Process for preparing microbicidal oxadiazole derivatives

Abstract

The present invention relates to a process according to Scheme 1 for the preparation of microbicidal 5-trifluoromethyl-1,2,4-oxadiazole derivatives of formula (I) suitable for use, e.g., as active ingredients, having microbicidal, in particular fungicidal, activity. TIFF2022529006000100.tif39160 Scheme 1

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of microbicidal oxadiazole derivatives having microbicidal, in particular fungicidal, activity and suitable for use, for example as active ingredients. [Background technology]

[0002] The formation of substituted 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles by reaction of amidoximes with trifluoroacetic anhydride in the presence of a base in a suitable solvent is described in WO 2017 / 055473.

[0003] Among the disadvantages of this reaction, mention may be made of the irreversible hydrolysis due to decomposition of the 5-trifluoromethyl-1,2,4-oxadiazole group, which can result in the formation of by-products and thus reduce the chemical yield of the oxadiazole derivative provided. Summary of the Invention [Means for solving the problem]

[0004] According to the present invention, a compound of formula (I): [ka] [In the formula, A is A-1 or A-2: [ka] (wherein A-1 and A-2 are each a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 and optionally substituted with 1 or 2 substituents independently selected from haloalkoxy. and; n is 0, 1 or 2; R 1 and R 2is hydrogen, halogen, cyano, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl; or R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropyl ring; Z is Z 1 Or Z 2 and; Z 1 is hydrogen, halogen, cyano, -OH, or -SH; Z 2 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -COOH, -C(=W)-X, -NR 3 R 4 , -NR 3 -C(=W)-X, -S(=O)2-R 5 , or -NR 3 -S(=O)2-R 5 or Z 2 is C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-2 Alkyl, Heterocyclyl, HeterocyclylC 1-2 Alkyl, Phenyl, Phenyl C 1-2 Alkyl, Heteroaryl, HeteroarylC 1-2 alkyl, or heterodiaryl, where the heterocyclyl moiety is selected from the group consisting of 1, 2, or 3 heteroatoms or O, S, N, NR 6 , C(═O) and S(═O)2, and the heteroaryl moiety is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; wherein any of the cycloalkyl, heterocyclyl, phenyl, heteroaryl, or heterodiaryl moieties is R 7optionally substituted with 1 or 2 substituents, which may be the same or different, selected from W is O or S; X is halogen, -NR 3 R 4 , R 5 , -NR 3 -[CR 8 R 9 ] m -CR 10 (=NR 5 ), -C(=O)-NR 3 R 4 , -C(=O)-R 5 , -C(=NC 1-4 Alkoxy)-R 5 , or -OR 11 and; R 3 and R 4 is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Haloalkoxy, C 1-2 Haloalkoxy C 1-4 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl, C 3-4 Alkenyloxy, C 3-4 Alkynyloxy, C 1-4 Alkylcarbonyloxy, NC 1-4 Alkylamino and N,N-diC 1-4 alkylamino; or R 3 and R 4 is C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-2 Alkyl, Heterocyclyl, HeterocyclylC 1-2 Alkyl, Phenyl, Phenyl C 1-2 Alkyl, Heteroaryl, and Heteroaryl C 1-2alkyl, where the heterocyclyl moiety is selected from 1, 2, or 3 heteroatoms or O, S, N, NR 6 , C(═O) and S(═O)2, and the heteroaryl moiety is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; wherein any of the cycloalkyl, heterocyclyl, phenyl, or heteroaryl moieties is R 7 optionally substituted with 1 or 2 substituents, which may be the same or different, selected from R 3 and X is R 3 together with the nitrogen atom to which it is attached and together with the group -C(=W), heterocyclyl, heterocyclylC 1-6 Alkyl, Heteroaryl, HeteroarylC 1-2 alkyl, or heterodiaryl; where the heterocyclyl moiety is selected from the group consisting of 1, 2, or 3 heteroatoms or O, S, N, NR 6 , C(═O) and S(═O)2, and the heteroaryl moiety is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; wherein any of the heterocyclyl, heteroaryl, or heterodiaryl moieties is R 7 optionally substituted with 1 or 2 substituents, which may be the same or different, selected from R 5 is C 1-4 Alkyl, C 1-4 Haloalkyl, Hydroxy C 1-4 Alkyl, Cyano C 1-4 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 1-4 Alkoxy C 1-4 Alkyl or C 1-2 Haloalkoxy C 1-4 is alkyl; or R 5 is C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-2 Alkyl, Heterocyclyl, HeterocyclylC 1-6 Alkyl, Phenyl, Phenyl C 1-2 Alkyl, Heteroaryl, HeteroarylC 1-2 alkyl, or heterodiaryl, where the heterocyclyl moiety is selected from the group consisting of 1, 2, or 3 heteroatoms or O, S, N, NR 6 , C(═O) and S(═O)2, and the heteroaryl moiety is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; wherein any of the cycloalkyl, heterocyclyl, phenyl, heteroaryl, or heterodiaryl moieties is R 7 optionally substituted with 1 or 2 substituents, which may be the same or different, selected from R 6 is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, formyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxycarbonyl, NC 1-4 Alkylaminocarbonyl, N,N-diC 1-4 Alkylaminocarbonyl, C 1-4 Alkylsulfonyl, NC 1-4 Alkylaminosulfonyl or N,N-diC 1-4 alkylaminosulfonyl; R 7 is halogen, cyano, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Alkenyloxy, C 3-4 Alkynyloxy, NC1-4 Alkylamino, N,N-diC 1-4 Alkylamino, C 1-4 Alkyl carbonyl, C 1-4 Alkoxycarbonyl, aminocarbonyl, C 1-4 Alkylcarbonylamino C 1-4 Alkyl, NC 1-4 Alkylaminocarbonyl, N,N-diC 1-4 Alkylaminocarbonyl, C 1-4 Alkoxycarbonylamino, NC 1-4 Alkoxyaminocarbonyl, NC 1-4 Alkyl-NC 1-4 Alkoxyaminocarbonyl, C 3-8 Cycloalkylaminocarbonyl, NC 3-8 Cycloalkyl C 1-2 Alkylaminocarbonyl, NC 1-4 Alkoxy C 1-4 Alkylaminocarbonyl, NC 1-4 Alkoxy C 1-4 Alkylimino, C 1-4 Alkylsulfinyl or C 1-4 is alkylsulfanyl; m is 0, 1 or 2; R 8 and R 9 is hydrogen, halogen, cyano, C 1-4 Alkyl, and C 1-4 haloalkyl; or R 8 and R 9 together with the carbon atom to which they are attached form a cyclopropyl ring; R 10 is hydrogen, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl, C 1-4 Haloalkyl, C 3-8 cycloalkyl, or phenyl; R 11 is C 1-8 Alkyl, C 1-4 Haloalkyl, Hydroxy C 1-6Alkyl, C 1-4 Alkoxy C 1-6 Alkyl, C 1-2 Haloalkoxy C 1-4 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl or C 1-4 alkylcarbonyloxy C1-C4 alkyl] A process for preparing a compound of the formula The method comprises reacting a compound of formula (II): [ka] (In the formula, A, n, R 1 , R 2 and Z is as defined for compounds of formula (I). with a compound of formula (III): [ka] (In the formula, R 12 is C 1-4 (It is alkyl) With a compound of the formula:

[0005] Surprisingly, it has now been found that the process of the present invention advantageously provides a means for preparing compounds of formula (I) in high isolated yields. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] The compounds of formula (I) can be used in the agricultural sector and related fields of use, for example, as active ingredients for controlling plant pests or against non-living organisms for controlling damaging microorganisms or organisms potentially harmful to humans.The novel compounds are distinguished by excellent activity at low application rates, by being well tolerated by plants and by being environmentally safe.They have very useful curative, preventive and systemic properties and can be used to protect a large number of cultivated plants.The compounds of formula (I) can be used to suppress or eradicate pests that appear on plants or plant parts (fruits, flowers, leaves, stems, tubers, roots) of different crops of useful plants, while at the same time also protecting those parts of the plants that grow later, for example, from phytopathogenic microorganisms.

[0007] The compound of formula (I) has a very advantageous level of biological activity for protecting plants from diseases caused by fungi.Therefore, the compound of formula (I) is particularly suitable for use as a fungicide.The term "fungicide" as used herein means a compound that inhibits, modifies or prevents the growth of fungi.According to this particular aspect of the present invention, this use can exclude the method of treatment of human or animal body by surgery or therapy.

[0008] The compounds of formula (I) are active, for example, against disease fungi and fungal vectors as well as phytopathogenic bacteria and viruses.

[0009] As used herein, the terms "halogen" or "halo" refer to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine.

[0010] As used herein, cyano refers to the group --CN.

[0011] As used herein, amino refers to the group --NH.

[0012] As used herein, hydroxy refers to the group --OH.

