TW200531963A - Substituted pyrazoles - Google Patents

Abstract

The invention relates to a sulfonamide compound of formula (I) or a pharmaceutically, veterinarily or agriculturally acceptable salt or solvate thereof, Where the groups R1-R5 are described in the description, to compositions comprising such compounds, processes for their synthesis and their use as parasiticides.

Description

200531963. IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a pesticidal compound and a preparation method thereof. More specifically, the present invention relates to a N- (i-arylpyridazol-4-yl) sulfonamide having parasiticidal activity. We have specifically identified a series of arylpyrazole-4-yl) pyramines with improved activity and / or longer duration of action and / or improved safety. Amine continuation groups (upside-down of lutein) of amines for controlling arthropods, plant nematodes, or worm insects have also been disclosed in, for example, EP-234119, US-2002016333, WO-0258690 and 10 DE-19511269 U sits better than cr. It has been disclosed, for example, in EP-0192951 and EP-302328 that 5-azolamine-1_aryl group which can be used as a herbicide can be used. Sit than α. US-5618945 relates to a method for treating compounds such as rs (〇) X (where X is usually I5 as C1) to sub-ferment compounds such as aryl σ ratio σ class; and discloses a formula RS (0) A compound of NH-Het, wherein Het may be N-arylpyrazole (although the substitution pattern indicated is unclear). WO-9315060 discloses a number of ° -to- ° sitting classes that have fungicidal activity and are used for crop protection. Among the many structures disclosed, some are 20 N-heterocyclooxazol-4-ylsulfonamides. WO 00/71532, WO 03/51833, WO 01/19788, WO 01/19798, WO 03/37274, WO 04/00318, WO 98/57937, and WO 96/12706 all widely describe 0 to 0 compounds, but their The use is irrelevant as described in the present invention. 5 200531963, the compounds described in the prior art do not always exhibit good antiparasitic activity or long periods of action. Similarly, some parasiticides can only be used on a narrow range of parasites. Modern insecticides must meet many needs, including long-term, broad range of action, low toxicity, and can be combined with other actives and / or differently formulated excipients. Resistance events may also occur. Therefore, there is a need to continuously search for new antiparasitic drugs, and in one or more of these perspectives, there is a continuing need for novel compounds superior to well-known compounds. [Summary of the Invention] 10 The object of the present invention is to provide a compound which can be conveniently administered with antiparasitic drugs. In particular, there is a search for a medicament that can be used to treat human or animal parasitic diseases or that can be used in agricultural or horticultural applications. One of the goals is to provide a pharmaceutical that can be used in humans, livestock (including sheep, pigs, and cattle) and companion animals (including cats, dogs, and horses). The agent is intended to control arthropods, spiders, nematodes and worms, including ropes, lice, mites and ticks. Another goal of Lu is to provide a compound with good pharmacokinetics and prolonged periods of action, so that it can prevent parasite infestation and re-establish for more than a long time. The further objective is to provide a compound suitable for oral, parenteral or topical administration, which is capable of killing parasites present and preventing parasite infestation. In terms of volume flexibility and labor costs, its advantages are that it is not necessary to take medication regularly and the schedule is easier. When successive doses cannot be ignored, they can in turn help reduce the recurrence of parasitic infections. The object of the present invention is to overcome the various shortcomings of the previously described technical compounds or to improve their properties. It is therefore an object of the present invention to provide an arylpyrazole which has improved activity relative to the antiparasitic compounds of the aforementioned technique. The compounds of the present invention have particularly good abilities (as shown by test results that reveal their potency and efficacy) to control a wide range of arthropod movements. We have surprisingly found that the compounds of the present invention have significantly greater class-like activity and / or have a longer period of action, overtaking similar prior art compounds. An advantage of the compounds of the present invention is that treatment with these compounds can also lead to a reduction in the incidence of allergic moles that are sensitive to parasitic infections. For example, it can reduce the incidence of argon allergy that can cause lice allergic skin inflammation. It is also desirable that the compounds of the present invention should have an improved pharmacokinetic profile, improved safety, longer half-life, improved persistence, and improved solubility. It is also desirable that the compound should result in a reduced incidence of vomiting. 15 Unfortunately, many of the powerful insecticidal arylpyrazoles and their derivatives also have unwanted effects (such as causing the animal to vomit), regardless of whether the animal is directly receiving treatment. This unwanted toxicity will limit the dose that can be used, and therefore the range of parasitic organisms that can be controlled. Therefore, the objective of the present invention is to meet the needs for the development and use of this new and effective pesticide. Animals in the affected area are non-toxic. A further object is to provide a method for the convenient and efficient synthesis of the arylpyrazole and intermediates of the present invention. The object of the present invention is also to provide a way for the compounds of the invention of this 200531963, which can provide good yields and ideally avoid the use of unnecessary synthetic steps and / or purification steps. The present invention meets some or all of the above objectives. Embodiment 3 According to the present invention, a compound of formula (I) or a pharmaceutically, veterinary or agronomically acceptable salt or solvate thereof has been provided,

11 / R3

R1 represents phenyl or heteroaryl, which can be optionally substituted by one or more groups each independently selected from the group consisting of halo, cyano, hydroxy, Cualkyl, Cm-alkyl, C! _6 Alkoxy, Cw haloalkoxy, Cw alkanoyl, Cw haloalkylfluorenyl, -SCCOnC ^ alkyl, -SCCOnCw haloalkyl, and pentafluorosulfanyl; R2 stands for fluorenyl, halo, cyano, schottyl, Ci_6 alkyl, Ci_6 halo, c2_6 alkenyl, C2_6 haloalkenyl, C2_6 alkynyl, C2_6 haloalkynyl, 4 (0) / ^ alkyl, -SCCOnC ^ haloalkyl,-(C〇_3 Alkyl) -0_3 cycloalkyl, Cw alkyl (which may be optionally substituted by Cw alkoxy), alkyl (which may be optionally substituted by Cw alkoxy, phenyl, het),-( C〇_3alkylene) N (Ra) Rb,-(C〇_3alkylene) -C (0) NRaRb or-(C〇_3alkylene) -N (Re) C (0) R6; R3 represents Ci_6 alkyl, Ci_6 haloalkyl, C2-6 dilute, C2-6_ dilute,-(C〇_3alkylene) -C3_8cycloalkyl, _ (CN3alkylene) 4 (0) / ^ 6 alkyl,-(Cw alkyl) 4 (0) / ^ haloalkyl,-(C0_3 alkyl) -N (Ra) Rb, 200531963-(C〇_3 (Alkylene) -phenyl,-(c0_3alkylene) -het,-(C2-3alkylene) _phenyl,-(C2-3alkylene ) -Het, C! _6alkyl, Ci-6 haloalkyl, or -N (Rc) C02R6; R4 represents hydrogen, Cu alkyl, Cu haloalkyl,-(C〇_3alkyl) -R7 Or " (Ci-3 alkylene) -R8; 5 or R3 and R4 are connected together with nitrogen and sulfur atoms to form a 4- to 7-membered ring; R5 represents hydrogen, hydroxyl, halo, Cw alkyl, C! _6 Haloalkyl, C2_6 alkenyl, C2-6 haloalkenyl, Cu alkoxy, Cu haloalkoxy, -N = C (R10) (C〇_5 alkylene) -Ru or -N (R12) R13; R6 represents alkyl or Cm haloalkyl; 10R7 represents C3-8 cycloalkyl, -S (0) nR9, phenyl, het, -C02R6 or C (0) N (Ra) Rb; R8 represents hydroxyl, C! _6 alkoxy, Cw haloalkoxy, cyano, -N (Ra) Rb or -0-C (0) R6; R9 represents c! _6 alkyl, Cw haloalkyl, C3-8 cycloalkane Group, -N (Ra) Rb, 15 phenyl or het; R1 () represents hydrogen, Cu alkyl or Cw haloalkyl; R11 represents hydrogen, hydroxyl, Cm alkoxy, -N (Ra) Rb, phenyl , Het or C3_8 cycloalkyl, with the condition that -N = C (R1G) (CG-5alkylene) -Ru is not -n = ch2; 20 R12 represents hydrogen, Cw alkyl, alkyl, Ci-6 Alkenyl or Cw haloalkenyl; R13 represents hydrogen, Cw alkyl, Cw haloalkyl, Cw alkenyl, Cw haloalkenyl, C3-8 cycloalkyl, phenyl, het,-(Cm alkylene) _R14, _C (0) pR15 or -CONCR ^ XCw alkylene) -R17; 9 200531963 R14 represents hydroxyl, Q_3 alkoxy, Cm-alkoxy, C3_8 cycloalkyl, Phenyl, het or -N (Ra) Rb; R15 represents Ci_6alkyl, Ci_6haloalkyl or-(Ci_6alkyl) -Ci_3alkyloxy; 5 R16 represents hydrogen, Cw alkyl or Cw haloalkyl; R17 represents hydrogen or N (Ra) Rb;

Ra and Rb each independently represent hydrogen, Ci_6 alkyl, C! _6 haloalkyl, C2_6 alkenyl or C2_6 haloalkenyl; or Ra additionally represents-(C () _ 3alkylene) -C3_8cycloalkyl,- (C0_3alkylene) -phenyl or-(C0_3alkylene) -het; or R ^^ Rb—from 10 to form a 4- to 7-membered ring, which can optionally be selected from one or more Each group is independently selected from the group consisting of a halo group, a mesity group, a Ci_6 alkyl group, a Ci_6_ alkyl group, a Cw alkoxy group, and a CwiS alkoxy group;

Re represents hydrogen, Cw alkyl, CN6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl,-(C0_3alkylene) -C3_8cycloalkyl,-(C0_3alkylene) -phenyl, or-(C〇 _3 15 alkyl) _het; η represents an integer selected from 0, 1 and 2; P represents an integer selected from 1 and 2; wherein het represents a heterocyclic group of 4 to 7 members, which may be Aromatic or non-aromatic, and it may contain one or more heteroatoms selected from nitrogen, oxygen, sulfur, and mixtures thereof; wherein heteroaryl represents a 5- or 6-membered aromatic ring containing 1-3 A heteroatom selected from N, O, and S, or 4 N atoms to form a tetrazolyl group; wherein, if the valence allows, both phenyl and het can be optionally selected by one or more each independently Substituted from the following substituents: _, hydroxy, 10 200531963 cyano, hetero, aryl, Cl. Phenyl, Ci4, U alkenyl, 1.6 alkoxy, c ′ alkoxy, c3 alkoxy, Cm group, Ci 6 fluorene group, Cj group weyl group, Ci ▲ oxygen minus and NRaRb; wherein the C3.8 ring group can be optionally selected from one or more groups independently selected from the following groups: Substitute HCI virtual group, U alkyl group, Ci 6 dilute group, Cl_6 dilute group By group, Cl-6 alkoxy and hospital burn C- group; and wherein any stretch or elongation lean burn yl group optionally by a - or more halo substituted.

According to formula (I), Cl.6i alkyl, Ci6i alkyl or u alkyl group 10 means-containing 1 to 5 independently selected mysteries (suitably gas groups) C "6-Alkyl, Cb6-Alkoxy or c" 6-Alkyl. In the same way, the term "," means-a group selected from fluorine, bromine, chlorine, bromine or iodine. 々 According to formula (I), Q_6alkynyl, Cl_6oxo, or ^ alkynyl (including corresponding halo-substituted groups) may be a straight bond or (if possible) have 15 branches. Dextrin refers to a linear or (if possible) branched bond group, and dilute refers to a-linking group containing a double bond. In order to avoid any doubt, the co-carbon group refers to a direct link between the linking groups. R1 is suitably a substituted phenyl group which is in one or both of the 2nd and 6th positions and at the 4th position, with substituents each independently selected from the group consisting of the following 20 Substitution: _ prime (such as chloro)% oxanyl (such as methyl), Cw alkyl (such as trifluoromethyl), Ci 0 alkoxy (such as methoxy), C! -6 alkylthio (such as Methylthio), Cl-6 haloalkoxy (such as trifluoromethoxy or monofluorofluorenyl), C6-6 haloalkylthio (such as trifluorofluorenylthio), and pentafluorothio. 11 200531963 Preferably, R1 is a substituted benzyl group, which is substituted by a halogen group (e.g., gas) at one or both of the second and sixth positions, and at the fourth position is selected from the group consisting of The following group substitutions: Cm alkyl (e.g. trifluoromethyl) substituted with one or more independently selected halo groups, Ci-4 alkoxy substituted with one or more independently selected halogen atoms 5 (Such as trifluoromethoxy or difluoromethoxy), ci 6 alkylthio (such as trifluoromethylthio) and pentafluorothio substituted with one or more independently selected from a prime atom. More preferably, R1 is a phenyl group, which carries a gas substituent at the 2nd and 6th positions, and a substituent selected from the following positions at the 4th position: trifluoro10methyl, difluoro Methoxy, trifluoromethoxy, trigas methylthio and pentagasthio. Still more preferably, R1 is a phenyl group, wherein the substituents at positions 2 and 6 are chlorine and the substituents at position 4 are selected from trifluoromethyl and pentafluorothio. If R is heteroaryl, then R1 is suitably disubstituted by 3,5_. Specific bite-2 · yl, in which the 3-substituent is selected from the group consisting of hydrogen and _; and the 5 · substituent is selected from the group consisting of 15 halo (eg, gas), pentafluorothio, S (〇) nCl-6 alkyl , SCCOnCw haloalkyl, Cw alkyl, Cm haloalkyl (such as trifluoromethyl), Ci 6 alkoxy 6 haloalkoxy. Het suitably represents a selectively substituted aromatic or non-aromatic 5- or 6-membered heterocyclic group containing 2 or 3 heteroatoms each independently selected from N, 020, or 8 atoms. het is more suitably a group selected from the group consisting of pyrazolyl, imidazolyl, humazolyl, isoxazolyl, oxazolyl, isothiazolyl, furanyl, phenylthio, pyrrolyl, triazolyl, Hydradiazolyl, acridinyl, pyrrolidinyl, piperidinyl, pyridyl, pyrimidinyl, pyrimidinyl, and morpholinyl; wherein the aforementioned groups may be optionally selected from-or a plurality of each independently Selected from 12 200531963 substituted with the following groups: Cw alkyl (such as methyl), Cl-6 haloalkyl (such as trifluoromethyl), halogen (such as fluorine), and N (Ra) Rb (such as amine). R2 is suitably selected from hydrogen, cyano, Cw haloalkyl (e.g. trifluoromethyl), Q · 8 cycloalkyl (e.g. cyclopropyl), Cu alkyl (e.g. ethyl ethyl) and 5-C (0) N (Ra) Rb (e.g., aminocarbonyl). R2 is more preferably selected from the group consisting of hydrogen, trifluoromethyl, cyclopropyl, ethylfluorenyl, aminocarbonyl and cyano. R2 is more preferably selected from trifluoromethyl and cyano. R2 is most preferably cyano. When R3 is-(C0_3alkylene) -N (Ra) Rb, N may suitably be directly connected to 10, and N (Ra) Rb may suitably be an amine group or a di-Q-6 alkylamino group (for example, N, N-dimethylamino). R3 may be suitably selected from the following: Ci_6 alkyl, such as methyl, ethyl, n-propyl, or isopropyl; < ^-6-alkyl, such as trifluoromethyl or 2,2,2-tris Fluoroethyl; C3_8 cycloalkyl, such as cyclopropyl;-(Ci-3alkylene) -alkyl15, such as methylfluorenylfluorenyl or 1-methylfluorenylethyl; N (Ra) Rb , Such as amine or N, N-diamidoamino; -N (Re) C02R6, such as tertiary butoxycarbonylamino; optionally substituted phenyl, such as by one or more halo groups (such as Fluoro) substitution; optionally substituted benzyl, such as substituted by one or more halo groups (such as fluorine);-(C2_3alkenyl) -phenyl, such as 2-phenylvinyl; and 20 alkyl , Such as propan-2-yl. R3 is preferably selected from the group consisting of: Cw alkyl, such as methyl, ethyl, n-propyl or isopropyl; Ci-6 haloalkyl, such as trifluoromethyl or 2,2,2-trifluoroethyl ; C3-8 cycloalkyl, such as cyclopropyl;-(Ci_3alkyl) -S (0) nCi-6 alkyl, such as fluorenylmethyl; and -N (Ra) Rb, such as amine or N, N-dimethylamino; 13 200531963 C! 6 alkyl, such as propionyl; _N (Ra) C02R6, such as tertiary butoxycarbonylamino; optionally from one or more halo Substituted phenyl, such as 3,4, difluorophenyl; and benzyl. R3 is more preferably selected from methyl, ethyl, trifluoromethyl and 2,2,2-trifluoroethyl. R3 is most preferably methyl. When R4 is-(Cmalkylene) -R7, the linkage may suitably be a direct or methylene linkage. When R4 is-(Cualkylene) -R8, the linkage may be suitably a methylene or ethylene linkage. 10 When r4 represents-(CG · 3alkylene) -S (0) nR9, η may be suitably 0 or 2, preferably 2; and R9 may be suitably selected from the following: Cl_6 alkyl, for example Methyl; alkyl, such as trifluoromethyl or 2,2,2-trifluoroethyl; Cm cycloalkyl, such as cyclopropyl; N (Ra) Rb, such as amine or N, N-dimethyl An amine group; and a phenyl group optionally substituted with one or more dentate groups such as fluorine. Preferably, η is 15 2. The alkylene group is directly connected and R9 represents a Cw alkyl group (for example, methyl group) or

Cw_alkyl (such as trifluorofluorenyl or 2,2,2-trifluoroethyl). If R4 represents-(Cmalkylene) -C3_8cycloalkyl, CG_3alkylene may suitably be a direct link or methylene, and C3_8cycloalkyl may suitably represent cyclodiyl, cyclobutyl or cyclo Amyl, which may be optionally substituted by one or more 20 halo (such as fluorine), Cw alkyl (such as methyl), or (^ -6 alkyl (such as trifluorofluorenyl). If R4 represents- (C0_3alkylene)-(: 3_8cycloalkyl, the preferred group is 1- (trifluoromethyl) cyclopropylmethyl. When R4 represents-(CG_3alkylene) -het, the The linkage may suitably be fluorenylene or ethylidene linkage and het may be suitably selected from the following: pyrazolyl, imidazole 200531963, 4 sigma group, isosaki tr group, saccharyl group, isosigma Selenium, safranyl, phenylthio, stilbyl, succinyl, stilbene 11, stilbyl, stilbene, pyryl, pyrimidinyl, and morpholine Group, wherein the aforementioned groups may be optionally substituted by one or more groups each independently selected from the group consisting of: Cu alkyl 5 (eg methyl), halogen (eg fluorine) and N (Ra) Rb (Eg amine). Preferably, when R4 represents-(Cualkylene In the case of -het, het may be selected from pyrazolyl, imidyl, iso-4 sigma group, sigmadol, trisyl, dithiol, tonyl, pyridyl, pyridyl, Pyrimidinyl and morpholinyl, in which the aforementioned groups can be optionally substituted by one or more groups independently selected from the following: Ci-6 alkyl, halogen (such as fluorine) and N (Ra ) Rb (eg, amine). More preferably, when R4 represents-(C0_3alkylene) -het, C0_3alkylene is methylene-linked and het may be selected from taste saliva Group, iso 4σ seat group, 4 amidenyl group, and ton sigma group, wherein each ring can be optionally substituted by alkyl (such as methyl). When R4 represents-(CG_3alkylene) -phenyl, benzene The group may suitably be optionally substituted with one or more halo groups such as fluorine, such as 4-fluoro. When R4 represents-(Cmalkylene) -N (Ra) Rb, it may suitably be 2- N, N-dimethylaminoethyl. When R4 represents-(Cm-alkylene) -C (0) N (Ra) Rb, it may suitably be aminoweilylmethyl. 20 R4 may be appropriately selected From the following: hydrogen; Cw alkyl, such as methyl, ethyl, or isopropyl; Q_6 haloalkyl, such as trifluoromethyl, 2,2,2- Fluoroethyl, 2,2-difluoroethyl, 2-fluoroethyl or 2,2,3,3,3 · pentafluoropropyl;-(C0_3alkylene) -C3_8cycloalkyl, For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylfluorenyl, (1-methylcyclopropyl) methyl, 2,2-difluorocyclopropyl, or 1- (trifluoromethyl) 15 200531963 cyclopropylmethyl, cyanomethyl, 2-hydroxyethyl;-(Cm alkylene) -het, such as pyrazol-3-ylmethyl, pyrimidin-4-ylmethyl, pyridine_3_ Methyl, 2-pyrrolidin-1-ylethyl, 2-morpholin-4-ylethyl, 1-fluorenyl-1H-imidazol-2-ylfluorenyl, σ-ratio-4-yl Methyl, tri-α-methoxyethyl, ι, 2,4-σquadito-3-ylfluorenyl, 5 ° specification 2-ylmethyl or (5-methylisoxazolyl-3 -Yl) methyl;-(C0_3alkylene) -phenyl 'such as benzyl or 4-fluorobenzyl;-(Qmalkylene) _S (0) nR9, such as 1, 1, 3 Fluoromethylfluorenyl, aminofluorenyl, N, N-dimethylaminosulfone, cyclopropylfluorenyl, methylfluorenyl, 4-fluorophenylfluorenyl, 2,4-difluorophenyl Fluorenyl, (methylsulfonyl) methyl, or 2,2,2-trifluoroethylfluorenyl;-(Cw alkane) -0-c (o) r6, such as tertiary butylcarbonyloxy methyl - (Ci 3 alkyl elongation) -C (0) N (Ra) Rb, aminocarbonyl e.g. methyl; & _c〇2R6, several groups such as methyl group. More preferably, R4 is selected from the group consisting of hydrogen, methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methylfluorenyl, and trifluoromethyl. Fluorenyl, 2,2,2-15 difluoroethylfluorenyl, aminofluorenyl, N, N-dimethylaminofluorenyl, methylsulfonemethyl, cyclopropyl, cyclobutyl, cyclopropyl Methyl, __ (trifluoromethyl) cyclopropylmethyl, cyanomethyl, methoxyweilyl, trisigmaethyl. dense. _4_ylmethyl, 1,2,4 "isooxazolyl, pyrazolyl, methyl, imidazol-2-yl, 5-methyl-isohumidazole-3 · Methyl, 2-pyridin-4-ylethyl, amine 20-carbonylcarbonyl, benzyl and 4-fluorobenzyl. When R3 and R4 form a 4- to 7-membered ring, it may be suitably one Two-sided oxoisothiazolidinyl, such as 1,1_ two-sided oxisothiazolidine_2_yl, or two-sided oxy-thiapyridyl, such as 1,1-dioxanyl_l52_thiagen When R5 is -N = C (R1G) (CG_5alkylene) Rn, R1 () may be suitably hydrogen 16 200531963 and CG_3alkylene may be suitably a direct link. Rii may be suitable Ground is & 3 alkoxy (e.g. ethoxy), -N (Ra) Rb (e.g. N, N-dimethyl) or phenyl (which may optionally be substituted by one or more hydroxyl groups). R12 may It is suitably hydrogen or methyl, and hydrogen is preferred. 5 When Rl3 represents-(Cl · 6alkylene) -R14, C! · 6alkylene may suitably be methylene, ethylidene, or Phenylene linkage; and 5 ^ 4 may suitably be alkoxy, such as ethoxy, phenyl; -N (Ra) Rb, such as N, N-dimethylamino; het, such as pyrrolidinyl, Morpholine, acryl Or Cw cycloalkyl, such as cyclopropyl. 10 If R13 represents c (0) pr15 and P represents 1, R15 may suitably be a Cw alkyl, such as methyl. When p In the case of 2, R15 may be a cw alkyl (for example, methyl) or a Cw haloalkyl (for example, 2, 2, 2, trifluoroethyl). If R13 is -CXC ^ NCRMXCw extended alkyl) -Rn Ri6 may suitably be hydrogen and alkylene may suitably be ethylene. Rn may suitably be amine. 15 Rl3 may be suitably selected from the following: hydrogen, methyl, benzyl, cyclopropylmethyl , 2-N, N-dimethylaminoethyl, ethanoyl, methoxymethylweilyl, methoxy%, 2,2,2 · digasethoxy, Ν-σ Billot. Nylethyl, n_morpholinylethyl, N-piperidinylethyl, pyridin-4-ylmethyl, N_azetidinylethyl, and aminoethylaminoamino. R13 is Hydrogen is preferred, and both R12 and R13 are preferably hydrogen. R5 may be suitably selected from the following: hydrogen; halo, such as gas; Ci 6 alkoxy, such as methoxy; _N = C (H) Rn, where Rii is ethoxy, N, N • dimethyl or phenyl, which may be optionally substituted by: one or more hydroxyl groups For example, 2,4-dioxo group; and _nr12r13, such as amine group, benzylamine group, pyridene 17 200531963 methylmethylamino group, 2-ethoxyethylamino group, methylamino group, hydrazone Methylmethylcarbonylamino, cyclopropylmethylamino'methylcarbonylamino, 2-N, N-dimethylaminoethyl (methyl) amino, 2-synazylethylamine Methyl, 2-N-piperidinylethylamino, 2-N-morpholinylethylamino, 2-N-piperidinylethylamino, 5-cyclopropylmethylamino, methoxy Carbonylamino, 2,2,2-trifluoroethoxycarbonylamino and 2-aminoethylaminocarbonylamino. R5 is preferably selected from the group consisting of hydrazone, amino, methoxymethylcarbonylamino, cyclopropylmethylamino, 3-N, N-dimethylaminopropylamino, 2-N- Acryl_aminoethylamino, 2-N-piperidinylethylamino, 2-N-piperidinylethylamino, 10 2-N_morpholinylethylamino, methoxy Carbonylamino, ethoxyimino, phenylimino and 2,4-dihydroxyimino. R5 is most preferably an amine group. A suitable subgroup of the present invention may be represented by a compound of formula (la):

