TW200840576A - Process for preparing fluorinated sulphanylamides and sulphinamidines and uses thereof - Google Patents

Abstract

The present invention relates to a process for preparing novel polyfluorinated sulphanylamides and sulphinamidines and also to the precursors thereof and to the potential use of these sulphanylamides as possible substitutes for hydrophobic groups or for carboxylic acids containing certain bioactive molecules or alternatively as a perfluoroalkylsulphanylation agent.

Description

200840576 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a process for preparing fluorinated sulphuric acid and sulphur. The present invention relates to a process for the preparation of novel polythioanisole and sulfoxide, and to possible precursors for their precursors, and such thioguanamines as hydrophobic groups or with certain biologically active molecules. Or as a potential use of perfluoroalkyl sulphur burners. [Prior Art] φ Fluorine chemistry has been an important factor in providing fluorinated molecules in various fields such as polymers, battery salts, surfactants, dyes, liquid crystals, coolants, pesticide chemicals, and pharmaceuticals over the past few decades. Has been greatly developed [(8)

Organics, B.E. Smart and JC Tatlow. Plenum Press, New York, 1994 (b) Chem. Bio. Chem.? 2004, No. 5, Numero Special , fFluorine in Life Sciences" (c) Chemistry of Organic Fluorine Compounds. Compounds II. A Critical Review. M. Hudlicky and AE Pavlath. ACS Washington, 1995 (d) Organofluorine 4 Compounds. Chemistry and Applications. T. Hiyama·

Springer, 2000] o In the field of medicine, the profile shows that at least one fluorine atom and the number of molecules in preclinical or clinical development has grown by a factor of 2.5 in two years [Inventory of Industrial Fluoro-Biochemicals. A. Becker. Eyrolles, Paris, 1996]. Corresponding therapeutic indications range from the central nervous system 128394.doc 200840576 system to anticancer agents, experiencing antibiotics, antidiabetic agents, anti-inflammatory agents and antihypertensive agents [Chimie Bioorganique et Medicinale du Fluor

(Bioorganic and Medicinal Fluorine Chemistry), J.P. Begue, D. Bonnet-Delpon, CNRS publications, 2005]. Due to its significant lipophilicity, small size and polar nature of the OF bond, Fluorine-Containing Molecules. Structure, Reactivity, Synthesis and Applications. JF Liebman, A. Greenberg, WR Dolbier. VCH? Weinheim, 1988 (b) Organofluorine Chemistry. K. Uneyama. Blackwell Publishing, Oxford, 2006 (c) Scholfield, HJ Fluorine Chem. 1999, 100, 7-11], so it is often better to introduce one or more fluorine atoms into biologically active molecules. Medical kinetic properties (due to increased resistance to metabolism and accelerated gastrointestinal absorption), and can improve enzyme or cell activity (due to accelerated penetration through the membrane, sometimes with the target to improve its cognition or its irreversible production) Use) [Biomedical Frontiers of Fluorine Chemistry. I.

Ojima, J.R. McCarthy, J.T. Welch, ACS, Washington, 1996]. The most commonly used polyfluoro groups in agrochemicals and pharmaceuticals are CF3, OCF3, SCF3, S02CF3, OCHF2 and SCHF2, all of which are characterized by significant hydrophobicity. There are several methods for introducing fluorine or polyfluoride groups and can be applied to aliphatic series and aromatic systems 1J [(a) Organofluorine Compounds. Chemistry and Applications. T. Hiyama. Springer, 2000 (b) Organofluorine Chemistry. K. Uneyama Blackwell Publishing, Oxford, 2006 (c) Houben-Weyl Methods of Organic Chemistry. 4th 128394.doc 200840576 edition. Organo-Fluorine Compounds. Volume El〇

George Thieme,

Baasner, H. Hagemanjn, J.C. Tatlow.

Verlag, Stuttgart, 1999 (d) Langlois, BR; Ration, S * . ·, ^aris, JM· L'actualitS Chimique 2006, No. 301-302, 56-66] In the reaction of Putian fire, Conversion of alcohol and carbonyl functional groups to corresponding fluorine and difluoro derivatives with diethylaminosulfur trifluoride (DAST)

Middleton, W.J. J. Org·Chem. 1975, 40, 574-578

Hudlicky, Μ· Org· React· 1988, 35, 513-637]; Halex

It should convert a haloarylene or a nitroarylene to a fluoroarylene [(a) Clark et al.

Chem. Soc. Rev. 1999, 28? 225-231 (b) The Roots of

Organic Development. P244-292. BR Langlois, L. Gilbert, G. Forat. Elsevier, Amsterdam, 1996]; Electrophilic fluorination of ketones with N-fluorite xanthine or Selectfluor® [(^6&111<:5,1^· J. Fluorine Chem. 1998, 87, 1-17 (b) Cahard et al. Chem. Rev. 2004, 6119-6146] or trifluoromethylation; nucleophilic process , the carbonylation compound of Ruppert's reagent (CF3TMS) [(^)

Prakash et al. Chem. Rev. 1997? 97, 757-786 (b) Langlois et a/. Synthesis 2003, 185-194]; and electrophilic processes with Umemoto's reagent [Umemoto, T. Chem. Rev. 1996, 96, 1757-1778] or a halogenated aromatic [Burton et al. J. Am. Chem. Soc. 1986, 70S, 832-834], such fluorination methods are often limited, limited to fluorine or The degree to which a polyfluoro group is introduced into a given position on a given molecule, however, in many cases, there are still difficult problems for the chemist. Given the importance of fluorinated molecules, improvements in the fluorination process or any newly discovered fluorination process or reagents will have greater utility in many fields. In particular, the newly discovered method of introducing a SCF3 group directly under mild conditions (a trifluoromethylsulfanation reaction in an aromatic or aliphatic series or a hetero atom) using a non-toxic reagent makes the process possible beyond the current method. Restricted and therefore more readily available to molecules that are of interest in potential applications of agrochemicals and medicines, often in the field of molecules containing SCF3 groups [(8) Inventory of Industrial Fluoro-Biochemicals. A. Becker. Eyrolles, Paris, 1996 (b Fluorine Compounds as Agrochemicals. 2nd Edition. SB Walker. BARK Information Services, Wokingham, UK, 1995]. The known direct method of trifluoromethylsulfanation is based on electrophilic properties (via scf3+ species), nucleophilic properties (via SCF3-species) or free radical properties (via SCF3 species) and reagents such as CF3SCl [Haas ei a/· : (a) Chem· Ber· 1976, 109, 2475-2484 (b) Helv. Chim. Acta 1979? 62, 1442-1450 (c) J. Fluorine Chem. 1984, 24, 363- 368], CF3SSCF3 [Peach, Μ. E. Can. J. Chem. 1967, 45, 429-432], CF3SH [Harris et al. J. Am. Chem. Soc. 1961, 83, 840-845] ^ Hg (SCF3)2 [Brandt et aL J. Chem. Soc. 1952, 2198-2205] ^ AgSCF3 [Emeleus et aL J. Chem. Soc. 1961, 2597-2599] > CuSCF3 [Yagulpolskii a/· Synthesis 1975, 721 -723] or MSCF3 (rfn M+=Cs+^ Me4N+) [Tyraa et al. J. Fluorine Chem. 2003, 779, 101-107], its toxicity is usually extremely high (or prepared from highly toxic compounds) and can not be transferred It is an industrial scale reaction (gaseous, costly and not easy to handle due to toxicity). 128394.doc 200840576

In the molecule with SCF3 group, the characterization of trifluoromethylthioguanamine with N-SCF3 group cannot be completely verified because it mainly reacts with amine (primary or secondary) or guanamine with CF3SC1 (toxic gas). Obtained [(4) Haas ei a/· J. Heterocycl. Chem. 1986, 23, 1079-1084 (b) Shreeve et aL Inorg. Chem. 1985, 24, 2126-2129 (c) Munavalli et aL Phosphorus, Sulphur Silicon Relat. Elem 2003, 178, 107-113], or CF3SSCF3 toxic to carbon helium [Peach, Μ. E. Can. J. Chem. 1967, 45, 429-432]. Other methods use CF3SNH2 [Haas Μ a/· Chem. Ber· 1982, " 5, 523-532] or CF3SNCO Haas et al. Chem. Ber. 1982, 775, 533-539 (b) Haas, A. Chem. Ber. 1966, PP, 3103-3107], these agents are also toxic to the preparation of derivatives and applications of cyclic thioguanamine or urethane. Although trifluoromethanethioguanamine is extremely difficult to obtain, it can have various biological properties as explained by the following molecules [Bayer A. G. Patent (W02002006277, 2002; DE2045441, 1972; DE2103199, 1972); Boehringer-

Mannheim patent (DE 2727550, 1979); Merck patent (GB 2266527, 1993; EP 481671, 1992; EP 199630, 1986)].

叩, person I

MeX.0 Me *1^-/ Me cN herbicide acaricide anticancer agent anti-inflammatory agent. Further, trifluoromethanesulfinium constitutes another molecule with scf3 group, the latter integrated in n=s (cf3) In the sequence of the -n class. These compounds are difficult to prepare differently than CF3SF3 [(a) Glemser ei α/. Ζ·128394.doc -10- 200840576

Naturforsch., B 1978? 33, 1417-1421 (b) Mews et aL Chem. Ber. 1991, 124, 2411-2416 (c) Yagupolskii et al. Zh. 〇rg. Khim· 1980, /(5, 863- 867] The reagent itself is prepared from SF4, which is not easy to handle, and illustrates the limitation of known trifluoromethylsulfinium. [Invention] The object of the present invention is to prepare a thioindole compound of the formula (1). And the method of formula (11) sulfoxide compound:

R

HN

SIR \u/

R hi-

SIR

R-N

R wherein a) R! is - optionally substituted aryl; - or optionally substituted heteroaryl; - or optionally substituted alkyl; - or optionally substituted cycloalkyl; - or substituted as appropriate a heterocycloalkyl group; or -S〇2_aryl, wherein the aryl group is optionally substituted; or -S〇2_heteroaryl, wherein the heteroaryl group is optionally substituted; -or- S02-fluoroalkyl; or -C〇2-aryl' wherein the aryl group is optionally substituted; - or -c〇2.heteroaryl, wherein the heteroaryl is optionally substituted; -or- C〇2_alkyl, wherein the alkyl group is optionally substituted; is -S-aryl, _S_heteroaryl or benzoxazole. 2_128394.doc • 11 - 200840576 fluoroalkyl or difluoro Methylene, the aryl, heteroaryl and benzoxazolyl groups are optionally substituted, c) Rs and & independently of each other are alkyl, alkoxyalkyl or cycloalkyl, or R3 and R4 The attached nitrogen atoms together form a saturated or unsaturated heterocyclic ring having 3 to 7 ring members, optionally including another hetero atom (such as a sigma sigma group, a sulphonium group or a morphine group); The method is characterized by the following steps: a first step in which an organic solvent, preferably a non-polar organic solvent such as methyl chloride, and a tertiary amine such as triethylamine, hydrazine, hydrazine-diisopropylethylamine, pyridine, 2,6- The compound of the formula (IV) is condensed with the compound of the formula (v) in the presence of lutidine, thereby obtaining a compound of the formula (wherein Ri, R2, r^r4 are as defined above, and R5, independently of each other a substituted aryl or alkyl group;

R6 (IV) - the second step 'wherein the tertiary amine in an organic solvent (such as triethylamine, N,N-diisopropylethylamine, 0 sigma, 2,6-dimethyl oxime bite The compound of the formula (III) itself is condensed with a compound of the formula r]Nh2 (the center of which is as defined above) to obtain a thioanthramine of the formula (1) or a sulfinium compound of the formula (11) wherein R and 2 , R3 and R4 are as defined above; 128394.doc -12- 200840576

R

R,

Ro R.

IS i R2 Chuan (1) The third step of the case where the sulfinium compound of the formula (11) is converted in the presence of an acid in the organic 4彳, thereby obtaining the thioindole compound of the formula (1), wherein R1 R2, 1 and 1 are as defined above.

