TWI646088B - Metalloenzyme inhibitor compounds - Google Patents

Abstract

The present invention describes a compound having a metalloenzyme-modulating activity, and a method of treating a disease, disorder or symptom mediated by such a metalloenzyme.

Description

Metal enzyme inhibitor compound

This specification relates to a compound of formula I as shown below, to its derivatives, and to its use as a fungicide. The compounds of the present invention provide better protection against ascomycetes, basidiomycetes, deuteromycetes and oomycetes.

Living organisms have developed a precise regulation process that specifically inputs metals, transports them to intracellular storage locations, and ultimately transports them to the location of use. One of the most important functions of metals (eg, zinc and iron) in biological systems is the activity of the metalloenzyme. Metalloenzymes are enzymes that allow metal ions to enter the active site of an enzyme and utilize 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 understood that preparations that bind to and inactivate the metal ions at the active site will greatly reduce the activity of the enzyme. Nature uses this same strategy to reduce the activity of certain metalloenzymes during periods when enzyme activity is not required. For example, the protein TIMP (a tissue inhibitor of metalloproteinases) binds to zinc ions at the active sites of various matrix metalloproteinases, thereby inhibiting enzyme activity. The pharmaceutical industry has adopted this same strategy to design medical agents. For example, the azole antifungal agents fluconazole and voriconazole contain a 1-(1,2,4-triazole) group that is present in the target enzyme lanosterol demethylase activity site. The blood matrix iron combines to inactivate the enzyme. Another item Examples include zinc-binding hydroxamic acid groups which have been incorporated into most of the disclosed inhibitors of matrix metalloproteinases and histone deacetylases. Another example is a zinc-binding carboxylic acid group that has been incorporated into most of the disclosed angiotensin-converting enzyme inhibitors.

When designing clinically safe and effective metalloenzyme inhibitors, the focus is on the use of the most appropriate metal-binding groups for specific targets and clinical indications. If a weakly bound metal-binding group is employed, it may be less than optimal. On the other hand, if a metal bond group which is extremely tightly bound is used, it is possible that the selectivity of the target enzyme is lower than the optimum value of the related metalloenzyme. Lack of optimal selectivity may result in clinical toxicity due to unintentional inhibition of these non-target metalloenzymes. One of these examples of clinical toxicity is the currently available azole antifungal agents fluconazole and voriconazole, which inadvertently inhibit human drug-metabolizing enzymes such as cytochrome P450 2C9 (CYP2C9), CYP2C19 and CYP3A4. . This non-target inhibition is mainly caused by the non-selective binding of 1-(1,2,4-triazole) currently used to the active sites of CYP2C9, CYP2C19 and CYP3A4. Another example of this is joint pain observed in many clinical trials of matrix metalloproteinase inhibitors. This toxicity has been considered to be related to the inhibition of non-target metalloenzymes due to the non-selective binding of hydroxamic acid groups to zinc at non-target active sites.

Therefore, the search for a metal-binding group that achieves a better balance between potency and selectivity remains an important goal, and it will address the need to address treatments and prevent diseases, disorders and their symptoms that are currently unsatisfactory. The medical agents and methods are important.

A fungicide is a compound of natural or synthetic origin that acts to protect Protect and heal plants to fight the damage caused by related fungi in agriculture. In general, no single fungicide is suitable for all conditions. Therefore, research continues to be made to produce fungicides that are more potent, easier to use, and less expensive.

The invention is a related compound (e.g., any of the compounds described herein), a method of modulating metalloenzyme activity, and a method of treating a disease, a condition, and a symptom thereof. This method can comprise a compound herein.

A method of controlling a disease caused by a pathogen in a plant at risk of a pathogenic disease comprising contacting one of the plants and an adjacent region of the plant with a composition of Formula I, or a salt, lysate, hydrate or prodrug thereof, among them:

MBG is a tetrazolyl group which is optionally substituted, a triazole group which is optionally substituted, and optionally substituted An azolyl group, optionally substituted pyrimidinyl, optionally substituted thiazolyl, or optionally substituted pyrazolyl; R ₁ is H, halo, alkyl or haloalkyl; R ₂ is H, halo a group, an alkyl group or a haloalkyl group; R ₃ is a 1,1'-biphenyl group substituted with 4'-OCH ₂ CF ₃ or 4'-F, or a heteroaryl group, which may be passed through 1, 2 or 3 as needed. Substituted independently R ₅ ; R ₄ is aryl, heteroaryl, alkyl or cycloalkyl, which is optionally substituted with 0, 1, 2 or 3 independent R ₆ ; each R _{5 is} independently H, halo a aryl group (which is optionally substituted by 1, 2 or 3 independent R ₆ ), a heteroaryl group, a haloalkyl group, a haloalkoxy group, a cyano group, a nitro group, an alkyl group, an alkoxy group, an alkenyl group , haloalkenyl, arylalkenyl, alkynyl, haloalkynyl, alkylaryl, arylalkynyl, arylalkyl, cycloalkyl, halocycloalkyl, sulfanyl, SF ₃ , SF ₆ , SCN, SO ₂ R ₇ , C(O)alkyl, C(O)OH, C(O)Oalkyl; each R _{6 is} independently alkyl, sulfanyl, cyano, haloalkyl, hydroxy, alkoxy, halo, haloalkoxy, -C (O) alkyl, -C (O) OH, -C (O) O _{-alkyl, SF 3, SF 6, SCN} , SO 3 H; and SO ₂ R _7; R ₇ is independently an alkyl group, an aryl group, The substituted aryl, heteroaryl or substituted heteroaryl of aryl group; R ₈ is _{H, -Si (R 9) 3} , -P (O) (OH) 2, -CH 2 -OP (O) (OH) ₂ or, optionally, -C(O)alkyl substituted by an amine group; R _{9 is} independently alkyl or aryl; and wherein R _{3 is} not substituted by 1, 2 or 3 independent R ₅ as desired - Pyridyl.

A further aspect is a compound of the formula: wherein R ₁ is fluoro; wherein R ₂ is fluoro; wherein R ₁ and R ₂ are fluoro; wherein R ₄ is phenyl, which is optionally 0, 1, 2 or 3 a single R ₆ substitution; wherein R ₄ is phenyl, which is optionally substituted with 0, 1, 2 or 3 independent halo; wherein R ₄ is phenyl, optionally 0, 1, 2 or 3 a separate fluorine substitution; wherein R ₄ is 2,4-difluorophenyl; wherein R ₅ is halo; wherein R ₃ is heteroaryl other than 2-pyridyl, which may be 1, 2 or 3 as desired Independent R ₅ substituted; wherein at least one R ₅ is halo; wherein: R ₁ is fluoro; R ₂ is fluoro; R ₄ is 2,4-difluorophenyl; and R ₃ is 2-pyridyl An aryl group substituted by 1, 2 or 3 independent R ₅ ; wherein: R ₁ is fluoro; R ₂ is fluoro; R ₄ is 2,4-difluorophenyl; and R ₃ is 1, 2 or 3 Independent R ₅ substituted bicyclic heteroaryl; wherein R ₃ is 2-quinolinyl substituted by 1, 2 or 3 independent R ₅ ; wherein MBG is optionally substituted tetrazolyl or optionally Substituted triazolyl; wherein MBG is 1H-tetrazol-1-yl, 2H-tetrazol-2-yl, 4H-1,2,4-triazol-4-yl; or 1H-1,2,4 -Triazole- 1-Base; wherein MBG is 1H-tetrazol-1-yl or 2H-tetrazol-2-yl; wherein MBG is 4H-1,2,4-triazol-4-yl, or 1H-1,2 , 4-triazol-1-yl; wherein R ₃ is thienyl, thiazolyl, quinolyl, pyridyl, benzothiazolyl, pyrimidinyl, quin Polinyl, pyridyl Base, or 嗒 a group optionally substituted by 1, 2 or 3 independent R ₅ ; wherein: R ₁ is fluorine; R ₂ is fluorine; R ₄ is 2,4-difluorophenyl; and R ₃ is thienyl, Thiazolyl, quinolyl, pyridyl, benzothiazolyl, pyrimidinyl, quin Polinyl, pyridyl Base, or 嗒 a group which is optionally substituted by 1, 2 or 3 independent R ₅ ; wherein R ₃ is thienyl, thiazolyl, quinolyl, pyridyl, benzothiazolyl, pyrimidinyl, quin Polinyl, pyridyl Base, or 嗒 a group optionally having 1, 2 or 3 independent alkyl, alkenyl, alkoxy, halo, cyano, haloalkyl, haloalkoxy, halophenyl substituted alkyl groups, Halophenyl substituted alkynyl, or haloalkyl substituted phenyl, haloalkoxy, halo, or cyano substituted.

The compounds herein include those compounds which are judged to form (at least partially) affinity with a metalloenzyme by forming one or more of the following chemical interactions or linkages with the metal: sigma bond, covalent bond, Bit-covalent, ionic, π, δ, or feedback bonding interactions. The compound can also interact through weak interactions with metals (eg van der Waals interaction, π cation interaction, π anion interaction, dipole-dipole interaction, ion-dipole interaction) Reaching affinity Sex. In one aspect, the compound is discriminated to pass through the 1-tetrazole moiety to interact with the metal; in another aspect, the compound is discriminated to pass through the N4 of the 1-tetrazole moiety. The metal has a bonding interaction; in another aspect, the compound is discriminated to interact with the metal through the N3-triazole moiety; in another aspect, the compound is discriminated through - N4 of the tetrazolyl moiety to have a bond interaction with the metal. In one aspect, the compound is discriminated to have a bond interaction with the metal through the 4-triazolyl moiety; in another aspect, the compound is discriminated to pass through the N1 of the 4-triazolyl moiety. The metal has a bonding interaction; in another aspect, the compound is identified to pass through the N3 of the 4-triazolyl moiety to have a bonding interaction with the metal.

Methods for analyzing metal-ligand binding interactions are known in the art of the following references, for example: "Principles of Bioinorganic Chemistry" by Lippard and Berg, University Science Books (1994) ); Basolo and Pearson's "Mechanisms of Inorganic Reactions", John Wiley & Sons Inc; 2nd Edition (September 1967); edited by Ivano Bertini, Harry Gray Ed Stiefel. Joan Valentine Biological Inorganic Chemistry", University Science Books (2007); Xue et al., Nature Chemical Biology, vol. 4, no. 2, 107-109 (2008).

In certain instances, the compounds of the invention are selected from the following compounds of formula I (and pharmaceutically acceptable salts, solvates or hydrates thereof): 1-(5-chlorothien-2-yl)-2-( 2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 1 ); 1-(4-bromothiazole-2-yl )-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 2 ); 4-(2-( 2-(2,4-Difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1 H -tetrazol-1-yl)propyl)thiazol-4-yl)benzonitrile ( 3 ); 1-(6-chloroquinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propene 2-ol ( 4 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(quinolin-2-yl)-3-(1 H -tetrazole-1- Propyl-2-ol ( 5 ); 1-(benzo[ d ]thiazol-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-( 1H -tetrazol-1-yl)propan-2-ol ( 6 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(pyrimidin-2-yl)-3-( 1 H -tetrazol-1-yl)propan-2-ol ( 7 ); 2-(4-chloro-2-fluorophenyl)-1-(6-chloroquinolin-2-yl)-1,1- Difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 8 ); 1-(6-bromoquinolin-2-yl)-2-(2,4-difluorophenyl) -1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 9 ); 1-(6-chloroquine Benz-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 10 ); -(6-chlorobenzo[ d ]thiazol-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl) Propan-2-ol ( 11 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(thiazole-2- Propyl-2-ol ( 12 ); 1-(5-bromothien-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H - Tetrazol-1-yl)propan-2-ol ( 13 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)- 1-(Thien-2-yl)propan-2-ol ( 14 ); 1-(6-chloroquinolin-2-yl)-1,1-difluoro-2-(4-methoxyphenyl)- 3-( 1H -tetrazol-1-yl)propan-2-ol ( 15 ); 1-(6-chloroquinolin-2-yl)-2-(2,4-difluorophenyl)-1, 1-difluoro-3-( 2H -tetrazol-2-yl)propan-2-ol ( 16 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-( 6-fluoroquinolin-2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 17 ); 2-(2,4-difluorophenyl)-1,1- Difluoro-3-(1 H -tetrazol-1-yl)-1-(6-(trifluoromethyl)quinolin-2-yl)propan-2-ol ( 18 ); 2-(2,4 -difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(6-(2,2,2-trifluoroethoxy)quinoline-2 - yl) propan-2-ol (19); 1- (6-chloro-quinolin-2-yl) -1,1-difluoro-2- (2-fluoro-4- ( Trifluoromethyl) phenyl) -3- (1 H - tetrazol-l-yl) propan-2-ol (20); 2- (2,4-difluorophenyl) -1,1-difluoro - 3-( 1H -tetrazol-1-yl)-1-(6-(trifluoromethoxy)quinolin-2-yl)propan-2-ol ( 21 ); 2-(2-chloro-4 -(Trifluoromethyl)phenyl)-1-(6-chloroquinolin-2-yl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 22 ); 1-(6-chloroquinolin-2-yl)-2-(3,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propene 2-ol ( 23 ); 2-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1 H -tetrazol-1-yl)propyl Quinoline-6-carbonitrile ( 24 ); 1-(6-(difluoromethyl)quinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro 3-( 1H -tetrazol-1-yl)propan-2-ol ( 25 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-methyl Quinoline-2-yl)-3-( 1H -tetrazol-1-yl)propan-2-ol ( 26 ); 1-(6-bromobenzo[ d ]thiazol-2-yl)-2- (2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 27 ); 1-(6-chloroquinolin-2- 2-(2,5-difluorophenyl)-1,1-difluoro-3-( 2H -tetrazol-2-yl)propan-2-ol ( 28 ); 1-(5, 6-Dichloroquinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 29); 2- (2,4-difluorophenyl) -1,1-difluoro--3- (1 H - four -Yl) -1- (5- (2,2,2-trifluoroethoxy) quinolin-2-yl) propan-2-ol (30); 1- (5-chloro-quinolin-2 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 31 ); 1-(6- Chloroquinolin-2-yl)-1,1-difluoro-2-(4-fluorophenyl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 32 ); 1-( 6-chloroquinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -1,2,4-triazol-1-yl)propane 2-alcohol ( 33 ); 2-(4-chloro-2-fluorophenyl)-1-(6-chloroquine 2-yl) -1,1-difluoro--3- (1 H - tetrazol-l-yl) propan-2-ol (34); 1- (6-Chloro-quinolin-2-yl) -2 -(2,4-difluorophenyl)-1,1-difluoro-3-(4 H -1,2,4-triazol-4-yl)propan-2-ol ( 35 ); 2-( 2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(6-(4-(2,2,2-trifluoroethoxy) Phenyl)pyridin-3-yl)propan-2-ol ( 36 ); 1-(7-chloroisoquinolin-3-yl)-2-(2,4-difluorophenyl)-1, 1-difluoro-3-( 1H -tetrazol-1-yl)propan-2-ol ( 37 ); 1-(6-bromoquine Benz-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 38 ); -(5-(4-(difluoromethoxy)phenyl)pyrene -2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 39 ); 1- (5-(4-chlorophenyl)pyridinium 2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 40 ); 2- (2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethyl) Oxy)phenyl)pyr -2-yl)propan-2-ol ( 41 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1- (5-(4-(trifluoromethoxy)phenyl)pyrene -2-yl)propan-2-ol ( 42 ); 1-(5-(4-bromophenyl)pyridinium 2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 43 ); 2- (2,4-difluorophenyl)-1-(5-(3,4-difluorophenyl)pyridinium -2-yl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 44 ); 1,1-difluoro-2-(4-fluorophenyl) )-3-(1 H -tetrazol-1-yl)-1-(5-(4-(trifluoromethoxy)phenyl)pyrene 2-yl)propan-2-ol ( 45 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-fluorophenyl)pyridinium -2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 46 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1- (5-(4-fluorophenyl)pyridinium -2-yl)-3-( 2H -tetrazol-2-yl)propan-2-ol ( 47 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1- (5-(4-methoxyphenyl)pyridyl -2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 48 ); 1-(5-chloropyridyl 2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 49 ); 2- (2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridinium -2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 50 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1- (5-((4-fluorophenyl)ethynyl)pyridinium -2-yl)-3-( 2H -tetrazol-2-yl)propan-2-ol ( 51 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1- (5-(4-fluorophenethyl)pyridinium -2-yl)-3-( 1H -tetrazol-1-yl)propan-2-ol ( 52 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1- (5-(4-fluorophenethyl)pyridinium -2-yl)-3-( 2H -tetrazol-2-yl)propan-2-ol ( 53 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3- (1 H -tetrazol-1-yl)-1-(6-(trifluoromethoxy)quinaquine Benz-2-yl)propan-2-ol ( 54 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-fluoroquinoline 2-(2- H -tetrazol-1-yl)propan-2-ol ( 55 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3 -(1 H -tetrazol-1-yl)-1-(6-(4-(trifluoromethyl)phenyl)anthracene 3-yl)propan-2-ol ( 56 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1- (6-(4-(trifluoromethoxy)phenyl)anthracene 3-yl)propan-2-ol ( 57 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-(4-fluorophenyl)fluorene 3-yl)-3-( 1H -tetrazol-1-yl)propan-2-ol ( 58 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3- (1 H -tetrazol-1-yl)-1-(6-vinylquin 2-yl) propan-2-ol (59); 2- (2,4-difluorophenyl) -1,1-difluoro--3- (1 H - tetrazol-l-yl) -1 -(4'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-4-yl)propan-2-ol ( 60 ); 2-(2,4- Difluorophenyl)-1,1-difluoro-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-3-(1 H -tetrazol-1-yl) Propan-2-ol ( 61 ).

In another aspect, the 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 wherein the compound inhibits (or is judged to be inhibited) lanosterol demethylase (CYP51).

In other aspects, the invention provides a compound of any of the formulae, wherein the compound is discriminated to have an active range for the target organism (eg, a minimum inhibitory concentration (MIC) < 0.25 against C. albicans Microgram/ml (μg/mL); minimum inhibitory concentration (MIC) to S. tritici <0.5 μg/ml (μg/mL); for example, minimal inhibition of P. triticina Concentration (MIC) <0.5 μg/ml (μg/mL)).

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

In other aspects, the invention provides a method of modulating metalloenzyme activity in an individual comprising contacting the individual with a compound of formula I in an amount and under conditions sufficient to modulate metalloenzyme activity.

In one aspect, the invention provides a method of treating an individual suffering from or susceptible to a metalloenzyme related disorder or disease comprising administering to the individual an effective amount of a compound of formula I or a pharmaceutical composition thereof.

In another aspect, the present invention provides a treatment for suffering or prone to suffering from gold A method of treating an individual with an enzyme-related disorder or disease, wherein the individual is determined to be in need of treatment for a metalloenzyme-related disorder or disease, comprising administering to the individual in need thereof an effective amount of a compound of formula I or a pharmaceutical composition thereof, The individual treats the condition.

In another aspect, the invention provides a method of treating an individual afflicted or susceptible to a condition or disease mediated by a metalloenzyme, wherein the individual is identified as being in need of treatment for a metalloenzyme mediated condition or disease, including The individual in need is administered an effective amount of a compound of formula I or a pharmaceutical composition thereof to modulate (e.g., down regulate, inhibit) the metalloenzyme activity of the individual.

The methods herein include diseases or conditions in which any of the following enzymes are mediated: 4-hydroxyphenylpyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, Aminopeptidase N, angiotensin converting enzyme, aromatase (CYP19), calcineurin, amine methotrexate synthase, carbonic anhydrase family, catechol-O-methyltransferase, epoxy Synthase family, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA aminotransferase, HIF-amidamine Hydroxylase, histone deacetylase family, HIV integrase, HIV-1 reverse transcriptase, isoalbumin tRNA ligase, lanosterol demethylase (CYP51), matrix metalloproteinase family, methyl thiamine Acid aminopeptidase, neutral endopeptidase, nitric oxide synthase family, phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, pyruvate iron redox oxidoreductase, renal peptidase , ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease or jaundice Oxidase.

The methods herein include diseases or conditions in which one of the following enzymes is mediated: 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), 17-alpha hydroxylase (CYP17) ), aldosterone synthase (CYP11B2), aminopeptidase P, anthrax lethal factor, arginase, β-endosaminolase, cytochrome P450 2A6, D-A1a D-A1a ligase, dopamine β-hydroxyl Chemase, endothelin-converting enzyme-1, glutamic acid carboxypeptidase II, glutaminyl cyclase, glyoxalase, blood matrix oxidase, HPV/HSVE1 helicase, indoleamine 2 , 3-dioxygenase, leukotriene A4 hydrolase, methionine aminopeptidase 2, peptide demethylase, phosphodiesterase VII, relaxase, retinoic acid hydroxylase (CYP26), TNF-α converting enzyme (TACE), UDP-(3-O-(R-3-hydroxymyristyl)-N-acetyl glucosamine deacetylase (LpxC), vascular adhesion protein-1 (VAP-1) or vitamin D hydroxylase (CYP24).

The methods herein include those in which the disease or condition 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 in which the disease or condition is prostate cancer, breast cancer, inflamed bowel disease, dryness, systemic fungal infection, cutaneous structural fungal infection, mucosal fungal infection, or onychomycosis.

The methods shown herein include those in which the individual is identified as requiring a particular treatment. The discrimination of an individual in need of such treatment may be subjective (eg, opinion) or objective judgment (eg, as determined by a test or diagnostic method) by the individual or health care professional.

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

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

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

definition

In order to make the invention easier to understand, certain terms are first defined for convenience.

The term "treating" a disorder as used herein includes preventing, alleviating, alleviating, and/or managing a condition and/or conditions that may cause the condition. The terms "treating" and "treating" refer to alleviating or eliminating the symptoms of the disease and/or its appearance. According to the present invention, "treating" includes preventing, blocking, inhibiting, attenuating, protecting against, regulating, reversing, and reducing the occurrence of a disorder such as a deleterious effect of a disorder.

As used herein, "inhibition" includes prevention, reduction, and repression of progression. It should be noted that "enzyme inhibition" (for example, metalloenzyme inhibition) is specifically described below.

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

The terms "isolated," "purified," or "purely biological" mean that there is substantially no or substantially no ingredient that would normally accompany the appearance in its natural state. Purity and homogeneity are usually determined by analytical chemistry techniques such as polypropylene-based guanamine gel electrophoresis or high performance liquid chromatography. In particular, in particular 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 introducing a compound (group) into an individual to perform its intended function. Examples of routes of administration that may be employed include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intraspinal), topical, oral, inhalation, transrectal and transdermal.

The term "effective amount" includes a dose that will effectively achieve the desired result over the period of time necessary. The effective amount of a compound can vary depending on factors such as the disease state of the individual, age and weight, and the ability of the compound to elicit a desired response in the individual. Dosage regimens can be adjusted to achieve the most appropriate medical response. An effective amount can also be an amount such that the pharmaceutical benefit of the inhibitor compound exceeds its toxic or detrimental effects (eg, side effects).

The phrase "systemic administration", "systemic administration", "peripheral administration" and "peripheral administration" as used herein means that the compound (group), drug or other material is administered to the systemic system of the patient, thus Metabolism and other similar processes can be performed.

The term "medically or agriculturally effective amount" means that the compound is administered in an amount sufficient to prevent its development or alleviation to some extent with respect to one or more symptoms of the condition or disorder being treated.

The medically effective amount (i.e., effective amount) of the compound can range from about 0.005 micrograms per kilogram of body weight (μg/kg) to about 200 milligrams per kilogram of body weight (mg/kg), preferably about 0.01 mg/kg body weight to Approximately 200 mg/kg body weight, more preferably from about 0.015 mg/kg body weight to about 30 mg/kg body weight. In other embodiments, the medically effective amount can range from about 1.0 picomolar concentration (pM) to about 10 micromolar concentration ([mu]M). Those familiar with this art know that certain factors may affect the dose required to effectively treat an individual, including (but not Limited to: the severity of the disease or condition, past treatment, general health and/or age of the individual, and other diseases that occur. In addition, treatments for treating an individual with a medically effective amount of a compound include a single treatment, or preferably may include continuous treatment. In one embodiment, the system is administered once a day to a compound ranging from about 0.005 μg/kg to about 200 mg/kg body weight for about 1 to 10 weeks, preferably 2 to 8 weeks, more preferably about 3 to 7 weeks. Even better, about 4, 5 or 6 weeks. In another example, the individual is treated daily for a chronic condition or disease for several years. It is also well understood that the effective dose of a compound for treatment may increase or decrease with a particular course of treatment.

The term "pivot" refers to a molecule that has no overlapping properties with its mirror counterpart, and the term "non-palphape" refers to a molecule that can overlap with its mirror counterpart.

The term "diastereomer" refers to a stereoisomer having 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 which are non-superimposable mirror images of each other. The molar mixture of the two enantiomers is referred to as the "racemic mixture" or "racemate".

The term "isomer" or "stereoisomer" refers to a compound that has the same chemical composition but differs in the arrangement of the atoms or groups in space.

The term "prodrug" includes compounds having a moiety that is metabolizable in vivo. Usually, the prodrug can be metabolized into an active drug by an esterase or by another machine in vivo. Examples of prodrugs are known in the art of their use (see, for example, 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 compound, or otherwise prepared by reacting the purified compound in the free acid form or its hydroxyl 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 or unsubstituted branched or unbranched lower alkyl ester moieties (eg, propionates), lower alkyl alkenyl esters, di-lower alkyls Alkyl-amino-lower alkyl-alkyl esters (eg, dimethylaminoethyl ester), mercaptoamine-based lower alkyl esters (eg, ethoxymethyloxymethyl ester), hydrazine Alkoxy lower alkyl esters (eg, pentyl methoxymethyl ester), aryl esters (phenyl esters), aryl-lower alkyl esters (eg, benzyl esters) An aryl group and an aryl-lower alkyl ester, a decylamine, a lower carbon-alkyl guanamine, substituted (for example, substituted with a methyl group, a halogen group or a methoxy substituent), Di-lower alkyl alkyl amides and hydroxy guanamines. Preferred prodrug moieties are propionates and mercaptoesters. It also includes drugs that can be converted into active forms through other in vivo mechanisms. In some aspects, the compounds of the invention are prodrugs of any of the formulas shown herein.

The term "individual" refers to an animal, such as a mammal, including but not limited to: primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. . In some embodiments, the individual is a human.

The terms "a", "an" and "the" are used to mean "one or more". Thus, for example, reference to "a sample" includes a plurality of the <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;

In the specification and claims, the terms "comprising", "including" and "comprising" are used as non-closed unless the context indicates otherwise.

When a numerical value is referred to herein, the term "about" is used to mean that there is a variation between it and the specified number. In some embodiments, it means that the variation with the specified amount is ±20%, at a certain ±10% in some embodiments, ±5% in some embodiments, ±1% in some embodiments, ±0.5% in some embodiments, and in certain embodiments In the specific examples, it is ±0.1%, as such variations are still suitable for carrying out the disclosed methods or applying the disclosed compositions.

The term "inhibitor" as used herein means a molecule having a metalloenzyme inhibiting activity. As used herein, "inhibiting" means that the activity of the metalloenzyme is less than the activity of the metalloenzyme in the absence of an inhibitor. In some embodiments, the term "inhibiting" means that the metalloenzyme activity is reduced by 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 specific embodiments, "inhibiting" means that the metalloenzyme activity is reduced by from about 5% to about 25%, from about 25% to about 50%, from about 50% to about 75%, or from about 75% to 100%. In some embodiments, "inhibiting" means that the metalloenzyme activity is reduced by about 95% to 100%, for example, a 95%, 96%, 97%, 98%, 99% or 100% reduction in activity. The degree of reduction can be measured using a variety of different techniques that have been recognized by those skilled in the art. Specific assays for determining individual activity are described below.

In addition, the compounds of the present invention include olefins having one of the following geometric properties: " Z " refers to the "cis" (same side) configurator, and " E " refers to the "trans" (opposite side) configuration. By. In the nomenclature of the palm center, the terms " d " and " l " are defined by the IUPAC Recommendations. The terms used: diastereomers, racemates, epimers and enantiomers will be used in the general context to illustrate the stereochemistry of the formulation.

The term 'R' as used throughout the specification refers to a group consisting of C _{1 -8} alkyl, C _3-8 alkenyl or C _3-8 alkynyl, unless otherwise stated.

The term "alkyl" as used herein, refers to a straight or branched chain hydrocarbon radical containing from 1 to 12 carbon atoms. The term "lower alkyl" refers to C ₁ -C ₆ alkyl chain. Examples of the alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a tert-butyl group and a n-pentyl group. The alkyl group is optionally substituted with one or more substituents.

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

The term "alkynyl" refers to an unsaturated hydrocarbon chain containing a straight or branched chain of 2 to 12 carbon atoms and at least one carbon-carbon reference. The alkynyl group is optionally substituted with one or more substituents.

The sp ² or sp carbon of the alkenyl group and the alkynyl group are respectively an attachment point of an alkenyl group or an alkynyl group.

