HK1121141A

HK1121141A - Substituted arylpyrazoles for use against parasitites

Info

Publication number: HK1121141A
Application number: HK08112838.3A
Authority: HK
Inventors: 丹尼斯．比伦; 杰西卡．波耶勒; 道格拉斯．詹姆斯．克里彻; 戴维．莫里斯．格辛; 基姆．托马斯．霍尔; 格雷厄姆．迈克尔．凯恩
Original assignee: 辉瑞有限公司
Priority date: 2005-06-15
Filing date: 2006-06-06
Publication date: 2009-04-17

Description

Substituted arylpyrazoles as parasiticides

The present invention relates to pyrazole derivatives having parasiticidal properties. The compound of interest is C4- (cyclopropyl) arylpyrazole, more particularly, the present invention relates to 1-aryl-4-cyclopropylpyrazole wherein the cyclopropyl group is substituted at the angular position. The above compounds have parasiticidal properties.

International patent application (WO)98/24767, european patent application (EP)933363, european patent application (EP)959071 and international patent application (WO)2005/060749 all describe arylpyrazoles having parasiticidal activity for controlling arthropods.

However, the existing compounds do not have good activity or long duration of action against parasites. Also, some of the existing parasiticidal agents are well-suited for use with narrow range parasites. In some cases, this is due to the compound having low bioavailability in the treated animals, and this also leads to poor activity. The object of the present invention is to overcome the disadvantages of the properties of the existing compounds or to improve the properties of the existing compounds. It is therefore an object of the present invention to provide arylpyrazoles which have the same or improved antiparasitic activity as the existing compounds. It is another object of the present invention to provide arylpyrazole compounds which have improved bioavailability and can maintain or improve their activity. As shown by the test results demonstrating efficacy and effectiveness of the compounds of the present invention, it has particularly excellent control effects on a wide range of arthropods. More specifically, the compounds of the present invention are significantly more effective against fleas than similar prior art compounds.

It is another object of the present invention to provide compounds having a long duration of action. Surprisingly, it has been found that improving the bioavailability of a compound does not adversely affect its duration of action. This prolonged duration of action is generally attributed to the increased half-life of the compound in the host mammal.

More ideally, the compounds of the present invention should have improved pharmacokinetic properties, improved safety, improved persistence and improved solubility.

Thus, according to the present invention there is provided a compound of formula (I):

wherein:

x is selected from CR¹⁰Or N;

R¹selected from halogen, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkanoyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, amino, C_1-6Alkylamino, di-C_1-6Alkylamino, het, phenyl, SF₅And S (O)_nR¹¹；

R²Selected from cyano, hydroxy, C (O) OH, het, phenyl, S (O)_nR¹¹、C(O)NR^aR^bAnd C (S) NR^aR^b；

Or R²Is selected from C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkanoyl radical, C (O) OC_1-6Alkyl, amino, C_1-6Alkylamino and di-C_1-6Alkylamino, each of the foregoing groups optionally and independently further substituted with one or more substituents selected from, where chemically available, the following: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR ^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

R^aAnd R^bIndependently selected from hydrogen, het, phenyl and S (O)_nR¹¹；

Or R^aAnd R^bEither or both of which are independently selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_1-6Alkanoyl and C (O) OC_1-6Alkyl radical, each of the radicals R^aOr R^bOptionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or R^aAnd R^bTogether with the N atom to which they are attached form a 3-to 7-membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring, which optionally contains one or more further N, O or S atoms, and which is optionally further substituted by one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR ^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or R²And R^eTogether with the R^eThe N atom attached forms a 6-to 7-membered saturated, partially saturated or unsaturated heterocyclic ring, which optionally contains one or more additional N, O or S atoms, and which is optionally further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

R³、R⁴、R⁵And R⁶Independently selected from hydrogen, halogen, cyano, hydroxy, C (O) OH, nitro, phenyl and S (O)_nR¹¹；

Or R³、R⁴、R⁵And R⁶Is independently selected from C_1-4Alkyl, C (O) NR^cR^d、C(S)NR^cR^d、C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C (O) OC _1-4Alkyl and amino, the R³、R⁴、R⁵And R⁶Optionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, hydroxy, C_1-4Alkyl and amino;

and R is³、R⁴、R⁵And R⁶No more than two of them are selected from cyano, hydroxy, C (O) OH, nitro, phenyl, S (O)_nR¹¹、C(O)NR^cR^d、C(S)NR^cR^d、C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C (O) OC_1-4Alkyl and amino;

R⁷selected from halogen, C_1-6Alkyl and C_1-6Alkoxy when R⁷Is C_1-6Alkyl or C_1-6At alkoxy radical, R⁷Optionally substituted with one or more halo substituents;

R⁸selected from the group consisting of hydrogen, cyano, hydroxy, C (O) OH, nitro, halo, het, phenyl and S (O)_nR¹¹；

Or R⁸Is selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkanoyl and C (O) OC_1-6Alkyl radical, the R⁸Optionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C _1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or R⁸Is amino, the R⁸Optionally and independently selected by one or more ofWhere used, the following substituents are further substituted: c (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, het, phenyl and S (O)_nR¹¹；

R⁹Selected from the group consisting of hydrogen, halogen, cyano, hydroxy, C (O) OH, nitro, het, phenyl, S (O)_nR¹¹And NR^eR^f；

Or R⁹Is selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl radical C_1-6Alkoxy radical, C_1-6Alkanoyl radical, C (O) OC_1-6Alkyl radical, the R⁹Optionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C _3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

R^eAnd R^fIndependently selectFrom hydrogen, het, phenyl and S (O)_nR¹¹；

Or R^eAnd R^fEither or both of which are independently selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_1-6Alkanoyl radical, C (O) OC_1-6Alkyl, -C (O) OC_1-6Alkyl radical C_3-8Cycloalkyl, -C (O) OC_3-8Cycloalkyl radical, each R of^eOr R^fOptionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or R^eAnd R^fTogether with the N atom to which they are attached form a 3-to 7-membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring, which optionally contains one or more further N, O or S atoms, and which is optionally further substituted by one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR ^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or R^eAnd R²Together with the atoms to which they are attached form the aforementioned 6-to 7-membered heterocyclic ring;

R¹⁰selected from halogen, C_1-6Alkyl and C_1-6Alkoxy, and when R¹⁰Is C_1-6Alkyl or C_1-6Alkoxy, which is optionally substituted with one or more halo substituents;

each R is^cAnd R^dIndependently selected from hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkanoyl radical, C_1-6Haloalkanoyl, C (O) OC_1-6Alkyl, het, phenyl and S (O)_nR¹¹；

Or R^cAnd R^dTogether with at least one of the N atoms to which they are attached form a 3-to 7-membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring, which ring system optionally contains one or more further N, O or S atoms;

each n is independently 0, 1 or 2;

each R is¹¹Independently selected from hydrogen, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, amino, C_1-6Alkylamino and di-C_1-6An alkylamino group;

each phenyl group may be optionally substituted with one or more other substituents selected from the group consisting of: halogen, cyano, nitro, hydroxy, C _1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, amino, C_1-6Alkylamino radical, di-C_1-6Alkylamino, -NHS (O)_nR¹¹And S (O)_nR¹¹；

And each het independently represents a 4-to 7-membered heterocyclic ring which is aromatic or non-aromatic, unsaturated, partially saturated or saturated and which contains one or more heteroatoms selected from nitrogen, N-oxide, oxygen, sulphur, and wherein the heterocyclic ring is optionally substituted, where the compound so allows, by one or more heteroatoms selected from halogen, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, OC (O) C_1-6Alkyl radical, C_1-6Alkanoyl radical, C (O) OC_1-6Alkyl and NR^gR^hWherein R is^gAnd R^hIndependently selected from hydrogen, C_1-6Alkyl and C_2-6Alkenyl, and each of the foregoing groups includes one or more, chemically useful, substituents selected from the group consisting of: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, C_1-6Alkylamino radical, di-C_1-6Alkylamino, phenyl and S (O) _nR¹¹；

Or a pharmaceutically acceptable salt or prodrug thereof.

Preferably, R¹Selected from: a cyano group; c_1-6Haloalkyl, e.g. trifluoromethyl or iso-C₃F₇；C_1-6Haloalkoxy, such as difluoromethoxy or trifluoromethoxy; SF₅(ii) a And S (O)_nR¹¹Wherein, for example, R¹¹Is C which may form, for example, a (trifluoromethyl) thio group, a (trifluoromethyl) sulfinyl group or a (trifluoromethyl) sulfonyl group_1-6A haloalkyl group. More preferably, R¹Is selected from C_1-6Haloalkyl, such as trifluoromethyl; c_1-6Haloalkoxy, such as difluoromethoxy and trifluoromethoxy; and SF₅. Even more preferably, R¹Selected from CF₃、OCF₃Or SF₅. Most preferably, R¹Is SF₅。

Suitably, R²Selected from: a cyano group; c (O) OH; het, e.g. 1-oxa-3, 4-oxadiazolyl or thiazolyl, which het may then be substituted by C_1-6Alkyl (e.g., methyl or ethyl) to form, for example, 5-methyl-1-3, 4-oxadiazol-2-yl; and S (O)_nR¹¹Wherein R is¹¹Is selected from C_1-6Alkyl, e.g. methyl or ethyl to form, e.g. methylthio, methylsulfinyl or methylsulfonyl, to form, e.g. aminosulfonyl, and di-C_1-6Alkylamino, such as dimethylamino to form, for example, (dimethylamino) sulfonyl; c (O) OC_1-6Alkyl, e.g. methoxycarbonyl or ethoxycarbonyl, the C (O) OC_1-6Alkyl is optionally subsequently substituted with halo (e.g., chloro or fluoro) to form, for example, fluoromethoxycarbonyl or trifluoromethoxycarbonyl; and an amino group.

Equally suitable, R²Selected from C (O) NR^aR^bAnd C (S) NR^aR^bWherein R is^aAnd R^bIndependently selected from: hydrogen to form, for example, aminocarbonyl or aminocarbothiophenoyl; s (O)_nR¹¹Wherein R is¹¹Is C_1-6Alkyl, e.g. to form e.g. (methylsulfonyl) amino]Methyl or ethyl of the carbonyl group; and C_3-8Cycloalkyl, for example to form cyclopropyl such as (cyclopropylamino) carbonyl. Equally suitable, R^aAnd R^bIndependently selected from C_1-6Alkyl, e.g. to form a methyl, ethyl, propyl, isopropyl or isobutyl group such as (methylamino) carbonyl, (dimethylamino) carbonyl, (ethylamino) carbonyl, (propylamino) carbonyl, (isopropylamino) carbonyl or (isobutylamino) carbonyl, C_1-6The alkyl group may then be optionally substituted with one or more substituents selected from: halogen, e.g. to form e.g. [ (trifluoro-) ]Methyl) amino group]Carbonyl or [ (2, 2, 2-trifluoroethyl) amino group]Fluorine of carbonyl group; to form, for example, [ (2-hydroxyethyl) amino]Carbonyl or [ (2-hydroxy-2-methylpropyl) amino group]A hydroxyl group of a carbonyl group; to form, for example, [ (1-methoxyethyl) amino]Carbonyl or [ (1-isopropoxypropyl) amino]C of carbonyl group_1-6An alkoxy group; c_3-8Cycloalkyl radicals, e.g. to form e.g., [ (cyclopropylmethyl) amino group]Cyclopropyl of carbonyl; or het, e.g. to form e.g. (pyridin-2-ylmethyl) amino ]Carbonyl, [ (pyridin-3-ylmethyl) amino]Carbonyl or [ (pyridin-4-ylmethyl) amino]Pyridyl of carbonyl groups or to form, for example, [ (4H-1, 2, 4-triazol-3-ylmethyl) amino]1, 2, 4 triazolyl of carbonyl, which 1, 2, 4 triazolyl may optionally be substituted by, for example, C_1-6Alkyl (e.g. methyl) further substituted to form, for example, { [ (5-methyl-4H-1, 2, 4-triazol-3-yl) methyl]Amino } carbonyl group.

At R^aAnd R^bTogether with the N atom to which they are attached form a 3-to 7-membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring (which ring system may optionally contain one or more further N, O or S atoms), which ring is suitably a saturated pyrrolidinyl ring.

At R²And R^eTogether with R^eIn the case where the N atom to which it is attached forms a 6-to 7-membered saturated, partially saturated or unsaturated heterocyclic ring (which may optionally contain one or more further N, O or S atoms), R²Preferably selected from C (O) NR^aR^bAnd C (S) NR^aR^bThen, R^aAnd R^eTogether with the N atom to which they are attached form a 6-to 7-membered saturated, partially saturated or unsaturated heterocyclic ring, which optionally contains one or more additional N, O or S atoms. Suitably, the ring is a partially unsaturated 1, 3-diazepinyl (diazepanyl), which may be substituted by C_1-6Alkyl (e.g. methyl) further substituted to form, for example, 7 '-methyl-5' -oxo-5 ', 6', 7 ', 8' -tetrahydropyrazolo [3, 4-d ][1，3]Diazepine (diazepine).

Preferably, R²Selected from: a cyano group; c (O) OH; het, for example 1-oxa-3, 4-oxadiazolyl or thiazolyl,the 1-oxa-3, 4-diazolyl group being subsequently substituted by C_1-6Alkyl (e.g., methyl) substitution; s (O)_nR¹¹Wherein R is¹¹Is selected from C_1-6Alkyl (e.g. methyl or ethyl), amino and di-C_1-6An alkylamino group; c (O) OC_1-6Alkyl, e.g. methoxycarbonyl or ethoxycarbonyl, the C (O) OC_1-6Alkyl optionally substituted with halo (e.g., chloro or fluoro); and an amino group. More preferred compounds include those wherein R is²Selected from C (O) NR^aR^bAnd C (S) NR^aR^bWherein R is^aAnd R^bIndependently selected from: hydrogen; s (O)_R ¹¹Wherein R is¹¹Is C_1-6Alkyl groups such as methyl or ethyl; c_3-8Cycloalkyl groups such as cyclopropyl; and C_1-6Alkyl, e.g. methyl, ethyl, isopropyl or isobutyl, C_1-6The alkyl group may then optionally be substituted with one or more groups selected from: halogen (e.g. fluorine), hydroxy, C_1-6Alkoxy radical, C_3-8Cycloalkyl (e.g. cyclopropyl) or het (e.g. pyridyl or 1, 2, 4 triazolyl), said 1, 2, 4 triazolyl being optionally substituted by, for example, C_1-6Alkyl (e.g., methyl) is further substituted.

Even more preferably, R²Selected from: a cyano group; s (O)_nR¹¹Wherein R is¹¹Is C_1-6Alkyl groups such as methyl or ethyl; and C (O) NR ^aR^bWherein R is^aIs hydrogen, and R^bSelected from hydrogen and C_1-6Alkyl, e.g. methyl or isopropyl, C_1-6Alkyl is optionally substituted with het (e.g., pyridyl) to form, for example, [ (pyridin-4-ylmethyl) amino]A carbonyl group.

Most preferably, R²Is C (O) NR^aR^bWherein R is^aAnd R^bAre both hydrogen.

Suitably, R³、R⁴、R⁵And R⁶Each independently selected from: hydrogen; halogen, such as chlorine or fluorine; or C_1-4Alkyl (e.g. methyl), the C_1-4Alkyl may be optionally substituted with 1 to 5 independently selected from chloro or fluoroTo form, for example, a trifluoromethyl group. Preferably, R³And R⁴Independently selected from: hydrogen; chlorine; fluorine; and C_1-4Alkyl (e.g. methyl), the C_1-4Alkyl is optionally substituted with 1 to 5 halo groups, and R⁵And R⁶Both of which are hydrogen. More preferably, R³And R⁴Both are identical to each other and are selected from: hydrogen; fluorine; chlorine; and methyl, and R⁵And R⁶Both of which are hydrogen. Most preferably, R³And R⁴Both are identical to each other and are selected from: hydrogen; fluorine; and chlorine, and R⁵And R⁶Both of which are hydrogen.

Suitable compounds include those wherein R is⁷In the case of halogen, preferred halogen substituents are fluorine, chlorine or bromine. More suitable compounds include those wherein R is⁷Is selected from C_1-6Alkyl or C_1-6Alkoxy, wherein the C_1-6Alkyl or C _1-6Alkoxy groups are optionally substituted with one or more halo substituents, with preferred halo substituents being fluoro, chloro or bromo. Preferably, R⁷Selected from chlorine or fluorine. Most preferably, R⁷Is chlorine.

Suitably, R⁸Selected from: a cyano group; halogen, such as chlorine or fluorine; c_1-6Alkyl (e.g. methyl or ethyl), the C_1-6Alkyl groups are optionally substituted with one or more fluoro groups to form, for example, trifluoromethyl; and C_1-6Alkanoyl, e.g. acetyl or propionyl, C_1-6Alkanoyl is optionally substituted with one or more substituents independently selected from: s (O)_nR¹¹E.g. wherein R¹¹Is C_1-6Alkyl, e.g. to form methyl or ethyl, e.g. (methylthio) carbonyl, halogen, e.g. chloro or fluoro to form trifluoroacetyl, or C to form e.g. 2-ethoxy-2-oxoethyl_1-6An alkoxy group.

Preferably, R⁸Selected from: a cyano group; c_1-6Alkyl radicals, e.g. methyl, C_1-6Alkyl optionally substituted with one or more fluoro groups; and C_1-6Alkanoyl radicalE.g. acetyl, the C_1-6Alkanoyl can be substituted by S (O)_nR¹¹Substituted, e.g. wherein R¹¹Is C_1-6An alkyl group. Most preferably, R⁸Is cyano.

Suitably, R⁹Selected from: hydrogen; a hydroxyl group; a cyano group; halogen, such as chlorine or fluorine; het, for example pyrazinyl, imidazolyl or pyridyl to form, for example, pyridin-2-yl or pyridin-4-yl, wherein the pyridyl is suitably further substituted, for example with hydroxy, to form, for example, 1-hydroxy-pyridyl; phenyl, which phenyl is then optionally substituted with one or more substituents selected from the group consisting of: halogen, e.g. chlorine or fluorine to form, e.g. 4-fluorophenyl or 3, 4-difluorophenyl, and S (O) _nR¹¹E.g. wherein R¹¹Methyl to form, for example, a 4- (methylsulfonyl) phenyl group; and S (O)_nR¹¹For example wherein R¹¹To form, for example, a methylthio group, a methanesulfinyl group or a methanesulfonyl group.

Other suitable compounds include those wherein R is⁹Is C_1-6Alkyl, e.g. methyl, ethyl, isopropyl or tert-butyl, C_1-6The alkyl group is then optionally substituted with one or more substituents selected from the group consisting of: halogen, for example fluorine or chlorine to form, for example, difluoromethyl, trifluoromethyl or trifluoroethyl; c_1-6Alkyl, such as to form a tert-butyl group such as tert-butylmethyl; c_3-8Cycloalkyl, such as cyclopropyl, cyclopentyl or cyclohexyl to form, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or cyclopropylethyl; c_1-6Alkoxy, for example to form methoxy or ethoxy, for example methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl; het, e.g. to form a pyrazinyl group such as a pyrazinylmethyl group or a pyrazinylethyl group, to form an imidazolyl group such as a (1H-imidazolyl) methyl group or a (1H-imidazolyl) ethyl group, to form a 1, 2, 4-triazolyl group such as a (4H-1, 2, 4-triazol-3-yl) methyl group or a (4H-1, 2, 4-triazol-3-yl) ethyl group, or to form a 1, 2, 4-triazolyl group such as a pyridin-2-ylmethyl group, a pyridin-2-ylethyl group, a pyridin-4-ylmethyl group or a pyridin-4-ylethyl group Wherein, where appropriate, the pyridyl group may be further substituted, for example by hydroxy, to form, for example, (1-hydroxy-pyridyl) methyl or (1-hydroxy-pyridyl) ethyl; to form a phenyl group, such as benzyl or phenethyl, which phenyl group is then optionally substituted with one or more substituents selected from: halo, e.g. chloro or fluoro to form, e.g. 4-fluorobenzyl, (4-fluorophenyl) ethyl, 3, 4-difluorobenzyl or (3, 4-difluorophenyl) ethyl, optionally substituted with one or more halo groups, e.g. chloro or fluoro, to form, e.g. (trifluoromethyl) benzyl or [ (trifluoromethyl) phenyl]C of ethyl radical_1-4Alkyl, or S (O)_nR¹¹E.g. wherein R¹¹To form, for example, a 4- (methylsulfonyl) benzyl or [4- (methylsulfonyl) phenyl group]Methyl of ethyl; -C (O) OC_1-6Alkyl, such as ethoxycarbonyl to form, for example, 2-ethoxy-2-oxoethyl; to form an amino group such as an aminomethyl or aminoethyl group; c_1-6Alkylamino, for example to form methylamino such as (methylamino) methyl, (methylamino) ethyl, (ethylamino) methyl or (ethylamino) ethyl; and S (O)_nR¹¹E.g. wherein R¹¹To form, for example, (methylthio) methyl, (methylthio) ethyl, (methylsulfinyl) methyl, (methylsulfinyl) ethyl, (methylsulfonyl) methyl or (methylsulfonyl) ethyl.

Other suitable compounds include those wherein R is⁹Selected from the group consisting of: c_2-6Alkenyl, e.g. vinyl, C_2-6Alkenyl may be further substituted by het (e.g. pyrazinyl, 1, 3, 4-triazolyl, imidazolyl or pyridyl), or C_2-6Alkenyl is, for example, phenyl which may be further substituted with the following substituents: e.g. halo, e.g. chloro or fluoro, to form, e.g. 4-fluorophenyl or 3, 4-difluorophenyl, optionally substituted by one or more halo (e.g. chloro or fluoro) groups to form, e.g. a trifluoromethyl phenyl group_1-4Alkyl, or S (O)_nR¹¹E.g. wherein R¹¹Is methyl which may form, for example, a 4- (methylsulfonyl) phenyl group; c_3-8Cycloalkyl radicals, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, C_3-8CycloalkanesOptionally substituted with one or more groups selected from halogen (e.g. fluoro or chloro), cyano and hydroxy; and C_3-8Cycloalkyl radical C_1-6Alkyl, e.g. cyclopropylmethyl or cyclopropylethyl, C_3-8Cycloalkyl radical C_1-6Alkyl groups may be optionally substituted with one or more groups selected from: halogen, e.g. fluorine or chlorine, to form, e.g., (1-fluorocyclopropyl) methyl, C_1-6Alkyl, e.g. to form a methyl or ethyl group such as (1-methylcyclopropyl) methyl or (1-ethylcyclopropyl) methyl, and to form a cyclopropyl group such as [ (1-trifluoromethyl) ]C of methyl_1-6A haloalkyl group.

Equally suitable, R⁹Is C_1-6Alkoxy, e.g. methoxy, ethoxy, isopropoxy or tert-butoxy, C_1-6The alkoxy group is then optionally substituted with one or more substituents selected from the group consisting of: halogen, for example fluorine or chlorine to form, for example, a trifluoromethoxy or trifluoroethoxy group; c_1-6Alkyl, such as to form a tert-butyl group such as tert-butylmethoxy; c_3-8Cycloalkyl, for example to form cyclopropyl, cyclopentyl or cyclohexyl, for example cyclopropylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy or cyclopropylethoxy; het, for example to form a pyrazinyl group, for example a pyrazinylmethoxy group, to form an imidazolyl group, for example a (1H-imidazolyl) methoxy group, to form a 1, 3, 4-triazolyl group, for example a (4H-1, 2, 4-triazol-3-yl) methoxy group or a (4H-1, 2, 4-triazol-3-yl) ethoxy group, or to form a pyridyl group, for example a pyridin-2-ylmethoxy group or a pyridin-4-ylmethoxy group, wherein, where appropriate, the pyridyl group may be further substituted, for example by a hydroxy group, to form, for example a (1-hydroxypyridyl) methoxy group; to form, for example, a benzyloxy group phenyl, which phenyl is then optionally substituted with one or more substituents selected from the group consisting of: halogen, e.g. chloro or fluoro to form, e.g. (4-fluorobenzyl) oxy or (3, 4-difluorobenzyl) oxy, optionally substituted with one or more halo (e.g. chloro or fluoro) to form, e.g., [ (trifluoromethyl) benzyl ]C of oxy radicals_1-4Alkyl, and S (O)_nR¹¹E.g. wherein R¹¹To form, for example, [4- (methylsulfonyl) benzyl]Of oxy groupsA methyl group; and-C (O) OC_1-6Alkyl, for example to form an ethoxycarbonyl group such as 2-ethoxy-2-oxoethyl.

Equally suitable, R⁹Is C_3-8Cycloalkyl radical C_1-6Alkoxy, e.g. cyclopropylmethoxy or cyclopropylethoxy, C_3-8Cycloalkyl radical C_1-6Alkoxy groups may be optionally substituted with one or more groups selected from: c_1-6Alkyl, for example to form a methyl or ethyl group such as a (1-methylcyclopropyl) methoxy or a (1-ethylcyclopropyl) methoxy group; or to form, for example, [1- (trifluoromethyl) cyclopropyl ]]C of methoxy group_1-6A haloalkyl group.

Still more suitable compounds include those wherein R is⁹Is NR^eR^fAnd each R is^eAnd R^fTo form, for example, an amino group.

Still more suitable compounds include those wherein R is⁹Is NR^eR^fAnd each R is^eOr R^fIndependently selected from hydrogen and C_1-6Alkyl, e.g. to form methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or n-pentyl radicals, e.g. methylamino, dimethylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino or pentylamino, C_1-6The alkyl group may then be substituted with one or more substituents selected from: to form a cyano group such as a (2-cyanoethyl) amino group; halogen, for example to form fluorine or chlorine such as (fluoroethyl) amino, (2-fluoro-2-methyl) propylamino, (trifluoromethyl) amino, (trifluoroethyl) amino, (2-fluoroethyl) amino, (3, 3, 3-trifluoropropyl) amino, (4, 4, 4-trifluorobutyl) amino or (5, 5, 5-trifluoropentyl) amino; to form a C (O) OH such as a (3-carboxypropyl) amino group; c (O) NR ^cR^dWherein R is^cOr R^dIndependently selected from the group consisting of: to form hydrogen, e.g. 2-carbamoyl-ethylamino, 3-carbamoyl-propylamino or 4-carbamoyl-butylamino, C_3-8Cycloalkyl radical C_1-6Alkyl radicals, e.g. to formFor example the cyclopropylmethyl group of (2-cyclopropylmethyl-carbamoyl) ethylamino, or C_1-6Haloalkyl, such as to form a trifluoroethyl group such as (trifluoroethyl-carbamoyl) ethylamino; c_1-6Alkyl, such as methyl, isopropyl, tert-butyl to form, for example, isopropylmethylamino or tert-butylmethylamino; c_1-6Alkoxy, for example to form methoxy, ethoxy or isopropoxy, for example as (2-methoxyethyl) (methyl) amino or (2-isopropoxyethyl) amino; het, e.g. to form a pyrazinyl group, e.g. pyrazinylmethylamino, to form an imidazolyl group, e.g. (1H-imidazol-2-yl) methylamino, to form a 1, 2, 4-triazol-3-yl group, e.g. (4H-1, 2, 4-triazol-3-yl) methylamino, (4H-1, 2, 4-triazol-3-yl) ethylamino, or (4H-1, 2, 4-triazol-1-yl) ethylamino, to form an isoxazolyl group, e.g. isoxazol-3-ylmethylamino, to form a thiazolyl group, e.g. 1, 3-thiazol-2-ylmethylamino or 1, 3-thiazol-4-ylmethylamino (which thiazolyl group is optionally further substituted with halogen, e.g. chlorine, to form, e.g. [ (2-chloro-1, 3-thiazol-4-yl) methyl ]Amino) to form a pyrazolyl group such as (1H-pyrazol-4-ylmethyl) amino or (1H-pyrazol-4-ylethyl) amino (which pyrazolyl group may optionally be selected from C_1-6Substituents of alkyl (e.g. methyl) or halogen (e.g. chloro) are further substituted to form, for example, [ (1-methyl-1H-pyrazol-4-yl) ethyl]Amino or [ (1-methyl-3-methyl-5-chloro-1H-pyrazol-4-yl) methyl]Amino) to form a tetrahydropyranyl group such as (tetrahydro-2H-pyran-4-ylmethyl) amino, or to form a pyridyl group such as (pyridin-2-ylmethyl) amino or (pyridin-4-ylmethyl) amino, wherein suitably the pyridyl group may be further substituted, for example by hydroxy, to form, for example [ (1-hydroxypyridin-4-yl) methyl]An amino group; to form a phenyl group such as a benzylamino group, the phenyl group being optionally substituted subsequently with one or more substituents selected from: halogen, e.g. chloro or fluoro to form, e.g. (4-fluorobenzyl) amino or (3, 4-difluorobenzyl) amino, optionally C substituted with one or more halogen groups (e.g. chloro or fluoro) to form, e.g. (trifluoromethylbenzyl) amino_1-6Alkyl, S (O)_nR¹¹E.g. wherein R¹¹To form, for example, [ (4-methanesulfonyl) benzyl]The methyl group of the amino group, Or wherein R is¹¹Is C_1-6Alkylamino, e.g. to form e.g. {4- [ (methylsulfonyl) amino]N-methyl, -NHS (O) of benzyl } amino_nR¹¹E.g. wherein R¹¹To form, e.g., {4- [ (methylamino) sulfonyl [ ]]Benzyl } amino methyl; and S (O)_nR¹¹E.g. wherein R¹¹To form, for example, the methyl group of the 3- (S-methylsulfide) propylamino group.

Still more suitable compounds include those wherein R is^eIndependently selected from hydrogen or C_1-6Alkyl (e.g., methyl), and R^fIndependently selected from the group consisting of: c_3-8Cycloalkyl, for example to form cyclopropyl such as cyclopropylamino; and C_3-8Cycloalkyl radical C_1-6Alkyl, e.g. cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, to form, for example, (cyclopropylmethyl) amino, (cyclopropylmethyl) (methyl) amino, (cyclopropylethyl) amino, (cyclobutylmethyl) amino, (cyclopentylmethyl) amino or (cyclohexylmethyl) amino, C_3-8Cycloalkyl radical C_1-6Alkyl groups may be optionally substituted with one or more groups selected from: halogen, e.g. to form e.g., [ (1-fluorocyclopropyl) methyl]Fluorine or chlorine of amino group; c_1-6Alkyl, e.g. to form e.g., [ (1-methylcyclopropyl) methyl]Amino or [ (1-ethylcyclopropyl) methyl ]Methyl or ethyl of amino; to form, for example, [ (1-aminocyclopropyl) methyl]An amino group of an amino group; c (O) NR^cR^dWherein R is^cAnd R^dTo form, for example, { [1- (aminocarbonyl) cyclopropyl]Methyl } amino; NR (nitrogen to noise ratio)^cR^dWherein R is^cOr R^dIndependently selected from the group consisting of: hydrogen, C (O) OC_1-6Alkyl (e.g. tert-butyloxycarbonyl) or S (O)_nR¹¹(wherein R is¹¹Is methyl) to form, for example { {1- [ (tert-butoxycarbonyl) amino]Cyclopropyl } methyl } amino or { {1- [ (methylsulfonyl) amino]Cyclopropyl } methyl } amino.

Still more suitable compounds include those wherein R is^eIndependently selected from hydrogen or C_1-6Alkyl (e.g. methyl) and R^fIndependently selected from: -C (O) OC_1-6Alkyl, such as methoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl to form, for example, (methoxycarbonyl) amino, (ethoxycarbonyl) amino, (isopropoxycarbonyl) amino or (methyl) (isopropoxycarbonyl) amino; -C (O) OC_3-8Cycloalkyl, for example to form a cyclobutoxycarbonyl group such as a (cyclobutoxycarbonyl) amino or a (methyl) (cyclobutoxycarbonyl) amino; and-C (O) OC_1-6Alkyl radical C_3-8Cycloalkyl, e.g. to form e.g. (cyclopropylmethoxy) carbonyl]Amino or (methyl) [ (cyclopropylmethoxy) carbonyl]Cyclopropyl methoxycarbonyl of amino group, — C (O) OC _1-6Alkyl radical C_3-8Cycloalkyl optionally substituted by, for example, C_1-6Haloalkyl (e.g., fluoromethyl) further substituted to form, for example { [1- (fluoromethyl) cyclopropyl { [1- (fluoromethyl)]Methoxy } carbonyl } amino.

Preferably, R⁹Selected from: hydrogen; halogen, such as chlorine; c_1-6Alkyl radicals, e.g. methyl, C_1-6The alkyl group is then optionally substituted with one or more substituents selected from the group consisting of: halogen, e.g. fluorine to form, e.g. difluoromethyl, or C_1-6Alkoxy, for example to form methoxy such as methoxymethyl; c_2-6Alkenyl groups such as vinyl; c_3-8Cycloalkyl radical C_1-6Alkoxy, such as cyclopropylmethoxy; and S (O)_nR¹¹E.g. wherein R¹¹Is methyl, to form, for example, methylthio, methylsulfinyl or methylsulfonyl.

Also preferred compounds include those wherein R is⁹Is NR^eR^fEach R is^eOr R^fIndependently selected from hydrogen and C_1-6Alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or n-pentyl, C_1-6The alkyl group may then be substituted with one or more substituents selected from: a cyano group; halogen, such as fluorine; c (O) OH; c (O) NR^cR^dWherein R is^cOr R^dIndependently selected from hydrogen, C_3-8Cycloalkyl radical C_1-6Alkyl (e.g. cyclopropyl)Methyl) or C _1-6Haloalkyl (e.g., trifluoroethyl); c_1-6Alkyl groups such as methyl, isopropyl, tert-butyl; c_1-6Alkoxy, such as methoxy, ethoxy or isopropoxy; het, e.g. pyrazinyl, imidazolyl, 1, 2, 4-triazolyl, isoxazolyl, thiazolyl (which thiazolyl may optionally be further substituted by halogen, e.g. chloro), pyrazolyl (which pyrazolyl may optionally be C_1-6Alkyl (e.g. methyl) or halogen (e.g. chloro) further substituted), tetrahydropyranyl or pyridinyl (where appropriate the pyridinyl may be further substituted by, for example, hydroxy); phenyl, which phenyl is then optionally substituted with one or more substituents selected from: halogen (e.g. fluorine), C optionally substituted by one or more halogen groups (e.g. fluorine)_1-6Alkyl, S (O)_nR¹¹E.g. wherein R¹¹Is methyl or wherein R¹¹Is C_1-6Alkylamino (e.g. N-methyl), -NHS (O)_nR¹¹E.g. wherein R¹¹Is methyl; and S (O)_nR¹¹E.g. wherein R¹¹Is methyl.

Also preferred compounds include those wherein R is⁹Is NR^eR^f，R^eIs hydrogen or C_1-6Alkyl, e.g. methyl, and R^fIs C_3-8Cycloalkyl radical C_1-6Alkyl, e.g. cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, C _3-8Cycloalkyl radical C_1-6Alkyl groups may be optionally substituted with one or more groups selected from: c_1-6Alkyl groups such as methyl; an amino group; c (O) NR^cR^dWherein R is^cAnd R^dAre all hydrogen; and NR^cR^dWherein R is^cAnd R^dIndependently selected from hydrogen, C (O) OC_1-6Alkyl (e.g. tert-butyloxycarbonyl) and S (O)_nR¹¹(wherein R is¹¹Methyl) group.

Also preferred compounds include those wherein R is⁹Is NR^eR^f，R^eIs hydrogen orC_1-6Alkyl, e.g. methyl, and R^fSelected from: -C (O) OC_1-6Alkyl, such as methoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl; -C (O) OC_3-8Cycloalkyl groups such as cyclobutyloxycarbonyl; and-C (O) OC_1-6Alkyl radical C_3-8Cycloalkyl radicals, e.g. cyclopropylmethoxycarbonyl, the radical-C (O) OC_1-6Alkyl radical C_3-8Cycloalkyl optionally substituted by, for example, C_1-6Haloalkyl (e.g., fluoromethyl) is further substituted.

Even more preferably, R⁹Selected from: halogen, such as chlorine; c_1-6Alkyl radicals, e.g. methyl, C_1-6Alkyl optionally substituted subsequently with halo (e.g., fluoro); NR (nitrogen to noise ratio)^eR^fWherein each R is^eOr R^fIndependently selected from hydrogen, C_1-6Alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or n-pentyl, C_1-6The alkyl group may be subsequently substituted with one or more substituents selected from the group consisting of: cyano, halogen (e.g. fluorine), C (O) NR ^cR^d(wherein R is^cAnd R^dAll hydrogen), het (e.g. 1, 2, 4-triazolyl) or S (O)_nR¹¹E.g. wherein R¹¹Is methyl; c_3-8Cycloalkyl radical C_1-6Alkyl radicals, e.g. cyclopropylmethyl, cyclopropylethyl, C_3-8Cycloalkyl radical C_1-6Alkyl is optionally substituted by C (O) NR^cR^dIs substituted in which R^cAnd R^dAre all hydrogen; -C (O) OC_1-6Alkyl, such as methoxycarbonyl, ethoxycarbonyl or isopropoxycarbonyl; and-C (O) OC_1-6Alkyl radical C_3-8Cycloalkyl groups, such as cyclopropylmethoxycarbonyl.

Most preferably, R⁹Selected from: chlorine; a methyl group; difluoromethyl; an amino group; a methylamino group; (2-cyanoethyl) amino; an isobutylamino group; (2-fluoroethyl) amino; (2-fluoro-2-methyl-propyl) amino; carbamoylmethylamino; (1, 2, 4-triazol-1-yl) ethylamino; [3- (methylthio) propyl group]An amino group; (cyclopropylmethyl) amino; (methyl) (cyclopropylmethyl) amino; { [1- (aminocarbonyl) cyclopropyl]Methyl } amino; (methoxycarbonyl) amino; (ethoxycarbonyl) amino; (different from each otherPropoxycarbonyl) amino; (methyl) (ethoxycarbonyl) amino; and [ (cyclopropylmethoxy) carbonyl group]An amino group.

Preferably, X is CR¹⁰. Suitable compounds include those wherein R is¹⁰Preferred halogen substituents for halogen are fluorine, chlorine or bromine. Other suitable compounds include those compounds where R is ¹⁰Is selected from C_1-6Alkyl or C_1-6Alkoxy, wherein the C_1-6Alkyl or C_1-6Alkoxy groups are optionally substituted with one or more halo substituents, with preferred halo substituents being fluoro, chloro or bromo. Preferably, R¹⁰Selected from chlorine or fluorine. Most preferably, R¹⁰Is chlorine. Other preferred compounds are those wherein R is⁷And R¹⁰All of which are identical. More preferably, R⁷And R¹⁰Are all Cl.

Another group of suitable compounds of the invention are compounds of formula (I) wherein:

R¹、R³to R¹¹、X、R^c、R^dN and het are as defined above for formula (I); and is

R²Selected from cyano, hydroxy, C (O) OH, het, S (O)_nR¹¹、C(O)NR^aR^bAnd C (S) NR^aR^b；

Or R²Is selected from C_1-6Alkanoyl, C (O) OC_1-6Alkyl and amino, each of which is optionally and independently further substituted with one or more substituents selected from, where chemically available, the following: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Wherein R is^aAnd R^bIndependently selected from hydrogen, het, phenyl and S (O) _nR¹¹(ii) a Or R^aAnd R^bEither or both of which are independently selected from C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, each of the radicals R^aOr R^bOptionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹Or R is^aAnd R^bTogether with the N atom to which they are attached form a 3-to 7-membered saturated, partially saturated or unsaturated or aromatic heterocyclic ring, which optionally contains one or more further N, O or S atoms, and which is optionally further substituted by one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C _1-6Alkyl halidesBase, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or a pharmaceutically acceptable salt or precursor thereof.

Preferably, in these compounds of formula (I): r¹Selected from CF₃、OCF₃Or SF₅；R³And R⁴Are identical to each other and are selected from: hydrogen; fluorine; and chlorine; r⁵And R⁶Are all hydrogen; r⁷Is chlorine; r⁸Is cyano; x is CR¹⁰Wherein R is¹⁰Is chlorine.

R¹to R⁸、X、R^c、R^d、n、R¹⁰To R¹¹And het are both as defined above for formula (I); and is

R⁹Selected from hydrogen, halogen and S (O)_nR¹¹；

Or R⁹Is selected from C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Alkoxy radical, the R⁹Optionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or R⁹Is NR^eR^fWherein R is^eAnd R^fIndependently selected from hydrogen; or R ^eAnd R^fOne or both of which are independently selected from C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl, C (O) OC_1-6Alkyl, -C (O) OC_1-6Alkyl radical C_3-8Cycloalkyl, -C (O) OC_3-8Cycloalkyl radical, each R of^eOr R^fOptionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or a pharmaceutically acceptable salt or prodrug thereof.

Preferably, in these compounds of formula (I): r¹Selected from CF₃、OCF₃Or SF₅；R³And R⁴Are identical to each other and are selected from: hydrogen, fluorine, and chlorine; and R is⁵And R⁶Are all hydrogen; r⁷Is chlorine; r⁸Is cyanogen; and X is CR¹⁰Wherein R is¹⁰Is chlorine.

Other suitable compounds of the invention are compounds of formula (I) wherein:

R¹、R³to R⁸、X、R^c、R^d、n、R¹⁰And R¹¹And het are both as described above for formula (I)Defining;

Or R²Is selected from C_1-6Alkanoyl, C (O) OC_1-6Alkyl and amino, each of which is optionally and independently further substituted with one or more substituents selected from, where chemically available, the following: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR ^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Wherein R is^aAnd R^bIndependently selected from hydrogen, het, phenyl and S (O)_nR¹¹(ii) a Or R^aAnd R^bEither or both of which are independently selected from C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, each of the radicals R^aOr R^bOptionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl radicals、C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹(ii) a Or R^aAnd R^bTogether with the N atom to which they are attached form a 3-to 7-membered saturated, partially saturated or unsaturated or aromatic heterocyclic ring, which optionally contains one or more further N, O or S atoms and which is optionally further substituted by one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR ^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

R⁹Selected from hydrogen, halogen and S (O)_nR¹¹；

Or R⁹Is selected from C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Alkoxy radical, the R⁹Optionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxy, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or R⁹Is NR^eR^fWherein R is^eAnd R^fIndependently selected from hydrogen; or R^eAnd R^fEither or both of which are independently selected from C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl, C (O) OC_1-6Alkyl, -C (O) OC_1-6Alkyl radical C_3-8Cycloalkyl, -C (O) OC_3-8Cycloalkyl radical, each R of^eOr R^fOptionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR ^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or a pharmaceutically acceptable salt or precursor thereof.

