HK1113060A

HK1113060A - Substituted arylpyrazoles as parasiticidal agents

Info

Publication number: HK1113060A
Application number: HK08108788.1A
Authority: HK
Inventors: Denis Billen; Nathan Anthony Logan Chubb; David Morris Gethin; Kim Thomas Hall; Lee Richard Roberts; Nigel Derek Arthur Walshe
Original assignee: 辉瑞有限公司
Priority date: 2005-06-15
Filing date: 2006-06-06
Publication date: 2008-09-26

Description

Substituted arylpyrazoles as parasiticidal agents

Technical Field

The present invention relates to pyrazole derivatives having parasiticidal properties. The compounds of interest are fluorinated cyclopropylarylpyrazoles, and more particularly, the invention relates to 1-aryl-4-cyclopropylpyrazoles in which at least one fluorine is attached to the cyclopropyl ring.

Background

International patent application publication No. (WO)9824767, European patent application publication No. (EP)933363 and EP957094 describe 4-cyclopropylarylpyrazoles having parasiticidal activity for controlling arthropods.

Disclosure of Invention

The compounds of the prior art do not necessarily have good activity against parasites or long duration of action. Similarly, some parasiticides are only applicable to a narrow range of parasites. It is an object of the present invention to overcome various disadvantages of the prior art compounds or to improve their properties. It is therefore an object of the present invention to provide arylpyrazoles having better antiparasitic activity compared to the compounds of the prior art. As shown by the test results demonstrating its efficacy and efficacy, the compounds of the present invention have a particularly excellent ability to control a wide range of arthropods. More specifically, the compounds of the present invention are significantly more active against fleas than similar prior art compounds.

Another object is to provide compounds with a long duration of action. Most preferably, the compound controls arthropod infestation for a period of at least 28 days. This prolonged duration of action is generally attributed to the prolonged half-life of the compound in the host mammal.

The compounds of the invention should also desirably have improved pharmacokinetic properties, improved safety, improved durability, and improved solubility.

Thus, according to the present invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof:

wherein:

R¹is CF₃、OCF₂H、OCF₃、-SCF₃、-SOCF₃、-SO₂CF₃Or SF₅；

R²Is H, fluorine or C optionally substituted with 1 to 5 halogen atoms independently selected from chlorine and fluorine_1-4An alkyl group;

R³、R⁴、R⁵and R⁶Independently represents H, C optionally substituted with 1 to 5 halogen atoms independently selected from chlorine and fluorine_1-4Alkyl, or chloro or fluoro;

R⁷is chlorine or fluorine;

x is CR⁸Or N, whichIn R⁸Is chlorine or fluorine; and is

R⁹Is NR^aR^b；

R^aSelected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl, C (O) OC_1-6Alkyl and C_1-6Alkanoyl, wherein each of the foregoing groups may include one or more optional substituents, if chemically available, independently selected from halogen, het, phenyl, hydroxy, -C (O) OH, -C (O) OC_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, amino, C_1-6Alkylamino and di-C_1-6An alkylamino group;

R^bselected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_1-6Alkanoyl and C (O) OC_1-6Alkyl, wherein each of the foregoing groups may independently include one or more optional substituents, if chemically available, independently selected from halogen, phenyl, hydroxy, -COOH, -C (O) OC_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, amino, C_1-6Alkylamino and di-C_1-6An alkylamino group;

or R^aAnd R^bTogether with the N atom to which they are attached may form a 3-to 7-membered heterocyclic ring containing one or more additional N, O or S atoms, and wherein the heterocyclic ring may have one or more optional substituents selected from oxo, halogen, het, phenyl, hydroxy, -COOH, -C (O) OC_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, amino, C_1-6Alkylamino and di-C_1-6An alkylamino group; and is

het represents a 4-to 7-membered heterocyclic group which is an aromatic or non-aromatic group and which contains one or more members selected from nitrogenOxygen, sulfur and mixtures thereof, and wherein said heterocycle is optionally substituted, as valence permits, with one or more substituents selected from the group consisting of halogen, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, OC (O) C_1-6Alkyl, C (O) C_1-6Alkyl, C (O) OC_1-6Alkyl and NR^cR^dWherein R is^cAnd R^dIndependently selected from hydrogen, C_1-6Alkyl and C_2-6Alkenyl, wherein each of the foregoing groups may include one or more optional substituents, if chemically available, independently selected from halogen, phenyl, hydroxy, -COOH, C (O) OC_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, amino, C_1-6Alkylamino and di-C_1-6An alkylamino group;

with the proviso that R²、R³、R⁴、R⁵And R⁶At least one of which is fluorine.

In the compounds according to formula (I), C_1-6Haloalkyl or C_1-6Haloalkoxy means C which may be substituted with 1 to 5 independently selected chloro or fluoro groups_1-6Alkyl or C_1-6An alkoxy group. Also, "halogen" means a group selected from fluorine, chlorine, bromine or iodine.

Suitably, R¹Is CF₃Or SF₅Preferably CF₃。

Suitably, R²Is CF₃Or CHF₂Preferably CF₃. In another suitable embodiment, R²Is fluorine.

Suitably, R³、R⁴、R⁵And R⁶Independently represents H or fluorine.

Preferably, R²Is CF₃And R is³、R⁴、R⁵And R⁶Independently represent 2, 3 or 4 fluoro groups, more preferably 2Fluoro group, most preferably R³And R⁴And R⁵And R⁶Represents H.

Also preferably, R²Is CHF₂And R is³、R⁴、R⁵And R⁶Independently represent 2, 3 or 4 fluoro groups, more preferably 2 fluoro groups, most preferably R³And R⁴And R⁵And R⁶Represents H.

Also preferably, R²Is fluorine and R³、R⁴、R⁵And R⁶Independently represent 2, 3 or 4 fluoro groups, more preferably R³And R⁴Are all fluorine, and R⁵And R⁶Represents H, or R³、R⁴、R⁵And R⁶All being fluorine.

X is preferably CR⁸。R⁸More preferably chlorine.

Other preferred compounds are those wherein R is⁷And R⁸The same compound. Most preferably, R⁷And R⁸Are all chlorine.

Suitably, R^aIs C (O) OC_1-6An alkyl group, such as ethyl, propyl or isopropyl, which may be optionally substituted with 1 to 5 fluoro groups, to form, for example, a2, 2, 2-trifluoroethyl group; di-C_1-6Alkylamino groups such as dimethylamino; and het, such as pyrrolidinyl, pyridyl, and imidazolyl. More suitably, R^aIs ethoxycarbonyl, dimethylaminoethoxycarbonyl, 2, 2, 2-trifluoroethoxycarbonyl, isopropyloxycarbonyl, 4-pyridylmethoxycarbonyl, 3-pyridylmethoxycarbonyl, 2-pyridylmethoxycarbonyl, 1H-imidazol-5-ylmethoxycarbonyl or 2-pyrrolidin-1-ylethoxycarbonyl.

Also suitably, R^aIs C_1-6Alkyl, such as methyl, which may be optionally substituted with 1 to 5 fluoro groups to form, for example, trifluoromethyl; c_3-8Cycloalkyl groups such as cyclohexyl; phenyl and het, for example pyridyl, such as 4-pyridyl, piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl. Is more suitably，R^aIs methyl or 4-picolyl.

Also suitably, R^aAnd R^bTogether with the N atom to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or 2-oxo-oxazolidinyl, for example 2-oxo-1, 3-oxazolidin-3-yl, more suitably 2-oxo-1, 3-oxazolidin-3-yl.

Suitably, R^bIs hydrogen.

Preferably or additionally, R⁹Is selected from NH₂；C_1-6Alkoxycarbonylamino optionally substituted on alkoxy by 1 to 5 fluoro, di-C_1-6Alkylamino and het substitution; and C_1-6Alkylamino, optionally consisting of 1 to 5 fluoro groups on the alkyl radical, C_3-8Cycloalkyl, phenyl and het. R⁹Most preferably NH₂。

Preferred individual compounds of the invention are selected from:

5-amino-1- [2, 6-dichloro-4-pentafluorophenylthio ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (1, 2, 2-trifluorocyclopropyl) -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (pentafluorocyclopropyl) -1H-pyrazole-3-carbonitrile;

5-amino-4- (2, 2-dichloro-1-fluorocyclopropyl) -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4-pentafluorosulfanyl ] -4- (pentafluorocyclopropyl) -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4-pentafluorosulfanyl ] -4- (1, 2, 2-trifluorocyclopropyl) -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (difluoromethyl) -2, 2-difluorocyclopropyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (2, 2-difluorocyclopropyl) -1H-pyrazole-3-carbonitrile;

5-amino-4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4-pentafluorophenylthio ] -4- [1- (difluoromethyl) -2, 2-difluorocyclopropyl ] -1H-pyrazole-3-carbonitrile;

5-amino-4- {1- [ chloro (fluoro) methyl ] -2, 2-difluorocyclopropyl } -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (difluoromethyl) -2, 2, 3, 3-tetrafluorocyclopropyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2, 3, 3-tetrafluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile;

1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -5- (methylamino) -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [1- (difluoromethyl) -2, 2, 3, 3-tetrafluorocyclopropyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [1- (difluoromethyl) -2, 2-difluorocyclopropyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (fluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (2, 2-difluoro-1-methylcyclopropyl) -1H-pyrazole-3-carbonitrile;

5-amino-1- {2, 6-dichloro-4- [ (trifluoromethyl) thio ] phenyl } -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile;

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid ethyl ester;

1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -5- (2-oxo-1, 3-oxazolidin-3-yl) -1H-pyrazole-3-carbonitrile;

5-amino-1- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile;

2- (dimethylamino) ethyl 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamate;

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid 2, 2, 2-trifluoroethyl ester;

5-amino-1- {2, 6-dichloro-4- [ (trifluoromethyl) sulfonyl ] phenyl } -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile;

1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -5- [ (pyridin-4-ylmethyl) amino ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (difluoromethoxy) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4-pentafluorophenylthio ] -4- [1- (difluoromethyl) -2, 2, 3, 3-tetrafluorocyclopropyl ] -1H-pyrazole-3-carbonitrile;

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid isopropyl ester;

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid pyridin-4-ylmethyl ester;

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid pyridin-3-ylmethyl ester;

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid pyridin-2-ylmethyl ester;

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid 1H-imidazol-5-ylmethyl ester;

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-t-pyrazol-5-ylcarbamic acid 2-pyrrolidin-1-ylethyl ester; and

5-amino-4- {1- [ chloro (difluoro) methyl ] -2, 2-difluorocyclopropyl } -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carbonitrile; or a pharmaceutically acceptable salt or prodrug thereof.

More preferred individual compounds of the invention are selected from:

(-) -5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile;

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (difluoromethyl) -2, 2, 3, 3-tetrafluorocyclopropyl ] -1H-pyrazole-3-carbonitrile; and

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2, 3, 3-tetrafluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile; or a pharmaceutically acceptable salt or prodrug thereof.

So-called "prodrugs" of the compounds of formula (I) are also within the scope of the present invention. Thus, certain derivatives of the compounds of formula (I) which themselves have little or no pharmacological activity are capable of being converted to compounds of formula (I) having the desired activity when administered in or on the body by, for example, hydrolytic cleavage. These derivatives are referred to as "prodrugs". It is understood that certain compounds of formula (I) may themselves be prodrugs of other compounds of formula (I). Other information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol.14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carrier Drug Design", Pergamon Press, 1987(ed.E B Roche, American Pharmaceutical Association).

Prodrugs of the invention may be made, for example, by substituting the 5-amino substituent on the pyrazole ring in compounds of formula (I) with a specific moiety known to those skilled in the art as a "prodrug moiety" in, for example, H Bundgaard, "Design of prodrugs" (Elsevier, 1985); "Design and application of drugs" Textbook of Drug Design and Discovery, (3)^rdEdition), 2002, 410-; and the references thereto。

Suitable prodrugs may have an N-containing group at the 5-position of the pyrazole ring of formula (I) and are bonded to the ring via the N. The 5-N group may be substituted once or twice. Examples of the substituent include: alkyl amines, aryl amines, amides, ureas, carbamates, cyclic carbamates, imines, enamines, imides, cyclic imides, sulfenamides, and sulfonamides. The hydrocarbon part of these radicals containing C_1-6Alkyl, phenyl, heteroaryl, e.g. pyridyl, C_2-6Alkenyl, and C_3-8A cycloalkyl group; wherein each of the foregoing groups may include one or more optional substituents, if chemically available, independently selected from: halogen, hydroxy, C_1-6Alkyl and C_1-6An alkoxy group.

Further examples of substituent groups according to the preceding examples, as well as examples of other prodrug types, can be found in the aforementioned references.

The prodrug according to the present invention can be easily confirmed by administering to a test animal and collecting the compound of formula (I) in body fluid.

In another aspect, the present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically, veterinary or agriculturally acceptable salt thereof, or a pharmaceutically, veterinary or agriculturally acceptable solvate (including hydrate) of any one of the entities as described below.

One skilled in the art will recognize that sensitive functional groups may need to be protected and deprotected during the synthesis of the compounds of the invention. This can be done by conventional methods such as those described in TW Greene and PGMWuts, "Protective Groups in Organic Synthesis," John Wiley & Sons Inc (1999), and references thereto.

Detailed Description

Thus, the following methods illustrate general synthetic methods that can be used to obtain the compounds of the present invention.

1. The compounds of formula (I) may be prepared by the following steps: cyclopropanation of an alkene of formula (II):

wherein R is¹、R²、R³、R⁴、R⁷And X is as previously defined for formula (I), and R⁹' represents R⁹Or R protected by N⁹Followed by deprotection if necessary. Suitable protection includes imidocarboxamide protection, for example using N, N-dimethyl imidocarboxamide, which may be deprotected under standard conditions. The compounds of formula (II) may be of the carbene type (: CR)⁵R⁶) Reaction of wherein R⁵And R⁶The carbene species may be generated in situ as defined above for formula (I). For example, when R is⁵＝R⁶Where F, a reactive species such as trimethylsilyl difluoro (fluorosulfonyl) acetate (TFDA), with R therein, may be reacted in the presence of sodium fluoride at elevated temperature using an optional nonpolar solvent⁹' represents N-protected R⁹To yield, after deprotection, a product of formula (I). Other specific methods include pyrolysis of suitable organometallic precursors of chloroform, such as aryl trifluoromethyl, trichloromethyl or phenyl (trifluoromethyl) mercury derivatives, treated with a diazoalkane in the presence of a transition metal catalyst and in the absence of a transition metal catalyst, preferably under phase transfer catalysis conditions, followed by pyrolysis of the intermediate pyrazoline, or generated from a thioylid.

Wherein R is obtained from (IV) by a transition metal catalyzed cross-coupling reaction of, for example, a compound of formula (IV) with a suitable vinylating reagent in a suitable solvent, optionally degassed⁹' A compound of formula (II) representing an N-protected group:

wherein X' is bromine or iodine, and R¹、R⁷And X is as defined before for formula (IIa). Suitably, the transition metal is palladium and the vinylating agent is an organotin, organoboronic acid or organozinc derivative. Alternatively, (IV) can be heated in the presence of tetrakis (triphenylphosphine) -palladium (O) and sodium bicarbonate in a suitable solvent under reflux using a suitably substituted alkenylboronic acid. Alternatively, (IV) may be treated with an organozinc compound such as activated zinc (e.g. Rieke zinc) in the presence of a palladium (O) species such as tetrakis (triphenylphosphine) palladium (O) in an aprotic solvent under an inert atmosphere using a suitable bromoalkene such as bromotrifluoroethylene or bromodifluoroethylene at elevated temperature. Alternatively, (IV) can be treated with active zinc (Rieke zinc) in an aprotic solvent to give an organozincate, which can then be cross-coupled to a haloalkene in an aprotic solvent at reflux in the presence of a palladium (II) species such as dichlorobis (triphenylphosphine) palladium (II) and a reducing agent such as diisobutylaluminum hydride.

The compounds of formula (IV) can be used to obtain intermediates of formula (V).

Thus, the desired ketones represented by formula (V) can be produced by treating formula (IV) with a Grignard reagent such as isopropyl magnesium chloride, followed by a chloroalkanoate chloride or anhydride under inert conditions at reduced temperature by warming to room temperature using an aprotic solvent.

Compounds of formula (V) may be used to obtain compounds of formula (II) wherein R³And R⁴Is H, and R⁹Is protected by N. Thus, it is possible to carry out the reaction under inert conditions at reduced temperatureFor example tetrahydrofuran, by treatment with wittig reagent.

Also obtainable from compounds of formula (V) wherein R⁹An N-protected compound of formula (II) by treatment with a haloalkene such as dibromodifluoromethane in the presence of triphenylphosphine and Rieke zinc in an aprotic solvent.

Alternatively, compounds of formula (IV) wherein R may be prepared from compounds of formula (IV) wherein R is an alcohol of appropriate tertiary order, followed by standard chlorination-dehydrochlorination procedures⁹A compound of formula (II) protected with N.

The compounds of formula (VI) wherein R is derived from a compound of formula (VI) wherein R is optionally substituted by two standard bromination/iodination and protection steps, either of which may be preceded by¹、R⁷And X is as defined before for formula (I) to obtain

A compound of formula (IV):

the compounds of formula (VI) can be easily protected, for example as imidocarboxamides, and can then be converted directly into compounds of formula (V) by reaction with reactive anhydrides in nonpolar solvents.

2. The compounds of formula (I) can also be prepared by the following steps: the desired carbene species is generated from a pyrazole-containing precursor and treated with the appropriate alkene. For example, an alkyl metal salt, preferably a lithium salt, of a compound of formula (VII):

wherein Ar is phenyl or naphthyl, any of which may be optionally substituted by C₁To C₄Alkyl radical, C₁To C₄Alkoxy or halogen substituted, and R¹、R²、R⁷、R⁹And X is as previously defined, in the presence of a transition metal catalyst such as rhodium (II) acetate and an alkene of formula (VIII):

wherein R is³、R⁴、R⁵And R⁶As defined before for formula (I), optionally in a suitable solvent such as dichloromethane, optionally under pressure, to give the compound of formula (I).

3. The compounds of formula (I) may be prepared by the Japp-Klingemann reaction. The reaction is described in org. react, 1959, 10, 143-. Additional synthetic steps are often necessary to form 3, 4, 5-trisubstituted pyrazoles with more different 4-substituents. Furthermore, the groups that can be introduced in this way are limited to those derived from the originally introduced 4-substituent. However, we have found a process which can directly produce 3, 4, 5-trisubstituted 1-arylpyrazoles in a reaction involving the coupling of an aryldiazonium species with a suitably substituted precursor having the desired substituent. The desired substituent is introduced simultaneously into the C-4 position in a process which does not involve any rearrangement. Moreover, this reaction directly produces trisubstituted pyrazoles. It can omit the lengthy synthetic procedure and the necessity of performing several treatments of intermediates, and can obtain good yield. A significant advantage of this process is that the C-4 substituent can be added to the original tetra-substituted ethane derivative, which is one of the starting materials, and which reacts with the aryldiazonium species to form the pyrazole. Therefore, it is necessary to control the substitution position on the formed pyrazole ring in this reaction. Furthermore, various 4-substituents can be introduced conveniently and directly.

Thus, wherein R⁹Is NH₂The compound of formula (I) can be prepared in the following mannerPreparation: reacting a compound of formula (IX)

With a compound of formula (X)

Optionally in the presence of an acid, wherein:

R¹to R⁸The above definition of the compounds of formula (I);

l is an activating group; and is

Z is a compatible compensating ion which is capable of compensating,

the L group is then removed.

The compensating ion Z^-May be any suitable counterion commonly found in diazo reactions. Z^-Preferably halogen, HSO₄ ^-Or tetrafluoroborate, and most preferably tetrafluoroborate.

The L group is an electron withdrawing group that can stabilize the anionic intermediate in the process. Thus, L is preferably a group that stabilizes the negative charge on the adjacent carbon atom. The L group must also be removable. L may be removed under basic conditions, for example by alkaline hydrolysis, or may be removed by reduction and/or elimination reactions. This L group is important because it serves to guide the reaction of the diazonium species with the compound of formula (IX) and is then removed in a later stage of the reaction. L is preferably an ester group or COR¹⁰A group. More preferably, L is a group selected from: -S (O)_pR¹¹Wherein p is 1 or 2, (R)¹¹O)₂PO、COOR¹¹and-COR¹⁰Wherein R is¹⁰Selected from: c_1-8Alkyl, di-C_1-8Alkylamino radical, C_1-8Alkylthio radical, C_3-8Cycloalkyl group, (CH)₂)_nPh and (CH)₂)_nHeteroaryl, wherein n ═ 0, 1 or 2, each of which may be optionally substituted on any carbon atom by one or more groups independently selected from: halogen, hydroxy, cyano, nitro, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkanoyl radical, C_1-4Haloalkanoyl group, C_1-4Alkylsulfinyl radical, C_1-4Haloalkylsulfinyl radical, C_1-4Alkylsulfonyl radical, C_1-4Haloalkylsulfonyl group, C_3-8Cycloalkyl and C_3-8A halocycloalkyl group; and R is¹⁰May be hydrogen; and wherein R¹¹Selected from: c_1-8Alkyl radical, C_3-8Cycloalkyl group, (CH)₂)_nPh and (CH)₂)_nHeteroaryl, wherein n ═ 0, 1 or 2, each of which may be optionally substituted on any carbon atom by one or more groups independently selected from: halogen, hydroxy, cyano, nitro, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkanoyl radical, C_1-4Haloalkanoyl group, C_1-4Alkylsulfinyl radical, C_1-4Haloalkylsulfinyl radical, C_1-4Alkylsulfonyl radical, C_1-4Haloalkylsulfonyl group, C_3-8Cycloalkyl and C_3-8A halocycloalkyl group; and R is¹¹May be hydrogen. L is preferably selected from COR¹⁰And COOR¹¹A group of (1). L is most preferably-COOMe or-COOEt.