[0013] As used herein, the term "C 1-6 "Alkyl" refers to a straight or branched hydrocarbon chain radical having from 1 to 6 carbon atoms, containing no unsaturation, consisting exclusively of carbon and hydrogen atoms, and attached to the remainder of the molecule by a single bond. 1-4 Alkyl" and "C 1-2 "Alkyl" should be construed accordingly. 1-6 Alkylene", "C 1-4 Alkylene" or "C 1-2 "Alkylene" groups are each defined as C, except that such groups are attached to the remainder of the molecule by two single bonds. 1-6 Alkyl, C 1-4 Alkyl or C 1-2 Refer to the corresponding definition of alkyl. 1-6 Examples of alkyl include, but are not limited to, methyl, ethyl, iso-propyl, n-propyl, and tert-butyl.

[0014] As used herein, the term "C 1-4 "Alkoxy" means a group of the formula -OR a where R a is a C 1-4 It is an alkyl group. 1-4 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, and propoxy.

[0015] As used herein, the term "C 1-4 Alkoxy C 1-4 "Alkyl" is a group of the formula R b -OR a -, where R b is a C 1-4 is an alkyl group, R a is a C 1-4 It is an alkylene group.

[0016] As used herein, the term "C 1-4 "Alkylsulfanyl" is a group of the formula -SR a where R a is a C 1-4 It is an alkyl group.

[0017] As used herein, the term "C 1-4 "Alkylsulfinyl" refers to a group of the formula -S(-O)R a where R a is a C 1-4 It is an alkyl group.

[0018] As used herein, the term "C 1-4 "Alkylsulfonyl" refers to a group of the formula -S(O)R a where R a is a C 1-4 It is an alkyl group.

[0019] As used herein, the term "C 2-4 "Alkenyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing at least one double bond which may be of either the (E)- or (Z)-configuration, having from 2 to 4 carbon atoms attached to the remainder of the molecule by a single bond. 3-4 "Alkenyl" should be construed accordingly. 2-4 Examples of alkenyl include, but are not limited to, ethenyl and prop-1-enyl.

[0020] As used herein, the term "C 2-6 "Alkynyl" refers to a straight or branched hydrocarbon chain radical having 2 to 4 carbon atoms, containing at least one triple bond, consisting exclusively of carbon and hydrogen atoms and attached to the remainder of the molecule by a single bond. 3-6 "Alkynyl" should be construed accordingly. 3-6Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, propargyl (prop-2-ynyl), but-1-ynyl, and 3-methyl-but-1-ynyl.

[0021] As used herein, the term "C 3-4 "Alkenyloxy" means a group of the formula -OR a where R a is a C 3-4 It is an alkenyl group.

[0022] As used herein, the term "C 3-4 "Alkynyloxy" means a group of the formula -OR a where R a is a C 3-4 It is an alkynyl group.

[0023] As used herein, the term "C 1-4 "Alkoxycarbonyl" means a group of the formula -C(O)OR a where R a is a C1-C4 alkyl group as generally defined above.

[0024] As used herein, the term "C 1-4 "Alkylcarbonyl" is a group of the formula -C(O)R a where R a is a C 1-4 It is an alkyl group.

[0025] As used herein, the term "formyl" refers to a group of formula -C(O)H.

[0026] As used herein, the term "C 1-4 "Alkylcarbonyloxy" is a group represented by the formula -OC(O)R a where R a is a C 1-4 It is an alkyl group.

[0027] As used herein, the term "C 1-4 "Haloalkoxy" means a C alkyl group as defined above substituted with one or more of the same or different halogen atoms. 1-4 Refers to an alkoxy group. 1-4 Examples of haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, and trifluoroethoxy.

[0028] As used herein, the term "C 1-2 Haloalkoxy C 1-4 "Alkyl" means a C alkyl group as defined above. 1-2 C as defined above substituted with haloalkoxy groups 1-4 Refers to an alkyl group.

[0029] As used herein, the term "C 1-4 "Haloalkyl" refers to a C alkyl group as generally defined above substituted with one or more of the same or different halogen atoms. 1-4 This refers to an alkyl group. 1-4 Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, and trifluoroethyl.

[0030] As used herein, the term "C 2-4 "Haloalkenyl" refers to any C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C31, C42, C53, C64, C76, C88, C98, C10, C11, C22, C1 2-4 This refers to an alkenyl group.

[0031] As used herein, the term "C 3-8 "Cycloalkyl" refers to a stable, monocyclic or bicyclic ring group that is saturated or partially unsaturated and contains 3 to 8 carbon atoms. 3-6 Cycloalkyl should be construed accordingly. 3-8Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0032] As used herein, the term "C 3-8 Cycloalkyl C 1-2 "Alkyl" means a C alkyl group as defined above. 1-2 C, as defined above, attached to the remainder of the molecule by an alkylene group. 3-8 The term "C" refers to a cycloalkyl ring. 3-6 Cycloalkyl C 1-2 Alkyl" and "C 3-4 Cycloalkyl C 1-2 "Alkyl" should be construed accordingly. 3-8 Cycloalkyl C 1-2 Examples of alkyl include, but are not limited to, cyclopropyl-methyl, cyclobutyl-ethyl, and cyclopentyl-propyl.

[0033] As used herein, the term "C 3-8 "Cycloalkylaminocarbonyl" refers to a group of the formula -C(O)NR a where R a is a C 3-8 It is a cycloalkyl group.

[0034] As used herein, the term "NC 3-8 Cycloalkyl C 1-2 "Alkylaminocarbonyl" refers to a group of the formula -C(O)NR a where R a is the C 3-8 Cycloalkyl C 1-2 It is an alkylene group.

[0035] As used herein, the term "C 1-4 "Alkoxycarbonylamino" means a group of the formula -NH-C(O)-OR a where R a is the C 1-4It is an alkyl group.

[0036] As used herein, the term "C 1-4 Alkoxycarbonylamino C 1-4 "Alkyl" is a group of the formula -R a C(O)NHR b where R a is the C 1-4 is an alkoxy group, R b is the C 1-4 It is an alkylene group.

[0037] As used herein, the term "C 1-4 "Alkylcarbonyloxy" is a group represented by the formula -OC(O)R a where R a is a C 1-4 It is an alkyl.

[0038] As used herein, the term "C 1-4 Alkylcarbonyloxy C 1-4 "Alkyl" is a group of the formula -R a O.C.(O)R b where R a is a C 1-4 is an alkylene group, R b is a C 1-4 It is an alkyl.

[0039] As used herein, oxo refers to a ═O group, e.g., a ketonyl (—C(O)—), sulfinyl (—S(O)—), or sulfonyl (—S(O)2—) oxygen.

[0040] As used herein, aminocarbonyl refers to the group -C(O)NH2.

[0041] As used herein, the term "NC 1-4 "Alkylamino" refers to a group of the formula -NH-R a where R ais the C 1-4 It is an alkyl group.

[0042] As used herein, the term "N,N-diC 1-4 "Alkylamino" refers to a group represented by the formula -N(R a )R a where each R a are C 1-4 It is an alkyl group.

[0043] As used herein, the term "N,N-diC 1-4 "Alkylaminocarbonyl" refers to a group of the formula -C(O)NR a (R a ) where each R a are C, which may be the same or different, as generally defined above. 1-4 It is an alkyl group.

[0044] As used herein, the term "NC 1-4 "Alkylaminocarbonyl" refers to a group of the formula -C(O)NHR a where R a is a C 1-4 It is an alkyl.

[0045] As used herein, the term "NC 1-4 Alkoxy C 1-4 "Alkylaminocarbonyl" refers to a group of the formula -C(O)NHR a OR b where R a is a C 1-4 is an alkylene group, R b is a C 1-4 It is an alkyl group.

[0046] As used herein, the term "NC 1-4 Alkoxyaminocarbonyl has the formula -C(O)NHOR a where R ais a C 1-4 It is an alkyl group.

[0047] As used herein, the term "NC 1-4 Alkyl-NC 1-4 Alkoxyaminocarbonyl is a group represented by the formula -C(O)N(R a ) OR b where R a is a C 1-4 is an alkyl group, R b is a C 1-4 Alkyl group (R a (same or different from).

[0048] As used herein, the term "C 1-4 Alkylcarbonylamino C 1-4 "Alkyl" is a group of the formula R b -C(O)NHR a -, where R b is C 1-4 is an alkyl group, R a is a C 1-4 It is an alkylene group.

[0049] As used herein, the term "NC 1-4 Alkoxy C 1-4 "Alkylimino" means a group of the formula -C(N)OR a where R a is a C 1-4 It is an alkyl group.

[0050] As used herein, the term "phenyl C 1-2 "Alkyl" means a C alkyl group as defined above. 1-2 Refers to a phenyl ring that is attached to the rest of the molecule by an alkylene group.

[0051] As used herein, the term "aryl" refers to an aromatic ring system consisting solely of carbon and hydrogen atoms, which may be monocyclic, bicyclic or tricyclic. Examples of such ring systems include phenyl, naphthalenyl, anthracenyl, indenyl or phenanthrenyl.

[0052] As used herein, the term "heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring group containing 1, 2, 3, or 4 heteroatoms individually selected from nitrogen, oxygen, and sulfur (unless otherwise specified). Heteroaryl groups can be bonded via a carbon atom or a heteroatom. Examples of heteroaryl include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, or pyridyl.