Preferably, in these compounds of formula (I): r¹Selected from CF₃、OCF₃Or SF₅；R³And R⁴Are identical to each other and are selected from: hydrogen, fluorine, and chlorine; and R is⁵And R⁶Are all hydrogen; r⁷Is chlorine; r⁸Is cyano; and X is CR¹⁰Wherein R is¹⁰Is chlorine.

An even more suitable group of compounds of the invention are the following compounds of formula (I):

R¹to R²、R⁷To R⁹、X、R^c、R^d、n、R¹¹And het are both as defined above for formula (I); and is

Or R³、R⁴、R⁵And R⁶Is independently selected from C_1-4Alkyl, C (O) NR^cR^d、C(S)NR^cR^d、C_1-4Alkoxy radical, C_1-4Alkanoyl, C (O) OC_1-4Alkyl, amino, the R³、R⁴、R⁵And R⁶Optionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, hydroxy, C_1-4Alkyl and amino; and wherein R³、R⁴、R⁵And R⁶No more than two of them are selected from cyano, hydroxy, C (O) OH, nitro, phenyl, S (O) _nR¹¹、C(O)NR^cR^d、C(S)NR^cR^d、C_1-4Alkoxy radical, C_1-4Alkanoyl, C (O) OC_1-4Alkyl and amino;

or a pharmaceutically acceptable salt or precursor thereof.

Preferably, in these compounds of formula (I): r¹Selected from CF₃、OCF₃Or SF₅；R⁷Is chlorine; r⁸Is cyano; and X is CR¹⁰Wherein R is¹⁰Is chlorine.

Preferred individual compounds of the invention are selected from:

5-amino-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -4- [1- (methylsulfonyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester;

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

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -N, N-dimethylcyclopropanecarboxamide;

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

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

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

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

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

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

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanesulfonamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (isobutylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N-isopropylcyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-fluoroethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- {5- [ (2-amino-2-oxoethyl) amino ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -cyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-dichlorocyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (pyridin-4-ylmethyl) cyclopropanecarboxamide;

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } carbamic acid isopropyl ester;

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [2- (1H-1, 2, 4-triazol-1-yl) ethyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxamide;

1- { 3-cyano-5- [ (2-cyanoethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- (5-amino-3-cyano-1- {2, 6-dichloro-4- [1, 2, 2, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] phenyl } -1H-pyrazol-4-yl) cyclopropanecarboxamide;

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [3- (methylthio) propyl ] amino } -1H-pyrazol-4-yl) -cyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- [ (5-methyl-4H-1, 2, 4-triazol-3-yl) methyl ] cyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) (methyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } carbamic acid [1- (fluoromethyl) cyclopropyl ] methyl ester;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (3, 3, 3-trifluoropropyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- (5- { [ (2-chloro-1, 3-thiazol-5-yl) methyl ] amino } -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl) cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (isoxazol-5-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

n to 3- {4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } - β -propylamine amide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (5, 5, 5-trifluorophenyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (propylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclobutylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (dimethylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-5-yl } carbamic acid ethyl ester;

2, 2-dichloro-1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } -2, 2-dichlorocyclopropanecarboxamide;

1- { 3-cyano-5- ({2- [ (cyclopropylmethyl) amino ] -2-oxoethyl } amino) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- {5- [ (4-amino-4-oxobutyl) amino ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (1, 3-thiazol-2-ylmethyl) amino ] -1H-pyrazol-4-yl } -cyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (2-methoxyethyl) cyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (2-hydroxyethyl) cyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (pyridin-2-ylmethyl) cyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (pyridin-3-ylmethyl) cyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (2-hydroxy-2-methylpropyl) cyclopropanecarboxamide;

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [2- (1-methyl-1H-pyrazol-4-yl) ethyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (dimethylamino) -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylthio) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-methoxyethyl) (methyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- (5- { [ (5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) methyl ] amino } -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl) cyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N-methylcyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -N-cyclopropylcyclopropane-carboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -N- (cyclopropylmethyl) -cyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -N-pyridin-2-cyclopropanecarboxamide;

1- { 5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

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

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (2, 2, 2-trifluoroethyl) -cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- (methylamino) -1H-pyrazol-4-yl } -2, 2-difluoro-cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- (methylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -N-methylcyclopropanecarboxamide

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-dimethylcyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (4H-1, 2, 4-triazol-3-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [ (1-methylcyclopropyl) methyl ] amino } -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- ({4- [ (methylamino) sulfonyl ] benzyl } amino) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- ({4- [ (methylsulfonyl) amino ] benzyl } amino) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (tetrahydro-2H-pyran-4-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (3-isopropoxypropyl) cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- ({ 2-oxo-2- [ (2, 2, 2-trifluoroethyl) amino ] ethyl } amino) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

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

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (methylthio) cyclopropyl ] -1H-pyrazole-3-thiocarboxylic acid S-methyl ester;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- {5- (benzylamino) -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -5- [ (pyridin-2-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -5- [ (2, 2-dimethylpropyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [4- (methylsulfonyl) benzyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- [ (pyridin-4-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- [ (2, 2, 2-trifluoroethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- [ (1H-imidazol-2-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 5-chloro-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 5-chloro-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide;

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

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-dimethylcyclopropanecarboxylic acid;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (difluoromethyl) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } carbamic acid cyclopropylmethyl ester;

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } methylcarbamic acid ethyl ester;

1- [ ({4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } amino) methyl ] cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5-methyl-1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } -cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-fluoro-2-methylpropyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

methyl {4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } carbamate;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide;

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } carbamic acid ethyl ester;

cyclopropyl methyl {4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } methylcarbamate;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (4, 4, 4-trifluorobutyl) amino ] -1H-pyrazol-4-yl } -cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (ethylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

{1- [ ({4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } amino) methyl ] cyclopropyl } carbamic acid tert-butyl ester;

1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [4- (trifluoromethyl) benzyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxamide;

1- { 3-cyano-5- (cyclopropylmethoxy) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-isopropoxyethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5-vinyl-1H-pyrazol-4-yl } cyclopropanecarboxamide;

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } carbamic acid cyclobutyl ester;

1- [ 5-amino-3-cyano-1- (2, 6-dichloro-4-cyanophenyl) -1H-pyrazol-4-yl ] cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (4-fluorobenzyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methoxymethyl) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-5-yl } carbamic acid ethyl ester;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- {5- (benzylamino) -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide;

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide;

4- (1-cyanocyclopropyl) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazole-3-carbonitrile;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarbothioamide;

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

1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (1-oxidopyridin-4-yl) methyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (methylsulfonyl) -cyclopropanecarboxamide;

1- { 3-cyano-5- [ (2-cyclopropylethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- [2, 6-dichloro-4-pentafluorothiophenyl ] -7-methyl-5-oxo-5, 6, 7, 8-tetrahydro-1H-spiro [ cyclopropane-1, 4-pyrazolo [3, 4-d ] [1, 3] diazepine ] -3-carbonitrile;

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

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (isopropylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- (isopropylamino) -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide;

4- (1-cyanocyclopropyl) -5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazole-3-carbonitrile;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ ({1- [ (methylsulfonyl) amino ] cyclopropyl } methyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- (5- { [ (1-aminocyclopropyl) methyl ] amino } -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl) cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methanesulfinyl) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylsulfonyl) -1H-pyrazol-4-yl } cyclopropanecarboxamide;

4- ({4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } amino) butanoic acid;

or a pharmaceutically acceptable salt or precursor thereof.

Even more preferred individual compounds of the invention are selected from:

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide;

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-fluoro-2-methylpropyl) amino ] -1H-pyrazol-4-yl) cyclopropanecarboxamide;

or a pharmaceutically acceptable salt or precursor thereof.

Most preferred individual compounds of the invention are selected from:

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl } -2, 2-difluoro-cyclopropanecarboxamide;

or a pharmaceutically acceptable salt or precursor thereof.

In the compounds of formula (I), the term "halogen" means a radical selected from fluorine, chlorine, bromine or iodine. Preferably, the term "halogen" means a group selected from fluorine, chlorine or bromine.

The alkyl, alkenyl, alkynyl and alkoxy groups containing the requisite number of carbon atoms may be unbranched or branched. The term "lower alkyl" shall mean C _1-6An alkyl group. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, primary-butyl and tertiary-butyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, primary-butoxy and tertiary-butoxy. Examples of alkylene (alkenyl) include methylene, 1-ethylene, 1, 2-ethylene, 1-propylene, 1, 2-propylene, 1, 3-propylene and 2, 2-propylene. The term "cycloalkyl" shall mean C_3-8A cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

In the compounds of formula (I), the term "phenyl" shall mean a 6-membered aromatic carbocyclic ring, which phenyl group may be substituted as described for compounds of formula (I).

In the compounds of formula (I), the term "het" shall mean a substituent which belongs to the definition set forth in claim 1. Preferably, the term "het "shall mean a substituent representing a 5-to 6-membered heterocyclic group which is aromatic or non-aromatic, unsaturated, partially saturated or saturated, and which contains one or more heteroatoms selected from nitrogen, N-oxide, oxygen and sulfur, and wherein the heterocyclic ring is optional, where valency allows, selected from halogen, C by one or more substituents _1-6Alkyl radical, C_1-6Haloalkyl, NR^gR^hWherein R is^gAnd R^hIndependently selected from hydrogen and C_1-6An alkyl group. More preferably, the term "het" shall mean a substituent representing a 5-to 6-membered heterocyclic group which is aromatic or non-aromatic, unsaturated, partially saturated or saturated, and which contains at least one nitrogen or oxygen atom, optionally up to two further heterocyclic atoms selected from nitrogen, oxygen and sulfur, and wherein the heterocyclic group is optionally, where valency allows, substituted by one or more groups selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, NR^gR^hWherein R is^gAnd R^hIndependently selected from hydrogen and C_1-6An alkyl group.

The substituent R for the compounds of the formula (I)²And R thereof^aOr R^bAnd other optional substituents, the most preferred term "het" shall mean a substituent representing a 5-to 6-membered heterocyclic ring which is aromatic, unsaturated or partially saturated, and which contains at least one nitrogen atom, optionally up to two other heterocyclic atoms selected from nitrogen, oxygen and sulfur, and wherein the heterocyclic ring is optionally, where valency allows, substituted with one or more substituents selected from halogen and C_1-6Alkyl substituents. Suitable preferred examples of such rings include 1-oxa-3, 4-oxadiazolyl, thiazolyl, 5-methyl-1-3, 4-oxadiazol-2-yl, pyridinyl or 1, 2, 4-triazolyl.

The substituent R for the compounds of the formula (I)⁹And R thereof^eOr R^fAnd other optional substituents, the most preferred term "het" shall mean a substituent representing a 5-to 6-membered heterocyclic ring, the 5-to 6-membered heterocyclic ring being aromatic, unsaturated, or cyclicIs saturated or saturated and contains at least one nitrogen atom or one oxygen atom, optionally contains up to two further heterocyclic atoms selected from nitrogen, oxygen or sulfur, and wherein the heterocyclic ring is optionally, where valency allows, substituted by one or more groups selected from halogen and C_1-6Alkyl substituents. Suitable preferred examples of such rings include pyrazinyl, imidazolyl, pyridyl, 1-hydroxy-pyridyl, 1, 2, 4-triazolyl, 1, 3, 4-triazolyl, isoxazolyl, thiazolyl, 2-chloro-1, 3-thiazol-4-yl, pyrazolyl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-3-methyl-5-chloro-1H-pyrazol-4-yl and tetrahydropyranyl.

In the compound of formula (I), each phenyl group is optionally and independently substituted as described in claim 1. More preferably, each phenyl group is optionally and independently substituted with one or more groups selected from halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, -NHS (O)_nR¹¹And S (O) _nR¹¹Other substituents of the group. More preferably, each phenyl group is optionally selected at the 4-position from the group consisting of halogen, C_1-6Haloalkyl, -NHS (O)_nR¹¹And S (O)_nR¹¹Substituents of the group.

The substituent R for the compounds of the formula (I)⁹And R thereof^eOr R^fAnd other optional substituents, it is preferred that each phenyl group is optionally selected at the 4-position from the group consisting of halogen, C_1-6Haloalkyl, -NHS (O)_nR¹¹And S (O)_nR¹¹Substituents of the group. Suitable examples of such phenyl groups include 4-fluorophenyl, 4-trifluoromethylphenyl, (4-methylsulfonyl) phenyl, 4- [ (methylsulfonyl) amino]Phenyl and 4- [ (methylamino) sulfonyl]A phenyl group.

It will be appreciated that the compounds of formula (I) may exist in the form of one or more geometric isomers. Accordingly, all possible geometric isomeric forms of the compounds of the present invention are included within the scope of the present invention. The geometric isomers are separated by conventional techniques known to those skilled in the art, such as chromatography and fractional crystallization.

It will be appreciated that the compounds of formula (I) may exist in the form of one or more tautomers. Accordingly, all possible tautomeric forms of the compounds of the invention are included within the scope of the invention.

It will be appreciated that the compounds of formula (I) may contain one or more asymmetric carbon atoms and thus the compounds of the invention may exist in 2 or more stereoisomeric forms. All stereoisomers, such as enantiomers and diastereomers, are included within the scope of the invention. Also included are acid addition salts or base salts in which the counterion is optically active, e.g., D-lactate or L-lysine, or racemic, e.g., racemic (DL) -tartrate or DL-arginine.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral High Performance Liquid Chromatography (HPLC).

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

The enantiomerically enriched form of the chiral compounds of the invention (and chiral precursors thereof) is obtainable by chromatography (typically HPLC) using the following conditions: the mobile phase of the asymmetric resin consists of a mixture containing 0 to 50% isopropanol (typically 2 to 20%) and 0 to 5% alkylamine (typically 0.1% diethylamine) hydrocarbon (typically heptane or hexane). Concentrating the eluate to obtain an enriched mixture.

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

Compounds having more than one isomeric type and one or more mixtures thereof are included within the scope of the present invention.

For the avoidance of doubt, it is to be understood that all references to pharmaceutically acceptable compounds throughout this application include veterinary or agronomically acceptable compounds. Moreover, reference throughout this application to pharmaceutical activity is to be understood to include veterinary or agronomic activity.

Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, methanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, salicylate (hibenzate), hydrochloride/chloride, bromate/bromide, iodate/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate (pamoate), phosphate/hydrogen phosphate/dihydrogen phosphate, hexonate, stearate, succinate, camphorate, naproxen, and the like, Tartrate, tosylate and trifluoroacetate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzarine, calcium, choline, diethylamine, dialcohol, glycinate, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Pharmaceutically, veterinarily and agriculturally acceptable acid addition salts of certain compounds of formula (I) may also be prepared in a conventional manner. 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. To summarize the appropriate salts, see Stahl and Wermuth, "Handbook of pharmaceutical salts: properties, Selection, and Use "(Wiley-VCH, Weinheim, Germany, 2002).

All references to compounds of formula (I) hereinafter and throughout this application include salts, solvates and complexes thereof, and solvates and complexes of salts thereof.

The present invention includes all polymorphs of the compound of formula (I) as defined below.

The compounds of the present invention may exist in unsolvated as well as solvated forms. The term "solvate" as used herein describes a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used. Pharmaceutically acceptable solvates according to the invention include those in which the solvent of the crystallization may be isotopically substituted, for example D ₂O、d₆-acetone, d₆-DMSO。

Complexes such as clathrates, drug-host inclusion complexes, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the aforementioned solvates, are included within the scope of the present invention. Also included are pharmaceutical complexes containing two or more organic and/or inorganic components that may be present in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized, or not ionized. To summarize this complex, see J Pharm Sci by Haleblian, 64(8), 1269-1288 (8/1975).

The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) wherein one or more atoms are replaced by an atom having the same atomic number, 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, such as²H and³h, isotopes of carbon, such as¹¹C、¹³C and¹⁴c, a chlorine isotope, such as³⁶Cl, isotopes of fluorine, such as¹⁸F, iodine isotopes, such as¹²³I and¹²⁵i, isotopes of nitrogen, such as¹³N and¹⁵n, isotopes of oxygen, such as¹⁵O、¹⁷O and¹⁸o, isotopes of phosphorus, such as ³²P, and sulfur isotopes, such as³⁵S。

So-called "prodrugs" of the compounds of formula (I) are also included within the scope of the present invention. Derivatives of compounds of formula (I) which are themselves hardly pharmacologically active or not pharmacologically active when administered into or onto the body may be converted into compounds of formula (I) having the desired activity by, for example, hydrolytic cleavage. Such derivatives are referred to as "prodrugs".

More information on prodrugs can be found in the following: "Pro-drugs asNovel Delivery Systems", Vol.14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Delivery", Pergamon Press, 1987(E B Roche eds., American Pharmaceutical Association).

Prodrugs according to the invention may be prepared, for example, by substituting suitable functional groups present in the compounds of formula (I) with certain fragments known to those skilled in the art as "pro-moieties", as described in Bundgarrd "Design of Prodrugs" (Elsevier, 1985).

Some examples of prodrugs according to the invention include:

(i) in the case where the compound of formula (I) contains a carboxylic acid function (-COOH) and esters thereof, for example with (C) ₁To C₈) Alkyl substituted hydrogen;

(ii) in the compounds of the formula (I) containing an alcohol function (-OH) andin the case of ethers thereof, e.g. with (C)₁To C₆) Alkanoyloxymethyl for hydrogen; and

(iii) containing primary or secondary amino functions (-NH) in the compounds of formula (I)₂or-NHR, where R.noteq.H) and amides thereof, for example with (C)₁To C₁₀) Alkanoyl substitutes one or two hydrogens.

For example, in H Bundgaard, "Design of produgs" (Elsevier, 1985); "Design and application of drugs", Textbook of Drug Design and discovery, (3 rd edition), 2002, 410-458(Taylor and Francis Ltd. London); and as described in the references herein, prodrugs of the invention may be prepared, for example, by substituting the 5-amino substituent on the pyrazole ring in compounds of formula (I) with certain moieties known to those skilled in the art as "prodrug moieties".

Suitable prodrugs 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 (such as pyridyl), C_2-6Alkenyl and C_3-8A cycloalkyl group; wherein each of the foregoing groups may include one or more, where chemically available, substituents independently selected from the group consisting of: halogen; a hydroxyl group; c_1-6Alkyl he C_1-6An alkoxy group.

Other examples of substituents and other precursor types according to the preceding examples can be found in the above references.

Prodrugs of the invention may be readily identified by administering to a host animal and sampling body fluids containing a compound of formula (I). Finally, certain compounds of formula (I) may themselves be prodrugs of other compounds of formula (I). The precursor may be split into the active drug by the metabolism of the host or by the parasite targeting the host.

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

It is known to those skilled in the art that sensitive functional groups need to be protected and deprotected during the synthesis of the compounds of the invention. This can be achieved, for example, by the conventional methods described in TW Greene and PGM Wuts, "protective groups in Organic Synthesis", John Wiley & Sons Inc (1999) and references therein.

The following methods illustrate general synthetic procedures that may be employed to obtain compounds of the invention and the like.

When R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰And R¹¹When one or more of them comprise a reactive functional group, additional protection may be provided during synthesis of the compound of formula (I) according to standard procedures. In the following process, R is the same for all synthesis precursors used in the synthesis of the compounds of formula (I)¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰And R¹¹In which R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰And R¹¹Optionally including suitably protected variables, P, as defined by formula (I)¹、P²、P³、P⁴、P⁵、P⁶、P⁷、P⁸、P⁹、P¹⁰And P¹¹. Suitable protecting groups mentioned above for these functional groups are described in the references listed below and, if necessary, the use of these protecting groupsThe scope of the process described herein for the preparation of the compounds of formula (I) and their precursors falls within the scope of the present invention. When appropriate protecting groups are used, these protecting groups must be removed to give the compounds of formula (I). Deprotection is achieved according to standard procedures including those described in the references listed below. For example when R in formula (I)⁹In the case of unsubstituted amino groups, it is necessary to convert the amino group of the precursor with protection, for example via an imidoformamide group (imidoformamide group), such as a compound of the formula (I), in which R is ¹To R⁸And R¹⁰As described in formula (I), and R⁹represents-N ═ C (H) -NR^cR^dWherein R is^cAnd R^dIndependently represents C₁To C₆Alkyl to form, for example, N-dimethyl. Such imidocarboxamides can be prepared by standard methods: the unprotected amine is typically refluxed in N, N-dimethylformamide dimethyl acetal for 2 to 16 hours, typically about 5 hours, followed by stirring at room temperature for 5 to 24 hours, typically overnight. The imidocarboxamide protecting group may be removed under standard conditions (such as at elevated temperature) in a solvent (such as methanol or dioxane) using an appropriate acid (such as hydrochloric acid or p-toluenesulfonic acid).

The compounds of formula (I) may be prepared by cyclopropanation of an alkene of formula (II):

wherein R is¹、R²、R³、R⁴、R⁷、R⁸、R⁹And X is as previously defined for formula (I). This can be achieved by generating the desired carbene, CR, in situ by a suitable method in the presence of (II)⁵R⁶(wherein R is⁵And R⁶As previously defined for formula (I).

Such a process may include subjecting a compound of formula (II) to reflux treatment with a reactant, such as trimethylsilyl difluoro (fluorosulfonyl) acetate (TFDA), in the presence of sodium fluoride to produce a product of formula (I), as described in j. fluor chem.2004, 125, 459 by Dolbier et al. Other methods for in situ generation of carbenes include treatment of chloroform or bromoform with a base, preferably under phase transfer catalysis; pyrolyzing a suitable organometallic precursor, such as an aryltrifluoromethyl, trichloromethyl, tribromomethyl or phenyl (trifluoromethyl) mercury derivative; or by treatment with a diazoalkane in the presence of a transition metal catalyst and in the absence of a transition metal catalyst, followed by pyrolysis of the intermediate (pyrazoline) or by formation from a thioylide (ylid).

The compound of formula (II) can be synthesized using an organozinc reagent of the following formula (III):

wherein R is¹、R⁷、R⁸、R⁹And X is as previously defined for formula (I). The procedure to obtain the organozinc reagent of formula (III) is: (IV), wherein the halogen is preferably bromine or iodine, is treated with active zinc (Rieke zinc) in a non-polar solvent such as tetrahydrofuran for several hours. The organozincate can then be cross-coupled to a haloolefin in a non-polar solvent such as tetrahydrofuran in the presence of a palladium (II) compound such as dichlorobis (triphenylphosphine) palladium (II) and a reducing agent such as diisobutylaluminum hydride at elevated temperatures, typically under reflux.

Alternatively, the compound of formula (II) can be obtained directly by the following method: the compound of formula (IV) is reacted with an organostannane at elevated temperature in the presence of a metal catalyst such as tetrakis (triphenylphosphine) palladium (0) for several hours.

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

Thus, the compound of formula (IV) can be treated with a Grignard reagent such as isopropyl-magnesium chloride at reduced temperature under inert conditions using a non-polar solvent, and then heated to room temperature using an acid chloride and an acid anhydride to produce the desired ketone represented by formula (V).

Compounds of formula (V) can be utilized to give compounds of formula (II) wherein R ³And R⁴Is H. Whereby the compound of formula (V) may be methyleneated by treatment with Witting reagent at reduced temperature in a solvent such as tetrahydrofuran under inert conditions.

The compounds of formula (II) can also be obtained from compounds of formula (V) by the following steps: the compound of formula (V) is treated with a haloolefin, such as dibromodifluoromethane, in the presence of triphenylphosphine and Rieke zinc in a non-polar solvent.

Likewise, the compound of formula (II) may be obtained by reacting the compound of formula (IV) with an organozinc reagent. Specific examples of compounds of formula (VI) may be prepared according to scheme 1 shown below. The reaction is carried out at elevated temperature (typically 110 ℃) in a suitable solvent (such as N, N-dimethylformamide) using a metal catalyst (such as tetrakis (triphenylphosphine) palladium (0)) for several hours (typically 10 hours). Intermediates used in the synthesis of compound (VI) can be obtained using conventional synthetic procedures, according to standard textbooks of organic chemistry or previous literature.

FIG. 1 schematically shows

Alternatively, a compound of formula (VII) wherein R¹、R⁷、R⁸、R⁹And X is as previously defined for formula (I), obtainable by the following steps: the compound of formula (IV) is reacted with a suitable grignard reagent (e.g. isopropyl magnesium chloride) in a suitable solvent such as tetrahydrofuran, followed by the addition of methyl pyruvate.

Subsequently, dehydration is carried out using a mild base and an activating reagent (such as methanesulfonyl chloride) to give a compound of formula (II) wherein R is²Is COOCH₃. Alternatively, the dehydration reaction can be carried out using the following two halogenation steps: halogenation in acetonitrile using thionyl chloride is followed by dehydrohalogenation by heating in an inert solvent such as p-xylene or by standard base catalyzed dehydrohalogenation procedures.

The compound of formula (IV) may be prepared from a compound of formula (VIII):

wherein R is¹、R⁷、R⁸、R⁹And X is as previously defined for formula (I) and is obtained by a conventional bromination process or iodination process. For example, when the halogen is iodine, (VIII) is treated with N-iodosuccinimide in a suitable solvent, such as acetonitrile, at a temperature of from about room temperature to about 85 ℃.

Alternatively, the compounds of formula (IV) may be prepared according to scheme 2 as follows:

FIG. 2 is a schematic view of

Wherein R is¹、R⁷、R⁸And X is as previously defined for formula (I), and R⁹Is SR^r、NR^rR^sOR OR^rWherein each R is^rAnd R^sIndependently H, alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroaralkyl, wherein each alkyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, heteroaralkyl is optionally substituted. The compounds of formula (X) may be prepared from compounds of formula (IX) via standard nucleophilic substitution procedures. The amine (XI) can then be optionally used in the presence of a catalyst (usually S) _nCl₂HCl or Fe/CaCl₂) Is reduced with an appropriate reducing agent in the presence of (2).

The compound of formula (IV) can be prepared from (XI) by the conventional Sandmeyer procedure.

For the preparation of compounds of formula (I) wherein R²Is CF₂O，R³、R⁴Is F, and R⁵、R⁶The specific method for H is as follows: intermediate oxonium ion (XIII) formed via reaction of a ketone of formula (XII) with TFDA in the presence of sodium fluoride, followed by hydride transfer and insertion of a carbene on the newly formed alkene to give cyclopropane.

Another cyclopropanation process is the reaction of a carbene formed in situ from a compound of formula (XIV) with an alkene of the formula:

wherein R is¹³Is an optionally substituted aryl or heteroaryl group. For example compounds of formula (I) wherein R²Is CF₃And R is³Is 4-chlorophenyl group and can be obtained by the following steps: reacting a compound of formula (XIV) wherein R²Is CF₃Stirred with 4-chlorostyrene at 60 ℃ in a suitable solvent (usually toluene) for a long time (usually 18 hours).

Azoalkanes (dizirine) (XIV) can be prepared from the corresponding diazirine using standard oxidizing Agents such as iodine or the oxidizing Agents described in "Handbook of Reagents for Organic Synthesis-oxidizing and Reducing Agents", edited by s.d. burke and r.l. danheiser.

Diazidine can be prepared by the following steps: reacting a compound of formula (XV) wherein R¹、R²、R⁷、R⁸、R⁹And X is as defined for formula (I) and R¹⁴Is the oxygen radical of toluene sulfonic acid,

with ammonia gas under high pressure, followed by reaction with a suitable base such as triethylamine.

Furthermore, the compounds of formula (I) may be prepared by the following steps: reacting a 4, 5-dihydropyrazole of the formula (XVI) in which R¹、R²、R⁷、R⁸、R⁹And X is as defined for formula (I), by heating at elevated temperature in a suitable non-polar solvent such as xylene. Another extrusion method uses ultraviolet light in the presence of an initiator such as benzophenone in a suitable non-polar solvent such as dichloromethane. At R²Is SO₂In the case of alkyl groups, this method is particularly suitable. In the preparation of compounds of formula (I) wherein R²Is SO₂NH₂In the process of (1), sulfurThe amide group needs to be protected as a sulfonylimino-carboxamide.

Dihydropyrazoles are prepared from compounds of formula (II) wherein R is¹、R²、R⁷、R⁸、R⁹And X is as defined for formula (I).

The arylpyrazoles of formula (I) can also be prepared by the Japp-Klingemann reaction. This reaction is described in org.react.1959, 10, 143-178. The 3, 4, 5-trisubstituted 1-arylpyrazoles are directly prepared in a reaction involving coupling an aryldiazonium with an appropriately substituted precursor bearing the desired substituent. The desired substituents are introduced simultaneously into the C-4 position in a process which does not include any rearrangement. Furthermore, various 4-substituents can be introduced conveniently and directly.

Thus, compounds of formula (I) wherein R⁹Is NH₂Optionally in the presence of an acid, by reacting a compound of formula (XVII)

With compounds of the formula (XVIII)

Carrying out a reaction wherein:

R¹to R¹⁰As defined above for compounds of formula (I);

l is an activating group; and

z is a compatible compensating ion that,

followed by removal of the L group.

Compensating ion Z^-May be any suitable counterion commonly found in diazo reactions. Preferably, Z^-Is halogen, HSO₄ ^-Or tetrafluoroborate, with tetrafluoroborate being most preferred.

The L group is an electron withdrawing group that stabilizes the anionic intermediate in the process. Thus, preferably, L is a group that can stabilize a negative charge on a neighboring carbon atom. The L group must also be removable. L may be removed under basic conditions, for example by basic hydrolysis, or by reduction and/or elimination reactions. The L group is important because it can be used to react the diazonium species with the compound of formula (XVII) and then be removed in a subsequent reaction stage. Preferably, L is an ester group or COR¹⁵A group. More preferably, L is selected from the group consisting of: -S (O)_pR¹⁶Wherein p is 1 or 2; (R)¹⁶O)₂PO；COOR¹⁶and-COR¹⁵Wherein R is¹⁵Selected 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 is 0, 1 or 2, each group optionally substituted on any carbon atom with 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_1-4Haloalkanesulfinyl radical, C_1-4Alkanesulfonyl group, C_1-4Haloalkanesulfonyl radical, C_3-8Cycloalkyl and C_3-8Halocycloalkyl radical and R¹⁵May be hydrogen, and wherein R¹⁶Selected from: c_1-8Alkyl radical, C_3-8Cycloalkyl, C (H)₂)_nPh and C (H)₂)_nHeteroaryl, wherein n is 0, 1 or 2, each group optionally being optionally substituted on any carbon atom by one or more groups independently selected fromAnd (3) substitution: halogen, hydroxy, cyano, nitro, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkanoyl radical, C_1-4Haloalkanoyl group, C_1-4Alkylsulfinyl radical, C_1-4Haloalkanesulfinyl radical, C_1-4Alkanesulfonyl group, C_1-4Haloalkanesulfonyl radical, C_3-8Cycloalkyl and C_3-8Halocycloalkyl radical and R¹⁵May be hydrogen. Preferably, L is selected from COR¹⁵COOR of (A)¹⁶A group of (1). Most preferably, L is-COOMe or-COOEt.

In some cases, the nature of the leaving group L means that the resulting intermediate is in an inappropriate oxidation state. Thus, where necessary, one or more reaction steps may be added to ensure that the correct oxidation state is achieved prior to cyclization to form the arylpyrazole.

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

The diazonium salt of formula (XVIII) may be prepared by conventional methods and may be prepared in situ for use in further reactions or may be isolated and used in a subsequent reaction step. For example, a solution of the corresponding aminobenzene in glacial acetic acid is added dropwise to a solution of sodium nitrite in a concentrated sulfuric acid/glacial acetic acid mixture at reduced temperature (typically 10 ℃), then heated at 50 ℃ for several hours (typically 1 hour) and allowed to cool to room temperature. The diazonium salt solution is then added dropwise to a solution of the compound of formula (XVII) in a suitable solvent, such as acetic acid, followed by stirring at room temperature for up to one hour. The reaction mixture is poured into water and extracted with a water-immiscible organic solvent such as dichloromethane. Aqueous ammonium hydroxide was added to the organic extract and stirred overnight to give the compound of formula (I). Aminobenzenes are generally commercially available. Other compounds can be prepared by standard literature procedures. For example, (XX) is readily prepared from (XIX) by a chlorination reaction using N-chlorosuccinimide in acetonitrile.

Alternatively, the compound of formula (XVII) may be represented by the formula (XXI) wherein R is²、R³、R⁴、R⁵、R⁶And L is as defined for formula (XVII), for example by treatment of a compound of formula (XXI) with a source of cyanide ions.

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

The compound of formula (XXIII) can be prepared, for example, by the following steps: alkyl cyanoalkanoates (e.g. methyl cyanoacetate) are condensed with acyl chloride in a non-polar 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, compounds of formula (XXI) may be obtained by Knoevenagel condensation of an appropriate aldehyde (such as (XXII) or ketone) with an alkyl alkanoate (such as methyl cyanoacetate). A compound of the formula (XXII), wherein R²Cooalkyl can be prepared by selective reduction of malonyl ester (XXIV).

A compound of formula (XXV) wherein L ═ CO₂C₁To C₆Alkyl, which can be synthesized by the following steps: glycolonitrile is slowly added to cyanoacetic acid C, optionally at reduced temperature, in a non-polar solvent such as dimethylformamide₁To C₆Alkyl esters, followed by the addition of a base (such as potassium carbonate).

Furthermore, it is within the scope of the present invention to vary the Japp-Klingemann reaction using standard conditions well known to those skilled in the art for the preparation of compounds of formula (I) and their precursors. For example, the aryldiazonium is reacted with a precursor of formula (XXVI):

carrying out a coupling reaction, which can be used to obtain R⁹A compound which is OH. These compounds can then be subjected to standard alkylation reactions, acylation reactions, carbamylation reactions, sulfonation reactions and other processes to produce, for example, the corresponding alkoxy derivatives.

Alternatively, the arylpyrazoles may be prepared by reacting an optionally substituted phenylhydrazine derivative with a compound of formula (XXVII) or (XXVIII):

wherein R is¹⁷Is lower alkyl or cycloalkyl.

In another aspect, the invention provides a process for preparing a compound of formula (I) from one compound of formula (I) by interconversion of functional groups. Compounds of formula (I) wherein R is²Is a methyl ester, and is saponified to an acid. Particularly useful processes include the addition of tetrahydrofuran, water and lithium hydroxide inStirring at room temperature for 1 to 60 hours, or adding pyridine and lithium iodide, and heating at high temperature for a long time. The acid may be reacted with a secondary, tertiary or cyclic amine compound or aqueous ammonia or ammonium hydroxide in the presence of a suitable base such as triethylamine and an activating agent such as ethyl chloroformate in a suitable solvent such as tetrahydrofuran to give an amide derivative. For example, a solution of ethyl chloroformate, cyclopropylmethylamine in tetrahydrofuran may be added to a compound of formula (I) where R is cooled to 0 deg.C ²Is CO₂H in solution in tetrahydrofuran and triethylamine and allowed to warm to room temperature to give a compound of formula (I) wherein R is²Is cyclopropanecarboxamide.

A compound of formula (I) wherein R²The carboxylic acid can be reduced by standard literature procedures, such as sodium borohydride, to give the corresponding alcohol.

Furthermore, compounds of formula (I), wherein R²For carboxylic acids, the rearrangement may be carried out under standard Curtius conditions to give carbamates which, when deprotected, give compounds of formula (I) wherein R is²Is NH₂。

Compounds of formula (I) wherein R is²Is an alkyl ester, converted to an amide, wherein R²Is CONH₂. For example, a solution of trimethylaluminum in hexane is added to a solution of ammonium chloride in a suitable solvent (typically toluene) at 0 ℃, optionally under nitrogen. After stirring at room temperature for 1 to 2 hours, a compound of formula (I) is added, wherein R²Is a solution of COO alkyl in a suitable solvent. It can be stirred at elevated temperature (typically 50 ℃) for 15 to 80 hours to effect conversion to the amide. Similarly, hydroxyamides (R) which can be prepared by reaction with substituted alcohols and by reaction with hydroxyamines²For CONHOH) reaction. Similarly, acylhydrazones and bis-acylhydrazones can be prepared using literature conditions. These bisacylhydrazones can be converted to 1, 2, 4-oxadiazoles by reaction with phosphorus oxychloride in a suitable solvent. Such acylhydrazones can be prepared by reaction with triethyl orthoformate in the presence of an acid catalyst, typically p-toluenesulfonic acid And then the mixture is refluxed and converted into 1, 2, 4-oxadiazole. These 1, 2, 4-oxadiazoles can be re-hydrolyzed to acylhydrazones in the presence of an acid such as hydrochloric acid by refluxing in a suitable solvent such as methanol: dioxane mixture.

A compound of formula (I) (wherein R²Is an amide) may be reacted with a compound of formula R¹-subjecting the compound of formula (ii) -Y (wherein Y is a suitable leaving group) to a standard alkylation reaction to give a substituted amide. A compound of formula (I) (wherein R²Is an amide) can be interconverted in a suitable solvent (usually tetrahydrofuran) by refluxing with Lawesson's reagent for several hours to produce a thioamide, or dehydrated in pyridine by reaction with trifluoroacetic anhydride and 1, 4-dioxane for a tertiary hour at 0 ℃ to give a nitrile, where R is²Is CN.

In more detail, of the formula (XXIX), wherein R¹To R⁸And X is as defined for formula (I) and can be cyclized to form (XXX) by the following steps: the acid catalyzed addition of the aldehyde is carried out to give the imine intermediate, followed by reduction in situ using a suitable reducing agent such as sodium borohydride.

A compound of formula (I) wherein R²The aminomethyl can be prepared by the following steps: a compound of formula (I), wherein R²For sulfamide, treatment with an alkylating agent such as triethyloxonium tetrafluoroborate is carried out at 0 ℃ in a suitable solvent, usually dichloromethane, to form a thioalkylated intermediate, which is then stirred for a prolonged period of time at room temperature and subjected to a reduction reaction with sodium borohydride at 0 ℃.

A compound of formula (I) wherein R²Is a sulfamide, can be reacted with a haloketone or haloaldehyde to give (I) wherein R²Is substituted thiazole. Analogously, with acylhydrazines to give compounds of the formula (I), in which R is²Is a substituted triazole。

A compound of formula (I) wherein R²For aminomethyl, further treatment with an anhydride in a suitable solvent (usually dichloromethane) and a mild base (such as triethylamine) can be carried out with stirring at room temperature for a prolonged period of time (usually 60 hours) to give the corresponding amide.

And compounds of the formula (I) in which R²For aminomethyl, the alkyl or aryl sulfonyl halides can be monosulfonated or disulfated under standard conditions well known to those skilled in the art.

A compound of formula (I) wherein R²For halogens, a standard nucleophilic substitution reaction can be performed to produce the corresponding ether or thioether, respectively, by: reflux is carried out over a prolonged period of time (typically 18 hours to days) using a suitable acid catalyst such as p-toluene sulfonic acid and alkyl mercaptans or alcohols. A compound of formula (I) wherein R²For S-alkyl, standard oxidants such as m-chloroperoxybenzoic acid or the oxidants described in the Handbook of Reagents for Organic Synthesis-oxidizing and reducing Agents (edited by S.D. Burke and R.L. Danheiser) can be used for oxidation to the corresponding sulfoxide or sulfone.

A compound of formula (I) wherein R²For formyl, standard literature procedures can be performed to perform the aldehyde conversion. For example with (trifluoromethyl) trimethylsilane in the presence of tetrabutylammonium fluoride in a suitable solvent such as tetrahydrofuran to give an intermediate of formula (XXXI). These intermediates can be demethanized in tetrahydrofuran using tetrabutylammonium fluoride to give primary alcohols of formula (XXXII).

A compound of formula (I) wherein R²Containing a secondary alcohol, can be oxidized at room temperature in a suitable solvent (usually dichloromethane) by stirring, for example, for 30 minutes using Dess Martin Periodinane to give the corresponding compoundA ketone. A compound of formula (I) wherein R²Containing a primary amine, can be oxidized to the corresponding aldehyde, e.g. R, by stirring, e.g. for 30 minutes, at room temperature in a suitable solvent, typically dichloromethane, using Dess Martin Periodinane²The hydroxymethyl group can be easily converted to R²Is a formyl group. A compound of formula (I) wherein R²By an acid of the formula (I), wherein R is²-COOH, by reduction. The acid may be activated by reaction with ethyl chloroformate in the presence of a base such as triethylamine in a suitable solvent such as tetrahydrofuran; the subsequent reduction reaction can be achieved using, for example, sodium borohydride.

A compound of formula (I) wherein R⁹Is NH₂Can be used for synthesizing imine by the following method: reacting the amino function of formula (I) with an aldehyde and a suitable acid catalyst (typically p-toluenesulfonic acid) at room temperature for a long time (typically 16 hours); or reacting the amino functionality of formula (I) with an aldehyde in the presence of a mild reducing agent, such as sodium triacetoxyborohydride, and a mild base to form a secondary amine. For example compounds of formula (I) wherein R⁹Is NH₂With isonicotinaldehyde and a mild base to give the corresponding imine function, which can be further reduced by reaction with a suitable reducing agent, such as sodium borohydride, to give a secondary amine. The secondary amine can be further oxidized using standard procedures to give the N-oxide. Similarly, compounds of formula (I) wherein R⁹Is NH₂Optionally substituted ketones.

Compounds of formula (I) wherein R is R may also be achieved by reaction with a suitable organic halide using a strong base such as sodium hydride in a suitable non-polar solvent such as N-methylpyrrolidone⁹Is NH₂N-alkylation, N-aryl alkylation and N-heteroaryl alkylation. The reaction is stirred at room temperature for 10 to 25 hours, usually overnight. One skilled in the art will recognize that mono-N substituted and di-N substituted products may be obtained using the appropriate sequence of synthetic procedures. The high reactivity of the alkyl halide requires lower reaction conditions. For example compounds of formula (I) wherein R ²Is NH₂Tert-butyl bromoacetate is reacted at elevated temperature (typically 55 ℃) in the presence of a weak base (typically potassium carbonate) in a suitable solvent such as acetonitrile.

A compound of formula (I) wherein R⁹Is NH₂The carbamylation can be carried out by the following steps: it is stirred with phosgene at 0 ℃ in the presence of a base such as pyridine in a suitable solvent, usually dichloromethane, and then reacted with a primary, secondary or tertiary alcohol at room temperature for 10 to 30 hours, usually overnight. A compound of formula (I) wherein R⁹Is NH₂Carbamylation may also be performed by reaction with chloroformates using standard literature conditions.

A compound of formula (I) wherein R⁹＝NH₂The reductive amination reaction of (a) can also be achieved using a protected aldehyde such as (XXXIII).

The tertiary-BOC protecting group may be removed by standard procedures, such as stirring with trifluoroacetic acid in a suitable solvent, such as dichloromethane, at room temperature for several hours (typically 2 hours) to give the compound of formula (XXXIV)

The primary amines in the compounds of formula (XXXIV) may be alkylated, acylated and sulpholated using conventional literature procedures. The typical sulfonation process is: with a sulfonyl chloride in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane.

