rock, etc.). The powder may suitably contain from about 1 wt% to about 10 wt% of the compound, based on the total weight of the powder.

The preparation may additionally contain auxiliary surfactantAnd (b) an organic solvent to facilitate deposition, wetting and penetration of the compound onto target crops and organisms. These co-surfactants may optionally be used as formulation components or as a pot mix. The amount of co-surfactant will generally vary from 0.01 to 1.0 vol%, preferably 0.05 to 0.5 vol%, based on the sparged volume of water. Suitable co-surfactants include, but are not limited to, ethoxylated nonylphenols, ethoxylated synthetic or natural alcohols, salts of sulfosuccinic acid or esters, ethoxylated silicones, ethoxylated fatty amines, mixtures of surfactants with mineral or vegetable oils, crop oil concentrates (mineral oil (85%) + emulsifiers (15%)); nonylphenol ethoxylate; benzyl coconut alkyl dimethyl quaternary ammonium salt; a mixture of petroleum hydrocarbons, alkyl esters, organic acids, and anionic surfactants; c₉～C₁₁An alkyl polyglycoside; a phosphorylated alcohol ethoxylate; natural primary alcohol (C)₁₂～C₁₆) An ethoxylate; di-sec-butylphenol EO-PO block copolymers; a polysiloxane-methyl cap; nonylphenol ethoxylate + urea ammonium nitrate; emulsifying the methylated seed oil; tridecyl alcohol (synthetic) ethoxylate (8 EO); tallow amine ethoxylate (15 EO); PEG (400) dioleate-99. The formulation may also include oil-in-water emulsions, such as those disclosed in U.S. patent application No. 11/495,228, the disclosure of which is expressly incorporated herein by reference.

The formulations may optionally include combinations comprising other pesticidal compounds. Such additional pesticidal compounds may be fungicides, insecticides, herbicides, nematocides, miticides, arthropodicides (arthopodides), bactericides or combinations thereof that are compatible with the compounds of the present invention in the medium of choice of application and do not antagonize the activity of the compounds of the present invention. Thus, in this embodiment, the other pesticidal compound is used as a supplemental toxicant for the same or different pesticidal uses. The compound of formula I and the pesticidal compound may generally be present in a weight ratio of from 1:100 to 100: 1.

The compounds of the present disclosure may also be combined with other fungicides to form fungicidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure are often used in combination with one or more other fungicides to control a wide variety of undesirable diseases. When used in combination with other fungicides, the compounds claimed in the present invention can be formulated with other fungicides, mixed with other fungicides in a tank, or used sequentially with other fungicides. Such other fungicides may include 2- (thiocyanomethylthio) -benzothiazole, 2-phenylphenol, 8-hydroxyquinoline sulphate, ametoctradin (ametocraddin), asulam (amisulbactam), antimycin, parasiticide (ampelomyces quisquilis), azaconazole (azaconazole), azoxystrobin (azoxystrobin), bacillus subtilis (Bacillus subtilis), benalaxyl (benalaxyl), benomyl (benomyl), benthiavalicarb (benthiavalicarb-isopyral), benomycotine (BABS) salt, bicarbonate, biphenyl, bismerthiazol (bismerthiazol), bitertanol (bixasol), bixafen, blasticidin-S, borax, Bordeaux (Bordeaux) mixture, boscalid (boscalid), bacteroides (bismerfenbuconazole), pyrimethanil (carbobenzopyrimethanil), carbobenzopyrimethanil (carbobenzopyrimethanil), carboxim (carboxim), carboxim (carboxim, Carvone, dicyclopentadienyl (chloroneb), chlorothalonil (chlorothalonil), ethiprole (chlorozolite), Coniothyrium minitans (Coniothyrium minitans), copper hydroxide, octanone, copper oxychloride, copper sulphate (tribasic), cuprous oxide, cyazofamid (cyazofamid), cyflufenamid (cyflufenamid), cymoxanil (cymoxanil), cyproconazole (cyproconazole), cyprodinil (cyprozolil), dazomet (dazomet), debacarb), ethylenebis- (dithiocarbamate) diammonium salt, benfluanid (dichlofluanid), dichlofenan (dichlorophthalen), dichlorphenamid (diclofenamid), diclofenamid (diclocyanide), pyridazone (diclomelane), nicamide (diclofenan), dichlorphenazine (diclofenapyr), dinotefuran (dichlorphenazine), dinotefuran (difenon), dinotefuran (fenpyr), dinotefuran (fenapyr (dimethrin), dinotefuran (fenpyr), dinotefuran (dimethofen), fenapyr (dimethoxin), dimethoxin (, Moroxydine (dodemorph), moroxydine acetate, dodine (dodine), dodine free base, edifenphos (edifenphos), enestrobin, epoxiconazole (epoxiconazole), ethaboxam (ethaboxam), ethoxyquin (ethloxyquin), hymexazole (etridiazole), famoxadone (famoxadone), fenamidone (fenamidone), fenamidol (fenarimol), fenbuconazole (fenbuconazole), methylfuran (fenfuram), fenhexamid (fenhexamide), fenhexamid (fenpropinil), fenpropidium (fenpropidium), fenpropidin (fenpropidium), fenpropimorph (fenpropidium), fenthifenpropidin (fenthifenthiuron), fenpropineb (fenpropineb), fenpropineb (fenpropizine), fenpropizine (fenpropizine), fenpropiconazole (fenpropiconazole), fenpropiconazole (fenpropiconazole), fenpropiconazole (flufenamidone), flufenamidofen (flufenamidofen), flufenamidofen (fenflurazone), flufenamidone (fenflurazone), flufenamidofen (fenflurazone), flufen-ethyl (fenflurazone), fenflurazone (fenflurazone), fenflurfenflurazone (fenflurazone), fenflurazone (fenflurfenflurfenflurazone), fenflurazone), fenflurfenflurazone (fenflurazo, fluthianil, flutolanil, flutriafol, fluxapyroxad, folpet, formaldehyde, triethylphosphonic acid, fosetyl-aluminum, fuberidazole, furalaxyl, guazatine acetate, GY-81, hexachlorobenzene, hexaconazole, hymexazol, imazalil sulfate, imibenconazole, iminoctadine triacetate, iminoctadine tris (octane benzenesulfonate), 3-iodo-2-propynyl-butylcarbamate (iodocarb), iprodione, isoprotuazone, isoproturon, isoprothiolane (isoprothiolane), isoproturon (isoproturon), isophytamide (isophytamide), isoprothiolane (isophytamide), isoprothiolane (isophytamide), isophytamide (isoprothiolane (isophytamide), isophytamide (isophytamide), isophyt, Kasugamycin hydrochloride hydrate, kresoxim-methyl, mancozeb, mandipropamid, maneb, mefenoxam, mepanipyrim, dinotefuran, mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl-M, methoprim, metam potassium, metam sodium, metconazole, sulbactam, methiocarb, iodomethane, methyl isothiocyanate, metiram, metominostrobin, metam, metominostrobin, metiroxoside, metiromone ketone, metrafenone, milbemycin, trifloxystrobin, oxine-copper (oxine-copper), oxpoconazole (oxpoconazole) fumarate, oxycarboxin (Oxycarboxin), pefurazoate (pefurazoate), penconazole (penconazole), pencycuron (pencycuron), penflufen (penflufen), pentachlorophenol, pentachlorophenyl laurate, penthiopyrad, phenylmercuric acetate, phosphonic acid, benzofuranone, picoxystrobin (picoxystrobin), polyoxin B, polyoxin, dactinomycin (oxypolyhm), potassium bicarbonate, potassium hydroxyquinoline sulfate, probenazole (probenazole), prochloraz (prochlororaz), procymidone (procymidone), propamocarb (propamocarb), propamocarb hydrochloride, propiconazole, zinc methidastream (prophyrazine), proquinazine (prothromazine), prothioconazole (prothioconazole), pyraclostrobin (pyraclostrobin), pyrimethanil (pyriproxyfen), pyriproxyfen (pyriproxyfen), pyriproxyfen (pyriproxyfen, pyriofenone, pyroquilon (pyroquilon), quinoxalone (quinoxyfen), quinoxyfen (quinoxyfen), quintozene (quintozene), giant knotweed (Reynotria sachalinensis) extract, sedaxane, silthiofam (silthiofam), simeconazole (simeconazole), sodium 2-phenylbenzoate, sodium bicarbonate, sodium pentachlorobenzoate, spiroxamine (spiroxamine), sulfur, SYP-Z071, SYP-Z048, tar, tebuconazole (tebuconazole), tebufloquin (tebufenoquine), tetraoxynitrobenzene (tecnazene), tetraconazole (tefluconazol), thiabendazole (thiabendazole), thifluzamide (thifluzamide), thiophanate-methyl (thiophanate-methyl), thiram (thiflufenamate), trifloxystrobin (trifloxystrobin), trifloxystrobin (trifloxystrobin), trifloxystrobin (trifloxystrob, Validamycin, valifenalate, cymoxanil (valiphilal), vinclozolin (vinclozolin), zineb (zineb), ziram (ziram), zoxamide (zoxamide), Candida olivaceus (Candida olephina), Fusarium oxysporum (Fusarium oxysporum), gliocladium sp, phyllobiopsis gigantea, Streptomyces griseoviridis, Trichoderma (Trichoderma, Trichoderma p.), (RS) -N- (3, 5-dichlorophenyl) -2- (methoxymethyl) -succinimide, 1, 2-dichloropropane, 1, 3-dichloro-1, 1,3, 3-tetrafluoroacetone hydrate, 1-chloro-2, 4-dinitronaphthalene, 1-chloro-2-nitropropane, 2- (2-alkyl-2-imidazolidinyl) ethanol, 2,3-dihydro-5-phenyl-1, 4-dithiine-1, 1,4,4-tetraoxide (2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4, 4-tetroxide), mercury 2-methoxyethylacetate, mercury 2-methoxyethyl chloride, mercury 2-methoxyethyl silicate, 3- (4-chlorophenyl) -5-methylrhodanine, 4- (2-nitroprop-1-enyl) phenylthiocyanateme, 1-aminopropyl phosphate (ampropylfos), trichlozoline (anilazine), thiram oxide (azothiiram), barium polysulfide, Bayer 32394, benoril (benodanil), trichlozen (benquinox), benzalurone (benzacril); isobutyl enoate (benzacril-isobutryl), cinnoline (benzamorf), binapacryl (binapacryl), dimemeryl sulfate, dibutyl tin oxide, buthionine (buthiobate), cadmium calcium copper zinc chromate sulfate, morcarb (carbamorph), CECA, fenpropiconazole (chlorobenhiazone), dichlofluanid (chlorendiform), 2- (2-chlorophenyl) -1H-benzimidazole (chlorofenazole), tetrachloroquinoxaline (chloroquinox), climbazole (climbazole), cyclbamine (cycloafuramid), cyhalothrin (cybendazole), ipropamid (cypiofum), decafentin (decafentone), dichloronaphthoquinone (dichloquinone), sclerotium (dinine), chlorotriadimenol (chlorodino), dinotefuran (chlorodinotefuran), dinotefuran (dinotefuran), dinotefuran (dineofos), dinotefuran (dinotefuran), dinotefuran (ethicone), dinotebutrin (ethicone), dinotebutrin (ethicone), dinotebensul), dinoteben), dinotebensul (E (ethicone (E (propiconazole), dinite), dinethicone (propiconazole), dineothiuron (propineb, Ethirimum (ethirim), dimetachlone (fenaminosulf), fenacet (fenapanil), pefurazote (fenitropan), triflumizole (flutriazole), difuramide (furacanil), furconazole (furconazole), cis-furconazole, fenchloramide (furmeclocox), furbensulfuron (furicaron), furbensulfuron (furocarone), glyodine (glyodine), griseofulvin (griseofulvin), quinolinylacrylate (halamate), Hercules 3944, cyclohexaphos (hexythiofos), ICIA0858, nonoxyphos (isopamphos), climbazole (isovalene), mefenamide (benil), benzocarb (mecarbizid), metachlorodiuron (metaxolone), furazamide (metiroxamine), thiflufenamidothiofenamide (fenamidothiofenamide), thiuracil (3-5-methyl-5-fenpropioamide (3-5-methyl-ethyl-sulfamethoxazole), thiuramicin (3-5-methyl-5, 3-chlorambucil, 3, 4-ethyl-sulfamethoxazole, 3-5, 5-N-sulfonylurea, thiuracil (furbenclamide, furazol, furamex, furbenclamide, thiuron, thi, Nickel bis (dimethyldithiocarbamate), OCH, phenylmercuric dimethyldithiocarbamate, phenylmercuric nitrate, phosophos (phosdiphen), picolinamide (picolinamide) UK-2A and its derivatives, propamocarb (prothiocarb); amphenicol hydrochloride, bifurcate (pyracarbolid), cyanophyte (pyridinitil), prochloraz (pyroxychlor), pyrrofuryl (pyroxyfur), hydroxyquinolinylone (quinacetol), hydroxyquinolinylone sulfate, quinophthalone (quinazamid), diniconazole (quinconazol), pyrimidazole (rabenzazole), salicylanilide, SSF-109, dapsone (Sultropen), thiram (tecoram), thiadiflor (thiocyofen), thiochlorobenzimide (thiochlorofenthim), thiophanate (thiophanate), gram (thioquinox), tioxymid (thiophanate), fenprophos (trimetaphorin), fenpyrad (trichlamid), fenpyrad (trichlamide), pyrimethanil (triafol), tetrachloraz (triazotriazole (triazaflavium), trichlamide (trichlamide), cyanamide (trichlamide), and camide (triazamide), and any combination thereof.