[Embodiment] The aryl group substituted by 5" means, in particular, an aryl group which is substituted with one or more (for example, 1 to 3) groups which are the same or different from each other, and which are substituted from the groups of the following atoms and groups. : • Halogen • Alkaline • alkoxy substituted as appropriate • Aryl group substituted as appropriate • Heteroaryl substituted as appropriate • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Substituted heteroaryl • Alkyl group 128394.doc -13- 200840576 • · s - fluoroalkyl group - as appropriate - s - aryl group - optionally substituted - S-heteroaryl

• -CN • -no2 • Heterocycloalkyl•,Ra)(Rb) • -N(Ra)CO(Rb) • -N(Ra)COO(Rc) • -N(Rc)CON(Ra)(Rb • _N(Ra)S02(Rc) • _oso2rc • _S〇2N(Ra)(Rb) • -S02(Rc) • _CON(Ra)(Rb) • -COR,, and • _C〇〇Rc where Ra and Rb is independently selected from a hydrogen atom, and optionally substituted (c(6)alkyl, (iv)) fluoroalkyl, cycloalkyl, optionally substituted aryl, optionally: substituted heteroaryl or heterocyclic county, and The group, except for hydrogen, wherein R^Rb, together with the nitrogen atom to which it is attached, forms a saturated or unsaturated heterocyclic ring having (1) a ring-forming shell and optionally other heteroatoms. The term "heteroaryl optionally substituted" especially means replacing one or more (eg, 1 to 3) groups of one or more of the following atoms and radicals selected from the following atoms and groups 128394.doc -14-200840576, as appropriate Heteroaryl: • Halogen • Substituted calcined base • Alkoxy group • Substituted aryl group • Substituted heteroaryl • alkenyl • alkynyl • fluoroalkyl • fluoroalkoxy • Substituting _〇-aryl • Substituted heteroaryl • -s-alkyl • - S - smoldering base - Substituting -S-aryl group as appropriate - Substituting -s -heteroaryl

• -CN • - Ν Ο 2 • Heterocycloalkyl • -N(Ra)(Rb) • -N(Ra)CO(Rb) • -N(Ra)COO(Rc) • -N(Rc)CON( Ra)(Rb) • -N(Ra)S02(Rc) 128394.doc -15- 200840576 • -OSC^Rc • -S02N(Ra)(Rb) • -S02(Rc) • -CON(Ra)(Rb • _CORb ' and • -COORe where Ra, Rb&Rc are as defined above. The term "substituted alkyl as appropriate" means, in particular, a group of one or more (e.g., 1 to 3) groups which are the same or different from each other and are substituted with a group selected from the following atoms and groups: • Halogen Substituted aryl group • Substituted heteroaryl • Heterocycloalkyl • alkoxy • fluoroalkyl • fluoroalkoxy • Substituted - 〇-aryl • Replacement - 0 - as appropriate Aryl•-S-alkyl--S-fluoroalkyl•Substituted as appropriate-S-aryl • Heteroaryl substituted as appropriate

• -CN 128394.doc -16- 200840576 • -no2 • -S02N(Ra)(Rb) • -S02(Rc) • -CORb • -COORc • -CON(Ra)(Rb) • -N(Ra)( Rb) • -N(Ra)CO(Rb) • -N(Ra)COO(Rc) • -N(Rc)CON(Ra)(Rb) and •N(Ra)S02(Rc) where Ra, 1^ And Rc is as defined above. In the context of the present invention, and unless the context dictates otherwise: - the noun "halogen atom" means: fluorine, gas, bromine or iodine; - the noun "burning base" means 1 to 12 carbon atoms ( It is preferably 1 to 6 carbon atoms) and is a straight bond or a branched saturated aliphatic group. For example, the description is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.; 3 alkyloxy means -〇-burning The base is defined as defined above; - the term ''alkoxyalkyl group') means a radical of the formula alkyl-hydrazino group, wherein the alkyl groups may be the same or different from each other and are as defined above; "Base" means an alkyl group as defined above and includes from 1 to 13 fluorine atoms, preferably from 1 to 5. For example, the recited are -CH2F, 128394.doc -17- 200840576 -CHF2, -CF3, -CH2CF3 and -cf2cf3. When each hydrogen atom of the alkyl group is replaced by a fluorine atom such as -CF2CF3, the group is referred to as a perfluoroalkyl group; - the term "fluoroalkoxy" means an alkoxy group as defined above and includes丨 to 9 fluorine atoms. For example, the descriptions are -〇_CH2F, -〇_CHF2, -CF3, -〇-CH2CF3, and -〇CF2CF3, -〇ch(CF3)2. When each hydrogen atom of the alkoxy group is replaced by a fluorine atom such as _0CF2CFS, the group is referred to as a perfluoroalkoxy group; - a fuliginic group means: having one or more unsaturations and containing 2 to u A stone anti-atomic, preferably a linear or branched hydrocarbon chain of 2 to 6 carbon atoms. Examples of alkylene substituents are ethenyl, fluorenyl-methylvinyl, propenyl, prop-2-enyl, methylpropenyl-alkenyl, n-methylpropanyl-alkenyl, Zl, 2-Dimethyl-propenylalkenyl, Εί dimethylpropanyl, buty-1,3-dienyl, 1-methylenepropenyl, z_2-methylbutadienyl, E-2 -methylbutyr-i,3-dienyl, methyl-; 1-methylenepropan-2-alkenyl, undecyl-1-alkenyl and undecyl_10-alkenyl substituent; noun Fast radical means: having at least two linear or branched hydrocarbons having at least two unsaturations from adjacent carbon atoms and having 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms. Substituent. Examples of alkynyl substituents are ethynyl, prop-1-ynyl, prop-2-ynyl and but-1-ynyl substituents; • The term "cycloalkyl" means: 3 to 12 carbon atoms Preferably, from 3 to 6 carbon atoms are saturated or partially unsaturated, mono- or polycyclic hydrocarbon-based groups. Examples of cycloalkyl substituents are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, bicyclo [2·2·1 Heptyl, cyclooctyl, bicyclo[2·2·2]octyl, adamantyl and perchlorinated 128394.doc -18 - 200840576 naphthyl substituent; /noun ''heterocyclyl,' means 4 to 8 ring members and (1) a ring carbon-based group selected from hetero atoms of chaotic, milk and sulfur. The heterocyclic group may be bonded to the nitrogen atom of the ring at any position, via one or more of the same or different selected lines, optionally substituted, and an alkoxy group, an alkoxy group, an oxo group, CF3, -OCF3, (10) hospital base, c〇NRR, (10) and

-NRR, a substituent substituted by a group, wherein the coffee is a hydrogen atom or an alkyl group. For example, 'what is the ♦ ♦, pyrrolidine, piperidine, piperazine, 2 - pyrrolidone, 2-piperidone, imidazoline and imidazolidinium 2, 4-dione; Aryl"#: a mono- or polycyclic aromatic substituent having 6 to 14 carbon atoms. Examples of aryl substituents are phenyl, naphthalene, naphthyl, cardioyl I2, 3, 4. Hydronaphthalen-5-yl and 1,2,3,4-tetrahydronaphthalene-6-yl substituent; _noun "heteroaryl" means: a single containing 13 carbon atoms and (1) a hetero atom And polycyclic heteroaromatic substituents. Examples of heteroaryl substituents are indole-1-yl, pyrrol-2-yl, pyrrole-3-yl, furyl, thienyl, imisteinyl... ;Saliva, sulphate, sulphate, sulphate, sulphate, sylvestre, sylvestre, sylvestre, sylvestre, sylvestre, sylvestre, sylvestre -Triazinyl" fluorenyl, benzo[b] thiol, benzo[noise phenyl L, benzo-wolyl, i-hetero, silk, quinalyl, isoindolyl, carbazolyl And an acridinyl substituent; _ noun "heteroatom" means: an atom other than at least divalent and carbon. Examples of heteroatoms are N, deuterium and s. The Ri as defined above according to the preparation method of the present invention may be as follows: 128394.doc -19- 200840576 - optionally, one or more (for example, 1 to 3) atoms selected from the following or different from each other Or a substituted aryl group: • Halogen • Substituted calcinyl group • Alkoxy group • Alkenyl substituted as appropriate • Heteroaryl alkenyl group substituted as appropriate

• alkynyl • fluoroalkyl • fluoroalkoxy • - S - gas-fired

• -CN • -N〇2 • Heterocycloalkyl • -N(Ra)(Rb) • -N(Ra)CO(Rb) • -N(Ra)COO(R〇) • -OS〇2R〇• -CON(Ra)(Rb) • -CORb, and • -COORc wherein Ra and Rb are independently selected from a hydrogen atom, and optionally substituted (CVC4) alkyl, (C-C4) fluoroalkyl, naphthenic Base, depending on the situation, take 128394.doc -20- 200840576 instead of aryl, optionally substituted heteroaryl or heterocycloalkyl, and Rc uses the base of na 'but hydrogen' or 'and its attached The nitrogen atom - forms a saturated or unsaturated heterocyclic ring having 3 to 7 ring members and optionally other heteroatoms; or optionally one or more (eg, up to 3) identical or different from each other selected from the following A heteroaryl group substituted with an atom and a group: • Halogen • optionally substituted alkyl • alkoxy • fluoroalkyl • fluoroalkoxy

• _CN • -N(Ra)(Rb) • -CORb, and • -CO〇Rc where Ra, Rb and Rc are as defined above; or as one or more (eg 1 to 3) are identical or different from each other as appropriate An alkyl group selected from the group consisting of the following atoms and groups: • Halogen • optionally substituted aryl • optionally substituted heteroaryl • heterocycloalkyl • alkoxy • -S-alkyl 128394.doc 21 200840576 • Fluoroalkyl • Fluoroalkoxy

• -CN • -no2 • -COORc • -CON(Ra)(Rb) • -N(Ra)(Rb) • -N(Ra)CO(Rb) • -N(Ra)COO(Rc) • -N (Re)CON(Ra)(Rb) and • -N(Ra)S02(Rc) wherein Ra, Rb&Rc are as defined above; or -so2-aryl, wherein the aryl group is one or more depending on the situation (for example, 1 to 3) may be the same or different from each other selected from the following atoms and groups: • Halogen • alkyl • alkoxy • fluoroalkyl • fluoroalkoxy

• -CH • -N〇2 • -N(Ra)(Rb) • -CORb and 128394.doc -22- 200840576 • -COORc where Ra, Rb and Rc are as defined above; -or-so2-heteroaryl Wherein the heteroaryl group is optionally substituted with one or more (e.g., 1 to 3) groups which may be the same or different from each other selected from the group consisting of: halogen, alkyl, alkoxy, fluoroalkyl, Gas alkoxy

• -CN • -N(Ra)(Rb) •-(3)Heart and • -COORc where Ra, 1^ and Rc are as defined above; -or _S02-fluoroalkyl; -or-C〇2_alkyl, Wherein the alkyl group may be substituted by one or more (for example, 1 to 3) groups which may be the same or different from each other selected from the following atoms and groups: • Fluorine • aryl group substituted as appropriate • Replacement as appropriate Aryl • Heterocycloalkyl • alkoxy 128394.doc • 23- 200840576 • -s-Alkyl • fluoroalkyl • fluoroalkoxy

• -CN • -N〇2 • -COORc • -CON(Ra)(Rb) • -N(Ra)(Rb) • -N(Ra)CO(Rb) • -N(Ra)COO(Rc) • - NXROCONdKRb) and • -N(Ra)S02(Rc) where Ra, Rb and Rc are as defined above. Furthermore, the preparation method according to the invention as defined above may be recited wherein Ri is: • optionally substituted by one or more (e.g., 1 to 3) groups which may be the same or different from each other selected from the group consisting of a halogen atom (such as C1 and F), and -((VC#)alkyl, -(C)_C4)alkoxy,-((VC4)perfluoroalkyl'-(Ci-C4) perfluoro Alkoxy, -N02, optionally substituted -(C3-C6)heterocycle, -N(Ra)(Rb), -N(Ra)CO(Rb), -0S02Rc, -c〇Rb or -COORc^ Wherein Ra&Rb is independently selected from a hydrogen atom, optionally substituted by -(Ci-CJ alkyl or -(C!-C4) perfluoroalkyl, and Re is substituted with Ra, except for hydrogen; or - An aryl group, wherein the aryl group is selected from one or more (for example, 128394.doc -24 - 200840576 1 to 3), which are the same or different from each other, selected from a halogen atom, and a _(Ci_ CU) alkyl group. , -(C1-C4) alkoxy, -(CVC4) perfluoroalkyl or -(cKc4)perfluoroalkoxy group; - or -S〇2_heteroaryl, wherein heteroaryl The case is one or more (for example, 1 to 3) which are the same or different from each other selected from a _ atom, and - (CVCO alkyl, -(CVC4) alkoxy, -(CVC4) perfluoro Or a group substituted with -Ci-Cd perfluoroalkoxy; - or 4〇2-((νί:4) perfluoroalkyl; - or -C〇2_(C)-C4)alkyl, wherein the alkane The base system is optionally selected from one or more (e.g., 1 to 3) groups selected from the group consisting of a fluorine atom, and -(CVC4) perfluoroalkyl group, -(CVC4) perfluoroalkoxy group, as the case may be. Substituents of aryl, -N02, -N(Ra)(Rb), -CORb or -CO〇Rc groups, wherein Ra, Rb& Rc are as defined above; - or optionally one or more (eg, 3) heteroaryl groups which may be the same or different from each other selected from the group consisting of a halogen atom, and -(Ci-CJ alkyl, -((^-(:4) all-gas alkyl, perfluoroalkoxy) a group, -(Cl_C4) alkoxy, -CN, -CORb or -COORe, wherein Rb and Re are as defined above; - optionally, one or more (e.g., i to 3) may be the same or different from each other _(CkC6)alkyl substituted with the following radicals: a fluorine atom, and -(cvc:4)perfluoroalkyl, _N〇2, -CN, optionally substituted aryl, optionally substituted heteroaryl or _NRdRe group, wherein the core is Η or -(CVC4) alkyl. According to the preparation method of the invention as defined above The aryl group which is substituted by one or more (for example, 1 to 3), which may be the same or different from each other, from the following groups: halogen atom, wherein: & 128394.doc • 25- 200840576 (such as C1 and F) and _(CrC4) alkyl, -(CVC4) alkoxy, _CF3, -N〇2, _NHC0Rd (where Rd is as defined above - cckc^c: 4) alkyl or a (C3-C6)heterocycloalkyl group optionally substituted by a (C i - C 2 ) alkyl group which is selected from the oxo group and optionally a heteroaryl group, as the case may be; Or a -SOy aryl group, wherein the aryl group is selected from one or more (for example, 1 to 3), which are the same or different from each other, selected from a halogen atom, and _(c "CO alkyl, -(Cl-C4) alkane. Oxyl, -(Cl-c4)perfluoroalkyl or -(C-C4) perfluoroalkoxy group; - or -S〇2_heteroaryl" wherein heteroaryl is optionally Or a plurality (for example, 1 to 3) which are the same or different from each other selected from a halogen atom, and a -(c)-c4)alkyl group, a -(Ci-C4) alkoxy group, a -(CrC^)perfluoroalkyl group Or -(C1-C4) perfluoroalkoxy group substituted; -or-S〇2_(Ci-C4) perfluoroalkyl; or -CO^Ci-C4)alkyl" Depending on the case, one or more (for example, 1 to 3) are the same or different from each other selected from a fluorine atom, and _(C]-C4) all-I-alkyl, -(Ci-C4) perfluoroalkoxy, Substituting the aryl group, -N〇2, -N(Ra)(Rb), _C0Rpt _c〇〇Rc, the base of the substituent, wherein Ra, Rb and Rc are as defined above; _ or one or more (for example, 1 to 3) heteroaryl groups which may be the same or different from each other selected from the group consisting of dentate atoms, and 128394.doc -26- 200840576 -(CrC4)alkyl, _(Cl_c4) perfluoroalkane a cyano-Ci-C4) perfluoroalkoxy, -(CKC4)alkoxy, -CN, -CORb or -COORc group, wherein Rb and Rc are as defined above; - or optionally one or more (eg, 1 to 3) an alkyl group-containing fluorine atom which may be the same or different from each other, and a _(cr c4)perfluoroalkyl group (such as _CF3, -CF2CF3), -N02, -CN, Alternate aryl, optionally substituted heteroaryl or _NRdRe-based 'wherein Rd and Re are deuterium or -(CVC4)alkyl. Preferably, the object of the present invention is to prepare a method for preparing a perfluoroalkyl group as defined above. The object of the present invention is also preferably as defined above, the center and the core thereof are independent of each other. A method for producing a morpholino group, which is an alkyl or alkoxyalkyl group, or a < and h with a nitrogen atom to which it is attached. Preferably, the object of the present invention is as defined above, wherein R5, heart and heart A method for preparing a methyl group. According to the present invention, preferably one to two equivalents of a tertiary amine (e.g., triethylamine, N,N-diisopropylethylamine) at a temperature of from _40 ° C to 40 ° C , pyridine, 2,6-dimethyl. In the presence of an organic solvent, preferably in a non-polar solvent such as dichloromethane, the compounds of formula (IV) and (V) are preferably based on (IV) /(V): a compound of the formula (III) obtained by reacting from 1 to 2 equivalents. 128394.doc -27- 200840576