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

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

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

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

The term "heteroaryl" refers to an aromatic 5 to 8 membered monocyclic ring, 8 to 12 membered bicyclic ring or 11 to 14 membered tricyclic ring system, and if it is a single ring, it has 1 to 4 ring heteroatoms, and if it is a double ring, Has 1 to 6 ring heteroatoms, or 1 to 9 ring heteroatoms if it is a tricyclic ring, the hetero atom is selected from O, N or S, and the remaining ring atoms are carbon (with appropriate hydrogen atoms unless otherwise There are instructions). The heteroaryl group is optionally substituted with one or more substituents. In a particular 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 pyridinyl, furyl, thienyl, pyrrolyl, Azolyl, Diazolyl, imidazolyl, thiazolyl, iso Azyl, quinolyl, pyrazolyl, isothiazolyl, anthracene Base, pyrimidinyl, pyridyl Base, three Base, isoquinolyl, oxazolyl and the like.

The term "nitrogen-containing heteroaryl" means a heteroaryl group having 1 to 4 ring nitrogen heteroatoms, and 1 to 4 ring nitrogen heteroatoms if monocyclic, if bicyclic It has 1 to 6 ring nitrogen hetero atoms or, if it is a tricyclic ring, 1 to 9 ring nitrogen hetero atoms.

The term "heterocycloalkyl" refers to a non-aromatic 3 to 8 membered monocyclic ring, a 7 to 12 membered bicyclic ring or a 10 to 14 membered tricyclic ring system which, if monocyclic, has from 1 to 3 heteroatoms, if bicyclic Then having 1 to 6 heteroatoms or, if tricyclic, having 1 to 9 heteroatoms selected from O, N, S, B, P or Si, wherein the non-aromatic ring system is fully saturated . The heterocycloalkyl group is optionally substituted with one or more substituents. In a particular embodiment, 0, 1, 2, 3 or 4 atoms in each ring of the heterocycloalkyl group may be substituted with a substituent. Representative heterocycloalkyl groups include piperidinyl, piperidine , tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxocyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiirenyl and the like .

The term "alkylamino" means that the amino substituent is further substituted with one or two alkyl groups. The term "aminoalkyl" means that the alkyl substituent is further substituted with one or more amine groups. The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent which is further substituted with one or more hydroxy groups. Alkylamino, aminoalkyl, thioalkyl, hydroxyalkyl, thioalkylalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl and alkylcarbonylalkyl The aryl or aryl moiety is optionally substituted with one or more substituents.

Suitable for use in the art of acids and bases suitable for use in the methods herein. The acid catalyst is any acidic chemical, which may be a mineral acid (for example: hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride) or an organic acid (for example: camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoromethanesulfonic acid) ytterbium). Acids are suitable for promoting chemical reactions in the amount of catalyst or stoichiometry. The alkali is any alkaline chemical, which can It is an inorganic base (for example: sodium hydrogencarbonate, potassium hydroxide) or an organic base (for example: triethylamine, pyridine). Bases are suitable for promoting chemical reactions in the amount of catalyst or stoichiometry.

The alkylating agent is any agent which can alkylate the functional group in question (for example, the oxygen atom of an alcohol, the nitrogen atom of an amine group). Alkylating agents are known in the art, including references cited therein, including alkyl halides (eg, methyl iodide, bromotoluene or chlorotoluene), alkyl sulfates (eg, methyl sulfate), or Other alkyl-debonding combinations are known in the art. The cleavage group is any stable group that can be detached from the molecule during the reaction (eg, elimination reaction, substitution reaction), and is known in the art (including references cited herein), including halide ions (eg, I-, Cl-, Br-, F-), hydroxyl, alkoxy (eg: -OMe, -Ot-Bu), alkoxy anion (eg: -OAc, -OC(O)CF ₃ ), sulfonate Sulfone (eg mesyl, tosyl), acetamide (eg -NHC(O)Me), carbamate (eg N(Me)C(O) Ot-Bu), phosphonates (for example: -OP(O)(OEt) ₂ ), water or alcohols (proton conditions), and the like.

In certain embodiments, any group (eg, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl) The substituent may be at any atom of the group, wherein any substituent group may be substituted (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl) The group, cycloalkyl, heterocycloalkyl) are optionally substituted by one or more (may be the same or different) substituents, each substituent being substituted for one hydrogen atom. Examples of suitable substituents include, but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroarylalkyl, aryl, hetero Aryl, halogen, haloalkyl, cyano, nitro, alkoxy, aryloxy, hydroxy, hydroxyalkyl, pendant oxy (ie carbonyl), carboxyl, carbaryl, alkylcarbonyl, alkane Carbocarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl, thio, thiol, thioalkyl, arylsulfonate Base, amine, aminoalkyl, dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, alkoxycarbonylamino, alkylamino, arylamino, diarylamine An alkylcarbonyl group or an aryl group substituted with an arylamine group; an arylalkylamino group, an aralkylaminocarbonyl group, a decylamino group, an alkylaminosulfonyl group, an arylaminosulfonyl group, Dialkylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, imido, formamide, amine methyl thiol, thiourea, thiocyanyl, sulfonamide A sulfonylalkyl group, a sulfonyl aryl group, a thioalkyl alkoxy group, an N-hydroxy fluorenyl group or an N'-aryl group, an N"-hydroxy fluorenyl group.

The compounds of the present invention can be prepared by organic synthesis methods known in the art. The optimization of the reaction conditions (to minimize the by-products of competition if necessary) is known to those skilled in the art. The optimization of the reaction and the scale of amplification advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (eg, Design and Optimization in Organic Synthesis, 2nd edition , edited by Carlson R, 2005; Elsevier Science Ltd.; Jähnisch, K. et al., Angew. Chem. Int. Ed. Engl. 2004 43 :406; and references therein). Other Responsive Sketches and Processes A structured search database software available from the product can be used by those skilled in the art (eg SciFinder ^® (Chemical Abstracts Service (CAS ^® ) division of the American Chemical Society) and CrossFire Beilstein ^® (Elsevier) MDL) is determined by searching for the appropriate keywords using a web search engine (eg Google ^® ) or a keyword database (eg, the US Patent and Trademark Office).

The compounds herein may also contain linkages (e.g., carbon-carbon bonds) in which the rotation of the linkage is limited by the particular linkage, for example, due to the presence of a ring or double bond. Therefore, all cis/trans and E / Z isomers are included in the present invention. The compounds herein may also be represented by a variety of tautomeric forms, in which case the invention will of course include all tautomeric forms of the compounds described herein, even though they may represent only one tautomeric form. All such isomers of such compounds are of course included in the invention. All crystalline forms and polymorphs of the compounds described herein are of course included in the present invention. Also included are extracts and dissolved fractions comprising the compounds of the invention. The term "isomer" includes diastereomers, enantiomers, positional isomers, structural isomers, rotamers, tautomers, and the like. For compounds containing one or more stereocenters (e.g., palmitic compounds), the methods of the invention can be carried out using enriched enantiomeric compounds, racemates or mixtures of diastereomers.

Preferably, the enantiomeric excess of the enantiomerically enriched compound is 50% or more, more preferably the enantiomeric excess of the compound is 60%, 70%, 80%, 90%, 95%, 98% or 99% or more. In a preferred embodiment, only one enantiomer or diastereomer of the palm compound of the present invention is administered to a cell or an individual.

In another aspect, the present invention provides a method for synthesizing the formula described herein. A method of the compound (or any of the formulae compounds shown herein). Another embodiment is a method of making any of the compounds of the formula shown herein using any of the reactions described herein, or a combination thereof. The method can include the use of one or more intermediates or chemical agents as described herein.

(treatment method)

In one aspect, the invention provides a method of modulating metalloenzyme activity in a cell of an individual comprising subjecting the individual to a compound of any of the formulae (eg, Formula I) described herein under conditions and conditions sufficient to modulate metalloenzyme activity contact.

In one aspect, the regulation is inhibition.

In another aspect, the invention provides a method of treating an individual afflicted or susceptible to a condition or disease mediated by a metalloenzyme, comprising administering to the individual an effective amount of any of the formulae described herein (eg, Formula I) a compound or a pharmaceutical or agricultural composition thereof.

In other aspects, the invention provides a method of treating an individual afflicted or susceptible to a condition or disease mediated by a metalloenzyme, wherein the individual is identified as needing to treat a condition or disease mediated by a metalloenzyme, including The individual is administered an effective amount of a compound of any of the formulae (e.g., Formula I) described herein, or a pharmaceutical or agricultural composition thereof, to treat the condition for the individual.

In certain embodiments, the invention provides a method of treating a disease, condition or condition, wherein the condition is cancer, cardiovascular disease, inflammatory disease or infectious disease. In other specific embodiments, the disease, disorder, or condition is a metabolic disease, an ophthalmic disease, a central nervous system (CNS) disease, Urological disease, or gastrointestinal disease. In certain embodiments, the disease is prostate cancer, breast cancer, inflamed bowel disease, dryness, systemic fungal infection, cutaneous structural fungal infection, mucosal fungal infection, and onychomycosis.

In some embodiments, the individual is a mammal, preferably a primate or a human.

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

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

In other specific embodiments, the invention provides a method as described above, wherein any of the formulae (eg, Formula I) herein is administered alone or in combination with one or more other medical agents. In another specific embodiment, the additional medical agent is an anticancer agent, an antifungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an anti-proliferative agent, a metabolic disease agent, an ophthalmic disease. Agent, central nervous system (CNS) disease agent, urological disease agent, or gastrointestinal disease agent.

Another object of the invention is the use of a compound described herein (e.g., a compound of any of the formulae herein) for the manufacture of a medicament for the treatment of a condition or disease mediated by a metalloenzyme. Another object of the invention is the use of a compound described herein (e.g., a compound of any of the formulae herein) for treating a condition or disease mediated by a metalloenzyme. Another object of the invention is to produce a compound described herein (e.g., a compound of any of the formulae herein) Use in agricultural or arable land management for the treatment or prevention of agricultural compositions mediated by metalloenzymes or diseases.

(medicine composition)

In one aspect, the invention provides a pharmaceutical composition comprising a compound of any of the formulae (eg, Formula I) herein and a pharmaceutically acceptable carrier.

In another embodiment, the invention provides a pharmaceutical composition further comprising an additional medical agent. In another specific embodiment, the additional medical agent is an anticancer agent, an antifungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an anti-angiogenic agent, a cytotoxic agent, an anti-proliferative agent, a metabolic disease agent, an ophthalmic disease. Agent, central nervous system (CNS) disease agent, urological disease agent, or gastrointestinal disease agent.

In one aspect, the invention provides a kit comprising an effective amount of a compound of any of the formulae herein (eg, Formula I) and instructions, which instructions for administering the compound to a subject or susceptible to a metalloenzyme A description of an individual mediated by a disease or condition, including cancer, solid tumor, cardiovascular disease, inflammatory disease, infectious disease. In other specific embodiments, the disease, condition, 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 salts" or "pharmaceutically acceptable carrier" is meant to include the active compound and the relatively non-toxic acid or base (depending on the particular substituents present on the compounds described herein) Salt formed. When the compound of the present invention contains a relatively acidic functional group, it may be among such compounds The serotype is contacted with a sufficient amount of the base (either in pure form or in a suitable inert solvent) to provide a base addition salt. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine groups, or magnesium salts or the like. When a compound of the invention contains a relatively basic functional group, the intermediate form of the compound can be contacted with a sufficient amount of the desired acid (either as a pure material or in a suitable inert solvent) to provide an acid addition salt. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogenic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen. Sulfuric acid, hydroiodic acid, or phosphorous acid and its analogs, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid , suberic acid, fumaric acid, lactic acid, mandelic acid, citric acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like. Also included are salts of amino acids such as arginine and its analogs, and salts of organic acids such as glucuronic acid or galacturonic acid and its analogs (see for example: Journal of Berge et al.) Of Pharmaecutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups which allow the compounds to be converted to bases or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are also suitable for use in the present invention.

The salt is contacted with a base or acid and isolated from the parent compound by conventional means to regenerate the neutral form of the compound. The parent compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents, but otherwise, the salts are equivalent to the parent compound for the purposes of the present invention.

In addition to the salt form, the present invention also provides a compound of a prodrug type. The prodrugs of the compounds described herein are those which readily undergo chemical changes under physiological conditions to form the compounds of the invention. In addition, prodrugs can be converted to the compounds of the invention via chemical or biochemical methods in an ex vivo environment. For example, the current drug can be slowly converted to the compound of the invention when placed in a perforated patch reservoir containing suitable enzymes or chemical reagents.

Certain compounds of the invention may be in a non-soluble and solvated form, including hydrated forms. Generally, fused versions are equivalent to non-dissolved forms and are included within the scope of the invention. Certain compounds of the invention may be in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent to the use of the invention and are included within the scope of the invention.

The invention also provides a pharmaceutical composition comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In a specific embodiment, the compound is administered to the individual using a pharmaceutically acceptable formulation, for example, after the pharmaceutically acceptable formulation is administered to the individual, the pharmaceutically acceptable formulation can continue to deliver the pharmaceutically acceptable formulation. The compound is administered to the individual for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks.

The actual dosage of the active ingredient in the pharmaceutical compositions of the present invention and the time course of administration can be varied to effectively achieve the desired pharmaceutical effect for a particular patient, composition and mode of administration without toxic (or unacceptable toxicity) to the patient.

When used, at least one compound according to the invention is contained in a pharmaceutical carrier by intravenous, intramuscular, subcutaneous or intraventricular injection or oral administration. Administration or topical administration administers a pharmaceutically effective amount to an individual in need thereof. According to the invention, the compounds of the invention may be administered alone or in combination with a second different agent. "Combination" means common, substantially simultaneous or sequential. In a specific embodiment, the compounds of the invention are administered acutely. Thus, the compounds of the invention may be administered in a short-term regimen, such as from about 1 day to about 1 week. In another embodiment, the compounds of the invention may be administered chronically to alleviate chronic conditions, such as, for example, from about one week to several months, depending on the condition being treated.

As used herein, "pharmaceutically effective amount" means that the amount of the compound of the present invention is sufficiently high to significantly correct the condition to be treated, but is also low enough to avoid serious side effects (at reasonable benefit/risk) Under the ratio). The pharmaceutically effective amount of a compound of the invention will vary depending on the particular goal of the program, the age and physical condition of the patient being treated, the severity of the original condition, the time course of the treatment, the nature of the concurrent therapy, and the particular compound employed. For example, a medically effective amount of a compound of the invention administered to a child or newborn will be proportionally reduced in accordance with a complete medical judgment. Thus, an effective amount of a compound of the invention will be the minimum amount that will provide the desired effect.

A significant advantage of the present invention is that the compound can be administered in a convenient manner, such as by intravenous, intramuscular, subcutaneous, oral or intracerebroventricular routes or by topical application, such as in the form of a cream or gel. Depending on the route of administration, the active ingredient comprising a compound of the invention may need to be coated in a material to protect the compound from enzymes, acids and other natural conditions which may deactivate the compound. In order to administer the compound of the invention in a parenteral manner, the compound may be coated with or with the material to prevent inactivation.

The compound can be administered parenterally or intraperitoneally. Also in the case For example, glycerin, liquid polyethylene glycol and mixtures thereof, and dispersions in oil.

Examples of certain materials which can be used as pharmaceutical carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose and ethylcellulose. And cellulose acetate; tragacanth powder; 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; acacia; alginic acid; pyrogen-free water; isotonic physiological saline; and phosphate buffer; skim milk powder; Non-toxic compatible substances of pharmaceutical formulations such as, for example, vitamin C, estrogen and Echinacea . Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tableting agents, stabilizers, antioxidants, and preservatives may also be present. Dissolving agents can also be used in the pharmaceutical compositions herein, including, for example, polyoxyethylated cremaphores and beta-cyclodextrin.

The pharmaceutical composition comprising the active compound (or a prodrug thereof) disclosed herein may be a conventional mixing method, a dissolution method, a granulation method, a sugar coating method, a grinding method, an emulsification method, an encapsulation method, an embedding method or a freeze drying method. Manufacturing. The composition can be used in a conventional manner by the use of one or more physiologically acceptable carriers, diluents, excipients or auxiliaries for assisting in the processing of the active compound into a pharmaceutically acceptable preparation.

The pharmaceutical composition trough disclosed herein can be in any form that is substantially suitable for administration, including, for example, topical, transocular, oral, buccal, whole body, Nasal, injection, skin, rectal, vaginal and similar forms, or in a form suitable for administration by inhalation or insufflation.

For topical administration, the active compound (group) or prodrug (group) can be formulated into solutions, gels, ointments, creams, suspensions and the like.

Systemic pharmaceutical formulations include those designed for injection administration, for example, subcutaneous, intravenous, intramuscular, intraspinal or intraperitoneal injection, and they are designed for transdermal, transmucosal, oral or meridian Pulmonary administration.

Suitable injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles. The composition may also contain formulating agents such as suspending agents, stabilizers and/or dispersing agents. Formulations for injection may be presented in unit dosage form (for example, in ampoules or in multi-dose containers), and preservatives may be added.

Alternatively, the injectable formulation may be in powder form and reconstituted with a suitable vehicle (including, but not limited to, sterile pyrogen free water, buffer, dextrose solution, and the like) prior to use. Thus, the active compound (group) can be dried by techniques known in the art, such as: lyophilization, and reconstituted prior to use.

When the mucosa is administered, a penetrant suitable for the barrier to be permeated is used in the formulation. Such penetrants are known to those skilled in the art.

For oral administration, the pharmaceutical composition may be, for example, a buccal tablet, a lozenge or a capsule, which is prepared in a conventional manner using a pharmaceutically acceptable excipient such as a binding agent (for example, pregelatinized corn). Starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (eg lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (eg magnesium stearate, talc or vermiculite); Decomposing agent (for example: potato starch or sodium starch glycolate); or a humidifying agent (for example: Sodium lauryl sulfate). Tablets may be coated by methods known in the art using, for example, sugar coatings or enteric coatings.

The oral pharmaceutical liquid preparation may be, for example, an elixirs, a solution, a syrup or a suspension, or it may be in the form of a dry product, which may be reconstituted with water or other suitable vehicle before use. These liquid preparations can be prepared in a conventional manner using pharmaceutically acceptable additives such as suspending agents (for example: sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (for example: lecithin or acacia) Gum); non-aqueous vehicles (eg, almond oil, oil esters, ethanol or fractionated vegetable oils); and preservatives (eg, methyl or propyl p-hydroxybenzoate or sorbic acid). The preparation may suitably contain buffer salts, preservatives, flavoring agents, coloring agents, and sweeteners, as appropriate.

Oral pharmaceutical preparations should be formulated into conventional controlled release active compounds or prodrugs.

When administered intravesically, the composition can be formulated into lozenges or buccal tablets in a conventional manner.

In the case of rectal and vaginal routes of administration, the active compound (s) may be formulated as solutions (for enema), suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

When administered intranasally or by inhalation or by insufflation, the active compound (group) or prodrug (group) is preferably in the form of an aerosol, using a suitable propellant from a pressurized tank or nebulizer (eg dichlorodifluoromethane) , trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas) spray delivery. In pressurized aerosols, the dosage unit can be determined by a valve that delivers a metered amount. Formulating capsules and cartridges for inhalers or insufflators (eg capsules and cartridges consisting of gelatin) A powder mixture comprising 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 ingredients: active compound or prodrug (0.5 to 20 mg/mL); benzalkonium chloride (0.1 to 0.2 mg/mL); polysorbate 80 (TWEEN ^® 80; 0.5 to 5 mg/mL); sodium carboxymethylcellulose or microcrystalline cellulose (1 to 15 mg/mL); phenylethanol (1 to 4 mg/ M)) and dextrose (20 to 50 mg/mL). The pH of the final suspension can be adjusted to a range from about pH 5 to pH 7, with a typical pH of about pH 5.5.

For administration to the eye, the active compound (group) or prodrug (group) can be formulated into solutions, emulsions, suspensions and the like suitable for administration to the eye. A variety of different mediators suitable for administering a compound to the eye are known in the art. Specific non-limiting examples are described in U.S. Patent No. 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. Patent No. 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, the disclosure of which is incorporated herein by reference. in.

For long-term delivery, the active compound (group) or prodrug (group) can be formulated into a depot preparation for administration via an implant or intramuscular injection. The active ingredient can be formulated with a suitable polymeric or hydrophobic material (for example, as an emulsion in an acceptable oil) or an ion exchange resin, or as a poorly soluble derivative (for example, a poorly soluble salt). Alternatively, it can be worn as a sticky disc or patch. A delivery system for slow release of the active compound (group) through the skin. For this purpose, osmotic boosters can be used to promote penetration of the active compound (group) through the skin. Suitable transdermal patches are described, for example, in U.S. Patent No. 5,407,713; U.S. Patent No. 5,352,456; U.S. Patent No. 5,332,213; U.S. Patent No. 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, the disclosure of This is fully incorporated herein by reference.

Alternatively, other medical delivery systems may be employed. The vesicles and emulsions are conventionally known delivery vehicles that can be used to deliver active compounds (groups) or prodrugs (groups). Some organic solvents such as dimethyl hydrazine (DMSO) can also be used.

If desired, the pharmaceutical composition can be in the form of a package or dispenser containing one or more unit dosage forms containing the active compound(s). The package may, for example, comprise a metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for directing the administration method.

The active compounds (groups) or prodrugs (groups) disclosed herein, or a combination thereof, are generally employed in an amount effective to achieve the desired result, for example, an amount effective to treat or prevent the particular condition being treated. Compounds (groups) can be administered medically for the purpose of achieving medical benefits or for prophylactic administration in order to achieve preventive benefits. Medical benefit means the eradication or alleviation of the original condition being treated and/or eradication or alleviation of one or more symptoms associated with the original condition to improve the patient's sensation or condition, although the patient may Still suffering from the original disease. For example, when a compound is administered to a patient suffering from an allergy, the medical benefits provided can not only eradicate or alleviate the original allergic reaction, but also reduce the severity or duration of allergy-related symptoms when the patient subsequently exposes to the allergen. . In another example, the medical benefits of asthma include improving the respiratory condition during an asthma attack or reducing the frequency and severity of an asthma attack. This medical benefit also includes the prevention or slowing of the progression of the disease, whether or not it achieves an improvement.

For prophylactic administration, the compound can be administered to a patient at risk of developing one of the aforementioned diseases. A patient at risk of developing a disease can be classified as a patient at risk by a suitable medical professional or group. A patient at risk may also be a patient who is generally or often in an environment where an existing disease that may be treated by a metalloenzyme inhibitor according to the present invention may occur. In other words, patients at risk are patients who are generally or frequently exposed to conditions that cause disease or illness or who may be exposed to acute exposure for a limited time. Alternatively, prophylactic administration can be performed to avoid symptoms in patients diagnosed with the original condition.

The amount of the compound to be administered will be determined by a variety of factors, including, for example, the particular indication being treated, the mode of administration, the benefit desired to be prophylactic or medical, the severity of the indication being treated, and the age and weight of the patient, Bioavailability of the particular active compound and similar factors. Those skilled in the art will be able to determine the effective dose.

The effective dose can be estimated by an in vitro assay. For example, the initial dose for the animal can be first formulated so that the concentration of the active compound in the circulating blood or serum is at or above the specific compound in an in vitro assay (eg, in vitro fungal MIC or minimum fungicidal concentration (MFC) and" examples of the "one another as described in vitro assay) of the IC ₅₀ determined. The ability to calculate the bioavailability of the particular compound to achieve such circulating blood or serum concentrations is within the capabilities of those skilled in the art. As a follow reference, see the description of Fingl & Woodbury, "General principles (General Principles)", described in: Goodman and Gilman's "pharmaceutically basis of medical agents (The Pharmaceutical Basis of Therapeutics)" , Chapter 1, pp.1 -46, 12th Edition, McGraw-Hill Professional, and references cited therein, the disclosure of which is incorporated herein by reference.

The initial dose can also be estimated from in vivo data (eg, animal model). Animal models suitable for testing the efficacy of a compound to treat or prevent the various diseases described above are also known in the art.

Typical dosages range from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower, among many other factors, depending on the activity of the compound, its organism. Availability, mode of administration and various factors mentioned above. The dose and dosing interval can be adjusted individually to provide a plasma concentration of the compound (group) sufficient to maintain a medical or prophylactic effect. If administered topically or selectively (eg, topical topical administration), the effective local concentration of the active compound (group) will not correlate with plasma concentration. Those skilled in the art will be able to determine the most appropriate and effective topical dosage without undue experimentation.

Compounds (groups) can be administered once a day, several times a day or several times a day, or even multiple times a day, depending on the indication being treated Judgment with the participating physicians.

Preferably, the compound (group) will provide a medical or prophylactic benefit without causing substantial toxicity. The toxicity of the compound (group) can be determined using standard pharmaceutical procedures. The dose ratio between toxic and medical (or prophylactic) effects is the medical index. It is preferred to have a compound (group) having a high medical index.

The list of chemical groups excerpted in any definition of a code herein includes the definition of the code of any single group or combination thereof of the listed groups. Specific embodiments for extracting the code in this document include any single embodiment or combination with any other specific embodiment or part thereof. The specific embodiments extracted herein include any single embodiment or any combination of any other specific embodiments or portions thereof.

(agricultural use)

The compounds of formula I can be formulated as agriculturally acceptable acid addition salts. There are no examples of amine functional groups with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid. And lactic acid, gluconic acid, ascorbic acid, maleic acid, aspartic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxymethanesulfonic acid and hydroxyethanesulfonic acid form salts. Further, it is not limited to salts which can be formed by acid functional groups, including those derived from alkali metals or alkaline earth metals and their salts derived from ammonia and amines. Examples of preferred cations include sodium, potassium and magnesium.

The compounds of formula I can be formulated as salt derivatives. Without limiting examples, the free base can be contacted with a sufficient amount of the desired acid to form a salt. The salt can be treated with a suitable dilute aqueous base (e.g., diluted sodium hydroxide (NaOH), potassium carbonate, aqueous ammonia and aqueous sodium bicarbonate) to yield the free base. In many cases, For example, 2,4-D pesticides can be converted into their dimethylamine salts to increase their water solubility.

Suitable salts include those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Preferred cations include sodium, potassium, magnesium and ammonium cations of the formula: R ¹⁰ R ¹¹ R ¹² R ¹³ N ⁺

Wherein R ¹⁰ , R ¹¹ , R ¹² and R ¹³ independently represent hydrogen or C ₁ -C ₁₂ alkyl, C ₃ -C ₁₂ alkenyl or C ₃ -C ₁₂ alkynyl, which are optionally subjected to one or more hydroxyl groups, respectively , C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylthio or phenyl substituted, but with the proviso that R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are sterically compatible. Further, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ together may represent an aliphatic difunctional moiety containing from 1 to 12 carbon atoms and up to 2 oxygen or sulfur atoms. The salt of the compound of the formula I can be prepared by using a metal hydroxide such as sodium hydroxide, and using an amine such as ammonia, trimethylamine, diethanolamine, 2-methyl-thiopropylamine or bisallyl. Amine, 2-butoxy-ethylamine, morpholine, cyclododecylamine or benzylamine) or use of a tetraalkylammonium hydroxide (eg tetramethylammonium hydroxide or choline hydrogen) The compound of formula I is treated with an oxide). The amine salt is generally a preferred form of the compound of formula I because it is soluble in water and can itself be made into the desired aqueous herbicidal composition.

The compounds and compositions herein are useful as methods of modulating the metalloenzyme activity of a microorganism on a plant, comprising contacting a compound (or composition) herein with a plant (eg, seed, seedling, grass, weed, grain). The compounds and compositions herein can be administered to the plant, field or other by administering a compound or composition (eg, contacting, applying, spraying, spraying, dusting, etc.) An agricultural area used to treat plants, fields, or other agricultural areas (eg, as herbicides, pesticides, growth regulators, etc.). The administration can be carried out before or after germination. The administration method can be a therapeutic or prophylactic treatment.

In one aspect, a method of treating or preventing a fungal disease or condition in or on a plant, comprising contacting a compound (or composition) of any of the formulae shown herein with a plant. Another aspect is a method of treating or preventing the growth of fungi in or on a plant comprising contacting a compound (or composition) of any of the formulae shown herein with a 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 shown herein with a plant.

The compounds and compositions herein can be used in a method for preventing or controlling a disease induced by a pathogen on a plant, which comprises subjecting the compound herein to a plant (eg, seed, seedling, grassland, weed, grain) or a region adjacent to the plant. contact. The compounds and compositions herein can be used to treat plants, fields, or other agriculture by administering a compound or composition (eg, contacting, applying, spraying, spraying, dusting, etc.) to the plant, field, or other agricultural area. region. The administration can be carried out before or after germination. The administration method can be a therapeutic or prophylactic treatment. Therefore, the compounds, compositions, and agricultural uses used herein include the application of lawns, turf, ornamental plants, homes and gardens, farms, pastures, and pastures. The pathogen can be any pathogen on the plant and includes those detailed herein.

A particular embodiment of the invention is the use of a compound of formula I for protecting a plant against a plant pathogen or treating a plant infected with a plant pathogen, comprising administering a compound of formula I or a composition comprising the compound To soil, plants, parts of plants, leaves and/or seeds.

Further, another embodiment of the present invention is a composition suitable for protecting plants against plant pathogenic bacteria and/or treating plants infected with plant pathogenic bacteria comprising a compound of formula I and a plant acceptable carrier material.

The compounds of the invention may be administered by any of the known techniques, which may be administered as a compound or a formulation comprising the compound. For example, the compound can be applied to the roots, seeds or leaves of a plant to control a variety of different fungi without damaging the commercial value of the plant.