In addition, the compounds of the present invention may be combined with other insecticides, nematicides, acaricides, arthropodicides, fungicides or combinations thereof which are compatible with the compounds of the present invention in the application of the chosen medium and which do not antagonize the activity of the compounds of the present invention to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure may be used in combination with one or more other pesticides to control a wider variety of harmful pests. When used in combination with other insecticides, the claimed compounds can be formulated with other insecticides, mixed with other insecticides in a tank, or used sequentially with other insecticides. Typical insecticides include, but are not limited to: 1, 2-dichloropropane, abamectin (abamectin), acephate (acephate), acetamiprid (acetamiprid), housefly phosphorus (acethion), acetoprole (acetoprole), flumethrin (acrinathrin), acrylonitrile, alanycarb (alanycarb), aldicarb (aldicarb), aldicarb (aldoxycarb), aldrin (aldrin), allethrin (allethrin), alodamin (alloamidin), carbaryl (alloxycarb), alpha-cypermethrin (cypermethrin), alpha-carboximide (alfa), thiobensulindac (amidophil), thiobensulide (amidothione), amifostine (amidophos), amifostine (azophos), pyradinium (azophos), tetramisothion (azathion), thiocarb (amidophos), azathion (azathion), azathiopyr (azathion), azathiocarb (azathion), thiopyr (azathion), azathiopyrathion (azathion), thiopyrathion (azathion), thiocarb (azophos), thion (azathion), azathion (azathion), thion (azathion), azathion (azathion), azathion, Benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin, bifenthrin, bioallethrin, bifenthrin, brobifenthrin, bromfenadine, bromodehydrophos, bromodithiopyr, bromophos, ethidium bromide, carbosulfan, buprofezin, carbosulfan, carbonotoximide, butoxycarb, buthionate, carbosulfan, calcium bisulfide, carbosulfan, Chlorantraniliprole (chlorantraniliprole), borneolum (chloronicotinene), chlordane (chloredane), chlordecone (chlorodebone), chlordimeform (chlorfenamate), chlorfenapyr (chlorfenapyr), chlorfluazuron (chlorfluazuron), chlormephos (chlormephos), chloroform, chloropicrin (chloropirrin), chlorfenapyr (chlorfenaxim), pyridinum (chlorozophores), chlorpyrifos (chlorpyrifos), chlorpyrifos-methyl, chlorfenamate (chlorfenapyr), cycloprothiofos (chlorofenapyr), cyhalothrin (cypermethrin I, cyfluthrin II, cyhalothrin (cypermethrin), chlorpyrifos (chlorpyrifos), chlopyrifos (chlorpyrifos), cyhalothrin (chlorpyrifos), cyhalothrin), chlorpyrifos (chlorpyrifos), chlorpyrifos (chlorpyrifos), cyhalothrin, chlorpyrifos (chlorpyrifos), cyhalothrin, chlorpyrifos (chlorpyrifos), cyhalothrin, chlorpyri, Cyantraniliprole (cyantraniliprole), cyhalothrin (cyethrin), cycloprothrin (cycloprothrin), cyfluthrin (cyfluthrin), cyhalothrin (cyhalothrin), cypermethrin (cypermethrin), cyphenothrin (cyphenothrin), cyromazine (cyromazine), fenthiofos (cythionate), DDT, decarbofuran, deltamethrin (deltamethrin), demeton (demephin), tianlephos-O, tianlephos-S, demeton (demeton), demeton-O, demeton-S, thiophosphoron-S, sulfothiotepa (demeton-S), diafenthiuron (diafenthiuron), chlorothiafos (diafenthiuron), dithiazine (diafenthiuron), dithianon (dithianon), dithianon (cyclomethidathion), dithiopyrafluthrin (cyclomethionin), dithiocarb (dithiocarb), dithiocarb (dithiocarb), dithiocarb (dithiocarb), dithiocarb, Meflofos (dimefox), dimethoate (dimethoan), dimethoate (dimethoate), bifenthrin (dimethlin), methoprene (dimethylvinphos), dichlorcaserin (dimetilan), dinotefuran (dinex), dinex-diclex, dinoropp (dinocan), dinetol (dinosam), dinotefuran (dinotefuran), benchol ether (diofenolan), dinotefuran (dioxabenzofos), dioxacarb (dioxacarb), diphenocarb (dioxazoc), dinothion (dioxathion), diethylpropion (disoprophos), dithicrons (dithifons), dithicrons, d-limonene, DNOC-ammonium salt, county-potassium salt, DNOC-sodium salt, doramectin (doramectin), phytosterol (ecdysterone), dieemamectin (mectins), benzoate, EMP (empenthrin), thionphos (thionoprin), thionphos (epoxythion), thionphos (epoxythione), thiomethoprene (isopropyl-N), thiomethoprene (ethiofenphos), thion (isopropyl-N), thiomethoprene, methoprene (isopropyl-N), thiomethoprene, methoprene, metho, Ethion (ethion), ethiprole (ethiprole), acerbate (ethofenprox), ethoprophos (ethoprophos), ethyl formate, ethyl-DDD, ethylene dibromide, ethylene dichloride, ethylene oxide, ethofenprox (ethofenprox), ethirimos (ethimfos), EXD, famshur (famshur), fenclofos (fenamiphos), fentrazole (fenzaflor), pyraflufos (fenchlophos), diethylphenol methyl carbamate (fentehacarb), pentafluorobenzene pyrethrin (fenflurthrin), fenthion (fenstrothion), fenobucarb (fenobucarb), fenoxacrimer, fenoxycarb (fenoxycarb), pycnaphenthrin (npirithrin), methrin (fenpropathrin), fenpropathrin (fenflurazon), fenfluroxyphos (fenflurazon), fenflurazon (fenflurazon, fenflurazon (fenflurazon), fenflurazon, Flufenoxuron (flufenoxuron), trifloxystrobin (flufenprox), butene-fipronil (flufiprole), flupyradiuron (fluvalinate), fonofos (fonofos), varroate (formanate), vamiprid (vaminium), vamiprid hydrochloride (vampire), formoxyl (formothrion), varroate (formosanate), clofentrazone hydrochloride (furametpyr), fentrazone (fenthion), fenthion (fosetyl), fosaprate (fosfamate), malathion (fosthion), furathiocarb (furathiocarb), pyrethrum (furathirin), gamma-cyhalothrin (cyhalothrin), gamma-HCH, benzoxim (halofenrox), chlorfenapyr (halofenozide), HCH (halofenozide), HEOD (heptachlor), heptenophos (hepethofen), hexythrozine (hexythrophos), hexythrophos (halothion), hexythrops (hexythrops), thiuron (propidium), chlorfenapyr (isopropyl), imidacloprid (isopropyl), pyrazone (propifos (propineb), pyrazone (propifos (propineb), imidacloprid (propifos (propidium), imidacloprid (propiconazole), imidacloprid, Isoprofos (isofenphos), methylisotalophos, isoprocarb (isoprocarb), isoprothiolane (isoprothiolane), isofenthion (isothioate), isoxathion (isoxathion), ivermectin (ivermectin), jasminum (jasmolin) I, jasminum II, iodophos (jodfenphos), juvenile hormone I, juvenile hormone II, juvenile hormone III, dioxolane (kelevan), methoprene (kinoprene), lambda-cyhalothrin (cyhalothrin), lead arsenate, lepimectin (lepimectin), bromophenol (leprophos), lindane (lindane), limphofos (lufenuron), thiothifenthion (lythifenphos), malathion (malathion), propathene (malonofezin), azathion (azathiozone), methidathion (methamphetan), methomethrin (methomethrin), methofen (methofen-methyl, Methiocarb (methoprene), ethofenphos (methocrotophos), methomyl (methomyl), methoprene (methoprene), methoxychlor (methoxychlor), methoxyfenozide (methoxyfenozide), methyl bromide, methyl isothiocyanate, methyl chloroform, methylene chloride, methofluthrin (methofluthrin), metolcarb (methoxazole), methoxazolone (methoxadiazole), methamphos (mefenphos), monocarbate (mexacarbate), milbemectin (milbemycin), milbemycin oxime (milbemycin oxide), propylamine fluoride (mipofox), mirarex (mirarex), monosultap (molosulfate), monocrotophos (monocrotophos), monosultap (monemorph), methoprene (fenozide), pyrifos (methoprene), pyrifenozide (fenozide), pyrifenozide (methoprene), pyribenazol (fenozide), pyribenazol), pyrifenozide (fenozide), pyribenazol (fenozide), pyribenazol), pyribenbenbenazol (fenozide (pyribenazol), pyribencarb (pyribencarb), pyribencarb (bencarb), pyri, Acephate (oxydemeton-methyl), sulfoisopulfone (oxydeprofos), sulfofenphos (oxydisulfoton), p-dichlorobenzene, parathion (parathion), methyl parathion, fluazuron (penfluron), pentachlorophenol, permethrin (permethrin), fenthion (phenokapton), phenothrin (phenothrin), phenthoate (phenoxate), phorate (phorate), phorate (phosate), phorate (phos), thiocyclophos (phosfolan), phosmet (phosmet), parathion (phosapor), phosphamidon (phosphamidon), phosphine, phoxim (phoxim), methyl phoxim, pirimiphos (pirimiphos), potassium methamidophos, thion (propylhomothion), propathrin (DDphosphocarb), propathrin (DDI), propathrin (propipons I), propathrin (propipons), propathrin (propipons (propathrin (I), propathrin (propathrin), prothromazine (propathrin (propipons (propathrin), propathrin (propathrin), benomyl), amipram (propetamphos), propoxur (prophogs), ethiofen (prothioconazole), prothioconazole (prothiochos), pomade (prothioconazole), protuberate (prothioate), protifenbate (pyraclofos), pyraclofos (pyraclofos), pyrafluprol (pyrazophos), pyrethrin (pyrethrin) I, pyrethrin II, pyrethrin (pyrethrin), pyridaben (pyridaben), pyridalyl (pyridalyl), pyridaphenthion (pyridaphenthion), pyrifluquinazon, pyriproxyfen (pyrimidin), pyrithion (pyrithion), pyrithion (pyrifluquinate), pyriproxyfen (pyriproxyfen), quassin (quinate), sodium silicate (quinalphos), methythion (quinate), pyrithion (pyraflufen), pyrithion (pyrafluthrin), thifluthrin (sodium benzoate), thifluthrin (sodium benzoate), thifluthrin (ben (fenphos (benfluoride), thiflubenazolate), thiflu, Spinosad (spinosad), spiromesifen (spiromesifen), spirotetramat (spirotetramat), sulcofuron sodium, sulfluramid (sulfluramid), sulfotep (sulfotep), sulfoxaflor (sulfoflur), sulfuryl fluoride, thioprophos (sulfoprofos), fluvalinate (tau-fluvalinate), thiafencarb (tazimcarb), TDE, tebufenozide (tebufenozide), tebufenpyrad (tebufenpyrad), butylpyrimidine (tebufirumps), teflubenzuron (tefluazuron), tefluthrin (tefluthrin), temephos (tefluthrin), tephrin (tephrin), TEPP, cycloprothrin (thiothrin), tebuthion (tetrachlorfens), tetrachloroethane, tebuforma (tetramethrin), tetramethrin (tetramethrin), thiofenthifenthifenphos (tetramethrin), thiofenthifenthifenprox (tetramethrin), thifenthifenthifenprox (tetramethrin), thifenthifenthifenthifenprox (tetram), thifenthifenthifenthifenthifenthifenthifenprox (tetram), thifenthifenthifenthifenthifenthifenthifenthifenthifenthifenthifenprox), thifenthifenthifenthifenthifenthifenprox (tetram), thifenthifenthifenthifenthifenthifenthifenthifen, Insecticidal bis (thiosulphate-sodium), monosultap (thiosulphate-sodium), benthiavalin (thiojinsin), tolfenpyrad (tolfenpyr), tralomethrin (tralomethrin), transfluthrin (transfluthrin), transpermethrin, fenazaquin (triaathene), triazamate (triazamate), triazophos (triazophos), trichlorfon (trichlopfon), triazophos (trichlorfon), triazophos (trichlorephos-3), triazophos (trichlore), triazophos (trichlorfon), profenofos (triflumuron), trimethacarb (trimethacarb), methoprene (triprene), triazophos (vamidothion), vanillyl (vanillyl), XMC, triazophos (zelnutro), triazacyclofos (triazacyclonothromazine), triazophos (triazophos), and mixtures thereof.

In addition, the compounds of the present invention may be combined with herbicides that are compatible with the compounds of the present invention in the medium of choice of application and do not antagonize the activity of the compounds of the present invention to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal compounds of the present disclosure can be used in combination with one or more herbicides to control a wide variety of harmful plants. When used in combination with a herbicide, the claimed compounds may be formulated with the herbicide, mixed with the herbicide in a tank, or used sequentially with the herbicide. Typical herbicides include, but are not limited to: 4-CPA; 4-CPB; 4-CPP; 2, 4-D; 3, 4-DA; 2, 4-DB; 3, 4-DB; 2, 4-DEB; 2, 4-DEP; 3, 4-DP; 2,3, 6-TBA; 2,4, 5-T; 2,4, 5-TB; acetochlor (acetochlor), acifluorfen (acifluorfen), aclonifen (aclonifen), acrolein (acrolein), alachlor (alachlor), butachlor (alidichlor), dicentrazon (alidochlor), diclofen (alloxidid), allyl alcohol, alorac, metrizalone (ametridione), ametryn (ametryn), tefluazinone (amicarbazone), amicarbazone (amicarbazone), amidosulfuron (amisulfuron), aminocyclopyrachlor (amicarbazone), aminopyralid (amicarbazone), amicarbazone (amicarbazone), amitrazine (amicarbazone), fenuron (aniron), asum), atrazine (amicarbazone), fentrazone (amicarbazone), fentrazine (fentrazone), flufentrazine (fentrazone), fentrazine (fentrazine), fentrazine (fentrazone (fentrazine), fenflurfenflurfenfluridone (fentrazine), fentrazine (fentrazine), fenfluridone (fentrazone (fentrazine), fenflurbenfluridone (fenfluridone (fentrazine), fenflurfenfluridone (fenfluridone (, Amino acid herbicide (benzadox), bensulfuron-methyl (benfendizone), benbenbencarb (bezipram), benzobicyclon (benzobicyclon), pyroxene (benzofenap), fluroxypyr (benzofluor), neodelphine (benzoxyprop), thifenuron (benzoazuron), bicyclopropylone, bifenox (bifenox), bialaphos (bialaphos), bispyribac (bispibiac), borax, bromacil (bromoacil), furofenapyr (bromobutyronitrile), bromobutachlor (bromobiuret), bromofenoxaprop (bromofenoxaprop), bromoxynil (bromoxynil), butafenapyr (bromoxynil), butachlor (butafenate), butachlor (butralin), butralin (butralin), butachlor (butralin), butralin (butralin), butralin (butralin) (butralin), butralin (butralin), butralin) (butralin), butralin (butralin), butralin (butralin), butralin (butralin, CDEA, CEPC, metoclopramide (chlorothoyfen), chloramben (chlor mben), diclofop (chlorenocryl), chlorazifop (clonazine), chlorsulfuron (chlorbromron), chlorfluazuron (chlorfluazuron), chloramburon (chloretone), trichlorofenac (chlorfenac), oatmeal (chlorfenphos), flufenacet (chlorfluazuron), policosanol (chlorflubenz), chlorphenamine (chlorfenazone), chlorimuron (chlorrimon), cumquat (chlorfenapyr), chlorropon (chlortoluron), chlortoluron (chlortoluron), fluazuron (chlorfluazuron), chlorfenapyr (chlorfenapyr), clofenapyr (chlorfenapyr), pyrin (chlorfenapyr), chlorfenapyr (clofenapyr), chlorfenapyr (chlorfenapyr), chlorfenapyr (chlorfenap), chlorfenapyr (chlorfenapyr), chlorfenapyr (clofenapyr), chlorfenapyr (clofenapyr (clofenap), chlorfenapyr (clofenap), clofenapyr (clofenap (clofenapyr (clofenap), clofenap (clofenapyr (clofenap), clofenapyr (clofenap), clofenap (clofenap), clofena, CPMF, CPPC, paraquat (cremazine), cresol, cumyluron (cumyluron), cyanazine (cycloxyyn), cyanazine (cyazone), cyhalofop (cyhalofop), cycloate (cycloate), sulforon (cyclosulfomuron), cycloxydim (cycloxydim), cyclouron (cyclouron), cyhalofop (cyhalofop), fast grass (cyperquat), cyromazine (cyromazine), trazofenacet (cyromazine), cyromazine (cyromazine), diumuron (diuron), dalton (dalapon), dazomet (dazomet), butachlor (delachlor), dichlofenan (desmediham), diclofen (desmethyn), diclofen (dimethomofen), diclofen (diclofen), diclofen (diclofen), diclofen (dic, Diflufenzopyr (diflufenzopyr), fenoxaprop (dimefuron), dimeglumine (dimepiperate), dimethenamid (dimethachllon), isovaleryl (dimethametryn), dimethenamid (dimethenamid), dimethenamid-P, dimethenamid (dimexano), pyridaben (dimodazon), dinoamine (dinitramine), dinotape (dinofenate), dinocap (dinoropp), dinocap (dinobam), dinocap (dinotefuran), dinotefuran (dinoseb), dinotefuran (dinotefuran), ipratron (dipamide), diquat (diquat), dinocap (dissultone), dithiopyr (dithiopyr), diuron (diuron), DMPA, OC, DSMA, Aegean (thion), sulfadiazinon (fenofos (dimethenan), Thiobensulfuron (TC), thiobac (fenoxafen (fenoxate (fenoxaprop-ethyl), thion (fenoxaprop-P), thiobencarb (dithiocarb), thion (dithiopyr), thiobencarb (dithiopyr), thiofon (dithiopyr (dithiocarb), thiofon (dithiocarb), dithiocarb (dithiocarb), dithiopyr (dithiocarb), dithiocarb (dithio, etnipromid, etobenemide (etobenazed), EXD, fenasulam, aldicacid (fenoprop), fenoxaprop (fenoxaprop), fenoxaprop-P, fenoxaprop, fenteracol, fenoxaprop-P, fluniprole (fenthiaprop), fentrazamide (fentrazamide), fenuron (fenoron), ferrous sulfate, lofop-butyl (fluproprop), lofop-M, flazasulfuron (fluzasulfuron), florasulam (flusilazole), flufenoxaprop-P, ipropyr (flufenoxaprop-P), fluazifop (flufenuron), flufenflurazone (flufenflurazon), flufenacet (flufenacet), flufenacet (flufen-P), flufenacet (flufenacet), flufen-P, flufenacet (flufen-P), flufenacet (flufen-P, flufenacet), flufenacet (flufen-P, flufen-n (flufenacet (flufen-P), flufen-n (flufen-n), flufen-n (flufen-methyl), flufenacet (flufen-n (flufen-methyl), flufenacet (flufen-n), flufenacet, Flupyrazoxazole (flupoxam), flupropacil, tetrafluoropropionic acid (flupropnate), flazasulfuron (flupyrsulfuron), fluazinone (fluridone), fludioxonil (fluuroxime), fluroxypyr (fluxapyr), flurtamone (flutatame), fluazifop (fluthiamide), fomesafen (fomesafen), glufosinate (fosfamuron), furazofen (furazafen), glufosinate (glufosinate), glufosinate-P, glyphosate (glyphosate), fluoronifloramide (halosafen), halosulfuron (halosulfuron), flurazidine (pyrazoxydine), fluroxypyr (haloxyfen), pyraflufen-P, pyraflufen (pyraflufen), pyrazosulfuron (pyrazosulfuron-ethyl), pyrazosulfuron-ethyl (pyrazosulfuron-ethyl), pyrazosulfuron (ethyl), pyrazosulfuron (ethyl, pyrazosulfuron), pyrazosulfuron (methyl), pyrazosulfuron (ethyl), pyrazosulfuron (pyrazosulfuron), pyrazosulfuron (methyl), pyrazosulfuron (ethyl, pyrazosulfuron), pyrazosulfuron (pyrazosulfuron), pyrazosulfuron (methyl, Methyl iodide, iodosulfuron (iodosulfuron), thifensulfuron (iofensulfuron), iofensulfuron (iofensulfuron), ioxynil (ioxynil), oxadiargyl (ipazine), ipfencarbazone, iprodiam, metalaxyl (isocarbamid), isofluridine (isoflurazone), butazone (isothiozin), isoproturon (isoflurane), isoproturon (isoproturon), isoxaflutole (isoxaflutole), isoxaflutole (isoxaflorotol), isoxaflutole (isoxaflutole), carboflutolate (ketospiradox), lactofen (isofluridone), clorac (isofluridone), pyributron (MCacil), metosultrin (MCP-4-methyl-2-metosultone (MCprofenon), metofen-4-methyl-2-ethyl, metosultrin (MCfluridone), metofen-P-4, metosultrin (MCfluridone, metosultrin-P-P, metosultrin (isofluridone), metosultrin (isofluridone, metosultrin-P, metosultrin (isofluridone, metosultrin, isoflurbensultrin, isofluridone, isoflurbensulbensulbensultrin, isoflurbenoxanil, isoflurbensulbensulbensultrin, mesotrione (mesotrione), metam (metam), metamifop (metamifop), metamitron (metamitron), metazachlor (metazachlor), metazosulfuron, metaflumuron (metaflumuron), methabenzthiazuron (methabenzthiazuron), methalpropalin (methazole), methbenencarb, methoxazole (methazolone), methiobencarb, methiozolin, methiconon (methabenzuron), metosulam (methabenzuron), metribuzin (methaprotrysone), metosulam (metosuluron), metosulam (metosultrin), metosulam (metosulam), metosulam (metosulron), metosulam (metosulpron), metosulpron (metoclopramide), metosulpron (metosulpron), metosulam), metosulpron (metoclopramide (metosulpron (metopron), metoclopramide (metosulam), metosulpron (metoclopramide (metosulpron-methyl, metosulam), metosulpron (metosulpron-methyl sulam), metosulam (metosulam), metosulpron (metosulam), metosulam (metosulam), metosulpron-methyl sulpron-methyl-, Benoxacor (nitrofen), norflurazon (norflurazon), cudweed (noruron), OCH, prosulfocarb (orbencarb), o-dichlorobenzene, orthosulfamuron (orthiosulfamuron), oryzalin (oryzalin), oxadiargyl (oxadiargyl), oxadiazon (oxadiarzonan), pyridaben (oxapyrazon), sulfosulfuron (oxasulfuron), oxadiargyl (oxaclomefone), oxyfluorfen (oxaflurazon), para-fluometuron (parafluuron), paraquat (paraquat), kephalam (pebuthalate), nonanoic acid, pendimethalin (penethamine), penoxsulam (oxyphenol), penoxfentrazone (penoxphil), penoxfenpyrane (penoxfenpyr), penoxsulam (penoxsulam), penoxsulam (penoxfen), penoxsulam (penoxsulam), penoxsulam (penoxfen), penoxfen-ethyl (penoxsulam), penoxfen), penoxsulam (penoxsulam), penoxsulam (pen, Potassium azide, potassium cyanate, pretilachlor (pretilachlor), primisulfuron (primisulfuron), propineb (procyclazine), prodiamine (prodiamine), flumetsulam (profluazol), cyflufen (proflualin), prothioconazole (profluodin), prothioconazole (profenodim), prometryn (prometryn), propachlor (propachlor), propanil (propaquizafop), propaquizafop (propazine), propaquiline (propham), propisochlor (propiochlor), propafenone (propaferon), propaferon (propaferon), pyrithiobac (propaferon), propaferon (propaferon), pyribencarb (propaferon), pyribensulfuron (propaferon), pyribensulam), pyribensulfuron (pyrazonyl), pyribensulfuron (pyriproxyfen (bensulfuron (benazol), pyriproxyfen (pyrazone), pyribenfurazon (benfurazon (bensulam), pyriproxyfen (bensulam), pyribensulfuron (bensulfuron), pyribensulfuron (bensulfuron (bensulam), pyribensulfuron (bensulfuron), pyribensulfuron (bensulfuron), pyribenazol), pyribensulbensulam), pyribenazol (benazol (bensulbensulam), pyribenazol (benazol), pyribenazol (benazol), pyribenazol (benazol), pyri, Pyriftalid (pyriftalid), pyriminobac-methyl (pyriminobac), pyriproxyfen (pyrimisulfan), pyrithiobac-methyl (pyrithiobac), pyroxasulfone, pyroxsulam (pyroxsulam), pyriftalid (quinclorac), chloromonovanic acid (quinmerac), chlorambucil (quinoxyne), quinozalin (quizalofop), quizalofop-P, thiocyananilide (rhodifanil), rimsulfuron (rimsulfuron), saflufenacil (saflufenacil), S-metolachlor (S-metolachlor), benthiazine (sebothylazine), dicentrazone (secbutumuron), sethoxydim (setron), thifenuron (silatran), thifenuron (silar), cetylamide (S-metosultone), thifensulfuron (S-methyl), metribuzin (fensulfuron), sodium sulfadiazine (sodium sulfadiazine), sodium sulfadiazine (sodium sulfadiazinon), sodium sulfadiazine (sodium sulfa), sodium sulfadiazine (sodium sulfa), sulfa (sodium sulfa), sulfosulfuron (sodium sulfas (thiamethoxam), sulfosulfuron (thiamethoxam), sulfosulfuron (bensulbensulfuron), bensulfuron), bensulbensulfuron (bensulfuron (, tefuryltrione, tembotrione, tepraloxydim, terfenadine (terbacil), terbutryn (terbucarb), terbutryn (terbuchlur), terbutylazron (terbuteton), terbutyron (terbuteton), terbuthylazine (terbutryzine), terbutryn (terfluron), tefluron (tefluron), methoxyfenacet (thenylchloride), thifluuron (thiazauron), thiazopyr (thiazopyr), thiadiazolidinium (thidiazuron), thidiazuron (thidiazuron), thifensulfuron (thifenuron), thifensulfuron-methyl), thifensulfuron (thifensulfuron-uron), thiofensulfolane (thiobencarbcarb), thiofenpyrone (thifentrazone), curon (thifenuron), thiobensultone (thifenuron), tiocarbazone (thifentrazone), thifentrazone (triafol), trifloxystrobin (trifloxystrobin), trifloxysulfuron (trifloxysulfuron), thifensulfuron (trifloxysulfuron), thiuron (trifloxysulfuron), thifensulfuron (trifloxysulfuron), thiuron (trifloxystrobin), thifensulfuron (trifloxystrobin), thifenpyrothiobenzosulfuron (trifloxystrobin), thifenpyrothiobenzothifensulfuron (trifloxysulfuron (trifloxystrobin), thiuron (trifloxystrobin), thifenuron (trifloxystrobin), thifenpyrothiobenuron (trifloxysulfuron (trifloxystrobin), thifensulfuron (trifloxys, Trihydroxytriazine, tritoluon, tripropinan, tritactritosulfuron, vernolate and xylacol.