[0053] As used herein, the term "heteroaryl 1-2 "Alkyl" means a C alkyl group as defined above. 1-2 Refers to a heteroaryl ring that is attached to the remainder of the molecule by an alkylene group.

[0054] As used herein, the term "heterodiaryl" refers to a 9- or 10-membered bicyclic aromatic ring system containing 1, 2, 3, or 4 heteroatoms individually selected from nitrogen, oxygen, and sulfur (unless otherwise specified). Heterodiaryl groups can be attached to the remainder of the molecule through a carbon atom or a heteroatom. Examples of heterodiaryl include, but are not limited to, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, or triazolopyridinyl.

[0055] As used herein, the term "heterocyclyl" or "heterocyclic" means (unless otherwise specified) a ring system containing one, two, or three heteroatoms individually selected from nitrogen, oxygen, and sulfur, or NR 6R refers to a stable 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring group containing groups independently selected from C(=O) and S(=O)2, where R 6 is as defined above. Heterocyclyl groups can be attached to the remainder of the molecule via a carbon atom or a heteroatom. Examples of heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, thietanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl, or perhydroazepinyl.

[0056] As used herein, the term "heterocyclyl 1-6 "Alkyl" means a C alkyl group as defined above. 1-6 The term "heterocyclyl ring" refers to a heterocyclyl ring that is attached to the rest of the molecule by an alkylene group. 1-4 Alkyl and Heterocyclyl C 1-2 "Alkyl" should be construed accordingly.

[0057] Compounds of formula (I) can be prepared by the process of the present invention as shown in the following Schemes 1-13, in which, unless otherwise indicated, the definition of each variable is as defined above for compounds of formula (I).

[0058] With respect to the compound of formula (I) obtained by the process of the present invention, n, m, A-1, A-2, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , Z(Z 1 , Z 2The symbols A, W and X generally apply to any compound of formula (IA), (IB) or (Ia), as well as to any compound of formula (II), including any compound of formula (II-A), (II-1), (II-2), (II-3) or (II-4), or to any compound of formula (IV), (V), (VI), (VII), (VIII), (IX) or (X), including any compound of formula (VII-A) or (VII-a).

[0059] Compounds of formula (I) are prepared according to the method of the present invention, which comprises reacting a compound of formula (II) with a compound of formula (III), which reaction is shown in Scheme 1. [ka] Scheme 1

[0060] For the purposes of the present invention, a compound of formula (II) may be used in the process of the present invention in any of its tautomeric forms of different (E) / (Z)-configuration.

[0061] Examples of compounds of formula (III) suitable for use in the method of the present invention include compounds of formula (III) 12 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, and iso-butyl. 12 is methyl or ethyl. The compound of formula (III) is more preferably methyl 2,2,2-trifluoroacetate or ethyl 2,2,2-trifluoroacetate.

[0062] In an embodiment of the process of the present invention, the compound of formula (I) is advantageously prepared from the compound of formula (II) by reaction with the compound of formula (III) in an amount of 1.0 to 2.0 equivalents.

[0063] In a preferred embodiment of the invention, the process of the invention is carried out in the presence of at least one base.

[0064] According to one embodiment, the process of the invention is carried out in the presence of at least one base and, optionally, at least one solvent.

[0065] Examples of suitable bases include inorganic bases and organic bases. Preferred bases are tertiary amines, substituted or unsubstituted pyridines, bicyclic amines and mixtures thereof, NaH, alkali metal C 1-6 Alkoxylates and alkaline earth metals C 1-6 Alkoxylates, for example, selected from the group consisting of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium pentoxide, potassium carbonate (K2CO3) and sodium carbonate (Na2CO3).

[0066] More preferably, the method of the present invention comprises the step of: 1-6 Alkoxylates and alkaline earth metals C 1-6 It is preferably carried out in the presence of at least one base selected from the group consisting of alkoxylates. Even more preferably, the process of the invention is carried out in the presence of sodium tert-butoxide or potassium tert-butoxide.

[0067] As used herein, the term "alkali metal" refers to an element in Group 1 of the periodic table, preferably lithium (Li), sodium (Na), or potassium (K).

[0068] As used herein, the term "alkaline earth metal" refers to elements in Group 2 of the periodic table, preferably magnesium (Mg) or calcium (Ca).

[0069] Examples of suitable solvents include, for example, methanol, ethanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, pyridine, pyrrolidine, N-methyl-2-pyrrolidone, toluene, and dioxane.

[0070] Typical reaction concentrations are usually in the range of 0.5 M to 2.0 M. Very good results have been obtained when the method of the invention is carried out at a concentration of 0.7 M.

[0071] The process of the invention is usually carried out at a temperature of 0° C. to 60° C., preferably 0° C. to 40° C., more preferably 0° C. to 25° C. Very good results have been obtained when the process of the invention is carried out at a temperature of 0° C. to 25° C.

[0072] The process of the present invention is usually carried out at a pressure of 1 atm to 5 atm.

[0073] Typical reaction times are usually in the range of 1 to 16 hours. Very good results have been obtained when the process of the invention is carried out at reaction times of 1 to 2 hours.

[0074] The reaction mixture generally results from the process of the invention, which comprises reacting a compound of formula (II) with a compound of formula (III), preferably in the presence of at least one base and, optionally, at least one solvent.

[0075] The process of the present invention typically further comprises the step of isolating the compound of formula (I) using an aqueous medium. The compound of formula (I) is advantageously isolated from the reaction mixture using an aqueous medium, typically by extractive work-up.

[0076] In a preferred embodiment of the method of the present invention, the aqueous medium is an aqueous acidic medium.The aqueous acidic medium is generally prepared by adding one or more acids to the aqueous medium.Preferably, the method of the present invention further comprises the step of isolating the compound of formula (I) using the aqueous acidic medium.

[0077] It has been found that an aqueous acidic medium during the reaction work-up can provide the most suitable medium for the purification of the compound of formula (I). In particular, it has been surprisingly found that an improvement in the isolated yield can be obtained by adding an aqueous acidic medium to the reaction mixture.

[0078] The aqueous acidic medium typically comprises an acid selected from the group consisting of acetic acid, citric acid, sulfuric acid, hydrochloric acid (HCl), HCl / water, HCl / dioxane. Preferably, the aqueous acidic medium comprises citric acid.

[0079] The aqueous acidic medium preferably has a pH of 2.0 to 6.0, more preferably 4.9 to 5.9.

[0080] The present invention also relates to any intermediate of formula (II-1), (II-2), (II-3) and (II-4) typically formed in the process of the present invention from the step of reacting a compound of formula (II) with a compound of formula (III). The intermediates so obtained may be characterized by any suitable analytical technique, such as NMR and IR spectroscopy.

[0081] It is understood that when in aqueous medium, the compound of formula (I) of the present invention may exist in reversible equilibrium with the corresponding hydrated intermediate of formula (II-4). This dynamic equilibrium may be important for the biological activity of the compound of formula (I). This reaction is shown in Scheme 2.

[0082] It is also understood that the use of an aqueous acidic medium advantageously makes it possible to avoid both the reverse hydration equilibrium giving the intermediate of formula (II-4) and the hydrolysis due to cleavage of the trifluoroacetyl group, which leads to the decomposition of the compound of formula (I) to the compound of formula (II). [ka] Scheme 2

[0083] The following list describes the substituents n, m, A-1, A-2, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , Z(Z 1, Z 2 Definitions, including preferred definitions, are provided for X, W, and X. Any of the definitions given below for any of these substituents may be combined with any definition of any other substituent given below or elsewhere in the present invention.

[0084] Preferably, n in the compounds of formula (I) is 0 or 1.

[0085] In a preferred embodiment, the present invention relates to a compound of formula (I), hereinafter referred to as compound of formula (IA), 2 The present invention relates to a method for preparing a compound of the formula:

[0086] Table 1.1: This table shows the formula (I-1): [ka] (wherein n is 1, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is as defined below in Table 1. The present invention discloses 206 specific compounds.

[0087] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0088] Each of Tables 1.2 to 1.11 (following Table 1.1) refers to Table 1 where Z is specifically defined, and includes a compound represented by formula (I-1) (wherein n, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 The present invention makes available 206 individual compounds of the formula (wherein R is as specifically defined in Tables 1.2-1.11).

[0089] Table 1.2: This table shows the compounds of formula (I-1) (wherein n is 1 and A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen, and A 1 is fluorine and Z is as defined above in Table 1.

[0090] Table 1.3: This table shows the compounds of formula (I-1) (wherein n is 1 and A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen, and A 1 is chlorine and Z is as defined above in Table 1.

[0091] Table 1.4: This table shows the compounds of formula (I-1) (wherein n is 1 and A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen, and A 1 is methyl and Z is as defined above in Table 1.

[0092] Table 1.5: This table shows the compounds of formula (I-1) (wherein n is 1 and A 1 , A 2 , A 4 , R 1 and R 2 is hydrogen, and A 3is fluorine and Z is as defined above in Table 1.