Among them: 15 Rla may be aryl or heteroaryl, which may be optionally substituted by one or more groups each independently selected from the group consisting of: hydrogen;! | Group; Cw alkyl group; Cl_6 alkoxy group, which may be optionally substituted with one or more independently selected function element atoms; -SCCOnaCi · 6 alkyl group; and pentafluorothio group; cyano group; Alkyl groups, which may be optionally substituted with one or more independently selected halo atoms; 2 ^ may be selected from the following: hydrogen; halo; Q6 alkyl; alkyl,-(CH2) maC3 · 8 cycloalkenyl 'can be optionally substituted with one or more substituents independently selected from the group consisting of: dentyl and Ci 6 alkyl; cyano; nitro; _ (CH2) maNRaaRba; Cw alkylfluorenyl, which may be optionally substituted with one or more groups each independently selected from _yl and c14 alkoxy; phenyl; fluorene difluorene; -C (0) NRaaRba; -NRaaC (0 ) Rba; C2_6 alkenyl; and (: 2-6 alkynyl; 5 R3a may be selected from the following: (^ _6 alkyl;-(CH2) mNRaaRba; • (CH2) maC3.8 cycloalkyl, which can be selected Is substituted with one or more substituents each independently selected from halo and C! _6 alkyl; _ (CH2) ma-phenyl; -CH = CH-phenyl; and-(CH2) ma_het; R4a May be selected from the group consisting of: hydrogen; Cw alkyl;-(CH2) ma-C3-alkyl, 10 which may be selected Is substituted with one or more substituents each independently selected from the group -Cw alkyl;-(CH2) maS (0) pR6a; -CCMCw alkyl);-(CH2) mahet; and -C (0 ) NRaaRba; or 113 & and ^ are linked together with nitrogen and sulfur atoms to form a 4- to 7-membered ring; R5a may be selected from the following: hydrogen; hydroxyl; Cu alkyl; NRaaRba; halo 15; and CV6 alkoxy R6a may be selected from the following: Cw alkyl; NRaaRba; C3-8 cycloalkyl, which may be optionally substituted with one or more substituents each independently selected from halo and Cw alkyl; het; and phenyl Each na is independently 0, 1 or 2; 20 each ma is independently 0, 1, 2 or 3; pa is 1 or 2; and wherein: het represents a 4 to 7 membered heterocyclic ring Group, which may be aromatic or non-aromatic, and contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, and mixtures thereof 19 200531963; and if the valence allows, the heterocyclic ring may be selected It is substituted and / or terminated with one or more substituents selected from the group consisting of: _, cyano, nitro, Cw alkyl, Ci-6 haloalkyl, Cw alkoxy, OCCCOCw alkyl, CCCOCw alkyl Base, CCCOOCk alkyl, and NRaaRba; 5 Each Ck alkyl group may be independently branched or unbranched, and optionally substituted with one or more groups each independently selected from: cyano; functional group; hydroxyl; nitro; alkane Oxy; NRaaRba; SCOUCw alkyl; S (0) naC3_8 cycloalkyl; SCCOnaCw alkylhet; (: 3_8 cycloalkyl; and phenyl; each phenyl can be selected independently by one or more of each independently selected Substituted from the following 10: cyano, halo, hydroxy, nitro, Cualkyl, CN6 haloalkyl, and d6alkoxy; and each of Raa and Rba may be independently selected from 氲, Ci · 6 alkyl and C3_8 cycloalkyl, which can be optionally substituted with one or more substituents each independently selected from the group consisting of dentino and C! _6 alkyl; or Raa and Rba can be attached to a nitrogen atom Together to form a 4 to 7 member ring. 15 Suitable compound groups of the formula (I) of the present invention are the following, of which: N- {5-Amino-3 · cyano small [2,6-diagas ice pentafluorothiophenyl] _1H " Fluoroethyl) Methanesulfonamide; Ν · {5 · Amino-3-cyano small [2,6-digasic pentathiothiophenyl]. Pyracyl group 丨 mountain 丨 trifluoro_Ν_ 甲Methanesulfonamide; 20 Ν- {5-amino · 3 · cyano- small dichlorobenzyl (trifluoromethyl) phenyl] qinpyrazole-4-ylbulfonium 3,4-difluorobenzidine Amine; Ν_ {5-amino-3-cyano small [2,6_digas_4_ (trifluoromethyl) phenyl] _1Η_pyrazol_4-yl} cyclopropanesulfonamide; Ν- {5 · Amino-3-cyano small [2,6_digas_4_ (trigasmethyl) phenyl] _m_ 20 200531963 pyrazole-4-*}-N- (cyclopropylmethyl) methanesulfonium Amine; N- {5-Amino-3-cyano-l- [2,6-dichloro-4- (trifluoromethyl) phenyl] -1H-pyrazole (cyanomethyl) methanesulfonium Amine; N · {5-amino-3 -amino-l- [2,6-digas-4- (difluoromethyl) phenyl] -1H-5 pyrazol-4-yl} -1 ^ -(Pyridin-2-ylmethyl) methanesulfonamide; N- {5-amino-3_amino-l- [2,6-dichloro-4_ (difluoromethyl) phenyl] -1H -Pyrazol-4-yl} -benzylmethanesulfonamide; ^^ • {5-amino-3-amino-1- [2,6- Dichloro-4- (digasmethyl) phenyl] -111-pyrazol-4-yl} -qin [2- (dimethylamino) ethyl] methanesulfonamide; 10 N- {5- Amino-3 -Gasyl-l- [2,6-digas-4- (digasmethyl) phenyl] -111- koubijun-4-yl} -1- (methylstyrenyl) methyl Ruthazinamine, N- {5-Amino-3 -Azo-l- [2,6-digas_4- (dimethyl) phenyl] -1H-pyrazole-4-*}- Ν- (2 · hydroxyethyl) methanesulfonamide; Ν · {5-amino-3-cyano-1 · [2,6-dichloro-4- (trifluoromethyl) phenyl] -1Η -15 0 ratio ° sitting 4-yl} _N-isopropyl methylamine amine, N- {5-amino-3_amino-1 · [2,6_dichloro-4 · (digas (Methyl) phenyl] -1H-pyrazole_4-yl}-^ 1 ^ ', >^'-trimethylthioxanamine; N- {5-amino-3-amino-1_ [2 , 6-Digas-4- (digasmethyl) phenyl] -1 Η_pyrazol-4-yl} -qin [(fluorenylthio) fluorenyl] methanesulfonamide; 20 Ν- {5-amine Yl-3-amino-1- [2,6-digas-4- (digasmethyl) phenyl] -1 Η_pyrazole-4-yl} -qin [(5-methylisoxazole- 3-yl) methyl] methanesulfonamide; Ν- {5-amino-3 -amino-1- [2,6-digas-4- (dibenzylmethyl) phenyl] -1Η_pyrazole (Cyclopropylmethyl) -N ', N'-dimethylthiosulfamine; Ν- {5-amino-3-cyano 1 · [2,6_Digas-4- (trifluorofluorenyl) phenyl] _1Η- 21 200531963 Pyrazol-4_ylbN-{[1- (trifluoromethyl) cyclopropyl] Methyl} methanesulfonamide; N- {5-amino-3 · cyano-l- [2,6-dichloro-4- (trifluoromethyl) phenyl] -1Η · pyrazole-4- }-; ^-(Cyclobutylmethyl) methanesulfonamide; 1 ^-{5-amino-3-cyano-1- [2,6-dichloro-4_ (trifluoromethyl) phenyl] -111-5 Pyrazol-4-yl group N- (fluorenylfluorenyl) cyclopropanesulfonamide; Ν- {5_amino · 3 · cyano_1 · [2,6. (Methyl) phenyl] -ιη-pyrazol-4-yl} -qin [(dimethylamino) fluorenyl] methanesulfonamide; 1 ^ {5-amino-3-cyano-1- [2 , 6-Digas-4_ (trifluoromethyl) phenyl] _1 ^ σ than 嗤 _4-yl} -2,2,2-trifluoro- > 1- (methyl hinderyl) ethistein Hydrazine; 10 Ν- {5-amino-3_cyano-1 · [2,6-digas-4- (trifluoromethyl) phenyl] _1Η_ oripizol_4-yl} -1, 1,1-trifluoro-N-{[1- (trifluoromethyl) cyclopropyl] fluorenyl sulfonamide; NH- {5-amino-3-cyano-1- [2, 6-Digas-4- (trifluoromethyl) phenyl] _1Η_pyrazol-4-yl}-: ^-(methylfluorenyl) methanesulfonamide; 15 N- {5-amino-3- Cyano-1- [2,6-dichloro-4- (trifluorofluorenyl) phenyl] -1 Η · pyrazol-4-yl}-> 1- (methylfluorenyl) methanesulfonamide; Ν- {5_amino-3-cyano-1- [2,6_digas-4- (Trifluoromethyl) phenyl > 1'-pyrazol-4-yl} methanesulfonamide; Ν · {5-amino-3-cyano-1- [2,6-digas-4- (Trifluoromethyl) phenyl] _1Η-20 pyrazol-4-yl} -methylmethanesulfonamide; Ν- {5_amino-3-cyano-1- [2,6-dichloro -4- (trifluorofluorenyl) phenyl] _1Η_pyrazol-4-yl} ethanesulfonamide; Ν '-{5-amino-3-cyano-1- [2,6_dichloro_ 4- (tris (methyl) phenyl) -1] -pyrazole-4-*} _ N, N-dimethylthiosulfamine; 22 200531963 N- {5-amino-3-cyano-l- [2 , 6-Digas-4- (trifluoromethyl) phenyl] -m-pyrazol-4-yl} -1-phenylmethanesulfonamide; N- {5_amino-3-cyano- 1 · [2,6-Digas-4- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl} -2,2,2-trifluoroethanesulfonamide; 5 (E) -N] 5-Amino_3_cyano_ 丨 _ [2,6-dichloro-4- (trifluoromethyl) phenyl] -1Η-pyrazole_4-jib 2-phenylethylenesulfonate Fluorenamine; N_ {5-amino-3_cyano-1_ [2,6-dichloro-4_ (trifluoromethyl) phenyl] · fluorene-pyrazol-4-yl} propane-1-sulfofluorene Amine; Ν- [5-amino-1- [2,6-dichloro-4-pentafluorothiophenyl] _3_ (trifluoromethyl10 group ΜΗ-. Bisynyl] -N_ (methyl hinderyl) methanesulfonamide; Ν- [5-amino-1- [2,6-dichloro-4-pentafluorothiophenyl] _3_ (trifluoro (Methyl) _1Η-pyrazol-4-yl] methanesulfonamide; 5-amino-1 · [2,6-digas-4- (trifluoromethyl) phenyl] -4- (1,1 -Two-sided oxisothiazolidine_2 · yl) _1H_pyrazole-3-carbonitrile; I5 Ν_ {5 · amino · 3 · gasyl_1 · [2,6 · digas-4 · (trifluoromethyl Phenyl] pyrazol-4-yl} -1,1,1-trifluoro-N-fluorenylmethanesulfonamide; Ν · {5-amino-3-cyano-1_ [2,6- Dichloro_4- (trifluoromethyl) phenyl] _1H_pyrazol-4-yl} -1 ^-(cyclopropylmethyl) -1, l, l-trifluoromethanesulfonamide; N- { 5-amino-3-cyano small [2,6-digas · 4- (trifluorofluorenyl) phenyl] _1H_ 20 σpyzolethylmethanesulfonamide; N- {5-amino-3 -Cyano small [2,6-digas-4- (trifluoromethyl) phenyl] _1H_pyrazol-4-yl} _qincyclobutylmethanesulfonamide; N- {5-amino-3 -Cyano small [2,6_dichloro_4_ (trifluorofluorenyl) phenyl] _1H_pyrazol-4-yl} -sylcyclopentylmethanesulfonamide; 23 200531963 N- {5-amino group- 3-Rhamnyl-1- [2,6-digas-4- (digasmethyl) benzyl] -1H-methylpyridin-4-yl} -N- (2,2,2-digasethane Methyl) methyl donkey amine, N- {5-amino -3-cyano small [2,6_dichloro_4- (trifluorofluorenyl) phenyl] -1H-pyrazole-4-yl} -1,1,1-trifluoro-N- (methyl Fluorenyl) methanesulfonamide; 5 N- {5-amino-3 -amino-l- [2,6-digas-4- (digasmethyl) phenyl] -1 H_ pyrazole- 4-yl} -sense [(methylfluorenyl) methyl] methanesulfonamide; N- {5-amino-3-cyano-l- [2,6-dichloro-4 · (trifluoromethyl (Phenyl) phenyl] -1H-orallysalylbutyl-1,1,1-diaziridine, N- {5-amino-3 -amino-l- [2,6-di Chloro-4- (digasmethyl) phenyl] -1H-10pyrazol-4-yl} -1,1,1-trifluoro-p-isopropylpyrrolidinesulfonamide; Ν- {5 · amine 3--3-cyano-1- [2,6 · dichloro · 4- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl} -pentacyclopentyl-1,1,1- Trifluoromethanesulfonamide; N- {5-amino-3-cyano-1 · [2,6-dichloro-4 · (digasmethyl) phenyl] · 1Η_ σbijun-4-yl } Propan-2-amine, 15 N- {5-amino-3-lactyl-1- [2,6_digas-4-pentathiothiophenyl] -1Η-0 ratio. _4_kib N- (methyl stone wind-based) methyl burned amine, Ν · {3_cyano-1 · [2,6-digas-4- (trifluoromethyl) phenyl] -1Η -Pyrazol-4-yl} -1,1,1-trifluoro-N-fluorenylmethanesulfonamide; N- {3-cyano-l- [2,6-digas-4- (trifluoro (Methyl) phenyl] -1H-pyrazole-4-20 group 丨 -N- (methylfluorenyl) methanesulfonamide; N- {3-cyano-l- [2,6-dichloro- 4- (trifluorofluorenyl) phenyl] _1H_pyrazol-4-yl}-^ [(5-methylisopurazol-3-yl) methyl] methanesulfonamide; Ν- {3 · cyanide 1_1- [2,6_digas_4_ (trifluoromethyl) phenyl] -1H · pyrazol-4-yl} -2,2,2-trifluoroethanesulfonamide; 24 200531963 N -{3-cyano · 1- [2,6-dichloro-4- (trifluorofluorenyl) phenyl] -1H-pyrazole-4_yl} -2,2,2-trifluoro-N- ( Methylfluorenyl) ethanesulfonamide; N- {3-cyano-l- [2,6-dichloro-4- (trifluoromethyl) phenyl] -1H-pyrazole-4 monoyl} _ ^ {[1- (trifluorofluorenyl) cyclopropyl] methyl} methanesulfonamide; 5 Ν- {3 · cyano small [2,6-digas-4-pentafluorothiophenyl] _ih-pyrazol-4-yl}-> ^ (methylfluorenyl) methanesulfonamide; N_ {3-cyano-1_ [2,6-dichloro · 4- (trifluoromethyl) phenyl ] _ΐΗ · σ 比 嗤 _4_ group} methanesulfonamide; Ν- {3-cyano-1- [2,6-dichloro -4- (trifluoromethyl) phenyl] -1Η-pyrazole-4- 10yl} -qin (2,2,2-trifluoroethyl) methanesulfonamide; Ν · {5_amino -3-cyano · 1- [2,6 · dichloro-4- (trifluoromethoxy) phenyl] -1Η_pyrazole_4-yl} _sense (2,2,2-trifluoroethyl Methanesulfonamide; Ν · {5-amino-3_cyano small [2,6-dichloro-4 · pentafluorothiophenyl] -1H ·. Than 嗤 _4-yl} _qin (2,2,2 · trifluoroethyl) methanesulfonamide; 15 meaning {5_amino-3-cyano_1_ [2,6-dichloro-4- Pentafluorothiophenyl] _1suppyridin-4-yl} -2,2,2-trifluoro-sense (methyl hinderyl) ethanesulfonamide; Ν] 5-amino-3-cyano基 小 [2,6-Digas ice (trifluorofluorenyl) phenyl] _1Η_ roar. _4Hn- (2,2-difluorocyclopropyl) methanesulfonamide; N- {5-amino-3-amino-l- [2,6-dichloro-4-pentafluorosulfanyl Phenyl] -ΐΗ-π ratio 20 嗤 _4-jib N_ [2_ (1H_1,2,4-triazol-1-yl) ethyl] pyranesulfonamide; N- {5-amino-3 -Cyano-1- [2,6-digas-4_pentafluorothiophenyl] _111_pyridine. Cis-4-yl} -1,1,1_trifluoromethanesulfonamide; 5 · Womenyl-l- [2,6-dichloro-4-pentafluorothiophenyl] -4- (l 1,1-dioxoisoxazolidin-2-yl) -1H-pyrazole-3-carbonitrile; 25 200531963 N- {5-amino-3-cyano small [2,6-dichloro-4- (Trifluoromethyl) phenyl] -1'-pyrazol-4-ylb N-[(l-methylcyclopropyl) methyl] pyranesulfonamide; 5-amino-4- [bis ( Methyl hinderyl) amino] -1- [2,6 · digas-4-pentafluorothiophenyl] -1Η-pyrazole-3-carboxamide; 5 Ν- {5-amino-3 -Gasyl_1- [2,6-dichloro-4- (dioxanthoxy) phenyl] sit-4-yl} -N- (methylstyrenyl) methyl pyroxanthanamine, Ν- ( 5. · Amino-3 -Gasyl-1 · {2,6-Digas-4-[(Digasmethyl) thio] phenyl}-] !!!!-11 ) -N_ (methyl hinderyl) methyl amine, Ν- {3-ethylethyl-5-amino-1 _ [2,6_digas-4-pentathiothiophenyl] -1 Η_ 10 ° than fluoren-4-yl} -N- (fluorenylsulfonyl) methyl amine, Ν- (5-amino-3-amino-1- {2,6-dichloro-4- [(Diaminomethyl) thio] phenyl} -111-pyrazol-4-yl) methanesulfanilamide; Ν- (5-amino-3 -amino-1- {2,6-di Chloro-4-[(dioxafluorenyl) thio] phenyl} -111-pyrazol-4-yl) -N- (2,2,2- Trifluoroethyl) methanesulfonamide; 15 Ν- {5-amino-3-nitro group_1- [2,6-dichloro-4- (difluoromethyl) phenyl] -1Η-ϋ Than sigma-4-yl} -1 ^-(fluorenyl hinderyl) methyl amine, N- {5-amino-3-amino-1-[2,6-digas-4-penta Gas-sulfur basic group] -1 Η-σbiazol-4-yl} methanesulfonamide; Ν- {5-amino-3-amino-1-[2,6-digas-4 · pentasulfur Phenyl] -1 H-ring ratio 20 azole_4-yl}-^ {[1- (trifluoromethyl) cyclopropyl] fluorenyl} methanesulfonamide; Ν- {5-amino-3 -Gasyl-1-[2,6_digas-4-pentathiothiophenyl] -1 Hu ratio σ sitting _4_yl} -1 ^-(methyl stone wind based) ethyl pyrochlore yellow amine, 5-amino-3 -amino-1- [2,6_dichloro-4- (difluoromethyl) phenyl] -1Η-σι; l: azole-4-yl (methylfluorenyl) amine Methyl formate; 26 200531963 N- {5-Amino-3Gas_l- [2,6-digas-4-pentasulfur basic group] -1 azole-4-yl} -qinmethylmethanesulfonate Hydrazine; N- {5-amino-3-amino-l- [2,6-digas_4_pentasulfur basic group] _ 1H-port ratio fluoren-4-yl} -N- (2 -Gas ethyl) methyl pyroxanthine, 5 N- {5-amino-3-aero-1--1- [2,6 · digas-4-pentasulfur basic group] -1 Η-σ ratio Azole-4-yl} -qin [(3-methylisohumazol-5-yl) methyl] Sulfanilamide; ^ {5-amino-3-amino-1- [2,6-digas-4-pentasulfur basic group] -111-port ratio sigma_4-yl} -N -(σ specific bite-2-ylmethyl) mesitolite, Ν- {5-amino-3 -muryl-1 · [2,6-digas-4-pentathiothio-benzene Group] -1Η_ 10 pyrazole (pyridin-4-ylmethyl) methanesulfonamide; N- {5-amino-3 -amino-1- [2,6-digas-4-pentathiol Phenyl] _ 1 Η_σbiazole-4-yl} -1 ^ (1,2,4-fluorenediazole_3-ylmethyl) methanesulfonamide; Ν2- {5 · amino · 3-cyano -1- [2,6-dichloro-4-pentafluorothiophenyl] -1] -pyrazol-4-yl}-#-(methylfluorenyl) glycine; 15 Ν- {5 -Amino-3_airyl_1- [2,6-digas-4-pentathiothiophenyl] -1Η · 口 比 σσ_4-yl} -1 ^ -isopropylmethyl Stuffed amine, Ν- {5_amino-3 -ranyl-1- [2,6_digas-4-pentathiothiophenyl] -1Η-port ratio σ sitting-4-yl} -Ν- (σ ratio ° determin-3-ylmethyl) sulfonium amine, N- {5-amino-3_cyano-1- [2,6-dichloro-4-pentafluorothiophenyl] -1Η_pyrazole 20azole-4-*}-N- (1Η-pyrazole-3 · ylmethyl) methanesulfonamide; Ν_ {5-amino-3-amino group-1_ [2,6- Digas-4-pentathiothiophenyl] -1Η-orbitazol-4-yl} -sense (2,2,3,3,3-pentafluoropropyl) Sulfanilamide; Ν- {5-amino-3-amino-1_ [2,6-digas-4-pentathiothiophenyl] -1Η-port ratio σ sitting _4_yl}-^ ^ (2-11 bilobit-1-ylethyl) methylamine, 27 200531963 N- {5_amino_3_gasyl_1_ [2,6_digas-4-pentasulfur Phenyl] -1 fluorene-orbitazol-4-yl} -qin (2-morpholine-4-ylethyl) methanesulfonamide; N- {5-amino-3-amino-1 -[2,6-Digas-4- (digasmethyl) phenyl] -1H · pyrazol-4-yl} -qinmethylethanesulfonamide; 5 N- {5-amino-3 -Amino-1- [2,6-digas-4- (digasmethyl) phenyl] -1H-. Specific σ sitting-4-yl} -N-methyl propane-1 -stone yellow amine, Ν- {5-amino-3 -amino-1- [2,6-digas-4- (bis Random methyl) phenyl] -111- ° ratio ^ methyl methyl phenylpropanite yellow amine, Ν- {5-amino-3 · cyano-1 · [2,6-digas-4- (Trifluoromethyl) phenyl] -1Η-10pyrazol-4-yl} -2,2,2-trifluoro-N-methylethanesulfonamide; Ν- {5-amino-3_ Gasyl-1 · [2,6-dichloro-4-pentathiothiophenyl] -azole-4 · *}-N-[(1-methyl-1H-imidazol-2-yl) methyl] Pinanesulfonamide; N- {5-amino-3-cyano-l- [2,6-dichloro-4-pentafluorothiophenyl] -1H-pyrazol-4-ylbuqin [ (5-fluorenylisoxazol-3-yl) fluorenyl] methanesulfonamide; 15 pivalic acid [{5_amino-3-cyano_1 _ [2,6_dichloro_4_penta Fluorothiophenyl] -1H-pyrazol-4-yl} (methylfluorenyl) amino] methyl ester; N- {5-amino-3 -ranyl-1- [2,6-digas -4-pentathiothiophenyl] -1 Η-σ ratio ϋ 4-4-yl} -N-ethyl methyl pyrolite yellow amine, Ν_ {5-amino-3 -airyl-1- [ 2,6 · dichloro-4-pentathiothiophenyl] · 1 Η-σ ratio 20 azole-4-yl} -qinbenzylmethanesulfonylamine; Ν_ {5-amino-3 -ranyl_ 1- [2,6-dichloro-4-pentathiothiophenyl] _ 1 H-orbitazole fluorobenzyl) methanesulfonamide; Ν- { 5-Amino-3 -Gasyl-1 · [2,6-dichloro-4- (didecylmethyl) phenyl] -111- ° than fluoren-4-yl} -1- (methylalkenyl ) Ethylamine, 28 200531963 N_ {5-amino-l- [2-Ga-4-pentathio-phenyl] -3-amino-1 H- ° tbΰ-4--4-} -N- (methylfluorenyl) methanesulfonamide; 5-amino-1- [2,6 · digas-4-pentathiothiophenyl] -4- (1,1-dioxo -Yl) _1Η · σ Bito-3, 5 Ν- {5- (benzylamino) -3-amino-1- [2,6_digas-4-pentathiothiophenyl]- 1Η-ϋ ratio (methyl stone wind based) methyl roasted amine, N- {3_cyano small [2,6_dichloro-4-pentafluorothiophenyl] -5 _ [(ethoxymethyl) Amine] -1H-pyrazole-4-*}-N- (methylfluorenyl) methanesulfonamide; N- [3-cyano-l- [2,6-digas-4-pentafluorosulfide Phenyl] -5- (fluorenylamine 10-yl) -1H-pyrazol-4-yl] methanesulfonamide; N- {3-amino-l- [2,6-dichloro-4-pentagas Thiophenyl] -4-[(methyl hinderyl) (2,2,2-trifluoroethyl) amino] -1H-pyrazol-5-yl} _2-methoxyacetamidamine; 4 -[Bis (methyl hinderyl) amino] -3-cyano-1- [2,6-digas-4-pentafluorothiophenyl] -1H_pyrazole-5_ylfluorenimine Ethyl formate; 15 N- {3-cyano-5-[(cyclopropylmethyl) amino]- l- [2,6-dichloro-4-pentafluorothiophenyl] -1H-pyrazol-4-yl} methanesulfonamide; N- {3-cyano-l- [2,6-di GA-4-pentafluorothiophenyl] -4-[(fluorenylfluorenyl) (2,2,2-trifluoroethyl) amino] -1H_pyrazol-5-yl} acetamidinium; N- {3-cyano small [2,6_dichloro-4-pentafluorothiophenyl] · 5-methoxy-1H-20 pyrazol-4-yl} methanesulfonamide; Ν- [ 3-cyano-1- [2,6_digas-4- (trifluoromethyl) phenyl] -5- (methylamino) -1Η-pyrazole-4_yl] _sense (methyl Fluorenyl) methanesulfonamide; N_ (3-cyano-l- [2,6-dichloro-4-pentafluorothiophenyl] -5 _ {[(dimethylamino) methylene] amine Base group) -N- (methylstyrenyl) methylamine 29 200531963 amine; N- (3-amino-1 · [2,6 · digas-4-pentathiothiobenzyl] -5- { [2- (monomethylamino) ethyl] amino} -1Η-pyrazol-4-yl) -N- (methylfluorenyl) methanesulfonamide; N_ {5_amino_3_gas Radical _ 1 _ [2,6_digas-4-pentasulfur basic group] _ 1 H-port ratio 5 seat_4-base} -N- (2,2,2-digas ethyl stone wind base) -2,2,2-Diranosynthrin, N- {3-cyano-l- [2,6-dichloro-4-pentafluorothiophenyl] -5-[(2- Pyrrolidine_ 1 -ylethyl) amino] · 1 H-ntb σ sitting-4-yl} -N- (methylstyrenyl) Burning amine, N- {3-cyano-1- [2,6-dichloro-4-pentafluorothiophenyl] -5 _ [(2-morpholine-4-ylethyl) amino ] -1Η-13 than σ sitting-4-yl} -N- (fluorenyl hindryl) mesitolite, 10 Ν- {3- 乳 基 -1- [2,6- 二 气 -4- Pentagasylthiophenyl] -5-[(2- ^ σ 定 -1_ethylethyl) amino] -1Η-pyrazole_4-yl} -sense (methylfluorenyl) methanesulfonamide; Ν -[3-cyano-1- [2,6 · digas-4-pentafluorothiophenyl] -5- (methylamino) · 1Η-σ ratio σ sitting-4-yl] -N · (Methyl hinderyl) methyl amine, N- {3-cyano-5-[(cyclopropylmethyl) amino] -1_ [2,6-digas_4-pentafluoro 15 thio Phenyl] -1Η-pyrazole-4_yl} -sense (methylfluorenyl) methanesulfonamide; Ν- {5-amino- 3-¾propyl-1 _ [2,6_digas- 4-pentasulfur basic group] _ 1 Η_ pyrazole-4-*}-N- (methylfluorenyl) methanesulfonamide; Ν- {5-amino-1 · [2,6 · digas- 4-pentathiothiophenyl] -1Η-17bitul-4-yl} methanesulfonamide; 20 Ν- {3-cyano-1- [2,6-dichloro-4-pentafluorothio Phenyl] -5-[(pyridin-4-ylfluorenyl) amino] -1H-pyrazol-4-yl} methanesulfonamide; Ν_ {5_amino-3-amino-1- [2 , 6-Digas-4-pentathiothiophenyl] _ 1 Η-σ ratio a sitting-4-S} -N- (amino group Wind-based) Methylamine, ({5-Amino-3 -Rhamnyl-1 · [2,6-dichloro-4-pentathiothiophenyl] -1H_port ratio 30 200531963 嗤 -4 -Yl} amino) carbamic acid tert-butyl g; N- {5-amino · 3-cyano-l- [2,6-dichloro-4-pentafluorothiophenyl] -1Η -Pyrazol-4-yl} -1 ^-(2-pyridin-4-ylethyl) methanesulfonamide; N- {5-amino-3-cyano small [2,6-dichloro-4 -Pentafluorothiophenyl] -1H-pyridine 5 17 hydrazyl} ·! ^ Pyrbiphen-2-ylmethyl) methylpyrrolamine; Ν · {5-amino-3-cyano_ 1- [2,6_dichloro-4-pentafluorothiophenyl] _1H-pyrazol-4-yl}-> 1-[(6-aminopyridin-3-yl) methyl] methanesulfonate Hydrazine; meaning {5-amino-3-cyano-1- [2,6-digas-4-pentafluorothiophenyl] -11 ^ orbitazol-4-yl} -sense (pyrimidine- 4-ylmethyl) methanesulfonylamine; 10 meaning {5-amino_3-cyano-1- [2,6-digas_4-pentathiothiophenyl] _1 仏. Biazole-4 · *}-N- (1-pyridin-4-ylethyl) methanesulfonamide; 1 ^-{3-cyano-1_ [2,6_digas-4-pentafluorosulfanyl group Phenyl] -11 ^ than 11-sit-4-yl} -2-lanthoxy-N- (2,2,2-trifluoroethyl) propan-1-ylpyramine; Ν_ (3-cyano- 1_ [2,6-dichloro-4-pentathiothiophenyl] · 5 _ {[3- (dimethyl15amino) propyl] amino} · 1Η ″ bizol-4-yl) _Ν_ ( 2,2,2 · trifluoroethyl) methanesulfonamide; Ν- {3_cyano-1_ [2,6 · dichloro_4_pentafluorothiophenyl] _5 _ [(2_ ^ σ 定Small ethyl group) 1 * group] -111- ° than '7 sitting-4-yl}-] ^-(2,2,2-trifluoroethyl) methanediamine; meaning {5-amino group -3-cyano-1- [2,6-digas-4-pentafluorothiophenyl] _11_1_0 than sialo-4_yl} _sense (2,2,2_difluoroethyl) thiamine ; 1 ^-{5-amino-3-cyano-1- [2,6-dichloro-4-pentafluorothiophenyl] _111_11 than sialo-4-yl} thiocarbamate; N- {5 -Amino-3-cyano-1- [2,6-digas-4_ (trifluoromethyl) phenyl]] fluorene 31 200531963 pyrazol-4-yl} -4-fluoro-N- (methyl Fluorenyl) benzenesulfonamide; N- {5-amino-3-cyano-1- [2,6 · dichloro-4- (trifluoromethyl) phenyl] -1H-pyrazole-4- } -2,4-difluoro-N- (methylfluorenyl) benzenesulfonamide; 3-amino-l- [2,6-digas-4-pentasulfur basic ] -4-[(methyl stone wind 5-based) (2,2,2-trifluoroethyl) amino] -1Η-pyrazol-5-ylcarbamic acid methyl ester; 3-cyano-1- [ 2,6-dichloro-4-pentafluorothiophenyl] -4-[(methylfluorenyl) (2,2,2-trifluoroethyl) amino] -1Η-pyrazol-5-yl Aminophosphonic acid 2,2,2-trifluoroethyl; N- {5-({[(2-aminoethyl) amino] carbonyl} amino) -3-cyano-1- [2, 6_ 10 dichloro-4-pentafluorothiophenyl] -1Η-pyrazole_4-yl} -sense (2,2,2-trifluoroethyl) methanesulfonamide; Ν · {5-[( 2-methyl-denyl-1-ylethyl) amino] -3 -muryl-l- [2,6 -digas-4-pentafluorothiophenyl] -1Η-pyrazol-4-yl } -Sense (2,2,2-trifluoroethyl) methanesulfonamide trifluoroacetate; 15 Ν · (3 · cyano small [2,6_dichloro_4 · pentafluorothiophenyl) ] -5-{[(2,4-Dihydroxyphenyl) methylene] amino} -1Η · pyrazol-4-yl) -N_ (2,2,2-trifluoroethyl) methanesulfonium Amine; N- (3-amino-l- [2,6-digas-4-pentathiothiophenyl] -5-{[benzylidene] amino} _1H-pyrazole-4- ) -N- (2,2,2_trifluoroethyl) methanesulfonamide; 20 N- {5-gas_3 · cyano-1- [2,6 · dichloro-4-pentafluorosulfide Phenyl] -1Η-pyrazole-4_S} -N- (2,2,2-digasethyl) methylpyramine, or N- (3-gas -L- [2,6-digas-4-pentathiothiophenyl] -5-{[3 · (difluorenylamino) ethyl] amino group-4-yl) -N- ( Methyl stone wind-based) methyl pyroxanthin, or a pharmaceutically, veterinary or agronomically acceptable salt or solvate thereof. 32 200531963 The compounds of formula (1) have the ability to kill parasites in human 'animals and agriculture. They are particularly useful for controlling ectoparasites. In a further point of view, the present invention provides a medicinal product of formula (I) or a medicinal, veterinary or agronomically acceptable salt thereof, or a whole medicine,. The methods of solvates (including hydrates) acceptable to a medical practitioner or agronomy are explained below. # The following elucidation method can be used to obtain the co-synthesis procedure of the compound of the present invention. One or more of R, R, R3, r4, and R5 containing a reactive functional group may provide additional protection during the synthesis of a compound of formula VII according to standard procedures. In the method described below, for all synthetic precursors used in the synthesis of the characterized formula, the definition of R1, R2, r3, y R5 (where Ri, r2, r3, R4AR5 is as shown in formula ⑴ Definition) Intended selection = sex includes appropriately protected variants, 1 > 1, 1 > 2, 1 > 3, 1 > 4, and 1 > 5. The protective groups of this person and quotient in this group are described in the reference material φ listed below, and the use of these protective groups (if necessary) is particularly intended to fall into the use described in the present invention. It is within the scope of a method of making a compound of formula (I) and its precursor. When a suitable protecting group is used, it needs to be removed to produce a compound of formula (I). Deprotection can be achieved according to standard procedures, including those listed in the 20 references below. For example, when R5 is an unsubstituted amine group in formula (I), some precursors may need to protect the amine group for the desired conversion, such as by imine amine group (such as A compound of formula (lb)), wherein rLr4 is as described in formula (I) and R5 represents -N = C (H) -NRaRb, wherein each of Ra and Rb independently represents 33 200531963 M alkyl (for example to form an H methyl group). The ammonium methylamines can be prepared using the methods described herein, and can be prepared under suitable acid conditions, such as at elevated temperatures, such as at f_20, to make suitable acids ( (Such as recording acid). According to the first common method, the compound of formula 伤 can be prepared from the compound of formula ⑻, where R4 is defined by ^ and Xin ⑴:

(II) where R1, R2, and R5 are as defined in the foregoing formula (i); they can be sulfonated in a standard state by a suitable% chemist (such as R3SO2Cl or sulfonic anhydride), such as 10 in a suitable solvent (such as , Digas methane) in the presence of a base (typically a pyridine / 4-diamidinoaminopyridine mixture) in an inert environment. Compounds of formula (I) where R4 is other than hydrogen can be prepared from compounds of formula VII where R4 is hydrogen using standard procedures. For example, a compound of formula (I) where R4 is R9S02- can be obtained by adding a suitable sulfonating agent (such as R9S02C1) to a compound of formula 15 in an aprotic solvent (such as acetonitrile or dichloromethane). The solution is prepared in the presence of a base (for example, triethylamine, potassium carbonate, or a pyridine / 4-dimethylaminopyridine mixture). The compound of formula (Π) can be disulfonated in a one-pot process under fairly well-known conditions to form a compound of formula VII. R4 and R3 are attached to nitrogen and sulfur atoms to form a 4 to 7 member compound of formula (I) with a single 20 amine ring, which can be obtained from the compound of formula (II) by the single 34 200531963- In the step, a chloro-Cw alkylsulfonyl gas is added to a solution of a compound of formula (II) in a suitable solvent such as pyridine, and the reaction is allowed to proceed, followed by the addition of a weak base (typically in a suitable solvent ( Such as n, n-dimethylformamidine) potassium potassium acid)) and heated at high temperature for several hours to prepare. 5 When R4 is S02R9 and R9 and R3 are attached to nitrogen and sulfur atoms to form a 4- to 7-membered bissulfonamide ring compound of formula (I), the compound of formula (η) In two steps, Cw alkylbissulfonamido chloride is added to a solution of a compound of formula (II) in a suitable solvent, such as pyridine, and heated under reflux for several hours (typically overnight) ) To prepare. A compound of formula (I) where 10 r4 is alkyl can be obtained, for example, by combining a compound of formula (I) with a suitable alkylating agent (e.g. R4-X, where X can be any leaving group, typically I , Br, a, OTs, OTf, 0-methanesulfonate or 0-trifluoromethylsulfonate) in a suitable solvent (such as acetone, dichloromethane, acetonitrile, monomethylformamide or N -Methyl σ bilobenone), prepared by reacting in the presence of a test (eg potassium carbonate, 15 cesium carbonate and sodium hydride). Other salts can assist the reaction, such as I or sodium iodide. Compounds of formula (I) wherein R4 is alkyl can be prepared by alkylating compounds of formula (I) wherein R4 is hydrogen using a suitable acidic alcohol reagent through a Mitsunobu reaction. 20 "The compound of formula (I) which is a Cw alkoxycarbonyl group can be obtained by letting R4 be a compound of formula (I) and an alkyl haloformate (such as a chloroformate) in a suitable solvent such as Acetone), using a suitable base (such as potassium carbonate), at a reflux temperature for several hours to prepare. Standard chemical procedures can be used to modify the compound of formula 3 R2, 35 200531963 RR and IU chain, restrictions Provided that any reactive functional group f_ # lai in the remaining side chain (as mentioned above). = For example, compounds of formula (I) where R2 is CN may be used by those skilled in the art. Under well-known standard conditions, compounds of formula (I) where R2 is -C (0) N (Ra) Rb and c! 6 5 alkylidene group are w. R is-(Qm extended alkyl) _cyclopropyl The compound of formula ⑴ can be prepared from a compound of formula ⑴ where R4 is a compatible alkenyl group by standard cyclopropane calcination procedures, such as converting a vinyl derivative to a corresponding digas cyclopropyl derivative ' It is prepared by heating a solution of 10% benzoate in a suitable solvent (such as toluene) at a high temperature, followed by the addition of trimethylamine dropwise. Shisyakyl-2,2-difluoro-2- (fluorofluorenyl) acetate is more than a few hours. This conversion is also described in WO98 / 24767. R4 is a C2 · 6 alkenyl of formula (I) Compounds can be prepared from the corresponding bromoalkyl compounds by dehydrobromiding under standard conditions. As in 15, compounds of formula r where r4 is bromoalkyl can also be used to prepare other formulas ( I) a compound (wherein the molybdenum group is substituted with a suitable nucleophilic group (such as a heteroaryl group) in a suitable polar solvent in the presence of a suitable test). R can be used as a oxidizable group Compounds of formula (I) to prepare another compound of formula (I), for example, using standard oxidants (such as Oxon 20 (OXone)) or described in "Reagent Handbook of Organic Synthesis-Oxidation and Reducing Agents," (by SD (Burke and R 丄 Danheiser (ed.)), Convert thioethers and alkyl substituted substituents to fluorene and Weiji derivatives, respectively. R4 is an acid or ketone group containing a compound of formula ⑴ can be used in the standard state of 36 200531963, such as Desma; Dess-Martin periodinane, in aprotic solvents (such as methane ) In the oxidation phase of the hydroxyalkyl group. The resulting aldehyde or ketone group can be further treated with a nucleophilic reagent in a suitable solvent (typically tetrahydrofuran) and optionally in the presence of a suitable catalyst5 to provide a nucleophilic substituted secondary or Tertiary alcohol. Compounds of formula (I), where R is-(Cu elongation) -C02H, can additionally be prepared by saponifying a corresponding carboxylic acid ester. A compound of formula (I) wherein R5 is NH2 can be used to prepare another compound of formula (I) by derivatization of an amine group, including methods for forming a R4 group of 10 as discussed above (e.g., Or incubation). Compounds of formula (I) where R5 represents an optionally substituted Ci_6iminoimine group can be additionally supplemented by heating the compound of formula (I) of which R5 represents NH2 with an aldehyde and a suitable catalyst (Typically p-toluene acid), and can optionally be prepared by adding molecular sieves. A compound of formula ⑴ 15 wherein R represents a optionally substituted Cw alkylimino group can be reduced by a suitable reducing agent (for example, sodium borohydride) in a suitable solvent (typically ethanol). Amine bonds to form different compounds of formula VII. Depending on the desired derivatization, R5 can be further manipulated as a compound of formula (I) with a derived amine group. For example, N-alkenyl derivatives can be oxidatively cleaved under standard conditions to produce aldehydes. This aldehyde derivative can be further manipulated to provide other derivatives, such as reductive amination under standard conditions to provide secondary and tertiary amines. Similarly, a compound of formula VII where R5 is NH2 reacts with a hydrazone or an acid anhydride in a non-synthetic > cereal (such as acetonitrile) and reflux overnight to produce a compound of formula (I) where R5 is -NHR, And Rn represents a optionally substituted Ck 37 200531963 alkylfluorenyl or G · 6alkoxycarbonyl. Furthermore, the coupling reaction of a carboxylic acid and an amine can be performed in the presence of a suitable coupling agent, such as water-soluble carbodiimide. Compounds of formula (I) where R is NH2 can be reacted with trialkyl orthoformate (such as triethyl orthoformate 5) under acidic conditions by heating at high temperature (typically 60 C) for several hours (typically 2 to 4 hours) to carry out the reaction to provide a compound of formula (I) wherein R5 is methylimino (substituted by a optionally substituted Ci6 alkoxy (eg, ethoxy)). These imino-ethers can be optionally refluxed with primary or secondary amines in a suitable solvent to provide other R5 as methylimino groups (from di 10 -Cl · 6 alkylamine groups (such as dimethyl Amine) substituted) compounds of formula (I). Compounds of formula (I) where R5 is fluorene can be prepared by a variety of standard diazotization procedures to diazotize compounds of formula IX where R is NH2. Compounds of formula (I) where R5 is NH2 can be converted using standard Sandmeyer reaction conditions to provide compounds of formula VII where R5 is halo. The compounds of formula (I) in which R5 is NH2 can also be converted into carbamates or ureas under standard conditions. Halo-substituted carbamates can be further reacted with nucleophilic groups (such as primary or secondary amines) in a suitable alcohol-containing solvent. Lithium iodide can be optionally added and stirred at room temperature for several hours. Provides 20 nucleophile-substituted products, such as derivatives substituted with secondary or tertiary amines. The compound of formula (II) can be prepared as shown in the following method 1, wherein RR and R are as defined previously; the -co2Me group is exemplified as any rhenium group and -C02 (CH2) 2Si (CH3 ) 2 is illustrated as any suitable amine protecting group resulting from Curtius recombination. 38 200531963

(" 0 (IV)

(νι) Method 1 A compound of formula (IV) can be obtained from a compound of formula (II) by conventional halogenation procedures, for example, treating ^ iodosuccinic acid 5 imine in a suitable solvent such as acetonitrile to provide the iodine Compounds. Compounds of formula (QV) can be carbonylated using conventional procedures (e.g., using a palladium catalyst) to provide compounds of formula (V). Saponification of methyl esters of formula (V) can be accomplished using standard ester hydrolysis conditions to provide acids of formula (VI). Compounds of formula (VII) can be prepared from compounds of formula (VI) by Curtis recombination of fluorenyl azide which has been prepared in situ using conventional procedures. For example, at high temperature, diphenyl Phosphonohydrazide is added dropwise to a solution of the compound of formula (VI), triethylamine, and 2- (trimethylsilyl) ethanol in Ershan. Defluorination can be achieved using a variety of fluoride-initiated desilylation procedures to produce an amine of formula (II), such as a compound of formula (VII) and fluorine heated in a suitable solvent (typically tetrahydrofuran) at elevated temperatures Tetra 39 200531963 solution of butyl ammonium. Another way to reach the compound of formula (II) is to provide a nitro compound of formula (vm) by nitriding the compound of formula (HI), and then reduce the nitro substituent of the compound of formula (vm) to formula (π Amines, as shown in method 2, 5 where R1, ruler 2 and ruler 5 are as defined for the compound of formula XI. Method 2

The compounds of formula (Satoshi) (where Rl and RW are as defined in the previous formula) can be prepared by the conventional electrophilic gasification procedure, and then using a variety of reducing agents (including the reagent manual described in "Organic Synthesis- Oxidation and reducing agents, (those edited by SD Thin Rail and RL Single Heather) to facilitate reduction of compounds of formula (). 5 Compounds of formulas (III) and (VIII) are—useful compounds, It can perform interconversion of functional groups at, for example, the R5 position, to provide different groups of formula (VIII) using the conversions described herein 15 and well-known by those skilled in the art. Compounds of formula (III) Tritium can be produced by reducing a compound of formula (IV) (wherein the halo group is angstrom). This can be achieved, for example, by combining with a suitable organometallic reagent such as a Grignard reagent, typically isopropyl chloride. Town), in a suitable solvent (such as tetrahydrofuran), at a reduced temperature, under the appropriate water 40 200531963, the metal transfer effect. The aryl ratio can be easily carried out. Sitting template The synthesis of R2 is selective from i group or C3_8 cycloalkane A compound of formula (III) substituted with a Cw alkyl group can be prepared from hydrazine of formula (IX) by reacting with an α-cyanone of formula (X) 5 at high temperature:

CN R '—! ΓΝΗ: (IX) (X)

Wherein R2 represents a Cw alkyl group optionally substituted with a halogen group or a C3-8 cycloalkyl group. Compounds of formula (X) are quite well known or can be prepared by methods which are quite well known to those skilled in the art. 10 The compound of formula (IX) can be prepared by diazotizing the compound of formula (XI), and it is mixed with sodium nitrite in an acidic mixture (such as glacial acetic acid and sulfuric acid) at a temperature of 5-60 ° C. React to provide a diazonium salt of formula (XII): +-

R1—NH2 R1—N Tri N (XI)-(XII) The diazonium salt of formula (XII) is then reduced in a concentrated acid (such as a hydrogen acid) with a reagent such as stannous gasification. Furthermore, R2 represents a optionally substituted Cw alkyl and methyl group compounds of formula (XIII) which illustrate any suitable carboxylate protecting group:

R1 (XIII) 41 200531963 which can be obtained from hydrazine of formula (IX) and compounds of formula (XIV) (wherein L is a leaving group (typically C1)),

Prepared in a suitable solvent, typically diethyl ether, with a suitable base, such as 5 potassium carbonate. R2 is hydrogen, a compound of the formula (III) optionally substituted with an i group or a C3_8 cycloalkyl group, and a compound of the formula (IX) and a compound of the formula (XV) (Wherein R2 is hydrogen and Cu substituted with halogen or alkyl optionally substituted; and L is a leaving group such as chlorine, molybdenum, iron).

R2 represents a C! _6 alkyl group, a Cw haloalkyl group, a c3-8 cycloalkyl group, or a cyano compound of formula (V), which can be used in a protic solvent In the presence of potassium carbonate, for example, a compound of formula (IX) is reacted with compound 15 of formula (XVI) (wherein preparation.

(XVI) Gas olefins of formula (XVI) can be obtained by gasifying olefins of formula (XVII) at room temperature using phosphorus pentagas in a solvent such as digas methane at 42 200531963.

R2 ^ _ ^ CNNaCo2Me (XVII) A wide variety of literature methods can be used to synthesize functionalized alkenes of formula (χνιι). 5 Furthermore, compounds of formula (III) where R2 represents CN and R5 represents OH or NH2 can be synthesized via Japp-Klingemann reaction: let

The aryl diazonium salt of formula (IX) is reacted with a compound of formula (XVIII) or (XIX) (wherein R and R "are alkyl groups).

NC CN RO

Ο (XVIII)

R.O

0 (XIX) 10 The diazonium salt of formula (IX) can typically be obtained, for example, by reducing the temperature (typically 10

° C), the amine benzene solution of the formula (VIII) in glacial acetic acid was added dropwise to a solution of sodium schistolithonate in a concentrated sulfuric acid / glacial acetic acid mixture, followed by 50 ° C. Heated at 0 ° C for several hours (typically 1 hour) and allowed to cool to room temperature to produce in situ. Then, this diazonium salt solution is added dropwise to a solution of a compound of formula (xviii) or (XIX) in a suitable solvent such as acetic acid 15, followed by stirring at room temperature for a maximum of 1 hour. The reaction mixture is poured into water and extracted with an organic solvent (such as digas methane) that cannot be mixed with water. Aqueous ammonium hydroxide was added to the organic extract and stirred overnight to provide a compound of formula (III). Compounds of formula (XIX) can be prepared by adding glycolonitrile to ... nitrile esters and stirring for several hours at room temperature in a suitable solvent in the presence of a weak base (typically potassium carbonate). An arylpyrazole compound of formula (XX) (wherein R1 is as previously defined and the methyl group is illustrated as any carboxylic acid protecting group):

It can be prepared by reacting hydrazine of formula (IX) with an electrophilic group (such as a compound of formula (XIX)) 'in an aprotic solvent (such as isopropyl alcohol) and refluxing for several hours.