Another embodiment of the present disclosure is a method of controlling or preventing fungal attack. The method comprises applying a fungicidally effective amount of one or more compounds of formula I to the soil, plant, root, foliage, seed or locus of the fungus, or to a locus in which infection is to be prevented (e.g., to a cereal plant). The compounds are suitable for treating a wide variety of plants at fungicidal levels while exhibiting low phytotoxicity. The compounds may be used in the form of protectants and/or eradicators.

The compounds have been found to have a significant fungicidal effect, in particular for agricultural use. Many of the compounds are particularly effective when used on agricultural and horticultural plants. Additional benefits may include, but are not limited to, improving the health of the plant; increasing the yield of a plant (e.g., increased biomass and/or increased content of valuable components); improving the vigor of the plant (e.g., improved plant growth and/or greener leaves); improving the quality of the plant (e.g., improved content or composition of certain ingredients); and increasing the tolerance of the plant to abiotic and/or biotic stress.

The composition of formula I may be effective against pathogen-induced diseases, wherein the plant fungal pathogen belongs to at least one species selected from the group consisting of: erysiphe (Blumeria), Sphaerotheca (Podosphaera), Sphaerotheca (Sphaerotheca), Uncaria (Uncinula), Erysiphe (Erysiphe), Puccinia (Puccinia), Hymenochaetes (Phakopsora), Gymnospora (Gymnospora), Camellia (Hemileia), Ruscus (Uromyces), Alternaria (Alternaria), Cercospora (Cercospora), Cladosporium (Cladosporium), Cochlospora (Cochliobolidolus), Colletotrichum (Coletotrichia), Macrochaeta (Magnaporthe), Mycosphaera (Mycosphaerella), Phaeophyceae (Phaeophyceae), Phaeophyceae (Pyrophora), Polyporus (Rhizoctonia), Aspergillus (Rhizoctonia), Rhizoctonia (Rhizoctonia), Rhizoctonia (Rhizoctonia), Rhizoctonia (Rhizoctonia), pseudocercospora (Pseudocercospora), Sclerotinia (Sclerotinia), Helminthosporium (Helminthosporium), Spodosporium (Stagonospora), Helminthosporium (Exserohilum) and Pyricularia (Pyricularia). Pathogens such as Venturia inaequalis, Septoria tritici (Septoria tritici), brown spot sugarbeet (Cecrosporbetula), brown spot peanut (Cecrosporia arachidicola), Colletotrichum cucumis (Colpolytrichum communis), Ruscus aculeatus (Colcotrichumlargenium), Puccinia graminis f.sp.tritici, Pucciniae (Puccinialondiatum tritici), Uncaria vinifera (Uncinula necator), Blumeria graminis (Blumeragramis) and Blakeslea melanosporum (Mycosphaerella fijiensis) can be controlled by the compositions of formula I. In addition, the compositions of formula I are effective in preventing or controlling diseases including apple scab, wheat leaf spot, sugar beet leaf spot, peanut leaf spot, cucumber anthracnose, wheat leaf rust, grape powdery mildew, wheat powdery mildew, and banana leaf spot.

The present invention provides kits for treating or preventing agricultural or plant diseases or disorders. In one embodiment, the kit comprises a composition comprising an effective amount of a compound herein in a form suitable for delivery to a site plant. In some embodiments, the kit comprises a container holding a compound herein (e.g., of any of the formulae herein); such containers may be boxes, ampoules, bottles, vials, tubes, bags, pouches, blister packs, or other suitable container forms known in the art. Such containers may be made of plastic, glass, laminated paper, metal foil, or other material suitable for holding the compound.

If desired, the compounds of the invention are provided with instructions for application to plants, fields, or other agricultural areas. The instructions generally include information for use of the composition for treating or preventing a metalloenzyme-mediated agricultural disease or disorder. In other embodiments, the instructions include at least one of the following: description of the compounds; dosage regimens and methods for treating or preventing metalloenzyme-mediated agricultural diseases or disorders; matters to be noted; a warning; a description of the survey study; and/or references. The instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate page, booklet, card or folder provided in or with the container.

The compounds of the present disclosure may be used in plants in amounts effective to inhibit disease and phytologically acceptable. The term "disease-inhibiting and phytologically acceptable amount" refers to an amount of a compound that kills or inhibits a plant disease in need of control, but does not have significant toxicity to the plant. This amount will generally be from about 0.1 to about 1000ppm (parts per million), preferably 1 to 500 ppm. The precise amount of the compound required will vary with the fungal disease to be controlled, the type of formulation used, the method of application, the particular plant species, the climatic conditions, and the like. Suitable application rates are generally largeAbout 0.10 to about 4 pounds per acre (about 0.01 to 0.45 grams per square meter, g/m)²) Within the range of (1).

Any ranges or desired values given herein can be extended or altered without losing the effect sought, as will be apparent to those skilled in the art in view of the teachings herein.

Examples

The invention will now be illustrated using specific examples, which should not be construed as limiting.

General Experimental procedure

The definitions of the variables in the structures in the schemes herein are commensurate with the definitions of the variables at the corresponding positions in the general formulae described herein.

Synthesis of azole targets

The synthesis of azole targets (compounds of formula I) can be accomplished using the exemplary synthesis shown below (scheme 1). In addition to the 2-pyridine example (D) below, a wide range of aromatic and heterocyclic rings can be prepared starting from functionalized haloaromatic starting materials (e.g., A). For the purposes of this example, R in formula I₄Is a halogenated benzene moiety.

An exemplary synthesis of the target of formula I begins with the condensation of A with copper-activated α -bromo-ethyl acetate followed by the condensation of the initial ethyl ester product with lithiated bromodifluorobenzene to give ketone B (scheme 1). the ketone is epoxidized with diazomethane to give C.the epoxide C is opened with n-butyllithium/trimethyl borate to give the corresponding boronic acid on treatment in the aqueous phase, which intermediate is converted to the alcohol via oxidation with oxone (oxone). Alcohol intermediate D can be prepared by using the necessary benzyl bromide (R)₅-Br; substituted benzyl ether) or converted to the corresponding ether (X ═ O) via aryl-boronic acid coupling (substituted phenyl ether). The epoxide is then opened with an azole to give the final product of formula I.

Route 1

Synthesis of 2- (5-bromopyridin-2-yl) -1- (2, 4-difluorophenyl) -2, 2-difluoroethanone (B)

To a suspension of copper powder (2.68 g (g), 42.2 mmol) in dimethylsulfoxide (DMSO; 35 mL (mL)) was added ethyl 2-bromo-2, 2-difluoroacetate (2.70mL, 21.10mmol), and the mixture was stirred at Room Temperature (RT) for 1h (h). 2, 5-dibromopyridine (2.50g, 10.55mmol) was then added and stirring continued at RT for 15 h. The reaction mixture was washed with aqueous phase (aq) ammonium chloride (NH)₄Cl) and quenched with dichloromethane (CH)₂Cl₂(ii) a 3 × 25 mL). The combined organic layers were washed with water (H)₂O) washing, washing with brine, and washing with anhydrous sodium sulfate (Na)₂SO₄) Dried and concentrated under reduced pressure to give a crude product mixture. Purification by column chromatography (eluting with ethyl acetate (EtOAc)/hexanes) gave the ethyl ester intermediate as a pale yellow oil (2.40g, 8.57mmol, 81%).¹H NMR(500MHz,CDCl₃):8.71(s,1H),8.00(d,J＝9.0Hz,1H),7.64(d,J＝9.0Hz,1H),4.42-4.35(m,2H),1.39-1.31(m,3H).

To a stirred solution of 1-bromo-2, 4-difluorobenzene (1.65g, 8.57mmol) in diethyl ether (Et) at-70 deg.C₂O; 10mL) was added to the solution in sequence 2.3 moles (M) of n-butyllithium (n-BuLi, hexane); 3.70mL, 8.57mmol), Et was added after 15min (min)₂O (5mL) of the above ester (2.40g, 8.57 mmol). The reaction mixture was stirred at-70 ℃ for 1h, warmed to RT and stirred for 2 h. The reaction mixture was washed with aq NH₄The Cl solution was quenched and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H₂O washing, brine washing, Na anhydrous₂SO₄Dried and concentrated under reduced pressure. The crude compound was purified by column chromatography (eluting with EtOAc/hexanes) to give ketone B as a yellow liquid (1.30g, 3.73mmol, 43%).¹H NMR(500MHz,CDCl₃):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):m/z 347,349[(M⁺+1)+2].

5-bromo-2- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridine (C)

Stirring Ketone B (1.30g, 3.73mmol) in Et at 0 deg.C₂To a solution in O (300mL) was added freshly prepared diazomethane and the mixture was warmed to RT. The reaction mixture was stirred for 2 h. Volatiles were removed under reduced pressure to give a crude product mixture. Column chromatography (eluting with EtOAc/hexanes) afforded ethylene oxide C (800mg, 2.20mmol, 59%) as a pale yellow solid.¹H NMR(500MHz,CDCl₃):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):m/z 362,364[(M⁺+1)+2].

6- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-ol (D)

To a stirred solution of n-BuLi (1.5M in hexane; 21mL, 33.13mmol) in dry Et at-78 deg.C₂To a solution of O (250mL) was added Compound C (8g, 22.09mmol) in Et₂Solution in O (50 mL). After stirring for 30min, trimethyl borate (5mL, 44.19mmol) was added to the reaction mixture at-78 deg.C and stirring continued for an additional 10 min. The reaction mixture was warmed to RT and stirred for 30 min. The reaction mixture was quenched with acetic acid (HOAc; 40mL) and H₂Diluted O (120mL) and stirred at RT for 1 h. The reaction mixture was made alkaline (pH-12) by adding 2 equivalents (N) of sodium hydroxide (NaOH), the organic layer was separated, and the aqueous layer was made acidic (pH-6) with 1N hydrochloric acid (HCl). The aqueous layer is replaced by CH₂Cl₂(2X 500 mL). The combined organic layers were washed with anhydrous Na₂SO₄Drying and concentrating under reduced pressure to give brown solidThe corresponding boronic acid as such (7g, 21.4mmol, 97%).¹H NMR(500MHz,CD₃OD):8.81(s,1H),8.15(d,J＝7.5Hz,1H),7.47(d,J＝8Hz,1H),7.36-7.35(m,1H),6.93-6.87(m,2H),3.42(d,J＝5.5Hz,1H),2.99-2.98(m,1H).MS(ESI):m/z 328.1[M⁺+1].