[0093] Table 1.6: This table shows the compounds of formula (I-1) (wherein n is 1 and A 2 , A 4 , R 1 and R 2 is hydrogen, and A 1 and A 3 is fluorine and Z is as defined above in Table 1.

[0094] Table 1.7: This table shows the compounds of formula (I-1) (wherein n is 1 and A 3 , A 4 , R 1 and R 2 is hydrogen, and A 1 and A 2 is fluorine and Z is as defined above in Table 1.

[0095] Table 1.8: This table shows the compounds of formula (I-1) (wherein n is 1 and A 2 , A 3 , R 1 and R 2 is hydrogen, A 1 and A 4 is fluorine and Z is as defined above in Table 1.

[0096] Table 1.9: This table shows the compounds of formula (I-1) (wherein n is 1 and A 1 , A 2 , R 1 and R 2 is hydrogen, and A 3 and A 4 is fluorine and Z is as defined above in Table 1.

[0097] Table 1.10: This table shows the compounds of formula (I-1) (wherein n is 1 and A 1 , A 2 , A3 , A 4 and R 1 is hydrogen, and R 2 is methyl and Z is as defined above in Table 1.

[0098] Table 1.11: This table shows the compounds of formula (I-1) (wherein n is 1 and A 1 , A 2 , A 4 and R 1 is hydrogen, and A 3 is fluorine, R 2 is methyl and Z is as defined above in Table 1.

[0099] Table 2.1: This table shows the formula (I-2): [ka] (wherein n is 1, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is as defined below in Table 2. 58 specific compounds of the formula:

[0100] [Table 2-1] [Table 2-2]

[0101] Each of Tables 2.2 to 2.3 (following Table 2.1) refers to Table 2, where Z is specifically defined, and includes a compound represented by formula (I-2) (wherein n, A 1 , A 2 , A 3 , A 4 , R 1 and R 2The present invention makes available 58 individual compounds of the following formula:

[0102] Table 2.2: This table shows the compounds of formula (I-2) (wherein n is 1 and A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen, and A 1 is fluorine and Z is as defined above in Table 2.

[0103] Table 2.3: This table shows the formula (I-2) (wherein n is 1 and A 1 , A 2 , A 4 , R 1 and R 2 is hydrogen, and A 3 is fluorine and Z is as defined above in Table 2.

[0104] Table 3.1: This table shows the formula (I-3): [ka] (wherein n is 1 and R 1 and R 2 is hydrogen and Z is as defined below in Table 3. The present invention discloses 373 specific compounds.

[0105] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8]

[0106] Table 3.2: This table shows the compounds of formula (I-3) (wherein n is 1 and R 1 and R 2 is hydrogen and Z is N-(2-methoxyethyl)-1H-pyrazole-4-carboxamide.

[0107] Table 3.3: This table shows the compounds of formula (I-3) (wherein n is 1 and R 1 is hydrogen, and R 2 is methyl and Z is as defined above in Table 3.

[0108] Table 4.1a: This table shows the formula (I-4a): [ka] (wherein n is 0, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -C(=W)-R 5 where W is O and R 5 is as defined below in Table 4) The present invention discloses 139 specific compounds.

[0109] [Table 4-1] [Table 4-2]

[0110] (Continued from Table 4.1a) Each of Tables 4.2a to 4.5a is 5 Formula (I-4a) (wherein n, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 The present invention makes available 139 individual compounds of the formula (as specifically defined in Tables 4.2a-4.5a).

[0111] Table 4.2a: This table shows the compounds of formula (I-4a) (wherein n is 0 and A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen, and A 1 is fluorine and Z is -C(=W)-R 5 where W is O and R 5 discloses 139 specific compounds of the formula (as defined above in Table 4).

[0112] Table 4.3a: This table shows the compounds of formula (I-4a) (wherein n is 0 and A 1 , A 2 , A 4 , R 1 and R 2 is hydrogen, and A 3 is fluorine and Z is -C(=W)-R 5 where W is O and R 5 discloses 139 specific compounds of the formula (as defined above in Table 4).

[0113] Table 4.4a: This table shows the compounds of formula (I-4a) (wherein n is 0 and A 2 , A 4 , R 1 and R 2 is hydrogen, and A 1 and A 3 is fluorine and Z is -C(=W)-R 5 where W is O and R5 discloses 139 specific compounds of the formula (as defined above in Table 4).

[0114] Table 4.5a: This table shows the formula (I-4a) (wherein n is 0 and A 3 , A 4 , R 1 and R 2 is hydrogen, and A 1 and A 2 is fluorine and Z is -C(=W)-R 5 where W is O and R 5 discloses 139 specific compounds of the formula (as defined above in Table 4).

[0115] Table 4.1b: This table shows the formula (I-4b): [ka] (wherein n is 1, A 1 , A 2 , A 3 , A 4 and R 1 is hydrogen, and R 2 is hydroxy and Z is R 5 where R 5 is as defined above in Table 4) The present invention discloses 139 specific compounds.

[0116] (Continued from Table 4.1b) Each of Tables 4.2b to 4.5b is 5 Formula (I-4b) (wherein n, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 The present invention makes available 139 individual compounds of the formula (wherein R is as specifically defined in Tables 4.2b-4.5b).

[0117] Table 4.2b: This table shows the compounds of formula (I-4b) (wherein n is 1 and A 2 , A3 , A 4 and R 1 is hydrogen, and R 2 is hydroxy, and A 1 is fluorine, Z is R as defined above in Table 4 5 The present invention discloses 139 specific compounds of the formula:

[0118] Table 4.3b: This table shows the compounds of formula (I-4b) (wherein n is 1 and A 1 , A 2 , A 4 and R 1 is hydrogen, and R 2 is hydroxy, and A 3 is fluorine, Z is R as defined above in Table 4 5 The present invention discloses 139 specific compounds of the formula:

[0119] Table 4.4b: This table shows the compounds of formula (I-4b) (wherein n is 1 and A 2 , A 4 and R 1 is hydrogen, and R 2 is hydroxy, and A 1 and A 3 is fluorine, Z is R as defined above in Table 4 5 The present invention discloses 139 specific compounds of the formula:

[0120] Table 4.5b: This table shows the compounds of formula (I-4b) (wherein n is 1 and A 3 , A 4 and R 1 is hydrogen, and R 2 is hydroxy, and A 1 and A 2 is fluorine, Z is R as defined above in Table 4 5 The present invention discloses 139 specific compounds of the formula:

[0121] Table 4.6b: This table shows the compounds of formula (I-4b) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 and R1 is hydrogen, and R 2 is hydroxy and Z is 5-methylpyrazin-2-yl.

[0122] Table 5.1: This table shows the formula (I-5): [ka] (wherein n is 0, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -C(=O)-C(=O)-NR 3 R 4 where R 3 is hydrogen, and R 4 is as defined below in Table 5) 40 specific compounds are disclosed.

[0123] [Table 5]

[0124] (Continued from Table 5.1) Each of Tables 5.2 to 5.5 is R 4 Formula (I-5) (wherein n, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 The present invention makes available 40 individual compounds of the formula (wherein R is as specifically defined in Tables 5.2 to 5.5).

[0125] Table 5.2: This table shows the compounds of formula (I-5) (wherein A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen, and A 1 is fluorine and Z is -C(=O)-C(=O)-NR 3 R 4where R 3 is hydrogen, and R 4 discloses 40 specific compounds of the formula (as defined above in Table 5).

[0126] Table 5.3: This table shows the compounds of formula (I-5) (wherein A 1 , A 2 , A 4 , R 1 and R 2 is hydrogen, and A 3 is fluorine and Z is -C(=O)-C(=O)-NR 3 R 4 where R 3 is hydrogen, and R 4 discloses 40 specific compounds of the formula (as defined above in Table 5).

[0127] Table 5.4: This table shows the compounds of formula (I-5) (wherein A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -C(=O)-C(=O)-NR 3 R 4 where R 3 is methyl, R 4 discloses 40 specific compounds of the formula (as defined above in Table 5).

[0128] Table 5.5: This table shows the compounds of formula (I-5) (wherein A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -C(=O)-C(=O)-NR 3 R 4 where R 3 is methoxy and R 4 discloses 40 specific compounds of the formula (as defined above in Table 5).

[0129] Table 6.1: This table shows the formula (I-6): [ka] (wherein n is 1, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-X, where R 3 is methyl, W is O, and X is as defined below in Table 6. 149 specific compounds of the formula:

[0130] [Table 6-1] [Table 6-2]

[0131] Each of Tables 6.2 to 6.11 (following Table 6.1) refers to Table 6 where X is specifically defined, and is a compound represented by formula (I-6) (wherein n, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 The present invention makes available 149 individual compounds of the following formula (wherein R is as specifically defined in Tables 6.2 to 6.11):

[0132] Table 6.2: This table shows the compounds of formula (I-6) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-X, where R 3 is ethyl, W is O, and X is as defined above in Table 6.

[0133] Table 6.3: This table shows the formula (I-6) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-X, where R 3 is isopropyl, W is O, and X is as defined above in Table 6.