S

S

COXH,

CN (XXI) 10 can use standard conditions to achieve the desired synthesis of 1-aminobenzenes. For example, 2,6-unsubstituted aniline derivatives can be added by adding N-chlorosuccinimidine. Suitable solvents (such as acetonitrile), and single or two gasification at high temperature (typically 45-55.0) for several hours (typically 1 to 3 hours). Furthermore, those skilled in the art will understand the description Variations and substitutions of methods to obtain compounds defined by formula (I). It will also be apparent to those skilled in the art that in some of the methods described, V changes the order of the synthetic steps used, and This will depend in particular on factors such as 44 15 200531963, such as the presence of other functional basics in the particular matrix, the availability of key intermediates, and the protective group strategy to be used, if any. This factor will It also clearly affects the choice of reagents that can be used in this synthetic step. It will also be appreciated that the exchange and conversion of multiple standard 5 substituents or functional groups in certain compounds of formula (I) will provide other formulas (I Those skilled in the art will appreciate that the compounds of the present invention can be used in addition to those described herein, using methods described herein, and / or employing techniques described in this art (such as those described herein). ), Or standard textbooks such as "Comprehensive Organic Transformations-A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later); `` March's Advanced Organic Chemistry-Reactions, Mechanisms, and Structures '', MB Smith, J. March, Wiley, (No. 5 Edition or later); "Advanced Organic Chemistry, Part 15 B, Reactions and Synthesis", Carey, FA, RJ Sundberg, Kluwer University / Plenum Publications , (2001 or later); "Organic Synthesis_Separation Method", Warren (Wiley), (1982 or later); "Design of Organic Synthesis", Sfrog Cold (Willie) (1983 or later); "There are 20 machine synthesis manuals", RK Mackie (Mackie) and DM Smith (Longman) (1982 or later) and so on; and the reference materials in it as Guide. It is important to understand that what is mentioned in this article The conversion methods are only typical, and they can be performed in many different programs to efficiently combine the compounds required by 45 200531963. Well-known chemists will use their judgment and skills to perform the most efficient reaction procedures to synthesize The subject compounds provided, for example, can be combined with special reactions to add substituents to those different intermediates mentioned hereafter, and / or chemical conversion afterwards. This will depend in particular on a number of factors, such as other functional basics present in the particular matrix, availability of key intermediates, and protective group strategies (if any) employed. The chemical form included will clearly affect the choice of reagents used in this synthesis step, the need for protecting groups and the type of which they will be used, and the procedures to achieve the synthesis. It is possible to use procedures with appropriate reactants, reagents, and other reaction parameters, in a manner that will be apparent to those familiar with the art, 10 with reference to standard textbooks and examples provided thereafter. It will be apparent to those skilled in the art that during the synthesis of the compounds of the present invention, it is necessary to protect and deprotect sensitive functional groups. This can be achieved by conventional methods such as described in "Protective Groups in Organic Synthesis," (by 15 TW Greene and PGM Watts, John Wiley & Sons Inc.) (1999)) and references therein. Pharmaceutically acceptable salts of compounds of formula (I) include acid additions and salts thereof to satisfy the acidity or characterization of the compounds. Suitable Acid addition salts can be formed from acids capable of forming non-toxic salts. 20 examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, hydrogen sulfate Salt / sulfate, borate, camphor sulfonate, citrate, oxalate, esylate, formate, fumarate, glucoheptanoate, glucose Acid salt, glucuronate salt, hexafluoroscale salt, hibenzate, hydrochloric acid / chloride, hydrobromic acid / bromide, hydrogen 46 200531963 iodic acid / iodide, isethionate, lactate, malate Salt, maleate, malonate, mesylate, sulfamate, naphthylate, 2-naphthalenesulfonate Salt, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, glycate, stearate , Succinate, tartrate, tosylate, and trifluoroacetate. Suitable test salts can be formed from bases that can form non-toxic salts. Examples include aluminum, arginine, benzamidine, | bow, bile test Amines, diethylamines, glycolamines, glycine, lysine, meglumine, meglumine, alcoholamine, potassium, sodium, tromethamine, and 10-salt salts. A review of suitable salts can be found in "Medicines Handbook of Salts (Han (jb00k of Pharmaceutical salts): Nature, Selection and Use), compiled by Stahl and Wermuth (William_VCH, Weinhdm, Germany) , 2002). 15 A pharmaceutically acceptable salt of a fine compound can be easily prepared by appropriately mixing a solution of a compound of formula (I) with a desired acid or test. The salt can be prepared by Precipitate from solution and collect over time, or can be recovered by hair loss solvent. The degree of ionization in the salt can be changed from fully ionized Almost unionized. 20 ". M exists in both unsolvated and solvated forms. The name "solvate," as used herein, describes a molecular complex that contains compound i or more of the invention Pharmaceutically acceptable i-agent molecules (for example, ethanol). When the solvent is water, it is named. 47 200531963 The complexes included within the scope of the present invention include compounds such as cage compounds, drug-host inclusion complexes (Which is compared with the aforementioned solvate, the drug and the host can be present in stoichiometric or non-stoichiometric amounts). Also included is a drug complex comprising two or more stoichiometric or non-stoichiometric amounts of organic and / or inorganic components. The resulting complex can be ionized, partially ionized, or unionized. A review of this complex can be found in j. Pharm Sd, Pat. 8), 1269_1288 (by Harley Brian (service oil) (August 1975)). After that, all references of the compound of formula (I) include the salts, solvates and complexes thereof and the solvates and complexes of salts thereof. The compounds of the present invention include the compounds of formula (I) as defined above, and all polymorphs and medicinal substances thereof. The present invention also includes all isomers (including optical, geometric, and tautomeric isomers) of compounds of formula (I) as defined hereinafter, and compounds of formula (I) that are isotopically calibrated. 15 The so-called "prodrugs of the compounds of formula (I) are also within the scope of the present invention. Therefore, certain derivatives of the compounds of formula (I) themselves have little or no pharmacological activity and should be administered when When in or on the body, it is converted (e.g., cleaved by hydrolysis) to a compound of formula (1) with the desired activity. Such derivatives are referred to as "prodrugs." It is understood that a certain Some of the compounds of formula VII themselves can be used as prodrugs of other compounds of formula (I). Further information on the use of predrugs can be found in "Prodrugs as Novel Delivery Systems 'Volume 14' ACS Forum" Series "(τ Higuchi and W Stella); and" Bioreversible Carriers in Drug Design, "Pergamon Press, 1987 (ed · EB Luo Found in Roche, US 48 200531963 American Pharmaceutical Association). Prior to the invention, the drug substance can be substituted, for example, by a moiety known to those skilled in the art as a "prodrug moiety" to replace the 5- on the pyrazole ring in the compound of formula (I). Manufactured by amine substituents, as described in Example 5 as in "Design of Prodrugs" by Bundgaard (Elsevier, 1985); "Design and Application of Prodrugs" Textbook of Drug Design and Discovery, (3rd edition), 2002, 410-458, (Taylor and Francis Ltd., London); and References therein. 10 A suitable prodrug may have a

N-containing group and bonded to the ring through N bond. The 5-N group may be substituted once or twice. Examples of the substituent include: alkylamines, arylamines, amidoamines, ureas, carbamates, cyclic carbamates, imines, dilute amines, amidines, Cyclic fluorene imines, amines and amines M. The hydrocarbon portion of these groups includes Ci_6 alkyl, phenyl, heteroaryl (such as t-radical), c2.6 alkenyl, and c3.8 cyclo slave; each of the above groups may include one or more optional Substituents, each of which may be chemically independently selected from fluorenyl, hydroxyl, Cw alkyl, and Cl 6 alkoxy. 20 Further examples of substitution groups according to the aforementioned examples and examples of other prodrug forms can be found in the aforementioned references. According to this fortune, it is easy to say goodbye to the test animal and take a sample of the body fluid of the compound of the formula (I) by borrowing the teutonic drug. Compounds of formula (I) containing one or more carbon atoms may have one or more stereoisomers. If the compound of negative formula () includes alkenyl or alkene 49 '200531963 radical, there may be geometric cis / trans (or Z / E) isomers. If the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomers ("tautomers") may occur. It is followed that a single compound may have more than one type of homogeneous isomer. 5 Also included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), which include compounds having more than one isomeric form and one or more mixture. It also includes optically active acid addition or base salts of counter ions, such as D-lactate or L-lysine; or racemates, such as DL-tartrate or DL-arginine. 10 Separation of cis / trans isomers can be made using conventional techniques already known to those skilled in the art, such as' chromatographic analysis and partial crystallization. Conventional techniques used to prepare / separate individual mirrors include palladium synthesis from suitable optically pure precursors; or the use of, for example, palladium high pressure liquid chromatography (HLPC) to resolve racemic salts (or Salt or derivative racemic 15 salts). Furthermore, the racemic salt (or a racemic precursor) may be reacted with a suitable optically active compound (for example, an alcohol); or in the case where the compound of Formula (I) includes an acidic or basic moiety, with an acid or a base (Such as tartaric acid or phenylethylamine). The resulting non-mirromeric isomers can be separated by chromatographic analysis and / or 20-part crystallization, and one or both of the non-mirromeric isomers can be converted into compatible compounds by methods well known to those skilled in the art. Pure mirror. The herbicidal compound of the present invention (and its palmitic precursor) can be subjected to chromatographic analysis (typically HLPC). On an asymmetric resin, a hydrocarbon (typically heptane or hexane) containing 0 to A mobile phase consisting of 50% isopropanol (typically 2 to 20%) and 5050 200531963 to 5% benzylamine (typically 0.1% diethylamine) to obtain a rich mirror image. The form of the structure. The concentration of the eluent provides this rich mixture. Aggregates of 5-stereoisomers can be separated using conventional techniques well known to those skilled in the art, see, for example, "Stereochemistry of Organic Compounds," by EL Ellier (E. (Samley, New York, 1994) The present invention includes all pharmaceutically acceptable isotopically labeled chelating substances of formula (I), in which-or more atoms are replaced by atoms having the same atomic number, but the atomic weight or mass number is the same as that normally found in nature. The atomic mass or mass number found is different. 15

Examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen: isotopes, such as 2H, and; carbon, such as nc, allowance;%, gas = C1, fluorine, such as 18F; iodine, such as 1231 and 1251 Nitrogen, such as% and N'oxygen 'such as 0, 17 and 18; phosphorus, such as 32p; and sulfur, such as 35S. Certain isotopically-labeled compounds of formula (I) (e.g., those incorporating radioisotopes) are useful in drug and / or matrix tissue distribution studies. For this purpose, the radioisotope plutonium (i.e., 3H) and carbon 14 (i.e., 14c) are particularly useful, given their easily incorporated and prepared detection equipment. Substituting heavier isotopes (such as deuterium, 2H) can get some therapeutic advantages of 20 points, which can produce greater metabolic stability, and for example, can increase the half-life in vivo or can reduce the dose requirements, so in some cases Better. Replacement with positron-emitting isotopes such as 11C, 15O, and πN can be used in positron tomography (PET) studies to check matrix receptor occupancy formula. Isotope-calibrated compounds are usually available by well-known techniques 51 200531963 Conventional techniques well known to those skilled in the art, or using methods similar to those described in the companion examples and preparations, using appropriate isotope-calibrated reagents in place of previously used uncalibrated reagents. Pharmaceutically acceptable solvates according to the present invention include those in which the crystalline solvent 5 can be substituted with isotopes, such as D20, d6-acetone, d6-DMS. The compounds of the present invention intended for use as medicines can be administered as crystalline or non-crystalline products. They can be obtained by methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying, and can be, for example, solid plugs, powders or films. Microwave or radio wave drying can be used for this purpose. 10 They can be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or if any combination thereof, the compounds of the invention can also be mixed with one or more biologically active compounds or agents , Including insecticides, acaricides, worm repellants, fungicides, nematicides, antiprotozoals, bactericides, growth regulators, insects 15 entomopathogenic bacteria, viruses or fungi, To form a multi-component insecticide that can provide an even wider range of medical, veterinary or agricultural uses. Therefore, the present invention also relates to a composition comprising a biologically effective amount of a compound of the present invention and an effective amount of At least one additional biologically active compound or agent, and may further include one or more surface active 20 agents, solid diluents, or liquid diluents. The biologically active compounds listed below that may be used with the compounds of the present invention are intended to be clarified Possible combinations, but not intended to impose any restrictions. For example, the compounds of the present invention may be co-administered or grouped with anthelmintics This helminth repellent includes chemical compounds selected from the group of macrolides 52 200531963 compounds, such as ivermectin, avermectin, abamitin, Emamectin, eprinomectin, doramectin, selamectin, moxidectin, nemadectin, and bemai Cardiac (milbemycin) derivatives, as described in EP-357460, EP-444964 and EP-594291. Additional anthelmintic agents include semi-synthetic and biosynthetic avermectin / beperioxin derivatives, such as described in US-5015630, WO-9415944, and WO-9522552. Additional worm repellents include benzimidazoles, such as albendazole 10, cambendazole, fenbendazole (fenbendazole), fluorobenzopyrazole aminocarboxylic acid, benzopyrazole methylaminocarboxylic acid, benzodiazepine, oxibendazole, parbendazole, and other member species. Additional anthelmintic agents include imidazosigma and tetrahydrobiters, such as Tetramisole, levamisole, levamisole, thiopyrimidine, or thiaphene. The compounds of the present invention can also be used as derivatives of paraherquamide / marcfortine worm repellents. And the like, in combination with parazoic oxazolins such as those disclosed in US-5478855, US-4639771 and DE-19520936. 20 The compound of the present invention can be co-administered or combined with general derivatives of bimorphine antiparasitic drugs and analogs (as described in WO-9615121), and can also be co-administered with anthelmintic drugs. Active cyclic peptides such as those described in WO-9611945, WO-9319053, WO-9325543, EP-626375, EP-382173, WO-9419334, EP-382173 and EP-503538 are used together 53 200531963 . The compounds of the present invention can be co-administered or used in combination with other ectoparasite insecticides, such as fipronil; pyrethroids; organophosphates, insect growth regulators, such as rofenac (lufenuron); dermatokine 5 hormone synergists' such as tebufenozide and its analogs; new classes such as imidacloprid and its analogs. Other examples of such biologically active compounds include (but are not limited to) the following: organic scale salts · acephate, azamethiphos, azonphos-ethyl, valley speed Pine 10 (azinphos-methyl), bromophos, bromophos-ethyl > cadusafos, chlorethoxyphos, chlorpyrifos, chlorpyrifos (chlorfenvinphos), chloromephos, systemic filling

(demeton), demeton-s-methyl, demeton-s-methyl sulphone, dialifos, diazinon, digassin (dichlorvos), dicrotophos, dimethoate, disulfoton, ethion, ethoprophos, etrimfos, ammonia famphur), fenamiphos, fenitrothion, fensulfothion, fenthion, flupyrazofos, fonofos, formothion, blessing Fosthiazate, heptenophos, isazophos, isothioate, isoxathion, marathion, methacriphos, methamidophos ), Methionone 54 200531963 (methidathion), methyl-parathion, mevinphos, monocrotophos, naled, omethoate, omethoate Pine (oxydemeton-methyl), paraoxon, parathion, methylparathion Pine 5 (parathion-methyl), phenthoate, phosfolan, phosphocarb, phosmet, phosphamidon, phorate, bar Phoxim,

Mouth scales (pirimiphos), atrims (pirimiphos-methyl), profenofos, propaphos, proetamphos, 10 prothiofos, pyraclofos, bifen Pine (pyridapenthion), quinalphos, sulprophos, temephos, terbufos, tebupirimfos, tetrachlorvinphos, thiophene (thimeton), triazophos, trichlorfon, vamidothion ○ Urethanes: alanycarb, aldicarb, methylamine Acid 2-secondary butyl phenyl ester, benfuracarb, carbaryl, carbofuran, butyl carbosulfan, cloethocarb, ifenk ( ethiofencarb), 20 fenoxycarb, fenthiocarb, furathiocarb, HCN-801, isoprocarb, indoxacarb, methiocarb , Namethide (methomyl), 5-methyl-m-cumenylbutanyl (methyl) carbamate g, Off (oxamyl), Bi Jiapu (pirimicarb), Andan (propoxur), sulfur enemy grams (thiodicarb), 55 200531963 sulfur cutting long (thiofanox), triazamate (triazamate), UC-51717. Pyrethroids: arinathin, propylene pyrethrin, alphametrin, (E) _ (1R) H2,2 · dimethyl_3- (2-oxosulfite) Oz-3-ylmethyl) cyclopropanecarboxylic acid 5-benzyl-3-furanyl methyl ester, bifenthrin, β-cyfluthrin, cyfluthrin, α-cyphenidine ( cypermethrin), β-semecinobine, bioallethrin, transpropional pyrethrum ((S) -cyclopentyl isomer), bioresmethrin, bifennine , NCI-85193, cycloprothrin, cyhalothrin, cythithrin, cyphenothrin, 10 deltamethrin, empenthrin, Yihua Esfenvalerate, ethofenprox, fenfluthrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin , Fluvalinate (D isomer), imiprothrin, cylonin, λ-15, cylonin, permethrin, phenothrin, phenothrin (prallet hrin), pyrethrins (natural product), resmethrin, tetramethrin, transfluthrin, η-saifenin, silafluofen, τ-Fuhuali, tefluthrin, tralomethrin, and phi. 20 Arthropod growth regulators: a) Chitin synthesis inhibitors: benzamidine ureas: chlorfluazuron, diflubenzuron, fluazuron, flucycloxuron , Flufenoxuron, hexaflumuron, lufenuron, novaluron, teflubenzuron, trifhimuron 56 200531963, bufofezin ), Diofenolan, hexythiazox, etoxazole, chlorfentazine; b) ecdysone antagonists: halofenozide, methoxyfenozide Tebufenozide; c) Juvenoids: pyriproxyfen, metoprene, fenoxycarb; d) Inhibition of lipid biosynthesis Agent: Spirodiclofen. Other antiparasitic drugs: acequinocyl, amitraz, AKD-1022, ANS-118, azadirachtin, Bacillus thuringiensis, bensultap, biphenyl Bifenazate, binapacryl, bromopropylate, BTG-504, BTG-505, camphechlor, cartap, chlorobenzilate, chlorbenzyl (Chlordimeform), chlorfenapyr, chromafenozide, clonidine

15 (clothianidine), cyromazine, diacloden, diafenthiuron, DBI-3204, diactin, dimeryl methyl dichatidine, Dinobuton, dinocap, endosulfan, ethiprole, ethofenprox, fenazaquin, flumite, 20 MTI -800, fenpyroximate, fluacrypyrim, flubenzimine, flubrocythrinate, flufenzine, flufenprox, fuxi Fluproxyfen, halofenprox, hydramethylnon, IKI-220, kanemite, NC-196, 57 200531963 neem guard, nidinorterfuran, 浠 σ Amine (nitenpyram), SD-35651, WL-108477, pirydaryl, propargite, protrifenbute, pymethrozine, pyridaben, pyridaben (pyrimidifen), 5 NC-1111, R-195, RH-0345, RH-2485, RRI-210, S-1283, S-l833, SI -8601, silafluofen, silomadine, spinosad, tebufenpyrad, demisite

(tetradifon), tetranactin, thiacloprid, thiocyclam, thiamethoxam, tolfenpyrad, triazamate, sanxi Triethoxyspinosyn, trinactin, verbutin, vertalec, YI-5301. Fungicides: acibenzolar, aldimorph, ampropylfos, andoprim, 15 azaconazole, azoxystrobin, Benalaxyl, benomyl, bialaphos, blasticidin-S, Bordeaux mixture, bromuconazole, bupirimate ), Carpropamid, captafol, captan, carbendazim, chlorfenazole, chloroneb, chloropicrin ( chloropicrin, chlorothalonil, chlozolinate, copper oxychloride, copper salts, cyflufenamid, cymoxanil, cyproconazolel, cyproline (cyprodinil), cyprofuram, 58 200531963

RH-7281, diclocymet, diclobutrazole, diclomezine, dicloran, difenoconazole, RP-407213, dimethomorph, and more Domoxystrobin, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole, famoxadone, Fenamidone, fenarimol, fenbuconazole, fencaramid, fenpiclonil, fenpropidin, fenpropimorph ), Fentin 10 acetate, fluazinam, fludioxonil, flumetover, flumorf / flumorlin, triphenyl classics Tin (fentin hydroxide), fluoxastrobin, fluquinconazole, flusilazole, flutolanil, flutriafol, fulpe ( folpet), fosetyl-aluminium, furalaxyl, Furametapyr, hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, g Krsoxim-methyl, mancozeb, maneb, 20 mefenoxam, mepronil, metalaxyl, metconazole ), Metominostrobin / fenominostrobin, metrafenone, myclobutanil, neo-asozin, niobifen, Ousha Zhaobin 59 200531963 (orysastrobin), oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb, general Propioconazole, proquinazid, prothioconazole, pyrifenox, pyraclostrobin, pirimethanil, pyroquilon, fastno Quinoxyfen, spiroxamine oxamine), sulfur, tebuconazole, tetrconazole, thiabendazo, thifluzamide, thiophanate-methyl, thiram, Thai Tiadinil, triadimefon, triadimenol, tricyclazole, trifloxystrobin, triticonazole, validamycin, exempt Vinclozin 〇 Biological preparations: Bacillus thuringiensis ssp Yasha 15 aizawai strain, kurstaki strain, Bacillus thuringiensis Delta endotoxin, baculovirus, insect-pathogenic bacteria , Viruses and fungi. Bactericides: Tetracycline, Oxytetracycline, Streptomycin. Generally, they will be administered in a combination with one or more pharmaceutically acceptable excipients. The name "excipient" as used herein means that 20 is any ingredient other than the compound of the present invention. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the solubility of the excipient And the effects of stability and the nature of the form in which they are taken. The compounds of the invention are particularly valuable in controlling parasites that are harmful to humans and domesticated animals (such as those mentioned above) or that can spread or act as vectors of disease 60 200531963 value, and more particularly, it can control ticks, concealed species, feathers, winds, rockers, and dwellers, harassment and rope sickness tanks. They are controlling the existence of host animals Arthropods that eat or suck blood internally or in or on the skin of animals are particularly useful; for this purpose, they can be administered orally, parenterally, transdermally or topically. 3 Pharmaceutical combinations suitable for delivering the compounds of the invention And its preparation method will be easily understood by those skilled in the art. This composition and its preparation method are described in, for example, "Remington, s sciences", No. 1 Found in the 9th edition (Mark Publishing Company, 1995). With regard to its use in mammals, the compound may be administered alone or in a formulation suitable for the particular use envisaged, the particular host mammal to be treated, and the parasite species it contains. The compounds of the invention can be administered orally. Oral administration can include swallowing to allow the compound to enter the gastrointestinal tract; or oral or sublingual administration can be used to allow the compound to enter the blood directly from the mouth. Formulations suitable for oral administration include solid formulations, such as lozenges; capsules containing microparticles, liquids, or powders; lozenges (including liquid fillers); chewing agents; poly and nano particles; gels; solid solutions; fats Granules; films (including 20 mucus adhesives); ovoid bodies; drug mists; and liquid formulations. Liquid formulations include suspensions, solutions, syrups, and medicinal solutions. This formulation can be used as a blend in soft or hard capsules and typically contains a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil and one or more emulsifiers and / Or suspension. Liquid formulations can also be prepared from solids, such as from powder. The compounds of the present invention can also be used in a fast-dissolving, fast-disintegrating administration form, such as Expert Opinion in Therapeutic Patents, (6), 981_986 (by Liang and Chen 5 ( Chen) (2001)). For the bond administration form, the drug may consist of a dosage form of 1% to 80% by weight, more typically a dosage form of 5% to 60% by weight. In addition to the drug, tablets usually include a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, sodium salt of methyl 10-cellulose, sodium croscarmellose, crosslinked polyethylene 11 crospovidone , Polyethylene σ ratio bite _, methyl cellulose, microcrystalline cellulose, propyl cellulose substituted with short chain cyano groups, powder, pregelatinized powder and sodium alginate. Generally, the disintegrant will contain a dosage form of 1 to 25% by weight, preferably 5 to 20% by weight. 15 Binders are often used to confer cohesive properties to lozenge formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized powder, propyl cellulose and hydroxypropyl Methylcellulose. Lozenges may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol 20, xylitol, dextrose, bismuth, sorbitol, micro Crystalline cellulose, powder, and dibasic calcium phosphate dihydrate. It may also optionally include a surfactant ' such as Laurel Sulfate Sulfate and Polysorbate 80; and a glidant such as Dioxane; 6th and Talc. When present, the surfactant may be from 0.2% to 5% by weight of the lozenge; and the flow aid may be from 0.2 to 1% by weight of the lozenge. Lozenges also typically contain lubricants such as magnesium stearate, osmium stearate, zinc stearate, sodium stearate, and a mixture of magnesium stearate and sodium lauryl sulfate. The amount of the lubricant is usually 0.25% to 105% by weight of the tablet, preferably 0.5% to 3% by weight. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents. A typical lozenge contains up to about 80% of the drug, about 10% to about 90% by weight of a binding agent, about 0% to about 85% by weight of a diluent, and about 2% by weight of 10 ° / ❻ to about 10 A disintegrant by weight and a lubricant from about 0.25% to about 10% by weight. The lozenge mixture can be compacted directly or by a roller to form a lozenge. In addition, the lozenge mixture or part of the mixture may be wetted, dried or melted into granules, melted or coagulated or extruded prior to tableting. The final formulation may include one or more layers and may be coated or uncoated; it may even be encapsulated. The lozenge formulation is in "Medicine taking form: lozenges, Vol. 1", (by Hieberman and L. Lachman 'Marcel Dekker, N_Υ · , N · Υ ·, 198G (ISBN G-8247-6918-X)). 2 solid formulations for oral administration can be formulated for immediate and / or modified release modified release Formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Suitable modified release formulations that can be used for the purposes of this invention are described in US Patent No. 6,106,864. Other suitable release technologies ( Details such as Gao 63 200531963 Energy Dispersion, Penetration, and Coated Particles) are available on Verma et al. Pharmaceutical Technology On-line, 25 (2), 1-14 (2001) Found in. The compounds of the present invention can also be administered directly to the bloodstream, to muscles or to 5 internal organs. Suitable parenteral administration methods include bolus, intravenous, intraarterial, intraperitoneal , Intrathecal, indoor, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable for non- Devices for enteral administration include needle (including microneedle) syringes, needleless syringes, and infusion technology. Parenteral formulations are typically aqueous solutions, which can include excipients (such as salts 10, carbohydrates) and buffers (Preferably 3 to 9); however, for some applications they can be more suitably formulated as a sterile non-aqueous solution or as a combination with a suitable vehicle such as sterile, pyrogen-free water The use of dry and comprehensive form. The preparation of this parenteral formula in a local state can be easily achieved using standard medical techniques 15 already known to those skilled in the art (eg, freeze-drying method). Π uses stomach-adapted formula technology (Such as incorporating a human solubility enhancer) to do = use of a compound of formula ⑴ in the preparation of parenteral solutions ^ 20 I enteral formulations can be formulated for immediate and / or modified release. Modified release formulas Bai Tuo M, M, release and stylized release sustained, pulsed, controlled, labeled with implanted L. Therefore, the compounds of the present invention can be formulated-solid, semi-solid Solid or negative release liquid. Examples of formulations include grafts and PGLA microspheres coated with the drug 64 200531963. The compounds of the present invention can also be administered topically to the skin or mucous membranes, that is, dermal or transdermal. Typical formulations useful for this purpose include dipping Liquid, gel, hydrogel, lotion, solution, cream, ointment, spray powder, dressing, foam material, film, skin patch, vaginal flat sheet, implant, sponge, fiber, bandage and Microemulsions. Lipids can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white soft paraffin, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated, see, for example, j. Phann Sci, 88 (10) ' 955-958, by Finnin and Morgan (October). The active ingredient can be prepared by dissolving the active ingredient in an acceptable liquid carrier vehicle such as butyl digob liquid paraffin or non-volatile ester, and optionally adding a volatile group (Such as propanol). Furthermore, the formulations can be prepared by coating, splashing, dripping or spraying so that the active agent residues remain on the surface of the animal. 15 Injectable formulations may be prepared in the form of a sterile solution, which may contain other substances (e.g., sufficient salt or glucose) to make the solution isotonic with blood. Other methods of topical administration include electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedles or needle-free methods (e.g., Powder Ject ) TM, BioJetCt ™, etc.) by injection. Topical formulations can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed releases. The compounds of the present invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (separately, as a mixture (e.g., dried with a lactose)) or as a mixed group. Separate particles (for example, with scaly lipids (such as egg ^) a)) 'or if from a pressurized container, pump, sprayer, or chemist (preferably using electrohydrodynamics (eia 杜 〇hydr 〇 (iynamiCS) to 5 atomizers that produce fine mists) or sprayers (which can be used with or without a suitable propellant (such as l1, 1, ^ teton yaki or 1, 1, 1, 2 , 3,3,3-heptafluoropropane)). For intranasal use, the powder may contain a bioadhesive, such as polychitosan or cyclodextrin. The pressurized container, pump A sprayer, nebulizer or sprayer comprises a solution or suspension of a compound of the present invention, which contains, for example, ethanol, an aqueous solution of ethanol or another agent, propellant suitable for dispersing, solubilizing or extending the release activity as a solvent. ; And an optional surfactant, such as sorbitan trioleate, oleic acid Polylactic acid is recruited. Prior to use in dry powder or suspension formulations, the drug product can be micronized to a size suitable for inhalation delivery (typically less than 5 microns). This can be achieved by any suitable milling method, such as spiral Jet milling, fluidized bed jet milling, supercritical fluid treatment to form nano particles, high-pressure homogenization, or spray-drying. Capsules for use in inhalers or insufflators (eg, made from gelatin or Hpmc 20) Can be formulated into a powder mixture containing the compound of the present invention, a suitable powder base (such as lactose or starch), and performance modifiers (such as 1-leucine, glycerol or Stearic acid). The lactose may be in the form of anhydrous or monohydrate, the latter being preferred. Other suitable excipients include glucosan, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and leaching 66 200531963 Sugar 0 A suitable solution formulation that can be used in a nebulizer that uses electrohydrodynamics to produce a fine mist can include driving a microgram to 20 milligrams of a compound of the invention each time. The drive volume can be changed from microliters to 100 microliters. 5 A typical formulation may include a compound of formula (1), propylene glycol, sterile water, ethanol, and sodium carbonate. Other solvents that can be used to replace propylene glycol include glycerol and Polyethylene glycol. Suitable flavorings (such as menthol and menthol) or sweeteners (such as saccharin or saccharin sodium) can be added to those formulations of the present invention intended for inhalation / intranasal administration. Inhalation / intranasal formulations can be formulated for immediate and / or modified release, such as using poly (DL-lactic-co-glycolic acid) (pGLA). Modified release formulations include delayed, sustained, pulsed , Controlled, targeted, and programmed release. In the case of dry powder inhalants and aerosols, the dosage unit can be determined by a valve that delivers a metered amount for a 15 in. Units according to the present invention will typically be arranged to administer a metered dose or "smoke," which contains from ⑺⑻ to ⑺⑻ micrograms of a compound of formula (I). Typical doses throughout the day range from 100 micrograms to 100 milligrams It can be administered in a single dose or more often in divided doses throughout the day. The compounds of the invention can be administered rectally or vaginally, for example in the form of suppositories, vaginal suppositories or enemas. Cocoa butter is a traditional suppository base, However, different substitutes may be used as appropriate. Rectal / vaginal formulations can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, labeled 67 200531963 and Stylized release. This compound can also be directly administered to the eyes or ears, in the form of drip isotonic pressure, adjusted by pH, no, shape, and package. 5 、 Formulas suitable for eye and ear administration include ointments, degradation (such as absorbable gel sponges, collagen), and biological: implantable (such as polysilicone oxygen) implants, vaginal tablets, Lenses and particles or small: Such as large vesicles (duties. Called or lipid granules.) Can be incorporated together with polymers (such as polyacrylic acid, polyethylene, hyaluronic acid 'cellulose polymers (for example = propyl methyl cellulose, hydroxyethyl cellulose Or methyl cellulose), or heteropoly = polymers (for example, gelan gum) and preservatives (such as gasified benzyl chloride). This formulation can also be delivered by iontophoresis. 疋Eye / ear administration formulations can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, rampant or stylized release. Π 15 The compounds of the present invention can be combined with Combination of soluble macromolecular entities (such as cyclodextrin and its suitable derivatives or polyethylene glycol-containing polymers) to modify the solubility, dissolution rate, and taste masking used in any of the aforementioned modes of administration , Bioavailability, and / or stability. For example, 'The funeral-J-dextrin complex has been found to be useful for most dosage forms and routes of administration. Inclusion and non-inclusion complexes can be used In addition to being directly linked to the drug, cyclodextrin can be used as a supplement Additives, that is, as a carrier, diluent or solubilizer. The most commonly used for these purposes are α-, 0- and y-cyclodextrin, examples of which can be found in International Patent Application No.% 0911/11172, Found in WO 94/02518 and WO 98/55148. 200531963 Acceptable liquid carriers include vegetable oils such as sesame oil; glycerides such as triacetin; esters such as benzyl benzoate, isopropyl myristate and Fatty acid derivatives of propylene glycol; and organic solvents such as pyrrolidin-2-one and glycerol acetal. The formula can be prepared by dissolving or suspending the active ingredient in the liquid 5 carrier, so the final formula contains 0.01 to 10% by weight of active ingredient 0 This formulation can be prepared in a conventional manner according to standard medicinal or veterinary practice.

These formulations will vary with respect to the weight of active compound contained therein, depending on the host animal species to be treated, the severity and type of infection, and the weight of the host. For parenteral, topical and oral administration, the typical dosage of the active ingredient is from 001 to 100 mg per kg of animal. The preferred range is from 0.01 to 10 mg / kg. 15 20 物 .rt 'The compound can be administered to non-human animals with drinking money feed; ^ r- compounds, a combination of disease-active compounds (for example, for the treatment of special medical doctors, at least one of which includes the root fine = The two medicine pouches contain two or more individual medicinal combinations, respectively: group: rr di r: compound; and for packaging. This example has a cooked one packaging tablet 69 200531963 blister packaging of the product. Sachets are particularly suitable for administering different dosage forms (eg, oral and parenteral), administering individual compositions at different dosage intervals, or titrating individual compositions with each other. To aid volume elasticity, the drug 5 The capsule will typically contain directions for administration and may provide so-called mnemonics. For administration to animal patients, the total daily dosage range of a compound of the present invention is typically from 0.1 mg / kg to 100 mg / kg, depending on the mode of administration For example, oral administration requires a total daily dose from 0.5 mg / kg to 100 mg / kg; meanwhile, intravenous doses only require 0.1 mg / kg to 10 10 mg / kg. The total daily dose can be single or Separating agent Administration. Veterinarians can easily determine dosages for individual animals based on age, weight and needs. The compounds of the invention have also been used to control plant pests, soil-dwelling pests and other environmental pests. Suitable for use in agriculture, horticulture The composition includes formulations suitable for use as, for example, medicinal mists, dusts, granules, smoke, swimming baths, emulsions. The active compound is usually applied to the site where arthropod or nematode parasite infestation is to be controlled, in a proportion of About 0.02 kg to about 20 kg of active compound per hectare of treated site. Negative weather conditions, pest resistance, and other factors will require the use of a higher proportion of active ingredients. For leaf coated 20 cloth, 0_01 to The ratio of 1 kg / ha. The compounds of the present invention can also be applied to the soil as a solid or liquid composition to mainly control those nematodes that inhabit it; but they can also be applied to the leaves to mainly control the aerial parts that attack plants Those nematodes. This active ingredient can be washed into the soil by spraying with water or natural rain 70 2 00531963 During or after application of the soil, the formula can be mechanically distributed in the soil if necessary. It can be applied before planting, during planting, after planting, but also before or after germination has occurred. The invention The compounds are particularly valuable in protecting fields, pastures, fodder, agricultural gardens, greenhouses, orchards, groves and vineyard crops; or vegetables & salds, ornamental flowers, dwarfs, agricultural gardens and forest trees. Use in the invention The effective dosage of the compound in can be varied within broad limits, especially depending on the nature of the pest to be eliminated or the degree of infestation by the parasite. Generally speaking, the composition according to the present invention usually comprises about 0.000. 5 to about 95% (by weight) of one or more active ingredients according to the present invention, about 1 to about 95% of one or more solid or liquid carriers, and selectivity from about 0 to about 50 /. One or more other compatible components (such as a surfactant or the like). 15 In this description, the name "carrier" refers to an organic or inorganic ingredient (natural or synthetic) to which the active ingredient is combined to make it easy to apply. Therefore, this carrier is usually inert and must be acceptable (for example , Agronomically acceptable, especially for treated plants). The carrier may be a solid, such as a milled natural mineral such as US 20 activated clay, bentonite, clay, chalk, diatomaceous earth, kaolin, Montmorillonite, quartz or talc; ground synthetic minerals such as alumina, silica or silicates; natural silicates, silica; resins; waxes; or solid fertilizers. As granular solid carriers, The following are suitable: crushed natural rocks, such as calcite, dolomite, marble, pumice, and sepiolite; 71 200531963 synthetic inorganic or organic coarse flour particles; organic material particles, such as coconut shells, corn cobs, corn Rind or wrong wood chips; absorbents, such as carbon black, diatomaceous earth or powdered cork; water-soluble polymers, resins, or solid fertilizers; if necessary, The solid composition may include one or more compatible 5 moisturizing, dispersing, emulsifying or coloring agents, and when it is a solid, it may also be provided as a diluent. 10 15 20 The carrier may be a liquid, such as: water; Alcohols (especially butanol or ethylene glycol), and their _ or @ purpose (especially methyl ethylene glycol acetate); hydrazones, especially acetone, cyclohexanone, methyl ethyl _, methyl alcohol Isoisobutyl_ or isophorone; petroleum products, such as fatty or aromatic hydrocarbons, especially xylenes; mineral or vegetable oils; chlorinated hydrocarbons, especially trichloroethanes, dichloromethanes Or random benzenes; soluble in water or strong polar solvents, such as dimethyl methylamine, dimethyl sulfide or N-methylpyrrolidone; or mixtures thereof. The surfactant can be ionic or non-ionic Emulsifier, dispersant or dragon agent, or this kind of silk. Miscellaneous ingredients and / or inert carriers are not or are slightly soluble in water and the carrier of the composition is water B, which is generally generally There must be at least one surfactant. The composition of Shuming can further include other additives, such as adhesives or colorants. . In this formula * 5 ^ 1 $ 'of phospholipids or celluloses: Γ: such as natural or synthetic, into polymers. It can use colorants, various. Emulsified iron, titanium oxide or m blue "歹 '〇. Materials, occasional organic materials, such as alizarin-dyed II wood cymbals or metal spent flower dyes, micronutrients such as boron, iron, iron, clock, copper, iron, or Salts of zinc. 72 200531963 Therefore, the accepted salt form. For its agricultural application, the compound of formula (I) or its killer is usually in the form of a composition, which can be a composition for different solids or waves. The solid forms are dust (compounds of formula 成 into 5 whose pesticidally acceptable salt content ranges up to 80%), powders or granules (including water-dispersible granules) that can be moistened, especially Extruded, dense, impregnated-granular vehicle or those obtained from granulation starting from the powder (in the powder or granules between φH, the compound of formula (1) or its insecticidally acceptable salt The content is between about 0.5 to about 80%). A solid homogeneous or heterogeneous composition (e.g., granules, pellets, bricks, or capsules) containing one or more compounds of formula (1) 10 or a pesticidally acceptable salt thereof may be used to treat Set or run for more than a period of time. Similar effects can be achieved using water-dispersible concentrate drops or intermittent feeding as described herein. For example, liquid compositions include aqueous or non-aqueous solutions or suspensions (such as emulsifiable concentrates, emulsions, flowing liquids, dispersions or solutions) or aerosol drones. In particular, liquid compositions also include emulsifiable concentrates, dispersions, emulsions, flowables, aerosols, wettable powders (or spraying powders), dry flow agents, or pastes in the form of compositions (It may be liquid or intended to form a liquid composition when applied), for example, as an aqueous spray (including low and ultra-low 20 volumes) or as a smoke or aerosol. For example, a liquid composition in the form of an emulsifiable or soluble concentrate most often contains from about 5 to about 80% by weight of active ingredient; while in this example, the emulsion or solution that is ready to be applied includes from about 0.001 to about 20% active ingredients. In addition to the solvent, the emulsifiable or soluble concentrate 73 200531963 may include from about 2 to about 50% of suitable additives, penetrants, preservatives, micronizers, etc., when needed. ^ Color 4 or adhesive. From these concentrates, it is possible to obtain a milky degree which is particularly suitable for the application of plants such as plants. This aspect is included in the scope of the present invention. The emulsion can be in the form of water in oil or oil in water. They can have a strong degree.