In some cases, the leaving group L is characterized as indicating that the intermediate formed is in the wrong oxidation state. Thus, if necessary, one or more reaction steps may be added to ensure that the correct oxidation state is achieved before cyclization to form the arylpyrazole.

The foregoing coupling methods may be used to prepare any of the compounds of formula (I). For example, the following schemes 1 and 2 illustrate general procedures suitable for the preparation of 5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile.

Scheme 1

Flow chart 2

Ideally, for the coupling reaction to form the compound of formula (I), the solvent should be a polar solvent that will not react with the diazonium salt or cation or the compound of formula (IX). The reaction may optionally be carried out under mildly acidic conditions.

The diazonium salt of formula (X) may be prepared by conventional methods and may be prepared in situ for further reaction or may be isolated and used in subsequent reaction steps.

Specific examples of compounds of formulae (IX) and (XI) are depicted in schemes 1 and 2. A compound of formula (XI) wherein R²、R³、R⁴、R⁵、R⁶And L is as defined above, further compounds of formula (IX) are similarly obtained, for example by treating a compound of formula (XI) with a source of cyanide ions.

The compound of formula (XI) can be obtained by reducing the compound of formula (XII) and then dehydrating.

For example, the compound of formula (XII) can be prepared by condensation reaction of an alkyl cyanoalkanoate, such as methyl cyanoacetate, with an acid chloride in an aprotic solvent, such as dichloromethane, in the presence of a lewis acid, such as magnesium chloride, and a mild base, such as triethylamine, at reduced temperature.

Alternatively, as shown in scheme 1, the compound of formula (XI) can be obtained by the Knoevenagel condensation reaction of a suitable aldehyde with an alkyl alkanoate such as methyl cyanoacetate.

Effective conditions for the preparation of cyclopropyl substituted compounds using 2, 2-difluoro-2- (fluorosulfonyl) acetic acid trimethylsilanyl ester (TFDA) (difluorocarbene source) are described by Dolbier et al in j.fluoro chem., 2004, 125, 459.

The compound of formula (VI) can also be synthesized by using the compound of formula (XIII) in a jap-kringle reaction by reacting with the compound of formula (X) under conditions similar to those described above.

Wherein L ═ CO₂C₁To C₆The synthesis of alkyl compounds of formula (XIII) is as follows: slowly adding glycolonitrile to cyanoacetic acid C, optionally at reduced temperature, in an aprotic solvent such as dimethylformamide₁To C₆Alkyl ester and then a base such as potassium carbonate is added.

Intermediates of formula (VIII), (XI) and (XII) can also be obtained from readily available starting materials by methods analogous to schemes 1 and 2 or by using conventional synthetic procedures according to standard textbooks on organic chemistry or the aforementioned literature, using appropriate reagents and reaction conditions.

4. In another aspect, the invention provides a process for preparing a compound of formula (I) from another compound of formula (I). For example, R can be reacted from⁹Represents NH₂Is prepared from a compound of formula (I) wherein R is⁹＝NR^aR^b(wherein R is^aAnd R^bA compound as defined in formula (I).

Can be derived from compounds of formula (XIV)

Wherein CO is₂R¹¹Represents a suitable ester group, and is converted to an amide (XV) which is subsequently reduced at elevated temperature with phosphorus oxychloride to produce the compound of formula (VI).

The compound of formula (XIV) may be obtained by reaction of a suitable 3-cyano-2-oxo-propanoate, for example ethyl ester, with a suitably substituted hydrazine of compound (XVII) at elevated temperature in an alcoholic solvent, followed by addition of a base, for example sodium carbonate, and further heating.

The compounds of formula (XVII) can be readily obtained using standard conditions, for example by substituting the corresponding fluoro derivative with a hydrazine reagent such as hydrazine monohydrate in an alcoholic solvent such as ethanol at reflux.

Wherein R can be conveniently made according to the following scheme 3²Is CF₃，R³And R⁴Is fluorine, R⁵And R⁶Is hydrogen, and R⁹Is NH₂A compound of formula (I):

flow chart 3

The N protecting group is a suitable acid labile protecting group, such as a dimethylaminocarboxamido group, which can be introduced according to the methods described herein and removed at elevated temperatures in methanol and dioxane under acidic conditions, such as hydrochloric acid. Such transformations are well known to those skilled in the art and are described in part herein in greater detail.

Those skilled in the art will appreciate that there are numerous variations and alternatives to the described methods for obtaining compounds defined by formula (I).

It will also be appreciated by those skilled in the art that in the particular methods described, the order of the synthetic steps used may vary and is dependent, inter alia, on the following factors: such as the identity of other functional groups present within a particular matrix, the availability of primary intermediates, and the protecting group strategy to be employed, if any. Obviously, these factors may also influence the choice of reagents suitable for use in the synthetic steps.

The skilled person will appreciate that the compounds of the invention may be prepared by: modifications other than the methods described herein, or methods known in the art, such as the techniques described herein, or using standard textbooks, such as "comprehensive organic Transformations-A guides to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later versions).

It is to be understood that the synthetic transformations disclosed herein are illustrative only and may be performed in a variety of different sequences to enable efficient production of the desired compounds. The skilled chemist can apply his judgment and techniques to use the most efficient reaction sequence to synthesize a particular target compound.

The invention also relates to intermediates of formula (IA):

wherein R is¹To R⁷X and R^aAnd R^bAs defined for the compounds of formula (I), and where applicable to R¹To R⁷The preferred definitions of X and X also apply to formula (IA). For formula (IA), suitable R^a＝R^bIs methyl.

It will be appreciated that the compounds of formula (I) may contain one or more asymmetric carbon atoms and that the compounds of the invention may therefore exist as 2 or more stereoisomers.

The scope of the present invention includes all stereoisomers, such as enantiomers and diastereomers, all geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one isomeric property, and mixtures of one or more thereof. Also included are acid addition or base salts in which the counterion is optically active, such as D-lactate or L-lysine, or racemic, such as DL-tartrate or DL-arginine.

The geometric isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

Conventional techniques for preparing/separating the individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with an optically active compound such as an alcohol, or in the case of compounds of formula (I) containing an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting mixture of diastereomers may be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers may be converted to the corresponding pure enantiomers by methods well known to those skilled in the art.

The chiral compounds of the invention (and chiral precursors thereof) in enantiomerically enriched form can be obtained using chromatography (typically HPLC) on an asymmetric resin with a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0 to 50% (typically 2 to 20% isopropanol), and 0 to 5% of an alkylamine (typically 0.1% diethylamine). The concentration of the eluent provides a concentrated mixture.

Stereoisomeric aggregates can be separated by conventional techniques known to those skilled in the art, see, e.g., E L Eliel, "stereospecificity of Organic Compounds" (Wiley, New York, 1994).

Pharmaceutically, veterinarily and agriculturally acceptable acid addition salts of certain compounds of formula (I) may also be prepared using conventional methods. For example, a solution of the free base may be treated with a suitable acid (neat or in a suitable solvent) and the salt formed isolated by filtration or evaporation of the reaction solvent under reduced pressure. For a review of suitable Salts, see Stahl and Wermuth, "Handbook of pharmaceutical Salts: properties, Selection, and Use (handbook of pharmaceutically acceptable salts: Properties, Selection, and applications) "(Wiley-VCH, Weinheim, Germany, 2002).

The compounds of the present invention may exist in unsolvated as well as solvated forms. The term "solvate" as used herein is a molecular complex that describes a compound comprising the compound of the present invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used.

The compounds of the invention, i.e. the compounds of formula (I), have parasiticidal activity in humans, animals and plants. It is particularly suitable for the treatment of ectoparasites.

For use of the compounds of the invention in mammals, it provides:

a pharmaceutical parasiticidal composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, and a pharmaceutically acceptable diluent or carrier, which is useful for oral, parenteral or topical administration;

a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a composition comprising any of the foregoing, for use as a medicament;

use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any one of the entities, or a composition comprising any one of the foregoing, in the manufacture of a medicament for the treatment of a parasitic infestation; and

a method of treating a parasitic infestation in a mammal, which comprises treating the mammal with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition comprising any of the foregoing.

According to a further aspect of the present invention there is provided a method of controlling arthropod, plant nematode or helminth pests at a locus which comprises treating the locus (e.g. by application or administration) with an effective amount of a compound of formula I or a pesticidally acceptable salt thereof.

The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by an atom having the same atomic order, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in compounds of the invention include hydrogen isotopes, for example²H and³h, carbon, e.g.¹¹C、¹³C and¹⁴c, chlorine, e.g.³⁶Cl, fluorine, such as¹⁸F, iodine, e.g.¹²³I and¹²⁵I，nitrogen, e.g.¹³N and¹⁵n, oxygen, such as¹⁵O、¹⁷O and¹⁸o, phosphorus, e.g.³²P, and sulfur, such as³⁵S。

The compounds of the present invention may also be mixed with one or more of the following biologically active compounds or agents to form multicomponent pesticides with a broader spectrum of pharmaceutical, veterinary or agricultural uses: an insecticide, an acaricide, an insect repellent, a fungicide, a nematicide, an antiprotozoal agent, a bactericide, a growth regulator, an insect-feeding bacterium, an insect-feeding virus, or an insect-feeding fungus. Thus, the present invention also relates to compositions comprising a biologically effective amount of a compound of the invention and an effective amount of at least one other biologically active compound or agent, and may further comprise one or more surfactants, solid diluents or liquid diluents. Specific other active compounds include those described in british patent application No. GB0406137.0, pages 37 to 41.

The following list of biologically active compounds and compounds of the invention which can be used is intended to illustrate the possible combinations and is not intended to be limiting in any way.

For example, the compounds of the present invention may be co-administered or used in combination with an insect repellent. These repellents include compounds selected from the macrocyclic lactone type compounds described in European patents EP-357460, EP-444964 and EP-594291, such as ivermectin (ivermectin), avermectin (avermectin), abamectin (abamectin), isomectin (emamectin), eprinomectin (eprinomectin), doramectin (doramectin), selamectin (selamectin), moxidectin (moxidectin), nemadectin (nemadectin) and milbemycin (milbemycin) derivatives. Further insect repellents include semi-synthetic and biosynthetic avermectin/milbemectin derivatives, such as the insect repellents described in US-5015630, WO-9415944 and WO-9522552. Other insect repellents include benzimidazoles such as albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, and other members of this class. Additional insect repellents include imidazothiazoles and tetrahydropyrimidines, such as tetraimidazole (tetramisole), levamisole (levamisole), pyrantel pamoate (pyrantel pamoate), oxantel (oxantel) or morantel (morantel). Other anthelmintics include trematocides such as triclabendazole (triclabendazole) and clorsulon (clorsulon), and tapecides such as praziquantel (praziquantel) and epsiprantel (epsiprantel).

The compounds of the invention may also be used in combination with derivatives and analogues of the paraherquamide/marcfortine (marcfortine) class of insect repellents, and antiparasitic oxazolines, such as those disclosed in US-5478855, US-4639771 and DE-19520936.

The compounds of the present invention may be co-administered or used in conjunction with derivatives and analogues of the general class of dioxymorpholine antiparasitic agents as described in WO-9615121, as well as anthelmintically active cyclic depsipeptides as described in WO-9611945, WO-9319053, WO-9325543, EP-626375, EP-382173, WO-9419334, EP-382173 and EP-503538.

The compounds of the present invention may be co-administered or used in combination with other ectoparasiticides; for example, fipronil (fipronil); pyrethroids (pyrethioids); an organic phosphate; insect growth regulators, such as octafluorourea (lufenuron); ecdysone agonists such as dibenzohydrazide (tebufenozide) and the like; neonicotinyl insecticides (neonicotinoids), such as imidacloprid (imidacloprid) and the like.

The compounds of the present invention may be co-administered or used in combination with terpene alkaloids, such as agents described in International patent application publication Nos. WO95/19363 or WO04/72086, particularly the compounds disclosed therein.

Other examples of such biologically active compounds include, but are not limited to, the following:

organic phosphates: acephate (acephate), azifop (azamethiphos), ethylglufosinate (azinphos-ethyl), methyl glufosinate, bromophos (bromophos), ethylbromophos (bromophos-ethyl), cathethophos (cadusafos), chlorophenoxyphos (chlorophenoxyphos), chlorfenafos (chlorophenoxy), chlorfenvinphos (chlorophenoxy), fenobucarb (chlorophenoxy), chlormephos (chlorophenoxy), demeton (demeton-S-methyl), demeton-S-methyl, phosphorochloridite (dichlofos), diazinon (diaphenon), dichlorvos (dichlorvos), chlorothos (diaphophos), dimethof (dimethofos), ethophos (dimetophos), ethophos (dimethione), ethophos (ethiophos), ethiophos (diethylphos), fenthiofos (fenthion), fenthion (fenpyrazofos (fenthion), fenthion (fenthion), fenthion (fenthion, Heptenophos (heptanophos), isoxaphos (isazophos), isothionate (isothionate), isoxazolophos (isoxathion), malathion (malathion), crotonofos (methacriphos), methamidophos (methamidophos), methidathion (methamidothion), mephos (mevinphos), monocrotophos (monocrotophos), naled (naled), omethoate (omethoate), demethoxydemeton (oxydemethophos-methyl), paraoxon (paraoxon), parathion (parathion), methylparathion (parathion), fenaminosulf (phenthoate), phosmet (phosalone), phosalone (phos), phosphoric acid (phosphate), phosphoramidite (phosphophosmet), propylthion (propylthion), propylthion (propylthion) (phora), propylthion (propylthion), propylthion (propylthion) (e), propylthion (propylthion) (e), propylthion (propylthion) (methyl-, Temephos (temephos), terbufos (terbufos), tebufenpyrad (tebutirimfos), tetrachlvinphos (tetrachlvinphos), cimetiton (thimeton), triazophos (triazophos), trichlorfon (trichlorfon), and valmiphos (vamidothion).

Carbamate ester: aniranaria (alanycarb), aldicarb (aldicarb), 2-sec-butylbenzene methylcarbamate, benfuracarb, carbaryl (carbaryl), carbafuran (carbafuran), carbasolamide (carbosulfan), cloethocarb, etiofencarb (ethiofencarb), fenoxacarb (fenoxycarb), fenthicarb (fenthiocarb), furacarb (furathiocarb), HCN-801, isoprocarb (isoprocarb), indoxacarb (indoxacarb), methiocarb (methiocarb), methomyl (methomyl), 5-methyl-m-cumenyl butyryl (methyl) carbamate, oxamyl, aphid (pirimicarb), propamocarb (propafenib), thiodicarb (thiodicarb), trimethacarb (51717), and trimethacarb (trifacil).

Pyrethroid: acrinatin (acrinathin), allethrin, alphamethrin (alphamethrin), (E) - (1R) -cis-2, 2-dimethyl-3- (2-oxytetrahydrofuran-3-ylmethyl) cyclopropanecarboxylic acid 5-benzyl-3-furyl methyl ester ((E) - (1R) -cis-2, 2-dimethyl-3- (2-oxothiolan-3-ylidenemethyl) cyclopropanacarbylate), bifenthrin (bifenthrin), beta-cyfluthrin (beta-cyfluthrin), cyfluthrin, alpha-cypermethrin (alpha-cypermethrin), beta-cypermethrin, prallethrin ((S) -cyclopentyl isomer), prallethrin (bioresmethrin), bifenthrin (bifenthrin) NCI-85193, Cyclopropyrin (cycloprothrin), cyhalothrin (cyhalothrin), cyhalothrin (cyththrin), cyphenothrin (cyphenothrin), deltamethrin (deltamethrin), enbenin (empenthrin), esfenvalerate (esfenvalete), isofenpropre (ethofenprox), fenflurrin (fenfluthrin), fenpropathrin (fenpropathrin), fenvalerate (fenvalerate), flucythrin (flucythrin), flusilate (flusethrin), fluthrin (fluvalinate) (D isomer), imipramilin (imiprothrin), gelilin, lambda-geliline, permethrin (permethrin), phenothrin (raphanin), lathhrin (prothrin), pyrethrin (pyrethrin), cyhalothrin (theta), cyhalothrin (fluthrin), cyhalothrin (theta), fluthrin (fluthrin), cyhalothrin (theta).

Arthropod growth regulator: a) chitin synthesis inhibitors: benzoyl urea: chlorofluoroconazole (chloredazuron), diflucortolone (diflubenzuron), fluazuron (fluazuron), flurazuron (fluracycloxuron), flufenuron (flufenoxuron), flufenuron (hexafluron), octaflubenzuron (lufuron), noberon (novaluron), teflubenzuron (tefluxuron), triflumuron (triflumuron), bupirizine (buprofecozin), difenolan (difenolan), hexzox (hexythiazox), etoxazole (etoxazole), clofentrazine (chlozolone); b) an ecdysone antagonist: halofenozide (halofenozide), methoxyfenozide (methoxyfenozide), dibenzhydrazide (tebufenozide); c) youth hormone (juvenoid): piroxifene (pyriproxyfen), methoprene (methoprene), fenoac (fenoxycarb); d) lipid biosynthesis inhibitors: spirodiclofen (spirodiclofen).

Other antiparasitic agents: acetylquinol (acequinocyl), amitraz (amitraz), AKD-1022, ANS-118, azadirachtin (azadirachtin), Bacillus thuringiensis (Bacillus thuringiensis), benzethol (bensultap), Bifenazate (bifenazate), binapacryl (binapacryl), bromopropylate (bromopropyrate), BTG-504, BTG-505, camphyl (camphechlor), Cartefop (caratap), dicofol (chlorobenzilate), acetamiprid (chloroforminid), clorfenozide (chlorofenzidine), cyclomazine (cymazine), diclofen (diclodenuron), dinotefuran (fenuron), dinotefuran (MTfenadine), dinotefuran (dihydrofenate), dinotefuran (dinotefuran), dinotefuran (thion (dinotefuran), dinotefuran (pyridine (thion), dinotefuran (E (thion (E), dinotefuran (thion (thiofuran), dinotefuran (E), dinotefuran (thion (thiofuran), dinotefuran (thion (e), thion (thiofuran), thion (bitone), flufen), flubenazomethine thiazole (flubenzimine), flufenvalerate bromide (flucythrinate), flufen-well (flufenzine), flufenpropril (flufenprox), fluprosifen (fluproxyfen), halofenpuro (halofenprox), hydromethylnon (hydrametylnon), IKI-220, Kenmite (kanemite), NC-196, neem protectant (neem guard), ninofol (nidinorfuran), nintedufuran (nitirfuran), ninted (nitenpyram), SD-35651, WL-108477, pyradifloram (pirydryl), propargite (parafenate), propafenib (protrybute), pyrimethanazine (pymetrozine), pyradifen (pyradifen), pyrifluben (pyridaben), pyrimidine (pyrimidifrin), RH-1111, R-195-RH, tetrapyrifos (fenpropathrin), silicon dioxide-3-1833, S-32, diphenyl urea-6-L-3, diphenyl urea-3 (fenfluridone), diphenyl urea-3, diphenyl urea-L-3, diphenyl urea-3 (fenfluramine), diphenyl urea-3, diphenyl urea-2, diphenyl urea-L-3, diphenyl urea (fenfluridone, diphenyl urea-3, diphenyl urea-2, diphenyl urea-L-2, diphenyl urea (fenfluramine, diphenyl urea, Thiocyclam (thiamethoxam), Thiamethoxan (thiamethoxam), tolfenpyrad (tolfenpyrad), triamazamide (triazamate), triethoxy spinosyn (triamcinolone), trimotoxin (trinactin), boston (verbutin), Potalacre (rotalec), YI-5301.

Fungicides: isazoxazole (acrilenazole), chlorfenapyr (aldimorph), amprophos (ampropylfos), ethopropril (andoprim), azaconazole (azaconazole), azoxystrobin (azoxystrobin), benzoxeloxib (benalaxyl), benomyl (benomyl), bial (bialaphos), blasticidin-S (blasticidin-S), Bordeaux (bordeax) mixture, bromoconazole (bronoumenozole), pyriproxyfen (bupirimate), propionamide (carpropamide), captafol (captofol), captan (captopril), carbendazim (carbendazim), clofenconazole (chlorofenazole), diclofenthiuron (chloroneb), chloroneb (chloroquine), chloroquine (chloroquine), propiconazole (chloroquinconazole), propiconazole (chloroquine), propiconazole (chloroquinconazole (propiconazole), propiconazole (chloroquinconazole), propiconazole (chloroquinconazole), propiconazole (chloroquinconazole), propi, Niclosamide (diclororan), difenoconazole (difenoconazole), RP-407213, dimorpholino (dimethomorph), domotoxin (domoxystron), diniconazole (diniconazole), diniconazole-M, dodine (dodine), edifenphos (edifenphos), epoxyconazole (epoxyconazole), famoxadone (famoxadone), femamiodarone (fennamide), fenbuconazole (fenbuconazole), fencamide (fencamide), fenpropimide (fenpropimide), fenpropinib (fenpropinil), fenpropidin (npropilin), fenpicrimol (fenpropimomoh), fentexine (fentefluzine), flufenamic acid (flufenamide), flufenapyr (flufenapyr), flufenacet (flufenacet), fluquindox (flufenacet), flufenacet (flufenacet), flufenacet (flufenacet), flufenacet (flufenacet, Furamelteon (furametpyr), hexaconazole (hexaconazole), epoconazole (ipconazol), iprobenfos (iprobenfos), isoprotundione (iprodione), iprothioxane (isoprothiolane), kasugamycin (kasugamycin), Methoxomil (kresoxim-methyl), Mancozeb (mancozeb), Maneb (maneb), mefenoxam (mefenoxam), mepronil (mepronil), metalaxyl (metrafoxanyl), miconazole (metconazol), metominostrobin (metominostrobin)/phenformin (fenostrobin), metocloprofenone (metrafenone), myclobutanil (neonostherein), propylbenzene (oxypropoxide), propiconazole (propiconazole), propiconazole (propiconazole), propiconazole) (propiconazole), propiconazole) (propi, Pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, terbuconazole, tertaconazole, thiabendazole, flutolanil, thiophanate-methyl, thiram, tiadinil, triadimefon, triadimenol, tricyclazole, tricyclotriazole, trifloxystron, tritozolon, validamycin, and vingilozole.