To a stirred solution of boric acid (0.6g, 1.83mmol) in acetone (5mL) at RT was added potassium persulfate (K)₂S₂O₈(ii) a 1.12g, 1.83mmol) in H₂O (5mL) and the mixture was stirred for 16 h. After consumption of the starting material (determined by Thin Layer Chromatography (TLC)), the volatiles were evaporated under reduced pressure and the residue was taken up in CH₂Cl₂(2X 30 mL). The combined organic layers were washed with saturated (santd) sodium bicarbonate (NaHCO)₃) The solution (5mL) was washed with brine (5mL) and dried over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography (SiO)₂100-; eluting with 10% EtOAc in hexanes) to give alcohol D as a white solid (0.3g, 1.0mmol, 54.6%).¹H NMR(500MHz,CDCl₃):8.81(s,1H),7.36-7.35(m,2H),7.25(d,J＝8Hz,1H),6.84(t,J＝8.5Hz,1H),6.73(t,J＝8.5Hz,1H),3.39(d,J＝5.5Hz,1H),2.99(d,J＝4.5Hz,1H).MS(ESI):m/z 299[M⁺+1].

Example 1

1- (5- (4-chloro-2-fluorobenzyloxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetra-benzyloxy) Azol-1-yl) propan-2-ol (1)

1- (bromomethyl) -4-chloro-2-fluorobenzene was prepared using the following two-step process. To a stirred solution of 4-chloro-2-fluorobenzaldehyde (1.0g,6.31mmol) in methanol (CH) at 0 deg.C₃OH; 15mL) was added sodium borohydride (NaBH)₄(ii) a 0.47g, 12.6 mmol). The reaction mixture was stirred at RT for 1 h. Consumption of starting MaterialAfter this time (as determined by TLC), the reaction mixture was quenched with ice and the volatiles were evaporated under reduced pressure. The residue is washed with H₂O (25mL) diluted and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with anhydrous Na₂SO₄Dried, filtered, and concentrated under reduced pressure. The crude material obtained is purified by column chromatography (SiO)₂100-200 mesh) to give the corresponding alcohol as a semi-solid (0.8g, 5.0mmol, 78.7%).¹H NMR(200MHz,CDCl₃):7.41(q,J＝8.0,15.6Hz,1H),7.17-7.05(m,2H),4.73(d,J＝6.2Hz,2H),1.83(t,J＝6.2Hz,1H).

To a stirring alcohol (0.8g, 5.0mol) in dry Et at 0 deg.C₂Phosphorus tribromide (PBr) was added to a solution in O (10mL)₃(ii) a 0.33mL, 3.5 mmol). The reaction mixture was stirred at RT for 3 h. After consumption of starting material (as determined by TLC), the reaction mixture was quenched with ice and the aqueous layer was extracted with EtOAc (2 × 75 mL). The combined organic layers were washed with saturated NaHCO₃Washing with anhydrous Na₂SO₄Drying, filtration, and concentration under reduced pressure gave 1- (bromomethyl) -4-chloro-2-fluorobenzene (0.6g,2.7mmol, 54%) as a pale yellow liquid.¹H NMR(200MHz,CDCl₃):7.41(q,J＝14.5,16.6Hz,1H),7.15-7.07(m,2H),4.46(s,2H).

To a stirred solution of alcohol D (0.2g, 0.66mmol) in N, N-dimethylformamide (DMF; 3mL) at RT was added 1- (bromomethyl) -4-chloro-2-fluorobenzene (0.14g, 0.66mmol) and potassium carbonate (K)₂CO₃(ii) a 0.09g, 0.66 mmol). The reaction mixture was gradually heated to 70 ℃ and stirred for 2 h. After consumption of the starting material (determined by TLC), the reaction mixture was washed with H₂Quench O and extract with EtOAc (2 × 50 mL). The combined organic layers were washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The crude material obtained is purified by column chromatography (SiO)₂100-; eluting with EtOAc/hexanes) to give Compound E as a white solid (0.25g,0.56mmol, 85%).¹H NMR(200MHz,CDCl₃):8.39(d,J＝2.8Hz,1H),7.46-7.27(m,4H),7.25-7.17(m,2H),6.88-6.68(m,2H),5.14(s,2H),3.43(d,J＝5.2Hz,1H),2.96(d,J＝5.2Hz,1H).

To a stirred solution of compound E (0.25g,0.56 mmol) in DMF (4mL) under inert atmosphere at RT was added 1H-tetrazole (0.05g, 0.85mmol) followed by K₂CO₃(0.07g, 0.56 mmol). The reaction mixture was gradually heated to 65 ℃ and stirred for 24 h. Subjecting the reaction mixture to hydrogenation with H₂Quench O and extract with EtOAc (2 × 50 mL). The combined organic layers were washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The crude material obtained is purified by column chromatography (SiO)₂100-; eluting with EtOAc/hexanes) to give 1 as an off-white solid (0.07g, 0.15mmol, 26%).¹H NMR(500MHz,CDCl₃):8.73(s,1H),8.25(d,J＝2.0Hz,1H),7.52(d,J＝8.5Hz,1H),7.49(s,1H),7.41-7.30(m,3H),7.20-7.16(m,2H),6.77-6.73(m,1H),6.67(t,J＝3.4Hz,1H),5.56(d,J＝14Hz,1H),5.14(s,2H),5.08(d,J＝14Hz,1H).MS(ESI):m/z 512.1[M⁺+1].HPLC:98.07％.

Using the same conditions as for compound 1 (example 1), compounds 19-74, 83 and 113-118 of Table 1 were prepared from intermediate D and the commercially available or prepared benzyl halide or alkyl halide (see Table 1 starting materials) and the commercially available azole.

Example 2

1- (5- (2, 4-difluorobenzyloxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazole- 1-Yl) propan-2-ol (2)

To a stirred solution of alcohol D (0.3g, 1.0mmol) in DMF (5mL) at RT was added K₂CO₃(0.27g, 2.0mmol) and 1- (bromomethyl) -2, 4-difluorobenzene (I-1, prepared as in example 13; 0.2g, 1.0 mmol). The reaction mixture was gradually heated to 70 ℃ and stirred for 5 h. After consumption of the starting material (as determined by TLC), the volatiles were evaporated under reduced pressure. The residue is washed with H₂O (5mL) diluted and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure. The crude material obtained is purified by column chromatography (SiO)₂100, 200 mesh) eluted with 7% EtOAc in hexanes to give the ether product as a semi-solid (0.25g, 0.59mmol, 58.6%).¹H NMR(500MHz,CDCl₃):8.38(d,J＝2.5Hz,1H),7.48-7.35(m,3H),7.27(d,J＝2.5Hz,1H),6.93-6.81(m,3H),6.75(t,J＝2.0Hz,1H),5.14(s,2H),3.42(d,J＝5.5Hz,1H),2.96(d,J＝5.5Hz,1H).MS(ESI):m/z 425[M⁺+1].

To a stirred solution of the ether product (0.25g, 0.58mmol) in DMF (5mL) at RT under an inert atmosphere was added 1H-tetrazole (0.06g, 0.88mmol) followed by K₂CO₃(0.08g, 0.58 mmol). The reaction mixture was gradually heated to 65 ℃ and stirred for 7 h. Removing the volatiles under reduced pressure; the residue is washed with H₂O (5mL) was diluted and extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with Na₂SO₄Dried and concentrated under reduced pressure. The crude material obtained is purified by column chromatography (SiO)₂100, 200 mesh) eluted with 20% EtOAc in hexanes to give 2 as an off-white solid (0.11g, 0.22mmol, 38%).¹HNMR(500MHz,CDCl₃):8.74(s,1H),8.25(d,J＝3.0Hz,1H),7.52(d,J＝11.0Hz,2H),7.45-7.41(m,1H),7.36-7.31(m,2H),6.95-6.90(m,1H),6.90-6.86(m,1H),6.77-6.73(m,1H),6.88-6.85(m,1H),5.57(d,J＝14.5Hz,1H),5.12(s,2H),5.08(d,J＝14.5Hz,1H).MS(ESI):m/z 495[M⁺+1].HPLC:98.89％.

Example 3

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (3-fluorobenzyloxy) pyridin-2-yl) -3- (1H-tetrazole-1- Base) propan-2-ol (3)

To be similar to the compound 1Compound 3 was prepared from 1- (bromomethyl) -3-fluorobenzene as a syrup (0.02g, 0.04mmol, 15.5%).¹H NMR(500MHz,CDCl₃):8.73(s,1H),8.25(d,J＝2.5Hz,1H),7.52(t,J＝3.5Hz,2H),7.40-7.26(m,3H),7.17(d,J＝9.5Hz,1H),7.12-7.04(m,2H),6.77-7.6.75(m,1H),6.66(t,J＝9.0Hz,1H),5.56(d,J＝14.0Hz,1H),5.12(s,2H),5.06(d,J＝14.5Hz,1H).MS(ESI):m/z 478.2[M⁺+1].HPLC:99.49％.

Example 4

1- (5- (4-chlorobenzyloxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-) Alkyl) propan-2-ol (4)

Compound 4 was prepared from 1- (bromomethyl) -4-chlorobenzene in analogy to compound 1, to give a slurry (0.04g, 0.08mmol, 28.7%).¹H NMR(500MHz,CDCl₃):8.73(s,1H),8.23(d,J＝2.0Hz,1H),7.51(d,J＝8.5Hz,2H),7.40(d,J＝8.5Hz,2H),7.34-7.29(m,2H),7.28(dd,J＝9.0,3.0Hz,1H),6.77-6.73(m,1H),6.67(t,J＝7.0Hz,1H),5.55(d,J＝14Hz,1H),5.09(s,2H),5.08(d,J＝14.5Hz,2H).MS(ESI):m/z 494.1[M⁺+1].HPLC:99.43％.

Example 5

4- (6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl Oxy) benzonitrile (5)

Molecular sieves under stirring (0.5g,) In CH₂Cl₂To the suspension (10mL) were added 4- (cyanophenyl) boronic acid (0.24g, 1.6mmol), alcohol D (0.5g, 1.6mmol), copper (II) acetate (Cu (OAc)₂(ii) a 0.31g, 1.6mmol) and pyridine (0.65mL, 8.0 mmol). The reaction mixture was stirred at RT for 24 h. After consumption of the starting material (as determined by TLC), the reaction mixture was passed throughFiltering with a pad, and filteringBed CH₂Cl₂(10mL) washing. The filtrate was washed with saturated copper (II) sulfate (CuSO)₄) The solution (25mL) was washed and CH was used₂Cl₂(3X50 mL). The combined organic layers were washed with anhydrous Na₂SO₄And (5) drying. After filtration and evaporation, the crude material is subjected to column chromatography (SiO)₂100-; eluting with EtOAc/hexanes) to give F as a liquid (0.1g, 0.25mmol, 15%).¹H NMR(200MHz,CDCl₃):8.47(d,J＝6.5Hz,1H),7.72(d,J＝6.5Hz,2H),7.55-7.36(m,3H),7.14-7.04(m,2H),6.91-6.70(m,3H),3.46(d,J＝13.0Hz,1H),3.01(d,J＝5.0Hz,1H).MS(ESI):m/z 401.5[M⁺+1].

To a stirred solution of compound F (0.12g, 0.3mmol) in DMF (2mL) at RT under inert atmosphere was added 1H-tetrazole (0.03g, 0.45mmol) followed by K₂CO₃(0.04g, 0.3 mmol). The reaction mixture was heated at 60 ℃ for 16 h. Subjecting the reaction mixture to hydrogenation with H₂O (20mL) diluted and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with Na₂SO₄Dried and concentrated under reduced pressure. The crude material obtained is purified by column chromatography (SiO)₂100-; eluting with EtOAc/hexanes) to give 5 as a yellowish liquid (0.03g, 0.06mmol, 21%).¹H NMR(500MHz,CDCl₃):8.73(s,1H),8.25(d,J＝2.5Hz,1H),7.73(d,J＝9.0Hz,2H),7.64(d,J＝9.0Hz,1H),7.49-7.42(m,2H),7.18(s,1H),7.13(d,J＝8.5Hz,2H),6.83-6.74(m,2H),5.40(d,J＝14.0Hz,1H),5.27(d,J＝14.5Hz,1H).MS(ESI):m/z471.1[M⁺+1].HPLC:99.33％.

Using the same conditions as compound 5 (example 5), compounds 75-82 in table 1 were prepared from intermediate D and commercially available boronic acids (see table 1 starting materials) and commercially available azoles.

Example 6

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (4-fluorophenoxy) pyridin-2-yl) -3- (1H-tetrazole-1- Yl) propan-2-ol (6)

Compound 6 was prepared from (4-fluorophenyl) boronic acid in a similar manner to compound 5 to give 6(0.1g, 0.22mmol, 42.4%) as a solid.¹H NMR(500MHz,CDCl₃):8.73(s,1H),8.20(d,J＝2.5Hz,1H),7.53(d,J＝9.0Hz,1H),7.43-7.38(m,2H),7.27(d,J＝2.5Hz,1H),7.26-7.03(m,4H),6.79-6.70(m,2H),5.49(d,J＝14.5Hz,1H),5.15(d,J＝14.5Hz,1H).MS(ESI):m/z 494.1[M⁺+1].HPLC:99.43％.

Example 7

1- (5- (4-chlorophenoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1- Alkyl) propan-2-ol (7)

Compound 7 was prepared from (4-chlorophenyl) boronic acid in a similar manner to compound 5 to give a solid (50mg, 0.1mmol, 35.7%).¹H NMR(500MHz,CDCl₃):8.73(s,1H),8.22(d,J＝2.5Hz,1H),7.54(d,J＝8.5Hz,1H),7.46-7.37(m,3H),7.30(dd,J＝3.0,9.0Hz,1H),7.04-7.00(m,2H),6.80-6.77(m,1H),6.76-6.71(m,1H),5.49(d,J＝14.5Hz,1H),5.16(d,J＝14.5Hz,1H).MS(ESI):m/z 479[M⁺+1].HPLC:98.43％.

Example 8

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5-methoxypyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-one Alcohol (8)

Compound 8 was prepared from 2-bromo-5-methoxypyridine in a similar manner to compound 1 to give a tan solid (28mg, 10%).¹H NMR(500MHz,CDCl₃):8.74(s,1H),8.19(s,1H),7.63(br s,1H),7.51(d,J＝8.5Hz,1H),7.34-7.33(m,1H),7.24-7.23(m,1H),6.75-6.74(m,1H),6.67-6.66(m,1H),5.58(d,J＝14.0Hz,1H),5.07(d,J＝14.0Hz,1H),3.88(s,3H).MS(ESI):m/z 382[M⁺-1].HPLC:92.37％.

Example 9

4- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-one) Yl) oxy) methyl) benzonitrile (9)

Compound 9 was prepared from 4- (bromomethyl) benzonitrile in a similar manner to compound 1 to give a white solid (80mg, 33%).¹H NMR(500MHz,CDCl₃):8.73(s,1H),8.24(s,1H),7.72(d,J＝7.5Hz,2H),7.75-7.52(m,3H),7.43(br s,1H),7.39-7.35(m,1H),7.31-7.29(m,1H),6.78-6.74(m,1H),6.70-6.67(m,1H),5.51(d,J＝14.0Hz,1H),5.18(s,2H),5.13(d,J＝14.0Hz,1H).MS(ESI):m/z 485[M⁺+1].HPLC:97.12％.

Compound 83 in table 1 was prepared from intermediate D using the same conditions as compound 9 (example 9).

Example 10

4- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-one) Yl) oxy) methyl) -2-fluorobenzonitrile (10)

Compound 10 was prepared from 4- (bromomethyl) -2-fluorobenzonitrile in a similar manner to compound 1 to give a white solid (90mg, 36%).¹H NMR(500MHz,CDCl₃):8.73(s，1H)，8.23(s，1H)，7.70-7.67(m,1H),7.56(d,J＝8.5Hz,1H),7.38-7.36(m,2H),7.32-7.29(m,3H),6.78-6.74(m,1H),6.71-6.68(m,1H),5.50(d,J＝14.5Hz,1H),5.17(s,2H),5.15(d,J＝14.5Hz,1H).MS(ESI):m/z 503[M⁺+1].HPLC:95.84％.

Example 11

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5-phenoxypyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-one Alcohol (11)

Compound 11 was prepared from phenylboronic acid in a similar manner to compound 5 to give a solid (30mg, 8.7%).¹HNMR(500MHz,CDCl₃):8.74(s,1H),8.25(s,1H),7.52(d,J＝8.5Hz,1H),7.49(br s,1H),7.45-7.35(m,3H),7.30-7.29(m,1H),7.28-7.27(m,1H),7.06(d,J＝7.5Hz,2H),6.79-6.74(m,1H),6.72-6.69(m,1H),5.54(d,J＝14.0Hz,1H),5.12(d,J＝14.0Hz,1H).MS(ESI):m/z446.8[M⁺+1].HPLC:99.5％.