In addition to normal agricultural use applications, the liquid compositions of the present invention can be used, for example, to treat substrates or sites parasitized or susceptible to infestation by arthropods (or other pests that can be controlled by the compounds of the present invention), including houses, H ) Indoor nuclear storage or processing area, container or equipment or standing or running water. All of these aqueous dispersants or emulsions or spray mixtures can be applied by any suitable method to, for example, agricultural buckets, mainly by spraying; the proportions of the spray mixtures are usually from about 100 to about 1,200 liters per hectare. , But can be higher or lower (such as low or ultra-low volume) depending on the desired or applied technology. The compound or composition according to the present invention can be conveniently applied to vegetation, especially to roots or leaves suffering from pests to be eliminated. Another method of applying a compound or composition according to the present invention is medicinal irrigation, that is, adding an active ingredient-containing formula to irrigation water. This irrigation can be sprinkler irrigation for leaf pesticides, or it can be land irrigation for soil or for systemic pesticides 20 or underground irrigation. Prepare a concentrated suspension that can be applied by spraying to produce a stable fluid product that does not settle (finely grind), and which typically includes about 10 to about 75% by weight of active ingredient, about 0.5 to about 30% Surfactants, about q 1 to about 10% thixotropic agents, about 0 to about 30% of suitable additives (such as anti-hair, gun 74 200531963 agents, residue inhibitors, stabilizers, penetrants, adhesives), And water or organic liquid (if the active ingredient is not soluble or insoluble) as a carrier. Some organic solids or inorganic salts can be dissolved in this vehicle to help prevent sinking or as an antifreeze for water. 5 Wettable powders (or spray powders) are usually prepared so that they contain from about 10 to about 80% by weight of active ingredient, from about 20 to about 90% of a solid carrier, from about 0 to about 5%. Wetting agents, about 3 to about 10% dispersants, and when needed, about 0 to about 80% of one or more stabilizers and / or other additives (such as penetrants, adhesives, anti-caking agents, coloring Agents or their analogs). In order to obtain these 10 settable powders, the active ingredient is completely mixed with additional substances in a suitable mixer, which can be impregnated on a porous filler and a mill or other suitable grinding can be used器 磨。 Grinding. This results in a powder that is smooth and has excellent wetting and suspending properties. They can be suspended in water to provide any desired concentration, and this suspension can be used very particularly advantageously for application to plant leaves. "Water-dispersible particles (WG), (particles that are easily dispersible in water) have compositions that are substantially close to a wettable powder. They can be described by granulation in the formula of wettable powders, by wet Route (let the finely divided active ingredient be mixed with an inert admixture and a small amount of water (e.g., 20% by weight); or contact with an aqueous solution of 20% of the agent or binder, followed by drying and screening), or by dry It can be prepared by compaction, followed by grinding and screening. The proportion and concentration of the formulated composition can be changed according to the application method or the nature of the composition or its application. Generally speaking, it is used to control arthropods and plant nematodes. , Worm, or protozoan pest composition generally comprises about 75 200531963 0.00001% to about 95% (more specifically, about 0.005% to about 50% by weight) of one or more of formula (I) Compounds, or their insecticidally acceptable salts, or total active ingredients (that is, compounds of formula ⑴ or their insecticidally acceptable salts with other substances that are toxic to arthropods or plant nematodes, anthelmintics, Coccidia 5 medicine, synergist, micro Element or stabilizer together). The actual composition used and its application ratio will be selected to achieve the desired effect of a farmer, livestock producer, medical or veterinary practitioner, pest control technician or other person skilled in the art. It is also useful to protect wood (upright, chopped, transformed, stored or built) from sawfly or beetle or termite attack. They have been applied to protect stored products (such as cereals, fruits, nut kernels) , Spices, and tobacco, whether whole, ground or mixed with products), from attack by rainbow worms, beetles, and snails. It also protects stored animal products such as skin, hair, natural or transformed forms of wool and feathers ( Such as carpets or textiles)) from rainbow 15 and beetles; also protect stored meat and fish from beetles, snails and flies. Locally applied to wood, stored products or solids from household items Or the liquid composition usually comprises about 0.00005% to about 90% (more specifically, about 0.001% to about 10% by weight / °) of one or more compounds of formula (I) or a pesticidally accessible compound thereof. For example, the compounds of the present invention (and their pharmaceutical, veterinary, and agronomically acceptable salts) can be used in the following applications and in the following pests: in the field of veterinary medicine or livestock breeding; or Maintain public health against arthropods that are internally or externally parasitic on vertebrates, especially warm-blooded vertebrates 'including humans and brushed animals' such as dogs, 76 200531963 cats, cattle, sheep, goats, horses, pigs, Poultry and fish. Similarly, in the field of controlling plant pests, soil-dwelling pests, and other environmental pests. Specific clarified parasites that can be controlled by the compounds of the present invention include arthropods, such as: 5 Actinedida / Pink Section (Acaridida): Chicken snails (Mesostigmata spp), such as chicken prickly skin concealment; pain Λ 疥 concealment (Sarcoptes spp), such as treatment

Conceal such as ·)); beast / conceal (Psoroptes spp, such as sheep itch conceal ovb); Chorioptes spp, such as cattle 10 hide conceal hv / s); conceal maggots (Trombicula spp), such as in / iecWwgaz ·; Damalinia spp; Demodex spp; Acarapis spp; Cheyletiella spp; Ornithocheyletia spp ); Meat concealed (Myobia spp); Concealed (Listrophorus spp); Powder concealed (Acarus 15 spp); Food brewed concealed (Tyrophagus spp); Tochi concealed (Caloglyphus spp); Hypodectes spp; Wing clothing (Pterolichus spp); Otodectes spp; Notoedres spp; Cytodites spp; Knemidocoptes spp; Laminiosioptes spp. Siphonapterida: Ctenocephalides 20 spp, such as dog head flea (C7), cat cat flea {Ctenocephalides felis); rat flea (Xenopsylla spp), such as Oriental rat flea (Jf⑼c / zeo / 7/51); human flea (Pulex spp), such as human flea CPw / ex; Ceratophyllus spp

Ticks: Argas spp, such as drgM 77 200531963, Ornithodorus spp, such as pure white wool ticks; ear ticks (〇t〇bius Spp), such as Mai I. blunt ticks (6 ^ do like megw / m ·); hard ticks (ix〇des spp), such as castor hard tick (/ you (9 ^ / to r / czTzws), hard red tick (/ X 9 also ^; Amblyomma spp, for example, American Amblyomma spp., Variegated pure eye stele-like sigh plus Booxus spp, for example, bovine tick 7 to ⑽), Boophilus decoloratus, micro, h noon tick (Boophilus

micrc ^ / ws); Dermacentor spp, such as forest leather ticks 10 CDermac⑼Mr W / varwm); Haemophysalis spp; Hyalomma spp 'e.g. Yuanbao glass eye ticks (// 少 "/ 〇 所All chemical compounds C (2, w / w); Fan ticks (Rhipicephalus spp), such as Rhipicephalus sanguineus, Rhipicephalus 叩 ⑼Acw / a / like (And ⑽everhz ·); Dermatys 15 mites (Dermanyssus spp); ear mites (railletia spp); lung thorn mites (Pneumonyssus spp); Stemostoma spp; Varroa spp; and other ticks, such as Phoenician short-beard concealed / 7b⑼ / c / a), alfalfa moss concealed Mb, Eotetranychus carpini, Eriophyes sheldoni, 20 Paratyranychus pilosus , Orange Record Butterfly (Phyllocoptruta (9 / to V (9ra), Polygonum full / Rugao), cinnabar leaf concealing czTmaZ ^ r / ⑽ * s〇, Kanzawa leaf concealing, Pacific red leaf concealing (Tfeir⑽ycAws, cotton Red leaf concealment (Tetranychus telarius). 78 200531963 Canning (Diptera): Angle rope (blood-blowing rope / rr / i⑽ * 9); it (former rainbow: category (Tabanus spp), such as bovine original it (7ί ^ ZwWwa)); barbed rope (廄 廄 绳 line; ink mosquito (Simulium spp)); deer flies (Chrysops spp); plumage flies (Mian 5 sheep tick flies (sigh ⑽⑽ ⑽⑽)); reins (glossina spp) 'such as tongue tongue (67〇 ^ / like; mosquitoes (Culex spp), such as Culex quinquefasciatus (Cw / exp / pz⑼⑼); Anopheles

spp) 'such as Plasmodium five spot; Aedes spp, such as Aedes aegypti (JMa class); outer /), harassing Aedes mosquito 10 vexaw); Eusimulium spp; Phlebotonius spp; Lutzomyia spp; Culicoides spp; Hybomitra spp; Yellow it (Atylotus spp); Haematopota spp; Philipomyia spp; Bee Roula (Braula spp); Hydrotaea spp; Morellia spp; Toilet rope (Fannia 15 spp) 'For example, yellow belly toilet snail (F⑽ 《/ a c⑽wew / arzj); Calliphora SPP; Wohlfahrtia spp); Sarcophaga spp; Hippobosca spp; Lipoptena spp; Melophagus spp; and other bifins such as Mexican orange solid rope / wt / ew); Mediterranean solid rope ( C ^ rai / along cap / iaM); Bristol's Golden Rope 20 (Chrysomya bezziana, ·, snail, spin gold weaving (Chrysomya hominivorax) ·, Roche gold rope mace // ar / fl); Add r / " / a sorghicola) · "" Cordylopia anthropophaga "·, Dacw cwcw /; Brassica viridis ftraw / c like); Malaysian stomach rope {Gasteroph ilus intestinatis); Haplodiplosis 79 200531963 equestris; seed rope; subdermal / ζΤζβαία); vegetable spotted rope (Zirb-ζα; gerbera spotted rope (Liriomyza trifolii); Lycoria pectoralis; Hessian mosquito (Μα 少 ⑺r); Home Rope; Deer Rope Rope 5 Like); Sheep Nose Rope); Swedish Straw Rope ((9 * ^ > 26 // (2 / " "); Beet Leaf Rope (/ ^ 《6 > All 3 ^ / ^ 6 ^ 3; (2All /);? 11011 ^

brassicae; Phorbia coarctata; cherry solid rope (7? / mgc? / like αcer); apple solid rope / 7⑽⑽e // a); Tipula oleraceam; European giant mosquito (7T / 7w ^ / ^ / ⑹; and Also fly flies; water flies; rock mosquitoes and slugs. 10 Parasitic rope flies: skin ropes (sheep nose ropes, yellow flies (Cuterebra spp)); Li flies (Phaenicia spp), mercerizing Green flies (zwcz7k; aeruginous ropes (Zwcz7 / a α //? Η >2ύ〇; spiral maggots (Paper human cone fly A⑽h> z / vwyd〇); leather fly larvae (subcutaneous flies); human skin fly homos. 15 Anoplurida: Vampire wind (Menopon spp; Bovicola spp); Bite wind (Haematopinus spp); Linognathus spp; Pipe lice (S〇lenoptes spp); genus (Phtirus spp)) 〇 Cultivation and general bugs (Cimicidae, such as temperate bed bug 20 (Cimex kciw / αη · ⑽)); (Triatoma spp), such as the red hunting saki (and hi / nz · ⑽〇 short-horned suborder (Brachycera): Mosquitoes; magpies; sand flies; sharp-eyed mosquitoes. Orthoptera: large maggots (Periplaneta spp); Berberis (Blatella 80 200531963 (〇711 € ^ 1 mouth 38 mouths), such as European salamanders (〇〇; // < 9 such as /; ^ "/ 7 // 〇 / (2 /; ^); zeia heart mai / ca); Dongfang 蜚蠊 (5 / (2ίία < 9rknia / z \ s〇; European ball 螋 〇p6 > r // cwZ (2; Madeira 蜚蠊 (Z ^ wc (9/7 / mefl

5 maAn2e); double-band grasshopper Meng feiWiiaiws); bare-legged grasshopper Meng (Melanoplus femur-rubrum); Mexican grasshopper Meng (Me / ⑽ 叩 / 以 m ^ x / canws); migratory grasshopper Meng; Rocky Mountain Grasshopper ^ (Melanoplus spretus); Momadacris septemfasciata; Palegrina grasshopper Meng (* 5 (: / 1 plus 6 ^ /? ^ Peregrina); Stauronotus 10 maroccanus; greenhouse general (Zhc / ^ cha. Dictyoptera ): Smoke (Periplaneta fuliginosa); Japanese cockroach 〇π / ρ / αη to a; American cockroach (Periplaneta americana). 15 20 Hymenoptera: Saw Ants; Honeybees; Vespas; Wasps. Lepidoptera: Tea leaf curl moth 04 such as 1677/1) ^ 〇 ^ 2 / ^); Orange small yellow leaf curl tiger (Agraik Myiwm); cotton leaf liquid moth // MZma); Lidou night moth (Ani / cary / a ymmaifl /)); Fruit tree leaf curl moth (Arc / nps Wh / hr); Archips rosana; apple fruit nest moth 〇4rg; y plant αί / π · α c6 ^ wge // (2); Gama leaf moth (Awiograp / m gamma); legume black spot silverworm (Awiograp / m mgrhgna); rapeseed cabbage nightworm (Barathra brassicae); pine feet 4 vines (jBwpa / wp / n / aWw); Cacoecia murinana; ^ (Caloptilia theivora); Capua reticulana; ^ ^ ^ (Carposina niponensis); Cheimatobia brumata; 81 200531963

Chilo polychrysus; dimorphic model, spruce leaf curler moth / wmz / er⑽a); western spruce leaf curler moth (Choristoneura occidentalism); American armyworm (Cirphis unipuncta) ·, rice vertical stability (Cnaphalocrosis medinalis Guenee) · 5 apple goose moth (CyAa / 7 (9m6 > / ze // fl); European pine caterpillar

pini) ·, Diaphania nitidalis ·, Diatraea grandiosella · Earias insulana BoisduvaT · Earias vittella Fabricius; small corn mold ££ 7 (9 / 7 (3 //? Like lignosellus); Eupoecilia ambiguella; Evetria bouliana; $ 10 ground tiger sw &errflwa); large scull (Ga // er / a me // ⑽e // (2); Li Xingoli Worm XGrapholitha funebrana) ·, Pear, i, carnivorous XGrapholitha; corn earworm (valence armgera); Yu Spodoptera (/ ie / z'coverpa (xww / ia); Spodoptera littoralis (iiWz'coverpazea); America in night E Heliothis virescens) ·, Hellula undalis ·, Hibernia 15 defoliaria; American white moth (// household price r / α cw-like α); apple nest moth (Hyponomeuta malinellus); Pan% moth {Keiferia / >^; ^ Γ57 · 6 ^ // α); Hemlockia spp .; Laphygma exigua; M ^} ^ i ^ (Leucoptera coffeella); Snailella scitella); Lithocolletis 20 blancardella; grapes and small fruit moths ⑽α); yellow-green stripe (Loxostege sticticalis) ·, monk ^ Qin Moth XLymantria monacha), test Leafminer (Ay⑽ buckle · α; tent caterpillar

"ewWrm); cabbage night moth (MameWra ZiraM / cae); rice borer; Notarcha derogata; Douglas fir moth (&9; rgyM 82 200531963 π⑼ and hwgWa); European corn borer; Asian corn tower (Ostrinia furnacalis) ) ·, I blessings (Parnara guttata &) ;, winter odor (Panolis flammea, ..., kL aeration (Pectinophora gossypiella) ·, spodoptera litura (sawc / α); round palm moth bucephala) ·, Orange lath moth (Phyllocnistis citrella); Pieris larvae (Pieris; cabbage butterfly CP / er resembles a plant pupae); diamondback moth (P / wie / k Yishao / asie / k); oriental armyworm CPsewi / a / Wk; Potato wheat moth

(Phthorimaea operculella) \ Phyltonorycter ringoneells; ^ ^ Green Good Moth (Plathypena scabm) ·, Great Standing Moth (Pseudoplusia 10; Pine Tip Leaf Moth (and ⑽ / a / n / Wr⑽α);

Scrobipalpula absoluta; wheat moth 0S7i (9irag (2; grape long whisker leaf moth 0S ^ rg plus j ^ 7 / en · ena); beet armyworm exigua) ·, Spodoptera frugiperda ·, sea ash wing Spodoptera littoralis ·, Spodoptera litura · 15 Thaumatopoea pityocampa; Quercus leaf leaf moth (7br / r / x ν / r / d⑽50); Spodoptera litura m · i / wZmer); Trouble (7 > Less / nceriw / w); Tuta absoluta; Spruce leaf curler moth (Ze / rapAera; Laminidae; poisonous moth and tiger moth; reticulate moth; negative pouched moth). Lepidoptera: Pear Changjiding 57 > 2 seems to add * 9); Striped tortoise shells (yigr / Wa 20 // like plus ⑽); dark gold needles (dgrbies; June scarabs (j such as / 如 / 以 / 以); Anisandrus dispar; furniture theft An (Anobium punctatum) ·, I beetle (Anoplophora malasiaca) ·, plum bell weevil (mi / s gr⑽also s ·); apple flower weevil (pomomm); erythema dermis (Anthrenus verbasci) Apate 83 200531963 monachus); Atomaria linearis; Huang Shougua ra femoralis) \ ^ (Blastophagus piniperda) \ Blitophaga undata; Bostrychos capucins; ^ {Bruchus rufiman us); Wandouxiang CffrwMws; Bruchis lentis; Apple Curly Leaf Elephant 5 {Byctiscus betulae) ·, Luliang l {Callosobruchus chinensis) ·, Cassida nebulosa; Bean Leaf In / wrcaia); Brassica yingxiangensis

Forma (25 ^ / 所 / " 5 ·); Ceuthorrhynchus napi; Beet tibialis; Chlorophorus pilosis; Co 草 i / erws; Asparagus (CWocerb 10 asparagi); ^ ψ (Diabrotica longicornis); Dendrobium pertinex; twelve-star melon leaf beetle; corn root leaf beetle vz > g7 / era); bamboo long 蠹 CDzTzWemy wz⑽zα); rice scale weevil (Echinocnemus squameus); Elilachna vigintioctopunctata; Ernobius mollis; Mexican bean ladybug 15 ( Epilachna varivestis) ·, Epitrix hirtipennis · Eutinobothrus brasiliensis; Heterobostrychus brunneus; Hylobius abietis · Hylotrupes bajulus · Egyptian alfalfa weevil; alfalfa weevil (/ / 少 / / 7〇5 ^ / cfl); Spruce eight-toothed pupae (/ outside; 20-shaped grasshoppers); Lema bilineata; Zebra slug (Zema pupae); Beet gold needles ⑽ / ⑽ca / zybr / z / cws); rice elephant beetle {Lissorhoptus oryzophilus) ·, paper-speaking green boom {Lyctus brunneus) ·, oak powder owl (Ayciws linearis); Lyctus pubescens; Melanotus communis; pollen beetle awe⑽; East Total lunar beetle 84 200531963 (Melolontha hippocastani) ·, Western mastiff Paper beetle ^ (Melolontha; Minthes rugicollis; Oryzae or less zae); Ortiorrhynchus sulcatus; Otiorrhynchus ovatus; Paederus fuscipes Teaching leaves " f (Phaedon cochleariae) ·,

5 Phyllotreta chrysocephala; Phyllotreta spp; Garden beetle; Phyllotreta nemomm · Phyllotreta striotata ·, yellow beetle ψ (Phylllotreta striotata) ayap⑽ica); Priobium carpini; comb-angled veins stealing; bowl bean leaf weevil " like βίΜ); Valley 10 ^ {Sitophilus granaria); Sphenophorus venatus;, Tomicus piniperda ·, XTribolium castaneum) · '

Trogoxyton aequale; n = (bW // (^ wm); Aupreous chafer; western corn rootworm; rice water weevil; adzuki bean beetle; yellow 15 yellow mealworm; red flour beetle; striped flea beetle; calabash leafworm; deathwatch beetle; drugetose beetle; Mexican bean ladybug (Mexican bean beetle); flea beetle; Japanese beetle; boll weevil; boll weevil; rice weevil; granary weevil; 20 metre rice (rice weevil); (Agriotes spp; Athous spp; Limonius spp); Xyleborus spp; Tryptodendron spp; Sinoxylon spp; Homoptera: Acyrthosiphon onobrychis; Larch Ballet (Adelges laricis); Aleurodes brassicae; Aphidula nasturtii; 85 200531963 Broad bean (ake); cotton (dp / ni; apple property pomi); Aphis sambuci; Aspiodotus hederae; ^ (Bemisia / Mac, ·); silver leaf Pink wind argw " yb / iz ·); Thistle short-tailed wealth (Bmchycaudus cardu i) ·, cabbage (Brevicoryne brassicae) ·, 5 Cerosipha gossypii; Cryptocarpus cryptophyllus aphis (〇 冲 ⑺rWs); wheat double-tailed wealth; Dreyfusia nordmannianae;

Dreyfusia piceae; Dysaphis radicola; Dysaulacorthum pseudosolani; broad bean leafhopper (five-0 like ca / aZ? Shen); apple cotton {Eriosoma lanigerum); Euscelis bilobatus; talented big tail 10 (/ ί 少 αη / η and Tni); Laodelphax stiateljus; Li 蠘 蛉 C6 > mz ·); Mai Changguancai (Macroy / p / zwm ave / zae); Euphorbia longi (Macrosiphum euphorbiae) ·, Qin Weii long pipe snail {Macrosiphon factory still (Meg⑽ra Wcz'ae); Metotophium dirhodum; Myzodes persicae; Cherry melanoma amount; 15 Peach red fortune (Mymy; rice brown fly wind; lettuce root loquat cotton money; Yan Fei chaos (corpse saccharicida) ·, Phowdon humuli ·, Jinben M ^ Psylla mW /); pear wood chaos CPs ^ // a /? zW); winter onion through tumor tumor ascalonicus) ·, corn wind field (Rhopalosiphum maidis), 20 Rhodolosiphum padi (Rhopalosiphum padi), Saissetia oleae, Pear Station Grass Choi ma / α); Ping Hong Zha Round-tail Choi (with Nakama ma / z '); Mai Er {Schizaphis graminum); Schizoneura lanuginose; tube snail (Sitobion ave / zae); greenhouse powdery mess (TWakwrc ^ es; grape root nodules) Choi v " zyb " z ·). 86 200531963 Hemiptera: potato long whisker (jw / acor from wm 5Ό / απζ ·); soybean wealth (Xp / n's g ^ yc / zza); Eysarcohs parvus; vegetable less t / ema; cotton woolworm Introduction;

(Laodelphax sthatellus) ·, Lets sell snails (Lipaphis erysimi) ·, H Caihui (Nephotettix cincticeps) ·, Orange powder metaphor (Planococcus citri) ·, Kangshi loses phenotype {Pseudococcus comstocki); rice bee clavatus) •, rice Ms4 (Scotinophora lurida) ·, Bai Lei Fei Liang (Sogatella / wrc (/ ^ ra); pear flower net culture παΜ /); Yazusuke (t / «(XS7 ^; small brown planthopper); brown Rice wind 10 (brown rice planthopper); whitebacked rice planthopper; stink bugs; whiteflies; lace bugs; jumping plantlice. And the following Species: Hymenoptera; Isoptera; Isopoda; Diplopoda; Lipopoda 15 (Chilopoda); Symphyla; Thysanura ); Dermaptera; and Heteroptera; in the field of veterinary medicine or animal husbandry; or in maintaining public health to control worms, nematodes and protozoa, such as: trematodes Class (Trematoda): Fasciola; Fascioloides; Fascioloides; P aramphistomum); Dicrocoelium; Eurytrema; Ophisthorchis; Fasciolopsis; Echinostoma; Paragonimus. Genus: Haemonchus; Haemachus; 2005 200531963 (Ostertagia); Ku J0 nematodes (Cooperia); Anopheles nematodes (Oesphagastomum); Nematodirus; Dictyocaulus Trichuris; Dirofilaria; Ancyclostoma; Ascaris; Trichostrongylus 5 Protozoa: Eimeria (Eimeria spp); Leishmania spp; Plasmodium spp; Babesis spp; Trichomonadidae spp; Toxoplasma spp) and Theileria spp. 10 In protecting stored products such as cereals (including grains or flour), groundnuts, animal feed, wood or household items (such as carpets and textiles), the compounds of the present invention are useful against arthropod attacks such as : Flour moths (Ephestia spp); Carpet beetles (Anthrenus spp)); Flour 15 beetles (Pseudo-piracy) (Tribolium spp)); grain weevils (Sitophilus spp); mites (Acarus spp). In the protection against soil-dwelling insects, such as: corn root leaf beetle, other Diabrotica spp, European chafer 20 and other winged insect larvae (c0ie〇pteran grubs) and iron Nematodes; adults and larvae of Hemiptera and Homoptera, including tarnished plant bugs and other piant bugs (Miridae), aster leafhoppers And other leafhoppers (Cicadellidae), rice planthopper (rice piant 88 200531963 hopper), brown planthopper and other flying species (Fulgoroidae), paylids, whiteflies (Aleurodidae), • aphids (Aphidae), pupae (Coccidae and Diaspididae), net crickets (net crickets) Family (Tingidae), pupae 5 (Pentamodidae), cinch bugs and other real pupae (Lygaeidae), cicadas (Cicadidae), mochi (CeReopids) , Margin * spring (c〇reidae), red_class and cotton-red_cotton Stainers (red * spring (Pyrrhocoridae)); concealed adults and larvae 'include European red mite, two 10 spotted mite, rust mites, McDanid mite and others Leaf-eating concealers; adults and incompletely developed bodies of the order Orthoptera, including grasshoppers; adults and incompletely developed bodies of the order Diptera, including leaf miners, chironomids, fruit ropes (Tephritidae) And soil maggots; adults and incompletely developed slugs, including onion thrips and 15 other thrips. • For the avoidance of doubt, the "treatment" mentioned in this article includes reference to treatment, mitigation, and preventative treatment; reference to "control" (parasites and / or pests, etc.) includes killing, expelling, expulsion, loss Ability, prestige, elimination, alleviation, reduction, elimination. 20 The compounds of the present invention control arthropods that are harmful to humans and leftover animals (such as those mentioned above) or that can spread or act as vectors of disease It is particularly valuable in animals, and it is more controllable. Wind, mosquitoes, stings, harassment and rope disease. They can be used to control the existence of the host animal or the skin of the animal. Or arthropods that have eaten or sucked on 200531963; for this purpose they can be administered orally, parenterally, transdermally or topically. Considering the use of the compounds of the invention in mammals, the following are available-the following: 5 A pharmaceutical or veterinary parasiticide composition comprising a compound of formula (1) or a pharmaceutically or veterinarily acceptable salt thereof, or a whole, pharmaceutically or veterinarily acceptable diluent Medicinal or veterinary acceptable solvates with agents or carriers; which can be used for oral, parenteral or topical administration; a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof Or a medicament, or a medicinal or veterinary acceptable solvate comprising any of the foregoing medicinal or veterinary medicinal compositions, which can be used as a medicament; the compound of formula (I) or its medicinal or veterinary Accepted salts, or medicinal or veterinarily acceptable solvates of any of the pharmaceutical or veterinary medicinal compositions described above, for use in the manufacture of a medicament for the treatment of 15 parasitic animal infestations; and A method for treating a parasitic infestation in a mammal, which comprises a compound of formula (I) or a pharmaceutically or veterinarily acceptable compound thereof, or a whole or comprising any of the foregoing pharmaceutical or veterinary pharmaceutical compositions Medical II 3 " Medically sensible solvates to treat the mammal. According to another aspect of the present invention, it is possible to provide an arthropod, a nematode or a terrestrial pest that controls it at the location method It includes treating the site with a compound of general formula 1 or a pesticidally acceptable salt thereof (for example, by coating or administration). The present invention also relates to a method for purifying healthy animals, which includes The compound of formula (i) or a veterinary acceptable salt is applied to the animal in 200531963. The purpose of this purification is to reduce or eliminate the parasitic infestation of human beings carried by animals and to improve the living environment of humans. Use of lice film feeding test ( flea membrane feed test) to measure the biological activity of the claimed compound of 5. This test includes an in vitro anti-head cat cat fleas test according to the following general procedures. Dog blood is used to culture lice in vitro. 25-30 adult cat cat head fleas are collected. (Cat lice) and placed in a test chamber (50 ml polystyrene tube, sealed with a fine nylon sieve at the end). Citrate dog blood was prepared by adding an aqueous sodium citrate solution (10 ml, 10 20% w / v, 20 grams of sodium citrate in 100 ml water) to dog blood (250 liters). The test compound was dissolved in dimethyl sulfene to provide a 4 mg / ml working stock solution. This stock solution (12.5 microliters) was added to dog blood (5 ml) of citrate to provide an initial test concentration of 10 µg / ml. For testing at 30 μg / ml, a working stock solution of 12 15 mg / ml was prepared. Dog blood containing citrate of the test compound (5 ml, 10 µg / ml) was placed in a plastic dish cover and kept at 37 C on a heating pad. The paraffin film is drawn over the top of the opening to form a tight feeding film for the lice. Carefully place the test containing the lice on the film, and let Feng Zi start eating. The lice were allowed to eat for 2 hours, then the test chamber was removed and stored at room temperature overnight. Observe the lice and record the percentage of lice killed. Initially tested at 10 μg / ml of compound, the associated dose response (100, 91 200531963 30, 10, 3 ,; 1, 0.3, 0.1 μg / ml) was repeated from then on and n was repeated = 5. Plot the data to produce ED80, ED90 and ED95 values. The compounds of the present invention have significantly better activity than the compounds of the prior art. All examples of the present invention have wind ED80 values of less than 100 micrograms per milliliter. The following shows results for some compounds. Example lice eating ED80 results 5 1 84 3 27 0.1

Device used to obtain characteristic data

Use Varian Inova 300, Varian Innova 400, Varian Mercury 400, Varian Union 10 (Unityplus) 400, and Bruker ( Bruket) AC 300MHz, Bruker AM 250MHz or Varian T60 MHz spectrometer to obtain nuclear magnetic resonance spectral data, the observed chemical shift is consistent with the proposed structure. Mass spectrometry data were obtained on a Waters Micromass ZQ or Hewlett Packard GCMS system model 5971 spectrometer. Calculated and observed ions in quotation marks refer to the lowest mass isotope composition. H L P C stands for high performance liquid chromatography. Room temperature means 20 to 25 ° C. The compounds of the present invention are exemplified below. Example 1 N- {5-Amino-3-cyano-1- [2,6 · digas-4-pentafluorothiophenyl] -1H-pyrazole20-4-yl} s (2,2 _Difluoroethyl) methanesulfonamide 92 200531963

N- {5-Amine-3-cyano-1- [2,6-digas-4-pentafluorothiobenzylHH-pyrazol-4-yl} methanesulfonate in acetonitrile (12 ml) To a mixture of amidine (200 mg, 0.42 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (600 mg, 2.80 mmol) 5 was added potassium carbonate (116 mg, 0.84 mmol) Moore). Then, the reaction mixture was stirred at 40 ° C. for 1 hour. To the reaction mixture was added ^ (10¾ liters) 'and the mixture was extracted with an ethyl scale (2.88 liters). The combined extracts were dried (MgS04) and concentrated in vacuo. The residue was dissolved in acetonitrile (1.5 ml) and an acetonitrile: water gradient [50:50 to 98: 2] was used, 10 by automated preparative liquid chromatography (Gilson system) , 150 mm < 30 mm of phenomonex (Luna 11) 10 micron C18 column) to purify the solution. The appropriate fractions were concentrated in vacuo to provide the title compound (145 mg). Experimental MH + 535.9; expected 536.0. 15 W-NMRPMSO): 3.05-3.09 (3Η), 3.53-3.77 (1Η), 3.86-4 · 09 (1Η), 5.99-6 · 27 (1Η) , 6.53-6 · 61 (2Η), 8.41-8 · 45 (2Η) Example 2 Ν- {5-amino-3-cyano-1- [2,6-digas · 4_5 Fluorothiophenyl-4-yl} -1,1,1-trifluoro_1 ^ -methylmethylite baicaline 93 200531963

Hydrogen acid (4N, 3 mL) was added to Preparation 14 in methanol (5 mL), and the reaction mixture was heated at 80 C overnight. The reaction mixture 'was concentrated in vacuo and the residue was distributed between ethyl acetate (20 ml) and water (20 ml) 5. The organic layer was separated, washed with water (2x20 mL), dried (Na2S04) and concentrated in vacuo. The crude product was dissolved in a mixture of acetonitrile, dimethyl sulfide and water (4 ·· 5: 1, 2 ml), and acetonitrile · water with a gradient of [60 ·· 40 to 95: 5] was used. An automated preparative liquid chromatograph (Gilson system, 150 mm x 30 mm Fanomonexru nanotube column) was purified at 100%. The appropriate fractions were concentrated in vacuo to provide the title compound (60 mg). Experimental MH + 539.9; Expected 539.9 ^ -NMRCCDCls): 3.53-3.55 (3H) ^ 4.08-4.12 (2H). 7.89-7.92 (2H) Prepared similarly ...

94 15 200531963

Example Rla R2 R4 R3 from preparation 3 cf3 CN H 3,4-dimeryl 1 4 ci cyclopropylmethyl Me 6 5 cc cyanomethyl Me 7 6 cc din-2-ylfluorenyl Me 8 7 cc Benzyl Me 9 8 cc 2- (N, N-dimethylamino) ethyl Me 13 9 cc 甲基 methyl hinderyl methyl 2 10 cc 2- via ethyl Me 10 11 cc methylthiomethyl Me 11 12 cc cyclopropylfluorenyl Me 17 13 cc Ν, Ν-difluorenyl β-based Me 18 14 4 c methyl maple Me 12 15 cc Η Me 15 16 6 4 苄 benzyl 4 17 cc Η 2- Phenylvinyl 5 18 sf5 cf3 methyl & wind-based Me 20 19 cf3 CN 〇50 Example 3 Experimental MH + 512.0; Expected 512.0 ^ -NMRCCDCIb): 3.46 · 3 · 46 (2Η), 6.28- 6.31 (1Η), 5 7 · 32-7 · 38 (1Η), 7.56 · 7 · 61 (2Η), 7.77-7 · 79 (2Η) Example 4 Experimental MΗ + 468.2; Expected 468.0 ^- NMRCCDCls): 0.17-0.23 (2H), 0.550-0 · 56 (2Η), 95 200531963 0.97-1.05 (1Η), 3.06-3.07 (3H), 3.50-3.55 (2H), 4.15-4 · 19 (2Η), 7.77-7 · 78 (2Η) Example 5 Experimental MH + 453.2; Expected 453.0 5 ^ -NMRCCDCls): 3.08-3 · 12 (3Η), 3.30-3 · 39 (2Η ), 4 · 49-4_52 (2Η), 7_69 · 7 · 72 ( 2Η) Example 6 MΗ + 505.3 of the experiment; expected 505.0 ^ -NMRCCDCls): 3.06-3 · 08 (3Η), 4 · 91-4 · 98 (2Η), 10 7 · 23-7.28 (2Η), 7.32 -7 · 36 (1Η), 7.71-7.73 (2Η), 8.51 · 8 · 54 (1Η) Example 7 MΗ + 504.3 of the experiment; expected 504.0 ^ -NMRCCDCls): 3_15 · 3 · 16 (3Η) , 3.66-3 · 71 (2Η), 7.24-7_28 (3Η), 7.29-7 · 33 (2Η), 7.67 · 7 · 69 (2Η) 15 Example 8 MΗ + 485.0 for the experiment 485.1 ^ -NMRCCDCls): 2.19-2 · 38 (638), 2.41_2 · 57 (2Η), 3.10 · 3 · 15 (3Η), 3.70-3 · 94 (2Η), 4.97-5 · 23 (2Η), 7.75-7 · 78 (2Η) Example 9 20 MΗ + 491.9 for experiments; Expected 492.0 ^ -NMRCDMSO): 3.19-3_22 (3Η), 4.98- 5 · 03 (2Η), 6.19-6_28 (2Η), 8.19-8 · 25 (2Η), 9.83-9 · 87 (1Η) Example 10 Experimental MΗ + 458.0; Expected 458.0 96 200531963 iH -NMRCCDSOD): 3.07-3.08 (3H), 3.6 · 1-3 · 75 (4Η), 7.98-8_01 (2Η) Example 11 i-NMRCCDClJ: 2.23 · 2 · 25 (3Η), 3.10-3.12 (3Η), 5 4 · 21 · 4 · 25 (2Η), 4.76-4 · 80 (2Η), 7.77-7.78 (2Η) Example 12 M 实验 + 517.9 of the experiment; expected 518.0 iH-NMRCCDsOD): 1 · 18 · 1 · 26 (4Η), 3.06-3 · 10 (1Η),

3.45 · 3.46 (3Η), 7.55-7 · 59 (2Η) 10 Example 13 M 实验 + 520.9 of the experiment; expected 521.0 'H-NMRCCDCls): 2.98-3.02 (6H) ^ 3.44-3 · 47 (3Η), 4.25 · 4 · 33 (2Η), 7.76-7 · 80 (2Η) Example 14 15 MΗ + 491.9 for experiments; expected 492.0 ^ -NMRCCDCls): 3.44-3 · 54 (6Η ), 4 · 11 · 4 · 23 (2Η), 7.75-7.85 (2Η) Example 15 MΗ + 414.0 for the experiment; expected 414_0. 20 ^ -NMRCCDsOD): 3.02-3.07 (3H) ^ 7.97-8.02 (2H) Example 16 Experimental MH + 490.0; Expected 490.0 b-NMRCCDsOD): 4.41 · 4.444 (2Η), 7.30-7 · 37 (3Η), 7.41 · 7 · 46 (2Η), 7.95-8 · 01 (2Η) 97 200531963 Example 17 Experimental MH + 502.0; Expected 502.0 iH-NMRCCDsOD): 6.97-7 · 03 ( 1Η), 7.25-7 · 31 (1Η), 7.35-7 · 40 (3Η), 7.52 · 7 · 56 (2Η), 7.90-7 · 95 (2Η) 5 Example 18 Experiment MΗ + 592.9; expected 592.9 ^ -NMRCCDCls): 3.38 · 3.2 · 42 (6Η), 4.06-4.12 (2H), 7.89-7 · 92 (2Η) Example 19 10 Μ 的 +440.0 for experiments; expected 440.0 ^ -NMRCCDCls): 2.54 · 2 · 67 (2Η), 3.33-3 · 44 (2Η), 3.79-3 · 89 (2Η), 4.20-4 · 36 (2Η), 7.73-7.81 (2Η) Example 20 Ν- {5-amino-3-cyano-1_ [2,6-dichloro · 4- (trifluoromethyl) phenyl] _1Η-pyrazole 15 · 4-*}-1,1,1-trifluoro-N-methylmethanesulfonamide

N- (3-cyano-1-[2,6-dichloro-4- (trifluorofluorenyl) phenyl]]-5-{[(dimethylamino) subunit in methanol (7 ml) Methyl] amino} -1Η-pyrazol-4-yl) -1,1,1-trifluoro-N-methylmethanesulfonamide (240 mg, 0.45 mmol) 20 solution was added with hydrogen Acid (4N, 4 mL) and the reaction was heated under reflux for 4 hours. The reaction mixture was concentrated under nitrogen and the residue was distributed between ethyl acetate and water. The two layers were separated and the aqueous layer was extracted with ethyl acetate (x2). The combined organic phases were dried (MgSCU) and concentrated under nitrogen. The crude product was dissolved in acetonitrile (4 ml), and an acetonitrile: water gradient [50:50 to 98: 2] was used, using an automated preparative liquid chromatography (Gilson system, 150 mm x 21_2 mm) (100 human C18 column). The appropriate fractions were concentrated in vacuo to provide the title compound (105 mg). Experimental MH + 482.0; Expected 482.0 H-NMR (CDC13) ·· 3.50-3 · 52 (3Η), 4.00-4 · 10 (2H), 7.71-7 · 76 (2Η) Example 21 Ν- {5- Amino-3-cyano-1- [2,6-dichloro-4- (trifluoromethyl) phenyl] · 丨 qinpyrazol-4-yl}-> 1_ (cyclopropylmethyl) -1,1,1_trifluoromethane

15 f N- (3 · cyano-l- [2,6-dichloro_4- (trifluoromethyl) benzyl] -5-{[(dimethylamino ) Methylene] amino} _1H_pyrazole_4_yldimooridamine (250¾g '0.48¾mol) solution, potassium carbonate (100mg, 0.72mmol) was added, The amount of sodium iodide and (methyl) 20 cyclopropane (69.5 microliters, 0.72 millimoles). Then, the reaction was allowed to react at 6 ° C, 200531963, and the reaction mixture was concentrated under a stream of nitrogen, And the residue was distributed between dichloromethane (20 mL) and water (20 mL). The two layers were separated and the organic phase was washed with water, dried (Na2S04) and concentrated in vacuo to provide the catalyst. Protected compound. To a solution of the protected compound 5 in methanol (5 mL), hydrochloric acid (4M, 3 mL) was added and the reaction mixture was heated under reflux. The reaction mixture was concentrated in vacuo, and The residue was extracted with ethyl acetate (20 ml). The organic phase was washed with water (2x20 ml), dried (Na2S04) and concentrated in vacuo. The crude product was dissolved in acetonitrile (1 ml), dimethylsulfide (2.4 ml) with water (0.6 ml) and using an acetonitrile: water gradient [60:10 40 to 95: 5] using an automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm Fenomonex Luna C18 (2) 10 micron column) purification. The appropriate fractions were concentrated in vacuo to provide the title compound (120 mg). Experimental MH + 522.3; expected 522.0 15 ^ -NMRCCDCls): 0.19-0.29 (2H) ^ 0.54-〇.64 (2H) ^ 0.999-1 · 1〇 (1Η), 3.53-3 · 78 (2Η), 4.0 · 1-4 · 13 (2Η), 7.72-7.84 (2Η) JT Example 22 Ν_ {5-amino-3-cyano-1- [2,6-digas-4- (trifluoromethyl) phenyl] _1Η · σΛσ sitting-4-kib N- (2,2,2-trifluoroethyl) methanesulfonamide