Biological preparation: bacillus thuringiensis (aizawai), Coriolus (kurstaki), Bacillus thuringiensis delta endotoxin, baculovirus, insect pathogen (entomophagic) bacteria, viruses and fungi.

A bactericide: chlortetracycline, oxytetracycline, streptomycin.

Suitable combinations according to the invention include compounds of formula (I), more suitably the compounds of the listed formula (I), even more suitably the preferred individual compounds listed hereinbefore, most suitably 5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile, in combination with one or more, preferably one, of the above active compounds, suitably an anthelmintic, for example a compound selected from the class of macrocyclic lactones, for example ivermectin, avermectin, abamectin, isomutane, eprinomectin, doramectin, selamectin, moxidectin and nemadectin, more suitably doramectin or selamectin.

The compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. Can be obtained, for example, as a solid plug, powder or film by, for example, precipitation, crystallization, freeze-drying or spray-drying or evaporation-drying. Microwave or radio frequency drying methods can be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or any combination thereof). In general, they may be administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" as used herein is intended to describe any ingredient other than a compound of the present invention. The choice of such excipients will depend primarily on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the characteristics of the dosage form.

Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. These compositions and their preparation can be found, for example, in Remington's Pharmaceutical Sciences, Remington's, 19 th edition (MackPublishing Company, 1995).

For their use in mammals, the compounds may be administered alone or in a formulation suitable for the particular use intended, the particular species of host mammal to be treated and the parasite involved.

Methods by which the compounds may be administered include oral administration via capsules, pellets, tablets, powders, lozenges, chewable tablets, composite and nanoparticle, gels, solid solutions, films, sprays, or liquid formulations. Liquid forms include suspensions, solutions, syrups, infusions and elixirs. The formulations may be used as fillers in soft or hard capsules and typically comprise a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations can also be made by reconstitution of solids, for example from sachets (sachets). Oral infusions are generally prepared by dissolving or suspending the active ingredient in a suitable medium.

Compositions which can therefore be used for oral administration can be prepared by mixing the active ingredient with suitable differentiating diluents and/or disintegrants and/or binders and/or lubricants and the like. Other possible ingredients include antioxidants, coloring agents, flavoring agents, preservatives, and taste-masking agents.

For oral dosage forms, the drug may constitute from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight, depending on the dosage. Examples of the disintegrator include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with a lower alkyl group, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant is present in an amount of from 1 to 25 weight percent, preferably from 5 to 20 weight percent of the dosage form.

Binders are typically used to give the tablet formulation cohesive properties. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Examples of diluents include lactose (monohydrate, spray dried monohydrate, anhydrate, etc.), mannitol, xylitol, dextrose, glucose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

Oral formulations may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80(polysorbate 80), and glidants such as silicon dioxide and talc. When present, the surfactant is present in an amount of 0.2% to 5% by weight of the tablet and the glidant is present in an amount of 0.2% to 1% by weight of the tablet.

Lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Generally, the lubricant is present in an amount of 0.25 to 10% by weight, preferably 0.5 to 3% by weight of the tablet.

Exemplary tablets contain up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant, and about 0.25% to about 10% lubricant.

Tablet formulations were described in "Pharmaceutical DosageForms" by h.lieberman and l.lachman: tablets (pharmaceutical dosage form: tablet), Vol.1 ", Marcel Dekker, N.Y., N.Y., 1980(ISBN 0-8247-6918-X).

The compounds may be administered topically, i.e. dermally or transdermally, to the skin or mucosa. Typical formulations for this purpose include pour-on (spot-on), drop-on (spot-on), dip (dip), spray, mousse (mousse), shampoo, powder formulation, gel, hydrogel, lotion, solution, emulsion, ointment, dusting powder, dressing, foam, film, skin patch, tablet, implant, sponge, fiber, bandage and microemulsion. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid mineralsFat, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be added-see, e.g., J Pharm Sci by Finnin and Morgan,88(10) 955- "958 (10 months 1999). Pour-on or drop-on formulations can be prepared by dissolving the active ingredient in an acceptable liquid carrier medium (e.g., diethylene glycol butyl ether, liquid paraffin, or a non-volatile ester), optionally with the addition of a volatile component (e.g., propan-2-ol). Alternatively, pour-on, drop-on or spray formulations can be made by encapsulation to leave a residue of the active agent on the animal's surface. Injectable formulations may be prepared in the form of sterile solutions which may contain other substances, for example, salts or glucose sufficient to make the solution isotonic with blood. Acceptable liquid carriers include vegetable oils such as sesame oil, glycerol esters such as triacetin, esters of fatty acid derivatives such as benzyl benzoate, isopropyl myristate and propylene glycol, and organic solvents such as pyrrolidin-2-one and glycerol formal. The formulations are prepared by dissolving or suspending the active ingredient in a liquid vehicle such that the final formulation contains 0.01 to 10% by weight of the active ingredient.

Alternatively, the compounds may be administered parenterally or injected directly into the bloodstream, muscle or internal organs. Suitable modes of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injectors, and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably at a pH of 3 to 9), but for some applications are more suitable for constitution with a sterile nonaqueous solution or for constitution with a powder in dry form to be combined with a suitable vehicle, for example sterile pyrogen-free water. Parenteral formulations are readily prepared under sterile conditions (e.g., by lyophilization) using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of formula (I) for use in preparing parenteral solutions can be increased by using suitable formulation techniques, such as the addition of solubility enhancing agents.

These formulations are prepared in a conventional manner according to standard medical or veterinary practice.

These formulations may vary with respect to the weight of the active compound contained therein, depending on the following factors: the type of host animal to be treated, the severity and type of infection, and the weight of the host. For parenteral, topical and oral administration. Typical dosage ranges for the active ingredient are from 0.01 to 100 mg per kg body weight of the animal. This range is preferably 0.1 to 10 mg per kg body weight.

The formulations can be directly and/or modified for controlled release. Controlled release formulations include delayed-, sustained-, pulsatile-, controlled, targeted, or planned release. For the purposes of the present invention, suitable modified release formulations are described in U.S. Pat. No. 6,106,864. Detailed descriptions of other suitable drug delivery techniques, such as high energy dispersions and osmotic and coated particles, can be found in Pharmaceutical Technology On-line, 25(2), 1-14(2001), Verma et al. The use of chewing gum to achieve controlled release of drugs is described in WO 00/35298. Alternatively, the compounds of the present invention may be formulated as a solid, semi-solid, or thixotropic liquid for use as an implanted reservoir for the active compound that provides modified release. Examples of such formulations include drug-coated stents (stents) and PGLA microspheres.

Alternatively, the compounds may be administered to non-human animals with feed, and for this purpose concentrated feed supplements or premixes suitable for mixing with normal animal feed may be prepared.

The compounds of the present invention are useful for controlling arthropod pests. It is particularly useful in the fields of veterinary medicine, livestock breeding and general health: against arthropods which are parasitic in or on vertebrates, in particular warm-blooded vertebrates, including humans and domestic animals; such as dogs, cats, cattle, sheep, goats, horses, pigs, poultry and fish. And can also be used for controlling plant pests, soil-dwelling pests and other environmental pests.

In addition to general agricultural applications, the liquid compositions of the present invention can be used, for example, to treat substrates or areas infested or susceptible to infestation by arthropods (or other pests controllable by the compounds of the present invention), including buildings, outdoor or indoor storage or processing areas, containers or equipment, or still or running water.

All of these aqueous dispersions or emulsions or spray mixtures can be applied by any suitable method, primarily by spraying, typically at a spray rate of from about 100 to about 1,200 liters of spray mixture per hectare, but can be higher or lower (e.g., low or ultra-low volume) depending on the need or application technique. The compounds or compositions according to the invention can be conveniently applied to plants, in particular to the roots or leaves of the pests to be removed. Another method of application of the compounds or compositions of the invention is by chemigation, i.e. adding a formulation containing the active ingredient to the irrigation water. The irrigation method may be sprinkler irrigation for foliar insecticides or may be soil irrigation or sub-irrigation for soil or systemic insecticides.

Concentrated suspensions, which can be applied by spraying to produce a stable fluid product that does not settle (micro-milling), are prepared and typically contain from about 10 to about 75% by weight of the active ingredient, which is poorly soluble or insoluble, from about 0.5 to about 30% of a surfactant, from about 0.1 to about 10% of a thixotropic agent, from about 0 to about 30% of a suitable additive, such as an antifoaming agent, a corrosion inhibitor, a stabilizer, a penetrant, an adhesive, and an aqueous or organic liquid as a vehicle. Some organic solids or inorganic salts may be dissolved in the vehicle to help avoid settling or to act as antifreeze for water.

Wettable powders (or powders for spraying) are typically prepared so that they contain from about 10 to about 80% by weight of the active ingredient, from about 20 to about 90% of a solid carrier, from about 0 to about 5% of a wetting agent, from about 3 to about 10% of a dispersing agent, and, if necessary, from about 0 to about 80% of one or more stabilizers and/or other additives, such as penetrants, binders, anti-caking agents, colorants, or the like. To obtain these wettable powders, the active ingredient is thoroughly mixed with the other substances which can be injected over the porous filler in a suitable mixer and ground using a mill or other suitable grinder. It can produce wettable powder, and the wettability and suspensibility of said wettable powder have the advantages. It can be suspended in water to give any desired concentration, and the suspension can be used particularly advantageously for application to the leaves of plants.

The "water dispersible granules (WG)" (granules that are readily dispersible in water) have a composition substantially similar to that of a wettable powder. They can be prepared by granulating formulations of the above-mentioned wettable powders by the wet process (contacting the differentiated active ingredient with an inert filler and a small amount of water, for example from 1 to 20% by weight, or with an aqueous solution of a dispersant or binder, followed by drying and sieving), or by the dry process (compacting, followed by grinding and sieving).

The proportion and concentration of the formulated composition may vary depending on the method of application or the nature of the composition or its use. In general, compositions for application to control arthropods, plant nematodes, helminths or protozoa typically contain from about 0.00001 to about 95%, more particularly from about 0.0005 to about 50%, by weight of one or more compounds of formula (I), or pesticidally acceptable salts thereof, or all of the active ingredients (i.e., the compound of formula (I), or pesticidally acceptable salt thereof, as well as other substances toxic to arthropods or plant nematodes, repellents, anticoccidial agents, synergists, trace elements or stabilizers). The actual composition used and the rate of application thereof can be selected by the farmer, livestock owner, physician or veterinarian, pest control operator, or other skilled artisan to achieve the desired effect.

The compounds of the invention can also be used for controlling arthropod pests of plants. The active compounds are usually applied to the locus where arthropod infestation is to be controlled at an application rate of from about 0.005 to about 25 kg of active compound per hectare (ha) of the locus to be treated, preferably from 0.02 to 2 kg/ha. Under ideal conditions, this lower application rate provides suitable protection depending on the pest to be controlled. On the other hand, adverse climatic conditions and other factors may require the use of the active ingredient in higher proportions. For foliar application, application rates of 0.01 to 1kg/ha may be used.

The locus is preferably the surface of the plant or the soil surrounding the plant to be treated.

The compounds of the present invention are particularly important in the control of arthropods which are harmful or transmissible to humans and domestic animals such as the animals hereinbefore described or which act as disease carriers, especially in the control of ticks, mites, lice, fleas, biting midges, and biting, nuisance and myiasigenic flies. It is particularly suitable for controlling arthropods present in livestock host animals or feeding or sucking the blood of the animals in or on the skin, for which purpose the compounds can be administered orally, parenterally, transdermally or topically.

They are also valuable in the protection of wood (erect, felled, transformed, stored or structured) infested by sawflies or beetles or termites. It can be used to protect stored products such as cereals, fruits, nuts, spices and tobacco (whether whole grain, ground or formulated into a product) from moth, beetles and mites. Stored animal products, such as hides, hair, wool, and feathers, in natural or transformed form (e.g., carpet or fabric), can also be protected from moth and beetle attack; and to protect stored meat and fish from beetles, mites, and flies. Solid or liquid compositions which can be applied topically to wood, stored products or household items generally contain from about 0.00005 to about 90% by weight, more particularly from about 0.001 to about 10% by weight, of one or more compounds of formula (I) or a pesticidally acceptable salt thereof.

The invention also relates to a method of cleaning a healthy animal comprising administering to the animal a compound of formula (I) or a veterinarily acceptable salt thereof. The purpose of such a cleaning method is to reduce or eliminate infestation of humans by parasites carried by the animal and to improve the environment in which humans live.

The compounds of the present invention are useful for controlling arthropod pests. It is particularly useful in the fields of veterinary medicine, livestock breeding and public health maintenance: against arthropods which are internally or externally parasitic in vertebrates, in particular warm-blooded vertebrates (including humans and domestic animals, such as dogs, cats, cattle, sheep, goats, horses, pigs, poultry and fish), such as Acarina, including ticks (e.g. louse (Ixodes spp.), tick (Boophilus spp.) such as Geobacillus microsporicus), tick (Amblyomma spp.), tick (Hyalomma spp.), tick (Hymenomylus spp.), tick (Hyalomylus spp.), tick (Hyalomystus spp.), tick (Rhipicephalus spp.), Paecilomyces sanguineus (Haemaphys spp.), tick (Dermacentor, Pernychus spp.), tick (Pirophus spp.), Pernychus spp.) such as Tetranychus scabies (mange), Pernychus spp.) (such as Tetranychus scabies) such as Tetranychus (Sarcophus spp.), tick (mange), Pernychus spp. (mange) such as Tetranychus (Sarcophus spp.) (mange), Acarina (mange., Sarcoptic (chlamydia spp.), folliculus (Demodex spp.), trombicula (trombicula spp.); from the order of the diptera (e.g., the genus Sphaeria (Aedespp.), Anopheles spp), Muscadae spp (Muscidae spp.) such as the crayfish (Stomoxys calcutirans) and the blood fly (Haematobia irliteans), Muscadae spp (Hypoderma spp.), Marasmus spp (Gastrophilus spp.), Blastomyelia (Simulium spp.); hemiptera (e.g., trypanosoma spp.); phylloxera (Phthiraptera) (e.g. hair lice (Damalinia spp.), dog lice (lagogenthus spp.)); siphonaptera (e.g., siphonostes spp.); dictyoptera (e.g., Periplaneta (Periplaneta spp.), Periplaneta (Blatella spp.)); and hymenoptera (e.g., Solenopsis invicta (Monomorium pharaonis)).

For the avoidance of doubt, reference to "treatment" as used herein includes curative, palliative and prophylactic treatment, and reference to "control" (of parasites and/or pests and the like) includes killing, repelling, incapacitating, hindering, removing, soothing, minimizing, eradicating.

Flea membrane feed screen (flea membrane fed screen) was used to determine the biological activity of the compounds to be protected. The assay included an in vitro test against Ctenocephalides felis (Ctenocepharas felis) performed according to the following general procedure.

Dog blood was used to grow fleas ex vivo. 25 to 30 mature Ctenocephalides felis (Daphnia felis) were collected and placed in a test container (50 ml polystyrene test tube with ends sealed with a micro nylon mesh). Citrated dog blood was made by adding aqueous sodium citrate (10 ml, 20% w/v, 20 g sodium citrate in 100 ml water) to dog blood (250 ml). The test compound was dissolved in dimethyl sulfoxide to give a working stock solution (4 mg/ml). The stock solution (12.5 μ l) was added to citrated dog blood (5 ml) to give an initial test concentration of 10 μ g/ml. For the experiments at 30. mu.g/ml, a working stock solution of 12 mg/ml was prepared.

Citrated dog blood (5 ml, 10. mu.g/ml) containing test compounds was placed in plastic Petri dish lids (Petri dish lid) and maintained at 37 ℃ on a hot plate. A sealing film is laid over the open top to form a tight film through which fleas can be fed. The test container containing the fleas was carefully placed on the sealing film and the fleas were fed.

Fleas were fed for 2 hours, then the test containers were removed and stored overnight at room temperature.

The fleas were observed and the percent mortality of the fleas was recorded. The activity of the compound at 10 μ g/ml was tested at lower doses. For the active molecule, a 4-point dose response (10, 3, 1, 0.3, 0.1 μ g/ml) was repeated (n ═ 5). The data were plotted to generate ED80 values.

Unlike the related comparative compounds of the prior art, such as the 3-cyano-5-aminoarylpyrazole compounds described in WO 98/24767 (in which there is a halogen on the 4-cyclopropyl ring), all exemplary compounds of the present invention tested had flea ED80 values of less than or equal to 3. E.g. at 30. mu.g/ml, at the ED mentioned above₈₀5-amino-3-cyano-4- (2, 2-dibromocyclopropyl) -1- (2, 6-dichlorophenyl-4-trifluoromethyl) pyrazole was inactive in flea screenings.

In the following detailed description of the experiments, nuclear magnetic resonance spectroscopy data were obtained using a Varian Inova 300, Varian Inova 400, Varian mercury 400, Varian Unityplus 400, Bruker AC 300MHz, Bruker AM 250MHz or Varian T60MHz spectrometer, and the observed chemical shifts were consistent with the proposed structure. Mass spectral data were obtained on a Finnigan Masslab Navigator, FisonsInstrument Trio 1000 or Hewlett Packard GCMS System Model 5971 spectrometer. The recited calculated and observed ions refer to the lowest mass isotope composition. HPLC means high performance liquid chromatography. Room temperature means 20 to 25 ℃.

Example 1

5-amino-1- [2, 6-dichloro-4-pentafluorophenylthio ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile

To a solution of preparative example 1(62 mg, 0.12 mmol) in methanol (10 ml) was added p-toluenesulfonic acid (0.5 g, 2.63 mmol) and the reaction mixture was heated under reflux overnight. The reaction mixture was poured into saturated sodium bicarbonate solution (50 ml) and the resulting mixture was extracted with ethyl acetate (2 × 20 ml). Over MgSO₄The combined extracts were dried and dried under vacuum. The crude product was dissolved in acetonitrile (1.5 ml) and water (0.9 ml) and purified by using a water/acetonitrile gradient [ 45: 55 to 5: 95%]The solution was purified by automated preparative liquid chromatography (Gilson System, 150 mm. times.30 mm Phenomenex LUNA C18(2) column). The appropriate fractions were combined and concentrated in vacuo to give the racemic title compound (22 mg).

MS(ES)：M/Z[MH⁺]523.2, respectively; the predicted mass for C14H6Cl2F10N4S + H was 523.0

¹H-NMR(CDCl₃): 2.05 to 2.20(1H), 2.42 to 2.53(1H), 3.83 to 3.99(2H), 7.87 to 7.93(2H)

Racemic example 1 was dissolved in ethanol/hexane (2: 3) and the enantiomers were separated by automated preparative liquid chromatography (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column) using ethanol/hexane [ 5: 95] as the mobile phase. The appropriate fractions were combined and concentrated to give two enantiomerically enriched products, example 1a and example 1 b.

Example 1 a: ms (es): MH⁺523.0, C14H6Cl2F10N4S + H requires 523.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 5: 95], residence time 10.73 minutes, enantiomeric purity 100%

Example 1 b: ms (es): MH⁺523.0, C14H6Cl2F10N4S + H requires 523.0

HPLC: (Gilson system, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 5: 95], retention time 12.23 minutes, enantiomeric purity 100%

Example 2

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile

To a solution of preparative example 2(234 mg, 0.45 mmol) in methanol (10 ml) was added p-toluenesulfonic acid (500 mg, 2.63 mmol) and the reaction mixture was heated under reflux overnight. Ethyl acetate (100 ml) was added to the reaction mixture and the organic phase was separated, washed with saturated aqueous sodium bicarbonate (2X 100 ml) and over MgSO₄Dried and concentrated in vacuo. By column chromatography (silica gel, 20 g) over dichloromethane/pentane [ 2: 1]]The residue was purified by elution. The appropriate fractions were combined and concentrated to give the racemic title compound as a pale yellow solid (160 mg).

MS(ES)：M/Z[MH⁺]465.1, respectively; the predicted mass of C15H6Cl2F8N4+ H was 465.0

¹H-NMR(CDCl₃): 2.05 to 2.20(1H), 2.42 to 2.53(1H), 3.86 to 3.95(2H), 7.74 to7.79(2H)

Racemic example 2 was dissolved in ethanol/hexane (1: 1) and the enantiomers were separated by automated preparative liquid chromatography (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column) using ethanol/hexane [ 1: 9] as the mobile phase. The appropriate fractions were combined and concentrated to give two enantiomerically enriched products, example 2a and example 2 b.