A compound of formula (I) wherein R⁹＝NH₂The reductive amination reaction of (a) can also be accomplished with a protected aldehyde such as (XXXV). The tertiary BOC protecting group may be in the dichloromethylThe alkane is removed with trifluoroacetic acid.

A compound of formula (I) wherein R⁹Is NH₂It is possible to react with triethyl orthoformate by heating at elevated temperature (generally 60 ℃) for several hours (generally 2 to 4 hours) under acidic conditions, to obtain (I) in which R is⁹is-N ═ CHOC₂H₅. In which R is⁹is-N ═ CHOC₂H₅This may be followed by further reduction with a suitable reducing agent such as sodium borohydride to give a compound of formula (I) wherein R is⁹is-NHCH₃. Analogous methods may be used to react compounds of formula (I) wherein R⁹Is NH₂And (4) functionalizing.

A compound of formula (I) wherein R⁹Is H, can be prepared by various standard diazotization procedures via compounds of formula (I) wherein R is⁹Is NH₂Diazotization.

In a similar manner, compounds of formula (I) wherein R⁹is-S-alkyl, obtainable by reacting a compound of formula (I) wherein R is⁹Is NH₂With a suitable nucleophile such as (alkyl S)₂) Coupling to form. Furthermore, compounds of formula (I), wherein R⁹For S-alkyl, oxidation can be carried out using standard oxidizing agents, such as hydrogen peroxide, to give the corresponding sulfoxides and sulfones.

A compound of formula (I) wherein R⁹Is NH₂Compounds of formula (I) wherein R is as defined above, can be obtained by conversion using standard Sandmeyer reaction conditions⁹Is halogen. These halogen compounds can be used in standard organometallic coupling procedures, for example in compounds of formula (I) wherein R is⁹＝-CF₃In the preparation process of (1).

A compound of formula (I) wherein R⁹Is CH₂Y or N-alkanesThe group-Y (where Y is a suitable leaving group, such as halogen) may undergo a variety of nucleophilic substitution reactions well known to those skilled in the art in the presence of a suitable base. Examples of such nucleophiles are cyanide ions, alcohols, phenols, thiols, primary amines, secondary amine amines and heterocycles such as 1, 2, 4-triazole. Typically the leaving group is a methane sulfonic acid group; this compound is prepared from a compound in which Y ═ OH by reaction with methanesulfonyl chloride in the presence of triethylamine in acetonitrile.

Furthermore, compounds of formula (I), wherein R⁹is-NH₂Or aminoalkyl groups, may be monosulfonated or disulfated using alkyl or arylsulfonyl halides under standard conditions well known to those skilled in the art to provide the corresponding sulfonamide.

Furthermore, compounds of formula (I), wherein R⁹is-NH₂Or aminoalkyl groups, may be acylated under standard conditions well known to those skilled in the art. The amide formed can be reduced to an amine by the following steps: by reaction with phosphorus pentachloride under reflux in toluene, cooling to room temperature, and pouring into a solution of sodium borohydride in a polar hydroxylic solvent such as methanol.

As shown in scheme 3 below, compounds of formula (I) wherein R⁹is-NH₂And also into compounds of the formula (I) in which R⁹is-CH₃or-CHF₂. First, compound (XXXVI) can be converted to (XXXVII) by arylation of methyl acrylate with the corresponding diazonium salt. The compound of formula (XXXVII) can be dehydrobrominated by stirring with a base such as DBU for several hours using standard conditions to give the enone (XXXVIII). The conversion of (XXXVIII) to (XXXIX) aldehyde can be achieved by the following steps: using O_SO₄The diol is formed, followed by oxidative cleavage using an oxidizing agent (such as sodium periodate) to give the aldehyde. The aldehyde of formula (XXXIX) may be reduced to formula (XL) by stirring with a reducing agent, typically sodium borohydride, or further reacted with a halogenating agent, such as diethylaminosulfur trifluoride, to give a compound of formula (I) wherein R is⁹Is difluoromethyl. (XL) was reacted with thionyl chloride and heated under reflux for several hours toThis intermediate is obtained and then, by reduction, for example using Rieke zinc, the chloro derivative of the compound of formula (XLI) is obtained.

Schematic diagram 3

Compounds of formula (XXXIX) and (XL) are useful in the preparation of compounds of formula (I) wherein R is⁹Including a variety of carbon-bonded substituents. Furthermore, in (XL), activation of the hydroxyl group, such as by mesylation or tosylation, provides intermediates that are capable of undergoing a variety of nucleophilic substitution reactions. The compounds of formula (XL) may also be acylated and alkylated using standard literature procedures. For example, with an alkyl halide such as methyl iodide in a suitable solvent, usually acetonitrile, in the presence of a base such as potassium carbonate, at room temperature for several days, usually 5 days. Aldehydes (XXXIX) can be readily converted to acids, nitriles, esters, amides and thioamides under standard conditions well known to those skilled in the art. Following the standard Wittig reaction of aldehyde (XXXIX), a conventional cyclopropanation procedure may be carried out to give a compound wherein R is ⁹Is a compound with a substituted cyclopropyl group. For example, the methylenation reaction can be achieved using a Wittig reaction, using Peterson's reagent, using Tebbe's reagent, or using the Lombardt process. Typically the Wittig reaction involves: adding a solution of n-butyllithium in hexane to a solution of methyltriphenylphosphonium bromide in tetrahydrofuran at 0 ℃ followed by a solution of an aldehyde of formula (XXIX) in tetrahydrofuran to give R⁹Compounds which are vinyl. The organometallic addition of an aldehyde (XXXIX) followed by oxidation of the primary alcohol, followed by Wittig olefination and cyclopropanation to produce a compound of formula (XLII), e.g. R¹²＝-CF₃。

Alternatively, the aldehyde (XXXIX) is organometallic added followed by standard procedures, such as with SOCl in the presence of a zinc catalyst₂Carrying out a reaction, eliminating the hydroxyl group, to obtain a compound of formula (I), wherein R⁹Is optionally substituted alkyl, optionally substituted aryl or aralkyl and optionally substituted heteroaryl or heteroaralkyl. The compounds of formula (XXXIX) may also be subjected to standard Knoevenagel type reactions followed by reduction and partial hydrolysis reactions and heating at elevated temperatures to give the corresponding ester derivatives which may be further derivatised. Alternatively, the methylenation reaction of the compound of formula (XXXIX) can be readily carried out using standard known reactions, such as the Wittig or Horner-Wadsworth-Emmons reaction. The compound of formula (I) formed, wherein R ⁹For the vinyl group, hydroxylation may be carried out using standard conditions, such as by reaction with hydrogen peroxide and a suitable base, to give a compound in which R is⁹is-CH₂CH₂A compound of OH. These compounds can then be further oxidized to give the corresponding aldehydes and acids, i.e., wherein R⁹is-CH₂CHO or-CH₂A compound of COOH. These aldehydes may be subjected to reactions well known to those skilled in the art, such as Wittig olefination and reductive amination. The acids can undergo a Crutius rearrangement to give compounds in which R is alkylated, acylated, sulfonated⁹is-CH₂NH₂A compound of formula (I), and other nucleophiles. And wherein R is⁹is-CH₂CH₂Compounds of OH, by addition of, for example, SOCl₂Or T_SCl, and with a variety of nucleophiles (such as^-CN、^-SR or^-OR) further reacted to give the corresponding alkylated derivative.

Alternatively, standard known catalytic cross-coupling reactions, such as Heck reaction, may be used to produce compounds of formula (I) wherein R is⁹Is a substituted vinyl derived from a vinyl derivative.

Oxidation of a compound of formula (XXXIX) using standard reaction conditions, followed by further derivatization of the acid formed, affords compounds of formula (I)) A compound of formula (I) wherein R⁹Is a heterocyclic fragment. For example, the oxidation product can be reacted with a substituted acyl hydrazide to give an oxadiazole. Those skilled in the art recognize that a variety of optionally substituted heterocycles can be synthesized from aldehydes (XXXIX) and the corresponding acids. These acids can also be derivatized using standard literature procedures.

Wherein R is⁸＝-C(O)SCH₃The compound of formula (I) can be represented by the formula (I) wherein R⁸is-CN by heating at elevated temperature (typically 80 ℃) for several hours (typically 16 hours) under high pressure to effect an acid-catalyzed addition reaction of methyl mercaptan. As described in organic chemistry textbooks and previous literature, wherein R⁸The nitrile reaction may be carried out with a compound of formula (I) which is-CN.

It will also be appreciated by those skilled in the art that in certain of the methods described, the order of the synthetic steps employed may vary and will depend inter alia on factors such as the nature of the other functional groups present in the particular substrate, the availability of primary intermediates and the protecting group approach (if any) to be employed. It will be apparent that these factors may also influence the choice of reagents used in the synthesis steps.

The skilled person will appreciate that the compounds of the invention may be prepared by the following method: methods other than, adaptations of, and/or adaptations of the methods described herein and/or adaptations of methods known in the art (e.g., the fields described herein), or using standard textbooks, such as "comprehensive organic Transformations-A Guide to Functional Group Transformations", RCLarock, Wiley-VCH (1999 or later).

It is also to be understood that the synthetic transformations referred to herein are merely illustrative examples and may be performed in a variety of different sequences to efficiently produce the desired compounds. The chemist of skill in the art can apply his judgment and techniques to optimize the reaction sequence for the synthesis of a particular target compound.

The invention also relates to intermediates of the following formula (L):

wherein:

R¹to R⁸、X、R^c、R^d、n、R¹¹And het are as defined above for formula (I); or a pharmaceutical salt or prodrug thereof. With respect to formula (L), suitably R^c＝R^dIs methyl.

The invention also relates to the following further intermediates of formula (LI):

wherein:

R¹to R⁸、X、n、R¹¹And het are both as defined above for formula (LI); wherein R is⁵⁰Independently selected from hydrogen, C_1-6Alkyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_2-6Alkenyl radical, C_1-6Alkanoyl radical, C (O) OC_1-6Alkyl, het, phenyl and S (O)_nR¹¹(ii) a Or a pharmaceutical salt or prodrug thereof. With respect to formula (LI), suitably R⁵⁰Is methyl.

It is to be understood that all statements made throughout this application with respect to formula (I) apply equally to the compounds of formulae (L) and (LI). Furthermore, it will be appreciated that the above R applies to formula (I)¹To R⁸、X、R^c、R^d、n、R¹¹And het are likewise suitable for the compounds of the formulae (L) and (LI).

The invention also relates to pharmaceutical compositions 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, suitable for oral, parenteral or topical administration.

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

The compounds may be administered alone or in formulations suitable for the particular use envisaged, the particular species of host animal to be treated and the parasite involved or agricultural pests to be treated if appropriate, and the crop plants to be treated. Generally, it is administered in a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound of the present invention. The choice of such excipients depends mainly on the following factors: such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

The compounds of the invention for pharmaceutical use can be administered as crystalline or amorphous products, for example spray-dried dispersions, or as products prepared by melt extrusion or nanomilling processes. The product may be obtained, for example, in the form of a solid plug, a powder or a film (e.g. a rapidly dissolving or mucoadhesive film) by methods such as precipitation, crystallization, lyophilization or spray drying or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

Methods of administering the compounds include oral administration via capsules, pellets, lozenges, powders, troches, chewable tablets, multi-and nanoparticles, gels, solid solutions, films, sprays, or liquid formulations. Liquid forms include suspensions, solutions, syrups, drinks and elixirs. Such formulations may serve as fillers in soft or hard capsules and typically comprise a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a soluble oil, and one or more emulsifying and/or suspending agents. Liquid formulations can also be prepared by solid reconstitution, e.g. sachets. Oral beverages are generally prepared by dissolving or suspending the active ingredient in a suitable medium.

Thus, compositions suitable for oral administration may be prepared by mixing the active ingredient with suitable finely divided diluents and/or disintegrants and/or binders, and/or lubricants and the like. Other useful ingredients include antioxidants, colorants, fragrances, preservatives, and taste-masking agents.

For oral dosage forms, depending on the dosage, the drug may constitute from 1% to 80% by weight of the dosage form, more usually from 5% to 60% by weight of the dosage form. Examples of disintegrants suitable for use herein include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, cross-linked povidone, methylcellulose, hydroxypropyl cellulose substituted with lower alkyl groups, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant may comprise from 1 to 25 weight percent, preferably from 5 to 20 weight percent of the dosage form.

Bonding agents are commonly used to impart cohesive properties to the lozenge formulation. Examples of binders suitable for use herein include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Examples of diluents include lactose (monohydrate, spray-dried monohydrate, anhydrate, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate dihydrate.

Oral formulations may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and flow agents such as silica and talc. When present, the surfactant can comprise 0.2% to 5% by weight of the lozenge and the flow agent can comprise 0.2% to 1% by weight of the lozenge.

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

Exemplary lozenges comprise 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.

Formulations of lozenges were measured in "Pharmaceutical DosageForms" by h.lieberman and l.lachman: tablets, Vol.1 ", Marcel Dekker, N.Y.N.Y.1980(ISBN 0-8247-6918-X).

The compounds may be administered topically, i.e., transdermally or transdermally, to the skin. The compounds may also be administered mucosally. Common formulations for this purpose include pour-on, drop-on, dip, spray, mousse, shampoo, powder formulations, gels, hydrogels, lotions, solutions, emulsions, ointments, powders, dressings, foams, films, skin patches, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin esters, white paraffin esters, glycerol, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated, see, for example, J Pharm Sci, 88(10), 955-958 (10 months 1999) of Finnin and Morgan. Pour-on or drop-on formulations can be prepared by the following method: the active ingredient is dissolved in an acceptable liquid carrier, such as butylene glycol, liquid paraffin, or a non-volatile ester, optionally with the addition of a volatile component, such as propan-2-ol. Alternatively, pour-on, drop-on or spray formulations can be prepared by encapsulation to leave active agent residues on the animal surface.

Injectable formulations may be prepared in the form of sterile solutions which may contain other substances, for example, enough salts or glucose to render the solution isotonic with blood. Acceptable liquid carriers include glycerol esters (such as glycerol triacetate) of vegetable oils (such as sesame oil), such as benzyl benzoate, isopropyl myristate and fatty acid derivatives of 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 carrier such that the final formulation contains from 0.01 to 10% by weight of the active ingredient. These formulations may be self-preserving, self-sterilizing or may be non-sterile, so preservatives may optionally be added.

Also suitably, the compound may be administered parenterally, or injected directly into the bloodstream, muscle or internal organs. Suitable modes of parenteral administration include intravenous, arterial, intraperitoneal, intravertebral, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous injection. Suitable devices for parenteral administration include needle (which includes microneedle) syringes, needleless injectors, and injection 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 suitably formulated as sterile nonaqueous solutions or as powders in anhydrous form in combination with a suitable vehicle such as sterile pyrogen-free water. Parenteral formulations can be readily prepared under sterile conditions (e.g., by freeze-drying) using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of formula (I) used to prepare the parenteral formulation can be increased by using suitable formulation techniques, such as the incorporation of solubility enhancers.

Such formulations are prepared in the usual manner in accordance with standard medical or veterinary practice.

These formulations may vary depending on the following factors, with respect to the weight of active compound contained therein: 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, the active ingredient is generally administered in an amount of 0.01 to 100 milligrams per kg of animal body weight. A preferred range is 0.1 to 10 milligrams per kg.

The formulations may be directly released or designed to have controlled or modified release properties. Modified release formulations include those with delayed-, sustained-, pulsed-, 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. Details of other suitable 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) of Verma et al. Methods of using chewing gum to control the rate of drug release are described in WO 00/35298. Alternatively, the compounds of the present invention may be formulated as a solid, semi-solid, or thixotropic liquid that is administered in the form of an implant to provide modified release of the active compound. Examples of formulations include drug-coated stents and PGLA microspheres.

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

All aqueous dispersions, emulsions or spray mixtures of the invention can be applied to, for example, crops by any suitable method, primarily by spraying, typically at a rate of from about 100 to about 1,200 liters of spray mixture per hectare, but can be increased or decreased (e.g., low or ultra-low volume) depending on the need or application technique. The compounds or compositions of the present invention are preferably applied to plants, more specifically to the roots or leaves of the pests to be removed. Another application method of the compounds or compositions according to the invention is via chemigation, that is to say that formulations containing the active ingredient are added to the irrigation water. The irrigation method may be a spray irrigation method suitable for foliar insecticides or may be a soil irrigation method or a subsoil irrigation method suitable for soil or systemic insecticides.

Stable fluid products that do not settle (micro-grinding) can be produced by spray application of concentrated suspensions, typically containing from about 10 to about 75% by weight of active ingredient, which has low or no solubility, from about 0.5 to about 30% of surfactant, from about 0.1 to about 10% of thixotropic agent, from about 0 to about 30% of suitable additives, such as defoamers, corrosion inhibitors, stabilizers, penetrants, stickers, and water or organic liquids as carriers. Some organic solids or inorganic salts may be dissolved in the vehicle to help avoid settling, or as an 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 the solid carrier, from about 0 to about 5% of the wetting agent, from about 3 to about 10% of the dispersing agent, and, if necessary, from about 0 to about 80% of one or more stabilizers and/or other additives such as penetrants, adhesives, anti-caking agents, colorants, and the like. To obtain these wettable powders, the active ingredient is thoroughly mixed with the other substances which can be impregnated on the porous filler in a suitable blender and ground using a mill or other suitable grinder. This produces a wettable powder which is advantageous in wettability and suspendability. It can be suspended in water to give any desired concentration and the suspension can be applied particularly advantageously to plant leaves.

"Water dispersible granules (WG)" (granules that readily disperse in water) have a composition substantially close to that of a wettable powder. They can be prepared by granulating the above wettable powder formulations by the wet process (contacting finely divided active ingredients with inert fillers and small amounts of water (e.g. 1 to 20% by weight), or with aqueous solutions of dispersants or binders, followed by drying and sieving) or by the dry process (compaction, followed by grinding and sieving).

The rate and concentration at which the composition is formulated may vary depending on the method of administration 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 preferably from about 0.0005 to about 50%, by weight of one or more compounds of formula (I) or pesticidally acceptable salts thereof, or of all active ingredients (i.e., a compound of formula (I) or pesticidally acceptable salt thereof, in admixture with other substances toxic to arthropods or plant nematodes, insect repellents, anti-mesochitic 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 may be combined with soluble macromolecular entities such as cyclodextrins or suitable derivatives thereof or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability suitable for any of the above modes of administration.

For example, drug-cyclodextrin complexes have been found to be generally suitable for most dosage forms and routes of administration. Occluded and non-occluded complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may act as an auxiliary additive, i.e. as a carrier, diluent or solubiliser. Cyclodextrins most commonly used for these purposes are alpha-, beta-and gamma-cyclodextrins, examples of which may be found in International patent applications WO91/11172, WO94/02518 and WO 98/55148.

The compounds of the present invention may be administered alone, or in combination with one or more other compounds of the present invention, or in combination with one or more other drugs (or in any combination thereof). For example, the compounds of the present invention may also be mixed with one or more biologically active compounds or agents, including pesticides, chiggers, insect repellents, fungicides, nematicides, protozoa, bactericides, growth regulators, vaccines (including live, inactivated or inactivated vaccines), entomopathogens, viruses or fungi, to form multi-component epidemic prevention agents having a broader range of pharmaceutical, veterinary or agricultural uses. Thus, the present invention relates to compositions comprising a biologically effective amount of a compound of the present invention and an effective amount of at least one other biologically active compound or agent, and which may further comprise one or more surfactants, solid diluents or liquid diluents. Specific other active compounds include those described in international patent application WO2005/090313, pages 39 to 44.

Since it is desirable to administer a combination of active compounds, for example, in the treatment of a particular disease or condition, two or more pharmaceutical compositions, at least one of which contains a compound of the invention and which are conveniently combined in a kit suitable for co-administration of the compositions, fall within the scope of the present invention.

Thus, the present invention also relates to a kit comprising, two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the invention, and a device for separately retaining the compositions, such as a container, a dispensing bottle or a dispensing foil packet. Examples of such kits are the well-known blister packages used for packaging tablets, capsules and the like.

The kit of the invention is particularly suitable for administration in different dosage forms, for example oral and parenteral administration, for administration of separate compositions at different dosage intervals, or for titration of separate compositions with one another. To assist compliance, the kit typically contains instructions for administration and may have a so-called memory aid.

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

The invention also relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any entity, or a pharmaceutical composition comprising any of the foregoing, as a medicament.

Another aspect of the invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, for the manufacture of a medicament for the treatment of parasitic infestations.

As used herein, the term "long duration of action" means a compound having a duration of action of 14 days or more, preferably 21 days or more, most preferably 28 days or more.

In one embodiment, the invention is suitable for use in the preparation of a medicament for the treatment of a parasitic infestation in a human.

In one embodiment, the invention is useful for the preparation of a medicament for the treatment of parasitic infestations of an animal.

Another aspect of the invention is directed to a method of treating parasitic infestations comprising treating an animal with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

Another aspect of the invention relates to a method of preventing parasitic infestation, the method comprising treating an animal with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any entity, or a pharmaceutical composition comprising any of the foregoing.

In another embodiment, the invention is also directed to a method of controlling disease transmission between animals, the method comprising treating the animals with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any entity, or a pharmaceutical composition comprising any of the foregoing.

In one embodiment, the invention is suitable for use in the preparation of a medicament for the treatment of a parasitic infestation of a plant.

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

In another aspect, the invention provides a method for controlling or eradicating a parasitic infestation in an environment, such as the locus where an animal (particularly a companion animal) lives or adapts, said method comprising treating the animal with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any entity, or a pharmaceutical composition comprising any of the foregoing.

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

The compounds of the present invention are useful for controlling arthropod pests. They are effective in treating resistant varieties which are uncontrollable by known parasiticides or compositions thereof. In particular, they are useful in veterinary medicine, livestock feeding and maintenance of public health: against arthropods which infest humans and animals (including mammals, poultry and fish) internally or externally. Examples of mammals include domestic animals such as dogs, cats, cows, sheep, goats, horses, and pigs. Examples of arthropods include mites, including the order muralis, such as diaphorina (Ixodes spp.), bovines (grapholitus spp.), such as ticks microductus (Boophilus microplus), pediculosis tropicalis (Amblyomma spp.), pediculosis longissima (Hyalomma spp.), pediculosis appendiculatus (Rhipicephalus spp.), pediculosis latus (Rhipicephalus appendagicola), pediculosis sanguinalis (Haemaphysalis p.), Dermacentor spp., Aceris (Ornithodoros spp.), leptospora (Ornithodoros spp.), such as Dermacentor spp.); from the order of the acaridae, for example the genera pediculosis (Damalinia spp.), Dermanyssus gallinae (Dermanyssus gallinae), Sarcoptes (Sarcoptes spp.) (for example, Sarcoptes scabies (Sarcoptes cabeii)) Sarcoptes (Psoroptes spp.), Sarcoptes (Sarcoptes spp.), folliculus (demodex spp.), tsutsutuki (Eutrombicula spp.); from the order of the diptera, for example the genus Sphaeria (Aedes spp.), Anopheles spp, Muscadae spp, for example the flies crayfish (Stomoxys calcutirans) and the blood flies (Haematobia irliteans), the genus Bothidae (Hypoderma spp.), the genus Marseus (Gastrophilus spp.), the black flies (Simulium spp.); hemiptera (e.g., trypanosoma spp.); pediculosis (e.g., hair lice, dog lice (linogathus spp.))); siphonaptera (e.g., siphonochaliensis (ctenochloreplidespp.))); the compounds of the invention are also useful for controlling plant pests, soil dwelling pests and other environmental pests, specific additional arthropod pests include those specifically described in international patent application WO2005/090313, pages 57 to 63.

The invention is particularly useful for controlling arthropod pests of humans and animals, particularly mammals. Preferably, the present invention is suitable for controlling arthropod pests of animals, including livestock animals such as cattle, sheep, goats, horses, pigs and companion animals such as dogs and cats.

The compounds of the invention are particularly important for controlling arthropods which are harmful or diffusible to humans and domestic animals such as the animals described hereinbefore or which act as carriers of diseases, more particularly for controlling ticks, mites, lice, fleas, midges and biting, nuisance and myiasigenic flies. The compounds of the present invention are particularly useful for controlling arthropods present in livestock host animals, or parasitic in or on the skin, or sucking the blood of animals, for which purpose they may be administered orally, parenterally, transdermally or topically.

The compound animals of the present invention are effective in treating and controlling various stages of the parasite's life cycle, including the egg, pupa, larva, nymph and adult stages.

In a further aspect of the present invention there is provided a method of controlling arthropod pests of insects which comprises treating the insects with an effective amount of a compound of formula (I) or an insecticidally acceptable salt thereof. The compounds of the invention are also useful in the treatment of infections caused by mites, particularly the varroa mite. More specifically, the compounds of the present invention are also useful for treating varroa mite infestations of honey bees.

In a further aspect of the invention there is provided a method of controlling arthropod pests of plants which comprises treating the plants with an effective amount of a compound of formula (I) or a pesticidally acceptable salt thereof. The compounds of the present invention can also be used for controlling arthropod pests of plants. The active compounds are usually applied to the locus to be controlled for arthropod infestation at a rate of from about 0.005kg to about 25kg, preferably from 0.02 to 2kg/ha, of active compound per hectare (ha) of the locus to be treated. Lower application rates provide suitable protection under ideal conditions, depending on the pest to be controlled. On the other hand, unfavorable climatic conditions and other factors require the use of the active ingredients in relatively high proportions. In the case of application to the leaves. Application rates of from 0.01 to 1kg/ha can be used. Preferably, the locus is the surface of the plant or the soil surrounding the plant to be treated.

In a further aspect of the invention there is provided a method of protecting wood which comprises treating the wood with an effective amount of a compound of formula (I) or a pesticidally acceptable salt thereof. The compounds of the present invention are also important for protecting wood (upright, felled, transported, stored or constructed) infested by sawflies or beetles or termites. It can be used to protect stored products such as shells, fruits, nuts, spices and tobacco (whether whole grain, ground or mixed product form) from moth, beetle and mite attack. Stored animal products, such as hides, hair, wool, and feathers, in natural or transformed form (e.g., felts or fabrics), can also be protected from moth and beetle attack; and to protect stored meat and fish from attack by beetles, mites and flies. Solid or liquid compositions for topical application to wood, stored products or household items typically contain from about 0.00005 to about 90% by weight, more preferably from about 0.001 to about 10% by weight, of one or more compounds of formula (I) or pesticidally acceptable salts thereof.

In addition to common 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 foundations, outdoor or indoor storage or processing areas, containers or equipment, or standing or flowing water.

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 object of this cleaning method is to reduce or eliminate the infestation of humans by parasites carried by the above-mentioned animals and to improve the human living environment.

A flea membrane feeding assay was used to determine the biological activity of the claimed compounds. This test consists in carrying out a cat lice (Ctenocephalides felis) in vitro test according to the following general procedure.

Dog blood was used to grow fleas in vitro. Between 25 and 30 adult cat lice were collected and placed in a test chamber (50 ml polystyrene test tube with ends sealed with a fine nylon mesh). Citrated dog blood was prepared by the following method: aqueous sodium citrate (10 ml, 20% w/v, 20 g sodium citrate in 100 ml water) was added to dog blood (250 ml). The test compound was dissolved in dimethyl sulfoxide to give a working stock solution (4 mg/ml). This stock solution (12.5 microliters) was added to citrated dog blood (5 milliliters) to give an initial test concentration of 10 micrograms/milliliter. For the test at 30. mu.g/ml, a working stock of 120 mg/ml was prepared.

Citrated dog blood (5 ml, 100. mu.g/ml) with test compound was placed in plastic petri dishes and maintained at 37 ℃ on a hot pad. A sealing film is applied over the open top to form a tight film through which the fleas can be fed. The chamber containing the fleas was carefully placed on the sealing film and fed with fleas.

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

Fleas were observed and the percent flea death recorded. Compounds were tested at 100 μ g/ml followed by the relevant dose response (100, 30, 10, 3, 1, 0.3, 0.1 μ g/ml) and n ═ 5 repeated. Data were plotted to generate ED80, ED90, and ED95 curves.

The activity of the compounds of the invention is significantly superior to that of the previous compounds. All examples of the invention have flea ED80 values of less than 100 micrograms/ml. The results for some compounds are as follows.

Examples of the invention	Flea-fed ED80 results microgram/ml
Examples of the invention	Flea-fed ED80 results microgram/ml	1	≤1
2	≤1	1	≤1
2	≤1	11	≤1
16	≤1	11	≤1
16	≤1	18	≤1
19	≤1	18	≤1
19	≤1	20	≤1
27	≤1	20	≤1
27	≤1	32	≤1
37	≤1	32	≤1
37	≤1	45	≤1
86	≤1	45	≤1
86	≤1	101	≤1

Examples of the invention

The following examples illustrate the preparation of compounds of formula (I).

In the experimental details described below, 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 T60 MHz spectrometer, with observed chemical shifts consistent with the proposed structure. Mass spectral data were obtained on a Finnigan Masslab Navigator, a Fisons Instrument Trio 1000 or Hewlett Packard GCMS System Model 5971 spectrometer. The enumerated calculation and observation 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-pentafluorothiophenyl ] -4- [1- (methylsulfonyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile

Hydrochloric acid (10%, 1 ml) was added to a solution of preparative 82(150 mg, 0.27 mmol) in dioxane (8 ml) and methanol (1 ml) and the reaction mixture was heated at 80 ℃ for 8 hours. The mixture was concentrated under a nitrogen stream and the residue was dissolved in acetonitrile/water (1: 1, 2.8 ml) and purified by automated preparative liquid chromatography using an acetonitrile/water gradient [ 50: 50 to 98: 2] (Gilson system, 150 mm. times.30 mm, Phenomenex LUNA C18(2)10 microliter column). The appropriate fractions were combined and concentrated to give the title compound (75 mg).

Experimental value MH⁺496.9, respectively; predicted value 497.0

¹H-NMR(CDCl₃): 1.36 to 1.43(2H), 1.85 to 1.91(2H), 2.90 to 2.95(3H), 4.38 to 4.48(2H), 7.89 to 7.92(2H)

Example 2

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Methanol (0.3 ml) and hydrochloric acid (1N, 0.3 ml) were added to a solution of example 61(53 mg, 0.12 mmol) in 1, 4-dioxane (1 ml). The reaction mixture was then heated at 100 ℃ for 2 hours. The reaction mixture was concentrated in vacuo, and ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue. The two layers were separated and the aqueous layer was extracted with ethyl acetate (× 2). The combined organic phases were dried (MgSO) ₄) And concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by automated preparative liquid chromatography using an acetonitrile: water gradient (Gilson system, 150 mm x 21.2 mm, Phenomenex LUNA C18(2)5 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (16 mg).

Experimental value MH⁺404.0; predicted value 404.0

¹H-NMR (acetone-d)₆): 1.01 to 1.07(2H), 1.46 to 1.52(2H), 5.77 to 5.87(2H), 6.01 to 6.15(1H), 6.34 to 6.46(1H), 8.02 to 8.06(2H)

Compounds prepared in a similar manner:

examples of the invention	R1	R3	R4	R5	R6	R2	Is obtained from
examples of the invention	R1	R3	R4	R5	R6	R2	Is obtained from	Example 3	CF3	H	H	H	H	-COOCH₃	Preparation method 64
Example 4	CF3	H	H	F	F	-SO2CH3	Preparation method 59	Example 3	CF3	H	H	H	H	-COOCH₃	Preparation method 64

Example 5	CF3	H	H	H	H	-N＝CH-N(CH₃)₂	Preparation method 51
Example 5	CF3	H	H	H	H	-N＝CH-N(CH₃)₂	Preparation method 51	Example 6	CF3	H	H	H	H	-SO2CH3	Preparation method 81
Example 7	CF3	H	H	F	F	-NH2	Preparation method 99	Example 6	CF3	H	H	H	H	-SO2CH3	Preparation method 81
Example 7	CF3	H	H	F	F	-NH2	Preparation method 99	Example 8	CF3	H	H	F	F	-SO2N(CH3)₂	Preparation method 57
Example 9	CF3	H	H	H	H	-CO-pyrrolidin-1-yl	Preparation method 52	Example 8	CF3	H	H	F	F	-SO2N(CH3)₂	Preparation method 57
Example 9	CF3	H	H	H	H	-CO-pyrrolidin-1-yl	Preparation method 52	Example 10	CF3	H	H	H	H	CN	Preparation method 2
Example 11	SF5	H	H	H	H	CN	Preparation method 1	Example 10	CF3	H	H	H	H	CN	Preparation method 2

Example 3

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Experimental value MH⁺419.0, respectively; predicted value 419.0

¹H-NMR(CDCl₃): 1.26 to 1.30(2H), 1.67 to 1.71(2H), 3.65 to 3.68(3H), 3.70 to 3.83(2H), 7.72 to 7.77(2H)

Example 4

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

Experimental value MH⁺475.0, respectively; predicted value 475.0

¹H-NMR(CDCl₃): 1.83 to 1.95(3H), 2.94 to 3.02(1H), 3.03 to 3.14(1H), 4.21 to 4.51(2H), 7.77 to 7.80(2H)

Example 5

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -N, N-dimethylcyclopropanecarboxamide

Experimental value MH⁺432.0 parts; predicted value 432.1

¹H-NMR(CDCl₃): 1.26 to 1.30(2H), 1.31 to 1.36(2H), 2.82 to 2.93(3H), 3.19 to 3.32(3H), 4.57 to 4.68(2H), 7.68 to 7.78(2H)

Example 6

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

Experimental value MH⁺438.8, respectively; predicted value 439.0

¹H-NMR(CDCl₃): 1.37 to 1.42(2H), 1.86 to 1.90(2H), 2.91 to 2.94(3H), 4.38 to 4.44(2H), 7.76 to 7.78(2H)

Example 7

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

¹H-NMR(CDCl₃): 1.87 to 1.90(1H), 1.92 to 1.95(2H), 1.97 to 1.99(1H), 5.98 to 6.05(2H), 7.81 to 7.84(2H)

Example 8

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

¹H-NMR(CDCl₃): 1.94 to 2.01(1H), 2.40 to 2.48(1H), 2.87 to 2.94(6H), 4.39 to 4.49(2H), 7.76 to 7.80(2H)

Example 9

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

Experimental value MH⁺458.0, respectively; predicted value 458.1

¹H-NMR(CDCl₃): 1.21 to 1.26(2H), 1.34 to 1.39(2H), 1.77 to 1.84(2H), 1.89 to 1.97(2H), 3.36 to 3.41(2H), 3.63 to 3.69(2H), 4.55 to 4.64(2H), 7.69 to 7.78(2H)

Example 10

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

Experimental value MH⁺386.1 of the total weight of the steel; predicted value is 386.0

¹H-NMR(CDCl₃): 1.44 to 1.50(2H), 1.71 to 1.76(2H), 3.93 to 4.04(2H), 7.74 to 7.77(2H)

Example 11

5-amino-4- (1-cyanocyclopropyl) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazole-3-carbonitrile

¹H-NMR(d₆-DMSO): 1.24 to 1.31(2H), 1.65 to 1.72(2H), 6.53 to 6.62(2H), 8.42 to 8.47(2H)

Example 12

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanesulfonamide

Hydrochloric acid (10%, 1 ml) was added to a solution of preparative 56(30 mg, 0.05 mmol) in 1, 4-dioxane (4 ml). The reaction mixture was heated at 85 ℃ for 6 hours, cooled to room temperature and concentrated under a stream of nitrogen. The residue was dissolved in acetonitrile/dimethylsulfoxide (650 μ l) and purified by automated preparative liquid chromatography (Gilson system, 150 mm x 21.2 mm, Phenomenex LUNA C18(2)5 micron column) using an acetonitrile: water gradient [ 45: 55 to 95: 5 ]. The appropriate fractions were concentrated in vacuo to give the title compound (7 mg).

Experimental value MH⁺476.0, respectively; predicted value 476.0

¹H-NMR(CDCl₃): 2.17 to 2.31(1H), 2.65 to 2.79(1H), 7.68 to 7.73(2H)

Example 13

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Ethyl chloroformate (140 μ l, 1.46 mmol) was added dropwise at-10 ℃ to a solution of preparative 5(615 mg, 1.33 mmol) and triethylamine (204 μ l, 1.46 mmol) in tetrahydrofuran (20 ml). The mixture was stirred at 0 ℃ for one hour, then a solution of ammonium hydroxide (35% in water, 737 μ l, 13.3 mmol) in tetrahydrofuran was added. The reaction mixture was then stirred at 0 ℃ for one hour. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined extracts were dried (MgSO)₄) And concentrated in vacuo to give the crude product. The residue was dissolved in acetonitrile (1 ml) and purified by using a gradient of acetonitrile: water [ 45: 55 to 95: 5 ]]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.50 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the titleCompound (95 mg).

Experimental value MH⁺462.0, respectively; predicted value 462.0

¹H-NMR(d₆-DMSO): 0.91 to 0.95(2H), 1.41 to 1.46(2H), 6.12 to 6.17(1H), 6.18 to 6.22(2H), 7.13 to 7.18(1H), 8.39 to 8.41(2H)

Example 14

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (isobutylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Triethylamine (28 μ l, 0.20 mmol) and ethyl chloroformate (48 μ l, 87 μmol) were added to a solution of preparative method 30(41 mg, 79 μmol) in tetrahydrofuran (2 ml) at 0 ℃. After stirring for 20 minutes, the mixture was warmed to room temperature and stirring was continued for one hour. Anhydrous ammonia gas was bubbled through the mixture for 15 minutes, followed by nitrogen bubbling through the mixture for 3 minutes. The reaction mixture was partitioned between hydrochloric acid (1M) and ethyl acetate, the organic layer was separated, washed with water and over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/water (0.45 ml) and purified by using an acetonitrile/water gradient [ 55: 45 to 95: 5 ]]The purification was carried out by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C18(2)10 μm column). The appropriate fractions were concentrated in vacuo to give the title compound (21 mg).

Experimental value MH⁺518.0; predicted value 518.1

¹H-NMR(CDCl₃): 0.78 to 0.86(6H), 1.22 to 1.29(2H), 1.56 to 1.66(1H), 1.74 to 1.83(2H), 2.86 to 2.92(2H), 3.49 to 3.62(1H), 5.55 to 5.74(2H), 7.90 to 7.95(2H)

Example 15

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N-isopropylcyclopropanecarboxamide

Triethylamine (227 microliters, 1.63 mmol) and ethyl chloroformate (69 microliters, 0.72 mmol) were added sequentially to a solution of preparative method 5(300 mg, 0.65 mmol) in tetrahydrofuran (6 ml) at 0 ℃ under nitrogen. After stirring at 0 ℃ for 30 min, the reaction mixture was warmed to room temperature and isopropylamine (278 μ l, 3.25 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (1.8 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm. times.50 mm, LUNA C18(2)10 micron column) using an acetonitrile/water gradient [ 55: 45 to 95: 5 ]. The appropriate fractions were concentrated in vacuo to give the title compound (103 mg).

Experimental value MH⁺504.3; predicted value 504.0

¹H-NMR(d₆-DMSO): 0.91 to 0.95(2H), 0.98 to 1.03(6H), 1.37 to 1.42(2H), 3.77 to 3.86(1H), 5.95 to 5.99(1H), 6.26 to 6.31(2H), 8.43 to 8.45(2H)

Example 16

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-fluoroethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Triethylamine (165 μ l, 1.20 mmol) and ethyl chloroformate (65 μ l, 0.60 mmol) were added successively to a solution of preparative method 8(150 mg, 0.30 mmol) in tetrahydrofuran (5 ml) at 0 ℃. After stirring for 30 minutes, the reaction of the mixture was stopped by adding an aqueous ammonium hydroxide solution. The reaction mixture was partitioned between water and ethyl acetate and the two layers were separated. The organic layer was washed with hydrochloric acid (10%) and brine over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/water (9: 1, 2 ml) and purified by using a gradient of acetonitrile/water [ 55: 45 to 95: 5 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C1810 micron column). The appropriate fractions were combined and concentrated to give the title compound (61 mg).

Experimental value MH⁺508.1; predicted value 508.0

¹H-NMR(d₆-acetone): 1.18 to 1.23(2H), 1.54 to 1.60(2H), 3.58 to 3.65(2H), 4.39 to 4.50(2H), 5.50 to 5.61(1H), 6.30 to 6.50(2H), 8.20 to 8.22(2H)

Example 17

1- {5- [ (2-amino-2-oxoethyl) amino ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -cyclopropanecarboxamide

Triethylamine (180 μ l, 1.31 mmol) and ethyl chloroformate (75 μ l, 0.79 mmol) were added successively to a solution of crude preparation 15 (about 0.26 mmol) in tetrahydrofuran (6 ml). After stirring for 30 minutes, excess ammonium hydroxide solution (30 wt%, 0.37 ml) was added and stirring continued for one hour. The reaction mixture was then concentrated in vacuo and the residue partitioned between water (10 ml) and ethyl acetate (20 ml). The organic layer was separated, washed with hydrochloric acid (1N, 10 mL) andwashed with brine (10 ml) over MgSO₄Dried and concentrated in vacuo. The retentate was dissolved in acetonitrile (2 ml) and purified by using a gradient of acetonitrile: water [ 40: 60 to 95: 5 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C18(2)10 μm column). The appropriate fractions were concentrated in vacuo to give the title compound (22 mg).

Experimental value MH⁺519.3, respectively; predicted value 519.0

¹H-NMR(d₆-acetone): 1.15 to 1.20(2H), 1.55 to 1.60(2H), 3.85 to 3.90(2H), 5.45 to 5.55(1H), 6.40 to 6.55(2H), 6.95 to 7.05(1H), 8.21 to 8.24(2H)

Example 18

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-dichlorocyclopropanecarboxamide

A solution of triethylamine (128 μ l, 0.92 mmol) and ethyl chloroformate (48 mg, 0.51 mmol) in tetrahydrofuran (0.5 ml) was added successively to a solution of preparative 31(244 mg, 0.46 mmol) in tetrahydrofuran (10 ml) at room temperature under nitrogen. After 30 minutes, ammonium hydroxide (0.27 ml, 2.30 mmol) was added dropwise and the reaction mixture was stirred for 18 hours and then concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm. times.50 mm, Sunfire LUNA C1810 micron column) using an acetonitrile/water gradient [ 45: 55 to 95: 5 ]. The appropriate fractions were combined and concentrated to give the title compound (132 mg).