100 20 200531963 N_ (3-cyano-H2,6_dichloro_4_ (trifluorofluorenyl) phenyl) in 1-methyl-2-pyrrolidone (anhydrous, 5 ml)] _ 5 _ {[(dihydrazone Methylamino) amidino] amino} -1'-pyrazol-4-yl) methanesulfonamide (25 mg, 0.53 mol) in the / valley solution 'sodium hydride (600) In oil, 16.6 mg, 0.69 mmoles) and 2,2,2-trifluoroethyl chloroformate (195 mg, 0.69 mmoles). The reaction mixture was then stirred at room temperature for 3 hours. To the reaction mixture was added methane (20 ml), and the resulting mixture was extracted with water (20 ml). The organic phase was washed with water (2x20 ml) and brine (2x20 ml), dried (NaAO4) and concentrated in vacuo. To the residue were added methanol (5 ml) and 10 hydrochloric acid (4M, 3 ml), and the mixture was heated under reflux for 60 hours. The reaction mixture was concentrated in vacuo, and ethyl acetate (20 ml) and water (20 ml) were added to the residue. The organic phase was separated, washed with water (2 x 20 ml) and brine (2 x 20 ml), dried (Na2SO4) and concentrated in vacuo. The crude product was dissolved in acetonitrile / dimethyl sulfide / water (1: 4: 1, 6 ml), and acetonitrile: water with a gradient of [52 · 5: 47.5 to 95: 5] was used, and was prepared by automation Purification using a liquid chromatography (Gilson system, 150 mm x 30 mm Fenomonex Runa C18 (2) 10 micron column). The appropriate fractions were concentrated in vacuo to provide the title compound (135 mg). Experimental MH + 496.2; Expected 496.0 20 lH-NMR (CDCl3): 3.10-3.14 (3Η), 4.07 < 33 (4Η), 7.74-7.80 (2Η) Example 23 Ν- {5-amine 3-Amino-3-cyano small [2,6-dichlorobenzyl (trifluoromethyl) benzyl] _ΐΗ "than fluoren-4-yl} -1,1,1-trifluoro (methyl fluoromethyl) methyl Lamine 101 200531963

N- {5-Amino-3-cyano-l- [2,6-dichloro-4- (trifluoromethyl) phenyl] in dichloromethane (4 ml) at 0 ° C To a solution of -1H-pyrazol-4-yl} methanesulfonamide (73 mg, 0.18 mmol), triethylamine (30 µl, 5 0.21 mmol) was added dropwise, followed by trifluoromethane Sulfonic anhydride (30 μl, 0.18 mmol). The reaction mixture was warmed to room temperature and stirred for 4 hours. Water and dichloromethane were added to the reaction mixture. The two layers were separated and the aqueous layer (x3) was extracted with dichloromethane. The combined organic phases were then dried (MgS04) and concentrated in vacuo. The crude product was dissolved in acetonitrile / water (7: 3, 5 ml), and acetonitrile · water with a gradient 10 of [55:45 to 95: 5] was used, and an automated preparative liquid chromatography (Gillson System, 150 mm x 30 mm Phenomnics Luna C18 (2) 10 micron column) purification. The appropriate fractions were concentrated in vacuo to provide the title compound (50 mg). Experimental MH + 543.9; expected 543.9 15 W-NMRCCDCh) ·· 3.57-3 · 58 (3Η), 4.12-4 · 20 (2Η), 7.77-7.81 (2Η) Example 24 Ν- {5-amino- 3-cyano-small [2,6-dichloro-4- (trifluoromethyl) phenyl] -1Η-pyrazol-4-yl}-] ^-[(methylcarbyl) fluorenyl] methyl Brewamine 102 200531963

N_ {5-Amino cyano-l- [2,6-digas-4- (trifluoromethyl) phenyl] -1H-pyrazole_4_kib N_ in acetone (35 ml) [(Methylthio) methyl] methane scutamine (108 mg, 0.23 mmol) was added to a solution of sodium carbonate (318 Φ 5 mg, 3.04 mmol), followed by water (12 Ml) of Oxon® (924 耄 '1.52¾ Moore). Then, the reaction mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgS04) and concentrated in vacuo. The crude product was dissolved in a mixture of acetonitrile (1 ml) and water (1 ml), 10 using an acetonitrile: water gradient [45:55 to 95: 5], using an automated preparative liquid chromatography (Gill Mori system, 150 mm x 30 mm, Phenomnics Luna C18 (2) 10 micron column) purification. The appropriate fractions were concentrated in vacuo to provide the title compound (55 mg). Experimental MH + 505.9; Expected 506.0 15 h-NMR ^ CDCls): 3.005-3 · 07 (3Η), 3.15-3 · 18 (3Η), 4.4 · 3-4 · 54 (2Η), 7.74- 7_80 (2Η) 1M21 Ν- {5-amino-3-cyano small [2,6_digas_4 · (trifluoromethyl) phenylfluorene-pyrazole_4-yl} -cyclobutyl -1,1,1-trifluoromethanesulfonamide 103 200531963

To a solution of Preparation 12 (250 mg, 0.43 mmol) in tetrahydrofuran (15 ml) was added hydrochloric acid (4M, 15 ml). The reaction mixture was then heated at reflux overnight. The reaction mixture was concentrated in vacuo and the 5 residue was distributed between water (50 mL) and dichloromethane (75 mL). The organic layer was separated, dried (NajO4) and concentrated in vacuo. The crude product was dissolved in acetonitrile (6 mL) and the solution was passed through a 0.45 microfilter. Then, using an acetonitrile · water with a gradient of [60: 40 to 95: 5], an automated preparative liquid chromatograph (Gilson system, 150 mm x 30 mm, Finomonex Luna II 10 microns) C18 column) to purify the solution. The appropriate fractions were concentrated in vacuo to provide the title compound (113 mg). Experimental MH + 522.0; expected 522.0 iH-NMR (acetone): 0.23-3.01 (2H), 0.56-0.664 (2Η), ^ 1.20 (111), 3.56-3.78 ( 2Η), 6.12_6 · 22 (2Η), 8.02-8.13 (2Η) 15 tM26 Amino-3-cyano · 1_ [2,6_dichloro-4-pentafluorothiophenyl] -1Η-pyridine Nazobenzyl N- (methyl hinderyl) methane scutamine

104 200531963 To a solution of 23 (200 mg, 0.45 mmol) in anhydrous dichloromethane (5 ml) at 0 ° C, add triethylamine (124 µl, 0.9 mmol) and methanesulfonic acid. Tritium base gas (70 μl, 0.9 moles). The reaction mixture was then stirred under nitrogen for 30 minutes. Dichloromethane (205 ml) was added to the reaction mixture, and the resulting mixture was extracted with water (20 ml). The organic phase was washed with water (2x20 ml) and brine (2x20 ml), dried (Na2S04) and concentrated in vacuo. To the residue were added methanol (5 ml) and hydrogen acid (4M, 3 ml), and the mixture was heated under reflux for 60 hours. The reaction mixture was concentrated in vacuo, and to the residue were added ethyl acetate (20 ml) and water (20 mmol and 10 liters). The organic phase was separated, washed 'dried (NajO4) with water (2x20 ml) and brine (2x20 ml) and concentrated in vacuo. The crude product was dissolved in a mixture of acetonitrile and water (1: 1: 5¾ liters), and an acetonitrile · water with a gradient of [60:40 to 95: 5] was used, using an automated preparative liquid chromatography (Gilson System, 150 mm x 30 mm Fenomonex Runa € 18 (2) 10 μm column) Purified 15%. The appropriate fractions were concentrated in vacuo to provide the title compound (80 mg). Experimental MH + 549.9; Expected 549.9 ^ -NMRCCDC ^): 3.41-3.47 (6H), 4.09-4.19 (2H) ^ 7.88-7.94 (2H) Example 27 2〇N- {3-cyano-1- [2, 6-dichloro-4- (trifluorofluorenyl) phenyl]] pyrazole_4-yl} -1,1,1-trifluoro-N-methylcarboxamide

105 200531963 To a solution of Example 20 (150 mg, 0.31 mmol) in tetrahydrofuran (5 ml) was added dropwise tert-butyl nitrite (111 µl, 0.93 mmol). The reaction mixture was then heated at 60 ° C. overnight. The reaction mixture was concentrated in vacuo, and the residue was distributed between ethyl acetate (20 mL) and water (205 strokes). The organic layer was separated, washed with brine (20 mL), dried (Na2S04) and concentrated in vacuo. The residue was purified by column chromatography (silica dioxide, 10 g) with dioxane / ethyl acetate [9: 1]. Combining with Shida's distilling knife to provide crude product. The crude product was dissolved in a mixture of ethidium, dimethyl hetero, and water (5: 丨, 2 ml), and acetonitrile: water with a gradient of 10 [60 · 40 to 95 · 5] was used, and an automated preparation type liquid phase Chromatograph (Gilson System, 150 mm x 30 mm Fanomonex Runa C18 (2) 1GU Minho) was purified. The appropriate fractions were concentrated on a vacuum towel to provide the title compound (80 mg). Experimental MH + 467.0; Expected 467 〇15 H-NMR (CDC13): 3.65-3.65 (3H) ^ 7.77-7.80 (2H) ^ 7.80-7.82 (1Η) Prepared similarly: Example 28 N_ {3- [2,6-Difluoromethyl (trifluoromethyl) phenyl] · 1Η-pyrazole · 4-20 卜 N- (fluorenylmethyl) methanite baicalinamineΆ〇〇

106 200531963 From the compound of Example 14 (从 .00 g, 2.03 mmol), the title compound (855 mg) was provided. ~ Experimental MH + 477.0; expected 477.0 h-NMRCCDCh): 3.45-3 · 46 (6Η), 7.75-7 · 78 (2Η), 5 7.80-7.83 (1Η) Example 29 Ν- {3-cyanide -1--1- [2,6-dichloro-4-pentafluorothiophenyl] -1 hydrazone-4 (methylfluorenyl) methanesulfonamide

10 To a solution of Example 26 (310 mg, 0.56 mmol) in tetrahydrofuran (4 ml) was added dropwise tert-butyl nitrite (200 µl, L 69 mmol). The reaction mixture was then heated under reflux for 16 hours. The reaction mixture was concentrated in vacuo, and the crude product was dissolved in acetonitrile (6 mL). The solution was passed through a 0.45 microfilter using acetonitrile: water with a gradient of [60:40 to 95: 5] using an automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm Fenomonex Luna η 10 μm Cl8 column) purification. The appropriate fractions were concentrated in vacuo to provide the title compound (169 mg). lH-NMR (acetone): 3.56-3.57 (6Η), 8.28-8 · 35 (2Η), 20 8.73-8.79 (1Η) 107 200531963 Example 30 N- {3-cyano-l- [2,6-dichloro-4- (trifluorofluorenyl) phenyl] -1H-pyrazol-4-yl} methanesulfonamide

F 5 To a solution of Example 28 (855 mg, 1.79 mmol) in tetrahydrofuran (20 ml) was added potassium carbonate (617 mg, 4.48 mmol) in methanol (20 ml), including several Dripping. Then, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and hydrochloric acid (2M, 50 ml) and dichloromethane (100 ml) were added to the residue. The organic phase was then separated, dried (Na2S04) and concentrated in vacuo. The residue was purified using an Isolute ™ cartridge (silicon dioxide, 20 g) with a cyclohexane: ethyl acetate gradient of [1: 0 to 1: 1]. The appropriate fractions and concentration were combined to provide the title compound (600 mg). Experimental MH + 399.0; expected 399.0 15 ^ -NMRCCDCh): 3.08-3_10 (3Η), 6.69_6.74 (1Η), 7.73-7 · 78 (2Η), 7.80-7 · 84 (1Η) Example 31 Ν- {3-cyano-1- [2,6-digas-4- (trifluoromethyl) phenyl] -1Η-pyrazol-4-yl} -qin (2,2,2- Trifluoroethyl) methanesulfonamide 108 200531963

Add Example 30 (115 mg, 0.29 mmol) in a solution of sodium hydride (60% in oil, 14 mg, 0.35 mmol) in 1-methyl-2-pyrrolidone (6 ml), This was followed by 2,2,2-trifluoro-5 ethyl chloroformate (185 mg, 0.66 mmol). The reaction mixture was then heated at 65 ° C for 6 days. The reaction mixture was concentrated in vacuo, and the residue was washed with an Essault cartridge (silicon dioxide, 5 g) with dichloromethane ·· methanol in a gradient of [100: 0 to 95: 5]. Purification. The appropriate fractions were combined and concentrated to provide the title compound (41 mg). 10 ^ -NMRCCDCIb): 3.09_3.13 (3Η), 4.27 · 34 · 34 (2Η), 7.72-7 · 79 (2Η), 7_83-7 · 87 (1Η) Example 32 N- {5_amine 3--3-cyano-1- [2,6-digas_4-pentafluorothiophenyl] -1Η-pyrazol-4-yl}-^ (2,2,2-trifluoroethyl) Pinanesulfonamide

To a solution of dioxin (2 ml) and methanol (1 ml) in 24 (80 mg, 109 200531963 0.13 mmol) was added hydrochloric acid (5N, 1 ml). The reaction mixture was then heated at 85 ° C overnight. The reaction mixture was concentrated in vacuo, and the residue was distributed between water (5 ml) and ethyl acetate (10 ml). The organic layer was separated, dried (MgS04) and concentrated in vacuo. The crude product 5 was dissolved in a mixture of acetonitrile and water (1: 2, 1.6 ml), and an acetonitrile: water with a gradient of [55: 45 to 95 ·· 5] was used, using an automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm Fenomonex Runa C18 (2) 10 micron column) purification. The appropriate fractions were concentrated in vacuo to provide the title compound (43 mg). 10 Experimental MH + 553.9; Expected 554.0 ^ -NMRCCDCls): 3 · 11-3 · 14 (3Η), 4_12-4 · 30 (4Η), 7.90-7 · 93 (2Η) Similar preparations are:

Examples of R, a Rla R2 R4 from preparation 33 sf5 CN 2 · (1 (-1,2,4-triazol-yl) ethyl 42 34 c conh2 methyl & wind-based 37 35 ocf3 CN "21 36 sf5 COCH3" 38 37 ochf2 CN "22 110 15 200531963 Example 33 Experimental MH + 567.0; Expected 567.0 ^ -NMRCCDCls): 2.97 · 3 · 02 (3Η), 4.05-4 · 18 (2Η), 4.34-4.42 (2Η), 4.69-4.96 (2Η), 7.88-7 · 91 (2Η), 5 7 · 91-7 · 95 (1Η), 8.34 · 8 · 39 (1Η) Example 34 MΗ + 567.9 of the experiment; expected 567.9 ^ -NMRCCDCls): 3.43-3 · 47 (6Η), 4.09-4 · 20 (2Η), 5.36 · 5 · 44 (1Η), 6.58-6 · 65 (1Η), 7 · 89 · 7 · 93 (2Η) 10 Example 35 Experimental MΗ + 507.9; Expected 508_0 ^ -NMRCCDCh): 3.43-3 · 46 (6Η), 4.08-4 · 12 (2Η), 7.39-7 41 (2Η) Example 36 15 MΗ + 566.9 for experiments; Expected 566.9 ^ -NMRCCDCls): 2 · 91-2 · 94 (3Η), 3 · 10-3 · 13 (3Η), 4 · 23-4 · 32 (2Η), 4.62 · 4 · 66 (2Η), 6.65-6 · 69 (1Η), 7.91-7 · 93 (2Η) Example 37 MΗ + 489.9 of the experiment; Expected 490.0 20 ^ -NMRCCDCls ): 3.43-3 · 46 (6Η), 4.09-4.13 (2H), 6.56-6 · 65 (1Η), 7.30-7 · 32 (2Η) Example 38 Ν- {5 · amino -3 · cyanogen 1- [2,6-dichloro-4-fluoro-phenyl thio] -1Η_ pyrazol-4-yl} amine A brewing burning performance 111 200 531 963

To a solution of Dioxin (4 ml) and methanol (1 ml) in Preparation 3 (121 mg, 0.23 mmol) was added hydrochloric acid (5 N, 0.5 ml). The reaction mixture was then heated at 90 ° C for 5 hours. The reaction mixture was concentrated in vacuo and the residue was distributed between ethyl acetate (5 mL) and water (5 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2x5 mL). The combined organic phases were dried (MgS04) and concentrated in vacuo. The crude product was dissolved in acetonitrile / dimethyl sulfide (1: 1, 0.15 ml), and acetonitrile: water with a gradient of [50:50 to 95: 5] was used, and an automated preparative liquid chromatography ( Gilson System, 10 150 mm x 30 mm Fenomonex Runa II 10 μm C18 column) to purify the solution. The appropriate fractions were concentrated in vacuo to provide the title compound (63 mg). Experimental MH + 471.8; Expected 472.0 h-NMRCCDCh) ··· 3 · 10-3 · 13 (3Η), 4 · 25 · 4 · 31 (2Η), 15 5 · 98-6 · 01 (1Η), 7 · 89_7 · 92 (2Η) Example 39 N- {5-Amino_3-cyano-1_ [2,6-dichloro-4-pentafluorothiophenyl] -1Η-pyrazole_4-*}- Ν-{[1- (trifluoromethyl) cyclopropyl] methyl} methanesulfonamide 112 200531963

To a solution of Er 25 (3 ml) and methanol (1 ml) in Preparation 25 (155 mg '0,24 mmol) was added hydrogen acid (5 N, 0.5 ml). Then, φ was heated at 90 C for 5 hours. The reaction mixture was concentrated in vacuo, and the residue was distributed between ethyl acetate (6 ml) and water (6 ml). The organic phase was separated, dried (MgS04) and concentrated in vacuo. The granulated product was dissolved in acetonitrile / dimethyl sulfide (1: 1, 1.2 ml), and acetonitrile: water with a gradient of [60:40 to 95: 5] was used, using automated preparative liquid chromatography Instrument (Gilson System, 150 mm x 30 mm Fenomonex Runa u 10 10 μm C18 column) to purify the solution. The appropriate fractions were concentrated in vacuo to provide the title compound (72 mg). Experimental MH + 593.9; expected 594.0 # lH-NMR (CDC13) ··· 61-0 · 87 (2Η), 0 · 99-1 · 06 (2Η), 3.00-3.04 (3Η) »3.44-3.64 (1Η ) ^ 4.14-4.38 (3Η) ^ 7.89-7.93 (2¾) 15 Example 40 Ν- {5-amino-3_cyano small [2,6-digas_4_pentafluorothiophenyl; 1 _Pyrazol-4-yl} -sense (methylfluorenyl) ethanesulfonamide

113 200531963 Example 38 (200 mg, 〇42 mmol) in acetonitrile (12 ml) and a mixture of acetonitrile (0.11 ml, L20 mmol) in potassium carbonate (116 mg '0.84) Mol). Then, the reaction mixture was stirred at room temperature for 66 hours. The reaction mixture was concentrated in vacuo, and the residue was partitioned between water (20 ml) and ethyl acetate (20 ml). Separate the two layers and dry (MgS04) # machine layer and concentrate under vacuum +. Dissolve the residue in Ethiopia / water (9: 4 liters) and use a gradient of [55: 45 to 95: 5]: Etiquette: water, using an automated preparative liquid chromatography (Gillson System, 15 mm x 30 mm Fenomonex Luna π αm 8 column) to purify the 10 solution. The appropriate fractions were concentrated in vacuo to provide the title compound (143 mg). Experimental MH 563.9; Expected 563 9 ^ -NMRCDMSO): 1.3M.37 (3H), 3.45-3.49 (3H) ^ 3.53 · 3 · 68 (2Η) '6.74-6 · 8ΐ (2Η), 8 · 40-8 · 44 (2Η) 15 Example 41 5-amino_3-cyano-1- [2,6-digas | (trigasmethyl) phenyl " Methylcarbamate

Example 15 in acetone (4¾ liters) (Qing milligram, Q24 millimolar solution 20), potassium hinderate (50 milligram, 0.36 millimolar) and methyl formate (22.4 114 200531963 micro Liters, 0.29 mmol). Then, the reaction mixture was heated under reflux; hours. The reaction mixture was concentrated in vacuo and the residue was distributed between dichloromethane and water. The two layers were separated and separated by Extract the aqueous layer (x3) with dichloromethane. Combine-combine organic I, then dry (MgS04) and concentrate and shrink in vacuo. Dissolve the crude product in acetonitrile 7 water (4: 1, 5 ml). And using an acetonitrile: water 'gradient [50:50 to 95: 5] using an automated preparative liquid chromatograph (Gilson system, 150 mm x 30 mm, Fromannik Luna C18 (2) 1 (^^ meter column) purification. Concentrate appropriate fractions in vacuo to provide the title compound • Experimental leg +471.8; expected 472.0 g) 10 ^ -NMRCCDsOD): 3.50-3.52 (3H), 3.85- 3.86 (3H). 7.96-8.00 (2H) Example 42 N- {5-amino group · 3 · cyano group · 1- [2,6_dichloro · 4_pentafluorothiophenyl group Methanesulfonamide

In an example of Otsuki (02 ml), 38 mg, 〇42 mol), and a mixture of Gekko Hyun (52 microliters, 0.84 mol), add carbon dioxide unzakizaki '0.84 mol ) ° Then, the reaction mixture was stirred at room temperature for 66 hours. The reaction mixture was distributed between hydrochloric acid (1M) and ethyl acetate, and the two layers were separated. The organic layer was washed with water, dried (MgS04) and concentrated in vacuo. The residue was dissolved in acetonitrile / water (9: 8 ml) and an acetonitrile: water gradient [50: 50 to 95: 5] was used, using an automated preparative liquid phase layer 115 200531963 Example 44 MH + of the experiment 553.9; expected 554.0 ^ -NMRCDMSO): 3.12-3.14 (3H) ^ 4.69-5.03 (2H) ^ 6.54-6 · 59 (2Η), 8.40-8 · 43 (2Η), 9.61-9 · 63 (1Η ) 5 Example 45 Experimental MΗ + 528.9; Expected 529.0 ^ -NMRCDMSO): 2.28-2.31 (3Η) ^ 3.46-3 · 57 (2Η), 4.00 · 4 · 01 (2Η), 7.36 · 7 · 38 (2Η) ❿ Example 46 10 experimental MΗ + 552.0; expected 552.0 ^ -NMRCCDCls): 3_15-3 · 20 (3Η), 4.90 · 4 · 97 (2Η), '5 · 43 · 5 · 57 (2Η), 6.40-6 · 43 (1Η), 7.61-7 · 65 (1Η), 7.87-7 · 90 (2Η) Example 47 MΗ + 603.9 of the experiment; estimated 604.0 15 ^- (NMRCCDCls): 3 · 10_3 · 14 (3Η), 4 · 20 · 4 · 27 (2Η), 7.90-7 · 93 (2Η) • Example 48 Experimental MΗ + 569 · 0; Expected 569.0 ^ -NMRCCDCh) : 1.67-1 · 83 (4Η), 2.41_2.76 (6Η), 20 3 · 08-3 · 15 (3Η), 3 · 51-3 · 99 (2Η), 5.02-5 · 30 (2Η), 7.88 · 7 · 91 (2Η) Example 49 MΗ + 585.0 of the experiment; expected 585.0 ^ -NMRCCDCIb): 2 · 41-2 · 55 (4Η), 2.56 · 2 · 59 (4Η), 3 · 09-3 · 14 (3Η), 3.6 · 1-3 · 73 (4Η), 4.72 · 4 · 91 (2Η), 7.88-7 · 91 ( 2Η) 117 200531963 Example 50 N- {5 -Amine_3 · amino-1_ [2,6_digas-4-pentathiothiophenyl] _ 1 Η-ton σ phenyl_4-yl}- ^ [(1-methyl-1Η-imidazol_2_yl) methyl] methanesulfonamide

5 Example 38 (200 mg, 0-42 mmol) in acetonitrile (12 ml) and 1- (N-methyl) -2-trifluoroimidazole (106 mg, 0.64 mmol) were added with carbonic acid Potassium (116 mg, 0.84 mmol). Then, the reaction mixture was stirred at 40 ° C for 18 hours. To the reaction mixture were added water (6 ml) and ethyl acetate (10 ml). The two layers were separated and the aqueous layer 10 (2x5 mL) was extracted with ethyl acetate. The combined organic phases were then dried (MgS04) and concentrated in vacuo. The residue was dissolved in acetonitrile / water (3 ml) using an acetonitrile: water gradient [45:55 to 95: 5] using an automated preparative liquid chromatography (Gilson system, 150x50 mm, Lu Nano II C18 10 micron column) to purify the solution. The appropriate fractions were concentrated to provide the title compound (98 mg). 15 Experimental MH + 565.9; Expected 566.0 W-NMRCCDCh): 2.88_2 · 91 (3Η), 3.70-3 · 74 (3Η), 4.80-5.03 (2Η), 6.09-6.18 (2Η), 6.87 -6_89 (1Η), 6.92-6.95 (1Η), 7.87 · 7 · 90 (2Η) Example 51 20 Ν- {5-amino-3-cyano-1- [2,6-dichloro -4-pentafluorothiophenyl] -1Η-pyrazole 118 200531963 _4_yl} _N · [(5 · methylisosalyl) methyl] methylpyramine

CI

To a mixture of Example 38 (200 mg, 0.42 mmol) in acetonitrile (12 ml) and 3-chloromethyl-5-methylisoisopropanol (84 mg, 0.64 mmol), add 5 Discharge in carbonic acid (116 mg, 0.84 mol). Then, the reaction mixture was dispensed under a simmer for 18 hours. To the reaction mixture were added water (6 ml) and ethyl acetate (1 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 mL). The combined organic phases were dried (MgS04) and concentrated in vacuo to provide a product mixture. The residue was dissolved in acetonitrile / water (31 mL), and 10 acetonitrile: water with a gradient of [50:50 to 95: 5] was used, using an automated preparative liquid chromatography (Gilson system, 150x50 Mm, Luna IIC18 10 micron column) to purify the solution. The appropriate fractions were concentrated to provide the title compound (144 mg). Experimental MH + 566.9; Expected 567.015 W-NMR ^ CDCh): 2.35-2 · 39 (3Η), 3.1 · 1-3 · 15 (3Η), 4.41-4.49 (2Η) »4.81-4.87 ( 2Η) ^ 6.01-6.04 (1Η) »7.86-7.89 (2Η) Example 52 Pivalic acid [{5-amino-3-cyano_1_ [2,6-dichloro-4-pentafluorothiophenyl) ] -1Η_pyrazol-4-yl} (fluorenylfluorenyl) amino; | methyl ester 119 200531963

To a solution of Example 26 (200 mg, 0_36 mmol) and potassium carbonate (150 mg, 1_08 mmol) in acetonitrile (5 ml) was added chloromethyl pivalate (0.16 ml, 1 ·· 〇8mmol) and hardened potassium (丨 0mg). The reaction mixture was then heated at 50 ° C. for 16 hours. The reaction mixture was passed through a silica plug and stripped with methanol / digas methane [5:95]. The filtrate was then concentrated in vacuo. The residue was dissolved in acetonitrile (15 ml) using acetonitrile: water with a gradient of [55:45 to 95 · 5] using an automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm The appropriate fractions were concentrated in the air by Finonemonex Runa to purify by 10 C18 (2) 10 micron column). The title compound (24 mg) was supplied in vacuo. 3.21-3.23 (3Η) Experimental MH + 586.0; Expected 586.〇 ^ -NMRCCDCh): 1.27.1.30 (9H), 4 · 22-4 · 27 (2Η) '5.58-5 · 61 (2Η) , 7.92-7 95 (2H) 15 Example 53

Ethylmethanesulfonamide

Ν 120 200531963 acetonitrile (12 mL)

hour. § Xuan reaction > The compound was distributed between 5 hydrochloric acid (1M) and ethyl acetate, and the two layers were separated. The organic layer was washed with water, dried (MgS04) and concentrated in vacuo. Dissolve the residue in acetonitrile / water (9: 1, 6 ml) and use an acetonitrile: water gradient [60:40 to 95: 5] using an automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm Fenomonex Runa II 10 micron C18 column) to purify the solution. The appropriate 10 fractions were concentrated in vacuo to provide the title compound (147 mg). Experimental MΗ + 499.9; expected 500.0 ^ -NMRCDMSO): 1.0-3-1.08 (3Η), 2.99-3.02 (3Η), 3.46 · 3.54 (2Η), 6.41- 6.45 (2Η), 8.41-8_44 (2Η) Example 54 15 Amine_3_cyano · 1_ [2,6-dichloro-4-pentafluorothiophenyl] -1 ± ° Bisa -4-yl} -benzylmethanesulfonamide

Example 38 in acetonitrile (12 ml) (200 mg, 0-42 mmol), potassium carbonate (116 mg, 0.84 mmol) and potassium effusion (140 mg, 0.84 mmol) To a mixture of 20, benzyl bromide (100 μl, 0.84 mmol) was added. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was distributed 121 200531963 between hydrochloric acid (2M) and Erqijiayuan, and the two layers were separated. Dry pen gS04) organic layer and concentrated in vacuo. The residue was dissolved in acetonitrile / water (4 ml) using an acetonitrile: water gradient [55:45 to 9: 5] using an automated preparative liquid chromatography (Gilson system, 15Gx50 mm, Luna ^ 5 10 micron column) to purify the solution. Concentrate the appropriate ingredients to provide the title compound (285 mg). Experimental MH + 561.9; Expected 562.0 ^ -NMRCDMSO): 3.10-3.14 (3H), 4.46-4.82 (2H) > 6.38-6.45 (2Η) '7.22-7 · 28 (5Η), 8.34_8 41 (2h) 10 Example 55 N {5Amino-3-cyano-l- [2,6-dichloroI pentafluorothiophenyl] -taclopeptidine_4-yl} 1 (4-fluorobenzyl) methanesulfonate Amidine

15 Example 38 (fine mg, Q.42 mmol) in acetonitrile (12 ml), carbonic acid = (116 mg, 0.84 mmol) and potassium selenium (14 mg, 0.84 mmol) Ear), add the desertification air knot (105 microliters, ⑽4 millimoles). The reaction mixture was then stirred for 16 hours at to. The reaction mixture was distributed between hydrochloric acid (2M) and dichloromethane, and dihydrazone was separated. The organic layer was dried (MgS04) and concentrated in vacuo. Dissolve the residue in acetonitrile / water (3 ml), and use acetic acid · water with a gradient of [55 ·· 45 to 95 ·· 5] using an automated preparative liquid chromatography (Gilson system , 150x50 mm, Lu 122 20 200531963 nano IIC18 10 micron column) to purify the solution. The appropriate fractions were concentrated to provide the title compound (269 mg). Experimental MH + 580.0; expected 580.0 H-NMR (DMSO) · 3.10-3.14 (3Η), 4 · 43-4 · 81 (2Η), 5 6 · 38 · 6 · 45 (2Η), 7_08_7 · 14 (2Η) , 7 · 24_7 · 29 (2Η), 8_36 · 8_41 (2Η) Example 56 N- {5-amino-3-cyano small [2,6-di-K (tri-I-methyl) phenyl] n- 4-yl} -1- (methylfluorenyl) acetofluorite

10 In a solution of Example 9 (90 mg, 0.18 mmol) in propionol (3 ml), add microliters of paraffin burner, 0.8 μmol) and carbon dioxide (π mg) . The reaction mixture was then stirred overnight under a 'dish' dish. The reaction mixture was concentrated in vacuo, and the residue was distributed between ethyl acetate (3 mL) and water (3 mL). Then, the organic phase was separated, dried and dissolved under vacuum in 15 to dissolve the crude product in a mixture of acetonitrile (0.5 ml) and dimethyl sulfide (0.3 ml), using a gradient of [10: 90 to% : 2] of acetonitrile · water was purified using an automated preparative liquid chromatography (Gilson system, 15G mm. Mm Fenomonex Luna II C18 10 micron column). Appropriate fractions were concentrated in vacuo to provide the title compound (21 mg lH-NMR (DMS0) · 1.55-1 · 60 (3Η), 3 · 21.3 22 (3Η), 123 200531963 5 · 20-5 · 26 (1Η), 6.38-6 · 49 (2Η), 8.22_8 · 24 (2Η) Example 57 Ν- {5-amino-1- [2 · chloroI pentafluorothio · benzyl] _3 cyano巧巧 布基} _N- (methyl hinderyl) methyl roasted amine k ° ΦΦ〇

Cl

Under nitrogen, touch in 10 ml of tetrahydrofuran (10 ml) solution solution, add desertification 6_ (3M in tetrahydro '0.09 ml, 0.27 mmol) . The reaction mixture was then left at room temperature overnight. The reaction was stopped by adding methanol and the mixture was concentrated in vacuo. The residue was distributed between dichloromethane, and the organic phase was separated, dried and concentrated in vacuo. The residue was dissolved in acetonitrile / water (1.5 ml) using acetonitrile: water with a gradient of [45 ·· 55 to 卯 · =: water, using an automated preparative liquid chromatography (Gilson system,] 150x30 milliliter, Luna II Cl 810 micron column) to purify the solution. The appropriate fractions were concentrated to provide the title compound (3 mg).彳 ,, experimental MH + 515.9; expected 516.0 'H-NMRCDMSO): 3.50-3.54 (6H) ^ 6.70-6.74 (2H), 7.87-7_91 (1Η)' 8.08-8 · 12 (1Η) , 8.39 · 8 · 41 (1Η) Preparation of another synthesis in dioxane (20 ml) 28 (68 mg, 189 mmol) 124 200531963

To the solution, triethylamine (1.52 ml, 7.56 mmol) was added, followed by methyl ethyl chloride (870 mg '7.56 mmol). Then, the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with hydrochloric acid (1N, 50 ml) and the organic phase was separated'dried (MgS04) and concentrated in vacuo. The residue was dissolved in acetonitrile / water (2 ml) using an acetonitrile: water gradient [50:50 to 95: 5] using an automated preparative liquid chromatography (Gilson system, 150 mm) x30 mm Luna II C18 10 micron column) to purify the solution. The appropriate fractions were combined and concentrated to provide the title compound (37 mg). Experimental MH + 514.1; Expected 514.0 iH-NMR ^ DMSO): 3.50-3.54 (6Η), 6.70-6 · 74 (2Η), 7.87-7 · 91 (1Η), 8.08-8 · 12 (1Η), 8.39-8 · 41 (1Η) Example 58 5-Amine · Η2,6-digas-4_pentafluorothiophenyl] ice (u two-sided oxygen-1, 2_ α 山 -2- 基) _ 1Η "bisa-3 -nitrile

To a solution of Preparation 43 (350 mg, 0.89 mmol) in pyridine (5 ml) was added 4-chlorobutane-1-sulfazine-based gas (WO 2 0005 0619 A1, 254 mg, 1.33 Mol). The reaction mixture was then allowed to cool at room temperature. The reaction mixture was distributed between dichloromethane (20 ml) and water (20 ml) and the organic phase was separated ', dried and concentrated in vacuo. To the residue 125 20 200531963 was added N, N-dimethylformamide (5 ml) and potassium carbonate (123 mg, about millimoles). The mixture was then heated at 85 ° C. for 60 hours. The reaction mixture was concentrated in vacuo and the residue was distributed between dichloromethane (25 mL) and water (25 mL). The organic phase was separated, dried and concentrated in vacuo. The residue was dissolved in ethidium / water (9: 2 ml) using acetonitrile: water with a gradient of [50:50 to 9: 5] using an automated preparative liquid chromatography (Gilson system, 150x30 mm, Luna IIC18 10 micron column) to purify the solution. The appropriate fractions were concentrated to provide the title compound (28 mg). Experimental MH + 511.9; Expected 512.0 lH-NMR (CDC13): 1.98-2 · 02 (2Η), 2.30-2 · 36 (2Η), 3.26 · 3 · 30 (2Η) '3.73 · 3 · 77 (2Η), 4.13 · 4 · 22 (2Η), 7.87-7 · 90 (2Η) Example 59 team {5 · (benzylamino) -3_cyano-1- [2, 6_dichloro · 4-pentafluorothiophenyl] -1Η-Upyrazolyl} _N_ (methylfluorenyl) methanesulfonamide

To a solution of Preparation 44 (120 mg, 0.18 mmol) in ethanol (5 ml) at 0 ° C was added sodium borohydride (14 mg, 0.36 mmol). Then, the reaction mixture was heated to room temperature for more than 2 hours. To the reaction mixture was added hydrogen acid (2N, 5 ml), followed by water (10 ml) and ethyl acetate (1520-X. Liters). The two layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The organic phase was combined 126 200531963, then washed with brine, dried (MgS04) and concentrated in vacuo. The residue was dissolved in acetonitrile / dimethyl sulfide (8: 2, 2 ml), and using an acetonitrile: water gradient [60:40 to 98: 2], using an automated preparative liquid chromatography ( Gilson system, 150x30 mm, Luna II C18 10 micron tube 5 columns) to purify the solution. The appropriate fractions were concentrated to provide the title compound (45 mg). Experimental MH + H639.9; Expected 640.0 iH-NMR pMSO): 3.36-3 · 38 (6Η), 4.41 · 4.4 · 44 (2Η), 7.13-7 · 29 (6Η), 8 · 35-8 · 36 (2Η) 1〇 Example 60 Cyano · ι_ [2,6-dichloro-4-pentafluorothiophenyl] 4-[(methyl hinderyl) (2,2,2- Trifluoroethyl) amino] · 1Η-pyrazol-5-yl} -2_methoxyacetamidamine

F

To a solution of Example 32 (200 mg, 0.36 mmol, 15 mol) in acetonitrile (5 ml) at 0 ° C, add ethoxyacetamidine (587 mg, 5.4 mmol) and σ to σ (142 mg, 1.80 mmol). Then, the reaction mixture was heated under reflux for 36 hours. The reaction mixture was concentrated in vacuo and the residue was distributed between ethyl acetate and water. The organic phase was separated, washed with brine, dried (MgS04) and concentrated in vacuo. The residue was dissolved in acetonitrile (3 ml) 20 using an acetonitrile: water gradient [60:40 to 98: 2] using an automatic 127 200531963 preparative liquid chromatography (Gillson system, ΐ50). x 30 mm, Luna IIC18 10 micron column) to purify the solution. The appropriate fractions were concentrated to provide the title compound (164 mg). Experimental MH + 625.9; Expected 626 01H_NMR (CDC13): 3.12_3 · 15 (3η), 3.41_3 · 44 (3Η), 3 · 82-3 · 86 (2Η) '4_2 (M.30 (2H), 7.83-7.86 (2Η), 8.74-8 · 79 (1Η) Example 61 4- [Bis (methyl hinderyl) amino] cyano small [2,6_dichlorom pentafluorothiobenzene Yl] -1Η-pyrazol-5-ylsulfonyl iminoformate

To a solution of Example 26 (200 mg, 036 mmol) in triethyl orthoacetate (8 ml), hydrochloric acid (concentrated, 2 ml) was added. Then, the reaction mixture was heated at 6 ° C for 2 ° C. The reaction mixture was concentrated in real concentration, and the residue was washed with toluene. The residue was dissolved in acetonitrile (2 ml), and the gradient of 15 was [55. 45]. To 95: 5] of acetonitrile: water, the solution was purified using an automated preparative liquid chromatograph (Gilson system, 150 x 30 mm, Luna II C18 10 micron official column). The appropriate fractions were concentrated to provide the title Compound (104 mg). Experimental MH 605.9; Expected 606.0 1h_NMR (CDC13): 1.19-1 · 24 (3Η), 3.4 · 1-3 · 45 (6Η), 128 20 200531963 4 · 09-4 · 16 (2Η), 7.84-7 · 87 (2Η), 8.23-8.25 (1Η) Example 62 = {3-cyano-5-[(cyclopropylmethyl) aminoΗ_ [2,6- Dichloro_4_pentafluorothiophenyl] -1Η-orbital acetomethyl} methylpyridamine