R 3 R / IN \ SIF FF-

SI /〆 F F

IN

3 R fr Rr2 (IV) According to the invention, a compound of the formula R!NH2 (preferably one equivalent) is added to the above reaction containing a compound of the formula (ΙΠ) via a temperature between -40 ° C and 40 ° C The thiolamine of the formula (1) and the slate of the formula are obtained in the mixture.

R SIR Λ

IN

R ~ 2 -N R1 4 R—

R SIR2 N/

R domain and

R

HN s

R \) / 01 ^ or the spontaneously prepared sulfinium intermediate of formula (II) can be isolated and stable, which can be carried out in an organic solvent such as dichloromethane in an organic or inorganic acid such as trifluoroacetic acid. 'Converted to the thioguanamine compound of formula (1) at a temperature between 〇C and the boiling point of the solvent. The present invention also relates to a process for producing a compound of the formula wherein RG is an alkyl group, an alkenyl group or an alkynyl group by alkylating a compound of the formula (1) which is defined by the above definition. Thus, in accordance with the present invention, a compound of formula (1) is employed in the presence of an organic or inorganic base such as sodium hydride NaH in an aprotic solvent such as dimethylformamide at a temperature between -2 (TC to 60 ° C). An alkyl group reaction of sRqX4Rg〇s〇2R (in which I is a halogen atom and R is an optionally substituted alkyl or aryl group in I28394.doc -28- 200840576) Η IR〇x ?° 2 R2 (丨) ( La) The present invention also relates to intermediate compounds of formula (I), (II) and (III): Η 1 r4 1 R/, S 1 I /Ν' R, 丫R3 F, /N, F, f X R2 r2 1 R2 (Ο (II) (III)

Wherein Ri, R2, 113 and R4 are as defined above, and processes for the preparation of the intermediates of formulae (1), (II) and (III). The thioguanamines (I), (la) and sulfoxides (II) of the present invention can be found in the field of agrochemicals and in the field of medicine as a pair containing a fluoroalkyl group, a fluoroalkoxy group, a fluoroalkylsulfanyl group. Or a fluoroalkylsulfonyl hydrophobic group, such as a substitute for molecules of cf3, OCF3, SCF3, and S〇2CF3, with NRGSR2 and N=S(R2)NR3R4 groups as described in the present invention (wherein R〇, r2 3 and & 4 are as defined above) in place of the hydrophobic group. By way of non-limiting example, the following molecule is an inhibitor of tyrosine kinase IGF 1-R [for a review of this kinase, see Baserga, R. Exp, Cell. Res., 1999, 253, 1-6]: 128394.doc - 29- 200840576

The table below shows that the biochemical and cellular activities of the molecules of R = NHSCF3 prepared in accordance with the present invention are comparable to the molecules described in patent FR 2850652 (R = OCF3, SCF3 or S02CF3). R IC50IGFI-R1 (nM) IC5〇 ELISA2 (nM) IC50MEF3 (nM) ocf3 162 337 274 scf3 86 136 197 so2cf3 82 47 16 nhscf3 200 395 472 128394.doc • 30- 1 : HTRF form. 2 : Inhibition of self-phosphorization of IGF1-R in cd/w/ο. 3: Inhibition of IGF 1-induced proliferation of MEF cell lines. 2 Thioamine (1) (wherein Ri is -S02-aryl, -S02-heteroaryl, -S02-fluoro-3-alkyl, -co2-alkyl, -C02-aryl or -C02-heteroaryl Where aryl, heteroaryl and alkyl are optionally substituted) can be found in the pharmaceutical field as an alternative to molecules containing carboxylic acid functional groups, as defined in the present invention -so2-nh-s- The r2 or -OCO-NH-S-R2 group replaces the carboxylic acid and R2 is as defined above. This substitution is made possible by the acidic nature of the UH-S-R2 compound in these examples. By way of non-limiting example, the pKa measured by the 1CH3-C6H4-S02-NH-SCF3 compound is 5.4 (at 25 ° C at 〇·15 Μ 200840576

In Me〇H/KC1, P·Ρ_ U ' and benzoic acid have a PKa of 4.2. Thioamine (1) or (4) (wherein Ri is an aryl group (preferably a phenyl group), & is a trimethylmethyl group, and for a compound of the formula (la), R〇 is a methyl group) may be based on the following three reactions The procedure 'uses an agent which is an internal gas-burning sulfur-sintering reaction, preferably a tri-sulfanyl-sintering and perfluoroethylsulfanation of aromatic, heteroaromatic, alkenyl and alkynyl compounds.

The purpose of this invention is also the use of the compounds of the formulae (I) and (la) as a reagent for the calcination of the total gas-based sulphur group of the following formula, heteroaryl, alkenyl and block-based compounds. According to the present invention, the molar amount of the unsaturated substrate and the compound (I) are in an excess amount of a sulfonic acid (preferably p-toluenesulfonic acid or camphorsulfonic acid) or an ether containing hydrochloric acid, or an excess of a sulfonate (more It is preferably in the presence of a sodium salt of terephthalic acid and a Lewis acid (e.g., ethyl trifluoroborate) in a non-polar solvent such as dichloromethane, and at 0 ° C to 40 ° C. The reaction is carried out at the temperature of the day, thereby obtaining a compound including the SR2 functional group.

/Sr2 R1-N \ ,r2 〇"R1—\ + A—H rso3h -—>* H (l) R〇(la) (ieq.) ch2ci2 where A=aryl or heteroaryl/SR2 SFL R1 -N or \ / ,x2 R1—N\ + Ria^Rib ch2ci2 HR〇(1eq.) RS03H or HCl/Et20 or BF3-Et20, (l) 〇a) RS09〇Na A—SR2 (VI) (eg a -scf3) Rc cd >R,b 〇S02R or Cl (VII) (eg SR2=SCF3 or SCF3 or scf2cf3) 128394.doc -31 - 200840576 SR.

R1—N

Rn

(la) ch2ci2 ------ RS03H or BF3-Et2〇, RS〇2〇Na R2S .OTs (eg sr2=scf3) R^e (VIII) Unidentified properties—Bei ^ early — Z or E Stereoisomer

Polyfluorinated compounds are known to be potentially beneficial compounds for a variety of applications, including agrochemicals and pharmaceuticals, for example as a building block for the construction of more complex biologically active molecules by thrips. The starting compounds and reagents, if not prepared as described below, are either commercially available or described in the reading, and may be prepared according to methods described in the art or methods known in the art (a). The invention is also described by the following examples which are provided to illustrate the invention. =, 5-dimethyl porphyrin·4_ylmethyl_3 ('trifluoromethylsulfanylamino-phenyl)imidazolidin-2,4·dione, trifluorohexanoate ) 1 3 nitrophenyl)-5,5-dimethyl_1_quinolin-4-ylmethylimidazolium _ 2,4-diindole