[0134] Table 6.4: This table shows the compounds of formula (I-6) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-X, where R 3 is cyclopropyl, W is O, and X is as defined above in Table 6.

[0135] Table 6.5: This table shows the formula (I-6) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-X, where R 3 is 2-methoxyethyl, W is O, and X is as defined above in Table 6.

[0136] Table 6.6: This table shows the compounds of formula (I-6) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-X, where R 3is 2,2,2-trifluoroethyl, W is O, and X is as defined above in Table 6.

[0137] Table 6.7: This table shows the formula (I-6) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-X, where R 3 is methoxy, W is O, and X is as defined above in Table 6.

[0138] Table 6.8: This table shows the formula (I-6) (wherein n is 1 and A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen, and A 1 is fluorine and Z is -NR 3 -C(=W)-X, where R 3 is methoxy, W is O, and X is as defined above in Table 6.

[0139] Table 6.9: This table shows the compounds of formula (I-6) (wherein n is 1 and A 1 , A 2 , A 4 , R 1 and R 2 is hydrogen, and A 3 is fluorine and Z is -NR 3 -C(=W)-X, where R 3 is methoxy, W is O, and X is as defined above in Table 6.

[0140] Table 6.10: This table shows the formula (I-6) (wherein n is 1 and A 2 , A 4 , R 1and R 2 is hydrogen, and A 1 and A 3 is fluorine and Z is -NR 3 -C(=W)-X, where R 3 is methoxy, W is O, and X is as defined above in Table 6.

[0141] Table 6.11: This table shows the compounds of formula (I-6) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-X, where R 3 is ethoxy, W is O, and X is as defined above in Table 6.

[0142] Table 7.1: This table shows the formula (I-7): [ka] (wherein n is 1, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-NR 3 R 4 where R 3 is methyl, W is O, and R 4 is as defined below in Table 7) 100 specific compounds of the formula:

[0143] [Table 7-1] [Table 7-2]

[0144] (Continued from Table 7.1) Each of Tables 7.2 to 7.7 is R 4 Formula (I-7) (wherein n, A 1 , A 2 , A 3 , A 4 , R 1 , R 2 and R 3 100 individual compounds of the formula (I) are as specifically defined in Tables 7.2 to 7.7.

[0145] Table 7.2: This table shows the compounds of formula (I-7) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-NR 3 R 4 where R 3 is ethyl, W is O, and R 4 Discloses 100 specific compounds of the formula (I) as defined above in Table 7.

[0146] Table 7.3: This table shows the formula (I-7) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-NR 3 R 4 where R 3 is i-propyl, W is O, and R 4 Discloses 100 specific compounds of the formula (I) as defined above in Table 7.

[0147] Table 7.4: This table shows the formula (I-7) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 , R1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-NR 3 R 4 where R 3 is cyclopropyl, W is O, and R 4 Discloses 100 specific compounds of the formula (I) as defined above in Table 7.

[0148] Table 7.5: This table shows the formula (I-7) (wherein n is 1 and A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-NR 3 R 4 where R 3 is methoxy, W is O, and R 4 Discloses 100 specific compounds of the formula (I) as defined above in Table 7.

[0149] Table 7.6: This table shows the compounds of formula (I-7) (wherein n is 1 and A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen, and A 1 is fluorine and Z is -NR 3 -C(=W)-NR 3 R 4 where R 3 is methoxy, W is O, and R 4 Discloses 100 specific compounds of the formula (I) as defined above in Table 7.

[0150] Table 7.7: This table shows the formula (I-7) (wherein n is 1 and A 1 , A 2 , A 4 , R 1 and R 2 is hydrogen, and A 3 is fluorine and Z is -NR 3-C(=W)-NR 3 R 4 where R 3 is methoxy, W is O, and R 4 Discloses 100 specific compounds of the formula (I) as defined above in Table 7.

[0151] Table 8.1: This table shows the formula (I-8): [ka] (wherein n is 1, A 1 , A 2 , A 3 , A 4 , R 1 and R 2 is hydrogen and Z is -NR 3 -C(=W)-X, where R 3 is hydrogen, W is O, and X is as defined below in Table 8. 107 specific compounds of are disclosed.

[0152] [Table 8-1] [Table 8-2]

[0153] (Continued from Table 8.1) Each of Tables 8.2 to 8.4 is R 4 Formula (I-8) (wherein n, A 1 , A 2 , A 3 , A 4 , R 1 , R 2 and R 3 The present invention makes available 107 individual compounds of the formula (wherein R is as specifically defined in Tables 8.2-8.4).

[0154] Table 8.2: This table shows the formula (I-8) (wherein n is 1 and A 2 , A 3 , A4 , R 1 and R 2 is hydrogen, and A 1 is fluorine and Z is -NR 3 -C(=W)-X, where R 3 is hydrogen, W is O, and X is as defined above in Table 8.

[0155] Table 8.3: This table shows the formula (I-8) (wherein n is 1 and A 1 , A 2 , A 4 , R 1 and R 2 is hydrogen, and A 3 is fluorine and Z is -NR 3 -C(=W)-X, where R 3 is hydrogen, W is O, and X is as defined above in Table 8.

[0156] Table 8.4: This table shows the formula (I-8) (wherein n is 1 and A 2 , A 4 , R 1 and R 2 is hydrogen, and A 1 and A 3 is fluorine and Z is -NR 3 -C(=W)-X, where R 3 is hydrogen, W is O, and X is as defined above in Table 8.

[0157] Table 9.1: This table shows the formula (I-9): [ka] (wherein n is 1, A is A-1, and R 1 is hydrogen, and R 2 is methoxy and Z is -C(=O)-NR 3 R 4 where -NR 3 R 4is as defined below in Table 9) Thirty-six specific compounds are disclosed.

[0158] [Table 9]

[0159] (Continued from Table 9.1) Each of Tables 9.2 to 9.4 is -NR 3 R 4 Formula (I-9) (wherein n, A, R 1 , R 2 , R 3 and R 4 The present invention makes available 36 individual compounds of the formula (wherein R is as specifically defined in Tables 9.2 to 9.4).

[0160] Table 9.2: This table shows the compounds of formula (I-9) where n is 1, A is A-1, and R 1 is hydrogen, and R 2 is ethoxy and Z is -C(=O)-NR 3 R 4 where -NR 3 R 4 discloses 36 specific compounds of the formula (as defined above in Table 9).

[0161] Table 9.3: This table shows the compounds of formula (I-9) (wherein n is 1, A is A-2, and R 1 is hydrogen, and R 2 is methoxy and Z is -C(=O)-NR 3 R 4 where -NR 3 R 4 discloses 36 specific compounds of the formula (as defined above in Table 9).

[0162] Table 9.4: This table shows the compounds of formula (I-9) where n is 1, A is A-2, and R 1 is hydrogen, and R 2 is ethoxy and Z is -C(=O)-NR 3 R4 where -NR 3 R 4 discloses 36 specific compounds of the formula (as defined above in Table 9).

[0163] Table 10.1: This table shows the formula (I-10): [ka] (wherein n is 0 and Z is -C(=O)-R 5 where R 5 is as defined below in Table 10) Thirty-seven specific compounds are disclosed.

[0164] [Table 10]

[0165] Table 10.2: This table shows the compounds of formula (I-10) (wherein n is 1 and R 1 is hydrogen, and R 2 is hydroxy and Z is R 5 where R 5 discloses 37 specific compounds of the formula (as defined above in Table 10).

[0166] Table 10.3: This table shows the formula (I-10) where n is 1 and R 1 is hydrogen, and R 2 is hydroxy and Z is 5-methylpyrid-2-yl.

[0167] According to an embodiment of the method of the present invention, a compound of formula (I), hereinafter referred to as a compound of formula (IB), 1 The compound of formula (IA) is advantageously used in the process for the preparation of a compound of formula (IA) to obtain a valuable intermediate. The process of the present invention thus comprises the steps of: 1 to react an intermediate compound of formula (IA) 2The method may further comprise the step of obtaining a compound of formula (I)

[0168] The present invention further provides a compound of formula IB, wherein Z is Z 1 The present invention relates to an intermediate compound of the formula (I).

[0169] In particular, the compound of formula (IB) 1 is hydrogen) can be reacted with a halogenating agent, optionally in the presence of a radical initiator such as dibenzoyl peroxide or azobisisobutyronitrile (AIBN), to give a compound of formula (IB), 1 is a halogen, preferably Cl, Br or I).

[0170] Examples of suitable halogenating agents include, for example, bromine or brominating agents such as N-bromosuccinimide. The reaction is typically carried out at a temperature of 55° C. to 100° C. For related examples, see WO 2017 / 055473; WO 2018 / 177894; Liu, S. et al Synthesis (2001), 14, 2078; and Kompella, A. et al Org. Proc. Res. Dev. (2012), 16, 1794.

[0171] Preferably, n in the compound of formula (IA) is 0 or 1. Preferably, n in the compound of formula (IB) is 0 or 1.