Example 12

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- (2,2, 2-trifluoroethoxy) pyri-dine Pyridin-2-yl) propan-2-ol (12)

Compound 12 was prepared from 1,1, 1-trifluoro-2-iodoethane in a similar manner to compound 1 to give a pale yellow solid (23.0mg, 50%).¹H NMR(500MHz,CDCl₃):8.73(s,1H),8.27(s,1H),7.56(d,J＝9.0Hz,1H),7.35-7.30(m,2H),7.21(br s,1H),6.78-6.73(m,1H),6.69-6.66(m,1H),5.55(d,J＝14.5Hz,1H),5.12(d,J＝14.5Hz,1H),4.43(q,J＝8.0Hz,2H).MS(ESI):m/z 452.1[M⁺+1].HPLC:98.05％.

EXAMPLE 13 preparation of intermediates

(1- (bromomethyl) -2, 4-difluorobenzene) (I-1)

To a stirred solution of 2, 4-difluorobenzaldehyde (500mg, 3.52mmol) in CH at 0 deg.C₃To a solution in OH (8mL) was added NaBH in portions₄(266mg, 7.04mmol) and the reaction mixture was stirred at 0 ℃ for 1 h. After completion of the reaction (confirmed by TLC), CH was removed under reduced pressure₃OH, cooling with ice H₂O (40mL) diluted and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with H₂O (40mL) and brine (40mL), washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Tong (Chinese character of 'tong')Purification by column chromatography on silica eluting with 10% EtOAc in hexanes provided alcohol G as a colorless liquid (450mg, 3.12mmol, 88%).¹H NMR(200MHz,CDCl₃):7.45-7.33(m,1H),6.83-6.75(m,2H),4.72(s,2H),1.79(br s,OH).

To compound G (450mg, 3.12mmol) in Et at 0 deg.C₂PBr was added to a solution in O (10mL)₃(0.2mL, 2.18mmol) and the mixture was stirred at RT for 2 h. After completion of the reaction (confirmed by TLC), the reaction mixture was cooled with ice H₂O (20mL) was quenched and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with H₂O (40mL) and brine (40mL), washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica eluting with 5% EtOAc in hexanes provided bromide I-1 as a colorless liquid (420mg, 2.02mmol, 65%).¹H NMR(200MHz,CDCl₃):7.43-7.31(m，1H)，6.92-6.77(m,2H),4.48(s,2H).

3-fluoro-4- (mercaptomethyl) benzonitrile (I-2)

A mixture of 4- (bromomethyl) -3-fluorobenzonitrile (0.8g, 3.7mmol) and thiourea (0.57g, 7.4mmol) in ethanol (EtOH; 20mL) was heated at reflux for 1 h. The progress of the reaction was monitored by TLC; the reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was washed with EtOAc (50mL), treated with 1.6N NaOH, and stirred at RT for 20 h. The reaction mixture was adjusted to pH 4 with concentrated HCl and diluted with Et2O (50 mL). Subjecting the organic layer to H₂O (25mL) and brine (25mL) and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give crude I-2(300 mg). The crude material was used without further purification.¹HNMR(500MHz,CDCl₃):7.45(dd,J＝9.5Hz,1.5Hz,1H),7.40-7.37(m,2H),3.76(s,2H).

1- (bromomethyl) -4- (2,2, 2-trifluoroethoxy) benzene (I-3)

To a stirred solution of 2,2, 2-trifluoroethanol (10.0g, 100mmol) in CH at 0 ℃ under an inert atmosphere₂Cl₂Triethylamine (Et) was added to the solution (100mL)₃N; 27.8mL, 200mmol), p-toluenesulfonyl chloride (19.1g, 100mmol) and a catalytic amount of 4-dimethylaminopyridine (DMAP; 10 mg). The reaction mixture was allowed to warm to RT and stirring was continued for 5 h. Subjecting the reaction mixture to hydrogenation with H₂Diluted with O (100mL) and CH₂Cl₂(3X 200mL) extraction. The combined organic extracts are washed with H₂O (50mL) and brine (50mL), washed with anhydrous Na₂SO₄Drying and concentration under reduced pressure gave compound H as a semi-solid (25.0g, 98.42 mmol; crude).¹H NMR(200MHz,CDCl₃):7.81(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,2H),4.35(q,J＝8.0Hz,2H),2.47(s,3H).MS(ESI):m/z256[M+2]⁺.

4-hydroxybenzaldehyde (0.24g, 1.97mmol) and K under stirring at RT under an inert atmosphere₂CO₃(1.36g, 9.84mmol) to a suspension in DMF (5mL) was added compound H (0.5g, 1.97 mmol). The reaction mixture was heated to 80 ℃ and stirred for 18 h. After completion of the reaction (confirmed by TLC), the reaction mixture was cooled with ice H₂O (25mL) was quenched and extracted with EtOAc (4X 25 mL). The combined organic extracts are washed with H₂O (25mL) and brine (25mL) and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica gel eluting with 10% EtOAc in hexanes provided Compound I as a pale yellow oil (0.4g, 1.8mmol, 93%).¹H NMR(200MHz,CDCl₃):9.93(s,1H),7.90(d,J＝9.0Hz,2H),7.06(d,J＝9.0Hz,2H),4.44(q,J＝8.0Hz,2H).

To stirring I (0.4g, 1.8mmol) in CH at 0 deg.C₃NaBH was added to a solution in OH (10mL)₄(0.14g, 3.6mmol) and the mixture was stirred for 1 h. After completion of the reaction (confirmed by TLC)Deemed) was added to the reaction mixture. The reaction mixture was then cooled with ice H₂O (40mL) diluted and extracted with EtOAc (2 × 40 mL). The combined organic extracts are washed with H₂O (40mL) and brine (40mL), washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by silica gel column chromatography eluting with 20% EtOAc in hexanes provided J as a colorless liquid (0.3g, 1.35mmol, 75%).¹H NMR(200MHz,CDCl₃):7.33(d,J＝9.0Hz,2H),6.93(d,J＝9.0Hz,2H),4.64(d,J＝6.0Hz,2H),4.35(q,J＝8.0Hz,2H),1.58(t,J＝6.0Hz,OH).

To a stirring mixture of Compound J (0.3g, 1.35mmol) in Et at 0 deg.C₂PBr was added to a solution in O (10mL)₃(0.25g, 0.95mmol) and the reaction mixture was stirred at RT for 1 h. After complete consumption of the starting material (confirmed by TLC), the reaction mixture was cooled with ice H₂O (30mL) quenched and extracted with EtOAc (3 × 30 mL). The combined organic extracts are washed with H₂O (30mL) and brine (30mL), over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica gel eluting with 10% EtOAc in hexanes provided compound I-3 as a colorless liquid (0.25g, 0.87mmol, 65%).¹H NMR(200MHz,CDCl₃)：7.36(d,J＝9.0Hz,2H),6.91(d,J＝9.0Hz,2H),4.49(s,2H),4.35(q,J＝8.0Hz,2H).

6- (bromomethyl) nicotinonitrile (I-4)

To a stirred solution of 6-methylnicotinonitrile (1.0g, 8.47mmol) in 1, 2-dichloroethane (30mL) was added N-bromosuccinimide (NBS; 1.52g, 8.54mmol) followed by 2,2' -azobis (isobutyronitrile) (AIBN; 0.14g, 0.85mmol) at RT. The reaction mixture was then heated to 80 ℃ and stirred for 14 h. After complete consumption of the starting material (confirmed by TLC), the reaction mixture was cooled to RT and the volatiles were removed under reduced pressure to give a crude material. Passing through a silica gel column layerPurification by chromatography eluting with 10% EtOAc in hexanes provided compound I-4 as a colorless liquid (0.6g, 3.05mmol, 36%).¹H NMR(500MHz,CDCl₃):7.67-7.62(m,2H),7.21(dd,J＝9.0,2.0Hz,1H),4.44(s,2H).

(3, 5-Difluoropyridin-2-yl) methyl 4-methylbenzenesulfonate (I-5)

To a solution of (3, 5-difluoropyridin-2-yl) methanol (0.25g, 0.7mmol) in tetrahydrofuran (THF; 10mL) was added potassium hydroxide (KOH; 0.14g, 2.55mmol) at RT and the mixture was stirred for 15 min. P-toluenesulfonyl chloride (0.42g, 2.21mmol) was added slowly at RT and the reaction mixture was stirred for a further 18 h. After complete consumption of the starting material (confirmed by TLC), the reaction mixture was washed with H₂O (50mL) diluted and extracted with EtOAc (2 × 25 mL). The combined organic extracts are washed with H₂O (25mL) and brine (25mL) and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica gel eluting with 15% EtOAc in hexanes provided compound I-5 as a colorless liquid (0.18g, 0.25mmol, 35%).¹H NMR(500MHz,CDCl₃):8.29(s,1H),7.82(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),7.20-7.16(m,1H),5.20(s,2H),2.45(s,3H).

3- (bromomethyl) -2-fluorobenzonitrile (I-6)

To a stirred solution of 2-fluoro-3-methylbenzonitrile (200mg, 1.5mmol) in 1, 2-dichloroethane (30mL) was added NBS (266mg, 1.49mmol) and AIBN (29mg, 0.15mmol) at RT. The reaction mixture was then heated to 80 ℃ and the reaction mixture was stirred for 2 h. After complete consumption of the starting material (confirmed by TLC), the reaction mixture was cooled to RT. Removing volatile matter under reduced pressureTo obtain a crude material. Purification by column chromatography on silica eluting with 2-3% EtOAc in hexanes provided compound I-6 as a colorless liquid (250mg, 1.15mmol, 78%).¹H NMR(500MHz,CDCl₃):7.69-7.65(m,1H),7.62-7.58(m,1H),7.28-7.25(m,1H),4.50(s,2H).

Example 14

1- (4- ((2, 4-difluorobenzyl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H- Tetrazol-1-yl propan-2-ol (13)

To a stirred solution of 2-bromopyridin-4-ol (84mg, 0.48mmol) in DMF (4mL) at RT was added K in turn₂CO₃(133mg, 0.96mmol) and Compound I-1(100mg, 0.48 mmol). The mixture was gradually heated to 70 ℃ and stirred for 3 h. After completion of the reaction (confirmed by TLC), the reaction mixture was cooled with ice H₂O (30mL) was quenched and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with H₂O (30mL) and brine (30mL), over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by silica gel column chromatography eluting with 15% EtOAc in hexanes afforded Compound K (70mg, 0.23mmol, 48%) as a yellow solid.¹H NMR(200MHz,CDCl₃):8.20(d,J＝5.6Hz,1H),7.44-7.36(m,1H),7.09(d,J＝2.2Hz,1H),6.98-6.82(m,3H),5.10(s,2H).MS(ESI):m/z 302[M+2]⁺.

To a suspension of copper powder (60mg, 0.93mmol) in DMSO (5mL) was added ethyl 2-bromo-2, 2-difluoroacetate (0.06mL, 0.46mmol) at RT under an inert atmosphere and the mixture was stirred for 1 h. To the resulting solution was added compound K (70mg, 0.23mmol) and stirring was continued at RT for 10 h. After completion of the reaction (confirmed by TLC), the reaction mixture was washed with saturated NH₄Cl solution (30mL) and quenched with CH₂Cl₂(3x 50mL) extracting. The combined organic layers were washed with H₂O (30mL) and brine (30mL), over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica eluting with 10% EtOAc in hexanes provided ester L as a semi-solid (30mg, 0.09mmol, 37%).¹H NMR(200MHz,CDCl₃):8.48(d,J＝5.8Hz,1H),7.51-7.39(m,1H),7.30(d,J＝2.2Hz,1H),6.98-6.83(m,3H),5.16(s,2H),4.37(q,J＝7.2Hz,2H),1.33(t,J＝7.2Hz,3H).MS(ESI):m/z 344[M+H]⁺.

To a stirred solution of 1-bromo-2, 4-difluorobenzene (0.01mL, 0.09mmol) in Et at-78 deg.C₂To a solution in O (3mL) was added n-BuLi (1.6M in hexane; 0.06mL, 0.09mmol) and the mixture was stirred under an inert atmosphere for 30 min. To the reaction mixture was added the ester L (30mg, 0.09mmol) in Et at-78 deg.C₂Solution in O (2mL) and stirring was continued for 2 h. After completion of the reaction (confirmed by TLC), the reaction mixture was washed with saturated NH₄The Cl solution (15mL) was quenched and extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (20mL) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica gel eluting with 20% EtOAc in hexanes provided ketone M as a colorless semi-solid (10mg, 0.02mmol, 27%).¹H NMR(200MHz,CDCl₃):8.38(d,J＝5.8Hz,1H),8.10-8.02(m,1H),7.50-7.42(m,2H),7.00-6.83(m,5H),5.18(s,2H).MS(ESI):m/z 412[M+H]⁺.

To a stirring mixture at-5 deg.C ketone M (350mg, 0.85mmol) in Et₂To the solution in O (10mL) was added freshly prepared diazomethane [ prepared by the following method: NMU (439mg, 4.26mmol) was dissolved in 10% KOH solution (20mL) and Et at 0 deg.C₂O (20mL) in a 1:1 mixture, the organic layer was then separated and dried with KOH tablets]The mixture was stirred for 2 h. The resulting reaction mixture was allowed to warm to RT and stirring was continued for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica eluting with 25% EtOAc in hexanes afforded epoxide N as a semi-solid (120mg, 0.28mmol, 33%).¹H NMR(200MHz,CDCl₃):8.50(d,J＝5.6Hz,1H),7.47-7.32(m，2H)，7.10-7.07(m,1H),6.97-6.69(m,5H),5.10(s,2H),3.46(d,J＝5.2Hz,1H),2.98-2.95(m,1H).MS(ESI):m/z 426[M+H]⁺.

To a stirred solution of epoxide N (120mg, 0.28mmol) in dry DMF (5mL) at RT under an inert atmosphere was added 1H-tetrazole (30mg, 0.42mmol) and K sequentially₂CO₃(39mg, 0.28 mmol). The resulting reaction mixture was gradually heated to 65 ℃ and stirred for 8 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled with ice H₂O (20mL) diluted and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20mL) and anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica eluting with 45% EtOAc in hexanes afforded 13 as a pale yellow semi-solid (35mg, 0.07mmol, 25%).¹H NMR(500MHz,CDCl₃):8.78(s,1H),8.32(s,1H)8.06(s,1H)7.41-7.32(m,2H),7.18(s,1H),6.94-6.80(m,3H),6.76-6.72(m,1H),6.68-6.60(m,1H),5.58(d,J＝14.5Hz,1H),5.14(s,2H).5.10(d,J＝14.5Hz,1H).MS(ESI):m/z 496[M+H]⁺.HPLC:96％.

Example 15

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- (vinyloxy) pyridin-2-yl) Propane-2-ol (14)

To compound O (10.0g, 30.5mmol) in acetone-H₂To a solution in O (1: 1; 300mL) was added oxone (93.9g, 153mmol) portionwise and the reaction mixture was stirred at RT for 18 h. After complete consumption of the starting material (confirmed by TLC), the volatiles were concentrated under reduced pressure. Subjecting the reaction mixture to hydrogenation with H₂O (150mL) diluted and extracted with EtOAc (2 × 150 mL). The combined organic extracts are washed with H₂O (150mL) and saltWashed with water (150mL) and Na anhydrous₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica eluting with 30% EtOAc in hexanes afforded Compound D (5.5g, 18.4mmol, 60%) as an off-white solid.¹H NMR(500MHz,CDCl₃):8.28(s,1H),7.40-7.38(m,2H),7.19(d,J＝8.0Hz,1H),6.83-6.81(m,1H),6.76-6.74(m,1H),5.91(br s,OH),3.42(d,J＝5.0Hz,1H),2.99(d,J＝5.0Hz,1H).MS(ESI):m/z 300[M+H]⁺.

Compound D (100mg, 0.33mmol), 1, 2-dibromoethane (310mg, 1.67mmol) and K₂CO₃A mixture of (460mg, 3.34mmol) in DMF (10mL) was stirred at 70 ℃ for 16 h. After complete consumption of the starting material (confirmed by TLC), the reaction mixture was cooled to RT and washed with H₂O (50mL) diluted and extracted with EtOAc (2 × 50 mL). The combined organic extracts are washed with H₂O (50mL) and brine (50mL), washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica eluting with 30% EtOAc in hexanes afforded Compound P (30mg, 0.07mmol, 22%) as an off-white solid.¹H NMR(500MHz,CDCl₃):8.35(d,J＝2.5Hz,1H),7.43-7.35(m,2H),7.21(dd,J＝9.0,2.5Hz,1H),6.85-6.82(m,1H),6.76-6.72(m,1H),4.36(t,J＝6.0Hz,2H),3.67(t,J＝6.0Hz,2H),3.43(d,J＝5.0Hz,1H),2.95(d,J＝5.0Hz,1H).