At the temperature, 600.600g of isocyanic acid 4-methybenzene is added to 1-methyl 2-methyl 2_[(喧琳_4_ylmethyl)amino]propionic acid methyl vinegar (based on 4 ml of tetrahydrofuran / gluten solution prepared by the process described in the application of FR 2,850,652. The resulting mixture was stirred at the same temperature for 8 hours, then 2 liters of methanol was added, and the mixture was stirred at ambient temperature for 15 minutes. And concentrating the obtained solution to obtain a yellow powder, which was placed in 15 〇^* 「 "τ. The obtained suspension was filtered through a sintered glass to obtain 1.4 gram of fresh powdered powder 3-(4-nitro- Phenyl)-5,5-dimethyl-1-quinoline_4-ylmethylimidyl X bit-2,4-:_(MS: M+=391 g/mol). 1·2 'Aminobenzene Base)-5,5-dimercapto-1-wowline 4-ylmethyl taste sniffing ~ 128394.doc -32- 200840576 2,4-dione at a temperature around 55 ° C, 4.4 ml The amine hydrate is added dropwise to 1.350 g of 3-(4-nitro-phenyl)-5,5-diindenylquinidinemethyl acridine-2, the diketone and 0.1 30 g of 5 % palladium/carbon in 70 ml of ethanol mixture. The resulting reaction mixture was stirred at the same temperature for 3 hours and 3 minutes and cooled again and filtered through celite. The obtained mixture was concentrated under reduced pressure to give 1.180 g of white powder. 3-(4-Aminophenyl)-5,5-diindenyl phthalocyanine-4-ylmethylimidazolidin-2,4-dione (MS: M+=360 g/m〇i). · 3 : 5,5-dimercapto-1-quinolin-4-ylmethyl-3-(4-trifluoromethylsulfanylaminophenyl)imidazolidin-2,4-dione, three Dunacetate in inert argon and at -20 35·1 35 ml of dimethylaminosulfur trifluoride (DAST) was added dropwise to a solution of 0·260 g of N,N-diisopropylethylamine in 15 ml of dioxane at a temperature around °C. The resulting mixture was stirred at the same temperature for 10 minutes, and then cooled to -20 ° C, followed by the addition of 0.15 ml of (trimethylmethyl)trimethylnonane and stirred at -20 ° C for 1 hour. 5.36〇 3-(4-Aminophenyl)-5,5-dimethyl-1-quinolin-4-ylmethylimidazolidin-2,4-dione in 5 ml of ethyl acetate And 5 ml of a dichloromethane suspension was slowly added to the obtained mixture, and the mixture was stirred under hydrazine for 3 hours, then at ambient temperature for 48 hours, and then a saturated sodium hydrogencarbonate solution was added. The organic phase was separated to sulfuric acid. The magnesium was dehydrated, filtered and concentrated under reduced pressure. The obtained residue was dissolved in 50 ml of dichloromethane, and 5% (10) ml of difluoroacetic acid was added dropwise at ambient temperature and the mixture was allowed to stand at the same temperature. After 8 hours, the solution was concentrated under reduced pressure, and the obtained residue was purified mjjjjjjj 〇〇1〇克 灰色粉128394.doc -33- 200840576 状5,5-Dimercapto-1-quinolin-4-ylmercapto-3-(4-trifluoromethylsulfanylamino) Phenyl) taste bite 2,4-dione, trifluoroacetate (yield 2%, ^18:!^1+=461 g/mol). 4 NMR (300MHz, DMSO d6) : δ ppm 8.90 (wide peak d, 1H); 8·50 (s, 1H); 8·29 (wide peak d, 1H); 8·1〇 (wide peak d, 1H); 7·85 (wide peak t, 1Η) ; 7·72 (wide peak t, 1H); 7.64 (wide peak d, 1H); 7·36 (wide peak d, 2H); 7·20 (wide peak d, 2H); 5·15 (wide peak) s, 2H) ; 1·42 (wide peak s, 6Η). Example 2: 4-Methyl-N-[(trifluoromethyl)thio]benzamide (Compound η) 2.1 . N-[. I. (二鼠曱基)-λ-thioalkyl]- N,N-diethylamine 0.135 ml of DAST was added dropwise to 0. 130 g of N,N-diisopropylethylamine in 2 ml of anhydrous dichloroethylene under inert nitrogen at a temperature around -20 °C. A burnt solution. The reaction medium was stirred at the same temperature for 10 minutes, followed by the addition of 0.150 ml of (trifluoromethyl)trimethylnonane. After stirring at -2 Torr: for 1 hour, 19F NMR detection of the reaction medium was carried out. The N-[difluoro(trifluoromethyl)-λ4_sulfanyl]_N,N_:ethylamine compound which was not isolated was quantitatively obtained. F NMR (282MHz, CFC13) : δ ppm +2·31 (q, 2F) ; -64.81 (t,3F) 〇2·2 · N-[(ethylamino)(trifluoromethyl)-λ4 - Sulfur-based]-4-methylphthalide xanthine (compound 37) Add 2 71 ml of anhydrous ethyl acetate in 0.171 g of 4-methylbenzenesulfonamide to the step 2 at -20 °C. · 1 in the reaction mixture. The reaction medium was then stirred at ambient temperature for 18 hours. The crude product of the reaction was then washed with aq. NaHC.sub.3 (.sub.6) and then dried over NkSO. The organic phase was concentrated and purified by silica gel chromatography (pentane/acetone: 8/1) in the presence of 128394.doc -34 - 200840576 0.5% triethylamine. 0.325 g of the desired product as a yellow oil (yield: lC/MS: M+ = 342 g/mol) 〇 2.3 : 4-methyl-N-[(trifluoromethyl)thio]benzenesulfonamide (compound) 21y Add 0.260 g of trifluoroacetic acid to 342·342 gΝ·[(diethylamino)(trifluoromethyl)-λ4-sulfinyl]-4-mercaptobenzenesulfonamide at ambient temperature 2 • Soar up in a gas purge. Then the reaction medium is stirred at 50° (: 24 hours). Finally, the crude product of the reaction is washed with water and then dehydrated with Na 2 s 4 . 〇 260 g of 4-methyl hydrazine-[(trifluoromethyl)thio]benzenesulfonamide as a white powder (yield 96%; LC/MS: M+= 271 g/m 〇l). NMR (300MHz, CDC13): δ ppm 7.81 (d5 2H); 7.35 (d? 2H); 6.75 (wide peak, 1H); 2.45 (s, 3H). Example 3: l-(4-{[(trifluoro) Methyl)thio]amino}phenyl)ethanone (Compound i8) 3·1 : 4-[Difluoro(trifluoromethyl)_λ4_sulfanyl]morpholine in inert nitrogen at -20 ° C 〇·137 ml of morpholinyl φ sulfur trifluoride was added dropwise to a solution of 0.130 g of N,N-diisopropylethylamine in 2 ml of anhydrous dioxane at a nearby temperature. The reaction medium was stirred at the same temperature for 1 ' minutes. Then 0.150 ml of trifluoromethyltrimethyl decane was added. After stirring at -20 ° C for 1 hour, 19F NMR detection of the reaction medium was carried out. . Isolation of 4-[difluoro(trifluoromethyl)-λ4-sulfanyl]morpholine compound. 19F NMR (282MHz5 CFC13) : δ ppm +2.06 (q, 2F) ; -63.72 (t, 3F 〇3.2: 1-(4-{[morpholin-4-yl(trifluoromethyl)44-sulfinyl]amino}phenyl)ethanone (Compound 36) 128394.doc -35- 200840576 A solution of 0. 135 g of 1-(4-aminophenyl)ethanone in 2 ml of anhydrous dichloromethane was added to the reaction mixture of step 3.1 at -20 ° C. The reaction medium was then allowed to stand at ambient temperature. After stirring for 4 hours, the crude product of the reaction was washed with aqueous NaHCO3 (6%) and then dried over Naj.sub.4, evaporated, evaporated and evaporated. 1-(4-{[morpholin-4-yl(trifluoromethyl)-indolyl-4-sulfinyl]amino}phenyl)ethanone as a white powder (yield 70%; LC/MS: M+=320 g/mol). H NMR (300MHz? CDC13) : δ ppm 7.81 (d, 2H) ; 7.35 (d _ 2H) ; 6.75 (wide peak, 1H); 2.45 (s, 3H). 3.3 : 1-(4-{[(Trifluoromethyl)thio]amino}phenyl)ethanone (Compound 18) 0.090 ml of trifluoroacetic acid was added dropwise to 〇32〇 at a temperature of 〇 °C The compound obtained in Step 3.2 was dissolved in 2 ml of dichloromethane. The reaction medium was then stirred at ambient temperature for 12 hours. Finally, the crude product of the reaction was washed with water, followed by dehydration with NadO4. After evaporating under reduced pressure, the residue was purified by silica gel chromatography (eluent/acetone: 60/1) to afford y······················ Amino}phenyl)ethanone (yield 88 〇/〇; lc/ms: M+ = 235 g/mol). ^ NMR (300MHz5 CDC13): δ ppm 7.91 (d? 2H); 7.16 (d5 • 2H); 611 (wide peak, 1H); 2·56 (s, 3H). Example 4 · 1-(4·{[(Difluoromethyl)thio]amino)phenyl)ethanone (Compound 18) Instead of Example 3, κtrifluoromethyl)thio]amine can be prepared according to the following procedure Base phenyl) Ethyl ketone: 2 liters of anhydrous dioxane methane solution containing aminophenyl phenyl ketone at -20 ° C was added to the reaction mixture of step 2. The reaction medium was then stirred at ambient temperature for 4 hours and then at 128394.doc -36-200840576

The NaHC 3 aqueous solution (6%) was washed and dehydrated with Na 2 S 〇 4 . After filtration and evaporation under reduced pressure, the crude reaction product was dissolved in 2 mL of anhydrous dichloromethane and then cooled to EtOAc. Then, 7 ml of trifluoroacetic acid was added dropwise, and the reaction medium was stirred at ambient temperature for a few hours. Finally, the crude product was reacted with water and dehydrated with NaJ〇4. Evaporation under reduced pressure and washing with EtOAc (yield: <RTI ID=0.0>>&&&&&&&&&&&& MS: M+=23 5 g/mol) 〇H NMR (300MHz, CDC13): δ ppm 7.91 (d, 2H); 7·16 (d, ® 2H); 6·11 (wide peak, 1H); 2.56 ( s, 3H). Example 5: [(Trifluoromethyl)thio] benzyl carbamate (Compound 22) 5·1 · [Diethylamino (trifluoromethyl)_9 4 sulphide] benzyl carbazate Ester (Compound 42) A solution of 0.151 g of benzyl urethane amide in 2 ml of anhydrous dichloromethane was added to the reaction mixture of step 2.1 at -20 °C. The reaction medium was then stirred at ambient temperature for 48 hours. After washing with NaHC03 aqueous solution _ (6%), it was dehydrated with NadO4. After evaporating under reduced pressure and purifying the crude product (yield: pentane/acetone: 15/1), 222 g (yield of dimethylbenzene) _ 9 4 _ sulphide] carbamic acid vinegar * (yield 69%; LC / MS: M + = 322 g / mol). - 5·2 ·[(Difluoromethyl)thio]amino decanoic acid vinegar (Compound 22) 0.260 ml of trifluoroacetic acid was added to 〇·322 g [diethylamino (trifluoro) at ambient temperature Methyl)-λ4-sulfinyl]benzyl carbamate in 2 ml of dichloromethane. The reaction medium was then stirred at 50 ° C for 24 hours. Finally, the reaction crude product was washed with water and then dehydrated with NazSO4. The pressure was reduced to 128,394.doc •37·200840576. After evaporation and washing with diethyl ether, EtOAc (yield: 80% of chloroform) MS: M+ = 251 g/mol). 4 NMR (300MHz, CDC13): δ ppm 7·43-7·39 (unresolved peak, 5Η); 6.15 (wide peak s, 1H); 5.42 (s, 2Η). Example 6: 4-Acidyl-indole·[(Trifluoromethyl)thio]aniline (Compound 1?) - 6J : Ν,Ν_Diethyltrifluoro-anthracene, -(4-nitrophenyl) Sulphinimidamide (Compound 33) 0.175 ml of N,N-diisopropylethylamine was added to the reaction mixture of step 2.1 at -20 C, followed by addition of ruthenium in 5 minutes. 〇14 gram of 4-nitroaniline. The reaction medium was then stirred at 0 °C for 3 hours. Finally, the crude product of the reaction was washed with aqueous NaHCOs (6%) and then dehydrated with NaJO4. Evaporated under reduced pressure and at 〇·5. /. The crude reaction product was purified by silica gel chromatography (pentane/acetone: 30/1) in the presence of triethylamine to obtain 0.247 g of N,N-diethyl-1,1, 丨-trifluoro-N as a brown oil. , -(4_Nitrophenyl)methanesulfinium iminoamine (yield 80%; LC/MS: M+ = 309 g/mol). 6·2 : 4-nitro·Ν_[(trifluoromethyl)thio]phenylamine (Compound 17) 0.090 ml of trifluoroacetic acid was added at 0.3 ° C in a solution containing 0.309 g of the compound obtained in step 6.1 • In milliliters of dichlorosilane solution. The reaction medium was then stirred at ambient temperature for 1 hour. Finally, the reaction crude product was washed with water and then dehydrated with Na2SO4. After evaporation under reduced pressure, 0.238 g of 4-nitro[(trifluoromethyl)thio]aniline as a powdery powder was obtained. The yield is quantitative (LC/MS: M+ = 238 g/mol) 〇]H NMR (300 MHz? CDC13): δ ppm 8.22 (m? 2H); 7.20 (m5 128394.doc -38- 200840576 2H); 64 (Broad bee s, 1H) Example 7: N-U1, benzoxazol-2-ylamine (compound 8) (monofluoro)methyl]thiophenyl L-phenyl- 7·1 · Ν·{ [1,3-Benzooxazole_2_yl (difluoromethane Ί χτ soil, chaotic) methyl] (one mouse)-λ4-sulfanyldiazine, hydrazine-diethylamine

G.135 ml of diethylaminotrifluorosulfide was added to a cold solution of ruthenium.130 g of hydrazine, hydrazine-diisopropylethylamine in 2 ml of anhydrous dichloromethane under inert nitrogen and at the temperature of the pin. . After the reaction medium was stirred at the same temperature for 1 minute, '0.241 g of 2-[difluoro(trimethyl sulphate) fluorenyl benzoxazole was stirred at ambient temperature for 1 hour, and then the reaction medium was subjected to 9F ^ ^ River rule detection. Quantitatively obtained [{丨'夂benzoxazole-2-yl(difluoro)methyl](difluoro)-λ4-thio}-N,N-diethylamine compound. F NMR (282MHz? CFC13) : δ ppm -0.92 (m5 2F) ; -9i.〇6 (m,3F) 〇7·2 : N-{[1,3-benzoxazole_2_yl (two Fluoro)methyl]thiophenylpyrazine-phenylguanamine (Compound 8) 0.110 ml of benzylamine was added to the ruthenium mixture of the step at ambient temperature. The reaction medium was then stirred at ambient temperature for 24 hours. Finally, the crude product of the reaction was washed with a NaHC 3 aqueous solution (6%), and then dehydrated with NazSCU. After evaporating under reduced pressure and the crude product was purified by silica gel chromatography (pentane/ethyl acetate······························· Difluoro)indenyl]thio}-l-phenylmethylamine (yield 35%; LC/MS: M+ = 306 g/mol). 4 NMR (300MHz, CDC13): δ ppm 7.86 (m,1H); 7.64 (m 128394.doc -39- 200840576 1H) ; 7·53·7·44 (unresolved peak, 2H); 7·4〇 _7·26 (unresolved peak 5Η); 4·28 (d, 2Η); 3.27 (wide peak s, 1Η). , Example 8: Ν'.{3. Fluorine-based small [2,6_di-air ice (trifluoromethyl) stupid base] "比峻五基}]\,~1-ethyl_1,1,2, 2,2_5 1 Ethylene sulphide 8^imine amine (Compound 25) 8.1 · Ν-[Fluoro(pentafluoroethyl)_λ4·sulfanyl]-oxime, Ν-diethylamine in inert Under nitrogen and at a temperature around -20 ° C, 35 ml of diethylaminosulfur trifluoride (DAST) was added dropwise to 2 liters of anhydrous dichloroanthracene containing 0.130 g of ice-diisopropylethylamine. The reaction medium was stirred at the same temperature for 10 minutes, followed by the addition of 〇18 mM (pentafluoroethyl)tridecyl decane. After stirring at -20 ° C for 1 hour, Bp NMR of the reaction medium was carried out. Detected. Quantitatively obtained N,-[difluoro(pentafluoroethyl)_λ4-thiopyrazine diethylamine compound. F NMR (282MHz? CFC13) : δ ppm +3.32 (m, 2F ; -78.52 (t,3F) ; ·1〇6·18 (m,2F). 8·2 · N - {3-cyano-ΐ·[2,6-dichloro-4-(trifluoroanthracene) Phenyl bromide 1H_pyrazole_ 5-yl b N,N-diethyl_ι,ι,2,2,2-pentafluoroethane sulfinimide amide (Compound 25) at -20 At the temperature of C, 〇·322 grams of solid state 1- (2,6-dioxa-4-trifluoromethyl phenyl)-3-cyano-5-amino hydrazine is added in reverse to the reaction mixture of step & 1 with nitrogen. The reaction medium is at ambient temperature. The mixture was stirred for 48 hours. Finally, the crude product of the reaction was washed with aqueous NaHCO3 (6%) and then dried over NadCU. After evaporation under reduced pressure and washing with hexanes, s. 3-cyano-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-111-° ratio 128394.doc -40- 200840576 17 sit-5-based}-1^,1 ^-Diethyl-1,1,2,2,2-pentafluoroethyl sulfinimide amide (yield 10%; LC/MS: M+ = 542 g/mol). NMR (300MHz, CDC13) ·· δ ppm 7,69 (m,2H) ; 5.90 (s, 1H) ; 3·40 (m,4H) ; 1·23 (t,6H). Example 9: Ν,Ν·diethyl-N '·[(pentafluoroethyl)thio]pentane-i,4-diamine (compound 7) 0.200 ml of N,N-diethylpentane-1,4 at a temperature of ·20° - The diamine was added to the reaction mixture of step 8.1. The reaction medium was then stirred at ambient temperature for 4 hours. Finally, the crude reaction product was washed with aqueous NaHCO3 (6%) and then dehydrated with Na2SO4. After evaporating under reduced pressure and purifying the crude product (yield: pentane/acetone: 1/1), 0.062 g of N,N-diethyl-N1-[(pentafluoroethyl)thio Pentane-1,4-diamine (yield 20%; LC/MS: M+ = 308 g/mol). 4 NMR (300MHz, CDC13) ·· δ ppm 3·34 (wide peak s, 1Η); 3·05 (m, 1H); 2·60 (q, 4H); 2·49 (t, 2H) ; · 55-1·44 (unresolved peak, 4H); 1·16 (d, 3H); 1.07 (t, 6H). Example 10: N-[(Trifluoromethyl)thio]aniline (Compound 9) 0.09 1 ml of aniline was added dropwise to the reaction mixture of Step 2.1 at a temperature of -20 °C. The reaction medium was then stirred at ambient temperature for 12 hours. Finally, the crude reaction product was washed with a NaHC 3 aqueous solution (6%) and then dehydrated with NazSCU. Evaporation under reduced pressure and purification of the crude product (yield: pentane/acetone: 60/1) afforded 156 g of N-[(trifluoromethyl)thio]aniline as a yellow oil (yield 81) % ; LC/MS : M+ = 193 g/mol). H NMR (300 MHz? CDC13): δ ppm 7.35 (m? 2H); 7.15 128394.doc -41 - 200840576 (m, 2H); 7.06 (m, 1H); 5.09 (broad peak s, 1H). Example 11: 4-Gas-N-indole (trifluoromethyl)thio]aniline (Compound n) 〇·127 g of 4-aniline with nitrogen was added in the reverse direction at a temperature of -20 C in step 2. 1 In the reaction mixture. The reaction medium was then stirred at ambient temperature for 12 hours. Finally, the reaction crude product was washed with a NaHC 3 aqueous solution (6%) and then dehydrated with NaJO 4 . Evaporation under reduced pressure and purification of the crude product of the reaction by chromatography (eluent / ethyl acetate: 50/1) afforded 〇·ΐ5〇克克色色状4·鼠-N-[(difluoro Aniline (yield 66%; LC/MS: M+ = 227 g/mol) ° !H NMR (300MHz? CDC13) : δ ppm 7.26 (d, 2H) ; 7.04 (d, 2H) ; 5.14 (wide peak s, 1H). Example 12: (4-{[(Trifluoromethyl)thio]amino}phenyl) carbamic acid carboxylic acid ester (Compound 19) 0.1753⁄4 liters of N,N-diisopropyl B at -2 0C The amine was added to the reaction mixture of step 2.j, and after 5 minutes, 242 g of (4-aminophenyl)carbamate benzyl ester was added in reverse with [sf2]. The reaction medium is then placed in a crucible. After stirring for 3 hours under ankle, it was washed with a NaHCCh aqueous solution (6%) and dehydrated with NaJO4. After filtration and evaporation under reduced pressure, the obtained crude material was dissolved in 2 ml of anhydrous dichloromethane and then cooled to 0 °C. Then, 0.030 ml of trifluoroacetic acid was added dropwise. After stirring at ambient temperature for 1 hour, the reaction medium was washed with water and then