Experimental value MH⁺529.9, respectively; predicted value 529.9

¹H-NMR (acetone-d)₆): 2.35 to 2.41(1H), 2.65 to 2.69(1H), 6.23 to 6.33(2H), 6.95 to 7.04(1H), 7.45 to 7.58(1H), 8.25 to 8.28(2H)

Example 19

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (pyridin-4-ylmethyl) cyclopropanecarboxamide

Triethylamine (119 μ l, 0.85 mmol) and ethyl chloroformate (41 μ l, 0.43 mmol) were added successively to a solution of preparative 6(110 mg, 0.21 mmol) in tetrahydrofuran (6 ml) at 0 ℃. The mixture was stirred for 10 minutes, then 4-aminomethylpyridine (111 μ l, 1.05 mmol) was added. After stirring at 0 ℃ for a further 3 hours, the reaction mixture is extracted with ethyl acetate, the combined extracts are washed with brine and dried (MgSO ₄) And concentrated in vacuo.

The residue was dissolved in acetonitrile (2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C1810 micron column) using an acetonitrile: 0.1% trifluoroacetic acid gradient [ 55: 45 to 95: 5 ]. The appropriate fractions were combined and concentrated to give the title compound (99 mg).

Experimental value MH⁺607.3, respectively; predicted value 607.1

¹H-NMR(d₆-DMSO): 0.00 to 0.01(2H), 0.20 to 0.30(2H), 0.79 to 0.83(1H), 1.02 to 1.11(2H), 1.40 to 1.48(2H), 2.90 to 2.99(2H), 4.38 to 4.43(2H), 7.58 to 7.62(2H), 8.40 to 8.44(2H), 8.62 to 8.70(2H)

Example 20

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } carbamic acid isopropyl ester

Triethylamine (330 μ l, 2.40 mmol) and ethyl chloroformate (120 μ l, 1.20 mmol) were added successively to a solution of crude preparation 22 (about 0.60 mmol) in tetrahydrofuran (2 ml) at 0 ℃. After stirring for 5 minutes, aqueous ammonium hydroxide (18M, 0.5 ml) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was adjusted to pH1 by addition of hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with water and over MgSO ₄Dried and concentrated under a nitrogen stream. The residue was dissolved in acetonitrile/dimethyl sulfoxide (1.5 ml) and purified by using a gradient of acetonitrile: water [ 50: 50 to 95: 5 ]]Purification was performed by automated preparative liquid chromatography (Gilson System, 150 mm. times.50 mm Sunfire LUNA C1810 micron column). The appropriate fractions were combined and concentrated to give the title compound (143 mg).

Experimental value MH⁺547.9, respectively; predicted value 548.0

¹H-NMR(CD₃OD): 1.09 to 1.15(8H), 1.55 to 1.60(2H), 4.70 to 4.80(1H), 8.19 to 8.21(2H)

Example 21

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [2- (1H-1, 2, 4-triazol-1-yl) ethyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxamide

Triethylamine (28 mg, 0.28 mmol) and chloroformic acidEthyl ester (26 mg, 0.24 mmol) was added to a solution of preparative method 24(103 mg, 0.19 mmol) in tetrahydrofuran (5 ml) one after the other. After stirring for 30 minutes, aqueous ammonium hydroxide (30 wt%, 0.2 ml) was added and stirring continued for one hour. The reaction mixture was then concentrated in vacuo and the residue partitioned between water (10 ml) and ethyl acetate (20 ml). The organic layer was separated, washed with hydrochloric acid (1N, 10 mL) and brine (10 mL) over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1.4 ml) and purified by using a gradient of acetonitrile: water [ 40: 60 to 98: 2 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C1810 micron column). The appropriate fractions were combined and concentrated to give the title compound (24 mg).

Experimental value MH⁺556.9, respectively; predicted value 557.0

¹H-NMR(CDCl₃): 1.15 to 1.20(2H), 1.60 to 1.65(2H), 3.61 to 3.67(2H), 4.25 to 4.31(2H), 7.90 to 7.92(1H), 8.18 to 8.20(2H), 8.25 to 8.27(1H)

Example 22

1- { 3-cyano-5- [ (2-cyanoethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Triethylamine (180 μ l, 1.31 mmol) and ethyl chloroformate (71 μ l, 0.65 mmol) were added successively to a solution of preparative method 25(223 mg, 0.44 mmol) in tetrahydrofuran (5 ml). After stirring for 30 minutes, excess ammonium hydroxide solution (0.61 ml) was added and stirring was continued for one hour. The reaction mixture was then concentrated in vacuo and the residue partitioned between water (10 ml) and ethyl acetate (20 ml). The organic layer was separated and washed with hydrochloric acid (1N, 10 mL) and brine (10)Ml) was washed over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (2 ml) and purified by using a gradient of acetonitrile: water [ 45: 55 to 95: 5 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C1810 micron column). The appropriate fractions were combined and concentrated to give the title compound (59 mg).

Experimental value MH⁺515.2; predicted value 515.0

¹H-NMR(CDCl₃): 1.21 to 1.26(2H), 1.61 to 1.68(2H), 1.54 to 1.60(2H), 3.50 to 3.56(2H), 8.19 to 8.22(2H)

Example 23

1- (5-amino-3-cyano-1- {2, 6-dichloro-4- [1, 2, 2, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] phenyl } -1H-pyrazol-4-yl) cyclopropanecarboxamide

Triethylamine (474 μ l, 3.40 mmol) and ethyl chloroformate (162 μ l, 1.70 mmol) were added successively to a solution of preparative method 23(430 mg, 0.85 mmol) in tetrahydrofuran (10 ml) at 0 ℃. The mixture was stirred for 5 minutes, then aqueous ammonium hydroxide (2 ml) was added. After stirring at room temperature for a further 18 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (3 ml) and purified by using a gradient of acetonitrile: water [ 50: 50 to 95: 5 ] ]The purification was carried out by automated preparative liquid chromatography (Gilson system, 150 mm. times.50 mm, Sunfire C18(2)10 micron column). The appropriate fractions were combined and concentrated to give the title compound (184 mg).

Experimental value MH⁺503.9, respectively; predicted value 504.0

¹H-NMR(CD₃OD): 1.07 to 1.11(2H), 1.55 to 1.60(2H), 7.90 to 7.92(2H)

Example 24

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [3- (methylthio) propyl ] amino } -1H-pyrazol-4-yl) -cyclopropanecarboxamide

Triethylamine (0.27 ml, 1.98 mmol) and ethyl chloroformate (0.09 μ l, 0.94 mmol) were added successively to a solution of crude preparation 21 (about 0.79 mmol) in tetrahydrofuran (10 ml) at 0 ℃. After stirring for 15 minutes, aqueous ammonium hydroxide (6 ml) was added and stirring continued for 30 minutes. The reaction mixture was adjusted to pH1 by addition of hydrochloric acid (1M) and the mixture was extracted with ethyl acetate (× 3). The combined extracts were washed with water and over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (1.5 ml) and purified by using a gradient of acetonitrile: water [ 50: 50 to 95: 5 ]]Purification was performed by automated preparative liquid chromatography (Gilson System, 150 mm. times.50 mm, Sunfire LUNA C1810 micron column). The appropriate fractions were combined and concentrated to give the title compound (73 mg).

Experimental value MH⁺549.9, respectively; predicted value 550.0

¹H-NMR(CD₃OD): 1.20 to 1.25(2H), 1.62 to 1.67(2H), 1.70 to 1.80(2H), 2.00 to 2.01(3H), 2.40 to 2.45(2H), 3.30 to 3.40(2H), 8.20 to 8.23(2H)

Example 25

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- [ (5-methyl-4H-1, 2, 4-triazol-3-yl) methyl ] cyclopropanecarboxamide

Triethylamine (177 μ l, 1.27 mmol) and ethyl chloroformate (41 μ l, 0.43 mmol) were added successively to a solution of preparative 6(110 mg, 0.21 mmol) in tetrahydrofuran (6 ml) at 0 ℃. The mixture was stirred for 10 minutes, then 1- [ 5-methyl-4H- (1, 2, 4) -triazol-3-yl was added]Methylamine (218 mg, 1.00 mmol). After stirring at 0 ℃ for a further hour, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (0.7 ml) and purified by using a gradient of acetonitrile: 0.1% trifluoroacetic acid [ 50: 50 to 98: 2 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C1810 micron column). The appropriate fractions were combined and concentrated to give the title compound (20 mg).

Experimental value MH⁺611.3, respectively; predicted value 611.1

¹H-NMR(d₆-DMSO): 0.00 to 0.01(2H), 0.20 to 0.27(2H), 0.70 to 0.85(1H), 1.05 to 1.10(2H), 1.45 to 1.51(2H), 2.25 to 2.30(3H), 2.90 to 2.98(2H), 4.21 to 4.26(2H), 8.40 to 8.42(2H)

Example 26

1- { 3-cyano-5- [ (cyclopropylmethyl) (methyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Lithium iodide (482 milli)G, 3.60 mmol) was added to a solution of preparative 192(200 mg, 0.36 mmol) in pyridine (5 ml) and the reaction mixture was stirred at 125 ℃ for 6 hours. The reaction mixture was concentrated in vacuo and the residue was washed with hydrochloric acid (10%) and then extracted with dichloromethane. The combined extracts were washed with brine, over MgSO₄Dried and concentrated in vacuo to give the acid. Triethylamine (330 μ l, 2.38 mmol) and ethyl chloroformate (136 μ l, 1.43 mmol) were added successively to a solution of the above acid (500 mg, 0.95 mmol) in tetrahydrofuran (10 ml) at 0 ℃. After stirring for 30 minutes at 0 ℃, ammonia (0.5 ml) was added and the reaction mixture was stirred for a further 30 minutes. The mixture was then quenched with water and extracted with ethyl acetate. The combined extracts were washed with brine, over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (0.3 ml) and purified by using a gradient of acetonitrile: water [ 60: 40 to 95: 5 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C18(2)10 μm column). The appropriate fractions were combined and concentrated to give the title compound (182 mg).

Experimental value MH⁺530.1; predicted value 530.1

Example 27

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorophenylyl ] -1H-pyrazol-5-yl } carbamic acid [1- (fluoromethyl) cyclopropyl ] methyl ester

Triethylamine (275 μ l, 2.00 mmol) and ethyl chloroformate (187 μ l, 1.00 mmol) were added successively to a solution of crude preparation 223 (about 0.50 mmol) in tetrahydrofuran (3 ml) from 0 ℃. After stirring for 30 minutes, the reaction of the mixture was stopped by adding aqueous ammonium hydroxide (2 ml). The reaction mixtureThe mixture was partitioned between water and ethyl acetate and the two layers were separated. The organic layer was washed with hydrochloric acid (10%) and brine over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (1 ml) and purified by using a gradient of acetonitrile: water [ 50: 50 to 98: 2 ] ]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C18(2)10 μm column). The appropriate fractions were combined and concentrated to give the title compound (42 mg).

MH according to the Experimental values⁺592.1, respectively; predicted value 592.0

¹H-NMR(CDCl₃): 0.51 to 0.62(4H), 1.18 to 1.23(2H), 1.65 to 1.75(2H), 4.00 to 4.06(3H), 4.18 to 4.20(1H), 7.91 to 7.95(2H)

Example 28

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide

Triethylamine (0.79 ml, 5.72 mmol) and ethyl chloroformate (0.20 mmol, 2.10 mmol) were added dropwise, followed by a solution of preparative 7(977 mg, 1.91 mmol) in tetrahydrofuran (20 ml). After stirring for 5 minutes, ammonium hydroxide (30 wt%, 2.20 ml, 19.10 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. Hydrochloric acid (2N, 50 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 30 ml). The combined extracts were extracted over MgSO₄Dried and concentrated in vacuo.

The residue was dissolved in acetonitrile (3.5 ml) and purified by automated preparative liquid chromatography using an acetonitrile: water gradient [ 50: 50 to 95: 5] (Gilson system, 150 mm. times.50 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were combined and concentrated to give the title compound (700 mg).

Experimental value MH⁺512.2, respectively; predicted value 512.0

¹H-NMR(d₆DMSO): 1.90 to 2.01(1H), 2.75 to 2.83(4H), 6.05 to 6.13(1H), 7.15 to 7.22(1H), 7.59 to 7.66(1H), 8.40 to 8.49(2H)

Compounds prepared in an analogous manner using the appropriate amine are:

examples of the invention	R1	R5	R6	R8	R9	R2	Is obtained from
examples of the invention	R1	R5	R6	R8	R9	R2	Is obtained from	Example 29	SF₅	H	H	CN	3, 3, 3-Trifluoropropylamino	Aminocarbonyl group^a	Preparation method 16
Example 30	SF₅	H	H	CN	[ 2-chloro (1, 3-thiazol-5-yl)]Methylamino radical	Aminocarbonyl group^a	Preparation method 17	Example 29	SF₅	H	H	CN	3, 3, 3-Trifluoropropylamino	Aminocarbonyl group^a	Preparation method 16
Example 30	SF₅	H	H	CN	[ 2-chloro (1, 3-thiazol-5-yl)]Methylamino radical	Aminocarbonyl group^a	Preparation method 17	Example 31	sF₅	H	H	CN	(isoxazol-5-yl) methylamino	Aminocarbonyl group^a	Preparation method 18
Example 32	SF₅	H	H	CN	-NH(CH₂)₂CONH₂	Amino groupCarbon-based^a	Preparation method 19	Example 31	sF₅	H	H	CN	(isoxazol-5-yl) methylamino	Aminocarbonyl group^a	Preparation method 18
Example 32	SF₅	H	H	CN	-NH(CH₂)₂CONH₂	Amino groupCarbon-based^a	Preparation method 19	Example 33	SF₅	H	H	CN	5, 5, 5-Trifluoropentylamino	Aminocarbonyl group^a	Preparation method 20
Example 34	SF₅	H	H	CN	Propylamino group	Aminocarbonyl group^a	Preparation method 41	Example 33	SF₅	H	H	CN	5, 5, 5-Trifluoropentylamino	Aminocarbonyl group^a	Preparation method 20
Example 34	SF₅	H	H	CN	Propylamino group	Aminocarbonyl group^a	Preparation method 41	Example 35	SF₅	H	H	CN	(cyclobutylmethyl) amino group	Aminocarbonyl group^a	Preparation method 32
Example 36	SF₅	H	H	CN	Dimethylamino group	Aminocarbonyl group^a	Preparation method 33	Example 35	SF₅	H	H	CN	(cyclobutylmethyl) amino group	Aminocarbonyl group^a	Preparation method 32
Example 36	SF₅	H	H	CN	Dimethylamino group	Aminocarbonyl group^a	Preparation method 33	Example 37	OCF₃	H	H	CN	Ethoxycarbonylamino group	Aminocarbonyl group^a	Preparation method 34
Example 38	SF₅	Cl	Cl	CN	Methylamino radical	Aminocarbonyl group^a	Preparation method 39	Example 37	OCF₃	H	H	CN	Ethoxycarbonylamino group	Aminocarbonyl group^a	Preparation method 34
Example 38	SF₅	Cl	Cl	CN	Methylamino radical	Aminocarbonyl group^a	Preparation method 39	Example 39	OCF₃	Cl	Cl	CN	NH₂	Aminocarbonyl group^a	Preparation method 40
Example 40	SF₅	H	H	CN	-NHCH₂CONHCH₂c-Pr	Aminocarbonyl group^a	Preparation method 42	Example 39	OCF₃	Cl	Cl	CN	NH₂	Aminocarbonyl group^a	Preparation method 40
Example 40	SF₅	H	H	CN	-NHCH₂CONHCH₂c-Pr	Aminocarbonyl group^a	Preparation method 42	Example 41	SF₅	H	H	CN	-NH(CH₂)₃CONH₂	Aminocarbonyl group^a	Preparation method 45
Example 42	SF₅	H	H	CN	(1, 3-Thiazol-2-ylmethyl) amino	Aminocarbonyl group^a	Preparation method 46	Example 41	SF₅	H	H	CN	-NH(CH₂)₃CONH₂	Aminocarbonyl group^a	Preparation method 45
Example 42	SF₅	H	H	CN	(1, 3-Thiazol-2-ylmethyl) amino	Aminocarbonyl group^a	Preparation method 46	Example 43	SF₅	H	H	CN	(Cyclopropylmethyl) amino	-CONH(CH₂)₂OCH₃ ^b	Preparation method 6
Example 44	SF₅	H	H	CN	(Cyclopropylmethyl) amino	-CONH(CH₂)₂OH^c	Preparation method 6	Example 43	SF₅	H	H	CN	(Cyclopropylmethyl) amino	-CONH(CH₂)₂OCH₃ ^b	Preparation method 6

Example 45	SF₅	H	H	CN	(Cyclopropylmethyl) amino	(pyridin-2-ylmethyl) aminocarbonyl^d	Preparation method 6
Example 45	SF₅	H	H	CN	(Cyclopropylmethyl) amino	(pyridin-2-ylmethyl) aminocarbonyl^d	Preparation method 6	Example 46	SF₅	H	H	CN	(Cyclopropylmethyl) amino	(pyridin-3-ylmethyl) aminocarbonyl^e	Preparation method 6
Example 47	SF₅	H	H	CN	(Cyclopropylmethyl) amino	-CONHCH₂C(CH₃)₂OH^f	Preparation method 6	Example 46	SF₅	H	H	CN	(Cyclopropylmethyl) amino	(pyridin-3-ylmethyl) aminocarbonyl^e	Preparation method 6
Example 47	SF₅	H	H	CN	(Cyclopropylmethyl) amino	-CONHCH₂C(CH₃)₂OH^f	Preparation method 6	Example 48	SF₅	H	H	CN	2- (1-methyl-1H-pyrazol-4-yl) ethylamino	Aminocarbonyl group^a	Preparation method 47
Example 49	SF₅	F	F	CN	Dimethylamino group	Aminocarbonyl group^a	Preparation method 198	Example 48	SF₅	H	H	CN	2- (1-methyl-1H-pyrazol-4-yl) ethylamino	Aminocarbonyl group^a	Preparation method 47
Example 49	SF₅	F	F	CN	Dimethylamino group	Aminocarbonyl group^a	Preparation method 198	Example 50	SF₅	H	H	CN	Methylthio group	Aminocarbonyl group^a	Preparation method 35
Example 51	SF₅	H	H	CN	(2-methoxyethyl) (methyl) amino	Aminocarbonyl group^a	Preparation method 44	Example 50	SF₅	H	H	CN	Methylthio group	Aminocarbonyl group^a	Preparation method 35
Example 51	SF₅	H	H	CN	(2-methoxyethyl) (methyl) amino	Aminocarbonyl group^a	Preparation method 44	Example 52	SF₅	H	H	CN	[ (5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) methyl]Amino group	Aminocarbonyl group^a	Preparation method 43
Example 53	SF₅	F	F	CN	NH₂	Aminocarbonyl group^a	Preparation method 10	Example 52	SF₅	H	H	CN		Aminocarbonyl group^a	Preparation method 43
Example 53	SF₅	F	F	CN	NH₂	Aminocarbonyl group^a	Preparation method 10	Example 54	OCF₃	H	H	CN	NH₂	Aminocarbonyl radical^a	Preparation method 11
Example 55	CF₃	F	F	CN	NH₂	Aminocarbonyl group^a	Preparation method 94	Example 54	OCF₃	H	H	CN	NH₂	Aminocarbonyl radical^a	Preparation method 11
Example 55	CF₃	F	F	CN	NH₂	Aminocarbonyl group^a	Preparation method 94	Example 56	SF₅	H	H	CN	NH₂	(methylamino) carbonyl^g	Preparation method 5
Example 57	CF₃	H	H	CN	NH₂	(Cyclopropylamino) carbonyl group^h	Preparation method 178	Example 56	SF₅	H	H	CN	NH₂	(methylamino) carbonyl^g	Preparation method 5
Example 57	CF₃	H	H	CN	NH₂	(Cyclopropylamino) carbonyl group^h	Preparation method 178	Example 58	CF₃	H	H	CN	NH₂	(Cyclopropylmethylamino) carbonyl^j	Preparation method 178
Example 59	CF₃	H	H	CN	NH₂	(pyridin-2-ylamino) carbonyl^d	Preparation method 178	Example 58	CF₃	H	H	CN	NH₂	(Cyclopropylmethylamino) carbonyl^j	Preparation method 178
Example 59	CF₃	H	H	CN	NH₂	(pyridin-2-ylamino) carbonyl^d	Preparation method 178	Example 60	CF₃	H	H	CF₃	NH₂	Aminocarbonyl group^a	Preparation method 28
Example 61	CF₃	H	H	CN	-N＝CH-N(CH₃)₂	Aminocarbonyl group^a	Preparation method 27	Example 60	CF₃	H	H	CF₃	NH₂	Aminocarbonyl group^a	Preparation method 28
Example 61	CF₃	H	H	CN	-N＝CH-N(CH₃)₂	Aminocarbonyl group^a	Preparation method 27	Example 62	SF₅	H	H	CN	NH₂	(2, 2, 2-trifluoroethylamino) carbonyl^j	Preparation method 5
Example 63	OCF₃	F	F	CN	Methylamino radical	Aminocarbonyl group^a	Preparation method 50	Example 62	SF₅	H	H	CN	NH₂	(2, 2, 2-trifluoroethylamino) carbonyl^j	Preparation method 5

Example 64	OCF₃	H	H	CN	Methylamino radical	Aminocarbonyl group^a	Preparation method 12
Example 64	OCF₃	H	H	CN	Methylamino radical	Aminocarbonyl group^a	Preparation method 12	Example 65	CF₃	H	H	CN	(Cyclopropylmethyl) amino	(methylamino) carbonyl^g	Preparation method 29
Example 66	CF₃	CH3	CH3	CN	NH₂	Aminocarbonyl group^a	Preparation method 89	Example 65	CF₃	H	H	CN	(Cyclopropylmethyl) amino	(methylamino) carbonyl^g	Preparation method 29
Example 66	CF₃	CH3	CH3	CN	NH₂	Aminocarbonyl group^a	Preparation method 89	Example 67	SF₅	H	H	CN	[ (4H-1, 2, 4-triazol-3-yl) methyl]Amino group	Aminocarbonyl group^a	Preparation method 13
Example 68	SF₅	H	H	CN	[ (1-methylcyclopropyl) methyl]Amino group	Aminocarbonyl group^a	Preparation method 14	Example 67	SF₅	H	H	CN	[ (4H-1, 2, 4-triazol-3-yl) methyl]Amino group	Aminocarbonyl group^a	Preparation method 13
Example 68	SF₅	H	H	CN	[ (1-methylcyclopropyl) methyl]Amino group	Aminocarbonyl group^a	Preparation method 14	Example 69	SF₅	H	H	CN	{4- [ (methylamino) sulfonyl group]Benzyl } amino group	Aminocarbonyl group^a	Preparation method 37
Example 70	SF₅	H	H	CN	{4- [ (methylsulfonyl) amino group ]Benzyl } amino group	Aminocarbonyl group^a	Preparation method 36	Example 69	SF₅	H	H	CN	{4- [ (methylamino) sulfonyl group]Benzyl } amino group	Aminocarbonyl group^a	Preparation method 37
Example 70	SF₅	H	H	CN	{4- [ (methylsulfonyl) amino group ]Benzyl } amino group	Aminocarbonyl group^a	Preparation method 36	Example 71	SF₅	H	H	CN	(tetrahydro-2H-pyran-4-ylmethyl) amino	Aminocarbonyl group^a	Preparation method 38
Example 72	SF₅	H	H	CN	(Cyclopropylmethyl) amino	-CONH(CH₂)₃Oi-Pr^k	Preparation method 6	Example 71	SF₅	H	H	CN	(tetrahydro-2H-pyran-4-ylmethyl) amino	Aminocarbonyl group^a	Preparation method 38
Example 72	SF₅	H	H	CN	(Cyclopropylmethyl) amino	-CONH(CH₂)₃Oi-Pr^k	Preparation method 6	Example 73	SF₅	H	H	CN	-NHCH₂CONHCH₂CF₃	Aminocarbonyl group^a	Preparation method 225

^aReagent-ammonia;

^breagent-methoxymethane;

^creagent-hydroxyethylamine;

^dreagent-pyridin-2-ylmethylamine;

^ereagent-pyridin-3-ylmethylamine;

^freagent-2-hydroxyisobutylamine;

^greagent-methylamine;

^hreagent-cyclopropylamine;

ⁱreagent-cyclopropylmethylamine;

^jreagent-2, 2, 2-trifluoroethylamine;

^kreagent-isopropyl oxypropylamine

Example 29

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (3, 3, 3-trifluoropropyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺558.0, respectively; predicted value 558.0

¹H-NMR(d₆-DMSO): 1.00 to 1.06(2H), 1.42 to 1.50(2H), 2.38 to 2.44(2H), 3.39 to 3.44(2H), 5.85 to 5.91(1H), 8.41 to 8.43(2H)

Example 30

1- (5- { [ (2-chloro-1, 3-thiazol-5-yl) methyl ] amino } -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl) cyclopropanecarboxamide

Experimental value MH⁺593.1; predicted value 593.0

¹H-NMR(d₆-DMSO): 1.00 to 1.06(2H), 1.41 to 1.48(2H), 4.40 to 4.49(2H), 6.43 to 6.50(1H), 6.64 to 6.71(1H), 7.17 to 7.23(1H), 7.39 to 7.41(1H), 8.40 to 8.22(2H)

Example 31

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (isoxazol-5-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺542.9, respectively; predicted value 543.0

¹H-NMR(d₆-DMSO): 0.97 to 1.02(2H), 1.39 to 1.45(2H), 4.44 to 4.51(2H), 6.20 to 6.23(1H), 6.57 to 6.64(2H), 7.17 to 7.23(1H), 8.39 to 8.43(3H)

Example 32

N-3- {4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } -beta-propylamine amide

MH according to the Experimental values⁺533.2; predicted value 533.0

¹H-NMR(d₆-DMSO): 0.99 to 1.05(2H), 1.40 to 1.45(2H), 2.15 to 2.22(2H), 3.30 to 3.38(2H), 8.40 to 8.42(2H)

Example 33

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (5, 5, 5-trifluorophenyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺586.2, respectively; predicted value 586.0

¹H-NMR(d₆-DMSO): 0.95 to 1.02(2H), 1.30 to 1.40(2H), 1.40 to 1.48(4H), 2.01 to 2.20(2H), 3.10 to 3.18(2H), 8.39 to 8.42(2H)

Example 34

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (propylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide

¹H-NMR(d₆-acetone): 0.75 to 0.80(3H), 1.10 to 1.15(2H), 1.40 to 1.50(2H), 1.55 to 1.60(2H), 3.20 to 3.29(2H), 5.30 to 5.38(1H), 6.25 to 6.55(2H), 8.20 to 8.22(2H)

Example 35

1- { 3-cyano-5- [ (cyclobutylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺530.1; predicted value 530.1

¹H-NMR(CDCl₃): 1.21 to 1.27(2H), 1.48 to 1.58(2H), 1.75 to 1.93(4H), 1.95 to 2.05(2H), 2.30 to 2.40(1H), 3.05 to 3.11(2H), 3.39 to 3.46(1H), 5.61 to 5.72(2H), 7.89 to 7.95(2H)

Example 36

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (dimethylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺490.1; predicted value 490.0

¹H-NMR(d₆-DMSO): 1.07 to 1.11(2H), 1.50 to 1.54(2H), 2.63 to 2.66(6H), 6.69 to 6.76(1H), 7.13 to 7.20(1H), 8.48 to 8.50(2H)

Example 37

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-5-yl } carbamic acid ethyl ester

Experimental value MH⁺492.3; predicted value 492.0

¹H-NMR(d₆-DMSO): 0.90 to 0.95(2H), 1.00 to 1.10(3H), 1.37 to 1.42(2H), 3.95 to 4.02(2H), 6.25 to 6.39(1H), 7.10 to 7.21(1H), 7.95 to 8.00(2H), 9.80 to 9.95(1H)

Example 38

2, 2-dichloro-1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH ⁺544.2 predicted value 543.9

¹H-NMR(d₆-acetone): 2.22 to 2.36(1H), 2.79 to 2.81(2H), 2.84 to 2.89(3H), 6.99 to 7.20(2H), 8.26 to 8.30(2H)

Example 39

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } -2, 2-dichlorocyclopropanecarboxamide

Experimental value MH⁺488.2, respectively; predicted value 487.9

¹H-NMR(d₆-acetone): 2.30 to 2.40(1H), 2.61 to 2.69(1H), 6.10 to 6.30(2H), 6.90 to 7.00(1H), 7.40 to 7.60(1H), 7.75 to 7.80(2H)

Example 40

1- { 3-cyano-5- ({2- [ (cyclopropylmethyl) amino ] -2-oxoethyl } amino) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experiment ofValue MH⁺573.3; predicted value 573.1

¹H-NMR(d₆-DMSO): 0.05 to 0.10(2H), 0.35 to 0.40(2H), 0.68 to 0.75(1H), 1.00 to 1.05(2H), 1.40 to 1.45(2H), 2.84 to 2.90(2H), 3.62 to 3.69(2H), 6.18 to 6.22(1H), 6.42 to 6.49(1H), 7.19 to 7.22(1H), 7.78 to 7.81(1H), 8.41 to 8.43(2H)

Example 41

1- {5- [ (4-amino-4-oxobutyl) amino ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺547.2, respectively; predicted value 547.1

¹H-NMR(d₆-DMSO): 0.95 to 1.02(2H), 1.39 to 1.45(2H), 1.50 to 1.63(2H), 1.90 to 1.99(2H), 3.10 to 3.17(2H), 8.39 to 8.42(2H)

Example 42

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (1, 3-thiazol-2-ylmethyl) amino ] -1H-pyrazol-4-yl } -cyclopropanecarboxamide

Experimental value MH⁺558.9, respectively; predicted value 559.0

¹H-NMR(d₆-DMSO): 0.90 to 0.99(2H), 1.35 to 1.41(2H), 4.50 to 4.52(2H), 7.55 to 7.63(2H), 8.37 to 8.40(2H)

Example 43

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (2-methoxyethyl) cyclopropanecarboxamide

Experimental value MH⁺574.3; predicted value 574.1

¹H-NMR(d₆-DMSO): 0.01 to 0.07(2H), 0.30 to 0.36(2H), 0.80 to 0.90(1H), 1.00 to 1.05(2H), 1.40 to 1.44(2H), 2.90 to 2.99(2H), 3.17 to 3.19(3H), 3.20 to 3.30(4H), 8.40 to 8.42(2H)

Example 44

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (2-hydroxyethyl) cyclopropanecarboxamide

Experimental value MH⁺560.3; predicted value 560.1

¹H-NMR(d₆-DMSO): 0.01 to 0.08(2H), 0.27 to 0.32(2H), 0.80 to 0.90(1H), 1.00 to 1.05(2H), 1.20 to 1.25(2H), 2.90 to 2.99(2H), 3.10 to 3.17(2H), 3.34 to 3.38(2H), 4.60 to 4.65(1H), 8.40 to 8.42(2H)

Example 45

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (pyridin-2-ylmethyl) cyclopropanecarboxamide

Experimental value MH⁺607.3, respectively; predicted value 607.1

¹H-NMR(d₆-DMSO): 0.00 to 0.01(2H), 0.10 to 0.14(2H), 0.79 to 0.83(1H), 1.02 to 1.09(2H), 1.41 to 1.46(2H), 2.90 to 2.99(2H), 4.35 to 4.40(2H), 7.18 to 7.23(2H), 7.60 to 7.70(2H), 8.40 to 8.42(2H)

Example 46

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (pyridin-3-ylmethyl) cyclopropanecarboxamide

Experimental value MH⁺606.9, respectively; predicted value 607.1

¹H-NMR(d₆-DMSO): 0.15 to 0.00(2H), 0.20 to 0.30(2H), 0.70 to 0.85(1H), 1.00 to 1.10(2H), 1.40 to 1.50(2H), 2.80 to 2.90(2H), 4.30 to 4.40(2H),7.82 to 7.95(2H), 8.35 to 8.41(2H), 8.50 to 8.58(2H)

Example 47

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (2-hydroxy-2-methylpropyl) cyclopropanecarboxamide

Experimental value MH⁺588.3, respectively; predicted value 588.1

¹H-NMR(CD₃OD): 0.09 to 0.15(2H), 0.41 to 0.49(2H), 0.90 to 1.00(1H), 1.16 to 1.18(6H), 1.25 to 1.30(2H), 1.63 to 1.69(2H), 3.05 to 3.10(2H), 3.19 to 3.21(2H), 8.20 to 8.22(2H)

Example 48

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [2- (1-methyl-1H-pyrazol-4-yl) ethyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxamide

Experimental value MH⁺570.2, respectively; predicted value 570.1

¹H-NMR(CD₃OD): 1.19 to 1.23(2H), 1.60 to 1.65(2H), 2.59 to 2.64(2H), 3.37 to 3.41(2H), 3.79 to 3.81(3H), 7.21 to 7.22(1H), 7.35 to 7.36(1H), 8.21 to 8.23(2H)

Example 49

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (dimethylamino) -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide

Experimental value MH⁺526.0, respectively; predicted value 526.0

¹H-NMR(CDCl₃): 1.96 to 2.04(1H), 2.74 to 2.77(6H), 2.81 to 2.90(1H), 5.74 to 5.81(2H), 7.91 to 7.93(2H)

Example 50

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylthio) -1H-pyrazol-4-yl } cyclopropanecarboxamide

¹H-NMR(CDCl₃): 1.35 to 1.38(2H), 1.85 to 1.89(2H), 2.35 to 2.37(3H), 7.93 to 7.94(2H)

Example 51

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-methoxyethyl) (methyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺534.1 of the total weight of the mixture; predicted value 534.1

¹H-NMR(CDCl₃): 1.21 to 1.26(2H), 1.75 to 1.80(2H), 2.90 to 2.93(3H), 3.01 to 3.04(2H), 3.12 to 3.14(3H), 3.20 to 3.25(2H), 5.60 to 5.80(2H), 7.89 to 7.92(2H)

Example 52

1- (5- { [ (5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) methyl ] amino } -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl) cyclopropanecarboxamide

Experimental value MH⁺604.3; predicted value 604.0

¹H-NMR(d₆-DMSO): 1.04 to 1.11(2H), 1.42 to 1.50(2H), 2.00 to 2.06(3H), 3.59 to 3.62(3H), 4.16 to 4.20(2H), 5.81 to 5.86(1H), 8.36 to 8.40(2H)

Example 53

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide

Experimental value MH⁺497.9, respectively; predicted value 498.0

¹H-NMR(d₆-DMSO): 1.74 to 1.84(1H), 2.51 to 2.61(1H), 6.26 to 6.35(2H), 7.13 to 7.22(1H), 7.44 to 7.53(1H), 8.40 to 1.408.46(2H)

Example 54

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺420.0 of the total weight of the mixture; predicted value 420.0

¹H-NMR(d₆-DMSO): 0.87 to 0.93(2H), 1.38 to 1.44(2H), 6.06 to 6.11(1H), 6.12 to 6.17(2H), 7.12 to 7.21(1H), 7.88 to 7.92(2H)

Example 55

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide

MH according to the Experimental values⁺440.0 of the total weight of the mixture; predicted value 440.0

¹H-NMR (acetone-d)₆): 1.91 to 1.99(1H), 2.60 to 2.69(1H), 5.93 to 6.03(2H), 6.70 to 6.88(2H), 8.03 to 8.08(2H)

Example 56

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N-methylcyclopropanecarboxamide

Experimental value MH⁺476.3, respectively; predicted value 476.0

¹H-NMR(d₆-DMSO): 0.84 to 0.89(2H), 1.38 to 1.43(2H), 2.57 to 2.61(3H), 6.14 to 6.21(2H), 6.74 to 6.80(1H), 8.38 to 8.41(2H)

Example 57

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -N-cyclopropylcyclopropane-carboxamide

Experimental value MH⁺443.9, respectively; the predicted value 444.1

¹H-NMR(CDCl₃): 0.30 to 0.36(2H), 0.65 to 0.72(2H), 1.05 to 1.11(2H), 1.55 to 1.62(2H), 2.57 to 2.64(1H), 7.71 to 7.75(2H)

Example 58

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -N- (cyclopropylmethyl) -cyclopropanecarboxamide

Experimental value MH⁺457.9, respectively; predicted value 458.1

¹H-NMR(CDCl₃): 0.08 to 0.13(2H), 0.40 to 0.46(2H), 0.80 to 0.87(1H), 1.10 to 1.14(2H), 1.64 to 1.68(2H), 3.04 to 3.08(2H), 3.96 to 4.02(2H), 5.68 to 5.73(1H), 7.76 to 7.79(2H)

Example 59

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -N-pyridin-2-cyclopropanecarboxamide

Experimental value MH⁺481.0, respectively; predictive value 481.1

¹H-NMR(CDCl₃): 1.28 to 1.34(2H), 1.75 to 1.82(2H), 4.10 to 4.31(2H), 7.09 to 7.14(1H), 7.73 to 7.78(2H), 7.81 to 7.87(1H), 8.14 to 8.19(1H), 8.28 to 8.32(1H), 9.47 to 9.60(1H)

Example 60

1- { 5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺447.0, respectively; predicted value 447.0

¹H-NMR(CDCl₃): 1.10 to 1.15(2H), 1.65 to 1.70(2H), 3.87 to 4.05(2H), 5.63 to 5.72(2H), 7.74 to 7.77(2H)

Example 61

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

Experimental value MH⁺459.0, respectively; predicted value 459.1

¹H-NMR (acetone-d)₆): 0.97 to 1.02(2H), 1.54 to 1.58(2H), 2.74 to 2.78(3H), 3.03 to 3.06(3H), 6.29 to 6.42(1H), 6.45 to 6.56(1H), 7.97 to 8.01(2H), 8.12 to 8.15(1H)

Example 62

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (2, 2, 2-trifluoroethyl) -cyclopropanecarboxamide

Experimental value MH⁺544.2, respectively; predicted value 544.0

¹H-NMR(d₆-DMSO): 0.96 to 1.01(2H), 1.44 to 1.49(2H), 3.82 to 3.93(2H), 6.17 to 6.24(2H), 7.24 to 7.29(1H), 8.40 to 8.42(2H)

Example 63

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- (methylamino) -1H-pyrazol-4-yl } -2, 2-difluoro-cyclopropanecarboxamide

Experimental value MH⁺470.2; predicted value 470.0

¹H-NMR(d₆-DMSO): 1.91 to 2.00(1H), 2.71 to 2.81(4H), 5.98 to 6.04(1H), 7.12 to 7.19(1H), 7.58 to 7.64(1H), 7.91 to 7.95(2H)

Example 64

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- (methylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺434.0, respectively; predicted value 434.0

¹H-NMR(d₆-DMSO): 1.03 to 1.07(2H), 1.44 to 1.48(2H), 2.78 to 2.82(3H), 5.87 to 5.92(1H), 6.39 to 6.45(1H), 7.20 to 7.26(1H), 7.90 to 7.93(2H)

Example 65

Experimental value MH⁺472.1, respectively; predicted value 472.1

¹H-NMR(d₆-DMSO): -0.01 to 0.05(2H), 0.26 to 0.32(2H), 0.83 to 0.88(1H), 0.95 to 1.00(2H), 1.39 to 1.44(2H), 2.55 to 2.60(3H), 2.88 to 2.94(2H), 5.84 to 5.89(1H), 7.10 to 7.16(1H), 8.20 to 8.24(2H)

Example 66

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-dimethylcyclopropanecarboxamide

Experimental value MH⁺432.0 parts; predicted value 432.1

¹H-NMR(CDCl₃): 1.03 to 1.14(3H), 1.24 to 1.32(1H), 1.32 to 1.38(3H), 1.42 to 1.52(1H), 4.72 to 4.93(2H), 5.39 to 5.52(1H), 5.79 to 5.92(1H), 7.74 to 7.80(2H)

Example 67

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (4H-1, 2, 4-triazol-3-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺543.2; predicted value 543.0

¹H-NMR(d₆-DMSO): 1.08 to 1.12(2H), 1.42 to 1.46(2H), 4.36 to 4.40(2H), 6.41 to 6.47(1H), 6.75 to 6.82(1H), 7.19 to 7.25(1H), 8.20 to 8.30(1H), 8.34 to 8.36(2H)

Example 68

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [ (1-methylcyclopropyl) methyl ] amino } -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺530.0; predicted value 530.1

¹H-NMR(d₆-DMSO): 0.00 to 0.04(2H), 0.14 to 0.18(2H), 0.79 to 0.83(3H), 0.88 to 0.93(2H), 1.29 to 1.34(2H), 2.94 to 2.98(2H), 5.58 to 5.64(1H), 6.28 to 6.38(1H), 6.99 to 7.09(1H), 8.26 to 8.29(2H)

Example 69

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- ({4- [ (methylamino) sulfonyl ] benzyl } amino) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺645.1, respectively; predicted value 645.0

¹H-NMR(d₆-acetone): 1.10 to 1.17(2H), 1.50 to 1.56(2H), 2.55 to 2.59(3H), 4.60 to 4.65(2H), 6.01 to 6.10(1H), 6.25 to 6.30(1H), 6.35 to 6.55(2H), 7.45 to 7.50(2H), 7.70 to 7.75(2H), 8.20 to 8.23(2H)

Example 70

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- ({4- [ (methylsulfonyl) amino ] benzyl } amino) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺645.2, respectively; predicted value 645.0

¹H-NMR(d₆-DMSO): 1.18 to 1.22(2H), 1.75 to 1.79(2H), 2.99 to 3.01(3H), 4.02 to 4.10(1H), 4.22 to 4.27(2H), 5.60 to 5.80(2H), 7.00 to 7.04(1H), 7.10 to 7.15(4H), 7.82 to 7.87(2H)

Example 71

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (tetrahydro-2H-pyran-4-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺560.2; predicted value 560.1

¹H-NMR(d₆-acetone): 1.00 to 1.10(2H), 1.18 to 1.21(2H), 1.55 to 1.60(4H), 1.60 to 1.75(1H), 3.15 to 3.25(4H), 3.78 to 3.81(2H), 5.40 to 5.50(1H), 6.35 to 6.60(2H), 8.21 to 8.24(2H)

Example 72

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (3-isopropoxypropyl) cyclopropanecarboxamide

Experimental value MH⁺616.0, respectively; predicted value 616.1

¹H-NMR(d₆-DMSO): 0.01 to 0.08(2H), 0.29 to 0.33(2H), 0.80 to 0.90(1H), 0.99 to 1.05(6H), 1.41 to 1.46(2H), 1.49 to 1.54(2H), 2.91 to 2.98(2H), 3.03 to 3.10(2H), 3.23 to 3.27(2H), 3.39 to 3.44(1H), 8.40 to 8.42(2H)

Example 73

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- ({ 2-oxo-2- [ (2, 2, 2-trifluoroethyl) amino ] ethyl } amino) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺601.1 of the total weight of the alloy; predicted value 601.0

¹H-NMR(d₆-DMSO): 0.90 to 1.00(2H), 1.30 to 1.39(2H), 3.80 to 4.00(2H), 6.00 to 6.10(2H), 6.90 to 7.00(2H), 8.55 to 8.65(2H)

Example 74

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

A stirred solution of preparative 96(250 mg, 0.60 mmol) and p-toluenesulfonic acid (250 mg, 1.32 mmol) in dichloromethane was saturated with methyl mercaptan (g) at room temperature. After stirring for 80 hours, the solution was transferred to a PTFE container and heated with stirring at 80 ℃ for 16 hours. The reaction mixture was concentrated in vacuo and dichloromethane was added to the residue. The solution was washed with aqueous sodium bicarbonate solution over MgSO₄Dried and concentrated in vacuo. The residue was purified using a Biotage column (silica, 10 × 2.5 cm) eluting with dichloromethane. The appropriate fractions were concentrated and acetonitrile/water (1 ml) was added to the residue. The solution was prepared by using a gradient of acetonitrile/water [ 55: 45 to 95: 5 ]]Purification was performed by automated preparative liquid chromatography (Gilson system, 250 mm. times.30 mm, Phenomenex LUNAC18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (19 mg).