Example 2 a: ms (es): MH⁺464.8, C15H6Cl2F8N4+ H requires 465.0

HPLC: (Gilson system, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 1: 9], retention time 12.09 minutes, enantiomeric purity 99%, (-) isomer.

Example 2 b: ms (es): MH⁺464.8, C15H6Cl2F8N4+ H requires 465.0

HPLC: (Gilson system, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 1: 9], residence time 14.63 minutes, enantiomeric purity 100%, (+) isomer.

The compound prepared in a similar manner was:

example 3

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (1, 2, 2-trifluorocyclopropyl) -1H-pyrazole-3-carbonitrile; from the compound of preparation 3(22 mg, 0.047 mmol) the title compound (9.4 mg)

MS(ES)：M/Z[MH⁺]415.1: the predicted mass of C14H6Cl2F6N4+ H was 415.0

¹H-NMR(CDCl₃): 2.16 to 2.27(2H), 4.02 to 4.12(2H), 7.76 to 7.80(2H)

Example 4

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (pentafluorocyclopropyl) -1H-pyrazole-3-carbonitrile; from the compound of preparation 4 (32 mg, 0.063 mmol) was obtained the title compound (10 mg).

MS(ES)：M/Z[MH⁺]451.1: the predicted mass of C14H4Cl2F8N4+ H was 451.0

¹H-NMR(CDCl₃): 4.16 to 4.24(2H), 7.77 to 7.81(2H)

Example 5

5-amino-4- (2, 2-dichloro-1-fluorocyclopropyl) -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 5 (29 mg, 0.06 mmol) the title compound was obtained as a white solid (5 mg).

MS(ES)：M/Z[MH⁺]446.8: the predicted quality of C14H6C14F4N4+ H was 447.0

¹H-NMR(CDCl₃): 2.25 to 2.34(1H), 2.41 to 2.47(1H), 4.09 to 4.18(2H), 7.75 to 7.80(2H)

Example 6

5-amino-1- [2, 6-dichloro-4-pentafluorosulfanyl ] -4- (pentafluorocyclopropyl) -1H-pyrazole-3-carbonitrile; from the compound of preparation 6(40 mg, 0.07 mmol) was obtained the title compound as a white solid (20 mg).

MS(ES)：M/Z[MH⁺]509.2: C13H4Cl2F10N4S + H is 509.0

¹H-NMR(CDCl₃): 4.16 to 4.22(2H), 7.91 to 7.93(2H)

Example 7

5-amino-1- [2, 6-dichloro-4-pentafluorosulfanyl ] -4- (1, 2, 2-trifluorocyclopropyl) -1H-pyrazole-3-carbonitrile; from the compound of preparation 7 (92 mg, 0.17 mmol) the title compound (46 mg) was obtained.

MS(ES)：M/Z[MH⁺]472.9；C13H6Cl2The prediction quality of F8N4S + H was 473.0

¹H-NMR(CDCl₃): 2.14 to 2.27(2H), 4.05 to 4.14(2H), 7.89 to 7.92(2H)

Example 8

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (difluoromethyl) -2, 2-difluorocyclopropyl ] -1H-pyrazole-3-carbonitrile

Methanol (5 ml) and hydrochloric acid (10% in water, 5 ml) were added to a solution of preparation 23(4.0 g, 8.0 mmol) in 1, 4-dioxane (50 ml). The reaction mixture was then heated at reflux for 4 hours.

Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the aqueous phase was separated and extracted with ethyl acetate (3 × 20 ml). Followed by a reaction over MgSO₄The combined organic phases were dried and concentrated in vacuo. Using a gradient elution method, petroleum ether: diethyl ether [ 1: 0 to 0: 1]]The residue was purified by column chromatography (silica gel, 70 g). The appropriate fractions were combined and concentrated to give racemic example 8(3.2 g).

MS(ES)：M/Z[MH⁺]448.9, respectively; the predicted mass of C15H7Cl2F7N4+ H was 447.0

¹H-NMR(CDCl₃): 2.04 to 2.11(1H), 2.13 to 2.20(1H), 3.82 to 3.90(2H), 5.63 to 5.89(1H), 7.73 to 7.79(2H)

Racemic example 8(88 mg) was dissolved in ethanol/hexane (1: 1) and the enantiomers were separated by automated preparative liquid chromatography (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column) using ethanol/hexane [ 2: 8] as the mobile phase. The appropriate fractions were combined and concentrated to give example 8a (40 mg) and example 8b (40 mg).

Example 8 a: ms (es): MH⁺446.8, C15H7Cl2F7N4+ H requires 447.0

HPLC: (Gilson system, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 2: 8], retention time 7.3 minutes, enantiomeric purity 100%.

Example 8 b: ms (es): MH⁺446.8, C15H7Cl2F7N4+ H requires 447.0

HPLC: (Gilson system, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 2: 8], residence time 17.4 minutes, enantiomeric purity 100%.

Example 9

5-amino-1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -4- (2, 2-difluorocyclopropyl) -1H-pyrazole-3-carbonitrile

Trimethylsilyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (700 mg, 2.8 mmol) was added to a solution of preparation 31(560 mg, 1.40 mmol) and sodium fluoride (4.0 mg, 0.12 mmol) in toluene (0.8 ml) at 100 ℃ over one hour using a syringe. The reaction mixture was then heated at reflux for 1 hour.

Silica gel was added to the cooled reaction mixture and the solution was concentrated in vacuo. By column chromatography in diethyl ether/hexane [ 1: 1]]The product/silica gel mixture was partially purified by elution and the fractions containing the product were concentrated in vacuo. Methanol (5 ml) and hydrochloric acid (2N, 5 ml) were added to the residue, and the reaction mixture was heated under reflux for 6 hours. The reaction mixture was concentrated in vacuo and the residue was separated between diethyl ether and water (20 ml). Separate the two layers and remove over MgSO₄The organic layer was dried and then concentrated in vacuo.

The residue was purified by column chromatography using gradient elution, diethyl ether: hexane [ 1: 2 to 1: 1 ]. The appropriate fractions were combined and concentrated to give example 9 as a white solid (96 mg).

MS(ES)：M/Z[MH⁺]397.1, respectively; the predicted mass of C14H7Cl2F5N4+ H was 397.0

¹H-NMR(CDCl₃): 1.74 to 1.83(1H), 1.95 to 2.05(1H), 2.44 to 2.56(1H), 3.72 to 3.84(2H), 7.76 to 7.81(2H)

The compound prepared in a similar manner to example 2 was:

example 10

5-amino-4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 10 (250 mg, 0.51 mmol) the title compound (11 mg) was obtained.

MS(ES)：M/Z[MH⁺]433.0, respectively; the predicted quality of C15H6F10N4+ H was 433.1

¹H-NMR(CDCl₃): 2.02 to 2.09(2H), 2.29 to 2.42(1H), 4.63 to 4.76(1H), 7.30 to 7.37(2H)

The compound prepared in analogy to example 8 was:

example 11

5-amino-1- [2, 6-dichloro-4-pentafluorophenylthio ] -4- [1- (difluoromethyl) -2, 2-difluorocyclopropyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 11 (655 mg, 1.17 mmol), racemic title compound (284 mg) was obtained.

MS(ES)：M/Z[MH⁺]504.9, respectively; the predicted mass of C14H7Cl2F9N4S + H was 505.0

¹H-NMR(CDCl₃): 2.00 to 2.09(1H), 2.12 to 2.20(1H), 3.87 to 3.96(2H), 5.61 to 5.90(1H), 7.88 to 7.91(2H)

Racemic example 11 was dissolved in ethanol/hexane (1: 1) and the enantiomers were separated by automated preparative liquid chromatography (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column) using ethanol/hexane [ 2: 8] as the mobile phase. The appropriate fractions were combined and concentrated to give two enantiomerically enriched products, example 11a and example 11 b.

Example 11 a: ms (es): MH⁺504.9, C14H7Cl2F9N4S + H requires 505.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 2: 8], retention time 6.40 min, enantiomeric purity 100%

Example 11 b: ms (es): MH⁺504.9, C14H7Cl2F9N4S + H requires 505.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 2: 8], residence time 13.89 minutes, enantiomeric purity 100%

Example 12

5-amino-4- {1- [ chloro (fluoro) methyl ] -2, 2-difluorocyclopropyl } -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 12 (100 mg, 0.19 mmol), racemic title compound (20 mg) was obtained.

MS(ES)：M/Z [MH⁺]462.8, respectively; the predicted mass for C15H7Cl3F6N4+ H was 463.0

¹H-NMR(CDCl₃): 2.03 to 2.11(1H), 2.16 to 2.25(1H), 3.84 to 3.95(2H), 6.02 to 6.16(1H), 7.73 to 7.80(2H)

Racemic example 12 was dissolved in ethanol/hexane (1: 1) and the enantiomers were separated by automated preparative liquid chromatography (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column) using ethanol/hexane [ 2: 8] as the mobile phase. The appropriate fractions were combined and concentrated to give two enantiomerically enriched products, example 12a and example 12 b.

Example 12 a: ms (es): MH⁺462.9, C15H7Cl3F6N4+ H requires 463.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 2: 8], residence time 7.07 min, enantiomeric purity 99%

Example 12 b: ms (es): MH⁺462.9, C15H7Cl3F6N4+ H requires 463.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 2: 8], residence time 21.44 minutes, enantiomeric purity 100%

Example 13

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (difluoromethyl) -2, 2, 3, 3-tetrafluorocyclopropyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 13 (48 mg, 0.09 mmol) the title compound (17 mg) was obtained.

MS(ES)：M/Z[MH⁺]482.7, respectively; the predicted mass of C15H5Cl2F9N4+ H was 483.0

¹H-NMR(CDCl₃): 3.84 to 3.91(2H), 5.95 to 6.24(1H), 7.76 to 7.79(2H)

Example 14

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2, 3, 3-tetrafluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 14 (7 mg, 0.01 mmol) the title compound (4 mg) was obtained.

MS(ES)：M/Z[MH⁺]500.9 of the total weight of the mixture; the predicted mass of C15H4Cl2F10N4+ H was 501.0

Example 15

1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -5- (methylamino) -1H-pyrazole-3-carbonitrile

Concentrated hydrochloric acid (drops) was added to a solution of example 2(500 mg, 1.08 mmol) in triethyl orthoformate (13.4 ml). The reaction mixture was then heated at reflux for 2.5 hours. The reaction was concentrated in vacuoThe mixture was combined and the residue redissolved in toluene and then re-concentrated (× 2). Sodium borohydride (90 mg, 2.37 mmol) was added to a solution of the residue in ethanol (10 ml) at 0 ℃. The reaction mixture was then stirred at room temperature overnight. Acetic acid (0.5 ml) and water (10 ml) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 10 ml). Over MgSO₄The combined organic phases were dried and concentrated in vacuo. The residue was purified by column chromatography (silica gel), column chromatography in toluene and elution with toluene. The appropriate fractions were combined and concentrated to give racemic example 15(323 mg).

MS(ES)：M/Z[MH⁺]478.8; the predicted mass of C16H8Cl2F8N4+ H was 479.0

¹H-NMR(CDCl₃): 2.07 to 2.23(1H), 2.42 to 2.58(1H), 2.71 to 2.76(3H), 3.51 to 3.66(1H), 7.73 to 7.77(2H)

Racemic example 15 was dissolved in ethanol/hexane (1: 1) and the enantiomers were separated by automated preparative liquid chromatography (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column) using ethanol/hexane [ 1: 9] as the mobile phase. The appropriate fractions were combined and concentrated to give two enantiomerically enriched products, example 15a and example 15 b.

Example 15 a: ms (es): MH⁺478.9, C16H8Cl2F8N4+ H requires 479.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 1: 9], residence time 8.67 min, enantiomeric purity 100%

Example 15 b: ms (es): MH⁺478.9, C16H8Cl2F8N4+ H requires 479.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 1: 9], residence time 11.26 minutes, enantiomeric purity 100%

The compound prepared in a similar manner to example 8 was:

example 16

5-amino-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile; the racemic title compound (630 mg) was obtained from the compound of preparation 15(1.0 g, 1.86 mmol).

MS(ES)：M/Z[MH⁺]480.9 of the total weight of the mixture; the predicted mass of C15H6Cl2F8N4O + H was 481.0

¹H-NMR(CDCl₃): 2.05 to 2.18(1H), 2.41 to 2.52(1H), 3.87 to 3.95(2H), 7.37 to 7.40(2H)

Racemic example 16 was dissolved in ethanol/hexane (1: 1) and the enantiomers were separated by automated preparative liquid chromatography (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column) using ethanol/hexane [ 5: 95] as the mobile phase. The appropriate fractions were combined and concentrated to give two enantiomerically enriched products, example 16a and example 16 b.

Example 16 a: ms (es): MH⁺480.9, C15H6Cl2F8N4O + H requires 481.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 5: 95], retention time 8.86 min, enantiomeric purity 99%

Example 16 b: ms (es): MH⁺480.9, C15H6Cl2F8N4O + H requires 481.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 5: 95], residence time 9.91 min, enantiomeric purity 100%

Example 17

5-amino-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [1- (difluoromethyl) -2, 2, 3, 3-tetrafluorocyclopropyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 16 (50 mg, 0.09 mmol) the title compound (10 mg) was obtained.

MS(ES)：M/Z[MH⁺]498.9, respectively; the predicted mass of C15H5Cl2F9N4O + H was 499.0

¹H-NMR(CDCl₃): 3.86 to 3.91(2H), 5.95 to 6.23(1H), 7.38 to 7.40(2H)

Example 18

5-amino-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [1- (difluoromethyl) -2, 2-difluorocyclopropyl ] -1H-pyrazole-3-carbonitrile; the racemic title compound (3.0 g) was obtained from the compound of preparation 17 (3.6 g, 7.0 mmol).

MS(ES)：M/Z[MH⁺]463.0; the predicted mass for C15H7Cl2F7N4O + H was 463.0

¹H-NMR(CDCl₃): 2.00 to 2.08(1H), 2.10 to 2.19(1H), 3.82 to 4.00(2H), 5.60 to 5.90(1H), 7.35 to 7.40(2H)

Racemic example 18 was dissolved in ethanol/hexane (1: 2) and the enantiomers were separated by automated preparative liquid chromatography (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column) using ethanol/hexane [ 1: 9] as the mobile phase. The appropriate fractions were combined and concentrated to give two enantiomerically enriched products, example 18a and example 18 b.

Example 18 a: ms (es): MH⁺463.0, C15H7Cl2F7N4O + H Requirements 463.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 1: 9], residence time 13.35 min, enantiomeric purity 99%

Example 18 b: ms (es): MH⁺463.0, C15H7Cl2F7N4O + H Requirements 463.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 1: 9], residence time 31.58 min, enantiomeric purity 100%

Example 19

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (fluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile; the racemic title compound (17 mg) was obtained from the compound of preparation 18 (100 mg, 0.21 mmol).

MS(ES)：M/Z[MH⁺]428.9, respectively; the predicted mass for C15H8Cl2F6N4+ H was 429.0

¹H-NMR(CDCl₃): 1.84 to 1.93(1H), 1.93 to 2.02(1H), 3.68 to 4.06(2H), 4.42 to 4.82(2H), 7.73 to 7.78(2H)

Racemic example 19 was dissolved in ethanol/hexane (1: 1) and the enantiomers were separated by automated preparative liquid chromatography (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column) using ethanol/hexane [ 1: 9] as the mobile phase. The appropriate fractions were combined and concentrated to give two enantiomerically enriched products, example 19a and example 19 b.

Example 19 a: ms (es): MH⁺429.0, C15H8Cl2F6N4+ H requires 429.0

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 1: 9], residence time 14.99 min, enantiomeric purity 100%

Example 19 b: ms (es): MH⁺429.0, C15H8Cl2F6N4+ H requires 429.01

HPLC: (Gilson System, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 1: 9], residence time 20.89 minutes, enantiomeric purity 100%

Example 20

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (2, 2-difluoro-1-methylcyclopropyl) -1H-pyrazole-3-carbonitrile; from the compound of preparation 19 (80 mg, 0.17 mmol) the title compound (56 mg) was obtained.

MS(ES)：M/Z[MH⁺]411.0; the predicted mass of C15H9Cl2F5N4+ H was 411.0

¹H-NMR(CDCl₃): 1.46 to 1.50(3H), 1.56 to 1.63(1H), 1.69 to 1.78(1H), 3.62 to 3.76(2H), 7.72 to 7.77(2H)

Example 21

5-amino-1- {2, 6-dichloro-4- [ (trifluoromethyl) thio ] phenyl } -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 20 (1.8 g, 3.3 mmol) the title compound (1.1 g) was obtained.

MS(ES)：M/Z[MH⁺]496.9, respectively; the predicted mass of C15H6Cl2F8N4S + H was 496.9

¹H-NMR(CDCl₃): 2.05 to 2.18(1H), 2.42 to 2.52(1H), 3.86 to 3.97(2H), 7.75 to 7.80(2H)

Example 22

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid ethyl ester

Sodium hydride (10 mg, 0.20 mmol) and 1-chloroethyl ethylcarbonate (37 mg, 0.24 mmol) were added sequentially to a solution of example 2a (100 mg, 0.20 mmol) in N, N-dimethylformamide (3 ml). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in acetonitrile (2 ml). The solution was purified by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm LUNA II C1810 micron column) using an acetonitrile/water gradient [ 60: 40 to 95: 5 ]. Appropriate fractions were combined and concentrated to give example 22(50 mg).

MS(ES)：M/Z[MH⁺]536.9 of the total weight of the mixture; the predicted mass of C18H10Cl2F8N4O2+ H was 537.0

¹H-NMR(CDCl₃): 1.07 to 1.14(3H), 2.09 to 2.19(1H), 2.48 to 2.57(1H), 3.99 to 4.06(2H), 6.16 to 6.24(1H), 7.71 to 7.76(2H)

The compound prepared in a similar manner was:

example 23

1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -5- (2-oxo-1, 3-oxazolidin-3-yl) -1H-pyrazole-3-carbonitrile; from the compound obtained in example 2a (135 mg, 0.30 mmol) and 2-bromoethyl chloroformate (60 mg, 0.33 mmol) the title compound (47 mg) was obtained.

MS(ES)：M/Z[MH⁺]534.9, respectively; the predicted mass of C18H8Cl2F8N4O2+ H was 535.0

¹H-NMR(CDCl₃): 2.31 to 2.39(1H), 2.54 to 2.64(1H), 4.00 to 4.10(2H), 4.43 to 4.50(2H), 7.75 to 7.78(2H)

The compound prepared in a similar manner to example 8 was:

example 24

5-amino-1- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 22 (164 mg, 0.34 mmol) the title compound (60 mg) was obtained.

MS(ES)：M/Z[MH⁺]432.0 parts; the predicted quality of C14H6ClF8N5+ H was 432.0

¹H-NMR(CDCl₃): 2.02 to 2.19(1H), 2.40 to 2.54(1H), 5.13 to 5.22(2H), 8.19 to 8.23(1H), 8.63 to 8.67(1H)

Example 25

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid 2- (dimethylamino) ethyl ester

Pyridine (40 μ l, 0.50 mmol) and molecular sieve (4A) were added to a solution of example 2a (100 mg, 0.22 mmol) in dry dichloromethane/toluene (3: 2, 2 ml). This solution was added to phosgene (20% in toluene, 1.7N, 300 μ l, 0.50 mmol) at 0 ℃ under nitrogen and the reaction mixture was allowed to stand for 1 hour. 2- (dimethylamino) ethanol (1 ml) was added and the reaction mixture was allowed to stand overnight, then concentrated in vacuo. The residue was dissolved in acetonitrile (1.8 ml), and the mixture was purified by using acetonitrile: the solution was purified by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm LUNA II C1810 micron column) with a 0.1% trifluoroacetic acid gradient [ 35: 65 to 95: 5 ]. The appropriate fractions were combined and concentrated, then hydrochloric acid was added to give example 25(100 mg).

MS(ES)：M/Z[MH⁺]580.0; the predicted mass of C20H 15 Cl2F8N5O2+ H was 580.1

¹H-NMR(CDCl₃): 2.21 to 2.30(1H), 2.47 to 2.56(2H), 2.84 to 2.88(6H), 3.19 to 3.24(2H), 4.27 to 4.39(2H), 7.71 to 7.74(2H)

The compound prepared in a similar manner was:

example 26

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid 2, 2, 2-trifluoroethyl ester; the title compound (100 mg) was obtained from the compound of example 2a (100 mg, 0.22 mmol) and 2, 2, 2-trifluoroethanol.

MS(ES)：M/Z[MH⁺]590.9, respectively; the predicted mass of C18H7Cl2F11N4O2+ H was 591.0

¹H-NMR (DMSO): 2.61 to 2.71(1H), 2.89 to2.99(1H), 4.62 to 4.73(2H), 8.26 to 8.29(2H), 10.89 to 10.97(1H)

Example 27

5-amino-1- {2, 6-dichloro-4- [ (trifluoromethyl) sulfonyl ] phenyl } -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile

A mixture of example 21(600 mg, 1.2 mmol) and 3-chloroperoxybenzoic acid (929 mg, 5.4 mmol) in dichloromethane (20 mL) was stirred at room temperature over a period of 48 hours. The reaction mixture was washed with aqueous sodium hydroxide, water and then brine. The organic phase was then dried and concentrated in vacuo. The residue was purified by flash chromatography (silica gel) eluting with a gradient of toluene: dichloromethane [ 1: 0 to 0: 1 ]. The appropriate fractions were combined and concentrated in vacuo.