The compounds of the invention may be used alone or in combination with other agricultural active agents. The use of the compound or composition (and group of constituents) of the present invention may further comprise other active agents, such as an azole fungicide selected from the group consisting of epoxiconazole, tebuconazole, fluoroquinazole ( Fluquinconazole), flutriafol, metconazole, myclobutanil, cycproconazole, prothioconazole, and propiconazole.

The use of the compound or composition (and group of constituents) of the present invention may further comprise other active agents, such as: an azole fungicide selected from the group consisting of trifloxystrobin, pyraclostrobin, and epothilone. (orysastrobin), fluoxastrobin and azoxystrobin.

Preferably, the compounds of the invention may be administered in a formulation comprising one or more compounds of formula I in an agricultural or vegetable acceptable carrier. The inclusion The composition of the compound may be, for example, a direct spray aqueous solution, a powder, a suspension type, and a highly concentrated aqueous, oily or other suspension or dispersion, emulsion, oil dispersion, paste, dust powder, spreading material or The granules are applied by spraying, atomizing, dusting, spreading or pouring.

The invention includes all agents that can be used to formulate one or more compounds for delivery and as a fungicide. Typically, the formulation is applied as an aqueous suspension or emulsion. Aqueous application 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 which are themselves or dissolved in oils or solvents can be homogenized in water using a wetting agent, tackifier, dispersant or emulsifier. However, it is also possible to prepare concentrates consisting of active substances, wetting agents, tackifiers, dispersing or emulsifying agents, and, if appropriate, solvents or oils, which are suitable for dilution with water.

Wettable powders which can be compressed into water-dispersible granules comprise one or more compounds of the formula I, a homogeneous mixture of an inert carrier and a surfactant. The concentration of the compound in the wettable powder may range from about 10% to about 90% by weight, more preferably from about 25% to about 75% by weight, based on the total weight of the wettable powder. When preparing a wettable powder formulation, the compound can be combined with any finely divided solid such as pyrophyllite, talc, chalk, gypsum powder, Fuller's earth, bentonite, strontium, starch, Casein, bran protein, montmorillonite, diatomaceous earth, purified citrate or the like. In such operations, the finely divided carrier and surfactant are typically blended with the compound (group) and ground.

Granules (for example: coated granules, impregnated granules and homogenous granules) can be lived Sexual ingredients (eg, the compounds herein) are prepared in combination with a solid carrier. The solid carrier is mineral soil, such as: vermiculite, tannin, niobate, talc, kaolin, limestone, lime, chalk, red basalt, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate, Magnesium oxide, synthetic material milling, fertilizers (eg ammonium sulphate, ammonium phosphate, ammonium nitrate, urea) and plant-derived products (eg cereal flour, bark flour, wood flour and core-shell flour), cellulose powder or other Solid carrier.

The compounds herein can be formulated into conventional lozenges, capsules, solids, liquids, lotions, slurries, oils, granules or powders suitable for administration in plants, fields or other agricultural areas. In a preferred embodiment, the formulation comprises from 1 to 95% (eg, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%) in the carrier or diluent. , 10%, 25%, 75%, 80%, 90%, 95%) of the compounds herein. The compositions shown herein include the compounds of the formulas shown herein, as well as other agricultural preparations that may be present, effective in controlling (eg, modulating, inhibiting) metalloenzyme-mediated agricultural diseases or conditions.

In one method, the compounds herein are provided as encapsulated formulations (liquid or powder). Specific materials suitable for use in the capsule material include, but are not limited to, porous particles or matrices such as vermiculite, perlite, talc, clay, pyrophyllite, diatomaceous earth, gelatin and gel, polymers (eg: Polyurea, polyurethane, polyamide, polyester, etc.), polymerizable particles or cellulose. These include, for example, hollow fibers, hollow tubes or tubules (which release the compounds specifically described herein through the tube wall), capillaries (which release compounds from the opening in the tube), polymeric blocks of different shapes (eg, strips) Shape, block, ingot, disk, which can release compounds from the polymer matrix), thin film system (which can be The compound remains in the impermeable container and is released through a metered amount of permeable membrane, and combinations thereof. Examples of such delivery compositions are polymer laminates, polyethylene chloride pellets and microcapillary.

The encapsulation process is mainly divided into chemical or mechanical. Examples of chemical encapsulation processes include, but are not limited to, complex coacervation, polymer-polymer incompatibility, interfacial polymerization in liquid media, in-situ polymerization, in-liquid drying, in liquid media Thermal coagulation and ionic coagulation, desolvation in liquid media, starch based chemistry, entrapment in cyclodextrin and formation of vesicles. Examples of mechanical encapsulation processes include, but are not limited to, spray drying, spray cooling, fluidized bed, electrostatic deposition, centrifugal extrusion, rotary disk or rotary suspension separation, annular spray encapsulation, Liquid-gas or solid-gas interface polymerization, solvent evaporation, pressure extrusion or spraying into a solvent extraction tank.

Microcapsules are also suitable for the long-term release of the active compounds herein. The microcapsules are small particles comprising a core material or an active ingredient, coated with a coating or an outer shell. Typical sizes of microcapsules vary from 1 to 1000 microns, capsules less than 1 micron are classified as nanocapsules, and capsules larger than 1000 microns are classified as large capsules. The coating layer typically varies between 0.1 and 98 weight percent. The microcapsules can have a variety of different configurations (continuous core/shell, multi-core or single) and have irregular or geometric shapes.

In another method, the compounds herein are provided in an oil delivery system. Oil release matrices include vegetable oils and/or mineral oils. In one embodiment, the matrix also contains a surfactant to allow the composition to be more readily dispersed in water; such formulations include wetting agents, emulsifying agents, dispersing agents, and the like.

The compounds of the invention may also be provided in an emulsion. The emulsion formulation can be in a water-in-oil (w/o) or oil-in-water (o/w) form. The droplet size can vary from nanometer size (colloidal dispersion) to hundreds of microns. The formulation typically contains a variety of different surfactants and thickeners to modify the droplet size, stabilize the emulsion, and modify the release profile.

The emulsifiable concentrate of the compound of formula I may comprise a suitable concentration in a suitable liquid (e.g., from about 10% to about 50% by weight based on the total weight of the concentrate). The compound is soluble in an inert carrier which is a water miscible solvent or a mixture of a water immiscible organic solvent and an emulsifier. The concentrate can be diluted with water and oil to form a spray mixture in the form of an oil-in-water emulsion. Suitable organic solvents include aromatics, especially high-boiling naphthalene and olefinic parts of petroleum, such as heavy aromatic naphtha. Other organic solvents may also be used, such as oxime solvents, including rosin derivatives, aliphatic ketones (eg, cyclohexanone), and complex alcohols (eg, 2-ethoxyethanol).

Emulsifiers suitable for use in the present invention are readily determined by those skilled in the relevant art and include various nonionic, anionic, cationic and amphoteric emulsifiers, or blends of two or more emulsifiers. Examples of nonionic emulsifiers suitable for use in the preparation of emulsifiable concentrates include polyalkylene glycol ethers, and alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, rings. A condensation product of oxypropane (e.g., an ethoxylated alkylphenol), and a carboxylic acid ester which can be dissolved using a polyol or a polyalkylene glycol. Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Anionic emulsifiers include oil-soluble salts of alkyl aryl sulfonic acids (e.g., calcium salts), oil-soluble salts of sulfated polyglycol ethers, and suitable salts of phosphorylated polyglycol ethers.

Representative organic liquids which can be used in the preparation of the emulsifiable concentrates of the compounds of the invention are aromatic liquids such as xylene, propylbenzene fractions; or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids, such as Dioctyl phthalate; kerosene; dialkyl decylamines of various fatty acids, specifically aliphatic diols and diol derivatives (eg, n-butyl ether of diethylene glycol, ethyl ether) Or methyl ether; methyl ether of triethyl ether glycol, petroleum distillate or hydrocarbon (such as mineral oil, aromatic solvent, paraffinic oil and its analogues) dimethyl decylamine; vegetable oil 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 and analogs thereof. Mixtures of two or more organic liquids may also be used to prepare emulsifiable concentrates. Organic liquids include xylene and propylbenzene fractions, and some examples are best in xylene. Liquid formulations usually use a table The active dispersing agent is used in an amount of from 0.1 to 20% by weight based on the combined weight of the dispersing agent and the one or more compounds. The formulation may also contain other compatible additives such as plant growth regulators and other biological activities for agricultural use. Compound.

The aqueous suspension comprises one or more water-insoluble compounds of formula I dispersed in an aqueous vehicle at a concentration ranging from about 5 to about 50% by weight based on the total weight of the aqueous suspension. The suspension is prepared by finely grinding one or more compounds, and the ground material is uniformly mixed with a medium composed of water and a surfactant selected from the same type as described above. Other components (such as inorganic salts and synthetic or natural rubber) may also be added to increase the density and viscosity of the aqueous vehicle. Usually the most effective method is simultaneous grinding and mixing, which is to prepare an aqueous mixture and such as: sand Homogenization in a mill, ball mill or piston type homogenizer.

The aqueous emulsion comprises an emulsion of one or more water-insoluble pesticidal active ingredients emulsified in an aqueous vehicle at a concentration ranging from about 5 to about 50 weight percent of the total weight of the aqueous emulsion. If the active ingredient of the pesticide is a solid, it must first be dissolved in a suitable solvent which is immiscible with water and then made into an aqueous emulsion. The emulsion process is carried out by emulsifying a liquid pesticidal active ingredient or a water-immiscible solution thereof in an aqueous medium which generally comprises a surfactant which promotes the formation and stabilization of the emulsion as described above. It is usually achieved by means of a high shear mixer or a homogenizer.

The compounds of formula I can also be administered in the form of granule formulations which are generally suitable for application to the soil. The granule formulation typically comprises from about 0.5 to about 10 weight percent of the compound (group) of the total weight of the granule formulation, dispersed in an inert carrier consisting essentially or predominantly of a coarsely divided inert material, such as magnesium strontium. Soil, bentonite, diatomaceous earth, clay or similar low-cost substances. Such formulations are typically prepared by dissolving the compound in a suitable solvent and coating onto a granule carrier of the appropriate size in the range of from about 0.5 to about 3 mm. Suitable solvents are those which substantially dissolve or completely dissolve the compound. These formulations may also be prepared by compressing and drying a carrier or a mixture of a carrier and a compound and a solvent to obtain the desired granules.

Alternatively, the compounds of the invention may be formulated as solid lozenges and comprise (and preferably consist essentially of) oils, protein/carbohydrate materials (preferably vegetal), sweeteners and metals suitable for the prevention or treatment of metals An enzyme that mediates the active ingredients of an agricultural disease or condition. In a specific embodiment, the present invention provides a solid tablet comprising (and preferably, consisting essentially of) oil, protein/carbon water A compound material (preferably vegetative), a sweetener and an active ingredient (for example, a compound herein or a combination thereof or a derivative thereof) suitable for preventing or treating a metalloenzyme mediated by an agricultural disease or disorder. Tablets typically comprise from about 4 to 40% by weight (eg, 5%, 10%, 20%, 30%, 40% by weight) of oil (eg, 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, oil sedge oil, hazelnut oil, avocado oil, sesame oil, croton oil, cocoa butter, linseed Oil, mustard seed oil and mustard oil, hydrogenated derivatives thereof; petroleum derived oils (eg, paraffin and petrolatum), and other water-immiscible hydrocarbons (eg, paraffins). The lozenge further comprises about 5 to 40% by weight (for example: 5% by weight, 10% by weight, 20% by weight, 30% by weight, 40% by weight) of vegetable protein/carbohydrate material. The material also contains a carbohydrate moiety (for example: derived from Grains such as: wheat, rye, barley, oats, corn, rice, millet, sorghum, birdseed, buckwheat, alfalfa, alfalfa, corn flour, soy flour, flour, wheat flour Head, wheat bran, corn bran protein powder, acacia powder, dry yeast Beans, rice) and protein parts.

A variety of different excipients and binding agents are used as needed to facilitate delivery of the active ingredient or to provide the proper structure for the tablet. Preferred excipients and binders include anhydrous lactose, microcrystalline cellulose, corn starch, magnesium stearate, calcium stearate, zinc stearate, sodium carboxymethylcellulose, ethylcellulose, hydroxypropyl Methylcellulose and mixtures thereof.

The dust powder comprising the compound of the formula I may be prepared by uniformly mixing one or more compounds in powder form with a suitable dusty agricultural carrier, for example, Such as: kaolin, grinding volcanic rocks and their analogues. The dust powder is suitably comprised of from about 1 to about 10% by weight of the total weight of the dusting powder.

The formulation may additionally comprise an adjunctive surfactant to promote deposition, wetting and penetration of the compound onto the target crop and organism. These auxiliary surfactants are used as a component of the formulation or as a large tank mixture as needed. The amount of the auxiliary surfactant is usually changed between 0.01 and 1.0 volume percent of the water spray volume, preferably 0.05 to 0.5 volume percent. Suitable auxiliary surfactants include, but are not limited to, ethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols, salts of esters or sulfosuccinic acids, ethoxylated organic fluorenones , ethoxylated fatty amines, blends of surfactants with mineral or vegetable oils, crop oil concentrates (mineral oil (85%) + emulsifier (15%)); nonylphenol ethoxylates; benzene Methyl coconut alkyl dimethyl quaternary ammonium salt; petroleum hydrocarbons, alkyl esters, blends of organic acids and anionic surfactants; C ₉ -C ₁₁ alkyl polyglycosides; phosphorylated alcohol ethoxylates Natural primary alcohol (C ₁₂ -C ₁₆ ) ethoxylate; di-second butyl phenol EO-PO block copolymer; polyoxyalkylene-methyl terminated; nonylphenol ethoxylate + urea ammonium nitrate Salt; emulsified methylated seed oil; tridecyl alcohol (synthetic) ethoxylate (8EO); stearylamine ethoxylate (15 EO); PEG (400) dioleyl ester-99. The formulation may also include an oil-in-water emulsion, such as those disclosed in U.S. Patent Application Serial No. 11/495,228, the disclosure of which is incorporated herein by reference.

The formulation optionally includes a combination of other pesticide compounds. These other pesticide compounds may be fungicides which are compatible with the compounds of the invention in the chosen application medium and which do not antagonize the activity of the compounds of the invention, Insecticides, herbicides, nematicides, acaricides, arthropodicides, bactericides, or combinations thereof. Thus, in such specific embodiments, the other pesticide compounds are used as supplemental toxic agents for the same or different pesticide uses. The weight ratio of the compound of the formula I to the pesticide compound in the combination is usually from 1:100 to 100:1.

The compounds of the invention may also be combined with other fungicides to form a fungicidal mixture with a synergistic mixture thereof. The fungicidal compounds of the invention are often combined with one or more other fungicides to control a variety of different undesirable diseases. When used in combination with other fungicides (groups), the compounds claimed in the present invention may be formulated with other fungicides (groups), mixed with other fungicides (groups) or with other fungicides (groups). Order application. Such other fungicides may include 2-(cyanothiomethylthio)-benzothiazole, 2-phenylphenol, 8-hydroxyquinoline sulfate, ametoctradin, amisulbrom , antimycin, Ampelomyces quisqualis , azaconazole, azoxystrobin, Bacillus subtilis , benalaxyl, benomyl , benthiavalicarb-isopropyl, benzylaminobenzene-sulfonate (BABS), bicarbonate, biphenyl, bismerthiazol, bitertanol, must Bixafen, blasticidin-S, borax, Bordeaux mixture, boscalid, bromuconazole, bupirimate, calcium polysulfide ), captafol, captan, carbendazim, carboxin, carpropamid, carvone, chloroneb , tetrachloro isophthalic carbonitrile (chlorothalonil), g to give chloro (chlozolinate), the micro-tanks Coniothyrium (Coniothyrium minitans), copper hydroxide, copper octanoate Copper oxychloride, copper sulfate, copper sulfate (tribasic), cuprous oxide, cyazofamid, cyflufenamid, cymoxanil, cyproconazole ), cyprodinil, dazomet, debacarb, diammonium bis-(dithiocarbamic acid) diammonium, dichlofluanid, dichlorophen , diclocymet, diclomezine, dichloran, diethofencarb, difenoconazole, difenzoquat ion, diflurane Diflumetorim), dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton, dinocap, diphenylamine , dithianon, dodemorph, dodemorph acetate, dodine, dodine free base, edifenphos, insazole Enestrobin), epoxiconazole, ethaboxam, ethoxyquin, etridiazole, 凡杀同 (f Amoxadone), fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, seed dressing (fenpiclonil), fenpropidin, fenpropimorph, fenpyrazamine, fentin, fentin acetate, fentin hydroxide ), ferbam, ferimzone, fluazinam, fludioxonil, flumorph, fluopicolide, flupirtine Fluopyram), fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutianil, Flutolanil, flurifaol, fluxapyroxad, folfet, formaldehyde, fosetyl, fosetyl-aluminum, wheat ears Fuberidazole, furalaxyl, furametpyr, guazatine, guazatine acetate, GY-81, hexachlorobenzene, phenanthrene Hexaconazole, hymexazol, imazalil, imazalil sulfate, imibenconazole, iminoctadine, iminoctadine triacetic acid Salt, iminoctadine tris (albesilate), iodopropynyl butyl methacrylate (iodocarb), ipconazole, ipfenpyrazolone, propyl philazone ( Iprobenfos), iprodione, iprovalicarb, isoprothiolane, isopyrazam, isotianil, laminarin, carbendazim Kasugamycin, kasugamycin hydrochloride hydrate, kresoxim-methyl, mancopper, mancozeb, mandipropamid, Manne, mefenoxam, mepanipyrim, mepronil, meptyl-dinocap, mercuric chloride, oxidized mercury, mercurous chloride, A Metalaxyl, metalaxyl-M, metam, metam-ammonium, metam-potassium, potassium Metam-sodium, metconazole, methasulfocarb, methyl iodide, methyl isothiocyanate, metiram, metominostrobin, fentanyl Metrafenone), mildiomycin, myclobutanil, nabam, nitrothal-isopropyl, nuarimol, octhilinone, furosemide (ofurace), oleic acid (fatty acid), orysastrobin, oxadixyl, oxine-copper, oxpoconazole fumarate, oxycarboxin , pefurazoate, penconazole, pencycuron, penflufen, pentachlorophenol, pentachlorophenyl laurate, penthiopyrad, Phenylmercuric acetate, phosphonic acid, phthalide, picoxystrobin, polyoxin B, apolipomycin, polyoxorim, carbonic acid Potassium hydrogen, hydroxyquinoline potassium sulfate, probenazole, prochloraz, procymidone, propamocarb, propamoca Rb) hydrochloride, propiconazole, propineb, proquinazid, prothioconazole, pyraclostrobin, pyramatetostrobin, positive Pyraoxystrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyriofenone ), pyroquilon, quinoclamine, quinoxyfen, quintozene, Reynoutria sachalinensis extract, sedaxane, sputum Silthiofam, simeconazole, sodium 2-phenylphenate, sodium bicarbonate, sodium pentachlorobenzene, spiroxamine, sulfur, SYP-Z071, SYP-Z048, Tar, tebuconazole, tebufloquin, tecnazene, tetraconazole, thiabendazole, thifluzamide, multi-safe ( Thiophanate)-methyl, thiram, tiadinil, tolclofos-a , tolylfluanid, triadimefon, triadimenol, triazoxide, tricyclazole, tridemorph, trifloxystrobin, race Tripus (triflumizole), triforine, triticonazole, validamycin, valifenalate, valiphenal, vinclozolin, dysen zinc (zineb), ziram (ziram), seat race amine (zoxamide), olive Candida (Candida oleophila), saprophytic Fusarium (Fusarium oxysporum) bacteria, colloidal Penicillium (Gliocladium spp.), dog-volt leather bacteria ( . Phlebiopsis gigantea), grayish green Streptomyces (Streptomyces griseoviridis), Trichoderma (Trichoderma spp), (RS) - N - (3,5- dichlorophenyl) -2- (methoxymethyl) - succinate Yttrium, 1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate, 1-chloro-2,4-dinitronaphthalene, 1-chloro- 2-nitropropane, 2-(2-heptadecyl-2-imidazolin-1-yl)ethanol, 2,3-dihydro-5-phenyl-1,4-dithiacyclohexene 1 , 1,4,4-Teoxide, 2-methoxyethylmercuric acetate, 2-methoxy Ethyl mercury chloride, 2-methoxyethyl mercury decanoate, 3-(4-chlorophenyl)-5-methyl rhodamine (rhodanine), 4-(2-nitropropyl thiocyanate) 1-Alkenyl)phenyl ester, ampropylfos, anilazine, azithiram, polysulfide, Bayer 32394, benodanil, 醌肟Benbenox, bentaluron, benzacril, benzacril-isobutyl, benzamorf, binapacryl, bis(methylmercury) Sulfate, bis(tributyltin) oxide, buthiobate, cadmium calcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone, chloraniformethan , chlorfenazole, chlorquinox, climbbazole, cyclafuramid, cypendazole, cyprofuram, decafentin ), dichlonone, dichlozoline, diclobutrazol, dimethirimol, dinotocton, dinosulfon, nitbutyl ester (dinote) Rbon), dipyrithione, ditalimfos, dodicin, drazoxolon, EBP, ESBP, etaconazole, etem, Ethirim, fenaminosulf, fenapanil, fenitropan, fluotrimazole, furcarbanil, furconazole ), furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin, halacrinate Hercules 3944, hexylthiofos, ICIA0858, isopamphos, isovaredione, mebenil, mecarbinzid, inter-chlorinated enemies Metazoxolon, methfuroxam, dicyandiamide, metsulfovax, milneb, mucochloric anhydride, myclozolin, N -3,5-dichlorophenyl-succinimide, N- 3-nitrophenyl-concamide, natamycin, N -ethylmercury-4-toluene benzene Amine, nickel bis(dimethyldithiocarbamate), OCH, phenylmercury dimethyldithiocarbamate, phenylmercury nitrate, phosdiphen, picolinamide UK-2A and its derivatives, prothiocarb, prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyroxychlor, clofibrate (pyroxyfur), quinacetol, quinacetol sulfate, quinazamid, quinconazole, rabenzazole, salicylanilide, SSF- 109, sultropen (sultropen), thiram, thiadifluor, thicyofen, thiochlorfenphim, thiophanate, chlorpyrifos Thioquinox), tioxymid, triamiphos, triarimol, triazbutil, trichlamide, urbacid, and seletonide (zarilamide) and any combination thereof.

Furthermore, the compounds of the invention may be combined with other pesticides, including those which are compatible with the compounds of the invention for use in the chosen application medium and which do not antagonize the activity of the compounds of the invention to form a mixture of pesticides and their synergistic mixtures, Nematicides, acaricides, arthropodicides, bactericides or combinations thereof. The fungicidal compounds disclosed herein can be administered in combination with one or more other pesticides to control a greater variety of unwanted pests. When combined with other pesticides, the compounds claimed in the present invention can be formulated with other pesticides (groups), mixed with other pesticides (groups), or sequentially with other pesticides (groups). Typical insecticides include, but are not limited to, 1,2-dichloropropane, abamectin, acephate, acetamiprid, acethion, ethiprole (acetoprole), acrinathrin, acrylonitrile, alanycarb, aldicarb, aldoxycarb, aldrin, allethrin ), allosamidin, allyxycarb, alpha-cypermethrin, alpha-ecdysone, alpha-endosulfan, race Amidithion, aminocarb, amiton, amiton oxalate, amitraz, anabasine, athidathion, azadirachtin Azadirachtin, azamethiphos, azinphos-ethyl, azinphos-methyl, azothoate, hexafluoroantimonate, stevioside (barthrin), bendiocarb, benfuracarb, bensultap, beta-cyfluthrin, beta-cypermethrin, bifenthrin , bioallethrin, bioethanomethrin, biopermethrin, bistrifluron, borax, boric acid, bromfenvinfos, Baomandan (bromocyclen), bromine-DDT, bromophos, bromophos-ethyl, bufencarb, buprofezin, butacarb, dipyridamole (butathiofos), butocarboxim, butonate, butoxycarboxim, cadusafos, calcium arsenate Calcium arsenate), calcium polysulfide, camphechlor, carbanolate, carbaryl, carbofuran, carbon disulfide, carbon tetrachloride, trisulfide Carbophenothion), carbosulfan, cartap, cartap hydrochloride, chlorantraniliprole, chlorbicyclen, chlordane, chlordecone Chlordecone), insecticide (chlordimeform), chlordimeform hydrochloride, chlorethoxyfos, chlorfenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chloroform , chloropicrin, chlorphoxim, chlorprazophos, chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, chromafenozide ), cinerin I, cinerin II, cinerins, cismethrin, cloethocarb, cyanamide Closantel), clothianidin, copper acetoarsenite, copper arsenate, copper naphthenate, copper oleate, coumaphos, coumi thoate, gram Crotamiton, crotoxyphos, crufomate, cryolite, cyanofenphos, cyanophos, cyanthoate, cyanide Cyantraniliprole, cyclethrin, cycloprothrin, cyprodin (c Yfluthrin), cyhalothrin, cypermethrin, cyphenothrin, cyromazine, cythioate, DDT, decarbofuran, deuterin (deltamethrin), methyl decephene, demephion-O, demephion-S, demeton, demeton-a Base, demeton-O, demeton-O-methyl, annihilation Demeton-S, demeton-S-methyl, demeton-S-methyl hydrazine, diafenthiuron, dialifos, diatomaceous earth, Diazinon, dicapthon, dichlofenthion, dichlorvos, dicresyl, dicrotophos, dicyclanil, earth Dieldrin, diflubenzuron, dilor, dimefluthrin, dimefox, dimetan, dimethoate, Dimethrin, dimethyvinlphos, dimetilan, dinex, dinex-diclexine, dinoprop, Dinosam, dinotefuran, diofenolan, dioxabenzofos, dioxacarb, dioxathion, disulfoton, benzene Dithicrofos, d-limonene, DNOC, DNOC-ammonium, DNOC-potassium, DNOC-sodium, doramectin, ecdysterone, due to extinction Emmectin, emamectin Benzoate, EMPC, empenthrin, endosulfan, endothion, endrin, EPN, epofenonane, eprinomectin ), esdepalléthrine, esfenvalerate, etaphos, ethiofencarb, ethion, ethiprole, ethoate )-methyl, ethoprophos, ethyl formate, ethyl-DDD, dibromoethane, Dichloroethane, ethylene oxide, etofenprox, etrimfos, EXD, famphur, fenamiphos, fenzazaflor, lenazol (fenchlorphos), fenethacarb, fenfluthrin, fenitrothion, fenobucarb, fenoxacrim, fenoxycarb, cypermethrin (fenpirithrin), fenpropathrin, fensulfothion, fenthion, fenthion-ethyl, fenvalerate, fipronil, fenfenk (flometoquin), flonicamid, flubendiamide, flucofuron, flucycloxuron, flucythrinate, flufenerim, flufenadol Flufenoxuron), flufenprox, flufiprole, flupyradifurone, fluvalinate, fonofos, formetanate, formetanate Hydrochloride, formothion, formparanate, formparanate hydrochloride, Fosmethilan, fospirate, fosthietan, furathiocarb, furethrin, gamma-cyhalothrin, γ-HCH , halfenprox, hafenfenzide, HCH, HEOD, heptachlor, heptenophos, heterophos, hexaflumuron, HHDN, Hydramethylnon, cyanidation Hydrogen, hydroprene, hyquincarb, imidacloprid, imiprothrin, indoxacarb, methyl iodide, IPSP, isazofos, carbon Isobenzan, isocarbophos, isodrin, isofenphos, isofenphos-methyl, isoprocarb, aficione Isoprothiolane), isothioate, isoxathion, ivermectin, jasmolin I, jasmolin II, iodphophos (jodfenphos) ), juvenile hormone I, juvenile hormone II, juvenile hormone III, kelevan (kelevan), kinoprene, lambda-cyhalothrin, lead arsenate, leimycin Lepimectin, leptophos, lindane, lirimfos, lufenuron, lythidathion, malathion, malonoben , mazidox, mecarbam, mecarphon, menazon, meperfluthrin, mephosfolan, chlorine Mercury, mesulfenfos, metaflumizone, metacrifos, methamidophos, methidathion, meticarb, insecticidal ethylene phosphorus (methocrotophos), methodomyl, methoprene, methoxychlor, methoxyfenozide, methyl bromide, methyl isothiocyanate, methyl chloroform, dichloro Methane, metofluthrin, metolcarb, Methoxadiazone, mevinphos, mexacarbate, milbemectin, milbemycin oxime, mipafox, mirex, kill Moldan (molosultap), monocrotophos, monomehypo, monosultap, morphothion, moxidectin, naftalofos, two Naled, naphthalene, nicotine, nifluridide, nitenpyram, nithiazine, nitrilacarb, novaluron , noviflumuron, omethoate, oxamyl, oxydemeton-methyl, oxydeprofos, oxydisulfoton, p-dichlorobenzene , parathion, parathion-methyl, penfluron, pentachlorophenol, permethrin, phenkapton, phenothrin , phenthoate, phorate, phosalone, phosfolan, phosmet, phosnichlor, blessing Pamamidon, phosphine, phoxim, phoxim-methyl, pirimetaphos, pirimicarb, pirimiphos )-ethyl, pirimiphos-methyl, potassium arsenite, potassium thiocyanate, pp'-DDT, prallethrin, precocene I, precocene II , precocene III, primidophos, profenofos, profluralin, promacyl, Promecarb, propaphos, propetamphos, propoxur, prothidathion, prothiofos, prothoate, puffer (protrifenbute), pyraclofos, pyrafluprole, pyrazophos, pyresmethrin, pyrethrin I, pyrethrin II, de-worming Pyrethrins, pyridaben, pyridalyl, pyridaphenthion, pyrifluquinazon, pyrimidifen, pyrimimate, Pyriprole, pyriproxyfen, quassia, quinalphos, quinalphos-methyl, quinothion, chlorophenyl iodide Amine (rafoxanide), resmethrin, rotenone, ryania, sabadilla, schradan, selamectin, scorpion ( Silafluofen), silicone, sodium arsenite, sodium fluoride, sodium hexafluoroantimonate, sodium thiocyanate, sophamide, spinetoram , spinosad, spiromesifen, spirotetramat, sulcofuron, sulcofuron-sodium, sulfluramid, strontium phosphate Sulfotep), sulfoxaflor, sulfonium fluoride, sulprofos, τ-fuvalinate, tazimcarb, TDE, tebufenozide, defenyl (tebufenpyrad), butyl pyrimidine (tebupirimfos), Defulong (teflubenzuron), tefluthrin (tefluthrin), tepephos, TEPP, terallethrin, terbufos, tetrachloroethane, tetrachlorvinphos, Tetramethrin, tetramethylfluthrin, θ-cypermethrin, thiacloprid, thiamethoxam, thicrofos, 肟Thiocarboxime, thiocyclam, thiocyclam oxalate, thiodicarb, thiofanox, thiometon, sulphur sulphate Thiosultap), thiosultap-disodium, thiosultap-monosodium, thuringiensin, tolfenpyrad, tralmethrin, tetrafluthrin Transfluthrin), transpermethrin, triarathene, triazamate, triazophos, trichlorfon, trichlormetaphos -3, trichloronat, trifenofos, triflumuron, trimethacarb, methicillin (Triprene), Fan dipropionate (vamidothion), pyrrole amine (vaniliprole), XMC, Seoul off lice (xylylcarb), ζ- race permethrin (ζ-cypermethrin), propylthiouracil isoxathion (zolaprofos) and any combination thereof.