5

To a suspension of Example 26 (100 mg, 0.018 mol) in toluene (4 ml) was added molecular sieves (400 mg), cyclopropane formic acid (40 microliters ㈣mmol) and p-toluene acid (Catalytic amount). The reaction mixture was heated under a thief for S hours, cooled and concentrated in a shirt. Next, to a solution of the 10 residue in ethanol (4 ml), sodium borohydride (16 mg, 0.36 mmol) was added. The reaction mixture was heated to room temperature and stirred overnight. The residue was dissolved in ethidium water (9.1 '1.5 ml) and using an acetonitrile: water gradient [50:50 to 95: 5] using an automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm Fanomonex Luna 匚 18 (2) 10 micron column) Purified 15%. The appropriate fractions were concentrated in vacuo to provide a mixture of the title compound (27 mg) and the bissulfonated compound. Experimental MH + 526.0; Expected 526.0 iH-NMR ^ CDCh): 0.09 · 0 · 13 (2Η), 0.4 ~ 0 · 50 (2Η), 0.8 ~ 0.59 (1Η), 2.78 -2 · 82 (2Η), 3 · 12_3 · 16 (3Η), 20 5 · 95-5.99 (1Η), 7.87-7 · 90 (2Η) 129 200531963 Example 63 N_ {3_cyano_l- [2,6-dichloro-4-pentafluorothiophenyl] -4 _ [(methylfluorenyl) (2,2,2-trifluoroethyl) amino] -imbsia_5_yl} acetamidine amine

5 Example 32 in dioxane (0.5 ml) in a solution of 50 (50 mg, 0.09 mmol) and 4-diamidinoaminopyridine (122 mg, 1.0 mmol) Add acetic anhydride (0.11 ml, 1.2 mmol) and N, N-dimethylformamide (1 drop). The reaction mixture was then stirred at room temperature for 4 hours. The reaction mixture was distributed between hydrogen acid (1M) and digasmethane, and the organic phase was separated, washed with water, dried (MgS04) and concentrated in vacuo. Dissolve the residue in acetonitrile (1-5 ml) and use an acetonitrile: water gradient [55:45 to 95: 5] using an automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm) Fenomonex Runa C18 (2) 10 micron column). The appropriate fractions were concentrated in vacuo to provide the title compound (34 mg). 15 Experimental MH + 596.0; expected 596.0 h-NMi ^ DMSO): 1.94-1 · 98 (3Η), 3.16-3 · 21 (3Η), 4.44-4 · 56 (2Η), 8. · 49-8_53 (2Η), 10 · 38-10 · 42 (1Η) Example 64 N- {3-cyano small [2,6-digas-4-pentafluorothiophenyl] -5_methoxy Welcome order 20-4-yl} methyl carbamide 130 200531963

A mixture of Example 66 (i40 mg, 0.25 mmol) and sodium hydroxide (1M, 0.5 ml, 0.5 mmol) in tetrahydrofuran (5 ml) was stirred at room temperature for 60 hours. . To the reaction mixture was added hydrogen acid (2v, 10ml) and the mixture was extracted with ethyl acetate (2x10ml). The combined extracts were dried (MgS04) and concentrated in vacuo. The residue was dissolved In acetonitrile (1 · 5 ml) and using a gradient of acetonitrile: water [50: 50 to 95: 5], an automated preparative liquid chromatography (Gilson system, 150 mm x 30 mm) was used. (Finomonex Luna C18 (2) 10 micron column) purification. Concentrate appropriate 10 fractions in vacuo to provide the title compound (67 mg). Experimental MH + 486.8; expected 487.0 ^ -NMRCCDCls): 3.19 -3.22 (3H) ^ 4.22-4.25 (3H) ^ 5.90-5 · 94 (1Η), 7.84_7 · 88 (2Η) Example 65 I5 Ν · [3_cyano · ι_ [2,6-Digas- 4- (trifluoromethyl) phenyl] _5_ (methylamino) -1Η-pyrazolebenzyl] _N · (methylfluorenyl) methanesulfonamide

131 200531963 Preparation of a mixture of 30 (35 mg, 010 mmol) and triethylamine (28 µl, 0.2 mmol) at 0 ° C in dichloromethane (0 ml). Methanesulfonyl chloride (16 μl, 0.20 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 2 hours. To the reaction mixture was added methylene chloride 5 (5 ml) 'and the solution was washed with hydrochloric acid (2N, 5 ml) and brine (5 ml), dried (MgSCXO and concentrated in vacuo. The residue was dissolved in Acetonitrile / dimethyl sulfide (1: 1 ml), using acetonitrile: water with a gradient of [45:55 to 98: 2] using an automated preparative liquid chromatography (Gilson System, Private 250x21 .2 mm, Luna II C18 5 micron column) to purify the solution. Concentrate 10 appropriate fractions to provide the title compound (7 mg). Experimental MH + 505.9; expected 506.0 ^ -NMRCCDCls): 2.82-2.86 (3H ) ^ 3.46-3.49 (6H) ^ 3.78-3 · 86 (1Η), 7.75-7.77 (2Η) Similar preparations are:

132 200531963 Example R2 R5 from Preparation 66 CN OMe 29 67 CN -N ^ rCH3 ch3 33 68 "[2- (dimethylamino) ethyl] amino 32 69" (2-pyrrolidin-1-ylethyl ) Amine 34 70 "(2-morpholin-4-ylethyl) amino 31 71" (2- ° C11-11-1-ylethyl) amino 36 72 cyclopropyl nh2 26 Example 66 b -NMRCCDCh): 3 · 48-3 · 52 (6Η), 4 · 07_4 · 10 (3Η), 5 7.87-7.90 (2) Example 67 MΗ + 605.0 of the experiment; expected 605.0 ^ -NMRCCDCla): 2.77 · 2.84 (3Η), 2.99-3 · 05 (3Η), 3.34 · 3 · 43 (6Η), 7.78-7 · 84 (2Η), 8.02-8.07 (1Η) 10 Examples 68 Experiments MΗ + 621_0; Expected 621.0 ^ -NMRCCDCls): 2.74 · 2 · 79 (6Η), 3.20-3.24 (2Η), 3.47 · 3 · 51 (6Η), 3.75 · 3 · 81 (2Η ), 7.11-7 · 17 (1Η), 7.85 · 7 · 87 (2Η) Example 69 15 MS (ES): M / Z [ΜΗ +] 647.0; The estimated mass of C18H21C12F5N604S3 + H is 647.0 ^- NMRCDMSO): 1.72-1 · 84 (2Η), 1_86-1 · 97 (2Η), 133 200531963 2.85-2.95 (2H), 3.15-3.22 (2H), 3.36-3.45 (2H), 3.56 · 3 · 64 (8Η), 6.88-6 · 93 (1Η), 8.43-8 · 46 (2Η) Example 70 MS (ES): Μ / Z [ΜΗ +] 663.1; C18H21C12F5N6 The estimated mass of 05S3 + H is 663.0 i-NMRCCDClO: 2.84-2 · 95 (2Η), 3.22-3 · 28 (2Η), 3.37-3.44 (2Η), 3.47-3.51 (6Η), 3 · 80-3 · 89 (4Η), 3 · 91-4 · 00 (2Η), 6.56-6 · 68 (1Η), 7.85-7 · 88 (2Η) Example 71 10 MS (ES) : Μ / Z [ΜΗ +] 661.0; The expected mass of C19H23C12F5N604S3 + H is 661.0 ^ -NMRCDMSO): 1.3 · 1-1 · 40 (1 (), 1.65-1 · 71 (1Η), 1.72-1 · 79 (4Η), 2.80-2.90 (2Η), 3.11-3.17 (2Η), 3.27-3.31 (2Η), 3.64 · 3 · 67 (6Η), 3.67-3.73 (2Η), 15 7 · 03- 7 · 07 (1Η), 8.46-8 · 48 (2Η) Example 72 MΗ + 565.0 of the experiment; expected 565.0 iH-NMRCCDCh): 0.90-0 · 98 (4Η), 1.83-1.91 (1Η), 3.41 · 3 · 45 (6Η), 3.75-3 · 89 (2Η), 7.82-7 · 85 (2Η) 20 Example 73 Ν- {5-amino-1- [2,6- Digas-4-pentafluorothiophenyl] -1Η-pyrazol-4-yl} methyl pyroxanthinamine 134 200531963

N-S-CH

To a mixture of Preparation 27 (177 mg, 0.33 mmol) and triethylamine (115 μl, 0.83 mmol) in methylene chloride (3 ml) and tetrahydrofuran (1 ml) was added methanesulfonyl Chlorine (53 μl, 0.83 mmol). Then, the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with hydrochloric acid (1M) and water, dried (MgS04) and concentrated in vacuo to provide the crude product. The residue was dissolved in acetonitrile / water (1.2 ml) using an acetonitrile: water gradient [35:65 to 95: 5] using an automated preparative liquid chromatography (Gilson system, 150x50 mm, Lu Nano II C18 10 micron column) was used to purify the solution. The appropriate fractions were concentrated to provide the title compound (74 mg). ^ -NMRCCDCh): 2.99 · 3 · 03 (3Η), 3.44-3 · 47 (2Η), 5.74 · 5 · 83 (1Η), 7.53 · 7 · 56 (1Η), 7 · 86 · 7 · 89 (2Η) Prepared similarly: Example 74 15 Ν · {3-cyano · 1- [2,6-dichloro-4-pentafluorothiophenyl] -5-[(pyridine -4-ylfluorenyl) amino] -1H-pyrazol-4-yl} methanesulfonamide

135 200531963 From the compound of Preparation 35 (257 mg, 0.53 mmol) and methanesulfonyl chloride (0.12 ml, 1.59 mmol) to provide the title compound (13 mg). Experimental MΗ + 562.9; Expected 563.0 h-NMR pMSO): 3.03-3 · 06 (3Η), 4.63-4 · 67 (2Η), 5 7.06-7.11 (1Η), 7.40-7.44 (2Η), 8.47-8.49 (2Η), 8.59-8 · 63 (2Η), 9.10-9 · 13 (1Η) Example 75 ({5-amino-3-cyano small [2,6-digas-4- Pentafluorothiophenyl] _1 {^ 比比 -4_ 基} amino) fluorenyl carbamic acid tert-butyl ester

Stir at room temperature before adding Preparation 43 (1.13 g, 2.87 mmol) and triethylamine (0.6 ml, 4.31 mmol) in difluoromethane (12 mL) dropwise. A mixture of tertiary butanol (0.27 ml, 2.87 mmol) in dioxane (12 ml) and isocyanate isocyanate (0.25 ml, 2.87 mmol) for 1 hour and 15 hours. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was distributed between hydrogen acid (0.5M) and dioxane, and the organic phase was separated, washed with water, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography, and extracted with ethyl acetate / cyclohexane [丨: 9]. The appropriate compound was combined and concentrated to provide the title compound (0.62 g). 20 Experimental MH + 573.0; Expected 573.0 136 200531963 1h-nmr (DMSO): 1.36-1 · 41 (9Η), 5.83-5 · 94 (2Η), 8.39 · 8 · 42 (2Η), 9 · 57-9 · 60 (1Η), 11 · 07-11 · 11 (1Η) Example 76 N- {5-amino-3-cyano_1- [2,6-digas-4-penta Fluorothiophenyl] -1Η · pyrazole_4 · kibN_ (2_π than pyridin_4_ylethyl) methanesulfonamide

Example 38 (200 mg, 0.42 mol) in anhydrous tetrahydrofuran (5 ml), 4- (2-hydroxyethyl) piperidine (52 mg, 0.42 mmol) and triphenylphosphine ( 167 grams of '0 64 mol) was cooled to 0 ° C, and π-gamma diacetic acid diethyl vinegar (0.1 ml, 0.64 mmol) was added. The reaction mixture was warmed to room temperature 'and stirred under nitrogen overnight. The reaction mixture was concentrated in vacuo, and the residue was distributed between dichloromethane and water. Then, the organic phase was separated and dried and concentrated in vacuo. Dissolve the residue in acetonitrile / water (4 mL) and use an acetonitrile · 0.1% trifluoroacetic acid with a gradient of [35: 65 to 95: 5] using an automated preparative liquid chromatography (Gillson System, 150x30 mm, Luna II C18 10 micron column) to purify the solution. The appropriate fraction was concentrated to provide the title compound (55 mg). Experimental MH + 577.0; Expected 577.0 ^ -NMRCCDCU): 2.99-3 · 04 (3Η), 3.1 · 1-3 · 18 (2Η), 4.12 · 4 · 17 (2Η), 4.19_4 · 41 (2Η), 7.62-7 · 69 (2Η), 137 200531963 7.86 · 7 · 89 (2Η), 8.59 · 8 · 67 (2Η) Prepared similarly: Example 77 Ν- {5- Amino-3-Gasyl-1-[2,6 -digas-4-pentasulfur basic group] _ 1 Η-ratio σ sitting 5 (pyracin-2-ylfluorenyl) methanesulfonamide

The title compound (100 mg) was provided from the compound of Example 38 (200 mg, 0.42 mmol) and pico-2-yl methanol (47 mg, 0.42 mmol). Experimental MΗ + 564.0; expected 564.0 10 ^ -NMRCCDCls): 3.19-3 · 23 (3Η), 4.98-5.06 (2H), 7.87-7 · 91 (2Η), 8.52-8 · 57 (2Η ); 8.61-8 · 66 (1Η) Example 78 Ν- {5-amino-3-ranyl-1 _ [2,6 -digas-4 -pentasulfur basic group] -1Η- ° ratio hydrazone-4_yl} -N-[(6-amino °°°° -3-yl) methyl] methycinite

The title compound was provided from the compound of Example 38 (200 mg, 0.42 mmol) and (6-aminopyridine 138 15 200531963 pyridin-3-yl) methanol (WO 2003000682 A, 53 mg, 0.043 mmol). (82 mg). Experimental MH + 578.0; expected 578.0 iH-NMR pMSO): 3.15 · 3.21 (3Η), 4.34-4 · 47 (1Η), 4.61-4.75 (1Η) > 6.48-6.57 (2Η), 6.91-6.95 (1Η), 7.69-7.73 (1Η) '7.78-7.83 (1Η)' 7.91-8 · 1〇 (2Η), 8.41-8 · 47 (2Η) 4 ^ 179 Ν_ {3-cyano-1- [2,6 · Digas-4-pentafluorothiobenzyl] _1Η · pyrazole-4_kib 2_ Side gas_Nβ (2,2,2_difluoroethyl) propane-1-sulfur Donkey amine

At 30 ° C, a solution of 47 (192 mg, 29 mmol) in tetrahydrobitan (2 ml) was added dropwise to the gasified isopropyl town (2M in tetrahydrofuran, 0.16 Ml, 0.32 mmol). After 30 minutes, acetoxane (41 microliters, 0.58 mmol) was added via a syringe, and the reaction mixture was heated to and allowed to stir for 2 hours. To the reaction mixture was added hydrogen acid (2N > 10¾.-τι \ υ home litre), and the mixture was extracted with ethyl acetate (2x10 ml). The combined extracts were dried (MgS04) and concentrated in vacuo to provide the product mixture. The residue was dissolved in acetonitrile (1 ml) using acetonitrile: 0.1% trifluoroacetic acid with a gradient of [60:40 to 98: 2] using an automated preparative liquid chromatography (Gilson system, 250 mm) X30 mm Fenomonex Rus 139 200531963 nano C18 (2) 10 micron column) was purified). The appropriate fractions were concentrated in vacuo to provide a mixture of the title compound (15 mg) and other products. Experimental MH + 580.9; Expected 581.0 1h_NMR (CDC13): 2.36-2 · 39 (3Η), 4.ΐ7, 4.2 ((2Η), 5 4 · 30-4 · 38 (2Η), 7.88-7 · 92 (3Η) Example 80 N- (3-cyano-1- [2,6-dichloro_4-pentafluorothiophenyl] _5-{[> (dimethylamino) • ethyl ] Amino group 1Η_〇 than salyl), 2,2_trifluoroethyl) methoxamine hydrochloride

To a mixture of Preparation 40 (505 mg, 0.91 mmol) and potassium carbonate (800¾ g, 5.80 mmol) in acetonitrile (10 ml) was added trigas methanesulfonic acid 2,2,2-tri Fluoroethyl (0.30 ml, 183 mmol). Then, in shame. (: The reaction mixture was heated for 19 hours. The reaction mixture was distributed between ethyl acetate and water and separated into two layers. The aqueous layer was extracted with ethyl acetate, and the combined organics were washed with saturated sodium bicarbonate solution and brine. Phase, dried iMgS04) and concentrated under vacuum. The residue was dissolved in ethidium (2 ml) with a gradient of acetonitrile [4〇 ·· 60 to 95 ·· 5] 〇1% trifluoroacetic acid, and the Wei phase chromatography (phase Mori system, 15Gx3G mm, Luna π 20 C18 Η) micron column) to purify the solution. Concentrate the appropriate collection to provide the trifluoroacetate of the compound desired. A solution of the trifluoroacetate in dioxane (10 ml) was washed with a saturated aqueous sodium bicarbonate solution (10 ml) and brine, dried (MgS04) and concentrated in vacuo. To a solution of the residue in diethyl ether (5 ml) and methanol (1 drop), add 5 gasified mice in diethyl ether (2 ml). Then, remove the reaction mixture for 5 minutes and place in vacuum Concentrated. To the residue were added acetonitrile (3 ml) and water (0.5 ml), and the solution was lyophilized to provide the title compound (35 mg). Experimental MH + 639.1; expected 639.0 'H-NMRCDMSO): 2.62-2.65 (6H) ^ 2.95-3.11 (2H) 10 3 · 29_3 · 30 (4Η), 3.35 · 3 · 37 (3Η), 4.55_4 · 63 (2Η), 8.52_8.54 (2Η) Example 81 Ν_ {3-cyano-fluorene- [2,6-digas · 4-pentafluorothiophenyl] _5 _ [(2_piperidine_丨 _ylethyl) aminoΗΗ + 44 · -N- (2,2,2_trifluoroethyl) methyl chloride hydrochloride

The title compound (175 mg) was provided from the compound of Preparation 41 (420 mg, 0.72 mmol) and chloroformic acid 2,2,2-trifluoroethyl acetate (0.30 ml, 1.83 mmol). MS (ES): M / Z [MH +] 665.1; The pre-calculated mass of C20H22C12F8N6〇2s2 + h is 665.1 141 200531963 ^ -NMRCDMSO): 1.63_1 · 74 (4Η), 2.72-2 · 85 (2Η ), 3.01-3.08 (2Η), 3.21-3.28 (4Η), 3.30 draw 3.33 (3Η), 3.47 · 3 · 77 (2Η), 4.43-4 · 52 (2Η), 6.74-6 · 79 (1Η), 8.41 · 8 · 45 (2Η) Example 82 5 Ν · {5_amino-3 -amino-1- [2,6-digas-4-pentathiothiophenyl ] -1Η-σ than sial-4-yl} thiamine

To a solution of Example 75 (150 mg, 0.26 mmol) in dioxane (2.4 ml) was added trifluoroacetic acid (0.6 ml, 7.79 mmol) at 0 ° C. 10 Then, the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in acetonitrile / water (2 mL). The solution was purified using an acetonitrile: water gradient [40:60 to 95: 5] using an automated preparative liquid chromatography (Gilson system, 150x30 mm, Luna II C18 10 micron column). The appropriate fractions were concentrated to provide the title compound (77 15 mg). Experimental MH + 472.8; Expected 473.0 h-NMR ^ DMSO): 6.02-6 · 07 (2Η), 6.81-6 · 85 (2Η), 8.41-8 · 44 (2Η), 8.51-8 57 (1H) Example 83 20 N- {5-Amino-3-Hanyl-1- [2,6-dichloro-4- (difluorofluorenyl) phenyl] -1 H-. Bisal 142 200531963 -4-yl} -4-Gas-N- (methylstyrenyl) benzolite xanthoamine

Example 15 in digas methane (4 ml) (200 mg, 0.48 mmol), 4-dimethylamino group ° specific bite (20 mg) and σ ratio ϋ (0.2 ml) To the full compound 5, 4-fluorobenzophenone base gas (93 mg, 0.48 mmol) was added. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was distributed between ethyl acetate (25 ml) and water (25 ml) and the two layers were separated. The organic layer was then dried (NaJO4) and concentrated in vacuo. The residue was purified using Exolute ™ g (silica dioxide, 25 g) and eluted with a gradient of [15 ·· 85 to 1: η acetic acid 10 ethyl acetate ·· cyclohexane. The appropriate fractions were combined and concentrated to provide the title compound (55 mg). Experimental MΗ + 571.9; Expected 572.0 h-NMR pMSO): 3.69-3.75 (3Η), 6.63-6 · 7〇 (2Η), 7.51-7 · 57 (2Η), 7.89 -7 · 95 (2Η), 8.19-8 · 29 (2Η) 15 are similarly prepared. Ν · {5-amino-3-cyano-1_ [2,6_digas-4- ( Trifluoromethyl) phenyl Hh_, bis_4_yl} -2,4-difluoro-N- (methylfluorenyl) benzenesulfonamide 143 200531963

The title compound (50 mg) was provided from the compound of Example 15 (200 mg, 0.48 mmol) and 2,4-difluorobenzenesulfonyl (102 mg, 0.48 mmol). 5 Experimental MH + 589.9; expected 590.0 h-NMF ^ CDCU): 3.58-3 · 60 (3Η), 4.26-4 · 34 (2Η), 7.00-7 · 10 (2Η), 7.75- 7.82 (2Η), 7.92-8 · 01 (1Η) Example 85 3-cyano-1- [2,6 · dichloro-4-pentafluorothiophenyl] · 4-[(methyl (Fluorenyl) (2,2,2-10 trifluoroethyl) amino] -1 methyl-pyrazol-5-ylaminocarboxylate

N_ {5-amino-3-cyano-1- [2,6-dichloro-4_penta] in toluene / digas methane (2: 3, 3.6 ml) at 0 ° C Fluorothiophenyl than fluoren-4-yl} -sense (2,2,2-trifluoroethyl) methanesulfonamide (200 mg, 0.6 mmol), 15 pyridine (73 μl, 0.90 To a solution of 3 mol) and 3 molecular sieves (0.2 g), carbon rhenium chloride (20% in toluene, 1.7 M, 2 ml) was added. After stirring at 0 ° C for 1 144 200531963 hours, methanol (2 ml) was added and the reaction mixture was warmed to room temperature. The reaction mixture was concentrated in vacuo to provide the crude product. The crude product was dissolved in acetonitrile / difluorenyl sulfide (1 ml), and acetonitrile with a gradient of [55: Kan 95: 5]: 0_1% of triacetic acid was used for automated preparative liquid chromatography Instrument (Gilson system, 250x30 mm, Luna n C18 omega column) to purify the solution. The appropriate fractions were concentrated to provide the title compound (02 mg). Experimental MH + 612.1; expected 612.0 4-NMR (DMSO): 3.18-3 · 22 (3Η), 3.54-3 · 58 (3Η), 104 · 44-4 · 60 (2Η), 8.51-8.55 (2Η), 10-30 ~ 10 · 35 (1η) are similarly prepared as: N- {5-({[((2 · aminoethyl) amino] amido} amino) _3_cyano Small [2,6_digas-4-pentafluorothiophenyl] -1Η ″ than 嗤 _4-yl} _sense (2,2,2_trifluoroethyl) pyridine 15

From Ν- {5-amino-3-cyano-H2,6-dichloro-4-pentafluorothiophenyl] -111-σ ratio ° + radicals} (2,2,2-trifluoro Ethyl) methanesulfonamide (100 mg, 0.8 mmol) and ethylenediamine (1 ml) to provide the title compound (12 mg). Experimental MΗ + 640.0; Expected 640.0 145 20 200531963 h-NMRCCDsOD): 3_23-3 · 26 (3Η), 3.75-3 · 81 (2Η), 3.94-3 · 99 (2Η), 4.11 -4 · 14 (2Η), 8.20-8 · 23 (2Η) Example 87 Ν · {5-[(2 · / ρ 旦 -1-ylethyl) amino] -3-cyano-1- [2,6-Dichloro_4-pentafluoro-5thiophenyl] -1H-pyrazol-4-ylbN- (2,2,2-trifluoroethyl) methanesulfonamide trifluoroacetic acid salt

Preparation of 48 (120 mg, 0.20 mmol), sodium triacetoxyborohydride (43 mg, 0.20 mmol), and acryl (η 10 μl) in digas methane (2 mL) (20 mmol), acetic acid (11 μl, 0.20 mmol) was added. The reaction mixture was then stirred at room temperature for 72 hours. The reaction mixture was distributed between an aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, dried (MgS04) and concentrated in vacuo. The residue was dissolved in acetonitrile / water (1 ml) and an acetonitrile: 02% 15 trifluoroacetic acid was used in a gradient of [4:60 to 95: 5] using an automated preparative liquid chromatography ( Gilson system, 150x30 mm, Luna II ci810 micron column) to purify the solution. The appropriate fractions were concentrated to provide the title compound (28 mg). Experimental MH + 637.1; Expected 637.0 h-NM ^ CDCh): 2 · 30 · 2 · 42 (1Η), 2.58 · 2 · 71 (1Η), 20 3 · 18-3 · 22 (3Η) '3.35-3.49 ( 2Η), 3.74-3.84 (1Η) 146 200531963 3.85-4_00 (2H), 4.09-4_19 (1Η), 4.21_4 · 33 (3Η), 4.40-4 · 54 (1Η), 6. · 54-6 · 63 (1Η), 7.82-7 · 88 (2Η) Example 88 Ν_ (3-cyano-1_ [2,6_dichloropentafluorothiophenyl] -5-{[(2,4 _Diphenyl) methylene] amino} -1Η-pyrazole_4_yl) _2,2,2-trifluoroethyl) methanesulfonamide

N- {5-amino-3-cyano small [2,6-dichloro-4-pentafluorothiophenyl] _ιη-π ratio 嗤 -4_ heated in toluene (15 ml) under reflux *} · N- (2,2,2-trifluoroethyl) methanesulfonamide (500 mg, 0.9 mmol), 2,3-dihydroxybenzyl (248 mg, 1.8 mmol) ), A mixture of molecular sieves and p-toluenesulfonic acid (17 mg) overnight. The reaction mixture was concentrated in vacuo, and the residue was washed with water, ethyl acetate and brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile / dimethyl sulfide (1 ml) using an acetonitrile: water gradient [65:35 to 95: 5] using an automated preparative liquid chromatography (Gilson system, 150x50 mm, Luna II C18 10 micron column) to purify the solution. The appropriate fractions were concentrated to provide the title compound (200 mg). Experimental MH + 673.9; Expected 674.0 i-NMR pMSO): 3.29-3.31 (3Η), 4.49-4 · 57 (2Η), 6.13-6 · 17 (1Η), 6.25-6 · 29 (1Η ), 7.34-7 · 39 (1Η), 8.52-8 · 54 (2Η), 8.87-8 · 90 (1Η) 147 200531963 Example 89 Ν · {5 · 气 -3-cyano + [2,6-Digas-4-pentafluorothiophenyl] -1H-pyrazole-4 · KibN- (2,2,2-trifluoroethyl) methanesulfonamide

5 N- {5-Amino-3-cyano-1- [2,6-dichloro-4 · pentafluorothiophenyl 1.1 · bizol-4-yl in acetonitrile (5 ml) } Shan (2,2,2-trifluoroethyl) methanesulfonamide (250 mg, 0.45 mmol) with copper (11) (30.3 mg, 2.25 mmol) To the mixture was added tert-butyl nitrite (102 µl, 0.68 mmol) in acetonitrile (1 ml). Then, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was distributed between ethyl acetate (10 ml) and water (10 ml). The two layers were separated and the aqueous layer (10¾ liters) was extracted with ethyl acetate. The combined organic phases were then dried (MgS04) and concentrated in vacuo. The residue was dissolved in acetonitrile (1 ml) using acetonitrile: water with a degree of [60 · 40 to 95: 5], using an automated preparative liquid chromatography (Gilson system, 150x30 mm, Lu Nano-H C18 10 micron column) was used to purify the solution. The appropriate fractions were concentrated to provide the title compound (58 mg). H-NMR (CDC13): 3.21-3.25 (3Η), 4.2 · 2-4_30 (2Η), 7.90-7 · 93 (2Η) 20 tM90 148 200531963 No. cyano 1 [2,6_ 一气 _4 _Pentafluorothiophenyl] Shijiuren methylamino) Ethyl] amino group Benzyl methyl hindryl) Methylamine

To a mixture of Preparation 33 (55.0 mg, 5 1.0 μmol) and triethylamine (0.33 mL, 2.3 mmol) in monochloromethane (ls mL) at 0 C was added dropwise to the mixture. Burn the base gas (0.19 ml, 2.3 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. To the reaction mixture was added water (10 ml) and the two layers were separated. The aqueous layer was extracted with methane (2 > < 20 ml) and the combined organic phases were washed with brine, dried (MgS04) and concentrated in vacuo to the title compound (600 mg). Experimental MH + 635.0; Expected 635.0 The following preparations illustrate the synthesis of certain intermediates used in the preparation of the foregoing examples. ΜΛΙ 15 N- (3-chalcyl-l- [2,6-digas-4- (tri Imethyl) phenyl] _5j [(dimethylamino) methylene] amine}}-1H- #b 峻 -4-yl) Preparation of 51,200 (200 mg, 0.51 mmol) solution of 3,4-difluorobenzidine in digas methane (4 ml), 4-dimethylamine was added Pyridyl (20 mg), pyridine (0.2 ml) and difluorobenzodiazepine (163 mg, 0.77 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated under a stream of nitrogen to provide the title compound (200 mg) as a mixture of mono and disulfonated products. Experimental MH + 567.1; 567.0 is expected to be similarly prepared from Preparation 51 (except Preparation 4, which is prepared from Preparation 23 5):

R, a Preparation of Rla R3 MS (ES): M / ZPVIH ^ (Estimated mass) 2 cf3 Methyl methyl methyl 547.0 (547.0) 3 sf5 Me 527.0 (527.0) 4 cf3 Benzyl 547.1 (545.1) 5 4 2- Phenylvinyl 555.2 (555.0) Preparation of 6 N- (3-cyano-H2,6-dichloro-4_ (trifluoromethyl) phenyl] · 5 _ {[(dimethylamino) 10 methylene ] Aminobubisalyl) -N- (cyclopropylamidino) pyridine was prepared in acetone (4ml) to a solution of 15 (100 mg, 0.21 mmol) and potassium carbonate (38 Milligrams, 0.28 millimoles), followed by bromocyclopropane (25 microliters, 0.26 millimoles). Then, the reaction mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under nitrogen and the residue was distributed between ethyl acetate and water. The two layers were separated and the aqueous layer was extracted with ethyl acetate (X2). The combined organic phases were dried (MgS04) and concentrated under nitrogen to provide the title compound 150 200531963 (100 mg). Experimental MH + 523.4; 523.1 is expected to be similarly prepared:

Preparation of Rla R4 R3 from Preparation Editor * 5 Tiger MS (ES): M / ZfMH "] (Estimated Mass) 7 cf3 Cyanofluorenyl Me 15 508.3; (508.0) 8 (Specific Methan-2-ylmethyl Me C 560.4 ; (560.1) 9 4 benzyl Me C 559.4; (559.1) 10 4 2-hydroxyethyl Me 4 515.0; (513.1) 11 methylthiomethyl Me (531.0; (529.0) 12 (cyclobutyltrifluoro Methyl 16 577.0; (577.1) 13 C 2_N, N-dimethylaminoethyl Me 15 540.0; (540.1) 14 sf5 Me trifluoromethyl 45 594.9; (595.0) Preparation of 15 N- (3-cyano -l- [2,6-dichloro_4- (trifluorofluorenyl) phenyl] · 5-{[(dimethylamino) methylene] amino} -1Η-pyrazole-4_yl ) Preparation of methanesulfonamide in a mixture of tetranine (35 ml) and methanol (35 ml) to prepare 19 (3.4 g, 6.21 mmol), and potassium carbonate (2.15 g, 15.53 Millimoles). Then, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and vinegar 151 200531963 was added to the residue. Hydrogen acid (IN) and brine The solution was washed and then concentrated in vacuo. The residue was purified by column chromatography (dioxide , 50 g), dichloromethane: methanol with a gradient of [100: 0 to 95: 5]. Combine the appropriate fractions and concentrate to provide the title compound (620 mg). IH-NMR (DMSO) : 2_67_2 · 70 (3Η), 2.90-2 · 95 (3Η), 2.99-3 · 02 (3Η), 8_19-8 · 23 (2Η), 8.30-8.33 (1Η), 9.43-9 · 47 ( 1)) Preparation of 16 N- (3-cyano-1- [2,6-dichloro · 4- (trifluoromethyl) phenyl] -5-{[(dimethylamino) methylene] amine Gib 1Η · pyrazol-4-yl) Preparation of 1,1,1_trifluoromethanesulfonamide 10 in trifluoroethanol (9 ml) 46 (650 mg, 0.99 mmol) was added to the solution Aqueous sodium hydroxide solution (2.5N, 16 drops). Then, the reaction mixture was stirred at room temperature under nitrogen for 1 hour. To the reaction mixture was added hydrogen acid (2M, 2 ml), and the mixture was concentrated in vacuo. Solution. The residue was distributed between ethyl acetate (20 ml) and water (20 ml) and the 15 phases were separated. The organic phase was washed with water (2 x 20 ml), dried (Na2S04) and concentrated in vacuo to provide The title compound (505 mg). Experimental MH + 523.2; 523.0 is expected to prepare 17 N- (3-cyano_1- [2,6-digasic (trifluoromethyl) phenyl] dimethylamino) 20 methylene] amino group Preparation of 1Η-ϋpyzol-4-yl) -N · (methylfluorenyl) cyclopropanesulfonamide in digas methane (3 ml) 15 (150 mg, 0.32) and triethylamine (66 彳Liter, 0.48 mmoles), add cyclopropane to burn the base gas (35 mg, 0.48 mmoles). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was purified using Asorut τμε (: 152 200531963 silica, 10 g) with a cyclohexane: ethyl acetate gradient of [3: 1 to 1: 1] Rush. The appropriate fractions were combined and concentrated to provide the title compound (150 mg). Experimental MH + 572.9; 573.0 similar preparations are expected:

Ο ^, Μθ

R4 Preparation Rla R2

From Preparation MS (ES): M / ZpVflf] (Expected mass) 18 CF3 CN N, N-dimethylaminofluorenyl 15 575.9; (576.0) 547.4; (547.1)

Ν '-{4 · amino_3 · cyano small [2,6_dichlorobenzylpentafluorothiophenyl] u-pyrazole 10 yl, Ν, Ν-dimethylamidoiminomethoxamine in Preparation of 53 (90 g, 15 15 mmol) in tetrahydrofuran (120 ml) was added tetrabutylfluoride (60.6 ml, 60.6 mmol =, min.). The reaction was heated at 50 t. The mixture was i hours at ~ room temperature. The reaction mixture was concentrated in vacuo and allowed to cool to 15 ethyl acetate (200 ml) and water (200 ml ^ M). The residue was separated at 9 ° in vinegar. The organic layer was washed with water 200531963 (2x200 liters) and brine (200 ml), dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography (silicon dioxide, 25.0 g), Ethyl acetate: gradient from [0 · 1 to 1 · 4]: dichloromethane. Combine the appropriate fractions and concentrate to provide the title compound (2 · 6 g). 5 Experimental MΗ 449.0; Expected 449.0 Another A synthesis A solution of 55 (100 g, 2100 mol) in methanol (300 ml) and platinum (5% on activated carbon, 1 g) was placed in a hydrogen atmosphere at room temperature. (50 lbs / flat Inches) for 2 hours. The reaction mixture was filtered and concentrated in vacuo for 10 times, and the residue was triturated with diethyl ether. The solution was concentrated in vacuo to provide the title compound (8.5 g). Η-NMR (CDC13 ): 2.74-2 · 78 (3Η), 2.96-2 · 99 (3Η), 7.76-7 · 81 (2Η), 8.18-8_21 (1Η) 15 Ν_ (3-cyano Small [2,6-dichloro-4-pentafluorothiophenyl] _5 _ {[(dimethylamino) methylene] amino} -1Η · pyrazol-4-yl) 4 (2,2 Of 2,2-trifluoroethyl) methanesulfonamide in 1-methyl-2-u-pylonolone (4 ml) 3 (239 mg, 0.45 Emole) solution, sodium hydride was added (60% in oil, 12 mg, 0.50 mmol). The mixture was stirred at room temperature for 5 minutes, and trichloromethane 20 acid 2,2,2-trifluoroethyl ester (166 Mg, 0.59 mmol). Then, the reaction mixture was stirred at room temperature overnight. To the reaction mixture was added brine (10 ml), and the pH of the mixture was adjusted to 4 by adding hydrogen acid (2N). The mixture was extracted with ethyl acetate (2x10 ml), the combined extracts were dried (MgS04) and concentrated in vacuo. The column layer was utilized Purify the residue (Dioxide 154 200531963 Shi Xi) and elute with ethyl acetate / hexane [1: 3]. Combine the appropriate fractions and concentrate to provide the title compound (82 mg). Experimental MH + 609.0; expected 609.0 Preparation 25 5 Sense (3-cyano-1- [2,6-digas-4-pentathiothiophenyl] _5 _ {[(dimethylamino) amidino] amine} -1Η · Preparation of pyrazol-4-yl) -N _ {[1- (trifluoromethyl) cyclopropyl] methyl} methanesulfonamide in acetonitrile (6 ml) 3 (147 mg, 0.28 mmol) Add '52 (107 mg, 0.36 mmol) in acetonitrile (2 mL), followed by 10 cesium carbonate (91 mg, 0.59 mmol) and potassium iodide (catalytic amount). Then, the reaction mixture was heated under reflux for 5 hours. The reaction mixture was concentrated in vacuo and the residue was distributed between water (10 ml) and ethyl acetate (15 ml). The two layers were separated, and the pH of the aqueous layer was adjusted to 1 by adding hydrochloric acid (2N), and extracted again with ethyl acetate (10 ml). The combined 15 organic phases were dried (MgS04) and concentrated in vacuo. The residue (silica dioxide) was purified by column chromatography 'and eluted with a gradient of ethyl acetate: hexane [丨: 4 to 1: 2]. The appropriate fractions were combined and concentrated to provide the title compound (155 mg). Experimental MH + 649.0; expected 649.0 to prepare 26 20 cyclocyclopropyl small [2,6_digas-4-pentafluorothiophenyl] -1H-pyrazole_4,5_diamine in ethanol (5 ml) To a solution of Preparation 56 (150 mg, 0.30 mmol) was added gasified tin (11) (288 mg, 1.52 mmol). The reaction mixture was heated under reflux for 6 hours, cooled and added with hydrochloric acid (6N, 0.5 ml "and then the reaction mixture was heated under reflux for another 16 hours. To the reaction mixture 155 200531963 was added ethyl acetate Ester (25 ml), water and saturated aqueous sodium bicarbonate solution. The two layers were separated and the organic layer was dried (MgSO) and concentrated in vacuo to provide the title compound (as a mixture of products). Experimental MH + 409.0 It is expected that 409.01 will be similarly prepared:

Jjt29

Preparation Rlb R2 From Preparation Number MS (ES): M / ZpVfff] (Estimated Mass) 27 Cl Η 57 369 · 0; (369 · 0) 28 Η CN 58 360.0; (360.0) 4_Amine small [2,6 · Dichloro · 4-pentafluorothiophenyl] -5-methoxy-1H_pyrazole_3_nitrile 10 in ethanol (10 ml) Preparation 59 (530 mg, 1.21 mmol) To the solution was added tin (11) chloride (1.14 g, 6.05 mmol), followed by hydrochloric acid (6N'1 ml). The reaction mixture was then heated under reflux for 2 hours. The reaction mixture was concentrated in vacuo, and ethyl acetate (40 ml) was added to the residue. The solution was then dried (Mss04) and concentrated in vacuo to provide the title compound (495 mg) with water (30 mL) and brine (30 mL). Experimental MH + 408.9; Expected 409.0 156 200531963 Preparation 30 4 · Aminyl [2,6_dichloro_4_ (trifluoromethyl) phenyl] (methylaminoxidazole-3-nitrile in ethanol (2_5 Preparation of 65 (40 mg, 0-11 mol) in solution 5 was added to iron powder (57 mg, ro mol), calcium carbonate (13 mg, mol mol) and water (0.5 ml) ). The reaction mixture was heated under reflux for 6 hours, and then stirred at room temperature for 8 hours. The reaction mixture was filtered through a plug of plastic ⑧, washed with ethyl acetate, and the filtrate was concentrated in vacuo. Ethyl acetate was added to the residue, and the solution was washed with a saturated aqueous sodium bicarbonate solution (10 mmol and 10 liters) and brine (10 mL), dried (MgS04) and concentrated in vacuo to provide the title compound ( 35 mg). Experimental MH + 349.9; expected 350.0 similar preparations are:

12 Preparation of R3a R4a from Preparation of MS (ES): M / ZfMH ^] (Estimated mass) 31 Η 2-morpholin-4-ylethyl 66 507.0; (507.1) 32 Η 2-N, N-dimethyl Aminoethyl 67 465.1; (465.1) 33 Me 2-N, N-dimethylaminoethyl 70 479 · 0; (479 · 1) 34 Η 2-pyrrole-1-ylethyl 68 491.0; (491.1) 35 Η Pyridinylmethyl 60 485.0; (485) 36 Η-Brigade 17-1 -ylethyl 69 505.0; (505.0) 157 200531963 Preparation 37 4- [Bis (methylstilbenzyl) amino ] · 1- [2,6-Digas-4 · Pentafluorothiophenyl] -5-{[((dimethylamino) methylene] amino) 1-pyrazole-3-carboxamide Blow hydrogen chloride through methanol (8 mL) for 10 minutes. To this solution was added Example 67 (441 mg, 0.73 mmol) and the gasified hydrogen flow was maintained for another 5 minutes. The reaction mixture was then sealed and left overnight. The reaction mixture was concentrated in vacuo, and methanol (20 mL) and hydrochloric acid (2N, 10 mL) were added to the residue. The mixture was stirred for 1 hour and water (30 mL) was added. The mixture was extracted with ethyl acetate (3 x 20 ml), the combined 10 extracts were dried (MgS04) and concentrated in vacuo to provide the title compound (450 mg), such as 20: 1 amidine and methyl A mixture of esters. Experimental MH + H623.0; 623.0 is expected to prepare 38 Ν- (3 · ethenyl_1 · [2,6 · dichloro-4-pentafluorothiophenyl] _5 _ {[(dimethylamine 15 group ) Methylene] amino group 1Η_pyrazolyl) _N_ (methylfluorenyl) methanesulfonamide Example 67 (500 mg, 0.83 mmol) in tetrahydrofuran (10 ml) at 0 ° C To the solution, methyl magnesium bromide (3M in diethyl ether, 0.8 ml, 2.48 mmol) was added dropwise. The reaction mixture was then stirred at room temperature for 2 days. The reaction mixture was poured onto ice, water and hydrogen acid (2N). The mixture was stirred for 30 minutes and then extracted with ethyl acetate (3x30 ml). The combined extracts were dried (MgS04) and concentrated in vacuo. The residue was dissolved in acetonitrile (2 mL) and an acetonitrile: water gradient [50:50 to 95: 5] was used, using an automated preparative liquid chromatography (Gillson system, 50x30). Mm, Luna II C18 10 micron column) to purify the solution. The appropriate fraction was concentrated to 158 200531963 to provide the title compound (97 mg). Experimental MH + H622.0; 622.0 is expected to make 39 N- {5-amino-3cyano-1 · [2,6-dichloro_4_ (trifluoromethoxy) phenyl] · 1H_pyr 5 Azole_4-yl} methanesulfonamide in Example 35 (120 mg, 0.24 mmol) in tetrahydrofuran (5 ml), a sodium hydroxide aqueous solution (1 M, 4.25 ml) was added, and the solution was kept at room temperature The reaction mixture was stirred for 2 hours. The reaction mixture was acidified by adding hydrogen acid (1M), and then extracted with dichloromethane. The combined 10 extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound (100 mg). Experimental MH + 429.9; 430.0 is expected to be similarly prepared ...