[0172] Formula (IA) (wherein Z is Z 2 (Ib) can be prepared from a compound of formula (IB) by reaction with a compound of formula (IV), typically in the presence of a base. In some cases, better reaction results can be obtained from the use of a catalyst (e.g., NaI or 4-dimethylaminopyridine) and with microwave irradiation. For relevant examples, see WO 2013 / 132253; and Garcia, M. et al Org. Biomol. Chem. (2004), 11, 1633. This reaction is shown in Scheme 3. [ka] Scheme 3

[0173] Formula (IB) (wherein n is 1 and Z 1 is Br) have been found to be particularly reactive towards compounds of formula (IV).

[0174] In one embodiment, the present invention relates to a compound of formula (IA), 2 Ha-NR 3 -C(=W)-X): [ka] The present invention relates to a method for preparing the compound of the formula:

[0175] Formula (IA) (where Z 2 is preferably -NR 3 -C(=W)-X) is a compound of formula (V), 3 is as defined above for compounds of formula (I)) or a salt thereof to give compounds of formula (IB) 1 is a halogen) to obtain a compound of formula (Ia) or a salt thereof. For related examples, see Miyawaki, K. et al Heterocycles (2001), 54, 887; WO 2003 / 028729; WO 2017 / 055473; WO 2018 / 177894; and WO 2013 / 066839. This reaction is shown in Scheme 4. [ka] Scheme 4

[0176] Z in the compound of formula (IB) 1 When is a halogen, it is preferably chlorine or bromine.

[0177] The compound of formula (Ia) or a salt thereof may be represented by the formula (VI) in which X and W are as defined above for the compound of formula (I) and T is halogen, hydroxy or C 1-4 and further reacting the compound of formula (IA) (wherein Z is an alkoxy) to form a compound of formula (IA) 2 Ha-NR 3 -C(=W)-X) can be obtained. For related examples, see Nelson, TD et al Tetrahedron Lett. (2004), 45, 8917; Senthil, K. et al Pest. Res. Journal (2009), 21, 133; Crich, D., Zou, YJ Org. Chem. (2005), 70, 3309; WO 2018 / 177894; and WO 2017 / 055473. This reaction is shown in Scheme 5. [ka] Scheme 5

[0178] Furthermore, the compound represented by formula (IA) (wherein Z 2 Ha-NR 3 A compound of formula (II), where Z is -NR 3 This reaction can be prepared according to the method of the present invention from a compound of formula (I) -C(=W)-X. This reaction is shown in Scheme 6. [ka] Scheme 6

[0179] Compounds of formula (II) can be prepared from compounds of formula (VII) by reaction with hydroxylamine or a salt thereof, such as hydroxylamine hydrochloride, optionally in the presence of one or more bases. This reaction is shown in Scheme 7. [ka] Scheme 7

[0180] Similarly, compounds of formula (II) where Z is hydrogen can be prepared from compounds of formula (VII) where Z is hydrogen by reaction with hydroxylamine or a salt thereof, such as hydroxylamine hydrochloride, optionally in the presence of one or more bases. This reaction is shown in Scheme 7.

[0181] In particular, the compound of formula (II-A) (wherein Z is -NR 3 A compound of formula (VII), where Z is -NR 3 -C(=W)-X) This reaction is shown in Scheme 8. [ka] Scheme 8

[0182] Examples of suitable bases include, for example, trimethylamine. The reaction can be carried out in a solvent, such as methanol. The reaction is typically carried out at a temperature between 0°C and 100°C. For related examples, see Kitamura, S. et al Chem.Pharm.Bull.(2001), 49,268; and WO 2013 / 066838.

[0183] Formula (VII-A) (wherein Z is -NR 3 -C(=W)-X) is reacted with a compound of formula (V), where R 3 can be prepared from a compound of formula (VII) (wherein Z is a halogen) by reaction with a compound of formula (VII) (as defined above for compounds of formula (I)) or a salt thereof. For relevant examples, see Miyawaki, K. et al Heterocycles (2001), 54, 887; and WO 2018 / 177894. This reaction is shown in Scheme 9. [ka] Scheme 9

[0184] The compound of formula (VII-a) or a salt thereof can be represented by the formula (VI) (wherein X and W are as defined above for compound (I) and T is halogen, hydroxy or C 1-4 to form a compound of formula (VII-A), 3 -C(=W)-X) can be obtained. For related examples, see WO 2018 / 177894. This reaction is shown in Scheme 10. [ka] Scheme 10

[0185] The compound of formula (II) (wherein Z is a halogen) can be prepared from the compound of formula (II) (wherein Z is a hydrogen) by reaction with a halogenating agent, optionally in the presence of a radical initiator such as dibenzoyl peroxide or azoisobutyronitrile (AIBN). Examples of suitable halogenating agents include bromine or N-bromosuccinimide, for example, as a brominating agent. The reaction is typically carried out at a temperature of 55°C to 100°C. For related examples, see J.Am.Chem.Soc.1951,73,455.

[0186] Additionally, compounds of formula (VII) can be prepared from compounds of formula (VIII) (wherein Y is a halogen, preferably Cl, Br or I) by metal-promoted reaction with a suitable cyanide reagent, such as Pd(0) / Zn(CN)2 or CuCN, in a suitable solvent (e.g., dimethylformamide or N-methylpyrrolidone). The reaction is typically carried out at a temperature of 100°C to 120°C. For relevant examples, see US Patent Publication No. 2007 / 0155739; and WO 2009 / 022746. This reaction is shown in Scheme 11. [ka] Scheme 11

[0187] Compounds of formula (VIII), where n is preferably 1, can be prepared from compounds of formula (IX), where Y is a halogen, preferably Cl, Br or I, by reaction with compounds of formula (X) in the presence of a base, such as K2CO3, Cs2CO3, or NaH, in a suitable solvent, such as dimethylformamide or tetrahydrofuran. The reaction is typically carried out at a temperature between 25°C and 110°C. In some cases, better reaction results can be obtained from the use of a catalyst, such as NaI or 4-dimethylaminopyridine, and using microwave irradiation. For relevant examples, see WO 2013 / 132253; WO 2018 / 177894; and Garcia, M. et al Org. Biomol. Chem. (2004), 11, 1633. This reaction is shown in Scheme 12. [ka] Scheme 12

[0188] Formula (IA) (where Z 2 Ha-NR 3 The process for the preparation of compounds of formula -C(=W)-X is preferably carried out according to any of the following routes: These reactions are shown in Scheme 13. [ka] Scheme 13

[0189] According to one embodiment of the present invention, a compound of formula (IA) (wherein Z 2 Ha-NR 3 A method for preparing a compound of formula (I) (wherein the formula is -C(=W)-X) is typically: (A-1) Formula (II) (where A, n, R 1 , R 2 and Z 1 is as defined for compounds of formula (I),12 is C 1-4 (Ib) to obtain a compound of formula (IB): [ka] (A-2) Formula (IB) (where Z 1 is a halogen) with a compound of formula (V), 3 is as defined above for compounds of formula (I)) or a salt thereof to obtain an intermediate compound of formula (Ia) or a salt thereof: [ka] and (A-3) The compound of formula (Ia) or a salt thereof is reacted with a compound of formula (VI) (wherein X and W are as defined above for the compound of formula (I) and T is halogen, hydroxy or C 1-4 with a compound of formula (I) [ka] Includes.

[0190] Compounds of formula (II) of this embodiment of the invention may be prepared as described above.

[0191] According to a further embodiment of the present invention, a compound of formula (IA), 2 Ha-NR 3 The method for preparing a compound of formula (II-A) (wherein A, n, R 1 , R 2 , R 3 , X and W are as defined above for compounds of formula (I), by reacting a compound of formula (III) 12 is C 1-4 with a compound of formula (I) wherein the compound is an alkyl group: [ka] Includes.

[0192] Compounds of formula (II-A) of this embodiment of the invention can be prepared as described above.

[0193] Substituents n, m, A-1, A-2, R in the compound of formula (I) 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , Z(Z 1 , Z 2 Preferred groups and values ​​for , W, and X, in any combination thereof, are as set out below in Tables A through E.

[0194] According to an embodiment of the method of the present invention, the compound of formula (I) is selected from compound no. A.01, A.02, A.03, A.04, A.05, A.06, A.07, A.08, A.09, A.10, A.11, A.12, A.13, A.14, A.15, A.16, A.17, or A.18 as defined in Table A below. More preferably, the compound of formula (I) is selected from compound no. A.01, A.08, A.09, A.10, A.11, A.17, or A.18 as defined in Table A below.

[0195] [Table 11-1] [Table 11-2] [Table 11-3]

[0196] The presence of an asymmetric carbon in compounds A.04 and A.07 means that these compounds can exist in chiral enantiomeric forms, namely (R)- and (S)-enantiomers as depicted below. [ka]

[0197] According to an embodiment of the method of the present invention, the compound of formula (I) is selected from compound no. B.01, B.02, B.03, B.04, B.05, B.06, B.07, B.08, B.09, B.10, B.11, B.12, B.13, B.14, B.15, B.16, B.17, B.18, B.19, B.20, B.21, B.22, B.23, B.24, or B.25 as defined in Table B below. More preferably, the compound of formula (I) is selected from compound no. B.01, B.04, B.07, B.14, B.24, or B.25 as defined in Table B below.