Furthermore, the compounds of the invention may be combined with herbicides, including herbicides which are compatible with the compounds of the invention in the chosen application vehicle and which do not antagonize the activity of the compounds of the invention, to form a mixture of pesticides and synergistic mixtures thereof. The fungicidal compound disclosed in the present invention may be combined with one or more herbicides. Use to control more kinds of unwanted weeds. When combined with a herbicide, the claimed compounds can be formulated with herbicides (groups), mixed with herbicides (groups), or sequentially with herbicides (groups). 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; 2,4,6-TBA; 2,4,5-T; 2,4,5-TB; acetochlor, acifluorfen ), alexifen, acrolein, alachlor, allidochlor, alloxydim, allyl alcohol, alarac, alanazinone Ametridione), ametryn, amibuzin, amizcarbazone, amidosulfuron, aminocyclopyrachlor, aminopyralid, Amiprofos-methyl, amitrol, ammonium aminesulfonate, anilofos, anisuron, asulam, attraton ), atrazine, azafenidin, azimsulfuron, aziprotryne, barban, BCPC, beflubutamid, herbicide Benzolin, bencarbazone, benfluralin, benfuresate, bensulfuron , bensulide, bentazone, benzadox, benzfendizone, benzipram, benzobicyclon, piracetone Benzofenap), benzofluor, benzoylprop, benzthiazuron, bicyclopyrone, bifenfen (bifenox), bianafos, bispyribac, borax, bromacil, bromobonil, bromobutide, bromofenoxim, bromine Bromoxynil, brompyrazon, butachlor, butafenacil, butamifos, butenachlor, buthimidazole ), buthiuron, butralin, butroxydim, buturon, butarate, cacodylic acid, benzophenazole (cafenstrole), calcium chlorate, calcium cyanamide, cambendichlor, carbasulam, carbetamide, carboxazole chlorprocarb, carfentrazone , CDEA, CEPC, chlomethoxyfen, chloramben, chloranocryl, chlorazifop, chlorazine, chlorbromuron, chloramphenicol Chlorbufam, chloreturon, chlorfenac, chlorfenprop, chlorflura Zole), chlorflurenol, chloridazon, chlorimuron, chlornitrofen, chloropon, chlorotoluron, chloroxuron ), chloroxynil, chlorpropham, chlorsulfuron, chlorthal, chlorthiamid, cinidon-ethyl, Cinmethylin, sylvestre (cinosulfuron), cisanilide, clethodim, cloodinate, clodinafop, clofop, clomazone, gram grass Clomeprop), cloprop, cloproxydim, clopyralid, cloransulam, CMA, copper sulfate, CPMF, CPPC, cedazine, Phenol, cumyluron, cyanatryn, cyanazine, cycloate, cyclosulfamuron, cycloxydim, cycluron , cyhalofop, cyperquat, cyprazine, cyprazole, cypromid, daimuron, dalapon ), dazomet, delachlor, desmedipham, desmetryn, di-allate, dicamba, dichalconitrile Dichlobenil), dichloralurea, dichlormate, dichlorprop, dichlorprop-P, diclofop, dichlorosulfur Amine (di Closulam), diethamquat, diethatyl, difenopenten, difenoxuron, difenzoquat, diflufenican, difluoro Diflufenzopyr, dimefuron, dimepiperate, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, Dimexano, dimidazon, dinitramine, Dinofenate, dinoprop, dinosam, dinoseb, dinoterb, diphenamid, dipropetryn, kill Diquat, disul, dithiopyr, diuron, DMPA, DNOC, DSMA, EBEP, eglinazine, endothal, triazole Epronaz, EPTC, erbon, esprocarb, ethalfluralin, ethametsulfuron, ethidimuron, ethiolate ), ethofumesate, ethoxyfen, ethoxysulfuron, etinofen, etnipromid, etobenzanid, EXD , fenasulam, fenoprop, fenoxaprop, fenoxaprop-P, fenoxasulfone, fenteracol, Fenthiaprop, fentrazamide, fenuron, ferrous sulfate, flamprop, flamprop-M, flazasulfuron, difluoro Florasulam, fluazifop, fluazifop-P, fluazolate, flucarbazone, flucetosulfuron, bethrazine Fluflualin, flufenacet, flufenican, flufenpyr, flumetsulam, flumezin, flumiclorac ), flomioxazin, flumipropyn, fluometuron, fluorodifen, flufenacetate (fluoroglycofen), fluoromidine, fluoronitrofen, fluothiuron, flupoxam, flupropacil, flupropanate, fluoride Flupyrsulfuron, fluridone, flurochloridone, fluroxypyr, flurtamone, fluthiacet, flufenacetate (fomesafen), foramsulfuron, fosamine, furyloxyfen, glufosinate, glufosinate-P, glyphosate, Halosafen, halosulfuron, haloxydine, haloxyfop, haloxyfop-P, hexachloroacetone, hexaflurate, Hexazinone, imazamethabenz, imazamox, imazapic, imazapyr, imazaquin, imazethapyr Imazethapyr), imazosulfuron, indanofan, indaziflam, iodobonil, methyl iodide, iodosulfonate (iodosulfuron), iofensulfuron, ioxynil, ipazine, ipfencarbazone, iprymidam, isocarbamid, exotic grass Isocil, isomethiozin, isororuron, isopolinate, isopropalin, isoproturon, isouron, Isoxaben, isoxachlortole, different Isoxaflutole, isoxapyrifop, karbutilate, ketospiradox, lactofen, lenacil, and lyon Linuron), MAA, MAMA, MCPA, MCPA-thioethyl, MCPB, mecoprop, mecoprop-P, medinoterb, mefenacet, beauty Mefluidide, mesoprazine, mesosulfuron, mesotrione, metam, metamifop, metamitron , metazachlor, metazosulfuron, metflurazon, methabenzthiazuron, metpalpropalin, metoclopramide (metapropalin) Methazole), methobencarb, methiozolin, methiuron, metometon, methoprotryne, methyl bromide, methyl isothiocyanate , methyldymron, metobenzuron, metobromuron, metolachlor, metosulam, and methotrexate Metoxuron), metribuzin, metsulfuron, molinate, monalide, monisouron, monochloroacetic acid, monolinuron , monuron, morfamquat, MSMA, naproanilide, napropamide, naptalam, neburon, nicosulfuron , nipyraclofen, nitralin, nitrofen, nitrofluorfen, norflurazon, Noruron, OCH, orbencarb, ortho-dichlorobenzene, orthosulfamuron, oryzalin, oxadiargyl, oxadiazon , oxapyrazon, oxasulfuron, oxaziclomefone, oxyfluorfen, parafluron, paraquat, pebulate ), n-decanoic acid, pendimethalin, penoxsulam, pentachlorophenol, pentanochlor, pentoxazone, perfluidone, pethoxamid , phenisopham, phenmedipham, phenmedipham-ethyl, phenobenzuron, phenylmercuric acetate, picloram, picolinafen , pinoxaden (pinoxaden), piperophos, potassium arsenite, potassium azide, potassium cyanate, pretilachlor, primisulfuron, procyazine ), prodiamine, profluazol, profluralin, profoxydim, Proglinazine, prometon, prometryn, propachlor, propanil, propaquizafop, propazine, propham , propisochlor, propoxycarbazone, propyrisulfuron, propyzamide, prosulfalin, prosulfocarb, fluoride Prosulfuron, proxan, prynachlor, Pyridalon, pyraclonil, pyraflufen, pyrasulfotole, pyrazoolynate, pyrazosulfuron, pyrazoxyfen ), pyribenzoxim, pyributicarb, pyriclor, pyridafol, pyridate, pyrifalid, pyrimethazine Pyrimanobac, pyrimisulfan, pyrithiobac, pyroxasulfone, pyroxullam, quinclorac, quinmerac ), quinoclamine, quinonamid, quizalofop, quizalofop-P, rhodetanil, rimsulfuron, pyrimidine Saflufenacil, Solamochlor, sebuthylazine, secbumeton, sethoxydim, siduron, simazine, west Simeton, simetryn, SMA, sodium arsenite, sodium azide, sodium chlorate, sulcotrione, ricotta Ulfallate), sulfentrazone, sulfometuron, sulfosulfuron, sulfuric acid, sugllycapin, swep, TCA, tebutam , tebuthiuron, tefuryltrione, tembotrione, tepraloxydim, terbacil, terbucarb, terbuchlor, Terbumeton, terbuthylazine, de-grass (terbutryn), tetrafluron, thenyl chloride, thiazafluron, thiazopyr, thidiazimin, thidiazuron, thioca Thiencarbazone - methyl, thifensulfuron, thiobencarb, tiocarbazil, tioclorim, topramezone, tralkoxydim , triafamone, tri-allate, triasulfuron, triaziflam, tribenuron, tricomic acid (tricamba), three Chloropyr, tridiphane, trietazine, trifloxysulfuron, trifluralin, triflusulfuron, trifop, fine Trifopsime, trihydroxytriazine, trimeturon, tripropindan, tritac, tritosulfuron, vernolate, and Xylachlor.

Another embodiment of the invention is a method of controlling or preventing fungal attack. This method comprises applying a fungicidally effective amount of one or more compounds of formula I at the soil, plant, root, leaf, seed or fungal locus, or where it is desired to prevent afgression (e.g., application to cereal plants). These compounds are suitable for treating a variety of different plants at fungicidal concentrations, but still retain low phytotoxicity. These compounds may be suitable as both protective and/or eradicating agents.

These compounds have been found to have significant fungicidal efficacy especially in agricultural applications. Many of these compounds are particularly effective for agricultural crops and horticulture plant. Other benefits include, but are not limited to, improving plant health; improving plant yield (eg, increasing biomass yield and/or increasing the content of valuable ingredients); improving plant vigor (eg, improving plant growth and/or deepening leaf green) Improve plant quality (eg, improve the content or composition of certain ingredients); and improve the abiotic and/or biological stress of plants.

The composition of formula I is effective against pathogenic bacteria-infected diseases, wherein the plant fungal pathogen belongs to at least one of the following species: Blumeria , Podosphaera , Sphaerotheca ), the genus Uncinula (Uncinula), Erysiphe (Erysiphe), Puccinia (Puccinia), Phakopsora (Phakopsora), gum genus rust (Gymnosporangium), camel genus Fusarium rust (Hemileia), Uromyces , Alternaria , Cercospora , Cladosporium , Cochliobolus , Colletotrichum , giant Magnaporthe , Mycosphaerella , Phaeosphaeria , Pyrenophora , Ramularia , Rhyncosporium, and Needle genus (Septoria), Venturia (Venturia), Ustilago (Ustilago), Streptomyces yeast (Aspergillus), Penicillium (Penicillium), Helminthosporium (Drechslera), Fusarium species (of Fusarium ), Botrytis (Botrytis), the genus Fusarium (Gibberella), silk Genus (Rhizoctonia), sham small tail Mortierella (Pseudocercosporella), the genus Sclerotinia (Sclerotinia), Helminthosporium (Helminthosporium), chitin Zymomonas (Stagonospora), Exserohilum Helminthosporium (Exserohilum), and Pyricularia . The composition of Formula I can be used to control pathogenic bacteria such as: Venturia inaequalis , Septoria tritici , Cercospora beticola , Cercospora arachidicola , Melon anthrax Colletotrichum lagenarium , Puccinia graminis f.sp.tritici , Puccinia recondita tritici , Uncinula necator , Blumeria Graminis) and Fiscus gigas (Mycosphaerella fijiensis) . In addition, the composition of formula I can effectively prevent or control diseases, including apple scab, wheat leaf spot, beet leaf spot, peanut leaf spot, courgette anthracnose, wheat leaf rust, grape powder, wheat flour mildew With black spot.

The present invention provides a kit for treating or preventing agricultural or plant diseases or disorders. In a specific embodiment, the kit comprises a composition comprising an effective amount of a compound herein, in a form suitable for delivery to a plant location. In some embodiments, the kit comprises a container containing a compound of formula I; such containers may be in the form of boxes, ampoules, bottles, vials, vials, bags, sachets, blister packs or other suitable container types known in the art. Such containers may be made of plastic, glass, laminated paper, metal foil or other material suitable for carrying the compound.

If desired, the compounds (groups) of the invention are provided with instructions for their administration to plants, fields or other agricultural areas. The instructions generally include instructions for indicating that the composition is useful in treating or preventing a metalloenzyme mediated agricultural disease or condition. In other specific embodiments, the instructions include the following At least one: a description of the compound; a dosage schedule and administration method for treating or preventing a metalloenzyme mediated agricultural disease or disorder; precautions; warnings; research notes; and/or references. The instructions may be printed directly on the container (if applicable), or attached to the container in the form of a label, or attached to or provided with a separate sheet of paper, booklet, card or fold.

The compounds of the invention are effective for use in plants in accordance with disease inhibition and plant acceptable amounts. The term "inhibition of disease and plant-acceptable amount" means that the amount of the compound can eliminate or inhibit the plant disease to be controlled, but is not significantly toxic to the plant. This amount is usually from about 0.1 to about 1000 ppm (parts per million), preferably from 1 to 500 ppm. The exact amount of compound required will vary with the fungal disease to be controlled, the type of formulation employed, the method of application, the particular plant variety, climatic conditions, and the like. Suitable application rates are generally in the range of from about 0.10 to about 4 pounds per hectare (about 0.01 to 0.45 grams per square meter, g/m ² ).

The person skilled in the art will understand from the teachings herein that any range or derivation value presented herein may be extended or altered without loss of its effect.

Instance

The invention will now be illustrated by way of specific examples, without being limited by the examples.

General experimental process

The definitions of the code numbers in the structural formulas of the reaction schemes herein correspond to their corresponding positions in the chemical formulas described herein.

Azole target compound synthesis

The synthesis of the azole target compound (compound of formula I) can be achieved by the example synthesis shown below (reaction Figure 1). A wide variety of heterocycles can be prepared starting from a functionalized halo-aromatic starting material (e.g., A). For this example, R ₄ is an aryl group further substituted with R ₆ . R ₃ may be a partially fused or unfused bicyclic ring system.

Reaction diagram 1

Example 1

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

Add N -chlorosuccinimide to a stirred solution of 2-iodothiophene (2.5 g (g), 11.9 mmol (mmol)) in n-hexane (25 mL (mL)) at room temperature (RT) After NCS; 1.58 g, 11.9 mmol), a catalyst (cat) amount of perchloric acid (HClO ₄ ) was added, and the mixture was stirred at room temperature for 24 hours (h). The reaction mixture was filtered and the filtrate with water (H ₂ O) was washed with brine, dried over anhydrous sodium sulfate (Na ₂ SO ₄₎ and concentrated in vacuo to dehydration to produce D (1.7g, 6.9mmol, 58% ) of a liquid. ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.18 (d, J = 4.2 Hz, 1H), 6.69 (d, J = 4.2 Hz, 1 H).

Copper powder (1.7 g, 27.9 mmol) was added to a stirred solution of ethyl 2-bromo-2,2-difluoroacetate (1.6 mL, 13.9 mmol). After stirring at room temperature for 1 h, 2-chloro-5-iodothiophene D (1.7 g, 6.. The progress of the reaction was followed by thin layer chromatography (TLC). Saturated (SATD) ammonium chloride (NH ₄ Cl) solution was quenched with dichloromethane _{(CH 2 Cl 2; 3 ×} 50mL) and extracted. Combined organic layers were washed with H ₂ O ₍₂ × 50mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by column chromatography (in EtOAc / hexanes eluting) to give Compound E ( 0.65 g, 2.7 mmol, 38%) of liquid. ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.19-7.17 (m, 1H), 6.89 (d, J = 3.8 Hz, 1H), 4.37 (q, J = 7.4 Hz, 2H), 1.36 (t, J =7.0 Hz, 3H).

Add n-butyllithium ( n - at a solution of 1-bromo-2,4-difluorobenzene (0.3 mL, 2.7 mmol) in ether (Et ₂ O; 20 mL) at -78 ° C under inert atmosphere. BuLi, 1.6 M in hexanes; 1.77 mL, 2.7 mmol). After stirring at -78 ° C for 15 minutes (min), a solution of the compound E (0.65 g, 2.7 mmol) in Et ₂ O (10 mL) was added to the reaction mixture, and the mixture was stirred at -78 ° C for 1 h and stirred at RT for 1 h. . The progress of the reaction was tracked by TLC. With saturated NH ₄ Cl solution was quenched with ethyl acetate (EtOAc; 3 × 30mL) and extracted. Combined organic layers were washed with H ₂ O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product which was purified by column chromatography (in EtOAc / hexanes eluting), to give compound F (0.5 g, 1.62mmol , 60%) solids. ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.90-7.79 (m, 1H), 7.15-7.12 (m, 1H), 7.04-6.86 (m, 3H).

Freshly prepared diazomethane [nitrite-methylurea (NMU; 0.9 g) in 10% hydroxide was added to a stirred solution of F (0.5 g, 1.62 mmol) in Et ₂ O (40 mL) at 0 ° C. Potassium (KOH; 40 mL)], then the reaction mixture was allowed to warm to RT. After stirring at room temperature for 2 h, the volatiles were evaporated in vacuo to give crude. The crude product was purified (in EtOAc / hexanes eluting) by column chromatography, to produce a solid epoxide G (0.3g, 0.93mmol, 57% ) of. ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.34-7.27 (m, 1H), 7.09-6.75 (m, 4H), 3.37 (d, J = 4.8 Hz, 1H), 2.98 (m, 1H).

Potassium carbonate (K) was added to a stirred solution of N,N -dimethylformamide (DMF; 5 mL) containing 1 H -tetrazole (0.039 g, 0.55 mmol) under nitrogen and nitrogen (N ₂ ) atmosphere. ₂ CO ₃ ; 0.064 g, 0.46 mmol). After stirring at room temperature for 10 min, epoxide G (0.15 g, 0.46 mmol) was added to the reaction mixture and the mixture was heated at 65 ° C for 8 h. The reaction mixture was cooled to room temperature, diluted with H ₂ O (40mL), then extracted with EtOAc (2 × 50mL). The combined organic phases were washed with H ₂ O ₍₂ × 25mL) and brine (25mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (elution with EtOAc / hexanes eluting) yielded the 1 (30mg, 0.13mmol, 16% ) of a solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.61 (s, 1H), 7.37-7.32 (m, 1H), 6.85 (d, J = 3.5 Hz, 1H), 6.80-6.74 (m, 3H), 5.60 (d, J = 14.5 Hz, 1H), 5.02 (d, J = 14.5 Hz, 1H). HPLC: 94.1%. MS (ESI): m/z 393 [M ⁺ +1].

The compounds 12 to 16 in Table 1 were prepared from the starting materials obtained from the product (shown in Table 1) under the same conditions as in the compound 1.

Example 2

1-(4-bromothiazol-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2- Alcohol (2)

Compound 2 was synthesized under the same conditions as Compound 1. Yield: 47% (0.022 g). ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.73 (s, 1H), 7.35 (m, 2H), 6.84-6.74 (m, 2H), 5.66 (d, J = 15.0 Hz, 1H), 5.59 (br) s, 1H), 5.19 (d, J = 15.0 Hz, 1H). HPLC: 96.6%. MS (ESI): m/z 438, 440 [ (M ⁺ +1) + 2].

Example 3

4-(2-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1 H -tetrazol-1-yl)propyl)thiazol-4- Benzocarbonitrile (3)

To a suspension of copper powder (1.04 g, 16.46 mmol) in EtOAc (20 mL) Then 2,4-dibromothiazole (1.0 g, 4.11 mmol) was added and stirred at room temperature for 16 h. The progress of the reaction was tracked by TLC. (15mL) suspension of the reaction, _{CH 2 Cl 2 (3 × 50mL} ) extracted with aq NH ₄ Cl (aq). Combined organic layers were washed with H ₂ O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. This was purified by column chromatography on EtOAc EtOAc (EtOAc) elute ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.47 (s, 1H), 4.45 - 4.33 (m, 2H), 1.41-1.33 (m, 3H).

Add n- BuLi (2.5 M hexane solution; 0.7 mL, 1.83) to a stirred solution of 1-bromo-2,4-difluorobenzene (0.20 mL, 1.83 mmol) in Et ₂ O (5 mL). Methyl), the mixture was stirred for 30 min. Et ₂ O (10 mL) containing the ester from the previous step (0.35 g, 1.22 mmol), and the mixture was stirred at -70 ° C for 1 h. Gradually increase the temperature to ambient temperature and continue stirring for 1 h. The reaction mixture quenched aq NH ₄ Cl, extracted with EtOAc (3 × 20mL). Combined organic layers were washed with H ₂ O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc (EtOAc) elute ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.10 - 8.02 (m, 1H), 7.51 (s, 1H), 7.07 - 6.85 (m, 2H).

At ℃, containing a ketone (0.13 g, 0.36mmol) was added the freshly prepared diazomethane of anhydrous Et ₂ O (30mL) stirred solution of [NMU (0.37g) in 10% KOH (20mL), the mixture was allowed to rise to Room temperature. After stirring at room temperature for 1 h, the solvent was evaporated under reduced pressure to give crude material. The crude product was purified by EtOAc EtOAc EtOAc elut elut elut elut ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.51-7.30 (m, 2H), 6.94 - 6.75 (m, 2H), 3.58 (d, J = 5.0 Hz, 1H), 3.05 - 3.03 (m, 1H).

Ether (0.1g, 0.27mmol) and 4-cyanophenylboronic acid (0.059g, 0.40mmol) in tetrahydrofuran (THF) / H ₂ O (20mL, 2: at room temperature and under inert atmosphere) 1) K ₂ CO ₃ (0.112 g, 0.81 mmol) was added to the stirred solution. After flushing with argon for 10 minutes (min), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf) ₂ Cl ₂ ; 0.049 g, 0.06 mmol) was added. To the reaction mixture under argon. The resulting mixture was stirred at 55 ° C for 16 h. The reaction mixture was quenched with EtOAc (3 <EtOAc > The combined organic phases were washed with H ₂ O and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by EtOAc EtOAc elut elut elut elut elut elut ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.99 (d, J = 6.6 Hz, 2H), 7.81-7.67 (m, 3H), 7.67-7.41 (m, 1H), 6.92-6.74 (m, 2H) , 3.66 (d, J = 5.0 Hz, 1H), 3.09-3.07 (m, 1H).

After adding 1 H -tetrazole (0.013 g, 0.19 mmol) to a stirred solution of the coupled product (0.065 g, 0.16 mmol) in DMF (2 mL) at room temperature and inert atmosphere, K ₂ CO ₃ ( 0.011 g, 0.08 mmol). The reaction mixture was stirred at 70 ° C for 16 h. The reaction mixture was cooled to room temperature, diluted with H ₂ O (5mL), extracted with EtOAc (2 × 20mL). The organic layer was washed with H ₂ O and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give a crude compound. The crude product was purified by EtOAc EtOAc EtOAcEtOAcEtOAc ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.71 (s, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.78 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.39-7.35 (m, 1H), 6.83-6.79 (m, 1H), 6.76-6.73 (m, 1H), 5.87 (s, 1H), 5.67 (d, J = 14.5 Hz, 1H), 5.24 (d, J = 14.5 Hz, 1H). HPLC: 95.8%. MS (ESI): m/z 461 [M ⁺ +1].

Example 4

1-(6-chloroquinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2- Alcohol (4)

Ethyl 2-bromo-2,2-difluoroacetate (4.99 g, 24.7 mmol) was added to a stirred suspension of copper powder (3.14 g, 47.4 mmol) in DMSO (50 mL). . After stirring at room temperature for 1 h, 2-bromo-6-chloroquinoline (3.0 g, 12.3 mmol). The reaction mixture was saturated (satd) NH ₄ Cl quenched to _{CH 2 Cl 2 (3 × 100mL} ) and extracted. Combined organic layers were washed with H ₂ O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc elut elut elut elut ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.26 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.78 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 9.0, 2.0 Hz, 1H), 4.44 - 4.39 (m, 2H), 1.38-1.34 (m, 3H). MS (ESI): m/z 286 [M ⁺ +1].

At -70 ℃ gas mask under N _2, was added n -BuLi (1.6 M solution in Et stirred in hexane containing 1-bromo-2,4-difluorobenzene (0.15 mL, 1.40 mmol) of ₂ O (20mL) Solution; 0.87 mL, 1.40 mmol). After stirring at -70 ℃ 15 min, containing the ester was added (0.4g, 1.40mmol) of Et ₂ O (5mL) solution was added to the reaction mixture of -70 ℃. The reaction mixture was stirred at 0 ° C for 1 h, then warmed to RT and then stirred 1 h. The progress of the reaction was tracked by TLC. The reaction with saturated NH ₄ Cl solution was quenched, extracted with EtOAc (3 × 10mL). Combined organic layers were washed with H ₂ O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc elut elut elut elut ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.30-8.23 (m, 1H), 8.14-8.07 (m, 1H), 7.96-7.87 (m, 2H), 7.76-7.65 (m, 2H), 7.01 6.98 (m, 1H), 6.80-6.76 (m, 1H). MS (ESI): m/z 355, 356 [ (M ⁺ +1) + 2].

At -5 deg.] C, in a ketone-containing Et (0.35g, 0.98mmol) of ₂ O (15mL) added dropwise with stirring a solution of freshly prepared diazomethane [NMU (0.8g) in 10% KOH (50mL) in], so that The mixture rose back to RT. After stirring at room temperature for 1 h, the volatiles were evaporated in vacuo to give crude. The crude product was purified with EtOAc EtOAc EtOAc EtOAc _{^{1 H NMR (200MHz, CDCl 3}} ): δ 8.16-8.06 (m, 2H), 7.88-7.85 (m, 1H), 7.74-7.58 (m, 2H), 7.43-7.28 (m, 1H), 6.87-6.68 (m, 2H), 3.50 (d, J = 5.2 Hz, 1H), 3.01 (br s, 1 H). MS (ESI): m/z 368 [M ⁺ +1].

After adding 1 H -tetrazole (0.026 g, 0.38 mmol) to a stirred solution of epoxide (0.14 g, 0.38 mmol) in DMF (10 mL) at room temperature under inert atmosphere, K ₂ CO ₃ ( 0.079 g, 0.57 mmol). The reaction mixture was stirred at 70 ° C for 6 h. The reaction mixture was cooled to room temperature, diluted with H ₂ O (5mL), extracted with EtOAc (2 × 20mL). The organic layer was washed with H ₂ O and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give a crude compound. The crude product was purified by EtOAc EtOAc EtOAc elut elut elut elut elut elut elut 2-(2,4-Difluorophenyl)-1,1-difluoro-3-( 2H -tetrazol-2-yl)propan-2-ol (16; 0.04 g, 0.09 mmol, 24%) White solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.76 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 9.5 Hz, 1H), 7.78 (s, 1H), 7.79 (dd, J = 9.0, 2.5 Hz, 1H), 7.67 (d, J = 9.0 Hz, 2H), 7.32-7.27 (m, 1H), 6.78-6.73 (m, 1H), 6.60-6.57 (m, 1H), 5.64 (d, J = 14.5 Hz, 1H), 5.19 (d, J = 14.5 Hz, 1H). HPLC: 98.6%. MS (ESI): m/z 438 [M ⁺ +1].