Experimental value MH⁺442.9, respectively; predicted value 443.0

¹H-NMR(CDCl₃): 1.96 to 2.03(1H), 2.15 to 2.23(4H), 3.86 to 3.94(2H), 7.75 to 7.78(2H)

The compounds prepared in a similar manner were:

example 75

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (methylthio) cyclopropyl ] -1H-pyrazole-3-thiocarboxylic acid S-methyl ester obtained by preparation method 96

Experimental value MH⁺492.0; predictionValue 492.0

¹H-NMR(CDCl₃): 1.86 to 1.96(2H), 2.13 to 2.16(3H), 2.36 to 2.39(3H), 3.65 to 3.79(2H), 7.73 to 7.76(2H)

Example 76

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Trimethylaluminum (3.51 ml, 7.02 mmol) was added dropwise to a suspension of ammonium chloride (373 mg, 6.91 mmol) in toluene (20 ml) at 0 ℃. After stirring at 0 ℃ for 20 minutes and then at room temperature for 40 minutes, a solution of preparation 131(654 mg, 1.38 mmol) in toluene (10 ml) was added dropwise at 0 ℃. The reaction mixture was stirred at 50 ℃ for 18 h, followed by the addition of hydrochloric acid (2N, 15 ml) followed by brine (15 ml). The mixture was extracted with ethyl acetate (2 × 20 ml) and the combined extracts were concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by automated preparative liquid chromatography (Gilson system, 250 mm. times.30 mm, Phenomenex LUNA C18(2)10 micron column) using an acetonitrile: 0.1% trifluoroacetic acid gradient [ 50: 50 to 95: 5 ]. The appropriate fractions were concentrated in vacuo to give the title compound (500 mg).

MH according to the Experimental values⁺457.9, respectively; predicted value 458.1

¹H-NMR(CD₃OD): 0.06 to 0.11(2H), 0.37 to 0.43(2H), 0.88 to 0.99(1H), 1.19 to 1.24(2H), 1.59 to 1.63(2H), 3.02 to 3.06(2H), 7.98 to 8.01(2H)

The compounds prepared in a similar manner were:

examples of the invention	R9	Is obtained from
examples of the invention	R9	Is obtained from	Example 77	Benzylamino group	Example 115
Example 78	(pyridin-2-ylmethyl) amino	Preparation method 145	Example 77	Benzylamino group	Example 115
Example 78	(pyridin-2-ylmethyl) amino	Preparation method 145	Example 79	(2, 2-dimethylpropyl) amino group	Preparation method 115
Example 80	[4- (methylsulfonyl) -benzyl]Amino group	Preparation method 116	Example 79	(2, 2-dimethylpropyl) amino group	Preparation method 115
Example 80	[4- (methylsulfonyl) -benzyl]Amino group	Preparation method 116	Example 81	(pyridin-4-ylmethyl) amino	Preparation method 146
Example 82	(2, 2, 2-trifluoroethyl) amino group	Preparation method 147	Example 81	(pyridin-4-ylmethyl) amino	Preparation method 146
Example 82	(2, 2, 2-trifluoroethyl) amino group	Preparation method 147	Example 83	(1H-imidazol-2-ylmethyl) amino	Preparation method 148

Example 77

1- {5- (benzylamino) -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺494.0; predicted value 494.1

¹H-NMR(CDCl₃): 1.16 to 1.21(2H), 1.70 to 1.74(2H), 4.21 to 4.26(2H), 5.50 to 5.68(2H), 7.05 to 7.10(2H), 7.22 to 7.25(3H), 7.64 to 7.67(2H)

Example 78

1- { 3-cyano-1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -5- [ (pyridin-2-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺494.9; predicted value 495.1

¹H-NMR(CDCl₃): 1.25 to 1.29(2H), 1.74 to 1.79(2H), 4.48 to 4.55(2H), 5.41 to 5.48(1H), 5.77 to 5.83(1H), 7.20 to 7.23(1H), 7.25 to 7.35(1H), 7.71 to 7.80(3H), 8.37 to 8.41(1H)

Example 79

1- { 3-cyano-1- [2, 6-difluoro-4- (trifluoromethyl) phenyl ] -5- [ (2, 2-dimethylpropyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺474.0; predictive value 474.1

¹H-NMR(CDCl₃): 0.73 to 0.77(9H), 1.19 to 1.23(2H), 1.73 to 1.77(2H), 2.74 to 2.79(2H), 3.38 to 3.46(1H), 5.47 to 5.54(1H), 5.61 to 5.68(1H), 7.75 to 7.77(2H)

Example 80

1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [4- (methylsulfonyl) benzyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxamide

Experimental value MH⁺572.0; predicted value 572.1

¹H-NMR(CDCl₃): 1.17 to 1.22(2H), 1.66 to 1.72(2H), 2.94 to 2.98(3H), 4.13 to 4.22(1H), 4.37 to 4.42(2H), 5.55 to 5.69(2H), 7.26 to 7.31(2H), 7.67 to 7.71(2H), 7.74 to 7.79(2H)

Example 81

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- [ (pyridin-4-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺495.1, respectively; predicted value 495.1

¹H-NMR(d₆-DMSO): 0.94 to 0.99(2H), 1.36 to 1.41(2H), 4.38 to 4.42(2H), 6.52 to 6.56(1H), 6.56 to 6.61(1H), 7.16 to 7.21(3H), 8.16 to 8.18(2H), 8.40 to 8.43(2H)

Example 82

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- [ (2, 2, 2-trifluoroethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺485.9, respectively; predicted value 486.0

¹H-NMR(CDCl₃): 1.24 to 1.29(2H), 1.74 to 1.78(2H), 3.62 to 3.72(2H), 3.88 to 3.95(1H), 5.51 to 5.64(2H), 7.76 to 7.80(2H)

Example 83

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- [ (1H-imidazol-2-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺484.0, respectively; predicted value 484.1

¹H-NMR(CDCl₃): 1.47 to 1.52(2H), 1.55 to 1.61(2H), 4.75 to 4.83(2H), 5.72 to 5.82(1H), 6.06 to 6.18(1H), 7.20 to 7.22(2H), 7.62 to 7.66(2H)

Example 84

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide

A solution of tert-butylnitrile (30 μ l, 0.24 mmol) in acetonitrile (1 ml) was added to a solution of example 53(100 mg, 0.20 mmol) and copper (II) chloride (41 mg, 0.30 mmol) in acetonitrile (2 ml). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between ethyl acetate and water. Separating the organic phase over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/water (0.5 ml) and purified by using a gradient of acetonitrile/water [ 50: 50 to 95: 5 ] ]By automated preparative liquid chromatography (Gilson System, 150 mm. times.21.2 mm, Phenomenex LUNA C18(2)5 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (13 mg) and 5-chloro compound example 87.

Experimental value MH⁺4760; predicted value 476.0

¹H-NMR(CDCl₃): 1.95 to 2.03(1H), 2.85 to 2.94(1H), 5.53 to 5.68(1H), 5.73 to 5.86(1H), 7.80 to 7.84(1H), 7.91 to 7.95(2H)

The compounds prepared in a similar manner were:

example 85

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide from example 13

Experimental value MH of acetonitrile adduct⁺488.1, respectively; predicted value 488.0

¹H-NMR(CDCl₃): 1.18 to 1.25(2H), 1.74 to 1.80(2H), 5.32 to 5.53(1H), 5.88 to 6.05(1H), 7.66 to 7.70(1H), 7.89 to 7.94(2H)

Example 86

1- { 5-chloro-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

A solution of tert-butylnitrile (30 μ l, 0.26 mmol) in acetonitrile (1 ml) was added to an agitated solution of example 13(100 mg, 0.22 mmol) copper (II) chloride (43 mg, 0.32 mmol) in acetonitrile (2 ml). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between ethyl acetate and water. Separating the organic phase over MgSO ₄Dried and concentrated in vacuo. The residue is dissolved in dimethylSulfoxide/water (1.4 ml) and purified by using a gradient of acetonitrile/water [ 50: 50 to 95: 5%]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, Phenomenex LUNAC18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (20 mg).

Experimental value MH of acetonitrile adduct⁺522.0, respectively; predicted value 522.0

¹H-NMR(CDCl₃): 1.24 to 1.30(2H), 1.81 to 1.87(2H), 5.23 to 5.44(1H), 5.76 to 5.95(1H), 7.92 to 7.97(2H)

Example 87

1- { 5-chloro-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide

A solution of tert-butylnitrile (0.11 ml, 0.89 mmol) in acetonitrile (4 ml) was added to an agitated solution of example 53(370 mg, 0.74 mmol) and copper (II) chloride (250 mg, 1.85 mmol) in acetonitrile (17 ml). The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water, and the organic phase was separated over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/water (0.5 ml) and purified by using a gradient of acetonitrile/water [ 50: 50 to 95: 5 ] ]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (110 mg).

¹H-NMR(CDCl₃): 2.04 to 2.13(1H), 2.86 to 2.95(1H), 5.50 to 5.63(1H), 5.64 to 5.78(1H), 7.93 to 7.97(2H)

Example 88

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

Phosphorus oxychloride (0.78 ml, 8.33 mmol) was slowly added via syringe to a solution of acetic acid (0.1 ml) in acetonitrile (10 ml) at room temperature. After 10 minutes, 1.16 ml of this solution was added to a solution of preparative method 162(75 mg, 0.18 mmol) in acetonitrile (3 ml). The reaction mixture was heated at reflux for 2 hours, cooled to room temperature and quenched with aqueous sodium bicarbonate. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. Separating the organic phase over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (0.5 ml) and purified by automated preparative liquid chromatography using an acetonitrile: water gradient (Gilson system, 150 mm x 30 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (3 mg).

Experimental value MH⁺442.9, respectively; predicted value 443.0

¹H-NMR(CDCl₃): 1.57 to 1.61(2H), 1.72 to 1.77(2H), 2.47 to 2.51(3H), 4.05 to 4.10(2H), 7.77 to 7.80(2H)

Another method

Phosphorus oxychloride (0.20 ml, 2.15 mmol) was added to a solution of preparative 159(250 mg, 0.54 mmol) in acetonitrile (20 ml) at room temperature. The reaction mixture was heated at reflux for 2 hours, cooled to room temperature and quenched with aqueous sodium bicarbonate. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate (3 × 20 ml). To be combinedExtract over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (0.5 ml) and purified by automated preparative liquid chromatography using an acetonitrile: water gradient (Gilson system, 150 mm x 30 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (28 mg).

Experimental value MH⁺442.9, respectively; predicted value 443.0

¹H-NMR(CDCl₃): 1.69 to 1.77(2H), 2.13 to 2.18(2H), 2.45 to 2.51(3H), 4.02 to 4.09(2H), 7.73 to 7.79(2H)

Example 89

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-dimethylcyclopropanecarboxylic acid

Lithium iodide (1.00 g, 7.00 mmol) was added to a solution of preparative method 98(300 mg, 0.70 mmol) in pyridine (5 ml) at 125 ℃ and the reaction mixture was heated at 125 ℃ for 48 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between hydrochloric acid (10%) and dichloromethane. The two layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic phases were washed with water and brine₄Dried above and concentrated in vacuo to give the title compound (300 mg).

Experimental value MH⁺433.0, respectively; predicted value 433.1

¹H-NMR(d₆-acetone): 1.10 to 1.20(3H), 1.30 to 1.34(1H), 1.39 to 1.42(3H), 1.71 to 1.74(1H), 5.38 to 5.55(2H), 8.02 to 8.04(2H)

Example 90

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Lithium hydroxide monohydrate (4.00 g, 96.50 mmol) was added to a solution of preparative 163(4.74 g, 9.65 mmol) in tetrahydrofuran/water (4: 1, 100 ml). The reaction mixture was stirred at room temperature for 16 hours and then adjusted to pH1 by addition of hydrochloric acid (1M). The reaction mixture was extracted with ethyl acetate and the combined extracts were washed with water over MgSO ₄Dried and concentrated in vacuo. Ethyl chloroformate (1.5 ml, 16.2 mmol) was added to a solution of the residue and triethylamine (3.4 ml, 24.1 mmol) in tetrahydrofuran (100 ml) at 0 ℃. After 20 minutes at 0 ℃, the mixture was warmed to room temperature and stirred for one hour. Anhydrous ammonia (gas) was bubbled through the reaction mixture for 15 minutes, followed by nitrogen bubbling through the reaction mixture for 3 minutes. The reaction mixture was then partitioned between ethyl acetate and hydrochloric acid (1M) and the organic phase was separated, washed with water and over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by using a gradient of acetonitrile: water [ 45: 55 to 95: 5 ]]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.50 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (3289 mg).

Experimental value MH⁺475.9; predicted value 476.0

¹H-NMR(CDCl₃): 1.26 to 1.30(2H), 1.76 to 1.81(2H), 2.88 to 2.92(3H), 3.54 to 3.76(1H), 5.65 to 5.75(2H), 7.91 to 7.94(2H)

Example 91

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (difluoromethyl) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Lithium hydroxide monohydrate (155 mg, 3.70 mmol) was added to a solution of preparative 190(190 mg, 0.37 mmol) in tetrahydrofuran/water (4: 1, 3.7 ml). The reaction mixture was stirred at room temperature for 24 hours, acidified with hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with water over MgSO₄Dried and concentrated in vacuo to give the acid. Triethylamine (160 μ l, 1.11 mmol) and ethyl chloroformate (53 μ l, 0.56 mmol) were added to a solution of the acid in tetrahydrofuran (3.7 ml) at 0 ℃. After stirring for 30 minutes, ammonium hydroxide (3 ml) was added and the solution was warmed to room temperature. The reaction mixture was adjusted to pH1 by addition of hydrochloric acid (1M) and then extracted with ethyl acetate. The combined extracts were washed with water and over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by using a gradient of acetonitrile: water [ 60: 40 to 95: 5 ]]By automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, PhenomenexLUNA C18(2)10 micron column). The appropriate fractions were combined and concentrated to give the title compound (172 mg).

¹H-NMR(d₆-DMSO): 1.10 to 1.21(2H), 1.55 to 1.62(2H), 6.70 to 6.85(1H), 7.10 to 7.22(1H), 7.10 to 7.40(1H), 8.56 to 8.59(2H)

Example 92

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } carbamic acid cyclopropylmethyl ester

Lithium hydroxide monohydrate (218 mg, 5.20 mmol) was added to a solution of preparative 184(310 mg, 0.52 mmol) in tetrahydrofuran/water (4: 1, 5.2 ml) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was acidified with hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with water and over MgSO₄Dried and concentrated in vacuo. Triethylamine (158 μ l, 1.30 mmol) and ethyl chloroformate (60 μ l, 0.62 mmol) were added to a solution of the residue in tetrahydrofuran (5.20 ml) at 0 ℃. After stirring for 30 min, aqueous ammonium hydroxide (3 ml) was added and the reaction mixture was warmed to room temperature. The reaction mixture was adjusted to pH1 by addition of hydrochloric acid (1M) and then extracted with ethyl acetate. The combined extracts were washed with water and over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by using a gradient of acetonitrile: water [ 50: 50 to 95: 5 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.50 mm, LUNA C18(2)10 μm column). The appropriate fractions were combined and concentrated to give the title compound (110 mg).

Experimental value MH⁺560.0; predicted value 560.0

¹H-NMR(d₆-DMSO): -0.00 to 0.04(2H), 0.24 to 0.29(2H), 0.80 to 0.86(3H), 1.25 to 1.29(2H), 3.65 to 3.69(2H), 6.21 to 6.29(1H), 6.97 to 7.03(1H), 8.33 to 8.35(2H), 9.85 to 9.92(1H)

Example 93

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } methyl carbamic acid ethyl ester

Lithium hydroxide monohydrate (193 mg, 4.60 mmol) was added to a solution of preparative method 193(257 mg, 0.46 mmol) in tetrahydrofuran/water (4: 1, 4.6 ml) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was acidified with hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with water and over MgSO₄Dried and concentrated in vacuo. Triethylamine (160 μ l, 1.15 mmol) and ethyl chloroformate (53 μ l, 0.55 mmol) were added to a solution of the residue in tetrahydrofuran (4.60 ml) at 0 ℃. After stirring for 30 min, aqueous ammonium hydroxide (3 ml) was added and the reaction mixture was warmed to room temperature. The reaction mixture was adjusted to pH1 by addition of hydrochloric acid (1M) and then extracted with ethyl acetate. The combined extracts were washed with water and over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (3 ml) and purified by using a gradient of acetonitrile: water [ 55: 45 to 95: 5 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C18(2)10 μm column). The appropriate fractions were combined and concentrated to give the title compound (96 mg).

Experimental value MH⁺548.0, respectively; predicted value 548.0

¹H-NMR(CDCl₃): 1.09 to 1.22(5H), 1.59 to 1.82(2H), 3.12 to 3.15(3H), 4.07 to 4.18(2H), 5.46 to 6.04(2H), 7.89 to 7.92(2H)

Example 94

1- [ ({4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } amino) methyl ] cyclopropanecarboxamide

Lithium hydroxide monohydrate (118 mg, 2)80 mmol) was added to a solution of preparation 229(83 mg, 0.14 mmol) in tetrahydrofuran/water (4: 1, 2.80 ml) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was acidified with hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with water and over MgSO₄Dried and concentrated in vacuo. Triethylamine (100 μ l, 0.73 mmol) and ethyl chloroformate (33 μ l, 0.35 mmol) were added to a solution of the residue in tetrahydrofuran (2.80 ml) at 0 ℃. After stirring for 30 min, aqueous ammonium hydroxide (1 ml) was added and the reaction mixture was warmed to room temperature. The reaction mixture was adjusted to pH1 by addition of hydrochloric acid (1M) and then extracted with ethyl acetate. The combined extracts were washed with water and over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by using a gradient of acetonitrile: water [ 40: 60 to 98: 2 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C18(2)10 μm column). The appropriate fractions were combined and concentrated to give the title compound (33 mg).

Experimental value MH⁺559.1, respectively; predicted value 559.1

¹H-NMR(d₆-DMSO): 0.60 to 0.64(2H), 0.90 to 0.94(2H), 1.03 to 1.07(2H), 1.44 to 1.48(2H), 3.35 to 3.38(2H), 5.76 to 5.81(1H), 6.68 to 6.77(2H), 6.82 to 6.88(1H), 7.16 to 7.21(1H), 8.41 to 8.43(2H)

Example 95

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5-methyl-1H-pyrazol-4-yl } cyclopropanecarboxamide

Lithium hydroxide monohydrate (350 mg, 0.84 mmol) was added to preparative 165(40 mg, 0.08 mmol) in tetrahydrofuranIn water (4: 1, 2 ml). The reaction mixture was stirred at room temperature for 16 hours and then adjusted to pH1 by the addition of hydrochloric acid (1M). The reaction mixture was extracted with ethyl acetate and the combined extracts were washed with water over MgSO₄Dried and concentrated in vacuo. Ethyl chloroformate (9 μ l, 0.09 mmol) was added to a solution of the residue and triethylamine (29 μ l, 0.21 mmol) in tetrahydrofuran (1 ml) at 0 ℃. After 20 minutes at 0 ℃, the mixture was warmed to room temperature and stirred for one hour. Anhydrous ammonia (gas) was bubbled through the reaction mixture for 15 minutes, followed by nitrogen bubbling through the reaction mixture for 3 minutes. The reaction mixture was then partitioned between ethyl acetate and hydrochloric acid (1M) and the organic phase was separated, washed with water and over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (0.3 ml) and purified by using a gradient of acetonitrile: water [ 60: 40 to 95: 5 ]]By automated preparative liquid chromatography (Gilson System, 150 mm. times.30 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (12 mg).

Experimental value MH⁺461.0, respectively; predicted value 461.0

¹H-NMR(CDCl₃): 1.18 to 1.23(2H), 1.79 to 1.84(2H), 2.17 to 2.22(3H), 5.30 to 5.45(1H), 5.53 to 5.65(1H), 7.92 to 7.96(2H)

Example 96

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } -cyclopropanecarboxamide

Lithium hydroxide monohydrate (575 mg, 13.70 mmol) was added to the reaction mixture of preparative 111(670 mg, 1.37 mmol) in tetrahydrofuran/water (4: 1,14 ml) was added. The reaction mixture was stirred at room temperature for 16 hours and then adjusted to pH1 by addition of hydrochloric acid (1M). The reaction mixture was extracted with ethyl acetate and the combined extracts were washed with water over MgSO₄Dried and concentrated in vacuo. Ethyl chloroformate (0.16 ml, 1.64 mmol) was added to a solution of the residue and triethylamine (0.48 ml, 3.43 mmol) in tetrahydrofuran (14 ml) at 0 ℃. After 20 minutes at 0 ℃, the mixture was warmed to room temperature and stirred for one hour. Anhydrous ammonia (gas) was bubbled through the reaction mixture for 15 minutes, followed by nitrogen bubbling through the reaction mixture for 3 minutes. The reaction mixture was then partitioned between ethyl acetate and hydrochloric acid (1M) and the organic phase was separated, washed with water and over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (1 ml) and purified by using a gradient of acetonitrile: water [ 55: 45 to 98: 2 ]]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.50 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (465 mg).

Experimental value MH⁺474.0; predictive value 474.1

¹H-NMR(d₆-DMSO): -0.01 to 0.05(2H), 0.24 to 0.30(2H), 0.81 to 0.90(1H), 0.95 to 1.01(2H), 1.37 to 1.43(2H), 2.89 to 2.95(2H), 5.74 to 5.79(1H), 6.40 to 6.48(1H), 7.10 to 7.20(1H), 7.85 to 7.88(2H)

Example 97

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-fluoro-2-methylpropyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Lithium hydroxide monohydrate (54 mg, 1.29 mmol) was addedTo a solution of preparative method 134(71 mg, 0.13 mmol) in tetrahydrofuran/water (4: 1, 2 ml) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was acidified to pH1 by addition of hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with brine, over MgSO₄Dried and concentrated in vacuo. Triethylamine (45 μ l, 0.32 mmol) and ethyl chloroformate (15 μ l, 0.16 mmol) were added to a solution of the residue in tetrahydrofuran (2 ml) at 0 ℃. After stirring for 30 min, aqueous ammonium hydroxide (1 ml) was added and the reaction mixture was warmed to room temperature. The reaction mixture was adjusted to pH1 by addition of hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with brine, over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by using a gradient of acetonitrile: water [ 55: 45 to 98: 2 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.4.6 mm, LUNA C18(2)5 μm column). The appropriate fractions were concentrated in vacuo to give the title compound (34 mg).

Experimental value MH⁺535.9, respectively; predicted value 536.1

¹H-NMR(d₆-DMSO): 1.00 to 1.10(2H), 1.15 to 1.25(6H), 1.60 to 1.70(2H), 3.35 to 3.40(2H), 8.38 to 8.41(2H)

Example 98

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } carbamic acid methyl ester

Lithium hydroxide monohydrate (248 mg, 5.90 mmol) was added to a solution of preparative method 185(318 mg, 0.59 mmol) in tetrahydrofuran/water (4: 1, 5.9 ml) and the reaction mixture was stirred at room temperatureFor 24 hours. The reaction mixture was acidified with hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with water and over MgSO₄Dried and concentrated in vacuo. Triethylamine (0.21 μ l, 1.48 mmol) and ethyl chloroformate (68 μ l, 0.71 mmol) were added to a solution of the residue in tetrahydrofuran (5.90 ml) at 0 ℃. After stirring for 30 min, aqueous ammonium hydroxide (5 ml) was added and the reaction mixture was warmed to room temperature. The reaction mixture was adjusted to pH1 by addition of hydrochloric acid (1M) and then extracted with ethyl acetate. The combined extracts were washed with water and over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by using a gradient of acetonitrile: water [ 45: 55 to 95: 5 ]]Was purified by preparative liquid chromatography (Gilson System, 150 mm. times.30 mm LUNA C18(2)10 micron column). The appropriate fractions were combined and concentrated to give the title compound (169 mg).

Experimental value MH⁺520.0 of the total weight of the alloy; predicted value 520.0

¹H-NMR(d₆-DMSO): 1.54 to 1.58(2H), 1.95 to 1.99(2H), 4.06 to 4.08(3H), 6.68 to 6.92(2H), 8.72 to 8.73(2H)

Example 99

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide

Preparation 93(500 mg, 1.06 mmol) was added to a solution of lithium hydroxide monohydrate (415 mg, 10.60 mmol) in water (4 ml) and tetrahydrofuran (16 ml). The reaction mixture was stirred at room temperature for 4 hours, acidified with hydrochloric acid (concentrated) and extracted with ethyl acetate. The combined extracts were extracted over MgSO₄Dried and concentrated in vacuo to give the acid. At 0 deg.CEthyl chloroformate (114 μ l, 1.20 mmol) was added to a solution of the acid (500 mg, 1.09 mmol) in tetrahydrofuran (15 ml) and triethylamine (379 μ l, 2.73 mmol). After stirring for 20 minutes, the reaction mixture was warmed to room temperature and stirred for one hour. Ammonium hydroxide (0.5 ml, 5.45 mmol) was added to the reaction mixture and the solution was stirred for 15 minutes and then nitrogen (gas) was bubbled through it for 5 minutes. The reaction mixture was adjusted to pH1 by addition of hydrochloric acid and then extracted with ethyl acetate. The combined extracts were washed with sodium hydroxide solution and the mixture was washed with brine, over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (1 ml) and purified by using a gradient of acetonitrile: water [ 45: 55 to 95: 5 ]]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were combined and concentrated to give the title compound (62 mg).

Experimental value MH⁺455.9; predicted value 456.0

¹H-NMR(d₆-DMSO): 1.74 to 1.82(1H), 2.49 to 2.58(1H), 6.19 to 6.27(2H), 7.12 to 7.19(1H), 7.44 to 7.51(1H), 7.89 to 7.93(2H)

Example 100

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } carbamic acid ethyl ester

Lithium hydroxide monohydrate (360 mg, 8.60 mmol) was added to a solution of preparative 188(474 mg, 0.86 mmol) in tetrahydrofuran/water (4: 1, 8.6 ml) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was acidified with hydrochloric acid (1M) and extracted with ethyl acetate. Mixing the extracts with waterWashing over MgSO 4₄Dried and concentrated in vacuo. Triethylamine (0.30 μ l, 2.15 mmol) and ethyl chloroformate (0.98 μ l, 1.03 mmol) were added to a solution of the residue in tetrahydrofuran (8.6 ml) at 0 ℃. After stirring for 30 min, aqueous ammonium hydroxide (5 ml) was added and the reaction mixture was warmed to room temperature. The reaction mixture was adjusted to pH1 by addition of hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with water and over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (1.3 ml) and purified by using a gradient of acetonitrile: water [ 45: 55 to 95: 5 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.50 mm, LUNA C18(2)10 μm column). The appropriate fractions were combined and concentrated to give the title compound (396 mg).

Experimental value MH⁺534.3, respectively; predicted value 534.0

¹H-NMR (DMSO): 0.93 to 0.97(2H), 1.03 to 1.07(3H), 1.36 to 1.41(2H), 3.93 to 4.01(2H), 6.40 to 6.50(1H), 7.07 to 7.14(1H), 8.45 to 8.47(2H), 9.92 to 9.96(1H)

The compounds prepared in a similar manner were:

examples of the invention	R1	R9	Is obtained from
examples of the invention	R1	R9	Is obtained from	Example 101	SF₅	(Cyclopropylmethoxycarbonyl) (methyl) amino	Preparation method 194
Example 102	SF₅	(4, 4, 4-trifluorobutyl) amino group	Preparation method 127	Example 101	SF₅	(Cyclopropylmethoxycarbonyl) (methyl) amino	Preparation method 194
Example 102	SF₅	(4, 4, 4-trifluorobutyl) amino group	Preparation method 127	Example 103	SF₅	Ethylamino group	Preparation method 128
Example 104	SF₅	(1-tert-BOC-amino-cyclopropyl) methylamino	Preparation method 205	Example 103	SF₅	Ethylamino group	Preparation method 128
Example 104	SF₅	(1-tert-BOC-amino-cyclopropyl) methylamino	Preparation method 205	Example 105	CF₃	(4-trifluoromethyl) benzylamino	Preparation method 124
Example 106	SF₅	Cyclopropyl methoxy group	Preparation method 65	Example 105	CF₃	(4-trifluoromethyl) benzylamino	Preparation method 124
Example 106	SF₅	Cyclopropyl methoxy group	Preparation method 65	Example 107	SF₅	Isopropoxyethylamino	Preparation method 136
Example 108	SF₅	Vinyl radical	Preparation method 227	Example 107	SF₅	Isopropoxyethylamino	Preparation method 136
Example 108	SF₅	Vinyl radical	Preparation method 227	Example 109	SF₅	Cyclobutyloxycarbonylamino	Preparation method 186
Example 110	CN	NH₂	Preparation method 173	Example 109	SF₅	Cyclobutyloxycarbonylamino	Preparation method 186
Example 110	CN	NH₂	Preparation method 173	Example 111	SF₅	(4-fluoro) benzylamino	Preparation method 117
Example 112	SF₅	Methoxymethyl group	Preparation method 197	Example 111	SF₅	(4-fluoro) benzylamino	Preparation method 117

Example 101

Cyclopropylmethyl {4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } methylcarbamate

Experimental value MH⁺574.2; predicted value 574.1

¹H-NMR(CDCl₃): 0.10 to 0.21(2H), 0.40 to 0.50(2H), 0.90 to 1.00(1H), 1.05 to 1.25(2H), 1.70 to 1.90(2H), 3.10 to 3.12(3H), 3.90 to 3.99(2H), 7.92 to 7.95(2H)

Example 102

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (4, 4, 4-trifluorobutyl) amino ] -1H-pyrazol-4-yl } -cyclopropanecarboxamide

Experimental value MH⁺571.9, respectively; predicted value of 572.0

¹H-NMR(d₆-DMSO): 0.95 to 1.01(2H), 1.39 to 1.42(2H), 1.50 to 1.60(2H), 2.05 to 2.20(2H), 3.18 to 3.25(2H), 8.39 to 8.41(2H)

Example 103

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (ethylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺489.8; predicted value 490.0

¹H-NMR(d₆-acetone): 1.01 to 1.09(3H), 1.15 to 1.18(2H), 1.65 to 1.68(2H), 3.30 to 3.40(2H), 5.24 to 5.32(1H), 6.30 to 6.50(2H), 8.20 to 8.22(2H)

Example 104

{1- [ ({4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } amino) methyl ] cyclopropyl } carbamic acid tert-butyl ester

Experimental value MH⁺631.4, respectively; predicted value 631.1

Example 105

1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [4- (trifluoromethyl) benzyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxamide

Experimental value MH⁺562.0, respectively; predicted value 562.1

¹H-NMR(CDCl₃): 1.19 to 1.23(2H), 1.70 to 1.74(2H), 4.01 to 4.20(1H), 4.29 to 4.33(2H), 5.59 to 5.70(2H), 7.18 to 7.22(2H), 7.42 to 7.46(2H), 7.60 to 7.62(2H)

Example 106

1- { 3-cyano-5- (cyclopropylmethoxy) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺517.3, respectively; predicted value 517.0

¹H-NMR(CDCl₃): 0.18 to 0.22(2H), 0.50 to 0.60(2H), 1.00 to 1.10(1H), 1.25 to 1.30(2H), 1.78 to 1.82(2H), 4.15 to 4.20(2H), 5.60 to 5.70(2H), 7.89 to 7.92(2H)

Example 107

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-isopropoxyethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺548.1, respectively; predicted value 548.1

¹H-NMR(d₆-acetone): 0.98 to 1.03(6H), 1.15 to 1.21(2H), 1.58 to 1.61(2H), 3.40 to 3.55(5H), 5.13 to 5.20(1H), 6.30 to 6.50(2H), 8.26 to 8.30(2H)

Example 108

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5-vinyl-1H-pyrazol-4-yl } cyclopropanecarboxamide

¹H-NMR(d₆-acetone): 1.16 to 1.20(2H), 1.67 to 1.72(2H), 5.65 to 5.70(1H), 5.82 to 5.88(1H), 6.21 to 6.32(1H), 6.45 to 6.58(2H), 8.32 to 8.36(2H)

Example 109

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } carbamic acid cyclobutyl ester

Experimental value MH⁺560.0; predicted value 560.0

¹H-NMR(d₆-DMSO): 1.54 to 1.60(2H), 1.94 to 2.08(3H), 2.10 to 2.20(1H), 2.33 to 2.44(2H), 2.61 to 2.71(2H), 5.22 to 5.31(1H), 6.66 to 6.92(2H), 8.70 to 8.75(2H), 9.33 to 9.45(1H)

Example 110

1- [ 5-amino-3-cyano-1- (2, 6-dichloro-4-cyanophenyl) -1H-pyrazol-4-yl ] cyclopropanecarboxamide

Experimental value MH⁺361.3, respectively; predicted value 361.0

¹H-NMR(d₆-DMSO): 0.85 to 0.90(2H), 1.38 to 1.42(2H), 6.10 to 6.20(3H), 8.38 to 8.40(2H)

Example 111

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (4-fluorobenzyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺570.0; predicted value 570.0

¹H-NMR(CDCl₃): 1.12 to 1.17(2H), 1.66 to 1.71(2H), 3.89 to 4.03(1H), 4.15 to 4.20(2H), 5.48 to5.64(2H), 6.85 to 6.92(2H), 6.97 to 7.03(2H), 7.72 to 7.75(2H)

Example 112

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methoxymethyl) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Experimental value MH⁺491.0, respectively; predicted value 491.0

¹H-NMR(d₆-acetone): 1.01 to 1.05(2H), 1.52 to 1.57(2H), 4.16 to 4.20(3H), 5.41 to 5.46(2H), 6.30 to 6.43(2H), 8.06 to 8.10(2H)

Example 113

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-5-yl } carbamic acid ethyl ester

Lithium hydroxide monohydrate (311 mg, 7.40 mmol) was added to a solution of preparative 183(379 mg, 0.74 mmol) in tetrahydrofuran/water (4: 1, 7.4 ml). The reaction mixture was stirred at room temperature for 4 hours, acidified with hydrochloric acid (concentrated) and extracted with ethyl acetate. The combined extracts were washed with water and over MgSO₄Dried and concentrated in vacuo to give the acid. Triethylamine (260 μ l, 1.85 mmol) and ethyl chloroformate (85 μ l, 0.89 mmol) were added to a solution of the acid in tetrahydrofuran (3.2 ml) at 0 ℃. After stirring for 30 minutes, ammonium hydroxide (3 ml) was added and the solution was warmed to room temperature. The reaction mixture was adjusted to pH1 by addition of hydrochloric acid (1M) and then extracted with ethyl acetate. The combined extracts were washed with water and over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by using a gradient of acetonitrile: water [ 45: 55 to 95: 5 ]]Automated preparative liquid chromatography of(Gilson System, 150 mm. times.30 mm, Phenomenex LUNAC18(2)10 micron column). The appropriate fractions were combined and concentrated to give the title compound (182 mg).

¹H-NMR(CDCl₃): 1.15 to 1.23(5H), 1.68 to 1.74(2H), 4.07 to 4.14(2H), 5.60 to 5.79(2H), 6.67 to 7.01(1H), 7.75 to 7.79(2H)

Example 114

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

A mixture of example 13(276 mg, 0.59 mmol), 4 Å molecular sieve, p-toluenesulfonic acid (2 mg), and cyclopropanecarboxaldehyde (134 μ l, 1.79 mmol) in toluene (10 ml) was heated in a sealed tube at 90 ℃ for 4 days. The reaction mixture was cooled to room temperature, washed with aqueous sodium bicarbonate (10%, 10 ml) and extracted with ethyl acetate (3 × 10 ml). The combined extracts were extracted over MgSO₄Dried and concentrated in vacuo. Sodium borohydride (20 mg, 0.53 mmol) was added to a solution of the residue (250 mg, 0.49 mmol) in methanol (10 ml) at 0 ℃ under nitrogen. The reaction mixture was then warmed to room temperature and stirred for 2 hours. Brine was added to the reaction mixture and the mixture was extracted with ethyl acetate (3 × 10 ml). The combined extracts were then extracted over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (4 ml) and purified by using a gradient of acetonitrile: water [ 55: 45 to 95: 5 ]]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (93 mg).

Experimental value MH⁺516.0；Predicted value 516.0

¹H-NMR(d₆-DMSO): -0.02 to 0.04(2H), 0.24 to 0.31(2H), 0.82 to 0.90(1H), 0.94 to 1.00(2H), 1.35 to 1.41(2H), 2.91 to 2.99(2H), 5.83 to 5.89(1H), 6.45 to 6.52(1H), 7.10 to 7.17(1H), 8.34 to 8.39(2H)

Another preparation method

O-benzotriazol-1-yl-N, N' -tetramethylammonium hexafluorophosphate (4.00 g, 10.50 mmol) and triethylamine (2.0 ml, 14.00 mmol) were added to a solution of preparation 6(3.60 g, 7.00 mmol) in acetonitrile (50 ml). The mixture was stirred at room temperature under nitrogen for 20 minutes, then hexamethyldisilazane (5.90 ml, 28.00 mmol) was added. The reaction mixture was stirred at room temperature for another 18 hours, then hydrochloric acid (2N, 50 ml) was added. After stirring for one hour, the mixture was diluted with water and extracted with ethyl acetate (2 × 150 ml). The combined extracts were washed with aqueous sodium hydroxide (2N), water and saturated brine solution over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by using a gradient of acetonitrile: water [ 50: 50 to 95: 5 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.50 mm, Sunfire LUNA C18(2)10 μm column). The appropriate fractions were concentrated in vacuo to give the title compound (911 mg).

Experimental value MH⁺515.9; predicted value 516.0

¹H-NMR (CDCl₃): -0.01 to 0.05(2H), 0.38 to 0.44(2H), 0.77 to 0.86(1H), 1.12 to 1.17(2H), 1.65 to 1.70(2H), 2.78 to 2.82(2H), 5.47 to 5.63(2H), 7.80 to 7.84(2H)

In a similar manner, the compounds are prepared as

Example 115

1- {5- (benzylamino) -3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester from preparation 152

Experimental value MH⁺508.8 of the total weight of the mixture; predicted value 509.1

¹H-NMR(CDCl₃): 1.21 to 1.25(2H), 1.62 to 1.67(2H), 3.60 to 3.61(3H), 3.78 to 3.82(1H), 4.12 to 4.17(2H), 7.07 to 7.10(2H), 7.19 to 7.23(3H), 7.60 to 7.61(2H)

Example 116

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide from preparation 150

Experimental value MH⁺552.1; predicted value 552.0

¹H-NMR(d₆-DMSO): 0.77 to 0.87(1H), 1.79 to 1.88(1H), 2.66 to 2.74(1H), 2.76 to 2.83(1H), 2.88 to 2.96(1H), 5.97 to 6.02(1H), 7.23 to 7.27(1H), 7.54 to 7.58(1H), 8.38 to 8.41(2H)

Example 117

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide from preparation 157

Experimental value MH⁺494.2; predicted value 494.1

Example 118

4- (1-cyanocyclopropyl) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazole-3-carbonitrile

Sodium borohydride (36 mg, 0.94 mmol) was added to a solution of preparative 141(209 mg, 0.43 mmol) in ethanol (4 ml) and 1, 4-dioxane (1 ml). The reaction mixture was stirred at room temperature for 10 hours, and then quenched with hydrochloric acid (2N). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer was separated, washed with brine, over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by using a gradient of acetonitrile: water [ 60: 40 to 95: 5 ]]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (86 mg).

Experimental value MH⁺457.9, respectively; predicted value 458.0

¹H-NMR(CDCl₃): 1.52 to 1.57(2H), 1.76 to 1.83(2H), 3.06 to 3.13(3H), 3.47 to 3.59(1H), 7.90 to 7.94(2H)

Example 119

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic sulfamide

Lawesson's reagent (2, 4-bis (4-methoxyphenyl) -1, 3-disulfide-2, 4-disulfide, 240 mg, 0.59 mmol) was added to a solution of example 2(400 mg, 0.99 mmol) in tetrahydrofuran (32 ml) under nitrogen. The reaction mixture was heated to reflux for 3 hours, cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate (. times.3) and the combined extracts were extractedExtracting with MgSO 2₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1.2 ml) and purified by using a gradient of acetonitrile: water [ 45: 55 to 95: 5 ]]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (64 mg).

¹H-NMR(CDCl₃): 1.36 to 1.41(2H), 2.03 to 2.08(2H), 3.99 to 4.08(2H), 6.89 to 6.97(1H), 7.38 to 7.48(1H), 7.76 to 7.79(2H)

Example 120

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

A mixture of example 119(100 mg, 0.24 mmol) and chloroacetaldehyde (22 mg, 0.28 mmol) in N, N-dimethylformamide (2 ml) was heated at 90 ℃ for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (× 3). The combined extracts were extracted over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (2 ml) and purified by using a gradient of acetonitrile: water [ 50: 50 to 98: 2 ]]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (10 mg).

Experimental value MH⁺444.0, respectively; predicted value 444.0

¹H-NMR(CDCl₃): 1.50 to 1.56(2H), 1.83 to 1.89(2H), 4.00 to 4.10(2H), 7.10 to 7.14(1H), 7.61 to 7.66(1H), 7.77 to 7.81(2H)

Example 121

1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (1-oxidopyridin-4-yl) methyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxamide

3-chloroperoxybenzoic acid (77%, 38 mg, 0.17 mmol) was added to a solution of example 81(57 mg, 0.12 mmol) in dichloromethane (0.5 ml). The reaction mixture was stirred at room temperature for 48 hours, and then an aqueous sodium bicarbonate solution was added. The organic layer was separated, washed with water and MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (0.4 ml) and purified by using a gradient of acetonitrile: water [ 30: 70 to 95: 5 ]]Purification was performed by automated preparative liquid chromatography (Gilson system, 250 mm. times.21.2 mm, Phenomenex LUNA C18(2)5 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (14 mg).