The residue was dissolved in acetonitrile/water (1 ml) and the solution was purified by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm LUNA II C1810 micron column) using an acetonitrile/water gradient [ 60: 40 to 95: 5 ]. Appropriate fractions were combined and concentrated to give example 27(27 mg).

MS(ES)：M/Z[MH⁺]529.0, respectively; the predicted mass of C15H6Cl2F8N4O2S + H was 529.0

¹H-NMR (DMSO): 2.11 to 2.22(1H), 2.59 to 2.70(1H), 6.68 to 6.73(2H), 8.55 to 8.59(2H)

Example 28

1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -5- [ (pyridin-4-ylmethyl) amino ] -1H-pyrazole-3-carbonitrile

To a solution of preparation 25(200 mg, 0.36 mmol) in dry methanol (10 ml) was added sodium borohydride (34 mg, 0.90 mmol) under nitrogen at 0 ℃. The reaction mixture was then stirred at room temperature for 2 hours. Water was added to the reaction mixture and hydrochloric acid (4N) was added) The mixture was adjusted to pH 2. The mixture was then neutralized by addition of saturated aqueous sodium carbonate solution, extracted with ethyl acetate (3 × 10 ml) and over MgSO₄The combined extracts were dried and then concentrated in vacuo. The residue was dissolved in acetonitrile/water (3.6 ml) and purified by using an acetonitrile/water gradient [ 55: 45 to 95: 5]]The solution was purified by automated preparative liquid chromatography (Gilson system, 150X 30 mm, LUNA II C1810 micron column). The appropriate fractions were concentrated to give example 28(34 mg).

MS(ES)：M/Z[MH⁺]556.0, respectively; the predicted mass of C21H11Cl2F8N5+ H was 556.0

¹H-NMR(CDCl₃): 2.20 to 2.34(1H), 2.53 to 2.67(1H), 4.10 to 4.17(1H), 4.18 to 4.28(2H), 7.01 to 7.05(2H), 7.60 to 7.63(2H), 8.44 to 8.48(2H)

The compound prepared in a similar manner to example 2 was:

example 29

5-amino-1- [2, 6-dichloro-4- (difluoromethoxy) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 26 (110 mg, 0.21 mmol) the title compound (48 mg) was obtained.

MS(ES)：M/Z[MH⁺]463.0; the predicted mass for C15H7Cl2F7N4O + H was 463.0

¹H-NMR(CDCl₃): 2.01 to 2.19(1H), 2.38 to 2.51(1H), 3.83 to 3.98(2H), 6.38 to 6.77(1H), 7.27 to 7.32(2H)

Example 30

5-amino-1- [2, 6-dichloro-4-pentafluorophenylthio ] -4- [1- (difluoromethyl) -2, 2, 3, 3-tetrafluorocyclopropyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 27 (138 mg, 0.23 mmol) the title compound (100 mg) was obtained.

MS(ES)：M/Z[MH⁺]541.0, respectively; the predicted mass of C14H5Cl2F11N4S + H was 541.0

¹H-NMR (DMSO): 6.51 to 6.71(1H), 6.73 to 6.76(2H), 8.43 to 8.46(2H)

The compound prepared in a similar manner to example 25 was:

example 31

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid isopropyl ester; the title compound (44 mg) was obtained from the compound of example 2a (50 mg, 0.11 mmol) and 2-propanol.

MS(ES)：M/Z[MH⁺]551.0, respectively; the predicted mass of C19H12Cl2F8N4O2+ H was 551.0

¹H-NMR (DMSO): 0.96 to 1.04(6H), 2.61 to 2.71(1H), 2.87 to 2.99(1H), 4.59 to 4.67(1H), 8.28 to 8.32(2H), 10.15 to 10.22(1H)

Example 32

Hydrochloride of pyridin-4-ylmethyl 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamate; from the compound from example 2a (50 mg, 0.11 mmol) and pyridine-4-methanol the title compound was obtained (5 mg).

MS(ES)：M/Z[MH⁺]600.0 of the total weight of the alloy; the predicted mass for C22H11Cl2F8N5O2+ H was 600.0

¹H-NMR(CD₃OD): 2.24 to 2.35(1H), 2.55 to 2.65(1H), 5.21 to 5.23(2H), 7.65 to 7.68(2H), 7.92 to 7.94(2H), 8.64 to 8.68(2H)

Example 33

Hydrochloride of pyridin-3-ylmethyl 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamate; from the compound of example 2a (50 mg, 0.11 mmol) and pyridine-3-methanol the title compound was obtained (24 mg).

¹H-NMR (DMSO): 2.63 to 2.73(1H), 2.84 to 2.95(1H), 5.11 to 5.16(2H), 7.68 to 7.74(1H), 7.95 to 8.01(1H), 8.20 to 8.26(2H), 8.61 to 8.64(1H), 8.68 to 8.73(1H), 10.55 to 10.68(1H)

Example 34

Hydrochloride of pyridin-2-ylmethyl 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-oxazol-5-ylcarbamate; from the compound of example 2a (50 mg, 0.11 mmol) and pyridine-2-methanol the title compound was obtained (31 mg).

¹H-NMR (DMSO): 2.65 to 2.75(1H), 2.86 to 2.97(1H), 5.05 to 5.11(2H), 7.11 to 7.16(1H), 7.31 to 7.37(1H), 7.77 to 7.82(1H), 8.21 to 8.28(2H), 8.46 to 8.51(1H), 10.56 to 10.70(1H)

Example 35

Hydrochloride of 1H-imidazol-5-ylmethyl 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamate; from the compound from example 2a (50 mg, 0.11 mmol) and 5- (hydroxymethyl) imidazole the title compound was obtained (2 mg).

MS(ES)：M/Z[MH⁺]589.0; the predicted mass of C20H10Cl2F8N6O2+ H was 589.0

Example 36

Hydrochloride of 2-pyrrolidin-1-yl ethyl 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamate; from the compound from example 2a (50 mg, 0.11 mmol) and 1- (2-hydroxyethyl) pyridine the title compound was obtained (10 mg).

MS(ES)：M/Z[MH⁺]606.1, respectively; the predicted mass of C22H17Cl2F8N5O2+ H was 606.1

¹H-NMR(CD₃OD): 1.93 to 2.01(4H), 2.31 to 2.38(1H), 2.56 to 2.64(1H), 3.18 to 3.23(4H), 3.30 to 3.35(2H), 4.21 to 4.26(2H), 7.95 to 7.99(2H)

The compound prepared in a similar manner to example 8 was:

example 37

5-amino-4- {1- [ chloro (difluoro) methyl ] -2, 2-difluorocyclopropyl } -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carbonitrile; from the compound of preparation 55 (124 mg, 0.23 mmol) the title compound (17 mg) was obtained.

MS(ES)：M/Z[MH⁺]480.9 of the total weight of the mixture; the predicted mass of C15H6Cl3F7N4+ H was 480.96

¹H-NMR(CDCl₃): 2.08 to 2.24(1H), 2.46 to 2.61(1H), 3.87 to 4.00(2H), 7.75 to 7.79(2H)

Racemic example 37 was dissolved in ethanol/hexane (1: 4) and the enantiomers were separated by automated preparative liquid chromatography (Gilson System, 250X 20 mm ID Chiralcel IA, 5 micron column) using ethanol/hexane [ 5: 95] as the mobile phase. The appropriate fractions were combined and concentrated to give one enantiomerically pure product, example 37a, and several fractions mixed.

Example 37 a: ms (es): MH⁺481.0, C15H6Cl3F7N4+ H requires 481.0

HPLC: (Gilson system, 250X 20 mm ID Chiralcel OD, 10 micron column), ethanol/hexane [ 5: 95], residence time 10.55 min, enantiomeric purity 98%

The following preparations are illustrative of the syntheses used to prepare certain intermediates of the foregoing examples.

Preparation example 1

N' - { 3-cyano-1- [2, 6-dichloro-4- (pentafluorothio) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethyl-imidocarboxamide

A mixture of preparation 32(264 mg, 0.5 mmol), methyl benzoate (100. mu.L) and sodium fluoride (6 mg) was heated at 105 ℃ under nitrogen. Trimethylsilyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (197 μ l, 1.0 mmol) was added dropwise over one hour, and the reaction mixture was stirred at 105 ℃. Trimethylsilyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (700 μ l, 3.6 mmol) was added over 7 hours, and the temperature of the reaction mixture was maintained at 105 ℃. Dichloromethane (15 ml) was added to the reaction mixture and the solution was washed with saturated aqueous sodium bicarbonate. The organic phase was separated over MgSO₄Dried and concentrated in vacuo. Using Isolute^TMThe residue was purified on a cartridge (cartridge) (silica gel, 20 g) eluting with toluene. Appropriate fractions were combined and concentrated to give preparation 1(62 mg) as an almost pure white solid.

MS(ES)：M/Z[MH⁺]578.3, respectively; the predicted mass for C17H11Cl2F10N5S + H was 578.0

¹H-NMR(CDCl₃): 2.15 to 2.20(1H), 2.45 to 2.55(1H), 2.79 to 2.81(3H), 3.01 to 3.03(3H), 7.79 to 7.81(2H), 7.88 to 7.90(1H)

The compound prepared in a similar manner was:

preparation example 2

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 33 (160 mg, 0.34 mmol) the title compound was obtained as a pale yellow solid (94 mg).

MS(ES)：M/Z[MH⁺]520.2 of the basic material; the predicted mass for C18H11Cl2F8N5+ H was 520.0

¹H-NMR(CDCl₃): 1.99 to 2.31(2H), 2.74 to 2.80(3H), 2.99 to 3.00(3H), 7.64 to 7.69(2H), 7.82 to 8.02(1H)

Preparation example 3

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [ (1R) -1, 2, 2-trifluorocyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide

To a solution of preparation 34(11 mg, 0.026 mmol) in toluene (0.2 ml) was added phenyl- (trifluoromethyl) -mercury (45 mg, 0.13 mmol) and sodium iodide (59 mg, 0.39 mmol) under nitrogen. The reaction mixture was then heated at 85 ℃ for 18 hours. Toluene (5 ml) was added to the reaction mixture and the solution was filtered through Arbocel to remove any Hg residues. The filtrate was concentrated in vacuo to afford preparation 3(22 mg).

MS(ES)：M/Z[MH⁺]470.2; the predicted mass of C17H11Cl2F6N5+ H was 470.0

¹H-NMR(CDCl₃): 2.08 to 2.31(2H), 2.81 to 2.84(3H), 3.04 to 3.08(3H), 7.65 to 7.69(2H), 7.85 to 7.88(1H)

The compound prepared in a similar manner was:

preparation example 4

N' - [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (pentafluorocyclopropyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide; from the compound of preparation 35 (46 mg, 0.1 mmol) the title compound was obtained as a white solid (35 mg).

MS(ES)：M/Z[MH⁺]506.2; the predicted mass of C17H9Cl2F8N5+ H was 506.0

¹H-NMR(CDCl₃): 2.85 to 2.87(3H), 3.07 to 3.09(3H), 7.67 to 7.69(2H), 7.69 to 7.71(1H)

Preparation example 5

N' - { 3-cyano-4- (2, 2-dichloro-1-fluorocyclopropyl) -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide; from the compound of preparation 34 (42 mg, 0.1 mmol) and phenyl (trichloromethyl) mercury (40 mg, 0.1 mmol) was obtained the title compound as a white solid (29 mg).

¹H-NMR(CDCl₃): 2.31 to 2.34(1H), 2.35 to 2.38(1H), 2.82 to 2.86(3H), 3.09 to 3.13(3H), 7.66 to 7.69(2H), 7.99 to 8.03(1H)

Preparation example 6

N' - [ 3-cyano-1- [2, 6-dichloro-4- (pentafluorothio) phenyl ] -4- (pentafluorocyclopropyl) -1H-pyrazol-5-yl ] -N, N-dimethyl-imidocarboxamide

Sodium fluoride (3 mg) was added to a solution of preparative example 37(102 mg, 0.20 mmol) in methyl benzoate (4 ml). The mixture was heated to 130 ℃ and trimethylsilyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (1 ml, 0.33 mmol) was added over 10 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica, 10 g) eluting with toluene. The appropriate fractions were combined and concentrated to give preparation 6(75 mg) as a pale yellow solid.

MS(ES)：M/Z[MH⁺]564.2, respectively; the predicted mass of C16H9Cl2F10N5S + H was 564.0

¹H-NMR 2.86 to 2.90(3H), 3.07 to 3.10(3H), 7.69 to 7.72(1H), 7.80 to 7.85(2H)

The compound prepared in analogy to preparation 3 was:

preparation example 7

N' - [ 3-cyano-1- [2, 6-dichloro-4- (pentafluorothio) phenyl ] -4- (1, 2, 2-trifluorocyclopropyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide; from the compound of preparation 38 (100 mg, 0.21 mmol) the title compound was obtained as a white solid (90 mg).

MS(ES)：M/Z[MH⁺]527.9, respectively; the predicted mass of C16H11Cl2F8N5S + H was 528.0

¹H-NMR(CDCl₃): 2.09 to 2.29(2H), 2.82 to 2.86(3H), 3.04 to 3.09(3H), 7.79 to 7.83(2H), 7.85 to 7.88(1H)

Preparation example 8

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (difluoromethyl) ethenyl ] -1H-pyrazol-5-yl } -N, N-dimethyl-imidocarboxamide

Butyl lithium (1.6M in hexane, 16 ml, 25.0 mmol) was added dropwise to a suspension of methyltriphenylphosphonium bromide (8.9 g, 25.0 mmol) in tetrahydrofuran (80 ml) at-10 ℃. The mixture was stirred at room temperature for 20 minutes, then a solution of preparation 39(7.6 g, 16.7 mmol) in tetrahydrofuran (16.5 ml) was added. The reaction mixture was then stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 50 ml). The combined organic phases were separated and concentrated on silica gel. The silica gel/product mixture was purified by column chromatography, eluting with dichloromethane. The appropriate fractions were then combined and concentrated to give preparation 8(5.2 g).

MS(ES)：M/Z[MH⁺]454.0, respectively; the predicted mass for C17H12Cl2F5N5+ H was 452.1

¹H-NMR(CDCl₃): 2.74 to 2.76(3H), 2.91 to 2.94(3H), 5.77 to 5.79(1H), 5.91 to 55.94(1H), 6.16 to 6.45(1H), 7.62 to 7.64(1H), 7.65 to 7.68(2H)

Preparation example 9

According to Achmatowicz, O., Jr; szymoniak, j. tetrahedron (1982), 38(9), 1299) and 1302 to give ethyl 3-cyano-2-oxo-propionate.

The compound prepared in analogy to preparation 1 was:

preparation example 10

N' - { 3-cyano-4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 40 (250 mg, 0.57 mmol) the title compound (250 mg) was obtained.

MS(ES)：M/Z[MH⁺]488.1, respectively; the predicted quality of C18H 11F 10N5+ H is 488.1

The compound prepared in analogy to preparation 3 was:

preparation example 11

N' - { 3-cyano-1- [2, 6-dichloro-4- (pentafluorosulfanyl ] -4- [1- (difluoromethyl) -2, 2-difluorocyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide the title compound (655 mg) was obtained from the compound of preparation 41 (820 mg, 1.61 mmol).

MS(ES)：M/Z[MH⁺]559.9, respectively; the predicted mass of C17H12Cl2F9N5S + H was 560.0

¹H-NMR(CDCl₃): 1.81 to 1.90(1H), 2.03 to 2.12(1H), 2.76 to 2.79(3H), 2.99 to 3.01(3H), 5.64 to 5.93(1H), 7.78 to 7.81(2H), 7.87 to 7.89(1H)

Preparation example 12

N' - {4- {1- [ chloro (fluoro) methyl ] -2, 2-difluorocyclopropyl } -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 42 (150 mg, 0.32 mmol) the title compound (100 mg) was obtained.

MS(ES)：M/Z[MH⁺]517.9 of the total weight of the mixture; the predicted mass of C18H12Cl3F6N5+ H was 518.0

¹H-NMR(CDCl₃): 1.86 to 1.97(1H), 2.05 to 2.15(1H), 2.73 to 2.80(3H), 2.95 to 3.01(3H), 6.06 to 6.22(1H), 7.63 to 7.71(2H), 7.88 to 7.94(1H)

Preparation example 13

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (difluoromethyl) -2, 2, 3, 3-tetrafluorocyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide; from the compound of preparation 43 (200 mg, 0.41 mmol) the title compound (48 mg) was obtained.

MS(ES)：M/Z[MH⁺]537.8; the predicted mass of C18H10Cl2F9N5+ H was 538.0

Preparation example 14

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2, 3, 3-tetrafluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide; from the compound of preparation 44(28 mg, 0.06 mmol) the title compound (7 mg) was obtained.

MS(ES)：M/Z[MH⁺]555.8, respectively; the predicted mass of C18H9Cl2F10N5+ H was 556.0

¹H-NMR(CDCl₃): 2.79 to 2.81(3H), 2.99 to 3.00(3H), 7.65 to 7.67(1H), 7.67 to 7.69(2H)

Preparation example 15

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide

Using Diazald at about 50 deg.C^®In a set, Diazald is added dropwise^®Solution in diethyl ether (45 ml) to a solution of potassium hydroxide (1M, 89 ml) in water and ethanol (10 ml). The collection was cooled to-30 ℃ and the Diazald addition was completed^®After this time, diethyl ether (10 ml) was added to the mixture. Distillation was continued until the distillate was colorless, and the diazomethane solution was added to a solution of preparation 45(1.0 g, 1.92 mmol) in diethyl ether (30 ml). The reaction mixture was then allowed to stand at room temperature overnight. Excess diazomethane was eliminated by the addition of acetic acid and the reaction mixture was evaporated to give preparation 15(1.0 g).

MS(ES)：M/Z[MH⁺]536.0, respectively; the predicted mass of C18H11 Cl2F8N5O + H was 536.0

The compound prepared in analogy to preparation 3 was:

preparation example 16

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [1- (difluoromethyl) -2, 2, 3, 3-tetrafluorocyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide;

the compound of preparation 47 (650 mg, 1.3 mmol) in toluene gave the title compound as a product mixture (50 mg).

MS(ES)：M/Z[MH⁺]553.9, respectively; the predicted mass of C18H10Cl2F9N5O + H was 554.0

Preparation example 17

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [1- (difluoromethyl) -2, 2-difluorocyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 48 (3.60 g, 7.7 mmol) the title compound (3.6 g) was obtained.

MS(ES)：M/Z[MH⁺]518.1, respectively; pre-treatment of C18H12Cl2F7N5O + HThe measured mass is 518.0

¹H-NMR(CDCl₃): 1.82 to 1.91(1H), 2.02 to 2.11(1H), 2.74 to 2.79(3H), 2.97 to 3.00(3H), 5.64 to 5.93(1H), 7.26 to 7.31(2H), 7.83 to 7.87(1H)

Preparation example 18

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (fluoromethyl) cyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 49 (100 mg, 0.23 mmol) the title compound (100 mg) was obtained.

MS(ES)：M/Z[MH⁺]484.0, respectively; the predicted mass of C18H13Cl2F6N5+ H was 484.1

Preparation example 19

N' - [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (2, 2-difluoro-1-methylcyclopropyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide; from the compound of preparation 50 (137 mg, 0.33 mmol) the title compound (80 mg) was obtained.

MS(ES)：M/Z[MH⁺]466.0, respectively; the predicted mass of C18H14Cl2F5N5+ H was 466.1

The compound prepared in analogy to preparation 15 was:

preparation example 20

N' - { 3-cyano-1- {2, 6-dichloro-4- [ (trifluoromethyl) thio ] phenyl } -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 51 (2.50 g, 4.6 mmol) the title compound (1.8 g) was obtained.

MS(ES)：M/Z[MH⁺]552.9, respectively; the predicted mass of C18H11Cl2F8N5S + H was 552.0

Preparation example 21

(2, 6-difluoro-4-trifluoromethyl-phenyl) hydrazine

A mixture of 1,2, 3-trifluoro-5- (trifluoromethyl) benzene (300 g, 1.5 mmol) and hydrazine monohydrate (300 g, 6.0 mmol) in ethanol (1200 ml) was heated under reflux overnight. The reaction mixture was concentrated in vacuo, and the residue was recrystallized from 2-propanol to give preparation 21(194 g).

MS(ES)：M/Z[MH⁺]213.2; the predicted mass of C7H5F5N2+ H was 213.1

¹H-NMR(CDCl₃): 3.81 to 4.08(2H), 5.23 to 5.41(1H), 7.03 to 7.14(2H)

The compound prepared in analogy to preparation 3 was:

preparation example 22

N' - {1- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -3-cyano-4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; obtained from the compound of preparation 52 (800 mg, 1.83 mmol) to give the title compound (260 mg).

MS(ES)：M/Z[MH⁺]487.2, respectively; the predicted quality of C17H11ClF8N6+ H was 487.1

Preparation example 23

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (difluoromethyl) -2, 2-difluorocyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 8 (4.52 g, 10.0 mmol) the title compound (4.0 g) was obtained.