Racemic 1-(6-chloroquinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-( 2H -tetrazol-2-yl)propane -2-Alcohol (minor product, 16): ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.26 (s, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 9.5 Hz, 1H), 7.85 (s, 1H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.41 - 7.36 (m, 1H), 6.98 (s) , 1H), 6.81-6.77 (m, 1H), 6.65-6.61 (m, 1H), 5.85 (d, J = 14.5 Hz, 1H), 5.49 (d, J = 14.5 Hz, 1H). HPLC: 97.8%. MS (ESI): m/z 438 [M ⁺ +1].

Enantiomeric separation of 4 (+ and -)

4 based enantiomers by high performance liquid chromatography of (HPLC), using CHIRALPAK IC ^® column (250 × 4.6mm, 5 μ) , using a mobile phase (A) n-hexane - (B) isopropanol (IPA) (equal concentration A: B = 70: 30) was separated from the flow rate of 1.00 mL/min.

Thinner: IPA: Hexane (20:80)

For palm preparative HPLC separation, 4-(-)([α] _D -7.5° ( c = 0.1% in methanol (CH ₃ OH) and 4-(+) ([α] _D 3.58° ( c = 0.1% in CH ₃ OH).

The compounds 17 to 33 in Table 1 were prepared by the same conditions as those of the compound 4, starting from the starting material or the intermediate prepared from the product (shown in Table 1).

Example 5

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

Compound 5 was prepared from 2-bromoquinoline using a condition of 4: 0.020 g was isolated as a cream solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.78 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 8.14 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.90-7.85 (m, 2H), 7.71-7.65 (m, 2H), 7.35-7.30 (m, 1H), 6.77-6.73 (m, 1H), 6.59-6.55 (m, 1H), 5.68 (d, J =14.0 Hz, 1H), 5.17 (d, J = 14.0 Hz, 1H). HPLC: 97.65%. MS (ESI): m/z 404 [M ⁺ +1].

Example 6

1-(Benzo[ d ]thiazol-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-( 1H -tetrazol-1-yl)propane-2 -alcohol (6)

Compound 6 was prepared from 2-bromobenzo[ d ]thiazole using a condition of 4: 0.027 g of a tan solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.75 (s, 1H) 8.12 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.63-7.60 (m, 1H) , 7.56-7.53 (m, 1H), 6.81-6.76 (m, 1H), 6.70-6.66 (m, 1H), 6.42 (s, 1H), 5.73 (d, J = 14.5 Hz, 1H), 5.17 (d , J = 14.5 Hz, 1H). HPLC: 96.1%. MS (ESI): m/z 410 [M ⁺ +1].

Example 7

2-(2,4-Difluorophenyl)-1,1-difluoro-1-(pyrimidin-2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol (7 )

Compound 7 was prepared from 2-iodopyrimidine using the conditions of 1 : 0.007 g of a tan solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.79 (d, J = 4.5 Hz, 2H), 8.73 (s, 1H), 7.47-7.45 (m, 1H), 7.36-7.31 (m, 1H), 6.79 - 6.75 (m, 1H), 6.70-6.67 (m, 1H), 6.39 (s, 1H), 5.60 (d, J = 14.5 Hz, 1H), 5.20 (d, J = 14.5 Hz, 1H). HPLC: 98.8%. MS (ESI): m/z 355 [M ⁺ +1].

Example 8

2-(4-Chloro-2-fluorophenyl)-1-(6-chloroquinolin-2-yl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propane-2 -alcohol (8)

Compound 8 was prepared from 2-bromo-6-chloroquinoline and 1-bromo-2-fluoro-4-chlorobenzene using conditions of 4: 0.021 g was isolated as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.76 (s, 1H), 8.23 (d, J = 9.0 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 2.0) Hz, 1H), 7.79 (dd, J = 9.0, 2.0 Hz, 1H), 7.72 (s, OH ), 7.67 (d, J = 9.0 Hz, 1H), 7.28-7.24 (m, 1H), 7.04 (dd , J =12.0, 2.0 Hz, 1H), 6.85 (dd, J = 8.5, 2.0 Hz, 1H), 5.64 (d, J = 14.5 Hz, 1H), 5.20 (d, J = 14.5 Hz, 1H). HPLC: 99.4%. MS (ESI): m/z 456 [M ⁺ +1].

Separation of the enantiomers of 8 by palm-preparative HPLC

Enantiomers (150mg, 0.33mmol) 8 of the system using preparative HPLC, using CHIRALPAK IC ^® column (250 × 20 mm, 5 μ ; Mobile phase (A) n-hexane - (B) ethanol (A: B =90:10) Separation from a flow rate of 15 mL/min afforded 8- (-) (30 mg, 0.066 mmol, 20%) as an off white solid.

Analytical data: HPLC on palm: 99.88% ee, R _t = 20.29 min (CHIRALPAK IC ^® column, 250 × 4.6 mm, 5 μ; mobile phase (A) n-hexane-(B) ethanol (A: B = 90) :10); flow rate 1.00 mL/min). Optical rotation [α] _D ²⁵ : -29.44 ° ( c = 0.1% in CH ₃ OH). ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.76 (s, 1H), 8.23 (d, J = 9.0 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 2.0) Hz, 1H), 7.79 (dd, J = 9.0, 2.0 Hz, 1H), 7.72 (s, OH ), 7.67 (d, J = 9.0 Hz, 1H), 7.28-7.24 (m, 1H), 7.04 (dd , J = 12.0, 2.0 Hz, 1H), 6.85 (dd, J = 8.5, 2.0 Hz, 1H), 5.64 (d, J = 14.5 Hz, 1H), 5.20 (d, J = 14.5 Hz, 1H). MS (ESI): m/z 454 [M ⁺ ]. HPLC: 99.29%.

Example 9

1-(6-bromoquinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propane-2 -alcohol (9)

Compound 9 was prepared from 2,6-dibromoquinoline using conditions of 4: 0.025 g was isolated as a yellow solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ (8.76 (s, 1H), 8.21. (d, J = 8.5 Hz, 1H), 8.06 (s, 1H), 7.97-7.91 (m, 2H), 7.67- 7.65 (m, 2H), 7.32-7.27 (m, 1H), 6.77-6.73 (m, 1H), 6.60-6.57 (m, 1H), 5.63 (d, J = 14.5 Hz, 1 H), 5.20 (d) , J = 14.5 Hz, 1 H). HPLC: 93.3%. MS (ESI): m/z 482, 484 [M ⁺ , M ^{+ +} 2].

Separation of 9-(+) enantiomers by palm-preparative HPLC

The 9 (150mg, 0.31mmol) based enantiomers using preparative HPLC, using CHIRALPAK IC ^® column (250 × 20 mm, 5 μ ), using a mobile phase (A) n-hexane - (B) [CH ₂ Cl ₂ -ethanol (80:20)] (A: B = 75: 25) was separated from a flow of 12 mL/min to afford 9-(+) (30 mg, 0.062 mmol, 20%) as an off white solid.

Analytical data: HPLC on palm: 99.90% ee, R _t = 21.25 min (CHIRALPAK IC ^® column, 250 × 4.6 mm, 5 μ; mobile phase (A) n-hexane-(B) ethanol (A: B = 90) :10); flow rate 1.00 mL/min). Optical rotation [α] _D ²⁵ : + 5.80 ° ( c = 0.1% in CH ₃ OH). ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.76 (s, 1H), 8.21. (d, J = 8.5 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.92 (dd, J = 9.0, 1.5 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.66 (br s, OH ), 7.32 - 7.27 (m, 1H), 6.77- 6.73 (m, 1H), 6.60-6.57 (m, 1H), 5.64 (d, J = 14.5 Hz, 1H), 5.20 (d, J = 14.5 Hz, 1H). HPLC: 99.55%. MS (ESI): m/z 482 [M ⁺ ].

Example 10

1-(6-chloroquine Benz-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol (10)

Compound 10 is based on the condition of 4, from 2-bromo-6-chloroquine Morphological synthesis. 2-bromo-6-chloroquine The preparation method of the porphyrin is as follows. 6-chloroquine Morpholine -2 (1 H) - one (1.0g, 5.5mmol) and phosphorus tribromide _{(PBr 3; 3.5mL, 36.1 mmol} ) The mixture was heated 4 h at 120 ℃. The reaction mass was cooled to room temperature, diluted with cold H ₂ O, and extracted in CH _{2 2} Cl. The combined organic extracts were dried over Na ₂ SO ₄ dried, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography eluting with EtOAc/hexanes to afford 2-bromo-6-chloroquine A solid of porphyrin (550 mg, 2.26 mmol, 42%). ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.86 (s, 1H), 8.11 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.75 (dd, J = 9.0, 2.4 Hz, H ). MS (ESI): m/z 243 [M ⁺ ].

Compound 10 (25 mg, 0.056 mmol, 26%) was isolated as an off white solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.01 (s, 1H), 8.72 (s, 1H), 8.18 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.85 (dd, J = 9.0, 2.0 Hz, 1H), 7.27 (s, 1H), 6.80-6.75 (m, 1H), 6.69-6.64 (m, 1H), 5.78 (s, 1H, OH ), 5.70 (d, J = 14.5) Hz, 1H), 5.20 (d, J = 14.5 Hz, 1H). HPLC: 97.9%. MS (ESI): m/z 437 [M ⁺ +1].

Separation of 10-(-) enantiomers by palm-preparative HPLC

The enantiomers 10 (70mg, 0.16mmol) system using preparative HPLC, using CHIRALPAK IA ^® column (250 × 20mm, 5 μ) , using a mobile phase (A) n-hexane - (B) ethanol (A: B = 70:30) Separation from a flow rate of 15 mL/min gave 10-(-) (20 mg, 0.046 mmol, 28%) as an off white solid.

Analytical data: HPLC on palm: 99.68% ee, R _t = 10.31 min (CHIRALPAK IA ^® column, 250 × 4.6 mm, 5 μ; mobile phase (A) n-hexane-(B) ethanol (A: B = 85) :15); Flow rate: 1.00 mL/min). Optical rotation [α] _D ²⁵ : -18.52 ° ( c = 0.1% in CH ₃ OH). ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.01 (s, 1H), 8.72 (s, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.84 (dd, J = 9.0, 2.0 Hz, 1H), 7.29-7.26 (m, 1H), 6.81-6.77 (m, 1H), 6.68-6.65 (m, 1H), 5.77 (s, OH ), 5.71 ( d, J = 14.5 Hz, 1H), 5.21 (d, J = 14.5 Hz, 1H). HPLC: 99.06%. MS (ESI): m/z 437 [M+H] ⁺ .

The compound 34 in Table 1 was prepared from the starting material obtained from the product (shown in Table 1) under the same conditions as the compound 10.

Example 11

1-(6-chlorobenzo[ d ]thiazol-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl ) propan-2-ol (11)

Compound 11 was prepared from 2-bromo-6-chlorobenzo[ d ]thiazole under the conditions of 4: 0.017 g was isolated as a cream solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.73 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.92 (s, 1H), 7.58 (dd, J = 9.0, 2.5 Hz, 1H ), 7.39-7.34 (m, 1H), 6.81-6.77 (m, 1H), 6.71-6.68 (m, 1H), 6.06 (s, 1H), 5.70 (d, J = 14.5 Hz, 1H), 5.20 ( d, J = 14.5 Hz, 1H). HPLC: 96.6%. MS (ESI): m/z 444 [M ⁺ +1].

Example 12 - Intermediate Method

2-bromo-6-(2,2,2-trifluoroethoxy)quinoline (I-A)

Triethylamine (Et ₃ N; 27.8 mL, was added to a stirred solution of 2,2,2-trifluoroethanol (10.0 g, 100 mmol) in CH ₂ Cl ₂ (100 mL). 200 mmol), p-toluenesulfonium chloride (19.1 g, 100 mmol) 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. The reaction mixture was diluted with H ₂ O (100mL), in _{CH 2 Cl 2 (3 × 200mL} ) and extracted. The combined organic extracts were washed using H ₂ O (50mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound H (25.0 g, 98.42mmol; crude) of semisolid. ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.81 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 4.35 (q, J = 8.0 Hz, 2H), 2.47 ( s, 3H). MS (ESI): m/z 256 [M+2] ⁺ .

K ₂ CO ₃ (5.71 g, 41.38 mmol) and Compound H (7.01 g, 27.59 mmol) were added to a stirred solution of 6-hydroxyquinoline (2.0 g, 13.79 mmol) in DMF (15 mL). The reaction temperature was gradually increased to 80 °C. The reaction mixture was stirred for a further 16 h at this time. After completion of reaction (by TLC track), and the reaction mixture was cooled to room temperature, diluted with H ₂ O (25mL), extracted with EtOAc (3 × 40mL). The combined organic extracts were washed with brine (30 mL The crude product was purified by EtOAc EtOAc EtOAc elut elut elut elut ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.83 (dd, J = 4.4, 1.8 Hz, 1H), 8.06-8.03 (m, 2H), 7.22 - 7.18 (m, 2H), 7.05 (d, J = 3.0, 1H), 4.50 (q, J = 8.0 Hz, 2H). MS (ESI): m/z 228 [M+H] ⁺ .

m -Chloroperoxybenzoic acid ( m- CPBA; 1.14 g, 6.63 mmol) was added to a stirred solution of EtOAc (25 mL). After completion of the reaction (6 h, to track TLC), the reaction mixture with saturated sodium bicarbonate (NaHCO ₃₎ solution (30mL) quenched, extracted with EtOAc (3 × 40mL). The organic extracts were combined using H ₂ O (30mL) and washed with brine (30mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.73 (d, J = 9.4 Hz, 1H), 8.44 (d, J = 6.2 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.46 ( Dd, J = 9.4, 2.8 Hz, 1H), 7.31 (dd, J = 8.2, 6.2 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H), 4.50 (q, J = 8.0 Hz, 2H). MS (ESI): m / z 244 [M + H] +.

A stirred solution of acetic anhydride (Ac ₂ O; 7 mL) containing quinoline N -oxide J (1.0 g, 4.11 mmol) was heated at 130-140 ° C under inert atmosphere for 5 h. The resulting mixture was cooled to room temperature, diluted with H ₂ O (25mL), extracted with EtOAc (3 × 30mL). The combined organic extracts were washed with brine (40 mL Phosphorus (III) ruthenium bromide (POBr ₃ ; 2.95 g, 10.28 mmol) was mixed with the obtained crude product, heated to 130-140 ° C, and stirred under inert atmosphere for 4 h. After completion of reaction (by TLC track), and the reaction mixture was cooled to room temperature, ice-cold H ₂ O (30mL) quenched, extracted with EtOAc (3 × 30mL). The organic extracts were combined using H ₂ O (30mL) and washed with brine (30mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc (EtOAcEtOAc , 1.79mmol, 43.7%). ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.01 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.42 ( Dd, J = 9.2, 2.8 Hz, 1H), 7.10 (d, J = 2.8 Hz, 1H), 4.46 (q, J = 8.0 Hz, 2H). MS (ESI): m/z 307 [M+H] ⁺ .

2-bromo-6-(trifluoromethoxy)quinoline (I-B)

At 0 ° C, containing 4-(trifluoromethoxy)aniline (1.0 g, 5.6 mmol), sodium 3-nitrobenzenesulfonate (1.89 g, 8.4 mmol), boric acid (0.55 g, 8.9 mmol) and sulfuric acid Concentrated sulfuric acid (H ₂ SO ₄ ; 3.4 mL) was added dropwise to a stirred solution of iron (II) heptahydrate (FeSO ₄ ‧7H ₂ O; 0.31 g, 1.1 mmol) in glycerol (14 mL). The reaction mixture was gradually heated to 150 ° C and stirred for 5 h. After completion of the reaction (trace by TLC), the mixture was poured into ice-cooled H ₂ O (100 mL), and then taken to basic with 50% aqueous sodium hydroxide (NaOH) (10 mL) to Et ₂ O (4×25 mL) extraction. The separated organic layer was washed with H ₂ O (50mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (12% EtOAc/hexanes) eluted ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.96-8.94 (m, 1H), 8.16 (d, J = 8.2 Hz, 2H), 7.65-7.56 (m, 2H), 7.47 (dd, J = 8.2, 4.2 Hz, 1H). MS (ESI): m/z 214 [M+H] ⁺ .

m- CPBA (1.5 g, 8.8 mmol) was added to a stirred solution of EtOAc (EtOAc. After completion of the reaction (after TLC assay), the reaction mixture was quenched with saturated NaHCO ₃ to EtOAc (2 × 50mL) and extracted. The combined organic extracts were washed using H ₂ O (20mL) and brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by hydrazine column chromatography (dissolved in 10% CH ₃ OH / CH ₂ Cl _{2 to} give L (0.72 g, 3.1 mmol, 70%) as a colorless liquid. ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.82 (d, J = 9.4 Hz, 1H), 8.55 (d, J = 6.2 Hz, 1H), 7.75-7.69 (m, 2H), 7.60 (dd, J = 9.4, 1.6 Hz, 1H), 7.39 (dd , J = 9.4, 6.2 Hz, 1H). MS (ESI): 230 [M+H] ⁺ .

A stirred solution of Ac ₂ O (10 mL) containing quinoline N -oxide L (1.0 g, 4.3 mmol) was heated at 130 to 140 ° C under inert atmosphere for 5 h. The resulting mixture was cooled to room temperature, diluted with H ₂ O (30mL), extracted with EtOAc (3 × 30mL). The combined organic extracts were washed with brine (30 mL POBr ₃ (2.2 g, 7.7 mmol) was added to the obtained crude product, and the mixture was heated at 130 to 140 ° C under inert atmosphere for 4 h. After completion of reaction (by TLC track), and the reaction mixture was cooled to room temperature, ice-cold H ₂ O (50mL) quenched, extracted with EtOAc (3 × 50mL). The combined organic extracts were washed with H ₂ O (50mL) and brine (50mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.09 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.64 - 7.59 (m, 3H). MS (ESI): 292 [M+H] ⁺ .

Quinoline-6-carbonitrile (I-C)

CuCN (3.0 g, 33.6 mmol) was added to a stirred solution of 6-bromoquinoline (2.0 g, 9.61 mmol) in pyridine (30 mL). The reaction mixture was gradually heated to 200 ° C and stirred for 8 h. After complete consumption of the starting material (via TLC assay), the reaction mixture was cooled to room temperature, ice-cold H ₂ O (100mL) was diluted, extracted with EtOAc (3 × 100mL). The combined organic extracts were washed with H ₂ O (50mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (30% EtOAc / EtOAc) elute ¹ H NMR (200 MHz, CDCl ₃ ): δ 9.08-9.05 (m, 1H), 8.25-8.19 (m, 3H), 7.86 (dd, J = 8.6, 1.8 Hz, 1H), 7.55 (dd, J = 8.6, 1.8 Hz, 1H). MS (ESI): 155 [M+H] ⁺ .

6-(difluoromethyl)quinoline (I-D)

0 ℃ under a mask with an inert gas, was added (diethylamino) sulfur trifluoride (DAST containing quinoline-6-carbaldehyde (200mg, 1.27 mmol) was stirred of CH ₂ Cl ₂ (10mL) solution; 0.2 mL, 1.53 mmol). The reaction mixture was allowed to warm to RT and stirred for 16 h. After complete consumption of the starting material (via TLC assay), the reaction mixture was diluted ₂ Cl ₂ (20mL) CH use, then with saturated NaHCO ₃ solution (40 mL) quenched. The organic layer was separated washed with ice-cold H ₂ O (20mL) and brine (20mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain ID (100mg, crude) of a yellow liquid. The product characteristics were analyzed using a ¹ H NMR spectrometer and used directly in the next step without further purification. ¹ H NMR (200 MHz, CDCl ₃ ): δ 9.00 (dd, J = 4.2, 1.4 Hz, 1H), 8.25-8.18 (m, 2H), 7.78 (s, 1H), 7.84 (dd, J = 8.8, 1.4 Hz, 1H), 7.48 (dd, J = 8.8, 4.2 Hz, 1H), 6.84 (t, J _{F, H} = 74.0 Hz, 1H). MS (ESI): 180 [M+H] ⁺ .

5-(2,2,2-trifluoroethoxy)quinoline (I-E)

At room temperature, the amine-H-containing 5-amino-quinoline (5.0 g, 34.67mmol) of ₂ O (100mL), was added sodium bisulfite _{(NaHSO 3; 25.2 g, 242.1mmol} ), stirred at reflux temperature The mixture was 36 h. The resulting solution was cooled to RT, NaOH (9.7 g, EtOAc. After completion of the reaction (trace by TLC), the reaction mixture was cooled to RT and adjusted to pH 7.0 using 6 eq. (N) hydrochloric acid (HCl). The precipitate was filtered off, washed with H ₂ O, and dried under high vacuum to afford the desired alcohol M (3.2 g, 22.04mmol, 64 %) of a pale yellow solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.92 (s, 1H), 8.58 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.5, 4.5 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.10 (br s, 1H). MS (ESI): m/z 146 [M+H] ⁺ .

Take alcohol M (3.2 g, 22.04 mmol), 2,2,2-trifluoroethyl-4-methylbenzenesulfonate (5.6 g, 22.04 mmol) and K ₂ CO ₃ (9.12 g, 66.08 mmol) The DMF (40 mL) stirred solution was heated at 120 ° C under inert atmosphere. After completion of the reaction (16 h, TLC to track), and the reaction mixture was cooled to room temperature, diluted with H ₂ O (30mL), then extracted with EtOAc (3 × 40mL). The combined organic extracts were washed with brine (40 mL) Purification by hydrazine gel column chromatography eluting EtOAc (EtOAc:EtOAc:EtOAc ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.94 (d, J = 6.0 Hz, 1H), 8.59 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.63 7.60 (m, 1H), 7.44 (dd, J = 8.5, 4.5 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 4.57-4.52 (m, 2H). MS (ESI): m / z 228.0 [M + H] +.

4,4,5,5-tetramethyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-1,3,2-dioxaborolane (IF )

After adding K ₂ CO ₃ (940 mg, 6.81 mmol) to a stirred solution of boronic acid ester N (300 mg, 1.36 mmol) in DMF (10 mL), ). The reaction mixture was gradually heated to 120 ° C and stirred for 24 h. The progress of the reaction was followed by TLC. Let the reaction mixture was cooled to RT, diluted with H ₂ O (50mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed using H ₂ O (50mL) and brine (50mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by EtOAc EtOAc EtOAc EtOAc ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.78 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 4.37 (q, J = 8.2 Hz, 2H), 1.36 ( s, 12H).

IF can also be synthesized in a two-step process. Adding toluenesulfonyl compound H after adding K ₂ CO ₃ (6.0 g, 43.3 mmol) to a stirred solution of p-bromophenol (1.5 g, 8.67 mmol) in DMF (15 mL) at room temperature under inert atmosphere (2.2 g, 8.67 mmol). The reaction mixture was gradually heated to 110 ° C for 4 h. After complete consumption of the starting material (via TLC assay), so that the reaction mixture was cooled to RT, diluted with H ₂ O (100mL), the aqueous layer extracted with EtOAc (2 × 100mL). The combined organic layer was washed using H ₂ O (50mL) and brine (50mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by EtOAc EtOAc EtOAc EtOAc ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.45-7.38 (m, 2H), 6.87-6.79 (m, 2H), 4.32 (q, J = 8.2 Hz, 2H).

At room temperature and inert atmosphere, in the presence of O (0.5g, 1.96mmol) 1,4-two After adding bis(pinacol) diboron (0.54 g, 2.15 mmol) to a stirred solution of aq. (50 mL), potassium acetate (KOAc; 0.576 g, 5.88 mmol) was added. After 10 min of N ₂ flushing, Pd(dppf) ₂ Cl ₂ (72 mg, 0.09 mmol) was added to the N ₂ vented reaction mixture. The mixture was gradually heated to 110 ° C and stirred for 2 h. After complete consumption of the starting material (via TLC assay), volatiles were evaporated under reduced pressure, the resulting residue was dissolved in H ₂ O (100mL), in EtOAc (3 x 50mL) and extracted. The combined organic extracts were washed with H ₂ O (50mL) and brine (50mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by EtOAc EtOAc EtOAc EtOAc ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.78 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 4.37 (q, J = 8.2 Hz, 2H), 1.36 ( s, 12H).

Example 13

1-(6-chloroquinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(4 H -1,2,4-triazole-4- Base) propan-2-ol (35)

Ethyl 2-bromo-2,2-difluoroacetate (2.6 mL, 20.62 mmol) was added to a stirred suspension of copper powder (2.6 g, 41.23 mmol) in DMSO (25 mL). . After stirring at room temperature for 1 h, 2-bromo-6-chloroquinoline (2.5 g, 10.31 mmol) was added to the reaction mixture and the mixture was further stirred at room temperature for 16 h. After completion of the reaction (after TLC assay), the reaction mixture satd NH ₄ Cl solution was quenched, extracted with EtOAc (2 × 200mL). The combined organic extracts were washed with H ₂ O (50mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography on EtOAc (EtOAc:EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.26 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.78 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 9.0, 2.0 Hz, 1H), 4.44 - 4.39 (m, 2H), 1.38-1.34 (m, 3H). MS (ESI): m/z 286[M+1] ⁺ .

At -78 deg.] C and under N ₂ gas mask, is added n -BuLi (2.5 M solution in Et stirred in hexane containing 1-bromo-2,4-difluorobenzene (0.6 mL, 4.89 mmol) of ₂ O (20mL) Solution; 2 mL, 4.89 mmol). After stirring for 15 min, Et ₂ O (10 mL) EtOAc (EtOAc) The progress of the reaction was tracked by TLC. The reaction with saturated NH ₄ Cl solution was quenched to _{CH 2 Cl 2 (2 × 50mL} ) and extracted. The combined organic extracts were washed with brine solution used in H ₂ O (50mL) and (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a ketone Q (0.5g, crude). The crude product mixture was used in the next step without purification. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.30-8.23 (m, 1H), 8.14-8.07 (m, 1H), 7.96-7.87 (m, 2H), 7.76-7.65 (m, 2H), 7.01-6.98 ( m, 1H), 6.80-6.76 (m, 1H). MS (ESI): m / z 354 [M + 1] +.

Freshly prepared diazomethane was added to a stirred solution of ketone Q (0.5 g, crude product) in Et ₂ O (50 mL). The method was prepared by taking NMU (2 g) in 10% KOH solution at -5 ° C (50 mL). ) in a 1:1 mixture with Et ₂ O (50 mL), then layered, and the organic layer was dehydrated using KOH pellets]. After stirring at room temperature for 1 h, the volatiles were evaporated, evaporated, The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (200 MHz, CDCl ₃ ): 8.16-8.06 (m, 2H), 7.88-7.85 (m, 1H), 7.74-7.58 (m, 2H), 7.43-7.28 (m, 1H), 6.87-6.68 (m, 2H), 3.50 (d, J = 5.2 Hz, 1H), 3.03-3.01 (m, 1H). MS (ESI): m/z 368 [M+1] ⁺ .

Aqueous ammonia (NH ₃ ; 5 mL) was added to a stirred solution of EtOAc (5 mL, EtOAc) The reaction mixture was gradually heated to 80 ° C and stirred for 3 h. The progress of the reaction was tracked by TLC. The volatiles were evaporated under reduced pressure and the residue was diluted withEtOAc. The organic layer was washed with H ₂ O (25mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification (at _{3% CH 3 OH / CH 2} Cl 2 fractions) silica gel column chromatography yielded the amine S (100mg, 0.26mmol, 31% ) of slurry. ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.14-8.01 (m, 2H), 7.85 (s, 1H), 7.70 (dd, J = 9.0, 2.2 Hz, 1H), 7.58-7.45 (m, 2H) , 6.82-6.70 (m, 2H), 3.85 (dd, J = 14.0, 4.8 Hz, 1H), 3.30 (d, J = 14.0 Hz, 1H). MS (ESI): m / z 385 [M + 1] +.

And at room temperature under an inert gas mask, containing N - n triethylorthoformate was added a stirred solution of methyl acyl hydrazine (16mg, 0.26 mmol) of _{CH 3 OH (5mL) (0.1mL} , 0.26mmol). The reaction mixture was then heated at 80 °C for 3 h; the progress of the reaction was followed by TLC. The reaction mixture was cooled to 40 &lt;0&gt;C, EtOAc (EtOAc (EtOAc) The volatiles were evaporated <RTI ID=0.0> The organic layer was washed with H ₂ O (25mL) and brine (25 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (elution with _{7% CH 3 OH / CH 2} Cl 2), to generate 35 (25mg, 0.05mmol, 44% ) of a colorless semisolid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.21. (d, J = 9.0 Hz, 1H), 8.16 (s, 2H), 8.08 (d, J = 9.0 Hz, 1H), 7.78 (s, 1H), 7.82-7.78 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.32-7.29 (m, 1H), 6.77-6.72 (m, 1H), 6.58-6.55 (m, 1H), 5.14 ( d, J = 14.0 Hz, 1H), 4.75 (d, J = 14.0 Hz, 1H). HPLC: 85.3%. MS (ESI): m / z 437 [M + 1] +.