NajCU is dehydrated. After evaporating under reduced pressure and purifying the crude product (yield: pentane/acetone: 8/1), the crude product was obtained as a brown powder (4_{[(trifluoromethyl)thio]amino} Benzyl) benzyl carbamate (yield 44%; lc/ms: M+ = 342 g/mol) ° 128394. doc • 42- 200840576 NMR (300MHz, CDC13) : δ ppm 7·4Κ7·26 (unresolved Peak 7H); 7·〇1 (m, 2H); 6·68 (wide peak s, 1H); 5·19 (s, 2H) $ w broad peak s, 1H). Example 13: N匕{3-Fluoro-1-fluorene 2,6-dioxa-4-(trifluoromethyl)phenyl]_ihpyrazol-5-yl}-1,1,1-trifluoromole ,^bis(2-methoxyethyl)methanesulfinylene·amine amide (Compound 27) ' 13.1 · [Difluoro(trifluoromethyl)·λ4-sulfanyl] bis(2-methoxy Base ethyl)amine in an inert nitrogen atmosphere at a temperature around -20 ° C, 0468 ml of commercially available 50 mol% bis(methoxyethyl)aminosulfur trifluoride (De〇xoflu plus The tetrahydrofuran solution was added dropwise to a solution of 0.130 g of N,N-diisopropylethylamine in 2 ml of anhydrous di-methane. After the reaction medium was stirred at the same temperature for 10 minutes, 0.150 ml (trifluoromethyl) was added. Trimethyl decane. After stirring for 1 hour at ° c, i9F NMR detection of the reaction medium was carried out to obtain quantitatively N-[difluoro(trifluoromethyl)-λ4_sulfanyl] bis 2_Methoxyethyl)amine • 19F NMR (282MHz5 CFC1s): δ ppm +2.04 (q? 2F); -65.53 (t,3F) 13.2 : Nf-{3-cyano-1-[2 ,6·Dichloro 4-(trifluoromethyl)phenyl]-1Η·〇λ. Zozodime, 1,1·trifluoro-N,N-bis(2-methoxy Ethyl)methanesulfinylene-amine amide (Compound 27) 0.322 g of solid 1·(2,6-dioxa-4-trifluoromethylphenyl)-3- at a temperature of -20 ° C The cyano-5-aminopyrazole was added in reverse to the reaction mixture of step 131. The reaction medium was then stirred at ambient temperature for 18 hours. Finally, the crude product of the reaction was washed with aqueous NaHCCh (6%) and then 128394.doc •43- 200840576 Dehydrated with NazSO4. Evaporated under reduced pressure and the crude product was purified by silica gel chromatography (pentane / propyl I: 10/1). -1·[2,6-Dichloro_4-(trifluoromethyl)phenyl]-111_.biazole_5•kib^·trifluoro-indole, fluorene-bis(2-methoxyethyl) Methane sulfinimide amide (yield 78%; LC/MS: M+ = 552 g/mol) H NMR (300 MHz, CDC13): δ ppm 7.69 (s, 2H); 6·15 (s, 1Η) ; 3·58-3·42 (unresolved peak, 8Η); 3·33 (s, 6Η). Example 14 · Ν-{丨 difluoro(phenylthio)methyl]thio)aniline (Compound 14) 14.1 : Nf{[difluoro(phenylthio)methyl](difluoro)-λ4_sulfanyl b, ν_: ethylamine in the month 0.135 ml of diethylaminosulfur trifluoride (DAST) was added to the sulphur-containing 130 g of hydrazine, hydrazine-diisopropylethylamine in 2 ml of anhydrous gas at a temperature of around -2 0 C. Chloroformate in the solution. After the reaction medium was allowed to be stirred at the same temperature for 10 minutes, 0.232 g of [difluoro(phenylthio)indenyl]trimethyllithium was added. After stirring at -20 C for 1 hour, NMR detection of the reaction medium was carried out. Quantitatively obtained non-isolated Ν'{[difluoro(phenylthio)indolyl κ difluoro λ4-sulfanyldiazine, hydrazine-diethylamine. 19F NMR (282MHz, CFC13): δ ppm -0·44 (m, 2F); -63,02 (m, 2F). 14·2 : N-{[difluoro(phenylthio)methyl]thio}aniline (Compound 14) 0.091 ml of aniline was added dropwise to the reaction mixture of the step 14.1 at a temperature of -20 °C. The reaction mixture was then stirred at ambient temperature for 48 hours. Finally, the reaction crude product was washed with a NaHCO 3 aqueous solution (6%) and then dehydrated with Na 2 S 〇 4 . Evaporation under reduced pressure and the crude product obtained was purified by EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: Methyl]thio}aniline (yield 56%; Lc/ms: m+ = 283 g/mol) NMR (300MHz, CDC13): δ ppm 7.69 (m, 2H); 7.55-7.42 (unresolved Peak, 3H); 7.24 (m, 2H); 7.00-6.92 (unresolved peak, 3H); 5, 23 (wide peak s, 1H). Example 15: N-Methyl-N-[(trifluoromethyl)thio]aniline (Compound 43) 0.048 g of NaH was added to 〇·193 g of N-[ (Trifluoromethyl)thio]aniline (Compound 9, Example 1) in 2 mL of anhydrous dimethylamine. The resulting mixture was maintained at this temperature for 10 minutes, and then 0.075 ml of methyl iodide was introduced dropwise. The reaction was then allowed to stir at ambient temperature for 4 hours. The resulting mixture was placed in a mixture of pentane/KbO. The organic phase was separated for dehydration and then concentrated in vacuo to give a residue which was purified by silica gel. Purification of alkane. Obtained 0.172 g of N-methyl-N{trifluoromethylsulfonyl]phenylamine as a colorless oil (yield: 83%, LC/MS: M+ = 207 g/mol). H NMR (300 MHz, CDC13 ) : δ ppm 7.34-7.22 (unresolved peak 4H); 6·97 (m, 1H); 3.50 (s, 3H). Example 16: N-[(trifluoromethyl)thio]-N-ten Monoalkylaniline (Compound 46) 48 g of NaH was added to _ι〇.^ containing 0' 193 g of N-[(difluoromethyl)thio]aniline (Compound 9) with vigorous stirring. Example 2 〇) 2 ml of anhydrous dimethylformamide solution. After the resulting mixture was maintained for 10 minutes, 0.278 ml of b-iododecane was introduced dropwise, and then the reaction medium was stirred at ambient temperature for 4 hours. The resulting mixture was then placed in pentane / 128394.doc -45 - 200840576