To a stirred solution of compound P (30mg, 0.07mmol) in t-butanol (t-BuOH; 10mL) was added potassium t-butoxide (KO)^tBu; 28mg, 0.25mmol), the mixture is stirred at RT for 16 h. After complete consumption of the starting material (confirmed by TLC), the volatiles were evaporated under reduced pressure to give a crude material. Purification by silica gel column chromatography eluting with 20% EtOAc in hexanes provided Compound Q as an off-white solid (15mg, 0.05mmol, 62%).¹H NMR(500MHz,CDCl₃):8.41(d,J＝3.0Hz,1H),7.44(d,J＝9.0Hz,1H),7.38-7.34(m,1H),7.33(dd,J＝9.0Hz,3.0Hz,1H),6.85-6.83(m,1H),6.76-6.72(m,1H),6.65(dd,J＝13.5Hz,6.0Hz,1H),4.92(dd,J＝13.5Hz,1.0Hz,1H),4.64(dd,J＝6.0Hz,1.0Hz,1H),3.44(d,J＝4.5Hz,1H),2.97(d,J＝4.5Hz,1H).

To a stirred solution of epoxide Q (150mg, 0.46mmol) in dry DMF (10mL) at RT under an inert atmosphere was added 1H-tetrazole (48mg, 0.69mmol) and K sequentially₂CO₃(63mg,0.46 mmol). The resulting reaction mixture was gradually heated to 65 ℃ and stirred for 16 h. After complete consumption of the starting material (determined by TLC), the reaction mixture was cooled with ice H₂O (30mL) diluted and extracted with EtOAc (2 × 30 mL). The combined organic extracts are washed with H₂O (30mL) and brine (30mL), over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica gel eluting with 40% EtOAc in hexanes provided 14 as a colorless thick syrup (25.5mg, 0.06mmol, 14%).¹H NMR(500MHz,CDCl₃):8.74(s,1H),8.27(s,1H),7.55(d,J＝8.5Hz,1H),7.38-7.31(m,3H),6.77-6.74(m,1H),6.69-6.66(m,1H),6.63-6.60(m,1H),5.57(d,J＝14.0Hz,1H),5.11(d,J＝14.0Hz,1H),4.96(d,J＝14.0Hz,1H),4.71(d,J＝4.5Hz,1H).MS(ESI):m/z 396[M+H]⁺.HPLC:99％.

Example 16

4- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-one) Yl) thio) methyl) -3-fluorobenzonitrile (15) and 4- (((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (2H- Tetrazol-2-yl) propyl) pyridin-3-yl) thio) methyl) -3-fluorobenzonitrile (16)

To a stirred solution of epoxide C (5g, 13.8mmol) in DMF (15mL) at RT was added K in turn₂CO₃(1.9g, 13.87mmol) and 1H-tetrazole (1.55g, 20.72 mmol). The resulting reaction mixture was heated to 65 ℃ and stirred for 16 h. The progress of the reaction was monitored by TLC. The reaction was cooled with ice H₂O (50mL) diluted and extracted with EtOAc (3 × 50 mL). To be combined withH for machine layer₂O (30mL) and brine (30mL), over anhydrous Na₂SO₄Drying to obtain a crude product. Purification by column chromatography on silica eluting with 35% EtOAc in hexanes afforded Compound S (1.0g, 2.31mmol, 17%) as a colorless syrup, which eluted with 40% EtOAc in hexanes afforded Compound R as an off-white solid (2.7g, 6.24mmol, 45%).¹H NMR(500MHz,CDCl₃):8.73(s,1H),8.62(s,1H),7.93(dd,J＝8.0,2.0Hz,1H),7.46(d,J＝8.0Hz,1H),7.31-7.28(m,1H),6.78-6.73(m,1H),6.70-6.66(m,1H),5.60(d,J＝14.5Hz,1H),5.14(d,J＝14.5Hz,1H).MS(ESI):m/z 433[M+H]⁺.

Stirring R (100mg, 0.23mmol), I-2(38mg, crude), diisopropylethylamine (DIEA; 0.07mL, 0.57mmol), tris (dibenzylideneacetone) dipalladium (0) (Pd)₂(dba)₃(ii) a 11mg, 0.011mmol) and xanthphos (13mg, 0.023mmol) in toluene (1mL) were heated under microwave conditions at 100 ℃ for 1 h. The progress of the reaction was monitored by LC-MS (for further confirmation). Passing the reaction mixture throughThe pad was filtered and the pad was washed with EtOAc (3 × 15 mL). The filtrate is treated with H₂O (50mL) and brine (50mL), washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by preparative High Performance Liquid Chromatography (HPLC) gave compound 15(15mg, 0.03mmol, 11%) as a colorless liquid.¹HNMR(400MHz,CDCl₃):8.73(s,1H),8.38(s,1H),7.65(d,J＝8.0Hz,1H),7.48(d,J＝8.0Hz,1H),7.42-7.28(m,4H),6.79-6.67(m,2H),5.50(d,J＝14.0Hz,1H),5.16(d,J＝14.0Hz,1H),4.19(s,2H).MS(ESI):m/z 519[M+H]⁺.HPLC:98％.

Stirring S (300mg, 0.69mmol), I-2(116mg, crude), DIEA (0.22mL, 1.7mmol), Pd₂(dba)₃A solution of (31mg, 0.03mmol) and xantphos (39mg, 0.069mmol) in toluene (3mL) was heated under microwave conditions at 100 ℃ for 1 h. The progress of the reaction was monitored by LC-MS. Passing the reaction mixture throughThe pad was filtered and the pad was washed with EtOAc (3 × 15 mL). The filtrate is treated with H₂O (50mL) and brine (50mL), washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by preparative HPLC afforded 16(50mg, 0.09mmol, 14%) as a colourless liquid.¹H NMR(500MHz,CDCl₃):8.43(s,1H),8.33(s,1H),7.66(dd,J＝8.5Hz,2.0Hz,1H),7.46(d,J＝8.5Hz,2H),7.41-7.33(m,4H),6.81-6.78(m,1H),6.71-6.68(m,1H),5.82(d,J＝14.5Hz,1H),5.36(d,J＝14.5Hz,1H),4.19(s,2H).MS(ESI):519[M+H]⁺.HPLC:96％.

Preparative HPLC method for purification of 15 and 16

Column: sunfire C-18(250X 19mm, 10. mu.)

Mobile phase: A) acetonitrile; B) 0.1% (aq) trifluoroacetic acid (TFA)

Flow rate: 15mL/min

Time (min)/% B: 0.01/55,3/55,20/45,26/40,26.1/0,35/0

Example 17

4- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3- Yl) oxy) -2-fluorobenzonitrile (17)

To a stirring mixture of Compound C (25.0g, 69.0mmol) in Et at-78 deg.C₂To a solution in O (250mL) was added n-BuLi (2.3M in hexanes; 86mL, 138 mmol). After stirring for 45min, trimethyl borate (15.6mL, 138mmol) in Et was added to the reaction mixture at-78 deg.C₂O (50mL) and stirring was continued for 30 min. The resulting reaction mixture was allowed to warm to RT and stirred for 2 h. Subjecting the reaction mixture toHOAc-H₂O (1: 2.5; 240mL) was quenched and stirring continued at RT for 1 h. The pH was adjusted to 14 with 2N NaOH solution. The organic layer was separated. The aqueous layer was adjusted to pH 6 with 1N HCl and CH₂Cl₂(2X 250mL) extraction. The combined organic layers were washed with H₂O (250mL) and brine (250mL), over anhydrous Na₂SO₄Drying and concentration under reduced pressure gave compound O as a brown solid (1.2g, 3.67mmol, 66%).¹H NMR(500MHz,CD₃OD):8.81(s,1H),8.20(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.36-7.35(m,1H),6.93-6.87(m,2H),3.42(d,J＝5.5Hz,1H),2.99-2.98(m,1H).MS(ESI):m/z 328.1[M+H]⁺.

To a solution of 2-fluoro-4-hydroxybenzonitrile (270mg, 1.99mmol) in CH₂Cl₂(20mL) to the suspension was added (6- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-yl) boronic acid (O; 500mg, 1.53mmol), Cu (OAc)₂(276mg, 1.53mmol), pyridine (0.6mL, 7.65mmol), powderMolecular sieves and the reaction mixture was stirred at RT under an oxygen atmosphere for 16 h. After consumption of the starting material (as determined by TLC), the reaction mixture was passed throughThe pad was filtered to remove the molecular sieve and the pad was washed with CH2Cl2(2 × 25 mL). The filtrate is treated with H₂O (25mL) and brine (25mL) and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica eluting with 30% EtOAc in hexanes provided Compound T (100mg, crude) as a colorless thick syrup. (note: in¹All characteristic protons observed in the H NMR spectrum).

To a stirred solution of epoxide T (120mg, crude) in dry DMF (10mL) at RT under an inert atmosphere was added 1H-tetrazole (56mg, 0.81mmol) and K sequentially₂CO₃(74mg, 0.53 mmol). The resulting reaction mixture was gradually heated to 65 ℃ and stirred for 16 h. Initiation sourceAfter complete consumption of material (as determined by TLC), the reaction mixture was cooled with ice H₂O (30mL) diluted and extracted with EtOAc (2 × 30 mL). The combined organic extracts are washed with H₂O (30mL) and brine (30mL), over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica gel eluting with 40% EtOAc in hexanes provided compound 17 as a colorless thick syrup (25mg, 0.04mmol, 3% over two steps).¹H NMR(500MHz,CDCl₃):8.73(s,1H),8.26(d,J＝2.0Hz,1H),7.69-7.66(m,2H),7.50-7.47(m,2H),7.04(s,OH),6.93-6.88(m,2H),6.83-6.76(m,2H),5.37(d,J＝15.0Hz,1H),5.32(d,J＝15.0Hz,1H).MS(ESI):m/z 487[M-H]^-.HPLC:98％.

Compounds 84-90 in table 1 were prepared from intermediate D and commercially available phenol (see table 1 starting material) and commercially available azoles using the same conditions as compound 17 (example 17).

Example 18

2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) -1- (5- ((2,2,2 trifluoroethyl) thio) Pyridin-2-yl) propan-2-ol (18)

To 2,2, 2-trifluoroethanethiol (0.17mL, 1.90mmol) was added sodium metal (50mg, 2.17mmol) portionwise at 0 deg.C and the mixture was stirred at RT for 2 h. To the above mixture was added a solution of compound R (200mg, 0.46mmol) in DMF (2.0mL) at 0 ℃. The resulting reaction mixture was gradually heated to 80 ℃ and stirred for 16 h. After complete consumption of the starting material (as determined by TLC), the reaction mixture was cooled with ice H₂O (30mL) and extracted with EtOAc (2 × 30 mL.) the combined organic layers were washed with H₂O (30mL) and brine (30mL), over anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by preparative HPLC to give the semi-productCompound 18(15mg, 0.032mmol, 6.94%) as a solid.¹H NMR(500MHz,CDCl₃):8.73(s,1H),8.58(s,1H),7.89-7.87(m,1H),7.52(d,J＝8.0Hz,1H),7.33-7.28(m,1H),7.03(s,OH),6.78-6.74(m,1H),6.69-6.65(m,1H),5.55(d,J＝15.0Hz,1H),5.14(d,J＝15.0Hz,1H),3.49(q,J＝9.5Hz,2H).MS(ESI):m/z 468[M+H]⁺.HPLC:98％.

Preparative HPLC method for purification of 18

Column: deltapak C-4 (300X 19mm, 15 mu)

Mobile phase: A) acetonitrile; B) 0.1% (aq) trifluoroacetic acid (TFA)

Flow rate: 15mL/min

Time (min)/% B: 0.01/80,4/80,15/30,20/30

Example 19

2- (6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-one Yl) thio) acetic acid methyl ester (91):

to a stirred solution of methyl 2-mercaptoacetate (206mg, 2.31mmol) in THF (10mL) at RT under an inert atmosphere was added cesium carbonate (Cs)₂CO₃(ii) a 752mg, 2.31mmol), then compound R (200mg, 0.46mmol) is added. The resulting reaction mixture was heated to 65 ℃ and stirred for 48 h. After complete consumption of the starting material (as determined by TLC), the reaction mixture was diluted with EtOAc (100 mL). The organic layer was washed with NaHCO₃Saturated solution (50mL), water (50mL) and brine (50mL), washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica gel (eluting with 45% EtOAc in hexanes) afforded 91(30mg, 0.06mmol, 14%).¹H NMR(500MHz,CDCl₃):8.75(s,1H),8.50(s,1H),7.80(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.34-7.27(m,2H),6.78-6.73(m,1H),6.69-6.66(m,1H),5.58(d,J＝14.0Hz,1H),5.10(d,J＝14.0Hz,1H),3.74(s,2H),3.70(s,3H).MS(ESI):m/z 458[M+H]⁺.HPLC:93％.

Example 20

1- (5- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (92)

In N₂To a magnetically stirred mixture of 6- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-ol (D) (250mg, 0.836mmol) and cesium carbonate (272mg, 0.836mmol) in dry DMSO (4.178mL) was added 2, 3-dichloro-5- (trifluoromethyl) pyridine (0.117mL, 0.836mmol) under an atmosphere in a dry 25mL vial the reaction mixture was stirred at 55 ℃ for 1h, then diluted with ice water and 2N HCl and extracted with DCM (2 ×) the combined organic extracts were evaporated and the crude residue was purified over silica (ISCO, 40g column, gradient to 20% EtOAc/hexane over 20 min) to give compound u.yield 386mg (92%) of clear oil.¹H NMR(400MHz,CDCl3)8.58(s,1H),8.27(d,J＝1.0Hz,1H),8.04(s,1H),7.62(dd,J＝8.4,2.1Hz,1H),7.58(d,J＝8.5Hz,1H),7.40(dd,J＝14.8,8.0Hz,1H),6.90-6.82(m,1H),6.77(td,J＝9.3,2.4Hz,1H),3.48(d,J＝5.0Hz,1H),3.10-2.92(m,1H).¹H-decoupling¹⁹F NMR(376MHz,CDCl3)-61.70(s),-106.70(d,J＝8.2Hz),-107.45(dd,J＝48.4,8.9Hz),-107.72(d,J＝8.2Hz),-108.41(d,J＝9.5Hz),-109.26(dd,J＝17.7,9.5Hz).MS(ESI):m/z 479.0(M+H)⁺.

In N₂Magnetically stirred 3-chloro-2- ((6- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-yl) oxy) in a dry 25mL vial under atmosphere) To a mixture of-5- (trifluoromethyl) pyridine (U) (356mg, 0.744mmol) and 1H-tetrazole (62.5mg, 0.892mmol) in dry DMSO (3.718mL) was added potassium carbonate (206mg, 1.487 mmol). The reaction mixture was stirred at 60 ℃ overnight, cooled to RT and diluted with ice cold water/2N HCl and DCM and the layers separated on a phase separator. The aqueous layer was extracted again with DCM and the combined organic extracts were evaporated. The crude residue was purified on silica (ISCO, 40 gram column, gradient to 40% EtOAc/hexanes over 20 minutes) to give the title compound. Yield 119mg (27.7%) of brown glass.¹H NMR(400MHz,CDCl₃)8.76(s,1H),8.50(d,J＝2.3Hz,1H),8.27(dd,J＝2.1,0.9Hz,1H),8.05(d,J＝2.0Hz,1H),7.74-7.63(m,2H),7.34(td,J＝8.9,6.4Hz,1H),7.21(s,1H),6.83-6.72(m,1H),6.72-6.64(m,1H),5.64(d,J＝14.3Hz,1H),5.13(d,J＝14.1Hz,1H).¹H-decoupling¹⁹F NMR(376MHz,CDCl₃)-61.74(s),-103.20(d,J＝15.0Hz),-103.72--104.09(m),-107.86(d,J＝10.9Hz),-110.78(d,J＝45.0Hz),-111.48(d,J＝45.0Hz).MS(ESI):m/z 549.1(M+H)⁺.

Compounds 93-101, 104-106 and 108-112 of Table 1 were prepared from intermediate D and commercially available aryl halides (see Table 1 starting materials) and commercially available oxazoles using the same conditions as for compound 92 (example 20).