Example 14

2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(6-(4-(2,2,2-three) Fluoroethoxy)phenyl)pyridin-3-yl)propan-2-ol (36)

Add n- BuLi (2.4 M hexane solution; 10.5 mL, 25.3 mmol) to a stirred solution of 2,5-dibromopyridine (5.0 g, 21.09 mmol) in Et ₂ O (200 mL). The reaction mixture was stirred under inert atmosphere for 1 h. Diethyl oxalate (4.0 mL, 25.3 mmol) was added to the reaction mixture at -78 ° C and stirring was continued for a further 10 min. The reaction mixture was allowed to warm to 0 ° C and stirred for 2 h. After the starting material was completely consumed (as determined by TLC), the reaction mixture was quenched with satd NH ₄ Cl solution and extracted with CH ₂ Cl ₂ (2×100 mL). The combined organic extracts were washed using H ₂ O (40mL) and brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.09 (s, 1H), 8.34 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 4.46 (q, J = 7.0) Hz, 2H), 1.44 (t, J = 7.0 Hz, 3H). MS (ESI): m / z 259.2 [M + H] +.

At 0 ℃ mask and under inert gas, containing compound T (180mg, 0.69mmol) of CH ₂ Cl ₂ (10mL), was added DAST (140mg, 0.87mmol). The resulting reaction mixture was allowed to rise to RT and stirred for 16 h. After complete consumption of the starting material (via TLC assay), the reaction mixture was diluted with ₂ Cl ₂ (50mL) CH, and ice-cold H ₂ O (50mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure , the crude product was obtained. Purification by column chromatography on EtOAc (EtOAc EtOAc) elute ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.62 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H) , 4.33 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 282 [M+2] ⁺ .

Add n- BuLi (2.3 M hexane solution; 0.16 mL, 0.38) to a stirred solution of 1-bromo-2,4-difluorobenzene (0.1 mL, 0.38 mmol) in Et ₂ O (5 mL). (mmol), the reaction mixture was stirred under inert atmosphere for 30 min. Add ester-containing U (90mg, 0.32mmol) of Et ₂ O (5mL) solution was added to the reaction mixture of -78 deg.] C, and stirring was continued for 2 h. After complete consumption of the starting material (via TLC assay), the reaction with saturated NH ₄ Cl solution was quenched, the reaction mixture was extracted with EtOAc (2 × 30mL). The organic extracts were combined using H ₂ O (30mL) and washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a ketone V (0.37 g, crude). It was used in the next step without further purification. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.60 (s, 1H), 7.91-7.87 (m, 1H), 7.77-7.75 (m, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.05 -7.01 (m, 1H), 6.93-6.88 (m, 1H). MS (ESI): m/z 348 [M+H] ⁺ .

The freshly prepared diazomethane was added to a stirred solution of ketone V (80 mg, crude product) in Et ₂ O (10 mL) at -5 ° C. The method was obtained by dissolving NMU (200 mg, 2.06 mmol) at 0 °C. A 1:1 mixture of % KOH solution (20 mL) and Et ₂ O (20 mL) was then layered, the organic layer was dehydrated using KOH pellets, and the reaction mixture was stirred for 2 h. The resulting reaction mixture was allowed to warm to RT and stirring was continued for a further 16 h. After the starting material was completely consumed (measured by TLC), the reaction mixture was concentrated under reduced pressure to give the crude product s. The crude product was confirmed by ¹ H-NMR analysis and used for the next reaction without further purification. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.37 (s, 1H), 7.57-7.52 (m, 2H), 7.28-7.2 (m, 1H), 6.87-6.78 (m, 2H), 3.28 (d, J = 5.0 Hz, 1H), 2.97 - 2.91 (m, 1H). MS (ESI): m/z 364[M+2] ⁺ .

After adding K ₂ CO ₃ (137 mg, 0.99 mmol) to a stirred solution of epoxide W (120 mg, 0.33 mmol) in THF / H ₂ O (20 mL, 8:2). Boronate IF (110 mg, 0.363 mmol) was added. After 45 min of N ₂ gas, Pd(dppf) ₂ Cl ₂ (12 mg, 0.016 mmol) was added to the reaction mixture under inert atmosphere, and the mixture was stirred at 70 ° C for 2 h. After complete consumption of the starting material (via TLC assay), so that the reaction mixture was cooled to RT, diluted with H ₂ O (100mL), the aqueous layer extracted with EtOAc (2 × 200mL). The combined organic extracts were washed using H ₂ O (100mL) and brine (100mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by EtOAc EtOAc EtOAc EtOAc EtOAc ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.63 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.75-7.69 (m, 2H), 7.31-7.28 (m, 1H), 7.06 (d, J = 9.0 Hz, 2H), 6.86-6.83 (m, 1H), 6.81-6.77 (m, 1H), 4.42 (q, J = 8.2 Hz, 2H), 3.32 (d, J = 5.0 Hz, 1H), 2.98-2.97 (m, 1H). MS (ESI): m/z 456 [MH] ^- .

After adding 1 H -tetrazole (28 mg, 0.37 mmol) to a stirred solution of epoxide X (115 mg, 0.25 mmol) in anhydrous DMF (10 mL) at room temperature under inert atmosphere, K ₂ CO ₃ ( 52 mg, 0.25 mmol). The reaction mixture was gradually heated to 65 ° C and stirred for 20 h. After complete consumption of the starting material (via TLC assay), the reaction mixture was ice-cold H ₂ O (30mL) was diluted in EtOAc (2 × 50mL) and extracted. The organic layer was separated using H ₂ O (30mL) and washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by EtOAc EtOAc EtOAc EtOAc ¹ H NMR (500 MHz, CD ₃ OD): δ 8.66 (s, 1H), 8.42 (s, 1H), 7.99 (d, J = 7.5 Hz, 2H), 7.63 (d, J = 7.5 Hz, 1H) , 7.55 (d, J = 7.0 Hz, 1H), 7.10-7.03 (m, 3H), 6.81-6.79 (m, 1H), 6.68-6.64 (m, 1H), 5.73 (d, J = 14.5 Hz, 1H ), 5.14 (d, J = 14.5 Hz, 1H), 4.44 (q, J = 8.2 Hz, 2H), 4.35 (s, OH ). HPLC: 96.1%. MS (ESI): m/z 528 [M+H] ⁺ .

Example 15

1-(7-chloroisoquinolin-3-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propene- 2-alcohol (37)

(: 1 v / v 45mL, 2) , was added NaCN (2.1 g, 42.68mmol (methylamino) acetonitrile hydrochloride (4.17g, 39.13mmol) of CH ₃ OH / H ₂ O containing 2- The reaction mixture was maintained at room temperature for 5 min. 4-Chlorobenzaldehyde (5.0 g, 35.56 mmol) of CH ₃ OH (30 mL) was slowly added dropwise to the above solution at the same temperature over 20 min, and then the temperature was gradually increased to 70 ° C for 8 h. After the reaction was completed (EtOAc EtOAc (EtOAc)EtOAc. The extracts were combined using H ₂ O (25mL), washed with brine (25mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc EtOAc EtOAc ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.48 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 4.86 (s, 1H), 3.47 (d, J =14.0) Hz, 1H), 3.45 (d, J = 14.0 Hz, 1H), 2.51 (s, 3H). MS (ESI): m/z 218 [MH] ^- .

A solvent-free mixture of dimethyl sulfonate (8.6 mL, 22.76 mmol) containing cyano compound Y (5.0 g, 22.76 mmol) was taken and heated at 120 ° C for 6 h under inert conditions. After completion of the reaction (TLC followed by 30% EtOAc / hexanes), the reaction mixture was cooled to RT and was applied to the next step.

An aqueous solution of NH ₃ (40 mL) was added to a stirred solution of CH ₂ Cl ₂ (50 mL) containing methyl sulfate Z (5.0 g, crude), and the mixture was maintained under the same conditions. Next 30min. After completion of reaction (by TLC tracking, 30% EtOAc / hexanes), the reaction mixture was diluted with H ₂ O (40mL), in _{CH 2 Cl 2 (3 × 50mL} ) and extracted. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product ^{AA 1 H NMR (500 MHz,} CDCl 3):. Δ 7.67 (s, 1H), 7.43-7.42 (m, 2H), 4.92 ( s, 1H), 3.94 (s, 2H), 2.30 (s, 6H). MS (ESI): m/z 234[M+H] ⁺ .

The obtained crude product AA (~5.0 g) was dissolved in ethanol (EtOH; 40 mL) and kept stirring under inert atmosphere. A solution of copper (II) sulfate pentahydrate (CuSO ₄ ‧5H ₂ O; 7.5 g, 30.03 mmol) in H ₂ O (40 mL) was added to this stirred solution at room temperature, and the mixture was gently heated to reflux for 30 min. After completion of the reaction (TLC, 30% EtOAc/hexanes), the mixture was cooled to RT then filtered. Extracted with _{CH 2 Cl 2 (2 × 70mL} ) and the filtrate used; the combined extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by hydrazine column chromatography (solvent in 15 to 20% EtOAc in hexane gradient) afforded AB (1.2 g, 6.68 <RTIgt; ¹ H NMR (500 MHz, CDCl ₃ ): δ 10.03 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.65 - 7.62 (m, 2H), 4.23 (s, 2H). MS (ESI): m/z 178 [MH] ^- .

4-methoxybenzylamine (PMBNH ₂ ; 1.91 g, 13.92 mmol) and the amount of catalyst were added to a stirred solution of benzaldehyde AB (2.0 g, 11.13 mmol) in EtOH (25 mL) at room temperature. Fluoroacetic acid (TFA; 5 mol%), the mixture was gradually heated to reflux temperature under inert atmosphere. After completion of the reaction (8 h, followed by TLC), the reaction mixture was cooled to RT and concentrated. The resulting solid was crystallized (50% CH ₂ Cl ₂ / pentane) to give isoquinoline derivatives of the AC colorless crystals (2.0g, 6.69mmol, 60%) . ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.75 (s, 1H), 7.72 (s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 6.46 (s, 1H), 5.02 (br s, 1H), 4.43 (s, 2H), 3.80 (s, 3H). MS (ESI): m / z 299 [M + H] +.

At room temperature, containing compound AC (2.0 g, 6.69mmol) of CH ₂ Cl ₂ (40mL), was added TFA (20mL), and refluxed under inert conditions for 3 h. After completion of reaction (by TLC track), and the reaction mixture was cooled to room temperature, saturated NaHCO ₃ solution (40 mL) quenched to _{CH 2 Cl 2 (3 × 40mL} ) and extracted. The combined extracts were washed with brine (25 mL The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.78 (s, 1H), 7.75 (s, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 9.0 Hz, 1H), 6.70 (s, 1H), 4.48 (br s, 2H). MS (ESI): m / z 179 [M + H] +.

Sodium nitrite (NaNO ₂ ; 0.58 g) was added dropwise to a stirred solution of an amine containing AD (1.0 g, 5.60 mmol) in 48% aqueous hydrobromide (HBr) (4.8 mL) at 0 ° C over 15 min. , 8.40 mmol) of H ₂ O (20mL) were added and the reaction mixture was kept at the same temperature for 1h. After completion of reaction (by TLC tracking, 40% EtOAc / hexanes), the reaction mixture was diluted with H ₂ O (20mL), 2 N NaOH aqueous solution was made basic (pH 8 to 9), then Et ₂ O ( 3 x 30 mL) extraction. The combined organic extracts were washed with brine (30 mL) The crude product was purified by EtOAc EtOAc EtOAc EtOAc EtOAc _{^{1 H NMR (500MHz, CDCl 3}} ): δ 8.97 (s, 1H), 7.95 (s, 1H), 7.89 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H). MS (ESI): m/z 242 [M ⁺ ].

Ethyl 2-bromo-2,2-difluoroacetate (0.55 mL, 4.13 mmol) was added to a stirred suspension of EtOAc (EtOAc). After stirring at room temperature for 1 h, compound AE (0.5 g, 2.06 mmol) After completion of the reaction (after TLC assay), the reaction mixture with saturated NH ₄ Cl solution (50mL) quenched, filtered through Celite ^® filler, and washed using _{CH 2 Cl 2 (3 × 50mL} ). The organic layer was washed with brine (50 mL) The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.20 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 4.38 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 286 [M+H] ⁺ .

Add n- BuLi (1.6 M hexane solution) to a stirred solution of 1-bromo-2,4-difluorobenzene (68 mg, 0.35 mmol) in Et ₂ O (6 mL) at -78 ° C under inert atmosphere. ; 0.22 mL, 0.35 mmol), the mixture was stirred for 20 min. Add Et ester containing AF (100mg, 0.35mmol) of ₂ O (5mL) solution was added to the -78 deg.] C the reaction mixture was continued at the same temperature for IH, then at room temperature for 15 min. The progress of the reaction was followed by TLC. The reaction with saturated NH ₄ Cl solution was quenched, the mixture was extracted with EtOAc (2 × 25mL). The combined organic extracts were washed using H ₂ O (20mL) and brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a ketone AG (100mg, crude). The crude product was used in the next step without further purification. MS (ESI): m/z 355 [M+H] ⁺ .

The freshly prepared diazomethane was added to a stirred solution of ketone AG (500 mg, crude product) in Et ₂ O (25 mL) at 0 ° C. [N.sub.10 (1.0 g, 9.71 mmol) dissolved in 0 ° C 10 % KOH solution water (50 mL) was mixed with Et ₂ O (25 mL), then layered, the organic layer was dehydrated using KOH pellets, and the reaction mixture was maintained at 0 ° C to RT for 4 h. The progress of the reaction (20% EtOAc/hexane) was followed by TLC. The reaction mixture was concentrated under reduced pressure to give a crude material. The crude product was purified by EtOAc EtOAc EtOAc elut elut elut elut elut elut elut 13%). ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.21 (s, 1H), 8. s (s, 1H), 7.85 (s, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.43-7.26 (m, 1H), 6.79-6.62 (m, 1H), 6.72-6.68 (m, 1H), 3.53 (d, J = 5.0 Hz, 1H), 3.01 (d, J = 5.0 Hz, 1H). HPLC: 99.9%. MS (ESI): m/z 372 [M+H] ⁺ .

At room temperature and under an inert gas mask, was added with stirring in anhydrous DMF 1 H epoxide containing AH (70mg, 0.19 mmol) of (5mL) - after tetrazole (20mg, 0.28mmol), was added K ₂ CO ₃ ( 26.3 mg, 0.19 mmol). The resulting reaction mixture was gradually heated to 65 ° C and stirred for 16 h; the progress of the reaction was followed by TLC. The reaction mixture was diluted with ice-H ₂ O used in EtOAc (2 × 30mL) and extracted. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.08 (s, 1H), 8.77 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.85 (d, J = 8.5 Hz, 1H ), 7.77-7.75 (m, 2H), 7.39-7.34 (m, 1H), 6.77-6.72 (m, 1H), 6.63-6.59 (m, 1H), 5.62 (d, J = 14.5 Hz, 1H), 5.13 (d, J = 14.5 Hz, 1H). HPLC: 99.9%. MS (ESI): m/z 448 [M+H] ⁺ .

Example 16

1-(6-bromoquine Benzan-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol (38)

At room temperature, in 6-bromoquine POBr ₃ (500 mg, 2.61 mmol) was added to oxaline-2( 1H )-one (250 mg, 1.11 mmol). The reaction mixture was gradually heated to 130 ° C and stirred for 2 h. After completion of the reaction (after TLC assay), the reaction mixture was cooled to 0 deg.] C, saturated NaHCO ₃ solution (50mL) and extracted with EtOAc (2 × 50mL). The combined organic extracts were washed with H ₂ O (50mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (10% EtOAc / EtOAc) elute ¹ H NMR (200 MHz, CDCl ₃ ): δ 8.84 (s, 1H), 8.30 (d, J = 9.0 Hz, 1H), 7.96-7.82 (m, 2H).

2-Bromo-2,2-difluoroacetic acid ethyl ester (0.15 mL, 1.04 mmol) was added to a stirred suspension of EtOAc (2 EtOAc) A solution of the compound AI (150 mg, 0.52 mmol) in DMSO (3 mL) was added to the reaction mixture and stirring was continued at room temperature for 16 h. After completion of the reaction (after TLC assay), the reaction mixture with saturated NH ₄ Cl solution (100 mL) quenched, extracted with EtOAc (2 × 150mL). The combined organic extracts were washed using H ₂ O (100mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (20% EtOAc / EtOAc) elute ¹ H NMR (200 MHz, CDCl ₃ ): δ 9.22 (s, 1H), 8.34 (dd, J = 8.0, 1.5 Hz, 1H), 8.02-7.94 (m, 2H), 4.40 (q, J = 7.0 Hz) , 2H), 1.36 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 331 [M] ⁺ .

Add n- BuLi (1.6 M hexane solution; 0.22 mL, 0.36) to a stirred solution of 1-bromo-2,4-difluorobenzene (0.1 mL, 0.36 mmol) in Et ₂ O (5 mL). Methyl), the mixture was stirred under inert atmosphere for 30 min. Add Et ester containing AJ (0.31g, 0.94mmol) of ₂ O (5mL) solution was added to the reaction mixture of -78 deg.] C, and stirring was continued for 5 min. The progress of the reaction was followed by TLC. The reaction with saturated NH ₄ Cl solution (40 mL) suspension of the reaction, the reaction mixture was extracted with EtOAc (2 × 50mL). The combined organic extracts were washed using H ₂ O (40mL) and brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (20% EtOAc / EtOAc) elute ¹ H NMR (200 MHz, CDCl ₃ ): δ 9.31 (s, 1H), 8.40 (s, 1H), 8.22-7.88 (m, 3H), 7.10-6.92 (m, 1H), 6.83-6.78 (m, 1H). MS (ESI): m/z 399 [M] ⁺ .

Freshly prepared diazomethane was added to a stirred solution of ketone AK (0.35 g, 0.87 mmol) in Et ₂ O (15 mL) at 0 ° C [N.sub.2 (1. 10% KOH solution (10 mL) and Et ₂ O (10 mL) in a 1:1 mixture, then layered, the organic layer was dehydrated using KOH pellets] and stirred for 30 min. The reaction mixture was allowed to warm to RT and stirring was continued for a further 4 h. The progress of the reaction was followed by TLC. The reaction mixture was concentrated under reduced pressure to give a crude material. Purification by column chromatography (10% EtOAc / hexanes) eluted ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.99 (s, 1H), 8.18 (s, 1H), 8.10-8.05 (m, 1H), 7.96-7.85 (m, 1H), 7.49-7.41 (m, 1H), 6.88-6.82 (m, 1H), 6.79-6.75 (m, 1H), 3.46 (d, J = 5.0 Hz, 1H), 3.03 (d, J = 5.0 Hz, 1H). MS (ESI): m/z 414 [M+H] ⁺ .

K ₂ CO _{3 was} added after adding 1 H -tetrazole (36 mg, 0.61 mmol) to a stirred solution of epoxide AL (140 mg, 0.34 mmol) in anhydrous DMF (5 mL). (56 mg, 0.45 mmol). The resulting reaction mixture was gradually heated to 65 ° C and stirred for 16 hours. The progress of the reaction was followed by TLC. The reaction mixture ₂ O (40mL) diluted with ice-H, in EtOAc (2 × 50mL) and extracted. The combined organic extracts were washed using H ₂ O (40mL) and brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (40% EtOAc/hexanes) afforded 38 (30 mg, 0.06 mmol, 18.4%) ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.00 (s, 1H), 8.73 (s, 1H), 8.37 (s, 1H), 8.06-7.93 (m, 2H), 7.25-7.24 (m, 1H) , 6.81-6.77 (m, 1H), 6.67-6.65 (m, 1H), 5.81 (s, OH ), 5.72 (d, J = 14.5 Hz, 1H), 5.21. (d, J = 14.5 Hz, 1H). HPLC: 96.5%. MS (ESI): m/z 495 [M+2] ⁺ .

Example 17

1-(5-(4-(difluoromethoxy)phenyl)pyrene -2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol (39)

At 0 deg.] C, was added H containing KOH (32.5g, 580.35mmol) of ₂ O (350 mL) added and the mixture was stirred for 5min maintained in acetonitrile (350 mL of) solution of 4-bromophenol (5g, 28.90mmol) of the liquid solution. At the same temperature, diethyl (bromodifluoromethyl)phosphonate (9.25 mL, 52.02 mmol) (exothermic reaction) was slowly added to this mixture over 15 minutes, and the mixture was stirred at room temperature. After stirring at rt for 10 h, EtOAc (EtOAc) The organic layer was washed with H ₂ O (40mL) and brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography on EtOAc (EtOAc:EtOAc:EtOAc ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.48 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 6.48 (t, J _FH = 74.0 Hz, 1H).

1,4-BDE with bromophenol derivative AM (2.0 g, 8.97 mmol) at room temperature under inert atmosphere To the stirred solution of the alkane (40 mL) was added bis(pinacol) diboron (2.28 g, 8.97 mmol) and KOAc (2.64 g, 26.90 mmol), and the mixture was degassed with argon gas for 20 min. To this solution was added Pd(dppf) ₂ Cl ₂ (0.33 g, 0.45 mmol) and the mixture was again degassed for 10 min. The reaction mixture was then heated to 80 and stirred at this temperature for 3 h. The progress of the reaction was followed by TLC. The reaction mixture was cooled to EtOAc (EtOAc) The resulting solution was filtered through Celite ^® filler, and the filtrate concentrated in vacuo. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.81 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.54 (t, J _FH = 74.0 Hz, 1H), 1.34 (s, 12H).

2,5-dibromopyridinium at room temperature (1.32 g, 5.55 mmol), boric acid ester AN (1.5 g, 5.55 mmol) and K ₂ CO ₃ (2.27 g, 16.45 mmol) in THF-H ₂ O (4:1; 25 mL). Degas for 20 minutes. To this solution was added Pd(dppf) ₂ Cl ₂ (0.4 g, 0.55 mmol), and the mixture was again degassed for 10 min. The resulting reaction mixture was maintained at the same temperature for 18 h; the progress of the reaction was followed by TLC. The reaction mixture was diluted with EtOAc (30 mL). The organic layer was separated and aqueous brine evaporated with EtOAc The combined organic layers were washed with brine (30 mL) Purification by column chromatography on EtOAc (EtOAc EtOAc (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.75 (s, 1H), 8.71 (s, 1H), 8.1 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 9.0 Hz, 2H), 6.58 (t, J _FH = 74.0 Hz, 1H).

2-Bromo-2,2-difluoroacetic acid ethyl ester (0.77 mL, 6.0 mmol) was added to a stirred suspension of EtOAc (EtOAc,EtOAc. A solution of the compound AO (900 mg, 2.99 mmol) in DMSO (2 mL) was added to the reaction mixture and stirring was continued at room temperature for 18 h. After completion of the reaction (after TLC assay), the reaction mixture satd NH ₄ Cl solution was quenched, filtered through Celite ^® filler. Celite ^® was filtered washed with fillers _{2 Cl 2 (3 × 50mL)} CH. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate The crude product was purified by EtOAc EtOAc EtOAc EtOAc EtOAc ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.02 (s, 1H), 9.1 (s, 1H), 8.09 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 9.0 Hz, 2H), 6.60 (t, J _FH = 73.0 Hz, 1H), 4.40 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 345 [M+H] ⁺ .

Add n- BuLi (2.5 M) to a stirred solution of 1-bromo-2,4-difluorobenzene (196 mg, 1.01 mmol) in Et ₂ O (10 mL) at -78 ° C under inert atmosphere. Alkane solution; 0.43 mL, 1.01 mmol), the mixture was stirred for 40 min. A solution of the ester-containing AP (350 mg, 1.01 mmol) in THF (5 mL) was added to the reaction mixture at -78 ° C and stirring was continued for further 10 min. The progress of the reaction was tracked by TLC. The reaction with saturated NH ₄ Cl solution was quenched, the mixture was extracted with EtOAc (2 × 25mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate The crude product AQ was confirmed by ¹ H-NMR analysis and was used in the next step without further purification. ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.10 (s, 1H), 8.95 (s, 1H), 8.11-8.07 (m, 3H), 7.29-7.26 (m, 2H), 7.04-7.01 (m, 1H), 6.87-6.85 (m, 1H), 6.60 (t, J _FH = 73.0 Hz, 1H). MS (ESI): m / z 413 [M + H] +.

The freshly prepared diazomethane was added to a stirred solution of ketone AQ (350 mg, crude product) in Et ₂ O (15 mL). </ RTI></RTI></RTI></RTI> NMU (438 mg, 4.25 mmol) in 10% aqueous KOH (0 mL) ) with a mixture of Et ₂ O (25 mL), then layered, the organic layer was dehydrated using KOH pellets, and the mixture was stirred for 3 h. The resulting reaction mixture was stirred at room temperature for additional 30 min. The progress of the reaction was tracked by TLC. The reaction mixture was concentrated under reduced pressure to give a crude material. Purification by hydrazine column chromatography (solvent in 15 to 20% EtOAc in hexane gradient) afforded EtOAc EtOAc (EtOAc: EtOAc: ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.02 (s, 1H), 8.75 (s, 1H), 8.09 (d, J = 9.0 Hz, 2H), 7.45-7.42 (m, 1H), 7.28 (d) , J = 9.0 Hz, 2H), 6.89-6.83 (m, 1H), 6.78-6.75 (m, 1H), 6.60 (t, J _FH = 73.0 Hz, 1H), 3.47 (d, J = 5.0 Hz, 1H ), 3.03 (d, J = 5.0 Hz, 1H).

At room temperature and under an inert gas mask, (5mL) was added a stirred solution of 1 H in anhydrous DMF containing epoxide AR (160mg, 0.37 mmol) - The after-tetrazole (40mg, 0.57mmol), was added K ₂ CO ₃ ( 52 mg, 0.37 mmol). The resulting reaction mixture was gradually heated to 65 ° C and stirred for 18 h. The progress of the reaction was tracked by TLC. The reaction mixture was diluted with ice-H ₂ O used in EtOAc (2 × 30mL) and extracted. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.89 (s, 1H), 8.81 (s, 1H), 8.72 (s, 1H), 8.07 (d, J = 9.0 Hz, 2H), 7.35-7.31 (m) , 1H), 7.28 (d, J = 9.0 Hz, 2H), 6.81-6.77 (m, 1H), 6.75-6.69 (m, 1H), 6.60 (t, J _{F, H} = 73.0 Hz, 1H), 6.01 (s, OH ), 5.64 (d, J = 15.0 Hz, 1H), 5.18 (d, J = 15.0 Hz, 1H). HPLC: 95.07%. MS (ESI): m/z 495 [M+H] ⁺ .

The compounds 40 to 48 in Table 1 were prepared under the same conditions as those of the compound 39 from the starting material or the intermediate obtained from the product (shown in Table 1).

Example 18

Separation of enantiomers of 42 by palm-preparative HPLC

Enantiomers (300mg, 0.58mmol) 42 of the system using preparative HPLC, using CHIRALPAK IC ^® column (250 × 20mm, 5 μ) , using a mobile phase (A) n-hexane - (B) EtOH (A: B = 90: 10) Separation from a flow rate of 15 mL/min gave 42 (+) (90 mg, 0.17 mmol, 30%) of white solid.

Analytical data: HPLC for palm: 100% ee, R _t = 15.22 min (CHIRALPAK IC ^® column, 250 × 4.6 mm, 5 μ; mobile phase (A) n-hexane - (B) EtOH (A: B = 90 :10); Flow rate: 1.00 mL/min). Optical rotation [α] _D ²⁵ : +33.04 ° ( c = 0.1% in CH ₃ OH). ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.90 (s, 1H), 8.82 (s, 1H), 8.72 (s, 1H), 8.09 (d, J = 9.0 Hz, 2H), 7.38 (d, J) = 9.0 Hz, 2H), 7.35-7.31 (m, 1H), 6.82-6.77 (m, 1H), 6.73-6.69 (m, 1H), 5.97 (s, OH ), 5.64 (d, J = 15.0 Hz, 1H), 5.20 (d, J = 15.0 Hz, 1H). HPLC: 99.78%. MS (ESI): m/z 515 [M+H] ⁺ .

Example 19

1-(5-chloropyridyl -2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol (49)

Add 2-bromo-2,2-difluoroacetate (4.7 g, 23.15 mmol) to a stirred suspension of copper powder (3.0 g, 46.51 mmol) in DMSO (10 mL). The mixture was stirred under inert atmosphere for 1 h. Add 2-bromo-5-chloropyridyl A solution of (3.0 g, 15.54 mmol) in DMSO (20 mL) was then evaporated. After consumption of the starting material (via TLC assay), the reaction mixture was diluted with ₄ Cl solution (40mL) NH, fillers filtered through Celite ^®, and washed using CH ₂ Cl ₂ (3 × 25mL). The filtrate was collected and washed using H ₂ O (30mL) and brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (solvent eluting with 20%EtOAcEtOAcEtOAc ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.78 (s, 1H), 8.62 (s, 1H), 4.38 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H).

N- BuLi (1.6 M hexane solution; 3.2 mL, was added dropwise to a stirred solution of 1-bromo-2,4-difluorobenzene (0.98 g, 5.08 mmol) in Et ₂ O (20 mL). 5.08 mmol), the mixture was stirred for 30 min. A solution of the compound AS (0.6 g, 2.54 mmol) in Et.sub.2O (8 <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt_;< / RTI></RTI> was added to the reaction mixture at -78 ° C and stirring was continued for a further 5 min. After consumption of the starting material (via TLC assay), the reaction mixture with saturated NH ₄ Cl solution (20mL) quenched, extracted with EtOAc (2 × 50mL). The combined organic extracts were washed with brine solution used in H ₂ O (40mL) and (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a ketone AT (0.7g, crude), which was used without further purification in the next reaction . ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.87 (s, 1H), 8.57 (s, 1H), 8.07-8.02 (m, 1H), 7.06-7.02 (m, 1H), 6.90-6.84 (m, 1H).