4H); 6.97 (m5 1Η); 3.73, and then vacuum) purification. Obtaining monoalkylaniline (produced CDC13) ·· δ ppm 7·33-7·22 (unresolved peaks >;3·73 (wide peak m, 2Η); 1,72 (m, 2Η) 1·33 -1·28 (unresolved peak, 16Η); 〇, 9 (t, 3Η). The compound obtained by the present invention is a perfluoroalkylsulfanation of aromatic, heteroaromatic, alkenyl and alkynyl compounds. The use is also illustrated by the following examples: Example 17: Sulfonic acid (1γ, 2ρ)-: Μ(trifluoromethyl)thio]cyclohexylmethylphenyl ester (Compound 68) 0.102 ml of cyclohexane was added to 〇193氺·((trifluoromethyl)thio]amine (Compound 9, Example 1) in 2 mL of di-methane in methane, and then, after 5 minutes, 〇·475 g of solid p-toluenesulfonic acid monohydrate The reaction medium was then heated at 50 ° C for 18 hours. Finally, the reaction crude product was washed with water and then dehydrated with NhSO 4 . After evaporation under reduced pressure, the residue was subjected to silica gel chromatography (eluent / acetone: 80 / 1) Purification. Obtained 276 g of a yellow powdery acid (lR*, 2R*)-2-[(trifluoromethyl)thio]cyclohexyl-4-pyrylphenyl ester (yield 78%, LC) /MS: M+=354 g/mol). lU NMR (300MHz, CDC13) δ ppm 7.80 (d? 2H); 7.35 (d? 2H); 4.49 (ddd, 1H); 3.29 (ddd? 1H); 2.44 (s, 3H); 2.22 (m, 1H); 2.03 (m, 1H) ; 1.69-1.65 (unresolved peak, 3H); 1·48-1·44 (unresolved peak, 3H). Example 18: sulfonic acid (ir%2Ra)-1-propyl-2-[(three Fluoromethyl)thio]pentyl _ 128394.doc •46· 200840576 4_Methylphenyl ester (Compound 61) 0.635 ml of a commercially available 48% BF3-Et20 solution was added dropwise to a solution containing 0· 207 g of N-mercapto*[(trifluoromethyl)thio]aniline (Compound 43, Shell 15) 0·112 g (Ζ)~oct-4-ene and 0,291 g of sodium p-toluenesulfonate 2 ml of dioxane solution. The resulting mixture was then stirred at ambient temperature for 4 mils and then diluted with a mixture of Et 2 〇 / H 2 。. The organic phase was separated and washed twice with 2 N HCl solution to Na 2 s. 4 dehydration, and then vacuum / condensed. The residue was purified by silica gel chromatography (pentane / acetone: ι / /) to obtain 246 g of colorless oily sulfonic acid (1R*, 2R*) small C Base |[(Trimethyl)thio]pentyl-4-methylphenyl ester (yield 64%; LC/MS: M+ = 384. lHNMR (3〇〇MHz, CDC13): 3Ppm7.81 (m, 2H); 7.37 (m, 2H); 4.68 (dt? 1H); 3.30 (dt, 1H); 2.45 (s? 3H); 1.80-1.48 (unresolved peak, 4H); my (unresolved peak, 3H); i i2(f), 1H); 〇·86 (t, 3H) ; 〇·81 (t, 3H). Example 19: (1R*'2R*)_2·cyclohexyl trifluoromethyl sulfide (compound % * 0.1 g of 1 ml cyclohexene added to G 193 g [[trimethyl)thio]aniline (Compound 9, Example 10) in 2 mL of dichloromethane solution. After a minute, a solution of 1 mL of 2N hydrochloric acid in diethyl ether was added dropwise. The reaction medium was then stirred at ambient temperature for 2 hours. The crude product was extracted with a mixture of /H.sub.2 mixture. The organic phase was separated, dried with NajO4 and then concentrated in vacuo to give 0.205 g of (10)» chlorocyclohexyltris. & Mol). NMR NMR (300MHz, CDC13) : δ ppm 4.l〇(m, 1H) . 3 45 (m called; 2.39 (111'1 printed; 2.22 (111,111); 186_167 (unresolved ^ 128394.doc - 47- 200840576 3H) ; 1·62-1·3 8 (unresolved peak, 3H). Example 20: Acid 1-U(trifluoromethyl)thio]methylene}heptyl-4-methyl Base ester (Compound 79) 635·635 ml of a commercially available 48% BF3-Et20 solution was added dropwise to 0.207 g of N-methyl[(trifluoromethyl)thio]aniline (compound 43) under vigorous stirring. Example 15), 0.1 52 g of sin·丨_alkyne and 0.291 g of sodium toluenesulfonate in 2 ml of dichlorohydrazine in a trough solution. The reaction medium was then stirred at ambient temperature for 48 k·° to react the crude product. After the Et2〇/H20 mixture was washed twice with 2 N HCl solution, the organic phase was dried over Na 2 S 〇 4 and the crude product was purified by silica gel chromatography (pentane/acetone: 100/1). 1-{[(Trifluoromethyl)thio]methylene}heptyl-l-decylphenyl sulfonate (yield 41%; LC/MS: M+ = 414 g/mol). H NMR (300 MHz, CDC13) : δ ppm 7.80 (m, 2H) ; 7.37 (m, 2H) ; 5.87 (s, 1H) ; 2.47 (s3 3H); 2.38 (t, 2H) ; 1.42 (m 5 2H) ; 1·32_1·17 (unresolved peak, 6H); 〇·86 (t, 3H). Example 21: 3-[(trifluoromethyl)thio]indole (compound 8〇) 117·117 g of hydrazine was added to a solution of 193 g of ice [(trifluoromethyl)thio]aniline (Compound 9, Example 1) in 2 ml of dichloromethane. After 5 minutes, 〇·485 was added. G-p-stanosulfonic acid monohydrate and then the reaction mixture was heated at 5 ° C for 18 hours. The crude product of the reaction was finally extracted with a 玢 2 〇 / 〇 mixture. The organic phase was separated, dehydrated with NkSCu and then concentrated in vacuo. The residue was purified by silica gel chromatography (pentane/acetone: 2 〇/1) to yield 156 g of 3-[(dimethylmethyl)thio] oxime (yield 72%; LC/MS: M+ = 217 g/mol) 〇128394.doc •48- 200840576 ]H NMR (300MHz, CDC13) : δ ppm 8.56 (wide peak s, 1H); 7·80 (m,1H) ; 7.53 (d,1H) ; 7.42 (m, 1H); 7·32-7·24 (unresolved peak, 2H). Example 22: 2,4-Dimethoxy[(trifluoromethyl)thio]benzene (Compound 88) 0.134 g of l,3-(dimethoxy)benzene was added to a mixture containing 0.193 g N -[(Trifluoromethyl)thio]aniline (Compound 9, Example 10) in 2 mL of dioxane. After 5 minutes, 〇·485 g of p-terephthalic acid monohydrate was added, and then the reaction mixture was heated at 50 ° C for 18 hours. The crude reaction product was finally extracted with an EhO/HzO mixture. The organic phase was separated, dried over NazSO4 and then concentrated in vacuo. The residue was purified by silica gel chromatography (pentane/acetone: 200/1) to afford 214 g of 2,4-dimethoxy[(trifluoromethyl)thio]benzene (yield 90%; LC /MS M+=238 g/mol) 〇!H NMR (300MHz5 CDCI3) : δ ppm 7.53 (m? 1H) ; 6.54-6.50 (unresolved peak, 2H); 3·88 (s,3H) ; 83 (s, 3H). Example 23 · 2-[(Difluoromethyl)thio]-i,2,3,4-tetrahydronaphthalene (Compound 77) 0.15 〇 phenyl phenyl-butadiene was added to the gram-containing trifluoromethyl group A solution of thio]aniline (Compound 9, Example 1) in 2 mL of dichloromethane. After 5 minutes, 〇·] 8 〇 ml of trifluoromethanesulfonic acid was added dropwise. The reaction medium was stirred at ambient temperature for 24 hours. The crude reaction product was finally extracted with a mixture of Et2?/H??. The organic phase was separated, dried over NajO4 and then concentrated in vacuo. The residue was purified by silica gel chromatography (pentane/acetone: 8 〇/1) to yield 65 g of 2 [(monofluoromethyl) yl)---------- : M+=232 g/mol). MHz, CDC13) ·· δ ppm 7·16-7.05 (unresolved peak, 128394.doc -49- 200840576 ) ' 3'69 (m,1H) ; 3.27 (m,1H) ; 3.04-2.86 3H); 2.30 (m, 1H^1 > 98(i^iH). The following table illustrates the formula, chemical structure and physical properties of the present invention. (Tables of some compounds of formula (II) and formula (III) Medium: and - Mp (melting point) column, representing oil at ambient temperature and "Et" for methyl and ethyl, respectively. 128394.doc 50- 200840576. 乐铋窠浪茫岑-^tr^(vfcl ) Hidden K3^ is called a disc 嘁璁 one: 嘁 two hits ^ fin shift 螂 4) 111 荽 <nq > s £ Φ Shuxiong e (Nln#^qM'i QT (a) wide V / N \ Η

Yield η 64% Procedure Direct preparation of compound III according to Example 10 Step 2.1 Step 2.1 a < ^ 窆8 Not measured 1 ^-NMR δ = (300 ΜΗζ, CDCI3) 8.90 (wide peak 〇 1,111); 8.50 (3, 1H); 8.29 (wide peak d, 1H); 8.10 (wide peak d, lH); 7, 85 (wide peak t, 1H); 7.72 (wide peak t, 1H); 7.64 (wide peak 41 print; 7.36 ( Broad peak (1, 211); 7.20 (wide peak (1,211); 5.15 (wide peak 3, 2 printing; 1.42 (wide peak 3, 6H) 1. 7.36-7.40 (unresolved peak, 5Η); 4.26 ( d,2 H); 3.17 (wide peak s, 1H) & m & Φ 6 ι·Η fN 128394.doc -51 - 200840576 Yield 36% 65% 41% 50% 20% Procedure according to Example 10 Direct preparation Direct preparation according to Example 10 Direct preparation according to Example 10 Direct preparation according to Example 9 Direct preparation According to Example 9 Direct preparation of compound III Step 8.1 Step 2.1 Step 2.1 Step 2.1 Step 8.1 Laugh ε face 1 Qian 1 1 ^-NMR δ = (300 ΜΗζ, CDC13) 7.36 -7.28 (unresolved peak, 5H); 4.24 (d, 2H); 3.06 (wide peak s, 1H) __ · ^ (N ® years ^ SS - • r\ · <N <N ^ as far as wm &lt ;N 2 ΓΠ · k inch 7·35-7·33 (unresolved peak, 5H); 4.28 (m,1H); 3.31 ( Wide peak s, 1H); 1.53(d,3H) 3.48(£,s,lH); 3.05(m, 1H);2.51 (q? 4H); 2.40(t? 2H); 1·53-1·41 (unresolved peak, 4H); 1.14 (d, 3H); 1.01 (t, 6H) 3.34 (wide peak 5, 111); 3.05 (111, 1H); 2.60 (q, 4H); 2·49 (t , 2H); 1.55-1.44 (unresolved peak, 4H); 1.16 (d, 3H); 1.07 (t, 6H) cf2cf3 m Ph U bm U CF2CF3 0? % MeO〆iO ω Έ f"> 0) Έ No. Tf m VO 卜 128394.doc -52- 200840576 Yield 35% 81% 56% 66% 68% 45% 56% Procedure according to step 7.2 Direct preparation according to Example 10 Direct preparation according to Example 10 Direct preparation according to Example 11 Direct Preparation according to Example 10 Direct Preparation According to Example 10 Direct Preparation According to Example 14 Direct Preparation of Compound III Step 7.1 Step 2.1 Step 8.1 Step 2.1 Step 2.1 Step 2.1 Step 2.1 46-47 1 1 1 1 1 1 ^NMR δ = (300 ΜΗζ, CDCI3) 7.86 (m? 1H); 7.64 (m? 1H); 7.53-7.44 (unresolved peak, 2H); 7·40-7·26 (unresolved peak, 5H); 4·28 (d5 2H); 3.27 (wide peak s, 1H) 7.35 (m, 2H); 7.15 (m, 2H); 7.06 (m, 1H); 5.09 (wide peak s5 1H) 7.28 (m? 2H); 7.08 (m? 2H); 6.97 (m,1H); 4.97 (wide peak s, 1H) 7.26 (d? 2H); 7.04 (d? 2H); 5.14 (wide peak s, 1H) 7.10 (d, 2H); 6.99 (d , 2H); 4.99 (wide peak 3, 1 printing; 2.31 (3, 3H) 7·02 (m, 2H); 6·85 (m, 2H); 4.97 (wide peak s, 1H); 3.78 (s, 3H) 7·69 (m, 2H); 7.55-7, 42 (unresolved peak, 3H); 7·24 (m, 2H); 7·00_6·92 (unresolved peak, 3H); 5.23 ( Wide peak s, 1H) P? Li.--U. Person 2 5 ro b CF2CF3 ro δ m U m U LL--U. CO ό bb ο 1 b No. 00 ON 〇f〇I28394.doc -53- 200840576 U"l 13⁄43⁄4 31% 35% 80% O QO 00 1 44% 70% 96% Procedure according to step 6.2 of TFA According to step 6.2 of TFA According to step 6·2 of TFA Example 3 or 4 of TFA Example 12 TFA Direct preparation of Example 2 TFA Compound III Steps 2·1 Step 2.1 Step 2.1 Step 2.1 or 3·1 Step 2.1 Step 2.1 Step 2.1 SB Surface 1 88-89 90-91 89-90 70-71 95-96 ^-NMR δ=(300ΜΗζ, CDC13) 7·00 -6·94 (unresolved peak, 4Η); 5·03 (wide peak s, 1Η) 7.54 (d? 2H); 7.16(d? 2H); 5,35 (wide peak 3,111) 8.22 (m , 2H); 7.20 (m? 2H); 5.64 (wide peak s, 1H) 7.91 (d, 2H); 7.16 (d, 2H); 6·11 (wide peak s, lH); 2.56 (s, 3H) 7.41-7.26 (unresolved peak, 7H); 7.01 (111,211); 6.68 (wide peak 3, lH); 5.19 (s, 2H); 5.14 (wide peak s, lH) 7.40-7.36 (unresolved Peak, 5H); 7.31 (wide peak s, 1Η); 7·31 (m, 1H); 7.07 (wide peak s, 1Η); 6.91 (m5 1Η); 6.83 (m? 1H); 5.42 (width Peak s, lH); 5.21 (s, 2H) 7.81 (d, 2H); 7.35 (d, 2H); 6.75 (Wide peak 3,111); 2.45(8, 3H) rn smemsmsmum & δ LL \ (χΛ❹ .=(21 ο b Φ 0) 6 VO 00 Os 128394.doc -54- 200840576 Yield 80% 25% Procedure Step 1·2 of TFA 1 According to Example 12, TFA Compound III Step 5.1 Step 2.1 a ^ Laughing e 73-74 92-93 ^-NMR δ=(300ΜΗζ, CDC13) 7·43-7·39 (unresolved peak , 5H); 6.15 (wide peak s, lH); 5.42 (s, 2H) 1 7.24 (m, 2H); 6.99 (m? 2H); 6.46 (wide peak s, 1H); 5.20 (wide peak s, 1H) ); 1.50(s,9H) m δ m 13⁄4 U ο b No· (9 force OSPNtaNHS00£) p^SN ffil 128394.doc -55 - 200840576 . #?III#^^S£去孤二#驷嘁酵^>哏茫哏茫移,#(^寸_寸2荽^^ 01 (一一), v\ or- II < Yield 49% 10% 24% Step or Example Steps 2·1 and 8.2 Example 8 Steps 3·1 and 8·2 Weng g 93-94 113-114 129-130 lU NMR δ=(300ΜΗζ, CDC13) 7·69 (s, 2H ; 5·96 (s, 1Η); 3.32 (q5 4Η); L18 (q,6Η) _1 7·69 (m, 2Η); 5·90 (s, 1Η); 3.40 (m, 4H); 1.23 (t, 6H) 7.70 (s, 2Η); 6·07 (s, 1Η); 3·80-3.65 (unresolved peak, 4Η); 3·41 (m, 2H); 3.19 (m, 2H) Ρί ω ω C? ω ω m & cf2cf3 m & c? CO ο z ·_ o Z Ά 128394.doc -56- 200840576

Yield 78% 31% 21% 35% 23% 57% Step or Example Example 13 Steps 2·1 and 6.1 Steps 2·1 and 3·2 (or 2·1 and 6.1) Steps 2·1 and 6· 1 Steps 2·1 and 3·2 (or 2·1 and 6.1) Steps 2·1 and 3·2 (4 2.1 and 6.1) Geisha u <25 II 1 1 I lU NMR δ=(300ΜΗζ, CDC13) 7.69(s,2H); 6.15(s, 1Η); 3·58-3·42 (unresolved peak, 8H); 3.33 (s,6H) W τί 尨功' v〇rn 1 · rv On ^ 7 · 56 (m, 1H); 7.41 (m, 1H); 6.99-6.90 (unresolved peak, 2H); 3.42 (m, 4H); 1.24 (t?6H) 1, 7,43 (d? 2H); 6.93 (d? 2H); 3.38 (q? 4H); 1.21 (t, 6H) 7·61 (m, 1Η); 7·38 (m, 1H); 6.98-6.92 (unresolved peak, 2H); 3.41 (q, 4H); 1.23 (t, 6Η) 7.72-7.68 (unresolved peak, 2H); 7.36 (m? 1H); 7.24 (m, 1H); 3·43 (q, 4H); 1.24(t,6H) ch2ch2- OMe ω ω W ω ω CH2CHr OMe ω ω m ω ω ro & m ΙΧι U m δ ms ro bm Ph u O z u_ No. 128394.doc -57- 200840576