Example 21

(E) -6- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyri-dine Pyridin-3-yl) oxy) nicotinaldehyde O-methyloxime (102)

In N₂To a magnetically stirred mixture of 6- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-yl) oxy) nicotinaldehyde (101) (60mg, 0.126mmol) in dry EtOH (1.265mL) in a 5mL vial was added under atmosphereO-methylhydroxylamine hydrochloride (21.13mg,0.253 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was evaporated and the crude residue was purified on silica (ISCO, 12g column, gradient to 75% EtOAc/hexanes over 25 min) to give the title compound. Yield 18mg (26.9%) as a white foam.¹H NMR(400MHz,CDCl₃)8.76(s,1H),8.47(d,J＝2.5Hz,1H),8.19(d,J＝2.3Hz,1H),8.11(dd,J＝8.7,2.4Hz,1H),8.04(s,1H),7.67(dd,J＝8.7,2.6Hz,1H),7.63(d,J＝8.8Hz,1H),7.45(s,1H),7.36(td,J＝8.8,6.4Hz,1H),7.05(d,J＝8.5Hz,1H),6.83-6.73(m,1H),6.73-6.64(m,1H),5.63(d,J＝14.3Hz,1H),5.10(d,J＝14.3Hz,1H),3.99(s,3H).¹H-decoupling¹⁹F NMR(376MHz,CDCl₃)-103.20(d,J＝17.7Hz),-103.89(ddd,J＝31.3,21.1,13.6Hz),-108.11(d,J＝9.5Hz),-110.21(d,J＝45.0Hz),-110.90(d,J＝45.0Hz).MS(ESI):m/z 504.2(M+H)⁺.

Compound 103 in table 1 was prepared from 101 and commercially available O-benzylhydroxylamine (see table 1 starting material) using the same conditions as compound 102 (example 21).

Example 22

2- ((6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3- Yl) oxy) thiazole-5-carbonitrile (107)

In N₂A magnetically stirred mixture of 6- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-ol (D) (550mg, 1.838mmol) and diisopropylammonium tetrazol-1-ide (630mg, 3.68mmol) in dry DMSO (6.127mL) was heated at 70 ℃ overnight under an atmosphere in a dry 25mL vial. The crude reaction mixture was cooled to RT, filtered, and purified on silica (ISCO, 40g column, gradient to 70% EtOAc/hexanes over 20 min) to giveTo compound V. Yield 52mg (3.83%) of brown oil.¹HNMR(300MHz,CDCl3)8.76(s,1H),8.13(d,J＝3.0Hz,1H),7.93(s,1H),7.41(d,J＝8.9Hz,1H),7.34(dd,J＝8.9,2.3Hz,1H),7.22(dd,J＝8.7,2.8Hz,1H),6.78-6.70(m,1H),6.69-6.63(m,1H),5.56(d,J＝14.2Hz,1H),5.06(d,J＝15.5Hz,1H).MS(ESI):m/z 370.1(M+H)⁺.

In N₂To a magnetically stirred mixture of 2-chlorothiazole-5-carbonitrile (14.68mg, 0.102mmol) and 6- (2- (2, 4-difluorophenyl) -1, 1-difluoro-2-hydroxy-3- (1H-tetrazol-1-yl) propyl) pyridin-3-ol (V) (25mg, 0.068mmol) in dry DMSO (1mL) was added potassium carbonate (18.71mg, 0.135mmol) under atmosphere in a dry 25mL vial. The reaction mixture was stirred at RT for 4h, then diluted with DCM and washed with 2N HCl/water. The organic extracts were evaporated and purified on silica (ISCO, 12g column, 15min gradient to 50% EtOAc/hexanes) to give the title compound. Yield 18mg (52.9%) as a yellowish white foam.¹H NMR(400MHz,CDCl₃)8.75(s,1H),8.63(d,J＝2.5Hz,1H),7.92(dd,J＝8.8,2.8Hz,1H),7.75(s,1H),7.68(d,J＝8.5Hz,1H),7.34(td,J＝8.9,6.4Hz,1H),6.90(s,1H),6.82-6.73(m,1H),6.73-6.64(m,1H),5.59(d,J＝14.3Hz,1H),5.16(d,J＝15.3Hz,1H).¹H-decoupling¹⁹F NMR(376MHz,CDCl₃)-103.63(d,J＝16.3Hz),-104.07(dd,J＝56.5,10.2Hz),-104.33(d,J＝16.3Hz),-107.58(t,J＝6.8Hz),-110.27(d,J＝39.5Hz),-110.97(d,J＝40.9Hz).MS(ESI):m/z 478.1(M+H)⁺.

Example 23

1- (5- (2, 2-difluoro-2-phenylethoxy) pyridin-2-yl) -2- (2, 4-difluorophenyl) -1, 1-difluoro-3- (1H-tetrazol-1-yl) propan-2-ol (119)

Magnetically stirred 6- ((2-To a mixture of (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-ol (100mg, 0.334mmol, Compound D) and 2-bromo-1-phenylethanone (100mg, 0.501mmol) in dry acetone (1671. mu.l) was added K₂CO₃(50.8mg, 0.368 mmol). The reaction mixture was stirred at rt for 3 days. After the reaction is completed, in a slow N₂Volatiles were removed from the stream. Bringing the resulting residue to CH₂Cl₂And H₂In a mixture of O and CH₂Cl₂Extraction was carried out three times. The combined organic layers were dried by passing them through a phase separator under gentle N₂The volatiles were removed from the stream and charged to SiO₂On a pad, purification (ISCO, 12g SiO)₂And (3) performing reaction for 10min, 5-25% of ethyl acetate-hexane and 5min below 25%) to obtain a compound W. Yield 144mg (98%) of colorless oil solidified upon standing.¹H NMR(400MHz,CDCl₃)8.39(d,J＝2.9Hz,1H),7.98(dd,J＝5.2,3.3Hz,2H),7.71-7.62(m,1H),7.54(t,J＝7.7Hz,2H),7.40(d,J＝8.7Hz,1H),7.39-7.33(m,1H),7.20(dd,J＝8.7,2.9Hz,1H),6.83(ddd,J＝11.2,5.6,1.7Hz,1H),6.78-6.69(m,1H),5.39(s,2H),3.42(d,J＝5.1Hz,1H),3.00-2.93(m,1H).¹H decoupling-¹⁹F NMR(376MHz,CDCl₃)-106.90(dd,J＝256.8,8.4Hz,1F),-107.41--108.36(m,2F),-109.33(q,J＝8.3Hz,1F).MS(ESI):m/z C₂₂H₁₅F₄NO₃Calculated value 417.353; measured value 418.8(M + H)⁺,416.4(M-H)^-.

In N₂Magnetically stirred 2- ((6- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-yl) oxy) -1-phenylethanone (140mg, 0.335mmol, Compound W) in a 20mL vial under an atmosphere₂Cl₂(1677. mu.l) to the mixture was added 50% in toluene(284. mu.l, 0.772 mmol). The reaction mixture was stirred at 0 ℃ for 30min, then warmed to rt and stirred overnight. The reaction was performed by dropwise addition of saturated NaHCO₃The aqueous solution was quenched (gas evolution was observed). The aqueous layer is replaced by CH₂Cl₂Extraction was carried out three times. The combined organic layers were dried by passing them through a phase separator and the volatiles were removed by rotary evaporation. Charging the resulting residue to SiO₂On a pad, purification (ISCO, 12 gSiO)₂The compound X is obtained by heating to 60% in 10min, 0-20% ethyl acetate-hexane, 3min below 20%, and 3min below. Yield 81mg (55.0%) of colorless oil.¹H NMR(400MHz,CDCl₃)8.32(d,J＝2.8Hz,1H),7.63-7.44(m,5H),7.43-7.32(m,2H),7.20(dd,J＝8.7,2.9Hz,1H),6.87-6.79(m,1H),6.73(ddd,J＝9.8,9.0,2.5Hz,1H),4.44(t,J＝11.9Hz,2H),3.41(d,J＝5.1Hz,1H),2.99-2.92(m,1H).¹H decoupling-¹⁹F NMR(376MHz,CDCl₃)-104.01(s,2F),-106.92(dd,J＝256.9,8.4Hz,1F),-107.46--108.33(m,2F),-109.36(q,J＝8.5Hz,1F).MS(ESI):m/z C₂₂H₁₅F₆NO₂Calculated value 439.350; measured value 440.9(M + H)⁺.

In N₂To a magnetically stirred mixture of 5- (2, 2-difluoro-2-phenylethoxy) -2- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridine (81mg, 0.184mmol, Compound X) and 1H-tetrazole (19.37mg, 0.277mmol) in dry DMSO (1229. mu.l) in a 20mL vial was added K under atmosphere₂CO₃(28.0mg, 0.203 mmol). The reaction mixture was stirred at 60 ℃ overnight. The reaction was cooled to rt and quenched with CH₂Cl₂Diluted and poured into a container containing saturated NH₄In a separatory funnel of aqueous Cl solution. The organic layer was washed, and then the aqueous layer was washed with CH₂Cl₂Back extraction was performed twice. The combined organic layers were then washed three times with water and dried by passing it through a phase separator. The volatiles were removed by rotary evaporation and the resulting residue was loaded onto SiO₂On a pad, purification (ISCO, 12g SiO)₂Ethyl acetate-hexanes at 20-60% for 7min, then 7min at 60%) to give the title compound 119. Yield 56mg (59.6%) of light yellow thick oil.¹H NMR(400MHz,CDCl₃)8.74(s,1H),8.21(d,J＝2.8Hz,1H),7.57-7.45(m,6H),7.41(s,1H),7.33-7.24(m,2H),6.80-6.70(m,1H),6.70-6.62(m,1H),5.58(d,J＝14.3Hz,1H),5.07(d,J＝15.1Hz,1H),4.42(t,J＝11.9Hz,2H).¹H decoupling-¹⁹F NMR(376MHz,CDCl₃)-102.97(dd,J＝261.4,15.2Hz,1F),-103.88(ddd,J＝43.5,14.9,9.8Hz,1F),-104.07(s,2F),-108.15(d,J＝9.7Hz,1F),-110.87(dd,J＝261.4,43.2Hz,1F).MS(ESI):m/z C₂₃H₁₇F₆N₅O₂Calculated value 509.404; measured value 510.2(M + H)⁺,508.6(M-H)-.

Compounds 120 to 122 in Table 1 were prepared from intermediate D and commercially available α -halo ketones (see Table 1 starting materials) and commercially available oxazoles using the same conditions as for compound 119 (example 23).

Example 24

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5- (2-fluoro-2-phenylethoxy) pyridin-2-yl) -3- (1H-tet-etrakis-phenyl) Azol-1-yl) propan-2-ol (Compound 123)

In N₂Magnetically stirred 2- ((6- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-yl) oxy) -1-phenylethanone (59mg, 0.141mmol, Compound W) in a 20mL vial under atmosphere in methanol (1.5mL) and CH₂Cl₂(1mL) to the mixture was added NaBH₄(5.35mg, 0.141 mmol). The reaction mixture was stirred at 0 ℃ for 10min, at which time it was washed with water and saturated NH₄The aqueous Cl solution was quenched and then allowed to warm to rt. The reaction mixture was washed with Et₂And extracting for three times. The combined organic layers were dried by passing them through a phase separator and the volatiles were removed by rotary evaporation. Charging the crude reaction mixture to SiO₂Pad and purification (ISCO, 4g SiO)₂5min, 15-35% ethyl acetate-hexane, 5min below 35%) to give compound Y as a mixture of diastereoisomers 1: 1. Yield 49mg (83%) of colorless oil.¹H NMR(400MHz,CDCl₃)8.35(s,1H),7.50-7.32(m,7H),7.20(dd,J＝8.7,2.8Hz,1H),6.83(td,J＝8.3,2.3Hz,1H),6.73(td,J＝9.4,2.5Hz,1H),5.16(dd,J＝7.9,3.3Hz,1H),4.19-4.08(m,2H),3.42(d,J＝5.1Hz,1H),2.99-2.93(m,1H).¹H decoupling-¹⁹F NMR(376MHz,CDCl₃)-106.58--107.45(m,1F),-107.52--108.38(m,2F),-109.38(p,J＝8.3Hz,1F).MS(ESI):m/zC₂₂H₁₇F₄NO₃Calculated value 419.369; measured value of 420.2(M + H)⁺.

In N₂Magnetically stirred 2- ((6- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) pyridin-3-yl) oxy) -1-phenylethanol (49mg, 0.117mmol, compound Y) in a 20mL vial under an atmosphere in dry CH₂Cl₂(1168. mu.l) to the mixture(86. mu.l, 0.234 mmol). The reaction mixture was stirred at rt for 1.5hr, at which time it was added dropwise to saturated NaHCO₃Aqueous solution (gas evolution was observed). Reacting the mixture with CH₂Cl₂Extraction was carried out three times. The combined organic layers were dried by passing them through a phase separator and the volatiles were removed by rotary evaporation. Charging the resulting residue to SiO₂On a pad, purification (ISCO, 4g SiO)₂At 8min, 5-20% ethyl acetate-hexane, 4min at 20%) to give compound Z as a mixture of diastereoisomers 1: 1. Yield 39mg (79%) of colorless oil.¹H NMR(400MHz,CDCl₃)8.37(d,J＝2.8Hz,1H),7.49-7.32(m,7H),7.22(dd,J＝8.7,2.9Hz,1H),6.83(td,J＝8.3,2.2Hz,1H),6.77-6.70(m,1H),5.85(ddd,J＝48.1,7.8,2.7Hz,1H),4.46-4.17(m,2H),3.43(dd,J＝5.1,2.3Hz,1H),3.01-2.92(m,1H).¹H decoupling-¹⁹FNMR(376MHz,CDCl₃)-106.60--107.40(m,1F),-107.48--108.39(m,2F),-109.36(dq,J＝11.9,8.4Hz,1F),-183.74(d,J＝5.4Hz,1F).MS(ESI):m/z C₂₂H₁₆F₅NO₂Calculated value 421.360; measured value 422.1(M + H)⁺.

In N₂In an atmosphere of 1To a magnetically stirred mixture of 2- ((2- (2, 4-difluorophenyl) oxiran-2-yl) difluoromethyl) -5- (2-fluoro-2-phenylethoxy) pyridine (37mg, 0.088mmol, Compound Z) and 1H-tetrazole (12.30mg, 0.176mmol) in dry DMSO (878. mu.l) in a 5mL vial was added K₂CO₃(24.27mg, 0.176 mmol). The reaction mixture was stirred at 60 ℃ for 3 days. The reaction was cooled to rt, then diluted with water and CH₂Cl₂The extraction was performed 3 times and the combined organic layers were dried by passing them through a phase separator and the volatiles were removed by rotary evaporation. Charging the resulting residue to SiO₂On a pad, purification (ISCO, 4g SiO)₂At 6min, 20-60% ethyl acetate-hexanes, 3min at 60%) to give title compound 123 as a mixture of diastereomer 1: 1. Yield 28mg (64.9%) of white foamy solid.¹H NMR(400MHz,CDCl₃)8.75(s,1H),8.24(t,J＝2.8Hz,1H),7.54(d,J＝4.0Hz,1H),7.51(d,J＝8.8Hz,1H),7.48-7.38(m,5H),7.35-7.24(m,2H),6.79-6.71(m,1H),6.66(ddd,J＝9.0,5.1,2.0Hz,1H),5.83(ddt,J＝48.1,7.7,2.4Hz,1H),5.58(dd,J＝14.3,3.1Hz,1H),5.12-5.04(m,1H),4.36(dddd,J＝17.6,11.0,7.8,5.4Hz,1H),4.24(dddd,J＝28.1,11.0,2.7,1.3Hz,1H).¹H decoupling-¹⁹F NMR(376MHz,CDCl₃)-103.02(ddd,J＝261.2,15.2,10.0Hz,1F),-103.62--104.04(m,1F),-108.26(dd,J＝9.6,4.2Hz,1F),-110.69(ddd,J＝261.2,42.8,11.9Hz,1F),-183.73(s,1F).MS(ESI):m/z C₂₃H₁₈F₅N₅O₂Calculated value 491.413; found value of 493.2(M + H)⁺,491.2(M-H)^-.

Compound 124 in table 1 was prepared from intermediate D and commercially available 2-bromo-1- (4-difluoromethoxy) phenyl) ethanone (see starting material in table 1) using the same conditions as compound 123 (example 24).

HPLC method

Method A specification:

column: aquity BEH C-18 (50X 2.1mm,1.7 μ)

Mobile phase: A) acetonitrile; B) 0.025% (aq) trifluoroacetic acid (TFA)

Flow rate: 0.50mL/min

Time (min)/% B: 0.01/90,0.5/90,3/10,6/10

Method B specification:

column: eclipse XDB C-18 (150X 4.6mm, 5.0. mu.)

Mobile phase: A) acetonitrile; B)5mM acetic acid

Flow rate: 1.0mL/min

Time (min)/% B: 0.01/80,2/80,15/10, 15.01/stop

Method C specification:

column: eclipse XDB C-18 (150X 4.6mm, 5.0. mu.)