Experimental value MH⁺511.1, respectively; predicted value 511.1

¹H-NMR(CDCl₃): 1.23 to 1.28(2H), 1.72 to 1.77(2H), 4.25 to 4.29(1H), 4.33 to 4.37(2H), 5.54 to 5.68(2H), 7.03 to 7.08(2H), 7.75 to 7.78(2H), 8.02 to 8.07(2H)

Example 122

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -N- (methylsulfonyl) -cyclopropanecarboxamide

Sodium hydride (60% in oil, 9 mg, 0.22 mmol) was added to a solution of example 13(100 mg, 0.22 mmol) in N, N-dimethylformamide (1.1 ml). After stirring for 20 min, methanesulfonyl chloride (34 μ l, 0.44 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was then partitioned between ethyl acetate and brine, and the organic layer was separated, washed with water, and over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (2.4 ml) and purified by using a gradient of acetonitrile: water [ 50: 50 to 95: 5 ] ]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give 52 mg of the title compound).

MH according to the Experimental values⁺540.0; predicted value 540.0

¹H-NMR(d₆-DMSO): 1.61 to 1.65(2H), 1.93 to 1.98(2H), 3.11 to 3.14(3H), 5.43 to 5.50(2H), 8.05 to 8.06(2H), 10.40 to 10.43(1H)

Example 123

1- { 3-cyano-5- [ (2-cyclopropylethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Cyclopropylacetaldehyde (54 mg, 0.64 mmol), p-toluenesulfonic acid (3 mg) and 4 Å molecular sieve (120 mg) were added to a solution of example 13(150 mg, 0.32 mmol) in toluene (3.2 ml). After stirring for 16 hours, the mixture was filtered, washed with toluene and concentrated in vacuo. The residue was dissolved in ethanol and the solution was cooled to 0 ℃. Sodium borohydride (27 mg) was added and the mixture was stirred at 0 ℃ for 15 minutes and then quenched with hydrochloric acid (1M)And (4) reacting. The mixture was extracted with ethyl acetate and the combined extracts were over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1.2 ml) and purified by using a gradient of acetonitrile: 0.1% trifluoroacetic acid [ 60: 40 to 95: 5 ] ]Purification was performed by automated preparative liquid chromatography (Gilson system, 150 mm. times.21.2 mm, Phenomenex LUNAC18(2)5 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (1.5 mg).

Experimental value MH⁺530.0; predicted value 530.1

Example 124

1 '- [2, 6-dichloro-4-pentafluorothiophenyl ] -7' -methyl-5 '-oxo-5', 6 ', 7', 8 '-tetrahydro-1' H-spiro [ cyclopropane-1, 4 '-pyrazolo [3, 4-d ] [1, 3] diazepine ] -3' -carbonitrile

Acetaldehyde (0.18 ml, 3.2 mmol), p-toluenesulfonic acid (3 mg) and 4 Å molecular sieve (120 mg) were added to a solution of example 13(150 mg, 0.32 mmol) in toluene (3.2 ml). After stirring for 16 hours, the mixture was filtered, washed with dichloromethane and concentrated in vacuo. The residue was dissolved in ethanol (6 ml) and the solution was cooled to 0 ℃. Sodium borohydride (20 mg) was added and the mixture was stirred at 0 ℃ for one hour, then quenched with hydrochloric acid (1M). The mixture was extracted with ethyl acetate and the combined extracts were over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/water (9: 1, 1.2 ml) and purified by using a gradient of acetonitrile/water [ 45: 55 to 95: 5 ] ]By automated preparative liquid chromatography (Gilson System, 150 mm. times.30 mm Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (51 mg).

Experimental value MH⁺488.1, respectively; preparation ofMeasured value 488.0

¹H-NMR(d₆-DMSO): 0.93 to 0.99(1H), 1.09 to 1.16(1H), 1.29 to 1.34(3H), 1.55 to 1.62(1H), 1.78 to 1.85(1H), 5.31 to 5.40(1H), 6.99 to 7.03(1H), 8.25 to 8.30(1H), 8.44 to 8.50(2H)

Example 125

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

3-Chloroperoxybenzoic acid (77%, 53 mg, 0.25 mmol) was added to a solution of example 74(100 mg, 0.23 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 18 h, diluted with dichloromethane (10 ml) and washed with saturated aqueous sodium bicarbonate (2 × 5 ml). The organic layer was separated over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (1: 1, 1 ml) and purified by using a gradient of acetonitrile: water [ 45: 55 to 95: 5 ]]Purification was performed by automated preparative liquid chromatography (Gilson system, 250 mm. times.30 mm, Phenomenex LUNAC18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (9 mg) and the second diastereomer.

Experimental value MH⁺459.0, respectively; predicted value 459.0

The compounds prepared in a similar manner were:

example 126

5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [2, 2-difluoro-1- (methylsulfinyl) cyclopropyl ] -1H-pyrazole-3-carbonitrile from example 74

Experimental value MH⁺459.0, respectively; predicted value 459.0

¹H-NMR(CDCl₃): 2.06 to 2.14(1H), 2.39 to 2.46(1H), 4.66 to 4.80(2H), 7.75 to 7.79(2H)

Example 127

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (isopropylamino) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Example 13(300 mg, 0.65 mmol), citric acid (50 mg, 0.26 mmol) and 12, 2-dimethoxypropane (2.54 g, 24.40 mmol) were placed in a sealed CEM microwave tube and heated at 120 ℃ with a 300 watt microwave for 60 minutes. The mixture was concentrated under a stream of nitrogen and sodium cyanoborohydride (1M in tetrahydrofuran, 3.0 ml, 3.00 mmol) was added to the residue. After stirring at room temperature for 18 h, the reaction mixture was poured into water (10 ml) and extracted with dichloromethane (3 × 5 ml). The combined extracts were washed with sodium bicarbonate solution (3X 10 mL) and water (2X 10 mL) over MgSO₄Dried and concentrated in vacuo. The residue was purified by thin layer chromatography to give the title compound (190 mg).

Experimental value MH⁺503.9, respectively; predicted value 504.0

¹H-NMR(CDCl₃): 1.08 to 1.13(6H), 1.24 to 1.28(2H), 1.76 to 1.81(2H), 3.21 to 3.29(1H), 3.43 to 3.55(1H), 5.44 to 5.52(1H), 5.68 to 5.75(1H), 7.91 to 7.94(2H)

The compounds prepared in a similar manner were:

example 128

1- { 3-cyano- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- (isopropylamino) -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide from example 99

Experimental value MH⁺498.3, respectively; predicted value 498.1

¹H-NMR(d₆-DMSO): 0.95 to 1.00(3H), 1.05 to 1.11(3H), 1.80 to 1.89(1H), 2.66 to 2.75(1H), 3.40 to 3.52(1H), 5.53 to 5.58(1H), 7.26 to 7.33(1H), 7.57 to 7.63(1H), 7.91 to 7.94(2H)

Example 129

4- (1-cyanocyclopropyl) -5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazole-3-carbonitrile

Trifluoroacetic anhydride (80 μ l, 0.57 mmol) and pyridine (0.15 ml, 1.90 mmol) were added to a solution of example 114(100 mg, 0.19 mmol) in 1, 4-dioxane (3 ml) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 2 hours, then at room temperature for 30 minutes, then partitioned between ethyl acetate and hydrochloric acid (1M). The organic phase was separated, washed with water, over MgSO ₄Dried and concentrated in vacuo to give the title compound (206 mg).

Experimental value MH^-495.5; predicted value 496.0

¹H-NMR(d₆-DMSO): -0.01 to 0.05(2H), 0.22 to 0.28(2H), 0.79 to 0.86(1H), 1.25 to 1.31(2H), 1.62 to 1.68(2H), 3.02 to 3.08(2H), 6.14 to 6.19(1H), 8.30 to 8.33(2H)

Example 130

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ ({1- [ (methylsulfonyl) amino ] cyclopropyl } methyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxamide

Triethylamine (43 μ l, 0.31 mmol) and methanesulfonyl chloride (6 μ l, 0.08 mmol) were added sequentially to a solution of example 131(50 mg, 0.08 mmol) in dichloromethane (2 ml). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by automated preparative liquid chromatography using an acetonitrile/water gradient [ 50: 50 to 98: 2] (Gilson system, 150 mm. times.30 mm, LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (35 mg).

Experimental value MH⁺607.1, respectively; predicted value 607.0

¹H-NMR(d₆-acetone): 0.79 to 0.83(2H), 0.95 to 1.00(2H), 1.15 to 1.20(2H), 1.55 to 1.60(2H), 2.85 to 2.90(3H), 3.45 to 3.50(2H), 8.22 to 8.25(2H)

Example 131

1- (5- { [ (1-aminocyclopropyl) methyl ] amino } -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl) cyclopropanecarboxamide

Trifluoroacetic acid (1.2 ml) was added to a solution of preparative 216(68 mg, 0.11 mmol) in dichloromethane (2.4 ml) at 0 ℃. The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in acetonitrile (0.25 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm. times.21.2 mm, LUNA C18(2)5 micron column) using an acetonitrile/water gradient [ 50: 50 to 95: 5 ]. The appropriate fractions were concentrated in vacuo to give the title compound (4 mg).

Experimental value MH⁺531.4; predicted value 531.1

Example 132

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methanesulfinyl) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Hydrogen peroxide (30 wt%, 1 ml, 9.79 mmol) was added to a solution of example 50(40 mg, 0.08 mmol) in glacial acetic acid (1 ml) and the reaction mixture was stirred at room temperature for 60 h. The mixture was extracted with dichloromethane and the combined extracts were washed with aqueous sodium bicarbonate and brine, and the mixture was purified over Na ₂SO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (1 ml) and purified by using a gradient of acetonitrile: water [ 50: 50 to 98: 2 ]]Was purified by preparative liquid chromatography (Gilson system, 150 mm. times.21.2 mm LUNA C18(2)5 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (4 mg) as one of several products.

Experimental value MH⁺509.2; predicted value 509.0

¹H-NMR(CDCl₃): 1.55 to 1.60(2H), 1.78 to 1.88(2H), 3.09 to 3.14(3H), 5.40 to 5.50(2H), 7.85 to 7.90(2H)

Example 133

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylsulfonyl) -1H-pyrazol-4-yl } cyclopropanecarboxamide

Hydrogen peroxide (30 wt%, 1 ml, 9.79 mmol) was added to a solution of example 50(40 mg, 0.08 mmol) in glacial acetic acid (1 ml) and the reaction mixture was stirred at room temperature for 60 h. The mixture was extracted with dichloromethane and the combined extracts were washed with aqueous sodium bicarbonate and brine, over Na₂SO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (1 ml) and purified by using a gradient of acetonitrile: water [ 50: 50 to 98: 2 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.21.2 mm, LUNA C18(2)5 μm column). The appropriate fractions were concentrated in vacuo to give the title compound (12 mg) as one of several products.

Experimental value MH⁺525.2, respectively; predicted value 525.0

¹H-NMR(d₆Acetone): 1.50 to 1.55(2H), 1.78 to 1.81(2H), 3.39 to 3.41(3H), 6.45 to 6.60(2H), 8.24 to 8.27(2H)

Example 134

4- ({4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } amino) butanoic acid

Trifluoroacetic acid (5 ml) was added dropwise to a solution of preparative 4(390 mg, 0.64 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 2.5 hours and then concentrated in vacuo. The residue was extracted with ethyl acetate and the combined extracts were washed with brine, over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (2 ml) and purified by using a gradient of acetonitrile: 0.1% trifluoroacetic acid [ 45: 55 to 95: 5%]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.30 mm, LUNA C18(2)10 μm column). The appropriate fractions were combined and concentrated to give the title compound (30 mg).

Experimental value MH⁺548.2, respectively; predicted value 548.0

¹H-NMR(d₆-DMSO): 0.98 to 1.03(2H), 1.40 to 1.45(2H), 1.55 to 1.62(2H), 2.05 to 2.12(2H), 3.10 to 3.19(2H), 8.40 to 8.42(2H)

Preparation method

The following preparations illustrate the synthesis of certain intermediates used in the preparation of the above examples.

Preparation method 1

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

Pyridine (2.7 ml, 33.80 mmol) and trifluoroacetic anhydride (1.4 ml, 10.20 mmol) were added to a solution of preparative method 3(1.75 g, 3.38 mmol) in 1, 4-dioxane (50 ml). After 2 hours at 0 ℃, the reaction mixture was warmed to room temperature and stirred for a further 30 minutes. The mixture was partitioned between hydrochloric acid (1M) and ethyl acetate, and the organic layer was separated, washed with water, over MgSO₄Upper dryingAnd concentrated in vacuo to give the title compound (2.88 g).

Experimental value MH⁺499.0, respectively; predicted value 499.0

The compounds prepared in a similar manner were:

preparation method 2

N' - { 3-cyano-4- (1-cyanocyclopropyl) -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide from example 61.

Experimental value MH⁺441.0, respectively; predicted value 441.1

Preparation method 3

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxamide

Ethyl chloroformate (0.39 ml, 4.14 mmol) was added at 0 ℃ to a mixture of preparative 9(1.95 g, 3.76 mmol) and triethylamine (1.3 ml, 9.40 mmol) in tetrahydrofuran (38 ml). After 20 minutes, the reaction mixture was warmed to room temperature and stirred for one hour. Anhydrous ammonia (gas) was bubbled through the mixture for 15 minutes, followed by nitrogen (gas) for 3 minutes. The reaction mixture was partitioned between ethyl acetate and hydrochloric acid (1M) and the organic phase was separated, washed with water and over MgSO ₄Dried above and concentrated in vacuo to give the title compound (1.96 g).

Experimental value MH⁺517.0, respectively; predicted value 517.0

Compounds prepared in a similar manner:

preparation method 4

Tert-butyl 4- ({4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } amino) benzoate from preparation 48

Experimental value MH⁺604.1; predicted value 604.1

Preparation method 5

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Lithium hydroxide monohydrate (69 mg, 1.64 mmol) was added to a solution of preparative 91(600 mg, 1.26 mmol) in tetrahydrofuran (30 ml). The reaction mixture was stirred at room temperature for 24 hours. Hydrochloric acid (2M) was added to the reaction mixture, and the mixture was concentrated in vacuo. The residue was extracted with ethyl acetate and the combined extracts were washed with hydrochloric acid (2M) over Na₂SO₄Dried and concentrated in vacuo to give the title compound (615 mg).

Experimental value MH⁺462.9, respectively; predicted value 463.0

Preparation method 6

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

A solution of lithium hydroxide (1.40 g, 33.10 mol) in water (25 ml) was added to a solution of preparative method 143(3.90 g, 7.34 mmol) in tetrahydrofuran (100 ml). The reaction mixture was stirred at room temperature for 18 hours, and then quenched with hydrochloric acid (2N). The mixture was extracted with ethyl acetate (2X 150 ml) and the combined extracts were washed with water and saturated brine solution over MgSO₄Dried above and concentrated in vacuo to give the title compound (3.60 g).

Experimental value MH⁺517.0, respectively; predicted value 517.0

Preparation method 7

1- [ 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl ] -2, 2-difluorocyclopropanecarboxylic acid

A mixture of preparation 138(960 mg, 1.83 mmol) and lithium hydroxide monohydrate (383 mg, 9.13 mmol) in tetrahydrofuran (30 ml) and water (10 ml) was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between hydrochloric acid (2N, 50 ml) and ethyl acetate (50 ml). The organic layer was separated, washed with brine (50 ml) and over MgSO₄Dried and concentrated in vacuo to give the title compound (977 mg).

Experimental value MH⁺512.9, respectively; predicted value 513.0

Preparation method 8

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-fluoroethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

A solution of lithium hydroxide monohydrate (80 mg, 2.00 mmol) in water (1 ml) was added to a solution of preparation 135(100 mg, 0.20 mmol) in tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature for 22 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and hydrochloric acid (10%) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic phases were over MgSO₄Dried above and concentrated in vacuo to give the title compound (100 mg).

Experimental value MH⁺509.1, respectively; predicted value 509.0

The compounds prepared in a similar manner were:

preparation method	R1	R3	R4	R5	R6	R8	R9	Is obtained from
preparation method	R1	R3	R4	R5	R6	R8	R9	Is obtained from	Preparation method 9	SF₅	H	H	H	H	CN	-N＝CH-N(CH₃)₂	Preparation method 61
Preparation method 10	SF₅	H	H	F	F	CN	NH₂	Preparation method 92	Preparation method 9	SF₅	H	H	H	H	CN	-N＝CH-N(CH₃)₂	Preparation method 61
Preparation method 10	SF₅	H	H	F	F	CN	NH₂	Preparation method 92	Preparation method 11	CF₃O	H	H	H	H	CN	NH₂	Preparation method 95
Preparation method 12	CF₃O	H	H	H	H	CN	-NHCH₃	Preparation method 137	Preparation method 11	CF₃O	H	H	H	H	CN	NH₂	Preparation method 95

Preparation method 13	SF₅	H	H	H	H	CN	[ (4H-1, 2, 4-triazol-3-yl) methyl]Amino group	Preparation method 144
Preparation method 13	SF₅	H	H	H	H	CN	[ (4H-1, 2, 4-triazol-3-yl) methyl]Amino group	Preparation method 144	Preparation method 14	sF₅	H	H	H	H	CN	[ (1-methyl-cyclopropyl) methyl]Amino group	Preparation method 125
Preparation method 15	SF₅	H	H	H	H	CN	-NHCH₂COOH	Preparation method 49	Preparation method 14	sF₅	H	H	H	H	CN	[ (1-methyl-cyclopropyl) methyl]Amino group	Preparation method 125
Preparation method 15	SF₅	H	H	H	H	CN	-NHCH₂COOH	Preparation method 49	Preparation method 16	sF₅	H	H	H	H	CN	-NH(CH₂)₂CF₃	Preparation method 130
Preparation method 17	SF₅	H	H	H	H	CN	[ (2-chloro-1, 3-thiazol-5-yl) methyl ]Amino group	Preparation method 112	Preparation method 16	sF₅	H	H	H	H	CN	-NH(CH₂)₂CF₃	Preparation method 130
Preparation method 17	SF₅	H	H	H	H	CN	[ (2-chloro-1, 3-thiazol-5-yl) methyl ]Amino group	Preparation method 112	Preparation method 18	SF₅	H	H	H	H	CN	(isoxazol-5-yl) methylamino	Preparation method 113
Preparation method 19	SF₅	H	H	H	H	CN	-NH(CH₂)₂COOH	Preparation method 133	Preparation method 18	SF₅	H	H	H	H	CN	(isoxazol-5-yl) methylamino	Preparation method 113
Preparation method 19	SF₅	H	H	H	H	CN	-NH(CH₂)₂COOH	Preparation method 133	Preparation method 20	SF₅	H	H	H	H	CN	-NH(CH₂)₄CF₃	Preparation method 132
Preparation method 21	SF₅	H	H	H	H	CN	-NH(CH₂)₃SCH₃	Preparation method 114	Preparation method 20	SF₅	H	H	H	H	CN	-NH(CH₂)₄CF₃	Preparation method 132
Preparation method 21	SF₅	H	H	H	H	CN	-NH(CH₂)₃SCH₃	Preparation method 114	Preparation method 22	SF₅	H	H	H	H	CN	-NHCOOi-Pr	Preparation method 189
Preparation method 23	i-C₃F₇	H	H	H	H	CN	NH₂	Preparation method 171	Preparation method 22	SF₅	H	H	H	H	CN	-NHCOOi-Pr	Preparation method 189
Preparation method 23	i-C₃F₇	H	H	H	H	CN	NH₂	Preparation method 171	Preparation method 24	SF₅	H	H	H	H	CN	[2- (4H-1, 2, 4-triazol-1-yl) ethyl group]Amino group	Preparation method 213
Preparation method 25	SF₅	H	H	H	H	CN	-NH(CH₂)₂CN	Preparation method 214	Preparation method 24	SF₅	H	H	H	H	CN	[2- (4H-1, 2, 4-triazol-1-yl) ethyl group]Amino group	Preparation method 213
Preparation method 25	SF₅	H	H	H	H	CN	-NH(CH₂)₂CN	Preparation method 214	Preparation method 26	CF3	H	H	F	F	CN	-N＝CH-N(CH₃)₂	Preparation method 55
Preparation method 27	CF3	H	H	H	H	CN	-N＝CH-N(CH₃)₂	Preparation method 64	Preparation method 26	CF3	H	H	F	F	CN	-N＝CH-N(CH₃)₂	Preparation method 55
Preparation method 27	CF3	H	H	H	H	CN	-N＝CH-N(CH₃)₂	Preparation method 64	Preparation method 28	CF3	H	H	H	H	CF3	NH2	Preparation method 97
Preparation method 29	CF3	H	H	H	H	CN	(Cyclopropylmethyl) amino-	Preparation method 131	Preparation method 28	CF3	H	H	H	H	CF3	NH2	Preparation method 97
Preparation method 29	CF3	H	H	H	H	CN	(Cyclopropylmethyl) amino-	Preparation method 131	Preparation method 30	SF5	H	H	H	H	CN	Isobutylamino group	Preparation method 110
Preparation method 31	SF5	H	H	Cl	Cl	CN	NH2	Preparation method 170	Preparation method 30	SF5	H	H	H	H	CN	Isobutylamino group	Preparation method 110
Preparation method 31	SF5	H	H	Cl	Cl	CN	NH2	Preparation method 170	Preparation method 32	CF3	H	H	H	H	CN	Cyclobutylmethylamino group	Preparation method 199
Preparation method 33	SF5	H	H	H	H	CN	Dimethylamino group	Preparation method 195	Preparation method 32	CF3	H	H	H	H	CN	Cyclobutylmethylamino group	Preparation method 199
Preparation method 33	SF5	H	H	H	H	CN	Dimethylamino group	Preparation method 195	Preparation method 34	CF₃O	H	H	H	H	CN	Ethoxycarbonylamino group	Preparation method 187
Preparation method 35	SF5	H	H	H	H	CN	Methylthio group	Preparation method 196	Preparation method 34	CF₃O	H	H	H	H	CN	Ethoxycarbonylamino group	Preparation method 187
Preparation method 35	SF5	H	H	H	H	CN	Methylthio group	Preparation method 196	Preparation method 36	SF5	H	H	H	H	CN	{4- [ (methylsulfonyl) amino group]Benzyl } amino group	Preparation ofMethod 126
Preparation method 37	SF5	H	H	H	H	CN	{4[ (methylamino) sulfonyl group]Benzyl } amino group	Preparation method 118	Preparation method 36	SF5	H	H	H	H	CN	{4- [ (methylsulfonyl) amino group]Benzyl } amino group	Preparation ofMethod 126
Preparation method 37	SF5	H	H	H	H	CN	{4[ (methylamino) sulfonyl group]Benzyl } amino group	Preparation method 118	Preparation method 38	SF5	H	H	H	H	CN	(tetrahydro-2H-pyran-4-ylmethyl) amino	Preparation method 119

Preparation method 39	SF5	H	H	Cl	Cl	CN	Methylamino radical	Preparation method 164
Preparation method 39	SF5	H	H	Cl	Cl	CN	Methylamino radical	Preparation method 164	Preparation method 40	CF₃O	H	H	Cl	Cl	CN	NH₂	Preparation method 172
Preparation method 41	SF5	H	H	H	H	CN	Propylamino group	Preparation method 129	Preparation method 40	CF₃O	H	H	Cl	Cl	CN	NH₂	Preparation method 172
Preparation method 41	SF5	H	H	H	H	CN	Propylamino group	Preparation method 129	Preparation method 42	SF5	H	H	H	H	CN	-NHCH₂CONHCH₂c-Pr	Preparation method 206
Preparation method 43	SF5	H	H	H	H	CN	[ (5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) methyl]Amino group	Preparation method 120	Preparation method 42	SF5	H	H	H	H	CN	-NHCH₂CONHCH₂c-Pr	Preparation method 206
Preparation method 43	SF5	H	H	H	H	CN		Preparation method 120	Preparation method 44	SF5	H	H	H	H	CN	-N(CH₃)(CH₂)₂OCH₃	Preparation method 210
Preparation method 45	SF5	H	H	H	H	CN	-NH(CH₂)₃COOH	Preparation ofMethod 212	Preparation method 44	SF5	H	H	H	H	CN	-N(CH₃)(CH₂)₂OCH₃	Preparation method 210
Preparation method 45	SF5	H	H	H	H	CN	-NH(CH₂)₃COOH	Preparation ofMethod 212	Preparation method 46	SF5	H	H	H	H	CN	(1, 3-Thiazol-2-ylmethyl) amino	Preparation method 122
Preparation method 47	SF5	H	H	H	H	CN	2- (1-methyl-1H-pyrazol-4-yl) ethylamino	Preparation method 123	Preparation method 46	SF5	H	H	H	H	CN	(1, 3-Thiazol-2-ylmethyl) amino	Preparation method 122
Preparation method 47	SF5	H	H	H	H	CN	2- (1-methyl-1H-pyrazol-4-yl) ethylamino	Preparation method 123	Preparation method 48	SF5	H	H	H	H	CN	tert-BOC-propylamino	Preparation method 121

Preparation method 9

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxylic acid

Experimental value MH⁺518.0; predicted value 518.0

Preparation method 10

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxylic acid

Experimental value MH⁺499.1, respectively; predicted value 499.0

Preparation method 11

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value M^-418.7, respectively; predicted value 419.0

Preparation method 12

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- (methylamino) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺434.9, respectively; predicted value 435.0

Preparation method 13

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (4H-1, 2, 4-triazol-3-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺543.9, respectively; predicted value 544.0

Preparation method 14

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [ (1-methylcyclopropyl) methyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxylic acid

Preparation method15

1- {5- [ (carboxymethyl) amino ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺520.8 of the total weight of the alloy; predicted value 521.0

Preparation method 16

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (3, 3, 3-trifluoropropyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺559.1, respectively; predicted value 559.0

Preparation method 17

1- (5- { [ (2-chloro-1, 3-thiazol-5-yl) methyl ] amino } -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl) cyclopropanecarboxylic acid

Experimental value MH⁺594.0, respectively; predicted value 593.9

Preparation method 18

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (isoxazol-5-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺544.0, respectively; predicted value 544.0

Preparation method 19

N- {4- (1-carboxycyclopropyl) -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } -beta-alanine

Experimental value MH⁺535.0; predicted value 535.0

Preparation method 20

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (5, 5, 5-trifluorophenyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺587.0, respectively; predicted value 587.0

Preparation method 21

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [3- (methylthio) propyl ] amino } -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺550.9, respectively; predicted value 551.0

Preparation method 22

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (isopropyloxycarbonyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺549.0, respectively; predicted value 549.0

Preparation method 23

1- (5-amino-3-cyano-1- {2, 6-dichloro-4- [1, 2, 2, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] phenyl } -1H-pyrazol-4-yl) cyclopropanecarboxylic acid

¹H-NMR(CDCl₃): 1.37 to 1.40(2H), 1.68 to 1.71(2H), 7.71 to 7.74(2H)

Preparation method 24

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [2- (1H-1, 2, 4-triazol-1-yl) ethyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxylic acid

Experimental value MH⁺557.9; predicted value 558.0

Preparation method 25

1- { 3-cyano-5- [ (2-cyanoethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺515.9; predicted value 516.0

Preparation method 26

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

Experimental value MH⁺495.9, respectively; predicted value 496.0

Preparation method 27

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

Experimental value MH⁺460.0 parts; predicted value 460.1

Preparation method 28

1- { 5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺448.0, respectively; predicted value 448.0

Preparation method 29

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺459.1, respectively; predicted value 459.1

Preparation method 30

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (isobutylamino) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value M^-517.0, respectively; predicted value 517.0

Preparation method 31

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-dichlorocyclopropanecarboxylic acid

Experimental value MH⁺530.8, respectively; predicted value 530.9

Preparation method 32

1- { 3-cyano-5- [ (cyclobutylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺531.0; predicted value 531.0

Preparation method 33

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (dimethylamino) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺491.0, respectively; predicted value 491.0

Preparation method 34

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- [ (ethoxycarbonyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Preparation method 35

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylthio) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

¹H-NMR(CDCl₃): 1.39 to 1.53(2H), 1.77 to 1.93(2H), 2.29 to 2.41(3H), 7.89 to 7.91(2H)

Preparation method 36

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- ({4- [ (methylsulfonyl) amino ] benzyl } amino) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺646.1, respectively; predicted value 646.0

Preparation method 37

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- ({4- [ (methylamino) sulfonyl ] benzyl } amino) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺645.9, respectively; predicted value 646.0

Preparation method 38

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (tetrahydro-2H-pyran-4-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺560.9, respectively; predicted value 561.0

Preparation method 39

2, 2-dichloro-1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺545.0, respectively; predicted value 544.9

Preparation method 40

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } -2, 2-dichlorocyclopropanecarboxylic acid

Experimental value MH⁺489.0, respectively; predicted value 488.9

Preparation method 41

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (propylamino) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺504.8, respectively; predicted value 505.0

Preparation method 42

1- { 3-cyano-5- ({2- [ (cyclopropylmethyl) amino ] -2-oxoethyl } amino) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺573.9, respectively; predicted value 574.1

Preparation method 43

1- (5- { [ (5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) methyl ] amino } -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl) cyclopropanecarboxylic acid

Experimental value MH⁺605.0, respectively; predicted value 605.0

Preparation method 44

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-methoxyethyl) (methyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺535.2; predicted value 535.0

Preparation method 45

1- {5- [ (3-carboxypropyl) amino ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺549.1, respectively; predicted value 549.0

Preparation method 46

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (1, 3-thiazol-2-ylmethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺560.1, respectively; predicted value 560.0

Preparation method 47

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [2- (1-methyl-1H-pyrazol-4-yl) ethyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxylic acid

Experimental value MH⁺570.9; predicted value 571.1

Preparation method 48

1- {5- [ (4-tert-butoxy-4-oxobutyl) amino ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Experimental value MH⁺605.1, respectively; predicted value 605.1

Preparation method 49

N- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -4- [1- (methoxycarbonyl) cyclopropyl ] -1H-pyrazol-5-yl } glycine

A solution of preparation 207(380 mg, 0.64 mmol) in trifluoroacetic acid (10 ml) was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate (30 ml) and water (30 ml) and the organic phase was separated, washed with brine (30 ml), over MgSO₄Dried and concentrated in vacuo to give the title compound (350 mg).

Experimental value MH⁺534.8, respectively; predicted value 535.0

Preparation method 50

1- [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- (methylamino) -1H-pyrazol-4-yl ] -2, 2-difluorocyclopropanecarboxylic acid

Hydrochloric acid (concentrated, 0.2 ml) was added to a solution of preparative 93(180 mg, 0.38 mmol) in triethyl orthoformate (5 ml). The reaction mixture was heated to reflux for one hour, toluene was added and the mixture was concentrated in vacuo. The process was repeated 3 times and the residue was dissolved in acetic acid. Sodium cyanoborohydride (53 mg, 0.84 mmol) was added to the solution over 2 hours. The reaction mixture was partitioned between water and dichloromethane and the organic phase was separated over MgSO₄Dried and concentrated in vacuo to give the methyl ester (200 mg). Lithium hydroxide monohydrate (172 mg, 4.10 mmol) was added to a solution of the methyl ester (200 mg, 0.41 mmol) in tetrahydrofuran (9 ml) and water (3 ml). The reaction mixture was stirred at room temperature for 2 hours and then acidified with hydrochloric acid. The mixture was extracted with ethyl acetateAnd the combined extracts were extracted over MgSO₄Dried above and concentrated in vacuo to give the title compound (200 mg).

Experimental value MH⁺471.0, respectively; predicted value 471.0

Preparation method 51

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

Magnesium sulfate, 1-hydroxybenzotriazole monohydrate (33 mg, 0.25 mmol), dimethylamine hydrochloride (29 mg, 0.35 mmol), N-methylmorpholine (64 μ l, 0.58 mmol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (49 mg, 0.26 mmol) were added sequentially to a solution of preparative 27(107 mg, 0.23 mmol) in N, N-dimethylformamide (5 ml). The reaction mixture was stirred at room temperature for one hour and a catalytic amount of 4-dimethylaminopyridine was added. The reaction mixture was then stirred for a further 3 hours. Water (30 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (3 × 10 ml). The combined extracts were extracted over MgSO₄Dried above and concentrated in vacuo to give the title compound (68 mg).

Experimental value MH⁺487.1, respectively; predicted value 487.1

The compounds prepared in a similar manner were:

preparation method 52

N' - { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- [1- (pyrrolidin-1-ylcarbonyl) cyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide obtained from preparation 27 and pyrrolidine

Experimental value MH⁺513.1; predicted value 513.1

Preparation method 53

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) -2, 2-difluorocyclopropane-carboxylic acid methyl ester

Trimethylsilyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (3.4 ml, 17.30 mmol) was added by syringe to a mixture of preparative 66(2.24 g, 4.32 mmol) and sodium fluoride (3 mg) in toluene (5.4 ml) at reflux. After heating at reflux for 4 hours, the reaction mixture was cooled to room temperature and stirred for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography using a gradient of eluent ethyl acetate: hexane [ 10: 90 to 35: 65 ]. The appropriate fractions were combined and concentrated to give the title compound (1.96 g)

Experimental value MH⁺568.1; predicted value 568.0

Preparation method 54

1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) -2, 2-difluorocyclopropanecarboxylic acid methyl ester

Potassium fluoride (20 mg) and trimethylsilyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (Dolbier Reagent, 10 ml) were added by syringe to a suspension of preparation 69(7.50 g, 15.80 mmol) in toluene (10 ml) over 6 hours. The reaction mixture was loaded onto a column (silica) and eluted with toluene. The appropriate fractions were combined and concentrated to give the title compound (7.20 g).

Experimental value MH⁺526.0, respectively; predicted value 526.0

The compounds prepared in a similar manner were:

preparation method	R1	R8	R2	Is obtained from
preparation method	R1	R8	R2	Is obtained from	Preparation method 55	CF3	CN	-COOCH₃	Preparation method 67
Preparation method 56	CF3	CN	-SO2NCHN(CH3)2	Preparation method 70	Preparation method 55	CF3	CN	-COOCH₃	Preparation method 67
Preparation method 56	CF3	CN	-SO2NCHN(CH3)2	Preparation method 70	Preparation method 57	CF3	CN	-SO2N(CH3)2	Preparation method 86
Preparation method 58	CF3	CN	F	Preparation method 72	Preparation method 57	CF3	CN	-SO2N(CH3)2	Preparation method 86
Preparation method 58	CF3	CN	F	Preparation method 72	Preparation method 59	CF3	CN	-SO2CH3	Preparation method 85

Preparation method 55

1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) -2, 2-difluorocyclopropanecarboxylic acid methyl ester

Experimental value MH⁺509.9, respectively; predicted value 510.1

Preparation method 56

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

Experimental value MH⁺585.9, respectively; predicted value 586.1

Preparation method 57

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

Experimental value MH⁺559.0, respectively; predicted value 559.1

Preparation method 58

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

Experimental value MH⁺470.2; predicted value 470.0

Preparation method 59

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

Experimental value MH⁺530.0; predicted value 530.0

Preparation method 60

1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) -2, 2-dimethylcyclopropanecarboxylic acid methyl ester

Lithium diisopropylamide (1.8N, 1.1 ml, 2.00 mmol in tetrahydrofuran) was added to a suspension of preparation 191(632 mg, 2.00 mmol) in ethylene glycol dimethyl ether (5 ml) and dichloromethane (100 μ l) at-78 ℃ under nitrogen. After stirring for 30 minutes, a solution of preparative method 67(460 mg, 1.00 mmol) in ethylene glycol dimethyl ether (9 ml) was added. The reaction mixture was stirred at-78 ℃ for one hour and then warmed to room temperature. Hydrochloric acid (10%) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 25 ml). The combined extracts were washed with hydrochloric acid (10%) over MgSO₄Dried and concentrated in vacuo. The residue was purified by using diethyl ether/pentane [ 1: 1 ]]Eluted column chromatography (silica) purification. The appropriate fractions were combined and concentrated to give the title compound (350 mg).

Experimental value MH⁺502.0; predicted value 502.1

Preparation method 61

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxylic acid methyl ester

Dimethyl sulfoxide (20 ml) was added to trimethyl sulfoxide iodide (892 mg, 4.05 mmol) and sodium hydride (60% in oil, 150 mg, 3.76 mmol). After stirring for one hour, the mixture was added to a solution of preparative 66(1.5 g, 2.89 mmol) in dimethyl sulfoxide (20 ml) at 0 ℃. The reaction mixture was warmed to room temperature and stirred overnight. Hydrochloric acid (1M) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water over Na₂SO₄Dried and concentrated in vacuo. The residue was purified on a Biotage column (silica, 100 g) eluting with dichloromethane. The appropriate fractions were combined and concentrated to give the title compound (1.0 g).

Experimental value MH⁺532.0, respectively; predicted value 532.0

The compounds prepared in a similar manner were:

preparation method 62

Methyl 1- {1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -3- (trifluoromethyl) -1H-pyrazol-4-yl } cyclopropanecarboxylate from preparative method 68

Experimental value MH⁺516.8, respectively; predicted value 517.1

Preparation method 63

Methyl 1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxylate resulting from preparation 69

Experimental value MH⁺462.8, respectively; predicted value 462.9

Preparation method 64

Methyl 1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxylate resulting from preparation 67

¹H-NMR(CDCl₃): 1.13 to 1.17(2H), 1.64 to 1.68(2H), 2.72 to 2.75(3H), 2.92 to 2.95(3H), 3.67 to 3.69(3H), 7.62 to 7.65(2H), 7.73 to 7.75(1H)

Preparation method 65

1- { 3-cyano-5- (cyclopropylmethoxy) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester from preparation 201

Experimental value MH⁺532.1; predicted value 532.0

Preparation method 66

Methyl 2- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) acrylate

Triethylamine (5.28 ml, 37.93 mmol) and methanesulfonyl chloride (1.81 ml, 23.54 mmol) were added to a solution of preparation 73(3.5 g, 6.54 mmol) in dichloromethane (30 ml). The reaction mixture was then stirred at room temperature for 24 hours. Hydrochloric acid (2M) and ice were added to the reaction mixture, and the mixture was extracted with dichloromethane. The combined extracts were washed with Na ₂SO₄Dried and concentrated in vacuo. The residue was purified on a Biotage column (silica, 100 g) eluting with dichloromethane. The appropriate fractions were combined and concentrated to give the title compound (1.5 g).

Experimental value MH⁺518.0; predicted value 518.0

The compounds prepared in a similar manner were:

preparation method 67

Methyl 2- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) acrylate from preparation 75

Experimental value MH⁺460.1; predicted value 460.1

¹H-NMR(CDCl₃): 2.72 to 2.75(3H), 2.88 to 2.92(3H), 3.73 to 3.76(3H), 6.02 to 6.05(1H), 6.48 to 6.51(1H), 7.50 to 7.53(1H), 7.64 to 7.69(2H)

Preparation method 68

Methyl 2- [1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -3- (trifluoromethyl) -1H-pyrazol-4-yl ] acrylate resulting from preparation 76

Experimental value MH⁺502.8; predicted value 503.0

Preparation method 69

Methyl 2- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) acrylate

Thionyl chloride (30 ml) was added dropwise to a solution of preparative method 74(24.50 g, 49.60 mmol) in acetonitrile (100 ml). After stirring at 50 ℃ for 2 days, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica) eluting with dichloromethane. The appropriate fractions were combined and concentrated to give the title compound (19.1 g).

Experimental value MH⁺476.0, respectively; predicted value 476.1

Preparation method 70

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

Tetrakis (triphenylphosphine) palladium (0) (10%, 150 mg) and the solution of preparative 101 (ca. 2.00 mmol) were added sequentially under nitrogen to a solution of preparative 219(670 mg, 1.30 mmol) in N, N-dimethylformamide (5 ml). Heating the reaction mixture at 110 deg.CAfter 10 hours, hydrochloric acid (10%) and water were added. The mixture was extracted with diethyl ether (3 × 15 ml) and the combined extracts were washed with water (15 ml) over MgSO₄Dried and concentrated in vacuo. The residue was purified by using a gradient of ethyl acetate: hexane [ 1: 0 to 0: 1%]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (300 mg) as a mixture of isomers.

Experimental value MH⁺536.0, respectively; predicted value 536.1

Compounds prepared in analogous manner

Preparation method 71

N' - { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -4- [1- (methylsulfonyl) -vinyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide from preparation 78 and preparation 180

Experimental value MH⁺538.0, respectively; predicted value 538.0

Preparation method 72

N' - [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4- (1-fluorovinyl) -1H-pyrazol-5-yl ] -N, N-dimethylaminoiminocarboxamide from preparative method 219 and preparative method 234

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 method 73

2- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) -2-hydroxypropionic acid methyl ester

Isopropyl magnesium chloride (2M, 3.09 ml, 6.19 mmol) was added to a solution of preparative method 78(3.15 g, 5.62 mmol) in anhydrous tetrahydrofuran (2 ml) at-78 ℃. At-78 deg.CThe mixture was stirred for 30 minutes then added to a solution of methyl pyruvate (0.76 ml, 8.44 mmol) in tetrahydrofuran (5 ml) at-30 ℃. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was acidified with hydrochloric acid (2M) and extracted with ethyl acetate (200 ml). The combined extracts were washed with Na₂SO₄Dried above and concentrated in vacuo to give the title compound (3.5 g).

Experimental value MH⁺536.0, respectively; predicted value 536.0

Preparation method 74

2- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) -2-hydroxypropionic acid methyl ester

Isopropyl magnesium chloride (2M in tetrahydrofuran, 4.5 ml, 90.00 mmol) was added dropwise to a solution of preparation 79(41.00 g, 79.00 mmol) in anhydrous tetrahydrofuran (250 ml) at-30 ℃ under nitrogen. After stirring for one hour at-30 ℃, methyl pyruvate (90%, 15.5 ml, 135.00 mmol) was added and the reaction mixture was stirred for one hour and then warmed to room temperature. The reaction mixture was quenched in ice/hydrochloric acid (2N) and extracted with ethyl acetate (3 × 200 ml). The combined extracts were extracted over MgSO₄Dried and concentrated in vacuo. The residue was purified by column chromatography (silica) eluting with dichloromethane then ethyl acetate. The appropriate fractions were combined and concentrated to give the title compound (24.50 g).