128394.doc -58- 200840576 Yield 67% 37% 丨84% 69% Steps or examples Steps 14·1 and 2.2 Steps 3·1 and 2·2 Steps 13·1 and 2·2 Steps 2·1 and 5 · 1 1 113-114 <25 I χΉ NMR δ = (300 ΜΗζ, CDCI3) 7.65 (m? 2H); 7.52 (m? 1H); 7.43 (m, 2H); 3·36 (m, 4H); ·19 (m,6H) 7.79 (m,2Η); 7·28 (m, 2Η); 3.71 (ddd? 2H); 3.61 (ddd, 2H); 3.43 (ddd? 2H); 3.24 (ddd? 2H) ; 2.41 (s, 3H) 7.74 (m, 2Η); 7.21 (m, 2H); 3·54-3·41 (unresolved peak, 8H); 3·26 (s, 6H); 2·35 ( s, 3H) 7·40-7·24 (unresolved peak, 5H); 5.18 (d? 1H); 5.13 (d, 1H); 3·35 (m, 4H); 1.20 (t, 6H) ω 0 CH2CH2- OMe ω I ch2ch2- OMe (3⁄4 LL--LL CO ό & m δ ro b oio 1 〇ά^〇Φ Ο. Earth. φ α> O b No. Ο 128394.doc -59- 200840576 CO —Q;

Q: — Z

CC.鹓 鹓 91 ^ ^ 1 苳驷 fin shift male 09_ ε inch attack φ ¥ yield 83% 79% 55% 1 76% 61% laugh e I 1 1 1 1 xil NMR δ = (300 ΜΗζ, CDCI3) 7.34-7.22 (not Analytical peak, 4H); 6.97 (m, 1H); 3,50 (s, 3H) 7·39_7·26 (unresolved peak, 5H); 4.26 (s, 2H); 2.88 (q, 3H) j 7.75 (d,2H); 7·34 (d,2H); 3.31 (s, 3H); 2.44 (s? 3H) 7.33-7.22 (unresolved peak, 4H); 6.97 (m, 1Η); 3·73 (wide peak m, 2Η); 1-72 (m, 2H); 1·33-1·28 (unresolved peak, 16H); 0·9 (t, 3H) 7·37-7· 26 (unresolved peak, 5H); 4·28 (s, 2Η); 2·98 (m, 2Η); 1.59 (m, 2H); 1·32-1 · 22 (unresolved peak, 16H) ; 0.88 (t9 3H) CD S (D 〇1 -(CH2)10- ch3 -(ch2)10- ch3 m & CF2CF3 r〇〇mb ro S (3⁄4 bo±o Φ 1 Έ b • o $ $ 128394 .doc •60- 200840576 Yield 27% 83% 73% 40% 99% 61% 1 1 1 1 1 1 lH NMR δ=(300ΜΗζ, CDCI3) 7.77 (m? 2H) ; 7.33 (m? 2H) ; 3.52 (Wide peak m, 2H); 2·45 (s, 3H); 1·64 (m, 2H); 1·33-1·16 (unresolved peak, 16H); 0·88 (t, 2H)莩2 S ON ffi 1 inch W ^ " ΓΟ ❼ ❼· 1 ^ a κ S ^ S ^ 7.38-7.26 (unresolved peak, 5H); 5·85 (ddt, 1Η); 5.24-5.14 (unresolved peak, 2H); 4.27 (s, 2H); 3.67 ( Broad peak m, 2H) ΊΠ1 (d? 2H); 7.33 (d? 2H); 5.68 (ddt, 1H); 5·26-5·17 (unresolved peak, 2H); 4.19 (wide peak m, 2H 7.33-7.21 (unresolved peak, 4H); 6.96 (m? 1H); 5.81 (ddt, 1H); 5.03-4.91 (unresolved peak, 2H); 3.72 (m, 2H); 2.04 (m? 2H); 1.71 (m, 2H) ; 1.32-1.26 (unresolved peak, 12H) 7·41_7·26 (unresolved peak, 9H); 7.00 (m, 1H); 5·07 (wide peak m, 2H) _(ch2)10· ch3 \ m Ph umembm & e rn δ 〇ά=〇Φ 0) bb 〇=士二. Φ Φ bb No· 128394.doc -61 - 200840576 Yield 89% 49% 75% 65% 55% 73% 21% Face 71-72 1 1 1 1 1 lU NMR δ=(300ΜΗζ, CDC13) 7.49-7.37 ( Unresolved peak, 10H); 4·35 (s, 4H) 7·78 (d, 2H); 7·36-7·33 (unresolved peak, 5H); 7.25 (m, 2H); 4.76 ( Broad peak m, 2H); 2·47 (s, 3H) 7.33-7.20 (unresolved peak, 9H); 6·99 (m, 1Η); 5·11 (q, 1Η); 1·74 (d , 3Η) 7.36-7.24 (unresolved peak, 4H); 7.02 (m, 1H); 6_00-5·56 (unresolved peak, 2H); 4.51 (m, 1H); 2.17-1.54 (unresolved Peak, 6H) 1 7·38-7·31 (unresolved peak, 4H); 7·03 (m, 1Η); 4·45 (wide peak m, 2Η); 1.84 (t, 3H) 7·38 -7·29 (unresolved peak, 5H); 4.33 (s, 2H); 3·73 (q, 2H); 1.87 (t, 3H) 7.81 (d, 2H); 7·33 (d, 2H) ;4·39 (wide peak m, 2H); 2.43 (s, 3H); 1.63 (t, 3H) % b 1! 1 II 1 II φ m & ΓΟ & mb δ m U δ υ 〇dr two. Φ 0) b b b 〇±〇 Φ 1 6 128394.doc -62· 200840576 . w 桕茫鳟道,#008_I 9#ΦΛ3> i4^wir^^冢 硪 domain bat 4mw^#4 fin shift: ΛΙ^

Synthesis conditions according to Example 17 Example 18 According to Example 17 According to Example 18 According to Example 17 | Yield 51% 64% 29% i 62% 50% Mp (°〇1 1 1 ιΈί NMR δ=(300ΜΗζ, CDC13) 7.81 (m? 2H) ; 7.37 (m? 2H) ; 4.68 (dt,1H) ; 3·30 (dt,1H) ; 2.45 (s, 3H) ; 1.80-1.48 (unresolved peak, 4H); 1.38-1.24 (not Peak of analysis, 3H); 1·12 (m, 1Η); 0.86 (t, 3Η); 0.81 (t, 3Η) • m CO ... inch - X ^ m 〇4 · ^ in * ^ rs 〇 W g Ffi 2 K inch W 〇〇• r\ * ^ £s^ - g ^ m (N · ^ \Q ^ -iZ" ^ Ch ^ 卜m 7.81-7.78 (unresolved peak, 2H); 7·37- 7.33 (unresolved peak, 2Η); 4·62 (m, 0.75H); 4.23 (dd? 0.25H); 4.04 (dd, 0.25H); 3.28 (m,0,25H); 3.12 (dd, 0.75 H) ; 3.01 (dd? 0.75H); 2.44-2.43 (unresolved peak, 3H); 1·74-1·62 (unresolved peak, 2H); 1·27-1·19 (unresolved Peak, 16H); 0.92-0.88 (unresolved peak, 3Η) Compound 0) Φ 〇: 0): 〇〆; < ω Φ O:co:〇〆;< MeO^!-cy_/scF3 —/ 1 〇/= • ο 3 fS VO 128394.doc -63- 200840576 Synthetic conditions are based on Example 18 According to Example 17, according to Example 18, according to Example 17, according to Example 18 跻ι^ι··Ι 13⁄43⁄4 67% 35% 61% 54% 73% P α I 1 1 I lH NMR δ=(300ΜΗζ, CDC13) 7.79 (m? 2H 7.34 (m5 2H) ; 4.62 (m,1H) ; 3.12 (dd,1H) ; 3,01 (dd, 1H) ; 2.44 (s? 3H) ; 1.69 (m? 2H); 1.25-1.17 (not Analytical peak, 16H); 0.88 (t, 3H) 7.82-7.76 (unresolved peak, 2H); 7.37-7.07 (unresolved peak, 7H); 4.68 (m, 0.75H); 4.28 (dd 0.25H); 4.10 (dd? 0.25H); 3.25 (m5 0.25H); 3·16 (dd, 0.75H); 3.07 (dd, 0.75H); 2.83 (m? 0.25H); 2.71-2· 46 (unresolved peak, 4.75H); 2.13-1.98 (unresolved and analyzed peak, 1.75Η); 1·83 (m? 0.25H) 7·81 (m, 2Η); 7.36 (m, 2Η) ; 7·30-7·20 (unresolved peak, 3H); 7.08 (m, 2H); 4.68 (m? 1H); 3.14 (dd, 1H); 3.05 (dd9 1H); 2.71-2.46 (not Peak of analysis, 5H); 2·05 (m, 2H) 7·79 (m, 2H); 7.35 (m, 2H); 4·82 (ddd, 1H); 3·62 (m, 1H); ·46 (s, 3H); 2.34 (m,1H); 2·11-1·57 (unresolved peak, 5H) Compound 0) φ 〇-(f)zz〇'x>& ο • ο z 'sQ £ 128 394.doc -64- 200840576 Synthesis conditions Example 17 According to Example 18 r- % % i ^ f ^ 5ΪΪΪ According to Example 17 Yield 78% 85% 70% 69% 33% Mp (°〇55-56 1 1 <25 NMR δ = (300 ΜΗζ, CDC13) 7.80 (d? 2H); 7.35 (d? 2H); 4.49 (ddd? 1H); 3.29 (ddd? 1H); 2.44 (s? 3H); 2.22 (m? 1H); 2.03 (m? 1H); 1.69-1.65 (unresolved peak, 3H); 1·48-1·44 (unresolved peak, 3H) 7.78 (d? 2H); 7.32 (d? 2H); 4.46 ( Ddd? 1H) ; 3.39 (ddd? 1H) ; 2.42 (s, 3H) ; 2.21 (m, 1H) ; 2.03 (m, 1H) ; 1.72-1.61 (unresolved peak, 3H); · 38 (unresolved peak, 3H) 4.71 (ddd, 2H); 3.69 (d9 1H); 3.65 (d? 1H); 3.41 (ddd9 2H); 3.09 (d, 1H); 3.06 (d, 1H); 2·53-2·17 (unresolved peak, 8H); 2·14-1·99 (unresolved peak, 6H); 1·78-1·40 (unresolved peak, 16H); 1.13 ( s? 3H) ; 1.12 (s? 3H); 0·89 (s, 3H); 0.88 (s, 3H) 7·79 (m, 2H); 7·33 (m, 2H); 4·60 (ddd 1H) ; 3.44 (ddd9 1H) ; 2.44 (s? 3H) ; 2.19 (m, 1H) ; 2.01 (m5 2H) ; 1·93-1·27 (unresolved peak, 9H) Compound CF3\ Ρ- δ^ΓΛ-Μβ t>. 〇 CF3CF2S. P-S~\ /-Me 0. 1 〇, =〇1 (7)人 ί lT zu (N 1 Φ 〇 2 (7) 〇: Ό 0 • ο QC ON A 0 128394.doc -65- 200840576 Synthesis conditions according to Example 18 According to Example 17 According to Example 18 Example 19 According to Example 17 according to Example 18 according to Example 17 | Yield 41% 46% 38% _1 94 % 60% 90% 14% Mp (°〇1 50-51 1 1 1 NMR δ=(300ΜΗζ, CDC13) 7.77 (m? 2H) ; 7.33 (m? 2H) ; 4.67 (m, 1H) ; 3.37 (m, 1H) ; 2.44 (s, 3H) ; 1.95-1.66 (unresolved peak, 10H); 1·52-1·43 (unresolved peak, 2H) ^ w 〇\ • - O (N · ^ a K inch; _ * m heart: s-^ ^ 5? ^ ^ — <N 4.10 (m? 1H) ; 3.45 (m 1H); 2.39 (m, 1H); 2.22 (m, 1H); 1.86-1.67 (unresolved peak, 3H); 1.62-1.38 (unresolved peak, 3H) 4·97 (m, 1H); 4.91 (m,1H) ; 3.84 (t,1H) ; 1.79 (m,3H) ; 1·67 (m, 2H) ; 1·35-1·28 (unresolved peak, 12H); 0·91 ( t,3H) 7.49-7.42 (unresolved peak, 2H); 7·36-7·25 (unresolved peak, 3Η); 3.68 (m, 2H) Compound CF3S pSH^KMe 0. IX) CO !/ Scf3 C〇scF3 reckless rs r〇in 128394.doc -66- 200840576 Conditional Example 23 According to Example 20 Example 20 Example 21 According to Example 21 | Yield 71% 73% 41% 72% 88% Mp (°〇II 1 1 48-49 lH NMR δ=(3〇〇ΜΗζ9 CDCI3) ΟΝ \ 〇^ 00 ...4 κ 〇— ^ ^ ^ S «Ν · Α ηΜ 遂二军κ wcn^ a ^ * wW 〇· ςτ 〇13⁄4 m ^ z ^ —· s γ w 7·83-7·81 (not Peak of analysis, 4H); 7·38-7·35 (unresolved peak, 4Η); 2·69 (t, 2H); 2.47 (s? 6H); 2.32 (s3 2.7H); 2·12 ( t,8H) ; 1.85 (s,3H) ; 1·52-1.33 (unresolved peak, 4H); 0,83 (t, 3H) ; 0.79 (t? 7H) K ® <N "T Pi ^ ^ ^ S ffi <N ^ . i έ^ϊ Bu (N 8·56 (wide peak s, 1H); 7.80 (m, 1H); 7.53 (d, 1H); 7.42 (m, 1H); 7.32 -7·24 (unresolved peak, 2H). £ ^ • CN SG mountain inch - Bu "〇...a ffi —C-召^ · CS K/1 Q ^ xT 00 Q\ in inch οό ϊ> caSCFj Ο ω g to, ^ V Φ 〇 〇, 〇i:o + 1 Φ Φ Me_G^t'〇\ H 0_>4 /^^ scf3 CQ • ο r- 00 % I28394.doc -67- 200840576