MS(ES)：M/Z[MH⁺]501.92, respectively; the predicted mass of C18H12Cl2F7N5+ H was 502.04

¹H-NMR(CDCl₃): 1.82 to 1.91(1H), 2.03 to 2.11(1H), 2.73 to 2.78(3H), 2.97 to 3.01(3H), 5.66 to 5.93(1H), 7.63 to 7.69(2H), 7.85 to 7.89(1H)

Preparation example 24

According to Hainzl, D.; cole, l.m.; casida, J.E.chemical Research in biology (1998), 11(12), 1529-.

Preparation example 25

1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -5- { [ (1E) -pyridin-4-ylmethylene ] amino } -1H-pyrazole-3-carbonitrile

4-Isonicotaldehyde (550. mu.l, 6.71 mmol) and p-toluenesulfonic acid (catalytic amount, 5 mg) were added to toluene (10 ml) in example 2a (120 mg, 0.26 mmol) and 4A molecular sieves. The reaction mixture was then heated at reflux using a Dean Stark apparatus for 9 days. Water was added to the reaction mixture and the mixture was adjusted to pH2 by the addition of hydrochloric acid (4N). The mixture was then neutralized by addition of saturated aqueous sodium carbonate solution, extracted with ethyl acetate (3 × 20 ml) and over MgSO₄The combined extracts were dried and concentrated in vacuo to give preparation 25(200 mg).

MS(ES)：M/Z[MH⁺]554.0, respectively; the predicted mass of C21H9Cl2F8N5+ H was 554.0

Compound prepared in analogy to the procedure of preparation 15:

preparation example 26

N' - { 3-cyano-1- [2, 6-dichloro-4- (difluoromethoxy) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 53 (104 mg, 0.21 mmol) the title compound (110 mg) was obtained.

MS(ES)：M/Z[MH⁺]518.0; the predicted mass for C18H12Cl2F7N5O + H was 518.0

¹H-NMR(CDCl₃): 2.05 to 2.21(1H), 2.41 to 2.55(1H), 2.77 to 2.81(3H), 2.98 to 3.00(3H), 6.36 to 6.72(1H), 7.18 to 7.21(2H), 7.22 to 7.24(1H)

Compound prepared in a similar manner to preparation 3:

preparation example 27

N' - { 3-cyano-1- [2, 6-dichloro-4-pentafluorophenylthio ] -4- [1- (difluoromethyl) -2, 2, 3, 3-tetrafluorocyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 54 (618 mg, 1.13 mmol) the title compound (138 mg) was obtained.

MS(ES)：M/Z[MH⁺]596.1; the predicted mass of C17H10Cl2F11N5S + H was 596.0

¹H-NMR(CDCl₃): 2.78 to 2.81(3H), 2.99 to 3.02(3H), 5.95 to 6.24(1H), 7.76 to 7.79(1H), 7.79 to 7.82(2H)

Preparation example 28

2, 6-dichloro-4-difluoromethoxy-aniline

N-chlorosuccinimide (25.2 g, 18.9 mmol) was added to 4- [ (difluoromethoxy) methyl]Aniline (15.0 g, 94.3 mmol) in acetonitrile (150 ml) and the reaction mixture stirred under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between diethyl ether (500 ml) and water (125 ml). The organic layer was separated, washed with aqueous sodium thiosulfate, water and brine, and over MgSO₄Dried and treated with charcoal. The solution was filtered and concentrated in vacuo. The residue was extracted with hexane (2 × 300 ml) and the combined extracts were concentrated in vacuo to give preparation 28(13.8 g).

MS(ES)：M/Z[MH⁺]228, and (b); the predicted mass of C7H5Cl2F2NO + H was 227.98

Preparation example 29

5-amino-1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carboxylic acid ethyl ester

To a solution of preparation 21(95.0 g, 0.45 mmol) to preparation 9(92.6 g, 0.66 mmol) in ethanol (2 l) was added and the reaction mixture was heated under reflux overnight. The reaction mixture was cooled and sodium bicarbonate (36.0 g, 0.43 mmol) was added. The mixture was then heated at reflux overnight. The reaction mixture was concentrated in vacuo and diethyl ether (1 l) was added to the residue. The solution was filtered, washed with water, hydrochloric acid and water, dried and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 70 g) eluting with toluene. Appropriate fractions were combined and concentrated to give preparation 29(40 g).

MS(ES)：M/Z[MH⁺]336.1; the predicted mass of C13H10F5N3O2+ H was 336.1

Preparation example 30

5-amino-1- (2, 6-dichloro-4-difluoromethoxy-phenyl) -1H-pyrazole-3-carbonitrile

Sodium nitrite (4.8 g, 69.6 mmol) was added to sulfuric acid (concentrated, 21 ml) at 15 ℃. After stirring for one hour, glacial acetic acid (17.3 ml) was added and a solution of preparative example 28(13.8 g, 60.3 mmol) in acetic acid (33.8 ml) was added dropwise, keeping the temperature of the mixture below 25 ℃. The solution was heated at 50 ℃ for 1h, cooled and added dropwise at 0 ℃ to a mixture of preparative example 24(10.6 g, 69.6 mmol), acetic acid (42.8 ml) and ice/water (55 ml). The reaction mixture was then stirred at room temperature overnight. Dichloromethane (300 ml) was added to the reaction mixture and the mixture was stirred. The two layers were separated and the organic layer was washed with water. Ammonium hydroxide (concentrated, 125 ml) and ice were added to the organic layer and the mixture was stirred at 5 ℃ for 4 hours. The organic layer was separated again and stirred over activated carbon overnight. Through Celite^®The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Biotage, silica gel, 90 g) eluting with dichloromethane. The appropriate fractions were combined and concentrated to give the preparationExample 30(3.1 g).

MS(ES)：M/Z[MH⁺]319.0, respectively; the predicted mass of C11H6Cl2F2N4O + H was 319.0

¹H-NMR(CDCl₃): 3.60 to 3.88(2H), 6.38 to 6.75(1H), 7.22 to 7.23(1H), 7.27 to 7.29(2H)

Preparation example 31

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4-vinyl-1H-pyrazol-5-yl } -N, N-dimethyl-imidocarboxamide

A solution of preparation 57(500 mg, 1.44 mmol) in N, N-dimethylformamide dimethyl acetal (6 ml) was heated under reflux for one hour.

The reaction mixture was cooled and concentrated in vacuo. Diethyl ether (10 ml) followed by hexane was added to the residue until precipitation occurred. The solution was then concentrated under a stream of nitrogen to give the crude product. The crude product was washed with hexane and dried under vacuum to give preparation 31 as a pale yellow solid (560 mg).

MS(ES)：M/Z[MH⁺]402.2; the predicted mass of C16H12Cl2F3N5+ H was 402.1

¹H-NMR(CDCl₃): 2.81 to 2.87(3H), 3.00 to 3.05(3H), 5.29 to 5.36(1H), 5.91 to 6.00(1H), 6.35 to 6.46(1H), 7.64 to 7.67(1H), 7.68 to 7.72(2H)

Preparation example 32

N' - { 3-cyano-1- [2, 6-dichloro-4- (pentafluorothio) phenyl ] -4- [1- (trifluoromethyl) ethenyl ] -1H-pyr-azol-5-yl } -N, N-methylimidazolyliminamide carboxamide

A mixture of preparation 58(4.0 g, 7.1 mmol), preparation 59(3.0 g, 14.0 mmol), aqueous sodium bicarbonate (1M, 40 ml), toluene (100 ml) and methanol (40 ml) was degassed and placed under a nitrogen atmosphere. Adding tetra (triphenyl)Phenylphosphine) palladium (O) (360 mg) was added to the mixture, and the reaction mixture was degassed and heated at reflux for 8 hours. The reaction mixture was partitioned between water (50 ml) and diethyl ether (75 ml). The two layers were separated and the aqueous layer was re-extracted with diethyl ether (3 × 50 ml). In Na₂SO₄The combined organic phases were dried and concentrated in vacuo. Using Isolute^TMThe residue was purified by gradient elution from a cartridge (silica gel, 25 g), ethyl acetate: cyclohexane [ 1: 3 to 1: 1%]. The appropriate fractions were combined and concentrated, then Isolute was used^TMThe residue was chromatographed again on a cartridge (silica gel, 70 g) eluting with toluene. The product-containing fractions were concentrated to give preparation 32(1.34 g).

MS(ES)：M/Z[MH⁺]528.0, respectively; the predicted mass of C16H11Cl2F8N5S + H was 528.0

¹H-NMR(CDCl₃): 2.74 to 2.78(3H), 2.92 to 2.97(3H), 5.85 to 5.89(1H), 6.20 to 6.24(1H), 7.63 to 7.66(1H), 7.79 to 7.82(2H)

The compound prepared in analogy to the procedure of preparation 31 is:

preparation example 33

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (trifluoromethyl) vinyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 60 (170 mg, 0.41 mmol) the title compound was obtained as a white solid (140 mg).

MS(ES)：M/Z[MH⁺]470.2; the predicted mass of C17H11Cl2F6N5+ H was 470.0

¹H-NMR(CDCl₃): 2.76 to 2.80(3H), 2.96 to 3.00(3H), 5.90 to 5.92(1H), 6.23 to 6.26(1H), 7.66 to 7.68(1H), 7.69 to 7.72(2H)

Preparation example 34

N' - [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (1-fluorovinyl) -1H-pyrazol-5-yl ] -N, N-dimethyl-imidocarboxamide

Tetrakis (triphenylphosphine) palladium (O) (330 mg, 0.3 mmol) was added under nitrogen to a solution of preparation 62(2.9 g, 5.7 mmol) and preparation 61(2.5 g, 7.5 mmol) in N, N-dimethylformamide (50 ml). The reaction mixture was then heated at 80 ℃ for 4 hours. Water (150 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 ml). The combined extracts were washed with water (2X 100 ml) and saturated brine (100 ml) over MgSO₄Dried and concentrated in vacuo. The residue was wet-milled with hexane and the precipitate was collected by filtration and dried to give preparation 34 as a brown solid (2.35 g).

¹H-NMR(CDCl₃): 2.76 to 2.78(3H), 2.99 to 3.01(3H), 4.92 to 5.10(2H), 7.66 to 7.68(2H), 7.70 to 7.73(1H)

Preparation example 35

N' - [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (trifluorovinyl) -1H-pyrazol-5-yl ] -N, N-dimethyl-imidocarboxamide

Diisobutylaluminum hydride (1.5M in toluene, 133 μ l) was added to a suspension of dichlorobis (triphenylphosphine) palladium II (70 mg) in tetrahydrofuran (2 ml). Bromofluoroethylene (200 mmol) and preparation 64(1.0 mmol) were added to the solution, and the reaction mixture was heated under nitrogen at reflux overnight. The reaction mixture was partitioned between ethyl acetate (50 ml) and water, and the organic phase was separated, washed with brine, over MgSO₄Dried and concentrated in vacuo. The residue was purified using an IsoluteTM column (silica gel, 20 g) eluting with dichloromethane. The appropriate fractions were combined and concentrated, and the residue was dissolved in hexane. The formed precipitate was separated and dried to obtain preparation example 35(200 mg) as a crystalline solid.

MS(ES)：M/Z[MH⁺]456.2, respectively; the predicted mass of C16H9Cl2F6N5+ H was 456.0

¹H-NMR(CDCl₃): 2.77 to 2.80(3H), 3.02 to 3.05(3H), 7.67 to 7.69(2H), 7.74 to 7.77(1H)

Preparation example 36

2, 6-dichloro-4-trifluoromethylthio-anilines

To a solution of preparation 97(4.8 g, 25.0 mmol) in acetonitrile (50 ml) was added N-chlorosuccinimide (6.7 g, 50.0 mmol) at 50 ℃. The reaction mixture was then stirred at 50 ℃ for 1 hour. Water (150 ml) was added to the reaction mixture and the mixture was extracted with dichloromethane (100 ml). Over MgSO₄The combined extracts were dried and concentrated in vacuo to afford preparation 36(1.0 g).

Preparation example 37

N' - [ 3-cyano-1- [2, 6-dichloro-4- (pentafluorothio) phenyl ] -4- (trifluorovinyl) -1H-pyrazol-5-yl ] -N, N-dimethyl-imidocarboxamide

Stirring Rieke under nitrogen atmosphere^TMSuspension of zinc in tetrahydrofuran (5%, 26 ml, 20 mmol). The nitrogen atmosphere was exchanged with bromotrifluoroethylene (about 40 mmol) and the solution was stirred for a further 3 hours. Nitrogen was passed through the solution and the excess zinc was allowed to settle, leaving a supernatant of the desired zinc reagent. This zinc reagent solution (12 ml, ca. 5.0 mmol) was added to a solution of preparative example 58(2.24 g, 4.0 mmol) and tetrakis (triphenylphosphine) palladium (O) (231 mg) in tetrahydrofuran (5 ml). The reaction mixture was then heated at reflux under nitrogen for 5 hours. Excess aqueous acetic acid (dilute) was added to the reaction mixture and the mixture was extracted with dichloromethane (150 ml). The extract was washed with brine, over MgSO₄Dried and concentrated in vacuo. Using Isolute^TMThe column (silica gel, 50 g) was eluted with toluene to purify the residue. The appropriate fractions were combined and concentrated to give preparation 37(913 mg).

MS(ES)：M/Z[MH⁺]514.2; the predicted mass of C15H9Cl2F8N5S + H was 514.0

¹H-NMR(CDCl₃): 2.79 to 2.82(3H), 3.03 to 3.06(3H), 7.75 to 7.77(1H), 7.80 to 7.83(2H)

The compound prepared in a manner analogous to that of preparation 34 was:

preparation example 38

N' - [ 3-cyano-1- [2, 6-dichloro-4-pentafluorosulfanyl ] -4- (1-fluorovinyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide; the title compound (85 mg) was obtained from the compound of preparation 58 (380 mg, 0.68 mmol) and preparation 61(295 mg, 0.88 mmol).

MS(ES)：M/Z[MH⁺]477.9; the predicted mass of C15H 11Cl2F6N 5S + H was 478.0

¹H-NMR(CDCl₃): 2.77 to 2.81(3H), 2.99 to 3.03(3H), 4.92 to 5.09(2H), 7.70 to 7.73(1H), 7.79 to 7.82(2H)

Preparation example 39

N' - [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (difluoroacetyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide

To a solution of preparation 62(12.5 g, 25.0 mmol) in tetrahydrofuran (50 ml) was added dropwise isopropyl magnesium chloride (2M in tetrahydrofuran, 13.75 ml, 27.5 mmol) at-30 ℃. The reaction mixture was stirred at-30 ℃ for 30 minutes, then difluoroacetic acid chloride (2M in tetrahydrofuran, 18.75 ml, 37.5 mmol) was added. The reaction mixture was then allowed to warm to room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate (× 3). The combined organic phases were washed with saturated sodium chloride solution over MgSO₄Dried and concentrated in vacuo. The residue was recrystallized from diethyl ether by the addition of petroleum ether to give preparation 39(7.6 g).

¹H-NMR(CDCl₃): 2.78 to 2.82(3H), 3.08 to 3.12(3H), 6.41 to 6.69(1H), 7.67 to 7.71(2H), 8.49 to 8.52(1H)

Preparation example 40

N' - { 3-cyano-1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -4- [1- (trifluoromethyl) ethenyl ] -1H-pyrazol-5-yl } -N, N-dimethyl-imidocarboxamide

To a solution of preparation 66(2.0 g, 4.26 mmol) and tetrakis (triphenylphosphine) palladium (O) (246 mg, 0.21 mmol) in N, N-dimethylformamide (70 ml) was added a solution of preparation 65 in tetrahydrofuran (15.75 ml, 6.3 mmol). The reaction mixture was then heated at 110 ℃ overnight in a device equipped with a Dean-Stark trap.

The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) eluting with toluene. The appropriate fractions were combined and concentrated to give preparation 40(1.5 g).

MS(ES)：M/Z[MH⁺]438.0; the predicted quality of C17H11F8N5+ H was 438.1

¹H-NMR(CDCl₃): 2.78 to 2.81(3H), 2.95 to 2.99(3H), 5.84 to 5.87(1H), 6.20 to 6.23(1H), 7.28 to 7.33(2H), 7.64 to 7.68(1H)

Preparation example 41

N' - { 3-cyano-1- [2, 6-dichloro-4-pentafluorophenylthio ] -4- [1- (difluoromethyl) ethenyl ] -1H-pyrazol-5-yl } -N, N-dimethyl-imidocarboxamide

N-butyllithium (1.6N, 3.2 ml, 5.05 mmol in hexanes) was added via syringe to a solution of methyltriphenylphosphonium bromide (1.80 g, 5.05 mmol) in tetrahydrofuran (20 ml) at 0 ℃. After stirring for 15 minutes, a solution of preparation 67(1.72 g, 3.37 mmol) in tetrahydrofuran (10 ml) was added and stirred at room temperatureThe reaction mixture was stirred for 2.5 hours. Water (50 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (3 × 30 ml). Over MgSO₄The combined organic phases were dried and concentrated in vacuo. By using gradient elution, ethyl acetate: hexane [ 1: 4 to 1: 2]The residue was purified by column chromatography (silica gel). The appropriate fractions were combined and concentrated to give preparation 41(1.40 g).

MS(ES)：M/Z[MH⁺]509.9, respectively; the predicted mass of C16H12Cl2F7N5S + H was 510.0

¹H-NMR(CDCl₃): 2.75 to 2.78(3H), 2.91 to 2.95(3H), 5.76 to 5.78(1H), 5.91 to 5.94(1H), 6.14 to 6.43(1H), 7.63 to 7.65(1H), 7.79 to 7.82(2H)

The compound prepared in a manner analogous to that of preparation 41 was:

preparation example 42

N' - {4- {1- [ chloro (fluoro) methyl ] vinyl } -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 68 (800 mg, 1.70 mmol) the title compound (800 mg) was obtained.

MS(ES)：M/Z [MH⁺]468.1, respectively; the predicted mass of C17H12Cl3F4N5+ H was 468.0

¹H-NMR(CDCl₃): 2.75 to 2.78(3H), 2.91 to 2.94(3H), 5.67 to 5.70(1H), 5.91 to 5.95(1H), 6.72 to 6.86(1H), 7.65 to 7.68(2H), 7.70 to 7.73(1H)

Preparation example 43

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (difluoromethyl) -2, 2-difluorovinyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide

Dibromodifluoromethane (420 mg, 2.0 mmol) to triphenylphosphine (524 mg, 2.0 mmol) was added under nitrogen to N, N-bisMethyl formamide (5 ml). The mixture was stirred at room temperature for 30 minutes, then preparative example 39(454 mg, 1.0 mmol) in N, N-dimethylformamide (1 ml) was added. Addition of Rieke^®Zinc (130 mg, 2.0 mmol) was added to the mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) eluting with dichloromethane. Appropriate fractions were combined and concentrated to give preparation 43(410 mg).

MS(ES)：M/Z[MH⁺]487.8, respectively; the predicted mass of C17H10Cl2F7N5+ H was 488.0

¹H-NMR(CDCl₃): 2.74 to 2.77(3H), 2.95 to 2.98(3H), 6.43 to 6.72(1H), 7.66 to 7.68(2H), 7.69 to 7.70(1H)

Preparation example 44

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) ethenyl ] -1H-pyrazol-5-yl } -N, N-dimethyl-imidocarboxamide

Make Rieke^®A suspension of zinc in tetrahydrofuran (15.6 ml, 12.0 mmol) settled and tetrahydrofuran was removed as much as possible. Then dry N, N-dimethylformamide (25 ml) was added to the Rieke^®Zinc and the solution was stirred under nitrogen. 2-bromopentafluoropropene (1.05 g, 5.0 mmol) was condensed in a cold vessel under nitrogen and slowly added to the zinc solution via syringe. The reaction mixture was then stirred at room temperature for 12 hours. A solution of the zinc reagent in N, N-dimethylformamide (12 ml, ca. 4.0 mmol) was added under nitrogen to preparative example 62(1.04 g, 2.0 mmol) and tetrakis (triphenylphosphine) palladium (O) (120 mg). The reaction mixture was stirred at 90 ℃ for 3 hours and then at 100 ℃ for 6 hours. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was separated over MgSO₄Dried and concentrated in vacuo. Using Isolute^TMThe column (silica gel, 50 g) was eluted with toluene to purify the residue. Concentrating the fraction containing the productAnd the residue was dissolved in acetonitrile/water/dimethylsulfoxide (12: 1: 3, 1.6 ml). Further by using an acetonitrile/water gradient [ 65: 35 to 95: 5%]The solution was purified by automated preparative liquid chromatography (Gilson System, 150X 30 mm LUNA C185 micron column). The appropriate fractions were concentrated in vacuo to afford preparation 44(28 mg).

MS(ES)：M/Z[MH⁺]506.0, respectively; the predicted mass of C17H9Cl2F8N5+ H was 506.0

¹H-NMR(CDCl₃): 2.74 to 2.81(3H), 2.96 to 3.02(3H), 7.62 to 7.66(1H), 7.66 to 7.71(2H)

Preparation example 45

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) ethenyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide

Triphenylphosphine (21.6 g, 82.3 mmol) and dibromodifluoromethane (8.6 g, 41.2 mmol) were added to a solution of preparation 71(6.7 g, 13.7 mmol) in N, N-dimethylformamide (60 ml). The reaction mixture was then stirred at room temperature under nitrogen for 5 days. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) using gradient elution, toluene: dichloromethane [ 1: 0 to 1: 2 ]. The appropriate fractions were combined and concentrated to give preparation 45(2.8 g).