Experimental value MH⁺494.0; predicted value 494.1

Compounds prepared in a similar manner:

preparation method 75

Methyl 2- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) -2-hydroxypropionate obtained in preparation process 219

Experimental value MH⁺478.1; predicted value 478.1

Preparation method 76

Methyl 2- [1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -3- (trifluoromethyl) -1H-pyrazol-4-yl ] -2-hydroxypropionate obtained in preparation 80

Experimental value MH⁺521.1; predicted value 521.1

Preparation method 77

Methyl 2- { 3-cyano-5- (cyclopropylmethoxy) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2-hydroxypropionate obtained in preparation 106

Experimental value MH⁺536.1 of the total weight of the mixture; predicted value 536.0

Preparation method 78

N' - { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -4-iodo-1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide

A solution of preparation 105(52 g, 103 mmol) in N, N-dimethylformamide dimethyl acetal (300 ml) was heated under reflux for 5 hours, cooled to room temperature and stirred overnight. The reaction mixture was purified by column chromatography (silica, 1 kg) eluting with a gradient of hexane: ethyl acetate [ 6: 1 to 4: 1 ]. The appropriate fractions were combined and concentrated to give the title compound as a light brown 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 method 79

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

N, N-dimethylformamide dimethyl acetal (1.93 g, 16.2 mmol) was added to a solution of preparative 107(6.8 g, 14.7 mmol) in dichloromethane (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 thin layer chromatography (silica) eluting with a gradient of toluene: dichloromethane [ 1: 10 to 1: 1 ]. The appropriate fractions were combined and concentrated to give the title compound (6.2 g).

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 method 80

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

A solution of preparation 109(13.0 g, 26.53 mmol) in N, N-dimethylformamide dimethyl acetal (100 ml) was heated under reflux for 5 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between dichloromethane and water. Separating the organic phase over MgSO₄Dried and concentrated in vacuo. The residue was purified by using cyclohexane/dichloromethane [ 4: 1]]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (12.0 g).

Experimental value MH⁺544.7, respectively; predicted value 544.9

Preparation method 81

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

A solution of preparation 83(110 mg, 0.20 mmol) in xylene (5 ml) was heated at 130 ℃ for 4 hours. The reaction mixture was concentrated in vacuo to give the title compound (150 mg).

Experimental value MH⁺493.8, respectively; predicted value 494.0

Compounds prepared in a similar manner:

preparation method 82

N' - { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -4- [1- (methylsulfonyl) cyclopropyl ] -1H-pyrazol-5-yl } -N, N-dimethylimidocarboxamide from preparation 84

Experimental value MH⁺552.0, respectively; predicted value 552.0

Preparation method 83

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

Using Aldrich Technical Bulletin AL-180, using Diazald^®(2.5 g, 11.4 mmol) to yield a solution of diazomethane in diethyl ether (15 ml). The diazomethane solution was added to a solution of preparative method 85(150 mg, 0.3 mmol) in diethyl ether (10 ml) and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated in vacuo to give the title compound (130 mg).

Experimental value MH⁺522.0, respectively; predicted value 522.1

Compounds prepared in a similar manner:

preparation method 84

N '- [ 3' -cyano-1 '- [2, 6-dichloro-4-pentafluorothiophenyl ] -3- (methylsulfonyl) -4, 5-dihydro-1' H, 3H-3, 4 '-bipyrazol-5' -yl ] -N, N-dimethylimidocarboxamide from preparation 71

Experimental value MH⁺579.9, respectively; predicted value 580.0

Preparation methodMethod 85

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

A solution of 1-bromo-1- (methylsulfonyl) ethylene (555 mg, 3.0 mmol) and preparative method 142 in tetrahydrofuran (0.2M, 10 ml, 2.0 mmol) was added via syringe to a solution of tetrakis (triphenylphosphine) palladium (0) (100 mg) in tetrahydrofuran (3 ml) that had been flushed with nitrogen. The reaction mixture was then heated to reflux for 60 hours. The reaction mixture was passed through Celite^®Filtration and concentration of the filtrate in vacuo gave the title compound (150 mg).

Experimental value MH⁺480.0 of the total weight of the mixture; predicted value 480.0

The compounds prepared in a similar manner were:

preparation method 86

1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) -N, N-dimethylethenesulfonamide from preparation 142 and preparation 88

Experimental value MH⁺509.0, respectively; predicted value 509.1

Preparation method 87

1-bromoethenesulfonamide

Triethylamine (4.6 ml, 36.00 mmol) was added dropwise to a solution of 1, 2-dibromoethanesulfonamide (preparation 103, 8.00 g, 30.00 mmol) in toluene (100 ml) and ethyl acetate (10 ml). The reaction mixture was stirred at room temperature for 18 hours and then filtered. The filtrate was washed with hydrochloric acid (10%, 10 ml) and water (20 ml) over MgSO₄Dried above and concentrated in vacuo to give the title compound (5.00 g).

¹H-NMR(CDCl₃): 4.88 to 5.05(2H), 6.11 to 6.14(1H), 6.83 to 6.86(1H)

Compounds prepared in a similar manner:

preparation method 88

1-bromo-N, N-dimethylvinylsulfonamide from preparation 90

¹H-NMR(CDCl₃): 2.90 to 3.00(6H), 6.20 to 6.25(1H), 6.76 to 6.80(1H)

Preparation method 89

1, 2-dibromo-N- (tert-butyl) ethanesulfonamide

Bromine (3.6 ml, 72.00 mmol) was added to a solution of preparative method 104(6.00 g, 36.00 mmol) in dichloromethane (50 ml) and the mixture was stirred at room temperature for 48 hours. The reaction mixture was then concentrated in vacuo to afford the title compound (12.00 g) and other impurities.

¹H-NMR(CDCl₃): 1.83 to 1.86(3H), 3.80 to 3.84(1H), 4.12 to 4.17(1H), 5.00 to 5.05(1H)

Compounds prepared in a similar manner:

preparation method 90

1, 2-dibromo-N, N-dimethylethanesulfonamide from preparation process 181.

¹H-NMR(CDCl₃): 2.95 to 3.05(6H), 3.60 to 3.70(1H), 4.15 to 2.05(1H), 4.90 to 5.00(1H)

Preparation method 91

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Hydrochloric acid (1M, 3.5 ml) was added to a solution of preparative method 61(1.0 g, 1.88 mmol) in 1, 4-dioxane (12.5 ml) and methanol (3.5 ml). The reaction mixture was then heated to reflux overnight. The reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The combined extracts were washed with water, dried and concentrated in vacuo to give the title compound (600 mg).

Experimental value MH⁺477.0; predicted value 477.0

Preparation method 92

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxylic acid methyl ester

A solution of preparation 53(3.00 g, 5.28 mmol) in p-toluenesulfonic acid (10% in methanol, 80 ml) was heated to reflux for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was separated, washed with brine, over MgSO ₄Dried and concentrated in vacuo. The residue was triturated with cold ethanol to give the title compound (500 mg).

Experimental value MH⁺513.0; predicted value 513.0

Preparation method 93

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxylic acid methyl ester

A mixture of preparative 54(7.20 g, 13.70 mmol) and hydrochloric acid (4N, 20 ml) in methanol (50 ml) was heated at reflux for 18 h. The reaction mixture was concentrated in vacuo to give the title compound (6.50 g).

Experimental value MH⁺470.9; predicted value 471.0

Compounds prepared in a similar manner:

preparation method	R1	R3	R4	R5	R6	R8	R2	Is obtained from
preparation method	R1	R3	R4	R5	R6	R8	R2	Is obtained from	Preparation method 94	CF3	H	H	F	F	CN	COOH	Preparation method 26
Preparation method 95	CF3O	H	H	H	H	CN	COOCH3	Preparation method 63	Preparation method 94	CF3	H	H	F	F	CN	COOH	Preparation method 26
Preparation method 95	CF3O	H	H	H	H	CN	COOCH3	Preparation method 63	Preparation method 96	CF3	H	H	F	F	CN	F	Preparation method 58
Preparation method 97	CF3	H	H	H	H	CF3	COOCH3	Preparation method 62	Preparation method 96	CF3	H	H	F	F	CN	F	Preparation method 58
Preparation method 97	CF3	H	H	H	H	CF3	COOCH3	Preparation method 62	Preparation method 98	CF3	H	H	CH3	CH3	CN	COOCH3	Preparation method 60

Preparation method 94

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxylic acid

Experimental value MH⁺440.8, respectively; predicted value 441.0

Preparation method 95

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Experimental value MH⁺435.0, respectively; predicted value 435.0

Preparation method 96

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

Experimental value MH⁺415.1; predicted value 415.0

Preparation method 97

1- { 5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Experimental value MH⁺462.0, respectively; predicted value 462.0

Preparation method 98

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -2, 2-dimethylcyclopropanecarboxylic acid methyl ester

Experimental value MH⁺447.0, respectively; predicted value 447.1

Preparation method 99

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

Trifluoroacetic acid (500 μ l) was slowly added to a solution of preparative method 100(30 mg, 0.05 mmol) in dichloromethane (1.5 ml). The reaction mixture was then sealed and stirred for 3 hours. The reaction mixture was concentrated under nitrogen to give the title compound (30 mg) which was used directly.

Preparation method 100

[1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) -2, 2-difluorocyclopropyl ] carbamic acid tert-butyl ester

Diphenylphosphoryl azide (77 μ l, 0.35 mmol) and triethylamine (50 μ l, 0.35 mmol) were added to a solution of preparation method 26(180 mg, 0.35 mmol) in t-butanol (5 ml). The reaction mixture was then heated at 90 ℃ for 3 hours. An aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, over MgSO ₄Dried and concentrated in vacuo. The residue was purified by using a gradient of ethyl acetate to cyclohexane [ 0: 1 to 1: 1%]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (30 mg).

Experimental value MH⁺567.1, respectively; predicted value 567.1

Preparation method 101

Bromo [1- ({ [ (dimethylamino) methylidene ] amino } sulfonyl) ethenyl ] zinc

Under nitrogen, Rieke^®Zinc (0.8N, 5 mL, 4.00 mmol in N, N-dimethylformamide) was added to preparation 102 (48)0 mg, 1.94 mmol) in N, N-dimethylformamide (2 ml). The reaction mixture was stirred under nitrogen for 4 hours and then filtered (waterman0.45 μm) to give a solution of the title compound which was used directly.

Preparation method 102

1-bromo-N- [ (dimethylamino) methylene ] ethenesulfonamide

N, N-dimethylformamide dimethyl acetal (595 mg, 5.00 mmol) was added to a solution of preparative 87(930 mg, 5.00 mmol) in dichloromethane (5 ml). The reaction mixture was heated at 50 ℃ for one hour and then concentrated in vacuo. The residue was purified by column chromatography (silica) eluting with a gradient of ethyl acetate: hexane [ 0: 1 to 1: 0 ]. The appropriate fractions were combined and concentrated to give the title compound (1.20 g).

¹H-NMR(CDCl₃): 3.05 to 3.13(3H), 3.15 to 3.23(3H), 6.01 to 6.10(1H), 6.83 to 6.91(1H), 8.01 to 8.09(1H)

Preparation method 103

1, 2-dibromo-ethanesulfonamide

Trifluoroacetic acid (30 ml) was added to a solution of preparative method 89(12.00 g, 56.00 mmol) in dichloromethane (30 ml) and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was then concentrated in vacuo to give the title compound (8.00 g).

¹H-NMR(CDCl₃): 3.79 to 3.84(1H), 4.11 to 4.17(1H), 5.00 to 5.03(1H), 5.03 to 5.11(2H)

Preparation method 104

N- (tert-butyl) ethenesulfonamide

Tert-butylamine (5.8 ml, 55.00 mmol) and triethylamine (7.6 ml, 55) were added at-78 ℃.00 mmol) was added to a solution of 2-chloroethanesulfonyl chloride (9.20 g, 55.00 mmol) in diethyl ether (50 ml). After the addition was complete, hydrochloric acid (10%, 10 ml) was added and the two layers were separated. The aqueous layer was extracted with dichloromethane (× 3) and the combined organic layers were washed with water over MgSO₄Dried above and concentrated in vacuo to give the title compound (6.00 g).

¹H-NMR(CDCl₃): 1.28 to 1.34(9H), 4.26 to 4.36(1H), 5.77 to 5.82(1H), 6.15 to 6.22(1H), 6.52 to 6.60(1H)

Preparation method 105

5-amino-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -4-iodo-1H-pyrazole-3-carbonitrile

N-iodosuccinimide (26.4 g, 117 mmol) was added to a solution of preparative 108(40.0 g, 106 mmol) in acetonitrile (400 ml) 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). The organic phase was washed with MgSO₄Dried above and concentrated in vacuo to give the title compound as a brown solid (53 g).

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

Preparation method 106

5- (cyclopropylmethoxy) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -4-iodo-1H-pyrazole-3-carbonitrile

Silver sulfate (4.30 g, 13.70 mmol) and iodine (3.50 g, 13.70 mmol) were added sequentially to a solution of preparative 204(2.97 g, 6.84 mmol) in ethanol (68 ml). After stirring for 3 hours, the solution was filtered and the precipitate was partitioned between aqueous sodium hydroxide (1M) and dichloromethane. The two layers were separated and the organic layer was washed with brine, over MgSO₄Dried and concentrated in vacuo. Residue ofThe material was filtered through silica, washed with ethyl acetate, and the filtrate was concentrated in vacuo to give the title compound (3.53 g).

Experimental value MH⁺(acetonitrile adduct) 600.8; predicted value 600.9

Preparation method 107

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

Reference material: WO9804530a 1; WO9707102A1

Preparation method 108

5-amino-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazole-3-carbonitrile

Reference material: WO9306089A1, EP605469A1

Preparation method 109

1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -4-iodo-3- (trifluoromethyl) -1H-pyrazol-5-amine

Reference material: WO9707102A1

Preparation method 110

1- [ 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (isobutylamino) -1H-pyrazol-4-yl ] cyclopropanecarboxylic acid methyl ester

Isobutyraldehyde (2.9 ml, 31.50 mmol) was added to a mixture of preparative 91(300 mg, 0.63 mmol), p-toluenesulfonic acid (12 mg), and 4 Å molecular sieve (300 mg) in toluene (17 ml). The reaction mixture was stirred at room temperature for 16 h, washed with ethyl acetate and concentrated in vacuo. Sodium borohydride (75 mg) was added to the solution of the residue in methanol at 0 ℃ and the mixture was stirred at room temperature for 14 hours. Hydrochloric acid (1M, 50 ml) was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with water and over MgSO ₄Drying and vacuum concentratingAnd (4) shrinking. The residue was dissolved in acetonitrile (1 ml) and purified by liquid chromatography using an automated preparative liquid acetonitrile: water gradient (Gilson system, 150 mm x 50 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (43 mg).

Experimental value MH⁺532.9, respectively; predicted value 533.1

Compounds prepared in an analogous manner from the appropriate aldehydes are:

preparation method	R1	Re	Experimental value MH⁺	Predicted value MH⁺	Is obtained from
preparation method	R1	Re	Experimental value MH⁺	Predicted value MH⁺	Is obtained from	Preparation method 111	CF₃O	Cyclopropyl methyl group	489.0	489.1	Preparation method 95
Preparation method 112	SF₅	(2-chloro-1, 2-thiazol-5-yl) methyl	607.9	608.0	Preparation method 91	Preparation method 111	CF₃O	Cyclopropyl methyl group	489.0	489.1	Preparation method 95
Preparation method 112	SF₅	(2-chloro-1, 2-thiazol-5-yl) methyl	607.9	608.0	Preparation method 91	Preparation method 113	SF₅	Isoxazol-5-ylmethyl	558.1	558.0	Preparation method 91
Preparation method 114	SF₅	Methylthio propyl group	565.1	565.0	Preparation method 91	Preparation method 113	SF₅	Isoxazol-5-ylmethyl	558.1	558.0	Preparation method 91
Preparation method 114	SF₅	Methylthio propyl group	565.1	565.0	Preparation method 91	Preparation method 115	CF₃	2, 2-Dimethylpropyl	489.1	489.1	Example 3
Preparation method 116	CF₃	(4-Methanesulfonyl)Benzyl radical	587.0	587.1	Example 3	Preparation method 115	CF₃	2, 2-Dimethylpropyl	489.1	489.1	Example 3
Preparation method 116	CF₃	(4-Methanesulfonyl)Benzyl radical	587.0	587.1	Example 3	Preparation method 117	SF₅	4-fluorobenzyl	585.1	585.0	Preparation method 91
Preparation method 118	SF₅	4[ (methylamino) sulfonyl group]Benzyl radical	660.0	660.0	Preparation method 91	Preparation method 117	SF₅	4-fluorobenzyl	585.1	585.0	Preparation method 91
Preparation method 118	SF₅	4[ (methylamino) sulfonyl group]Benzyl radical	660.0	660.0	Preparation method 91	Preparation method 119	SF₅	(tetrahydro-2H-pyran-4-yl) methyl	574.9	575.1	Preparation method 91

Preparation method 120	SF₅	(5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) methyl	619.0	619.0	Preparation method 91
Preparation method 120	SF₅	(5-chloro-1, 3-dimethyl-1H-pyrazol-4-yl) methyl	619.0	619.0	Preparation method 91	Preparation method 121	SF₅	tert-BOC-propyl	619.1	619.1	Preparation method 91
Preparation method 122	SF₅	(1, 3-Thiazol-2-Yl) methyl	574.0	574.0	Preparation method 91	Preparation method 121	SF₅	tert-BOC-propyl	619.1	619.1	Preparation method 91
Preparation method 122	SF₅	(1, 3-Thiazol-2-Yl) methyl	574.0	574.0	Preparation method 91	Preparation method 123	SF₅	2- (1-methyl-1H-pyrazol-4-yl) ethyl	585.0	585.1	Preparation method 91
Preparation method 124	CF₃	(4-trifluoromethyl) benzyl	577.1	577.1	Example 3	Preparation method 123	SF₅	2- (1-methyl-1H-pyrazol-4-yl) ethyl	585.0	585.1	Preparation method 91
Preparation method 124	CF₃	(4-trifluoromethyl) benzyl	577.1	577.1	Example 3	Preparation method 125	SF₅	(1-methylcyclopropyl) methyl group	545.0	545.1	Preparation method 91
Preparation method 126	SF₅	4- [ (methylsulfonyl) amino group]Benzyl radical	660.1	660.0	Preparation method 91	Preparation method 125	SF₅	(1-methylcyclopropyl) methyl group	545.0	545.1	Preparation method 91
Preparation method 126	SF₅	4- [ (methylsulfonyl) amino group]Benzyl radical	660.1	660.0	Preparation method 91	Preparation method 127	SF₅	4, 4, 4-Trifluorobutyl	586.9	587.0	Preparation method 91
Preparation method 128	SF₅	Ethyl radical	505.3	505.1	Preparation method 91	Preparation method 127	SF₅	4, 4, 4-Trifluorobutyl	586.9	587.0	Preparation method 91
Preparation method 128	SF₅	Ethyl radical	505.3	505.1	Preparation method 91	Preparation method 129	SF₅	Propyl radical	518.8	519.0	Preparation method 91

Compounds which can also be prepared in a similar manner

Preparation method 130

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (3, 3, 3-trifluoropropyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester from preparation 91

Preparation method 131

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Sodium hydride (60% in oil, 16 mg, 0.40 mmol) was added to a solution of example 3(150 mg, 0.36 mmol) in 1-methyl-2-pyrrolidone (5 ml). After stirring for 30 min, (bromomethyl) cyclopropane (53 mg, 0.40 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in acetonitrile (1 ml) and purified by automated preparative liquid chromatography using an acetonitrile: water gradient (Gilson system, 150 mm x 50 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (32 mg).

Experimental value MH⁺472.9; predicted value 473.1

The compounds prepared in a similar manner were:

preparation method 132

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (5, 5, 5-trifluoropentyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester resulting from preparative method 91 and 5-iodo-1, 1, 1-trifluoropentane

Experimental value MH⁺601.0, respectively; predicted value 601.0

Preparation method 133

N- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -4- [1- (methoxycarbonyl) cyclopropyl ] -1H-pyrazol-5-yl } -beta-alanine methyl ester

A solution of preparation 91(250 mg, 0.52 mmol), p-toluenesulfonic acid (20 mg), 4 Å molecular sieve and methyl 3, 3-dimethoxypropionate (223. mu.l, 1.57 mmol) in dry dichloroalkane (4 ml) was stirred at room temperature for 18 hours. The reaction mixture was then filtered and the filtrate was added to a solution of sodium borohydride (200 mg, 5.20 mmol) in methanol (10 ml) at 0 ℃. After stirring for 18 hours, the mixture was quenched with water and extracted with ethyl acetate. The combined extracts were washed with brine, over MgSO₄Dried and concentrated in vacuo. The residue was purified by washing with cyclohexane/ethyl acetate [ 3: 2 ]]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (131 mg).

Experimental value MH⁺563.0, respectively; predicted value 563.0

Preparation method 134

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-fluoro-2-methylpropyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Preparation 231(0.5 ml) was added dropwise to preparation 91(200 mg, 0.42 mmol), (1, 1, 1-triacetoxy) -1, 1-bisHydro-1, 2-phenyliodoxy-3 (1H) -one ((1, 1, 1-triacyloxy) -1, 1-dihydro-1, 2-benzidoxol-3 (1H) -one) (863 mg, 2.04 mmol) and p-toluenesulfonic acid (20 mg) in dichloromethane (3 ml). After stirring for 10 min, the addition was added dropwise to a solution of sodium borohydride (154 mg, 4.07 mmol) in methanol (5 ml) at 0 ℃. After stirring for 30 minutes at 0 ℃, the mixture was partitioned between water and ethyl acetate. The two layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (2 ml) and purified by using a gradient of acetonitrile: water [ 65: 35 to 98: 2 ]]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.50 mm, LUNA C18(2)10 μm column). The appropriate fractions were concentrated in vacuo to give the title compound (72 mg). The compound can be used directly.

Preparation method 135

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-fluoroethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

2-Fluoroethanol (160 mg, 2.50 mmol) and Dess-Martin oxidant Dess-Martin periodinane) (1.15 g, 2.50 mmol) were added sequentially to a solution of preparative 91(250 mg, 0.50 mmol) in dichloromethane (5 mL). After stirring at room temperature for 5 hours, the solution was passed through Celite^®Filtration and the filtrate was carefully added to a solution of sodium borohydride (200 mg, 5.00 mmol) in methanol (5 ml) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30 minutes, then water and ethyl acetate were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with aqueous sodium bicarbonate and brine over MgSO₄Dried and concentrated in vacuo to give the title compound (100 mg).

¹H-NMR(CDCl₃): 1.35 to 1.40(2H), 1.71 to 1.78(2H), 3.20 to 3.32(2H), 3.65 to 3.67(3H), 4.30 to 4.45(2H), 7.90 to 7.94(2H)

Compounds prepared in a similar manner:

preparation method 136

Methyl 1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-isopropoxyethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylate obtained from preparation 91 and isopropoxyethanol

Experimental value MH⁺563.1; predicted value 563.1

Preparation method 137

1- [ 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- (methylamino) -1H-pyrazol-4-yl ] cyclopropanecarboxylic acid methyl ester

Sodium borohydride (54 mg, 1.44 mmol) was added to a solution of preparative 139(280 mg, 0.58 mmol) in ethanol (10 ml) and the reaction mixture was stirred at room temperature for 18 h. Hydrochloric acid (2N) was added to the reaction mixture and the solution was concentrated in vacuo. The residue was partitioned between ethyl acetate (15 ml) and water (15 ml) and the two layers were separated. The organic phase is reacted with MgSO₄Dried above and concentrated in vacuo to give the title compound as a product mixture (200 mg).

Experimental value MH⁺448.9, respectively; predicted value 449.0

Compounds prepared in a similar manner:

preparation method 138

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxylic acid methyl ester from preparation 140

Experimental value MH⁺526.9; predicted value 527.0

Preparation method 139

1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- { [ ethoxymethylene ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxylic acid methyl ester

A mixture of preparation 95(250 mg, 0.58 mmol) and hydrochloric acid (concentrated, 2 drops) in triethyl orthoformate (8 ml) was heated at 50 ℃ for 30 minutes and then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was azeotroped with toluene to give the title compound (280 mg).

Experimental value MH⁺490.7, respectively; predicted value 491.1

Preparation method 140

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [ ethoxymethylene ] amino } -1H-pyrazol-4-yl) -2, 2-difluorocyclopropanecarboxylic acid methyl ester

A mixture of preparation 92(223 mg, 0.44 mmol) and hydrochloric acid (one drop) in triethyl orthoformate (6 ml) was heated at 50 ℃ for 2 hours and then stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue was dissolved in toluene and re-concentrated to give the title compound (250 mg).

Experimental value MH⁺568.9; predicted value 569.0

The compounds prepared in a similar manner were:

preparation method 141

Methyl { 3-cyano-4- (1-cyanocyclopropyl) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } imide carboxylate from example 11.

Experimental value MH⁺486.3, respectively; predicted value 486.0

Preparation method 142

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

Rieke slurried in tetrahydrofuran (26 ml) under nitrogen^®Zinc (1.31 g, 20.0 mmol) was added to a solution of preparative 219(5.02 g, 10.0 mmol) in tetrahydrofuran (24 ml). The reaction mixture was then stirred at room temperature overnight. The excess zinc metal was allowed to settle and the solution containing the title compound (0.2 mol per liter) was used directly in the next stage.

Preparation method 143

1- { 3-cyano-5- [ (cyclopropylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

A mixture of method 151(22.00 g, 44.00 mmol) and borane-pyridine complex (6.7 ml, 66.00 mmol) in methanol (250 ml) was prepared and stirred at room temperature for 2 hours. Additional borane-pyridine complex (6.7 ml, 66.00 mmol) was added and the reaction mixture was stirred for 48 hours. The reaction mixture was quenched with hydrochloric acid (2N) and partitioned between ethyl acetate and water. The two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine solution over MgSO₄Dried and concentrated in vacuo. The residue was taken up on silica and purified by column chromatography (silica) eluting with dichloromethane. Appropriate fractions were combined and concentrated to give the title compound (11.00 g).

Compounds prepared in a similar manner:

preparation method	R1	R9	Experimental value MH⁺	Predicted value MH⁺	Is obtained from
preparation method	R1	R9	Experimental value MH⁺	Predicted value MH⁺	Is obtained from	Preparation method 144	SF₅	[ (4H-1, 2, 4-triazol-3-yl) methyl]Amino group	558.0	558.0	Preparation method 149
Preparation method 145	CF₃	(pyridin-2-ylmethyl) amino	510.0	510.1	Preparation method 153	Preparation method 144	SF₅	[ (4H-1, 2, 4-triazol-3-yl) methyl]Amino group	558.0	558.0	Preparation method 149
Preparation method 145	CF₃	(pyridin-2-ylmethyl) amino	510.0	510.1	Preparation method 153	Preparation method 146	CF₃	(pyridin-4-ylmethyl) amino	510.0	510.1	Preparation method 154
Preparation method 147	CF₃	(2, 2, 2-trifluoroethyl) amino group	501.0	501.0	Preparation method 155	Preparation method 146	CF₃	(pyridin-4-ylmethyl) amino	510.0	510.1	Preparation method 154
Preparation method 147	CF₃	(2, 2, 2-trifluoroethyl) amino group	501.0	501.0	Preparation method 155	Preparation method 148	CF₃	(1H-imidazol-2-ylmethyl) amino	499.1	499.1	Preparation method 156

Preparation method 149

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [1H-1, 2, 4-triazol-5-ylmethylene ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxylic acid methyl ester

A mixture of preparation 91(500 mg, 1.04 mmol), p-toluenesulfonic acid (20 mg, 0.11 mmol) and 4H-1, 2, 4-triazole-3-carbaldehyde (302 mg, 3.12 mmol) in toluene (50 ml) was heated under reflux for 3 hours. The reaction mixture was concentrated in vacuo to give the title compound (500 mg) which was used directly.

Preparation method 150

1- { 3-cyano-5- { [ (cyclopropylmethylene) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxamide

A mixture of example 53 (00 mg, 0.20 mmol), p-toluenesulfonic acid (4 mg, 0.02 mmol), 4 Å molecular sieve and cyclopropanecarboxaldehyde (42 mg, 0.60 mmol) was heated at 115 ℃ for 18 hours. The reaction mixture was then concentrated in vacuo to give the title compound (111 mg).

Experimental value MH⁺550.1 of the raw material; predicted value 550.0

Preparation method 151

1- { 3-cyano-5- [ (cyclopropylmethylene) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

A mixture of preparative method 91(21.00 g, 44.00 mmol), cyclopropanecarboxaldehyde (9.85 ml, 132.00 mmol) and 4 Å molecular sieve (21.00 g) in toluene (210 ml) was stirred at room temperature for 60 hours. The reaction mixture was passed through Celite^®Filtered and concentrated in vacuo to give the title compound (22.00 g).

Compounds prepared in a similar manner:

preparation method	R5	R6	R9	R10	MH according to the example⁺	Predicted value MH⁺	Is obtained from
preparation method	R5	R6	R9	R10	MH according to the example⁺	Predicted value MH⁺	Is obtained from	Preparation method 152	H	H	Phenylmethyleneamino	OCH3	506.8	507.1	Example 3
Preparation method 153	H	H	(pyridin-2-yl) methyleneamino	OCH3	508.0	508.1	Example 3	Preparation method 152	H	H	Phenylmethyleneamino	OCH3	506.8	507.1	Example 3
Preparation method 153	H	H	(pyridin-2-yl) methyleneamino	OCH3	508.0	508.1	Example 3	Preparation method 154	H	H	(pyridin-4-yl) methyleneamino	OCH3	508.0	508.1	Example 3
Preparation method 155	H	H	(2, 2, 2-trifluoroethylene) amino group	OCH3			Example 3	Preparation method 154	H	H	(pyridin-4-yl) methyleneamino	OCH3	508.0	508.1	Example 3
Preparation method 155	H	H	(2, 2, 2-trifluoroethylene) amino group	OCH3			Example 3	Preparation method 156	H	H	(1H-imidazol-2-ylmethylene) amino	OCH3	497.0	497.1	Example 3
Preparation method 157	F	F	Cyclopropyl methylene amino group	NH2	4922	492.0	Example 55	Preparation method 156	H	H	(1H-imidazol-2-ylmethylene) amino	OCH3	497.0	497.1	Example 3

Preparation method 158

2- { [1- (3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- { [ (dimethylamino) methylene ] amino } -1H-pyrazol-4-yl) cyclopropyl ] carbonyl } diaminocarboxylic acid tert-butyl ester

Preparation of 27(500 mg, 1.10 mmol), 1-hydroxybenzotriazole hydrate (178 mg) at room temperatureA mixture of 1.32 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (253 mg, 1.32 mmol), t-butyl carbazate (174 mg, 1.32 mmol) and N-methylmorpholine (0.30 ml, 2.75 mmol) in N, N-dimethylformamide (8 ml) was stirred for 18 hours. The reaction mixture was then poured into water (40 ml) and the product was extracted with ethyl acetate (3 × 30 ml). The combined extracts were washed with brine (50 ml) over MgSO₄Dried and concentrated in vacuo. The residue was purified by using a gradient of cyclohexane to ethyl acetate [ 3: 1 to 1: 1%]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (692 mg).

Experimental value MH⁺573.9, respectively; predicted value 574.1

The compounds prepared in a similar manner were:

preparation method 159

N' -acetyl-1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropane carbonyl trap from preparation 178

Experimental value MH⁺460.9, respectively; predicted value 461.1

Preparation method 160

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

Hydrogen chloride (4N in 1, 4-dioxane, 1 ml) was added to a solution of preparative 158(60 mg, 0.11 mmol) in 1, 4-dioxane (1 ml) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 4 hours. The solution was then concentrated in vacuo to give the title compound as a mixture of product and starting material.

Experimental value MH⁺473.9, respectively; predictive value 474.1

Preparation method 161

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

A mixture of preparation 160 (ca. 0.11 mmol), triethyl orthoformate (3 ml) and p-toluenesulfonic acid (2 mg) was heated under reflux for 4 hours. The reaction mixture was then concentrated in vacuo to give the title compound (50 mg).

Experimental value MH⁺483.9, respectively; predicted value 484.1

Preparation method 162

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropane carbonyl trap

A mixture of preparation 161(250 mg, 0.52 mmol) and hydrochloric acid (5N, 1 ml) in methanol (2 ml) and 1, 4-dioxane (8 ml) was heated at reflux for 2 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). Separating the organic phase over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) and purified by liquid chromatography using an automated preparative liquid acetonitrile: water gradient (Gilson system, 150 mm x 50 mm, Phenomenex LUNA C18(2)10 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (75 mg).

Experimental value MH⁺418.9; predicted value 419.0

Preparation method 163

1- [ 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl ] cyclopropanecarboxylic acid methyl ester

Hydrochloric acid (concentrated, 0.5 ml) was added to preparation 91(6.84 g, 14.30 mmol) in triethyl orthoformate (180 ml)) And the reaction mixture was heated at 50 ℃ for 2 hours. The mixture was concentrated in vacuo and ethanol (120 ml) was added to the residue. The solution was cooled to 0 ℃ and sodium borohydride (1.20 g, 31.50 mmol) was added over 5 minutes. After stirring at room temperature for 16 hours, acetic acid (2.5 ml) and water (300 ml) were added. After a further 10 minutes, the mixture was extracted with ethyl acetate and the combined extracts were washed with MgSO₄Dried and concentrated in vacuo. The residue was purified by washing with ethyl acetate/hexane [ 1: 3 ]]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (4.74 g).

Experimental value MH⁺491.0, respectively; predicted value 491.0

Compounds prepared in a similar manner:

preparation method 164

Ethyl 2, 2-dichloro-1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylamino) -1H-pyrazol-4-yl } cyclopropanecarboxylate from preparation 170

Experimental value MH⁺573.0, respectively; predicted value 572.9

Preparation method 165

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5-methyl-1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

A mixture of preparation 166(232 mg, 0.47 mmol) and thionyl chloride (69 μ l, 0.94 mmol) was heated under reflux for 2 hours. The mixture was concentrated in vacuo and tetrahydrofuran (4.7 ml) was added to the residue. The solution was cooled to 0 ℃ and Rieke was added^®Zinc (0.76M in tetrahydrofuran, 3.1 ml, 2.35 mmol). After stirring for 30 minutes, the reaction mixture was warmed to room temperature and additional Rieke was added^®Zinc (0.76M in tetrahydrofuran, 15.5 ml, 11.78 mmol). After stirring for a further 18 hours, the reaction mixture was poured slowly into ice/hydrochloric acid (1M). Extraction with ethyl acetateThe mixture was combined and the combined extracts were extracted over MgSO₄Dried and then concentrated in vacuo. The residue was purified by using a gradient of ethyl acetate to cyclohexane [ 5: 95 to 15: 85% ]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (40 mg).

Experimental value MH⁺475.9; predicted value 476.0

Preparation method 166

1- [ 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (hydroxymethyl) -1H-pyrazol-4-yl ] cyclopropanecarboxylic acid methyl ester

Sodium borohydride (60 mg, 1.57 mmol) was added dropwise to a solution of preparative 167(671 mg, 1.21 mmol) in methanol (12 ml) at 0 ℃. After one hour, the reaction mixture was warmed to room temperature and poured into hydrochloric acid (1M, excess). The mixture was extracted with ethyl acetate and the combined extracts were over MgSO₄Dried and then concentrated in vacuo. The residue was purified by using a gradient of ethyl acetate to cyclohexane [ 1: 9 to 3: 7%]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (406 mg).

Experimental value MH⁺491.9, respectively; predicted value 492.0

Preparation method 167

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5-formyl-1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Osmium tetroxide (1.5 ml, 0.12 mmol) was added to a solution of preparative 168(663 mg, 1.21 mmol) in aqueous acetone (10%, 10 ml) followed by sodium periodate (2.60 g, 12.1 mmol) over 4 hours. After stirring at room temperature for 14 hours, the reaction mixture was filtered, washed with acetone, and the filtrate was concentrated in vacuo. The residue was passed through a silica plug and eluted with ethyl acetate/cyclohexane [ 1: 1 ]. The appropriate fractions were combined and concentrated to give the title compound (0.98 g) as a 4: 1 mixture with the starting material.

¹H-NMR(CDCl₃): 1.48 to 1.53(2H), 1.94 to 1.98(2H), 3.70 to 3.74(3H), 7.88 to 7.91(2H), 9.94 to 9.95(1H)

Preparation method 168

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ 3-methoxy-3-oxoprop-1-en-1-yl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

1, 8-diazabi [5.4.0 ] bis at 0 deg.C]Undec-7-ene (DBU, 250 μ l, 1.68 mmol) was added to a solution of preparative 169(0.96 g, 1.53 mmol) in toluene (7.5 ml). The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was partitioned between hydrochloric acid (1M) and ethyl acetate, and the organic phase was separated, washed with water, over MgSO₄Dried and concentrated in vacuo. The residue was taken up with a silica plug and extracted with ethyl acetate/cyclohexane [ 3: 7 ]]And (5) eluting for purification. The appropriate fractions were combined and concentrated to give the title compound (0.84 g).

Experimental value MH⁺545.8, respectively; predicted value 546.0

Preparation method 169

1- {5- (2-bromo-3-methoxy-3-oxopropyl) -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

A solution of preparation 91(1.20 g, 2.50 mmol) in acetonitrile (12 ml) was added dropwise to a solution of methyl acrylate (4.5 ml, 50.00 mmol), copper (II) bromide (0.84 g, 3.75 mmol) and tert-butylnitrile (0.48 ml, 4.00 mmol) in acetonitrile (25 ml) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 10 minutes and then at room temperature for one hour. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and ethyl acetate. Separating the organic phase over MgSO ₄Dried and concentrated in vacuo. The residue is passed throughGradient solution solubility ethyl acetate to cyclohexane [ 2: 98 to 10: 90%]Purification was performed by column chromatography (silica). The appropriate fractions were combined and concentrated to give the title compound (0.98 g).

Experimental value MH⁺625.7, respectively; predicted value 625.9

Preparation method 170

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } -2, 2-dichlorocyclopropanecarboxylic acid ethyl ester

Tetrafluoroboric acid (48% in water, 1.0 ml, 7.35 mmol) and isovaleronitrile (0.32 ml, 3.85 mmol) were added sequentially to a solution of preparative 182(1.00 g, 3.50 mmol) in ethanol (5 ml) at 0 ℃. The reaction mixture was then stirred for 40 minutes. The product was collected by filtration and dried to give 2, 6-dichloro-4-pentafluorosulfanylbenzenediazotetrafluoroborate (121 mg, 0.31 mmol). A solution of preparation 187(100 mg, 0.31 mmol) and pyridine (75 μ l) in methanol (2 ml) was stirred at 0 ℃ for 15 minutes, then 2, 6-dichloro-4-pentafluorosulfanylbenzenediazotetrafluoroborate (121 mg, 0.31 mmol) was added. The reaction mixture was then stirred at room temperature for 30 minutes. Diethyl ether (20 ml) was added to the reaction mixture and the solution was washed with water and brine. Separating the organic layer over Na ₂SO₄Dried and concentrated in vacuo to give the title compound (220 mg).

Experimental value MH⁺558.8, respectively; predicted value 558.9

The compounds prepared in a similar manner were:

preparation method 171

Ethyl 1- (5-amino-3-cyano-1- {2, 6-dichloro-4- [1, 2, 2, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] phenyl } -1H-pyrazol-4-yl) cyclopropanecarboxylate from preparative method 216 and preparative method 220

¹H-NMR(CDCl₃)：1.19To 1.22(3H), 1.27 to 1.30(2H), 1.65 to 1.70(2H), 4.09 to 4.14(2H), 7.71 to 7.74(2H)

Preparation method 172

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } -2, 2-dichlorocyclopropanecarboxylic acid ethyl ester resulting from preparative 209 and preparative 174

Experimental value MH⁺516.9, respectively; predicted value 517.0

Preparation method 173

Ethyl 1- [ 5-amino-3-cyano-1- (2, 6-dichloro-4-cyanophenyl) -1H-pyrazol-4-yl ] cyclopropanecarboxylate from preparative 208 and preparative 220

Experimental value MH⁺390.0; predicted value 390.1

Preparation method 174

2, 2-dichloro-1- (1, 2-dicyano-3-methoxy-3-oxopropyl) cyclopropane-carboxylic acid ethyl ester

Potassium cyanide (267 mg, 4.10 mmol) was added to a solution of preparative 175(1.00 g, 3.42 mmol) in methanol (15 ml) at 0 ℃ under nitrogen and the reaction mixture was stirred for one hour. Glacial acetic acid (390 μ l) and silica (1.00 g) were added and the mixture was concentrated in vacuo. The product/silica mixture was purified by column chromatography (silica) eluting with a gradient of diethyl ether to cyclohexane [ 3: 7 to 1: 1 ]. The appropriate fractions were combined and concentrated to give the title compound (440 mg).

¹H-NMR(CDCl₃): 1.39 to 1.41(3H), 1.65 to 2.00(1H), 2.42 to 2.70(1H), 3.32 to 3.41(1H), 3.89 to 3.99(3H), 4.21 to 4.27(1H), 4.35 to 4.42(2H)

Preparation method 175

2, 2-dichloro-1- [ 2-cyano-3-methoxy-3-oxoprop-1-en-1-yl ] -cyclopropanecarboxylic acid ethyl ester

A mixture of preparation 176(8.60 g, 40.00 mmol), methyl cyanoacetate (3.5 ml, 40.00 mmol) and piperidine (1.2 ml, 12.00 mmol) in acetic acid (30 ml) was heated at reflux under nitrogen for 60 hours. The reaction mixture was poured into water (500 ml) and extracted with dichloromethane (2 × 150 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate (200 ml) over Na₂SO₄Dried and concentrated in vacuo. The residue was purified by washing with diethyl ether/cyclohexane [ 2: 8 ]]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (6.00 g).

¹H-NMR(CDCl₃): 1.19 to 1.28(3H), 2.25 to 2.30(1H), 2.81 to 2.85(1H), 3.91 to 3.94(3H), 4.29 to 4.41(2H), 7.89 to 7.92(1H)

Preparation method 176

2, 2-dichloro-1-formylcyclopropanecarboxylic acid ethyl ester

A solution of preparation 177(5.00 g, 19.67 mmol) in dichloromethane (50 ml) was flushed with nitrogen and cooled to-78 ℃. Diisobutylaluminum hydride (1M in dichloromethane, 39.4 ml, 39.40 mmol) was added dropwise to the solution, ensuring that the temperature did not exceed about-65 ℃. After stirring at this temperature for 2 hours, saturated aqueous ammonium chloride solution and hydrochloric acid (2N, 5 ml) were added successively, and the mixture was warmed to room temperature. The reaction mixture was filtered, washed with brine, over Na ₂SO₄Dried and concentrated in vacuo. The residue was purified by washing with diethyl ether/cyclohexane [ 2: 8 ]]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (900 mg).