Mobile phase: A) acetonitrile; B)5mM NH₄OAc

Flow rate: 1.0mL/min

Time (min)/% B: 0.01/80,3/80,10/10,20/10

Method D specification:

column: develosil ODS-HG-3 (50X 4.6mm)

Mobile phase: A) acetonitrile; B)10mM NH₄OAc

Flow rate: 1.0mL/min

Time (min)/% B: 0.01/90,1/90,4/10,10/10

Method E Specification:

column: X-Bridge, C₁₈，3.5μm，4.6×75mm

Mobile phase: A) 0.1% TFA in acetonitrile; B) h₂0.1% aq.TFA in O

Flow rate: 0.8mL/min

Time (min)/% B: 0/98,2.2/55,3.0/10,7.5/10,7.8/98

Method F specification:

column: acquity UPLC^TMBEH，C₁₈，1.7μm，2.1×50mm

Mobile phase: A) 0.1% TFA in acetonitrile; B) h₂0.1% aq.TFA in O

Flow rate: 0.4mL/min

F (1) time (min)/% B: 0/100,1.8/100,3.8/25,4.5/5,6/5,6.01/100

F (2) time (min)/% B: 0/95,1/95,3/20,6/20,6.01/95

Method G specification:

column: acquity UPLC^TMBEH，C₁₈，1.7μm，2.1×30mm

Mobile phase: A) 0.03% aq. acoh; B) 0.03% AcOH in acetonitrile

Flow rate: 1.3mL/min

Time (min)/% B: gradient 0/5 to 0.8/95, hold to 1.5/95

Method H specification:

column: symmetry, C-18, 3.5 μm, 4.6X 50mm

Mobile phase: A) acetonitrile; B) h₂0.1% aq.TFA in O

Flow rate: 0.8mL/min

Time (min)/% B: 0/98,2/98,4/10,6/10,6.5/2,8/2,8.01/98

Method I Specification:

column: X-Bridge, C₁₈，3.5μm，4.6×75mm

Mobile phase: A) acetonitrile; B)5mM NH₄OAc

Flow rate: 0.8mL/min

I (1) time (min)/% B: 0/100,2/55,2.8/5,6.8/5,7.5/100

I (2) time (min)/% B: 0/98,1.5/98,3/10,7/10,8.01/98

Method J Specification:

column: sunfire^TMC18OBD^TM5 μm 4.5 × 50mm column

Mobile phase: A) h₂0.1% AcOH, 5% MeCN in O; B) in MeCN

0.1％AcOH

Flow rate: 3.0mL/min

I (1) time (min)/% B: 0/5,5/95

TABLE 1 Structure of example Compounds

TABLE 2 analytical data for the compounds of the examples in Table 1

Example 25: metalloenzyme activity

A. Minimum Inhibitory Concentration (MIC) (candida albicans (c.))

The compounds of the present disclosure were tested for their ability to inhibit the growth of the common fungal strain candida albicans using a standardized method (CLSI M27-a 2).

Stock solutions of test compounds and standards (Candida albicans) were prepared at a concentration of 1,600. mu.g/mL in DMSO. in 96-well plates, 11 serial half dilutions of compounds were prepared in RPMI + MOPS. cell suspensions of Candida albicans were prepared at assay concentrations ranging from 8-0.001. mu.g/mL (Candida albicans), and at about 3.7 × 10 per mL³The concentration of colony forming units (cfu/mL) was added to each well. All tests were repeated twice. The inoculated plates were incubated at 35. + -. 1 ℃ for about 48 h. After incubation, look atThe wells of each plate were evaluated for the presence of fungal growth.

For fluconazole and test compounds, MIC is the concentration at which growth is significantly reduced (by about 50%), for voriconazole, MIC is the concentration at which candida albicans growth is reduced by 50% (according to CLSI, M27-a2) for QC purposes, candida krusei (c.krusei) isolate ATCC 6258(4.0 × 10) was included in the VOR assay³cfu/mL). This isolate did not show a creeping growth (trailing growth) against voriconazole, so the MIC was the concentration at which growth was completely inhibited.

B. Inhibition of hepatocyte cytochrome P450 enzymes

Solutions of each test compound at concentrations of 20000, 6000, 2000, 600, 200 and 60 μ M were prepared by serial dilution with DMSO: acetonitrile (MeCN) (50:50v/v), respectively. Each test compound solution was then diluted 20-fold with DMSO: MeCN: deionized water (5:5:180v/v/v) to concentrations of 1000, 300, 100, 30, 10, and 3. mu.M. Mixtures of isozyme inhibitors (sulfaphenazole, tranylcypromine and ketoconazole as specific inhibitors of isozymes 2C9, 2C19 and 3a4, respectively) containing the respective inhibitors at concentrations of 6000, 2000, 600, 200, 60, 20,6 and 2 μ M were prepared by serial dilution with DMSO: MeCN (50:50 v/v). The mixed inhibitor solution was then diluted 20-fold with DMSO: MeCN: deionized water (5:5:180v/v/v) to concentrations of 300, 100, 30, 10, 3, 1, 0.3, and 0.1. mu.M. The percentage of organic solvent in the final reaction mixture attributable to the test compound or inhibitor mixture was 2% v/v.

The combined human liver microsome suspension (20mg/mL) was diluted with phosphate buffer to give a 5mg/mL suspension. NADPH solution was prepared in phosphate buffer at a concentration of 5 mM. Individual stock solutions of each substrate were prepared in DMSO: MeCN (50:50v/v), mixed, and diluted in phosphate buffer to give solutions containing five times their assay K_mConcentration of a single solution of each substrate. The percentage of organic solvent in the final reaction mixture attributable to the substrate mixture was 1% v/v.

The substrate solution and the microsomal suspension were combined at a 1:1 volume ratio, mixed, and dispensed into reaction wells of a PCR plate. Individual test compounds or combined inhibitor solutions at each concentration were added to the wells and mixed by repeated pump-release cycles. For the activity control, a blank phosphate buffer was added instead of the test compound solution. The reaction mixture was allowed to equilibrate at 37 ℃ for about 2 minutes before adding the NADPH solution to initiate the reaction, and then the reaction mixture was mixed with a pipette. 10 minutes after the addition of NADPH, the reaction mixture was quenched with cold acetonitrile. The samples were mixed by vortexing for about 1 minute and centrifuged at 2900RCF for 10 minutes. A portion of the supernatant was analyzed by gradient reverse phase HPLC and detected by electrospray ionization triple quadrupole mass spectrometry in positive ion mode.

The data were fitted to sigmoidal dose-response curves and the inhibitory potency of each test compound was determined as its IC₅₀The value is obtained.

Results

Compounds were tested for their ability to inhibit the growth of the common fungal plant pathogen, septoria tritici (ATCC 26517), using a method based on the Clinical and Laboratory Standards Institute (CLSI) guidelines for microdilution assay procedures for filamentous fungi.

Stock solutions of test compounds and standards were prepared in DMSO at 6400. mu.g/mL. Each stock was used to prepare a 2-fold dilution series (11 compound concentrations in total) of 16-0.016. mu.g/mL in RPMI-1640(Roswell Park Memori institute) medium containing 3- (N-morpholino) propanesulfonic acid (MOPS) buffer and 2% DMSO. A100. mu.L aliquot of the dilution was added to columns 1 (16. mu.g/mL compound) to 11 (0.016. mu.g/mL compound) of a 96-well microtiter plate. This pattern is repeated in the second row of the microtiter plate. Thus, each microtiter plate may comprise 11 concentrations of four test or control compounds in duplicate. To column 12 of the microtiter plate (no compound control) was added 100. mu.L aliquots of RPMI-1640/MOPS/2% DMSO medium.

Approximately 5 × 10 per ml of RPMI/MOPS medium prepared without DMSO using a fresh culture of Septoria tritici⁴A100 μ L aliquot of this solution was added to all 96 wells of a microtiter plate, which allowed each test or control compound to contain 1% DMSO and about 2.5 × 10⁴The final concentration of cfu/mL in 200. mu.L RPMI/MOPS medium of Septoria tritici was 8. mu.g/mL to 0.008. mu.g/mL. The assay plates were incubated at 22 ℃ in the dark without shaking for 7 days. The MIC of each compound was visually determined as the concentration that caused a 50% reduction in growth of septoria tritici compared to the control (column 12). The results can be seen in table 3.

In each case according to Table 3, the rating scale for Septoria is as follows:

MIC(μg/mL)	grade
		≤0.5	A
>0.5–1.5	B
		>1.5–4	C
>4	D
		Not tested	E

D. Against leaf rust (pathogenic factor Puccinia recondita tritici ═ Puccinia) triticina); bayer code PUCCRT) evaluation of fungicidal Activity

Wheat plants (variety Yuma) were grown in soilless peat based pot mix (Metromix) starting from the seed until the seedlings had the first leaf fully extended. Each pot contains 3-8 seedlings. These plants were sprayed with formulated test compound until wet. Compounds were formulated to 50ppm in 10 vol.% acetone plus 90 vol.% Triton X water (deionized water 99.99 wt% +0.01 wt% Triton X100) to give "formulated test compounds". The formulated test compounds were applied to plants using a turntable atomizer equipped with two opposing air atomizing nozzles delivering a spray volume of about 1500L/ha. On the next day, the leaves were inoculated with an aqueous spore suspension of puccinia triticina and the plants were kept at high humidity overnight to allow the spores to germinate and infect the leaves. The plants were then transferred to the greenhouse until disease developed on untreated control plants. And after 7-9 days, evaluating the severity of the disease depending on the speed of disease development.

In each case of table 3, the scale of puccinia is as follows:

TABLE 3 biological data for the compounds in TABLE 1

Citation of references

The contents of all references (including references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are expressly incorporated herein by reference in their entirety.

Equivalent means

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A compound of formula I or a salt thereof, wherein:

R₁is H, halogen, alkyl or haloalkyl;

R₂is H, halogen, alkyl or haloalkyl;

R₄is aryl, heteroaryl or cycloalkyl, optionally substituted with 0,1, 2 or 3 independent R₃Substitution;

R₆is alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

R₈independently is an alkyl or aryl group;

R₉independently is H, alkyl, halogen or haloalkyl; and is

X is O.

2. The compound of claim 1, wherein R₁Is fluorine.

3. The compound of claim 1, wherein R₂Is fluorine.

4. The compound of claim 1, wherein R₁And R₂Is fluorine.

5. The compound of claim 1, wherein R₄Is optionally substituted by 0,1, 2 or 3 independent R₃A substituted phenyl group.

6. The compound of claim 1, wherein R₄Is phenyl optionally substituted with 0,1, 2 or 3 independent halogens.

7. The compound of claim 1, wherein R₄Is phenyl optionally substituted with 0,1, 2 or 3 independent fluoro.

8. The compound of claim 1, wherein R₄Is 2, 4-difluorophenyl.

9. The compound of claim 1, wherein R₅Is optionally substituted by 0,1, 2 or 3 independent R₃A substituted aryl group.

10. The compound of claim 1, wherein R₅Is optionally substituted by 0,1, 2 or 3 independent R₃Substituted arylalkyl.

11. The compound of claim 1, wherein R₅Is optionally substituted by 0,1, 2 or 3 independent R₃Substituted heteroarylalkyl.

12. The compound of claim 1, wherein R₅Is optionally substituted by 0,1, 2 or 3 independent R₃A substituted heteroaryl group.

13. The compound of claim 1, wherein:

R₁is fluorine;

R₂is fluorine;

R₄is 2,4-difluorophenyl; and is

R₅Is optionally substituted by 0,1, 2 or 3 independent R₃A substituted aryl group.

14. The compound of claim 1, wherein:

R₁is fluorine;

R₂is fluorine;

R₄is 2, 4-difluorophenyl; and is

R₅Is optionally substituted by 0,1, 2 or 3 independent R₃A substituted heteroaryl group.

15. The compound of claim 1, wherein:

R₁is fluorine;

R₂is fluorine;

R₄is 2, 4-difluorophenyl; and is

R₅Is optionally substituted by 0,1, 2 or 3 independent R₃Substituted arylalkyl.

16. The compound of claim 15, wherein:

17. The compound of claim 15, wherein:

R₅is optionally substituted by 0,1, 2 or 3 independent R₃substituted-CH₂-a heteroaryl group.

18. The compound of claim 15, wherein:

R₅is optionally substituted by 0,1, 2 or 3 independent R₃substituted-CH₂-CF₂-an aryl group.

19. The compound according to claim 1, which is one of the following compounds:

2- (2, 4-difluorophenyl) -1, 1-difluoro-1- (5-phenoxypyridin-2-yl) -3- (1H-tetrazol-1-yl) propan-2-ol (11); or

20. A method for inhibiting metalloenzyme activity for non-therapeutic purposes comprising contacting a compound of any one of claims 1-19 with a metalloenzyme.

21. The method of claim 20, wherein the contacting is in vitro.

22. The method of claim 20, wherein the metalloenzyme comprises a metal atom that is iron, zinc, heme iron, manganese, magnesium, iron sulfide cluster, nickel, molybdenum, or copper.

23. The method of claim 20, wherein the metalloenzyme is a member of an enzyme class selected from cytochrome P450 family, histone deacetylases, matrix metalloproteinases, phosphodiesterases, cyclooxygenases, carbonic anhydrases, and nitric oxide synthases.

24. The method of claim 20, wherein the metalloenzyme is lanosterol demethylase (CYP 51).

25. The method of claim 20, wherein the metalloenzyme is 4-hydroxyphenylpyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase n, angiotensin converting enzyme, aromatase (CYP19), calcineurin, carbamyl phosphate synthase, carbonic anhydrase family, catechol o-methyltransferase, cyclooxygenase family, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA aminotransferase, HIF-prolyl hydroxylase, histone deacetylase family, HIV integrase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51), matrix metalloproteinase family, methionine aminopeptidase, neutral endopeptidase, and the like, Nitric oxide synthase family, phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, pyruvate ferredoxin oxidoreductase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease, and xanthine oxidase.

26. The method of claim 20, wherein the metalloenzyme is 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), 17-alpha hydroxylase/17, 20-lyase (CYP17), aldosterone synthase (CYP11B2), aminopeptidase P, anthrax lethal factor, arginase, beta-lactamase, cytochrome P4502 a6, d-ala d-ala ligase, dopamine beta-hydroxylase, endothelin converting enzyme-1, 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, releasese, retinoic acid hydroxylase (CYP26), TNF-alpha converting enzyme (TACE), UDP- (3-O- (R-3-hydroxytetradecanoyl)) -N-acetylglucosamine deacetylase (LpxC), vascular adhesion protein-1 (VAP-1), or vitamin D hydroxylase (CYP 24).

27. The method of claim 20, wherein the compound of formula I is identified as having a range of activity against a target organism.

28. Use of a compound of claim 1 in the manufacture of a medicament for modulating metalloenzyme activity in a subject.

29. Use of a compound of claim 1 in the manufacture of a medicament for treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease.

30. Use of a compound of claim 1 in the manufacture of a medicament for treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, such that the subject is treated for the disorder, wherein the subject has been identified as in need of treatment for the metalloenzyme-related disorder or disease.

31. Use of a compound of claim 1 in the manufacture of a medicament for treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, such that metalloenzyme activity in the subject is modulated, wherein the subject has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease.

32. The use of claim 30, wherein the disease or disorder is caused by 4-hydroxyphenylpyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase n, angiotensin converting enzyme, aromatase (CYP19), calcineurin, carbamyl phosphate synthase, carbonic anhydrase family, catechol o-methyltransferase, cyclooxygenase family, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA aminotransferase, HIF-prolyl hydroxylase, histone deacetylase family, HIV integrase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51), matrix metalloproteinase family, methionine aminopeptidase, neutral endopeptidase, histone deacetylase, Nitric oxide synthase family, phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, pyruvate ferredoxin oxidoreductase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease, or xanthine oxidase.

33. The use of claim 30, wherein the disease or disorder is caused by 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), 17-alpha hydroxylase/17, 20-lyase (CYP17), aldosterone synthase (CYP11B2), aminopeptidase P, anthrax lethal factor, arginase, beta-lactamase, cytochrome P4502 a6, d-ala d-ala ligase, dopamine beta-hydroxylase, endothelin converting enzyme-1, 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, releasese, retinoic acid hydroxylase (CYP26), TNF-alpha converting enzyme (TACE), UDP- (3-O- (R-3-hydroxytetradecanoyl)) -N-acetylglucosamine deacetylase (LpxC), vascular adhesion protein-1 (VAP-1), or vitamin D hydroxylase (CYP 24).

34. The use of claim 30, wherein the disease or disorder is cancer, cardiovascular disease, endocrine disease, inflammatory disease, infectious disease, gynecological disease, metabolic disease, ophthalmic disease, Central Nervous System (CNS) disease, urological disease, or gastrointestinal disease.

35. The use of claim 30, wherein the disease or condition is a systemic fungal infection or onychomycosis.

36. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

37. The composition of claim 36, further comprising an additional therapeutic agent.

38. The composition of claim 36, further comprising an additional therapeutic agent that is an anti-cancer agent, an antifungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an antiproliferative agent, a metabolic disease agent, an ophthalmic disease agent, a Central Nervous System (CNS) disease agent, a urologic disease agent, or a gastrointestinal disease agent.