MS(ES)：M/Z[MH⁺]522.0, respectively; the predicted mass of C17H9Cl2F8N5O + H was 522.0

Preparation example 46

2, 3-Dicyanopropionic acid ethyl ester

Glycolonitrile (700.0 g, 6.75 mol) (55% solution) in water was slowly added to a solution of ethyl cyanoacetate (916.0 g, 8.10 mol) in N, N-dimethylformamide (2.5 l). Potassium carbonate (932.7 g, 6.75 moles) was added to the mixture over 1.5 hours to ensure the reaction temperatureThe degree rise does not exceed 30 ℃. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was adjusted to pH3 by addition of acid. The organic phase was separated and partially concentrated in vacuo. Diethyl ether (1 l) was added to the concentrate and the solution was washed with water (5X 1 l) over MgSO₄Dried above and concentrated in vacuo to afford preparation 46(803 g).

¹H-NMR(CDCl₃): 1.28 to 1.34(3H), 2.95 to 3.01(2H), 3.84 to 3.89(1H), 4.27 to 4.33(2H)

The compound prepared in a manner analogous to that of preparation 43 was:

preparation example 47

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [1- (difluoromethyl) -2, 2-difluorovinyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 72 (1.1 g, 2.3 mmol) the title compound (650 mg) was obtained.

¹H-NMR(CDCl₃): 2.74 to 2.78(3H), 2.93 to 2.98(3H), 6.42 to 6.71(1H), 7.28 to 7.31(2H), 7.65 to 7.69(1H)

Preparation example 48

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- [1- (difluoromethyl) ethenyl ] -1H-pyrazol-5-yl } -N, N-dimethyl-imidocarboxamide

A mixture of potassium tert-butoxide (1M solution, 11.7 ml, 11.7 mmol) and methyltriphenylphosphonium bromide (3.91 g, 14.0 mmol) in cyclohexane (50 ml) was stirred at 50 ℃ over 45 minutes and then cooled to 10 ℃. A solution of preparative 72(4.40 g, 9.36 mmol) in dichloromethane (20 ml) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) using gradient elution, toluene: dichloromethane [ 1: 0 to 0: 1 ]. The appropriate fractions were combined and concentrated to give preparation 48(3.6 g).

MS(ES)：M/Z[MH⁺]468.0, respectively; the predicted mass of C17H12Cl2F5N5O + H was 468.0

¹H-NMR(CDCl₃): 2.74 to 2.78(3H), 2.90 to 2.95(3H), 5.76 to 5.80(1H), 5.89 to 5.93(1H), 6.16 to 6.46(1H), 7.27 to 7.31(2H), 7.58 to 7.62(1H)

The compound prepared in a similar manner was:

preparation example 49

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (fluoromethyl) ethenyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 73(370 mg, 0.85 mmol) the title compound (242 mg) was obtained.

MS(ES)：M/Z[MH⁺]434.0, respectively; the predicted mass of C17H13Cl2F4N5+ H was 434.1

¹H-NMR(CDCl₃): 2.78 to 2.81(3H), 2.92 to 2.95(3H), 4.95 to 4.98(1H), 5.07 to 5.10(1H), 5.61 to 5.64(2H), 7.61 to 7.64(1H), 7.65 to 7.68(2H)

Preparation example 50

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4-isopropenyl-1H-pyrazol-5-yl } -N, N-dimethyl-imidocarboxamide

Molecular sieves (4 Å, 3.0 g) were added to a solution of tetrabutylammonium chloride (204 mg, 0.69 mmol) in acetonitrile (7 ml). After 30 minutes, the solution was decanted and added to preparation 74(100 mg, 0.23 mmol). The mixture was cooled to-10 ℃ and thionyl chloride (33.5 μ l, 0.46 mmol) was added dropwise. After stirring for 15 min, sodium methyl mercaptide (32 mg, 0.46 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo and dichloromethane (50 ml) was added to the residueThe residue is left. The solution was washed with water (3X 35 ml) over MgSO₄Dried and concentrated in vacuo. The residue was passed through a plug of silica gel eluting with dichloromethane.

The filtrate was concentrated in vacuo to give preparation 50 (137 mg).

MS(ES)：M/Z[MH⁺]416.0, respectively; the predicted mass for C17H14Cl2F3N5+ H was 416.1

¹H-NMR(CDCl₃): 2.01 to 2.03(3H), 2.76 to 2.78(3H), 2.93 to 2.97(3H), 5.20 to 5.22(1H), 5.30 to 5.33(1H), 7.59 to 7.60(1H), 7.64 to 7.67(2H)

The compound prepared in a manner analogous to that of preparation 43 was:

preparation example 51

N' - { 3-cyano-1- {2, 6-dichloro-4- [ (trifluoromethyl) thio ] phenyl } -4- [2, 2-difluoro-1- (trifluoromethyl) ethenyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 75 (6.50 g, 12.9 mmol) the title compound (2.5 g) was obtained.

MS(ES)：M/Z[MH⁺]537.9, respectively; the predicted mass of C17H9Cl2F8N5S + H was 538.0

¹H-NMR(CDCl₃): 2.74 to 2.77(3H), 2.96 to 2.99(3H), 7.60 to 7.63(1H), 7.68 to 7.72(2H)

The compound prepared in analogy to the procedure of preparation 48 was:

preparation example 52

N' - {1- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -3-cyano-4- [1- (trifluoromethyl) vinyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 76 (1.00 g, 2.3 mmol) the title compound (820 mg) was obtained.

MS(ES)：M/Z[MH⁺]437.0, respectively; predicted quality of C16H11ClF6N6+ HIs 437.1

¹H-NMR(CDCl₃): 2.89 to 2.91(3H), 2.98 to 3.01(3H), 5.96 to 5.98(1H), 6.26 to 6.28(1H), 7.65 to 7.68(1H), 8.14 to 8.16(1H), 8.69 to 8.71(1H)

The compound prepared in a manner analogous to that of preparation 43 was:

preparation example 53

N' - { 3-cyano-1- [2, 6-dichloro-4- (difluoromethoxy) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) vinyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 77 (425 mg, 0.9 mmol) the title compound (107 mg) was obtained.

MS(ES)：M/Z[MH⁺]504.0, respectively; the predicted mass of C17H10Cl2F7N5O + H was 504.0

¹H-NMR(CDCl₃): 2.77 to 2.80(3H), 2.96 to 2.99(3H), 6.36 to 6.72(1H), 7.20 to 7.22(2H), 7.58 to 7.60(1H)

Preparation example 54

N' - { 3-cyano-1- [2, 6-dichloro-4-pentafluorophenylthio ] -4- [1- (difluoromethyl) -2, 2-difluorovinyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 67 (1.02 g, 2.0 mmol) the title compound was obtained (612 mg).

MS(ES)：M/Z[MH⁺]546.1; the predicted mass of C16H10Cl2F9N5S + H was 546.0

The compound prepared in a manner analogous to that of preparation 3 was:

preparation example 55

N' - {4- {1- [ chloro (difluoro) methyl ] -2, 2-difluorocyclopropyl } -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 78 (100 mg, 0.2 mmol) the title compound (124 mg) was obtained.

MS(ES)：M/Z[MH⁺]535.9, respectively; the predicted mass of C18H11Cl3F7N5+ H was 536.0

Preparation example 56

5-amino-1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carboxylic acid amide

A mixture of preparation 29(600 mg, 1.79 mmol), methanol (5 ml) and ammonium hydroxide (5 ml) was heated at 50 ℃ for 5 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel) eluting with dichloromethane/ethyl acetate [ 1: 1 ]. The appropriate fractions were combined and concentrated to give the title compound (210 mg).

MS(ES)：M/Z[MH⁺]307.1, respectively; the predicted mass of C11H7F5N4O + H was 307.06

¹H-NMR(CD₃OD): 5.93 to 5.95(1H), 7.58 to 7.64(2H)

Preparation example 57

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4-vinyl-1H-pyrazole-3-carbonitrile may be prepared according to EP933363A1, WO9824767 or WO 9804530.

The compound prepared in a manner analogous to that of preparation 31 is:

preparation example 58

N' - { 3-cyano-1- [2, 6-dichloro-4- (pentafluorothio) phenyl ] -4-iodo-1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide; from the compound of preparation 79 (52 g, 103 mmol) the title compound was obtained as a beige solid (45 g).

¹H-NMR(CDCl₃): 2.77 to 2.81(3H), 3.02 to 3.05(3H), 7.78 to 7.81(2H), 8.21 to 8.24(1H)

Preparation example59

1- (trifluoromethyl) vinylboronic acid

Trimethyl borate (68.13 ml, 0.6 mol) was added dropwise to magnesium turnings (5.83 g, 0.24 mol) in tetrahydrofuran (400 ml). The reaction mixture was cooled to 0 ℃ and 2-bromo-3, 3, 3-trifluoropropene (20.75 ml, 0.2 mol) was added dropwise. The reaction mixture was then allowed to warm to room temperature and stirred under nitrogen overnight. The reaction mixture was again cooled to 0 ℃ and hydrochloric acid (5M, 200 ml) was added dropwise to ensure that the temperature of the solution was maintained below 10 ℃. The reaction mixture was then stirred under nitrogen for 48 hours. Diethyl ether (100 ml) and water (200 ml) were added to the reaction mixture to obtain two phases. The aqueous layer was separated and extracted with diethyl ether (100 ml). The combined organic layers were washed with water (100 ml) over MgSO₄Dried and concentrated in vacuo. Cyclohexane (50 ml) was added to the residue, resulting in the formation of a precipitate. The precipitate was isolated by decanting the solution, washed with cyclohexane, and dried in vacuo to afford preparation 59 as a white solid (2.62 g, 0.02 mol).

¹H-NMR (DMSO): 5.50 to 5.57(1H), 5.80 to 5.88(1H), 6.22 to 6.36(2H)

Preparation example 60

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (trifluoromethyl) vinyl ] -1H-pyrazole-3-carbonitrile

A solution of tetrakis (triphenylphosphine) palladium (O) (2 mol%, 23 mg) in toluene (10 ml) and methanol (2 ml) was added under nitrogen to a mixture of preparation 82(223 mg, 0.5 mmol) and preparation 59(212 mg, 1.0 mmol). Aqueous sodium carbonate (1M, 2 ml) was added to the mixture and the biphasic reaction mixture was heated at 85 ℃ under nitrogen for 22 h. The reaction mixture was cooled, diluted with diethyl ether and the organic layer was separated. Then washed with water (2X 5 ml) over MgSO₄Dried and concentrated under a stream of nitrogen. Using Isolute^TMCartridges (silica gel, 10 g) were washed with a gradientThe residue is purified by dehydration in cyclohexane/dichloromethane [ 3: 2 to 1: 1%]. Appropriate fractions were combined and concentrated to give preparation 60(138 mg).

MS(ES)：M/Z[MH⁺]415.1; the predicted mass of C14H6Cl2F6N4+ H was 415.0

¹H-NMR(CDCl₃): 3.90 to 3.98(2H), 5.96 to 5.99(1H), 6.25 to 6.28(1H), 7.80 to 7.82(2H)

Preparation example 61

Tributyl (1-fluorovinyl) stannane

Bis (tributyltin) oxide (6 ml, 11.7 mmol) and cesium fluoride (500 mg, 1.94 mmol) were added under nitrogen to a solution of preparation 83(4.7 g, 19.4 mmol) in dry N, N-dimethylformamide (50 ml). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml) and extracted with a mixture of hexane and diethyl ether (3: 1, 150 ml). The extract was washed with water (2X 50 ml) and saturated brine solution (50 ml) over MgSO₄Dried above and concentrated in vacuo to give preparation 61 as a colourless oil (5.1 g).

¹H-NMR(CDCl₃): 0.85 to 0.89(9H), 0.91 to 1.06(6H), 1.27 to 1.35(7H), 1.40 to 1.63(6H), 4.41 to 4.64(1H), 5.14 to 5.43(1H)

The compound prepared in a manner analogous to that of preparation 31 is:

preparation example 62

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4-iodo-1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide; from the compound of preparation 82 (0.5 g, 1.12 mmol) the title compound was obtained as a yellow crystalline solid.

MS(ES)：M/Z[MH⁺]502.1; the predicted mass of C14H9Cl2F3IN5+ H was 501.9

¹H-NMR(CDCl₃): 2.78 to 2.82(3H), 3.03 to 3.08(3H), 7.67 to 7.71(2H), 8.23 to 8.27(1H)

Preparation example 63

N' - { 3-cyano-1- [2, 6-dichloro-4- (difluoromethoxy) phenyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 30(3.1 g; 9.7 mmol) the title compound was obtained (3.5 g).

MS(ES)：M/Z[MH⁺]374.0, respectively; the predicted mass of C14H11Cl2F2N5O + H was 374.0

¹H-NMR(CDCl₃): 2.76 to 2.80(3H), 2.99 to 3.03(3H), 6.14 to 6.17(1H), 6.35 to 6.72(1H), 7.11 to 7.15(1H), 7.21 to 7.24(1H), 7.70 to 7.73(1H)

Preparation 64

(3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (1E) - (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) (iodo) zinc

Addition of Rieke under nitrogen^®A slurry of zinc (1.31 g, 20.0 mmol) in tetrahydrofuran (26 ml) to a solution of preparation 62(5.02 g, 10.0 mmol) in tetrahydrofuran (24 ml). The reaction mixture was then stirred at room temperature. The excess zinc metal was allowed to settle and the solution containing preparation 64 (0.2 moles per liter) was used directly in the next stage.

Preparation example 65

Add 2-bromo-3, 3, 3-trifluoroprop-1-ene (14.0 g, 80.0 mmol) to Rieke under nitrogen^®Zinc (5% in tetrahydrofuran, 7.8 g, 157 ml, 120.0 mmol) In solution in tetrahydrofuran (43 ml). The reaction mixture was stirred overnight and the solution of preparation 65 was used without further purification.

The compound prepared in a manner analogous to that of preparation 31 is:

preparation example 66

N' - { 3-cyano-1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -4-iodo-1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide; from the compound of preparation 84 (2.2 g, 5.3 mmol) the title compound (2.3 g) was obtained.

¹H-NMR(CDCl₃): 2.79 to 2.82(3H), 3.03 to 3.06(3H), 7.27 to 7.33(2H), 8.22 to 8.25(1H)

The compound prepared in analogy to the procedure of preparation 39 was:

preparation example 67

N' - [ 3-cyano-1- [2, 6-dichloro-4-pentafluorophenylthio ] -4- (difluoroacetyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide; the compound from preparation 58 (2.50 g, 4.47 mmol) and isopropylmagnesium (1.72 g).

MS(ES)：M/Z[MH⁺]511.8; the predicted mass of C15H10Cl2F7N5OS + H was 512.0

¹H-NMR(CDCl₃): 2.81 to 2.83(3H), 3.09 to 3.13(3H), 6.41 to 6.69(1H), 7.82 to 7.85(2H), 8.51 to 8.54(1H)

Preparation example 68

N' - {4- [ chloro (fluoro) acetyl ] -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; the compound from preparation 62(1.0 g, 1.99 mmol) and magnesium isopropyl (800 mg).

MS(ES)：M/Z[MH⁺]470.0, respectively; the predicted mass of C16H10Cl3F4N5O + H was 470.0

¹H-NMR(CDCl₃): 2.79 to 2.84(3H), 3.07 to 3.12(3H), 7.20 to 7.24(1H), 7.67 to 7.71(2H), 8.45 to 8.48(1H)

Preparation example 69

5-amino-1- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -1H-pyrazole-3-carbonitrile can be prepared according to EP500209

Preparation example 70

5-amino-1- {2, 6-dichloro-4- [ (trifluoromethyl) thio ] phenyl } -1H-pyrazole-3-carbonitrile

Sodium nitrite (224 mg, 3.25 mmol) was added carefully to sulfuric acid (concentrated, 1 ml) to ensure that the temperature did not rise above 30 ℃. After stirring for one hour at 15 ℃, acetic acid (2 ml) was added followed by a solution of preparation 36(850 mg, 3.24 mmol) in acetic acid (3 ml). The reaction mixture was then heated at 50 ℃ for 1 hour and cooled to room temperature. A solution of ice water (5 ml) and diazonium salt was added dropwise to a solution of preparation 24(500 mg, 3.29 mmol) in acetic acid (5 ml) at 0 ℃. After complete addition, ammonium hydroxide (6 ml) was added and the reaction mixture was stirred at room temperature overnight.

Via Arbocel^®The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue is partitioned between dichloromethane and water and the organic phase is separated in Na₂SO₄Dried and concentrated in vacuo to afford preparation 70(1.0 g).

MS(ES)：M/Z[MH⁺]353.0, respectively; the predicted mass of C11H5Cl2F3N4S + H was 353.0

¹H-NMR(CDCl₃): 6.01 to 6.03(1H), 7.75 to 7.78(2H)

Preparation 71

N' - [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- (trifluoroacetyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide

Trifluoroacetic anhydride (4.32 ml, 6.4 g, 30.6 mmol) was added dropwise to a solution of preparative example 87(6.0 g, 15.3 mmol) in pyridine (75 ml). The reaction mixture was then stirred at room temperature under nitrogen overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) eluting with toluene. The appropriate fractions were combined and concentrated to give a mixture of protected and deprotected products. Dichloromethane and N, N-dimethylformamide dimethyl acetal (5 ml) were added to the residue. The mixture was stirred at room temperature overnight and then concentrated in vacuo to afford preparation 71(6.7 g).

MS(ES)：M/Z[MH⁺]488.0, respectively; the predicted mass of C16H9Cl2F6N5O2+ H was 488.0

¹H-NMR(CDCl₃): 2.80 to 2.84(3H), 3.09 to 3.13(3H), 7.30 to 7.33(2H), 8.30 to 8.34(1H)

The compound prepared in analogy to the procedure of preparation 39 was:

preparation example 72

N' - [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4- (difluoroacetyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide; from the compound of preparation 89 (6.20 g, 12.0 mmol) and isopropylmagnesium (4.4 g).

MS(ES)：M/Z[MH⁺]470.0, respectively; the predicted mass of C16H10Cl2F5N5O2+ H was 470.0

¹H-NMR(CDCl₃): 2.79 to 2.83(3H), 3.08 to 3.12(3H), 6.41 to 6.69(1H), 7.30 to 7.33(2H), 8.46 to 8.49(1H)

Preparation example 73

N' - [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (fluoroacetyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide

N, N-dimethylformamide dimethyl acetal (190 mg, 1.59 mmol) was added to a solution of preparation 91(550 mg, 1.44 mmol) in dichloromethane (10 ml) and the reaction mixture was stirred at 35 ℃ for 1 hour. The reaction mixture was concentrated in vacuo and the residue was passed through a plug of silica gel eluting with dichloromethane. The filtrate was concentrated in vacuo to give preparation 73(370 mg).

¹H-NMR(CDCl₃): 2.77-2.79 (3H), 3.08-3.11 (3H), 5.43-5.46 (1H), 5.55-5.57 (1H), 7.67-7.70 (2H), 8.63-8.66 (1H)

Preparation example 74

N' - [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (1-hydroxy-1-methylethyl) -1H-pyrazol-5-yl ] -N, N-dimethyl-imidocarboxamide

To a solution of preparation 62(1.0 g, 2.0 mmol) in tetrahydrofuran (15 ml) was added dropwise isopropyl magnesium chloride (2M in tetrahydrofuran, 1.2 ml, 2.4 mmol) at-30 ℃ under nitrogen. After stirring for one hour, acetone (5 ml) was added via syringe and the reaction mixture was allowed to warm to room temperature. Water (7 ml) and solid sodium carbonate (ca. 20 g) were added to the reaction mixture. The mixture was stirred for 15 minutes, filtered and the residue was washed with dichloromethane. The organic phase is then separated, dried and concentrated in vacuo. The residue was passed through a plug of silica gel eluting with dichloromethane and then diethyl ether. The filtrate was concentrated in vacuo to give the title compound (280 mg).

MS(ES)：M/Z[MH⁺]434.0, respectively; the predicted mass of C17H16Cl2F3N5O + H was 434.1

¹H-NMR(CDCl₃): 1.65 to 1.69(6H), 2.79 to 2.82(3H), 2.85 to 2.88(3H), 3.36 to 3.41(1H), 7.40 to 7.42(1H), 7.65 to 7.69(2H)

Preparation example 75

N' - [ 3-cyano-1- {2, 6-dichloro-4- [ (trifluoromethyl) thio ] phenyl } -4- (trifluoroacetyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide

Trifluoroacetic anhydride (8.75 g, 41.6 mmol) was added dropwise to a solution of preparative example 92(8.50 g, 20.8 mmol) in anhydrous pyridine (100 ml). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel) using gradient elution, toluene: dichloromethane [ 1: 0 to 1: 1 ]. The appropriate fractions were combined and concentrated to give preparation 75(7.1 g).

MS(ES)：M/Z[MH⁺]504.0, respectively; the predicted mass of C16H9Cl2F6N 5OS + H was 504.0

¹H-NMR(CDCl₃): 2.78 to 2.81(3H), 3.09 to 3.12(3H), 7.70 to 7.73(2H), 8.34 to 8.37(1H)

The compound prepared in a manner analogous to that of preparation 31 is:

preparation example 76

N' - [1- [ 3-chloro-5- (trifluoromethyl) pyridin-2-yl ] -3-cyano-4- (trifluoroacetyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide; from the compound of preparation 93 (5.98 g, 15.6 mmol) the title compound (6.3 g) was obtained.