GH Preparation of R5a from Preparation of MS (ES): M / Z [MH +] (Expected Mass) 40 (2- (dimethylamino) ethyl) (methyl) amine 111 557.0; (557.0) 41 (2- ° Benzyl-1-ylethyl) amine Examples 71 583.0; 583.1 15 Ware 42 N-〇cyano-1- [2,6-digas-4_pentafluorothiophenyl] _5 _ {[( Dimethylamino) methylene] amino} -1Η.嗤 · 4 · yl) -N_ [2_ (1Η-1,2,4-trijun-1-yl) ethyl] methanesulfonamide 159 200531963 in acetonitrile (1 ml), 74 (154 mg, (〇24mmol) and 1,2,4-tri. Sit (42 mg '0.61 millimolar) into the mixture and force carbonate (40 mg, 0.29 millimolar) into the mouth. The reaction mixture was then heated at 60 ° C overnight. The reaction mixture was concentrated in vacuo and the residue was distributed between dichloromethane (10 ml) and water (10 ml). The organic phase was separated, Dry (MgS04) and concentrate in vacuo to provide the title compound (155 mg of experimental MH + 622.0; expected 622.0. Preparation 43 4,5-diamine-l- [2,6-dichloro-4-pentafluorosulfide Phenylphenylazole pyridazole ^ nitrile 10 in a solution of methanol (8 ml) and dioxin (1 ml) 23 (300 mg, 0.67 mmol) was added with hydrogen acid ( 2M, 8 ml). Then, the reaction mixture was heated under reflux overnight. The reaction mixture was concentrated in vacuo and the residue was distributed between ethyl acetate and water. The organic layer was separated and dried (MgS04) And concentrated in vacuo to provide the title compound (273 15 mg). Experimental MH + 394.0; expected 394.0 Preparation of 44 N- (3-cyano small [2,6_dichloro | pentafluorothiophenyl] · 5_ Example of [[phenylmethylene] amino group 1H't4j) _N_ (methylfluorenyl) methanesulfonamide in toluene (5 ml) 26 (100 mg, 〇18 mmol In Mol solution, benzaldehyde (0.04 ml, 0.36 mmol), p-toluenesulfonic acid (catalyzed) and some 4A molecular sieves were added. The reaction mixture was heated at 9 (rc for 8 hours, and then Stir at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and the residue was distributed between ethyl acetate (10 ml) and water (10 ml). 160 16031963 The second layer was separated and ethyl acetate was added. Ester-extracted aqueous layer (2x10 ml). Washed with brine and combined

The organic phase was dried (MgS04) and concentrated in vacuo to provide the title compound (120 mg). Experimental MH + 637.9; expected 638.0 5 Preparation of 45 Ν-Οcyano 1- [2,6-digas-4-pentafluorothiophenyl] -5-{[(dimethylamino) methylene ] Amine} -1,1 -pyrazol-4-yl) Preparation of 1,1,1-trifluoromethanesulfonamide at 0 ° C in anhydrous dichloromethane (5 ml) 23 (200 mg, 0.45 mmol), triethylamine (124 µl, 0.89 mmol) 10 and trifluoromethanesulfonic anhydride (150 µl, 0.89 mole) were added. The reaction mixture was then stirred under nitrogen for 30 minutes. To the reaction mixture were added dichloromethane and hydrogen acid (4M, 3 ml). The organic phase was separated, washed with hydrochloric acid (4M) and brine, dried (Na2S04) and concentrated in vacuo. The residue was purified by column chromatography (silicon dioxide, 25 g), and washed with ethyl acetate: cyclohexane with a gradient of [2: 1 to 1: 0] 15 followed by methanol. The appropriate fractions were combined with acetone to provide the title compound (200 mg). Experimental MH + 580.9; 581.0 is expected to be similarly prepared: MM46 2〇Ν · (3-cyano small [2,6_digas_4_ (trifluorofluorenyl) phenyl] dimethylamino) methylene ] Amineb 1Η-pyrazole ice-based hydrazone bis ^^ fluorofluoromethane) baicaleamine from Preparation 51 (800 mg, 2.05 mmol) and trifluoromethanesulfonic anhydride (860 ° F, 2.05 Mol ) To provide the title compound (3 g). Experimental MH + 655.3; expected 655.0 161 200531963 The second layer was separated and the aqueous layer was extracted with ethyl acetate (2x10 ml). The turbulent organic phase was washed with brine, dried (MgS04) and concentrated in vacuo to provide the title compound (120 mg). Experimental MH + 637.9; expected 638.0 5 Preparation of N- (3-lactyl small [2,6-monochloro-4_pentafluorothiophenyl] _5 _ {[(dimethylamino) methylene] amino) } · 1Η · Zirazole_4_yl) Preparation of 1,1,1-trifluoromethanesulfonamide at 0C in anhydrous dichloromethane (5 ml) 23 (200 mmol # g, 0.45 To the solution, triethylamine (124 µl, 0.89 mmol) 10 and trifluoromethanesulfonic anhydride (150 µl, 0.89 mole) were added. The reaction mixture was then stirred under nitrogen for 30 minutes. To the reaction mixture were added dichloromethane and hydrogen acid (4M, 3 ml). The organic phase was separated, washed with hydrochloric acid (4M) and brine, dried (Na2S04) and concentrated in vacuo. The residue was purified by column chromatography (silica dioxide, 25 g), and washed with ethyl acetate · cyclohexane at a gradient of [2: 1 to 1: 0] 15 followed by methanol. The appropriate fractions were combined and concentrated to provide the title compound (200 mg). Call for experimental MH + 580.9; 581.0 is expected to be similarly prepared as: Preparation of 46 20 N- (3_cyano-1_ [2,6-digasic (trifluoromethyl) phenyl] -5-{[(dihydrazone Amino) methylene] amino} -1H-pyrazol-4-yl) -N, N-bis- (1,1,1-trifluoromethane) sulfonamide from Preparation 51 (800 mg, 2.05 Millimoles) and triflic acid anhydride (860 microliters, 2_05 moles) to provide the title compound (1.3 g). Experimental MH + 655.3; Expected 655.0 161 200531963 Preparation of 47 N- {3-cyano-l- [2,6-dichloro-4-pentafluorothiophenyl] -5-iodo-1H-pyrazole-4- } -N- (2,2,2-trifluoroethyl) methanesulfonamide in acetonitrile (10 ml) Example 32 (447 mg, 0.81 mmol) and iodine 5 (881 mg, 3.47 mmol) Ear) was added to a mixture of isoamyl nitrite (0.13 ml, 0.97 mmol). Then, the reaction mixture was heated at 50 ° C. for 1 hour. To the reaction mixture was added a saturated aqueous sodium thiosulfate solution (30 liters) 'and the mixture was extracted with ethyl acetate (2 x 20 ml). The combined extracts were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. 10 Dissolve the residue in acetonitrile (2 ml) using acetonitrile: water with a gradient of [55:45 to 95: 5] using an automated preparative liquid chromatography (Gilson system, 150 mm x 50 mm phenanthrene Normonex Runa ^ ^ phantom micron column) purification. The appropriate fractions were concentrated in vacuo to provide the title compound (283 mg). 15 lH-NMR (CDCl3): 3.24-3 · 28 (3Η), 4.07-4 · 20 (1Η), 4.35-4 · 49 (1Η), 7.90-7 · 93 (2Η ) Preparation of 48 Ν- {3-cyano-1- [2,6-digas-4-pentadenylthiophenyl] -5 _ [(2 · oxyethyl) amino] -1H Of phenyl} -sense (2,2,2-trifluoroethyl) methylpyramine 20 in acetone aqueous solution (10%, 16.6 ml) in 75 (560 mg, 0.94 mmol) solution Add osmium tetroxide solution (2 5%, 33 μmol). To this mixture was added steel peracetate (mg, 2.0 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was passed through and the eluate was concentrated in vacuo. The residue was distributed between dichloromethane and water. The organic layer was separated, dried (MgS04) and concentrated in vacuo to provide the title compound (134 mg). ^ -NMRCCDC ^): 3.17-3.20OH), 4.20-4.29 (2H), 4.32-4.46 (2H), 4.76-4.81 (1Η), 7.91-7.93 (2H), 9.58-9.59 (1Η) 5 Preparation of 49 N -(3-cyano-l- [2,6-dichloro-4- (difluoromethyl) phenyl] · 5, [(dimethylaminometridinyl) amino] 1HH4-yl) -1,1,1_trifluoro * methylmethanamine was prepared at a temperature of 0 ° C in a solution of 46 (1.3 g, millimolar) in tetrahydrofuran (11 ml), and added in methanol ( 11 ml) and 10 potassium carbonate (685 mg, 4.96 mmol) in water (3 drops). Then, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and digas methane was added to the residue. The solution was washed with hydrochloric acid (1N) and brine, dried (MgSOO and concentrated in vacuo. The residue was purified by column chromatography (silica, 50 g) with a gradient of [1: 0 to 0: 1] Cyclohexane: Dimethylmethane 15 eluent, followed by digas methane: methanol [95: 5]. Combined with appropriate considerations and concentrated to provide the title compound (240 mg). IH-NM ^ CDClJ : 2 · 79-2_85 (3Η), 3.0 · 2-3 · 08 (3Η), 3.45 · 3 · 51 (3Η), 7.69-7 · 74 (2Η), 8.02-8 · 07 (1) Preparation of 50 2N ′-[3-cyano-small [2,6-digas-4- (trifluoromethyl) phenyl] -4 · (1,1-dioxoisothiazolidine- 2-yl) -1H-pyrazol-5-yl] -N, N-dimethylamidoiminoformamide at room temperature, stirred at N, N-dimethylformamide (2 ml) Preparation of a mixture of 76 (127 mg, 0.24 mmol) and potassium carbonate (36 mg, 0.26 mmol) for 2 hours. To the reaction mixture was added ethyl acetate (10 ml) 163 200531963 and water (ίο Zhaisheng), and the two layers were separated. The aqueous layer was extracted with ethyl acetate, the combined organic phase was dried (MgS04) and concentrated in the air to provide the title. Compound 6 (110 mg). Experimental MH + 495.2; Expected 495.0 5 Preparation of 51 N '-{4-amino-3 · cyano · 1- [2,6-dichloro · 4 · (trifluoromethyl) Phenyl] _1H ♦ -5--5-}-N, N-dimethylamidoiminoformamidine in tetrahydrofuran (15 ml) in the preparation of 77 (423 mg, 0.79 mmol), Add tetrabutylammonium fluoride (訄 in tetrahydrofuran, 3.2 ml, 10 3.2 mmol). Then, heat the reaction mixture at 50 ° C for 1 hour. Shrink the reaction mixture in vacuo. And the residue was distributed between dichloromethane (20 ml) and water (20 ml). The organic phase was separated, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography Extract with ethyl acetate: hexane with a gradient [丨: 2 to 4: 1]. Combine the appropriate fractions and concentrate to provide the title compound (220 mg, 71%) with I5. Experimental MH + 391.2; expected 391.1 Another Synthesis Place a solution of Preparation 61 (1.20 g, 2.85 mmol) in methanol (25 ml) and platinum (5% on activated carbon) at room temperature in a large hydrogen atmosphere (15 lbs / 20 square inches) 3 The reaction mixture was filtered through an Arbocel® pad, washed with dichloromethane / methanol and the filtrate was concentrated in vacuo. Purified using an Extrudate 'box (silica dioxide, 25 g) The residue was stripped with digas methane / methanol [99: 1]. The appropriate fractions were combined and concentrated to provide the title compound (1.0 g). 164 200531963 Experimental MH + 391.1; expected 391.1 Preparation 52 4-methylbenzenesulfonic acid [1- (trifluorofluorenyl) cyclopropyl] fluorenyl ester at 0 ° C in dichloromethane (50 ml) (Trifluoromethyl) cycloprop 5-yl] methanol (J. Fluorine Chem., 20 (H, 109, 2, 95, 8 18 g, 58.4 mmol)) was added with triethylamine (50 Ml), each dimethylaminopyridine (713 mg, 5.84 mmol) and p-toluenesulfonyl chloride (111 g, 584 mmol). The reaction mixture was warmed to room temperature and stirred overnight. Under vacuum The reaction mixture was concentrated in Celite® and the residue was distributed between diethyl ether (250 mmol, 10 liters) and hydrochloric acid (0.5 M, 100 mL). The two layers were separated and tested with diethyl ether. (100 liters) extract the aqueous phase. Wash the combined organic phases with a saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dry (MgS04) and shrink in vacuum / Ten. Residue used Biotage ™ was quickly purified by a system of 40, with diethyl ether: cyclohexane gradient [5: 95 to 20: 80]. 15 Combined with appropriate fractions and concentrated to provide Title compound ( 11,8 g). H-NMR (CDC13): 0.810.089 (2Η), 1.09-1_16 (2Η), 2.44-2 · 48 (3Η), 4.09-4 · 12 (2Η), 7.33_7 · 39 (2Η), 7.77-7_82 (2Η) Preparation 53 3-cyano small [2,6-digas-4_pentafluorothiophenyl] -5- { [(Dimethylamino) methylene 20 methyl] amino 1-pyrazolylaminocarbamic acid 2- (trimethylsilyl) ethyl ester in 1,4-dihydrazone, mountain (100 ml) It was prepared in a solution of 78 (67 g, 140 mmol), diethylamine (2.14 ml, 15.4 mmol) and 2-trimethylsilylethanol (2.21 ml, 15.4 mmol) Diphenylphosphonium azide (3.34 liters' 15.4 millimoles) was added. The reaction mixture was heated under reflux for 3 hours 165 200531963. Afterwards: stir at room temperature overnight. In the reaction mixture Add acetic acid-(200 ml) 'and wash the mixture with hydrogen acid (M, 2 > 250 ml). Extract the aqueous phase with ethyl acetate (200 ml) and combine the organic phase with brine Wash (200 ml) 'dried (Na2S04) and concentrated in vacuo. Purify the residue (silica dioxide, 300 g) by column chromatography 5 [0: 100 to 5:95] methanol: dichloromethane eluent. Combine appropriate fractions and concentrate to provide the title compound (9.0 g). Experimental MΗ + 593.0; expected 593.1 similarly prepared Yes: 1〇M it 54 dichloro-4-pentafluorothiophenyl] dimethylamino) methylene] amino group 3- (trifluoromethyl group pyrazolylaminoamino acid 2 (Trimethylsilyl) ethyl ester prepared from 80 compounds (.22 g, 2.35 mmol), diphenylphosphonium hydrazide 15-based azide (0.56 ml, 2.59 mmol) and 2-silylethanol (0.37 ml, 2.59 mol) to provide the title compound (0.91 g). Experimental MH + 636.0; 636.1 is expected to prepare SN '· {3-cyano small [2,6-digas ice pentafluorothiophenyl] -4_nitro_out_pyrazole 20 _5Hn, n_dimethyl To a solution of nitroiminoformamidine in acetonitrile (15 ml) nitrate tetrafluoroborate (47 mg, 3.5 mmol) was added to prepare 8 mg (1.0 g, 2.9 mmol) . Then, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated saline solution, dried (MgS04) and concentrated in vacuo 166 200531963 to provide the title compound (960 mg). Experimental MH + 478.8; expected 479.0 similarly prepared Have:

Preparation Rla Rlb R2a R3a from Preparation MS (ES): M / Z [Mtf] (Estimated Mass) 56 sf5 Cl cyclopropyl, N'OH3 ch3 82 494.0; (494.0) 57 "H" 83 454.0; (454.0 ) 58 "H CN" 84 59 "Cl" OMe 93 氺 60 C i pyridin-4-ylmethyl) amino 94 514.9; (515.0) 61 cf3 c ", N ~ lsrCH3 ch3 85 氺 氺 62 ocf3 c" "87 437.0; (437.0) 63 scf3 c" "88 453.0; (453.0) 64 ochf2 c" "89 419.0; (419.0) ♦ ^ -NMR ^ DCls): 4.24-4.33 (3H)» 7.89-7.96 (2H) ** 1H-NMR (DMSO): 2.73-2.77 (3H) »3.06-3.09 (3H)» 8.20-8.27 (2H) 8.53-8.56 (lH) Preparation 65 10 l- [2,6-Digas-4_ ( Trifluorofluorenyl) phenyl] · 5 · (methylamino) -4-nitro-1H-pyrazole-3-carbonitrile 167 200531963 5-bromo-1- [2,6 at 55 ° C Dichloro-4- (trifluoromethyl) phenyl] -4-nitro-1H-pyrazole-3-carbonitrile (EP 295118 A1, 50 mg, 0.12 mmol) and methylamine (2M in tetrahydrofuran, 1.0 mmol, 2.0 mmol) for 2.5 hours. To the reaction mixture was added water (5 mL), followed by ethyl acetate 5 (5 mL). The two layers were separated and extracted with ethyl acetate. The aqueous layer (3x5 mL). The organic phase was dried (MgSO4) and concentrated in vacuo bound to provide the title compound (42 mg).

h-NMRCCDCU): 2.65-2 · 69 (3Η), 7.29-7 · 37 (1Η), 7.76-7.80 (2Η) 10 Similarly prepared from Preparation 92 are:

Preparation of R12 R13 MS (ES): M / Z [MH +] (Estimated mass) 66 Η 2-Morphoxyl-4-ylethyl 537.0; (537.0) 67 Η 2- (dimethylamino) ethyl 495.0; (495.0) 68 hydrazone-1-ylethyl 521.1; (521.0) 69 Η 2-piperidin-1-ylethyl 535.0; (535.0) 70 Me 2- (dimethylamino) ethyl 509.0 (509.0) Preparation 71 N '-[4-Amino-1- [2,6-dichloro-4-pentafluorothiophenyl] -3- (trifluorofluorenyl) -1H-pyrazole-5 -Yl] -N, N-dimethylamidoiminomethoxamine 168 200531963 Preparation in tetrahydrofuran (27 ml) 54 (0.91 g, i.43 mmol) solution, added via injection Tetrabutylammonium fluoride (57 ml, 5.7 mmol). The reaction mixture was then heated at 50 C for 1 hour. The reaction mixture 'was concentrated in vacuo and the residue was distributed between 5 gas stations and water. The organic phase was then separated, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography, and the gradient was: 4 to 2: 3] acetic acid, ethyl acetate: cyclohexane burning. Combine appropriate care and concentration to provide the title compound (0.64 g). Experimental MΗ + 491.9; Expected 492 〇10 to prepare 72 N′aminoamino cyano-1- [2,6 · digas-4_ (trifluoromethoxy) phenyl}, azole_5-*}- Preparation of N, N-difluorenimidine iminoformamide in methanol 62 (750 mg, ι · 91 mmol) solution was added platinum (10% by weight on carbon), and the mixture was placed under hydrogen The atmosphere is flat (15 square inches) for 8 hours. The reaction mixture was filtered through Aposir® and the eluate was concentrated in the air. The residue was distributed between Erqijiayuan and water and the organic phase was separated, dried and concentrated in vacuo to provide the title compound (650 mg). Experimental MΗ + 407.0; expected 407.0 20 Preparation of 73 Ν- {4-amino-3-cyano-1- [2,6-digas-4- (difluoromethoxy) phenyl] -1Η_pyridine Fluoren-5-yl} -Qimidine dimethylamidoiminomethoxamine From compound 64 (850 mg, 2.03 mmol) was prepared to provide the title compound (580 mg). 169 200531963 Experimental MH + 389.0; Expected 389 〇 Preparation of 74 N- (2-bromoethylcyano + [2,6_digas_4_pentafluorothiophenyl] -5 _ {[(dimethylamino ) Methylene] amino} _m_n than sialo_4_yl) methylamine 5 Preparation of amidine in acetic acid 02 ml) 3 (166 mg, 0.32 mmol) and 1,2-dimerol Add potassium carbonate (52 gram, G.38 $ mol) to a mixture of benzyl alcohol (0.14 ml 'U8 mmol). Then, the reaction mixture was heated under a thief overnight. The reaction mixture was concentrated in vacuo and the residue was allowed to distribute between H2O (30 mL) and water (30 mL). The organic phase was separated, dried (MgS04) and concentrated in the air to provide the title compound (154 mg). Experimental MH + 632.9; 632.9 is expected to prepare 75 Ν_ {5 · (allylamino) _3cyano_W2,6_digas_4_pentafluorothiobenzene 15yl] · 1Η · pyrazole Iyl (2,2,2-Trifluoroethyl) methanesulfonamide at 0C in Example 32 (3.0 g, 5.4 mmol) in tetrahydrofuran (27 ml) was added to a solution of sodium hydride (0.24 G, 5.94 millimoles). The mixture was warmed to room temperature and propylpropyl bromide (2.3 ml, 27.0 mmol) was added. Then, the reaction mixture was stirred at room temperature for 2 days. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography and washed with ethyl acetate: cyclohexane with a gradient of [5: 95 to 1.5]. The appropriate fractions were combined and concentrated to provide the title compound (1.34 g). Experimental MΗ + 594.1; expected 594.0 170 200531963 Preparation 76 3_Ga-N- (3_cyano small [2,6-digas_4_ (trifluoromethyl) phenyl] _5 _ {[(diamidylamine (Methylene) methylene] amino group 1H-pyrazol-4-yl) propane-1-sulfonamide under nitrogen in pyridine (2 ml) Preparation 51 (100 mg, 0.265 mmol) ) To the solution, 3-chloropropanesulfonyl chloride (34 microns, 0.28 mmol) was added, and the reaction mixture was stirred at room temperature overnight. To the reaction mixture were added ethyl acetate (10 ml) and water (10 ml), and the two layers were separated. The aqueous layer (x2) was extracted with ethyl acetate, and the combined organic phases were washed with hydrochloric acid (1M), water and brine, dried (MgS04) and concentrated in vacuo to provide the title compound (127 mg). Experimental MH + 529.1; 529.0 is expected to prepare 77 3-cyano small [2,6_digas_4_ (trifluorofluorenyl) phenyl (dimethylamino) methylene] amino) -1Η-pyrazole 4- (4-methylamino) ethyl 15-aminocarbamate 15 in a solution of 4,4,2,4-diamine (6 ml) 79 (420 mg, 1.0 mmol) , Add triethylamine (0.15 ml, 1.1 mmol) and 2 • (trimethylsilyl) ethanol (0.16 ml, 1.1 mmol), followed by dropwise addition of dibenzyl phosphate Nitrogen (0.24 ml, u millimoles). The reaction mixture was then heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue 20 was distributed between ethyl acetate (20 ml) and hydrogen acid (1 N, 20 ml). The organic phase was separated, dried and barked and concentrated in vacuo. The residue was purified by the tube layer method with a gradient of [1: 2 to 2: 2ethyl acetate: hexane; , ',. (5) Considerable concentration and concentration to provide the title compound (mg). Experimental MH + 535.4; expected 535.1 171 200531963 Preparation 78 3-cyano-l- [2,6-dichloropentafluorothiophenyl] -5-{[(dimethylamino) methylene] amine Preparation of sigma-ice acid in 95% (8.0 g, 16.25 mmol) 5 solution in anhydrous 0-bitalumine (80 ml) was added to the solution (10.9 g, 81.25 mmol). The reaction mixture was then heated under reflux overnight under nitrogen. The reaction mixture was concentrated in vacuo and the residue was distributed between ethyl acetate (200 ml) and hydrogen acid (2N, 200 ml). The organic layer was separated, washed with hydrogen acid (2N, 2 x 2000 ml) and brine (200 ml), dried (Na2SO4) and concentrated in vacuo. The residue (silica dioxide, 300 g) was purified by column chromatography, and was eluted with a gradient of [0: 5: 95_5 to 10:90] in methanol: dichloromethane. The appropriate fractions were combined and concentrated to provide the title compound (6.7 g). Experimental MΗ + 477.8; 478.0 is expected to be similarly prepared: 15 Preparation 79 3-cyano-1- [2,6-digas-4- (trifluoromethyl) phenyl] -5-{[(dimethylformate Aminoamino) methylene] amino} -1H-pyrazole-4-carboxylic acid from Preparation 90 (2.0 g, 4.61 mmol) to provide the title compound (1.5 g). 20 Experimental MH + 420.2; Expected 420.0 Preparation of 80 1- [2,6 · Digas-4-pentafluorothiophenyl] · 5 · [[(dimethylamino) methylene] amine}}-3 -(Trifluoromethyl) _1Η "pyrazole-4-conic acid From the compound of Preparation 91 (2.12 g, 4.1 mmol), the title 172 200531963 compound (1.22 g) was provided. Experimental MH + 521.0; 521.0 is expected to make 81 N _ {3-muryl-1- [2,6-monogas-4-pentathiothiophenyl] -1H-w than salsa-5 · »5 groups}- Add dimethyl ammonium sulfamidine at a temperature of -30 ° C to a solution of 86 (2.2 g, 3.9 mmol) in dry tetrahydrofuran (30 ml), and add vaporized isopropyl Magnesium (2M in N, N-dimethylformamide, 2.2 ml, 4.4 mmol). The reaction mixture was then heated to room temperature for more than 1 hour. To the reaction mixture were added a saturated aqueous solution of ammonium chloride 10 (10 ml) and ethyl acetate (excess). The organic layer was separated, washed ' dried (MgS04) with a saturated saline solution and concentrated in vacuo to provide the title compound (1.6 g). Experimental MH + 433.8; Expected 434.0 1 ^ 82 15 N '_ {3-cyclopropyl small [2,6_digas-4-pentafluorothiophenyl] -1H-pyrazole-5 · Kib N, Preparation of N-dimethylphosphonium iminoformamide under heating in N, N-dimethylphosphonium amine acetal (15 mL) 96 (3.3 g, 8.40 mmol) ) Solution for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was taken up on silica, purified by 20-column chromatography, and extracted with cyclohexane / ethyl acetate [4: 丨]. The appropriate fractions were combined and concentrated to provide the title compound (3.7 g). Experimental MH + 449.0; 449.0 is expected to be similarly prepared: 173 200531963

R1a

Preparation Rla Rlb R2a R3a From Preparation MS (ES): M / Z [ΜΗ "] (Estimated mass) 83 sf5 Cl Η Η 97 409.0; (409.01) 84 "H CN" 99 400.0; (400.0) 85 cf3 Cl ""氺 * 氺 * 86 sf5 "" I 氺 氺 氺 氺 氺 氺 87 ocf3 "" Η 104 392.0; (392.0) 88 scf3 "" "103 408.0; (408.0) 89 ochf2" "" 106 374.0; (374.0) 90 cf3 "" -C〇2Me 107 434.2; (434.1) 91 sf5 "cf3" 108 535.0; (535.0) * 5-amino-l- [2,6-dichloro-4- (trifluoromethyl) phenyl] -1H-pyrazole-3-nitrile (WO 9839302 Al) ** 5-amino-1- [2,6-digas-4-pentafluorothiophenyl] -4-iodo-1H-pyrazole- 3-Guess (WO 9824761 A1, WO 9804530 Al) φ 5 *** 1H-NMR (DMSO): 2.63-2.65 (3H) »2.96-2.98 (3H) ^ 6.61-6.63 (1H)» 8 · 13-8 · 15 (1Η), 8.16-8 · 18 (2Η) **** 1H-NMR (CDC13): 2.77-2.81 (3H) »3.02-3.05 (3H) ^ 7.78-7.81 (2H) ^ 8.21- 8.24 (1H) 10 Preparation 92 Preparation of 5-mo-1- [2,6 · dichloropentafluorothiophenyl] -4nitro_1H4 oxazonitrile in acetonitrile (50 ml) 98 (5.0 g, 12.0 millimolar) and bromoform (16 ml, 18.3¾ mole), dropwise Three acid butyl ester (8 mL, 67 2.3 mmol) 'Then, the reaction mixture was heated 17420053196316 hours at hunger. The reaction mixture was concentrated in vacuo, and the residue was recrystallized from cyclohexane / ethyl acetate [20: 1] to provide the title compound (31 g). ^ -NMR ^ DCls) · 7.92-7.97 (2H) Preparation of 93 5 —Gas_4_pentaIthiophenyl] _5 · methoxy_ΐΗϋ3_nitrile in acetonitrile (15 ml) 100 (650 Mg, 71 · 71 mmoles) solution was added with carbonic acid (708 mg, 5.13 mmoles) and NaCl (0.32 ml '5.14 ¾ moles)' and the reaction mixture was heated at 40 ° C overnight . The reaction mixture was shrunk in vacuo and the residue was distributed between water (30 ml) 10 and ethyl acetate (30 liters). The two layers were separated and washed with brine (1 mL). The organic layer was dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography and extracted with hexane: ethyl acetate with a gradient of [5 ·· 1 to 3: 1]. The appropriate fractions were combined and concentrated to provide the title compound (474 mg). Experimental MH + 393.9; 394.0 15 is expected to prepare M 1- [2,6-digas-4-pentafluorothiophenyl] -5-[(command; bite-4-ylfluorenyl) amino]- 111-u Bijun-3-Riding 5-amino-l- [2,6-digas-4-pentafluorothiophenyl] -1H-pyrazole-3_ in toluene (20 ml) To a mixture of nitrile (WO 9306089 A, 1.00 g, 2.63 mmol) 20 and p-toluene acid (5 mg), was added 4% acetic acid (0.35 ml, 3.68 mmol). Then, the reaction mixture was heated under reflux for 1.5 hours. The reaction mixture was distributed between ethyl acetate and water and the organic layer was separated, washed with water, dried (MgS04) and concentrated in vacuo. A solution of the residue in methanol (48 ml) was added to pendant sodium hydride (48 mg, 1.26 mmol 175 200531963 ears) 'and the mixture was shaken at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was distributed between ethyl acetate and water. An organic layer was separated, dried (MgSO4) and concentrated in vacuo to provide the title compound (1.26 g). 5 Experimental MH + 470.0; expected 470_0 to prepare 95 3 -amino-1-[2,6_monogas-4_pentafluorothiophenyl] -5-{[(dimethylamino) methylene] amine Gib 1H_pyrazole-4-methyl carboxylate • Preparation of 86 (50.0 g, 89.3 mmol) in methanol 10 (500 ml) by heating in carbon monoxide (150 psi) at 65 ° C Ear), triethylamine (24.9 ml, 178.6 mol) and [1,1'_bis (diphenylphosphino) bis (cyclopentadiene) ferrous iron] dichloropalladium (II), dichloromethane (2.0 grams) of the mixture for 8 hours. Water (2 liters) was added to the reaction mixture and the mixture was stirred for 30 minutes. The precipitate was collected using transition and air-dried to provide the title compound (43.3 g). 15 iH-NMR (DMSO): 2.67-2 · 70 (3Η), 3.0 · 00-3 · 〇3 (3Η), 3.72-3 · 77 (3Η), 8.36 · 8 · 38 (1Η), 8.41 · 8 · 43 (2Η) _ Preparation 96 3-¾propyl-1- [2,6-digas-4-pentafluorothiophenyl] -1 Η 11 ratio σ Preparation of 5-amine in 2-propanol (30 ml) 101 (1.55 g, 14.2 mmol) dissolved in 20 solution, added to prepare 102 (4.28 g, 14.2 mmol) ). The reaction mixture was heated under reflux for 16 hours. The mixture was cooled to room temperature, and concentrated sulfuric acid (0.1 ml) was added, followed by acetic acid (0.6 ml). Then, the reaction mixture was heated under reflux for another 4 hours. The reaction mixture was concentrated in vacuo, and to the residue were added water and a saturated aqueous sodium bicarbonate solution (30 ml). Extract the noodles with vinegar 176 200531963 ethyl acetate, dry (MgS04) binder extracts and absorb the residues of agricultural chemicals in vacuum onto the dioxide and purify by column chromatography with a gradient of [ 4 ·; [to 2: cyclohexane burning: ethyl acetate _ stripping. Combine the appropriate fractions and concentrate to provide the title compound (# 5 Preparation 97 1- [2,6-dichloro · 4-pentafluorothiophenyl] _1H_pyrazole_5_amine in methanol (40 mL ) In a solution of Preparation 102 (4.0 g, 13.2 mmol) with ethylenediamine tetraacetic acid disodium salt (catalytic amount), heated to reflux, and added 2-gas acrylonitrile (3.2 ml, 39 6) dropwise. MM). Before adding sulfuric acid (10 concentrated, 1.2 ml, 2U mM), the reaction mixture was heated under reflux overnight. After heating under reflux for another 6 hours, anhydrous sodium carbonate (4.2 G, 39.6 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and water (150 ml) was added to the residue. The mixture was stirred for 15 hours and filtered using The resulting precipitate was collected, washed with water and dried to provide the title compound (4.2 g).