Freshly prepared diazomethane was added to a stirred solution of ketone AT (0.6 g, crude product) in Et ₂ O (10 mL) at 0 ° C. [N.sub.2 (1.0 g, 9.70 mmol) was dissolved in 0 ° C 10% aqueous KOH (50 mL) and Et ₂ O (50 mL), then layered, organic layer dehydrated using KOH pellets, and stirred at 0 ° C for 30 min. The resulting reaction mixture was allowed to warm to RT and stirred for 16 h. The progress of the reaction was tracked by TLC. The reaction mixture was concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.62 (s, 1H), 8.51 (s, 1H), 7.42-7.37 (m, 1H), 6.89-6.86 (m, 1H), 6.79-6.77 (m, 1H), 3.43 (d, J = 5.0 Hz, 1H), 3.00 (d, J = 5.0 Hz, 1H).

Add 1 H -tetrazole (65 mg, 0.93 mmol) and K ₂ CO ₃ (86 mg, in a stirred solution of EtOAc ( EtOAc, EtOAc) 0.62 mmol). The resulting reaction mixture was gradually heated to 70 ° C and stirred for 16 hours. After consumption of the starting material (via TLC assay), cool the reaction mixture to room temperature, diluted with H ₂ O (30mL), in EtOAc (2 × 25mL) and extracted. The organic extracts were combined using H ₂ O (30mL) and washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product mixture. The crude product was purified by EtOAc EtOAc EtOAc EtOAc ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.65 (s, 1H), 8.59 (s, 1H), 8.56 (s, 1H), 7.28-7.25 (m, 1H), 6.81-6.74 (m, 2H) , 5.63 (d, J = 14.0 Hz, 1H), 5.23 (s, OH ), 5.15 (d, J = 14.0 Hz, 1H). HPLC: 95.27%. MS (ESI): m/z 390 [M+2] ⁺ .

Example 20

2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridinium 2-yl)-3-( 1H -tetrazol-1-yl)propan-2-ol (50) with 2-(2,4-difluorophenyl)-1,1-difluoro-1- (5-((4-fluorophenyl)ethynyl)pyridinium -2-yl)-3-( 2H -tetrazol-2-yl)propan-2-ol (51)

At room temperature, the epoxide-containing AU (94mg, 0.29mmol), 1- ethynyl-4-fluorobenzene _{(57mg, 0.47mmol), Et 3} N (0.1mL, 0.72mmol) of THF (15mL) stirred solution of Copper (I) iodide (CuI; 3 mg, 0.015 mmol) was added. After flushing with inert gas 10 min, add dichlorobis (triphenylphosphine) palladium _{(II) (Pd (PPh 3} ) 2 Cl 2; 10.4mg, 0.15mmol) to the reaction mixture of the inert gas in the mask. The reaction mixture was gradually heated to 70 ° C and stirred for 3 h. After consumption of the starting material (via TLC assay), the reaction mixture was filtered through Celite ^® filler, use was washed with EtOAc (4 × 15mL). The filtrate was washed with H ₂ O (50mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc EtOAc ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.74 (s, 1H), 8.69 (s, 1H), 7.63 (dd, J = 9.0, 5.5 Hz, 2H), 7.42-7.38 (m, 1H), 7.12 -7.09 (m, 2H), 6.89-6.86 (m, 1H), 6.79-6.75 (m, 1H), 3.46 (d, J = 4.5 Hz, 1H), 3.01 (d, J = 4.5 Hz, 1H).

K ₂ CO ₃ (90 mg, 0.65 mmol) and 1 H -tetrazole were added sequentially to a stirred solution of epoxide AV (260 mg, 0.65 mmol) in anhydrous DMF (10 mL) at room temperature under inert atmosphere. 70 mg, 0.97 mmol). The reaction mixture was gradually heated to 65 ° C and stirred for 16 hours. After consumption of the starting material (via TLC assay), cool the reaction mixture to room temperature, diluted with H ₂ O (50mL) used, extracted with EtOAc (2 × 50mL). The separated organic layer was dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography eluting with EtOAc (EtOAc: EtOAc (EtOAc:EtOAc) The hexane was dissolved in a pale brown solid. ^{50: 1 H NMR (500 MHz} , CDCl 3): δ 8.74 (s, 1H), 8.71 (s, 1H), 8.62 (s, 1H), 7.63-7.60 (dd, J = 13.5,7.5 Hz, 2H) , 7.30-7.28 (m, 1H), 7.13-7.09 (m, 2H), 6.81-6.77 (m, 1H), 6.74-6.70 (m, 1H), 5.64 (d, J = 14.5 Hz, 1H), 5.61 (s, OH ), 5.17 (d, J = 14.5 Hz, 1H). HPLC: 93.5%. MS (ESI): m / z 472 [MH] - .51: 1 H NMR (500 MHz, CDCl 3): δ 8.72 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 7.64 -7.62 (m, 2H), 7.30-7.27 (m, 1H), 7.12-7.09 (m, 2H), 6.81-6.77 (m, 1H), 6.72-6.69 (m, 1H), 6.02 (d, J = 14.5 Hz, 1H), 5.37 (d, J = 14.5 Hz, 1H), 5.10 (s, OH ). HPLC: 98.3%. MS (ESI): m/z 472 [MH] ^- .

Example 21

2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-fluorophenethyl)pyridinium -2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol (52)

Under an inert gas mask, (10mL) was added 10% was stirred in EtOAc containing 50 (25mg, 0.053mmol) of palladium / carbon (Pd / C; 5mg), at room temperature with H ₂ gas mask (balloon pressure) The mixture was stirred for 2 h. After consumption of the starting material (via TLC assay), the reaction mixture was filtered through Celite ^® filler, washed with EtOAc (3 × 10mL). The filtrate was concentrated under reduced pressure to give a crude material. Purification by column chromatography (30% EtOAc / EtOAc) elute ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.72 (s, 1H), 8.70 (s, 1H), 8.18 (s, 1H), 7.28-7.24 (m, 1H), 7.07-7.05 (m, 2H) , 6.96-6.93 (m, 2H), 6.80-6.76 (m, 1H), 6.70-6.67 (m, 1H), 6.08 (s, OH ), 5.59 (d, J = 14.5 Hz, 1H), 5.15 (d , J = 14.5 Hz, 1H), 3.15 (t, J = 7.0 Hz, 2H), 3.05 (t, J = 7.0 Hz, 2H). HPLC: 88.8%. MS (ESI): m/z 447 [M+H] ⁺ .

Example 22

2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-fluorophenethyl)pyridinium -2-yl)-3-( 2H -tetrazol-2-yl)propan-2-ol (53)

10% Pd/C (6 mg) was added to a stirred solution of 51 (30 mg, 0.063 mmol) EtOAc (10 mL), and the mixture was stirred at room temperature under H ₂ atmosphere (balloon pressure) for 2 h. After consumption of the starting material (via TLC assay), the reaction mixture was filtered through Celite ^® filler, washed with EtOAc (3 × 10mL). The filtrate was concentrated under reduced pressure to give a brown brown solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.69 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 7.29-7.27 (m, 1H), 7.09-7.07 (m, 2H) , 6.97-6.93 (m, 2H), 6.80-6.76 (m, 1H), 6.69-6.66 (m, 1H), 5.95 (d, J = 14.5 Hz, 1H), 5.34 (d, J = 14.5 Hz, 1H ), 5.32 (s, OH ), 3.15 (t, J = 7.5 Hz, 2H), 3.05 (t, J = 7.5 Hz, 2H). HPLC: 91.7%. MS (ESI): m/z 447 [M+H] ⁺ .

Example 23

2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(6-(trifluoromethoxy)quinaquine Phenan-2-yl)propan-2-ol (54)

10% Pd/C (1.2 g) was added to a stirred solution of 2-nitro-5-(trifluoromethoxy)aniline (5.0 g, 22.5 mmol) in EtOH (50 mL). The resulting reaction mixture was stirred at RT and H ₂ gas mask 16h. After consumption of the starting material (via TLC assay), the reaction mixture was filtered through Celite ^® filler, washed with EtOAc (3 × 50mL). The filtrate was concentrated under reduced pressure to give crystals of compound AW (4.0 g, 20.83 mmol, 93%). ¹ H NMR (500 MHz, DMSO- d ₆ ): δ 6.50-6.45 (m, 2H), 6.29 (d, J = 8.0 Hz, 1H), 4.76-4.75 (br s, 4H). MS (ESI): m/z 194 [M+2] ⁺ .

At 0 ℃, 2-oxo acetic acid (2.3mL, 20.83 mmol) in CH containing compound AW (4.0g, 20.83mmol) of ₃ OH (40mL) was stirred solution. The resulting reaction mixture was allowed to warm to RT and stirred for 24 h. After consumption of the starting material (via TLC assay), the reaction mixture using H ₂ O (50mL) was diluted and stirred 5 min. The precipitated solid was filtered off, washed with _{H 2 O (3 × 50mL)} . The crude solid was purified using EtOAc EtOAc (EtOAc) elute ¹ H NMR (500 MHz, DMSO- d ₆ ): δ 12.6 (br s, 1H), 8.25 (s, 1H), 7.78 (s, 1H), 7.60 (d, J = 7.0 Hz, 1H), 7.04 ( d, J = 8.5 Hz, 1H). MS (ESI): m/z 230 [M+H] ⁺ .

POBr ₃ (2.1 g, 7.34 mmol) was added to compound AX (0.85 g, 3.69 mmol) at room temperature. The reaction mixture was gradually heated to 130 ° C and stirred for 2 h. After complete consumption of the starting material (via TLC assay), cool the reaction mixture to room temperature, diluted with ice-cold H ₂ O (30mL), saturated NaHCO ₃ solution (25mL) was made basic (pH ~ 8), extracted with EtOAc (2 x 50 mL) extraction. The combined organic extracts were washed with H ₂ O (50mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (2% EtOAc / EtOAc) elute ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.89 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.94 (s, 1H), 7.65 (dd, J = 9.0, 2.0 Hz, 1H ). MS (ESI): m / z 295.9 [M + 2] +.

2-Bromo-2,2-difluoroacetic acid ethyl ester (0.9 g, 4.45 mmol) was added to a stirred mixture of EtOAc (EtOAc) Compound AY (0.65 g, 2.22 mmol) was added <RTI ID=0.0> After complete consumption of the starting material (via TLC assay), the reaction mixture with saturated NH ₄ Cl solution (100 mL) quenched, extracted with EtOAc (3 × 30mL). The combined organic extracts were washed with H ₂ O (50mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (2% EtOAc / hexanes) elute ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.26 (s, 1H), 8.21. (d, J = 9.5 Hz, 1H), 8.02 (s, 1H), 7.71 (d, J = 9.5 Hz, 1H), 4.42 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H).

Add n- BuLi (1.6 M hexane solution; 1.5 mL, 2.45) to a stirred solution of 1-bromo-2,4-difluorobenzene (0.27 mL, 2.45 mmol) in Et ₂ O (5 mL). Methyl), the mixture was stirred under inert atmosphere for 30 min. A solution of the ester AZ (0.55 g, 1.63 mmol) in THF (5 mL). After complete consumption of the starting material (via TLC assay), the reaction mixture with saturated NH ₄ Cl solution (50mL) quenched to EtOAc (2 × 25mL) and extracted. The combined organic extracts were washed using H ₂ O (25mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography on EtOAc (EtOAc EtOAc) elute ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.34 (s, 1H), 8.12-8.11 (m, 2H), 8.03 (s, 1H), 7.67-7.65 (m, 1H), 7.07-7.05 (m, 1H), 6.83-6.79 (m, 1H). MS (ESI): 405 [M+H] ⁺ .

Freshly prepared diazomethane was added to a stirred solution of ketone BA (0.4 g, 0.99 mmol) in Et ₂ O (15 mL) at 0 ° C. [M. A 1:1 mixture of % KOH solution (40 mL) and Et ₂ O (40 mL) was then layered and the organic layer was dried using KOH pellets and stirred for 30 min. The resulting reaction mixture was allowed to warm to RT and stirring was continued for a further 4 h. After the starting material was completely consumed (determined by TLC), the volatiles were evaporated under reduced pressure. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.02 (s, 1H), 8.22 (d, J = 9.5 Hz, 1H), 8.00 (s, 1H), 7.70 (dd, J = 9.5, 2.5 Hz, 1H ), 7.46-7.43 (m, 1H), 6.89-6.85 (m, 1H), 6.78-6.74 (m, 1H), 3.46 (d, J = 5.0 Hz, 1H), 3.03 (d, J = 5.0 Hz, 1H). MS (ESI): 419 [M+H] ⁺ .

The sodium salt of tetrazolium (95 mg, 1.03 mmol) was added to a stirred solution of EtOAc EtOAc (EtOAc: EtOAc. The resulting reaction mixture was gradually heated to 65 ° C and stirred for 16 hours. After complete consumption of the starting material (via TLC assay), the reaction mixture was ice-cold H ₂ O (30mL) was diluted in EtOAc (2 × 25mL) and extracted. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) _{^{1 H NMR (500MHz, CDCl 3}} ): δ 9.04 (s, 1H), 8.72 (s, 1H), 8.13 (d, J = 9.5 Hz, 1H), 8.00 (s, 1H), 7.73 (dd, J = 9.5, 2.0 Hz, 1H), 7.30-7.28 (m, 1H), 6.80-6.78 (m, 1H), 6.69-6.68 (m, 1H), 5.73 (d, J = 14.5 Hz, 1H), 5.67 (s) , OH ), 5.21 (d, J = 14.5 Hz, 1H). HPLC: 98.3%. MS (ESI): m/z 495 [M+H] ⁺ .

Compound 55 in Table 1 was prepared under the same conditions as Compound 54 from the starting material or the intermediate prepared from the product (shown in Table 1).

Example 24

2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(6-(4-(trifluoromethyl)phenyl) )despair -3-yl)propan-2-ol (56)

At room temperature, in the presence of 3,6-dibromofluorene (200 mg, 0.84 mmol) and a solution of 4-(trifluoromethyl)phenylboronic acid (159.7 mg, 0.84 mmol) in 1,2-dimethoxyethane (DME; 12 mL), 1 M sodium carbonate (Na) ₂ CO ₃ ; 1.2 mL, 1.26 mmol), the mixture was flushed with argon for 30 min. (Triphenylphosphine)palladium(0) (Pd(PPh ₃ ) ₄ ; 29.1 mg, 0.025 mmol) was added to the obtained mixture, and the mixture was then evaporated to room temperature for 5 min. The reaction mixture was stirred at reflux for 18 h. After complete consumption of the starting material (via TLC assay), cool the reaction mixture to room temperature, diluted with H ₂ O (50mL) used in EtOAc (2 × 50mL) and extracted. The combined organic extracts were washed using H ₂ O (40mL) and brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by hydrazine column chromatography (dissolved in 12% EtOAc / hexanes) afforded EtOAc (150 mg, mp. 2:1). (Note: Both compounds eluted at the same R _f ; all characteristic protons appeared in the ¹ H NMR spectrum). MS (ESI): 303 [M+H] ⁺ .

Ethyl 2-bromo-2,2-difluoroacetate (1.2 g, 5.92 mmol) was added to a stirred suspension of copper powder (0.75 g, 11.81 mmol) in DMSO (3 mL). . A solution of compound BC (0.9 g, mixture) in DMSO (7 mL) was added to the reaction mixture and stirring was continued at room temperature for 18 h. After completion of the reaction (after TLC assay), the reaction mixture with saturated NH ₄ Cl solution (100 mL) quenched, extracted with EtOAc (2 × 200mL). The combined organic extracts were washed with H ₂ O (50mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by hydrazine column chromatography (solvent eluting 15% EtOAc / hexanes) to afford crude product BD (0.7 g, as mixture) which was used in the next step without purification. (Note: all characteristic protons appear in the ¹ H NMR spectrum). LC-MS: 347.8 [M+H] ⁺ , 4.49 RT (purity 73.75%).

Add n- BuLi (1.6 M hexane solution; 0.27 mL, 0.43 mmol) to a stirred solution of 1-bromo-2,4-difluorobenzene (83.67 mg, 0.43 mmol) in THF (5 mL). And stirred under inert atmosphere for 1 h. A solution of the ester BD (100 mg, crude material) in THF (3 mL) The progress of the reaction was tracked by TLC. The reaction uses satd NH ₄ Cl solution (50mL) quenched, extracted with EtOAc (2 × 50mL). The combined organic extracts were washed with brine solution used in H ₂ O (50mL) and (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a ketone BE (100mg, crude). The mixture was used in the next step without purification. (Note: all characteristic protons appear in the ¹ H NMR spectrum). MS (ESI): 415 [M+H] ⁺ .

The freshly prepared diazomethane was added to a stirred solution of ketone BE (100 mg, crude product) in Et ₂ O (20 mL) at 0 ° C. The method was obtained by dissolving NMU (240 mg, 2.41 mmol) at 0 °C. A 1:1 mixture of % KOH solution (40 mL) and Et ₂ O (40 mL) was then layered, the organic layer was dried using KOH pellets, and the mixture was stirred for 1 h. The resulting reaction mixture was allowed to warm to RT and stirring was continued for a further 5 h. The progress of the reaction was tracked by TLC. The reaction mixture was concentrated under reduced pressure to give BF (60mg, crude). The resulting crude product mixture was used in the next step without purification. (Note: all characteristic protons appear in the ¹ H NMR spectrum). MS (ESI): 429.9 [M+H] ⁺ .

K ₂ CO _{3 was} added after adding 1 H -tetrazole (19.25 mg, 0.27 mmol) to a stirred solution of epoxide BF (60 mg, crude) in anhydrous DMF (4 mL). (19.25 mg, 0.14 mmol). The resulting reaction mixture was gradually heated to 65 ° C and stirred for 20 h. The progress of the reaction was tracked by TLC. The reaction mixture ₂ O (50mL) diluted with ice-H, extracted with EtOAc (2 x 50mL). The combined organic extracts were washed with H ₂ O (50mL) and brine (50mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified via preparative TLC (in 40% EtOAc / hexanes eluting; R _f = 0.2), generating 56 (11.5mg, 0.02mmol) of a colorless semisolid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.80 (s, 1H), 8.19-8.17 (m, 2H), 8.1 (d, J = 8.5 Hz, 1H), 7.83-7.81 (m, 3H), 7.41 - 7.37 (m, 1H), 6.80-6.68 (m, 3H), 5.70 (d, J = 14.5 Hz, 1H), 5.28 (d, J = 14.5 Hz, 1H). HPLC: 97.6%. MS (ESI): m / z 499.4 [M + H] +.

Compounds 57 and 58 in Table 1 were prepared from the starting materials obtained from the commercial product (shown in Table 1) under the same conditions as Compound 56.

Example 25

2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(6-vinylquin Phenan-2-yl)propan-2-ol (59)

At room temperature, in 6-bromoquine POBr ₃ (2.54 g, 8.88 mmol) was added to oxaline-2( 1H )-one (1.0 g, 4.44 mmol). The reaction mixture was gradually heated to 130 ° C and stirred for 2 h. After complete consumption of the starting material (via TLC assay), the reaction mixture was cooled to room temperature, neutralized with saturated NaHCO ₃ solution at 0 deg.] C, in EtOAc (2 × 100mL) and extracted. The combined organic extracts were washed using H ₂ O (100mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (10% EtOAc / EtOAc) elute ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.84 (s, 1H), 8.30 (d, J = 9.0 Hz, 1H), 7.96-7.82 (m, 2H).

Ethyl 2-bromo-2,2-difluoroacetate (1.23 g, 6.09 mmol) was added to a stirred suspension of copper powder (0.77 g, 12.1 mmol) in DMSO (15 mL). 1 h. A solution of compound BG (0.85 g, 3.04 mmol) in EtOAc (5 mL) was then evaporated. After complete consumption of the starting material (via TLC assay), the reaction mixture with saturated NH ₄ Cl solution (50mL) quenched to EtOAc (2 × 25mL) and extracted. The combined organic extracts were washed with H ₂ O (50mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (20% EtOAc / EtOAc) elute ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.22 (s, 1H), 8.34 (dd, J = 8.0, 1.5 Hz, 1H). 8.02-7.94 (m, 2H), 4.40 (q, J = 7.0 Hz , 2H), 1.36 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 332 [M+H] ⁺ .

Add n- BuLi (1.6 M hexane solution; 0.1 mL, 1.66) to a stirred solution of 1-bromo-2,4-difluorobenzene (0.32 g, 1.66 mmol) in Et ₂ O (30 mL). (mmol), the reaction mixture was stirred under inert atmosphere for 30 min. Et ester containing added BH (0.55g, 1.66mmol) of ₂ O (10mL) solution was added to the reaction mixture of -78 deg.] C, and stirring was continued for 5 min. After complete consumption of the starting material (via TLC assay), the reaction mixture with saturated NH ₄ Cl solution (50mL) quenched to EtOAc (2 × 25mL) and extracted. The combined organic extracts were washed using H ₂ O (25mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (20% EtOAc / EtOAc) elute ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.31 (s, 1H), 8.40 (s, 1H), 8.22-7.88 (m, 3H), 7.10-6.92 (m, 1H), 6.83-6.78 (m, 1H). MS (ESI): m/z 400 [M+H] ⁺ .

Freshly prepared diazomethane was added to a stirred solution of ketone-containing BI (0.59 g, 1.46 mmol) in Et ₂ O (10 mL) at 0 ° C. [M. A 10% KOH solution (20 mL) was mixed with Et ₂ O (20 mL) in 1:1, then layered, and the organic layer was dehydrated using KOH pellets. The mixture was stirred for 30 min. The resulting reaction mixture was allowed to warm to RT and stirring was continued for a further 4 h. After the starting material was completely consumed (determined by TLC), the reaction mixture was concentrated under reduced pressure to give crude material. Purification by column chromatography (10% EtOAc / hexanes) eluted ¹ H NMR (500 MHz, CDCl 3 ): δ 8.99 (s, 1H), 8.18 (s, 1H), 8.10-8.05 (m, 1H), 7.96-7.85 (m, 1H), 7.49-7.41 (m, 1H) ), 6.88-6.82 (m, 1H), 6.79-6.75 (m, 1H), 3.46 (d, J = 5.0 Hz, 1H), 3.03 (d, J = 5.0 Hz, 1H). MS (ESI): m/z 414 [M+H] ⁺ .

The compound BJ (0.32 g, 0.72 mmol) and tetravinyltin (0.115 g, 0.72 mmol) were taken at room temperature. The alkane (20 mL) stirred solution was degassed by inert gas purge for 10 min. Pd(PPh ₃ ) ₄ (0.08 g, 0.073 mmol) was added to the reaction mixture, and the mixture was degassed at room temperature for 10 min. The reaction mixture was stirred at 70 ° C for 3 h. After complete consumption of the starting material (via TLC assay), the reaction mixture was cooled to room temperature, filtered through Celite ^® pad and the filtrate was concentrated under reduced pressure to give the crude product. Purification by column chromatography on EtOAc (EtOAc EtOAc) elute This material still contained a small amount of tin impurities and was used in the next step without further purification. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.95 (s, 1H), 8.11-8.09 (m, 2H), 8.10 (d, J = 9.5 Hz, 1H), 7.99-7.97 (m, 1H), 7.45- 7.43 (m, 1H), 6.87-6.84 (m, 1H), 6.77-6.74 (m, 1H), 6.04 (d, J = 17.5 Hz, 1H), 5.55 (d, J = 11.5 Hz, 1H), 3.46 (d, J = 5.0 Hz, 1H), 3.03 (d, J = 5.0 Hz, 1H). MS (ESI): m/z 381 [M+H] ⁺ .

After adding 1 H -tetrazole (43 mg, 0.61 mmol) to a stirred solution of epoxide BK (150 mg, 0.41 mmol) in anhydrous DMF (10 mL) at room temperature under inert atmosphere, K ₂ CO ₃ ( 57 mg, 0.41 mmol). The resulting reaction mixture was gradually heated to 65 ° C and stirred for 16 hours. After complete consumption of the starting material (via TLC assay), the reaction mixture was ice-cold H ₂ O (30mL) was diluted in EtOAc (2 × 30mL) and extracted. The organic extracts were combined using H ₂ O (30mL) and washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography (40% EtOAc / EtOAc) elute ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.98 (s, 1H), 8.74 (s, 1H), 8.06 (s, 1H), 8.02 (d, J = 9.5 Hz, 2H), 7.31-7.29 (m) , 1H), 6.96-6.93 (m, 1H), 6.80-6.76 (m, 1H), 6.65-6.63 (m, 1H), 6.22 (s, 1H), 6.06 (d, J = 17.5 Hz, 1H), 5.71 (d, J = 14.5 Hz, 1H), 5.60 (d, J = 11 Hz, 1H) 5.21 (d, J = 14.5 Hz, 1H). HPLC: 94%. MS (ESI): m/z 431 [M+H] ⁺ .

Example 26

2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(4'-(2,2,2-trifluoroethyl) Oxy)biphenyl-4-yl)propan-2-ol (60)

Ethyl 2-bromo-2,2-difluoroacetate (1.8 mL, 14.13 mmol) was added to a suspension of copper powder (1.8 g, 28.3 mmol) in DMSO (20 mL). The mixture was stirred for 1 h. 1-Bromo-4-iodobenzene (2.0 g, 7.07 mmol) was added to the obtained solution, and stirred at room temperature for 10 h. After complete consumption of the starting material (via TLC assay), the reaction mixture with saturated NH ₄ Cl solution (30mL) suspension of the reaction, _{CH 2 Cl 2 (3 × 50mL} ) and extracted. The organic extracts were combined using H ₂ O (30mL) and washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by hydrazine column chromatography (solvent eluting with 2.5% EtOAc / hexanes) ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.59 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 9.0 Hz, 2H), 4.30 (q, J = 7.0 Hz, 2H), 1.30 ( t, J = 7.0 Hz, 3H).

Add n- BuLi (1.6 M hexane solution; 1.1 mL, 1.79) to a stirred solution of 1-bromo-2,4-difluorobenzene (0.2 mL, 1.79 mmol) in Et ₂ O (5 mL). Methyl), the mixture was stirred under inert atmosphere for 30 min. Add ester-containing BL (500mg, 1.79mmol) of Et ₂ O (5mL) solution was added to the reaction mixture of -78 deg.] C, and stirring was continued for 2 h. After the starting material was completely consumed (as determined by TLC), the reaction mixture was quenched with saturated NH ₄ Cl solution and extracted with CH ₂ Cl ₂ (2×50 mL). The organic extracts were combined using H ₂ O (30mL) and washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification by column chromatography on EtOAc (EtOAc EtOAc) elute ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.85-7.80 (m, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 6.99-6.96 (m) , 1H), 6.89-6.85 (m, 1H).

Freshly prepared diazomethane was added to a stirred solution of ketone BM (1.7 g, 4.91 mmol) in Et ₂ O (15 mL) at -5 ° C [N.sub.2 (2.5 g, 24.56 mmol) dissolved in 0 ° C A 10% KOH solution (25 mL) was mixed with Et ₂ O (25 mL) in a 1:1 mixture, then layered, and the organic layer was dehydrated using KOH pellets. The mixture was stirred for 2 h. The resulting reaction mixture was allowed to warm to RT and stirring was continued for a further 16 h. The progress of the reaction was followed by TLC. The reaction mixture was concentrated under reduced pressure to give a crude material. Purification by column chromatography on silica gel eluting with EtOAc / EtOAc (EtOAc) ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.55-7.51 (m, 2H), 7.29-7.21 (m, 3H), 7.86-6.71 (m, 2H), 3.25 (d, J = 5.0 Hz, 1H) , 2.97-2.91 (m, 1H).

Add Na ₂ CO ₃ (90 mg, in a stirred solution of THF-H ₂ O (15 mL, 8:2 v/v ) containing epoxide BN (100 mg, 0.33 mmol) at room temperature under inert atmosphere. 0.83 mmol) with borate IF (120 mg, 0.33 mmol). After 10 min of nitrogen purge, Pd(dppf) ₂ Cl ₂ (68 mg, 0.083 mmol) was added to the reaction mixture under inert atmosphere, and the mixture was stirred at 70 ° C for 4 h. Let the reaction mixture was cooled to RT, diluted with H ₂ O (15mL), in EtOAc (2 × 50mL) extraction. The combined organic extracts were washed using H ₂ O (20mL) and brine (20mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (200 MHz, CDCl ₃ ): δ 7.62-7.43 (m, 5H), 7.28-7.22 (m, 3H), 7.04-7.00 (m, 1H), 6.84-6.76 (m, 2H), 4.40 ( q, J = 8.0 Hz, 2H), 3.28 (dd, J = 5.6, 2.0 Hz, 1H), 2.95-2.92 (m, 1H). MS (ESI): m / z 455 [MH] -.

At room temperature and under an inert gas mask, was added with stirring in anhydrous DMF 1 H-containing epoxide BO (120mg, 0.26 mmol) of (5mL) - after tetrazole (28mg, 0.39mmol), was added K ₂ CO ₃ ( 73 mg, 0.52 mmol). The resulting reaction mixture was gradually heated to 65 ° C and stirred for 8 h; the progress of the reaction was followed by TLC. The reaction mixture was diluted with ice-H ₂ O using, extracted with EtOAc (3 × 20mL). The separated organic layer was washed with H ₂ O (50mL) and brine (50mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by EtOAc EtOAc EtOAc (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.65 (s, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 7.5 Hz, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.17-7.12 (m, 1H), 7.07-7.01 (m, 3H), 6.78-6.75 (m, 1H), 6.68-6.66 (m, 1H), 5.70 (d, J = 14.5 Hz, 1H), 5.07 (d, J = 14.5 Hz, 1H), 4.42-4.37 (q, J = 8.0 Hz, 2H). MS (ESI): m/z 527 [M+H] ⁺ .