¹H-NMR(CDCl₃): 1.35 to 1.38(3H), 2.40 to 2.50(2H), 4.31 to 4.39(2H), 9.96 to 9.99(1H)

Preparation method 177

2, 2-Dichloropropane-1, 1-dicarboxylic acid diethyl ester

Reference material: synthetic Communications (1989), 19(1-2), 141-6.

Preparation method 178

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Hydrochloric acid (0.5N, 0.5 ml) was added to a solution of preparative 179(33 mg, 0.06 mmol) in 1, 4-dioxane (2 ml) and methanol (0.5 ml). The reaction mixture was then heated at 80 ℃ overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (5 ml) and ethyl acetate (5 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 5 ml). The combined organic layers were then washed over MgSO₄Dried and concentrated in vacuo. The crude product was dissolved in an acetonitrile/water mixture (1: 1, 650. mu.l) and purified by using a gradient of acetonitrile/water (which contains 0.1% trifluoroacetic acid) from 45: 55 to 98: 2 ]Purification was performed by automated preparative liquid chromatography (Gilson system, 250 mm. times.21.2 mm, Phenomenex LUNA C18(2)5 micron column). The appropriate fractions were concentrated in vacuo to give the title compound (8 mg).

Preparation method 179

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

A suspension of potassium tert-butoxide (575 mg, 5.13 mmol) in water (50 μ l) and diethyl ether (10 ml) was cooled to 0 ℃ and stirred for 30 min. A solution of preparative method 64(303 mg, 0.64 mmol) in diethyl ether (5 ml) and tetrahydrofuran (1 ml) was added dropwise to the solution. The reaction mixture was then stirred for 10 minutes. The reaction mixture was poured into ice/water (30 ml). The mixture was then acidified by addition of hydrochloric acid (2N) and washed with waterEthyl acetate (3 × 20 ml) was extracted. The combined extracts were extracted over MgSO₄Dried and concentrated in vacuo. The residue was purified by using a gradient of hexane: ethyl acetate [ 3: 1 to 1: 3%]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (33 mg).

Preparation method 180

1-bromo-1- (methylsulfonyl) ethene

Reference material: JACSC1972, 94(3), 1012-

Preparation method 181

N, N-dimethyl ethanesulfonamide

Reference material: US2004013980A1, WO9206973A1

Preparation method 182

2, 6-dichloro-4-pentafluorothioaniline

Reference material: WO9306089A1

Preparation method 183

1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -5- [ (ethoxycarbonyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Phosgene (1.7M in toluene, 4.4 ml, 7.40 mmol) was added to a mixture of example 3(310 mg, 0.74 mmol) and pyridine (0.30 ml, 3.70 mmol) in dichloromethane (7.4 ml) at 0 ℃. After stirring for one hour, ethanol (10 ml) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between hydrochloric acid (1M) and ethyl acetate. The organic phase was separated, washed with water, over MgSO₄Dried and concentrated in vacuo to give the title compound (379 mg).

Experimental value MH⁺491.0, respectively; predicted value 491.1

Preparation method 184

1- (3-cyano-5- { [ (cyclopropylmethoxy) carbonyl ] amino } -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl) cyclopropanecarboxylic acid methyl ester

Phosgene (20% in toluene, 2.70 ml, 5.20 mmol) was added to a solution of preparative 91(250 mg, 0.52 mmol) and pyridine (0.21 ml, 2.60 mmol) in dichloromethane (5.2 ml) at 0 ℃. After stirring for one hour at 0 ℃, cyclopropylmethanol (2 ml) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between hydrochloric acid (1M) and ethyl acetate. The organic phase was separated, washed with water, over MgSO₄Dried and concentrated in vacuo to give the title compound (310 mg).

Experimental value MH⁺575.0; predicted value 575.0

The compounds prepared in a similar manner were:

preparation method 185

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (methoxycarbonyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester from preparation 91 and methanol

Experimental value MH⁺535.0; predicted value 535.0

Preparation method 186

Methyl 1- (3-cyano-5- { [ (cyclobutoxy) carbonyl ] amino } -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl) cyclopropanecarboxylate resulting from preparative method 91 and cyclobutanol

Experimental value MH⁺575.0; predicted value 575.0

Preparation method 187

Methyl 1- { 3-cyano-1- [2, 6-dichloro-4- (trifluoromethoxy) phenyl ] -5- [ (ethoxycarbonyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylate, obtained from preparative method 95 and ethanol.

Experimental value MH⁺506.9, respectively; predicted value 507.0

Preparation method 188

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (ethoxycarbonyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester from preparation 91 and ethanol

Experimental value MH⁺549.0, respectively; predicted value 549.0

Preparation method 189

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (isopropyloxycarbonyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester from preparation 91 and isopropanol

Experimental value MH⁺563.0, respectively; predicted value 563.0

Preparation method 190

1- [ 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (difluoromethyl) -1H-pyrazol-4-yl ] cyclopropanecarboxylic acid methyl ester

(diethylamino) sulfur trifluoride (DAST, 120 μ l, 0.90 mmol) was added to the solution of preparation 167(400 mg, 0.82 mmol) at-78 ℃. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was extracted with dichloromethane and the combined extracts were over MgSO₄Dried and then concentrated in vacuo. The residue was purified by washing with cyclohexane/ethyl acetate [ 9: 1 ]]The eluted column chromatography was purified. The appropriate fractions were combined and concentrated to give the title compound (190 mg).

¹H-NMR(CDCl₃): 1.41 to 1.45(2H), 1.84 to 1.87(2H), 3.70 to 3.72(3H), 6.54 to 6.82(1H), 7.90 to 7.93(2H)

Preparation method 191

Isopropyl (diphenyl) sulfonium tetrafluoroborate (isoprophyl) sulfonium tetrafluoroborate)

Reference material: synthesis (1982), (4), 291-4).

Preparation method 192

1- { 3-cyano-5- [ (cyclopropylmethyl) (methyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Paraformaldehyde (143 mg, 4.75 mmol) and sodium cyanoborohydride (298 mg, 4.75 mmol) were added to a solution of preparation 143(500 mg, 0.95 mmol) in glacial acetic acid (20 ml). The reaction mixture was stirred at room temperature for 60 hours and then quenched with water. After stirring for an additional 20 minutes, the mixture was extracted with ethyl acetate and the combined extracts were washed with brine, over MgSO₄Dried and concentrated in vacuo to give the title compound (200 mg) which was used directly.

The compounds prepared in a similar manner were:

preparation method 193

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (ethoxycarbonyl) (methyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester from preparation 188

Experimental value MH⁺563.0, respectively; predicted value 563.0

Preparation method 194

Methyl 1- (3-cyano-5- { [ (cyclopropylmethoxy) carbonyl ] (methyl) amino } -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl) cyclopropanecarboxylate from preparation 184

Experimental value MH⁺589.1, respectively; predicted value 589.1

Preparation method 195

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (dimethylamino) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Paraformaldehyde (158 mg, 5.25 mmol) and sodium cyanoborohydride (330 mg, 5.25 mmol) were added sequentially to a solution of preparation 91(500 mg, 1.05 mmol) in glacial acetic acid (15 ml). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. Water (30 ml) was added to the residue and the mixture was extracted with ethyl acetate (3 × 50 ml). The combined extracts were dried over MgSO4 and concentrated in vacuo, then the residue was re-dissolved in toluene and concentrated (× 3) to give the title compound (450 mg).

Experimental value MH⁺504.9, respectively; predicted value 505.0

Preparation method 196

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methylthio) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Tert-butylnitrile (0.32 ml, 2.72 mmol) was added dropwise to a solution of preparative 91(500 mg, 1.05 mmol) and dimethyl disulfide (0.19 ml, 2.10 mmol) in dichloromethane (15 ml) at 0 ℃. The reaction mixture was stirred at 0 ℃ for one hour and then at room temperature for 18 hours. Dichloromethane (25 ml) was added to the reaction mixture and the organic phase was separated, washed with brine (50 ml), over MgSO ₄Dried and concentrated in vacuo. The residue was purified by using a gradient of ethyl acetate to cyclohexane [ 8: 92 to 60: 40%]The eluted column chromatography was purified. The appropriate fractions were combined and concentrated to give the title compound (300 mg).

Experimental value MH⁺549.1 (acetonitrile adduct); predicted value 549.0

Preparation method 197

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (methoxymethyl) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Methyl iodide (2.76 ml, 44.64 mmol) and potassium carbonate (169 mg, 1.22 mmol) were added to a solution of preparative 166(300 mg, 0.61 mmol) in acetonitrile (3 ml). The reaction mixture was stirred at room temperature for 5 days, then concentrated in vacuo. The residue was partitioned between ethyl acetate and water, and the organic phase was separated over MgSO₄Dried and concentrated in vacuo. The residue was purified by using a gradient of ethyl acetate to cyclohexane [ 5: 95 to 12: 88%]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (125 mg).

Experimental value MH⁺506.0, respectively; predicted value 506.0

Preparation method 198

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (dimethylamino) -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxylic acid

A mixture of preparation 228(100 mg, 0.19 mmol) and lithium hydroxide monohydrate (78 mg, 1.85 mmol) in tetrahydrofuran/water (4: 1, 4 mL) was stirred at room temperature for 2 hours. Hydrochloric acid (2N, 5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 5 ml). The combined extracts were extracted over MgSO₄Dry above and concentrate in vacuo to give the title compound (100 mg).

Experimental value MH⁺527.0, respectively; predicted value 527.0

Preparation method 199

1- { 3-cyano-5- [ (cyclobutylmethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Preparation method 200(100 mg, 0.18 mmol) and phosphorus pentachloride (40 mg, 19.00 mmol)Mol) in toluene (5 ml) was heated to reflux for 2 h, cooled to room temperature and then poured into a solution of sodium borohydride (20 mg, 0.50 mmol) in methanol (5 ml). After stirring for 30 min, the reaction mixture was quenched with water (10 ml) and concentrated in vacuo. The residue was extracted with ethyl acetate (3 × 10 ml) and the combined extracts were washed with MgSO₄Dried above and then concentrated in vacuo to give the title compound (30 mg).

Experimental value MH⁺545.0, respectively; predicted value 545.1

Preparation method 200

1- { 3-cyano-5- [ (cyclobutylcarbonyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Cyclobutanecarbonyl chloride (0.23 ml, 2.00 mmol) was added to a solution of preparation 91(500 mg, 1.00 mmol) and pyridine (0.20 ml, 2.50 mmol) in dichloromethane (5 ml) at 0 ℃ under nitrogen. The reaction mixture was heated in a microwave (300 watts) at 55 ℃ for 40 minutes and then concentrated in vacuo to give the title compound (100 mg).

Experimental value MH⁺559.0, respectively; predicted value 559.0

Preparation method 201

2- { 3-cyano-5- (cyclopropylmethoxy) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } acrylic acid methyl ester

A solution of preparation 202(420 mg, 0.76 mmol) in p-xylene (15 ml) was heated to reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography eluting with a gradient of ethyl acetate: cyclohexane [ 5: 95 to 25: 75 ]. The appropriate fractions were combined and concentrated to give the title compound (159 mg).

Experimental value MH⁺517.9 of the total weight of the mixture; predicted value 518.0

Preparation method 202

2-chloro-2- { 3-cyano-5- (cyclopropylmethoxy) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } propanoic acid methyl ester

Thionyl chloride (0.51 ml, 6.93 mmol) was added to a solution of preparative 77(1.24 g, 2.31 mmol) in acetonitrile (23 ml). The reaction mixture was heated at 50 ℃ for 3 hours and then concentrated in vacuo. The residue was purified by column chromatography using a gradient of ethyl acetate: cyclohexane [ 3: 97 to 15: 85 ]. The appropriate fractions were combined and concentrated to give the title compound (850 mg).

Experimental value MH⁺554.0, respectively; predicted value 554.0

Preparation method 203

Lithium hydroxide monohydrate (147 mg, 3.5 mmol) was added to a solution of preparative method 205(226 mg, 0.35 mmol) in tetrahydrofuran/water (4: 1, 3.5 ml) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was acidified with hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with water and over MgSO₄Dried and concentrated in vacuo. Triethylamine (120 μ l, 0.88 mmol) and ethyl chloroformate (40 μ l, 0.42 mmol) were added to a solution of the residue in tetrahydrofuran (3.5 ml) at 0 ℃. After stirring for 30 min, aqueous ammonium hydroxide (1 ml) was added and the reaction mixture was warmed to room temperature. The reaction mixture was adjusted to pH 1 by addition of hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with water over MgSO ₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (1.5 ml) and purified by using a gradient of acetonitrile: water [ 55: 45 to 95: 5 ]]Automated preparative liquid chromatography (Gilson System, 150 mm. times.50 mm, LUNA C18(2)10 μm)Column) was purified. The appropriate fractions were concentrated in vacuo to give the title compound (72 mg).

Experimental value MH⁺631.4, respectively; predicted value 631.1

Preparation method 204

5- (cyclopropylmethoxy) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazole-3-carbonitrile

(bromomethyl) cyclopropane (6.5 ml, 67.20 mmol) was added to a mixture of preparative 222(6.37 g, 16.80 mmol) and potassium carbonate (7.00 g, 50.40 mmol) in acetonitrile (75 ml). The reaction mixture was stirred at room temperature for one hour and then at 50 ℃ for 3 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between hydrochloric acid (1M) and ethyl acetate. The two layers were separated and the organic layer was washed with water over MgSO₄Dried and concentrated in vacuo. The residue was purified by using a gradient of ethyl acetate to cyclohexane [ 2: 98 to 20: 80%]The eluted column chromatography was purified. The appropriate fractions were combined and concentrated to give the title compound (2.97 g).

Experimental value MH⁺433.9; predicted value 434.0

Preparation method 205

1- {5- [ ({1- [ (tert-butoxycarbonyl) amino ] cyclopropyl } methyl) amino ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

A solution of preparation 91(425 mg, 0.89 mmol) in toluene/dichloroethane (4: 1, 12 ml) was heated at 90 ℃ for 5 minutes, then (1-formyl-cyclopropyl) -carbamic acid tert-butyl ester (0.50 g, 2.70 mmol) and p-toluenesulfonic acid (17 mg) were added. The reaction mixture was heated at 90 ℃ for one hour using a Dean-Stark apparatus, then heated to reflux for 2 hours. The mixture was concentrated in vacuo and the residue azeotroped with toluene. Sodium borohydride (85 mg, 2.23 mmol) was added to the residue in methanol (16 ml) at 0 ℃And the reaction mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for one hour. Hydrochloric acid (1M) and ethyl acetate were added to the mixture. Separating the organic phase over MgSO₄Dried and concentrated in vacuo to give the title compound (226 mg).

Experimental value MH⁺646.2, respectively; predicted value 646.1

Preparation method 206

1- { 3-cyano-5- ({2- [ (cyclopropylmethyl) amino ] -2-oxoethyl } amino) -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

A solution of triethylamine (0.15 ml, 1.09 mmol) and ethyl chloroformate (31 μ l, 0.33 mmol) in tetrahydrofuran (0.5 ml) were added sequentially to a solution of preparative method 49(145 mg, 0.27 mmol) in tetrahydrofuran (6 ml). After stirring for 30 minutes, (aminomethyl) cyclopropane hydrochloride (88 mg, 0.82 mmol) was added and the reaction mixture was stirred at room temperature for one hour. The mixture was concentrated in vacuo and the residue was partitioned between hydrochloric acid (0.5N, 20 ml) and ethyl acetate (20 ml). The organic phase was separated, washed with brine (20 ml) over MgSO₄Dried and concentrated in vacuo to give the title compound (150 mg).

Experimental value MH⁺587.9, respectively; predicted value 588.1

Preparation method 207

1- {5- [ (2-tert-butoxy-2-oxoethyl) amino ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

A mixture of preparation 91(487 mg, 1.02 mmol), tert-butyl bromoacetate (0.23 ml, 1.53 mmol) and potassium carbonate (423 mg, 3.10 mmol) in acetonitrile (20 ml) was heated at 55 ℃ for 48 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml) and the organic phase was partitioned Separated, washed with brine (30 ml) over MgSO₄Dried and concentrated in vacuo. The residue was purified by using a gradient of cyclohexane to ethyl acetate [ 4: 1 to 2: 1%]The eluted column chromatography was purified. The appropriate fractions were combined and concentrated to give the title compound (380 mg).

Experimental value MH⁺590.8, respectively; predicted value 591.1

Preparation method 208

2, 6-dichloro-4-cyanophenyldiazonium tetrafluoroborate (2, 6-dichoro-4-cyanobenezediazonium tetrafluoroborate)

Tetrafluoroboric acid (2.80 ml, 21.27 mmol) was added dropwise to a solution of 4-amino-3, 5-dichlorobenzonitrile (2.00 g, 10.63 mmol) in acetonitrile (12 ml). After stirring for 10 min, isopentonitrile (1.50 ml, 10.63 mmol) was added and the reaction mixture was cooled to 0 ℃. After a further 10 minutes, diethyl ether (50 ml) was added and the precipitate formed was collected by filtration and dried to give the title compound (1.9 g).

¹H-NMR(D₂O): 8.36 to 8.40(2H)

The compounds prepared in a similar manner were:

preparation method 209

2, 6-dichloro-4- (trifluoromethoxy) benzenediazonium tetrafluoroborate from 2, 6-dichloro-4-trifluoromethoxyaniline

Preparation method 210

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-methoxyethyl) (methyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Potassium hydroxide (103 mg, 1.84 mmol) and methyl iodide (1.1 ml, 1.84 mmol) were added sequentially to a solution of preparative 211(120 ml, 0.23 mmol) in dimethyl sulfoxide (2 ml). After stirring at room temperature for one hour, diethyl ether (20 ml) and water (15 ml) were added and the two layers were separated. The organic layer was washed with brine, over MgSO₄Dried above and concentrated in vacuo to give the title compound (95 mg).

Experimental value MH⁺549.1, respectively; predicted value 549.1

Preparation method 211

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ (2-hydroxyethyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Triethylamine (150 μ l, 1.05 mmol) and ethyl chloroformate (100 μ l, 1.05 mmol) were added successively to a solution of preparative 49(330 mg, 0.62 mmol) in tetrahydrofuran (5 ml) at 0 ℃. The mixture was stirred at 0 ℃ for 15 minutes and then at room temperature for 20 minutes. Passing the mixture through Celite^®Filtered and added to a solution of sodium borohydride (70 mg, 1.85 mmol) in tetrahydrofuran (3 ml). Methanol (4 ml) was then added carefully and the reaction mixture was warmed to room temperature. After one hour, hydrochloric acid (2N, 5 ml) was added and the mixture was concentrated in vacuo. Ethyl acetate (25 ml) was added to the residue and the solution was washed with hydrochloric acid (2N, 15 ml), sodium bicarbonate solution (15 ml) and brine (15 ml) over MgSO ₄Dried and concentrated in vacuo to give the title compound (304 mg).

Preparation method 212

4- ({ 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -4- [1- (methoxycarbonyl) cyclopropyl ] -1H-pyrazol-5-yl } amino) butanoic acid

Trifluoroacetic acid (5 ml) was added dropwise to a solution of preparative 121(159 mg, 0.25 mmol) in dichloromethane (5 ml). After stirring for one hour, the reaction mixture was concentrated in vacuo to give the title compound (180 mg).

Experimental value MH⁺563.1; predicted value 563.0

Preparation method 213

1- (3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- { [2- (1H-1, 2, 4-triazol-1-yl) ethyl ] amino } -1H-pyrazol-4-yl) cyclopropanecarboxylic acid methyl ester

1, 2, 4-triazole (55 mg, 0.79 mmol) and potassium carbonate (132 mg, 0.95 mmol) were added sequentially to a solution of preparative 215(190 mg, 0.32 mmol) in acetonitrile (4 ml). The reaction mixture was stirred at 60 ℃ for one hour, cooled and concentrated in vacuo to give the title compound (150 mg) which was used directly.

Experimental value MH⁺571.9, respectively; predicted value of 572.0

The compounds prepared in a similar manner were:

preparation method 214

Methyl 1- { 3-cyano-5- [ (2-cyanoethyl) amino ] -1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-4-yl } cyclopropanecarboxylate from preparative method 215 and 2-cyanoethylamine

Experimental value MH⁺529.9, respectively; predicted value 530.0

Preparation method 215

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- ({2- [ (methylsulfonyl) oxy ] ethyl } amino) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Triethylamine (0.12 ml, 0.85 mmol) and methanesulfonyl chloride (78 mg, 0.68 mmol) were added sequentially to a solution of preparation 211(295 mg, 0.57 mmol) in dichloromethane (10 ml). After stirring at room temperature for 2 hours, dichloromethane was added and the solution was washed with hydrochloric acid (0.5N, 25 ml) and brine (25 ml) over MgSO₄Drying and vacuum concentrating to obtainTo the title compound (300 mg).

Experimental value MH⁺598.8, respectively; predicted value 599.0

Preparation method 216

2, 6-dichloro-4- [1, 2, 2, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] aniline

N-chlorosuccinimide (1.02 g, 6.66 mmol) was added to a solution of preparation 217(1.00 mg, 3.33 mmol) in acetonitrile (10 ml). The reaction mixture was heated at 50 ℃ for 5 hours, diluted with water and then extracted with ethyl acetate. The combined extracts were washed with water and over MgSO₄Dried and concentrated in vacuo. The residue was purified by using ethyl acetate/cyclohexane [ 2: 3 ]]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (630 mg).

¹H-NMR(CDCl₃): 4.65 to 4.80(2H), 7.38 to 7.41(2H)

Preparation method 217

4- [1, 2, 2, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] aniline

To a solution of aniline (1.32 g, 14.19 mmol) in t-butyl methyl ether (25 ml) and water (25 ml) was added 2-iodoheptafluoropropane (5.00 g, 17.06 mmol), sodium thiosulfate (3.50 g, 17.06 mmol), sodium bicarbonate (1.73 g, 17.06 mmol) and tetrabutylammonium hydrogen sulfate (0.53 g, 17.06 mmol) in that order. The reaction mixture was stirred at room temperature for 18 hours, and the two layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with hydrochloric acid (2N), aqueous sodium bicarbonate and brine over MgSO₄Dried above and concentrated in vacuo to give the title compound (1.00 g).

¹H-NMR(CDCl₃): 6.65 to 4.78(2H), 7.30 to 7.35(2H)

Preparation method 218

2-fluoro-2-methylpropan-1-ol

Reference material: zeitschrift fuer Chemie (1965), 5(10), 380-1

Preparation method 219

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

Reference material: WO-9828078

Preparation method 220

1- (1, 2-dicyano-3-methoxy-3-oxopropyl) cyclopropanecarboxylic acid ethyl ester

Potassium cyanide (4.30 g, 65.80 mmol) was added to a mixture of preparative 221(9.35 g, 65.80 mmol), piperidine (0.65 ml, 6.58 mmol), methyl cyanoacetate (5.80 ml, 65.80 mmol) and potassium carbonate (0.91 g, 6.58 mmol) in isopropanol (120 ml). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was partitioned between hydrochloric acid (1M) and ethyl acetate and the two layers were separated. The aqueous layer was extracted with ethyl acetate and the combined extracts were washed with brine, over MgSO₄Dried and concentrated in vacuo.

The residue was purified by column chromatography eluting with a gradient of ethyl acetate: cyclohexane [ 5: 95 to 35: 65 ]. The appropriate fractions were combined and concentrated to give the title compound (13.44 g).

¹H-NMR(CDCl₃): 1.20 to 1.25(3H), 1.40 to 1.60(4H), 3.89 to 3.92(3H), 4.20 to 4.30(2H), 4.50 to 4.65(1H)

Preparation method 221

1-Formylcyclopropanecarboxylic acid ethyl ester

At 0 deg.C, saturatedSodium bicarbonate solution (50 ml), TEMPO (659 mg, 4.00 mmol) and sodium bromide (400 mg, 4.00 mmol) were added sequentially to a solution of preparation 232 (ethyl 1-hydroxymethyl-cyclopropanecarboxylate, 3.00 g, 21.00 mmol) in dichloromethane (50 ml). After stirring for 5 minutes, sodium hypochlorite solution (10%, 14.00 mmol) was slowly added followed by saturated sodium thiosulfate solution (50 ml). The two layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic phases were washed with water and brine ₄Dried above and concentrated in vacuo to give the title compound (3.00 g).

¹H-NMR(CDCl₃): 1.25 to 1.35(3H), 1.55 to 1.64(4H), 4.21 to 4.30(2H), 10.39 to 10.41(1H)

Preparation method 222

1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5-hydroxy-1H-pyrazole-3-carbonitrile

Sodium nitrite (1.32 g, 19.1 mmol) was carefully added to sulfuric acid (concentrated, 6.8 ml) and the solution was cooled to 0 ℃. The solution was heated to 60 ℃ for 30 minutes, cooled and then diluted with acetic acid (12 ml). A solution of preparative 182(5.0 mg, 17.4 mmol) in acetic acid (11 ml) was added to the solution and the reaction mixture was heated at 55 ℃ for one hour. The diazonium salt solution, a solution of sodium acetate (24.2 g) in water (42 ml) was added dropwise to a solution of preparation 248(3.09 g, 18.1 mmol) in acetic acid (24 ml) and water (36 ml) one after the other. The reaction mixture was then stirred at room temperature for 30 minutes. The reaction mixture was poured into ice/water (200 ml) and the mixture was extracted with dichloromethane (4 × 60 ml). The combined extracts were then washed with ammonium hydroxide (48 ml), dried and concentrated in vacuo. A solution of the residue in methanol (100 ml) was added dropwise to a solution of sodium methoxide (25 wt%, 11.5 ml, 50.1 mmol) in methanol (450 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and water was added to the residue. The solution was adjusted to pH by addition of hydrochloric acid (4N) 1 and the mixture was extracted with dichloromethane (3 × 100 ml). The combined extracts were extracted over MgSO₄Dried and concentrated in vacuo.

The residue was purified by column chromatography eluting with hexane/ethyl acetate [ 3: 1 ]. The appropriate fractions were combined and concentrated to give the title compound (4.5 g).

Experimental value MH⁺379.8, respectively; predicted value 380.0

Preparation method 223

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ ({ [1- (fluoromethyl) cyclopropyl ] methoxy } carbonyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Lithium hydroxide monohydrate (200 mg, 5.00 mmol) was added to a solution of preparative 224(300 mg, 0.50 mmol) in tetrahydrofuran/water (10: 1, 5 ml) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was acidified with hydrochloric acid (1M) and extracted with ethyl acetate. The combined extracts were washed with water and over MgSO₄Dried and concentrated in vacuo to give the title compound (295 mg).

Experimental value MH⁺593.0, respectively; predicted value 593.0

Preparation method 224

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- [ ({ [1- (fluoromethyl) cyclopropyl ] methoxy } carbonyl) amino ] -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Pyridine (450 mg, 5.00 mmol) was added to a solution of preparative 91(250 mg, 0.50 mmol) in dichloromethane (5 ml). The mixture was cooled to 0 ℃, then phosgene (20% in toluene, 5.5 ml, 2.50 mmol) was added, followed by preparative 230(100 mg, 1.00 mmol). The reaction mixture was allowed to warm to room temperature for 2 hours with stirring and water was added. The mixture was extracted with ethyl acetate and the combined extracts were combinedThe material was washed with brine, over MgSO₄Dried and concentrated in vacuo to give the title compound (300 mg).

Experimental value MH⁺607.1, respectively; predicted value 607.0

Preparation method 225

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- ({ 2-oxo-2- [ (2, 2, 2-trifluoroethyl) amino ] ethyl } amino) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid

Lithium hydroxide monohydrate (80 mg, 1.91 mmol) was added to a solution of preparation 226(180 mg, 0.34 mmol) in tetrahydrofuran (4 ml) and water (0.5 ml) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was quenched with hydrochloric acid (0.5N) and extracted with ethyl acetate (2 × 10 ml). The combined extracts were extracted over MgSO ₄Dried and concentrated in vacuo to give the title compound (75 mg).

Experimental value MH⁺602.0; predicted value 602.0

Preparation method 226

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- ({ 2-oxo-2- [ (2, 2, 2-trifluoroethyl) amino ] ethyl } amino) -1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

Triethylamine (0.19 ml, 1.35 mmol) and ethyl chloroformate (44 mg, 0.41 mmol) were added dropwise, followed by a solution of preparative method 49(180 mg, 0.34 mmol) in tetrahydrofuran (8 ml). After 15 min, 2, 2, 2-trifluoroethylamine hydrochloride (137 mg, 1.02 mmol) was added and the reaction mixture was stirred at room temperature for 8 h. The mixture was diluted with hydrochloric acid (0.5N, 20 ml) and extracted with ethyl acetate (2 × 20 ml). The combined extracts were extracted over MgSO₄Dried and concentrated in vacuo.

The residue was purified by column chromatography eluting with a gradient of ethyl acetate: cyclohexane [ 1: 2 to 2: 1 ]. The appropriate fractions were combined and concentrated to give the title compound (80 mg).

Experimental value MH⁺616.0, respectively; predicted value 616.0

Preparation method 227

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5-vinyl-1H-pyrazol-4-yl } cyclopropanecarboxylic acid methyl ester

N-butyllithium (1.34M in hexane, 0.48 ml, 0.64 mmol) was added to a solution of methyltriphenylphosphonium bromide (241 mg, 0.67 mmol) in tetrahydrofuran (12.2 ml) at-78 ℃. After 10 minutes, the mixture was warmed to 0 ℃ and added to a solution of preparation 167(300 mg, 0.61 mmol) in tetrahydrofuran (12.2 ml) at-78 ℃ using a loop addition. The reaction mixture was stirred at-78 ℃ for 20 minutes and then warmed to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined extracts were then extracted over MgSO₄Dried and concentrated in vacuo. The residue was purified by using a gradient of ethyl acetate to cyclohexane [ 4: 96 to 12: 88%]The eluted column chromatography (silica) was purified. The appropriate fractions were combined and concentrated to give the title compound (30 mg).

¹H-NMR(CDCl₃): 1.31 to 1.36(2H), 1.81 to 1.86(2H), 3.68 to 3.71(3H), 5.51 to 5.60(2H), 6.15 to 6.23(1H), 7.89 to 7.92(2H)

Preparation method 228

1- { 3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -5- (dimethylamino) -1H-pyrazol-4-yl } -2, 2-difluorocyclopropanecarboxylic acid methyl ester

Paraformaldehyde (30 mg, 0.98 mmol) and sodium cyanoborohydride (60 mg, 0.98 mmol) were added to a solution of preparative 92(100 mg, 0.20 mmol) in glacial acetic acid (4 ml) under nitrogen. The reaction mixture was stirred at room temperature for 60 hours, and then quenched with water (50 ml). Stirring again After stirring for 30 min, the mixture was extracted with ethyl acetate (50 ml) and the combined extracts were extracted with brine over MgSO₄Dried and concentrated in vacuo to give the title compound (100 mg).

Experimental value MH⁺540.9, respectively; predicted value 541.0

Preparation method 229

1- [ ({4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorothiophenyl ] -1H-pyrazol-5-yl } amino) methyl ] cyclopropanecarboxylic acid ester

Preparation 221(390 mg, 2.74 mmol) was added to a solution of preparation 91(434 mg, 0.91 mmol) and p-toluenesulfonic acid (17 mg, 91 micromoles) in toluene (43 ml). The reaction mixture was heated to reflux for 3 hours using a Dean-Stark apparatus, then cooled and concentrated in vacuo. The residue was dissolved in methanol (17 ml) and the solution was cooled to 0 ℃. Sodium borohydride (86 mg, 2.28 mmol) was added portionwise and the mixture was stirred at 0 ℃ for one hour. The mixture was partitioned between hydrochloric acid (1M) and ethyl acetate and the two layers were separated. The aqueous layer was extracted with ethyl acetate and the combined extracts were washed with water over MgSO₄Dried and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulfoxide (2 ml) and purified by using a gradient of acetonitrile: water [ 70: 30 to 95: 5 ] ]The purification was carried out by preparative liquid chromatography (Gilson system, 150 mm. times.50 mm, LUNA C18(2)10 μm column). The appropriate fractions were concentrated in vacuo to give the title compound (83 mg) which was used directly.

Preparation method 230

[1- (fluoromethyl) cyclopropyl ] methanol

Lithium aluminum hydride (1M in diethyl ether, 20 ml, 20.00 mmol) was added to a solution of preparation method 231(3.00 g, 20.00 mmol) in diethyl ether (50 ml) at 0 ℃. After stirring for 30 min at 0 ℃, water was carefully added and the mixture was diluted with diethyl ether. AddingHydrochloric acid (3 drops) and the two layers were separated. The aqueous layer was extracted with diethyl ether and the combined organic phases were washed with brine, over MgSO₄Dried and concentrated in vacuo. The residue was purified by column chromatography eluting with diethyl ether/pentane and the appropriate fractions were combined and concentrated to give the title compound (1.00 g).

¹H-NMR(CDCl₃): 0.59 to 0.63(4H), 3.59 to 3.62(2H), 4.25 to 4.45(2H)

Preparation method 231

1- (fluoromethyl) cyclopropanecarboxylic acid ethyl ester

(diethylamino) sulfur trifluoride (DAST, 3.56 g, 22.00 mmol) was added to a solution of preparation 232(3.00 g, 20.00 mmol) in dichloromethane (50 ml) at-78 ℃ under nitrogen. The reaction mixture was allowed to warm to room temperature for 2 hours and then stirred for 18 hours. Hydrochloric acid (10%, 5 drops) and water (50 ml) were added to the mixture and the two layers were separated. The aqueous layer was extracted with dichloromethane and the combined organic phases were washed with water and brine over MgSO ₄Dried above and concentrated in vacuo to give the title compound (3.00 g).

¹H-NMR(CDCl₃): 0.92 to 1.00(2H), 1.20 to 1.28(3H), 1.35 to 1.40(2H), 4.10 to 4.21(2H), 4.42 to 4.59(2H)

Preparation method 232

1-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester

Reference material: tetrahedron Letters (1999), 40(30), 5467-5470.

Preparation method 233

2-cyano-succinic acid dimethyl ester

Reference material: WO-2005090313

Preparation method 234

Tributyl- (1-fluoro-vinyl) -stannane

Reference material: WO-0560749

Claims

1. A compound of formula (I)

Wherein:

x is selected from CR¹⁰Or N;

R¹selected from halogen, cyano, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkanoyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, amino, C_1-6Alkylamino radical, di-C_1-6Alkylamino, het, phenyl, SF₅And S (O)_nR¹¹；

Or R²Is selected from C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkanoyl radical, C (O) OC_1-6Alkyl, amino, C_1-6Alkylamino and di-C_1-6Alkylamino, each of the foregoing groups optionally and independently further substituted with one or more substituents selected from, where chemically available, the following: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

R^aAnd R^bIndependently selected from hydrogen, het, phenyl and S (O)_nR¹¹；

Or R^aAnd R^bEither or both of which are independently selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C _1-6Alkyl radical, C_1-6Alkanoyl and C (O) OC_1-6Alkyl, each of the above R^aOr R^bThe groups are optionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen,Oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or R^aAnd R^bTogether with the N atom to which they are attached form a 3-to 7-membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring, which optionally contains one or more further N, O or S atoms, and which is optionally further substituted by one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C _1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or R³、R⁴、R⁵And R⁶Is independently selected from C_1-4Alkyl, C (O) NR^cR^d、C(S)NR^cR^d、C_1-4Alkoxy radical, C_1-4Alkanoyl radical, C (O) OC_1-4Alkyl and amino, the R³、R⁴、R⁵And R⁶Optionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, hydroxy, C _1-4Alkyl and amino;

R⁷selected from halogen, C_1-6Alkyl and C_1-6Alkoxy, wherein when R⁷Is C_1-6Alkyl or C_1-6At alkoxy radical, R⁷Optionally substituted with one or more halo substituents;

Or R⁸Is selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkanoyl and C (O) OC_1-6Alkyl radical, the R⁸Optionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or R⁸Is amino, the R⁸Optionally and independently further substituted with one or more substituents selected from, where chemically available: c (O) OH, C (O) NR ^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, het, phenyl and S (O)_nR¹¹；

Or R⁹Is selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl radical C_1-6Alkoxy radical, C_1-6Alkanoyl radical, C (O) OC_1-6Alkyl radical, the R⁹Optionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

R^eAnd R^fIndependently selected from hydrogen, het, phenyl and S (O)_nR¹¹；

Or R^eAnd R^fEither or both of which are independently selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C _3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_1-6Alkanoyl radical, C (O) OC_1-6Alkyl, -C (O) OC_1-6Alkyl radical C_3-8Cycloalkyl, -C (O) OC_3-8Cycloalkyl radical, each of the above R^eOr R^fThe groups are optionally and independently further substituted with one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

Or R^eAnd R^fTogether with the N atom to which they are attached form a 3-to 7-membered saturated, partially saturated, unsaturated or aromatic heterocyclic ring, which optionally contains one or more further N, O or S atoms, and which is optionally further substituted by one or more substituents selected from, where chemically available: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC _1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, NR^cR^dHet, phenyl and S (O)_nR¹¹；

R¹⁰selected from halogen, C_1-6Alkyl and C_1-6Alkoxy, wherein when R¹⁰Is C_1-6Alkyl or C_1-6Alkoxy, which is optionally substituted with one or more halo substituents;

each of the above R^cAnd R^dThe groups are independently selected from hydrogen and C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkanoyl radical, C_1-6Haloalkanoyl, C (O) OC_1-6Alkyl, het, phenyl and S (O)_nR¹¹；

each n is independently 0, 1 or 2;

And each het independently represents a 4-to 7-membered heterocyclic ring which is aromatic or non-aromatic, unsaturated, partially saturated or saturated and which contains one or more heteroatoms selected from nitrogen, N-oxide, oxygen, sulphur, and wherein the heterocyclic ring is optionally, where valency allows, substituted by one or more heteroatoms selected from halogen, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy, OC (O) C_1-6Alkyl radical, C_1-6Alkanoyl radical, C (O) OC_1-6Alkyl and NR^gR^hWherein R is^gAnd R^hIndependently selected from hydrogen, C_1-6Alkyl and C_2-6Alkenyl, and each of the above groups includes one or more, where chemically available, substituents selected from the group consisting of: cyano, nitro, halogen, oxo, hydroxy, C (O) OH, C (O) NR^cR^d、NR^cC(O)R^d、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkanoyl, -C (O) OC_1-6Alkyl radical, C_1-6Haloalkyl, C_3-8Halocycloalkyl radical, C_1-6Haloalkoxy, C_1-6Haloalkanoyl, -C (O) OC_1-6Haloalkyl, amino, C_1-6Alkylamino radical, di-C_1-6Alkylamino, phenyl and S (O) _nR¹¹；

Or a pharmaceutically acceptable salt or prodrug thereof.

2. The compound of claim 1, wherein R¹Selected from CF₃、OCF₃Or SF₅。

3. A compound as claimed in claim 1 or claim 2 wherein R is²Selected from: a cyano group; s (O)_nR¹¹(ii) a And C (O) NR^aR^bWherein R is^aIs hydrogen, and R^bSelected from hydrogen and C_1-6Alkyl radical, C_1-6Alkyl is optionally substituted with het.

4. The compound of claim 3, wherein R²Is C (O) NR^aR^bWherein R is^aAnd R^bAre both hydrogen.

5. The compound of any one of claims 1 to 4, wherein R³And R⁴Are identical to each other and are selected from: hydrogen; fluorine; chlorine; and methyl, and R⁵And R⁶Are both hydrogen.

6. The compound of any one of claims 1 to 5, wherein R⁸Is cyano.

7. The compound of any one of claims 1 to 6, wherein R⁹Selected from: hydrogen; halogen; c_1-6Alkyl radical, C_1-6Alkyl is then optionally substituted with one or more substituents selected from halogen and C_1-6Substituent substitution of alkoxy; c_2-6An alkenyl group; c_3-8Cycloalkyl radical C_1-6An alkoxy group; and S (O)_nR¹¹。

8. The compound of any one of claims 1 to 6, wherein R⁹Is NR^eR^fWherein each of R mentioned above^eOr R^fThe groups are independently selected from hydrogen: c_1-6Alkyl radical, C_1-6The alkyl group may then be substituted with one or more substituents selected from: cyano, halogen, C (O) OH, C (O) NR ^cR^d、C_1-6Alkyl radical, C_1-6Alkoxy, het, phenyl and S (O)_nR¹¹。

9. The compound of any one of claims 1 to 6, wherein R⁹Is NR^eR^fWherein R is^eIs hydrogen or C_1-6Alkyl, and R^fIs C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl groups may be optionally substituted with one or more of the following groups: c_1-6An alkyl group; an amino group; c (O) NR^cR^dWherein R is^cAnd R^dAre all hydrogen; and NR^cR^dWherein R is^cAnd R^dIndependently selected from hydrogen, C (O) OC_1-6Alkyl and S (O)_nR¹¹Group (d) of (a).

10. The compound of any one of claims 1 to 6, wherein R⁹Is NR^eR^fWherein R is^eIs hydrogen or C_1-6Alkyl, and R^fSelected from: -C (O) OC_1-6An alkyl group; -C (O) OC_3-8A cycloalkyl group; and-C (O) OC_1-6Alkyl radical C_3-8Cycloalkyl radical, the group-C (O) OC_1-6Alkyl radical C_3-8Cycloalkyl optionally substituted by C_1-6Haloalkyl is further substituted.

11. The compound of any one of claims 1 to 10, wherein X is CR¹⁰And R is¹⁰Is chlorine.

12. The compound of claim 11, wherein R⁷And R¹⁰Are all Cl.

13. A compound selected from the group consisting of:

{4- [1- (aminocarbonyl) cyclopropyl ] -3-cyano-1- [2, 6-dichloro-4-pentafluorophenylyl ] -1H-pyrazol-5-yl } carbamic acid [1- (fluoromethyl) cyclopropyl ] methyl ester;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } -N-cyclopropylcyclopropanecarboxamide;

1- { 5-amino-3-cyano-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } cyclopropane-methionamide;

or a pharmaceutically acceptable salt or prodrug thereof.

14. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or prodrug thereof.

15. A pharmaceutical composition comprising a compound of any one of claims 1 to 14 and a pharmaceutically acceptable carrier.

16. A compound according to any one of claims 1 to 14 for use as a medicament.

17. Use of a compound according to any one of claims 1 to 14 for the manufacture of a medicament for the treatment of parasitic infections.

18. A method of treating parasitic infections comprising treating an animal with an effective amount of a compound of claims 1 to 14.