Experimental MH + 354.0; expected 354.0 MM9S 5-amino-l- [2,6-digas-4-pentafluorothiophenyl] -4-nitro-1H_pyrazole-3-nitrile 20 in dihum To a solution of 55 (10.0 g, 20.9 mmol) in thorium (160 ml), methanol (20 ml) and hydrogen acid (10%, 20 ml) were added. The reaction mixture was heated at 90 ° C for 56 hours, and additional hydrogen acid (concentrated, 2 mL) was added. The reaction mixture was then heated at 90 ° C for another 15 hours. To the reaction mixture were added an aqueous sodium bicarbonate solution (50 ml) and ethyl acetate (177 ml 200531963) (100 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 1000 mL). The combined organic phases were washed with brine, dried (MgS04) and concentrated in vacuo. The residue was triturated with dichloromethane to provide the title compound (6.6 g). Experimental MH + 424.0; expected 424.0 5 Preparation of 99 5-amino-l- [2-chloro-4-pentafluorothio-phenyl] -ΐΗ-π ratio 嗤 _3_ Riding in sulfuric acid (concentrated, 1.75 ml) Carefully add sodium nitrite (432 mg, 6.26 mmol), followed by glacial acetic acid (2.5 ml). At 10. The solution was stirred at 0 ° C for 1 hour before preparing 10 105 (1.44 g '5-69 mmol) in glacial acetic acid (1 ml) dropwise. The mixture was heated at 50 ° C for 1 hour, allowed to cool to room temperature, and then added dropwise to ethyl 2,3-dicyanopropionate (1 ml) in acetic acid (1 ml) and ice water (2 ml) Hainzl, D ·; Cole, LM ·; Casida, JE · Chemical Research in Toxicology (1998), 11 (12), 15 1529- 1535, 864 mg, 5.69 millimoles). The reaction mixture was then stirred at room temperature for 45 minutes. The reaction mixture was poured into water (200 ml) and the mixture was extracted with methane (100 ml). An aqueous ammonium hydroxide solution (880, 25 ml) and water (25 ml) were added to the organic extract, and the mixture was shaken at room temperature overnight. The reaction mixture was distributed between dichloromethane (100 ml) and water (100 ml). The organic phase was separated, dried (MgS04) and concentrated in vacuo to provide the title compound (700 mg). Experimental MH + 345.1; expected 345.0 Preparation of 100 1- [2,6-monofluoro-4-pentafluorothiophenyl] -5-yl-3-carbonitrile 178 200531963 Sodium oxalic acid (1.32 g ' 19.1 mmol) was carefully added to sulfuric acid (concentrated, 6.8 ml) while cooling the solution to 0 ° C. The solution was heated to 60 ° C for 30 minutes, allowed to cool, and then diluted with acetic acid (12 mL). To this solution, 2,6-digas-4-pentafluorothiophenylamine 5 (WO 9421606 A 5.0 mg, 17.4 mmol) was added in acetic acid (11 ml) and the temperature was at 55 ° C. The reaction mixture was heated for 1 hour. 2-fL radicals in white acetic acid (Hall, Κ ··, JR ·; Ykman, P ·, acetic acid (24 ml) and water (36 ml) J. Am. Chem. Soc. (1975), 97 (4), 800-807, 3.09 g, 18.1 mmol.), Dropwise addition of a diazonium salt solution, followed by water (42 ml) 10 Sodium acetate (24.2 g). 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 dioxane (4 x 60 mL). The combined extracts were then washed with ammonium hydroxide (48 mL), dried and concentrated in vacuo. To a solution of sodium methoxide (25 wt.%, 11.5 ml, 50.1 mmol) in methanol (45 ml) was added dropwise a solution of the residue in methanol (100 ml). Then, 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 pH of this solution was adjusted to 1 by adding hydrochloric acid (4N), and the mixture was extracted with dioxane (3 x 100 ml). The combined extracts were dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography 20 and eluted with hexane / ethyl acetate [3: 1]. The appropriate fractions were combined with "Cinnamon 'to provide the title compound (4.5 g). Experimental MΗ + 379.8; expected 380.0 Preparation of 101 3-cyclopropyl-3_oxopropionitrile 179 200531963 Cyanoacetic acid in tetrahydrofuran (80 ml) and methane (40 ml) at 0 ° C (4.25 g, 50.0 mmol), isopropylmagnesium chloride (2M in tetrahydrofuran, 50 ml, 100 mmol) was added. In a separate reaction vessel, at 0 ° C, 1,1 carbamobiimidazole (0.55 g, 25.0 mmol) was added to cyclopropylacetic acid (0.8 ml) in tetrahydrofuran (80 ml). 2.15 grams, 25.0 millimoles). The two mixtures were combined with additional tetrahydrofuran (60 ml), and the reaction mixture was stirred at room temperature for 60 hours. Hydrochloric acid (2N) was added to the reaction mixture at 0 ° C, and the mixture was stirred for 1 hour. The mixture was concentrated in vacuo and water was added to the residue. After extraction with diethyl ether 10 (2 × 1000 ml), the combined extracts were washed with saturated aqueous sodium bicarbonate solution (60 ml) and water (60 ml), dried (MgS04) and dried in vacuo. Fine 'to provide the title compound (1.5 g). W-NMRCCDCh): 1 · 02_1 · 08 (2Η), 1 · 13 · 1.18 (2H), 2 · 03 · 2 · 09 (1Η), 3 · 57-3 · 60 (2Η) 15 Preparation 102 [2, 6-Dichloro-4-pentafluorothiophenyl] hydrazine at 10 ° C in a mixture of sulfuric acid (concentrated, 24 ml) and sodium nitrite (6.0 g, 87.0 mmol) 2,6-Dichloro-4-pentathiophenylamine (WO 9421606 A1, 23.5 g, 82.0 mmol 20 mol) in glacial acetic acid (92 ml) was added over 20 minutes. The reaction mixture was stirred at 25 ° C for 20 minutes, and then heated at 60 ° C for 1 hour. The reaction mixture was cooled to 5 ° C, and gasified tin (π) (65. 6 g, 0.35 mol) in hydrogen acid (concentrated, 56 ml) was added. After stirring for 30 minutes, the precipitate was collected by filtration and added to ammonia (400 ml) and ice (100 ml). This mixed 180 200531963 compound was extracted with diethyl ether (5x200 ml), the combined extracts were dried (MgS04) and concentrated in vacuo to provide the title compound (19.3 g). 4-NMR (CDC13): 3.61 · 3.28 (2Η), 5.75-5 · 91 (1Η), 7.60-7 · 65 (2Η) 5 Preparation 103 5-amino-1- { 2,6-Dichloro-4-[(difluoromethyl) thio] phenyl} -1 | ^ -13 is more caustic sodium nitrite (224 mg, 3.25 mmol) Add to sulfuric acid (concentrated, 1 ml), keeping the temperature not higher than 30 ° C. After stirring at 15 ° C for 1 hour, acetic acid (2 ml) was added, followed by preparation 10 109 (850 mg, 3.24 mmol) in acetic acid (3 ml). Then, the reaction mixture was heated at 50 ° C for 1 hour and cooled to room temperature. Ethyl 2,3-dicyanopropionate in acetic acid (5 ml) (Hance, D ·; Kor, LM ·; Cassida, JE · Chemistry of Toxicology (1998), 11 (12 ), 1529-1535, 500 mg, 3.29 mmol), ice water (5 ml) was added, followed by dropwise addition of the diazonium salt 15 solution at 0 ° C. After the addition was complete, sodium hydroxide (6 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through Aposir® and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane and water and the organic phase was separated, dried (NajO4) and concentrated in vacuo to provide the title compound (1.0 g). 20 Experimental MH + 353.0; expected 353.0 I for 104 5-amino_1- [2,6-digas-4_ (trioxymethoxy) phenyl] _ih- ° ratio 嗤 _3-nitrile in sulfuric acid (18M , 54 ml) was added sodium nitrite (13.9 g, 201.2 hamol) 'and the solution was stirred at 15 C for 1 hour. To this solution was added 181 200531963 acetic acid (200 ml), followed by 2,6-digas-4- (trifluorofluorenyloxy) aniline (45.0 g, 182.9 mmol) in acetic acid (90 ml). ), Make sure the solution temperature is not higher than 20 ° C. After the addition was complete, the mixture was heated at 50 ° C for 1 hour, cooled to room temperature, and added dropwise to 2,3-dicyanoic acid in acetic acid (115 ml) and ice-cold water 5 (145 ml). Ethyl Propionate (Heinz, D .; Kal, LM; Cassida 'JE · Chemical Research in Toxicology (1998), 11 (12), 1529-1535, 27.8 g, 182.9 mmol) . Then, the reaction mixture was stirred at room temperature overnight. Dichloromethane (500 ml) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The two phases were separated and the organic phase (200 mmol) was washed with water 'and ammonia (0.88, 400 ml) was added dropwise, and the temperature of the mixture was maintained below 10 ° C. The mixture was stirred at room temperature overnight, the organic phase was separated and concentrated in vacuo. The residue was recrystallized from toluene / pentane [2: 1] to provide the title compound (22.4 g). Experimental MH + 337.0; Expected 337.0 15 JA105 4- (pentafluorothio) phenylamine in acetonitrile (15 ml) at 45C (WO 9421606 A To a solution of 1.29 g, 5.89 mmol, N • chlorosuccinimide (786 mg, 5.89 mmol) was added. Then, the reaction mixture was stirred at 4rc for 20 hours. The reaction mixture was concentrated in vacuo and the residue was distributed between methane (20 mL) and water (20 mL). The organic phase was separated, dried and concentrated in vacuo to provide the title compound (g). Experimental MH + 254.1; Expected 254.0 ^ 106 182 200531963 5-amino-l- [2,6-digas difluoromethoxy) phenyl] -1H-pyrazolenitrile at 15 ° C in sulfuric acid (concentrated , 21 ml) was added sodium nitrite (4.8 g, 69.6 mmol). After stirring for 1 hour, glacial acetic acid (17.3 ml) was added, followed by the preparation 110 (13.8 g, 5 60 · 3 mmol) in acetic acid (33.8 ml) dropwise, and the mixture was mixed. The temperature is kept below 25 ° C. The solution was heated at 50 ° C for 1 hour, cooled, and added dropwise to ethyl 2,3-dicyanopropionate (Heinz, D .; LM, Kasida) at 0 ° C. '' JE · Toxicology Chemical Research (1998), 11 (12), 1529-1535, 10.6 g, 69-6 mol), a mixture of acetic acid (42.8 ml) and ice / water (55 ml). The reaction mixture was then stirred at room temperature overnight. To the reaction mixture was added methane (300 ml) and the mixture was stirred. The two layers were separated and the organic layer was washed with water. To the organic layer were added ammonium hydroxide (concentrated, 125 ml) and ice, and the mixture was stirred at 5 ° C for 4 hours. The organic layer was separated again and stirred overnight with activated carbon. The mixture was filtered through a plastic plug and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Beautigue, Dioxide '90 g) and extracted with digas methane. The appropriate fractions were combined and concentrated to provide Preparation 136 (3.1 g). Experimental MH + 319.0; 319.0 107 2 0 aminocyano · 1_ [2,6-digas-4- (trifluoromethyl) phenyl] · 1H_pyrazole | The carboxylic acid motif will be in methanol ( 150 ml) of 5_amino small [2,6 · dipantrol (trifluoromethyl) benzyl] _4_ moth-1H_pyrazole-3_nitrile (WO 9828278 A 18 g, 40 3 mmol Mol), a mixture of [1, Γ-bis (diphenylphosphino) bis (cyclopentadiene) ferrous] digas palladium 183 200531963 (11) (600 mg) and triethylamine (10 ml) When placed under pressure ☆ and heated at 60 ° C in carbon monoxide (100 psi). The reaction mixture was filtered through a plug of plastic and the solution was concentrated in vacuo. To the residue was added ethyl acetate, and the solution was washed with hydrochloric acid (0.2 M) and water. The organic phase is then separated, dried and reduced in vacuo. The residue was purified by flash column chromatography and eluted with ethyl acetate / hexane. Combine the appropriate fractions and concentrate to recrystallize the residue from methanol to provide the title compound (100 mg).

Experimental MΗ + 379.0; expected 379.0 10 Preparation of 108 5-amino-Η2,6-dichloro. 4-pentafluorothiophenyl] _3 • (triamethylazole-4-carboxylic acid ethyl ester at 0C In a mixture of 10 (395 g, 13.1 mmol) and potassium carbonate (2.16 g, 15.6 mmol) prepared in diethyl ether (15 ml), 15 drops were added in (2Z) _3-Chloro_2-cyano-4,4,4-trifluorobut-2-enoate hydrazone_ (W〇87〇3781 A1, 2.79 g in diethyl ether (6 ml)) , Ϊ́3 ιmole). Then, the reaction mixture was stirred at room temperature overnight. The reaction mixture was allowed to absorb on silica in advance and purified by column chromatography with a gradient of [4 · 1 to 2 · 1] of hexane: ethyl acetate extraction. Combined with appropriate concentration and concentration to provide the title compound (2.3 g). H NMR (CDC13): 3.86-3_88 (3Η), 5.30 -5 · 40 (2Η), 7.86-7.91 (2Η) Preparation 109 2,6-Digas · 4-[(trifluorofluorenyl) thio] phenylamine 184 200531963 at 50 ° C in acetonitrile (50 (Ml) of 4-[(trifluoromethyl) thio] benzylamine (EP 546391A2, 4.8 g, 25.0 mmol) was added to chlorosuccinimide (6 ·· 7 g, 50.0 mmol). Then, the reaction mixture was stirred at 50 ° C. for 1 hour. To the reaction mixture was added water (150 mL), and 5 was extracted with dichloromethane (100 μm). L) of this mixture. The combined extract was dried (MgS04) and concentrated in vacuo to provide the title compound (10 g). Preparation 110 2,6-Digas-4- (difluoromethoxy) A solution of phenylamine in 4-[(difluoromethoxy) methyl] aniline (150 10 g, 94.3 mmol) in acetonitrile (150 ml) was added with n-gaso succinimide (25.2 g , 18.9 mmol), and the reaction mixture was stirred under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue was distributed between diethyl ether (500 mL) and water (125 mL) The organic layer was separated, washed with aqueous sodium thiosulfate solution, water and brine, dried (MgS04) and treated with activated carbon. Then, the solution was filtered and concentrated in vacuo. Extracted with hexane (2x300 ml) This residue was concentrated in vacuo to combine the extracts to provide the title compound (13.8 g). Experimental MΗ + 228.0; Based on 228.0 Preparation of 111 20 N- (3-cyano-1- [2,6-digas-4_pentafluorothiophenyl] -5-{[3- (diamidoamino) propyl) amine Preparation of 1 (1-oxazolyl-4-yl) -N- (methylfluorenyl) methanesulfonamide at 0 ° C in dichloromethane (15 ml) 33 (55 mg, 1.0 mg) To a mixture of trimole) and triethylamine (0.33 mL, 2.3 millimoles), methanesulfonylsulfonyl gas (0-19 mL, 2.3 millimoles) was added dropwise. The reaction was mixed and heated to room temperature and stirred for 16 hours. To the reaction mixture was added water (10 ml) and the two layers were separated. The aqueous layer was extracted with dichloromethane (2x20 mL) and the combined organic phases were washed with salt. Water, dried (MgS04) and concentrated in vacuo to provide the title compound (600 mg). 5 Experimental MH + 635.0; Expected 635.0 [Schematic description 3 (none) [Description of main component symbols] • (none)

186

Claims (1)

200531963 10. Scope of patent application: or its medicine 1. Compounds or solvates of formula (I), veterinary or agronomically acceptable salts 5 10 Where: Sole = Benyl or Heteroaryl 'which may be optionally substituted by-or more groups each independently selected from the group consisting of: hydrazone, cyano, meridian, c ―-roasting group, _s ( 0) nCi ▲ group, _s (〇) nC "6ki group and pentathio group; 15 R2 represents hydrogen, i-based, cyano, schottky, Ci • ring, c_alkenyl, C2-6 alkenyl, C2-6_alkenyl, C2_6 alkynyl, C2-6_alkynyl, alkyl, _S (〇) nCi 6 haloalkyl,-(c0 3 alkyl cycloalkyl, Cw alkyl alkynyl (which can optionally be substituted by d 6 alkoxy substituted haloalkyl fluorenyl (which can optionally be 6-alkoxy, phenyl, het substituted),-(C0_3alkylene) -N (Ra) Rb,-(CV3alkylene) -C (0) NRaRb or _ (c〇alkylene -N (Rc) C02R6; R3 represents Cw alkyl, Ck haloalkyl, C2-6 alkenyl, C2.6_,-(c0_3alkylene) -c3_8cycloalkyl,-(Cmalkyl Alkyl) -s (conei6alkyl,-(Cwalkylalkyl),-(C0-3alkyl) -N (Ra) Rb,-(C0_3alkyl) Phenyl,-(C0_3endenyl) hexyl, 187 20 200531963-(C2_3endenyl) -phenyl,-(C2_3endenyl) -het, C! _6alkylfluorenyl, halofluorenyl Or -N (Re) C02R6; R4 represents hydrogen, Cw alkyl, alkyl, _ (CG_3alkylene) -R7 or-(Chalkylene) -R8; 5 or R3 and R4 with nitrogen and sulfur atoms Joined together to form a 4- to 7-membered ring; R5 represents hydrogen, hydroxyl, i group, Cm alkyl, Cw haloalkyl, C2_6 alkenyl, C2_6 haloalkenyl, C w alkoxy, Cw haloalkoxy, N = C (R1G) (C0_5alkylene) -Rn or -N (R12) R13; R6 represents Q_6 alkyl or Cw haloalkyl; 10 R7 represents (: 3-8 cycloalkyl, -S (0) nR9, phenyl, het, -C02R6 or C (0) N (Ra) Rb; R8 represents hydroxyl, Q-6 alkoxy, Cw haloalkoxy, cyano, -N (Ra) Rb or -0-C (0) R6; R9 represents Cw alkyl, Cw i alkyl, c3-8 cycloalkyl, 15 -N (Ra) Rb, phenyl or het; R1G represents hydrogen, Cm Alkyl or Q_6 haloalkyl; R11 represents hydrogen, hydroxy, Q_3 alkoxy, -N (Ra) Rb, phenyl, het or C3_8 cycloalkyl, with the condition that _N = C (R1G) (CG_5 butane -Ru is not -N = CH2; 20 R12 represents hydrogen, Cw alkyl, Cw haloalkyl, Cw alkenyl or haloalkenyl; R13 represents hydrogen, Cw alkyl, Cwi alkyl, C! _6 alkenyl , Cw haloalkenyl, c3_8 cycloalkyl, phenyl, het,-(Cw extended alkyl) _R14, -C (0) pR15 or -CONCR ^ XCw extended alkyl) -R17; 188 200531963 R14 represents hydroxyl, Cm Alkoxy, cK6l | alkoxy, c3_8 cycloalkyl, phenyl, het, or -N (Ra) Rb; R represents Ci_6 alkyl, Ck halo, or _ ((^ 16 extending group) -Ci_3 alk Oxygen; R16 represents hydrogen, Ci_6 alkyl or Ci-6_ alkyl; R17 Table hydrogen or N (Ra) Rb; Ra and Rb each independently represent hydrogen, CK6 alkyl, Cl_6 haloalkyl, C2 · 6 dilute or C2 · 6 alkenyl; or Ra additionally represents _ (C () _ 3 (Cycloalkyl) _c3_8 cycloalkyl, _ (CG-3alkyl) · phenyl or-(C0-3alkyl) -het; 4Ra and 0 together form a 4- to 7-membered ring, which can be Selectivity is substituted by one or more groups each independently selected from the group consisting of self-radical, hydroxy, Cl_6 alkyl, Cl-6_alkyl, Cw alkoxy, and (^ -6_alkoxy; Re Represents hydrogen, Ci-6 alkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 haloalkenyl,-(C0-3 alkylene) -C3_8 cycloalkyl,-(C0_3 alkylene) -phenyl Or-(C0-3alkylene) -het; η represents an integer selected from 0, 1 and 2; P represents an integer selected from 1 and 2; wherein het represents a 4- to 7-membered heterocyclic group Group, which may be aromatic or non-aromatic, and which contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and mixtures thereof; wherein heteroaryl represents a 5- or 6-membered aromatic ring comprising 1-3 heteroatoms selected from N, 0 and S, or 4 N atoms to form a tetrazolyl group; where valence is acceptable, either phenyl or het is optional Is substituted by one or more substituents each independently selected from the group consisting of: dentyl, hydroxyl 189 200531963, cyano, nitro, Cw alkyl, Ci 6i alkyl, Ci 6 alkenyl, Cl 6 halogenated Group, Q · 6 alkoxy group, Cu alkoxy group, c3-8 ring alkynyl group, Ci alkyl group, d alkyl group, Cl-6 alkylcarbonyloxy group, Cw alkoxycarbonyl group and NRaRb; 5 Wherein the cycloalkyl group may be optionally substituted by one or more groups each independently selected from the group consisting of: i group, C1_6 alkyl group, c16_alk '^ 1-6 alkenyl group, Cm haloalkenyl group, hydroxyl group, Cl_6 Alkoxy and oxoalkoxy; and any of the alkylene or alkylene groups may be optionally substituted with one or more halo 10 groups. 2. If the compound in the scope of application for the first item of the patent, wherein ri may be benzyl, it carries a gas substituent at the 2nd and 6th positions, and at the * position has a substituent selected from the following: three Fluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio and pentafluorothio. 15) · If the compound in the scope of patent application No. 1 or 2, r2 may be selected from hydrogen, cyano, CK6 haloalkyl, C3-8 cycloalkyl (such as cyclopropyl), Cl-6 alkyl and- C (0) N (Ra) Rb. 4. The compound according to item 3 of the patent application, wherein R 2 is cyano. 5. The compound according to any one of claims 1 to 4, wherein R3 2o can be selected from CN6 alkyl, Cwi alkyl, C3-8 cycloalkyl,-(Cw-alkyl) -SCCOnCu alkyl -N (Ra) Rb, Cw alkyl, -N (Ra) C02R6, this group (which may be optionally substituted by one or more halo groups), and a benzyl group. 6. The compound according to item 5 of the patent application, wherein R3 is a fluorenyl group. 7. The compound according to any one of claims 1 to 6, wherein R4 190 200531963 can be selected from hydrogen, Ci-6 alkyl, Q_6 haloalkyl, and (C0_3 alkylene)- C3_8 Cycloalkyl, cyanomethyl, 2-Ethyl, _ (Ci 2alkyl) _het, _ (c〇3alkyl) > phenyl,-(C (Malkylene) -S (0) nR9,-(c! _3alkylene)> 0_C (0) r6,-(Ci-3alkylene) C (0) N (Ra) Rb, and _C02R6. 5 8 · If the scope of patent application The compound according to item 7, wherein R4 may be selected from the group consisting of amidine, methyl, ethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methyl maple, Trifluoromethylfluorenyl, 2,2,2-trifluoroethylfluorenyl, aminothiosulfone, Ν, Ν-dimethylaminofluorenyl, methylfluorenylmethyl, cyclopropyl, mount Butyl, cyclopropylmethyl, [_ (trifluoromethyl) cyclopropylmethyl, cyano-0 methyl, methoxycarbonyl, triazolylethyl, pyrimidin-4-ylmethyl, 1,2,4- * oxadiazol-3-ylmethyl, pyrazol-3-ylmethyl, 1-methyl-1fluoren-imidazol-2-yl, 5-methyl-isoxazole_3 -Methyl, 2-pyridylethyl, ethylaminomethyl, benzyl, and 4-fluorobenzyl. The compound of any one of the patent scope 1 to 8, wherein R5 can be selected from hydrogen, halo, c! _6 alkoxy, -N = C (H) RU (where R11 • can be ethoxy, N, N-dimethyl or phenyl) and _NRi2Ri3. 10. The compound according to item 9 of the scope of patent application, wherein R5 is an amine group. U. A compound of formula (I), which may be selected from: N -{5-Amino-3-cyano · 1_ [2,6-digas-4-pentafluorothiobenzyl 20 hydrazine > 111_pyrazol-4-yl} _ > 1- (2,2 -Difluoroethyl) methanesulfonamide; N · {5-amino-3-cyano · 1- [2,6-digas-4-pentafluorothiophenylphosphonium-pyrazol-4-yl } _1,1,1_trifluoromethylmethanesulfonamide; amine-3-cyano-1- [2,6-digas-4_ (trifluoromethyl) phenyl] -1Η-pyrazole- 4-yl} -3,4-difluorobenzenesulfonamide; 191 200531963 N- {5-amino-3-cyano-l- [2,6-dichloro-4_ (trifluorofluorenyl) phenyl ] -1H-pyrazole · 4-*}-N- (cyclopropylmethyl) methanesulfonamide;. N- {5-amino-3-cyano-1- [2,6-dichloro- 4- (trifluoromethyl) benzene.yl] -1H-pyrazol-4-yl} -sense (cyanomethyl) methanesulfonamide; 5 N- {5-amino-3-nitro-1 · [2,6-Dichloro-4- (digasmethyl) phenyl] -1H-pyrazole-4 -Yl} -sense (pyridin-2-ylmethyl) methanesulfonamide; N- {5 -amino-3-cyano-1- [2,6-dichloro-4- (difluoromethyl) Phenyl] -1H-pyrazol-4-yl} -benzylmethanesulfonamide; # N- {5-amino-3-cyano-1- [2,6 · dichloro_4_ (trifluoro Methyl) benzene 10-yl] · 1Η-pyrazole-4 · kib N- [2- (dimethylamino) ethyl] methanesulfonamide; 'Ν- {5-amino-3-cyano -1- [2,6-dichloro-4- (trifluorofluorenyl) phenyl] -1H-pyrazol-4-yl} -1- (methylfluorenyl) methanesulfonamide; N- {5 -Amino-3-anyl-1- [2,6-dichloro-4- (difluoromethyl) benzene 15-yl] -1H-pyrazol-4-yl} -sense (2-hydroxyethyl) Methanesulfonamide; N_ {5 -amino-3-lactyl-1- [2,6-digas-4- (digasmethyl) benzene_yl] -1H_pyrazol-4-yl}- Qin [(methylthio) methyl] methanesulfonylamine; N- {5-aminoamino-3-anyl-1- [2,6-digas-4- (difluoromethyl) phenyl]- 111-11 better than sial-4-yl} -1 ^-(methylmapleyl) diamine, 20 N- {5-amino-3-amino-1- [2,6-digas -4- (difluorofluorenyl) phenyl] -1H-pyrazol-4-yl} -qin [(dimethylamino) fluorenyl] methanesulfonamide; N- {5-amino-3- Cyano · 1- [2,6-Digas_4- (trifluorofluorenyl) phenyl] -1Η-pyrazole _4-yl} -sense (methylfluorenyl) methanesulfonamide; Ν- {5-amino-3-cyano-1_ [2,6-dichloro-4- (trifluoromethyl) benzene 192 200531963 Group] -1H-pyrazol-4-yl} methanesulfonamide; N_ {5-amino_3 · cyano_1- [2,6-dichloro · 4_ (trifluoromethyl) phenyl]- 1Η-pyrazole-4-ylbu phenylmethanesulfonamide; (E) -N- {5-amino-3-cyano-1- [2,6-digas-4_ (trifluoromethyl) Phenyl) benzene 5yl] -1Η-pyrazole-4-ylb 2.phenylethylenesulfonamide; Ν_ [5-amino-1_ [2,6-dichloro-4-pentafluorothiophenyl] -3- (trifluoromethylpyridin-4-yl) -N · (methylphosphino) methanediamine; 5-amino-1- [2,6-dichloro-4- (trifluoromethyl) Phenyl] phenyl] -4- (1,1_bioxoisothiazolidine-2-yl) _1H_pyrazole-3 · nitrile; 10 N- {5_amino_3 · amino_1 · [ 2,6-dichloro-4_ (trifluoromethyl) phenyl] -1'-pyrazole-4-ylb 1,1,1-trifluoro-N-methylmethanesulfonamide; Ν- {5_ Amino_3_cyano-1_ [2,6 · digas_4 · (trifluoromethyl) phenyl] -1Η-11_4_yl_N_ (cyclopropylmethyl) -1, 1,1_trifluoromethanesulfonamide; 15 Ν_ {5-amino_3_cyano_1- [2,6_digas-4- (trifluoromethyl) benzyl] -1H_pyridine Azole-4-kib N- (2,2,2-tri Fluoroethyl) methanesulfonamide; N- {5 -amino_3_cyano_1_ [2,6_digas-4- (trifluoromethyl) phenyl] -1H-pyrazole-4- } -1,1,1_trifluoro · N- (methylfluorenyl) methanesulfonamide; 2〇 · {5_amino_3_cyano small [2,6_digas-4- (Trifluoromethyl) phenyl] -1H-pyrazole-4-ylb-N-cyclobutyl-1,1,1-trifluoromethanesulfonamide; N- {5-amino-3-cyano -l- [2,6-Digas-4-pentafluorothiophenyl] -1H-pyrazole_4-kib N- (fluorenylfluorenyl) methanesulfonamide; Ν · {3_cyanide Small [2,6-digasic (trifluoromethyl) phenyl] _ih_pyrazole 193 200531963 -4-yl} -1,1,1_trifluorosmall-methylmethanesulfonamide; N_ { 3-cyano-small [2,6-dichloro-4- (trifluoromethyl) phenyl] -1H_pyrazol-4-yl} -1 ^-(methylstyrenyl) methyl pyroxanthinamine, N- {3-cyano-l- [2,6-dichloro-4-pentafluorothiophenyl] -1H-pyrazole 5 -4-*}-N_ (methylfluorenyl) methanesulfonamide ; N_ {3_cyano-small [2,6-dichloro-4- (trifluoromethyl) phenyl] _1Η · pyrazol-4-yl} pyrimidine, N- {3-cyano- 1 · [2,6-dichloro-4- (trifluoromethyl) phenyl] -1Η-pyrazol-4-yl} -qin (2,2,2 · trifluoroethyl) methanesulfonamide; 10 Ν- {5-amino_3_cyanide -1- [2,6-Digas-4-pentafluorothiophenyl] -1Η-pyrazol-4-yl} -qin (2,2,2-trifluoroethyl) methanesulfonamide; Ν -{5-amino-3-muryl · 1- [2,6 · dichloro-4-pentathiothiophenyl] -1Η-pyrazole- ^ ylbuyi 卩-!: 1 !!-: ^ /-Triazol-1-yl) ethyl] methane scutamine; 15 5-amino-4- [bis (methyl hinderyl) amino] -1- [2,6-digas-4 -Pentafluorothiophenyl] -1Η-pyrazole-3-carboxamide; Ν · {5_amino-3 -amino group · 1- [2,6-dichloro-4 · (difluoromethyl milk (Phenyl) phenyl] _1Η-pyrazole-4 _ *}-N- (methylfluorenyl) methanesulfonamide; Ν- {3-ethynyl-5_amino-1-[2,6-digas -4-pentasulfur basic 20 groups] -1Η-pyrazol-4-yl} -sense (methylfluorenyl) methanesulfonamide; Ν- {5 -amino-3 -cyano-1- [2 , 6-dichloro-4- (difluorofluorenyloxy) phenyl] -1H-pyrazol-4-yl}-(methylfluorenyl) methanesulfonamide; N- {5-amino- 3-muryl_1- [2,6-dichloro-4-pentathiothiophenyl] -1H-pyrazol-4-yl} methanesulfonamide; 194 200531963 N- {5 · amino- 3-muryl · 1- [2,6-digas-4-pentasulfur basic group] -1Η-pyrazole · 4-*}-N-{[1- (trifluoromethyl) cyclopropyl] Methyl} methane. Fluorenamine; Ν- {5-amino-3- Gas-1--1- [2,6-digas-4-pentasulfur basic 5 groups] · 1 H-ntb ° Sat-4-yl} -N_ (methyl stone wind-based) ethyl pyroxanthine, 5- Amino-3-cyano small [2,6 · dichloro-4- (trifluoromethyl) phenyl] -1Η-pyrazole-4-yl (methylfluorenyl) carbamate; Ν- { 5-Amino-3-amino-1- [2,6-dichloro-4-pentathiothiobenzene #yl] -1Η-pyrazol-4-yl} -methylsulfonylamidine; 10 Ν- {5-amino-3-nitro-1- [2,6-dichloro-4-pentathiothiophenyl] -1Η-pyrazole_4-yl}-仏 (2-fluoroethyl ) Methanesulfonamide; Ν- {5-amino-3-amino-1- [2,6-digas-4-pentasulfur basic group] -111_pyrazole_4_yl} -qin ( 1,2,4_fluoradiazol-3-ylmethyl) methanesulfonamide; 15 Ν2- {5-amino-3-muryl-1- [2,6-dichloro-4-pentasulfur Phenyl] -1Η-pyrazol-4-yl} _ #-(methylfluorenyl) glycine glutamate; _N- {5-amino-3-amino-1- [2,6- Digas-4-pentasulfur basic group] -1Η-pyrazol-4-yl group N- ^ Η-pyrazol-3-ylmethyl) methanesulfonamide; Ν- {5-amino-3- Aryl-1- [2,6-digas-4-pentathiothiobenzene 20-yl] -1Η-pyrazol-4-yl} -qin (2,2,3,3,3-pentafluoropropyl ) Methanesulfonamide; Ν- {5-amino-3-amino-1- [2,6-digas_4_ Gasothiophenyl] -1Η-pyrazole-4-*}-N- (2-pyrrolidin-1-ylethyl) methanesulfonamide; Ν- {5-amino-3-lactyl- 1_ [2,6-Digas-4-pentasulfur basic group] -1Η-pyrazole-4-*}-N · (2-morpholin-4-ylethyl) methanesulfonamide; 195 200531963 N- {5-Amino_3_amino-l- [2,6-digas-4-pentasulfur basic group] -1H-pyrazol-4-yl} -qin [(1-methyl- 1H-imidazol-2-yl) methyl] methane, sulfonamide; ^ N- {5-amino-3-amino-1- [2,6-digas-4_pentathiothiobenzene 5-yl ] -1 H-0tbσ sitting-4-yl} -N-[(5-methyliso ° number. S_3.yl) methyl] methylpyramine; [{5-amino-3-cyano-l- [2,6-dichloro-4-pentafluorothiophenyl] -1H-pyridine Azole-4-yl} (methylfluorenyl) amino] methyl pivalate; N_ {5 · amino-3-lactyl · 1 · [2,6_digas-4-pentasulfur Benzyl 10-yl] -1H-pyrazol-4-yl} -pentylethylmethanesulfonamide; Ν- {5-amino-3-muryl-1- [2,6-digas-4-penta Gasothiophenyl] · 1Η-ϋ 比 σ sitting-4-yl} -N · benzyl fluorite flavonol amine, Ν_ {5-amino-3-airyl_1- [2,6-di Qi-4-pentathiothiophenyl] -lm- ^ Bitu-dou-Ki ^^ Heartanyl) methyl pyroxanthinamine, 15 N- {5 -amino-3-cyano-l -[2,6-dichloro-4- (dimethylidene) phenyl] _1H-pyrazol-4-yl} -1- (methylfluorenyl) ethanesulfonamide; N- {5-amine -L- [2-Gas_4 · pentathiothio-phenyl] -3 -lactyl-1H-supapyl-4-yl} · ^-(fluorenyl stone wind based) mesitolite , 5-Amino-1- [2,6-dichloro-4-pentathiothiophenyl] -4- (1,1-dimeric 20-lane-1,2- ° plug wells. Shan- 2-based) · 1Η-ΰ ratio σ sitting-3 · riding, Ν- {5- (benzylamino) -3 -ranyl-1- [2,6-digas-4-pentathiothiophenyl ] 坐 -4- 基} _1 ^-(methyl stone wind-based) continuous roasting , N- {3_cyano-l- [2,6-dichloro-4-pentafluorothiophenyl] -4-[(methyl hinderyl) (2,2,2-difluoroethyl) Amino group] · 1 ratio σ-situ-5-yl} -2 · fluorenyl ethyl 196 200531963 fluorenylamine; 4- [bis (methyllithino) amino] -3 -cyano-1-[2,6- Dichloro-4-pentafluoro ^ thiophenyl] -1H-pyrazol-5-ylfluorenimidoethyl; N- {3-cyano_5-[(cyclopropylmethyl) amino ] -l- [2,6-dichloro-4-penta-5fluorothiophenyl] -1H-pyrazol-4-yl} methanesulfonamide; N · {3 -amino-1- [2, 6-Digas-4-pentasulfur basic group] -4-[(methylfluorenyl) (2,2,2-trifluoroethyl) amino] -1H-pyrazol-5-yl} acetamidine Amines; N- {3_cyano-1_ [2,6-dichloro-4-pentafluorothiophenyl] -5-methoxy • -1H-pyrazol-4-yl} methanesulfonamide; 10 N- [3-cyano-small [2,6-dichloro-4- (trifluoromethyl) phenyl] -5_ (methylamino) -1Η_pyrazole_4 · yl] -N- ( Methylfluorenyl) methanesulfonamide; ^ N_ (3-cyano-1- [2,6 · dichloro-4-pentafluorothiophenyl] -5 · {[(dimethylamino) methylene Group] amino group 1′-pyrazol-4-yl) -N_ (methylfluorenyl) methanesulfonamide; 15 Ν- (3-cyano-1_ [2,6-dichloro-4-pentafluorosulfide) Phenyl] -5-{[2 · (difluorenyl ) Ethyl] amino} -1H-pyrazol-4-yl) -N- (methyl hinderyl) methanesulfonamide; N- {3-cyano-1_ [2,6-digas- 4-pentafluorothiophenyl] -5-[(2 · pyrozine stilbene_yl_ylethyl) amino] Η-σ ratio sigma-4-yl} -N- (methyl hinder) Methyl sulfonamide 20; Ν- {3-cyano-1- [2,6-digas-4-pentafluorothiophenyl] _5-[(2-morpholin-4-ylethyl) Amine] -1 Η-π than sialo_4-yl} -N- (methyl hinderyl) methyl amine; Ν_ {3 -lactyl-1- [2,6-digas-4 · 5 Gas Thiophenyl] -5-[(2- ° Bottom 197 200531963 Pyridin-1_ylethyl) amino] -1H-pyrazol-4-yl}-(methylfluorenyl) methanesulfonamide ;, N- {5-amino-3-bad propyl-1-[2,6-digas-4-pentasulfur basic group] -1H-pyrazol-4-yl} -sense (methyl hydrazone Group) methanesulfonamide; test 5 N- {5-amino-1_ [2,6-dichloro-4-pentathiothiophenyl] -1H-ntbfluoren-4-yl} methanesulfonamide; N- {3_cyano-1_ [2,6-dichloro-4-pentafluorothiophenyl] -5-[(pyridin-4-ylmethyl) amino] _1H-pyrazol-4-yl } Methanesulfonamide; ({5-amino-3 -amino · 1- [2,6-digas-4-pentathiothiophenyl] -1H-10 pyrazol-4-yl} amino Tertiary carbamic acid tertiary Ester; Ν- {5-amino-3 · amino-1_ [2,6-digas_4-pentathiothiobenzene'yl] -1Η-pyrazol-4-yl} -sense (2-pyridine 4-ylethyl) methanesulfonamide; Ν_ {5-amino-3-amino-1- [2,6-dichloro-4-pentathiothiophenyl] -1 sigma-4- } -N-Otbπ well-2-ylfluorenyl) amine, 15 Ν- {5-amino-3-amino-1- [2,6-digas-4-pentathio Phenyl] -1Η-pyrazol-4-yl} -sense [(6-aminopyridin-3-yl) methyl] methanesulfonyl amine; Ν- {3-cyano-1- [2,6 · Digas-4-pentafluorothiophenyl] -1Η-pyrazol-4-yl}-2-side milk-N_ (2,2,2-digasethyl) propan-1 , 20 Ν- (3-amino-1- [2,6_dichloro-4-pentathiothiophenyl] _5 _ {[3- (dimethylamino) propyl] amino} _1 H- atb sialo_4_yl) -N- (2,2,2-digasethyl) methanesulfonamide; Ν- {3-amino-1- [2,6-digas-4-pentasulfur Phenyl] -5-[(2-σChenylethyl) amino] -1Η- ° ratio σ-Crean-4-yl} · N- (2,2,2-Digasethyl) 198 200531963 Methane Sulfonamide; N- {5-Amino-3-amino-l- [2,6-digas-4_pentasulfur basic • radical] -1Η-σbijun-4-yl} sulfanamine , Ν- {5 · amino-3-nitro group_1- [2,6-dichloro-4- (difluoromethyl Benzene-5yl] -1H · pyrazol-4-yl} -4-fluoro-N- (methylfluorenyl) benzenesulfonamide; N- {5 -amino-3-cyano-1- [2, 6-dichloro-4- (digasmethyl) phenyl] sit-4-yl} -2,4-digas-N_ (methylcarbyl) benzamine, 3-cyano-l- [ 2,6-Digas-4-pentafluorothiophenyl] -4-[(methylfluorenyl) (2,2,2-trifluoroethyl) amino] -1H-pyrazole-5- Methylaminocarbamate; 10 N- {5-({[(2-aminoethyl) amino] carbonyl} amino) -3-cyano_1_ [2,6_dichloro-4-penta Fluorothiophenyl] -1H-pyrazole_4-yl} -Qin (2,2,2-'trifluoroethyl) methanesulfonamide; fluoran-1-ylethyl) amine] _3_ Lactyl-1_ [2,6-digas-4-pentafluorothiophenyl] -1H-pyrazol-4-yl} -sense (2,2,2-trifluoroethyl) methane Amine trifluoroacetate; Ν · (3-muryl-l- [2,6-digas-4-pentathiothiophenyl] -5-{[(2,4_ ® dihydroxyphenyl) Methyl] amino} -1Η-pyrazol-4-yl) -N_ (2,2,2-trifluoroethyl) pyranesulfonamide; N- {5-Ga-3-amino-l- [2,6-dichloro-4-pentathiothiophenyl] -1H-20 pyrazol-4-yl}-^ (2,2,2-trifluoroethyl) methanesulfonamide; or N- (3-Amino-1- [2,6-dichloro-4-pentathiothiophenyl] -5-{[3- (dimethylamine ) Ethyl] amino} -1Η- pyrazol-4-yl) -N- (methyl SA-yl) methane stone yellow Amides; or a pharmaceutically acceptable salt or solvate thereof. 199 200531963 12. A pharmaceutical or veterinary pharmaceutical composition comprising a compound as claimed in any one of claims 1-11, or a pharmacologically or veterinarily acceptable salt or solvate thereof, and a suitable compound Form or vehicle. % 9 13. A compound such as any one of claims 1-11 or 5 a pharmacologically or veterinarily acceptable salt or solvate thereof, which can be used in medical treatment. 14. Use of a compound according to any one of the scope of patent application M1 or a pharmacologically or veterinarily acceptable salt or solvate thereof, which may allow # to be used for the manufacture of parasite-killers for humans or animals. 10 15. A method of treating a parasitic infection in a human or an animal, which comprises administering a therapeutically acceptable amount of a compound as described in any one of the claims 1-11 or its pharmacological or veterinary Acceptable salts or solvates. 200 200531963. 7. Designated Representative Map: (1) The designated representative map in this case is: (). (2) Brief description of the component symbols in this representative picture: 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 4