MS(ES)：M/Z[MH⁺]439.0, respectively; the predicted quality of C15H9ClF6N6O + H was 439.1

¹H-NMR(CDCl₃): 2.83 to 2.86(3H), 3.11 to 3.14(3H), 8.13 to 8.15(1H), 8.33 to 8.35(1H), 8.76 to 8.79(1H)

The compound prepared in analogy to the procedure of preparation 39 was:

preparation example 77

N' - [ 3-cyano-1- [2, 6-dichloro-4- (difluoromethoxy) phenyl ] -4- (trifluoroacetyl) -1H-pyrazol-5-yl ] -N, N-dimethylimidocarboxamide; from the compound of preparation 94 (0.50 g, 1.0 mmol) the title compound (425 mg) was obtained.

The compound prepared in analogy to the procedure of preparation 48 was:

preparation example 78

N' - {4- {1- [ chloro (difluoro) methyl ] vinyl } -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 96 (1.20 g, 2.5 mmol) the title compound (1.1 g) was obtained.

MS(ES)：M/Z[MH⁺]485.9, respectively; the predicted mass of C17H11Cl3F5N5+ H was 486.0

¹H-NMR(CDCl₃): 2.72 to 2.75(3H), 2.93 to 2.95(3H), 5.76 to 5.78(1H), 6.18 to 6.20(1H), 7.66 to 7.68(2H), 7.74 to 7.77(1H)

Preparation example 79

5-amino-1- [2, 6-dichloro-4- (pentafluorothio) phenyl ] -4-iodo-1H-pyrazole-3-carbonitrile

To a solution of preparative example 95(40.0 g, 106 mmol) in acetonitrile (400 ml) was added N-iodosuccinimide (26.4 g, 117 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (1 l) and washed with aqueous sodium thiosulfate (10%, 3 × 500 ml) and brine (500 ml). Over MgSO₄The organic phase was dried and concentrated in vacuo to afford preparation 79 as a brown solid (53 g).

¹H-NMR(CDCl₃): 3.87 to 3.94(2H), 7.88 to 7.90(2H)

Preparation example 80

5-amino-4- (2-bromo-acetyl) -1- (2, 6-dichloro-4-trifluoromethyl-phenyl) -1H-pyrazole-3-carbonitrile can be prepared according to US6069157 or EP846686

The compound prepared in analogy to the procedure of preparation 79 was:

preparation example 81

5-amino-1- (2, 6-dichloro-4-trifluoromethoxy-phenyl) -4-iodo-1H-pyrazole-3-carbonitrile; from the compound of preparation 88 (5.0 g, 14.8 mmol) the title compound (6.8 g) was obtained.

MS(ES)：M/Z[MH⁺]462.8, respectively; the predicted mass of C11H4Cl2F3IN4O + H was 462.9

Preparation example 82

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4-iodo-1H-pyrazole-3-carbonitrile can be prepared according to US6069157, EP933363, WO 9828278.

Preparation example 83

(1-fluorovinyl) (methyl) diphenylsilane

To a solution of chloromethyldiphenylsilane (15.8 ml, 75 mmol) and a catalytic amount of iodine in lithium wire (2.08 g, 300 mmol) in dry tetrahydrofuran (150 ml) was added. The reaction mixture was sonicated for 40 minutes and then stirred at room temperature overnight. The reaction mixture was cooled to-78 ℃ and 1, 1-difluoroethylene (about 225 mmol) was passed through the mixture, taking 30 minutes. The mixture was stirred at-78 ℃ for 2 hours and then warmed to room temperature.

The reaction mixture was quenched with saturated ammonium chloride solution and extracted with cyclohexane (. times.2). The combined extracts were washed with brine, over MgSO₄Dried and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1 kg), eluting with hexane and then cyclohexane. Appropriate fractions were combined and concentrated to give preparation 83 as a colorless oil (7 g))。

¹H-NMR(CDCl₃): 0.76 to 0.81(3H), 4.82 to 5.01(1H), 5.48 to 5.60(1H), 7.39 to 7.51(6H), 7.61 to 7.71(4H)

The compound prepared in analogy to the procedure of preparation 79 was:

preparation example 84

5-amino-1- [2, 6-difluoro-4-trifluoromethyl-phenyl ] -4-iodo-1H-pyrazole-3-carbonitrile; from the compound of preparation 90 (2.00 g, 6.9 mmol) the title compound (2.2 g) was obtained.

¹H-NMR(CDCl₃): 3.89 to 4.04(2H), 7.39 to 7.45(2H)

Preparation example 85

Difluoro-acetyl chloride

Phosphorus pentachloride (14.3 g, 68.8 mmol) was added to difluoroacetic acid (6.0 g, 3.93 ml, 62.5 mmol) at-10 ℃. The reaction mixture was stirred at 0 ℃ for 10 minutes and then heated to 80 ℃.

The reaction mixture was distilled and product fractions were collected at-78 ℃ to obtain preparation example 85(30 g) [ boiling point 25 to 30 ℃).

¹H-NMR(CDCl₃): 5.76 to 6.07(1H)

Preparation example 86

Chlorofluoroacetyl chloride

Chlorofluoroacetic acid (5.0 g, 44.6 mmol) was added dropwise to phosphorus pentachloride (10.2 g, 49.1 mmol) at 0 ℃.

The reaction mixture was allowed to warm to room temperature and distilled at ambient pressure (× 2) to afford preparation 86(5.0 g, b.p. 65 ℃).

¹H-NMR(CDCl₃): 6.29 to 6.44(1H)

The compound prepared in a manner analogous to that of preparation 31 is:

preparation example 87

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 88 (7.0 g, 20.8 mmol) the title compound (6.2 g) was obtained.

MS(ES)：M/Z[MH⁺]392.0, respectively; the predicted mass of C14H10Cl2F3N5O + H was 392.0

¹H-NMR(CDCl₃): 2.77 to 2.82(3H), 3.00 to 3.04(3H), 6.15 to 6.17(1H), 7.27 to 7.31(2H), 7.70 to 7.75(1H)

Preparation example 88

5-amino-1- (2, 6-dichloro-4-trifluoromethoxy-phenyl) -1H-pyrazole-3-carbonitrile

Sodium nitrite (13.9 g, 201.2 mmol) was added to sulfuric acid (18M, 54 ml) and the solution was stirred at 15 ℃ for 1 hour. A solution of acetic acid (200 ml), 2, 6-dichloro-4- (trifluoromethoxy) aniline (45.0 g, 182.9 mmol) in acetic acid (90 ml) was added to the solution successively, ensuring that the temperature of the solution did not rise above 20 ℃. After the addition was complete, the mixture was heated at 50 ℃ for 1 hour, cooled to room temperature and added dropwise to a solution of preparative example 46(27.8 g, 182.9 mmol) in acetic acid (115 ml) and ice-cold water (145 ml). The reaction mixture was then stirred at room temperature overnight. Dichloromethane (500 ml) was added to the reaction mixture and the mixture was stirred for 10 minutes. The phases were separated and the organic phase was washed with water (200 ml) and then aqueous ammonia (0.88M, 400 ml) was added dropwise, maintaining the temperature of the mixture below 10 ℃. The mixture was stirred at room temperature overnight, and the organic phase was separated and concentrated in vacuo.

The residue was recrystallized from toluene/pentane [ 2: 1] to give preparation 88(22.4 g).

MS(ES)：M/Z[MH⁺]337.0; the predicted mass of C11H5Cl2F3N4O + H was 337.0

¹H-NMR(CDCl₃): 3.66 to 3.82(2H), 5.99 to 6.01(1H), 7.35 to 7.38(2H)

The compound prepared in a manner analogous to that of preparation 31 is:

preparation example 89

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -4-iodo-1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide; from the compound of preparation 81 (6.8 g, 14.7 mmol) the title compound (6.2 g) was obtained.

¹H-NMR(CDCl₃): 2.76 to 2.79(3H), 3.01 to 3.04(3H), 7.27 to 7.30(2H), 8.17 to 8.20(1H)

Preparation example 90

5-amino-1- (2, 6-difluoro-4-trifluoromethyl-phenyl) -1H-pyrazole-3-carbonitrile

A solution of preparative example 56(400 mg, 1.19 mmol) in phosphorus oxychloride (20 ml) was heated at reflux for 1 hour. The reaction mixture was quenched by addition of water and the subsequent mixture was extracted with dichloromethane. Then over MgSO₄The combined extracts were dried and concentrated in vacuo. The residue was purified by column chromatography (silica gel), eluting with dichloromethane. Appropriate fractions were combined and concentrated to give preparation 90(250 mg).

MS(ES)：M/Z[MH⁺]289.0, respectively; the predicted quality of C11H5F5N4+ H was 289.1

¹H-NMR(CDCl₃): 3.76 to 3.87(2H), 6.02 to 6.04(1H), 7.37 to 7.43(2H)

Preparation example 91

5-amino-1- (2, 6-dichloro-4-trifluoromethyl-phenyl) -4- (2-fluoro-acetyl) -1H-pyrazole-3-carbonitrile

To a solution of preparative example 80(800 mg, 1.80 mmol) in toluene (20 ml) was added a solution of 18-crown-6 (85.6 mg, 3.24 micromole), and potassium fluoride (anhydrous, 210 mg, 3.60 mmol) in toluene (20 ml). The reaction mixture was then heated at 90 ℃ for 2 days. The reaction mixture was concentrated in vacuo and the residue was passed through a plug of silica gel, eluting with diethyl ether. The filtrate was concentrated in vacuo to give preparation 91(500 mg).

MS(ES)：M/Z[MH⁺]380.9, respectively; the predicted mass of C13H6Cl2F4N4O + H was 381.0

¹H-NMR(CDCl₃): 5.38 to 5.40(1H), 5.50 to 5.52(1H), 5.84 to 5.90(2H), 7.79 to 7.81(2H)

The compound prepared in a manner analogous to that of preparation 31 is:

preparation example 92

N' - (3-cyano-1- {2, 6-dichloro-4- [ (trifluoromethyl) thio ] phenyl } -1H-pyrazol-5-yl) -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 70(1.0 g, 2.93 mmol) the title compound (720 mg) was obtained.

MS(ES)：M/Z[MH⁺]408.0, respectively; the predicted mass of C14H10Cl2F3N5S + H was 408.0

¹H-NMR(CDCl₃): 2.80 to 2.84(3H), 3.01 to 3.06(3H), 6.18 to 6.22(1H), 7.68 to 7.70(2H), 7.71 to 7.73(1H)

Preparation example 93

5-amino-1- (3-chloro-5-trifluoromethyl-pyridin-2-yl) -4- (2, 2, 2-trifluoro-acetyl) -1H-pyrazole-3-carbonitrile

Trifluoroacetic anhydride (8.8 ml, 62.6 mmol) was added dropwise to a solution of preparation 69(4.50 g, 15.6 mmol) in pyridine (45 ml) at 0 ℃. The reaction mixture was then stirred at room temperature for 3 hours.

The reaction mixture was concentrated in vacuo and tetrahydrofuran (20 ml) and hydrochloric acid (10%, 20 ml) were added to the residue. The reaction mixture was then heated at reflux for 1.5 hours.

Ethyl acetate was added to the reaction mixture and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 30 ml) and the combined organic phases were washed with hydrochloric acid (10%, 2 × 30 ml) and aqueous sodium bicarbonate (3 × 30 ml) over MgSO₄Dried and concentrated in vacuo to afford preparation 93(6.1 g).

MS(ES)：M/Z[MH⁺]383.9, respectively; the predicted quality of C12H4ClF6N5O + H was 384.0

¹H-NMR(CDCl₃): 7.54 to 7.64(2H), 8.24 to 8.27(1H), 8.67 to 8.69(1H)

The compound prepared in analogy to the procedure of preparation 79 was:

preparation 94

N' - { 3-cyano-1- [2, 6-dichloro-4- (difluoromethoxy) phenyl ] -4-iodo-1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide; from the compound of preparation 63 (2.44 g, 6.5 mmol) the title compound (3.1 g) was obtained.

MS(ES)：M/Z[MH⁺]500.0 of the total weight of the mixture; the predicted mass of C14H10Cl2F2IN5O + H was 499.9

Preparation example 95

5-amino-1- [2, 6-dichloro-4- (pentafluorothio) phenyl ] -1H-pyrazole-3-carbonitrile can be prepared according to WO9306089, EP605469

The compound prepared in analogy to the procedure of preparation 39 was:

preparation example 96

N' - {4- [ chloro (difluoro) acetyl ] -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-5-yl } -N, N-dimethylaminoiminocarboxamide; from the compound of preparation 62(5.0 g, 10.0 mmol) the title compound (2.9 g) was obtained.

MS(ES)：M/Z[MH⁺]487.9, respectively; the predicted mass of C16H9Cl3F5N5O + H was 488.0

¹H-NMR(CDCl₃): 2.80 to 2.83(3H), 3.09 to 3.13(3H), 7.68 to 7.71(2H), 8.28 to 8.31(1H)

Preparation example 97

4-Trifluoromethylthio-anilines can be prepared according to EP546391A 2.

Preparation example 98

5-amino-1- (2, 6-dichloro-4-trifluoromethyl-phenyl) -4- (1-hydroxy-2, 2, 2-trifluoro-1-trifluoromethyl-ethyl) -1H-pyrazole-3-carbonitrile

5-amino-3-cyano-1- (2, 6-dichloro-4-trifluoromethylphenyl) pyrazole (see EP295117) (15 g, 46 mmol, 1 eq) was dissolved in hexafluoroacetone sesquihydrate and the reaction mixture was heated at 100 ℃. After 2 hours, the LC-Ms showed completion (unimodal [487 ]). After cooling to room temperature, ethyl acetate (500 ml) was added and all the crude product was washed with water (50 ml) then brine (2 × 50 ml) then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a brown solid (22 g) containing trace amounts of solvent, which was used as such in the next step.

Preparation example 99

N' - [4- (1-hydroxy-2, 2, 2-trifluoro-1-trifluoromethyl-ethyl) -5-cyano-2- (2, 6-dichloro-4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl ] -N, N-dimethyl-formamidine

The compound of preparation 92 (22 g from the crude product described above, about 46 mmol, 1 eq) was suspended in Dichloromethane (DCM) under nitrogen. The dimethoxyacetal dimethylformamide (99+,7 g, 8 ml, 56 mmol, 1.2 eq) into the reaction mixture (over 1 min). The reaction mixture was heated to 40 ℃ and stirred for one hour. The crude mixture was then concentrated in vacuo and diluted with ether (600 ml) then washed with water (2 × 50 ml) and dried over powdered MgSO₄Dry, filter and concentrate in vacuo to give the title compound as a brown solid (20.5 g).

Preparation example 100

N' - [4- (1-chloro-2, 2, 2-trifluoro-1-trifluoromethyl-ethyl) -5-cyano-2- (2, 6-dichloro-4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl ] -N, N-dimethyl-formamidine

The compound of preparation 99 (20.5 g, 37 mmol, 1 eq) was dissolved in anhydrous acetonitrile and thionyl chloride (44 g, 27 ml, 370 mmol, 10 eq) was added slowly by syringe. The reaction mixture was heated to 85 ℃ for 2 hours to complete the heating, then 200 ml of cyclohexane were added to the cooled mixture and the pale yellow powder (9 g) was filtered off. The residual crude product was then adsorbed on silica gel, dried and eluted with DCM on a pad of silica gel. The desired fractions were combined and concentrated to give a pale yellow oil which solidified by standing (11 g) to give a combined yield of 20 g of the title compound.

LCMS[561]

Preparation example 101

N' - [ 5-cyano-2- (2, 6-dichloro-4-trifluoromethyl-phenyl) -4- (2, 2-difluoro-1-trifluoromethyl-vinyl) -2H-pyrazol-3-yl ] -N, N-dimethyl-formamidine

The compound of preparation 100 (20 g, 35 mmol) was dissolved in 500 ml of anhydrous THF and 150 ml of a 5 g/100 ml suspension of Rieke zinc (7.5 g, 110 mmol, 3 eq) was added. After 3 hours LCMS showed quantitative conversion to perfluoroisopropenyl compound (singlet [506 ]). The crude mixture was filtered through a pad of celite and then adsorbed onto silica gel. The pad of silica gel was then eluted with toluene to give the title compound as a white solid (16 g).

Preparation example 102

N' - [ 5-cyano-2- (2, 6-dichloro-4-trifluoromethyl-phenyl) -4- (2, 2-difluoro-1-trifluoromethyl-cyclopropyl) -2H-pyrazol-3-yl ] -N, N-dimethyl-formamidine

Diazomethane was generated on 15 grams of dimethylnitrosobenzenesulfonamide using the Aldrich dimethylnitrosobenzenesulfonamide (diazald) set (procedure AL-180). The newly prepared diazomethane solution was mixed with the compound of preparation 101 (16 g, 31 mmol, soluble in anhydrous THF) and the resulting yellow solution was allowed to stand at room temperature for 2 hours. LC-Ms showed complete conversion (91% title compound [520], 5% by-product assumed to be the corresponding pyrazoline [548], and 4% unknown by-product). After concentration in vacuo, no further purification was required and the yellow solid (17 g) formed was used in the next step.

Claims

1. A composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, and one or more additional therapeutic agents:

wherein:

R¹is CF₃、OCF₂H、OCF₃、-SCF₃、-SOCF₃、-SO₂CF₃Or SF₅；

R³、R⁴、R⁵and R⁶Independently represents H, C optionally substituted with 1 to 5 halo independently selected from chloro and fluoro_1-4Alkyl, or chloro or fluoro;

R⁷is chlorine or fluorine;

x is CR⁸Or N, wherein R⁸Is chlorine or fluorine; and is

R⁹Is NR^aR^b；

R^bselected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_1-6Alkanoyl and C (O) OC_1-6Alkyl, wherein each of the foregoing groups may include one or more optional substituents, if chemically available, independently selected from halogen, phenyl, hydroxy, -COOH, -C (O) OC_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, amino, C_1-6Alkylamino and di-C_1-6An alkylamino group;

or R^aAnd R^bTogether with the N atom to which they are attached may form a 3-to 7-membered heterocyclic ring containing one or more additional N, O or S atoms, and wherein the heterocyclic ring may have one or more optional substituents selected from oxygen, halogen, het, phenyl, hydroxy、-COOH、-C(O)OC_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, amino, C_1-6Alkylamino and di-C_1-6An alkylamino group; and is

het represents a 4 to 7 membered heterocyclic group which is aromatic or non-aromatic and which contains one or more heteroatoms selected from nitrogen, oxygen, sulphur and mixtures thereof and wherein said heterocyclic group, if valency permits, may be optionally substituted by one or more substituents selected from: halogen, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, OC (O) C_1-6Alkyl, C (O) C_1-6Alkyl, C (O) OC_1-6Alkyl and NR^cR^dWherein R is^cAnd R^dIndependently selected from hydrogen, C_1-6Alkyl and C_2-6Alkenyl, wherein each of the foregoing groups may include one or more optional substituents, if chemically available, independently selected from halogen, phenyl, hydroxy, -COOH, C (O) OC_1-6Alkyl radical, C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, amino, C_1-6Alkylamino and di-C_1-6An alkylamino group;

with the proviso that R²、R³、R⁴、R⁵Or R⁶At least one of which is fluorine.

2. The composition of claim 1, wherein R¹Is CF₃Or SF₅。

3. The composition of claim 1 or 2, wherein R²Is F, CF₃Or CHF₂。

4. The composition of any one of claims 1-3, wherein R³And R⁴All represent fluorine, andR⁵and R⁶Represents hydrogen.

5. The composition of any one of claims 1-4, wherein R²Is CF₃，R³And R⁴All represent fluorine, and R⁵And R⁶Represents hydrogen.

6. The composition of any one of claims 1-5, wherein X is CR⁸And R is⁷And R⁸Are all chlorine.

7. The composition of any one of claims 1-6, wherein R⁹Is selected from NH₂；C_1-6Alkoxycarbonylamino group, the alkyl group of which may optionally be substituted by one or more fluoro groups, di-C_1-6Alkylamino and het substitution; c_1-6Alkylamino, the alkyl of which may optionally be substituted by one or more fluoro groups, C_3-8Cycloalkyl, phenyl and het.

8. The composition of any one of claims 1-7, wherein R⁹Is NH₂。

9. The composition of claim 1, wherein the compound of formula (I) is selected from:

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-yl ] -carbamic acid pyridin-3-ylmethyl ester;

3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (trifluoromethyl) cyclopropyl ] -1H-pyrazol-5-ylcarbamic acid 2-pyrrolidin-1-ylethyl ester; and

5-amino-4- {1- [ chloro (difluoro) methyl ] -2, 2-difluorocyclopropyl } -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carbonitrile; or a pharmaceutically acceptable salt thereof.

10. The composition of any one of claims 1-9, wherein the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more other antiparasitic agents.

11. The composition of claim 10, wherein the one or more other antiparasitic agents are selected from the group consisting of ivermectin, avermectin, abamectin, imazetidine, epristerine, doramectin, selamectin, moxidectin, nemadectin, albendazole, canabendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxbendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxtaral, morantel, triclabendazole, praziquantel, etamol, fipronil, octaflubenzuron, ecdysone, diphenozide, and imidacloprid.

12. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, in the manufacture of a medicament for use in the treatment of a parasitic infection in combination with one or more further therapeutic agents as claimed in any one of claims 1, 10 or 11.

13. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, one or more further therapeutic agents as defined in any one of claims 1, 10 or 11, and a pharmaceutically suitable excipient.