fH η tH (S fH cs (4) nn 漤¥ ¥ IK «ft*/, 跻黑跻ill η ON 00 o\ ON s © Os t> (N inch Ρ in vn VO Ο 1 r—HI TH 1 c\ ψ i α 1 r—^ ^T) 1 ro wo in t—HC\ Ο r—Η NMR δ=(300ΜΗζ, CDC13) i ^ 〇Β mw 〇! • ^ 〇\ ffi ^ -—ffi ” S - w (N 〇〇C\ ^ w 1H) ; 8.46 (m, ;7.94 (dd,1H); 3.91 (s,3H)1 1H) ; 8·63 (m, ;8.17 (m? 1H); 1H)1 ^ ffi g (N *s O life ^ W a ffi invites two; 7·66 (m, 1H); peak, 2H); 7.18 Η); 2.74 (t? 2Η) inch Ό • 39 (wide peak s , ;8.00 (d,1H) 65 (dd,1H); heart ffidan^ wr-w o on °iv〇00 9 * «Ν二四旦χη ^^^ cn W inch ο ^ CN匕(wide peak s , 2H) 7·29 (unresolved Η); 3·28 (t,2 — ^ \〇^ <N 00 k τ—H w^* ^ ffi rH :H ^ —ffi rH d two ffi τ-Η -t ο ^ ^ s 00 ι> w ^JPO 〇a B CO 逵·^工工«ο Ο δ C0 V- 〇w Η Τί 1 Έ \=JW Έ · ο n oo m 00 IT) 00 ν〇00 128394.doc -68- 200840576 Synthesis conditions I according to Example 21 Example 22 Yield 19% 90% s 0. α 50-51 1 !Η NMR δ = (300 ΜΗζ, CDC13) 9_69 (wide peak s, 1 Η); 7.65 (m, 1 Η); 7.36-7.25 (unresolved peak, 2H); 7·14 (m,1Η);3.12-3.10 (unresolved peak, 4Η); 2·27 (wide peak s) 1 7·53(Π1,1Η); 6.54-6.50 (unresolved peak, 2Η) ;3·88 (s,3Η) ; 3·83 (s, 3H) Compound j CO cm LL OMe SCF3 οο £ 00 00 (9-p1«nhwoo£) Ή1ΛΙΝ Hj 128394.doc -69

Claims (1)

200840576 X. Patent application scope: 1 · A method for preparing a sulfonamide compound of the formula (I) and a sulfurous compound of the formula (II), Λ SI (I) R〇(Π) wherein a) l is - as the case may be Substituted aryl; - or optionally substituted heteroaryl; - or optionally substituted alkyl; or optionally substituted cycloalkyl; - or optionally substituted heterocycloalkyl; - or -SOy aryl Wherein the aryl group is optionally substituted; - or -S〇2_heteroaryl, wherein the heteroaryl is optionally substituted; -4_so2-fluoroalkyl; - or -C〇2_aryl, Wherein the aryl group is optionally substituted; - or -C〇2_heteroaryl, wherein the heteroaryl group is optionally substituted; - or -C〇2-alkyl, wherein the alkyl group is optionally Substituting; b) R2 is a perfluoroalkyl or difluoroindenylene group substituted with an aryl group, an -S-heteroaryl group or a benzin-2-yl group, the aryl group, a heteroaryl group and a benzo group. The oxazolyl group is optionally substituted, 128394.doc 200840576 0m is independently of each other a fluorenyl, anthracenyl or cycloalkyl group, or R3 and R4 together with the nitrogen atom to which they are attached form 3 to 7 member members. The n-branched includes a saturated or unsaturated heterocyclic ring of another hetero atom (such as piperidinyl, pyrrolidinyl or morpholinyl); the method is characterized by the following steps: Step 'In the organic solvent and in the tertiary amine Condensation of a compound of formula (V) with a compound of formula (V) in the presence of a compound of formula (HJ), wherein Ri, I, ^ and I are as defined above, and the heart, heart and R7 are independently selected from the optionally substituted aryl or alkyl group; R. F\/N, (V) R3 F + R, I5 1 r2 Si\ V \RR6 (IV) R, (III) - a second step in which a compound of the formula (III) itself is condensed with a compound of the formula j^NH2 (wherein, as described above) in an organic solvent in the presence of a tertiary amine (I) thiamine or a sulfinium compound of the formula (H) wherein Ri, R2, R3 and R4 are as defined above; F1 r4 ' - 2 r2 (III) (II) R. (l), s I FL 128394.doc 200840576 - a third step, as the case may be, wherein a sulfinium compound of the formula (π) is converted in an organic solvent in the presence of an acid, thereby obtaining an acid-cracking amine compound of the formula (1), wherein r, R2 , Rs and R4 are as defined above. 2. The method of claim 1, wherein when the aryl group is substituted, it is an aryl group substituted with one or more groups which are the same or different from each other selected from the group consisting of the following atoms and groups: & Halogen • Alkyla • alkoxy substituted as appropriate • Aryl group substituted as appropriate • Heteroaryl alkenyl • alkynyl • fluoroalkyl • fluoroalkoxy optionally substituted aryl group optionally substituted Substituted as appropriate - 〇-heteroaryl • -S-alkyl • -S-fluoroalkyl • Substituted as appropriate - S-aryl • As appropriate - S, heteroaryl • CN • -no2 Heterocycloalkyl 12B394.doc 200840576 • -N(Ra)(Rb) • -N(Ra)CO(Rb) • -N(Ra)COO(Rc) • -N(Re)CON(Ra)(Rb) • -N(Ra)S02(Rc) • -oso2rc • -S02N(Ra)(Rb) • -so2(rc) • -CON(Ra)(Rb) • -CORb, and • -COORc where Ra and Rb are independently selected from a hydrogen atom, and optionally substituted alkyl, (CrC4) fluoroalkyl, cycloalkyl, as appropriate An aryl group i, a heteroaryl or heterocycloalkyl group substituted by a twenty month, and Rc is a group of Ra, except for hydrogen, or Ra and Rb are formed together with a nitrogen atom to which they are attached, having 3 to 7 rings. Members and optionally include saturated or unsaturated heterocycles of other heteroatoms. 3. The method of claim 1 or 2, wherein when the heteroaryl group is substituted, it is a heteroaryl substituted with one or more groups selected from the group consisting of the following atoms and groups Halogen • Halogen • Alkaline • alkoxy substituted as appropriate • Aryl group substituted as appropriate 128394.doc 200840576 • Substituted heteroaryl • alkenyl • alkynyl • fluoroalkyl • fluoroalkoxy • Replace the -0-aryl group as appropriate • Replace the -0-heteroaryl group as appropriate - - S -alkyl group - - S - gas group • Replace the -S-aryl group as appropriate - Replace it as appropriate - S-heteroaryl • -CN • -N〇2 • Heterocycloalkyl • -N(Ra)(Rb) • -N(Ra)CO(Rb) • -N(Ra)COO(Rc) • -N (Rc)CON(Ra)(Rb) • -N(Ra)S02(Rc) • -OS〇2Rc • -S02N(Ra)(Rb) • -so2(rc) • -CON(Ra)(Rb) • -CORb, and 128394.doc 200840576 • -C〇〇R〇 where Ra, 1 and Rc are as defined in request 2. 4. A method according to the claims &&" to the term to the term, wherein the substitution is %, which is an alkyl group substituted by one or more groups which are the same or different from each other and a group: • Halogen • Substituted aryl group • Substituted heteroaryl • Heterocycloalkyl • alkoxy • Murray • Fluoroalkoxy • O-aryl substituted as appropriate • Replaced by -2 _heteroaryl•-S-alkyl When - ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ ─ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ )(Rb) • -so2(rc) • -C0Rb • -COORc 128394.doc -6- 200840576 • -C0N(Ra)(Rb) • -N(Ra)(Rb) • -N(Ra)CO(Rb • -N(Ra)COO(Rc) • -N(Rc)CON(Ra)(Rb), and • N(Ra)S02(Rc) where Ra, Rb and 11. As defined in request 2. 5. The method of claim 1, characterized in that the core is: a) an aryl group substituted with one or more (e.g., 1 to 3) atoms or groups selected from the group consisting of: • Alkali • alkoxy substituted as appropriate • aryl substituted as appropriate • heteroaryl substituted as appropriate • divalent alkynyl • fluoroalkyl • alkoxylated • • S-fluoroalkyl • CN • -N〇2 • Heterocycloalkyl • -N(Ra)(Rb) I28394.doc -7- 200840576 • -N(Ra)CO(Rb) • -N(Ra)CO〇(Rc) • - OS〇2Rc • -CON(Ra)(Rb) • -CORb, and • -CO〇Rc where Ra and Rb are independently selected from hydrogen atoms and, as appropriate, A· CU), (CVC4) fluorocarbon a base, a cycloalkyl group, an optionally substituted aryl group, optionally substituted heteroaryl or heterocycloalkyl, and employing a group of, except for hydrogen, or Ra&Rb and its attached nitrogen atom a saturated or unsaturated heterocyclic ring having 3 to 7 ring members and optionally including other heteroatoms; b) or optionally one or more (e.g., up to 3) identical or different from each other selected from the following atoms and Heteroaryl substituted by a group: • Halogen • Alkenyl alkoxy • fluoroalkyl • fluoroalkoxy • _CN • -N(Ra)(Rb) • -CORb, and • -CO 〇Rc wherein Ra, Rb and 1 are as defined above; 128394.doc -8 - 200840576 C) or optionally one or more (for example 1 to 3) groups which are identical or different from each other selected from the group consisting of the following atoms and groups Substituted alkyl: • Halogen • Alkenyl substituted as appropriate • Heteroaryl substituted as appropriate ^ • Heterocyclic alkyl group • • Alkoxy group • -S-alkyl group • Fluoroalkyl group • Fluoroalkoxy group • -CN • -N Ο 2 • -COORc • -CON(Ra)(Rb) • -N(Ra)(Rb) φ · -N(Ra)CO(Rb) • -N(Ra)COO(Rc) • -N(Rc)CON(Ra)(Rb), and '·-N(Ra)S02(Rc) . wherein Ra, Rb and Rc are as defined above; d) or -S02-aryl, wherein the aryl group The case may be substituted by one or more (for example, 1 to 3) groups which may be the same or different from each other selected from the following atoms and groups: • Halogen 128394.doc -9- 200840576 • Alkyl • alkoxy • fluoroalkyl • fluoroalkoxy • -CH • -N〇2 • -N(Ra)(Rb) -CORb ' and ? -COORc wherein Ra, Rb & Rc are as defined above; e) or -S02-heteroaryl, wherein the heteroaryl group may be identical to each other via one or more (e.g., 1 to 3) Different substituents selected from the following atoms and groups: • Halogen • alkyl • alkoxy • oxime • fluoroalkoxy • -CN • -N(Ra)(Rb) • -CORb, and • - COORc wherein Ra, Rb & Rc are as defined above; f) or -so2-fluoroalkyl; -10-128394.doc A 200840576 g) or -C〇2-alkyl, wherein the alkyl group is one or more (for example, three of the summer solstices) may be the same or different from each other and are selected from the following atoms and groups: • Fluorine • Alkenyl substituted as appropriate • Heteroaryl optionally substituted with heterocycloalkyl • alkoxy • - S-alkyl group • fluoroalkyl • fluoroalkoxy • CN • -no2 • -COORc • -CON(Ra)(Rb) • -N(Ra)(Rb) • -N(Ra)CO( Rb) • -N(Ra)CO〇(Rc) • -N(Rc)CON(Ra)(Rb), and • -N(Ra)S02(Rc) are characterized by the fact that R3 and R4 are independent of each other. Wherein Ra, 1 and Rc are as defined above. 6. A method according to any one of claims 1 to 5, which is a fluoroalkyl group. 7. The method of any one of claims 1 to 6 128394.doc -11 - 200840576 is formed as a decyl or decyloxy group, or R3 and R4 together with the nitrogen atom to which they are attached form a morpholinyl group. The method of any one of claims 1 to 7, characterized in that &, & and the heart is a methyl group. 9. The method of any one of claims 1, 6, 7, or 8 wherein the compound of formula (10) is reacted by reacting a compound of formula (IV) with a compound of formula (v) at a temperature of from 40 c to shoulder. And get. I 0 · Method of seeking item 1, bean Nn--s^^,, Temple is the tertiary amine selected from triethylamine, N-isopropylethylamine, pyridine or ? II Jm ^ II, — methyl bite. U. The method of spraying the permanent item 1, wherein the characteristic agent ' is preferably digas methane. 'Bathing agent is non-polar soluble 128394.doc -12- 200840576 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If the case has a chemical formula, please reveal the best display. Chemical formula of the invention: H Ri'N, f (1) (II) OI 128394.doc