The compound 61 in Table 1 was prepared from the starting material obtained from the product (shown in Table 1) under the same conditions as the compound 60.

HPLC Method A Description

Column: Aquity BEH C-18 (50 × 2.1mm, 1.7 μ)

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

Flow rate: 0.50mL/min

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

Example 27: Metalloenzyme activity A. Minimum inhibitory concentration (MIC) (C. albicans )

Using standard processes (CLSI M27-A2) analysis of the compounds of this invention inhibit the common fungus Candida albicans (C. albicans) the ability to grow.

The mother solution of the test compound and the standard was made in DMSO to make 1,600 μg/mL (C. albicans ). In a 96-well plate, compounds were serially diluted in RPMI + MOPS to give 11 concentrations. Analytical concentrations ranged from 8 to 0.001 μg/mL (Candida albicans). A cell suspension of Candida albicans was prepared and added to each well at a concentration of about 3.7 x 10 ³ colony forming units per ml (cfu/mL). All experiments were performed in duplicate. The inoculated assay plates were incubated at 35 ± 1 ° C for approximately 48 h. At the end of the culture, the fungal growth results of each well of each assay disk were visually observed.

The MIC of fluconazole and the test compound is the concentration at which the growth is significantly reduced (about 50% reduction). The MIC of voriconazole was the concentration at which C. albicans growth was reduced by 50% (measured by CLSI, M27-A2). For quality control, Candida C. krusei isolated strain ATCC 6258 (4.0 x 10 ³ cfu/mL) was included in the VOR assay. This isolated strain did not show a tendency to troiconazole, so the MIC was the concentration at which growth was completely inhibited.

B. Inhibition of hepatic cytochrome P450 enzyme

A solution of each test compound was prepared and serially diluted in DMSO: acetonitrile (MeCN) (50:50 v/v) to prepare concentrations of 20,000, 6000, 2000, 600, 200 and 60 μM. Each test compound solution was further diluted 20 times by DMSO: MeCN: deionized water (5:5:180 v/v/v) to give concentrations of 1000, 300, 100, 30, 10 and 3 μM. Preparation of an isozyme inhibitor mixture containing each inhibitor (sulfaphenazole, tranylcypromine and ketoconazole (ketoconazole) as isozyme 2C9, 2C19 and 3A4 specific inhibitor), diluted in DMSO:CH ₃ CN (50:50 v / v) to obtain concentrations of 6000, 2000, 600, 200, 60, 20, 6 and 2 μM. DMSO: MeCN: 20 times diluted with deionized water (5:5:180 v/v/v) to give concentrations of 300, 100, 30, 10, 3, 1, 0.3 and 0.1 μM. The percentage of organic solvent makes the test compound or The inhibitor mixture was 2% v/v in the final reaction mixture.

Human liver microsome suspension (20 mg/mL) was pooled and diluted in phosphate buffer to give a 5 mg/mL suspension. A solution of 5 mM concentration of NADPH in phosphate buffer was prepared. The mother liquor of each substrate was prepared in DMSO:MeCN (50:50 v/v), mixed, and diluted in phosphate buffer to obtain a single solution containing each substrate, and the concentration was the K _m concentration determined by the experiment. 5 times. The percentage of organic solvent is such that the substrate is 1% v/v in the final reaction mixture.

The substrate and the microsome suspension were combined in a 1:1 volume ratio, mixed, and dispensed into a reaction well of a PCR assay disk. Each test compound or a combination of inhibitor solutions at various concentrations was added to each well and mixed by the action of repeated suction/release cycles. In the active control group, a blank phosphate buffer was added instead of the test compound solution. Allow the reaction mixture to equilibrate at 37 ° C for about 2 minutes, then add NADPH solution to start the reaction, then use the suction The reaction mixture was mixed with a measuring tube. Ten minutes after the addition of NADPH, the reaction of the reaction mixture was quenched with cold acetonitrile. The sample was shaken for about 1 minute using a wraparound mixer and centrifuged at 2900 RCF for 10 minutes. A portion of the supernatant was subjected to gradient reverse phase HPLC and electrospray ionization triple quadrupole mass spectrometer was used to detect and analyze in a cationic mode.

The data to the S-shaped dose - response curves, inhibition determined by IC ₅₀ value of each test compound's potency.

result

C. Minimum inhibitory concentration (MIC) (Septoria tritici )

The compound of the present invention was assayed for inhibition of the common plant pathogenic fungus Septoria tritici (ATC ) using a microdilution assay based on the "Clinical and Laboratory Standards Institute (CLSI)) for filamentous fungi. 26517) The ability to grow.

The mother solution of the test compound and the standard was made in DMSO to make 6,400 μg/mL. Each mother solution was passed through a medium containing RPMI-1640 (Roswell Park Memorial Institute) containing 3-( N -morpholino)propanesulfonic acid (MOPS) buffer and 2% DMSO. Serial dilutions were made to achieve concentrations ranging from 16 to 0.016 μg/mL (a total of 11 compound concentrations). A 100 μL aliquot of the dilution was added to line 1 (16 μg/mL of compound) to line 11 (0.016 μg/mL of compound) in a 96-well microtiter plate. Repeat this format in the second column of the microtiter plate. Thus each microtiter plate can comprise 11 concentrations of four test compounds or control compounds, each repeated twice. Add 100 μL of RPMI-1640/MOPS/2% DMSO medium to line 12 of the microtiter plate (control group without compound).

Fresh cultures of S. tritici were used to make about 5 x 10 ⁴ colony forming units per ml (cfu/mL) in DMSO-free RPMI/MOPS medium. 100 μL of this solution was added to all 96 wells of the microtiter plate. The final concentration of each test or control compound in 200 μL of RPMI/MOPS medium containing 1% DMSO was from 8 μg/mL to 0.008 μg/mL, and about 2.5×10 ⁴ cfu/mL of A. glabrata. The assay plates were incubated for 7 days without shaking at 22 ° C in the dark. The MIC of each compound was visually observed, and compared with the control group (12th straight), the concentration at which the growth of the wheat sclerotium was reduced by 50% was determined. In each of the examples in Table 3, the classification is as follows:

D. For fungal activity analysis of leaf rust (pathogenic source is Puccinia recondita tritici = Puccinia triticina ; Bayer code PUCCRT).

Wheat seeds (Yuma variety) were grown in a peat matrix pot mix (Metromix) with less soil to form seedlings with fully developed first leaves. Each pot contains 3 to 8 seedlings. The plants were sprayed to the wet using the formulated test compound. The compound was adjusted to 50 ppm in 10% by volume of acetone + 90% by volume of Triton X water (deionized water 99.99% by weight + 0.01% by weight of Triton X100) to give a "proposed test compound". The formulated test compound was applied to the plants using a rotatable sprayer with two spray nozzles in opposite positions to deliver a spray volume of approximately 1500 L/ha. The next day, the leaves were inoculated with an aqueous spore suspension of Puccinia striiformis, and the plants were kept at high humidity overnight, allowing the spores to germinate and infect the leaves. The plants are then transferred to the greenhouse until the untreated control plants develop disease. After 7 to 9 days, the severity of the disease was assessed based on the rate of disease progression. Compounds 4 (-), 9 (+), 11, 13, 18, 21, 25, 26, 27, 28, 32, 34, 37, 38, 39, 42, 43, 48, 51, 52, 56 were selected. 57 and 59, tested against PUCCRT at 50 ppm. Compounds that can control >80% of diseases at 50 ppm include 4(-), 9(+), 11, 13, 18, 21, 25, 26, 27, 28, 32, 34, 37, 38, 39, 42, 43, 48, 52, 56 and 57.

references

The contents of all of the references (including the literature report, the approved patent, the published patent application, and the patent application in the same application), which is hereby incorporated by reference in its entirety herein in its entirety herein in its entirety in its entirety herein

Equivalent

Many equivalents to the specific embodiments of the invention described herein will be apparent to those skilled in the art. These equivalents are included in the scope of the following patent application.

Claims (50)

A compound of formula I or a salt thereof, wherein: MBG is a tetrazolyl group which is optionally substituted; R ₁ is a halogen group; R ₂ is a halogen group; and R ₃ is a thienyl group, a thiazolyl group, a quinolyl group, a benzothiazolyl group, and a quinine group. Polinyl, pyridyl Base or 嗒 a group which is optionally substituted by 1, 2 or 3 independent R ₅ ; R ₄ is a phenyl group which is optionally substituted with 0, 1, 2 or 3 independent R ₆ ; each R _{5 is} independently H, Halo, aryl (which may be substituted by 1, 2 or 3 independent R ₆ as desired), heteroaryl, haloalkyl, haloalkoxy, cyano, nitro, alkyl, alkoxy, alkene , haloalkenyl, arylalkenyl, alkynyl, haloalkynyl, alkylaryl, arylalkynyl, arylalkyl, cycloalkyl, halocycloalkyl, sulfanyl, SF ₃ , SF _6. SCN, SO ₂ R ₇ , C(O)alkyl, C(O)OH, C(O)Oalkyl; each R _{6 is} independently alkyl, sulfanyl, cyano, haloalkyl, hydroxy , alkoxy, halo, haloalkoxy, -C (O) alkyl, -C (O) OH, -C (O) O _{-alkyl, SF 3, SF 6, SCN} , SO 3 H; and SO ₂ R ₇ ; R _{7 is} independently alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R ₈ is H, or optionally substituted with an amine group -C(O) alkyl. The compound of claim 1, or a salt thereof, wherein R ₁ is fluorine. The compound of claim 1, or a salt thereof, wherein R ₂ is fluorine. The compound of claim 1, or a salt thereof, wherein R ₁ and R ₂ are fluorine. The compound of claim 1 or a salt thereof, wherein R ₄ is phenyl, which is optionally substituted with 0, 1, 2 or 3 independent halo groups. The compound of claim 1 or a salt thereof, wherein R ₄ is phenyl, which is optionally substituted with 0, 1, 2 or 3 independent fluorines. The compound of claim 1, or a salt thereof, wherein R ₄ is 2,4-difluorophenyl. The compound of claim 1, or a salt thereof, wherein R ₅ is a halogen group. The compound of claim 1 or a salt thereof, wherein R ₃ is heteroaryl, which is optionally substituted by 1, 2 or 3 independent R ₅ ; at least one R ₅ is halo. The compound of claim 1, or a salt thereof, wherein: R ₁ is fluorine; R ₂ is fluorine; R ₄ is 2,4-difluorophenyl; and R ₃ is thienyl, thiazolyl, quinolin Olinyl, benzothiazolyl, quin Polinyl, pyridyl Base or 嗒 Bases, each of which is optionally substituted by 1, 2 or 3 independent R ₅ . The compound of claim 1 or a salt thereof, wherein: R ₁ is fluorine; R ₂ is fluorine; R ₄ is 2,4-difluorophenyl; and R ₃ is quinolinyl, benzothiazole Base or quin A phenyl group, each of which is optionally substituted by 1, 2 or 3 independent R ₅ . The compound or a salt thereof according to claim 1, wherein: R ₃ is a 2-quinolyl group substituted by 1, 2 or 3 independent R ₅ groups. The compound of claim 1 or a salt thereof, wherein R ₃ is quinolin substituted by 1, 2 or 3 independent R ₅ Alkyl group. The compound or a salt thereof according to claim 1, wherein the compound is one of the following: 1-(5-chlorothien-2-yl)-2-(2,4-difluorophenyl)-1, 1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 1 ); 1-(4-bromothiazol-2-yl)-2-(2,4-difluorobenzene -1,1-difluoro-3-( 1H -tetrazol-1-yl)propan-2-ol ( 2 ); 4-(2-(2-(2,4-difluorophenyl)) -1,1-difluoro-2-hydroxy-3-(1 H -tetrazol-1-yl)propyl)thiazol-4-yl)benzonitrile ( 3 ); 1-(6-chloroquinoline-2 -yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 4 ); 2-(2 ,4-difluorophenyl)-1,1-difluoro-1-(quinolin-2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 5 ); -(Benzo[ d ]thiazol-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-( 1H -tetrazol-1-yl)propan-2- Alcohol ( 6 ); 2-(4-chloro-2-fluorophenyl)-1-(6-chloroquinolin-2-yl)-1,1-difluoro-3-(1 H -tetrazole-1- Propan-2-ol ( 8 ); 1-(6-bromoquinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 9 ); 1-(6-chloroquine Benz-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 10 ); -(6-chlorobenzo[d]thiazol-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl) Propan-2-ol ( 11 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(thiazole-2- Propyl-2-alcohol ( 12 ); 1-(5-bromothien-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H - Tetrazol-1-yl)propan-2-ol ( 13 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)- 1-(Thien-2-yl)propan-2-ol ( 14 ); 1-(6-chloroquinolin-2-yl)-1,1-difluoro-2-(4-methoxyphenyl)- 3-( 1H -tetrazol-1-yl)propan-2-ol ( 15 ); 1-(6-chloroquinolin-2-yl)-2-(2,4-difluorophenyl)-1, 1-difluoro-3-( 2H -tetrazol-2-yl)propan-2-ol ( 16 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-( 6-fluoroquinolin-2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 17 ); 2-(2,4-difluorophenyl)-1,1- Difluoro-3-(1 H -tetrazol-1-yl)-1-(6-(trifluoromethyl)quinolin-2-yl)propan-2-ol ( 18 ); 2-(2,4 -difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(6-(2,2,2-trifluoroethoxy)quinoline-2 - yl) propan-2-ol (19); 1- (6-chloro-2-yl) -1,1-difluoro-2- (2-fluoro-4- (C Methyl) phenyl) -3- (1 H - tetrazol-l-yl) propan-2-ol (20); 2- (2,4-difluorophenyl) -1,1-difluoro-3 -(1 H -tetrazol-1-yl)-1-(6-(trifluoromethoxy)quinolin-2-yl)propan-2-ol ( 21 ); 2-(2-chloro-4- (Trifluoromethyl)phenyl)-1-(6-chloroquinolin-2-yl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 22 1-(6-chloroquinolin-2-yl)-2-(3,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propene- 2-alcohol ( 23 ); 2-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1 H -tetrazol-1-yl)propyl) Quinoline-6-carbonitrile ( 24 ); 1-(6-(difluoromethyl)quinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro- 3-( 1H -tetrazol-1-yl)propan-2-ol ( 25 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-methylquinaline Benz-2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 26 ); 1-(6-bromobenzo[ d ]thiazol-2-yl)-2-( 2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 27 ); 1-(6-chloroquinolin-2-yl )-2-(2,5-difluorophenyl)-1,1-difluoro-3-( 2H -tetrazol-2-yl)propan-2-ol ( 28 ); 1-(5,6 -dichloroquinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 29 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazole-1 -yl)-1-(5-(2,2,2-trifluoroethoxy)quinolin-2-yl)propan-2-ol ( 30 ); 1-(5-chloroquinolin-2-yl) -2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 31 ); 1-(6-chloroquinoline -2-yl)-1,1-difluoro-2-(4-fluorophenyl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 32 ); 2-(4- Chloro-2-fluorophenyl)-1-(6-chloroquine Benz-2-yl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 34 ); 1-(7-chloroisoquinolin-3-yl) -2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 37 ); 1-(6-bromoquine Benz-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol ( 38 ); 1- (5-(4-(difluoromethoxy)phenyl)pyrene -2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 39 ); 1- (5-(4-chlorophenyl)pyridinium 2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 40 ); 2- (2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethyl) Oxy)phenyl)pyr -2-yl)propan-2-ol ( 41 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1- (5-(4-(trifluoromethoxy)phenyl)pyrene -2-yl)propan-2-ol ( 42 ); 1-(5-(4-bromophenyl)pyridinium 2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 43 ); 2- (2,4-difluorophenyl)-1-(5-(3,4-difluorophenyl)pyridinium -2-yl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 44 ); 1,1-difluoro-2-(4-fluorophenyl) )-3-(1 H -tetrazol-1-yl)-1-(5-(4-(trifluoromethoxy)phenyl)pyrene 2-yl)propan-2-ol ( 45 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-fluorophenyl)pyridinium -2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 46 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1- (5-(4-fluorophenyl)pyridinium -2-yl)-3-( 2H -tetrazol-2-yl)propan-2-ol ( 47 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1- (5-(4-methoxyphenyl)pyridyl -2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 48 ); 1-(5-chloropyridyl 2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)propan-2-ol ( 49 ); 2- (2,4-difluorophenyl)-1,1-difluoro-1-(5-((4-fluorophenyl)ethynyl)pyridinium -2-yl)-3-(1 H -tetrazol-1-yl)propan-2-ol ( 50 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1- (5-((4-fluorophenyl)ethynyl)pyridinium -2-yl)-3-( 2H -tetrazol-2-yl)propan-2-ol ( 51 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1- (5-(4-fluorophenethyl)pyridinium -2-yl)-3-( 1H -tetrazol-1-yl)propan-2-ol ( 52 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1- (5-(4-fluorophenethyl)pyridinium -2-yl)-3-( 2H -tetrazol-2-yl)propan-2-ol ( 53 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3- (1 H -tetrazol-1-yl)-1-(6-(trifluoromethoxy)quinaquine Benz-2-yl)propan-2-ol ( 54 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-fluoroquinoline 2-(2- H -tetrazol-1-yl)propan-2-ol ( 55 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3 -(1 H -tetrazol-1-yl)-1-(6-(4-(trifluoromethyl)phenyl)anthracene 3-yl)propan-2-ol ( 56 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1- (6-(4-(trifluoromethoxy)phenyl)anthracene 3-yl)propan-2-ol ( 57 ); 2-(2,4-difluorophenyl)-1,1-difluoro-1-(6-(4-fluorophenyl)fluorene 3-yl)-3-( 1H -tetrazol-1-yl)propan-2-ol ( 58 ); 2-(2,4-difluorophenyl)-1,1-difluoro-3- (1 H -tetrazol-1-yl)-1-(6-vinylquin Phenyl-2-yl)propan-2-ol ( 59 ). The compound or a salt thereof according to any one of claims 1 to 14, wherein the compound achieves affinity with a metalloenzyme by forming one or more of the following chemical interactions or bonds with the metal: σ Bond, covalent bond, coordination covalent bond, ionic bond, π bond, δ bond or feedback bond interaction. The compound or a salt thereof according to any one of claims 1 to 14, wherein the compound is bonded to a metal. The compound or a salt thereof according to any one of claims 1 to 14, wherein the compound is bound to iron, zinc, blood matrix iron, manganese, magnesium, iron sulfide cluster, nickel, molybdenum or copper. The compound or a salt thereof according to any one of claims 1 to 14, wherein the compound inhibits an enzyme selected from the group consisting of a cytochrome P450 family, a histone deacetylase, a matrix metalloproteinase, a phosphodiester Enzyme, cyclooxygenase, carbonic anhydrase and nitric oxide synthase. The compound or a salt thereof according to any one of claims 1 to 14, wherein the compound inhibits an enzyme selected from the group consisting of 4-hydroxyphenylpyruvate dioxygenase, 5-lipoxygenase, Adenosine deaminase, alcohol dehydrogenase, aminopeptidase N, angiotensin converting enzyme, aromatase (CYP19), calcineurin, amine methotrexate synthase, carbonic anhydrase family, children Tea phenol- O -methyltransferase, cyclooxygenase family, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA Aminotransferase, HIF-Amidinosteroid Hydroxylase, Histone Deacetylase Family, HIV Integrase, HIV-1 Reverse Transcriptase, Isoleucine tRNA Ligase, Wool Sterol Demethylase (CYP51), matrix metalloproteinase family, methionine aminopeptidase, neutral endopeptidase, nitric oxide synthase family, phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, acetone Acid iron redox protein oxidoreductase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase Tyrosinase enzyme, xanthine oxidase or urease. The compound or a salt thereof according to any one of claims 1 to 14, wherein the compound inhibits an enzyme selected from the group consisting of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), 17-α-hydroxylase/17,20-decomposing enzyme (CYP17), aldosterone synthase (CYP11B2), aminopeptidase P, anthrax lethal factor, arginase, β-endoguanase , cytochrome P450 2A6, D-Ala D-Ala ligase, dopamine β-hydroxylase, endothelin converting enzyme-1, glutamic acid carboxypeptidase II, glutamine amidyl cyclase, glyoxalase , blood matrix oxidase, HPV/HSV E1 helicase, guanamine 2,3-dioxygenase, leukotriene A4 hydrolase, methionine aminopeptidase 2, peptide demethylase, phosphoric acid Diesterase VII, relaxase, retinoic acid hydroxylase (CYP26), TNF-α converting enzyme (TACE), UDP-(3-O-(R-3-hydroxymyristyl)-N-B Mercaptoglucosamine deacetylase (LpxC), vascular attachment protein-1 (VAP-1) or vitamin D hydroxylase (CYP24). The compound of any one of claims 1 to 14 or A salt thereof, wherein the compound is judged to be bound to a metal. The compound or a salt thereof according to any one of claims 1 to 14, wherein the compound is judged to be bound to iron, zinc, blood matrix iron, manganese, magnesium, iron sulfide cluster, nickel, molybdenum or Copper bonding. The compound or a salt thereof according to any one of claims 1 to 14, wherein the compound is judged to inhibit an enzyme selected from the group consisting of a cytochrome P450 family, a histone deacetylase, a matrix metalloproteinase, Phosphodiesterase, cyclooxygenase, carbonic anhydrase and nitric oxide synthase. The compound or a salt thereof according to any one of claims 1 to 14, wherein the compound is judged to inhibit an enzyme selected from the group consisting of 4-hydroxyphenylpyruvate dioxygenase, 5-lipid Oxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase N, angiotensin converting enzyme, aromatase (CYP19), calcineurin, amine methotrexate synthase, carbonic anhydrase Family, catechol- O -methyltransferase, cyclooxygenase family, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumaric acid Reductase, GABA-Aminotransferase, HIF-Amidoxime Hydroxylase, Histone Deacetylase Family, HIV Integrase, HIV-1 Reverse Transcriptase, Isoleucine tRNA Ligase, Wool Sterol Methylase (CYP51), matrix metalloproteinase family, methionine aminopeptidase, neutral endopeptidase, nitric oxide synthase family, phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, pyruvate iron redox oxidoreductase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CVP5a), thyroid Oxidase, tyrosinase, xanthine oxidase or urease. The compound or a salt thereof according to any one of claims 1 to 14, wherein the compound inhibits (or is judged to be inhibited) lanosterol demethylase (CYP51). The compound or a salt thereof according to any one of claims 1 to 14, wherein the compound is judged to have a range of activity for the target organism. A method of inhibiting the activity of a metalloenzyme, which comprises contacting a compound of any one of claims 1 to 14 or a salt thereof with a metalloenzyme, wherein the contact is in vitro. The method of claim 27, wherein the metalloenzyme comprises a metal atom which is iron, zinc, blood matrix iron, manganese, magnesium, iron sulfide cluster, nickel, molybdenum or copper. The method of claim 27, wherein the metalloenzyme is a member selected from the group consisting of a cytochrome P450 family, a histone deacetylase, a matrix metalloproteinase, a phosphodiesterase, a cyclooxygenase Carbonic anhydrase and nitric oxide synthase. The method of claim 27, wherein the metalloenzyme is lanosterol demethylase (CYP51). The method of claim 27, wherein the metalloenzyme is 4-hydroxyphenylpyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, amino peptide Enzyme N, angiotensin converting enzyme, aromatase (CYP19), calcineurin, amine methotrexate synthase, carbonic anhydrase family, catechol- O -methyltransferase, cyclooxygenase Family, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA-aminotransferase, HIF-amine hydrazide hydroxylation Enzyme, histone deacetylase family, HIV integrase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51), matrix metalloproteinase family, methionine Peptidase, neutral endopeptidase, nitric oxide synthase family, phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, pyruvate iron redox oxidoreductase, renal peptidase, ribose Nucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease or xanthine oxidase. The method of claim 27, wherein the metalloenzyme is 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), 17-α-hydroxylase/17,20 - degrading enzyme (CYP17), aldosterone synthase (CYP11B2), aminopeptidase P, anthrax lethal factor, arginase, β-endosaminolase, cytochrome P450 2A6, D-Ala D-Ala ligase , dopamine β-hydroxylase, endothelin-converting enzyme-1, glutamic acid carboxypeptidase II, branamine sulfhydryl cyclase, glyoxalase, blood matrix oxidase, HPV/HSV E1 helicase, Indoleamine 2,3-dioxygenase, leukotriene A4 hydrolase, methionine aminopeptidase 2, peptide demethylase, phosphodiesterase VII, relaxase, retinoic acid hydroxylase (CYP26), TNF-α converting enzyme (TACE), UDP-(3-O-(R-3-hydroxymyristyl)-N-acetylglucamide deacetylase (LpxC), blood vessels Attached protein-1 (VAP-1) or vitamin D hydroxylase (CYP24). The method of claim 27, wherein the compound of formula I is judged to have a range of activity for the target organism. A compound or a salt thereof for use in claim 1 It is used to manufacture medicines for regulating the activity of metalloenzymes in subjects. A use of a compound according to claim 1 or a salt thereof for the manufacture of a medicament for treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease. Use of a compound according to claim 1 or a salt thereof for the manufacture of a medicament for treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, wherein the subject is determined to be in need of treatment for a metalloenzyme A disease or disease. The use of claim 36, wherein the disease or condition is mediated by any one of the following: 4-hydroxyphenylpyruvate dioxygenase, 5-lipoxygenase, adenosine deamination Enzyme, alcohol dehydrogenase, aminopeptidase N, angiotensin converting enzyme, aromatase (CYP19), calcineurin, amine methotrexate synthase, carbonic anhydrase family, catechol-O -methyltransferase, cyclooxygenase family, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA amine transfer Enzyme, HIF-Amidinosteroid Hydroxylase, Histone Deacetylase Family, HIV Integrase, HIV-1 Reverse Transcriptase, Isoleucine tRNA Ligase, Rum Sterol Demethylase (CYP51), Matrix metalloproteinase family, methionine aminopeptidase, neutral endopeptidase, nitric oxide synthase family, phosphodiesterase III, phosphodiesterase IV, phosphodiesterase V, iron pyruvate iron redox Protein oxidoreductase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase Xanthine oxidase or urease. Use as described in claim 36, wherein the disease or disease The affected line is mediated by either: 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), 17-alpha hydroxylase/17,20-degrading enzyme (CYP17) , aldosterone synthase (CYP11B2), aminopeptidase P, anthrax lethal factor, arginase, β-endoaminase, cytochrome P450 2A6, D-Ala D-Ala ligase, dopamine β-hydroxylation Enzyme, endothelin-converting enzyme-1, glutamic acid carboxypeptidase II, glutamine cyclase, glyoxalase, blood matrix oxidase, HPV/HSV E1 helicase, guanamine 2,3-double Oxygenase, leukotriene A4 hydrolase, methionine aminopeptidase 2, peptide demethylase, phosphodiesterase VII, relaxase, retinoic acid hydroxylase (CYP26), TNF-α transformation Enzyme (TACE), UDP-(3-O-(R-3-hydroxymyristyl)-N-acetylglucosamine deacetylase (LpxC), vascular attachment protein-1 (VAP-1) ) or vitamin D hydroxylase (CYP24). The use according to claim 36, wherein the disease or condition 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. The use of claim 36, wherein the disease or condition is a systemic fungal infection or an onychomycosis. A composition comprising the compound of claim 1 or a salt thereof and an agriculturally acceptable carrier. A method of treating or preventing a fungal disease or a disease in a plant or a plant, which comprises contacting the compound or a salt thereof according to any one of claims 1 to 26 with the plant or seed. A method for treating or preventing fungal growth in plants or plants, The compound or a salt thereof according to any one of claims 1 to 26 is contacted with the plant or seed. A method of inhibiting a microorganism in a plant or on a plant, which comprises contacting the compound or a salt thereof according to any one of claims 1 to 26 with the plant or seed. The composition of claim 41, further comprising an azole fungicide selected from the group consisting of epoxiconazole, tebuconazole, fluquinconazole, and hydrazine ( Flutriafol), metconazole, myclobutanil, cycproconazole, prothioconazole and propiconazole. The composition of claim 41, further comprising a strobilurin fungicide selected from the group consisting of trifloxystrobin, pyraclostrobin, and epothilone ( Orysastrobin), fluoxastrobin and azoxystrobin. A composition comprising the compound of claim 1 or a salt thereof and a pharmaceutically acceptable carrier. The composition of claim 47, which further comprises an additional medical agent. The composition according to claim 47, which further comprises an anticancer agent, an antifungal agent, a cardiovascular agent, an anti-inflammatory agent, a chemotherapeutic agent, an antiangiogenic agent, a cytotoxic agent, an antiproliferative agent, and a metabolic property. Disease agent, ophthalmic disease agent, central nervous system (CNS) disease agent, urology disease Or an additional medical agent for a gastrointestinal agent. A compound or a salt thereof, which is 1-(6-chloroquinolin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazole-1 -yl)propan-2-ol (4).