[0198] [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4]

[0199] The presence of an asymmetric carbon atom in compounds B.04, B.06, B.12 and B.13 means that these compounds can exist in chiral enantiomeric forms, namely (R)- and (S)-enantiomers as depicted below. [ka]

[0200] According to an embodiment of the method of the present invention, the compound of formula (I) is selected from compound no. C.01, C.02, C.03, C.04, C.05, C.06, C.07, C.08, C.09, C.10, C.11, C.12, C.13, C.14, C.15, C.16, C.17, C.18, C.19, C.20 or C.21 as defined in Table C below. More preferably, the compound of formula (I) is selected from compound no. C.03, C.06, C.07, C.15, C.16 or C.17 as defined in Table C below.

[0201] [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4]

[0202] The presence of an asymmetric carbon atom in compounds C.21 means that these compounds can exist in chiral enantiomeric forms, namely (R)- and (S)-enantiomers as depicted below. [ka]

[0203] According to an embodiment of the method of the present invention, the compound of formula (I) is selected from compound no. D.01, D.02, D.03, D.04, D.05, D.06, D.07, D.08, D.09, D.10, D.11, D.12, D.13, D.14, D.15, D.16, D.17, D.18, or D.19 as defined in Table D below. More preferably, the compound of formula (I) is selected from compound no. D.01, D.02, D.03, D.04, D.05, D.06, D.07, D.10, or D.19 as defined in Table D below.

[0204] [Table 14-1] [Table 14-2] [Table 14-3]

[0205] According to an embodiment of the method of the present invention, the compound of formula (I) is selected from compound no. E.01, E.02, E.03, E.04, E.05, E.06, E.07, E.08, E.09, E.10, E.11, E.12, E.13, E.14, E.15, E.16, E.17, E.18, E.19, E.20, E.21, or E.22 as defined in Table E below. More preferably, the compound of formula (I) is selected from compound no. E.01, E.02, E.03, E.05, E.10, E.12, E.13, E.14, E.15, E.16, E.17, E.18, E.19, E.20, or E.22 as defined in Table E below.

[0206] [Table 15-1] [Table 15-2] [Table 15-3]

[0207] The presence of an asymmetric carbon atom in compounds E.03, E.04, E.05, E.06, E.07, E.12, E.14 and E.22 means that these compounds can exist in chiral enantiomeric forms, i.e., (R)- and (S)-enantiomers, as depicted below. [ka]

[0208] Enantiomerically pure final compounds may be obtained from racemic starting materials by standard physical separation techniques, such as reverse-phase chiral chromatography, if necessary, or by stereoselective synthesis techniques, for example by using chiral starting materials. EXAMPLES

[0209] Preparation Examples The following examples serve to illustrate the invention: Compounds of formula (I) may be prepared according to the synthetic techniques described above.

[0210] The preparation of N-[[4-(N-hydroxycarbamimidoylphenyl]methyl]-N-methoxy-cyclopropanecarboxamide and N'-hydroxy-4-methyl-benzamidine is detailed in WO 2018 / 177894 and WO 2017 / 055473.

[0211] Example 1: This example illustrates the preparation of N-methoxy-N-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]cyclopropanecarboxamide. [ka] To a 50 mL flask was added N-[[4-(N-hydroxycarbamimidoyl)phenyl]methyl]-N-methoxy-cyclopropanecarboxamide (89% purity, 0.20 g, 0.7 mmol) and tetrahydrofuran (2 mL) and 4 Å molecular sieves (150 mg). After cooling to 0° C., sodium tert-butoxide (0.1 g, 1 mmol) was introduced portionwise over 5 min. To the resulting suspension was added ethyl 2,2,2-trifluoroacetate (0.58 g, 4.40 mmol) dropwise over 5 min and the ice bath was removed. After 2 h, water (20 mL) and ethyl acetate (40 mL) were introduced, the contents were stirred for 10 min, the layers were separated and the aqueous layer was extracted with ethyl acetate. All combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.18 g (60% yield, 82% purity) of the title compound as a brown amorphous solid. 1 H NMR(400MHz,CDCl3)δ ppm:8.09(d,2H),7.53(d,2H),4.87(s,2H),3.73(s,3H),2.19(m,1H),1.05(m,2H),0.86(m,2H). 19 F NMR(400MHz,CDCl3)δ ppm:-65.33(s).

[0212] Example 2: This example illustrates the preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole: [ka] To a 50 mL flask was added N'-hydroxy-4-methyl-benzamidine (96% purity, 1.0 g, 6.39 mmol), tetrahydrofuran (10 mL), and 4 Å molecular sieves (150 mg). After cooling to 0° C., a 1 M solution of potassium tert-butoxide in tetrahydrofuran (6.39 mL, 6.39 mmol) was introduced dropwise. To the resulting suspension was added ethyl 2,2,2-trifluoroacetate (0.58 g, 4.40 mmol) over 5 min and the ice bath was removed. After 1 h, the reaction conversion was 92% complete and the reaction mixture had a pH of 10.3 (measured using a pH meter). Citric acid (50 g) was added dropwise and the contents were stirred for 10 min to achieve a pH 5.9 reaction mixture. The crude reaction contents were filtered over Celite, washed twice with tetrahydrofuran (20 mL), and the filtrate was concentrated under reduced pressure. The resulting crude mass was diluted with dichloromethane (20 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted twice with dichloromethane. All combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 1.22 g of the title compound as a pale yellow liquid (80% yield, QNMR purity 96%). 1 H NMR(400MHz,CDCl3)δ ppm:8.00(d,2H),7.32(d,2H),2.45(s,3H). 19 F NMR(400MHz,CDCl3)δ ppm:-65.41(s).

[0213] Table T1 below depicts additional variations in the conditions of the reaction detailed for 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole. [ka] Yet another aspect of the present invention may be as follows. [1] Formula (I): [ka] [In the formula, A is A-1 or A-2: [ka] (wherein A-1 and A-2 are each a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 and optionally substituted with 1 or 2 substituents independently selected from haloalkoxy. and; n is 0, 1 or 2; R 1 and R 2 is hydrogen, halogen, cyano, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 haloalkyl; or R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropyl ring; Z is Z 1 Or Z 2 and; Z 1 is hydrogen, halogen, cyano, -OH, or -SH; Z 2 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -COOH, -C(=W)-X, -NR 3 R 4 , -NR 3 -C(=W)-X, -S(=O) 2 -R 5 , or -NR 3 -S(=O) 2 -R 5 or Z 2 is C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-2 Alkyl, Heterocyclyl, HeterocyclylC 1-2 Alkyl, Phenyl, Phenyl C 1-2 Alkyl, Heteroaryl, HeteroarylC 1-2 alkyl, or heterodiaryl, wherein the heterocyclyl moiety contains 1, 2 or 3 heteroatoms or O, S, N, NR 6 , C(=O) and S(=O) 2 wherein the heteroaryl moiety is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms individually selected from N, O, and S; wherein any of the cycloalkyl, heterocyclyl, phenyl, heteroaryl, or heterodiaryl moieties is R 7 optionally substituted with 1 or 2 substituents, which may be the same or different, selected from W is O or S; X is halogen, -NR 3 R 4 、R 5 , -NR 3 -[CR 8 R 9 ] m -CR 10 (=NR 5 ), -C(=O)-NR 3 R 4 , -C(=O)-R 5 , -C(=NC 1-4 Alkoxy)-R 5 , or -OR 11 and; R 3 and R 4 is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, Hydroxy C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Haloalkoxy, C 1-2 Haloalkoxy C 1-4 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl, C 3-4 Alkenyloxy, C 3-4 Alkynyloxy, C 1-4 Alkylcarbonyloxy, NC 1-4 Alkylamino and N,N-diC 1-4 alkylamino; or R 3 and R 4 is C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-2 Alkyl, Heterocyclyl, HeterocyclylC 1-2 Alkyl, Phenyl, Phenyl C 1-2 Alkyl, Heteroaryl, and Heteroaryl C 1-2 alkyl, wherein the heterocyclyl moiety is selected from 1, 2 or 3 heteroatoms or O, S, N, NR 6 , C(=O) and S(=O) 2 wherein the heteroaryl moiety is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms individually selected from N, O, and S; wherein any of the cycloalkyl, heterocyclyl, phenyl, or heteroaryl moieties is R 7 optionally substituted with 1 or 2 substituents, which may be the same or different, selected from R 3 and X is R 3 together with the nitrogen atom to which it is attached and together with the group -C(=W), heterocyclyl, heterocyclylC 1-6 Alkyl, Heteroaryl, HeteroarylC 1-2 alkyl, or heterodiaryl; wherein the heterocyclyl moiety contains 1, 2 or 3 heteroatoms or O, S, N, NR 6 , C(=O) and S(=O) 2 wherein the heteroaryl moiety is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms individually selected from N, O, and S; 7 optionally substituted with 1 or 2 substituents, which may be the same or different, selected from R 5 is C 1-4 Alkyl, C 1-4 Haloalkyl, Hydroxy C 1-4 Alkyl, Cyano C 1-4 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 1-4 Alkoxy C 1-4 Alkyl or C 1-2 Haloalkoxy C 1-4 is alkyl; or R5 is C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-2 Alkyl, Heterocyclyl, HeterocyclylC 1-6 Alkyl, Phenyl, Phenyl C 1-2 Alkyl, Heteroaryl, HeteroarylC 1-2 alkyl, or heterodiaryl, wherein the heterocyclyl moiety contains 1, 2 or 3 heteroatoms or O, S, N, NR 6 , C(=O) and S(=O) 2 wherein the heteroaryl moiety is a 5- or 6-membered monocyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms individually selected from N, O, and S; wherein any of the cycloalkyl, heterocyclyl, phenyl, heteroaryl, or heterodiaryl moieties is R 7 optionally substituted with 1 or 2 substituents, which may be the same or different, selected from R 6 is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, formyl, C 1-4 Alkyl carbonyl, C 1-4 Alkoxycarbonyl, NC 1-4 Alkylaminocarbonyl, N,N-diC 1-4 Alkylaminocarbonyl, C 1-4 Alkylsulfonyl, NC 1-4 Alkylaminosulfonyl or N,N-diC 1-4 alkylaminosulfonyl; R 7 is halogen, cyano, hydroxy, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Alkenyloxy, C 3-4 Alkynyloxy, NC 1-4 Alkylamino, N,N-diC 1-4 Alkylamino, C 1-4 Alkyl carbonyl, C 1-4 Alkoxycarbonyl, aminocarbonyl, C 1-4 Alkylcarbonylamino C 1-4 Alkyl, NC 1-4 Alkylaminocarbonyl, N,N-diC1-4 Alkylaminocarbonyl, C 1-4 Alkoxycarbonylamino, NC 1-4 Alkoxyaminocarbonyl, NC 1-4 Alkyl-NC 1-4 Alkoxyaminocarbonyl, C 3-8 Cycloalkylaminocarbonyl, NC 3-8 Cycloalkyl C 1-2 Alkylaminocarbonyl, NC 1-4 Alkoxy C 1-4 Alkylaminocarbonyl, NC 1-4 Alkoxy C 1-4 Alkylimino, C 1-4 Alkylsulfinyl or C 1-4 is alkylsulfanyl; m is 0, 1 or 2; R 8 and R 9 is hydrogen, halogen, cyano, C 1-4 Alkyl, and C 1-4 haloalkyl; or R 8 and R 9 together with the carbon atom to which they are attached form a cyclopropyl ring; R 10 is hydrogen, C 1-6 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl, C 1-4 Haloalkyl, C 3-8 cycloalkyl, or phenyl; R 11 is C 1-8 Alkyl, C 1-4 Haloalkyl, Hydroxy C 1-6 Alkyl, C 1-4 Alkoxy C 1-6 Alkyl, C 1-2 Haloalkoxy C 1-4 Alkyl, C 2-4 Alkenyl, C 2-6 Alkynyl or C 1-4 Alkylcarbonyloxy C 1 ~C 4 is alkyl] A process for preparing a compound of the formula The method comprises reacting a compound of formula (II):

change

change

change

change

change

change

change

[10] The method according to any one of [1] to [6] above, wherein the method comprises reacting a compound represented by formula (II-A):

change

change

[11] The method according to

[10] , wherein the method comprises the step of:

change

[12] The method according to

[10] or

[11] , wherein the method comprises the step of reacting a compound represented by formula (VII-a):

change

change

[13] The method according to any one of [1] to

[12] above, further comprising a step of isolating the compound of formula (I) using an aqueous acidic medium.

[14] The method according to

[13] , wherein the aqueous acidic medium contains citric acid.

[15] The method according to

[13] or

[14] , wherein the aqueous acidic medium has a pH of 2.0 to 6.0.

[0214]

Table 16

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, A is A-1: 【Chemistry 2】 and n is 1; R 1 and R 2 is hydrogen; Z is Z 2 And Z 2 is -NR 3 -C(=W)-X; W is O; X is R 5 and R 3 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, or C 3-8 is cycloalkyl; R 5 is C 1-4 Alkyl, C 1-4 Haloalkyl, C 2-4 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 1-4 Alkoxy C 1-4 is alkyl; or R 5 is C 3-8 cycloalkyl or heterocyclyl; wherein the heterocyclyl moiety is selected from the group consisting of 1, 2, or 3 heteroatoms or O, S, N, NR 6 , C(=O) and S(=O) 2 and wherein any of the cycloalkyl and heterocyclyl are unsubstituted or selected from R 7 and is substituted with 1 or 2 substituents independently selected from R 6 is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, formyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxycarbonyl, N—C 1-4 Alkylaminocarbonyl, N,N-diC 1-4 Alkylaminocarbonyl, C 1-4 Alkylsulfonyl, N-C 1-4 Alkylaminosulfonyl, or N,N-diC 1-4 alkylaminosulfonyl; and R 7 is a halogen. A process for preparing a compound of the formula The method comprises reacting a compound of formula (II): 【Chemistry 3】 (In the formula, A, n, R 1 , R 2 and Z are as defined for compounds of formula (I)) with a compound of formula (III): 【Chemistry 4】 (In the formula, R 12 is C 1-4 wherein the compound is an alkyl group; The process is carried out in the presence of at least one base; The base is an alkali metal 1-6 Alkoxylates and alkaline earth metals C 1-6 alkoxylates; and The method further comprises the step of isolating the compound of formula (I) using an aqueous acidic medium.

2. The method of claim 1, wherein the base is sodium tert-butoxide or potassium tert-butoxide.

3. 3. The method according to claim 1 or 2, wherein the method comprises reacting a compound of formula (VII): 【Chemistry 5】 (In the formula, A, n, R 1 , R 2 and Z is defined as in the compound of formula (I). with hydroxylamine or a salt thereof to obtain said compound of formula (II).

4. Formula (IA): 【Chemistry 6】 [In the formula, A is A-1: 【Chemistry 7】 and n is 1; R 1 and R 2 are hydrogen; W is O; X is R5; R 3 is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl, or C 3-8 cycloalkyl; R 5 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, or C 1-4 alkoxyC 1-4 alkyl; or R 5 is a C 3-8 cycloalkyl or heterocyclyl; where said heterocyclyl moiety is a 4-6 membered non-aromatic ring containing 1, 2 or 3 heteroatoms or groups independently selected from O, S, N, NR 6 , C(═O) and S(═O) 2 ; and where either of said cycloalkyl and heterocyclyl are unsubstituted or substituted with 1 or 2 substituents independently selected from R 7 ; R 6 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, formyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, N—C 1-4 alkylaminocarbonyl, N,N-diC 1-4 alkylaminocarbonyl, C 1-4 alkylsulfonyl, N—C 1-4 alkylaminosulfonyl or N,N-diC 1-4 alkylaminosulfonyl; and R 7 is halogen. A process for preparing a compound of the formula The method comprises reacting a compound represented by formula (IB): 【Chemistry 8】 (In the formula, Z 1 is selected from hydrogen, halogen, cyano, —OH, or —SH; A, n, R 1 , and R 2 is defined as in the above compound of formula (IA)) to obtain a compound of formula (IA): 【Chemistry 9】 obtaining a compound of The method comprises reacting a compound of formula (II): 【Chemistry 10】 wherein Z is Z 1 , Z 1 is selected from hydrogen, halogen, cyano, —OH, or —SH, and A, n, R 1 , and R 2 are as defined for the compound of formula (IA), with a compound of formula (III): 【Chemistry 11】 wherein R 12 is C 1-4 alkyl to give a compound of formula (IB): 【Chemistry 12】 obtaining a compound of formula (I); The process is carried out in the presence of at least one base; said base is selected from the group consisting of alkali metal C 1-6 alkoxylates and alkaline earth metal C 1-6 alkoxylates; and The method further comprises the step of isolating the compound of formula (IB) using an aqueous acidic medium.

5. The method according to claim 4, wherein the method comprises the step of: 【Chemistry 13】 (In the formula, Z 1 is a halogen; A, n, R 1 , and R 2 is defined as in the compound of formula (IA) above), by reacting a compound of formula (V): 【Chemistry 14】 (In the formula, R 3 is defined as in the compound of formula (IA). or a salt thereof to obtain a compound of formula (I-a): 【Chemistry 15】 (In the formula, A, n, R 1 , R 2 and R 3 is defined as in said compound of formula (IA) or a salt thereof.

6. The method according to claim 5, wherein the method comprises reacting the compound of formula (I-a) or a salt thereof with a compound of formula (VI): 【Chemistry 16】 wherein X and W are defined as in the compound of formula (IA) and T is halogen, hydroxy or C. 1-4 alkoxy) to obtain a compound of formula (IA): 【Chemistry 17】 The method further comprises obtaining the compound of formula (1).

7. The method of claim 1 or 4, wherein the aqueous acidic medium comprises citric acid.

8. The method of claim 7, wherein the aqueous acidic medium has a pH of from 2.0 to 6.0.

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